PAPER
Efficient and Chemoselective Access to 3-(Chloromethyl)coumarins
533
1
H NMR (400 MHz, CDCl ): δ = 1.51 [9 H, s, C(CH ) ], 4.29 (1 H,
s, C=CH ), 5.81 (1 H, d, J = 3.4 Hz, CHOH), 6.61 (1 H, s, ArOH),
3
3
3
2
d, J = 3.0 Hz, OH), 5.48 and 6.23 (2 H, 2 × s, C=CH ), 5.69 (1 H, d,
6.82 (3 H, s, ArH).
2
J = 3.0 Hz, CHOH), 6.85–7.20 (4 H, series of m, ArH), 8.09 (1 H,
s, ArOH).
13
C NMR (100 MHz, CDCl ): δ = 28.0 [C(CH ) ], 56.0 (OCH ),
3
3
3
3
6
9.9 (CHOH), 81.7 [C(CH ) ], 125.4 (C=CH ), 110.5, 119.6, 119.7,
3 3 2
1
3
C NMR (100 MHz, CDCl ): δ = 28.1 [C(CH ) ], 74.0 (CHOH),
126.3, 142.0, 143.8 and 147.1 (C=CH and ArC), 166.2 (C=O).
3
3
3
2
8
1
2.7 [C(CH ) ], 127.0 (C=CH ), 117.6, 119.8, 124.1, 127.8, 129.6,
+
3
3
2
MS (EI): m/z = 280 (M , 4.2), 161 (100).
40.8 and 156.1 (C=CH and ArC),166.8 (C=O).
2
HRMS: m/z calcd for C H O , 280.13107; found, 280.13073.
+
15 20
5
MS (EI): m/z (%) = 250 (M , 1.2) and 131 (100).
HRMS: m/z calcd for C H O : 250.12051; found: 250.11914.
tert-Butyl 3-(3-Ethoxy-2-hydroxyphenyl)-3-hydroxy-2-methyl-
1
4
18
4
enepropanoate (12c)
Pale-yellow oil; yield: 1.65g, 56%.
3
-(Chloromethyl)coumarin (10a)7
Concd HCl (4 mL) was added to a solution of 12a (0.51 g, 2.0
mmol) in HOAc (2 mL). The mixture was boiled under reflux for 2
1
H NMR (400 MHz, CDCl ): δ = 1.43 [12 H, s and overlapping t,
3
C(CH ) and OCH CH ], 3.63 (1 H, d, J = 4.6Hz, CHOH), 4.09 (2
H, q, J = 6.9 Hz, OCH CH ), 5.66 and 6.22 (2 H, 2 × s, C=CH ),
5
H, overlapping m, ArH).
1
3
3
2
3
h, allowed to cool to r.t. and then poured into ice-cooled H O
2
2
3
2
(
10mL). Stirring for ca. 30 min gave a precipitate, which was fil-
.81 (1 H, d, J = 4.6 Hz, CHOH), 6.45 (1 H, s, ArOH), 6.78–6.83 (3
tered off and washed with hexane to afford 10a as a grey solid (0.39
g, 98%).
3
C NMR (100 MHz, CDCl ): δ = 14.8 (CH CH ), 28.0 [C(CH ) ],
3
2
3
3 3
64.5 (OCH CH ), 69.4 (CHOH), 81.5 [C(CH ) ], 111.3, 119.5,
3
-(Iodomethyl)coumarin (9a)7
2
3
3 3
1
1
19.6, 125.1, 126.6, 142.2, 143.6 and 146.1 (C=CH and ArC),
66.1 (C=O).
Concd HI (2 mL) was added to a solution 12a (52 mg, 0.21 mmol)
in a mixture of HOAc (1 mL) and Ac O (1 mL). The mixture was
boiled under reflux for 2 h, allowed to cool to r.t. and then poured
into ice-cooled H O (5 mL). Stirring for ca., 30 min gave a precipi-
2
2
+
MS (EI): m/z (%) = 294 (M , 18.2), 220 (100).
2
HRMS: m/z calcd for C H O , 294.14672; found, 294.14688.
1
6
22
5
tate, which was filtered off and washed with hexane to afford 9a as
a pink solid (10 mg, 17%).
tert-Butyl 3-(5-Bromo-2-hydroxyphenyl)-3-hydroxy-2-methyle-
nepropanoate (12e)
White crystals; yield: 2.07g, 66%; mp 186–188 °C.
tert-Butyl 2H-1-Chromene-3-carboxylate 13 and 3-(acetoxyme-
thyl)coumarin (14)
A mixture of 12a (0.14 g, 0.56 mmol) in HOAc (12 mL) was boiled
1H NMR (400 MHz, CDCl
br s, OH), 5.56 and 6.26 (2 H, 2 × s, C=CH
): δ = 1.51 [9 H, s, C(CH
) ], 4.26 (1 H,
3 3
3
under reflux for 6 h. H O (10 mL) was added to the cooled solution
), 5.63 (1 H, s, CHOH),
2
2
and the resulting mixture was extracted with CHCl . The organic
6.79 (1 H, d, J = 8.7 Hz, ArH), 7.09 (1 H, d, J = 2.1 Hz, ArH), 7.28
(1 H, dd, J = 2.1 and 8.7 Hz, ArH), 8.18 (1 H, br s, ArOH).
