Substituted cyclopropylamines from pyridinium ylide: Complexes of pentacarbonyl tungsten and enamines

Article abstract of DOI:10.1055/s-1998-2181

Enamines derived from cyclic ketones react very easily with a series of pyridinium ylide complexes of tungsten pentacarbonyl (CO)₅W^--C(R)(H) Py⁺ to give either at room temperature (for R = Ph) or at 40°C (for R = alkyl) substituted cyclopropylamines as mixtures of stereoisomers.

Full text of DOI:10.1055/s-1998-2181

1
534
Papers
SYNTHESIS
Substituted Cyclopropylamines from Pyridinium Ylide: Complexes of Pentacarbonyl
Tungsten and Enamines
Blanca Martín-Vaca, Thomas Durand-Réville, Max Audouin, Henri Rudler*
Laboratoire de Synthèse Organique et Organométallique, UMR 7611, Université P. et M. Curie,
Tour 44-45, 4 place Jussieu, F-75252 Paris Cedex 5, France
Fax +33(1)44277089; E-mail: rudler@ccr.jussieu.fr
Received 1 February 1998; revised 9 March 1998
Abstract: Enamines derived from cyclic ketones react very easily
with a series of pyridinium ylide complexes of tungsten pentacar-
–
+
bonyl (CO) W –C(R)(H) Py to give either at room temperature
5
(for R = Ph) or at 40˚C (for R = alkyl) substituted cyclopropyl-
amines as mixtures of stereoisomers.
Key words: enamines, cyclopropanation, aminocyclopropanes,
tungsten ylides
Cyclopropanes are important building blocks in organic
synthesis; those bearing an amino group are part of a va-
riety of biologically active compounds or their precusors.1
Whereas a few classical entries in the synthesis of cyclo-
propylamines already existed,2–6 new access to such struc-
7
,8
tures appeared recently in the literature.
The purpose of this paper is to describe a new approach to
highly substituted aminocyclopropanes which broadens
the range of accessible derivatives of this family of com-
pounds. This new approach relies on the reaction of shelf-
stable pyridinium ylide complexes of the general structure
+
(
CO) W–C(R)(H)Pyridine (1), the preparation of which
5
from Fischer-type alkoxycarbene complexes of tungsten
9
and dihydropyridines has recently been outlined. These
N-ylide complexes result from the stabilization of alkyl-
idene complexes of W(0) by pyridine. Although they react
only sluggishly with simple olefins to give cyclopropanes,
Scheme 1
satisfactory results were observed in the case of more nu- for the exo-isomer (trans-relationship). Application of the
9
cleophilic olefins such as enol ethers. We surmised that same separation technique to the cyclopropylamines ob-
enamines might be the substrates of choice for such cyclo- tained from enamine 4a led to an unexpected result: only
propanation reactions due to the nucleophilic character of one cyclopropylamine, the endo-isomer could be isolated
their double bond. And this was indeed the case. Thus, in 45% yield. The fate of the exo-isomer could, however,
when a slight excess of an enamine in dichloromethane be established since a second product, the known 2-ben-
10
was added to a solution of the benzylidene ylide complex zylcyclopentanone was also isolated in 46% yield. Thus
in the same solvent, a fast consumption of the ylide was a rearrangement of the exo-isomer, induced by silica gel,
observed by TLC. That the reaction took place instanta- followed by hydrolysis, had taken place. A similar behav-
1
neously was confirmed by H NMR spectroscopy: in the iour was observed for the cyclopropylamines derived
case of the enamine 3a, derived from cyclopentanone and from the enamine of cyclohexanone. It led, after chroma-
morpholine, the formation of a 1:1 mixture of two isomer- tography to a mixture of cyclopropylamines (21% exo,
ic cyclopropylamines was observed. This was also the 41% endo) together with 21% of the rearranged/hydro-
11
case for the enamine 4b derived from cyclopentanone and lyzed product, 2-benzylcyclohexanone: thus only partial
pyrrolidine (Table 1).
hydrolysis/rearrangement of the exo-isomer took place.
No such rearrangements were however observed in the
cases of the cyclopropylamines derived from the pyridin-
ium ylides 1b and 1c [R = Me, (CH ) Ph] which were eas-
In the first experiment leading to 7a,b, separation of the
two isomers was easily achieved by column chromatogra-
phy on silica gel, the exo-isomer obtained in 48% yield
being the less polar compound, whereas the more polar
2
3
ily purified by chromatography on silica gel.
