3-azabicyclo[3.1.0]hex-1-ylamines by Ti-mediated intramolecular reductive cyclopropanation of α-(N-allylamino)-substituted N,N-dialkylcarboxamides and carbonitriles

Article abstract of DOI:10.1002/1099-0690(200208)2002:15<2499::AID-EJOC2499>3.0.CO;2-V

A variety of tris- and monoprotected derivatives with the 1-amino-3-azabicyclo[3.1.0]hexane and 1-amino-3-azabicy- clo[4.1.0]heptane skeleton 10 have been synthesized by intramolecular reductive cyclopropanation of α-(N-allylamino)-substituted N,N-dialkylcarboxamides 6, 8, and 9. Starting from derivatives of the naturally occurring amino acid serine (4a, 4b), the enantiomerically pure compounds 10a and 10b were obtained with endo/exo ratios of 2.5:1 (a) and 2:1 (b), in 26 and 30% overall yields, respectively. The unprotected bicyclic amines 11aa, 11ab, 11ba, and 11ad have been prepared by palladium-catalyzed hydrogenative deprotection of 10aa, 10ab, 10ba and 10ad, respectively, under acidic conditions, in 91, 95, 96, and 99% yields, respectively. X-ray crystal structure analyses of 10aa and 10ad in each case found an equatorial position of the N-benzyl group on the heterocycle and a common boat conformation for the 3-azabicyclo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane skeletons as a whole. One-step preparations of the bicyclic diamiries 11ac (41% yield) and 14a (48% yield) have been performed by application of the Kulinkovich-de Meijere procedure to the nitriles 12a and 12b. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200208)2002:15<2499::AID-EJOC2499>3.0.CO;2-V

FULL PAPER
3-Azabicyclo[3.1.0]hex-1-ylamines by Ti-Mediated Intramolecular Reductive
Cyclopropanation of α-(N-Allylamino)-Substituted N,N-Dialkylcarboxamides
and Carbonitriles
Martina Gensini,[a] Sergei I. Kozhushkov,[a] Dmitrii S. Yufit,[b] Judith A. K. Howard,[b]
Mazen Es-Sayed,[c] and Armin de Meijere*[a]
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 70th birthday
Keywords: Amides / Cyclopropanations / Lewis acids / Nitriles / Titanium
A variety of tris- and monoprotected derivatives with the 1-
tions, in 91, 95, 96, and 99% yields, respectively. X-ray crystal
amino-3-azabicyclo[3.1.0]hexane and 1-amino-3-azabicy- structure analyses of 10aa and 10ad in each case found an
clo[4.1.0]heptane skeleton 10 have been synthesized by in-
tramolecular reductive cyclopropanation of α-(N-allylamino)-
equatorial position of the N-benzyl group on the heterocycle
and common boat conformation for the 3-azabicy-
a
substituted N,N-dialkylcarboxamides 6, 8, and 9. Starting clo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane skeletons as
from derivatives of the naturally occurring amino acid serine
(4a, 4b), the enantiomerically pure compounds 10a and 10b
were obtained with endo/exo ratios of 2.5:1 (a) and 2:1 (b),
in 26 and 30% overall yields, respectively. The unprotected
bicyclic amines 11aa, 11ab, 11ba, and 11ad have been pre-
pared by palladium-catalyzed hydrogenative deprotection of
10aa, 10ab, 10ba and 10ad, respectively, under acidic condi-
a whole. One-step preparations of the bicyclic diamines 11ac
(41% yield) and 14a (48% yield) have been performed by
application of the Kulinkovich−de Meijere procedure to the
nitriles 12a and 12b.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
The transformations of carboxylic acid esters and N,N- at a well defined distance, as is the isomeric 1-amino-3-aza-
dialkylcarboxamides into cyclopropanols and cyclopro- bicyclo[3.1.0]hexane (2), some derivatives of which (3a, 3b)
pylamines, respectively, by the action of low-valent titanium have been prepared as 2:1 mixtures of exo and endo diaster-
reagents produced in situ from titanium alkoxides and or- eomers by intramolecular reductive cyclopropanation of N-
ganomagnesium halides (the so-called Kulinkovich reaction allyl-α-aminocarboxylic acid N,N-dimethylamides.[5]
and its de Meijere variant) developed over the last 12 years
have demonstrated their wide applicability in the syntheses
of natural products and other compounds with potentially
useful properties.[1] One of the most recent examples is the
elegant synthesis of the enantiomerically pure amino acid
(S)-cleonin, elaborated by Taddei et al.[2] Another biologic-
ally
interesting cyclopropylamine, the
3-azabicy-
clo[3.1.0]hexylamine 1, a key constituent of the highly act-
ive antibiotic trovafloxacin,[3] has also been successfully
prepared by this approach.[4] This bicyclic diamine is also
interesting as a rigid scaffold with two nitrogen atoms held
In order to be able to utilize these scaffolds in combinat-
orial approaches to libraries of compounds containing at
least two different aromatic or heteroaromatic substituents
on the two nitrogen atoms, these nitrogen atoms would have
to be chemically addressable individually and selectively.
For the diamine 1a, this problem has recently been solved
by a high-yield preparation of the Boc-protected derivative
1b.[4] For the isomer 2, we embarked on a project to prepare
a variety of tris- and monoprotected derivatives incorporat-
ing the 1-amino-3-azabicyclo[3.1.0]hexane and the homo-
logous 3-azabicyclo[4.1.0]heptane skeletons through intra-
[a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ49-(0)551/399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b]
Department of Chemistry, University of Durham,
Durham, South Rd., DH1 3LE, England
[c]
Bayer AG, GB Pflanzenschutz
40789 Monheim, Germany
Eur. J. Org. Chem. 2002, 2499Ϫ2507  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0815Ϫ2499 $ 20.00ϩ.50/0
2499

A. de Meijere et al.
FULL PAPER
molecular cyclopropanation of N-allyl and N-homoallyl
benzylmethyl- and dibenzylamides of types 8 and 9.
The starting N-allylserine amides 6a and 6b were pre-
pared from N-benzylserine 4a or its methyl ester 4b by ap-
plication of an established set of procedures, as shown in
Scheme 1. The N-allylglycine N,N-dialkylamides 8 and 9aa
were prepared in good yields from 2-bromoacetamides 7a
and 7b by nucleophilic substitution[9,10] with the appropri-
ately N-substituted allyl- or homoallylamine (Scheme 1).
Compound 8ac (R1 ϭ R2 ϭ Bn, R3 ϭ Boc, not shown in
Scheme 1) was obtained by treatment of 2-bromoacetamide
7a with allylamine in THF, followed by Boc-protection of
the nitrogen moiety.[11]
Scheme 2. Intramolecular reductive cyclopropanation of α-(N-
allylamino)-substituted N,N-dialkylcarboxamides 6a, 6b, 8, and 9aa
The structural features of the homologous N,N,3-triben-
zyl-3-azabicyclo[3.1.0]hex-1-ylamine (10aa) and N,N,3-tri-
benzyl-3-azabicyclo[4.1.0]hept-1-ylamine (10ad) were estab-
lished by X-ray crystal structure analyses (Figure 1). Their
crystal parameters are very similar,[14] and in both cases the
two phenyl rings of the dibenzylamino fragment are ortho-
gonal with respect to each other. The N-benzyl group on
the heterocycle adopts an equatorial position in both cases,
bending the envelope of the azacyclopentane moiety in 10aa
and the chair of the azacyclohexane in 10ad in such a way
that the azabicyclo[3.1.0]hexane and azabicyclo[4.1.0]hep-
tane systems adopt overall boat conformations.
Both compounds were racemates and therefore crystal-
lized in a centrosymmetric space group. The geometries of
the molecules and their packing in the crystals are quite
similar, but the conformations of the molecules are differ-
ent, as demonstrated by superposition of the molecules with
their three-membered ring carbon and the nitrogen atoms
of their dibenzylamino groups held in the same place (Fig-
ure 1). Molecule 10aa has an ap orientation (with respect
to the heterobicycle) of the quasiequatorial N2ϪC20 bond
[dihedral angle C2ϪN2ϪC20ϪC21 ϭ Ϫ163.0(1)°] and an
sc orientation of the quasiaxial N2ϪC13 bond [angle
C2ϪN2ϪC13ϪC14 ϭ 69.7(1)°]. In contrast, molecule 10ad
has an ap orientation of the quasiaxial bond N2ϪC14 and
an sc orientation of the quasiequatorial bond N2ϪC7 [di-
Scheme 1. Preparations of the starting α-(N-allylamino)-substituted
N,N-dialkylcarboxamides 6a, 6b, 8, and 9aa
Under the conditions previously published [cPentMgCl, hedral angles C1ϪN2ϪC14ϪC15
ClTi(OiPr)3, THF, room temp.] for the reductive intramole- C1ϪN2ϪC7ϪC8 ϭ 66.0(1)°, respectively].
