1-Substituted cyclopentylamines from nitriles and tetramethylenebismagnesium dibromide in the presence of Ti(OiPr)4

Article abstract of DOI:10.1002/ejoc.200900817

Various 1-substituted cyclopentylamines (25 examples, 1089 % yield) have been prepared according to a one-pot procedure by the addition of tetramethylenebismagnesium. di- bromide in the presence of Ti(OiPr)₄ to aliphatic, aromatic and heteroaromatic nitriles, respectively.

Full text of DOI:10.1002/ejoc.200900817

FULL PAPER
DOI: 10.1002/ejoc.200900817
1-Substituted Cyclopentylamines from Nitriles and
Tetramethylenebismagnesium Dibromide in the Presence of Ti(OiPr)4
Olesya A. Tomashenko,[a] Andrei E. Rudenko,[a] Viktor V. Sokolov,*[a]
Alexander A. Tomashevskiy,[a] and Armin de Meijere*[b]
Keywords: Amines / Nitriles / Nucleophilic addition / Grignard reagents
Various 1-substituted cyclopentylamines (25 examples, 10–
89% yield) have been prepared according to a one-pot pro-
cedure by the addition of tetramethylenebismagnesium di-
bromide in the presence of Ti(OiPr)4 to aliphatic, aromatic
and heteroaromatic nitriles, respectively.
transformation can be considered as the aza analogue of
the formation of tertiary alcohols by the twofold addition
of Grignard reagents to esters. Since 1-substituted cycloalk-
anols can be prepared analogously from esters employing
bifunctional Grignard reagents, i.e. α,ω-bis(bromomagne-
sio)alkanes,[6] it was of interest to test whether 1-substituted
cycloalkylamines can also be obtained from nitriles and 1,4-
bis(bromomagnesio)butane and probably its higher homo-
logues according to the protocol developed for acyclic pri-
mary tert-alkylamines.
Indeed, propionitrile (1a), cyclopropanecarbonitrile (1c),
o-tolunitrile (1e) and 4-(trifluoromethyl)benzonitrile (1l)
upon reaction with 1,4-bis(bromomagnesio)butane, pre-
pared from 1,4-dibromobutane with metallic magnesium in
the presence of titanium tetraisopropoxide, furnished 1-eth-
ylcyclopentylamine (2a), 1-cyclopropylcyclopentylamine
(2c), 1-(o-tolyl)cyclopentylamine (2e) and 1-[3-(trifluoro-
methyl)phenyl]cyclopentylamine (2l) in low yields (31, 23,
20 and 25%, respectively). Moderate to good yields (40–
80%) were obtained from isobutyronitrile (1b), benzonitrile
(1d) and various p-substituted benzonitriles (Scheme 1,
Table 1). The low yield of 1-(4-bromophenyl)cyclopent-
ylamine (2j) (28%) is probably due to a competing transme-
tallation reaction.
Introduction
Synthetic approaches to 1-alkylsubstituted cycloalk-
ylamines are the same as those to acyclic primary tert-alk-
ylamines.[1] The situation is quite different in the case of 1-
aryl- and especially 1-hetaryl-substituted cycloalkylamines:
the most general and widely used method, the Ritter reac-
tion, fails for these compounds.[2] The poor ability of 1-
arylcycloalkanols or 1-arylcycloalkenes to form the corre-
sponding amides in the Ritter reaction with HCN, MeCN
or ClCH2CN is apparently due to the low electrophilicity
of the intermediate carbenium ions. Only two general meth-
ods are known for the synthesis of 1-arylsubstituted cyclo-
alkylamines. The first one is the Curtius degradation of acyl
azides, prepared from the respective carboxylic acids by em-
ploying the usual mixed anhydride protocol.[3] An obvious
drawback of this approach is the poor availability of 1-aryl-
cycloalkanecarboxylic acids. The second method is the
transformation of a 1-arylcycloalkanol or a corresponding
alkene into an azide by treatment with hydroazotic acid or
its equivalent with subsequent reduction.[4] This method is
not likely to be suitable for the synthesis of 1-hetarylcylo-
alkylamines containing an acid-sensitive hetaryl fragment
such as furan or pyrrole.
Results and Discussion
As we have previously reported, acyclic primary tert-alk-
ylamines can be prepared by twofold addition of Grignard
reagents to nitriles in the presence of Ti(OiPr)4.[5] This
[a] Chemical Department, Saint-Petersburg State University,
Universitetsky Pr., 26, 198504 Saint-Petersburg, Russian Feder-
ation
Scheme 1. Synthesis of 1-substituted cycloalkylamines. For details
see Table 1.
