Synthesis of cis-2-alkoxycyclopropylamines via intramolecular cyclization of 2-azaallylic anions derived from alkoxybrominated N-(arylidene)-2-methyl-2- propenylamines

Article abstract of DOI:10.1016/j.tet.2013.02.094

N-(Arylidene)-2-alkoxy-3-bromo-2-methylpropylamines, obtained in a straightforward way via regiospecific alkoxybromination of the corresponding N-(2-methyl-2-propenyl)imines, represent promising densely functionalized synthetic building blocks. The substi

Full text of DOI:10.1016/j.tet.2013.02.094

Tetrahedron 69 (2013) 3728e3735
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of cis-2-alkoxycyclopropylamines via intramolecular
cyclization of 2-azaallylic anions derived from alkoxybrominated
N-(arylidene)-2-methyl-2-propenylamines
Sven Mangelinckx, Santosh T. Kadam, Elena Semina, Gert Callebaut, Filip Colpaert,
*
Dirk De Smaele, Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
N-(Arylidene)-2-alkoxy-3-bromo-2-methylpropylamines, obtained in a straightforward way via re-
giospecific alkoxybromination of the corresponding N-(2-methyl-2-propenyl)imines, represent promis-
ing densely functionalized synthetic building blocks. The substituted N-(3-bromopropyl)imines were
deprotonated to the corresponding 2-azaallylic anions, which underwent a highly diastereoselective
intramolecular ring closure to new cis-N-(arylidene)-2-alkoxy-2-methylcyclopropylamines (cis:trans up
to 99:1) in good to excellent yields (62e95%). These cis-cyclopropylamines proved to be excellent pre-
Received 24 October 2012
Received in revised form 22 February 2013
Accepted 28 February 2013
Available online 5 March 2013
Keywords:
cursors of new conformationally constrained b-amino ethers.
Cyclopropylamines
Amino ethers
Imines
Ó 2013 Elsevier Ltd. All rights reserved.
2-Azaallylic anions
1. Introduction
growth regulators. Under the influence of several bases, 2-
[N-(arylidene)amino]-4-chlorobutyronitriles or the corresponding
esters were transformed via intramolecular nucleophilic sub-
In contrast to the well-studied chemistry of halogenated
1-azaallylic anions derived from
and reactivity of halogenated 2-azaallylic anions derived from
N-( -haloalkyl)imines 1 has been far less studied. The imination of
u
-haloalkylimines,1 the synthesis
stitution to a
-ACC derivatives.2c,4 Previously, it was demonstrated
that the nucleophile-induced cyclization of N-(2-alkoxy-3-bromo-
2-methylpropyl)imines 10, like other N-(3-haloalkyl)imines 1,5 is
a valuable method for the synthesis of functionalized azetidines 4.6
In the present report, the reactivity of N-(2-alkoxy-3-bromo-2-
methylpropyl)imines 10 upon treatment with non-nucleophilic
bases is evaluated for the first time. It was envisioned that this
approach would provide access to N-(arylidene)-2-alkoxy-2-
methylcyclopropylamines as precursors of new conformationally
u
a primary amine significantly increases the acidity of the proton at
carbon-1 of the amine side chain, and facilitates the formation of
the corresponding 2-azaallylic anions,2a thus promoting further
cyclization reactions.2bed Therefore, in combination with the
presence of a halogen as a potential leaving group in the N-sub-
stituent of N-(u-haloalkyl)imines 1, a base-mediated formation of
a 2-azaallylic anion 2 can achieve the formation of a carbocyclic
compound 3 via subsequent intramolecular nucleophilic sub-
constrained b-amino ethers belonging to the synthetically and bio-
logically interesting class of amino- and alkoxy-substituted cyclo-
stitution. Nature uses this imination/
strategy in the biosynthesis of 1-aminocyclopropane-1-carboxylic
acid ( -ACC), the direct precursor of the plant hormone ethylene,
a-deprotonation/ring closure
propanes.7,8
a
from S-adenosylmethionine (SAM) catalyzed by the pyridoxal
phosphate (PLP)-dependent enzyme ACC synthase.3 Analogously,
the study of the reactivity of N-(3-halopropyl)imines has especially
2. Results and discussion
N-(2-Methyl-2-propenyl)imines 7aec, as precursors of the
highly functionalized N-(arylidene)-2-alkoxy-3-bromo-2-methyl-
propylamines 10, were easily obtained by imination of the corre-
sponding aromatic aldehydes 5 with the hydrochloride salt of
2-methyl-2-propenylamine 6 in dichloromethane under reflux in
the presence of triethylamine and magnesium sulfate in 83e93%
yield (Scheme 1).6,9
focused on the synthesis of a-ACC and analogues as potential plant
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 21; e-mail
addresses: Sven.Mangelinckx@UGent.be (S. Mangelinckx), norbert.dekimpe@
UGent.be (N. De Kimpe).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.094

S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
3729
R3
( )n
R3
R4
( )n
N
R3
N
R4
X
R3
N
R4
X
Nu
( )n
( )n
Base
N
R1
Nu
R1
R1
1 (X = leaving group)
R4
R2
R1 R2
R2
R2
4
2
3
form (purity >92%) to perform base-induced intramolecular cycli-
zation to the corresponding cyclopropylamines 11.
1.0 equiv
3.0 equiv Et3N
2.0 equiv MgSO4
CH Cl , , 2 h
Cl H3N
H
6
The optimization of thebase-mediated intramolecular cyclization
of N-(3-bromopropyl)imine 10a, involving substitution of the neo-
pentylic bromo substituent, with different non-nucleophilic bases
was performed by evaluation of different combinations of solvent,
temperature, and reaction time (Table 2). In the first attempts,
N-(benzylidene)-3-bromo-2-methoxy-2-methylpropylamine 10a
was treated with LiHMDS resulting only in unreacted starting ma-
terial (Table 2, entries 1 and 2). The use of KHMDS in THF or diethyl
ether afforded the desired cyclopropylamine 11a with a low dia-
stereoselectivity (entries 3e5). Subsequently, similar poor results
were obtained when imine 10a was treated with 3 equiv of potas-
sium tert-butoxide in THF (entries 6 and 7). Interestingly, the use of
diethyl ether and tert-butanol as reaction solvents resulted in ex-
cellent cis-stereoselectivity, i.e., 97:3 and 99:1, respectively, with
goodyields(80%) after stirring for 1 h at reflux temperature (entries8
and 9). The cyclization reaction in THF in the presence of 1 equiv of
tert-butanol resulted yet again in a poor cis-stereoselectivity (entry
10) demonstrating the disadvantageous effect of THF on the dia-
stereoselectivity. Theyield ofcyclopropane11a wasfurtherincreased
when the reaction was performed with 3 equiv of potassium tert-
butoxide in diethyl ether at reflux temperature for 3 h, which gave
good cis-stereoselectivity combined with a high yield of 91% (entry
11). Lowering the amount of potassium tert-butoxide resulted in
incomplete conversion of the starting imine 10a (entries 12 and 13).
O
R1
N
R1
H
Δ
2
2
7a-c
5
7a R1 = C6H5 (93%)
7b R1 = 4-MeC6H4 (90%)
7c R1 = 4-ClC6H4 (83%)
Scheme 1. Synthesis of N-(2-methyl-2-propenyl)imines 7.
N-(Diphenylmethylidene)-2-methyl-2-propenylimine
9
was
synthesized by transimination of benzophenone imine 8 with the
hydrochloride salt of 2-methyl-2-propenylamine 6 in 77% yield
(Scheme 2).6
NH
H N
3
Cl
1.0 equiv
6
N
CH2Cl2, rt, 12 h
8
9
(77%)
Scheme 2. Synthesis of N-(diphenylmethylidene)-2-methyl-2-propenylimine 9.
Table 2
Optimization of the intramolecular cyclization of N-(benzylidene)-3-bromo-2-
methoxy-2-methylpropylamine 10a
In a next step, the resulting imines 7aec and 9 underwent
regioselective alkoxybromination using N-bromosuccinimide and
the corresponding alcohols leading to the formation of N-(aryli-
dene)-2-alkoxy-3-bromo-2-methylpropylamines 10aej in excel-
lent yield (85e97%) (Table 1). The alkoxybrominations of imines
7aec and 9 to the corresponding N-(3-bromopropyl)imines 10aej
were performed in methanol, ethanol, isopropanol or n-propanol
as alkoxy source, in combination with N-bromosuccinimide at
ambient temperature for 6 h. N-(Arylidene)-2-alkoxy-3-bromo-2-
methylpropylamines 10aej were obtained in sufficiently pure
H
H
base
N
Br
OMe
N
OMe
solvent, temp, time
(see table)
10a
11a
Entry
Base (equiv)
Solvent
Temp/time (h)
cis:transa
Yieldb (%)
1
2
3
4
5
6
7
8
LiHMDS (3)
LiHMDS (3)
KHMDS (3)
KHMDS (3)
KHMDS (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (1)
KOtBu (2.1)
THF
Et2O
THF
Et2O
Et2O
THF
rt/4
rt/4
rt/2
rt/2
d
d
d
d
60:40
69:31
58:42
68:32
74:26
97:3
99:1
78:22
91:9
11a (75)
11a (79)
11a (99)
11a (83)
11a (75)
11a (80)
11a (80)
11a (86)
11a (91)
dd
Table 1
D/0.5
Synthesis of N-(arylidene)-2-alkoxy-3-bromo-2-methylpropylamines 10aej
rt/8
R2
R2
THF
D/1
D/1
D/1
D/3
D/3
D/3
D/3
1.0 equiv NBS
Et2O
t-BuOH
THFc
Et2O
Et2O
Et2O
R1
N
R1
N
Br
OR3
R3OH, rt, 6 h
9
10
11
12
13
7a-c (R2 = H)
10a- j
9 (R1 = R2 = C6H5)
>99:1
>99:1
de
Based on 1H NMR analysis of the crude reaction mixture.
