New simple synthesis of quinoline-4-carbonitriles

Article abstract of DOI:10.1055/s-0032-1317380

Alkylation of 2-nitrobenzyl cyanides with α-halomethyl ketones furnishes ketonitriles which upon reduction with tin(II) chloride form quinoline-4-carbonitriles in good yields.

Full text of DOI:10.1055/s-0032-1317380

2682▌
LETTER
lNetteerw Simple Synthesis of Quinoline-4-carbonitriles
Synthesis of Quinoline-4-carbonitriles
Robert Bujok,a Adam Trawczyński,b Zbigniew Wróbel,a Krzysztof Wojciechowski*a
a
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, P.O. Box 58, 01-224 Warszawa, Poland
Fax +48(22)6326681; E-mail: krzysztof.wojciechowski@icho.edu.pl
b
Department of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland
Received: 31.07.2012; Accepted after revision: 12.09.2012
Bromoacetophenone was used alone in twofold excess;
whereas chloroketones were used in twofold excess in
combination with a stoichiomeric amount of KI. It is note-
worthy that, with iodoacetone prepared separately by stir-
ring chloroacetone with two equivalents of KI in DMF for
30 minutes, the alkylation of 5-chloro-2-nitrophenyl-
acetonitrile was complete within 30 minutes at room tem-
perature.
Abstract: Alkylation of 2-nitrobenzyl cyanides with α-halomethyl
ketones furnishes ketonitriles which upon reduction with tin(II)
chloride form quinoline-4-carbonitriles in good yields.
Key words: quinolines, reduction, nitriles, alkylation, ketones, tin
The quinoline framework can be found in many synthetic
and natural compounds of biological importance1 so there
is continuous interest in new methods of its construction.2
4-Cyanoquinolines, versatile starting materials for the
synthesis of many quinoline derivatives, are usually syn-
thesized via direct introduction of a cyano group3a or dis-
placement of halogen3b in the quinoline moiety. Direct
synthesis of 4-cyanoquinolines has been reported by
Soederberg,4a who found that palladium-catalyzed reduc-
tion of 1-cyano-1-(2-nitroaryl)alkenes with carbon mon-
oxide in the presence of a palladium complex and DBU
led to 4-cyanoquinolines; while without additional base,
3-cyanoindoles were obtained. We have utilized the same
starting materials to form quinoline N-oxides upon treat-
ment with ethanolic NaOH4b,c or trimethylchlorosilane in
the presence of Et3N.4c More complex 4-cyanoquinoline-
N-oxides were obtained from 2-nitrobenzyl cyanides
upon treatment with 2,4,6-triarylpyrylium salts in the
presence of sodium methoxide in methanol.4d Key starting
materials for these syntheses are ortho-nitroarylacetoni-
triles, readily available from nitroarenes via vicarious nu-
cleophilic substitution (VNS)5 – a powerful tool for the
modification of nitroarenes at both ortho or para positions
to the nitro group. Other syntheses of 4-cyanoquinolines
include reaction of Schiff bases with acrylonitrile in the
presence of peroxides6a or tandem Diels–Alder/retro-
Diels–Alder reaction of 4-cyanoquinazoline with N,N-di-
ethyl-N-prop-1-ynylamine.6b
1) NaH, DMF
CN
CN
R
r.t., 15 min
2) RCOCH2Y
80 °C, 1–2 d
X
X
O
NO2
NO2
1
2a–i
2a
SnCl2
EtOAc–EtOH
r.t., 24 h
Fe, AcOH
70 °C
Cl
CN
X
N
4a
R
N
3b–i
Scheme 1
Table 1 Ketonitriles 2 and Cyanoquinolines 3
Entry
X
R
Yield of
Yield of
ketonitrile 2 (%)
quinoline 3 (%)
1
2
3
4
5
6
7
8
9
Cl
Me
t-Bu
Ph
2a 91
2b 55
2c 82
2d 91
2e 88
2f 92
2g 78
2h 80
2i 78
3a –a
Cl
3b 72
3c 79
3d 76
3e 29b
3f 61
3g 39c
3h 79
3i 94
Cl
Herein we present a synthesis of 4-cyanoquinolines via re-
ductive cyclization of 2-(2-nitroaryl)-4-oxo-alkanenitriles
2 (Scheme 1). These starting materials are readily avail-
able from o-nitroarylacetonitriles 1 upon alkylation with
α-halomethyl ketones. 5-Chloro-2-nitrophenylacetonitrile
was alkylated with α-bromoacetophenone in the presence
of sodium hydride as a base. Under these conditions, ad-
dition of the alkylating agent to the carbanion prepared in
advance led to the expected ketonitrile 2c in 82% yield.