E-mail: vsokolo@mail.ru
As for hetarenecarbonitriles, electron-deficient pyridine-
carbonitriles 1m–o gave the corresponding amines 2m–o in
low yields, while quinoline-2-carbonitrile (1p) produced the
product 2p in moderate yield (56%) and in the case of pyr-
[b] Institut für Organische und Biomolekulare Chemie, Georg-
August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49-551-399475
E-mail: ameijer1@gwdg.de
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1574–1578

Synthesis fo 1-Substituted Cyclopentylamines
Table 1. 1-Substituted cycloalkylamines 2, 3 from nitriles 1 and benzonitrile (1h), which provided 1-(4-ethoxyphenyl)cyclo-
α,ω-bis(bromomagnesio)alkanes (see Scheme 1).
pentylamine (2h) in very good yield (80%), with pentameth-
ylenebismagnesium dibromide produced a complex mix-
Nitrile 1
R
n
Product
% Yield
ture, from which the desired amine could not be isolated.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Et
iPr
cPr
Ph
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
31
71
23
40
20
43
76
80
56
28
55
25
10
20
21
56
0
47
61
67
44
59
47
89
67
13
Conclusions
2-MeC6H4
4-MeC6H4
4-MeOC6H4
4-EtOC6H4
3,4-(MeO)2C6H3
4-BrC6H4
3-CF3C6H4
4-CF3C6H4
pyrid-2-yl
Mechanistically, this newly observed reaction of nitriles
is quite remarkable. It is known that tetramethylenebismag-
nesium dibromide rapidly reacts with Ti(OiPr)4 to initially
furnish titanacyclopentane 5,[7] which, by analogy with the
known bis(cyclopentadienyl)titanacyclopentane,[8] appar-
ently equilibrates with the titanacyclopropane-ethylene
complex 6. With esters such as methyl pentanoate, mixture
5/6 reacts as a 1,2-dicarbanion equivalent[7] to yield 1-sub-
stituted cyclopropanols, albeit in moderate yields. When the
order of reagent addition is different, tetramethylenebis-
magnesium dibromide reacts with nitriles as a typical 1,4-
dicarbanionic building block due to the double transmetal-
lation reaction with Ti(OiPr)4, furnishing the seven-mem-
bered cyclic intermediate 10, and subsequent ring contrac-
tion to 1-substituted cyclopentylamines 2.[9] By analogy, the
reaction of pentamethylenebismagnesium dibromide and
Ti(OiPr)4 with a nitrile would have to proceed via an eight-
membered ring intermediate analogous to 10, and the less
favorable formation of eight-membered rings may be the
reason for the low yield of 3d from 1d (Scheme 3).
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
2y
3d
pyrid-3-yl
pyrid-4-yl
quinolin-2-yl
pyrimidin-2yl
fur-2-yl
2-methylfur-3-yl
benzofur-2-yl
thien-2-yl
2-methyloxazol-4-yl
5-methylisoxazol-3-yl
1-methylpyrazol-3-yl
1-methylpyrazol-5-yl
Ph
s
t
u
v
w
x
y
d
imidine-2-carbonitrile (1q) no amine 2q was formed at all.
Electron-rich hetarenecarbonitriles such as furan-2-car-
bonitrile (1r), 2-methylfuran-3-carbonitrile (1s), benzofu-
ran-2-carbonitrile (1t) and thiophene-2-carbonitrile (1u)
furnished the corresponding amines 2r–u in moderate yields
(44–67%). Some other hetarenecarbonitriles 1v–y provided
1-hetarylcyclopentylamines 2v–y in moderate to high yields,
and the best yield (89%) was obtained in the case of 1-
methyl-1H-pyrazole-3-carbonitrile (1x).
As 4-chlorobutyronitrile (1z) reacts with phenylmagne-
sium bromide to give 2,2-diphenylpyrrolidine (42%), tetra-
methylenebismagnesium dibromide was expected to react
with nitrile 1z to yield 1-azaspiro[4.4]nonane (4), but the
only isolated amine was 1-propylcyclopentylamine (2z)
(19%), which can be produced through a transmetallation
reaction (Scheme 2).
Scheme 3. Varying behavior of a tetramethylenebismagnesium di-
bromide.
Experimental Section
Scheme 2. Reaction of 4-chlorobutyronitrile (1z) with tetramethyl-
General Remarks: NMR spectra were recorded with a Bruker DPX
300 instrument at 300 (1H) and 75 (13C and DEPT) MHz. All spec-
tra were calibrated against tetramethylsilane as an internal stan-
dard (δ = 0 ppm) or the signals of residual protons of deuterated
solvents: δ = 7.26 for CHCl3, δ = 2.50 for [D5]DMSO. Multiplicities
of signals are described as follows: s = singlet, d = doublet, t =
enebismagnesium dibromide.
Pentamethylenebismagnesium dibromide in its reaction
with benzonitrile (1d) under the same conditions gave 1-
phenylcyclohexylamine (3d), yet in only 13% yield and with
greater difficulty in the isolation of the product. 4-Ethoxy- triplet, q = quadruplet, mc = centered multiplet. Coupling con-
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1575

V. V. Sokolov, A. de Meijere et al.
FULL PAPER
stants (J) are given in Hz; J values in 13C NMR spectra refer to
13C-19F couplings. Mass spectra were recorded with a Finnigan
MAT 95 spectrometer. Analytical TLC was performed on Mach-
ery–Nagel ready-to-use plates AluGram® Sil G/UV254. Detection
was achieved by development with molybdatophosphoric acid solu-
tion (5% in EtOH). Column chromatography: Merck silica gel 60
(0.063–0.200 mm). Elemental analyses were carried out with a
CHN-analyzer Hewlett–Packard 185B. In the case of compounds
with two or more nitrogen atoms, the hydrochlorides often contain
water. Solvents were purified by standard procedures.
