Further studies of benzothiazine metalation

Article abstract of DOI:10.1055/s-0033-1338444

Treatment of benzothiazines 3 and 8 with butyllithium resulted in deprotonation at C3 to afford the corresponding organolithium species. These compounds could be trapped with a variety of electrophiles to give products in high yield. Some limitations to the processes chiefly based on steric effects were uncovered. Interesting and potentially useful side reactions were also established. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338444

PAPER
▌1785
paper
Further Studies of Benzothiazine Metalation
Benzothiazine Metalation
Nathan L. Calkins,1 Michael Harmata*
Department of Chemistry, University of Missouri-Columbia, 601 South College Avenue, Columbia, MO 65211, USA
Fax +1(573)8822754; E-mail: harmatam@missouri.edu
Received: 22.03.2013; Accepted: 02.04.2013
Dedicated to Professor Scott E. Denmark on the occasion of his 60th birthday
A reasonably diverse selection of electrophiles was stud-
ied in order to probe the reactivity of the organolithium
species derived from 3. Several silyl chlorides of various
sizes were used to trap the lithiocarbanion. The yields de-
Abstract: Treatment of benzothiazines 3 and 8 with butyllithium
resulted in deprotonation at C3 to afford the corresponding organo-
lithium species. These compounds could be trapped with a variety
of electrophiles to give products in high yield. Some limitations to
the processes chiefly based on steric effects were uncovered. Inter- creased slightly as the steric bulk of the silyl alkyl groups
esting and potentially useful side reactions were also established.
increased, but all yields remained above 80% (Table 1,
entries 1–4). Very near stoichiometric amounts of chlo-
rotrimethylsilane were needed to prevent formation of
bis-trimethylsilyl product 6 (Figure 2). This type of by-
product had been observed in the reaction of the carbanion
of 1 with the same electrophile, suggesting polylithiation
as a possibility.2 This phenomenon will be reported else-
where. Due to what we ascribe to the acidity of our silica
gel, loss of the trimethylsilyl group was an issue during
chromatography; however, bulkier silyl groups were not
removed during chromatography. Interestingly, no prod-
ucts like 6 were observed with other silyl electrophiles.
Key words: heterocycles, benzothiazine, metalation, alkylation,
sulfoximine
Some years ago, we reported the metalation chemistry of
benzothiazine 1 as a means of functionalizing the ring sys-
tem (Scheme 1).2 At that time, the methodology we had
developed for benzothiazine synthesis produced only ra-
cemic species.3 Later work allowed us to prepare benzo-
thiazines that were essentially enantiomerically pure.4
This renewed our interest in the functionalization of ben-
zothiazines, as we anticipated that such compounds could
be used as chiral ligands5 or intermediates in natural prod-
uct synthesis.6 This report details our study of the scope of
metalation of benzothiazines using two substrates as mod-
els for the process.
H
TMS
O
S
TMS
N
6
H
O
CO2allyl
O
1. n-BuLi, THF
–78 °C, 15 min
2. allyl chloroformate
76%
Figure 2
S
S
N
N
p-Tol
p-Tol
1
2
An aromatic aldehyde, 2-bromobenzaldehyde, reacted
very smoothly to give the product 5g in 94% yield as a
1.4:1 mixture of diastereomers (Table 1, entry 7). Both cy-
clic and acyclic symmetrical ketones were trapped
smoothly to give the corresponding products in greater
than 85% yields for all examples (Table 1, entries 6, 10,
13, and 17). Ethylene oxide reacted uneventfully to give
5o in 91% yield (Table 1, entry 15). Polymeric paraform-
aldehyde provided alcohol 5n in 76% yield; however, the
reaction was very exothermic and could not be reproduced
on a larger scale. Other electrophiles such as 1,2-dibromo-
1,1,2,2-tetrachloroethane, iodine, and N,N-dimethylform-
amide gave very clean reactions in respectable to excel-
lent yields (Table 1, entries 8, 9, and 12).
Scheme 1
We began our new studies with what might be called the
‘parent’ benzothiazine 3, the simplest structure that could
be prepared using our methodology, using the sulfoximine
4 (Figure 1).7 We quickly found that 3 was as well-
behaved as 1 in that lithiation and trapping could be con-
ducted under essentially the same conditions. The results
of this work are summarized in Table 1.
H
NH
S
H
O
Me
Ph
Two electrophiles failed to provide any products. First,
tert-butyl bromoacetate neither alkylated in an SN2 fash-
ion nor reacted at the ester functional group (Table 1,
entry 16). The second poor electrophile was diphe-
nylphosphinic chloride (not given in Table 1), which pro-
vided no recovered starting material or product. It
appeared that many new very polar products were formed,
but none could be isolated and identified. Two other elec-
S
N
O
4
Ph
3
Figure 1
SYNTHESIS 2013, 45, 1785–1790
Advanced online publication: 08.05.2013
DOI: 10.1055/s-0033-1338444; Art ID: SS-2013-C0229-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1786
N. L. Calkins, M. Harmata
PAPER
We next turned our attention to the 4-phenyl-substituted
benzothiazine 8. This was easily accessible using method-
ology that we had already developed and afforded a steric
impediment at the lithiation site, a feature we desired to
explore in more detail.
Table 1 Lithiation and Trapping of Benzothiazine 3
H
N
H
N
H
O
E
1. n-BuLi (1.2 equiv),
THF, –78 °C, 10 min
2. electrophile (1.4 equiv)
S
S
O
Ph
3
Ph
5
The scope of our studies with 8 were not as broad as those
with 3, as certain electrophiles proved too bulky to react.
