Regiocontrolled synthesis of polysubstituted pyrroles starting from terminal alkynes, sulfonyl azides, and allenes

Article abstract of DOI:10.1021/ol401340u

1-Sulfonyl-1,2,3-triazoles, readily prepared from terminal alkynes and sulfonyl azides, react with allenes in the presence of a nickel(0) catalyst to produce the corresponding isopyrroles. The initially produced isopyrroles are further converted to a wide

Full text of DOI:10.1021/ol401340u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regiocontrolled Synthesis of Polysubstituted
Pyrroles Starting from Terminal Alkynes,
Sulfonyl Azides, and Allenes
Tomoya Miura,* Kentaro Hiraga, Tsuneaki Biyajima, Takayuki Nakamuro, and
Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Katsura, Kyoto 615-8510, Japan
tmiura@sbchem.kyoto-u.ac.jp; murakami@sbchem.kyoto-u.ac.jp
Received May 14, 2013
ABSTRACT
1-Sulfonyl-1,2,3-triazoles, readily prepared from terminal alkynes and sulfonyl azides, react with allenes in the presence of a nickel(0) catalyst to
produce the corresponding isopyrroles. The initially produced isopyrroles are further converted to a wide range of polysubstituted pyrroles
through double bond transposition and Alder-ene reactions.
Pyrroles are privileged structural motifs found in a
number of natural products, pharmaceutical compounds,
and functional materials. Thus, the development of effi-
cient methods for their synthesis, particularly regiocon-
trolled synthesis of those containing multiple substituents,
from readily accessible compounds is of ever-increasing
importance.1,2
On the other hand, 4-substituted 1-sulfonyl-1,2,3-tria-
zoles are easily prepared from terminal alkynes and sulfo-
nyl azides by the well-established method using a copper(I)
catalyst.3 It has recently been disclosed that they act
as precursors for reactive transition metal complexes of
R-imino carbenes.4ꢀ7 If compared with related R-oxo
carbene complexes, the nitrogen atom of the R-imino
group is considerably more nucleophilic and thus this
moiety possibly participates in the cycloaddition reaction
with unsaturated compounds to construct N-heterocycles.
For example, the reactions with nitriles,5a alkynes,5d,6 alde-
hydes,5j and isocyanates5l furnish the corresponding imida-
zoles, pyrroles, oxazolines, and imidazolones, respectively.
(4) For a pioneering work using pyridotriazoles, see: Chuprakov, S.;
Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757.
(5) For rhodium(II)-catalyzed reactions, see: (a) Horneff, T.; Chuprakov,
S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130,
14972. (b) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V.
J. Am. Chem. Soc. 2009, 131, 18034. (c) Grimster, N.; Zhang, L.; Fokin, V. V.
J. Am. Chem. Soc. 2010, 132, 2510. (d) Chattopadhyay, B.; Gevorgyan, V.
Org. Lett. 2011, 13, 3746. (e) Chuprakov, S.; Malik, J. A.; Zibinsky, M.;
Fokin, V. V. J. Am. Chem. Soc. 2011, 133, 10352. (f) Miura, T.; Biyajima, T.;
Fujii, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 194. (g) Selander, N.;
Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 2477. (h) Miura, T.; Funakoshi,
Y.; Morimoto, M.; Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012,
134, 17440. (i) Selander, N.; Worrell, B. T.; Fokin, V. V. Angew. Chem., Int.
Ed. 2012, 51, 13054. (j) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed.
2013, 52, 1507. (k) Miura, T.; Tanaka, T.; Biyajima, T.; Yada, A.; Murakami
Angew. Chem., Int. Ed. 2013, 52, 3883. (l) Chuprakov, S.; Kwok, S. W.;
Fokin, V. V. J. Am. Chem. Soc. 2013, 135, 4652. (m) Parr, B. T.; Green, S. A.;
Davies, H. M. J. Am. Chem. Soc. 2013, 135, 4716. For reviews, see: (n)
Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed. 2012, 51, 862. (o)
Gulevich, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2013, 52, 1371.
