Convenient synthesis of ethenylcyclopropane and some 2- cyclopropylcyclopropane derivatives

Article abstract of DOI:10.1055/s-0031-1289600

Ethenylcyclopropane (5) was prepared from cyclopropyl methyl ketone (1) in four simple, easily scalable steps (bromination, reduction to the bromohydrin, acetylation of the latter, and reductive elimination with Zn/Cu) in an overall yield of 56%. 1-Bromo-2-cyclopropylcyclopropane (7) (approximately 1:1 mixture of cis- and trans-7) was prepared from 5 via the dibromide 6, and from 7 the boronate cis/trans-8 (ratio 1:1) was obtained in 96% yield. Rhodium(II)- catalyzed cyclopropanation of 5 with ethyl diazoacetate gave ethyl 2-cyclopropylcyclopropanecarboxylate (cis/trans-9, ratio 1:1.4) in 80% yield. The latter was also prepared in 79% overall yield by sequential cyclopropanation of buta-1,3-diene with ethyl diazoacetate [under RhOAc)catalysis] and diiodomethane/diethylzinc/trifluoroacetic acid. Curtius degradation of 2-cyclopropylcyclopropanecarboxylic acid (obtained by hydrolysis of the ester) gave 2-cyclopropylcyclopropanamine (1:1.2 mixture of cis- and trans-isomers) in 58% yield. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289600

372
PRACTICAL SYNTHETIC PROCEDURES
Convenient Synthesis of Ethenylcyclopropane and Some 2-Cyclopropylcyclo-
propane Derivatives1
Valentin A. Rassadin,a Viktor V. Sokolov,a Alexander F. Khlebnikov,a Nikolay V. Ulin,a Sergei I. Kozhushkov,b
Armin de Meijere*b
a
Department of Chemistry, Saint Petersburg State University, Universitetskii Prospekt 26, Petrodvorets, 198504 St. Petersburg,
Russian Federation
b
Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen,
Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)23422; E-mail: ameijer1@uni-goettingen.de
Received 16 August 2011; revised 4 October 2011
Dedicated to Professor Oleg M. Nefedov on the occasion of his 80th birthday
PSP
No214
Abstract: Ethenylcyclopropane (5) was prepared from cyclopropyl methyl ketone (1) in four simple, easily scalable steps (bromination,
reduction to the bromohydrin, acetylation of the latter, and reductive elimination with Zn/Cu) in an overall yield of 56%. 1-Bromo-2-cy-
clopropylcyclopropane (7) (approximately 1:1 mixture of cis- and trans-7) was prepared from 5 via the dibromide 6, and from 7 the boronate
cis/trans-8 (ratio 1:1) was obtained in 96% yield. Rhodium(II)-catalyzed cyclopropanation of 5 with ethyl diazoacetate gave ethyl 2-cyclo-
propylcyclopropanecarboxylate (cis/trans-9, ratio 1:1.4) in 80% yield. The latter was also prepared in 79% overall yield by sequential cy-
clopropanation of buta-1,3-diene with ethyl diazoacetate [under Rh2(OAc)4 catalysis] and diiodomethane/diethylzinc/trifluoroacetic acid.
Curtius degradation of 2-cyclopropylcyclopropanecarboxylic acid (obtained by hydrolysis of the ester) gave 2-cyclopropylcyclopropan-
amine (1:1.2 mixture of cis- and trans-isomers) in 58% yield.
Key words: bromination, reduction, elimination, alkenes, cyclopropanation, small rings
Br2, MeOH
0–10 °C, 1.5 h
NaBH4, MeOH
0 °C, 40 min
Br
Br
80%
(over two steps)
O
O
OH
1
2
3
Zn/Cu/AcOH, AcONa
110–120 °C, 1 h
Ac2O, Py
20 °C, 15 h
Br
77%
OAc
91%
4
5
Scheme 1 Four-step preparation of ethenylcyclopropane (5) from cyclopropyl methyl ketone (1)
including 2-cyclopropylcyclopropanamine,9 we came
upon the necessity of making ethenylcyclopropane (5) as
Introduction
Ethenylcyclopropanes are important structural units in a precursor available in multigram quantities from inex-
various biologically active natural products2 as well as pensive starting materials. Here is the result of our en-
composite multifunctional construction units, e.g. for the deavor.
creation of cyclopentene3 and oligocyclopropyl deriva-
tives,4 which have gained considerable importance in
recent years.5 The unsubstituted building block ethenylcy- Results and Discussion
clopropane (5), nonsystematically also called vinylcyclo-
propane, has been prepared in a number of ways,6 the best Bromination of cyclopropyl methyl ketone (1) in meth-
of which is by Hofmann elimination from (1-cyclopropyl- anol under standard conditions gave the a-bromo ketone
ethyl)trimethylammonium hydroxide.6a The latter can be 210 and its reduction with sodium borohydride in
prepared in five steps from cyclopropyl methyl ketone (1), methanol11 furnished the bromohydrin 3 (80% yield over
the overall yield of 5 in this six-step sequence is approxi- two steps),10 which was treated with acetic anhydride in
mately 30%. For the preparation of bicyclopropyl7 and pyridine to give the vicinal bromoacetoxy derivative 4
various 2-substituted cyclopropylcyclopropane derivatives8 (91%) (Scheme 1). Reductive elimination in 4 was
brought about with copper-activated zinc (zinc-copper
couple) and gave ethenylcyclopropane (5) in 77% yield.
