Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-diaryloxazoles

Article abstract of DOI:10.1021/acs.joc.6b01280

2-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The corresponding α-sulfonyl anion reacts smoothly with diverse alkyl halides giving monoalkylated (47-90%), dialkylated (50-97%), and cyclic (59-93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products in the range of 66-97%. The anti-inflammatory Oxaprozin was prepared using the α-sulfonyl carbanion strategy along with optimized desulfonylation.

Full text of DOI:10.1021/acs.joc.6b01280

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Note
Synthesis of Extended Oxazoles III: Reactions
of 2-(Phenylsulfonyl)methyl-4,5-Diaryloxazoles
Pravin Chaitram Patil, and Frederick Anthony Luzzio
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01280 • Publication Date (Web): 21 Jul 2016
Downloaded from http://pubs.acs.org on July 21, 2016
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Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-
4,5-Diaryloxazoles
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Pravin C. Patil and Frederick A. Luzzio*ꢀ
Department of Chemistry, University of Louisville, 2320South Brook Street, Louisville, Kentucky 40292
Faluzz01@louisville.edu
*Corresponding Author
ꢀISHC Member
Email: faluzz01@louisville.edu
Phone: 502ꢁ852ꢁ7323
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Abstract
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2ꢁ((Phenylsulfonyl)methyl)ꢁ4,5ꢁdiphenyloxazole is a useful scaffold for synthetic elaboration at the 2ꢁ
methylene position thereby affording extended oxazoles. The corresponding αꢁsulfonyl anion reacts
smoothly with diverse alkyl halides giving monoalkylated (47ꢁ90%), dialkylated (50ꢁ97%) and cyclic
(59ꢁ93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products
was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products
in the range of 66ꢁ97%. The antiꢁinflammatory Oxaprozin was prepared using the α–sulfonyl carbanion
strategy along with optimized desulfonylation.
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The utilization of α–sulfonyl carbanions in carbonꢁcarbon bond forming strategy takes
advantage of mild reaction conditions and is applicable to the synthetic elaboration of many
types of preꢁformed oxygen and nitrogen heterocycles.1 For example, the Ciufolini group
prepared and utilized a dualꢁfunctionalized 2ꢁ(phenylsulfonylmethyl)ꢁ4,5ꢁdisubstituted oxazole
as a conjunctive intermediate in their synthesis of the siphonazoles.2 3ꢁ(Phenylsulfonylmethyl)
oxindoles, 3ꢁ and 4ꢁ(arylsulfonylꢁmethyl) pyridines, 2ꢁ(arylsulfonylmethyl) quinolines and 2ꢁ
(phenylsulfonylmethyl)pyrimidines have been designed so that the sulfonylꢁactivated methylene
group facilitates the construction of extended or otherwise more elaborate fused heterocycles.3 In
medicinal chemistry, the need for increased structural diversity and large numbers of therapeutic
candidates as potential antiꢁinflammatories has driven the strategy for extension and elaboration
at the 2ꢁposition of 2ꢁsubstitutedꢁ4,5ꢁdiaryloxazoles.4 As functioning units in total synthesis, 2ꢁ
substituted 4,5ꢁdiaryloxazoles carry with them a fullyꢁmasked carboxyl group, thereby allowing
a great range of reactions to be performed on the synthon prior to the release of the carboxylate.5
Hence the strategy whereby the carboxyl group, embedded in 4,5ꢁdiaryloxazole framework and
oxidatively deprotected in later stages, was put to practice by the Evans group in their synthesis
of oasomycin.6 Therefore, the development of carbonꢁcarbon bondꢁforming methods at the 2ꢁ
methylene position of the trisubstituted oxazole would be a complementary strategy to the use of
the heterocycle as a protecting group. Our ongoing work with the use of 2,4,5ꢁtrisubstituted
oxazole scaffolds as “click”7 components of biofilm inhibitors involved the preparation of
several 2ꢁ(azidoalkyl)ꢁ and 2ꢁ(azidoaryl)ꢁsubstituted 4,5ꢁdiaryloxazoles.8 In a previous
communication we described the functionalization of 2ꢁ(halomethyl)ꢁ4,5ꢁdiaryloxazoles using an
array of nitrogen, oxygen and sulfur nucleophiles.8b Our examples included the preparation of 2ꢁ
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(phenylthiomethyl)ꢁ4,5ꢁdiphenyl oxazole 2 from the corresponding 2ꢁ(chloromethyl)ꢁ4,5ꢁ
diphenyloxazole 1 and thiophenol (Fig. 1). Oxidation of 2 with 3ꢁchloroperbenzoic acid
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(MCPBA, 2.5 eq/CH2Cl2/rt) gave the corresponding sulfone 3 (84%) as a crystalline solid. We
note that during the MCPBA oxidation the intermediate sulfoxide could be detected and isolated.
In our initial experiments, deprotonation of 3 with commerciallyꢁavailable potassium tertꢁ
butoxide (1.1 eq) in THF followed by slow addition of iodomethane (1.05 eq, 5°C to rt) gave the
2ꢁ(α–sulfonylethyl)ꢁ4,5ꢁdiphenyloxazole 5 (90%, Table 1). Similarly, the monoalkylated
sulfones 6, 7, 8 and 9 could be prepared in isolated yields ranging from 47 to 76% (Table 1). In
almost all cases, a small amount of dialkylated product was detected by thinꢁlayer
chromatography (TLC) and was easily separable from the monoalkylated product by column
chromatography. Dialkylated products were then targeted which required the employment of 2.5
equivalents of base followed by 2.5 equivalents of alkylating agent (Table 1, Compounds 11-
14). For the examples in which the alicyclic sulfones 15-17 were prepared (Table 1), conditions
similar to the dialkylation experiments were employed. Hence, 2.2 equivalents of base followed
by one equivalent of dihaloalkane was used (See 15, 16 and 17). Interestingly, alkylation of 3
with 1,6ꢁdibromohexane under conditions of dialkylation provided only the bromohexyl
homologue 10 (Table 1) and no sevenꢁmember sulfonyloxazole despite heating over extended
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Table 1. Alkylation of 2ꢁ(Sulfonylmethyl)ꢁ4,5ꢁDiphenyloxazoles1
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7
8
R1
R1
R1
R1
R1
R1
N
O
R
R
R
N
O
N
O
a
SO2Ph
-OR-
SO2Ph
SO2Ph
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11-17
3
5-10
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Monoalkylated Product
Dialkylated Product
R1
N
R1
N
O
SO2Ph
R1
R1
O
SO2Ph
11 (97%)
5 (90%)
R1
R1
R1
R1
N
N
O
SO2Ph
O
SO2Ph
12 (50%)
6 (74%)
R1
R1
N
O
SO2Ph
7 (53%)
R1
R1
R1
R1
N
N
O
SO2Ph
SO2Ph
O
SO2Ph
SO2Ph
8 (76%)
13 (66%)
R1
R1
R1
R1
N
N
O
O
9 (47%)
14 (82%)
R1
R1
R1
R1
N
O
N
O
( )n
Br
SO2Ph
SO2Ph
15, n=1(59%);
16, n=2 (78%);
17, n=3(93%).
