Au(I)-catalyzed rearrangement reaction of propargylic aziridine: synthesis of trisubstituted and cycloalkene-fused pyrroles

Article abstract of DOI:10.1021/ol901649p

A rearrangement reaction of propargylic aziridine, catalyzed by PPh ₃AuCI/AgOTf, forming trisubstituted and cycloalkene-fused pyrroles is described which involves an unusual tandem cyclization/ring-opening/Wagner- Meerwein process. The unique s

Full text of DOI:10.1021/ol901649p

ORGANIC
LETTERS
2009
Vol. 11, No. 17
4002-4004
Au(I)-Catalyzed Rearrangement Reaction
of Propargylic Aziridine: Synthesis of
Trisubstituted and Cycloalkene-Fused
Pyrroles
Xiong Zhao, En Zhang, Yong-Qiang Tu,* Yong-Qiang Zhang, Dao-Yi Yuan,
Ke Cao, Chun-An Fan, and Fu-Min Zhang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received July 20, 2009
ABSTRACT
A rearrangement reaction of propargylic aziridine, catalyzed by PPh3AuCl/AgOTf, forming trisubstituted and cycloalkene-fused pyrroles is
described which involves an unusual tandem cyclization/ring-opening/Wagner-Meerwein process. The unique structures of the products
demonstrated its potential applications for synthesizing structurally diverse alkaloids.
Pyrroles are ubiquitous structural units that extensively exist
in numerous pharmaceuticals and natural products.1 As more
and more pyrrole derivatives are identified that possess
significant biological activity,2 the development of highly
efficient methodology for synthesizing structurally diverse
pyrroles has attracted the attention of chemists.1,3 Although
various methods, especially those based on transition-metal
catalysis, are available,4 efficient construction of cycloalkene-
fused pyrroles has been rarely achieved, and even fewer of
these have been derived through the annulation of a multi-
functionalized aziridine with a C-C triple bond.5 Recently,
our independent research efforts in gold catalysis as well as
aziridine chemistry have made some interesting contributions
to synthetic methodology.6 One example involves the
construction of a quaternary carbon-containing aminoalkyne
(1) (a) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, p 119. (b) Fan, H.; Peng, J.; Hamann, M. T.; Hu,
J.-F. Chem. ReV. 2008, 108, 264.
(2) (a) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson,
E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic,
D. R.; Stratton, C. D.; Wilson, M. W. J. Med. Chem. 1991, 34, 357. (b)
Perrin, D.; van Hille, B.; Barret, J.-M.; Kruczynski, A.; Etievant, C.; Inbert,
T.; Hill, B. T. Biochem. Pharmacol. 2000, 59, 807.
(4) For selected examples, see: (a) Kel’in, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (b) Gorin, D. J.; Davis,
N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (c) Kamijo, S.;
Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (d)
Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (e) Lu, Y.; Fu, X.;
Chen, H.; Du, X.; Jia, X.; Liu, Y. AdV. Synth. Catal. 2009, 351, 129. (f)
Merkul, E.; Boersch, C.; Frank, W.; Mu¨ller, T. J. J. Org. Lett. 2009, 11,
2269. (g) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005,
44, 5664.
(3) (a) Ferreira, V. F.; De Souza, M. C. B. V.; Cunha, A. C.; Pereira,
L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411. (b)
Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I. Chem.
ReV. 2004, 104, 2481. (c) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith,
J. A.; Wong, D. J. Eur. J. Org. Chem. 2006, 3043
.
(5) Davies, P. W.; Martin, N. Org. Lett. 2009, 11, 2293.
10.1021/ol901649p CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