Nevertheless, they were clearly indicative of a steric ef-
fect in the efficacy of the reaction of the carbanion derived
from 8 with electrophiles. Furthermore, certain electro-
philes that proved untenable with 3 could be used with 8.
The results are shown in Table 2.
Entry Electrophile
E
Product Yield (%)
1
TMSCl
TMS
TES
5a
5b
5c
5d
5e
5f
98
2
TESCl
94
3
TIPSCl
TIPS
TBS
94
The reactivity pattern of 8 was quite different from that of
3. Chlorotriisopropylsilane did not react with the sulfoxi-
mine-stabilized vinyl carbanion of benzothiazine 8, most
likely due to steric effects (Table 2, entry 1). Both the eno-
lizable acetone and non-enolizable benzophenone were
unreactive with the organolithium derived from 8, al-
though they were very reactive with 3 (Table 2, entries 2
and 3). Note that benzaldehyde reacted smoothly to give
9f in 75% yield with slightly improved diastereoselectivi-
ty as compared to 3. This increase in diastereomeric ratio
is likely due to steric crowding near the adjacent 4-phenyl
substituent.
4
TBSCl
85
5
PhSSPh
benzophenone
SPh
38–92
91
6
C(OH)Ph2
7
2-Br(C6H4)CHO 2-BrC6H4(HO)CH 5g
94a
81
8
C2Br2Cl4
I2
Br
5h
5i
9
I
96
10
11
12
13
14
15
16
17
cyclohexanone
i-BuOCOCl
DMF
C(OH)(CH2)5
CO2-i-Bu
CHO
5j
97
5k
5l
11–51
92
It is most likely the case that benzothiazine 8 is sufficient-
ly hindered that conjugate addition becomes slow. Indeed,
the conjugate base of 8 reacted with disulfides in high
yield, except for the very sterically hindered di-tert-butyl
disulfide, which led to only an approximately 19% yield
pentan-3-one
(CH2O)n
oxirane
C(OH)Et2
CH2OH
CH2CH2OH
CH2CO2Bu
C(OH)Me2
5m
5n
5o
5p
5q
85
76
91
BrCH2CO2Bu
acetone
0
Table 2 Lithiation and Trapping of Benzothiazine 8
85
Ph
Ph
a dr = 1.4:1.
H
O
E
1. n-BuLi, THF
–78 °C, 10 min
2. electrophile
S
S
O
N
N
Ph
Ph
8
9
trophiles gave particularly large yield ranges; both diphe-
nyl disulfide and isobutyl chloroformate were
problematic in achieving respectable yields consistently.
During the isolation of sulfide 5e, the most polar compo-
nents were flushed off the silica gel column and collected
in a vial; a single crystal grew out of this residue. An X-
ray quality crystal was obtained and evidence for new
benzothiazine reactivity was seen. Perhaps not surprising-
ly, the carbanion derived from 3 was apparently able to
add to the product 5e to afford 7 (Figure 3).8
Entry
Electrophile
E
Product
Yield (%)
1
TIPSCl
TIPS
9a
0
2
acetone
C(OH)Me2 9b
0
3
benzophenone
I2
C(OH)Ph2
9c
9d
9e
0
4
I
74
95
75a
98
94
88
98
19
5
C2Br2Cl4
PhCHO
MeSSMe
PhSSPh
EtSSEt
Br
6
CH(OH)Ph 9f
7
SMe
SPh
9g
9h
9i
N
S
8
O
H
9
SEt
SPh
O
10
11
CySSCy
t-BuSSt-Bu
SCy
St-Bu
9j
S
N
7
9k
a dr = 2.4:1.
Figure 3
Synthesis 2013, 45, 1785–1790
© Georg Thieme Verlag Stuttgart · New York

PAPER
Benzothiazine Metalation
1787
3-Iodo-2,4-diphenyl-2,1-benzothiazine 2-Oxide (9d); Typical
Procedure B for Lithiation
of product (Table 2, entry 11); this compound was not
completely characterized.
To an oven-dried, N2-cooled flask with stirbar, benzothiazine 8
(0.052 g, 0.164 mmol) was added and covered with a rubber sep-
tum. The flask was charged with argon, and freshly distilled THF (2
mL) was added via syringe. The reaction was then cooled to –78 °C
with a dry ice/acetone bath. Then 2.10 M BuLi (0.0936 mL, 0.196
mmol) was added dropwise to the cooled soln resulting in a dark or-
ange soln. After 10 min, I2 (0.0582 g, 0.229 mmol) was added in
THF (1 mL) through the rubber septum by syringe. The mixture was
stirred further for up to 3 h (or until completion was observed by
TLC). The mixture was quenched with sat. NH4Cl (2 mL) and ex-
tracted with CH2Cl2 (3 × 5 mL); the combined organic extracts were
dried (MgSO4) and concentrated in vacuo. Purification by flash
chromatography [silica gel, 25% EtOAc–hexane; TLC Rf = 0.24
(25% EtOAc–hexanes). green long UV spot] afforded 9d (0.537 g,
74%) as an orange solid.
We obtained evidence that electrophiles of the type R2PCl
reacted with both anions used in this work. However,
problems with phosphorus oxidation have, as yet, pre-
cluded the isolation of products of suitable quality for rig-
orous characterization. Further studies are necessary to
resolve this difficulty.
In conclusion, we have demonstrated some of the scope of
the lithiation and electrophilic trapping of two 2,1-benzo-
thiazines. Since these species can be made in enantiomer-
ically pure form, it is conceivable that certain
modifications could lead to families of chiral ligands that
are useful in asymmetric catalysis. Further results will be
reported in due course.
