A convenient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo[b][1,4]thiazines and antibiotic levofloxacin

Article abstract of DOI:10.1016/j.tetlet.2009.05.104

A series of 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 8a-g were synthesized via- a copper-catalyzed intramolecular N-aryl amination reaction on substituted 2-(2-bromophenylthio)-ethanamines which were synthesized by the nucleophilic substitution re

Full text of DOI:10.1016/j.tetlet.2009.05.104

Tetrahedron Letters 50 (2009) 4703–4705
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A convenient synthesis of chiral amino acid derived
3,4-dihydro-2H-benzo[b][1,4]thiazines and antibiotic levofloxacin q
*
Maloy Kumar Parai, Gautam Panda
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 8a–g were synthesized via- a copper-cata-
lyzed intramolecular N-aryl amination reaction on substituted 2-(2-bromophenylthio)-ethanamines
which were synthesized by the nucleophilic substitution reaction of 2-bromobenzenethiol with Boc-pro-
tected amino alcohol derivatives. This strategy provides a short and an efficient entry to (S)-3-methyl-
1,4-benzoxazine 12, an advanced synthetic intermediate for the synthesis of levofloxacin.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 April 2009
Revised 15 May 2009
Accepted 27 May 2009
Available online 30 May 2009
Benzothiazine derivatives represent one of the most important
classes of organic molecules. Among several 1,2-, 1,4-, and 1,3-ben-
zothiazine rings, 1,4-benzothiazines (1,4-BTs), in particular, are of
significant interest and have been extensively studied because of
their profound biological activities1a–g including anti-inflamma-
tory, anti-hypertensive, anti-cancer, anti-fungal, anti-tumor, immu-
nostimulating, anti-aldoso-reductase, anti-rheumatic, anti-allergic,
The importance and utility of this family of compounds have led
to the development of numerous synthetic routes.5,6 Several ap-
proaches have been employed toward synthesis of benzothiazine
derivatives, for example (i) by condensation of 2-aminobenzeneth-
iol with
a
,b-unsaturated acids or esters,7 electron-deficient
alkynes,8 (ii) by treatment of N-unsubstituted and N,N-dialkyldi-
thiodianilines with an enolizable dicarbonyls or esters,9 (iii) by
vasorelaxant, anti-arrhythmic, neuroprotective, cytotoxic, KATP
-
reaction of 2-aminobenzenethiol with a-haloketones, a-haloacetic
channel openers, and anti-HIV activities. The diverse activities
illustrate that 1,4-BT is a template potentially useful in medicinal
chemistry research and therapeutic applications. Examples include
anti-hypertensive drug2 semotiadil (1), calcium antagonists (2),3
anti-fungal agent (3)4 (Fig. 1).
acids, acid chlorides, or esters,10a,10b and (iv) by condensation of
benzil or p-methoxy benzil with an aromatic amine.11 Ring
enlargement of 2-chloromethylbenzothiazole11 and ring contrac-
tion of benzothiazepinones12 have also been reported to produce
benzothiazinones. To the best of our knowledge, synthesis of ami-
no acid based 1,4-benzothiazine derivatives by copper-catalyzed
aryl amination reaction has not been reported so far.
In our ongoing program we are engaged in the synthesis of
S-amino acid based benzo-fused heterocyclic structures bearing
nitrogen, oxygen, and sulfur atoms.13 Interest in the use of easily
accessible and versatile proteinogenic amino acids as a chiral pool
for the synthesis of enantiomerically pure heterocycles has been
growing because of their response to the enantiospecificity shown
by most biological systems and the increased demand to market
chiral drugs as single enantiomers. We recognized that the cop-
per-catalyzed aryl amination approach for the formation of car-
bon-heteroatom bond offers a better and more convenient route
to the synthesis of 3-substituted chiral 3,4-dihydro-2H-
benzo[b][1,4]thiazines in optically pure form.
