Mono- and disubstituted N,N-dialkylcyclopropylamines from dialkylformamides via ligand-exchanged titanium - Alkene complexes

Article abstract of DOI:10.1002/1521-3765(20020816)8:16<3789::AID-CHEM3789>3.0.CO;2-R

Dibenzylformamide was treated with cyclohexylmagnesium bromide in the presence of either titanium tetraisopropoxide or methyltitanium triisopropoxide and a variety of cyclic and acyclic alkenes and alkadienes to give new mono- and disubstituted as well as bicyclic dialkylcyclopropylamines (Tables 1-3) in yields ranging from 18 to 90% (in most cases around 55%). 3-Benzyl-6-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]hexane (10a) and the orthogonally bisprotected 3-tert-butoxycarbonyl-6-(N,N-dibenzyl)- 3-azabicyclo[3.1.0]hexane (10d) as well as the analogous 6-(N,N-dibenzylamino)bicyclo[3.1.0]hexane (12) were obtained as pure exo diastereomers in particularly high yields (87, 90, and 88%, respectively) from N-benzylpyrroline (15a), N-Boc-pyrroline (15d; Boc = tert-butyloxycarbonyl) and cyclopentene (19). 1,3-Butadiene (52) and substituted 1,3-butadienes were also aminocyclopropanated quite well to give 2-ethenylcyclopropylamines in good yields (51-64%). Except for alkenyl and aryl-substituted compounds, N,N-dibenzylcyclopropylamines can be debenzylated by catalytic hydrogenation to the primary cyclopropylamines as demonstrated for 10a and 10d to yield the fully deprotected 10e (93%) and mono-Boc-protected 10f (98%), respectively. The latter are interesting templates for combinatorial syntheses of libraries of small molecules with a well defined distance of 4.3 A between two nitrogen atoms.

Full text of DOI:10.1002/1521-3765(20020816)8:16<3789::AID-CHEM3789>3.0.CO;2-R

FULL PAPER
Mono- and Disubstituted N,N-Dialkylcyclopropylamines from
Dialkylformamides via Ligand-Exchanged Titanium Alkene Complexes**
Armin de Meijere,*[a] Craig M. Williams,[b] Alexandre Kourdioukov,[c] Sergei V. Sviridov,[a]
Vladimir Chaplinski,[a] Markus Kordes,[a] Andrei I. Savchenko,[a] Christian Stratmann,[a]
and Mathias Noltemeyer[d]
Dedicated to Professor Hans Paulsen on the occasion of his 80th birthday
Abstract: Dibenzylformamide
was
as the analogous 6-(N,N-dibenzylami-
no)bicyclo[3.1.0]hexane (12)were ob-
tained as pure exo diastereomers in
particularly high yields (87, 90, and
88%, respectively)from N-benzylpyrro-
line (15a), N-Boc-pyrroline (15d;
Boc ˆ tert-butyloxycarbonyl)and cyclo-
pentene (19). 1,3-Butadiene (52)and
substituted 1,3-butadienes were also
aminocyclopropanated quite well to give
2-ethenylcyclopropylamines in good
yields (51 64%). Except for alkenyl-
and aryl-substituted compounds, N,N-
dibenzylcyclopropylamines can be de-
benzylated by catalytic hydrogenation
to the primary cyclopropylamines as
demonstrated for 10a and 10d to yield
the fully deprotected 10e (93%)and
mono-Boc-protected 10 f (98%), re-
spectively. The latter are interesting
templates for combinatorial syntheses
of libraries of small molecules with a
well defined distance of 4.3 ä between
two nitrogen atoms.
treated with cyclohexylmagnesium bro-
mide in the presence of either titanium
tetraisopropoxide or methyltitanium
triisopropoxide and a variety of cyclic
and acyclic alkenes and alkadienes to
give new mono- and disubstituted as
well as bicyclic dialkylcyclopropyla-
mines (Tables 1 3)in yields ranging
from 18 to 90% (in most cases around
55%).
3-Benzyl-6-(N,N-dibenzylami-
(10a)
no)-3-azabicyclo[3.1.0]hexane
Keywords: amines ¥ cyclopropana-
tion ¥ cyclopropylamines ¥ N ligands
¥ titanium ¥ transition metals
and the orthogonally bisprotected
3-tert-butoxycarbonyl-6-(N,N-dibenzyl)-
3-azabicyclo[3.1.0]hexane (10d)as well
Introduction
[a] Prof. Dr. A. de Meijere, Dr. S. V. Sviridov, Dr. V. Chaplinski,
Dr. M. Kordes, Dr. A. I. Savchenko, C. Stratmann
Institut f¸r Organische Chemie
The aminocyclopropyl moiety plays a significant role in a
variety of naturally occurring amino acids[1] and quite a
number of biologically active non-natural compounds.[2]
Three convincing examples are the antidepressant Tranylcy-
promine (1)[3] as well as the two broad-spectrum antibacterials
Ciprofloxacin (2),[4] and Trovafloxacin (3)[5] which are actual
commercially available drugs. There are only a few reasonably
general routes to cyclopropylamines,[6] the classical ones being
Hofmann (or an analogous)degradation of a carboxylic acid
derivative,[7] g-elimination on a C3 fragment containing a
halogen (or other good leaving group)and a C-H-acidifying
amino group equivalent,[7, 8] as well as the more recently
reported reductive amination of a cyclopropanone equivalent
(acetal or hemiacetal).[9] These processes can be quite tedious
or not viable for certain cyclopropylamines. Our recently
developed titanium-mediated cyclopropanation of N,N-dia-
lkylcarboxamides,[10, 11] an adaptation of the Kulinkovich
protocol for the conversion of esters to cyclopropanols,[12] is
more general and conveniently applicable towards the syn-
thesis of a large variety of 1- and 2-substituted, 1,2-, 2,2-, and
Georg-August-Universit‰t Gˆttingen
Tammannstrasse 2, 37077 Gˆttingen (Germany)
Fax : (‡49)551-399475
E-mail: armin.demeijere@chemie.uni-goettingen.de
[b] Dr. C. M. Williams
Chemistry Department
University of Queensland
St. Lucia, 4067, QlD (Australia)
[c] Dr. A. Kourdioukov
Centre of Scientific Information Technologies
Kazan State Technological University
Karl Marx Street 68, Kazan 420015 (Russia, Tartastan, GUS)
[d] Dr. M. Noltemeyer
Institut f¸r Anorganische Chemie
Georg-August-Universit‰t Gˆttingen
Tammannstrasse 4, 37077 Gˆttingen (Germany)
[**] Part 79 in the series ™Cyclopropyl Building Blocks for Organic
Synthesis∫. For part 78 see: M. Gensini, S. I. Kozhushkov, D. S. Yufit, J.
A. K. Howard, M. Es-Sayed, A. de Meijere, Eur. J. Org. Chem. 2002,
2499 2507; part 77: H. N¸ske, S. Br‰se, S. I. Kozhushkov, M.
Noltemeyer, M. Es-Sayed, A. de Meijere, Chem. Eur. J. 2002, 8, 2350
2369.
Chem. Eur. J. 2002, 8, No. 16
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A. de Meijere et al.
FULL PAPER
Results and Discussion
NH2
O
N
F
CO2H
Initial attempts were made with styrene (38a)and 1,3-
butadiene (52)following the original protocol of Kulinkovich
et al.[13] using ethylmagnesium bromide and [Ti(OiPr)4]. The
correspondingly substituted cyclopropylamines 39a, 53 de-
rived from N,N-dibenzylformamide were obtained, albeit in
unsatisfactory yields. According to Sato et al., propene tita-
nium intermediates generated from [XTi(OiPr)3] (X ˆ iPrO,
Cl)and isopropylmagnesium halides undergo ligand exchange
more rapidly than the parent ethylene titanium complex.[14]
Therefore, the use of isopropylmagnesium bromide in diethyl
ether and in tetrahydrofuran in the presence of [Ti(OiPr)4]
was tested for the ligand exchange with N-benzylpyrroline
(15a)and subsequent aminocyclopropanation with N,N-
dibenzylformamide. Indeed, exo-6-(dibenzylamino)-3-ben-
zyl-3-azabicyclo[3.1.0]hexane (10a)was obtained in both
cases, yet 10a was always accompanied by equal amounts of
a mixture of cis- and trans-2-methyl-N,N-dibenzylcyclopro-
pylamine (11), apparently formed by direct attack of the
propene titanium complex on the formamide. When 15a was
treated with isopropylmagnesium bromide in the presence of
[Ti(OiPr)4] and N,N-dibenzylformamide at room temper-
ature, it gave, in addition to 10a and 11, N-benzyl-3-
isopropylpyrrolidine (18)in large proportions (Scheme 2.)
N
HN
1, Tranylcypromine
2, Ciprofloxacin
O
F
CO2H
F
N
N
N
F
.
.
H2N
3, Trovafloxacin
2,3-disubstituted as well as 1,2,2- and 1,2,3-trisubstituted
cyclopropylamines. One obvious limitation of this method,
however, can arise from the unavailability of a suitably
substituted Grignard reagent 8 which is required to generate
the titanacyclopropane reactive intermediate 7 that actually
transfers the two-carbon fragment to the acid dialkylamide 4
(Scheme 1). This difficulty, though, can be overcome by the
–
R1
R1
O
O
NR22
+
NR22
(iPrO)2Ti
(iPrO)2Ti
O
.
.
.
.
–
BnN
NBn2
NBn2
NBn2
BnN
R1
NR22
(R4) R3
(R4)
R
3
4
5a
5b
10a
11
12
13
R3
N
Ti(OR)2
Ti(OR)2
[(iPrO)2Ti=O]n
Bn
(iPrO)2Ti
(iPrO)2Ti
Ti(OR)2
15
R4
R4
R3
(R4) R3
7a
7b
N
RO
OR
R1
BnN
Bn
Ti
16
17
NR22
R3
or
R3
6
14
+ XTi(OiPr)3
CH4
MgBr
N
(X = Me)
8
9
18 Bn
X = iPrO, Cl, Me
Scheme 2.
Scheme 1.
possibility of generating the appropriately substituted titana-
cyclopropane intermediate 7a from another one 7b, prepared
by the Grignard route, by alkene ligand exchange, as was
first shown by Kulinkovich et al. for styrene in the preparation
of phenyl-substituted cyclopropanols,[13] and later applied by
Sato et al.[14] as well as Cha et al.[15, 16] The latter authors favor
the use of commercially available cyclopentylmagnesium
chloride which yields a 2-titanabicyclo[3.1.0]hexane, corre-
sponding to a titanium cyclopentene complex, that rapidly
undergoes ligand exchange with monosubstituted alkenes.[15b]
In view of the importance of more highly substituted cyclo-
propylamines such as exo-6-amino-3-azabicyclo[3.1.0]hexane
(10e)which is an essential fragment in Trovafloxacin ( 3) , we
embarked on a project to develop improved conditions for the
cyclopropanation of acid dialkylamides via titanacyclopro-
pane reactive intermediates generated by alkene ligand
exchange.
The latter was the major product (up to ca. 50% yield)when
this same reaction was carried out in the absence of N,N-
dibenzylformamide. This type of reductive coupling of an
alkene titanium intermediate to another alkene has liter-
ature precedence and was first described as an ethylene
dimerization reaction.[17, 18]
Far better yields of the trisbenzyl-protected bicyclic dia-
mine 10a were obtained by using a cyclohexylmagnesium
halide (chloride or bromide).[15b] Optimization of all the
parameters for the reaction conditions (solvent, temperature,
nature of the titanium species, excess of Grignard reagent)
was eventually achieved and gave 10a as the pure exo
diastereomer in up to 87% yield (Table 1, entry 1)without any
other cyclopropylamine side product.[19] The configuration of
10a was unequivocally proved by an X-ray crystal structure
analysis of the debenzylated diamine 10e (see Figure 1).[20]
Unreacted N-benzylpyrroline (15a)and N,N-dibenzylforma-
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N,N-Dialkylcyclopropylamines
3789 3801
Table 1. N,N-Dibenzylcyclopropylamines from N,N-dibenzylformamides and 1,2-disubstituted alkenes via
ligand-exchanged titanacyclopropane intermediates.
titanium reagents with terminal
alkenes, was applied for com-
parison in the transformation of
15a, three products were ob-
tained, the expected 10a
(34%), exo-6-(N,N-dibenzyla-
mino)bicyclo[3.1.0]hexane (12)
(49%), apparently arising by
the direct reaction of the tita-
nium intermediate from cyclo-
Entry
Alkene
Conditions[a]
Product
Yield
[%]
d.r.
(cis/trans
or endo/exo)
1
A
87
< 2:98
2
3
4
E
E
A
68
67
90
< 2:98
< 2:98
< 2:98
pentylmagnesium
chloride
(without ligand exchange), and
N-benzylpyrrolidine (13)(ca.
28%)arising from formal hy-
drogenation of N-benzylpyrro-
line (15a), probably by hydro-
lysis of the titanacyclopropane
intermediate formed from 15a.
With the optimized protocol
(that is with the use of cyclo-
hexylmagnesium bromide and
[MeTi(OiPr)3]),[11] it appears
that nonterminal alkenes can
be used to generate ligand-ex-
changed titanium alkene spe-
cies that react with N,N-diben-
zylformamide (and other N,N-
dialkylformamides)without
problems, and thus a number
of other cyclic alkenes and
dienes were tested (Table 1).
Cyclopentene (19), cyclohex-
ene (22), cyclooctene (24), and
cycloocta-1,5-diene (26), all re-
acted to give the corresponding
bicyclic cyclopropylamines in
poorer yields (11 33%)than
N-benzylpyrroline (15a)(Ta-
ble 1, entries 5, 7 9); all these
B
C
28
< 2:98
< 2:98
5
88[b]
6
7
B
43
< 2:98
C
C
27
< 2:98
< 2:98
8
9
33[c]
A
B
11
< 2:98
< 2:98
1.5
10
A
26
13
1:2:6
11
12
13
A
B
1:14:15
A
trace
58
14
B
< 2:98
bicyclic
cyclopropylamines
were pure exo diastereomers,
in none of the cases could the
endo isomer be detected. The
yield of exo-6-dibenzylaminobi-
cyclo[3.1.0]hexane (12)could
be increased to 88%, when
[a] Under all conditions 1.0 equivalent of the respective formamide was used. A: alkene/diene and [Ti(OiPr)4]
(1.1 equiv), MeMgCl (or MeMgBr) and cHexMgBr (1.2 equiv). B: alkene/diene and [Ti(OiPr)4] (1.0 equiv),
cHexMgBr (2.0 2.5 equiv). C: cycloalkene and [Ti(OiPr)4] (1.0 equiv), cHexMgBr (3.1 equiv). E: alkene
(1.0 equiv), [Ti(OiPr)4] (1.01 equiv), cHexMgBr (3.33 equiv). [b] cC5H9MgBr was used instead of cHexMgBr.
[c] cC8H15MgBr was used instead of cHexMgBr.
mide could easily be removed by filtration through a pad of
silica gel and/or short path distillation under reduced pressure.