2-Phenyl-3-(trimethylsilyl)-2,1-benzothiazine 2-Oxide (5a)
Typical procedure A; yellow solid; yield: 136 mg (98%); mp 183 °C.
IR (NaCl): 3015, 2964, 1605, 1577, 1531, 1308, 1289, 1254, 1206,
990, 845, 729, 426 cm–1.
1H NMR: (250 MHz, CDCl3): δ = 0.05 (s, 9 H), 6.99 (t, J = 8.0 Hz,
1 H), 7.24 (d, J = 7.9 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.43 (t,
J = 6.9 Hz, 1 H), 7.49–7.63 (m, 3 H), 7.74 (s, 1 H), 7.87 (d, J = 7.0
Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = –0.7, 116.3, 119.7, 121.4, 123.7,
128.7, 129.3, 129.7, 132.3, 133.2, 142.5, 145.6, 146.0.
HRMS: m/z [M + Na]+ calcd for C17H19NOSSiNa: 336.0849; found:
336.0851.
All reactions performed were carried out under anhydrous condi-
tions involving either N2 or argon gas. Glassware was oven dried
(125 °C) and cooled by a continuous flow of dry N2. Solvents were
distilled under anhydrous and O2-free conditions. Et2O, toluene, and
THF were dried over Na metal and O2 was removed by generation
of a benzophenone ketyl. CH2Cl2 was dried over CaH2 in a dry N2
atmosphere. In most cases, reagents were distilled prior to use if liq-
uid; solids reagents were crystallized or used directly from a newly
purchased commercial container. Handling of pyrophoric reagents,
namely organometallic reagents, was performed with glass, gas-
tight syringes, rubber septa, and argon-filled balloons. Air and
moisture sensitive reagents were handled with a dry N2-filled plastic
glove bag. Molecular sieves were freshly activated by heating to
200 °C under full vacuum (<2.67 mbar) for several hours. Reaction
mixtures were concentrated using rotary evaporators with both wa-
ter aspiration and pneumatic vacuum pump sources depending on
the boiling point of the solvent removed; residual solvent was re-
moved by full vacuum when necessary. Silica gel used in chromato-
graphic separations was purchased from Silicycle (230–400 mesh).
Reactions were monitored by glass-backed silica gel TLC plates
purchased from Sigma Aldrich and visualized using UV irradiation.
Melting points were obtained on a Fisher-Johns melting point appa-
ratus. IR spectra were recorded via a liquid NaCl chamber on a
2-Phenyl-3-(triethylsilyl)-2,1-benzothiazine 2-Oxide (5b)
Typical procedure A; yellow solid; yield: 143 mg (94%); mp 60 °C.
IR (NaCl): 2959, 2912, 2878, 1605, 1576, 1529, 1308, 1289, 1308,
1224, 1127, 1004, 848, 787, 723, 667, 580, 438 cm–1.
1H NMR (250 MHz, CDCl3): δ = 0.30–0.44 (m, 3 H), 0.63–0.71 (m,
3 H), 0.84 (t, J = 7.7 Hz, 9 H), 6.98 (t, J = 6.8 Hz, 1 H), 7.24 (d,
J = 7.8 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.42 (t, J = 8.4 Hz, 1 H),
7.47–7.62 (m, 3 H), 7.71 (s, 1 H), 7.87 (d, J = 6.9 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 3.1, 6.8, 116.1, 118.4, 119.5,
123.5, 128.4, 129.0, 129.6, 132.1, 133.1, 142.7, 145.5, 147.0.
HRMS: m/z [M + Na]+ calcd for C20H25NOSSiNa: 378.1318; found:
378.1313.
1
Perkin Elmer 1600 series FT-IR spectrophotometer. H and 13C
NMR were taken on one of three Bruker ARX-250, ARX-300, or
ARX-500 Ultrashield spectrometers with internal TMS standard
(δ = 0.0); spectra were taken as CDCl3 solns. 13C NMR spectra tak-
2-Phenyl-3-(triisopropylsilyl)-2,1-benzothiazine 2-Oxide (5c)
Typical procedure A; orange solid; yield: 64 mg (94%); mp 115 °C.
1
en were H decoupled and contained a CDCl3 (δ = 77.0) internal
standard. HRMS were analyzed by a Bruker 12 Tesla Apex-Qe
FTICR-MS with an Apollo II ion source.
IR (NaCl): 3013, 2949, 2869, 1605, 1527, 1467, 1448, 1313, 1206,
1127, 1097, 988, 883, 844, 787, 727, 684, 643, 478 cm–1.
1H NMR (250 MHz, CDCl3): δ = 0.75 (d, J = 6.6 Hz, 9 H), 0.95–
1.11 (m, 12 H), 6.88 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.3 Hz, 1 H),
7.25 (d, J = 7.7 Hz, 1 H), 7.32 (t, J = 8.5 Hz, 1 H), 7.34–7.50 (m, 3
H), 7.69 (s, 1 H), 7.75 (d, J = 6.7 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 11.7, 18.2, 18.5, 115.8, 117.2,
119.4, 123.3, 128.4, 128.8, 129.7, 132.3, 133.0, 144.1, 145.4, 148.7.