Yield of crude product.
t-BuOH (1 equiv) was added.
Conversion to cyclopropane 11a was 18%.
Conversion to cyclopropane 11a was 81%.
a
Entry
R1
R2
R3
Yielda (%)
b
c
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
H
H
H
C6H5
H
H
H
H
H
Me
Et
i-Pr
Me
Me
Et
i-Pr
n-Pr
Me
Et
10a (91)
10b (97)
10c (92)
10d (91)
10e (88)
10f (91)
10g (85)
10h (85)
10i (94)
10j (93)
d
e
Analogously, N-(arylidene)-2-alkoxy-2-methylcyclopropylamines
11aej were prepared with excellent cis-stereoselectivity (up to 99:1)
and good to excellent yield (62e95%) by using the optimized reaction
conditions (Table 3). In order to investigate the effectof variousalkoxy
groups on the stereoselectivity of the intramolecular cyclization
10
H
a
Yield of crude product.

3730
S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
Table 3
Synthesis of cis-N-(arylidene)-2-alkoxy-2-methylcyclopropylamines 11aej and cis-N-(arylmethyl)-2-alkoxy-2-methylcyclopropylamines 12aej
R2
3.0-6.0 equiv NaBH4
3.0 equiv KOtBu
Et2O, , 3 h
N
OR3
HN
OR3
R1
N
Br
OR3
Δ
Δ
MeOH, , 3-6 h
R1 R2
R1 R2
10a-j
11a-j
12a-j
Entry
R1
R2
R3
cis:transa
Yield of 11b (%)
Yield of 12c (%)
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
H
H
H
C6H5
H
H
H
H
H
Me
Et
i-Pr
Me
Me
Et
i-Pr
n-Pr
Me
Et
91:9
95:5
95:5
99:1
92:8
97:3
89:11
92:8
97:3
97:3
11a (91)
11b (62)
11c (92)
11d (81)c
11e (90)
11f (95)
11g (89)
11h (89)
11i (86)
11j (91)
12a (68)
12b (62)
12c (69)
12d (52) (75)d
12e (48)
12f (60)
12g (67)
12h (72)
12i (65)
10
H
12j (73)
a
Based on 1H NMR analysis of crude reaction mixture.
Yield of crude product.
Isolated yield after purification via flash chromatography.
b
c
d
Reduction was performed with 2.0 equiv of sodium cyanoborohydride at room temperature.
reaction, methoxy, ethoxy, isopropoxy, and n-propoxy groups
were screened. In all cases, a similar cis-stereoselectivity was ob-
served. Noteworthy, upon cyclization of N-(diphenylmethylidene)-
2-methoxy-3-bromo-2-methylpropylamine 10d (R1¼R2¼C6H5),
the corresponding N-(diphenylmethylidene)-2-methoxy-2-methyl-
cyclopropylamine 11d was obtained with the highest cis-stereo-
selectivity (cis:trans 99:1, Table 3, entry 4). This indicates that the
introduction of extra sterical hindrance by a second phenyl group in
the imine moiety improves the cis-stereoselectivity of the intra-
molecular cyclization.
δ
2.73 ppm
δ
1.03 ppm
(dd, J = 7.7, 5.0 Hz)
(dd, J = 7.7, 5.5 Hz)
2.6%
2.0%
Hc
Me
0.3%
OMe
Me
Ha
0.4%
Hb
Ha
Hc
CDCl3
OMe
Ph
Hb
N
N
1.50 ppm
δ
Ph
(dd, J = 5.5, 5.0 Hz)
Ph
11d
Ph
11d
Fig. 2. Determination of the cis-stereochemistry of cyclopropane 11d via NOE exper-
The proposed reaction mechanism involves the deprotonation
iments and 1H NMR data.
of an
a-N-proton of N-(3-bromopropyl)imines 10 by potassium
tert-butoxide, resulting in the formation of the planer 2-azaallylic
anion K-10, leading to the preferential formation of the cis-cyclo-
propanes 11(Fig. 1). The formation of the cis-cyclopropanes, sta-
bilized by the interaction between the K-cation, the arylidenamino
group and the alkoxy substituent in the five-membered bidentate
chelated complex cis-K-11,10 is sterically favored since the methyl
substituent, which is sterically more demanding than the alkoxy
groups based on A-values,11 is positioned trans to the aryliden-
amino function. This steric effect also explains the excellent cis-
stereoselectivity observed for the cyclization of ketimine 10d
(R1¼R2¼C6H5).
protons of cyclopropanes in cis-position to a methoxy function (i.e.,
Hb for cyclopropane 11d), as compared to trans-positioned protons
(i.e., Ha and Hc), is shifted downfield.12 Therefore, in the cis-isomers
11 the proton Hc has a chemical shift in the upfield range
2.73e2.96 ppm, whereas the corresponding proton in the minor
trans-isomers absorbs downfield (3.01e3.18 ppm, data not pre-
sented). Noteworthy, the chemical shifts for the geminal protons Ha
(cis-positioned to the methyl group) and Hb (cis-positioned to the
methoxy and the diphenylmethylidenamino function) at C-3 in cis-
cyclopropane 11d are quite different (1.03 and 1.50 ppm).12
Me
K
R3
R2
R2
R2
O
KOtBu
- KBr
H2O
H
R1
N
Br
R1
N
Br
N
R1
N
OR3
Br
K
R2
- tBuOH
OR3
OR3
Me
Me
R1
cis-K-11
10
K-10
cis-11
Fig. 1. Proposed mechanistic rationalization.
The cis-configuration of cyclopropanes 11a and 11d was con-
firmed by DIFNOE-NMR experiments. For example, for cyclopro-
pane 11d, the fact that after irradiation of proton Hc, the most
shielded proton (Ha) and the methyl group exhibit the highest NOE,
proves that Ha and Hc are positioned cis to the methyl substituent
(Fig. 2). This interaction indicates that the diphenylmethylidena-
mino function holds a cis-position to the methoxy group. Moreover,
it has been reported in the literature that the resonance signal of
Furthermore, in the next step the cis-N-(arylidene)-2-alkoxy-2-
methylcyclopropylamines 11aej could be easily reduced with
3 equiv of sodium borohydride at reflux temperature to the corre-
sponding cis-N-(arylmethyl)-2-alkoxy-2-methylcyclopropylamines
12aej, which were isolated after purification by flash chromato-
graphy in moderate to good yields (48e75%) (Table 3). Remarkably,
when cis-N-(diphenylmethylidene)-2-methoxy-2-methylcyclopro-
pylamine 11d was treated with 3 equiv of sodium borohydride at

S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
3731
reflux temperature for 3 h, an incomplete conversion of 87% to the
desired cis-N-(benzhydryl)-2-methoxy-2-methylcyclopropylamine
12d was observed. Hence, when cis-N-(diphenylmethylidene)-2-
methoxy-2-methylcyclopropylamine 11d was treated with 6 equiv
of sodium borohydride in two portions at reflux temperature for 6 h,
the corresponding cis-N-(benzhydryl)-2-methoxy-2-methylcyclo-
propylamine 12d was isolated after purification via flash chroma-
tography in 52% yield (Table 3, entry 4). In contrast to sodium bo-
rohydride, treatment of cis-N-(diphenylmethylidene)-2-methoxy-2-
methylcyclopropylamine 11d with 2 equiv of sodium cyanoboro-
hydride in the presence of 1 equiv of acetic acid at room tempera-
ture for 6 h afforded the corresponding cis-N-(benzhydryl)-2-
methoxy-2-methylcyclopropylamine 12d in 75% yield after purifi-
cation via flash chromatography (Table 3, entry 4). Noteworthy,
during the reduction of cis-N-(arylidene)-2-alkoxy-2-methyl-
cyclopropylamines 11aej in all cases the cyclopropane skeleton
remained intact without forming any side products resulting from
ring opening. This fact is certainly attributed to the two vicinal do-
nor heteroatom substituents of the cyclopropanes, making them
more stable as compared to donor-acceptor substituted cyclopro-
panes.7,13 Furthermore, cis-N-(arylmethyl)-2-alkoxy-2-methylcyclo-
propylamines 12aej were obtained with the same cis/trans ratio
(cis:trans >89:11) as obtained for cis-N-(arylidene)-2-alkoxy-2-
methylcyclopropylamines 11aej.