The overall yield in this four-step sequence obtained in
several runs was around 56%. The sequence is easily scal-
SYNTHESIS 2012, 44, 372–376
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289600; Art ID: E80311SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

PRACTICAL SYNTHETIC PROCEDURES
Ethenylcyclopropane and 2-Cyclopropylcyclopropane Derivatives
373
able and requires only inexpensive reagents. In length this pane (5) with dibenzylformamide in the presence of meth-
sequence is comparable to or shorter than most of the yltitanium triisopropoxide and cyclohexylmagnesium
known procedures for the preparation of 5,6 and all of the bromide, as previously developed for a wide range of alk-
required substrates and reagents are conveniently han- enes.17 However, several attempts to perform this conver-
dled.
sion were not met with success. This may be due to the
fact that the essential intermediate, formed by ligand ex-
change on titanium with ethenylcyclopropane, has a cy-
clopropylcarbinyltitanium substructure and as such would
be prone to undergo a rapid rearrangement of the type (cy-
clopropylcarbinyl)metal to (homoallyl)metal.18 The re-
sulting titanacyclohex-3-ene might not be reactive enough
to undergo insertion of the dibenzylformamide, but sim-
ply be hydrolyzed upon aqueous work-up to yield pent-2-
ene, which would have been lost due to its volatility. In or-
der to access 2-cyclopropylcyclopropanamine (13), ethyl
2-cyclopropylcyclopropanecarboxylate (9) was prepared
in 80% yield by rhodium(II)-catalyzed cyclopropanation
of 5 with ethyl diazoacetate (Scheme 3).
Ethenylcyclopropane (5) is a suitable precursor to various
2-cyclopropylcyclopropane derivatives, which have be-
come relevant entities in recent years.5,12 For example, di-
bromocarbene addition to
5
furnishes 2,2-
dibromobicyclopropyl (6)13 in 82% yield,4b and the latter
can be reduced to a mixture of the diastereomeric mono-
bromides cis-7 and trans-7 (ratio 45:55) with ethylmagne-
sium bromide in the presence of titanium
tetraisopropoxide (45% yield)14 or tri-n-butyltin hydride
(75% yield) (Scheme 2).15 Bromine–lithium exchange on
cis/trans-7 under conditions as previously published for
1-bromobicyclopropyl,16 and subsequent trapping of the
2-lithiobicyclopropyl with isopropyl pinacol borate pro-
duced the 2-cyclopropylcyclopropaneboronate cis/trans-8 Alternatively, 9 was prepared in 79% overall yield by se-
(ratio 1:1, 96%). The latter can be employed in Suzuki quential cyclopropanation of buta-1,3-diene (10) with eth-
cross-coupling reactions, as has been shown for the pure yl diazoacetate under dirhodium tetraacetate catalysis19
trans-diastereomer trans-8 prepared along a different route.8c and diiodomethane/diethylzinc/trifluoroacetic acid.20
Curtius degradation of 2-cyclopropylcyclopropanecar-
boxylic acid (11), obtained upon hydrolysis of the ester 9,
(a) or (b)
Br
employing the Weinstock protocol21 just like in the syn-
Br
Br
thesis of 1-cyclopropylcyclopropanamine,1 furnished the
N-Boc-protected 2-cyclopropylcyclopropanamine 12.
Deprotection of 12 with hydrogen chloride in diethyl ether
and subsequent treatment with sodium hydroxide gave
6
cis-/trans-7
(45:55)
(a): EtMgBr, Ti(Oi-Pr)4, Et2O, 20 °C, 1 h (45%)
(b): n-Bu3SnH, 35–40 °C, 1 h (75%)
pure (after distillation) 2-cyclopropylcyclopropanamine
(13) in an overall yield of 55% (from 11).
