Highly efficient access to iminoisocoumarins and α-iminopyrones via AgOTf-catalyzed intramolecular enyne-amide cyclization

Article abstract of DOI:10.1021/jo9023478

(Chemical Equation Presented) Iminoisocoumarins and α-iminopyrones are prepared via Sonogashira coupling and AgOTf-catalyzed 6-endo-dig O-cyclization of the enyne-amide system in dichloroethane, in one pot or stepwise, respectively.

Full text of DOI:10.1021/jo9023478

pubs.acs.org/joc
Highly Efficient Access to Iminoisocoumarins and
r-Iminopyrones via AgOTf-Catalyzed
Intramolecular Enyne-Amide Cyclization
Ming Bian, Weijun Yao, Hanfeng Ding, and Cheng Ma*
Department of Chemistry, Zhejiang University, Hangzhou,
310027, People’s Republic of China
mcorg@zju.edu.cn
Received November 2, 2009
FIGURE 1. Intramolecular cyclization of o-(1-alkynyl)benzami-
des 1.
Imidates are known to be important pharmacophores and
useful synthetic building blocks.5 Whereas most of the
present synthetic approaches take advantage of Pinner-type
reactions,6 some difficulties are often encountered such as
low yields, harsh conditions, and rather limited substrate
scope. Therefore, new synthetic methods, especially for the
production of cyclic imidates, have been investigated.7 Here-
in, we report a highly efficient synthesis of iminoisocoumarin
and R-iminopyrone imidates via AgOTf-catalyzed intramo-
lecular cyclizations of enyne amide systems.8
We initiated our study with the intramolecular cyclization
of 2-(phenylethynyl)benzamide 1a upon treatment with var-
ious coin-metal catalysts under nitrogen (Table 1). Whereas
copper or gold catalysts afforded low yields or only trace
amount of products (entries 6-10, Table 1), we were pleased
to discover that such transformation can proceed smoothly
to afford the desired product (Z)-2a with AgOTf (5%mmol)
as the catalyst in dichloroethane (DCE) at room temperature
(entry 1, Table 1).9 While at 60 °C in DCE the reaction
finished within 2.5 h in excellent yield (96%, entry 2, Table 1),
other silver salts including AgNO3 and AgOAc in appro-
priate solvents only afforded a trace amount of 2a, respec-
tively (entries 3-5, Table 1). In contrast, the employment of
a strong Bronsted acid of TfOH proved unfavorable to this
conversion, and the desired product 2a was isolated in only
5% yield (entry 11, Table 1).
Iminoisocoumarins and R-iminopyrones are prepared via
Sonogashira coupling and AgOTf-catalyzed 6-endo-dig
O-cyclization of the enyne-amide system in dichloro-
ethane, in one pot or stepwise, respectively.
The carbon-carbon triple bond is one of the most
important functional groups in organic chemistry and has
been widely utilized in organic synthesis as well as mecha-
nistic studies.1 During the past decade, transition metal-
catalyzed cyclization of alkynes possessing a nucleophile
in close proximity to the triple bond is one of the most
important processes and has emerged as a powerful tool for
the construction of a variety of heterocycles.2 In this context,
previous researches related to the annulation of enyne-
amide systems 1 were focused on the N-nucleophility of the
amide group onto C-C triple bonds, giving rise to pyridi-
none and/or pyrrolone derivatives;3 however, few O-cycliza-
tion counterparts which can provide isochromenes or benzo-
furan imidates exist (Figure 1).4
The optimized reaction conditions allowed a wide range of
o-(1-alkynyl)benzamides 1, giving 6-endo-dig O-cyclization
(5) (a) Neilson, D. G. In The Chemistry of Amdines and Imidates; Patai, S.,
Ed.; John Wiley & Sons: London, UK, 1975; Chapter 8. (b) Kantlehner, W.
Synthesis of Iminium Salts, Orthoesters and Related Compounds. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 2, pp 485-599.
(1) Hart, H. In The Chemistry of Triple-Bonded Functional Groups; Patai,
S., Ed.; John Wiley & Sons Ltd.: New York, 1994.
(2) For reviews, see: (a) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc.