[D6]DMSO/CCl4, 25 °C): δ = 23.3 (2 CH2), 38.0 (2 CH2), 55.8
(CH3), 65.7 (C), 115.2 (2 CH), 128.6 (2 CH), 133.7 (C), 159.6 (C)
ppm. MS (70 eV): m/z (%) = 191 (13) [M – HCl]+, 162 (100), 134
(24), 39 (43), 36 (47). C12H17NO·HCl (227.73): calcd. C 63.29, H
7.97, N 6.15; found C 63.23, H 7.94, N 6.11.
1-(4-Ethoxyphenyl)cyclopentylamine Hydrochloride (2h): From 4-
ethoxybenzonitrile (1h) (1.47 g, 10 mmol) the product 2h was ob-
tained after recrystallization (iPrOH/Et2O) as a colorless solid
(1.93 g, 80%), m.p. 205–207 °C. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.42 (t, J = 7.5 Hz, 3 H), 1.75 (mc, 2 H), 1.90–2.13 (m,
General Procedure for the Synthesis of 1-Substituted Cyclopent- 4 H), 2.28 (mc, 2 H), 4.02 (q, J = 6.5 Hz, 2 H), 6.85 (d, J = 8.7 Hz,
ylamines 2a–y and 1-Phenylcyclohexylamine (3d): To a two-phase
mixture of tetramethylenebismagnesium dibromide or pentameth-
ylenebismagnesium dibromide obtained from 1,4-dibromobutane
2 H), 7.47 (d, J = 8.7 Hz, 2 H), 8.47 (br. s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 15.2 (CH3), 23.1 (2 CH2), 38.0 (2
CH2), 63.7 (CH2), 67.2 (C), 115.0 (2 CH), 128.5 (2 CH), 132.4 (C),
(4.32 g, 20 mmol) or 1,5-dibromopentane (4.6 g, 20 mmol) and 159.1 (C) ppm. MS (70 eV): m/z (%) = 205 (17) [M – HCl]+, 176
magnesium turnings (1.06 g, 44 mmol) in Et2O (50 mL) according
to a standard procedure, a solution of the respective nitrile
(10 mmol) in Et2O (10 mL) was added at room temp. After stirring
for an additional 30 min, a solution of Ti(OiPr)4 (2.84 g, 10 mmol)
in Et2O (5 mL) was added. Stirring was continued at r. t. for 24 h,
then 10% aq. NaOH (30 mL) was added. The mixture was filtered
and the filtrate extracted with diethyl ether (3ϫ30 mL). The com-
bined ether phases were extracted three times with dilute (5%) aq.
HCl. The combined aqueous layers were washed with CH2Cl2
(1ϫ10 mL), made basic by addition of 10% aq. NaOH and ex-
tracted with CH2Cl2 (3ϫ30 mL). The combined organic phases
were dried (Na2SO4), and a few mL of 6  HCl in Et2O or iPrOH
were added to acidify the solution. The solution was concentrated
to dryness to leave the crude amine hydrochloride, which was puri-
fied by column chromatography on silica gel, eluting with chloro-
form/methanol and/or by recrystallization (iPrOH/Et2O).
(100), 148 (37), 36 (33), 39 (28). C13H19NO·HCl (241.76): calcd. C
64.59, H 8.34, N 5.79; found C 64.37, H 8.32, N 5.99.
1-(3,4-Dimethoxyphenyl)cyclopentylamine Hydrochloride (2i): From
3,4-dimethoxybenzonitrile (1i) (1.63 g, 10 mmol) the product 2i was
obtained after recrystallization (iPrOH/Et2O) as a colorless solid
1
(1.46 g, 56%), m.p. 215–217 °C. H NMR (300 MHz, [D6]DMSO/
CCl4, 25 °C): δ = 1.71 (mc, 2 H), 1.93–2.19 (m, 4 H), 2.29 (mc, 2
H), 3.79 (s, 3 H), 3.86 (s, 3 H), 6.84 (d, J = 9.0 Hz, 1 H), 6.97 (dd,
J = 9.0 and 2.4 Hz, 1 H), 7.34 (d, J = 2.1 Hz, 1 H), 8.67 (br. s, 3
H) ppm. 13C NMR (75 MHz, [D6]DMSO/CCl4, 25 °C): δ = 23.3 (2
CH2), 37.9 (2 CH2), 56.2 (CH3), 56.5 (CH3), 66.0 (C), 111.6 (CH),
112.1 (CH), 118.9 (CH), 134.1 (C), 149.4 (C), 149.6 (C) ppm. MS
(70 eV): m/z (%) = 221 (18) [M – Cl]+, 192 (100), 162 (18), 41 (26),
36 (24). C13H19NO2·HCl (256.76): calcd. C 60.58, H 7.82, N 5.43;
found C 60.33, H 7.70, N 5.36.
