A novel synthesis of 2,3-disubstituted benzopyran-4-ones and application to the solid phase

Article abstract of DOI:10.1016/S0040-4020(99)01045-5

The development of a novel synthesis of 2,3-disubstituted benzopyran-4- ones and application to the solid phase are reported. Following model studies using benzyl alcohol as a surrogate for polystyrene hydroxymethyl resin, we utilized our previously established traceless diisopropylsilyloxy tinker methodology to synthesize a small library of target benzopyranones in generally high yield and purity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01045-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 515–519
A Novel Synthesis of 2,3-Disubstituted Benzopyran-4-ones and
Application to the Solid Phase
†
*
Lalgudi S. Harikrishnan and H. D. Hollis Showalter
Chemistry Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105, USA
Received 12 October 1999; revised 30 November 1999; accepted 1 December 1999
Abstract—The development of a novel synthesis of 2,3-disubstituted benzopyran-4-ones and application to the solid phase are reported.
Following model studies using benzyl alcohol as a surrogate for polystyrene hydroxymethyl resin, we utilized our previously established
traceless diisopropylsilyloxy linker methodology to synthesize a small library of target benzopyranones in generally high yield and purity.
᭧ 2000 Elsevier Science Ltd. All rights reserved.
Substituted benzopyranones encompass an important class
of pharmacophores that possess a wide range of interesting
biological activities.1 Although there are several publica-
tions on the synthesis of 2,3-disubstituted benzopyran-4-
ones in the solution phase,2 there have been no reports on
their synthesis on the solid phase apart from the synthesis
of large libraries of the related dihydrobenzopyran
template.3 Thus, our objective was to develop solution-
phase methodology that would be readily amenable to
solid-phase application.
linker4a that is closely related to earlier reported silicon
linker methodologies.4a–d
Classically, 2,3-disubstituted benzopyranones 1 are synthe-
sized by intramolecular condensation of compound 2,2e
which is usually obtained by Baker–Venkataraman
rearrangement of compound 3 or via Claisen ester conden-
sation (Scheme 1). Most approaches require harsh acidic
conditions for the final condensation step. In our initial
work, we carried out model studies to access solid-
supported benzopyranone 4 utilizing similar chemistry to
build up the pyranone ring. Since our diisopropylsilyloxy
linker is sensitive to acidic conditions, we resorted to the
In doing so, we wished also to demonstrate a broader utility
of our previously established traceless diisopropylsilyloxy
Scheme 1.
Keywords: benzopyran-4-ones; solid-phase synthesis; traceless linker.
* Corresponding author. E-mail: hollis.showalter@wl.com
†
Present address: Albany Molecular Research, Inc., 21 Corporate Circle, Albany, NY 12203, USA.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01045-5

516
L. S. Harikrishnan, H. D. H. Showalter / Tetrahedron 56 (2000) 515–519
Scheme 2. Reagents and conditions: (i) BnMgCl, THF, 4 h; (ii) Swern; iii) IBX, DMSO/THF; (iv) 6% TFA, DCM, 0ЊC; (v) 4% TFA, DCM, 0ЊC; (vi) N,N-
dimethylacetamide dimethyl acetal, THF, 40ЊC, 6 h; (vii) 0.01 M TBAF, THF, 1 h; (viii) saturated CsF, DMF, 60ЊC, 16 h or 0.2 M TBAF, THF/DMF (1:4),
45ЊC, 30 min.
relatively less common condensation under basic conditions
(typically piperidine in refluxing pyridine for several hours).
Preliminary work showed that these conditions on poly-
styrene support led to poor swelling properties and gave
products of low purity. We therefore set as our goal to
develop a short, high yielding synthesis that would avoid
some of the extreme conditions previously utilized, and
furthermore would be amenable to solid-phase combinatorial
library generation.
reagents that were not commercially available were synthe-
sized by reacting magnesium anthracene with substituted
benzyl halides in THF.5 The benzylic alcohol was oxidized
with IBX6 (1-hydroxy-1,2-benziodoxol-3(1H)-one) in
DMSO/THF to the corresponding ketone 7b, which was
then treated with 4% TFA in dichloromethane to selectively
remove the MOM group in the presence of the silyloxy
linker. The resin-bound silicon–oxygen bond in MOM
ether 7b was considerably more sensitive to TFA than the
corresponding solution-phase analog 7a. The phenol 8b was
treated with the amide acetal in THF to give the resin-bound
benzopyranone 9b. For library synthesis, amide acetals
that were not commercially available were synthesized by
Retrosynthetically, 2,3-disubstituted benzopyran-4-ones 1
can be thought of as being derived from salicyl aldehydes
5 (Scheme 1). The R1 substituents can be introduced by
various organometallic reagents, and the R2 substituents
should be derivable from orthoesters or amide acetals.