ϭ
Ϫ169.9(1)° and
cular cyclopropanation of α-substituted N-allylglycine N,N-
The unprotected diamines 11aa and 11ad and the par-
dialkylamides to yield compounds 3a and 3b,[5] the serine tially unprotected diamines 11ba, 11ab, and 11ac were ob-
and glycine N,N-dibenzyl-, N,N-dimethyl-, and N-benzyl-N- tained by catalytic hydrogenation under appropriate condi-
methylamides of types 6, 8, and 9 did not cyclize to the tions (Scheme 3).
bicyclic diamines. However, the target 1-amino-3-azabicy-
However, these derivatives still did not allow the potential
clo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane derivatives aryl substituents on the primary amino group to be fully
10 were obtained from 6a, 6b, 8, and 9aa in moderate to controlled. The best way to solve this problem would be by
good yields by use of a slightly different procedure (methyl- way of a one-step preparation of the bicyclic diamines with
titanium triisopropoxide[12] in place of chlorotitanium trii- a protected secondary amino group and an unprotected
sopropoxide and cyclohexylmagnesium bromide[13] instead primary amino group. By the logic of the titanium-mediated
of cyclopentylmagnesium chloride) (Scheme 2).
transformation, this might be achievable by the use of
2500
Eur. J. Org. Chem. 2002, 2499Ϫ2507

Ti-Mediated Intramolecular Reductive Cyclopropanation
FULL PAPER
nitriles as starting materials. Early attempts to convert ali-
phatic nitriles into primary cyclopropylamines by use of
Grignard reagents and Ti(OiPr)4, however, met with only
very moderate success.[15] Szymoniak et al., though, found
out that nitriles did react with titanacyclopropane interme-
diates generated in situ to form remarkably stable azatitana-
cyclopentane intermediates, which Ϫ on activation with an
added Lewis acid (LA) such as boron trifluorideϪdiethyl
ether Ϫ eventually underwent ring-contraction to give
Lewis acid complexed primary cyclopropylamines. Aqueous
workup under basic conditions then furnished the primary
cyclopropylamines in moderate to good yields.[16] In an in-
dependent development, it was found that aromatic nitriles
in particular could be converted into primary cyclopro-
pylamines by treatment with dialkylzinc reagents in the
presence of Ti(OiPr)4 and addition of lithium isopropoxide
or lithium iodide.[17]
The appropriate starting nitrile for an intramolecular ap-
plication of this approach Ϫ compound 12a Ϫ was pre-
pared by a published procedure.[18] Treatment of chloroace-
tonitrile with allylamine, Et3N, and K2CO3 in DMF, fol-
lowed by protection with Boc2O and Et3N in MeOH, af-
forded compound 12b in 35% overall yield.[19]
Intramolecular reductive cyclopropanation of nitriles 12a
and 12b upon treatment with methyltitanium triisopropox-
ide and cyclohexylmagnesium bromide with subsequent ad-
dition of a Lewis acid did indeed provide the 3-benzyl-3-
azabicyclo[3.1.0]hex-1-ylamine (14a) and 3-tert-butoxy-
carbonyl-3-azabicyclo[3.1.0]hex-1-ylamine (11ac), albeit in
moderate yields (Scheme 4).
Figure 1. Molecular structures of N,N,3-tribenzyl-3-azabicy-
clo[3.1.0]hex-1-ylamine (10aa) and N,N,3-tribenzyl-3-azabicy-
clo[4.1.0]hept-1-ylamine (10ad) in the crystal (top, displacement
ellipsoids are shown at the 50% probability level) and their super-
position (bottom)[14]
Scheme 4. Intramolecular reductive cyclopropanation of N-allyl-
aminocarbonitriles 12a and 12b
While only traces of the product 14a were detected under
the conditions developed by Szymoniak et al. to accelerate
the ring-contraction of the intermediate azatitanacyclopen-
Scheme 3. Deprotection of the benzyl-protected 3-azabicy-
clo[3.1.0]hex-1-ylamines 10 and N,N,3-tribenzyl-3-azabicy-
clo[4.1.0]hept-1-ylamine (10ad)
Eur. J. Org. Chem. 2002, 2499Ϫ2507
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A. de Meijere et al.
FULL PAPER
AMX 300 and Inova 600 instruments in CDCl3 solution if not
otherwise specified, with CHCl3/CDCl3 as internal reference; δ in
ppm, J in Hz. IR: Bruker IFS 66 (FT-IR) spectrophotometer,
measured as KBr pellets or oils between KBr plates. MS (EI): Fin-
nigan MAT 95 spectrometer. Optical rotations: PerkinϪElmer 241
digital polarimeter, 1 dm cell. M.p.: Büchi 510 capillary melting
point apparatus, uncorrected values. TLC: MachereyϪNagel pre-
coated sheets, 0.25 mm Sil G/UV254. Column chromatography:
Merck silica gel, grade 60, 230Ϫ400 mesh. Starting materials: An-
hydrous diethyl ether and THF were obtained by distillation from
tene (i.e., addition of BF3·OEt2 as a Lewis acid at ambient
temperature), compound 14a could be obtained by heating
the reaction mixture at 70 °C for 2 h. The reaction, however,
proceeded more cleanly, to give the bicyclic diamine 14a in
48% yield, when the reaction mixture was heated at 70 °C
for 3 h after addition of 2 equivalents of lithium iodide. No
by-products could be isolated; only unidentified oligomeric
materials were detected. The structure of the diamine 14a
was confirmed by X-ray crystal structure analysis of its
hemihydrochloride 14a·0.5 HCl (Figure 2). In contrast to sodium benzophenone ketyl, CH2Cl2 and DMF from CaH2, and
acetonitrile from P4O10. Compounds 4a and 4b,[18] 5b,[7a] 7a and
the behavior of 12a and 12b, the homologous N-allyl-N-
7b,[9a] alkylallylamines,[9b] alkylhomoallylamines,[10a] and 12a[18]
benzyl-3-aminopropionitrile and 2-amino-N-benzyl-N-
were prepared by published procedures. Cyclohexylmagnesium
homoallylacetonitrile predominantly gave the 1-benzyl-4-
bromide was prepared from cHexBr and Mg in Et2O, MeTi(OiPr)3
methylpiperidin-3-one (17,[20] 45%) and 1-benzyl-3-methyl-
from MeLi and ClTi(OiPr)3 in Et2O, ClTi(OiPr)3 from TiCl4 and
piperidin-4-one (18,[21] 35%) resulting from hydrolysis of
Ti(OiPr)4 in Et2O. All other chemicals were used as commercially
available (Merck, Acro˜s, BASF, Bayer, Hoechst, Degussa AG, and
Hüls AG). All reactions were performed under an Ar atmosphere.
Organic extracts were dried over MgSO4.
the intermediate azatitanacyclopentenes 15 and 16, respect-
ively, these compounds apparently being particularly stable
in these cases, with only traces of the corresponding aza-
bicyclo[4.1.0]heptane derivatives.
(S)-2-Benzylamino-N,N-dibenzyl-3-(tert-butyldimethylsilyloxy)-
propionamide: tert-Butyldimethylsilyl chloride (1.1 mmol, 300 mg
of a 55% solution in toluene) was added dropwise at 0 °C to a
suspension of (S)-2-benzylamino-3-hydroxypropionic acid (4a,
390 mg, 2.00 mmol) and imidazole (150 mg, 2.20 mmol) in anhyd-
rous DMF (10 mL). After the addition was complete, the mixture
was stirred for 2 days at room temperature to give crude (S)-2-
benzylamino-3-(tert-butyldimethylsilyloxy)propionic acid (5a). Di-
cyclohexylcarbodiimide (DCC, 310 mg, 1.5 mmol), hydroxybenzo-
triazole (HOBT, 150 mg, 1.1 mmol), and dibenzylamine (1.5 mmol,
0.3 mL) were then added, and stirring was continued for an addi-
tional 16 h. EtOAc (10 mL) was added, the mixture was filtered
through Celite, and the solvent was removed under reduced pres-
sure. EtOAc (10 mL) was again added, and the organic phase was
washed with NaHCO3, H2O, and brine, dried, and concentrated
under reduced pressure. Column chromatography of the residue
(Rf ϭ 0.60, Et2O/hexane, 1:1) gave (S)-2-benzylamino-N,N-di-
benzyl-3-(tert-butyldimethylsilyloxy)propionamide (236 mg, 48%)
as a colorless oil. [α]2D0 ϭ Ϫ12.0 (c ϭ 0.5, CHCl3). 1H NMR
(250 MHz): δ ϭ 0.05 (s, 3 H), 0.09 (s, 3 H), 0.90 (s, 9 H), 2.52 (s,
1 H, NH), 3.50 (d, J ϭ 12.5 Hz, 1 H), 3.75Ϫ3.97 (m, 4 H), 4.15
(d, J ϭ 14.7 Hz, 1 H), 4.26 (d, J ϭ 17.4 Hz, 1 H), 5.00 (d, J ϭ
17.4 Hz, 1 H), 5.33 (d, J ϭ 14.7 Hz, 1 H), 7.19Ϫ7.41 (m, 15 H)
ppm. 13C NMR (62.9 MHz): δ ϭ Ϫ5.5 (2 CH3), 18.3 (C), 25.9 (3
CH3), 48.9 (CH2), 49.4 (CH2), 51.9 (CH2), 59.0 (CH), 66.0 (CH2),
126.6 (CHar), 127.0 (CHar), 127.4 (CHar), 127.6 (CHar), 128.1
(CHar), 128.3 (CHar), 128.4 (3 CHar), 128.6 (2 CHar), 128.9 (2
CHar), 129.1 (2 CHar), 136.9 (Car), 137.1 (Car), 139.9 (Car), 174.7
(CϭO) ppm. IR: ν˜ ϭ 3032 cmϪ1, 2929, 2856, 1656, 1453, 1115,
785. MS (EI): m/z (%) ϭ 488 (26) [Mϩ], 473 (71), 343 (18), 264
(100), 91 (44). C30H40N2O2Si (488.75): calcd. C 73.72, H 8.25, N
5.73; found C 73.58, H 8.33, N 5.54.
Figure 2. Molecular structure (left) and crystal packing (right)
of 3-benzyl-3-azabicyclo[3.1.0]hex-1-ylamine hemihydrochloride
(14a·0.5 HCl) in the crystal (displacement ellipsoids are shown at
the 50% probability level)[14]
The structure of 14a·0.5HCl is another example of the
conformational flexibility of this class of compounds. The
unit cell contains two independent molecules, both partially
disordered. The independent molecules are different con-
formers. The dihedral angle C6ϪN5ϪC7ϪC8, describing
the conformation of the benzyl group relative to the bicyclic
system, is 172.5(2)° in one independent molecule and
Ϫ72.8(2)° in the second. Molecules in crystals of 14a·0.5
HCl are linked together by a network of hydrogen bonds of
NϪH···Cl and NϪH···N types, forming a layered structure.
Preparation of Allylbenzylamino Propionic Acid Derivatives. General
Procedure 1 (GP1):[22] Allyl bromide (0.57 mmol) was added drop-
wise at 0 °C to a suspension of the corresponding benzylamino
propionic acid derivative (0.41 mmol) and K2CO3 (0.82 mmol) in
anhydrous MeCN (8 mL). After the addition was complete, the re-
action mixture was stirred for 16 h at 60 °C. EtOAc (5 mL) and
NaHCO3 (5 mL) were added, and the organic phase was washed
with brine and dried. Evaporation of the solvent under reduced
Experimental Section
General: 1H and 13C NMR: spectra were recorded at 250, 300, 600
(1H), and 62.9, 75.5 [13C, additional DEPT (Distortionless En- pressure gave the crude products, which were purified by column
hancement by Polarization Transfer)] MHz on Bruker AM 250,
2502
chromatography on silica gel.
