Synthesis of 1,4-Diketones: Unusual Coupling of Tin Enolates with α-Chloro Ketones Catalyzed by Zinc Halides

Full text of DOI:10.1021/jo971624z

8282
J . Org. Chem. 1997, 62, 8282-8283
Sch em e 1
Syn th esis of 1,4-Dik eton es: Un u su a l
Cou p lin g of Tin En ola tes w ith r-Ch lor o
Keton es Ca ta lyzed by Zin c Ha lid es
Makoto Yasuda, Shoki Tsuji, Ikuya Shibata, and
Akio Baba*
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, 2-1 Yamadaoka, Suita, Osaka 565, J apan
at the halide carbon.9 R-Halocarbonyls could be the
most practical substrates if their reaction manner would
be controlled selectively, since a variety of them are
available and their preparation methods are well-known.8
We have already attained partial success in this work
for the synthesis of 1,4-diketones by the coupling of
R-bromo ketones with highly coordinated tin enolates.10,11
In the highly coordinated tin system, a direct nucleo-
philic substitution at the bromide moiety occurs selec-
tively.10b This system, however, entails serious defects
and limitations; (i) it requires more than an equimolar
amount of additives as ligands to tin and (ii) it was
not applicable to the coupling with R-chloro ketones
at all.
Herein, we report a novel reaction course for the
catalytic synthesis of 1,4-diketones from tin enolates 1
and R-chloro ketones 2. The carbonyl addition of tin
enolate and the subsequent rearrangement proceed via
zinc halide catalysis, and no direct substitution occurs.
This new system greatly expands the scope for the
synthesis of unsymmetric 1,4-diketones owing to the
direct use of R-chlorinated ketones.12
Received September 3, 1997
1,4-Diketones are widely used as synthetic building
blocks for further elaboration into furans, cyclopenten-
ones, or pyrroles.1 One of the most versatile processes
to 1,4-diketones is the conjugate acylation of an enone,
and a variety of acyl anion equivalents have been
developed.2 Considering the applicability, a linkage of
two carbonylmethyl units could be a powerful synthetic
method for the synthesis of various types of 1,4-diketones.
Although a number of homo-coupling reactions of carbo-
nylmethyl radicals,3 metal enolates,4 or R-halocarbonyls5
were reported, the cross-coupling of carbonylmethyl units
remains a challenging problem.6 The most straightfor-
ward process into unsymmetric 1,4-diketones is the
coupling between the carbonylmethyl anion and carbo-
nylmethyl cation (eq 1). Thus, many groups have devel-
oped different types of carbonylmethyl cation equivalents
masked at the carbonyl moiety for the preparation of 1,4-
diketones.7
Initially, we attempted the coupling of the tin enolate
1a with three different types of R-chloro ketones 2a -c
as shown in Scheme 1 and Table 1. Under uncatalyzed
conditions, only aldol-type reactions were observed, af-
fording the functionalyzed chlorohydrin derivatives 4a -c
via carbonyl addition (Table 1, entries 1, 3, and 5) without
any 1,4-diketones 3.13 Tin enolates inherently attack to
the carbonyl carbon selectively rather than the halide
carbon.13-15 Gratifyingly, a dramatic change in the reac-
tion course was achieved by the addition of a catalytic
amount of ZnCl2, affording the 1,4-diketones 3 exclusively
(Table 1, entries 2, 4, and 6).
The direct use of R-halocarbonyl compounds as the
carbonylmethyl cation equivalent has been avoided7h
owing to their multiple reactivity8 such as carbonyl
addition or R-proton abstraction besides the substitution
(1) (a) Bosshard, P.; Eugster, C. H. Adv. Heterocycl. Chem. 1966, 7,
384-387. (b) Ellison, R. A. Synthesis 1973, 397-412. (c) Baltazzi, E.;
Krimen, L. I. Chem. Rev. (Washington, D.C.) 1963, 63, 511-556.
(2) (a) Corey, E. J .; Hegedus, L. S. J . Am. Chem. Soc. 1969, 91,
4926-4928. (b) McMurry, J . E.; Melton, J . J . Am. Chem. Soc. 1971,
93, 5309-5311. (c) Mukaiyama, T.; Narasaka, K.; Furusato, M. J . Am.
Chem. Soc. 1972, 94, 8641-8642. (d) Katritzky, A. R.; Yang, Z.; Lam,
J . N. J . Org. Chem. 1991, 56, 6917-6923. (e) Kubota, Y.; Nemoto, H.;
Yamamoto, Y. J . Org. Chem. 1991, 56, 7195-7196. (f) Katritzky, A.
R.; Lang, H.; Wang, Z.; Lie, Z. J . Org. Chem. 1996, 61, 7551-7557.
(3) Kharasch, M. S.; Mcbay, H. C.; Urry, W. H. J . Am. Chem. Soc.
1948, 70, 1269-1274.
(4) (a) Rathke, M. W.; Lindert, A. J . Am. Chem. Soc. 1971, 93, 4605-
4606. (b) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J . Am. Chem.
