An unexpected silver triflate catalyzed reaction of 2-alkynylbenzaldehyde with 2-isocyanoacetate

Article abstract of DOI:10.1021/ol300901x

An unexpected silver triflate catalyzed reaction of 2-alkynylbenzaldehyde with 2-isocyanoacetate provides an efficient route for the generation of isoquinolines. The reaction proceeds smoothly in air under mild conditions with high efficiency.

Full text of DOI:10.1021/ol300901x

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2655–2657
An Unexpected Silver Triflate Catalyzed
Reaction of 2-Alkynylbenzaldehyde with
2-Isocyanoacetate
Danqing Zheng,† Shaoyu Li,† and Jie Wu*,†,‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
jie_wu@fudan.edu.cn
Received April 8, 2012
ABSTRACT
An unexpected silver triflate catalyzed reaction of 2-alkynylbenzaldehyde with 2-isocyanoacetate provides an efficient route for the generation of
isoquinolines. The reaction proceeds smoothly in air under mild conditions with high efficiency.
In the past decade, we have witnessed significant pro-
gress in the pursuit of efficient methods for the preparation
of natural product-like compounds with privileged scaffolds
in the studies of chemical genetics.1 We have also been
involved in the construction of small libraries of N-hetero-
cycles using the strategy of diversity-oriented synthesis.2
Recently, we reported an efficient route for the synthesis
of tetrahydroindeno[2,1-b]pyrroles via a base-promoted
tandem reaction3 of (E)-2-alkynylphenylchalcone with
2-isocyanoacetate (Scheme 1, eq 1).2a From this result,
we recognized that 2-isocyanoacetate, which has been
widely used in organic synthesis,4,5 was a useful building
block for the generation of N-heterocycles. Since (E)-2-
alkynylphenylchalcone is prepared from a condensation of
2-alkynylbenzaldehyde with an active methylene com-
pound, we envisioned that 2-alkynylbenzaldehyde might
be applied in the reaction with isocyanoacetate as well due
to their structural similarity. The proposed transformation
is presented in Scheme 1. We anticipated that an oxazole-
incorporated compound C would be formed via a similar
process (Scheme 1, eq 2). We began our studies with the
† Fudan University.
‡ Chinese Academy of Sciences.
(1) (a) Walsh, D. P.; Chang, Y.-T. Chem. Rev. 2006, 106, 2476. (b)
Arya, P.; Chou, D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40,
339. (c) Schreiber, S. L. Science 2000, 287, 1964. (d) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (e) Schreiber, S. L.
Nature 2009, 457, 153. (f) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74. (g)
Cordier, C.; Morton, D.; Murrison, S.; Nelson, A.; O’Leary-Steele, C.
Nat. Prod. Rep. 2008, 25, 719.
(2) For recent selected examples: (a) Zheng, D.; Li, S.; Luo, Y.; Wu,
J. Org. Lett. 2011, 13, 6402. (b) Ye, S.; Liu, G.; Pu, S.; Wu, J. Org. Lett.
2012, 14, 70. (c) Luo, Y.; Wu, J. Org. Lett. 2012, 14, 1592. (d) Qiu, G.;
Liu, G.; Pu, S.; Wu, J. Chem. Commun. 2012, 48, 2903. (e) Qiu, G.; He,
Y.; Wu, J. Chem. Commun. 2012, 48, 3836. (e) Pan, X.; Luo, Y.; Liu, G.;
Pu, S.; Wu, J. Adv. Synth. Catal. 2012, 354, 171.
(4) For reviews: (a) Suginome, M.; Ito, Y. In Science of Synthesis, Vol.
€
19; Murahashi, S.-I., Ed.; Thieme: Stuttgart, 2004; p 445. (b) Domling,
€
A. Chem. Rev. 2006, 106, 17. (c) Domling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 3168. (d) Lygin, A. V.; Meijere, A. D. Angew. Chem., Int.
Ed. 2010, 49, 9094. (e) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.;
Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235.
(3) For reviews, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004,
43, 3890. (b) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem.
Rev. 1996, 96, 365. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Grigg,
R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65. (e) Miura, T.;
Murakami, M. Chem. Commun. 2007, 217. (f) Malacria, M. Chem. Rev.
