Simple and efficient procedure for a multigram synthesis of both trans - And cis -1-Amino-2-(trifluoromethyl)cyclopropane-1-carboxylic Acid

Article abstract of DOI:10.1055/s-0029-1217141

A simple and efficient procedure for the multigram synthesis of both (±)-trans- and (±)-cis-1-amino-2-(trifluoromethyl)cyclopropane-1- carboxylic acid was developed. The key step of the synthesis is the addition of 1-diazo-2,2,2-trifluoroethane to methyl 2-[(tert-butoxycarbonyl)amino]acrylate, followed by thermal decomposition of the resulting pyrazoline. Gram quantities of trans- and cis-1-amino-2-(trifluoromethyl)cyclopropane-1-carboxylic acid were easily prepared from l-serine in one synthetic run. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217141

PAPER
443
Simple and Efficient Procedure for a Multigram Synthesis of Both trans- and
cis-1-Amino-2-(trifluoromethyl)cyclopropane-1-carboxylic Acid
1
-Amino-2-(trifluo
l
rometh
e
yl)cyclopro
x
pane-1-carb
ioxylic
y
Acid S. Artamonov,a,b Pavel K. Mykhailiuk,*a,b Nataliia M. Voievoda,a,b Dmitry M. Volochnyuk,b,c
Igor V. Komarova,b
a
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska St. 64, 01033 Kyiv, Ukraine
Enamine Ltd., Oleksandra Matrosova St. 23, 01103 Kyiv, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska St. 5, 02660 Kyiv-94, Ukraine
b
c
Fax +380(44)2351273; E-mail: pashamk@gmx.de
Received 30 September 2009; revised 20 October 2009
milligram scale only (50 mg of 1a, 5 steps, 20% overall
Abstract: A simple and efficient procedure for the multigram syn-
thesis of both ( )-trans- and ( )-cis-1-amino-2-(trifluoromethyl)cy-
clopropane-1-carboxylic acid was developed. The key step of the
synthesis is the addition of 1-diazo-2,2,2-trifluoroethane to methyl
yield; 5 mg of Boc-1b, 6 steps, 5% overall yield).7b,c In
addition, several steps of the abovementioned synthesis
included the use of butyllithium, sodium hydride, and so-
2-[(tert-butoxycarbonyl)amino]acrylate, followed by thermal de- dium hexamethyldisilazide, which require great caution,
composition of the resulting pyrazoline. Gram quantities of trans-
thereby making the scale-up procedure rather unlikely. In
2003, another strategy to ( )-1a was described.7d Howev-
er, in that publication neither detailed experimental de-
tails, nor the scale of the synthesis was given. Recently,
we reported a new approach to both ( )-1a and ( )-1b
(Scheme 1).7e
and
cis-1-amino-2-(trifluoromethyl)cyclopropane-1-carboxylic
acid were easily prepared from L-serine in one synthetic run.
Key words: fluorine, alkenes, amino acids, catalysts, diazo com-
pounds
1-Aminocyclopropane-1-carboxylic acid (Acc, Figure 1)
is a natural compound isolated first from cider apples and
perry pears.1 Since its identification as the intermediate in
the biosynthesis of ethylene,2 Acc has been of consider-
able interest to biologists and chemists alike.3 Moreover,
in recent years Acc has attracted much attention in medic-
inal chemistry as a valuable building block.4 In addition,
derivatives of Acc have been used as enzyme inhibitors
and biosynthetic and mechanistic probes.5 On the other
hand, introduction of fluorine-containing substituents into
Acc could advantageously modify its properties by chang-
ing the chemical stability and electronic effects.6 Little is,
however, known to date on the fluorinated analogues of
Acc.7 Therefore, in the present work we wish to report a
simple and efficient procedure for the practical multigram
synthesis of trifluoromethyl-substituted analogues of Acc:
isomeric amino acids 1a and 1b (Figure 1).
a
CF3
CF3
+
AcHN
AcHN
23%
AcHN
CO2Me
CO2Me
CO2Me
2a
2b
3
CF3
CF3
H2N
H2N
COOH
COOH
1a
1b
Scheme 1 Reagents and conditions: (a) Rh2(OAc)4, CF3CHN2 (5
equiv), CH2Cl2.