Rev. 1999, 28, 199. (b) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104. (c)
Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43,
3368. (d) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
(e) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (f) Nakamura, I.;
Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (g) Patil, N.; Yamamoto, Y.
Chem. Rev. 2008, 108, 3395.
(3) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. (b) Zhang,
H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359. (c) Kundu, N. G.; Khan,
M. W. Tetrahedron 2000, 56, 4777. (d) Yu, Y.; Gregory, A.; Stephenson,
G. A.; Mitchell, D. Tetrahedron Lett. 2006, 47, 3811.
(6) (a) Pinner, A.; Klein, F. Chem. Ber. 1877, 10, 1889. (b) Gavin, D. J.;
Mojica, C. A. Org. Process Res. Dev. 2001, 5, 659. (c) For a review, see:
Roger, R.; Neilson, D. G. Chem. Rev. 1961, 61, 179.
(7) (a) Bez, G.; Zhao, C.-G. Org. Lett. 2003, 5, 4991. (b) Cacchi, S.;
Fabrizi, G.; Marinelli, F. Synlett 1999, 4, 401. (c) Saluste, C. G.; Crumpler,
S.; Furberb, M.; Whitbya, R. J. Tetrahedron Lett. 2004, 45, 6995. (d) Cui,
S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517.
(8) For recent reviews on silver-mediated heterocyclizations, see: (a)
ꢀ
Weible, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149. (b) Alvarez-
~
Corral, M.; Munoz-Dorado, M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108,
3174.
(9) The structure of 2a was confirmed by X-ray crystallography, for
details see the Supporting Information.
(4) For 5-exo-dig O-cyclization of N-propargylamides resulting in sub-
stituted oxazole derivatives, see: (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey,
W.; Bats, J. W. Org. Lett. 2004, 6, 4391. (b) Arcadi, A.; Cacchi, S.; Cascia, L.;
Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3, 2501.
DOI: 10.1021/jo9023478
r
Published on Web 12/08/2009
J. Org. Chem. 2010, 75, 269–272 269
2009 American Chemical Society

Bian et al.
JOCNote
TABLE 1. Optimization of Conditions for the Cyclization to 2aa
TABLE 2. Cyclization of o-(1-Alkynyl)benzamides 1a
entry
catalyst
solvent
T [°C]
time [h]
yield [%]b
1
2
3
4
5
6
7
8
9
AgOTf
AgOTf
AgNO3
AgNO3
AgOAc
HAuCl4
AuCl
AuCl3
CuI
Cu(OTf)2
TfOH
DCE
DCE
DCE
acetone
DMF
DCE
DCE
DCE
DCE
DCE
DCE
25
60
60
60
60
60
60
60
60
60
60
6
2.5
48
48
48
12
24
24
48
48
24
76
96
trace
trace
trace
20
18
trace
15
trace
5
10
11
aReaction conditions: 1a (0.5 mmol), catalyst (5 mol %), solvent
(5 mL), under N2 atmosphere. bYields of isolated products.
products of (Z)-2 in good to excellent yields (Table 2). The
presence of aryl or alkyl substitutents (R2) on the alkyne
moiety of 1 presented no difficulties to furnish the expected
products. Notably, free hydroxyl groups, primary or
β-tertiary, were also tolerated in this conversion, and produ-
ced 2d and 2e in 92% and 87% yield, respectively (entries 4
and 5, Table 2). On the aromatic tether, not only electron-
rich but also electron-poor benzamides 1 underwent the
cyclization clearly, although an extended reaction time
was required to obtain a good yield for electron-defficient
counterpart (entries 12 and 13, Table 2). A heteroaromatic
system involving a pyridine unit had also been employed in
this process to give 2k in 91% yield after 3 h (entry 11,
Table 2). Finally, there was no obvious difference on the
reactivity of N-alkyl- and N-aromatic-substituted substrates,
and they all afforded similar high yields.
This intramolecular reaction was not restricted to the use
of (hetero) aromatic systems. Under the standard conditions,
the aliphatic analogous 3 performed similar reactions with-
out any problem to provide R-iminopyrones 4 in good to
excellent yields (Table 3). During the spectroscopic charac-
terization of 4a-e, we noted the presence of E-Z isomers
arising from the imine group in the solution of CDCl3 at
25 °C by NMR spectra. The ratio of E-Z isomers is
approximately 3:1 in these compounds. However, a similar
result was not observed for products 2 and 4f. As expected,
no isomers of 4e were detected in d6-DMSO by NMR at
80 °C.10 These observations can be rationalized by steric and
resonance considerations similar to that discussed in pre-
vious literature.11
Notably, based on these experimental results, the current
reaction displayed excellent regioselectivity, and nearly only
6-endo-dig O-cyclization products had been observed for those
examined substrates, though both 5-exo-dig and 6-endo-dig
cyclizations are favorable according to Baldwin’s rule.12,13
aConditions: 0.5 mmol of o-(1-alkynyl)benzamide 1, 5 mol % of
AgOTf in 5 mL of DCE under N2 atmosphere. bYields of isolated
products.
(10) For NMR experiments, see the Supporting Information.
(11) For a review, see: (a) Dugave, C.; Demange, L. Chem. Rev. 2003, 103,
Considering the potential tolerance of Sonogashira coup-
ling and our annulation transformation, we therefore inves-
tigated the feasibility of combining these two reactions in one
pot. Disappointingly, whereas the Sonogashira coupling of
iodides 5 with terminal alkynes proceeded well treated by
CuI and PdCl2(PPh3)2 in the presence of triethylamine, the
subsequent O-cyclization cannot take place, no matter
when AgOTf was added, before or after the coupling. We
envisioned that the byproduct of the coupling reaction,
triethylamine hydroiodide salts, as well as the excess amount
of NEt3, might destroy the catalytic activity of AgOTf. To
ꢀ
2475. (b) Nsikabaka, S.; Harb, W.; Ruiz-Lopez, M. F. J. Mol. Struct.
(Theochem) 2006, 764, 161. (c) Lehn, J. M. Chem.;Eur. J. 2006, 12, 5910.
(d) Johnson, J. E.; Silk, N. M.; Arfan, M. J. Org. Chem. 1982, 47, 1958. (e)
Padwa, A.; Albrecht, F. J. Am. Chem. Soc. 1974, 96, 4849.
(12) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
(13) For some cyclization reactions which cannot be explained in terms of
Baldwin’s rule, see: (a) Uchiyama, M.; Koike, M.; Kameda, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1996, 118, 8733. (b) Uchiyama, M.;
Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934. (c) Uchiyama, M.; Ozawa,
H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T.
Org. Lett. 2006, 8, 5517.
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TABLE 3. AgOTf-CatalyzedCyclizationof(Z)-Alk-2-en-4-ynamides3a
TABLE 4. One-Pot Formation of 2 and 4a
aConditions: 0.5 mmol of o-(1-alkynyl)benzamide 1, 5 mol % of
AgOTf in 5 mL of DCE under N2 atmosphere. R = p-tol. Yields of
isolated products.
b
c
our delight, the employment of AgNO3 (1.2 equiv) could
diminish this inhibition effect, and a proposed one-pot three-
step protocol, without isolation of intermediates, has been
successfully achieved for accessing to product 2a from iodide
5a and phenylacetylene in 93% total yield. To evaluate the
scope of this one-pot process, we examined several examples
randomly, and all entries gave excellent yield of final pro-
ducts as expected (Table 4).
In conclusion, we have developed a highly efficient
AgOTf-catalyzed intramolecular cyclization reaction of
o-(1-alkynyl)benzamide 1 or (Z)-alk-2-en-4-ynamides 3
for the synthesis of iminoisocoumarin and R-iminopyrone
derivatives, respectively, via a selective 6-endo-dig type, O-
nucleophilic attacking onto the tethered C-C triple bond.
The current catalyst system tolerates a wide range of
aromatic and aliphatic substrates. In addition, we have
discovered that the target products are obtainable using an
operationally simpler one-pot procedure directly from
halide functionalized aromatic/aliphatic amides and al-
kynes.
aAll reaction were run by mixing 2 mol % of PdCl2(PPh3)2, 4 mol % of
CuI, 1.2 equiv of Et3N, 1.1 equiv of the alkyne, and 1.0 equiv of orgnic
iodide in DCE (5.0 mL). Once the iodide was consumed, 5 mol % of
AgOTf was added followed by 1.2 equiv of AgNO3. bYields of isolated
products based on 5.
purified by column chromatography on silica gel to afford 2a
(142 mg, 96%).
