Synthesis of heterocyclic derivatives of alkyl 2-(cyanomethyl)-4-methyl-3- quinolinecarboxylates

Article abstract of DOI:10.1002/jhet.705

The article reports reactions of a series of known alkyl 2-(cyanomethyl)-4-methyl-3-quinolinecarboxylates. In the course of the present study the synthesis of new heterocyclic derivatives of alkyl 2-(cyanomethyl)-4-methyl-3-quinolinecarboxylates was achie

Full text of DOI:10.1002/jhet.705

September 2011 Synthesis of Heterocyclic Derivatives of Alkyl 2-(Cyanomethyl)-
4-methyl-3-quinolinecarboxylates
1149
Alexey S. Degtyarenko,a* Andrey A. Tolmachev,b and Yulian M. Volovenkoa
aChemistry Department, Organic Division, Kiev National Taras Shevchenko University, 01033,
Kiev, Ukraine
bEnamine Ltd., Alexandra Matrosova str. 23, 01103, Kiev, Ukraine
*E-mail: degtyarenko@chem.univ.kiev.ua
Received March 15, 2010
DOI 10.1002/jhet.705
Published online 8 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
The article reports reactions of a series of known alkyl 2-(cyanomethyl)-4-methyl-3-quinolinecarboxy-
lates. In the course of the present study the synthesis of new heterocyclic derivatives of alkyl 2-(cyano-
methyl)-4-methyl-3-quinolinecarboxylates was achieved.
J. Heterocyclic Chem., 48, 1149 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
Quinolineacetonitrile core is found in many biologi-
cally potent compounds. In this context, many synthetic
routes to quinilineacetonitriles were developed [1–9].
Synthetic interest in these compounds has been stimu-
lated by two factors: (i) the chemical activity of the
nitrile unit in addition reactions and (ii) the chemical ac-
tivity of the methylene group in electrophilic substitu-
tion reaction. The mentioned groups have been used in
many step-by-step domino-type syntheses leading to a
number of structurally diverse heterocyclic compounds
[10]. Besides quinolineacetonitriles other hetarylacetoni-
triles belong to a little investigated class of compounds
with considerable synthetic potential. This work was
undertaken to prepare novel hetarylacetonitriles and
investigate their chemical properties.
Methylene group of arylacetonitriles is known to readily
react with anhydrides and chloroanhydrides of carboxylic
acids [12–16]. We carried out this reaction with alkyl-2-
chloromethyl-4-methyl-3-quinolinecarboxylates
using
chlorides of aliphatic and aromatic carboxylic acids as acy-
lating agents (Scheme 1). The reaction proceed quickly
under mild conditions giving products 2 in 69–94% iso-
lated yields. 1H-NMR spectra of compounds 2 display sin-
glets of NH protons near 16.5 ppm. The considerable low-
field chemical shift is indicative of a strong intramolecular
hydrogen bonding of NH-proton with carbonyl oxygen.
As shown in Scheme 2, the active chlorine of ethyl 2-
(3-chloro-1-cyano-2-oxopropyl)-4-methylquinolino-3-car-
boxylate 2d is readily substituted with sulfide anion
giving rise to the corresponding thioether 3. Interestingly,
similar reaction of compound 2d with aromatic amines
does not yield the substitution product. The expected sec-
ondary amine 50 (Scheme 2) underwent an intramolecular
addition reaction with nitrile moiety followed by an intra-
molecular acylation. Thus, the derivatives of the new
heterocyclic system benzo[b]pyrrolo[2,3-h]naphthyridine
5a–c were obtained by a domino-type process reaction
depicted in Scheme 2.
In our recent paper, we described the synthesis and
chemical properties of some 2-chloromethyl-4-methyl-3-
quinolinecarboxylates and alkyl 2-(cyanomethyl)-4-
methyl-3-quinolinecarboxylates [11]. These compounds
bear four selectively addressable reactive groups, such as
ester, nitrile, methylene group, and the ring nitrogen.
Here, we investigate the reactivity of these groups toward
different electrophilic and nucleophilic reagents.
