Unusual reaction of 6-formyl-2-oxo-2H-benzo[h]chromene-3-carboxylic acid ethyl ester with aliphatic amines

Article abstract of DOI:10.1080/00397910902916056

The unusual reaction of coumarone systems when exposed to aliphatic amines is described. The stability and formation of these compounds is discussed with respect to its substituents at para position, and it was found that the para substituents have no rol

Full text of DOI:10.1080/00397910902916056

Synthetic Communications1, 40: 21–28, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902916056
UNUSUAL REACTION OF 6-FORMYL-2-OXO-
2H-BENZO[h]CHROMENE-3-CARBOXYLIC ACID
ETHYL ESTER WITH ALIPHATIC AMINES
Koneni V. Sashidhara, Jammikuntla N. Rosaiah,
and Abdhesh Kumar
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, India
The unusual reaction of coumarone systems when exposed to aliphatic amines is described.
The stability and formation of these compounds is discussed with respect to its substituents
at para position, and it was found that the para substituents have no role to play.
Keywords: 1-Hydroxynaphthalene-2,4-dicarbaldehyde; keto-enamine; NMR spectroscopy; regioselectivity;
Schiff bases
INTRODUCTION
Coumarins and their derivatives have attracted considerable attention from
organic and medicinal chemists for many years because a large number of natural
products contain this heterocyclic nucleus,[1] and they exhibit various biological
activities such as anticancer activity,[2] inhibition of platelet aggregation,[3] inhibition
of steroid 5a-reductase,[4] and anti-HIV activity.[5] In continuation of our drug dis-
covery program, we have reported the synthesis and potential antidyslipidemic and
antioxidant activity of novel Schiff bases from 7-hydroxy-4-methyl-2-oxo-2H-
benzo[h]chromene-8,10 dicarbaldehyde in which the reactions were regioselective
and products were in the keto-enamine form, in which the aromaticity of the relevant
ring was disrupted.[6,7] Further, our efforts to bring the free aldehyde at position
4 into reaction failed both with increasing molar ratio of the alkyl amine and
also by increasing the reaction temperature to reflux, and we rather discovered
vicarious nucleophilic substitution in enamine derivatives of 1-hydroxynaphtha-
lene-2,4-dicarbaldehyde.[8]
To prepare a variety of coumarin derivatives and their Schiff bases, we
embarked upon synthesis of coumarins from 1-hydroxynaphthalene-2,4-
dicarbaldehyde 1, which in turn was obtained from Duff reaction of a-naphthol
(Scheme 1). Our synthetic strategy began with the widely used Knoevenagel
Received December 29, 2008.
CDRI Communication No. 7463.
Address correspondence to Koneni V. Sashidhara, Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow 226 001, India. E-mail: sashidhar123@gmail.com
21

22
K. V. SASHIDHARA, J. N. ROSAIAH, AND A. KUMAR
Scheme 1. Synthesis of 2a,b and conversion to 4a–d.
reaction[9] between
1 and a diketoester to give 3-acetyl-2-oxo-2H-benzo
[h]chromene-6-carbaldehyde 2a. The product formed was unambiguously character-
ized by spectroscopic studies including 2D NMR [correlation spectroscopy (COSY),
heteronuclear multiple quantum correlation (HMBC), and heteronuclear single
quantum correlation (HSQC)] (Fig. 1). We tried to introduce the nitrogenous side
chain to product 2a (which has a free aldehyde) to improve its pharmacological
activity. The results of investigations form the subject matter of this letter.
RESULTS AND DISCUSSION
When treated with aliphatic amines under ethanolic conditions, compounds 2a
and 2b furnished compounds within a short time, which we thought to be 3a–d.
Electrospray ionization–mass spectrometry (ESI-MS) of the product gave a
1
molecular ion at m=z 214. The H NMR of the product in addition to other signals
showed a signal at d 9.77 for a free aldehyde, and the product existed in the
keto-enamine form as the NH proton gave a cross peak with enamine proton at d
8.45 in the COSY spectrum. In 13C NMR, there was no peak corresponding to lac-
tone moity at d 155.6 ppm. The final analysis with all the spectral data led to the dis-
covery that the compound 2a was converted to 4a on addition of a methylamine. It is
interesting to note the same product was also formed directly from 1-hydroxy
naphthalene-2,4-dicarbaldehyde 1 on treatment with methyl amine.[8]
Figure 1. Selected HMBC corelations of compound 2a in CDCl3.