1) t-BuLi, Et2O, –78 °C, 45 min
2) i-PrOB(OR)2
B(OR)2
cis-/trans-7
–78 to 20 °C, 3 h
96%
1H and 13C NMR spectra were recorded at 300 MHz (1H) or 75.5
MHz (13C, additional DEPT) on a Varian Mercury VX300 instru-
ment in CDCl3 solutions, CHCl3/CDCl3 as internal references. IR
spectra were obtained with a Bruker Alpha FT-IR instrument. 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, respectively. Elemental analyses were per-
formed in St. Petersburg with a Hewlett-Packard CHN-Analyzer
HP 185B. TLC analyses were performed on precoated sheets (0.25
mm Sil G/UV254) from Macherey-Nagel. All chemicals were used
as commercially available. Anhyd Et2O was obtained by distillation
from sodium benzophenone ketyl, acetone by distillation from an-
hyd K2CO3, and pyridine by distillation from CaH2. Organic ex-
cis-/trans-8
(50:50)
O
O
B
B(OR)2
=
Scheme 2 Preparation of and bromine–lithium exchange on 2-bro-
mobicyclopropyl cis/trans-7 with subsequent electrophilic substitu-
tion
The most straightforward approach to a dibenzyl-protect-
ed 2-cyclopropylcyclopropanamine would be by direct
(dibenzylamino)cyclopropanation of ethenylcyclopro-
N2CHCO2Et
[Rh(OAc)2]2 (0.9 mol%)
CH2Cl2, 0 to 20 °C, 8 h
1) N2CHCO2Et, [Rh(OAc)2]2
2) CH2I2, ZnEt2, CF3CO2H
CH2Cl2, 0 to 20 °C, 16 h
80%
(42:58)
79%
(45:55)
5
CO2Et
cis-/trans-9
10
1) ClCO2Et, Et3N
Me2CO, 0 °C, 2.5 h
2) NaN3, Me2CO–H2O
1) 5 N HCl, Et2O
0–20 °C
0 °C, 1.5 h
3) t-BuOH, 80 °C
83%
CO2H
NCO2t-Bu
2) NaOH, H2O
70%
H
NH2
cis-/trans-13
cis-/trans-11
cis-/trans-12
(45:55)
(45:55)
(45:55)
Scheme 3 Preparation of 2-cyclopropylcyclopropanamine (13)
© Thieme Stuttgart · New York
Synthesis 2012, 44, 372–376

374
V. A. Rassadin et al.
PRACTICAL SYNTHETIC PROCEDURES
1-Bromo-2-cyclopropylcyclopropane (cis/trans-7)
tracts were dried over MgSO4, if not otherwise specified. All
reactions in anhyd solvents were carried out under an argon atmo-
sphere in flame-dried glassware.
Method a: To a solution of 2,2-dibromobicyclopropyl4c (6, 32.0 g,
0.133 mol) and Ti(Oi-Pr)4 (2.0 mL, 6.7 mmol) in anhyd Et2O (22
mL) was added, with continuous stirring and cooling in a water bath
under an atmosphere of N2, 0.95 M EtMgBr in Et2O (245 mL, 0.23
mol) within 45 min. The mixture was stirred for an additional 10
min, before H2O (54 mL), then 15% H2SO4 (220 mL), were added
cautiously. The aqueous phase was extracted with pentane (2 × 70
mL), the combined organic phases were washed with H2O and
brine, and then dried (MgSO4). The solvents were slowly distilled
off through a 30-cm Vigreux column with a distillation head, and
the residue was distilled through the same column under reduced
pressure (bp 69–72 °C/48 Torr). For the final purification the prod-
uct was diluted with pentane (10 mL) and subjected to flash column
chromatography (silica gel, 120 mL, pentane). The resulting solu-
tion was carefully concentrated on a rotatory evaporator at 25–30
°C bath temperature. The residue was pure 7 (9.7 g, 45%); ratio cis/
trans 45:55.
Bromomethyl Cyclopropyl Ketone (2)10
To a solution of cyclopropyl methyl ketone (1, 52.4 g, 0.623 mol)
in MeOH (370 mL), kept at 0–10 °C, was added with continuous
stirring Br2 (99.6 g, 31.9 mL, 0.623 mol) within 1 h. The reaction
was autocatalytic and proceeded slowly at the beginning. The re-
sulting colorless solution was stirred at 0–10 °C for an additional 30
min, before H2O (190 mL) was added, and the mixture stirred for an
additional 15 min. Then H2O (1 L) was added and the mixture ex-
tracted with CH2Cl2 (4 × 100 mL). The combined organic phases
were washed with 2 M Na2CO3 solution, H2O, and brine, dried
(MgSO4), and cautiously concentrated (30 °C/100–200 Torr). As 2
is extremely lachrymatory, it was used without further purification.
2-Bromo-1-cyclopropylethanol (3)10
To a solution of crude 2 [from 1 (52.4 g)] in MeOH (350 mL) was
added with stirring at 0 °C NaBH4 (5.9 g, 0.16 mol) in several por-
tions within 20 min, and the resulting clear solution was stirred at 0
°C for an additional 20 min, then diluted with H2O (500 mL) and ex-
tracted with CH2Cl2 (4 × 50 mL). The combined organic phases
were washed with half-concentrated NaCl solution, dried (MgSO4),
and carefully concentrated (40 °C/100–200 Torr). The bromohydrin
3 can be distilled under reduced pressure (bp 88–95 °C/13–18 Torr),
but this is not necessary for the next step; yield: 82.5 g (80% over
two steps).
1H NMR (300 MHz, CDCl3): d = 0.0–0.9 (m, 7 H), 1.08 (m, 0.55
H), 1.32 (m, 0.45 H), 2.60 (m, 0.45 H), 3.03 (m, 0.55 H).