endo-isomer was isolated in 30% yield. Their geometry As far as the mechanism of this new cyclopropanation re-
was assessed on the grounds of the coupling constants be- action is concerned, it is likely that the first step of the
tween the two vicinal hydrogens on the cyclopropane, cyclopropanation is a S 2 type reaction with the concerted
N
which is higher for the endo-isomer (cis-relationship) than formation of a carbon–carbon bond and displacement of

October 1998
SYNTHESIS
1535
Table 1. Reactions Between Ylide Complexes and Enamines
Starting
materials
Products
R
n
X
Reaction Conditions
Yield
(%)
exo: endo
Ratiob
T (°C)
t (min)
1a + 2a
1a + 2b
1a + 3a
1a + 3b
1a + 4a
1a + 4b
1b + 2a
1b + 2b
1b + 3a
1b + 4a
1c + 2a
1c + 3a
1c + 4a
1d + 4a
5a, 5b
6a, 6b
7a, 7b
8a, 8b
9b
10a, 10b
11a, 11b
12a
13a, 13b
14a
15a, 15b
16a, 16b
17a
Ph
Ph
Ph
Ph
Ph
Ph
1
2
1
2
1
2
1
2
1
1
1
1
1
1
CH CH2
20
20
20
20
20
20
40
40
40
40
40
40
40
40
5
5
5
5
5
70
50
80
50
91
83
38
16
56
32
72
67
66
67
1 : 1.9
1 : 1.5
1.6 : 1
1.5 : 1
0 : 1c
1 : 2
4.9 : 1
1 : 0c
1.6 : 1
1 : 0c
1 : 1
2
CH CH2
2
CH O
2
CH O
2
CH2
CH2
5
Me
Me
Me
Me
(CH ) Ph
(CH ) Ph
(CH ) Ph
(CH ) CH(OMe)
CH CH2
240
360
420
90
210
300
120
420
2
CH CH2
2
CH O
2
CH2
CH CH2
2
3
2
CH O
3.8 : 1
1 : 0
1 : 0
2
3
2
CH2
CH2
2
3
18
2
4
2
a
b
c
All reactions were carried out in CH Cl .
Ratio of isolated products.
Detected by NMR of the reaction mixture.
2
2
pyridine by the interaction of the nucleophilic β-carbon of
the enamine double bond with the quaternary carbon atom
of the ylide complex (Scheme 2). Interaction of the nega-
tively charged metal with the carbon of the iminium
would then lead to two diastereomeric tungstacyclobu-
tanes. Reductive elimination of the metal might finally
give the two isomeric cyclopropylamines. The remarkable
point is the ease by which the transfer of the alkylidene
group to the double bond takes place giving in high to me-
dium yields a large range of substituted cyclopropyl-
amines. This contrasts strongly with the observed reaction
of alkoxycarbene complexes of the Fischer-type which
led only in very modest yields and under rather harsh con-
ditions to mixtures of cyclopropylamines and ring-opened
1
d [R = (CH ) CH(OMe) ] into the cyclopropylamine 18
2
4
2
in 67% yield.
All reactions were carried out under Ar in predried glassware. Ylide
complexes 1a, 1b and 1c were prepared according to the literature
procedure.9 CH Cl2 was dried by distillation over P O5 and was
stored and transferred under Ar. Enamines were prepared from com-
mercially available ketones and amines according to the literature
procedures.1 Column chromatography was performed with Merck
silica gel (70–230 mesh) using various ratios of light petroleum ether
CH Cl and light petroleum ether/Et O as eluents. Instrumental anal-
2
2
3,14
1
2
products.
2
2
2
yses: NMR spectra were recorded on Bruker AC200 or ARX400 in-
struments, in CDCl or C D . Chemical shifts (δ) are listed in ppm
3
6
6
relative to TMS and coupling constants (J) are given in Hertz (Table
).
2
Aminocyclopropanes 5–18; General Procedure:
Enamine 2–4 (2 mmol) was added to a solution of the ylide complex 1
(
0.5 mmol) in CH Cl (10 mL). The mixture was stirred until complete
2 2
consumption of the ylide complex (temperatures and time of reaction
are gathered in Table 1). The solvent was evaporated under vacuum and
the residue was transferred onto a column of silica gel. Elution with
petroleum ether/CH Cl mixtures gave complex W(CO) Py and with
2
2
5
petroleum ether/Et O mixtures the aminocyclopropanes.
2
1-(6-Phenylbicyclo[3.1.0]hex-1-yl)piperidines:
5
a: exo-isomer; R 0.92 (EtOAc/cyclohexane, 20:80); light petroleum
Scheme 2
f
ether/Et O (98:2) as eluent; yield: 24%.
2
5
b: endo-isomer; R 0.44; light petroleum ether/Et O (90:10) as elu-
f
2
ent; yield: 46%.
HRMS: m/z Obsd (Calcd) for C H N : 241.1830 (241.1829).