UNUSUAL REACTION OF COUMARONE SYNTHESIS
23
Though efforts are ongoing in our laboratory to delineate the mechanism of
this reaction, the most plausible mechanism seems to be a ring opening (by transes-
terification=solvent assisted) and retro-Knoevenagel condensation,[10] resulting in the
regeneration of the aromatic dicarbaldehyde (starting material) and then its sub-
sequent reaction with the amine present, giving rise to enamine product. Overall,
we believe, it is a stepwise process with participation of protic solvent (ethanol).
These perplexing results forced us to delineate the role of electron-withdrawing
para aldehyde in compound 1. We thought the electron-withdrawing aldehyde group
at the para position was responsible for this existence in keto-enamine form and its
unusual stability.
It is worth mentioning that the aldehyde at position 2 that was in chelation
(hydrogen bonded) with OH was more reactive and in NMR resonated at d 10.25
compared with the aldehyde at position 4, which in turn resonated at d 9.98.
Hence, the addition of either alkyl or aromatic amine instantaneously resulted in
the enamine derivatives, leaving the free aldehyde at position 4.
Recently, Blanco and Ferretti[11] have studied the solvent and substituent
effects on the conformational equilbria and intramolecular hydrogen bonding of
4-substituted-2-hydroxybenzaldehydes. The key findings of this study were that
the electron-withdrawing groups, by decreasing the O11H13O12 H-bond angle,
increase the corresponding O11–H13 interaction distance and consequently the
strength of the intramolecular hydrogen bonding decreases (Fig. 2).
Hence, in the 1-hydroxynaphthalene-2,4-dicarbaldehyde 1 system, we thought
because of the electron-withdrawing group at position 4 the molecule occurs in the
least stable conformer (i.e., open cis conformer rather than stable closed cis confor-
mer or trans conformer) (Fig. 2). This could explain the high reactivity of this
system, containing a reactive electrophilic aldehyde group at position 2.
To our surprise, when 1-hydroxy-4-methyl-naphthalene-2-carbaldehyde 6
(isolated and characterized as a minor side product of the Duff reaction) was treated
with n-butyl amine and also with p-toluidine, it instantaneously resulted in the
respective keto-enamine products 7b and 7c (Scheme 2). These results indicate that
Schiff bases derived from ortho-hydroxy benzaldehyde group in naphthalene-based
system invariable exist in keto-enamine regardless of the nature of the substituent at
the para-position.
Robert et al. have synthesized highly stable 3-carbaxamide coumarins from
3-carbaxylic ester coumarins.[9] To the best of our knowledge, this is the first example
Figure 2. Open cis conformation of 1-hydroxynaphthalene-2,4-dicarbaldehyde.

24
K. V. SASHIDHARA, J. N. ROSAIAH, AND A. KUMAR
Scheme 2. Synthesis of keto-enamine 4a, 7a–c.
of rearrangement of stable benzocoumarin with an alkyl amine. The benzocoumar-
ins (2a and 2b) underwent reaction not only with methylamine but also with ethyl,
propyl, and butyl amine; the reaction times and yields were comparable with those
of reaction products of methyl amine. All the reactions were rapid, and almost
70–75% of the reactant underwent reaction to the corresponding keto-enamine.
Finally, the exceptional stability of the final keto-enamine product deserves
some comments. The extra stabilization due to extended conjugation in these sys-
tems helps to overcome the aromatic stabilization. There are two reasons that con-
tribute to the additional stability. First, the carbon–carbon single bond between the
two double bonds in a conjugated diene is derived from the overlap of two carbon
sp2 orbitals (i.e., it is in fact an sp2–sp2 single bond and hence stronger). Second,
there is the overlap of 2p orbitals across the carbon–carbon bond, connecting the
two-alkene units. That is, k bonding not only occurs within each of the alkene units
but between them as well. Thus, the 2p orbitals on the central carbon are in the par-
allel alignment necessary for overlap. The additional bonding associated with this
overlap provides additional stability to the molecule.
CONCLUSIONS
In conclusion, we are the first group to discover this unusual reaction
in benzocoumarin derivatives. Also, the role of para substituent (both electron with-
drawing and releasing) in the ortho-hydroxy benzaldehyde group in naphthalene-
based system seems to have no effect on the final outcome of its reaction with
primary amines.
EXPERIMENTAL
Melting points were recorded on a Buchi-530 capillary melting point apparatus
1
and are uncorrected. H NMR spectra were run on Bruker Avance DPX 300-MHz
spectrometer in CDCl3 (d 7.28) or DMSO-d6 (2.50), and tetramethylsilane (TMS)
was used as internal standard. Data reported are as follows: chemical shift [multi-
plicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling con-
stant(s) in Hertz, integration assignment]. ESI mass spectra were recorded on a Jeol
S ꢀ 102=DA-6000. Silica gel (60–120 mesh) was used as stationary phase to isolate
the compounds.

UNUSUAL REACTION OF COUMARONE SYNTHESIS
25
Synthesis of 6-Formyl-2-oxo-2H-benzo[h]chromene-3-carboxylic Acid
Ethyl Ester (2a)
Pyridine (15 ml) was added to an equivalent mixture of 1-hydroxy
naphthalene-2,4-dicarbaldehyde 1 (2 g, 10 mmol) and diethyl malonate (2.4 g,
15 mmol). The mixture was vigorously refluxed for 12 h. After completion of the
reaction, it was neutralized with aq. HCl and extracted with CHCl3 (3 ꢀ 50 ml).
CHCl3 extract was dried over anhy. Na2SO4 and concentrated in a strong vacuum.
The crude product thus obtained was purified by column chromatography (60–120)
to furnish 1.63 g (55% yield) of pure benzocoumarin 2a as a white solid.
6-Formyl-2-oxo-2H-benzo[h]chromene-3-carboxylic Acid
Ethyl Ester (2a)
1H NMR (CDCl3, 300 MHz) d 10.36 (s, 1H), 9.30 (d, J ¼ 8.6 Hz, 1H), 8.73
(s, 1H), 8.64 (d, J ¼ 7.8 Hz, 1H), 8.08 (s, 1H), 7.89 (t, J ¼ 7.0, 1H), 7.78 (t, J ¼ 7.8 Hz,
Hz, 1H), 4.46 (q, J ¼ 7.2 Hz, 2H), 1.45 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3,
75 MHz) d 190.08, 161.42, 155.74, 154.43, 147.36, 134.42, 131.61, 131.31, 127.41,
127.28, 124.05, 122.28, 121.72, 116.75, 111.12, 61.14, 12.94; ESI (m=z) 297 [M þ H]þ;
; IR (KBr, cmꢁ1): 3433, 2980, 2875, 1622, 1610; yield: 55%; solid; mp 199ꢂC.
3-Acetyl-2-oxo-2H-benzo[h]chromene-6-carbaldehyde (2b)
1H NMR (CDCl3, 300 MHz) d 10.39 (s, 1H), 9.32 (d, J ¼ 8.9 Hz, 1H), 8.71(s,
1H), 8.65 (d, J ¼ 7.9 Hz, 1H), 8.10 (s, 1H), 7.90 (t, J ¼ 7.9, 1H), 7.79 (t, J ¼ 7.4 Hz,
1H), 2.80 (s, 3H); 13C NMR (CDCl3, 50 MHz) d 199.53, 197.13, 163.35, 161.85,
152.95, 142.51, 137.81, 137.57, 133.73, 133.63, 130.56, 129.18, 128.44, 127.89,
118.32, 35.52; ESI (m=z) 267 [M þ H]þ; IR (KBr, cmꢁ1): 3435, 2984, 2865, 1625,
1605; yield: 50%; solid; mp 208ꢂC.
Synthesis of 3-Methylaminomethylene-4-oxo-3,4-dihydro-
naphthalene-1-carbaldehyde (4a)
Absolute ethanol (5 ml) was added to the benzocoumarin 2a (0.2 g, 0.67 mmol)
and methylamine (0.041 g, 1.34 mmol) and stirred at room temperature for 1 to
2 min. After completion of the reaction, ethanol was removed tin a strong vacuum,
and the mixture was filtered and washed with water. The crude product was purified
by column chromatography over silica (60–120) to provide pure enamine 4a as
yellow solid.
3-Methylaminomethylene-4-oxo-3,4-dihydro-naphthalene-1-
carbaldehyde (4a)
1H NMR (DMSO-d6, 300 MHz) d 12.43 (s, 1H), 9.77, (s, 1H), 9.11 (d,
J ¼8.2 Hz, 1H), 8.45 (d, J ¼ 13.8 Hz, 1H), 8.32 (d, J ¼ 8.8 Hz, 1H), 7.85 (s, 1H),
7.7–7.65 (m, 1H), 7.5–7.45 (m, 1H), 3.39 (s, 1H); ESI (m=z) 214 [M þ H]þ;
IR (KBr cmꢁ1): 3444, 2938, 1633, 1596, 1351; yield: 75%; solid; mp 213ꢂC.

26
K. V. SASHIDHARA, J. N. ROSAIAH, AND A. KUMAR
3-Ethylaminomethylene-4-oxo-3,4-dihydro-naphthalene-
1-carbaldehyde (4b)
1H NMR (CDCl3, 300 MHz) d 13.22 (s, 1H), 9.88 (s, 1H), 9.2 (d, J ¼ 12.4 Hz,
1H), 8.49 (d, J ¼ 9.1 Hz, 1H), 7.9 (d, J ¼ 12.5 Hz, 1H), 7.74–7.68 (m, 1H), 7.54–7.5
(m, 2H), 3.73–3.64 (m, 2H), 1.48 (t, J ¼ 7.2 Hz, 3H); ESI (m=z) 228 [M þ H]þ; IR
(KBr cmꢁ1): 3442, 2941, 1632, 1595, 1350; yield: 72%; solid; mp 225ꢂC.
3-Butylaminomethylene-4-oxo-3,4-dihydro-naphthalene-
1-carbaldehyde (4c)
1H NMR (CDCl3, 300 MHz) d 13.14 (s, 1H), 9.85 (s, 1H), 9.17 (d, J ¼ 8.2 Hz,
1H), 8.46 (d, J ¼ 8.3 Hz, 1H), 7.82 (d, J ¼ 9.9 Hz, 1H), 7.68 (t, J ¼ 9.2 Hz, 1H),
7.52–7.46 (m, 2H), 3.57 (m, 2H), 1.78–1.70 (m, 2H), 1.52–1.43 (m, 2H), 0.99
(t, J ¼ 7.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 189.39, 180.09, 161.1, 145.11,
132.79, 130.82, 129.2, 124.92, 124.45, 123.99, 118.96, 106.71, 49.41, 30.76, 18.44,
12.22; ESI (m=z) 256 [M þ H]þ; IR (KBr cmꢁ1): 3426, 2925, 2845, 1628, 1594,
1352; Yield: 74%; solid; mp 95ꢂC.
3-Heptylaminomethylene-4-oxo-3,4-dihydro-naphthalene-
1-carbaldehyde (4d)
1H NMR (CDCl3, 300 MHz) d 13.17 (s, 1H), 9.87 (s, 1H), 9.19 (d, J ¼ 8.2 Hz,
1H), 8.48–8.45, (m, 1H), 7.9 (d, J ¼ 12.8, 1H), 7.69 (m, 1H), 7.54–7.48 (m, 2H),
3.67–3.58 (m, 2H), 1.46–1.22 (m, 10H), 0.89 (t, J ¼ 6.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz) d 189.42, 180.12, 159.46, 145.13, 132.8, 130.84, 129.23, 125.02, 124.41,
124.06, 119.04, 106.54, 56.37, 36.09, 30.25, 24.4, 21.18, 20.11, 12.71; ESI (m=z) 298
[M þ H]þ; IR (KBr, cmꢁ1): 3429, 2923, 2860, 1632, 1595, 1352; yield: 70%; liquid.
1-Hydroxy-4-methyl-naphthalene-2-carbaldehyde (6)
1H NMR (CDCl3, 200 MHz) d 12.33 (s, 1H), 9.68 (s, 1H), 8.28 (d, J ¼ 9.8 Hz,
1H), 7.7 (d, J ¼ 8.5 Hz, 1H), 7.52 (t, J ¼ 8.5 Hz, 1H), 7.38 (t, J ¼ 7.3 Hz, 1H), 7.0
(s, 1H), 2.39 (s, 3H); 13C NMR (CDCl3, 50 MHz) d 194.93, 159.20, 135.45, 129.16,
124.59, 124.41, 124.01, 123.45, 123.27, 122.81, 112.41, 12.98; ESI (m=z) 186
[M þ H]þ; IR (KBr, cmꢁ1): 3432, 2980, 2865, 1625, 1593, 1350; yield: 10%; solid;
mp 69ꢂC.
4-Oxo-3-(p-tolylamino-methylene)-3,4-dihydro-naphthalene-
1-carbaldehyde (7a)
1H NMR (CDCl3, 300 MHz) d 15.11 (s, 1H), 9.98 (s, 1H), 9.2 (d, J ¼ 8.04 Hz,
1H), 8.51 (d, J ¼ 8.3 Hz, 1H), 8.38 (d, J ¼ 10.9 Hz, 1H), 7.76–7.71 (m, 1H), 7.64
(s, 1H), 7.58–7.53 (m, 1H), 7.3–7.27 (m, 4H), 2.43 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 189.65, 179.61, 152.95, 144.42, 136.42, 134.8, 132.61, 131.23, 129.45,
128.68, 125.35, 124.54, 124.18, 120.59, 117.38, 107.92, 19.8; ESI (m=z) 290 [M þ H]þ;
; IR (KBr cmꢁ1): 3416, 2922, 2815, 1595, 1443, 1353; yield: 95%; solid; mp 186ꢂC.

UNUSUAL REACTION OF COUMARONE SYNTHESIS
27
2-Butylaminomethylene-4-methyl-2H-naphthalen-1-one (7b)
1H NMR (CDCl3, 300 MHz) d 13.28 (s, 1H), 8.50 (d, J ¼ 7.9 Hz, 1H), 7.71–7.41
(m, 3H), 7.44 (t, J ¼ 7.8 Hz, 1H), 6.71 (s, 1H) 3.46 (t, J ¼ 6.7 Hz, 2H), 2.4 (s, 3H),
1.72–1.62 (m, 2H), 1.49–1.33 (m, 2H) 0.97–0.88 (m, 3H); 13C NMR (CDCl3,
75 MHz) d 175.80, 159.14, 136.10, 129.09, 128.95, 125.80, 124.63, 123.54, 122.70,
118.01, 106.96, 49.67, 31.32, 18.55, 17.46, 12.34; ESI (m=z) 242 [M þ H]þ; IR
(KBr, cmꢀ1): 3425, 2945, 2875, 1630, 1593; yield: 98%; liquid.
4-Methyl-2-(p-tolylamino-methylene)-2H-naphthalen-1-one (7c)
1H NMR (CDCl3, 300 MHz) d 14.73 (s, 1H), 8.49 (d, J ¼ 7.3, 1H), 8.23 (s, 1H),
7.74 (d, J ¼ 7.6 Hz, 1H), 7.6 (t, J ¼ 6.3 Hz, 1H), 7.47 (t, J ¼ 7.6 Hz, 1H), 7.22–7.16
(m, 4H), 6.86 (s, 1H), 2.44 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 172.36, 155.14, 140.84, 137.07, 136.40, 130.68, 130.53, 129.01, 127.21, 125.82,
125.6, 124.45, 122.52, 119.46, 115.72, 110.84, 21.40, 19.2; ESI (m=z) 276 [M þ H]þ;
IR (KBr, cmꢀ1): 3442, 2933, 1622, 1590, 1350; yield: 95%; solid; mp 84ꢁC.
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