The partially p-methoxybenzyl-protected analogues of 10a,
the bicyclic diamines 10b,c could also be prepared according
to the same protocol from N-(p-methoxybenzyl)pyrroline
(15b)and dibenzylformamide or N-benzylpyrroline (15a)
and N-benzyl-N-(p-methoxybenzyl)formamide, respectively
(Table 1, entries 2, 3). An even better result was achieved with
N-(tert-butoxycarbonyl)pyrroline[21] (15c)giving the syntheti-
cally useful orthogonally bisprotected diamine 10d in 90%
yield.[22, 23]
cyclopentylmagnesium bromide (or chloride)in the presence
[24]
of cyclopentene (19)was used.
Norbornene (20)with its
strained double bond, and the conjugated 1,3-cyclohexadiene
(36)gave significantly better yields of 21 and 37 (43 and 58%,
respectively; Table 1, entries 6 and 14)than cyclohexene ( 22).
Cycloocta-1,5-diene (26)afforded, in addition to 11% of the
mono-aminocyclopropanation product 27, a small amount
(1.5% yield)of the twofold aminocyclopropanation product
28 as colorless crystals which could be characterized by an
X-ray structural analysis as the exo,exo-5,10-bis(dibenzylami-
no)-anti-tricyclo[7.1.0.04, 6]decane (28)(see below, Fig-
ure 1).[20] Cyclopentadiene (33)apparently is only deproto-
nated by the basic organometallic intermediates, and thus
When cyclopentylmagnesium chloride, which has been
favored by Cha et al.[16] in generating ligand-exchanged
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A. de Meijere et al.
FULL PAPER
recovered unchanged, whereas
spiro[2.4]heptadiene (34)gave
the corresponding cyclopropyl-
amine 35 only in trace amounts.
This must be due to steric
hindrance of complexation at
one of its double bonds by the
neighboring spirocyclopropane
moiety.
The acyclic nonterminal al-
kenes cis-2-pentene (29)and
trans-3-hexene (31)could be
converted to the corresponding
2,3-disubstituted cyclopropyla-
mines 30 and 32, albeit in low
yields (26 and 13%, respective-
ly), and without retention of the
original alkene configuration
(Table 1, entries 10, 11), as
Table 2. N,N-Dialkylcyclopropylamines from N,N-dialkylformamides and terminal alkenes via ligand-ex-
changed titanacyclopropane intermediates.
Entry
Alkene
Conditions[a]
Product
Yield
[%]
d. r.
(cis/trans)
1
A
a X ˆ H
66
1:3.1
2
3
A
A
b X ˆ 4-OMe
c X ˆ 2-Br
45
30
11[b]
18
46[b]
9[b]
1:1.2
< 2:98
4
5
6
7
A
A
A
A
a 2-CF3
1:4
0:1
1:11.5
1:16
b 4-CF3
c 3-CF3
d 3,5-(CF3)2
8
A
43
1:4
1:0
9
A
D
4
three
diastereomers
were
a R ˆ Me
b R ˆ Bn
44[c]
39
1:5
1:4
10
formed in both cases.
Terminal alkenes generally
give better yields than open-
chain internal ones. Styrene
(38a)and substituted styrenes
38b,c as well as 40a d (Ta-
ble 2)were tested preferential-
ly, since not only trans-2-phe-
nylcyclopropylamine (1, Tranyl-
cypromine)[3] is well known as a
pharmacologically active com-
pound, but a number of (2-
11
12
D
D
59
28
0:1
0:1
[a] A: see Table 1. D: alkene/diene (1.0 1.2 equiv), [MeTi(OiPr)3] (1.0 1.5 equiv), cHexMgBr (1.5 2.4 equiv).
[b] Addition of cyclohexylmagnesium bromide within 20 min. [c] N,N-Dimethylformamide was used instead of
N,N-dibenzylformamide.
arylcyclopropyl)urea derivatives have been shown to be
particularly potent inhibitors of HIV-1 reverse transcrip-
tase.[25] In fact, (2-phenylcyclopropyl)-N,N-dibenzylamine
(39a)was obtained from styrene ( 38a)as a 1:3.1 mixture of
cis and trans isomers in 66% yield. The substituted styrenes
38b,c and 40a d were converted to the corresponding (2-
arylcyclopropyl)amines 39b,c and 41a d in 9 46% yield
with the 4-methoxy- and 3-trifluoromethyl-substituted com-
pounds giving the best results (Table 2, entries 2 7). Most
probably for steric reasons, 2-bromostyrene (38c)only gave
the trans-2-(2'-bromophenyl)-substituted cyclopropylamine
39c. While 2-ethenylfuran (42)furnished 2-furylcyclopropyl-
amine (43)in 43% yield, 2-ethenylpyridine did not react at all.
Ethenyl ethyl ether (44)underwent aminocyclopropanation
in extremely low yield (4%)(Table 2, entry 9,) but allyldi-
benzylamine (46)as well as ethenyltrimethylsilane ( 48)[26] and
allyltrimethylsilane (50)provided the correspondingly sub-
stituted cyclopropylamines 47b, 49, 51 in moderate to good
yields (39, 59, and 28%, respectively).
Acyclic conjugated dienes with at least one terminal double
bond turned out to be particularly good ligands, such as
cyclohexadiene (36), and could rather efficiently be amino-
cyclopropanated to furnish 2-ethenylcyclopropylamines in
moderate to good yields (up to 64%, Table 3, entries 1 8).[27]
Surprisingly, the reaction with substituted 1,3-butadienes
such as isoprene (54), 4-methyl-1,3-pentadiene (57), and
myrcene (61)all gave the alkenyldibenzylaminocyclopro-
panes derived from putative attack on the more highly
substituted double bond of the conjugated diene unit rather
than the expected product which would have been formed by
attack on the least substituted double bond (Table 3, entries 2,
4, 7). As these expected products were not detected in any
case, and control experiments with 2,3-dimethylbutadiene
(56)and 2,5-dimethyl-2,4-hexadiene ( 60)did not yield any
cyclopropylamine, it must be concluded that the alkenyldii-
sopropyloxytitanacyclopropane 67 with the least substituted
double bond of the conjugated diene attached to the titanium
center, is kinetically–and possibly thermodynamically–fa-
vored. The formamide then cycloadds to this alkenyltitana-
cyclopropane 67 by way of a metalla ene reaction with a six-
center transition state to yield an oxatitanacycloheptene 68.
This intermediate can cyclorevert to an (iminiumallyl)titani-
um oxide 1,8-zwitterion 69, which subsequently can only
cyclize to a cyclopentenylamine or to the observed, more
highly substitued cyclopropylamine 70 (Scheme 3).[27]
The formation of the same cyclopropylamine from 2-meth-
yl-1,3-pentadiene (59)as from 4-methyl-1,3-pentadiene ( 57)
(entries 5, 4 in Table 3)most probably arises by initial
isomerization of the former to the latter under the conditions
employed. The fact that the conjugated 6-methyl-1,3,5-hepta-
triene (65)yields only the 2,3-dialkenylcyclopropylamine 66
(Table 3, entry 9), which arises from putative attack at the
central double bond in 65, may also be taken to indicate that
the initially formed intermediate is actually the less substi-
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N,N-Dialkylcyclopropylamines
3789 3801
Table 3. N,N-Dibenzylcyclopropylamines from N,N-dibenzylformamides and conjugated dienes via ligand-
exchanged titanacyclopropane intermediates.
anol in the presence of 5 mol%
acetic acid or 2n hydrochloric
acid. No ring opening occurred,
as demonstrated for the trisben-
zyl-protected bicyclic diamine
10a, to afford pure exo-6-ami-
no-3-azabicyclo[3.1.0]hexane
(10e)in excellent yield (93%)
using 1.7 mol% of Pd/C catalyst
(Scheme 4). Debenzylation of
compounds 10a and 10d under
neutral conditions gave dia-
mine 10e and mono-N-Boc-
protected diamine 10 f in high
yields (93 and 98%, respective-
ly), but it required larger
amounts of catalyst to go to
completion [ca. 10 mol% of
Pd/C 10%)]. On a larger scale,
though, deprotection of 10d
could be carried out under
neutral conditions with only
3 mol% of the Pd/C catalyst.
Reaction of 10d with trifluoro-
acetic acid gave the hydrotri-
fluoroacetate of 10g from
which the amine 10g was liber-
ated in 98% overall yield by
Entry
Alkene
Conditions[a]
Product
Yield
d.r.
[%]
(cis/trans)
1
2
3
D
A
A
56
59
< 2:98
< 2:98
[b]
4
A
64
27
1:5.3[c]
5
6
A
A
1:3[c]
[b]
7
A
51
< 2:98
8
9
A
A
9
1:0
treatment with
a polymeric
base such as poly-(4-vinylpyri-
dine).
54
1:1.5:1.5[c]
To rigorously prove the con-
figuration of the bicyclic dia-
mines 10 and to determine the
influence of substituents on the
two nitrogen atoms on the con-
[a] A, D: see Table 1, 2. [b] No conversion of diene observed. [c] The ratio of isomers was calculated on the basis
of H NMR spectra of obtained chromatography fractions.
1
NBn2
formation of the skeleton, X-ray crystal structure analyses
were performed on the free diamine 10e as well as the two
3-Boc-protected derivatives 10d and 10 f (Figure 1.)[20] In all
three compounds of type 10, the 3-azabicyclo[3.1.0]hexane
skeleton adopts a flattened boat-type conformation with the
nitrogen corner in the five-membered heterocycle being bent
towards the cyclopropyl group. This bending angle is rather
similar in 10d (23.18)and 10e (27.28), but significantly smaller
(only 11.28)in the mono-Boc-protected diamine 10 f. Con-
sequently, the nitrogen nitrogen distance is largest in 10 f
NBn2
O
O
Ti(OiPr)2
Ti(OiPr)2
R
R
67
68
+
NBn2
R
NBn2
O –
Ti(OiPr)2
R
69
70
Scheme 3.
tuted titanacyclopropane of type 67, which reacts in a metal-
la ene reaction mode rather than the conceivable most
highly substituted titanacyclopropane arising from coordina-
tion on the trisubstituted double bond in 65.
In most cases, N,N-dibenzylformamide was used to prepare
N,N-dibenzylcyclopropylamines, but other N,N-dialkylforma-
mides can be employed as well. Except for aryl- and alkenyl-
substituted compounds, N,N-dibenzylcyclopropylamines can
be debenzylated to give the primary cyclopropylamines by
catalytic hydrogenation over palladium on charcoal in meth-
Scheme 4.
Chem. Eur. J. 2002, 8, No. 16
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A. de Meijere et al.
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Figure 1. Structures of 3-tert-butoxycarbonyl-6-exo-(N,N-dibenzylamino-3-azabicyclo[3.1.0]hexane (10d) , 6e-xo-amino-3-azabicyclo[3.1.0]hexane (10e),
6-exo-amino-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane (10 f), and exo,exo-5,10-bis(dibenzylamino)-anti-tricyclo[7.1.0.04, 6]decane (28)in the crys-
tals.[20]
(4.31 ä), and it is slightly shorter in 10d and 10e (4.22 and
4.28 ä, respectively).
The tricyclic skeleton of 28, in the crystal, adopts an ideal
71
crown shape with the central eight-membered ring in a chair
conformation[28] (Figure 1). As is usual in cyclopropyl-
O
NBn2
O
NBn2
amines,[29] and in donor-substituted cyclopropane derivatives
in general,[30] the distal bond (with respect to the amino
substituent)is longer than the proximal bonds in all four
H
NBn2
c HexMgBr
H
Ti(OiPr)2
O
Ti
Ti
iPrO
74
OiPr
73
iPrO
molecules (1.517(2)vs. 1.498(2)(av)in
1.508(2)in 10e; 1.512(3)vs. 1.502(3)in
1.510(2)in 28).
10d; 1.511(4)vs.
10 f; 1.522(2)vs.
72
NBn2
O
NBn2
–c C6H10
In all cases, in which no or only low yields of cyclopropyl-
amines were produced, three by-products were observed in
varying amounts. One of them was, naturally, exo-7-(N,N-
dibenzylamino)bicyclo[4.1.0]heptane (23)resulting from non-
ligand exchanged cyclopropanation with the 6-titanabicy-
clo[4.1.0]heptane intermediate originally formed from cyclo-
hexylmagnesium bromide. The second and third went un-
identified for some time, however, they were finally assigned
as 1,1'-bicyclohexyl (71)[18] and dibenzyl(cyclohexylmethyl)-
amine (76)[31] by comparison with authentic samples. In most
cases these by-products could be removed from the crude
reaction mixtures either by distillation or chromatography.
The major fraction of 71 resulted from a Wurtz type
reaction in the preparation of the Grignard reagent, in which
the yield of 1,1'-bicyclohexyl (71)amounted up to 60%, when
THF was used as the solvent. However, it is yet unknown, how
the tertiary amine 76 would be formed. It cannot arise from
hydrolysis of the unreacted oxatitanacyclopentane intermedi-
ate 73 of type 7 formed from the titanabicyclo[4.1.0]heptane
72 (from cyclohexylmagnesium bromide and MeTi(OiPr)3)
and N,N-dibenzylformamide. One possible rationalization is
that 73 reacts with another molecule of cyclohexylmagnesium
bromide to yield 74 in which a b-hydride is transferred to the
O,N-acetal carbon atom (Scheme 5). The resulting intermedi-
Ti
OiPr
75
76
Scheme 5.
ate 75, upon hydrolysis, would yield 76. This mechanism is
unprecedented in the literature, if operable, however, it might
also explain the formation of 3-isopropyl-N-benzylpyrrolidine
18 from N-benzylpyrroline 15 (see above).
Conclusion
In conclusion, the newly developed conditions constitute a
significant advance towards a rather general synthesis of
various substituted cyclopropylamines from cyclic and acyclic
alkenes, alkadienes, and even trienes. Many of these virtually
functionalized cyclopropylamines were previously difficult or
even impossible to obtain. The bicyclic diamine 10, especially
in its mono-Boc-protected form 10 f, is an interesting template
for the combinatorial synthesis of libraries of small molecules
with a well-defined distance between two nitrogen atoms.[32]
3794
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Chem. Eur. J. 2002, 8, No. 16

N,N-Dialkylcyclopropylamines
3789 3801
General procedure D for the aminocyclopropanation of alkenes (GP D):
Cyclohexylmagnesium bromide solution in diethyl ether (1.5 2.4 equiv)
over 10 s 1 h was added to a solution of the corresponding alkene (1.0
1.2 equiv), N,N-dimethyl-, or N,N-dibenzylformamide (1 equiv)and meth-
yltitanium triisopropoxyde (1.0 1.5 equiv)in THF at ambient temperature
under an atmosphere of argon. After additional stirring the above work-up
Experimental Section
1H (250 MHz)and 13C (62.9 MHz)NMR: Bruker AM 250, CDCl as
3
solvent, chemical shifts based on residual CHCl3 relative to SiMe4, coupling
constants are reported in Hz. Mass spectra (MS): Varian MAT CH7, MAT
731, and high-resolution mass spectra (HRMS): Varian MAT 311A. The
molecular compositions were determined by high-resolution mass spec-
trometry with preselected ion peak matching at R ꢀ 10000 to be within
Æ2 ppm of the exact masses. Melting points were determined on a B¸chi
510 melting point apparatus and are uncorrected. Microanalyses were
performed by the Mikroanalytisches Laboratorium des Instituts f¸r
Organische Chemie der Georg-August-Universit‰t Gˆttingen. Experiments
were conducted either under an atmosphere of nitrogen or argon and tetra-
hydrofuran (THF)was freshly distilled from sodium/benzophenone. All
cyclic alkenes, dienes and trienes were commercially available from either
Sigma-Aldrich, Merck-Schuchardt or Fluka companies. These alkenes were
further purified by distillation under reduced pressure or distillation from
calcium hydride under an atmosphere of argon and then stored at À248C.
