Unexpected behavior of the reaction between acyl thioformanilides and acetonitrile derivatives-a useful entry to new penta-substituted dipyrrole disulfides

Article abstract of DOI:10.1016/j.tetlet.2009.09.020

A convenient and unexpected synthesis of penta-substituted dipyrrole disulfides starting from readily available acyl thioformanilides and acetonitrile derivatives has been developed. The overall process leads to the creation of two C-C bonds, two C-N bond

Full text of DOI:10.1016/j.tetlet.2009.09.020

Tetrahedron Letters 50 (2009) 6247–6251
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected behavior of the reaction between acyl thioformanilides
and acetonitrile derivatives—a useful entry to new penta-substituted
dipyrrole disulfides
a
a
b,
*
Ming Li a, Guo-Rui Cao a, Jing-Wei Zhao a,b, Li-Rong Wen a, , Yong-Jun Liu , Ya-Mu Xia , Shi-Zheng Zhu
*
a Key Laboratory of Eco-Chemical Engineering, Ministry of Education, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2009
Revised 2 September 2009
Accepted 3 September 2009
Available online 6 September 2009
A convenient and unexpected synthesis of penta-substituted dipyrrole disulfides starting from readily
available acyl thioformanilides and acetonitrile derivatives has been developed. The overall process leads
to the creation of two C–C bonds, two C–N bonds, and one S–S bond with the concomitant formation of
two pyrrole rings and disulfide from the fact that only two reagents need to be mixed together, and it
complements the existing pyrrole disulfides chemistry.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Disulfide
Pyrrole
S–S coupling
Thioformanilide
The S–S bond functional group exists not only in proteins,
but also in numerous natural products.1 Modern methods for
the formation of S–S bond are required for the synthesis of
many biologically active compounds involved in chemical and
biological processes. The pyrrole core is a structural motif of
particular interest in the fields of natural products, medicinal
chemistry, and material science.2 A variety of synthetic methods
for the preparation of disulfides3 and pyrroles4 have been devel-
oped owing to their wide range of activities and importance.
Surprisingly, there are only two examples bearing both charac-
teristic groups together that have been employed to give dipyr-
rol disulfides.5 However, these methods suffer from high
toxicity, low overall yields, and relatively inaccessible starting
materials used.
ior makes it an important candidate for developing a new synthetic
strategy in medicinal and material chemistries.
In connection with our methodology of ongoing project on the
development of novel heterocyclic compounds,7 we had occasion
to examine the cross-condensation of 1 with acetonitrile deriva-
tives. Surprisingly, a new type of penta-substituted dipyrrole disul-
fides 4 was found as a major product along with the formation of a
small amount of the monosulfides 5. The products 4 were easily
separated from 5 by recrystallization or flash chromatography
(Scheme 1).
So far, to the best of our knowledge, there have been no reports
on the synthetic application of acyl thioformanilides 1 with aceto-
nitrile derivatives. The results of our studies, which led to an
unprecedented synthesis of penta-substituted dipyrrole disulfides,
are presented herein.
In initial studies, we first envisioned the reaction of the precur-
sor 2-oxo-N,2-diphenylethanethioamide 1a with ethyl 2-cyanoac-
etate 2 in the presence of base at room temperature. Notably, the
reaction of the anion of 2 with 1a regioselectively affords a novel
and unexpected hydroxylated product 3a, ethyl 2-amino-4-hydro-
xy-1,4-diaryl-5-thioxo-4,5-dihydro-1H-pyrrole-3-carboxylate, but
not the corresponding dehydrated product. The intermediate 3a
was subsequently characterized by IR, 1H NMR, 13C NMR, HMBC,
HMQC, and MS analysis.8
Acyl thioformanilides 16 are versatile building blocks in organic
synthesis owing to their ready accessibility and good reactivity.
The chemical properties of precursors 1 are determined by the four
active centers. Two nucleophilic centers are localized on the het-
eroatoms, the other two electrophilic centers are associated with
the carbon atoms of carbonyl and thiocarbonyl groups. This behav-
* Corresponding authors. Tel.: +86 532 84022990; fax: +86 532 84023927
(L.-R.W.); tel.: +86 021 54925185; fax: +86 021 64166128 (S.-Z.Z.).
