1,2-Sulfanyl group migration as a driving force: New approach to pyrroles by reaction of allenic aldehydes with amines

Article abstract of DOI:10.1021/ol070205d

Equation presented Acid-promoted reaction of sulfanyl group substituted allenic aldehyde with amine affords pyrrole derivatives in high yields. The neighboring group participation of the sulfanyl group is the driving force in this transformation.

Full text of DOI:10.1021/ol070205d

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1445-1448
1,2-Sulfanyl Group Migration as a
Driving Force: New Approach to
Pyrroles by Reaction of Allenic
Aldehydes with Amines
Lingling Peng, Xiu Zhang, Jie Ma, Zhenzhen Zhong, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Green Chemistry Center
(GCC) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, China
wangjb@pku.edu.cn
Received January 26, 2007
ABSTRACT
Acid-promoted reaction of sulfanyl group substituted allenic aldehyde with amine affords pyrrole derivatives in high yields. The neighboring
group participation of the sulfanyl group is the driving force in this transformation.
Pyrroles have attracted attention due to their importance in
the fields of natural products, medicinal chemistry, and
material sciences.1-3 Efforts have been directed to the
development of efficient methods to synthesize this type of
heterocycle.4 The classic methods for preparing pyrroles
include the condensation of R-haloketones with â-keto esters
in the presence of amines (Hantzsch procedure),5 the reaction
of 1,4-diketones and amines (Paal-Knorr synthesis),6 and
the condensation of R-amino ketones with â-dicarbonyl
compounds (Knorr synthesis).7 Recently, new approaches
based on transition-metal-catalyzed processes have been
(4) For reviews on pyrrole synthesis, see: (a) Sundberg, R. J. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 119. (b)
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849. (c) Balme, G.
Angew. Chem., Int. Ed. 2004, 43, 6238. For selected recent references, see:
(d) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468. (e)
Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313. (f) Kamijo, S.;
Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (g) Gorin,
D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (h)
Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664. (i)
Shimizu, M.; Takahashi, A.; Kawai, S. Org. Lett. 2006, 8, 3585. (j) Winkler,
J. D.; Ragains, J. R. Org. Lett. 2006, 8, 4031. (k) Crawley, M. L.; Goljer,
I.; Jenkins, D. J.; Mehlmann, J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E.
Org. Lett. 2006, 8, 5837. (l) Dong, C.; Deng, G.; Wang, J. J. Org. Chem.
2006, 71, 5560. (m) Crawley, M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann,
J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org. Lett. 2006, 8, 5837. (n)
St. Cyr, D. J.; Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9, 449. (o)
Huang, X.; Shen, R.; Zhang, T. J. Org. Chem. 2007, 72, 1534. (p) Be´langer,
G.; April, M.; Dauphin, EÄ .; Roy, S. J. Org. Chem. 2007, 72, 1104.
(5) For recent examples of Hantzsch synthesis of pyrroles, see: (a)
Kameswaran, V.; Jiang, B. Synthesis 1997, 5, 530. (b) Trautwein, A. W.;
Sussmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381. Palacios,
F.; Aparico, D.; de los Santos, J. M.; Vicario, J. Tetrahedron 2001, 57,
1961. (c) Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk,
Y. V.; Pidlypnyi, N. I. Chem. Heterocycl. Comp. 2004, 40, 1218.
(1) For general reviews on pyrroles, see: (a) Jones, R. A. In Pyrroles,
Part II, The Synthesis, ReactiVity and Physical Properties of Substituted
Pyrroles; Wiley: New York, 1992. (b) Gilchrist, T. L. Heterocyclic
Chemistry, 3rd ed.; Addison-Wesley Longman: Essex, 1997; pp 192-209.
(c) ComprehensiVe Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon
Press: Oxford, 1996; Vol. 2. (d) Joule, J. A.; Mills, K. In Heterocyclic
Chemistry; Blackwell Science: Oxford, 2000; Chapter 13.
(2) For recent reviews of pyrroles in natural products, see: (a) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2003, 42, 3582. (b) Hoffmann, H.; Lindel, T.
Synthesis 2003, 1753. For selected recent reports, see: (c) Boger, D. L.;
Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 54. (d) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120,
2817. (e) Sayah, B.; Pelloux-Leon, N.; Vallee, Y. J. Org. Chem. 2000, 65,
2824. (f) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org.
Chem. 2000, 65, 3587. (g) Brower, J. O.; Lightner, D. A.; McDonagh, A.
F. Tetrahedron 2001, 57, 7813.
(3) For reviews of the pyrrole structure in materials, see: (a) Electronic
Materials: The Oligomer Approach; Mu¨llen, K., Wegner, G., Eds.; Wiley-
VCH: Weinheim, 1997. (b) Deronzier, A.; Moutet, J.-C. Curr. Top.
Electrochem. 1994, 3, 159-200. (c) Higgins, S. Chem. Soc. ReV. 1997, 26,
247. For recent reports, see: (d) Yamaguchi, S.; Tamao, K. J. Organomet.
Chem. 2002, 653, 223. (e) Domingo, V. M.; Aleman, C.; Brillas, E.; Julia,
L. J. Org. Chem. 2001, 66, 4058.
10.1021/ol070205d CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/22/2007