However, the isomers 2a/2b were obtained in milligram
quantities, with the key transformation 3→2a/2b per-
formed with a yield of only 23%.7e Moreover, this proce-
dure required the use of rather expensive dirhodium(II)
tetraacetate (Scheme 1). Therefore, as reported here, we
have optimized the abovementioned strategy in order to
easily obtain both ( )-1a and ( )-1b in multigram quanti-
ties from L-serine without use of rhodium reagents.
CF3
CF3
H2N
H2N
H2N
COOH
Acc
COOH
COOH
1a
1b
Since the dirhodium(II) tetraacetate mediated addition of
1-diazo-2,2,2-trifluoroethane to alkene 3 led to 2a/2b in
very poor yield (Scheme 1),7e a ‘pyrazoline strategy’4a,7a,8
was attempted next (Scheme 2). Indeed, 1-diazo-2,2,2-tri-
fluoroethane reacted smoothly with 3 at room temperature
to form pyrazoline 4, which was thermally decomposed to
afford an isomeric mixture of 2a and 2b in an overall yield
of 86%.
Figure 1 1-Aminocyclopropane-1-carboxylic acid (Acc) and its
trifluoromethyl-substituted analogues 1a and 1b
Several syntheses of 1a and 1b have been described in the
literature. In 2000, Uneyama et al. reported the first stereo-
selective approach to optically active 1a and 1b, but on a
SYNTHESIS 2010, No. 3, pp 0443–0446
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217141; Art ID: Z20409SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0
However, although isomers 2a and 2b were previously
separated by flash column chromatography on the milli-
gram scale, separation of gram quantities of 2a/2b turned

444
O. S. Artamonov et al.
PAPER
carbonyl group afforded the final amino acids 1a (19 g)
and 1b (5 g) (Scheme 5).
CF3
CO2Me
CF3
CO2Me
+
AcHN
AcHN
AcHN
CO2Me
3
2a
2b
b
a
CF3
CO2Me
CF3
COOH
8a
CF3
COOH
1a⋅HCl
BocHN
BocHN
H2N
CF3
82%
96%
a
b
N
7a
86% (from 3)
N
AcHN
CO2Me
b
a
CF3
CO2Me
CF3
COOH
CF3
COOH
4
BocHN
BocHN
H2N
76%
93%
Scheme 2 Reagents and conditions: (a) CF3CHN2 (5 equiv),
CH2Cl2; (b) 70 °C, 1 h.
7b
8b
1b⋅HCl
Scheme 5 Reagents and conditions: (a) 1. LiOH (4 equiv), MeOH,
2 h; 2. HCl; (b) HCl, 65 °C, 2 h.
out to be completely ineffective, because of a too small
difference in their retention factors (Rf; see the experimen-
tal section). To facilitate a practical separation of the dia-
stereomers, we replaced the acetyl residue in 2a/2b with
the much bulkier N-protecting group tert-butoxycarbonyl.
The corresponding starting compound 5 was easily ob-
tained from L-serine in 77% yield by following literature
procedures9 (Scheme 3).
The stereoconfiguration of the amino acids thus obtained
was determined by NOESY experiments of compound 8b
(Figure 2).10
H
CO2Me
H
strong NOE
weak NOE
F3C
Boc
N
H
HO
H
a–d
8b
77%
H2N
COOH
BocHN
CO2Me
Figure 2 Determination of the stereochemistry of 8b by H,H-NOE-
SY experiments
L-serine
5
Scheme 3 Reagents and conditions: (a) SOCl2, MeOH, 20 h, r.t.; (b)
Boc2O (1.2 equiv), Et3N (2.5 equiv), CH2Cl2, r.t., 3 h; (c) Boc2O
(2.2 equiv), DMAP (0.1 equiv), MeCN, r.t., 12 h; (d) TFA (1.5 equiv),
CH2Cl2, r.t., 12 h.