(Z)-N-(3-Phenyl-1H-isochromen-1-ylidene)aniline (2a): pale
yellow solid; mp 115-116 °C; 1H NMR (400 MHz, CDCl3,
25 °C, TMS) δ 8.40 (d, J = 8.0 Hz, 1H), 7.61-7.53 (m, 3H),
7.45-7.41 (m, 3H), 7.35-7.33 (m, 4H), 7.30-7.26 (m, 2H), 7.17
(t, J = 7.0 Hz, 1H), 6.72 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3, 25 °C, TMS) δ 151.6, 133.9, 132.4, 132.3, 129.4, 128.8,
128.6, 128.1, 127.5, 125.6, 124.6, 123.6, 122.4, 100.8 ppm; IR
(KBr) v 3026, 1627, 1660, 1592, 1489, 1340, 1212, 1069 cm-1
;
HRMS (ESI) calcd for C21H15NONa [M þ Na]þ 320.1046,
Experimental Section
found 320.1029.
Typical Procedure for the Cyclzation of 1 and 3. To a solution
of alkynylamide 1a (148 mg, 0.5 mmol) in DCE (5 mL) was
added AgOTf (6.5 mg, 0.025 mmol) under nitrogen. The mixture
was stirred at 60 °C for 2.5 h. On completion of the reaction, the
solvent was removed under vacuum, and the residue was
Typical Procedure for One-Pot Formation of 2 and 4. To a
solution of iodide 5a (323 mg, 1.0 mmol) and phenylacetylene
(112 mg, 1.1 mmol) in DCE (5.0 mL) were added CuI (7.6 mg,
0.04 mmol), PdCl2(PPh3)2 (28 mg, 0.02 mmol), and NEt3 (121
mg, 1.2 mmol) under nitrogen. The resulting mixture was then
J. Org. Chem. Vol. 75, No. 1, 2010 271

Bian et al.
JOCNote
heated to refluxing temperature with stirring. Once iodide 5a
was completely consumed, the reaction mixture was cooled to
room temperature, and then AgNO3 (202 mg, 1.2 mmol) was
added. After 15 min, followed by the addition of AgOTf (12.8
mg, 0.05 mmol), the mixture was stirred for an additional 3 h at
60 °C. On completion of the reaction, salts were removed by
filtration and the solvent was evaporated under vacuum, the
residue was then purified by column chromatography on silica
gel to afford 2a (276 mg, 93% yield).
MHz, CDCl3, 25 °C, TMS) δ 156.9, 151.0, 143.4, 134.5, 132.9,
131.8, 129.9, 129.2, 128.7, 124.6, 122.4, 119.4, 99.9, 20.9 ppm; IR
(KBr) v 3026, 1661, 1616, 1548, 1504, 1129, 821, 759 cm-1
;
HRMS (ESI) calcd for C18H15NONa [M þ Na]þ 284.1046,
found 284.1053.
Acknowledgment. We are grateful to the Science and
Technology Commission of Zhejiang Province (Grant Nos.
2007C21G2010067) for financial support.
4-Methyl-N-(6-phenyl-2H-pyran-2-ylidene)aniline (4a): the
ratio of isomers (3/1) was determined by 1H NMR of the crude
1
Supporting Information Available: Experimental proce-
dures, compound characterization data, and crystallographic
information files (CIFs) of 2. This material is available free of
charge via the Internet at http://pubs.acs.org.
product; yellow solid; mp 109-112 °C; H NMR (400 MHz,
CDCl3, 25 °C, TMS) δ 7.58 (t, J = 3.6 Hz, 2H), 7.36-7.35 (m,
3H), 7.19-7.14 (m, 3H), 6.90-6.86 (m, 2H), 6.40 (d, J = 9.6 Hz,
1H), 6.35 (d, J = 6.4 Hz, 1H), 2.38 (s, 3H) ppm; 13C NMR (100
272 J. Org. Chem. Vol. 75, No. 1, 2010