Gold-catalyzed cyclization of alkynylaziridines as an efficient approach toward functionalized N-phth pyrroles

Article abstract of DOI:10.1021/jo902357x

(Chemical Equation Presented) An efficient access to N-phth pyrrroles via gold-catalyzed cycloisomerization of N-phth alkynylaziridines has been described. Functionalized pyrroles including pyrrole-2-carboxylates or 2-pyrrolyl ketone are easily constructe

Full text of DOI:10.1021/jo902357x

pubs.acs.org/joc
applications in pharmaceutical use2 and material science.3
Gold-Catalyzed Cyclization of Alkynylaziridines as
an Efficient Approach toward Functionalized
N-Phth Pyrroles
Furthermore, substituted pyrroles are of significant interest
since they are useful and versatile synthetic intermediates for
further structural elaboration.4 As a consequence, much
attention has been paid to the synthesis of pyrrole derivatives
either by classic methods such as the Paal-Knorr5 and
Hantzsch syntheses6 or by transition metal-catalyzed reac-
tions.7 In particular, protocols relying on intramolecular
cyclization of alkynes bearing proximate nucleophiles utiliz-
ing gold as catalyst have received considerable attention.8 In
a recent example, Hashmi et al. had reported an elegant
application for the transformation of alkynyl epoxides to
furans catalyzed by AuCl3.9 We have also developed several
gold-catalyzed processes for the efficient construction of
furans, pyrroles, indole-fused carbocycles, etc. from eny-
nols.10 We envisioned that if the double bond of these enyne
substrates is further elaborated to the aziridine moiety, it
may afford functionalized pyrroles. During our ongoing
work, several groups have reported gold-catalyzed cycliza-
tion of alkynylaziridines to N-Ts11a,b or N-Bn11c pyrroles. In
their reports, the functional groups have rarely been intro-
duced, and only disubstituted pyrroles were prepared. There-
fore, increasing the functional group tolerance and structure
scope of the current procedures is still highly attractive.
Herein we’d like to report a gold-catalyzed cyclization of
Xiangwei Du, Xin Xie, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
yhliu@mail.sioc.ac.cn
Received November 3, 2009
An efficient access to N-phth pyrrroles via gold-catalyzed
cycloisomerization of N-phth alkynylaziridines has been
described. Functionalized pyrroles including pyrrole-2-
carboxylates or 2-pyrrolyl ketone are easily constructed
in generally good yields by this method. The resulting
pyrroles can be further converted to N-amino pyrrole or
2-acyl pyrrole, which are important synthetic intermedi-
ates for amplification of molecular complexity.
(4) For example see: Boger, D. L.; Boyce, C. W.; Labrilli, M. A.; Sehon,
C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54.
(5) (a) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635. (b) Paal, C. Chem.
Ber. 1885, 18, 367.
(6) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
(7) Recent examples see: (a) Gabriele, B.; Salerno, G.; Fazio, A. J. Org.
Chem. 2003, 68, 7853. (b) Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181.
(c) Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007,
72, 1510. (d) Li, E.; Xu, X.; Li, H.; Zhang, H.; Xu, X.; Yuan, X.; Li, Y.
Tetrahedron 2009, 65, 8961. (e) Martın, R.; Larsen, C. H.; Cuenca, A.;
´
€
Buchwald, S. L. Org. Lett. 2007, 9, 3379. (f) Braun, R. U.; Zietler, K.; Muller,
T. J. J. Org. Lett. 2001, 3, 3297. (g) Nishibayashi, Y.; Yoshikawa, M.; Inada,
Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42,
2681. (h) Shiraishi, H.; Nishitani, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
1998, 63, 6234. (i) Gorin, D. J.; Davis, N. R.; Toste, D. F. J. Am. Chem. Soc.
