A convenient and improved Baylis-Hillman synthesis of 3-substututed 2H-1-benzopyran-2-ones

Article abstract of DOI:10.1055/s-2002-35984

Halogen acid-catalysed deprotection and cyclisation of Baylis-Hillman products obtained using O-benzylated salicylaldehyde precursors has been shown to afford 3-(halomethyl)coumarins (3-halomethyl-2H-1-benzopyran-2-ones) chemoselectively and in good yield.

Full text of DOI:10.1055/s-2002-35984

PAPER
2701
A Convenient and Improved Baylis–Hillman Synthesis of 3-Substututed
2H-1-benzopyran-2-ones
Synthesis of
3
e
-Substituted
r
2
H
-1-b
r
enzopyr
y
Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa
Fax +27(46)6225109; E-mail: P.Kaye@ru.ac.za
Received 9 September 2002
chromenes from salicylaldehyde precursors 1 afforded
complex mixtures of chromene and coumarin
derivatives16,17 via, as we have suggested, cyclisation of
putative Baylis–Hillman intermediates 3 (Figure 1). At-
tention was subsequently focussed on controlling the regi-
oselectivity of cyclisation to afford either chromene or
coumarin derivatives. Chemoselective access to 2H-1-
chromenes has been achieved18 using activated alkenes
that preclude acyl substitution and, in a recent communi-
cation,19 we have reported the use of Baylis–Hillman
methodology to prepare 3-substituted coumarin deriva-
tives (7 and 8, Scheme 1). The strategy adopted to inhibit
the formation of chromene derivatives (Path I, Figure 1)
followed an approach previously identified by Drewes et
al.20 and involved three phases: i) protection of the salicyl-
aldehyde phenolic hydroxyl group as a benzyl ether; ii)
nucleophilic interception of the electrophilic vinylic cen-
tre in the Baylis–Hillman product using benzylamine or
piperidine; and iii) deprotection of the phenolic oxygen
(via hydrogenolysis in the presence of 10% Pd/C catalyst)
to permit cyclisation to coumarins via acyl substitution.
We now report an extension of this approach that elimi-
nates the need for a separate nucleophilic interception
step.
Abstract: Halogen acid-catalysed deprotection and cyclisation of
Baylis–Hillman products obtained using O-benzylated salicylalde-
hyde precursors has been shown to afford 3-(halomethyl)coumarins
(3-halomethyl-2H-1-benzopyran-2-ones) chemoselectively and in
good yield.
Key words: heterocycles, synthesis, coumarins, 2H-1-benzopyran-
2-ones, Baylis–Hillman reaction
The coumarin (2H-1-benzopyran-2-one) nucleus is
present in many compounds that exhibit pharmacological
activity.1 These include antibiotics, such as novobiocin,2
the anticoagulant, dicoumarol,3 and the calanolides A and
B, which act as in vitro inhibitors of HIV-1 replication.4 4-
Hydroxycoumarin derivatives have also shown promise
as HIV-1 integrase- and non-peptidic HIV-1 protease in-
hibitors.5,6 Various methods for preparing coumarin de-
rivatives have been developed, including the classic
Pechmann,7 Claisen,8 Wittig9 and Knoevenagel10 reac-
tions. There is, nevertheless, a continuing interest in the
synthesis of these important systems. Bogdal,11 for exam-
ple, has recently reported a microwave-assisted Knoeve-
nagel condensation that affords coumarins in yields of up
to 94%, while Santana and co-workers12 have applied
Wittig and Reformatsky methodology in the synthesis of
potential antipsychotic compounds containing the cou-
marin nucleus.
The benzyl ethers 4a–f, obtained in good yield by treating
the salicylaldehyde precursors 1a–f with benzyl bromide
in the presence of K2CO3 and NaI, were reacted with me-
thyl acrylate 2 in the presence of DABCO to afford the O-
benzylated Baylis–Hillman products 5a–f (Scheme 1).19
Ethers are typically cleaved on heating with concentrated
hydriodic acid or hydrobromic acid, and Santana and co-
workers12 have reported the use of hydriodic acid in the
In our own research on applications of Baylis–Hillman
methodology in the construction of benzannulated hetero-
cycles, we have developed convenient syntheses of in-
dolizines,13 quinolines14 and 2H-1-thiochromenes.15
Earlier attempts to use this approach to access 2H-1-
Figure 1 Cyclisation of putative Baylis–Hillman intermediates via conjugate addition (I) or acyl substitution (II) pathways
Synthesis 2002, No. 18, Print: 19 12 2002.