Although polymerization rather than cyclopropanation is
observed in the case of enamines derived from linear ke-
tones, no limitations as far as the nature of the R group in
the ylide complexes is concerned have been observed up
to now: support to this comes from the transformation of
+
17
23
1-(7-Phenylbicyclo[4.1.0]hept-1-yl)piperidines:
6a: exo-isomer; R 0.92 (EtOAc/cyclohexane, 25:75); light petroleum
f
ether/Et O (98:2) as eluent; yield: 20%.
2

1
536
Papers
Table 2. NMR Data of Products 5–18
SYNTHESIS
Prod-
uct
1H NMRa
δ, J (Hz)
13C NMRa
δ
5
a
1.18–1.31 (m, 7 H, H-4', 3 CH ), 1.52 (dd, 1 H, J = 4.6, 4.6, H- 21.5 (C-4), 23.3 (C-3), 24.8 (CH ), 26.3 (2 CH ), 27.5 (C-5), 31.7
2 2 2
2
), 1.59–1.68 (m, 3 H, H-4, H-5', H-3'), 1.75 (m, 1 H, H-5), 1.82 (C-6), 33.9 (C-2), 50.7 (2 NCH ), 60.8 (C-1), 124.6, 126.9, 128.2,
2
(d, 1 H, J = 4.6, H-6), 1.93 (m, 1 H, H-3), 2.27–2.36 (m, 4 H, 2 139.9 (Ph)
NCH ), 7.03–7.20 (m, 5 H, Ph)
2
5
b
0.07 (m, 1 H, H-4'), 1.33 (m, 1 H, H-4), 1.47 (m, 2 H, CH ), 1.62 20.9 (C-5), 22.7 (C-4), 24.7 (CH ), 25.3 (C-3), 26.4 (2 CH ), 30.3
2
2
2
(
m, 6 H, H-3', 2 CH , H-5'), 1.69 (m, 1 H, H-2), 1.91 (m, 1 H, H- (C-2), 33.4 (C-6), 51.2 (2 NCH ), 59.2 (C-1), 125.9, 128.3, 128.5,
2
2
3
), 2.02 (m, 1 H, H-5), 2.28 (d, 1 H, J = 9.0, H-6), 2.67 (m, 2 H, 138.1 (Ph)
CHHNCHH), 2.85 (m, 2 H, CHHNCHH), 7.21–7.32 (m, 5 H,
Ph)
6
a
1.20–1.45 (m, 11 H, 3CH , H-2, H-3, H-3', H-5, H-5'), 1.54– 21.4 (C-3), 22.6 (C-4, C-5), 24.2 (C-6), 24.9 (CH ), 26.2 (2 CH ),
2 2 2
1
1
.62 (m, 1H, H-6'), 1.70–1.80 (m and d, 2 H, J = 6.6, H-7, H-4'), 29.2 (C-2), 36.8 (C-7), 49.5 (CH NCH ), 51.2 (C-1), 124.7,
.95 (m, 1 H, H-4), 2.11 (m, 1 H, H-6), 2.25 and 2.46 (m, 2 H 127.0, 127.9, 140.6 (Ph)
2 2
each, CH NCH ), 7.11–7.36 (m, 5 H, Ph)
2
2
6
b
0.46 (m, 1 H, H-4'), 0.97 (m, 2 H, H-2, H-5'), 1.14 (m, 1 H, H-4), 18.1 (C-6), 21.4 (C-3), 21.8 (C-4), 22.7 (C-5), 23.9 (C-2), 24.7
.30–1.41 (m, 2 H, H-5, H-6'), 1.46 (m, 2 H, CH ), 1.55–1.65 (CH ), 26.4 (2 CH ), 32.7 (C-7), 46.8 (C-1), 49.4 (2 NCH ),
1
2
2
2
2
(
m, 4 H, 2 CH ), 1.86–1.96 (m, 2 H, H-3, H-3'), 2.04 (m, 1 H, H-6), 125.8, 128.2, 131.0, 138.3 (Ph)
2
2
.10 (d, 1 H, J = 8.7, H-7), 2.71 (m, 4 H, 2 NCH ), 7.18–7.38
2
(m, 5 H, Ph)
7
a
1.41 (m, 1 H, H-4'), 1.69 (dd, 1 H, J = 4.3, 4.3, H-2), 1.74–1.82 23.5 (C-3), 28.5 (C-4), 29.3 (C-5), 31.6 (C-2), 33.1 (C-6), 49.6 (2
(