Table 1. (yields based on starting hydroxymethyl polystyrene; purity based
on HPLC after filtration through alumina)
To determine the feasibility of this strategy for solid-phase
synthesis, we first carried out solution model studies in
which benzyl alcohol was used as a surrogate for hydroxy-
methyl polystyrene resin. Our initial target was 11 with
R1ˆPh and R2ˆMe (Scheme 2). Addition of benzylmagne-
sium chloride to the aldehyde 6a4a followed by Swern
oxidation gave the ketone 7a. Removal of the MOM
protecting group in the presence of the silyloxy linker was
accomplished by treatment of 7a with 6% TFA in dichloro-
methane at 0ЊC. Reaction of the resulting phenol 8a with
trimethylorthoformate or N,N-dimethylformamide dimethyl
acetal yielded the benzopyranone 9a. Selective cleavage of
the silicon–oxygen bond (to get the silanol 10) or the
silicon–carbon bond (to obtain the benzopyranone 11)
was achieved by fluoride ion under appropriate reaction
conditions.
The solution-phase conditions were then applied to the
solid-phase (Scheme 2). Encapsulation of the resin-bound
௣
aldehyde 6b4a in IRORI MacroKan reactors, followed by
treatment with the benzyl Grignard reagent gave the corre-
sponding alcohol. For library synthesis, the Grignard

L. S. Harikrishnan, H. D. H. Showalter / Tetrahedron 56 (2000) 515–519
517
treatment of N,N-dimethyl amides with trimethyloxonium
tetrafluoroborate followed by sodium methoxide.7 Treat-
ment of resin 9b with CsF or 0.2 M TBAF in DMF gave
the target benzopyranone 11, whereas 0.01 M tetrabutyl-
ammonium fluoride in THF yielded the silanol 10. The
resin reactions were followed by TLC and mass
spectrometry on the silanols obtained by treatment of a
small portion of the resin-bound intermediates with 1.0 M
tetrabutylammonium fluoride in THF. One set of resin-
bound compounds 6b–9b was characterized by gel-phase
13C NMR spectroscopy. Library benzopyranones were
was gradually warmed to 25ЊC and stirred for 4 h. The
mixture was carefully quenched with H2O and extracted
with ether. The ether phase was washed with H2O (2×)
and then with brine, dried and concentrated to give
crude alcohol intermediate as a pale yellow gum. Purifica-
tion by column chromatography (20:1 to 10:1 hexanes/
EtOAc) gave 1-[5-[bis(1-methylethyl)(phenylmethoxy)-
silyl]-2-(methoxymethoxy)phenyl]-2-phenylethanol
1
(4.04 g, 82%) as a colorless viscous liquid. H NMR d
7.47–7.35 (m, 6H), 7.29–7.11 (m, 7H), 5.24–5.14 (m,
3H), 4.86 (s, 2H), 3.51 (s, 3H), 3.14 (dd, Jˆ13.4, 5.4 Hz,
1H), 3.02 (dd, Jˆ13.4, 5.8 Hz, 1H), 2.53 (d, Jˆ5.6 Hz, 1H),
1.32 (m, 2H), 1.09 (d, Jˆ7.3 Hz, 6H), 1.03 (m, 6H); 13C
NMR: d 155.3, 141.4, 138.5, 135.3, 133.5, 131.3, 129.5,
128.3, 128.2, 126.9, 126.5, 126.3, 125.9, 113.1, 94.3, 71.8,
65.4, 56.3, 44.3, 17.7, 17.6, 17.4, 12.3. A solution of DMSO
(1.42 mL, 20.05 mmol) in DCM (10 mL) was added drop-
wise to a solution oxalyl chloride (2.0 M in DCM, 5.01 mL,
10.03 mmol) precooled to Ϫ78ЊC. The mixture was stirred
for 2 min at Ϫ78ЊC and then treated by slow addition of a
solution of the above alcohol (4.0 g, 8.35 mmol) in 50 mL
DCM. The mixture was stirred for 15 min at Ϫ78ЊC, treated
with triethylamine (5.8 mL, 41.78 mmol) and allowed to
gradually warm to 25ЊC. The mixture was diluted with
DCM (200 mL) and washed with H2O ꢀ3×100 mL†
followed by saturated aqueous NH4Cl ꢀ1×100 mL†: The
organic layer was dried and concentrated to leave a residue
that was chromatographed (20:1 hexanes/EtOAc) to give 7a
1
characterized by H and 13C NMR spectroscopy, chemical
ionization mass spectrometry and HPLC. A representative
array is shown in Table 1.
