The design of efficient and selective routes to pyridyl analogues of 3-oxo-3,4-dihydro-2H-1,4-(benzothiazine or benzoxazine)-6-carbaldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.07.095

This Letter describes the synthesis of challenging pyridyl analogues of 3-oxo-3,4-dihydro-2H-1,4-(benzothiazine or benzoxazine)-6-carbaldehydes. The six different routes described are high yielding, contain no major purification issues and have been used to give gram quantities of each aldehyde.

Full text of DOI:10.1016/j.tetlet.2010.07.095

Tetrahedron Letters 51 (2010) 5035–5037
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The design of efficient and selective routes to pyridyl analogues of
3-oxo-3,4-dihydro-2H-1,4-(benzothiazine or benzoxazine)-6-carbaldehydes
Gerald Brooks b, Steven Dabbs a, David T. Davies b, Alan J. Hennessy a, Graham E. Jones b, Roger E. Markwell b,
b
c
c
Timothy J. Miles a, , Nathan A. Owston , Neil D. Pearson , Tony W. Peng
*
a Antibacterial Discovery Performance Unit, Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
b Antibacterial Discovery Performance Unit, Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK
c Antibacterial Discovery Performance Unit, Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the synthesis of challenging pyridyl analogues of 3-oxo-3,4-dihydro-2H-1,4-(benzo-
thiazine or benzoxazine)-6-carbaldehydes. The six different routes described are high yielding, contain
no major purification issues and have been used to give gram quantities of each aldehyde.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 April 2010
Revised 29 June 2010
Accepted 16 July 2010
Available online 22 July 2010
As part of an antibacterial medicinal chemistry programme we
used commercially available 3-oxo-3,4-dihydro-2H-(1,4-benzothi-
azine and benzoxazine)-6-carbaldehydes 1 and 2 (Fig. 1). We also
required an access to the non-commercial pyridyl analogues of
these aldehydes 3–8.
give alcohol 19. Oxidation was carried out using MnO2 as the oxi-
dant to afford the desired aldehyde 4 in 55% yield.
Aldehyde 5 was synthesised from commercially available 5-hy-
droxy-2-methylpyridine (20) (Scheme 3).6 The first step involved
formation of the N-oxide using m-CPBA, then alkylation with
methyl bromoacetate to give compound 21 in 53% yield over two
steps. This material was then nitrated selectively and the resulting
free acid was re-protected with MeI to give methyl ester 22. Rear-
rangement of 22 gave TFA-protected alcohol 23 in 34% yield. Dur-
ing purification by column chromatography of 23, some cleavage of
the TFA group was observed. Both TFA-protected and unprotected
23 were carried through the next steps to give alcohol 24. This in-
volved reduction of the nitro group with spontaneous cyclisation
and deprotection to give the desired alcohol 24 in 66% yield over
Although the synthesis of both 3-oxo-3,4-dihydro-2H-1,4-(ben-
zothiazine and benzoxazine)-6-carbaldehydes 1 and 2 was known,1
aldehydes 3–8 were unknown in the literature at this time.
For compound 3 we opted to start from commercially available
nitrophenol 9 (Scheme 1).2 Firstly, we protected the phenol as the
methoxy derivative, then brominated and removed the methyl
group to give the desired bromo nitro alcohol 10 in 96% yield over
three steps. Bromo nitro alcohol 10 was then alkylated with bromo
ethyl acetate using K2CO3 as base to give 11 in 89% yield. The nitro
group was reduced by iron which gave the free aniline, that imme-
diately cyclised to give bromide 12. From here many possible
routes are plausible to give the desired aldehyde 3. In the interest
of producing 13 on large scale we opted for a Suzuki reaction fol-
lowed by oxidative cleavage. Using this route we were able to pro-
duce aldehyde 3 on kilogram scale.
O
O
O
O
O
O
H
N
H
N
O
O
O
O
O
O
H
H
H
H
H
H
O
S
For aldehyde 4 (Scheme 2),4 a literature search revealed a key
intermediate 5-bromo-amino ester 15.5 This was synthesised from
commercially available pyridine 14 using the procedure described
by Kelly,5 via bromination to give 15 in a 1:1 mixture with the
undesired 3-bromo isomer 16. Both isomers were easily separated
by column chromatography. The bromine of 15 was then displaced
by ethyl 2-mercaptoacetate and the intermediate cyclised immedi-
ately to give ester 17. This ester was converted into the acid, then
activated with iso-butyl chloroformate and reduced using NaBH4 to
1
2
5
6
O
O
H
N
H
N
H
N
O
O
N
N
H
H
N
N
O
O
O
N
N
7
8
3
4
H
N
H
N
H
N
S
S
S
* Corresponding author. Tel.: +44 1438769482.