13C NMR (75.5 MHz, CDCl3): d = 2.3 (CH2), 3.2 (CH2), 3.9*
(CH2), 4.2* (CH2), 11.0 (CH), 11.4* (CH), 13.7 (CH2), 13.8* (CH2),
18.6 (CH), 20.5* (CH), 23.3*(CH), 24.5 (CH). * Refers to major
diastereomer.
1H NMR (300 MHz, CDCl3), IR, MS, as well as elemental analysis
data have been reported before.8a
Method b: To 2,2-dibromobicyclopropyl4c (6, 78.0 g, 0.325 mol)
warmed at 30 °C was added dropwise n-Bu3SnH (94.5 g, 0.325 mol)
at such rate that the internal temperature did not exceed 45 °C (exo-
thermic reaction). The mixture was stirred at 35–40 °C for an addi-
tional 1 h, the product was distilled twice under reduced pressure to
yield cis/trans-7 (39.0 g, 75%); bp 78 °C/70 Torr.
2-Bromo-1-cyclopropylethyl Acetate (4)
To a solution of crude bromohydrin 3 (82.5 g) in anhyd pyridine
(120 mL) was added, with stirring and cooling in a water bath, Ac2O
(71 g, 0.70 mol) within 1 h. The resulting solution was left standing
overnight, then a mixture of H2O (400 mL) and ice (100 g) was add-
ed. The mixture was extracted with Et2O (300 mL), the organic
phase was washed with 2 M HCl, H2O, and brine, dried (MgSO4),
and cautiously concentrated (40 °C/100–200 Torr). The residue was
distilled under reduced pressure (bp 90–92 °C/10 Torr) to give 4
(93.7 g, 91%).
2-(Bicyclopropyl-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(8)
To a solution of 1-bromo-2-cyclopropylcyclopropane (cis/trans-7,
1.66 g, 10.3 mmol) in anhyd Et2O (35 mL), kept at dry ice/acetone
temperature, was added, with stirring under an atmosphere of N2,
1.2 M t-BuLi in pentane (10 mL) within 15 min, and the mixture
was stirred at the same temperature for an additional 30 min. From
a syringe, 2-isopropoxy-1,3,2-dioxaborolane (1.92 g, 10.3 mmol)
was added within 10 min, and the mixture was stirred at dry ice tem-
perature for 3 h, then the mixture was warmed up to r.t. and the re-
action quenched by addition of sat. NH4Cl solution (10 mL). The
aqueous phase was extracted with Et2O (3 × 10 mL), the combined
organic phases were washed with brine, dried (MgSO4), and con-
centrated under reduced pressure on a rotatory evaporator. The re-
sidue was taken up in Et2O–pentane (1:10, 2 mL) and subjected to
flash column chromatography (Rf = 0.5) to yield cis/trans-8 (2.06 g,
96%); ratio 1:1.
IR (neat): 3087, 3012, 1733, 1369, 1223, 1017, 978 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.35 (m, 1 H), 0.48 (m, 1 H), 0.59
(m, 2 H), 1.11 (m, 1 H), 2.10 (s, 3 H), 3.51 (dd, J = 10.8, 6.4 Hz, 1
H), 3.59 (dd, J = 10.8, 4.0 Hz, 1 H), 4.41 (m, 1 H).
13C NMR/APT (75.5 MHz, CDCl3): d = 3.0 (CH2), 3.4 (CH2), 13.8
(CH), 20.9 (CH3), 34.1 (CH2), 76.6 (CH).
HRMS (ESI+): m/z [M + Na]+ calcd for C7H11BrNaO2: 230.9820/
228.9840; found: 230.9814/228.9835.
Anal. Calcd for C7H11BrO2: C, 40.60; H, 5.35. Found: C, 40.45; H,
5.45.
Ethenylcyclopropane (5)
IR (neat): 3076, 2978, 1409, 1315, 1214, 1143, 858 cm–1.
A mixture of bromohydrin acetate 4 (82.5 g, 0.432 mol), AcONa
(37 g, 0.45 mol), and Zn/Cu couple (75 g, prepared from zinc dust
according to the established protocol19) in glacial AcOH (550 mL)
was slowly heated with stirring to 110–120 °C (bath temperature),
during which time the formed ethenylcyclopropane (5) was distilled
off through a 30-cm Vigreux column into a receiving flask cooled
with dry ice/acetone. The vigorous phase of the reaction lasted for
about 20 min, and within another 30 min the distillation of the prod-
uct was complete (bp 40–70 °C). The distillate was washed with
H2O, dried (MgSO4), and distilled once more over a 30-cm Vigreux
column (bp 40–41 °C) to give 5 (20.9 g, 77%). The spectroscopic
data were as published before.6f
1H NMR (300 MHz, CDCl3): d = –0.40 to 0.80 (m, 9 H), 1.20 (s, 6
H), 1.22 (s, 3 H), 1.25 (s, 3 H).