Other nitrobenzyl cyanides reacted similarly (Table 1).7
F
Ph
MeO
MeO
CF3
Ph
t-Bu
Ph
Ph
t-Bu
Ph
Ph
a Inseparable mixture of products.
b Additionally 2-tert-butyl-6-methoxyquinoline (4e) was formed in
27% yield.
SYNLETT 2012, 23, 2682–2686
Advanced online publication: 12.10.2012
c Additionally 2-phenyl-6-(trifluoromethyl)quinoline (4g) was
formed in 21% yield
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317380; Art ID: ST-2012-D0633-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Quinoline-4-carbonitriles
2683
CN
CN
CN
CN
CN
R
R
X
X
X
X
SnCl2
X
– H2O
O
R
O
NH
OH
N
N
O
R
N
R
NO2
OH
OH
OH
2
5
6
7
8
SnCl2
CN
– H2O
CN
CN
N
R
e R = t-Bu, X = OMe
g R = Ph, X = CF3
X
X
X
X
– H2O
– HCN
O
R
NH2
N
R
N
R
9
10
4
3
Scheme 2
Attempted reduction of the model ketonitrile 1c with zinc substituent10 enabling formation of imine and subsequent
and ammonium chloride in ethanol–water led to a com- HCN elimination seems the dominant pathway.
plex mixture of products. Fortunately, reduction of 1c
with SnCl2 in an ethyl acetate–ethanol mixture led to
6-chloro-2-phenylquinoline-4-carbonitrile (3c) in 79%
A similar process involving a two-step reduction of the ni-
tro group to hydroxylamine and amine was observed dur-
11a
ing reduction of 2-nitrochalcones with SnCl2
and
yield. Other ketonitriles 2b–j reacted similarly giving the
expected quinoline-4-carbonitriles 3b–j in good yields.8
The exceptions are methoxy and trifluoromethyl deriva-
tives 2e and 2g, respectively, which gave a mixture of
products. The desired quinoline-4-carbonitriles 3e and 3g
were accompanied by decyanated derivatives 4e and 4g.
The reduction of the ketonitrile 2a deserves additional
comments. Under the standard conditions a complex mix-
ture of products was formed in which small amounts of
6-chloro-2-methylquinoline-4-carbonitrile (3a) and its
N-oxide were detected by GC–MS, but the isolation of
these products proved impossible. With other reducing
systems (catalytic hydrogenation over palladium in acetic
acid, zinc in acetic acid, iron in water–acetic acid) com-
plex mixtures of undefined products were also formed.
Only with iron in acetic acid did reduction of 2a lead to
the known 6-chloro-2-methylquinoline (4a)9 in 26% yield
at room temperature and in 67% yield at 70 °C.
reduction of 3-(nitrophenyl)-3-hydroxypropanones with
metal, zinc, or tin, combined with NH4Cl.11b In the case of
nitrochalcones, condensation of the intermediate hydrox-
ylamine with a carbonyl group resulted in the N-oxide,
while cyclization of the amine led to the quinoline.11a In
the reduction of 3-(nitrophenyl)-3-hydroxypropanones to
quinolines and the corresponding N-oxides final aromati-
zation occurred via elimination of water from the interme-
diate cyclic nitrone or Schiff base.11b
We employed this reaction for the synthesis of more com-
plex condensed quinoline derivatives; namely benzo- and
pyrroloquinolines. Alkylation of 1-nitro-2-naphthylaceto-
nitrile (11)12 with α-bromocetophenone gave ketonitrile
12 that, upon reduction, formed 4-cyano-2-phenyl-
benzo[h]quinoline (13,8 Scheme 3).