Art Id.1437-210X,E;2002,0,18,2701,2706,ftx,en;P05002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2702
P. T. Kaye, M. A. Musa
PAPER
Scheme 1
demethylation and subsequent cyclisation of ethyl 3-cy- chloromethyl analogues 10a–f were obtained in even bet-
clohexyl-3-hydroxy-3-(2,5-dimethoxyphenyl)prop-2-
enoate to afford 4-cyclohexyl-6-methoxycoumarin in
yields of up to 68%. The O-benzylated Baylis–Hillman
products 5a–f were therefore treated with hydriodic acid
in a mixture of acetic acid and acetic anhydride at reflux
temperature to afford, after workup, the 3-(iodometh-
yl)coumarins 9a–f in yields ranging from 61 to 85%
(Table 1). Hydriodic acid, however, is relatively expen-
sive and unpleasant to handle and concentrated hydro-
chloric acid was investigated as an alternative reagent.
When the O-benzylated Baylis–Hillman products 5a–f
were reacted with concentrated hydrochloric acid, the 3-
ter yields (up to 94%)!
The formation of the novel 3-(halomethyl)coumarins 9
and 10 presumably involves: conjugate addition of the
halogen acid to the , -unsaturated ester moiety and acid-
catalysed dehydration (i.e. 5
11
12);21 cleavage of
the benzyl ether; and, finally, cyclisation (Scheme 2). Ad-
dition of the halogen acid to the double bond appears to in-
hibit cyclisation of the intermediates 12 to the chromene
analogues. This approach thus eliminates the need to use
an amine to ‘protect’ the double bond, and permits depro-
tection of the O-benzyl ethers 5 and cyclisation in one-pot
and in high yield.
Scheme 2
Synthesis 2002, No. 18, 2701–2706 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substututed 2H-1-benzopyran-2-ones
2703
Scheme 3
Acrylonitrile (13) also serves as an activated alkene in
Baylis–Hillman reactions and, consequently, was reacted
with the O-benzylated salicylaldehydes 4b,d,e to afford
the corresponding adducts 14b,d,e (Scheme 3). These ad-
ducts were then treated with concentrated hydrochloric
acid in a reluxing mixture of acetic acid and acetic anhy-
dride for 45 minutes to give the 3-(chloromethyl)cou-
marin derivatives 10b,d,e in yields of up to 87%
(Scheme 3, Table 1). Acidic hydrolysis of nitriles typical-
ly affords carboxylic acids (or the intermediate amides),
and in situ hydrolysis of the nitrile function, followed by
intramolecular acyl substitution, would account for the
formation of the coumarins (Scheme 3, Path I). An alter-
native pathway (Path II) could be envisaged, however, in
which cyclisation proceeds via acid-catalysed nucleophilc
addition to an intermediate nitrile 16, followed by hydrol-
ysis of the resulting imine 17.
Table 1 Coumarin Derivatives 9 and 10 Prepareda
No.
Substrate
R1
Product
No.
Yield (%)b
R2
H
Y
I
5a
H
9a
10a
9b
67
80
62
87
61
94
85
94
61
79
61
90
69
87
75
Cl
I
5b
5c
5d
5e
5f
H
OMe
OEt
H
10b
9c
Cl
I
H
10c
9d
Cl
I
Cl
Br
Br
10d
9e
Cl
I
H
In summary, one-pot, acid-catalysed deprotection and cy-
clisation of O-benzylated Baylis–Hillman adducts has
been shown to provide a convenient, efficient and
chemoselective access to a range of 3-halomethylcou-
marins.
