Expeditious synthesis of C2- or N4-aryl-1,4-benzothiazin-3-one via orthogonal Pd-catalyzed C-arylation and Cu-catalyzed N-arylation

Article abstract of DOI:10.1016/j.tetlet.2013.11.053

Direct, chemo-specific arylation at C-2 or N-4 of 1,4-benzothiazin-3-one with aryl halides, based on Pd or Cu catalyst system, respectively, provided easy entry to arylated derivatives, a class of molecules not easily accessible via existing methods. Under Pd-catalysis conditions with LiHMDS as the base, N-arylation of 1,4-benzothiazin-3-one was inhibited leading to Cα-arylation of a secondary amide without the need for protection and de-protection of more acidic amido NH.

Full text of DOI:10.1016/j.tetlet.2013.11.053

Tetrahedron Letters 55 (2014) 441–444
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expeditious synthesis of C2- or N4-aryl-1,4-benzothiazin-3-one via
orthogonal Pd-catalyzed C-arylation and Cu-catalyzed N-arylation
⇑
Wei-Sheng Huang , Rongsong Xu, Rory Dodd, William C. Shakespeare
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct, chemo-specific arylation at C-2 or N-4 of 1,4-benzothiazin-3-one with aryl halides, based on Pd or
Cu catalyst system, respectively, provided easy entry to arylated derivatives, a class of molecules not
easily accessible via existing methods. Under Pd-catalysis conditions with LiHMDS as the base, N-aryla-
Received 18 October 2013
Revised 9 November 2013
Accepted 13 November 2013
Available online 21 November 2013
tion of 1,4-benzothiazin-3-one was inhibited leading to C
need for protection and de-protection of more acidic amido NH.
Ó 2013 Elsevier Ltd. All rights reserved.
a-arylation of a secondary amide without the
Keywords:
C-arylation
N-arylation
Pd-catalysis
Cu-catalysis
1,4-Benzothiazin-3-one
Heterocycle synthesis
1,4-Benzothiazin-3-one (BZTZN) is
a
heterocyclic scaffold
C2-aryl-BZTZNs.14 The synthesis of N4-aryl-BZTZN is very rare;
only isolated examples have been reported including: (i) introduc-
tion of the 4-fluorophenyl group from Cu(OAc)2-mediated
oxidative coupling of corresponding aryl boronic acid with a 2,2-
disubstituted BZTZN,15 (ii) N-(4-hydroxyphenyl) derivatization
via the reaction of 4-acetoxy BZTZN with phenol,16 (iii) phenyla-
tion via the reaction of BZTZN with phenyl bromide under
refluxing condition (bp 156 °C) in the presence of excessive copper
powder,17 or lately via Cu-catalyzed coupling of N-(2-iodophenyl)-
N-phenyl-2-chloroacetamide with thioacetic acid.18 More recently,
a new synthesis of N-aryl-BZTZN was developed from condensa-
tion of 3,4-difluorobenzonitrile with certain 2-mercapto-N-arylac-
etamides via Smiles rearrangement.19 These existing methods
suffer a number of drawbacks such as limited availability of diverse
starting materials or lengthy synthesis of requisite starting materi-
als, multi-step reaction sequences, harsh reaction conditions, nar-
row reaction scopes, poor regioselectivity, and in many cases,
low yields. These limitations prompted us to develop convenient
and general syntheses of C2- and N4-aryl BZTZNs from easily
accessible starting materials.
frequently used in drug design. For example, Sesamodil, an 2-
aryl-4-methyl BZTZN compound has been clinically used as an
antihypertensive and antiarrhythmic agent.1 Compounds based
on the BZTZN motif were also reported as histamine H1 antago-
nist,2 anticonvulsant/antifungal agents,3 sodium glucose co-trans-
ported 2 inhibitors,4 Ca2+-activated potassium channel opener,5
phosphodiesterase 7 inhibitors,6 5-HT3 antagonists,7 and Na+/H+
exchange inhibitors.8
Very recently, we reported a novel one-step synthesis of BZTZNs
from Cu-catalyzed coupling of readily available substituted 2-iod-
oanilines with 2-mercaptoacetate. This methodology allows easy
introduction of structural diversity at the phenyl ring of BZTZN
nuclei.9 To further derivatize BZTZN, we were particularly inter-
ested in its C2- or N4-aryl analogs. Literature survey indicated
studies on the synthesis of these types of molecules were limited.