Grignard reagents were also purchased from the above companies except
for cyclohexylmagnesium bromide,[33] molar concentrations were deter-
mined by acid/base titration against phenolphthalein. Radial chromatog-
raphy was performed on a Chromatotron, Model 7924T using silica gel PF-
254 with CaSO4 ¥ 1/2H2O type 60 for TLC, E. Merck, Darmstadt. Column
chromatography was performed on flash silica gel 60 mesh or alumina B,
(see GP
A or B)gave a residue that was subjected to column
chromatography or Kugelrohr distillation.
General procedure E for the aminocyclopropanation of alkenes (GP E): A
cold solution of N-arylmethylpyrroline 15b,c (7.50 mmol), titanium tetrai-
sopropoxide (7.55 mmol), and N,N-bis(arylmethyl)formamide (7.50 mmol)
in THF (5 10 mL)was added in one portion to a cooled (0 8C)solution of
cyclohexylmagnesium bromide, obtained by addition of cyclohexyl bro-
mide (25.0 mmol)in THF (10 mL)to magnesium turnings (0.60 g,
25.0 mmol). The mixture was slowly warmed up to room temperature over
a period of 30 45 min and then heated under reflux for 60 120 min. The
resulting reaction mixture was quenched with a solution of saturated
sodium sulfate (2 mL)and diluted with petroleum ether (20 mL.) The
colorless precipitate was removed by filtration and the solvent evaporated
in vacuo. The residue was dissolved in ethyl acetate (20 mL)and treated
with 25% H2SO4 (10 mL). The aqueous phase was separated, treated with
30% NaOH solution (4 mL), and extracted with petroleum ether (50 mL).
The organic layer was dried (K2CO3)and evaporated to give the crude
product 10b,c which was distilled in a Kugelrohr or used without additional
purification.
ICN. 13C and H NMR spectra only of major diastereomers are reported,
1
unless stated otherwise, because of too many overlapping indistinguishable
peaks in the spectra of diastereomeric mixtures.
3-Benzyl-6-exo-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]hexane
(10a):
According to GP A, the mixture of N-benzylpyrroline (15a)(1.49 g,
9.37 mmol)and [Ti(O iPr)4] (2.84 g, 10.0 mmol)in THF (5 mL)was treated
with MeMgCl (3.4 mL, 3 m in THF, 10.2 mmol), then a solution of N,N-
dibenzylformamide (2.25 g, 10.0 mmol)in THF (10 mL)was added in one
portion. Cyclohexylmagnesium bromide (14.0 mL, 21.4 mmol, 1.53 m in
THF/benzene 3:1)was added at ambient temperature over 50 min and the
reaction mixture was heated under reflux for 15 min. After work-up the
residue was filtered through a pad of silica gel; elution with petroleum
ether/ethyl acetate (15:1). Distillation (1708C/10À4 Torr)of the crude
product in a Kugelrohr gave the product 10a as a pale yellow oil (3.00 g,
87%). 1H NMR (CDCl3): d ˆ 1.27 (s, 2H), 2.21 (s, 1H), 2.31 (d, J ˆ 8.7 Hz,
2H), 2.88 (d, J ˆ 8.7 Hz, 2H), 3.56 (s, 2H), 3.65 (s, 4H), 7.26 7.33 ppm (m,
15H); 13C NMR (CDCl3): d ˆ 25.6, 45.0, 54.4, 58.8, 59.1, 126.7, 126.8, 127.9,
128.1, 128.4, 129.4, 138.9, 139.5 ppm; HRMS calcd for C26H28N2 368.2252,
General procedure A for the aminocyclopropanation of alkenes (GP A):
Methylmagnesium chloride (1.79 mL, 3m solution in THF)was added
dropwise over 5 10 min at 0 58C to a solution of titanium tetraisoprop-
oxide (1.43 mL, 4.88 mmol)in anhydrous THF (15 mL). After the mixture
had been stirred for a further 5 min, a solution of N,N-dibenzylformamide
(1.00 g, 4.44 mmol)in anhydrous THF (6 mL)was added over 30 s followed
by addition of the respective alkene (4.88 mmol). Cyclohexylmagnesium
bromide (2.69 mL, 2.0 m solution in diethyl ether)was then added dropwise
over 45 50 min. The reaction mixture was allowed to warm to room
temperature over 9- 26 h before it was quenched with water (2.5 mL)
(exothermic reaction). After the resulting precipitate became white in
color (ca. 15 min)it was removed by vacuum filtration. The precipitate was
washed with diethyl ether (20 mL)and the combined filtrates were
concentrated. The residue was purified affording pure product. Yields
given below are based on N,N-dibenzylformamide used.
‡
found 368.2252; MS (EI ): m/z (%): 368 (12), 277 (50), 249 (44), 210 (5),
172 (6), 158 (54), 131 (10), 106 (2), 91 (100).
6-exo-(N,N-Dibenzylamino)-3-(p-methoxybenzyl)-3-azabicyclo[3.1.0]hex-
ane (10b): A solution of N-(p-methoxybenzyl)pyrroline (15b)(0.73 g
3.85 mmol), [Ti(OiPr)4] (1.11 g, 3.90 mmol)and N,N-dibenzylformamide
(0.88 g, 3.90 mmol)in THF (5 mL)was treated with cyclohexylmagnesium
bromide (13.30 mmol in THF (5 mL)) according to GP E. Yield: 1.05 g
(68%). 1H NMR (CDCl3): d ˆ 1.32 (bs, 2H), 2.26 (bs, 1H), 2.33 2.36 (bd,
J ˆ 8.5 Hz, 2H), 2.92 (d, J ˆ 8.8 Hz, 2H), 3.55 (s, 2H), 3.71 (s, 4H), 3.86 (s,
3H), 6.91 6.94 (m, 2H), 7.23 7.26 (m, 2H), 7.31 7.41 ppm (m, 10H);
13C NMR (CDCl3): d ˆ 25.6, 44.9, 54.3, 55.2, 58.4, 59.5, 113.4, 126.7, 127.9,
129.4, 129.6, 131.5, 138.9, 158.4 ppm; HRMS calcd for C27H30N2O: 398.2358,
General procedure B for the aminocyclopropanation of alkenes (GP B):
Titanium tetraisopropoxide (1 equiv)was added over 5 min at room
temperature to a solution of equivalent amounts of alkene or diene (13.3
39.6 mmol, 1 equiv)and N,N-dibenzylformamide (1 equiv)in anhydrous
THF (40 60 mL). Cyclohexylmagnesium bromide (2.0 2.5 equivalents of
a 2.1 2.2 m solution in diethyl ether)was added over 35 45 min at room
temperature followed by further stirring for 12 h. The resultant black-
brown suspension was quenched with water (3.0 5.0 mL)(exothermic
reaction), and the mixture stirred until the precipitate became white in
color. The precipitate was removed by vacuum filtration and was washed
with deithyl ether (35 50 mL). The combined filtrate was dried (MgSO4)
and the solution concentrated under reduced pressure to give a residue
which was purified providing pure product.
‡
found 398.2358; MS (EI ): m/z (%): 398 (12), 91 (100).
3-Benzyl-6-exo-[N-benzyl-N-(p-methoxybenzyl)amino]-3-azabicy-
clo[3.1.0]hexane (10c): A solution of N-benzylpyrroline (15a)(1.20 g,
7.54 mmol), [Ti(OiPr)4] (2.13 g, 7.50 mmol)and N-benzyl-N-(p-methoxy-
benzyl)formamide (1.91 g, 7.48 mmol) in THF (10 mL) was treated with
cyclohexylmagnesium bromide (25.0 mmol in THF (10 mL)) according to
General procedure C for the aminocyclopropanation of alkenes (GP C): A
solution of the corresponding cycloalkylmagnesium bromide (31.0 mmol)
in THF/benzene (3:1)was added dropwise by syringe to a solution of N,N-
dibenzylformamide (2.25 g, 10.0 mmol), titanium tetraisopropoxide (2.84 g,
10.0 mmol)and cycloalkene (10.0 mmol)in THF (10 mL)at room temper-
ature over a period of 20 min. The mixture was then stirred under reflux for
10 min, quenched with water (15 mL), and diluted with petroleum ether
(10 mL). The precipitate was removed by vacuum filtration and washed
with petroleum ether (50 mL). The combined organic extracts were
evaporated in vacuo and the residue was dissolved in diethyl ether
(50 mL)and treated with 25% aqueous sulfuric acid (15 mL). The aqueous
phase contained a white solid precipitate which was treated with 30%
sodium hydroxide solution (10 mL)and extracted with diethyl ether
(75 mL). The diethyl ether solution was dried (Na2SO4)and the solvent
evaporated in vacuo affording the pure product.
1
GP E. Yield: 2.01 g (67%). H NMR (CDCl3): d ˆ 1.29 (bs, 2H), 2.21 (bs,
1H), 2.33 2.36 (bd, J ˆ 8.5 Hz, 2H), 2.91 (d, J ˆ 8.8 Hz, 2H), 3.59 (s, 2H),
3.63 (s, 2H), 3.67 (s, 2H), 3.84 (s, 3H), 6.88 6.93 (m, 2H), 7.22 7.40 ppm
(m, 12H); 13C NMR (CDCl3): d ˆ 25.6, 44.8, 54.4, 55.2, 58.0, 58.7, 59.1,
113.2, 126.7, 127.9, 128.1, 128.5, 129.4, 130.6, 130.9, 139.0, 139.5, 158.5 ppm;
‡
HRMS calcd for C27H30N2O: 398.2358, found 398.2358; MS (EI ): m/z (%):
398 (8), 121 (100), 91 (60).
3-tert-Butyloxycarbonyl-6-exo-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]-
hexane (10d): According to GP A, a mixture of N-Boc-pyrroline (15d)
(4.37 g, 25.8 mmol)and [Ti(O iPr)4] (9.20 mL, 30.9 mmol)in THF (70 mL)
was treated with MeMgCl (10.4 mL, 3 m solution in THF, 31.2 mmol), and
then a solution of N,N-dibenzylformamide (6.98 g, 30.9 mmol)in THF
Chem. Eur. J. 2002, 8, No. 16
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3795

A. de Meijere et al.
FULL PAPER
(25 mL)was added in one portion. cHexMgBr (23.5 mL, 51.7 mmol, 2.2 m
in Et2O)was added at ambient temperature over 3 h, and the reaction
mixture was heated under reflux for 15 min. After work-up the crude
compound 10d (9.90 g)was purified by column chromatography on basic
alumina with activity grade II; elution with pentane/diethyl ether (5:1). The
product 10d (8.75 g, 90%)was obtained as a colorless solid. M.p. 79 8C.
1H NMR (C6D6): d ˆ 1.02 1.14 (bm, 2H), 1.39 1.43 (m, 1H), 1.52 (s, 9H),
3.05 (dd, J ˆ 4.4, 10.6 Hz, 1H), 3.21 (dd, J ˆ 4.4, 11.0 Hz, 1H), 3.38 (d, J ˆ
10.6 Hz, 1H), 3.45 (s, 4H), 3.62 (d, J ˆ 11.0 Hz, 1H), 7.10 7.35 ppm (m,
10H); 13C NMR (CDCl3): d ˆ 25.3, 25.9, 28.5, 47.6, 47.7, 47.9, 58.9, 79.2,
127.0, 128.1, 129.4, 138.5, 154.6 ppm; HRMS calcd for C24H30N2O2 378.2307,
affording 1,1'-bicyclooctyl (0.63 g), starting N,N-dibenzylformamide
(0.12 g), dibenzyl(cyclooctylmethyl)amine (0.27 g; 17%), and the title
compound 25 (0.53 g; 33%)as a pale yellow oil. 1H NMR (CDCl3): d ˆ
0.58 0.63 (m, 1H), 0.87 0.95 (m, 2H), 1.17 1.26 (m, 4H), 1.29 1.63 (m,
6H), 1.78 1.85 (m, 2H), 3.54 (s, 4H), 7.22 7.38 ppm (m, 10H); 13C NMR
(CDCl3): d ˆ 25.6, 25.7, 26.1, 29.3, 48.4, 58.6, 126.7, 127.9, 129.4, 139.0 ppm.
exo-9-(N,N-Dibenzylamino)bicyclo[6.1.0]non-4-ene (27): According to GP
A, 1,5-cyclooctadiene (26)(0.528 g, 4.88 mmol)after 22 h, gave a crude
product which was passed through a plug of silica gel; elution with tert-butyl
methyl ether/hexane (2:98)afforded two fractions. The first one, which
contained unreacted starting material and side products, was discarded.
The second fraction (0.50 g)contained a mixture of the title compound 27,
exo-7-(N,N-dibenzylamino)bicyclo[4.1.0]heptane (23), and cyclohex-
yl(N,N-dibenzylamino)methane (72). This fraction was placed on a column
containing silver nitrate impregnated silica gel.[34] The column was eluted
(ethyl acetate/n-hexane 1:4)in the dark until eluting impurities could not
be detected by TLC (silver nitrate impregnated)analysis. The impregnated
silica gel was then quickly dried in vacuo and transferred from the column
to a conical flask to which was added aqueous ammonia (25%). The slurry
was extracted with n-hexane (2 Â 100 mL)to give the product 27 (ꢁ90%
pure)which was further purified by careful radial chromatography ( tert-
butyl methyl ether/n-hexane, 2:98)followed by Kugelrohr distillation
(150 1708C/0.01 Torr)to afford 27 as a colorless oil (0.15 g; 11%).
1H NMR (CDCl3): d ˆ 0.70 0.90 (m, 2H), 1.18 1.39 (m, 3H), 1.80 2.01
(m, 4H), 2.09 2.28 (m, 2H), 3.63 (s, 4H), 5.52 5.60 (m, 2H), 7.12
7.47 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 26.6, 26.8, 28.5, 51.3, 58.7,
126.7, 127.9, 129.4, 130.2, 139.1 ppm; HRMS calcd for C23H27N 317.2143,
‡
found 378.2307; MS (EI ): m/z (%): 378 (48), 287 (33), 231 (44), 225 (35),
187 (72), 134 (42), 91 (100); elemental analysis calcd (%) for C24H30N2O2
(378.5): C 76.16, H 7.99; found: C 76.22, H 7.91. X-ray crystal structure
analysis: see below.[20]
Carried out on a larger scale, this procedure furnished, from N-Boc-
pyrroline (15d)(101 g, 0.60 mol)and [Ti(O iPr)4] (187 g, 0.66 mol)in THF
(1.8 L), MeMgCl (219 mL, 3 m solution in THF, 0.66 mol), N,N-dibenzyl-
formamide (148 g, 0.66 mol)and cHexMgBr (811 mL, 1.62 m solution in
Et2O), 10d in 76% yield (172.5 g).
exo-6-(N,N-Dibenzylamino)bicyclo[3.1.0]hexane (12): According to GP B,
cyclopentene (19)(2.70 g, 39.6 mmol,) N,N-dibenzylformamide (8.99 g,
39.9 mmol)in anhydrous THF (15 mL,) and cyclohexylmagnesium bro-
mide (41.5 mL, 87.2 mmol, 2.1 m solution in diethyl ether)gave a crude
product that was subjected to vacuum distillation (50 908C/0.05 Torr)to
remove 1,1'-dicyclohexyl. The residue was then subjected to column
chromatography (hexanes)on silica gel to provide exo-7-(N,N-dibenzyla-
mino)bicyclo[4.1.0]heptane (23)(1.30 g; 11%)as colorless crystals (m.p.