O
NO2
Ph
NO2
The plausible reaction pathways leading to products 3b–i
are presented in Scheme 2. The reduction of the nitro
group leads to hydroxylamine 5 which is a prerequisite to
the formation of quinoline-4-carbonitriles. The nitrone 7
rearranges to 1-hydroxy-1,4-dihyroquinoline-4-carbo-
nitrile 8 which then aromatizes by elimination of another
molecule of water to form the final quinoline-4-carbo-
nitrile 3. The methoxy derivative 2e upon reduction gives
a mixture of 2-tert-butyl-6-methoxyquinoline-4-carboni-
trile (3e) and 2-tert-butyl-6-methoxyquinoline (4e). Since
the addition of hydroxylamine to the carbonyl group is a
reversible process, in this instance it is to some extent hin-
dered by the bulky tert-butyl substituent. Thus, a compet-
ing further reduction of hydroxylamine to amine enables
formation of imine 10 which aromatizes to 4e by an elim-
ination of HCN. Similar reasoning can explain formation
of 6-(trifluoromethyl)quinoline 4g from the ketonitrile 2g.
In this case, preferential reduction of the nitro group para
to the strongly electron-withdrawing trifluoromethyl
1) NaH, DMF
2) PhCOCH2Br
CN
CN
12
11
SnCl2
EtOAc–EtOH
Ph
N
CN
13
Scheme 3
The synthesis of pyrroloquinolines started from cyano-
methyl nitroindoles, which is easily available from nitro-
indoles via VNS with 4-(chlorophenoxy)acetonitrile.13
Alkylation of (4-nitroindol-5-yl)acetonitrile derivative 14
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2682–2686

2684
R. Bujok et al.
LETTER
O
R
R
NO2
R
NO2
N
N
1) NaH, DMF
2) RCOCH2X
SnCl2
EtOAc–EtOH
+
NC
NC
Ph
Ph
N
NC
Ph
N
Ph
n-C8H17
N
N
n-C8H17
n-C8H17
n-C8H17
14
15a R = t-Bu, 76%
15b R = Ph, 81%
16
–
60%
17
49%
14%
a R = t-Bu
b R = Ph
Scheme 4
O
Ph
O-p-ClC6H4
CN
CN
CN
Ph
CN
PhCOCH2Br
DBU
SnCl2
AcOEt–EtOH
O2N
O2N
O2N
N
t-BuOK–DMF
Me
N
84%
33%
88%
N
N
N
BOM
BOM
BOM
BOM
18
19
20
21
BOM = CH2OCH2Ph
Scheme 5
with halomethyl ketones furnished ketonitriles 15a,b7
that, upon reduction with tin(II) chloride, formed
pyrrolo[2,3-h]quinolines 16 and 178 (Scheme 4). In a sim-
ilar reaction sequence (5-nitroindol-4-yl)acetonitrile de-
rivative 19 was transformed into 9-cyanopyrrolo[3,2-
f]quinoline 218 (Scheme 5).
References and Notes
(1) (a) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18,
1488. (b) Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J.
Med. Chem. 2010, 3245.
(2) (a) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008,
12, 1116. (b) Kouznetsov, V. V.; Méndez, L. Y. V.; Gomez,
C. M. M. Curr. Org. Chem. 2005, 9, 141.
It is noteworthy that, when the reduction of ketonitriles,
for example 2f, was performed with hydrogen at atmo-
spheric pressure over 10% Pd/C catalyst, the major prod-
uct was 1,2,3,4-tetrahydroquinoline derivative 22
(Scheme 6).14 Similar reductive cyclization of 2-(2-nitro-
benzyl)-substituted β-keto esters leading, depending on
reaction conditions, to tetrahydroquinolines and quino-
lines has been described by Bunce.15
(3) (a) Okamoto, T.; Tani, H. Chem. Pharm. Bull. 1959, 7, 925.
(b) Vu, A. T.; Cohn, S. T.; Manas, E. S.; Harris, H. A.;
Mewshaw, R. E. Bioorg. Med. Chem. Lett. 2005, 15, 4520.
(4) (a) Banini, S. R.; Turner, M. R.; Cummings, M. M.;
Soederberg, B. C. G. Tetrahedron 2011, 67, 3603.
(b) Wróbel, Z.; Kwast, A.; Mąkosza, M. Synthesis 1993, 31.
(c) Wróbel, Z.; Mąkosza, M. Tetrahedron 1993, 49, 5315.
(d) Zimmermann, T.; Sicker, D.; Pink, M. J. Prakt. Chem.
1993, 335, 390.
(5) For reviews on VNS, see: (a) Mąkosza, M. Synthesis 2011,
2341. (b) Mąkosza, M. Chem. Soc. Rev. 2010, 39, 2855.