reported.8-10 In those approaches, the transition-metal cata-
lysts usually activate unsaturated bonds of alkynes8 or
allenes,9 which then accept intramolecular nucleophilic attack
by nitrogen. Herein, we report a novel cyclization reaction
leading to multisubstituted pyrrole products by acid-promoted
reaction of allenic aldehydes with amines. The cyclization
procedure, which can be accelerated by acids, does not need
a transition metal to activate the allene moiety. The 1,2-thio
group migration is the driving force in this cyclization.
We have recently reported transition-metal-catalyzed reac-
tion of allenic sulfides, which gives furan derivatives through
1,4-sulfanyl group migrations (eq 1).11 Naturally, we ex-
pected to observe a similar reaction for imines, which would
give pyrrole derivatives with 1,4-migration of the thio group
(eq 2).
Table 1. Reaction of 1a and Aniline under Various Conditions
entry catalysta solvent temp (°C) time (h) 2a, yield (%)b
1
2
3
4
5
6
7
8
9
none
none
none
CH2Cl2
neat
DCE
25
25
60
25
60
25
25
25
25
60
48
30
24
24
3
24
5
24
12
3
90
97
84
98
97
92
53
95
87
83
TsOH‚H2O CH2Cl2
TsOH‚H2O DCE
HCl
BF3‚Et2O
AuCl
AgOTf
AuCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
10
a
For entries 4-7, 10 mol % of catalyst was used; for entries 8-10, 5
mol % of catalyst was used. b Isolated yield after column chromatography.
1). Lewis acids, such as BF3‚Et2O, AuCl, and AgOTf, all
can accelerate the reaction. Protonic acids, such as TsOH‚
H2O and HCl, also promote this reaction. Thus, with 10 mol
% of TsOH‚H2O, the reaction of 1a with aniline in CH2Cl2
at room temperature afforded the pyrrole product in 98%
yield.
This unexpected pyrrole formation can be explained by
two pathways, path a and path b, as shown in Scheme 2. In
For this purpose, we tried to prepare the allenic imine
substrate 3 by the reaction of allenic aldehyde 1a with aniline
at room temperature. Surprisingly, the expected allenic imine
sulfide 3 was not isolated. Instead, 2-thio-substituted pyrrole
derivative 2a was obtained in high yield (Scheme 1).
Scheme 2
Scheme 1
Further experiments indicated that raising the temperature
could shorten the reaction time for the formation of 2a (Table
(6) For recent examples of Paal-Knorr reactions, see: (a) Minetto, G.;
Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277. (b)
Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K. Tetrahedron Lett.
2005, 46, 2643. (c) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6,
2465. (d) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389.
(e) Banik, B. K.; Samajdar, S.; Banik, I. J. Org. Chem. 2004, 69, 213. (f)
Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.; Suo, J. Tetrahedron Lett.
2004, 45, 3417. (g) Banik, B. K.; Samajdar, S.; Banik, I. J. Org. Chem.
2004, 69, 213.
(7) For an example of Knorr pyrrole synthesis, see: Alberola, A.; Ortega,
A. G.; Sadaba, M. L.; Sanudo, C. Tetrahedron 1999, 55, 6555.
(8) (a) Harrison, T. J.; Kozak, J. A.; Corbella-Pane´, M.; Dake, G. R. J.
Org. Chem. 2006, 71, 4525. (b) Ishikawa, T.; Aikawa, T.; Watanabe, S.;
Saito, S. Org. Lett. 2006, 8, 3881. (c) Ramanathan, B.; Keith, A. J.;
Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6, 2957. (d) Hiroya, K.;
Matsumoto, S.; Ashikawa, M.; Ogiwara, K.; Sakamoto, T. Org. Lett. 2006,
8, 5349. (e) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 11260. (f) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem.
2003, 68, 7853.
both cases, the reaction of 1a with aniline first generates
imine intermediate 3. In path a, intramolecular nucleophilic
attack of the nitrogen atom to the middle carbon of the allene
(9) (a) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (b) Kel’in,
A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(c) Yu, H.-Y.; Dieter, R. K. Org. Lett. 2001, 3, 3855. (d) Kim, J. T.; Kel’in,
A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98. (e) Lee, C. -F.;
Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.; Tseng, J.-C.; Luh, T.-Y. J. Am.
Chem. Soc. 2000, 122, 4992.
1446
Org. Lett., Vol. 9, No. 8, 2007