To further explore the scope of accessible cyclopropanes, the
suitability of N-allylimines 13 as substrates for the synthesis of the
corresponding 2-alkoxycyclopropylamines was investigated.
When N-allylimines 13a,b were treated with N-bromosuccini-
mide in methanol at ambient temperature for 6 h (Scheme 3), the
alkoxybromination was not regioselective,14 and an inseparable
mixture of two regioisomers in a 3:2 ratio was formed in good yield
(67e95%). Subsequently, this mixture of regioisomers underwent
the base-induced intramolecular cyclization, by using the opti-
mized reaction conditions as in the synthesis of cyclopropanes 11,
to afford the crude cyclopropylamines 14. The more stable cis-N-
(diphenylmethylidene)-2-methoxycyclopropylamine 14b was iso-
lated by column chromatography in 53% yield. Chromatographic
purification of the less stable crude N-benzylidene-2-methoxy-
cyclopropylamine 14a was not possible and, therefore, the crude
reaction mixture was immediately reduced with 3 equiv of sodium
borohydride at reflux temperature to the corresponding cis-N-
(benzyl)-2-methoxycyclopropylamine 15, which was isolated after
purification by flash chromatography in moderate yield (26%)
(Scheme 3).
The cis-configuration of cyclopropanes 15 and 14b was con-
firmed by analysis of the coupling constants (J values) of the
cyclopropyl protons and by comparison of the sum of the coupling
P
P
constants ( JCHO¼15.4e16.0 Hz and JCHN¼17.6e19.3 Hz) of the
heteroatom-substituted cyclopropyl protons with literature
P
values of cis-2-phenoxycyclopropylamine ( JCHO¼16.0 Hz and
P
JCHN¼19.2 Hz).8a
It is remarkable that the ring closure of the methoxybrominated
N-allylimines 13, without the presence of a more sterically de-
manding methyl-substituent on the C2-position, is still leading to
cis-2-methoxycyclopropylamine derivatives 14 and 15. The forma-
tion of the latter sterically crowded cis-cyclopropanes supports the
proposed mechanism in which the favorable interaction between
the K-cation, the arylidenamino group and the alkoxy substituent
in
important.
In the final step, the cis-N-(arylidene)-2-alkoxy-2-methyl-
a five-membered bidentate chelated complex cis-K-11 is
cyclopropylamines 11aej were converted to the corresponding
2-alkoxy-2-methylcyclopropylamine hydrochlorides by acidic hy-
drolysis. Initially, cis-N-(benzylidene)-2-methoxy-2-methylcyclo-
propylamine 11a was treated with 1 M aqueous oxalic acid and
Et2O for 16 h at reflux. Unfortunately, a complex mixture was ob-
tained after work up. Nevertheless, treatment of cis-N-(benzyli-
dene)-2-ethoxy-2-methylcyclopropylamine 11b with 2 M aqueous
hydrochloric acid and Et2O for 16 h at reflux, afforded the corre-
sponding cis-2-ethoxy-2-methylcyclopropylamine hydrochloride
16b in good yield (81%, cis:trans 95:5) (Scheme 4). In a similar way,
imines 11c, 11i, and 11h could be easily N-deprotected to the cor-
responding 2-isopropoxy-2-methylcyclopropylamine hydrochlo-
ride 16c, 2-methoxy-2-methylcyclopropylamine hydrochloride 16i,
and 2-propoxy-2-methylcyclopropylamine hydrochloride 16h in
good yields (61e88%) (Scheme 4).
1) 1 equiv NBS
MeOH, r.t., 6 h
R1
(67-95%a)
N
OMe
3 equiv NaBH4
MeOH, , 3 h
R1 = H
HN
Ph
OMe
Ph
N
Ph
R1
Δ
2) 3 equiv KOtBu
Et2O, , 3 h
Δ
14a (91%a)
14b (53%)
13a (R1 = H)
13b (R1 = Ph)
15 (26%)
a Yield of crude product
Scheme 3. Synthesis of cis-N-(arylidene)-2-methoxycyclopropylamines 14a,b and cis-N-benzyl-2-methoxycyclopropylamine 15.
N
OR3
2M HCl (aq.)
Et2O, , 16 h
Δ
H
Cl H3N
OR3
R
11b R = H, R3 = Et (cis:trans 95:5)
11c R = H, R3 = iPr (cis:trans 95:5)
11i R = Cl, R3 = Me (cis:trans 97:3)
11h R = Me, R3 = n-Pr (cis:trans 92:8)
16b R3 = Et (81%) (cis:trans 95:5)
16c R3 = iPr (61%) (cis:trans 95:5)
16i R3 = Me (88%) (cis:trans 97:3)
16h R3 = n-Pr (88%) (cis:trans 92:8)
Scheme 4. Synthesis of cis-2-alkoxy-2-methylcyclopropylamine hydrochlorides 16.

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S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
3. Conclusion
(300 MHz, CDCl3):
d
1.17 (d, J¼6.1 Hz, 3H), 1.21 (d, J¼6.1 Hz, 3H), 1.41
(s, 3H), 3.48 (d, J¼10.5 Hz, 1H), 3.57 (d, J¼10.5 Hz, 1H), 3.63 (dꢁd,
J¼12.4, 1.1 Hz,1H), 3.82 (dꢁd, J¼12.4, 1.1 Hz,1H), 3.96 (sept, J¼6.1 Hz,
1H), 7.36e7.43 (m, 3H), 7.71e7.76 (m, 2H), 8.29 (s, 1H). 13C NMR
In conclusion, a novel synthetic method has been demonstrated
in which cis-N-(arylidene)-2-alkoxy-2-methylcyclopropylamines
were obtained in good to excellent yields and with high cis-stereo-
selectivity. The key-step involved base-induced intramolecular ring
closure, assisted by interactions of the metal ion with the present
alkoxy and amino groups, of the corresponding N-(arylidene)-2-
alkoxy-3-bromo-2-methylpropylamines. Furthermore, these cyclo-
propylamines smoothly underwent reduction with sodium borohy-
dride to the corresponding cis-N-(arylmethyl)-2-alkoxy-2-methyl-
cyclopropylamines. Moreover, cis-N-(arylidene)-2-alkoxy-2-methyl-
cyclopropylamines proved to be excellent precursors of new con-
(75 MHz, CDCl3):
d 21.5, 24.8, 25.0, 39.6, 64.5, 67.2, 76.4, 128.1 (2C),
128.5 (2C), 130.7, 136.1, 162.4. MS (ES, pos. mode) m/z (%): 298/300
(MþHþ, 100). HRMS (ES) calcd for C14H20BrNO: 298.0801 MHþ;
found: 298.0805.
4.2.1.4. N-(Diphenylmethylidene)-3-bromo-2-methoxy-2-methyl-
propylamine 10d.6 Pale yellow oil, 91%. HRMS (ES) calcd for
C18H20BrNO: 346.0801 MHþ; found: 346.0802.
formationally constrained hydrochloride salts of
b-amino ethers.
4.2.1.5. N-(4-Methylbenzylidene)-3-bromo-2-methoxy-2-methyl-
propylamine 10e.6 Light brown oil, 88%. HRMS (ES) calcd for
C13H18BrNO: 284.0644 MHþ; found: 284.0651.
4. Experimental
4.1. General
4.2.1.6. N-(4-Methylbenzylidene)-3-bromo-2-ethoxy-2-methyl-
propylamine 10f. Light brown oil, 91%. IR (cmꢀ1): nmax 1646, 1090.
Flame-dried glassware was used for all non-aqueous reactions.
Diethyl ether (Et2O) was freshly distilled under a nitrogen atmo-
sphere from sodium/benzophenone ketyl prior to use. 1H NMR
(300 MHz), 13C NMR (75 MHz) spectra were recorded in deuterated
1H NMR (300 MHz, CDCl3):
d
1.19 (t, J¼7.2 Hz, 3H), 1.36 (s, 3H), 2.35
(s, 3H), 3.51 (q, J¼7.2 Hz, 2H), 3.52 (d, J¼11.0 Hz, 1H), 3.57 (d,
J¼11.0 Hz, 1H), 3.59 (d, J¼12.1, 1H), 3.81 (d, J¼12.1 Hz, 1H), 7.18 (d,
J¼8.3 Hz, 2H), 7.62 (d, J¼8.3 Hz, 2H), 8.24 (s, 1H). 13C NMR (75 MHz,
solvents with tetramethylsilane (TMS,
d¼0 ppm) as internal standard
CDCl3): d 15.6, 20.6, 21.2, 38.3, 56.9, 66.2, 75.3, 127.9 (2C),128.9 (2C),
unless specified otherwise. Mass spectra were recorded using a di-
rect inlet system (ESI, 4000 V). IR spectra were obtained from sam-
ples in neat form with an ATR (Attenuated Total Reflectance)
accessory. Elementary analyzes were performed using a CHNS/O
elementary analyzer. HRMS analysis was performed using an Agilent
1100 series HPLC coupled to an Agilent 6220 TOF-Mass Spectrometer
equipped with ESI/APCI-multimode source. Melting points of crys-
talline compounds were determined in open-end capillary tubes
using a hot stage apparatus and were not corrected. The purification
of the reaction mixtures was performed by column chromatography
with silica gel (particle size 0.035e0.070 mm, pore diameter ca.