10e
9f
Cl
I
Br
10f
10b
10d
10e
Cl
Cl
Cl
Cl
14b
14d
14e
H
OMe
H
NMR spectra were recorded on Bruker AMX400 or Avance 400
MHz spectrometers at 303 K in CDCl3 or DMSO-d6, and calibrated
using solvent signals. IR spectra were recorded on a Perkin Elmer
FT-IR Spectrum 2000 spectrometer. Low-resolution (EI) mass
spectra were obtained on a Finnigan GCQ mass spectrometer and
high-resolution (EI) mass spectra on a VG70-SEQ Micromass dou-
ble-focusing magnetic sector spectrometer (Cape Technikon Mass
Spectrometry unit). The O-benzylated Baylis–Hillman adducts 5a–
f and their O-benzylated salicylaldehyde precursors 4a–f were pre-
pared as described previously.19 The synthetic procedures for other
compounds in this study are illustrated by the following examples
of typical procedures.
Cl
Br
H
a See Schemes 1 and 3.
b Isolated product.
Synthesis 2002, No. 18, 2701–2706 ISSN 0039-7881 © Thieme Stuttgart · New York

2704
P. T. Kaye, M. A. Musa
PAPER
3-(Iodomethyl)coumarin (9a); Typical Procedure
MS (EI): m/z (%) = 365 [MH+(35Cl), 38.9], 239 (100).
Concd. HI (57%, 10 mL) was added to a solution of 5a (0.31 g, 1.0
mmol) in a mixture of AcOH (5 mL) and Ac2O (5 mL). The mixture
was boiled under reflux for 2 h, allowed to cool to r.t. and then
poured into ice-cold water (10 mL). Stirring for ca. 30 min gave a
precipitate, which was filtered off and washed with hexane to afford
9a as a grey solid (0.20 g, 67%); mp 150–152 °C.
IR (KBr): 1709 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): = 4.34 (2 H, s, CH2I), 7.22–7.52 (4
H, series of mutiplets, Ar-H), 7.81 (1 H, s, 4-H).
HRMS: m/z calcd for C10H779BrIO2, 364.86747; found, 364.86850.
6,8-Dibromo-3-(iodomethyl)coumarin (9f)
Pink solid; yield: 0.28 g (61%); mp 208–210 °C.
IR (KBr): 1747 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): = 4.36 (2 H, s, CH2I), 7.56 (1 H, d,
J = 2.0 Hz, Ar-H), 7.70 (1 H, s, Ar-H), 7.87 (1 H, d, J = 2.0 Hz, Ar-
H).
13C NMR (100 MHz, CDCl3): = –3.1 (CH2I), 111.3, 117.2, 121.4,
129.2, 129.5, 137.3, 138.5, 149.3 (C=C and Ar-C), 158.2 (C=O).
MS (EI): m/z (%) = 442 [M+(79Br2), 0.5], 317 (100).
13C NMR (100 MHz, CDCl3): = –1.6 (CH2I), 116.7, 119.1, 124.7,
127.2, 127.6, 131.9, 140.4, 153.5 (C=C and Ar-C), 159.7 (C=O).
MS (EI): m/z (%) = 287 (MH+, 0.21), 159 (100).
HRMS: m/z calcd for C10H579Br2IO2, 441.77010; found, 441.77080.
HRMS: m/z calcd for C10H8IO2, 286.9554; found, 286.9569.
3-(Chloromethyl)coumarin (10a)
3-(Iodomethyl)-8-methoxycoumarin (9b)
Light-yellow solid; yield: 0.20 g (61%); mp 184–186 °C.
IR (KBr): 1718 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): = 3.96 (3 H, s, OCH3), 4.37 (2 H, s,
CH2I), 7.05 (1 H, dd, J = 1.0, 8.0 Hz, Ar-H), 7.07 (1 H, d, J = 8.0
Hz, Ar-H), 7.20 (1 H, t, J = 8.0 Hz, Ar-H), 7.80 (1 H, s, 4-H).
13C NMR (100 MHz, CDCl3): = –1.7 (CH2I), 56.3 (OCH3), 113.8,
119.1, 119.8, 124.6, 127.6, 134.6, 140.6, 143.0 (C=C and Ar-C),
159.2 (C=O).
