Palladium-catalyzed transformation of cyclobutanone O-benzoyloximes to nitriles via C-C bond cleavage

Article abstract of DOI:10.1021/jo049385k

Palladium-catalyzed transformation of cyclobutanone O-benzoyloximes to a variety of nitriles is described. The reaction may proceed via two important steps, that is, (i) oxidative addition of the N-O bond of oximes to Pd(0) to give a cyclobutylideneaminopalladium(II) species and (ii) β-carbon elimination of this species to afford a reactive alkylpalladium species. The kind of products is very dependent on the nature of substituents on the cyclobutane ring. The direction of the C-C bond cleavage is controlled by the kind of ligand employed. The sequential reaction composed of the C-C bond cleavage and the subsequent intra- and intermolecular C-C bond formations via the corresponding alkylpalladium species is also demonstrated. For example, an oxime having an alkynyl moiety at a suitable position reacts with a variety of alkenes to afford nitriles bearing dienylcyclopentane moiety in moderate to good yields.

Full text of DOI:10.1021/jo049385k

P a lla d iu m -Ca ta lyzed Tr a n sfor m a tion of Cyclobu ta n on e
O-Ben zoyloxim es to Nitr iles via C-C Bon d Clea va ge
Takahiro Nishimura,* Yoshiki Nishiguchi, Yasunari Maeda, and Sakae Uemura*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510, J apan
takahiro@scl.kyoto-u.ac.jp; uemura@scl.kyoto-u.ac.jp
Received April 13, 2004
Palladium-catalyzed transformation of cyclobutanone O-benzoyloximes to a variety of nitriles is
described. The reaction may proceed via two important steps, that is, (i) oxidative addition of the
N-O bond of oximes to Pd(0) to give a cyclobutylideneaminopalladium(II) species and (ii) â-carbon
elimination of this species to afford a reactive alkylpalladium species. The kind of products is very
dependent on the nature of substituents on the cyclobutane ring. The direction of the C-C bond
cleavage is controlled by the kind of ligand employed. The sequential reaction composed of the
C-C bond cleavage and the subsequent intra- and intermolecular C-C bond formations via the
corresponding alkylpalladium species is also demonstrated. For example, an oxime having an alkynyl
moiety at a suitable position reacts with a variety of alkenes to afford nitriles bearing dienylcy-
clopentane moiety in moderate to good yields.
SCHEME 1
In tr od u ction
We have so far developed a novel Pd catalytic system,
which affords ketones from cyclobutanols via C-C bond
cleavage (Scheme 1). The system involves â-carbon elimi-
nation1,2 from an intermediate palladium(II)-alcoholate
(A), where the strain release from cyclobutane ring is a
driving force.3 Similar â-carbon elimination is expected
to occur to give nitriles if a cyclobutylideneaminopalla-
dium(II) species such as B is formed as an intermediate
by oxidative addition of the N-O bond to Pd(0) in the
reaction with cyclobutanone oximes (Scheme 1).
More specifically, â-carbon elimination from an inter-
mediate B′ might give a γ-cyanoalkylpalladium species
SCHEME 2
(1) (a) Nishimura, T.; Ohe, K.; Uemura, S. J . Am. Chem. Soc. 1999,
121, 2645. (b) Nishimura, T.; Ohe, K.; Uemura, S. J . Org. Chem. 2001,
66, 1455. (c) Nishimura, T.; Uemura, S. J . Am. Chem. Soc. 1999, 121,
11010. (d) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S. Chem.
Commun. 2002, 50. (e) Nishimura, T.; Matsumura, S.; Maeda, Y.;
Uemura, S. Tetrahedron Lett. 2002, 43, 3037. (f) Matsumura, S.;
Maeda, Y.; Nishimura, T.; Uemura, S. J . Am. Chem. Soc. 2003, 125,
8862. (g) Nishimura, T.; Araki, H.; Maeda, Y.; Uemura, S. Org. Lett.
2003, 5, 2997.
(2) For examples of the reaction involving â-carbon elimination from
transition metal alcoholates, see: (a) Harayama, H.; Kuroki, T.;
Kimura, M.; Tanaka, S.; Tamaru, Y. Angew. Chem., Int. Ed. Engl.
1997, 36, 2352. (b) Kondo, T.; Kodoi, K.; Nishinaga, E.; Okada, T.;
Morisaki, Y.; Watanabe, Y.; Mitsudo, T. J . Am. Chem. Soc. 1998, 120,
5587. (c) Park, S.-B.; Cha, J . K. Org. Lett. 2000, 2, 147. (d) Okumoto,
H.; J innai, T.; Shimizu, H.; Harada, Y.; Mishima, H.; Suzuki, A. Synlett
2000, 629. (e) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M.
J . Am. Chem. Soc. 2001, 123, 10407. (f) Terao, Y.; Wakui, H.; Nomoto,
M.; Satoh, T.; Miura, M.; Nomura, M. J . Org. Chem. 2003, 68, 5236.
(3) For reviews of the reaction of small ring compounds, see: (a)
Small Ring Compounds in Organic Synthesis I-IV. In Topics in
Current Chemistry; de Meijere, A., Ed.; Springer-Verlag: Berlin, 1986
(Vol. 133); 1987 (Vol. 135); 1988 (Vol. 144); 1990 (Vol. 155). (b) Durst,
T.; Breau, L. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, pp 675-697.
(c) Hudlicky, T.; Reed, J . W. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5,
pp 899-970. (d) Piers, E. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, pp 971-
998. (e) Bronson, J . J .; Danheiser, R. L. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K.,
1991; Vol. 5, pp 999-1035.
(C), the formation of which leads to several nitriles
depending on the kind of substituents R′ and R′′ via
depalladation (Scheme 2). The step of oxidative addition
of ketone O-acyloximes to Pd(0) to afford such an alkyl-
ideneaminopalladium(II) species has been postulated by
Narasaka and co-workers in the synthesis of heterocyclic
compounds from the oximes.4,5 Their work prompted us
to develop a new method for the synthesis of nitriles
involving two unique steps, namely, oxidative addition
of the N-O bond giving B′ followed by â-carbon elimina-
tion to afford C. In this article we describe the results of
the palladium(0)-catalyzed intra- and intermolecular
reactions of cyclobutanone O-benzoyloximes having vari-
ous kinds of substituents on cyclobutane ring leading to
a variety of nitriles.6,7
10.1021/jo049385k CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/02/2004
5342
J . Org. Chem. 2004, 69, 5342-5347

Transformation of Cyclobutanone O-Benzoyloximes
SCHEME 3
SCHEME 5
SCHEME 4
TABLE 1. Effect of Liga n d s in th e Rea ction of (Z)-7
entry
ligand (mol %)
GLC yield (8 + 9,%)
ratio (8/9)a
Resu lts a n d Discu ssion
1
2b
3
4
5
6
7
8
9
(R)-BINAP (7.5)
(R)-BINAP (7.5)
(R)-MeO-MOP (20)
(S)-H-MOP (20)
PPh3
PCy3 (10)
(R)-(S)-PPFA (10)
(R)-(S)-PPFCyA (10)
(R)-(S)-PPFAdA (10)
63
88
82
82
39
51
15
74
47
25/75
25/75
19/81
49/51
57/43
75/25
28/72
84/16
70/30
F or m a tion of Nitr iles Ha vin g Ca r bon -Ca r bon
Un sa tu r a ted Bon d s. The first attempt to prepare
nitriles from 3-phenylcyclobutanone O-benzoyloxime (1)
via C-C bond cleavage was carried out in the presence
of a palladium(0) catalyst, 2,2′-bis(diphenylphosphino)-
1,1′-binaphthyl (BINAP), and K2CO3 in tetrahydrofuran
(THF) (Scheme 3).6 The major product was the R,â-
unsaturated nitrile 3 in this case.
c
Determined by GLC. b For 39 h. c 5 mol % Pd(PPh3)4 was used.
a
The interesting selectivity was observed when O-
benzoyloxime 4 was used as a substrate.Thus, its (E)-
isomer (E)-4 afforded the nitrile 5 as a major product in
86% yield together with 8% of the nitrile 6, while (Z)-4
(Z-isomer) gave 5 and 6 in 37% and 48% yields, respec-
tively (Scheme 4). When the reaction of (Z)-4 was carried
out at lower temperature (in diethyl ether at reflux), 5
became the main product (83%).
The plausible pathway for the formation of these
products is shown in Scheme 5. The oxidative addition
of the N-O bond of (E)-4 occurs to give an alkylidene-
aminopalladium species E-I,8 and successive â-carbon
syn-elimination followed by â-hydrogen elimination af-
fords the nitrile 5 as a major product. On the other hand,
(Z)-4 gives Z-I, which leads to the nitrile 6 via similar
elimination. In the case of (Z)-4, the formation of 5
implies that an isomerization of Z-I to E-I occurs during
the reaction, since the E/Z-isomerization of 4 was not
observed at all in the absence of a Pd(0) catalyst.
F IGURE 1.
According to the results described above, the C-C bond
cleavage generally favors the formation of a sterically less
hindered primary alkylpalladium species. It was also ob-
served that the direction of the C-C bond cleavage was
affected by the configuration of the isomers (E) or (Z) in
some extent. To investigate how the selectivity of direc-
tion of the C-C bond cleavage is affected by a kind of
ligand, 3,3-diisobutyl-2-allylcyclobutanone O-benzoylox-
ime (7) was treated in the presence of Pd(0) catalyst and
a phosphine ligand. Treatment of (Z)-7 in the presence
of Pd(dba)2, (R)-BINAP, and K2CO3 in THF at 90 °C gave
nitriles 8 and 9 in 88% yield (8/9 ) 25/75, Table 1, entries
1 and 2). The reaction using MeO-MOP9 as a ligand also
gave 9 preferentially (entry 3). On the other hand, when
the reaction was carried out with ligands such as PCy3,
PPFCyA, and PPFAdA (Figure 1),1f the nitrile 8 was
obtained as a major product (entries 6, 8, and 9).
(4) (a) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45. (b) Tsutsui,
H.; Narasaka, K. Chem. Lett. 2001, 526. (c) Kitamura, M.; Zaman, S.;
Narasaka, K. Synlett 2001, 974. (d) Kitamura, M.; Chiba, S.; Saku,
O.; Narasaka, K. Chem. Lett. 2002, 606. (e) Narasaka, K. Pure Appl.
Chem. 2002, 74, 143. (f) Tsutsui, H.; Kitamura, M.; Narasaka, K. Bull.
Chem. Soc. J pn. 2002, 75, 1451. (g) Kitamura, M.; Narasaka, K. Chem.
Rec. 2002, 2, 268. (h) Zaman, S.; Kitamura, M.; Narasaka, K. Bull.
Chem. Soc. J pn. 2003, 76, 1055.
(5) For examples of oxidative addition of oximes to metal, see: (a)
Deeming, A. J .; Owen, D. W.; Powell, N. I. J . Organomet. Chem. 1990,
398, 299. (b) Ferreira, C. M. P.; Guedes da Silva, M. F. C.; Kukushkin,
V. Y.; Frau´o da Silva, J . J . R.; Pombeiro, A. J . L. J . Chem. Soc., Dalton
Trans. 1998, 325.
(6) (a) Nishimura, T.; Uemura, S. J . Am. Chem. Soc. 2000, 122,
12049. (b) Nishimura, T.; Uemura, S. Synlett 2004, 201.
(7) For examples of palladium-induced Beckmann fission of oximes
to give nitriles, see: (a) Maeda, K.; Moritani, I.; Hosokawa, T.;
Murahashi, S.-I. J . Chem. Soc., Chem. Commun. 1975, 689. (b)
Leusink, A. J .; Meerbeek, T. G.; Noltes, J . G. Recl. Trav. Chim. Pays-
Bas 1976, 95, 123.
The formation of two products is explained as shown
in Scheme 6. First, oxidative addition of the N-O bond
(8) For an example of the isolation of N-metalloimine complex
containing Re, see: Hevia, E.; Pe´rez, J .; Riera, V.; Miguel, D. Angew.
Chem., Int. Ed. 2002, 41, 3858.
(9) (a) Uozumi, Y.; Hayashi, T. J . Am. Chem. Soc. 1991, 113, 9887.
(b) Uozumi, Y., Suzuki, N., Ogiwara, A.; Hayashi, T. Tetrahedron 1994,
50, 4293.
J . Org. Chem, Vol. 69, No. 16, 2004 5343

Nishimura et al.
