Efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur

Article abstract of DOI:10.1021/ol3020368

An efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur under solvent-free conditions has been developed.

Full text of DOI:10.1021/ol3020368

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Efficient and Selective Multicomponent
Oxidative Coupling of Two Different
Aliphatic Primary Amines into Thioamides
by Elemental Sulfur
Thanh Binh Nguyen,* Ludmila Ermolenko, and Ali Al-Mourabit
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex, France
nguyen@icsn.cnrs-gif.fr
Received July 23, 2012
ABSTRACT
An efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur under
solvent-free conditions has been developed.
Simple and effective reactions including multicompo-
nent coupling processesusingreadily availablereagentsare
seen as a key solution for the 21st century pollution
problems generated by large scale chemistry. With this
vision, the use of elemental sulfur in organic syntheses
appears to be highly desirable to maximize atom economy
and to avoid expensive complex catalysts. For this pur-
pose, we have selected the study of the synthesis of
thioamides by a coupling reaction between two amines.
Molecules containing a thioamide1 moiety play an impor-
tant role in chemistry. Thioamide functions are also pre-
sent in a variety of biologically active molecules.2 They
are also known as building blocks in the synthesis of
heterocycles and other compounds containing both nitro-
gen and sulfur within their backbones.3
Different synthetic methods have been discovered for
the synthesis of thioamides. Among these strategies, thio-
nation of amide analogues with Lawesson’s reagent is the
most common,4 but this reaction cannot been classified as
an atom economical approach because of crucial limita-
tions: only one oxygen atom is replaced by a sulfur atom,
and no other new bond was created. Thus, it is worthwhile
to provide a practical and environmentally benign method
to synthesize thioamides. Because sulfur is nontoxic, stable
under ambient conditions, easy to handle, and readily
available, its use in the preparation of thioamides is highly
desireable as exemplified by the WillgerodtÀKindler reac-
tion, starting from aryl alkyl ketones, elemental sulfur, and
secondary amines such as morpholine.5
(1) (a) Hurd, R. N.; Delamater, G. Chem. Rev. 1961, 61, 45.
€
(b) Bauer, W.; Kuhlein, K. Houben-Weyl’s Methoden der Organischen
Chemie; Georg Thieme Verlag: Stuttgart, New York, 1985; Vol. E5,
ꢀ
pp 1218À1279. (c) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
(d) Leung, P. H.; Qin, Y.; He, G.; Mok, K. F.; Vittal, J. J. J. Chem.
Soc., Dalton Trans. 2001, 309. (e) Murai, T.; Sano, H.; Kawai, H.; Aso,
H.; Shibahara, F. J. Org. Chem. 2005, 70, 8148.
(4) (a) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.
(b) Brillon, D. Sulfur Rep. 1992, 12, 297.
(5) (a) Willgerodt, C. Ber. Dtsch. Chem. Ges. 1888, 21, 534.
(b) Kindler, K. Liebigs Ann. Chem. 1923, 431, 187. (c) Wegler, R.;
Kuhle, E.; Schafer, W. Angew. Chem. 1958, 70, 351. For recent examples
of thioamide synthesis by reaction of sulfur with imines or aldehydes and
amines, see: (d) Zbruyev., O. I.; Stiasni, N.; Kappe, C. O. J. Comb. Chem.
2003, 5, 145. (e) Okamoto, K.; Yamamoto, T.; Kanbara, T Synlett 2007,
2687.
(6) (a) Davis, R. E.; Nakshbendi, H. F. J. Am. Chem. Soc. 1962, 84,
2085. (b) Hodgson, W. G.; Buckler, S. A.; Peters, G. J. Am. Chem. Soc.
1963, 85, 543. (c) Thomson, J. W.; Nagashima, K.; Macdonald, P. M.;
Ozin, G. A. J. Am. Chem. Soc. 2011, 133, 5036.
(2) (a) Mehanna, A. S.; Belani, J. D.; Kelley, C. J.; Pallansc, L. A.
J. Med. Chem. 2007, 3, 513. (b) Yu, K. L.; Torri, A. F.; Luo, G.; Cianci,
C.; Grant-Young, K.; Danetz, S.; Tiley, L.; Krystalb, M.; Meanwella,
N. A. Bioorg. Med. Chem. Lett. 2002, 12, 3379.
(3) For selected recent examples, see: (a) Lo, W. S.; Hu, W. P.; Lo,
H. P.; Chen, C. T.; Kao, C. L.; Vandavasi, J. K.; Wang, J. J. Org. Lett.
2010, 12, 5570. (b) Iwata, M.; Yazaki, R.; Chen, I. H.; Sureshkumar, D.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5554.
(c) Goossen, L. J.; Blanchot, M.; Salih, K. S. M.; Karch, R.; Rivas-Nass,
A. Org. Lett. 2008, 10, 4497.
r
10.1021/ol3020368
XXXX American Chemical Society