In conclusion, we have developed a simple and efficient
procedure for the multigram synthesis of both ( )-trans-
and ( )-cis-1-amino-2-(trifluoromethyl)cyclopropane-1-
carboxylic acids (1a/1b). Thus, 1a (19 g) and 1b (5 g)
were easily synthesized from L-serine in one synthetic
run.
Next, the reaction of alkene 5 with 1-diazo-2,2,2-trifluo-
roethane to form pyrazoline 6 was carried out (Scheme 4).
Subsequently, thermal decomposition of 6 afforded the
mixture 7a/7b (4:1) in 65% yield. Separation of ca. 45 g
of 7a/7b was easily performed by flash column chroma-
tography, since the retention factors of isomers 7a/7b in-
deed had a larger difference than those of the cyclo-
propanes 2a/2b (see the experimental section).
Solvents were purified according to standard procedures. Alkenes
3
11 and 59 were synthesized from L-serine by following procedures
described in the literature. All other materials were purchased from
Aldrich and Enamine. Melting points are uncorrected. Analytical
TLC was perfomed on Polychrom SI F254 plates. Column chroma-
tography was performed on Kieselgel Merck 60 (230–400 mesh) as
the stationary phase. 1H-, 13C-, and 19F NMR spectra were recorded
either on a Varian Unity Plus 400 spectrometer (at 400.4, 100.7, and
376.7 Hz, respectively) or on a Bruker Avance 500 spectrometer (at
499.9 MHz, 124.9, and 470.3 MHz, respectively). Chemical shifts
are reported in ppm downfield from TMS (1H, 13C) or CFCl3 (19F)
as internal standards. IR spectra were obtained on a Hewlett Pack-
ard UR 20 spectrometer. Mass spectra by the CI method were re-
corded on an Agilent 1100 LCMSD SL instrument.
CF3
CO2Me
CF3
CO2Me
+
BocHN
BocHN
BocHN
CO2Me
5
7a
7b
CF3
a
b
N
N
65% (from 5)
Methyl 3-(Acetylamino)-5-(trifluoromethyl)-4,5-dihydro-3H-
pyrazole-3-carboxylate (4)
BocHN
CO2Me
A soln of CF3CHN2·HCl (116 g, 1.68 mol, 5 equiv) in H2O (150
mL) was slowly added (~5–7 h) to a stirred mixture of a soln of
NaNO2 (227 g, 1.68 mol, 5 equiv) in H2O (300 mL) and dodecane
(200 mL). Upon addition, the CF3CHN2 that had formed was grad-
ually blown off by an inert gas through a drying tube (MgSO4) into
a vessel containing a stirring soln of 3 (48 g, 335 mmol, 1 equiv) in
CH2Cl2 (200 mL). After the addition had been completed, the sol-
vent was gently removed on a rotary evaporator in vacuum at r.t.;
this gave crude 4.
6
Scheme 4 Reagents and conditions: (a) CF3CHN2 (5 equiv),
CH2Cl2; (b) 70 °C, 1 h.
Finally, basic hydrolysis of the methoxycarbonyl group,
followed by a standard acidic cleavage of the tert-butoxy-
Synthesis 2010, No. 3, 443–446 © Thieme Stuttgart · New York

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1-Amino-2-(trifluoromethyl)cyclopropane-1-carboxylic Acid
445
Yield: 84 g (100%); white solid; mp >40 °C (dec).
19F NMR (470 MHz, CDCl3): d = –61.48 (br s, CF3).
1H NMR (500 MHz, CDCl3): d = 7.36 (br s, 1 H, NH), 5.82 (m, 1 H,
CHCF3), 3.87 (s, 3 H, OCH3), 2.25 (dd, J = 13.5, 10.0 Hz, 1 H,
CH2), 2.09 (dd, J = 13.5, 7.0 Hz, 1 H, CH2), 2.05 (s, 3 H, CH3CO).
