WO2000050377A1 - Efficient synthesis of secondary amines by selective alkylation of primary amines - Google Patents

Abstract

A method for selective mono-N-alkylation of primary amines to produce secondary amines that are substantially free of overalkylated tertiary amines and quaternary ammonium salts, under mild reaction conditions without the necessity of protecting groups. Compounds of the class of secondary amines are produced by reacting an alkyl halide with an alkyl amine in anhydrous solvent, preferably dimethyl sulfoxide or N,N-dimethylformamide, in the presence of 0.1 to 3 molar equivalents of a cesium base. Optionally, the extent and selectivity of mono-N-alkylation is enhanced by addition to the reaction mixture of a powdered molecular sieve material for removal of water produced by the reaction, and/or tetrabutylammonium iodide to promote halide exchange. The invention permits selective and efficient mono-N-alkylation of a wide variety of substrates at 23 °C; does not cause racemization when used with enantiomerically-pure chiral substrates such as L-α-aminoesters; and is applied to solid phase synthesis whereby either the alkyl amine or alkyl halide is immobilized. The method is additionally used to produce polyamines, such as N-(2-(2-aminoethylthio)ethyl)ethylenediamine in 73 % yield.

Description

EFFICIENT SYNTHESIS OF SECONDARY AMINES BY SELECTIVE ALKYLATION OF

PRIMARY AMINES

RELATED APPLICATIONS

The present application claims priority to U.S. Provisional application 60/121,867; filed February 26, 1999, U.S. Provisional application 60/126,108, filed March 25, 1999, and U.S. Provisional application 60/138,655, filed June 14, 1999 each of which is incorporated herein by reference in its respective entirety.

1. FIELD OF THE INVENTION

The present invention relates to the N-alkylation of organic nitrogen compounds containing a primary amine group and, in particular, to such N-alkylation performed by reacting an alkyl amine with an organic electrophile in the presence of a base catalyst under conditions such that substantially mono- N-alkylation of the alkyl amine occurs, resulting in a high yield of secondary amine.

2. BACKGROUND OF THE INVENTION Secondary amines are widely used in the synthesis of numerous products including surfactants, textiles, agricultural products and medicines. Thus, an efficient means for the synthesis of secondary amines has long been sought. However, all the known direct alkylation methods give mainly over- alkylation products such as tertiary amines and quaternary ammonium salts instead of the desired secondary amines. See for example, M. S. Gibson, "The Chemistry of the Amino Group" (S. Patai, ed.), Interscience, 1968, p.45, and Mitsunobu, "Comprehensive Organic Chemistry", (H.D.Barton, ed.), Pergamon Press, 1979, 7:65.

The general scheme for production of secondary (2), tertiary (3) and quaternary (4) amines by successive N-alkylation reactions of primary amine (1) with an organic electrophile R'-X is as follows:

Because secondary amines are more nucleophilic than their corresponding primary amines, further alkylation to form tertiary (3) or quaternary (4) amines is thermodynamically favorable and difficult to suppress Even with a limited amount of alkylatmg agent, the equihbπation of protonated dialkyl product (2') with the neutral primary amine (1) is sufficiently fast that a mixture of all alkylation products is obtained

The resultmg complex product mixture usually provides a low yield of secondary amine, and purification can be difficult To avoid problems associated with overalkylation, reductive alkylation methods have been widely employed, wherem ammes are reacted with aldehydes and the -mine intermediates are reduced by sodium cyanoborohydπde or a similar reductant to produce secondary ammes, as descπbed m Szardenings et al , J Org Chem (1996) 61 6720, and Klyuev & Khidekel, Russian Chemical Rev (1980) \ 49 Dependmg on the choice of substrate, these methods typically give overalkylation products In addition, aldehydes are usually unstable and expensive, limiting reactant availability, and reducmg agents are both expensive and difficult to handle

High temperatures are often required to achieve base-catalyzed direct N-alkylation To minimize the need for harsh reaction conditions, activated reactants are frequently used For example. U S patent 4,209,463 to Maender et al discloses the use of activated formyl denvatives of aryl ammes m the formation of mtrodiarylammes, U S patent 4,417,048 to Soula et α/ descπbes N-alkylation of compounds bearing a labile hydrogen, and Fukuyama et al . Tetrahedron Lett (1995) 36 6373 descπbes the use of 2,4-dmιtrobenzenesulfonamιdes as activated N-alkylating agents

Vaπous additives that promote N-alkylation are known These include phase-transfer catalysts, as described in Masse, Synthesis (1977) p 342, tertiary amine sequestering agents, as descπbed m U S patent 4,417.048 to Soula et al , and alkali cation exchange zeolites or molecular sieves, that improved selectivitv of N-alkylation of aniline, as disclosed by Onaka et al . in Chem Lett (1982) 1783, and J Chem Soc Chem Commun (1985) 1202 While these additives are effective in promotmg certain specific N-alkylation reactions, there remains a need for reliable, efficient and generally-applicable N-alkylation procedures effective for a wide range of reactants, as required, for example, in the construction of peptidomimetic hbraπes. as discussed in Reichwem & Liskamp, Tetrahedron Lett (1998) 39 1243

Indirect methods of N-alkylation can provide substantially mono-N-alkylated products through the use of protecting groups that prevent further N-alkylation See Fukuyama et al , Tetrahedron Lett (1995) 36 6373, and Croce et al , J Chem Res (S) (1988) 347 These methods are of particular importance in the field of pharmaceuticals, see Sharm & Moniot "Isoquinoline Alkaloid Research' (1972), Plenum Press, solid phase synthesis, as descπbed in Reichwem & Liskamp, Tetrahedron Lett (1998) 39 1243 and Hemonen & Lonnberg, Tetrahedron Lett (1997) 38 8569. and in the synthesis of peptidomimetic compounds such as N-alkylated peptides After N-alkylation. the protecting group is removed to yield the secondary armne product While the benefit of substantially mono-N-alkylation is achieved, and racemization of chiral centers is suppressed, additional synthetic steps and expense are required as compared to direct N-alkylation methods

Therefore, there exists m this field a need for methods of simple, efficient N-alkylation of primary ammes that yield substantially secondary amines, require only mildly reactive alkylatmg agents, such as alkyl bromides, which are generally more readily available than correspondmg activated compounds, and can be performed under mild reaction conditions to minimize side reactions

BRIEF SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide an improved process for mono-N- alkylation of pπmary alkyl amines which avoids the aforementioned disadvantages and drawbacks

It is a further object of the present invention to provide a process that obviates harsh reaction conditions, suppresses over-alkylation, and avoids the use of protectmg groups

It is a further object of the present mvention to provide a process characteπzed by reaction of an organic electrophile with a pπmary amine m the presence of a cesium base at mild temperatures It is a further object of the present invention to provide a process broadly compπsmg providmg a cesium base catalyst, preferably CsOH or Cs₂C0₃, in an anhydrous solvent, and optionally including a molecular sieve for the removal of water and or a hahde-exchange promoting agent such as tetrabutyl ammonium iodide (TBAI)

It is a further object of the present invention to provide a process whereby unprotected

ammes are smoothly N-monoalkylated using more than one equivalent of alkylatmg agent in the presence of cesium hydroxide m DMF, givmg rise to respectable yields and selectivity through an N- alkylation protocol that is direct, efficient and utilizes mild reaction conditions, and which can be exploited for other synthetic purposes

These and other objects of the present invention will become obvious to those skilled m the art upon review of the following disclosure

Disclosed herein is an efficient synthetic protocol for secondary alkyl amines, which can be generated by cesium hydroxide promoted N-alkylation of various pπmary alkyl ammes with alkyl halides Unlike the known methods, these protocols produce either mainly or exclusively secondary alkyl amines m high yields All kmds of aliphatic amines are compatible with this technology and a vaπety of alkyl halides are readily incorporated to furnish dialkylammes efficiently In a preferred embodiment, cesium hydroxide is used as a base m a catalytic amount when reactive halides such as benzyl bromide are employed This catalytic process allows for the efficient and inexpensive preparation of vaπous secondary ammes essential to mdustπal and practical applications The developed methodologies disclosed herewith are also believed to make significant contπbutions to the mateπal sciences by providing new types of secondary ammes m an economical fashion Thus a process providing a secondary armne of the general formula. R-NH-R', is disclosed wherein an orgamc electrophile, R-X, is reacted with a pπmary amme R'-NH₂ m an anhydrous solvent containing a cesium base m an amount sufficient to preferentially promote mono-N-alkylation of said pπmary amme by said orgamc electrophile, to provide a secondary armne R and R' each comprise the same or a different hydrocarbon having one or more carbon atoms and X compπses a leaving group The carbon atom covalently bonded to the leaving group and the carbon atom covalently bonded to the amme nitrogen atom are both saturated The hydrocarbon has one or more carbon atoms More preferably, the hydrocarbon has about 1-50 carbon atoms, and in a preferred embodiment, the hydrocarbon has about 1-30 carbons

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A illustrates the use of alternative solvents Figure IB illustrates N-alkylation of compounds containing alternative electrophiles to bromide

Figure IC illustrates obtainmg a "one pot" N-alkylation of a suitable pπmary alcohol in the presence of suitable reagents Figure 2 illustrates the use of Cs₂C0₃ as a cesium base

Figure 3 A and 3B illustrate application of N-alkylation for peptidomimetic synthesis

Figure 4 illustrates N-alkylation of halogenated compounds resulting in secondary amine enantiomers

DETAILED DESCRIPTION OF THE INVENTION More particularly according to the present invention, one starting material is advantageously an organic nitrogen compound having the structural formula

R-NH₂ m which R contains one or more saturated carbon atoms, one of which is covalently bonded to the pπmary amme nitrogen, and the R moieties compπse any substituents that are unreactive under the disclosed conditions of N-alkylation It will be apparent to one skilled in the art that pπmary ammes are sometimes referred to as mono-substituted ammes in which the carbon adjacent to (bound to) the amme mtrogen is saturated This saturated carbon may be a pπmary, secondary, or tertiary carbon, more preferably a secondary carbon, and most preferably a pπmary carbon One of ordinary skill m the art would also appreciate that the pπmary amme of the present invention may have aliphatic hydrocarbons that are acyclic, cyclic, or polycychc Aliphatic aromatic hydrocarbons are also possible pπmary am e substrates of the instant invention, provided that aromatic substituent is not bonded directly to the amme mtrogen Also, the secondary amme product of the present invention may at times be refeπed to as di-substituted ammes, and that overalkylated tertiary or quaternary ammes are sometimes refeπed to as tn-substituted or tetra-substituted ammes, respectively

The N-alkylating agent is an orgamc electrophile. having the structural formula

R,-X m which X is a halide and the Ri moiety contains one or more saturated carbon atoms, one of which is covalently bonded to the halide, and the Ri moieties comprise any substituents that are unreactive under the disclosed conditions of N-alkylation It will be apparent to one skilled in the art that all organic electrophiles comprising unreactive Ri moieties in which the carbon adjacent to the halide is saturated are included within this definition, which is herein designated as alkyl halide The term orgamc electrophile includes orgamc halides such as chloπdes. bromides, and iodides, as well as other organic electrophiles such as those containing mesyl (O-Ms) or tosyl (O-Ts) groups, silyl halides, or other organic compounds which are activated for electrophihc reaction In prefened embodiments, chlorides and bromides are used Most preferably, bromides are used

The N-alkylation reaction is performed in an inert, anhydrous solvent, that also serves to regulate temperature, and which is preferably about 23°C The anhydrous solvent is preferabh dimethyl sulfoxide, N.N-dimethylformamide (DMF), l-methyl-2-pyrrohdinone (NMP), N,N- dimethylacetamide (DMAC), or a mixture thereof The most prefened anhydrous solvent is N.N- dimethylformamide Other solvents can be used, mcludmg but not limited to acetonitπle, methylene chloπde and toluene, but these tend to either cause the reaction not to go to completion, or to produce less selective mono-N-alkylation An additional constraint upon the choice of solvent is that the cesium base must be adequately soluble withm it

The concentration of alkyl amme in the reaction is not cπtical and the prefened concentration is about 0 2 M Dilute solutions lead to a larger percentage of free anions. as discussed m Le Noble (1970) Synthesis 1 1 The prefened concentration of alkyl halide, relative to the concentration of alkyl amme, is between a slight excess and a several-fold excess Suppression of further N-alkylation by the cesium base renders the concentration of alkyl halide non-critical An advantage of the present invention is that efficient N-alkylation can be obtained with only a slight excess of alkyl halide, reducmg expense and simplifying puπfication

Prefened N-alkylating agents are those in which X is Cl, Br or I The most prefened alkyl halides are those m which X is Br, m which case insolubility of CsBr produced by the N-alkylation reaction helps to dπve the reaction to completion Alkyl chlondes react more slowly, except m activated systems, but specific mono-N-alkylation is still obtained Alkyl iodides react more slowly than alkyl bromides, and may be prone to elimination reactions

The base in the present invention is chosen from cesium carbonate, cesium bicarbonate, and cesium hydroxide The prefened base is CsOH. except where milder reaction conditions are advantageous, as m example 3, where cesium carbonate is prefened The preferred amount of base. measured relative to alkyl amme concentration, is between 0 1 and 3 The higher concentrations of base are prefened for stencally-hindered alkyl ammes. such as species 4, 6, and 13-15 of Table 1 The base concentration is easily optimized by one skilled in the art for a particular reaction

Inclusion in the reaction of a powdered molecular sieve mateπal. well known to those of skill in the art, for sequestering water produced by the N-alkylation reaction, is prefened, though not essential In prefened embodiments, the pore size of the molecular sieve is 3-5 A. and in the most prefened embodiments the pore size is 4 A The removal of water is believed to secure the amine from protonation and help drive the reaction to completion

Optionally. TBAI can be mcluded in the reaction in an amount roughly equimolar with the alkyl amme TBAI accelerates N-alkylation of stencally-hindered secondary bromides Thus, m a preferred embodiment, the coupling of bromide (6) with in situ generated cesium amide (5) selectively forms the desired N-alkylated product (2) as shown

In order to further illustrate the present mvention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in no

