An efficient synthesis of N-cyclopropylanilines by a smiles rearrangement

Article abstract of DOI:10.1055/s-0032-1318389

Treatment of 2-chloro-N-cyclopropylacetamide with phenols gave the corresponding 2-aryloxy-N-cyclopropylacetamides, which on treatment with a base gave the corresponding N-cyclopropylanilines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1318389

PAPER
▌1039
paper
An Efficient Synthesis of N-Cyclopropylanilines by a Smiles Rearrangement
N-Cyclopropylanilines
Veera Reddy Arava,* Sreenivasula Reddy Bandatmakuru
R&D Laboratory, Suven Life Sciences Ltd., #18, Phase-III, IDA, Jeedimetla, Hyderabad 500055, India
Fax +91(40)23193541; E-mail: reddyvenis@rediffmail.com
Received: 12.01.2013; Accepted after revision: 15.02.2013
R
PBr3
OEt
OEt
OEt
Br
NaBH4
ArNHR
Abstract: Treatment of 2-chloro-N-cyclopropylacetamide with
phenols gave the corresponding 2-aryloxy-N-cyclopropylacet-
amides, which on treatment with a base gave the corresponding N-
cyclopropylanilines.
N
BF3•OEt2
R
N
OTMS
Ar
4
3
Ar
6
5
Key words: rearrangements, amines, cyclopropanes
Scheme 1 Preparation of N-cyclopropylanilines
An improved one-step version of the reductive amination
with siloxane 3 results in cyclopropanation of aromatic
amines, as exemplified in Scheme 2, but yields are low.12
The discovery of fluoroquinoline antibacterials was a ma-
jor breakthrough in curtailing bacterial infections. Cipro-
floxacin (1) is an example of a blockbuster drug of this
class (Figure 1). The cyclopropyl group at its N-1 position
is critical for its activity. Among the many methods avail-
able for synthesizing such compounds, their preparation
from N-cyclopropylanilines 2 has created a great deal of
interest from process scientists.1 N-Cyclopropylanilines
can be used in detecting nitrogen-centered radicals,2 and
they also exhibit a range of biological activities.3–7 1,2,3-
Trisubstituted cyclopropanes were conceived as peptido-
mimetics,8 and they have been found to be active com-
pounds.
OEt
NaBH3CN
NH
NH2
+
AcOH, MeOH
OTMS
3
40%
Scheme 2 One-step reductive amination
Cui and co-workers made effective use of Buchwald–
Hartwig procedures for the synthesis of N-cyclopropylan-
ilines 6 in moderate-to-good yields, as exemplified in
Scheme 3.2
O
F
CO2H
Pd2(dba)3, BINAP, NaOt-Bu
Br
+
NH
H2N
N
toluene, 80 °C, 24 h
R
N
N
H
2
HN
6 43–99%
ciprofloxacin (1)
Scheme 3 Palladium-catalyzed arylation of a cyclopropylamine
Figure 1 Structures of ciprofloxacin and N-cyclopropylanilines
The pharmaceutical industry has also developed several
methods for this synthesis.1 The method developed by
Caludio and co-workers1b (Scheme 4) is worth mention-
ing, although it suffers the limitation of requiring the pres-
ence of a strong electron-withdrawing group in the
position adjacent to the leaving group.
N-Aliphatic cyclopropylamines can often be prepared by
nucleophilic substitution of a leaving group with an ap-
propriate amino nitrogen atom. However, N-cyclopropyl-
anilines are rarely prepared by this method because of the
poor reactivity of cyclopropyl halides towards nucleo-
philes.9 Indirect methods have therefore been developed
to prepare N-cyclopropylanilines.10
F
NO
F
NO2
NH
2 DMSO, Na2CO3
H2N
quinolone
antibiotics
The first and most widely used method begins with the
conversion of [(1-ethoxycyclopropyl)oxy](trimethyl)si-
lane (3) into 1-bromo-1-ethoxycyclopropane (4), which
subsequently reacts with an aromatic amine to generate
the cyclopropyl hemiaminal ether 5 (Scheme 1).11 Reduc-
tion of this intermediate then gives the desired amine 6.
