Short and efficient synthesis of oxazinone-and thiazinone-containing bicyclic heteroaromatic aldehydes

Article abstract of DOI:10.1080/00397911.2013.781183

Short and efficient route for the synthesis of oxazinone-and thiazinone-containing bicyclic heteroaromatic aldehydes, which involves the key step of palladium-catalyzed reductive carbonylation, is described. Overall routes for the synthesis of these aldehydes are short, versatile, and scalable with good yields of the product. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.781183

This article was downloaded by: [Istanbul Universitesi Kutuphane ve Dok]
On: 05 September 2013, At: 10:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Short and Efficient Synthesis of
Oxazinone- and Thiazinone-Containing
Bicyclic Heteroaromatic Aldehydes
Shahul Hameed P. a , Gajanan Shanbhag a , Vikas Shinde a , Murugan
Chinnapattu a , Praveena Manjrekar a , Jayashree Puttur a , Vikas
Patil a & Bheemarao Ugarkar a
a Department of Medicinal Chemistry , AstraZeneca India ,
Bangalore , India
Published online: 05 Sep 2013.
To cite this article: Shahul Hameed P. , Gajanan Shanbhag , Vikas Shinde , Murugan Chinnapattu ,
Praveena Manjrekar , Jayashree Puttur , Vikas Patil & Bheemarao Ugarkar (2013) Short and Efficient
Synthesis of Oxazinone- and Thiazinone-Containing Bicyclic Heteroaromatic Aldehydes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:24, 3315-3321
To link to this article: http://dx.doi.org/10.1080/00397911.2013.781183
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 43: 3315–3321, 2013
Copyright # AstraZeneca India Pvt. Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.781183
SHORT AND EFFICIENT SYNTHESIS OF OXAZINONE-
AND THIAZINONE-CONTAINING BICYCLIC
HETEROAROMATIC ALDEHYDES
Shahul Hameed P., Gajanan Shanbhag, Vikas Shinde,
Murugan Chinnapattu, Praveena Manjrekar,
Jayashree Puttur, Vikas Patil, and Bheemarao Ugarkar
Department of Medicinal Chemistry, AstraZeneca India, Bangalore, India
GRAPHICAL ABSTRACT
Abstract Short and efficient route for the synthesis of oxazinone- and thiazinone-containing
bicyclic heteroaromatic aldehydes, which involves the key step of palladium-catalyzed
reductive carbonylation, is described. Overall routes for the synthesis of these aldehydes
are short, versatile, and scalable with good yields of the product.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Benzoxazinone; bicyclic aldehydes; carbonylation; pyridoxazinone
INTRODUCTION
Benzoxazinone and pyridoxazinone ring systems are very frequently encoun-
tered structural features in antibacterial research. Most notably they are integral parts
of a popularly known class of molecules called amino-piperidines (Fig. 1) that inhibit
bacterial DNA Gyrase and have been the subject of a large number of patents and
publications.[1–6]
Synthesis of these molecules requires key intermediates containing pyrid-
oxazinone, pyridothiazinone, and benzoxazinone aldehydes (Fig. 2) to enable rapid
synthesis of compound libraries for drug discovery efforts. In the literature, few
Received December 21, 2012.
Address correspondence to Shahul Hameed, Department of Medicinal Chemistry, AstraZeneca
India, Bellary Road, Habbal, Bangalore 560024, India. E-mail: shahul.mehar@astrazeneca.com
3315

