A practical, one-pot multicomponent synthesis of α-amidosulfides and their application as latent N-acylimines in the Friedel-Crafts reaction

Article abstract of DOI:10.1002/ejoc.201100426

A novel one-pot, three-component synthesis of N-acyl or N-carbamoyl-α-amidosulfides 4 is described. The three-component reaction of aldehydes 1, primary carbamates (or amides) 2 and phenylsulfinic acid (6a) afforded α-amidosulfones 7, which after addition

Full text of DOI:10.1002/ejoc.201100426

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100426
A Practical, One-Pot Multicomponent Synthesis of α-Amidosulfides and Their
Application as Latent N-Acylimines in the Friedel–Crafts Reaction
Nicolas George,[a] Mathieu Bekkaye,[a] Géraldine Masson,*[a] and Jieping Zhu*[b]
Keywords: Sulfur / Aldehydes / Imine precursors / Multicomponent reactions / Alkylation
A novel one-pot, three-component synthesis of N-acyl or N-
yields. We demonstrated that silver salts or Brønsted acids
carbamoyl-α-amidosulfides 4 is described. The three-compo- were able to promote the formation of aliphatic and aromatic
nent reaction of aldehydes 1, primary carbamates (or amides)
2 and phenylsulfinic acid (6a) afforded α-amidosulfones 7,
which after addition of sodium thiolate were in situ trans-
formed into stable α-amidosulfides 4 in good to excellent
N-acylimines from 4 in quantitative yield under mild condi-
tions. The phosphoric acid catalyzed Friedel–Crafts alkyl-
ation of 3-substituted indoles with α-amidosulfides 4 leading
to 2,3-disubstitued indoles was also documented.
pot synthesis of α-amidosulfides.[9] Our initial studies were
carried out with 3-phenylpropionaldehyde (1a), tert-butyl
carbamate (2a), and ethanethiol (3a) in the presence of
Lewis or Brønsted acids. Unfortunately, formation of α-
amidosulfide 4a was never observed under a variety of con-
ditions tested. In most cases, dithiane 5 was isolated as a
main product (Scheme 1).[10]
Introduction
α-Amidosulfides (N,S-acetals) are an important class of
structural motifs found in numerous pharmaceutical
agents[1] and heterocycles such as 4-thiazolidinones.[2] Inter-
estingly, although N,S-acetals are sufficiently stable under
mild acidic and basic conditions, which makes them valu-
able protecting groups,[3] they can also act as useful syn-
thetic intermediates in organic synthesis.[4] For instance, α-
amidosulfides constitute an interesting stable masked form
of N-acyl- and N-carbamoylimines (or iminium ions) in the
presence of a soft Lewis acid.[4a–4f,5,6] Recently, we reported
a silver tetrafluoroborate mediated cyclization of tethered
α-amidosulfides and silyl enol ethers and successfully ap-
plied this transformation in the synthesis of (–)-quinocarcin
as well as the aglycon of (–)-lemonomycin.[5m,5n] Interest-
ingly, in spite of their synthetic utilities, few methods are
known for the preparation of α-amidosulfides, and most of
them involve multistep processes that have limited applica-
tion scope.[7] Therefore, the development of general, simple,
and convenient methods for the construction of α-amido-
sulfides will be of great interest.
Scheme 1.
In this context, we envisaged another approach involving
the nucleophilic addition of thiol to highly reactive N-carb-
amate imines generated in basic media from α-amidosulf-
ones 7.[11,12] To investigate the feasibility of this approach,
we selected sodium ethanethiolate (8a) as a base to trigger
the formation of imine from 7 and also as a nucleophile to
trap the in situ generated imine. To evaluate this hypothesis,
we initiated our studies by treating sodium ethanethiolate
(8a) with α-amidosulfone 7a prepared from aldehyde 1a,
phenylsulfinic acid (6), and tert-butyl carbamate (2a).[12]
When the reaction was carried out in ethanol at room tem-
perature α-amidosulfide 4a was isolated in 83% yield
(Table 1, Entry 1). In spite of these encouraging results, the
N,O-acetal resulting from nucleophilic addition of ethanol
to the imine intermediate was also isolated as a side prod-
uct. This competitive reaction was suppressed by using a
sterically bulky protic solvent such as tert-butyl alcohol
(Table 1, Entry 2) or aprotic solvents (THF or DMF;
Table 1, Entries 3 and 4). Because conditions for the three-
component synthesis of α-amidosulfone 7a and those of the
subsequent substitution process leading to 4a are poten-
Results and Discussion
In continuation of our work in multicomponent reac-
tions (MCRs),[8] we were interested in developing a one-
[a] Centre de Recherche de Gif,
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette Cedex, France
Fax: +33-1-69077247
E-mail: masson@icsn.cnrs-gif.fr
[b] Institute of Chemical Sciences and Engineering,
Ecole Polytechnique Fédérale de Lausanne (EPFL),
EPFL-SB-ISIC-LSPN,
1015 Lausanne, Switzerland
Fax: +41-21-6939740
E-mail: jieping.zhu@epfl.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100426.
Eur. J. Org. Chem. 2011, 3695–3699
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3695

N. George, M. Bekkaye, G. Masson, J. Zhu
SHORT COMMUNICATION
tially compatible, we next sought to merge these two steps carbamate, sodium phenylsulfinate, formic acid/water)[14]
into a one-pot process. Thus, a CH2Cl2 solution of aldehyde expected amidosulfides 4 were isolated in excellent yields
1a, 6, and 2a in the presence of MgSO4 was stirred at room (Table 2, Entries 16–19).
temperature for 12 h.[13] Upon complete consumption of
the aldehyde, 8a was added. The resulting mixture was
stirred for an additional 3 h, and the corresponding α-ami-
Table 2. One-pot sequential multicomponent synthesis of α-amido-
sulfides.
dosulfide 4a was obtained in 72% overall yield (Table 1,
Entry 5). Subsequently, it was found that the reaction per-
formed in a mixture of solvents (CH2Cl2/THF, 1:1) pro-
duced compound 4a in 96% yield from 1a, which is much
higher than the two-step procedure (Table 1, Entry 6 vs. 3).
Table 1. Optimization of reaction conditions.
Entry[a] Solvent A[b] Solvent B[c]
Time
[min]
Yield
[%]
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/
THF
EtOH
tBuOH
THF
5
5
180
60
180
180
83[d] (69)[e]
92[d] (76)[e]
91[d] (75)[e]
92[d] (76)[e]
72[f,g]
DMF
CH2Cl2
CH2Cl2/
THF
96[f,g]
[a] General conditions: 1a/2a/6 = 1.0:1.2:1.2 (c = 0.1). [b] Solvent
used for the synthesis of 7a. [c] Solvent used for the synthesis of
4a. [d] Yield refers to chromatographically pure product calculated
from 7a. [e] Yield refers to chromatographically pure product calcu-
lated from 1a. [f] Sequential one-pot 3CR/substitution process.
[g] Yield refers to chromatographically pure product calculated
from 1a.
[a] General conditions: 1/2/6 = 1.0:1.2:1.2 in CH2Cl2/THF (1:1, c
= 0.1) followed by addition of R3SNa 8. [b] Yield refers to chro-
matographically pure product. [c] Experimental conditions: 1/2/6 =
1.0:1.2:1.2 in CH2Cl2 (1:1, c = 0.1) followed by evaporation of
CH2Cl2 and addition of R3SNa in THF. [d] Prepared from α-ami-
dosulfone 7.
The scope of this novel synthesis of α-amidosulfides was
next examined by varying the aldehydes, carbamates
(amides), and thiolates. As shown in Table 2, the sequential
multicomponent process can be applied to both aliphatic
and aromatic thiolates, affording corresponding α-amido-
sulfides 4 in high yields (Table 2, Entries 1–3 and 7–10).
Benzamide derivatives 2 also participated in the reaction to
give 4 in reasonable to excellent yield (Table 2, Entries 11–
15). When benzyl carbamate was subjected to the same con-
ditions, the yield was significantly reduced. However, when
the amidosulfone prepared in CH2Cl2 was treated with so-
dium thiolate in THF, desired amidosulfide 4 was isolated
in excellent yield (Table 2, Entry 16). For the aldehyde part,
aliphatic including linear or α-branched aldehydes partici-
pated well in this transformation. Except in the case of
bulky pivaldehyde (Table 2, Entry 9), reactions of heptanal,
benzyloxyacetaldehyde, isobutyraldehyde, cyclopropane-
carboxaldehyde, and cyclohexanecarboxaldehyde gave the
expected products in good yields. On the other hand, benz-
aldehyde failed to participate in this one-pot procedure, due
to problems inherent to the synthesis of aromatic α-amido-
sulfones from phenylsulfinic acid 6. Nevertheless, using pre-
Two plausible mechanistic pathways could be postulated
for the conversion of α-amidosulfones 7 into α-amidosul-
fides 4 (Scheme 2): Path a: An SN1 manifold involving for-
mation of discrete N-carbamoyl imine intermediate 9 fol-
lowed by addition of thiolate 3.[15] Path b: An SN2 mecha-
nism involving the direct displacement of benzenesulfinate
by sodium ethanethiolate (8a). Although the exact mecha-
nism has not been fully elucidated, we are currently in favor
of path b. Firstly, we never observed the tautomerization of
Scheme 2. SN1 or SN2 mechanism for the formation of α-amido-
synthesized α-amidosulfones 7 (aromatic aldehyde, benzyl- sulfides 4 from 7.
3696
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Eur. J. Org. Chem. 2011, 3695–3699