C
V
2011 HeteroCorporation

1150
A. S. Degtyarenko, A. A. Tolmachev, and Y. M. Volovenko
Vol 48
Scheme 1
Scheme 3
The structure and purity of compounds 5 were fully
confirmed by means of NMR and IR spectroscopy and
LCMS analysis. Signals pertaining to nitrile and ester
1
groups are absent in the IR spectra of 5a–c. In H-NMR
1
As appears from H-NMR spectrum of compound 6
recorded in DMSO-d6, keto-enol tautomeric equilibrium
is shifted to the enol form (60%).
spectra of 5a–c, the signal of methyl group in position 4
of the quinoline ring is low-field shifted by 1 ppm com-
pared with the corresponding proton signal in com-
pounds 2. The latter effect is the result of magnetic field
of conformationally restricted amide oxygen with
respect to the methyl group in 5.
All attempts to substitute the chlorine atom of 2d by
reactions with aliphatic amines or alcohols were unsuc-
cessful. As shown in Scheme 3, the reaction only leads
to the product of intramolecular alkylation 6. Most prob-
ably, O- and N-nucleophiles act as bases with respect to
NH-proton of compound 2d.
The attempts to use quinoline 1 in Knovenagel conden-
sation with various aldehydes in the presence of bases
such as morpholine or pyrimidine were unsuccessful.
Therefore, we have optimized the reaction conditions for
obtaining the Knoevenagel adducts 7 (Scheme 4). The
condensation proceeded successfully in pyridine in the
presence of chlorotrimethylsilan affording compounds 7 in
exclusively Z-isomeric form in nearly quantitative yields.
The quinoline nitrogen is easily alkylated [17–19]. An
intramolecular alkylation of the quinoline nitrogen
securing the quinoline aromatic system is the most pre-
ferred reaction of this type. Thus, a condensation of 1
and 1,3-dichloro-2-propanone under Knoevenagel condi-
tions gives rise to a novel derivative of pyrrolo[1,2-
a]quinoline 8 (Scheme 5). No open chain Knoevenagel
adduct 80 was isolated. The structure of 8 was proved
by single crystal X-ray analysis (Fig. 1).
Scheme 2
We investigated the chemical reactivity of chlorine
atom in compound 8 toward nucleophilic agents, such
as benzylamine. As shown in Scheme 6, the reaction of
8 with benzylamine yields open chain secondary amine
9. All attempts at the subsequent intramolecular cycliza-
tion reaction of 9 to obtain tricyclic derivative 10 were
hitherto unsuccessful.
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis of Heterocyclic Derivatives of Alkyl 2-(Cyanomethyl)-
4-methyl-3-quinolinecarboxylates
1151
Scheme 5
Scheme 6
room temperature. The reaction mixture was stirred at 50ꢀC
for 1 h. The solvent was removed under reduced pressure, and
the residue was triturated with water (10 mL). The precipitated
solid was filtered, washed with water, and dried in vacuum to
give pure derivatives 2a–c. Compounds 2 could additionally
be purified by recrystallization from EtOH.
All starting materials were purchased from commer-
cial sources and used without additional purification.
Commercial DMF was additionally dried by distillation
over P2O5 under reduced pressure. Melting points were
determined in open capillary tubes in a Thiele apparatus
and uncorrected. 1H and 13C-NMR spectra were
recorded on a Varian UNITYplus 400 spectrometer (400
2-(1-Cyano-2-oxopropyl)-4-methyl-3-quinolinecarboxylic acid,
1
methyl ester (2a). Yield 94%. M.p. 199ꢀC (EtOH). H-NMR: d
1
MHz for H and 100 MHz for 13C) in DMSO-d6 solu-
¼ 2.33 (s, 3H, CH3CO), 2.55 (s, 3H, 4-CH3), 3.90 (s, 3H,
COOCH3), 7.56 (t, 1H, J ¼ 7.5 Hz), 7.76 (d, 1H, J ¼ 8 Hz),
7.81(t, 1H, J ¼ 7 Hz), 8.06(d, 1H, J ¼ 7.5 Hz), 16.5 (s, 1H,
NH). 13C-NMR: d ¼ 16.6 (CH3), 28.2 (CH3), 53 (OCH3), 76.1
(COCHCN), 119.3 (CN), 120.1, 122.1, 123.2, 125.1, 126.5,
133.6, 135.2, 148.1, 150.2, 166.0 (COO), 195.5 (CO). Anal.