10 (53%)
1Reagents/Conditions: (a) KOtꢁBu/THF/5oC to rt; 5, 11/MeI; 6,12/EtI;
7/isoꢁBuI; 8,13/allylꢁBr; 9,14/propargylꢁBr; 10/1,6ꢁdibromohexꢁ
ane; 15/1,3ꢁdiiodopropane; 16/1,4ꢁdibromobutane; 17/1,5ꢁdibromoꢁ
pentane.
reaction periods.
Examination of the reagents and conditions for reductive desulfonylation of many of the
synthetic intermediates and products listed in Table 1 were warranted as well as determination of
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ꢁelimination of the phenylsulfonyl group.9 Such complementary
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the optimal conditions for
β
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transformations involving deletion of the sulfonyl group would broaden the scope and utility of
the heterocyclic sulfone alkylation scheme. While reductive desulfonylation with Raney nickel
precluded its employment with substrates 8, 9, 13, and 14 due to unwanted reduction of
unsaturated sites, we found it ineffective with simple substrates such as sulfonylmethyloxazole 3.
Attempted reductive desulfonylation of 3 with amalgamated active metals such as zinc and
magnesium, including the classical ‘15 second’ amalgamated aluminum foil method of Corey,10
were of no consequence, and led to the recovery of only unreacted substrate. Interestingly, some
definitive changes to the Corey aluminumꢁmediated desulfonylation method, however, did lead
to positive results (Eq. 1).
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The addition of solid mercuric chloride to a mixture of foodꢁgrade aluminum foil and sulfone 3
in methanol was optimal for the conversion of the 2ꢁ(phenylsulfonylmethyl)oxazole 3 to the 2ꢁ
methyloxazole 4 (Eq. 1). The heterogeneous mixture required heating at reflux until the
aluminum metal disappeared and afforded the 2ꢁmethylꢁ4,5ꢁdiphenyloxazole 4 cleanly in 96%
yield after workup and chromatography. In separate experiments, the 2ꢁ(phenylsulfonylꢁ
methyl)oxazole 3 was desulfonylated to provide 4 in 98% isolated yield using magnesium
turnings with solid mercuric chloride in methanol.11 However, the aluminum/HgCl2
desulfonylation was not optimal for unsaturated substrates 8 or 9 (Table 2), so the same
conditions for the magnesiumꢁmediated reductive desulfonylation of 3 were applied to the entire
range of monalkylated and dialkylated sulfone substrates 5-9, 11ꢁ12 and 15-17. The
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desulfonylated products 18ꢁ24 and 25-27 (Table 2) were obtained as pure compounds after
column chromatography on silica gel. The synthetic utility of oxazole sulfone 3 is demonstrated
by our synthesis of the nonꢁsteroidal antiꢁinflammatory Oxaprozin 32 (Scheme 1).12 In contrast
to our earlier communication where we described the preparation of Oxaprozin using the
electrophilic (chloroalkyl)oxazole synthon 1,8a we now employ the readilyꢁprepared and versatile
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nucleophilic scaffold 3. Deprotonation of 3 (5°C/KOtꢁBu/THF) followed by addition of ethyl
bromoacetate (5°C to rt) afforded the
β–sulfonyl ester 28 (72%). Baseꢁmediated (5°C/KOtꢁ
Bu/THF) elimination of the phenylsulfonyl group from 28 provided the α,β–unsaturated ester 29
(65%). Catalytic reduction of the unsaturated ester 29 (H2/10% PdꢁC/MeOH) gave Oxaprozin
ethyl ester 30 (80%). Alternatively, 28 could be reductively desulfonylated (Mg/HgCl2/MeOH)
which gives rise to the methyl ester 31 of oxaprozin through transesterification. Mild hydrolysis
of the ethyl ester group of 30 with dilute aqueous acid then afforded Oxaprozin 32 (68%).
In summary, we have demonstrated the synthetic utility of a basic trisubstituted heterocyclic
scaffold that has potential applications in synthetic and medicinal chemistry. Single and multiple
carbonꢁcarbon bondꢁforming reactions may be executed as well as effective removal of the
activating phenylsulfonyl group within the diaryloxazole scaffold A new synthesis of the
extended oxazole nonꢁsteroidal antiꢁinflammatory compound Oxaprozin was demonstrated and
utilized the sulfonylmethyl synthon 3 which further demonstrated that it is wellꢁsuited for its
application in the preparation of diverse analogues.
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Experimental
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Solvents and reagents are ACS grade and were used as commercially supplied. Analytical thinꢁ
layer chromatography (TLC) utilized 0.25 mm preꢁcut glassꢁbacked plates (Silica Gel 60 F254).
Thinꢁlayer chromatograms were visualized during chromatographic and extraction runs by
rapidly dipping the plates in anisaldehyde/ethanol/sulfuric acid stain or phosphomolybdic
acid/ethanol stain and heating (hot plate). Column chromatography was carried out in gravity
mode using silica gel 60 (70ꢁ230 mesh), and used combinations of hexanes and ethylacetate.
Melting points were determined on a capillary melting point apparatus and are uncorrected.
Reaction mixtures, extracts and chromatographic fractions were concentrated with a standard
rotary evaporator under water aspirator vacuum. Nuclear magnetic resonance (1H and l3C NMR)
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spectra were recorded with 400 MHz (100 MHz, C) or 700 MHz (175 MHz, C) instruments
using CDCl3 as a solvent and TMS as internal standard. Infrared spectra (Fourier Transform
Infrared Spectroscopy, FTIR) were analyzed as films and are reported in wavenumbers (cmꢁ1).
4,5-Diphenyl-2-((phenylsulfonyl)methyl)oxazole (3). To a preꢁchilled solution of 4,5ꢁdiphenylꢁ
2ꢁ((phenylthio)methyl)oxazole 2 (1.0 g, 2.91 mmol) in dichloromethane (40 mL) was added
MCPBA (1.26 g, 7.27 mmol) while stirring. The reaction mixture was stirred at room
temperature (3 h). After completion of the reaction as indicated by TLC, the reaction mixture
was washed with saturated aqueous NaHCO3 (2 X 30 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was submitted to
gravityꢁcolumn chromatography on silica gel (hexane/ethyl acetate, 9:1) to afford 3 as white
o
crystals (0.92 g, 84%); mp 94ꢁ96 C; Rf = 0.26 (hexane/ethyl acetate, 5:1); FTꢁIR (neat film):
1
3067, 2972, 1558, 1318, 1148 cmꢁ1; H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H),
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7.70ꢁ 7.67 (m, 1H), 7.57ꢁ7.47 (m, 6H), 7.35ꢁ7.34 (m, 6H), 4.66 (s, 2H) ppm; C NMR (100
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MHz, CDCl3) δ 151.5, 147.6, 138.2, 136.2, 134.3, 131.6, 129.3, 129.1, 128.7, 128.65, 128.60,
128.4, 128.1, 127.9, 126.6, 55.9 ppm; HRMS (ESIꢁTOF) m/z calcd for C22H17NO3S [M+H]+
376.1007, found 376.1019.
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General procedure for the Preparation of Alkylated Sulfones (5-17). To a stirred solution of
2ꢁ(phenylsulfonyl)methylꢁ4,5ꢁdiphenyloxazole 3 (0.27 mmol, 1.0 equiv) in dry THF (10 mL)
was added potassium tertꢁbutoxide (0.29 mmol, 1.1 equiv) at 5°C. Stirring of the resultant
yellow reaction mixture was continued under a nitrogen atmosphere (30 min). The alkyl halide
(0.028 mmol, 1.05 equiv) was then slowly added to the reaction mixture by syringe, and the
reaction mixture was allowed to warm to room temperature and stirring was continued (16 h). At
the end of the reaction period, cold water (10 mL) was added to the reaction mixture followed by
extraction with dichloromethane (2 x 20 mL). The organic layers were combined, washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was submitted
to gravityꢁcolumn chromatography (hexane/ethyl acetate, 9:1) to afford the corresponding
products 5-10. For the preparation of the dialkylated compounds 11-14 the same procedure was
used with the exception that, potassium tertꢁbutoxide (0.66 mmol, 2.5 equiv) and corresponding
alkylating reagent (0.66 mmol, 2.5 equiv) were employed. For the cyclic compounds 15-17,
potassium tertꢁbutoxide (0.58 mmol, 2.2 equiv) and dihaloalkane (0.29 mmol, 1.1 equiv) were
employed. The methods for purification of 11-17 were the same as for the monoalkyl sulfones 5-
10.
4,5-Diphenyl-2-(1-(phenylsulfonyl)ethyl)oxazole (5). Offꢁwhite solid (93 mg, 90%); mp 95ꢁ97
oC; Rf = 0.25 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3069, 2974, 1562, 1446, 1319, 1147
1
cmꢁ1; H NMR (400 MHz, CDCl3) δ 7.73ꢁ7.70 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45ꢁ7.38 (m,
13
6H), 7.27ꢁ7.25 (m, 6H), 4.57 (q, J = 7.6 Hz, 1H), 1.82 (d, J = 6.8 Hz, 3H) ppm; C NMR (175
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MHz, CDCl3) δ 155.5, 147.0, 136.7, 136.0, 134.2, 131.7, 129.3, 128.99, 128.97, 128.7, 128.6,
128.4, 128.1, 128.0, 126.6, 60.5, 12.2 ppm; HRMS (ESIꢁTOF) m/z calcd for C23H19NO3S
[M+H]+ 390.1164, found 390.1180.
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4,5-Diphenyl-2-(1-phenylsulfonyl)propyl)oxazole (6). Colorless oil (80 mg, 74%); Rf = 0.25
1
(hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3060, 2974, 1558, 1446, 1319, 1148 cmꢁ1; H
NMR (400 MHz, CDCl3) δ 7.78ꢁ7.76 (m, 2H), 7.65ꢁ7.61 (m, 1H), 7.51ꢁ7.46 (m, 6H), 7.37ꢁ7.32
(m, 6H), 4.43 (dd, J = 11.6 Hz, 4.0 Hz, 1H), 2.49ꢁ2.39 (m, 1H), 2.38ꢁ2.31 (m, 1H), 1.06 (t, J =
7.6 Hz, 3H) ppm; 13C NMR (175 MHz, CDCl3) δ 154.8, 147.1, 137.2, 136.0, 134.1, 131.7, 129.2,
129.0, 128.9, 128.7, 128.6, 128.4, 128.2, 127.9, 126.5, 67.3, 20.5, 11.7 ppm; HRMS (ESIꢁTOF)
m/z calcd for C24H21NO3S [M+H]+ 404.1320, found 404.1332.
2-(3-Methyl-1-(phenylsulfonyl)butyl)-4,5-diphenyloxazole (7). Colorless oil (61 mg, 53%); Rf
1
= 0.36 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3064, 1447, 1322, 1149, 1084 cmꢁ1; H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.51ꢁ7.46 (m, 6H),
7.35ꢁ7.33 (m, 6H), 4.58 (dd, J = 11.6 Hz, 4.0 Hz, 1H), 2.36 (ddd, J = 16.8 Hz, 12.0 Hz, 4.4 Hz,
1H), 2.17 (ddd, J = 16.8 Hz, 9.2 Hz, 4.4 Hz, 1H), 1.70ꢁ1.64 (m, 1H), 0.95 (t, J = 6.8 Hz, 6H)
13
ppm; C NMR (175 MHz, CDCl3) δ 155.0, 147.0, 137.3, 135.9, 134.0, 131.7, 129.1, 128.94,
128.93, 128.6, 128.5, 128.3, 128.2, 127.9, 126.5, 64.5, 34.8, 26.0, 23.0, 21.3 ppm; HRMS (ESIꢁ
TOF) m/z calcd for C26H25NO3S [M+H]+ 432.1633, found 432.1648.