A Practical, One-Pot Multicomponent Synthesis of α-Amidosulfides
N-acyl or N-carbomoyl imines during these experiments,[16] is applicable to a wide range of aldehydes, amides or carb-
which suggests a mechanism without formation of interme- amates, and thiols. In view of the widespread use of α-amido-
diate imines. Secondly, a control experiment showed that sulfides as latent N-acylimine species, we believed that the
ethanethiol 3[15] or sodium ethanethiolate (8a) did not react ready accessibility of α-amidosulfides could popularize
with aliphatic or aromatic N-Boc imines under our stan- their use in organic synthesis as N-acylimine precursors. We
dard conditions.[14b,17]
stress that the conditions for generating the imine from α-
Having examined the scope of this new N,S-acetal-form- amidosulfides (in the presence of soft Lewis or Brønsted
ing reaction, our attention turned to the synthetic applica- acids)[12a–12l] is complementary to those from α-amidosulf-
tions of α-amidosulfides 4 as stable precursors of imines.[5] ones (basic conditions or in the presence of strong Lewis
A variety of silver salts (AgBF4, AgOTf, AgOAc, Ag2SO4) acid). Therefore, starting from α-amidosulfides, different re-
known to have high affinity for sulfides[18] and Brønsted action conditions could in principle be envisaged for per-
acids (p-toluenesulfonic acid, camphorsulfonic acid, acetic forming the subsequent α-functionalization of amines.
acid) were screened. Among them, AgOAc and p-tolu-
enesulfonic acid gave the best results, converting aliphatic
and aromatic α-amidosulfides 4a and 4q, respectively, into
imines 9 at room temperature within 10 min. Encouraged
Experimental Section
General Procedure for the One-Pot Synthesis of α-Amidosulfides 4:
A flask equipped with a stirring bar and charged with anhydrous
magnesium sulfate (0.83 equiv.) was placed under vacuum and
flame dried. Phenylsulfinic acid (6, 1.2 equiv.) and amine 2
(1.2 equiv.) were added at room temperature, and the flask was
purged with argon. The solids were dissolved in a mixture of THF/
by these results, we next investigated the aminoalkylation
of 3-(2-bromoethyl) indole 10[12p,12t,12u,19] with 4 for the
synthesis of 2,3-disubstituted indoles 11,[20,21] which are
useful intermediates in the synthesis of tetrahydro-β-carbol-
ines.[22] Phosphoric acids that are well established to be ex-
cellent catalysts for the Friedel–Crafts reaction were se-
DCM (1:1, c = 0.1 m). A solution of appropriate aldehyde 1
lected to promote both the imine formation and C-2 alk- (1.0 equiv.) was added dropwise, and the resulting reaction mixture
ylation of 10.[21a,23–25] After a survey of reaction param-
was stirred overnight at room temperature. Sodium thiolate 8
(2.0 equiv.) was then added in one portion, and the solution was
stirred for an additional 3 h, during which time the sodium sulfin-
ate precipitated as a white solid. This residue was removed by fil-
tration and washed with Et2O, and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography on
neutral aluminum oxide (heptane/EtOAc = 9:1) to give α-amido-
sulfides 4 as white solids.
eters, solvents, and temperatures, the optimized conditions
consist of performing the alkylation of 10 in CH2Cl2 in the
presence of phosphoric acid 12 (20 mol-%). As shown in
Table 3, α-amidosulfides 4a–l and 4o, whether linear or α-
branched, effectively participate in this reaction, leading to
2-indolylmethanamines 11 in good yields. The development
of an enantioselective version of this reaction is currently
underway.
4b: Yield: 96%. M.p. 74–75 °C. IR: ν = 3278, 2925, 2857, 1673,
˜
1521, 1366, 1295, 1249, 1161, 1046, 1023 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.27 (s, 9 H), 1.84–2.07 (m, 2 H), 2.71 (t,
J = 8.0 Hz, 2 H), 4.25 (d, J = 9.5 Hz, 1 H), 5.04–5.09 (m, 1 H),
7.05–7.45 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.3
(3 CH3), 32.7 (CH2), 37.9 (CH2), 58.7 (CH), 79.9 (Cq), 126.1 (2
CH), 127.8 (CH), 128.5 (2 CH), 128.5 (2 CH), 128.9 (2 CH), 132.5
(Cq), 133.7 (CH), 140.8 (Cq), 154.5 (Cq) ppm. HRMS (ESI-TOF):
calcd. for C20H25NO2SNa [M + Na]+ 366.1504; found 366.1504.
Table 3. Reaction of indole 10 with α-amidosulfide 4.
Acknowledgments
Entry[a]
R1
R2
Yield [%][b]
Financial support from Centre National de la Recherche Sci-
entifique (CNRS) is gratefully acknowledged. N. G. thanks L’Insti-
tut de Chimie des Substances Naturelles (ICSN) for a doctoral fel-
lowship.
1
2
3
4
5
Ph(CH2)2
Ph(CH2)2
BnOCH2
iPr
Ph
87 (11a)
83 (11b)
60 (11c)
85 (11d)
75 (11e)
p-OMeC6H4
Ph
Ph
Ph
C6H13
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3697

N. George, M. Bekkaye, G. Masson, J. Zhu
SHORT COMMUNICATION
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Received: March 28, 2011
Published Online: May 17, 2011
Eur. J. Org. Chem. 2011, 3695–3699
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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