Titanium-mediated synthesis of bicyclic cyclopropylamines from unsaturated nitriles

Article abstract of DOI:10.1016/S0040-4039(03)00325-3

Here we report an easy synthesis of bicyclic primary cyclopropylamines directly from unsaturated nitriles. The described reaction involves Ti(II)-mediated intramolecular coupling of alkene and nitrile moieties.

Full text of DOI:10.1016/S0040-4039(03)00325-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2485–2487
Titanium-mediated synthesis of bicyclic cyclopropylamines from
unsaturated nitriles
Christophe Laroche, Philippe Bertus* and Jan Szymoniak*
UMR 6519-Re´actions Se´lectives et Applications, CNRS-Universite´ de Reims Champagne-Ardenne, UFR Sciences, BP 1039,
51687 Reims Cedex 2, France
Received 11 December 2002; revised 3 February 2003; accepted 3 February 2003
Abstract—Here we report an easy synthesis of bicyclic primary cyclopropylamines directly from unsaturated nitriles. The
described reaction involves Ti(II)-mediated intramolecular coupling of alkene and nitrile moieties. © 2003 Elsevier Science Ltd.
All rights reserved.
The cyclopropane ring is encountered in a variety of
biologically active compounds.1 In particular, the
aminocyclopropyl moiety is present in natural aminocy-
clopropane carboxylic acids (ACC),2 and in several
synthetic drugs.3 We recently reported a new synthetic
method for preparing primary cyclopropylamines from
nitriles and Grignard reagents in the presence of
Ti(OiPr)4.4,5 The described reaction is similar to the
Kulinkovich or de Meijere reactions which allow to the
preparation of cyclopropanols and tertiary cyclopropyl-
amines respectively from carboxylic esters and N,N-
dialkylamides.6 However, in our case, the subsequent
addition of a Lewis acid is important for the reaction to
occur (Scheme 1).
bicyclic cyclopropanols8,9 and tertiary cyclopro-
pylamines10–12 were obtained by the intramolecular
cyclopropanation of unsaturated esters and amides.
However, de Meijere et al. had very recently reported12
that bicyclic cyclopropylamines were not formed
efficiently13 from d,o-unsaturated nitriles, under the
conditions described previously.4 These results
prompted us to report our work relating to the prepara-
tion of bicyclic cyclopropylamines by intramolecular
cyclization of unsaturated nitriles.
First, competing inter- and intramolecular reactions, as
shown in Scheme 2, were considered. In fact, the ini-
tially formed titanacyclopropane can directly insert the
CꢀN bond to afford A as a final product (path (i)).
Alternatively, the alkene exchange with the CꢁC bond
of the nitrile can result in the intramolecular reaction to
afford B (path (ii)). Since the alkene exchange may be
greatly influenced by the nature of the Grignard
reagent, we thus investigated several organomagnesium
halides with the aim of favoring the intramolecular
cyclopropanation (path (ii)). In these preliminary
experiments, Grignard reagents were added to a mix-
ture of the unsaturated nitrile 1 and Ti(OiPr)4 in Et2O.
The results are summarized in Table 1.
Since the development of the ligand-exchange method-
ology for the generation of titanacyclopropane interme-
diates,7–10 the scope of the Kulinkovich and de Meijere
reactions had been extended. In this way, a number of
By using EtMgBr,7 only the product 2a was obtained,
resulting from a direct addition to the nitrile moiety
(entry 1). With higher Grignard reagents such as n-
BuMgBr8 or iPrMgCl9 (entries 2 and 3), the bicyclic
product 3 is obtained, albeit in poor yield and accom-
panied by a large amount of cyclopropylamines 2b and
2c. Cyclic organomagnesium halides8b,10–12 have proven
to be efficient in the preparation of low-valent titanium
Scheme 1.
Keywords: bicyclic compounds; cyclizations; cyclopropanes; nitriles;
titanium.
* Corresponding authors. Fax: +33 326 913 166; e-mail:
philippe.bertus@univ-reims.fr; jan.szymoniak@univ-reims.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00325-3

2486
C. Laroche et al. / Tetrahedron Letters 44 (2003) 2485–2487
The 3-azabicyclo[3.1.0]hex-1-ylamine framework can be
constructed efficiently using the optimized procedure
(entries 1–4). An additional double bond in 4 did not
interfere with the reaction (entry 2). Starting from the
nitrile 6 bearing a gem-disubstituted double bond, the
cyclopropylamine 7 was obtained without decrease of
the yield (entry 3).18 To our knowledge, this is the first
example for the insertion of a disubstituted alkene in
Ti-mediated intramolecular cyclopropanation. All-car-
bon bicycles can also be obtained as shown by the
synthesis of diastereomeric 3-phenylbicyclo[3.1.0]hex-1-
ylamines 11a and 11b (entry 5).
The reaction is not limited to the elaboration of cyclo-
propylamines with a five-membered ring. Thus, the
bicyclo[4.1.0]heptane framework can be formed (entries
6–7).13,18 In these cases, Lewis acid is required to obtain
a good yield of cyclopropylamine. The seven-membered
ring homologue 17 can also be obtained, albeit in poor
yield (entry 8).
In summary, the Ti-mediated intramolecular coupling
of unsaturated nitriles was investigated. The described
reaction makes it possible to prepare various bicyclic
primary cyclopropylamines.
Scheme 2.
Table 1.
Table 2. Ti-mediated synthesis of bicyclic cyclopropyl-
amines17
Entry
R1
R2
Yield (%)a
Ratio of products
1
2
3
4
5
H
Et
H
-(CH2)3-
-(CH2)4-
H
H
Me
60
67
61
60
69b
2a/3
100/0
84/16
78/22
83/17
B2/98
2b/3
2c/3
2d/3
2e/3
Conditions: Ti(OiPr)4 1.1 equiv., Grignard reagent 2.2 equiv. in Et2O,
then BF3·OEt2 2 equiv.
a
Overall yield of 2 and 3.
66% yield without addition of Lewis acid.
b
and minimization of undesired intermolecular process.
We then tested cyclopentyl- and cyclohexylmagnesium
chlorides. Whereas a mixture of 2d (major) and 3 was
formed in the first case, the intramolecular product 3
was solely obtained in the second (entries 4 and 5).
Interestingly, 3 was also obtained without the addition
of BF3·OEt2, with only a slight decrease of the yield
(66%).14 The amount of Grignard reagent used is
important. A lower yield of 3 (37%) was observed when
using 3 equiv. of the reagent.15
With these optimal conditions in hands, we next studied
the scope of the reaction with various unsaturated
nitriles.16 As shown in Table 2, the reaction employing
cyclohexylmagnesium chloride proceeded smoothly to
afford the corresponding bicyclic cyclopropylamines.17

C. Laroche et al. / Tetrahedron Letters 44 (2003) 2485–2487
2487
References
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43.0, 59.2, 60.6, 68.8, 126.7, 128.0, 128.5, 139.1; MS (EI)
+
’
m/z (%): 202 (M , 13), 147 (2), 120 (4), 111 (14), 91
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1H NMR (CDCl3, 250 MHz) l: 0.65 (m, 2H), 0.95 (m,
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2.20 (d, J=10.4 Hz, 1H), 2.45 (m, 1H), 2.95 (d, J=10.4
Hz, 1H), 3.45 (s, 2H), 7.25–7.35 (m, 5H); 13C NMR
(CDCl3, 250 MHz) l: 18.4, 19.3, 24.7, 34.4, 50.9, 61.2,
62.7, 126.8, 128.1, 128.7, 138.8; MS (EI) m/z (%): 202
+
’
(M , 10), 187 (10), 161 (11), 132 (15), 120 (25), 91 (100).
13. In the paper cited in Ref. 12, the reaction of 1 with