In summary we have designed a short, efficient synthesis of
2,3-disubstituted benzopyran-4-ones and have applied this
to the solid phase. We have also demonstrated further
versatility of our previously reported solid-supported
diisopropylsilyloxy traceless linker. We are extending this
methodology to the synthesis of other fused heterocyclic
templates, and will report on this work in future disclosures.
Experimental
Materials and methods
1
(3.6 g, 90%) as a colorless viscous liquid. H NMR d 7.82
Standard reagents were obtained from commercial suppliers
and used without further purification. Column chromato-
graphy was carried out using E. Merck 60 (230–400
mesh) silica gel. Thin layer chromatography was performed
(d, Jˆ1.4 Hz, 1H), 7.65 (dd, Jˆ8.4, 1.5 Hz, 1H), 7.41–7.19
(m, 12H), 5.29 (s, 2H), 4.88 (s, 2H), 4.30 (s, 2H), 3.50 (s,
3H), 1.35 (sep, Jˆ7.5 Hz, 2H), 1.09 (d, Jˆ7.3 Hz, 6H), 1.03
(d, Jˆ7.5 Hz, 6H); 13C NMR d 200.5, 156.9, 141.1, 139.8,
136.6, 135.1, 129.7, 128.5, 128.4, 128.3, 127.0, 126.9,
126.7, 125.9, 114.1, 94.3, 65.5, 56.6, 50.2, 17.5, 17.4,
12.2; CIMS m/z: 477 (MHϩ, 39%); HRMS m/z calcd:
477.2461(MHϩ), found: 477.2466.
using Merck 60 F254 0.25 mm silica gel plates. H and 13C
1
NMR spectra were obtained on a Varian Unity 400 MHz
spectrometer at 400 and 101 MHz, respectively. Spectra
were obtained in CDCl3 with TMS as the internal standard
and are reported in ppm. Chemical ionization mass spectra
(CIMS) were recorded on a Fisons Trio 2A instrument with
1% ammonia in methane as the reagent gas. Atmospheric
pressure chemical ionization mass spectra (APCIMS) were
recorded using a VG Trio 2000 mass spectrometer in a
matrix of MeOH/CH3CN/DMSO. Following normal
work-up procedures, organic extracts were dried over
anhydrous Na2SO4 prior to concentration. A single lot of
hydroxymethyl polystyrene resin (Bachem California,
Catalog #D-2105, Lot #ZN996, 1% cross-linked, 100–200
mesh) was used for all solid-phase synthesis. Library synth-
1-[5-[Bis(1-methylethyl)(phenylmethoxy)silyl]-2-
(hydroxy)phenyl]-2-phenylethanone (8a). To a vigorously
stirred solution of 7a (1.0 g, 2.1 mmol) in DCM (15 mL) at
0ЊC was added TFA (0.75 mL, 9.7 mmol). The mixture was
stirred at 0ЊC for 1 h, diluted with DCM, and washed with
H2O (3×) and then brine. The organic phase was dried and
concentrated to an oil that was chromatographed (40:1
hexanes/EtOAc) to give 8a (0.85 g, 94%) as a pale brown
1
liquid. H NMR d 12.32 (s, 1H), 8.02 (d, Jˆ1.4 Hz, 1H),
௣
7.61 (dd, Jˆ8.2, 1.4 Hz, 1H), 7.44–7.15 (m, 11H), 6.99 (d,
Jˆ8.4 Hz, 1H), 4.89 (s, 2H), 4.08 (s, 2H), 1.33 (sep,
Jˆ7.5 Hz, 2H), 1.09 (d, Jˆ7.5 Hz, 6H), 1.02 (d,
Jˆ7.5 Hz, 6H); 13C NMR d 204.4, 163.9, 142.3, 141.1,
137.7, 134.0, 129.3, 128.7, 128.4, 127.2, 127.1, 125.9,
123.5, 118.9, 118.2, 65.5, 45.3, 17.5, 17.3, 12.1; CIMS
m/z: 433 (MHϩ, 100%).
esis was carried out in IRORI MacroKans . Abbreviations
used: TFAˆtrifluoroacetic acid; TBAFˆ tetrabutyl-
ammonium fluoride; DCMˆdichloromethane.
