Studies on the intramolecular Kulinkovich-de Meijere reaction of disubstituted alkenes bearing carboxylic amide groups

Article abstract of DOI:10.1039/b306719j

The intramolecular Kulinkovic-de Meijere cylcopropanation of some distributed alkenes bearing amide groups was studied. These reactions proved to be moderately efficient but highly distereoselective: single diastereoisomers were obtained from diastereoiso

Full text of DOI:10.1039/b306719j

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Studies on the intramolecular Kulinkovich–de Meijere reaction of
disubstituted alkenes bearing carboxylic amide groups
Nouara Ouhamou and Yvan Six*
Institut de Chimie des Substances Naturelles, U.P.R. 2301 du C.N.R.S., Avenue de la Terrasse,
9
1198 Gif-sur-Yvette, France. E-mail: Yvan.Six@icsn.cnrs-gif.fr; Fax: 33 (1) 69 07 72 47;
Tel: 33 (1) 69 82 30 83
Received 16th June 2003, Accepted 31st July 2003
First published as an Advance Article on the web 5th August 2003
1
,2-Disubstituted olefins bearing an acetamide group were
To the best of our knowledge, apart from special cases like
9 10,11
found to undergo intramolecular Kulinkovich–de Meijere
cyclopropanation in moderate yield but almost complete
diastereoselectivity.
cycloalkenes or conjugated dienes,
the only disubstituted
alkenes having been reported to give cyclopropyl amines or
2
alcohols after ligand exchange with dialkoxy(η -alkene)-
titanium complexes are (Z)-pent-2-ene and (E)-hex-3-ene, in
modest yield and with poor diastereoselectivity.
1–4
12
The de Meijere variation of the Kulinkovich reaction is an
efficient method for the synthesis of cyclopropyl amines from
carboxylic amides. It was initially performed by treating the
We reasoned that in the case of intramolecular reactions,
better results were likely to be achieved, the amide group being
able to coordinate to the titanium and direct the ligand
exchange process. Indeed, the related intramolecular cyclo-
propanation of a gem-disubstituted alkene with a nitrile in
good yield (Szymoniak’s variation of the Kulinkovich reac-
tion) has just been described. This prompts us to report the
preliminary results of our own investigations.
Four alkenes (Z)-2a, (E)-2a, (Z)-2b and (Z)-2c were pre-
5
amide with a stoichiometric amount of Ti(Oi-Pr) and more
4
than two equivalents of a Grignard reagent. The commonly
accepted mechanism operates via a dialkoxytitanacyclopropane
intermediate 1, arising from an initially formed dialkoxy-
2
13
14
(
dialkyl)titanium complex. Organotitanium species 1 have6
been demonstrated to undergo ligand exchange with alkenes.
This provides an easy access to more substituted products, and
allows intramolecular reactions to be performed in an efficient
pared and put under study using a modification of a literature
7
15
and convenient way (Scheme 1).
procedure. Four types of products were isolated and identi-
fied: the expected cyclopropyl amines 3, secondary amines 4,
16
cyclopropyl amines 5 and tertiary amines 6 (Scheme 3).
Scheme 1
Scheme 3
We have recently developed a novel two-step sequence featur-
ing an intramolecular Kulinkovich–de Meijere reaction and an
intramolecular Friedel–Crafts type alkylation leading to nitro-
Amines 4 might be formed by direct attack of the starting
amides by the Grignard reagent. We believe products 5 and 6
stem from a common intermediate 7 resulting from attack of
8
2
gen-containing polycyclic systems (Scheme 2). In a view to
the amide group by the in situ-generated dialkoxy(η -cyclo-
applying this method to the total synthesis of alkaloids, we
were interested in the possibility of using disubstituted olefins
as starting materials.
pentene)titanium complex before the ligand exchange takes
place (Scheme 4). To the best of our knowledge, only one report
describing a process similar to the one that leads to the
12
unexpected amines 6 can be found in the literature. In our
case, the mechanism proposed by the authors is inconsistent
with our observation that replacing titanium() iso-propoxide
with titanium() tert-butoxide or titanium() cresylate com-
pletely suppresses the formation of 6. Although further studies
are needed, we tentatively propose the mechanism depicted in
Scheme 4 that involves intramolecular hydride shift from one of
the iso-propoxide ligands of titanium.
Various solvents were used: heptane, toluene, diethyl ether
and tetrahydrofuran. Our best results are presented in Table 1.
Scheme 2
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 0 7 – 3 0 0 9
3007

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a
Table 1 Intramolecular Kulinkovich–de Meijere cyclopropanations from disubstituted alkenes
b
c
Starting amide
Solvent
Toluene
Cyclopropyl amine (yield)
Other isolated products (yield)
(Z)-2a
(E)-2a
(Z)-2b
Starting material (19%)
Amine (Z)-4a (17%)
Amines (Z)-5a and (Z)-6a (12%)
Et O
Starting material (35%)
Amine (E)-4a (12%)
Amines (E)-5a and (E)-6a (12%)
2
Et O
Starting material (19%)
Amine (Z)-4b (7%)
Amines (Z)-5b and (Z)-6b (19%)
2
(
Z)-2c
THF
Starting material (59%)
a
b
In each case 1.5 equiv. of Ti(Oi-Pr) and 4.0 equiv. of c-C H MgCl were used. (cis) and (trans) refer to the relative configurations of the amino and
4
5
9
c
d
ethyl groups of the cyclopropanes 3. After purification by neutral alumina (activity 2) column chromatography. The yield was 12% when the
reaction was performed in toluene.
ation of (trans)-3c was determined by two-dimensional
NOESY NMR spectroscopy. The high diastereoselectivity of
the cyclopropanation may be rationalised as depicted in
Scheme 5. After ligand exchange with the originally formed di-
2
iso-propyloxy(η -cyclopentene)titanium complex and cyclis-
ation onto the amide, an oxatitanacyclopentane intermediate is
formed. Subsequent carbon–oxygen bond cleavage and rotation
around a carbon–carbon single bond generates a zwitterion
where the titanium is placed in such a way as to reduce steric
interactions with the five-membered ring. In this conformation,
Scheme 4
Replacing cyclopentyl magnesium chloride with cyclohexyl
magnesium chloride had no beneficial effect on these reactions.
The intramolecular cyclopropanations were moderately effi-
cient but highly diastereoselective. In each case one of the two
possible diastereoisomers was either produced in trace amounts
1
or could not be detected at all by H NMR analysis of the crude
product. It is also noteworthy that (E)-2a performed less well
17
than the corresponding (Z) alkene (Z)-2a. Only poor conver-
sion occured from the indole derivative (Z)-2c in all the sol-
vents listed above. We have no satisfactory explanation for this
fact at present (compare with the result shown in Scheme 2).
The determination of the relative configuration of (trans)-3a
was based on two-dimensional ROESY NMR spectroscopy
and on the value of the coupling constant between the two
3
cyclopropyl vicinal protons ( J = 5 Hz, in agreement with the
18
trans relationship). For (cis)-2a, which was a different com-
pound as shown by NMR spectroscopy, the other possible
stereochemistry was thus assigned. The stereochemistry of
(
trans)-3b was assigned on the basis of the coupling constant
3
between the cyclopropyl protons ( J = 5 Hz). Moreover, it dis-
played NMR signals very similar to those of (trans)-3a for the
ring protons alpha to the nitrogen atom. The relative configur-
Scheme 5
3
008
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 0 7 – 3 0 0 9

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cyclopropane ring-closure may proceed with inversion of con-
figuration by electrophilic substitution of the titanium with the
amino-stabilised carbonium ion.
2 O. G. Kulinkovich, S. V. Sviridov and D. A. Vasilevski, Synthesis,
991, 234.
Theoretical study: Y.-D. Wu and Z.-X. Yu, J. Am. Chem. Soc., 2001,
23, 5777–5786.
1
3
1
Interestingly, aerobic oxidation occurred more or less exten-
sively when aminocyclopropanes 3 were flash-chromatographed
on silica gel. This autocatalytic process has been described
4
5
Review: O. G. Kulinkovich, Chem. Rev., 2003, 103, 2597–2632.
V. Chaplinski and A. de Meijere, Angew. Chem., Int. Ed. Engl., 1996,
35, 413–414.
19
recently. Less substituted but otherwise very similar com-
pounds previously prepared by us from mono-substituted
6 O. G. Kulinkovich, A. I. Savchenko, S. V. Sviridov and D. A. Vasilev-
ski, Mendeleev Commun., 1993, 230–231.
7 Review: O. G. Kulinkovich and A. de Meijere, Chem. Rev., 2000,
8
alkenes have proven much less sensitive. The enhanced reactivi-
1
00, 2789–2834.
ties of cyclopropanes 3 are probably due to a lowering of their
ionisation potentials by the extra ethyl group. The phenoxy sub-
stitution of 3b would be expected to lower it further. Indeed,
oxidation of 3b was especially facile: after running silica gel
thin-layer chromatographies of this compound, only peroxides
8
9
L. Larquetoux and Y. Six, manuscript in preparation.
J. Lee, H. J. Kim and J. K. Cha, J. Am. Chem. Soc., 1996, 118, 4198–
4199.
10 C. M. Williams, V. Chaplinski, P. R. Schreiner and A. de Meijere,
Tetrahedron Lett., 1998, 39, 7695–7698.
11 G.-D. Tebben, K. Rauch, C. Stratmann, C. M. Williams and A. de
Meijere, Org. Lett., 2003, 5, 483–485.
2 A. de Meijere, C. M. Williams, A. Kourdioukov, S. V. Sviridov,
V. Chaplinski, M. Kordes, A. I. Savchenko, C. Stratmann and
M. Noltemeyer, Chem. Eur. J., 2002, 8, 3789–3801.
20
(
trans)-8b and (cis)-8b could be detected. Accordingly, when
the crude product of the reaction from (Z)-2b was purified by
silica gel column chromatography, no expected cyclopropyl
amine 3b was obtained at all, but diastereoisomers 8b were iso-
lated in 31% yield (Scheme 6). Diastereoselectivity was poor,
1
13 P. Bertus and J. Szymoniak, Chem. Commun., 2001, 1792–1793.
14 C. Laroche, P. Bertus and J. Szymoniak, Tetrahedron Lett., 2003, 44,
19
which is consistent with a literature precedent. Replacing
silica gel with neutral alumina (activity 2) suppressed the
formation of these peroxides and enabled the purification of
cyclopropyl amines 3.
2
485–2487.
1
1
5 J. Lee and J. K. Cha, J. Am. Chem. Soc., 1997, 62, 1584–1585.
6 Experimental procedure for the preparation of (trans)-3a: titaniu-
m() iso-propoxide (750 µmol, 221 µL) was added at room temper-
ature to a solution of (Z)-2a (500 µmol, 109 mg) in toluene (20 mL).
Cyclopentylmagnesium chloride (2.00 mmol, 2.14 M in Et O, 935
2
µL) was then added dropwise. The mixture turned yellow, and then
black. After 15 minutes of stirring at room temperature, water (100
mL) was added carefully, followed by diethyl ether (100 mL). The
aqueous layer was extracted with diethyl ether (2 × 50 mL). The
combined organic phases were dried over sodium sulfate, filtered
1
and concentrated. H NMR analysis of the crude product revealed
that it contained only traces of the diastereoisomer (cis)-3a. Purifi-
cation by flash column chromatography led to the isolation of a
3
3/67 mixture of (Z)-5a and (Z)-6a (17 mg, 8% and 4% respect-
ively), starting material (Z)-2a (20 mg, 19%), and a 70/30 mixture of
trans)-3a and (Z)-4a (56 mg, 40% and 17% respectively). (trans)-3a
could be purified further by flash column chromatography. (trans)-
3a: colourless liquid (Found: C, 83.27; H, 9.63. C14 19N requires C,
3.53; H, 9.51%); νmax(film)/cm 2959, 2931, 2870, 1601, 1500, 1482,
51, 695; δH (300 MHz; CDCl ; Me Si) 0.78 (1H, td, J 7 and 5 Hz,
(
Scheme 6
H
Ϫ1
8
7
3
4
In summary, we have studied the intramolecular Kulinko-
vich–de Meijere cyclopropanation of some disubstituted
alkenes bearing amide groups. These reactions proved to be
moderately efficient but highly diastereoselective: single dia-
stereoisomers were obtained from diastereoisomerically pure
alkenes. We believe the modesty of the yields arises from the
poor efficiency of the ligand exchange step. Our next studies
will be devoted to the resolution of this problem.
cyclopropane CH), 0.97 (1H, t, J 5 Hz, cyclopropane CH), 1.06 (3H,
t, J 7 Hz, CH ), 1.45 (2H, m, CH CH ), 1.48 (3H, s, CH ), 1.95 (1H,
3
2
3
3
ddd, J 12, 9 and 3 Hz, CH ), 2.29 (1H, dtd, J 12, 9 and 5 Hz, CH ),
2
2
2.87 (1H, q, J 9 Hz, NCH ), 3.93 (1H, td, J 9 and 3 Hz, NCH ), 6.75
2
2
(1H, t, J 7 Hz, ArH), 6.79 (2H, d, J 8 Hz, ArH), 7.22 (2H, dd, J 8
and 7 Hz, ArH); δ (75.4 MHz; CDCl ; Me Si) 14.1, 15.1, 23.4, 26.8,
C
3
4
3
1
1.1, 32.3, 46.9, 53.4, 116.3, 117.6, 128.8, 149.9; m/z (EI) 172, 173,
86, 201 (MH ).
ϩ
1
7 This is in agreement with the earlier observation that (Z)-pent-2-ene
gave a better result than (E)-hex-3-ene in an intermolecular Kulink-
ovich–de Meijere cyclopropanation. See ref. 12.
8 D. J. Patel, M. E. H. Howden and J. D. Roberts, J. Am. Chem. Soc.,
1963, 85, 3218–3223.
9 K. Wimalasena, H. B. Wickman and M. P. D. Mahindaratne, Eur. J.
Org. Chem., 2001, 3811–3817.
Acknowledgements
1
1
2
We wish to thank the Centre National de la Recherche
Scientifique (C.N.R.S.) for funding.
0 (trans)-8b and (cis)-8b could not be separated. Their structures have
been assigned on the basis of mass, infra-red, 1D and 2D NMR
spectroscopies. Their relative stereochemistries were determined
according to the coupling constants found between the ring-junction
Notes and references
1
O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevskii and T. S. Prityt-
3
skaya, Zh. Org. Khim., 1989, 25, 2244–2245 (J. Org. Chem. USSR
proton and the CH proton alpha to the ethyl group: J = 2.5 Hz in
3
(
Engl. Trans.), 1989, 25, 2027–2028).
(trans)-8b and J = 5 Hz in (cis)-8b.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 0 7 – 3 0 0 9
3009