Diene-titanium complexes as synthetic intermediates for the construction of three or five-membered carbocycles

Article abstract of DOI:10.1021/ol702917c

It has been shown that diene-titanium complexes exhibit substrate-dependent 1,2- or 1,4-dicarbanion reactivity. On this basis, 3-cyclopen-tenylamines and spiro-vinylcyclopropane lactams were easily prepared by using homoallylic Grignard reagents, Ti(O-i-P

Full text of DOI:10.1021/ol702917c

ORGANIC
LETTERS
2008
Vol. 10, No. 5
777-780
Diene−Titanium Complexes as Synthetic
Intermediates for the Construction of
Three- or Five-Membered Carbocycles
Philippe Bertus,*,† Christine Menant, Chloe´ Tanguy, and Jan Szymoniak*
ICMR - UMR 6229, CNRS - UniVersite´ de Reims Champagne-Ardenne, BP 1039,
51687 Reims Cedex 2, France
philippe.bertus@uniV-lemans.fr; jan.szymoniak@uniV-reims.fr
Received December 3, 2007
ABSTRACT
It has been shown that diene−titanium complexes exhibit substrate-dependent 1,2- or 1,4-dicarbanion reactivity. On this basis, 3-cyclopen-
tenylamines and spiro-vinylcyclopropane lactams were easily prepared by using homoallylic Grignard reagents, Ti(O-i-Pr)4, and nitriles or
cyanoesters, respectively.
Titanacyclopropanes (A1), which can also be considered as
π-complexes (A2), are typically formed by transmetalation
and a successive â-fragmentation (Scheme 1).1 These putative
Following the discovery of the Kulinkovich reaction, Ti-
(II) chemistry has been widely developed,1 particularly due
to the 1,2-dicarbanion pattern of titanacyclopropanes. In
addition, exchange of alkenes, imines, or alkynes starting
from the initial Ti(II)-alkene complex has broadened the
scope of the cyclopropanation and other reactions.5
Scheme 1
In contrast to A, reactions of diene-titanium complexes
B have been less investigated.6-10 This species can be
(4) (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792. (b) Bertus,
P.; Szymoniak, J. Synlett 2007, 1346.
(5) Some recent examples: Alkenes: (a) Keaton, K. A.; Phillips, A. J.
Org. Lett. 2007, 9, 2717. (b) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J.
K. Angew. Chem., Int. Ed. 2002, 41, 2160. Imines: (c) Takahashi, M.;
Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514. (d) Fukuhara, K.;
Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145. Alkynes: (e) Bahadoor, A.
B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 2005, 127, 3694. (f)
Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe,
H. J. Am. Chem. Soc. 2005, 127, 7474.
(6) (a) Williams, C. M.; Chaplinski, V.; Schreiner, P. R.; de Meijere, A.
Tetrahedron Lett. 1998, 39, 7695. (b) de Meijere, A.; Williams, C. M.;
Kourdioukov, A.; Sviridov, S. V.; Chaplinski, V.; Kordes, M.; Savchenko,
A. I.; Stratmann, C.; Noltenmeyer, M. Chem. Eur. J. 2002, 8, 3789.
(7) (a) Urabe, H.; Kasatkin, A.; Sato, F. Chem. Commun. 1996, 197. (b)
Urabe, H.; Takeda, T.; Sato, F. Tetrahedron Lett. 1996, 37, 1253. (c) Urabe,
H.; Mitsui, K.; Ohta, S.; Sato, F. J. Am. Chem. Soc. 2003, 125, 6074.
(8) Laroche, C.; Bertus, P.; Szymoniak, J. Chem. Commun. 2005, 3030.
intermediates are involved in the Kulinkovich hydroxycy-
clopropanation of esters2 as well as in the related syntheses
of tertiary3 and primary4 cyclopropylamines from amides and
nitriles, respectively.
† Present address: UMR 6011 - UCO2M, CNRS - Universite´ du Maine,
72085 Le Mans cedex 9, France.
(1) (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789.
(b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835.
(2) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A. Synthesis
1991, 234. (b) Kulinkovich, O. G. Eur. J. Org. Chem. 2004, 4517.
(3) (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413. (b) de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. J.
Organomet. Chem. 2004, 689, 2033.
10.1021/ol702917c CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/30/2008

Scheme 2
Scheme 4
described by several canonical forms, η2 or η4, including
metalacycles (B1 or B2) or π-complexes (B3 or B4) (Scheme
2).
from Ti(O-i-Pr)4 and a homoallylic Grignard reagent ac-
cording to Goeke et al. (Scheme 4).10 When 3-butenylmag-
nesium bromide (2 equiv) was added at -70 °C to
benzonitrile and Ti(O-i-Pr)4 in Et2O and the mixture allowed
to warm to -30 °C during 1 h, the ketone 2a was obtained
in 59% yield after hydrolysis at -30 °C, in agreement with
Goeke’s results. Interestingly, when the reaction mixture was
warmed to room temperature the cyclopentenylamine 1a was
obtained after hydrolysis, albeit in low yield (20%), and no
trace of 2a was detected. This result clearly indicated that
the contraction of the azatitanacycle intermediate C, leading
to a five-membered carbocycle, occurred only at temperatures
higher than -30 °C.
It should be noted that the simultaneous use of homoallylic
Grignard reagent and a nitrile is possible. This is in contrast
to the ligand-exchange method in which the nitrile must be
added only after the Grignard reagent-promoted transmeta-
lation-fragmentation and ligand-exchange processes occur.8
As a consequence, an efficient room-temperature procedure
for directly preparing cyclopentenylamines could be envi-
sioned. The feasibility of such reactions was checked by
simply adding the homoallylic Grignard reagent to a mixture
of the nitrile and Ti(O-i-Pr)4 at room temperature. The
reactions were carried out for about 1 h, followed by a
hydrolytic workup. Some results obtained by employing
aromatic and aliphatic nitriles as well as unsubstituted and
substituted Grignard reagents are presented in Scheme 5.
Two approaches for generating diene-titanium complexes
are known. The ligand exchange between (η2-alkene)Ti(Oi-
Pr)2 and 1,3-dienes (Scheme 2, path i) is a convenient
procedure.6-9 More recently, the low temperature addition
of homoallylic Grignard reagents to titanium isopropoxide
(path ii) has been reported.10 In some cases, 1,4-dicarbanion
reactivity has been revealed. Thus, the addition of electro-
philes such as aldehydes, ketones, or nitriles led to the
corresponding open-chain products.7,10 In contrast, 1,2-
dicarbanion reactivity has been observed when using N,N-
dialkylamides as starting materials.6 In these reactions,
performed under ligand-exchange conditions, 2-vinylcyclo-
propylamines were exclusively formed. Based on the di-
chotomous 1,4- vs 1,2-dicarbanion pattern of diene-titanium
complexes, we describe herein simple synthetic approaches
to three- and five-membered carbocyclic compounds which
use nitriles or cyanoesters and homoallylic Grignard reagents
as starting materials.
As a part of our work on the titanium-mediated synthesis
of cyclopropylamines from nitriles,4 we studied the feasibility
of preparing 2-vinylcyclopropylamines. The ligand-exchange
procedure with the initial propene-titanium complex and
isoprene was applied. To make the exchange efficient, the
temperature was allowed to slowly increase from -78 to 20
°C and during this period a nitrile was added. When the
nitrile addition took place at about -20 °C, 3-cyclopente-
nylamines 1 were formed in good yields (Scheme 3).
Scheme 5
Scheme 3
To gain a better insight into this [4 + 1] assembly reaction,
the diene-titanium intermediate of type B was then generated
With this room-temperature-based protocol, the corre-
sponding cyclopentenylamines were obtained in moderate
to good yields. The unsubstituted cyclopentenylamines 1a
(9) Baraut, J.; Perrier, A.; Comte, V.; Richard, P.; Le Gendre, P.; Moise,
C. Tetrahedron Lett. 2006, 47, 8319.
(10) Goeke, A.; Mertl, D.; Jork, S. Chem. Commun. 2004, 166.
778
Org. Lett., Vol. 10, No. 5, 2008

and 1b were formed by using 3-butenylmagnesium bromide,
which amounts to the ligand-exchange-based protocol in-
volving the gaseous 1,3-butadiene. This straightforward
method uses readily available and simple starting materials.
Starting from nitriles, no trace of the vinylcyclopropy-
lamine derivative was observed. This contrasted sharply with
the exclusive formation of 2-vinylcyclopropylamines from
N,N-dialkylamides.6 In the case of cyanoesters, a 1,2-
dicarbanion pattern was observed which was similar to
amides and different from nitriles. Thus, 4a was the only
product formed from ethyl 3-cyanopropionate (3a) under the
conditions employed for nitriles (Scheme 6).
Table 1. Ti-Mediated Synthesis of Spirocyclic Lactams from
Cyanoesters and Homoallylic Grignard Reagents
Scheme 6
The formation of the azaspirocyclic compound 4a can be
explained as depicted in Scheme 6. The chemoselective
insertion of the CN group into B produces the intermediate
D. The carboxylate-induced ring opening of D affords the
allyltitanium intermediate E, which in turn reacts intramo-
lecularly with the N-acylimine moiety to give the spiro-
vinylcyclopropane lactam 4a after hydrolysis.11,12
As depicted in Table 1, the titanium-mediated reaction of
cyanoesters or cyanocarbonates with homoallylic Grignard
reagents led to 1-azaspirocyclic compounds 4a-f, having a
vinylcyclopropylamine (and not a cyclopentenylamine) moi-
ety.
When using THF instead of Et2O as solvent, 4a was
obtained in higher yield and in almost pure diastereomeric
form (entry 1).13 With a substituted Grignard reagent, i.e.,
3-methyl-3-butenylmagnesium bromide, the regioisomers 4b
and 4c were obtained in a 2:1 ratio regardless of the solvent
used (entry 2). The presence of both 4b and 4c supported
the intermediacy of complex B, followed by a nonselective
insertion of the CN group.14 Mixtures of diastereomeric
spirocyclic lactams 4d and 4e (entries 3 and 4) could be
separated by flash chromatography.15 Finally, the oxazoli-
a Isolated yields. b Only the major diastereomer is depicted. Diastereoi-
someric ratio is given in parentheses. c 3-Methyl-3-butenylmagnesium
bromide was used.
dinone 4f, prepared from Boc-protected glycononitrile (3d),
was obtained as a unique stereoisomer in THF (entry 5).
In summary, diene-titanium complexes, generated from
homoallylic Grignard reagents and Ti(O-i-Pr)4, exhibit
substrate-dependent 1,2- or 1,4-dicarbanion reactivity. On
this basis, a straighforward access to 3-cyclopentenylamines
from nitriles and spiro-vinylcyclopropane lactams from
cyanoesters has been developed. The simultaneous presence
of aminocyclopropane16 and vinylcyclopropane17 moieties
would make the latter compounds versatile synthetic inter-
(16) For some synthetic uses of cyclopropylamines, see: (a) Madelaine,
C.; Six, Y.; Buriez, O. Angew. Chem., Int. Ed. 2007, 46, 8046. (b) Osipova,
A.; Yufit, D. S.; de Meijere, A. Synthesis 2007, 131. (c) Tanguy, C.; Bertus,
P.; Szymoniak, J.; Larionov, O. V.; de Meijere, A. Synlett 2006, 2339. (d)
Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Schu¨tz, C.; Vogel, P.;
Plantier-Royon, R. Bioorg. Med. Chem. 2006, 14, 4047.
(17) Vinylcyclopropanes are involved in a number of ring expansion and
cycloaddition reactions; see, for example: (a) Wender, P. A.; Gamber, G.
G.; Williams, T. J. In Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 13. (b) Trost, B.
M.; Shen, H. C.; Horne, D. B.; Toste, F. D.; Steinmetz, B. G.; Koradim, C.
Chem. Eur. J. 2005, 11, 2577. (c) Baldwin, J. E. Chem. ReV. 2003, 103, 1197.
(11) An analogous allyltitanium intermediate has been postulated for the
cyclopropanation of N,N-dialkylamides with 1,3-dienes; see ref 6.
(12) An alternative mechanism, similar to the vinylcyclopropane-
cyclopentene rearrangement can also be considered; see, for example: (a)
Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107,
4579. (b) Rieke, R. D.; Sell, M. S.; Xiong, H. J. Am. Chem. Soc. 1995,
117, 5429.
(13) The relative stereochemistry of 4a was elucidated by NOE.
(14) Similar results were obtained by applying the ligand-exchange
procedure.
(15) See the Supporting Information.
Org. Lett., Vol. 10, No. 5, 2008
779

mediates. Mechanistic investigations and synthetic applica-
tions are underway in our laboratory.
Supporting Information Available: Experimental pro-
cedures and characterization data and NMR spectra of
compounds 1a-e and 4a-f. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
CNRS and the Reims-Champagne-Ardenne University. C.M.
acknowledges the Region Champagne-Ardenne for the
financial support.
OL702917C
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Org. Lett., Vol. 10, No. 5, 2008