New, general, and practical enamine cyclopropanation using dichloromethane

Article abstract of DOI:10.1021/ol0604365

Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkene moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane promoted by TiCl ₄-Mg.

Full text of DOI:10.1021/ol0604365

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2261-2263
New, General, and Practical Enamine
Cyclopropanation Using
Dichloromethane
Chia-Chung Tsai, I-Lin Hsieh, Tsung-Ting Cheng, Ping-Kuei Tsai,
Kuo-Wei Lin, and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing UniVersity, Taichung 400,
Taiwan, Republic of China
thyan@mail.nchu.edu.tw
Received February 19, 2006
ABSTRACT
Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkene
moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane
promoted by TiCl4−Mg.
The utility of cyclopropylamines as valuable building blocks
for molecular construction1 and the ease of access to
enamines make the conversion of the latter into the former
a useful transformation. The most common method for the
preparation of these cyclopropane derivatives involves the
addition of methylene to the enamine double bond induced
by diazomethane-CuCl1a,2a or diiodomethane-ZnEt2.1a,2b,c
However, the requirement of the use of potentially unstable
and expensive reagents to generate carbenoids greatly limits
the general utility of the method. The direct cyclopropanation
of alkenes with gem-dibromides promoted by Cu3 or Zn-
Cu4 constitutes a useful cyclopropane ring forming process.
However, this process does not generally extend to enamines.
The reported metal carbenoid generated from dibro-
momethane-Zn-Cu4 added to a simple enamine of cyclo-
hexanone in yields ranging from 8 to 22%. In searching for
new strategies based on a simple metathesis-like mechanism,
we turned our attention to evaluating the feasibility of an
enamine cyclopropanation via an electrophilic Fischer-type
carbene complex.5 To our knowledge and despite the vast
number of carbonyl olefinations mediated by nucleophilic
titanium carbenoids,6,7 no enamine cyclopropanations pro-
moted by titanium-methylene complexes have been re-
corded. Earlier work from our laboratories established the
feasibility of the CH2Cl2-TiCl4-Mg system as a highly
nucleophilic carbene complex to effect carbonyl methylena-
(1) (a) Kuehne, M. E.; King, J. C. J. Org. Chem. 1973, 38, 304. (b)
Blanchard, E. P.; Simmons, H. E.; Taylor, J. S. C. J. Org. Chem. 1965, 30,
4321. (c) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331. (d) Larionov,
O. V.; de Meijere, A. Org. Lett. 2004, 6, 2153. (e) Moreau, B.; Charette,
A. B. J. Am. Chem. Soc. 2005, 127, 18014. (f) For the use of strained rings
as building blocks for molecular construction, see: Trost, B. M. Strain and
its Implication in Organic Chemistry. NATO AdV. Study Inst. Ser., Ser. C
1989, 273.
(2) (a) Muck, D. L.; Wilson, E. R. J. Org. Chem. 1968, 33, 419. (b)
Nishimura, J.; Furukawa, J.; Kawabata, N.; Kitayama, M. Tetrahedron 1971,
27, 1799. (c) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968,
24, 53.
(4) (a) Friedrich, E. C.; Lewis, E. J. J. Org. Chem. 1990, 55, 2491. (b)
Friedrich, E. C.; Lunetta, S. E.; Lewis, E. J. J. Org. Chem. 1989, 54, 2388.
(c) Durandetti, S.; Sibille, S.; Perichon, J. J. Org. Chem. 1991, 56, 3255.
(5) (a) Casey, C. P.; Polichnowski, S. W.; Shusterman, S. J.; Jones, C.
R. J. Am. Chem. Soc. 1979, 101, 7282. (b) Casey, C. P.; Albin, L. D.;
Burkhardt, T. J. J. Am. Chem. Soc. 1977, 99, 2533. (c) Fischer, E. O.; Dotz,
K. H. Chem. Ber. 1972, 105, 1356. (d) Fischer, E. O.; Dotz, K. H. Chem.
Ber. 1972, 105, 3966. For reviews, see: (e) Brookhardt, M.; Studabaker,
W. B. Chem. ReV. 1987, 87, 411. (f) Doyle, M. Chem. ReV. 1986, 86, 919.
(3) Kawabata, N.; Naka, M.; Yamashita, S. J. Am. Chem. Soc. 1976,
98, 2676.
10.1021/ol0604365 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/25/2006