(6) For a nickel(0)-catalyzed reaction, see: Miura, T.; Yamauchi, M.;
Murakami, M. Chem. Commun. 2009, 1470.
(1) For a general review on transition-metal-mediated synthesis of
monocyclic aromatic heterocycles, see: (a) Gulevich, A. V.; Dudnik,
A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. For
reviews on pyrrole synthesis, see: (b) Balme, G. Angew. Chem., Int. Ed.
2004, 43, 6238. (c) Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095.
(2) For selected recent examples of pyrrole synthesis, see: (a) Lourdusamy,
E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed. 2010, 49, 7963. (b) Trost,
B. M.; Lumb, J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011, 133, 740. (c)
Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew. Chem., Int.
Ed. 2011, 50, 1338. (d) Xu, X.; Ratnikov, M. O.; Zavalij, P. Y.; Doyle,
M. P. Org. Lett. 2011, 13, 6122. (e) Chen, F.; Shen, T.; Cui, Y.; Jiao, N.
Org. Lett. 2012, 14, 4926. (f) Wang, L.; Ackermann, L. Org. Lett. 2013,
15, 176. (g) Reddy, B. V. S.; Reddy, M. R.; Rao, Y. G.; Yadav, J. S.;
Sridhar, B. Org. Lett. 2013, 15, 464. (h) Michlik, S.; Kempe, R. Nat.
Chem. 2013, 5, 140.
(3) (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.
(7) For a silver(I)-catalyzed reaction, see: Liu, R.; Zhang, M.;
Winston-McPherson, G.; Tang, W. Chem. Commun. 2013, 49, 4376.
r
10.1021/ol401340u
XXXX American Chemical Society

We now report a nickel(0)-catalyzed transannulation reac-
tion of 1-sulfonyl-1,2,3-triazoles with allenes.8 Thisreaction
provides a highly versatile approach to polysubstituted
pyrroles starting from terminal alkynes, sulfonyl azides,
and allenes with position control of the substituents.
4-Phenyl-1-tosyl-1,2,3-triazole (1a) was initially prepared
from phenylethyne and tosyl azide according to Fokin’s
procedure using copper(I) thiophene-2-carboxylate (CuTC)
(eq 1).3b Then, 1a (0.20 mmol) was treated with undeca-1,2-
diene (2a, 1.5 equiv) in 1,4-dioxane at 80 °C in the presence of a
nickel(0) catalyst, generated in situ from Ni(cod)2 (10 mol %)
and rac-2,4-bis(diphenylphosphino)pentane (bdpp).9,10
groups at the 4-position reacted well with allene 2a to
afford the corresponding pyrroles 4baꢀda in yields
ranging from 86% to 99% (entries 1ꢀ3). Electron-donating
and -withdrawing substituents were both tolerated on
the benzenesulfonyl group (entries 4 and 5). 4-Alkyl-
substituted substrates 1gꢀi also gave the pyrroles
4gaꢀia in good yields (entries 6ꢀ8). Given the mecha-
nism proposed below, the low propensity for 1,2-hydride
migration is a substantial advantage of the present
nickel case.
Table 1. Transannulation of 4-Substituted 1-Sulfonyl-1,2,3-
triazoles 1bꢀi with Undeca-1,2-diene (2a)a
1
The H NMR spectrum of the crude reaction mixture
indicated that 3-methylene-2,3-dihydropyrrole 3aa was
formed as a single detectable transannulation product.2b,11
Thus, the azo moiety (ꢀNdNꢀ) was extruded out of 1a
and instead the allene 2a was incorporated therein. When
the reaction mixture was directly subjected to chromato-
graphic isolation, 3aa partly underwent double bond
transposition to afford a mixture of 3aa and 3-methyl-2-
octyl-4-phenyl-1-tosyl-pyrrole (4aa). On the other hand,
direct addition of p-toluenesulfonic acid to the reaction
mixture accelerated the double bond transposition, and
4aa was isolated in 90% yield (eq 2).
