Pericyclic cascade reactions of (bicyclo[1.1.0]butylmethyl)amines

Article abstract of DOI:10.1002/anie.200600723

(Chemical Equation Presented) Direct access: Phase-transfer N-allylation and N-propargylation of (bicyclo[1.1.0]butylmethyl)amines initiate diastereoselective pericyclic cascade reactions that culminate in novel spirocyclic and tricyclic pyrrolidine heterocycles through formal ene or [2+2] pathways.

Full text of DOI:10.1002/anie.200600723

Communications
Cycloaddition Reactions
DOI: 10.1002/anie.200600723
Pericyclic Cascade Reactions of (Bicyclo-
[1.1.0]butylmethyl)amines**
Peter Wipf* and Maciej A. A. Walczak
Dedicated to Professor Heinz Heimgartner
Cyclopropanes and cyclobutanes are often used as scaffolds in
selective functionalizations and in the expansion of molecular
complexity.[1,2] In contrast, applications of bicyclo-
[1.1.0]butanes[3] in organic synthesis have been much more
limited.[4] Because of their impressive strain energy of
64 kcalmolÀ1,[5] the latter compounds readily undergo electro-
philic, nucleophilic, and radical additions as well as cyclo-
addition reactions.[3] Of special interest for bicyclobutane
À
chemistry is the high p character of the central C C bond,
which can be utilized for the synthesis of cyclobutene
derivatives.[6]
We recently described a cascade reaction initiated by the
hydrozirconation of alkynes followed by transmetalation to
dimethylzinc and addition to alkynyl imines.[7] Exposure of
the resulting N-metalated intermediates to the cyclopropa-
nation conditions developed by Furukawa et al.[8] resulted in
À
an unprecedented series of C C bond-formation and
-cleavage processes, thus leading to bicyclo[1.1.0]butanes
and (dicyclopropylmethyl)amines.[7a]
Bicyclo[1.1.0]butanes can also be obtained by direct
cyclopropanation
of
propargyl
phosphinylamides[9]
(Scheme 1). Treatment of 1a–c with Me2Zn followed by
addition of (CH2I)2Zn at À508C provided 2a–c.[10] Conju-
gated propargylamides with electron-withdrawing substitu-
Scheme 1. Synthesis of bicyclobutanes by a directed Simmons–Smith
reaction.
[*] Prof. P. Wipf, M. A. A. Walczak
Department of Chemistry
University of Pittsburgh
Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-0787
E-mail: pwipf@pitt.edu
[**] This work was supported by the National Science Foundation (CHE-
0315205). We thank Dr. Steve Geib for the X-ray crystallographic
analysis and Juan Arredondo for help with the acquisition of the
NMR spectra.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Reactions of bicyclobutanes with allyl and propargyl bromides.
ents in the aryl group provide higher yields in this trans-
formation. Alternatively, bicyclobutanes 2 can be accessed by
addition of bicyclo[1.1.0]butyllithium to the activated imines
(Scheme 2).[11] Treatment of 3 with MeLi followed by trans-
metallation with tBuLi and addition to imines 4 furnished
bicyclobutanes 2d–f in high yields.
Entry Substrates
Product
Yield [%]
1
2
3
4
2a, allyl bromide
82
2a, 3-bromo-2-methyl-
propene
66[a,b]
51[a]
87
2b, (E)-crotyl bromide
2a, propargyl bromide
Scheme 2. Synthesis of bicyclobutanes by addition of bicyclo-
[1.1.0]butyllithium. PG=protecting group, Ts=p-toluenesulfonyl.
2a, 3-phenylpropargyl
bromide
5
6
49
62
Based on the ease of insertion of zinc carbenoids into the
bicyclobutane scaffold,[7] we decided to explore the intra-
molecular cycloadditions with alkenes and alkynes.[12] Under
modified phase-transfer conditions[13] (allyl bromide,
Bu4NHSO4, 50% aq. NaOH, toluene), N-allylation of 2e
proceeded efficiently; however, instead of the expected
product, we found that the initial product underwent a
spontaneous formal ene reaction[14] to give spirocycle 5 in
63% yield as the only detectable diastereomer based on the
1H NMR spectroscopic analysis of the crude reaction mixture
(Scheme 3).[15]
2d, 3-triisopropylsilyl-
propargyl bromide
[a] The reaction was carried out in the presence of a mixture of powdered
NaOH and K2CO3. [b] Obtained as a 2.9:1 mixture of diastereoisomers; only
the major isomer is shown.
Table 2: Reactions of bicyclobutanes with cinnamyl bromides.
Entry Substrates
Product
Yield [%]
93
1
2
3
2a, (E)-cinnamyl bromide
Scheme 3. Cascade N-allylation—an Alder ene reaction.
For a further investigation of the scope of this novel
cascade process (Table 1), various bicyclobutane derivatives
were reacted with allyl, 2-methylallyl, crotyl, propargyl, 3-
phenylpropargyl, and 3-triisopropylsilylpropargyl bromides
(entries 1–6, respectively). The course of the reaction was
dependent on the substitution of the allyl moiety and the
electronic environment at the bicyclobutane ring. For exam-
ple, reaction of 2a with 3-bromo-2-methylbutene led to the N-
allylated intermediate (90% yield), which underwent con-
version into 7 in 80% yield under reflux conditions in toluene.
To directly convert 2a into 7, our initial conditions had to be
modified—the reaction was carried out at elevated temper-
atures in the presence of a mixture of powdered NaOH and
K2CO3 (entry 2).[12] Interestingly, when bicyclobutanes 2 were
treated with cinnamyl bromides, the pathway changed from
an Alder ene reaction to a formal [2+2] cycloaddition, thus
leading to the first synthesis of 3-azatricyclo[5.1.1.01,5]nonanes
(Table 2).[16,17] Yields in this remarkable conversion ranged
from modest (32% with the pyridine-substituted 2c; entry 2)
to excellent (93%; entry 1), and both aromatic and aliphatic
groups a to the pyrrolidine nitrogen atoms were well
2c, (E)-cinnamyl bromide
32
68
2d, 1-((E)-3-bromoprop-1-enyl)-
4-(trifluoro-methyl)benzene
4
5
2e, (E)-cinnamyl bromide
2 f, (E)-cinnamyl bromide
59
54
tolerated. It is, however, important to note that with our
current experimental protocol only bicyclobutanes conju-
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Communications
gated to aromatic rings were found to undergo either the
the bifurcation in the reaction pathway with the cyclopropane
substituent at R1 supports our hypothesis of a common
intermediate for both spirocycle and tricycle formation. A
nonconcerted pathway for the formal [2+2] process was
further supported by the reaction of 2a with (Z)-cinnamyl
bromide, which afforded 12 in 52% yield under our standard
conditions instead of the diastereomeric product derived from
a stereospecific process.[21b] Thus, the lifetime of the inter-
mediate biradical is sufficiently long to allow s-bond rotation
at R1 to give the more stable anti conformer.
intramolecular ene or the [2+2] reaction.[18]
Scheme 4 summarizes our mechanistic model of the two
competing reaction pathways for the reactions of bicyclobu-
In summary, we have established a direct synthetic access
to (bicyclo[1.1.0]butylmethyl)amines from propargyl phos-
phinamides through a Simmons–Smith reaction with Et2Zn/
CH2I2 or by addition of bicyclo[1.1.0]butyllithium to activated
imines. Phase-transfer conditions proved optimal for the
introduction of N-allyl or N-propargyl substituents, and the
resulting amides underwent highly diastereoselective cascade
rearrangements by formal ene or [2+2] pathways to yield
novel spirocyclic and tricyclic pyrrolidine heterocycles.
Received: February 24, 2006
Published online: May 19, 2006
Keywords: bicyclobutanes · cascade reactions ·
.
pericyclic reactions · pyrrolidines · spirocycles
Scheme 4. A mechanistic hypothesis that involves ene and [2+2] reac-
tion pathways of bicyclobutanes 2.
[1] a) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem.
Rev. 2003, 103, 977 – 1050; b) W. A. Donaldson, Tetrahedron
2001, 57, 8589 – 8627.
[2] a) N.-Y. Fu, S.-H. Chan, H. N. C. Wong in The Chemistry of
Cyclobutanes (Eds.: Z. Rappoport, J. F. Liebman), Wiley, New
York, 2005, pp. 357 – 440; b) J. C. Namyslo, D. E. Kaufmann,
Chem. Rev. 2003, 103, 1485 – 1538; c) E. Lee-Ruff, G. Mlade-
nova, Chem. Rev. 2003, 103, 1449 – 1484.
[3] S. Hoz in The Chemistry of Cyclopropyl Group (Ed.: Z.
Rappoport), Wiley, New York, 1987, pp. 1121 – 1192.
[4] a) Y. Gaoni, Tetrahedron 1989, 45, 2819 – 2840; b) H. Takaya, T.
Suzuki, Y. Kumagai, M. Hosoya, H. Kawauchi, R. Noyori, J. Org.
Chem. 1981, 46, 2854 – 2861; c) P. G. Gassman, M. J. Mullins,
Tetrahedron Lett. 1980, 21, 2219 – 2222.
[5] K. B. Wiberg, G. M. Lampman, R. P. Ciula, D. S. Connor, P.
Schertler, J. Lavanish, Tetrahedron 1965, 21, 2749 – 2769.
[6] a) J. M. Schulman, G. J. Fisanick, J. Am. Chem. Soc. 1970, 92,
6653– 6654; b) W. R. Moore, C. R. Costin, J. Am. Chem. Soc.
1971, 93, 4910 – 4912.
tanes with allyl bromides. A stepwise addition of the p system
À
across the central bicyclobutane C C s bond leads to a
putative biradical species,[12b,c,d,e,19] which in case of alkyl
substituents at R1 rapidly abstracts the inside hydrogen atom
to form the spirocyclic butene.[12c] If the biradical species is
stabilized by an aromatic group at R1, its prolonged lifetime
allows for a ring inversion of the cyclobutane and radical
recombination in a formal [2+2] cycloaddition process, thus
yielding the tricyclic pyrrolidine system.
To probe the lifetime of the proposed biradical interme-
diates[12b,c,d,e,19] in the conversion of 2a into 6 and 12, we
introduced a cyclopropylallyl substituent (Scheme 5).[20] Bicy-
clobutane 2a was allowed to react with freshly prepared
bromide 17 and the unstable amide 18 was obtained in 68%
yield. Compound 18 underwent spontaneous conversion into
equimolar amounts of 19a and 19b upon standing at room
temperature. The lack of cyclopropane ring-opened products
is not unusual for short-lived biradical intermediates,[21a] and
[7] a) P. Wipf, C. R. J. Stephenson, K. Okumura, J. Am. Chem. Soc.
2003, 125, 14694 – 14695; b) P. Wipf, C. Kendall, C. R. J.
Stephenson, J. Am. Chem. Soc. 2003, 125, 761 – 768.
[8] a) J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron 1968,
24, 53– 58; b) A. B. Charette, N. Wilb, Synlett 2002, 176 – 178.
[9] P. Wipf, C. R. J. Stephenson, M. A. A. Walczak, Org. Lett. 2004,
6, 3009 – 3012.
[10] The remainder of the material was starting material 1 or
rearranged allylcyclopropylbenzylamine.
[11] a) A. Duker, G. Szeimies, Tetrahedron Lett. 1985, 26, 3555 –
3558; b) J. Weber, U. Haslinger, U. H. Brinker, J. Org. Chem.
1999, 64, 6084 – 6086.
[12] a) E. P. Blanchard, Jr., A. Cairncross, J. Am. Chem. Soc. 1966,
88, 487 – 495; b) A. Cairncross, E. P. Blanchard, Jr., J. Am.
Chem. Soc. 1966, 88, 496 – 504; c) M. Pomerantz, G. W. Gruber,
R. N. Wilke, J. Am. Chem. Soc. 1968, 90, 5040 – 5041; d) P. G.
Gassman, G. D. Richmond, J. Am. Chem. Soc. 1970, 92, 2090 –
Scheme 5. A mechanistic study with cyclopropane as a radical trap.
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Chemie
2096; e) M. Pomerantz, R. N. Wilke, G. W. Gruber, U. Roy, J.
Am. Chem. Soc. 1972, 94, 2752 – 2758.
[13] E. Slusarska, A. Zwierzak, Synthesis 1980, 717 – 719.
[14] a) W. Oppolzer, Pure Appl. Chem. 1981, 53, 1181 – 1201; b) K.
Mikami, M. Shimizu, Chem. Rev. 1992, 92, 1021 – 1050.
[15] The structure of 5 was assigned based on the X-ray analysis of
the ketoaldehyde derived from cleavage of the cyclobutene ring.
[16] The relative stereochemistry of 12 was assigned based on
NOESY analysis.
[17] A steric argument was used to rationalize the selectivity of the
ene versus [2+2] pathway for simple bicyclo[1.1.0]butanes (see
reference [12]); prior pericyclic reactions of bicyclo-
[1.1.0]butanes were limited to structurally simple substrates,
and no further synthetic applications were reported.
[18] Reaction of 3-phenylbicyclo[1.1.0]butyllithium with acetalde-
hyde or benzaldehyde followed by phase-transfer alkylation
resulted in a low yield of the alkylated product.
[19] For a demonstration of the radical nature of reactions of
bicyclo[2.1.0]pentane with alkenes, see: a) P. G. Gassman, K. T.
Mansfield, T. J. Murphy, J. Am. Chem. Soc. 1969, 91, 1684 – 1689;
b) P. G. Gassman, K. T. Mansfield, J. Am. Chem. Soc. 1968, 90,
1524 – 1526.
[20] J. P. Stevenson, W. F. Jackson, J. M. Tanko, J. Am. Chem. Soc.
2002, 124, 4271 – 4281.
[21] a) T. Linker, Angew. Chem. 1997, 109, 2150 – 2152; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2060 – 2062; b) alkene Z/E
isomerization during N-alkylation was not responsible for the
lack of stereospecificity; (Z)-cinnamyl bromide when treated
with N-(3-phenylprop-2-ynyl)diphenylphosphinylamide gives an
alkylated product with an intact Z double-bond configuration in
67% yield.
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