508C)and 12 (3.12 g; 28%)as a colorless oil.
‡
found 317.2143; MS (EI ): m/z (%): 317 (14), 288 (3), 262 (4), 240 (5), 236
(8), 226 (29), 210 (5), 172 (1), 158 (6), 132 (9), 106 (10), 91 (100).
exo-7-(N,N-dibenzylamino)bicyclo[4.1.0]heptane (23): 1H NMR (CDCl3):
d ˆ 0.85 (s, 2H), 1.10 1.35 (m, 4H), 1.45 1.60 (m, 3H), 1.70 1.90 (m, 2H),
3.70 (s, 4H), 7.25 7.45 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 19.8, 21.8,
22.9, 48.6, 58.4, 126.8, 128.0, 129.5, 138.6 ppm; HRMS calcd for C21H25N
291.1987, found 291.1986; MS (EI ): m/z (%): 291 (6), 262 (2), 236 (1), 210
(1), 200 (100), 181 (1), 161 (9), 146 (10), 132 (2), 118 (6), 106 (34), 91 (78).
exo,exo-5,10-Bis(N,N-dibenzylamino)-anti-tricyclo[7.1.0.04, 6]decane (28):
With one equivalent of 1,5-cyclooctadiene (26)(1.20 g, 11.1 mmol)
according to GP B, except that two equivalents of dibenzylformamide
(5.00 g, 22.2 mmol), [Ti(OiPr)4] (6.31 mL, 21.4 mmol)in THF (60 mL)and
four equivalents of cyclohexylmagnesium bromide (27.6 mL, 1.77 m,
49 mmol)were used. After 23 h the above work-up gave a mixture of
compounds 23, 27, 28, and 72 in a molar ratio of 1.20:1.35:0.34:1.00
(according to 1H NMR spectroscopy). Column chromatography on silica
gel (hexane)gave the only pure fraction containing compound 28 (85 mg;
1.5% based on diene)as a crystalline solid. M.p. 154 8C. 1H NMR (CDCl3):
d ˆ 0.70 (s, 8H), 1.30 (s, 2H), 1.90 (s, 4H), 3.60 (s, 8H), 7.20 7.40 ppm (m,
20H); 13C NMR (CDCl3): d ˆ 26.9, 28.3, 51.1, 58.6, 126.7, 127.9, 129.4,
‡
exo-6-(N,N-Dibenzylamino)bicyclo[3.1.0]hexane (12): 1H NMR (CDCl3):
d ˆ 0.98 1.12 (m, 1H), 1.20 (br s, 2H), 1.50 1.68 (m, 6H), 3.65 (s, 4H),
7.26 7.39 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 22.5, 27.2, 27.4, 44.3, 58.4,
126.9, 128.0, 129.6, 138.5 ppm; HRMS calcd for C20H23N 277.1830, found
‡
277.1830; MS (EI ): m/z (%): 277 (6), 249 (1), 234 (1), 210 (7), 186 (100),
167 (3), 158 (6), 131 (3), 118 (5), 106 (30), 91 (42); elemental analysis calcd
(%)for C 20H23N (277.4): C 86.59, H 8.36; found: C 86.53, H 8.45.
‡
138.9 ppm; HRMS calcd for C38H42N2 526.3348, found 526.3347; MS (EI ):
m/z (%): 526 (5), 435 (100), 344 (2), 330 (3), 292 (13), 240 (6), 196 (7), 172
exo-6-(N,N-Dibenzylamino)bicyclo[3.1.0]hexane (12): According to GP C,
cyclopentene (19)(0.68 g, 10.0 mmol)and cyclopentylmagnesium bromide
(23.0 mL, 1.35 m, 31 mmol)in THF/benzene (3:1)after work-up gave pure
12 as a colorless oil (2.44 g, 88%).
(4), 120 (5), 106 (23), 91 (97). X-ray crystal structure analysis: see below.[20]
1-(N,N-Dibenzylamino)-2-ethyl-3-methylcyclopropane (30): According to
GP A, cis-3-pentene (29)(0.26 mL, 0.171 g, 2.44 mmol)after 26 h gave a
crude product that was subjected to column chromatography (ethyl
acetate/n-hexane, 5:95)on silver nitrate impregnated silica gel, [34] affording
three fractions. The first fraction (54 mg)contained the title compound 30
as a mixture of two diastereomers, and the second fraction (107 mg)
contained a third diastereomer of 30, overall yield 161 mg (26%). The two
minor diastereomers could not be further separated. Two minor diaster-
eomers: 1H NMR (CDCl3): d ˆ 0.14 0.26 (m, 1H), 0.39 0.49 (m, 1H),
0.91 (d, J ˆ 6.1 Hz, 3H), 1.01 (t, J ˆ 7.4 Hz, 3H), 1.36 1.53 (m, 1H), 1.56
1.71 (m, 2H), 3.46 (d, J ˆ 13.5 Hz, 2H), 3.76 (d, J ˆ 13.5 Hz, 2H), 7.24
7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 14.6, 17.8, 20.35, 20.42, 29.2,
exo-3-(N,N-Dibenzylamino)tricyclo[3.2.1.02, 4]octane (21): According to
GP B, norbornene (20)(1.30 g, 13.8 mmol)and cyclohexylmagnesium
bromide (15.7 mL, 34.5 mmol, 2.2 m solution in diethyl ether)gave, after
column chromatography (hexanes)on silica gel, 21 as colorless crystals
1
(1.80 g, 43%), m.p. 31 338C. H NMR (CDCl3): d ˆ 0.58 (d, J ˆ 10.2 Hz,
1H), 0.70 (s, 2H), 0.93 (d, J ˆ 10.2 Hz, 1H), 1.19 (m, 2H), 1.33 (m, 2H), 1.72
(s, 1H), 2.20 (s, 2H), 3.57 (s, 4H), 7.25 7.30 ppm (m, 10H); 13C NMR
(CDCl3): d ˆ 25.4, 29.3, 29.4, 35.6, 39.1, 58.0, 126.7, 127.9, 129.5, 138.5 ppm;
‡
HRMS calcd for C22H25N 303.1987, found 303.1986; MS (EI ): m/z (%): 303
(6), 274 (4), 226 (6), 212 (36), 200 (5), 167 (1), 144 (3), 118 (1), 107 (3), 91
(100); elemental analysis calcd (%) for C 22H25N (303.5): C 87.08, H, 8.30;
found: C 86.95, H 8.45.
1
49.8, 58.4, 126.7, 127.9, 129.4, 138.9 ppm; H NMR (CDCl3): d ˆ 0.21 0.32
(m, 1H), 0.51 0.63 (m, 1H), 0.83 (t, J ˆ 7.3 Hz, 3H), 1.15 (d, J ˆ 6.1 Hz,
3H), 1.36 1.53 (m, 1H), 1.56 1.71 (m, 2H), 3.56 (d, J ˆ 13.7 Hz, 2H), 3.69
(d, J ˆ 13.7 Hz, 2H), 7.24 7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 12.6,
13.3, 20.0, 25.7, 29.1, 48.1, 58.2, 126.7, 127.9, 129.4, 138.5 ppm; HRMS calcd
exo-7-(N,N-Dibenzylamino)bicyclo[4.1.0]heptane (23): According to GP
C, cyclohexene (22)(0.82 g, 10.0 mmol)and cyclohexylmagnesium bromide
(20.0 mL, 1.5 m, 30.0 mmol in THF/benzene 3:1)gave a crude product
(1.35 g)that was subjected to column chromatography (petroleum ether/
ethyl acetate, 20:1)on silica gel to afford 23 (0.80 g; 27%)as a colorless oil,
and dibenzyl(cyclohexylmethyl)amine (76)(0.53 g; 18%.) Spectroscopic
and analytical data as reported above.
‡
for C20H25N 279.1986, found 279.1986; MS (EI ): m/z (%): (mixture of two
minor isomers) 279 (5), 264 (4), 250 (12), 224 (1), 188 (90), 181 (4), 146 (2),
132 (2), 118 (5), 106 (22), 91 (100); elemental analysis calcd (%) for
C20H25N (279.4):
C 85.97, H 9.02; found: C 86.20, H 8.99. Major
diastereomer: 1H NMR (CDCl3): d ˆ 0.26 0.33 (m, 1H), 0.54 0.61 (m,
1H), 0.70 0.85 (m, 1H), 0.88 (t, J ˆ 7.2 Hz, 3H), 0.91 1.11 (m, 1H), 1.14
1.40 (m, 3H), 1.63 (sept, J ˆ 3.3 Hz, 1H), 3.69 (d, J ˆ 13.6 Hz, 2H), 3.75 (d,
J ˆ 13.6 Hz, 2H), 7.26 7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 14.0,
14.4, 21.7, 22.2, 34.7, 43.7, 57.2, 126.7, 127.9, 129.4, 138.8 ppm; HRMS calcd
N,N-Dibenzyl-9-exo-aminobicyclo[6.1.0]nonane (25): According to GP C,
cyclooctene (24)(0.54 g, 4.9 mmol)and cyclooctylmagnesium bromide
(18.5 mL, 0.825 m, 15.26 mmol)in THF/benzene 3:1 gave, without acid/
base purification, a crude product (2.28 g)that was subjected to column
chromatography (petroleum ether/ethyl acetate, 20:1)on silica gel,
3796
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0816-3796 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 16

N,N-Dialkylcyclopropylamines
3789 3801
‡
for C20H25N 279.1986, found 279.1986; MS (EI ): m/z (%): 279 (2), 250 (1),
isomers of 39b. The major diastereomer was isolated as a colorless oil
1
236 (2), 188 (39), 146 (1), 132 (2), 118 (5), 106 (10), 91 (100).
(371 mg; 25%). H NMR (CDCl3): d ˆ 0.72 0.83 (m, 1H), 0.93 1.04 (m,
1H), 1.96 2.16 (m, 2H), 3.33 (d, J ˆ 13.4 Hz, 2H), 3.58 (d, J ˆ 13.4 Hz,
2H), 3.81 (s, 3H), 6.82 6.91 (m, 2H), 7.04 7.14 (m, 3H), 7.16 7.33 ppm
(m, 9H); 13C NMR (CDCl3): d ˆ 13.4, 23.0, 43.2, 55.3, 57.3, 113.0, 126.7,
127.8, 129.2, 129.5, 130.2, 138.4, 157.7 ppm; HRMS calcd for C24H25NO
1-(N,N-Dibenzylamino)-2,3-diethylcyclopropane (32): According to GPA,
trans-3-hexene (31)(0.411 g, 4.88 mmol)after 18 h gave a crude product
which was passed through a plug of silica gel (tert-butyl methyl ether/n-
hexane, 1:4), then subjected to column chromatography (ethyl acetate/n-
hexane, 5:95/10:90 gradient)on silver nitrate impregnated silica gel. [34] The
first fraction contained one diastereomer of the title compound 32 (88 mg,
7%), other following fractions contained mixtures of two other diaster-
eomers and cyclohexyl(N,N-dibenzylamino)methane (72). A second silver
nitrate impregnated silica gel column (ethyl acetate/n-hexane, 2:98/5:95
gradient)removed amine 72 from the mixture to give an impure minor
diastereomer of 32 (6 mg; 0.5%)(only benzyl group signals could be seen
in the 1H NMR spectrum)and the second diastereomer (81 mg; 6%). First
diastereomer: 1H NMR (CDCl3): d ˆ 0.22 0.39 (m, 1H), 0.45 0.60 (m,
1H), 0.89 (t, J ˆ 6.9 Hz, 3H), 0.92 1.04 (m, 1H), 1.07 (t, J ˆ 7.4 Hz, 3H),
1.34 1.54 (m, 2H), 1.61 1.79 (m, 2H), 3.58 (d, J ˆ 13.7 Hz, 2H), 3.78 (d,
J ˆ 13.7 Hz, 2H), 7.26 7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 13.4,
14.6, 20.3, 25.8, 28.2, 28.3, 48.7, 58.1, 126.6, 127.9, 129.4, 138.9 ppm. Second
diastereomer: 1H NMR (CDCl3): d ˆ 0.68 0.79 (bm, 1H), 0.87 (t, J ˆ
7.3 Hz, 6H), 1.06 1.39 (m, 5H), 1.55 1.70 (bm, 1H), 3.65 (bs, 3H), 3.75
(s, 1H), 7.23 7.44 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 14.2, 20.3, 28.1,
50.4, 57.9, 58.1, 126.6, 126.8, 127.9, 128.2, 128.7, 129.2, 139.2 (m), 139.6 ppm;
‡
343.1936, found 343.1936; MS (EI ): m/z (%): 343 (14), 252 (47), 222 (30),
197 (3), 161 (2), 147 (8), 121 (100), 117 (4), 106 (5), 91 (86). The minor
diastereomer was isolated as a colorless solid, m.p. 68 708C (315 mg,
1
20%). H NMR (CDCl3): d ˆ 0.91 1.11 (m, 2H), 1.8 1.9 (m, 1H), 1.98
2.17 (m, 1H), 3.72 (d, J ˆ 13.5 Hz, 2H), 3.85 (d, J ˆ 13.5 Hz, 2H), 3.82 (s,
3H), 6.73 6.85 (m, 4H), 7.27 7.43 ppm (m, 10H); 13C NMR (CDCl3): d ˆ
17.0, 25.6, 47.2, 55.2, 58.4, 113.4, 126.76, 126.80, 128.0, 129.3, 134.0, 138.7,
‡
157.5 ppm; HRMS calcd for C24H25NO 343.1936, found 343.1936; MS (EI ):
m/z (%): 343 (17), 252 (46), 222 (32), 210 (7), 197 (3), 147 (9), 121 (94), 117
(5), 106 (4), 91 (100); elemental analysis calcd (%) for C24H25NO (343.5): C
83.93, H 7.34; found: C 83.90, H 7.56.
2-(2-Bromophenyl)-1-(N,N-dibenzylamino)cyclopropane (39c): Accord-
ing to GP A (but adding cHexMgBr within 20 min), 2-bromostyrene
(38c)(0.894 g, 4.88 mmol)after 20 h gave a crude product that was
subjected to careful radial chromatography (tert-butyl methyl ether/n-
hexane, 2:98)on silica gel, affording the title compound 39c (533 mg)as a
colorless oil with unidentified minor impurities (2%). The calculated yield
of pure 39c is 522 mg (30%). Major diastereomer: 1H NMR (CDCl3): d ˆ
0.91 1.02 (m, 1H), 1.09 1.21 (m, 1H), 2.13 2.23 (m, 1H), 2.36 2.48 (m,
1H), 3.71 (d, J ˆ 13.6 Hz, 2H), 3.88 (d, J ˆ 13.6 Hz, 2H), 6.75 6.83 (m,
1H), 6.98 7.08 (m, 1H), 7.15 7.45 (m, 11H), 7.51 7.58 ppm (m, 1H);
13C NMR (CDCl3): d ˆ 18.7, 26.0, 47.0, 57.6, 125.5, 126.8, 126.9, 127.2, 128.1,
129.1, 129.4, 132.5, 138.2, 140.9 ppm; HRMS calcd for C23H22BrN 391.0935,
‡
HRMS calcd for C21H27N 293.2143, found 293.2143; MS (EI ): m/z (%):
293 (5), 278 (1), 264 (22), 202 (70), 181 (3), 172 (2), 144 (1), 118 (3), 106 (9),
91 (100); elemental analysis calcd (%)for C 21H27N (293.5): C 85.95, H 9.27;
found: C 86.21, H 9.53.
