Synthesis of 2H-1,2-benzothiazine 1,1-dioxides via heteroannulation reactions of 2-iodobenzenesulfonamide with ketone enolates under SRN1 conditions

Article abstract of DOI:10.1021/jo050964e

2-Iodobenzenesulfonamide (1a) underwent photostimulated S_RN1 reactions in liquid NH₃ with the potassium enolates derived from acetone, pinacolone, butanone, and 3-methyl-2-butanone to give fair to good yields of 2H-1,2-benzothiazine 1,1-dioxides 2. Reductive dehalogenation of 1a was found to predominate in photoinduced reactions of 1a with 3-pentanone, 2-methyl-3-pentanone, and 2,4-dimethyl-3-pentanone, the extent of reduction being proportional to the number of β-hydrogen atoms present in the ketone enolate. Isotopic labeling studies with 2,4-dimethyl-3-pentanone-d₁₄ (24) confirmed the major role of the β-hydrogens in the reduction process. Reactions of 1a with cyclopentanone, cyclohexanone, and cyclooctanone enolates afforded new tricyclic benzothiazine derivatives 26-29. Attempts to extend the heteroannulation reaction to the preparation of 2H-1,2-benzothiazin-3(4H)-one 1,1-dioxides 3 (R = H, Ph) through reactions of 1a with tert-butyl acetate and ethyl phenylacetate enolates resulted only in hydrodehalogenation of 1a. However, oxazoline anion 30, a synthetic equivalent of ethyl phenylacetate, was successfully employed in an alternative S_RN1-based synthesis of benzothiazine 3 (R = Ph).

Full text of DOI:10.1021/jo050964e

Synthesis of 2H-1,2-Benzothiazine 1,1-Dioxides via
Heteroannulation Reactions of 2-Iodobenzenesulfonamide with
Ketone Enolates under SRN1 Conditions§
William J. Layman, Jr.,† Thomas D. Greenwood,† Aaron L. Downey,† and James F. Wolfe*,†,‡
Department of Chemistry, Virginia Polytechnic Institute and State University,
Blacksburg, Virginia 24061-0212, and Division of Biomedical Sciences, Edward Via Virginia College of
Osteopathic Medicine, 2265 Kraft Drive, Blacksburg, Virginia 24060
wolfe@vcom.vt.edu
Received May 13, 2005
2-Iodobenzenesulfonamide (1a) underwent photostimulated SRN1 reactions in liquid NH3 with the
potassium enolates derived from acetone, pinacolone, butanone, and 3-methyl-2-butanone to give
fair to good yields of 2H-1,2-benzothiazine 1,1-dioxides 2. Reductive dehalogenation of 1a was found
to predominate in photoinduced reactions of 1a with 3-pentanone, 2-methyl-3-pentanone, and 2,4-
dimethyl-3-pentanone, the extent of reduction being proportional to the number of â-hydrogen atoms
present in the ketone enolate. Isotopic labeling studies with 2,4-dimethyl-3-pentanone-d14 (24)
confirmed the major role of the â-hydrogens in the reduction process. Reactions of 1a with
cyclopentanone, cyclohexanone, and cyclooctanone enolates afforded new tricyclic benzothiazine
derivatives 26-29. Attempts to extend the heteroannulation reaction to the preparation of 2H-
1,2-benzothiazin-3(4H)-one 1,1-dioxides 3 (R ) H, Ph) through reactions of 1a with tert-butyl acetate
and ethyl phenylacetate enolates resulted only in hydrodehalogenation of 1a. However, oxazoline
anion 30, a synthetic equivalent of ethyl phenylacetate, was successfully employed in an alternative
SRN1-based synthesis of benzothiazine 3 (R ) Ph).
Introduction
has been the facile construction of benzo-fused hetero-
cyclic ring systems via reactions of 2-substituted aryl
halides with ketone enolates and subsequent cyclo-
dehydration of the intermediate SRN1 substitution prod-
ucts as outlined in Scheme 1.
This substitution-cyclization process pioneered
by Beugelmans2 has been applied to the synthesis
of indoles,3 azaindoles,4 benzofurans,5 isoquinolones,6
The synthetic utility of the radical chain nucleophilic
aromatic substitution (SRN1) reaction is well established
and has been the subject of several comprehensive
reviews.1 A particularly useful application of this reaction
* To whom correspondence should be addressed. Phone: (540) 231-
8200. Fax: (540) 231-8890.
† Virginia Polytechnic Institute and State University.
‡ Edward Via Virginia College of Osteopathic Medicine.
(2) Beugelmans, R. Bull. Soc. Chim. Belg. 1984, 93, 547-556.
(3) (a) Beugelmans, R.; Roussi, G. J. Chem. Soc., Chem. Commun.
1979, 950-951. (b) Bard, R. R.; Bunnett, J. F. J. Org. Chem. 1980,
45, 1547-1548. (c) Boujlel, K.; Simonet, J.; Roussi, G.; Beugelmans,
R. Tetrahedron Lett. 1982, 23, 173-176. (d) Beugelmans, R.; Chbani,
M. Bull. Soc. Chim. Fr. 1995, 132, 306-313.
(4) (a) Beugelmans, R.; Boudet, B.; Quintero, L. Tetrahedron Lett.
1980, 21, 1943-1944. (b) Fontan, R.; Galvez, C.; Viladoms, P.
Heterocycles 1981, 16, 1473-1474. (c) Estel, L.; Marsais, F.; Que´quiner,
G. J. Org. Chem. 1988, 53, 2740-2744.
(5) Beugelmans, R.; Ginsburg, H. J. Chem. Soc., Chem. Commun.
1980, 508-509.
§ Abstracted in part from the Ph.D. dissertation of W.J.L., Jr.,
Virginia Polytechnic Institute and State University, September, 1990.
(1) For reviews on SRN1 reactions, see: (a) Rossi, R. A.; de Rossi, R.