1-(4-Bromophenyl)cyclopentylamine Hydrochloride (2j): From 4-
bromobenzonitrile (1j) (1.82 g, 10 mmol) the product 2j was ob-
tained after recrystallization (iPrOH/Et2O) as a colorless solid
Analytical Data of New Compounds
1-Isopropylcyclopentylamine Hydrochloride (2b): From isobutyro-
nitrile (1b) (690 mg, 10 mmol) the product 2b was obtained after
recrystallization (iPrOH/Et2O) as a colorless solid (1.17 g, 71%),
1
(774 mg, 28%), m.p. Ͼ 250 °C. H NMR (300 MHz, [D6]DMSO/
CCl4, 25 °C): δ = 1.71 (mc, 2 H), 1.93–2.17 (m, 4 H), 2.34 (mc, 2
m.p. Ͼ 250 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.11 (d, J H), 7.54 (d, J = 8.7 Hz, 2 H), 7.46 (d, J = 8.7 Hz, 2 H), 8.84 (br.
= 6.6 Hz, 6 H), 1.58–1.82 (m, 4 H), 1.89–2.14 (m, 5 H), 8.25 (br. s, s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 23.0 (2 CH2),
3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 18.3 (2 CH3),
24.9 (2 CH2), 35.6 (2 CH2), 36.7 (CH), 69.7 (C) ppm. MS (DCI):
m/z (%) = 128 (100) [M – Cl]+. C8H17N·HCl (163.69): calcd. C
58.70, H 11.08, N 8.56; found C 58.98, H 11.14, N 8.39.
37.8 (2 CH2), 67.2 (C), 123.1 (2 CH), 129.2 (2 CH), 132.1 (C),
139.1 (C) ppm. MS (DCI): m/z (%) = 242/240 (100) [M – Cl]+.
C11H14BrN·HCl (276.60): calcd. C 47.77, H 5.47, N 5.06; found C
48.20, H 5.41, N 5.19.
1-(4-Methylphenyl)cyclopentylamine Hydrochloride (2f): From p-
tolunitrile (1f) (1.17 g, 10 mmol) the product 2f was obtained after
recrystallization (iPrOH/Et2O) as a colorless solid (910 mg, 43%),
m.p. 235–237 °C. The amine 2f has previously been reported, but
without any experimental data.[10] 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.77 (mc, 2 H), 1.93–2.16 (m, 4 H), 2.24–2.38 (m, 2 H),
2.34 (s, 3 H), 7.14 (d, J = 7.8 Hz, 2 H), 7.44 (d, J = 8.1 Hz, 2 H),
8.52 (br. s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 21.5
1-[(3-Trifluoromethyl)phenyl]cyclopentylamine Hydrochloride (2k):
From 3-trifluoromethylbenzonitrile (1k) (1.71 g, 10 mmol) the
product 2k was obtained after recrystallization (iPrOH/Et2O) as a
colorless solid (1.45 g, 55%), m.p. 197–199 °C. 1H NMR
(300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.75 (mc, 2 H), 1.98–2.20
(m, 4 H), 2.41 (mc, 2 H), 7.58–7.65 (m, 2 H), 7.85 (s, 1 H), 7.85–
7.95 (m, 1 H), 8.61 (br. s, 3 H) ppm. 13C NMR (75 MHz, [D6]
DMSO/CCl4, 25 °C): δ = 23.5 (2 CH2), 38.3 (2 CH2), 65.9 (C),
3
1
(CH3), 23.2 (2 CH2), 38.0 (2 CH2), 67.3 (C), 127.0 (2 CH), 129.6 124.0 (q, JC,F = 4 Hz, CH), 124.7 (q, JC,F = 270 Hz, CF3), 125.3
3
2
(2 CH), 137.6 (C), 138.2 (C) ppm. MS (70 eV): m/z (%) = 175 (15) (q, JC,F = 4 Hz, CH), 130.0 (CH), 130.4 (q, JC,F = 32 Hz, 1 C),
[M – HCl]+, 146 (100), 118 (30), 41 (30), 39 (39). C12H17N·HCl 131.5 (CH), 143.2 (C) ppm. MS (ESI): m/z (%) = 230 (50) [M – Cl]
(211.73): calcd. C 68.07, H 8.57, N 6.62; found C 68.07, H 8.56, N
6.72.
+, 213 (100) [M – HCl – NH2]+. C12H14F3N·HCl (265.71): calcd.
C 54.27, H 5.69, N 5.27; found C 54.10, H 5.82, N 5.26.