6 nm). Thin layer chromatography (TLC) was performed on glass
plates coated with silica gel 60 F254, using UV and KMnO4 as a visu-
alizing agent.
133.4, 140.5, 162.0. MS (ES, pos. mode) m/z (%): 298/300 (MþHþ,
100). HRMS (ES) calcd for C14H20BrNO: 298.0801 MHþ; found:
298.0802.
4.2.1.7. N-(4-Methylbenzylidene)-3-bromo-2-isopropoxy-2-methyl-
propylamine 10g. Pale yellow oil, 85%. IR (cmꢀ1): nmax 1648, 1109. 1H
NMR (300 MHz, CDCl3):
d
1.16 (d, J¼6.1 Hz, 3H), 1.20 (d, J¼6.1 Hz, 3H),
1.40 (s, 3H), 2.36 (s, 3H), 3.48 (d, J¼10.5 Hz, 1H), 3.56 (d, J¼10.5 Hz,
1H), 3.61 (d, J¼12.1, 1H), 3.80 (d, J¼12.1 Hz, 1H), 3.96 (sept, J¼6.1 Hz,
1H), 7.19 (d, J¼8.3 Hz, 2H), 7.62 (d, J¼8.3 Hz, 2H), 8.26 (s,1H). 13C NMR
(75 MHz, CDCl3): d 21.46, 21.51, 24.9, 25.0, 39.7, 64.5, 67.3, 76.4, 128.1
(2C),129.2 (2C),133.6,140.9,162.3. MS (ES, pos. mode) m/z (%): 312/14
(MþHþ, 100). HRMS (ES) calcd for C15H22BrNO: 312.0957 MHþ;
found: 312.0957.
4.2. Synthetic procedures
4.2.1.8. N-(4-Methylbenzylidene)-3-bromo-2-methyl-2-propoxy-
propylamine 10h. Light brown oil, 85%. IR (cmꢀ1): nmax 1647, 1067. 1H
4.2.1. Synthesis of N-(arylidene)-2-alkoxy-3-bromo-2-methylpropyl-
amines 10aej. The synthesis of N-(benzylidene)-2-methoxy-3-
bromo-2-methylpropylamine 10a is representative.6 To a stirred
solution of N-(2-methyl-2-propenyl)imine 7a (0.50 g, 3.14 mmol,
1.0 equiv) in MeOH (30 mL), N-bromosuccinimide (0.55 g, 3.14 mmol,
1.0 equiv) was added at room temperature. The reaction mixture was
allowed to stir for 6 h at room temperature. Subsequently, MeOH was
evaporated in vacuo and pentane was added. The suspension was
filtered over CeliteÒ and the solid was washed with pentane. After
evaporation of the filtrate, N-(benzylidene)-2-methoxy-3-bromo-2-
methylpropylamine 10a (0.78 g) was obtained in sufficiently pure
form (purity >92%) for further use in the next step (91%, 2.90 mmol).
All the spectroscopic data for compounds 10a,b,d, and e were in good
agreement with the reported data of these compounds.6
NMR (300 MHz, CDCl3):
d
0.92 (t, J¼7.2 Hz, 3H),1.37 (s, 3H),1.58 (sext,
J¼7.2 Hz, 2H), 2.36 (s, 3H), 3.41 (t, J¼7.2 Hz, 2H), 3.52 (d, J¼11.0 Hz,
1H), 3.58 (d, J¼11.0 Hz, 1H), 3.60 (d, J¼12.1, 1H), 3.82 (d, J¼12.1 Hz,
1H), 7.19 (d, J¼8.3 Hz, 2H), 7.62 (d, J¼8.3 Hz, 2H), 8.25 (s,1H).13C NMR
(75 MHz, CDCl3):
d 10.7, 20.8, 21.4, 23.5, 38.6, 63.3, 66.4, 75.4, 128.1
(2C), 129.2 (2C), 133.6, 140.8, 162.4. MS (ES, pos. mode) m/z (%): 312/
14 (MþHþ, 100). HRMS (ES) calcd for C15H22BrNO: 312.0957 MHþ;
found: 312.0959.
4.2.1.9. N-(4-Chlorobenzylidene)-3-bromo-2-methoxy-2-methyl-
propylamine 10i. Pale yellow oil, 94%. IR (cmꢀ1): nmax 1629, 1066. 1H
NMR (300 MHz, CDCl3):
d
1.39 (s, 3H), 3.33 (s, 3H), 3.52 (d, J¼11.0 Hz,
1H), 3.58 (d, J¼11.0 Hz, 1H), 3.64 (dꢁd, J¼12.1, 1.1 Hz, 1H), 3.82 (dꢁd,
J¼12.1,1.1 Hz,1H), 7.37 (d, J¼8.8 Hz, 2H), 7.68 (d, J¼8.8 Hz, 2H), 8.27 (s,
H). 13C NMR (75 MHz, CDCl3):
d 20.0, 37.8, 49.6, 65.8, 75.6, 128.6 (2C),
4.2.1.1. N-(Benzylidene)-3-bromo-2-methoxy-2-methylpropylamine
10a.6 Pale yellow oil, 91%. HRMS (ES) calcd for C12H16BrNO:
270.0488 MHþ; found: 270.0491.
129.2 (2C), 134.4, 136.4, 161.1. MS (ES, pos. mode) m/z (%): 304/6/8
(MþHþ, 100). HRMS (ES) calcd for C12H15BrClNO: 304.0098 MHþ;
found: 304.0097.
4.2.1.2. N-(Benzylidene)-3-bromo-2-ethoxy-2-methylpropylamine
10b.6 Light brown oil, 97%. HRMS (ES) calcd for C13H18BrNO:
284.0644 MHþ; found: 284.0647.
4.2.1.10. N-(4-Chlorobenzylidene)-3-bromo-2-ethoxy-2-methyl-
propylamine 10j. Light brown oil, 93%. IR (cmꢀ1): nmax 1648, 1088. 1H
NMR (300 MHz, CDCl3):
d
1.19 (t, J¼7.2 Hz, 3H), 1.37 (s, 3H), 3.51 (q,
J¼7.2 Hz, 2H), 3.51 (d, J¼11.0 Hz, 1H), 3.57 (d, J¼11.0 Hz, 1H), 3.60 (d,
4.2.1.3. N-(Benzylidene)-3-bromo-2-isopropoxy-2-methylpropyl-
J¼12.1, 1H), 3.82 (d, J¼12.1 Hz, 1H), 7.34 (d, J¼8.3 Hz, 2H), 7.65 (d,
amine 10c. Pale yellow oil, 92%. IR (cmꢀ1): nmax 1646, 1110. 1H NMR
J¼8.3 Hz, 2H), 8.23 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 15.8, 20.7,

S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
3733
38.3, 57.1, 66.2, 75.4, 128.6 (2C), 129.2 (2C),134.5, 136.4,161.0. MS (ES,
pos. mode) m/z (%): 318/20/22 (MþHþ, 100). HRMS (ES) calcd for
C13H17BrClNO: 318.0254 MHþ; found: 318.0255.
4.2.2.6. cis-N-(4-Methylbenzylidene)-2-ethoxy-2-methylcyclo-
propylamine 11f. Light brown oil, 95%. IR (cmꢀ1): nmax 1630, 1066.
1H NMR (300 MHz, CDCl3):
d
1.03 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.16 (t,
J¼7.2 Hz, 3H), 1.42 (s, 3H), 1.48 (dꢁd, J¼6.1, 5.0 Hz, 1H), 2.33 (s, 3H),
2.91 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.41 (dꢁq, J¼8.8, 7.2 Hz, 1H), 3.61
(dꢁq, J¼8.8, 7.2 Hz,1H), 7.16 (d, J¼8.3 Hz, 2H), 7.61 (d, J¼8.3 Hz, 2H),
4.2.2. Synthesis of N-(arylidene)-2-alkoxy-2-methylcyclopropylamines
11aej. The synthesis of N-(benzylidene)-2-ethoxy-2-methylcyclo-
propylamine 11b is representative. In a flame dried flask, potassium
tert-butoxide (1.38 g,12.40 mmol, 3.0 equiv) was added to a solution of
N-(benzylidene)-2-ethoxy-3-bromo-2-methylpropylamine 10b (1.17 g,
4.13 mmol) in diethyl ether (80 mL) at room temperature. The mixture
was stirred at reflux temperature for 3 h. Subsequently, the reaction
mixturewas quenched byadding water(20mL)and was extractedwith
diethyl ether (3ꢁ20 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated in vacuo to yield 0.52 g of N-(benzy-
lidene)-2-ethoxy-2-methylcyclopropylamine 11b (2.56 mmol, 62%).
8.32 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 15.4, 20.5, 21.3, 23.2, 53.4,
62.5, 62.8, 127.5 (2C), 129.0 (2C), 134.0, 139.9, 158.4. MS (ES, pos.
mode) m/z (%): 218 (MþHþ, 100). HRMS (ES) calcd for C14H19NO:
218.1539 MHþ; found: 218.1543.
4.2.2.7. cis-N-(4-Methylbenzylidene)-2-isopropoxy-2-methyl-
cyclopropylamine11g. Lightbrownoil, 89%.IR(cmꢀ1): nmax 1629, 1119.
