Scalable synthesis of (1-cyclopropyl)cyclopropylamine hydrochloride

Article abstract of DOI:10.3762/bjoc.7.113

1-Cyclopropylcyclopropanecarboxylic acid (2), which is accessible on a large scale (900 mmol) from 1-bromo-1-cyclopropylcyclopropane (1) in 64% yield (89% on a 12.4 mmol scale), has been subjected to a Curtius degradation employing the Weinstock protocol to furnish the N-Boc-protected (1-cyclopropyl)cyclopropylamine 3 (76%). Deprotection of 3 with hydrogen chloride in diethyl ether gave the (1-cyclopropyl)cyclopropylamine hydrochloride (4?HCl) in 87% yield.

Full text of DOI:10.3762/bjoc.7.113

Scalable synthesis of (1-cyclopropyl)cyclo-
propylamine hydrochloride
Sergei I. Kozhushkov*1, Alexander F. Khlebnikov2, Rafael R. Kostikov2,
Dmitrii S. Yufit3 and Armin de Meijere*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1003–1006.
1Institut für Organische und Biomolekulare Chemie der
Georg-August-Universität Göttingen, Tammannstrasse 2, 37077
Göttingen, Germany, Fax: +49-551-399475, 2Department of
Chemistry, Saint Petersburg State University, Universitetskii Prosp.
26, Petrodvorets, 198504 St. Petersburg, Russia and 3Department of
Chemistry, University of Durham, South Rd., Durham DH1 3L, UK
doi:10.3762/bjoc.7.113
Received: 17 May 2011
Accepted: 16 June 2011
Published: 21 July 2011
This article is part 159 of the Series "Cyclopropyl Building Blocks for
Organic Synthesis." For part 158 and 157 see [1] and [2], respectively.
Email:
Sergei I. Kozhushkov* - skozhus@gwdg.de;
Alexander F. Khlebnikov - alexander.khlebnikov@pobox.spbu.ru;
Rafael R. Kostikov - rakostikov@yandex.ru; Dmitrii S. Yufit -
d.s.yufit@durham.ac.uk; Armin de Meijere* -
ameijer1@uni-goettingen.de
Associate Editor: J. Murphy
© 2011 Kozhushkov et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
amines; building blocks; carboxylic acids; Curtius degradation;
cyclopropanes
Abstract
1-Cyclopropylcyclopropanecarboxylic acid (2), which is accessible on a large scale (900 mmol) from 1-bromo-1-cyclopropylcyclo-
propane (1) in 64% yield (89% on a 12.4 mmol scale), has been subjected to a Curtius degradation employing the Weinstock
protocol to furnish the N-Boc-protected (1-cyclopropyl)cyclopropylamine 3 (76%). Deprotection of 3 with hydrogen chloride in
diethyl ether gave the (1-cyclopropyl)cyclopropylamine hydrochloride (4·HCl) in 87% yield.
Introduction
Several recent patent applications have stirred an increasing active and pharmacologically relevant compounds. For
interest in research departments of pharmaceutical and agro- example, a number of derivatives of (1-cyclopropyl)cyclo-
chemical companies concerning 1- and 2-substituted 1,1'-bicy- propylamine (4) have been found to be useful variously for the
clopropyl derivatives. Among them, intermediates containing a treatment of hepatitis C [3,4], as pest control agents [5], as
(1-cyclopropyl)cyclopropylamine moiety appear to be particu- inhibitors of methicillin-resistant Staphylococcus aureus [5], as
larly important and desirable for the preparation of biologically pesticides, insecticides and acaricides [7-13] and more. This
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Beilstein J. Org. Chem. 2011, 7, 1003–1006.
amine has been prepared from cyclopropyl cyanide [3-13] by protected (1-cyclopropyl)cyclopropylamine 3 in 76% yield. It
application of the Szymoniak–Kulinkovich reductive cyclopro- was essential to carefully dry the solution of the intermediate
panation procedure [14,15]. In our hands, however, this azide, otherwise the yield of 3 dropped dramatically, and the
patented protocol [3-13] provided poor yields (15–20%) of desired product was accompanied by 1,3-di(bicyclopropyl)urea
impure 4 [16], which had to be purified by conversion to the (5) in up to 50% yield (Scheme 1). The structure of the latter
corresponding tert-butyl carbamate and subsequent column was confirmed by an X-ray crystal structure analysis (Figure 1)
chromatography. Thus, this procedure was not easily scalable to [26].
10–50 g quantities. To meet such demands, we have developed
an alternative route to 4 from the easily available corres-
ponding carboxylic acid 2 [17,18] by Curtius degradation
[19,20].
Results and Discussion
Preparation of the acid 2 from the known 1-bromo-1-cyclo-
propylcyclopropane (1) [21,22] according to the published
procedure [17] was accomplished on a 100 g scale (Scheme 1).