SCHEME 6
SCHEME 7
SCHEME 9
SCHEME 8
SCHEME 10
of (Z)-7 to Pd(0) occurs to give a (Z)-alkylideneaminopal-
ladium species. Then, the C-C bond a is cleaved to afford
a secondary-alkylpalladium species, and the nitrile 9 is
produced by the successive â-hydrogen elimination. On
the other hand, the (Z)-alkylideneaminopalladium species
isomerizes to the (E)-isomer, which affords a sterically
less hindered primary-alkylpalladium species. The spe-
cies undergoes intramolecular cyclization with alkenic
moiety followed by â-hydrogen elimination to afford the
nitrile 8.
The direction of the C-C bond cleavage is controlled
by the configuration of oximes (E or Z) in the reaction
using ligands such as BINAP and MOPs, while the use
of PCy3, PPFCyA, and PPFAdA makes the C-C bond
cleave to afford the sterically less hindered primary-
alkylpalladium species from both (E)- and (Z)-oximes.
These observations are consistent with the result of the
reaction of (E)-7 in the use of BINAP as a ligand, where
the nitrile 8 was obtained as a major product opposite to
the result of (Z)-7 case (Scheme 7).
the corresponding nitriles in moderate to good yields
(Scheme 8).
F or m a tion of Cyclop r op a n eca r bon itr iles. Cyclo-
butanone O-benzoyloximes such as 19 and 21 having no
hydrogen available to be eliminated after the formation
of an alkylpalladium intermediate afforded cyclopropan-
ecarbonitriles via an intramolecular cyclization (Scheme
9). For example, cyclopropanecarbonitriles 20 and 22
were obtained from oximes 19 and 21 in 79% and 67%
yields, respectively. 3,3-Dibenzylcyclobutanone O-ben-
zoyloxime (23) produced a mixture of cyclopropanecar-
bonitrile 24 and a nitrile having indane framework 25
in good yields. The formation of these cyclopropanes may
be explained by the reaction pathway shown in Scheme
10. Thus, an intramolecular attack of an active methylene
carbon of an intermediate alkylpalladium benzoate spe-
cies to the palladium in the presence of a base affords a
palladacyclobutane, the reductive elimination of Pd(0)
species from which gives the products. The nitrile 25
might be formed via an intramolecular C-H activation10
Similar reactivity was also observed in the reaction of
other oximes such as 10, 13, and 16, all of which afforded
5344 J . Org. Chem., Vol. 69, No. 16, 2004

Transformation of Cyclobutanone O-Benzoyloximes
SCHEME 11
SCHEME 12
TABLE 2. Effect of Liga n d s in th e Rea ction of 26
TABLE 3. Effect of Liga n d s in th e Rea ction of 28 w ith
Styr en e
entry
ligand (mol %)
isolated yield of 29 (%)
entry
ligand (mol %)
solvent time (h) GLC yield (%)
1
2a
3
4
5
6
7
8
PCy3 (10)
PPh3 (10)
dppe (7.5)
dppb (7.5)
PPFCyA (10)
dppf (7.5)
(R)-MeO-MOP (20)
(R)-BINAP (7.5)
0
tr
0
tr
tr
24
57
75
1a
2
3
4
5
(R)-BINAP (7.5)
(R)-MeO-MOP (20)
(R)-MeO-MOP (20)
(R)-BINAP (7.5)
PPFCyA (10)
THF
THF
DME
DME
DME
72
48
24
24
24
12
21
31
27
5
a
K2CO3 (0.1 mmol) was used. DME ) 1,2-dimethoxyethane
a
Pd(PPh3)4 (5 mol %) was used.
at benzene ring in an alkylpalladium intermediate
formed by â-carbon elimination.
Next, the oxime 28, which has an alkynyl moiety in
the molecule, was prepared. This compound is expected
to give a vinylpalladium species via â-carbon elimination
followed by an intramolecular palladation. The species
may undergo a Mizoroki-Heck type of reaction to afford
a new C-C bond-forming product if alkenes were present
in the system (Scheme 12).13
F or m a t ion of Nit r iles H a vin g a Cyclop en t a n e
F r a m ew or k . Several methods for the transformation of
an alkylpalladium species have so far been established.11
Especially, the C-C bond formation is useful to construct
the target organic molecules.12 It was expected that the
oxime 26 having a nucleophilic carbon center might
afford cyclopentane derivatives via an intramolecular
cyclization of an alkylpalladium intermediate formed
from an alkylideneaminopalladium species by â-carbon
elimination (Scheme 11). Thus, we prepared the oxime
26 and carried out its Pd(0)-catalyzed reaction. Although
several reaction conditions were tested to obtain the
desired product, the product yield was low, unfortunately,
as summarized in Table 2.
First, the reaction of the oxime 28 with styrene was
examined in the presence of Pd(dba)2, a phosphine ligand,
and K2CO3 in refluxing THF (bath temp 90 °C) for 48 h
(Table 3). Phosphine ligands such as PCy3, PPh3, dppe,
dppb, and PPFCyA were not effective for this reaction
(entries 1-5). The desired product 29a was obtained
when such ligands as dppf, MeO-MOP, and BINAP were
employed in which BINAP was most effective to give 29a
in 75% yield (entry 8). Next, the effect of solvents was
investigated using BINAP as a ligand (Table 4). Among
solvents, aprotic polar solvents such as DMF (N,N-
dimethylformamide) and DMA (N,N-dimethylacetoam-
ide) were revealed to be more effective than THF, 1,4-
dioxane, NMP (N-methylpyrrolidinone), and toluene to
give 29a in 83% and 82% yields, respectively (Table 4,
entries 6 and 8).
As the product nitrile 27 has a chiral carbon center, it
might be possible to obtain the optically active nitrile if
the enantioselective C-C bond cleavage could occur from
the chiral ligands-ligated aminopalladium species. No
asymmetric induction, however, was actually observed
in this reaction despite the use of several chiral ligands.
(10) For recent reviews, see: (a) Shilov, A. E.; Shul’pin, G. B. Chem.
Rev. 1997, 97, 2879. (b) Dyker, G. Angew., Chem. Int. Ed. 1999, 38,
1698. (c) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (d)
Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(11) Tsuji, J . Palladium Reagents and Catalysis; Innovations in
Organic Synthesis; Wiley: New York, 1995.
(13) For recent reviews of domino reaction using a palladium
catalyst, see: (a) de Meijere, A.; Bra¨se S. J . Organomet. Chem. 1999,
576, 88. (b) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000,
56, 5959.
(12) For example, see: Grigg, R.; Sridharan, V. J . Organomet. Chem.
1999, 576, 65.
J . Org. Chem, Vol. 69, No. 16, 2004 5345

Nishimura et al.
TABLE 4. Effect of Solven ts in th e Rea ction of 28 w ith
Styr en e
SCHEME 13
entry
solvent
THF
bath temp (°C) time (h) isolated yield (%)
above are initiated by the oxidative addition of N-O bond
to Pd(0). This step was first proposed by Narasaka and
co-workers in the transformation of γ,δ-unsaturated
ketone O-pentafluorobenzoyloximes to pyrrole deriva-
tives. They detected the formation of some palladium
complexes in the reaction of Pd(PPh3)4 with 4,4′-bis-
(trifluoromethyl)benzophenone O-methylsulfonyloxime
by 31P NMR spectroscopy.4f To confirm the presence of
an intermediate alkylideneaminopalladium species in our
reaction system, we tried to isolate the oxidative addition
product of 3,3-diphenylcyclobutanone O-benzoyloxime 30
to Pd(PPh3)4. An equimolar mixture of 30 and Pd(PPh3)4
was stirred in THF at 50 °C. After 4 h, the complete
conversion of 30 was detected by TLC analysis. After
concentration of the reaction mixture, a resulting yellow
solid was collected by filtration and washed with diethyl
ether. By the measurement of 1H NMR of this solid,
however, the peaks of the methylene protons of cyclobu-
tane ring could not be observed at around δ 3-4 ppm [at
3.89 ppm (br s, 4H, in CDCl3) for methylene protons of
30], suggesting that the yellow solid was not the desired
complex 30′.14 Then, we monitored the stoichiometric
1
90
90
90
120
120
90
90
90
90
48
48
40
13
19
15
8
75
5
2a
3
THF
toluene
toluene
1,4-dioxane
DMF
DMF
DMA
29
40
57
83
59
82
56
4
5
6
7b
8
15
15
9
NMP
a
b
Styrene (0.2 mmol) was used. DMF (0.5 mL) was used.