1-(4-Methoxyphenyl)cyclopentylamine Hydrochloride (2g): From 4-
methoxybenzonitrile (1g) (1.33 g, 10 mmol) the product 2g was ob-
tained after recrystallization (iPrOH/Et2O) as a colorless solid
1-[4-(Trifluoromethyl)phenyl]cyclopentylamine Hydrochloride (2l):
From 4-(trifluoromethyl)benzonitrile (1l) (1.71 g, 10 mmol) the
product 2l was obtained after recrystallization (iPrOH/Et2O) as a
(1.74 g, 76%), m.p. Ͼ 250 °C. The amine 2g has previously been colorless solid (652 mg, 25%), m.p. 217–220 °C. The amine 2l has
reported, but without any experimental data.[10] 1H NMR previously been reported, but without any experimental data.[11] 1
(300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.70 (mc, 2 H), 1.91–2.16 NMR (300 MHz, CDCl3, 25 °C): δ = 1.75–2.11 (m, 6 H), 2.21–2.36
(m, 4 H), 2.30 (mc, 2 H), 3.79 (s, 3 H), 6.88 (d, J = 9.0 Hz, 2 H), (m, 2 H), 7.63 (d, J = 9.0 Hz, 2 H), 7.70 (d, J = 8.7 Hz, 2 H), 8.61
7.49 (d, J = 8.7 Hz, 2 H), 8.64 (br. s, 3 H) ppm. 13C NMR (75 MHz, (br. s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 22.9 (2
H
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Synthesis fo 1-Substituted Cyclopentylamines
CH2), 37.8 (2 CH2), 67.4 (C), 124.2 (q, 1JC,F = 270 Hz, CF3), 126.0 colorless solid (880 mg, 47%), m.p. 209–210 °C. An analytically
3
2
(q, JC,F = 4 Hz, 2 CH), 127.9 (2 CH), 131.1 (q, JC,F = 30 Hz, 1
C), 143.8 (C) ppm. MS (ESI): m/z (%) = 230 (64) [M – Cl]+, 213
(100) [M – HCl – NH2]+. C12H14F3N·HCl (265.71): calcd. C 54.27,
H 5.69, N 5.27; found C 54.33, H 5.67, N 5.26.
pure sample was obtained after column chromatography on silica
gel, eluting with chloroform/methanol, 10:1 and subsequent
recrystallization (iPrOH/Et2O). 1H NMR (300 MHz, [D6]DMSO/
CCl4, 25 °C): δ = 1.58–1.73 (mc, 2 H), 1.89–2.02 (mc, 2 H), 2.12–
2.25 (m, 4 H), 6.38 (dd, J = 3.3 and 1.7 Hz, 1 H), 6.50 (d, J =
3.3 Hz, 1 H), 7.53 (d, J = 1.7 Hz, 1 H), 8.93 (br. s, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO/CCl4, 25 °C): δ = 23.1 (2 CH2), 36.1
(2 CH2), 60.8 (C), 107.1 (CH), 110.3 (CH), 142.2 (CH) 153.6 (C)
ppm. MS (ESI): m/z (%) = 152 (100) [M – Cl]+. C9H13NO·HCl
(187.08): calcd. C 57.60, H 7.52, N 7.46; found C 57.29, H 7.64, N
7.21.
1-(Pyrid-2-yl)cyclopentylamine Dihydrochloride (2m): From pyr-
idine-2-carbonitrile (1m) (1.04 g, 10 mmol) the product 2m was ob-
tained after column chromatography on silica gel, eluting with
chloroform/methanol, 3:1 and subsequent recrystallization (iPrOH/
1
Et2O) as a colorless solid (0.24 g, 10%), m.p. Ͼ250 °C. H NMR
(300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.83 (mc, 2 H), 2.05 (mc,
2 H), 2.2–2.3 (m, 4 H), 7.36 (dd, J = 7.8 and 4.8 Hz, 1 H), 7.69
(br. d, J = 7.8 Hz, 1 H), 7.87 (dt, J = 7.8 and 1.8 Hz, 1 H), 8.59
(br. d, J = 4.8 Hz, 1 H), 8.84 (br. s, 4 H) ppm. 13C NMR (75 MHz,
D2O, 25 °C): δ = 23.8 (2 CH2), 38.1 (2 CH2), 66.7 (C), 124.8 (CH),
127.0 (CH), 145.2 (CH) 146.0 (CH), 154.7 (C) ppm. MS (ESI): m/z
(%) = 163 (100) [M – Cl – Cl]+. C10H14N2·2HCl·1͞3H2O (240.56):
calcd. C 49.92, H 6.96, N 11.64; found C 49.98, H 6.96, N 11.94.
1-(2-Methylfur-3-yl)cyclopentylamine Hydrochloride (2s): From 2-
methylfuran-3-carbonitrile (1s) (1.07 g, 10 mmol), obtained from
ethyl 2-methylfuran-3-carboxylate by a standard procedure,[14] the
product 2s was obtained as a colorless solid (1.230 g, 61%), m.p.
204–205 °C. An analytically pure sample was obtained after col-
umn chromatography on silica gel, eluting with chloroform/meth-
anol, 10:1 and subsequent recrystallization (iPrOH/Et2O). 1H
NMR (300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.63–1.75 (mc, 2
H), 1.93–2.06 (m, 4 H), 2.26–2.37 (mc, 2 H), 2.41 (s, 3 H), 6.51 (d,
J = 2.0 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 8.53 (br. s, 3 H) ppm.
13C NMR (75 MHz, [D6]DMSO/CCl4, 25 °C): δ = 13.5 (CH3), 22.7
(2 CH2), 36.9 (2 CH2), 60.4 (C), 111.4 (CH), 119.8 (C), 139.4 (CH)
148.0 (C) ppm. MS (ESI): m/z (%) = 166 (35) [M – Cl]+.
C10H15NO·HCl (201.09): calcd. C 59.55, H 8.00, N 6.94; found C
59.41, H 8.04, N 6.80.