Cl
F
Cl
Scheme 4 Direct cyclopropanation
When we attempted to scale up the synthesis of silane 3,
even to 100–200 g, we found that it was difficult to main-
tain the same yields. We therefore devised a different
strategy for the synthesis of N-cyclopropylanilines that is
both scalable and reproducible. In this approach, we used
the Smiles rearrangement to prepare N-cyclopropylani-
lines 6 (Scheme 5).
SYNTHESIS 2013, 45, 1039–1044
Advanced online publication: 06.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318389; Art ID: SS-2013-Z0041-OP
© Georg Thieme Verlag Stuttgart · New York

1040
V. R. Arava, S. R. Bandatmakuru
PAPER
Table 1 Synthesis of Ethers 9 and N-Cyclopropylanilines 6
(continued)
NH2
+
ClCH2COCl
NHCOCH2Cl
7
Entry Phenol
Yielda (%) of 9 Yield (%) of 6
O
OH
KOH, NMP
6–8 h
110–115 °C
13 h
+
7
HN
O
R1–5
5
78
95
722
OH
R1–5
8
9
8e
OH
N
O
6
772
OMe
N
OH
R1–5
R1–5
H
8f
6
OH
Scheme 5 The Smiles rearrangement method
7
82
83
7711a
8g
Substituted phenols 8 reacted with 2-chloro-N-cyclopro-
pylacetamide (7)13 under basic conditions to give good
yields of the corresponding ethers 9. All these ethers were
well characterized from their spectral data. Under basic
conditions, the ethers 9 rearranged to form the corre-
sponding N-cyclopropylanilines 6 in good yields (Table
1).
OH
OH
8
5611a
8h
N
9
–
30b
70c
Table 1 Synthesis of Ethers 9 and N-Cyclopropylanilines 6
8i
Entry Phenol
Yielda (%) of 9 Yield (%) of 6
OH
10
90
OH
8j
a Yields calculated on the basis of the recovered starting phenol.
b Intermediate 9i was not isolated, and product 6i was obtained direct-
ly.
1
96
7311a
Cl
F
c 4-PhC6H4NH2 (10%) was also isolated by HPLC.
8a
OH
The dihalo compound 6a is a useful intermediate for pre-
paring quinoline antibiotics. Most of the relevant
patents1a,c,e report that this aniline reacts with diethyl eth-
oxymethylenemalonate to give a product that cyclizes to
the ester 10, which undergoes hydrolysis to give good
yields of the quinolinecarboxylic acid 11 (ciprofloxacin
Q-acid; Scheme 6).
2
94
81
7611a
Br
Cl
8b
OH
3
71
F
EtO2C
CO2Et
OEt
heat
8c
+
OH
Cl
NH
622
6a
4
88
O
O
N
Cl
8d
F
CO2Et
F
CO2H
–OH
Cl
N
Cl
10
11
Scheme 6 Preparation of ciprofloxacin Q-acid
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1039–1044

PAPER
N-Cyclopropylanilines
ESI-MS: m/z = 244.2 [M + H]+.
1041
However, when we repeated this reaction with compound
6a, we found that, together with 10, the unwanted isomer
12 was also formed in 45% yield (HPLC), which none of
the patents reported. We have characterized both the ester
12 and its parent acid 13 (Scheme 7).
2-(3-Bromophenoxy)-N-cyclopropylacetamide (9b)
Yellow solid; yield: 19.0 g (94%); mp 83.6–85.5 °C.
IR (KBr): 3292, 3068, 1654, 1474, 1228, 772 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.55–0.62 (m, 2 H), 0.77–0.86 (m,
2 H), 2.75–2.81 (m, 1 H), 4.44 (s, 2 H), 6.58 (s, 1 H), 6.81–6.84 (m,
1 H), 7.08 (s, 1 H), 7.14–7.22 (m, 2 H).
Cl
O
Cl
O
–OH
F
CO2Et
F
CO2H
13C NMR (100 MHz, CDCl3): δ = 6.40, 22.06, 67.34, 113.06,
118.29, 122.94, 125.20, 130.77, 157.67, 168.81.
ESI-MS: m/z = 270 [M + H]+.
N
N
2-(3-Chlorophenoxy)-N-cyclopropylacetamide (9c)
Off-white solid; yield: 13.68 g (81%); mp 78.1–80.0 °C.
12
13
IR (KBr): 3292, 3072, 1655, 1478, 1230 cm–1.
Scheme 7 Hydrolysis of unwanted isomer 12
1H NMR (400 MHz, CDCl3): δ = 0.57–0.63 (m, 2 H), 0.77–0.90 (m,
2 H), 2.75–2.81 (m, 1 H), 4.44 (s, 2 H), 6.58 (s, 1 H), 6.77–6.79 (dd,
J = 2.16, 2.16 Hz, 1 H), 6.91–6.95 (t, J = 1.92 Hz, 1 H), 7.00–7.02
(d, J = 7.76 Hz, 1 H), 7.21–7.27 (m, 1 H).
In conclusion, we have developed a simple and reproduc-
ible method for the preparation of N-cyclopropylanilines
from phenols through a Smiles rearrangement.
13C NMR (100 MHz, CDCl3): δ = 6.39, 22.05, 67.34, 112.59,
115.38, 122.28, 130.47, 135.10, 157.64, 168.84.
ESI-MS: m/z = 226.1 [M + H]+.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded by
using a Bruker 400 Spectrometer with TMS as internal standard. IR
spectra were recorded on a PerkinElmer Spectrum 100 FTIR spec-
trophotometer as KBr pellets or with the neat products. Mass spec-
tra were recorded on an API 2000 LCMS/MS Applied BioSystems
MDS Sciex spectrometer. Microanalysis was performed on a
Perkin-Elmer 240CHN elemental analyzer. Analytical TLC was
conducted on E-Merck 60F254 aluminum-backed plates of silica
gel (0.2 mm). Developed plates were visualized by using UV light
or in an iodine chamber. HPLC was performed by using a Shimadzu
2010 instrument.
2-(4-Chlorophenoxy)-N-cyclopropylacetamide (9d)
Off-white solid; yield: 30.0 g (88%); mp 76.6–78.2 °C.
IR (KBr): 3284, 1655, 1489, 1241, 824 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.54–0.58 (m, 2 H), 0.76–0.85 (m,
2 H), 2.74–2.80 (m, 1 H), 4.42 (s, 2 H), 6.59 (s, 1 H), 6.81–6.83 (d,
J = 8.92 Hz, 2 H), 7.25–7.27 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 6.37, 22.04, 67.50, 115.82,
126.99, 129.55, 155.60, 169.00.
2-Chloro-N-cyclopropylacetamide (7)
ESI-MS: m/z = 226.2 [M + H]+.
Cyclopropylamine (100.0 g, 1.75 moles) was added to a stirred so-
lution of K2CO3 (484.21 g, 3.5 moles) in DCE (1 L), and the mixture
was cooled to 5–10 °C. ClCH2COCl (208.15 g, 1.84 moles) was
added at 5–10 °C over 1 h. The mixture was maintained at 20–25 °C
for 1 h then heated to 50 °C for 3 h. The solvent was evaporated un-
der vacuum at 40 °C, and the residue was mixed with hexane (300
mL) at 20–25 °C. The product was isolated by filtration and washed
with hexane to give a white solid; yield: 168 g (71%); mp 85.8–
86.9 °C.
N-Cyclopropyl-2-phenoxyacetamide (9e)
White solid; yield: 8.0 g (78%); mp 68.7–70.0 °C.
IR (KBr): 3292, 3067, 1651, 1544, 1252, 753 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.55–0.59 (m, 2 H), 0.80–0.85 (m,
2 H), 2.75–2.81 (m, 1 H), 4.46 (s, 2 H), 6.63 (s, 1 H), 6.89–6.91 (d,
J = 8.12 Hz, 2 H), 7.00–7.04 (t, J = 7.36 Hz, 1 H), 7.24–7.33 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 6.38, 22.01, 67.25, 114.51,
122.02, 129.68, 157.02, 169.50.
ESI-MS: m/z = 192.3 [M + H]+.
IR (KBr): 3273, 3066, 1650, 1552, 1250 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.52–0.59 (m, 2 H), 0.77–0.86 (m,
2 H), 2.71–2.78 (m, 1 H), 4.02 (s, 2 H), 6.63 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 6.20, 22.68, 42.33, 167.36.