2-Phenyl-3-(trimethylsilyl)-2,1-benzothiazine 2-Oxide (5a);
Typical Procedure A for Lithiation
To an oven-dried, N2-cooled flask with stirbar, benzothiazine 3
(0.107 g, 0.443 mmol) was added and covered with a rubber sep-
tum. The flask was charged with argon, and freshly distilled THF (4
mL) was added via syringe. The reaction was then cooled to –78 °C
with a dry ice/acetone bath. Then 2.08 M BuLi (0.256 mL, 0.532
mmol) was added dropwise to the cooled soln resulting in a dark or-
ange soln. After 10 min, TMSCl (0.0793 mL, 0.621 mmol) was add-
ed through the rubber septum by syringe. The mixture was stirred
further for up to 3 h (or until completion was observed by TLC). The
mixture was quenched with sat. NH4Cl (2 mL) and extracted with
CH2Cl2 (3 × 5 mL); the combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Purification by flash chroma-
tography [silica gel, 25% EtOAc–hexane; TLC Rf = 0.40 (25%
EtOAc–hexanes), yellow long UV spot] afforded 5a (0.136 g, 98%)
as a yellow solid.
HRMS: m/z [M + Na]+ calcd for C23H31NOSSiNa: 420.1788; found:
420.1791.
3-(tert-Butyldimethylsilyl)-2-phenyl-2,1-benzothiazine 2-Oxide
(5d)
Typical procedure A; yellow solid; yield: 58 mg (85%); mp 117 °C.
IR (NaCl): 3067, 3015, 1605, 1579, 1531, 1286, 1224, 1206, 1097,
991, 728, 685, 438 cm–1.
1H NMR (300 MHz, CDCl3): δ = -0.20 (s, 3 H), 0.17 (s, 3 H), 0.87
(s, 9 H), 6.97 (t, J = 8.1 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 1 H), 7.34 (d,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1785–1790

1788
N. L. Calkins, M. Harmata
PAPER
J = 7.8 Hz, 1 H), 7.41 (t, J = 8.3 Hz, 1 H), 7.48–7.60 (m, 3 H), 7.80–
7.84 (m, 3 H).
HRMS: m/z [M + Na]+ calcd for C21H16BrNO2SNa: 447.9977;
found: 448.0019.
13C NMR (75 MHz, CDCl3): δ = –5.1, –4.8, 17.7, 26.5, 115.8, 119.0,
119.6, 123.5, 128.5, 128.9, 129.7, 132.4, 132.9, 143.7, 145.4, 148.3.
HRMS: m/z [M + Na]+ calcd for C20H25NOSSiNa: 378.1318; found:
378.1315.
3-Bromo-2-phenyl-2,1-benzothiazine 2-Oxide (5h)
Typical procedure A; yellow solid; yield: 12 mg (81%); mp 105 °C.
IR (NaCl): 3069, 3014, 2930, 1604, 1535, 1444, 1342, 1288, 1225,
1206, 1098, 995, 918, 786, 728, 569, 534 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.06 (t, J = 7.4 Hz, 1 H), 7.32 (d,
J = 8.3 Hz, 2 H), 7.46 (t, J = 7.5 Hz, 1 H), 7.56–7.70 (m, 3 H), 7.82
(s, 1 H), 7.93 (d, J = 7.5 Hz, 2 H).
2-Phenyl-3-(phenylthio)-2,1-benzothiazine 2-Oxide (5e)
Typical procedure A; yellow solid; yield: 177 mg (38–92%); mp
104 °C.
IR (NaCl): 3015, 2960, 2860, 1605, 1575, 1529, 1468, 1310, 1257,
1205, 1097, 988, 844, 811, 728, 667 cm–1.
13C NMR (75 MHz, CDCl3): δ = 103.2, 118.6, 120.8, 123.8, 128.8,
128.9, 130.1, 132.1, 133.9, 138.4, 141.3, 143.5.
1H NMR (250 MHz, CDCl3): δ = 7.05 (t, J = 8.0 Hz, 1 H), 7.11 (s,
5 H), 7.32–7.54 (m, 7 H), 7.80 (d, J = 7.2 Hz, 1 H), 7.98 (s, 1 H).
HRMS: m/z [M + Na]+ calcd for C14H10BrNOSNa: 341.9559;
found: 341.9570.
13C NMR (62.5 MHz, CDCl3): δ = 116.0, 118.5, 120.4, 124.0,
127.2, 128.5, 128.9, 129.2, 129.7, 130.1, 132.8, 133.4, 134.6, 138.5,
145.4, 147.9.
HRMS: m/z [M + Na]+ calcd for C20H15NOS2Na: 372.0487; found:
372.0470.
3-Iodo-2-phenyl-2,1-benzothiazine 2-Oxide (5i)
Typical procedure A; orange solid; yield: 76 mg (96%); mp 103 °C.
IR (NaCl): 3069, 3014, 1604, 1528, 1342, 1288, 1207, 1097, 992,
787, 729, 434, 426 cm–1.
1H NMR (250 MHz, CDCl3): δ = 7.04 (t, J = 7.3 Hz, 1 H), 7.26–7.35
(m, 2 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.55–7.70 (m, 3 H), 7.91 (d,
J = 6.9 Hz, 2 H), 8.03 (s, 1 H).
3-(Hydroxydiphenylmethyl)-2-phenyl-2,1-benzothiazine 2-
Oxide (5f)
Typical procedure A; tan solid; yield: 80 mg (91%); mp 176 °C.
13C NMR (62.5 MHz, CDCl3): δ = 74.2, 118.9, 120.5, 123.9, 128.7,
IR (NaCl): 3579, 3064, 3018, 1608, 1447, 1292, 1223, 1206, 1188,
729, 702, 471, 445 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.86 (br s, 1 H), 6.97–7.10 (m, 6
H), 7.15–7.47 (m, 12 H), 7.59 (d, J = 7.2 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 81.6, 116.6, 120.3, 123.5, 126.6,
127.1, 127.6, 127.9, 128.0, 128.3, 128.4, 130.0, 130.3, 131.9, 132.6,
138.3, 139.5, 141.3, 144.4, 145.8.
128.8, 130.0, 132.3, 133.8, 139.5, 144.2, 148.6.