MS (CI): m/z = 284 [M + 1]+.
( )-Methyl (1S,2S)-1-[(tert-Butoxycarbonyl)amino]-2-(trifluo-
romethyl)cyclopropane-1-carboxylate (7b)
Yield: 9 g (14% from 5); white solid; Rf = 0.3; mp 53–54 °C.
IR (KBr): 1737 (nC=O, CO2Me), 1695 (nC=O, NHBoc) cm–1.
1H NMR (500 MHz, CDCl3): d = 5.10 (br s, 1 H, NH), 3.75 (s, 3 H,
OCH3), 2.45 (m, 1 H, CHCF3), 1.96 (m, 1 H, CHH), 1.79 (m, 1 H,
CHH), 1.43 (s, 9 H, (CH3)3C).
13C NMR (125 MHz, DMSO-d6): d (rotamers) = 167.44 (s,
COOMe), 156.03 (s, NCO), 126.23 (q, J(C,F) = 272.3 Hz, CF3),
79.22 (s, OC(CH3)3), 53.14 (s, OCH3), 37.86 (s, NCCOOH), 28.52,
28.17 (2 s, OC(CH3)3), 25.85 (2J(C,F) = 36.5 Hz, CHCF3), 16.95 (s,
CH2).
13C NMR (125 MHz, CDCl3): d = 169.46 (s, COO), 167.57 (s,
CONH), 123.61 (q, 1J(C,F) = 278.8 Hz, CF3), 102.82 (s, NHCCO),
2
93.10 (q, J(C,F) = 28.8 Hz, CHCF3), 54.44 (s, OCH3), 25.70 (s,
CH2), 23.44 (s, CH3CO).
19F NMR (470 MHz, CDCl3): d = –72.09 (s, CF3).
MS (CI): m/z = 226 [M – N2 + 1]+.
1
Methyl 1-(Acetylamino)-2-(trifluoromethyl)cyclopropane-1-
carboxylate (2a/2b)
After the CH2Cl2 had been completely removed during the isolation
of 4 (see the previous step), the temperature of the water bath was
increased to 50–70 °C; this led to exothermic evolution of N2. After
4 had been heated at 70 °C for 1 h, the reaction was completed to
form cyclopropanes 2a/2b.
19F NMR (470 MHz, CDCl3): d = –49.04 (d, J(F, H) = 4.7 Hz,
CF3).
MS (CI): m/z = 284 [M + 1]+.
3
Although small quantities (mg scale) of 2a/2b had been separated
by flash column chromatography,7e the difference between the Rf
values of 2a and 2b was too small to make separation feasible for
gram quantities of 2a/2b [Rf difference <0.05; Rf = ~0.4 (CH2Cl2–
MeOH, 5:1)].
( )-(1S,2R)-1-[(tert-Butoxycarbonyl)amino]-2-(trifluorometh-
yl)cyclopropane-1-carboxylic acid (8a)
LiOH·H2O (20 g, 476 mmol, 4 equiv) was slowly added to a stirring
soln of 7a (34 g, 117 mmol, 1 equiv) in MeOH–THF (3:4, 1.4 L).
The mixture was then stirred for 3 h at r.t. and evaporated to produce
a yellowish solid. The mixture thus formed was dissolved in H2O
(~500 mL) and extracted with CH2Cl2 (3 × 70 mL). The organic
phase was discarded and the aqueous phase was acidified to pH 4
by use of aq HCl. The thus formed suspension was extracted again
with EtOAc (3 × 100 mL). The organic phase was separated, dried
over Na2SO4, and evaporated to produce 8a.
Total yield: 65 g (86%); oil.
LC-MS (CI): m/z = 226 (2 peaks) [M + 1]+.
Methyl 3-[(tert-Butoxycarbonyl)amino]-5-(trifluoromethyl)-
4,5-dihydro-3H-pyrazole-3-carboxylate (6)
Crude 6 was obtained from alkene 5 (46 g, 229 mmol) analogously
to the synthesis of 4 from alkene 3. It was immediately used in the
next step without purification.
