Elemental Sulfur/DMSO-Promoted Multicomponent One-pot Synthesis of Malonic Acid Derivatives from Maleic Anhydride and Amines

Article abstract of DOI:10.1002/adsc.201900160

Malonic acid derivatives could be conveniently prepared with high degree of functional flexibility via redox condensation reactions between anhydride maleic, amines, elemental sulfur and DMSO as oxidant. This multicomponent decarboxylative transformation consists in a cascade of ring opening, decarboxylative oxidative thioamidation at temperature as low as 50 °C. (Figure presented.).

Full text of DOI:10.1002/adsc.201900160

Title: Elemental Sulfur/DMSO-Promoted Multicomponent One-pot
Synthesis of Malonic Acid Derivatives from Maleic Anhydride and
Amines
Authors: Le Anh Nguyen, pascal retailleau, and Thanh Binh Nguyen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900160
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10.1002/adsc.201900160
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Elemental Sulfur/DMSO-Promoted Multicomponent One-pot
Synthesis of Malonic Acid Derivatives from Maleic Anhydride
and Amines
Le Anh Nguyen,b,c Pascal Retailleaua and Thanh Binh Nguyena,*
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1
avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Email: thanh-binh.nguyen@cnrs.fr
Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi,
b
Vietnam
c
Graduate University of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
required in general multistep sequences with narrow
range of functional group distinction for the two
carbonyl moieties (Scheme 1).[3]
Abstract. Malonic acid derivatives could be
conveniently prepared with high degree of functional
flexibility via redox condensation reactions between
anhydride maleic, amines, elemental sulfur and DMSO
as oxidant. This multicomponent decarboxylative
transformation consists in a cascade of ring opening,
decarboxylative oxidative thioamidation at temperature
as low as 50 °C.
Keywords: sulfur; decarboxylation; DMSO; oxidative
condensation; multicomponent reactions
Organic chemists have long strived to develop new
multicomponent reactions to construct complex and
high added value molecules from many simple starting
materials. This strategy with high atom-, step-, and
redox economy is designed to reduce waste, time and
work compared to classical approaches involving only
sequence of separated simple transformations.[1] For
this purpose, we have been developing in recent years
the use of elemental sulfur as a versatile tool to
promote such transformations using only simple,
inexpensive and readily available starting materials.
We report here a straightforward synthesis of malonic
acid derivatives with high degree of functional
flexibility (amide, thioamide, ester, ketone, 2-
azaheterocycle). This multicomponent reaction was
based on decarboxylative cascade redox condensation
between cheap, bench-stable, user-friendly and
commercially available starting materials such as
anhydride maleic, amines, elemental sulfur and DMSO
as oxidant. Such products have a wide range of
applications such as bioactive scaffolds for
development of new drug, and starting materials for the
synthesis of complex and polyfunctional molecules
(Figure 1).[2] Access to such malonic derivatives
Figure 1. Selective synthetic applications of
monothioamide malonic acid derivatives
a
In spite of the simple appearance of sulfur, this
element exhibits a wide range of reactivities that could
be exploited in both redox and non-redox
transformations by appropriately changing external
activator, substrates and reaction conditions.[4]
At the outset of our study, upon dissolution with
vigorous vortex shaking of benzylamine A1 (2 equiv)
and anhydride maleic (1 equiv, 1 mmol) in DMSO (4.5
equiv) at rt followed by addition of elemental sulfur
(1.25 equiv, 32 mg.mol-1) and then heating at 50 °C for
1
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10.1002/adsc.201900160
Advanced Synthesis & Catalysis
16 h, we observed the formation of amide-thioamide amine A7 was used, the amide-thioamide product B7
B1 in excellent yield (Table 1, entry 1). The yields was obtained as a single product with only one set of
dropped when the reaction was performed at higher or NMR signals (entry 9). On the other hand, when A8
lower temperature (entries 2 and 3). We proceeded to and A9 were used as racemic mixture, two couple of
explore the reactivities of other primary aliphatic diastereomers (S,S & R,R) vs (R,S & S,R) were formed
amines, namely A2-A10 at the optimal temperature 50 in practically equimolar amounts with readily
°C. These reacted in similar manner, leading to various distinguishable 1H NMR signals (entries 10-11). When
amide-thioamide products B2-B10 in high yields.
another aromatic/aliphatic secondary amine function
was present in the amine substrate as in A10, the
reaction proceeded without any event (entry 12).