HRMS: m/z [M + Na]+ calcd for C14H10INOSNa: 389.9420; found:
389.9421.
3-(1-Hydroxycyclohexyl)-2-phenyl-2,1-benzothiazine 2-Oxide
(5j)
Typical procedure A; yellow-tan solid; yield: 47 mg (97%); mp
135 °C.
HRMS: m/z [M + Na]+ calcd for C27H21NO2SNa: 446.1185; found:
446.1185.
IR (NaCl): 3574, 3016, 2939, 2861, 1608, 1447, 1343, 1295, 1224,
1206, 1096, 993, 787, 728, 523, 467, 430 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.08–1.22 (m, 1 H), 1.38–1.92 (m,
9 H), 2.07 (s, 1 H), 7.01 (t, J = 8.0 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1
H), 7.33 (d, J = 7.8 Hz, 1 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.48–7.60 (m,
3 H), 7.61 (s, 1 H), 7.83 (d, J = 6.8 Hz, 2 H).
3-[(2-Bromophenyl)(hydroxy)methyl]-2-phenyl-2,1-benzothi-
azine 2-Oxide (5g)
Typical procedure A; off-white solid; yield: 104 mg (94% overall);
racemic mixture of 2 diastereomers (1.4:1).
13C NMR (75 MHz, CDCl3): δ = 21.5, 21.5, 25.0, 38.3, 40.5, 74.0,
116.4, 120.0, 123.1, 128.5, 128.9, 129.4, 130.1, 131.6, 132.8, 135.6,
143.8, 143.9.
HRMS: m/z [M + Na]+ calcd for C20H21NO2SNa: 362.1185; found:
362.1178.
Major Diastereomer
Mp 204 °C.
IR (NaCl): 3540, 3068, 3015, 1612, 1446, 1288, 1217, 1185, 1129,
1096, 1014, 991, 831, 771, 534 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.49 (d, J = 2.3 Hz, 1 H), 5.57 (d,
J = 1.6 Hz, 1 H), 6.94 (s, 1 H), 6.98 (d, J = 8.0 Hz, 1 H), 7.15–7.21
(m, 2 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.39–7.46 (m, 3 H), 7.53–7.58
(m, 2 H), 7.65 (t, J = 7.3 Hz, 1 H), 7.78 (d, J = 7.7 Hz, 1 H), 8.00 (d,
J = 7.3 Hz, 2 H).
Isobutyl 2-Phenyl-2,1-benzothiazine-3-carboxylate 2-Oxide
(5k)
Typical procedure A; yellow solid; yield: 8–21 mg (11–51%); mp
93 °C.
13C NMR (75 MHz, CDCl3): δ = 70.4, 116.8, 120.5, 122.2, 123.4,
123.6, 127.7, 128.9, 129.0, 129.7, 130.1, 130.3, 132.2, 132.7, 133.7,
137.0, 137.5, 138.0, 144.7.
HRMS: m/z [M + Na]+ calcd for C21H16BrNO2SNa: 447.9977;
found: 447.9979.
IR (NaCl): 3027, 2963, 2875, 1712, 1609, 1533, 1448, 1287, 1206,
1152, 1098, 986, 469 cm–1.
1H NMR (250 MHz, CDCl3): δ = 0.74 (d, J = 6.7 Hz, 3 H), 0.80 (d,
J = 6.7 Hz, 3 H), 1.75 (septet, J = 6.7 Hz, 1 H), 1.38–1.92 (dd, J1 =
6.7 Hz, J2 = 3.8 Hz, 2 H), 7.07 (t, J = 7.1 Hz, 1 H), 7.31 (d, J = 8.2
Hz, 1 H), 7.49–7.65 (m, 5 H), 7.92 (d, J = 6.7 Hz, 2 H), 8.56 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): δ = 18.9, 18.9, 27.5, 72.0, 111.8,
116.3, 120.7, 124.0, 128.5, 129.3, 131.3, 133.2, 134.8, 141.5, 145.7,
147.3, 161.9.
Minor Diastereomer
Mp 193 °C.
IR (NaCl): 3592, 3067, 3014, 1612, 1545, 1446, 1343, 1292, 1227,
1194, 1097, 991, 775, 765, 521 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.62 (d, J = 5.7 Hz, 1 H), 5.90 (d,
J = 5.6 Hz, 1 H), 7.03 (t, J = 8.1 Hz, 1 H), 7.08 (t, J = 7.7 Hz, 1 H),
7.22–7.28 (m, 2 H), 7.33 (m, 7 H), 7.65 (s, 1 H), 7.70 (d, J = 7.3 Hz,
2 H).
HRMS: m/z [M + Na]+ calcd for C19H19NO3SNa: 364.0978; found:
364.0968.
2-Phenyl-2,1-benzothiazine-3-carbaldehyde 2-Oxide (5l)
Typical procedure A; yellow solid; yield: 45 mg (92%); mp 119 °C.
13C NMR (75 MHz, CDCl3): δ = 72.3, 116.7, 120.3, 121.8, 122.6,
123.4, 127.6, 128.7, 129.1, 129.1, 129.9, 130.0, 132.2, 132.9, 133.2,
138.6, 139.3, 140.5, 144.7.
IR (NaCl): 3022, 2928, 2855, 1688, 1609, 1586, 1531, 1291, 1223,
1206, 1153, 729, 426 cm–1.
