Synthesis of isomeric 6-trifluoromethyl-3-azabicyclo[31.0]hexanes: Conformationally restricted analogues of 4-trifluoromethylpiperidine

Article abstract of DOI:10.1055/s-0032-1316831

Two isomeric conformationally restricted analogues of 4- trifluoromethylpiperidine were designed. The synthesis was performed in four steps from commercially available N-benzylmaleimide. The key reaction was the [3+2] cycloaddition between trifluoromethyl

Full text of DOI:10.1055/s-0032-1316831

PAPER
▌225
paper
Synthesis of Isomeric 6-Trifluoromethyl-3-azabicyclo[3.1.0]hexanes:
Conformationally Restricted Analogues of 4-Trifluoromethylpiperidine
6-Trifluoromethyl-3-azabicyclo[3.1.0]hexanes
Olexiy S. Artamonov,a Evgeniy Y. Slobodyanyuk,b,c Oleg V. Shishkin,d Igor V. Komarov,b,c Pavel K. Mykhailiuk*b,c
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv-94 02660, Ukraine
b
Enamine Ltd., Vul. Oleksandra Matrosova 23, 01103 Kyiv, Ukraine
E-mail: Pavel.Mykhailiuk@gmail.com
c
Department of Chemistry, and Kyiv National Taras Shevchenko University, Vul. Volodymyrska 64, Kyiv 01033, Ukraine
d
STC, ‘Institute for Single Crystals,’ National Academy of Science, 60 Lenina ave., Kharkiv 61001, Ukraine
Received: 02.11.2012; Accepted after revision: 29.11.2012
Piperidine ring is rather flexible, whereas conformational-
Abstract: Two isomeric conformationally restricted analogues of
ly restricted compounds are often more efficient and se-
4-trifluoromethylpiperidine were designed. The synthesis was per-
lective ligands for various targets compared to their
formed in four steps from commercially available N-benzylma-
flexible counterparts, due to fixation of the biologically
active conformation.8 3-Azabicyclo[3.1.0]hexane frag-
ment is frequently used in drug design as a conformation-
ally restricted analogue of the piperidine motif.9 Potent
antibacterial agent 4,9a selective muscarinic antagonist
5,9h and the launched antimicrobial trovafloxacine10 are
the representative examples of the successful application
of this concept (Figure 2).
leimide. The key reaction was the [3+2] cycloaddition between
trifluoromethyldiazomethane and N-benzylmaleimide.
Key words: amines, trifluoromethyl group, cyclopropane, 4-tri-
fluoromethylpiperidine, drug design
The piperidine motif is historically popular within medic-
inal chemistry. It is present in more than one hundred
FDA-approved drugs.1 Therefore, substituted piperidine
analogues are frequently used in drug discovery projects
as common starting materials. Most of them are substitut-
ed at the C-4 atom.2 It is not surprising therefore that 4-tri-
fluoromethylpiperidine has proven to be a valuable
building block in drug design.3 During the last decade it
has been successfully used in fifty medicinal projects4 re-
sulting in more than forty bioactive derivatives.5 Among
them are the potent dopamine D3 receptor antagonist 1,3c,g
the γ-secretase inhibitor 2,3b and the promising nootropic
agent 3,3a which have reached preclinical trials (Figure 1).
In all cases, the trifluoromethyl group6 served as a ‘meta-
bolically stable lipophilic group,’ which was involved in
the hydrophobic ligand-protein interactions,7 increasing
thereby the ligand binding efficiency.
Given the high pharmacological potential of 4-trifluoro-
methylpiperidine, its isomeric analogues 6a and 6b seem
to be interesting for drug discovery (Figure 3). They can
be formally considered as 4-trifluoromethylpiperidine,
which is ‘frozen’ at the different conformations by a sin-
gle C-3–C-5 bond. Importantly, this type of conforma-
tional restriction does not bring any elements of chirality
to the molecule, preserving its nonchiral structure. In this
work, we report on the synthesis of both the compounds
6a and 6b.