4,5-Diphenyl-2-(1-(phenylsulfonyl)but-3-enyl)oxazole (8). Colorless oil (84 mg, 76%); Rf =
0.28 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3065, 2915, 1553, 1447, 1299, 1134 cmꢁ1; 1H
NMR (700 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 7.7 Hz, 1H), 7.51ꢁ7.45 (m, 6H),
7.34ꢁ7.31 (m, 6H), 5.78ꢁ5.72 (m, 1H), 5.20 (d, J = 16.8 Hz, 1H), 5.09 (d, J = 9.8 Hz, 1H), 4.57
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(dd, J = 11.2 , 4.2 Hz, 1H), 3.17ꢁ3.08 (m, 2H) ppm; 13C NMR (175 MHz, CDCl3) δ 154.4, 147.1,
137.0, 136.0, 134.2, 132.0, 131.7, 129.2, 129.0, 128.9, 128.7, 128.5, 128.4, 128.1, 127.9, 126.6,
119.3, 65.2, 30.7 ppm; HRMS (ESIꢁTOF) m/z calcd for C25H21NO3S [M+H]+ 416.1320, found
416.1338.
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4,5-Diphenyl-2-(1-(phenylsulfonyl)but-3-ynyl)oxazole (9). Colorless oil (52 mg, 47%); Rf: =
0.24 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3286, 3068, 1448, 1310, 1150 cmꢁ1; 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.53ꢁ7.47 (m, 6H), 7.38ꢁ7
33 (m, 6H), 4.72 (dd, J = 8.8 Hz, 7.2 Hz, 1H), 3.30ꢁ3.28 (m, 2H), 1.99 (t, J = 2.4 Hz, 1H) ppm;
13C NMR (175 MHz, CDCl3) δ 153.7, 147.4, 136.6, 136.1, 134.5, 131.6, 129.2, 129.1, 129.0,
128.6, 128.5, 128.4, 128.1, 127.9, 126.6, 126.1, 77.9, 71.6, 64.2, 17.5 ppm; HRMS (ESIꢁTOF)
m/z calcd for C25H19NO3S [M+H]+ 414.1164, found 414.1179.
2-(7-Bromo-1-(phenylsulfonyl)heptyl)-4,5-diphenyloxazole (10). Colorless oil (76 mg, 53%);
Rf = 0.54 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3069, 2959, 1690, 1447, 1321, 1148,
687 cmꢁ1; 1H NMR (700 MHz, CDCl3) δ 7.78 ꢁ7.76 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.52ꢁ7.47
(m, 6H), 7.38ꢁ7.33 (m, 6H), 4.51 (dd, J = 10.0 Hz, 5.2 Hz, 1H), 3.36 (t, J = 7.2 Hz, 2H), 2.40ꢁ
2.37 (m, 2H), 1.83ꢁ1.80 (m, 2H), 1.45ꢁ1.37 (m, 6H) ppm; 13C NMR (175 MHz, CDCl3) δ 154.8,
147.0, 137.1, 136.0, 134.0, 131.6, 129.0, 128.92, 128.89, 128.6, 128.5, 128.3, 128.0, 127.8,
126.5, 65.7, 33.6, 32.4, 28.0, 27.6, 26.7, 26.3 ppm; HRMS (ESIꢁTOF) m/z calcd for
C28H28BrNO3S [M+H]+ 538.1052, found 538.1066.
4,5-Diphenyl-2-(2-(phenylsulfonyl)propan-2-yl)oxazole (11). Offꢁwhite solid (104 mg, 97%);
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mp 103ꢁ106 C; Rf: = 0.34 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3065, 2939, 1446,
1305, 1154 cmꢁ1; 1H NMR (400 MHz, CDCl3) δ 7.67ꢁ7.60 (m, 3H), 7.49ꢁ7.44 (m, 6H), 7.35ꢁ7.33
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(m, 6H), 1.93 (s, 6H) ppm; C NMR (175 MHz, CDCl3) δ 158.8, 146.9, 135.9, 135.3, 134.0,
131.9, 130.1, 128.9, 128.7, 128.63, 128.59, 128.3, 128.2, 128.0, 126.5, 64.2, 20.5 ppm; HRMS
(ESIꢁTOF) m/z calcd for C24H21NO3S [M+H]+ 404.1320, found 404.1341.
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4,5-Diphenyl-2-(3-(phenylsulfonyl)pentan-3-yl)oxazole (12). Colorless oil (57 mg, 50%); Rf: =
0.41 (hexane/ethyl acetate, 4:1); FTIR (neat film): 3062, 2936, 1442, 1306, 1154 cmꢁ1; 1H NMR
(400 MHz, CDCl3) δ 7.59ꢁ7.57 (m, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.47ꢁ7.36 (m, 6H), 7.35ꢁ7.32
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(m, 6H), 2.70ꢁ2.63 (m, 2H), 2.42ꢁ2.35 (m, 2H), 1.61 (t, J = 7.6 Hz, 6H) ppm; C NMR (175
MHz, CDCl3) δ 158.1, 146.5, 136.8, 135.8, 133.6, 132.0, 129.6, 128.8, 128.6, 128.53, 128.50,
128.3, 128.0, 126.4, 72.0, 22.3, 8.4 ppm; HRMS (ESIꢁTOF) m/z calcd for C26H25NO3S [M+H]+
432.1633, found 432.1624.
4,5-Diphenyl-2-(4-(phenylsulfonyl)hepta-1,6-dien-4-yl)oxazole (13). Colorless oil (80 mg,
66%); Rf: = 0.4 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3060, 2923, 1683, 1446, 1307,
1146 cmꢁ1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.49ꢁ
7.46 (m, 2H), 7.44ꢁ7.41 (m, 4H), 7.37ꢁ7.33 (m, 6H), 5.98 (ddt, J = 17.4, 10 Hz, 7.6 Hz, 2H),
5.27 (dd, J = 17.2, 1.6 Hz, 2H), 5.22 (d, J = 10 Hz, 2H), 3.31 (dd, J = 14.8, 7.2 Hz, 2H), 3.15
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(dd, J = 14.8, 7.2 Hz, 2H) ppm; C NMR (175 MHz, CDCl3) δ 157.2, 146.8, 136.2, 135.8,
134.0, 131.8, 131.1, 129.8, 129.0, 128.64, 128.62, 128.5, 128.3, 128.2, 127.9, 126.5, 120.4, 70.2,
34.5 ppm; HRMS (ESIꢁTOF) m/z calcd for C28H25NO3S [M+H]+456.1633, found 456.1645.
