A Simple strategy for the preparation of 6-substituted 3H-benzoxazol-2-ones and 3H-benzothiazol-2-ones

Article abstract of DOI:10.1080/00397911.2010.519093

The double metallation of 6-bromo-3H-benzothiazol-2-one and 6-bromo-3H-benzoxazol-2-one with methyl magnesium bromide and alkyllithium bases is described. Alkylation with a variety of electrophiles occurs at the 6-position of the heterocycles in good yiel

Full text of DOI:10.1080/00397911.2010.519093

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A Simple Strategy for the Preparation of
6-Substituted 3H-Benzoxazol-2-ones and
3H-Benzothiazol-2-ones
Russell J. DeOrazio a , Jun-Ho Maeng a , David D. Manning a , Brian
A. Sherer a , Ian L. Scott a & Sham S. Nikam b
a AMRI , Albany , New York , USA
b Pfizer Inc. , Ann Arbor , Michigan , USA
Accepted author version posted online: 30 Jun 2011.Published
online: 09 Jun 2011.
To cite this article: Russell J. DeOrazio , Jun-Ho Maeng , David D. Manning , Brian A. Sherer ,
Ian L. Scott & Sham S. Nikam (2011) A Simple Strategy for the Preparation of 6-Substituted 3H-
Benzoxazol-2-ones and 3H-Benzothiazol-2-ones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:23, 3551-3555, DOI:
10.1080/00397911.2010.519093
To link to this article: http://dx.doi.org/10.1080/00397911.2010.519093
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Synthetic Communications1, 41: 3551–3555, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.519093
A SIMPLE STRATEGY FOR THE PREPARATION OF
6-SUBSTITUTED 3H-BENZOXAZOL-2-ONES AND 3H-
BENZOTHIAZOL-2-ONES
Russell J. DeOrazio,1 Jun-Ho Maeng,1 David D. Manning,1
Brian A. Sherer,1 Ian L. Scott,1 and Sham S. Nikam2
1AMRI, Albany, New York, USA
2Pfizer Inc., Ann Arbor, Michigan, USA
GRAPHICAL ABSTRACT
Abstract The double metallation of 6-bromo-3H-benzothiazol-2-one and 6-bromo-3H-
benzoxazol-2-one with methyl magnesium bromide and alkyllithium bases is described. Alky-
lation with a variety of electrophiles occurs at the 6-position of the heterocycles in good yields.
Keywords Benzothiazolidinone; benzoxazolidinone; metallation
INTRODUCTION
Our efforts to generate subtype-selective NR1a=2B NMDA (N-methyl-D-
aspartate) receptor antagonists[1] prompted us to investigate synthetic methods that
allow for substitution at the 6-position of benzoxazolidinone and benzothiazolidi-
none heterocycles. Previous work by other investigators has primarily relied on
Friedel–Crafts acylation methodology or strategies that require protection of the
heterocyclic nitrogen, and these were not suitable for our needs.[2–6]
We have developed a simple method (Scheme 1) to prepare 6-substituted
benzoxolidinones by the double metallation of unprotected bromides 1 and 2.[7,8]
RESULTS AND DISCUSSION
Initially, we sought to activate bromide 1 toward reaction with carbon electro-
philes by preparing the dianion using alkyllithium bases. Treatment of 1 with 2 equiva-
lents of sec-butyllithium followed by subsequent reaction with 1,4-cyclohexanedione
Received March 10, 2010.
Address correspondence to David D. Manning, Discovery R&D Chemistry, AMRI, 26 Corporate
Circle, P. O. Box 15098, Albany, NY 12212-15098, USA. E-mail: David.Manning@amriglobal.com
3551