1H NMR (300 MHz, CDCl3):
d
1.04 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.15 (d,
J¼6.1 Hz, 3H), 1.20 (d, J¼6.1 Hz, 3H), 1.44 (s, 3H), 1.47 (dꢁd, J¼6.1,
5.0 Hz, 1H), 2.34 (s, 3H), 2.89 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.82 (sept,
J¼6.1 Hz,1H), 7.17 (d, J¼8.3 Hz, 2H), 7.61 (d, J¼8.3 Hz, 2H), 8.31 (s,1H).
4.2.2.1. cis-N-(Benzylidene)-2-methoxy-2-methylcyclopropylamine
11a. Light brown oil, 91%. IR (cmꢀ1): nmax 1632, 1067. 1H NMR
13C NMR (75 MHz, CDCl3):
d 21.4, 23.0, 23.3, 23.4, 24.0, 54.1, 62.9, 70.1,
(300 MHz, CDCl3):
d
1.07 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.42 (s, 3H), 1.47
127.7 (2C), 129.2 (2C), 134.1, 140.0, 158.5. MS (ES, pos. mode) m/z (%):
232 (MþHþ, 100). HRMS (ES) calcd for C15H21NO: 232.1695 MHþ;
found: 232.1702.
(dꢁd, J¼6.1, 5.0 Hz, 1H), 2.94 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.33 (s, 3H),
7.34e7.40 (m, 3H), 7.71e7.76 (m, 2H), 8.40 (s, 1H). 13C NMR (75 MHz,
CDCl3): d 19.7, 23.4, 53.8, 54.5, 63.6, 127.7 (2C), 128.4 (2C), 130.1, 136.6,
159.1. MS (ES, pos. mode) m/z (%): 190 (MþHþ, 100). HRMS (ES) calcd
4.2.2.8. cis-N-(4-Methylbenzylidene)-2-methyl-2-propoxycyclo-
for C12H15NO: 190.1226 MHþ; found: 190.1229.
propylamine 11h. Light brown oil, 89%. IR (cmꢀ1): nmax 1630, 1075.
1H NMR (300 MHz, CDCl3):
d
0.90 (t, J¼7.2 Hz, 3H), 1.04 (dꢁd, J¼7.7,
4.2.2.2. cis-N-(Benzylidene)-2-ethoxy-2-methylcyclopropylamine
6.1 Hz, 1H), 1.42 (s, 3H), 1.48 (dꢁd, J¼6.1, 5.0 Hz, 1H), 1.50e1.63 (m,
2H), 2.34 (s, 3H), 2.92 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.35 (dꢁt, J¼8.8,
6.6 Hz, 1H), 3.49 (dꢁt, J¼8.8, 6.6 Hz, 1H), 7.17 (d, J¼8.3 Hz, 2H), 7.60
11b. Light brown oil, 62%. IR (cmꢀ1): nmax 1629, 1119. 1H NMR
(300 MHz, CDCl3):
d
1.06 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.17 (t, J¼7.2 Hz,
3H), 1.42 (s, 3H), 1.50 (dꢁd, J¼6.1, 5.0 Hz, 1H), 2.94 (dꢁd, J¼7.7,
5.0 Hz, 1H), 3.41 (dꢁq, J¼8.8, 7.2 Hz, 1H), 3.62 (dꢁq, J¼8.8, 7.2 Hz,
1H), 7.34e7.39 (m, 3H), 7.69e7.74 (m, 2H), 8.37 (s, 1H). 13C NMR
(d, J¼8.3 Hz, 2H), 8.33 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 10.7, 20.5,
21.2, 23.1, 23.2, 53.5, 62.7, 68.7, 127.5 (2C), 129.0 (2C), 134.1, 139.8,
158.3. MS (ES, pos. mode) m/z (%): 232 (MþHþ, 100). HRMS (ES)
calcd for C15H21NO: 232.1695 MHþ; found: 232.1702.
(75 MHz, CDCl3): d 15.6, 20.6, 23.5, 53.6, 62.7, 63.1, 127.7 (2C), 128.5
(2C), 130.0, 136.7, 158.6. MS (ES, pos. mode) m/z (%): 204 (MþHþ,
100). HRMS (ES) calcd for C13H17NO: 204.1382 MHþ; found:
204.1385.
4.2.2.9. cis-N-(4-Chlorobenzylidene)-2-methoxy-2-methylcyclo-
propylamine 11i. Pale yellow oil, 86%. IR (cmꢀ1): nmax 1631, 1088. 1H
NMR (300 MHz, CDCl3):
d
1.10 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.43 (s, 3H),
4.2.2.3. cis-N-(Benzylidene)-2-isopropoxy-2-methylcyclopropyl-
1.46 (dꢁd, J¼6.1, 5.0 Hz,1H), 2.95 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.33 (s, 3H),
amine 11c. Light brown oil, 92%. IR (cmꢀ1): nmax 1631, 1018. 1H NMR
7.35 (d, J¼8.3 Hz, 2H), 7.67 (d, J¼8.3 Hz, 2H), 8.37 (s, 1H). 13C NMR
(300 MHz, CDCl3):
d
1.06 (dꢁd, J¼7.7, 5.5 Hz, 1H), 1.15 (d, J¼6.1 Hz,
(75 MHz, CDCl3): d 19.7, 23.6, 53.9, 54.6, 63.8, 128.7 (2C), 128.9 (2C),
3H), 1.20 (d, J¼6.1 Hz, 3H), 1.44 (s, 3H), 1.49 (dꢁd, J¼5.5, 5.0 Hz, 1H),
2.90 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.82 (sept, J¼6.1 Hz, 1H), 7.33e7.37 (m,
3H), 7.70e7.74 (m, 2H), 8.34 (s, 1H). 13C NMR (75 MHz, CDCl3):
135.1, 135.9, 157.8. MS (ES, pos. mode) m/z (%): 224/26 (MþHþ, 100).
HRMS (ES) calcd for C12H14ClNO: 224.0837 MHþ; found: 224.0834.
d
23.1, 23.5, 23.6, 24.1, 54.2, 63.1, 70.2, 127.8 (2C), 128.5 (2C), 130.0,
4.2.2.10. cis-N-(4-Chlorobenzylidene)-2-ethoxy-2-methylcyclo-
136.7, 158.6. MS (ES, pos. mode) m/z (%): 218 (MþHþ, 100). HRMS
propylamine 11j. Light brown oil, 91%. IR (cmꢀ1): nmax 1631, 1087. 1H
(ES) calcd for C14H19NO: 218.1539 MHþ; found: 218.1546.
NMR(300 MHz, CDCl3):
d
1.09(dꢁd, J¼7.7, 6.1 Hz,1H),1.17 (t, J¼7.2Hz,
3H),1.44 (s, 3H),1.50 (dꢁd, J¼6.1, 5.0 Hz,1H), 2.96 (dꢁd, J¼7.7, 5.0 Hz,
1H), 3.39(dꢁq, J¼8.8, 7.2 Hz,1H), 3.63(dꢁq, J¼8.8, 7.2 Hz,1H), 7.35 (d,
J¼8.3 Hz, 2H), 7.65 (d, J¼8.3 Hz, 2H), 8.34 (s, 1H). 13C NMR (75 MHz,
4.2.2.4. cis-N-(Diphenylmethylidene)-2-methoxy-2-methylcyclo-
propylamine 11d. Rf¼0.36 (petroleum ether/EtOAc 9:1). Yellow
crystals, 81%. Mp 88e89 ꢂC. IR (cmꢀ1): nmax 1606, 1066. 1H NMR
CDCl3): d 15.3, 20.2, 23.4, 53.2, 62.3, 63.0,128.4 (2C),128.5 (2C),135.0,
(300 MHz, CDCl3):
d
1.03 (dꢁd, J¼7.7, 5.5 Hz, 1H), 1.28 (s, 3H), 1.50
135.4,156.7. MS(ES, pos. mode) m/z (%): 238/240 (MþHþ,100). HRMS
(dꢁd, J¼5.5, 5.0 Hz, 1H), 2.73 (dꢁd, J¼7.7, 5.0 Hz, 1H), 3.44 (s, 3H),
(ES) calcd for C13H16ClNO: 238.0993 MHþ; found: 238.0995.
7.25e7.35 (m, 5H), 7.41e7.51 (m, 3H), 7.58e7.63 (m, 2H). 13C NMR
(75 MHz, CDCl3):
d
19.4, 24.8, 48.3, 54.6, 64.5, 127.9 (2C), 128.1 (2C),
4.2.2.11. cis-N-(Diphenylmethylidene)-2-methoxycyclopropylamine
128.2 (2C), 128.3, 128.4 (2C), 129.3, 137.0, 140.0, 166.7. MS (ES, pos.
mode) m/z (%): 266 (MþHþ, 100). HRMS (ES) calcd for C18H19NO:
266.1539 MHþ; found: 266.1540.
14b. Rf¼0.07 (petroleum ether/EtOAc 9:1). Yellow oil, 53%. IR
(cmꢀ1): nmax 1610, 1062. 1H NMR (300 MHz, CDCl3):
d
1.16 (dꢁdꢁd,
J¼7.7, 6.1, 6.1 Hz, 1H), 1.40 (dꢁdꢁd, J¼6.1, 5.0, 5.0 Hz, 1H), 2.84
(dꢁdꢁd, J¼7.7, 5.0, 5.0 Hz, 1H), 3.37 (dꢁdꢁd, J¼6.1, 5.0, 5.0 Hz, 1H),
3.49 (s, 3H), 7.25e7.38 (m, 5H), 7.41e7.52 (m, 3H), 7.57e7.64 (m, 2H).
