Productive syntheses of 1-ethynylcyclopropylamine and 1- ethynylcyclobutylamine

Article abstract of DOI:10.1055/s-0030-1258964

The new 1,1-dimethylpropargylamine surrogates, 1-ethynylcyclopropylamine (3) and 1-ethynylcyclobutylamine (5), were prepared as hydrochlorides from cyclopropylacetylene and 6-chlorohex-1-yne in overall yields of 39 and 25%, respectively, on a scale of up to 300 mmol. The amine 3 was converted into the new ethynyl-extended 1-aminocyclopropanecarboxylic acid 4, and both the amine 3 as well as the amino acid 4 were made available as their N-Fmoc-protected derivatives. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258964

PRACTICAL SYNTHETIC PROCEDURES
3967
Productive Syntheses of 1-Ethynylcyclopropylamine and
1-Ethynylcyclobutylamine1
1
-Ethynylcycl
e
rne and 1
g
-Ethynylcyc
e
i
e
I. Kozhushkov,a Karsten Wagner-Gillen,a Alexander F. Khlebnikov,b Armin de Meijere*a
a
Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen,
Germany
Fax +49(551)23422; E-mail: ameijer1@uni-goettingen.de
Department of Chemistry, Saint Petersburg State University, Universitetskii Prosp. 26,
b
Petrodvorets, 198504 St. Petersburg, Russian Federation
Received 3 September 2010; revised 19 October 2010
Dedicated to Professor Günter Helmchen on the occasion of his 70th birthday
PSP
No197
Abstract: The new 1,1-dimethylpropargylamine surrogates, 1-ethynylcyclopropylamine (3) and 1-ethynylcyclobutylamine (5), were pre-
pared as hydrochlorides from cyclopropylacetylene and 6-chlorohex-1-yne in overall yields of 39 and 25%, respectively, on a scale of up
to 300 mmol. The amine 3 was converted into the new ethynyl-extended 1-aminocyclopropanecarboxylic acid 4, and both the amine 3 as
well as the amino acid 4 were made available as their N-Fmoc-protected derivatives.
Key words: alkynes, amines, amino acids, Curtius degradation, small rings
SiMe3
procedure 1
1) n-BuLi, Et2O, 14–15 h
2) CO2, –78 to 20 °C
SiMe3
n
n
CO2H
8 n = 0 (65%)
7 n = 0
16 n = 1
17 n = 1 (63%)
SiMe3
procedure 2
1) ClCO2Et, Et3N, acetone, 0 °C
2) NaN3, acetone–H2O, 0 °C
8 or 17
n
3) t-BuOH, 80 °C, 11–14 h
N
Boc
H
9 n = 0 (87%)
18 n = 1 (60%)
H
H
procedure 3
HCl, Et2O
KF, DMF–H2O
20 °C, 24 h
9 or 18
0 to 20 °C, 6 h
n
n
N
Boc
NH2⋅HCl
H
10 n = 0 (95%)
19 n = 1 (91%)
3⋅HCl n = 0 (90%)
(48% overall)
5⋅HCl n = 1 (91%)
(31% overall)
Scheme 1 General procedure for the preparation of 1-ethynylcyclopropylamine (3) and 1-ethynylcyclobutylamine (5)
terms of enhanced metabolic inertness, the 1,1-disubsti-
tuted cyclopropane moiety has previously been employed
Introduction
The 3,3-disubstituted oxetane moiety is currently being as a mimic for gem-dimethyl groups.3 Such a cyclopro-
promoted as a mimic for gem-dimethyl substitution in pane group is smaller than an isopropyl moiety4 and, due
biologically active and pharmacologically relevant com- to the enhanced electronegativity of its carbon atoms, also
pounds.2 Due to its polarity, it reduces the increase in li- more polar.5 Recently, 3-ethynyloxetan-3-amine (2) has
pophilicity that gem-dimethyl substitution causes, and been reported6 as a surrogate for 1,1-dimethylpropargyl-
thereby supposedly improves metabolic robustness. In amine (1) (Figure 1), which is a useful building block for
certain pharmacophores.7
With the aim of accessing the ethynyl-extended analogue
4 of 1-aminocyclopropanecarboxylic acid (ACC) for in-
corporation in various peptidomimetics,8 we developed a
SYNTHESIS 2010, No. 23, pp 3967–3973
Advanced online publication: 09.11.2010
DOI: 10.1055/s-0030-1258964; Art ID: T17810SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

3968
S. I. Kozhushkov et al.
PRACTICAL SYNTHETIC PROCEDURES
CO2H
H
SiMe3
1) n-BuLi, Et2O,
20 °C, 14 h
1) MeLi, Et2O, –78 °C
2) Me3SiCl, –78 to 20 °C
80%
O
2) CO2, –78 to 20 °C
6
7
NH2
NH2
NH2
NH2
NH2
65%
SiMe3
5
1
2
3
4
SiMe3
1) ClCO2Et, Et3N, acetone, 0 °C
2) NaN3, acetone–H2O, 0 °C
Figure 1 Amines 1–5
KF, DMF–H2O
20 °C, 24 h
3) t-BuOH, 80 °C, 14 h
87%
95%
N
Boc
productive synthesis of 1-ethynylcyclopropylamine (3),
another interesting surrogate for 1 and for 2. Various oligo-
substituted analogues of 3 with complex substituents at
the acetylene terminus have been prepared either from cy-
clopropanone equivalents under different conditions, by
selective dihalocyclopropanation of appropriately func-
tionalized enamines or via cyclopropene intermediates.9
CO2H
H
H
8
H
9
HCl, Et2O
0 °C, 6 h
(39% overall yield)
N
Boc
NH2⋅HCl
3⋅HCl
90%
H
10
While the structural and conformational properties of the Scheme 2 Preparation of 1-ethynylcyclopropylamine hydrochlo-
ride (3·HCl)
parent 3 had been published without preparative details by
us before,10 the (1-ethynylcyclobutyl)amine (5) (Figure 1)
boxylated, and finally the N-Boc group in 11 removed by
has been unknown so far. A number of compounds with a
(1-ethynylcyclobutyl)amine moiety have demonstrated an
enhanced anticancer activity.11 However, the preparation
of the parent (1-ethynylcyclobutyl)amine (5) had not been
disclosed. This holds true also for the amino acid 4, the
ethyl ester of which – an important synthetic intermediate
towards antimicrobial drugs – has previously been
synthesized12 applying a Wittig alkenation/Fritsch–
treatment with hydrogen chloride in diethyl ether. The
amine hydrochloride 4·HCl was thus obtained from 10 in
81% overall yield (Scheme 3).
