Formation of cyclopropanes by the reductive coupling of 1,3-dihalides promoted by titanocene(II) species

Article abstract of DOI:10.1246/cl.2002.290

The treatment of various 1,3-dihalides including the ones bearing an ester group with the titanocene(II) species produced cyclopropanes in good yields. The reaction of dihalides possessing two secondary halogens proceeded stereoselectively to afford trans

Full text of DOI:10.1246/cl.2002.290

290
Chemistry Letters 2002
Formation of Cyclopropanes by the Reductive Coupling of 1,3-Dihalides
Promoted by Titanocene(II) Species
Takeshi Takeda,ꢀ Keiko Shimane, Tooru Fujiwara, and Akira Tsubouchi
Department of Applied Chemistry, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588
(Received November 13, 2001; CL-011144)
Table 1. Cyclization of 1,3-dihalides 2
The treatment of various 1,3-dihalides including the ones
bearing an ester group with the titanocene(II) species produced
cyclopropanes in good yields. The reaction of dihalides possess-
ing two secondary halogens proceeded stereoselectively to afford
trans-isomers as major products.
The reductive coupling of 1,3-dihalides is an attractive way
for the construction of three-membered rings and various reagents
have been investigated for this transformation. Magnesium,1
sodium,2 and zinc3 metals are employed for the synthesis of
unfunctionalized cyclopropanes. The reductive couplings
6
mediated by cobalt4 and nickel5 complexes and LiAlH4 have
been studied. Cyclization of primary 1,3-dihalides with alkyl-
lithium7 or a Grignard reagent-FeCl3 system8 has also been
reported.
In spite of these extensive studies, the reductive coupling of
conformationally mobile 1,3-dihalides to form 1,2-disubstituted
cyclopropanes including its stereoselectivity has not been fully
studied yet. Kochi and Singleton studied the reductive coupling of
meso- and dl-2,4-dibromopentane with ethylenediaminechro-
mium(II) reagent and found that there is no stereospecificity and
stereoselectivity in cyclopropane formation.9 The lack of
selectivity was also observed in the formation of cyclopropane
by the nickel-salen complex mediated electrochemical reduction
of two diastereomers of 2,4-dibromopentane.10
Recently we reported the titanocene(II) Cp2Ti[P(OEt)3]2 1-
promoted intramolecular cyclopropanation of !,!-dihalo-1-
alkenes, in which a ꢀ-haloalkyltitanium intermediate is suggested
to be formed and its intramolecular substitution affords a three-
membered ring.11 In connection with the mechanism of this
reaction, we were intrigued with the reductive coupling of 1,3-
dihalides 2 with the titanocene(II) reagent 1. In this communica-
tion, we describe preliminary results of the formation of
cyclopropanes 3 by the treatment of various types of 1,3-dihalides
2 with 1 and its stereoselectivity (Scheme 1).
The treatment of 2,2-dibenzyl-1,3-dichloropropane 2a with
1.5 equiv of titanocene(II) species 1 at room temperature for 2 h
gave the cyclopropane 3a in 61% yield along with a substantial
amount of starting material (34%). When the reaction was carried
out using 3 equiv of 1, the cyclopropane 3a was produced in high
yield (Table 1, Entry 1). The corresponding dibromide 2b also
can be employed for the present reaction giving 3a in comparable
yield (Entry 3). In a similar manner, the reactions of various
dihalides 2were performed, and thecorresponding cyclopropanes
3 were obtained in good to high yields with small amounts of the
dehalogenated hydrocarbons 4.12
When 1,2-disubstituted cyclopropanes are produced, the
trans-isomers are formed preferentially. Considering the stereo-
isomeric purity of the starting materials and products, it is obvious
that this reaction is not stereospecific. Kochi and Singleton noted
that the lack of stereospecificity in the reductive coupling of 2,4-
dibromopentane with the chromium(II) complex is due to the
formation of ꢀ-halo radical intermediate.9 Therefore it is
reasonable to assume that the present reaction also proceeds via
the formation of ꢀ-haloalkyltitanium intermediate 5 through
Scheme 1.
Scheme 2.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
291
atom transfer process,13 which involves a radical intermediate 6
as shownin Scheme 2. Intramolecular nucleophilicsubstitution of
5 affords cyclopropane 3 and titanocene dichloride.14;15
This paper is dedicated to Prof. Teruaki Mukaiyama on the
occasion of his 75th birthday.
Grubbs and coworkers studied the formation of cyclopro-
panes by cleavage of titanacyclobutane with iodine and
concluded that the cyclization of the intermediate ꢀ-iodoalky-
ltitanocene iodide proceeds by a stereospecific intramolecular
SN2 process, with retention at the ꢁ-carbon attached to the
titanium atom and inversion at the ꢀ-carbon.16 If the present
reaction follows a similar pathway, the stereochemistry is
established during the formation of ꢀ-haloalkyltitanium 5.
However alternative mechanism, in which trans-stereoselectivity
is dependent on the steric non-bonding interaction between the
alkyl substituents in the transition state of cyclization TS
(Scheme 3), should also be considered because the formation of
5 with a high degree of diastereoselectivity is unlikely. Such
process involves the equilibrium between the two diastereomers
of 5 through a radical intermediate 6, and trans-3 is preferentially
produced via the transition state trans-TS, which has less steric
interaction.
References and Notes
1
2
3
J. T. Gragson, K. W. Greenlee, J. M. Derfer, and C. E. Boord, J.
Am. Chem. Soc., 75, 3344 (1953).
K. B. Wiberg and G. M. Lampman, Tetrahedron Lett., 1963,
2173.
a) R. W. Shortridge, R. A. Craig, K. W. Greenlee, J. M. Derfer,
and C. E. Boord, J. Am. Chem. Soc., 70, 946 (1948), and
references cited therein. b) M. E. Jason, P. R. Kurzweil, and C.
C. Cahn, Synth. Commun., 11, 865 (1981).
4
5
P. B. Chock and J. Halpern, J. Am. Chem. Soc., 91, 582 (1969).
S. Takahashi, Y. Suzuki, and N. Hagihara, Chem. Lett., 1974,
1363.
6
7
M. S. Newman, G. S. Cohen, R. F. Cunico, and L. W.
Dauernheim, J. Org. Chem., 38, 2760 (1973).
a) W. F. Bailey and R. P. Gagnier, Tetrahedron Lett., 23, 5123
(1982). b) K. B. Wiberg and J. V. McClusky, Tetrahedron Lett.,
28, 5411 (1987).
8
a) M. S. Kharasch, M. Weiner, W. Nudenberg, A. Bhattacharya,
T.-I. Wang, and N. C. Yang, J. Am. Chem. Soc., 83, 3232 (1961).
b) C. H. DePuy, G. M. Dappen, K. L. Eilers, and R. A. Klein, J.
Org. Chem., 29, 2813 (1964), and references cited therein.
J. K. Kochi andD. M. Singleton, J. Org. Chem., 33, 1027(1968).
9
10 C. E. Dahm and D. G. Peters, J. Electroanal. Chem., 406, 119
(1996).
11 T. Fujiwara, M. Odaira, and T. Takeda, Tetrahedron Lett., 42,
3369 (2001).
Scheme 3.
12 The following is a typical experimental procedure. Finely
powdered molecular sieves 4 A (150 mg), magnesium turnings
(37 mg, 1.5 mmol; purchased from Nacalai Tesque Inc. Kyoto,
Japan) and Cp2TiCl2 (374 mg, 1.5 mmol) were placed in a flask
and dried by heating with a heat gun under reduced pressure (2–
3 mmHg). After cooling, THF (6.7 ml) and P(OEt)3 (0.51 ml,
3.0 mmol) were added successively with stirring at room
temperature under argon, and the reaction mixture was stirred
for 3 h. A THF (10 ml) solution of 2,2-dibenzyl-1,3-dichloro-
propane (2a) (147 mg, 0.5 mmol) was added to the reaction
mixture dropwise over 15 min. After stirring for 2 h, the reaction
was quenched by addition of 1 M NaOH (30 ml). The insoluble
materials were filtered off through celite and washed with ether
(10 ml). The layers were separated, and the aqueous layer was
extracted with ether(2 ꢂ 20 ml). The combined organic extracts
were dried over Na2SO4. The solvent was removed at
atmospheric pressure, and the residue was purified by PTLC
(hexane) to yield 108 mg of 1,1-dibenzylcyclopropane (3a)
contaminated with a trace amount of 2,2-dimethyl-1,3-diphen-
ylpropane (4a). The yields (3a; 93%, 4a; 4%) were determined
by NMR analysis.
The present reductive coupling showed the tolerance to ester
group. The treatment of dihaloesters 2l and 2m with 1 at 0 ꢁC and
then at room temperature gave the ethyl cyclopropanecarboxy-
lates 3h and 3i, respectively (Scheme 4, Table 2). In these cases,
the formation of rearrangement products 7a and 7b was observed.
The ratio of rearrangement product 7 to cyclopropane 3 increased
when the reaction was initiated at room temperature (Entry 3).
Since it was confirmed that the cyclopropane 3i was not
transformed into the ꢂ-methylene ester 7b by the treatment with
the titanocene(II) reagent, 7 would be formed directly from the ꢀ-
halotitanium intermediate 5.
In summary, we have found that the titanocene(II) species 1 is
useful for the stereoselective reductive coupling of 1,3-dihalides.
Further application of the titanocene(II) reagent for the reduction
of organic halides is currently in progress.
This research was supported by a Grant-in-Aid for Scientific
Research (No. 11440213) and by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘‘Exploitation of Multi-Element
Cyclic Molecules’’ (No. 13029029) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
13 J. K. Kochi, ‘‘Organometallic Mechanisms and Catalysis,’’
Academic Press, New York (1978), p 138.
14 A similar mechanism is proposed for the formation of
benzylcyclopropane in the zirconium-catalyzed alkylation of
silanes with secondary Grignard reagent in the presence of 2-
benzyl-1,3-dibromopropane. Y. Ura, R. Hara, and T. Takahashi,
Chem. Commun., 2000, 875.
15 According to the reaction mechanism shown in Scheme 2, one
equiv of titanocene(II) reagent 1 is theoretically needed. Since
more than two equiv of 1 is necessary to complete the reaction, it
is assumed that the reagent 1 is consumed by the reduction of the
resulting titanocene dichloride to form a titanocene(III) species.
16 S. C. H. Ho, D. A. Straus, and R. H. Grubbs, J. Am. Chem. Soc.,
106, 1533 (1984).
Scheme 4.
Table 2. Preparation of ethyl cyclopropanecarboxylates
Temp/ꢁC (Time/h) Products (Yield/%)
Entry 1,3-Dihalides 2
1
2
3
2l: R ¼ Ph(CH2)2 0(1) then rt (2)
2m: R ¼ PhCH2 0(1) then rt (2)
2m rt(3)
3h(71)
3i(65)
3i(48)
7a(9)
7b(12)
7b(32)