4.2.2.5. cis-N-(4-Methylbenzylidene)-2-methoxy-2-methylcyclo-
propylamine 11e. Light brown oil, 90%. IR (cmꢀ1): nmax 1630, 1075.
13C NMR (75 MHz, CDCl3):
d 17.2, 41.5, 58.8, 61.8, 128.0 (2C), 128.27
1H NMR (300 MHz, CDCl3):
d
1.04 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.40 (s,
(2C), 128.30 (2C), 128.4, 128.5 (2C), 129.5, 137.2, 140.1, 167.5. MS (ES,
3H), 1.44 (dꢁd, J¼6.1, 5.0 Hz, 1H), 2.33 (s, 3H), 2.90 (dꢁd, J¼7.7,
5.0 Hz, 1H), 3.31 (s, 3H), 7.16 (d, J¼8.3 Hz, 2H), 7.62 (d, J¼8.3 Hz, 2H),
pos. mode) m/z (%): 252 (MþHþ, 100).
8.35 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
19.3, 20.9, 22.8, 53.4, 54.0,
4.2.3. Synthesis of N-(arylmethyl)-2-alkoxy-2-methylcyclopropyl-
amines 12aej. The synthesis of N-(benzyl)-2-ethoxy-2-methyl-
cyclopropylamine 12b is representative. Sodium borohydride (0.34 g,
8.86 mmol, 3.0 equiv) was added to a solution of N-(benzylidene)-2-
63.0, 127.3 (2C), 128.7 (2C), 133.7, 139.6, 158.6. MS (ES, pos. mode)
m/z (%): 204 (MþHþ, 100). HRMS (ES) calcd for C13H17NO:
204.1382 MHþ; found: 204.1384.

3734
S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
ethoxy-2-methylcyclopropylamine 11b (0.60 g, 2.95 mmol, 1.0 equiv)
in methanol (5 mL) at room temperature. After a reflux period of 3 h,
the reaction mixture was poured in ice cold water (10 mL) and three
times extracted with dichloromethane (3ꢁ10 mL). The combined or-
ganic layers were dried over MgSO4, filtered, and evaporated in vacuo.
The crude product was purified by column chromatography (silica gel,
Rf¼0.26, petroleum ether/EtOAc 5:5) yielding 0.38 g of N-(benzyl)-2-
ethoxy-2-methylcyclopropylamine 12b (1.84 mmol, 62%).
136.4, 137.5. MS (ES, pos. mode) m/z (%): 234 (MþHþ,100). HRMS (ES)
calcd for C15H23NO: 234.1852 MHþ; found: 234.1851.
4.2.3.7. cis-N-(4-Methylbenzyl)-2-methyl-2-propoxycyclopropyl-
amine 12h. Light brown oil, 72%. IR (cmꢀ1): nmax 3343, 1074. 1H NMR
(300 MHz, CDCl3):
d
0.45 (dꢁd, J¼5.8, 5.0 Hz, 1H), 0.51 (dꢁd, J¼7.7,
5.8 Hz,1H), 0.90 (t, J¼7.2 Hz, 3H),1.30 (s, 3H),1.56 (sext, J¼7.2 Hz, 2H),
1.69 (br s, 1H), 2.07 (dꢁd, J¼7.7, 5.0 Hz, 1H), 2.32 (s, 3H), 3.34 (dꢁt,
J¼8.8, 6.6 Hz,1H), 3.56 (dꢁt, J¼8.8, 6.6 Hz,1H), 3.77 (d, J¼13.2 Hz,1H),
3.81(d, J¼13.2 Hz, 1H), 7.12 (d, J¼8.3 Hz, 2H), 7.25 (d, J¼8.3 Hz, 2H).13C
4.2.3.1. cis-N-(Benzyl)-2-methoxy-2-methylcyclopropylamine
12a. Pale yellow oil, 68%. IR (cmꢀ1): nmax 3334, 1068. 1H NMR
NMR (75 MHz, CDCl3): d 10.8, 18.6, 20.7, 21.0, 23.3, 43.0, 53.4, 60.0,
(300 MHz, CDCl3):
d
0.47 (d, J¼6.1 Hz, 2H), 1.26 (s, 3H), 1.78 (br s,
68.6, 128.2 (2C), 128.9 (2C), 136.2, 137.5. MS (ES, pos. mode) m/z (%):
234 (MþHþ, 100). HRMS (ES) calcd for C15H23NO: 234.1852 MHþ;
found: 234.1851.
1H), 2.04 (t, J¼6.1 Hz, 1H), 3.31 (s, 3H), 3.78 (d, J¼13.8 Hz, 1H), 3.83
(d, J¼13.8 Hz, 1H), 7.16e7.36 (m, 5H). 13C NMR (75 MHz, CDCl3):
d
18.0, 19.5, 42.6, 53.4, 54.0, 60.8, 126.5, 128.0 (4C), 140.1. MS (ES,
pos. mode) m/z (%): 192 (MþHþ, 100). HRMS (ES) calcd for
4.2.3.8. cis-N-(4-Chlorobenzyl)-2-methoxy-2-methylcyclopropyl-
C12H17NO: 192.1383 MHþ; found: 192.1382.
amine 12i. Light brown oil, 65%. IR (cmꢀ1): nmax 3334, 1069. 1H NMR
(300 MHz, CDCl3):
d 0.45e0.55 (m, 2H), 1.29 (3H, s), 1.77 (br s, 1H),
4.2.3.2. cis-N-(Benzyl)-2-ethoxy-2-methylcyclopropylamine
2.04 (dꢁd, J¼7.2, 5.0 Hz,1H), 3.34 (s, 3H), 3.76 (d, J¼13.2 Hz, 1H), 3.81
12b. Light brown oil, 62%. IR (cmꢀ1): nmax 3335, 1066. 1H NMR
(d, J¼13.2 Hz, 1H), 7.24e7.32 (m, 4H). 13C NMR (75 MHz, CDCl3):
(300 MHz, CDCl3):
d
0.48 (dꢁd, J¼6.1, 5.0 Hz, 1H), 0.52 (dꢁd, J¼7.2,
d 18.1, 19.6, 42.7, 52.8, 54.2, 60.9, 128.2 (2C), 129.5 (2C), 132.3, 138.8.
6.1 Hz,1H),1.18 (t, J¼7.2 Hz, 3H),1.30 (s, 3H),1.70 (br s,1H), 2.06 (dꢁd,
J¼7.2, 5.0 Hz, 1H), 3.47 (dꢁq, J¼8.8, 7.2 Hz, 1H), 3.65 (dꢁq, J¼8.8,
7.2 Hz, 1H), 3.80 (d, J¼13.2 Hz, 1H), 3.85 (d, J¼13.2 Hz, 1H), 7.19e7.39
MS (ES, pos. mode) m/z (%): 226/28 (MþHþ,100). HRMS (ES) calcd for
C12H16ClNO: 226.0993 MHþ; found: 226.0986.
(m, 5H). 13C NMR (75 MHz, CDCl3):
d
15.5, 18.4, 20.5, 42.6, 53.4, 59.8,
4.2.3.9. cis-N-(4-Chlorobenzyl)-2-ethoxy-2-methylcyclopropyl-
62.0,126.5,128.0 (4C),140.3. MS (ES, pos. mode) m/z (%): 206 (MþHþ,
amine 12j. Pale yellow oil, 73%. IR (cmꢀ1): nmax 3332, 1066. 1H NMR
100). HRMS (ES) calcd for C13H19NO: 206.1539 MHþ; found: 206.1544.