However, the yield of the carboxylation on a scale of 12.4
mmol, 900 mmol and 1400 mmol, was 89, 64 and 62%, respect-
ively. This is associated with the longer reaction time employed
on a larger scale, during which the intermediate 1-cyclopropyl-
1-lithiocyclopropane may be trapped by the by-product tert-
Figure 1: Structure of 1,3-di(bicyclopropyl)urea (5) in the crystal [26].
butyl bromide, leading to isobutene by dehydrobromination
[23,24]. Indeed, the reaction on a 200 mmol scale, but over a
period of 3 h, furnished 2 in 46% yield only. According to The carbamate 3 was deprotected by treatment with hydrogen
previous experience, this undesired side reaction can be chloride in diethyl ether affording the amine hydrochloride
suppressed by employing two equivalents of tert-butyllithium 4·HCl in 87% yield. The latter was thus obtained from 1-bromo-
[23]. Thus, the yield of 2 may be improved even for large scale 1-cyclopropylcyclopropane (1) on a scale of 50 g in 42%
preparation.
overall yield (Scheme 1).
Conclusion
The newly developed procedure allows the preparation of
1-(cyclopropyl)cyclopropylamine (4) in five steps from
commercially available methyl cyclopropanecarboxylate, repro-
ducibly, on a 50 g and even larger scale. In this respect it is
superior to the previously published and patented access to 4
from cyclopropanecarbonitrile, which in the hands of five
different researchers in our laboratory required chromato-
graphic separation of the intermediately prepared N-Boc deriva-
tive, which involved the rather costly di-tert-butyl pyrocar-
bonate and made that an overall three-step procedure.
Experimental
1H and 13C NMR spectra were recorded at 300 MHz [1H] and
62.9 MHz [13C, additional DEPT (Distortionless Enhancement
by Polarization Transfer)] on Bruker AM 250 and Varian
Mercury Vx300 instruments in CDCl3 and D2O solutions,
CHCl3/CDCl3 and DHO as internal references. EI-MS, ESI-MS
and HRMS spectra were measured with Finnigan MAT 95 (70
Scheme 1: Preparation of 1-(cyclopropyl)cyclopropylamine hydrochlo-
ride (4·HCl).
Curtius degradation of the acid 2 via the corresponding azide, eV), Finnigan LCQ and Bruker Daltonic APEX IV 7T FTICR
according to the Weinstock protocol [19,20] as previously instruments, respectively. Melting points were determined on a
employed in different examples [2,25], furnished the N-Boc- Büchi 510 capillary melting point apparatus, values are uncor-
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Beilstein J. Org. Chem. 2011, 7, 1003–1006.
rected. TLC analyses were performed on precoated sheets (0.25 pressure at 0 °C/20–30 Torr. The residue was taken up with
mm Sil G/UV254) from Macherey-Nagel). All chemicals were pentane (300 mL), dried and concentrated under the same
used as received. 1-Bromo-1-cyclopropylcyclopropane (1) was conditions. It was then dissolved in anhydrous t-BuOH (200
obtained according to the previously published procedure [21]. mL), and this solution was added dropwise to anhydrous
A 5.0 N solution of HCl in Et2O was prepared by saturation of t-BuOH (1300 mL) kept at 80 °C under vigorous stirring over a
anhydrous Et2O with gaseous HCl at 0 °C. Anhydrous diethyl period of 2.5 h. The resulting solution was heated under reflux
ether was obtained by distillation from sodium benzophenone for an additional 9 h. The main volume of t-BuOH (ca. 1300
ketyl, acetone by distillation from anhydrous potassium mL) was distilled off under ambient pressure in a nitrogen flow.
carbonate. Anhydrous tert-butyl alcohol was obtained After cooling, the residue mixture was dried at 20 °C/0.1 Torr
employing molecular sieves (4 Å) [27]. Organic extracts were to give essentially pure carbamate 3 (84.0 g, 76%) as a color-
dried over MgSO4. All reactions in anhydrous solvents were less solid, mp 69–70 °C, Rf 0.38 (hexane/Et2O 5:1), which was
carried out under an argon atmosphere in flame-dried glass- used in the next step without further purification. 1H NMR (300
ware.
MHz, CDCl3) δ 4.91 (br s, 1H, NH), 1.39 (s, 9H, 3 CH3),
1.30–1.20 (br m, 1H, cPr-H), 0.64–0.57 (br m, 2H, cPr-H),
0.52–0.45 (br m, 2H, cPr-H), 0.37–0.31 (m, 2H, cPr-H),
0.09–0.04 (m, 2H, cPr-H); 13C NMR (62.9 MHz, CDCl3) δ
Synthesis of 1-cyclopropylcyclopropanecar-
boxylic acid (2)
Under mechanical stirring and cooling with pentane/liq. N2, a 155.2 (C), 79.0 (C), 34.1 (C), 28.3 (3 CH3), 15.6 (CH), 11.9 (2
solution of t-BuLi (1.7 M in pentane, 560 mL, 952.0 mmol) was CH2), 2.6 (2 CH2); EIMS (70 eV) m/z: 141 (M+ − C4H8), 126,
added dropwise to a solution of 1-bromo-1-cyclopropylcyclo- 96, 82, 58, 57, 43; HRMS–ESI (m/z): calcd for C11H19NNaO2,
propane (1) (146.0 g, 907.0 mmol) in anhydrous Et2O (2.2 L) at 220.1308; found, 220.1314.
