Convergent integration of three self-sorting domino sequences: Three-component direct synthesis of 3-methylthio-4-aryl-maleimides from methyl ketones with acetonitrile and DMSO

Article abstract of DOI:10.1016/j.tetlet.2014.09.099

An I₂-promoted three-component coupling reaction was described for the construction of 3-(methylthio)-4-aryl-1H-pyrrole-2,5-diones from methyl ketones with acetonitrile and DMSO. This transformation involved the in situ generation and application of α-ketoimides. Furthermore, DMSO was converted to DMS in situ, which subsequently served as a methylthiolation reagent in the reaction. To the best of our knowledge, this protocol provided the first known example of convergent integration of three self-sorting domino sequences.

Full text of DOI:10.1016/j.tetlet.2014.09.099

Accepted Manuscript
Convergent integration of three self-sorting domino sequences: three-compo-
nent direct synthesis of 3-methylthio-4-aryl-maleimides from methyl ketones
with acetonitrile and DMSO
Qinghe Gao, Shan Liu, Xia Wu, Anxin Wu
PII:
S0040-4039(14)01614-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.099
TETL 45193
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 July 2014
17 September 2014
22 September 2014
Please cite this article as: Gao, Q., Liu, S., Wu, X., Wu, A., Convergent integration of three self-sorting domino
sequences: three-component direct synthesis of 3-methylthio-4-aryl-maleimides from methyl ketones with
acetonitrile and DMSO, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.09.099
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sequences: three-component direct synthesis of
3-methylthio-4-aryl-maleimides from methyl ketones
with acetonitrile and DMSO
Qinghe Gao, Shan Liu, Xia Wu, and Anxin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China

1
Tetrahedron Letters
journal homepage: www.els evier.com
Convergent integration of three self-sorting domino sequences: three-component
direct synthesis of 3-methylthio-4-aryl-maleimides from methyl ketones with
acetonitrile and DMSO
Qinghe Gao, Shan Liu, Xia Wu, and Anxin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
An I2-promoted three-component coupling reaction was described for the construction of 3-
(methylthio)-4-aryl-1H-pyrrole-2,5-diones from methyl ketones with acetonitrile and DMSO.
This transformation involved the in situ generation and application of α-ketoimides.
Furthermore, DMSO was converted to DMS in situ, which subsequently served as a
methylthiolation reagent in the reaction. To the best of our knowledge, this protocol provided
the first known example of convergent integration of three self-sorting domino sequences.
Received in revised form
Accepted
Available online
Keywords:
Convergent integration
Self-sorting
2009 Elsevier Ltd. All rights reserved.
Maleimides
1. Introduction
Thioethers are common functionalities in many biologically