13C NMR/APT (75.5 MHz, CDCl3): d = –2 (br, CH), 2.6 (CH2), 3.2
(CH2), 4.6 (CH2), 4.9 (CH2), 9.2 (CH2), 9.9 (CH2), 11.7 (CH), 13.0
(CH), 19.9 (CH), 21.8 (CH), 24.5 (CH3), 24.6 (CH3), 24.7 (CH3),
25.1 (CH3), 82.8 (C).
MS (EI): m/z = 207 (M+), 193, 179, 165, 151, 123, 107, 84, 67, 55.
Ethyl 2-Cyclopropylcyclopropanecarboxylate (cis/trans-9)
from Ethenylcyclopropane (5)
A solution of ethyl diazoacetate (10.0 g, 88.1 mmol) in CH2Cl2 (30
mL) was added dropwise (syringe pump) to a stirred solution of
ethenylcyclopropane (5, 5.00 g, 73.4 mmol) and [Rh(OAc)2]2 (0.15
Synthesis 2012, 44, 372–376
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Ethenylcyclopropane and 2-Cyclopropylcyclopropane Derivatives
375
g) in CH2Cl2 (30 mL) at 0 °C within 6 h. After 2 h of additional stir-
ring, the solvent was removed by distillation, and the product was
isolated by column chromatography (silica gel, pentane–Et2O,
20:1). After removal of the solvent, the residue was distilled in vac-
uo to give cis/trans-9 (9.08 g, 80%) as a colorless liquid; ratio cis/
trans ca. 1:1.4; bp 74–76 °C/8 Torr.
MHz, CDCl3): d = 2.6/3.7 (CH2), 4.5/5.0 (CH2), 8.5/11.5 (CH),
14.1/14.2 (CH2), 19.0/19.2 (CH), 25.9/27.1 (CH), 179.8/181.0
(C=O).
tert-Butyl N-(2-Cyclopropylcyclopropyl)carbamate (cis/trans-
12)
To a mechanically stirred solution of the acid cis/trans-11 (39.1 g,
ca. 310 mmol) in anhyd acetone (940 mL), was added Et3N (42.2 g,
58.1 mL, 417 mmol) dropwise at –5 °C. After additional stirring at
this temperature for 15 min, neat ethyl chloroformate (57.4 g, 50.4
mL, 529 mmol) was added at the same temperature over a period of
30 min, and the resulting mixture was stirred at this temperature for
an additional 2 h. Then a solution of NaN3 (41.5 g, 0.554 mmol) in
H2O (110 mL) was added over a period of 1 h. The mixture was
stirred at 0 °C for 1.5 h, concentrated under reduced pressure at 0 °C
to about half of the original volume, poured into ice-cold H2O (1.1
L), and the mixture extracted with Et2O (4 × 200 mL) and pentane
(2 × 180 mL). The combined organic solutions were washed with
ice-cold H2O (2 × 200 mL), dried (under stirring with MgSO4, 0 °C,
1 h) and concentrated under reduced pressure (0 °C/20–30 Torr).
The residue was taken up with pentane (200 mL), dried, and con-
centrated under the same conditions. It was then dissolved in anhyd
t-BuOH (110 mL), and this solution was added dropwise to anhyd
t-BuOH (720 mL) kept at 80 °C under vigorous stirring over a peri-
od of 2.5 h. The resulting solution was heated under reflux for an ad-
ditional 9 h. The main volume of t-BuOH (ca. 700 mL) was distilled
off at ambient pressure under a flow of N2. After cooling, the resi-
due was dried (20 °C/0.1 Torr) to give essentially pure carbamate
cis/trans-12 (51.0 g, 83%) as a viscous oil, which was used in the
next step without further purification.
IR (thin film): 3081 (cPr–H), 1721 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 0.05–0.20 (m, 1.2 H, cPr-H),
0.25–0.56 (m, 2 H, cPr-H), 0.64–0.70 (m, 0.5 H, cPr-H), 0.96–1.14
(m, 1.2 H, cPr-H), 1.22–1.31 (m, 2.6 H, CH3, cPr-H), 1.36–1.47 (m,
1 H, cPr-H), 1.62–1.71 (m, 0.5 H, cPr-H), 4.06–4.19 (m, 4 H,
CH2O).
13C NMR (75 MHz, CDCl3): d = 2.5/3.6 (CH2), 4.4/4.9 (CH2), 8.6/
11.5 (CH), 13.0/13.2 (CH2), 14.2/14.3 (CH3), 19.1/19.2 (CH), 24.6/
25.7 (CH), 60.2/60.3 (CH2), 172.8/174.3 (C=O).
MS (EI): m/z = 154 (M+), 125, 109, 97, 81, 79, 54.
Ethyl 2-Cyclopropylcyclopropanecarboxylate (cis/trans-9)
from Buta-1,3-diene
Ethyl 2-Ethenylcyclopropanecarboxylate
Ethyl diazoacetate (67 g, 0.587 mol) was added dropwise (30 min)
to a solution of buta-1,3-diene (10, 259 mL, 165 g, 3.07 mol) and
[Rh(OAc)2]2 (0.95 g) in CH2Cl2 (260 mL) at –3 to –5 °C for 4.5 h.