1996, 96, 289. (g) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem.
Commun. 2003, 551. (h) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
(5) For recent examples, see: (a) Fayol, A.; Zhu, J. Org. Lett. 2004, 6,
115. (b) Fayol, A.; Zhu, J. Org. Lett. 2005, 7, 239. (c) Mossetti, R.; Pirali, T.;
Tron, G. C.; Zhu, J. Org. Lett. 2010, 12, 820. (d) Wang, S.; Wang, M.;
Wang, D.; Zhu, J. Org. Lett. 2007, 9, 3615. (e) Yue, T.; Wang, M.; Wang,
D.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 6717. (f) Bonne,
D.; Dekhane, M.; Zhu, J. Angew. Chem., Int. Ed. 2006, 45, 2485. (g) Fayol,
A.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41, 3633. (h) Lalli, C.; Bouma,
M. J.; Bonne, D.; Masson, G.; Zhu, J. Chem.;Eur. J. 2011, 17, 880. (i) Li,
Y.;Xu, X.;Tan, J.;Xia, C.;Zhang, D.;Liu, Q.J. Am. Chem. Soc. 2011, 133,
1775. (j) Zhou, H.; Zhang, W.; Yan, B. J. Comb. Chem. 2010, 12, 206. (k)
Monge, D.; Jensen, K. L.; Marın, I.; Jørgensen, K. A. Org. Lett. 2011, 13, 328.
€
Angew. Chem., Int. Ed. 2006, 45, 7134. (i) Enders, D.; Grondal, C.; Huttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (j) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 2006.
r
10.1021/ol300901x
2012 American Chemical Society
Published on Web 05/22/2012

reaction of 2-alkynylbenzaldehyde 1a with isocyanoacetate
2a. Initially, the reaction was performed in the presence of
DBU (1.0 equiv) in MeCN at 80 °C (Table 1, entry 1). To
our surprise, isoqunioline 3a was obtained instead of com-
pound C with a 62% isolated yield.
silver-catalyzed tandem cycloisomerization/dipolar cyclo-
addition.9a However, efficient catalytic methods for the
generation of diverse isoquinolines are still in great de-
mand. This unexpected result would provide an alternative
route for these molecules. Additionally, we believe this
protocol would represent a significant advance in the area
ofisoquinoline chemistry. Withthe above interestingresult
in hand, we started to explore the optimal conditions
(Table 1). Different bases were examined (Table 1, en-
tries 2À7). However, no improvement was observed.
We further explored the reaction in various solvents,
and acetonitrile was demonstrated as the best choice
(Table 1, entries 8À14). A similar outcome (65% yield)
was obtained when the reaction was performed at 110 °C
(Table 1, entry 15). The yield was lower when the re-
action temperature was reduced. Since the process was
related to a cyclization of the triple bond, metal salts
were then screened (Table 1, entries 16À24). Gratify-
ingly, the reaction worked efficiently when silver triflate
was added, which afforded the corresponding product
3a in 90% yield.
Scheme 1. A Proposed Reaction of 2-Alkynylbenzaldehyde with
Isocyanoacetate
It is well-known that isoquinoline is a ubiquitous core
in many natural products and small molecule chemo-
therapeutics, which possess diverse pharmacological prop-
erties.6 So far, a remarkable advance has been made in the
synthesis of isoquinolines.7À9 For instance, isoquinoline
derivatives could be generated via a metal-catalyzed cycli-
zation of ortho-alkynylaryl aldimines.8 Pyrrolo-isoquino-
lines related to the Lamellarins could be prepared using a
Table 1. Initial Studies for the Reaction of 2-Alkynylbenzalde-
hyde 1a with 2-Isocyanoacetate 2a
(6) For selected examples, see: (a) Bentley, K. W. The Isoquinoline
Alkaloids; Harwood Academic: Australia, 1998; Vol. 1. (b) Trotter, B. W.;
Nanda, K. K.; Kett, N. R.; Regan, C. P.; Lynch, J. J.; Stump, G. L.; Kiss,
L.; Wang, J.; Spencer, R. H.; Kane, S. A.; White, R. B.; Zhang, R.;
Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.; Beshore, D. C.;
Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006, 49, 6954. (c)
Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y. J. Nat. Prod. 1999, 62, 780.
