Chemistry of ketone α,β-dianions. Acylation reactions of dianion cuprates by acid chlorides

Article abstract of DOI:10.1016/S0040-4039(01)02346-2

The cross-coupling reaction of dianion cuprates, generated from ketone α,β-dianions and copper salts, with acid chlorides, was studied. The reaction gave good to moderate yields of unsymmetrical 1,4-diketones. The consecutive treatment of a dianion cuprate with cyclohexanecarbonyl chloride and methyl iodide or two different acid chlorides gave 2-methyl-substituted 1,4-diketone or triketone, respectively.

Full text of DOI:10.1016/S0040-4039(01)02346-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1257–1259
Chemistry of ketone a,b-dianions. Acylation reactions of dianion
cuprates by acid chlorides
Ilhyong Ryu,*,† Masanobu Ikebe, Noboru Sonoda,‡ Shin-ya Yamato, Go-hei Yamamura and
Mitsuo Komatsu
Department of Chemistry, Faculty of Arts and Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan and
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 2 November 2001; revised 3 December 2001; accepted 7 December 2001
Abstract—The cross-coupling reaction of dianion cuprates, generated from ketone a,b-dianions and copper salts, with acid
chlorides, was studied. The reaction gave good to moderate yields of unsymmetrical 1,4-diketones. The consecutive treatment of
a dianion cuprate with cyclohexanecarbonyl chloride and methyl iodide or two different acid chlorides gave 2-methyl-substituted
1,4-diketone or triketone, respectively. © 2002 Elsevier Science Ltd. All rights reserved.
In spite of the rapid growth of the anion chemistry in
organic synthesis,1 the potential of dianions as synthetic
intermediates has yet to be fully explored. Of particular
interest to us is the use of ketone dianions (enolate
anions having another carbanion function) as a plat-
form for the construction of a ketone framework and,
related to this, we have previously reported on the
generation of ketone a,b-dianions 2 and their reactions
with electrophiles.2,3 Dianion cuprates 34 are unique,
since, in contrast to dianion zincates,5 which undergo a
normal mode of conjugate addition to enones to give
unsymmetrical 1,6-diketones, they undergo formal [3+2]
cycloadditions with enones to give bicyclic alcohols
(Scheme 1). Since the reaction of organocuprate
reagents with acid halides is one of the most popular
reactions available for the synthesis of unsymmetrical
ketones,6 this fact led us to examine the reaction of
dianion cuprates with acid chlorides. In this communi-
cation, we report that (i) the desired cross-coupling
reaction takes place even with the case of dianion
cuprates, thus providing a new route to unsymmetrical
1,4-diketones, and (ii) the consecutive addition of an
acid chloride and methyl iodide or two different acid
chlorides gave the corresponding three-component
assembled products.
The formation of ketone a,b-dianions 2 and their con-
version to the corresponding cuprates 3 were carried
out according to our previously reported protocol and
involved the direct reaction of b-dichlorobutylstannyl
ketones 1 with n-BuLi.4 Typically, dianion cuprates 3,
which were prepared by the consecutive treatment of 1
(1 mmol) with n-BuLi (4 mmol) and CuCN (0.5 mmol)
in THF, were then treated with acid chlorides (0.5
OH
O
CuCN
(0.5 equiv)
O
.
1)
2)
LiO
CuLi LiCN
LiO
Li
R
(Ref. 4)
2
-78 to 0 ˚C
30 min
R
R
H+
3
2
R'COCl
This work
Scheme 1.
* Corresponding author. E-mail: ryu@ms.cias.osakafu-u.ac.jp
† Osaka Prefecture University.
‡ Present address: Department of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-0073, Japan.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02346-2

