Synthesis of bicyclic imidazoles via [2 + 3] cycloaddition between nitriles and regioselectively generated α-imino gold carbene intermediates

Article abstract of DOI:10.1021/ol302102h

The cyclic α-imino gold carbene intermediate B is most likely generated in situ via regioselective nitrene transfer from an azido group to a tethered terminal alkyne in the presence of a gold catalyst and at ambient temperature. This highly electrophilic intermediate can react with a weakly nucleophilic nitrile, which is used as the reaction solvent, to deliver a bicyclic imidazole rapidly in an overall bimolecular [2 + 2 + 1] cycloaddition and in mostly serviceable yield. The competing intramolecular Huisgen reaction, although likely also catalyzed by gold, is minimized by using AuCl₃ as the catalyst.

Full text of DOI:10.1021/ol302102h

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4662–4665
Synthesis of Bicyclic Imidazoles via
[2 þ 3] Cycloaddition between Nitriles
and Regioselectively Generated
r‑Imino Gold Carbene Intermediates
Yuanjing Xiao and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, United States
zhang@chem.ucsb.edu
Received July 30, 2012
ABSTRACT
The cyclic r-imino gold carbene intermediate B is most likely generated in situ via regioselective nitrene transfer from an azido group to a tethered
terminal alkyne in the presence of a gold catalyst and at ambient temperature. This highly electrophilic intermediate can react with a weakly
nucleophilic nitrile, which is used as the reaction solvent, to deliver a bicyclic imidazole rapidly in an overall bimolecular [2 þ 2 þ 1] cycloaddition
and in mostly serviceable yield. The competing intramolecular Huisgen reaction, although likely also catalyzed by gold, is minimized by using
AuCl3 as the catalyst.
Imidazole is an important N-heterocycle that can be
found as a critical building block in bioactive molecules1
and/or natural products.2 It also serves as a versatile sub-
stratestructure for varioussynthetic transformations,3 and
its derivatives are used as ionic liquids4 and precursors of
N-heterocyclic carbenes employed as ligands in various
metal complexes.5 Owing to its importance, novel and
efficient methods for constructing this heteroarene
ring are still of contemporary importance to the
synthetic community and have received continuous
attention.6
We have recently engaged in extensive studies of the
reactivities of R-oxo gold carbenes7 that are generated as
highly reactive intermediates in situ via gold-catalyzed
intermolecular oxidation of alkynes.8 Among the various
(6) For selected reviews, see: (a) Kamijo, S.; Yamamoto, Y. Chem.
Asian J. 2007, 2, 568–578. (b) Grimmett, M. R. In Science of Synthesis;
Georg Thieme Verlag KG: Stuttgart, 2002; Vol. 12, p 325.
(7) (a) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010,
132, 3258–3259. (b) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010,
132, 8550–8551. (c) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011,
8482–8485. (d) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011,
50, 3236–3239. (e) He, W.; Xie, L.; Xu, Y.; Xiang, J.; Zhang, L. Org.
Biomol. Chem. 2012, 10, 3168–3171. (f) Wang, Y.; Ji, K.; Lan, S.; Zhang,
L. Angew. Chem., Int. Ed. 2012, 51, 1915–1918.
(8) For selected works done by other groups, see: (a) Vasu, D.; Hung,
H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem., Int.
Ed. 2011, 50, 6911–6914. (b) Davies, P. W.; Cremonesi, A.; Martin, N.
Chem. Commun. 2011, 47, 379–381. (c) Mukherjee, A.; Dateer, R. B.;
Chaudhuri, R.; Bhunia, S.; Karad, S. N.; Liu, R.-S. J. Am. Chem. Soc.
2011, 133, 15372–15375. (d) Qian, D.; Zhang, J. Chem. Commun. 2011,
47, 11152–11154. (e) Liu, R.-S.; Dateer, R. B.; Pati, k. k. Chem.
Commun. 2012, 48, 7200–7202. (f) Bhunia, S.; Ghorpade, S.; Huple,
D. B.; Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 2939–2942. (g) Qian,
D.; Zhang, J. Chem. Commun. 2012, 48, 7082–7084.
(1) (a) Shalini, K.; Sharma, P. K.; Jumar, N. Chem. Sin. 2010, 1, 36–
47. (b) Baroniya, S.; Anwer, Z.; Sharma, P. K.; Dudhe, R.; Kumar, N.
Pharm. Sin. 2010, 1, 172–182.
(2) (a) Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931–48. (b) Jin, Z.
Nat. Prod. Rep. 2011, 28, 1143–1191. (c) De, L. L. Curr. Med. Chem.
2006, 13, 1–23.
(3) (a) Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry
II: Five-Membered Heterocycles; Springer: Berlin, 2011. (b) Hofmann, K.
Imidazole and Its Derivatives. Part 1; Wiley-Interscience: New York, 2007.
(4) Welton, T. Chem. Rev. 1999, 99, 2071–2083.
(5) (a) Jacobsen, H.; Correa, A.; Poater, A.; Costabile, C.; Cavallo, L.
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€
€
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r
10.1021/ol302102h
Published on Web 08/23/2012
2012 American Chemical Society

methods developed,7,8 the rapid assembly of oxazole in a
[2 þ 2 þ 1] cycloaddition is the first example of efficient
intermolecular trapping of the highly electrophilic gold
carbene moiety (Scheme 1a).7c To extend the oxidation
strategy, we have developed approaches to the generation
of the related R-imino gold carbenes and thereafter new
reactions harvesting their reactivities.9,10 Among the nitrene-
transfer reagents employed, the azido group is deemed
ideal as an intramolecular variant due to its ease of in-
corporation and atom economy.9b,c,10 With respect to the
oxazole chemistry,7c we reasoned that a similar reaction via
the intermediacy of a corresponding R-imino gold carbene
would lend a facile access to imidazoles instead of oxazoles.
As shown in Scheme 1b, the reaction would commence with
a5-exo-dig cyclization of a tethered azido group onto a gold-
activated terminal alkyne, followed by the formation of the
R-imino gold carbene intermediate B upon dinitrogen ex-
pulsion; the assumed 5-exo selectivity is in line with related
precedents in gold catalysis.11 Notably, in our recent work,
an electronic bias of the CꢀC triple bond was necessary to
achieve the same regioselectivity for internal alkynes.9c The
carbene B, likely highly electrophlic, could then be trapped
by a nitrile to form a nitrile ylide-type intermediate C, which
can cyclize to yield a bicyclic imidazole.12 This imidazole
formation13 can be considered as an overall bimolecular [2 þ
2 þ 1] cycloaddition and a [3 þ 2] cycloaddition between a
nitrile and the carbene B. Herein, we disclose the successful
implementation of this design.
Our reaction discovery used 5-azidopent-1-yne (i.e., 1a)
as the substrate. It was readily synthesized from commercially
available pent-4-yn-1-ol in two steps.14 In anticipation of the
strongly electrophilic nature of B, as in the case of the oxazoles
synthesis, acetonitrile was used as solvent to achieve efficient
trapping of B. Table 1 shows the reaction discovery and
7d
optimization. When BrettPhosAuNTf2 was used as the
gold catalyst, the expected imidazole 3a was indeed formed,
albeit in only 11% yield. The undesired intramolecular
Huisgen reaction product,15 i.e., the triazole 4a (11%) and
the remaining substrate (76%) accounted for the mass
balance (entry 1). The slow reaction was expected and
consistent with the fact that the basic imidazole and triazole
Table 1. Initial Reaction Discovery and Condition
Optimizationa
yield of
entry
catalyst
conditions 3a:4a 3ac (%)
1
2
3
4
5
6
7
8
BrettPhosAuNTf2
BrettPhosAuNTf2
IPrAuNTf2
60 °C, 11 hb
60 °C, 11 h
60 °C, 11 h 2.4:1
1:1
11
38
68
48
41
88
93d
ꢀ
1:1.6
(C6F5)3PAuNTf2
(4-CF3Ph)3PAuNTf2
rt, 10 h
4.4:1
4.6:1
6.3:1
25:1
ꢀ
rt, 10 h
dichloropicolinatogold(III) rt, 10 h
AuCl3
rt, 10 h
Scheme 1. (a) Published Oxazole Synthesis and (b) Design for a
Related Imidazole Synthesis
no catalyst
60 °C, 11 h
a [1a] = 0.05 M. b No MsOH added. c Yields were determined by
1H NMR spectroscopy using CH2Br2 as the internal standard. d 89%
isolated yield.
