Titanocene(II)-promoted carbonyl cyclopropylidenation utilizing 1,1-dichlorocyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2007.03.110

A variety of alkylidenecyclopropanes bearing various substituents on their cyclopropane ring were obtained by the titanocene(II)-promoted reaction of 1,1-dichlorocyclopropane derivatives with carbonyl compounds including esters and lactones.

Full text of DOI:10.1016/j.tetlet.2007.03.110

Tetrahedron Letters 48 (2007) 3521–3524
Titanocene(II)-promoted carbonyl cyclopropylidenation
utilizing 1,1-dichlorocyclopropanes
Tomohiro Shono, Takehiro Nagasawa, Akira Tsubouchi and Takeshi Takeda*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Received 5 March 2007; revised 19 March 2007; accepted 20 March 2007
Available online 23 March 2007
Abstract—A variety of alkylidenecyclopropanes bearing various substituents on their cyclopropane ring were obtained by the
titanocene(II)-promoted reaction of 1,1-dichlorocyclopropane derivatives with carbonyl compounds including esters and lactones.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Because of their unique reactivity, highly strained alkyl-
idenecyclopropanes are useful intermediates in organic
rides and the titanocene(II) reagent Cp Ti[P(OEt) ] 1.
2 3 2
1
2
13
Alkylidenation, dichloromethylidenation, and vinyl-
1
14
synthesis. These compounds are employed, for exam-
idenation are successfully achieved by the low-valent
2
3
5
ple, for [3+2] cycloaddition, [4+2] cycloaddition,
[
titanium reagent 1-promoted reactions of carbonyl com-
pounds with the corresponding gem-dichlorides. Here
we describe the cyclopropylidenation of carbonyl com-
pounds 2 utilizing a dichlorocyclopropane 3-titano-
cene(II) 1 system, which provides a convenient tool for
the preparation of alkylidenecyclopropanes 4 (Scheme
1). The procedure enjoys advantages over the above
conventional methods that a variety of starting materi-
als, dichlorocyclopropanes 3, are readily available by
4
2+2] cycloaddition, and preparation of cyclobutenes.
Therefore, a number of methods have been developed
3
b,6
for their preparation.
Among them, cyclopropylide-
nation of carbonyl compounds is the most straightfor-
7
8
ward and the Wittig, Horner–Wadsworth–Emmons,
Peterson,
2
a,9
5a
and Julia-Kocienski reactions have been
used for the transformation of aldehydes and ketones
to alkylidenecyclopropanes. The Julia-Lythgoe olefin-
ation, which requires multi-step conversion, has also
the dichlorocyclopropanation of olefins with CHCl –
3
1
0
15
been employed for this purpose. These reactions, how-
ever, suffer two major drawbacks: there is considerable
difficulty in the introduction of substituents on the
cyclopropane ring and they cannot be applied to the
cyclopropylidenation of carboxylic acid derivatives.
Although Petasis and Bzowej have overcome the latter
difficulty by the use of cyclopropylidenetitanocene gen-
erated by the a-elimination of dicyclopropyltitano-
cene,1 the procedure requires the preparation of
cyclopropyllithiums, and hence the preparation of alkyl-
idenecyclopropanes bearing substituents on the cyclo-
propane ring seems to be troublesome.
NaOH and it can be applied to the cyclopropylidena-
tion of esters and lactones as well as aldehydes and
ketones.
When 7,7-dichlorobicyclo[4.1.0]heptane (3a) (2 equiv)
was successively treated with the titanocene(II) reagent
1 (5 equiv) and 1,5-diphenylpentan-3-one (2a), alkyli-
denecyclopropane 4a was obtained in 64% yield (Table
1, entry 1). Similarly titanocene(II) 1-promoted reaction
of 1,1-dichlorocyclopropanes 3 bearing different substit-
1
R2
We have developed a new procedure for the Wittig-type
olefination of carbonyl compounds using gem-dichlo-
Cl
Cl
/ Cp Ti[P(OEt) ]
2 3 2
R2
1
O
R3
3
R1
R1
X
R3
Keywords: Cyclopropanes; Carbonyl compounds; Olefination;
Titanocene(II).