Calcd. for C16H14N2O3: C, 68.07, H, 5.00, N, 9.45. Found: C,
68.11, H, 5.06, N, 9.47. Ms: m/z 283, 284 (Mþ.).
tions. Chemical shifts (d) are given in ppm with TMS as
internal standard. LC/MS analyses were performed on
an Agilent 1100 instrument. The structure and purity of
all compounds were confirmed by 1H- and 13C-NMR,
LC/MS, and elemental analysis.
2-(1-Cyano-4-methyl-2-oxopentyl)-4-methyl-3-quinolinecar-
boxylic acid, methyl ester (2b). Yield 89%. M.p. 190ꢀC
(EtOH). 1H-NMR: d ¼ 0.94 (d, 6H, J ¼ 6.5 Hz, (CH3)2CH),
2.16 (m, 1H, J ¼ 6.5 Hz, (CH3)2CH), 2.55 (d, 2H, J ¼ 7 Hz,
CH2CH), 2.58 (s, 3H, 4-CH3), 3.91 (s, 3H, COOCH3), 7.58 (t,
1H, J ¼ 7.25 Hz), 7.83 (w.s, 2H), 8.1 (d, 1H, J ¼ 8 Hz), 16.5
(s, 1H, NH). 13C-NMR: d ¼ 17.0 (CH3), 22.9 ((CH3)2), 26.1
(CH2), 53.3 (OCH3), 76.2 (COCHCN), 119.3 (CN), 120.1,
122.0, 123.1, 125.8, 126.8, 134.1, 135.5, 148.4, 149.8,
166.1(COO), 195.5 (CO). Anal. Calcd. for C19H20N2O3 : C,
70.35, H, 6.21, N, 8.64. Found: C, 70.46, H, 6.30, N, 8.66.
Ms: m/z 325, 326 (Mþ.).
EXPERIMENTAL
General procedure for the acylation of 1. Cyanomethyl
quinolin 1 (1 g., 4 mmol) and pyridine (4.2 mmol) were dis-
solved in 4 mL of 1,4-dioxane. Then, an acid chloranhydride
(4.2 mmol) was added drop wise to the stirred solution at
2-(1-Cyano-2-oxo-2-phenylethyl)-4-methyl-3-quinolinecar-
boxylic acid, methyl ester (2c). Yield 88%. M.p. 263ꢀC
(EtOH). 1H-NMR: d ¼ 2.63 (s, 3H, 4-CH3), 3.91 (s, 3H,
COOCH3), 7.56 (w.s, 2H,), 7.76 (d, 1H, J ¼ 8 Hz), 7.81(t, 1H,
J ¼ 7 Hz), 7.91 (w.s, 4H), 8.06(d, 1H, J ¼ 7.5 Hz), 16.5 (s,
1H, NH). 13C-NMR: d ¼ 16.2 (CH3), 27.0 (OCH3), 53.1
(COCHCN), 116.2, 124.1, 125.8, 126.5, 128.0, 129.5, 130.1,
130.9, 131.3, 134.8, 145.2, 147.1, 168.2. Anal. Calcd. for
C21H16N2O3: C, 73.24, H, 4.68, N, 8.13. Found: C, 73.45, H,
4.58, N, 8.10. Ms: m/z 345, 346 (Mþ).
2-(3-Chloro-1-cyano-2-oxopropyl)-4-methyl-3-quinolinecar-
boxylic acid, ethyl ester (2d). Cyanomethylquinolin 1 (1 g., 4
mmol) and pyridin (4.2 mmol) were dissolved in 5 mL of 1,4-
dioxane. The solution was cooled on an ice bath to ca. 5ꢀC.
Then, chloroacetylchloride (4.2 mmol) was added drop wise to
the stirred solution. The reaction mixture was stirred at room
Figure 1. X-ray molecular structure of methyl 2-(chloromethyl)-3-
cyano-5-methyl-pyrrolo[1,2-a]quinoline-4-carboxylat 8.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1152
A. S. Degtyarenko, A. A. Tolmachev, and Y. M. Volovenko
Vol 48
temperature for 3 h. The precipitated solid was filtered, washed
with water, and dried in vacuum to give pure 2d. Yield 69%.
M.p. 180ꢀC (EtOH). 1H-NMR: d ¼ 1.34 (t, 3H, J ¼ 7 Hz,
OCH2CH3), 2.63 (s, 3H, 4-CH3), 4.41 (k, 2H, J ¼ 7 Hz,
OCH2CH3), 4.59 (d, 2H, J ¼ 2.5 Hz, COCH2Cl), 7.63 (t, 1H,
J ¼ 7.5 Hz), 7.88 (m, 2H, J ¼ 7.5 Hz), 8.14 (d, 1H, J ¼ 7.5
Hz), 16.5 (s, 1H, NH). 13C-NMR: d ¼ 14.0(OCH2CH3), 16.7
(OCH2CH3), 47.1, 62.6, 74.3, 118.7(CN), 119.6, 122.9, 123.4,
125.8, 127.0, 133.9, 134.9, 148.9, 149.3, 165.3 (COO),
188.9(CO). Anal. Calcd. for C17H15ClN2O3 :C, 61.73, H, 4.57,
Cl, 10.72, N, 8,47. Found: C, 61.90, H, 4.63, Cl, 10.65, N,
8,44. Ms: m/z 333, 334 (Mþ).
perature a solid precipitate was formed. The precipitated solid
was filtered, washed with water, and dried in vacuum to give
pure 5a–c.
3-(4-Bromophenyl)-6-methyl-2,3-dihydro-1H-benzo[b]-pyr-
rolo[2,3-h]-1,6-naphthiridine-1,5(11H)-dione (5a). Yield 38%.
M.p. >300ꢀC. 1H-NMR (TFA): d ¼ 3.60 (s, 3H, CH3), 7.46
(w.s, 2H), 7.88 (w.s, 2H), 8.04 (w.s, 1H), 8.31 (w.s, 2H), 8.71
(w.s, 1H). 13C-NMR (TFA): d ¼ 16.9, 71.4, 91.0, 110.9,
113.2, 115.4, 117.7, 119.2, 125.35, 125.8, 126.6, 127.3, 129.0,
131.4, 134.2, 136.8, 138.5, 143.8, 163.3, 168.5, 191.6. Anal.
Calcd. for C21H14BrN3O2: C, 60.02, H, 3.36, N, 10,00. Found:
C, 60.10, H, 3.41, N, 9.91. Ms: m/z 421 (Mþ).
General procedure for Knoevenagel reaction of 1 with
4. Cyanomethylquinoline 1 (1 g., 4 mmol) and benzaldehyde
(4.2 mmol) were dissolved in 5 mL of pyridine. Then TMS-Cl
(0.86 g, 8.2 mmol) was poured carefully in one portion to the
solution. The reaction mixture was heated at 50–55ꢀC for 1 h
and then left overnight at room temperature. The precipitated
solid was filtered, washed with water, and dried in vacuum to
give pure compounds 7a–c. Compounds 7 could be addition-
ally purified by recrystallization from EtOH.
3-(4-Chlorophenyl)-6-methyl-2,3-dihydro-1H-benzo[b]-pyr-
rolo[2,3-h]-1,6-naphthiridine-1,5(11H)-dione (5b). Yield 35%.