entry
1
R1
R3
4
yield (%)b
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
4-MeO-C6H4
4-CF3-C6H4
3-thienyl
Ph
4-Tol
4-Tol
4-Tol
4ba
4ca
4da
4ea
4fa
99
86
86
74
82
82
81c
69d
4-MeO-C6H4
4-F-C6H4
4-Tol
Ph
1g
1h
1i
n-Hex
4ga
4ha
4ia
(CH2)4OBz
Cy
4-Tol
4-Tol
a Conditions: 1 (0.20 mmol), 2a (0.30 mmol), Ni(cod)2 (10 mol %),
and bdpp (10 mol %) in 1,4-dioxane (4 mL) at 80 °C for 4 h, then at rt for
5 min in the presence of TsOH (20 mol %) unless otherwise noted.
b Isolated yields. c 6 h. d 8 h.
Next, the variation of allenes 2 was examined in the
reaction of triazole 1a (Table 2). Monosubstituted allenes
2bꢀf having primary and secondary alkyl groups gave the
corresponding pyrroles4abꢀafinyields ranging from 83%
to 90% (entries 1ꢀ5). In the case of tert-butyl-substituted
allene 2g, the double bond transposition was slow, prob-
ably due to steric reasons, to furnish the isopyrrole 3ag in
87% isolated yield (entry 6). Phenyl-substituted allene 2h
gave the product 4ah in 58% yield together with unidenti-
fied byproducts (entry 7).13
The isopyrrole 3aa facilely gained aromatic stabilization also
by Alder-ene reactions (eq 3).12 Addition of Echenmoser’s
salt, diethyl ketomalonate, and diethylazodicarboxylate to
the reaction mixture produced the corresponding pyrroles
5aa, 6aa, and 7aa, respectively.
Although 1,3-disubstituted cyclic allene 2i participated
in the reaction to afford the pyrrole 4ai in 57% yield (eq 4),
(8) The following paper describing a rhodium(II)-catalyzed intramo-
lecular transannulation reaction of 1-sulfonyl-1,2,3-triazoles with al-
lenes recently appeared during preparation of this manuscript: Schultz,
E. E.; Sarpong, R. J. Am. Chem. Soc. 2013, 135, 4696.
(9) Other bisphosphine ligands gave inferior results (NMR yield/%):
dppm (0), dppe (0), and dppp (23). Although the bulky monophosphine
ligand [P(n-Bu)Ad2] was the optimal ligand for the transannulation with
alkynes,6 it failed to effect the transannulation with allenes.
(10) Rhodium(II) catalysts gave inferior results for intermolecular
transannulation. For example, 3aa was not obtained with Rh2(OCOtBu)4
(1.0 mol %, 80 °C, 4 h, 1,2-dichloroethane).
(11) For the synthesis of isopyrroles, see: Larock, R. C.; Doty, M. J.;
Han, X. Tetrahedron Lett. 1998, 39, 5143.
(12) For related Alder-ene reactions of isoindoles, see: Tidwell, J. H.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797.
(13) Ethoxycarbonyl-substituted allene failed to participate in the
transannulation reaction to give a complex mixture.
Other 1,4-disubstituted triazoles 1bꢀi were also pre-
pared from the corresponding terminal alkynes and sulfonyl
azides, and the generality of the transannulation reaction
was examined (Table 1). Substrates 1bꢀd possessing aryl
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Transannulation of 4-Phenyl-1-tosyl-1,2,3-triazole (1a)
with Allenes 2bꢀha
entry
2
R4
4
yield (%)b
1
2
3
4
5
6
7
2b
2c
2d
2e
2f
Et
4ab
4ac
4ad
4ae
4af
83c
90
(CH2)2Ph
(CH2)4OBn
89
(CH2)4OSi(t-Bu)Me2
86
Other 1,5-disubstituted triazoles 1kꢀn were also prepared
from the corresponding terminal alkynes and sulfonyl
azides via lithium acetylides, and their transannulation
reaction was also examined (Table 3). Substrates 1kꢀn
possessing aryl and alkyl groups at the 5-position afforded
the corresponding products 4kaꢀna in yields ranging
from 68% to 80% (entries 1ꢀ4). As with the case of 1,4-
disubstituted triazoles, various allenes 2 were successfully
incorporated into the 1,5-disubstituted triazolyl skeleton
of 1j (entries 5ꢀ8). Thus, 2,3,5-trisubstituted pyrroles were
selectively synthesized from terminal alkynes, tosyl azide,
and allenes.