Method 1: Conc. HCl (10 mL) was added to a solution of 5a (0.31
g, 1.0 mmol) in AcOH (5 mL) and Ac2O (5 mL). The mixture was
boiled under refluxed for 2 h, allowed to cool to r.t. and then poured
into ice-cooled water (10 mL). Stirring for ca. 30 min gave a precip-
itate, which was filtered off and washed with hexane to afford 10a
as a purple solid (0.16 g, 79%); mp 108–110 °C.
IR (KBr): 1713 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): = 4.55 (2 H, s, CH2Cl), 7.27–7.56 (4
H, series of multiplets, Ar-H), 7.88 (1 H, s, 4-H).
MS (EI): m/z (%) = 317 (MH+, 62), 189 (100).
13C NMR (100 MHz, CDCl3): = 41.0 (CH2), 116.7, 118.8, 124.7,
125.0, 128.1, 132.0, 141.1, 153.5 (C=C and Ar-C), 160.1 (C=O).
MS (EI): m/z (%) = 194 (M+, 31.4), 159 (100).
HRMS: m/z calcd for C11H10IO3, 316.9675; found, 316.9666.
8-Ethoxy-3-(iodomethyl)coumarin (9c)
Brown solid; yield: 0.21 g (62%); mp 120–122 °C.
HRMS: m/z calcd for C10H735ClO2, 194.01346; found, 194.01346.
IR (KBr): 1714 cm–1 (C=O).
3-(Chloromethyl)-8-ethoxycoumarin (10c)
Pale-pink solid; yield: 0.23 g (94%); mp 122–124 °C.
IR (KBr): 1709 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): = 1.49 (3 H, t, J = 7.0 Hz, CH3), 4.20
(2 H, q, J = 7.0 Hz, OCH2CH3), 4.37 (2 H, s, CH2I), 7.03 (1 H, dd,
J = 1.0, 8.0 Hz, Ar-H), 7.06 (1 H, dd, J = 1.0, 8.0 Hz, Ar-H), 7.18
(1 H, t, J = 7.8 Hz, Ar-H), 7.80 (1 H, s, 4-H).
13C NMR (100 MHz, CDCl3): = –1.5 (CH2I), 14.7 (OCH2CH3),
65.0 (OCH2CH3), 115.0, 119.1, 119.9, 124.6, 127.4, 140.7, 143.4,
146.3 (C=C and Ar-C), 159.4 (C=O).
1H NMR (400 MHz, CDCl3): = 1.49 (3 H, t, J = 7.0 Hz,
OCH2CH3), 4.18 (2 H, q, J = 7.0 Hz, OCH2CH3), 4.55 (2 H, d, J =
0.8 Hz, CH2Cl), 7.07 (2 H, d, J = 7.6 Hz, Ar-H), 7.20 (1 H, t, J = 7.6
Hz, Ar-H), 7.85 (1 H, s, 4-H).
13C NMR (100 MHz, CDCl3): = 14.7 (OCH2CH3), 41.0 (CH2Cl),
55,1 (OCH2CH3), 115.2, 119.4, 119.6, 124.6, 125.1, 141.3, 143.4,
146.5 (C=C and Ar-C), 159.8 (C=O).
MS (EI): m/z (%) = 330 (M+, 1.2), 203 (100).
HRMS: m/z Found: 329.97490. C12H11IO3 requires: 329.97530.
HRMS: m/z calcd for C12H11IO3, 329.97530; found, 329.97490.
MS (EI): m/z (%) = 238 (M+, 28.5), 175 (100).
HRMS: m/z calcd for C12H1135ClO3, 238.03967; found, 238.03987.
6-Chloro-3-(iodomethyl)coumarin (9d)
Yellow solid; yield: 0.28 g (85%); mp 188–190 °C.
6-Chloro-3-(chloromethyl)coumarin (10d)
Pale-pink solid: yield: 0.33 g (94%); mp 112–114 °C.
IR (KBr): 1729 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): = 4.54 (2 H, s, CH2Cl), 7.29 (1 H, d,
IR (KBr): 1747 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): = 4.35 (2 H, s, CH2I), 7.29–7.48 (3
H, series of multiplets, Ar-H), 7.75 (1 H, s, Ar-H).
J = 8.8 Hz, Ar-H), 7.47–7.51 (2 H, m, Ar-H), 7.81 (1 H, s, 4-H).
13C NMR (100 MHz, CDCl3): = 40.8 (CH2), 118.1, 119.8, 126.3,
127.3, 130.0, 131.9, 139.7, 151.8 (C=C and Ar-C), 159.5 (C=O).
MS (EI): m/z (%) = 228 [M+(35Cl2), 23.2], 193 (100).
HRMS: m/z calcd for C10H635Cl2O2, 227.97448; found, 227.97476.
13C NMR (100 MHz, CDCl3): = –2.3 (CH2I), 118.2, 120.1, 126.9,
128.7, 130.0, 131.7, 140.0, 151.9, 159.1(Ar-C and C=O).
MS (EI): m/z (%) = 321 [MH+(35Cl), 62.8], 193 (100).
HRMS: m/z calcd for C10H635ClINaO2, 342.8979; found, 342.8998.
6-Bromo-3-(iodomethyl)coumarin (9e)
Grey solid; yield: 0.23 g (64%); mp 148–150 °C.
6-Bromo-3-(chloromethyl)coumarin (10e)
Pale-pink solid; yield: 0.22 g (78%); mp 116–118 °C.
IR (KBr): 1722 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): = 4.53 (2 H, s, CH2Cl), 7.23 (1 H, d,
J = 8.8 Hz, Ar-H), 7.61, 7.63 (1 H, dd, J = 2.0, 8.8 Hz, Ar-H), 7.66
(1 H, d, J = 2.0 Hz, Ar-H), 7.80 (1 H, s, 4-H).
IR (KBr): 1722 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): = 4.35 (2 H, s, CH2I), 7.20–7.61 (3
H, series of overlapping signals), 7.74 (1 H, s, 4-H).
13C NMR (100 MHz; CDCl3): = –2.4 (CH2I), 117.3, 118.5, 120.6,
128.6, 130.0, 134.6, 138.9, 152.3 (C = C and Ar-C), 159.1 (C=O).
Synthesis 2002, No. 18, 2701–2706 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substututed 2H-1-benzopyran-2-ones
2705
13C NMR (100 MHz; CDCl3): = 40.8 (CH2), 117.3, 118.4, 120.3,
126.3, 130.3, 134.7, 139.6, 142.3 (C=C and Ar-C), 159.4 (C=O).
MS (EI): m/z (%) = 272 [M+(35Cl79Br), 60.7], 237(100).
HRMS: m/z calcd for C10H679Br35ClO2, 271.92397; found,
271.92412.
1H NMR (400 MHz, CDCl3): = 2.88 (1 H, d, J = 6.0 Hz, OH),
5.05, 5.08 (2 H, 2 d, J = 11.6Hz, OCH2Ph), 5.54 (1 H, d, J = 6.0 Hz,
CHOH), 5.94, 5.98 (2 H, 2 d, J = 1.6 Hz, C=CH2), 6.89 (1 H, d, J =
8.8 Hz, Ar-H), 7.24–7.42 (7 H, series of multiplets, Ar-H).
13C NMR (100 MHz, CDCl3): = 69.6 (CHOH), 70.9 (OCH2Ph),
130.3 (C=CH2), 113.5, 116.8, 125.2, 126.6, 127.6, 127.8, 128.5,
128.8, 129.2, 129.6, 135.8 (C=CH2 and Ar-C), 154.3 (C N).
6,8-Dibromo-3-(chloromethyl)coumarin (10f)
Pink solid; yield: 0.32 g (88%); mp 166–168 °C.
MS (EI): m/z = 299 [M+(35Cl), 18.1], 91 (100).
IR (KBr): 1727 cm–1 (C=O).
HRMS: m/z calcd for C17H1435ClNO2, 299.07131; found,
299.07235.
1H NMR (400 MHz, CDCl3): = 4.54 (2 H, s, CH2Cl), 7.58 (1 H, d,
J = 2.2 Hz, Ar-H), 7.78 (1 H, s, 4-H), 7.88 (1 H, d, J = 2.2 Hz, Ar-H).
13C NMR (100 MHz, CDCl3): = 40.5 (CH2), 111.2, 117.3, 121.1,
127.1, 129.6, 137.5, 139.2, 149.3 (C=C and Ar-C), 158.48 (C=O).
