Synthesis of pyrroles from terminal alkynes, N-sulfonyl azides, and alkenyl alkyl ethers through 1-sulfonyl-1,2,3-triazoles

Article abstract of DOI:10.1021/ol500718s

A method for synthesis of substituted pyrroles has been developed. 1-Sulfonyl-1,2,3-triazoles generated from terminal alkynes gave α-imino rhodium carbene complexes, which when reacted with alkenyl alkyl ethers afforded substituted pyrroles. The method can be efficiently applied to a one-pot sequential reaction starting from terminal alkynes.

Full text of DOI:10.1021/ol500718s

Letter
pubs.acs.org/OrgLett
Synthesis of Pyrroles from Terminal Alkynes, N‑Sulfonyl Azides, and
Alkenyl Alkyl Ethers through 1‑Sulfonyl-1,2,3-triazoles
Cheol-Eui Kim,† Sangjune Park,† Dahan Eom, Boram Seo, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: A method for synthesis of substituted pyrroles
has been developed. 1-Sulfonyl-1,2,3-triazoles generated from
terminal alkynes gave α-imino rhodium carbene complexes,
which when reacted with alkenyl alkyl ethers afforded substituted pyrroles. The method can be efficiently applied to a one-pot
sequential reaction starting from terminal alkynes.
a
Table 1. Reaction Optimization
yrroles are significant structural motifs found not only in
1
Pvaluable bioactive molecules but also in a massive range of
natural products.2 They also find broad applications in
supramolecular chemistry and materials science as conjugated
polymers.3 Thus, the development of a streamlined method for
their synthesis having a variety of substituents starting from
easily available materials is required.4 Because a sequential
reaction is very important from the viewpoint of synthetic
efficiency, we herein describe a one-pot sequential method for
the synthesis of pyrroles from terminal alkynes, N-sulfonyl
azides, and alkenyl alkyl ethers (Scheme 1).
b
entry
cat. (mol %)
solvent
time (h)
yield (%)
1
2
3
4
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (0.5)
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (1.0)
Cu(OAc)2 (5.0)
Cu(OTf)2 (5.0)
PhCH3
CHCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
12
6
29
96
c
3
100 (99)
d
12
3
51 (12)
f
e
5
(95)
g
e
6
3
(94)
h
7
d
8
57 (15)
i
d
Scheme 1. Construction of Pyrroles Starting from Terminal
Alkynes, N-Sulfonyl Azides, and Alkenyl Alkyl Ethers
8
8
(83)
h
d
9
8
(83)
h
10
8
0
a
Reactions were carried out with 1a (0.2 mmol) and 2a (3 equiv) in
b
solvent (0.2 mL, 1.0 M) at 80 °C. NMR yield using CH2Br2 as an
internal standard. Isolated yield of 3a. NMR yield of 1a. NMR yield
of 4a.
c
d
e
Recently, 1-sulfonyl-1,2,3-triazoles, which can be simply
generated from a copper-catalyzed 1,3-dipolar cycloaddition
reaction of terminal alkynes with N-sulfonyl azides,5 have
gained widespread attention as precursors of α-imino metal
carbenes.6 Because the metal carbene species have an inherently
electrophilic character, they can react with a wide range of
nucleophiles. On the contrary, the nitrogen atom of the α-
imino group is nucleophilic in nature to react with various
electrophiles. Therefore, these α-imino metal carbenes having
both electrophilic and nucleophilic character can easily react
with a variety of unsaturated compounds such as nitriles,7
alkynes,8 allenes,9 isocyanates and isothiocyanates,10 furans,11
aldehydes,12 α,β-unsaturated aldehydes,13 indoles,14 and
arenes15 to provide the corresponding N-heterocyclic com-
pounds. Inspired by these methods, we envisioned the potential
of alkenyl alkyl ethers as the reaction partner. We commenced
our studies with the reaction of 4-phenyl-1-tosyl-1,2,3-triazole
(1a) prepared from phenylacetylene and tosyl azide in the
presence of CuTC5b with ethyl vinyl ether 2a (Table 1).
Treatment of 1a with 2a in the presence of Rh2(OAc)4 (1.0
mol %) in toluene produced 3-phenyl-1-tosylpyrrole 3a (29%)
after 12 h through transannulation followed by elimination of
f
g
DCE (0.4 mL, 0.5 M) was used. DCE (1.0 mL, 0.2 M) was used.
h
i
2a (2 equiv) was used. 2a (1.5 equiv) was used.
ethanol (entry 1). Gratifyingly, the reaction in chloroform and
DCE gave 3a in quantitative yield (entries 2 and 3). When
Rh2(OAc)4 (0.5 mol %) was used in DCE, the reaction was not
completed even if after 12 h (entry 4). Dilution of
concentration to 0.5 and 0.2 M afforded only transannulated
product 4a, in 95% and 94% NMR yields, respectively (entries
5 and 6). The unstable dihydropyrrole was converted to the
pyrrole 3a through elimination of ethanol during the column
chromatography. Use of 2a (3 equiv) is crucial for successful
results due to low boiling point (entries 3, 7, and 8). Cu(OAc)2
and Cu(OTf)2 as catalyst are totally ineffective (entries 9 and
10).
Received: February 7, 2014
Published: March 24, 2014
© 2014 American Chemical Society
1900
dx.doi.org/10.1021/ol500718s | Org. Lett. 2014, 16, 1900−1903

