A new pyrrole synthesis via silver(I)-catalyzed cycloaddition of vinylogous diazoester and nitrile

Article abstract of DOI:10.1021/ol400062w

A new synthesis of di- and trisubstituted pyrroles was achieved by treating in situ generated vinylogous diazoesters and readily available nitriles with a catalytic amount of silver(I) antimony hexafluoride at room temperature. This method showcased the potential of utilizing silver(I) carbenoids in preparing heterocyclic compounds.

Full text of DOI:10.1021/ol400062w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A New Pyrrole Synthesis via
Silver(I)-Catalyzed Cycloaddition of
Vinylogous Diazoester and Nitrile
Roland J. Billedeau, Klara R. Klein, Daniel Kaplan, and Yan Lou*,†
Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development,
Small Molecule Research, Discovery Chemistry, 340 Kingsland Street, Nutley,
New Jersey 07110, United States
yan.lou@gmail.com
Received January 9, 2013
ABSTRACT
A new synthesis of di- and trisubstituted pyrroles was achieved by treating in situ generated vinylogous diazoesters and readily available nitriles
with a catalytic amount of silver(I) antimony hexafluoride at room temperature. This method showcased the potential of utilizing silver(I)
carbenoids in preparing heterocyclic compounds.
Pyrroles are an essential structural component of many
biologically active natural products and medicines.1 Since
the first reported synthesis of pyrroles,2 much effort has
been devoted to the development of new synthetic methods
to prepare functionalized pyrroles with well-defined
substitution patterns under mild conditions,3 some of
which were facilitated by metal catalysis.4
Inspired by Moody’s synthesis of oxazoles using rho-
dium(II) catalyzed cycloaddition ofdiazoesters and nitriles
(Scheme 1),5 we conceived a synthetic route to pyrroles
via cycloaddition of vinylogous diazoesters and nitriles.
(Scheme 2)
† Present address: Novartis Institute of Biomedical Research, Global
Discovery Chemistry, 4560 Horton Street, Emeryville, CA 94608.
(1) (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilcrist, T. L., Eds; Pergamon:
Oxford, 2003; Vol. 15, p 167. (b) Boger, D. L.; Boyce, C. W.; Labrili,
M. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (c) Muchowski, J. M.
Adv. Med. Chem. 1992, 1, 109.
Scheme 1. Moody’s Oxazole Synthesis via Possible 1,5-Cycli-
zation of Nitrile Ylide
(2) Knorr, L. Chem. Ber 1884, 17, 1635.
(3) Selected reviews and articles: (a) Bergman, J.; Janosik, T. Modern
Heterocyclic Chemistry 2011, 1, 269. (b) Joule, J. A.; Mills, K. Hetero-
cyclic Chemistry; Blackwell Science: Oxford, U.K., 2000; Chapter 13. (c)
Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238. (d) Qi, X.; Xu, X.; Park,
€
C.-M. Chem. Commun. 2012, 48, 3996. (e) Bauer, I.; Knolker, H.-J. Top.
Curr. Chem. 2012, 309, 203. (f) Estevez, V.; Villacarpa, M.; Menendez,
J. C. Chem. Soc. Rev. 2010, 39, 4402.
(4) Selected examples: (a) Wang, H.-Y.; Mueller, D. S.; Sachwani,
R. M.; Kapadia, R.;Londino, H. N.;Anderson, L. L. J. Org. Chem. 2011,
76, 3203. (b) Yamamoto, H.; Sasaki, I.; Mitsutake, M.; Karasudani, A.;
Imagawa, H.; Nishizawa, M. Synlett 2011, 19, 2815. (c) Patil, N. T.;
Yamamoto, Y. ARKIVOC 2007, 121. (d) Dudnik, A. S.; Scromek, A. W.;
Rubina, M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc.
2008, 130, 1440. (e) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012,
14, 4926. (f) Zhang, Y.; Zhang, J. Synlett 2012, 23, 1389. (g) Kim, J. H.;
Lee, S. B.; Lee, W. K.; Yoon, D.-H.; Ha, H.-J. Tetrahedron 2011, 67,
3553. (h) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12, 312. (i) Dong,
H.; Shen, M.; Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.; Driver, T. G.
Org. Lett. 2007, 9, 5191. (j) Gabriele, B.; Salerno, G.; Fazio, A. J. Org.
Chem. 2003, 68, 7853.
Surprisingly, we found few literature reports on the
synthesis, properties, and reactivity of simple vinylogous
diazoesters.6 Therefore, we performed a proof-of-concept
(5) Doyle, K. J.; Moody, C. J. Tetrahedron 1994, 50, 3761. For
selected general reviews of diazo compounds: (a) Ye, T.; Mckervey,
M. A. Chem. Rev. 1994, 94, 1091. (b) Zhang, Z.; Wang, J. Tetrahedron
2008, 64, 6577.
(6) Gant, T. G.; Noe, M. C.; Corey, E. J. Tetrahedron Lett. 1995, 36,
8745.
r
10.1021/ol400062w
XXXX American Chemical Society

Table 1. Screened Catalytic Conditions To Form Pyrrole 3a
with Diazoester 1 and Benzonitrilea
Scheme 2. Proposed Pyrrole Synthesis via 1,5-Cyclization of
Vinylogous Nitrile Ylide
yieldb
entry
catalyst
solvent
CHCl3
temperature
of 3a
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
Cu(OTf)2
TMSOTf
In(OTf)3
(Ph3P)AuOTf
AgOBz
rt to reflux
reflux
reflux
reflux
reflux
reflux
reflux
rt
none
none
none
none
none
trace
3%
CHCl3
ClCH2CH2Cl
CHCl3
experiment to examine whether vinylogous diazoesters
could undergo [3 þ 2] cycloaddition with a nitrile. For
simplicity, (E)-5-diazo-pent-3-enoic acid ethyl ester (1) was
chosen. Diazoester 1 was prepared in one pot by treating
(E)-4-oxo-but-2-enoic acid ethyl ester with tosyl hydrazine
followed by exposure to triethyl amine and DBU (eq 1).7
After purification, diazoester 1 was found to be stable for
weeks when stored below ꢀ10 °C either neat or as solu-
tion in dichloromethane. However, at room temperature, 1
slowly and cleanly rearranges over days to 1H-pyrazole-3-
carboxylic acid ethyl ester (2) (eq 2).
CHCl3
CHCl3
AgOTf
CHCl3
AgOTf
CHCl3
10%
62%
AgSbF6
CH2Cl2
rt
a All reactions were carried out by adding 0.1 mmol of diazoester 1
via syringe pump over 1 h into a solution of 1 mmol of benzonitrile and
0.01 mmol of catalyst in 5 mL of respective solvent. b Isolated yield.
about 40ꢀ60% yields (Table 2). The reaction was tolerant
of both electron-rich (entry 4) and electron-deficient aryl
nitriles(entry 7). Steric hindrancedid not seem toadversely
affect the yield as 2,6-dimethyl benzonitrile (entry 8) and
tert-butyl nitrile (entry 10) gave 64% and 45% of the
desired products, respectively, within the general range of
this reaction under standard conditions. Further improve-
ment of the yield might be possible with more vigorously
anhydrous conditions, assessment of the catalyst loading,
and screening of other Ag salts.
Encouraged by the general reaction scope with diazo-
ester 1 to prepare disubstituted pyrroles, we decided to ex-
plore a possible extension to more substituted diazos such
as diazoester 4 to make more heavily substituted pyrroles.
Though diazoester 4 could be prepared in an analogous
fashion asdiazoester1, it seemed to be much less stable and
the isolated product usually contained ∼20% of the corre-
sponding cyclized pyrazole 5.
With diazoester 1 in hand, a variety of Lewis acid
catalysts were screened to catalyze its reaction with benzo-
nitrile to form pyrrole 3a. As can be seen from the results in
Table 1, Rh2(OAc)4 did not promote the desired reaction
at room temperature or at reflux in chloroform or toluene.
AgOBz was the first catalyst to give a trace amount of the
desired product (entry 6). When the more Lewis acidic
AgOTf was used, the desired pyrrole product 3a was ob-
tained in 10% yield at room temperature. When AgSbF6
was used, the yield improved to 62% (entry 9). Interest-
ingly, during our investigation, the use of Ag(I) catalysts
was reported by others for cycloaddition reactions with stable
diazo compounds and shown to be more effective than
Rh(II) catalysts in cyclopropanation8 and cyclopropenation9
reactions with donor-/acceptor-substituted diazo com-
pounds. Our results further support the hypothesis8 that
silver carbenoids can provide differerentiated reactivity
from more commonly used rhodium carbenoids.
AgSbF6 was found to be capable of catalyzing similar
cycloaddition reactions with diazoester 4 and various
nitriles to form trisubstituted pyrroles 6aꢀe, albeit at lower
yields (Table 3). There are multiple factors that could
contribute to the lower yields with diazoester 4: the sub-
optimal reactivity of the corresponding silver carbenoid,
the comparably lower stability of diazoester 4, and the
likelihood of interference by impurity 5. However, further
studies are warranted to fully evaluate the electronic and
steric impact of different substituents on the stability and
reactivity of these vinylogous diazoesters.
The substrate scope of the reaction catalyzed by AgSbF6
appeared tobequitebroad. Thereaction workedwith both
alkyl and aryl nitriles, giving desired pyrroles 3aꢀk in
(7) Note: in order to minimize decomposition during purification,
vacuum concentration of the crude mixture was performed at 0 °C.
(8) Thompson, J.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
6090.
(9) Briones, J. F.; Davies, H. M. L. Org. Lett. 2011, 13, 3984.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. AgSbF6 Catalyzed Pyrrole Formation with Diazoester
1 and Various Nitrilesa
Table 3. AgSbF6 Catalyzed Pyrrole Formation with Diazoester
4 and Various Nitrilesa
a All reactions were carried out by adding 0.1 mmol of diazoester 4 in
1.25 mL of CH2Cl2 via syringe pump over 1 h into a solution of 1 mmol
of corresponding nitrile and 0.01 mmol of AgSbF6 in 5 mL of CH2Cl2.
b Isolated yield.
new synthetic approach to di- and trisubstituted pyrroles.
This new reactivity of silver carbenoids may find wider
application in preparing other types of pyrroles and other
heterocyclic compounds.
Acknowledgment. This work was supported by Hoff-
mann-La Roche summer intern programs (K.K. was a
2007 summer intern, and D.K. was a 2010 summer intern).
The authors would like to thank Roche colleagues
Fernando Padilla, Shelley Gleason, and Saul Jaime
Figueroa for their assistance in retrieving 1H NMR data
for some compounds.
a All reactions were carried out by adding 0.1 mmol of diazoester 1 in
1.25 mL of CH2Cl2 via syringe pump over 1 h into a solution of 1 mmol
of corresponding nitrile and 0.01 mmol of AgSbF6 in 5 mL of CH2Cl2.
b Isolated yield.
Supporting Information Available. Detailed experimen-
tal procedures and full characterization including 1H
NMR, 13C NMR, FTIR, and HRMS for new com-
pounds. This material is free of charge via the Internet
at http://pubs.acs.org.
In summary, we have discovered that AgSbF6 can
effectively catalyze cycloaddition reactions of vinylogous
diazo compoundsand readily available nitriles toprovide a
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C