Synthesis 2013, 45, 1785–1790
© Georg Thieme Verlag Stuttgart · New York

PAPER
Benzothiazine Metalation
1789
1H NMR (250 MHz, CDCl3): δ = 7.10 (t, J = 7.0 Hz, 1 H), 7.35 (d,
J = 8.0 Hz, 1 H), 7.50–7.68 (m, 5 H), 7.96 (d, J = 7.2 Hz, 2 H), 8.23
(s, 1 H), 9.57 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): δ = 116.4, 119.1, 121.2, 124.6,
128.8, 129.9, 131.5, 133.8, 135.9, 139.5, 147.2, 148.6, 184.7.
HRMS: m/z [M + Na]+ calcd for C15H11NO2SNa: 292.0403; found:
292.0345.
HRMS: m/z [M + Na]+ calcd for C17H17NO2SNa: 322.0872; found:
322.0869.
3-Iodo-2,4-diphenyl-2,1-benzothiazine 2-Oxide (9d)
Typical procedure B; orange solid; yield: 38 mg (74%); mp 83 °C.
IR (NaCl): 3064, 2928, 2855, 2252, 1600, 1566, 1515, 1490, 1326,
1249, 1218, 1098, 996, 959, 699, 650, 589, 545, 508, 499, 473 cm–1.
1H NMR (250 MHz, CDCl3): δ = 6.84 (t, J = 8.2 Hz, 1 H), 6.94 (d,
J = 8.2 Hz, 1 H), 7.07–7.11 (m, 1 H), 7.24–7.68 (m, 9 H), 7.99 (d,
J = 7.0 Hz, 2 H).
3-(3-Hydroxypentan-3-yl)-2-phenyl-2,1-benzothiazine 2-Oxide
(5m)
Typical procedure A; tan solid; yield: 12 mg (85%); mp 156 °C.
13C NMR (62.5 MHz, CDCl3): δ = 80.9, 119.2, 120.3, 124.0, 128.0,
IR (NaCl): 3574, 3018, 2975, 1608, 1446, 1344, 1296, 1224, 1206,
1094, 989, 792, 668, 528 cm–1.
128.6, 128.7, 129.0, 130.1, 131.9, 133.7, 140.1, 140.9, 144.6, 156.3.
HRMS: m/z [M + Na]+ calcd for C20H14INOSNa: 465.9733; found:
465.9728.
1H NMR (300 MHz, CDCl3): δ = 0.63 (t, J = 7.4 Hz, 3 H), 0.90 (t,
J = 7.4 Hz, 3 H), 1.38 (sextet, J = 6.9 Hz, 1 H), 1.64 (sextet, J = 7.3
Hz, 1 H), 1.77 (q, J = 7.4 Hz, 2 H), 2.50 (s, 1 H), 7.02 (t, J = 7.0 Hz,
1 H), 7.27 (d, J = 7.3 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1 H), 7.37 (s, 1
H), 7.42 (t, J = 8.4 Hz, 1 H), 7.48–7.60 (m, 3 H), 7.85 (d, J = 7.1 Hz,
2 H).
13C NMR (75 MHz, CDCl3): δ = 7.5, 7.9, 33.3, 34.9, 78.2, 116.4,
120.1, 123.2, 126.5, 128.4, 129.5, 131.6, 133.0, 136.2 143.0, 144.1.
HRMS: m/z [M + Na]+ calcd for C19H21NO2SNa: 350.1185; found:
350.1179.
3-Bromo-2,4-diphenyl-2,1-benzothiazine 2-Oxide (9e)
Typical procedure B; yellow solid; yield: 76 mg (95%); mp 174 °C.
IR (NaCl): 3065, 2927, 2855, 1600, 1567, 1523, 1492, 1330, 1252,
1222, 1098, 970, 605, 589, 545, 495, 476, 447, 408 cm–1.
1H NMR (250 MHz, CDCl3): δ = 6.88–7.01 (m, 2 H), 7.16–7.18 (m,
1 H), 7.39–7.71 (m, 9 H), 8.05 (d, J = 7.1 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 104.1, 119.7, 120.5, 124.1,
128.4, 128.5, 128.7, 128.9, 130.1, 131.6, 131.9, 133.8, 136.9, 138.7,
143.8, 150.8.
3-(Hydroxymethyl)-2-phenyl-2,1-benzothiazine 2-Oxide (5n)
Typical procedure A; orange solid; yield: 47 mg (76%); mp 134 °C.
HRMS: m/z [M + Na]+ calcd for C20H14BrNOSNa: 417.9872;
found: 417.9866.
IR (NaCl): 3601, 3465, 3067, 3014, 2874, 1616, 1447, 1340, 1287,
1224, 1205, 1097, 991, 728, 686, 666, 532 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.05 (br s, 1 H), 4.36 (s, 2 H), 7.05
(t, J = 8.1 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1
H), 7.46 (t, J = 6.9 Hz, 1 H), 7.54–7.70 (m, 4 H), 7.90 (d, J = 6.8 Hz,
2 H).
3-[Hydroxy(phenyl)methyl]-2,4-diphenyl-2,1-benzothiazine 2-
Oxide (9f)
Typical procedure B; tan solid; yield: 80 mg (75%); inseparable
2.4:1 diastereomeric mixture characterized as a mixture.
IR (NaCl): 3468, 3064, 2924, 2854, 1601, 1572, 1530, 1336, 1248,
1248, 1208, 1190, 1153, 1127, 1039, 541, 538 cm–1.
13C NMR (75 MHz, CDCl3): δ = 60.7, 116.9, 120.5, 121.6, 123.7,
1H NMR (250 MHz, CDCl3): δ (major diastereomer) = 3.60 (d,
J = 5.2 Hz, 1 H), 5.78 (d, J = 5.2 Hz, 1 H), 7.64 (d, J = 7.4 Hz, 2 H);
δ (minor diastereomer) = 2.59 (s, 0.4 H), 5.60 (s, 0.4 H), 7.96 (d,
J = 6.7 Hz, 0.8 H); remaining: 6.68–7.42 (m, 25 H; 18 × 1 for major
+ 0.4 × 18 for minor = 25).
