Transition-Metal-Mediated Cascade Reactions: C,C-Dicyclopropylmethylamines by Way of Double C,C-σ-Bond Insertion into Bicyclobutanes

Article abstract of DOI:10.1021/ja038623a

The organometallic multicomponent reaction of alkenyl zirconocene, alkynyl imine, and zinc carbenoid in the presence of dimethylzinc leads to novel C,C-dicyclopropylmethylamines. The formation of intermediate bicyclo[1.1.0]butanes represents the first synthetically useful example of a double C,C-σ-bond insertion, and the increase in structural complexity from starting materials is highlighted by the formation of nine new C,C-bonds in the final product. Copyright

Full text of DOI:10.1021/ja038623a

Published on Web 11/06/2003
Transition-Metal-Mediated Cascade Reactions:
C,C-Dicyclopropylmethylamines by Way of Double C,C-σ-Bond Insertion into
Bicyclobutanes
Peter Wipf,* Corey R. J. Stephenson, and Kazuo Okumura
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received September 19, 2003; E-mail: pwipf@pitt.edu
Scheme 1. Reaction Manifolds in Zirconocene Additions to Imines
The multicomponent cascade reactions of organozirconocenes
reveal novel reaction manifolds that culminate in the stereoselective
formation of multiple C,C-bonds and allow the rapid assembly of
complex and diverse products from simple building blocks.1 In
toluene, the dimethylzinc-mediated addition of alkenylzirconocenes
to diphenylphosphinoyl imines leads to allylic amine 3; in contrast,
in the presence of CH2I2 or when CH2Cl2 is used as the solvent,
the reaction provides homoallylic amine 4 or C-cyclopropylalkyl-
amine 5 (Scheme 1).2 While organolithium and Grignard reagents
suffer from poor functional group tolerance, the hydrozirconation3
of alkynes is selective in the presence of many electrophilic groups,
and the intermediate alkenylzirconocenes can be added to alde-
hydes,4 ketones,5 enones,6 epoxides,7 esters,8 isocyanates,9 and
nitrones.10
Scheme 2. One-Pot Formation of C,C-Dicyclopropylmethylamine
Recently, we discovered that the addition of hexenylzirconocene
to alkynyl imine 6 in the presence of dimethylzinc and the zinc
carbenoid Zn(CH2I)211 leads to C,C-dicyclopropylmethylamines 7
as single diastereomers in 60% yield (Scheme 2). During the course
of this unprecedented cascade process, 10 C,C-bonds are formed
(nine remain in the product), while two C,C-bonds are broken,
including the alkyne triple bond in imine 6! Upon reaction
optimization, we were able to decrease the amount of Cp2ZrHCl,
Me2Zn, and alkyne significantly and increase the yield to 68% when
dichloroethane was used as the solvent (Table 1, entry 4).12
For a further investigation of the scope of this new reaction, a
series of alkynes and alkynylimines13 were subjected to the
optimized reaction conditions (Table 2). The methodology tolerates
a number of the common protecting groups used in synthesis such
as silyl ethers, carbamates and sulfonamides, as well as silyl and
ortho esters.14 Interestingly, when internal alkynes are used, the
rare bicyclobutane scaffold is obtained upon quenching at 0 °C
(entries 9-11).
Table 1. Optimization of the Formation of 7 from Alkyne 1 and
Imine 6
equiv of
entry Cp2ZrHCl
equiv
of 1
equiv of
Me2Zn
equiv of
temp
[°C]
yield
[7, %]
Zn(CH I)2
solvent
2
1
2
3
4
3
3
3
3
4
4
4
CH2Cl2
toluene
(CH2Cl)2
(CH2Cl)2
rt
rt
rt
0
60
<50
60
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
68
Reexposure of allylic amine and bicyclobutane to the reaction
conditions led to the formation of the corresponding C,C-dicyclo-
propylmethylamines. Accordingly, the formation of the bicyclo-
butane intermediate provides valuable evidence for the mechanistic
pathway of this cascade process (Figure 1). Upon transmetalation
of the alkenylzirconocene to dimethylzinc, addition to the imine
proceeds to give 30. Alkyl group exchange generates the zinc
carbenoid 31 which undergoes triple cyclopropanation at the allylic
alkene as well as the alkyne moiety to give the bicyclo[1.1.0]butane
32. These reactive intermediates are known to undergo a double
σ-bond insertion with carbenes, thus producing the skipped diene
33; however, prior work15 has been limited to unfunctionalized
model systems, and no synthetically useful application of the double
σ-bond insertion process has been reported. A final cyclopropana-
tion of the allylic amine, undoubtedly assisted by the metalated
proximal amide, affords 34.16 The relative configuration of all
alkynyl imine adducts was assigned on the basis of ref 2a.
Figure 1. Proposed mechanism.
In summary, we have been able to demonstrate a novel
organometallic multicomponent reaction that represents the first
synthetically useful example of a double C,C-σ-bond insertion.17
This reaction proceeds under mild conditions via the rare bicyclo-
[1.1.0]butanes, and the increase in structural complexity from
starting materials is highlighted by the formation of nine new C,C-
bonds in the final product. The unprecedented C,C-dicyclopropyl-
methylamine scaffold can now be prepared diastereoselectively in
a single step, allowing for the preparation of structurally diverse
compounds from readily available starting materials. Studies of the
biological profile of C,C-dicyclopropylmethylamines and further
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J. AM. CHEM. SOC. 2003, 125, 14694-14695
10.1021/ja038623a CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Multicomponent Condensation of Alkynes, Imines, and Zinc Carbenoids to Give C,C-Dicyclopropylmethylamines
a Yields of isolated products are based upon imines. b Microwave conditions.
(7) Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 825.
(8) Wipf, P.; Xu, W. J. J. Org. Chem. 1993, 58, 5880.
investigations of unique reactivity patterns in the combination of
Zr and Zn chemistry will be reported in due course.
(9) Negishi, E.; Swanson, D. R.; Miller, S. R. Tetrahedron Lett. 1988, 29,
1631.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0078944).
(10) Pandya, S. U.; Garcon, C.; Chavant, P. Y.; Py, S.; Valle´e, Y. Chem.
Commun. 2001, 1806.
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Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1. (c) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
(12) The lifetime of the alkenylzinc reagent generated under these conditions
is significantly shorter in CH2Cl2, and excess reagent is required: Wipf,
P.; Kendall, C., unpublished results.
Supporting Information Available: Experimental procedures, 1H
and 13C spectra for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561.
(14) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron 1997, 53, 16575.
(15) (a) Jackson, J. E.; Mock, G. B.; Tetef, M. L.; Zheng, G.-X.; Jones, M.,
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Ciula, R. P.; Connor, D. S.; Schertler, P.; Lavanish, J. Tetrahedron 1965,
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(16) Deuterium-labeling experiments with Zn(CD2I)2 led to incorporation of
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