m, 3 H, H-4, H-5', H-4), 1.87 (m, 1 H, H-5), 1.98 (d, 1 H, J = NCH ), 60.1 (C-1), 67.3 (2 OCH ), 121.4, 125.0, 127.1, 128.4
2
2
4
.3, H-6), 2.05 (m, 1 H, H-3'), 2.47–2.52 (m, 4 H, 2 NCH2), (Ph)
3
.43–3.55 (m, 4 H, 2 OCH ), 7.13–7.28 (m, 5 H, Ph)
2
7
b
0.08 (m, 1 H, H-4'), 1.36 (m, 1 H, H-4), 1.60–1.68 (m, 2 H, H- 21.2 (C-4), 22.6 (C-3), 25.3 (C-5), 29.9 (C-6), 33.3 (C-2), 50.1 (2
3
', H-5'), 1.70 (m, 1 H, H-2), 1.91 (m, 1 H, H-5), 2.01 (m, 1 H, NCH ), 59.1 (C-1), 67.5 (2 OCH ), 126.0, 128.3, 128.9, 137.6
2
2
H-3), 2.28 (d, 1 H, J = 8.7, H-6), 2.70–2.75 (m, 2 H, (Ph)
CHHNCHH), 2.86–2.91 (m, 2 H, CHHNCHH), 3.74 (m, 4 H,
OCH ), 7.21–7.42 (m, 5 H, Ph)
2
8
8
9
1
1
1
a
1.21–1.49 (m, 5 H, H-2, H-3, H-3', H-5, H-5'), 1.64 (m, 1 H, H- 21.3 (C-3), 22.4 (C-4), 22.5 (C-5), 24.1 (C-6), 28.2 (C-2), 36.5 (C-
6
'), 1.74 (m, 1 H, H-4'), 1.80 (d, 1 H, J = 6.4, H-7), 1.95 (m, 1 H, 7), 48.4 (2 NCH ), 50.3 (C-1), 67.3 (2 OCH ), 125.1, 127.2,
2
2
H-4), 2.13 (m, 1 H, H-6), 2.53 (m, 4 H, 2 NCH ), 3.49 (m, 4 H, 128.0, 129.9 (Ph)
2
2
OCH ), 7.12–7.34 (m, 5 H, Ph)
2
b
0.37 (m, 1 H, H-4'), 0.82–0.94 (m, 2 H, H-5, H-5'), 1.04 (m, 1 H, 18.8 (C-6), 21.8 (C-3), 22.3 (C-4), 23.1 (C-5), 24.1 (C-2), 32.9 (C-
H-4), 1.26–1.38 (m, 2 H, H-2, H-6'), 1.85–1.75 (m, 2 H, H-3, H- 7), 46.9 (C-1), 49.1 (2 NCH ), 68.0 (2 OCH ), 126.6, 128.9,
2
2
3
4
'), 1.92–1.99 (m, 2 H, H-6 and inside d, J = 9.6, H-7), 2.67 (m, 135.6, 138.4 (Ph)
H, 2 NCH ), 3.62 (m, 4 H, 2 OCH ), 7.10–7.22 (m, 5 H, Ph)
2
2
b
0.10 (m, 1 H, H-4'), 1.34 (m, 1 H, H-4), 1.60–1.75 (m, 3 H, H- 22.5 (C-4), 22.7 (C-3), 23.9 (CH ), 25.4 (C-5), 29.5 (C-2), 31.0
2
2
5
2
, H-3', H-5'), 1.84 (m, 4 H, 2 CH ), 1.84–2.02 (m, 2 H, H-3, H- (C-6), 49.6 (2 NCH ), 55.0 (C-1), 125.9, 128.2, 129.0, 130.0 (Ph)
), 2.35 (d, 1 H, J = 9.1 Hz, H-6), 2.78 (m, 2 H, CHHNCHH),
.87 (m, 2 H, CHHNCHH), 7.20–7.35 (m, 5 H, Ph)
2
2
0a
0b
1a
1.15–1.55 (m, 7 H, H-2, H-3', H-3, H-5', H-5), 1.60–1.80 (m, 3 20.0 (C-3), 21.7 (C-4), 21.8 (C-5), 22.9 (C-6), 23.0 (2 CH ), 27.4
2
H, H-4', CH ), 1.74 (d, 1 H, J = 6.2, H-7), 1.95 (m, 1 H, H-6'), (C-2), 35.3 (C-7), 44.9 (C-1), 45.9 (2 NCH ), 123.5, 126.0, 127.3,
2
2
2
.00–2.10 (m, 2 H, H-4, H-6), 2.30 (m, 2 H, CHHNCHH), 2.57 139.8 (Ph)
(m, 2 H, CHHNCHH), 7.00–7.25 (m, 5 H, Ph)
0.38 (m, 1 H, H-4'), 0.93 (m, 2 H, H-5', H-5), 1.08 (m, 1 H, H- 19.4 (C-6), 21.4 (C-3), 22.0 (C-4), 23.2 (C-2, C-5), 24.1 (CH2),
4
3
2