4,5-Diphenyl-2-(4-(phenylsulfonyl)hepta-1,6-diyn-4-yl)oxazole (14). Colorless oil (99 mg,
82%); Rf: = 0.30 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3293, 1448, 1325, 1149, 1083
cmꢁ1; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.52ꢁ7.44
(m, 6H), 7.36ꢁ7.34 (m, 6H), 3.59 (dd, J = 17.6 Hz, 2.8 Hz, 2H), 3.47 (dd, J = 17.6, 2.8 Hz, 2H),
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2.14 (t, J = 2.8 Hz, 2H) ppm; C NMR (175 MHz, CDCl3) δ 155.8, 147.4, 136.0, 135.4, 134.4,
131.6, 130.0, 129.1, 128.9, 128.65, 128.57, 128.4, 128.0, 127.9, 126.7, 72.6, 68.3, 21.6 ppm;
HRMS (ESIꢁTOF) m/z calcd for C28H21NO3S [M+H]+ 452.1320, found 452.1336.
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4,5-Diphenyl-2-(1-(phenylsulfonyl)cyclobutyl)oxazole (15). Colorless oil (65 mg, 59%); Rf: =
0.33 (hexane/ethyl acetate = 1:4); FTꢁIR (neat film): 3064, 2953, 1553, 1446, 1306, 1147 cmꢁ1;
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.61ꢁ7.58 (m, 1H), 7.53ꢁ7.45 (m, 6H),
7.37ꢁ7.32 (m, 6H), 3.29ꢁ3.21 (m, 2H), 2.87ꢁ2.80 (m, 2H), 2.28ꢁ2.21 (m, 1H), 2.10ꢁ2.09 (m, 1H)
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ppm; C NMR (175 MHz, CDCl3) δ 158.2, 147.0, 136.2, 135.9, 133.9, 131.9, 129.3, 128.9,
128.8, 128.6, 128.5, 128.3, 128.2, 128.0, 126.5, 65.4, 28.1, 15.7 ppm; HRMS (ESIꢁTOF) m/z
calcd for C25H21NO3S [M+H]+ 416.1320, found 416.1329.
4,5-Diphenyl-2-(1-(phenylsulfonyl) cyclopentyl) oxazole (16). Colorless oil (89 mg, 78%); Rf:
= 0.43 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3062, 2960, 1686, 1446, 1305, 1140 cmꢁ1;
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.50ꢁ7.42 (m,
6H), 7.37ꢁ7.33 (m, 6H), 2.75ꢁ2.71 (m, 4H), 2.00ꢁ1.97 (m, 2H), 1.77ꢁ1.73 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3) δ 158.8, 147.1, 137.0, 136.0, 133.8, 132.0, 129.6, 128.9, 128.7, 128.6, 128.5,
128.3, 128.0, 126.5, 74.4, 33.0, 25.4 ppm; HRMS (ESIꢁTOF) m/z calcd for C26H23NO3S [M+H]+
430.1477, found 430.1494.
4,5-Diphenyl-2-(1-(phenylsulfonyl)cyclohexyl)oxazole (17). Colorless oil (110 mg, 93%); Rf: =
0.47 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3069, 2952, 1690, 1505, 1446, 1296, 1146
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cmꢁ1; H NMR (400 MHz, CDCl3) δ 7.61ꢁ7.57 (m, 3H), 7.51ꢁ7.41 (m, 6H), 7.37ꢁ7.33 (m, 6H),
2.78ꢁ2.75 (m, 2H), 2.21ꢁ2.15 (m, 2H), 1.88ꢁ1.86 (m, 2H), 1.67ꢁ1.65 (m, 1H), 1.37ꢁ1.32 (m, 3H)
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ppm; C NMR (100 MHz, CDCl3) δ 157.0, 147.0, 136.1, 135.6, 133.8, 132.0, 130.0, 128.8,
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128.6, 128.54, 128.52, 128.4, 128.3, 128.0, 126.6, 69.2, 28.0, 24.7, 22.6 ppm; HRMS (ESIꢁTOF)
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m/z calcd for C27H25NO3S [M+H]+ 444.1633 , found 444.1650.
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Typical Procedure for Aluminum/HgCl2-Mediated Desulfonylation for Synthesis of 4 (Eq.
1) and 18 (Table 2). To a solution of the alkylated 2ꢁ(sulfonylethyl)ꢁ4,5ꢁdiphenyloxazole 5 (0.12
mmol, 1.0 equiv) and crystals of mercuric chloride (0.034 mmol, 0.3 equiv), in methanol (15
mL), was added an excess of foodꢁgrade aluminum foil (2.32 mmol, 20 equiv) with vigorous
stirring under a nitrogen atmosphere. The resulting heterogeneous mixture was heated at reflux
until the metal disappeared. The reaction mixture was then allowed to cool to room temperature
and filtered through a Celite bed followed by washing with methanol (2 x 15mL). The filtrate
was concentrated to a crude residue which was submitted to gravityꢁcolumn chromatography on
silica gel to provide 2ꢁmethylꢁ4,5ꢁdiphenyloxazole 4 (96%) or 2ꢁethylꢁ4,5ꢁdiphenyloxazole 18
(97%).
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General procedure for Magnesium/HgCl2-Mediated Desulfonylation of Alkylated Sulfones
5-17. To a stirred solution of an alkylated 2ꢁ(phenylsulfonyl)methylꢁ4,5ꢁdiphenyloxazole (0.12
mmol, 1.0 equiv. from Table 1) in methanol (5 mL) was added magnesium turnings (1.73 mmol,
15 equiv) and crystals of mercuric chloride (0.012 mmol, 0.1 equiv) at room temperature. The
reaction mixture was stirred at room temperature (2 h) while monitoring the reaction progress by
TLC. After the reaction was complete, the reaction mixture was filtered through a Celite bed
followed by washing with methanol (2 x 10 mL). The filtrate was concentrated and the resultant
crude residue was submitted to gravityꢁcolumn chromatography on silica gel (hexane/ethyl
acetate) to afford the pure products 18ꢁ27 listed in Table 2.