3552
R. J. DEORAZIO ET AL.
Scheme 1. Preparation of 6-substituted benzoxazolidinones and benzothiazolidinones.
mono-ethylene ketal did not provide any of the desired addition product. Protection of
the heterocyclic nitrogen with a benzyl group followed by attempted metallation with
sec-butyllithium was unsuccessful because of benzylic deprotonation. Faced with these
two results, we hypothesized that the selection of an appropriate base may allow for
selective deprotonation of the heterocyclic nitrogen. Subsequent transmetallation with
an alkyllithium should give a doubly differentiated metallated intermediate that would
presumably react at the 6-postion with electrophiles.
To test our hypothesis, we chose to formylate heterocycles 1 and 2; the corre-
sponding aldehydes were key intermediates for our program, and the preferred
electrophile, dimethylformamide, was expected to be sufficiently reactive under the
reaction conditions. Our results are shown in Table 1.
Treatment of a suspension of bromide 1 in tetrahydrofuran with methyl
magnesium bromide at ꢀ78 ꢁC resulted in deprotonation of the heterocyclic nitrogen
as evidenced by off-gassing of methane. Subsequent addition of 2 equivalents of tert-
butyllithium at ꢀ78 ꢁC generated a thick white suspension. Dimethylformamide was
added to the cold reaction mixture, and after warming to room temperature, the reac-
tion was quenched with water. Following workup, the aldehyde was obtained in a
moderate yield and was contaminated with unreacted bromide 1. We found that
the magnesium species of 1 could be titrated with tert-butyllithium to give a bright
yellow solution upon complete consumption of the bromide. Aldehyde of good yield
and purity could be obtained using this protocol. No further purification of the pro-
duct aldehyde was necessary. Application of this methodology to benzothiazolidi-
none 2 was equally successful.
Table 1. 6-Substituted benzoxazolidinones and benzothiazolidinones
Entry
Substrate
Eþ
R
Yield (%)
1
2
1
2
DMFa
DMFa
CHO
CHO
81
96
3
4
5
6
1
2
1
1
57
54
69
51
atert-Butyl lithium was used instead of sec-butyl lithium for step ii, Scheme 1.

6-SUBSTITUTED 3H-BENZOXAZOLIDIONES
3553
This methodology is also applicable to ketones (Table 1, entries 3–6). The
yields are somewhat less than those from the formylation reaction and may be
attributed to enolization of the ketone.
In conclusion, we have developed a useful method for the preparation of
6-substituted benzoxazolidinone and benzothiazolidinone heterocycles. The
6-carboxaldehydes (Table 1, entries 1 and 2) are anticipated to be of general interest
as useful synthetic intermediates.
EXPERIMENTAL
Proton NMR spectra were obtained at 300 MHz on a Bruker AC 300 spec-
trometer and at 500 MHz on a Bruker AMX 500 spectrometer using tetramethylsi-
lane as an internal reference. Melting points were determined using a Mel-Temp II
melting-point apparatus and are uncorrected. Mass spectra were obtained on a
Varian 1200L quadrupole MS (ESI). Elemental analyses were performed by Intertek
QTI in Whitehouse, N.J., USA. Compound 1 was prepared according to literature
protocol,[9] and compound 2 was purchased from Aldrich.
Procedure A: Formylation of Bromide 1
To a ꢀ78 ꢁC solution of 1 (20.0 g, 93.4 mmol) in tetrahydrofuran (THF, 180 mL)
was added MeMgBr (34.5 mL of a 3.0 M solution in diethyl ether, 103 mmol). After
45 min, anhydrous THF (750 mL) was added at a rate that maintained the internal
reaction temperature below a threshold of ꢀ50 ꢁC. After the solution returned to
ꢀ78ꢁC, tert-butyl lithium (200 mL of a 1.7 M solution in pentane, 196 mmol) was
added dropwise. After 15 min, DMF (44 mL, 561 mmol) was added to the yellow mix-
ture, and the cold bath was removed. After 2 h, the reaction was quenched with water,
and the THF was removed under reduced pressure. The residue was partitioned
between EtOAc and 1 N HCl. The aqueous layer was extracted with EtOAc (2ꢂ).
The combined organic extracts were washed with saturated NaCl, dried (Na2SO4),
and concentrated under reduced pressure. Precipitation from hexanes=EtOAc gave
2-oxo-2,3-dihydrobenzoxazole-6-carboxaldehyde (12.4 g, 81%) as an off-white solid:
mp 208–209 ꢁC; 1H NMR (500 MHz, DMSO-d6): d 12.13 (s, 1H), 9.92 (s, 1H), 7.78 (d,
J ¼ 8 Hz, 1H), 7.75 (s, 1H), 7.29 (d, J ¼ 8 Hz, 1H); ESI MS m=z 164 [M þH]þ. Anal.
calcd. for C8H5NO3: C, 58.90; H, 3.09; N, 8.59. Found: C, 58.64; H, 2.97; N, 8.54.
2-Oxo-2,3-dihydrobenzothiazole-6-carboxaldehyde
Following procedure A, bromide 2 was transformed into the corresponding alde-
1
hyde (3.74 g, 96%), which was isolated as a white solid: mp 227–228 ꢁC; H NMR
(500 MHz, DMSO-d6): d 12.39 (s, 1H), 9.90 (s, 1H), 8.17 (d, J ¼ 1 Hz, 1H), 7.85 (dd,
J ¼ 8, 1 Hz, 1H), 7.30 (d, J ¼ 8 Hz, 1H); ESI MS m=z 180 [M þH]þ. Anal. calcd. for
C8H5NO2Sꢃ0.1H2O: C, 53.09; H, 2.90; N, 7.74. Found: C, 53.14; H, 3.10; N, 7.37.
Procedure B: Alkylation of Ketone Substrates
Bromide 1 (1.50 g, 7.00 mmol) was dissolved in anhydrous THF (45 mL), and
the solution was cooled to ꢀ78 ꢁC. Solutions of MeMgBr (2.60 mL of a 3.0 M

3554
R. J. DEORAZIO ET AL.
solution in Et2O, 7.70 mmol), sec-BuLi (5.90 mL of a 1.3 M solution in cyclohexane,
7.70 mmol), and 1,4-cyclohexanedione mono-ethylene ketal (1.30 g, 8.40 mmol) in
anhydrous THF (10 mL) were added sequentially at 30-min intervals. After the final
addition, the reaction mixture was allowed to warm to room temperature. The
reaction was quenched by the addition of saturated NH4Cl (20 mL). The reaction
mixture was diluted with EtOAc (200 mL), washed with saturated NaCl (100 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by
flash chromatography (silica, 1:1 hexanes=EtOAc to 1:3 hexanes=EtOAc) gave
6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-3H-benzoxazol-2-one (1.16 g, 57%) as a
1
white foam: mp 185–186 ꢁC; H NMR (300 MHz, DMSO-d6): d 11.52 (s, 1H), 7.34
(s, 1H), 7.23 (dd, J ¼ 8, 1 Hz, 1H), 7.02 (d, J ¼ 8 Hz, 1H), 4.98 (s, 1H), 3.88 (s,
4H), 1.99–1.86 (m, 4H), 1.65–1.52 (m, 4H); ESI MS m=z 292 [M þH]þ. Anal. calcd.
for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.55; H, 6.10; N, 4.85.
6-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-3H-benzothiazol-2-one
Following procedure B, bromide 2 was metallated and then condensed with
1,4-cyclohexanedione mono-ethylene ketal. Purification of the crude product by flash
chromatography (silica, 1:1 to 1:2 hexanes=EtOAc) gave the alcohol (1.81 g, 54%) as
a white foam: mp 196–197 ꢁC; 1H NMR (500 MHz, DMSO-d6): d 11.78 (s, 1H), 7.63
(s, 1H), 7.35 (d, J ¼ 8 Hz, 1H), 7.05 (d, J ¼ 8 Hz, 1H), 4.93 (s, 1H), 3.88 (s, 4H),
2.07–1.87 (m, 4H), 1.69–1.47 (m, 4H); ESI MS m=z 308 [MþH]þ. Anal. calcd. for
C15H17NO4S: C, 58.61; H, 5.57; N, 4.56. Found: C, 58.58; H, 5.64; N, 4.54.
6-(1-Benzyl-4-hydroxypiperidin-4-yl)-3H-benzoxazol-2-one
Following procedure B, bromide 1 was metallated and then condensed with
1-benzylpiperidin-4-one. Purification of the crude product by flash chromatography
1
(silica, 4:1 CH2Cl2=MeOH) gave the alcohol (6.31 g, 69%) as an off-white solid: H
NMR (300 MHz, CD3OD): d 7.40–7.25 (m, 7H), 7.02 (d, J ¼ 8 Hz, 1H), 3.62 (s, 2H),
2.80 (d, J ¼ 11 Hz, 2H), 2.58 (dt, J ¼ 12, 2 Hz, 2H), 2.11 (dt, J ¼ 13, 4 Hz, 2H), 1.73
(d, J ¼ 12 Hz, 2H); ESI MS m=z 325 [MþH]þ. Anal. calcd. for C19H20N2O3ꢃ
0.25H2O: C, 69.39; H, 6.28; N, 8.52. Found: C, 69.70; H, 6.17; N, 8.48.
6-(1-Benzyl-3-hydroxypyrrolidin-3-yl)-3H-benzoxazol-2-one
Following procedure B, bromide 1 was metallated and then condensed with
1-benzylpyrrolidin-3-one. Purification of the crude product by flash chromatography
(silica, 4:1 CH2Cl2=MeOH) gave the alcohol (1.80 g, 51%) as a pale brown solid: 1H
NMR (300 MHz, CD3OD): d 7.40–7.22 (m, 7H), 7.02 (d, J ¼ 8 Hz, 1H), 3.77 (br s,
2H), 3.07–2.76 (m, 4H), 2.35–2.25 (m, 1H), 2.19–2.11 (m, 1H); ESI MS m=z 311
[MþH]þ. Anal. calcd. for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.36; H, 5.95; N, 8.95.
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