13C NMR (62.5 MHz, CDCl3): δ = 70.6, 70.9, 118.7, 102.1, 124.1,
124.8, 125.4, 126.3, 127.5, 127.6, 127.8, 128.1, 128.3, 128.5, 128.6,
128.8, 129.2, 129.6, 130.4, 131.5, 132.9, 135.5, 139.8, 140.7, 144.6,
148.6.
129.1, 129.4, 129.7, 132.0, 133.6, 137.4, 139.3, 144.7.
HRMS: m/z [M + Na]+ calcd for C15H13NO2SNa: 294.0559; found:
294.0573.
3-(2-Hydroxyethyl)-2-phenyl-2,1-benzothiazine 2-Oxide (5o)
Typical procedure A; yellow solid; yield: 29 mg (91%); mp 74 °C.
IR (NaCl): 3620, 3487, 3067, 3016, 1613, 1447, 1289, 1223, 1206,
1099, 993, 729, 470, 426 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.37–2.46 (m, 1 H), 2.58–2.67 (m,
1 H), 3.66–3.85 (m, 2 H), 7.02 (t, J = 7.1 Hz, 1 H), 7.27–7.35 (m, 2
H), 7.42 (t, J = 8.1 Hz, 1 H), 7.48 (s, 1 H), 7.51–7.67 (m, 4 H), 7.89
(d, J = 6.7 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 34.1, 62.0, 117.3, 120.1, 120.4,
123.5, 129.1, 129.1, 129.5, 131.4, 133.5, 138.1, 138.9, 143.8.
HRMS: m/z [M + Na]+ calcd for C16H15NO2SNa: 308.0716; found:
308.0726.
HRMS: m/z [M + Na]+ calcd for C27H21NO2SNa: 446.1185; found:
446.1183.
3-(Methylthio)-2,4-diphenyl-2,1-benzothiazine 2-Oxide (9g)
Typical procedure B; yellow solid; yield: 74 mg (98%); mp 137 °C.
IR (NaCl): 3065, 3045, 2925, 1601, 1562, 1515, 1490, 1448, 1332,
1245, 1210, 1153, 1097, 996, 971, 821, 590, 550, 491, 463, 431, 428
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.93 (s, 3 H), 6.81–6.86 (m, 1 H),
6.91 (d, J = 7.8 Hz, 1 H), 7.12–7.15 (m, 1 H), 7.37–7.63 (m, 9 H),
8.03 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.4, 116.0, 119.1, 119.7, 124.1,
128.1, 128.1, 128.2, 128.2, 128.4, 128.8, 129.0, 129.8, 131.9, 133.2,
136.3, 139.5, 145.1, 157.4.
3-(2-Hydroxypropan-2-yl)-2-phenyl-2,1-benzothiazine 2-Oxide
(5q)
Typical procedure A; green-tan solid; yield: 473 mg (85%); mp
175 °C.
IR (NaCl): 3534, 2975, 2361, 1608, 1546, 1447, 1345, 1322, 1296,
1202, 990, 910, 521, 507, 502, 408 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.28 (s, 3 H), 1.50 (s, 3 H), 2.58
(br s, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 7.24 (d, J = 7.9 Hz, 1 H), 7.36
(d, J = 5.9 Hz, 1 H), 7.41 (t, J = 8.5 Hz, 1 H), 7.46–7.61 (m, 3 H),
7.63 (s, 1 H), 7.85 (d, J = 6.7 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 30.9, 32.6, 72.6, 116.5, 120.1,
123.0, 128.6, 129.3, 129.4, 129.5, 131.6, 133.0, 135.4, 142.8, 143.8.
HRMS: m/z [M + Na]+ calcd for C21H17NOS2Na: 386.0644; found:
386.0640.
2,4-Diphenyl-3-(phenylthio)-2,1-benzothiazine 2-Oxide (9h)
Typical procedure B; yellow solid; yield: 255 mg (94%); mp
120 °C.
IR (NaCl): 3065, 3042, 2926, 1601, 1560, 1512, 1490, 1331, 1244,
1213, 1153, 1097, 995, 972, 819, 684, 590, 553, 474, 444, 441 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1785–1790

1790
N. L. Calkins, M. Harmata
PAPER
1H NMR (300 MHz, CDCl3): δ = 6.81–6.89 (m, 3 H), 6.95–6.98 (m,
4 H), 7.07–7.11 (m, 1 H), 7.21–7.48 (m, 9 H), 7.93 (d, J = 7.8 Hz, 2
HRMS: m/z [M + Na]+ calcd for C24H23NOS2Na: 428.1113; found:
428.1115.
H).
13C NMR (75 MHz, CDCl3): δ = 113.7, 119.6, 119.9, 124.3, 126.3,
127.9, 128.2, 128.3, 128.3, 128.4, 128.7, 128.8, 129.3, 129.7, 130.3,
132.3, 133.2, 135.2, 135.8, 138.3, 145.7, 158.3.
HRMS: m/z [M + Na]+ calcd for C26H19NOS2Na: 448.0800; found:
448.0797.
Acknowledgment
This work was supported by the National Science Foundation and
the Petroleum Research Fund, administered by the American
Chemical Society. We thank Dr. Charles L. Barnes (Missouri-
Columbia) for acquisition of X-ray data. Thanks to Ms. Carissa S.
Hampton for assistance in preparing the manuscript.