3
solution was dried over anhyd Na SO , filtered and evaporated in
2
4
vacuo to afford a yellow solid, which was purified using preparative
13
C NMR (100 MHz, CDCl ): δ = 28.0 [C(CH ) ], 72.9 (CHOH),
3
3 3
layer chromatography (CHCl –hexane, 3:1) to afford 13 and 14.
3
8
1
3.0 [C(CH ) ], 111.8, 119.5, 126.5, 127.2, 130.3, 132.2, 140.3 and
55.1 (C=CH and ArC), 166.7 (C=O).
3 3
2
tert-Butyl 2H-1-chromene-3-carboxylate (13)12
Pale-yellow oil; yield: 50 mg, 38%.
+
79
MS (EI): m/z (%) = 328 [M ( Br), 3.7], 211 (100).
HRMS: m/z calcd for C H O479Br, 328.03102; found, 328.03063.
1
H NMR (400 MHz, CDCl ): δ = 1.53 [9 H, s, C(CH ) ], 4.94 (2 H,
14 17
3
3 3
d, J = 0.8 Hz, CH ), 6.82 (1 H, d, J = 8.0 Hz, ArH), 6.86–7.23 (3 H,
series of m, ArH), 7.32 (1 H, s, 4-H).
2
tert-Butyl 3-(3,5-Dibromo-2-hydroxyphenyl)-3-hydroxy-2-me-
thylenepropanoate (12f)
White crystals; yield: 1.70g, 41%; mp 186–188 °C.
1
3
C NMR (100 MHz, CDCl ): δ = 28.1 [C(CH ) ], 64.6 (CH ), 81.2
3
3
3
2
[
C(CH ) ], 116.0, 121.1, 121.6, 124.3, 128.7, 131.6, 132.5 and
2 3
1
H NMR (400 MHz, CDCl ): δ = 1.48 [9 H, s, C(CH ) ], 4.24 (1 H,
1
55.0 (ArC), 163.9 (C=O).
3
3 3
br s, OH), 5.62 and 6.26 (2 H, 2 × s, C=CH ), 5.67 (1 H, s, CHOH),
2
+
MS (EI): m/z (%) = 232 (M , 47.6), 131 (100).
7
.16 (1 H, d, J = 2.0 Hz, ArH), 7.56 (1 H, d, J = 2.0 Hz, ArH), 8.12
HRMS: m/z calcd for C H O , 232.10994; found, 232.11056.
(1 H, br s, ArOH).
1
4
16
3
1
3
C NMR (100 MHz, CDCl ): δ = 28.0 [C(CH ) ], 71.5 (CHOH),
3
3 3
3
-(Acetoxymethyl)coumarin (14)13
Pale-yellow solid; yield: 80mg, 65%; mp 106–110 °C (lit. 107–
09 °C).
8
1
2.9 [C(CH ) ], 112.0, 112.1, 127.0, 128.4, 129.7, 134.4, 140.3 and
3 3
1
3
51.0 (C=CH and ArC), 166.3 (C=O).
2
1
+
79
14
MS (EI): m/z = 406 [M ( Br ), 0.4%], 57 (100).
2
1
H NMR (400 MHz, CDCl ): δ = 2.15 (3 H, s, CH ), 5.06 (2 H, s,
3
3
7
9
HRMS: m/z calcd for C H O Br , 405.94153; found, 405.94240.
CH OAc), 7.26–7.55 (4 H, series of m, ArH), 7.74 (1 H, s, 4-H).
14 16
4
2
2
1
3
C NMR (100 MHz, CDCl ): δ = 20.9 (CH ), 61.2 (CH ), 116.7,
3
3
2
1
1
18.7, 123.6, 124.6, 128.0, 131.8, 140.7 and 153.5 (ArC),160.3 and
70.5 (2 × C=O).
Acknowledgements
The authors thank the National Research Foundation (NRF) for a
bursary (X.W.N.), and Rhodes University and the NRF for generous
financial support.
MS (EI): m/z (%) = 218 (M , 11), 175 (100).14
+
HRMS: m/z calcd for C H O , 218.05791; found, 218.05797.
1
2
10
4
tert-Butyl 3-Hydroxy-3-(2-hydroxy-3-methoxyphenyl)-2-meth-
ylenepropanoate (12b)
References
Pale-yellow oil; yield: 1.53g, 55%.
(
1) Murray, R. D. H. In Progress in the Chemistry of Natural
Products; Herz, W.; Grisebach, H.; Kirby, G. W., Eds.;
Springer-Verlag: New York, 1978, 199–429.
1
H NMR (400 MHz, CDCl ): δ = 1.45 [9 H, s, C(CH ) ], 3.68 (1 H,
3
3 3
br d, J = 3.4 Hz, OH), 3.87 (3 H, s, OCH ), 5.64 and 6.22 (2 H, 2 ×
3
Synthesis 2003, No. 4, 531–534 ISSN 0039-7881 © Thieme Stuttgart · New York