After 1 h at this temperature, the excess buta-1,3-diene was allowed
to evaporate. The solvent was removed on a rotatory evaporator,
and the product was isolated by distillation to give ethyl 2-ethenyl-
cyclopropanecarboxylate (73.0 g, 88%) as a colorless liquid; ratio
cis/trans ca. 1:1.2; bp. 55–65 °C/8 Torr.
13C NMR (75 MHz, CDCl3): d = 14.0/15.4 (CH2), 14.2/14.3 (CH3),
20.9/21.8 (CH), 24.7/25.4 (CH), 60.4/60.5 (CH2), 114.7/116.0
(=CH2), 135.3/138.0 (=CH), 171.9/173.3 (C=O).
1H NMR (300 MHz, CDCl3): d = 4.71/4.64 (br s, NH), 2.59/2.25 (br
s, cPr-H), 1.45/1.44 (s, CH3), 1.28–1.22 (br m, cPr-H), 1.02–0.93
(br m, cPr-H), 0.92–0.83 (br m, cPr-H), 0.82–0.72 (br m, cPr-H),
0.66–0.57 (br m, cPr-H), 0.57–0.43 (m, cPr-H), 0.41–0.30 (m, cPr-
H), 0.23–0.15 (m, cPr-H), 0.12–0.04 (m, cPr-H).
1H NMR, IR, MS spectra were published previously along with the
CuCl-catalyzed cyclopropanation of buta-1,3-diene with ethyl di-
azoacetate, which gave the title compound in only 27% yield.8a
2-Cyclopropylcyclopropan-1-amine (cis/trans-13)
Ethyl 2-Cyclopropylcyclopropanecarboxylate (cis/trans-9)
Et2Zn (79.8 g, 66 mL, 646 mmol) was added to anhyd CH2Cl2 (1.5
L) at 0 °C in an inert atmosphere, and then to this solution was add-
ed TFA (73.7 g, 49.5 mL, 646 mmol) dropwise at 0 °C over a period
of 2 h. To the solution was added CH2I2 (173 g, 52.0 mL, 646 mmol)
dropwise over a period of 15 min. The resulting solution was stirred
at 0 °C for 30 min, at which time ethyl 2-ethenylcyclopropanecar-
boxylate (41.17 g, 294 mmol) was added. The mixture was stirred
at 0 °C for 30 min and then at r.t. for 16 h. The reaction was
quenched by addition of sat. aq NH4Cl (600 mL). The organic layer
was separated and washed with H2O (300 mL), dried, and filtered,
and the solvent was removed on a rotatory evaporator. The resulting
liquid was distilled under reduced pressure. The fraction boiling at
69–73 °C/7 Torr was collected to give cis/trans-9 (40.8 g, 90%) as
a colorless liquid; ratio cis/trans ca. 1:1.2.
Under stirring, a solution of cis/trans-12 (51.0 g, 259 mmol) in Et2O
(60 mL) was added to a ca. 5.0 N HCl solution in Et2O (400 mL) in
one portion at 0 °C. The mixture was stirred at 0 °C for 4 h and at
r.t. for 20 h. The solvent was removed on a rotatory evaporator, and
the residue was dissolved in H2O (300 mL), the solution was
washed with Et2O (2 × 70 mL), and the aq solution of the hydrochlo-
ride was alkalified with 30% aq NaOH to pH 10–11 under cooling.
The amine was extracted with Et2O (6 × 100 mL), the extract was
dried (Na2SO4), and the solvent was removed by distillation through
a 30-cm Vigreux column. The product was purified by distillation
(bp 63–65 °C/65 Torr) to give cis/trans-13 (17.66 g, 70%) as a col-
orless liquid; ratio cis/trans ca. 1:1.2.
1H NMR (300 MHz, CDCl3): d = 2.33–2.27 (m, cPr-H), 2.07–2.03
(m, cPr-H), 1.49 (br s, NH), 0.78–0.68 (m, cPr-H), 0.62–0.42 (m,
cPr-H), 0.38–0.14 (m, cPr-H), 0.07–0.04 (m, cPr-H).
13C NMR (75 MHz, CDCl3): d = 2.6/3.2 (CH2), 3.9/4.1 (CH2), 7.6/
2-Cyclopropylcyclopropanecarboxylic Acid (cis/trans-11)
A solution of KOH (27.0 g, 0.481 mol) in H2O (80 mL) was slowly
added to a stirred solution of the ester cis/trans-9 (49.6 g, 0.322
mol) in MeOH (270 mL) and the mixture was stirred at r.t. for 15 h.
The mixture was concentrated on a rotatory evaporator, and the re-
sidue was acidified with HCl to pH 2–3. The product was extracted
with Et2O, and the extract was washed with brine and dried. The sol-
vent was removed on a rotatory evaporator to give the practically
pure acid cis/trans-11 (39.1 g, 95%; cis/trans ca. 1:1.2), which was
used without further purification.
11.0 (CH), 12.5/12.7 (CH2), 20.9/23.3 (CH), 28.6/29.6 (CH).