3316
S. HAMEED P. ET AL.
Figure 1. Novel DNA gyrase inhibitors as antibacterial agents.
Figure 2. Key oxazinone and thiazinone containing aldehydes.
synthetic procedures[1–6] exist for the construction of such ring systems. Recently
Brooks and Dabbs[7] reported synthesis of a few key pyridine-containing bicylic
aldehyde analogs. These methods are elegant in nature, but they involve a minimum
of 6–8 steps, making the overall processes lengthy and poor yielding.
Hence we embarked on an endeavor to develop shorter and high-yielding
routes to these intermediates. The key step in simplifying the overall synthesis of this
class of compound was to introduce the aldehyde function via palladium-catalyzed
reductive carbonylation.
In this study, we are pleased to report short and efficient routes for synthesis of
these aldehydes with good yields. We also demonstrate the use of palladium-
catalyzed reductive carbonylation to synthesize the aldehydes (2a–f) from their
bromo precursors (1a–f) with excellent yields. Although palladium-catalyzed carbo-
nylation of various phenyl halides and simple halo-pyridines is well established,[8–11]
to the best of our knowledge similar reactions on halo benzoxazinones, pyridoxazi-
nones, and pyridothiazinones have not been reported.
RESULTS AND DISCUSSION
In our preliminary studies based on a reported literature method, 3-oxo-3,
4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (2a) was taken as model
substrate. The reported synthesis of 2a involves seven steps starting with 2-nitro-3-
hydroxypyridine, which includes ozonolysis in the last step,[7] rendering it a difficult
intermediate for making multiple analogs or scaling up desired products.

BICYCLIC HETEROAROMATIC ALDEHYDES
3317
Scheme 1. Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde. Reagents and
conditions: (a) K2CO3, DMF, 80 ꢀC, 12 h, 85%; (b) Fe=CH3COOH, 80 ꢀC, 1 h, 80%; (c) HCOONa, PdCl2
(PPh3)2, CO (60 psi), DMF, 110 ꢀC, 2 h, 40% (2a þ 6).
As shown in Scheme 1, we devised a simpler route starting from commercially
available 6-bromo-2-nitropyridin-3-ol 3, which was condensed with ethyl bromoace-
tate to furnish the intermediate 5 in 85% yield. Reductive cyclization of 5 using iron
and acetic acid afforded bromo compound 1a in 80% yield.[7] This bromo precursor
was subjected to palladium-catalyzed carbonylation using HCOONa, PdCl2(PPh3)2,
and CO (60 psi), dimethyl formamide (DMF) at 110 ꢀC for 2 hr and resulted in 2a in
40% yield[11] along with debrominated product 6, which was difficult to separate.
To improve the yield and to minimize the debrominated product, we optimized
the reaction condition by screening various combinations of catalyst, base, and
hydride source as shown in Table 1. In the literature, there are reports wherein
triethylsilane is used as a hydride source in reductive carbonylation to minimize the
formation of debrominated product.[12] We applied the same methodolgy for carbo-
nylation. From the experimental results it is evident that carbonylation of 1a using
triethylsilane as hydride source, triethyl amine, PdCl2(dppf) ꢁ CH2Cl2, CO (60 psi),
and DMF at 110 ꢀC for 12 h afforded aldehyde 2a in 70% yield without debromina-
tion product. When sodium carbonate was used as base (Table 1, entry 6), we did not
observe product formation.
We believe that the improvement in yield may be due to the slow release
of hydride from triethylsilane=triethylamine over a longer period of time, thereby
Table 1. Optimization of reaction conditions
Entry
Catalyst
Base
Hydride source
Yielda (%)
1
2
3
4
5
6
PdCl2(PPh3)2
—
Sodium formate
Sodium formate
Triethylsilane
Triethylsilane
Triethylsilane
40b
50b
5c
PdCl2(dppf) ꢁ CH2Cl2
PdCl2(dppf) ꢁ CH2Cl2
PdCl2(PPh3)2
—
—
Triethylamine
55
70
—
PdCl2(dppf) ꢁ CH2Cl2 Triethylamine
PdCl2(dppf) ꢁ CH2Cl2 Sodium carbonate Triethylsilane
aIsolated yields after column purification.
bMixture of compounds 2a and 6.
cOnly debrominated product 6.