tion.7 To expand the scope of titanium carbenoid-mediated
reactions, we considered the prospect of a TiCl4-Mg
bimetallic complex-promoted cyclopropanation of enamine
with CH2Cl2 as a possibility (Scheme 1). In this communica-
conversion with most of the remainder being a hydrolysis
product derived from 1a. On the other hand, simply decreas-
ing the amount of TiCl4 dramatically improved the cyclo-
propylamine formation, with the yield varying from 8 to 85%
(entries 2-4). Most revealing was the catalytic effect of
TiCl4, in that as little as 15% can effect complete cyclopro-
panation to 2a. The addition of a solution of 1a (2 mmol) in
THF (1.5 mL) to a suspension of TiCl4 (0.3 mmol) and Mg
(10 mmol) in CH2Cl2 at 25 °C was adopted as the standard
protocol, and it produced the desired cyclopropylamine 2a.
More gratifyingly, the reaction directly scales up; thus, adduct
2a was obtained in 84% yield on a 10 mmol scale using 0.1
equiv of TiCl4 and 4 equiv of Mg.
Scheme 1. Ti-Mg-Promoted CH2 Transfer of CH2Cl2
Having established the feasibility of the cyclopropanation,
we studied its generality with respect to the enamine partner.
The variation of the ring size was briefly explored. Switching
from the six-membered ring cyclohexenylamine to either the
five- or seven-membered analogue had little effect (Table
2, entries 1 and 2). Thus, both 1b and 1c reacted efficiently
tion, we report a new, practical, and general approach for
the construction of cyclopropylamines which is based on the
use of CH2Cl2 to generate an electrophilic carbenoid
equivalent.
Table 2. Cyclopropanation of Enamines (2 mmol) with CH2Cl2
Promoted by Ti-Mg Bimetallic Complexes
The cyclopropanation of cyclohexanone enamine 1a with
CH2Cl2 was chosen to test the feasibility of the process (Table
1). Using a 1:1 Mg/TiCl4 ratio did not promote CH2 transfer
Table 1. Reaction Conditions for Cyclopropanation of
Enamine 1aa with CH2Cl2
TiCl4/Mg THF/CH2Cl2 reaction temp conv yield
entry
(mmol)
(mL)
(°C)
(%)b
(%)c
1
2
3
4
5
6
7
8
2:2
2:5
2:10
1.5/7.0
25
25
25
25
25
25
25
0
0
5
8
50
100
90
80
85
0
5
8
32
85
67
56
63
1.5/7.0
1.5/7.0
1.5/7.0
1.5/5.0
1.0/5.0
0.5/5.0
1.5/5.0
1:10
0.3:10
0.3:10
0.3:10
0.3:10
a All reactions were performed on a 2 mmol scale. b The conversion was
determined by NMR analysis of the corresponding crude product. Most of
the remainder was a hydrolysis product derived from 1a. c Isolated yield.
from CH2Cl2. Increasing the amount of Mg did indeed
produce cyclopropylamine 2a but only in less than 10%
(6) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611. (b) Pine, S. H.; Zahier, R.; Evans, D. A.; Grubbs, R. H.
J. Am. Chem. Soc. 1980, 102, 3270. (c) Takai, K.; Hotta, Y.; Oshima, K.;
Nozaki, H. Tetrahedron Lett. 1978, 19, 2417. (d) Lombardo, L. Org. Synth.
1987, 65, 81. (e) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron
Lett. 1985, 26, 5581. (f) Petasis, N. A.; Bzoweej, E. I. J. Am. Chem. Soc.
1990, 112, 6392.
a Isolated yield. b To a suspension of TiCl4 and magnesium powder in
THF (2 mL) at 0 °C was added a solution of enamine (2 mmol) in THF (6
mL)/CH2Cl2 (1 mL). c The reaction was performed at 0-5 °C.
(7) (a) Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C.
Org. Lett. 2004, 6, 4961. (b) Yan, T.-H.; Chien, C.-T.; Tsai, C.-C.; Lin,
K.-W.; Wu, Y.-H. Org. Lett. 2004, 6, 4965.
with CH2Cl2-derived titanium carbenoid to give the desired
cyclopropanation products 2b (72%) and 2c (83%), respec-
2262
Org. Lett., Vol. 8, No. 11, 2006

