Nucleophilic addition of 4-hydroxycoumarin to baylis-hillman acetate adducts

Article abstract of DOI:10.1055/s-0028-1083313

The exploration of 4-hydroxycoumarin for nucleophilic addition on to Baylis-Hillman acetate adducts has been described for the first time. The reactions of various Baylis-Hillman acetate adducts were examined with 4-hydroxycoumarins in the presence of bas

Full text of DOI:10.1055/s-0028-1083313

PAPER
399
Nucleophilic Addition of 4-Hydroxycoumarin to Baylis–Hillman Acetate
Adducts
Nucleophilic
A
dd
h
ition to Ba
y
a
lis–Hillman
d
A
cetate Add
a
ucts Raji Reddy,*a Nayani Kiranmai,a Kancharla Johny,a Mrunal Pendke,a Police Nareshb
a
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: rajireddy@iict.res.in
b
Nuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 August 2008; revised 26 September 2008
substituted 4-hydroxycoumarins 3 for the first time
(Scheme 1).
Abstract: The exploration of 4-hydroxycoumarin for nucleophilic
addition on to Baylis–Hillman acetate adducts has been described
for the first time. The reactions of various Baylis–Hillman acetate
adducts were examined with 4-hydroxycoumarins in the presence
of base to produce the corresponding 3-substituted 4-hydroxycou-
marins in good yields.
The initial reaction of BH acetate adduct 1a with 4-hy-
droxycoumarin (2a) in the presence of potassium carbon-
ate in anhydrous DMF at 75 °C afforded the
corresponding 3-substituted 4-hydroxycoumarin 3a. The
reaction was complete in three hours to give the product
in 92% yield with exclusive E-selectivity (Table 1, entry
1). The reaction did not proceed either at room tempera-
ture or in the absence of base. The stereochemistry of the
product was established based on extensive 2D NMR
studies including NOESY, DQFCOSY, and TOCSY ex-
periments.
Key words: Baylis–Hillman adduct, hydroxycoumarin, nucleo-
philic addition, 3-substituted coumarin, potassium carbonate
The Baylis–Hillman adducts (the products of Baylis–
Hillman reactions) are multifunctional allylic alcohol de-
rivatives that serve as extremely handy building blocks in
organic synthesis.1–7 In particular, Baylis–Hillman (BH)
acetate adducts have received considerable attention in re-
cent times, which undergo a variety of nucleophilic addi-
tion reactions often with good control of regioselectivity/
stereoselectivity. Thus far, a number of substitution/addi-
tion reactions using various nucleophiles have been ex-
plored.1,6,8,9 However, to the best of our knowledge 4-
hydroxycoumarins have not been explored as nucleo-
philes in the addition reactions of BH acetate adducts.
This addition reaction provides an easy access to 3-substi-
tuted 4-hydroxycoumarins, which are valuable deriva-
tives in medicinal chemistry and for diversity oriented
organic synthesis.10–13
The E-stereochemistry of 3a was assigned on the basis of
1H and 13C NMR chemical shifts in comparison with liter-
ature values.15 The structure was supported by NOE cross
peaks between Ha–Hb, Ha–Hi, He–Hg, and Hf–Hg
(Figure 1).
H2 i
C
Hb
Ha
O
H
CH3
Hk
c
j
O
OHh
CH2
g
Hd
Hf
Hl
He
In continuation of our work on BH acetate adducts,14 here-
in, we report on the nucleophilic addition of 4-hydroxy-
coumarins on BH acetate adducts to produce the 3-
O
O
Hm
3a
Hn
Figure 1 NOE cross-peak assignments for 3a
CO2Et
OH
R
X = CO2Et
OH
OAc
K2CO3, DMF
X
O
O
R
+
OH
O
75 °C, 3–7 h
O
O
X = CN
1
R
2a
CN
R = aryl, alkyl
O
3, 10 examples
72–92% yield
Scheme 1
SYNTHESIS 2009, No. 3, pp 0399–0402
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083313; Art ID: Z20008SS
© Georg Thieme Verlag Stuttgart · New York

400
C. Raji Reddy et al.
PAPER
A second example employed 1b, derived from benzalde- To demonstrate the efficiency and scope, we applied the
hyde and acrylonitrile, with 4-hydroxycoumarin (2a) was present method to a variety of BH acetate adducts derived
also proceeded to give 3b in good yield (82%) with exclu- from aromatic as well as aliphatic aldehydes and ethyl
sive Z-selectivity (entry 2). The structure of 3b was sup- acrylate or acrylonitrile. The results indicated that the re-
ported by NOE cross peaks between Ha-Hb and Ha-Hg actions proceeded well in DMF at 75 °C to give the corre-
(Figure 2).