(300 MHz, CDCl3):
d
0.46 (dꢁd, J¼6.1, 5.0 Hz, 1H), 0.51 (dꢁd, J¼7.2,
6.1 Hz, 1H), 1.18 (t, J¼7.2 Hz, 3H),1.30 (s, 3H),1.70 (br s,1H), 2.03 (dꢁd,
J¼7.2, 5.0 Hz, 1H), 3.46 (dꢁq, J¼8.8, 7.2 Hz, 1H), 3.65 (dꢁq, J¼8.8,
7.2 Hz, 1H), 3.76 (d, J¼13.2 Hz, 1H), 3.82 (d, J¼13.2 Hz, 1H), 7.22e7.33
4.2.3.3. cis-N-(Benzyl)-2-isopropoxy-2-methylcyclopropylamine
12c. Light brown oil, 69%. IR (cmꢀ1): nmax 3346, 1122. 1H NMR
(300 MHz, CDCl3):
d
0.49e0.57 (m, 2H), 1.13 (d, J¼6.1 Hz, 3H), 1.21
(m, 4H). 13C NMR (75 MHz, CDCl3):
d 15.5, 18.4, 20.5, 42.5, 52.7,
(d, J¼6.1 Hz, 3H),1.32 (s, 3H),1.68 (br s,1H), 2.00 (dꢁd, J¼7.2, 5.0 Hz,
1H), 3.80 (d, J¼14.9 Hz, 1H), 3.85 (d, J¼14.9 Hz, 1H), 3.87 (sept,
59.8, 62.1, 128.1 (2C), 129.4 (2C), 132.2, 138.9. MS (ES, pos. mode) m/z
(%): 240/42 (MþHþ, 100). HRMS (ES) calcd for C13H18ClNO:
240.1150 MHþ; found: 240.1145.
J¼6.1 Hz, 1H), 7.19e7.39 (m, 5H). 13C NMR (75 MHz, CDCl3):
d 18.6,
22.6, 23.4, 23.8, 42.2, 53.4, 59.2, 69.4, 126.6, 128.0 (2C), 128.1 (2C),
140.5. MS (ES, pos. mode) m/z (%): 220 (MþHþ, 100). HRMS (ES)
calcd for C14H21NO: 220.1696 MHþ; found: 220.1696.
4.2.3.10. cis-N-Benzyl-2-methoxycyclopropylamine 15. Rf¼0.16
(petroleum ether/Et2O 3:2). Yellow oil, 26%. IR (cmꢀ1): nmax 3328,
1056. 1H NMR (300 MHz, CDCl3):
d
0.41 (dꢁdꢁd, J¼6.1, 6.1, 3.3 Hz,
4.2.3.4. cis-N-(4-Methylbenzyl)-2-methoxy-2-methylcyclopropyl-
1H), 0.67 (dꢁdꢁd, J¼7.2, 6.1, 6.1 Hz,1H),1.68 (br s,1H), 2.17 (dꢁdꢁd,
J¼7.2, 6.1, 6.1 Hz,1H), 3.19 (dꢁdꢁd, J¼6.1, 6.1, 3.3 Hz,1H), 3.43 (s, 3H),
3.85 (d, J¼12.7 Hz,1H), 3.89 (d, J¼12.7 Hz,1H), 7.18e7.41 (m, 5H). 13C
amine 12e. Light brown oil, 48%. IR (cmꢀ1): nmax 3336, 1069. 1H NMR
(300 MHz, CDCl3): d 0.45e0.54 (m, 2H),1.29(s, 3H),1.71 (brs,1H), 2.06
(dꢁd, J¼6.6, 5.5 Hz, 1H), 2.32 (s, 3H), 3.34 (s, 3H), 3.77 (d, J¼13.2 Hz,
NMR (75 MHz, CDCl3): d 12.0, 35.1, 53.8, 58.4, 58.8,126.9,128.31 (2C),
1H), 3.81 (d, J¼13.2 Hz, 1H), 7.12 (d, J¼7.7Hz,2H), 7.23(d, J¼7.7 Hz, 2H).
128.34 (2C), 140.4. MS (ES, pos. mode) m/z (%): 178 (MþHþ, 100).
13C NMR (75 MHz, CDCl3):
d 18.1,19.5, 20.8, 42.6, 53.2, 54.1, 60.9,128.0
(2C), 128.7 (2C), 135.9, 137.1. MS (ES, pos. mode) m/z (%): 206 (MþHþ,
4.2.3.11. Synthesis of cis-N-(benzhydryl)-2-methoxy-2-methylcyclo-
propylamine 12d. Acetic acid (0.31 g, 0.53 mmol,1.0 equiv) was added
dropwise to a solution of cis-N-(diphenylmethylidene)-2-methoxy-2-
methylcyclopropylamine 11d (0.14 g, 0.53 mmol, 1.0 equiv) in
methanol (5 mL) at room temperature. Subsequently, sodium cya-
noborohydride (0.65 g, 1.06 mmol, 2.0 equiv) was added in portions
during 5 min. The reaction mixture was allowed to stir for 6 h at room
temperature. After completion, the reaction mixture was poured in
ice cold water (10 mL) and three times extracted with dichloro-
methane (3ꢁ10 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated in vacuo. The crude product was
purified by column chromatography (silica gel, Rf¼0.24, petroleum
ether/EtOAc 9:1) yielding 0.105 g of N-(benzhydryl)-2-methoxy-2-
methylcyclopropylamine 12d (0.39 mmol, 75%).
100). HRMS (ES) calcd for C12H19NO: 206.1539 MHþ; found: 206.1538.
4.2.3.5. cis-N-(4-Methylbenzyl)-2-ethoxy-2-methylcyclopropylamine
12f. Pale yellow oil, 60%. IR (cmꢀ1): nmax 3331, 1067. 1H NMR (300 MHz,
CDCl3):
d
0.47 (dꢁd, J¼6.1, 5.0 Hz, 1H), 0.52 (dꢁd, J¼7.2, 6.1 Hz, 1H),1.18
(t, J¼7.2 Hz, 3H), 1.30 (3H, s), 1.75 (br s, 1H), 2.06 (dꢁd, J¼7.2, 5.0 Hz,
1H), 2.32 (s, 3H), 3.47 (dꢁq, J¼8.8, 7.2 Hz, 1H), 3.64 (dꢁq, J¼8.8, 7.2 Hz,
1H), 3.77 (d, J¼13.8 Hz, 1H), 3.81 (d, J¼13.8 Hz, 1H), 7.12 (d, J¼8.3 Hz,
2H), 7.25 (d, J¼8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d 15.4, 18.4, 20.4,
20.8, 42.6, 53.1, 59.8, 62.0, 128.0 (2C), 128.7 (2C), 135.9, 137.2. MS (ES,
pos. mode) m/z (%): 220 (MþHþ, 100). HRMS (ES) calcd for C14H21NO:
220.1696 MHþ; found: 220.1695.
4.2.3.6. cis-N-(4-Methylbenzyl)-2-isopropoxy-2-methylcyclopropyl-
amine 12g. Light brown oil, 67%. IR (cmꢀ1): nmax 3329, 1121. 1H NMR
4.2.3.12. cis-N-(Benzhydryl)-2-methoxy-2-methylcyclopropylamine
(300 MHz, CDCl3):
d
0.51 (dꢁd, J¼6.1, 5.0 Hz, 1H), 0.54 (dꢁd, J¼7.2,
12d. White crystals, 75%. Mp 128e129 ꢂC. IR (cmꢀ1): nmax 3346, 1067.
6.1 Hz, 1H), 1.13 (d, J¼6.1 Hz, 3H), 1.21 (d, J¼6.1 Hz, 3H), 1.32 (s, 3H),
1.79 (br s, 1H), 2.00 (dꢁd, J¼7.2, 5.0 Hz, 1H), 2.33 (s, 3H), 3.76 (d,
J¼13.8 Hz, 1H), 3.81 (d, J¼13.8 Hz, 1H), 3.87 (sept, J¼6.1 Hz, 1H), 7.12
(d, J¼7.7 Hz, 2H), 7.25 (d, J¼7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3):
1H NMR (300 MHz, CDCl3):
d 0.43e0.50 (m, 2H),1.27 (s, 3H),1.87 (br s,
1H), 2.02 (dꢁd, J¼6.6, 5.5 Hz, 1H), 3.33 (s, 3H), 4.85 (s, 1H), 7.16e7.23
(m, 2H), 7.24e7.33 (m, 4H), 7.42e7.50 (m, 4H). 13C NMR (75 MHz,
CDCl3):
d 18.1, 19.8, 42.2, 54.4, 61.0, 67.5, 126.91, 126.94, 127.3 (2C),
d
18.8, 21.1, 22.8, 23.6, 24.1, 42.4, 53.3, 59.4, 69.7, 128.3 (2C), 129.0 (2C),
127.5 (2C), 128.39 (2C), 128.44 (2C), 144.0, 144.4. MS (ES, pos. mode)

S. Mangelinckx et al. / Tetrahedron 69 (2013) 3728e3735
3735
m/z (%): 268 (MþHþ, 100). HRMS (ES) calcd for C18H21NO:
Science and Technology-Flanders (IWT-Vlaanderen) for the Aspir-
antship of G.C. and Ghent University (BOF) for financial support.
268.1695 MHþ; found: 268.1692.
4.2.4. Synthesis of cis-2-alkoxy-2-methylcyclopropylamines hydro-
chlorides 16. The synthesis of 2-methoxy-2-methylcyclopropylamine
hydrochloride 16i is representative. To a solution of N-(4-chloro-
benzylidene)-2-methoxy-2-methylcyclopropylamine 11i (0.50 g,
2.24 mmol,1.0 equiv) in diethyl ether (3 mL) wasadded a 2 M aqueous
hydrochloric acid solution (3 mL) at room temperature. The mixture
was allowed to stir for 16 h at reflux temperature. Subsequently, ex-
traction with dichloromethane (3ꢁ5 mL), drying of the combined
extracts, evaporation in vacuo and further precipitation of the residue
in diethyl ether afforded, after filtration, 0.27 g of pure 2-methoxy-2-
methylcyclopropylamine hydrochloride 16i (1.98 mmol, 88%).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.094.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
1. (a) Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev. 2004, 104, 2353; (b)
Giubellina, N.; Aelterman, W.; De Kimpe, N. Pure Appl. Chem. 2003, 75, 1433; (c)
Florio, S.; Capriati, V.; Luisi, R. Curr. Org. Chem. 2004, 8, 1529.