N-Cyclopropyl-2-(3-methoxyphenoxy)acetamide (9f)
Colorless liquid; yield: 7.8 g (95%).
2-(3-Chloro-4-fluorophenoxy)-N-cyclopropylacetamide (9a);
Typical Procedure
IR (neat): 3419, 3289, 3077, 3009, 1667, 1602, 769 cm–1.
3-Chloro-4-fluorophenol (6a; 21.94 g, 0.149 moles) and 2-chloro-
N-cyclopropylacetamide (7; 8.0 g, 0.059 moles) were added to a
stirred soln of K2CO3 (20.67 g, 0.149 moles) in toluene (200 mL) at
20–25 °C. The mixture was heated at 105–110 °C for 6–8 h then the
solvent was then evaporated under vacuum at 50 °C. The residue
was added to 10% aq NaOH (200 mL) at 20–25 °C and the mixture
was stirred for 2 h at 20–25 °C. The precipitate was isolated by fil-
tration and washed with H2O to give an off-white solid; yield [based
on recovered phenol 6a (13.0 g)]: 14.0 g (96%); mp 85.9–87.2 °C.
1H NMR (400 MHz, CDCl3): δ = 0.51–0.58 (m, 2 H), 0.70–0.79 (m,
2 H), 2.71–2.75 (m, 1 H), 3.73 (s, 3 H), 4.38 (s, 2 H), 6.42–6.44 (d,
J = 8.44 Hz, 2 H), 6.51–6.53 (d, J = 7.83 Hz, 1 H), 6.69 (s, 1 H),
7.13–7.17 (t, J = 8.08 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 6.32, 22.01, 55.17, 67.26, 101.17,
106.46, 107.45, 130.10, 158.22, 160.82, 169.40.
ESI-MS: m/z = 222.1 [M + H]+.
N-Cyclopropyl-2-(2-naphthyloxy)acetamide (9g)
IR (KBr): 3290, 3074, 1652, 1495, 1254, 1209, 766 cm–1.
Off-white solid; yield: 14.8 g (82%); mp 114.7–117.1 °C.
1H NMR (400 MHz, CDCl3): δ = 0.55–0.59 (m, 2 H), 0.82–0.87 (m,
2 H), 2.75–2.80 (m, 1 H), 4.41 (s, 2 H), 6.54 (s, 1 H), 6.74–6.78 (m,
1 H), 6.95–6.97 (q, 1 H), 7.06–7.10 (t, J = 8.76 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 6.38, 22.06, 68.00, 133.81,
116.63, 121.48, 152.28, 153.20, 154.70, 168.62.
IR (KBr): 3354, 1654, 1542, 1367, 1212, 1054, 844 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.59–0.64 (m, 2 H), 0.78–0.86 (m,
2 H), 2.79–2.82 (m, 1 H), 4.59 (s, 2 H), 6.68 (s, 1 H), 7.13–7.17 (m,
2 H), 7.36–7.40 (t, J = 7.36 Hz, 1 H), 7.45–7.49 (t, J = 7.43 Hz, 1
H), 7.73–7.80 (m, 3 H).
© Georg Thieme Verlag Stuttgart · New York
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1042
V. R. Arava, S. R. Bandatmakuru
PAPER
13C NMR (100 MHz, CDCl3): δ = 6.42, 22.08, 67.30, 107.47,
117.92, 124.29, 126.68, 126.80, 127.56, 129.36, 129.80, 134.15,
154.86, 169.40.
Hz, 1 H), 6.68–6.72 (dd, J = 2.11, 1.03 Hz, 1 H), 6.800–6.809 (t, J =
1.69 Hz, 1 H), 7.07–7.11 (t, J = 7.99 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.38, 24.94, 111.45, 112.62,
ESI-MS: m/z = 242.3 [M + H]+.
117.43, 129.92, 134.78, 149.75.
ESI-MS: m/z = 168.0 [M + H]+.
N-Cyclopropyl-2-(1-naphthyloxy)acetamide (9h)
Off-white solid; yield: 14.9 g (83%); mp 121.3–122.4 °C.
Anal. Calcd for C9H10ClN: C, 64.48; H, 6.01; N, 8.36. Found: C,
64.32; H, 6.12; N, 8.32.