MS (EI): m/z (%) = 350 [M+ (35Cl79Br2), 40.9], 317 (100).
HRMS: m/z calcd for C10H579Br235ClO2, 349.83448; found:
3-(2-Benzyloxy-5-bromophenyl)-3-hydroxy-2-methylenepro-
panenitrile (14e)
Pale-yellow crystals; yield: 0.88 g (51%); mp 80–82 °C.
IR (KBr): 3413 (OH), 2231 cm-1 (C N).
1H NMR (400 MHz, CDCl3): = 2.83 (1 H, d, J = 5.4 Hz, OH),
5.05, 5.08 (2 H, 2 d, J = 11.6 Hz, OCH2Ph), 5.54 (1 H, d, J = 5.4 Hz,
CHOH), 5.94, 5.98 (2 H, 2 d, J = 1.4 Hz, C=CH2), 6.85 (1 H, d, J =
8.8 Hz, Ar-H), 7.35–7.42 (6 H, series of overlapping signals, Ar-H),
7.52 (1 H, d, J = 2.4 Hz, Ar-H).
13C NMR (100 MHz, CDCl3): = 69.5 (CHOH), 70.8 (OCH2Ph),
130.3 (C=CH2), 113.8, 113.9, 116.8, 125.2, 127.6, 128.5, 128.8,
129.6, 130.7, 132.6, 135.7 (C=CH2 and Ar-C), 154.8 (C N).
349.83490.
3-(Chloromethyl)-8-methoxycoumarin (10b)
Method 2: Concd HCl (10 mL) was added to a solution of 14b (vide
infra) (0.30 g, 1.0 mmol) in AcOH (5 mL) and Ac2O (5 mL). The
mixture was boiled under reflux for ca. 1 h, allowed to cool to r.t.
and then poured into ice-cold water (10 mL). Stirring for ca. 30 min
gave a precipitate, which was filtered off and washed with hexane
to afford 10b as a purple solid (0.16 g, 70%); mp 146–148 °C.
MS (EI): m/z (%) = 343 [M+(79Br), 13.2), 92 (100).
IR (KBr): 1720 cm–1 (C=O).
HRMS: m/z calcd for C17H1479BrNO2, 343.02079; found,
343.02079.
1H NMR (400 MHz, CDCl3): = 3.96 (3 H, s, OCH3), 4.55 (2 H, s,
CH2Cl), 7.10 (2 H, d, J = 8.0 Hz, Ar-H), 7.23 (1 H, t, J = 8.0 Hz, Ar-
H), 7.86 (1 H, s, 4-H).
13C NMR (100 MHz, CDCl3): = 41.0 (CH2), 56.3 (OCH3), 113.8,
119.4, 119.43, 124.6, 125.2, 141.2, 143.2, 147.2 (C=C, Ar-C), 159.6
(C=O).
Acknowledgement
The authors thank the National Research Foundation and Rhodes
University for generous financial support.
MS (EI): m/z (%) = 224 (M+), 75.9], 189 (100).
HRMS: m/z calcd for C11H935ClO3, 224.02402; found, 224.02470.
References
(1) Murray, R. D. H. In Progress in the Chemistry of Natural
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(2) (a) Periers, A.-M.; Laurin, P.; Benedetti, Y.; Lachaud, S.;
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G.; Musicki, B. Tetrahedron Lett. 2000, 41, 867.
(b) Peixoto, C.; Laurin, P.; Klich, M.; Dupuis-Hamelin, C.;
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(3) (a) Hermodson, M. A.; Barker, W. M.; Link, K. P. J. Med.
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1994, 4, 1961.
3-(2-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methylenepro-
panenitrile (14b)
A mixture of 4b (1.21 g, 5.0 mmol), acrylonitrile 13 (1.72 mL, 26.3
mmol) and DABCO (294 mg, 2.63 mmol) in CDCl3 (0.25 mL) was
stirred in a stoppered reaction flask for 21 d. The mixture was con-
centrated in vacuo to give a dark brown oil (1.67 g), which was
chromatographed [flash chromatography on silica gel; elution with
hexane–EtOAc (3:1)] to afford 14b (0.90 g, 61%) as a pale yellow
oil.