E-mail address: tim.j.miles@gsk.com (T.J. Miles).
Figure 1. Required pyridyl analogues of 3-oxo-3,4-dihydro-2H-1,4-(benzothiazine
and benzoxazine)-6-carbaldehydes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.095

5036
G. Brooks et al. / Tetrahedron Letters 51 (2010) 5035–5037
a - b
NO2
OH
N
a - c
NO2
OH
N
Br
N+
-
OMe
N
O
O
OH
53% over 2 steps
96% over 3 steps
O
20
21
c - d
9
10
22% over
2 steps
89%
d
OTFA
N
H
N
O
NO2
e
N
Br
NO2
e
NO2
N
Br
N+
OMe
OMe
-
O
34%
O
f
O
OEt
O
O
80%
O
23
O
O
O
22
12
O
11
66% over
2 steps
f - g
58%
OH
N
Ph
O
H
N
H
N
H
N
O
H
N
O
N
h
H
O
g
N
H
N
O
O
O
66%
O
5
82%
24
3
13
Scheme 3. Synthetic approach to 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-
7-carbaldehyde (5).3 Reagents and conditions: (a) m-CPBA, CHCl3, rt, 1 h; (b)
BrCH2CO2Me, K2CO3, rt, o/n; (c) fuming HNO3, concd H2SO4, 65 °C, o/n; (d) MeI,
K2CO3, rt, 3 days; (e) (CF3CO)2O, reflux, o/n; (f) AcOH, Fe, 60 °C, 1 h; (g) NaOH, 1,4-
dioxane, H2O, rt, o/n; (h) MnO2, THF, ClCH2CH2Cl, 60 °C, 20 h.
Scheme 1. Synthetic approach to 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-
6-carbaldehyde (3).3 Reagents and conditions: (a) NaOMe, MeOH, rt; (b) Br2, 0 °C,
30 min; (c) AcOH; (d) BrCH2CO2Et, K2CO3, Me2CO, reflux, 10 h; (e) NH4Cl, Fe, H2O,
MeOH, reflux, o/n; (f) (HO)2BCH = CHPh, K2CO3, Pd(PPh3)4, H2O, 1,4-dioxane, reflux,
o/n; (g) O3, CH2Cl2, À78 °C, 15 min, then Me2S, À78 °C, 3 h then rt, o/n. o/n,
overnight.
a - b
37% over 2 steps
NH2
+
NH2
Br
N
MeO2C
N
MeO2C
Br
NH2
N
MeO2C
-
N
N
a
F
O
NH2
+
26
25
16 25%
15 25%
14
73% over
2 steps
c - d
b
Quant.
OAc
NO2
e
NO2
S
H
N
O
H
N
N
HO2C
c
O
+
MeO2C
N
OEt
N
OEt
N
-
S
27%
O
S
28
O
O
O
86%
S
27
18
53% over
2 steps
17
f - g
74% over
2 steps
d - e
OH
O
H
N
O
H
H
N
OH
O
H
H
N
h
O
N
N
f
H
O
N
N
N
S
77%
S
S
S
6
55%
29
4
19
Scheme 4. Synthetic approach to 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thia-
zine-7-carbaldehyde (6).3 Reagents and conditions: (a) HBF4, BunONO, EtOH,
À5 °C, 3 h; (b) m-CPBA, CH2Cl2, rt, o/n; (c) fuming HNO3, concd H2SO4, 70 °C,
5.5 h; (d) HSCH2CO2Et, 1,4-dioxane, NaH, rt, 3 days; (e) Ac2O, 80 °C, 6 h; (f) AcOH,
Fe, 60 °C, 3 h; (g) NaOH, 1,4-dioxane, H2O, rt, o/n; (h) MnO2, THF, ClCH2CH2Cl, 65 °C,
o/n.
Scheme 2. Synthetic approach to 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thia-
zine-6-carbaldehyde (4).3 Reagents and conditions: (a) Br2, CHCl3, rt; (b)
HSCH2CO2Et, NaH, DMF, 0 °C, 1 h, then 15, rt, o/n; (c) NaOH, H2O, 1,4-dioxane,
reflux, o/n; (d) ClCO2Bui, Et3N, THF, À10 °C, 20 min; (e) NaBH4, H2O, À10 °C, 30 min,
then HCl, H2O, rt, pH 7; (f) MnO2, THF, CH2Cl2, rt, o/n.
two steps. Finally, we obtained aldehyde 5 in 66% yield via oxida-
tion of alcohol 24 using MnO2.