H. Aromatic Substitution by the SRN1 Mechanism; ACS Monograph
178; American Chemical Society: Washington, DC, 1983. (b) Bowman,
W. R. Chem. Soc. Rev. 1988, 17, 283. (c) Rossi, R. A.; Pierini, A. B.;
Palacios, S. M. In Advances in Free Radical Chemistry; Tanner, D. D.,
Ed.; JAI Press: Greenwich, CT, 1990; Chapter 5; J. Chem. Educ. 1989,
66, 720. (d) Norris, R. K. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergammon: New York, 1991; Vol. 4. (e) Saveant, J.-M.
Tetrahedron 1994, 50, 10117. (f) Rossi, R. A.; Pierini, A. B.; Penenory,
A. B. In The Chemistry of Functional Groups, Suppl. D, The Chemistry
of Halides, Pseudo-halides and Azides; Patai S., Rappoport, Z., Eds.;
Wiley: New York, 1995; Chapter 24. (g) Rossi, R. A.; Pierini, A. B.;
Santiago, A. N. Org. React. 1999, 54, 1-271.
(6) (a) Beugelmans, R.; Bois-Choussy, M. Synthesis 1981, 729-731.
(b) Beugelmans, R.; Ginsburg, H.; Bois-Choussy, M. J. Chem Soc.,
Perkin Trans. 1 1982, 1149-1152. (c) Beugelmans, R.; Bois-Choussy,
M. Tetrahedron 1992, 48, 8285-8294.
10.1021/jo050964e CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/15/2005
J. Org. Chem. 2005, 70, 9147-9155
9147

Greenwood et al.
SCHEME 1
of KNH2 in liquid NH3. The results of reactions of ketone
enolates with 1a are summarized in Table 1. In general,
enolates derived from methyl ketones reacted cleanly and
efficiently with 1a under the influence of near-UV (350
nm) irradiation to afford good yields (67-90%) of the
corresponding benzothiazines 2 (entries 1, 3, and 6).
Evidence that these substitution reactions were proceed-
ing via the photoinduced radical-chain SRN1 mechanism
was provided by the failure of 1a to react with pinacolone
enolate in the absence of illumination (entry 2). In the
case of 3-methyl-2-butanone (entry 6) where two different
enolates are possible, a single product, 2g, was obtained
in 67% yield from the reaction of 1a with the enolate
formed by deprotonation at C-1. This result is consistent
with the estimated equilibrium composition of enolates
for 3-methyl-2-butanone which favors the C-1 enolate by
a factor of 49:1.14 The reaction of the enolate mixture from
butanone with 1a afforded benzothiazines 2c and 2d in
a ratio of 2:1, respectively (entry 4). Similar product
mixtures have been reported for SRN1 reactions of bu-
tanone enolate with other substrates.5,15 Although it was
not possible to achieve separation of regioisomers 2c and
2d using the normal workup procedure, pure 2c was
ultimately obtained in 27% yield following selective aerial
oxidation of 2d to the 4-hydroxy compound,16 which
facilitated its separation from 2c by flash chromatogra-
phy, vide infra. In contrast to the favorable results
obtained with methyl ketone enolates, yields of benzo-
thiazine products were low in reactions with ethyl ketone
enolates (entries 7 and 8) where reduction of substrate
1a to benzenesulfonamide (1b) predominated. For ex-
ample, reaction of 1a with 3-pentanone afforded 20% of
the desired benzothiazine 2f along with 42% of 1b. With
2-methyl-3-pentanone, the yield of the expected benzo-
thiazine 2g was only 9%, while 58% of 1b was isolated.
These results indicate that the reduction of 1a is favored
over the more sterically constrained process (substitution)
as the size of the R-groups of the enolate increases.
Furthermore, this increase in size corresponds to an
increase in the number of â-hydrogens in the enolate,
suggesting the involvement of these hydrogens in the
reduction process.17 Another factor contributing to the
modest yields of benzothiazines 2f and 2g was the
difficulty encountered in purifying these compounds due
to their tendency to undergo aerial oxidation to the
corresponding alcohols 4 and 5.18 Small amounts of
cyclohexenone 6 and pyridine derivative 7 from dimer-
ization reactions of 3-pentanone and 2-methyl-3-
SCHEME 2
isocumarones,6bisoquinolines,7 quinolines,7c benzo[c]phen-
anthridines,6b,8 benzo[c]phenanthridones,8 berberines,6b
3-benzazepines,9 3-benzoxepines,9 furo[3,2-h]quinolines,10
furo[3,2-b]pyridines,10 benz[e]indoles,11 and benz[g]in-
doles.11 In light of this synthetic versatility, we became
interested in determining if 2-iodobenzenesulfonamide
(1a) might also participate in photoinduced SRN1 reac-
tions with ketone and ester enolates and thus afford
convenient access to the biologically important12 benzo-
thiazine ring system (Scheme 2). Specifically, reactions
of 1a with ketone enolates would furnish either 3-sub-
stituted or 3,4-disubstituted-2H-1,2-benzothiazine 1,1-
dioxides 2, whereas ester enolates would afford 2H-1,2-
benzothiazin-3(4H)-one 1,1-dioxides 3. These heterocyclic
annulation reactions represent a potentially convenient
one-step approach to the preparation of benzothiazines
2 and 3 that compares very favorably with earlier
multistep syntheses of these ring systems.12a,13 We now
report that the success of SRN1 reactions of 1a with ketone
enolates does occur but is dependent on the nature of the
enolate, with hydrodehalogenation (reduction) of 1a being
a competing side reaction when â-hydrogen atoms are
present adjacent to the site of deprotonation of the
ketone. With ester enolates, reduction of 1a becomes the
major or exclusive mode of reaction.
Results and Discussion
Photostimulated reactions of 1a with both ketone and
ester enolates were carried out in the presence of 4 equiv
of the appropriate potassium enolate generated by means
(13) (a) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1971,
14, 973-977. (b) Catsoulacos, P. J. Heterocycl. Chem. 1971, 8, 947-
950. (c) Hauser, C. R.; Wantanabe, H.; Mao, C.-L.; Barnish, I. T. J.
