Intramolecular transannulation of alkynyl triazoles via alkyne-carbene metathesis step: Access to fused pyrroles

Article abstract of DOI:10.1021/ol4027655

An intramolecular Rh-catalyzed transannulation reaction of alkynyl triazoles has been developed. This method allows efficient construction of various 5,5-fused pyrroles, including tetrahydropyrrolo and spiro systems. The method demonstrates excellent functional group compatibility. A rhodium carbene-alkyne metathesis mechanism is proposed for this transformation.

Full text of DOI:10.1021/ol4027655

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Intramolecular Transannulation of Alkynyl
Triazoles via AlkyneꢀCarbene Metathesis
Step: Access to Fused Pyrroles
Yi Shi and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607, United States
vlad@uic.edu
Received September 24, 2013
ABSTRACT
An intramolecular Rh-catalyzed transannulation reaction of alkynyl triazoles has been developed. This method allows efficient construction
of various 5,5-fused pyrroles, including tetrahydropyrrolo and spiro systems. The method demonstrates excellent functional group compatibility.
A rhodium carbeneꢀalkyne metathesis mechanism is proposed for this transformation.
Rhodium-imino carbenes B, which are easily generated
from N-sulfonyl-1,2,3-triazoles (A),1,2 open wide opportu-
nities for formation of diverse heterocycles C through
various transannulation reactions (eq 1).3ꢀ7 We have
recently reported a transannulation of triazoles with ter-
minal alkynes into pyrroles E, which operates via an ylide
mechanism (D).5
Apparently, the ylide path limits this method to terminal
alkynes, which disqualifies the possibility of an intra-
molecular transannulation reaction toward valuable fused
pyrroles. Inspired by a recent report by May,8 in which
a carbeneꢀalkyne metathesis9 has been employed as a
key step in an efficient synthesis of bridged polycyclic ring
systems, we hypothesized that this key step can potentially
be employed in an intramolecular transannulation reac-
tion. Thus, iminocarbene F would undergo a carbeneꢀ
alkyne metathesis to form a new Rh carbene intermediate
G. A subsequent nucleophilic attack of the N atom at the
Rh carbene and the following tautomerization would
(1) For synthesis of N-sulfonyl-1,2,3-triazoles, see: (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) Fokin, V. V.; Raushel, J.
Org. Lett. 2010, 12, 4952. (c) Liu, Y.; Wang, X.; Xu, J.; Zhang, Q.; Zhao,
Y.; Hu, Y. Tetrahedron 2011, 67, 6294.
(2) For reviews, see: (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.
(3) For reports on transannulation of pyridotriazoles, see:
(a) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int. Ed.
2007, 46, 4757. (b) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463.
(4) For the first report on transannulation of N-sulfonyl-1,2,3-tria-
zoles, see: Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.;
Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972.
(7) When our work was underway, Sarpong reported an intramole-
cular transannulation of triazoles with allenes to form 6,5-fused pyrrole
systems efficiently. Schultz, E. E.; Sarpong, R. J. Am. Chem. Soc. 2013,
135, 4696.
(5) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13, 3746.
(6) (a) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52,
1507. (b) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652. (c) Parr, B. T.; Green, S. A.; Davies, H. M. L. J. Am.
Chem. Soc. 2013, 135, 4716. (d) Spangler, J. E.; Davies, H. M. L. J. Am.
Chem. Soc. 2013, 135, 6802. (e) Miura, T.; Biyajima, T.; Fujii, T.;
Murakami, M. J. Am. Chem. Soc. 2012, 134, 194. (f) Funakoshi, Y.;
Morimoto, M.; Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012,
134, 17440. (g) Miura, T.; Tanaka, T.; Hiraga, K.; Stewart, S. G.;
Murakami, M. J. Am. Chem. Soc. 2013, 135, 13652.
(8) Jansone-Popova, S.; May, J. A. J. Am. Chem. Soc. 2012, 134,
17877.
(9) For earlier reports on the carbeneꢀalkyne metathesis mechanism
in Rh-catalyzed reactions of diazocarbonyl compounds, see: (a) Padwa,
A.; Kassir, J. M.; Semones, M. A.; Weingarten, M. D. Tetrahedron Lett.
1993, 34, 7853. (b) Padwa, A.; Austin, D. J.; Gareau, Y.; Kassir, J. M.;
Xu, S. L. J. Am. Chem. Soc. 1993, 115, 2637.
r
10.1021/ol4027655
XXXX American Chemical Society