For aldehyde 7 (Scheme 5),6 Berrie et al. had synthesised 6-
chloro-5-nitro-nicotinic acid methyl ester (31) via nitration fol-
lowed by chlorination of 6-hydroxynicotinic acid (30) in 41% yield
over three steps.8 We displaced the chloride of 31 using ethyl
hydroxyacetate to give ethyl ester 32. This ester was then reduced
with iron and cyclised to afford acid 33 in 72% over two steps. The
acid 33 was then activated with iso-butyl chloroformate and re-
duced using NaBH4 to give alcohol 34. Oxidation of alcohol 34
using MnO2 gave the desired aldehyde 7 in 72% yield.
Scheme 4 shows our route which utilises intermediate 26 to
give aldehyde 6.4 Blanz et al. had synthesised compound 26 using
commercially available 5-amino-2-picoline (25),7 via a Sandmeyer
reaction, then N-oxidation to give N-oxide 26 in 37% yield over two
steps. The first step of our synthesis involved nitration of 26 fol-
lowed by a fluoride displacement using ethyl 2-mercaptoacetate
to give methyl ester 27 in 73% yield over two steps. The N-oxide
rearrangement was performed using Ac2O instead of trifluoroacetic
anhydride (TFAA), otherwise the synthesis followed a very similar
path as that for aldehyde 5 in Scheme 3.
For the final aldehyde 8 we used the same general route as for
aldehyde 7 (Scheme 6),4 but used methyl 2-mercaptoacetate in-
stead of ethyl hydroxyacetate for the chlorine displacement. As

G. Brooks et al. / Tetrahedron Letters 51 (2010) 5035–5037
5037
HO2C
In conclusion, we have demonstrated that all six aldehydes can
be accessed and that all the routes were able to deliver multi-gram
quantities of material.
NO2
Cl
a - c
MeO2C
N
41% over 3 steps
N
31
30
Acknowledgements
68%
d
O
H
N
O
e - f
NO2
O
Acknowledgement is given to Steve Richards and Richard Upton
for NMR support, Bill Leavens for mass spectroscopy support and
all the chemists involved in this work.
MeO2C
HO
OEt
O
N
72% over 2 steps
N
33
O
O
32
39% over
2 steps
g - h
References and notes
OH
O
H
H
N
H
N
1. (a) Belliotti, T. R.; Wustrow, D. J.; Brink, W. A.; Zoski, K. T.; Shih, Y.; Whetzel, S.
Z.; Georgic, L. M.; Corbin, A. E.; Akunne, H. C.; Heffner, T. G.; Pugsley, T. A.; Wise,
L. D. J. Med. Chem. 1999, 42, 5181–5187; (b) Giannopoulos, T.; Ferguson, J. R.;
Wakefield, B. J.; Varvounis, G. Tetrahedron 2000, 56, 447–453.
O
i
O
N
72%
O
N
2. (a) Davies, D. T.; Jones, G. E.; Markwell, R. E.; Miller, W.; Pearson, N. D.
WO2002056882; Chem. Abstr. 2002, 137, 125092.; (b) Miller, W. H.; Price, A. T.
WO2007118130; Chem. Abstr. 2007, 147, 462228.
7
34
3. Selected analytical data: Compound 3: White solid; mp 208–211 °C; 1H NMR
(600 MHz, DMSO-d6): d = 4.81 (s, 2H), 7.51 (d, J = 12 Hz, 1H), 7.62 (d, J = 12 Hz,
1H), 9.77 (s, 1H), 11.63 (br s, 1H). 13C NMR (151 MHz, DMSO-d6): d = 66.9, 119.8,
123.1, 142.0, 143.4, 144.4, 165.4, 191.0 ESI-HRMS: m/z calcd for C8H7N2O3:
179.0457; found 179.0456 [M+H]+.
Scheme 5. Synthetic approach to 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-
7-carbaldehyde (7).3 Reagents and conditions: (a) fuming HNO3, concd H2SO4, 50 °C,
3 h; (b) SOCl2, DMF, 80 °C, o/n; (c) MeOH, 30 min; (d) HOCH2CO2Et, 1,4-dioxane,
NaH, rt, o/n; (e) AcOH, Fe, 60 °C, 2.5 h; (f) NaOH, THF, H2O, rt, 2.5 h; (g) ClCO2Bui,
CH3Cl, DMF, THF, 0 °C, 2 h; (h) NaBH4, H2O, 0 °C, 1 h, then HCl, H2O, rt, pH 7; (i)
MnO2, THF, CH3Cl, rt, o/n.