Retrosynthetic Analysis
Previously, it was shown that substituted trifluoromethyl-
cyclopropanes could be obtained in two steps from tri-
fluoromethyldiazomethane (CF3CHN2) and electron-
deficient alkenes.11 This tactic was also adopted by us for
HO2C
CF3
N
CF3
N
H
N
N
N
O2S
CF3
N
N
O
F3C
CN
CF3
dopamine D3 antagonist (1)
γ-secretase modulator (2)
Biogen, 2011
nootropic agent (3)
GSK, 2009
Merck, 2005
Figure 1 Some pharmacologically relevant derivatives of 4-trifluoromethylpiperidine
SYNTHESIS 2013, 45, 0225–0230
Advanced online publication: 18.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316831; Art ID: SS-2012-Z0853-OP
© Georg Thieme Verlag Stuttgart · New York

226
O. S. Artamonov et al.
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H
O
HO2C
HO2C
F
F
N
N
F
H
O
H
N
N
N
F
N
O
NH2
O
O
H
Ph
OH
F
AcHN
antibacterial agent (4)
muscarinic antagonist (5)
trovafloxacine
Pfizer, 1998
Ranbaxy, 2005
Vicuron Pharm., 2005
Figure 2 Some biologically active compounds with a 3-azabicyclo[3.1.0]hexane fragment
of the stereogenic centers were not determined, as these
were lost in the next synthesis step. Unexpectedly, the re-
action of alkene 7 with CF3CHN2 in diethyl ether as the
solvent led to quantitative formation of the isomeric Δ2-
pyrazoline 9. Less active alkenes 10 and 11 did not react
with CF3CHN2 under the above described conditions.
CF3
CF3
CF3
H
H
H
H
N
H
N
H
N
H
4-trifluoromethylpiperidine
6a
6b
N
Figure 3 Structure of 4-trifluoromethylpiperidine and amines 6a, 6b
CF3
N
CF3CHN2
CH2Cl2
r.t.
quant.
the synthesis of amines 6a and 6b (Scheme 1).12,13 The
key step was supposed to be a reaction between electron-
deficient maleimide 7 and CF3CHN2.14
O
O
N
Ph
8
O
O
N
Ph
CF3
CF3
CF3CHN2
Et2O
N
CF3
HN
7
CF3CHN2
– N2
r.t.
quant.
O
O
N
O
O
O
O
N
H
N
N
PG
PG
Ph
9
6a/6b
7
CF3CHN2
CH2Cl2
PG: protecting group
O
N
no reaction
Scheme 1 Retrosynthetic analysis of amines 6a and 6b
r.t., 10h
Ph
10
Chemistry
The N-benzyl group was chosen to protect the nitrogen
atom in compound 7, because the N–CH2Ph bond could
be subsequently cleaved in quantitative yield by hydroge-
nolysis. An excess of CF3CHN2 (bp 13 °C)15 was generat-
ed by the reaction of commercially available
CF3CH2NH2·HCl with one equivalent of NaNO2 in water.
CF3CHN2
CH2Cl2
no reaction
N
r.t., 10h
Boc
11
The formed volatile compound was gradually blown off Scheme 2 Reaction of CF3CHN2 with alkenes 7, 10, and 11
by an argon stream into a reaction vessel containing the
stirred solution of alkene 7 in dichloromethane at room
The decomposition of pyrazolines 8 and 9 was studied
temperature. Indeed, the reaction proceeded smoothly, as
next. Thermal decomposition of pyrazoline 8 was easily
1
judged by TLC and H NMR monitoring. No nitrogen
performed by heating the compound at 150 °C for one
evolution was observed, indicating formation of a stable
hour. During the reaction a vigorous nitrogen evolution
product. After completion of the reaction, the solvent was
was observed leading to the formation of cyclopropanes
12a/12b (4.3:1.0) in 63% overall yield (Scheme 3). Iso-
mers 12a/12b were easily separated by flash column chro-
matography. The trans-isomer 12a was obtained as the
evaporated under reduced pressure to provide the corre-
sponding Δ1-pyrazoline 8 in quantitative yield (Scheme
2). It is worth noting that only one stereoisomer of com-
pound 8 was formed. However, the relative configurations
main reaction product. The pyrazoline 9 was more stable
Synthesis 2013, 45, 225–230
© Georg Thieme Verlag Stuttgart · New York

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6-Trifluoromethyl-3-azabicyclo[3.1.0]hexanes
227
CF3
CF3
N
N
CF3
N
H
H
H
H
150 °C
63%
O
O
O
O
N
N
O
O
Ph
12a (51%)
Ph
12b (12%)
Ph
8
LiAlH4
Et2O
LiAlH4
Et2O
99%
98%
CF3
CF3
CF3
CF3
H
H
H2, Pd
MeOH
H2, Pd
MeOH
H
H
H
H
H
H
95%
N
H
96%
N
H
N
N
6a
Ph
6b
Ph
13a
13b
Scheme 3 Synthesis of amines 6a, 6b
than compound 8, and all attempts to perform its thermal
decomposition (150–260 °C) led to the formation of the
desired product in less than 10% yield.
Reduction of the carbonyl groups in 12a with LiAlH4 in
diethyl ether smoothly gave the N-protected pyrrolidine
13a in an excellent yield of 99%. Importantly, no cyclo-
propane ring cleavage was observed. Finally, cleavage of
N-benzyl group in pyrrolidine 13a by hydrogenation us-
ing 10% palladium on charcoal as the catalyst furnished
the target amine 6a in 95% yield. Again, the cyclopropane
ring was stable under the reaction conditions. The isomer-
ic amine 6b was prepared from amide 12b following the
same synthetic approach in 94% yield over two steps.
Figure 4 X-ray crystal structures of (a) compound 14, and (b) com-
pound 12a
pound 12a (Figure 4b). Single crystals of the compound
were obtained by slow evaporation of a dilute solution of
12a in ethyl acetate.
Assignment of the Stereoconfiguration
To determine stereoconfiguration of the synthesized com-
pounds, acylation of amine 6a was performed by reaction
with 4-nitrobenzoyl chloride to afford the crystalline de-
rivative 14 (Scheme 4). Single crystals of the product
were obtained by slow evaporation of a dilute solution in
methanol. X-ray diffractional analysis of amide 14 re-
vealed the trans-configuration of the pyrrolidine ring and
the trifluoromethyl group within the cyclopropane core
(Figure 4a).
In summary, isomeric 6-trifluoromethyl-3-azabicyc-
lo[3.1.0]hexanes 6a and 6b were designed as nonchiral
conformationally restricted analogues of pharmacologi-
cally relevant 4-trifluoromethylpiperidine. Synthesis of
both the compounds was performed in four steps from
commercially available N-benzylmaleimide (7). The key
step was a [3+2] cycloaddition between alkene 7 and tri-
fluoromethyldiazomethane. With the reported rapid syn-
thesis, we believe that isomeric amines 6a and 6b will find
true practical application in drug discovery projects, espe-
cially in those where 4-trifluoromethylpiperidine is in-
volved.
CF3
CF3
H
H
4-O2NC6H4COCl
Et3N, THF
H
H
93%
N
N
H
Solvents were purified according to standard procedures. All reac-
tions were performed in argon atmosphere. All the other starting
materials were provided by Enamine Ltd. Column chromatography
was performed using silica gel Merck 60 (230–400 mesh) as the sta-
O
NO2
6a
14
1
tionary phase. H, 19F, and 13C NMR spectra were recorded on
Scheme 4 Synthesis of amide 14
Bruker Avance 500 spectrometer at 499.9 MHz, 470.3 MHz, and
124.9 MHz, respectively. Chemical shifts are reported in ppm
Later, trans-stereoconfiguration of amine 6a was addi- downfield from TMS (1H, 13C) or CFCl3 (19F) as internal or external
tionally confirmed by X-ray diffractional analysis of com-
(D2O, TMS) standard. Mass spectra were recorded on Agilent 1100
LCMSD SL instrument by chemical ionization (CI).