), 1.37 (m, 2 H, H-2, H-6'), 2.73 (m, 4 H, 2 CH ), 1.80–1.92 (m, 31.4 (C-7), 41.8 (C-1), 48.1 (2 NCH ), 126.2, 128.5, 131.5, 138.5
H, H-3', H-3, H-6), 2.05 (d, 1 H, J = 10.0, H-7), 2.90 (m, 4 H, (Ph)
2
2
NCH ), 7.12–7.25 (m, 5 H, Ph)
2
0.86 (m, 1 H, H-6), 0.91 (m, 1 H, H-2), 1.23 (m, 1 H, H-4'), 1.39 11.5 (CH ), 20.5 (C-6), 22.1 (C-4), 22.6 (C-5), 25.0 (CH ), 26.7
3
2
(
d, 3 H, J = 6.0, CH ), 1.50 (m, 2 H, CH ), 1.58 (m, 1 H, H-4), (2 CH ), 27.1 (C-3), 31.3 (C-2), 51.3 (2 NCH ), 57.2 (C-1)
3
2
2
2
1
1
.64 (m, 1 H, H-3'), 1.66 (m, 4 H, 2 CH ), 1.73 (m, 1 H, H-5'),
.79 (m, 1 H, H-3), 1.97 (m, 1 H, H-5), 2.57 (m, 2 H,
2
CHHNCHH), 2.72 (m, 2 H, CHHNCHH)

October 1998
SYNTHESIS
1537
Prod-
uct
1H NMRa
δ, J (Hz)
13C NMRa
δ
1
1b
0.90 (d, 3 H, J = 6.8, CH ), 1.19 (m, 1 H, H-6), 1.25–1.95 (m, 6 8.9 (CH ), 25.2 (C-4, C-6), 25.3 (C-5), 25.7 (CH ), 27.3 (2 CH ),
3 3 2 2
H, H-3', H-3, H-4', H-4, H-5', H-5), 1.31 (m, 2 H, CH ), 1.40 (m, 27.6 (C-3), 30.4 (C-2), 52.0 (2 NCH ), 60.1 (C-1)
2
2
1
2
H, H-2), 1.52 (m, 4 H, 2 CH ), 2.40 (m, 2 H, CHHNCHH),
.51 (m, 2 H, CHHNCHH)
2
1
2a
0.39 (m, 1 H, H-2), 0.45 (m, 1 H, H-7), 1.02 (m, 1 H, H-4'), 1.09 13.0 (CH ), 22.4 (C-4), 23.0 (C-6), 23.3 (C-5), 24.8 (C-3), 25.6
3
(
d, 3 H, J = 5.6, CH ), 1.13 (m, 1 H, H-5'), 1.20 (m, 1 H, H-5), (CH ), 26.0 (C-7), 27.2 (2 CH ), 27.3 (C-2), 50.6 (2 NCH ), 53.3
3
2
2
2
1
.24 (CH ), 1.28 (m, 1 H, H-4), 1.32 (m, 1 H, H-6'), 1.45 (m, 4 (C-1)
2
H, 2 CH ), 1.58 (m, 1 H, H-3'), 1.76 (m, 1 H, H-3), 1.99 (m, 1
2
H, H-6), 2.45 (m, 4 H, 2 NCH2)
13a
13b
14a
15a
0.73 (m, 1 H, H-2), 0.76 (m, 1 H, H-6), 1.07 (d, 3 H, J = 6.0, 11.56 (CH ), 20.3 (C-6), 22.0 (C-4), 22.8 (C-5), 27.0 (C-3), 30.8
3
CH ), 1.14 (m, 1 H, H-4'), 1.51 (m, 1 H, H-5'), 1.59 (m, 1 H, H- (C-2), 50.2 (2 NCH ), 56.6 (C-1), 67.6 (2 OCH )
3
2
2
3
2
4
'), 1.64 (m, 1 H, H-3), 1.67 (m, 1 H, H-4), 1.86 (m, 1 H, H-5),
.49 (dt, 2 H, J = 11.2, 4.6, CHHNCHH), 2.64 (dt, 2 H, J = 11.2,
.6, CHHNCHH), 3.63 (t, 4H, J = 4.6, 2 OCH2)
0.93 (d, 3 H, J = 6.8, CH ), 1.25 (m, 1 H, H-2), 1.32 (m, 1 H, H- 7.8 (CH ), 20.0 (C-6), 23.9 (C-4), 24.4 (C-5), 26.3 (C-3), 28.8 (C-
3
3
4
1
'), 1.42 (m, 1 H, H-5'), 1.45 (m, 1 H, H-6'), 1.70 (m, 1 H, H-3'), 2), 49.9 (2 NCH ), 58.4 (C-1), 67.4 (2 OCH )
.75 (m, 1 H, H-4), 1.90 (m, 1 H, H-5), 2.04 (m, 1 H, H-3), 2.51
2
2
(dt, 2 H, J = 11.2, 4.6, CHHNCHH), 2.65 (dt, 2 H, J = 11.2, 4.6,
CHHNCHH), 3.63 (t, 4 H, J = 4.6, 2 OCH2)
0.72 (m, 1 H, H-2), 0.79 (m, 1 H, H-6), 1.07 (d, 3 H, J = 6.0, 11.8 (CH ), 20.3 (C-6), 22.0 (C-4), 22.3 (C-5), 24.4 (CH ), 27.1
3
2
CH ), 1.13 (m, 1 H, H-4'), 1.19 (m, 1 H, H-3'), 1.52 (m, 1 H, H- (C-3), 31.2 (C-2), 49.2 (2 NCH ), 52.3 (C-1)
3
2
5
'), 1.60 (m, 1 H, H-3), 1.70 (m, 4 H, 2 CH ), 1.79 (m, 1 H, H-
2
5
), 1.86 (m, 1 H, H-4), 2.57 (m, 2 H, CHHNCHH), 2.70 (m, 2
H, CHHNCHH)
0.67 (m, 1 H, H-6), 0.79 (m, 1 H, H-2), 1.10 (m, 1 H, H-4'), 1.36 22.1 (C-4), 22.9 (C-5), 25.0 (CH ), 26.4 (C-7), 26.6 (2 CH , C-6),
2
2
(
(
(
(
m, 2 H, CH ), 1.47 (m, 1 H, H-5'), 1.49 (m, 4 H, 2 CH ), 1.54 27.2 (C-3), 30.1 (C-2), 32.1 (C-8), 36.3 (C-9), 51.3 (2 NCH2),
2
2
m, 1 H, H-4), 1.58 (m, 2 H, CH -7), 1.64 (m, 1 H, H-3'), 1.72 57.5 (C-1), 125.5, 128.2, 128.4, 143.3 (Ph)
2
m, 1 H, H-3), 1.75 (m, 2 H, CH -8), 1.83 (m, 1 H, H-5), 2.42
2
m, 2 H, CHHNCHH), 2.58 (m, 2 H, CHHNCHH), 2.61 (m, 2
H, CH -9), 7.15–7.28 (m, 5 H, Ph)
2
1
5b
1.13 (m, 1 H, H-6), 1.22 (m, 2 H, CH -7), 1.25 (m, 1 H, H-4'), 20.1 (C-5), 23.4 (C-7), 24.4 (C-3), 24.9 (CH ), 26.6 (2 CH ), 27.1
2
2
2
1
.31 (m, 1 H, H-5'), 1.35 (m, 2 H, CH ), 1.37 (m, 1 H, H-2), 1.39 (C-4), 29.8 (C-6), 32.1 (C-2), 32.4 (C-8), 36.1 (C-9), 50.4 (2
2
(
m, 1 H, H-3'), 1.50 (m, 4 H, 2 CH ), 1.68 (m, 2 H, CH -8), 1.70 NCH ), 59.5 (C-1), 125.7, 128.3, 128.5, 142.7 (Ph)
2 2 2
(
2
m, 1 H, H-4), 1.82 (m, 1 H, H-3), 1.95 (m, 1 H, H-5), 2.42 (m,
H, CHHNCHH), 2.55 (m, 2 H, CH -9), 2.58 (m, 2 H, CH-
2
HNCHH), 7.04–7.18 (m, 5 H, Ph)
1
1
1
6a
6b
0.66 (dt, 1 H, J = 8.4, 4.2, H-6), 0.73 (t, 1 H, J = 4.2, H-2), 1.08 22.0 (C-4), 23.1 (C-5), 26.3 (C-7), 26.7 (C-6), 27.2 (C-3), 29.7 (C-
m, 1 H, H-4), 1.36 (m, 1 H, H-7'), 1.42–1.63 (m, 7H, H-3, H-3', 2), 32.1 (C-8), 36.2 (C-9), 50.3 (2 NCH ), 56.9 (C-1), 67.5 (2
(
2
H-4, H-5', H-7, CH -8), 1.78 (td, J = 11.5, 8.5, H-5), 2.42 (dt, 2 OCH ), 125.6, 128.2, 128.4, 143.1 (Ph)
2
2
H, J = 11.5, 4.6, CHHNCHH), 2.57 (m, 4 H, CHHNCHH, CH2-
9
), 3.53 (t, 4 H, J = 4.6, OCH ), 7.07–7.23 (m, 5 H, Ph)
2
1.03 (dt, 1 H, J = 8.0, 7.6, H-6), 1.15–1.37 (m, 6 H, H-2, H-3', 20.6 (C-5), 23.3 (C-7), 24.4 (C-3), 26.9 (C-4), 29.2 (C-2), 31.5 (C-
H-4', H-5', CH -7), 1.74 (q, 2 H, J = 7.9, CH -8), 1.79–1.98 (m, 6), 32.3 (C-8), 36.1 (C-9), 49.9 (2 NCH ), 58.9 (C-1), 67.4 (2
2
2
2
2
1
9
H, H-3, H-4), 2.05 (td, 1 H, J = 11.4, 6.0, H-5), 2.55 (dt, J = OCH ), 125.7, 128.3, 128.4, 142.7 (Ph)
1.2, 4.6, CHHNCHH), 2.64–2.73 (m, 4 H, CHHNCHH, CH2-
2
), 3.67 (t, 4 H, J = 4.6, OCH ), 7.18–7.33 (m, 5 H, Ph)
2
7a
8
0.67 (dt, 1 H, J = 8.0, 4.0, H-6), 0.84 (t, 1 H, J = 4, H-2), 1.15 22.0 (C-4), 22.6 (C-5), 24.5 (2 CH ), 26.7 (C-3, C-6), 27.3 (C-7),
2
(
m, 1 H, H-4'), 1.40–1.80 (m, 11 H, H-3', H-3, H-4, H-5', H-5, 30.1 (C-2), 32.3 (C-8), 36.2 (C-9), 49.3 (2 NCH ), 52.6 (C-1),
2
CH -7, CH -8, CH ), 2.50–2.85 (m, 6 H, NCH , CH -9), 7.07– 125.5, 128.2, 128.4, 143.3 (Ph)
2
2
2
2
2
7
.22 (m, 5 H, Ph)
1
0.65 (m, 1 H, H-6), 0.84 (m, 1 H, H-5), 1.18 (m, 1 H, H-3), 1.30– 20.70 (CH ), 21.95 (CH ), 24.54 (2 CH ), 24.7 (CH ), 26.6 (C-6,
2
2
2
2
1
.80 (m, 6 H, 2 H-4, H-3, H-2), 1.85 (m, 1 H, H-2), 2.59 (m, 2 C-4), 29.7 (CH ), 30.0 (CH , C-5), 32.63 (CH ), 49.8 (NCH ),
2 2 2 2
H, NCH ), 2.74 (m, 2 H, NCH ), 3.33 (s, 6 H, 2 OCH ), 4.39 (t, 52.7 (OCH ), 104.7 (CHOCH )
2
3
3
3
3
1
H, J = 5.6 Hz, CH)
a
Solvent for 5–10, 12–14, 16–18: CDCl . Solvent for 11, 15: C D .
3
6
6

Papers
b: endo-isomer; R 0.52; light petroleum ether/Et O (90:10) as elu-
SYNTHESIS
1
538
6
1-(6-Methylbicyclo[3.1.0]hex-1-yl)pyrrolidine:
14a: exo-isomer; R 0.42; light petroleum ether/Et O (94:6) as eluent;
f
2
ent; yield: 30%.
f
2
+
HRMS: m/z Obsd (Calcd) for C H N : 255.1988 (255.1989).
yield: 24%.
MS: m/z = (M –CH , 150).
1
8
25
+
3
1
-(6-Phenylbicyclo[3.1.0]hex-1-yl)morpholines:
7
a: exo-isomer; R 0.65 (EtOAc/cyclohexane, 20:80); light petroleum
1-{6-(3-Phenylprop-1-yl)bicyclo[3.1.0]hex-1-yl}piperidines:
f
ether/Et O (98:2) as eluent; yield: 48%.
15a: exo-isomer; R 0.98; light petroleum ether/Et O (98:2) as eluent;
2
f
2
7
b: endo-isomer R 0.24; light petroleum ether/Et O (90:10) as elu-
yield: 36%.
15b: endo-isomer; R 0.67; light petroleum ether/Et O (90:10) as elu-
f
2
ent; yield: 30%.
f
2
+
HRMS: m/z Obsd (Calcd) for C H NO : 243.1623 (243.1623).
ent; yield: 36%.
HRMS: m/z Obsd (Calcd) for C H N : 283.2300 (283.2300).
1
6
21
+
20
29
1
-(7-Phenylbicyclo[4.1.0]hept-1-yl)morpholines:
8
a: exo-isomer; R 0.77 (EtOAc/cyclohexane, 25:75); light petroleum
1-{6-(3-Phenylprop-1-yl)bicyclo[3.1.0]hex-1-yl}morpholine:
f
ether/Et O (98:2) as eluent; yield: 30%.
16a: exo-isomer; R 0.60; light petroleum ether/Et O (98:2) as eluent;
2
f
2
8
b: endo-isomer; R 0.40; light petroleum ether/Et O (90:10) as elu-
yield: 53%.
16b: endo-isomer; R 0.32; light petroleum ether/Et O (90:10) as elu-
f
2
ent; yield: 20%.
f
2
+
HRMS: m/z Obsd (Calcd) for C H NO : 257.1780 (257.1780).
ent; yield: 14%.
