A new strategy for the synthesis of β-benzylmercaptoethylamine derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.01.133

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.

Full text of DOI:10.1016/j.tetlet.2009.01.133

Tetrahedron Letters 50 (2009) 1723–1726
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A new strategy for the synthesis of b-benzylmercaptoethylamine derivatives
*
Subrata Ghosh, Gregory P. Tochtrop
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Here, we describe a new experimental approach to the synthesis of the b-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 care-
fully developed LiOH–water–ethanol reaction mixture, we were able to produce a diverse collection of b-
benzylmercaptoethylamines containing a range of sensitive functional groups in excellent yields. To fur-
ther illustrate their utility in molecular library synthesis, we also report the use of b-benzylmercaptoeth-
ylamines in five different multi-component reactions.
Received 7 January 2009
Revised 23 January 2009
Accepted 26 January 2009
Available online 30 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The b-benzylmercaptoethylamine functionality and its deriva-
tives are widely utilized with applications in organic,1 inorganic,2
medicinal,3 and cosmetic chemistry.4 For example, this functional-
ity played a critical role in the synthesis of pantetheine (a cyste-
amine derivative of pantothenic acid–Vitamin B5).3a Reisner
reported the synthesis of D/L-c-sulfamyl-a-amino acids as potential
anti-metabolites utilizing b-benzylmercaptoethylamine as a key
intermediate.3b When Okarvi et al. were exploring an alternative
of 131I-hippuran (a renal radiopharmaceutical), they synthesized
Table 2
Reaction between various benzyl halides and cysteamine hydrochloride using
combination of LiOH–H2O–EtOH
a
Entry
Benzyl halidea
Product
Yieldb (%)
Scheme 1. General synthesis of b-benzylmercaptoethylamine and its derivatives
using a combination of LiOH–water–ethanol.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Z = H, X = Br
Z = H
Z = 4-OMe
Z = 3-OMe
Z = 3-F, X = Br
Z = 3-F
Z = 3-Cl
Z = 3-Br
Z = 3-I
Z = 2-NO2
Z = 3-NO2
Z = 4-NO2, X = Br
Z = 4-NO2
Z = 3-CO2Me
Z = 3-CN
Z = 3-Me
Z = H
Z = H
Z = 4-OMe
Z = 3-OMe
Z = 3-F
Z = 3-F
Z = 3-Cl
Z = 3-Br
Z = 3-I
Z = 2-NO2
Z = 3-NO2
Z = 4-NO2
Z = 4-NO2
Z = 3-CO2Me
Z = 3-CN
90
90
94
85
83
82
86
85
85
78
82
75
75
60c
80d
82
80
82
81
80
78
80
Table 1
A
systematic evaluation of solvent systems and bases for the formation of b-
benzylmercaptoethylamines
Base used
Solvent used
Yield (%)
LiOH
LiOH
LiOH
NaOH
NaOH
KOH
CsOH
K2CO3
K2CO3
Et3N
EtOH
EtOH–H2O (3:1)
H2O
72
86
20
66
78
75
75
30
50
25
5
EtOH
EtOH–H2O (3:1)
EtOH–H2O (3:1)
EtOH–H2O (3:1)
EtOH
EtOH–H2O (3:1)
EtOH
Z = 3-Me
Z = 3-CF3
Z = 3-CF3
Z = 4-t-Butyl
Z = 2,3-Di-OMe
Z = 2,6-Di-Cl
Z = 3-Cl-5-OMe
Z = 2-CN-3-Cl
Z = 4-t-Butyl
Z = 2,3-Di-OMe
Z = 2,6-Di-Cl
Z = 3-Cl-5-OMe
Z = 2-CN-3-Cl, X = Br
Et3N
DCM
The reported yields are for reaction 7 from Table 2. All entries reacted for 40 min at
35 °C.
a
Unless otherwise stated, X = Cl and reaction time is 40 min.
Isolated yield.
Reaction time was 15 min.
b
c
* Corresponding author. Tel.: +1 2163682351; fax: +1 2163683006.
E-mail address: tochtrop@case.edu (G.P. Tochtrop).
d
Reaction time was 30 min.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.133