Organic Letters
Letter
With the optimized conditions in hand, the variation of the
sulfonyl group at the N1 of triazoles 1 was studied in the
reaction with 2a using Rh2(OAc)4 as the catalyst (Scheme 2).
Table 2. Rh-Catalyzed Synthesis of Pyrroles Using Various
Vinyl Ethers
a
Scheme 2. Rh-Catalyzed Synthesis of Pyrroles Using Various
a
Triazoles
a
Reactions were carried out with 1 (0.2 mmol) and 2a (3 equiv) in
DCE (0.2 mL, 1.0 M) at 80 °C.
Alkylsulfonyl groups were effective in a one-pot sequential
reaction; n-butyl- and isopropylsulfonyl triazoles 1b,c were all
adequate substrates. Both electron-withdrawing and -donating
substituents were also tolerated on the arylsulfonyl group.
Thus, the reaction was well established with respect to the R2
substituent on the sulfonyl group at N1 of triazoles 1. Because
triazole 1a obtained from tosyl azide gave the best results, a
variety of triazoles 1 having an N-tosyl group were subjected to
2a under the optimum conditions. Triazoles 1g and 1h
possessing 3-methyl and 4-methyl groups on the phenyl ring at
C4 were treated with Rh2(OAc)4 as the catalyst in DCE for 5 h,
producing the corresponding pyrroles 3g and 3h in 80% and
88% yields, respectively. An electron-donating methoxy group
did not influence the efficiency of the reaction. To our delight,
transannulation followed by elimination took place with
triazoles 1k, 1l, 1m, and 1n bearing electron-withdrawing
trifluoromethyl, chloro, and bromo groups on the phenyl ring
at C4, affording the desired pyrroles 3k, 3l, 3m, and 3n in yields
ranging from 60% and 72%. However, 4-alkyl-substituted 1-
tosyl-1,2,3-triazoles did not react with 2a.16,17
a
Reactions were carried out with 1 (0.2 mmol) and 2 (3 equiv) in
b
DCE (0.2 mL, 1.0 M) at 80 °C. TMSOTf (5 mol %) was added to
reaction mixture after transannulation, and then it was stirred for 30
min.
To expand the synthetic utility of this reaction, we next
examined the affect of substituents of alkenyl alkyl ether on
transannulation followed by elimination (Table 2). Subjecting
1a to 1-ethoxyprop-1-ene (2b) and 1-ethoxybut-1-ene (2c)
gave 1,3,4-trisubstituted pyrroles 5a and 5b in 80% and 86%
yields, respectively (entries 1 and 2). Treatment of 1a with (2-
ethoxyvinyl)benzene (2d) in the presence of Rh catalyst
afforded 3,4-diphenyl-1-tosylpyrrole 5c in 73% yield (entry 3).
When trizole 1a was treated with 1-(2-ethoxyvinyl)-4-
(trifluoromethyl)benzene (2e), dihydropyrrole (4b) was
isolated in 88% yield. Addition of TMSOTf (5 mol %) to the
reaction mixture at 25 °C without isolation of 4b produced 5d
in 89% yield (entry 4). Similarly, 1-chloro-4-(2-(octyloxy)-
1901
dx.doi.org/10.1021/ol500718s | Org. Lett. 2014, 16, 1900−1903

