Friedlander synthesis of benzo[h]naphthyridines from o-aminoaldehydes

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Friedlander Synthesis of
Benzo[h]naphthyridines from o-
Aminoaldehydes
Ramhari V. Rote a , Deepak P. Shelar a , Sandeep R. Patil a &
Madhukar N. Jachak a
a Department of Chemistry, Organic Chemistry Research Centre , K.
T. H. M. College, Gangapur Road , Nashik-, 422 002, (M. S.), India
Published online: 06 Oct 2011.
To cite this article: Ramhari V. Rote , Deepak P. Shelar , Sandeep R. Patil & Madhukar N. Jachak
(2011) Friedlander Synthesis of Benzo[h]naphthyridines from o-Aminoaldehydes, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 43:5, 457-466, DOI:
10.1080/00304948.2011.613702
To link to this article: http://dx.doi.org/10.1080/00304948.2011.613702
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Organic Preparations and Procedures International, 43:457–466, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.613702
Friedlander Synthesis of Benzo[h]naphthyridines
from o-Aminoaldehydes
Ramhari V. Rote, Deepak P. Shelar, Sandeep R. Patil,
and Madhukar N. Jachak
Department of Chemistry, Organic Chemistry Research Centre,
K. T. H. M. College, Gangapur Road, Nashik-422 002, (M. S.), India
The Friedlander reaction is one of the simplest methods for the synthesis of quinoline,1–3
pyrazolopyridine,4 pyrazolonaphthyridine5 and benzonaphthyridine6 derivatives. In its most
general and classical form, it is the base (t-BuLi, KOH, NaOH, piperidine etc.) or acid
promoted condensation of an aromatic 2-amino substituted carbonyl compound (aldehyde,
ketone, or an equivalent thereof) with an appropriately substituted carbonyl derivative
containing a reactive α-methylene group followed by cyclodehydration. In recent years,
7,8
modified methods using Bronsted acids (protic acid) catalysts such as HCl, AcOH, H2SO4
as well as Lewis acid catalysts such as FeCl3, ZnCl2, Bi(OTf)3, Sc(OTf)3, AuCl3 and ionic
liquids have been reported.9–13 Friedlander condensations under solvent-free conditions
using solid catalysts such as sulfamic acid, solid silica-supported-HClO4 and Amberlyst-
15 have been described.14–16 However, the stability and reactivity of the o-aminocarbonyl
component toward an acidic or basic medium plays an important role and is dependent
upon the functional groups attached to the aromatic ring of o-aminocarbonyl compound
and nucleophilicity and/ or electrophilicity of the amino and carbonyl substituents.
Benzonaphthyridines have recently been patented as novel generation growth
regulators, fungicides, bactericides, herbicides and insecticides.17–20 Moreover, some
benzo[h]naphthyridines exhibit remarkable biological and pharmacological activities such
as antimalarials21,22 and antagonists of 5-HT4 receptor.23 The functionalized quinolines
and their benzo/hetero-fused analogues present in numerous natural products, show
wide spectrum physiological activities.24 Recently, we reported the use of 4-amino-
6-chloroquinoline-3-carbalde hyde (1) as a key intermediate for the synthesis of var-
ious benzo[3,4-h][1,6]naphthyridine derivatives.25 The importance of these derivatives
and our interest in this area have led us to explore the synthesis of new polysubsti-
tuted benzo[h][1,6]naphthyridine and pyrimido[5,4-c]quinoline derivatives starting from
1. Heterocyclic o-aminoaldehydes have wide applicability for the annelation of various
Received April 29, 2011; in final form August 3, 2011.
Address correspondence to Madhukar N. Jachak, Department of Chemistry, Organic Chemistry
Research Centre, K. T. H. M. College, Gangapur Road, Nashik-422 002, (M. S.), India. E-mail:
mnjachak@hotmail.com
457

458
Jachak et al.
heterocycles.26–30 The present communication describes the synthetic utility of 4-amino-6-
chloroquinoline-3-carbaldehyde (1) for the synthesis of various benzo[h][1,6]naphthyridine
derivatives under acidic, basic and neutral conditions.