TABLE 5. Rea ction s of 28 w ith Alk en es
1
reaction between 30 and Pd(PPh3)4 by H and 31P NMR
spectroscopy. First, the reaction in benzene-d6 in an NMR
1
tube at 25 °C was monitored by H NMR. As a result,
the peaks (3.33-3.41 ppm, 4H) for methylene protons of
30 were gradually disappeared, while new peaks at 3.32,
3.53, and 2.93 ppm appeared. The singlet peak at 3.32
ppm could be assigned as 3,3-diphenylcyclobutanone (31).
After 23 h, the mixture was heated at 50 °C for 1 h,
resulting in the increase of the formation of 31. The
measurement of 31P NMR on this reaction at 25 °C in
THF-d8 showed new peaks at 29.5, 22.7, and 14.7 ppm
after 2 h. After heating at 50 °C for 1 h, only two peaks
at 22.7 and 21.0 ppm were observed. These results
suggest that an intermediate produced in the reaction
of the benzoyloxime with Pd(PPh3)4 is not stable enough
to be detected even by NMR and decomposes to the
ketone 31 as a result of the hydrolysis by a small amount
of water contained in a solvent.4a Next, benzoyloximes
32 and 34 were treated under our reaction conditions as
shown in Scheme 14, the latter of which are known to
afford the pyrrole 33 under Narasaka’s conditions.4 In
fact, the pyrrole 33 was also obtained in both reactions
under our reaction conditions, although the yields were
low. These results suggest that an alkylideneaminopal-
ladium species is also formed in our case, although the
exact structure of it could not be determined at the
present stage.
a
b
Alkene (2.0 mmol) was used. Alkene (3.0 mmol) was used.
c In THF at reflux. Yield after hydrolysis.
d
The product 29a has a chiral carbon center, but no
asymmetric induction was observed under the reaction
conditions. The reaction of the oxime 28 with several
other alkenes in DMF was also carried out, and typical
results are shown in Table 5. The use of p-chlorostyrene
and 1-octene gave the corresponding nitriles 29b and 29c
in 72% and 67% yields, respectively (entries 1 and 2).
The reaction of 28 with 3,3-dimethyl-1-butene was very
slow, and the product yield was low (entries 3-5),
whereas trimethylvinylsilane and allyldiphenylphosphine
oxide gave the corresponding nitriles in moderate to good
yields (entries 6-8). Ethyl acrylate also afforded 29g in
55% yield after 72 h in refluxing THF. In the case of an
electron-rich alkene, such as butyl vinyl ether, a normal
selectivity of the direction of alkene insertion was ob-
served11 and R,â-unsaturated ketone 29h was obtained
after hydrolysis of the initial product (Scheme 13).
Stoich iom etr ic Rea ction of 3,3-Dip h en ylcyclobu -
ta n on e O-Ben zoyloxim e w ith P d (P P h 3)4: Attem p t
to Isola te a n In ter m ed ia te. It is assumed that whole
reactions of cyclobutanone O-benzoyloximes described
(14) The yellow solid might be a palladium complex such as Pd-
(PPh3)n.
5346 J . Org. Chem., Vol. 69, No. 16, 2004

Transformation of Cyclobutanone O-Benzoyloximes
Typ ica l P r oced u r e for Rea ction of Cyclobu ta n on e
O-Ben zoyloxim es (1, 4, 19, 21, 23). To a mixture of Pd2(dba)3‚
CHCl3 (0.0125 mmol), (R)-(+)-BINAP (0.0375 mmol), and THF
(2 mL) in a 10-mL two-necked flask were added K2CO3 (0.50
mmol), cyclobutanone O-benzoyloxime (0.50 mmol), and THF
(3 mL) under N2, and the mixture was stirred at 90 °C (bath
temp) until the reaction had reached completion by monitoring
with TLC analysis. The reaction mixture was cooled to room
temperature and then filtered through a pad of Florisil. The
filtrate was concentrated under vacuum to give a yellow oil,
which was subjected to column chromatography on SiO2 with
diethyl ether-hexane (4/96) as an eluent. All major products
were isolated and identified by 1H and 13C NMR, IR, and C,
H, N combustion analysis.