H
CO2H
1) n-BuLi, THF, –78 °C, 1 h
2) CO2, –78 to 20 °C
Boc
83%
N
N
Boc
H
Buttenberg–Wiechell
(FBW-type)
rearrangement
H
10
11
sequence13 to 1-tert-butoxyxcarbonylaminocyclopropane
carbaldehyde. The latter can be prepared from dimethyl
malonate or from ACC and its derivatives in four to five
steps.14 The productive syntheses of 1-ethynylcyclopro-
pylamine (3), of its cyclobutane analogue 5 (Scheme 1),
and of the amino acid 4 are reported here.
CO2H
HCl, Et2O
0 to 20 °C, 12 h
98%
(81% overall yield)
NH2⋅HCl
4⋅HCl
Scheme 3 Synthesis of 3-(1-aminocyclopropyl)propiolic acid hy-
drochloride (4·HCl)
Results and Discussion
For further elaboration, the amine hydrochloride 3·HCl
and the amino acid hydrochloride 4·HCl can be reprotect-
ed applying routine procedures.22,23 For example, the
Fmoc derivatives 12 and 13, the latter to be employed in
automated oligopeptide synthesis,24 were thus prepared in
90 and 81% yield, respectively (Scheme 4).
Cyclopropylacetylene (6),15 which is now commercially
available, was deprotonated with methyllithium in diethyl
ether, and the resulting anion silylated with trimethylsilyl
chloride adopting a published procedure16 to give (tri-
methylsilylethynyl)cyclopropane (7) in 80% yield.17 The
latter was then deprotonated with n-butyllithium in dieth-
yl ether,18 and the resulting propargyl anion treated with
dry ice to yield the acid 8 (65%) (Scheme 2).
H
H
Fmoc-Cl, Na2CO3
THF–H2O, 0 to 20 °C, 12 h
Curtius degradation of the acid 8 according to the
Weinstock protocol19 as previously employed in a differ-
ent example,20 furnished the N-Boc-protected 1-(trimeth-
ylsilylethynyl)cyclopropylamine 9 (95% yield), which
was fully deprotected by treatment with potassium fluo-
ride in dimethylformamide–water and subsequently with
hydrogen chloride in diethyl ether. The amine hydrochlo-
ride 3·HCl was thus obtained from cyclopropylacetylene
(6) in 39% overall yield (Scheme 2).
N
Fmoc
NH3Cl
3⋅HCl
CO2H
90%
H
12
CO2H
Fmoc-OSu, Et3N
CH2Cl2–MeOH, 0 to 20 °C, 15 h
81%
N
Fmoc
NH3Cl
4⋅HCl
H
13
Scheme 4 N-Fmoc protection of the amine 3 and the amino acid 4
The N-Boc-protected amine 10 was also used to prepare
the new acetylene-extended 1-aminocyclopropanecarbox-
ylic acid (4). Towards that end, 10 was deprotonated with
n-butyllithium in tetrahydrofuran,21 the acetylide then car-
The starting material in the current synthesis of (1-ethy-
nylcyclobutyl)amine (5), cyclobutylacetylene, has previ-
ously been prepared as a solution in tetrahydrofuran by
treatment of commercially available 6-chlorohex-1-yne
Synthesis 2010, No. 23, 3967–3973 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1-Ethynylcyclopropylamine and 1-Ethynylcyclobutylamine
3969
(14) with n-butyllithium25a or bis(dialkylamino)magne-
siums.25b For the synthesis of the fully protected 1-ethy-
nylcyclobutylamine 18 it turned out to be better to first
protect the terminal acetylene 14 with a trimethylsilyl
group and then treat the resulting 6-chloro-1-trimethylsi-
lylhex-1-yne (15) with lithium diisopropylamide in
tetrahydrofuran to furnish 2-cyclobutyl-1-trimethylsilyl-
acetylene (16) in an overall yield of 81%. Deprotonation
of 16 at the propargylic position had to be carried out with
n-butyllithium at ambient temperature without cooling, in
fact the temperature rose to 31 °C for six hours, and sub-
sequent treatment with powdered dry ice gave the crude
carboxylic acid 17 in 63% yield. Curtius degradation of 17
specified. All reactions in anhydrous solvents were carried out un-
der an argon atmosphere in flame-dried glassware.
Starting Materials
(Cyclopropylethynyl)trimethylsilane (7)
Compound 7 was prepared adopting a published protocol,16 which
had not been applied to ethynylcyclopropane (6).15 A magnetically
stirred solution of the alkyne 6 (66.0 g, 84.6 mL, 1.064 mol) in an-
hyd Et2O (300 mL), cooled to –78 °C, was treated with MeLi (1.18
mol, 550 mL of a 2.15 M solution in Et2O) at such a rate that the
temperature was maintained below –60 °C. After stirring the solu-
tion at –78 °C for an additional 2 h, Me3SiCl (119.5 g, 139.6 mL,
1.1 mol) was added, again taking care to maintain the temperature
below –60 °C. The resulting mixture was stirred at –40 °C for an ad-
ditional 2 h, then allowed to warm up to r.t. After an additional stir-
again employing the Weinstock protocol19,20 furnished the ring at r.t. for 1 h, the reaction mixture was poured into ice-cold H2O
(1 L). The layers were separated, and the aqueous layer was extract-
ed with Et2O (300 mL). The combined organic layers were washed
with brine (300 mL) and dried. The solvent was removed by distil-
N-Boc-protected 1-(trimethylsilylethynyl)cyclobutylamine
18 in 38% overall yield from the silylated acetylene 16.