OMe
O
O
N
S
Me
N
O
N
O
O
Me
Semotiadil 1
OMe
N
O
S
N
S
O
N
Cl
CH3
Toward this objective, 4-methylbenzenesulfonate derivatives
5a–g were prepared from N-Boc amino alcohols which were
obtained from N-Boc-amino acids. Intermolecular nucleophilic
substitution reaction between commercially available 2-bromo-
benzenethiol 4 and 5a–g under NaH/THF condition gave 6a–g in
73–78% yields. Deprotection of Boc functionality in 6a–g fur-
nished 7a–g which under copper iodide and anhy. K2CO3 cata-
lyzed N-arylation reaction in N,N-dimethylacetamide afforded
O
3
2
Figure 1. Structures of some biologically important 1,4-BTs.
q
CDRI communication number 7744.
* Corresponding author. Tel.: +91 522 2612411 18x4385, 4469, 4474; fax: +91
522 2623405.
E-mail address: gautam.panda@gmail.com (G. Panda).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.104

4704
M. K. Parai, G. Panda / Tetrahedron Letters 50 (2009) 4703–4705
enantiomerically pure 3,4-dihydro-2H-benzo[b][1,4]thiazines 8a–g
(Scheme 1).
The scope of this methodology has been further extended to-
ward the formal asymmetric synthesis of the potent antibiotic drug
levofloxacin.14 The major challenge associated with developing an
asymmetric entry to levofloxacin lies in identifying efficient routes
to the key chiral benzoxazine core 12, and in this regard, several
approaches have been reported.15 We have achieved the synthesis
Br
R
Br
S
BocHN
a
+
R
SH
OTs
5a-g
6a-g
4
NHBoc
b
R=CH3
=CH(CH3)2
H
N
Br
R
c
=CH2CH(CH3)2
=CH(CH3)CH2CH3
=CH2C6H5
=CH2(4-OBn)C6H4
= -CH2CH2CH2-
R
S
7a-g
S
8a-g
NH2
of 12 from the reaction between
L-alanine-derived 4-methylben-
zenesulfonate derivative 5a and 6-bromo-2,3-difluorophenol16
9
Scheme 1. Reagents and conditions: (a) NaH, THF, rt, 2–3 h; (b) 10% TFA in CH2Cl2,
rt, 4–5 h; (c) 0.20 equiv CuI, K2CO3, DMA, 100–110 °C, 48 h.
through the formation of 10 and 11 using the methodology de-
scribed in this Letter (Scheme 2). This intermediate can easily be
converted to levofloxacin by reported methods.15a–d
Br
Br
Me
In conclusion, we have demonstrated an efficient synthesis
BocHN
+
a
of
a new series of enantiomerically pure 3,4-dihydro-2H-
Me
F
O
F
OH
benzo[b][1,4]thiazines 8a–g and a formal synthesis of antibiotic
levofloxacin 13 from naturally abundant chiral amino acids via-
copper-catalyzed intramolecular aryl amination reaction. Ease of
the reaction sequence gave an access to enantiomerically pure chi-
ral benzothiazines and benzoxazines, which could have interesting
biological properties (Table 1).
OTs
F
NHBoc
F
9
5a
10
b
O
N
H
CO2H
F
Br
N
Me
c
Me
N
F
O
F
O
N
O
F
NH2
F
Me
Me
Acknowledgments
13
12
11
This research project was partly supported by Department of
Science and Technology (SR/S1/OC-23/2005) and ICMR, New Delhi,
India. Maloy thanks CSIR for providing fellowships.
Scheme 2. Reagents and conditions; (a) NaH, DMF, 100 °C, 5–6 h; (b) 10% TFA in
CH2Cl2, rt, 4–5 h; (c) 0.20 equiv CuI, K2CO3, DMA, 100–110 °C, 36 h.
Supplementary data
Table 1
Entry
Product
% ee
>99
Yield (%)
66
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.104.
H
N
1
References and notes
S
8a
1. 1,4-Benzothiazines (a) as anti-inflammatory agents: (i) Lombardino, J. G.;
Wiseman, E. H. Med. Res. Rev. 1982, 2, 127; (ii) Turk, C. F. J. Med. Chem. 1973, 16,
776. (b) as anti-hypertensive agents: (i) Prasad, R. N. J. Med. Chem. 1969, 12,
290; (ii) Cecchetti, V.; Fravolini, A.; Schiaffella, F.; DeRegis, M.; Orzalesi, G.;
Volpato, I. Farmaco. Ed. Sci. 1983, 38, 35. (c) As anti-cancer agents: (i) Gupta, R.