formed can deactivate the gold catalyst via coordina-
tion.16 The addition of MsOH (1.1 equiv) avoided the
problem, and the reaction proceeded to completion in 11 h,
but the yield remained relatively low, and worse yet the
Huisgen reaction was dominant (entry 2). Screening different
gold catalysts proved to be fruitful. While IPrAuNTf2 at
60 °C led to improvement on both the chemoselectivity and
the reaction yield (entry 3), the more acidic (C6F5)3PAuNTf2
(entry 4) and (4-CF3Ph)3PAuNTf2 (entry 5) allowed the
reaction to proceed to completion in a reasonable time frame
at ambient temperature. Moreover, the chemoselectiv-
ities were further improved. The breakthrough came
when Au(III) catalysts (entries 6 and 7) were examined,
and the prototypical Au(III) salt, AuCl3 gave an excel-
lent yield of the bicyclic imidazole 3a while the amount
(9) (a) Li, C.; Zhang, L. Org. Lett. 2011, 13, 1738–1741. (b) Lu, B.;
Luo, Y.; Liu, L.; Ye, L.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed.
2011, 8358–8362. (c) Yan, Z.-Y.; Xiao, Y.; Zhang, L. Angew. Chem., Int.
Ed. 201210.1002/anie.201203678.
(10) For work done by other groups, see: (a) Wetzel, A.; Gagosz, F.
Angew. Chem., Int. Ed. 2011, 50, 7354–7358. (b) Gorin, D. J.; Davis,
N. R.; Toste, F. D. 2005, 127, 11260-11261; (c) Hiroya, K.; Matsumoto,
S.; Ashikawa, M.; Ogiwara, K.; Sakamoto, T. Org. Lett. 2006, 8, 5349–
5352.
(11) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org.
Lett. 2004, 6, 4391–4394. (b) Harkat, H.; Weibel, J. M.; Pale, P.
Tetrahedron Lett. 2006, 47, 6273–6276. (c) Hashmi, A. S. K.; Rudolph,
M.; Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905–
4909. (d) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst, T.;
Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.;
Rominger, F.; Frey, W.; Bats, J. W. Chem.;Eur. J. 2010, 16, 956–963.
(12) Various gold catalyses have been run in acetonitrile without
solvent participation; for an example, see: Hashmi, A. S. K.; Frost,
T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553. For an exception,
see: Ibrahim, N.; Hashmi, A. S. K.; Rominger, F. Adv. Synth. Catal.
2011, 353, 461.
(14) Saito, Y.; Matsumoto, K.; Bag, S. S.; Ogasawara, S.; Fujimoto,
K.; Hanawa, K.; Saito, I. Tetrahedron 2008, 64, 3578–3588.
(15) Huisgen, R. Proc. Chem. Soc. 1961, 357–396.
(16) (a) Wang, D.; Gautam, L. N. S.; Bollinger, C.; Harris, A.; Li, M.;
Shi, X. Org. Lett. 2011, 13, 2618–2621. (b) Wang, D.; Zhang, Y.; Harris,
A.; Gautam, L. N. S.; Chen, Y.; Shi, X. Adv. Synth. Catal. 2011, 353,
2584–2588. (c) Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov,
N. G.; Shi, X. J. Am. Chem. Soc. 2009, 131, 12100–12102.
(13) For a recent gold-catalyzed case, see: Li, S.; Li, Z.; Yuan, Y.;
Peng, D.; Li, Y.; Zhang, L.; Wu, Y. Org. Lett. 2012, 14, 1130–1133.
Org. Lett., Vol. 14, No. 17, 2012
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of the triazole 4a was negligible (entry 7). Notably, with-
out a gold catalyst, neither 3a nor 4a was formed at 60 °C
even in the presence of MsOH (entry 8), suggesting that
the intramolecular Huisgen reaction is also catalyzed by
the gold catalyst.17 While PtCl4, PtCl2, and AgNTf2 were
ineffective catalysts, KAuCl4 and AuBr3 were surprisingly
inferior to AuCl3 as the reaction proceeded very slowly
and with low yields (72 h, <20% yield).
Our attempts to limit the amount of the nitrile compo-
nent to 3 equivalents in either a neat or solvated reaction
were unfortunately resulted in the formation of complex
mixtureswiththe desired imidazoles in low yields (typically
<30%). This limitation is attributed to the high reac-
tivities of the in situ generated R-imino gold carbene
intermediates.
With the optimal reaction conditions (as in Table 1
entry 7) established, the reaction scope was then examined
(Table 2). 5-Azidopent-1-ynes with different substituents
on the aliphatic linker were first studied in acetonitrile.
Substituents such as 5-methyl (entry 1), 3-propyl (entry 2),
and a benzyloxy group at either the 3-position (entry 3) or
the 4-position (entry 4) all posed no problem, and the
bicyclic imidazoles were formed in mostly good yields. The
linker could also be fused to a benzene ring. Though the
reaction was not complete in 20 h, a serviceable yield was
still achieved (entry 5). This reaction also permitted the use
of a range of other nitriles as the reaction solvent (entries
6ꢀ14). Compared to acetonitrile, propionitrile (entry 6)
and isobutyronitrile (entry 7) led to increasingly lower
reaction yields. This phenomenon, though explainable by
the increasing steric hindrance, might be in part rationa-
lized by the decreasing concentrations of the solvent
(CH3CN, 19.2 M; EtCN, 14.0 M; iPrCN, 11.2 M), which
would be consistent with the likely highly reactivenature of
the R-imino gold carbene intermediate B. 3-Chloropropio-
nitrile was a suitable substrate, and no HCl elimination
from the product 3i was detected during the reaction,
suggesting the mild nature of the reaction conditions
(entry 8). However, this elimination did occur to some
extent during reaction workup and column chromatogra-
phy under basic environment. Nitriles containing a con-
jugated (entry 9) and a skipped (entry 10) CꢀC double
bond were also tolerated; notably, the skipped double
bond remained intact in the imidazole 3k, indicating that
the final ring closure was facile. Phenylacetonitrile
(entry 11), benzonitrile (entry 13), and the methyl-
substituted counterparts (entries 12 and 14) reacted
smoothly, affording the corresponding imidazoles in
moderate to good yields. The intramolecular Huisgen
reaction was the major side reaction in most of the
discussed cases, but the corresponding bicyclic triazoles,
formed in mostly <20% yield, are highly polar and were
readily removed by column chromatography.
Table 2. Reaction Scopea,b
For 6-azidohex-1-yne that possesses a four-carbon linker
between the CꢀC triple bond and the azido group, an
excellent yield of the corresponding 6-membered-ring fused
imidazole derivative 3p was achieved in acetonitrile (entry
15). Its reaction in other nitriles also proceeded well (entries
16 and 17). In the case of 7-azidohept-1-yne, the formation
of the 7-membered ring-fused imidazole 3s did occur albeit
in a low yield (entry 2), and the major product was the
corresponding bicyclic triazole.
a [1] = 0.05 M. b Isolated yields are given; the yield in parentheses was
for the corresponding triazole and estimated by 1H NMR analysis.
c 14% of the azide substrate recovered.
(17) For a Huisgen reaction involving stoichiometric gold, see:
Partyka, D. V.; Updegraff, J. B.; Zeller, M.; Hunter, A. D.; Gray,
T. G. Organometallics 2007, 26, 183–186.
4664
Org. Lett., Vol. 14, No. 17, 2012

In summary, we have developed a AuCl3-catalyzed
bimolecular [2 þ 2 þ 1] cycloaddition between a nitrile
and an azidoalkyne. The reaction is rationalized by the
generation of a highly electrophilic R-imino gold carbene,
via a gold-promoted regioselective nitrene transfer from an
azido group to the tethered terminal CꢀC triple bond,
followed by its in situ reaction with a weakly nucleophilic
nitrile in a [3 þ 2] annulation. The nitrile is used as the
reaction solvent to achieve good reaction efficiency. The
competing intramolecular Huisgen reaction, the main side
reaction, is minimized by using AuCl3 as the catalyst.
Acknowledgment. We thank NSF (CAREER CHE-
0969157) and UCSB for generous financial support. Y.X.
thanks the China Science Council for scholarship and
East China Normal University for support.
Supporting Information Available. Full experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4665