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Published in final edited form as: Tetrahedron Lett. 2009 Apr;50(15):1723–1726. doi: 10.1016/j.tetlet.2009.01.133

A new strategy for the synthesis of β-benzylmercaptoethylamine derivatives

Subrata Ghosh 1, Gregory P Tochtrop 1,*
PMCID: PMC3670100  NIHMSID: NIHMS102290  PMID: 23741077

Abstract

Here we describe a new experimental approach to the synthesis of the β-benzylmercaptoethylamine functionality and illustrate its synthetic utility in multi-component reactions. Although prevalent in modern organic synthesis, no general methods have been described for this functionality. Using a carefully developed LiOH-water-ethanol reaction mixture we were able to produce a diverse collection of β-benzylmercaptoethylamines containing a range of sensitive functional groups in excellent yields. To further illustrate their utility in molecular library synthesis, we also report the use of β-benzylmercaptoethylamines in five different multi-component reactions.

The β-benzylmercaptoethylamine functionality and its derivatives are widely utilized with applications in organic,1 inorganic,2 medicinal,3 and cosmetic chemistry.4 For example, this functionality played a critical role in the synthesis of pantetheine (a cysteamine derivative of pantothenic acid–Vitamin B5).3a Reisner reported the synthesis of D/L-γ-sulfamyl-α-amino acids as potential anti-metabolites utilizing β-benzylmercaptoethylamine as a key intermediate.3b When Okarvi et al. was exploring an alternative of 131I-hippuran (a renal radiopharmaceutical), they synthesized a number of S-protected derivatives of MAG3 (mercaptoacetyltriglycine) and discovered that the p-methoxy derivative of β-benzylmercaptoethylamine was a key starting material.3l Finally, in order to prove the necessity of the disulfide unit present in a series of psammaplin A type antibacterial agents (prepared by a novel combinatorial disulfide exchange strategy), Nicolaou et al. used β-benzylmercaptoethylamine as a thioether containing primary amine coupling partner.3k

Despite the wide reaching implications of this functionality, the disparate methods for producing it have afforded varying yields, and a systematic synthetic study is lacking. Some conditions that have been utilized with varying degrees of success include NaOMe-methanol,3a hydrazine hydrate-methanol,3b thiourea-NaOH-ethanol,1e ethyleneimine-ethanol,1b K2CO3-ethanol,1c,3k NaOEt-ethanol,1d Na/liq. NH3,1h NaI-NaOEt,2c TFA-CH2Cl2,2f and NaOH-ethanol.3i These methods suffer from various disadvantages such as long reaction times,1b,2f,3i,k refluxing conditions,1b,3a,b the use of moisture sensitive solvents and reagents,1h extensive work-up procedures,2f or a two step reaction procedure.1e

During the course of synthesizing a small library of molecules to modulate the secretion of the Aβ peptide by a neuronal cell line, we became interested in a specific molecule that contained the β-benzylmercaptoethylamine functionality. It was during these studies that we identified the need to develop the method described here.

In our initial consideration of this reaction, and after a careful evaluation of previously reported reaction conditions, we hypothesized that the general reaction (depicted in Scheme 1) could possibly be proceeding via a borderline/SN1-type reaction mechanism, in contrast to the prototypical SN2-type pathway. Thus, we envisioned that a careful optimization of both the solvent conditions and the base used would be critical for developing a superior method. Towards the first point, and lending support to our borderline mechanism hypothesis, we were able to identify mixtures of water and ethanol as ideal for smooth conversions. Further lending support to our hypothesis, we found that simple ionic bases further facilitated smooth conversions (Scheme 1).

Scheme 1.

Scheme 1

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General synthesis of β-benzylmercaptoethylamine and its derivatives using a combination of LiOH-water-ethanol.

Here we report a LiOH-water-ethanol reaction system that, with the corresponding benzyl chlorides/bromides and cysteamine hydrochloride, affords excellent yields, rapid reaction times, and a facile workup.5 We have subsequently tested this methodology utilizing a wide range of substrates, and we illustrate the utility of these β-benzylmercaptoethylamines in combinatorial chemistry and diversity oriented synthesis through five separate multi-component reactions (MCRs).

Table 1 illustrates a sampling of the reaction conditions we studied. Our initial exploration focused primarily on alcoholic solvents; however we quickly determined that varying amounts of water played an important role in both reaction time and yield. It is likely that the 3:1 ratio of ethanol:water provided a balance between solvent dielectric for the reaction pathway while still allowing the reagents to be soluble in the media. Keeping the ethanol:water ratio fixed, we subsequently screened the effect of various alkali metal and organic bases to find LiOH the most effective.

Table 1.

A systematic evaluation of solvent systems and bases for the formation of β-benzylmercaptoethylamines. The reported yields are for reaction 7 from Table 2. All entries reacted for 40 minutes at 35°C.

Base used Solvent used Yield
LiOH EtOH 72%
LiOH EtOH-H2O (3:1) 86%
LiOH H2O 20%
NaOH EtOH 66%
NaOH EtOH-H2O (3:1) 78%
KOH EtOH-H2O (3:1) 75%
CsOH EtOH-H2O (3:1) 75%
K2CO3 EtOH 30%
K2CO3 EtOH-H2O (3:1) 50%
Et3N EtOH 25%
Et3N DCM 5%
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Using this approach, not only were our yields superior to those previously reported, but we were also able to accomplish the conversions in a minimal amount of time (approximately 40 minutes) and at low temperatures (35°C). For the reactions listed in Table 1 we utilized 3-chlorobenzyl chloride as the representative benzyl halide mainly due to its importance in the molecules we were synthesizing to modulate Aβ secretion.

