Rh-Catalyzed Synthesis of Coumarin Derivatives from Phenolic Acetates and Acrylates via C-H Bond Activation

Article abstract of DOI:10.1021/acs.joc.5b01713

An efficient annulation strategy involving the reaction of phenolic acetates with acrylates in the presence of [Rh₂(OAc)₄] as catalyst and formic acid as reducing agent, leading to the high yield synthesis of coumarin derivatives, has been developed. The addition of NaOAc as a base increased the yield of the products. The reaction is quite successful for both electron-rich as well as electron-deficient phenolic acetates, affording coumarins with excellent regioselectivity, and proceeds via C-H bond activation proven by deuterium incorporation studies.

Full text of DOI:10.1021/acs.joc.5b01713

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Note
Rh-Catalyzed Synthesis of Coumarin Derivatives from
Phenolic Acetates and Acrylates via C-H Bond Activation
Sunita Khanderao Gadakh, Soumen Dey, and Arumugam Sudalai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01713 • Publication Date (Web): 28 Oct 2015
Downloaded from http://pubs.acs.org on October 29, 2015
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RhꢀCatalyzed Synthesis of Coumarin Derivatives from Phenolic Acetates
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and Acrylates via CꢀH Bond Activation
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Sunita K. Gadakh, Soumen Dey and Arumugam Sudalai*
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Chemical Engineering & Process Development Division, CSIR-National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra, India-411008.
a.sudalai@ncl.res.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
An efficient annulation strategy involving the reaction of phenolic acetates with acrylates in
the presence of [Rh2(OAc)4] as catalyst and formic acid as reducing agent, leading to the high
yield synthesis of coumarin derivatives, has been developed. The addition of NaOAc as a
base increased the yield of the products. The reaction is quite successful for both electronꢀ
rich as well as –deficient phenolic acetates affording coumarins with excellent
regioselectivity and proceeds via CꢀH bond activation proven by deuterium incorporation
studies.
The activation of CꢀH bonds of aromatic hydrocarbons is one of the most challenging
processes since these CꢀH bonds are relatively strong for chemical transformations. It is also
an environmentꢀfriendly process as it does not require toxic halogens for activation.1 Thus,
directed metallation of aromatic substrates has emerged as one of the most versatile methods
to functionalize the CꢀH bonds of aromatic hydrocarbons.2 Coumarin derivatives3 are useful
natural products widely found in plants and exhibit excellent biological and pharmacological
activity including antiꢀtumor,4a antiꢀHIV,4bꢀc antiꢀcoagulation, antiꢀbacterial,4d antiꢀ
inflammatory4eꢀf and antiꢀoxidant.4g In addition, they are also widely used as food additives,
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as optical brightening agents, lightꢀemitting diodes, as fluorescent probes and laser dyes5
(Fig. 1).
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Figure 1. Some of bioactive coumarin derivatives
Traditionally, the most common approach to their synthesis is undoubtedly the Pechmann
condensation6 and its related reactions.7 Unfortunately, these classical methods employ
stoichiometric quantities of strong Lewis or Brønsted acids, often leading to mixtures of
regioisomers. To a certain extent, some of these difficulties have been overcome by transition
metalꢀcatalyzed coupling reactions.8 However, starting materials (halides and organometallic
reagents) for such processes need to be prefunctionalized making these reactions unfavorable
environmentally. Recently Trost and others have reported Pdꢀcatalyzed atom economical
method for the synthesis of coumarins via CꢀH bond activation leading to many applications.9
However, these reactions are applicable to only electronꢀrich phenols probably following a
Friedel–Crafts pathway. Alkenylation of phenols with acrylates using Pd/Cu as catalysts and
employing expensive ligands, provides another strategy for the synthesis of coumarins10
(equation iꢀii, Scheme 1).
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Scheme 1. Synthesis of coumarins via CꢀH activation strategy
As part of our ongoing research on new catalytic synthesis of heterocyclic scaffolds, we have
recently reported an elegant Rh(II)/HCO2H catalytic system for the synthesis of quinoline
carboxylates proceeding through rhodacycle as an intermediate.11 In this communication, we
wish to report, a Rhꢀcatalyzed ortho C−H bond activation of phenolic acetates with acrylates
in presence of NaOAc as base and HCO2H as reducing agent that produces synthetically
useful coumarin derivatives 3aꢀω (equation iii, Scheme 1).
Our initial efforts toward the synthesis of coumarin structural units via annulation of phenyl
acetate (1 mmol) with methyl acrylate (1.2 mmol) focused on catalytic system comprising
Rh(II) acetate (5 mol %) in excess formic acid (1 mL) and heating at 70 °C (Table 1).
However, under these conditions, only 18% of the desired coumarin 3a was obtained.