HRMS: m/z Obsd (Calcd) for C H NO : 285.2092 (285.2093).
1
7
23
+
19
23
1
-(6-Phenylbicyclo[3.1.0]hex-1-yl)pyrrolidine:
9
b: endo-isomer; R 0.10; light petroleum ether/Et O (60:40) as elu-
1-{6-(3-Phenylprop-1-yl)bicyclo[3.1.0]hex-1-yl}pyrrolidine:
f
2
ent; yield: 45%.
HRMS: m/z Obsd (Calcd) for C H N : 227.1674 (227.1674).
17a: exo-isomer; R 0.65; light petroleum ether/Et O (98:2) as eluent;
f
2
+
yield: 66%.
HRMS: m/z Obsd (Calcd) for C H N : 269.2143 (269.2143).
1
6
21
+
19
27
2
-Benzylcyclopentanone10 (rearranged product):
Light petroleum ether/Et O (98:2) as eluent; yield: 46%.
1-{6-(5,5-Dimethoxypentyl)bicyclo[3.1.0]hex-1-yl}pyrrolidine:
2
1
8: endo-isomer; R 0.85; light petroleum ether/Et O (70:30) as elu-
f
2
1
-(7-Phenylbicyclo[4.1.0]hept-1-yl)pyrrolidines:
ent; yield: 67%.
MS: m/z Obsd (Calcd) for C H O N : 281 (281).
+
1
0a: exo-isomer; R 0.74; light petroleum ether/Et O (94:6) as eluent;
f
2
17 31 2
yield: 21%.
1
0b: endo-isomer: R 0.10; light petroleum ether/Et O (60:40) as elu-
f
2
ent; yield: 41%.
HRMS: m/z Obsd (Calcd) for C H N : 241.1829 (241.1830).
(1) The Chemistry of the Cyclopropyl Group, Rappoport, Z., Ed.;
Wiley, Chichester, 1987.
+
1
7
23
(
2) Blanchard, E.P.; Simmons, H.E.; Taylor, J.S. J. Org. Chem.
2
-Benzylcyclohexanone11 (rearranged product):
Light petroleum ether/Et O (98:2) as eluent; yield: 21%.
1965, 30, 4321.
(3) Pandit, U.K.; de Graaf, S.A.G.; Braams, C.T.; Raaphorst, J.S.T.
Rec. Trav. Chim. 1972, 91, 799, and references cited therein.
(4) Rynbrandt, R.H.; Dutton, F.E. Tetrahedron Lett. 1972, 19,
1933.
2
1
-(6-Methylbicyclo[3.1.0]hex-1-yl)piperidines:
1
1a: exo-isomer; R 0.93; light petroleum ether/Et O (99:1) as eluent;
f
2
yield: 32%.
(5) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2146.
(6) Muck, D.L.; Wilson, E.R. J. Org. Chem. 1967, 33, 419.
(7) Lee, J.; Cha, J.K. J. Org. Chem. 1997, 62, 1589.
(8) Chaplinski, V.; de Meijere, A. Angew. Chem. 1996, 108, 491;
Angew. Chem., Int. Ed. Engl. 1996, 35, 413.
1
1b: endo-isomer; R 0.27; light petroleum ether/Et O (96:4) as elu-
f
2
ent; yield: 6.5%.
HRMS: m/z Obsd (Calcd) for C H N : 179.1677 (179.1674).
+
1
2
21
1
1
-(7-Methylbicyclo[4.1.0]hept-1-yl)piperidine:
(9) Rudler, H.; Audouin, M.; Parlier, A.; Martín-Vaca, B.; Gou-
mont, R.; Durand-Réville, T.; Vaissermann, J. J. Am. Chem.
Soc. 1996, 118, 12045.
2a: exo-isomer; R 0.85; light petroleum ether/Et O (98:2) as eluent;
f
2
yield:16%.
+
HRMS: m/z Obsd (Calcd) for C H N : 193.1830 (193.1830).
(10) Schwartz, C.E.; Curran, D.P. J. Am. Chem. Soc. 1990, 112,
1
3
23
9272.
1
1
-(6-Methylbicyclo[3.1.0]hex-1-yl)morpholines:
(11) Bates, R.B.; Taylor, S.R. J. Org. Chem. 1993, 58, 4469.
(12) Dötz, K.H.; Pruskill, I. Chem. Ber. 1981, 114, 1980.
(13) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.
3a: exo-isomer; R 0.86; light petroleum ether/Et O (99:1) as eluent;
f
2
yield: 34.5%.
1
3b: endo-isomer; R 0.45: light petroleum ether/Et O (96:4) as elu-
f
2
ent; yield: 21.5%.
MS: m/z = (M –CH , 166).
(14) Taguchi, K.; Westheimer, F.H. J. Org. Chem. 1971, 36, 1570.
+
3