1-(Pyrid-3-yl)cyclopentylamine Dihydrochloride (2n): From pyr-
idine-3-carbonitrile (1n) (1.04 g, 10 mmol) the product 2n was ob-
tained after column chromatography on silica gel, eluting with
chloroform/methanol, 4:1 and subsequent recrystallization (iPrOH/
Et2O) as a colorless solid (470 mg, 20%), m.p. 234–235 °C. The
amine 2n has previously been reported, but without any experimen-
tal data.[12] 1H NMR (300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.80
(mc, 2 H), 2.0–2.3 (m, 4 H), 2.50 (mc, 2 H), 8.09 (dd, J = 8.3 and
5.6 Hz, 1 H), 8.85–8.95 (m, 2 H), 9.15 (d, J = 2.0 Hz, 1 H), 9.28
(br. s, 3 H) ppm. 13C NMR (75 MHz, D2O, 25 °C): δ = 23.0 (2
CH2), 37.7 (2 CH2), 65.2 (C), 128.5 (CH), 140.6 (CH), 140.7 (C)
142.4 (CH), 145.9 (CH) ppm. MS (ESI): m/z (%) = 163 (100) [M –
Cl – Cl]+. C10H14N2·2HCl·1/2H2O (244.16): calcd. C 49.19, H 7.02,
N 11.47; found C 49.41, H 6.76, N 11.23.
1-(Benzofur-2-yl)cyclopentylamine Hydrochloride (2t): From benzo-
furan-2-carbonitrile (1t) (1.43 g, 10 mmol) the product 2t was ob-
tained after recrystallization (iPrOH/Et2O) as a colorless solid
1
(1.60 g, 67%), m.p. 224–226 °C. H NMR (300 MHz, [D6]DMSO/
CCl4, 25 °C): δ = 1.78 (mc, 2 H), 2.04 (mc, 2 H), 2.25–2.35 (m, 4
H), 6.97 (s, 1 H), 7.2–7.3 (m, 2 H), 7.47 (br. d, J = 8.0 Hz, 1 H),
7.59 (br. d, J = 7.7 Hz, 1 H), 9.18 (br. s, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO/CCl4, 25 °C): δ = 23.5 (2 CH2), 36.4 (2 CH2),
61.2 (C), 103.6 (CH), 110.8 (CH), 121.0 (CH), 122.7 (CH), 124.2
(CH), 127.5 (C), 154.1 (C), 156.4 (C) ppm. MS (ESI): m/z (%) =
202 (47) [M – Cl]+. C13H15NO·HCl (237.09): calcd. C 65.68, H
6.78, N 5.89; found C 65.42, H 6.89, N 5.84.
1-(Pyrid-4-yl)cyclopentylamine Dihydrochloride (2o): From pyr-
idine-3-carbonitrile (1o) (1.04 g, 10 mmol) the product 2o was ob-
tained after column chromatography on silica gel, eluting with
chloroform/methanol, 3:1 and subsequent recrystallization (iPrOH/
Et2O) as a colorless solid (500 mg, 21%), m.p. 245–250 °C. The
amine 2o has previously been reported, but without any experimen-
tal data.[12] 1H NMR (300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.85
(mc, 2 H), 2.0–2.2 (m, 4 H), 2.42 (mc, 2 H), 8.35 (d, J = 5.7 Hz, 2
H), 9.02 (d, J = 5.7 Hz, 2 H), 9.50 (br. s, 4 H) ppm. 13C NMR
(75 MHz, D2O, 25 °C): δ = 24.4 (2 CH2), 39.5 (2 CH2), 66.7 (C),
125.2 (2 CH), 142.6 (2 CH), 161.4 (C) ppm. MS (ESI): m/z (%) =
163 (100) [M – Cl – Cl]+. C10H14N2·2HCl (234.07): calcd. C 51.08,
H 6.86, N 11.91; found C 51.05, H 7.12, N 11.73.
1-(Thien-2-yl)cyclopentylamine Hydrochloride (2u): From thio-
phene-2-carbonitrile (1u) (1.09 g, 10 mmol) the product 2u was ob-
tained as a colorless solid (890 mg, 44%), m.p. 212–213 °C. An
analytically pure sample was obtained after column chromatog-
raphy on silica gel, eluting with chloroform/methanol, 10:1 and
subsequent recrystallization (iPrOH/Et2O). 1H NMR (300 MHz,
[D6]DMSO/CCl4, 25 °C): δ = 1.72 (mc, 2 H), 2.00 (mc, 2 H), 2.20
(mc, 2 H), 2.36 (mc, 2 H), 7.02 (dd, J = 5.1 and 3.6 Hz, 1 H), 7.36
(dd, J = 5.1 and 0.9 Hz, 1 H), 7.40 (dd, J = 3.6 and 0.9 Hz, 1 H),
8.94 (br. s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO/CCl4,
25 °C): δ = 22.7 (2 CH2), 38.9 (2 CH2), 62.3 (C), 124.7 (CH), 126.2
(CH), 127.0 (CH) 144.9 (C) ppm. MS (ESI): m/z (%) = 168 (64)
[M – Cl]+. C9H13NS·HCl (203.05): calcd. C 53.06, H 6.93, N 6.88;
found C 53.07, H 7.03, N 6.74.