Complete deprotection of 18 was achieved as above for 9
to give the amine hydrochloride 5·HCl in an overall yield
of 25% from 6-chlorohex-1-yne (14) (Scheme 5).
lation at atmospheric pressure through a 25 cm column packed with
Aldrich® glass helices, coil I.D. ~ 3 mm. Vacuum distillation of the
residue yielded 119.9 g (80%) of 7 as a colorless liquid; bp 87 °C/
1
137 mbar (Lit.15b bp 49–52 °C/20 mbar). The H and 13C NMR
spectra were identical to the published ones.15b This compound is
commercially available as well; the lowest price is US $ 1755.00/kg
from Shanghai FWD Chemicals.
1) n-BuLi, Et2O–hexane
–78 °C, 35 min
H
SiMe3
2) Me3SiCl, –78 to 20 °C
94%
Cl
Cl
14
15
6-Chloro-1-trimethylsilylhex-1-yne (15)
1) n-BuLi, Et2O–hexane
20 °C, 15 h
LDA, THF
A solution of 6-chlorohex-1-yne (14; 47.2 g, 49.8 mL, 0.412 mol)
in anhyd Et2O (0.8 L) was treated at –78 °C with n-BuLi (0.450 mol,
180 mL of a 2.5 M solution in hexane). After stirring for 35 min,
Me3SiCl (53.6 g, 62 mL, 0.492 mol) was added. The mixture was
warmed up to r.t. and then hydrolyzed with a sat. aq NH4C1 solution
(400 mL). The aqueous phase was extracted with Et2O (3 × 200
mL), the combined organic layers were washed with brine (200
mL), and dried (Na2SO4). The solvent was removed on a rotary
evaporator, and the residue purified by distillation under reduced
pressure to give 72.9 g (94%) of 15 as a colorless liquid; bp 90–92
SiMe3
–78 to 20 °C
86%
2) CO2, –78 to 20 °C
63%
16
SiMe3
SiMe3
1) ClCO2Et, Et3N, acetone, –5 °C, 2 h
2) NaN3, acetone–H2O, 0 °C, 2 h
3) t-BuOH–toluene, 80 °C, 9 h
60%
CO2H
N
Boc
17
H
18 (38% from 16)
H
H
°C/37 mbar (Lit.26a bp 104 °C/760 Torr). The H and 13C NMR
1
spectra were identical to the published ones.26
KF, DMF–H2O
HCl–Et2O
20 °C, 24 h
91%
20 °C, 6 h
91%
(25% overall)
(Cyclobutylethynyl)trimethylsilane (16)
NH2⋅HCl
5⋅HCl
N
Boc
A solution of (i-Pr)2NH (78.12 g, 109 mL, 0.772 mol) in anhyd THF
(1.5 L) was treated at 0 °C with n-BuLi (0.772 mol, 309 mL of a 2.5
M solution in hexane), and the mixture stirred for 20 min. After
cooling down to –78 °C, a solution of 15 (72.9 g, 0.386 mol) in an-
hyd THF (200 mL) was added slowly. The mixture was warmed up
to r.t. and hydrolyzed with a sat. aq NH4C1 solution (800 mL). The
aqueous phase was extracted with pentane (5 × 200 mL), the com-
bined organic layers were washed with brine (200 mL), and dried
(Na2SO4). The solvent was removed on a rotary evaporator, and the
residual yellow liquid was purified by vacuum distillation under re-
duced pressure to yield 50.53 g (86%) of 16 as a colorless liquid; bp
70–72 °C/54 mbar.
1H NMR (300 MHz, CDCl3): d = 3.08–2.97 (m, 1 H), 2.30–2.23 (m,
2 H), 2.23–2.05 (m, 2 H), 1.94–1.79 (m, 2 H), 0.15 [s, 9 H,
Si(CH3)3].
13C NMR (125.7 MHz, CDCl3): d = 111.2 (C≡), 84.6 (C≡), 30.0 (2
CH2), 25.9 (CH), 19.1 (CH2), 0.20 (3 CH3).
H
19
Scheme 5 Preparation of 1-ethynylcyclobutylamine hydrochloride
(5·HCl)
1H and 13C NMR spectra were recorded at 250 (1H), 300 (1H), 62.9
[13C, additional DEPT (Distortionless Enhancement by Polarization
Transfer)] and 125.7 MHz (13C) on Bruker AM 250, Varian Mercu-
ry Vx300 and Inova-500 instruments in CDCl3, D2O, THF-d8, and
DMSO-d6 solutions, CHCl3/CDCl3, DHO, C4HD7O and
CD3SOCD2H as internal references. EI-MS, ESI-MS, and HRMS
spectra were measured with Finnigan MAT 95 (at 70 eV), Finnigan
LCQ and Bruker Daltonic APEX IV 7T FTICR instruments, respec-
tively. Melting points were determined on a Büchi 510 capillary
melting point apparatus and are uncorrected. TLC analyses were
performed on precoated sheets (0.25 mm Sil G/UV254) from
Macherey-Nagel). All chemicals were used as commercially avail-
able. Ethynylcyclopropane (6) was obtained by distillation from its
commercially available 50% solution in toluene (bp 52–53 °C). An-
hyd Et2O, THF, and toluene were obtained by distillation from so-
dium benzophenone ketyl; acetone by distillation from anhyd
K2CO3. Organic extracts were dried over MgSO4, if not otherwise
MS (EI, 70 eV): m/z = 152 (M+), 137, 124, 109, 83.