3318
S. HAMEED P. ET AL.
Scheme 2. Synthesis of aldehydes 2b–d. Reagents and conditions: (a) (I) NaH, THF, Rt, 1 h, 82% (9b), (II)
TEA, DCM, Rt, 1 h, 80% (9c), (III) K2CO3, CH3CN, 75 ꢀC, o=n, 30% (9d); (b) Fe=CH3COOH, 80 ꢀC,
1 h, ꢂ85%; (c) Et3SiH, PdCl2(dppf) ꢁ CH2CL2, TEA, CO (60 psi), DMF, 110 ꢀC, 12 h, 80% (2b); 84% (2c);
89% (2d).
avoiding the debromination product.[12] Sodium formate readily decomposes and
provides hydride more quickly, thereby favoring the debrominated product along
with the required aldehyde. Encouraged by this result, we have applied this optimized
condition to the preparation of other aldehydes as shown in Fig. 2.
The reported synthesis for compounds 2b and 2c involves nine steps starting
with nicotinic acid.[7] As shown in Scheme 2, we devised a simpler route starting from
commercially available 3-bromo-6-chloro-5-nitropyridine 7, which was condensed
with respective glycolates (8b–d) to furnish the desired intermediates (9b–d) in good
yields (75–80%). Reductive cyclization of 9 using iron and acetic acid gave bromo
compounds (1b–d), which upon palladium-catalyzed carbonylation using triethylsi-
lane, triethyl amine, PdCl2(dppf) ꢁ CH2Cl2, CO (60 psi), and DMF, at 110 ꢀC for
12 h gave the desired aldehydes (2b–d) in excellent yields. In the case of 1b and 1c car-
bonylation afforded aldehydes 2b and 2c in 80% and 84% yields respectively. The
novel aldehyde 2d was synthesized starting from (S)-methyl-2-hydroxypropionate
8c in three steps and the palladium-catalyzed carbonylation step afforded the desired
aldehyde in 89% yield.
Similarly, novel aldehyde 2e was synthesized from commercially available
3-amino-5-bromo-6-methylpyridin-2-ol 10, which was condensed with 2-chloroacetyl
chloride in a mixture of methyl isobutylketone and aqueous sodium bicarbonate sol-
ution to get the cyclized product 1e in a single step similar to a reported procedure[13]
Scheme 3. Synthesis of 6-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbaldehyde (2e).
Reagents and conditions: (a) NaHCO3, MIBK–water (7:3), reflux, 4 h, 66%; (b) Et3SiH, PdCl2(dpph) ꢁ
CH2Cl2. TEA, CO (60 psi), DMF, 110 ꢀC, 12 h, 75%.