© Georg Thieme Verlag Stuttgart · New York
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Dihydro-5-(phenylmethyl)-3-(trifluoromethyl)pyrrolo[3,4-
c]pyrazole-4,6(3H,5H)-dione (8)
12a
1H NMR (500 MHz, CDCl3/TMS): δ = 7.33 (5 H, m, C6H5), 4.55 (2
3
A solution of 3,3,3-trifluoroethylamine hydrochloride (54.5 g, 790
mmol, 5 equiv) in H2O (200 mL) was slowly added (~5–7 h) to a
stirred mixture of NaNO2 [106.7 g, 790 mmol, 5 equiv; dissolved in
H2O (200 mL)] and dodecane (200 mL). Upon addition, the formed
CF3CHN2 was gradually blown off by argon through a drying tube
(MgSO4) into a vessel containing a stirred solution of 7 (29.6 g, 158
mmol, 1 equiv) in CH2Cl2 (400 mL) at r.t. Thereafter, the solvent
was gently removed on a rotary evaporator under vacuum at r.t. to
afford crude 8 as a white solid (47.0 g, 158 mmol, ~100%); mp
>40 °C (dec.). According to NMR data, the compound was of ~90%
purity, and it was used in the next step without additional purifica-
tion.
H, s, NCH2Ph), 2.81 (2 H, d, JH,H = 3.0 Hz, CH), 2.56 (1 H, m,
CHCF3).
13C NMR (125 MHz, CDCl3/TMS): δ = 170.96 (s, NCO), 135.29 (s,
C, Ph), 128.87 (s, CH, Ph), 128.67 (s, CH, Ph), 128.28 (s, CH, Ph),
1
122.15 (q, JC,F = 271.3 Hz, CF3), 42.26 (s, CH2Ph), 31.25 (d,
2JC,F = 38.8 Hz, CHCF3), 31.25 (d, 3JC,F = 1.3 Hz, CHCHCF3).
19F NMR (470 MHz, CDCl3/CFCl3): δ = –69.05 (d, 2JF,H = 4.7 Hz,
CF3).
MS: m/z = 269 (M)+.
Anal. Calcd for C13H10F3NO2: C, 58.00; H, 3.74; N, 5.20. Found: C,
58.35; H, 3.47; N, 5.32.
1H NMR (500 MHz, DMSO-d6/TMS): δ = 7.37–7.24 (5 H, m,
3
C6H5), 6.41 (1 H, d, JH2,H = 6.0 Hz, NCHCO), 6.19 (1 H, br s,
12b
NCHCF3), 4.55 (1 H, d, JH,H = 15.0 Hz, AB system, NCHHPh),
4.54 (1 H, d, 2JH,H = 15.0 Hz, AB system, NCHHPh), 3.61 (1 H, m,
CHCHCF3).
Further elution gave isomer 12b (1.6 g, 5.9 mmol, 12%) as a white
solid; mp 114–116 °C; Rf = 0.3 (hexanes–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3/TMS): δ = 7.40–7.32 (5 H, m, C6H5),
4.54 (2 H, s, NCH2Ph), 2.82 (2 H, d, 3JH,H = 9.0 Hz, CH), 2.49 (1 H,
m, CHCF3).
13C NMR (125 MHz, CDCl3/TMS): δ = 169.84 (s, NCO), 135.03 (s,
C, Ph), 129.16 (s, CH, Ph), 128.61 (s, CH, Ph), 128.09 (s, CH, Ph),
13C NMR (125 MHz, DMSO-d6/TMS): δ = 173.45 (s, NCO), 169.12
(s, NCO), 135.72 (s, C, Ph), 128.96 (s, CH, Ph), 128.17 (s, CH, Ph),
1
128.10 (s, CH, Ph), 123.53 (q, JC,F = 278.8 Hz, CF3), 96.48 (s,
2
NCHCO), 90.81 (q, JC,F = 27.5 Hz, CHCF3), 42.71 (s, CH2Ph),
38.91 (s, CHCHCO).