NH2
N
Cl
N
9
CN
Method A,
B, C and D
8
R1
O
O
O
H
CN
R1
N
N
NC
NH2
N
O
NH2
6 a-c
N
N
N
O
Me
Cl
Cl
Cl
2
H
Method D
Method A,
B, C and D
1
3
7 a-c
O
O
Method A,
B, C and D
7
a
b
R1
H
Me
Me
4
CH3
O
Me
c
Ph
Method A = DMF, HCl,
Method B = DMF, ZnCl2,
Method C = DMF, piperidine,
Method D = Neat, 160-180 °C
Me
N
N
Cl
5
Scheme 1
The first method (Method A) involves the condensation of 4-amino-6-chloroquinoline-
3-carbaldehyde (1) with various active methylene compounds under acidic conditions
(Bronsted acid, HCl). Thus, reaction of 1 with CH acidic compounds such as ethyl cyanoac-
etate 2, acetylacetone 4 and benzyl cyanide 8 in DMF with a catalytic amount of HCl
under reflux for 4–5 h afforded 9-chloro-1,2-dihydro-2-oxobenzo[h][1,6]naphthyridine-3-
carbonitrile (3), 1-(9-chloro-2-methylbenzo[h][1,6]naphthyridin-3-yl)ethanone (5) and 9-
chloro-3-phenylbenzo[h][1,6]naphthyridin-2-amine (9), respectively, in moderate
(55–59%) yields. However, analogous condensation of 1 with neutral substrates such as
amides 6 was unsuccessful (Scheme 1). Compound 1 reacted also with various cyclic ke-
tones such as cetralene (10), indanone (12a), 5,6-dimethoxyindanone (12b), cyclohexanone
(14a), substituted cyclohexanones (14b–d), cyclopentanone (18), N-methylpiperidone
(20a), N-acetylpiperidone (20b) and N-Boc-piperidone (20c) in DMF with a catalytic
amount of HCl under reflux for 4–5 h to give 2-chloro-9-(3,4-dichloro-phenyl)-8,9-di-
hydrobenzo[h]naphtho[1,2-b][1,6]naphthyridine(11), 2-chloro-8H-benzo[h]indeno[1,2-b]
[1,6]naphthyridine (13a), 2-chloro-10,11-dimethoxy-8H-benzo[h]indeno[1,2-b][1,6]
naphthyridine
(13b),
2-chloro-8,9,10,11-tetrahydrodibenzo[b,h][1,6]naphthyridine
(15a), 2-chloro-11-methyl-8,9,10,11-tetrahydrodibenzo[b,h][1,6]naphthyridine (15b), 2-

Friedlander Synthesis
459
chloro-10-methyl-8,9,10,11-tetrahydrodibenzo[b,h][1,6]naphthyridine (15c), 2-chloro-9-
methyl-8,9,10,11-tetrahydrodibenzo[b,h][1,6]naphthyridine(15d), 2-chloro-9,10-dihydro-
8H-benzo[h]cyclopenta[b][1,6]naphthyridine (19), 2-chloro-9-ethyl-8,9,10,11-tetrahydro-
5,9,12-triazabenzo[a]anthracene (21a), 1-(2-chloro-10,11-dihydro-8H-5,9,12-triazabenzo
[a]anthracen-9-yl)ethanone (21b) and 2-chloro-10,11-dihydro-8H-5,9,12-triazabenzo
[a]anthracene-9-carboxylic acid t-butyl ester (21c), respectively, in moderate yields
(54–63%, Scheme 2).
O
O
Cl
R1
N
Cl
Cl
R1
N
Cl
N
N
N
10
20 a-c
Cl
Cl
Method A,
B, C and D
Method A,
B, C and D
N
11
21a; R1 = CH3
21 a-c
21b; R1 = COCH3
R2
R1
21c; R1 = COOC(CH3)3
O
O
R1
R2
N
N
N
N
Cl
Cl
12 a-b
18
13a; R1,R2 = H
13b; R1,R2 = OCH3
1
Method A,
B, C and D
Method A,
B, C and D
13 a-b
19
R2
R2
O
R1
R1
O
R3
R1
N
R1
R2
R2
O
R3
N
N
O
Cl
Cl
16 a-b
14 a-d
N
Method D
Method A,
B, C and D
17 a-b
15 a-d
15a; R1,R2,R3 = H
17a; R1,R2 = H
17b; R1,R2 = CH3
Method A = DMF, HCl,
Method B = DMF, ZnCl2,
Method C = DMF, KOH,
15b; R1 = CH3; R2,R3 = H
15c; R1,R3 = H; R2 = CH3
15d; R1,R2 = H; R3 = CH3
Method D = Neat, 160-180 °C
Scheme 2
All of these compounds were characterised by spectral and analytical data. However, it
was observed that the analogous condensation of 1 with dimedones (16) was unsuccessful
presumably due to the greater enolic character of the latter.
In order to improve the yields and to reduce the reaction times, we reported all of
these condensations using a Lewis acid (ZnCl2) as catalyst (Method B). Thus, compound
1 reacted with active methylene compounds in DMF with an equimolar amount of an-
hydrous zinc chloride as a catalyst under reflux for 1.5–3 h to furnish the corresponding

460
Jachak et al.
Table 1
Comparative Reaction Time and Yield for Methods A, B, C and D
Method Aa
Method Bb
Method Cc
Method Dd
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
Time
(min)
Yield
(%)
Cmpd
3
5
7a
7b
7c
9
11
13a
13b
15a
15b
15c
15d
17a
17b
19
4.5
4
NRe
NRe
NRe
4
58
55
—
—
—
59
61
55
57
61
63
54
62
—
—
60
56
58
55
2
2.5
NRe
NRe
NRe
1.5
1.5
3
2.5
1.5
2
1.5
1.5
NRe
NRe
2
57
61
—
—
—
63
58
60
65
59
61
64
59
—
—
66
62
58
59
2.5
2.5
NRe
NRe
NRe
2
3
2
2.5
2
2.5
2
91
87
—
—
—
92
85
87
91
93
89
92
86
—
—
85
88
90
92
20
25
15
25
25
15
30
20
15
25
25
30
20
25
25
15
30
25
20
53
56
55
54
56
50
57
52
54
50
51
55
52
56
54
52
55
50
53
5
4.5
4.5
5
5
5
4.5
NRe
NRe
4.5
5
2
NRe
NRe
3
21a
21b
21c
3
2.5
2.5
2.5
2
2
4.5
5
a) HCl, b) ZnCl2, c) Piperidine/ KOH, d) Sealed tube 160–180◦C, e) NR = no reaction.
benzo[h]naphthyridine derivatives in moderate yields (58-66%, Schemes 1 and 2). How-
ever, once again cyclocondensation of 1 with amides 6 and dimedones 16 did not give
satisfactory results. It is interesting that this method (Method B) reduced the reaction times
compared to method A (Table 1) because the ring formation via attack on the nitrile or
carbonyl group is facilitated by coordination with the metal ion, which greatly increases its
electrophilic character.
In a further attempt to improve the yield and to find more convenient methods for the
Friedlander, the condensation of 4-amino-6-chloroquinoline-3-carbaldehyde 1 with vari-
ous active methylene compounds, all of these reactions were carried out in basic medium
(Method C). Thus, when compound 1 was treated with CH acidic compounds such as ethyl
cyanoacetate (2), acetylacetone (4) and benzyl cyanide (8) in DMF in the presence of a
catalytic amount of piperidine under reflux for 2–3 h, the corresponding
benzo[h]naphthyridine derivatives 3, 5 and 9 were formed in excellent yields (86–93%,
Scheme 1). Although piperidine is found to be sufficiently basic for cyclocondensation in
these reactions, the analogous condensation of 1 with cyclic ketones was unsuccessful in
piperidine due to the lower acidity of the methylene group of the ketones. Thus, treatment

Friedlander Synthesis
461
Table 2
Mps and Elemental Analysis of New Compounds
Elemental Analysis (Found)
Cmpd
mp (◦C)
C
H
N
3
5
7a
7b
7c
9
11
13a
13b
15a
15b
15c
15d
17a
17b
19
243–244
238–239
213–214
253–254
249–250
241–242
258–259
247–248
261–262
233–234
244–245
257–258
245–246
261–262
256–257
254–255
259–260
251–252
263–264
61.07 (60.91)
66.54 (66.31)
61.26 (61.53)
62.75 (62.46)
69.98 (69.82)
70.70 (70.48)
67.62 (67.95)
75.37 (75.05)
69.52 (69.71)
71.51 (71.78)
72.20 (71.86)
72.20 (71.88)
72.20 (72.42)
67.97 (68.21)
69.56 (69.44)
70.73 (70.47)
67.72 (67.51)
65.49 (65.24)
64.95 (65.08)
2.36 (2.12)
4.09 (4.23)
2.80 (2.61)
3.51 (3.32)
3.45 (3.74)
3.95 (4.04)
3.27 (3.16)
3.66 (3.84)
4.16 (3.93)
4.87 (4.68)
5.36 (5.47)
5.36 (5.23)
5.36 (5.18)
3.92 (3.62)
4.86 (5.02)
4.35 (4.04)
4.97 (4.96)
4.52 (4.68)
5.45 (5.29)
16.43 (16.11)
10.34 (10.10)
19.48 (19.74)
18.29 (17.98)
14.46 (14.15)
13.74 (13.39)
6.06 (6.32)
9.25 (9.16)
8.81 (8.59)
10.42 (10.75)
9.91 (9.77)
9.91 (9.66)
9.91 (9.64)
9.90 (10.17)
9.01 (8.79)
10.99 (11.16)
14.80 (14.67)
13.47 (13.08)
11.36 (11.57)
21a
21b
21c
of 1 with various cyclic ketones such as cetralene (10), indanone (12a), 5,6 dimethoxyin-
danone (12b), cyclohexanone (14a), substituted cyclohexanones (14b–d), cyclopentanone
(18), N-methylpiperidone (20a), N-acetylpiperidone (20b) and N-Boc-piperidone (20c)
in DMF with a catalytic amount of KOH under reflux for 2-3 h gave the correspond-
ing benzo[h]naphthyridine derivatives 11, 13, 15, 19 and 21 in 85–93% yields (Table 1,
Schemes 1 and 2). All of these compounds were characterised with spectral and analytical
data (Tables 1–3). It is interesting that this method gives better results with respect to time
and yields in this reaction.
Alternatively, all these reactions could be performed under neutral conditions and
this was achieved by heating a mixture of o-aminoaldehyde 1 and the active methylene
compound at 160–180◦C for 15–30 min without solvent and catalyst. Thus, when compound
1 and active methylene compounds 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 were heated in a
sealed tube at 160–180◦C, corresponding benzo[h]naphthyridine derivatives 3, 5, 7, 9, 11,
13, 15, 17, 19 and 21 were formed in low yields. In this method, it is noteworthy that the
Friedlander condensation of 1 with amides 6 and dimedones 16 occurred though they were
unsuccessful in previous methods. This method requires shorter reaction times as compared
to Methods A, B and C; however, the yield of products are not satisfactory and may be due

462
Jachak et al.
Table 3
IR, 1H NMR, 13C NMR and Mass Spectra of Compounds
Cmpd
IR (cm−1
)
1H NMRa (δ)
13C NMRb (δ)
Mass Spectra
3
3317, 3011, 2237, 7.93 (d, 1H, J = 8.5 Hz),
1677, 1645, 1473. 8.19 (d, 1H, J = 8.5 Hz),
172.35, 144.24, 142.15,
139.54, 137.63, 133.26,
9.01 (s, 1H), 9.06 (s, 1H), 132.13, 132.06, 129.18
255[M]+, 257[M+2]
9.25 (s, 1H), 12.83 (bs,
1H, NH).
3029, 2977, 1703, 2.74 (s, 3H, CH3), 2.92 (s, 171.46, 169.47, 147.85,
1636, 1586, 1478. 3H, COCH3), 7.94 (d, 1H, 144.56, 144.01, 143.24,
(2 C’s), 117.92, 108.36,
96.71.
5
270[M]+, 272[M+2]
J = 9.0 Hz), 8.15 (d, 1H,
139.15, 136.32, 135.52,
J = 9.0 Hz), 8.93 (s, 1H), 133.41, 129.13 (2 C’s),
9.17 (s, 1H), 9.47 (s, 1H). 120.63, 24.78, 19.37.
7a
7b
3011, 2992, 1628, 7.93 (d, 1H, J = 8.4 Hz),
215[M]+, 217[M+2]
229[M]+, 231[M+2]
1597, 1488.
8.21 (d, 1H, J = 8.4 Hz),
9.05 (s, 1H), 9.42 (s, 1H),
9.57 (s, 1H), 9.71 (s, 1H).
3033, 2972, 1607, 3.27 (s, 3H, CH3), 7.92 (d, 169.23, 152.65, 151.12,
1487.
1H, J = 7.5 Hz), 8.19 (d,
150.56, 147.53, 146.56,
143.33, 139.17, 134.45,
1H, J = 7.5 Hz), 9.02 (s,
1H), 9.38 (s, 1H), 9.47 (s, 130.13, 129.41, 24.07.
1H).
7c
9
3027, 2999, 1625, 7.21–7.45 (m, 5H, Ar-H),
291[M]+, 293[M+2]
305[M]+, 307[M+2]
1578, 1472.
8.12 (d, 1H, J = 7.6 Hz),
8.27 (d, 1H, J = 7.6 Hz),
8.97 (s, 1H), 9.43 (s, 1H),
9.49 (s, 1H).
3343, 3338, 3005, 7.09–7.28 (m, 5H, Ar-H),
2997, 1629, 1592, 7.81 (d, 1H, J = 7.4 Hz),
1469.
8.04 (d, 1H, J = 7.4 Hz),
8.23 (bs, 2H, NH2), 8.86
(s, 1H), 8.94 (s, 1H), 9.17
(s, 1H).
11
3012, 2957, 1623, 3.07 (d, 2H, J = 402 Hz),
461[M]+, 463[M+2],
465[M+4],
1564.
3.95 (t, 1H, J = 4.2 Hz),
7.07-7.23 (m, 7H, Ar-H),
7.91 (d, 1H, J = 8.4 Hz),
8.17 (d, 1H, J = 8.4 Hz),
8.33 (s, 1H), 8.87 (s, 1H),
9.42 (s, 1H).
467[M+6]
13a 3025, 2977, 1619, 3.74 (s, 2H), 7.11-7.29 (m,
1599, 1467, 1154. 4H, Ar-H), 7.86 (d, 1H,
J = 7.5 Hz), 8.19 (d, 1H,
302[M]+, 304[M+2]
362[M]+, 364[M+2]
J = 7.5 Hz), 8.62 (s, 1H),
9.24 (s, 1H), 9.47 (s, 1H).
13b 3057, 2959, 1632, 3.21 (s, 2H), 3.57 (s, 6H,
1593, 1456, 1246, 2OCH3), 6.93 (s, 1H,
163.52, 148.25, 146.23,
143.42, 143.12, 139.85,
1067.
Ar-H), 7.02 (s, 1H, Ar-H), 139.26, 138.04, 136.87,
7.96 (d, 1H, J = 7.5 Hz),
136.58, 132.12, 131.05,
130.56, 130.19, 129.76,
8.21 (d, 1H, J = 7.5 Hz),
8.49 (s, 1H), 8.97 (s, 1H), 127.68, 127.31 (2 C’s),
9.91 (s, 1H).
37.33, 29.15, 27.09.
(Continued on next page)

Friedlander Synthesis
463
Table 3
IR, 1H NMR, 13C NMR and Mass Spectra of Compounds (Continued)
Cmpd
IR (cm−1
)
1H NMRa (δ)
13C NMRb (δ)
Mass Spectra
15a 3042, 2976, 1626, 1.98–2.11 (m, 4H), 2.87 (t,
1567, 1453, 1132. 2H, J = 6.3 Hz), 3.01 (t,
2H, J = 6.3 Hz), 7.49 (d,
268[M]+, 270[M+2]
282[M]+, 284[M+2]
282[M]+, 284[M+2]
1H, J = 8.5 Hz), 7.69 (d,
1H, J = 8.5 Hz), 7.92 (s,
1H), 8.73 (s, 1H), 8.97 (s,
1H).
15b 3031, 2976, 1622, 1.82 (d, 3H, CH3, J = 4.2
1596, 1459, 1118. Hz), 2.74-2.95 (m, 4H),
3.04 (t, 2H, J = 6.5 Hz),
3.16 (m, 1H), 7.67 (d, 1H,
J = 8.0 Hz), 7.79 (d, 1H, J
= 8.0 Hz), 7.92 (s, 1H).
8.81 (s, 1H), 8.90 (s, 1H).
15c 3026, 2985, 1603, 1.26 (d, 3H, CH3, J = 4.6
1469, 1022.
Hz), 1.93 (m, 2H), 2.17
(m, 1H), 2.67 (t, 2H, J =
6.5 Hz), 2.74 (d, 2H,
J = 4.3 Hz), 7.72 (d, 1H, J
= 8.5 Hz), 7.90 (d, 1H, J
= 8.5 Hz), 8.12 (s, 1H),
8.69 (s, 1H), 8.88 (s, 1H).
15d 3053, 2962, 1611, 1.63 (d, 3H, J = 4.2 Hz),
282[M]+, 284[M+2]
1485.
1.87 (m, 1H), 2.72 (m,
2H), 2.93 (d, 2H, J = 6.2
Hz), 3.01 (m, 2H), 7.92 (d,
1H, J = 7.5 Hz), 8.19 (d,
1H, J = 7.5 Hz), 8.96 (s,
1H), 9.07 (s, 1H), 9.47 (s,
1H).
17a 3025, 2967, 1697, 2.13 (m, 2H, CH2), 2.44 (t,
1621, 1595, 1457, 2H, CH2, J = 4.8 Hz),
282[M]+, 284[M+2]
1449, 1022.
2.91 (t, 2H, CH2, J = 4.5
Hz), 8.02 (d, 1H, J = 8.1
Hz), 8.20 (d, 1H, J = 8.1
Hz), 8.97 (s, 1H), 9.17 (s,
1H), 9.57 (s, 1H).
17b 3067, 2986, 1707, 1.11 (s, 6H, 2CH3), 2.74 (s, 169.25, 164.32, 149.54,
1629, 1597, 1473, 2H, CH2), 3.13 (s, 2H, 147.59, 147.65, 142.35,
1053.
310[M]+, 312[M+2]
254[M]+, 256[M+2]
CH2) 7.97 (d, 1H, J = 7.5 141.45, 137.59, 137.36,
Hz), 8.19 (d, 1H, J = 7.5
Hz), 8.96 (s, 1H), 9.12 (s,
1H), 9.56 (s, 1H).
132.21, 128.96, 128.53,
126.72, 35.65, 30.63,
24.62, 16.91, 14.11.
19
3042, 2976, 1610, 2.09 (m, 2H), 2.91 (t, 2H, J 171.21, 152.17, 146.35,
1352.
= 5.6 Hz), 3.03 (t, 2H, J = 144.01, 137.23, 132.04,
6.2 Hz), 7.51 (d, 1H, J =
130.31, 129.27, 129.22,
126.12, 122.25, 119.54,
8.4 Hz), 7.63 (d, 1H, J =
8.4 Hz), 7.86 (s, 1H), 8.72 34.65, 30.26, 22.17.
(s, 1H), 8.83 (s, 1H).

464
Jachak et al.
Table 3
IR, 1H NMR, 13C NMR and Mass Spectra of Compounds (Continued)
Cmpd
IR (cm−1
)
1H NMRa (δ)
13C NMRb (δ)
Mass Spectra
21a 3017, 2985, 1603, 2.50 (s, 2H, CH2), 2.82 (t,
283[M]+, 285[M+2]
1481.
2H, CH2, J = 6.0 Hz),
3.22 (t, 2H, CH2, J = 6.0
Hz), 3.75 (s, 3H, N-CH3),
7.85 (d, 1H, J = 8.4 Hz),
8.11 (d, 1H, J = 8.4 Hz),
8.28 (s, 1H), 8.83 (s, 1H),
9.13 (s, 1H).
21b 3031, 2985, 1713, 2.14 (s, 3H, CH3), 3.30 (t, 168.29, 163.56, 149.69,
311[M]+, 313[M+2]
1642.
2H, J = 5.6 Hz), 3.91 (t,
2H, J = 5.6 Hz), 4.23 (s,
2H, CH2), 7.89 (d, 1H, J
= 8.5 Hz), 8.15 (d, 1H, J
= 8.5 Hz), 8.51 (s, 1H),
8.91 (s, 1H), 9.41 (s, 1H).
148.25, 146.42, 143.13,
142.79, 139.93, 137.61,
136.19, 132.46, 132.02,
129.83, 43.15, 42.51,
30.62, 29.21.
21c 3075, 2997, 2985, 1.56 (s, 9H, (CH3)3), 3.37 (t,
1736, 1605, 1487. 2H, J = 6.0 Hz), 3.98 (t,
2H, J = 6.0 Hz), 4.21 (s,
369[M]+, 371[M+2]
2H, CH2), 7.92 (d, 1H, J
= 7.5 Hz), 8.17 (d, 1H, J
= 7.5 Hz), 8.62 (s, 1H),
9.01 (s, 1H), 9.46 (s, 1H).
a) 300 MHz in DMSO-d6, b) 75 MHz in DMSO-d6.
to the decomposition of the product under the high temperatures used (Table 1, Schemes 1
and 2).
In conclusion, the Friedlander condensation of 1 with various reactive methylene
compounds was performed under different reaction conditions. The comparative data show
that the base-catalyzed condensations are more convenient with respect to yield and reaction
times (except for 7 and 17, Table 1). The Friedlander condensation of 1 with reactive
methylene compounds performed by neat heating provides a green approach, albeit in
low yields, as this method does not require solvent and involves simple work-up. It was
observed that the strength of catalyst and reactivity of active methylene compounds or
neutral compounds are the major contributing factors for the heteroannulation.
Experimental Section
Mps were determined on a Barnstead Electrothermal melting point apparatus, Mod. No.
IA-9200 in open capillary tubes and are uncorrected. The 1H (300 MHz) and 13C (75 MHz)
NMR spectra were measured on a Varian XL-300 spectrometer using tetramethylsilane
as the internal standard. The solvent for NMR spectra was DMSO-d6. The IR spectra
were recorded using a Shimadzu IR-408 instrument as potassium bromide discs. Mass
spectra were recorded on Shimadzu GC-MS QP 2010A mass spectrometer with an ion-
ization potential of 70 eV. Elemental analyses were performed on a Hosli CH-Analyzer
and are within 0.3% of the theoretical values. All reactions were monitored by thin

Friedlander Synthesis
465
layer chromatography on 0.2 mm silica gel 60 F254 (Merck) plates using UV light (254
and 366 nm) for detection. Column chromatography was carried out on silica gel (SD
Fine Chemicals, 60–120 mesh). Common reagent-grade chemicals are either commercially
available and were used without further purification or prepared by standard literature
procedures.
General Procedure for the Synthesis of Benzo[h]naphthyridine Derivatives
Method A: A mixture of 1 (0.206 g, 1 mmol) and the corresponding active methylene
compound (1 mmol) in DMF (5 mL) with a catalytic amount of HCl (2 drops) was heated
under reflux for 4.5 h. After completion of reaction (TLC check, hexane:ethyl acetate;
8:2), solvent was evaporated under reduced pressure. The crude solid was triturated with
methanol, collected, dried under high vacuum and recrystallized from ethanol:DMF to
furnish the corresponding benzo[h]naphthyridine derivative.
Method B: A mixture of 1 (0.206 g, 1 mmol), the corresponding active methylene
compound (1 mmol) and anhydrous ZnCl2 (0.136 g, 1 mmol) in dry DMF (5 mL) was heated
under reflux for 1.5-3 h. After completion of reaction (TLC check, hexane:ethyl acetate;
8:2), the reaction mixture was quenched with ice cold water (10 mL) and extracted with
ethyl acetate (5 mL × 3). The combined organic layer was washed with water (5 mL ×
3), dried over anhydrous sodium sulfate and the solvent was evaporated under reduced
pressure. The crude solid was triturated with methanol, collected, dried under high vacuum
and recrystallized from ethanol: DMF to give the corresponding benzo[h]naphthyridine
derivative.
Method C: A mixture of 1 (0.206 g, 1 mmol), the corresponding active methylene
compound (1 mmol) in DMF (5 mL) and a catalytic amount of piperidine/ KOH was heated
under reflux for 2-3 h. After completion of reaction (TLC check, hexane:ethyl acetate;
8:2), the solvent was evaporated under reduced pressure. The crude solid was triturated
with methanol, collected, dried under high vacuum and recrystallized from ethanol:DMF
to furnish the corresponding benzo[h]naphthyridine derivative.
Method D: A mixture of 1 (0.206 g, 1 mmol) and the corresponding active methylene
compound (1 mmol) was heated in a sealed tube at 160–180◦C for 15–30 min. After
completion of reaction (TLC check, hexane:ethyl acetate; 8:2), the molten mass was allowed
to cool and stirred in ethanol (2 mL) for 15 min. The separated crude solid was collected and
purified by column chromatography (hexane:ethyl acetate; 8:2) to afford the corresponding
benzo[h]naphthyridine derivative.
Acknowledgements
The authors thank CSIR and UGC, New Delhi, India, for financial support to this project,
Prof. D. D. Dhavale, Department of Chemistry, University of Pune, Pune, India, for ana-
lytical data and Dr. V. B. Gaikwad, Principal. K. R. T. Arts, B. H. Commerce and A. M.
Science College, Nashik-02, MS, India, for facilities.

466
Jachak et al.
References
1. S. Yamada and I. Chibata, Chem. Pharm. Bull., 3, 21 (1955); Chem. Abstr., 50, 1819 (1956).
2. P. Friedlander and G. F. Gohring, Ber., 16, 1833 (1883).
3. J. A. Kepler, M. C. Wani, J. N. McNaull, M. E. Wall and S. G. Levine, J. Org. Chem., 34, 3853
(1969).
4. A. Zheng, W. Zhang and J. Pan, Synth. Commun., 36, 1549 (2006).
5. M. N. Jachak, S. M. Bagul, M. A. Kazi and R. B. Toche, J. Heterocycl. Chem., 46, 1 (2009).
6. A. Godard and G. Queguiner, J. Heterocycl. Chem., 17, 465 (1980).
7. L. Strekowski, A. Czarny and H. Lee, J. Fluorine Chem., 104, 281 (2000).
8. E. A. Fehnel, J. Org. Chem., 31, 2899 (1966).
9. J. Wang, X. Fan, X. Zhang and L. Han, Can. J. Chem., 82, 1192 (2004).
10. A. Areadi, M. Chiarini, S. Di Giuseppe and F. Arielle, Synlett, 203 (2003).
11. Y. Z. Hu, G. Zang and R. P. Thummel, Org. Lett., 2251 (2003).
12. J. Wa, H. G. Xia and K. Gao, Org. Biomol. Chem., 4, 126 (2006).
13. S. K. De and R. A. Gibbs, Tetrahedron Lett., 46, 1647 (2005).
14. J. S. Yadav, P. P. Rao, D. Sreenu, R. S. Rao, V. N. Kumar, K. Nagaiag and A. R. Prasad,
Tetrahedron Lett., 46, 7249 (2005).
15. M. Narasimhulu, T. S. Reddy, K. C. Mahesh, P. Prabhakar, C. B. Rao and Y. Venkateswarlu,
J. Mol. Catal. A: Chem., 266, 114 (2007).
16. B. Das, K. Damodar, N. Chowdhury and R. A. Kumar, J. Mol. Catal. A: Chem., 274, 148 (2007).
17. A. S. Noravyan, E. G. Paronikyan and S. A. Vartanyan, Khim-Farm. Zh., 19, 790 (1985); Chem.
Abstr., 104, 186324 (1985).
18. V. P. Litvinov, S. V. Roman and V. D. Dyachenko, Usp. Khim., 69, 218 (2000). [Engl. transl.
Russ., 69, 201 (2000)]
19. L. Chrzastek and W. Sliwa, Australian J. Chem., 47, 2129 (1994).
20. B. Barbara and Z. Teresa, ARKIVOC, 6, 77 (2001).
21. K. Roseman, M. Gould, M. Linfield and B. Edwards, J. Med. Chem., 13, 230 (1970).
22. K. Gorlitzer, M. Bode, P. G. Jones, H. Jomaa and J. Wiesner, Pharmazie, 62, 15 (2007).
23. A. Hinschberger, S. Butt, V. Lelong, M. Boulouard, A. Dumuis, F. Dauphin, R. Burau, B. Pfeifffer,
P. Renard and S. Rault, J. Med. Chem., 46, 138 (2003).
24. J. Michael, Nat. Prod. Rep., 14, 605 (1997).
25. R. V. Rote, S. M. Bagul, D. P. Shelar, S. R. Patil, R. B. Toche and M. N. Jachak, J. Heterocycl.
Chem., 48, 301 (2011).
26. R. Clemo and D. G. Felton, J. Chem. Soc., 1658 (1952).
27. J. H. Markgraf, R. J. Katt, W. L. Scott and R. N. Shefrin, J. Org. Chem., 34, 4134 (1969).
28. T. K. Liao, W. Nyberg and C. C. Cheng, J. Heterocycl. Chem., 8, 373 (1971).
29. C. S. F. Tang, C. J. Morrow and H. Rapoport, J. Am. Chem. Soc., 97, 159 (1975).
30. A. Settimo, G. Primofore, O. Livo, P. L. Ferrarini and S. Spinelli, J. Heterocycl. Chem., 8, 373
(1971).