Yield: 26 g (82%); white solid; mp 152–153 °C.
White solid; mp >40 °C (dec).
1H NMR (500 MHz, CDCl3): d = 2.19 (m, 2 H, CH2), 1.62 (m, 1 H,
CHCF3), 1.46 (s, 9 H, (CH3)3C).
13C NMR (125 MHz, DMSO-d6): d = 171.70 (s, COOMe), 156.22
(s, NCO), 125.42 (q, 1J(C,F) = 272.9 Hz, CF3), 79.02 (s,
OC(CH3)3), 38.47 (s, NCCOOH), 29.53 (q, 2J(C,F) = 37.7 Hz,
CHCF3), 28.59 (s, OC(CH3)3), 18.71 (s, CH2).
1H NMR (500 MHz, CDCl3): d = 6.48 (br s, 1 H, NH), 5.79 (m, 1 H,
CHCF3), 3.86 (s, 3 H, OCH3), 2.24 (dd, J = 13.5, 9.0 Hz, 1 H, CH2),
2.13 (dd, J = 13.5, 7.0 Hz, 1 H, CH2), 1.39 (s, 9 H, (CH3)3C).
MS (CI): m/z = 284 [M – N2 + 1]+.
( )-Methyl Cyclopropanecarboxylates 7a and 7b
19F NMR (470 MHz, DMSO-d6): d = –62.39 (br s, CF3).
MS (CI): m/z = 270 [M + 1]+.
The crude mixture 7a/7b was obtained from pyrazoline 6 (71 g, 229
mmol) by the same procedure applied for preparing 2a/2b from 4.
To remove impurities of the alkenes that had formed, the crude 7a/
7b mixture was dissolved in CH2Cl2 (700 mL), triturated with 10%
aq KMnO4 (1 L), washed with H2O (1 L), dried over MgSO4, and
evaporated. The diastereomeric mixture 7a/7b (~45 g) was separat-
ed by flash column chromatography (silica gel, hexane–EtOAc,
10:1). For an efficient separation of the whole quantity of 7a/7b, ~1
kg silica gel was used. The isomer 7a (51% from 5) eluted first
(Rf = 0.4). Further elution afforded isomer 7b (Rf = 0.3) (14% from
5).
( )-(1S,2S)-1-[(tert-Butoxycarbonyl)amino]-2-(trifluorometh-
yl)cyclopropane-1-carboxylic acid (8b)
Compound 8b was obtained from 7b (9 g, 32 mmol) by an analo-
gous method to that used to obtain 8a from 7a.
Yield: 6.5 g (76%); white solid; mp 157–158 °C.
1H NMR (500 MHz, CDCl3): d = 5.14 (NH), 2.50 (br s, 1 H,
CHCF3), 2.00 (br s, 1 H, CHH), 1.80 (br s, 1 H, CHH), 1.46 (s, 9 H,
(CH3)3C).
13C NMR (125 MHz, DMSO-d6): d (rotamers) = 171.90, 171.68 (2
s, COOMe), 156.00, 155.33 (2 s, NCO), 125.35 (q, 1J(C,F) =
271.6 Hz, CF3), 78.93 (s, OC(CH3)3), 38.55, 37.66 (2 s, NCCOOH),
28.56, 28.19 (2 s, OC(CH3)3), 25.62 (q, 2J(C,F) = 32.7 Hz, CHCF3),
16.79 (s, CH2).
19F NMR (470 MHz, DMSO-d6): d = –61.48 (br s, CF3).
MS (CI): m/z = 270 [M + 1]+.
( )-Methyl (1S,2R)-1-[(tert-Butoxycarbonyl)amino]-2-(trifluo-
romethyl)cyclopropane-1-carboxylate (7a)
Yield: 33 g (51% from 5); Rf = 0.4 (hexane–EtOAc, 10:1; white sol-
id; mp 53–54 °C.