1258
I. Ryu et al. / Tetrahedron Letters 43 (2002) 1257–1259
n-BuLi
(4 mmol)
.
CuCN
(0.5 mmol)
O
SnBuCl2
LiO
Li
LiO
CuLi LiCN
R
2
R
R
THF
-78 to 0 °C, 30 min
(1 mmol)
-78 to 0 °C, 30 min
2
3
1a : R = tert-Bu
1b :
1c :
sec-Bu
n-Hex
O
H+
R'
R'
R'COCl
(0.5 mmol)
O
LiO
R
R'
O
O
R'
R
R
-78 °C, 1 h
O
R''X
OLi
O
R
R''
Scheme 2.
Table 1. Reaction of dianion cuprates 3 with acid chloridesa
isolated yieldb
58%
α,β-dianion 2
LiO Li
reagents (conditions)
run
1
product
O
1) CuCN (-78 to 0 ˚C)
2) PhCOCl (-78 ˚C)
O
2a
4
OMe
O
O
1) CuCN (-78 to 0 ˚C)
64%
2
3
2) p-MeOPhCOCl (-78 ˚C)
O
O
5
6
1) CuCN (-78 to 0 ˚C)
2) 2-NaphthylCOCl (-78 ˚C)
54%
40%
O
O
1) 2-ThienylCu(CN)Li
(1 equiv, -78 ˚C)
2) 1-NaphthylCOCl (-78 ˚C)
4
O
O
7
1) CuCN (-78 to 0 ˚C)
5
6
53%
41%
2) CyclohexylCOCl (-78 ˚C)
8
9
1) CuCN (-78 to 0 ˚C)
O
O
2) CyclohexylCOCl (-78 ˚C)
3) MeI (5 equiv, -78 to -45 ˚C
O
O
with HMPA)
OMe
1) CuCN (-78 to 0 ˚C)
59%c
76%
2) p-MeOPhCOCl (-78 ˚C)
7
8
3) PhCOCl
(4 equiv, -78 to -40 ˚C)
O
O
Ph
10
LiO
Li
1) CuCN (-78 to 0 ˚C)
2) PhCOCl (-78 ˚C)
O
O
2b
11
O
O
1) CuCN (-78 to 0 ˚C)
2) 2-FurylCOCl (-78 ˚C)
68%
43%
9
O
12
13
14
1) 2-ThienylCu(CN)Li
(1 equiv, -78 ˚C)
2) t-ButylCOCl (-78 ˚C)
10
O
1) CuCN (-78 to 0 ˚C)
2) MeCOCl (-78 ˚C)
O
LiO
Li
11
49%
O
2d
a For a general procedure, see footnote 6. b Flash chromatography on silica gel was performed for
isolation. c 2,4,4-Trimethyl-1-phenyl-1,3-pentanedione was formed as a principal byproduct.