Eur. J. Org. Chem. 2002, 2499Ϫ2507

Ti-Mediated Intramolecular Reductive Cyclopropanation
FULL PAPER
(S)-2-(Allylbenzylamino)-N,N-dibenzyl-3-(tert-butyldimethyl-
silyloxy)propionamide (6a): Derivative 6a (139 mg, 64%) was ob-
tained from (S)-N,N-dibenzyl-2-benzylamino-3-(tert-butyldime-
benzylamine (13.2 mmol) were added dropwise at 0 °C to a solution
of N-alkyl,N-benzyl-bromoacetamide (7, 12 mmol) in anhydrous
THF (25 mL). After the addition was complete, the reaction mix-
thylsilyloxy)propionamide (200 mg, 0.41 mmol), K2CO3 (113 mg, ture was stirred for an additional 20 h at ambient temperature.
0.82 mmol), and allyl bromide (0.57 mmol, 0.05 mL) according to
Water (10 mL) and EtOAc (10 mL) were added, and the organic
phase was washed with saturated aq. NaHCO3 solution (20 mL),
GP1, as a colorless oil, Rf (Et2O/hexane, 1:5) ϭ 0.60, [α]2D0 ϭ Ϫ2.0
(c ϭ 0.94, CHCl3). 1H NMR (250 MHz): δ ϭ 0.10 (s, 3 H), 0.12 brine (30 mL), and dried. Evaporation of the solvent under reduced
(s, 3 H), 0.94 (s, 9 H), 3.25 (dd, J ϭ 7.7, 14.0 Hz, 1 H), 3.44 (dd, pressure gave compounds 8 as yellow oils, which were purified by
J ϭ 5.2, 14.0 Hz, 1 H), 3.71 (d, J ϭ 13.8 Hz, 1 H), 3.87 (dd, J ϭ
5.4, 7.2 Hz, 1 H), 3.95 (d, J ϭ 14.8 Hz, 1 H), 4.02Ϫ4.24 (m, 4 H),
4.66 (d, J ϭ 17.2 Hz, 1 H), 5.03Ϫ5.21 (m, 3 H), 5.70Ϫ5.86 (m, 1
H), 7.08Ϫ7.39 (m, 15 H) ppm. 13C NMR (62.9 MHz): δ ϭ Ϫ5.4
(2 CH3), 18.3 (C), 25.9 (3 CH3), 47.8 (CH2), 49.0 (CH2), 53.9
(CH2), 54.5 (CH2), 59.7 (CH2), 60.1 (CH), 117.8 (CH2, CHϭCH2),
126.6 (2 CHar), 126.9 (CHar), 127.2 (CHar), 128.1 (5 CHar), 128.5
(2 CHar), 128.6 (2 CHar), 128.9 (2 CHar), 136.2 (Car), 136.9 (CH,
CHϭCH2), 137.4 (Car), 139.6 (Car), 171.8 (CϭO) ppm. IR: ν˜ ϭ
3028 cmϪ1, 2927, 2855, 1652, 1452, 1256, 1099. MS (EI): m/z (%) ϭ
528 (15) [Mϩ], 513 (35), 437 (33), 383 (12), 304 (100), 91 (25).
C33H44N2O2Si (528.81): calcd. C 74.95, H 8.39, N 5.30; found C
75.08, H 8.22, N 5.21.
column chromatography on silica gel.
2-(Allylbenzylamino)-N,N-dibenzylacetamide (8aa): Compound 8aa
(37.9 g, 93%) was obtained from the bromoacetamide 7a (33.7 g,
0.106 mol), Et3N (0.202 mol, 28 mL), and allylbenzylamine
(17.27 g, 0.117 mol) according to GP2, as a colorless oil, Rf (hex-
ane/Et2O, 2:1) ϭ 0.33. 1H NMR (250 MHz): δ ϭ 3.27 (d, J ϭ
6.5 Hz, 2 H), 3.40 (s, 2 H), 3.77 (s, 2 H), 4.49 (s, 2 H), 4.60 (s, 2
H), 5.13Ϫ5.26 (m, 2 H), 5.88 (ddt, J ϭ 6.6, 10.2, 17.1 Hz, 1 H),
7.06Ϫ7.38 (m, 15 H) ppm. 13C NMR (62.9 MHz): δ ϭ 47.6 (CH2),
49.3 (CH2), 55.7 (CH2), 57.0 (CH2), 58.1 (CH2), 118.7 (CH2, CHϭ
CH2), 126.5 (2 CHar), 127.0 (CHar), 127.3 (2 CHar), 128.1 (4 CHar),
128.5 (2 CHar), 128.6 (2 CHar), 129.1 (2 CHar), 135.0 (CH, CHϭ
CH2), 136.6 (Car), 137.2 (Car), 138.3 (Car), 171.0 (CϭO) ppm. IR:
ν˜ ϭ 3028 cmϪ1, 2922, 1650, 1494, 1451, 1213, 1076, 734. MS (EI):
m/z (%) ϭ 384 (6) [Mϩ], 343 (14), 293 (48), 160 (78), 91 (100).
C26H28N2O (384.52): calcd. C 81.21, H 7.34, N 7.28; found C
81.04, H 7.11, N 7.09.
Methyl (S)-2-(Allylbenzylamino)-3-(tert-butyldimethylsilyloxy)pro-
pionate:[23] This compound (1.14 g, 82%) was obtained from methyl
(S)-2-benzylamino-3-(tert-butyldimethylsilyloxy)propionate
(5b,
1.11 g, 3.71 mmol), K2CO3 (1.03 g, 7.42 mmol), and allyl bromide
(5.4 mmol, 0.5 mL) according to GP1, as a colorless oil, Rf (Et2O/
hexane, 1:10) ϭ 0.50. H NMR: δ ϭ 0.01 (s, 6 H), 0.85 (s, 9 H),
2-(Allylmethylamino)-N,N-dibenzylacetamide (8ab): Compound 8ab
(19 g, 98%) was obtained from the bromoacetamide 7a (20 g,
63 mmol), Et3N (126 mmol, 17.5 mL), and allylmethylamine
(6.57 mL, 69 mmol) according to GP2, as a colorless oil, Rf (hex-
ane/Et2O, 1:2) ϭ 0. 28. 1H NMR (250 MHz): δ ϭ 2.36 (s, 3 H),
3.10 (d, J ϭ 6.6 Hz, 2 H), 3.29 (s, 2 H), 4.57 (s, 2 H), 4.60 (s, 2 H),
5.08Ϫ5.20 (m, 2 H), 5.82 (ddt, J ϭ 6.5, 10.3, 17.0 Hz, 1 H),
7.15Ϫ7.39 (m, 10 H) ppm. 13C NMR (62.9 MHz): δ ϭ 42.6 (CH3),
47.8 (CH2), 49.5 (CH2), 59.7 (CH2), 60.8 (CH2), 118.3 (CH2, CHϭ
CH2), 126.7 (2 CHar), 127.4 (CHar), 127.5 (CHar), 128.3 (2 CHar),
128.6 (2 CHar), 128.9 (2 CHar), 135.0 (CH, CHϭCH2), 136.8 (Car),
137.3 (Car), 170.7 (CϭO) ppm. IR: ν˜ ϭ 3029 cmϪ1, 2919, 2788,
1649, 1451, 1233, 699. MS (EI): m/z (%) ϭ 308 (7) [Mϩ], 279 (11),
217 (3), 91 (26), 84 (100). C20H24N2O (308.43): calcd. C 77.88, H
7.84, N 9.08; found C 77.59, H 7.61, N 8.97.
1
3.16 (dd, J ϭ 7.3, 14.5 Hz, 1 H), 3.33Ϫ3.35 (m, 1 H), 3.60Ϫ3.68
(m, 2 H), 3.72 (s, 3H), 3.81Ϫ3.99 (m, 3 H), 5.09Ϫ5.25 (m, 2 H),
5.79Ϫ5.81 (m, 1 H), 7.22Ϫ7.38 (m, 5 H) ppm. 13C NMR: δ ϭ Ϫ5.2
(2 CH3), 18.1 (C), 25.7 (3 CH3), 51.1 (CH3), 54.5 (CH2), 55.1
(CH2), 62.7 (CH2), 63.6 (CH), 117.1 (CH2, CHϭCH2), 126.8
(CHar), 128.1 (2 CHar), 128.5 (2 CHar), 136.6 (CH, CHϭCH2),
140.1 (Car), 172.2 (CϭO) ppm. IR: ν˜ ϭ 3064 cmϪ1, 2953, 2884,
1739, 1472, 1257, 1106.
(S)-2-(Allylbenzylamino)-3-(tert-butyldimethylsilyloxy)-N,N-di-
methylpropionamide (6b): Me3Al (12.2 mL of a 2  solution in hex-
ane) was added at 5 °C over a period of 1 h to a solution of
Me2NH·HCl (2.00 g, 24.5 mmol) in anhydrous benzene (10 mL).
The solution was stirred for 2 h at 20 °C and transferred to a solu-
tion (precooled to 5 °C) of methyl (S)-2-(allylbenzylamino)-3-(tert-
butyldimethylsilyloxy)propionate (1.11 g, 3.06 mmol) in a mixture
of anhydrous benzene (50 mL) and THF (15 mL). After the addi-
tion was complete, the reaction mixture was stirred for 2 days at
70 °C, and then cooled in an ice bath and carefully quenched with
aq. 10% NaOH solution (50 mL). EtOAc (10 mL) was added, and
the organic phase was washed with brine (50 mL), dried, and con-
centrated under reduced pressure. Column chromatography of the
residue gave 6b (587 mg, 51%) as a colorless oil, Rf (Et2O/hexane,
2-(Allylbenzylamino)-N-benzyl-N-methylacetamide (8ba): Com-
pound 8ba (3.15 g, 85%) was obtained from the bromoacetamide
7b (2.9 g, 12 mmol) and allylbenzylamine (1.95 g, 13.2 mmol) ac-
cording to GP2, as a colorless oil, Rf (hexane/Et2O, 1:1) ϭ 0.39.