Organic Letters
Letter
vinyl)benzene (2f) was converted to 5e in 75% yield thorugh
transannulation followed by elimination (entry 5). Next, 1-
(prop-1-en-2-yloxy)octane (2g) and (1-ethoxyvinyl)benzene
(2h) were used in order to obtain pyrroles having substituent at
C2. Delightedly, exposure of 1a to 2g produced 2-methyl-4-
phenyl-1-tosylpyrrole 5f in 91% yield (entry 6). We were
pleased to obtain 5g in 84% yield from the reaction of 1a with
2h through a one-pot procedure (enrtry 7). The present
method worked equally well with 1-ethoxycyclohexene (2j)
(entry 9). In analogy with 1a, 4-(4-methoxyphenyl)-1-tosyl-
1,2,3-triazole 1i reacted with alkenyl ethyl ethers 2b−d having
substituents at β-position of double bond to provide 1,3,4-
trisubstituted pyrroles 5j−l in yields ranging from 71% to 83%
yields (entries 10−12). 1-Chloro-4-(1-ethoxyvinyl)-benzene
(2i) was converted to the corresponding pyrroles 5h (77%)
and 5n (82%) after treatment of TMSOTf (5 mol %) at 25 °C
(entries 8 and 14).
Scheme 4. Plausible Mechanism
the electrophilic carbene center of B generates the rhodium-
bound zwitterionic intermediate C. Then, anionic rhodium of C
releases an electron pair, which flows into the imine moiety to
make the nitrogen atom nucleophilic enough to react cationic
oxocarbenium moiety to afford 2,3-dihydropyrrole 4 with
regeneration of the rhodium(II) catalyst. Finally, 4 is smoothly
transformed to substituted pyrrole 5 through elimination of
alcohol. In addition, another pathway can explain the formation
of the pyrrole. α-Imino rhodium(II) carbenoid B reacts with
the electron-rich alkene to provide alkoxy cyclopropyl imine D.
The presence of the electron-withdrawing N-sulfonylimine
combined with the electron-donating methoxy group facilitates
the cleavage of the cyclopropane ring and generates a stabilized
zwitterionic intermediate E, which collapses into the corre-
sponding dihyrdopyrrole 4. However, because the alkoxycyclo-
propylimine was not observed in NMR studies in DCE-d4, the
intermediate D is ruled out in the catalytic cycle (see the
Supporting Information).
As an extension of this work, we next conducted a three-
component one-pot synthesis of substituted pyrroles 3 and 5
from terminal alkynes 6 (Scheme 3).18 Phenylacetylene 6a
Scheme 3. Synthesis of Pyrroles by Rh-Catalyzed Sequential
a
Reaction
In conclusion, we have reported the synthetic method of
substituted pyrroles from the transannulation of α-imino
rhodium carbenes generated in situ from 1-sulfonyl-1,2,3-
triazoles with a wide reage of alkenyl alkyl ethers followed by an
elimination reaction. Moreover, it has also been demonstrated
that pyrroles can be prepared from terminal alkynes, tosyl azide,
and alkenyl alkyl ethers through a one-pot sequential reaction.
a
Reactions were carried out with 6 (0.2 mmol), 7 (0.2 mmol), and 2
(3 equiv) in DCE (1.0 mL, 0.2 M).
(0.20 mmol), tosyl azide 7 (0.20 mmol), 2a (0.6 mmol), CuTC
(10 mol %), Rh2(OAc)4 (1.0 mol %), and DCE (1 mL) were
placed in a reaction vessel, and the reaction mixture was stirred
at 25 °C. After consumption of both 6a and 7 for 3 h, the
reaction mixture was successively stirred at 80 °C for an
additional 4 h. After chromatographic separation, the pyrrole 3a
was obtained in 71% yield. These results indicate that the
catalytic amount of copper remaining in the reaction mixture
after the first cycloaddition step does not influence largely on
the formation and reactivity of the carbenoid. In addition,
electron-donating groups such as methyl and methoxy on the
phenyl ring worked equally well. Also, 4-ethynyl-α,α,α-
trifluorotoluene underwent sequentially cycloaddition, trans-
annulation, and elimination in one-pot, producing 3k in 66%
yield. When 2b and 2c were used in the reaction of 6a and 7,
the corresponding pyrroles 5a and 5b were isolated in 65% and
67% yields, respectively.
A plausible mechanism for the formation of pyrrole (3 and
5) from 1-sulfonyl-1,2,3-triazole 1 and alkenyl alkyl ether 2 is
shown in Scheme 4. First, a reversible ring−chain tautomeriza-
tion of 1-sulfonyl-1,2,3-triazole 1 gives rise to α-diazo imine
A.19 The following irreversible reaction of A with rhodium(II)
provides α-imino rhodium(II) carbenoid B together with
liberation of molecular nitrogen. Nucleophilic addition of 2 to
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (No. 2011-0018355).
1902
dx.doi.org/10.1021/ol500718s | Org. Lett. 2014, 16, 1900−1903