(d) Kaneda, T.; Takeuchi, Y.; Matsui, H.; Shimizu, K.; Urakawa, N.;
Nakajyo, S. J. Pharmacol. Sci. 2005, 98, 275. (e) Marchand, C.; Antony,
S.; Kohn, K. W.; Cushman, M.; Ioanoviciu, A.; Staker, B. L.; Burgin,
A. B.; Stewart, L.; Pommier, Y. Mol. Cancer Ther. 2006, 5, 287.
(7) For selected reviews, see: (a) Balasubramanian, M.; Keay, J. G.
Isoquinoline Synthesis. In Comprehensive Heterocyclic Chemistry II;
McKillop, A. E., Katrizky, A. R., Rees, C. W., Scrivem, E. F. V., Eds.;
Elsevier: Oxford, 1996; Vol. 5, pp 245À300. (b) Chrzanowska, M.;
Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341.
(8) For selected examples: (a) Huang, Q.; Larock, R. C. J. Org.
Chem. 2003, 68, 980. (b) Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68,
920. (c) Dai, G.; Larock, R. C. J. Org. Chem. 2002, 67, 7042. (d) Huang,
Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437. (e) Roesch,
K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. (f) Roesch, K. R.;
Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042. (g) Dai, G.;
Larock, R. C. Org. Lett. 2001, 3, 4035. (h) Obika, S.; Kono, H.; Yasui,
Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462. (i) Asao, N.;
Yudha, S., S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005,
44, 5526. (j) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew.
Chem., Int. Ed. 2006, 45, 3822. (k) Asao, N.; Iso, K.; Yudha, S. S. Org.
Lett. 2006, 8, 4149.
yield
entry
cat.
base
DBU
solvent
MeCN
(%)a
1
À
À
À
À
À
À
À
À
À
À
À
À
À
À
À
62
2
NaOH
Cs2CO3
Et3N
K3PO4
NaOCH3
t-BuOK
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
24
3
31
4
N.D.
58
5
6
30
7
42
8
trace
25
9
DBU
DMSO
toluene
1,4-dioxane
THF
10
11
12
13
14
15b
16
17
18
19
20
21
22
23
24
DBU
30
DBU
N.D.
20
DBU
DBU
DCE
N.D.
27
DBU
EtOH
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
65
AgOTf
Cu(OTf)2
FeCl3
DBU
90
DBU
58
DBU
58
CuCl2
DBU
30
Bi(OTf)3
CuI
DBU
35
DBU
65
(9) For selected examples, see: (a) Beeler, A. B.; Su, S.; Singleton, C. A.;
Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 1413. (b) Mori, S.; Uerdingen,
M.; Krause, N.; Morokuma, K. Angew. Chem., Int. Ed. 2005, 44, 4715. (c)
Niu, Y.-N.; Yan, Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji, K.-G.;
Liang, Y.-M. J. Org. Chem. 2009, 74, 2893. (d) Yang, Y.-Y.; Shou, W.-G.;
Chen, Z.-B.; Hong, D.; Wang, Y.-G. J. Org. Chem. 2008, 73, 3928. (e)
Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto,
Y. J. Am. Chem. Soc. 2008, 130, 15720. (f) Movassaghi, M.; Hill, M. D. Org.
Lett. 2008, 10, 3485. (g) Su, S.; Porco, J. A. Org. Lett. 2007, 9, 4983.
PdCl2
DBU
73
Pd(OAc)2
AuCl
DBU
44
DBU
63
a Isolated yield based on 2-alkynylbenzaldehyde 1a. b The reaction
occurred at 110 °C.
2656
Org. Lett., Vol. 14, No. 11, 2012

A possible mechanism is presented in Scheme 2. We
hypothesized that isocyanoacetate 2 would attack 2-alky-
nylbenzaldehyde 1 first inthe presenceofa base togenerate
an intermediate a. Then isocyanide would be involved to
afford oxazole b, which would undergo a rearrangement to
furnish compound c.10 The subsequent 6-exo cyclization
would occur in the presence of silver triflate to generate the
isoquinoline 3 with a loss of carbon monoxide.11
isoquinoline 3n was unambiguously illustrated by X-ray
diffraction analysis (see the Supporting Information).