sponding substituted coumarins 3c–j in good yields
(Table 1). The reactions of BH adducts with ester group
1c–g gave the E-isomers selectively (entries 3–8) while
the BH adduct with nitrile group 1h gave the Z-isomer
predominantly (entry 8). Finally, the reactions of 1a and
1c with 7-chloro-4-hydroxycoumarin were also success-
ful to provide the corresponding substituted coumarins 3i
and 3j, respectively (entries 9 and 10), useful structural
motifs for diversity, in good yields.
Hb
Ha
OHh
O
Hi
H2g
C
H
Hj
c
NC
Hd
O
Hk
Hf
Hl
He
3b
Figure 2 NOE cross-peak assignments for 3b
Table 1 Addition of 4-Hydroxycoumarin (2a) to BH Acetate Adductsa
Entry
BH acetate adduct
Time (h)
Product
Yield (%)b
92
CO2Et
OH
OAc
CO2Et
1
1a
3.5
3a
3b
O
O
OH
O
OAc
OAc
CN
2
3
1b
1c
4
82
85
CN
O
CO2Et
OH
CO2Et
3.5
3c
Br
O
O
O
Br
OAc
CO2Et
OH
CO2Et
OAc
4
5
6
1d
1e
1f
6
5
6
3d
3e
3f
72
89
73
NO2
O
NO2
CO2Et
OH
CO2Et
MeO
MeO
O
O
OAc
CO2Et
OH
CO2Et
OAc
O
O
OAc
CO2Et
OH
Ph
OAc
7
8
1g
1h
6
4
3g
3h
78
82
CO2Et
Ph
O
O
NO2
OH
NO2 OAc
CN
CN
O
O
Synthesis 2009, No. 3, 399–402 © Thieme Stuttgart · New York

PAPER
Nucleophilic Addition to Baylis–Hillman Acetate Adducts
401
Table 1 Addition of 4-Hydroxycoumarin (2a) to BH Acetate Adductsa (continued)
Entry
9c
BH acetate adduct
Time (h)
3.5
Product
Yield (%)b
86
CO2Et
OH
OAc
OAc
CO2Et
CO2Et
1a
3i
Cl
Cl
O
O
O
CO2Et
OH
10c
1c
3.5
3j
91
Br
O
Br
a Reaction conditions: K2CO3, DMF, 75 °C.
b Isolated yields.
c 7-Chloro-4-hydroxycoumarin (2b) was used as the nucleophile.
HRMS (EI): m/z calcd for C21H18O5 + Na (M + Na)+: 373.1051;
found: 373.1055 and 351.1242.
In conclusion, we have demonstrated first examples of a
nucleophilic addition reaction of 4-hydroxycoumarins
with Baylis–Hillman acetate adducts affording an effi-
cient method to synthesize 3-substituted 4-hydroxycou-
marins. This reaction should be useful due to the wide
utility of these compounds in organic synthesis.
3b
Off-white solid; mp 191.3–193.3 °C.
IR (KBr): 3227, 2925, 2210, 1669, 1632, 761 cm–1.
1H NMR (600 MHz, CDCl3 + DMSO-d6): d = 11.1 (br s, 1 H, Hh),
8.02 (dd, JH,H = 8.0, 1.5 Hz, 1 H, Hi), 7.71 (d, JH,H = 8.2 Hz, 2 H, Hb,
Hf), 7.54 (ddd, JH,H = 9.7, 7.2, 1.5 Hz, 1 H, Hk), 7.36 (m, 3 H, Hc,
Hd, He), 7.33 (m, 1 H, Hl), 7.30 (m, 1 H, Hj), 7.14 (s, 1 H, Ha), 3.78
(d, JH,H = 1.4 Hz, 2 H, Hg).
13C NMR (150 MHz, CDCl3 + DMSO-d6): d = 163.6, 162.3, 152.8,
144.1, 133.8, 131.9, 129.8, 129.3, 128.7, 123.7, 123.6, 119.3, 116.6,
116.3, 108.1, 100.4, 22.6.