7-(N,N-Dibenzylamino)spiro(cyclopropane-1,4'-bicyclo[3.1.0]hex-2-ene)
(35): According to GP A, spiro[2.4]heptadiene (34)(0.450 g, 4.88 mmol)
after 20 h, gave a crude product that was subjected to radial chromatog-
raphy (tert-butyl methyl ether/n-hexane, 2:98/10:90 gradient)on silica gel
to afford one fraction which contained a mixture of products including the
title compound 35 (< 1%). HRMS calcd for C22H23N 301.1830, found
301.1830.
‡
found 391.0935; MS (EI ): m/z (%): 393/391 (4/4), 391 (4), 312 (1), 300 (39),
287 (5), 222 (13), 210 (6), 196 (4), 169 (10), 116 (8), 91 (100). The minor
diastereomer (> 1%)was obtained as a mixture with other products which
could not be further purified.
1-(N,N-Dibenzylamino)-2-(2-trifluoromethylphenyl)cyclopropane (41a):
According to GP A, 2-trifluoromethylstyrene (40a)(0.420 g, 2.44 mmol)
after 20 h gave after above work-up a residue that was subjected to column
chromatography (ethyl acetate/n-hexane, 5:95)on silver nitrate impreg-
nated silica gel[34] to afford the title compound 41a as a mixture of
diastereomers (4:1), which was further purified by Kugelrohr distillation
(1708C/0.01 Torr)to give a colorless oil (90 mg, 11%). 1H NMR (CDCl3):
d ˆ 0.93 1.03 (m, 1H), 1.18 1.26 (m, 1H), 2.27 2.49 (m, 2H), 3.68 (d, J ˆ
13.6 Hz, 2H), 3.82 (d, J ˆ 13.6 Hz, 2H), 6.88 (d, J ˆ 7.8 Hz, 1H), 7.14 7.45
(m, 12H), 7.62 ppm (d, J ˆ 7.9 Hz, 1H); 13C NMR (CDCl3): d ˆ 20.8, 22.2,
46.8, 57.3, 117.2, 124.7 (q, J ˆ 274.2 Hz), 124.9, 125.1, 125.7 (q, J ˆ 23.0 Hz),
126.9, 128.1, 129.4, 131.6, 138.0, 141.8 ppm (q, J ˆ 5.4 Hz); HRMS calcd for
exo-7-(N,N-Dibenzylamino)bicyclo[4.1.0]hept-2-ene (37): According to
GP B at 5 108C, 1,3-cyclohexadiene (36)(1.10 g, 13.7 mmol)gave a crude
product which was passed through a plug of silica gel (hexanes). The
resulting pale yellow oil was subjected to vacuum distillation (133 1408C/
0.05 Torr), affording the title compound 37 (2.30 g, 58%). 1H NMR
(CDCl3): d ˆ 1.15 2.05 (m, 7H), 3.75 (s, 4H), 5.45 (m, 1H), 5.95 (m, 1H),
7.30 7.50 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 17.4, 20.2, 21.7, 23.9, 48.1,
58.4, 123.6, 126.8, 127.2, 128.0, 129.5, 138.6 ppm; HRMS calcd for C21H23N
‡
289.1830, found 289.1830; MS (EI ): m/z (%): 289 (7), 246 (1), 210 (5), 200
(13), 181 (4), 144 (2), 118 (3), 91 (100); elemental analysis calcd (%) for
C21H23N (289.4): C 87.14, H 8.02; found: C 87.24, H 8.23.
‡
C24H22F3N 381.1704, found 381.1704; MS (EI ): m/z (%): 381 (9), 326 (1),
306 (32), 290 (100), 286 (12), 265 (6), 251 (7), 242 (7), 224 (16), 222 (14), 185
(5), 159 (16), 127 (23), 106 (9), 91 (88); elemental analysis calcd (%) for
C24H22F3N (381.4): C 75.57, H 5.81; found: C 75.80, H 5.98.
1-(N,N-Dibenzylamino)-2-phenylcyclopropane (39a): According to GP A,
styrene (38a)(0.49 mL, 4.88 mmol)after 17 h gave a crude product that was
subjected to radial chromatography (tert-butyl methyl ether/n-hexane,
2:98/10:90 gradient)on silica gel. This afforded the E isomer as a colorless
solid (697 mg; 50%). M.p. 44 468C. Major diastereomer: 1H NMR
(CDCl3): d ˆ 0.87 1.12 (m, 2H), 1.81 1.88 (m, 1H), 2.02 2.1 (m, 1H),
3.68 (d, J ˆ 13.5 Hz, 2H), 3.81 (d, J ˆ 13.5 Hz, 2H), 6.78 6.86 (m, 2H),
7.10 7.20 ppm (m, 13H); 13C NMR (CDCl3): d ˆ 17.6, 26.4, 47.6, 58.4, 125.3,
125.7, 126.8, 127.9, 128.0, 129.3, 138.6, 142.0 ppm; HRMS calcd for C23H23N
1-(N,N-Dibenzylamino)-2-(4-trifluoromethylphenyl)cyclopropane (41b):
According to GP A, 4-trifluoromethylstyrene (40b)(0.721 mL, 0.841 g,
4.88 mmol)gave after 10 h a crude product that was subjected to radial
chromatography (tert-butyl methyl ether/n-hexane, 2:98)on silica gel,
affording 41b as a single diastereomer, as a colorless solid (300 mg; 18%).
M.p. 54 568C. 1H NMR (CDCl3): d ˆ 0.96 1.07 (m, 1H), 1.08 1.19 (m,
1H), 1.75 1.86 (m, 1H), 2.00 2.10 (m, 1H), 3.63 (d, J ˆ 13.4 Hz, 2H), 3.85
(d, J ˆ 13.4 Hz, 2H), 6.80 (d, J ˆ 8.1 Hz, 2H), 7.24 7.39 (m, 10H), 7.44 ppm
(d, J ˆ 8.1 Hz, 2H); 13C NMR (CDCl3): d ˆ 17.8, 26.6, 48.3, 58.8, 124.4 (q,
J ˆ 270.7 Hz), 124.8 (q, J ˆ 3.8 Hz), 125.8, 127.0, 127.5 (q, J ˆ 32.1 Hz),
128.1, 129.3, 138.6, 146.3 ppm; HRMS calcd for C24H22F3N 381.1704, found
‡
313.1830, found 313.1830; MS (EI ): m/z (%): 313 (5), 225 (22), 222 (43),
210 (58), 200 (6), 181 (4), 162 (2), 148 (7), 117 (6), 106 (4), 91 (100);
elemental analysis calcd (%)for C 23H23N (313.4): C 88.14, H 7.40; found: C
88.39, H 7.76. The Z isomer was isolated as a colorless oil (223 mg, 16%).
Minor diastereomer: 1H NMR (CDCl3): d ˆ 0.87 0.97 (m, 1H), 1.00 1.11
(m, 1H), 2.06 2.26 (m, 2H), 3.38 (d, J ˆ 13.4 Hz, 2H), 3.64 (d, J ˆ 13.4 Hz,
2H), 7.02 7.18 (m, 4H), 7.18 7.54 ppm (m, 11H); 13C NMR (CDCl3): d ˆ
13.5, 23.8, 43.7, 57.3, 125.4, 126.7, 127.5, 127.8, 128.4, 129.5, 138.2, 138.3 ppm;
‡
381.1704; MS (EI ): m/z (%): 381 (2), 362 (2), 290 (53), 222 (5), 200 (15),
185 (6), 159 (13), 131 (4), 118 (5), 106 (16), 91 (100); elemental analysis
calcd (%)for C 24H22F3N (381.4): C 75.57, H 5.81; found: C 75.40, H 5.82.
‡
HRMS calcd for C23H23N 313.1830, found 313.1830; MS (EI ): m/z (%):
1-(N,N-Dibenzylamino)-2-(3-trifluoromethylphenyl)cyclopropane (41c):
According to GP A, 3-trifluoromethylstyrene (40c)(0.420 g, 2.44 mmol)
and N,N-dibenzylformamide (500 mg, 2.22 mmol)gave after 24 h a crude
product that was subjected to column chromatography (ethyl acetate/n-
hexane, 5:95)on silver nitrate impregnated silica gel, [34] affording 41c as a
mixture of diastereomers (11.5:1), as a colorless oil (390 mg; 46%).
1H NMR (CDCl3): d ˆ 1.06 1.23 (m, 2H), 1.80 1.89 (m, 1H), 2.05 2.13
(m, 1H), 3.69 (d, J ˆ 13.3 Hz, 2H), 3.96 (d, J ˆ 13.3 Hz, 2H), 6.91 7.0 (m,
313 (1), 222 (12), 181 (2), 165 (1), 132 (4), 117 (6), 106 (5), 91 (100);
elemental analysis calcd (%)for C 23H23N (313.4): C 88.14, H 7.40; found: C
88.28, H 7.35.
1-(N,N-Dibenzylamino)-2-(4-methoxyphenyl)cyclopropane (39b): Ac-
cording to GP A, 4-methoxystyrene (38b)(0.655 g, 4.88 mmol)after 12 h
gave a crude product that was subjected to radial chromatography (tert-
butyl methyl ether/n-hexane, 2:98)on silica gel, affording the E and Z
Chem. Eur. J. 2002, 8, No. 16
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0816-3797 $ 20.00+.50/0
3797

A. de Meijere et al.
FULL PAPER
2H), 7.25 7.50 ppm (m, 12H); 13C NMR (CDCl3): d ˆ 17.0, 26.7, 48.2, 59.0,
122.1 (q, J ˆ 15.2 Hz), 122.7 (q, J ˆ 15.0 Hz), 124.6 (q, J ˆ 226.4 Hz), 127.0,
128.15, 128.24, 128.6, 129.3, 130.1 (m), 138.6, 143.0 ppm; HRMS calcd for
1-(N,N-Dibenzylamino)-2-(N,N-dibenzylaminomethyl)cyclopropane
(47b): According to GP D, N,N-dibenzylformamide (2.00 g, 8.88 mmol),
N,N-dibenzylallyamine (46)(2.32 g, 9.78 mmol,) [MeTi(O iPr)3] (2.56 g,
10.7 mmol)in anhydrous THF (40 mL,) and cyclohexylmagnesium bro-
mide (12.2 mL, 17.8 mmol, 1.46 m solution in diethyl ether, addition within
‡
C24H22F3N 381.1704, found 381.1704; MS (EI ): m/z (%): 381 (5), 362 (1),
326 (1), 306 (58), 290 (67), 286 (18), 265 (7), 251 (7), 242 (10), 224 (26), 222
(11), 185 (3), 168 (6), 159 (20), 133 (12), 127 (41), 106 (3), 91 (100);
elemental analysis calcd (%)for C 24H22F3N (381.4): C 75.57, H 5.81; found:
C 75.87, H 5.94.
1
2 min)gave the crude product 47b which was further purified by column
chromatography on deactivated (NEt3)silica gel (petroleum ether/diethyl
ether, PE/DE 10:1)to yield a mixture (1:4, according to 1H NMR
spectroscopy)of two diastereomers (1.53 g; 39%.) Minor diastereomer:
1H NMR (CDCl3): d ˆ 0.24 (m, 1H), 0.71 (m, 1H), 1.04 (m, 1H), 1.92 (m,
1H), 2.48 2.64 (m, 2H), 3.40 3.80 (m, 8H); 7.00 7.50 ppm (m, 20H);
13C NMR (CDCl3): d ˆ 12.8, 17.1, 41.1, 51.5, 58.0, 58.5, 126.6, 127.9, 128.1,
128.7, 128.9, 129.3, 138.4, 140.1 ppm. Major diastereomer: 1H NMR
(CDCl3): d ˆ 0.32 (m, 1H), 0.63 (m, 1H), 0.97 (m, 1H), 1.58 (m, 1H),
2.03 (dd, J ˆ 13.2, 7.9 Hz, 1H), 2.42 (dd, J ˆ 13.2, 5.5 Hz, 1H), 3.51 (d, J ˆ
13.7 Hz, 2H), 3.59 (d, J ˆ 13.7 Hz, 2H), 3.65 (d, J ˆ 13.5 Hz, 2H), 3.73 (d,
J ˆ 13.5 Hz, 2H), 7.10 7.50 ppm (m, 20H); 13C NMR (CDCl3): d ˆ 14.5,
19.3, 42.4, 55.8, 57.9, 58.4, 126.7, 126.8, 128.0, 128.1, 128.6, 129.3, 138.8,
1-(N,N-Dibenzylamino)-2-[3,5-bis(trifluoromethyl)phenyl]cyclopropane
(41d): According to GP A, 3,5-bis(trifluoromethyl)styrene (40d)(1.173 g,
4.88 mmol)gave after 24 h a crude product that was subjected to column
chromatography (ethyl acetate/n-hexane, 5:95)on silver nitrate impreg-
nated silica gel[34] to afford 41d as a mixture of diastereomers (16:1), which
was further purified by Kugelrohr distillation (1708C/0.01 Torr)to give a
colorless oil (172 mg; 9%). 1H NMR (CDCl3): d ˆ 1.05 1.27 (m, 2H),
1.69 1.80 (m, 1H), 1.96 2.41 (m, 1H), 3.58 (d, J ˆ 13.2 Hz, 2H), 3.97 (d,
J ˆ 13.2 Hz, 2H), 6.98 (s, 2H), 7.10 7.50 (m, 10H), 7.66 ppm (s, 1H);
13C NMR (CDCl3): d ˆ 16.7, 27.0, 48.9, 59.6, 119.1 (sextet, J ˆ 3.9 Hz), 123.4
(q, J ˆ 272.6 Hz), 125.6 (m), 127.2, 128.3, 129.3, 131.0 (q, J ˆ 32.8 Hz), 138.9,
144.6 ppm; HRMS calcd for C25H21F6N 449.1578, found 449.1578; MS
‡
139.9 ppm. Diastereomeric mixture: MS (EI ): m/z (%): 446 (<1), 355 (8),
249 (20), 236 (20), 210 (80), 91 (100); elemental analysis calcd (%) for
C32H34N2 (446.4): C 86.05, H 7.67; found: C 85.87, H 7.91.
‡
(EI ): m/z (%): 449 (6), 430 (3), 358 (100), 287 (3), 253 (4), 224 (9), 222 (6),
trans-1-(N,N-Dibenzylamino)-2-trimethylsilylcyclopropane (49): Accord-
ing to GP D, N,N-dibenzylformamide (2.00 g, 8.88 mmol), ethenyltrime-
thylsilane (48)(1.07 g, 10.66 mmol), [MeTi(O iPr)3] (2.56 g, 10.65 mmol)in
anhydrous THF (20 mL), and cyclohexylmagnesium bromide (17.0 mL,
22.6 mmol, 1.33 m solution in diethyl ether, addition over 1 h)gave the
crude product 49 which was purified from side products [1,1'-bicyclohexyl
(71)] by distillation in a Kugelrohr at 100 8C/0.01 Torr. The pure 49 was
obtained by repeated distillation at 150 1758C/0.01 Torr (colorless oil,
1.62 g; 59%)as the single trans isomer according to H,H NOESY. 1H NMR
(CDCl3): d ˆ À0.24 to À0.14 (m, 1H), À0.07 (s, 9H), 0.34 0.41 (m, 1H),
0.56 0.63 (m, 1H), 1.79 1.84 (m, 1H), 3.64 (d, J ˆ 13.6 Hz, 2H), 3.76 (d,
J ˆ 13.6 Hz, 2H), 7.23 7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ À2.2,
7.5, 11.8, 41.0, 58.7, 126.7, 128.0, 128.1, 139.1 ppm; HRMS calcd for
C20H27NSi: 309.1912, found 309.1912; MS: m/z (%): 309 (30), 294 (5), 236
(75), 218 (15), 91 (100), 73 (20); elemental analysis calcd (%) for C20H27NSi
(309.5): C 77.61, H 8.79; found: C 77.59, H 9.02.
196 (3), 160 (6), 130 (2), 118 (3), 91 (71).
1-(N,N-Dibenzylamino)-2-furanylcyclopropane (43): According to GP A,
2-ethenylfuran (42)(0.460 g, 4.89 mmol)gave after 24 h a crude product
that was subjected to radial chromatography (tert-butyl methyl ether/n-
hexane, 5:95)on silica gel to afford a mixture ( cis/trans ˆ 1:4)of 43
(576 mg; 43%)and trace amounts of exo-7-(N,N-dibenzylamino)bicy-
clo[4.1.0]heptane (23)as a colorless oil. Minor diastereomer: 1H NMR
(CDCl3): d ˆ 0.88 0.94 (m, 1H), 1.01 1.10 (m, 1H), 2.01 2.10 (m, 1H),
2.13 2.20 (m, 1H), 3.40 (d, J ˆ 13.6 Hz, 2H), 3.72 (d, J ˆ 13.6 Hz, 2H),
6.01 6.12 (m, 1H), 6.37 6.40 (m, 1H), 7.09 7.45 ppm (m, 11H); 13C NMR
(CDCl3): d ˆ 13.0, 17.0, 42.7, 57.1, 106.3, 110.3, 126.7, 127.9, 129.4, 138.3,
140.8, 153.9 ppm. Major diastereomer: 1H NMR (CDCl3): d ˆ 0.95 1.09
(m, 2H), 1.85 1.93 (m, 1H), 2.16 2.22 (m, 1H), 3.77 (dd, J ˆ 13.5, 15.5 Hz,
4H), 5.80 5.82 (m, 1H), 6.28 (dd, J ˆ 1.9, 3.2 Hz, 1H), 7.24 7.46 ppm (m,
11H); 13C NMR (CDCl3): d ˆ 15.7, 19.4, 44.5, 58.0, 103.7, 110.2, 126.9, 128.0,
129.4, 138.3, 140.2, 155.5 ppm; HRMS calcd for C21H21NO 303.1623, found
1-(N,N-Dibenzylamino)-2-trimethylsilylmethylcyclopropane (51): Accord-
ing to GP D, N,N-dibenzylformamide (2.00 g, 8.88 mmol), allyltrimethylsi-
lane (50)(1.217 g, 10.65 mmol,) [MeTi(O iPr)3] (2.133 g, 8.88 mmol)in
anhydrous THF (20 mL)and cyclohexylmagnesium bromide (9.1 mL,
13.3 mmol, 1.46 m solution in diethyl ether, addition within 1 2 min)gave
the crude product 51 which was further purified by column chromatog-
raphy on silica gel (PE/DE 10:1, Rf ˆ 0.60)to yield one single diastereomer
(0.805 g; 28%). 1H NMR (CDCl3): d ˆ À0.10 0.10 (br s, 10H), 0.19 (m,
1H), 0.54 (m, 2H), 0.73 (m, 1H), 1.50 (m, 1H), 3.60 (d, J ˆ 13.3 Hz, 2H),
3.75 (d, J ˆ 13.3 Hz, 2H), 7.20 7.50 ppm (m, 10H); 13C NMR (CDCl3): d ˆ
À1.5, 16.0, 17.4, 20.1, 45.2, 58.6, 126.7, 127.9, 129.4, 139.0 ppm; HRMS calcd
‡
303.1623; MS (EI ): m/z (%): (mixture) 303 (8), 287 (1), 224 (4), 222 (7),
212 (19), 210 (5), 181 (2), 146 (2), 132 (2), 117 (4), 106 (9), 91 (100).
1-(N,N-Dibenzylamino)-2-ethoxycyclopropane (45): According to GP A,
ethenyl ethyl ether (44)(0.352 g, 4.88 mmol)gave after 9 h a crude product
that was subjected to radial chromatography (tert-butyl methyl ether/n-
hexane, 2:98/10:90 gradient)on silica gel to afford 45 (52 mg; 4%)as a
colorless oil. 1H NMR (CDCl3): d ˆ 0.60 0.70 (m, 1H), 0.77 0.85 (m, 1H),
1.08 (t, J ˆ 7.0 Hz, 3H), 2.0 2.06 (m, 1H), 3.1 3.15 (m, 1H), 3.19 3.44 (m,
2H), 3.68 (s, 4H), 7.22 7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 15.0,
15.5, 43.2, 57.4, 60.9, 65.4, 126.8, 128.0, 129.2, 138.4 ppm; HRMS calcd for
‡
‡
C19H23NO 281.1779, found 281.1779; MS (EI ): m/z (%): 281 (4), 252 (18),
for C21H29NSi 323.2069, found 323.2069; MS (EI ): m/z (%): 323 (8), 308
225 (3), 210 (6), 190 (26), 181 (4), 146 (6), 132 (2), 91 (100).
(5), 250 (15), 232 (70), 91 (100), 73 (42); elemental analysis calcd (%) for
C21H29NSi (323.6): C 77.79, H 8.92; found: C 77.88, H 9.02..
1-(N,N-Dimethylamino)-2-(N,N-dibenzylaminomethyl)cyclopropane
(47a): According to GP D, cyclohexylmagnesium bromide (12.0 mL,
16.80 mmol, 1.4 m solution in THF)was added over 10 s to a solution of
N,N-dibenzylallylamine (46)(2.00 g, 8.43 mmol), N,N-dimethylformamide
(0.616 g, 8.43 mmol), and [MeTi(OiPr)3] (3.04 g, 12.65 mmol)in anhydrous
THF (20 mL)at ambient temperature under an atmosphere of argon. After
5 h the above mentioned work-up gave a crude product that was subjected
to column chromatography (diethyl ether/petroleum ether/triethylamine,
1:1:0/49:49:2 gradient)on silica gel to afford a mixture (1:5)of two
1-(N,N-Dibenzylamino)-2-ethenylcyclopropane (53): According to GP D,
cooled solutions (08C)of [MeTi(O iPr)3] (16.10 g, 67.0 mmol)in THF
(20 mL)and N,N-dibenzylformamide (15.1 g, 67.0 mmol)in THF (20 mL)
were added to a solution of butadiene (9.10 g, 168.2 mmol)in anhydrous
THF (150 mL)at À408C under nitrogen. Cyclohexylmagnesium bromide
(46 mL, 80.5 mmol, 1.75 m in diethyl ether)was added at À208C within
5 min. After 1 h at À20 to À108C and stirring at ambient temperature for
12 h, the reaction was quenched with water (50 mL)and worked up as
above. Column chromatography (hexanes)on silica gel gave the title
compound 53 (9.90 g; 56%). 1H NMR (CDCl3): d ˆ 0.81 (m, 1H), 0.96 (m,
1H), 1.50 (m, 1H), 1.99 (m, 1H), 3.80 (d, J ˆ 14.0 Hz, 2H), 3.91 (d, J ˆ
14.0 Hz, 2H), 5.01 (dd, J ˆ 1.7, 17.7 Hz, 1H), 5.03 (dd, J ˆ 1.7, 9.6 Hz, 1H),
5.46 5.60 (m, 1H), 7.25 7.50 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 16.0,
25.5, 45.3, 58.4, 112.3, 126.9, 128.1, 129.5, 138.7, 139.8 ppm; HRMS calcd for
1
diastereomers (1.09 g; 44%). Minor diastereomer: H NMR (CDCl3): d ˆ
0.24 (m, 1H), 0.74 (m, 1H), 0.98 (m, 1H), 1.55 (m, 1H), 2.24 (s, 6H), 2.40
(dd, J ˆ 8.1, 13.0 Hz, 1H), 3.00 (dd, J ˆ 4.4, 13.0 Hz, 1H), 3.54 (d, J ˆ
13.8 Hz, 2H), 3.82 (d, J ˆ 13.8 Hz, 2H), 7.20 7.45 ppm (m, 10H);
13C NMR (CDCl3): d ˆ 12.6, 16.7, 43.6, 45.9, 52.6, 58.2, 126.6, 128.0, 128.8,
140.0 ppm. Major diasteromer: 1H NMR (CDCl3): d ˆ 0.28 (m, 1H), 0.62
(m, 1H), 1.11 (m, 1H), 1.31 (m, 1H) 2.22 (dd, J ˆ 7.4, 13.3 Hz, 1H), 2.33
2.42 (m, 7H), 3.61 (d, J ˆ 13.7 Hz, 2H), 3.69 (d, J ˆ 13.7 Hz, 2H), 7.20
7.45 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 13.0, 18.4, 45.2, 46.4, 55.9, 58.1,
‡
C19H21N 263.1673, found 263.1673; MS (EI ): m/z (%): 263 (9), 234 (5), 172
(48), 91 (100); elemental analysis calcd (%) for C19H21N (263.4): C 86.65, H
8.04; found: C 86.79, H 8.11.
‡
126.7, 128.2, 128.6, 139.9 ppm; MS (EI ): m/z (%): 294 (3), 250 (20), 210
1-(N,N-Dibenzylamino)-2-ethenyl-2-methylcyclopropane (55): According
to GPA, isoprene (54)(0.333 g, 4.89 mmol)gave after 15 h a crude product
that was subjected to radial chromatography (tert-butyl methyl ether/n-
(100), 91 (90); elemental analysis calcd (%) for C20H26N2 (294.4): C 81.59, H
8.90; found: C 81.35, H 8.78.
3798
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0816-3798 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 16

N,N-Dialkylcyclopropylamines
3789 3801
hexane, 2:98/10:90 gradient)on silica gel to afford the title compound 55 as
a colorless oil (730 mg; 59%). 1H NMR (CDCl3): d ˆ 0.51 (t, J ˆ 4.8 Hz,
1H), 0.81 (dd, J ˆ 4.8, 7.4 Hz, 1H), 1.24 (s, 3H), 1.90 (dd, J ˆ 4.8, 7.4 Hz,
1H), 3.60 (d, J ˆ 13.6 Hz, 2H), 3.66 (d, J ˆ 13.6 Hz, 2H), 4.87 (s, 1H), 4.92
(d, J ˆ 10.4 Hz, 1H), 5.45 (dd, J ˆ 10.4, 17.3 Hz, 1H), 7.25 7.38 ppm (m,
10H); 13C NMR (CDCl3): d ˆ 15.2, 21.5, 26.0, 49.9, 57.8, 109.7, 126.8, 128.0,
129.5, 138.3, 145.6 ppm; HRMS calcd for C20H23N 277.1830, found 277.1830;
MS (EI ): m/z (%): 277 (10), 262 (3), 249 (5), 224 (11), 222 (7), 200 (3), 186
(31), 159 (1), 132 (4), 117 (3), 106 (7), 91 (100); elemental analysis calcd (%)
for C20H23N (277.4): C 86.59, H 8.36; found: C 86.37, H 8.18.
(m, 2H), 3.48 (d, J ˆ 13.5 Hz, 2H), 3.50 (d, J ˆ 13.7 Hz, 2H), 3.78 (d, J ˆ
13.7 Hz, 2H), 3.81 (d, J ˆ 13.5 Hz, 2H), 4.62 (bd, J ˆ 9.3 Hz, 1H), 4.80 (m,
2H), 5.01 5.23 (m, 2H), 5.30 (bd J ˆ 9.3 Hz, 1H), 5.37 5.52 (m, 1H),
5.93 6.08 (m, 1H), 7.25 7.48 ppm (m, 20H); 13C NMR (CDCl3): d ˆ 18.1,
18.2, 25.5, 25.8, 27.5, 29.3, 32.6, 33.1, 50.1, 50.5, 57.2, 57.3, 112.3, 113.6, 122.3,
124.7, 126.8, 127.97, 128.00, 129.4, 129.5, 131.7, 131.9, 137.2, 138.2, 138.3,
1
139.1 ppm. Minor, mixture of three: H NMR (CDCl3): d ˆ 1.28 1.35 (m,
‡
1H), 1.49 1.62 (m, 1H), 1.55 (s, 3H), 1.71 (s, 3H), 1.91 1.94 (m, 1H), 3.71
(s, 4H), 4.98 (d, J ˆ 16.2 Hz, 1H), 5.01 5.23 (m, 2H), 5.93 6.07 (m, 1H),
7.26 7.42 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 18.2, 25.7, 28.4, 32.6, 51.9,
57.8, 114.5, 121.2, 126.8, 128.0, 129.4, 133.3, 136.5, 138.1 ppm; HRMS calcd
1-(N,N-Dibenzylamino)-2-ethenyl-3,3-dimethylcyclopropane (58): Ac-
cording to GP A, 4-methyl-1,3-pentadiene (57)(0.401 g, 4.88 mmol)gave
after 10 h a crude product that was subjected to radial chromatography
(tert-butyl methyl ether/n-hexane, 2:98/10:90 gradient)on silica gel to
afford 58 as a colorless oil (824 mg; 64%), 1:5.3 mixture of diastereomers
according to 1H NMR. Major diastereomer: 1H NMR (CDCl3): d ˆ 0.99 (s,
3H), 1.09 (s, 3H), 1.14 (dd, J ˆ 4.0, 9.3 Hz, 1H), 1.70 (d, J ˆ 4.0 Hz, 1H),
3.60 (s, 4H), 4.90 (m, 1H), 4.95 (s, 1H), 5.49 (m, 1H), 7.22 7.41 ppm (m,
10H); 13C NMR (CDCl3): d ˆ 20.7, 21.0, 26.5, 35.9, 56.0, 57.9, 114.1, 126.8,
128.0, 129.5, 137.5, 138.3 ppm. Minor diastereomer: 1H NMR (CDCl3): d ˆ
1.07 (s, 6H), 1.39 (dd, J ˆ 7.3, 10.01 Hz, 1H), 1.85 (d, J ˆ 7.3 Hz, 1H), 3.50
(d, J ˆ 13.9 Hz, 2H), 3.68 (d, J ˆ 13.9 Hz, 2H), 5.02 (dd, J ˆ 2.2, 10.3 Hz,
1H), 5.15 (dd, J ˆ 2.2, 17.2 Hz, 1H), 5.91 (dt, J ˆ 10.3, 17.2 Hz, 1H), 7.22
7.41 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 15.1, 24.3, 27.0, 33.5, 52.1, 56.3,
114.7, 126.8, 128.0, 129.6, 135.8, 137.7 ppm; HRMS calcd for C21H25N
‡
for C23H27N 317.2143, found 317.2143; MS (EI )(mixture:) m/z (%):317
(20), 302 (7), 274 (2), 248 (4), 226 (9), 222 (5), 184 (2), 177 (5), 158 (6), 132
(9), 106 (5), 91 (100).