References
(1) For one of us (A. d. M.), this is considered to be Part 160 in
the series ‘Cyclopropyl Building Blocks for Organic
Synthesis.’ (a) Part 159: Kozhushkov, S. I.; Khlebnikov, A.
F.; Kostikov, R. R.; Yufit, D. S.; de Meijere, A. Beilstein J.
Org. Chem. 2011, 7, 1003; http://www.beilstein-
1H NMR (300 MHz, CDCl3): d = 0.06–0.59 (m, cPr-H), 0.74–0.93
(m, cPr-H), 1.05–1.19 (m, cPr-H), 1.38–1.44 (m, cPr-H), 1.48–1.56
(m, cPr-H), 1.66–1.73 (m, cPr-H), 11.73 (br s, OH). 13C NMR (75
journals.org/bjoc. (b) Part 158: de Meijere, A.; Kozhushkov,
S. I. Mendeleev Commun. 2010, 20, 301.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 372–376

376
V. A. Rassadin et al.
PRACTICAL SYNTHETIC PROCEDURES
(2) For example, the well-known pyrethrins: (a) For a review
see: Grombie, L.; Eliott, M. Prog. Chem. Org. Nat. Prod.
1961, 19, 121. (b) The fungicide FR 900848:Yoshida, M.;
Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shigematsu, N.;
Okuhara, M.; Kohsaka, M.; Harikoshi, K. J. Antibiot.
(Tokyo) 1990, 43, 748. (c) The inhibitor of the cholesteryl
ester transfer protein U 106305: Kuo, M. S.; Zielinski, R. J.;
Cialdella, J. I.; Marschke, C. K.; Dupius, M. J.; Li, G. P.;
Klosterman, D. A.; Spilmann, C. H.; Marshall, V. P. J. Am.
Chem. Soc. 1995, 117, 10629.
(3) For reviews on the vinylcyclopropane to cyclopentene
rearrangement see: (a) Hudlicky, T.; Becker, D. A.; Fan, R.
L.; Kozhushkov, S. I. In Houben-Weyl, Vol. E 17c;
de Meijere, A., Ed.; Thieme: Stuttgart, 1997, 2538.
(b) Hudlicky, T.; Fan, R. L.; Reed, J. W.; Gadamasetti, K. G.
Org. React. 1992, 41, 1. (c) Baldwin, J. E. In The Chemistry
of the Cyclopropyl Group, Vol. 2; Rappoport, Z., Ed.; Wiley:
Chichester, 1995, 469. (d) Baldwin, J. E. J. Comput. Chem.
1998, 19, 222. (e) Baldwin, J. E. Chem. Rev. 2003, 103,
1197. (f) Hudlicky, T.; Reed, J. W. Angew. Chem. Int. Ed.
2010, 49, 4864; Angew. Chem. 2010, 122, 4982. For recent
applications, see: (g) Binger, P.; Wedemann, P.;
(9) 2-Cyclopropylcyclopropanamine has been mentioned as a
component of certain benzamides in a number of patents, but
no procedure for its preparation has been published. See,
e.g. (a) Dumas, D. J. WO 2009111553 A1, 2009; Chem.
Abstr. 2009, 151, 313544. (b) Dumas, D. J.; Casalnuovo, A.
WO 2009085816 A1, 2009; Chem. Abstr. 2009, 151,
123984. (c) Grushin, V.; Casalnuovo, A. WO 2009061991
A1, 2009; Chem. Abstr. 2009, 150, 539706. (d) Annis, G.
D. WO 2009006061 A2, 2009; Chem. Abstr. 2009, 150,
121640. (e) Annis, G. D.; Bruening, J.; Currie, M. J.;
Dumas, D. J.; Shapiro, R. WO 2008082502 A2, 2008; Chem.
Abstr. 2009, 149, 152831.
(10) The bromo ketone 2 and the bromohydrin 3 have previously
been prepared, but no experimental details have been
reported: Pirrung, M. C.; McGeehan, G. M. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1044; Angew. Chem. 1985, 97, 1074.
(11) The bromo ketone 2 is extremely lachrymatory, therefore
care must be taken in handling it. A one-pot reaction for the
bromination and ensuing NaBH4 reduction without isolation
of the bromo ketone gave only a poor yield of impure
bromohydrin 3.
(12) A quick search in the REAXYS data file disclosed 64
references for 2-cyclopropylcyclopropane derivatives, many
of which are patents and of rather recent vintage.
(13) In earlier reports, the yield of 6 was only 51%; see:
(a) Roth, W. R.; Schmidt, T.; Humbert, H. Chem. Ber. 1975,
108, 2171. (b) Farnoth, W. E.; Thomsen, M. W. J. Org.
Chem. 1982, 47, 4851.
(14) Al Dulayymi, J. R.; Baird, M. S.; Bolesov, I. G.; Nizovtsev,
A. V.; Tverezovsky, V. V. J. Chem. Soc., Perkin Trans. 2
2000, 1603.