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2-Methyl-4,5-diphenyloxazole (4).13 Colorless oil (30 mg, 96%); Rf: = 0.42 (hexane/ethyl
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acetate, 4:1); FTꢁIR (neat film): 3061, 2985, 1572, 1438, 1052 cmꢁ1; 1H NMR (400 MHz, CDCl3)
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δ 7.65ꢁ7.63 (m, 2H), 7.59ꢁ7.56 (m, 2H), 7.36ꢁ7.30 (m, 6H), 2.56 (s, 3H) ppm; C NMR (175
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MHz, CDCl3) δ 160.2, 145.3, 135.2, 132.5, 129.1, 128.6, 128.5, 128.3, 128.0, 127.8, 126.4, 14.0
ppm.
2-Ethyl-4,5-diphenyloxazole (18).14 Colorless oil (31 mg, 97 %); Rf = 0.46 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 3059, 2984, 1570, 1444, 1059 cmꢁ1; 1H NMR (700 MHz, CDCl3)
δ 7.63 (dd, J = 8.4 Hz, 1.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1.4 Hz, 2H), 7.36ꢁ7.29 (m, 6H), 2.88 (q,
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J = 7.7 Hz, 2H), 1.41 (t, J = 7.7 Hz, 3H) ppm; C NMR (175 MHz, CDCl3) δ 164.5, 145.0,
135.0, 132.6, 129.2, 128.6, 128.5, 128.3, 127.94, 127.92, 126.4, 21.8, 11.3 ppm.
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4,5-Diphenyl-2-propyloxazole (19).15 white solid (24.8 mg, 76 %); mp 62ꢁ64 C [Lit. 64 oC] 15;
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Rf: 0.60 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3061, 2982, 1571, 1441, 1056 cmꢁ1; H
NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.4 Hz, 1.6 Hz, 2H), 7.59 (dd, J = 8.4 Hz, 1.6 Hz, 2H),
7.39ꢁ7.31 (m, 6H), 2.83 (t, J = 8.0 Hz, 2H), 1.92ꢁ1.86 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H) ppm; 13C
NMR (175 MHz, CDCl3) δ 163.6, 145.0, 135.0, 132.6, 129.2, 128.6, 128.5, 128.2, 127.92,
127.91, 126.4, 30.1, 20.7, 13.8 ppm.
2-Isopentyl-4,5-diphenyloxazole (20). Colorless oil (22.3 mg, 66 %); Rf = 0.65 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 3064, 2956, 1570, 1444, 1059 cmꢁ1; 1H NMR (400 MHz, CDCl3)
δ 7.64 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.38ꢁ7.29 (m, 6H), 2.86 (t, J = 8.0 Hz, 2H),
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1.79ꢁ1.66 (m, 3H), 0.98 (d, J = 6.4 Hz, 6H) ppm; C NMR (175 MHz, CDCl3) δ 163.9, 145.0,
135.0, 132.7, 129.2, 128.6, 128.5, 128.3, 128.0, 126.4, 36.0, 27.8, 26.3, 22.3 ppm; HRMS (ESIꢁ
TOF) m/z calcd for C20H21NO [M+H]+ 292.1701, found 292.1697.
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2-(But-3-enyl)-4,5-diphenyloxazole (21). Colorless oil (32 mg, 97%); Rf = 0.53 (hexane/ethyl
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acetate, 4:1); FTꢁIR (neat film): 3064, 2924, 1675, 1448, 1211, 1059 cmꢁ1; H NMR (400 MHz,
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CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 6.8 Hz, 2H), 7.38ꢁ7.29 (m, 6H), 5.94 (ddt, J =
17.2, 10.4, 6.4 Hz, 1H), 5.14 (dd, J = 17.2, 1.6 Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H), 2.96 (t, J = 7.8
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Hz, 2H), 2.62 (dd, J = 14.8, 7.0 Hz, 2H) ppm; C NMR (175 MHz, CDCl3) δ 162.9, 145.1,
136.6, 135.0, 132.6, 129.1, 128.6, 128.5, 128.3, 127.97, 127.90, 126.4, 115.9, 31.0, 27.8 ppm;
HRMS (ESIꢁTOF) m/z calcd for C19H17NO [M+H]+ 276.1388, found 276.1402.
2-(But-3-ynyl)-4,5-diphenyloxazole (22). Colorless oil (32 mg, 96%); Rf = 0.45 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 3296, 2919, 1580, 1448, 1211, 1059 cmꢁ1; H NMR (400 MHz,
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CDCl3) δ 7.64 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.38ꢁ7.30 (m, 6H), 3.10 (t, J = 7.6
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Hz, 2H), 2.76 (td, J = 7.6 Hz, 2.0 Hz, 2H), 2.03 (t, J = 2.6 Hz, 1H) ppm; C NMR (175 MHz,
CDCl3) δ 161.4, 145.5, 135.1, 132.4, 129.0, 128.6, 128.5, 128.4, 128.1, 128.0, 126.5, 82.3, 69.5,
27.7, 16.6 ppm; HRMS (ESIꢁTOF) m/z calcd for C19H15NO [M+H]+ 274.1232, found 274.1247.
2-Isopropyl-4,5-diphenyloxazole (23).16 Colorless oil (29 mg, 90%); Rf = 0.64 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 3064, 2973, 1671, 1448, 1210 cmꢁ1; 1H NMR (400 MHz, CDCl3)
δ 7.65 (d, J = 6.8 Hz, 2H), 7.59 (d, J = 6.8 Hz, 2H), 7.38ꢁ7.29 (m, 6H), 3.22ꢁ3.15 (m, 1H), 1.43
(d, J = 7.2 Hz, 6H) ppm.; 13C NMR (175 MHz, CDCl3) δ 167.6, 144.8, 134.9, 132.7, 129.2,
128.6, 128.5, 128.2, 128.0, 127.9, 126.3, 28.5, 20.5 ppm.