5-[Bis(1-methylethyl)(phenylmethoxy)silyl]-2-(methoxy-
methoxy)benzaldehyde (6a). Aldehyde 6a was synthesized
according to the procedure reported earlier by our group4a
and recrystallized from hexanes to give a colorless crystal-
line solid. mp 52.5–53.0ЊC; HRMS m/z calcd: 387.1991
(MHϩ), found: 387.1996.
6-[Bis(1-methylethyl)(phenylmethoxy)silyl]-2-methyl-3-
phenyl-4H-1-benzopyran-4-one (9a). To a solution of 8a
(0.08 g, 0.18 mmol) in THF (5.0 mL) was added N,N-
dimethylacetamide dimethyl acetal (0.25 mL, 1.5 mmol)
and the mixture was stirred at 40ЊC for 6 h. After cooling,
the mixture was diluted with ether, washed with H2O and
then saturated aqueous ammonium chloride. The organic
phase was dried and concentrated to a residue that was
1-[5-[Bis(1-methylethyl)(phenylmethoxy)silyl]-2-
(methoxymethoxy)phenyl]-2-phenylethanone (7a). To a
solution of benzylmagnesium chloride (2.0 M in THF,
10.3 mL, 20.6 mmol) at 0ЊC was added a solution of alde-
hyde 6a4a (4.0 g, 10.3 mmol) in THF (20 mL). The mixture

518
L. S. Harikrishnan, H. D. H. Showalter / Tetrahedron 56 (2000) 515–519
chromatographed (20:1 to 10:1 hexanes/EtOAc) to provide
9a (0.072 g, 85%) as a colorless gum. H NMR d 8.47 (d,
disappeared, indicating the complete consumption of
starting alcohol. 13C NMR d 94.4, 65.5, 56.5, 50.3, 17.5,
12.2.
1
Jˆ1.4 Hz, 1H), 7.88 (dd, Jˆ8.2, 1.4 Hz, 1H), 7.46–7.26 (m,
11H), 4.93 (s, 2H), 2.33 (s, 3H), 1.42 (sep, Jˆ7.5 Hz, 2H),
1.11 (d, Jˆ7.5 Hz, 6H), 1.05 (d, Jˆ7.5 Hz, 6H); 13C NMR d
176.8, 163.2, 156.9, 140.9, 139.3, 133.2, 132.9, 131.2,
130.4, 128.4, 128.3, 127.8, 127.1, 126.0, 124.1, 122.8,
117.0, 65.6, 19.6, 17.5, 17.3, 12.2; CIMS m/z 457 (MHϩ,
100%).
1-[5-[Bis(1-methylethyl)(polystyrylmethoxy)silyl]-2-
(hydroxy)phenyl]-2-phenylethanone (8b). To a vigor-
ously stirred suspension of resin-bound ketone 7b
ꢀ3×0:264 g† in DCM (50 mL) at 0ЊC was gradually added
TFA (2.0 mL) along the inner walls of the flask. The
mixture was stirred at 0ЊC for 1 h. The solution was
decanted and the resin was washed successively with
DCM ꢀ3×50 mL† and THF ꢀ3×50 mL†: The resin was
dried under vacuum at 25ЊC overnight to give 8b
(0.254 g/can). 13C NMR d 209.5, 164.0, 145.7, 142.4,
137.7, 134.1, 128.1, 118.3, 65.5, 45.4, 17.5, 12.2.
6-[Hydroxybis(1-methylethyl)silyl]-2-methyl-3-phenyl-
4H-1-benzopyran-4-one (10). To a solution of benzo-
pyranone 9a (46 mg, 0.1 mmol) in THF (15 mL) was
added TBAF (1.0 M solution in THF, 0.15 mL,
0.15 mmol), and the mixture was stirred for 1 h at 25ЊC.
The mixture was diluted with H2O, and extracted with
ether. The combined ether layers were dried, filtered
through a plug of silica gel and concentrated to give silanol
10 (32 mg, 89%) as a colorless oil. CIMS m/z (rel int) 367
(MHϩ, 100%).