2. (a) Pearson, W. H.; Stoy, P. Synlett 2003, 903; (b) De Kimpe, N.; Sulmon, P.;
Schamp, N. Tetrahedron Lett. 1989, 30, 5029; (c) De Kimpe, N.; Sulmon, P.;
Stevens, C. Tetrahedron 1991, 47, 4723; (d) Boeykens, M.; De Kimpe, N.;
Abbaspour Tehrani, K. J. Org. Chem. 1994, 59, 6973.
4.2.4.1. cis-2-Ethoxy-2-methylcyclopropylamine
16b. Light brown crystals, 81%. Mp 140e141 ꢂC. IR (cmꢀ1): nmax 2874,
1065. 1H NMR (300 MHz, CDCl3):
hydrochloride
d
0.89 (dꢁd, J¼7.7, 7.7 Hz, 1H), 1.19
(dꢁd, J¼7.7, 4.4 Hz, 1H), 1.27 (t, J¼7.2 Hz, 3H), 1.39 (s, 3H), 2.51e2.62
(m, 1H), 3.52 (dꢁq, J¼8.3, 7.2 Hz, 1H), 3.72 (dꢁq, J¼8.3, 7.2 Hz, 1H),
3. Fontecave, M.; Atta, M.; Mulliez, E. Trends Biochem. Sci. 2004, 29, 243.
€
4. (a) Salaun, J.; Marguerite, J.; Karkour, B. J. Org. Chem. 1990, 55, 4276; (b) De
8.50 (br s, 3H). 13C NMR (75 MHz, CDCl3):
d 15.4, 17.1, 19.3, 32.2, 57.0,
€
Kimpe, N.; Sulmon, P. Synlett 1990, 161; (c) Gaucher, A.; Ollivier, J.; Salaun, J.
Synlett 1991, 151; (d) Salaun, J.; Tondu, S. Fr. Demande, FR 2652082, 1991. Chem.
€
63.3. MS (ES, pos. mode) m/z (%): 116 (MꢀHClþHþ, 100).
Abstr. 1991, 115, 207567d; (e) Gaucher, A.; Ollivier, J.; Marguerite, J.; Paugam, R.;
€
Salaun, J. Can. J. Chem. 1994, 72, 1312; (f) O’Donnell, M. J.; Alsina, J.; Scott, W. L.
Tetrahedron Lett. 2003, 44, 8403; (g) De Kimpe, N.; Sulmon, P.; Boeykens, M.
Tetrahedron 1991, 47, 3389; (h) Sulmon, P.; De Kimpe, N.; Schamp, N. J. Chem.
Soc., Chem. Commun. 1986, 1677; (i) Belokon, Y. N.; Maleev, V. I.; Savel’eva, T. F.;
Moskalenko, M. A.; Pripadchev, D. A.; Khrustalev, V. N.; Vorontsov, E. V.; Sag-
iyan, A. S.; Babayan, E. P. Russ. Chem. Bull., Int. Ed. 2005, 54, 981.
4.2.4.2. cis-2-Isopropoxy-2-methylcyclopropylamine hydrochlo-
ride 16c. Light brown crystals, 61%. Mp 143e144 ꢂC. IR (cmꢀ1): nmax
2896, 1122. 1H NMR (300 MHz, CDCl3):
d
0.95 (dꢁd, J¼8.3, 7.7 Hz,
1H), 1.14 (dꢁd, J¼7.7, 6.1 Hz, 1H), 1.22 (d, J¼6.1 Hz, 3H), 1.25 (d,
€ €
5. (a) Kiss, L.; Mangelinckx, S.; Fulop, F.; De Kimpe, N. Org. Lett. 2007, 9, 4399; (b)
J¼6.1 Hz, 3H), 1.39 (s, 3H), 2.45e2.58 (m, 1H), 3.95 (sept, J¼6.1 Hz,
€€
€ €
Callebaut, G.; Mangelinckx, S.; Kiss, L.; Sillanpaa, R.; Fulop, F.; De Kimpe, N. Org.
Biomol. Chem. 2012, 10, 2326.
1H), 8.36 (br s, 3H). 13C NMR (75 MHz, CDCl3):
d 17.5, 21.2, 23.1, 23.6,
31.4, 55.6, 70.6. MS (ES, pos. mode) m/z (%): 130 (MꢀHClþHþ, 100).
6. De Kimpe, N.; De Smaele, D. Tetrahedron 1995, 51, 5465 for other cyclization
reactions of this type, see: De Smaele, D.; De Kimpe, N. J. Chem. Soc., Chem.
Commun. 1995, 2029.
7. (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151; (b) Gnad, F.; Reiser, O.
Chem. Rev. 2003, 103, 1603; (c) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61,
321; (d) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4493; (e) Wong, H.
N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89,
165; (f) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
4.2.4.3. cis-2-Methyl-2-propoxycyclopropylamine hydrochloride
16h. Light brown crystals, 88%. Mp 144e145 ꢂC. IR (cmꢀ1): nmax
2875, 1066. 1H NMR (300 MHz, CDCl3):
d 0.84e0.93 (m, 1H), 0.93 (t,
J¼7.2 Hz, 3H), 1.15 (dꢁd, J¼7.4, 4.4 Hz, 1H), 1.38 (s, 3H), 1.67 (sext,
J¼7.2 Hz, 2H), 2.48e2.61 (m, 1H), 3.41 (dꢁt, J¼8.3, 7.2 Hz, 1H), 3.59
(dꢁt, J¼8.3, 7.2 Hz, 1H), 8.52 (br s, 3H). 13C NMR (75 MHz, CDCl3):
8. (a) Finkelstein, J.; Chiang, E.; Vane, F. M.; Lee, J. J. Med. Chem. 1966, 9, 319; (b) de
Meijere, A.; Williams, C. M.; Kourdioukov, A.; Sviridov, S. V.; Chaplinski, V.;
Kordes, M.; Savchenko, A. I.; Stratmann, C.; Noltemeyer, M. Chem.dEur. J. 2002,
8, 3789.
d
10.7, 17.2, 19.2, 23.0, 32.1, 56.9, 69.4. MS (ES, pos. mode) m/z (%):
130 (MꢀHClþHþ, 100).
ꢀ
9. (a) Sulmon, P.; De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N. Synthesis 1986,
192; (b) Sulmon, P.; De Kimpe, N.; Schamp, N.; Tinant, B.; Declercq, J.-P. Tet-
€
rahedron 1988, 44, 3653; (c) Dekeukeleire, S.; D’hooghe, M.; Muller, C.; Vogt, D.;
4.2.4.4. cis-2-Methoxy-2-methylcyclopropylamine hydrochloride
De Kimpe, N. New J. Chem. 2010, 34, 1079.
16i. Light brown crystals, 88%. Mp 138e139 ꢂC. IR (cmꢀ1): nmax 2856,
10. For a related discussion on the importance of stable five-membered zinc
complexes in the diastereoselective synthesis of sterically unfavored cis-cy-
clopropane-1,2-diols, see: Matsubara, S.; Ukai, K.; Fushimi, H.; Yokota, Y.;
Yoshino, H.; Oshima, K.; Omoto, K.; Ogawa, A.; Hioki, Y.; Fujimoto, H. Tetrahe-
dron 2002, 58, 8255.
1063. 1H NMR (300 MHz, CDCl3):
d
0.88 (dꢁd, J¼8.3, 7.7 Hz, 1H), 1.22
(dꢁd, J¼7.7, 4.4 Hz, 1H), 1.39 (s, 3H), 2.61 (dꢁd, J¼8.3, 4.4 Hz, 1H),
3.41 (s, 3H), 8.49 (br s, 3H). 13C NMR (75 MHz, CDCl3):
d 16.7, 18.4,
32.3, 54.9, 58.0. MS (ES, pos. mode) m/z (%): 102 (MþHþꢀHCl, 100).
11. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley &
Sons: New York, NY, 1994.
12. Reichelt, I.; Reissig, H.-U. Chem. Ber. 1983, 116, 3895.
Acknowledgements
13. For useful transformations of 1-alkoxycyclopropylamines, see: (a) De Kimpe,
N.; De Buck, K.; Booten, K. Tetrahedron Lett. 1992, 33, 393; (b) De Kimpe, N.;
Abbaspour Tehrani, K.; Fonck, G. J. Org. Chem. 1996, 61, 6500.
14. For a related non-regioselective bromofluorination of N-allylimines, see: Van
Brabandt, W.; Verniest, G.; De Smaele, D.; Duvey, G.; De Kimpe, N. J. Org. Chem.
2006, 71, 7100.
The authors are indebted to the Research Foundation-Flanders
(FWO-Vlaanderen) for the Postdoctoral Fellowships of S.M., S.T.K.
and F.C., the Institute for the Promotion of Innovation through