An efficient synthesis of 1-bromo-1-cyanocyclopropane

Article abstract of DOI:10.3184/174751914X14024165307800

An efficient process for the synthesis of 1-bromo-1-cyanocyclopropane has been developed starting from inexpensive γ-butyrolactone via bromination, cyclisation, ammoniation and dehydration reaction. The sequence proceeds in good yield.

Full text of DOI:10.3184/174751914X14024165307800

418 RESEARCH PAPER
VOL. 38 JULY, 418–419
JOURNAL OF CHEMICAL RESEARCH 2014
An efficient synthesis of 1‑bromo‑1‑cyanocyclopropane
Feng Xue*, Chang‑Gong Li, Yong Zhu and Tian‑Jun Lou
Key Laboratory of Functional Organic Molecules of Xinxiang City Henan Province, College of Chemistry and Chemical Engineering, Henan
Institute of Science and Technology, Xinxiang Henan, 453002, P.R. China
An efficient process for the synthesis of 1‑bromo‑1‑cyanocyclopropane has been developed starting from inexpensive
γ‑butyrolactone via bromination, cyclisation, ammoniation and dehydration reaction. The sequence proceeds in good yield.
Keywords: 1‑bromo‑1‑cyanocyclopropane, bromination, cyclisation, ammoniation, dehydration
An increasing number of therapeutic agents, including
antiarrhythmic, antipsychotic, and antitumour compounds,
have structures which incorporate a cyclopropane ring.1,2
Compoundscontainingacyclopropaneringhavebeenattracting
attention as pharmaceutical intermediates. The physiological
importance of cyclopropane‑containing compounds has led
to various synthetic methods for these three‑membered rings.3
Among the approaches reported are those involving:
Results and discussion
Inexpensive γ‑butyrolactone 1 was sequentially treated with
Br2 and CH3OH by bromination and esterification in a one‑pot
procedure to prepare methyl 2,4‑dibromobutanoate 2 based on a
modified synthetic method.10 When the reaction was completed,
simple aqueous workup was used to obtain relatively pure methyl
2,4‑dibromobutanoate 2. This was used in the next step without
a relatively laborious purification process. The intramolecular
cyclisation of methyl 2,4‑dibromobutanoate 2 to methyl
1‑bromocyclopropanecarboxylate 3 worked well under two‑
phase, solid–liquid‑phase conditions in CH3CN as solvent instead
of the toluene used in the previously reported method.10 This
contributed to a decrease in the reaction time from 40 h10 to 20 h.
Next, 1‑bromocyclopropanecarboxylamide 4 was easily obtained
by treatment with 26% ammonium hydroxide. The dehydration
reaction then followed. Through careful exploration of reaction
conditions, P2O5 was chosen as the optimal dehydrating agent in
place of SOCl2, POCl3 and COCl2. This made the reactions safe
and practical for large‑scale synthesis. The reaction solvent was
also examined which showed that acetonitrile was the optimal
solvent instead of toluene, acetone and dioxane. These reduced
the previously reported harsh dehydrating reaction conditions
and improved the yield of the product. When the reaction was
conducted smoothly at 80 °C, 1‑bromocyclopropanecarbonitrile
5 was obtained in 85% yield (Scheme 1).
(a) curtius rearrangement of 1‑phenyl‑, or 1‑substituted
cyclopropanecarboxylic acids;4,5
(b) cyclopropanation of benzylidene‑oxazolones, 2‑azido‑2‑
alkenoates, or α‑ethylenic α‑amino acids by diazomethane
or sulfoxonium;6
(c) cyclopropanation of olefins by an aminocarboxycarbene;7
(d) cycloalkylationofglycinederivativesby1,2‑dibromoethane;6
(e) enzymatic or base‑induced cyclisation of methionine
derivatives;8 and
(f) α‑haloimines cyanation.9
Despite some success in the preparation of
these
carbonylcyclopropane
compounds
such
as
l‑aminocyclopropanecarboxylic acid (ACC), there has been no
report relating to the synthesis of 1‑bromo‑1‑cyanocyclopropane
so far. As an extension of our program dealing with the
preparation of cyclopropane compounds of biological interest,
the procedure described here affords an efficient method for
the synthesis of 1‑bromo‑1‑cyanocyclopropane. Since it uses a
readily available starting material, and can be applied to the