Cyclic secondary amines A11-A14 were found to be
competent substrates, providing tertiary amide-
thioamides B11-B14 in excellent yields (entries 13-
16). As in previous cases with benzylic amines, no
undesirable oxidation of the benzylic position of amine
A14 was observed. The product M14 was obtained in
high yield as a mixture of four possible rotamers (by
1H NMR).
Scheme 1. Four-component access to malonic acid
derivatives B
It should be emphasized that although benzylamines
A2-A3 (entries 4-5) and A7-A9 (entries 9-11) were
known to undergo sulfurative dimerization when
heating with sulfur, such a reaction was found to occur
Next, we studied the scope of the reaction for
aromatic amine (Table 2). Because of the low basicity
of aniline A15, which resulted in an inefficient
activation of elemental sulfur, it was not surprising that
the similar transformation failed in the absence of
only to
a lesser extent, suggesting that the
decarboxylative oxidative thioamidation took place
much more rapidly and efficiently than other side
reactions.[5] Moreover, the formation of carboxylate
salt between amine A and anhydride maleic 1 (see
Scheme 4, 1ii) could limit the direct sulfuration of
amine A by sulfur.
additive. On the other hand, addition of
a
stoichiometric amount of N-methylpiperidine (NMP),
which was found to be a good sulfur activator,[6]
overcame this drawback and led cleanly to the desired
product B15 (entry 1). Extension of these conditions to
other anilines A16-A21 provided the expected
products B16-B21. In general, anilines with electron-
donating groups such as OMe, OH (A17 and A22) gave
better yields.
Table 1. Reaction with alkylamines A with anhydride maleic,
sulfur and DMSO
Table 2. Reaction of aniline A with anhydride maleic, sulfur
and DMSO
entry
1
R-NH-R1
BnNH2
BnNH2
BnNH2
3-MeOC6H4CH2NH2
4-ClC6H4CH2NH2
PhCH2CH2NH2
cyclopentylamine
cyclohexylamine
(S)-Ph(Me)CHNH2
B, yield (%)
B1, 76
B1, 71
B1, 67
B2, 78
B3, 72
B4, 75
B5, 69
B6, 73
B7, 77
A
A1
A1
A1
A2
A3
A4
A5
A6
A7
2a
3b
4
entrya
ArNH2
PhNH2
M, yield (%)
B15, 71
B16, 32
B17, 75
B18, 68
B19, 63
B20, 62
B21, 65
B22, 71
A
1
2
3
4
5
6
7
8
A15
A16
A17
A18
A19
A20
A21
A22
5
6
7
8
2-MeC6H4NH2
4-MeOC6H4NH2
3-MeOC6H4NH2
3-ClC6H4NH2
4-BrC6H4NH2
4-IC6H4NH2
4-HOC6H4NH2
9
10
11
12
13
14
15
16
B8, 71
B9, 75
B10, 65
B11, 71
B12, 72
B13, 70
A8
A9
()-2-Naphthyl(Me)CHNH2
()-Ph(Et)CHNH2
PhNHCH2CH2NH2
pyrrolidine
piperidine
morpholine
A10
A11
A12
A13
A14
The reaction conditions tolerated free hydroxy
(A22) and halogen (Cl, Br, I in A19-A21) substituents.
The reactions o-substituted aniline A16 gave less
efficient formation of amide-thioamide product B16.
At this stage, we wanted to explore the flexibility in
installing two amine moieties to the malonic skeleton.
It should be noted that while the first step of ring
opening of maleic anhydride occurred spontaneously
and rapidly with a stoichiometric amount of aliphatic
and aromatic amines (< 5 min at rt for completion), the
second step of decarboxylative thioamidation required
an effective activation of sulfur by an aliphatic amine
and longer reaction time.