1724
S. Ghosh, G. P. Tochtrop / Tetrahedron Letters 50 (2009) 1723–1726
a number of S-protected derivatives of MAG3 (mercaptoacetyltri-
glycine), and discovered that the p-methoxy derivative of b-ben-
zylmercaptoethylamine 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 anti-bacterial agents (prepared by a novel
combinatorial disulfide exchange strategy), Nicolaou et al. used
b-benzylmercaptoethylamine as a thioether containing primary
amine coupling partner.3k
Despite the wide ranging 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 and a two-step reaction procedure.1e
During the course of synthesizing a small library of molecules to
modulate the secretion of the Ab peptide by a neuronal cell line, we
became interested in a specific molecule that contained the b-ben-
zylmercaptoethylamine 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 hypoth-
esized that the general reaction (depicted in Scheme 1) could pos-
sibly be proceeding via a borderline/SN1-type reaction mechanism,
in contrast to the prototypical SN2-type pathway. Thus, we envi-
sioned that a careful optimization of both the solvent conditions
and the base used would be critical for developing a superior meth-
od. Toward 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 sup-
port to our hypothesis, we found that simple ionic bases further
facilitated smooth conversions (Scheme 1).
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 b-benzylmercaptoethylamines in combinatorial chemistry
Scheme 2. The use of b-benzylmercaptoethylamine and its derivatives in various multi-component reactions.

S. Ghosh, G. P. Tochtrop / Tetrahedron Letters 50 (2009) 1723–1726
1725
and diversity-oriented synthesis through five separate multi-com-
Acknowledgment
ponent reactions (MCRs).
Table 1 illustrates a sampling of the reaction conditions we
studied. Our initial exploration focused primarily on alcoholic sol-
vents; 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 eth-
anol/water ratio fixed, we subsequently screened the effect of var-
ious alkali metal and organic bases to find LiOH the most effective.
Using this approach, not only were our yields superior to those
previously reported, but we were also able to accomplish the con-
versions in a minimal amount of time (approximately 40 min) and
at low temperatures (35 °C). For the reactions listed in Table 1, we
utilized 3-chlorobenzyl chloride as the representative benzyl ha-
lide mainly due to its importance in the molecules we were syn-
thesizing to modulate Ab 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 compara-
tively lower yields for the nitro derivatives. Among all other nitro
derivatives, p-nitro (Table 2, entries 12 and 13) gave the lowest
yield, further substantiating a borderline/SN1-type mechanism,
where at least a partial charge builds at the benzylic position. Fur-
ther, the best yields were obtained for the substrates containing an
electron-donating functional group such as –OCH3 (Table 2, entry
3). It is worth pointing out that the reaction was highly compatible
with a number of functional groups including –OCH3, –NO2, halo-
gens, –CN, –CO2CH3, –CH3, and –CF3. Benzyl chlorides and bro-
mides gave similar yields (Table 2, compare entry 1 and entry 2,
entry 5 and entry 6, entry 12 and entry 13).
This work was supported by the NIH (AG015885 & HL053315).
Supplementary data
Supplementary data (experimental procedure, NMR spectra,
high resolution mass spectra and compound characterization data
are available) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.01.133.
References and notes
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a-aminophosphonates due, in large part, to their
a
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reaction following a literature procedure.13 As compared to prece-
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5. Typical reaction procedure: LiOH (0.245 g, 10.2 mmol) was dissolved in 5 mL of
water, and 15 mL of ethanol was added. The resulting solution was added to a
flask containing cysteamine hydrochloride (0.568 g, 5 mmol), followed by the
dropwise addition of benzyl halides (5 mmol) with continuous stirring. The
reaction mixture was stirred for 40 min at 35 °C, and ethanol was removed in
vacuo. Twenty millilitres of water were subsequently added, and the mixture
was extracted with dichloromethane (3 Â 30 mL), dried over anhydrous
Na2SO4, concentrated in vacuo, and purified via column chromatography over
silica gel (60 Å, 230–400 mesh, SiliCycle) using a mobile phase consisting of a
suitable mixture of dichloromethane–methanol (gradient from 2% v/v
methanol/dichloromethane to 20% v/v methanol/dichloromethane) to afford
the
chromatographically
pure
desired
b-benzylmercaptoethylamine
derivatives.
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