preparation of large quantities of cyclopropanecarbonitrile,
this method of synthesis provides easy access to 1‑bromo‑1‑
cyanocyclopropane.
In conclusion, we have reported an efficient process for the
preparation of 1‑bromocyclopropanecarbonitrile involving
simple reaction procedures from readily available starting
materials. This allows for further development of other halogens
according to choice. The overall process is more environmentally
friendly as well as cost‑effective. We are presently applying this
strategy to the synthesis of other derivatives.
Br
Br
K2CO3/n-Bu3NHSO4
O
1) Br2/PBr3
2) CH3OH
O
O
r
B
H
COOC
3
H N
C 3C
H
OC
3
3
2
1
NH4OH
r
B
Br
P
2O5
CONH2
CN
H N
C 3C
4
5
Scheme 1 Preparation of 1‑bromocyclopropanecarbonitrile.
* Correspondent. E‑mail: fxuehist@sina.com
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JOURNAL OF CHEMICAL RESEARCH 2014 419
concentrated under reduced pressure. H2O was added, and the mixture
was vigorously stirred, filtered, and the filter cake was dried to give
Experimental
Solvents and reagents were purchased from Sigma‑Aldrich and used
without further purification. Melting points were determined on
a Mettler FP5 apparatus and are uncorrected. NMR spectra were
recorded on Bruker DRX 400 MHz spectrometer using CDCl3 as
solvent, and TMS as the internal standard. High resolution mass
spectra were recorded on Applied Biosystems Mariner System 5303.
Methyl 2,4-dibromobutanoate (2): A 500 mL, three‑necked flask
was charged with γ‑butyrolactone 1 (196 g, 2.28 mol) and phosphorus
tribromide (234.5 g, 0.87 mol) under N2 and cooled to –10 °C.
Bromine (420 g, 2.64 mol) was added dropwise at a rate that kept
the reaction temperature below 30 °C. After the reaction had slowed
down, external cooling was removed and a second portion of bromine
(279.2 g, 1.76 mol) was added and the temperature rose to 40–50 °C.
The reaction mixture was stirred for 3 h at 80 °C and cooled to –5 °C
and methanol (150 mL) was slowly added. The mixture was distributed
between diethyl ether (200 mL) and water (200 mL), and the aqueous
phase was discarded. The organic phase was washed with a saturated
solution of Na2S2O3 and dried (MgSO4), and the solvent was removed
on a rotary evaporator, to give crude 2, which was used without further
purification in the next step.
the corresponding 1‑bromocyclopropanecarbonitrile
4 (102.8 g,
1
94% yield) as a colourless solid; m.p. 95–97 °C. H NMR (CDCl3) δ
1.32–1.35 (m, 2 H), 1.65–1.71 (m, 2 H), 6.68–6.75 (b, 2 H); 13C NMR
(CDCl3) δ 172.3, 28.7, 20.0; HRMS calcd for C4H6BrNO [M]+ 162.9654;
found: 162.9665.
1-Bromocyclopropanecarbonitrile (5).
A
solution of the
1‑bromocyclopropanecarbonylamide 4 (108.5 g, 0.67 mol) in dry
CH3CN (400 mL) was dehydrated over P2O5 (187.5 g, 1.34 mol) for
5 h at 80 °C. After the reaction was complete, the mixture was diluted
with CH2Cl2, washed with dilute NaHCO3, water, dried over MgSO4,
filtered, and the solvent was removed on a rotary evaporator, to give
crude 5, which was purified by distillation under reduced pressure
(b.p. 55–58 °C/2 mmHg) to afford 1‑bromocyclopropanecarbonitrile 5
(81.5 g, 85% yield) as a colourless oil. 1H NMR (CDCl3) δ 1.46–1.51 (m,
2 H), 1.69–1.72 (m, 2 H); 13C NMR (CDCl3) δ 119.6, 19.1, 4.59; HRMS
calcd for C4H4BrN [M]+ 144.9534; found: 144.9540.
Received 21 April 2014; accepted 20 May 2014
Paper 1402621 doi: 10.3184/174751914X14024165307800
Published online: 12 July 2014
Methyl 1-bromocyclopropanecarboxylate (3): K2CO3 (122.0 g,
0.88 mol) and n‑Bu3NHSO4 (0.68 g, 0.02 mol) were mixed with
dibromo ester 2 (104 g, 0.4 mol) in CH3CN (150 mL). The suspension
was stirred for 20 h at 80°C. After being cooled to room temperature,
the mixture was filtered by suction through a Buchner funnel and the
filtercake was washed several times with ether. The combined organic
phases were dried, filtered and concentrated under reduced pressure
to provide crude 3, which was used without further purification in the
next step.
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