1,2,3,4-tetrahydroisoquinoline B14, 72
a Reaction performed at 60 °C. b Reaction performed at 40 °C
The same procedure could be applied successfully
to a range of primary aliphatic amines with increasing
steric hindrance on the branched alpha carbon atom
(A5-A9, entries 7-11). When enantiomerically pure
2
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10.1002/adsc.201900160
Advanced Synthesis & Catalysis
Based on this analysis, we could introduce two process
different amine moieties into the final malonic acid heterofunctionalization. [6d]
derived amide-thioamide at the expected positions by
of
decarboxylation
and
Since these nitrogen nucleophiles are weakly basic,
simply changing the order of addition of these amines. the presence of NMP was necessary. We emphasized
When the secondly added amine is aliphatic, the that although these heterocyclic products did not
decarboxylative
thioamidation
proceeded contain sulfur, their formation required stoichiometric
spontaneously at 50 °C. In cases of anilines, the amount of sulfur. Indeed, using only 0.5 equiv sulfur
presence of (NMP) was necessary to achieved the resulted in very low yield of the benzazole products.
expected transformation. Such strategy resulted in a When aliphatic diamines were used as the secondly
reasonable yield of product B23 from benzylamine A1 added amines, depending on the distance between two
and its 3-methoxy derivative A2 (Table 3, entry 1). By amino function, we could obtain the corresponding
simple changing the order of addition A2 then A1, cyclic amidine C7 or bis-thioamides D1-D2. In case of
isomeric product B24 was obtained in the same manner. ethylenediamine, due to its strong interaction with
Similar reaction with alkylamine(1)/alkylamine(2) sulfur, the reaction resulted in a complexed mixture in
(entries 3-4) or aniline/ alkylamine (entries 5-15) or which we could detect the presence of the expected
aniline(1)/aniline(2)
(entries
16-17)
or amidine C6.
alkylamine/aniline (entry 18) furnished a wide range of
products with high functional group tolerance
(halogens, ester, nitro, heterocycle, tertiary amine) and
high structural diversity.
Table 3. Reaction of two different amines with anhydride
maleic, sulfur and DMSO
entrya R/R1 - R2/R3
M, yield (%)
B23, 65
B24, 67
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16a
17a
18a
H/Bn - H/3-MeOC6H4CH2
H/m-MeOC6H4CH2 - H/Bn
H/p-ClC6H4CH2 - H/PhNH(CH2)2 B25, 63
n-Bu/n-Bu - H/Bn
H/o-MeOC6H4 - H/Bn
Me/Ph - H/Bn
H/2-FC6H4 - H/Bn
H/1-Naphthyl - H/Bn
H/m-MeO2CC6H4 - H/Bn
H/m-O2NC6H4 - H/Bn
H/3-Pyridyl - H/Bn
H/Ph - H/CH2CH2Ph
H/p-IC6H4 - H/ CH2CH2Ph
H/Ph - piperidino
B26, 64
B27, 68
B28, 71
B29, 68
B30, 62
B31, 61
B32, 62
B33, 65
B34, 70
B35, 65
B36, 69
B37, 73
B38, 63
B39, 59
B40, 56
a Without NMP. b Diamine (0.5 equiv) was used.
Scheme 2. Reaction of cyclizable amines
The structures of amide-thioamide malonic
derivatives B4 and B30 were confirmed
unambiguously by X-ray diffraction study as presented
in Figure 2.
H/Ph - morpholino
H/4-BrC6H4 - H/Ph
H/Ph - H/4-BrC6H4
H/Me2NCH2CH2CH2 - H/Ph
a NMP (99 mg, 1 mmol) as added if A’ is an aromatic aniline.
When the secondly added amine A’ was an aniline
bearing an o-cyclizable group such as OH or NH2, i.e.
o-aminophenols or o-phenylenediamine, the final
malonamide derivatives C1-C6 obtained did not
contain any thioamide moiety but a corresponding
benzazole ring in generally good yields (Scheme 2).