E-mail addresses: wenlirong@qust.edu.cn (L.-R. Wen), zhusz@mail.sioc.ac.cn
(S.-Z. Zhu).
Interestingly, the unexpected compounds bis(2-amino-1,4-di-
phenyl-3-ethoxycarbonyl-1H-pyrrole-5-yl)disulfide 4a and bis(2-
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.020

6248
M. Li et al. / Tetrahedron Letters 50 (2009) 6247–6251
R1
O
OH
*
R2
H
S
N
ethanol 15 mL
CN
R1
N
NaOH 20 mmol% RT
S
COOEt
EtOOC
R2
NH2
2
1
3
AcOH 2mL
MW 400 W 78 ºC
R2
NH2
R2
NH2
COOEt
R1
N
COOEt
N
R1
S
S
R1
R1
S
N
N
EtOOC
EtOOC
R2
NH2
R2
NH2
4
5
Scheme 1. Couplings of acyl thioformanilide 1 with ethyl 2-cyanoacetate 2 to disulfides.
5b
4b
Figure 1. The structures of compounds 4b and 5b. Displacement ellipsoids are drawn at the 30% probability level.
Table 1
One-pot reactions to obtain disulfidesa
R2
CN
COOEt
O
O
R2
H
RT
1. 20 mmol% NaOH
2. AcOH, MW
R1
O
N
CN
4
R1
S
COOEt
N
OEt
2
1
NH2
6
Entry
1
R1
R2
Time
Product (yield, %)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
2.5 hb, 5 minc
1.5 hb, 5 minc
2 hb, 5 minc
2 hb, 5 minc
3 hb, 5 minc
3 hb, 5 minc
2 hb, 5 minc
0.5 hb, 3 minc
4.5 hb, 5 minc
0.4 hb, 5 minc
5 hb, 5 minc
5 hb, 5 minc
4a (46) 6a (8)
p-F
p-Cl
p-Br
p-OCH3
p-CH3
o-F
p-F
p-F
p-Cl
p-CH3
p-CH3
4b (53) 6b (trace)
4c (51) 6c (10)
4d (49) 6d (trace)
4e (41) 6e (8)
4f (43) 6f (9)
4g (34) 6g (trace)
4h (55) 6h (7)
4i (45) 6i (6)
4j (54) 6j (trace)
4k (31) 6k (trace)
4l (28) 6l (4)
p-OCH3
p-NO2
p-OC2H5
p-OC2H5
p-Cl
10
11
12
1j
1k
1l
a
b
c
Reaction condition: acyl thioformanilide (3 mmol), ethyl 2-cyanoacetate (3 mmol), EtOH (15 mL), catalyst.
The first step, 20 mmol % NaOH, rt.
The second step, AcOH, MW, 400 W, 60 °C.

M. Li et al. / Tetrahedron Letters 50 (2009) 6247–6251
6249
Encouraged by this successful transformation from 3a to 4a, we
tested this protocol for the synthesis of other disulfide derivatives
using various 1 and 2. The results showed that all reactions pro-
duced penta-substituted dipyrrole disulfides 4 as the major prod-
uct along with the formation of
a small amount of the
monosulfides 5. The structures of 4b, 4h, and 5b were confirmed
by X-ray crystallographic analysis (Fig. 1).
From a synthetic point of view, one-pot procedures begin-
ning with simple substrate provide ideal strategies for the for-
mation of target molecules. In order to improve the yields of
the disulfides 4, we attempted to combine the two-step reac-
tions in a one-pot sequence without the isolation of intermedi-
ates 3.
At the end of the condensation of 1 with 2, acetic acid (2 mL)
was added to the mixture solution under microwave irradiation.
Similarly, the desired products 4 were the major products with
higher yields, but an unexpected white solid, ethyl 2-amino-4-(1-
cyano-2-ethoxy-2-oxoethyl)-5-oxo-1,4-diaryl-4,5-dihydro-1H-
pyrrole-3-carboxylates 6, and ABB03CR9 products were formed as
the minor adducts, which correspond to the reaction of the remain-
ing 2 with 3 (Table 1). The structural determination of 6l was
achieved following their spectral data and X-ray single crystal dif-
fraction analysis (Fig. 2).