2
4
X
4
4
X = H, R , OR
*
Corresponding author. Tel./fax: +81 42 388 7034; e-mail: takeda-t@
cc.tuat.ac.jp
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.110

3522
T. Shono et al. / Tetrahedron Letters 48 (2007) 3521–3524
a
Table 1. Preparation of alkylidenecyclopropanes 4
b
Entry
Dichloride 3
Carbonyl compound 2
Alkylidenecyclopropane 4 (yield/%)
O
Cl
Cl
1
Ph
Ph
Ph
3a
2a
Ph
Ph
4
a (64)
Cl Cl
Ph
2
3
2a
Bu
4b (58)
3
b
Bu
Cl Cl
(
CH ) Si
Ph
3
3
2a
2a
(
3 3
CH ) Si
3
c
4c (56)
Ph
Ph
Cl Cl
4
Ph
Ph
Ph
Ph
3
d
4d (59)
Ph
O
(
CH ) Si
3 3
Ph
5
6
7
8
3c
Ph
Ph
Ph
2
b
e (51; 50 : 50c)
4
Cl Cl
O
O
C H
5 11
O
C H
C H
5 11
5
11
2
c
C H
5 11
4f (41)
3
e
O
Ph
Bu
3b
2
d
Ph
4
g (54)
O
3a
C H
3 7
Ph
Ph
C H
3 7
2
e
Ph
Ph
4
h (58)
O
9
3a
H
Ph
2
f
4i (44)
Ph
H
a
b
c
All the reactions were performed with a similar procedure as described in the text.
Isolated yields based on carbonyl compounds used.
Ratio of stereoisomers.
uents with ketones gave alkylidenecyclopropanes 4
and subjected to the cyclopropylidenation to produce
the olefination products 4c, 4e, and 4f (entries 3, 5,
and 6). Diene 4h was successfully prepared by the reac-
tion of a,b-unsaturated ketone 2e (entry 8). Aldehyde 2f
could be employed as a carbonyl component though the
(
entries 2–7). Synthetic advantage of this method was
demonstrated by the use of heteroatom-substituted
dichlorocyclopropanes 3c and 3e, which were easily pre-
pared from the corresponding allylsilane and allyl ether

T. Shono et al. / Tetrahedron Letters 48 (2007) 3521–3524
3523
yield of alkylidenecyclopropane 4i was moderate (entry
).
solvent under reduced pressure, the residue was purified
by PTLC (hexane) to give 4a (102 mg, 64%).
9
The typical procedure for the alkylidenation of ketones
is as follows: finely powdered molecular sieves 4 A
Contrary to the above results, the titanocene(II) 1-pro-
moted reaction of 2a with 7,7-bis(phenylthio)bicyclo-
[4.1.0]heptane 5 was rather complicated. After the
treatment of 5 (2 equiv) with 1 (5 equiv) at 25 ꢁC for
15 min, 2a was added to the reaction mixture to produce
cyclopropylidenation product 4a only in low yield along
with alcohol 6 formed by the reduction of 2a with 1
(Scheme 2). Substantial amounts of the starting materi-
als 2a (24%) and 5 (15%) were also recovered. The result
is in a sharp contrast with the fact that a titanocene(II)
1-1,1-bis(phenylthio)cyclobutane system is effective for
˚
(
250 mg), magnesium turnings (61 mg, 2.5 mmol), and
Cp TiCl (623 mg, 2.5 mmol) were placed in a flask
2
2
and dried by heating with a heat gun under reduced
pressure (2–3 mm Hg). After cooling, THF (5 mL) and
triethyl phosphite (0.86 mL, 5.0 mmol) were added suc-
cessively with stirring at 25 ꢁC under argon, and the
reaction mixture was stirred for 3 h. A THF (0.8 mL)
solution of 3a (165 mg, 1.0 mmol) was added to the mix-
ture at À10 ꢁC and stirring was continued for 1 h at the
same temperature. A THF (0.8 mL) solution of 2a
(
119 mg, 0.5 mmol) was added to the mixture which
SPh
was then refluxed for 2 h. After cooling to room temper-
ature, the reaction was quenched by addition of 1 M
NaOH (30 mL). The insoluble materials were filtered
off through Celite and washed with ether (40 mL). The
layers were separated, and the aqueous layer was
extracted with ether (2 · 20 mL). The combined organic
extracts were dried over Na SO . After removal of the
SPh
OH
5 (2 equiv) / 1 (5 equiv)
2
a
4a
+
Ph
Ph
6
26%
2
3%
Scheme 2.