The C2-aryl-BZTZN has been synthesized via methods involving: (i)
SN2 substitution reaction of 2-aminothiophenol and alpha-halo-
arylacetate followed by cyclization,10 (ii) condensation of 2-amino-
thiophenol and aryltrichlorocarbinol,11 (iii) Friedel–Crafts reaction
of C2-Cl derivative with benzenes bearing directing groups such as
alkoxy and hydroxyl,12 and (iv) base-mediated condensation of
2,20-diaminodiphenyl disulfides with arylacetates.13 A recent study
on the condensation of 3-aryl-2,2-oxiranedicarbonitrile with
In view of tremendous advances in Pd- and Cu-catalyzed N- and
C-arylation,20 one can envisage direct, catalytic arylation of parent
BZTZN with aryl halides could provide easy access to 2- or 4-aryl
BZTZNs. To our surprise, such an arylation has not been applied
to BZTZN hitherto.21 One issue associated with arylation of BZTZN
is chemoselectivity between C-2 and N-4. In this regard, chemose-
lective arylation at C-3 and N-1 of oxindole has been investigated;
while Pd-catalysis promoted C-arylation,22a,b Cu-catalysis favored
2-aminothiophenol included
a few examples of synthesis of
⇑
Corresponding author. Tel.: +1 617 621 2341; fax: +1 617 494 8144.
E-mail address: wei-sheng.huang@ariad.com (W.-S. Huang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.053

442
W.-S. Huang et al. / Tetrahedron Letters 55 (2014) 441–444
N-arylation.22a,c Unlike oxindole bearing an amide moiety and a
methylene group with comparable pKa (ꢀ18.5), the methylene pro-
tons (pKa ꢀ26) in the BZTZN are less acidic than its amide NH (pKa
ꢀ19).23 Owing to competing N-arylation, C-arylation of BZTZN was
expected to be more challenging relative to C-arylation of oxindole.
Upon optimization of reaction conditions we have discovered that
using lithium bis(trimethylsilyl)amide as the base chemo-specific
C-arylation of BZTZN can be achieved under Pd-catalysis condi-
tions. To the best of our knowledge, C2-arylation of BZTZN re-
ported herein represents the first example of an inter-molecular,
chemo-specific arylation at the alpha carbon of amides bearing
more acidic, unprotected amido NH.24
To explore Cu-catalyzed N-arylation of BZTZN, we initially
adopted a catalyst system consisting of 5% CuI and 10% trans-
N,N0-dimethylcyclohexane-1,2-diamine. This combination of Cu
source and ligand has proved particularly efficient in promoting
amidation of aryl halides.20b We were pleased to find this catalyst
system was also highly effective at driving N-arylation of BZTZN.
As shown in Table 1, both meta- and para-substituted aryl iodides
and bromides reacted smoothly under mild conditions, furnishing
the desired N-aryl derivative as the sole product and in high yield.
In all examples, no C2-aryl products were detected based on LC–
MS analysis of crude reaction mixtures and/or comparison of HPLC
traces of crude mixtures with those generated from Pd-catalyzed
C2-arylation (vide infra). The electronic nature of substituents on
the aryl ring had little effect on the reaction as aryl halides bearing
electron-withdrawing (entries 3 and 4) or electron-donating (en-
tries 5–7) groups reacted equally well. All reactions proceeded to
completion after heating at 100 °C overnight; the difference in iso-
lated yields largely resulted from material loss in workup and puri-
fication. Under standard conditions, ortho- substituted aryl halides
were not suitable coupling partners as 1-fluoro-2-iodobenzene
could not be coupled using the same catalyst system. Analogous
resistance of ortho-substituted aryl halide was also observed in
Cu-catalyzed N-arylation of oxindoles.22a,c
resulted from arylation at free NH.25 For example, employing either
Pd, Cu or Fe-catalysis conditions, arylation of 2-pyrrolidinone al-
ways occurred at the more acidic NH;20a-b,26 no direct C-arylation
was reported on this simple lactam substrate. To effect a chemo-
specific C-arylation of BZTZN, inhibition of N-arylation at the more
acidic amido NH needs to be addressed. We selected the coupling
of BZTZN 1 and PhBr as model reaction to screen reaction condi-
tions. Initially this coupling was run in m-xylene under microwave
irradiation at 150 °C using Pd2(dba)3/xantphos catalyst system. As
shown in Table 2, the base appeared to have played a critical role in
the C-arylation of BZTZN. Among the two bases employed in C-ary-
lation of oxindole, K2CO3 was completely ineffective for C-arylation
of BZTZN whereas NaOt-Bu yielded 50% conversion of 1 and 1:1
mixture of C- and N-phenyl products. Cs2CO3 was a more efficient
base leading to 62% conversion with a 3:1 selectivity ratio (C– vs
N–). Under otherwise identical conditions, one equivalent of the
strong base lithium bis(trimethylsilyl)amide (LHMDS) did not fur-
nish any arylation product; starting 1 was completely recovered.