M.p. >300ꢀC. 1H-NMR (TFA): d ¼ 3.45 (s, 3H, CH3), 7.46
(w.s, 2H), 7.52 (w.s, 2H), 7.85 (w.s, 1H), 8.17 (w.s, 2H), 8.47
(w.s, 1H). 13C-NMR (TFA): d ¼ 17.0, 111.1, 113.3, 115.6,
117.9, 126.7, 127.4, 129.2, 131.2, 137.9, 138.6, 163.3, 168.6,
191.8. Anal. Calcd. for C21H14ClN3O2: C, 67.12, H, 3.75, Cl,
9.43, N, 11.18. Found: C, 67.16, H, 3.80, Cl, 9.42, N, 11.15.
Ms: m/z 376, 377 (Mþ).
2-{(Z)-1-Cyano-2-phenyletenyl}-4-methyl-3-quinolinecarbox-
1
3-(3,5-Dimethylphenyl)-6-methyl-2,3-dihydro-1H-benzo[b]-
pyrrolo[2,3-h]-1,6-naphthiridine-1,5(11H)-dione (5c). Yield
36%. M.p. >300ꢀC. 1H-NMR (TFA): d ¼ 2.33 (s, 6H, CH3),
3.45 (s, 3H, CH3), 6.95 (w.s, 2H), 7.18 (w.s, 1H), 7.83 (w.s,
1H), 8.20 (w.s, 2H), 8.51 (w.s, 1H). 13C-NMR (TFA): d ¼
17.0, 19.5, 111.2, 113.4, 115.5, 118.0, 119.1, 122.3, 126.1,
127.5, 129.2, 132.8, 138.7, 142.2, 163.3, 168.4, 191.0. Anal.
Calcd. for C23H19N3O2: C, 74.78, H, 5.18, N, 11.37. Found:
C, 74.75, H, 5.16, N, 11.30. Ms: m/z 370, 371 (Mþ).
ylic acid, ethyl ester (7a). Yield 80%. M.p. 95ꢀC (EtOH). H-
NMR: d ¼ 1.29 (t, 3H, J ¼ 6.5 Hz, OCH2CH3), 2.77 (s, 3H,
4-CH3), 4.39 (k, 2H, J ¼ 6.5 Hz, OCH2CH3), 7.56 (m, 3H),
7.76 (t, 1H, J ¼ 7.5 Hz), 7.92 (m, 4H), 8.10 (d, 1H, J ¼ 8
Hz), 8.26 (d, 1H, J ¼ 8 Hz). 13C-NMR: d ¼ 14.2, 16.0, 62.5,
110.6, 117.7, 125.4, 126.0, 126.6, 128.7, 129.6, 129.7, 130.0,
131.9, 132.0, 133.3, 145.1, 146.7, 149.2, 149.6, 167.5(CO).
Anal. Calcd. for C22H18N2O2: C, 77.17, H, 5.30, N, 8.18.
Found: C, 77.06, H, 5.24, N, 8.13. Ms: m/z 343, 344(Mþ.).
2-{(Z)-1-Cyano-2-[4-(dimethylamino)phenyletenyl]}-4-methyl-
3-quinolinecarboxylic acid, ethyl ester (7b). Yield 85%. M.p.
158ꢀC (EtOH). 1H-NMR: d ¼ 1.27 (t, 3H, J ¼ 6.5 Hz,
OCH2CH3), 2.71 (s, 3H, 4-CH3), 3.04 (s, 6H, (Me)2N), 4.37
(k, 2H, J ¼ 6.5 Hz, OCH2CH3), 6.82 (d, 2H, J ¼ 8 Hz), 7.70
(m, 2H), 7.87 (d, 3H, J ¼ 7.5 Hz), 8.05 (d, 1H, J ¼ 8 Hz),
8.21 (d, 1H, J ¼ 8 Hz). 13C-NMR: d ¼ 14.3 (OCH2CH3), 15.9
(OCH2CH3), 62.3, 102.1, 112.1, 119.2, 120.5, 125.3, 126.1,
128.0, 129.8, 132.1, 144.4, 146.8, 149.3, 150.5, 152.8,
167.9(CO). Anal. Calcd. for C24H23N3O2: C, 74.78, H, 6.01,
N, 10.90. Found: C, 74.87, H, 6.09, N, 10.79. Ms: m/z 386,
387 (Mþ.).
2-{(Z)-1-Cyano-2-[4-nitrophenyl]etenyl]}-4-methyl-3-quino-
linecarboxylic acid, ethyl ester (7c). Yield 89%. M.p. 204ꢀC
(EtOH). 1H-NMR: d ¼ 1.29 (t, 3H, J ¼ 6.5 Hz, OCH2CH3),
2.77 (s, 3H, 4-CH3), 4.39 (k, 2H, J ¼ 6.5 Hz, OCH2CH3),
7,79 (t, 1H, J ¼ 7.5 Hz), 7.93 (t, 1H, J ¼ 7.5 Hz), 8.08 (s,
1H), 8.12(d, 1H, J ¼ 8 Hz), 8.16 (d, 2H, J ¼ 8 Hz), 8.28(d,
1H, J ¼ 8 Hz), 8.39(d, 2H, J ¼ 8 Hz). 13C-NMR: d ¼ 14.2,
15.9, 62.6, 114.4, 116.9, 124.1, 124.6, 125.4, 125.9, 126.8,
128.9, 130.1, 130.2, 132.0, 139.3, 145.5, 146.7, 146.8, 148.9,
167.3 (CO). Anal. Calcd. for C22H17N3O4: C, 68.16, H, 4.38,
N, 10.85. Found: C, 68.05, H, 4.25, N, 10.78. Ms: m/z 388,
389 (Mþ.).
2-{1-Cyano-3-[(2-etoxy-2-oxoethyl)thio]-2-oxopropyl}--4-methyl-
3-quinolinecarboxylic acid, ethyl ester (3). Quinoline 2d (1g., 3
mmol) and ethyl ester of mercaptoacetic acid (0.28 g, 3 mmol)
were dissolved in 4 mL of DMF. Then, triethylamine (3.1
mmol, 0.43 mL) was added to the solution. The reaction mix-
ture was stirred for 24 h at room temperature. The solvent was
removed under reduced pressure. The solid residue was tritu-
rated with water (5 mL), filtered, and recrystallized from i-
PrOH to yield compound 3. Yield 94%. M.p. 123ꢀC. 1H-
NMR: d ¼ 1.18 (t, 3H, J ¼ 7 Hz), 1.34 (t, 3H, J ¼ 7 Hz),
2.62 (s, 3H), 3.48 (s, 2H), 3.78 (s, 2H), 4.09 (k, 2H, J ¼ 7
Hz), 4.40 (k, 2H, J ¼ 7 Hz), 7.61 (t, 1H, J ¼ 8,5 Hz), 7.87
(w.s., 2H), 8.13 (d, 1H, J ¼ 8.5 Hz), 16.5 (s, 1H, ANH). 13C-
NMR:
d
¼
14.0(OCH2CH3), 14.4, 16.7, 33.7, 61.3,
62.5(OCH2CH3), 75.0, 119.4, 119.5, 122.9, 123.5, 125.9,
126.8, 133.8, 135.0, 148.5, 149.7, 165.4, 170.0, 192.8. Anal.
Calcd. for C21H22N2O5S: C, 60.85, H, 5.35, N, 6.76. Found:
C, 60.79, H, 5.34, N, 6.72. Ms: m/z 415, 417 (Mþ.).
3-Cyano-2-hydroxy-5-methylpyrrolo[1,2-a]quinoline-4-carbox-
ylic acid, ethyl ester (6). Cyanomethylquinoline 1 (1 g., 4
mmol) and pyridine (4.2 mmol) were dissolved in 5 mL of
1,4-dioxane. Chloroacetylchloride (4.2 mmol) was added drop
wise to the stirred solution cooled on an ice bath. The reaction
mixture was stirred at 50ꢀC for 4 h. The solvent was removed
under reduced pressure and the residue was triturated with
water (10 mL). The precipitated solid was filtered and washed
General procedure for the preparation of benzo[b]-pyr-
rolo[2,3-h]-naphthyridines 5a–c. Quinoline 2d (1g., 3 mmol)
and aniline (12 mmol) were dissolved in a minimal volume of
dimethylformamide at room temperature with the aid of soni-
cation. The mixture was kept for 5 days at room temperature
and then heated at 50ꢀC for 2 h. Upon cooling to room tem-
1
with water to give 6. Yield 95%. M.p. 206ꢀC. H-NMR: (enol-
form; 60%) d ¼ 1.34 (t, 3H, J ¼ 6.5 Hz, OCH2CH3), 4.41 (k,
2H, J ¼ 6.5 Hz, OCH2CH3), 7.55 (t, 1H, J ¼ 8 Hz), 7.75
(t, 2H), 8.05 (d, 1H, J ¼ 8 Hz), 8.26 (d, 1H, J ¼ 8 Hz), 10.36
(s, 1H, OH); (keton-form; 40%) d ¼ 1.34 (t, 3H, J ¼ 6.5 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis of Heterocyclic Derivatives of Alkyl 2-(Cyanomethyl)-
4-methyl-3-quinolinecarboxylates
1153
OCH2CH3), 2.61 (s, 3H, 4-CH3), 4.41 (k, 2H, J ¼ 6.5 Hz,
OCH2CH3), 4.85 (s, 2H), 7.50 (t, 1H, J ¼ 8 Hz), 7.59 (d, 1H,
J ¼ 8 Hz), 7.83 (t, 1H, J ¼ 8 Hz), 8.10 (d, 1H, J ¼ 8 Hz).
13C-NMR: (enol-form; 60%) d ¼ 14.0(OCH2CH3), 20.3,
60.0(OCH2CH3), 91.6, 104.9, 111.2, 119.5, 119.6, 125.3,
125.9, 128.8, 129.9, 139.8, 141.7, 144.6, 146.2, 162.7; (keton-
form; 40%) d ¼ 14.0(OCH2CH3), 20.3, 52.2, 62.2, 80.75,
111.5, 113.8, 115.3, 122.8, 124.9, 126.1, 130.2, 139.6, 152.0,
167.1, 178.8, 187.9. Anal. Calcd. for C17H14N2O3: C, 69.38,
H, 4.79, N, 9.52. Found: C, 69.35, H, 4.77, N, 9.56. Ms: m/z
295, 296 (Mþ.).
2-(Chloromethyl)-3-cyano-5-methylpyrrolo[1,2-a]quinoline-4-
carboxylic acid, methyl ester (8). Cyanomethylquinolin 1 (1 g.,
4 mmol) and 1,3-dichloro-2-propanone (0.52 g, 4.1 mmol)
were dissolved in 3 mL of DMF. Chlorotrimethylsilane (0.9 g,
8.2 mmol) was added to the solution, and reaction mixture
was stirred at 56ꢀC for 16 h. The precipitated solid was filtered
and recrystallized from i-PrOH to give 8. Yield 66%. M.p.
187ꢀC. 1H-NMR: d ¼ 3.95 (s, 3H, OCH3), 4.95 (s, 2H,
CH2Cl), 7.58 (t, 1H, J ¼ 8 Hz), 7.76 (t, 1H, J ¼ 8 Hz), 8.05
(d, 1H, J ¼ 8 Hz), 8.32 (d, 1H, J ¼ 8 Hz), 8.58 (s, 1H).
13C-NMR: d ¼ 20.3, 38.2, 51.3 (OMe), 91.4, 114.5, 115.4,
119.3, 123.0, 125.2, 125.3, 125.9, 128.5, 130.0, 141.5, 142.8,
145.9, 162.5. Anal. Calcd. for C17H13 ClN2O2: C, 65.29, H,
4.19, Cl, 11.34, N, 8.96. Found: C, 65.18, H, 4.19, Cl, 11.36;
N, 8.99. Ms: m/z 313, 314 (Mþ).
123.0, 125.3, 126.1, 126.5, 126.9, 127.0, 127.8, 130.4, 135.6,
143.3, 143.8, 147.4, 162.5. Anal. Calcd. for C24H21N3O2: C,
75.18, H, 5.52, N, 10.96. Found: C, 75.13, H, 5.55, N, 10.85.