Organic Letters
Letter
(17) 4-tert-Butyl-1-tosyl-1,2,3-triazole was converted to α,β-unsatu-
rated N-tosylimine via rearrangement of the methyl group. Selander,
N.; Worrell, B. T.; Fokin, V. V. Angew. Chem., Int. Ed. 2012, 51, 13054.
(18) (a) Miura, T.; Tanaka, T.; Biyajima, T.; Yada, A.; Murakami, M.
Angew. Chem., Int. Ed. 2013, 52, 3883. (b) Miura, T.; Tanaka, T.; Yada,
A.; Murakami, M. Chem. Lett. 2013, 42, 1308.
DEDICATION
■
This paper is dedicated to Professor Ung Chan Yoon (Pusan
National University) on the occasion of his honorable
retirement.
(19) (a) Grunanger, P.; Finzi, P. V. Tetrahedron Lett. 1963, 4, 1839.
̈
REFERENCES
■
(b) Harmon, R. E.; Stanley, F., Jr.; Gupta, S. K.; Johnson, J. J. Org.
Chem. 1970, 35, 3444. (c) Mckinney, M. A.; Patel, P. P. J. Org. Chem.
1973, 38, 4059. (d) Himbert, G.; Frank, D.; Regit, M. Chem. Ber. 1976,
109, 370. (e) Kwok, S. W.; Zhang, L.; Grimster, N. P.; Fokin, V. V.
Angew. Chem., Int. Ed. 2014, 53, 3452.
(1) (a) Jones, R. A. In The Chemistry of Heterocyclic Compounds Part
1: Pyrroles; Wiley: New York, 1990; Vol. 48. (b) Gilchrist, T. L. J.
Chem. Soc., Perkin Trans. 1 1999, 2849. (c) Huffman, J. W. Curr. Med.
Chem. 1999, 6, 705. (d) Thompson, R. B. FASEB J. 2001, 15, 1671.
(2) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Bird, C. W., Eds.;
Elsevier Science, Ltd.: Oxford, 1996; Vol. 2, pp 119−206. (b) Boger,
D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem.
Soc. 1999, 121, 54. (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(d) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (e) Hoffmann,
̈
H.; Lindel, T. Synthesis 2003, 1753. (f) Weinreb, S. M. Nat. Prod. Rep.
2007, 24, 931. (g) Dong, G. Pure Appl. Chem. 2010, 82, 2231.
(h) Reyes, J. C. P.; Romo, D. Angew. Chem., Int. Ed. 2012, 51, 7050.
(3) (a) Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. Rev. 1991,
20, 391. (b) 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. (c) Chen, Y.; Zeng,
D.; Xie, N.; Dang, Y. J. Org. Chem. 2005, 70, 5001.
(4) (a) Lourdusamy, E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed.
2010, 49, 7963. (b) Xu, X.; Ratnikov, M. O.; Zavalij, P. Y.; Doyle, M.
P. Org. Lett. 2011, 13, 6122. (c) Huestis, M. P.; Chan, L.; Stuart, D. R.;
Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338. (d) Trost, B. M.;
Lumb, J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011, 133, 740.
(e) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926.
(f) Michlik, S.; Kempe, R. Nat. Chem. 2013, 5, 140. (g) Reddy, B. V.
S.; Reddy, M. R.; Rao, Y. G.; Yadav, J. S.; Sridhar, B. Org. Lett. 2013,
15, 464. (h) Wang, L.; Ackermann, L. Org. Lett. 2013, 15, 176.
(5) (a) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730.
(b) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952. (c) Liu, Y.;
Wang, X.; Xu, J.; Zhang, Q.; Zhao, Y.; Hu, Y. Tetrahedron 2011, 67,
6294.
(6) (a) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed.
2012, 51, 862. (b) Gulevich, A. V.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2013, 52, 1371.
(7) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin,
V. V. J. Am. Chem. Soc. 2008, 130, 14972.
(8) (a) Miura, T.; Yamauchi, M.; Murakami, M. Chem. Commun.
2009, 1470. (b) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13,
3746. (c) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394.
(9) (a) Miura, T.; Hiraga, K.; Biyajima, T.; Nakamuro, T.; Murakami,
M. Org. Lett. 2013, 15, 3298. (b) Schultz, E. E.; Sarpong, R. J. Am.
Chem. Soc. 2013, 135, 4696.
(10) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652.
(11) Parr, B. T.; Green, S. A.; Davies, H. M. J. Am. Chem. Soc. 2013,
135, 4716.
(12) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52, 1507.
(13) Miura, T.; Tanaka, T.; Hiraga, K.; Stewart, S. G.; Murakami, M.
J. Am. Chem. Soc. 2013, 135, 13652.
(14) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
6802.
(15) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014,
136, 2272.
(16) When 4-n-butyl-1-tosyl-1,2,3-triazole was treated with 2a in the
presence of rhodium catalyst, the N-tosylimine of hexanal was
obtained in 10% yield through β-hydride migration. (a) Taber, D.
F.; Herr, R. J.; Pack, S. K.; Geremia, J. M. J. Org. Chem. 1996, 61, 2908.
(b) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin,
V. V. J. Am. Chem. Soc. 2008, 130, 14972. (c) Grimster, N.; Zhang, L.;
Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510. (d) Miura, T.;
Biyajima, T.; Fujii, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 194.
1903
dx.doi.org/10.1021/ol500718s | Org. Lett. 2014, 16, 1900−1903