The fact that N-arylation was not observed after deprotonation of
the amide NH by 1 equiv LHMDS suggested that chemospecific
C-arylation might be possible once another equivalent of base
was added to deprotonate the C-2 methylene of BZTZN. Indeed,
reaction in the presence of 2.5 equiv LHMDS led to 80% conversion
of starting 1 into a new compound which was determined to be 2-
phenyl BZTZN after purification. HPLC comparison of the crude
mixture with an authentic sample of 4-phenyl BZTZN generated
from Cu-catalyzed N-arylation revealed that no N4-phenylation
product was formed in this Pd-catalyzed reaction. Detailed study
to understand the role of LHMDS in this reaction was not yet car-
ried out. Presumably the amide was converted into a trimethylsilyl
imidate upon deprotonation, thereby blocking reaction at the
amide site. Such a dual function of LHMDS was observed by Buch-
wald in the Pd-catalyzed regio-specific N-arylation of amines in
the presence of an amide moiety.27
Having identified LHMDS as a suitable base for chemospecific
C2-arylation, we briefly examined how additional factors such as
solvent, method of heating, and catalyst systems influenced cou-
pling. In 1,4-dioxane the reaction also yielded C-arylation product
exclusively albeit with a lower conversion. Similarly, reactions
employing conventional heating retained chemospecificity but
exhibited lower conversions. A small catalyst screen did not yield
more successful results. With Pd2(dba)3 as Pd source, three differ-
ent phosphorus ligands, namely xantphos, X-phos, or 2,20-bis(dicy-
clohexylphosphino)-1,10-biphenyl, were examined. All provided
C-arylation product exclusively upon heating at 100 °C overnight
with xantphos exhibiting the highest conversion (50%). Another li-
gand, t-Bu-xantphos, proved ineffective along with [PdP(t-Bu)3Br]2,
a system with Pd pre-bound to bulky, electron rich phosphorus
ligand.
With easy access to N4-aryl-BZTZN discovered, we next turned
our attention to arylation at the other reactive C2 site. Since 1998,
considerable progress has been made in the area of Ca-arylation of
tertiary amides but similar reaction of primary and secondary
amides remains underdeveloped, presumably due to complication
Table 1
Cu-catalyzed N-arylation of 1,4-benzothiazin-3-one 1
O
O
NHMe
NHMe
X
10 mol%
NH
N
+
S
S
R
5 mol% CuI
R
2 equiv Cs2CO3
dioxane, 100 oC, 18 h
X = Br, I
3
2
1
The scope of chemospecific C-arylation of BZTZN was investi-
gated under microwave irradiation and with Pd2(dba)3/xantphos
as the catalyst system. Despite reactions with PhI, PhBr, or PhCl
leading to different conversions, all afforded C-arylation products
exclusively (Table 3, entries 1–3). The chemospecificity from
highly reactive PhI is remarkable since similar C-arylation of oxin-
dole employed aryl chlorides in most cases.22a,b A range of substi-
tuted aryl halides bearing electron-neutral, electron-donating
(entries 4–8), and moderately electron-withdrawing groups (en-
tries 9 and 10) at ortho, meta, or para positions reacted smoothly,
furnishing the C-aryl products in moderate yields. Steric hindrance
did not significantly affect this reaction as ortho-substituted sub-
strates reacted almost equally well (entries 5 and 8). The chemo-
specificity of these reactions was verified by the presence of only
one arylation product peak in HPLC and LC–MS trace of each crude
mixture. The moderate isolated yields could be due to dehalogen-
ation and/or catalyst deactivation, which led to 80–90% conversion
Entry
1
2
Yield of 3 (%)
92 (3a)
Entry
5
2
Yield of 3 (%)
86 (3d)
I
I
OMe
Br
I
I
2
3
87 (3a)
65 (3b)
6
7
62 (3e)
82 (3f)
H2N
I
MeO
I
NO2
I
F
4
65 (3c)
8
0 (3g)
CN

W.-S. Huang et al. / Tetrahedron Letters 55 (2014) 441–444
443
Table 2
Reaction condition optimization for C-arylation of 1 with PhBr
Reaction conditions
Conversion
C- vs N-Ph
2.5 equiv K2CO3, 5% Pd2(dba)3, 10% xantphos, microwave, 150 °C, 1 h, m-xylene