HRMS (EI): m/z calcd for C9H16Si: 152.0121; found: 152.0120.
Anal. Calcd for C9H16Si (152.31): C, 70.97; H, 10.59. Found: C,
71.14; H, 10.38.
Synthesis 2010, No. 23, 3967–3973 © Thieme Stuttgart · New York

3970
S. I. Kozhushkov et al.
PRACTICAL SYNTHETIC PROCEDURES
Carboxylation of Me3Si-Protected Cycloalkylacetylenes 7 and
16; Preparation of the Acids 8 and 17; General Procedure 1 (GP
1)
tion was then heated under reflux for 9–11 h. After cooling, the
reaction mixture was concentrated under reduced pressure, the res-
idue was taken up with Et2O, washed with H2O, dried, and concen-
trated again. The residue was purified as indicated below.
The acids 8 and 17 were prepared according to a modified published
procedure.13 To a solution of 7 or 16 (0.250 mol) in anhyd Et2O (500
mL) was added a solution of n-BuLi in hexane. The reaction mix-
ture was stirred at r.t. for 9–14 h, then the dark-yellow solution was
cooled to –78 °C, and a large excess of powdered dry ice was added
in several portions. The reaction mixture was allowed to warm up
to 20 °C and poured into ice-cold H2O (400 mL). The layers were
separated; the aqueous layer was washed with Et2O (2 × 100 mL),
acidified by adding 12 N aq HCl solution (21 mL) and extracted
with Et2O (4 × 100 mL). The combined organic layers were dried
and concentrated under reduced pressure to give 8 or 17 as colorless
solids, which were used without further purification; analytical
samples were obtained by recrystallization from hexane.
tert-Butyl 1-[(Trimethylsilyl)ethynyl]cyclopropylcarbamate (9)
The acid 8 (93.94 g, 515.3 mmol) in acetone (1900 mL) was treated
with Et3N (66.6 g, 91.7 mL, 658.2 mmol), ClCO2Et (90.7 g, 79.9
mL, 836.0 mmol) in acetone (400 mL), and NaN3 (56.94 g, 875.9
mmol) in H2O (230 mL) according to GP 2. The reaction mixture
was poured into ice-cold water (3 L), the mixture extracted with
Et2O (5 × 400 mL) and pentane (3 × 200 ml). The combined organic
solutions were worked up as described in GP 2 using ice-cold H2O
(500 mL) and anhyd toluene (250 mL), and the crude azide was
heated in anhyd t-BuOH (1600 mL, 11 h heating under reflux). The
residue after concentration of the reaction mixture was taken up
with Et2O (1200 mL), the solution washed with H2O (2 × 300 mL),
dried and concentrated again to give 113.7 g (87%) of the carbamate
9 as a colorless solid, which was used without further purification;
an analytical sample was obtained by recrystallization from hexane;
mp 86 °C.
1-[(Trimethysilyl)ethynyl]cyclopropanecarboxylic Acid (8)
According to GP 1, from 7 (34.6 g, 42.2 mL, 0.250 mol) and n-BuLi
(0.250 mol, 98.8 mL of a 2.53 M solution in hexane; 14 h stirring at
r.t.) was obtained the acid 8 (29.5 g, 65%) as a colorless solid, which
was used without further purification; mp 69–71 °C.
1H NMR (250 MHz, CDCl3): d = 1.64–1.53 and 1.49–1.39 (m
AA¢BB¢, 4 H), 0.16 [s, 9 H, Si(CH3)3].
1H NMR (250 MHz, CDCl3): d = 4.99 (br s, 1 H), 1.46 (s, 9 H),
1.22–1.01 (m AA¢BB¢, 4 H), 0.12 [s, 9 H, Si(CH3)3].
13C NMR (62.9 MHz, CDCl3): d = 156.0 (C), 107.6 (C), 82.4 (C),
79.9 (C), 28.3 (3 CH3), 24.2 (C), 18.3 (2 CH2), –0.05 (3 CH3),
13C NMR (62.9 MHz, CDCl3): d = 178.4 (C), 103.8 (C), 84.5 (C),
21.9 (2 CH2), 16.4 (C), –0.1 (3 CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H23NO2Si + Na:
HRMS (EI): m/z calcd for C9H14O2Si: 182.0763; found: 182.0760.
276.1396; found: 276.1390.
1-[(Trimethylsilyl)ethynyl]cyclobutanecarboxylic Acid (17)
According to GP 1, a solution of 16 (39.89 g. 0.263 mol) was rapid-
ly treated with n-BuLi (0.290 mol, 116 mL of a 2.50 M solution in
hexane) without external cooling. The temperature of the mixture
reached 31 °C and remained for 6 h, then slowly it began to fall
down to r.t. The reaction mixture was stirred for an additional 9 h
and then treated with powdered dry ice according to GP 1 to give
32.27 g (63%) of 17 as a colorless solid, which was used without
further purification; mp 69–71 °C.
1H NMR (300 MHz, CDCl3): d = 2.73–2.63 (m, 2 H), 2.47–2.38 (m,
2 H), 2.22–1.95 (m, 2 H), 0.18 [s, 9 H, Si(CH3)3].
13C NMR (125.7 MHz, CDCl3): d = 178.7 (C), 106.1 (C), 88.2 (C),
41.7 (C), 33.6 (2 CH2), 16.7 (CH2), –0.0 (3 CH3).
tert-Butyl 1-[(Trimethylsilyl)ethynyl]cyclobutylcarbamate (18)
The acid 17 (37.44 g, ca.190 mmol) in acetone (740 mL) was treated
with Et3N (25.9 g, 35.6 mL, 255.5 mmol), ClCO2Et (35.2 g, 31 mL,
324.5 mmol) in acetone (150 mL), and NaN3 (22.1 g, 340 mmol) in
H2O (90 mL) according to GP 2. The reaction mixture was poured
into ice-cold H2O (1.1 L) and the mixture extracted with Et2O
(4 × 100 mL) and pentane (3 × 100 ml). The combined organic so-
lutions were worked up as described in GP 2 using ice-cold H2O
(200 mL) and anhyd toluene (100 mL), and the crude azide was
heated in anhyd t-BuOH (620 mL, 9 h heating under reflux). The
residue after concentration of the reaction mixture was taken up
with Et2O (400 mL), the solution washed with H2O (2 × 100 mL),
dried, and concentrated again. Column chromatography of the resi-
due (silica gel, Et2O–pentane, 1:20) afforded 27.08 g (60%) of the
carbamate 18 as a colorless solid; mp 91–92 °C.