BICYCLIC HETEROAROMATIC ALDEHYDES
3319
Scheme 4. Synthesis of 8-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (2f). Reagents
and conditions: (a) K2CO3, DMF, 80 ꢀC, 12 h, 85%; (b) Fe=CH3COOH 80 ꢀC, 1 h, 80%; (c) Et3SiH,
PdCl2(dppf) ꢁ CH2Cl2, TEA, CO (60 psi), DMF, 110 ꢀC, 12 h, 76%.
(Scheme 3), which was converted to the corresponding aldehyde 2e in good
yield (75%).
In our effort to explore the benzoxazinone system, we synthesized aldehyde 2f in
76% yield from corresponding bromo precursor 1f, which was synthesized in three
steps (Scheme 4), whereas the reported synthesis of aldehyde 2f involves oxidative
cleavage using osmium tetraoxide=sodium periodate in the last step with moderate
yield.[14]
In conclusion, we have demonstrated short and efficient routes for the synthesis
of oxazinone and thiazinone containing bicyclic heteroaromatic aldehydes in excel-
lent yields, which are key intermediates for the synthesis of antibacterial compounds.
We have also demonstrated the use of palladium-catalyzed reductive carbonylation to
introduce the aldehyde functionality on such ring systems. We believe that the routes
presented here are amenable to synthesis of similar diversly substituted aldehydes.
EXPERIMENTAL
Methyl 2-(5-Bromo-3-nitropyridin-2-ylthio)acetate (9c): Method II
Methyl 2-mercaptoacetate (0.753 mL, 8.42 mmol) was dissolved in dichloro-
methane (DCM) (20 mL), and triethyl amine (TEA) (3.52 mL, 25.27 mmol) was
added and stirred for 5 min. A solution of 5-bromo-2-chloro-3-nitropyridine
(2.000 g, 8.42 mmol) in 3 ml of DCM was added to this mixture and stirred at Rt
for 1 h. The progress of the reaction was monitored through liquid chromato-
graphy–mass spectrometry (LCMS), and the profile showed the absence of starting
material and the formation of the required product. The reaction mixture was
diluted with DCM and washed with aqueous sodium hypochlorite solution. The
solvent was evaporated under vacuum and the crude residue was purified by flash
column using 100–200 silica gel to get methyl 2-(5-bromo-3-nitropyridin-2-ylthio)
acetate (2.300 g, 89%). 1H NMR (300 MHz, DMSO-d6) d ¼ 3.65 (s, 3 H), 4.08
(s, 2 H), 8.86 (d, J ¼ 2.07 Hz, 1 H), 8.95 (d, J ¼ 2.07 Hz, 1 H); ESI-MS: m=z
309.07 (M þ 2).

3320
S. HAMEED P. ET AL.
7-Bromo-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (1c)
Methyl 2-(5-bromo-3-nitropyridin-2-ylthio)acetate (2.000 g, 6.51 mmol) was
dissolved in acetic acid (20 mL), and iron (1.818 g, 32.56 mmol) was added portion-
wise. The reaction mixture was heated to 80 ꢀC for 1 h. The progress of the reaction
was monitored through LCMS, and the profile showed the formation of required
product. The reaction mixture was diluted with ethylacetate, filtered through celite,
and washed with 5% MeOH=DCM. The solvent was concentrated under vacuum,
and the crude residue was triturated with hexane and dried under vacuum to get
7-bromo-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (1.500 g, 94%).
1H NMR (300 MHz, DMSO-d6) d ¼ 3.70 (s, 2H), 7.42 (d, J ¼ 2.07 Hz, 1 H),
8.22 (d, J ¼ 2.07 Hz, 1 H), 10.75 (br. s., 1 H); 13C NMR (300 MHz, DMSO-d6):
d ¼ 28.32, 116.57, 125.05, 134.87, 142.09, 143.15, 164.45; ESI-MS: m=z 247.06
(M þ 2). HRMS m=z (EI) calcd. for C7H5BrN2OS 243.9306; found 244.9340
[M þ H]þ.
2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carbaldehyde (2c)
A 120-mL steel bomb was charged with 7-bromo-1H-pyrido[2,3-b][1,4]
thiazin-2(3H)-one (200 mg, 0.82 mmol), triethylsilane (0.261 mL, 1.63 mmol), PdCl2
(dppf) ꢁ CH2Cl2 (0.033 g, 0.04 mmol), and TEA (0.341 mL, 2.45 mmol) in dry DMF
(10 mL). The steel bomb was pressurized with CO gas at 60 psi and heated to
110 ꢀC for 12 h. The pressure was released carefully, the reaction mixture was filtered,
and the filtrate was evaporated. The residue was neutralized with saturated NaHCO3
solution and extracted with 5% methanol in dichloromethane (3 ꢃ 15 ml). The
combined organic extracts were washed with water (1 ꢃ 10 ml), and the organic layer
was dried over anhydrous Na2SO4. Solvent was evaporated under vacuum, and
the residue was purified by flash column chromatography (100–200 silica gel,
DCM=MeOH) to give 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carbalde-
hyde (133 mg, 84%). 1H NMR (300 MHz, DMSO-d6) d ¼ 3.79 (s, 2 H), 7.58
(d, J ¼ 1.88 Hz, 1 H), 8.62 (d, J ¼ 1.70 Hz, 1 H), 10.01 (s, 1 H), 10.92 (s, 1 H); 13C
NMR (300 MHz, DMSO-d6): d ¼ 28.3, 120.5, 129.4, 134, 145.7, 150.2, 164.1, 191.3;
ESI-MS: m=z 193.1 (M ꢄ 1). HRMS m=z (EI) calcd. for C8H6N2O2S 194.0150; found
195.0247 [M þ H]þ.
SUPPORTING INFORMATION
1
Full experimental details, H and 13C NMR spectra, and HPLC traces can be
found via the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
We deeply acknowledge the analytical support provided by Suresh Rudrapatna,
Sandesh Jatheendranath, and Sreenivasaiah Menasinkai. We also thank Eknath
Bellale for proofreading this article.

BICYCLIC HETEROAROMATIC ALDEHYDES
3321
REFERENCES
1. Axten, J. M.; Brooks, G.; Brown, P.; Davies, D.; Galagher, T. F.; Markwell, R. E.; Miller,
W. H.; Pearson, N. D.; Seefeld, M. WO Patent 2004058144.
2. Miller, W. H.; Rouse, M. B.; Seefeld, M. A. WO Patent 2006081179.
3. Kiyoto, T.; Tanaka, T.; Tsutsui, Y.; Ando, J.; Motono, M.; Kawaguchi, Y.; Noguchi, T.;
Ushiki, Y.; Ushiyama, F.; Urabe, H. WO Patent 2006137485.
4. Kiyoto, T.; Ando, J.; Tanaka, T.; Tsutsui, Y.; Yokotani, M.; Noguchi, T.; Ushiyama, F.;
Urabe, H.; Horikiri, H. WO Patent 2007138974.
5. Geng, B.; Comita-Prevoir, J.; Eyermann, C. J.; Reck, F.; Fisher, S. Bioorg. Med. Chem.
Lett. 2011, 21, 5432–5435.
6. Reck, F.; Alm, R.; Brassil, P.; Newman, J.; DeJonge, B.; Eyermann, C. J.; Breault, G.;
Breen, J.; Comita-Prevoir, J.; Davis, H.; Cronin, M.; Ehmann, D.; Galullo, V.; Geng,
B.; Grebe, T.; Morningstar, M.; Phil, W.; Barry, H.; Fisher, S. J. Med. Chem. 2011, 54,
7834–7847.
7. Brooks, G.; Dabbs, S.; Davies, T. D.; Hennessy, A. J.; Jones, G. E.; Markwell, R. E.;
Miles, T. J.; Owston, N. A.; Pearson, N. D.; Peng, T. W. Tetrahedron Lett. 2010, 51,
5035–5037.
8. Brennfuhrer, A.; Neumann, H.; Klaus, S.; Riermeier, T.; Almena, J.; Beller, M. Tetrahedron
2007, 63, 6252–6258.
9. Pri-Bar, I.; Buchman, O. J. Org. Chem. 1984, 49, 4009–4011.
10. Okano, T.; Harada, N.; Kiji, J. Bull. Chem. Soc. Jpn. 1994, 67, 2329–2332.
11. Klaus, S.; Neumann, H.; Alexander, Z.; Struebing, D.; Huebner, S.; Almena, J.;
Riermeier, T.; Gross, P.; Sarich, M.; Krahnert, W.; Rossen, K.; Beller, M. Angew. Chem.
Int. Ed. 2005, 45, 154–158.
12. Ashfield, L.; Barnard, C. F. J. Org. Proc. Res. Dev. 2007, 11, 39–43.
13. Istvan, T.; Gyula, D. J. Heterocycl. Chem. 1988, 25, 273–277.
14. Miller, W. H.; Rouse, M. B.; Seefeld, M. A. WO2006014580.