6-[Bis(1-methylethyl)(polystyrylmethoxy)silyl]-2-
methyl-3-phenyl-4H-1-benzopyran-4-one (9b). To a sus-
pension of resin-bound phenol 8b ꢀ2 × 0:254 g† in THF
(10 mL) was added N,N-dimethylacetamide dimethyl acetal
(0.5 mL, 3.0 mmol). The mixture was heated at 40ЊC for
6 h. The mixture was cooled and the resin was washed
with THF ꢀ6×30 mL† and then dried under vacuum at
25ЊC overnight to give 9b (0.256 g/can). 13C NMR d 65.3,
19.6, 17.5, 12.3.
2-Methyl-3-phenyl-4H-1-benzopyran-4-one8 (11; A2 of
Table 1). To a solution of 9a (0.05 g, 0.11 mmol) in DMF
(1 mL) was added TBAF (0.25 mL, 1.0 M solution in THF,
0.25 mmol) and the mixture was stirred at 45ЊC for 0.5 h.
The mixture was cooled, diluted with H2O, and extracted
with ether (2×). The combined ether layers were washed
with H2O, brine, and dried. Concentration provided a resi-
due that was chromatographed (20:1 to 10:1 hexanes/
EtOAc) to obtain 11 (0.02 g, 84%) as a colorless solid.
2-Methyl-3-phenyl-4H-1-benzopyran-4-one (11; A2 of
Table 1) by cleavage of resin-bound 9b. To a suspension
of 9b (0.256 g) in DMF (8.0 mL) was added TBAF (1.0 M
solution in THF, 2.0 mL). The mixture was stirred at 45ЊC
for 30 min, cooled to 25ЊC, diluted with H2O, and extracted
with ether. The combined ether layers were washed with
H2O (3×) and brine, dried, and evaporated to a concentrated
solution that was filtered through a plug of alumina to give
11 (26 mg, 65% overall yield from 6b). The spectral data
were identical to those given above.
1
mp 138.0–138.5ЊC; H NMR d 8.20 (d, Jˆ7.8 Hz, 1H),
7.62 (t, Jˆ8.0 Hz, 1H), 7.42–7.22 (m, 7H), 2.29 (s, 3H);
13C NMR d 176.8, 163.2, 155.9, 133.3, 133.1, 130.4, 128.4,
127.7, 126.3, 124.8, 123.7, 123.5, 117.6, 19.5; CIMS m/z
(rel int) 237 (MHϩ, 100); HRMS m/z calcd: 237.0915
(MHϩ), found: 237.0915.
1-[5-[Bis(1-methylethyl)(polystyrylmethoxy)silyl]-2-
(methoxymethoxy)phenyl]-2-phenylethanone (7b). To
resin-bound aldehyde 6b4a (0.7 mmol/g) in five Macro-
Kans ꢀ5×0:250 g† was added anhydrous THF (50 mL).
General procedure for preparation of a library of benzo-
pyranones (Table 1). IRORI MacroKans௣ were marked by
hand (using a needle) with a unique alphanumeric code, and
then loaded with resin-bound aldehyde 6b4a (0.15 g/can).
The cans were subjected to the same sequence of reactions
as described in Scheme 2.
௣
The suspension was stirred under N2 for 5 min and then
the THF was decanted. To the resin was added anhydrous
THF (50 mL) followed by benzylmagnesium chloride
(2.0 M in THF, 2.5 mL, 5.0 mmol) providing ϳ0.1 M final
concentration. The mixture was stirred vigorously for
15 min, and the THF solution was decanted. This cycle of
Grignard reagent treatment was repeated and the resulting
yellow colored resin was quenched with H2O and then
washed successively with saturated aqueous ammonium
chloride ꢀ3×50 mL†; H2O ꢀ4×50 mL†; isopropanol
ꢀ3×50 mL† and THF ꢀ3×50 mL† to leave an off-white
resin. The resin was dried under vacuum at 25ЊC overnight
to give the intermediate resin-bound alcohol (0.264 g/can).
13C NMR d 155.2, 94.2, 71.8, 65.4, 56.3, 44.3, 17.5, 12.2.
To a suspension of the resin-bound alcohol ꢀ4×0:264 g† in
THF (25 mL) was added a solution of IBX (2.0 g, 7.1 mmol)
in DMSO (25 mL). The mixture was stirred for 1 h at 25ЊC.