MS (EI, 70 eV): m/z = 196 (M+), 181, 153, 135, 125, 109, 99, 75.
1H NMR (300 MHz, CDCl3): d = 4.84 (br s, 1 H), 2.40–2.37 (m, 4
HRMS (EI): m/z calcd for C10H16O2Si: 196.0921; found: 196.0920.
H), 2.05–1.83 (m, 2 H), 1.44 (s, 9 H), 0.14 [s, 9 H, Si(CH3)3].
Anal. Calcd for C10H16O2Si (196.32): C, 61.18; H, 8.21. Found: C,
61.34; H, 8.04.
13C NMR (125.7 MHz, CDCl3): d = 154.8 (C), 109.4 (C), 79.8 (C),
50.0 (C), 35.6 (2 CH2), 28.3 (3 CH3), 15.2 (CH2), –0.04 (3 CH3).
MS (EI, 70 eV): m/z = 210 (M+ – C4H9), 196, 183, 166, 139, 124,
97, 73, 57.
Curtius Degradation of the Acids 8 and 17; Preparation of the
Protected Ethynylamines 9 and 18; General Procedure 2 (GP 2)
The carbamates 9 and 18 were prepared and deprotected in two con-
secutive steps applying a modified protocol of our previously pub-
lished procedure.20 To a stirred solution of the crude acid 8 or 17 in
anhyd acetone was added Et3N dropwise at –5 °C. After additional
stirring at this temperature for 15 min, a solution of ethyl chlorofor-
mate in acetone was added at the same temperature over a period of
1 h, and the resulting mixture was stirred at this temperature for an
additional 1.5 h. Then a solution of NaN3 in H2O was added over a
period of 1 h, and the reaction mixture was stirred at 0 °C for 1.5 h,
then poured into ice-cold water and extracted with Et2O and pen-
tane. The combined organic solutions were washed with ice-cold
H2O, dried with stirring for 2 h, and concentrated on a rotary evap-
orator under reduced pressure at 0 °C. To the concentrate was added
anhyd toluene, and ca. 50% of the toluene was removed on a rotary
evaporator under reduced pressure. The remainder was added drop-
wise to boiling anhyd t-BuOH within 1.5 h, and the resulting solu-
Anal. Calcd for C14H25NO2Si (267.44): C, 62.87; H, 9.42; N, 5.24.
Found: C, 63.08; H, 9.64; N, 5.06.
Deprotection of the Carbamates 9 and 18; Preparation of the
Amine Hydrochlorides 3·HCl and 5·HCl; General Procedure 3
(GP 3)
To a solution of KF in a 10:1 mixture of DMF and H2O was added
the respective carbamate 9 or 18, and the reaction mixture was
stirred at r.t. for 24 h. The resulting mixture was poured into H2O,
and extracted with Et2O (3 × 80 mL). The combined organic layers
were washed with H2O and brine, then dried and very carefully con-
centrated under reduced pressure at 0 °C. The residue was sublimed
at 0.05 Torr to give the desilylated carbamate 10 or 19, respectively,
which was taken up in ca. 5.0 N HCl solution in Et2O (500 mL) and
intensively stirred at 0–20 °C in the dark for 6 h. The formed pre-
Synthesis 2010, No. 23, 3967–3973 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1-Ethynylcyclopropylamine and 1-Ethynylcyclobutylamine
MS (EI): m/z = 95 (M+ – HCl), 94, 80, 67, 52, 40.
3971
cipitate was collected on a filter, washed with Et2O (200 mL), and
dried in a vacuum desiccator over P4O10 overnight.
Anal. Calcd for C6H10ClN (131.60): C, 54.76; H, 7.66; N, 10.64.
Found: C, 54.58; H, 7.79; N, 10.38.
1-Ethynylcyclopropylamine Hydrochloride (3·HCl)
The residue, obtained from the carbamate 9 (105.1 g, 415 mmol)
and KF (72.4 g, 1.244 mol) in a DMF–H2O mixture (660 mL) ac-
cording to GP 3 (2 L H2O and 3 × 800 mL Et2O for the workup),
was sublimed at 85 °C to give 71.5 g (95%) of tert-butyl 1-(ethy-
nyl)cyclopropylcarbamate (10) as a highly volatile colorless solid;
mp 68–70 °C.
3-[1-(tert-Butoxycarbonylamino)cyclopropyl]propiolic Acid
(11)
The amino acid 11 was prepared applying a modified previously
published procedure.21 To a cooled (–78 °C) mechanically stirred
solution of the carbamate 10 (5.78 g, 31.87 mmol) in anhyd THF
(200 mL) was added dropwise n-BuLi (71.7 mmol; 20.7 mL of a
3.47 M solution in hexane). After stirring at this temperature for an
additional 1 h, a large excess of powdered dry ice was added in one
portion. The reaction mixture was allowed to warm up to 20 °C
overnight and then poured into ice-cold water (400 mL). The layers
were separated; the aqueous layer was washed with Et2O (2 × 100
mL), acidified by adding a 2 N aq HCl solution (36 mL) and imme-
diately extracted with Et2O (2 × 100 + 2 × 50 mL). The combined
organic layers from these last four extractions were dried and con-
centrated under reduced pressure to give 5.95 g (83%) of 11 as a col-
orless oil, which solidified upon standing at +4 °C overnight. This
colorless solid was used without further purification; an analytical
sample was obtained by recrystallization from hexane–THF (–20 °C,
overnight); mp 136 °C (dec. with vigorous gas evolution).