Kozhushkov, S. I.; de Meijere, A. Eur. J. Org. Chem. 1998,
113. (h) Brandi, A.; Cicchi, S.; Brandl, M.; Kozhushkov, S.
I.; de Meijere, A. Synlett 2001, 433. (i) Voigt, T.; Winsel,
H.; de Meijere, A. Synlett 2002, 1362. (j) Baldwin, J. E.;
Leber, P. A. Org. Biomol. Chem. 2008, 6, 36. (k) Ohta, A.;
Dahl, K.; Raab, R.; Geittner, J.; Huisgen, R. Helv. Chim.
Acta 2008, 91, 783.
(4) (a) For a review, see: Pietruszka, J. Chem. Rev. 2003, 103,
1051. (b) de Meijere, A.; Kozhushkov, S. I.; Schill, H.
Chem. Rev. 2006, 106, 4926. (c) For more recent examples,
see: von Seebach, M.; Kozhushkov, S. I.; Frank, D.; Boese,
R.; Benet-Buchholz, J.; Yufit, D. S.; Schill, H.; de Meijere,
A. Chem. Eur. J. 2007, 13, 167.
(5) (a) O’Sullivan, A. C.; Hughes, D.; Jeanguenat, A.;
Muehlbach, M.; Loiseur, O. (SYNGENTA AG) WO
2006040113 A2, 2006; Chem. Abstr. 2006, 144, 364548.
(b) Walter, H.; Zeun, R.; Ehsenfreund, J.; Tohler, H.; Corsi,
C.; Lamberth, C. (SYNGENTA AG) WO 2006015866 A1,
2006; Chem. Abstr. 2006, 144, 186456.
(6) (a) Demjanov, N. J.; Dojarenko, M. Ber. Dtsch. Chem. Ges.
1922, 55, 2718. (b) Overberger, C. G.; Borchert, A. E.
J. Am. Chem. Soc. 1960, 82, 4896. (c) Kirmse, W.; Bülow,
B. G.; Schepp, H. Justus Liebigs Ann. Chem. 1966, 691, 41.
(d) Dzhemilev, U. M.; Dokichev, V. A.; Sultanov, S. Z.;
Khusnutdinov, R. I.; Tomilov, Yu. V.; Nefedov, O. M.;
Tolstikov, G. A. Izv. Akad. Nauk SSSR, Ser. Khim. 1989,
1861. (e) Baldwin, J. E.; Villarica, K. A. Tetrahedron Lett.
1994, 35, 7905. (f) Larock, R. C.; Yum, E. K. Tetrahedron
1996, 52, 2743.
(15) For applications of n-Bu3SnH in reductions of dibromo-
cyclopropanes, see refs. 8a,b.
(16) de Meijere, A.; Khlebnikov, A. F.; Sünnemann, H. W.;
Rauch, K.; Yufit, D. S. Eur. J. Org. Chem. 2010, 3295.
(17) de Meijere, A.; Williams, C. M.; Kourdioukov, A.; Sviridov,
S. V.; Chaplinski, V.; Kordes, M.; Savchenko, A. I.;
Stratmann, C.; Noltemeyer, M. Chem. Eur. J. 2002, 8, 3789.
(18) For examples of rapid (cyclopropylcarbinyl)metal-to-
(homoallyl)metal rearrangements, see: (a) Zhao, L.;
de Meijere, A. Adv. Synth. Catal. 2006, 348, 2484.
(b) Kurahashi, T.; Wu, Y.-T.; Meindl, K.; Rühl, S.;
de Meijere, A. Synlett 2005, 805. (c) Kurahashi, T.;
de Meijere, A. Synlett 2005, 2619. (d) Kurahashi, T.;
de Meijere, A. Angew. Chem. Int. Ed. 2005, 44, 7881;
Angew. Chem. 2005, 117, 8093. (e) Larock, R. C.;
Varaprath, S. J. Org. Chem. 1984, 49, 3432. (f) Trost, B.
M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122,
2379. (g) Wender, P. A.; Williams, T. J. Angew. Chem. Int.
Ed. 2002, 41, 4550; Angew. Chem. 2002, 114, 4732.
(h) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.;
Pleuss, N. Tetrahedron 1998, 54, 7203.
(7) de Meijere, A.; Lüttke, W.; Heinrich, F. Justus Liebigs Ann.
Chem. 1974, 306.
(8) See, for example: (a) Landgrebe, J. A.; Becker, L. W.
J. Org. Chem. 1968, 33, 1173. (b) Schrumpf, G.; Lüttke, W.
Justus Liebigs Ann. Chem. 1969, 730, 100. (c) Löhr, S.;
de Meijere, A. Synlett 2001, 489. (d) Ref. 4c.
(19) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1;
Wiley: New York, 1967, 292.
(20) Yang, Z.; Lorentz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39,
8621.
(21) (a) Weinstock, J. J. Org. Chem. 1961, 26, 3511.
(b) Jandralla, H. Chem. Ber. 1980, 113, 3585.
Synthesis 2012, 44, 372–376
© Thieme Stuttgart · New York