Effects of substituent and catalyst on the intramolecular Povarov reaction - Synthesis of chromenonaphthyridines

Article abstract of DOI:10.1016/j.tetlet.2011.11.130

2-(N-Alkenyl-N-aryl)aminochromone-3-carbaldehyde undergoes intramolecular Povarov reaction with aromatic amines in the presence of Ph₃P· HClO₄ to produce chromenonaphthyridine. The effects of substituent and catalyst have been studie

Full text of DOI:10.1016/j.tetlet.2011.11.130

Tetrahedron Letters 53 (2012) 694–696
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effects of substituent and catalyst on the intramolecular Povarov
reaction—synthesis of chromenonaphthyridines
⇑
Sourav Maiti, Suman Kalyan Panja, Koushik Sadhukhan, Jaydip Ghosh, Chandrakanta Bandyopadhyay
Department of Chemistry, R.K. Mission Vivekananda Centenary College, Rahara, Kolkata 700 118, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(N-Alkenyl-N-aryl)aminochromone-3-carbaldehyde undergoes intramolecular Povarov reaction with
aromatic amines in the presence of Ph3PÁHClO4 to produce chromenonaphthyridine. The effects of substi-
tuent and catalyst have been studied. The substituent on the alkenyl part of aminochromone controls the
mode of reaction as well as the stereochemistry of the product.
Received 16 October 2011
Revised 24 November 2011
Accepted 26 November 2011
Available online 3 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Povarov reaction
Chromone
1-Benzopyran
Naphthyridine
2-Aminochromone-3-carbaldehyde
Triphenylphosphonium perchlorate
[1,6]-Naphthyridine is a basic unit of many pharmaceutically
important compounds. 7-Substituted-[1,6]-naphthyridine deriva-
tives are potential tyrosine kinase inhibitors.1 A series of [1,6]-naph-
thyridines exhibited potent activity against Human Cytomega
lovirus.2 7-Carbamoyl-8-hydroxy derivatives act as novel inhibitors
of HIV-I integrase in vitro and in infected cells.3 3-Oxadiazolyl-[1,6]-
naphthyridine derivatives are useful as benzodiazedine receptor
agonist.4 Naphthyridines fused with various carbocyclic and hetero-
cyclic rings display characteristic properties in multifarious
pharmacological and chemotherapeutic activities. Some of them
exhibit antimicrobial activities.5
Intramolecular imino-Diels–Alder reaction (Povarov reaction)
has widely been studied in the last decade. Although the pioneer-
ing work of Povarov6 was accomplished using BF3ÁEt2O as catalyst,
other catalysts like FeCl3, DDQ, Ln(OTf)3,7 GdCl3,8 InCl3,9 SbCl3,10
KSF-clay,11 CAN,12 Yb(OTf)3,13 PPh3ÁHClO4 (TPP),14 and glycerol15
have also been employed. Intramolecular Povarov reaction is an
important tool for the synthesis of two rings by a single operation
and is utilised for the synthesis of tertahydroquinoline ring system
fused with carbocycles15 or different heterocycles like indolylpyr-
role,16 benzopyran.14,17
nitrone19 or azomethine ylide20 and intramolecular inverse elec-
tron demand [4+2] cycloaddition reaction.21 The results of the reac-
tion of compound 2 with aromatic amines 3 and the effects of
substituent and catalyst on this reaction are reported herein.
With the intention of performing intramolecular imino-Diels–
Alder (IIDA) reaction on 7 (A or B) (Scheme 2), a mixture of 2a
(0.25 mmol) and aromatic amine 3a (0.25 mmol) was stirred in
acetonitrile at room temperature. But, the reaction mixture pro-
duced a mixture of 418b and 518f along with unreacted 2a (Table
1, entry 1) (Scheme 1). Formation of 5 may be explained by consid-
ering the nucleophilic substitution of 3°-amine moiety in 2a by 3a
to form 4. It reacts with the second molecule of 3a to form the
Schiff-base, which tautomerises to 5. The mechanism demands
two equivalents of 3a to produce 5. Indeed, compound 5 was iso-
lated in good yield (80%) when 2 equiv of 3a was employed.