10
1H NMR (250 MHz, CDCl3): d = 5.03 (br s, 1 H), 2.13 (s, 1 H), 1.45
(s, 9 H), 1.29–1.03 (m AA¢BB¢, 4 H).
13C NMR (62.9 MHz, CDCl3): d = 155.3 (C), 65.6 (C), 78.0 (C),
61.6 (CH), 28.2 (3 CH3), 23.3 (C), 17.8 (2 CH2).
Anal. Calcd for C10H15NO2 (181.23): C, 66.27; H, 8.34; N, 7.73.
Found: C, 66.55; H, 8.03; N, 7.45.
3·HCl
Carbamate 10 (63.444 g, 350.0 mmol) was treated with a ca. 5.0 N
HCl solution in Et2O (500 mL) according to GP 3 to give 37.0 g
(90%) of 3·HCl as a slightly yellowish solid; mp 185–186 °C (dec.).
1H NMR (250 MHz, CDCl3): d = 5.15 (br s, 1 H, NH), 1.47 (s, 9 H),
1.42–1.24 (m AA¢BB¢, 4 H).
1H NMR (250 MHz, D2O): d = 2.66 (s, 1 H, C≡H), 1.14–1.11 (m, 4
H).
13C NMR (62.9 MHz, CDCl3): d = 156.8 (C), 155.3 (C), 92.0 (C),
81.9 (C), 71.1 (C), 28.2 (3 CH3), 23.1 (C), 19.2 (2 CH2).
1H NMR (250 MHz, DMSO-d6): d = 8.91 (br s, 3 H, +NH3), 2.28 (s,
1 H, C≡H), 1.40–1.34 and 0.96–0.90 (m AA¢BB¢, 4 H).
13C NMR (62.9 MHz, D2O): d = 82.2 (C≡H), 75.4 (C), 26.7 (C),
15.9 (2 CH2).
Anal. Calcd for C11H15NO4 (225.24): C, 58.66; H, 6.71. Found: C,
59.05; H, 7.07.
Anal. Calcd for C5H8ClN (117.58): C 51.08; H, 6.86; N, 11.91.
Found: C, 50.03; H, 7.11; N, 11.67.
3-(1-Aminocyclopropyl)propiolic Acid Hydrochloride (4·HCl)
Carbamate 11 (3.29 g, 14.6 mmol) was treated with a ca. 5.0 N HCl
solution in Et2O (50 mL) according to GP 3 (0–20 °C, 12 h stirring)
to give 2.12 g (96%) of 4·HCl as a colorless solid; mp 134–135 °C
(dec. with vigorous gas evolution).
1H NMR (250 MHz, D2O): d = 1.29–1.27 (m, 4 H).
13C NMR (62.9 MHz, D2O): d = 158.8 (C), 85.9 (C), 78.0 (C), 26.3
(C), 17.2 (2 CH2).
1-Ethynylcyclobutylamine Hydrochloride (5·HCl)
The residue, obtained from the carbamate 18 (27.08 g, 101 mmol)
and KF (17.6 g, 303 mmol) in a DMF–H2O mixture (165 mL) ac-
cording to GP 3 (400 mL H2O and 3 × 100 mL Et2O for the work-
up), was sublimed at 90 °C to give 17.94 g (91%) of tert-butyl 1-
(ethynyl)cyclobutylcarbamate (19) as a colorless solid; mp 70–
72 °C.
Anal. Calcd for C6H8ClNO2 (161.57): C, 44.60; H, 4.99; N, 8.67.
Found: C, 44.35; H, 5.11; N, 8.54.
19
1H NMR (300 MHz, CDCl3): d = 4.84 (br s, 1 H), 2.38 (s, 1 H),
(9H-Fluoren-9-yl)methyl 1-(Ethynyl)cyclopropylcarbamate
(12)
2.49–2.35 (m, 4 H), 2.11–1.87 (m, 2 H), 1.45 (s, 9 H).
13C NMR (125.7 MHz, CDCl3): d = 87.2 (C), 79.9 (C), 69.3 (C),
49.1 (C), 35.6 (2 CH2), 28.3 (3 CH3), 15.4 (CH2).
MS (EI, 70 eV): m/z = 138 (M+ – C4H9), 111, 95, 77, 67, 57.
HRMS (ESI): m/z [M + Na]+ calcd for C11H17NO2 + Na: 218.1151;
To a stirred suspension of the amine hydrochloride 3·HCl (2.41 g,
20.5 mmol) in THF (50 mL) was added a 10% aq solution of
Na2CO3 (200 mL). The reaction mixture was cooled to 0 °C, and a
solution of Fmoc-Cl (6.89 g, 26.6 mmol) in THF (50 mL) was added
at this temperature over a period of 0.5 h. The reaction mixture was
allowed to warm up to 20 °C overnight, then poured into sat. aq
NH4Cl solution (150 mL), and the mixture was extracted with
CH2Cl2 (2 × 100 mL). The combined organic layers were washed
with brine (100 mL), dried, and concentrated under reduced pres-
sure. The solid residue was recrystallized from hexane–EtOAc (1:1;
ca. 200 mL, –20 °C overnight) to give 5.62 g (90%) of 12 as a col-
orless solid; mp 163 °C.
1H NMR (250 MHz, CDCl3): d = 7.51–7.79 (m, 8 H), 5.30 (br s, 1
H), 4.46–4.39 (m, 2 H), 4.23 (br s, 1 H), 2.16 (s, 1 H), 1.30–1.05 (m
AA¢BB¢, 4 H).