Org. Chem. 1969, 34, 919-926.
(14) Brown, C. A. J. Org. Chem. 1974, 39, 1324-1325.
(15) Rossi, R. A.; Bunnett, J. F. J. Org. Chem. 1973, 38, 3020-3025.
(16) The facile oxidation of 2d compared to that of 2c is probably
due to relief of steric interactions between the C-4 methyl group in 2d
and the aryl hydrogen at C-5. This oxidation process likely proceeds
via epoxidation of the C-3,4 double bond leading to pyrimidalization
of the C-4 carbon.
(17) (a) Bunnett, J. F.; Sundberg, J. E. J. Org. Chem. 1976, 41,
1702-1706. (b) Semmelhack, M. F.; Bargar, T. M. J. Org. Chem. 1977,
42, 1481-1482. (c) Wolfe, J. F.; Moon, M. P.; Sleevi, M. C.; Bunnett,
J. F.; Bard, R. R. J. Org. Chem. 1978, 43, 1019-1020. (d) Semmelhack,
M. F.; Bargar, T. M. J. Am. Chem. Soc. 1980, 102, 7765-7774.
(18) In an identical experiment, when the reaction mixture from 1a
and potassio-2-methyl-3-pentanone was treated with H2O2, 18% of pure
5 was obtained.
(7) (a) Beugelmans, R.; Chastanet, J.; Roussi, G. Tetrahedron Lett.
1982, 23, 2313-2314. (b) Beugelmans, R.; Chastanet, J.; Roussi, G.
Tetrahedron 1984, 40, 311-314. (c) Beugelmans, R.; Bois-Choussy, M.
J. Org. Chem. 1991, 56, 2518-2522.
(8) Beugelmans, R.; Chastanet, J.; Ginsburg, H.; Quintero-Cortes,
L.; Roussi, G. J. Org. Chem. 1985, 50, 4933-4938.
(9) Beugelmans, R.; Ginsburg, H. Heterocycles 1985, 23, 1197-1203.
(10) Beugelmans, R.; Bois-Choussy, M. Heterocycles 1987, 26, 1863-
1871.
(11) Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132,
729-733.
(12) (a) Sianesi, E.; Redaelli, R.; Magistretti, M. J.; Massarani, E.
J. Med. Chem. 1973, 16, 1133-1137. (b) Lombardino, J. G. Chron. Drug
Discovery 1982, 1, 173-200. (c) Camoutsis, C.; Catsoulacos, P. J.
Heterocycl. Chem. 1992, 29, 569-570. (d) Proudfoot, J. R.; Patel, U.
R.; Dyatkin, A. B. J. Org. Chem. 1997, 62, 1851-1853.
9148 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of 2H-1,2-Benzothiazine 1,1-Dioxides
TABLE 1. Reactions of 1a with Ketone Enolates
irradiation
entry
enolate derived from
time, min
product
yield,a %
80
1b
1
2
pinacolone
8
15b
8
15
15
8
15
15
8
15
15
45
2a (R ) H, R′ ) t-Bu)
c
pinacolone
3
acetone
2b (R ) H, R′ ) Me)
2c (R ) H, R′ ) Et); 2d (R ) R′ ) Me)
2c (R ) H, R′ ) Et)
2e (R ) H, R′ ) i-Pr)
2f (R ) Me, R′ ) Et)
2g (R ) Me, R′ ) i-Pr)
90
4
butanone
31;d 16
9
5
butanone
27e
6
3-methyl-2-butanone
3-pentanone
67
6
42
58
90h
10
29
7
20d,f
9d,g
8
2-methyl-3-pentanone
2,4-dimethyl-3-pentanone
cyclopentanone
cyclohexanone
cyclooctanone
9
10
11
12
26 -(CH2)3-
27 -(CH2)4-
28 -(CH2)6-
45
45
65i
a Yields of pure products after chromatography and recrystallization. b Dark reaction. c 90% of 1a recovered. d Anaerobic workup. e Aerobic
workup. f Cyclohexenone 6 (10%) and a trace of alcohol 4 were also obtained. g Pyridine 7 (1%) and alcohol 5 were also produced. h Ketone
dimer 8 (86%) was also obtained. i Yield of oxidation product 29.
pentanone, respectively, were also isolated from these
reactions.
or abstract a â-hydrogen atom from enolate 10 to yield
the reduction product benzene (17), as shown in eq 6.
On the other hand, in the reaction of 1a with enolate 10,
the more sterically constrained benzenesulfonamide radi-
cal 13b apparently reacts exclusively by â-hydrogen atom
abstraction from 10 to afford benzenesulfonamide (1b)
and enolate radical anion 16 (eq 6). At this point, the
different rates of reduction of iodobenzene (9a) and
2-iodobenzenesulfonamide anion (9b) may be rationalized
in terms of their ability to accept an electron from radical
anion 16. The slow reduction of 9a has been attributed
to the reluctance of resonance-stabilized radical anion 16
to transfer an electron to the π-system of iodobenzene
(9a) to generate radical anion 12a (eq 10) through which
Treatment of 1a with potassio-2,4-dimethyl-3-pen-
tanone (10) under photostimulation led to rapid (8 min)
and complete reduction of 1a to benzenesulfonamide (1b)
with concomitant generation of an equivalent amount of
ketone dimer 8 (eq 1). Similar results were reported by
reduction may occur via a radical chain, i.e., eqs 3, 6, and
10. Rather, it was postulated that 16 alternatively
undergoes a chain-breaking disproportionation reaction
to provide enone 18 for subsequent Michael reaction with
enolate 10 to give ketone dimer 817c (eqs 7, 9). In contrast
to 9a, the more easily reducible aryl ring of 9b may accept
an electron from 16 according to eq 8. This chain
propagating step provides both enone 18, required for the
production of dimer 8, and radical dianion 12b needed
to continue the reduction cycle (eqs 3, 6, and 8). Thus,
the reduction of 9b and formation of 18 are both part of
the same rapid, radical-chain process. Evidence for such
radical-chain character in the reduction mechanism was
obtained when the reaction of 1a with enolate 10 was
severely inhibited by the presence of 10 mol % of the
radical scavenger di-tert-butyl nitroxide (DTBN), result-
ing in the recovery of 88% of 1a.
