Facile synthesis of β-azidocyclopropanecarboxylates by MIRC reaction

Article abstract of DOI:10.1081/SCC-200057974

Two β-azidocyclopropanecarboxylates are readily synthesized from β-bromoalkyliden malonates via a Michael-initiated ring closure (MIRC) reaction in moderate yields, which are regarded as precursors of β-aminocyclopropanecarboxylic acids. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200057974

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Facile Synthesis of
β‐Azidocyclopropanecarboxylates
by MIRC Reaction
Jiangtao Su a , Guofu Qiu a , Shucai Liang a &
Xianming Hu a
a College of Pharmacy, Wuhan University, Wuhan,
China
Version of record first published: 17 Dec 2010.
To cite this article: Jiangtao Su , Guofu Qiu , Shucai Liang & Xianming Hu (2005):
Facile Synthesis of β‐Azidocyclopropanecarboxylates by MIRC Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:11, 1427-1433
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Synthetic Communicationsw, 35: 1427–1433, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057974
Facile Synthesis of
b-Azidocyclopropanecarboxylates by
MIRC Reaction
Jiangtao Su, Guofu Qiu, Shucai Liang, and Xianming Hu
College of Pharmacy, Wuhan University, Wuhan, China
Abstract: Two b-azidocyclopropanecarboxylates are readily synthesized from
b-bromoalkyliden malonates via a Michael–initiated ring closure (MIRC) reaction
in moderate yields, which are regarded as precursors of b-aminocyclopropane-
carboxylic acids.
Keywords: MIRC, cyclopropane, b-azido acid
The overwhelming importance of a-amino acids in biologically relevant
processes has also been manifested for many cyclopropane-containing deriva-
tives.[1] With the growing realization that some b-amino acids also display
significant biological activities[2] and because the latter are valuable constitu-
ents in peptides, b-cyclopropyl-substituted analogues have attracted wide-
spread attention in recent years. In addition, cyclopropyl-modified
b-alanines have been proved to be useful intermediates in organic syntheses
and make use of the amino, the carboxyl, and the cyclopropyl group as
reactive functionalities.[3]
Azido acids are versatile precursors for natural and nonnatural amino
acids and can be incorporated into peptides and subsequently reduced to
amino acids.[4] There are possibilities that b-azido acid 1 can be fused
directly with a cyclopropane ring: the cyclopropyl group can be placed like
Received in Japan December 14, 2004
Address correspondence to Xianming Hu, College of Pharmacy, Wuhan University,
Wuhan, China. E-mail: jiangtsu@yahoo.com.cn
1427

1428
J. Su et al.
two geminal substituents in the a position of 1 as depicted in 2, or incorporat-
ing the a and b positions as shown in 3.
Of the methods available in the synthesis of cyclopropanes, the Michael-
initiated ring closure (MIRC) reaction was used to synthesize 1-amino-
cyclopropanecarboxylic acids.[5] It could be facile to synthesis of
2,2-dimethylcyclopropanes in mild conditions.
As the name of the reaction indicates, the process is started by a Michael
addition of a nucleophile to an olefin, which is doubly activated by electron-
withdrawing groups (EWG) in the a position and a leaving group (X) in the g
position. The intermediate carbanion produced by the addition of the nucleo-
phile is thought to displace the leaving group to give the desired cyclopropane.
It has been suggested that the mechanism of MIRC reactions of this type
involve a nucleophilic displacement of the intermediate carbanion regardless
of whether a primary, secondary, or tertiary halide is used. An SN2 displace-
ment may be operating with primary and possibly secondary halides, but
cyclopropanes are often the only product for tertiary halides (see Scheme 1).
Not all the nucleophiles could be applied in the MIRC reaction. Some
reported nucleophiles, such as sodium methoxide, potassium cyanide,
sodium thiophenoxide, and sodium phenoxide, were chosen and correspond-
ing cyclopropane derivatives were obtained. In recently years, alkyl imidazo-
lyl sulfoxides[6] and P(OR)3[7] were reported and the mechanisms were studied
as new nucleophiles. In the MIRC reaction, some carbon–oxygen, carbon–
carbon, and carbon–sulfur bonds could be formed in the cyclopropane
skeleton, except for carbon–nitrogen bond. Only exclusively substitution
products were obtained when primary and secondary amines were used as
nucleophiles.[8] The MIRC reaction was affected by the stability of substituted
Scheme 1.