IR (KBr): 3432 (OH), 2227 cm–1 (C N).
1H NMR (400 MHz, CDCl3): = 2.76 (1 H, d, J = 5.6 Hz, OH), 3.90
(3 H, s, OCH3), 5.06, 5.14 (2 H, 2 d, J = 11.2 Hz, OCH2Ph), 5.43 (1
H, d, J = 5.6 Hz, CHOH), 5.89, 5.92 (2 H, 2 d, J = 1.4 Hz, C=CH2),
6.93–7.42 (8 H, series of overlapping signals, Ar-H).
13C NMR (100 MHz, CDCl3): = 55.8 (OCH3), 69.6 (CHOH) 74.9
(OCH2Ph), 128.9 (C=CH2), 113.0, 117.1, 119.4, 124.6, 125.8,
128.2, 128.3, 128.5, 133.0, 137.2, 145.2 (C=CH2 and Ar-C), 152.5
(C N).
(5) Zhao, H.; Neamati, N.; Hong, H.; Mazumder, A.; Wang, S.;
Sunder, S.; Milne, G. W. A.; Pommier, Y.; Burke, T. R. Jr.
J. Med. Chem. 1997, 40, 242.
(6) Hariprasad, V.; Talele, T. T.; Kulkarni, V. M. Pharm.
Pharmacol. Commun. 1998, 4, 365.
MS (EI): m/z (%) = 295 (M+, 35.2), 187 (100).
(7) John, E. V. O.; Israelstam, S. S. J. Org. Chem. 1961, 26, 240.
(8) Panetta, J. A.; Rapoport, H. J. Org. Chem. 1982, 47, 946.
(9) Mali, R. S.; Yadav, V. J. Synthesis 1977, 464.
(10) Hepworth, J. D. In Comprehensive Heterocyclic Chemistry,
Vol. 3; Boulton, A. J.; McKillop, A., Eds.; Pergamon:
Oxford, 1984, 881.
HRMS: m/z calcd for C18H17NO3, 295.12084; found, 295.12122.
3-(2-Benzyloxy-3-chlorophenyl)-3-hydroxy-2-methylenepro-
panenitrile (14d)
Pale-yellow oil; yield: 0.82 g (55%).
IR (KBr): 3397 (OH), 2227 cm–1 (C N).
(11) Bogdal, D. J. Chem. Res., Synop 1998, 468.
Synthesis 2002, No. 18, 2701–2706 ISSN 0039-7881 © Thieme Stuttgart · New York

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(12) Fall, Y.; Teran, C.; Teijeira, M.; Santana, L.; Uriarte, E.
Synthesis 2000, 643.
(13) Bode, M. L.; Kaye, P. T. J. Chem Soc., Perkin Trans 1 1990,
2612.
(14) Familoni, O. B.; Kaye, P. T.; Klaas, P. J. Chem. Commun.
1998, 2563.
(15) Kaye, P. T.; Nocanda, X. W. Synthesis 2001, 2389.
(16) Kaye, P. T.; Robinson, R. S. Synth. Commun. 1996, 26,
2085.
(18) (a) Kaye, P. T.; Nocanda, X. W. J. Chem. Soc.,
Perkin.Trans. 1 2000, 1331. (b) Kaye, P. T.; Nocanda, X.
W. J. Chem. Soc., Perkin.Trans. 1 2002, 1318.
(19) Kaye, P.T.; Musa, M.A. Synth. Commun., in press (SC-
2002-051).
(20) Drewes, S. E.; Njamela, O. L.; Emslie, N. D.; Ramesar, N.;
Field, J. S. Synth. Commun. 1993, 23, 2807.
(21) Athough an allylic displacement (SN ) pathway cannot be
excluded, there are some precedents for the addition-
elimination sequence outlined in Scheme 2. See Ref.15 for
further comment.
(17) (a) Bacsa, J.; Kaye, P. T.; Robinson, R. S. S. Afr. J. Chem.
1998, 51, 47. (b) Bode, M. L.; English, R. B.; Kaye, P. T. S.
Afr. J. Chem. 1992, 45, 25.
Synthesis 2002, No. 18, 2701–2706 ISSN 0039-7881 © Thieme Stuttgart · New York