The formation of such heterocyclic compounds is
remarkable in view of low temperature of the whole
Figure 2. X-ray structures of B4 and B30
In both structures, the carbonyl and the thiocarbonyl
group are in a gauche conformation. The bonds N1–C2
and N2–C3 (averaged 1.315(2) Å, 1.320(2) Å resp.) are
still remarkably short, while the attached C=O
(1.242(2) Å, 1.226(2) Å resp.) and the C=S (1.677(2)
3
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10.1002/adsc.201900160
Advanced Synthesis & Catalysis
Å, 1.667(2) Å) bonds are slightly elongated. Bond DMSO-assisted oxidation of adduct v would yield the
lengths and angles around the central methylene final thioamide B. In case of 1,2-bis-nucleophiles such
carbon atom C1 are as expected (C–C averaged as o-aminophenols, the reaction of such nucleophiles
1.512(2) Å, 1.516(2) Å resp.; C–C–C 111.3(2)°, with thioaldehyde iv would give benzoxazoline vi,
109.5(2)° resp.).
readily oxidized to give the final benzoxazole vii. It
Finally, we extended our strategy to acrylic acids should be noted that a similar decarboxylative
E1-E3 bearing an electron-withdrawing group on the thioamidation of cinnamic acids with either aliphatic

position (Scheme 3). Similar reactivity of amines,[7] small N,N-dialkylformamide[8] or o-
decarboxylative thioamidation of the acrylic acid aminophenols[9] was described at higher temperatures
moiety was observed with monoethyl ester of either (80, 100 and 130 °C, respectively) with excess use of
maleic acid E1 as well as its E isomer fumaric acid E2 elemental sulfur as both sulfur source and oxidant. The
in the reaction with 2-phenethylamine and scope of such reaction is thus not applicable to amine
cyclohexylamine.
nucleophiles that can react with sulfur such as benzylic
Other cyclic aliphatic secondary amines ones. Favored by the presence of both carbonyl groups,
(pyrrolidine, morpholine) and aromatic amines (p- decarboxylative thioamidation in our case could occur
anisidine and o-aminophenol) reacted with acid E2 in at much lower temperature and undoubtedly
the similar manner. Although a Willgerodt reaction of compatible with a wide range of amines.
morpholine with the benzoyl moiety of acid E3 could
be potentially problematic, the expected product was
obtained in good yield.
a Reaction performed without NMP.
Scheme 4. Proposed Mechanism
Scheme 3. Reaction of -substituted acrylic acids
In summary, we have reported a multicomponent
Although the detailed mechanism is not fully
access to malonic acid derivatives starting with maleic
elucidated for the moment, based on the obtained
anhydride, elemental sulfur and amines in the presence
product structures as well as previous observations, we
of DMSO as oxidant under mild conditions.[10] The
suggest a possible reaction pathway (Scheme 4). The
method is characterized by its simplicity and a high
interaction of aliphatic amine A with cyclooctasulfur
level of structural diversification by simply varying the
could provide highly nucleophilic polysulfide I
amines as well as the order of amine addition. The
according to equation (1). In the presence of amine A,
transformation is highlighted by a decarboxylation at
anhydride maleic 1 is readily transformed into
temperature as low as 50 °C.[11] The generality of this
ammonium carboxylate ii via ring opening. Although
method was further demonstrated with other acrylate
the C=C bond of acrylate ii is substituted by two
derivatives -substituted by an electron withdrawing
electron withdrawing groups, its  position is more
group such as ester and ketone. Further exploration of
electrophilic since the carboxamide group is more
this decarboxylative heterofunctionalization of
electron attracting than the anionic carboxylate group.
carboxylic acids is underway in our laboratory and the
Consequently, addition of sulfur-amine complex i to
related results will be reported in due course.
maleate ii would provide regioselectively to give
succinate iii. Subsequent decarboxylative and
desulfurative deamination of iii would lead to
thioaldehyde iv. Addition of amine, followed by an
Experimental Section
4
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10.1002/adsc.201900160
Advanced Synthesis & Catalysis
Reaction with only one amine (Tables 1 and 2)
V. V. Dotsenko, S. G. Krivokolysko, Chem. Heterocycl.
Compd. 48, 2013, 1568.
Amine A (2 mmol) and DMSO (0.3 mL, 4.5 equiv) was
added to a 7-mL test tube containing solid anhydride maleic.