Synthesis of b-Azidocyclopropanecarboxylates
1429
cyclopropane. Donor electrons of nitrogen are the major reason of instability
of donor-acceptor substituted cyclopropanes.[3] There are two other successful
examples: one is the synthesis of aminopurine-substituted cyclopropane
by MIRC reaction,[9] another is 4-formylimidazole as a nitrogen nucleo-
phile.[10] That is because of the absence of a lone electron in the related
reaction system, which has been involved in the conjugated system (see
Scheme 1).[9]
NaBH4 and LiAlH4 were also used as nucleophiles, and corresponding
substituted cyclopropanes were obtained. The cyclopropane 1 from
diethyl 2-bromo-2-methyl-propylidene malonate offered a simple but
most effective entry into a-2,2-dimethylcyclopropane-b-azido acid 5.
Monoester 2 could be obtained by hydrolysis in alkali solution and sub-
sequently reduced to give 3 by reduction of a mixed anhydride.
Hydroxy group was converted to azido group easily when PBr3 or MsCl
was used (see Scheme 2).
In the work, sodium azide serves as a good nucleophile group reacted by
the MICR reaction. The azidocyclopropane 6 was also obtained when the
diethyl 2-bromo-2-methyl-propylidene malonate and one equivalent of
NaN3 were refluxed in ethanol for 10–12 h in moderate yields. The crude
product 6 could be obtained by chromatography over silica gel. It is
hazardous to distill because azide compounds can explode. When cyanoace-
tate was used, 6b was also obtained (see Scheme 3).
However, nearly all the attempts to reduce the azido group into the amino
group were not successful when ester existed, because of cyclopropane ring
opening. Reduction of the carbonyl group (ester and acid) and azido group
at the same time by strong reductants such as LiAlH4 also failed. After sapo-
nification, selective reduction of monoester 7 could proceed in good yield.
Using NaBH4/CaCl2 in EtOH as the reducing agent, the b-azidocyclopropane
acid 8 was obtained. The compound 9 was prepared by reduction of a mixed
anhydride[11] (see Scheme 4).
In our research for b-cyclopropane amino acids, especially peptides, these
new cyclopropane derivatives as a new series of cyclopropane frameworks
were useful building blocks in pharmaceutical design.
Scheme 2. (a) NaBH4, EtOH, rt; (b) NaOH, EtOH, rt; (c) CICOOH3, NaBH4, 2788C;
(d) PBr3, Pyr; (e) NaN, DMF.

1430
J. Su et al.
Scheme 3. (a) Piperidine, acetic acid, benzene; (b) NBS, AIBN, CCI4; (c) NaN3, EtOH,
reflux.
EXPERIMENTAL
Analytical Instrument
Melting points were uncorrected XT-4 melting point measurement and uncor-
rected. H1NMR spectra were recorded using Varian Mercury VX-300
(300 MHz) spectrometer in CDCl3 solution with TMS as internal standard.
IR spectra were measured on KBr plates with 170-SX-FT-ir spectrometer.
Knoevenagel condensation of aldehydes with ethyl malonate in benzene
in the presence of piperidine acetate gave diethyl alkylidenemalonates, which
were brominated with N-bromo succinimide (NBS). The product bromo-
alkyliden malonate could be used without further purification.
Ethyl 2-azido-3,3-dimethylcyclopropanedicarboxylate 6a: A mixture
of bromoalkyliden malonate (24.86 g, 84.8 mmol) and sodium azide (5.52 g,
84.9 mmol) in ethanol (150 mL) was reflux for 8 h. During this time,
reaction progress was monitered by TLC. When the starting materials dis-
appeared, most of the ethanol was removed under reduced pressure. Then
the mixture was poured into ice water and extracted by dichloromethane
(3 Â 50 mL). The organic phase was washed with water and brine and dried
by MgSO4. After concentration and purification by column chromatography
on silica gel (ethyl acetate/petroleum ether 1:6), the light green liquid
1
product 6a (16.97 g, 78.4%) was obtained. IR (film) cm21: 1728, 2112. H
Scheme 4. (d) NaOH, EtOH, rt; (e) Ca(BH4)2, EtOH, rt; (f) CICOOCH3, NaBH4,
2788C THF; (g) SOCI2, EtOH.