19F NMR (470 MHz, DMSO-d6/CFCl3): δ = –72.17 (d, 2JF,H = 9.4
1
123.21 (q, JC,F = 273.8 Hz, CF3), 42.93 (s, CH2Ph), 32.86 (d,
2JC,F = 38.8 Hz, CHCF3), 24.91 (d, 3JC,F = 1.3 Hz, CHCHCF3).
Hz, CF3).
MS: m/z = 269 (M – 28)+.
19F NMR (470 MHz, CDCl3/CFCl3): δ = –60.21 (d, 2JF,H = 4.7 Hz,
CF3).
MS: m/z = 269 (M)+.
Dihydro-5-(phenylmethyl)-3-(trifluoromethyl)pyrrolo[3,4-
c]pyrazole-4,6(1H,5H)-dione (9)
Anal. Calcd for C13H10F3NO2: C, 58.00; H, 3.74; N, 5.20. Found: C,
58.24; H, 3.65; N, 5.53.
A solution of 3,3,3-trifluoroethylamine hydrochloride (5.5 g, 79
mmol, 5 equiv) in H2O (20 mL) was slowly added (~5–7 h) to a
stirred mixture of NaNO2 (10.7 g, 79 mmol, 5 equiv; dissolved in
H2O (20 mL)] and dodecane (20 mL). Upon addition, the formed
CF3CHN2 was gradually blown off by argon through a drying tube
(MgSO4) into a vessel containing a stirred solution of 7 (3.0 g, 15.8
mmol, 1 equiv) in Et2O (40 mL) at r.t. Thereafter, the solvent was
gently removed on a rotary evaporator under vacuum at r.t. to give
pure 9 as a white solid (4.7 g, 15.8 mmol, ~100%); mp 116 °C.
trans-3-Benzyl-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane
(13a)
A solution of compound 12a (6.05 g, 22.5 mmol) in anhyd Et2O (50
mL) was added dropwise to a stirred suspension of LiAlH4 (2.13 g,
56.1 mmol) in anhyd Et2O (50 mL). The formed suspension was
heated at reflux for 3 h. The reaction mixture was cooled to r.t. and
H2O (3 mL) was added dropwise. The solution was evaporated un-
der vacuum and H2O (50 mL) was added. The mixture was extract-
ed with CH2Cl2 (3 × 50 mL). The combined organic phases were
dried (Na2SO4) and evaporated under vacuum to give product 13a
(5.37 g, 22.3 mmol, 99%) as an oil. The material was sufficiently
pure to be used in the next step without additional purification.
1H NMR (500 MHz, CDCl3/TMS): δ = 7.31 (5 H, s, C6H5), 6.95 (1
H, br s, NH), 4.84 (1 H, d, 3JH,H = 10.5 Hz, COCHNH), 4.70 (1 H,
2
2
d, JH,H = 14.0 Hz, NCHHPh), 4.64 (1 H, d, JH,H = 14.0 Hz,
NCHHPh), 4.40 (1 H, d, 3JH,H = 10.5 Hz, COCHNH).
13C NMR (125 MHz, CDCl3/TMS): δ = 174.01 (s, NCO), 170.57 (s,
NCO), 135.15 (q, 2JC,F = 38.8 Hz, CCF3), 134.61 (s, C, Ph), 128.86
(s, CH, Ph), 128.70 (s, CH, Ph), 128.43 (s, CH, Ph), 119.76 (q,
1JC,F = 268.8 Hz, CF3), 63.54 (s, CHCO), 51.31 (s, CHCO), 43.24
(s, CH2Ph).
19F NMR (470 MHz, DMSO-d6/CFCl3): δ = –64.99 (s, CF3).
MS: m/z = 269 (M – 28)+.
1H NMR (500 MHz, CDCl3/TMS): δ = 7.36–7.25 (5 H, m, C6H5),
2
3.63 (2 H, s, NCH2Ph), 3.05 (2 H, d, JH,H = 9.0 Hz, NCHHCH),
2
2.40 (2 H, d, JH,H = 9.0 Hz, NCHHCH), 2.05 (1 H, m, CHCF3),
1.78 (2 H, s, CH of cyclopropane).
19F NMR (470 MHz, CDCl3/CFCl3): δ = –68.07 (d, 2JF,H = 9.4 Hz,
CF3).