active compounds.5 Among them, methyl aryl sulfides have
attracted much attention due to widespread existence in nature.6
As a consequence, the preparation of aryl methyl thioethers
usually involves the reduction of sulfoxides,7 and the direct or
heteroatom-facilitated lithiation of aromatic C–H bonds followed
by electrophilic substitution with dimethyl disulfide.8 Recently,
Ma and co-workers reported their successes in methylthiolation
In recently years, many novel and versatile synthetic strategies
have been proposed and utilized to generate a diverse range of
valuable target molecules.1 In particular, the in situ trapping of
unstable intermediates via linear domino reactions has become a
major topic of research interest, due to their high reactivity and
ease of transformation to miscellaneous novel structures.2
Recently, we reported an efficient in situ cross-trapping strategy,3
and several groups were involved and many synthetically useful
procedure using aryl iodines and sulfur by
a multistep
transformation.9 Qing10a and Cheng10b independently described
the direct use of DMSO as the reagent for copper-mediated
methylthiolation. Very recently, Yu et al. also achieved
methylthiolation of heteroarenes with DMSO by using AgF as
catalyst and Cu(OAc)2 as mediator/oxidant.10c Inspired by our
previous work,11 the methylthiolation using DMSO as the
terminal methylthiolation source is described here.
transformations have been reported4 (Scheme 1a). As
a
continuation of our work, we envisioned that substrates could be
simultaneously involved in three different domino sequences,
with the in situ trapping of respectively generated intermediates
converging on the desired product (Scheme 1b). We report herein
an I2-promoted three-component coulping reaction of methyl
ketones with acetonitrile and DMSO to construct 3-(methylthio)-
4-aryl-1H-pyrrole-2,5-diones via convergent integration of three
self-sorting domino sequences.
Recently, the construction of α-ketoamides has been developed
via oxidative coupling of RH with NH of amines.12 However, in
contrast to NH of amines, the weak nucleophilicity especially
−H of amides,13
free
N
have not been well investigated.
Pleasingly, our research established that methyl ketones could be
converted in situ to the corresponding α-ketoaldehydes in the
presence of I2 and DMSO. It was envisaged that the higher
reactivity in the aldehyde of 2-oxoaldehyde could facilitate the
cross-trapping of an in situ formed acetamide from acetonitrile to
afford α-ketoimides. Subsequently, direct α-Csp3–H bonds
activation of α-ketoimides could trap DMS generated in situ from
DMSO to realize an annulation in one-pot (Scheme 2). This work
provided the first known example of metal-free cross-
coupling/annulation of methyl ketones with acetonitrile and
Scheme 1. In situ trapping strategies.
———
* Corresponding author. Tel./fax: +86 027 6786 7773; e-mail: chwuax@mail.ccnu.edu.cn (A. Wu)