Synthesis of b-Azidocyclopropanecarboxylates
1431
NMR (300 Hz, CDCl3, ppm): 1.220, 1.256 (dd, 6H, 2 Â 22CH3), 1.298–1.252
(t, 6H, 22CH3, J ¼ 13.8), 3.651 (s, 1H, 22CH22), 4.211–4.243 (m, 4H,
22CH222, J ¼ 4.9). 13C NMR (CDCl3, ppm): 14.150 (22CH2CH3), 14.17
(22CH2CH3), 17.95 (22CH3), 19.58 (22CH3), 30.82 (22CH-N3), 42.80
[22C(COOEt)2], 51.67 (22CMe2), 61.50 (22CH2CH3), 61.97 (22CH2CH3),
165.35 (22COOEt), 167.45 (22COOEt).
Ethyl 1-cyano-2-azido-3,3-dimethylcyclopropanecarboxylate 6b: 6b
was obtained by a similar procedure. 72.6%. IR (film) cm21: 1728, 2112,
1
2244. H NMR (300 Hz, CDCl3, ppm): 1.203, 1.159 (s, 6H, 2 Â 22CH3),
1.350 (t, 3H,22CH3), 3.675 (s, 1H,22CH22), 4.210–4.264 (m, 2H,22CH222).
2-Azido-3,3-dimethyl-1-(ethoxycarbonyl)cyclorpoane-1-dicarboxylic
acid 7: To a solution of diethyl 2,2-dimethylcyclopropane-1,1-dicarboxylic
ester 6a (17.65 g, 69.2 mmol) in EtOH (70 mL) was added 1 N aqueous
NaOH (70 mL). After stirring for 12 h at room temperature, ethanol was evap-
orated in vacuo. The residual was added to water (20 mL) and then extracted
by ether (2 Â 20 mL). The water layer was acidified by means of a saturated
KHSO4 solution and extracted with EtOAc (3 Â 20 mL). The combined
extracts were dried (MgSO4) and evaporated to give monoester 7 (8.48 g,
1
54%). Crystal mp 108–1108C. IR (KBr) cm21: 1745, 1694, 2117. H NMR
(300 Hz CDCl3, ppm): 1.262, 1.315 (dd, 6H, 2 Â 22CH3), 1.356 (t, 3H,
22CH3), 3.781–3.814 (d 1H, 22CH22), 4.255–4.298 (m, 4H,
2 Â 22CH222), 10.863(br, 1H, 22COOH). 13C NMR (CDCl3, ppm): 14.196
(22CH2CH3), 18.296 (22CH3), 19.631 (22CH3), 32.818 (22CH22N3),
42.627 (22C22COOEt), 52.777 (22CMe2), 62.192 (22CH2CH3), 165.592
(22COOEt), 173, 438 (22COOH).
Ethyl 2-azido-3,3-dimethyl-1-(hydroxymethyl)cyclorpoane-1-carbox-
ylate 9: Et3N (3.2 mL) was added at 08C to a stirred solution of monoester 7
(3.54 g, 15.59 mmol) in THF (30 mL), and then methyl chloroformate
(1.2 mL) was introduced dropwise at the same temperature. The reaction
was allowed to proceed for 1 h, and then the reaction mixture was filtered
and the precipitate was washed with cooled THF. Filtrate was cooled to
2788C, NaBH4 (2.36 g, 62.4 mmol) was introduced portionwise, and
methanol (10 mL) was added dropwise over 30 min. After 1 h more at the
same temperature, the cooling bath was removed and 10% HCl solution
was added slowly until no residual NaBH4 remained. Evaporation of THF,
extravtion with CH2Cl2 (3 Â 20 mL), drying (MgSO4), evaporation, and
column chromatography on silica gel (ethyl acetate/petroleum ether 1:6)
provided the colorless liquid 9: (2.97 g, 89.6%). IR (film) cm21: 3431,
1
2107, 1728. H NMR: 4.276–4.071 (m, 2H, 22CH222), 3.878–3.836 (d, H,
22CH2O, J ¼ 12.3), 3.707–3.666 (d, H, 22CH2O, J ¼ 12.3), 2.560
(s, broad, H, OH, D2O-disappear), 3.058 (s, H, 22CH22N3), 1.345–1.166
(m, 3H, 22CH2CH3), 1.211 (s, 3H,22CH3), 1.255 (s, 3H,22CH3).
2-Azido-3,3-dimethyl-1-(hydroxymethyl)cyclorpoane-1-carboxylic
acid 8: A solution of KOH (1.08 g, 19.2 mmol) and of CaCl2 (4.3 g,
38.7 mmol) in EtOH (30 mL) was mixed to a solution of monoester 7