It is likely that ketone dimerization products 6 and 7
obtained in the reactions of 1a with 3-pentanone and
2-methyl-3-pentanone, respectively, (entries 7 and 8,
Table 1) also arise via mechanisms that feature Michael
addition of the enolate to the corresponding enone 20a,b19
as the key step. Subsequent intramolecular aldol con-
densation of Michael adduct 21 from 3-pentanone and
Bunnett and Sundberg17a for the SRN1 reaction of iodo-
benzene (9a) with enolate 10. However, this reaction was
extremely sluggish and only 20% of benzene and dimer
8 were obtained after a 3 h irradiation period along with
32% of the expected substitution product and 48% of
recovered 9a. Thus, the rate and extent of reduction of
substrates 1a and 9a by enolate 10 are markedly differ-
ent. These differences may be rationalized by consider-
ation of the diverse mechanistic pathways leading to the
reduction of these two substrates (Scheme 3). In contrast
to the slow, nonchain character previously ascribed to
the reduction of 9a,17c we propose that the reduction of
1a proceeds via a rapid radical-chain process.
The commonly accepted initiation and propagation
steps for substitution reactions occurring via the radical-
chain SRN1 mechanism are shown in eqs 2-5 of Scheme
3. In the case of iodobenzene (9a), phenyl radical 13a
generated in eq 3 may either combine with enolate 10,
ultimately leading to substitution product 15 (eqs 4, 5),
(19) It is postulated that enones 20a,b likely arise via electron-
transfer steps analogous to step 7 of Scheme 3.
J. Org. Chem, Vol. 70, No. 23, 2005 9149

Greenwood et al.
SCHEME 3
TABLE 2. Deuterium Labeling Studies of the
Photostimulated Reduction of 1a
20a followed by dehydration would yield cyclohexenone
6. The genesis of pyridine derivative 7 may be envisioned
in a similar sequence of steps that include condensation
of NH3 with the Michael addition product 22 to give imine
23 followed by cyclodehydration and aerial oxidation of
the penultimate dihydropyridine intermediate.
a
entry
aryl halide
enolate from
solvent
% d1
1
2
3
4
1a
1a
[(CD3)2CD]2CdO
[(CH3)2CH]2CdO
[(CH3)2CH]2CdO
[(CH3)2CD]2CdO
NH3
ND3
ND3
ND3
80
5
b
1a, N-d2
5c
6c
b
1a, N-d2
a Based on the ratio of C6H5
to C6H4D• + from the mass
• +
spectrum after correction for the 13C natural abundance. b Gen-
c
erated in situ from 2-iodobenzenesulfonyl chloride and ND3. 2H
NMR analysis showed deuterium was not incorporated exclusively
at the ortho position.
found to be 80% d1 and 20% d0 (entry 1). The location of
the incorporated deuterium was shown by 13C NMR and
2H NMR to be exclusively ortho to the sulfonamide
function. These results show that intermolecular â-hy-
drogen atom transfer from the enolate is the major but
perhaps not the only mode of reduction. Although the
reduction of aryl radicals via hydrogen atom transfer
To substantiate the role of â-hydrogen atom abstraction
in the reduction of 1a with enolate 10 and to uncover
other potential hydrogen atom sources, a series of
deuterium labeling experiments was conducted. The
results of this study are summarized in Table 2. Irradia-
tion of 1a in the presence of the potassium enolate
derived from 2,4-dimethyl-3-pentanone-d14 (24)20 in liquid
NH3 for 30 min afforded a 55% isolated yield of benzene-
sulfonamide (1b), which by mass spectral analysis was
(20) Compound 24 was prepared in 95% purity (98 atom %D) in
three steps from 2-propanol-d8.
9150 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of 2H-1,2-Benzothiazine 1,1-Dioxides
from solvents such as THF,21 DMSO,22 and CH3CN22 in
SCHEME 4
SCHEME 5
S
RN1 reactions has been documented in studies using
deuterated solvents, no such experimental evidence has
been offered for reduction through abstraction of hydro-
gen atoms from liquid NH3. A two-electron reduction of
2-iodobenzenesulfonamide anion (9b) and subsequent
protonation by NH3 as proposed previously by Bunnett17a
was deemed a plausible reduction pathway for the
production of nondeuterated benzenesulfonamide (1b) (eq
11).
We also considered other possible hydrogen atom
donors that might be involved in the formation of 1b. It
is conceivable that aryl radical 13b might abstract a
hydrogen atom from the adjacent sulfonamide group via
a five membered cyclic activated complex to ultimately
yield 1b (Scheme 4). Based on the likelihood of hydrogen-
deuterium exchange between the NH3 solvent and the
R-deuterium atoms of deuterated ketone 24, another
reduction scheme involving hydrogen atom transfer from
the un-ionized R-carbon of enolate 25 might account for
the formation of 1b (Scheme 5). To test these hypotheses,
further labeling experiments were conducted (Table 2).
The reaction of sulfonamide 1a with unlabeled enolate
10 in liquid ND3 resulted in 5% of deuterium incorpora-
tion (entry 2), indicating that a two-electron reduction
mechanism could be a possible minor source of 1b.
However, because of the possibility of deuterium ex-
change between ND3 and the sulfonamide hydrogens or
the R-protons of the ketone prior to the reduction, this
experiment can neither exclude nor support mechanisms
featuring deuterium atom transfer from those sources.