I. Ryu et al. / Tetrahedron Letters 43 (2002) 1257–1259
1259
mmol) at −78°C for 1 h. Aqueous workup and purification
of the crude mixture by silica gel chromatography gave
1,4-diketones (Scheme 2).7 As summarized in Table 1,
both aromatic and aliphatic acid chlorides undergo the
expected cross-couplings at −78°C, to give good to
moderate yields of 1,4-diketones. Mixed cuprates com-
prised of a,b-dianions and 2-thienylCu(CN)Li were also
found to give unsymmetrical ketones, albeit in rather
modest yields (runs 4 and 10). It should be noted that,
in the case of 1:1 reactions, we frequently observed the
formation of a symmetrical 1,6-diketone as a byproduct,
which is likely formed via the dimerization of lithioxyal-
lylcopper(I), arising from the first acylation of the
cuprates 3.8
4. Ryu, I.; Nakahira, H.; Ikebe, M.; Sonoda, N.; Yamato, S.;
Komatsu, M. J. Am. Chem. Soc. 2000, 122, 1219.
5. Ryu, I.; Ikebe, M.; Sonoda, N.; Yamato, S.; Yamamura, G.;
Komatsu, M. Tetrahedron Lett. 2000, 41, 5689.
6. For selected examples of the reaction of organocuprate
reagents with acid halides, see: (a) Su, N.-S.; Yu, S.; Kabalka,
G. W. Organometallics 1998, 17, 3815; (b) Dieter, R. K.;
Sharma, R. R.; Ryan, W. Tetrahedron Lett. 1997, 38, 783;
(c) Cristau, H.-J.; Mbianda, X. Y.; Beziat, Y.; Gasc, M.-B.
J. Organomet. Chem. 1997, 529, 301; (d) Knochel, P.; Yeh,
M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53,
2390; (e) Wehmeyer, R. M.; Rieke, R. D. Tetrahedron Lett.
1988, 29, 4513; (f) Bertz, S. H.; Dabbagh, G.; Villacorta, G.
M. J. Am. Chem. Soc. 1982, 104, 5824; (g) Posner, G. M.;
Whitten, C. E.; McFarland, P. E. J. Am. Chem. Soc. 1972,
94, 5106; (h) Posner, G. M.; Whitten, C. E. Tetrahedron Lett.
1970, 4647. Also see a review: (i) Lipshutz, B. H.; Sengupta,
S. Org. React. 1992, 41, 135.
We also attempted to trap the resulting enolates, which
would lead to three-component coupling reactions. Thus,
the consecutive treatment of dianion cuprate 3 with
cyclohexanecarbonyl chloride (1 mol equiv.) and MeI (5
mol equiv., with HMPA) gave the predicted 2-methylated
1,4-diketone 9 in 41% yield (run 6). An experiment using
two different acid chlorides was also successful and gave
triketone 10 in 59% yield, in which the second reagent
underwent C-acylation of the enolate portion (run 7).
7. A typical procedure for the reaction of cuprates with acid
chlorides (run 8): To a cooled solution (−78°C) of b-
dichlorobutylstannyl ketone 1b (360 mg, 1 mmol) in THF
(10 mL) was added n-BuLi (2.59 mL, 1.54 M solution in
hexane, 4 mmol) dropwise over a period of 5 min under an
atmosphere of argon. This solution was allowed to warm to
0°C followed by stirring for 30 min. To a suspension of
copper cyanide (45 mg, 0.5 mmol) in THF (2 mL) was added
a precooled solution (−78°C) of the resulting a,b-dianion 2b
(1 mmol, 10 mL in THF) via a cannula at −78°C. The reaction
mixture was allowed to warm to 0°C over a 20 min period
and was stirred for 10 min at 0°C. After cooling to −78°C,
benzoyl chloride (54 mL, 0.5 mmol) was added to this
homogeneous solution of lithium cuprate 3b. Stirring was
continued for 1 h at −78°C, and the resulting dark purple
solutionwasthentreatedwithamixtureofsaturatedaqueous
NH4Cl and concentrated NH4OH solutions (1:1, 2 mL) at
−78°C. The reaction mixture was warmed to ambient
temperature and poured into saturated aqueous NH4Cl (40
mL). The aqueous layer was separated and extracted with
Et2O (40 mL×3), and the organic phases were combined,
dried, and concentrated in vacuo. Purification by flash
chromatography (elution with hexane/Et2O, 8:1) provided
the desired 1,4-diketone 11 (83 mg, 76%) as a colorless oil.
1H NMR (270 MHz, CDCl3) l 0.91 (t, 3H, J=7.6 Hz), 1.13
(d, 3H, J=6.8 Hz), 1.44 (m, 1H), 1.76 (m, 1H), 2.57 (m, 1H),
2.94 (t, 2H, J=6.4 Hz), 3.27 (t, 2H, J=6.4 Hz), 7.45–7.56
(m, 3H), 7.98 (d, J=6.8 Hz, 2H); 13C NMR (68 MHz, CDCl3)
l 11.6, 15.9, 26.0, 32.2, 34.8, 48.0, 128.0, 128.5, 133.0, 136.8,
198.7, 213.2; EIMS m/z (relative intensity, %) 218 (M+, 10),
161 (M+−C4H9, 100), 105 (38), 77 (Ph, 21), 57 (C4H9, 21);
IR (neat, cm−1) 1712 (wCꢀO), 1689 (wCꢀO); HRMS calcd for
C14H18O2: 218.1307. Found: 218.1305; anal. calcd for
C14H18O2: C, 77.03; H, 8.31. Found: C, 76.96; H, 8.37.
8. This was tested in a separate experiment. A THF solution
involving dianion copper(I), separately generated from
dianion 2a and an equimolar amount of copper cyanide at
−78°C, when warmed to 0°C, gave the symmetrical 1,6-dike-
tone in 45% yield after proton quenching. For examples of
homo-coupling reactions observed in the related allyl cuprate
reagents, see: (a) Lipshutz, B. H.; Ellsworth, E. L.; Dimock,
S. H.; Smith, R. A. J. Org. Chem. 1989, 54, 4977; (b) (with
dioxygen) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser,
F. J. Am. Chem. Soc. 1993, 115, 9276; (c) (with dioxygen)
Whitesides, G. M.; SanFilippo, J., Jr.; Casey, C. P.; Panek,
E. J. J. Am. Chem. Soc. 1967, 89, 5302.
In summary, we have shown that the cross-coupling
reaction of organocuprate 3 with acid chlorides gives
unsymmetrical 1,4-diketones in good to moderate yields.
The resulting enolate can be further methylated at the
a-position or acylated with a different acid chloride to
give the corresponding three-component coupling prod-
ucts. Efforts to extend ketone dianion chemistry to other
useful processes are now underway and will be reported
in due course.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports
and Culture, Japan. I.R. wishes to thank the Nagase
Science Foundation for partial financial support of this
work.
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