1432
J. Su et al.
(1.7 g, 7.49 mmol) in EtOH (10 mL). The mixture was cooled to 08C and then
suspension of NaBH4 (2 g, 52.88 mmol) in EtOH (20 mL) was added with
stirring. The reaction was allowed to proceed for 17 h at rt, then cooled to
08C. Addition of 10% HCl solution at the same temperature to attain pH2–3,
evaporation of EtOH, adding of water, saturation with NaCl, extraction with
CH2Cl2, drying (MgSO4), and then evaporation provided practically pure 8
(0.95 g, 68.6%) as an oil that crystallized slowly upon standing. Mp 82–
1
838 C. IR (KBr) cm21: 3372, 2104, 1693. H NMR (300 Hz, CDCl3, ppm):
1.291 (s, 3H, 22CH3), 1.258 (s, 3H, 22CH3), 3.665 (s, 1H, 22CH22), 3.885–
3.801 (d, H, 22CH255, J ¼ 12.3), 4.029–3.988 (d, H, 22CH222, J ¼ 12.3).
13C NMR (CDCl3, ppm): 176.6 (22COOH), 59.81 (22CH222OH),
52.02(22CMe2), 39.26 (22C22COOH), 31.47(22CH-N3), 21.79(22CH3),
17.03 (22CH3).
Synthesis of ethyl 2,2-dimethyl-1-(azidomethyl)cyclorpoane-1-car-
boxylate 5: Bromoalkyliden malonate was the starting material and was
ring-closed with sodium borohydride in absolute ethanol to afford ethyl 2,
2-dimethylcyclopropane dicarboxylate 1. Then, 2, 3 were obtained after
monosaponification and reduction by a similar procedure. To a solution of 3
in anhydrous methylene chloride and dried pyridine was added PBr3
dropwise at 08C. The mixture was stirred at room temperature overnight.
After the usual workup, light oil 4 was obtained. Then, a solution of 4 in
DMF was treated with NaN3 at room temperature for 6 h and 5 was obtained:
2: Colorless oil. 64%. IR (film) cm21: 3090–2642, 1730, 1689. 1H NMR:
8.275 (s, broad, H, OH),4.302–4.174 (m, 2H, 22CH2CH3), 1.791–1.711
(m, 3H, 22CH2CH3), 1.279 (s, 3H, 22CH3), 1.325 (s, 3H, 22CH3), 1.181–
1.259 (m, 2H, 22CH222).
1
3: colorless liquid. 80.6%. IR (film) cm21: 3461, 1717, 1030. H NMR:
2.751 (s, broad, H, 22OH, D2O-disappear), 4.193–4.123 (m, 2H,
22CH2CH3, J ¼ 14.1), 1.162 (s, 3H, 22CH3,), 1.271 (s, 3H, 22CH3), 1.205–
1.260 (m, 3H, 22CH3), 3.958–3.918 (m, H, 22CH2O, J ¼ 12), 3.546–3.582
(m, H, 22CH2O, J ¼ 12), 1.348–1.333 (d, H, 22CH222), 0.681–0.667
(d, H, 22CH222, J ¼ 4.2).
5: colorless liquid. 69.3%. IR (KBr) cm21: 2110, 1734. 1H NMR (300 Hz,
CDCl3, ppm): 1.119 (s, 3H, 22CH3), 1.165(s, 3H, 22CH3), 0.702–0.686(d, H,
22CH222, J ¼ 4.8), 1.426–1.411(d, H, 22CH222, J ¼ 4.8), 1.236–1.212
(t, 3H, 22CH3, J ¼ 3.6), 4.152–4.113 (m, 2H, 22CH222, J ¼ 4.8), 3.374–
3.418 (d, H, 22CH222,J ¼ 13.2), 3.591–3.635 (d, H, 22CH222, J ¼ 13.2).
REFERENCES
1. (a) Salaun, J. Top. Curr. Chem. 2000, 207, 1; (b) Cativiela, C.; Diaz-de-
Viellgas, M. D. Tetrahedron: Asymmetry 2000, 11, 645.
2. Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117.
3. Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603.

Synthesis of b-Azidocyclopropanecarboxylates
1433
4. Meldal, M.; Juliano, M. A.; Jansson, A. M. Tetrahedron Lett. 1997, 38, 2531.
5. (a) De Kimpe, N.; Boeykens, M. J. Org. Chem. 1994, 59, 8215; (b) Salgado, A.;
Huybrechts, T.; De Kimpe, N. Tetrahedron 2001, 57, 2781.
6. (a) Rambaud, R. Compt. Rend. 1949, 228, 1595; (b) Casey, M.; Keaveney, C. M.;
Walker, A. J. ARKIVOC 2002, 1, 91.
7. Stevens, C. V.; Van Heecke, G.; Barbero, C. Synlett 2002, 1089.
8. Verhe, R.; De Kimpe, N.; De Buyck, L.; Courtheyn, D.; Schamp, N. Bull. Soc.
Chim. Belg. 1977, 86, 55.
9. Geen, G. R.; Kincey, P. M.; Choudary, B. M. Tetrahedron Lett. 1992, 33, 4609.
10. Su, Q.; Wood, J. L. Synth. Commun. 2000, 30, 3383.
11. Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647.