2, a versatile Mannich base, from propargylic aziridine 1 as
presented in Scheme 1. This result led us to envision that
knowledge, this type of reaction has not been reported.
Herein we present our experimental results in detail.
Given the information above, 4 was selected as a model
substrate to pursue optimization of reaction conditions using
different gold/silver complexes and solvents (Table 1). Gratify-
ingly, under promotion of 5 mol % of PPh3AuCl/AgOTf at
reflux temperature in toluene, the reaction of 4 gave rise to the
desired product 5 in 63% yield (entry 1). When the reaction
was performed in dry toluene, a lower yield of 5 was obtained
(entry 2). Changing the PPh3AuCl catalyst with AuCl slightly
decreased the yield (entry 3). No desired product was obtained
when the PPh3AuCl catalyst was replaced with AuCl3 (entry
4). No reaction was observed if the reaction was run at room
temperature (entry 5) or with sole AuCl or PPh3AuCl catalysts
(entries 6 and 7). Also, no expected product was obtained when
AgOTf was solely used (entry 8). Control experiments to
examine the simple Brønsted acid catalysis with 5 mol % of
TfOH (entry 9) were also performed that indicated no desired
product could be obtained.11
Scheme 1. Previous Work
treatment of propargylic aziridine 1 with a suitable gold
catalyst would permit a tandem semipinacol rearrangement
and a 5-endo-dig cyclization7 to produce the 2,3-dihydro-
pyrrole 3 in one pot.8
Our preliminary treatment of 1 with 10 mol % of
PPh3AuCl/AgOTf in CH2Cl2, however, did not provide the
expected dihydropyrrole 3 but, not surprisingly, a semipi-
nacol rearrangement product 2. Further tests using several
gold and silver complexes in different solvents still failed
to produce 3. To our delight, when the substrate 4 (Table 1)
With the optimal conditions (Table 1, entry 1) in hand,
the scope of this rearrangement reaction was further inves-
tigated. Initially, we inspected the substitution effect of R at
the triple bond terminal. The results obtained (Table 2)
Table 1. Optimization of Au-Catalyzed Reaction Conditions of
Table 2. Au-Catalyzed Reactions of Ring-Fused Propargylic
4a
Aziridinesa
entry
catalyst
PPh3AuCl/AgOTf toluene, 110 °C, 4 h
conditions
yieldb (%)
entry
n
Rb
product
time (h)
yieldc (%)
1
2
3
4
5
6
7
8
9
63
55
50
0
0
0
0
0
0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
0
0
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
4.0
2.5
4.0
3.0
4.0
1.0
3.0
0.1
0.1
63
65
76
76
90
93
88
60
55
PPh3AuCl/AgOTf
AuCl/AgOTf
AuCl3/AgOTf
PPh3AuCl/AgOTf
AuCl
dry toluene, 110 °C, 3.5 h
toluene, 110 °C, 2 h
toluene, 110 °C, 3 h
toluene, rt, 24 h
toluene, 110 °C, 24 h
toluene, 110 °C, 24 h
toluene, 110 °C, 2 h
toluene, rt, 5 min
4-MeOC6H4
4-F3CC6H4
n-pentyl
cyclopropyl
3-thiophenyl
2-naphthyl
Ph
PPh3AuCl
AgOTf
TfOH
4-MeOC6H4
a Reaction conditions: The propargylic aziridine 4 (0.5 M in toluene)
a The reaction was performed on a 0.5 mmol scale in 10 mL of toluene
with 5 mol % of PPh3AuCl and 5 mol % of AgOTf at reflux temperature.
b For a diastereomeric ratio of the substrates, see the Supporting Information.
c Isolated yield.
was treated with 5 mol % of catalysts. b Isolated yield.
with a hydroxyl group protected by TBSCl was subjected
to treatment using the above catalysts in toluene at reflux
temperature, a light yellow solid was obtained, which was
identified as N-phthaloylcycloheptene-2,3-fused-5-phenylpyr-
role 5.9 This transformation was important as it involved a
unique sequential N-addition to a C-C triple bond, ring-
opening of an aziridine, and a Wagner-Meerwein-type
C-to-C rearrangement10 and also efficiently constructed the
3-vinyl-2,3,5-trisubstituted pyrrole. To the best of our
indicated that this reaction was tolerant of both electron-
rich and electron-poor aryl groups (entries 1-3) as well as
the acyclic and cyclic alkyl groups (entries 4 and 5), and
the corresponding products 7a-e could be obtained in
moderate to high yields. Analogously, heteroaryl and fused
aryl substitutions for R were also compatible with this
reaction (entries 6 and 7). Successively, the size of carbocycle
fused to the aziridine was investigated, and the result revealed
that reactions of five-membered ring substrates (entries 8 and
9) proceeded much faster than those of the six-membered
ring substrates, possibly because the formation of six-
(6) (a) Zhang, E.; Tu, Y.-Q.; Fan, C.-A.; Zhao, X.; Jiang, Y.-J.; Zhang,
S.-Y. Org. Lett. 2008, 10, 4943. (b) Zhang, Y.-Q.; Chen, Z.-H.; Tu, Y.-Q.;
Fan, C.-A.; Zhang, F.-M.; Wang, A.-X.; Yuan, D.-Y. Chem. Commun. 2009,
2706.
Org. Lett., Vol. 11, No. 17, 2009
4003