1H NMR (250 MHz): δ ϭ 2.86 (s, 3 H, minor rotamer), 2.88 (s, 3
H, major rotamer), 3.20Ϫ3.23 (m, 2 H), 3.33 (s, 2 H), 3.69 (s, 2 H),
minor), 3.74 (s, 2 H, major), 4.54 (s, 2 H, minor), 4.56 (s, 2 H,
major), 5.12Ϫ5.26 (m, 2 H), 5.77Ϫ5.95 (m, 1 H), 7.05Ϫ7.38 (m, 10
H) ppm. 13C NMR (62.9 MHz): δ ϭ 33.6 (CH3, minor), 34.6 (CH3,
major), 50.8 (CH2, major), 52.8 (CH2, minor), 55.8 (CH2, major),
56.0 (CH2 minor), 57.1 (CH2, major), 57.3 (CH2, minor), 58.1
(CH2, major), 58.2 (CH2, minor), 118.3 (CH2, minor, CHϭCH2),
118.4 (CH2, major, CHϭCH2), 126.5 (CHar), 127.0 (CHar), 127.2
(CHar), 128.2 (2 CHar), 128.5 (2 CHar), 128.7 (CHar), 129.2 (2
CHar), 135.2 (CH, minor, CHϭCH2), 135.3 (CH, major, CHϭ
CH2), 136.9 (Car, minor), 137.3 (Car, major), 138.5 (Car, minor),
138.7 (Car, major), 170.7 (CϭO) ppm. IR: ν˜ ϭ 3028 cmϪ1, 2920,
2836, 1646, 1452, 1261, 1103, 699. MS (EI): m/z (%) ϭ 308 (7)
[Mϩ], 267 (14), 217 (48), 160 (88), 91 (100). C20H24N2O (308.43):
calcd. C 77.88, H 7.84, N 9.08; found C 77.99, H 7.97, N 8.89.
1
1:1) ϭ 0.58, [α]2D0ϭ Ϫ11.4 (c ϭ 1, CHCl3). H NMR (250 MHz):
δ ϭ 0.04 (s, 3 H), 0.07 (s, 3 H), 0.88 (s, 9 H), 2.88 (s, 3 H), 2.90 (s,
3 H), 3.23Ϫ3.33 (m, 2 H), 3.75Ϫ4.02 (m, 5 H), 5.06Ϫ5.21 (m, 2
H), 5.73Ϫ5.86 (m, 1 H), 7.17Ϫ7.34 (m, 5 H) ppm. 13C NMR
(62.9 MHz): δ ϭ Ϫ5.4 (2 CH3), 18.1 (C), 25.8 (3 CH3), 35.4 (CH3),
37.2 (CH3), 54.2 (CH2), 54.6 (CH2), 59.4 (CH), 62.1 (CH2), 116.9
(CH2, CHϭCH2), 126.6 (CHar), 128.0 (2 CHar), 128.6 (2 CHar),
136.9 (CH, CHϭCH2), 140.2 (Car), 172.1 (CϭO) ppm. IR: ν˜ ϭ
3063 cmϪ1, 2928, 1699, 1494, 1361, 1257, 1102. MS (CI): m/z (%) ϭ
377 (100%) [M ϩ Hϩ], 337 (3), 287 (5), 232 (3). HRMS (EI) calcd.
for C21H36N2O2Si [Mϩ] 376.2546, found 376.2546.
Preparation of N-Alkyl-2-allylalkylamino-N-benzylacetamides 8.
General Procedure 2 (GP2): Et3N (24 mmol, 3.3 mL) and alkyl-
2-[(Allyl)(tert-butoxycarbonyl)amino]-N,N-dibenzylacetamide (8ac):
Et3N (9.1 mmol, 1.26 mL) and allylamine (286 mg, 5.01 mmol)
Eur. J. Org. Chem. 2002, 2499Ϫ2507
2503

A. de Meijere et al.
FULL PAPER
were added dropwise at 0 °C to a solution of N,N-dibenzyl(bro-
moacetyl)amide (7a, 1.45 g, 4.56 mmol) in anhydrous THF
(15 mL). After the addition was complete, the reaction mixture was
stirred for an additional 12 h at ambient temperature. Saturated aq.
NaHCO3 solution (10 mL) and EtOAc (10 mL) were added, and
the organic phase was washed with brine (20 mL), dried, and con-
centrated under reduced pressure to give an oil, which was used
without further purification. This oil was taken up in a mixture of
H2O (7 mL) and dioxane (15 mL), and to this solution were added
a solution of NaOH (160 mg, 4.0 mmol) in H2O (7 mL) and di-
tert-butyl pyrocarbonate (Boc2O, 1.09 g, 5 mmol). The mixture was
stirred for an additional 2 days, concentrated to about 50% of its
original volume, and extracted with Et2O (3 ϫ 15 mL). The com-
bined organic phases were washed with brine (20 mL), dried, and
concentrated under reduced pressure. Column chromatography of
the residue gave 8ac (1.02 g, 57%) as a colorless oil, Rf (Et2O/hex-
ane 2:1) ϭ 0.59. 1H NMR (250 MHz): δ ϭ 1.40 (s, 9 H), 3.64Ϫ3.70
(m, 2 H), 3.88 (s, 2 H), 4.47 (s, 2 H), 4.58 (s, 2 H), 5.04Ϫ5.19 (m,
2 H), 6.85 (m, 1 H), 7.05Ϫ7.32 (m, 10 H) ppm. 13C NMR
(62.9 MHz): δ ϭ 28.3 (3 CH3), 43.0 (CH2), 48.4 (CH2), 50.7 (CH2),
60.3 (CH2), 79.1 (C), 115.5 (CH2, CHϭCH2), 126.4 (2 CHar), 127.6
(CHar), 127.9 (CHar), 128.0 (2 CHar), 128.6 (2 CHar), 129.0 (2
CHar), 135.0 (CH, CHϭCH2), 135.7 (Car), 136.4 (Car), 155.8 (Cϭ
O), 167.4 (CϭO) ppm. IR: ν˜ ϭ 3031 cmϪ1, 2978, 1700, 1652,
1448, 1172.
under reduced pressure gave compounds 10, which were purified
by column chromatography on silica gel.
endo- and exo-(1R,2R,5S)-N,N,3-Tribenzyl-2-(tert-butyldimethylsi-
lyloxymethyl)-3-azabicyclo[3.1.0]hex-1-ylamine (10a): 3-Azabicy-
clo[3.1.0]hex-1-ylamine 10a (265 mg, 83%) was obtained from
compound 6a (330 mg, 0.62 mmol), methyltitanium triisopropox-
ide (206 mg, 0.858 mmol), and cyclohexylmagnesium bromide
(2.87 mmol, 3.5 mL of a 0.82  solution in Et2O) according to
GP3, in an endo/exo ratio of 2.5:1. endo-10a: Colorless oil, Rf (hex-
1
ane/Et2O, 10:1) ϭ 0.20. [α]2D0 ϭ ϩ3.6 (c ϭ 0.5, CHCl3). H NMR
(600 MHz): δ ϭ 0.15 (s, 3 H), 0.17 (s, 3 H), 0.53 (dd, J ϭ 4.0,
8.5 Hz, 1 H, CH2 cPr), 0.85Ϫ0.91 (m, 2 H, CH and CH2 cPr), 1.02
(s, 9 H), 1.86 (dd, J ϭ 3.5, 8.5 Hz, 1 H, CH2N), 2.46 (d, J ϭ 8.5 Hz,
1 H, CH2N), 3.25 (t, J ϭ 5.0 Hz, 1 H, CHN), 3.37 (d, J ϭ 13.5 Hz,
1 H, CH2Ph), 3.75 (dd, J ϭ 4.5, 10.5 Hz, 1 H, CH2O), 3.84 (s, 2
H), 3.85 (s, 2 H), 3.92 (dd, J ϭ 5.0, 10.5 Hz, 1 H, CH2O), 4.06 (d,
J ϭ 13.5 Hz, 1 H, CH2Ph), 7.18Ϫ7.32 (m, 15 H) ppm. 13C NMR
(62.9 MHz): δ ϭ Ϫ5.2 (2 CH3), 13.9 (CH2, CH2 cPr), 18.4 (C),
25.4 (CH, CH cPr), 26.1 (3 CH3), 53.1 (CH2, CH2N), 53.2 (C),
56.8 (2 CH2), 58.1 (CH2, CH2Ph), 62.5 (CH, CHN), 64.8 (CH2,
CH2O), 126.6 (CHar), 126.7 (2 CHar), 127.9 (5 CHar), 128.0 (2
CHar), 128.9 (5 CHar), 131.8 (Car), 139.1 (Car), 140.6 (Car) ppm.
IR: ν˜ ϭ 3027 cmϪ1, 2927, 1453, 1256, 873, 698. MS (EI): m/z (%) ϭ
512 (6) [Mϩ], 421 (40), 381 (100), 367 (39), 316 (25), 276 (19), 91
(44). C33H44N2OSi (512.81): calcd. C 77.29, H 8.65, N 5.46; found
C 77.12, H 8.55, N 5.51.
N,N-Dibenzyl-2-[(benzyl)(but-3-enyl)amino]acetamide (9aa): A so-
lution of N-benzylbut-3-enylamine (322 mg, 2 mmol) in DMF
(3 mL) was added at 0 °C to a suspension of NaH (104 mg of a
60% suspension in mineral oil, 2.6 mmol) in DMF (4 mL). The
reaction mixture was stirred for 10 min at 0 °C, N,N-dibenzylbro-
moacetamide (7a, 732 mg, 2.3 mmol) was then added in one por-
tion, and stirring was continued for an additional 2 h at ambient
temperature. The reaction mixture was cooled with an ice bath, and
a 2:1 mixture of sat. aq. NH4Cl solution and 25% aq. NH4OH
solution (6 mL) was added. The aqueous layer was extracted with
Et2O, and the combined organic phases were washed with brine
and dried. After evaporation of the solvent, the residue was purified
by column chromatography on silica gel to give 9aa (605 mg, 76%)
as a yellow oil, Rf (hexane/Et2O, 2:1) ϭ 0.37. 1H NMR (250 MHz):
δ ϭ 2.20Ϫ2.29 (m, 2 H), 2.71 (ps t, J ϭ 7.2 Hz, 2 H), 3.37 (s, 2
H), 3.72 (s, 2 H), 4.50 (s, 2 H), 4.56 (s, 2 H), 4.92Ϫ5.02 (m, 2 H),
5.82 (ddt, J ϭ 6.7, 10.2, 17.1 Hz, 1 H), 7.05Ϫ7.39 (m, 15 H) ppm.