IR (KBr): 1730 (br, nC=O) cm–1.
1H NMR (500 MHz, CDCl3): d = 5.33 (br s, 1 H, NH), 3.75 (s, 3 H,
OCH3), 2.18 (m, 2 H, CH2), 1.61 (m, 1 H, CHCF3), 1.43 (s, 9 H,
(CH3)3C).
( )-(1S,2R)-1-Carboxy-2-(trifluoromethyl)cyclopropylammo-
nium Chloride (1a)
An 8 N aq soln of HCl (45 mL) was added to a soln of 8a (26 g, 96
mmol) in THF (200 mL). The stirred mixture was heated for 2 h at
65 °C. After cooling to r.t., the reaction mixture was washed with
13C NMR (125 MHz, CDCl3): d = 168.79 (s, COOMe), 155.36 (s,
1
NCO), 125.13 (q, J(C,F) = 269.1 Hz, CF3), 80.92 (s, OC(CH3)3),
52.84 (s, OCH3), 38.74 (s, NCCOOH), 31.33 (br s, CHCF3), 28.16
(s, OC(CH3)3), 18.72 (s, CH2).
Synthesis 2010, No. 3, 443–446 © Thieme Stuttgart · New York

446
O. S. Artamonov et al.
PAPER
EtOAc (3 × 70 mL). The organic phase was discarded, and the
aqueous phase was evaporated in vacuum; this produced 1a·HCl.
(4) (a) Stammer, C. H. Tetrahedron 1990, 46, 2231.
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4493. (g) Brackmann, F.; de Meijere, A. Chem. Rev. 2007,
107, 4538.
Yield: 19 g (96%); white solid; mp >200 °C.
1H NMR (500 MHz, D2O): d = 2.57 (m, 1 H, CHCF3), 2.11 (t,
J = 8.0 Hz, 1 H, CHH), 1.35 (tq, J = 9.0, 1.5 Hz, 1 H, CHH).
13C NMR (125 MHz, D2O): d = 168.38 (s, COOH), 123.55 (q,
3
1J(C,F) = 271.3 Hz, CF3), 37.74 (q, J(C,F) = 2.5 Hz, NCCOOH),
2
3
27.75 (q, J(C,F) = 40.0 Hz, CHCF3), 15.46 (q, J(C,F) = 2.5 Hz,
(5) (a) Baldwin, J. E.; Adlington, R. M.; Lajoie, G. A.;
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Tetrahedron 2001, 57, 6019.
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(10) The 1H NMR spectrum of the isomer 8b is identical to that
described in ref. 7b (see the experimental section).
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Asymmetry 1998, 9, 47.
CH2).
19F NMR (470 MHz, D2O): d = –60.82 (d, 3J(F,H) = 9.4 Hz, CF3).
MS (CI): m/z = 170 [M – Cl]+.
( )-(1S,2S)-1-Carboxy-2-(trifluoromethyl)cyclopropylammoni-
um Chloride (1b)
Compound 1b·HCl was obtained from 8b (6.5 g, 24 mmol) by an
analogous method to that used to obtain 1a·HCl from 8a.
Yield: 4.6 g (93%); white solid; mp 157–158 °C.
1H NMR (500 MHz, D2O): d = 2.77 (m, 1 H, CHCF3), 1.93 (t,
J = 8.0 Hz, 1 H, CHH), 1.83 (t, J = 8.0 Hz, 1 H, CHH).
13C NMR (125 MHz, D2O): d = 169.90 (s, COOH), 124.10 (q,
1J(C,F) = 272.9 Hz, CF3), 37.13 (s, NCCOOH), 24.75 (q,
2J(C,F) = 37.7 Hz, CHCF3), 15.02 (q, 3J(C,F) = 1.3 Hz, CH2).
19F NMR (470 MHz, D2O): d = –60.47 (d, 3J(F, H) = 9.3 Hz, CF3).
MS (CI): m/z = 170 [M – Cl]+.
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