Ms: m/z 384 (Mþ.).
REFERENCES AND NOTES
[1] Braun, H. Chem Ber 1930, 63, 3191.
[2] Borsche, W.; Manteuffel, R. Justus Liebigs Ann Chem 1932,
516, 48.
[3] Borsche, W.; Vorbach, O. Justus Liebigs Ann Chem 1939,
537, 18.
[4] Borsche, W.; Manteuffel, R. Justus Liebigs Ann Chem 1936,
526, 22.
[5] Moon, M. P.; Komin, A. P.; Wolf, J. F.; Morris, G. F. J
OrgChem 1983, 14, 2392.
[6] Hamana, M.; Fujimura, Y.; Haradahira, T. Heterocycles
1987, 25, 229.
[7] Hamana, M.; Iwasaki, G.; Saeki, S. Heterocycles 1982, 17, 177.
[8] Hamana, M.; Iwasaki, G.; Saeki, S. Heterocycles 1982, 19, 162.
[9] Borror, A. L; Haeberer, A. F. J Org Chem 1965, 30, 243.
[10] Reznyanskaya, E. V.; Shokol, T. V.; Tverdokhlebov, A. V.;
Volovenko, Yu. M. Khim Heterocycl Compd 1999, 10, 1412.
[11] Degtyarenko, A. S.; Tolmachev, A. A.; Volovenko, Yu. M.;
Tverdokhlebov, A. V. Synthesis 2007, 24, 3891.
[12] Babichev, F. S.; Volovenko, Yu. M. Khim Heterocycl
Compd 1975, 11, 1005.
3-Cyano-5-methyl-2-[[(phenylmethyl)amino]methyl]pyrrolo[1,2-
a]quinoline-4-carboxylic acid, methyl ester (9). Compound 8
(1 g, 3.2 mmol) and benzylamine (0.72 g, 6.7 mmol) were dis-
solved in 7 mL of DMF. The reaction mixture was stirred at
100ꢀC for 6 h. The solvent was removed under reduced pres-
sure, and the residue was triturated with water (10 mL). The
precipitated solid was filtered and recrystallized from i-PrOH
[13] Babichev, F. S.; Volovenko, Yu. M. Ukr Khim J 1977, 43, 41.
[14] Babichev, F. S.; et al. Khim Heterocycl Compd 1977, 13,
1515.
[15] Volovenko, Yu. M.; Blyumin, E. V.; Shokol, T. V.; Dubi-
nina, G. G.; Babichev, F. S. Khim Heterocycl Compd 1997, 4, 520.
[16] Babichev, F. S.; Volovenko, Yu. M. Khim Heterocycl
Compd 1976, 12, 1147.
1
to give 9. Yield 72%. M.p. 153ꢀC. H-NMR : d ¼ 3.92 (s, 3H,
[17] Kozinchenko, A. P.; Volovenko, Yu. M.; Babichev, F. S.;
Promonenkov, B. K. Khim Heterocycl Compd 1990, 1, 85.
[18] Nemazany, A. G.; Haider, N. J Heterocycl Chem 1996, 33,
1147.
OCH3), 3.94 (s, 2H), 3.97 (s, 2H), 7.26 (t, 1H, J ¼ 7.5 Hz),
7.34 (t, 2H, J ¼ 7.5 Hz), 7.45 (d, 2H, J ¼ 7.5 Hz), 7.58
(t, 1H, J ¼ 8 Hz), 7.76 (t, 1H, J ¼ 8 Hz), 8.05 (d, 1H, J ¼ 8
Hz), 8.32 (d, 1H, J ¼ 8 Hz), 8.58 (s, 1H). 13C-NMR: d ¼
20.3, 41.0, 51.4 (OMe), 56.0, 94.7, 115.3, 116.5, 118.6, 122.5,
[19] Volovenko, Yu. M.; Shokol, T. V. Khim Heterocycl Compd
2003, 39, 629.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet