Unusual ambiphilic carbenoid equivalent in amide cyclopropanation

Article abstract of DOI:10.1021/ol060438p

The titanium-methylene complexes derived from the TiCl₄-Mg- CH₂Cl₂ system serve as a novel class of ambiphilic carbenoid equivalents, which not only efficiently effect cyclopropanations of a variety amides but also exhibit

Full text of DOI:10.1021/ol060438p

ORGANIC
LETTERS
2
006
Vol. 8, No. 11
265-2267
Unusual Ambiphilic Carbenoid
Equivalent in Amide Cyclopropanation
2
Kuo-Wei Lin, Shiuan Yan, I-Lin Hsieh, 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
4 2 2
The titanium−methylene complexes derived from the TiCl −Mg−CH Cl system serve as a novel class of ambiphilic carbenoid equivalents,
which not only efficiently effect cyclopropanations of a variety amides but also exhibit high chemoselectivity.
The importance of cyclopropane rings as valuable building
(O-iPr)
4
.3,4 To develop new strategies based on the concept
1
blocks for further structural elaboration and as important
of simple tandem methylene transfer reactions, we were
attracted to the carbonyl cyclopropanations promoted by an
ambiphilic carbenoid 2, which not only could function as a
Schrock-type carbene complex to effect carbonyl methyl-
2
skeletons in a variety of biologically active compounds has
stimulated the development of new methods for their
construction. Among the most useful recently developed
3
5
methods are carbonyl cyclopropanations (Scheme 1), which
enation but also played the role of a Fischer-type carbene
complex to promote further cyclopropanation of the alkene.6
To our knowledge, despite the vast number of metallocar-
bene-mediated carbonyl olefinations and olefin cyclopropa-
nations, progress in metallocarbene-promoted carbonyl cy-
Scheme 1. Carbonyl Cyclopropanation
7
clopropanations has been slow to evolve. The reason stems
(
3) For reviews, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV.
2
7
000, 100, 2789. (b) Sato, F.; Okamoto, S. AdV. Synth. Catal. 2001, 343,
59. (c) Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597. (d) Kulinkovich,
O. G. Russ. Chem. Bull., Int. Ed. 2004, 53, 1065.
involve the reductive coupling of carbonyl compounds with
the presumed titanacyclopropane intermediate 1 formed via
the direct coupling of a suitable Grignard reagent with Ti-
(
4) (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413. (b) Lee, J.; Kang, C. H.; Kim, H.; Cha, J.-K. J. Am. Chem. Soc.
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1) (a) Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic Synthesis;
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Zefirov, N. S. J. Org. Chem. 1993, 58, 502. (h) Kulinkovich, O. G.; Sviridov,
S. V.; Vaslievskii, D. A.; Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244.
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J. Org. Chem. 1993, 58, 502. (l) de Meijere, A.; Kozhushkov, S. I.;
Khlebnikov, A. F. Russ. J. Org. Chem. 1996, 32, 1555. (m) Horikawa, Y.;
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Tetrahedron Lett. 2005, 46, 775.
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Organic Chemistry. NATO AdV. Study Inst. Ser., Ser. C 1989, 273. (c) Wong,
H. N. C.; Hong, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T.
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1
0.1021/ol060438p CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/25/2006

from the nature of the metallocarbenes. We report that the
titanium-methylene complexes derived from the TiCl
4
0.8 equiv of TiCl effected complete carbonyl methylenation
4
-
and alkene cyclopropanation within 4 h to give the desired
cyclopropylamine 6a in 81% yield (entry 1). The reaction
directly scales up; thus, adduct 6a was obtained in 72% yield
2 2
Mg-CH Cl
system5 serve as a novel class of ambiphilic
f,g
carbenoid equivalents, which not only efficiently effect
cyclopropanations of a variety of amides but also exhibit
high chemoselectivity.
The indication that such an ambiphilic methylene complex
may exist came as a result of our probing the effect of the
4
on a 5 mmol scale using 2.8 equiv of TiCl and 30 equiv of
Mg. Pyrrolidine amide 4b and piperidine amide 4c gave
similar results under our standard conditions (entries 2 and
3). The reaction is best envisioned as involving interception
of the enamine 5 formed via a nucleophilic attack of a
presumed titanium chloromethylene complex 3a (path a) or
amount of Mg relative to TiCl
4
on the CH
2
transfer reaction
Cl
of CH Cl . The reaction of a simple amide 4a with CH
2
2
2
2
5
was chosen to test the feasibility of the process (Table 1).
methylene complexes 3b and 3c (path b) on the carbonyl
carbon by a Simmons-Smith-type complex 3a8 or an
electrophilic titanium methylidene 3c followed by reductive
elimination to product 6 as shown in Scheme 2. Although
a
2 2
Table 1. Typical Amide Cyclopropanation with CH Cl
Scheme 2. Proposed Mechanism for Amide Cyclopropanation
this scheme accounts for our current observations, we cannot
rule out the involvement of some titanacyclopropane complex
as the active entity. Further mechanistic work is clearly
required before any definite conclusions can be reached.
(
5) (a) Tebbe, F. N. G.; Parshall, W.; Reddy, G. S. J. Am. Chem. Soc.
1
978, 100, 3611. (b) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H.
J. Am. Chem. Soc. 1980, 102, 3270. (c) Takai, K.; Hotta, Y.; Oshima, K.;
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Takai, K.; Nozaki, H. Tetrahedron Lett. 1985, 26, 5581. (e) Petasis, N. A.;
Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392. (f) Yan, T.-H.; Tsai,
C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C. Org. Lett. 2004, 6, 4961. (g)
Yan, T.-H.; Chien, C.-T.; Tsai, C.-C.; Lin, K.-W.; Wu, Y.-H. Org. Lett.
2004, 6, 4965.
a
Reactions were run on a 1 mmol scale in CH2Cl2/THF (1 mL) at 0-25
b
c
°
C, unless otherwise noted. Isolated yield. Cyclopropanation performed
on a 5 mmol scale.
(6) (a) Fischer, E. O.; Dotz, K. H. Chem. Ber. 1972, 105, 1356. (b)
Fischer, E. O.; Dotz, K. H. Chem. Ber. 1972, 105, 3966. (c) Casey, C. P.;
Albin, L. D.; Burkhardt, T. J. J. Am. Chem. Soc. 1977, 99, 2533. (d) Casey,
C. P.; Polichnowski, S. W.; Shusterman, S. J.; Jones, C. R. J. Am. Chem.
Soc. 1979, 101, 7282. (e). Brookhardt, M.; Studabaker, W. B. Chem. ReV.
4
Exposing morpholine amide 4a to 2 equiv of TiCl and 8
equiv of Mg did indeed produce the cyclopropanation adduct
but only in less than 5% yield. Remarkably, using less than
equiv of TiCl
electrophilic additions, leading to smooth amide cyclopro-
panations. Thus, reacting 4a with CH Cl at 0-25 °C using
1
987, 87, 411. (f) Doyle, M. Chem. ReV. 1986, 86, 919.
(
7) (a) Brown-Wensley, K. A.; Buchwald, S. L.; Cannizzo, L. F.; Clauson,
L.; Ho, S.; Meinhardt, D.; Stille, J. R.; Straus, D.; Grubbs, R. H. Pure Appl.
Chem. 1983, 55, 1733. (b) Klindukhova, T. K.; Suvorova, G. N.; Koroleva,
L. B.; Komendantov, M. I. Zh. Org. Khim. 1984, 20, 529. (c) Pine, S. H.;
Pettit, R.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R.
D. J. Org. Chem. 1985, 50, 1212.
1
4
dramatically improved the nucleophilic and
2
2
2266
Org. Lett., Vol. 8, No. 11, 2006

gave an analogous result with titanium-methylene com-
plexes (Table 2, entry 1) wherein the spiro amine 6k was
obtained in 72% yield. Switching from the seven-membered
ring lactam to the five-membered analogue also gave
satisfactory results (entry 2). Notably, the ring size in the
lactam substrate had some effect on cyclopropanation (entries
Table 2. Direct Cyclopropanation of Cyclic Amides and
Amides Containing Functional Groupsa
3
and 4). Surprisingly, performing the cyclopropanation on
4
m and 4n at -10 °C for 16 h increased the yield of 6m
4
j
and 6n to 64% and 67%, respectively.
The reaction exhibits good chemoselectivity. As expected,
acetal and sulfide have no effect (entries 5 and 6). Remark-
ably, both acetylenes and alkenes are also tolerated (entries
7
-9). The latter is particularly noteworthy because the
reductive coupling of terminal olefins with carboxylates
promoted by the titanacyclopropane intermediate had been
3
,4
noted previously.
The efficiency and practicality of this chemistry is il-
lustrated by the very simple synthesis of deuterated cyclo-
propylamines such as 7a, 7k, and 7r by simple tandem Ti-
2 2 2
Mg-promoted CD -transfer reactions of CD Cl (Scheme 3).
Scheme 3. Synthesis of Deuterated Cyclopropylamines
Performing the reaction in ClCH
only 4-5 mmol of CD Cl
The TiCl -Mg-promoted tandem methylene transfer reac-
tions of CH Cl serve as a novel class of ambiphilic
2 2
CH Cl allowed the use of
2
2
.
4
a
Reactions were conducted on a 1 mmol scale in CH2Cl2/THF (1 mL)
2
2
b
c
at 0-25 °C, unless otherwise noted. Isolated yield. 2.5-3 mL of THF
was used. Performing the reaction at -10 °C.
d
carbenoid equivalents that effect complete nucleophilic and
electrophilic additions. Not only is this titanium-methylene
complex highly reactive but it also seems highly selective
in amide cyclopropanations and might become a practical
cyclopropanation reagent. The novel nature involved suggests
several intriguing directions which are currently under active
investigation. Further studies will determine whether this
carbenoid formation promoted by Ti-Mg complexes will
be generally useful for other geminal dihalides such as 1,1-
dichloroethane.
Changing the substrate to aromatic amide 4d and cyclo-
hexanecarbonyl amide 4e led to equally gratifying results
entries 4 and 5). Variation of the substituents at nitrogen
was briefly explored. Cyclopropanation onto the acyclic
amine-derived amides 4f-h (entries 6-8) was equally
effective. Some dependence on the nature of the amide was
observed because cyclopropanation on formamides 4i and
j gave inferior results, giving a moderate yield of 6i and
j (entries 9 and 10).
(
9
4
6
Acknowledgment. We thank the National Science Coun-
Extension of these observations to other substrates such
cil of the Republic of China for generous support.
as lactams confirms their generality. The cyclic amide 4k
Supporting Information Available: Experimental pro-
1
13
(
8) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323.
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C
(
b) Simmons, H. E.; Blanchard, E. P.; Smith, R. D. J. Am. Chem. Soc.
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available free of charge via the Internet at http://pubs.acs.org.
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OL060438P
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