13C NMR (62.9 MHz): δ ϭ 31.4 (CH2), 47.8 (CH2), 49.3 (CH2),
53.6 (CH2), 56.8 (CH2), 58.4 (CH2), 115.8 (CH2, CHϭCH2), 126.4
(2 CHar), 127.2 (CHar), 127.3 (CHar), 127.4 (CHar), 128.2 (2 CHar),
128.3 (2 CHar), 128.6 (2 CHar), 128.8 (2 CHar), 129.2 (2 CHar),
136.5 (Car), 136.7 (CH, CHϭCH2), 137.2 (Car), 138.4 (Car), 171.1
(CϭO) ppm. IR: ν˜ ϭ 3062 cmϪ1, 3028, 2921, 1650, 1451, 1211,
698. MS (EI): m/z (%) ϭ 398 (3) [Mϩ], 357 (37), 174 (82), 91 (100).
HRMS (EI) calcd. for C27H30N2O [Mϩ] 398.2358, found 398.2358.
exo-10a: Colorless solid, Rf (hexane/Et2O, 10:1) ϭ 0.32, m.p.
1
54Ϫ56 °C, [α]2D0ϭ ϩ17.0 (c ϭ 0.5, CHCl3). H NMR (250 MHz):
δ ϭ 0.06 (s, 3 H), 0.12 (s, 3 H), 0.78Ϫ0.84 (m, 3 H), 0.89 (s, 9 H),
1.60Ϫ1.66 (m, 1 H), 2.50 (d, J ϭ 8.1 Hz, 1 H), 2.81 (t, J ϭ 3.4 Hz,
1 H), 2.86 (dd, J ϭ 3.4, 8.1 Hz, 1 H), 3.60Ϫ3.84 (m, 5 H),
3.90Ϫ3.97 (m, 2 H), 7.15Ϫ7.37 (m, 15 H) ppm. 13C NMR
(62.9 MHz): δ ϭ Ϫ5.3 (2 CH3), 14.6 (CH2), 18.0 (C), 24.3 (CH),
26.1 (3 CH3), 26.9 (CH2), 30.2 (CH2), 51.7 (C), 52.1 (CH2), 54.6
(CH2), 61.7 (CH2), 65.9 (CH), 126.3 (2 CHar), 126.7 (CHar), 127.9
(6 CHar), 128.1 (5 CHar), 129.5 (CHar), 138.1 (Car), 140.9 (2 Car)
ppm. IR: ν˜ ϭ 3027 cmϪ1, 2926, 1452, 1255, 1099, 697. MS (EI):
m/z (%) ϭ 512 (3) [Mϩ], 421 (50), 381 (100), 367 (51), 316 (27), 276
(33), 91 (9). C33H44N2OSi (512.81): calcd. C 77.29, H 8.65, N 5.46;
found C 77.07, H 8.42, N 5.55.
endo- and exo-(1R,2R,5S)-3-Benzyl-2-(tert-butyldimethylsilyloxy-
methyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hex-1-ylamine (10b): Com-
pound 10b (1.83 g, 89%) was obtained from the N,N-dialkylpro-
pionamide 6b (2.15 g, 5.7 mmol), methyltitanium triisopropoxide
(2.06 g, 8.6 mmol), and cyclohexylmagnesium bromide (34 mmol,
35 mL of a 0.98  solution in Et2O) according to GP3, in an endo/
exo ratio of 2:1. endo-10b: Colorless oil, Rf (hexane/Et2O, 2:1) ϭ
0.29, [α]2D0 ϭ ϩ13.8 (c ϭ 1, CHCl3). 1H NMR (300 MHz): δ ϭ 0.07
(s, 6 H, 2 CH3), 0.61 (dd, J ϭ 4.3, 8.6 Hz, 1 H, CH2 cPr), 0.91 (s,
9 H, 3 CH3), 1.04 (t, J ϭ 4.0 Hz, 1 H, CH2 cPr), 1.26Ϫ1.33 (m, 1
H, CH cPr), 2.35 (dd, J ϭ 4.0, 9.0 Hz, 1 H, CH2N), 2.47 (s, 6 H,
Preparation of 3-Azabicyclo[3.1.0]hex-1-ylamine and 3-Azabicy-
clo[4.1.0]hept-1-ylamine 10. General Procedure 3 (GP3): Cyclohex- 2 CH3), 2.71 (d, J ϭ 9.0 Hz, 1 H, CH2N), 3.02 (t, J ϭ 4.5 Hz, 1
ylmagnesium bromide (5 mmol, 5 mL of a 1  solution in Et2O)
was added dropwise at room temperature to a well stirred solution
of N,N-dialkylpropionamide 6, 8, or 9 (1 mmol) and methyltita-
H, CHN), 3.30 (d, J ϭ 13.5 Hz, 1 H, CH2Ph), 3.70 (dd, J ϭ 4.5,
10.5 Hz, 1 H, CH2O), 3.89 (dd, J ϭ 4.5, 10.5 Hz, 1 H, CH2O), 4.21
(d, J ϭ 13.5 Hz, 1 H, CH2Ph), 7.18Ϫ7.28 (m, 5 H) ppm. 13C NMR
nium triisopropoxide (351 mg, 1.46 mmol) in anhydrous THF (75.5 MHz): δ ϭ Ϫ5.4 (2 CH3), 14.7 (CH2), 18.3 (C), 23.3 (CH),
(30 mL). After addition was complete, the mixture was stirred for
12 h, and then poured into ice-cold water (10 mL) and stirred for
26.0 (3 CH3), 42.0 (2 CH3), 54.2 (CH3), 54.3 (C), 58.7 (CH2), 62.5
(CH), 65.3 (CH2), 128.0 (CHar), 128.5 (2 CHar), 128.5 (2 CHar),
an additional 1 h. The mixture was filtered through Celite, the 139.8 (C) ppm. IR: ν˜ ϭ 2927 cmϪ1, 2855, 1453, 1257, 1100. MS
aqueous phase was extracted with Et2O (3 ϫ 50 mL), and the com-
bined ethereal phases were washed with sat. aq. NaHCO3 solution
(EI): m/z (%) ϭ 360 (12) [Mϩ], 316 (66), 229 (79), 215 (100), 123
(11), 91 (21). HRMS (EI) calcd. for C21H36N2OSi [Mϩ] 360.2597,
(100 mL) and brine (100 mL) and dried. Evaporation of the solvent found 360.2597.
2504
Eur. J. Org. Chem. 2002, 2499Ϫ2507

Ti-Mediated Intramolecular Reductive Cyclopropanation
FULL PAPER
exo-10b: Colorless oil, Rf (hexane/Et2O, 2:1) ϭ 0.77, [α]2D0 ϭ ϩ34.9
(c ϭ 1, CHCl3). H NMR (250 MHz): δ ϭ 0.07 (s, 3 H), 0.08 (s, 3
[Mϩ], 201 (40), 173 (46), 158 (43), 91 (100). C20H24N2 (292.43):
calcd. C 82.15, H 8.27, N 9.58; found C 81.91, H 8.06, N 9.37.
1
H), 0.66 (dd, J ϭ 3.5, 8.5 Hz, 1 H), 0.85Ϫ0.89 (m, 1 H), 0.94 (s, 9
H), 1.57Ϫ1.64 (m, 1 H), 2.21 (s, 6 H), 2.61 (d, J ϭ 7.8 Hz, 1 H),
3.01Ϫ3.06 (m, 2 H), 3.78 (d, J ϭ 13.9 Hz, 1 H), 3.85Ϫ3.88 (m, 2
H), 4.00 (d, J ϭ 13.9 Hz, 1 H), 7.30Ϫ7.22 (m, 5 H) ppm. 13C NMR
(62.9 MHz): δ ϭ Ϫ5.5 (2 CH3), 14.1 (CH2), 18.1 (C), 22.9 (CH),
26.9 (3 CH3), 43.3 (2 CH3), 52.5 (C), 53.4 (CH2), 54.4 (CH2), 61.0
(CH), 64.5 (CH2), 126.4 (CHar), 128.0 (3 CHar), 128.1 (CHar), 139.6
(Car) ppm. IR: ν˜ ϭ 3027 cmϪ1, 2925, 1461, 1254, 1042. MS (EI):
m/z (%) ϭ 360 (6) [Mϩ], 316 (25), 229 (53), 215 (100), 123 (26), 110
(29), 91 (21). HRMS (EI) calcd. for C21H36N2OSi [Mϩ] 360.2597,
found 360.2597.
N,N-Dibenzyl-(3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hex-1-
ylamine (10ac): The amine 10ac (262 mg, 43%) was obtained from
the N,N-dialkylpropionamide 8ac (635 mg, 1.61 mmol), methyltita-
nium triisopropoxide (581 mg, 2.42 mmol), and cyclohexylmagnes-
ium bromide (8.06 mmol, 10 mL of a 0.8  solution in Et2O) ac-
cording to GP3, as a colorless oil, Rf (hexane/Et2O, 2:1) ϭ 0.56.