moiety and the simultaneous elimination of the thiophenyl
anion generate a five-membered iminium intermediate A.
Then, the thiophenyl anion attacks the iminium carbon to
afford B, which isomerizes to 2a. Alternatively, the reaction
may follow path b. From imine 3, the thiophenyl group
assists the nucleophilic attack of imine nitrogen to gen-
erate intermediate C, which contains a three-centered
thiirenium ring. Opening of the thiirenium ring leads
to D, which is deprotonated to afford 2a. The difference
between path a and b is that in path a the 1,2-thio group
migration12,13 is intermolecular whereas in path b it is
intramolecular.
Table 2. TsOH-Catalyzed Reaction of 1a and Amines 6a-k
entry
amine 6 (R)
time (h)
7, yield (%)a
1
2
3
4
5
6
7
8
9c
10
11
12
6a, p-MeC6H4
6b, p-BrC6H4
6c, p-ClC6H4
6d, m-MeC6H4
6e, p-NO2C6H4
6f, Ac
6g, Ms
6h, Bn
6h, Bn
6i, Bu
12
24
24
7a, 92
7b, 86
7c, 98
7d, 97
7e, trace
nrb
To differentiate the two pathways, a crossover experiment
was carried out (Scheme 3). A 1:1 mixture of 1a and 4 with
24
120
120
120
12
48
12
nr
7h, 81
7h, 96
Scheme 3
d
-
6j, allyl
6k, tert-Bu
12
12
7j, 41
7k, trace
a
b
Isolated yield after column chromatography. Starting material was
recovered. c Reaction was carried out without TsOH‚H2O. d Reaction gave
a complex mixture.
Because this reaction provides a straightforward way to
form multisubstituted pyrrole derivatives from readily avail-
able starting material, this transformation may find utilities
in organic synthesis. Thus, with cheap TsOH‚H2O as the
catalyst, we proceeded to expand the substrate scope (Table
aniline was treated with 10 mol % of TsOH‚H2O at room
temperature. It gave pyrrole derivatives 2a and 5 in 95%
and 76% yield, respectively. No crossover products could
be detected. This result demonstrated that the 1,2-sulfur
migration was intramolecular, thus supporting path b as the
more likely reaction mechanism.
Scheme 4
It is worthwhile to note that only unreacted starting
materials and the pyrrole product could be isolated if the
reaction was stopped before completion. No intermediate
allenic imine 3 could be identified. This observation indicates
that in allenic imine 3 intramolecular imine nitrogen attack
to the allene is highly facile. The long reaction time when
the reaction was carried out in the absence of acid was due
to the slow reaction of the imine formation step. The role of
acid in accelerating the overall transformation is obviously
to promote the imine formation. It is also noted that under
the same reaction conditions allenic aldehyde 1a did not
undergo a similar reaction to afford the corresponding furan
products. This result indicates that the strong nucleophilicity
of the imine nitrogen is also critical in this process.
(10) (a) Takaya, H.; Kojima, S.; Murahashi, S. -I. Org. Lett. 2001, 3,
421. (b) Shen, H.-C.; Li, C.-W.; Liu, R.-S. Tetrahedron Lett. 2004, 45,
9245. (c) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313. (d) Kamijo,
S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (e)
Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664. (f)
Lu, L.-h.; Chen, G.-f.; Ma, S.-M. Org. Lett. 2006, 8, 835.
(11) Peng, L.; Zhang, X.; Ma, M.; Wang, J. Angew. Chem., Int. Ed. 2007,
46, 1905.
(12) For a review on thio group migration, see: Fox, D. J.; House, D.;
Warren, S. Angew. Chem., Int. Ed. 2002, 41, 2462.
(13) 1,2-Thio group migration to the sp2 carbon of iminium has been
known. See: (a) Plate, R.; Nivard, R. J. F.; Ottenheijm, H. C. J. Tetrahedron
1986, 42, 4503. (b) Hamel, P. J. Org. Chem. 2002, 67, 2854.
Org. Lett., Vol. 9, No. 8, 2007
1447