2005, 127, 11260. (j) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074. (k) Declerk, V.; Ribiere, P.; Martinez, J.;
Lamaty, F. J. Org. Chem. 2004, 69, 8372. (l) Kamijo, S.; Kanazawa, C.;
Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (m) Larionov, O. V.; de
Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664.
Pyrroles are one of the most important classes of hetero-
cyclic compounds as they widely occur as key structural
subunits in numerous natural products which exhibit
interesting biological activities,1 and can find a variety of
(8) For recent reviews on gold-catalyzed reactions, see: (a) Hashmi,
A. S. K. Chem. Rev. 2007, 107, 3180. (b) Ma, S.; Yu, S.; Gu, Z. Angew. Chem.,
Int. Ed. 2006, 45, 200. (c) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108,
3239. (d) Lipshutz, B. H.; Yamamoto, Y. Chem. Rev. 2008, 108, 2793. (e)
(1) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katritsky, A. R., Rees, C. W., Scriven E. F. V., Eds.; Elsevier: Oxford, UK,
1996; Vol. 2. For selected examples, see : (b) Aiello, A.; D'Esposito, M.;
Fattorusso, E.; Menna, M.; Mueller, W. E. G.; Perovic-Ottstadt, S.; Schroeder,
H. C. Bioorg. Med. Chem. 2006, 14, 17. (c) Lewer, P.; Chapin, E. L.; Graupner,
P. R.; Gilbert, J. R.; Peacock, C. J. Nat. Prod. 2003, 143. (d) F€urstner, A. Angew.
Chem., Int. Ed. 2003, 42, 3582. (e) Balme, G. Angew. Chem., Int. Ed. 2004, 43,
6238. (f) Jacquot, D. E. N.; ZGllinger, M.; Lindel, T. Angew. Chem., Int. Ed.
2005, 44, 2295. (g) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.;
Doundoulakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765. (h)
Gottesfeld, J. M.; Neely, L.; Trauger, J. W.; Baird, E. E.; Dervan, P. B. Nature
1997, 387, 202.
ꢀ
ꢀ~
Arcadi, A. Chem. Rev. 2008, 108, 3266. (f) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Rev. 2008, 108, 3326. (g) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. Rev. 2008, 108, 3351. (h) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008,
108, 3395.
(9) (a) Hashmi, A. S. K.; Sinha, P. Adv. Synth. Catal. 2004, 346, 432. For
related papers see: (b) Yoshida, M.; Al-Amin, M.; Matsuda, K.; Shishido, K.
Tetrahedron Lett. 2008, 49, 5021. (c) Blanc, A.; Tenbrink, K.; Weibel, J.; Pale,
P. J. Org. Chem. 2009, 74, 4360. (d) Blanc, A.; Tenbrink, K.; Weibel, J.; Pale,
P. J. Org. Chem. 2009, 74, 5342.
(2) For selected examples, see: (a) Clark, B. R.; Capon, R. J.; Lacey, E.;
Tennant, S.; Gill, J. H. Org. Lett. 2006, 8, 701. (b) Bode, H. B.; Irschik, H.;
Wenzel, S. C.; Reichenbach, H.; Mueller, R.; Hoefle, G. J. Nat. Prod. 2003,
1203. (c) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705.
(3) (a) Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. Rev. 1991, 20,
391. For selected examples, see: (b) Ogawa, K.; Rasmussen, S. C. Macro-
molecules 2006, 35, 1771. (c) Facchetti, A.; Abbotto, A.; Beverina, L.; van der
Boom, M. E.; Dutta, P.; Evmenenko, G.; Pagani, G. A.; Marks, T. J. Chem.
Mater. 2003, 15, 1064.
(10) (a) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7,
5409. (b) Du, X.; Song, F.; Lu, Y.; Chen, H.; Liu, Y. Tetrahedron 2009, 65,
1839. (c) Guo, S.; Song, F.; Liu, Y. Synlett 2007, 964. (d) Lu, Y.; Fu, X.;
Chen, H.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 129. (e) Lu, Y.;
Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 1517. (f) Chen, Y.; Lu,
Y.; Li, G.; Liu, Y. Org. Lett. 2009, 11, 3838.