produce a fused pyrrole 2 (eq 2).10,11 Herein we report that
indeed this concept can be realized. Hence, a novel, general,
and efficient method for the construction of 5,5-fused
pyrrole units12 from easily available alkynyl triazoles has
been developed.
To test the above hypothesis, alkynyl triazole 1a was
subjected to the reaction with rhodium octanoate. To our
delight, the desired 5,5-fused pyrrole 2a was formed in
60% yield (Table1, entry 1). A briefoptimization indicated
reaction conditions of entry 9 to be sufficient for this
transformation.
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
solvent
t/°C
yield/%b
1
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(S-NTTL)4
Rh2(esp)2
ClCH2CH2Cl
CHCl3
dioxane
THF
80
80
80
80
80
80
80
80
90
70
60
50
62d(60c)
63d
2
3
19
4
trace
0
5
PhMe
6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
41d
7
63d
8
Rh2(S-DOSP)4
Rh2(esp)2
Rh2(esp)2
46d
Figure 1. Transannulation of alkynyl triazoles: R substituent
variations.a,b a 1 (0.2 mmol) and Rh2(esp)2 (1 mol %) were
dissolved in CHCl3 (3.0 mL) and heated at 90 °C for 2 h.
b Isolated yields. c Heated at 60 °C for 15 h.
9
78e
10
11
12
76d,f
Rh2(esp)2
78 (78c,f
59g
)
Rh2(esp)2
a 1a (0.1 mmol) and Rh(II) (1 mol %) were dissolved in solvent
(1.0 mL) and heated at the indicated temperature for 12 h. b GC yield.
c Isolated yield. d Desilylation of product was observed. e Heated for 2 h.
f Heated for 15 h. g Heated for 42 h.
Likewise, naphthalene- (2l) and heterocycle-substituted
pyrroles (2m) were obtained in good yields. It was also
(10) The relative rate comparison indicated that the triazoles bearing
an electron-deficient aryl group (1h and 1i) reacted faster than those
having electron-neutral (1b) or electron-rich (1c) aryl groups. This result
does not support an ylide mechanism, which strongly favors electron-
rich alkynes.5
Next, the scope of this transformation has been exam-
ined. First, we tested a series of aryl substituents at the
alkyne moiety (Figure 1, bꢀm). It was found that a variety
of groups, including OMe (d, j), F (g), Br (f), CO2Me (h),
CF3 (i), and protected diol (e), were perfectly tolerated
under these reaction conditions to produce the correspond-
ing fused pyrroles 2dꢀm in reasonable to excellent yields.
B
Org. Lett., Vol. XX, No. XX, XXXX

alkenyl (o) groups can also be efficiently utilized in this
transformation to produce the corresponding pyrroles
possessing an unsaturated unit at the C-2 position. Nota-
bly, the reaction of alkynyl triazole bearing a phenylthio
group proceeded smoothly to afford thiopyrrole 2p in
excellent yield. Moreover, TMS (2a) and Br (2q) groups
were compatible with these reaction conditions, thus pro-
viding opportunities for further functionalization of the
obtained pyrroles .13,14
We also investigated the scope of the reaction with
respect to a triazoleꢀalkyne tether (Figure 2). It was found
that substrates possessing a C-315 tether reacted well,
including those possessing ketone (2r), nitrile (2t), and
protected alcohol (2u, 2v) functional groups to produce
the corresponding fused pyrroles in good yields. Nota-
bly, this method also allows efficient access to polycyclic
spiro systems 2r, 2s. Furthermore, a substrate with
a nitrogen tether underwent a smooth transannulation
reaction to give a bicyclic tetrahydropyrrolo-pyrrole
skeleton 2w.
In summary, we developed an efficient rhodium-
catalyzed intramolecular transannulation reaction of
alkynyl N-tosyltriazoles, which involves a Rh-carbeneꢀ
alkyne metathesis step. This new method provides
expeditious access to various 5,5-fused pyrroles from
easily available starting materials. It can also be used
for the efficient construction of spiro systems, as well as
fused tetrahydropyrrolo-pyrrole cores.
Figure 2. Transannulation of alkynyl triazoles: tether varia-
tionsa,b a 1 (0.2 mmol) and Rh2(esp)2 (1 mol %) combined in CHCl3
(3.0 mL) and heated at 90 °C for 2 h. b Isolated yields. c Heated at
60 °C for 15 h. d Heated at 90 °C for 15 h.
Acknowledgment. We thank the National Institutes of
Health (GM-64444) for financial support of this work.
found that triazoles, bearing ortho- or meta-substituted
aryl groups, could also participate in this transannulation
reaction to give fused pyrroles 2j, k.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Further investigation indicated that this reaction is not
limited to aryl alkynes. Thus, we found that alkynyl (n) or
(11) Although a direct [3 þ 2] cycloaddition path cannot be com-
pletely ruled out at this point, our numerous unsuccessful attempts on
the transannulation of tosyltriazoles with a number of electron-deficient
alkynes and alkenes do not support this possibility.
(12) For 5,5-fused pyrrole cores found in biologically active mole-
cules, see for example: (a) Portevin, B.; Tordjman, C.; Pastoureau, P.;
Bonnet, J.; Nanteuil, G. D. J. Med. Chem. 2000, 43, 4582. (b) Oesterlin,
R.; Bell, M. R.; Hlavac, A. G.; McGarry, R. H.; Gelotte, K. O. J. Med.
Chem. 1980, 23, 945.
(13) For transformations of 2-silyl-pyrroles, see: (a) Aikawa, K.; Hioki,
Y.; Mikami, K. Chem.;Asian J. 2010, 5, 2346. (b)Maitin,R.;Larsen,C. H.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379. (c) Ito, H.; Sensui,
H.-O.; Arimoto, K.; Miura, K.; Hosomi, A. Chem. Lett. 1997, 7, 639.
(14) For transformations of 2-bromo-pyrroles, see: (a) Chen, W.;
Cava, M. P. Tetrahedron Lett. 1987, 28, 6025. (b) Hesp, K. D.; Lundgren,
R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194. (c) Korsager, S.;
Taaning, R. H.; Skrydstrup, T. J. Am. Chem. Soc. 2013, 135, 2891. (d)
Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J. E. Org.
Lett. 2010, 12, 3578.
(15) Attempts on employment of alkynyltriazoles possessing C-2 or
C-4 tethers were not successful.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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