Debenzylation
of
3-benzyl-6-exo-(N,N-dibenzylamino)-3-azabicy-
clo[3.1.0]hexane (10a): 6-exo-amino-3-azabicyclo[3.1.0]hexane (10e):
10% Pd/C (1.06 g, 10 mol%)was added to a stirred solution of 3-benzyl-
6-exo-(dibenzylamino)-3-azabicyclo[3.1.0]hexane
(10a)(3.70 g,
10.05 mmol)in methanol (40 mL.) Hydrogen was passed through the
suspension for 12 h. The catalyst was removed by using a celite pad, which
was then washed with methanol (50 mL). The combined filtrates were
evaporated at reduced pressure, the residue dissolved in diethyl ether
(50 mL), and dried (KOH). The diethyl ether was removed in vacuo and
the residue subjected to Kugelrohr distillation (1108C/6 Torr), affording
exo-6-amino-3-azabicyclo[3.1.0]hexane (10e)(0.92 g; 93%)as colorless
crystals. M.p. 508C. 1H NMR (CDCl3): d ˆ 1.17 1.19 (bdd, J ˆ 2.1, 3.2,
2H), 1.58 (s, 3H), 1.90 1.91 (bt, J ˆ 2.1, 1H), 2.67 2.72 (m, 2H), 2.84 ppm
‡
291.1986, found 291.1986; MS (EI )(mixture of diastereomers): m/z (%):
291 (18), 276 (34), 248 (4), 234 (3), 224 (9), 222 (6), 200 (18), 181 (3), 174
(14), 158 (2), 146 (10), 132 (6), 117 (5), 106 (2), 91 (100); elemental analysis
calcd (%)for C 21H25N (291.4): C 86.55, H 8.65; found: C 86.78, H 8.49.
‡
(d, J ˆ 11.3, 2H); 13C NMR (CDCl3): d ˆ 26.6, 31.4, 47.8 ppm; MS (CI ):
m/z (%): 197 (100), 116 (84). X-ray crystal structure analysis: see below.[20]
1-(N,N-Dibenzylamino)-2-ethenyl-2-(4-methylpent-3-en-1-yl)cyclopro-
pane (62): According to GP A, 0.923 mL of 90% myrcene (61)(0.665 g of
pure 61, 4.88 mmol)gave after 16 h a crude product that was subjected to
radial chromatography (tert-butyl methyl ether/n-hexane, 2:98/10:90 gra-
dient)on silica gel to afford 62 as a colorless oil (783 mg, 51%). 1H NMR
(CDCl3): d ˆ 0.49 (t, J ˆ 5.0 Hz, 1H), 0.91 (bt, J ˆ 5.0 Hz, 1H), 1.62 (s, 3H),
1.73 (s, 3H), 1.81 (dd, J ˆ 5.0, 7.2 Hz, 1H), 1.85 2.05 (m, 2H), 2.05 2.29
(m, 2H), 3.59 (d, J ˆ 13.8 Hz, 2H), 3.66 (d, J ˆ 13.8 Hz, 2H), 4.84 (dd, J ˆ
1.3, 17.3 Hz, 1H), 4.91 (dd, J ˆ 1.3, 10.6 Hz, 1H), 5.17 (m, 1H), 5.65 (dd, J ˆ
10.6, 17.3 Hz, 1H), 7.25 7.35 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 17.7,
19.2, 25.7, 26.7, 29.8, 30.8, 50.9, 57.6, 110.8, 125.0, 126.8, 128.0, 129.5, 131.1,
138.2, 143.5 ppm; HRMS calcd for C25H31N 345.2457, found 345.2456; MS
Debenzylation
of
3-benzyl-6-exo-(N,N-dibenzylamino)-3-azabicy-
clo[3.1.0]hexane (10a) in the presence of acetic acid: 6-exo-amino-3-
azabicyclo[3.1.0]hexane (10e): Acetic acid (1.5 mL)was added to a stirred
solution of 3-benzyl-6-exo-(dibenzylamino)-3-azabicyclo[3.1.0]hexane
(10a)(4.85 g, 13.16 mmol)in methanol (80 mL). After 10 min 10% Pd/C
(234 mg, 1.7 mol%)was added. Hydrogen was then passed through the
suspension for 20 h. The catalyst was removed by using a celite pad, which
was then washed with methanol (50 mL). The combined filtrates were
evaporated at reduced pressure, the residue dissolved in diethyl ether
(50 mL)and dried with KOH. The diethyl ether was removed in vacuo and
the residue subjected to Kugelrohr distillation (1108C/6 Torr), affording
exo-6-amino-3-azabicyclo[3.1.0]hexane (10e)(1.20 g; 93%)as a colorless
solid.
‡
(EI ): m/z (%): 345 (17), 316 (1), 287 (2), 276 (38), 254 (6), 239 (2), 224 (21),
210 (12), 200 (7), 181 (6), 174 (1), 146 (7), 106 (6), 91 (100); elemental
analysis calcd (%)for C 25H31N (345.5): C 86.90, H 9.04; found: C 87.10, H
9.18.
Debenzylation of 3-tert-butoxycarbonyl-6-exo-(N,N-dibenzylamino)-3-
azabicyclo[3.1.0]hexane (10d): 3-tert-butoxycarbonyl-6-exo-amino-3-aza-
bicyclo[3.1.0]hexane (10 f): Hydrogen was passed through the mixture of
10% Pd/C (0.50 g, 11 mol%)in MeOH (10 mL)over 1 h, and a solution of
3-tert-butoxycarbonyl-6-exo-(dibenzylamino)-3-azabicyclo[3.1.0]hexane
(10d)(1.56 g, 4.12 mmol)in methanol (15 mL)was added in one portion,
and hydrogen was passed through the stirred suspension for additional
12 h. The catalyst was removed by using a celite pad, which was then
washed with methanol (20 mL). The combined filtrates were evaporated at
reduced pressure affording 10 f as a colorless solid (803 mg, 98%). M.p.
418C. 1H NMR (C6D6): d ˆ 1.10 1.25 (bm, 2H), 1.46 (s, 9H), 1.68 (t, J ˆ
2.0 Hz, 1H), 1.71 (bs, 2H), 3.10 (dd, J ˆ 3.7, 10.4 Hz, 1H), 3.25 (dd, J ˆ 3.9,
10.9 Hz, 1H), 3.38 (d, J ˆ 10.5 Hz, 1H), 3.65 ppm (d, J ˆ 10.9 Hz, 1H);
13C NMR (CDCl3): d ˆ 25.4, 26.2, 28.5, 35.5, 48.0, 78.7, 154.2 ppm; HRMS
trans-1-(N,N-Dibenzylamino)-2-phenyl-3-(2-phenylethenyl)cyclopropane
(64): According to GP A, 1,4-diphenylbutadiene (63)(2.014 g, 9.76 mmol)
gave after 20 h a crude product that was passed through a plug of silica gel
(tert-butyl methyl ether/n-hexane, 3:7)to afford a mixture of 64 and exo-7-
(N,N-dibenzylamino)bicyclo[4.1.0]heptane (23). The mixture was subjected
to Kugelrohr distillation (110 1208C/0.01 Torr)which removed 23 to leave
a residue which was washed with small amounts of cold n-hexane to afford
64 (327 mg, 9%)as a colorless solid, which was recrystallized from n-
hexane, m.p. 88 898C. (Note: Prolonged heating of the title compound 64
was found to partially isomerize the double bond). 1H NMR (CDCl3): d ˆ
2.09 (dt, J ˆ 3.7, 9.7 Hz, 1H), 2.55 2.65 (m, 2H), 3.84 (d, J ˆ 13.5 Hz, 2H),
4.01 (d, J ˆ 13.5 Hz, 2H), 5.69 (dd, J ˆ 9.7, 15.8 Hz, 1H), 6.29 (d, J ˆ
15.7 Hz, 1H), 7.23 7.48 ppm (m, 20H); 13C NMR (CDCl3): d ˆ 33.3, 33.8,
50.4, 58.1, 125.6, 126.0, 126.6, 126.9, 127.7, 128.1, 128.3, 128.8, 129.3, 129.4,
130.2, 137.6, 137.8, 138.4 ppm; HRMS calcd for C31H29N 415.2299, found
‡
calcd for C10H18N2O2 198.1368, found 198.1368; MS (CI ): m/z (%): 198 (2),
142 (12), 125 (12), 69 (100), 57 (28); elemental analysis calcd (%) for
C10H18N2O2 (198.3): C 60.58, H 9.15; found: C 59.65, H 9.15. X-ray crystal
structure analysis: see below.[20]
‡
415.2299; MS (EI ) m/z (%): 415 (35), 338 (3), 324 (20), 310 (9), 298 (7), 246
Carried out on larger scale, this hydrogenative debenzylation of 10d
(35.0 g, 92.4 mmol)with Pd/C (10%, Merck Lot S 30499 135)(3.0 g,
2.8 mmol)gave 10 f (18.0 g; 98%).
(2), 233 (5), 219 (6), 193 (12), 167 (2), 156 (4), 129 (5), 117 (18), 91 (100).
1-(N,N-Dibenzylamino)-2-ethenyl-3-(2-methylpropenyl)cyclopropane
(66): According to GP A, 6-methyl-1,3,5-heptatriene (65)(0.528 g,
4.88 mmol)gave after 26 h a crude product that was subjected to radial
chromatography (tert-butyl methyl ether/n-hexane, 8:92)on silica gel,
affording a mixture of the title compound 66 (758 mg, 54%)(ratio of
diastereomers 1:1.5:1.5 according 1H NMR)and trace amounts of exo-7-
(N,N-dibenzylamino)bicyclo[4.1.0]heptane (23)as a colorless oil. Two
major diastereomers: 1H NMR (CDCl3): d ˆ 1.29 1.36 (m, 1H), 1.47 (s,
3H), 1.49 1.62 (m, 3H), 1.69 (s, 3H), 1.73 (s, 3H), 1.78 (s, 3H), 2.05 2.11
6-exo-N,N-Dibenzylamino-3-azabicyclo[3.1.0]hexane (10g): A solution of
3-N-tert-butoxycarbonyl-6-exo-N,N-dibenzylamino-3-azabicyclo[3.1.0]hex-
ane (10d)(10 g, 26.4 mmol)in trifluoroacetic acid (20 mL, 261 mmol)was
stirred at ambient temperature for 1 h. The excess trifluoroacetic acid was
evaporated under reduced pressure, and the residue taken up in methanol
(30 mL). Poly-4-vinylpyridine (5.0 g) was added to this solution, and the
mixture was stirred for 1 h. The solution was filtered, and the solvent
Chem. Eur. J. 2002, 8, No. 16
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A. de Meijere et al.
FULL PAPER
evaporated under reduced pressure to give 10g (7.21 g; 98%)as a light
yellow solid, m.p. 68.08C. 1H NMR (300 MHz, CDCl3): d ˆ 1.86 (bs, 2H,
1-H, 5-H), 2.69 (bs, 1H, 6-H), 3.08 (bs, 4H, 2-H, 4-H), 4.21 (s, 4H, benzyl-
H), 7.31 7.43 ppm (m, 10H, aryl-H); 13C NMR (50.3 MHz, CDCl3,
additional APT): d ˆ 22.7 (‡) , 41.9 ‡( ), 46.6 (À), 60.2 (À), 129.1 (‡),
129.9 (‡), 130.1 (À), 131.1 (‡); MS (EI): m/z (%): 278 (10), 249 (20), 187
(41), 158 (39), 131 (8), 91 (100), 41 (9); elemental analysis calcd (%) for
C19H22N2 (278.2): C 82.09, H 7.98; found: C 82.24, H 7.72.
slow concentration of a dilute solution in hexane (28). The data were
collected on a STOE AED2 diffractometer using graphite-monochromated
MoKa radiation. The structure solutions and refinements were performed
with the SHELX program suite (Version 5.10).[20b] All non-hydrogen atoms
were refined anisotropically. The hydrogen atoms were located in a
difference Fourier map and refined as riding groups with the 1.2 fold
isotropic displacement parameter of the corresponding C atom. Relevant
N-Benzyl-3-isopropylpyrrolidine (18): Isopropylmagnesium chloride
(15.3 mL, 30.2 mmol, 1.96 m in THF)was added within 10 min to a solution
of [Ti(OiPr)4] (3.05 mL, 10.4 mmol)and N-benzyl-3-pyrroline[35] (15a)
(1.50 g, 9.4 mmol)in anhydrous THF (40 mL)under an atmosphere of
nitrogen at ambient temperature. The mixture was heated under reflux for
30 min, and then the reaction was quenched by addition of water (50 mL)
to the hot mixture. Stirring was continued until the precipitate had turned
colorless. The precipitate was removed by filtration and washed with
diethyl ether (2 Â 30 mL). The combined filtrates were dried (MgSO4)and
concentrated under reduced pressure, giving a residue that was subjected to
flash column chromatography (hexane/EtOAc 10:1)on silica gel to give
four fractions. Fraction I, after Kugelrohr distillation (0.602 g)consisted of
the title compound 18 and N-benzylpyrrole in a ratio of 12.5:1 (according to
1H NMR spectroscopy). Fraction II (0.212 g) was pure 18.[36] Fraction III
(0.127 g)contained 18, N-benzylpyrrolidine,[37] the starting material 15, and
an unidentified compound in a ratio of 9:8:1:2. The total amount of 18 in
Table 4. Crystal and data collection parameters for compounds 10d f, and 28.