Therefore, two more labeling experiments were per-
formed. Reaction of N-d2-2-iodobenzenesulfonamide with
unlabeled enolate 10 in liquid ND3 (entry 3) again
afforded only 5% of 1b-d1 and thus did not provide
evidence for intramolecular hydrogen atom transfer from
the sulfonamide function. Similarly, treatment of N-d2-
2-iodobenzenesulfonamide with 2,4-dideuterio-2,4-di-
methyl-3-pentanone enolate in liquid ND3 (entry 4) ruled
out a reduction mechanism involving the R-hydrogen
atom of the enolate and confirms the results of the initial
labeling study that it is the â-hydrogens of the enolate
that are primarily involved in the reduction of 1a. At this
time, we must conclude that small amounts of impurities
with labile hydrogen atoms likely account for the non-
deuterated benzenesulfonamide obtained in the reaction
of 1a with the perdeuterated enolate of 24.
reactions with potassium enolates derived from cyclo-
pentanone, cyclohexanone, and cyclooctanone under photo-
stimulation to afford fair to good yields of tricyclic 1,2-
benzothiazine derivatives 26-28, respectively (eq 12,
entries 10-12, Table 1).
These new heterocycles have properties that are in-
teresting in their own right. Unlike all other ketone-
derived products prepared during the course of this study,
which are protonated by the NH4Cl employed to quench
the reaction mixture, compound 26 required acidification
of the NH4Cl solution with 5% HCl to pH 3 for isolation.26
Heterocycles 27 and 28 are of interest as a result of their
sensitivity toward oxidants. It was noted earlier that
benzothiazines 2f and 2g also exhibited a similar sus-
ceptibility toward oxidation. Although compound 27 can
be obtained in pure form with some difficulty, the
isolation of compound 28 was unsuccessful because of
rapid aerial oxidation. Consequently, the yield of 28 was
quantified by oxidation to the corresponding alcohol 29
with magnesium monoperoxyphthalate hexahydrate
(MMPP) (eq 13). An X-ray crystal structure was deter-
mined to verify the structure of 29.
Enolate anions derived from cyclic ketones have been
reported to participate in photoinduced SRN1 reactions
with a variety of aryl halides to afford good to excellent
yields of substitution products.3a,4b,6a,7b,17a,23-25 We were,
therefore, interested in determining if sulfonamide 1a
would also function as a suitable substrate in photo-
stimulated reactions with cyclic ketone enolates. We have
now found that 1a undergoes substitution-cyclization
Although substitution was favored over reduction in
all reactions of 1a with cyclic ketone enolates, competing
reduction was responsible for the lower yields observed
with cyclopentanone and cyclohexanone compared with
(23) Komin, A.; Wolfe, J. F. J. Org. Chem. 1977, 42, 2481-2486.
(24) Hay, J. V.; Wolfe, J. F. J. Am. Chem. Soc. 1975, 97, 3702-
3706.
(25) Nair, V.; Chamberlain, S. D. J. Am. Chem.. Soc. 1985 107,
2183-2185.
(26) Compound 26 was readily soluble in a 10% NaHCO3 solution.
(21) Quintard, J.-P.; Hauvette-Frey, S.; Pereyre, M. J. Organomet.
Chem. 1978, 159, 147-164.
(22) M’Halla, F.; Pinson, J.; Saveant, J. M. J. Electroanal. Chem.
1978, 89, 347-361.
J. Org. Chem, Vol. 70, No. 23, 2005 9151

Greenwood et al.
SCHEME 6
cyclooctanone (Table 1). Presumably, cyclooctanone eno-
late is a poor hydrogen atom donor since no benzene-
sulfonamide could be detected in its reaction with 1a.
This predominance of substitution in reactions of 1a with
cyclic ketone enolates was somewhat surprising in light
of an earlier report by Beugelmans6a that the analogous
S
RN1 reaction of 2-bromobenzamide with cyclohexanone
enolate favored reduction over substitution by a 2:1 ratio.
In contrast to the efficient synthesis of 1,2-benzo-
thiazine 1,1-dioxides achieved using methyl and cyclic
ketones, attempts to extend this reaction to the prepara-
tion of 2H-1,2-benzothiazin-3(4H)-one 1,1-dioxides 3 via
reactions of 1a with ester enolates were unsuccessful.
Photostimulation of 1a in the presence of the potassium
enolate of either tert-butyl acetate or ethyl phenylacetate
resulted in the reduction of 1a, and none of the expected
benzothiazine products 3 (R ) H) or 3 (R ) Ph) were
obtained. However, we were able to prepare benzo-
thiazine 3 (R ) Ph) by an alternative route starting with
potassio-2-benzyl-4,4-dimethyl-2-oxazoline (30)27 as a
ethyl phenylacetate enolate equivalent as outlined in
Scheme 6. Substrate 1a underwent photoassisted SRN1
aromatic substitution in the presence of 3 equiv of anion
30 to yield an inseparable mixture of 31 and oxazoline
ring opened products derived from 31 (1H NMR analysis),
along with 27% of benzenesulfonamide (1b). Methanoly-
sis of this mixture afforded a 25% yield of methyl ester
32 from which benzothiazine 3 (R ) Ph) was obtained
through cyclization by means of NaH in THF.
However, the preparation of benzothiazine 3 (R ) Ph)
was accomplished by employing the oxazoline ester
equivalent 30 of ethyl phenylacetate in an SRN1 reaction
with 1a followed by cyclization of the resulting substitu-
tion product 32.