MS: m/z = 241 (M)+.
trans-3-Benzyl-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-
2,4-dione (12a) and cis-3-Benzyl-6-(trifluoromethyl)-3-azabicy-
clo[3.1.0]hexane-2,4-dione (12b)
cis-3-Benzyl-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane
(13b)
Compound 13b was prepared from 12b (1.20 g, 4.5 mmol) follow-
ing the same experimental procedure used in the synthesis of 13a;
yield: 1.05 g (4.4 mmol, 98%); oil.
1H NMR (500 MHz, CDCl3/TMS): δ = 7.30 (5 H, m, C6H5), 3.65 (2
H, s, NCH2Ph), 3.20 (2 H, d, 2JH,H = 9.5 Hz, NCHHCH), 2.55 (2 H,
d, 2JH,H = 9.5 Hz, NCHHCH), 1.78 (2 H, d, J = 8.0 Hz, CH of cyclo-
propane), 1.51 (1 H, m, CHCF3).
13C NMR (125 MHz, CDCl3/TMS): δ = 139.34 (s, C, Ph), 128.44 (s,
CH, Ph), 128.09 (s, CH, Ph), 126.80 (s, CH, Ph), 127.21 (q,
1JC,F = 273.8 Hz, CF3), 58.93 (s, CH2Ph), 52.25 (s, CH2NCH2Ph),
23.52 (d, 2JC,F = 37.5 Hz, CHCF3), 22.01 (s, CHCHCF3).
Compound 8 (15.1 g, 51.0 mmol) was heated in an oil bath under
vacuum (20 mmHg) at 150 °C during 1 h; an exothermic evolution
of N2 was observed. The formed crude 12a/12b mixture was dis-
solved in CH2Cl2 (500 mL), triturated with 5% aq KMnO4 (500
mL), washed with H2O (150 mL), dried (MgSO4), and evaporated.
The obtained residue was purified by flash column chromatogra-
phy. Elution with hexane–EtOAc mixture (2:1) afforded first 12a
(7.0 g, 26.0 mmol, 51%) as a white solid; mp 114–116 °C; Rf = 0.4
(hexanes–EtOAc, 2:1). Crystals of compound 12a suitable for X-
ray structural analysis were obtained by slow evaporation of a dilute
solution of 12a in EtOAc.
Synthesis 2013, 45, 225–230
© Georg Thieme Verlag Stuttgart · New York

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6-Trifluoromethyl-3-azabicyclo[3.1.0]hexanes
229
19F NMR (470 MHz, CDCl3/CFCl3): δ = –56.28 (d, 2JF,H = 9.4 Hz,
CF3).
19F NMR (470 MHz, DMSO-d6/CFCl3): δ = –62.70 (d, 2JF,H = 9.4
Hz, CF3).
MS: m/z = 241 (M)+.
Crystals of compound 14 suitable for X-ray structural analysis were
obtained by slow evaporation of a dilute solution of 14 in MeOH.
trans-6-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane Hydro-
chloride (6a·HCl)
Compound 13a (5.0 g, 20.7 mmol) was added to a sat. solution of
anhyd HCl in MeOH (50 mL). The suspension was evaporated un-
der vacuum to provide pure 13a·HCl. The compound was dissolved
in MeOH (50 mL) and the formed solution was hydrogenated for 12
h (50 atm, 35 °C) using 10% Pd/C (50 mg) as a catalyst. The reac-
tion mixture was filtered off, the filtrate was evaporated under vac-
uum, and Et2O (20 mL) was added to the residue. The resulting
white solid was collected by filtration to give pure 6a·HCl (3.7 g,
19.7 mmol, 95%); white solid; mp >200 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of NMR spectra and crystallographic data for compounds
12a and 14.SnufpgIrpoi
o
nmtiratSnuIpfoprimntgirat
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1
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19F NMR (470 MHz, D2O/CFCl3): δ = –68.39 (d, 2JF,H = 4.7 Hz,
CF3).