1H NMR (250 MHz): δ ϭ 0.35 (t, J ϭ 4.7 Hz, 1 H), 0.78Ϫ0.83 (m,
1 H), 1.00Ϫ1.03 (m, 1 H), 1.45 (s, 9 H, major rotamer), 1.49 (s, 9
H, minor rotamer), 3.08Ϫ3.12 (m, 1 H), 3.19 (d, J ϭ 10.6 Hz, 1 H,
major), 3.27 (d, J ϭ 10.6 Hz, 1 H, minor), 3.40 (d, J ϭ 10.4 Hz, 1
H, minor), 3.54 (d, J ϭ 10.5 Hz, 1 H, major), 3.58Ϫ3.87 (m, 5 H),
7.22Ϫ7.32 (m, 10 H) ppm. 13C NMR (62.9 MHz): δ ϭ 18.7 (CH2
minor), 18.9 (CH2 major), 24.3 (CH minor), 24.7 (CH major), 28.4
(3 CH3 major), 28.5 (3 CH3 minor), 44.6 (CH2 major), 44.9 (CH2
minor), 47.6 (CH2 minor), 48.0 (CH2 major), 49.3 (CH2 major),
50.0 (C), 56.8 (CH2 minor), 56.9 (CH2 major), 79.3 (C), 127.0 (2
CHar), 128.1 (4 CHar), 129.0 (4 CHar), 139.5 (2 Car), 155.1 (CϭO)
ppm. IR: ν˜ ϭ 3027 cmϪ1, 2978, 2862, 1692, 1401, 1116. MS (EI):
m/z (%) ϭ 378 (23) [Mϩ], 287 (38), 231 (100), 187 (23), 91 (59),
57 (62).
N,N,3-Tribenzyl-3-azabicyclo[3.1.0]hex-1-ylamine
(10aa):
The
amine 10aa (32 g, 58%) was obtained from the N,N-dialkylpropion-
amide 8aa (57 g, 0.15 mol), methyltitanium triisopropoxide (54.1 g,
0.225 mol), and cyclohexylmagnesium bromide (0.75 mol, 930 mL
of a 0.8  solution in Et2O) according to GP3, as a colorless solid,
Rf (hexane/Et2O, 2:1)
ϭ
0.56, m.p. 76Ϫ79 °C. 1H NMR
(250 MHz): δ ϭ 0.56Ϫ0.60 (m, 1 H), 0.97Ϫ1.04 (m, 2 H), 2.20 (dd,
J ϭ 2.7, 8.5 Hz, 1 H), 2.71 (d, J ϭ 13.1 Hz, 1 H), 2.74 (d, J ϭ
12.7 Hz, 1 H), 2.96 (d, J ϭ 8.2 Hz, 1 H), 3.65 (s, 2 H), 3.75 (d, J ϭ
13.2 Hz, 2 H), 3.85 (d, J ϭ 13.2 Hz, 2 H), 7.23Ϫ7.41 (m, 15 H)
ppm. 13C NMR (62.9 MHz): δ ϭ 16.5 (CH2), 24.4 (CH), 49.8 (C),
50.8 (CH2), 54.2 (CH2), 56.9 (2 CH2), 59.4 (CH2), 126.7 (3 CHar),
127.9 (4 CHar), 128.1 (2 CHar), 128.5 (2 CHar), 128.9 (4 CHar),
139.2 (Car), 140.1 (2 Car) ppm. IR: ν˜ ϭ 3022 cmϪ1, 2929, 2793,
1493, 1454, 1210, 735. MS (EI): m/z (%) ϭ 368 (18) [Mϩ], 277
(100), 158 (16), 91 (67). C26H28N2 (368.52): calcd. C 84.74, H 7.66,
N 7.60; found C 84.70, H 7.51, N 7.50.
N,N,3-Tribenzyl-3-azabicyclo[4.1.0]hept-1-ylamine (10ad): The
amine 10ad (1.1 g, 59%) was obtained from the N,N-dialkylpro-
pionamide 9aa (1.94 g, 4.87 mmol), methyltitanium triisopropoxide
(1.76 g, 7.33 mmol), and cyclohexylmagnesium bromide
(19.5 mmol, 19.5 mL of a 1  solution in Et2O) according to GP3,
as a colorless solid, Rf (hexane/Et2O, 5:1) ϭ 0.52, m.p. 82Ϫ84 °C.
1H NMR (250 MHz): δ ϭ 0.49 (dd, J ϭ 3.9, 6.3 Hz, 1 H), 0.57
(dd, J ϭ 3.8, 9.8 Hz, 1 H), 1.49Ϫ1.60 (m, 1 H), 0.73Ϫ0.82 (m, 1
H), 1.67Ϫ1.80 (m, 1 H), 1.99Ϫ2.06 (m, 1 H), 2.15Ϫ2.24 (m, 1 H),
2.62 (d, J ϭ 11.1 Hz, 1 H), 3.04 (d, J ϭ 11.2 Hz, 1 H), 3.51 (d, J ϭ
5.7 Hz, 2 H), 3.74 (s, 4 H), 7.16Ϫ7.53 (m, 15 H) ppm. 13C NMR
(62.9 MHz): δ ϭ 19.8 (CH), 19.9 (CH2), 24.3 (CH2), 42.8 (C), 49.5
(CH2), 52.9 (CH2), 55.9 (2 CH2), 63.0 (CH2), 126.6 (2 CHar), 126.7
(CHar), 127.9 (4 CHar), 128.2 (2 CHar), 128.7 (2 CHar), 129.2 (4
CHar), 139.3 (Car), 140.4 (2 Car) ppm. IR: ν˜ ϭ 3027 cmϪ1, 2912,
2770, 1452, 1124, 753. MS (EI): m/z (%) ϭ 382 (15) [Mϩ], 291 (22),
210 (24), 166 (12), 91 (100).
N,N-Dibenzyl-3-methyl-3-azabicyclo[3.1.0.]hex-1-ylamine
(10ab):
The amine 10ab (193 mg, 66%) was obtained from the N,N-dial-
kylpropionamide 8ab (308 mg, 1 mmol), methyltitanium triisoprop-
oxide (351 mg, 1.46 mmol), and cyclohexylmagnesium bromide
(5 mmol, 5 mL of a 1  solution in Et2O) according to GP3, as a
colorless oil, Rf (CH2Cl2/MeOH, 15:1, ϩ 1% NH3) ϭ 0.50. 1H
NMR (250 MHz): δ ϭ 0.53 (dd, J ϭ 4.0, 8.3 Hz, 1 H), 0.88 (ps t,
J ϭ 4.3 Hz, 1 H), 1.05Ϫ0.98 (m, 1 H), 2.11 (dd, J ϭ 3.5, 8.8 Hz, 1
H), 2.29 (s, 3 H), 2.61 (d, J ϭ 8.4 Hz, 1 H), 2.94 (d, J ϭ 8.4 Hz, 1
H), 2.70 (d, J ϭ 8.8 Hz, 1 H), 3.76 (s, 2 H), 3.78 (s, 2 H), 7.19Ϫ7.34
(m, 10 H) ppm. 13C NMR (62.9 MHz): δ ϭ 16.8 (CH2), 24.8 (CH),
42.0 (CH3), 50.5 (C), 53.2 (CH2), 56.7 (CH2), 56.8 (2 CH2), 126.8
(2 CHar), 127.9 (4 CHar), 128.9 (4 CHar), 139.9 (2 Car) ppm. IR:
ν˜ ϭ 3027 cmϪ1, 2885, 2776, 1453, 1198, 748. MS (EI): m/z (%) ϭ
292 (13) [Mϩ], 201 (100), 158 (14), 91 (44). HRMS (EI) calcd. for
C20H24N2 [Mϩ] 292.1939, found 292.1939.
Preparation of 3-Azabicyclo[3.1.0]hex-1-ylamine Dihydrochlorides
11. General Procedure 4 (GP4): A solution of 10 (1 mmol) in a
mixture of MeOH (15 mL) and HCl (1.2 mL of a 5  solution in
iPrOH) was hydrogenated for 3 h (if not otherwise specified) at 20
°C under Pd/C catalysis and ambient pressure. The reaction mix-
ture was filtered through Celite and concentrated under reduced
pressure. The product was obtained as a colorless solid and purified
by recrystallization from MeOH/Et2O, 2:1.
N,3-Dibenzyl-N-methyl-3-azabicyclo[3.1.0]hex-1-ylamine
(10ba): The amine 10ba (10.32 g, 56%) was obtained from the N,N-
dialkylpropionamide 8ba (19.4 g, 63 mmol), methyltitanium triiso-
propoxide (23 g, 96 mmol), and cyclohexylmagnesium bromide
(315 mmol, 308 mL of a 1.02  solution in Et2O) according to
GP3, as a colorless oil, Rf (hexane/Et2O, 2:1) ϭ 0.45. 1H NMR
(250 MHz): δ ϭ 0.71 (dd, J ϭ 3.7, 8.5 Hz, 1 H), 1.16 (ps t, J ϭ
3.9 Hz, 1 H), 1.35Ϫ1.41 (m, 1 H), 2.30 (s, 3 H), 2.44 (dd, J ϭ 3.5,
8.6 Hz, 1 H), 2.61 (d, J ϭ 8.2 Hz, 1 H), 2.84 (d, J ϭ 8.6 Hz, 1 H),
2.93 (d, J ϭ 8.2 Hz, 1 H), 3.56Ϫ3.70 (m, 3 H), 3.80 (d, J ϭ 13.0 Hz,
1 H), 7.21Ϫ7.34 (m, 10 H) ppm. 13C NMR (62.9 MHz): δ ϭ 17.0
(CH2), 24.2 (CH), 39.2 (CH3), 50.3 (CH2), 52.1 (C), 54.8 (CH2),
59.6 (CH2), 59.8 (CH2), 126.8 (CHar), 128.1 (4 CHar), 128.5 (2
3-Azabicyclo[3.1.0]hex-1-ylamine Dihydrochloride (11aa): The dihy-
drochloride 11aa (156 mg, 91%) was obtained from the 3-azabicy-
clo[3.1.0]hexane 10aa (368 mg, 1 mmol) and HCl (1.2 mL of a 5 
solution in iPrOH) by use of 5% Pd/C (184 mg) according to GP4,
as a colorless solid, m.p. 200Ϫ203 °C. 1H NMR (250 MHz,
CD3OD): δ ϭ 1.20Ϫ1.26 (m, 1 H), 1.41 (t, J ϭ 8.2 Hz, 1 H),
2.15Ϫ2.22 (m, 1 H), 3.34 (d, J ϭ 11.7 Hz, 1 H), 3.56Ϫ3.68 (m, 3
H) ppm. 13C NMR (62.9 MHz, CD3OD): δ ϭ 14.3 (CH2), 22.4
(CH), 40.6 (C), 49.6 (2 CH2) ppm. IR: ν˜ ϭ 3441cmϪ1, 2882, 2534,
1588, 1452, 1217. MS (CI): m/z (%) ϭ 197 (10) [2M ϩ Hϩ], 116
(33) (M ϩ NH4ϩ], 99 (100) [M ϩ Hϩ]. C5H10N2·2 HCl (171.07):
calcd. C 35.11, H 7.07, N 16.38; found C 35.20, H 6.97, N 16.67.