IR (KBr): 3305, 1669, 1651, 1536, 1268, 793 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.56–0.59 (m, 2 H), 0.83–0.86 (m,
2 H), 2.80–2.83 (m, 1 H), 4.68 (s, 2 H), 6.68 (s, 1 H), 6.79–6.81 (d,
J = 7.51 Hz, 1 H), 7.36–7.41 (m, 1 H), 7.50–7.54 (m, 3 H), 7.83–
7.85 (m, 1 H), 8.15–8.17 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 6.55, 22.11, 67.79, 105.65,
121.09, 121.78, 125.02, 125.64, 125.67, 126.62, 127.75, 134.50,
152.77, 169.59.
4-Chloro-N-cyclopropylaniline (6c)
Yellow liquid; yield: 4.6 g (62%).
IR (neat): 3404, 1600, 1496, 817 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.48–0.52 (m, 2 H), 0.71–0.75 (m,
2 H), 2.38–2.4 (m, 1 H), 4.12 (s, 1 H), 6.69–6.72 (d, J = 8.71 Hz, 2
H), 7.12–7.14 (d, J = 8.72 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 7.35, 25.19, 114.11, 122.16,
128.81, 147.15.
ESI-MS: m/z = 242.3 [M + H]+.
2-(Biphenyl-4-yloxy)-N-cyclopropylacetamide (9j)
ESI-MS: m/z = 168.1 [M + H]+.
Off-white solid; yield: 18.0 g (90%); mp 146.1–148.2 °C.
N-Cyclopropylaniline (6e)
Colorless liquid; yield: 4.5 g (72%).
IR (neat): 3391, 3087, 3009, 1603, 1504, 1020, 749 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.53 (m, 2 H), 0.70–0.76 (m, 2 H),
2.42–2.45 (m, 1 H), 4.17 (s, 1 H), 6.74–6.82 (m, 3 H), 7.19–7.23 (t,
J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 7.30, 25.15, 113.07, 117.64,
129.02, 148.60.
IR (KBr): 3261, 1662, 1651, 1645, 825, 757 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.57–0.61 (m, 2 H), 0.79–0.86 (m,
2 H), 2.78–2.82 (m, 1 H), 4.49 (s, 2 H), 6.74 (s, 1 H), 6.95–6.97 (d,
J = 8.54 Hz, 2 H), 7.30–7.33 (t, J = 7.24 Hz, 1 H), 7.42–7.46 (t, J =
8.31 Hz, 2 H), 7.52–7.54 (d, J = 8.11 Hz, 4 H).
13C NMR (100 MHz, CDCl3): δ = 6.41, 22.09, 67.41, 114.86,
126.66, 126.91, 128.32, 128.70, 135.15, 140.19, 156.56, 169.53.
ESI-MS: m/z = 268.1 [M + H]+.
ESI-MS: m/z = 134.2 [M + H]+.
3-Chloro-N-cyclopropyl-4-fluoroaniline (6a); Typical Proce-
dure
N-Cyclopropyl-3-methoxyaniline (6f)
Colorless liquid; yield: 4.5 g (77%).
Acetamide 7a (14.0 g, 0.057 moles) was added to a stirred soln of
KOH (6.43 g, 0.114 moles) and NMP (70 mL) in toluene (280 mL)
at 20–25 °C. The mixture was heated to 120–130 °C for 12 h then
cooled to 40–45 °C. H2O (200 mL) was added with stirring. The
layers were separated and the aqueous layer was extracted with tol-
uene (100 mL). The organic layers were combined, washed with
H2O (2 × 200 mL), and concentrated to give a yellow liquid; yield:
7.84 g (73%).
IR (neat): 3389, 3002, 1603, 1155, 1048, 760 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.52–0.56 (m, 2 H), 0.72–0.77 (m,
2 H), 2.42–2.47 (m, 1 H), 3.78 (s, 3 H), 4.21 (s, 1 H), 6.33–6.35 (t,
J = 4.59 Hz, 1 H), 6.40–6.42 (d, J = 7.25 Hz, 2 H), 7.10–7.14 (t, J =
7.96 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.33, 25.13, 54.98, 99.07, 102.65,
IR (neat): 3412, 3090, 2965, 1504, 1364, 1226, 1050, 806 cm–1.
106.30, 129.74, 150.07, 160.66.
ESI-MS: m/z = 164.1 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 0.48–0.51 (m, 2 H), 0.68–0.76 (m,
2 H), 2.35–2.40 (m, 1 H), 4.11 (s, 1 H), 6.54–6.58 (m, 1 H), 6.79–
6.81 (dd, J = 2.59, 2.55 Hz, 1 H), 6.91–6.96 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.29, 25.35, 112.17, 133.82,
116.42, 120.89, 145.48, 152.23.
Cyclopropyl(2-naphthyl)amine (6g)
White solid; yield: 14.5 g (77%); mp 52.4–53.4 °C.
IR (KBr): 3374, 2955, 1625, 1361, 826, 750 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.64–0.67 (m, 2 H), 0.86–0.90 (m,
2 H), 2.57–2.62 (m, 1 H), 4.32 (s, 1 H), 6.97–6.99 (dd, J = 1.92, 1.92
Hz, 1 H), 7.242–7.245 (d, J = 1.1 Hz, 1 H), 7.32–7.36 (t, J = 7.44
Hz, 1 H), 7.49–7.53 (t, J = 7.49 Hz, 1 H), 7.73–7.75 (d, J = 8.74 Hz,
1 H), 7.79–7.82 (t, J = 6.74 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 7.48, 25.33, 105.60, 117.69,
122.04, 126.10, 126.27, 127.70, 127.80, 128.78, 135.19, 146.38.
ESI-MS: m/z = 186.1 [M + H]+.
3-Bromo-N-cyclopropylaniline (6b)
Brown liquid; yield: 6.0 g (76%).
IR (neat): 3418, 3091, 2986, 1548, 820 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.49–0.53 (m, 2 H), 0.70–0.77 (m,
2 H), 2.38–2.43 (m, 1 H), 4.21 (s, 1 H), 6.64–6.67 (dd, J = 1.54, 1.45
Hz, 1 H), 6.83–6.88 (d, J = 7.48 Hz, 1 H), 6.94–6.94 (d, J = 1.69 Hz,
1 H), 7.00–7.04 (t, J = 7.99 Hz, 1 H).
ESI-MS: m/z = 184.2 [M + H]+.
Cyclopropyl(1-naphthyl)amine (6h)
13C NMR (100 MHz, CDCl3): δ = 7.33, 24.91, 111.85, 115.50,
White solid; yield: 6.3 g (56%); mp 50.1–51.4 °C (Lit.2 36–37 °C).
120.31, 123.04, 130.22, 149.90.
ESI-MS: m/z = 213.1 [M + H]+.
IR (KBr): 3391, 1575, 1518, 1284, 766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.651–0.656 (m, 2 H), 0.85–0.91
(m, 2 H), 2.58–2.59 (m, 1 H), 4.87 (s, 1 H), 7.04–7.08 (d, J = 7.46
Hz, 1 H), 7.23–7.29 (m, 1 H), 7.35–7.47 (m, 3 H), 7.72–7.81 (d, J =
7.78 Hz, 1 H), 7.79–7.81 (d, J = 7.64 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.47, 25.41, 105.74, 117.69,
119.62, 123.10, 124.58, 125.55, 126.52, 128.58, 134.12, 143.78.
3-Chloro-N-cyclopropylaniline (6c)
Yellow liquid; yield: 4.0 g (71%).
IR (neat): 3405, 2972, 1600, 1495, 1364, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.51–0.54 (m, 2 H), 0.71–0.78 (m,
2 H), 2.39–2.44 (m, 1 H), 4.22 (s, 1 H), 6.61–6.63 (dd, J = 1.65, 1.61
ESI-MS: m/z = 184.2 [M + H]+.
Synthesis 2013, 45, 1039–1044
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Cyclopropylanilines
ESI-MS: m/z = 227.2 [M + H]+.
1043
N-Cyclopropylquinolin-8-amine (6i)
Note: In this example, the acetamido 9i was not isolated, but was
converted directly into 6i.
Anal. Calcd for C14H14NO2: C, 74.31; H, 6.24; N, 12.38. Found: C,
74.52; H, 6.23; N, 12.35.
Yellow liquid; yield: 1.6 g (30%).
Ethyl 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquin-
oline-3-carboxylate (10) and Ethyl 5-Chloro-1-cyclopropyl-6-
fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (12)
A mixture of diethyl {[(3-chloro-4-fluorophenyl)(cyclopropyl)ami-
no]methylene}malonate (5.0 g, 0.014 moles) and PPA (20 g) was
stirred for 2 h at 70–80 °C. The mixture was cooled and then chilled
H2O (100 mL) was added. The resulting mixture was stirred for 1 h
at 20–25 °C. The product was collected by filtration, washed with
H2O (20 mL), and purified by column chromatography to give the
desired product 10 together with its 5-chloro isomer 12 as an un-
wanted byproduct.
IR (neat): 3397, 3038, 2961, 1575, 1519, 1478, 1380, 817, 790, 743
cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.68–0.79 (m, 2 H), 0.81–0.88 (m,
2 H), 2.55–2.58 (m, 1 H), 6.39 (s, 1 H), 7.09–7.11 (d, J = 7.92 Hz,
2 H), 7.24–7.44 (m, 2 H), 8.05–8.07 (t, J = 4.24 Hz, 1 H), 8.69–8.70
(t, J = 1.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 7.09, 24.57, 106.18, 114.38,
121.22, 127.63, 128.42, 135.91, 137.89, 145.18, 146.83.
ESI-MS: m/z = 185.2 [M + H]+.
Anal. Calcd for C12H12N2: C, 78.23; H, 6.57; N, 15.21. Found: C,
78.31; H, 6.62; N, 15.24.
10
Yield: 2.27 (52%); mp 220.1–221.9 °C.
IR (KBr): 2999, 1726, 1614, 1479, 1330, 1034.
Biphenyl-4-yl(cyclopropyl)amine (6j)
Off-white solid; yield: 9.7 g (70%); mp 42.4–44.0 °C.
1H NMR (400 MHz, CDCl3): δ = 1.16 (m, 2 H), 1.36–1.42 (m, 5 H),
3.44–3.46 (m, 1 H), 4.36–4.42 (q, 2 H), 7.99–8.00 (d, j = 5.72 Hz, 1
H), 8.19–8.21 (d, j = 8.96 Hz, 1 H), 8.57 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 8.15, 14.29, 34.63, 61.77, 110.71,
113.63, 118.81, 126.73, 137.07, 148.71, 154.30, 156.79, 165.12,
172.64.
IR (KBr): 3406, 2981, 1612, 1489, 822, 758 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.55–0.57 (m, 2 H), 0.72–0.79 (m,
2 H), 2.46–2.50 (m, 1 H), 4.25 (s, 1 H), 6.86–6.88 (d, J = 8.38 Hz,
2 H), 7.25–7.28 (t, J = 7.31 Hz, 1 H), 7.38–7.42 (t, J = 7.64 Hz, 2
H), 7.45–7.47 (d, J = 8.38 Hz, 2 H), 7.54–7.56 (d, J = 7.54 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 7.41, 25.19, 123.34, 125.99,
126.29, 127.76, 128.57, 130.62, 141.29, 148.05.
12
White solid, yield: 1.87 g (43%); mp 251.2–252.8 °C.
IR (KBr): 2988, 1726, 1624, 1609, 1474, 1301, 1241, 814 cm–1.
ESI-MS: m/z = 210.0 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 1.13–1.14 (m, 2 H), 1.24–1.42 (m,
5 H), 3.40–3.46 (m, 1 H), 4.36–4.41 (q, 2 H), 7.45–7.49 (t, J = 8.62
Hz, 1 H), 7.86–7.89 (dd, J = 4.36, 4.36 Hz, 1 H), 8.50 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.20, 19.09, 39.96, 65.28,
116.46, 121.29, 121.38, 124.46, 124.71, 130.19, 143.70, 152.26,
159.13, 169.35.
Anal. Calcd for C15H15N: C, 86.08; H, 7.22; N, 6.69. Found: C,
86.16; H, 7.26; N, 6.75.
Biphenyl-4-ylamine (Byproduct of Synthesis of 6j)
[CAS Reg. No. 92-67-1]
White solid; yield: 1.08 g (10%); mp 53.6–54.9 °C.
IR (KBr): 3423, 3391, 3294, 3197, 3030, 1487, 1258, 831, 762, 694
cm–1.
ESI-MS: m/z = 310.2 [M + H]+.
Anal. Calcd for C15H13ClFNO3: C, 58.17; H, 4.23; N, 4.52. Found:
C, 58.28; H, 4.21; N, 4.59.
1H NMR (400 MHz, CDCl3): δ = 3.73 (s, 2 H), 6.76–6.78 (d, J =
8.44 Hz, 2 H), 7.26–7.30 (t, J = 7.91 Hz, 1 H), 7.39–7.44 (m, 4 H),
7.54–7.56 (d, J = 7.58 Hz, 2 H).
5-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-
3-carboxylic Acid (13)
13C NMR (100 MHz, CDCl3): δ = 115.37, 126.25, 126.37, 127.97,
A mixture of ester 12 (350 mg, 0.0011 moles), EtOH (0.3 mL), and
2 M aq NaOH (10 mL) was refluxed with stirring for 2 h. The mix-
ture was cooled and then acidified with 50% aq HCl (10 mL). The
resulting product was collected by filtration and washed with H2O
(10 mL) to give a white solid; yield: 200 mg (63%); mp 276.82–
279.66 °C.
128.67, 131.45, 141.13, 145.87.
ESI-MS: m/z = 170.0 [M + H]+.
N-(3-Chloro-4-fluorophenyl)-N-cyclopropylacetamide (N-Ace-
tyl 6a)1b
White solid; yield: 0.5 g (80%); mp 53.4–54.8 °C (Lit.1b 50–52 °C).
IR (KBr): 3445, 3119, 3064, 1724, 1614, 1455, 1435, 1219, 821 cm–1.
IR (KBr): 3095, 3015, 1660, 1501, 1377, 1325, 1235, 843, 818, 712
cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.49 (m, 2 H), 0.85 (m, 2 H), 2.11
(br s, 3 H), 3.02 (m, 1 H), 6.99 (s, 1 H), 7.07–7.11 (t, J = 8.35 Hz, 1
H), 7.17–7.18 (d, J = 4.85 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 10.15, 23.17, 31.45, 116.39,
120.86, 126.97, 129.36, 138.67, 138.71, 172.35.
1H NMR (400 MHz, CDCl3): δ = 1.16–1.31 (m, 4 H), 3.82 (s, 1 H),
8.04–8.08 (t, J = 9.00 Hz, 1 H), 8.33–8.37 (dd, J = 4.32, 4.36 Hz, 1
H), 8.73 (s, 1 H), 14.87 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 8.32, 37.14, 108.66, 119.73,
122.29, 123.03, 140.25, 148.97, 154.81, 157.25, 165.25, 178.28.
ESI-MS: m/z = 282.0 [M + H]+.
ESI-MS: m/z = 228.1 [M + H]+.
Anal. Calcd for C13H9ClFNO3: C, 55.43; H, 3.22; N, 4.97. Found:
C, 55.38; H, 3.18; N, 4.85
N-Cyclopropyl-N-quinolin-8-ylacetamide (N-Acetyl 6i)
White solid; yield: 0.6 g (80%); mp 110.4–115.8 °C.
IR (KBr): 3060, 3011, 1663, 1593, 1573, 1426, 1383, 797 cm–1.
Acknowledgment
1H NMR (400 MHz, CDCl3): δ = 0.53 (m, 2 H), 0.87 (m, 2 H), 1.67
(s, 3 H), 3.40 (m, 1 H), 7.44–7.45 (d, J = 6.56 Hz, 2 H), 7.53–7.57
(t, J = 7.64 Hz, 1 H), 7.81–7.83 (d, J = 7.76 Hz, 1 H), 8.17–8.19 (d,
J = 8.12 Hz, 1 H), 8.94 (s, 1 H).
The authors are grateful to the management of Suven Life Sciences
for allowing them to publish these results.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1039–1044

1044
V. R. Arava, S. R. Bandatmakuru
PAPER
(6) Macdonald, T. L.; Zirvi, K.; Burka, L. T.; Peyman, P.;
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Synthesis 2013, 45, 1039–1044
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