R.; Dev, P. K.; Sharma, M. L.; Rajoria, C. M.; Gupta, A.; Nyati, M. Anticancer Drugs
1993, 4, 589; (ii) Todorov, D. K.; Ilarionova, M. V.; Gupta, R. R.; Molnar, J.;
Motohashi, N. Heterocycl. Commun. 1995, 1, 153. (d) as anti-fungal agent: (i)
Schiaffella, F.; Macchiarulo, A.; Milanese, L.; Vecchiarell, A.; Fringuell. R. Bioorg.
Med. Chem. 2006, 14, 5196; (ii) Fringuelli , R .; Schiaffella, F.; Bistoni, F.;
Pitzurra, L.; Vecchiarelli, A. Bioorg. Med. Chem. 1998, 6, 103. (e) as anti-tumour
agent: (i) Coughlin, S. A.; Danz, D. W.; Robinson, R. G.; Klingbeil, K. M.;
Wentland, M. P.; Corbett, T. H.; Waud, W. R.; Zwelling, L. A.; Altsschuler, E.
Biochem. Pharmacol. 1995, 50, 111. (ii) Hasegawa, K.; Ito, S.; Inoue, S.;
Wakamatsu, K.; Ozeki, H.; Ishiguro, I. Biochem. Pharmacol. 1997, 53, 1435. (iii)
Inoue, S.; Hasegawa, K.; Wakamatsu, K.; Ito, S. Melanoma Res. 1998, 8, 105. (f) as
KATP-Channel Openers (i) Cecchetti, V.; Calderone, V.; Tabarrini, O.; Sabatini, S.;
Filipponi, E.; Testai, L.; Spogli, R.; Martinotti, E.; Fravolini, A. J. Med. Chem. 2003,
46, 3670. (g) as anti-HIV agent: (i) Grandolini. G;, Perioli.L;, Ambarogi. V. Eur. J.
Med. Chem. 1999, 34, 701; h) as CETP inhibitors: (i) Kuo, G.; Wang, A.; Rano, T.;
Prouty, C.; Demarest, K. T.; Pelton, P. US patent, 2007, WO/134149.
H
N
2
3
4
5
6
7
>99
>99
>99
>99
>99
>99
64
68
63
65
72
61
S
8b
8c
H
N
S
H
N
S
8d
8e
8f
H
N
2. Morino, T.; Yamamoto, T. J. Chem. Eng. Jpn. 1997, 30, 1005.
3. Corelli, F.; Manetti, F.; Tafi, A.; Campiani, G.; Nacci, V.; Botta, M. J. Med. Chem.
1997, 40, 125.
4. Macchiarulo, A.; Costantino, G.; Fringuelli, D.; Vecchiarelli, A.; chiaffella, F.;
Fringuelli, R. Bioorg. Med. Chem. 2002, 10, 3415.
S
5. (a) Babudri, F.; DiNunno, L.; Florio, S. Tetrahedron 1982, 38, 3059; (b) Babudri,
F.; DiNunno, L.; Florio, S. Synthesis 1983, 230; (c) Huang, X.; Chan, C.-C.
Synthesis 1984, 851; (d) Marfat, A.; Carta, M. P. Synthesis 1987, 515; (e) Trapani,
G.; Latrofa, A.; Reho, A.; Liso, G. J. Heterocycl. Chem. 1989, 26, 721; (f) Singh, H.;
Singh, D. J.; Kumar, S. Indian J. Chem. Sect. B 1992, 31B, 217; (g) Rai, D.; Gupta,
V.; Gupta, R. R. Heterocycl. Commun. 1996, 2, 273.