10d
10e
10 f
28
formula
C24H30N2O2 C5H10N2
C10H18N2O2 C38H42N2
molecular mass
temperature [K]
crystals
378.50 98.15
203(2)150(2)150(2)152(2)
monoclinic monoclinic monoclinic monoclinic
198.26 526.74
crystal size [Â10 mm]
8 Â 6 Â 4
10 Â 8 Â 1
7 Â 5 Â 5
6 Â 4 Â 2
space group
a [ä]
b [ä]
c [ä]
a [8]
P2(1)/n
Cc
P2(1)
P2(1)/n
8.7624(18)9.501(2) 8.3030(17)12.563(2)
27.821(9)5.7455(115).9438(129).632(3)
8.8431(18)10.150(2) 11.349(2) 12.690(2)
90
99.224(14)103.50(3) 93.56(3) 99.82(2)
90 90 90
2127.9(9)538.8(2) 559.0(2) 1513.1(5)
90
90
90
90
2
b [8]
g [8]
V [ä3]
Z
1
these fractions corresponds to a yield of 44%. H NMR (CDCl3): d ˆ 0.85
4
4
2
(d, J ˆ 6.6 Hz, 3H), 0.88 (d, J ˆ 6.6 Hz, 3H)1.40 1.60 (m, 2H), 1.90 2.05
(m, 1H), 2.05 2.15 (m, 2H), 2.35 2.45 (m, 1H), 2.80 3.00 (m, 2H), 3.61
(d, J ˆ 12.7 Hz, 1H), 3.67 (d, J ˆ 12.7 Hz, 1H), 7.25 7.34 ppm (m, 5H);
13C NMR (CDCl3): d ˆ 21.2, 21.3, 29.0, 33.0, 45.4, 54.3, 59.1, 61.0, 126.8,
128.2, 128.8, 139.3 ppm; HRMS calcd for C14H21N 203.1673, found
F (000)816
216
216
568
1 [gcmÀ3
]
1.181
0.075
1.210
0.076
1.178
0.082
1.156
0.066
m [mmÀ1
T [K]
]
203(2)150(2)150(2)153(2)
‡
qmax [8]
25.26
5010
3742
27.51
1542
1241
25.00
2170
1965
25.02
4445
2666
203.1673; MS (EI ): m/z (%): 203 (75), 188 (4), 175 (2), 160 (8), 132 (16),
refl. collected
refl. independent
Rint
wR2(F 2)0.1193
R(F)0.0502
126 (32), 112 (43), 106 (3), 91 (100); elemental analysis calcd (%) for
C14H21N (203.3): C 82.69, H 10.42; found: C 82.42, H 10.16.
0.0779
0.1135
0.0561
0.0253
When the same reaction was carried out with isopropylmagnesium bromide
instead of the chloride, 18 was obtained in 77% yield and in addition
contaminated with a small amount of N-benzylpyrrole (less than 5 mol%)
0.2536
0.0903
0.1242
0.0456
0.1064
0.0632
no. parameters. refined 257
GOF 1.024
64
1.071
130
1.107
181
1.029
1
and N-benzylpyrrolidine (about 20 mol%, according to H NMR spectro-
scopy).
1,1'-Bicyclohexyl (71): A solution of cyclohexylmagnesium bromide was
prepared from magnesium turnings (1.20 g, 50 mmol)and cyclohexyl
bromide (8.2 g, 50 mmol)in anhydrous THF (50 mL.) According to
titration, this solution was 0.67 m. An aliquot (10 mL)was quenched with
10% aqueous H2SO4 (100 mL), and the mixture was extracted with Et2O
(100 mL), dried over Mg2SO4, and filtered. The combined filtrates were
evaporated under reduced pressure and the residue subjected to Kugelrohr
distillation (40 508C/0.05 Torr), affording 71 (0.33 g; 59%)as a colorless
oil. 1H NMR (CDCl3): d ˆ 0.86 1.10 (m, 6H), 1.10 1.36 (m, 6H), 1.58
1.86 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 26.9, 30.2, 43.5 ppm; HRMS
parameters of crystal data collections and structure refinements are
presented in Table 4.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
416, Project A3), the Bayer AG, and the Fonds der Chemischen Industrie as
well as BASF AG, Chemetall GmbH, Degussa AG, and H¸ls AG
(chemicals). C. M. W. is indebted to the Alexander von Humboldt
Foundation for a postdoctoral Research Fellowship, and A. K. is grateful to
Dr. S. I. Kozhushkov for invaluable discussions. The authors thank Dr. B.
Knieriem, Gˆttingen, for his careful proofreading of the final manuscript.
‡
calcd for C12H22 166.1721, found 166.1721; MS (EI ): m/z (%): 166 (15), 104
(7), 91 (15), 83 (96), 81 (31), 67 (28), 55 (84), 41 (100).
Cyclohexyl(N,N-dibenzylamino)methane (76): Benzyl bromide (2.21 mL,
18.6 mmol)was added dropwise over 25 min at
0 5 8C under an
atmosphere of argon to a solution of cyclohexylmethyl)amine (1.00 g,
8.83 mmol)and triethylamine (2.59 mL, 18.6 mmol)in anhydrous dichloro-
methane (20 mL). The mixture was allowed to warm to room temperature
over 24 h, then heated under reflux for 4 h. The solvent was evaporated,
water (20 mL)and tert-butyl methyl ether (20 mL)was added and to the
residue. The organic layer was dried (MgSO4)and concentrated to give a
residue that was subjected to radial chromatography (tert-butyl methyl
ether/n-hexane, 1:9), affording 76 (726 mg; 28%)as a colorless solid which
was recrystallized from n-hexane at À788C, m.p. 608C (ref. [28] 508C).
1H NMR (CDCl3): d ˆ 0.65 0.83 (m, 2H), 0.90 1.30 (m, 3H), 1.50 1.80
(m 4H), 1.80 2.06 (m, 2H), 2.18 (d, J ˆ 7.4 Hz, 2H), 3.50 (s, 4H), 7.13
7.46 ppm (m, 10H); 13C NMR (CDCl3): d ˆ 26.3, 26.9, 31.7, 35.8, 58.9, 60.9,
126.7, 128.1, 128.8, 140.2 ppm; HRMS calcd for C21H27N 293.2143, found:
[1] a)G. A. Rosenthal, Nonprotein Amino and Imino Acids: Biological,
Biochemical and Toxicological Properties, Academic Press, New York,
1982; b)C. H. Stammer, Tetrahedron 1990, 46, 2231–2254, and
references therein.
[2] According to a recent survey, 191 pharmaceutically relevant com-
pounds contain an aminocyclopropyl moiety. a)See footnote (1)in:
M. L. Gillaspy, B. A. Lefker, W. A. Hada, D. J. Hoover, Tetrahedron
Lett. 1995, 36, 7399 7402; for reviews see: b)J. Sala¸n, M. S. Baird,
Curr. Med. Chem. 1995, 2, 511 542; c)J. Sala¸n, Top. Curr. Chem.
2000, 207, 1 67.
‡
293.2143); MS (EI ): m/z (%): 293 (6), 210 (100), 200 (3), 181 (11), 118 (4),
106 (3), 91 (85).
[3] See: T. Fujita, J. Med. Chem. 1973, 16, 923 930.
Crystal structure determinations: Suitable crystals were grown by slow
cooling of a saturated solution in pentane with a few drops of Et2O (10d),
by evaporation of a methanol solution (10 f), by sublimation (10e), and by
[4] See: a)D. M. Campoli-Richards, J. P. Monk, A. Price, P. Benfield,
P. A. Todd, A. Ward, Drugs 1988, 35, 373 447; b)R. Wise, J. M.
Andrews, L. J. Edwards, Antimicrob. Chemother. 1983, 23, 559 564.
3800
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Chem. Eur. J. 2002, 8, No. 16

N,N-Dialkylcyclopropylamines
3789 3801
[5] a)K. E. Brighty, WO Patent 91/02526, 1991; EU Patent 413.455, 1991;
(Chem. Abstr. 1991, 115, 232216); U. S. Patent 5.164.402, 199;: (Chem.
Abstr. 1993, 119, 117227); b) K. E. Brighty, M. J. Castaldi, Synlett 1996,
1097 1099; c)E. Vilsmaier, T. Goerz, Synthesis 1998, 739 744.
[6] a)M. Es-Sayed, C. Gratkowski, N. Krass, A. I. Meyers, A. de Meijere,
Synlett 1992, 962 964; b)M. Es-Sayed, C. Gratkowski, N. Krass, A. I.
Meyers, A. de Meijere, Tetrahedron Lett. 1993, 34, 289 292; c)J. M.
[23] Inter- as well as intramolecular competition experiments have shown
that tert-butyl esters react much more slowly than N,N-dialkylcarbox-
amides with the titanacyclopropane intermediates generated from
alkylmagnesium halides and titanium alkoxides. See:S. Wiedemann, I.
Marek, A. de Meijere, Synlett 2002, submitted.
[24] The bicyclic cyclopropylamine 12 was also obtained in 92% yield from
cyclopentylmagnesium bromide and dibenzylformamide in the pres-
ence of [MeTi(OiPr)3] without added cyclopentene. A. de Meijere, V.
Chaplinski, H. Winsel, M. Kordes, S. V. Sviridov, A. I. Savchenko, B.
Stecker, Eur. J. Org. Chem. in press.
¬
¬
ƒ
Jimenez, J. Rife, R. M. Ortuno, Tetrahedron: Asymmetry 1996, 7, 537
558.
[7] E. Vilsmeier, ™Aminocyclopropanes∫ in The Chemistry of the Cyclo-
propyl Group (Ed.: Z. Rappoport)Wiley, Chichester, 1987, pp. 1341
1454.
[8] See also: a)T. Inoue, O. Kitagawa, O. Ochiai, T. Taguchi, Tetrahedron:
Asymmetry 1995, 6, 691 692; b)J. Sala¸n, J. Marguerite, B. Karkour,
J. Org. Chem. 1990, 55, 4276 4281.
¬
[25] M. Hˆgberg, C. Sahlberg, P. Engelhardt, R. Noreen, J. Kangasmets‰,
N. G. Johansson, B. ÷berg, L. Vrang, H. Zhang, B.-L. Sahlberg, T.
Unge, S. Lˆvgren, K. Fridborg, K. B‰ckbrˆ, J. Med. Chem. 1999, 42,
4150 4160.
[26] Ethenyltrimethylsilane (48)has recently been reported to form a
relatively stable titanacyclopropane intermediate. See: R. Mizojiri, H.
Urabe, F. Sato, J. Org. Chem. 2000, 65, 6217 6222.
[9] M. L. Gillaspy, B. A. Lefker, W. A. Hada, D. J. Hoover, Tetrahedron
Lett. 1995, 36, 7399 7402.
[10] V. Chaplinski, A. de Meijere, Angew. Chem. 1996, 108, 491 492;
Angew. Chem. Int. Ed. Engl. 1996, 35, 413 414.
[11] V. Chaplinski, H. Winsel, M. Kordes, A. de Meijere, Synlett 1997, 111
114.
[12] a)O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, Synthesis 1991,
234; b)for a recent review see: O. G. Kulinkovich, A. de Meijere,
Chem. Rev. 2000, 100, 2789 2834.
[13] O. G. Kulinkovich, A. I. Savchenko, S. V. Sviridov, D. A. Vasilevski,
Mendeleev Commun. 1993, 230 231.
[14] A. Kasatkin, F. Sato, Tetrahedron Lett. 1995, 36, 6079 6082.
[15] a)J. H. Lee, C. H. Kang, H. Kim, J. K. Cha, J. Am. Chem. Soc. 1996,
118, 291 292; b)J. Lee, Y. G. Kim, J. G. Bae, J. K. Cha, J. Org. Chem.
1996, 61, 4878 4879; c)J. Lee, H. Kim, J. K. Cha, J. Am. Chem. Soc.
1996, 118, 4198 4199.
[16] J. Lee, J. K. Cha, J. Org. Chem. 1997, 62, 1584 1585.
[17] a)J. X. McDermott, G, M. Whitesides, J. Am. Chem. Soc. 1974, 96,
947 948; b)J. X. McDermott, M. E. Wilson, G. M. Whitesides, J. Am.
Chem. Soc. 1976, 98, 6529 6536.
[18] Cha et al. have also observed analogous side-products from reductive
dimerization of alkenes. See footnote 11 in ref. [16].
[19] A. de Meijere, V. Chaplinski, A. Kourdioukov, German Offen. No.
DE19 647 615.A1, 18 Nov. 1996.
[20] CCDC-180275 (10d), CCDC-171573 (10e), CCDC-180276 (10 f), and
CCDC-171572 (28)contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.can.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Centre, 12 Union Road, Cambridge CB21EZ, UK;
Fax : (‡44)1223-336033; or deposit@ccdc.cam.ac.uk).
a)G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467 473;
b)G. M. Sheldrick, SHELXL-93, program for crystal structure refine-
ment, University of Gˆttingen, 1993.
[27] Preliminary communication: C. M. Williams, V. Chaplinski, P. R.
Schreiner, A. de Meijere, Tetrahedron Lett. 1998, 39, 7695 7698.
[28] a)This same configuration and conformation has previously been
found for a 1:2,5:6-bisspiropentyl-annelated cyclooctane. See: H.
Irngartinger, S. Gries, P. Klaus, R. Gleiter, Chem. Ber. 1992, 125,
2503 2512. b)The twofold addition of photochemically generated
monoiodocarbene to 1,5-cyclooctadiene, however, gave the endo,en-
do-5,10-diodo-syn-tricyclo[7.1.0.04, 6]decane as the major diastereom-
er. See: E. V. Dehmlow, J. Soufi, H. G. Stammler, B. Neumann, Chem.
Ber. 1993, 126, 499 502.
[29] Cf. A. de Meijere, V. Chaplinski, H. Winsel, M. A. Kusnetsov, P.
Rademacher, R. Boese, T. Haumann, M. TrÒtteberg, P. von R.
Schleyer, T. Zywietz, H. Jiao, P. Merstetter, F. Gerson, Angew. Chem.
1999, 111, 2582 2585; Angew. Chem. Int. Ed. 1999, 38, 2430 2433.
[30] Reviews see: a)A. de Meijere, Angew. Chem. 1979, 91, 867 884;
Angew. Chem. Int. Ed. Engl. 1979, 18, 809 826; b)K. B. Wiberg in
Methods of Organic Chemistry (Houben-Weyl), Vol. E17a (Ed.: A.
de Meijere), Thieme, Stuttgart 1997, pp. 1–27, and references therein.
[31] P. A. S. Smith, R. N. Loeppky, J. Am. Chem. Soc. 1967, 89, 1147 1157.
[32] C. Stratmann, V. Belov, S. V. Sviridov, M. Es-Sayed, A. de Meijere,
unpublished results.
[33] R. Lespieau, M. Bourguel, Org. Synth. 1953, Vol. 1, 186.
[34] C. M. Williams, L. N. Mander, Tetrahedron 2001, 57, 425 447; L. J.
Morris, Chem. Ind. 1962, 1238–1240. Silica gel (200 g)was suspended
in acetonitrile (ca. 400 mL)to which was added a solution of silver
nitrate (40 g)in acetonitrile (ca. 50 mL). The solvent was then slowly
evaporated (1 Torr), and the silica gel placed in an oven (808C)or
under high vacuum (0.01 Torr)for 24 h.
[35] The N-protected 3-pyrrolines 15a, b were obtained from the respec-
tive primary amines and cis-1,4-bismethanesulfonyloxybut-2-ene
according to a published protocol. Z. Z. Ding, J. J. Tufariello, Synth.
Commun. 1990, 20, 227 230.
[21] For an efficient synthesis of 1-Boc-2,5-dihydro-1H-pyrrole see: R.
St¸rmer, B. Sch‰fer, V. Wolfart, H. Stahr, U. Kazmaier, G. Helmchen,
Synthesis 2001, 46 48.
[36] G. Bettoni, C. Cellucci, J. Heterocyclic Chem. 1982, 19, 1541 1543.
[37] M. E. Garst, D. Lukton, J. Org. Chem. 1981, 46, 4433 4438.
[22] An application of the tert-butoxycarbonyl (Boc)protecting group on
nitrogen in the Kulinkovich transformation of lactones has been
reported. See: A. Esposito, M. Taddei, J. Org. Chem. 2000, 65, 9245
9248.
Received: March 1, 2002 [F3915]
Chem. Eur. J. 2002, 8, No. 16
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0947-6539/02/0816-3801 $ 20.00+.50/0
3801