3-(Ethylthio)-2,4-diphenyl-2,1-benzothiazine 2-Oxide (9i)
Typical procedure B; yellow solid; yield: 213 mg (88%); mp
164 °C.
Supporting Information for this article is available online at
IR (NaCl): 3066, 3048, 2929, 1601, 1561, 1514, 1490, 1448, 1331,
1245, 1210, 1154, 1097, 996, 971, 821, 685, 590, 550, 467, 403
cm–1.
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1H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3 H), 2.33–2.43
(m, 2 H), 6.81–6.87 (m, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 7.10–7.13
(m, 1 H), 7.35–7.44 (m, 5 H), 7.45–7.64 (m, 4 H), 8.02 (d, J = 6.8
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 32.2, 115.0, 119.2, 119.7,
124.1, 128.0, 128.1, 128.1, 128.4, 128.6, 129.0, 129.1, 129.9, 131.8,
133.2, 136.4, 139.5, 145.1, 157.0.
References
(1) Present address: N. L. Calkins, Mineral Area College, 5270
Flat River Road, P.O. Box 1000, Park Hills, MO 63601.
(2) Harmata, M. Tetrahedron Lett. 1988, 29, 5229.
(3) (a) Harmata, M.; Schlemper, E. O. Tetrahedron Lett. 1987,
28, 5997. (b) Harmata, M.; Claassen, R. J. II; Barnes, C. L.
J. Org. Chem. 1991, 56, 5059. (c) Harmata, M.; Kahraman,
M. J. Org. Chem. 1998, 63, 6845. (d) Harmata, M.;
Kahraman, M.; Jones, D. E.; Pavri, N.; Weatherwax, S. E.
Tetrahedron 1998, 54, 9995.
(4) (a) Harmata, M.; Pavri, N. Angew. Chem. Int. Ed. 1999, 38,
2419. (b) Harmata, M.; Hong, X. Synlett 2007, 969.
(c) Yongpruksa, N.; Calkins, N. L.; Harmata, M. Chem.
Commun. 2011, 47, 7665.
HRMS: m/z [M + Na]+ calcd for C22H19NOS2Na: 400.0800; found:
400.0797.
3-(Cyclohexylthio)-2,4-diphenyl-2,1-benzothiazine 2-Oxide (9j)
Typical procedure B; yellow solid; yield: 270 mg (98%); mp 56 °C.
IR (NaCl): 3023, 2932, 2854, 1600, 1560, 1512, 1490, 1449, 1331,
1245, 1213, 1153, 1096, 970, 820, 618, 590, 479, 473, 403 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.71–0.82 (m, 1 H), 0.91–0.98 (m,
4 H), 1.39–1.58 (m, 5 H), 2.45–2.52 (m, 1 H), 6.79–6.88 (m, 1 H),
6.95 (d, J = 8.2 Hz, 1 H), 7.09–7.14 (m, 1 H), 7.36–7.45 (m, 5 H),
7.47–7.64 (m, 4 H), 8.03 (d, J = 6.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 25.2, 25.6, 25.7, 32.5, 32.8, 49.8,
115.1, 119.2, 119.7, 124.1, 127.9, 128.0, 128.4, 128.9, 129.0, 129.6,
130.1, 133.1, 136.3, 139.5, 145.1, 156.3.
(5) (a) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321.
(b) Harmata, M.; Calkins, N. L.; Baughman, R. G.; Barnes,
C. L. J. Org. Chem. 2006, 71, 3650. (c) Yongpruksa, N.;
Pandey, S.; Baker, G. A.; Harmata, M. Org. Biomol. Chem.
2011, 9, 7979.
(6) (a) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett.
2003, 44, 7261. (b) Harmata, M.; Hong, X. Org. Lett. 2005,
7, 3581. (c) Harmata, M.; Hong, X. Tetrahedron Lett. 2005,
46, 3847. (d) Harmata, M.; Hong, X.; Schreiner, P. R.
J. Org. Chem. 2008, 73, 1290. (e) Harmata, M.; Cai, Z.;
Chen, Y. J. Org. Chem. 2009, 74, 5559. (f) Harmata, M.;
Zheng, P. Heterocycles 2009, 77, 279. (g) Chen, Y.;
Harmata, M. Tetrahedron Lett. 2011, 52, 4069.
HRMS: m/z [M + Na]+ calcd for C26H25NOS2Na: 454.1270; found:
454.1270.
3-(tert-Butylthio)-2,4-diphenylbenzo[c][1,2]thiazine 2-Oxide
(9k)
Typical procedure B; orange semi-solid; yield: 50 mg (19%).
(7) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(8) Crystallographic data (excluding structure factors) for the
structure in this paper has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 930341 (5f), 930342 (5g),
930343 (5j), 930344 (5m), 930345 (5n), 930346 (5q), and
930340 (7). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(1223)336033 or e-mail:
deposit@ccdc.cam.ac.uk].
IR (NaCl): 3463, 3061, 2925, 1601, 1571, 1529, 1448, 1321, 1247,
1193, 1154, 1097, 991, 699, 682, 603, 523, 504, 499, 439 cm–1.
1H NMR (250 MHz, CDCl3): δ = 0.99 (s, 9 H), 6.86 (t, J = 8.2 Hz,
1 H), 7.04 (d, J = 8.4 Hz, 1 H), 7.13–7.62 (m, 20 H), 7.97 (d, J = 6.7
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 31.4, 50.1, 119.3, 119.7, 124.3,
127.6, 127.9, 128.2, 128.4, 129.6, 129.9, 130.4, 130.6, 132.1, 133.1,
136.8, 140.1, 145.7.
Synthesis 2013, 45, 1785–1790
© Georg Thieme Verlag Stuttgart · New York