2
Tetrahedron Letters
DMSO via α-ketoimides generation and application in situ has
been developed.
coupling reaction thus used a variety of Brønsted acid and base
catalysts. Unfortunately, they were found unable to effectively
promote the reaction (Table 1, entries 10−20). Finally, a range of
different temperatures were examined for improved yield (Table
o
1, entries 21–24), and 110 C was determined as optimal for the
cascade reaction.
With the optimized conditions in hand, the generality and
scope of the molecular iodine-promoted direct synthesis of
maleimides was subsequently explored. To our delight, the
reaction demonstrated a wide scope for the structure of aromatic
ketones (Table 2). Aryl methyl ketones bearing electron-neutral
(4-H, 4-Me), electron-rich (4-OMe, 3-OMe, 2-OMe, 3,4-OCH2O,
3,4-OCH2CH2O), and electron- deficient (4-NO2, 3-NO2, 4-Ph)
groups were directly converted into the corresponding products
in moderate to good yields (31–82%; 3a–j). The electronic and
steric nature of the aromatic ketones was shown to influence the
reaction efficiency. Much to our satisfaction, the optimized
conditions also demonstrated good compatibility with aromatic
ketones bearing halogen substituents (4-F, 4-Cl, 4-Br, 3,4-Cl2),
with the corresponding products 3k–n being obtained in 45–68%
yields. Notably, 2-naphthyl methyl ketone and 1-naphthyl methyl
ketone also reacted smoothly under the optimized conditions to
provide 3o and 3p in 72 and 24% yields, respectively. Moreover,
the reactions conditions were successfully applied to several
heteroaryl ketones, including thienyl, benzofuryl, and indolyl
ketones, which provided the desired products in moderate to
good yields (59–70%; 3q–s).
Scheme 2. Design strategy: α-ketoimides generation and application in
situ.
2. Results and discussion
The reaction of acetophenone (1a) with acetonitrile (2) was
selected as a model reaction to assess the feasibility of our new
strategy. When acetophenone (1a) was reacted with acetonitrile
(2) in the presence of I2 in DMSO at 100 °C, the direct annulation
reaction occurred to afford the expected 3-(methylthio)-4-phenyl-
1H-pyrrole-2,5-dione (3a)14 in 37% yield. This result was
unambiguously confirmed by X-ray crystallography (Supporting
Information, Figure S4).15 Increased amounts of 2a to 15 equiv
provided 3a in 73% yield (Table 1, entry 4). However, further
increases in the amount of I2 did not provide any additional
increases in the yield. And it was determined that the reaction
could not occur in the absence of I2 (Table 1, entry 9), which
suggested that I2 played an important role in the reaction.
Generally, the in situ hydration of the nitrile group is performed
in the presence of Brønsted acid or base. In this work, the
Table 2. Scope of methyl ketonesa
Table 1. Optimization of the reaction conditionsa
Entry
1 (R)
3
Yieldsb (%)
1
2
1a (C6H5)
3a
3b
3c
3d
3e
3f
82
45
76
40
31
77
43
41
42
65
45
62
68
67
72
24
68
70
59
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (3-MeOC6H4)
1e (2-MeOC6H4)
1f (3,4-OCH2OC6H3)
1g (3,4-OCH2CH2OC6H3)
1h (4-NO2C6H4)
1i (3-NO2C6H4)
1g (4-PhC6H4)
I2
Temp
Yield
Entry
Acid
Base
(equiv)
1.5
1.5
1.5
1.5
0.5
1.0
1.2
2.0
−
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
(oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
(%)b
37
42
64
73
< 5
35
64
74
0
3
1
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
4
2c
5
3d
4e
6
5e
7
3g
3h
3i
6e
8
7e
8e
9
9e
−
CF3SO3H
PTSA
HOAc
CH3SO3H
TFA
H2SO4
10
11
12
13
14
15
16
17
18
19
3j
10e
11e
12e
13e
14e
15e
16e
17e
18e
19e
20e
21e
22e
23e
24e
56
45
60
41
42
54
< 10
< 5
0
0
0
0
71
82
81
1k (4-FC6H4)
3k
3l
1l (4-ClC6H4)
1m (4-BrC6H4)
1n (3,4-Cl2C6H3)
1o (2-Naphthyl)
1p (1-Naphthyl)
1q (3-Thienyl)
3m
3n
3o
3p
3q
3r
3s
−
DIPEA
DBU
Et3N
K3PO4
NaHCO3
−
−
−
−
−
−
−
−
−
−
1r (2-Benzofuryl)
1s (3-Indolyl)
a Reaction conditions: 1 (0.5 mmol), 2 (7.5 mmol), and I2 (0.75 mmol)
−
−
−
90
110
120
in DMSO (2 mL) at 110 oC.
b Isolated yields.
a Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), acid or base (0.5 mmol),
To improve the practicability of this protocol, acetimidamide
hydrochloride was evaluated as a source of acetamide through
the procedure. Using 200 mol% acetimidamide hydrochloride, 3a
was obtained in 53% yield accompanying another product 2-oxo-
2-phenylacetamide (5a) in 38% yield. It was supposed that 5a
DMSO (2 mL).
b Isolated yields.
c2 (2.5 mmol).
d2 (5.0 mmol).
e2 (7.5 mmol).