In order to facilitate inverse electron demand IIDA reaction, the
energy of HOMOdienophile in 7 was increased by introducing one
methyl group into the alkenyl part of 2 by the alkenylation of 1
with crotyl bromide. But the reaction of 2b with 3a in CH3CN again
produced 5 (entry 2). Interestingly, use of 2c (having one more
methyl group in the dienophile) and 3a yielded a mixture of 5
and a small amount of the desired product 6b (entry 3) (Scheme
2). These results gave us an impetus to study this IIDA reaction
more explicitly. Regarding the choice of solvent, CH3CN was found
to be the most effective solvent among MeOH, EtOH, toluene, DMF
and CH3CN. Realising the effect of increasing the energy of
HOMOdienophile in the inverse electron demand IIDA reaction, we
became interested to lower the energy of LUMOheterodiene by
2-(N-Alkyl-/N-aryl)aminochromone-3-carbaldehyde (1) is
a
building block for the synthesis of different heterocycles.18 2-(N-
Alkenyl-N-aryl)aminochromone-3-carbaldehyde (2) has been
employed for the intramolecular [3+2] cycloaddition reaction via
⇑
Corresponding author.
E-mail address: kantachandra@rediffmail.com (C. Bandyopadhyay).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.130

S. Maiti et al. / Tetrahedron Letters 53 (2012) 694–696
695
R4
R3
N
For 2
: R11 = Me; R2 = Ph; R3 = R4 = H
a
R3
R4
: R = R4 = Me; R2 = Ph; R3 = H
b
c: R1 = R3 = R4 = Me; R2 = Ph
O
NHR2
CHO
Br
d: R1 =H; R2 = Ph; R3 = R4 = Me
e: R1 = Me; R2 = p-tolyl; R3 = R4 = H
f: R1 = R3 = H; R2 = R4 =Ph
O
O
R2
K2CO3,NaI
CH3CN
R1
R1
CHO
O
1
g: R1 = Me; R2 = p -tolyl; R3 = H; R4 = Ph
2
Me
Me
NH2
For 3
CH3CN, RT
O
N
N
5
a
: R5 = Me
2a
3a
+
O
O
NH
+
Me
b
: R = OMe
R5
CHO
O
3
Me
H
4
5
Me
Scheme 1. Reaction between 2a and 3a in absence of catalyst.
2
+ 3
Ph3P.HClO4
Na2SO4
CH3CN, RT
R2
N
R2
N
O
O
R3
R4
O
R1
R1
N
N
O
R5
R3
R5
7B
7A
R4
Exo-approach
Endo-approach
R2
R2
Ha
Ha
O
N
Hb
R3
O
N
Hb
R3
7
H
7
12
14b
14
H
6a
12
6a
R1
6
14b
R4
14
H
H
R1
R4
H
H
O
6
N
O
5
1
N
5
1
8
2
R5
6
2
R5
For 6
a
1
4
5
2
3
For 8
a: R1 = R3 = H; R2 = R4 = Ph; R5 = Me
b: R1 = R5 = Me; R2 = p-tolyl; R3 = H; R4 = Ph
: R = R = R =Me, R = Ph, R = H
b: R1 = R3 = R4 = R5 = Me, R2 = Ph
1
2
3
: R = H, R = Ph, R = R4 = R5 =Me
c
: R1 = R3 = H; R2 = R4 = Ph; R5 = OMe
d: R1 = R3 = R4 = Me, R2 = Ph, R5 = OMe
c
d
: R1 = Me; R2 = p-tolyl; R3 = H; R4 = Ph; R5 = OMe
e: R1 = H, R2 = Ph, R3 = R4 = Me, R5 = OMe
Scheme 2. Reaction between 2 and 3 in presence of catalyst.
employing Lewis acid. With that intention a few catalysts like
FeCl3, BF3ÁEt2O, InCl3 and TPP were screened for the optimisation
of this reaction. FeCl3 showed some detrimental effect (entry 4),
which may be due to complexation between 2c and FeCl3. BF3ÁEt2O
gave poor yield of 6b (entry 5), but InCl3 gave a moderate yield
(53%) of 6b in 15 h (entry 6). Use of TPP shortens the reaction time
with a little improvement in yield of 6b22 (entry 7).
Catalyst loading of TPP was standardised based on the reaction
of 2c and 3a in acetonitrile. It was observed that use of 40 mol % of
TPP gave the best result (entries 7–10). Use of 10 mol % of TPP gave
a mixture of 5 and 6b (entry 8). A few more reactions for the
synthesis of 6 having different substituent on chromone 2 and
amine 3 were performed (entries 11–13). To check the effective-
ness of the catalyst, TPP (40 mol %) was employed into an equimo-
lar mixture of 2b and 3a in CH3CN. After stirring for 20 h, the
reaction mixture produced 5 as the major product and small
amount of 6a (5%) (entry 14). When the same reaction using 2e
and 3a was carried out, InCl3 or TPP failed to cause IIDA reaction
and compound 5 along with unreacted material 2e was isolated
(entries 15 and 16). These results clearly indicate that the individ-
ual effect of increasing the energy of HOMOdienophile or decreasing
the energy of LUMOheterodiene is not sufficient for 7 to take part in

696
S. Maiti et al. / Tetrahedron Letters 53 (2012) 694–696
Table 1
Med/14/1239/2006) is gratefully acknowledged. We are thankful
to IICB, Jadavpur for spectral analysis and finally the college
authorities for providing research facilities.
Results of the reaction between 2 and 3 under different conditions
Entry
2
3
Catalyst (mol %) Time (h) Product Yield (%) Mp (°C)
1
2
3
2a 3a
2b 3a
2c 3a
—
—
—
20
15
30
5a
5
5
29b
25b
15c
13
06
26
53
57
45
05
87
85
89
90
58
30c
05
25b
22b
63
65
77
58
214–21618f
212–214
214–216
154–156
154–156
154–156
154–156
154–156
154–156
214–216
154–156
154–156
198–200
150–154
196–198
214–216
160–162
214–216
214–216
262–264
170–172
250–252
218–220
References and notes
1. Thompson, A. M.; Hollis Shoalter, H. D.; Denny, W. A. J. Chem. Soc., Perkin Trans.
1 2000, 1843–1852.
2. Chan, L.; Jin, H.; Stefanac, P.; Lavallee, J. F.; Falardeau, G.; Wang, W.; Bedard, J.;
May, S.; Yuen, L. J. Med Chem. 1999, 42, 3023–3025.
3. Melamed, J. Y.; Eqbertson, M. S.; Varga, S.; Vacca, J. P.; Moyer, G.; Gabryelski, L.;
Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Schleif, W. A.; Hajuda, D. J.; Leinard,
Y.; Jin, L.; Ellis, J. D.; Young, S. D. Bioorg. Med. Chem. Lett. 2008, 18, 5307–5310.
4. Furukawa, K.; Odai, O.; Ohno, K.; Oka, M.; Tominaqa, Y. U.S. Patent, 1994,
5367078.
5. Suresh, T.; Dhanabal, T.; Nandha Kumar, R.; Mohan, P. S. Indian J. Chem. 2005,
44B, 2375–2379. and refernces therein.
6. Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656–670.
7. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031–15070.
8. Ma, Y.; Qian, C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64, 6462–6467.
9. Zhang, J.; Li, C.-J. J. Org. Chem. 2002, 67, 3969–3971.
10. Maiti, G.; Kundu, P. Tetrahedron Lett. 2006, 47, 5733–5736.
11. Yadav, J. S.; Reddy, B. V. S.; Sadasiv, K.; Reddy, P. S. R. Tetrahedron Lett. 2002, 43,
3853–3856.
6b
6b
6b
6b
6b
6b
5
6b
6b
6c
6d
6e
5
6a
5
5
8a
8b
8c
8d
4
5
6
7
8
2c 3a FeCl3(20)
2c 3a BF3ÁEt2O
2c 3a InCl3 (20)
2c 3a TPP (20)
2c 3a TPP (10)
5
4
15
8
12
9
2c 3a TPP (40)
2c 3a TPP (60)
2d 3a TPP (40)
2c 3b TPP (40)
2d 3b TPP (40)
2b 3a TPP (40)
6
6
6
6
6
20
10
11
12
13
14
15
16
17
18
19
20
2e 3a InCl3(20)
2e 3a TPP (40)
2f 3a TPP (40)
2g 3a TPP (40)
2f 3b TPP (40)
2g 3b TPP (40)
15
15
5
6
5
12. (a) Sabitha, G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589–3593; (b)
Sridharan, V.; Avendano, C.; Menendez, J. C. Tetrahedron 2007, 63, 673–681.
13. Kudale, A. K.; Kendall, J.; Miller, D. O.; Collins, J. L.; Bodwell, G. J. J. Org. Chem.
2008, 73, 8437–8447.
6
14. Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2003, 44,
3653–3657.
15. Nascimento, J. E. R.; Barcellos, A. M.; Sachini, M.; Perin, G.; Lenardao, E. J.; Alves,
D.; Jacob, R. G.; Missau, F. Tetrahedron Lett. 2011, 52, 2571–2574.
16. Manian, R. D. R. S.; Jayashankaran, J.; Raghunathan, R. Tetrahedron Lett. 2007,
48, 4139–4142.
Ar = p-C6H4(Me).
a
Use of 2 equiv of 3a produced 80% of 5.
b
c
10–15% of 2 was recovered and trace amount of 4 was detected.
Very small amount of 4 was also isolated.
17. (a) Ramesh, S.; Gaddam, V.; Nagarajan, R. Synlett 2010, 757–760; (b)
Majumdar, K. C.; Ponra, S.; Taher, A. Synthesis 2011, 463–468.
18. (a) Singh, G.; Singh, R.; Girdhar, N. K.; Ishar, M. P. S. Tetrahedron 2002, 58,
2471–2480; (b) Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Banerjee, S. J. Chem.
Res. (S) 2003, 459–460. J. Chem. Res. (m), 2003, 847–856; (c) Singh, G.; Singh, G.;
Ishar, M. P. S. Helv. Chim. Acta 2003, 86, 169–180; (d) Singh, G.; Singh, L.; Ishar,
M. P. S. Tetrahedron 2002, 58, 7883–7890; (e) Maiti, S.; Panja, S. K.;
Bandyopadhyay, C. Tetrahedron Lett. 2009, 50, 3966–3969; (f) Maiti, S.; Panja,
S. K.; Bandyopadhyay, C. Indian J. Chem., Sect. B 2009, 48, 1447–1452; (g) Maiti,
S.; Panja, S. K.; Bandyopadhyay, C. J. Heterocycl. Chem. 2010, 47, 973–981; (h)
Maiti, S.; Panja, S. K.; Bandyopadhyay, C. J. Chem. Res. 2011, 84–86; (i) Maiti, S.;
Panja, S. K.; Bandyopadhyay, C. Tetrahedron Lett. 2011, 52, 1946–1948; (j) Maiti,
S.; Mallick, S.; Panja, S. K.; Pal, C.; Bandyopadhyay, C. Synlett 2011, 2001–2004.
19. Singh, G.; Ishar, M. P. S.; Gupta, V.; Singh, G.; Kalyan, M.; Bhella, S. S.
Tetrahedron 2007, 63, 4773–4778.
IIDA reaction but their combined effect led to the desired result.
Structure of 6 was assigned on the basis of IR, 1H NMR, 13C NMR
and mass spectral analysis.23 The cis stereochemistry of CD-ring
juncture in 6 was assigned on the basis of small coupling constant
value (J = 2.7 Hz) at d 5.13 for C14b–H.
The above methodology was then extended with 2f and 2g. An
equimolar mixture of 2f or 2g and 3a or 3b in CH3CN was stirred at
room temperature for 5–6 h in the presence of TPP (40 mol %) and
Na2SO4 to produce 8a–d in moderate yields (entries 17–20). The
noticeable thing is that the CD-ring juncture in 8 is trans in nature,
which is observed from the large coupling constant value
(J = 9.9 Hz) at d 4.6 for C14b–H.
Formation of 6 and 8 may be rationalised as follows: 2 reacts
with 3 to form the aldimine 7, which attains conformation 7A or
7B for performing [4+2] cycloaddition reaction. Endo-approach of
dienophile in 7A is favoured when R4 = Me to form 6, whereas
exo-approach in 7B led to the formation of trans-fused product 8
when R4 = Ph (Scheme 2). In the exo-approach (7B) (R4 = Ph), this
phenyl group becomes endo to the heterodiene and is supposed
to exert additional secondary bonding interaction.
20. Maiti, S.; Lakshmykanth, T. M.; Panja, S. K.; Mukhopadhyay, R.; Datta, A.;
Bandyopadhyay, C. J. Heterocycl. Chem. 2011, 48, 763–768.
21. Maiti, S.; Panja, S. K.; Bandyopadhyay, C. Tetrahedron 2010, 66, 7625–7632.
22. General procedure for the synthesis of 6:
A solution of 2
(R3 = R4 = Me)
(0.25 mmol) and 3 (0.25 mmol) in dry CH3CN (5 mL) containing anhydrous
Na2SO4 (355 mg, 2.5 mmol) was stirred with TPP (36 mg, 40 mol %) at room
temperature for appropriate time (Table 1). After completion (TLC), the
reaction mixture was poured into water (50 mL). The resulting turbid
solution was extracted with EtOAc. The EtOAc solution was dried over
Na2SO4 and purified by column chromatography over silica gel (100–200) to
obtain 6 in good yield using benzene as eluent.
23. 4,6,6,12-Tetramethyl-8-phenyl-1,6,6a,7,8,14b-hexahydro-benzo[b]chromeno
In conclusion, we have reported a substituent- and catalyst-
controlled intramolecular imino-Diels–Alder reaction involving 2-
[2,3-h][1,6]naphthyridin-14(14H)-one (6b): IR (KBr)
mmax: 3350, 2968, 2912,
2866, 1611, 1550 cmÀ1 1H NMR (CDCl3) d: 1.39 (3 H, s, 6-CH3), 1.43 (3 H, s, 6-
;
CH3), 1.99–2.05 (1H, m, 6a-H), 2.23 (3 H, s, 4-CH3), 2.42 (3 H, s, 12-CH3), 3.60
(1H, dd, J = 11.7, 3.9 Hz, 7-Ha), 3.73 (1H, dd, J = 12.0, 11.7 Hz, 7-Hb), 4.46 (1H, br
s, exchangeable, 1-H), 5.13 (1H, d, J = 2.7 Hz, 14b-H), 6.38 (1H, d, J = 8.1 Hz, 2-
H), 6.82 (1H, br d, J = 8.1 Hz, 3-H), 6.93 (1H, br s, 5-H), 6.95 (1H, d, J = 8.1 Hz,
10-H), 7.28–7.36 (4H, m, ArH), 7.40–7.46 (2H, m, ArH), 7.98 (1H, br s, 13-H);
13C NMR (CDCl3) d: 20.7, 20.8, 25.9, 33.8, 34.4, 41.2, 41.9, 49.6, 98.8, 114.0,
116.1, 122.6, 125.0, 125.7, 125.9, 126.0, 126.5, 126.8, 127.9, 129.1, 132.9, 134.4,
138.3, 141.8, 151.3, 158.3, 175.0; Mass m/z: 437 (M++H), 459 (M++Na); Anal.
calcd for C29H28N2O2: C, 79.79; H, 6.46; N, 6.42%. Found: C, 79.63; H, 6.39; N,
6.36%.
(N-alkenyl-N-aryl)aminochromone-3-carbaldehyde
amines, which led to the synthesis of hitherto unreported
chromenonaphthyridines.
and
aryl
Acknowledgments
S.M. is grateful to CSIR, India for SRF. Financial assistance from
the Department of Biotechnology (DBT), India (No. BT/PR8217/