6. (a) Lanoquist, J. K. Six membered Ring Systems. In Comprehensive Organic
Chemistry; Barton, D., Ollis, W. D., Sammes, P. G., Eds.; Heterocyclic
Compounds; Pergamon Press: Oxford, 1979; Vol. 4, p 1092; (b) Brown, C.;
Davidson, R. M. Adv. Heterocycl. Chem. 1985, 38, 135; (c)Phenothiazines and 1,4-
Benzothiazines: Chemical and Biomedical Aspects; Gupta, R. R., Ed.Bioactive
Molecules; Elsevier: Amsterdam, Neth, 1988; Vol. 4, (d) Sainsbury, M. 1,4-
Thiazines, 1,4-Benzothiazines, Phenothiazines and Related Compounds, 2nd
H
N
S
OBn
N
S
8g

M. K. Parai, G. Panda / Tetrahedron Letters 50 (2009) 4703–4705
4705
ed.. In Rodd’s Chemistry of Carbon Compounds; Elsevier: Amsterdam, Neth, 1998;
Vol. 4, pp 575–608 (Part G (partial)/Part H).
7. Kirchner, F. K.; Alexander, E. J. J. Am. Chem. Soc. 1959, 81, 1721.
8. Balasubramaniyan, V.; Balasubramaniyan, P.; Shaikh, A. S. Tetrahedron 1986, 42,
2731.
9. Florio, S.; Capriati, V.; Colli, G. Tetrahedron 1997, 53, 5839.
10. (a) Unger, O. Chem. Ber. 1897, 30, 607; (b) Unger, O.; Graff, G. Chem. Ber. 1897,
30, 2389.
11. Charrier, J. D.; Landreau, C.; Deniaud, D.; Reliquet, F.; Reliquet, A.; Meslin, J. C.
Tetrahedron 2001, 57, 4195.
12. Erker, T.; Bartsch, H. Liebigs Ann. Chem. 1992, 403.
13. (a) Mishra, J. K.; Panda, G. J. Comb. Chem. 2007, 9, 321; (b) Srivastava,
A. K.; Panda, G. Chem. Eur. J. 2008, 14, 4675–4688; (c) Mishra, J. K.;
Panda, G. Synthesis 2005, 1881–1887; (d) Mishra, J. K.; Garg, P.; Dohare,
P.; Kumar, A.; Siddiqi, M. I.; Ray, M.; Panda, G. Bioorg. Med. Chem. Lett.
2007, 17, 1326–1331.
14. Ellsworth, E. L.; Tran, T. P.; Showalter, D. H.; Sanchez, J. P.; Watson, B. M.; Stier,
M. A.; Domagala, J. M.; Gracheck, S. J.; Joannides, E. T.; Shapiro, M. A.; Dunham,
S. A.; Hanna, D. L.; Huband, M. D.; Gage, J. W.; Bronstein, J. C.; Liu, J. Y.; Nguyen,
D. Q.; Singh, R. J. Med. Chem. 2006, 49, 6435. and references cited therein.
15. (a) Hayakawa, I.; Atarashi, S.; Imamura, M.; Yokohama, S.; Higashihashi, N.;
Sakano K.; Ohshima, M. US patent, 1986, 5, 53, 407.; (b) Atarashi, S.; Yokohama,
S.; Yamazaki, K.; Sakano, K.; Imamura, M.; Hayakawa, I. Chem. Pharm. Bull.
1987, 35, 1896; (c) Sakano, K.; Yokohoma, S.; Hayakawa, I.; Atarashi, S.;
Kadoya, S. Agric. Biol. Chem. 1987, 51, 1265; (d) Mitscher, L. A.; Sharma, P. N.;
Chu, D. T. W.; Shen, L. L.; Pernet, A. G. J. Med. Chem. 1987, 30, 2283; (e) Atarashi,
S.; Tsurumi, H.; Fujiwara, T.; Hayakawa, I. J. Heterocycl. Chem. 1991, 28, 329; (f)
Kang, S. B.; Ahn, E. J.; Kim, Y.; Kim, Y. H. Tetrahedron Lett. 1996, 37, 9317; (g)
Satoh, K.; Inenaga, M.; Kanai, K. Tetrahedron: Asymmetry 1998, 9, 2657; (h)
´
Adrio, J.; Carretero, J. C.; Ruano, J. L. G.; Pallares, A.; Vicioso, M. Heterocycles
1999, 51, 1563.
16. Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 3283.