The solution was decanted and the treatment was repeated.
The resin was washed successively with DMSO ꢀ3×50 mL†;
THF ꢀ3×50 mL† and DCM ꢀ3×50 mL†; and then dried under
vacuum at 25ЊC overnight to give 7b (0.264 g/can). The
13C NMR absorption of the starting material at d 71.8
General procedure for cleavage of resin-bound benzo-
pyranones with CsF. The MacroKans௣ containing the
resin-bound benzopyranones were placed in vials and to
each of these was added a saturated solution of CsF in
anhydrous DMF (10 mL). The vials were capped and heated
at 60ЊC on a shaker at 150 rpm for 16 h. The vials were
cooled to 25ЊC, diluted with H2O (20 mL) and extracted
into ether (20 mL). (Alternatively, the DMF can be evapo-
rated over a stream of N2 overnight, and the residue taken up
in ether.) The ether layer was washed with H2O (2×), brine,
and dried. The ether layer was filtered through a short plug
of alumina to give the benzopyranones in the yields and
purity shown in Table 1.
Analytical data
3-Phenyl-4H-1-benzopyran-4-one8,9(A1). 1H NMR d 8.29
(dd, Jˆ8.1, 0.7 Hz, 1H), 7.99 (s, 1H), 7.66 (t, Jˆ7.0 Hz,
1H), 7.55–7.34 (m, 7H); 13C NMR d 176.2, 156.2, 153.0,

L. S. Harikrishnan, H. D. H. Showalter / Tetrahedron 56 (2000) 515–519
519
133.6, 131.8, 128.9, 128.5, 128.2, 126.4, 125.4, 125.2,
References
124.6, 118.0; CIMS m/z (rel int) 223 (MHϩ, 100).
1. (a) Testa, R.; Taddei, C.; Poggesi, E.; Destefani, C.; Cotecchia,
S.; Hieble, J. P.; Sulpizio, A. C.; Naselsky, D.; Bergsma, D.; Ellis,
C.; Swift, A.; Ganguly, S.; Ruffolo, R. R.; Leonardi, A. Pharmacol.
Commun. 1995, 6, 79. (b) Testa, R.; Sironi, G.; Colombo, D.;
Greto, L.; Leonardi, A. Neuriurol. Urodyn. 1994, 13, 471. (c)
Wu, E. S. C.; Loch, J. T.; Toder, B. H.; Borrelli, A. R.; Gawlak,
D.; Radov, L. A.; Gensmantel, N. P. J. Med. Chem. 1992, 35, 3519.
(d) Peterson, G.; Barnes, S. Biochem. Biophys. Res. Commun.
1991, 179, 661. (e) Achaiah, G.; Reddy, V. M. Indian J. Pharm.
Sci. 1991, 53, 253. (f) Ellis, G. P.; Baker, G. Prog. Med. Chem.
1973, 9, 65.
2. (a) Bhat, A. S.; Whetsone, J. L.; Brueggemeier, R. W. Tetra-
hedron Lett. 1999, 40, 2469. (b) Dixon, R. A.; Howles, P. A.;
Lamb, C.; He, X.; Thirupathi, J. Adv. Exp. Med. Biol. 1998, 439,
55. (c) Boland, G. M.; Donnelly, D. M. X. Ire. Nat. Prod. Rep.
1998, 15, 241. (d) Hepworth; J. D. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 3, p 737. (e) Ellis, G. P. The Chemistry of Heterocyclic
Compounds. In Chromenes, Chromanones, and Chromones; Ellis,
G. P., Ed.; Interscience: USA, 1977; Vol. 33, pp 495–555.
3. (a) Burbaum, J. J.; Ohlmeyer, M. H. J.; Reader, J. C.; Hender-
son, I.; Dillard, L. W.; Li, G.; Randle, T. L.; Sigal, N. H.; Chelsky,
D.; Baldwin, J. J. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6027. (b)
Breitenbucher, J. G.; Hui, H. C. Tetrahedron Lett. 1998, 39, 8207.
4. (a) Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996, 61,
6498. (b) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60,
6006. (c) Finkelstein, J. A.; Chenera, B.; Veber, D. F. J. Am. Chem.
Soc. 1995, 117, 11999. (d) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703.