(c) Mąkosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
2631. (d) Mąkosza, M.; Wojciechowski, K. Heterocycles
2001, 54, 445.
(6) (a) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G. Gazz.
Chim. Ital. 1989, 119, 637. (b) Miyashita, A.; Taido, N.;
Sato, S.; Yamamoto, K.-i.; Ishida, H.; Higashino, T. Chem.
Pharm. Bull. 1991, 39, 282.
(7) Alkylation of 2-Nitrophenylacetonitriles 1 with α-
Halomethyl Ketones: Synthesis of 2-(5-Chloro-2-
nitrophenyl)-4-oxo-4-phenylbutyronitrile (2c) – Typical
Procedure
Ph
CN
MeO
H2, Pd/C
O
MeOH, r.t., 2 d
NO2
CN
2f
CN
MeO
MeO
+
Ph
Ph
N
H
N
3f (4%)
22 (62%)
To a solution of 5-chloro-2-nitrophenylacetonitrile (2 mmol)
in DMF (15 mL) NaH (55 mg, 2.3 mmol) was added. The
reaction mixture was stirred for 20 min and then α-
bromoacetophenone (0.80 g, 4 mmol) was added (in the case
of α-chloro ketones an equimolar amount of KI was also
added). The reaction mixture was stirred at 80 °C for 12–24
h until the starting material 1 had disappeared (TLC). The
reaction mixture was then poured into dilute HCl, extracted
with EtOAc (3 × 30 mL) and dried with Na2SO4. After
filtration and evaporation of solvent, the residue was purified
Scheme 6
Acknowledgment
This research was supported by the National Scientific Center,
Grant NN 204 193 038.
Synlett 2012, 23, 2682–2686
© Georg Thieme Verlag Stuttgart · New York

LETTER
by column chromatography (SiO2, hexane–EtOAc, 4:1);
Synthesis of Quinoline-4-carbonitriles
2685
H), 8.11–8.18 (m, 3 H), 8.20 (s, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 115.36, 118.66, 123.59, 123.63, 125.15, 127.37,
129.20, 130.58, 132.04, 132.41, 134.97, 137.28, 146.59,
156.83. IR (KBr): ν = 3056, 2229, 1590, 1542, 1484, 1445,
1384, 1341, 1234, 1089, 1026, 891, 826, 774, 762 cm–1. MS
(EI, 70 eV): m/z (%) = 266 (35) [M+ + 2], 264 (100), 229
(40), 201 (7). HRMS (EI): m/z calcd for C16H9N235Cl:
264.0454; found: 264.0443.
yield 91%; yellow oil. 1H NMR (500 MHz, CDCl3): δ = 3.70,
3.73, 5.29 (ABX, J = 17.9, 8.2, 5.1 Hz, 3 H), 7.46–7.53 (m,
2 H), 7.52 (dd, J = 8.8, 2.2 Hz, 1 H), 7.59–7.64 (m, 1 H), 7.88
(d, J = 2.2 Hz, 1 H), 8.07 (d, J = 8.8 Hz, 1 H). 13C NMR (100
MHz): δ = 29.04, 43.47, 118.99, 127.25, 128.12, 128.89,
129.87, 130.89, 132.36, 134.12, 135.19, 140.86, 193.56.
ESI-HRMS: m/z calcd for C16H11N2O3ClNa: 337.0350;
found: 337.0367.
2-tert-Butyl-6-methoxyquinoline (4e)
Selected Data
Colorless crystals. 1H NMR (500 MHz, CDCl3): δ = 1.45 (s,
9 H), 3.91 (s, 3 H), 7.03 (d, J = 2.9 Hz, 1 H), 7.31 (dd, J =
9.2, 2.9 Hz, 1 H), 7.47 (d, J = 8.7 Hz, 1 H), 7.95 (d, J = 9.2
Hz, 1 H), 7.96 (d, J = 8.7 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 30.18, 37.80, 55.45, 104.93, 118.39, 121.41,
127.19, 130.76, 134.74, 143.40, 157.16, 166.78. IR (CHCl3):
ν = 2961, 1625, 1601, 1563, 1498, 1471, 1378, 1229, 1163,
1102, 1032, 852, 834 cm–1.