2.5 equiv Cs2CO3, 5% Pd2(dba)3, 10% xantphos, microwave, 150 °C, 1 h, m-xylene
2.5 equiv NaOBut, 5% Pd2(dba)3, 10% xantphos, microwave, 150 °C, 1 h, m-xylene
1 equiv LHMDS, 5% Pd2(dba)3, 10% xantphos, microwave, 150 °C, 1 h, m-xylene
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% xantphos, microwave, 150 °C, 1 h, m-xylene
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% xantphos, microwave, 150 °C, 1 h, 1,4-dioxane
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% xantphos, overnight, 130 °C, 20 h, m-xylene
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% xantphos, overnight, 100 °C, 20 h, m-xylene
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% X-phos, overnight, 100 °C, 20 h, m-xylene
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% b(dchp)bpa, overnight, 100 °C, 20 h, m-xylene
2.5 equiv LHMDS, 5% Pd2(dba)3, 10% t-Bu-xantphos, overnight, 100 °C, 20 h, m-xylene
2.5 equiv LHMDS, 5% [PdP(t-Bu)3Br]2, overnight, 100 °C, 20 h, m-xylene
No reaction
60%
50%
No reaction
80%
46%
55%
50%
32%
38%
75:25
50:50
C-Ph only
C-Ph only
C-Ph only
C-Ph only
C-Ph only
C-Ph only
No reaction
No reaction
a
2,20-Bis(dicyclohexylphosphino)-1,10-biphenyl.
Table 3
isolated yields. Particularly noteworthy is the C
a
-arylation of a
Pd-catalyzed C2-arylation of 1,4-benzothiazin-3-one 1
secondary amide without the need for protection of more acidic
amido NH. We hope our results can provide some insights for C-
arylation of unprotected secondary or primary amides.
X
5 mol% Pd2(dba)3
S
S
10 mol% Xantphos
+
R
N
H
O
2.5 equiv LiHMDS
xylene
N
H
O
R
X = Cl, Br, I
microwave
Acknowledgements
150 oC,
1 h
1
4
5
The authors are grateful to D.M.P.K. group at ARIAD for their
assistance in obtaining HRMS data. We also thank the ResTech
group for their work32 that aroused our interest in developing
methodologies for the synthesis of 2- and 4-arylated1,4-benzothia-
zin-3-ones.
Entry
1
4
Yield of 5 (%) Entry
4
Yield of 5 (%)
72 (5d)
I
I
52 (5a)
6
Me
Br
I
References and notes
2
3
58 (5a)
40 (5a)
7
8
57 (5e)
41 (5f)
Me
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of starting 1 in all cases. Difficult separation of starting 1 and its C-
aryl derivative on silica gel column also compromised isolated
yields. Increasing the molar ratio of aryl halides did not markedly
improve yields as the formation of C-2 di-aryl product often
complicated the reaction and purification. Doubling catalyst load-
ing resulted in only 5% increased isolated yield for the reaction
with 4-iodoanisole. Aryl halides bearing strong electron-withdraw-
ing groups appeared to be troublesome substrates. Under standard
conditions, complicated mixtures were generated from reactions of
para- or meta-(trifluoromethyl)chlorobenzene and the desired C-
arylation products were obtained in 0% and 15% yields,
respectively. With a N-heterocyclic carbene—Pd complex as the
catalyst,28 the reaction of 1-chloro-4-(trifluoromethyl)benzene un-
der otherwise identical conditions was clean but furnished 4-(tri-
fluoromethyl)aniline, a product of direct amination at the chloro
position.29
In summary, we have developed an efficient synthesis of 2- and
4-arylated 1,4-benzothiazin-3-ones via orthogonal, direct arylation
at C-2 or N-4 of parent 1,4-benzothiazin-3-one with aryl halides,
based on Pd or Cu catalyst systems, respectively30,31. The new
synthetic methods offer clear advantages over existing approaches
for their one-step simple operation, wider reaction scope, chemo-
specificity between C- and N-arylation, and moderate to excellent

444
W.-S. Huang et al. / Tetrahedron Letters 55 (2014) 441–444
24. For intramolecular examples: (a) Wolfe, J. F.; Sleevi, M. C.; Goehring, R. R. J. Am.
Chem. Soc. 1980, 102, 3646; (b) Bignan, G. C.; Battista, K.; Connolly, P. J.; Orsini,
M. J.; Liu, J.; Middleton, S. A.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2005, 15, 5022;
(c) Sole, D.; Serrano, O. J. Org. Chem. 2008, 73, 9372.