3-(4-Methoxyphenyl)-4H-1-benzopyran-4-one8,9 (B1). 1H
NMR d 8.28 (d, Jˆ8.0 Hz, 1H), 7.96 (s, 1H), 7.63 (dt,
Jˆ8.5, 1.2 Hz, 1H), 7.49–7.37 (m, 3H), 6.94 (d,
Jˆ8.7 Hz, 2H), 3.81 (s, 3H); 13C NMR d 176.4, 159.6,
156.2, 152.4, 133.5, 130.1, 126.4, 125.1, 125.0, 124.5,
124.1, 118.0, 114.0, 55.3; CIMS m/z (rel int) 253 (MHϩ,
100).
3-(4-Chlorophenyl)-4H-1-benzopyran-4-one9 (C1). 1H
NMR d 8.23 (d, Jˆ8.1 Hz, 1H), 7.95 (s, 1H), 7.63 (t,
Jˆ7.3 Hz, 1H), 7.51–7.33 (m, 6H); 13C NMR d 175.9,
156.2, 153.0, 134.2, 133.8, 130.3, 130.2, 128.7, 126.4,
125.4, 124.5, 124.3, 118.1; CIMS m/z (rel int) 257 (MHϩ,
100).
3-(4-Methoxyphenyl)-2-methyl-4H-1-benzopyran-4-one
1
(B2). H NMR d 8.19 (dd, Jˆ7.8, 1.2 Hz, 1H), 7.61 (dt,
Jˆ7.3, 1.7 Hz, 1H), 7.45–7.32 (m, 2H), 7.18 (d,
Jˆ8.8 Hz, 2H), 6.94 (d, Jˆ8.8 Hz, 2H); 13C NMR d
176.9, 159.1, 135.5, 133.2, 131.5, 126.3, 124.7, 117.6,
115.5, 113.9, 55.3, 19.5; CIMS m/z (rel int) 267 (MHϩ,
100).
3-(4-Chlorophenyl)-2-methyl-4H-1-benzopyran-4-one
1
(C2). H NMR d 8.18 (dd, Jˆ8.1, 1.2 Hz, 1H), 7.63 (m,
1H), 7.42–7.33 (m, 4H), 7.22–7.19 (m, 2H), 2.29 (s, 3H);
13C NMR d 176.5, 167.3, 156.0, 133.3, 133.1, 130.3, 128.4,
127.7, 126.3, 124.8, 123.2, 123.1, 117.6, 26.2; CIMS m/z
(rel int) 271 (MHϩ, 100).
5. (a) Raston, C. L.; Salem, G. J. Chem. Soc., Chem. Commun.
1984, 1702. (b) Engelhardt, L. M.; Papasergio, R. I.; Raston, C. L.;
Salem, G.; White, A. H. J. Chem. Soc., Dalton Trans. 1986, 789.
6. Caution! IBX has been reported to detonate upon heavy impact
and heating over 200ЊC. In our hands some batches of IBX
exploded at its melting point, while most other batches
decomposed with browning: (a) Frigerio, M.; Santagostino, M.
Tetrahedron Lett. 1994, 35, 8019. (b) Frigerio, M.; Santagostino,
M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60, 7272.
7. Bredereck, H.; Kantlehner, W.; Schweizer, D. Chem. Ber. 1971,
104, 3475.
3-(4-Chlorophenyl)-2-ethyl-4H-1-benzopyran-4-one
(C3). 1H NMR d 8.19 (d, Jˆ8.1 Hz, 1H), 7.64 (t, Jˆ8.3 Hz,
1H), 7.44–7.34 (m, 4H), 7.22–7.17 (m, 2H), 2.55 (q,
Jˆ7.6 Hz, 2H), 1.23 (t, Jˆ7.6 Hz, 3H); 13C NMR d 176.8,
167.4, 156.0, 133.8, 133.5, 131.7, 131.5, 128.7, 126.2,
124.9, 123.3, 117.7, 26.1, 11.9; CIMS m/z (rel int) 285
(MHϩ, 100).
Acknowledgements
8. Levai, A.; Sebok, P. Synth. Commun. 1992, 22, 1735.
9. Khanna, M. S.; Singh, O. V.; Garg, C. P.; Kapoor, R. P. J. Chem.
Soc., Perkin Trans. 1 1992, 19, 2565.
We thank Prof. A. G. M. Barrett, Dr Gary Bolton and Mr
Mark Barvian for their suggestions. We thank Mr Allen
Howard for determining the purity of the combinatorial
library. We are grateful to many other colleagues for their
technical assistance.