13C NMR (62.9 MHz, CDCl3): d = 163.7 (C), 143.8 (2 C), 141.3 (2
C), 127.7 (2 CH), 127.0 (2 CH), 125.0 (2 CH), 120.0 (2 CH), 85.1
(CH), 67.1 (C), 66.8 (CH2), 47.1 (CH), 23.7 (C), 17.8 (2 CH2).
found: 218.1157.
Anal. Calcd for C11H17NO2 (195.26): C, 67.66; H, 8.78; N, 7.17.
Found: C, 67.48; H, 8.57; N, 7.06.
5·HCl
Carbamate 19 (20.109 g, 103 mmol) was treated with a ca. 5.0 N
HCl solution in Et2O (200 mL) according to GP 3 to give 12.34 g
(91%) of 5·HCl as a colorless solid; mp 220 °C (dec.).
1H NMR (300 MHz, D2O): d = 3.23 (s, 1 H), 2.67–2.51 (m, 4 H),
2.30–2.04 (m, 2 H).
1H NMR (300 MHz, DMSO-d6): d = 9.05 (br s, 3 H, +NH3), 2.57–
2.47 (m, 2 H), 2.49 (s, 1 H), 2.34–2.25 (m, 2 H, CH2), 2.05–1.89 (m,
2 H).
13C NMR (125.7 MHz, D2O): d = 81.7 (C), 76.1 (C), 48.9 (C), 33.5
(2 CH2), 14.1 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C20H17NO2 + Na: 326.1157;
found: 326.1155.
Synthesis 2010, No. 23, 3967–3973 © Thieme Stuttgart · New York

3972
S. I. Kozhushkov et al.
PRACTICAL SYNTHETIC PROCEDURES
3-{1-(9H-Fluoren-9-yl)methoxycarbonylamino]cyclopro-
pyl}propiolic Acid (13)
B: Org. Chem. Incl. Med. Chem. 1977, 15, 133. (g) Aoyagi,
E. I. US Patent 4271306, 1981; Chem. Abstr. 1981, 95:
97786.
Et3N (3.05 g, 4.2 mL, 30.2 mmol) was added dropwise to an ice-
cooled solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide
(Fmoc-OSu) (6.06 g, 18.0 mmol), and the amino acid hydrochloride
4·HCl (2.12 g, 14.4 mmol) in a mixture of MeOH (100 mL) and
CH2Cl2 (100 mL) was then added at 0 °C over a period of 0.5 h. The
reaction mixture was allowed to warm up to 20 °C overnight, and
the solvents were evaporated. The residue was taken up with a H2O–
Et2O mixture (100 + 100 mL), acidified by adding 1 N aq HCl so-
lution (35 mL) and the mixture immediately extracted with Et2O
(3 × 100 mL). The combined organic layers were dried and concen-
trated under reduced pressure. The residue was stirred with a hot
hexane–THF mixture (80 + 5 mol) for 5 min and then kept at –20 °C
overnight to yield 4.11 g (81%) of the pure compound 13 as a col-
orless solid, which is poorly soluble in CDCl3; mp 181–183 °C
(dec.).
(8) For peptidomimetics containing 1-aminocyclopropane-
carboxylic acid (ACC) residues, see: Brackmann, F.;
de Meijere, A. Chem. Rev. 2007, 107, 4493; and references
cited therein.
(9) See, for example: (a) Mertin, A.; Thiemann, T.; Hanss, I.;
de Meijere, A. Synlett 1991, 87. (b) Liu, J.; An, Y.; Jiang,
H.-Y.; Chen, Z. Tetrahedron Lett. 2008, 49, 490.
(c) Bieraugel, H.; Akkerman, J. M.; Lapierre Armande, J. C.;
Pandit, U. K. Recl. Trav. Chim. Pays-Bas 1976, 95, 266.
(d) Liese, T.; de Meijere, A. Chem. Ber. 1986, 119, 2995.
(e) Shavrin, K. N.; Gvozdev, V. D.; Budanov, D. V.; Yurov,
S. V.; Nefedov, O. M. Mendeleev Commun. 2006, 73.
(10) Marstokk, K.-M.; de Meijere, A.; Wagner-Gillen, K.;
Møllendal, H. J. Mol. Struct. 1999, 509, 1.
(11) See, for example: (a) Moser, H.; Lu, Q.; Patten, P. A.;
Wang, D.; Kasar, R.; Kaldor, S.; Patterson, B. D. Patent WO
2008154642 A2, 2008; Chem. Abstr. 2008, 150, 56532.
(b) Letrent, S. P. Patent WO 2006129163 A1, 2006; Chem.
Abstr. 2006, 146, 39020. (c) Connell, R. D.; Denis, L. J.;
Jani, J. P. US Patent 2005101618 A1, 2005; Chem. Abstr.
2005, 142, 441833. (d) Kath, J. C.; Bhattacharya, S. K.;
Morris, J. Patent WO 2001098277 A2, 2001; Chem. Abstr.
2001, 136, 69816. (e) Sendzik, M. Patent WO 2005019174
A1, 2005; Chem. Abstr. 2005, 142, 280045.
1H NMR (250 MHz, THF-d8): d = 7.79–7.62 (m, 4 H), 7.37–7.25
(m, 5 H), 4.43–4.30 (m, 2 H), 4.19 (m s, 1 H), 1.30–1.13 (m
AA¢BB¢, 4 H, cyclopropane CH2).
13C NMR (62.9 MHz, THF-d8): d = 156.5 (C), 154.3 (C), 145.2 (2
C), 142.3 (2 C), 128.3 (2 CH), 127.8 (2 CH), 125.9 (2 CH), 120.6 (2
CH), 90.3 (C), 72.5 (C), 66.8 (CH2), 48.2 (CH), 24.1 (C), 19.0 (2
CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C21H17NO4 + Na: 370.1055;
found: 370.1050.