3
was formed by a hydrolysis reaction in the presence of excessive
HCl. Several aryl methyl ketones were subjected to the procedure
and the corresponding products were repeatedly obtained in
reasonable yields after slight adjustments to the reaction
conditions (Table 3).
Table 3. Scope of methyl ketonesa
Entry
1 (R)
3
Yieldsb (%)
1
2
3
4
5
6
7
1a (C6H5)
3a
3b
3c
53
55
48
45
78
64
57
1b (4-MeC6H4)
1c (4-MeOC6H4)
1h (4-NO2C6H4)
1m (4-BrC6H4)
1o (2-Naphthyl)
1q (3-Thienyl)
3h
3m
3o
3q
a Reaction conditions: 1 (0.5 mmol), 4 (1.0 mmol), and I2 (0.75 mmol)
in DMSO (2 mL) at 110 oC.
b Isolated yields.
Scheme 3. The controlled experiments.
A series of control experiments were performed to gain some
insights into the mechanism. First, -iodo acetophenone (1aa) and
hydrated hemiacetal (1ab) were subjected to the standard
conditions to provide 3a in 76 and 17% yields, respectively
(Scheme 3a and 3b). The reaction of 1ab with acetamide (2aa)
was performed under standard conditions to obtain the desired
product 3a in good yield (Scheme 3c). Phenacyl iodine (1aa),
phenylglyoxal (1ac) and acetamide (2aa) were thus confirmed as
key intermediates in this transformation. However, 3a was not
provided with the application of the standard conditions to 2-
iodoacetamide (2ab) (Scheme 3d), which indicated that 2-
iodoacetamide (2ab) was not an intermediate in this reaction
process. Furthermore, B converted to the desired product 3a in
excellent yields under the standard conditions (Scheme 3e). This
indicated that the reaction incorporated the oxidative amidation
of acetophenone (1a) with acetamide (2aa). Finally, DMSO-d6
examined to explore the potential role of DMSO in the
methylthiolation process. DMSO was supported as
methylthiolation source by a deuterium labeling experiment
(Scheme 3f), where the partially deuterated product 3c-d3 was
generated from DMSO-d6.
Scheme 4. The possible mechanism.
Based on our preliminary results and previous works,16
a
3. Conclusion
possible mechanism was proposed for the iodine-promoted
cascade annulation reaction of acetophenone (1a) with
acetonitrile (2) (Scheme 4). Where, substrate 1a would be
converted to α-iodo acetophenone (1aa) in the presence of I2. The
subsequent oxidation of 1aa by DMSO would provide
phenylglyoxal (1ac). Then, the reaction between the aldehyde
group of phenylglyoxal (1ac) and the in situ formed acetamide
(2aa) from the hydrolysis of acetonitrile (2) would afford A,
which would be rapidly oxidized by I2 to produce α-ketoimide
B.17 Subsequent enolization would provide isomer B', which
would afford N-(2-iodoacetyl)-2-oxo-2-phenylacetamide (C) in
the presence of I2.18 Compound C would react with DMS
generated in situ from the reduction of DMSO11 to provide
dimethyl(2-oxo-2-(2-oxo-2-phenylacetamido)ethyl)sulfonium
iodine (D). After the loss of MeI, compound D would then
undergo an intramolecular aldol-type condensation reaction to
produce 3-hydroxy-4-(methylthio)-3-phenylpyrrolidine-2,5-dione
(E), which would subsequently undertake a dehydration reaction
to yield 3a.
In summary, an I2-promoted three-component cross-
coupling/annulation reaction has been described for the
construction of 3-(methylthio)-4-aryl-1H-pyrrole-2,5-diones from
methyl ketones with acetonitrile and DMSO. Initial studies of the
mechanism have suggested that this reaction occurred via
convergent integration of three self-sorting domino sequences.
Notably, the DMS generated in situ from DMSO served as a
methylthiolation reagent. More importantly, this metal-free
transformation integrated the in situ generation and application of
α-ketoimides. Further explorations of this strategy will be
reported in due course.
Acknowledgments
We thank the National Natural Science Foundation of China
(Grant 21032001 and 21272085). We also thank Dr. Xianggao
Meng for his help with X-ray diffraction analysis and Dr.
Chuanqi Zhou, Hebei University, for analytical support.

4
Tetrahedron Letters
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Supplementary Material
Evidence in support of the hypothetic mechanism, and 1H and
13C NMR spectra and X-ray crystal data for 3a. Supplementary
data related to this article can be found online at doi:
7. For selected examples, see: (a) Bahrami, K.; Khodaei, M. M.;
Karimi, A.; Synthesis 2008, 2543; (b) Khurana, J. M.; Sharma, V.
S.; Chacko, A. Tetrahedron 2007, 63, 966; (c) Harrison, D. J.;
Tam, N. C.; Vogels, C. M.; Langler, R. F.; Baker, R. T.; Decken,
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