(11) (a) Davies, P. W.; Martin, N. Org. Lett. 2009, 11, 2293. (b) Chen, D.;
Hou, X.; Dai, L. Tetrahedron Lett. 2009, 50, 6944. (c) Yoshida, M.; Al-Amin,
M.; Shishido, K. Synthesis 2009, 2454.
510 J. Org. Chem. 2010, 75, 510–513
Published on Web 12/14/2009
DOI: 10.1021/jo902357x
r
2009 American Chemical Society

Du et al.
JOCNote
SCHEME 1
TABLE 1. Optimization Studies for the Formation of Pyrrole-2-carboxy-
late
temp time
(°C)
yield (%)
of 3ba
entry
catalyst
solvent
(h)
1
2
3
4
5
6
7
5% Ph3PAuCl/AgOTf THF
5% Ph3PAuCl/AgOTf DCE
5% Ph3PAuCl/AgOTf MeOH 50
2% Ph3PAuCl/AgOTf THF
5% Ph3PAuCl/AgOTf THF
50
50
1
1.5
1
3
6
97
83
90
90
SCHEME 2
50
rt
50
96
5% AgOTf
10% PtCl2
THF
toluene 80
13
21
NRb
61
aIsolated yield. bNR = no reaction.
alkynyl N-phth-aziridines, in which various substituted pyr-
roles with functional groups can be generated efficiently.
The alkynylaziridine substrates 2 were synthesized accord-
ing to Che and Yudin’s procedure with use of the N-amino-
phthalimide/phenyliodine(III) diacetate (PIDA) system.12
This method was reported to be versatile with regard to the
electronic nature of olefin, and also with high diastereoselec-
tivity. A series of cis-aziridine 2 compounds with -CH(OH)R,
-CO2R, and -COR functionalities were conveniently prepared
in 41-85% yield from cis-enynes by this method (Scheme 1). In
several cases, the aziridine 2 exists as a mixture of invertomers as
determined by 1H NMR.
TABLE 2. Synthesis of Pyrroles through Gold(I)-Catalyzed Cyclization
of Alkynylaziridines
In an initial experiment, we investigated the reaction of
aziridine 2a under our previous gold-catalyzed cycloisome-
rization conditions.10a To our surprise, monophenyl-substi-
tuted pyrrole 3a was obtained in 44% yield (Scheme 2)
(containing 7% of inseparable byproduct13). It is obvious
that a C-C bond cleavage occurred during the process.
Since the functional group was easily lost using alcoholic
substrate 2a, we turned our attention to the use of aziridine-
2-carboxylate 2b. Satisfyingly, the reaction proceeded
smoothly, and the desired pyrrole-2-carboxylate 3b was
obtained in 97% yield at 50 °C in THF for 1 h with use of
5 mol % of (PPh3)AuCl and 5 mol % of AgOTf as catalysts
(Table 1, entry 1). The reaction could also be performed in
DCE or MeOH, although lower yields (83-90%) were
observed (entries 2 and 3). AgOTf alone did not promote
any transformations (entry 6). PtCl2 gave a reduced yield of
61% and a longer reaction time (21 h, entry 7).
We chose the reaction conditions shown in Table 1, entry
1, to examine the scope of this reaction. The method is
applicable to a wide range of suitably substituted cis-azir-
idines as illustrated in Table 2. We first investigated the
electronic effects of the arene substitutent on alkyne termi-
nus R3. While a -Cl substituent afforded 3c in 93% yield, the
electron-donating group -OMe afforded a lower yield of
aIsolated yield. bThe desilytion product was obtained. cAfter depro-
tection of the phthaloyl group with hydrazine monohydrate. dThe
reaction was carried out in MeOH.
(12) (a) Krasnova, L. B.; Hill, R. M.; Chernoloz, O. V.; Yudin, A. K.