Experimental Section
1H and 13C NMR spectra were measured at either 270 or
400 MHz. Chemical shift values are reported relative to TMS
(1H) or NMR solvent (13C), either CDCl3 (77.0 ppm) or acetone-
2
d6 (206.0 ppm). H NMR spectra were recorded at 200 MHz,
and deuterium chemical shifts are referenced to acetone-d6
(2.04 ppm). Photostimulated reactions were carried out in an
inert atmosphere using a Rayonet RPR-240 photoreactor
equipped with four 12.5 W lamps emitting maximally at 350
nm. Flash chromatography was performed using 230-400
mesh Kiesegel 60 silica gel. Unless otherwise stated, all
chemical reagents from commercial sources were used as
received. Di-tert-butyl nitroxide was prepared from 2-methyl-
2-nitropropane as previously described.28
Conclusions
In the present study, we report a convenient and
General Procedure for Photostimulated Reactions of
2-Iodobenzene-sulfonamide (1a)29 in Liquid NH3. 3-tert-
Butyl-2H-1,2-benzothiazine 1,1-Dioxide (2a). Anhydrous
NH3 was condensed under nitrogen flow into a vacuum
jacketed photoreaction tube equipped with a metal stirring bar
and sidearm adapter surmounted by a dry ice condenser and
stopper. A catalytic quantity of ferric nitrate was then added,
followed by the portionwise addition of potassium metal (2.21
g, 56.5 mmol). After the dark blue color was discharged,
pinacolone (4.25 g, 42.4 mmol) was added via syringe and the
solution was stirred for 5 min. The lights of the photoreactor
were then turned on and 1a (3.00 g, 10.6 mmol) was added as
a solid in portions. The slightly heterogeneous mixture was
then irradiated for 8 min. The resulting homogeneous reaction
mixture was quenched by pouring slowly (caution!) over excess
solid NH4Cl in a 2-L beaker and the NH3 was allowed to
evaporate overnight. The solid residue was partitioned be-
tween CH2Cl2 and H2O and the separated aqueous layer was
extracted twice more with CH2Cl2. The combined CH2Cl2
extracts were dried over Na2SO4, filtered, and concentrated.
Flash chromatography of the residue with hexanes-EtOAc (7:
3) and recrystallization from CCl4 gave 2.0 g (80%) of (2a),
mp 193-195 °C, (lit.30 mp 196-199 °C).
efficient synthesis of certain 3-substituted-2H-1,2-benzo-
thiazine 1,1-dioxides 2 involving photoinduced SRN
1
reactions of 2-iodobenzenesulfonamide (1a) with methyl
ketone enolates in liquid NH3. This heteroannulation
process was also applied to the preparation of the
previously unknown tricyclic heterocycles 26-28 from
reactions of 1a with cyclic ketones. Hydrodehalogenation
of 1a was found to compete with substitution in reactions
with acyclic ketone enolates possessing â-hydrogen at-
oms, the extent of reduction being proportional to the
number of â-hydrogens present in the enolate. The photo-
stimulated reaction of 1a with potassio-2,4-dimethyl-3-
pentanone resulted in rapid and complete reduction of
1a via a radical-chain mechanism featuring â-hydrogen
atom transfer from the ketone enolate to the intermediate
aryl radical. Attempts to prepare 2H-1,2-benzothiazin-
3(4H)-one 1,1-dioxides 3 (R ) H, Ph) through reactions
of 1a with potassium ester enolates derived from tert-
butyl acetate and ethyl phenylacetate, respectively, were
unsuccessful and resulted only in the reduction of 1a.
(27) Wong, J.-W.; Natalie, K. J.; Nwokogu, G. C.; Pisipati, J. S.;
Flaherty, P. T.; Greenwood, T. D.; Wolfe, J. F. J. Org. Chem. 1997, 62,
6152-6159.
(28) Hoffman, A. K.; Feldman, A. M.; Geblum, E.; Hodgson, W. G.
J. Am. Chem. Soc. 1964, 86, 639-646.
(29) Leffler, J. E.; Jaffe, H. J. Org. Chem. 1975, 40, 797-799.
9152 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of 2H-1,2-Benzothiazine 1,1-Dioxides
3-Methyl-2H-1,2-benzothiazine 1,1-Dioxide (2b). Flash
chromatography of the oily reaction mixture with CHCl3-
EtOAc (4:1) followed by recrystallization from CHCl3-hexane
afforded colorless crystals of 2b, mp 110-112 °C. IR (KBr)
NMR (CDCl3) δ 1.22 (t, J ) 7.1 Hz, 3H), 1.66 (s, 3H), 2.90-
2.96 (m, 3H), 7.44-7.80 (m, 4H); 13C NMR (acetone-d6) δ 9.3,
28.2, 30.6, 124.8, 124.9, 128.9, 132.5, 133.2; MS (CI mode) m/z
(rel intensity) 240 (45), 222 (100), 120 (15), 105 (40). Anal.
Calcd for C11H13NO3S: C, 55.21; H, 5.47; N, 5.85. Found: C,
55.18; H, 5.46; N, 5.81.
3300-3100, 1665, 1425, 1315, 1180, 765 cm-1 1H NMR
;
(CDCl3) δ 2.16 (s, 3H), 6.04 (s, 1H), 7.13 (br s, 1H), 7.30-7.87
(m, 4H); 13C NMR (CDCl3) δ 20.9, 105.3, 121.2, 126.4, 126.6,
130.1, 132.2, 133.7, 137.0; MS (70 eV) m/z (rel intensity) 195
(100), 130 (100), 117 (80), 90 (20); HRMS calcd for C9H9NO2S
195.0354, found 195.0351.