SCHEME 14
Typ ica l P r oced u r e for Rea ction of Cyclobu ta n on e
O-Ben zoyloxim es (7, 10, 13, 16, 23). To a mixture of Pd-
(dba)2 (0.005 mmol), (R)-MeO-MOP(0.02 mmol) or (R)-N-
cyclohexyl-N-methyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]-
ethylamine (0.01 mmol), K2CO3 (0.10 mmol), and THF (0.5 mL)
were added allyl-substituted cyclobutanone O-benzoyloxime
(0.10 mmol) and THF (1.5 mL) under N2, and the mixture was
stirred at 90 °C (bath temp) for 24 h. After completion of the
reaction, the reaction mixture was cooled to room temperature
and then filtered through a pad of Florisil. The filtrate was
concentrated under vacuum to give a yellow oil, which was
subjected to column chromatography on SiO2. All major
products were isolated and identified by 1H and 13C NMR and
C, H, N combustion analysis or mass spectroscopy.
Con clu sion
Novel transformations of cyclobutanone O-benzoyl-
oximes to nitriles via a C-C bond cleavage by palladium
catalysis have been demonstrated where the direction of
the C-C bond cleavage was very dependent on the kind
of phosphine ligands employed. The reaction seems to
proceed via oxidative addition of the N-O bond to Pd(0)
to afford an alkylideneaminopalladium intermediate
followed by â-carbon elimination. The sequential reaction
composed of the C-C bond cleavage and the subsequent
intra- and intermolecular C-C bond formations via the
corresponding alkylpalladium species have also been
demonstrated to construct a variety of nitrile derivatives.
The findings disclosed here afford the new methodology
for nitrile synthesis.
Typ ica l P r oced u r e for Rea ction of 26. The procedure
of the reaction of the compound 26 was the same as that of
the reaction of allyl-substituted cyclobutanone O-benzoyl-
oximes. The yield of the compound 27 was determined by GLC
using pentamethylbenzene as an internal standard.
Typ ica l P r oced u r e for Rea ction of 28 w ith Alk en es.
To a mixture of Pd(dba)2 (0.0050 mmol), (R)-(+)-BINAP (0.0075
mmol), K2CO3 (0.10 mmol), and DMF (0.5 mL) were added
alkene (1.0 mmol), 28 (0.10 mmol) and DMF (1.5 mL) under
N2, and the resulting mixture was stirred at 90 °C until the
reaction completed. After completion of the reaction, the
reaction mixture was cooled to room temperature and then
filtered through a pad of Florisil. The filtrate was concentrated
under vacuum to give a yellow oil, which was subjected to
column chromatography on SiO2. All major products were
isolated and identified by 1H and 13C NMR and C, H, N
combustion analysis or mass spectroscopy.
Exp er im en ta l Section
Gen er a l Meth od . 1H NMR spectra were obtained in CDCl3
or C6D6 at 300 or 400 MHz with Me4Si as an internal standard.
13C NMR spectra were obtained at 75.5 or 100 MHz. 31P NMR
spectra were obtained at 161.9 MHz.
Ma ter ia ls. Commercially available organic and inorganic
compounds were used without further purification except for
solvent, which was distilled by the known method before use.15
Pd(dba)2 (dba ) dibenzylideneacetone) was synthesized by the
literature method.16 Cyclobutanone O-benzoyloximes were
prepared according to the reported procedures from the
corresponding cyclobutanone oximes.4f Cyclobutanones were
obtained from the reduction of 2,2-dichlorocyclobutanones,
which were prepared from the corresponding alkenes and
trichloroacetyl chloride.17 (R)-MeO-MOP and (S)-H-MOP9 were
prepared according to the reported procedures.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research (no. 14750680) from
the Ministry of Education, Culture, Sports, Science and
Technology, J apan.
(15) Perrin, D. D.; Armarego, W. L. F.; Perrin D. R. Purification of
Laboratory Chemicals, 2nd ed.; Pergamon Press: Oxford, U.K., 1980.
(16) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J . J .; Ibers, J . A. J .
Organomet. Chem. 1974, 65, 253.
(17) (a) Krepski, L. R.; Hassner, A. J . Org. Chem. 1978, 43, 2879.
(b) Greene, A. E.; Luche, M.-J .; Serra, A. A. J . Org. Chem. 1985, 50,
3957. (c) Ramnauth, J .; Lee-Ruff, E. Can. J . Chem. 1999, 77, 1245.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and characterization data for all compounds and X-ray
crystal structure of 29f (CIF format). This material is available
free of charge via the Internet at http://pubs.acs.org.
J O049385K
J . Org. Chem, Vol. 69, No. 16, 2004 5347