2-(5-Chloro-2-nitrophenyl)-4-oxopentanenitrile (2a)
Pale yellow crystals; mp 113–115 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.22 (s, 3 H), 3.14, 3.17, 5.06 (ABX, J = 18.2,
8.2, 5.1 Hz, 3 H), 7.51 (dd, J = 8.8, 2.1 Hz, 1 H), 7.79 (d, J =
2.1 Hz, 1 H), 8.05 (d, J = 8.8 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 28.77, 29.40, 47.56, 118.74, 127.26, 129.89,
130.79, 132.07, 140.90, 145.90, 201.85. ESI-HRMS: m/z
calcd for C11H9N2O3ClNa: 275.0194; found: 275.0197.
2-(5-Fluoro-2-nitrophenyl)-4-oxo-4-phenylbutyronitrile
(2d)
2-Phenyl-6-(trifluoromethyl)quinoline (4g)
Colorless crystals; mp 119–120 °C (lit.16 mp 120–122 °C).
1H NMR (500 MHz, CDCl3): δ = 7.47–7.61 (m, 3 H), 7.90
(dd, J = 9.1, 1.8 Hz, 1 H), 7.98 (d, J = 8.6 Hz, 1 H), 8.15 (s,
1 H), 8.18–8.22 (m, 2 H), 8.28 (d, J = 9.1 Hz, 1 H), 8.31 (d,
J = 8.6 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 120.05,
124.07 (q, J = 273 Hz), 125.31 (q, J = 3.0 Hz), 125.43 (q, J
= 4.4 Hz), 126.06, 127.66, 128.00 (q, J = 32.8 Hz), 128.95,
129.94, 130.85, 137.46, 138.90, 149.24, 159.32. 19F NMR
(470 MHz, CDCl3): δ = –62.27.
Orange-red oil. 1H NMR (500 MHz, CDCl3): δ = 3.71, 3.75,
5.32 (ABX, J = 18.0, 7.9, 5.3 Hz, 3 H), 7.24 (ddd, J = 9.2,
6.8, 2.7 Hz, 1 H), 7.46–7.51 (m, 2 H), 7.59–7.63 (m, 2 H),
7.91–7.95 (m, 2 H), 8.19 (dd, J = 9.2, 5.1 Hz, 1 H). 13C NMR
(125 MHz, CDCl3): δ = 29.35, 43.37, 116.80 (d, J = 22.4
Hz), 118.17 (d, J = 24.8 Hz), 119.05, 128.12, 128.84 (d, J =
9.8 Hz), 128.89, 133.94 (J = 8.3 Hz), 134.12, 135.22, 143.86,
163.06 (d, J = 272 Hz), 193.57. 19F NMR (470 MHz,
CDCl3): δ = –100.44 (ddd, J = 8.6, 6.8, 5.1 Hz). ESI-HRMS:
m/z calcd for C16H11N2O3Na: 321.0646; found: 321.0654.
5,5-Dimethyl-1-(1-octyl-4-nitro-2-phenyl-1H-indol-5-yl)-
5-oxohexanenitrile (15a)
2-Phenylbenzo[h]quinoline-4-carbonitrile (13)
Yield 55%; yellow crystals, mp 177–180 °C. 1H NMR (500
MHz, CDCl3): δ = 7.46–7.60 (m, 3 H), 7.72–7.80 (m, 2 H),
7.88–7.95 (m, 2 H), 7.99 (d, J = 9.4 Hz, 1 H), 8.20 (s, 1 H),
8.24–8.30 (m, 2 H), 9.39 (d, J = 7.8 Hz, 1 H). 13C NMR (125
MHz, CDCl3): δ =116.21, 118.97, 121.32, 121.79, 123.56,
124.91, 127.32, 127.84, 128.10, 129.10, 129.32, 130.14,
130.36, 131.20, 133.93, 137.85, 146.68, 155.03. IR (KBr): ν
= 3059, 2225, 1621, 1582, 1548, 1499, 1442, 1375, 1333,
1275, 1027, 894, 821, 759, 681 cm–1. MS (EI, 70 eV): m/z
(%) = 280 (100) [M+], 253 (5), 252 (5), 251 (6). HRMS (EI):
m/z calcd for C20H12N2: 280.1001; found: 280.1009.
8-tert-Butyl-3-octyl-2-phenyl-3H-pyrrolo[2,3-
Yield 76%; orange-red oil. 1H NMR (400 MHz, CDCl3): δ =
0.85 (t, J = 6.8 Hz, 3 H),1.17 (s, 9 H), 1.09–1.30 (m, 10 H),
1.61–1.70 (m, 2 H), 3.25, 3.27, 5.10 (ABX, J = 18.1, 8.1, 5.0
Hz, 3 H), 4.21 (t, J = 7.6 Hz, 2 H), 6.96 (s, 1 H), 7.46–7.53
(m, 5 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.02, 22.53, 26.20, 26.55,
28.88, 28.95, 29.45, 29.99, 31.62, 42.81, 43.97, 44.40,
102.06, 115.45, 120.59, 121.80, 122.85, 123.34, 128.79,
129.10, 129.35, 131.45, 138.79, 139.44, 146.39, 210.31.
ESI-HRMS: m/z calcd for C30H37N3O3Na: 510.2727; found:
510.2736.
h]quinoline (17a)
Yield 49%; yellow oil. 1H NMR (500 MHz, CDCl3): δ = 0.84
(t, J = 7.2 Hz, 3 H), 1.10–1.27 (m, 10 H), 1.51 (s, 9 H), 1.62–
1.72 (m, 2 H), 4.28 (t, J = 7.7 Hz, 2 H), 7.38 (s, 1 H), 7.38 (s,
1 H), 7.39–7.58 (m, H), 7.44 (d, J = 8.5 Hz, 1 H), 8.10 (d, J
= 8.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 14.04,
22.57, 26.62, 29.01, 30.37, 30.48, 31.70, 38.12, 44.21,
102.49, 111.50, 115.47, 121.03, 121.45, 124.63, 127.68,
128.45, 129.54, 133.52, 135.94, 136.26, 139.74, 142.91,
168.02. IR (KBr): ν = 2955, 2927, 2856, 1604, 1517, 1478,
1465, 1404, 1362, 1335, 1130, 833, 761, 699 cm–1.
3-Octyl-2,8-diphenyl-3H-pyrrolo[2,3-h]quinoline-6-
carbonitrile (16b)
(8) Reduction of Ketonitriles – General Procedure
To a solution of ketonitrile 2, 12, 15, or 20 (1 mmol) in
EtOAc (5 mL) and EtOH (1 mL) was added SnCl2 (0.76 g, 4
equiv). The reaction mixture was stirred at r.t. until the
starting material disappeared (12–24 h, TLC). After
completion, the reaction mixture was diluted with EtOAc
(20 mL) washed with 10% aq KF (2 × 10 mL) dried with
Na2SO4, filtered, and evaporated. The residue was purified
by column chromatography (SiO2, hexane–EtOAc, 2:1).
Selected Data
2-tert-Butyl-6-chloroquinoline-4-carbonitrile (3b)
Colorless crystals; mp 137–140 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.47 (s, 9 H), 7.73 (dd, J = 9.0, 2.3 Hz, 1 H), 8.07
(d, J = 9.0 Hz, 1 H), 8.11 (d, J = 2.3 Hz, 1 H). 13C NMR (125
MHz, CDCl3): δ = 29.80, 38.49, 115.65, 117.87, 123.28,
123.37, 124.51, 131.76, 131.77, 134.33, 145.74, 169.18. IR
(KBr): ν = 2953, 2227, 1588, 1548, 1480, 1461, 1445, 1364,
1206, 1150, 1108, 1078, 924, 893, 834 cm–1. MS (EI, 70 eV):
m/z (%) = 244 (24) [M+], 243 (12), 231 (42), 229 (100), 202
(20), 188 (6). HRMS (EI): m/z calcd for C14H1335ClN2:
246.0767; found: 244.0760.
Yield 60%; yellow solid; mp 103–105 °C. 1H NMR (500
MHz, CDCl3): δ = 0.82 (t, J = 7.6 Hz, 3 H), 1.10–1.30 (m, 10
H), 1.70–1.80 (m, 2 H), 4.30 (t, J = 6.8 Hz, 2 H), 7.42–7.60
(m, 9 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H),
8.10 (s, 1 H), 8.24–8.28 (m, 2 H). 13C NMR (125 MHz,
CDCl3): δ = 14.05, 22.57, 26.60, 28.96, 29.03, 30.58, 31.67,
44.46, 103,16, 114.77, 116.92, 117.56, 118.85, 119.51,
120.52, 124.90, 127.33, 128.23, 128.66, 128.96, 129.53,
129.78, 132.72, 136.83, 138.40, 141.19, 143.96, 154.87. IR
(KBr): ν = 2918, 2850, 2229, 1584, 1539, 1466, 1422, 1399,
1343, 1299, 1170, 1024, 888, 816, 773, 752, 693 cm–1. ESI-
HRMS: m/z calcd for C32H32N3: 458.2591; found: 458.2613.
6-Chloro-2-phenylquino-line-4-carbonitrile (3c)
Yellow crystals; mp 176–179 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.50–7.58 (m, 3 H), 7.78 (dd, J = 8.9, 2.5 Hz, 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2682–2686

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R. Bujok et al.
LETTER
described in: Wojciechowski, K.; Mąkosza, M. Synthesis
3-(Benzyloxymethyl)-2-methyl-7-phenylpyrrolo[3,2-
h]quinoline-9-carbonitrile (21)
1989, 106.
Pale yellow crystals; mp 190–192 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.59 (d, J = 0.9 Hz, 3 H), 4.47 (s, 2 H), 5.68 (s,
2 H), 7.25–7.38 (m, 6 H), 7.46–7.58 (m, 4 H), 7.85 (d, J =
9.1 Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 8.15–8.18 (m, 2 H),
8.19 (s, 1 H). 13 C NMR (125 Hz, CDCl3): δ = 12.69, 69.76,
71.95, 103.44, 115.45, 116.16, 118.86, 120.65, 122.56,
123.82, 127.10, 127.77, 128.15, 128.60, 128.73, 129.02,
129.54, 134.57, 136.72, 137.09, 138.29, 146.17, 153.24.
HRMS (EI): m/z calcd for C27H21N3O: 403.1685; found:
403.1682.
(14) 6-Methoxy-2-phenyl-1,2,3,4-tetrahydroquinoline-4-
carbonitrile (22): Selected Data
1H NMR (500 MHz, CDCl3): δ = 2.32 (ddd, J = 13.0, 12.1,
11.3 Hz, 1 H), 2.48 (ddd, J = 12.2, 5.4, 2.6 Hz, 1 H), 3.77 (s,
3 H), 4.27 (dd, J = 11.3, 2.6 Hz, 1 H), 4.34 (dd, J = 12.1, 5.4
Hz, 1 H), 6.53 (d, J = 8.6 Hz, 1 H), 6.74 (dd, J = 8.6, 2.7 Hz,
1 H), 6.93 (d, J = 2.7 Hz, 1 H), 7.32–7.42 (m, 5 H). 13C NMR
(125 MHz, CDCl3): δ = 29.98, 35.03, 55.89, 56.08, 112.97,
116.37, 120.51, 126.53, 126.65, 128.35, 128.83, 128.87,
141.96, 152.58. IR (KBr): ν = 3379, 3341, 2237, 1503, 1343,
1286, 1245, 1231, 1165, 1113, 1034, 811, 765, 702 cm–1. MS
(EI, 70 eV): m/z (%) = 264 (100) [M+], 263 (34), 224 (10),
187 (27), 160 (7). HRMS (EI): m/z calcd for C17H16N2O:
264.1263; found: 264.1270.
(9) Ramesh, C.; Kavala, V.; Kuo, C.-W.; Yao, C.-F.
Tetrahedron Lett. 2010, 51, 5234.
(10) Kuhn, A.; von Eschwege, K. G.; Conradie, J. J. Phys. Org.
Chem. 2012, 25, 58.
(11) (a) Barros, A. I. R. N. A.; Silva, A. M. S. Tetrahedron Lett.
2003, 44, 5893. (b) Okuma, K.; Seto, J.-i.; Nagahora, N.;
Shioji, K. J. Heterocycl. Chem. 2010, 47, 1372.
(12) Mąkosza, M.; Winiarski, J. J. Org. Chem. 1984, 49, 1494.
(13) The starting materials 14 and 19 were obtained from the
corresponding nitroindoles following the procedure
(15) Bunce, R. A.; Schammerhorn, J. E.; Slaughter, L. M. J.
Heterocycl. Chem. 2007, 44, 1051.
(16) Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. J.
Org. Chem. 2008, 73, 74.
Synlett 2012, 23, 2682–2686
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