2-(Pentan-3-yl)-4,5-diphenyloxazole (24). Colorless oil (28 mg, 82%); Rf = 0.68 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 3064, 2962, 1566, 1444, 1058 cmꢁ1; 1H NMR (400 MHz, CDCl3)
δ 7.67 ꢁ7.65 (m, 2H), 7.60ꢁ7.58 (m, 2H), 7.38ꢁ7.28 (m, 6H), 2.80 (tt, J = 14.4 Hz, 6.0 Hz, 1H),
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1.90ꢁ1.75 (m, 4H), 0.96 (t, J = 7.2 Hz, 6H) ppm; C NMR (175 MHz, CDCl3) δ 166.3, 144.8,
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(ESIꢁTOF) m/z calcd for C20H21NO [M+H]+ C20H21NO [M+H]+ 292.1701, found 292.1713.
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2-Cyclobutyl-4,5-diphenyloxazole (25). Colorless oil (23 mg, 69%); Rf = 0.52 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 2944, 2860, 1566, 1444, 1059 cmꢁ1; 1H NMR (400 MHz, CDCl3)
δ 7.65ꢁ7.63 (m, 2H), 7.60ꢁ7.58 (m, 2H), 7.38ꢁ7.29 (m, 6H), 3.76ꢁ3.68 (m, 1H), 2.60ꢁ2.50 (m,
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2H), 2.46ꢁ2.38 (m, 2H), 2.16ꢁ1.98 (m, 2H) ppm; C NMR (175 MHz, CDCl3) δ 165.8, 144.9,
135.1, 132.7, 129.2, 128.6, 128.5, 128.2, 128.0, 127.9, 126.4, 33.2, 27.4, 18.7 ppm; HRMS (ESIꢁ
TOF) m/z calcd for C19H17NO [M+H]+ 276.1388, found 276.1397.
2-Cyclopentyl-4,5-diphenyloxazole (26). Colorless oil (31 mg, 92 %); Rf = 0.55 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 3064, 2957, 1681, 1448, 1210 cmꢁ1; 1H NMR (400 MHz, CDCl3)
δ 7.64 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.38ꢁ7.28 (m, 6H), 3.31 (q, J = 8.0 Hz, 1H),
2.18ꢁ2.10 (m, 2H), 2.06ꢁ1.97 (m, 2H),1.89ꢁ1.80 (m, 2H), 1.75ꢁ1.69 (m, 2H) ppm; 13C NMR (175
MHz, CDCl3) δ 166.8, 144.8, 134.9, 132.8, 129.3, 128.6, 128.5, 128.2, 128.0, 127.9, 126.3, 38.6,
31.5, 25.6 ppm. HRMS (ESIꢁTOF) m/z calcd for C20H19NO [M+H]+ 290.1545, found 290.1560
2-Cyclohexyl-4,5-diphenyloxazole (27).16 Colorless oil (33 mg, 97%); Rf = 0.66 (hexane/ethyl
acetate, 4:1); FTꢁIR (neat film): 2913, 2854, 1566, 1443, 1056 cmꢁ1; 1H NMR (700 MHz, CDCl3)
δ 7.66ꢁ7.64 (m, 2H), 7.60ꢁ7.58 (m, 2H), 7.38ꢁ7.29 (m, 6H), 2.91ꢁ2.88 (m, 1H), 2.17ꢁ2.15 (m,
2H), 1.88ꢁ1.86 (m, 2H), 1.75ꢁ1.67 (m, 3H), 1.45ꢁ1.39 (m, 2H), 1.35ꢁ1.32 (m, 1H) ppm; 13C NMR
(175 MHz, CDCl3) δ 166.9, 144.6, 134.9, 132.8, 129.3, 128.6, 128.5, 128.2, 128.0, 127.9, 126.3,
37.6, 30.7, 25.8, 25.7 ppm.
Ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate (28). To a prechilled solution
of 2ꢁ(phenylsulfonyl)methylꢁ4,5ꢁdiphenyloxazole 3 (100 mg, 0.27 mmol) in dry THF (15 mL)
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was added potassium tertꢁbutoxide (33 mg, 0.29 mmol) under a nitrogen atmosphere. The
resulting yellow solution was stirred (5°C) for 30 min. To the reaction mixture was slowly added
ethyl bromoacetate (49 mg, 32.4 ꢂL, 0.29 mmol) and stirring was continued (16 h) at room
temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was
quenched with cold water (20 mL) and extracted with dichloromethane (2 x 20 mL). The organic
layers were combined, dried over anhydrous sodium sulfate and concentrated to obtain a crude
oily residue. The residue was submitted to gravityꢁcolumn chromatography on silica gel
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(hexane/ethyl
acetate,
4:1)
afford
pure
ethyl
3ꢁ(4,5ꢁdiphenyloxazolꢁ2ꢁyl)ꢁ3ꢁ
(phenylsulfonyl)propanoate 28 as offꢁwhite solid ( 88 mg, 72%); mp = 30ꢁ33 °C; Rf = 0.25
(hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3062, 1733, 1447, 1324, 1148 cmꢁ1; 1H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.54ꢁ7.49 (m, 4H), 7.45ꢁ7.41
(m, 2H), 7.35ꢁ7.32 (m, 6H), 5.04 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 4.18ꢁ4.08 (m, 2H), 3.42 (d, J = 8.0
Hz, 1H), 3.42 (d, J = 5.6 Hz
1H), 1.21 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (175 MHz, CDCl3)
δ 169.2, 154.3, 147.2, 136.7, 136.0, 134.5, 131.8, 129.3, 129.2, 129.0, 128.6, 128.5, 128.4, 128.1,
127.9, 126.6, 61.5, 61.4, 31.9, 14.1 ppm; HRMS (ESIꢁTOF) m/z calcd for C26H23NO5S [M+H]+
462.1375; found 462.1379.