Cy
88
2g
2h
t-Bu
Ph
3ag
4ah
87
58d
a The same reaction conditions as those in Table 1 unless otherwise
noted. b Isolated yields. c Using 2.0 equiv of 2b. d Using 3.0 equiv of 2h
and 20 mol % of Ni(cod)2/bdpp for 5 h.
other disubstituted allenes such as penta-2,3-diene and
3-methylbuta-1,2-diene failed to participate in the trans-
annulation reaction and a large amount of triazole 1a was
recovered. The disubstituted allenes were considerably less
reactive, and the nickel catalyst deteriorated upon reaction
with 1a.
Table 3. Transannulation of 5-Substituted 1-Sulfonyl-1,2,3-
triazoles 1jꢀn with Various Allenes 2a
5-Phenyl-1-tosyl-1,2,3-triazole (1j) was prepared from
phenylethyne and tosyl azide according to Croatt’s proce-
dure via lithium acetylides.14 The transannulation reaction
of 1j with allene 2a under the same reaction conditions
produced 3-methylene-2,3-dihydropyrrole 3ja.
entry
1
R2
2
R4
4
yield (%)b
1
2
3
4
5
6
7
8
1k
1l
4-MeO-C6H4 2a Oct
4ka
4la
80
71
68
73
77
85
71
85c
4-CF3-C6H4
2a Oct
2a Oct
2a Oct
2b Et
1m n-Hex
1n Cy
4ma
4na
4jb
1j
1j
1j
1j
Ph
Ph
Ph
Ph
2d (CH2)4OBn 4jd
2f Cy
2j (CH2)3CN
4jf
4jj
a Conditions: 1 (0.20 mmol), 2 (0.40 mmol), Ni(cod)2 (10 mol %), and
bdpp (10 mol %) in 1,4-dioxane (4 mL) at 80 °C for 3 h, then at rt for 5 min
in the presence of TsOH (20 mol %). b Isolated yields. c TsOH (110 mol %).
When p-toluenesulfonic acid was directly added to the
crude mixture of 3ja, octyl-5-phenyl-1-tosyl-pyrrole (4ja)
was isolated in 85% yield (eq 6). The isopyrrole 3ja was also
reacted with Echenmoser’s salt to produce the pyrrole 5ja in
74% yield. Interestingly, the tosyl group on the nitrogen
transferred onto the exo-methylene carbon upon heating
3ja at 180 °C under microwave irradiation for 1 h, yielding
N-H pyrrole 8ja in 82%.15
It is generally difficult in organic reactions to discern
different alkyl groups of similar electronic as well as
steric characters. Therefore, regiocontrolled synthesis
of pyrroles having multiple alkyl substituents presents
a significant challenge.2c For example, the nickel(0)-
catalyzed transannulation reaction of 1a with pent-2-yne
gave an almost 1:1 mixture of two isomeric pyrroles.6,16
We applied the nickel(0)-catalyzed transannulation re-
action with allenes to the synthesis of pyrrole having
~
(14) Meza-Avina, M. E.; Patel, M. K.; Lee, C. B.; Dietz, T. J.; Croatt,
M. P. Org. Lett. 2011, 13, 2984.
(15) The tosyl group of isopyrrole 3aa failed to transfer under the
same reaction conditions. For a precedence of N- to C-transfer of a
sulfonyl group with dihydropyridones, see: Simal, C.; Lebl, T.; Slawin,
A. M. Z.; Smith, A. D. Angew. Chem., Int. Ed. 2012, 51, 3653.
(16) See the Supporting Information for more details.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Transannulation of 4-Substituted 5-Pentyl-1-
tosyl-1,2,3-triazoles 1qꢀu with Undeca-1,2-diene (2a)a
Scheme 1. Plausible Mechanism for the Nickel(0)-Catalyzed
Synthesis of Isopyrrole 3 from Triazole 1 and Allene 2
entry
1
R1
4
yield (%)b
1
2
3
4
5
1q
1r
1s
1t
Me
4qa
4ra
4sa
4ta
4ua
73
78c
90
86
99
Si(t-Bu)Me2
C(O)n-Pr
C(O)Ph
A plausible mechanism for the production of isopyrrole
3 from triazole 1 and allene 2 is depicted in Scheme 1.