The chemicals such as 4-hydroxycoumarins, aldehydes used for the
preparation of Baylis–Hillman adduct, and other reagents/catalysts
were purchased from Aldrich and used as received. DMF was dis-
tilled over CaH2. IR spectra were recorded on a Perkin-Elmer 683
1
spectrometer. H (200 MHz, 300 MHz, and 600 MHz) and 13C
NMR (150 MHz and 50 MHz) spectra of samples in CDCl3 were re-
corded on a Bruker Avance spectrometer. Chemical shifts are re-
ported in ppm with respect to internal TMS. Coupling constants (J)
are quoted in Hz. Mass spectra were obtained on an Agilent Tech-
nologies LC/MSD Trap SL mass spectrometer.
HRMS (EI): m/z calcd for C19H13NO3 + Na (M + Na)+: 326.0793;
found: 326.0790.
3c
Nucleophilic Addition of 4-Hydroxycoumarins to Baylis–
Hillman Acetate Adducts; General Procedure
Pale yellow solid; mp 131.0–131.8 °C.
IR (KBr): 3248, 2924, 1715, 1672, 1610, 1201, 759 cm–1.
To a stirred solution of the appropriate Baylis–Hillman acetate ad-
duct 1 (1 mmol) in anhyd DMF (2 mL) was added K2CO3 (414 mg,
3 mmol) followed by the respective 4-hydroxycoumarin (0.95
mmol) and the mixture was stirred at 75 °C for the given time
(Table 1). After completion of the reaction (monitored by TLC), the
mixture was diluted with H2O (3 mL). The product was extracted
with EtOAc (3 × 10 mL) and the combined organic extracts were
dried (Na2SO4). The solvent was evaporated under vacuum and the
crude product was purified by column chromatography (eluent:
hexanes–EtOAc) to afford the corresponding product.
1H NMR (200 MHz, CDCl3): d = 10.4 (s, 1 H), 7.91 (d, J = 7.34 Hz,
1 H), 7.80 (s, 2 H), 7.69 (d, J = 7.34 Hz, 1 H), 7.48 (t, J = 7.34 Hz,
2 H), 7.37–7.20 (m, 3 H), 4.33 (q, J = 7.34 Hz, 2 H), 3.74 (s, 2 H),
1.38 (t, J = 7.34 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 172.0, 163.6, 162.5, 152.7, 142.1,
137.2, 132.4, 132.0, 130.1, 129.8, 128.2, 124.0, 123.9, 122.6, 116.8,
116.4, 102.7, 62.9, 22.9, 14.2.
HRMS (EI): m/z calcd for C21H18BrO5 (M + H)+: 429.0337; found:
429.0332.
3a
3d
Colorless solid; mp 144.2–145.2 °C.
Off-white solid; mp 156.6–157.6 °C.
IR (KBr): 3081, 2925, 1710, 1672, 1618, 1100, 758 cm–1.
IR (KBr): 3403, 2925, 1706, 1657, 1620, 752 cm–1.
1H NMR (600 MHz, CDCl3): d = 10.5 (s, 1 H, Hh), 7.92 (dd, JH,H
=
1H NMR (300 MHz, CDCl3): d = 10.4 (s, 1 H), 8.4 (s, 1 H), 8.25 (dd,
J = 1.51, 8.30 Hz, 1 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.92 (m, 2 H), 7.64
(t, J = 8.3 Hz, 1 H), 7.50 (dt, J = 1.51, 8.30 Hz, 1 H), 7.32–7.20 (m,
2 H), 4.36 (q, J = 6.79 Hz, 2 H), 3.74 (s, 2 H), 1.39 (t, J = 6.79 Hz,
3 H).
13C NMR (50 MHz, CDCl3): d = 172.0, 162.3, 154.0, 148.0, 140.8,
137.0, 135.2, 131.9, 130.9, 129.4, 124.2, 123.8, 123.4, 116.2, 116.4,
102.0, 63.0, 22.5, 14.0.
8.0, 1.6 Hz, 1 H, Hk), 7.90 (s, 1 H, Ha), 7.69 (d, JH,H = 7.5 Hz, 2 H,
Hf, Hb), 7.49 (m, 1 H, Hm), 7.47 (m, 1 H, Hd), 7.45 (m, 1 H, He), 7.39
(m, 1 H, Hc), 7.26 (dd, JH,H = 8.0, 7.0 Hz, 1 H, Hl), 7.23 (d, JH,H = 8.1
Hz, 1 H, Hn), 4.33 (q, JH,H = 7.1 Hz, 2 H, Hi), 3.81 (s, 2 H, Hg), 1.37
(t, JH,H = 7.1 Hz, 3 H, Hj).