6l
Figure 2. The structure of compound 6l. Displacement ellipsoids are drawn at the
30% probability level.
amino-1,4-diphenyl-3-ethoxycarbonyl-1H-pyrrole-5-yl) monosul-
fide 5a were obtained when acetic acid (2 mL) was added to 3a under
conventional heating, but the yields were only 27% and 3%,
respectively.
The effect of solvents (C2H5OH, CH3OH, CH3CN, THF, and
DMSO) was investigated using the reaction of 1a and 2 as mod-
el reaction by employing 20 mmol % NaOH as the catalyst. The
results showed that C2H5OH is the best solvent. We attempted
to change the amount of NaOH, and use of 20 mmol % NaOH
relative to acyl thioformanilide was the best choice. Moreover,
NaOH was the most effective catalyst compared to another
two bases, Et3N and Na2CO3. Another two acids 10% HCl and
ZnCl2 for the second step were also tested, but the yields of
disulfide 4a were only 20% and 23%, respectively, lower than
that in acetic acid.
As shown in Table 1, the methodology was tolerant of a vari-
ety of electronically different para substituents (Table 1, entries
1–6) to compounds 1. Different derivatives of 1 with a variety
of different R1 and R2 substituents were also submitted to reac-
tion conditions to consistently provide the corresponding disul-
fides (Table 1, entries 8–12). Notably, for substrates 1 with an
electron-withdrawing R1 group and an electron-donating R2
group, the desired disulfides were afforded in higher yields and
shorter time (Table 1, entries 8 and 10).
The simplicity of the described reaction prompted us to explore
the scope and generality of this reaction. We further chose to
Table 2
One-pot couplings of acyl thioformanilide 1 with malononitrile 7a
R2
NH2
CN
N
O
H
N
O
H
R1
R2
R1
R2
S
S
R1
N
CN
CN
ethanol
R1
NC
CN
S
N
NC
R2
NH2
1
7
9
8
Entry
1
R1
R2
Time
Product (yield, %)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
H
H
H
5 hb, 5 minc
2 hd, 5 minc
10 mine
5 minf
8a (30) 9a (trace)
8a (35) 9a (trace)
8a (50) 9a (trace)
8a (38) 9a (trace)
8b (56) 9b (12)
8c (54) 9c (trace)
8d (52) 9d (10)
8e (43) 9e (10)
8f (46) 9f (trace)
8h (58) 9h (8)
p-F
p-Cl
p-Br
p-OCH3
p-CH3
p-F
10 mine
5 mine
15 mine
20 mine
15 mine
10 mine
10
1h
p-OCH3
a
b
c
d
e
f
Reaction condition: acyl thioformanilide (3 mmol), malononitrile (3 mmol), solvent (15 mL).
The first step, 0.2 equiv NaOH, ꢀ20 °C.
The second step, MW, 400 W, 60 °C, acetic acid (2 mL).
0.5 equiv NaOH, ꢀ20 °C.
1 equiv NaOH, ꢀ20 °C.
1.5 equiv NaOH, ꢀ20 °C.

6250
M. Li et al. / Tetrahedron Letters 50 (2009) 6247–6251
investigate the reactions of 1 with malononitrile 7 at low temper-
ature (ꢀ20 °C) (Table 2).
featuring a hydroxy group at the a-position of thiocarbonyl
group, is essential for this reaction to take place. Then, interme-
diate 3 might undergo a [1,3] hydroxyl migration to form the
pyrrole sulfenic acid C, which could not be trapped because of
its high reactivity, but it has been implicated as key intermedi-
ate in a wide variety of reactions including biological transfor-
Interestingly, when 1 equiv of NaOH was added to the solution
of 1 and 7, disulfides 8 were directly obtained from the mixture
with moderate yield of 50% without the addition of acetic acid.
However, the minor amount of H2S-released adducts 2-(2-oxo-
2-aryl-1-(arylamino) ethylidene)malononitriles 9 was also ob-
served, but the monosulfides were not observed. The structure
of 8a was confirmed by X-ray single crystal diffraction analysis
(Fig. 3).
mation.10 Finally, the sulfenic acids
C
are converted to
dimmers 4 by releasing of hydrogen peroxide according to the
results reported by Davis et al.11 Although we have not estab-
lished the mechanism of this reaction in an experimental man-
ner, it actually provides an efficient and unusual synthetic
entry into a new class of penta-substituted dipyrrole disulfides
based on the reaction of acyl thioformanilides and acetonitrile
derivatives.