CHar), 128.8 (3 CHar), 139.5 (Car), 139.7 (Car) ppm. IR: ν˜ ϭ 3026 3-Methyl-3-azabicyclo[3.1.0]hex-1-ylamine Dihydrochloride (11ab):
cmϪ1, 2896, 2787, 1452, 1378, 1027. MS (EI): m/z (%) ϭ 292 (39) The dihydrochloride 11ab (2.6 g, 95%) was obtained from the 3-
Eur. J. Org. Chem. 2002, 2499Ϫ2507
2505

A. de Meijere et al.
FULL PAPER
azabicyclo[3.1.0]hexane 10ab (4.3 g, 14.7 mmol) and HCl
The combined organic phases were washed with brine (30 mL),
(45.6 mmol, 7.6 mL of a 6  solution in iPrOH) by use of 5% Pd/ dried, and concentrated under reduced pressure. Column chroma-
C (2.16 g) according to GP4 (6 h reaction time), as a colorless solid, tography of the residue gave 12b (1.7 g, 35%) as a colorless oil, Rf
m.p. 227Ϫ230 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ 1.37 (ps (Et2O/hexane, 2:1) ϭ 0.33. 1H NMR (250 MHz): δ ϭ 1.40 (s, 9 H),
t, J ϭ 8.0 Hz, 1 H, CH2 cPr), 1.68 (dd, J ϭ 5.3, 6.8 Hz, 1 H, CH2 3.88Ϫ4.19 (m, 4 H), 5.23Ϫ5.29 (m, 2 H), 6.68Ϫ6.85 (m, 1 H) ppm.
cPr), 2.13Ϫ2.19 (m, 1 H, CH cPr), 2.76 (s, 3 H), 3.28 (br. s, 2 H), 13C NMR (62.9 MHz): δ ϭ 28.1 (3 CH3), 33.5 (CH2), 48.7 (CH2),
1
3.38Ϫ3.50 (m, 2 H, 4-H), 3.55 (d, J ϭ 11.3 Hz, 1 H, 2-H), 3.73 (d,
81.8 (C), 115.9 (CH2, CHϭCH2), 119.2 (CϵN), 132.1 (CH, CHϭ
J ϭ 11.3 Hz, 1 H, 2-H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): CH2), 158.5 (CϭO) ppm. IR: ν˜ ϭ 2980 cmϪ1, 2249, 1699, 1401,
δ ϭ 11.7 (CH2, CH2 cPr), 19.4 (CH, CH cPr), 38.6 (C), 39.5 (CH3), 1250, 1168. MS (EI): m/z (%) ϭ 196 (2) [Mϩ], 140 (25), 123 (12),
55.7 (2 CH2, CH2N) ppm. IR: ν˜ ϭ 3437 cmϪ1, 2868, 2654, 1456,
1158. MS (EI): m/z (%) ϭ 112 (15) [Mϩ], 82 (9), 69 (100), 44 (15).
C6H12N2·2 HCl (185.09): calcd. C 38.93, H 7.62, N 15.13; found C
38.88, H 7.51, N 15.18.
57 (100), 41 (46). HRMS (EI) calcd. for C10H16N2O2 [Mϩ]
196.1212, found 196.1212.
Preparation of 3-Azabicyclo[3.1.0]hex-1-ylamines 14a and 11ac.
General Procedure
5 (GP5): Cyclohexylmagnesium bromide
(4 mmol, 4 mL of a 1  solution in Et2O) was added dropwise at
ambient temperature to a well stirred solution of allylaminoaceton-
itrile 12 (2 mmol) and methyltitanium triisopropoxide (529 mg,
2.2 mmol) in anhydrous THF (40 mL). After the addition was com-
plete, the mixture was stirred for 2 h at 20 °C, and LiI (535 mg,
4 mmol) was then added in one portion. The mixture was stirred
for an additional 3 h at 70 °C, cooled to 0 °C, quenched with 10%
aq. NaOH solution (5 mL), and filtered through Celite. The aque-
ous phase was extracted with Et2O (3 ϫ 20 mL), and the combined
organic phases were washed with brine, dried, and concentrated
under reduced pressure. The residue was purified by column chro-
matography.
N-Methyl-3-azabicyclo[3.1.0]hex-1-ylamine Dihydrochloride (11ba):
The dihydrochloride 11ba (3.91 g, 96%) was obtained from the 3-
azabicyclo[3.1.0]hexane 10ba (6.44 g, 22 mmol) and HCl (0.13 mol,
22 mL of a 6  solution in iPrOH) by use of 5% Pd/C (3.22 g)
according to GP4, as a colorless solid, m.p. 192Ϫ195 °C. 1H NMR
(300 MHz, D2O): δ ϭ 1.15 (dd, J ϭ 5.0, 8.5 Hz, 1 H, CH2 cPr),
1.55 (dt, J ϭ 2.0, 8.9 Hz, 1 H, CH2 cPr), 2.36 (quint, J ϭ 4.5 Hz,
1 H, CH cPr), 2.76 (s, 3 H), 3.41 (d, J ϭ 11.5 Hz, 1 H, 4-H), 3.63
(dd, J ϭ 4.5, 11.5 Hz, 1 H, 4-H), 3.69 (dd, J ϭ 2.0, 11.5 Hz, 1 H,
2-H), 3.78 (d, J ϭ 11.5 Hz, 1 H, 2-H) ppm. 13C NMR (62.9 MHz,
D2O): δ ϭ 14.3 (CH2), 22.8 (CH), 34.4 (CH3), 47.7 (C), 48.2 (CH2),
49.6 (CH2) ppm. IR: ν˜ ϭ 3423 cmϪ1, 2924, 2680, 2550, 1580, 1411.
MS (EI): m/z (%) ϭ 112 (4) [Mϩ], 97 (2), 83 (100), 68 (21).
C6H12N2·2 HCl (185.09): calcd. C 38.93, H 7.62, N 15.13; found C
38.74, H 7.51, N 14.96.
3-Benzyl-3-azabicyclo[3.1.0]hex-1-ylamine (14a): The amine 14a
(181 mg, 48%) was obtained from [(allyl)(benzyl)amino]acetonitrile
(12a, 372 mg, 2 mmol) according to GP5, as a colorless oil, Rf
(CH2Cl2/MeOH, 8:1, ϩ 1% NH3) ϭ 0.25. 1H NMR (250 MHz):
δ ϭ 0.64 (m, 1 H), 1.09 (ps t, J ϭ 4.2 Hz, 1 H), 1.16Ϫ1.21 (m, 1
H), 2.28 (br. s, 2 H, NH2), 2.32 (d, J ϭ 8.3 Hz, 1 H), 2.49 (dd, J ϭ
3.6, 8.6 Hz, 1 H), 2.83 (d, J ϭ 8.6 Hz, 1 H), 3.00 (d, J ϭ 8.3 Hz, 1
H), 3.58 (s, 2 H), 7.20Ϫ7.28 (m, 5 H) ppm. 13C NMR (62.9 MHz):
δ ϭ 15.4 (CH2), 23.7 (CH), 40.7 (C), 54.7 (CH2), 59.1 (CH2), 61.2
(CH2), 126.8 (CHar), 128.1 (2 CHar), 128.6 (2 CHar), 139.0 (Car)
ppm. IR: ν˜ ϭ 3278 cmϪ1, 3061, 2925, 2787, 1452, 1156. MS (EI):
m/z (%) ϭ 188 (24) [Mϩ], 120 (32), 97 (17), 91 (100), 69 (86).
HRMS (EI) calcd. for C12H16N2 [Mϩ] 188.1313, found 188.1302.
3-Azabicyclo[4.1.0]hept-1-ylamine Dihydrochloride (11ad): The di-
hydrochloride 11ad (407 mg, 99%) was obtained from the 3-aza-
bicyclo[4.1.0]heptane 10ad (850 mg, 2.22 mmol) and HCl
(15 mmol, 2.5 mL of a 6  solution in iPrOH) by use of 5% Pd/C
(425 mg) according to GP4 (14 h reaction time), as a colorless
solid, m.p. 175Ϫ177 °C. 1H NMR (300 MHz, CD3OD): δ ϭ
1.12Ϫ1.21 (m, 1 H, CH2 cPr), 1.37 (dt, J ϭ 2.5, 7.0 Hz, 1 H, CH2
cPr), 1.70Ϫ1.78 (m, 1 H, CH cPr), 1.95 (dt, J ϭ 1.5, 4.5 Hz, 1 H,
5-H), 2.42 (m, 1 H, 5-H), 2.88 (dq, J ϭ 1.5, 4.5 Hz, 1 H, 4-H),
3.18Ϫ3.24 (m, 1 H, 4-H), 3.32 (s, 2 H, NH2), 3.57 (dd, J ϭ 1.5,
19.0 Hz, 1 H, 2-H), 3.72 (d, J ϭ 19.0 Hz, 1 H, 2-H) ppm. 13C NMR
(75.5 MHz, CD3OD): δ ϭ 15.2 (CH), 15.9 (CH2), 19.7 (CH2), 30.1
(C), 39.7 (CH2), 45.2 (CH2) ppm. IR: ν˜ ϭ 3430 cmϪ1, 2956, 1616,
1471, 1046. MS (CI): m/z (%) ϭ 112 (11) [Mϩ], 95 (19), 82 (100),
71 (43), 42 (38). HRMS (EI) calcd. for C6H12N2 [Mϩ] 112.1000,
found 112.1000. C6H12N2·2 HCl (185.09): calcd. C 38.93, H 7.62;
found C 39.04, H 7.40.