First, a reversible ringꢀchain tautomerization of 1-sulfonyl-
1,2,3-triazole 1 generates R-diazo imine 10.17 The gen-
erated 10 reacts with nickel(0) in an irreversible manner
to afford R-imino nickel carbene A with extrusion of
molecular nitrogen. Nucleophilic addition of allene 2 to
the electrophilic carbene center of A occurs in preference to
1,2-hydride migration (vide supra) to furnish zwitterionic
intermediate B. With the allyllic cation moiety of B, a more
positive charge is distributed at the more substituted
carbon. The anionic nickel of B releases an electron pair,
which flows into the imine moiety to make the nitrogen
atom nucleophilic enough to couple with the more sub-
stituted, and hence more positively charged, allylic carbon
atom. Thus, the isopyrrole 3 is selectively formed.
1u
CO2Bn
a The same reaction conditions as those in Table 3 unless otherwise
noted. b Isolated yields. c Adding 4.0 equiv of 2a in two portions.
three different alkyl groups (eq 7). Thus, 1,4- and 1,5-
disubstituted triazoles 1o and 1p were prepared starting
from pent-1-yne, as mentioned above. Each of them was
subjected to the transannulation reaction with pent-1,2-
diene (2b). The following double bond transposition selec-
tively furnished 2-ethyl-3-methyl-4-propyl-1-tosyl-pyrrole
(4ob) and 2-ethyl-3-methyl-5-propyl-1-tosyl-pyrrole (4pb),
respectively.
In conclusion, we have reported a new synthetic path-
way to polysubstituted pyrroles. Although it is difficult
to synthesize them with position control of multiple sub-
stituents, the present protocol renders it possible to selec-
tively synthesize isomeric pairs of polysubstituted pyrroles
4aa/4ja, 4ba/4ka, 4ab/4jb, 4ob/4pb, 5aa/5ja, etc., in which the
positions of the multiple substituents are different. It is also
demonstrated that not only 1,4-disubstituted triazoles but
also 1,5-disubstituted and 1,4,5-trisubstituted ones are easily
accessible precursors of reactive R-imino carbene complexes.
4,5-Disubstituted 1-sulfonyl-1,2,3-triazoles were also
prepared according to Croatt’s procedure.14 The 1,3-dipolar
cycloaddition reaction of a lithium acetylide with tosyl
azide gave rise to a 4-lithiated triazole, which was then
reacted with electrophiles such as methyl iodide, chlorosi-
lane, and acid chlorides. The resulting 4-substituted 5-pen-
tyl-1-tosyl-1,2,3-triazoles were reacted with 2a under the
standard reaction conditions (Table 4). Substrates 1q
and 1r possessing methyl and silyl groups at the 4-position
were smoothly transformed to the corresponding fully
substituted pyrroles 4qa and 4ra (entries 1 and 2). In
particular, substrates 1sꢀu possessing a carbonyl group
at the 4-position were highly reactive to quantitatively afford
the pyrroles 4saꢀua, probably due to the enhanced electro-
philicity of the nickel carbene intermediate (entries 3ꢀ5).
Acknowledgment. We thank Dr. Motoshi Yamauchi
(Daiichi Sankyo Co., Ltd.) for making a valuable discov-
ery at an early stage. This work was supported by MEXT
(Grant-in-Aid for Scientific Research on Innovative Areas
Nos. 22105005 and 24106718, Scientific Research (B) No.
23350041, Young Scientists (A) No. 23685019), JST (ACT-C),
and the Takeda Science Foundation.
Supporting Information Available. Experimental details
and spectra data for new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(17) McKinney, M. A.; Patel, P. P. J. Org. Chem. 1973, 38, 4059.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX