Titanium- And Lewis acid-mediated cyclopropanation of imides

Article abstract of DOI:10.1021/ol062938o

We report a straightforward synthesis of 1-azaspirocyclopropane lactams from imides. Following the described procedure, polycyclic nitrogen heterocycles containing a cyclopropane unit could be obtained from unsaturated imides.

Full text of DOI:10.1021/ol062938o

ORGANIC
LETTERS
2007
Vol. 9, No. 4
659-662
Titanium- and Lewis Acid-Mediated
Cyclopropanation of Imides
Philippe Bertus* and Jan Szymoniak
UMR 6519, Re´actions Se´lectiVes et Applications, CNRS, UniVersite´ de Reims
Champagne-Ardenne, BP 1039, 51687 REIMS Cedex 2, France
philippe.bertus@uniV-reims.fr
Received December 4, 2006
ABSTRACT
We report a straightforward synthesis of 1-azaspirocyclopropane lactams from imides. Following the described procedure, polycyclic nitrogen
heterocycles containing a cyclopropane unit could be obtained from unsaturated imides.
The Kulinkovich reaction, i.e., titanium-mediated formation of
cyclopropanols from carboxylic esters and Grignard reagents,
has extensively been studied since its discovery in 1989.1,2
carbonates4 have been employed, leading, respectively, to
tertiary cyclopropylamines and cyclopropanone hemiacetals
after hydrolysis. In contrast, Cha and co-workers reported
that cyclic imides did not afford cyclopropane compounds
under the Kulinkovich conditions.5 N-Acyl hemiaminals were
solely obtained, resulting from the hydrolysis of the five-
membered ring intermediate C, stable in this case (Scheme
2, eq 1).6 The reaction was applied to the synthesis of
This reaction involves the formation of titanacyclopropane
intermediates A and insertion of esters to afford B, which
spontaneously rearrange to afford cyclopropanol derivatives
after hydrolysis (Scheme 1).
Scheme 1. Kulinkovich Reaction
Scheme 2. Reaction of Titanacyclopropanes with Imides
The scope of substrates has gradually been extended,
leading to the preparation of a wide range of substituted
cyclopropanes. In addition to carboxylic esters used in the
original Kulinkovich reaction, tertiary amides3 and dialkyl
pyrrolizidine, indolizidine, and related alkaloids by a titanium-
mediated cyclization of ω-vinyl imides (Scheme 2, eq 2).5,7
More recently, we have developed a synthesis of primary
cyclopropylamines, based on the reaction of titanacyclopro-
panes (A) with nitriles (Scheme 3).8 Whereas under the
(1) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A.; Pritytskaja,
T. S. Zh. Org. Khim. 1989, 25, 2244-2245; J. Org. Chem. USSR 1989,
25, 2027-2028.
10.1021/ol062938o CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/20/2007

Scheme 3. Ti-Mediated Cyclopropanation of Nitriles
Scheme 4. Proposed Paths for the Lewis Acid Activation of C
Kulinkovich conditions the ketone was the major product
of hydrolysis, the addition of BF3‚OEt2 to the metallacycle
modified dramatically the outcome of the reaction, affording
cyclopropylamines in good yields. The Lewis acid was
assumed to induce the ring contraction of the five-membered
metallacycle in this case.
of Ti(Oi-Pr)4 and 1a in THF led to the N-acyl hemiaminal
2a in 89% yield (Table 1, entry 1).
The formation of cyclopropane derivatives would similarly
be expected through a Lewis acid activation of C (Scheme
4). In this case, two products can be anticipated, depending
on the selectivity of the Lewis acid addition. Following path
a, the coordination of a Lewis acid on the carbonyl moiety
would induce the formation of the homoenolate equivalent
E, in the way analogous to that encountered in the Kulink-
ovich cyclopropanation of esters, to produce the amide-
substituted cyclopropanol 3.9 In path b, coordination of the
Lewis acid on the oxygen linked to titanium would produce
the azaspirocyclic compound 4 through the iminium inter-
mediate G.10
Table 1. Ti-Mediated Addition of EtMgBr to Imide 1a
yield (%)a
entry
[Ti] (equiv)
n
1a
2a
4a
5a
1b
2
Ti(Oi-Pr)4 (1.2)
Ti(Oi-Pr)4 (1.2)
Ti(Oi-Pr)4 (1.2)
ClTi(Oi-Pr)3 (1.2)
MeTi(Oi-Pr)3 (1.2) 1.2 49
MeTi(Oi-Pr)3 (1.5) 1.5
MeTi(Oi-Pr)3 (1.5) 1.5
2.4
2.4
2.4
2.4
-
-
-
-
89 (75)
-
49
50
62
38
79 (75)
78 (74)
-
34
39
21
2
Initial experiments were carried out with N-benzylsuccin-
imide (1a). As expected, the addition of EtMgBr to a solution
-
-
-
-
-
-
3c
4
(2) Reviews: (a) Kulinkovich, O. G. Eur. J. Org. Chem. 2004, 4517-
4529. (b) de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. In Titanium
and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Wein-
heim, Germany, 2002; pp 390-434. (c) de Meijere, A.; Kulinkovich, O.
G. Chem. ReV. 2000, 100, 2789-2834.
(3) Review: de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. J.
Organomet. Chem. 2004, 689, 2033-2055.
(4) Lee, J.; Kim, Y. G.; Bae, J. G.; Cha, J. K. J. Org. Chem. 1996, 61,
4878-4879.
5
6
7d
-
-
2
3
a NMR yields; isolated yields in parentheses. bReaction performed without
c
d
the addition of BF3‚OEt2. Reaction carried out in Et2O. Me3SiOTf used
instead of BF3‚OEt2.
(5) (a) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127-
8128. (b) Lee, K.; Kim, S.-E.; Cha, J. K. J. Org. Chem. 1998, 63, 9135-
9138. (c) Sung, M. J.; Lee, C.-W.; Cha, J. K. Synlett 1999, 561-562. (d)
Kim, S.-H.; Park, Y.; Choo, H.; Cha, J. K. Tetrahedron Lett. 2002, 43,
6657-6660. (e) Santra, S.; Masalov, N.; Epstein, O.; Cha, J. K. Org. Lett.
2005, 7, 5901-5904.
A successive addition of BF3‚OEt2 to the reaction mixture
led to the formation of two new products, the enamide 5a,
resulting probably from the dehydration of 2a, and the
azaspirocyclic compound 4a as the sole cyclopropane-
containing derivative (entry 2). Whereas the use of ClTi-
(Oi-Pr)3 instead of Ti(Oi-Pr)4 had a moderate effect on the
4a/5a ratio (entry 4), the use of MeTi(Oi-Pr3)11 was found
to significantly increase the ratio of the cyclopropane 4a to
the detriment of 5a (entries 5-7). In fact, MeTi(Oi-Pr3)
requires only one equivalent of EtMgBr to form the titana-
cyclopropane, thus limiting side reactions resulting from the
(6) Similarly to imides, N-acylpyrroles did not afford cyclopropane
derivatives under Kulinkovich conditions; see: Epstein, O. L.; Seo, J. M.;
Masalov, N.; Cha, J. K. Org. Lett. 2005, 7, 2105-2108.
(7) (a) Kim, S.-H.; Kim, S.-I.; Lai, S.; Cha, J. K. J. Org. Chem. 1999,
64, 6771-6775. (b) Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113-2116.
(c) Ollero, L.; Mentink, G.; Rutjes, F. P. J. T.; Speckamp, W. N.; Hiemstra,
H. Org. Lett. 1999, 1, 1331-1334.
(8) (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792-1793.
(b) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965-3968. (c)
Bertus, P.; Szymoniak, J. Synlett 2003, 265-267. (d) Laroche, C.; Bertus,
P.; Szymoniak, J. Tetrahedron Lett. 2003, 44, 2485-2487. (e) Bertus, P.;
Szymoniak, J. J. Org. Chem. 2003, 68, 7133-7136. (f) Laroche, C.; Harakat,
D.; Bertus, P.; Szymoniak, J. Org. Biomol. Chem. 2005, 3, 3482-3487.
(g) Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Plantier-Royon, R.
Eur. J. Org. Chem. 2005, 5084-5088. See also: (h) Gensini, M.;
Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A. K.; Es-Sayed, M.; de Meijere,
A. Eur. J. Org. Chem. 2002, 2499-2507.
(10) (a) According to the referee’s remark, 4 could also arise from the
Lewis acid coordination on the alkoxy ligands. (b) Another site of
coordination is the nitrogen atom. The expected final product would be the
same as that in path a, i. e., the cyclopropanol 3.
(11) MeTi(Oi-Pr)3 was prepared from ClTi(Oi-Pr)3 and MeLi; see: Reetz,
M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek,
R.; Maus, S. Chem. Ber. 1985, 118, 1421-1440.
(9) Closely related to imides, acyloxazolidinones afforded cyclopropanols
under Kulinkovich conditions; see: Mizojiri, R.; Urabe, H.; Sato, F. J. Org.
Chem. 2000, 65, 6217-6222.
660
Org. Lett., Vol. 9, No. 4, 2007

use of a larger amount of Grignard reagent.12 A slightly
higher excess of titanium and Grignard reagents was however
required to obtain a total conversion of the starting imide
(entry 6). The use of Me3SiOTf gave similar results (entry
7). In all the experiments involving 1a, the spirocyclic lactam
4a was the only cyclopropane-containing product obtained.
No trace of the cyclopropanol 3a was detected, suggesting
that the cyclopropanation reaction occurred via path b solely.
An overcyclopropanation of 1a, possible with an excess
of reagent, to afford the dispirocyclic amine 6 was not
observed (Scheme 5). The amine 6 could be obtained from
Table 2. Cyclopropanation of Imides 1a-e
Scheme 5. Preparation of the Dispirocyclic Amine 6
the isolated amide 4a, without the subsequent use of a Lewis
acid. In this case, a large excess of reagents was required to
afford a total conversion of the starting amide.
The optimized conditions for efficiently preparing 4a from
1a were successfully applied to a series of imides and
Grignard reagents, to afford the spirocyclopropane lactams
4b-g, as shown in Table 2.
Good yields of 4b-e were obtained from EtMgBr and
the cyclic imides 1b-e (entries 1-4). Particularly noteworthy
is the regioselective cyclopropanation of the R-diethylami-
nosuccinimide 1e at the less-hindered carbonyl moiety (entry
4). The use of higher Grignard reagents (n-BuMgBr and Ph-
(CH2)3-MgBr) afforded the corresponding substituted cyclo-
propanes 4f and 4g with a low diastereocontrol (entries 5
and 6). In contrast, N,N-diacetylbenzylamine, the acyclic
analogue of 1a, was not a suitable substrate because only
N-acetylbenzylamide was obtained in this case.13
a Isolated yields. bRatio of diastereomers is in parentheses. cThe
configuration of the major stereoisomer was determined by NOE.
magnesium chloride, followed by the addition of BF3‚OEt2
(Scheme 6). The cyclization was extended to the formation
of polycyclic compounds with various cycle sizes leading
We next turned to the cyclopropanation of N-alkenyl
imides. Cha and co-workers extensively studied the regio-
and stereocontrol of the titanium-mediated cyclization of
unsaturated imides, providing an efficient access to substi-
tuted nitrogen heterocycles (Scheme 2, eq 2).5 The scope of
this method would be significantly extended if cyclopropane-
containing polycyclic compounds are obtained by the addi-
tion of Lewis acids. Initial attempts to prepare the tricyclic
amide 8a from imide 7a by activating the metallacycle H
(generated following the reported procedures, c-C5H9MgCl/
ClTi(Oi-Pr)35a or n-BuLi/Ti(Oi-Pr)45e) with BF3‚OEt2 led to
low yields of 8a. The amide 8a was obtained in 65% yield
by the use of an excess of MeTi(Oi-Pr)3 and cyclohexyl-
Scheme 6. Cyclopropanation of ω-Vinylimides
(12) MeTi(Oi-Pr)3 was initially used by de Meijere and co-workers for
the cyclopropanation of tertiary amides and was found to be generally more
efficient than Ti(Oi-Pr)4: Chaplinski, V.; Winsel, H.; Kordes, M.; de
Meijere, A. Synlett 1997, 111-114.
(13) Acyclic imides are known to be much more reactive toward
nucleophiles than the cyclic ones. See, for example: (a) Murakami, Y.;
Kondo, K.; Miki, K.; Akiyama, Y.; Watanabe, T.; Yokoyama, Y. Tetra-
hedron Lett. 1997, 38, 3751-3754. (b) Sykes, N. O.; Macdonald, S. J. F.;
Page, M. I. J. Med. Chem. 2002, 45, 2850-2856.
Org. Lett., Vol. 9, No. 4, 2007
661

to amides 8b-e in 46-62% isolated yields. These com-
pounds were obtained in a totally diastereoselective fashion.14
A short preparation of such polycyclic frameworks is very
rare in the literature.15 By a suitable use of substituted ω-vinyl
tethered starting imides, this method should present a short
access to new cyclopropane-containing pyrrolizidine and
indolizidine derivatives.16
applied by Cha and co-workers, mainly the use of MeTi-
(Oi-Pr)3 as a titanium reagent and the addition of BF3‚OEt2,
gave 1-azaspirocyclopropane lactams in 48-78% yield. The
described method allows a direct access to polycyclic
nitrogen heterocycles bearing a cyclopropane unit from
readily available starting materials.
In summary, we have presented the unprecedented cyclo-
propanation of imides. The modification of the conditions
Acknowledgment. This work was supported by CNRS
and the Reims-Champagne-Ardenne university.
(14) The relative stereochemistry of compounds 8a-e has not been
established.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Only two methods for preparing the tricyclic core of 8a were
reported in the literature, whereas the other polycyclic frameworks of 8b-e
are unknown to date: (a) Hanessian, S.; Buckle, R.; Bayrakdarian, M. J.
Org. Chem. 2002, 67, 3387-3397. (b) Beak, P.; Wu, S.; Yum, E. K.; Jun,
Y. M. J. Org. Chem. 1994, 59, 276-277.
(16) (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603-626. (b) Liddell,
J. R. Nat. Prod. Rep. 2002, 19, 773-781 and references therein.
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