The resulting mixture was shaken vigorously with a vortex
mixer (0.5-1 min) to give a viscous pale yellow to brown
solution (in cases of some anilines, the dissolution of
anhydride maleic result in a slurry). Sulfur (40 mg, 1.25
mmol), N-methylpiperidine (99 mg, 1 mmol) (used for
aniline derivatives) and a magnetic stir bar were added. The
tube was closed with a septum, purged with Ar. An Ar
balloon was put on the top of the septum and the tube was
stirred at 50 °C for 16 h. The reaction mixture was purified
by column chromatography on silica gel (eluent
CH2Cl2:EtOAc 1:0 to 20:1 or CH2Cl2:MeOH:NH3).
[3] For selected examples, see: a) G. W. Spears, K. Tsuji, T.
Tojo, H. Nishimura, T. Ogino, J. Heterocycl. Chem.
2002, 39, 799; b) T. Tojo, G. W. Spears, K. Tsuji, H.
Nishimura, T. Ogino, N. Seki, A. Sugiyama, M. Matsuo,
Bioorg. Med. Chem. Lett. 2002, 12, 2427; c) P. Huang,
D. Xiang, Y. Zhou, Y. Liang, T. Na, D. Dong, Synthesis
2009, 1797; d) K. Janikowska, S. Makowiec, J. Rachon,
Hel. Chim. Acta 2012, 95, 461; e) F. Liang, Y. Li, D. Li,
X. Cheng, Q. Liu, Tetrahedron Lett. 2007, 48, 7938; f)
G. C. Nandi, M. S. Singh, H. Ila, H. Junjappa, Eur. J.
Org. Chem. 2012, 967; g) H. Takahata, K. Yamabe, T.
Yamazaki, Synthesis 1986, 1063.
Reaction with two amines (Table 3 and Schemes 2-3)
Amine A (1 mmol) and DMSO (0.3 mL, 4.5 equiv) was
added to a 7-mL test tube containing solid anhydride maleic.
The resulting mixture was shaken vigorously with a vortex
mixer (5 min) to give a viscous pale yellow to brown
solution (in cases of some anilines, the dissolution of
anhydride maleic result in a slurry). Amine A' (1 mmol),
sulfur (40 mg, 1.25 mmol), N-methylpiperidine (99 mg, 1
mmol) (used if A' is an aniline) and a magnetic stir bar were
added. The next step was performed as in the previous cases.
[4] For reviews on organic reactions involving elemental
sulfur, see: a) T. B. Nguyen, Adv. Synth. Catal. 2017, 359,
1066; b) T. B. Nguyen, Asian J. Org. Chem. 2017, 6, 477.
[5] T. B. Nguyen, L. Ermolenko, A. Almourabit, Org. Lett.
2012, 14, 4274.
[6] a) T. B. Nguyen, J. Cheung-Lung, Eur. J. Org. Chem.
2018, 5815; b) T. B. Nguyen, P. Retailleau, Org. Lett.
2018, 20, 186; c) T. B. Nguyen, P. Retailleau, Org. Lett.
2017, 19, 4858; d) T. B. Nguyen, P. Retailleau, Org. Lett.
2017, 19, 3887; e) T. B. Nguyen, L. Ermolenko,
M. Corbin, A. Almourabit, Org. Chem. Front. 2014, 1,
1157.
CCDC-1885231 and CCDC-1885232 (compounds B4 and
B30 respectively) contain contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[7] T. Guntreddi, R. Vanjari, K. N. Singh, Org. Lett. 2014,
16, 3624.
Acknowledgements
We thank ICSN-CNRS for financial support and Dr. A. Marinetti
(ICSN-CNRS) for her helpful support. We thank Institute of
Chemistry (VHH2018.01.04) for financial support for L. A. Nguyen.
[8] S. Kumar, R. Vanjari, T. Guntreddi, K.N. Singh
Tetrahedron 2016, 72, 2012.
[9] T. Guntreddi, R. Vanjari, S. Kumar, R. Singh, N. Singh,
P. Kumar, K. N. Singh, RSC Adv. 2016, 6, 81013.
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5
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10.1002/adsc.201900160
Advanced Synthesis & Catalysis
COMMUNICATION
Elemental Sulfur/DMSO-Promoted
Multicomponent One-pot Synthesis of Malonic
Acid Derivatives from Maleic Anhydride and
Amines
Adv. Synth. Catal. Year, Volume, Page – Page
Le Anh Nguyen, Pascal Retailleau and Thanh Binh
Nguyen*
6
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