(12) (a) Takemura, M.; Kimura, Y.; Takahashi, H.; Kimura, K.;
Miyauchi, S.; Ohki, H.; Sugita, K.; Miyauchi, R. US Patent
6121285 A, 2000; Chem. Abstr. 2000, 133, 237871.
(b) Takemura, M.; Takahashi, H.; Sugita, K.; Ohki, H.;
Miyauchi, S.; Miyauchi, R. Patent WO 9852939 A1, 1998;
Chem. Abstr. 1998, 130, 13992.
(13) For a review, see: Knorr, R. Chem. Rev. 2004, 104, 3795.
(14) (a) Kimura, Y.; Atarashi, S.; Takahashi, M.; Hayakawa, I.
Chem. Pharm. Bull. 1994, 42, 1442. (b) Schroeder, M. C.;
Kiely, J. S. J. Heterocycl. Chem. 1988, 25, 1769.
(c) Graupe, M.; Link, J. O.; Röpel, M. G. Patent WO
2006102243 A2, 1996; Chem. Abstr. 1996, 145, 357108.
(d) Link, J. O. Patent WO 2006102423 A1, 2006; Chem.
Abstr. 2006, 145, 377571.
(15) (a) Corley, E. G.; Thompson, A. S.; Huntington, M. Org.
Synth. 2000, 77, 231. (b) Militzer, H. C.; Schömenauer, S.;
Otte, C.; Puls, C.; Hain, J.; Bräse, S.; de Meijere, A.
Synthesis 1993, 998. (c) Wang, Z.; Campagna, S.; Yang, K.;
Xu, G.; Pierce, M. E.; Fortunak, J. M.; Confalone, P. N.
J. Org. Chem. 2000, 65, 1889. (d) Schmidt, S. E.; Salvatore,
R. N.; Jung, K. W.; Kwon, T. Synlett 1999, 1948.
(e) Henningsen, M.; Stamm, A.; Fischer, M.; Siegel, W.
German Patent DE 19709401 A1, 1998; Chem. Abstr. 1998,
129, 202703. (f) Gandy, R.; Cremins, P. J.; Timms, A. W.
British Patent GB 2329384 A, 1999; Chem. Abstr. 1999,
130, 324960.
References
(1) (a) Cyclopropyl Building Blocks for Organic Synthesis, 157.
For Part 156, see: de Meijere, A.; Chaplinski, V.; Winsel, H.;
Kordes, M.; Stecker, B.; Gazizova, V.; Savchenko, A. I.;
Schill, F. Chem. Eur. J. 2010, in press; DOI: 10.1002/
chem.201001550. (b) For Part 155, see: Lygin, A.; Limbach,
M.; Janssen, A.; Korotkov, V. S.; Funke, C.; de Meijere, A.
Eur. J. Org. Chem. 2010, 3665.
(2) (a) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer,
H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M.
Angew. Chem. Int. Ed. 2006, 45, 7736; Angew. Chem. 2006,
118, 7900. (b) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.;
Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner,
B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.;
Schweizer, W. B.; Müller, K.; Carreira, E. M. Angew. Chem.
Int. Ed. 2008, 47, 4512; Angew. Chem. 2008, 120, 4588.
(3) For example, for spirocyclopropane analogues of penicillins
and cephalosporins, see the review: Brackmann, F.;
de Meijere, A. Chem. Rev. 2007, 107, 4538; and references
cited therein.
(4) The steric effect of a cyclopropyl group is rather well
accounted for by the set of S f(R) values: Beckhaus, H. D.
Angew. Chem., Int. Ed. Engl. 1978, 17, 593; Angew. Chem.
1978, 90, 633: S f(R) = 0.00 (Me), 0.86 (Et), 1.33
(cyclopropyl), 1.81 (cyclopentyl), 2.29 (i-Pr), 3.82 (t-Bu).
(5) See, for example: Wiberg, K. B. Introduction In Methods of
Organic Chemistry (Houben-Weyl), Vol. E 17a; de Meijere,
A., Ed.; Thieme: Stuttgart, 1997, 1.
(16) Miller, R. B.; McGarvey, G. J. Org. Chem. 1978, 43, 4424.
(17) For an alternative synthesis of 7 from trimethylsilyl-
acetylene, see ref. 15b.
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Meng, K.; Timberlake, J. W. Tetrahedron Lett. 1987, 28,
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W. J. Jr.; Stevens, E. D.; Timberlake, J. W. J. Org. Chem.
1984, 49, 1208. (e) Chiu, S.-K.; Keifer, L.; Timberlake, J.
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(b) Jandralla, H. Chem. Ber. 1980, 113, 3585.
(20) Brandl, M.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A.
K.; de Meijere, A. Eur. J. Org. Chem. 1998, 2785.
(21) The procedure was adapted from the supporting information
associated with: Hornberger, K. R.; Hamblett, C. L.;
Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894.
Synthesis 2010, No. 23, 3967–3973 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1-Ethynylcyclopropylamine and 1-Ethynylcyclobutylamine
3973
(22) Oppolzer, W.; Lienard, P. Helv. Chim. Acta 1992, 75, 2572.
(23) Brunsveld, L.; Watzke, A.; Durek, T.; Alexandrov, K.;
Goody, R. S.; Waldmann, H. Chem. Eur. J. 2005, 11, 2756.
(24) Cabrele, C.; Kozhushkov, S. I.; de Meijere, A., unpublished
results.
(26) (a) van der Louw, J.; van der Baan, J. L.; Komen, C. M. D.;
Knol, A.; De Kanter, F. J. J.; Bickelhaupt, F.; Klumpp, G.
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van der Baan, J. L.; De Kanter, F. J. J.; Bickelhaupt, F.;
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(c) Stadtmüller, H.; Vaupel, A.; Tucker, C. E.; Stüdemann,
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Synthesis 2010, No. 23, 3967–3973 © Thieme Stuttgart · New York