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Table 1. Rhodium catalyzed reaction of phenyl acetate with methyl acrylate: optimization
studiesa
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entry
catalyst
catalyst
mol %
5
solvent
additive
t
3ab
(%)
18
50
68
71
71
41
19
20
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30
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25
62
11
30
31
ꢀ
(2 mL)
(°C)
70
1
Rh2(OAc)4
ꢀ
ꢀ
2
5
ꢀ
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
K2CO3
Cs2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
70
3
5
ꢀ
80
4
5
ꢀ
100
100
100
100
100
100
100
100
100
100
80
5
2.5
1
ꢀ
6
ꢀ
7
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
ꢀ
ꢀ
8
ꢀ
9
ꢀ
10
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12
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18
PhCH3
PhH
DMF
cEDC
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Rh/Al2O3
100
100
100
100
[RhCOCl2]2
Pd(OAc)2
No catalyst
a Phenyl acetate (1 mmol), methyl acrylate (1.2 mmol), 98% HCO2H (1 mL, 26 mmol), additive (1.5 mmol), 4 Å
molecular sieves, 12 h. b Isolated yield of 3a after chromatographic purification. c 1,2ꢀdichloroethane.
However, conducting the reaction in presence of NaOAc (1.5 equiv) as a base moderately
increased the yield of 3a (50%), which could be gradually improved to 71% by increasing the
temperature from 80 to 100 °C. Screening of other bases was attempted and found to be less
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effective to promote ortho CꢀH bond activation (entry 7ꢀ9); so also with other catalysts (entry
15ꢀ17). Interestingly, by lowering catalyst loading to 2.5 mol %, the product yield (71%) was
not affected, although further lowering to 1 mol % led to a significant reduction in the yield
of the product (41%). Thus, proper choice of catalyst and base is critical in order to realize
high yields of 3a. Also, by lowering the concentration of HCO2H (5 mmol) a decrease in
yield of 3a was observed. Use of other solvents such as toluene, benzene, 1,2ꢀdichloroethane,
or DMF was found to be less suitable for the reaction (only 20ꢀ30% yield). Control
experiment has however proven that, in the absence of catalyst, no reaction took place. Also,
with use of AcOH or TFA as reaction medium instead of HCO2H, only deprotection of
phenyl acetate took place forming phenol exclusively; thus proving that HCO2H acts as a
better reducing agent in addition to being used as solvent.
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We have then applied the optimized procedure of Rhꢀcatalyzed annulation process to a
variety of phenolic acetates (1bꢀr) to determine the scope of the process and the results are
presented in Table 2. Thus, several phenolic acetates with electronꢀdonating and –
withdrawing groups underwent this annulation process successfully and produced the
corresponding coumarin derivatives (3bꢀr) in excellent yields. Remarkably, substrates having
–CHO, ꢀBr, ꢀCN, ꢀNO2 and –COCH3 groups (3lꢀq) were wellꢀtolerated under the reaction
conditions. In the case of unsymmetrical phenolic acetates, complete regiocontrolled products
were obtained as CꢀH activation has occurred at the less sterically hindered position
exclusively (3b, 3eꢀf, 3h, 3jꢀk). 2ꢀNaphthyl acetate was also annulated regiospecifically with
methyl acrylate to afford the corresponding coumarin 3r in 90% yield.
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Table 2. Substrate scope for Rh catalyzed annulationa,b
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a
Phenolic acetates (1 mmol), methyl acrylate (1.5 mmol), Rh2(OAc)4 (2.5 mol %), NaOAc (1.5 mmol), 4 Å
molecular sieves, 98% HCO2H (1 mL), 100 °C, 3ꢀ12 h. b Isolated yield after column purification.
Next, we turned our attention to examine the substituent’s effect on acrylates and the results
are given in Table 3. As can be seen, sterically hindered acrylate 2c (R2 = Ph) showed
comparable activity for the annulation process as that of acrylate 2b (R2 = Me). Here again,
substrates with electronꢀdonating and –withdrawing groups have reacted smoothly with βꢀ
substituted acrylates to afford coumarin derivatives 3sꢀω in excellent yields.
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Table 3. Olefin variation in the annulation processa,b
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a For reaction conditions, refer to the footꢀnote under Table 1 and methyl crotonate or cinnamate (1.2 mmol)
was used. b Isolated yield after column chromatographic purification.
Scheme 2 shows results of several control experiments that were carried out in order to obtain
some insights into mechanistic course of the reaction: (i) when 3,5ꢀdimethoxyphenol 1g' was
subjected to oxidative coupling with methyl acrylate under the reaction conditions, only 10%
of the desired product 3g was obtained, indicating that directing acetate group is required for
forming rhodacycle II; (ii) competitive experiments (1g and 1b) have shown that electronꢀ
rich phenolic acetates have generally reacted faster for the annulation process via CꢀH bond
activation giving 3g:3b (2:1) in 81% combined yield; (iiiꢀiv) we have conducted the
following two experiments to establish whether this reaction proceeds by alkenylation or
esterification. Thus, when phenyl acrylate (4) or (E)ꢀmethyl(2ꢀhydroxy phenyl acrylate (5) is
reacted under the same reaction condition (Rh/HCO2H/NaOAc), product 3a was isolated in
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13% and 68% yields, respectively; indicating that the reaction undergoes alkenylation first
via CꢀH activation followed by lactonization; (v) when 1g was reacted with D2O in the
absence of methyl acrylate under the same reaction conditions, product dꢀ1g was isolated in
55% yield, in which 40% of deuterium was incorporated at the Cꢀ4 and 50% each at Cꢀ2 and
Cꢀ6 positions of dꢀ1g;
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Scheme 2. Control experiments to probe mechanism
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(vi) when 1g was reacted with methyl acrylate in the presence D2O under the reaction
conditions, product dꢀ3g was isolated in 50% yield, in which 40% of deuterium was
incorporated at the Cꢀ3 and Cꢀ4 position of the coumarin derivative, along with 53%
deuterium incorporation each at Cꢀ6 and Cꢀ8 of dꢀ3g. This result clearly supports that the
ortho CꢀH bond cleavage in phenolic acetate occurs in a reversible manner.12
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A probable catalytic cycle based on the control experiments for the formation of coumarin
derivatives 3aꢀω is shown in Scheme 3. Coordination of the carbonyl group of phenyl acetate
to Rh species I, obtained from [Rh2(OAc)4] on reduction with formic acid, followed by orthoꢀ
metallation provides a 6ꢀmembered rhodacycle intermediate II. Coordinative regioselective
insertion of alkenic ester 2 into the Rh−C bond of intermediate II gives the intermediate III
followed by the βꢀhydride elimination releasing the alkenated product IV in situ. Acetate
deprotection under acidic condition followed by intramolecular cyclization produced
coumarins 3. Finally, Rh(L)H species on reduction with formic acid liberates reactive Rh(I)
species for the next catalytic cycle.
Scheme 3. Proposed catalytic cycle for coumarin derivatives 3
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In conclusion, we have disclosed a simple annulation strategy that affords a variety of
substituted coumarin derivatives 3aꢀω in excellent yields from the corresponding phenolic
acetates and acrylates via rhodium catalyzed CꢀH bond activation in a single step. This
protocol is quite useful in the case of phenolic substrates with electronꢀdeficient groups and is
complementary to the reported methods generally applicable for electronꢀdonating substrates
only; thus providing for the diversityꢀoriented synthesis of bioactive coumarin derivatives in
high yields. This cyclization strategy proceeds through rhodacycle as the intermediate formed
by the ortho CꢀH bond activation of phenolic acetates and is well supported by deuterium
incorporation studies. We believe that this method may find applications in the synthesis of
various bioactive coumarin derivatives as it is convenient to carry out under mild conditions
displaying a wide range of substrate scope.
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EXPERIMENTAL SECTION
Solvents were distilled and dried by standard procedures before use; petroleum ether with
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boiling range 60ꢀ80 °C was used. Melting points were uncorrected. H NMR and 13C NMR
spectra were recorded on 200, 400, and 500 MHz NMR spectrometers. Infrared spectra were
recorded on FTIR system and absorption is expressed in cmꢀ1. HRMS data for new
compounds were recorded using an Orbitrap mass analyzer associated with an Accela 1250
pump. Rhodium diacetate was purchased from SigmaꢀAldrich. Purification was done using
column chromatography (230ꢀ400 mesh).
General experimental procedure for the synthesis of phenolic acetates: Phenolic acetates
(1aꢀr) were readily prepared from the corresponding phenols as follows: Phenols (1
mmol) were dissolved in 5 mL dry pyridine and the resulting mixture was cooled to 0 °C.
Acetic anhydride (1.5 mmol) was added dropwise to it. The reaction mixture was allowed to
rise to room temperature and stirred for 0.5ꢀ1 h. Then pyridine was removed under high
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vacuo and the remaining reaction mass dissolved in ethyl acetate. The organic layer was
washed with water/aq HCl/water, dried over anhydrous Na2SO4, concentrated to give the pure
phenolic acetates (1aꢀr), which were used further for studies without purification.
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General experimental procedure for the preparation of coumarin derivatives (3aꢀω):
To a mixture of substituted phenolic acetates (1aꢀr) (1 mmol), Rh2(OAc)4 (2.5 mol %),
commercially available 98% formic acid (1 mL), NaOAc (1.5 mmol) and 4Å MS under
nitrogen atmosphere was added methyl acrylate 2a or methyl crotonate 2b or cinnamate 2c
(1.2 mmol) as the case may be. The resulting brown solution was stirred at 100 °C for 3ꢀ12 h.
After completion of reaction (monitored by TLC), it was diluted with ethyl acetate (10 mL),
and washed with water (10 mL), 5% aqueous sodium bicarbonate (15 mL), and brine (10
mL). The organic layer was dried over anhydrousNa2SO4 and concentrated in vacuo to give
brown solids. On purification with flash chromatography using pet ether and ethyl acetate
(7:3), coumarin derivatives (3aꢀ ω) were obtained as solids.
2HꢀChromenꢀ2ꢀone (3a): Yield: 71%; 0.110 g; colorless solid, mp: 71 °C (lit.7g mp 70ꢀ72
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°C); IR (CHCl3, cmꢀ1): υmax 3060, 2958, 1715, 1605, 1453, 1106; H NMR (200 MHz,
CDCl3): δ 7.70 (d, J = 9.6 Hz, 1H), 7.45ꢀ7.60 (m, 2H), 7.24ꢀ7.39 (m, 2H), 6.42 (d, J = 9.5 Hz,
1H); 13C NMR (50 MHz, CDCl3): δ 160.4, 154.2, 143.2, 131.8, 127.8, 124.4, 118.9, 117.0,
116.9; HRMS (ESI): calc. for [(C9H6O2)H] (M+H) 147.0446, found 147.0440.
7ꢀMethylꢀ2Hꢀchromenꢀ2ꢀone (3b): Yield: 81%; 0.120 g; colorless solid, mp: 165ꢀ167 °C;
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IR (CHCl3, cmꢀ1): υmax 3079, 2930, 1716, 1620, 1573, 1530; H NMR (200 MHz, CDCl3): δ
7.67 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.06ꢀ7.14 (m, 2H), 6.35 (d, J = 9.5 Hz,
1H), 2.45 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 161.1, 154.1, 143.4, 143.1, 127.5, 125.6,
117.0, 116.4, 115.4, 21.8; HRMS (ESI): calc. for [(C10H8O2)H] (M+H) 161.0603, found
161.0605.
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5,7ꢀDimethylꢀ2Hꢀchromenꢀ2ꢀone (3c): Yield: 83%; 0.118 g; colorless solid, mp: 104ꢀ105
°C; IR (CHCl3, cmꢀ1): υmax 1710, 1623, 1437; 1H NMR (200 MHz, CDCl3): δ 7.87 (d, J = 9.8
Hz, 1H), 6.97 (s, 1H), 6.93 (s, 1H), 6.35 (d, J = 9.8 Hz, 1H), 2.48 (s, 3H), 2.40 (s, 3H); 13C
NMR (50 MHz, CDCl3): δ 161.1, 154.7, 142.7, 140.4, 135.6, 126.9, 115.3, 115.0, 114.6,
21.6, 18.1; HRMS (ESI): calc. for [(C11H10O2)H] (M+H) 175.0759, found 175.0765.
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6ꢀ(tertꢀButyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3d): Yield: 77%; 0.081 g; liquid; IR (CHCl3,
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cmꢀ1): υmax 2936, 1728, 1610, 1556, 1507, 1282; H NMR (200 MHz, CDCl3): δ 7.71 (d, J =
9.5 Hz, 1H), 7.58 (dd, J = 8.7, 2.3 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H),
6.41 (d, J = 9.5 Hz, 1H), 1.36 (s, 9H); 13C NMR (50 MHz, CDCl3): δ 161.1, 152.0, 147.5,
143.9, 129.5, 124.1, 118.2, 116.4, 116.4, 31.3; HRMS (ESI): calc. for [(C13H14O2)H] (M+H)
203.1072, found 203.1077.
7ꢀHydroxyꢀ2Hꢀchromenꢀ2ꢀone (3e): Yield: 92%; 0.120 g; colorless solid, mp: 235 °C (lit.8g
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mp 234ꢀ237 °C); IR (CHCl3, cmꢀ1): υmax 3220, 1705, 1670, 1380, 1237, 1077, 986, 570; H
NMR (200 MHz, CDCl3): δ 7.86 (d, J = 9.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 6.83 (dd, J =
8.4, 2.0 Hz, 1H), 6.75 (s, 1H), 6.16 (d, J = 9.5 Hz, 1H); 13C NMR (50 MHz, CDCl3): δ 162.3,
161.2, 157.1, 144.8, 130.5, 113.9, 112.9, 112.8, 103.4; HRMS (ESI): calc. for [(C9H6O3)H]
(M+H) 163.0395, found 163.0398.
7ꢀMethoxyꢀ2Hꢀchromenꢀ2ꢀone (3f): Yield: 88%; 0.124 g; colorless solid, mp: 122ꢀ123 °C;
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IR (CHCl3, cmꢀ1): υmax 2936, 1728, 1610, 1556, 1507, 1282; H NMR (200 MHz, CDCl3): δ
7.62 (d, J = 9.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.78ꢀ6.87 (m, 2H), 6.24 (d, J = 9.5 Hz,
1H), 3.88 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 162.8, 160.8, 156.0, 143.1, 128.6, 113.2,
112.6, 112.5, 100.8, 55.6; HRMS (ESI): calc. for [(C10H8O3)H] (M+H) 177.0552, found
177.0558.
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5,7ꢀDimethoxyꢀ2Hꢀchromenꢀ2ꢀone (3g): Yield: 95%; 0.127 g; colorless solid, mp: 148ꢀ150
°C (lit.8g mp 147ꢀ148 °C); IR (CHCl3, cmꢀ1): υmax 2936, 1725, 1615, 1552, 1509, 1382, 1130;
1H NMR (200 MHz, CDCl3): δ 7.95 (d, J = 9.6 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 6.26 (d, J =
2.2 Hz, 1H), 6.15 (d, J = 9.7 Hz, 1H), 3.86 (s, 3 H), 3.90 (s, 3H); 13C NMR (50 MHz,
CDCl3): δ 163.7, 161.2, 156.9, 138.5, 111.1, 104.0, 94.8, 92.8, 55.9, 55.7; HRMS (ESI): calc.
for [(C11H10O4)H] (M+H) 207.0657, found 207.0654.
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6,7ꢀDimethoxyꢀ2Hꢀchromenꢀ2ꢀone (3h): Yield: 85%; 0.113 g; colorless solid, mp: 140ꢀ142
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°C; IR (CHCl3, cmꢀ1): υmax 2970, 1725, 1615, 1552, 1509; H NMR (200 MHz, CDCl3): δ
7.60 (d, J = 9.5 Hz, 1H), 6.84 (s, 2H), 6.28 (d, J = 9.5 Hz, 1H), 3.92 (s, 3H), 3.95 (s, 3H); 13C
NMR (50 MHz, CDCl3): δ 161.0, 152.8, 150.1, 146.3, 143.0, 108.0, 100.0, 56.2; HRMS
(ESI): calc. for [(C11H10O4)H] (M+H) 207.0657, found 207.0659.
5,6,7ꢀTrimethoxyꢀ2Hꢀchromenꢀ2ꢀone (3i): Yield: 88%; 0.113 g; colorless solid, mp: 147ꢀ
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149 °C; IR (CHCl3, cmꢀ1): υmax 2933, 1722, 1617, 1558, 1509, 1382, 1130; H NMR (200
MHz, CDCl3): δ 7.91 (d, J = 9.5 Hz, 1H), 6.60 (s, 1H), 6.22 (d, J = 9.5 Hz, 1H), 4.03 (s, 3H),
3.93 (s, 3H), 3.85 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 160.9, 157.1, 151.5, 149.2, 138.6,
138.0, 112.5, 107.1, 95.4, 61.7, 61.1, 56.2; HRMS (ESI): calc. for [(C12H12O5)H] (M+H)
237.0763, found 237.0757.
6Hꢀ[1,3]Dioxolo[4,5ꢀg]chromenꢀ6ꢀone (3j): Yield: 89%; 0.122 g; colorless solid, mp: 218ꢀ
220 °C (lit.8g mp 223 °C); IR (CHCl3, cmꢀ1): υmax 3087, 1721, 1640, 1500, 1455, 1146, 1130;
1H NMR (200 MHz, CDCl3): δ 7.57 (d, J = 9.1 Hz, 1H), 6.82 (s, 2H), 6.27 (d, J = 9.3 Hz,
1H), 6.07 (s, 2H); 13C NMR (50 MHz, CDCl3): δ 161.0, 151.3, 144.9, 143.3, 113.5, 112.7,
105.0, 102.3, 98.5; HRMS (ESI): calc. for [(C10H6O4)H] (M+H) 191.0344, found 191.0349.
6ꢀHexanoylꢀ7ꢀhydroxyꢀ2Hꢀchromenꢀ2ꢀone (3k): Yield: 87%; 0.110 g; colorless solid, mp:
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202ꢀ203 °C; IR (CHCl3, cmꢀ1): υmax 3220, 1710, 1670, 1380, 1224, 1056, 967, 580; H NMR
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(200 MHz, CDCl3): δ 7.66 (d, J = 9.4 Hz, 1H), 7.17 (s, 1H), 7.18 (s, 1H), 6.22 (d, J = 9.5 Hz,
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1H), 2.64 (d, J = 7.3 Hz, 2H), 1.51ꢀ1.72 (m, 2H), 1.27ꢀ1.42 (m, 6H), 0.81ꢀ0.95 (m, 3H); C
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NMR (50 MHz, CDCl3): δ 163.2, 159.3, 153.9, 144.8, 128.4, 128.1, 111.8, 111.4, 102.8,
31.8, 29.7, 29.5, 29.2, 22.7, 14.2; HRMS (ESI): calc. for [(C15H18O3)H] (M+H) 247.1334,
found 247.1331.
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8ꢀMethoxyꢀ2ꢀoxoꢀ2Hꢀchromeneꢀ6ꢀcarbaldehyde (3l): Yield: 91%; 0.122 g; colorless solid,
mp: 182ꢀ183 °C; IR (CHCl3, cmꢀ1): υmax 3085, 1729, 1717, 1615, 1506, 1440, 1136, 1125; 1H
NMR (200 MHz, CDCl3): δ 9.99 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.60 (d, J = 3.1 Hz, 2H),
6.54 (d, J = 9.5 Hz, 1H), 4.04 (s, 4H); 13C NMR (50 MHz, CDCl3): δ 190.1, 159.0, 148.3,
147.9, 142.9, 132.8, 123.5, 119.3, 118.0, 111.1, 56.4; HRMS (ESI): calc. for [(C11H8O4)H]
(M+H) 205.0501, found 205.0505.
2ꢀOxoꢀ2Hꢀchromeneꢀ6ꢀcarbaldehyde (3m): Yield: 90%; 0.128 g; colorless solid, mp: 192ꢀ
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194 °C; IR (CHCl3, cmꢀ1): υmax 3085, 1727, 1714, 1630; H NMR (200 MHz, CDCl3): δ
10.05 (s, 1H), 7.99ꢀ8.16 (m, 2H), 7.81 (d, J = 9.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 6.54 (d, J
= 9.6 Hz, 1H); 13C NMR (50 MHz, CDCl3): δ 190.0, 159.5, 157.7, 142.8, 132.8, 132.4, 130.0,
119.1, 117.9, 117.9; HRMS (ESI): calc. for [(C10H6O3)H] (M+H) 175.0395, found 175.0390.
6ꢀBromoꢀ2Hꢀchromenꢀ2ꢀone (3n): Yield: 75%; 0.078 g; colorless solid, mp: 156ꢀ158 °C
(lit.7g mp 156ꢀ159 °C); IR (CHCl3, cmꢀ1): υmax 3085, 1727, 1615, 1556, 1470, 1126, 1130; 1H
NMR (200 MHz, CDCl3): δ 7.51ꢀ7.77 (m, 4H), 7.22 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 9.6 Hz,
1H); 13C NMR (50 MHz, CDCl3): δ 159.5, 153.0, 141.9, 134.6, 130.1, 120.3, 118.7, 118.0,
117.0; HRMS (ESI): calc. for [(C9H5BrO2)H] (M+H) 224.9551, found 224.9555.
2ꢀOxoꢀ2Hꢀchromeneꢀ6ꢀcarbonitrile (3o): Yield: 71%; 0.075 g; colorless solid, mp: 150ꢀ
152 °C; IR (CHCl3, cmꢀ1): υmax 3096, 2990, 2219, 1727; 1H NMR (200 MHz, CDCl3): δ 7.76ꢀ
7.88 (m, 2H), 7.72 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H); 13C
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NMR (50 MHz, CDCl3): δ 158.9, 156.3, 141.8, 134.7, 132.3, 119.4, 118.7, 118.3, 117.4,
108.6; HRMS (ESI): calc. for [(C10H5NO2)H] (M+H) 172.0399, found 172.0398.
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6ꢀNitroꢀ2Hꢀchromenꢀ2ꢀone (3p): Yield: 64%; 0.088 g; colorless solid, mp: 181ꢀ183 °C
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(lit.7g 180ꢀ182 °C); IR (CHCl3, cmꢀ1): υmax 3070, 1735, 1610, 1518, 1340; H NMR (200
MHz, CDCl3): δ 8.45 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 9.2, 2.8 Hz, 1H), 7.82 (d, J = 9.8 Hz,
1H), 7.48 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 9.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): δ 158.8,
157.5, 144.0, 142.2, 126.6, 123.7, 118.8, 118.1; HRMS (ESI): calc. for [(C9H5NO4)H]
(M+H) 192.0297, found 192.0295.
6ꢀAcetylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3q): Yield: 85%; 0.089 g; colorless solid, mp: 122ꢀ
123 °C; IR (CHCl3, cmꢀ1): υmax 3070, 1730, 17122, 1610, 1515, 1344; H NMR (200 MHz,
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CDCl3): δ 8.11ꢀ8.24 (m, 2H), 7.79 (d, J = 9.5 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H), 6.51 (d, J =
9.5 Hz, 1H), 2.66 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 196.0, 159.8, 156.9, 143.2, 133.5,
131.7, 128.6, 118.6, 117.6, 117.3, 26.6; HRMS (ESI): calc. for [(C11H8O3)H] (M+H)
189.0552, found 189.0558.
2HꢀBenzo[g]chromenꢀ2ꢀone (3r): Yield: 90%; 0.122 g; colorless solid, mp: 119ꢀ121 °C; IR
(CHCl3, cmꢀ1): υmax 3077, 2929, 1717, 1630, 1563, 1514, 1175; 1H NMR (200 MHz, CDCl3):
δ 8.48 (d, J = 9.6 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.2
Hz, 1H), 7.68 (td, J = 7.7, 1.1 Hz, 1H), 7.53ꢀ7.61 (m, 1H), 7.47 (d, J = 9.2 Hz, 1H), 6.57 (d, J
= 10.1 Hz, 1H); 13C NMR (50 MHz, CDCl3): δ 160.7, 154.0, 139.0, 133.1, 130.4, 129.1,
128.3, 126.1, 121.4, 117.2, 115.8, 113.0; HRMS (ESI): calc. for [(C13H8O2)H] (M+H)
197.0603, found 197.0609.
4ꢀMethylꢀ2Hꢀchromenꢀ2ꢀone (3s): Yield: 78%; 0.132 g; colorless solid, mp: 83 °C (lit.5b
mp 83ꢀ84 °C); IR (CHCl3, cmꢀ1): υmax 3075, 2988, 1725, 1605, 1453; H NMR (200 MHz,
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CDCl3): δ 7.45ꢀ7.65 (m, 2H), 7.26ꢀ7.39 (m, 2H), 6.29 (d, J = 1.1 Hz, 1H), 2.46 (d, J = 1.3 Hz,
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3H); 13C NMR (50 MHz, CDCl3): δ 160.4, 153.7, 151.9, 131.7, 124.5, 124.1, 120.0, 117.2,
115.4, 18.7; HRMS (ESI): calc. for [(C10H8O2)H] (M+H) 161.0603, found 161.0610.
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4ꢀPhenylꢀ2Hꢀchromenꢀ2ꢀone (3t): Yield: 80%; 0.188 g; viscous liquid; IR (CHCl3, cmꢀ1):
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υmax 3050, 2930, 1715, 1675, 1353; H NMR (200 MHz, CDCl3): δ 7.49ꢀ7.60 (m, 5H), 7.15ꢀ
7.32 (m, 2H), 6.78ꢀ6.97 (m, 2H), 6.38 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 160.6, 155.6,
154.3, 135.3, 131.9, 129.7, 129.6, 128.9, 128.5, 127.0, 124.2, 120.5, 119.1, 117.4, 115.3;
HRMS (ESI): calc. for [(C15H10O2)H] (M+H) 223.0759, found 223.0760.
6,7ꢀDimethoxyꢀ4ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone (3u): Yield: 79%; 0.088 g; colorless solid,
mp: 128ꢀ129 °C; IR (CHCl3, cmꢀ1): υmax 3060, 2958, 1715, 1605, 1453, 1106, 1018, 956; 1H
NMR (200 MHz, CDCl3): δ 6.92 (s, 1H), 6.82 (s, 1H), 6.15 (s, 1H), 3.93 (s, 3H), 3.94 (s, 3H),
2.41 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 161.2, 152.7, 152.1, 149.4, 146.1, 112.4, 112.3,
105.1, 100.0, 56.3, 56.2, 18.8; HRMS (ESI): calc. for [(C12H12O4)H] (M+H) 221.0814, found
221.0810.
5,7ꢀDimethoxyꢀ4ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone (3v): Yield: 80%; 0.114 g; colorless solid,
mp: 171ꢀ173 °C (lit.8h mp 174 °C; IR (CHCl3, cmꢀ1): υmax 3110, 2999, 1722, 1625, 1453,
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1230, 1051, 986; H NMR (200 MHz, CDCl3): δ 6.41 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.3
Hz, 1H), 5.88ꢀ5.99 (m, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 2.52 (s, 3H); 13C NMR (50 MHz,
CDCl3): δ 162.8, 160.8, 159.1, 157.1, 154.2, 111.5, 104.9, 95.5, 93.4, 55.7, 55.6, 24.2;
HRMS (ESI): calc. for [(C12H12O4)H] (M+H) 221.0814, found 221.0810.
8ꢀMethylꢀ6Hꢀ[1,3]dioxolo[4,5ꢀg]chromenꢀ6ꢀone (3w): Yield: 80%; 0.118 g; colorless solid,
mp: 120ꢀ121 °C; IR (CHCl3, cmꢀ1): υmax 3033, 2984, 1711, 1605, 1453; 1H NMR (200 MHz,
CDCl3): δ 6.93 (s, 1H), 6.81 (s, 1H), 6.15 (s, 1H), 6.07 (s, 2H), 2.37 (s, 3H); 13C NMR (50
MHz, CDCl3): δ 161.0, 152.2, 151.0, 150.7, 144.9, 113.8, 112.4, 102.3, 102.1, 98.5, 19.2;
HRMS (ESI): calc. for [(C11H8O4)H] (M+H) 205.0501, found 205.0505.
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7ꢀHydroxyꢀ4ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone (3x): Yield: 88%; 0.140 g; colorless solid, mp:
183ꢀ186 °C; IR (CHCl3, cmꢀ1): υmax 3165, 1675, 1383, 1237, 1067, 985, 856, 758, 572, 525,
426; 1H NMR (200 MHz, CDCl3): δ 9.63 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 6.85 (dd, J = 8.7,
2.3 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.07 (s, 1H), 2.38ꢀ 2.42 (m, 3H); 13C NMR (50 MHz,
CDCl3): δ 162.0, 161.2, 156.3, 154.0, 127.3, 113.6, 111.8, 103.3, 18.6; HRMS (ESI): calc.
for [(C10H8O3)H] (M+H) 177.0552, found 177.0555.
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6ꢀBromoꢀ4ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone (3y): Yield: 81%; 0.112 g; colorless solid, mp: 186ꢀ
187 °C (lit.7g 187ꢀ189 °C); IR (CHCl3, cmꢀ1): υmax 3092, 2929, 1748, 1590, 1550, 1479, 1413,
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1385, 1257; H NMR (200 MHz, CDCl3): δ 7.72 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.7, 1.8
Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.33 (s, 1H), 2.43 (s, 3H); 13C NMR (50 MHz, CDCl3): δ
160.0, 152.3, 151.2, 134.5, 127.2, 121.5, 118.7, 116.9, 116.0, 18.6; HRMS (ESI): calc. For
[(C10H7BrO2)H] (M+H) 238.9708, found 238.9710.
4ꢀmethylꢀ6ꢀnitroꢀ2Hꢀchromenꢀ2ꢀone (3z): Yield: 70%; 0.103 g; colorless solid, mp: 183ꢀ
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185 °C; IR (CHCl3, cmꢀ1): υmax 3077, 1736, 1610, 1518, 1344; H NMR (200 MHz, CDCl3):
δ 8.54 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 9.1, 2.7, Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 6.46 (s,
1H), 2.55 (s, 3H); 13C NMR (200 MHz, CDCl3): δ 158.9, 157.1, 151.3, 150.0, 126.6, 120.8,
120.3, 118.2, 116.9, 29.7, 18.7; HRMS (ESI): calc. For [(C10H7NO4)H] (M+H) 206.0453,
found 206.0458.
6ꢀNitroꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3ω): Yield: 72%; 0.138 g; colorless solid, mp: 209ꢀ
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210 °C; IR (CHCl3, cmꢀ1): υmax 3077, 1730, 1616, 1555, 1240; H NMR (200 MHz, CDCl3):
δ 8.41ꢀ8.46 (m, 2H), 7.59ꢀ7.64 (m, 3H), 7.55 (d, J = 9.8 Hz, 1H), 7.48 (dd, J = 6.6, 2.9 Hz,
2H), 6.53 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 159.0, 157.7, 154.7, 144.0, 133.8, 130.5,
129.4, 128.2, 126.7, 123.1, 119.3, 118.5, 116.7; HRMS (ESI): calc. for [(C15H9NO4)H]
(M+H) 268.0610, found 268.0615.
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(E)ꢀmethyl 3ꢀ(2ꢀhydroxyphenyl)acrylate (5): The 5 was synthesized according to the
literature.8h The characterization data was as follows: 1H NMR (200 MHz, CDCl3): δ 7.98 (d,
J = 16.2 Hz, 1H), 7.48 (dd, J = 1.6, 7.7 Hz, 1H), 7.38ꢀ7.27 (m, 1H), 7.08ꢀ6.95 (m, 1H), 6.81
(dd, J = 0.9, 8.1 Hz, 1H), 6.58 (d, J = 16.2 Hz, 1H), 3.82 (s, 3H).
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ASSOCIATED CONTENT
Supporting Information: Characterization data, 1H, and 13C NMR spectra for new
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGEMENT
S.K.G and S.D. thank CSIR, New Delhi for the reward of senior research fellowship and DST
(no.SR/S1/OCꢀ42/2010), New Delhi. Authors also thank Dr. V. V. Ranade, Chair and Head,
Chemical Engineering and Process Development Division for his constant encouragement.
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Graphical Abstract
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