Synthesis of some novel spiro substituted pyrido[2,3-c]coumarins by exploring ‘tertiary amino effect’ reaction strategy

Article abstract of DOI:10.1016/j.tetlet.2013.10.055

Some novel spiro substituted pyrido[2,3-c]coumarin derivatives were synthesized from 4-hydroxycoumarin by exploring ‘tertiary amino effect’ reaction strategy.

Full text of DOI:10.1016/j.tetlet.2013.10.055

Tetrahedron Letters 54 (2013) 6949–6951
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of some novel spiro substituted pyrido[2,3-c]coumarins
by exploring ‘tertiary amino effect’ reaction strategy
⇑
⇑
Pallabi Borah , Pulak J. Bhuyan
Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Some novel spiro substituted pyrido[2,3-c]coumarin derivatives were synthesized from 4-hydroxycoum-
arin by exploring ‘tertiary amino effect’ reaction strategy.
Received 16 September 2013
Revised 9 October 2013
Accepted 11 October 2013
Available online 19 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Coumarin
Pyrido[2,3-c]coumarin
Tertiary amino effect
Spiro compound
Coumarins are an important class of naturally occurring com-
pounds which have diverse pharmaceutical and biological activi-
ties depending on the substituent in the benzopyran ring.1
Among those, pyridine fused coumarin derivatives have drawn
remarkable attention due to their varied biological activities like
DNA adduct formation,2 energy transfer in photophysical pro-
cesses,3 antitumor,4 anticholinergic,5 antidiabetic, anticoagulant,
antiallergic, analgesic, antipsychotic,6 hypotensive activators7 and
antimicrobial8 activities (Fig. 1). Therefore, considerable efforts
have been made towards the preparation and synthetic manipula-
tion of pyridocoumarin. But most of these reported methods have
many disadvantages like use of organic solvent, costly catalyst etc.9
Spiro substituted diverse heterocyclic compounds are available
in nature with interesting biological activity.10 In coumarin, spiro
substituted pyranocoumarins are well known and have been
extensively studied for their biological activity particularly as anti-
oxidant.11 However, spiro substituted pyrido coumarin is not
reported so far.
O
O
O
H
N
N
O
O
N
O
MeO
COOR
O
O
Antimicrobial
Thymine dimer
photosensitizer
Santiagonamine
Antibiotic
N
Figure 1. Some biologically important pyrido coumarins.
amines in coumarins by utilizing appropriately substituted couma-
rin derivatives and acyclic active methylene compounds. The reac-
tions were performed under drastic conditions in acidic medium
(refluxing acetic acid) and different types of products were ob-
tained depending on the nature of active methylene compounds.15
As a part of our continuing efforts towards the synthesis of var-
ious heterocyclic compounds,16 particularly annelated coumarins
of biological importance,17 we report here the synthesis of some
novel functionalized spiro substituted pyrido[2,3-c]-coumarin
derivatives 7 from the reaction of 4-amino-3-formyl coumarins 4
with N,N-dimethylmethyl-barbituric acid/N-methylbarbituric acid
5 by exploring ‘tertiary amino effect’ reaction strategy (Scheme 1).
In the reaction protocol, 4-hydroxycoumarins 1 were chosen as the
starting material. The key intermediate 4-chloro-3-formylcouma-
rins 2 were prepared from 4-hydroxycoumarins 1 following the
existing reported method18 with little modification.19 The reaction
of 2a with diethylamine in the presence of Et3N using dichloro-
methane (DCM) as solvent was found to be a suitable method to
generate 3-formyl-4-tertiaryamino coumarin derivative 4a.20
a-Cyclization of tertiary amine, which is named as ‘tertiary
amino effect’ by Meth Cohn, is an important reaction strategy that
involves 1,5- or 1,6-electrocyclizations to form five or six mem-
bered ring systems.12 These reactions are mechanistically intrigu-
ing and synthetically very useful, and thus have been extensively
used for the synthesis of various annelated pyridine and pyrroli-
dine derivatives of biological importance.13,14 Recently, Ivanov
and his co-workers reported an example of a-cyclization of tertiary
⇑
Tel.: +91 376 2370121; fax: +91 376 2370011.
E-mail addresses: pallabibora0123@gmail.com (P. Borah), pulak_jyoti@yahoo.
com (P.J. Bhuyan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.055

6950
P. Borah, P. J. Bhuyan / Tetrahedron Letters 54 (2013) 6949–6951
Table 1
O
O
O
HN
Synthesis of spiro substituted pyrido[2,3-c]coumarin
CHO
N
CHO
Cl
O
O
O
DMF + POCl3
OH
R1
R2
[X]n
R3
Pd.
R.T. (h)
3a
Ent.
Et3N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
Cl
Me
Me
H
H
H
H
Me
H
H
H
Me
H
H
H
Me
H
H
H
Me
H
H
H
H
—
—
—
—
—
—
—
—
[CH2]1
[CH2]1
[CH2]1
[CH2]1
[CH2]1
[CH2]1
[CH2]1
[CH2]1
[CH2]2
[CH2]2
[CH2]2
[CH2]2
[CH2]2
[CH2]2
Me
Me
Me
Me
H
H
H
H
Me
Me
Me
Me
H
H
H
H
7a
7b
7c
7d
7e
7f
2.5
3
3
2.5
3.5
4
R2
R2
R2
R1
R1
R1
4a-d
2a-d
1a-d
R1 = H, Cl, Me
R2= H, Me
Cl
O
O
R3
N
O
Me
Me
H
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
3.5
3
O
O
CHO
O
R3
O
O
EtOH
DIPEA
N
3.5
4.5
3.5
3.5
4
4.5
3.5
3.5
4.5
4.5
4
N
N
O
N
Cl
N
O
Me
Me
H
R2
R2
5a-b
R1
R1
R3 = H, Me
6a-h
4a-d
R3
Cl
Me
Me
H
Cl
Me
H
O
O
N
N
O
O
N
EtOH
Me
Me
Me
H
H
H
O
R2
5
R1
O
Cl
Me
H
H
7u
7v
4.5
4.5
7a-h
[X]n
CHO
N
O
O
CHO
Cl
O
[X]n
Ent. = Entry; Pd. = Product; R.T. = Reaction time.
R2
N
Et3N
R1
H
R2
R1
4e-k
O
3b-c
R3
N
O
O
2a-d
O
O
O
N
N
O
O
N
N
O
O
CHO
N
CHO
Cl
O
O
O
Et2NH
O
N
O
O
O
CHO
N
O
R3
O
3
O
DIPEA
EtOH
5a
N
N
Et3N
O
N
N
O
R2
R2
[X]n
[X]n
4a
O
6a
2a
R1
R1
4e-k
5a-b
R3= H, Me
6i-v
O
N
O
O
O
N
O
R3
N
1,5-hydride shift
O
N
O
N
O
O
O
N
O
O
N
N
O
EtOH
O
N
7a
R2
[A]1,6-dipole
[X]n
R1
7i-v
Scheme 2.
Scheme 1.
In our study, it was found that acyclic amino coumarins are
more reactive compared to the cyclic amino group, and N,N-dim-
ethylbarbituric acid shows better reactivity in comparison with
N-methyl-barbituric acid.
The possible mechanism which could be accounted for the for-
mation of spiro substituted pyrido[2,3-c]coumarin 7a is shown in
Scheme 2. Initial Knoevenagel condensation takes place between
compounds 4a and 5a which gives an aminodiene system 6a. The
intermediate 6a under thermal condition undergoes 1,5-hydride
shift (sigmatropic shift) to generate 1,6-dipole which subsequently
cyclized to give the desired product 7a.
In summary, we have reported the synthesis of some novel
spiro substituted pyrido[2,3-c]coumarin derivatives from a cheap
and easily available starting material viz 4-hydroxycoumarin by
exploring ‘tertiary amino effect’ reaction strategy. The reaction
procedure is mild, work-up procedure is simple and the products
were isolated by filtration and washing with ethanol. Further, the
reaction protocol can be utilized for the synthesis of many other
heterocyclic compounds of importance.
Compound 4a so obtained was reacted with N,N-dimethylbarbitu-
ric acid 5a in the presence of a catalytic amount of diisopropyleth-
ylamine (DIPEA) in ethanol at room temperature which afforded
the Knoevenagel condensed product 6a.21 The final
a-cyclization
of tertiary amine in 6a was carried out under refluxing condition
using ethanol as solvent which gave spiro substituted pyrido[2,3-
c]coumarin derivative 7a.22 The product was obtained in 77% yield
after purification. The structure of the compound was ascertained
from spectroscopic data and elemental analysis. The 1H NMR
showed the absence of aldehydic proton and presence of two
N-Me groups at d 3.39 and 3.28, respectively, which indicates the
involvement of N,N-dimethylbarbituric acid in the reaction pro-
cess. The presence of two isolated protons at d 2.98 as singlet
and one multiplet at d 3.80 for a single proton evidenced the for-
mation of cyclized product. Moreover, the mass spectra supported
the formation of cyclized product by showing the sharp molecular
ion peak at 384.5 (M+H)+. The generality of the reaction was estab-
lished by synthesizing various cyclic and acyclic tertiary amino
coumarin derivatives 4a–k, and utilizing them with N,N-dimethyl-
barbituric acid/N-methylbarbituric acid in the presence of base to
obtain 6, which under thermal condition gave the spiro substituted
pyrido[2,3-c]-coumarin derivatives 7a–v in good yield. Our obser-
vations are depicted in Table 1.
Acknowledgement
The authors thank DST and CSIR, New Delhi, for financial
support (CAAF-NE Project).

P. Borah, P. J. Bhuyan / Tetrahedron Letters 54 (2013) 6949–6951
6951
On storing the mixture overnight, a pale yellow solid appeared, which was
filtered and washed first with 5% Na2CO3 solution and then with water. The
compound was recrystallized from acetone. The structure of the compound
was ascertained as 2a from spectroscopic data. Compound 2a: Yield = 610 mg
(61%). mp 117–118 °C (lit mp 120–122 °C23); 1H NMR (300 MHz, CDCl3): d
7.38–7.49 (m, 2H), 7.72–7.78 (m, 1H), 8.13–8.16 (m, 1H), 10.40 (s, 1H). MS
(ESI): 209.2 (M+H)+. Similarly, compounds 2b–d were synthesized and
characterized.
References and notes
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20. Representative procedure for the synthesis of compound 4: 4-Chloro-3-
formylcoumarin 2a (1 mmol, 208 mg), diethylamine 3a (1 mmol, 73 mg) and
triethylamine (1 mmol, 101 mg) in 5 ml DCM were taken in a round bottomed
flask and stirred at room temperature for 3 h. After completion of the reaction
(as indicated by TLC), the solution was poured in water, and extracted with
DCM. The solvent was evaporated and the residue was purified by column
chromatography on silica gel using 8:2 hexane and ethyl acetate as eluent. The
structure of the isolated compound was ascertained as 4a from spectroscopic
data and elemental analysis. Yield: 190 mg (78%); Compound 4a: Brown solid;
mp 181 °C. IR (CHCl3): m ;
max 1635, 1719, 1702 cmÀ1 1H NMR (CDCl3, 300 MHz):
d 10.07 (s, 1H), 7.53 (m, 4H), 3.73 (m, 4H), 1.35 (m, 6H); 13C NMR (CDCl3,
75 MHz): d 14.8 (2C), 45.6 (2C), 107.8, 122.3, 124.4, 125.6, 125.8, 128.7, 156.7,
167.8, 187.7, 193.5; MS (ESI): 246.3 (M+H)+; Anal. Calcd for C14H16NO3: C,
68.56; H, 6.16; N, 5.71. Found: C, 68.34; H, 6.09; N, 5.64. Similarly, other
compounds 4b–k were synthesized and characterized.
21. Representative procedure for the synthesis of compound 6:
A mixture of
compound 4a (1 mmol, 245 mg) and 5a (1 mmol, 156 mg) was taken in a
round bottomed flask containing ethanol (5 ml). To this, catalytic amount of
diisopropylethylamine (DIPEA) was added and the reaction mixture was
stirred at room temperature for 1 h. The solid formed in the reaction process
was filtered and purified by washing with ethanol and dried. The structure of
the compound was ascertained as 6a from spectroscopic data. Yield: 270 mg
(70%); Compound 6a: Light yellow; 1H NMR (CDCl3, 300 MHz): d 7.79 (s, 1H),
7.47 (m, 4H), 3.73 (m, 4H), 3.39 (s, 3H), 3.28 (s, 3H), 1.35 (m, 6H). Similarly,
other compounds 6b–v were synthesized and characterized.
12. Meth-cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem. 1972, 14, 211.
13. (a) Jiang, S.; Janousek, Z.; Viehe, H. G. Tetrahedron Lett. 1994, 35, 1185; (b) De
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Ojea, V.; Muinelo, I.; Quintela, J. M. Tetrahedron 1998, 54, 927; (d) Ojea, V.;
Muinelo, I.; Figueroa, M. C.; Ruiz, M.; Quintela, J. M.; Quintela, J. M. Synlett
1995, 622; (e) Kaval, N.; Dehaen, W.; Matyus, P.; Vander Eycken, E. Green Chem.
2004, 6, 125.
22. Representative procedure for the synthesis of compound 7: Compound 6a
(2 mmol, 766 mg) was refluxed in ethanol (5 ml) for 2.5 h. After completion
of the reaction (as indicated by TLC), the reaction mixture was cooled to room
temperature and the solid formed was filtered. Finally the product was purified
by recrystallization from ethanol. The structure of the compound was
ascertained as 7a from spectroscopic data and elemental analysis. Yield: 77%
(295 mg); Compound 7a: Yellow solid; mp 258.6–259.3 °C. IR (CHCl3): mmax
14. (a) Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2009, 50, 243; (b) Majumder, S.;
Bhuyan, P. J. Synlett 2010, 173.
15. Glasnov, T. N.; Belaj, F.; Ivanov, I. C. J. Heterocycl. Chem. 2008, 45, 177.
16. (a) Baruah, B.; Bhuyan, P. J. Tetrahedron 2009, 65, 7099; (b) Naidu, P. S.; Bhuyan,
P. J. Tetrahedron Lett. 2012, 53, 426; (c) Deb, M. L.; Majumder, S.; Baruah, B.;
Bhuyan, P. J. Synthesis 2010, 929; (d) Naidu, P. S.; Borah, P.; Bhuyan, P. J.
Tetrahedron Lett. 2012, 53, 4015; (e) Majumder, S.; Bhuyan, P. J. Tetrahedron
Lett. 2012, 53, 137.
17. (a) Borah, P.; Naidu, P. S.; Bhuyan, P. J. Tetrahedron Lett. 2012, 53, 5034; (b)
Majumder, S.; Borah, P.; Bhuyan, P. J. Mol. Diversity 2012, 16, 279.
18. Sabatie, A.; Vegh, D.; Loupy, A.; Floch, L. ARKIVOC 2001, vi, 122.
19. Representative procedure for the formation of compound 2: To a stirred solution
of 4-hydroxycoumanin 1a (6.17 mmol, 1 g) in anhydrous DMF (5.2 ml), POCl3
(3.2 ml, 0.02 mmol) was added drop wise at À10 to À5 °C. The stirring was
continued for 1 h at room temperature and then heated at 60 °C for 2 h. The
reaction mixture was cooled and then poured into ice under vigorous stirring.
1606.4, 1685.1, 1749.0, 2878.1 cmÀ1 1H NMR (CDCl3, 300 MHz): d 7.21–7.51
;
(m, 4H), 3.80 (m, 1H), 3.39 (s, 3H), 3.28 (s, 3H), 2.98 (s, 2H), 2.67 (m, 2H), 1.46
(t, 3H), 1.12 (d, J = 6.81 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 14.92, 17.65,
22.27, 28.79, 29.75, 49.04, 51.85, 103.48, 116.41, 117.86, 123.34, 123.64,
130.57, 149.32, 151.34, 152.77, 161.85, 168.51, 169.42; MS (ESI): 384.5
(M+H)+; Anal. Calcd for C20H22N3O5: C, 62.65; H, 5.52; N, 10.96. Found: C,
62.33; H, 5.45; N, 10.41. Similarly, compounds 7b–v were synthesized and
characterized.
23. Heber, D.; Ivanov, I. C.; Karagiosov, S. K. J. Heterocycl. Chem. 1995, 32, 505.