tively. Notably, the 2-methylcyclohexanone-derived enamine
1d also gave satisfactory results with the CH2Cl2-Mg-
TiCl4-THF system (entry 3). The C1-C2 stereochemistry
of the adduct 2d was established by the presence of an NOE
between the cyclopropyl methylene protons and the methyl
protons.8 Surprisingly, increasing the degree of steric hin-
drance at the enamine did not impede cyclopropanation.
Thus, cyclopropanation onto the enamine 1e derived from
2,2-dimethylcyclohexanone was equally effective, leading to
2e in 85% yield (entry 4). To demonstrate the scope of this
cyclopropane-forming method further, the utility of this
protocol was examined in the cyclopropanation with the
acyclic ketone-derived enamines: 1f and 1g gave the desired
cyclopropylamines 2f (73%) and 2g (70%), respectively
(entries 5 and 6). Changing the substrate to pyrrolidine and
morpholine enamines of aromatic ketones led to equally
gratifying results (entries 7 and 8) with formation of
cyclopropylamines 2h (65%) and 2i (70%).
Scheme 3. Enamine Cyclopropanation via Electrophilic
Titanium-Methylene Complexes
the reductive elimination of the presumed titanacyclobutane
4 formed via an electrophilic addition of the Fischer-type
titanium-methylene complex 3 to the double bond accounts
for the formation of cyclopropylamine and the generation
of an active chain-propagating titanium species 5. Left
unanswered by this proposal is the strong dependence of the
formation of the Fischer-type methylene complex on the
relative amount of TiCl4 to Mg and THF. Further mechanistic
work is clearly required before any definite conclusions can
be reached.
The use of enamines 1j and 1k (entries 9 and 10)
highlights the possible chemoselectivity of the process. As
expected, internal and terminal alkenes are completely
unaffected. Only additions to the enamine double bonds to
give adducts 2j and 2k were observed. An NOE experiment
provided additional support for the assignment of the C1-
C2 stereochemistry as depicted in 2k.
To demonstrate the practicability of titanium-methylene
complex-mediated enamine cyclopropanation further, a very
simple preparation of deuterated cyclopropylamines 6a and
6d was carried out (Scheme 2). Performing the reaction in
The ability to elaborate CH2Cl2 into a novel class of
electrophilic titanium-methylene complexes via titanium-
catalyzed oxidative addition of an unactivated C-Cl bond
should prove to be a particularly valuable method that
enhances synthetic efficiency. The successful application of
the CH2Cl2-Mg-TiCl4-mediated cyclopropanation of vari-
ous enamines highlights the unusual reactivity and selectivity
of this new electrophilic titanium carbenoid, which serves
as a practical reagent applicable to large-scale syntheses. The
novel electrophilicity involved suggests several intriguing
directions which are currently under active investigation.
Scheme 2. Conversion of Enamine to Deuterated
Cyclopropylamine
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for generous support.
toluene allowed the use of only 3 equiv of CD2Cl2.
The above results can be rationalized in terms of a
metathesis-like mechanism as shown in Scheme 3, wherein
Supporting Information Available: Experimental pro-
1
cedures and spectral data, including copies of H and 13C
NMR spectra for 2a-k, 6a, and 6d. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Fisher, G. B.; Goralski, C. T.; Nicholson, L. W.; Hasha, D. L.; Zakett,
D.; Singaram, B. J. Org. Chem. 1995, 60, 2026.
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