Efficient and chemoselective access to 3-(chloromethyl)coumarins via direct cyclisation of unprotected Baylis-Hillman adducts

Article abstract of DOI:10.1055/s-2003-37655

Reaction of substituted 2-hydroxybenzaldehydes with t-butyl acrylate in the presence of DABCO has been shown to afford isolable Baylis-Hillman adducts, acid-catalysed cyclisation of which affords the corresponding 3-(chloromethyl)coumarins directly and in

Full text of DOI:10.1055/s-2003-37655

PAPER
531
Efficient and Chemoselective Access to 3-(Chloromethyl)coumarins via Direct
Cyclisation of Unprotected Baylis–Hillman Adducts
E
P
fficient
a
ndC
e
hemoselec
r
tive
A
cc
r
e
ss to3-
y
(Chloromethyl)cou
T
m
arins . Kaye,* Musiliyu A. Musa, Xolani W. Nocanda
Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa
Fax +27(46)6225109; E-mail: P.Kaye@ru.ac.za
Received 6 December 2002; revised 16 January 2003
The major challenge in this approach has been to achieve8
Abstract: Reaction of substituted 2-hydroxybenzaldehydes with t-
butyl acrylate in the presence of DABCO has been shown to afford
isolable Baylis–Hillman adducts, acid-catalysed cyclisation of
regioselective cyclisation since the somewhat elusive,
unprotected analogues 3 (considered to act as pivotal in-
which affords the corresponding 3-(chloromethyl)coumarins direct- termediates) tend to cyclise directly to form complex mix-
ly and in high yield.
tures of chromene and coumarin derivatives (Scheme 1).9
Initially, attention was given to the use of protecting
groups to obtain coumarins chemoselectively, and O-ben-
zylated 2-hydroxybenzaldehydes 4 were successfully
used as substrates, permitting isolation of the correspond-
ing Baylis–Hillman adducts 5. Cyclisation to the
chromenes via conjugate addition (Path I; Scheme 1) was
prevented by nucleophilic interception of the electrophilic
vinylic centre through the addition of either an amine
Key words: heterocycles, synthesis, coumarins, 2H-1-benzopyran-
2
-ones, Baylis–Hillman reaction
The coumarin nucleus is well represented in natural prod-
ucts, and in a variety of pharmacologically active com-
1
pounds. Recently reported examples include: coumarin-
2
7
-xylosides, as oral anti-thrombotic agents; synthetic an-
6
7
(
benzylamine or piperidine) or a halogeno acid. Subse-
alogues of the naturally-occuring anti-bacterials, novo-
biocin and clorobiocin; and khellactone derivatives as
potential HIV-1 inhibitors. Various syntheses of cou-
3
quent removal of the O-benzyl protecting group and cycli-
sation via acyl substitution then afforded the 3-substituted
coumarins 7, 8, 9 or 10 (Scheme 2). We now report an ap-
plication of Baylis–Hillman methodology in which 3-
4
5
marin derivatives have been developed and, in recent
6
,7
communications, we have reported the application of
Baylis–Hillman methodology in the preparation of 3-sub-
stituted coumarins.
(
chloromethyl)coumarins are produced chemoselectively
without any recourse to the use of protecting groups.
Scheme 1
Scheme 2
Synthesis 2003, No. 4, Print: 18 03 2003.
Art Id.1437-210X,E;2003,0,04,0531,0534,ftx,en;P06902SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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PAPER
When salicylaldehyde 1a was reacted with t-butyl acry- forded the 3-(chloromethyl)coumarins 10b,c,e and f in ex-
late 11 in the presence of DABCO, the Baylis–Hillman cellent yield (86–98%). The reaction presumably involves
adduct 12a was obtained as a surprisingly stable and isol- initial conjugate addition of HCl (or HI) to the α,β-unsat-
8
able product (Scheme 3). In order to explore its potential urated ester moiety prior to acid-catalysed lactonisation,
to undergo direct cyclisation to chromene or coumarin thus inhibiting formation of chromenes as competition
products, the adduct 12a was treated with DABCO in products.
1
CDCl . H NMR analysis of the reaction mixture, howev-
3
In summary, stable salicylaldehyde-derived Baylis–Hill-
man adducts have been isolated and cyclised under acidic
conditions to produce 3-(chloromethyl)coumarins
chemoselectively, in high yield and without the need to
use any protecting groups.
er, revealed that the adduct 12a had, in fact, reverted to the
1
0
precursors 1a and 11, confirming the possibility of ret-
1
1
ro-Baylis–Hillman processes. The adduct 12a was then
heated in refluxing acetic acid to afford a 1:2 mixture of
the chromene-2-carboxylic ester 13 and the 3-(acetoxy-
methyl)coumarin 14, supporting the assumption that such
adducts can provide access to chromene and coumarin de-
rivatives – albeit under acidic conditions! Formation of
the acetoxy derivative 14 is attributed to addition of acetic
acid either prior to or following cyclisation of the adduct
NMR spectra were recorded on a Bruker AVANCE 400 MHz spec-
trometer at 303 K in CDCl and calibrated using solvent signals. In-
3
frared spectra were recorded on a Perkin Elmer FT-IR Spectrum
2
000 spectrometer. Low-resolution (EI) mass spectra were obtained
on a Finnigan GCQ mass spectrometer and high-resolution (EI)
1
1
2a, as outlined in Scheme 4. However, when the adduct mass spectra on a VG70-SEQ Micromass double-focusing magnet-
2a was treated with hydrochloric acid in refluxing acetic ic sector spectrometer (Cape Technikon Mass Spectrometry Unit).
Full characterisation of the 3-(halomethyl)coumarins 9 and 10, pre-
acid for one hour, the 3-(chloromethyl)coumarin 10a was
obtained in 98% yield! Surprisingly, use of hydriodic acid
6
,7
pared in this study, has been reported previously. The general syn-
thetic procedures are illustrated by the following examples.
(
instead of hydrochloric acid) and a mixture of acetic acid
and acetic anhydride (as solvent) gave the 3-iodomethyl
analogue 9a in only 17% yield.
tert-Butyl 3-Hydroxy-3-(2-hydroxyphenyl)-2-methylenepro-
panoate (12a)
A mixture of salicylaldehyde 1a (98%; 1.0 mL, 9.2 mmol), tert-bu-
tyl acrylate 11 (2.1 mL, 23mmol) and DABCO (0.86 g, 7.7 mmol)
Given the success of these preliminary results, a series of
2
-hydroxybenzaldehydes (1b,c,e and f) was reacted with
in CDCl (3 mL) was stirred in a stoppered reaction flask for 14 d.
3
t-butyl acrylate 11 in the presence of DABCO to afford
the corresponding Baylis-Hillman adducts 12b,c,e and f,
The mixture was concentrated in vacuo to give a dark brown oil,
which was purified using flash chromatography (hexane–EtOAc,
in yields ranging from 41–66%. Reaction of these adducts 4:1) to afford 12a (0.95g, 41%) as a colourless oil which later crys-
with hydrochloric acid in refluxing acetic acid then af- tallised; mp 108–110 °C.
Scheme 3
Scheme 4
Synthesis 2003, No. 4, 531–534 ISSN 0039-7881 © Thieme Stuttgart · New York

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%.
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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

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PAPER
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Synthesis 2003, No. 4, 531–534 ISSN 0039-7881 © Thieme Stuttgart · New York