cyanoformamides. They rapidly undergo nucleophilic ad-
dition and substitution reactions with mild nucleophiles.8
Cyanoformate esters 1a will decarboxylate to form nitriles
like 3a when heated to high temperatures (Scheme 1).9
Transition metal activation of the C-CN bonds forms I,
which is also susceptible to various decomposition path-
ways. We suspect that I might undergo a metal-catalyzed
decarboxylation, providing nitrile 3a via a different me-
chanistic pathway. Decarbonylation ofI provides II, which
upon protonation provides alcohol 5a (vide infra). Nishihara
observed that intermediates like II can undergo dispropor-
tionation in the presence of 1a to form carbonates like 4a.10
readily prepared in one step by treating commercially
available 4-phenyl-3-butyn-1-ol with carbonyl cyanide.13
Successful cyanoesterification would provide functiona-
lized lactones such as 2a in just two steps from commer-
cially available 3-butynols. An intramolecular reaction
provides control over regioselectivity issues encountered
in intermolecular reactions, in which the nitrile might add
to either alkyne terminus.
Table 1. Optimization of Intramolecular Cyanoesterification
Scheme 1. Potential Reactions of Cyanoformate Esters
Pd(PPh3)4
(mol %)
t
concn
(M)
6a
entry
solvent (οC)
time 6a:4aa (%)b
1
10
10
25
25
25
10
10
10
0
PhMe
PhMe
PhMe
DMF
DMF
DMF
PhMe
DMF
DMF
110 0.1
24 h
-
0c
17c
16c
45
50
73
21
80e
0
2
115 0.03 48 h
115 0.03 24 h
115 0.03 24 h
115 0.03 1.5 h
1:1.5
1:1.5
2.8:1
4:1
3
4
5
6
130 0.1
130 0.1
200 0.1
200 0.1
1.5 h
1.5 h
3.9:1
1:1.3
7
8d
9d
5 min 16:1
5 min
-
1
a Ratio determined by H NMR spectroscopy of the crude reaction
mixture. b Yields determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as internalstandard.c Asignificantamount ofstarting
material was observed. d Reaction performed in microwave reactor.
e Isolated yield. Carbonate 5a (5%) was also isolated. Bold conditions
(entry 8) indicate those used for exploring the reaction scope, Table 2.
Due to a multitude of potential side reactions, very few
selective processes involving C-C σ bond activation of
cyanoformate esters have been reported. Nishihara re-
ported the first example of Pd-catalyzed intermolecular
cyanoesterification of norbornenes and norbornadienes
with cyanoformate esters.10 More recently, Nakao and
Hiyama reported a Ni-catalyzed cyanoesterification of
allenes11 and alkynes,12 also in an intermolecular context.
In this report, we describe an intramolecular cyanoes-
terification of alkynes with Pd catalysts to produce
butenolides by successfully suppressing competitive dec-
arbonylation. We chose cyanoformate ester 1a, which is
We began with Nishihara’s conditions,10 which resulted
only in unconsumed starting material (Table 1, entry 1).
When the reaction was diluted to 0.03 M in toluene (entry
2), carbonate 4a was formed as the major product, but a
minor amount of another compound with a molecular
weight corresponding to that of 2a was also observed.
Closer inspection of the NMR spectra indicated that the
product was a structural isomer of 2a, but with an endo-
cyclic alkene (6a), likely resulting from isomerization of 2a.
Trials to increase the ratio of 6a:4a by varying temperature,
catalyst loading, and concentration failed (not shown).
Recalling our previous successes with Lewis basic additives
in somewhat similar cyanoamidation reactions,6b,7 we
added stoichiometric amounts of N,N-dimethylpropylene
urea (DMPU) and N-methylpyrollidinone (NMP), think-
ing that the Lewis basic additives will coordinate to Pd to
stabilize intermediate complexes. Although stoichiometric
amounts of Lewis basic additives were not particularly
fruitful (results not shown), a much higher ratio of 6a:4a
was observed when DMPU was used as a solvent. The
subsequent removal of DMPU and isolation proved diffi-
cult, however (not shown). Our success with DMPU
prompted us to employ a more convenient, lower boiling,
(9) Sheppard, W. A. J. Org. Chem. 1962, 27, 3756.
(10) (a) Nishihara, Y.; Inoue, Y.; Itazaki, M.; Takagi, K. Org. Lett.
2005, 7, 2639. (b) Nishihara, Y.; Inoue, Y.; Izawa, S.; Miyasaka, M.;
Tanemura, K.; Nakajima, K.; Takagi, K. Tetrahedron 2006, 62, 9872. (c)
Nishihara, Y.; Miyasaka, M.; Inoue, Y.; Yamaguchi, T.; Kojima, M.;
Takagi, K. Organometallics 2007, 26, 4054.
(11) (a) Nakao, Y.; Hirata, Y.; Hiyama, T. J. Am. Chem. Soc. 2006,
128, 7420. (b) Hirata, Y.; Inui, T.; Nakao, Y.; Hiyama, T. J. Am. Chem.
Soc. 2009, 131, 6624.
(12) (a) Hirata, Y.; Yada, A.; Morita, E.; Nakao, Y.; Hiyama, T.;
Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2010, 132, 10070.
(13) (a) Linn, W. J. Org. Synth. 1969, 49, 103. (b) Mander, L. N.;
Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425. (c) Childs, M. E.; Weber,
W. P. J. Org. Chem. 1976, 41, 3486. (d) Martin, E. L. Org. Synth. 1971,
51, 70.
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