The interaction of sulfur with amines has been the
subject of several studies.6À8 McMillan observed the for-
mation of N-benzylthiobenzamide when benzylamine and
sulfur were heated together which is, to our knowledge, the
only example of such a transformation.7 In the same
report, the reaction has also been applied for an equimolar
mixture of benzylamine and morpholine and resulted
in a low yield of the corresponding N-(thiobenzoy1)
morpholine (40.6%). No information concerning the com-
position of the reaction mixture has been collected. To our
knowledge, such a reaction with two different aliphatic
primary amines has never been disclosed. In this paper, we
wish to report a new synthetic approach to thioamide via a
sulfur-mediated selective thionationÀcoupling reaction
starting from two different amines (Scheme 1).
2a and 3a (vide infra), an appropriate additional quantity
of 2a would help increase the conversion into 3c and at the
same time lower the amount of 3a. To our delight, adding
just 20% of 2a to the reaction mixture substantially
increased the conversion of 3a (entry 7). However, adding
more 2a favored the formation of 3b (entry 8).
Table 1. Reaction Conditions Screeninga
Scheme 1. ThionationÀCoupling Reaction of Two Amines
1a
2a
temp
conversion
(%)b
entrya
(mmol)
(mmol)
(°C)
3a:3b:3c
1e
2
3
4
5
6
7
8
5
5
5
0
0
5
5
5
0
190
110
100
150
130
130
130
130
100c
100:0:0
100:0:0
100:0:0
0:100:0
0:100:0
13:3:86
5:3:92
0
>98c
80c
0
5
>98d
60d
>98c
>98c (87)f
>98c
5
5
6
The reaction of sulfur with two different aliphatic pri-
mary amines (benzylamine 1a and 2-phenethylamine 2a,
for instance), in principle, can afford four possible thioa-
mides (Table 1).
7.5
4:6:90
a Conditions: sulfur (7.5 mmol for entries 1À5 or 15 mmol for entries
6À8, 32.1 g/mol), 16 h unless otherwise stated. b Based on 1H NMR.
c Based on the consumption of 1a. d Based on the consumption of 2a.
e Reaction time 1 h. f 87% Isolated yield of 3c.
Such a reaction that is capable of providing a single
cross-coupled thioamide selectively from two amines is
highly desireable. To evaluate the potential of elemental
sulfur as a thionationÀcoupling reagent, the homocou-
pling reaction conditions of McMillan were reproduced by
heating benzylamine 1a with an equimolar amount of
sulfur at reflux (190 °C, 1 h) (Table 1, entry 1). Since full
conversion of 1a into N-benzylthiobenzamide 3a was
achieved rapidly (less than 1 h), we decided to lower the
reaction temperature. At 110 °C, high conversion in 3a
(>98%) was obtained after 16 h (entry 2; compare with
entry 3). The same reaction was next investigated for
2-phenethylamine 2a and required a higher temperature
(150 °C) to afford a comparable high conversion (>98%)
of homocoupled thioamide (entry 4). Lowering the tem-
perature to 130 °C resulted in incomplete conversion of 3b
(40%, entry 5). We decided to use an equimolar mixture of
1a and 2a for reaction at 130 °C (entry 6). In this case, the
1H NMR spectrum of the crude mixture displayed the
presence of both homocoupled thioamides 3a and 3b, only
one heterocoupled thioamide 3c, a small quantity of 2a
(∼5%), and onlya trace of 1a. Interestingly, the percentage
of heterocoupled thioamide 3c is very high (92% of
thioamides). Because 3c can be yielded by the reaction of
In subsequent studies, we applied the optimized condi-
tions to investigate the generality of this reaction and to
demonstrate its synthetic utility (Table 2). With N-methyl-
benzylamine 1b (entry 1), 3c was obtained in high yield. In
this reaction, no product resulting from the homocoupling
of 1b could be observed. Moreover, N-methylthiobenza-
mide was the only observable intermediate of the reaction.
With N,N-dimethylbenzylamine 1c (entry 2), because the
formation of homocoupling of 1c is not possible, the only
intermediate of the reaction N,N-dimethylthiobenzamide
can react exclusively with 2a to yield 3c. When dibenzyla-
mine 1d (0.5 equiv, entry 3) or tribenzylamine 1e (0.33
equiv, entry 4) was used with 2a, all benzyl groups of 1dÀe
are successively transformed into the thiobenzoyl moiety
of the final thioamide 3c. Other functional benzylamines
(1fÀg) and 3- and 4- picolinamines (1hÀi) could also be
used as the amine 1 component in this reaction without any
incidents. Different substrates could be used as the amine 2
component, including functionalized amine (2b), simple
aliphatic amines (n-octylamine and n-hexylamine 2cÀd),
alicyclic amine (2e), and secondary amine (morpholine 2f).
To our delight, 4-picolinamine is more prone to oxida-
tion, allowing the reaction to occur at lower temperature
(entries 8À12). Interestingly, 1-phenethylamine 1j could
also be successfully employed in place of the benzylamine,
leading to phenylthioacetamides 3b and 3m in moderate to
high yields. Obviously, in these two cases, the transformation
(7) (a) McMillan, F. H. J. Am. Chem. Soc. 1948, 70, 868. For related
work, see: (b) Aghpoor, K.; Darabbi, H. R.; Tabar-Heydar, K. Phos-
phorus, Sulfur and Silicon 2002, 177, 1183.
(8) For a mechanistic study of the room temperature reaction of
sulfur with benzylamine, see:Sasaki, Y.; Olsen, F. P. Can. J. Chem. 1971,
49, 283.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Conversion of Two Different Amines into N-Substituted Thioamidesa
a Reaction conditions: amine 1 (5 mmol), amine 2 (6 mmol), sulfur (15 mmol). b Isolated yield. c 2.5 mmol. d 1.7 mmol.
involves a Willgerodt rearrangement. Finally, the coupled
product of 1a with 4-hydroxybutylamine 2g provides an
attractive example in which the hydroxy group of 2g
remained intact during the reaction and may be useful for
Org. Lett., Vol. XX, No. XX, XXXX
C

further functionalization. In general, higher conversions of
cross-coupledthioamide3 were observedwhenthe reaction
mixture was heated for a longer time at appropriate tem-
peratures which could not induce the oxidation of amine 2
components or other side reactions.
When 2-phenethylamine2a was involved in the reaction,
it could react either with both imines 4aÀb via transimina-
tion (steps f and h) or with thioamide 5 and 3a via
transthioamidation (steps i and j). Due to the similar
nucleophilic nature and boiling points of amines 1a and
2a, steps h and j might be reversible. However, the forma-
tion of 3c in step j and 4c in step h can be driven by
continuous oxidation of the benzylamine. Since 4b and 4c
could be oxidized further to 3a and 3c (steps e and g), step j
might be the rate-determining step. Obviously, the success
of the reaction depends on the difference in reactivity of
benzylamine1aand 2-phenethylamine 2ainthefirst stepof
amine oxidation.
Plausible mechanisms are described in Scheme 2. The
upper part presents the mechanism when benzylamine 1a
was the only amine component.8 The first step (step a) of
the reaction could be the oxidation of 1a into benzaldimine
4a. Imine 4a is transformed into thiobenzamide 3a via two
possible pathways: (i) oxidation by sulfur (step b) to afford
thiobenzamide 5 followed by a transthioamidation (step c)
with benzylamine 1a;9 (ii) transimination10 (step d) of imine
4a with amine 1a to provide 4b and subsequent oxidation
(step e) of 4b by sulfur. Since the oxidation using the sulfur of
imine 4aÀb (steps b and e) is faster than that of an amine 1a
(step a), the presence of imines 4aÀb could not be observed
under our conditions. Because the transthioamidation
(step c) is highly favorable when ammonia is driven off
on heating,11 once generated, thiobenzamide is consumed
immediately. Consequently, only 1a and 3a could be ob-
served in the reaction mixture by NMR spectroscopy. The
rate-determining step is therefore step a. Contrary to one of
the McMillan hypotheses7 which suggested that 3a could be
obtained by condensation of two benzylamine molecules
followed by oxidation, we reasoned that this condensation
under gentle heating conditions is likely impossible, although
reaction of dibenzylamine and sulfur can give rise to 3a.
Scheme 2. Proposed Reaction Mechanism
(9) In contrast to benzamide which is relatively inert to benzylamine,
thiobenzamide is more labile towards a transamidation reaction. For
uncatalyzed transthioamidation, see: (a) Schlatter, M. J. J. Am. Chem.
Soc. 1942, 64, 2722. For selected examples of catalyzed transamidation,
see: (b) Zhang, M.; Imm, S.; Bahn, Neubert, S. L.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2012, 51, 3905. (c) Nguyen, T. B.; Sorres, J.;
Tran, M. Q.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2012, 14, 3202.
(d) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2006, 128, 5177. (e) Kissounko, D. A.; Guzei, L. A.; Gellman, S. H.;
Stahl, S. S. Organometallics 2005, 24, 5208. (f) Eldred, S. E.; Stone,
D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422.
(g) Stephenson, N. A.; Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2009, 131, 10003. (h) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.;
Cui, Q.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 647. (i) Kissounko,
D. A.; Hoerter, J. M.; Guzei, L. A.; Cui, Q.; Gellman, S. H.; Stahl, S. S.
J. Am. Chem. Soc. 2007, 129, 1776. (j) Allen, C. L.; Atkinson, B. N.;
Williams, J. M. J. Angew. Chem., Int. Ed. 2012, 51, 1383.
In summary, a three-component reaction involving ele-
mental sulfur and two different amines has been achieved
for the first time and offers a straightforward and an
efficient strategy for the synthesis of various thioamides.
Further studies of the reaction mechanism and applica-
tions are in progress.
Acknowledgment. Financial support from CNRS and
ICSN is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, product characterization, and copies of the H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Belowich, M. E.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 2003.
(11) Wallach reported that the reaction in a sealed tube (without
ammonia removal) at 180° C of benzylamine with sulfur gave thioben-
zamide:Wallach, O. Ann. 1890, 259, 300. On the other hand, step c was
not favored if N-methyl- was used due to steric hindrance or was not
possible if N,N-dimethylbenzylamine was used.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX