Chemo- and regio-selective functionalization of Morita-Baylis-Hiliman bromides with anthranilic acid

Article abstract of DOI:10.1139/V09-128

Nucleophilic substitution products of Morita Baylis Hillman adducts and their derivatives are valuable synthons. In an attempt to ameliorate the functionality of these functionalized motifs, we report the regio- and chemo-selective functionalization of Mo

Full text of DOI:10.1139/V09-128

1682
Chemo- and regio-selective functionalization of
Morita–Baylis–Hillman bromides with anthranilic
acid
Yusuf Zulykama, Ulagamani Uma, Palanisamy Chitra Devi, and
Paramasivan T. Perumal
Abstract: Nucleophilic substitution products of Morita–Baylis–Hillman adducts and their derivatives are valuable syn-
thons. In an attempt to ameliorate the functionality of these functionalized motifs, we report the regio- and chemo-selective
functionalization of Morita–Baylis–Hillman bromides with anthranilic acid.
Key words: Morita–Baylis–Hillman reaction, Morita–Baylis–Hillman bromides, nucleophilic substitution, anthranilic acid.
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Resume : Les produits de substitution nucleophile des adduits de Morita–Baylis–Hillman et de leurs derives sont des syn-
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thons tres utiles. Afin d’ameliorer la fonctionnalite de ces motifs fonctionnalises, on a realise la fonctionnalisation regio-
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et chimio-selective des bromures de Morita–Baylis–Hillman avec l’acide anthranilique.
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Mots-cles : reaction de Morita–Baylis–Hillman, bromures de Morita–Baylis–Hillman, substitution nucleophile, acide an-
thranilique.
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[Traduit par la Redaction]
Introduction
Fig. 1. The Morita–Baylis–Hillman adduct.
The Morita–Baylis–Hillman reaction1–4 (MBH), a power-
ful C–C bond forming reaction, has earned overwhelming
popularity in recent years. The MBH adduct comprise of a
contiguous assembly of three different functionalities and a
chiral center. The versatility of the functionality of MBH ad-
ducts have made them valuable synthetic intermediates. Ef-
forts of various research groups contributing to the widening
of the substrate scope1 of the MBH reaction have further di-
versified the functionality of MBH adducts (Fig. 1).
Functionalization of MBH adducts and their derivatives is
an active area of research, as it provides valuable synthetic in-
termediates, which have been successfully translated into var-
ious useful synthetic targets, including substituted alkenes,5
carbocycles,6 heterocycles,7 and several biologically relevant
molecules.1e,1g The repertoire of nucleophiles added to MBH
adducts includes carbon,8 hydrogen,9 heteroatomic nucleo-
philes,10 aromatics,11 and heteroaromatics.12 In addition to
newer nucleophiles13 being added to MBH acetates/bromides,
the synthetic potential of previously reported nucleophilic
substitution products is illustrated by newer applications.14
Nucleophilic substitution of MBH adducts and their deriv-
atives with monofunctional aromatics and their further elab-
oration to several synthetic targets have been extensively
studied.15 Basavaiah et al.16 synthesized chromones from
phenol16b–16d substitution products and successfully applied
the same strategy to the synthesis of antifungal agents.
Aniline substitution products have been elaborated to syn-
thesize indenoquinolinones,17a polysubstituted quinolines,17b
quinolones, quinolinols, indanones and indenoindenones,17c
and b-lactam.17d,17e The fascinating post modifications of
nucleophilic substitution products of monofunctional aro-
matics made the nucleophilic substitution of bifunctional ar-
omatics intriguing. However, literature scanning reveals only
a few reports of nucleophilic substitution of MBH deriva-
tives with bifunctional aromatics.18 Kim et al.18a added o-
phenylenediamine on Baylis–Hillman acetates and subse-
quently converted to benzodiazepinones and benzoimida-
zoles. Basavaiah and Satyanarayana18b reported one-pot
transformation of the Baylis–Hillman acetates to fused pyri-
midones via a reaction with 2-aminopyridine in aqueous me-
dia. The synthetic utility of dinaphthol substitution products
were illustrated in the synthesis of bis-chromones.18c In this
context, we were prompted to explore this avenue of MBH
chemistry, and herein, we wish to report the results of our
Received 12 May 2009. Accepted 24 July 2009. Published on
the NRC Research Press Web site at canjchem.nrc.ca on
6 November 2009.
Y. Zulykama, U. Uma, P.C. Devi, and P.T. Perumal.1 Organic
Chemistry Division, Central Leather Research Institute, Adyar,
Chennai-20, India.
1Corresponding author (e-mail: ptperumal@gmail.com).
Can. J. Chem. 87: 1682–1691 (2009)
doi:10.1139/V09-128
Published by NRC Research Press

Zulykama et al.
1683
Scheme 1.
investigation of the chemo- and regio-selectivity of nucleo-
philic substitution of MBH bromides with anthranilic acid.
was characterized by IR, NMR, and Mass studies. The IR
spectrum of the product exhibited only one stretching ab-
sorption, suggesting secondary amine functionality. The al-
lylic protons were observed at d 4.26 ppm (as compared
with the O-linked allylic protons at d 4.92–5.15 ppm), con-
firming the formation of N-linked product 3a. Small cou-
pling was observed in the allylic proton signal due to the
NH proton further confirming the formation of N-linked
products. However, the carboxyl proton was not detected in
Results and discussion
Recently, we have reported the functionalization of MBH
bromides with symmetric and asymmetric bifunctional aro-
matics,19 and in continuation of our interest in this avenue
of MBH chemistry, we intended to study the functionaliza-
tion of MBH bromides with anthranilic acid. Accordingly, a
solution of MBH bromide (1a) in DMF was treated with an-
thranilic acid in the presence of potassium carbonate to fur-
nish 2a in 61% isolated yield (Scheme 1).
The presence of two stretching absorptions in the IR spec-
trum of 2a (3266 and 3468 cm–1) indicated that the N-termi-
nal of the anthranilic acid moiety is free. Moreover, the
downfield appearance of the allylic protons (d 5.15 ppm)
confirmed the formation of O-linked products. The reaction
was then extended to other MBH bromides (1b–1i), and the
results are assembled in Table 1.
The stereochemistry of the products 2a–2i was settled on
the basis of difference nuclear Overhauser effect (NOE) ex-
periments on 2f. Irradiation of the methylene protons at
d 5.0 ppm led to the enhancement of the aromatic signal
at d 7.33 by 5.25%. However, there was comparatively
less enhancement in the olefinic signal (0.69%) implying
they are spatially far, and thus confirming E stereochemis-
try (Fig. 2). Further irradiation of the ester methyl proton
resulted in the enhancement of the olefinic peak, confirm-
ing their spatial proximity.
1
the H NMR spectrum, and the presence of the carboxyl
group in the product was confirmed through IR and 13C
spectral analysis.
Interestingly, on heating O-linked anthranilic acid, substi-
tution products 2a in DMF with K2CO3 at 80 8C, N-linked
SN2 products 3a was obtained in comparatively good yields
(Scheme 1).20 The generality of the reaction was demon-
strated by the successful conversion of O-linked products
2b, 2c, and 2h to 3b, 3c, and 3d, respectively (Table 2).
With the O-linked anthranilic acid products in our hands,
we intended to further derivatize these substitution products
by treatment with trifluoroacetic anhydride (Scheme 2).
Consequently, 2a was stirred in trifluoroacetic anhydride at
ice temperature under nitrogen atmosphere, and we observed
solidification of the reaction mixture immediately. TLC pro-
file of the reaction mixture showed two new spots. The ma-
jor product was assigned the structure 4a and the minor
product was found to be 5a.20
The formation of 5a can be explained as the result of the
1
reaction of 4a with 2a. In the H NMR spectrum of 5a, the
signal for the BH moiety was observed in duplicate, indicat-
ing that the bisfunctionalisation21 of anthranilic moiety with
the MBH bromides at both the N- and O-terminal had oc-
curred.
The diastereotropic methylenic protons were observed as
four doublets at d 4.46, 5.02, 5.11, and 5.36 ppm. Further
To study the regio- and chemo-selective outcome of the
reaction, we further treated MBH bromide with anthranilic
acid in the presence of K2CO3 in DMF at 80 8C. TLC mon-
itoring revealed the formation of a new minor product in ad-
dition to O-linked product. Prolonging the heating did not
improve the yield of the minor product. The new product
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Can. J. Chem. Vol. 87, 2009
Fig. 2. Difference NOE studies of 2f.
Table 1. SN2 substitution of Morita–Baylis–Hillman bromides with
anthranilic acid.
Table 2. Syntheses of SN2 N-linked anthranilic acid substitution
products.
mass spectral analysis [604 (M+ + Na)] confirmed the for-
mation of the product. Next, it was our interest to obtain
SN2’ anthranilic acid substitution products adopting
DABCO-salt strategy.22 In accordance, the MBH bromide
(1a) was stirred with an equivalent of DABCO in acetone
for 30 min at ambient temperature. After the salt formation
as indicated by the TLC, anthranilic acid and potassium car-
bonate were added and stirring continued for an hour to af-
ford 6a (Scheme 3).
1
In the H NMR of 6a, two singlets were obtained for the
olefinic protons and were observed at d 5.63 and 6.39 ppm,
confirming the formation of SN2’ products. The signal due to
the benzylic proton at d 5.87 ppm was split into a doublet by
the NH proton (J = 6.1 Hz), and also the signal for the NH
proton was observed as a doublet at d 8.11 ppm (J =
6.1 Hz), confirming that the SN2’ product was N-linked. For
1
6a–6h, the carboxyl proton was not detected in H NMR
spectra. However, the presence of the carboxyl group in the
product was confirmed through IR and 13C spectral analyses.
Table 3 reveals the results of SN2’ substitution of MBH bro-
Published by NRC Research Press

Zulykama et al.
1685
Scheme 2.
Scheme 3.
1
mides with anthranilic acid. Salt formation of anthranilic
acid with DABCO explains the formation of N-linked SN2’
product and not the O-linked SN2’ product.
Bruker spectrometer or a JEOL spectrometer. H NMR spec-
tra were recorded at 300 MHz or 500 MHz in CDCl3 or
DMSO-d6 combination with tetramethylsilane as internal
standard. 13C NMR spectra were recorded at 75 MHz or
125 MHz spectrometer in CDCl3 or DMSO-d6 combination
with the same internal standard. The chemical shifts are
given in d in ppm scale. Mass spectra were recorded on a
varian VG 70–70H mass spectrometer or on a Thermo Fin-
nigan LCQ Advantage MAX 6000 ESI spectrometer. TLC
was performed on silica gel alumina plates. Column chro-
matography was carried out using 100–200 mesh silica gel.
Conclusion
In conclusion, we have demonstrated a simple and practi-
cal methodology for the chemo- and regio-selective func-
tionalization of MBH bromides with anthranilic acid.
Extension of the same methodology to other bifunctional nu-
cleophiles and their chemical transformation to synthetically
important scaffolds are underway.
General procedure for the syntheses of 2a–2i
To a stirred solution of Baylis–Hillman bromide (0.3 g,
1.18 mmol) in DMF (5 mL) was added anthranilic acid
(0.16 g, 1.18 mmol) and K2CO3 (0.19 g, 1.18 mmol). The
reaction mixture was stirred at room temperature. After the
disappearance of the starting compound (TLC), reaction
mixture was poured into water and extracted with ethyl ace-
Experimental section
Melting points were determined in open capillary tubes
and are uncorrected. IR measurements were carried out us-
ing KBr pellets in PerkinElmer Spectrometer RXI FTIR.
Nuclear magnetic resonance spectra were recorded on a
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Can. J. Chem. Vol. 87, 2009
Table 3. SN2’ substitution of BH bromides with anthranilic acid.
1H), 6.63 (t, J = 9.15 Hz, 1H), 7.38–7.44 (m, 6H), 7.82 (t,
J = 8.05 Hz, 1H), 8.04 (s, 1H). 13C NMR (125 MHz,
CDCl3) d: 52.49, 59.34, 110.58, 111.66, 116.34, 116.79,
126.82, 128.91, 129.67, 129.75, 131.47, 134.34, 145.92,
150.75, 167.6, 167.88. MS m/z: 311 (M+). Anal. calcd. for
C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.20; H,
5.49; N, 4.52.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-(2-
methylphenyl) prop-2-enoate (2b)
Brown solid; mp 60 8C. IR (KBr) n: 1616, 1692, 2944,
1
3373, 3483 cm–1. H NMR (500 MHz, CDCl3) d: 2.33 (s,
3H), 3.84 (s, 3H), 5.03 (s, 2H), 5.73 (br s, 2H), 6.61 (d, J =
7.65 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 7.18–7.28 (m, 5H),
7.81 (d, J = 7.65 Hz, 1H), 8.13 (s, 1H). 13C NMR
(125 MHz, CDCl3) d: 20.12, 52.45, 59.46, 110.71, 116.36,
116.73, 126.05, 127.63, 128.86, 129.49, 130.33, 131.46,
133.68, 134.28, 137.21, 145.04, 150.62, 167.37, 167.75. MS
m/z: 325 (M+). Anal. calcd. for C19H19NO4: C, 70.14; H,
5.90; N, 4.30. Found: C, 70.25; H, 5.92; N, 4.29.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-(3-
chlorophenyl) prop-2-enoate (2c)
Pale yellow solid; mp 130 8C. IR (KBr) n: 1050, 1630,
1
1684, 2928, 3372, 3480 cm–1. H NMR (500 MHz, CDCl3)
d: 3.83 (s, 3H), 5.11 (s, 2H), 5.75 (br s, 2H), 6.59 (t, J =
8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 6.85 Hz,
1H), 7.29–7.36 (m, 3H), 7.43 (s, 1H), 7.79 (d, J = 7.65 Hz,
1H), 7.95 (s, 1H). 13C NMR (125 MHz, CDCl3) d: 52.60,
58.93, 110.39, 111.6, 115.3, 116.35, 116.78, 127.47, 128.33,
129.58, 129.63, 130.16, 131.37, 144.0, 150.77, 167.17,
167.66. MS m/z: 346 (M+), 348 (M+ + 2). Anal. calcd. for
C18H16ClNO4: C, 62.52; H, 4.66; N, 4.05. Found: C,62.41;
H, 4.65; N, 4.04.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-(2-
chlorophenyl) prop-2-enoate (2d)
Yellow solid; mp 84 8C. IR (KBr) n: 1052, 1629, 1685,
2926, 3475, 3482 cm–1. 1H NMR (500 MHz, CDCl3) d:
3.86 (s, 3H), 5.03 (s, 2H), 5.73 (br s, 2H), 6.60 (t, J =
8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.65 Hz,
2H), 7.29 (t, J = 7.65 Hz, 1H), 7.39 (d, J = 7.65 Hz, 1H),
7.41 (d, J = 7.65 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 8.13 (s,
1H). 13C NMR (125 MHz, CDCl3) d: 52.58, 59.35, 110.50,
116.35, 116.75, 127.07, 128.82, 129.83, 129.98, 130.38,
130.68, 131.41, 133.05, 134.36, 142.51, 150.68, 166.94,
167.63. MS m/z: 345 (M+), 347 (M+ + 2). Anal. calcd. for
C18H16ClNO4: C, 62.52; H, 4.66; N, 4.05. Found: C, 62.42;
H, 4.64; N, 4.06.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-(2-
fluorophenyl) prop-2-enoate (2e)
Yellow solid; mp 54 8C. IR (KBr) n: 1239, 1616, 1717,
2951, 3373, 3480 cm–1. 1H NMR (500 MHz, CDCl3) d:
3.85 (s, 3H), 5.11 (s, 2H), 5.79 (br s, 2H), 6.58 (t, J =
7.45 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.6 Hz,
1H), 7.11 (t, J = 8 Hz, 1H), 7.21 (t, J = 8 Hz, 1H), 7.32 (q,
J = 7.45 Hz, 1H), 7.41 (t, J = 8 Hz, 1H), 7.76 (d, J =
8.6 Hz, 1H), 8.08 (s, 1H). 13C NMR (125 MHz, CDCl3) d:
52.55, 59.43, 110.37, 115.54, 115.97(d, J = 38.1 Hz),
116.78, 122.37 (d, J = 13.1 Hz), 124.51, 128.97, 130.44,
131.37, 131.62 (d, J = 8.35 Hz), 131.92, 134.37, 138.07,
tate (3 Â 30 mL). The organic layer was dried over Na2SO4
and evaporated under reduced pressure. Column purification
(15% ethyl acetate in hexane) furnished the products.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-phenyl
prop-2-enoate (2a)
Yellow solid; mp 68 8C. IR (KBr) n: 1617, 1692, 2952,
1
3366, 3468 cm–1. H NMR (500 MHz, CDCl3) d: 3.83 (s,
3H), 5.15 (s, 2H), 5.79 (br s, 2H), 6.60 (d, J = 9.15 Hz,
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Zulykama et al.
1687
150.81, 166.99, 167.72. MS m/z: 329 (M+). Anal. calcd. for
C18H16FNO4: C, 65.65; H, 4.90; N, 4.25. Found: C, 65.72;
H, 4.89; N, 4.26.
General procedure for the syntheses of 3a–3d
To a solution of 2a (0.3 g, 0.96 mmol) in DMF (5 mL)
was added K2CO3 (0.133 g, 0.96 mmol). The reaction mix-
ture was heated at 80 8C. After the completion of the reac-
tion as indicated by TLC, the reaction mixture was poured
into water and extracted with ethyl acetate. The excess sol-
vent was removed, and column purification (10% ethyl ace-
tate in hexane) furnished the products.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-(2,4-
dichlorophenyl) prop-2-enoate (2f)
Yellow solid; mp 144 8C. IR (KBr) n: 1049, 1621, 1680,
1
2926, 3370, 3484 cm–1. H NMR (500 MHz, CDCl3): 3.86
(s, 3H), 5.0 (s, 2H), 5.75 (br s, 2H), 6.60 (t, J = 6.9 Hz,
1H), 6.64 (d, J = 7.65 Hz, 1H), 7.24–7.27 (m, 2H), 7.33 (d,
J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 8.03
(s, 1H). 13C NMR (125 MHz, CDCl3) d: 52.68, 59.19,
110.29, 116.37, 116.79, 127.49, 129.36, 129.77, 131.10,
131.31, 131.59, 134.47, 135.13, 136.05, 141.20, 150.71,
166.73, 167.54. MS m/z: 382 (M+), 384 (M+ + 2), 386 (M+
+ 4). Anal. calcd. for C18H15Cl2NO4: C, 56.86; H, 3.98; N,
3.68. Found: C, 56.80; H, 3.97; N, 3.67.
Methyl 2-(2-carboxyphenylaminomethyl)-3-phenyl prop-2-
enoate (3a)
Yellow solid; mp 110 8C. IR (KBr) n: 1655, 1717, 2956,
1
3370 cm–1. H NMR (500 MHz, CDCl3) d: 3.86 (s, 3H),
4.26 (br s, 2H), 6.44 (d, J = 8.4 Hz, 1H), 6.60 (t, J =
8.4 Hz, 1H), 7.27 (t, J = 8.4 Hz, 2H), 7.37–7.41 (m, 5H),
7.95 (s, 1H), 7.97 (t, J = 6.1 Hz, 1H). 13C NMR (125 MHz,
CDCl3) d: 39.70, 52.32, 109.50, 111.77, 115.16, 116.46,
116.83, 129.29, 130.24, 132.14, 134.71, 135.49, 143.24,
151.08, 167.93, 173.62. MS m/z: 311 (M+). Anal. calcd. for
C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 6955; H,
5.48; N, 4.51.
Methyl 2-(2-aminophenylcarbonyloxymethyl)-3-(2-
nitrophenyl) prop-2-enoate (2g)
Yellow oil. IR (neat) n: 1351, 1524, 1620, 1721, 2955,
1
3374, 3482 cm–1. H NMR (500 MHz, CDCl3) d: 3.85 (s,
Methyl 2-(2-carboxyphenylaminomethyl)-3-(2-
methylphenyl)prop-2-enoate (3b)
3H), 4.92 (s, 2H), 5.72 (br s, 2H), 6.58 (t, J = 6.9 Hz, 1H),
6.60 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.40 (d,
J = 7.65 Hz, 1H), 7.49 (t, J = 7.65 Hz, 1H), 7.60 (t, J =
7.65 Hz, 1H), 7.68 (d, J = 7.65 Hz, 1H), 8.15 (d, J =
8.4 Hz, 1H), 8.26 (s, 1H). 13C NMR (125 MHz, CDCl3) d:
52.64, 59.06, 110.18, 116.26, 116.73, 125.19, 128.32,
130.01, 130.77, 131.03, 131.27, 134.0, 134.40, 142.40,
147.37, 150.71, 166.49, 167.42. MS m/z: 356 (M+). Anal.
calcd. for C18H16N2O6: C, 60.67; H, 4.53; N, 7.86. Found:
C, 60.78; H, 4.52; N, 7.89.
Pale yellow solid; mp 125 8C. IR (KBr) n: 1660, 1725,
1
2953, 3355 cm–1. H NMR (500 MHz, CDCl3) d: 2.24 (s,
3H), 3.86 (s, 3H), 4.20 (br s, 2H), 6.22 ((d, J = 8.4 Hz,
1H), 6.55 (t, J = 7.65 Hz, 1H), 7.18–7.27 (m, 5H), 7.93 (d,
J = 7.65 Hz, 1H), 7.93 (t, J = 6.1 Hz, 1H), 7.96 (s, 1H). MS
m/z: 325 (M+). Anal. calcd. for C19H19NO4: C, 70.14; H,
5.89; N, 4.31. Found: C, 70.06; H, 5.88; N, 4.30.
Methyl 2-(2-carboxyphenylaminomethyl)-3-(3-
chlorophenyl)prop-2-enoate (3c)
Ethyl 2-(2-aminophenylcarbonyloxymethyl)-3-phenyl prop-
2-enoate (2h)
Pale yellow solid; mp 130 8C. IR (KBr) n: 1037, 1657,
1719, 2950, 3360 cm–1. 1H NMR (500 MHz, CDCl3) d:
3.85 (s, 3H), 4.25 (br s, 2H), 6.44 (d, J = 8.4 Hz, 1H), 6.60
(t, J = 7.65 Hz, 1H), 7.28 (t, J = 6.9 Hz, 1H), 7.37–7.41 (m,
5H), 7.94 (s, 1H), 7.95 (t, J = 6.1 Hz, 1H). 13C NMR
(125 MHz, CDCl3) d: 39.76, 52.40, 109.53, 111.83, 115.22,
128.25, 128.84, 129.01, 129.36, 129.47, 132.78, 134.45,
134.78, 135.56, 143.32, 151.14, 167.98, 173.70. MS m/z:
346 (M+), 348 (M+ + 2). Anal. calcd. for C18H16ClNO4: C,
62.52; H, 4.66; N, 4.05. Found: C,62.60; H, 4.68; N, 4.04.
Orange solid; mp 80 8C. IR (KBr) n: 1625, 1689, 2949,
1
3357, 3466 cm–1. H NMR (500 MHz, CDCl3) d: 1.30 (t,
J = 6.9 Hz, 3H), 4.28 (q, J = 6.9 Hz, 2H), 5.15 (s, 2H),
5.73 (br s, 2H), 6.60 (t, J = 8.4 Hz, 1H), 6.65 (d, J =
8.4 Hz, 1H), 7.24 (t, J = 6.9 Hz, 1H), 7.36 (q, J = 7.6 Hz,
4H), 7.44 (d, J = 6.9 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H). 13C
NMR (125 MHz, CDCl3) d: 14.35, 59.29, 61.32, 110.73,
116.63, 116.73, 127.26, 128.77, 128.85, 129.60, 131.48,
134.28, 134.45, 145.42, 150.65, 167.05, 167.86. MS m/z:
325 (M+). Anal. calcd. for C19H19NO4: C, 70.14; H, 5.89;
N, 4.31. Found: C, 70.26; H, 5.91; N, 4.30.
Ethyl 2-(2-carboxyphenylaminomethyl)-3-phenyl prop-2-
enoate (3d)
Brown oil. IR (neat) n: 1655, 1720, 2985, 3360 cm–1.1H
NMR (500 MHz, CDCl3) d: 1.34 (t, J = 6.9 Hz, 3H), 4.26
(s, 2H), 4.29 (q, J = 6.9 Hz, 2H), 6.42 (d, J = 8.4 Hz, 1H),
6.59 (t, J = 7.65 Hz, 1H), 7.26–7.30 (m, 2H), 7.37–7.41 (m,
5H), 7.93 (s, 1H), 7.95 (t, J = 6.1 Hz, 1H). MS m/z: 325
(M+). Anal. calcd. for C19H19NO4: C, 70.14; H, 5.89; N,
4.31. Found: C, 70.01; H, 5.87; N, 4.32.
Ethyl 2-(2-aminophenylcarbonyloxymethyl)-3-(2-
chlorophenyl) prop-2-enoate (2i)
Brown oil. IR (neat) n: 1620, 1690, 2952, 3365, 3472 cm–1.
1H NMR (500 MHz, CDCl3) d: 1.31 (t, J = 7.65 Hz, 3H), 4.30
(q, J = 6.9 Hz, 2H), 5.05 (s, 2H), 5.83 (br s, 2H), 6.60 (t, J =
8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz,
2H), 7.27 (t, J = 7.65 Hz, 1H), 7.39 (t, J = 7.65 Hz, 2H), 7.78
(d, J = 7.65 Hz, 1H), 8.11 (s, 1H). 13C NMR (125 MHz,
CDCl3) d: 14.33, 59.35, 61.30, 110.50, 116.35, 116.75,
127.07, 128.82, 129.83, 129.98, 130.38, 130.68, 131.41,
133.05, 134.36, 142.51, 150.68, 166.94, 167.63. MS m/z: 360
(M+), 362 (M+ + 2). Anal. calcd. for C19H18ClNO4: C, 63.42;
H, 5.04; N, 3.89. Found: C, 63.50; H, 5.06; N, 3.90.
General procedure for the syntheses of 4 and 5
2a (0.5 g, 1.6 mmol) was taken in a 50 mL RB flask, and
1 mL of TFAA was added under ice temperature in N2 at-
mosphere. The reaction mixture solidified and was extracted
with ethyl acetate. The excess solvent was removed and col-
Published by NRC Research Press

1688
Can. J. Chem. Vol. 87, 2009
umn purified (25% ethyl acetate in hexane) to obtain 4a
(63%) and 5a (11%).
7.65 Hz, 1H), 7.48 (t, J = 7.65 Hz, 1H), 7.76 (s, 1H), 7.89
((d, J = 6.9 Hz, 1H), 8.05 (s, 1H). 13C NMR (125 MHz,
CDCl3) d: 52.38, 52.53, 58.28, 60.65, 115.2 (q, J =
291.4 Hz), 115.66 (d, J = 21.4 Hz), 115.83 (d, J =
29.7 Hz), 121.86 (d, J = 13.1 Hz), 122.12 (d, J = 14.3 Hz),
128.1, 128.45, 129.62, 129.75, 130.30, 131.14, 131.20,
131.67, 131.74, 132.03, 132.13, 133.09, 135.12, 137.07,
138.66 (d, J = 15.5 Hz), 145.59, 156.02 (q, J = 35.7 Hz),
163.9, 166.60, 166.97. MS m/z: 617 (M+). Anal. calcd. for
C31H24F5NO7: C, 60.29; H, 3.92; N, 2.27. Found: C, 60.20;
H, 3.93; N, 2.28.
Methyl2-(2-trifluoroacetamidophenylcarbonyloxymethyl)-3-
phenyl prop-2-enoate (4a)
White solid; mp 108 8C. IR (KBr) n: 1616, 1635, 1685,
1
2955, 3332 cm–1. H NMR (500 MHz, CDCl3) d: 3.86 (s,
3H), 5.24 (s, 2H), 7.21 (t, J = 7.65 Hz, 1H), 7.39–7.41 (m,
5H), 7.61 (t, J = 8.45 Hz, 1H), 8.06 (d, J = 8.45 Hz, 1H),
8.11 (s, 1H), 8.65 (d, J = 7.65 Hz, 1H), 12.24 (s, 1H). 13C
NMR (125 MHz, CDCl3) d: 52.57, 60.84, 114.63 (q, J =
287 Hz), 116.15, 116.93, 120.80, 124.85, 125.81, 128.99,
129.47, 129.97, 131.36, 134.07, 135.20, 139.10, 146.70,
154.92 (q, J = 36.9 Hz), 167.14, 167.96. MS m/z: 407 (M+).
Anal. calcd. for C20H16F3NO5: C, 58.97; H, 3.96; N, 3.44.
Found: C, 58.85; H, 3.96; N, 3.45.
General procedure for the syntheses of 6a–6h
To a stirred solution of Baylis–Hillman bromide (0.3 g,
1.18 mmol) in acetone (5 mL), DABCO (0.132 g,
1.18 mmol) was added. The reaction mixture was stirred for
30 min. The salt formation was confirmed by TLC. After
the salt formation, anthranilic acid (0.16 g, 1.18 mmol) and
K2CO3 (0.163 g, 1.18 mmol) were added. The reaction mix-
ture was stirred at room temperature. After the formation of
the product, as indicated by TLC, the reaction mixture was
poured into water and extracted with ethyl acetate (3 Â
30 mL). The organic layers were dried over Na2SO4 and
evaporated under reduced pressure. Column purification
(20% ethyl acetate in hexane) furnished the products.
Methyl2-(2-trifluoroacetamidophenylcarbonyloxymethyl)-3-
(2-fluoro-phenyl) prop-2-enoate (4b)
White solid; mp 120 8C. IR (KBr) n: 1230, 1618, 1620,
1642, 1680, 2958 cm–1. 1H NMR (500 MHz, CDCl3) d:
3.86 (s, 3H), 5.18 (s, 2H), 7.10 (t, J = 7.65 Hz, 1H), 7.14 (t,
J = 7.65 Hz, 1H), 7.19 (t, J = 7.65 Hz, 1H), 7.32 (t, J =
7.65 Hz, 1H), 7.37 (t, J = 7.65 Hz, 1H), 7.60 (t, J = 8.4 Hz,
1H), 7.98 (d, J = 7.65 Hz, 1H), 8.09 (s, 1H), 8.63 (d, J =
8.4 Hz, 1H), 12.19 (s, 1H). 13C NMR (125 MHz, CDCl3) d:
52.64, 60.91, 114.63 (q, J = 288.5 Hz), 116.02 (d, J =
22.7 Hz), 120.78, 122.12 (d, J = 11.9 Hz), 122.23, 124.50,
124.81, 128.09, 130.21, 131.30, 131.79 (d, J = 7.2 Hz),
131.85, 135.20, 139.03, 139.06, 154.93 (q, J = 39.3 Hz),
166.54, 167.80. MS m/z: 425 (M+). Anal. calcd. for
C20H15F4NO5: C, 56.48; H, 3.55; N, 3.29. Found: C, 56.39;
H, 3.56; N, 3.30.
Methyl 3-(2-carboxylphenylamino)-2-methylene-3-phenyl
propanoate (6a)
Yellow solid; mp 150 8C. IR (KBr) n: 1664, 1716, 2951,
1
3365 cm–1. H NMR (500 MHz, CDCl3) d: 3.74 (s, 3H),
5.63 (s, 1H), 5.87 (d, J = 6.1 Hz, 1H), 6.39 (s, 1H), 6.60 (d,
J = 8.5 Hz, 1H), 6.63 (t, J = 7.7 Hz, 1H), 7.30 (d, J =
7.7 Hz, 1H), 7.34–7.37 (m, 3H), 7.39 (d, J = 6.9 Hz, 2H),
7.98 (d, J = 7.7 Hz, 1H), 8.11 (d, J = 6.1 Hz, 1H). 13C
NMR (125 MHz, CDCl3) d: 52.18, 57.61, 109.55, 112.68,
115.70, 126.24, 127.48, 127.96, 128.96, 132.72, 135.72,
140.06, 140.47, 150.19, 166.67, 173.89. MS m/z: 311 (M+).
Anal. calcd. for C18H17NO4: C, 69.44; H, 5.50; N, 4.50.
Found: C, 69.37; H, 5.51; N, 4.49.
2-(Methoxycarbonyl)-3-phenyl-2-propenyl-2-[2-(methoxy
carbonyl)-3-phenylpropenyl]trifluoroacetamidobenzene
carboxylate (5a)
Yellow oil. IR (neat) n: 1617, 1620, 1637, 2945, 3340 cm–1.
1H NMR (500 MHz, CDCl3) d: 3.61 (s, 3H), 3.80 (s, 3H), 4.46
(d, J = 14.5 Hz, 1H), 5.02 (d, J = 11.45 Hz, 1H), 5.11 (d, J =
11.45 Hz, 1H), 5.36 (d, J = 14.5 Hz, 1H), 6.96–6.98 (m, 3H),
7.22–7.23 (m, 3H), 7.32–7.34 (m, 5H), 7.38 (t, J = 7.65 Hz,
1H), 7.43 (t, J = 7.65 Hz, 1H), 7.76 (s, 1H), 7.94 (d, J =
8.4 Hz, 1H), 8.03 (s, 1H). 13C NMR (125 MHz, CDCl3) d:
44.78, 52.23, 52.42, 60.61 115.6 (q, J = 282 Hz), 115.30,
117.60, 125.87, 125.98, 128.71, 128.84, 129.0, 129.39,
129.50, 129.66, 129.77, 132.08, 132.12, 132.98, 133.88,
134.10, 136.93, 145.88, 146.25, 155.84 (q, J = 34.6 Hz),
167.14, 167.46. MS m/z: 604 (M+ + Na). Anal. calcd. for
C31H26F3NO7: C, 64.03; H, 4.51; N, 2.43. Found: C, 64.14;
H, 4.53; N, 2.44.
Methyl 3-(2-carboxylphenylamino)-2-methylene-3-(2-
methylphenyl) propanoate (6b)
White solid; mp 158 8C. IR (KBr) n: 1667, 1724, 2955,
1
3354 cm–1. H NMR (500 MHz, DMSO-d6) d: 2.28 (s, 3H),
3.62 (s, 3H), 5.66 (d, J = 6.9 Hz, 1H), 5.88 (s, 1H), 6.31 (s,
1H), 6.53 (d, J = 8.4 Hz, 1H), 6.58 (t, J = 7.65 Hz, 1H),
7.14–7.20 (m, 4H), 7.30 (t, J = 8.4 Hz, 1H), 7.79 (d, J =
7.65 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H). 13C NMR
(125 MHz, DMSO-d6) d: 19.15, 52.59, 53.76, 111.28,
112.43, 115.90, 126.44, 126.82, 126.91, 128.31, 131.29,
132.28, 135.18, 136.65, 138.42, 140.06, 149.86, 166.53,
170.52. MS m/z: 325 (M+). Anal. calcd. for C19H19NO4: C,
70.14; H, 5.89; N, 4.31. Found: C, 70.06; H, 5.91; N, 4.32.
2-(Methoxycarbonyl)-3-(2-fluorophenyl)-2-propenyl-2-[2-
(methoxycarbonyl)-3-(2-fluorophenyl)propenyl]
trifluoroacetamidobenzene carboxylate (5b)
Yellow oil. IR (neat) n: 1225, 1619, 1640, 1689 cm–1.
1H NMR (500 MHz, CDCl3) d: 3.68 (s, 3H), 3.85 (s, 3H),
4.34 (d, J = 13.75 Hz, 1H), 4.93 (d, J = 12.25 Hz, 1H),
5.03 (d, J = 11.45 Hz, 1H), 5.35 (d, J = 14.5 Hz, 1H), 6.86
(t, J = 7.65 Hz, 1H), 6.92 (t, J = 9.2 Hz, 1H), 6.98 (t, J =
7.65 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.07–7.11 (m, 2H),
7.23 (t, J = 8.4 Hz, 2H), 7.32–7.35 (m, 1H), 7.39 (t, J =
Methyl 3-(2-carboxylphenylamino)-2-methylene-3-(3-
chlorophenyl) propanoate (6c)
Pale yellow solid; mp 162 8C. IR (KBr) n: 1035, 1660,
1720, 2955, 3362 cm–1. 1H NMR (500 MHz, CDCl3) d:
3.75 (s, 3H), 5.58 (d, J = 5.35 Hz, 1H), 5.87 (s, 1H), 6.42
(s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H),
7.28–7.29 (m, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.37 (s, 1H),
Published by NRC Research Press

Zulykama et al.
1689
7.99 (d, J = 6.9 Hz, 1H), 8.11 (d, J = 6.15 Hz, 1H). 13C
NMR (125 MHz, CDCl3) d: 52.31, 57.17, 109.73, 112.54,
116.02, 125.62, 127.03, 127.68, 128.22, 130.25, 132.78,
134.75, 135.77, 139.97, 142.25, 149.97, 166.38, 173.74. MS
m/z: 346 (M+), 348 (M+ + 2). Anal. calcd. for C18H16ClNO4:
C, 62.52; H, 4.66; N, 4.05. Found: C, 62.46; H, 4.65; N,
4.04.
C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.0; H,
5.91; N, 4.30.
Ethyl 3-(2-carboxylphenylamino)-2-methylene-3-(2-
chlorophenyl) propanoate (6h)
Brown solid; mp 110 8C. IR (KBr) n: 1038, 1656, 1715,
1
2984, 3356 cm–1. H NMR (500 MHz, CDCl3) d: 1.21 (t,
J = 6.9 Hz, 3H), 4.19 (m, 2H), 5.68 (s, 1H), 6.02 (d, J =
4.6 Hz, 1H), 6.43 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.63 (t,
J = 7.65 Hz, 1H), 7.23–7.25 (m, 2H), 7.32 (t, J = 7.65 Hz,
1H), 7.39–7.42 (m, 2H), 7.96 (d, J = 7.65 Hz, 2H). 13C
NMR (125 MHz, CDCl3) d: 14.13, 54.34, 61.25, 109.59,
112.54, 115.90, 127.31, 127.63, 128.44, 129.19, 130.05,
132.64, 133.97, 135.83, 137.50, 139.74, 150.25, 165.95,
173.75. MS m/z: 360 (M+), 362 (M+ + 2). Anal. calcd. for
C19H18ClNO4: C, 63.42; H, 5.04; N, 3.89. Found: C, 63.50;
H, 5.05; N, 3.88.
Methyl 3-(2-carboxylphenylamino)-2-methylene-3-(2-
chlorophenyl) propanoate (6d)
Yellow solid; mp IR (KBr) n: 1037, 1656, 1723, 2944,
1
3352 cm–1. H NMR (500 MHz, CDCl3) d: 3.76 (s, 3H),
5.70 (s, 1H), 6.04 (d, J = 6.1 Hz, 1H), 6.44 (s, 1H), 6.56 (d,
J = 8.4 Hz, 1H), 6.63 (t, J = 8.4 Hz, 1H), 7.23–7.25 (m,
2H), 7.32 (t, J = 6.9 Hz, 1H), 7.40–7.42 (m, 2H), 7.97 (d,
J = 6.9 Hz,1H), 8.01 (d, J = 6.1 Hz, 1H). 13C NMR
(125 MHz, CDCl3) d: 52.37, 54.25, 109.67, 112.57, 115.96,
127.34, 128.03, 128.40, 129.24, 130.13, 132.66, 133.97,
135.85, 137.38, 139.50, 150.20, 166.45, 173.91. MS m/z:
346 (M+), 348 (M+ + 2). Anal. calcd. for C18H16ClNO4: C,
62.52; H, 4.66; N, 4.05. Found: C, 62.63; H, 4.67; N, 4.04.
Acknowledgement
YZ thanks the Council of Scientific and Industrial Re-
search (CSIR), India for the financial support.
Methyl 3-(2-carboxylphenylamino)-2-methylene-3-(2-
fluorophenyl) propanoate (6e)
References
White solid; mp 130 8C. IR (KBr) n: 1222, 1672, 1720,
(1) (a) For reviews see: Drewes, S. E.; Roos, G. H. P. Tetrahe-
dron 1988, 44 (15), 4653–4670. doi:10.1016/S0040-4020(01)
86168-8.; (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetra-
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1
3011, 3357 cm–1. H NMR (500 MHz, CDCl3) d: 3.75 (s,
3H), 5.85 (s, 1H), 5.94 (d, J = 6.1 Hz, 1H), 6.42 (s, 1H),
6.63–6.65 (m, 2H), 7.06–7.10 (m, 1H), 7.11 (t, J = 7.65 Hz,
1H), 7.26–7.29 (m, 1H), 7.34 (q, J = 8.4 Hz, 2H), 7.98 (d,
J = 8.4 Hz, 1H), 8.14 (d, J = 6.1 Hz, 1H). 13C NMR
(125 MHz, CDCl3) d: 51.20, 52.26, 109.64, 112.46, 115.82
(d, J = 38.15 Hz), 127.03 (d, J = 13.1 Hz), 127.13, 128.67,
129.66 (d, J = 8.35 Hz), 129.73, 132.72, 135.82, 139.39,
150.07, 159.65, 161.61, 166.36, 173.88. MS m/z: 329 (M+).
Anal. calcd. for C18H16FNO4: C, 65.65; H, 4.90; N, 4.25.
Found: C, 65.58; H, 4.88; N, 4.26.
Methyl 3-(2-carboxylphenylamino)-2-methylene-3-(2,4-
dichlorophenyl) propanoate (6f)
Brown solid; mp 114 8C. IR (KBr) n: 1043, 1656, 1722,
1
2948, 3355 cm–1. H NMR (500 MHz, CDCl3) d: 3.76 (s,
3H), 5.71 (s, 1H), 5.95 (d, J = 5.35 Hz, 1H), 6.45 (s, 1H),
6.51 (d, J = 8.4 Hz, 1H), 6.65 (t, J = 7.65 Hz, 1H), 7.21 (t,
J = 8.4 Hz, 1H), 7.34 (t, J = 8.4 Hz, 2H), 7.43 (s, 1H), 7.98
(d, J = 7.65 Hz, 2H). 13C NMR (125 MHz, CDCl3) d: 52.41,
54.02, 109.76, 112.45, 116.23, 127.64, 128.23, 129.35,
129.98, 132.74, 134.37, 134.69, 135.91, 136.14, 139.08,
149.96, 166.22, 173.75. MS m/z: 380 (M+), 382 (M+ + 2),
384 (M+ + 4). Anal. calcd. for C18H15Cl2NO4: C, 56.86; H,
3.98; N, 3.68. Found: C, 56.92; H, 3.99; N, 3.69.
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Bode, M. L.; Kaye, P. T. Tetrahedron Lett. 1991, 32 (40),
5611–5614.
doi:10.1016/0040-4039(91)80098-Q.;
(b)
Drewes, S. E.; Emslie, N. D.; Field, J. S.; Khan, A. A.; Ra-
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Ethyl 3-(2-carboxylphenylamino)-2-methylene-3-phenyl
propanoate (6g)
White solid; mp 124 8C. IR (KBr) n: 1650, 1719, 2982,
1
3359 cm–1. H NMR (500 MHz, DMSO-d6) d: 1.08 (d, J =
7.65 Hz, 3H), 4.04 (m, 2H), 5.58 (d, J = 7.6 Hz, 1H), 5.81
(s, 1H), 6.24 (s, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.59 (d, J =
8.4 Hz,1H), 7.30–7.34 (m, 5H), 7.79 (d, J = 7.65 Hz, 2H),
8.44 (d, J = 7.65 Hz, 1H). 13C NMR (125 MHz, DMSO-d6)
d: 14.34, 57.42, 61.14, 111.33, 112.69, 115.73, 126.47,
127.66, 128.13, 129.19, 132.25, 135.01, 140.76, 140.91,
149.81, 165.79, 170.54. MS m/z: 325 (M+). Anal. calcd. for
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Published by NRC Research Press

1690
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Published by NRC Research Press

Zulykama et al.
in organic chemistry, 2nd ed; Pergamon: Oxford, 1969;
1691
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Published by NRC Research Press