After our careful optimization, we applied this methodology to a wide range of substrates summarized in Table 2 using a uniform set of reaction conditions.5 Interestingly, we obtained comparatively lower yields for the nitro derivatives. Among all other nitro derivatives, p-nitro (entries 12 and 13, Table 2) gave the lowest yield, further substantiating a borderline/SN1-type mechanism, where at least a partial charge builds at the benzylic position. Further, the best yields were obtained for the substrates containing an electron donating functional group such as -OCH3 (entry 3, Table 2). It is worth pointing out that the reaction was highly compatible with a number of functional groups including -OCH3, -NO2, halogens, -CN, -CO2CH3, -CH3, -CF3. Benzyl chlorides and bromides gave similar yields (compare entries 1 and 2, 5 and 6, 12 and 13: Table 2).

Table 2.

Reaction between various benzyl halides and cysteamine hydrochloride using a combination of LiOH-H2O-EtOH.

Entry Benzyl halidea Product Yieldb
(%)
graphic file with name nihms-102290-t0003.jpg graphic file with name nihms-102290-t0004.jpg
1 Z = H, X = Br Z = H 90
2 Z = H Z = H 90
3 Z = 4-OMe Z = 4-OMe 94
4 Z = 3-OMe Z = 3-OMe 85
5 Z = 3-F, X = Br Z = 3-F 83
6 Z = 3-F Z = 3-F 82
7 Z = 3-Cl Z = 3-Cl 86
8 Z = 3-Br Z = 3-Br 85
9 Z = 3-I Z = 3-I 85
10 Z = 2-NO2 Z = 2-NO2 78
11 Z = 3-NO2 Z = 3-NO2 82
12 Z = 4-NO2, X =
Br		 Z = 4-NO2 75
13 Z = 4-NO2 Z = 4-NO2 75
14 Z = 3-CO2Me Z = 3-CO2Me 60c
15 Z = 3-CN Z = 3-CN 80d
16 Z = 3-Me Z = 3-Me 82
17 Z = 3-CF3 Z = 3-CF3 80
18 Z = 4-t-Butyl Z = 4-t-Butyl 82
19 Z = 2,3-di-OMe Z = 2,3-di-OMe 81
20 Z = 2,6-di-Cl Z = 2,6-di-Cl 80
21 Z = 3-Cl-5-
OMe		 Z = 3-Cl-5-OMe 78
22 Z = 2-CN-3-Cl,
X = Br		 Z = 2-CN-3-Cl 80
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a

Unless otherwise stated, X = Cl and reaction time 40 min

b

= Isolated yield.

c

Reaction time was 15 min.

d

Reaction time was 30 min

In conjunction with our efforts to synthesize small libraries that modulate Aβ-peptide excretion we became further interested in exploiting β-benzylmercaptoethylamines in MCRs, as they create significant possibilities for molecular diversity in one step, affording more economical synthetic approaches as compared to linear syntheses.6 We explored five separate MCRs with aims of generating a broad swath of diverse small molecules quickly (Scheme 2). We first explored α-aminophosphonates due, in large part, to their well documented, diverse biological activities.7 As a first trial, we synthesized the novel α-aminophosphonate 23 by following a literature procedure utilizing 2-(3-nitrobenzylsulfanyl)-ethylamine as the amine component. The reaction proceeded smoothly, affording a similar yield (70%) to those previously reported utilizing the Zr(IV) catalyst.8 Because of the well known therapeutic value of barbiturates,9 next we turned our attention towards the synthesis of 24 via a three component reaction using 2-benzylsulfanyl-ethylamine. Our 68% yield is in line with the 72%-90% yields previously reported in the water-based solvent system.10 Due to the prevalence of the thiazoles across diverse pharmaceutical targets,11 we utilized the methodology of Yavari et al.12 to synthesize 25 via a four component reaction with 2-(3-chlorobenzylsulfanyl)-ethylamine.12 The reaction proceeded with reasonable yield (65%) after 24 hours. We further explored the synthesis of novel bis-2,3-dihydroquinazolin-4(1H)-one derivatives 26 utilizing a three component reaction following a literature procedure.13 As compared to precedent, our substrate proved as effective a reagent in the p-toluenesulfonic acid catalyzed reaction affording 26 in 50% yield. Finally, since its discovery, the ‘Ugi four-component reaction’ is one of the best known, and most popular multicomponent reactions. In this reaction an aldehyde/ketone, an amine, a carboxylic acid, and an isocyanide form an α-acylamino carboxamide through a one pot condensation.14 The final application is illustrated by the formation of 27, derived from 2-(4-methoxybenzylsulfanyl)-ethylamine, in 72% yeild.14c

Scheme 2.

Scheme 2

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The use of β-benzylmercaptoethylamine and its derivatives in various multicomponent reactions.

Supplementary Material

1

Acknowledgments

This work was supported by the NIH (AG015885 & HL053315).

Footnotes

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Supplementary Material: Experimental procedure, NMR spectra, high resolution mass spectra and compound characterization data are available for all molecules.

References

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Supplementary Materials

1
NIHMS102290-supplement-1.doc (3.6MB, doc)

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