A direct and selective syntheses of α,α-dichloro-and α-chloro-ethyl ketones by the reaction of alkyl carboxylates with 1,1-dichloroethyllithium

Article abstract of DOI:10.1246/cl.2000.190

1,1-Dichloroethyllithium (5), generated by treating 1,1-dichloroethane (4) with lithium diisopropylamide (LDA) or n-butyllithium, reacted with alkyl carboxylates to afford the corresponding α,α-dichloro-or α-monochloro-ethyl ketones selectively in good to

Full text of DOI:10.1246/cl.2000.190

Chemistry Letters 2000
190
A Direct and Selective Syntheses of α,α-Dichloro- and α-Chloro-ethyl Ketones
by the Reaction of Alkyl Carboxylates with 1,1-Dichloroethyllithium
Isamu Shiina, Yumiko Imai, Akifumi Kagayama, and Teruaki Mukaiyama
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received November 10, 1999; CL-990965)
carboxylates and yields of the produced ketones, together with
reaction conditions were examined in detail based on the reac-
tion mechanism.
1,1-Dichloroethyllithium (5), generated by treating 1,1-
dichloroethane (4) with lithium diisopropylamide (LDA) or n-
butyllithium, reacted with alkyl carboxylates to afford the cor-
responding α,α-dichloro- or α-monochloro-ethyl ketones
selectively in good to high yields. According to the above
alkylation method, synthetic intermediates of Taxol, optically
active α,α-dichloroethyl polyoxyketone 2 and α-chloroethyl
polyoxyketone 3, were respectively synthesized from optically
active methyl polyoxycarboxylate 1 in good yields.
In the first place, alkylations of methyl benzoate with sever-
al alkyl metals such as EtMgBr, nBuLi and chloromethyllithium
were studied in order to compare behavior of these alkylating
reagents. When EtMgBr (2.0 eq.) and nBuLi (1.0 eq.) were used
as alkylating reagents, only the corresponding tertiary alcohols
were produced in ether and THF mixed solvents (EtMgBr; 56%
at 0 °C, nBuLi; 39% at -78 °C). In the case of using
chloromethyllithium7b (2.0 eq.), on the other hand, the corre-
sponding monoalkylated α-chloromethyl ketone was selectively
obtained in 93% yield at -78 °C under same reaction conditions.
It was confirmed that reactions of simple alkyl carboxylates with
in situ formed α-haloalkyllithium gave monoalkylated ketones
preferentially while conventional alkylating reagents such as
Grignard reagents, etc. gave tertiary alcohols.
Total syntheses of Taxol and its derivatives were recently
reported from our laboratory.1 According to our strategy, the
basic frameworks of taxoids were constructed from optically
active polyoxy 8-membered ring compounds which were pre-
pared by cyclization of chiral linear polyoxy compounds.
Reaction conditions for the generation of 54 were re-exam-
ined in detail concerning bases, solvents, additives, reaction
time and temperature. It was then proven that LDA and nBuLi
were quite suitable bases, whereas others such as LHMDS and
LTMP gave poor results. The desired monoalkylated α,α-
dichloroethyl ketone (ketone a) was obtained in 85% yield at
-78 °C by the reaction of methyl benzoate with 5 generated
from 2.5 molar amounts of 4 and 2.0 molar amounts of LDA at
-100 °C in ether and THF mixed solvent containing HMPA
(conditions A). Further, ketone a was also obtained in 91%
yield at -78 °C from methyl benzoate on treatment with 5 pre-
pared from 8.4 molar amounts of 4 and 4.2 molar amounts of
nBuLi at -100 °C (conditions B). In the above reaction, n-buty-
lated tertiary alcohol was not detected under the reaction con-
In the previous paper,2 an improved method for the syn-
thesis of chiral linear polyoxy compound was preliminarily
reported, namely, i) intermediate methyl carboxylate 1 was
prepared by starting from D-pantolactone, ii) the corresponding
α,α-dichloroethyl polyoxyketone 2 was yielded by alkylation
of 1 with 1,1-dichloroethyllithium (5), iii) α-chloroethyl poly-
oxyketone 3 was produced by partial reduction of 2 with
nBu3SnH. It was noticed there that the alkylations of 1 with α-
haloalkyllithiums3-7 gave exclusively the corresponding
monoalkylated ketones without accompanying the undesirable
tertiary alcohols formed by double alkylations, whereas only
the corresponding tertiary alcohol resulted when 1 was treated
with MeLi. Concerning alkylation of alkyl carboxylates with
alkyl metals, it was already reported that methyl or ethyl car-
boxylates containing heteroatom(s) at α-positions sometimes
afforded the corresponding ketones without forming the terti-
ary alcohols.7c,8,9 Further, Villieras et al. reported selective
monoalkylations of methyl benzoate and 2-methylpropanoate
with 5 prepared from 1,1-dichloroethane (4) and sBuLi.4b,5a,7a
In this communication, we would like to describe an effec-
tive method for the one-pot syntheses of α,α-dichloro- and α-
monochloroethyl ketones from simple alkyl carboxylates such
as methyl or ethyl carboxylates by the reaction with 5 which
was prepared on treatment of 4 with LDA or nBuLi.
Furthermore, relation between the structure of starting alkyl
n
ditions suggesting that BuLi was quite quickly consumed to
form 5. However, in the absence of HMPA, generation of 5 by
n
deprotonation of 4 with BuLi was relatively slow and 46% of
n-butylated secondary alcohol was produced by the reaction of
benzaldehyde together with 44% of 2,2-dichloroethylated sec-
ondary alcohol. Since 5 is not stable and it decomposes imme-
diately under the reaction conditions, an excess amount of the
alkylating reagent is required to obtain the desired ketone a in
good yield. When LDA was used as a base, on the other hand,
the generation of 5 seems to take place gradually in accordance
with the reaction proceeding. It is noted that the amounts of the
n
above mentioned organometals such as LDA and BuLi in the
present alkylation depend on the rate of generation of 5, an
unstable intermediate, from 4. In order to confirm the reaction
intermediate, chlorotrimethylsilane was added to the reaction
mixture of methyl benzoate and 5 prepared according to condi-
tions A. There, methyl trimethylsilyl mixed acetal was trapped
in good yield (88%) and it suggested that in situ formed lithium
salt of hemiacetal a' would resist a further attack of 5 under the
reaction conditions and no tertiary alcohol resulted (Scheme 2).
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
191
The desired ketones a were produced in high yields with
complete selectivities from methyl 2-benzyloxypropanoate (6)
and methyl 2-(t-butyldiphenylsiloxy)propanoate (7) by the use
of 5 generated on treating 4 with each alkyl metal, LDA and
nBuLi (from 6; 85% and 73%, from 7; 85% and 92%). As
methyl trimethylsilyl mixed acetal was obtained in 70% yield
by adding chlorotrimethylsilane to the reaction mixture of 7
and 5, it was also revealed that an initially formed lithium salt
of hemiacetal a' would resist the further attack of 5.
ketone b (21.4 mg, 65%) and recovered 8 (2.6 mg, 9%) as col-
orless oils (Entry 1).
Finally, usefulness of the present method for the synthesis
of α-haloethyl ketones from simple alkyl carboxylates was
examined by taking Taxol intermediate 1, an alkyl polyoxycar-
boxylate containing anti-configuration at C2,C3 positions, as a
model. Expectedly, α,α-dichloroethyl polyoxyketone 2, one
of the intermediates of Taxol, was obtained in 54% yield (and
28% of 1 was recovered) when 1 was treated with 5 generated
from 4 and LDA (14 eq., conditions A without HMPA). It is
noteworthy that the one-pot and highly selective synthesis of
intermediate of Taxol 3, an α-monochloroethyl polyoxyketone,
from 1 was attained in 91% yield on treatment with 5, prepared
from 4 and nBuLi (30 eq.).
Next, alkylations of ethyl 2-methyl-3-phenylpropanoate
(8) and ethyl 2,2-dimethyl-3-phenylpropanoate (9) with 5 were
tried (Table 1, Entries 1 and 2). The corresponding α,α-
dichloroethyl ketones (ketones a) were obtained in good yields
under the conditions A while α-monochloroethyl ketones
(ketones b) were exclusively produced in one-pot when 5, gen-
erated according to conditions B, was used. In order to exam-
ine the difference between the above two reactions, an excess
amount of 5, prepared from 8.4 molar amounts of 4 with 4.2
molar amounts of LDA, was used for the reaction of 8, and the
corresponding ketone b was obtained in 42% yield. Further,
reduction of 4,4-dichloro-2-methyl-1-phenylpentan-3-one (14),
an example of ketones a, with 5 generated according to condi-
tions A, proceeded smoothly to give the corresponding ketone
b, 4-chloro-2-methyl-1-phenylpentan-3-one, in 68% yield.
These indicate that the amount of 5 influences the yields of
two ketones (ketone a and ketone b). Since dechlorinated enol
silyl ether was obtained in 25% yield by the addition of t-
butylchlorodimethylsilane to the reaction mixture of 14 and 5,
the above one-pot monochloroethylation of alkyl carboxylates
was assumed to have taken place stepwise: that is, i) addition
of 5 to alkyl carboxylates to form ketones a, and ii) successive
dehalogenation of thus formed ketones a to form ketones b via
lithium enolates b' by reduction with excess 5 (Scheme 2).
The results of monoalkylation using various simple alkyl
carboxylates are summarized in Table 1. When alkyl 1,2-di-
substituted carboxylates were treated with 5, prepared from 4
under conditions A, the corresponding ketones a were selec-
tively obtained (Entries 3-6). On the other hand, alkylations of
Thus, α,α-dichloro- and α-monochloro-ethyl ketones
were respectively synthesized in good to high yields by the
alkylation of simple alkyl carboxylates with 5 generated from
4 using LDA and nBuLi.
This work was supported by Grant-in-Aids for Scientific
Research from the Ministry of Education, Science and Culture.
References and Notes
1
T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T. Nishimura, N.
Ohkawa, H. Sakoh, K. Nishimura, Y. Tani, M. Hasegawa, K.
Yamada, and K. Saitoh, Chem. Eur. J., 5, 121 (1999), and refer-
ences cited therein; H. Iwadare, H. Sakoh, H. Arai, I. Shiina, and T.
Mukaiyama, Chem. Lett., 1999, 817.
2
3
I. Shiina, J. Shibata, Y. Imai, R. Ibuka, H. Fujisawa, I. Hachiya, and
T. Mukaiyama, Chem. Lett., 1999, 1145.
For a review, see: G. Cainelli, A. U. Ronchi, F. Bertini, P. Grasselli,
and G. Zubiani, Tetrahedron, 27, 6109 (1971); G. Köbrich, Angew.
Chem. Int. Ed. Engl., 11, 473 (1972).
4
5
6
7
1,1-Dichloroethyllithium: a) J. Villieras, P. Perriot, and J. F.
Normant, Bull. Soc. Chim. Fr., 1977, 765. b) J. Villiéras and M.
Rambaud, C. R. Acad. Sci., Ser. C, 291, 105 (1980).
n
10-13 with 5, prepared by conditions B (ratio; 4 / BuLi = 2 /
1), gave the corresponding ketones b in good yields.
Dichloromethyllithium: a) C. Bacquet, J. Villieras, and J. F.
Normant, C. R. Acad. Sci., Ser. C, 278, 929 (1974). b) J. Grosser
and G. Köbrich, Chem. Ber., 108, 328 (1975). See also, Ref. 4a.
1-Chloroethyllithium: R. Tarhouni, B. Kirschleger, and J. Villieras,
J. Organomet. Chem., 272C, 1 (1984); J. Villieras, R. Tarhouni, B.
Kirschleger, and M. Rambaud, Bull. Soc. Chim. Fr., 1985, 825.
Chloromethyllithium: a) R. Tarhouni, B. Kirschleger, M. Rambaud,
and J. Villieras, Tetrahedron Lett., 25, 835 (1984). b) K. M. Sadhu
and D. S. Matteson, Tetrahedron Lett., 27, 795 (1986). c) J.
Barluenga, B. Pedregal, and J. M. Concellón, Tetrahedron Lett., 34,
4563 (1993), and references cited therein. See also, Ref. 6.
Alkoxy groups: M. Larchevêque and Y. Petit, Synthesis, 1986, 60,
and references cited therein.
A typical experimental procedure is described for the reac-
tion of 8 with 5 (conditions B): To a solution of HMPA (0.14
mL) in ether (3.0 mL) and THF (2.3 mL) was added a solution
n
of BuLi in hexane (1.57 M, 0.42 mL, 0.66 mmol). 1,1-
Dichloroethane (4) (0.11 mL, 1.31 mmol) was added to the
reaction mixture at -100 °C. After the reaction mixture was
stirred for 30 min, a solution of 8 (30.0 mg, 0.156 mmol) in
ether (0.8 mL) was added at -100 °C. The reaction mixture
was stirred for 45 min at -78 °C and then saturated aqueous
ammonium chloride was added. After usual work-up, the
crude product was purified by TLC to afford the corresponding
8
9
Amino groups: J. Barluenga, B. Baragaña, J. M. Concellón, A. P.
Nicolás, M. R. Díaz, and S. G. Granda, J. Org. Chem., 64, 5048
(1999), and references cited therein.