Soc. 1977, 99, 1487-1493. (c) Moriarty, R.; Prakash, O.; Duncan, M.
P. J . Chem. Soc., Perkin Trans. 1 1987, 559-561. (d) Fujii, T.; Hirao,
T.; Ohshiro, Y. Tetrahedron Lett. 1992, 33, 5823-5826. (e) Paquette,
L. A.; Bzowej, E. I.; Branan, B. M.; Stanton, K. J . J . Org. Chem. 1995,
60, 7277-7283.
(5) (a) Chassin, C.; Schmidt, E. A.; Hoffmann, H. M. R. J . Am. Chem.
Soc. 1974, 96, 606-608. (b) De Kimpe, N.; Yao, Z.-P.; Schamp, N.
Tetrahedron Lett. 1986, 27, 1707-1710. (c) Iyoda, M.; Sakaitani, M.;
Kojima, A.; Oda, M. Tetrahedron Lett. 1985, 26, 3719-3722.
(6) The cross-coupling into unsymmetric 1,4-diketones necessitated
strictly controlled conditions; see ref 4b,d.
(7) (a) Miyano, M.; Dorn, C. R. J . Org. Chem. 1972, 37, 268-274.
(b) Brown, E.; Ragault, M. Tetrahedron Lett. 1973, 1927-1930. (c)
Cuvigny, T.; Larcheveque, M.; Normant, H. Tetrahedron Lett. 1974,
1237-1240. (d) Stork, G.; J ung, M. E. J . Am. Chem. Soc. 1974, 96,
3682-3686. (e) Miyashita, M.; Yanami, T.; Yoshikoshi, A. J . Am. Chem.
Soc. 1976, 98, 4679-4681. (f) J acobson, R. M.; Raths, R. A.; McDonald,
J . H., III J . Org. Chem. 1977, 42, 2545-2549. (g) Dauben, W. G.; Hart,
D. J . J . Org. Chem. 1977, 42, 3787-3793. (h) Sum, P. E.; Weiler, L.
Can. J . Chem. 1978, 56, 2301-2304.
In the course of our investigation of other metal halides
as catalysts, MgCl2, LiCl, CuCl2, or AlCl3 failed in the
(8) De Kimpe, N.; Verhe´, R. The Chemistry of R-Haloketones,
R-Haloaldehydes and R-Haloimines; Patai, S., Rappoport, Z., Eds.; J ohn
Wiley & Sons: Chichester, 1988.
(9) For the Pd- or Ru-catalyzed coupling of R-bromo ketones
bearing bulky or aryl substituents with tin enolate, see: Kosugi, M.;
Takano, I.; Sakurai, M.; Sano, H.; Migita, T. Chem. Lett. 1984, 1221-
1224.
(10) The five-coordinate tin enolate is derived from the four-
coordinate tin enolate and an appropriate ligand. (a) Baba, A.; Yasuda,
M.; Yano, K.; Shibata, I.; Matsuda, H. J . Chem. Soc., Perkin Trans. 1
1990, 3205-3207. (b) Yasuda, M.; Oh-hata, T.; Shibata, I.; Baba, A.;
Matsuda, H. J . Chem. Soc., Perkin Trans. 1 1993, 859-865. (c) Yasuda,
M.; Katoh, Y.; Shibata, I.; Baba, A.; Matsuda, H.; Sonoda, N. J . Org.
Chem. 1994, 59, 4386-4392. (d) Yasuda, M.; Morimoto, J .; Shibata, I.;
Baba, A. Tetrahedron Lett. 1997, 38, 3265-3266.
(11) For reviews, see: (a) Shibata, I.; Baba, A. Org. Prep. Proc. Int.
1994, 26, 85-100. (b) Yasuda, M.; Shibata, I.; Baba, A.; Matsuda, H.
Recent Res. Dev. Pure Appl. Chem. 1997, 1, 55-71.
(12) R-Halo imines are often used instead of R-halo ketones. De
Kimpe, N.; De Cock, W.; Stevens, C. Tetrahedron 1992, 48, 2739-2760.
(13) Pri-Bar, I.; Pearlman, P. S.; Stille, J . K. J . Org. Chem. 1983,
48, 4629-4634.
(14) Kosugi, M.; Takano, I.; Hoshino, I.; Migita, T. J . Chem. Soc.,
Chem. Commun. 1983, 989-990.
(15) (a) Yasuda, M.; Oh-hata, T.; Shibata, I.; Baba, A.; Matsuda,
H.; Sonoda, N. Tetrahedron Lett. 1994, 35, 8627-8630. (b) Yasuda,
M.; Oh-hata, T.; Shibata, I.; Baba, A.; Matsuda, H.; Sonoda, N. Bull.
Chem. Soc. J pn. 1995, 68, 1180-1186.