2
4
a
Table 2. Preparation of (1-alkoxyalkylidene)cyclopropanes 4
b
Entry
Dichloride 3
Carboxylic acid derivative 2
Alkylidenecyclopropane 4 (yield/%)
O
1
3a
Ph
Ph
OMe
2
g
Ph
4j (60)
OMe
O
2
3a
OEt
Ph
Ph
2
h
4
4
k (66)
l (49)c
OEt
OEt
3
4
3b
3a
2h
Bu
O
Ph
Ph
OEt
2i
4
m (64)
OEt
O
5
3a
C13H27
OEt
C13H27
OEt
2
j
4
n (46)
O
Cl
Cl
6
7
H
OBu
H
3
f
2k
4
o (51)
OBu
3a
O
O
O
2l
4
p (55)d
a
b
c
All the reactions were carried out with a similar procedure as described in Ref. 17.
Isolated yields based on the carboxylic acid derivatives used.
Mixture of stereoisomers. The ratio was not determined.
d
Contaminated with triethyl phosphite and triethyl phosphate. The yield was corrected for the contaminants.

3524
T. Shono et al. / Tetrahedron Letters 48 (2007) 3521–3524
R2
2. (a) Shook, C. A.; Romberger, M. L.; Jung, S.-H.; Xiao,
1
(2 equiv)
Cp TiCl2
2
M.; Sherbine, J. P.; Zhang, B.; Lin, F.-T.; Cohen, T. J.
Am. Chem. Soc. 1993, 115, 10754; (b) Nakamura, E.;
Yamago, S. Acc. Chem. Res. 2002, 35, 867; (c) Fujita, M.;
Fujiwara, K.; Okuyama, T. Chem. Lett. 2006, 35, 382; (d)
Fujita, M.; Oshima, M.; Okuno, S.; Sugimura, T.;
Okuyama, T. Org. Lett. 2006, 8, 4113.
3
-
R3
2
Cp Ti
2
7
R2
4
3. (a) Thiemann, T.; Ohira, D.; Li, Y.; Sawada, T.; Mataka,
S.; Rauch, K.; Noltemeyer, M.; de Meijere, A. J. Chem.
Soc., Perkin Trans. 1 2000, 2968; (b) de Meijere, A.;
Leonov, A.; Heiner, T.; Noltemeyer, M.; Bes, M. T. Eur.
J. Org. Chem. 2003, 472.
Cp Ti
2
R3
O
- Cp Ti=O
2
X
R1
8
Scheme 3.
4
. Nakamura, I.; Nemoto, T.; Yamamoto, Y.; de Meijere, A.
Angew. Chem., Int. Ed. 2006, 45, 5176.
5
. (a) F u¨ rstner, A.; A ¨ı ssa, C. J. Am. Chem. Soc. 2006, 128,
6306; (b) Shi, M.; Liu, L.-P.; Tang, J. J. Am. Chem. Soc.
the cyclobutylidenation of a wide variety of carbonyl
compounds.
1
6
2
006, 128, 7430.
6
. (a) Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589; (b)
Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45, 347; (c)
Nordvik, T.; Mieusset, J.-L.; Brinker, U. H. Org. Lett.
2004, 6, 715; (d) Simaan, S.; Masarwa, A.; Bertus, P.;
Marek, I. Angew. Chem., Int. Ed. 2006, 45, 3963; (e) Xu,
L.; Huang, X.; Zhong, F. Org. Lett. 2006, 8, 5061.
. (a) Schweizer, E. E.; Berninger, C. J.; Thompson, J. G. J.
Org. Chem. 1968, 33, 336; (b) Okuma, K.; Ikari, K.; Ono,
M.; Sato, Y.; Kuge, S.; Ohta, H.; Machiguchi, T. Bull.
Chem. Soc. Jpn. 1995, 68, 2313.
This olefination is also applicable to carboxylic acid
derivatives. Alkylidenecyclopropanes 4 bearing an enol
ether substructure were obtained by the reaction of 3
with esters (Table 2, entries 1–5). The reactions of for-
mic ester 2k and lactone 2l also gave the corresponding
enol ethers 4 (entries 6 and 7). Since these enol ethers are
readily hydrolyzed under the work-up and purification
conditions described above, the special care should be
7
1
7
taken to isolate them in pure forms.
8
. Lewis, R. T.; Motherwell, W. B. Tetrahedron Lett. 1988,
2
9, 5033.
As in the cases of the olefination using gem-dichlorides
previously reported, the olefination with 1,1-dichloro-
cyclopropanes 3 is assumed to proceed via the formation
of titanium cyclopropylidene complexes 7 generated by
the reductive titanation of 3 with 1 (Scheme 3). The sub-
sequent reaction of carbene complexes 7 with carbonyl
compounds 2 affords oxatitanacyclobutanes 8, which
give alkylidenecyclopropanes 4 through the expulsion
of titanocene oxide.
9
. (a) Cohen, T.; Sherbine, J. P.; Matz, J. R.; Hutchins, R.
R.; McHenry, B. M.; Willey, P. R. J. Am. Chem. Soc.
1984, 106, 3245; (b) Cohen, T.; Jung, S.-H.; Romberger,
M. L.; McCullough, D. W. Tetrahedron Lett. 1988, 29,
25.
1
1
1
1
0. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett
004, 1064.
1. Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34,
43.
2. Takeda, T.; Sasaki, R.; Fujiwara, T. J. Org. Chem. 1998,
3, 7286.
2
9
6
In conclusion, we have developed the first practical pro-
cedure for the preparation of alkylidenecyclopropanes
bearing various substituents on their cyclopropane ring
utilizing readily available 1,1-dichlorocyclopropanes
and titanocene(II) reagent 1. This procedure is applica-
ble to the cyclopropylidenation of highly enolizable
ketones and carboxylic acid derivatives.
3. Takeda, T.; Endo, Y.; Reddy, A. C. S.; Sasaki, R.;
Fujiwara, T. Tetrahedron 1999, 55, 2475.
14. Shono, T.; Ito, K.; Tsubouchi, A.; Takeda, T. Org.
Biomol. Chem. 2005, 3, 2914.
15. (a) Makosza, M.; Wawrzyniewicz, M. Tetrahedron Lett.
1
969, 10, 4659; (b) Joshi, G. C.; Singh, N.; Pande, L. M.
Tetrahedron Lett. 1972, 13, 1461; (c) Juli a´ , S.; Ginebreda,
A. Synthesis 1977, 682.
1
6. Fujiwara, T.; Iwasaki, N.; Takeda, T. Chem. Lett. 1998,
741.
Acknowledgments
1
7. The typical procedure for the cyclopropylidenation of
carbocylic acid derivatives is as follows: To a THF (3 mL)
solution of titanocene(II) reagent 1, prepared from
This work was supported by Grant-in-Aid for Scientific
Research (No. 18350018) and Grant-in-Aid for Scien-
tific Research on Priority Areas ‘Advanced Molecular
Transformations of Carbon Resources’ (No. 18037017)
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan. This work was also carried
out under the 21st Century COE program of ‘Future
Nanomaterials’ in Tokyo University of Agriculture
and Technology.
magnesium turnings (38 mg, 1.6 mmol), Cp
2 2
TiCl
(
374 mg, 1.5 mmol), and P(OEt)3 (0.5 mL, 2.9 mmol) in
˚
the presence of molecular sieves 4 A (150 mg), was added
a THF (1 mL) solution of 3a (99 mg, 0.6 mmol) at 25 ꢁC.
After stirring for 10 min, a THF (1 mL) solution of 2h
(
49 mg, 0.3 mmol) was added to the reaction mixture,
which was then refluxed for 2 h. After cooling, triethyl-
amine (0.3 mL) was added and the reaction mixture was
diluted with hexane (20 mL). The insoluble materials were
filtered off through Celite and washed with hexane
References and notes
(
K
10 mL). The combined hexane solutions were dried over
CO . After removal of the solvent under reduced
2
3
1
. (a) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002,
44, 111; (b) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti,
A. Chem. Rev. 2003, 103, 1213.
pressure, the residue was chromatographed over alumina
gel (eluted with 0.5% triethylamine in hexane) to give 4k
(48 mg, 66%).
3