−78 °C within 40 min. After stirring at −78 °C for an additional
Synthesis of (1-cyclopropyl)cyclopropyl-
25 min, an excess of dry ice was added in several portions (T ≤
−70 °C), and the mixture was allowed to slowly warm up to amine hydrochloride (4·HCl)
ambient temperature during a period of 2 h. The reaction was Under stirring, a solution of the carbamate 3 (84.0 g, 425.8
quenched with an ice-cold solution of KOH (60.0 g, 1.070 mol) mmol) in Et2O (100 mL) was added to a ca. 5.0 N HCl solution
in H2O (1 L), the aqueous layer was washed with ether (3 × 100 in Et2O (700 mL) in one portion at 0 °C. The reaction mixture
mL), and then acidified with conc. aq. HCl solution at 0–5 °C was stirred at 0 °C for 4 h and at ambient temperature for 20 h.
(ca. 175 mL). The resulting mixture was extracted with ether (4 The formed precipitate was filtered off, washed with Et2O (200
× 300 mL), the combined organic phases were dried and mL) and dried in a vacuum desiccator over P4O10 overnight to
concentrated under reduced pressure to give the acid 2 (73.2 g, give 4·HCl (49.7 g, 87%) as a colorless powder, which slowly
64%) as colorless crystals, mp 50–51 °C (lit. [17]: mp: 51–52 decomposes above ca. 135 °C and melts at 196–198 °C (dec.);
°C), which was used in the next step without further purifica- 1H NMR (300 MHz, D2O) δ 1.30–1.26 (m, 1H, cPr-H),
tion. Its NMR spectra were identical to the published ones [17]. 0.71–0.60 and 0.60–0.55 (m AA'BB', 4H, cPr-H), 0.49–0.42
and 0.13–0.08 (m AA'BB', 4H, cPr-H).
Synthesis of tert-butyl 1-(cyclopropyl)cyclo-
propylcarbamate (3)
When a solution of the intermediate azide in the preparation of
To a mechanically stirred solution of the acid 2 (70.60 g, ca. 3 was not sufficiently dried, the thermolysis in t-BuOH along
560.0 mmol) in anhydrous acetone (1.7 L), was added Et3N with tert-butylcarbamate 3 gave the 1,3-di(bicyclopropyl)urea
(76.2 g, 105.0 mL, 753.0 mmol) dropwise at −5 °C. After add- (5) in up to 50% yield. Compound 5 was isolated as a colorless
itional stirring at this temperature for 15 min, neat ethyl chloro- solid after deprotection of 3 with HCl/Et2O by evaporation of
formate (103.7 g, 91.0 mL, 956.0 mmol) was added at the same the mother liquor followed by recrystallization of the residue
temperature over a period of 30 min, and the resulting mixture from hexane/CHCl3; mp 159–161 °C. The structure of 5 was
was stirred at this temperature for an additional 2 h. Then a confirmed by X-ray crystal structure analysis [26]. 5: 1H NMR
solution of NaN3 (75.0 g, 1.0 mol) in H2O (200 mL) was added (300 MHz, CDCl3) δ 5.21 (br s, 2H, NH), 1.28–1.16 (m, 2H, 2
over a period of 1.5 h. The reaction mixture was stirred at 0 °C CH cPr-H), 0.73–0.61 (m AA'BB', 8H, 4 CH2, cPr-H),
for 1.5 h, concentrated under reduced pressure at 0 °C to about a 0.44–0.41 and 0.17–0.13 (m AA'BB', 8H, 4 CH2, cPr-H); 13C
half of the original volume, poured into ice-cold water (2 L), NMR (62.9 MHz, CDCl3) δ 158.8 (C), 33.9 (2 C), 15.5 (2 CH),
and the mixture extracted with diethyl ether (4 × 400 ml) and 12.6 (2 CH2), 2.8 (6 CH2); EIMS (70 eV) m/z: 219 (M+ − H),
pentane (2 × 350 ml). The combined organic solutions were 205 (M+ − H−CH2), 191 (M+ − H−C2H4), 124 (M+ −
washed with ice-cold water (2 × 400 mL), dried under stirring H−NC6H9), 96 (M+ − H−NC6H9−CO), 82 (M+
with MgSO4 at 0 °C for 1 h and concentrated under reduced H−NC6H9−CH2−CO).
−
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Beilstein J. Org. Chem. 2011, 7, 1003–1006.
15.Bertus, P.; Szymoniak, J. Synlett 2007, 1346–1356.
Acknowledgements
doi:10.1055/s-2007-980342
This work was supported by the Land Niedersachsen.
16.According to the SciFinder data bank, compound 4·HCl is commercially
available from ChemBridge Corporation and other suppliers, however,
at a price of 475 USD/g.
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