S0022-3263(97)01624-1 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 24, 1997 8283
Ta ble 1. Selective Rea ction of Tin En ola te 1a w ith r-Ch lor o Keton e 2 w ith or w ith ou t Zn Cl2 Ca ta lyst (Sch em e 1)a
entry
2
R1
Ph
R2
H
catalyst
time/h
yield/%
ratio of 3/4
1
2
3
4
5
6
2a
none
ZnCl2
none
ZnCl2
none
ZnCl2
6
2
24
2
24
6
>99
>99
62
64
>99
82
<1:>99 (3a a /4a )
>99:<1
2b
2c
Me
H
<1:>99 (3a b/4b)
>99:<1
-(CH2)4-
<1:>99 (3a c/4cb)
>99:<1
a
Tin enolate 1 (2.0 mmol) and R-chloro ketone 2 (1.0 mmol) were employed in THF (1 mL) at 40 °C. ZnCl2 (0.1 mmol) was added in
b
entries 2, 4, and 6. Diastereomer ratio (60:40); ref 15.
Ta ble 2. Syn th esis of 1,4-Dik eton e 3 in th e
Zn Cl2-Ca ta lyzed Rea ction of Tin En ola te 1 w ith r-Ch lor o
Keton e 2a
Sch em e 2
tively (Table 2, entries 7 and 8). Various types of tin
enolates 1a -d were applied to the coupling reactions.18
Interestingly, no reactions were observed in the treat-
ment of 1a with ethyl 2-chloroacetate or allyl chloride in
the presence of ZnCl2, which are typical types of reactive
organic chlorides. The direct substitution reaction at a
halide moiety, therefore, is unlikely to occur. The indis-
pensable presence of a reactive carbonyl group attached
to the chlorinated carbon strongly indicates the incorpo-
ration of the addition of a tin enolate to the carbonyl
carbon in the first step. To investigate the reaction
mechanism, the following experiment was carried out.
After completion of the uncatalyzed addition of 1a to the
carbonyl group in 2a under the conditions noted in entry
1 of Table 1, the addition of a catalytic amount of ZnCl2
led to the transformation into 3a a in high yield (92%).
On the basis of this result, a plausible catalytic cycle is
proposed in Scheme 2.
a
All reactions were carried out in THF (1 mL) using tin enolate
At first, the tin enolate 1 adds to the R-halo ketone 5
at the carbonyl carbon to form 6. The transmetalation
of tin in 6 with zinc halide gives the reactive intermediate
zincate 7, which can readily transform to the 1,4-diketone
by rearrangement of the oxoalkyl group.19 A generation
of the zinc enolate that is formed by the transmetalation
of 1 with zinc halide is also likely. Although we cannot
provide the precise mechanism at this point, the inter-
mediate zincate 7 certainly plays an important role in
the rearrangement, which is prompted by the affinity of
zinc with halogen in 7.20
1 (2.0 mmol), chloro ketone 2 (1.0 mmol), and ZnCl2 (0.1 mmol) at
b
40 °C. ZnBr2 was used instead of ZnCl2. c The reaction was
carried out at 60 °C.
effective synthesis of the 1,4-diketone, affording a com-
plex mixture that included the substituted furan via
carbonyl addition followed by cyclization14,16 and low
yields of 3a (17, 10, 16, 40%) in the reaction of 1a with
2a under the same conditions. These results illustrated
the effectiveness of ZnCl2 for the “unusual” coupling.
We then explored the generality of the ZnCl2-catalyzed
reaction by varying tin enolates 1 and R-chloro ketones
2. Table 2 summarizes these results. In all cases, the
effective and exclusive formation of 1,4-diketones 3 was
observed. Of course, the reaction of 1 with R-bromo
ketone afforded 3 effectively.17 The use of ZnBr2 also
catalyzed the reactions (Table 2, entries 2, 6, and 10).
The high yield of 3a c from cyclic chloro ketone 2c was
noteworthy (Table 2, entries 5 and 6) because no cyclic
halo ketones gave 1,4-diketones by using the system of
the highly coordinated tin enolate.10b Even the sterically
hindered chloro ketones 2d and 2e reacted smoothly to
give 1,4-diketones 3a d and 3a e in high yields, respec-
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research on Priority Area No.
09231229 from the Ministry of Education, Science,
Sports, and Culture, of the J apanese Government.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds (6
pages).
J O971624Z
(18) Organotin enolates exist as equilibrium mixtures of keto and/
or enol forms; 1b and 1d exclusively exist in keto and enol forms,
respectively, and 1a and 1c is a mixture of both forms. Pereyre, M;
Bellegarde, B; Mendelsohn, J ; Valade, J . J . Organomet. Chem. 1968,
11, 97-110.
(19) Kel’in, A. V.; Kulinkovich, O. G. Synthesis 1996, 330-332.
(20) Katritzky, A. R.; Xie, L.; Toader, D.; Serdyuk, L. J . Am. Chem.
Soc. 1995, 117, 12015-12016.
(16) Padmanabhan, S.; Ogawa, T.; Suzuki, H. Bull. Chem. Soc. J pn.
1989, 62, 2114-2116.
(17) The 1,4-diketone 3a a was obtained from 1a and 2-bromo-
acetophenone catalyzed by ZnBr2 in 78% yield at 40 °C for 2 h.