Intramolecular titanium-mediated aminocyclopropanation of terminal alkenes: Easy access to various substituted azabicyclo[n.1.0]alkanes

Article abstract of DOI:10.1021/ol027352q

(Matrix presented) A variety of substituted azabicyclo[n.1.0]alkanes were synthesized by intramolecular titanium-mediated cyclopropanation of N-benzyl-N-(2-alkylalk-3-enyl)formamides and N-benzyl-N-alkadienylformamides. N-Benzylpyrroline upon treatment with Grignard reagents undergoes a titanium-mediated carbomagnesiation to yield N-benzyl-N-(2-alkylbut-3-enyl)amines.

Full text of DOI:10.1021/ol027352q

ORGANIC
LETTERS
2003
Vol. 5, No. 4
483-485
Intramolecular Titanium-Mediated
Aminocyclopropanation of Terminal
Alkenes: Easy Access to Various
Substituted Azabicyclo[n.1.0]alkanes1
Gerd-Dieter Tebben, Karsten Rauch, Christian Stratmann, Craig M. Williams, and
Armin de Meijere*
Institut fu¨r Organische Chemie der Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, D-37077 Go¨ttingen, Germany
armin.demeijere@chemie.uni-goettingen.de
Received November 26, 2002
ABSTRACT
A variety of substituted azabicyclo[n.1.0]alkanes were synthesized by intramolecular titanium-mediated cyclopropanation of N-benzyl-N-(2-
alkylalk-3-enyl)formamides and N-benzyl-N-alkadienylformamides. N-Benzylpyrroline upon treatment with Grignard reagents undergoes a titanium-
mediated carbomagnesiation to yield N-benzyl-N-(2-alkylbut-3-enyl)amines.
Much attention during the last two decades has been focused
on the utilization of organotitanium compounds in organic
synthesis.2 In particular, interest in titanium(IV) alkoxides
has significantly increased since the discovery of Kulinkovich
et al., who found that a large variety of esters could be
converted to cyclopropanols utilizing titanium(II) intermedi-
ates generated in situ from Ti(OiPr)4 and alkylmagnesium
halides or even with subsequent ligand exchange.3
An extrapolation of this methodology has led to a
convenient general synthesis of N,N-dialkylcyclopropyl-
amines from N,N-dialkylcarboxamides.4
The scope of this new cyclopropylamine synthesis has
been substantially extended by applying the ligand exchange
protocol.5
Here we report a further extension of this methodology
to a number of intramolecular cases, making azabicyclo-
[n.1.0]alkanes accessible from N-benzyl-N-alkenylform-
amides.
Two of the precursors were synthesized starting from
n-but-3-enol (1), the tosylate of which was converted to
N-benzyl-N-but-3-enylamine (2) by reaction with benzyl-
amine. Upon reaction of 2 with ethyl formate, N-benzyl-N-
but-3-enylformamide (3) was obtained in an overall yield
of 60%.
(1) Part 88 in the series Cyclopropyl Building Blocks for Organic
Synthesis. For Part 87, see: Larionov, O. V.; Savel’eva, T. F.; Kochetkov,
K. A.; Ikonnokov, N. S.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A.
K.; Khrustalev, V. N.; Belokon, Y. N.; de Meijere, A. Eur. J. Org. Chem.
2003, in press. Part 86: de Meijere, A.; Kuchuk, I. D.; Sokolov, V. V.;
Labahn, T.; Rauch, K.; Es-Sayed, M.; Kra¨mer, T. Eur. J. Org. Chem. 2003,
in press.
(2) (a) Reetz, M. T. Organotitanium Reagents in Organic Synthesis;
Springer: Berlin, 1986. (b) Seebach, D.; Weidmann, B.; Widler, L. In
Modern Synthetic Methods. Transition Metals in Organic Synthesis;
Scheffold, R., Ed.; Salle: Frankfurt, 1993; p 217. (c) Reetz, M. T. Top.
Curr. Chem. 1982, 106, 1. (d) Kulinkovich, O. G.; de Meijere, A. Chem.
ReV. 2000, 100, 2789. (e) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV.
2000, 100, 2835.
(3) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis
1991, 234 and references therein. (b) Kulinkovich, O. G.; Savchenko, A.
I.; Sviridov, S. V.; Vasilevski, D. A. MendeleeV Commun. 1993, 230. (c)
de Meijere, A.; Kozhushkov, S. I.; Spa¨th, T.; Zefirov, N. S. J. Org. Chem.
1993, 58, 502. (d) Epstein, O. L.; Savchenko, A. I.; Kulinkovich, O. G.
Tetrahedron Lett. 1999, 40, 5935. (e) Lee, J. C.; Sung, M. J.; Cha, J. K.
Tetrahedron Lett. 2001, 42, 2059.
(4) (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413. (b) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A. Synlett
1997, 111. (c) Winsel, H.; Gazizova, V.; Kulinkovich, O. G.; Pavlov, V.;
de Meijere, A. Synlett 1999, 1999. (d) de Meijere, A.; Kozhushkov; S. I.;
Savchenko A. I. In Titanium and Zirconium in Organic Synthesis; Marek,
I., Ed.; VCH-Wiley: Weinheim, Germany, 2002; p 390. (e) Wiedemann,
S.; Marek, I.; de Meijere, A. Synlett 2002, 6, 879.
(5) (a) Kourdioukov, A.; Chaplinski, V.; de Meijere, A. German Offen.
No. 19647615.1, 1996. (b) de Meijere, A.; Williams, C. M.; Chaplinski,
V.; Kourdioukov, A.; Sviridov, S. V.; Savchenko, A.; Kordes, M.;
Stratmann, C. Chem. Eur. J. 2002, 8, 3789.
10.1021/ol027352q CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/21/2003

Toward the homologous N-benzyl-N-pent-4-enylform-
amide (5), the tosylate of 1 was treated with NaCN in
DMSO. Reduction of the resulting nitrile 4 with LiAlH4
provided 4-pentenylamine, which was quantitatively con-
verted to the corresponding formamide by reaction with ethyl
formate. Deprotonation of the amide and benzylation with
benzyl bromide led to 5 in 19% overall yield (Scheme 1).
albeit with yields of only 23 and 32%, respectively.9 Since,
however, the primary attack of the first titanium intermediate
most probably occurs at the terminal double bond, the
trajectory for intramolecular carbonyl attack is rather dis-
favored, and this may be one reason for the poor yield.10
Surprisingly, the analogous treatment of N-benzyl-N-hepta-
4,6-dienylformamide (10) did not yield the expected 2-azabi-
cyclo[4.1.0]heptane derivative but yielded only 15% of exo-
N-benzyl-6-propenyl-2-azabicyclo[3.1.0]hexane (11) (Scheme
2).
Scheme 1a
Scheme 2a
a Reaction conditions: (a) TsCl, Py, 0 °C, 3 days; (b) BnNH2
(2.5 equiv), MeCN, 60 °C, 3 h. (c) NaCN, DMSO, 25 °C, 24 h.
(d) EtOCHO, 65 °C, 24 h. (e) LiAlH4, Et2O, 25 °C, 36 h. (f) (1)
NaH, DMF, 60 °C, 1 h; (2) BnBr, DMF, 25 °C, 24 h. (g) Ti(OiPr)4
(1.1 equiv), cHexMgBr (3.3 equiv), THF, 25 °C, 24 h.
a Reaction conditions: (a) Ti(OiPr)4 (1.1 equiv), cHexMgBr (3.3
equiv), THF, 25 °C, 24 h.
This product most probably arises by initial isomerization
of the precursor 10 under the conditions employed.
In another context,5 we came upon a new synthesis of
2-substituted 3-butenylamines, which were quite welcome
as precursors to 4-substituted 2-azabicyclo[3.1.0]hexanes 14.
Upon treatment of N-benzylpyrroline (12) with 2.5 equiv
of an alkylmagnesium halide in the presence of 1.2 equiv of
titanium tetraisopropoxide, N-benzyl-N-(2-alkylbut-3-enyl)-
amines (alkyl ) ethyl, isopropyl, sec-butyl, cyclopentyl) were
obtained. This transformation must arise from a titanium-
mediated carbomagnesiation of N-benzylpyrroline (12) with
ring opening. It resembles the zirconium-catalyzed carbo-
magnesiations discovered by Dzhemilev et al.11 and further
developed by Hoveyda et al. as well as others.12 However,
in those reactions, only isopropyl- and ethylmagnesium
halides were used.
The intramolecular reductive cyclopropanations of 3 and
5 were carried out by adding 3.3 equiv of cyclohexylmag-
nesium bromide to a THF solution containing 1.1 equiv of
titanium(IV) tetraisopropoxide and 1.0 equiv of the respective
formamide. Conversion of the N-benzyl-N-alkenylform-
amides 3 and 5, after acid/base workup, gave the expected
N-benzyl-2-azabicycloalkanes 6 and 7 in good yields (84 and
67% respectively, Scheme 1).6
In view of this result and the fact that 1,3-dienes are
particularly good ligands on titanium,5,7 the analogous
N-benzyl-N-alkadienylformamides8 were also subjected to
the established cyclization conditions. In accordance with
previous observations that substituted 1,3-dienes with one
terminal vinyl group always undergo aminocyclopropanation
at the more highly substituted double bond, both the (E)-
and (Z)-isomer of N-benzyl-N-hexa-3,5-dienylformamide
(E,Z)-8 gave exo-N-benzyl-6-vinyl-2-azabicyclo[3.1.0]hexane
(9) derived from supposed attack on the internal double bond,
Upon reaction of the crude mixtures of the homoallyl-
amines with ethyl formate, the corresponding formamides
(9) An attempted analogous cyclization of N-benzyl-N-(3-methylenepent-
4-enyl)formamide gave a minute amount (9%) of 2-benzyl-5-methylene-
2-azabicyclo[4.1.0]heptane and traces of a second cyclization product,
possibly the expected exo-N-benzyl-5-vinyl-2-azabicyclo[3.1.0]hexane.
(10) In contrast to the unsubstituted azabicycloalkanes 6 and 7, com-
pounds 9 and 11 upon attempted purification by acid/base workup or
distillation underwent rapid polymerization. Therefore, they had to be
purified by column chromatography, which probably also contributed to
the decreased yields.
(11) (a) Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet. Chem. 1985,
285, 43. (b) Lehmkuhl, H. Bull. Soc. Chim. Fr. II 1967, 87.
(12) (a) Hoveyda, A. H.; Xu, Z. J. Am. Chem. Soc. 1991, 113, 5079. (b)
Houri, A. F.; Didiuk, M. T.; Xu, Z.; Horan, N. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 1993, 115, 6614. (c) Lewis, D. P.; Whitby, R. J. Tetrahedron
1995, 51, 4541. (d) Uesaka, N.; Mori, M.; Okamura, K.; Date, T. J. Org.
Chem. 1994, 59, 4542.
(6) A single example of a similar reaction has been reported by Cha et
al. leading to 1-methyl-N-phenyl-2-azabicyclo[3.1.0]hexane: Lee, J.; Cha,
J. K. J. Org. Chem. 1997, 62, 1584.
(7) Williams, C. M.; Chaplinski, V.; Schreiner, P. R.; de Meijere, A.
Tetrahedron Lett. 1998, 39, 7695 and references therein.
(8) N-Benzyl-N-alkadienylformamides 8 and 10 were synthesized in an
analogous manner as the monoene precursors by using hexa-3,5-dienol as
starting material instead of but-3-enol (1). Preparation of (E)-hexa-3,5-
dienol: Martin, S. F.; Tu, C.-y.; Chou, T.-s. J. Am. Chem. Soc. 1980, 102,
5274. (Z)-Hexa-3,5-dienol: Aerrsens, M. H. P. J.; van der Heiden, R.; Heus,
S.; Brandsma, L. Synth. Commun. 1990, 20, 3421.
484
Org. Lett., Vol. 5, No. 4, 2003

13a-d were obtained in overall yields of 31-46%. These
were also subjected to the above-mentioned cyclization
conditions to afford the 4-substituted 2-azabicyclo[3.1.0]-
hexanes 14a-d in good yields as mixtures of exo and endo
diastereomers in ratios ranging from 3:1 to 10:1 (Scheme
3).
In summary, we have demonstrated that a number of
variably substituted azabicyclo[n.1.0]alkanes are easily ac-
cessible by intramolecular titanium-mediated cyclopropana-
tion of carboxylic acid amides. A number of precursors for
the cyclization were synthesized by a new titanium-mediated
carbomagnesiation reaction of N-benzylpyrroline.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 416, Projekt A14),
the Fonds der Chemischen Industrie, and the Bayer AG.
Generous gifts of chemicals from BASF AG, Bayer AG, and
Degussa AG are kindly acknowledged. G.-D. Tebben is
indebted to the Studienstiftung des deutschen Volkes for a
fellowship. The authors are grateful to Dr. Burkhard Knieri-
em, Go¨ttingen, for his careful reading of the final manuscript.
Scheme 3a
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 3, 5-11, 13a-
d, and 14a-d. This material is available free of charge via
the Internet at http://pubs.acs.org.
a Reaction conditions: (a) Ti(OiPr)4, RMgBr, Et2O, -20 °C, 4
h. (b) EtOCHO, 65 °C, 24 h. (c) Ti(OiPr)4 (1.1 equiv), cHexMgBr
(3.3 equiv), THF, 25 °C, 24 h.
OL027352Q
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