Gem-Dialkylthio vinylallenes: Alkylthio-regulated reactivity and application in the divergent synthesis of pyrroles and thiophenes

Article abstract of DOI:10.1039/c2cc33857b

gem-Dialkylthio vinylallenes were obtained for the first time and applied to the divergent synthesis of fully-substituted pyrroles and thiophenes by domino cyclizations. These two cyclization pathways were regulated by alkylthio groups. Plausible reaction

Full text of DOI:10.1039/c2cc33857b

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gem-Dialkylthio vinylallenes: alkylthio-regulated reactivity and
application in the divergent synthesis of pyrroles and thiophenesw
Zhongxue Fang,a Haiyan Yuan,a Ying Liu,a Zixun Tong,a Huiqin Li,a Jin Yang,a
Badru-Deen Barry,a Jianquan Liu,a Peiqiu Liao,a Jingping Zhang,*a Qun Liu*a and Xihe Bi*ab
Received 30th May 2012, Accepted 12th July 2012
DOI: 10.1039/c2cc33857b
gem-Dialkylthio vinylallenes were obtained for the first time and
applied to the divergent synthesis of fully-substituted pyrroles
and thiophenes by domino cyclizations. These two cyclization
pathways were regulated by alkylthio groups. Plausible reaction
mechanisms were presented and supported by DFT calculations.
An unprecedented metal-free carbothiolation was discovered in
the formation of thiophenes.
of gem-dialkylthiopenten-4-ynes;9 (2) unique structural feature
integrating ketene dithioacetal (blue) and allene (green) units into
a vinylallene system (yellow) (Fig. 1); (3) alkylthio group-dependent
reactivity in which the alkylthio group not only acts as a regulator
but also as a reactive group in the cyclizations as verified
by the divergent synthesis of pyrroles10 and thiophenes;11 and
(4) unprecedented metal-free carbothiolation of gem-dialkylthio
vinylallenes bearing acyclic alkylthio groups.12
Initially, the reaction of gem-dialkylthiopenten-4-yne 1a1
containing a 1,3-dithiolane moiety with benzylamine was per-
formed. To our delight, this reaction was complete within 5 h
under the optimal conditions (DMSO as solvent at 100 1C; for
details see Table S2w) and gave pyrrole 3a1 in 85% yield
(Scheme 1). In a stepwise experiment, gem-dialkylthio vinylallene
2a1 was exclusively produced in 95% yield by quenching the
reaction within 1–2 min, and further reaction with benzylamine
gave 3a1 in 87% yield, thus indicating that 2a1 was the real
precursor of 3a1. Benzylamine appears to play a dual role in the
domino cyclization by acting both as a base and a reactant.
Notably, 2a1 can be prepared on a multigram-scale in a one-pot
operation and is stable under ambient conditions (Fig. S1w).
Encouraged by this preliminary result, we began to investi-
gate the reaction scope (Table 1). Under optimal conditions,
Design and utilization of novel multi-functionalized synthons
constitutes a powerful strategy to build useful molecules, parti-
cularly through step-economic domino reactions.1 Vinylallenes
are a unique class of allene derivatives2 that have been recognized
as a versatile synthon in organic synthesis.3 Significant substitu-
ent effects have been observed on the reactivity of vinylallenes,
however, it is limited to previously known reactions such as
1,4-electrocyclization, [1,5]-sigmatropic rearrangement and other
annulation process for silyl-,4a boryl-,4b phosphinoyl,4c sulfinyl-
and sulfonyl-substituted4d and titanated vinylallenes.4e Most of
these substituents were not involved in the reactions. Hence,
combining the regulation effect and the intrinsic reactivity of
substituents would be a useful strategy to develop novel reactions
for vinylallenes. Of particular relevance to this is a recent example
reported by Sherburn et al., who showed that 1,1-divinylallene
reacted with three maleimides to produce a complex hexacycle.5
In the synthetic utility of ketene dithioacetals,6 the reactions
tuned by dialkylthio groups are especially important for the
synthesis of useful and complex compounds.7 Therefore, we
envisaged that the introduction of dialkylthio groups onto the
skeleton of vinylallene could elicit novel reactivity and synthetic
use.8 Herein, we report our preliminary results in this direction
and describe the first preparation of gem-dialkylthio vinylallenes
and their alkylthio-dependent reactivity. As a new class of
multifunctional groups-integrated synthon (MFGIS), the
gem-dialkylthio vinylallenes possess several useful features,
including: (1) ready in situ generation through the isomerization
Fig. 1 gem-Dialkylthio vinylallenes.
a Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: bixh507@nenu.edu.cn,
liuqun@nenu.edu.cn, zhangjingping66@yahoo.cn
b State Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, China
w Electronic supplementary information (ESI) available: Experimental
procedures, analytical data, and spectra copies of all compounds. See
DOI: 10.1039/c2cc33857b
Scheme 1 Cyclization between gem-dialkylthiopenten-4-yne 1a1 and
benzylamine.
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Table 1 Synthesis of fully-substituted pyrroles 3aa
Scheme 2 A plausible reaction mechanism for pyrroles.
Based on the above results and our previous reports,7a,15
a
plausible reaction mechanism for the formation of pyrroles
was proposed and supported by DFT calculations (Scheme 2,
with 1a1 as an example; key geometry structures of the path-
way are presented, for more details, see Fig. S2w). First,
isomerization of the propargyl moiety of 1a1, which is pro-
moted by benzylamine, takes place yielding gem-dialkylthio
vinylallene 2a1. Then, the 1,3-dithiolane moiety of 2a1 under-
goes ring-opening by benzylamine (Re2) to furnish thioamide
intermediate Re1. Following the selective attack of benzyl-
amine on the allenic carbon, an enamine intermediate Int7 is
produced along with significant reduction of relative energy
(DE) to ꢀ35.43 kcal molꢀ1. Subsequently, enol intermediate
Int8 is formed through keto–enol tautomerization, in which
H2O presumably assisted this transformation by forming an
eight-membered ring transition state TS4b,16 as suggested
by theoretical calculations. Following the intramolecular
1,4-conjuation addition, an intermediate Int9 is formed
through TS5 that required an activation energy (DDEz) as
high as 29.58 kcal molꢀ1. Finally, pyrrole 3a1 is produced with
the elimination of H2O. Obviously, the ring-closing reaction
from Int8 to Int9 would make a major contribution to the rate-
limiting step because of the highest activation barrier, which
appears reasonable in view of the fact that the reaction needed
to be performed at 100 1C for 5 h (Scheme 1).
a
Isolated yields.
the reactions of substrates 1a2–1a11 bearing a carbonyl group
(EWG = R0CO) with various amines produced the corresponding
pyrroles 3a2–3a18 in good to high yields. A series of functional
groups including aryl, heteroaryl, fused aryl, alkyl, hydroxyl,
alkenyl and cyclopropyl can be easily incorporated into the pyrrole
scaffold. In addition, gem-dialkylthio vinylallenes 2a2–2a11 bearing
a 1,3-dithiolane functionality can be quickly prepared in nearly
quantitative yields from 1a2–1a11 through base-promoted isomeri-
zation (Table S1w). Furthermore, 2-aminopyrroles 3a19–3a28 were
synthesized in good to high yields from the reactions of gem-
dialkylthiopenten-4-ynes 1 that has a cyano group (EWG = CN)
with amines (Table 1). The structures of 3a8 and 3a26 were
unambiguously confirmed by X-ray diffraction. In spite of the fact
that numerous methods for pyrrole syntheses are well established,10
few examples are known for the preparation of 2-aminopyrroles,13
which have great potential to make pharmaceutical compounds.14
Interestingly, when substrate 1b1 containing 1,3-dithiane func-
tionality was subjected to the same reaction conditions as above,
gem-dialkylthio vinylallene 2b1 was obtained in 91% yield within
10 min (eqn (1)). However, no pyrrole product (for example, 3a1)
could be detected even after a prolonged reaction time. This result
gave further support to our previous observations that the
1,3-dithiolane ring of a-oxo ketene dithioacetals was broken under
basic conditions, whereas 1,3-dithiane appeared to be stable.7a,15
Similarly, such a regulation effect existed in gem-dialkylthio vinyl-
allenes. Therefore, the ring-opening of 1,3-dithiolane is likely to be
the initial step in the domino cyclization of 2a1 with benzylamine.