Additionally, a ketone was a suitable substrate as well in
the reaction of ethyl 2-isocyanoacetate under the standard
conditions, which gave rise to product 3p in 61% yield.
In conclusion, we have described an efficient silver
triflate catalyzed reaction of 2-alkynylbenzaldehyde with
2-isocyanoacetate. The reaction occurs in air under mild
conditions without loss of efficiency, leading to isoquinolines
in good yields. Use of 2-isocyanoacetates for the generation
other N-heterocycles is ongoing in our laboratory.
Scheme 2. A Proposed Mechanism for the Generation of Iso-
quinioline 3 via a Reaction of 2-Alkynylbenzaldehyde 1 with
2-Isocyanoacetate 2
Scheme 3. Scope Investigation for the Silver Triflate Catalyzed
Reaction of 2-Alkynylbenzaldehyde 1 with 2-Isocyanoacetate 2
We next explored the scope of this cascade reaction of
2-alkynylbenzaldehyde 1 with 2-isocyanoacetate 2 under
the optimized conditions (1.0 equiv of DBU, 10 mol %
of AgOTf, MeCN, 80 °C). The results are summarized in
Scheme 3. We found that the substituents on the aromatic
ring of 2-alkynylbenzaldehyde 1 did not hamper the reac-
tion process. Reactions of methyl-, methoxy-, chloro-, or
fluoro-substituted 2-alkynylbenzaldehyde 1 with 2-isocya-
noacetates 2 all worked well to afford the desired products
in good yields. However, the group attached on the triple
bond of 2-alkynylbenzaldehyde 1 was crucial for the
successful transformation. It was found that the reactions
were suitable for the 2-alkynylbenzaldehydes1 withanaryl
group attached to the triple bond. The reactions failed
when 2-alkynylbenzaldehydes 1 with an alkyl group at-
tached to the triple bond were employed. Methyl and tert-
butyl 2-isocyanoacetates were examined in the meantime.
As expected, the reactions proceeded smoothly to give the
corresponding products in good yields. The structure of
a Isolated yield based on 2-alkynylbenzaldehyde 1.
Acknowledgment. Financial support from National
Natural Science Foundation of China (Nos. 21032007
and 21172038) is gratefully acknowledged.
(10) (a) Meng, T.; Zou, Y.; Khorev, O.; Jin, Y.; Zhou, H.; Zhang, Y.;
Hu, D.; Ma, L.; Wang, X.; Shen, J. Adv. Synth. Catal. 2011, 353, 918. (b)
Cai, Q.; Li, Z.; Wei, J.; Ha, C.; Pei, D.; Ding, K. Chem. Commun. 2009,
48, 7581. (c) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem.
2007, 5, 143. (d) Enders, D.; Chen, Z.; Raabe, G. Synthesis 2005, 306.
(11) (a) Sharma, S. K.; Gupta, S.; Saifuddin, M.; Mandadapu, A. K.;
Agarwal, P. K.; Gauniyal, H. M.; Kundu, B. Tetrahedron Lett. 2011, 52,
65. (b) Claveau, E.; Noirjean, E.; Bouyssou, P.; Coudert, G.; Gillaizeau,
I. Tetrahedron Lett. 2010, 51, 3130. (c) Chaignaud, M.; Gillaizeau, I.;
Ouhamou, N.; Coudert, G. Tetrahedron 2008, 64, 8059. (d) Mousset, D.;
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3, and a CIF file of compound 3n. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Gillaizeau, I.; Sabatie, A.; Bouyssou, P.; Coudert, G. J. Org. Chem.
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2006, 71, 5993. (e) Hamersak, Z.; Litvic, M.; Sepac, D.; Lesac, A.; Raza,
Z.; Sunjic, V. Synthesis 2002, 2174. (f) Xu, Z.; Kozlowski, M. C. J. Org.
Chem. 2002, 67, 3072.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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