1-(Quinolin-2-yl)cyclopentylamine Hydrochloride (2p): From quin-
oline-2-carbonitrile[13] (1p) (770 mg, 5 mmol), the product 2p was
obtained as a colorless solid (700 mg, 56%), m.p. Ͼ 250 °C. An
analytically pure sample was obtained after column chromatog-
raphy on silica gel, eluting with chloroform/methanol, 4:1 and sub-
1
sequent recrystallization (iPrOH/Et2O). H NMR (300 MHz, [D6]-
DMSO/CCl4, 25 °C): δ = 1.89 (mc, 2 H), 2.12 (mc, 2 H), 2.2–2.4
(m, 4 H), 7.59 (m, 1 H), 7.7–7.8 (m, 2 H), 7.94 (d, J = 8.0 Hz, 1
H), 8.04 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 8.7 Hz, 1 H), 8.92 (br.
s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO/CCl4, 25 °C): δ =
24.5 (2 CH2), 38.4 (2 CH2), 66.8 (C), 117.9 (CH), 126.4 (CH), 126.7
(C), 127.4 (CH), 128.9 (CH), 129.5 (CH), 137.3 (CH), 145.7 (C),
160.3 (C) ppm. MS (ESI): m/z (%) = 213 (100) [M – Cl]+.
C14H16N2·HCl (248.75): calcd. C 67.60, H 6.89, N 11.26; found C
67.52, H 7.00, N 11.01.
1-(2-Methyloxazol-4-yl)cyclopentylamine Hydrochloride (2v): From
2-methyloxazole-4-carbonitrile[15] (1v) (1.08 g, 10 mmol) the prod-
uct 2v was obtained as a brown solid (1.20 g, 59%), m.p. 200–
202 °C. An analytically pure sample was obtained after column
chromatography on silica gel, eluting with chloroform/methanol,
4:1 and subsequent recrystallization (iPrOH/Et2O). 1H NMR
(300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.68 (mc, 2 H), 1.91 (mc,
2 H), 2.05–2.15 (m, 4 H), 2.41 (s, 3 H), 7.92 (s, 1 H), 8.76 (br. s, 3
H) ppm. 13C NMR (75 MHz, [D6]DMSO/CCl4, 25 °C): δ = 13.4
1-(Fur-2-yl)cyclopentylamine Hydrochloride (2r): From furan-2-car-
bonitrile (1r) (930 mg, 10 mmol) the product 2r was obtained as a
Eur. J. Org. Chem. 2010, 1574–1578
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1577

V. V. Sokolov, A. de Meijere et al.
FULL PAPER
(CH3), 23.3 (2 CH2), 36.6 (2 CH2), 60.2 (C), 135.1 (CH), 141.3 (C),
160.7 (C) ppm. MS (ESI): m/z (%) = 167 (100) [M – Cl]+, 150 (36)
[M – HCl – NH2]+. C9H14N2O·HCl·1/4H2O (207.19): calcd. C
52.17, H 7.54, N 13.52; found C 52.20, H 7.57, N 13.18.
[1]
[2]
a) A. Koziara, K. Osowska-Pacewicka, S. Zawadzki, A. Zwier-
zak, Synthesis 1987, 487–489; b) A. Koziara, A. Zwierzak, Tet-
rahedron Lett. 1987, 28, 6513–6516; c) F. A. Davis, P. A. Manci-
nelli, J. Org. Chem. 1977, 42, 398–399.
A. Jirgensons, V. Kauss, I. Kalvinsh, M. R. Gold, Synthesis
2000, 1709–1712.
C. Kaiser, J. Weinstock, Org. Synth. 1971, 51, 48–52.
D. Balderman, A. Kalir, Synthesis 1978, 24–26.
a) O. Tomashenko, V. Sokolov, A. Tomashevskiy, A. de Mei-
jere, Synlett 2007, 652–654; b) O. A. Tomashenko, V. V. Soko-
lov, A. A. Tomashevskiy, A. A. Potekhin, A. de Meijere, Russ.
J. Org. Chem. 2007, 43, 1421–1426.
For example: a) P. Canonne, M. Belley, G. Fytas, J. Plamon-
don, Can. J. Chem. 1988, 66, 168–173; b) S. Hayashi, M. Furu-
kawa, Y. Fujino, T. Ohkawara, Chem. Pharm. Bull. 1969, 17,
1054–1057.
a) O. G. Kulinkovich, S. V. Sviridov, A. I. Savchenko, Metall-
org. Khim. 1990, 3, 881–882; b) O. Kulinkovich, A. de Meijere,
Chem. Rev. 2000, 100, 2789–2834.
1-(5-Methylisoxazol-3-yl)cyclopentylamine Hydrochloride (2w):
From 5-methylisoxazole-3-carbonitrile[16] (1w) (1.08 g, 10 mmol)
the product 2w was obtained as a brown solid (950 mg, 47%), m.p.
161–163 °C. An analytically pure sample was obtained after col-
umn chromatography on silica gel, eluting with chloroform/meth-
anol, 4:1 and subsequent recrystallization (iPrOH/Et2O). 1H NMR
(300 MHz, [D6]DMSO/CCl4, 25 °C): δ = 1.80 (mc, 2 H), 2.05 (mc,
2 H), 2.2–2.3 (m, 4 H), 2.53 (s, 3 H), 6.66 (s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO/CCl4, 25 °C): δ = 11.9 (CH3), 23.3 (2 CH2),
36.6 (2 CH2), 60.4 (C), 100.3 (CH), 164.9 (C), 169.6 (C) ppm. MS
(ESI): m/z (%) = 167 (44) [M – Cl]+, 150 (100) [M – HCl –
NH2]+. C9H14N2O·HCl·1/4H2O (207.19): calcd. C 52.17, H 7.54,
N 13.52; found C 52.49, H 7.52, N 13.20.