membered rings in 7h and 7i via ring expansion was more
favorable than the seven-membered rings in 7a-g. Addition-
ally, when an acyclic propargylic aziridine substrate 8 was
subjected to the reaction under the general conditions, a 2,3,5-
trisubstituted pyrrole 9 was also smoothly obtained in 76%
yield (Scheme 2).12,13 Finally, to further explore the structural
Scheme 3. Further Examples
Scheme 2. Screening of Acyclic Substrate
Scheme 4
.
Proposed Mechanism of the Au(I)-Catalyzed
Reaction of Propargylic Aziridine
diversity of pyrroles that could be synthesized using our
methodology, a reaction with the hydroxycyclohexane-fused
aziridine 10 and a two-component reaction of the substrate
of entry 2 in Table 2 with N-methylindole were conducted
separately, and the expected ketone carbonyl 1114 and
R-indolyl-substituted products 12 were successfully obtained,
respectively (Scheme 3).
On the basis of these results and literature reports,5,15
a
plausible mechanism for the reaction is outlined (Scheme
4). It commences with a 5-endo-dig cyclization of the N-atom
of the aziridine with the Au(I)-activated C-C triple bond,
forming an ammonium cation intermediate A. Unlike our
previous work where A underwent an aziridine ring-opening
between the N atom and the quaternary C1, instead A would
undergo a ring-opening between the N atom and the C2,
which would be followed by elimination of a ꢀ-proton to
give a spirocycle intermediate B and regenerate the catalytic
gold species. Successively, a Au(I)-catalyzed ionization of
spirocycle B would lead to the formation of an allylic cation
C, which could undergo a Wagner-Meerwein rearrange-
ment/ring expansion leading to a 1,2-fused bicycle D.
Subsequent elimination of a proton from D would afford the
final product.16
In summary, we have disclosed a Au(I)-catalyzed rear-
rangement of propargylic aziridine. This reaction is suggested
to involve an unusual tandem cyclization/ring-opening/
Wagner-Meerwein rearrangement sequence, and it provides
a useful entry into cycloalkene-fused and trisubstituted
pyrroles. Further studies on the detailed mechanism and its
application to alkaloid synthesis will be reported in due
course.
(7) For recent examples, see: (a) Brawn, R. A.; Panek, J. S. Org. Lett.
2009, 11, 473. (b) Wender, P. A.; Strand, D. J. Am. Chem. Soc. 2009, 131,
7528.
(8) For selected reviews on Au catalysis, see: (a) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395. (b) Hashmi, A. S. K. Chem. ReV. 2007, 107,
3180. (c) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239. (d)
Arcadi, A. Chem. ReV. 2008, 108, 3266. (e) Yamamoto, Y.; Patil, N. T.
Chem. ReV. 2008, 108, 3395. (g) Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410.
Acknowledgment. This work was supported by the NSFC
(Nos. 20621091, 20672048 and 20732002) and the “111”
program of the Chinese Education Ministry.
(9) For similar substrates, see: (a) Motamed, M.; Bunnelle, E. M.;
Singaram, S. W.; Sarpong, R. Org. Lett. 2007, 9, 2167. (b) Schomaker,
J. M.; Geiser, A. R.; Huang, R.; Borhan, B. J. Am. Chem. Soc. 2007, 129,
3794.
(10) For selected reviews, see: (a) Pocker, Y. In Molecular Rearrange-
ments; De Mayo, P., Ed.; Wiley-VCH: New York, 1963; Vol. 1, p 1. (b)
Hanson, J. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 705. (c) Saunders, M.;
Jimenez-Vazquez, H. A. Chem. ReV. 1991, 91, 1625.
(11) For an entire examination of catalysts, see the Supporting Informa-
tion.
Supporting Information Available: General experimental
procedures, characterization data for all products, and X-ray
crystallographic data for compounds 7b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901649P
(12) We also obtained 2-methyl-5-phenyl-N-phthalimidepyrrole 13 in
19% yield.
(13) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem.
Soc. 2006, 128, 2528.
(16) Formation of the product 13 is proposed to follow the mechanism
shown here.
(14) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed.
2005, 44, 609.
(15) Lin, C.-C.; Teng, T.-M.; Tsai, C.-C.; Liao, H.-Y.; Liu, R.-S. J. Am.
Chem. Soc. 2008, 130, 16417.
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Org. Lett., Vol. 11, No. 17, 2009