In conclusion, we have characterized and determined the
structure of a highly unusual and quite unexpected products of
a simple reaction that result in the formation of elaborate sub-
structures, namely, the disulfide moiety and pyrrole structure
motif systems. The process, which leads to the creation of two
C–C bonds, two C–N bonds, and one S–S bond with the concom-
itant formation of two pyrrole rings and disulfide from the fact
that only two reagents need to be mixed together, complements
the existing pyrrole and disulfides chemistries. Although the reac-
tion yields are moderate, it is an entirely new approach for the
conversion of acyl thioformanilides and active methylene com-
pounds into a novel penta-substituted dipyrrole disulfides struc-
tural motifs. Effort is in progress to elucidate further the
mechanistic details of these reactions and understand their scope
and limitations.
A possible mechanism for this reaction is proposed in Scheme
2. Firstly, a proton of ethyl 2-cyanoacetate 2 is deprived by
NaOH to produce a carbon nucleophilic center A, which attacks
the carbon of carbonyl group of 1 to give B. An intramolecular
cyclization is conducted by nucleophilic attack of the nitrogen
in B to the triple bond in the CN group, then rearrangement
leads to the isolated 3, which as a highly reactive intermediate,
Acknowledgments
Financial support from the National Natural Science Foundation
of China (No. 20872074) and Natural Science Foundation of Shan-
Figure 3. The structure of compound 8a. Displacement ellipsoids are drawn at the
30% probability level.
EtOH
O
H
N
OH
S
R1
R1
OH
S
R2
R1
S
HN
1
N
EtOOC
EtOOC
O
O
R2
H
CN
CN
NH
R2
OH
N
O
O
H-OH
2
B
A
R1
OH
R1
S
N
S OH
1
OH2
R
S
- H
+ H
N
EtOOC
EtOOC
N
EtOOC
NH2
R2
NH2
R2
R2
NH2
C
3
R2
NH2
COOEt
R1
R1
R1
EtOOC
OH
N
S
S
S
R1
N
N
S
- OH
EtOOC
R2
R2
NH2
NH2
N
EtOOC
R2
3
NH2
4
Scheme 2. Possible mechanism for coupling of acyl thioformanilides with ethyl 2-cyanoacetate to disulfides 4.

M. Li et al. / Tetrahedron Letters 50 (2009) 6247–6251
6251
12366–12367; (d) Tejedor, D.; González-Cruz, D.; García-Tellado, F.; Marrero-
Tellado, J.; López Rodríguez, M. J. Am. Chem. Soc. 2004, 126, 8390–8391; (e)
Misra, N. C.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72, 1246–1251.
5. (a) Jagodzinski, T. S.; Sohicki, J.; Jagodzinska, E. J. Prakt. Chem. 1996, 338, 578–
580; (b) Adhikari, R.; Jones, D.; LiepaA, A. J.; Mackay, M. F. Aust. J. Chem. 1999,
52, 63–67.
dong Province (No. Y2006B11 and Z2008B03) is gratefully
acknowledged.
Supplementary data
´
6. (a) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197–227; (b) Adiwidjaja, G.; Gunther,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.020.
H.; Voss, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 563–568; (c) Liu, B.; Davis, R.;
Joshi, B.; Reynolds, D. W. J. Org. Chem. 2002, 67, 4595–4598; (d) Coleman, C. M.;
MacElroy, J. M. D.; Gallagher, J. F.; O’Shea, D. F. J. Comb. Chem. 2002, 4, 87–93;
(e) Mu, X. J.; Zou, J. P.; Zeng, R. S.; Wu, J. C. Tetrahedron Lett. 2005, 46, 4345–
4347; (f) Adiwidjaja, G.; Gunther, H.; Jurgen, V. Liebigs Ann. Chem. 1983, 116–
120; (g) Bose, D.; Idrees, M. Tetrahedron Lett. 2007, 48, 669–672.
7. (a) Wen, L. R.; Sun, J. H.; Li, M.; Sun, E. T.; Zhang, S. S. J. Org. Chem. 2008, 73,
1852–1863; (b) Li, M.; Sun, E. T.; Wen, L. R.; Sun, J. H.; Li, Y. F.; Yang, H. Z. J.
Comb. Chem. 2007, 9, 903–905; (c) Li, M.; Zuo, Z. Q.; Wen, L. R.; Wang, S. W. J.
Comb. Chem. 2008, 10, 436–441; (d) Li, M.; Yang, W. L.; Wen, L. R.; Li, F. Q. Eur. J.
Org .Chem. 2008, 16, 2751–2758.
References and notes
1. (a) Mealli, C.; Ienco, A.; Poduska, A.; Hoffmann, R. Angew. Chem., Int. Ed. 2008,
47, 2864–2868; (b) Block, E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135–1178;
(c) Takada, T.; Barton, J. K. J. Am. Chem. Soc. 2005, 127, 12204–12205; (d) Na, Y.;
Wang, S.; Kohn, H. J. Am. Chem. Soc. 2002, 124, 4666–4677; (e) Roy, B.;
Chambert, S.; Lepoivre, M.; Aubertin, A.-M.; Balzarini, J.; Dcout, J.-L. J. Med.
Chem. 2003, 46, 2565–2568; (f) Wang, W.; Wang, L. Q.; Palmer, B. J.; Exarhos, G.
J.; Li, A. D. Q. J. Am. Chem. Soc. 2006, 128, 11150–11159; (g) Witt, D. Synthesis
2008, 16, 2491–2509.
2. (a) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238–6241; (b) Fürstner, A. Angew.
Chem. 2003, 115, 3706–3728; (c) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc.
2004, 126, 468–469.
3. (a) Dhar, P.; Ranjan, R.; Chandrasekaran, S. J. Org. Chem. 1990, 55, 3728–3729;
(b) Carril, M.; SanMartin, R.; Domínguez, E.; Tellitu, I. Green Chem. 2007, 9, 315–
317; (c) Fang, X. Q.; Bandarage, U. K.; Wang, T. S.; Schroeder, J. D.; Garvey, D. S.
J. Org. Chem. 2001, 66, 4019–4021; (d) Sonavane, S. U.; Chidambaram, M.;
Almog, J.; Sasson, Y. Tetrahedron Lett. 2007, 48, 6048–6050; (e) Christoforou, A.;
Nicolaou, G.; Elemes, Y. Tetrahedron Lett. 2006, 47, 9211–9213.
8. The 13C NMR, HMBC, HMQC spectra clearly showed the presence of nineteen
carbons with one methyl, one methylene, and seventeen quaternary carbons,
and the mass spectra displayed molecular ion peak at the appropriate m/z
value.
9. (a) Tejedor, D.; García-Tellado, F. Chem. Soc. Rev. 2007, 36, 484–491; (b) Tejedor,
D.; Santos-Expósitoab, A.; García-Tellado, F. Chem. Commun. 2006, 2667–2669;
(c) Janvier, P.; Bois-Choussy, M.; Bienaymé, H.; Zhu, J. P. Angew. Chem. 2003,
115, 835–838.
10. (a) Davis, F. A.; Billme, R. L. J. Am. Chem. Soc. 1981, 103, 7016–7018; (b) Goto, K.;
Holler, M.; Okazaki, R. J. Am. Chem. Soc. 1997, 119, 1460–1461; (c) Nagy, P.;
Ashby, M. T. J. Am. Chem. Soc. 2007, 129, 14082–14091; (d) Graber, D. R.; Morge,
R. A.; Sih, J. C. J. Org. Chem. 1987, 52, 4620–4622; (e) Denu, J. M.; Tanner, K. G.
Biochemistry 1998, 37, 5633–5642.
4. (a) López-Pérez, A.; Robles-Machín, R.; Adrio, J.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2007, 46, 9261–9264; (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed.
2008, 47, 2836–2839; (c) Cyr, D. J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129,
11. Davis, F. A.; Jenkins, R. H. J. Am. Chem. Soc. 1980, 102, 7967–7969.