ARKIVOC 2005, 4, 26. (b) Li, J.; Liang, J.-L.; Chan, P. W. H.; Che, C.-M.
Tetrahedron Lett. 2004, 45, 2685. (c) Krasnova, L. B.; Yudin, A. K. Org. Lett.
2006, 8, 2011. For related paper, see: (d) Zhang, E.; Tu, Y.-Q.; Fan, C.-A.;
Zhao, X.; Jiang, Y. J.; Zhang, S.-Y. Org. Lett. 2008, 10, 4943.
(13) The byproduct was assigned to be the imine of 2-(benzylideneamino)-
isoindoline-1,3-dione by comparison of the 1H NMR spectra of the mixture to
1H NMR spectra of the authentic sample.
72% (entries 2 and 3). When R3 is an alkyl group, the
reaction proceeded smoothly to produce 3e in 87% yield
(entry 4). When 2f containing a siloxymethyl group on R3
was used, a partial desilylation occurred within 1 h. Extension
J. Org. Chem. Vol. 75, No. 2, 2010 511

Du et al.
JOCNote
SCHEME 3
SCHEME 5
SCHEME 4
cis-aziridines, however, the ester and the alkynyl group are
located in the same direction, thus the triple bond could be
sufficiently activated. When trans-2k was used, the corre-
sponding 3k was isolated in a lower yield of 45%.
of the reaction time to 10 h resulted in complete desilylation,
leading to the primary alcohol 3f in 55% yield (entry 5).
Trisubstituted aziridines 2g-i were also compatible under
the cyclization conditions, yielding 3,5-disubstituted pyr-
role-2-carboxylates 3g-i in 59-92% yields (entries 6-8).
However, with a ketone present in the aziridine 2j, the yield
dropped to 39% after deprotection of the phthalyl group. In
this case, the desired N-phth pyrrole could not be separated
from the byproducts upon isolation by column chromatog-
raphy (entry 9). It is noted that when the phenyl group was
placed on the aziridine ring instead of the ester group, the
corresponding pyrrole 3k was formed in a lower yield of 45%
in THF; however, the yield could be improved to 75% by
switching the solvent to MeOH (entry 10).
We propose the following mechanism for these cycliza-
tions as depicted in Scheme 5, which involves coordination of
the triple bond by gold, nucleophilic attack of the aziridine
nitrogen on the alkyne, followed by ring-opening to afford 7,
then deprotonation to give the aromatized gold species 8,
which further undergoes deauration to afford pyrrole 3. The
formation of aryl-gold intermediate 8 has been supported in
a deuteration experiment; a high deuterium incorporation of
94% was observed when the reaction was carried out in
CD3OD. To account for the formation of monosubstituted
pyrrole 3a from alcoholic substrate 2a, a nucleophlic attack
of the adjacent OH group to the cationic center in 9 to form
oxabutane 10 followed by ring-opening is proposed.15
In summary, we have developed an Au/Ag-catalyzed
cyclization of alkynylaziridines to N-phth pyrroles under
mild reaction conditions. The method is particularly attrac-
tive for assembling multisubstituted pyrrole-2-carboxylates
with high diversity and in a regioselective manner. These
compounds are potentially useful in pharmaceutical and
material science.
Removal of a phthalyl protecting group from pyrroles 3 to
-NH2-substituted pyrroles can be accomplished with use of
N2H4 H2O in EtOH, as already exemplified in product 3j
3
(Table 2, entry 9). In an additional case, amino-pyrrole 4 was
obtained in 83% yield from the corresponding N-protected
pyrrole 3b (Scheme 3, eq 1). This type of substrate is known
to be the key intermediate for the synthesis of biologically
active substances such as protein kinase inhibitors.14 Oxida-
tion of 3i by IBX in DMSO/THF afforded 5-formyl-1-
pyrrole-2-carboxylate 5 in 80% yield, which has the potential
to access further synthetic applications (Scheme 3, eq 2).