Ethyl 3-(4,5-diphenyloxazol-2-yl)acrylate (29). To a cooled (5°C) solution of sulfonyloxazole
ester 28 (225 mg, 0.49 mmol) in dry THF was added potassium tertꢁbutoxide (60.2 mg, 0.54
mmol) under nitrogen and the reaction mixture was then stirred at 5ꢁ10°C (2 h) while monitoring
by TLC. After completion of the reaction, the reaction mixture was extracted with
dichloromethane (2 x 25 mL) followed by washing the extracts with water and brine then drying
over anhydrous Na2SO4. Removal of the drying agent and concentration of the filtrate gave a
crude residue which was submitted to gravityꢁcolumn chromatography (hexane/ethylacetate, 4:1)
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to provide unsaturated oxazole ester 29 as a colorless oil (100 mg, 65%); Rf = 0.49 (hexane/ethyl
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acetate, 4:1); FTꢁIR (neat film): 3064, 1712, 1653, 1256, 1159 cmꢁ1; H NMR (CDCl3, 400
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MHz): δ 7.67ꢁ7.62 (m, 4H), 7.51 (d, J = 16.0 Hz, 1H), 7.40ꢁ7.36 (m, 6H), 6.83 (d, J = 16.0 Hz,
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1H), 4.29 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H) ppm; C NMR (175 MHz, CDCl3) δ
165.8, 157.6, 147.0, 137.8, 134.9, 133.0, 131.8, 129.9, 129.2, 129.0, 128.8, 128.7, 128.5, 128.5,
128.2, 128.0, 126.7, 124.8, 61.0, 14.2 ppm; HRMS (ESIꢁTOF) m/z calcd for C20H17NO3[M+H]+
320.1287, found 320.1281.
Ethyl 3-(4,5-diphenyloxazol-2-yl)propanoate (30).17 The unsaturated oxazole ester 30 (160
mg, 0.50 mmol) was dissolved in methanol (25 mL) then 10% Pd/C (16 mg, 10% wt/wt) was
added at room temperature. The reaction mixture was purged with nitrogen while stirring
followed by the addition of hydrogen gas (balloon) and then stirring was continued (16 h) under
an atmosphere of hydrogen. Upon completion of reaction, the reaction mixture was filtered
through a bed of Celite while washing with methanol (2 x 30 mL). The combined filtrates were
concentrated and the crude residue was submitted to gravityꢁcolumn chromatography
o
(hexane/ethyl acetate, 4:1) to afford 30 as an offꢁwhite solid (129 mg, 80%); mp 68ꢁ70 C [Lit.
69.5ꢁ71 oC] 17; Rf = 0.36 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film): 3068, 2980, 1734, 1444,
1060 cmꢁ1; H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H),
1
7.38ꢁ7.30 (m, 6H), 4.19 (q, J = 6.8 Hz, 2H), 3.19 (t, J = 7.2 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H),
13
1.27 (t, J = 7.2 Hz, 3H) ppm; C NMR (175 MHz, CDCl3) δ 172.0, 161.8, 145.4, 135.1, 132.5,
129.0, 128.6, 128.5, 128.4, 128.0, 127.9, 126.5, 60.8, 31.2, 23.6, 14.2 ppm.
Methyl 3-(4,5-diphenyloxazol-2-yl)propanoate (31).13 To a clear solution of sulfonyloxazole
ester 28 (80 mg, 0.173 mmol) in methanol (10 mL) was added magnesium turnings (63 mg, 2.60
mmol) followed by solid mercuric chloride (4.7 mg, 0.017 mmol) at room temperature. The
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resulting reaction mixture was stirred (2 h) while monitoring the reaction progress by TLC. After
completion of the reaction, the heterogeneous mixture was then filtered through a Celite bed
followed by washing with methanol (2 x 15 mL). The methanolic filtrates were combined and
concentrated to afford a crude residue. The residue was submitted to gravityꢁcolumn
chromatography (hexane/ethylacetate, 4:1) to provide ester 31 as an offꢁwhite solid (52 mg,
97%); mp 58ꢁ61oC [Lit. 58ꢁ59 oC] 13; Rf = 0.29 (hexane/ethyl acetate, 4:1); FTꢁIR (neat film):
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3061, 2957, 1731, 1438, 1056 cmꢁ1; H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.2 Hz, 2H),
7.57 (d, J = 7.2 Hz, 2H), 7.38ꢁ7.29 (m, 6H), 3.73 (s, 3H), 3.19 (t, J = 7.6 Hz, 1H), 2.92 (t, J = 7.6
13
Hz, 3H) ppm; C NMR (175 MHz, CDCl3) δ 172.5, 161.7, 145.4, 135.1, 132.5, 129.0, 128.6,
128.5, 128.4, 128.0, 127.9, 126.5, 51.9, 30.9, 23.5 ppm.
3-(4,5-Diphenyloxazol-2-yl)propanoic acid (Oxaprozin) (32).13 Ethyl ester 30 (128 mg, 0.39
mmol) or methyl ester 31 (65 mg, 0.21 mmol) and 20% aquous NaOH solution (3 mL) was
stirred overnight at room temperature. Upon completion of reaction as indicated by TLC, the
reaction mixture was slowly acidified to pH 3ꢁ4 using conc. HCl (3 mL) at room temperature and
stirring was continued (3 h). After the neutralization was complete the reaction mixture was
diluted with cold water (15 mL) and extracted with dichloromethane (2 x 15 mL). The organic
extracts were combined, dried over anhydrous Na2SO4 and concentrated to give a white solid
residue. The residue was submitted to gravityꢁcolumn chromatography (chloroform/methanol,
9:1) to afford pure Oxaprozin 32 as white solid (80 mg, 68%, from the ethyl ester 30) or (60 mg,
o
o
97%, from the methyl ester 31). mp = 158ꢁ160 C [Lit. 160.5ꢁ161.5 C]13; Rf = 0.27
1
(methanol/chloroform, 1:9); FTꢁIR (neat) 3156, 2948, 1714, 1568; H NMR (400 MHz, CDCl3)
δ 7.62ꢁ7.50 (m, 2H), 7.56ꢁ7.54 (m, 2H), 7.37ꢁ7.30 (m, 6H), 3.17 (t, J = 7.2 Hz, 2H), 2.94 (t, J =
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7.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.8, 161.9, 145.5, 134.8, 132.0, 128.7, 128.6,
3
4
5
6
128.5, 128.1, 127.9, 126.4, 31.0, 23.2 ppm.
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ACKNOWLEDGMENT The measurement of highꢁresolution mass spectra by Dr. Bo Wang of
the Texas A&M University Laboratory for Biological Mass Spectrometry is acknowledged.
Financial support from the NIH/NIDCR through grant 1RO1DE023206 is gratefully
acknowledged.
Supporting Information Available. Copies of spectra for compounds 3-32 are included.
This material is available free of charge via the Internet at http://pubs.acs.org
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