Compound 4: White solid; mp 187–189 °C; 1H NMR (600 MHz, DMSO-d6):
d = 3.67 (s, 2H), 7.55 (d, J = 12 Hz, 1H), 8.07 (d, J = 12 Hz, 1H), 9.78 (s, 1H), 11.33
(br s, 1H). 13C NMR (151 MHz, DMSO-d6): d = 28.3, 117.2, 122.8, 136.4, 148.5,
149.7, 165.8, 192.0. ESI-HRMS: m/z calcd for C8H7N2O2S: 195.0228; found
195.0229 [M+H]+.
NO2
Cl
MeO2C
Compound 5: White solid; mp 211–213 °C; 1H NMR (600 MHz, DMSO-d6):
d = 4.83 (s, 2H), 7.39 (s, 1H), 8.36 (s, 1H), 9.82 (s, 1H), 11.31 (s, 1H). 13C NMR
(151 MHz, DMSO-d6): d = 66.9, 108.2, 134.4, 137.8, 143.4, 147.5, 164.2, 192.3.
ESI-HRMS: m/z calcd for C8H7N2O3: 179.0457; found 179.0458 [M+H]+.
Compound 6: White solid; mp 216–218 °C; 1H NMR (600 MHz, DMSO-d6):
d = 3.66 (s, 2H), 7.40 (s, 1H), 8.65 (s, 1H), 9.86 (s, 1H), 11.18 (s, 1H). 13C NMR
(151 MHz, DMSO-d6): d = 27.7, 108.3, 121.9, 144.5, 147.6, 150.8, 164.7, 192.8.
ESI-HRMS: m/z calcd for C8H7N2O2S: 195.0228; found 195.0219 [M+H]+.
Compound 7: White solid; mp 261–263 °C; 1H NMR (600 MHz, DMSO-d6):
d = 4.82 (s, 2H), 7.39 (s, 1H), 8.36 (s, 1H), 9.82 (s, 1H), 11.31 (s, 1H). 13C NMR
(151 MHz, DMSO-d6): d = 66.9, 108.2, 134.4, 137.8, 143.4, 147.5, 164.2, 192.3.
ESI-HRMS: m/z calcd for C8H7N2O3: 179.0457; found 179.0458 [M+H]+.
Compound 8: White solid; mp 204–207 °C; 1H NMR (600 MHz, DMSO-d6):
d = 3.72 (s, 2H), 7.58 (s, 1H), 8.60 (s, 1H), 10.01 (s, 1H), 10.90 (br s, 1H). 13C NMR
(151 MHz, DMSO-d6): d = 28.6, 120.5, 129.4, 134.0, 145.7, 149.8, 164.0, 191.3.
ESI-HRMS: m/z calcd for C8H7N2O2S: 195.0228; found 195.0227 [M+H]+.
4. Davies, D. T.; Jones, G. E.; Markwell, R. E.; Miller, W.; Pearson, N. D.
WO2002056882. Chem. Abstr. 2002, 137, 125092.
N
31
76%
a
O
H
N
O
b - c
NO2
S
MeO2C
HO
O
S
N
Quant. over 2 steps
N
36
O
35
52% over
2 steps
d - e
OH
O
H
H
N
O
N
O
f
H
S
N
58%
5. (a) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623–4633; (b) Ontoria, J. M.;
Martin Hernando, J. I.; Malancona, S.; Attenni, B.; Stansfield, I.; Conte, I.;
Ercolani, C.; Habermann, J.; Ponzi, S.; Di Filippo, M.; Koch, U.; Rowley, M.; Narjes,
F. Bioorg. Med. Chem. Lett. 2006, 16, 4026–4030.
6. Brooks, G.; Davies, D. T.; Jones, G. E.; Markwell, R. E.; Pearson, N. D.
WO2003087098; Chem. Abstr. 2003, 139, 337959.
7. Blanz, E. J.; French, F. A.; DoAmaral, J. R.; French, D. A. J. Med. Chem. 1970, 13,
1124–1130.
8. Berrie, A. H.; Newbold, G. T.; Spring, F. S. J. Chem. Soc. 1951, 2590–2594.
S
N
8
37
Scheme 6. Synthetic approach to 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thia-
zine-7-carbaldehyde (8).3 Reagents and conditions: (a) HSCH2CO2Me, CH2Cl2,
Et3N, rt, 1 h; (b) AcOH, Fe, 60 °C, 1 h; (c) NaOH, THF, H2O, rt; (d) ClCO2Bui, Et3N,
THF, À10 °C, 20 min; (e) NaBH4, H2O, 0 °C, 30 min, then HCl, H2O, rt, pH 7; (f) MnO2,
THF, CH3Cl, rt, 18 h.
for aldehyde 7 this route was able to deliver gram quantities of
aldehyde 8.