2). The reactions of 1a with a series of amines were
examined. With aromatic amines, the reaction gave high
yields of the corresponding pyrrole derivatives. The exception
is for the amine 6e, in which the aromatic group of amine is
p-nitrophenyl. This low yield is likely due to the unfavorable
formation of the imine intermediate. Similarly, no reaction
occurred with AcNH2 and MsNH2 even after stirring for 5
days (entries 6 and 7). The reaction with benzylamine gave
a little lower yield when catalyzed with TsOH‚H2O (entry
8). When the reaction with benzylamine was carried out in
the absence of TsOH‚H2O, it gave a high yield of the pyrrole
product, although the reaction took longer. The reaction
with allyl amine afforded the pyrrole product in 41% yield
(entry 11). However, the reaction with n-butyl amine was
found to give only a complex mixture, whereas the reaction
with tert-butyl amine proceeded very slowly (entries 10 and
12).
Then, the scope and limitations of this reaction were
further demonstrated by the reaction of a series of allenic
aldehydes with aniline, as summarized in Scheme 4. Pyrrole
products were isolated in high yields, except in the case of
1i, which might be due to the steric and electronic effects of
the terminal alkyl group in the allene moiety. It was
noteworthy that the allenic substrate 1h, in which R3 was
the methyl group, also worked well to give 2h in good yield.
Finally, the reaction of allenic aldehyde 1j, in which the
aromatic substituent was replaced with a methyl group, also
gave the corresponding pyrrole products, although the yield
was diminished.
In conclusion, we have developed an acid-promoted
cyclization reaction of allenic aldehydes with amines, which
gives various 2-thio-substituted pyrrole14 products in good
to excellent yields. This reaction provides a new entry to
this type of substituted pyrroles.
Acknowledgment. The project is generously sup-
ported by the Natural Science Foundation of China (Grant
Nos. 20572002, 20521202, 20225205, 20390050) and the
Ministry of Education of China (Cheung Kong Scholars
Program).
Supporting Information Available: Experimental pro-
1
cedure, characterization data, and H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL070205D
(14) (a) Katritzky, A. R.; Wang, X. J.; Denisenko, A. J. Org. Chem.
2001, 66, 2850. (b) Nedolya, N. A.; Brandsma, L.; Verkruijsse, H. D.;
Trofimov, B. A. Tetrahedron Lett. 1997, 38, 7247.
1448
Org. Lett., Vol. 9, No. 8, 2007