(m, 6H), 6.40 (dd, J = 1.2, 8.2 Hz, 1H), 3.79 (s, 3H), 3.65 (s, 2H). 13C NMR
(400 MHz, DMSO-d6): d 164.9, 158.7, 141.2, 131.8, 129.9 (2C), 128.0, 126.8,
123.1, 122.1, 119.4, 114.9 (2C), 55.4, 30.7. HRMS (ESI) m/z: [M+H]+ Calcd for
272.0745; Found 272.0731.
25. (a) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676; (b)
Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
26. (a) Shakespeare, William. C. Tetrahedron Lett. 1999, 40, 2035; (b) Correa, A.;
Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862.
27. Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885.
28. Chloro[(1,2,3-eta)-3-phenyl-2-propenyl][1,3-bis(2,6-di-i-propylphenyl)-4,5-
dihydroimidazol-2-ylidene]palladium(II).
29. (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729; (b) Huang, X.;
Buchwald, S. L. Org. Lett. 2001, 3, 3417.
31. General procedure for C-arylation of 1,4-benzothiazin-3-one (Table 3). In a
microwavable tube were placed benzothiazin-3-one (1 mmol), Pd2(dba)3
(0.05 mmol), and xantphos (0.1 mmol). This mixture was carefully purged
with N2 before the tube was capped. Under stirring, anhydrous xylene (2.5 mL)
and a 1.0 M solution of LiHMDS in THF (2.5 mL) were sequentially added. The
resulting mixture was stirred at rt for 10 min before aryl halides (pre-degassed
with N2) was added. This mixture was subjected to microwave irradiation at
150 °C for 1 h. After cooling to rt, filtration was carried out. The combined
filtrates were concentrated on rotavap and the residue was subjected to silica
gel column chromatograph purification (20–30% ethyl acetate in heptane),
furnishing desired products as yellowish solids. 2-(2-Methoxyphenyl)-2H-
benzo[b][1,4]thiazin-3(4H)-one (5c): 163 mg, 60%. 1H NMR (400 MHz, CDCl3) d
9.23 (s, 1H, NH), 7.21–7.27 (m, 3H), 7.12–7.17 (m, 2H), 6.97 (dt, J = 1.2, 7.6 Hz,
1H), 6.92 (dd, J = 1.2, 8.0 Hz, 1H), 6.89 (dd, J = 0.8, 8.4 Hz, 1H), 6.84 (dt, J = 0.8,
7.6 Hz, 1H), 5.19 (s, 1H, CHS), 3.85 (s, 3H, OCH3). 13C NMR (400 MHz, CDCl3): d
167.2, 156.7, 136.2, 129.5, 128.3, 128.0, 127.1, 123.9, 123.6, 120.7, 120.2, 116.9,
111.0, 55.7, 39.6. HRMS (ESI) m/z: [M+H]+ Calcd for 272.0745; Found 272.0733.
32. Kohlmann, A.; Zech, S. G.; Li, F.; Zhou, T.; Squillace, R. M.; Commodore, L.;
Greenfield, M. T.; Lu, X.; Miller, D. P.; Huang, W.-S.; Qi, J.; Thomas, R. M.; Wang,
Y.; Zhang, S.; Dodd, R.; Liu, S.; Xu, R.; Xu, Y.; Miret, J. J.; Rivera, V.; Clackson, T.;
Shakespeare, W. C.; Zhu, X.; Dalgarno, D. C. J. Med. Chem. 2013, 56, 1023.
30. General procedure for N-arylation of benzothiazin-3-one (Table 1).
A
suspension of 1,4-benzothiazin-3-one (1 mmol), aryl halide (1.5 mmol),
copper (I) iodide (0.05 mmol), trans-N,N0-dimethylcyclohexane-1,2-diamine
(0.1 mmol), and cesium carbonate (1.2 mmol) in dry 1,4-dioxane (4 mL) in a
vial was degassed by bubbling N2 into the suspension for 3 min while stirring.
The vial was then capped tightly. The mixture was heated at 100 °C (oil bath
temperature) for 15 h. After cooling to rt, filtration was carried out. The
combined filtrates were concentrated on rotavap and the residue was
subjected to silica gel column chromatograph purification (20–30% ethyl
acetate in heptane), furnishing desired products as yellowish solids. 4-(4-
Methoxyphenyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (3d): 233 mg, 86%. Mp 158–
160 °C. 1H NMR (400 MHz, DMSO-d6): d 7.43 (dd, J = 1.4, 7.6 Hz, 1H), 6.99–7.12