When trans-aziridines were used, however, we observed
different results. The trans-2b (invertomer ratio is 2.3:1) led
to no formation of pyrrole (Scheme 4), and most of the
starting materials was recovered, which may be due to the
competed coordination of the trans-ester group and the
phthalyl carbonyl group or nitrogen lone pair in different
invertomers versus the alkynyl group with gold catalyst,
thus the π-bond could not be activated efficiently. In the
Experimental Section
A Typical Procedure for Gold-Catalyzed Cycloisomerization
of Alkynylaziridine 2b. To a solution of (2R*,3R*)-ethyl-1-(1,3-
dioxoisoindolin-2-yl)-3-(phenyl-ethynyl)aziridine-2-carboxylate 2b
(72.1 mg, 0.2 mmol) in 2.0 mL of THF was added 5 mol % of
(PPh3)AuCl followed by AgOTf (5 mol %, used as a 0.05 M
solution in THF) at room temperature. The resulting solution
was stirred at 50 °C for 1 h until the reaction was complete as
monitored by thin-layer chromatography. The solvent was removed
under reduced pressure and the residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate 4:1)
to afford the pyrrole derivative 3b as a pale yellow solid in 97% yield.
Ethyl 1-(1,3-dioxoisoindolin-2-yl)-5-phenyl-1H-pyrrole-2-carboxy-
(14) (a) Hynes, J., Jr.; Dyckman, A. J.; Lin, S.; Wrobleski, S. T.; Wu, H.;
Gillooly, K. M.; Kanner, S. B.; Lonial, H.; Loo, D.; McIntyre, K. W.; Pitt, S.;
Shen, D. R.; Shuster, D. J.; Yang, X.; Zhang, R.; Behnia, K.; Zhang, H.;
Marathe, P. H.; Doweyko, A. M.; Tokarski, J. S.; Sack, J. S.; Pokross, M.;
Kiefer, S. E.; Newitt, J. A.; Barrish, J. C.; Dodd, J.; Schieven, G. L.; Leftheris,
K. J. Med. Chem. 2008, 51, 4. (b) Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-
Brown, J.; Fargnoli, J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.; Wautlet,
B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. J. Med. Chem. 2004, 47, 4054.
1
late (3b): mp 166-168 °C; H NMR (CDCl3, Me4Si, 300 MHz)
(15) Zhao, X.; Zhang, E.; Tu, Y.; Zhang, Y.; Yuan, D.; Cao, K.; Fan, C.;
Zhang, F. Org. Lett. 2009, 11, 4002.
512 J. Org. Chem. Vol. 75, No. 2, 2010

Du et al.
JOCNote
δ 1.16 (t, J = 7.2 Hz, 3H), 4.14 (q, J = 7.2 Hz, 2H), 6.45 (d, J = 4.2
Hz, 1H), 7.19 (d, J = 4.5 Hz, 1H), 7.28-7.32 (m, 3H), 7.42-7.45
(m, 2H), 7.75-7.78 (m, 2H), 7.89-7.92 (m, 2H); 13C NMR
(CDCl3, Me4Si, 100.6 MHz) δ 14.0, 60.2, 108.6, 118.0, 122.2,
124.3, 128.2, 128.6, 128.7, 129.6, 129.9, 134.8, 141.8, 159.5, 165.1;
IR (neat) 2991, 1746, 1468, 1073, 880, 751 cm-1; HRMS (EI) calcd
for C21H16N2O4 360.1110, found 360.1114.
20821002), Chinese Academy of Science, Science and Tech-
nology Commission of Shanghai Municipality (Grant No.
08QH14030), and the Major State Basic Research Development
Program (Grant No. 2006CB806105) for financial support.
Supporting Information Available: Experimental details and
spectroscopic characterization of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20872163, 20732008, and
J. Org. Chem. Vol. 75, No. 2, 2010 513