3-tert-Butoxycarbonyl-3-azabicyclo[3.1.0]hex-1-ylamine (11ac): The
amine 11ac (162 mg, 41%) was obtained from [(allyl)(tert-butoxy-
carbonyl)amino]acetonitrile (12b) (393 mg, 2 mmol) according to
GP5, as a colorless solid, Rf (CH2Cl2/MeOH, 8:1 ϩ 1% NH3) ϭ
0.33. Alternatively, the compound 11ac (100 mg, 76%) was pre-
pared from the 3-azabicyclo[3.1.0]hexane 10ac (250 mg, 0.66 mmol)
by use of 5% Pd/C (125 mg) according to GP4. Colorless solid,
1
m.p. 57Ϫ59 °C. H NMR (250 MHz): δ ϭ 0.46 (t, J ϭ 4.7 Hz, 1
[(Allyl)(tert-butoxycarbonyl)amino]acetonitrile (12b): Chloroaceto-
nitrile (1.9 g, 25 mmol) and allylamine (25 mmol, 1.87 mL) were
added dropwise at 0 °C to a suspension of K2CO3 (7.0 g, 51 mmol),
NaI (7.5 g, 50 mmol), and Et3N (0.1 mol, 14 mL) in anhydrous
DMF (50 mL). After the addition was complete, the reaction mix-
ture was stirred for 20 h at ambient temperature. Et2O (30 mL) and
Celite (1 g) were added, and the solid was filtered off. Ice-cold water
(30 mL) was added to the filtrate, and the aqueous layer was separ-
ated, cooled to 0 °C, saturated with NaCl, and extracted several
times with EtOAc (20 mL each). The combined organic phases
were dried, and removal of the solvent gave (N-allylamino)aceto-
nitrile as a brown oil pure enough to be used without further puri-
fication. To a solution of this in MeOH (50 mL) were added Et3N
(36 mmol, 5 mL) and a solution of Boc2O (6.0 g, 27.5 mmol) in
MeOH (50 mL) at 0 °C. The resulting mixture was stirred for 2 h
at 60 °C and the solvent was removed. Water (30 mL) was added,
H), 0.88Ϫ0.94 (m, 1 H), 1.32Ϫ1.35 (m, 1 H), 1.40 (s, 9 H), 1.62
(br. s, 2 H, NH2), 3.17Ϫ3.21 (m, 1 H), 3.43 (m, 2 H), 3.63Ϫ3.76
(m, 1 H) ppm. 13C NMR (62.9 MHz): δ ϭ 17.4 (CH2), 23.4 (CH,
minor rotamer), 23.9 (CH, major rotamer), 28.4 (3 CH3), 40.8 (C,
major), 41.2 (C, minor), 48.1 (CH2, major), 48.5 (CH2, minor), 54.0
(CH2, minor), 54.4 (CH2, major), 79.2 (C, minor), 79.4 (C, major),
154.6 (CϭO) ppm. IR: ν˜ ϭ 3505 cmϪ1, 2973, 2881, 1684, 1411,
1172. MS (EI): m/z (%) ϭ 198 (3) [Mϩ], 142 (30), 125 (14), 69
(100), 57 (48). HRMS (EI) calcd. for C10H18N2O2 [Mϩ] 198.1368,
found 198.1368.
Acknowledgments
This work was supported by Bayer AG, the Fonds der Chemischen
Industrie, and the EPSRC (UK). The authors are grateful to the
and the aqueous layer was extracted several times with CH2Cl2. companies BASF AG, Bayer AG, Chemetall GmbH, and Degussa
2506 Eur. J. Org. Chem. 2002, 2499Ϫ2507

Ti-Mediated Intramolecular Reductive Cyclopropanation
FULL PAPER
The hydrogen atoms in structures 10aa and 10ad were located
by difference Fourier synthesis and refined isotropically. The
two independent molecules of 14a in the crystal are partially
disordered. Disordered atoms were refined with fixed site occu-
pation factors of 0.8 and 0.2, the atoms of minor components
were refined isotropically. The hydrogen atoms in 14a were
placed in ideal positions and refined in ‘‘riding mode’’ with the
1.2-fold isotropic displacement parameter of the corresponding
C atom. 10aa: C26H28N2, crystal size 0.42 ϫ 0.30 ϫ 0.22 mm3,
AG for generous gifts of chemicals. We are particularly grateful to
Dr. B. Knieriem, Göttingen, for careful reading of the final manu-
script.
[1]
[1a]
Reviews:
O. G. Kulinkovich, A. de Meijere, Chem. Rev.
[1b]
2000, 100, 2789Ϫ2834.
B. Breit, J. Prakt. Chem. 2000, 342,
211Ϫ214. [1c] F. Sato, H. Urabe, S. Okamoto, Chem. Rev. 2000,
[1d]
100, 2835Ϫ2886.
F. Sato, H. Urabe, S. Okamoto, Synlett
2000, 753Ϫ775. [1e] A. de Meijere, S. I. Kozhushkov, A. I. Sav-
chenko, in Titanium and Zirconium in Organic Synthesis (Ed.:
I. Marek), 2002, pp. 390Ϫ434.
triclinic, a ϭ 5.9783(2), b ϭ 10.6105(4), c ϭ 16.7535(7) A, α ϭ
˚
3
˚
84.071(2), β ϭ 87.981(2), γ ϭ 76.457(2)°, V ϭ 1027.58(7) A ,
Ϫ3
¯
Z ϭ 2, space group P1, T ϭ 100.0(2) K, ρ ϭ 1.191 g cm
,
[2]
A. Esposito, P. P. Piras, D. Ramazzotti, M. Taddei, Org. Lett.
2001, 3, 3273Ϫ3275.
intensities measured: 12029 (2θmax ϭ 60.8°), independent: 5541
(Rint ϭ 0.0254), 365 parameters refined, R1 ϭ 0.0409 for 4890
reflections with I ϭ 4σ(I), wR2 (all data) ϭ 0.1177, Goof ϭ
0.993, maximum and minimum residual electron density 0.362
[3] [3a]
K. E. Brighty, WO Patent 91/02526, 1991; EU Patent
[3b]
413455 A2, 1991, Chem. Abstr. 1991, 115, 232216.
US Pa-
Ϫ3
tent 5,164.402, 1992, Chem. Abstr. 1993, 119, 117227. [3c] K. E.
Brighty, M. J. Castaldi, Synlett 1996, 1097Ϫ1099.
and Ϫ0.183
e
A
.
10ad: C27H30N2, crystal size
˚
0.42 ϫ 0.28 ϫ 0.06 mm3, triclinic, a ϭ 6.0829(4), b ϭ 9.8909(6),
c ϭ 18.028(1) A, α ϭ 96.586(2), β ϭ 90.077(2), γ ϭ 91.642(2)°,
[4] [4a]
˚
A. de Meijere, V. Chaplinski, A. Kourdioukov, Ger. Offen
3
˚
¯
DE 196 47 615.1 (Cl. C07C211/35, 20 May 1998, Appl. 196 47
V ϭ 1077.0(1) A , Z ϭ 2, space group P1, T ϭ 100.0(2) K,
ρ ϭ 1.180 g cmϪ3, intensities measured: 12494 (2θmax ϭ 59.0°),
independent: 5730 (Rint ϭ 0.0334), 382 parameters refined,
R1 ϭ 0.0475 for 4305 reflections with I ϭ 4σ(I), wR2 (all
data) ϭ 0.1271, Goof ϭ 1.021, maximum and minimum resid-
[4b]
615. 1 18 Nov 1996), Chem. Abstr. 1998, 129, 16045.
A. de
Meijere, C. M. Williams, V. Chaplinski, A. Kourdioukov, S. V.
Sviridov, A. I. Savchenko, M. Kordes, C. Stratmann, Chem.
Eur. J. 2002, in press.
[5]
[6]
˚
´
B. Cao, D. Xiao, M. M. Joullie, Org. Lett. 1999, 1, 1799Ϫ1801;
ual electron density 0.357 and Ϫ0.193 e AϪ3. 14a·0.5 HCl:
Org. Lett. 2000, 2, 1009.
C12H16N2·0.5HCl, crystal size 0.55 ϫ 0.54 ϫ 0.04 mm3, ortho-
˚
J. E. Baldwin, A. C. Spivey, C. J. Schofield, Tetrahedron: Asym-
metry 1990, 881Ϫ884.
rhombic, a ϭ 10.2447(3), b ϭ 39.482(1), c ϭ 11.5005(3) A, V ϭ
3
˚
4651.7(2) A , Z ϭ 16, space group Aba2, T ϭ 120(2) K, ρ ϭ
1.179 g cmϪ3, intensities measured: 15492 (2θmax ϭ 55.0°), in-
dependent: 5318 (Rint ϭ 0.0653), 298 parameters refined, R1 ϭ
0.0421 for 3770 reflections with I ϭ 4σ(I), wR2 (all data) ϭ
0.0962, Goof ϭ 0.957, maximum and minimum residual
[7] [7a]
K. Goodall, A. F. Parsons, Tetrahedron 1996, 52,
6739Ϫ6758. [7b] J. E. Baldwin, S. C. M. Turner, M. G. Moloney,
Tetrahedron 1994, 9411Ϫ9424.
E. Carceller, M. Merlos, M. Giral, C. Almansa, J. Bartrolı, J.
[8]
[9]
´
˚
G. Rafanell, J. Forn, J. Med. Chem. 1993, 2984Ϫ2997.
[9a] Y. Aoyagi, R. Asakura, N. Kondoh, R. Yamamoto, T. Kur-
omatsu, A. Shimura, A. Ohta, Synthesis 1996, 970Ϫ974. [9b] D.
electron density 0.240 and Ϫ0.231 e AϪ3. CCDC-178102
(10aa), CCDC-178103 (10ad) and CCDC-178104 (14a·0.5
HCl) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk].
Under typical conditions for the preparation of N,N-dialkylcy-
clopropylamines,[1a] nitriles gave primary cyclopropylamines in
15% yield at best: [15a] N. V. Masalov, H. Winsel, O. G. Kulinko-
vich, A. de Meijere, unpublished results.[15b] H. Winsel, Dip-
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Crystals of the compounds 10aa, 10ad, and 14a·0.5 HCl were
grown by slow evaporation of their solutions in Et2O/hexane
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Received February 25, 2002
[O02109]
Eur. J. Org. Chem. 2002, 2499Ϫ2507
2507