_ /^H csOH Θ Θ ^{R Br} , ^R\_N__R, ₊ ^R\_N _,

R— N. R— N Cs g H S^"R

\ DMF, 4 A MS I ^{π κ H} H 2 3

1 5

R= _a|ky_| R - alkyl, major minor alkenyl, benzyl, allyl way limitative N-alkylatιons are initially studied usmg a limited amount of phenethylamme and a slight excess of 1 -bromobutane Several vaπables are considered such as vaπation in base, solvent, temperature, as well as the use of additives such as molecular sieves, acid scavengers, and phase transfer catalysts Compared to cesium carbonate, bicarbonate, and fluoπde and other alkali metal hydroxides, the preferred base is cesium hydroxide when usmg DMF, DMSO, NMP. or DMAC as the solvent The prefened concentration of the amme m DMF is about 0 20 M

EXAMPLE 1

The effect of cesium hydroxide and powdered 4 A molecular sieve upon the N-alkylation of phenethylamme by bromobutane is tested A flame dned 25-mL round-bottomed flask equipped with a magnetic stirπng bar, rubber septum, and mtrogen inlet, is flushed with dry mtrogen and charged with activated powdered 4 A molecular sieves (500 mg) and anhydrous DMF (8 3 mL) Under a mtrogen purge, cesium hydroxide monohydrate (0 28g. 1 7 mmol) is added, and the mixture is stined vigorously for 10 minutes After phenethylamme (7) (0 21 mL, 1 7 mmol) is added, the mixture is stined for an additional 30 minutes By syringe, 1 -bromobutane (8 (0 21 mL, 2 0 mmol) is added to the white suspension, which is stined at room temperature for an additional 20 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved morganic salts, and washed several times with ethyl acetate After the filtrate is concentrated to a nominal volume by air, the residue is taken up m 1 N NaOH, and transfened to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 ml) , and the combmed organic layers are washed with bπne. dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil The resulting crude mixture of products is separated and puπfied by silica gel column chromatography usmg a mixture of ethyl acetate-alcohol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme (2) (0 26g. 1 5 mmol. 89%) as a

colorless oil as well as tπalkylamme (3) (0 04g. 0 17 mmol. 10%) as a pale yellow oil Standard reaction conditions are as follows

Changes from these standard reaction conditions in the following examples are as noted The yield of conesponding secondary dialkylamine moiety (2) and tertiary ammes tnalkylamine adduct (3) are 89% and 10%, respectively, in the presence of CsOH and molecular sieve, while m their absence 25% secondary amme (2) and 72% tertiary amme (3) are formed Therefore, inclusion of cesium hydroxide and powdered 4 A molecular sieve m the reaction promotes mono-N- alkylation over di-N-alkylation by a ratio of approximately 9 1, while m the absence of cesium hydroxide and molecular sieve, tertiary amme (3) is the major product

Thus, in the absence of cesium base the tertiary amme/tπalkylamme adduct is the predominant product, while in the presence of cesium base, the selectivity is reversed affording secondary amine/dialkylamine moiety

EXAMPLE 2

Variations in the equivalents of cesium hydroxide are also investigated

The optimum conditions for selective mono-N-alkylation of a vaπety of alkyl ammes and alkyl bromides are summaπzed m Table 1 (infra) Conditions are optimized for CsOH concentration and reaction time The temperature is room temperature, or about 23°C and the alkyl bromide is present at slight excess (1 2 fold) compared to amme Other reaction conditions are standard conditions as given m example 1

In each example, the conesponding secondary amme is obtained m high yield, typically in 5-15 fold higher than the conesponding tertiary armne Optimum CsOH concentrations ranged from 0 1 to 3 molar equivalents relative to alkyl amme less CsOH is found to be required for activated bromides (benzyl and allyl systems), while 3 equivalents are preferred for stericallv-hmdered ammes Similarh . activated bromides require less reaction time for the reaction to complete than non-activated bromides

Inclusion of certain additives are also found to be effective Molecular sieves improve the selectivity and yield of the secondary armne This manipulates the equihbπum by removing adventitious water that may retard the reaction rate The addition of acid scavengers (Et₃N,DBU) or phase transfer catalysts (Bu N⁺HS0₄) fail to enhance selectivity further The presence of CsOH alone is enough to suppress armne protection Tetrabutylammonium iodide assists in accelerating the monoalkylation of steπcally hmdered secondary bromides

Several of the examples set forth represent alkyl ammes containing a chiral center The L- aminoesters are selectively mono-N-alkylated by three different alkyl bromides in high yield Most significantly, racemization of the chiral center is not detected m any example the chirahty of the reactant's chiral center is preserved in the conesponding product Even m the absence of protecting groups, better yields of the secondary ammes of entnes are obtamed than were reported by Bowman & Coghlan, Tetrahedron (1997) 53 15787, usmg 2-nιtrophenylsulfonyl protected L-valme methyl ester for alkylation The absence of racemization m performing the present mvention, and absence of protectmg groups, is believed to be sigmficant to biological applications m which enantiomeric puπty is generally cπtical For example, these results have tremendous implications in peptidomimetic synthesis

Thus unprotected pπmary ammes are smoothly N-monoalkylated usmg more than one equivalent of alkylatmg agent m the presence of cesium hydroxide in DMF, givmg rise to respectable yields and selectivity

Table 1. CsOH-Promoted N- Alkylation of Various Primary Amines

R'Br, CsOH-H₂0 R'

R-N-R¹

R-NH₂ + H R-N-R'

4 A MS, DMF, 23 °C B

Table 2. CsOH-Promoted N-Alkylation of Primary Amines with Various Bromides

R'

R'Br, CsOH.H₂Q H I

.N.

Ph"^^{1 2} Ph^^'^^{^}R' ^ Ph-^- R'

4 A MS, DMF, 23 °C A B

entry R'Br (Bromide) CsOH-H₂0 Time Yield (A) Yield (B)

1 ^'Br 1 eq 21 h 89% 10% 2 PIT Br 1 eq 24 h 85% 10%

3 Br 0.1 eq 4.5 h 85% 15% 4 Pfi B irr 0.1 eq 4 h 85% 15%

5 3r 3 eq 24 h 74% 0%

3 eq 48 h 80% 0%

7 3 eq 24 h 70 % 0%

Br

8 .NBn, 1 eq 36 h 54% 0%

Br"

-Ph

1 eq

,NBn, 28 h 45% 0%

Br'

Table 3. CsOH-Promoted N-Alkylation of Multifunctional Primary Amines

R'Br, CsOH-H₂0 R-Ν-R' + ?

R-ΝH₂ H R-N-R'

4 A MS, DMF, 23 °C A B

entry RNH, R'Br Time Yield (A) Yield (B)

,NHc

MeO' Ph-^-^Br 22 h 84% 15%

EXAMPLE 3

Peptidomimetic compounds of pharmaceutical mterest can be prepared as secondary amines by N-alkylation, and such synthesis is frequently employed to generate hbraπes of compounds for activity screening N-Alkylation for peptidomimetic synthesis is demonstrated usmg the present mvention as shown in Table 2, by N-alkylation under standard reaction conditions of the L-leucine analog (11), in which the hydroxyl was optionally Bn-protected Alkyl halide (10), an analog of L- lsoleucme, is prepared in 90% yield by brommation of the conespondmg alcohol (9) by treatment with thionyl bromide m benzene with catalytic N.N-dimethylformamide N-Alkylation of (11) by (10) is performed under standard reaction conditions descπbed above to produce the O-protected peptidomimetic (12) The N-alkylated. O-protected, secondary amme (12) is deprotected by catalytic hydrogenation over a palladium catalyst to yield the product peptidomimetic (13) In both cases (R=H and R=Bn, Table 2), N-alkylation yields more than 50% of the conespondmg secondary amme

TABLE 4

R 10 11 Time 12 13

(Equiv) (Equiv) (h) (Yield) (Yield)

H 1 2 1 14 60 52

Bn 1 2 1 14 52 48

16

17

EXAMPLE 4

Solid phase synthesis of peptides, peptidomimetics and other bioactive compounds is widely used in the chemical and pharmaceutical industries. Solid phase N-alkylation using the present invention is performed by N-alkylation of (14), as shown in example 4, in which L-leucine is esterified to Merrifield resin by conventional methods known to those of skill in the art, to produce N-t-BOC-L- leucine (14). N-alkylation of N-t-BOC-L-leucine (14) by Bn₂-protected alkyl halide (10), an analog of L-isoleucine, yields the immobilized secondary amine (15). The N-alkylated secondary amine product (17) is cleaved from the resin in high yield by refluxing with lithium aluminum hydride in tetrahydrofuran. Cesium carbonate, a weaker base than cesium hydroxide, is used in this example to minimize premature cleavage from the resin.

EXAMPLE 5

19. CsOH

DMF. 4 A MS, 23 °C, 12h In embodiments of the present mvention where the alkyl amme is a diamme or polyamme, or a diamme or polyamme is produced as an mtermediate by the N-alkylation reaction, then polyammes can be produced by the present invention N-Alkylation for synthesis of polyamme was demonstrated by synthesis of N-(2-(2-ammoethylthιo)ethyl)ethylenediamme (21) For an alternative synthesis see U S Patent 3,362,996 (1968) to Teumac, incorporated herem m its entirety by reference 2- aminoethanethiol hydrochloπde (18) is alkylated by 2-bromoethylamιne hydrobrormde (19 under standard conditions for 44 hours to yield diamme (20) and polyamme (21) m 44% and 24% yields, respectively Diamme (20) is an mtermediate m the synthesis of polyamine (21), and further alkylation for 12 hours under standard conditions results m N-alkylation of the remaining (20) to yield 73% N-(2- (2-aιmnoethylthιo)ethyl)ethylenedιanune (21)

EXAMPLE 6

Additional examples of the utility of the present mvention in promotmg N-alkylation of various pπmary ammes are presented in Table 3 Entnes 1-3 show that 75%, or better, yields of secondary amme can be obtamed usmg mildly steπcally crowded reagents such as branched alkanes, cyclooctane denvatives, or benzyl denvatives Examples 4 and 5 demonstrate use of the present mvention in the case of multifunctional pπmary ammes in both cases good yields of secondary ammes were obtained, obviating the need for protectmg groups for the hydroxyl groups and tryptopan side cham

EXAMPLE 7

Figure 1A illustrates the use of alternative solvents Both DMSO. NMP and DMAC result m high yields of secondary ammes in the presence of CsOH, with yields of secondary and tertiary amines only slightly inferior to those obtained using DMF (cf Table 1. entry 1) Thus, while use of each of these solvents is acceptable. DMF is the preferred solvent Figure IB illustrates N-alkylation of compounds containing alternative electrophiles to bromide Use of iodide m place of bromide generally yields a more sluggish reaction, slightly lower yield, and, carries an increased risk of undesired elimination side-reactions Entries 2 and 3 demonstrate that O Ms and O Ts denvatives can also be N-alkylated by the present invention in moderate to good yields As these functional groups are widely used in the art, this enhances the usefulness of the present mvention for applications mvolvmg solid phase and/or peptidomimetic applications Figure IC illustrates obtainmg a "one-pot" N-alkylation of a suitable pπmary alcohol m the presence of suitable reagents Brommation (example 1) or mesylation (example 2) of a pπmary alcohol is achieved by standard procedures and reagents m DMF, and subsequent addition of a pπmary amme to the same reaction mixtures results m good yields of the product corresponding to N-alkylation of the 10 pπmary alcohol

EXAMPLE 8

Figure 2 illustrates an alternative embodiment of the present invention wherem Cs₂C0₃ is used m place of CsOH Alkylation of a pπmary amme provides direct compaπson with the use of CsOH, 15 from which it can be seen that a lower yield (71%) of the secondary armne is obtamed usmg Cs₂C0₃ in place of CsOH (89%) Despite the lower yield, usmg the milder Cs₂C0₃ in place of CsOH can be advantageous where other functional groups on the reagents are sensitive to CsOH N-alkylation of sensitive ammo esters is shown m the second set of examples in Figure 2 good yields of the desired secondary ammes are obtamed with the ester group intact

20 The third example of Figure 2 illustrates combmed N-alkylation and esteπfication m the presence of Cs₂C0₃ in place of CsOH and also where 10% (v/v) water is present

EXAMPLE 9

Cyclic products can be easily obtamed in the present mvention through the use of bifunctional 25 reagents Figure 9 illustrates synthesis of Ts-cyclen (24) from the conespondmg tπamme (23) and O- Ts protected dialcohol (22) The Ts-cyclen is a useful mtermediate m the svnthesis of metal-chelating cyclen denvatives for use as MRI imaging reagents

EXAMPLE 10

30 Figure 3 illustrates a synthetic scheme for synthesis of the peptidomimetic tπpeptide analogue of Leu-Ile-Leu Following N-alkylation to form the Bn-protected dipeptide analogue of Ile-Ile,

Ts

deprotection is achieved by catalytic hydrogenation, exposing the primary amme for further N- alkylation to produce the tπpeptide analogue Clearly, this cycle of N-alkylation and deprotection could be repeated to yield longer ohgomeπc peptidomimetic compounds

EXAMPLE 11

Figure 4 illustrates how the pπor examples, m which N-alkylation is preceded by halogenation of the conespondmg alcohol, can be exploited to control the stereochemistry of N-alkylation Beginning from the identical stereoisomer of an alcohol, the stereochemistry of halogenation is controlled, through the choice of halogenation method, to provide either inversion (first method) or preservation (second method) of the chiral center As demonstrated previously in Table 1, N-alkylation by the present invention proceeds with inversion of chirality Therefore N-alkylation of the halogenated compounds m Figure 4 results m both secondary amme enantiomers

EXAMPLE 12

Preparation of dialkylamine El.

A flame dried 25 mL round-bottomed flask equipped with a magnetic stirring bar. rubber septum, and mtrogen inlet, is flushed with dry nitrogen and charged with activated powdered 4 A molecular sieves (500 mg) and anhydrous DMF (8 3 mL) Under a nitrogen purge, cesium hydroxide monohydrate (280 mg, 1 7 mmol. 1 eq ) is added, and the mixture is vigorously stirred for 10 minutes After phenethylamine (0 21 mL. 1 7 mmol, 1 eq ) is added, the mixture is stirred for an additional 30 mmutes By syrmge, 1 -bromobutane (0.21 mL, 2 0 mmol. 1 2 eq ) is added to the white suspension and the reaction is allowed to proceed at room temperature for 18 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved inorganic salts, and washed several times with ethyl acetate After the filtrate is concentrated to a nominal volume by air. the residue is taken up in 1 N NaOH, and transfened to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL), and the combmed orgamc layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil The resulting crude mixture of products is separated and puπfied by silica gel column chromatography usmg a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamine El (260 mg, 89%) as a colorless oil as well as tπalkylamine E2 (40 mg, 10%) as a pale yellow oil Data for El: IR (thin film) 3290, 3063, 3027, 2956, 2872, 2815,1496, 1453, 1125, 748 cm ^] Η NMR (360 MHz, CDC1₃) δ 0 89 (t, J = 7 4 Hz, 3 H), 1 25-1 35 (m, 2 H), 1 36-1 64 (m, 2 H). 1 75 (s, NH), 2 60 (t, J -7 0 Hz, 2 H), 2 49-2 69 (m, 2 H), 2 77-2 92 (m, 2 H), 7 16-7 35 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 13 78. 20 27, 31 82, 36 13, 49 33, 51 00, 125 88, 128 22, 128 47, 139 86 Data for E2: IR (thin film) 3026, 2930, 2871, 2861, 2800, 1453, 1100, 697 cm ' Η NMR (360 MHz, CDC1₃) δ 0 89-0 98 (m, 6 H), 1 25-1 35 (m, 4 H), 1 40-1 53 (m, 4 H), 2 41-2 51 (m. 4 H), 2 67-2 75 (m, 4 H), 7 12-7 33 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 14 08, 20 74, 29 29. 33 44. 53 80. 56 11. 125 80, 128 27, 128 69, 140 90

EXAMPLE 13

Preparation of dialkylamine FI.

Under an atmosphere of mtrogen, activated 4 A molecular sieves (500 mg) and cesium hydroxide monohydrate (280 mg, 1 65 mmol, 1 eq ) are placed in anhydrous NN-dimethylformamide (8 3 mL) Phenethylamme (0 21 mL. 1 65 mmol. 1 eq ) is injected ten minutes later mto the turbid solution and stined for 30 mmutes l-Bromo-3-phenylpropane (0 38 mL, 2 5 mmol, 1 5 eq ) is added to the solution by syπnge and the reaction is allowed to proceed at room temperature under nitrogen for 24 hours The reaction mixture is then filtered and the undissolved solids are washed with ethyl acetate After the filtrate is concentrated to a nominal volume by blowing air. the residue is taken up in

1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (3 \ 30 mL), followed by bπne (30 mL). and then dned using anhydrous sodium sulfate Solvent is removed in vacuo and the residue is puπfied via flash column chromatography (9 1 EtOAc EtOH) to yield the desired dialkylamine FI (330 mg, 85%) as a clear oil and the tπalkylamine F2 (60 mg. 10%) as a pale yellow oil Data for FI: 1H NMR (360 MHz. CDC1₃) δ 1 55 (s, NH), 1 76-1 85 (m. 2 H),

2 59-2 67 (m. 4 H), 2 78-2 93 (m. 4 H), 7 06-7 31 (m, 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 31 17, 32 57, 34 41, 46 32, 48 28, 123 7, 124 01, 126 15. 136 73. 139 20 Data for F2: *H NMR (360 MHz, CDC1₃) δ 1 76-1 89 (m, 4 H), 2 56 (t, J =7 1 Hz 4 H). 2 65 (t. J =7 8 Hz, 4 H), 2 73 (s. 4 H) 7 18-7 31 (m, 15 H) ¹³C NMR (90 MFlz, CDC1₃) δ 28 79, 33 39, 33 63, 53 33, 55 87, 125 64, 125 82, 128 23, 128 67, 140 68, 142 28

EXAMPLE 14

Preparation of dialkylamine Gl.

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and nitrogen inlet, is flushed with dry mtrogen and phenethylamme (0 21 mL, 1 7 mmol. 1 eq ), activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (28 mg. 0 165 mmol, 0 1 eq ) are dissolved m anhydrous NN-dimethylformamide (8 3 mL) and allowed to stir for 30 minutes at room temperature Allyl bromide (0 17 mL, 2 0 mmol, 1 2 eq ) is added by syringe to the white suspension with vigorous stirring The reaction is allowed to proceed at ambient temperature for 4 5 hours The reaction suspension is then filtered, and rinsed with ethyl acetate The filtrate is concentrated by blowmg air, and the residue is dissolved in 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL), bπne (30 mL). and dned over anhydrous sodium sulfate Concentration of the solvent, and puπfication usmg flash column chromatography (9 1 EtOAc EtOH) yields the desired dialkvlamme Gl (220 mg, 85%) as a clear oil and the tπalkylamme G2 (50 mg, 15 %) as a vellow oil Data for Gl: IR (thin film) 3313. 3077 3063, 2956, 2924, 2854, 2816,1495. 1453. 918 749 cm ¹ *H NMR (360 MHz. CDC1₃) δ 2 07 (s. NH), 2 82-2 91 (m, 4 H), 3 27 (d. J = 6 5 Hz, 2 H), 5 13 (m. 2 H), 5 88 (ddt, J=17, 10 3. 6 Hz, IH), 7 18-7 31 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 36 13, 50 32, 52 11, 116 19, 126 13. 128 25, 136 25, 139 80 Data for G2: ^XH NMR (360 MHz, CDC1₃) δ 2 72-2 80 (m, 4 H), 3 20 (d, J = 6 4 Hz, 4 H), 5 16 (m, 4 H), 5 86 (ddt, J-17 1, 10 4, 6Hz, 2 H), 7 17-7 30 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 33 11, 55 00, 56 71. 117 55. 125 85. 128 25, 128 64, 135 41, 140 43 EXAMPLE 15

Preparation of dialkylamine HI.

Under an atmosphere of mtrogen, activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (30 mg, 0 165 mmol, 0 1 eq ) are placed in anhydrous NN-dimethylformamide (8 2 mL) Phenethylamme (0 21 mL, 1 65 mmol, 1 eq ) is injected ten mmutes later into the turbid solution and stined for an additional 30 mmutes Benzyl bromide (0 22 mL, 1 8 mmol, 1 1 eq ) is added to the solution by syringe and the reaction is allowed to proceed at room temperature under mtrogen for 4 hours The reaction mixture is then filtered to remove molecular sieves and undissolved inorganic salts and nnsed with ethyl acetate After the filtrate is concentrated to a nominal volume b} blowmg air, the residue is taken up in 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (3 x 30 mL), followed by brine (30 mL), and then dned usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is puπfied via flash column chromatography (9 1 EtOAc EtOH) to yield the desired dialkylamine HI (290 mg, 85%) as a clear oil and the tnalkylamine H2 (71 mg, 15%) as a pale yellow oil Data for HI: IR (thin film) 3350, 3026, 2925, 2872, 2815,1497, 1455, 696 cm^"1 *H NMR (360 MHz, CDC1₃) δ 1 87 (s. NH), 2 72-2 92 (m, 4 H), 3 79 (s. 2 H), 7 07-7 49 (m. 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 36 10, 50 33, 53 63, 126 10. 126 94. 128 10, 128 33, 128 39. 128 65, 139 80 Data for H2: 'H NMR (360 MHz. CDC1₃) δ 2 59- 2 61 (m, 4 H), 3 52 (s. 4 H). 6 94-7 21 (m, 15 H) ¹³C NMR (90 MHz. CDC1₃) δ 33 26, 54 88. 57 98, 125 67, 126 69, 128 03, 128 19, 128 55, 128 66, 128 84, 139 9, 140 0

EXAMPLE 16

Preparation of dialkylamine II.

Into a solution of phenethylamme (0 21 mL, 1 65 mmol, leq ) in anhydrous N, N- dimethylformamide (8 3 mL), are added successively activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (910 g, 5 4 mmol, 3 2 eq ), then the resultmg suspension is stined under a mtrogen atmosphere for 30 mmutes By syπnge, l-bromo-2-methylpropane (0 42 mL, 4 0 mmol, 2 4 eq ) is added and the reaction is allowed to proceed under mtrogen for 24 hours at room temperature The reaction mixture is then filtered to remove molecular sieves and undissolved inorganic salts, and πnsed several times with ethyl acetate The combmed filtrates are concentrated to a nominal volume by blowmg air, and the residue is taken up in 1 Ν ΝaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL), bπne (30 mL), and dried over anhydrous sodium sulfate The solvent is concentrated in vacuo and the residue is puπfied b flash column chromatography (9 1 EtOAc EtOH) to give the desired dialkylamme II (220 mg. 74%) as a colorless oil The tπalkylamme 12 is not observed Data for II ^!H ΝMR (360 MHz, CDC1₃) δ 0 81 (d, J=6 5 Hz. 6 H), 1 22 (s, ΝH). 1 60-1 71 (m. 1 H). 2 36 (d. J =6 7 Hz. 2 H), 2 73-2 79 (m 4 H), 6 99-7 24 (m, 5 H) ¹³C ΝMR (90 MHz, CDC1₃) δ 20 48, 28 08. 36 22, 51 14, 57 69. 125 90, 128 24, 128 57, 139 98

EXAMPLE 17

Preparation of dialkylamine Jl.

A flame dried 25 mL round-bottomed flask equipped with a magnetic stimng bar, rubber septum, and mtrogen inlet, is swept with dry nitrogen Phenethylamme (0 21 mL, 1 7 mmol, 1 eq ), activatived 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (690 mg. 4 1 mmol. 2 4 eq ) are dissolved in anhydrous N N-dimethylformamide (8 3 ml) and allowed to stir for 30 mmutes at room temperature 2-Bromobutane (0 9 mL. 8 2 mmol. 5 0 eq ) is added by synnge to the white suspension with vigorous stirring The reaction is allowed to proceed at ambient temperature for 48 hours The reaction is then filtered and rinsed with

l acetate The filtrate is concentrated b} blowing air, and the residue is dissolved in 1 Ν ΝaOH. and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (2 x 30 mL), bπne (30 mL), and dned over anhydrous sodium sulfate Concentration of the solvent, and punfication using flash column chromatography (9 1 EtOAc EtOH) yields the desired dialkylamme Jl as a clear oil (230 mg, 80%) and the tπalkylamme J2 is not observed Data for Jl: IR (thin film) 3306, 3084, 3061, 3025, 2931, 2855, 2810, 1495, 1457, 1125, 745 cm ' 1H NMR (360 MHz, CDC1₃) δ 0 82 (t, J = 7 5 Hz, 3 H), 1 00 (d, J = 6 1 Hz, 3 H), 1 24-1 31 (m, 2 H), 1 42-1 48 (m, 1 H), 2 51-2 56 (m, 1 H), 2 78-2 89 (m, 4 H), 7 12-7 39 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 10 00, 19 54, 29 28, 35 35, 48 35, 54 21, 125 89, 128 21, 128 45. 139 91

EXAMPLE 18

Preparation of dialkylamine Kl.

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirπng bar, rubber septum, and nitrogen inlet, is flushed with dry nitrogen and charged with activated powdered 4 A molecular sieves (500 mg) and anhydrous DMF (8 3 mL) Under a mtrogen purge, cesium hydroxide monohydrate (280 mg, 1 7 mmol. 1 eq ) is added, and the mixture is vigorously stined for 10 mmutes After phenethylamme (0 21 mL, 1 7 mmol, 1 eq ) is added, and the mixture is stined for an additional 30 minutes By synnge, 2-bromopropane (0 47 mL, 5 mmol. 3 eq ) is added to the white suspension which is stirred at room temperature for an additional 24 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved morganic salts, and rinsed several times with ethvl acetate After the filtrate is concentrated to a nominal volume by blowing air, the residue is taken up m I N NaOH, and transfened to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL), and the combined organic layers are washed with bnne, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil

The resulting crude mixture of products are separated and purified by silica gel column chromatography using a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme Kl (180 mg. 70%) as a colorless oil The tπalkylamine K2 is not observed Data for Kl: 'H NMR (360 MHz, CDC1₃) δ 1 09 (d, J = 8 2 Hz, 6 H), 1 54 (s, NH), 2 62-2 89 (m, 5 H), 7 21-7 31 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 22 72. 36 37, 48 49, 48 65. 126 03, 128 58, 139 93 EXAMPLE 19

Preparation of dialkylamine Yl.

A flame dried 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and mtrogen inlet, is flushed with dry nitrogen and charged with activated powdered 4 A molecular sieves (500 mg) and anhydrous DMF (11 mL) Under a mtrogen purge, cesium hydroxide monohydrate (360 mg, 2 1 mmol, 1 eq ) is added, and the mixture is vigorously stined for 10 mmutes After phenethylamme (0 26 mL, 2 0 mmol, 1 eq ) is added, the mixture is stined for an additional 30 mmutes NN-dibenzyhsoleucinol bromide (960 mg, 2 7 mmol. 1 28 eq ) is added to the white suspension which is stirred at room temperature for an additional 36 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved morganic salts, and rinsed with ethyl acetate After the filtrate is concentrated to a nominal volume by blowing air, the residue is taken up m 1 N NaOH, and transfened to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL). and the combmed orgamc layers are washed with bπne, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil

The resultmg crude mixture of products is separated and puπfied by silica gel column chromatography using a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme Yl (450 mg, 54%) as a colorless oil The tπalkylamine Y2 is not observed Data for Yl: ^lU NMR (360 MHz, CDC1₃) δ 0 87-0 92 (m, 6 H), 1 17-1 21 (m, 1 H), 1 43-1 47 (m, 1 H), 1 88 (m, 1 H), 2 57 (d. J = 8 5 Hz. 2 H). 2 66-2 79 (m, 5 H), 2 8 (s, NH). 2 97-3 46 (AB, J^ = 13 4 Hz. 2 H), 3 74-3 78 (AB, J_AB = 13 7 Hz, 2 H), 7 12-7 41 (m, 15 H) ¹³C NMR (90 MHz, CDC1₃) δ 12 13, 16 43. 29 07. 32 52, 36 48. 47 31. 51 25, 54 36, 60 95, 126 41, 127 03, 128 42, 128 63, 129 09. 140 25, 140 40 EXAMPLE 20

Preparation of dialkylamine Wl.

Under an atmosphere of mtrogen, activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (75 mg, 0 41 mmol, 1 eq ) are added to anhydrous NN-dimethyl-formamide (2 ml) Phenethylamme (50 mg, 0 61 mmol, 1 eq ) is mjected ten mmutes later mto the turbid solution and stined for an additional 30 mmutes N, N-dibenzylphenylalaninol bromide (222 mg, 0 55 mmol, 1 5 eq ) is added to the solution and the mixture is allowed to proceed at room temperature under nitrogen for 28 hours The reaction is then filtered and washed with ethyl acetate The filtrate is concentrated to a nommal volume by blowing air and the residue is taken up m 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (3 x 30 mL). followed by bπne (30 mL), and then dried usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is purified via flash column chromatography (9 1 EtOAc EtOH) to yield the desired dialkylamme Wl (60 mg,

45%) as a clear oil The tπalkylamme W2 was not observed Data for Wl: ^XH NMR (360 MHz, CDC1₃) δ 2 10 (s, NH), 2 34-2 64 (m, 8 H), 2 92-3 10 (m, 1 H), 3 39 (AB, J_AB = 13 4 Hz, 2 H), 3 73

(AB, J_AB - 13 4 Hz. 2 H), 7 05-7 30 (m. 20 H) ¹³C NMR (90 MHz. CDC1₃) δ 34 23, 38 44, 49 66.

51 29, 53 63, 59 46. 124 35, 125 00. 126 99, 128 38, 128 77. 129 05. 139 50

EXAMPLE 21 Preparation of dialkylamine LI.

L1 (93 %)

,NH₂

CsOH H2O, 4 A MS DMF, 23 °C, 24 h r^ L2 (0 %)

Into a solution of w-octylamine (0 26 mL, 1 57 mmol, 1 eq ) m anhydrous N, N - dimethylformamide (8 0 mL), are added successively activated 4 A molecular sieves (500 mg) and cesium hydroxide monohydrate (260 mg, 1 56 mmol. 1 eq ) The suspension is stined under a nitrogen atmosphere for 30 mmutes By syπnge, 1 -bromobutane (0 20 mL, 2 0 mmol, 1 2 eq ) is added with stirring and the reaction is allowed to proceed under mtrogen for 24 hours at room temperature The reaction mixture is then filtered to remove molecular sieves and undissolved inorganic salts, followed by washing with ethyl acetate After the filtrate is concentrated to a nommal volume by blowmg air, the residue was taken up m 1 N NaOH solution and extracted with ethyl acetate (3 x 30 mL) The orgamc layer was washed with water (2 x 30 mL), bπne (30 mL), and dned over anhydrous sodium sulfate The solution is concentrated in vacuo, and the residue was punfied by flash column chromatography (9 1 EtOAc EtOH) to give the desired dialkylamme LI (270 mg, 93%) as a colorless oil The tπalkylamine L2 is not observed Data for LI: 1H NMR (360 MHz, CDC1₃) δ 0 86-0 91(m, 6 H), 1 25 (m, 12 H), 1 39 (m, 4 H), 2 35-2 39 (m, 4 H) ¹³C NMR (90 MHz, CDC1₃) δ 14 06, 20 77, 22 63, 26 96, 27 63, 29 14, 29 29, 29 57, 31 83. 53 90, 54 21

EXAMPLE 22

Preparation of dialkylamine Ml.

M1 (80%)

Br Ph

,NH₂

CsOH H2O, 4 A MS ,Ph DMF, 23 °C, 22 h

Ph M2 (10 %)

To a solution of «-octylaιmne (0 26 mL, 1 6 mmol. 1 eq ) m anhydrous N,N- dimethylformamide (8 mL), 4 A activated molecular sieves (500 mg) and powered cesium hydroxide monohydrate (260 mg, 1 6 mmol. 1 eq ) are added consecutively, and the resulting suspension is stirred vigorously stined for 30 mmutes under a mtrogen atmosphere Usmg a syringe, l-bromo-3- phenylpropane (0 28 mL, 1 9 mmol, 1 2 eq ) is injected mto the milky white mixture and the reaction is stirred for 22 hours under an atmosphere of nitrogen at ambient temperature The reaction mixture is filtered and washed with ethyl acetate After the filtrate is evaporated to a nommal volume usmg a gentle stream of air, the residue is taken up in 1 N NaOH and extracted with ethyl acetate (3 x 30mL) The resulting organic layer is washed consecutively with water (2 x 30 mL). bπne (30 mL). and dried usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is subjected to flash column chromatography (9 1 EtOAc EtOH) to afford the desired dialkylamme Ml (310 mg, 80%) as a colorless oil and the tπalkylamine M2 (58 mg, 10%) as a yellow oil Data for Ml : 1H NMR (360 MHz, CDCI₃) δ 0 85 (t, J= 6 8 Hz, 3 H), 1 20-1 35 (m, 8 H), 1 40-1 50 (m, 2 H), 1 78-1 80 (m, 4 H), 3 50-3 70 (m, 6 H), 7 10-7 28 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 13 96, 22 52, 27 40, 29 29, 29 39. 29 54, 31 62, 33 56, 40 20, 49 06, 53 61, 126 58. 128 15. 128 31, 141 34 Data for M2: 'H NMR (360 MHz, CDC1₃) δ 0 90 (t, J= 6 9 Hz, 3 H), 1 29 (m, 12 H). 1 90 (t, J = 6 4 Hz, 4 H), 2 40- 2 49 (m, 6 H), 2 60-2 71 (m, 4 H), 7 16-7 30 (m, 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 14 04, 22 60,

27 30, 28 10, 29 19, 29 56, 30 11, 31 55, 37 89, 53 61, 54 12, 127 15, 128 33, 128 41, 139 30

EXAMPLE 23

Preparation of dialkylamine Nl.

N2 (13 %)

Under an atmosphere of mtrogen, activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (310 mg, 1 84 mmol, 1 eq ) is added to anhydrous N, N-dimethylformamide (9 4 ml) Benzylamine (0 20 mL, 1 83 mmol, 1 eq ) is injected ten minutes later into the turbid solution and stined for an additional 30 mmutes 1 -Bromooctane (0 39 mL, 2 2 mmol, 1 2 eq ) is added to the solution by syrmge and the reaction is allowed to proceed at room temperature under the protection of mtrogen for 22 hours The reaction is then filtered to remove molecular sieves and undissolved morganic salts and rmsed with ethyl acetate After the filtrate is concentrated to a nommal volume by blowing air, the residue is taken up in 1 Ν ΝaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (3 x 30 mL). followed by bπne (30 mL). and then dried using anhydrous sodium sulfate Solvent is removed n vacuo and the residue is purified via flash column chromatography (9 1 EtOAc EtOH) to give the desired dialkylamme Νl (300 mg, 75%) as a clear oil and the tπalkylamine Ν2 (75 mg, 13%) as a pale yellow oil Data for Nl: *H NMR (360 MHz. CDC1₃) δ 0 88 (t, J= 7 0 Hz, 3 H), 1 26-1 31 (m, 10 H), 1 47-1 52 (m. 2 H), 2 25 (s, NH), 2 60 (t, J = 7 2 Hz, 2 H), 3 77 (s, 2 H), 7 20-7 33 (m, 5 H) ¹³C NMR (90 MHz, CDCI3) δ 14 04. 22 59, 27 25. 29 19, 29 41, 29 56, 31 76, 49 06, 53 61, 127 10. 128 33. 128 40, 139 25 Data for N2: ^lB NMR (360 MHz, CDCI₃) δ 0 86 (t, J = 6 8 Hz. 6 H). 1 25-1 31 (m. 20 H). 1 43-1 47 (m, 4 H). 2 38 (t, J = 7 2 Hz, 4 H), 3 53 (s, 2 H). 7 21-7 33 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 14 07, 22 65. 27 01. 27 42, 29 32, 29 53, 31 86, 53 79, 58 63, 126 49, 127 95. 128 06. 128 29. 128 74, 140 24 EXAMPLE 24

Preparation of dialkylamine 01.

Into a solution of cyclohexylmethyl-amine (0 23 mL, 1 78 mmol, 1 eq ) m anhydrous N, N,- dimethylformamide (9 mL), are added successively activated 4 A molecular sieves (500 mg) and cesium hydroxide monohydrate (300 mg. 1 78 mmol, 1 eq ), then the suspension is stined under a mtrogen atmosphere for 30 mmutes By syπnge. l-bromo-3-phenylpropane (0 33 mL. 2 1 mmol, 1 2 eq ) is added with stirring, and the reaction is allowed to proceed under mtrogen for 22 hours at room temperature The reaction mixture is then filtered to remove molecular sieves and undissolved morgamc salts, followed by washmg with ethyl acetate After the filtrate is concentrated to a nommal volume by blowmg air, the residue was taken up m 1 Ν ΝaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL), brine (30 mL), and dried over anhydrous sodium sulfate The solution is concentrated in vacuo, and the residue is purified by flash column chromatography (9 1 EtOAc EtOH) to give the desired dialkylamine Ol (370 mg, 90%) as a colorless oil, and the tnalkylamme O2 (62 mg, 10%) as a yellow oil Data for Ol: IR (thm film) 3320, 3084, 3062, 3025, 2850, 2807,1495, 1457, 1128, 745 cm ' *H ΝMR (360 MHz, CDC1₃) δ 0 80-0 90 (m, 2 H), 1 18-1 26 (m, 4 H), 1 39-1 51 (m, 1 H). 1 68-1 82 (m, 6 H), 2 40 (d. J = 6 8 Hz. 2 H). 2 58-2 65 (m, 4 H), 7 10-7 28 (m, 5 H) ¹³C ΝMR (90 MHz. CDCI3) δ 24 67. 24 82. 29 72, 29 87, 31 68, 36 10, 47 82, 123 84, 126 32, 126 47, 140 32 Data for M2: *H ΝMR (360 MHz, CDC1₃) δ 0 85-0 87 (m, 2 H), 1 23 (m, 4 H), 1 40-1 45 (m, 1 H), 1 73-1 83 (m. 8 H), 2 18 (d, J = 3 8 Hz, 2 H). 2 44 (s, 4 H), 2 65 (s, 4 H), 7 18-7 30 (m, 10 H) ¹³C ΝMR (90 MHz, CDC1₃) δ 26 10, 26 80, 28 88. 31 87, 32 79, 33 57, 36 07, 54 10, 61 61, 125 48, 128 26, 128 37. 142 42

EXAMPLE 25

Preparation of dialkylamine PI.

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and mtrogen inlet, is flushed with dry mtrogen and charged with activated powdered 4 A molecular sieves (500 mg) and anhydrous DMF (18 mL) Under a mtrogen purge, cesium hydroxide monohydrate (590 mg, 3 5 mmol, 1 eq ) is added, and the mixture is vigorously stined for 10 minutes After cyclopropylamme (0 25 mL, 3 5 mmol, 1 eq ) was added, and the mixture is stined for an additional 30 mmutes By syrmge, l-bromo-3-phenylpropane (0 7 mL, 4 6 mmol, 1 3 eq ) was added to the white suspension which is stined at room temperature for an additional 18 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved morgamc salts, and rinsed several times with ethyl acetate After the filtrate is concentrated to a nominal volume by blowing air, the residue is taken up in 1 N NaOH, and transferred to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL), and the combmed orgamc layers are washed with bπne, dried over anhydrous sodium sulfate, filtered, and concentrated m vacuo to give a pale yellow oil

The resultmg crude mixture of products is separated and punfied by silica gel column chromatography usmg a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme PI (525 mg, 83%) as a colorless oil as well as the tπalkylamme P2 (150 mg, 12%) as a pale yellow oil Data for PI: 1H NMR (360 MHz, CDC1₃) δ 0 56-0 64 (m, 4 H), 2 03-2 05 (m, 2 H), 2 26-2 31 (m. 1 H). 2 73 (t, J = 7 7 Hz. 2 H), 2 88 (t, J = 7 2 Hz, 2 H) 4 35 (s, NH), 7 25-7 38 (m. 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 4 17, 28 11, 30 29, 32 89, 48 37. 126 03, 128 20, 128 35, 140 31 Data for P2: *H NMR (360 MHz, CDC1₃) δ 0 56-0 59 (m, 4 H), 1 80-1 86 (m. 1 H). 1 96 (d, J = 2 3 Hz 4 H). 2 70-2 78 (m, 8 H). 7 09-7 53 (m. 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 6 75, 28 51. 33 83. 36 53. 54 89. 125 55. 128 16. 128 25 142 37

EXAMPLE 26

Preparation of dialkylamine Ql.

Under an atmosphere of mtrogen, activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (170 mg, 1 65 mmol, 1 eq) is added to anhydrous N, N-dimethylformamide (8 ml) Cyclooctylamine (0 22 mL, 1 65 mmol, 1 eq ) is mjected ten mmutes later mto the turbid solution and stined for an additional 30 mmutes l-Bromo-3-phenylpropane (0 29 mL, 1 9 mmol, 1 2 eq ) is added to the solution by syπnge and the reaction is allowed to proceed at room temperature under the protection of mtrogen for 22 hours The reaction is then filtered to remove molecular sieves and undissolved morgamc salts and nnsed with ethyl acetate The filtrate is concentrated to a nommal volume by blowing air, and the residue is taken up m 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (3 x 30 mL), followed by bπne (30 mL), and then dned usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is purified via flash column chromatography (9 1 EtOAc EtOH) to yield the desired dialkylamme Ql (300 mg, 75%) as a clear oil and the tπalkylamme Q2 (58 mg. 10%) as a pale yellow oil Data for Ql: ^JH NMR (360 MHz, CDC1₃) δ 1 27-1 86 (m, 17 H), 2 61-2 65 (m. 5 H). 7 17-7 39 (m, 5 H) ¹³C NMR (90 MHz. CDCI₃) δ 24 00, 25 61, 27 10, 31 78, 32 52, 33 63, 46 86, 57 78, 125 55, 128 12, 128 17, 141 96 Data for Q2: 1H NMR (360 MHz, CDC1₃) δ 1 26-1 89 (m, 22 H), 2 54-2 64 (m, 5 H), 7 21-7 33 (m, 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 23 95, 25 57, 27 06. 31 73, 32 48, 33 59, 46 81, 57 74, 125 50, 128 07, 128 13, 141 92

EXAMPLE 27

Preparation of dialkylamine Rl.

' C CssOOHH HH ,₂00 44 AA MMSS I

DMF 23 *C 22 h R1 ( 90 %) R2 (0 %)

To a flame dned 25mL round-bottomed flask equipped with a magnetic stirnng bar, rubber septum, and mtrogen inlet, is swept with dry mtrogen The flask is charged with tert-butylamme (0 29 mL, 2 7 mmol, 1 eq ). anhydrous NN-dimethylformamide (14 mL), activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (450 mg. 2 7 mmol. 1 eq ) The resulting mixture is allowed to stir for 30 minutes at room temperature l-Bromo-3-phenylpropane (0 5 mL, 3 2 mmol, 1 2 eq ) is added by syrmge to the white suspension with vigorous stirring The reaction was allowed to proceed at ambient temperature for 22 hours The reaction is then filtered and the undissolved inorganic solids are rinsed with ethyl acetate The filtrate is concentrated by blowing air, and the residue is dissolved in 1 N NaOH, and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL), bπne (30 mL), and dried over anhydrous sodium sulfate Concentration of the solvent, and puπfication usmg flash column chromatography (9 1 EtOAc EtOH) affords the desired dialkylamme Rl as a clear oil (450 mg, 90%) The tπalkylamme R2 is not observed Data for Rl: IR (thin film) 3300, 3062, 3026, 2933, 2859, 2824, 2815, 1496, 1453, 1232 744 cm \ *H NMR (360 MHz, CDC1₃) δ 1 08 (s, 9 H), 1 78-1 83 (m, 2 H), 2 05 (s, NH), 2 56-2 64 (m, 4 H), 7 14-7 25 (m, 5 H) ¹³CNMR (90 MHz, CDC1₃) δ 28 73, 32 26, 33 63, 41 88, 50 31, 125 53, 128 09, 128 17, 141 92

EXAMPLE 28

Preparation of dialkylamine UI.

DMF,23 , 12 h U1 (87 %) U2 ( 0 %)

Into a solution of tert-octylamme (0 25 mL, 1 55 mmol, 1 eq ) m anhydrous N,N,- dimethylformamide (8 mL), are added successively activated 4 A molecular sieves (500 mg) and cesium hydroxide monohydrate (260 mg, 1 55 mmol, 1 eq ) The reaction mixture is stined under a mtrogen atmosphere for 30 minutes By syrmge, benzyl bromide (0 22 mL, 1 85 mmol, 1 2 eq ) is added and the reaction is allowed to proceed under nitrogen for 12 hours at 23 °C The reaction mixture is then filtered to remove molecular sieves and undissolved morgamc salts, which are washed with ethyl acetate The filtrate is concentrated to a nominal volume by blowing air and the residue is taken up in 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL), bπne (30 mL), and dned over anhydrous sodium sulfate The solvent is concentrated in vacuo, and the residue is punfied by flash column chromatography (9 1 EtOAc EtOH) to yield the desired dialkylamine UI (300 mg. 87%) as a colorless oil The tnalkylamme U2 is not observed Data for UI: *H NMR (360 MHz, CDC1₃) δ 1 00 (s, 9 H), 1 17 (s, 6 H), 1 45 (s, 2 H). 3 68 (s, 2 H), 7 04-7 30 (m, 5 H) ¹³C NMR (90 MHz. CDC1₃) δ 29 04, 31 72, 46 57. 53 01, 54 44, 126 53, 128 07, 128 24, 141 57 EXAMPLE 29

Preparation of dialkylamine Tl.

To a solution of 1-adamantylamιne (200 mg, 1 32 mmol, 1 eq ) m anhydrous N,N- dimethylformamide (6 6 mL), 4 A activated molecular sieves (500 mg) and powered cesium hydroxide monohydrate (220 mg, 1 32 mmol, 1 eq ) are added consecutively, and the resulting suspension is vigorously stined for 30 mmutes under a mtrogen atmosphere Cinnamyl bromide (310 mg, 1 58 mmol, 1 2 eq ) is added into the milky white mixture and the reaction is stined for 18 hours under an atmosphere of mtrogen at ambient temperature The reaction mixture is filtered and washed w th ethyl acetate After the filtrate is evaporated to a nominal volume usmg a gentle stream of air, the residue is taken up m 1 N NaOH and extracted with ethyl acetate (3 x 30mL) The resultmg orgamc layer is washed consecutively with water (2 x 30 mL), brine (30 mL), and dried using anhydrous sodium sulfate Solvent is removed in vacuo and the residue is subjected to flash column chromatography (9 1

EtOAc EtOH) to afford the desired dialkylamine Tl (230 mg, 66%) as a colorless oil The tπalkylamme TT2 is not observed Data for TTl: *H NMR (360 MHz, CDC1₃) δ 1 58-1 75 (m, 15

H), 2 50 (s, NH), 3 44 (d, J = 7 9 Hz, 2 H), 6 35 (dt. J = 16 8, 7 4 Hz, 1 H), 6 53 (d, J = 16 8 Hz, 1

H), 7 19-7 39 (m. 5 H) ¹³C NMR (90 MHz. CDC1₃) δ 29 42. 36 47, 42 16. 42 88. 51 46. 126 19

127 21, 128 38, 131 36, 136 99

EXAMPLE 30

Preparation of dialkylamine SI.

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and nitrogen mlet, is flushed with dry nitrogen and charged with activated powdered 4 A molecular sieves (500 mg) and anhydrous DMF (8 3 mL) Under a mtrogen purge, cesium hydroxide monohydrate (655 mg, 3 9 mmol, 3 eq ) is added, and the mixture is vigorously stined for 10 mmutes After 1-adamantylamme (200 mg, 1 3 mmol, 1 eq ) is added, and the mixture is stined for an additional 30 mmutes By syrmge, l-bromo-3-phenylpropane (0 32 mL, 2 1 mmol, 1 6 eq ) is added to the white suspension which is stined at room temperature for an additional 18 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved morgamc salts, and rinsed several times with ethyl acetate After the filtrate is concentrated to a nommal volume by air, the residue is taken up m 1 N NaOH, and transfened to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL), and the combmed organic layers are washed with bnne, dned over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil The resulting crude mixture of products is separated and puπfied by silica gel column chromatography usmg a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme SI (290 mg. 82%) as a colorless oil The tnalkylamme S2 is not observed Data for SI: *H NMR (360 MHz, CDC1₃) δ 1 57-1 72 (m, 15 H), 1 81-1 90 (m, 2 H), 2 10 (s, NH), 2 62-2 68 (m, 4 H), 7 16-7 30 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 29 29, 29 58, 32 14, 33 83, 36 67, 39 86, 41 99, 42 28, 51 48, 125 83, 128 29, 128 44, 141 86

EXAMPLE 31

Preparation of dialkylamine XI.

Into a solution of 2-methoxyethylamιne (0 23 mL, 2 7 mmol. 1 eq ) in anhydrous N,N- dimethylformamide (13 5 mL), are added successively activated 4 A molecular sieves (500 mg) and cesium hydroxide monohydrate (450 mg, 2 7 mmol, 1 eq ), then the suspension is stirred under a mtrogen atmosphere for 30 mmutes By syrmge, l-bromo-3-phenylpropane (0 57 mL. 3 7 mmol. 1 4 eq ) is added with stining, and the reaction is allowed to proceed under nitrogen for 22 hours at room temperature The reaction mixture is then filtered to remove molecular sieves and undissolved morganic salts, followed by washmg with ethyl acetate After the filtrate is concentrated to a nommal volume by blowing air, the residue is taken up m 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL). bπne (30 mL). and dried over anhydrous sodium sulfate The solvent is concentrated in vacuo, and the residue is puπfied by flash column chromatography (9 1 EtOAc EtOH) to give the desired dialkylamme XI as a colorless oil (440 mg, 84%), and the tnalkylamme X2 (130 mg, 15%) as a yellow oil Data for XI: 1H NMR (360 MHz, CDC1₃) δ 1 84-1 90 (m, 2 H), 2 63-2 70 (m, 4 H), 2 80 (t, J = 5 1 Hz, 2 H), 3 12 (s, NH), 3 34 (s, 3 H), 3 50 (t, J= 5 0 Hz, 2 H), 7 12-7 33 (m, 5 H) ¹³C NMR (90 MHz, CDCI3) δ 30 93, 33 30, 48 79, 48 99, 58 63, 71 17, 125 68, 128 21, 141 66 Data for X2: *H NMR (360 MHz, CDC1₃) δ 1 77-1 85 (m, 4 H), 2 53-2 57 (m, 4 H), 2 63-2 70 (m, 6 H), 3 33 (s, 3 H), 3 40 (t, J = 6 2 Hz, 2 H), 7 17-7 37 (m, 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 28 65, 33 57, 53 34, 54 07, 58 67, 71 12, 125 70, 128 17, 128 28, 142 25

EXAMPLE 32 Preparation of dialkylaminoester VI.

Under an atmosphere of mtrogen, activated 4 A molecular sieves (500 mg). and cesium hydroxide monohydrate (240 mg, 1 43 mmol, 1 2 eq ) are added to anhydrous NN-dimethylformamide (12 mL) L-Valme methyl ester hydrochloride (200 mg, 1 2 mmol, 1 eq ) is added ten mmutes later mto the turbid solution and the mixture is stined for an additional hour Benzyl bromide (0 134 mL, 1 2 mmol, 1 3 eq ) is added to the solution by syπnge with stirring and the reaction is allowed to proceed at room temperature under nitrogen for 4 5 hours The reaction is then filtered and washed with ethvl acetate After the filtrate is concentrated to a nominal volume by blowing air, the residue is purified via flash column chromatography (1 1 hexanes EtOAc) to yield the desired dialkylammoester VI (172 mg 65 %) as a clear oil The tnalkylamme V2 is not observed Data for VI: Η NMR (360 MHz, CDC1₃) δ 0 94 (d, J= 6 8 Hz, 6 H), 1 77 (s, NH), 1 89-1 94 (m, 1 H). 3 01 (d, J = 6 1 Hz, 1 H). 3 58 (AB, J_AB = 12 5 Hz, 1 H), 3 71 (s, 3 H), 3 82 (AB, J^ = 12 5 Hz. 1 H), 7 23-7 7 32 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 18 54, 19 20, 31 59, 51 26, 52 43. 66 44. 126 86, 128 13. 128 16, 139 97. 175 65 EXAMPLE 33

Preparation of dialkylammoester Zl.

To a solution of L-vahne methylester hydrochloπde (1 g, 6 0 mmol, 1 eq ) m anhydrous N,N- dimethylformamide (30 mL), 4 A activated molecular sieves (2 5 g) and powered cesium hydroxide monohydrate (1 1 g, 6 0 mmol, 1 1 eq ) are added consecutively, and the resultmg suspension is vigorously stined for 30 mmutes under a mtrogen atmosphere Usmg a syπnge, 5-bromo-l-pentene (0 85 mL, 7 2 mmol, 1 2 eq ) is mjected mto the milky white mixture and the reaction is stined for 10 hours under an atmosphere of mtrogen at ambient temperature The reaction mixture is then filtered and rinsed with ethyl acetate After the filtrate is washed with water (3x30 mL), bπne (30 mL), and the orgamc layer is dned over anhydrous sodium sulfate The solvent is removed in vacuo and the crude product is distilled under reduced pressure to give the dialkylammoester Zl as a colorless oil (722 mg, 61%) The tnalkylamme Z2 is not observed Data for Zl: *H NMR (360 MHz, CDC1₃) δ 0 95 (d, J=6 8 Hz, 3 H), 0 96 (d. J=6 8 Hz, 3 H), 1 5-1 64 (m, 2 H). 1 62 (s, 1 H), 1 93 (m, 1 H), 2 13 (m, 2H), 2 41 (m, IH), 2 61 (m, IH), 2 95 (d, J=6 1. IH), 3 70 (s. 3 H), 4 95 (dd, J=10 2, 1 3 Hz. 1 H), 5 01 (m, 1 H), 5 80 (IH, m) ¹³C NMR (90 MHz, CDC1₃) δ 18 81 19 15. 29 33. 31 38. 31 65. 48 12, 51 35, 67 48, 114 30, 138 50, 175 90

EXAMPLE 34

Preparation of dialkylammoester AA1.

AA1 (67%) AA2 (0%)

A flame dned 100 mL round-bottomed flask equipped with a magnetic stirring bar. rubber septum, and nitrogen mlet, is flushed with dry mtrogen and charged with activated powdered 4 A molecular sieves (2 5 g) and anhydrous DMF (30 mL) Under a nitrogen purge, cesium hydroxide monohydrate (1 1 g, 6 6 mmol, 1 1 eq ) is added, and the mixture is vigorously stined for 10 mmutes After L-valme methyl ester hydrochloπde (1 g, 6 0 mmol, 1 eq ) is added, the mixture is stined for an additional 30 mmutes By syπnge, allyl bromide (0 62 mL, 7 2 mmol, 1 2 eq ) is added to the white suspension which is stined at room temperature for an additional 10 hours The reaction mixture is then filtered and rinsed with ethyl acetate After the filtrate is washed with water (3x30 mL), bπne (30 mL), and the orgamc layer is dned over anhydrous sodium sulfate The solvent is removed in vacuo and the crude product is distilled under reduced pressure to give the dialkylammoester AA1 as a colorless oil (700 mg, 67%) The tnalkylaminoester AA2 is not observed Data for AA1: *H NMR (360 MHz, CDC1₃) δ 0 90 (d, J= 6 8 Hz, 3 H), 0 91 (d, J= 6 8 Hz, 3 H), 1 55 (m, NH). 1 83 (m, IH), 3 02-3 06 (m, 2 H), 3 26 (m, 1 H), 3 65 (s, 3 H), 4 97 (m, 1 H), 5 12 (m, 1 H), 5 80 (ddt, J = 17 0, 10 4, 6 0 Hz, I H) ¹³C NMR (90 MHz, CDC1₃) δ 18 35, 19 21, 31 34, 50 21, 51 03. 66 05, 115 84, 136 31, 156 03, 175 38

EXAMPLE 35

Preparation of dialky lamino alcohol BBl.

BB1 (74 %) BB2 (0 %)

A flame dned 25 mL round-bottomed flask containing a magnetic stirring bar. a rubber septum, is swept with dry nitrogen and charged with L-valinol (0 21 mL, 1 88 mmol, 1 eq ). anhydrous NN-dimethylformamide (10 ml), activatived 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (32 mg, 0 18 mmol, 0 1 eq ) The white suspension is allowed to stir for 30 minutes at room temperature, at which pomt benzyl bromide (0 27 mL, 2 2 mmol, 1 2 eq ) is added by syrmge and the reaction is allowed to proceed at ambient temperature for 12 hours The reaction is then filtered and the undissolved solids are washed with ethyl acetate The filtrate is concentrated by air. and direct puπfication using flash column chromatography (9 1 EtOAc EtOH) afforded the desired dialkyl amino alcohol BBl as a clear oil (224 mg, 62%) The tnalkylamino alcohol BB2 is not observed Data for BBl: IR (thin film) 3348, 3104, 3072, 3032, 2960, 2868. 1472, 1038, 709 cm ', 1H NMR (360 MHz, CDCI₃) δ 0 90 (d, J= 6 8 Hz, 3 H), 0 94 (d, J= 6 8 Hz. 3 H), 1 84-1 89 (m, 1 H), 2 44-2 45 (m, 3 H), 3 37 (dd, J= 17 0, 7 2 Hz, 1 H), 3 62 (dd, J = 17 0. 7 2 Hz, 1 H), 3 72-3 81 (m, 2 H), 7 09-7 31 (m, 5 H), ¹³C NMR (90 MHz, CDC1₃) δ 18 39, 19 55, 28 79, 51 32, 60 35, 63 82, 127 10, 128 12. 128 46 EXAMPLE 36 Preparation of dimer CC1.

A flame dned 50 mL round-bottomed flask contai ng a magnetic stining bar, a rubber septum, is flushed with dry nitrogen and charged with L-leucmol (500 mg, 4 3 mmol, 1 eq ), activatived 4 A molecular sieves (1 g), and cesium hydroxide monohydrate (717 mg, 4 2 mmol. 1 eq ) are dissolved m anhydrous NN-dimethylformamide (20 ml) and allowed to stir for 30 mmutes at room temperature NN-dibenzyhsoleucinol bromide (1885 mg, 4 3 mmol, 1 2 eq ) is added to the white suspension with vigorous stirring The reaction is allowed to proceed at ambient temperature for 14 hours The reaction is then filtered and the undissolved solids are washed with ethyl acetate The filtrate is concentrated by air, and the residue is puπfied usmg flash column chromatography (5 1 hexanes EtOAc) which yields the desired dialkylamme CC1 as a clear oil (1005 mg, 60%) The tπalkylamme is not observed Data for CC1: *H NMR (360 MHz, CDC1₃) δ 0 86-0 93 (m, 12 H),

1 17-1 19 (m, 2 H), 1 41 (m, 1 H), 1 51-1 54 (m. 2 H), 2 15 (s, 2 H), 2 40-2 47 (m, 2 H), 2 70-2 76 (m, 2 H), 3 30 (m, 1 H), 3 44 (AB, J∞ = 13 5 Hz, 2 H), 3 50-3 53 (m, 1 H), 3 73 (AB, _B = 13 5 Hz,

2 H), 7 23-7 37 (m, 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 11 48, 15 92. 16 32. 26 78, 32 77, 46 00. 54 02, 54 48, 58 32, 59 17, 62 84, 127 09. 128 14, 128 95, 139 7

EXAMPLE 37

Preparation of dialkylamine MM1.

Phenethylamme (0 21 mL, 1 65 mmol, 1 eq ) is dissolved in anhydrous N,N- dimethylformamide (8 3 mL) and powered cesium carbonate (1 610 mg, 6 mmol, 3 eq ), are added consecutively and vigorously stined for 30 minutes under the protection of mtrogen Using a syrmge, 1 -bromobutane (0 21 mL, 2 0 mmol, 1 2 eq ) is injected mto the milky white mixture and the reaction is stined for 23 5 hours under mtrogen at ambient temperature The reaction mixture is quenched with aqueous 1 N NaOH to dissolve morgamc salts, and extracted with ethyl acetate (3 x 30 mL) The resultmg orgamc layer is washed consecutively with water (2 x 30 mL), bnne (30 mL), and dned usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is subjected to flash column chromatography (9 1 EtOAc EtOH) to afford the desired dialkylamme MMl (208 mg, 71%) as a colorless oil and the tnalkylamme MM2 (120 mg, 31%) as a yellow oil

EXAMPLE 38

Preparation of dialkylamine OO1.

001 (97%) 002 (3%) Into a solution of DL-methyl benzyl am e (200 mg, 1 65 mmol. 1 eq ) in anhydrous N,N- dimethylformanude (8 3 mL) is added powdered cesium carbonate (540 mg, 1 65 mmol. 1 eq ), and stined under a nitrogen atmosphere for 30 minutes Dropwise. benzyl bromide (0 24 mL. 2 0 mmol, 1 2 eq ) is added with efficient stirring and the reaction is allowed to proceed under the protection of mtrogen for 5 hours at room temperature The reaction mixture is then filtered to remove undissolved morgamc salts and continually washed with ethyl acetate The filtrate is concentrated to a nominal volume by blowing air and the residue is taken up in l N NaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (2 x 30 mL). bπne (30 mL), and dned over anhydrous sodium sulfate The solvent is concentrated in vacuo, and the residue is punfied bv flash column chromatography (9 1 EtOAc/EtOH) to afford the desired dialkylamme OO1 (340 mg. 97%) as an oil, and the tπalkylamme OO2 (15 mg, 3%) Data for OO1: *H NMR (360 MHz, CDC1₃) δ 1 33 (d, J = 6 5 Hz, 3 H), 1 71 (s, NH), 3 55 (AB J^ = 14 4 Hz, 1 H), 3 62 (AB, J_AB = 14 4 Hz, IH), 3 77 (q, J = 6 5 Hz, 1 H), 7 15-7 32 (m, 10 H) ¹³C NMR (90 MHz, CDC1₃) δ 24 40, 51 86, 57 41. 126 62, 126 77, 126 86, 128 06, 128 28, 128 39 Data for OO2: ^XH NMR (360 MHz, CDC1₃) δ 1 34 (d, J = 6 8 Hz. 3 H), 3 37 (AB, J^ = 13 8 Hz. 2 H), 3 52 (AB, J^ = 13 8 Hz, 2 H), 3 80-3 86 (q. J = 6 8 Hz 1 H) 7 01-7 31 (m, 15 H) ¹³C NMR (90 MHz, CDC1₃) δ 13 73. 53 54. 56 13, 126 70, 127 93, 128 00. 128 16, 128 62, 140 42, 142 71 EXAMPLE 39

Preparation of dialkylammoester EE1.

EE1 (50 %) EE2 (0 %)

A flame dried 25 mL round-bottomed flask equipped with a magnetic stining bar, rubber septum, and nitrogen mlet, is flushed with dry mtrogen and charged with anhydrous DMF (8 3 mL)

Under a nitrogen purge, powdered cesium carbonate (39 mg, 0 12 mmol, 0 1 eq ) is added, and the mixture is vigorously stined for 10 mmutes After L-valme methyl ester (200 mg, 1 2 mmol, 1 eq ) is added, and the mixture is stined for an additional 1 hour By syπnge, benzyl bromide (0 17 mL, 1 44 mmol, 1 2 eq ) is added to the white suspension and stined at room temperature for 4 hours under mtrogen The reaction mixture is then filtered to remove the molecular sieves and undissolved morgamc salts, and washed several times with ethyl acetate After the filtrate is concentrated to a nommal volume by blowmg air, the residue is directly punfied by silica gel column chromatography using a mixture of hexanes ethyl acetate(5 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylammo ester EE1 (130 mg, 50%) as a colorless oil The tnalkylamme EE2 is not observed

EXAMPLE 40

Preparation of dialkylammoester FF1.

Cl © Br^Ph

H₃N^ C0₂Et *" PrT^N^'^COzEt ₊ H^ N^COzEt

Cs_∑COs. D F I

23 °C, 12 h Ph

FF1 (51 %) FF2 (0 %)

Glycme ethyl ester hydrochlonde (200 mg. 1 4 mmol. 1 eq ) is dissolved m anhydrous NN- dimethylformamide (8 mL, 0 2 M). and powered cesium carbonate (910 mg, 2 8 mmol, 2 eq ) are added consecutively and vigorously stirred for 30 minutes under a nitrogen atmosphere Using a svπnge. benzyl bromide (0 18 mL, 1 54 mmol, 1 1 eq ) is injected mto the milky white mixture and the reaction is stirred for 12 hours at ambient temperature The reaction mixture is filtered and rinsed with ethyl acetate The filtrate is concentrated to a nommal volume usmg a gentle stream of air, and the residue is subjected to flash column chromatography (1 1 hexanes EtOAc) to afford the desired dialkylammoester FF1 (138 mg, 51%) as a colorless oil The tπalkylamme FF2 is not observed Data for FF1 1H NMR (360 MHz, CDC1₃) δ 1 20 (t, J= 12 0 Hz, 3 H), 1 90 (s, NH), 3 28 (s, 2 H), 3 75 (s, 2 H), 4 09 (q, J = 9 6 Hz, 2 H), 7 15-7 35 (m, 5 H)

EXAMPLE 41

Preparation of dialkylammoester HH1.

A flame dried 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and mtrogen inlet, is flushed with dry mtrogen and charged with anhydrous DMF (8 mL) and distilled water (0 8 mL) (10 1 v/v) Under a mtrogen purge, powered cesium carbonate (487 mg, 1 5 mmol, 1 eq ) is added, and the mixture is vigorously stined for 10 mmutes After L-isoleucine (196 mg,

1 5 mmol, 1 eq ) is added, and the mixture is stined for 30 mmutes By syringe, benzyl bromide (0 36 mL, 3 0 mmol, 2 eq ) is added to the white suspension, which is stined at room temperature for an additional 3 5 hours The reaction mixture is then filtered to remove the undissolved morgamc salts, and washed several tunes with ethyl acetate After the filtrate is concentrated to a nommal volume by blowmg air, the residue is puπfied by silica gel column chromatography usmg a mixture of hexanes ethyl acetate (5 1 v/v) as the elutmg solvent The common fractions are combined and evaporated to afford dialkylammoester HH1 (256 mg, 55%) as a colorless oil The tπalkylammoester HH2 is not observed ^UH NMR (360 MHz. CDC1₃) δ 0 81-0 96 (m, 6 H), 1 23-1 29 (m, 1 H), 1 60-

1 64 (m, 1 H), 1 64-1 78 (m, 1 H), 1 88 (s. NH), 3 20 (d. J= 6 2 Hz, 1 H), 3 64 (AB, J^ = 12 9 Hz, 1

H), 3 87 (AB, J_AB = 12 9 Hz, 1 H), 5 22 (s, 2 H), 7 25-7 43 (m, 10 H)

EXAMPLE 42

Preparation of dialkylamine III.

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and nitrogen mlet, is flushed with dry mtrogen and anhydrous DMSO (8 3 mL) is added Under a nitrogen purge, cesium hydroxide monohydrate (285 mg, 1 7 mmol, 1 eq ) is added, and the mixture is vigorously stined for 10 mmutes After phenethylamme (0 21 mL, 1 7 mmol, 1 eq ) is added, the mixture is stined for an additional 30 mmutes By syrmge. 1 -bromobutane (0 21 mL. 2 0 mmol, 1 2 eq ) is added to the white suspension which is stined at room temperature for an additional 23 5 hours The reaction mixture is then filtered to remove the molecular sieves and undissolved morgamc salts, and rmsed several times with ethyl acetate After the filtrate is concentrated to a nominal volume by blowing air, the residue is taken up in 1 N NaOH. and transfened to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL), and the combmed orgamc layers are washed with bnne, dned over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil The resulting crude mixture of products is separated and puπfied by silica gel column chromatography usmg a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme III (209 mg, 70%) as a colorless oil as well as tnalkylamme 112 (43 mg. 11 %) as a pale yellow oil

EXAMPLE 43 Preparation of dialkylamine JJ1.

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and mtrogen inlet, is flushed with dry mtrogen and charged with phenethylamme (0 21 mL, 1 65 mmol, 1 eq ), anhydrous l-methyl-2-pyπohdιnone (8 3 mL), activatived 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (285 mg, 1 65 mmol, 1 eq ) The white suspension is allowed to stir for 30 mmutes at room temperature 1 -Bromobutane (0 2 mL, 2 0 mmol, 1 2 eq ) is added by syrmge to the white suspension and the reaction is vigorously stined at ambient temperature for 23 5 hours under a mtrogen atmosphere The reaction is then filtered and the undissolved solids are rmsed with ethyl acetate The filtrate is concentrated by blowing air, and the residue is dissolved m 1 N NaOH, and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 x 30 mL), bπne (30 mL), and dned over anhydrous sodium sulfate Concentration of the solution, and punfication usmg flash column chromatography (9 1 EtOAc EtOH) yielded the desired dialkylamine JJ1 as a clear oil (242 mg, 83%) and the tπalkylamme JJ2 (38 mg. 10%) as a yellow oil

EXAMPLE 44

Preparation of dialkylamine KK1.

Under an atmosphere of nitrogen, with stirring, activated 4 A molecular sieves (500 mg). and cesium hydroxide monohydrate (280 mg, 1 65 mmol. 1 eq ) is added to anhydrous N,N- dimethylacetamide (8 3 mL) Phenethylamme (0 21 mL, 1 65 mmol. 1 eq ) is mjected ten minutes later mto the turbid solution and stined an additional 30 mmutes at room temperature 1 -Bromobutane (0 21 mL, 2 0 mmol, 1 2 eq ) is added to the solution by syπnge and the reaction is allowed to proceed at room temperature under mtrogen for 24 hours The reaction is then filtered to remove undissolved solids and rinsed with ethyl acetate The filtrate is concentrated by evaporating using air to a nominal volume and the residue is taken up in 1 Ν ΝaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (3 x 30 mL). followed by bπne (30 mL), and then dned over anhydrous sodium sulfate Solvent is removed in vacuo and the residue is purified via flash column chromatography (9 1 EtOAc EtOH) to afford the desired dialkylamme KK1 (213 mg, 73%) as a clear oil and the tnalkylamme KK2 (60 mg, 15%) as a pale yellow oil EXAMPLE 45

Preparation of dialkylsilylamine DDL

TIPSCI, c_S2co₃ ^^, .,-TIPS

Ph^NH₂ *^■ PrT ^N^

DMF, 23 °C, 12 h, 50 % ^H

DD1

Under an atmosphere of mtrogen, with stirring, powdered cesium carbonate (920 mg, 2 8 mmol, 1 5 eq ) is added to anhydrous N, N-dimethylformamide (9 5 ml) Benzylamine (0 5 mL, 1 86 mmol, 1 eq ) is mjected ten mmutes later mto the turbid solution and stined for an additional 30 mmutes Trusopropylsilyl chloπde (0 40 mL, 2 05 mmol. 1 1 eq ) is added to the solution by synnge with stirring and the reaction is allowed to proceed at room temperature under the protection of mtrogen overnight The reaction is then filtered to remove undissolved solids and washed with ethyl acetate The filtrate is washed with water (3 x 30 mL) and the orgamc layer is washed with bπne (30 mL), and dried usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is puπfied via flash column chromatography (5 1 hexanes EtOAc) to yield the desired silyl protected dialkylamme DD1 (200 mg, 50 %) as a clear yellow oil Data for DD1: *H NMR (360 MHz, CDC1₃) δ 0 89-0 90 (m, 21 H), 2 90 (s, NH), 4 25 (s, 2 H), 7 10-7 25 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 12 23, 17 61, 41 93, 126 81, 126 97, 127 60, 128 54

EXAMPLE 46

Preparation of dialkylamine LL1.

Phenethylamme (0 15 mL, 1 2 mmol, 1 eq ) is dissolved m anhydrous N,N- dimethylformamide (6 mL), 4 A activated molecular sieves (500 mg) and powered cesium hydroxide monohydrate (200 mg, 1 2 mmol. 1 eq ) are added consecutively and the suspension is vigoroush stirred for 30 mmutes under nitrogen Dropwise, a solution of 3 -phenyl- 1 -propyl mesylate (308 mg. 1 5 mmol, 1 44 eq ) is dissolved in DMF and injected mto the milky white solution The reaction is stined for 21 5 hours under an atmosphere of nitrogen at ambient temperature The reaction mixture is filtered to remove imdissolved sieves and morganic salts, and rmsed with ethyl acetate The filtrate is evaporated to a nominal volume usmg a gentle stream of air, and the residue is taken up m 1 N NaOH and extracted with ethyl acetate (3 x 30mL) The resultmg orgamc layer is washed consecutively with water (2 x 30 mL), bπne (30 mL), and dned usmg anhydrous sodium sulfate Solvent is removed in vacuo and the residue is subjected to flash column chromatography (9 1 EtOAc EtOH) to afford the desired dialkylamme LL1 (173 mg, 60%) as a colorless oil

EXAMPLE 47

Preparation of dialkylamine LL1'.

Into a solution of phenethylamme (75 mg, 0 62 mmol, 1 eq ) in anhydrous N,N- dimethylformamide (4 mL) are added successively activated 4 A molecular sieves (500 mg), and cesium hydroxide monohydrate (100 mg, 0 62 mmol, 1 eq ), and the turbid white mixture is stined for 30 mmutes Dropwise, a solution of 3 -phenyl- 1 -propyl tosylate m DMF (220 mg, 0 75 mmol, 1 2 eq ) formed by a known literature procedure, is added with stirπng and the reaction is allowed to proceed under mtrogen for 21 5 hours at 23 °C The reaction mixture is then filtered to remove molecular sieves and undissolved morgamc salts and continually rinsed with ethyl acetate The filtrate is concentrated to a nommal volume by blowmg air and the residue is taken up in 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The organic layer is washed with water (2 \ 30 mL). brine (30 mL), and dned over anhydrous sodium sulfate The solvent was concentrated in vacuo and the residue was punfied by flash column chromatography (9 1 EtOAc EtOH) to afford the desired dialkylamme LL1' (74 mg, 50%) as a colorless oil

EXAMPLE 48

One Pot preparation of dialkylamine LL1".

Into a solution of 3-phenyl-l-propanol (0 2 mL, 1 46 mmol, 1 eq ) m anhydrous N,N- (hmethylformamide (8 mL) are added successively dry tπethylamine (0 31 mL, 2 2 mmol, 1 5 eq ), and tnphenylphosphine dibromide (800 mg, 2 mmol, 1 3 eq ) The reaction mixture is then stirred under a mtrogen atmosphere for 1 hour at 0 °C Upon consumption of the starting matenal (alcohol), by syπnge, phenethylamme (0 15 mL, 2 0 mmol, 1 2 eq ) and cesium hydroxide monohydrate (200 mg, 1 65 mmol, 1 2 eq ) are added with stirring and the reaction is allowed to proceed for 36 hours The reaction mixture is then filtered to remove molecular sieves and undissolved morgamc salts and contmually rmsed with ethyl acetate The filtrate is concentrated to a nommal volume by blowing air and the residue is taken up m 1 Ν ΝaOH, and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (2 x 30 mL), brme (30 mL), and dried over anhydrous sodium sulfate The solvent is concentrated in vacuo, and the residue is puπfied by flash column chromatography (9 1 EtOAc EtOH) to give (140 mg, 52%) of the desired dialkylam e LL1" as a clear oil

EXAMPLE 49

One Pot preparation of dialkylamine LL1'".

CsOH HP, 4 A MS LL1"

DMF, 23 "C, 36 h 59%

Into a solution of 3-phenyl-l-propanol (0 21 mL, 1 55 mmol. 1 eq ) in anhydrous N,N- dimethylformamide (8 mL) are added successively dry tnethylamme (0 26 mL, 1 86 mmol, 1 2 eq ) catalytic amount of dimethylaminopyndine (DMAP). followed by methanesulfonyl chloπde (0 143 mL, 1 86 mmol, 1 2 eq ) and the reaction is stined under a nitrogen atmosphere for 1 hour at 0 °C Upon consumption of the starting matenal (alcohol), by syrmge, phenethylamme (0 15 mL. 1 2 mmol, 1 0 eq ) and cesium hydroxide monohydrate (200 mg, 1 2 mmol, 1 eq ) is added with stirπng and the reaction is allowed to proceed for 36 hours at room temperature The reaction mixture is then filtered to remove molecular sieves and undissolved morganic salts and contmually washed with ethyl acetate The filtrate is concentrated to a nommal volume by blowing air and the residue is taken up in 1 N NaOH and extracted with ethyl acetate (3 x 30 mL) The orgamc layer is washed with water (2 x 30 mL), bπne (30 mL), and dned over anhydrous sodium sulfate The solvent is concentrated in vacuo, and the residue is punfied by flash column chromatography (9 1 EtOAc EtOH) to give the desired dialkylamme LL1"¹ (170 mg, 59 %) as a clear oil

EXAMPLE 50

One-Pot Preparation of dialkylamine NN1.

MsCI, Et₃N CH₂CI₂, 0 "C

BnNH concentrate t thhoenn, HH₂-.MN "P Phh e O . ° cat Cspθ₃, DMF _NN1

23 °C, 24 h 56 %

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and nitrogen inlet, is flushed with dry nitrogen and charged with δ-butyrolactone (0 16 mL, 1 94 mmol, 1 eq ), and dry methylene chloπde ( 10 mL) The reaction mixture is cooled to 0 °C and dry tnethylamme (0 33 mL, 2 2 mmol, 1 2 eq ), methanesulfonyl chloride (0 17 mL, 2 2 mmol, 1 2 eq ) are added and the reaction is allowed to warm to room temperature and allowed to stir for two hours The crude reaction mixture is evaporated and taken up in NN-dimethylformamide (10 mL) and benzylamine (0 21 mL, 1 94 mmol. 1 eq ) is added, followed by a catalytic amount of powered cesium carbonate (50 mg) The reaction is stirred at room temperature for 24 hours under the protection of a nitrogen atmosphere The reaction is quenched with water to dissolve inorganic salts, and transferred to a 125 mL separatory funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL). and the combmed orgamc layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil The resulting crude mixture punfied by silica gel column chromatography usmg a mixture of hexanes ethyl acetate ( 1 1 v/v) as the elutmg solvent The common fractions are combined and evaporated to afford dialkylamme NN1 (246 mg. 56%) as an oil Data for NN1: *H NMR (360 MHz. CDC1₃) δ 1 77 (s, NH), 2 20 (dd, J= 7 2, 3 4 Hz, 1 H). 2 50 (dd. J- 7 5, 4 5 Hz, 1 H), 3 50-3 55 (m, 1 H), 3 65 (m, 2 H), 3 94 (dd. J= 7 5, 3 7 Hz. 1 H), 4 21 (dd, J = 7 5, 5 7 Hz, 1 H), 7 15-7 21 (m, 5 H) ¹³C NMR (90 MHz, CDC1₃) δ 35 37, 51 32, 53 46, 73 10, 127 46, 127 69, 128 52, 139 09, 176 09

EXAMPLE 51 One-Pot Preparation of dialkylamine NN2.

HQ C --Hr.₂2C<-.Ii2,, 0 υ -C _{BBnn NNHH} ^^ concentrate v

>_ ° then,H₂N^Ph ^^O cat Cs2Cθ₃, DMF 23 'C, 24 h, 35 % NN2

A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and nitrogen inlet, is flushed with dry nitrogen and charged with δ-butyrolactone (0 16 mL. 1 96 mmol, 1 eq ), and dry methylene chloride (10 mL) The reaction mixture is cooled to 0°C and tnphenylphosphine dibromide (1082 mg, 2 54 mmol, 1 3 eq ) is added and the reaction is allowed to warm to room temperature and allowed to stir for two hours Upon completion of the starting matenal (alcohol), the crude reaction mixture is evaporated and taken up m NN-dimethylformamide (10 mL) and benzylamine (0 2 mL, 1 96 mmol, 1 eq ) is added followed by a catalytic amount of powered cesium carbonate (50 mg) The reaction is then stined at room temperature for 24 hours under the protection of nitrogen The reaction is quenched with water to dissolve morgamc salts, and transfened to a 125 mL separator}' funnel The basic aqueous phase is extracted with ethyl acetate (4 x 20 mL), and the combined orgamc layers are washed with brine, dried over anhydrous sodium sulfate. filtered, and concentrated in vacuo to give a pale yellow oil The resulting crude mixture puπfied by silica gel column chromatography usmg a mixture of ethyl acetate-ethanol (9 1 v/v) as the elutmg solvent The common fractions are combmed and evaporated to afford dialkylamme NN2 (156 mg, 35%) as an oil

EXAMPLE 52

Synthesis of l,8-diamino-3-thia-6-azaoctane from 2-thioethylamine hydrochloride. In a 500 mL round bottom flask, are placed 2-thιoethylamme hydrochloride (2 0 g. 18 mmol),

DMF (90 mL), 4 A molecular sieves (10 g), cesium hydroxide monohydrate (21 g, 130 mmol). and 2- bromoethylamine hydrobromide (11 g, 54 mmol) The reaction mixture is mechanically stined at room temperature for 44 h at which time the reaction is quenched with 200 mL of 1 M NaOH Following filtration, the solution is evaporated by blowing on the surface with a stream of air The resulting solid is then taken up m a small amount of methanol, triturated with Et₂0, subsequently filtered, and reduced to dryness in vacuo Tπturation is repeated two more times to ensure the removal of the inorganic salts The resulting thick yellow oil is then subjected to silica gel chromatography using a mobile phase of 5% NH OH in MeOH, followed by 15% NH4OH m MeOH Following concentration of the appropπate fractions, 0 96 g (44% yield) of mtermediate l,5-dιamιno-3-thιapentan and 0 716 g (24% yield) of l,8-dιammo-3-thιa-6-azaoctane is obtamed EXAMPLE 53

Synthesis of l,8-diamino-3-thia-6-azaoctane from l,5-diamino-3-thiapentane.

In a 250 mL round bottom flask, are placed l,5-dιamιno-3-thιapentane (1 1 g, 8 8 mmol), DMF (45 mL), 4 A molecular sieves (5 0 g), cesium hydroxide monohydrate (3 7 g, 22 mmol), and 2- bromo-ethylamine hydrobromide (2 7 g, 13 mmol) The reaction mixture is mechanically stined at room temperature for 12 h at which time the reaction is quenched with 100 mL of 1 M NaOH Following filtration, the solution is evaporated by blowing on the surface with a stream of air The resultmg solid is then taken up in a small amount of methanol, triturated with Et₂0. subsequently filtered, and reduced to dryness in vacuo Tnturation is repeated two more times to ensure the removal of the morganic salts The resultmg thick yellow oil is then subjected to silica gel chromatography usmg a mobile phase of 5% NH4OH m MeOH, followed by 15% NH4OH m MeOH Collection of the fractions containing l,8-dιammo-3-thιa-6-azaoctane resulted in 1 04 g (73% yield) of pure matenal

EXAMPLE 54

Preparation of dimer RR2.

RR1 (52 %) RR2 (48%)

A flame dried 25 mL round-bottomed flask containing a magnetic stirring bar, a rubber septum, is flushed with dry mtrogen and charged with L-leucine benzyl ether (88 mg, 0 4 mmol. 1 eq ), prepared by a known literature procedure, activatived 4 A molecular sieves (100 mg). and cesium hydroxide monohydrate (70 mg, 0 4 mmol, 1 eq ) are dissolved in anhydrous N N-dimethvlformamide (2 ml) and allowed to stir for 30 minutes at room temperature NJV-dibenzyhsoleucinol bromide (220 mg, 0 6 mmol, 1 5 eq ) is added to the white suspension with vigorous stining The reaction is allowed to proceed at ambient temperature for 14 hours The reaction is then filtered and the undissolved solids are washed with ethyl acetate The filtrate is concentrated by air. and the residue is punfied using flash column chromatography (1 1 hexanes EtOAc) which yielded the desired protected dimer RR1 as an oil (100 mg, 52%) The tnalkylamme is not observed Protected dimer RR1 is then hydrogenated to give dimer RR2 (22 mg, 48 % yield) Data for RR1 : *H ΝMR (360 MHz, CDC1₃) δ 0 85-0 93 (m, 12 H), 1 15-1 20 (m, 2 H), 1 41 (m, 1 H), 1 51-1 54 (m, 2 H), 2 15 (s, 2 H), 2 40-2 47 (m, 2 H), 2 7-2 76 (m, 2 H), 3 30 (m, 1 H), 3 44 (AB, J_AB=13 5 Hz, 2 H), 3 47 (m, 1 H), 3 71 (AB, J_AB=13 5 Hz, 2 H), 4 59- 4 53 (m 2 H), 7 24-7 33 (m, 15 H)

EXAMPLE 55 Preparation of dimer SS2.

A flame dried 250 mL round-bottomed flask containing a magnetic stirring bar. a rubber septum, is flushed with dry nitrogen and charged with L-Isoleucinol (1730 mg. 14 8 mmol), activatived 4 A molecular sieves (1000 mg), and cesium hydroxide monohvdrate (2500 mg, 14 8 mmol, 1 eq ) are dissolved m anhydrous N, N-dimethylformamide (74 ml) and allowed to stir for 30 mmutes at room temperature NN-dibenzyhsoleucinol bromide (6350 mg, 17 6 mmol, 1 2 eq ) is added to the white suspension with vigorous stirring The reaction is allowed to proceed at ambient temperature for 36 hours The reaction is then filtered and the undissolved solids are washed with ethyl acetate The filtrate is concentrated by air, and the residue is puπfied usmg flash column chromatography (1 1 hexanes EtOAc) which yielded the desired protected dimer SSI as an oil (3000 mg, 52%) The tnalkylamme is not observed Protected dimer SSI is then deprotected by hydrogentation to give the dimer SS2 (900 mg, 40 % yield) Data for SSI: 1H ΝMR (360 MHz, CDC1₃) δ 0 74-0 92 (m. 12 H), 1 09 (m, 1 H), 1 21-1 26 (m, 2 H), 1 60-1 63 (m. 2 H), 1 88 (m, 2 H), 2 19 (s. 2 H), 2 57-2 65 (m, 3 H), 2 88 (m, 1 H), 3 53-3 54 (m. 1 H), 3 60 (AB, J_AB=13 5 Hz, 2 H). 3 88 (m, 1 H). 3 88 (AB. J_AB=13 5 Hz, 2 H), 7 25-7 38 (m. 10 H) Data for SS2: 'H ΝMR (360 MHz, CDC1₃) δ 0 74-0 86 (m, 12 H), 1 22-1 52 (m, 5 H), 1 73-1 85 (m, 2 H), 2 87-2 93 (m, 2 H), 3 34 (m. 1 H), 3 71-3 73 (m, 1 H), 3 80-3 83 (m, 1 H), 6 88 (br s, 4 H)

EXAMPLE 56 Preparation of Trimer TTl

A flame dned 50 mL round-bottomed flask containing a magnetic stirring bar, a rubber septum, is flushed with dry mtrogen and charged with dimer SS2 (181 mg, 0 84 mmol), activatived 4 A molecular sieves (250 mg), and cesium hydroxide monohydrate (140 mg, 0 84 mmol, 1 eq ) are dissolved in anhydrous N, N-dimethylformamide (10 ml) and allowed to stir for 30 mmutes at room temperature NN-dibenzylleucinol bromide (500 mg, 1 26 mmol, 1 5 eq ) is added to the white suspension with vigorous stirring The reaction is allowed to proceed at ambient temperature for 36 hours The reaction is then filtered and the undissolved solids are washed with ethyl acetate The filtrate is concentrated by air, and the residue is punfied usmg flash column chromatography (10 % MeOH/CH₂Cl₂ (v/v)) which yielded the desired protected tnmer TTl as a yellow oil (190 mg, 46%) Data for TTl: *H NMR (360 MHz, CDC1₃) δ: 0 70-0 93 (m. 12 H), 1 07 (s. 6 H), 1 29 -1 42 (m, 8 H), 2 45-2.51 (m, IH), 2 73-2 76 (m, 1 H). 3 19 (s. 3 H), 3 39-3 47 (m, 6 H), 3 86 (AB, J=13 5 Hz, 2 H), 4 00 (AB, J=13 4 Hz, 2 H), 7 08-7 38 (m, 10 H)

EXAMPLE 57

Solid Phase Synthesis of Dimer (Ile-Ile).

31% in 4 steps based on Wang resin

Alkoxide resm (lg, 1 3 mmol) is esterified with tert-butoxycarbonyl protected isoleucme (930 mg, 4 mmol). DCC (825 mg. 4 mmol). lmidazole (4 eq). and a catalytic amount of DMAP in a 1 4 mixture of DMF/CH₂C1₂ at 0 C to room temperature overnight The resm is washed with H₂0, MeOH/H₂0, H₂0, THF, CH₂C1₂. and MeOH, then dned under high vacuum IR 3434. 3059. 3025,

2923, 1717, 1612, 1512. 1425, 1367, 1244, 1159, 1017, 758. 698, 542 on ¹

Boc-ammo acid resm is treated with 5% TFA in CH₂CI₂ at room temperature for 2 hours Ammo acid resm is filtered, washed with water, CH₂C1₂, tnethyl amine, ethanol, water. CHC1₃, and ether, then dired under high vacuum The FT-IR spectrum exhibited a strong absorbance at 1738 cm^'1 A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, is purged with dry nitrogen Amino acid resin and cesium carbonate (1 3 g, 4 mmol) are dissolved m anhydrous NN-dimethylforamide (10 mL), then the mixture is stined for 30 minutes at room temperature N/V- Dibenzyhsoleucmyl bromide (1 44 g, 4 mmol) is added to the white suspension with vigorous stirnng The reaction is allowed to proceed at ambient temperatures for 48 h The resm is washed with MeOH/H₂0, H₂0, 0 2 N HCl, H₂0, THF, CH₂C1₂, and MeOH, then dned under high vacuum The FT-IR spectrum exhibits a strong absorbance at 1738 cm ^!

A flame dned 25 mL round-bottomed flask, equipped with a magnetic stinmg bar, is charged with 20 mL of THF and N-alkylated-resin under an atmosphere of mtrogen The suspension is cooled to 0 °C, and 113 mg (3 mmol) of lithium aluminum hydride is added The mixture is stined for 7 hours at room temperature and cooled to 0 °C The mixture is carefully worked up by the dropwise and sequential addition of 0 1 mL of water, 0 1 mL of a 15% aqueous sodium hvdroxide solution, and an 0 34 mL of water The reaction mixture is filtered through coarse filtration frits to remove aluminum salts, and the latter are washed four times with 8 mL of diethvl ether The combmed filtrates are dried over sodium sulfate and concentrated under reduced pressure The crude product is purified using flash chromatography (10 1 hexanes EtOAc) to provide dialkylamme as a clear oil (154 mg, 31%) The tπalkyamme is not observed

EXAMPLE 58

Solid Phase Synthesis of Dimer (Ile-Leu).

28% in 4 steps based on Wang resin

Alkoxide resm (lg, 1 3 mmol) is esteπfied with tert-butoxycarbonyl protected leucine (930 mg 4 mmol), DCC (825 mg, 4 mmol), lmidazole (4 eq). and a catalvtic amount of DMAP in a 1 4 mixture of DMF/CH₂CI₂ at 0 C to room temperature overnight The resm is washed with H₂0, MeOH/H₂0, H₂0, THF, CH₂C1₂, and MeOH, then dned under high vacuum IR 3434, 3059, 3025, 2921, 2869, 1717, 1612, 1512, 1452, 1367, 1159, 1017, 758, 698, 542 cm '

Boc-amino acid resm is treated with 5% TFA in CH₂C1₂ at room temperature for 2 hours Ammo acid resm is filtered, washed with water, CH₂C1₂, tnethyl amme, ethanol, water, CHC1₃, and ether, then dired under high vacuum The FT-IR spectrum exhibits a strong absorbance at 1743 cm ' A flame dned 25 mL round-bottomed flask equipped with a magnetic stirring bar, is purged with dry mtrogen Ammo acid resm and cesium carbonate (1 3 g, 4 mmol) are dissolved m anhydrous NN-dimethylforamide (10 mL), then the mixture is stined for 30 mmutes at room temperature NN- Dibenzyhsoleucinyl bromide ( 1 44 g, 4 mmol) is added to the white suspension with vigorous stirnng The reaction is allowed to proceed at ambient temperatures for 48 h The resm is washed with MeOH/H₂0, H₂0, 0 2 -V HCl, H₂0, THF, CH₂C1₂, and MeOH. then dned under high vacuum The FT-IR spectrum exhibited a strong absorbance at 1749 cm '

A flame dried 25 mL round-bottomed flask, equipped with a magnetic stirnng bar, is charged with 20 mL of THF and N-alkylated-resin under an atmosphere of mtrogen The suspension is cooled to 0 °C, and 113 mg (3 mmol) of lithium aluminum hydnde is added The mixture is stined for 7 hours at room temperature and cooled to 0 °C The mixture is carefully worked up by the dropwise and sequential addition of 0 1 mL of water, 0 1 mL of a 15% aqueous sodium hydroxide solution, and an 0 34 mL of water The reaction mixture is filtered through coarse filtration frits to remove aluminum salts, and the latter are washed four times with 8 mL of diethyl ether The combined filtrates are dried over sodium sulfate and concentrated under reduced pressure The crude product is puπfied usmg flash chromatography (10 1 hexanes EtOAc) to provide dialkylamme as a clear oil (139 mg, 28%) The tπalkyamine is not observed

While the invention has been described in terms of various preferred embodiments, those skilled m the art will recognize that various modifications, substitutions, omissions, and changes

be made without departing from the spiπt of the present mvention Accordmgly, it is mtended that the scope of the present invention be limited solely by the scope of the following claims

Claims

What is claimed is

I A process providing a secondary armne of the general formula, R-NH-R', compπsmg providing an orgamc electrophile, R-X, and a pπmary armne R'-NH₂, wherein R and R' each compnses the same or a different hydrocarbon having one or more carbon atoms and X compπses a leavmg group, provided that the carbon atom covalently bonded to said leavmg group and the carbon atom covalently bonded to said amme mtrogen atom are both saturated, and reactmg said orgamc electrophile with said primary amme in an anhydrous solvent containing a cesium base m an amount sufficient to preferentially promote mono-N-alkylation of said primary armne by said orgamc electrophile, to provide a secondary armne 2 The process as in claim 1, wherem said leavmg group X is selected from the group consistmg of chloride, bromide, iodide, O-Ms and O-Ts

3 The process as m claim 1 , wherem said solvent compπses a polar aprotic solvent

4 The process of claim 1, wherem said solvent is selected from the group consistmg of dimethyl sulfoxide, N,N-dιmethylformamιde, NMP, DMAC and mixtures thereof 5 The process as m claim 1, further compnsmg removing water produced by said reaction of said orgamc electrophile with said primary amme

6 The process as in claim 5, wherem removing water further compπses adding a molecular sieve having a pore size of about 3-5 A

7 The process as m claim 1, further compnsmg adding a hahde-exchange promotmg agent

8 The process as m claim 7, wherein the hahde-exchange promotmg agent compnses tetrabutylammomum iodide

9 The process as m claim 8, wherein about 0 1 to 2 0 moles of tetrabutylammonium iodide is added per mole of said primary amme 10 The process as in claim 1, wherem said organic electrophile is covalently attached to an insoluble support matrix durmg reaction of said orgamc electrophile with said primary amme

I I The process as m claim 10. wherein said insoluble support matrix comprises a Mernfield resm or Wang resm

12 The process as in claim 1. wherein said pπmary amme is covalently bonded to an insoluble support matrix durmg reaction of said orgamc electrophile with said pnmary amine

13 The process as in claim 12, wherem said insoluble support matπx compnses a Mernfield resin or a Wang resm 14 The process as m claim 1, wherem said orgamc electrophile further compπses at least one chiral center, wherein each said chiral center is preserved dunng reaction of said orgamc electrophile with said pnmary armne

15 The process as m claim 1, wherem said pnmary amme further compnses at least one chiral center, wherem each said chiral center is preserved dunng reaction of said orgamc electrophile with said primary amme

16 The process as m claim 1, wherem said cesium base is selected from the group consistmg of cesium carbonate, cesium bicarbonate, cesium hydroxide, and a mixture thereof

17 A process for providing polyammes, compπsmg, providing an orgamc electrophile R-X wherem X is selected from the group consisting of chloπde, bromide, iodide, O-Ts and O-Ms, and R compπses a hydrocarbon havmg 1-50 carbon atoms, provided that the carbon atom covalently bonded to X is saturated, and a pnmary amme R'-NH₂, wherem R' compnses a hydrocarbon havmg 1-50 carbon atoms, provided that the carbon atom covalently bonded to the amme mtrogen atom is saturated, and R' further compπses a thiol substituent, and reacting said organic electrophile with said pπmary amine in an anhydrous solvent comprising a cesium base m an amount sufficient to preferentially provide N-alkylated polyamme

18 The process as m claim 17, wherein said pπmary amme is 2-amιnoethanethιol hydrochloπde

19 The process as m claim 17, wherem said organic electrophile is 2-bromoethylamιne hydrobrormde

20 The process as in claim 17, wherem said reaction further comprises adding a reaction- promoting amount of a molecular sieve with a pore size of about 3-5 A[, 18] 21 The process as m claim 17, [wherem] wherem said N-alkylated polyamme is N-(2-(2- ammoethylthιo)ethyl)ethylenedιamme 22 The process as m claim 17, wherein said cesium base is selected from the group consistmg of cesium carbonate, cesium bicarbonate, cesium bromide, cesium hydroxide, and mixtures thereof

23 A polyamme provided by the process of claim 17

24. A library comprising a plurality of compounds, each of the compounds of said library having the general formula R-NH-R', wherein each of said compounds is prepared by the process of claim 1.