Next, we were interested in evaluating gem-dialkylthio
vinylallenes containing acyclic alkylthio groups (Scheme 3).
Unexpectedly, thiophene 3c1 was isolated from the reaction mixture
of 1c1 with benzylamine. Further optimization of the reaction
conditions increased the yield of 3c1 to 88% in the presence of
DBU (30 mol%) in DMSO at room temperature (see Table S3w).
ð1Þ
Scheme 3 Intramolecular cyclization of acyclic gem-dialkylthio
vinylallene 1c1.
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Table 2 Synthesis of fully-substituted thiophenes 3ca
This work was supported by NSFC (20902010, 21172029)
and the Fundamental Research Funds for the Central Uni-
versities (10JCXK005, 11CXPY005). Many thanks to Prof.
Haibo Yang for his critical reading of the manuscript.
Notes and references
1 L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006.
2 Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi,
Wiley-VCH Verlag GmbH & Co, 2004.
3 For recent examples, see: (a) J. M. Robinson, T. Sakai, K. Okano,
T. Kitawaki and R. L. Danheiser, J. Am. Chem. Soc., 2010,
132, 11039; (b) J. H. Lee and F. D. Toste, Angew. Chem., Int. Ed.,
2007, 46, 912.
4 (a) M. Murakami, H. Amii, K. Itami and Y. Ito, Angew. Chem.,
Int. Ed. Engl., 1995, 34, 1476; (b) M. Murakami, S. Ashida and
T. Matsuda, J. Am. Chem. Soc., 2004, 126, 10838; (c) J. A. Palenzuela,
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Chem. Soc., 1987, 109, 7499; (e) C. Delas, H. Urabe and F. Sato,
J. Am. Chem. Soc., 2001, 123, 7937.
a
Isolated yields.
Interestingly, vinylallene 2c1 was not isolatable probably due
to its quick conversion into thiophene 3c1. A DFT calculation
also supported this conclusion (Scheme 3; for details, see
Fig. S3w). The formation of thiophenium intermediate Int-a
seemed to be involved in the ring-closing step of gem-dialkylthio
vinylallene 2c1 through an unprecedented carbothiolation of
allene under metal-free conditions. Following a 1,3-alkyl
migration of the ethyl group from sulfur atom to benzylic
carbon, thiophene 3c1 was produced. Carbothiolation of
p-bond systems including alkynes, allenes and alkenes through
C–S s-bond addition affords an opportunity to install C–C
and C–S bonds in a single reaction.12 Although remarkable
progress has been made since the first report of carbothiola-
tion by Choi et al.,17 the presence of a transition-metal catalyst
such as Pd, Pt, Rh, Au is generally required.18 Moreover, little
has been known about the carbothiolation of allenes (only two
isolated examples available in 25 and 76% yields, respectively).19
To the best of our knowledge, the carbothiolation of p-bond
systems under metal-free conditions has not been reported.19,20
Therefore, the ring-closing of 2c1 represents the first example
of metal-free carbothiolation, which constitutes an atom-
economic and cost-effective approach to thiophenes.
5 K. M. Cergol, C. G. Newton, A. L. Lawrence, A. C. Willis,
M. N. Paddon-Row and M. S. Sherburn, Angew. Chem., Int. Ed.,
2011, 50, 10425.
6 L. Pan and Q. Liu, Synlett, 2011, 1073.
7 For selected examples, see: (a) Y. Li, X. Xu, J. Tan, C. Xia,
D. Zhang and Q. Liu, J. Am. Chem. Soc., 2011, 133, 1775;
(b) J. Tan, X. Xu, L. Zhang, Y. Li and Q. Liu, Angew. Chem.,
Int. Ed., 2009, 48, 2868; (c) T. Kobatake, D. Fujino, S. Yoshida,
H. Yorimitsu and K. Oshima, J. Am. Chem. Soc., 2010, 132, 11838;
(d) P. J. Kocienski, A. Pontiroli and Q. Liu, J. Chem. Soc., Perkin
Trans. 1, 2001, 2356.