13C NMR (150 MHz, CDCl3): d = 172.3, 163.5, 162.2, 152.5, 143.9,
135.0, 131.7, 129.5, 129.0, 128.4, 128.2, 123.8, 123.6, 116.7, 116.2,
102.9, 62.6, 22.6, 14.1.
HRMS (EI): m/z calcd for C21H17 NO7 + Na (M+ Na)+: 418.0337;
found: 418.0880.
Synthesis 2009, No. 3, 399–402 © Thieme Stuttgart · New York

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3e
C. Raji Reddy et al.
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13C NMR (50 MHz, CDCl3): d = 172.5, 163.1, 161.3, 151.1, 144.4,
135.1, 131.8, 129.7, 129.3, 129.2, 128.7, 128.2, 123.6, 118.1, 117.8,
104.0, 62.9, 22.9, 14.3.
Pale yellow solid; mp 107–108 °C.
IR (KBr): 3423, 2923, 1708, 1657, 1604, 1261, 1174, 1091, 1028,
751 cm–1.
HRMS (EI): m/z calcd for C21H18ClO5 (M + H)+: 385.0842; found:
385.0845.
LCMS: m/z = 385 (M + H)+.
1H NMR (200 MHz, CDCl3): d = 10.79 (s, 1 H), 7.92 (d, J = 7.5 Hz,
1 H), 7.8 (m, 3 H), 7.5 (m, 1 H), 7.25 (m, 2 H), 6.94 (m, 2 H), 4.38
(q, J = 6.7 Hz, 2 H), 3.86 (s, 5 H), 1.38 (t, J = 6.7 Hz, 3 H).
3j
13C NMR (50 MHz, CDCl3): d = 173.1, 164.0, 162.7, 160.6, 152.7,
143.8, 132.2, 131.8, 127.4, 125.8, 124.0, 123.8, 117.0, 116.3, 114.1,
103.1, 62.7, 55.5, 23.0, 14.3.
Colorless solid; mp 144.2–146.2 °C.
IR (KBr): 3248, 2928, 1715, 1666, 1622, 1260, 756 cm–1.
HRMS (EI): m/z calcd for C22H21O6 (M + H)+: 381.1338; found:
381.1330.
1H NMR (200 MHz, CDCl3): d = 10.6 (br s, 1 H), 7.95 (m, 3 H), 7.62
(m, 1 H), 7.55–7.21 (m, 4 H), 4.3 (q, J = 7.0 Hz, 2 H), 3.75 (s, 2 H),
1.4 (t, J = 7.0 Hz, 3 H).
3f
13C NMR (50 MHz, CDCl3): d = 172.0, 161.4, 151.1, 142.5, 137.1,
132.4, 132.1, 131.9, 130.2, 129.5, 129.4, 128.1, 123.6, 122.7, 118.0,
117.9, 103.6, 63.1, 22.9, 14.2.
Pale yellow sticky liquid.
IR (KBr): 3422, 2925, 1734, 1667, 1618, 1166, 1030, 749 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.75 (s, 1 H), 7.9 (d, J = 8.3 Hz,
1 H), 7.8 (s, 1 H), 7.6 (s, 1 H), 7.5 (m, 1 H), 7.3 (m, 3 H), 7.05 (d,
J = 8.5 Hz, 1 H), 6.9 (d, J = 8.5 Hz, 1 H), 4.15 (q, J = 7.5 Hz, 2 H),
3.8 (s, 2 H), 2.1 (s, 3 H), 1.35 (t, J = 7.5 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.1, 164.0, 162.7, 160.6, 152.7,
143.8, 132.2, 131.8, 127.4, 125.8, 124.0, 123.8, 117.0, 116.3, 114.1,
103.1, 55.5, 23.0, 14.3.
HRMS (EI): m/z calcd for C21H16BrClO5 + Na (M + Na)+:
484.9767; found: 484.9764.
Acknowledgment
N.K., K.J., and P.N. thank CSIR and UGC, New Delhi, for financial
assistance. C.R.R. is grateful to Dr. J. S. Yadav and Dr. S. Chand-
rasekhar, Indian Institute of Chemical Technology, Hyderabad, for
their support and encouragement.