[3]
[4]
[5]
[6]
[7]
1-(1-Methyl-1H-pyrazol-3-yl)cyclopentylamine Hydrochloride (2x):
From
1-methyl-1H-pyrazole-3-carbonitrile[17]
(1x)
(1.07 g,
10 mmol) the product 2x was obtained as a colorless solid (1.80 g,
89%), m.p. 208–210 °C. An analytically pure sample was obtained
after recrystallization (iPrOH/Et2O). 1H NMR (300 MHz, [D6]
DMSO/CCl4, 25 °C): δ = 1.8 (mc, 2 H), 1.93 (mc, 2 H), 2.05–2.30
(m, 4 H), 3.85 (s, 3 H), 6.45 (br. s, 1 H), 7.58 (br. s, 1 H), 8.66 (br.
s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO/CCl4, 25 °C): δ =
23.2 (2 CH2), 37.1 (2 CH2), 38.3 (CH3), 61.5 (C), 102.9 (CH), 131.6
(CH), 152.4 (C) ppm. MS (ESI): m/z (%) = 166 (72) [M – Cl]+, 149
(100) [M – HCl – NH2]. C9H15N3·HCl (201.70): calcd. C 53.59, H
8.00, N 17.58; found C 54.15, H 8.03, N 17.46.
[8]
[9]
R. H. Grubbs, A. Miyahita, J. Am. Chem. Soc. 1978, 100,
1300–1302.
A somewhat related formation of cyclopent-3-enylamines from
nitriles and 1,3-diene-titanium complexes, yet according to a
different mechanism, has been reported: a) C. Laroche, P.
Bertus, J. Szymoniak, Chem. Commun. 2005, 3030–3032; b) P.
Bertus, C. Menant, C. Tanguy, J. Szymoniak, Org. Lett. 2008,
10, 777–780.
[10] O. Kirino, H. Matsumoto, S. Hashimoto, H. Oshio, Ger. Offen.
1980, ##DE 2945388; Chem. Abstr. 1980, 93, 167873.
[11] R. C. Andrews, C. M. Cribbs, S. V. Frye, C. D. Haffner, P. R.
Maloney, Ger. Offen. 1994, ##WO 9414833 A2; Chem. Abstr.
1995, 122, 81743.
[12] T. Ehara, P. Grosche, O. Irie, Y. Iwaki, T. Kanazawa, S. Kawak-
ami, K. Konishi, M. Mogi, M. Suzuki, F. Yokokawa, PCT,
2007, WO 2007/077005 A1. Chem. Abstr. 2007, 147, 166201.
[13] W. E. Feely, E. M. Beavers, J. Am. Chem. Soc. 1959, 81, 4004–
4007.
1-(1-Methyl-1H-pyrazol-5-yl)cyclopentylamine
Dihydrochloride
(2y): From 1-methyl-1H-pyrazole-5-carbonitrile[17] (1y) (1.07 g,
10 mmol) the product 2y was obtained as a colorless solid (1.60 g,
67%), m.p. 195–197 °C. An analytically pure sample was obtained
after recrystallization (iPrOH/Et2O). 1H NMR (300 MHz, [D6]-
DMSO/CCl4, 25 °C): δ = 1.75 (mc, 2 H), 2.0–2.2 (m, 4 H), 2.45
(mc, 2 H), 4.04 (s, 3 H), 6.32 (br. s, 1 H), 7.32 (br. s, 1 H), 8.88 (br.
s, 3 H), 10.52 (br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO/
CCl4, 25 °C): δ = 22.9 (2 CH2), 37.2 (2 CH2), 59.8 (C), 106.9 (CH),
136.4 (CH), 142.0 (C) ppm. MS (ESI): m/z (%) = 166 (100) [M –
[14] S. Divald, M. C. Chun, M. M. Joullie, J. Org. Chem. 1976, 41,
2835–2846.
[15] T. P. Sycheva, T. K. Trupp, M. N. Shchukina, S. Ordzhoni-
kidze, Zh. Obshch. Khim. 1962, 32, 1071–1077.
[16] Y. Terui, M. Yamakawa, T. Honma, Y. Tada, K. Tori, Hetero-
cycles 1982, 19, 221–228.
[17] M. L. Castellanos, M. Llinas, M. Bruix, J. de Mendoza, M. M.
Rosario, J. Chem. Soc. Perkin Trans. 1 1985, 1209–1215.
Received: July 21, 2009
Cl
–
HCl]+, 149 (90) [M
–
HCl
–
HCl
–
NH2].
C9H15N3·2HCl·0.2H2O (241.76): calcd. C 44.71, H 7.25; found C
45.22, H 7.27.
Acknowledgments
Published Online: January 29, 2010
This work was supported by KAdemCustomChem GmbH,
Göttingen and by the Land Niedersachsen.
1578
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1574–1578