8 Very few thio-substituted vinylallenes were found in the literature,
see: (a) K. Banert, M. Hagedorn and A. Muller, Eur. J. Org.
Chem., 2001, 1089; (b) S. Florio, L. Ronzini, E. Epifani and
R. Sgarra, Tetrahedron, 1993, 49, 10413; (c) J.-F. Biellmann and
J.-B. Ducep, Org. React. (N. Y.), 1982, 27, 180.
9 J.-N. Song, Z. Fang, Y. Liu, R. Li, L. Xu, B.-D. Barry, Q. Liu,
X. Bi and P. Liao, Synlett, 2011, 2551.
10 For recent examples on the synthesis of pyrroles, see: (a) Y. Jiang,
W. C. Chan and C.-M. Park, J. Am. Chem. Soc., 2012, 134, 4104;
(b) X. Xin, D. Wang, X. Li and B. Wan, Angew. Chem., Int. Ed.,
2012, 51, 1693, and references therein.
11 For recent examples on the synthesis of thiophenes, see:
(a) L. K. Ransborg, Ł. Albrecht, C. F. Weise, J. R. Bak and
K. A. Jørgensen, Org. Lett., 2012, 14, 724; (b) W. You, X. Yan,
Q. Liao and C. Xi, Org. Lett., 2010, 12, 3930, and references therein.
12 P. Bichler and J. A. Love, Top. Organomet. Chem., 2010, 31, 39.
13 L. V. Frolova, N. M. Evdokimov, K. Hayden, I. Malik, S. Rogelj,
A. Kornienko and I. V. Magedov, Org. Lett., 2011, 13, 1118, and
references therein.
14 M. T. Migawa, J. C. Drach and L. B. Townsend, J. Med. Chem.,
2005, 48, 3840.
15 Y. Li, F. Liang, X. Bi and Q. Liu, J. Org. Chem., 2006, 71, 8006.
16 For water assisted [1,2]-H shift, see: Y. Liang, H. Zhou and
Z.-X. Yu, J. Am. Chem. Soc., 2009, 131, 17783.
17 N. Choi, Y. Kabe and W. Ando, Tetrahedron Lett., 1991, 32, 4573.
18 For recent examples on carbothiolation, see: (a) J. F. Hooper,
A. B. Chaplin, C. Gonzalez-Rodrıguez, A. L. Thompson,
A. S. Weller and M. C. Willis, J. Am. Chem. Soc., 2012,
134, 2906; (b) M. Iwasaki, D. Fujino, T. Wada, A. Kondoh,
H. Yorimitsu and K. Oshima, Chem.–Asian J., 2011, 6, 3190,
and references therein.
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H. Kuniyasu and N. Kambe, Org. Lett., 2008, 10, 3957;
(b) M. Toyofuku, E. Murase, H. Nagai, S. Fujiwara, T. Shin-ike,
H. Kuniyasu and N. Kambe, Eur. J. Org. Chem., 2009, 3141.
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48, 2276.
The reaction scope of this cyclization reaction is broad.
Variation of the substituents (EWG, R1, R2 and R) has no
influence on the rearrangement, leading to thiophenes 3c2–3c9
in good to high yields (Table 2), among which the structure of
3c2 was unambiguously confirmed by X-ray crystallography.
Of note is the presence of diversified functional groups such as
the alkylthio, cinnamoyl, acetyl, amide and aryl on thiophenes
3c1–3c9, thereby allowing for further synthetic modifications.
For example, the alkylthio group has the potential to be
converted into hydrogen, sulfoxide or (hetero)aryl groups
through reduction,21 oxidation,7c and Liebeskind–Srogl cou-
pling reactions.22
In conclusion, we have described the first gem-dialkylthio
vinylallenes and their alkylthio-regulated reactivity. A wide
range of pyrroles and thiophenes were separately prepared
from gem-dialkylthio vinylallenes simply by choosing an
appropriate alkylthio group, thus constituting a novel and
powerful route to these two important heterocycles. DFT
calculations provided mechanistic insights, and disclosed an
unprecedented metal-free carbothiolation.
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Chem. Commun.