HRMS (EI): m/z calcd for C23H20O7 + Na (M + Na)+: 431.1106;
found: 431.1096.
3g
References and Notes
Pale yellow solid; mp 92–93 °C.
IR (KBr): 3415, 2925, 1707, 1661, 1621, 1306, 1107, 756 cm–1.
(1) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
(2) Batra, S.; Singh, V. Tetrahedron 2008, 64, 4511.
(3) Basavaiah, D.; Aravindu, K. Org. Lett. 2007, 9, 2453.
(4) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem.
Soc. 2005, 26, 1481.
(5) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627.
(6) Basavaiah, D.; Rao, P. D.; Suguna, H. R. Tetrahedron 1996,
52, 8001.
1H NMR (200 MHz, CDCl3): d = 10.9 (s, 1 H), 7.88 (dd, J = 7.8, 1.5
Hz, 1 H), 7.48 (m, 1 H), 7.30–7.02 (m, 8 H), 4.28 (q, J = 7.0 Hz, 2
H), 3.5 (s, 2 H), 3.02 (q, J = 7.0 Hz, 2 H), 2.79 (t, J = 7.0 Hz, 2 H),
1.34 (t, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 172.3, 164.0, 162.4, 152.8, 148.4,
141.3, 131.8, 128.7, 128.5, 126.2, 124.0, 123.8, 116.9, 116.3, 103.0,
62.6, 35.0, 31.3, 22.1, 14.2.
(7) Drews, S. E.; Ross, G. H. P. Tetrahedron 1988, 44, 4653.
(8) Kim, S. J.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48,
1069; and references cited therein.
HRMS (EI): m/z calcd for C23H23O5 (M + H)+: 379.1545; found:
379.1544.
(9) Basavaiah, D.; Aravindu, K. Org. Lett. 2007, 9, 2453; and
references cited therein.
(10) Raj, G.; Kumar, R.; McKinney, W. P. Am. J. Med. Sci. 1994,
307, 128.
3h
Off-white solid; mp 202–204 °C.
IR (KBr): 3193, 2924, 2209, 1672, 1629, 1109, 763 cm–1.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 7.99 (m, 1 H), 7.69
(11) Hadler, M. R.; Shadbolt, R. S. Nature 1975, 253, 275.
(12) Estevez-Braun, A.; Gonzalez, A. G. Nat. Prod. Rep. 1997,
14, 465.
(13) Wang, S.; Milne, G. W. A.; Yan, X.; Posey, I. J.; Nicklaus,
M. C.; Graham, L.; Rice, W. G. J. Med. Chem. 1996, 39,
2047.
(14) Reddy, C. h. R.; Kiranmai, N.; Babu, G. S. K.; Sarma, G. D.;
Jagadeesh, B.; Chandrasekhar, S. Tetrahedron Lett. 2007,
48, 215.
(m, 2 H), 7.6–7.2 (m, 5 H), 7.14 (s, 1 H), 3.74 (s, 2 H).
13C NMR (50 MHz, CDCl3 + DMSO-d6): d = 163.5, 162.5, 152.8,
144.1, 143.2, 134.2, 132.7, 131.9, 130.7, 130.4, 129.6, 127.5, 124.0,
123.6, 116.6, 116.3, 111.9, 100.0, 24.4.
HRMS (EI): m/z calcd for C19H12N2O5 + Na (M + Na)+: 371.0643;
found: 371.0637.
(15) (a) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B.
Synthesis 2000, 545. (b) Basavaiah, D.; Krishnamacharyulu,
M.; Hyma, R. S.; Sarma, P. K. S.; Kumaragurubaran, M.
J. Org. Chem. 1999, 64, 1197.
3i
Colorless solid; mp 167.8–169.8 °C.
IR (KBr): 3415, 2929, 1716, 1663, 1622, 1265, 761 cm–1.
1H NMR (200 MHz, CDCl3): d = 10.7 (br s, 1 H), 7.9 (m, 2 H), 7.65
(m, 2 H), 7.55–7.35 (m, 4 H), 7.20–7.12 (m, 1 H), 4.3 (q, J = 7.0 Hz,
2 H), 3.80 (s, 2 H), 1.4 (t, J = 7.0 Hz, 3 H).
Synthesis 2009, No. 3, 399–402 © Thieme Stuttgart · New York