Anal. Calcd for C6H9ClF3N: C, 38.42; H, 4.84; N, 7.47. Found: C,
38.35; H, 4.97; N, 7.32.
cis-6-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane Hydrochlo-
ride (6b·HCl)
Compound 6b·HCl was prepared from 13b (1.00 g, 4.1 mmol) fol-
lowing the same experimental procedure used in the synthesis of 6a;
yield: 0.74 g (4.0 mmol, 96%); white solid; mp >200 °C.
1H NMR (500 MHz, D2O/TMS): δ = 3.77 (2 H, d, 2JH,H = 13.0 Hz,
NCHHCH), 3.53 (2 H, d, 2JH,H = 13.0 Hz, NCHHCH), 2.37 (2 H, br
s, CH), 2.02 (1 H, m, CHCF3).
1
13C NMR (125 MHz, D2O/TMS): δ = 126.93 (q, JC,F = 271.3 Hz,
CF3), 45.82 (s, NCH2), 25.01 (d, 2JC,F = 35.0 Hz, CHCF3), 23.15 (d,
3JC,F = 1.3 Hz, CHCHCF3).
19F NMR (470 MHz, D2O/CFCl3): δ = –59.37 (d, 2JF,H = 9.4 Hz,
CF3).
Anal. Calcd for C6H9ClF3N: C, 38.42; H, 4.84; N, 7.47. Found: C,
38.30; H, 4.99; N, 7.63.
trans-3-(4-Nitrobenzoyl)-6-(trifluoromethyl)-3-azabicyc-
lo[3.1.0]hexane (14)
Et3N (0.45 mL, 3.21 mmol) was added to a solution of 6a·HCl (200
mg, 1.07 mmol) in THF (5 mL) under stirring at 0 °C. A solution of
4-nitrobenzoyl chloride (218 mg, 1.18 mmol) in THF (5 mL) was
added dropwise, while keeping the reaction temperature below
5 °C. The reaction mixture was stirred at r.t. for 2 h and then evap-
orated under vacuum. EtOAc (30 mL) was added, and the organic
layer was washed with 15% aq citric acid (1 × 10 mL), sat. aq
NaHCO3 (1 × 10 mL), and brine (1 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and evaporated under vacuum.
The residue was recrystallized from Et2O–hexane (1:4) to afford the
pure amide 14 (298 mg, 1.00 mmol, 93%) as a white solid; mp
90 °C.
(4) The search was performed in July 2012 in ‘Reaxys’
database.
(5) The search was performed in February 2011 in ‘MDL Drug
data report’ database.
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Org. Proc. Res. Dev. 2008, 12, 305. (b) Filler, R.; Saha, R.
Future Med. Chem. 2009, 1, 777. (c) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
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1H NMR (500 MHz, DMSO-d6/TMS): δ = 8.28 (2 Harom, d,
3
3JH,H = 8.0 Hz), 7.75 (2 Harom, d, JH,H = 8.0 Hz), 4.00 (1 H, d,
2JH,H = 12.5 Hz, NCHHCH), 3.67 (2 H, m, NCHHCH), 3.45 (2 H,
the signals are hidden by the signal of residual water, NCH2), 2.11
(1 H, m, CHCHCF3), 2.06 (1 H, m, CHCHCF3), 1.96 (1 H, m,
CHCF3).
13C NMR (125 MHz, DMSO-d6/TMS): δ = 167.78 (s, C=O), 148.40
(s, Carom), 143.32 (s, Carom), 129.90 (s, CHarom), 126.51 (q,
1JC,F = 267.5 Hz, CF3), 124.03 (s, CHarom), 50.02 (s, NCH2), 47.32
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drug design, In Protein-Ligand Interactions; Bohm, H. J.;
Schneider, G., Eds.; Wiley-VCH: Weinheim, 2003, 3.
2
(s, NCH2), 21.90 (q, JC,F = 35.0 Hz, CHCF3), 20.26 (br s,
CHCHCF3), 18.84 (br s, CHCHCF3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 225–230

230
O. S. Artamonov et al.
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Synthesis 2013, 45, 225–230
© Georg Thieme Verlag Stuttgart · New York