3-(1-Methylethyl)-4-methyl-2H-1,2-benzothiazine 1,1-
Dioxide (2g). The liquid NH3 solution was evaporated to a
volume of ca. 10 mL and 250 mL of hexane was added
cautiously and then heated on a steam bath to remove the
remainder of the NH3. The hexane solution was decanted and
combined with a second hexane wash of the salts. Concentra-
tion of the hexane solution gave a brown oil that was dissolved
in 40 mL of CCl4. The CCl4 solution was extracted with a 5%
HCl solution and the acidic extract was neutralized with 10%
NaOH and then extracted with CHCl3. The CHCl3 solution
was dried over anhydrous K2CO3, vacuum filtered through a
1-in. plug of silica gel to remove colored impurities and
concentrated. Preparative TLC (CHCl3) gave 0.02 g (1%) of 2,6-
(1-methylethyl)-3-methylpyridine (7) as the first band, which
was 95% pure by GPC analysis. IR (thin film) 1605, 1585, 1485,
3-Ethyl-2H-1,2-benzothiazine 1,1-Dioxide (2c) and 3,4-
Dimethyl-2H-1,2-benzothiazine 1,1-Dioxide (2d). Follow-
ing flash chromatography with CHCl3, 1.2 g of an inseparable
solid mixture of 2c and 2d was obtained. 1H NMR analysis of
the mixture indicated a ratio of 2:1 for 183c:184c. HR-GCMS
calcd for C10H11NO2S 209.0510, found 209.0510 for 2c and
209.0498 for 2d. Further elution with CHCl3-EtOAc (4:1)
afforded 0.15 g (9%) of benzenesulfonamide, mp 150-152 °C.
In an identical experiment, when the crude solid reaction
mixture was pulverized and exposed to the air for 12 h,
subsequent flash chromatography with CHCl3-EtOAc (9:1)
and recrystallization from CCl4 gave 0.60 g (27%) of 2c as
colorless crystals, mp 116.5-118 °C. IR (KBr) 3225, 1660,
1
1465 cm-1; H NMR (CDCl3) δ 1.24 (d, J ) 4.1 Hz, 6H), 1.77
(d, J ) 4.2 Hz, 6H), 2.27 (s, 3H), 2.96 (m, J ) 4.1 Hz, 1H),
3.20 (m, J ) 4.1 Hz, 1H), 6.83 (d, J ) 7.7 Hz, 1H), 7.26 (d, J
) 8.0 Hz, 1H); 13C NMR (CDCl3) δ 18.1, 21.7, 22.6, 31.5, 35.9,
117.1, 126.3, 137.7, 163.6, 163.9; MS (70 eV), m/z (rel intensity)
177 (25), 176 (30), 162 (100), 149 (70). The solid residue from
the original hexane extraction was extracted with EtOAc and
the combined extracts were concentrated to give 1.77 g of an
orange solid, which was washed with hot CCl4 leaving 0.95 g
(58%) of crude 1b, mp 145-150 °C. The CCl4 solution was
concentrated to an orange oil that was chromatographed using
CH2Cl2-hexane (9:1) to afford 0.23 g (9%) of 2g as a colorless
1425, 1315, 1170, 765 cm-1 1H NMR (CDCl3) δ 1.22 (t, 7.5
;
Hz, 3H), 2.40 (q, J ) 7.5 Hz, 2H), 6.02 (s, 1H), 7.24-7.69 (m,
5H); 13C NMR (CDCl3) δ 11.3, 27.2, 103.9, 121.2, 126.6, 130.5,
132.1, 133.7, 142.2; MS (70 eV) m/z (rel intensity) 209 (92),
194 (2), 144 (25), 130 (100). Anal. Calcd for C10H11NO2S: C,
57.39; H, 5.30; N, 6.69. Found: C, 57.30; H, 5.28; N, 6.66.
3-(1-Methylethyl)-2H-1,2-benzothiazine 1,1-Dioxide (2e).
Following flash chromatography using hexanes-EtOAc (4:1)
and recrystallization from hexanes-EtOAc (6:1), 1.59 g (67%)
of 2e30 was obtained as small colorless prisms, mp 107.5-109
°C. 13C NMR (CDCl3) δ 20.3, 33.2, 102.9, 121.0, 126.6, 126.8,
130.7, 131.9, 133.7, 146.2. The eluent was changed to hex-
anes-EtOAc (1:1) and 0.1 g (6%) of benzenesulfonamide was
obtained as a light tan solid, mp 150-152 °C.
solid, mp 143-145 °C. IR (KBr) 3300, 1315, 1190, 765 cm-1
;
1H NMR (CDCl3) δ 1.19 (d, J ) 6.9 Hz, 6H), 2.18 (s, 3H), 3.18
(m, J ) 6.9 Hz, 1H), 6.90 (br s, 1H), 7.38-7.85 (m, 4H); 13C
NMR (CDCl3) δ 13.4, 19.4, 29.3, 110.1, 121.1, 124.6, 126.6,
131.8, 132.2, 135.7, 140.0; MS (70 eV) m/z (rel intensity) 273
(100), 222 (55), 158 (47), 104 (57), 77 (28); HRMS calcd for
C12H15NO2S 237.0646, found 237.0796. Anal. Calcd for C12H15-
NO2S: C, 60.76; H, 6.33; N, 5.91. Found: C, 60.48; H, 6.32;
N, 6.01. The eluent was changed to CH2Cl2-2% MeOH and
0.09 g of (()-4-hydroxy-3-(1-methylethyl)-4-methyl-2H-1,2-
benzothiazine 1,1-dioxide 5, mp 194-196 °C was obtained.
Recrystallization from CCl4 yielded 0.06 g (2%) of pure 5, as
clear colorless needles, mp 195.5-196.5 °C. IR (KBr) 3535,
3-Ethyl-4-methyl-2H-1,2-benzothiazine 1,1-Dioxide (2f).
The residue from evaporation of the NH3 was extracted first
with hexane and then with CH2Cl2. The hexane extract was
concentrated in vacuo to yield an oil that was chromatographed
with hexanes-EtOAc (5:1) to afford 0.17 g of a yellow oil,
which was distilled in a Kugelrohr apparatus at 40-45 °C (0.5
mm) to give 0.10 g of (()-3-ethyl-1,6-dimethyl-2-cyclohexene-
1-one (6), which was 99% pure by GPC analysis. IR (thin film)
3050-2900, 1670 cm-1 1H NMR (CDCl3) δ 1.04 (t, J ) 7.6
;
1
1645, 1350, 1180, 780 cm-1; H NMR (CDCl3) δ 1.19 (d, J )
Hz, 3H), 1.10 (d, J ) 6.8 Hz, 3H), 1.60 (m, 1H), 1.74 (t, J )
1.5 Hz, 3 H), 1.92-2.33 (m, 6H); 13C NMR (CDCl3) δ 10.6, 11.7,
15.7, 28.2, 49.8, 129.6, 159.0, 202.0; MS (70 eV) m/z (rel
intensity) 152 (46), 137 (8), 123 (4), 110 (100), 67 (71).
Concentration of the CH2Cl2 extract followed by flash chro-
matography of the resulting solid with hexanes-EtOAc (2:1)
afforded 0.47 g (20%) of 2f, mp 130.5-132 °C. IR (KBr) 3100-
6.7 Hz, 3H), 1.28 (d, J ) 6.7 Hz, 3H) 1.67 (s, 3H), 2.96 (br s,
1H), 3.65 (m, J ) 6.7 Hz, 1H), 7.59-7.92 (m, 4H); 13C NMR
(acetone-d6) δ 21.2, 21.4, 32.8, 70.4, 124.6, 126.3, 129.2, 133.6,
143.0, 198.8; MS (CI mode) m/z (rel intensity) 254 (60), 236
(100), 222 (10), 212 (17), 120 (20), 105 (60). Anal. Calcd for
C12H15NO3S: C, 56.89; H, 5.97; N, 5.53. Found: C, 56.66; H,
5.97; N, 5.47. In a similar reaction, when the orange oil
obtained by concentration of the hot CCl4 extract was dissolved
in CHCl3 and stirred for 2 h with a solution of 20 mL of 1%
NaHCO3 and 0.5 mL of 30% H2O2, 0.49 g (18%) of 5 was
obtained following chromatography and recrystallization from
CCl4.
1
3350, 1655, 1425, 1320, 1180, 785 cm-1. H NMR (CDCl3) δ
1.22 (t, J ) 7.5 Hz, 3H), 2.15 (s, 3H), 2.44 (q, J ) 7.5 Hz, 2H),
6.97 (br s, 1H), 7.38-7.87 (m, ArH, 4H); 13C NMR (CDCl3) δ
11.7, 13.4, 25.8, 109.9, 121.1, 124.3, 126.5, 131.9, 135.4, 137.1;
MS (70 eV) m/z (rel intensity) 223 (100), 144 (57), 104 (35), 77
(27), 56 (33); HRMS calcd for C11H13NO2S 223.0667, found
223.0681. Anal. Calcd for C11H13NO2S: C, 59.20; H, 5.90; N,
6.27. Found: C, 58.94; H, 5.90; N, 6.20. The eluent was then
changed to CH2Cl2-EtOAc (1:1) and a trace of alcohol 4,
followed by 0.70 g (42%) of benzenesulfonamide (1b) were
obtained.
Reaction of 1a with the Enolate Anion Derived from
2,4-Dimethyl-3-pentanone. To a stirred solution of 43.8
mmol of KNH2 in 500 mL of liquid NH3 was added 2,4-
dimethyl-3-pentanone (4.00 g, 35.1 mmol) followed by 1a (2.48
g, 8.77 mmol) and the mixture was irradiated for 8 min. The
residue obtained upon quenching the reaction and evaporation
of the NH3 was extracted with 300 mL of hexane. Concentra-
tion of the hexane solution yielded 2.0 g (86%) of 2,4,4,6,8-
pentamethylnonane-3,7-dione (8).17c Further extraction of the
solid residue with hot EtOAc gave 1.48 g (90%) of 1b, mp 150-
152 °C. When this reaction was repeated in the presence of
10 mol % of DTBN, 2.57 g (88%) of 1a was recovered along
with 0.08 g (5%) of 1b and 0.09 g (4%) of 8.
When this reaction was repeated and the crude reaction
mixture was pulverized and exposed to the air for 24 h, 0.29
g (12%) of (()-3-ethyl-4-hydroxy-4methyl-4H-1,2-benzothiazine
1,1-dioxide (4), mp 160-161 °C, was isolated by flash chro-
1
matography. IR (KBr) 3560, 1670, 1320, 1205, 800 cm-1; H
(30) Takeuchi, Y.; Liu, Z.; Satoh, A.; Shiragami, T.; Shibata, N.
Chem. Pharm. Bull. 1999, 47, 1730-1733.
J. Org. Chem, Vol. 70, No. 23, 2005 9153

Greenwood et al.
Reaction of 1a with the Enolate Derived from 2,4-
Dimethyl-3-pentanone-d14 (24). To a solution of the potas-
sium enolate of 24 prepared from 9.76 mmol of KNH2 and 24
(1.00 g, 7.80 mmol) was added 1a (0.55 g, 1.90 mmol). The
mixture was irradiated for 30 min, quenched over NH4Cl, and
worked up as before to afford 0.11 g of 1b, mp 150-154 °C.
The mass spectrum indicated that this compound was 80% d1
and 20% d0. The 2H NMR (acetone) showed only one resonance
of δ 7.96 relative to acetone-d6 as an internal reference.
Reaction of 1a with the Enolate Derived from 2,4-
Dimethyl-3-pentanone in Liquid ND3. To a stirred solution
of 5.50 mmol of KND2 in 50 mL of liquid ND3 was added 2,4-
dimethyl-3-pentanone (0.50 g, 4.38 mmol) followed by 1a (0.31
g, 1.10 mmol). The reaction mixture was irradiated for 30 min
and then quenched by the introduction of excess MeOD. The
solution was then transferred to a beaker containing 3 g of
NH4Cl, the ND3 was allowed to evaporate, and 1b was isolated
as before. The mass spectrum assay indicated it to be 95% d0
and 5% d1. The 2H NMR spectrum showed one weak resonance
at δ 7.96 relative to acetone-d6.
to obtain 1.13 g (45%) of 27, mp 146-148 °C, followed by 0.48
g (29%) of benzenesulfonamide. An analytical sample of 27 was
prepared by recrystallization from toluene, mp 148.5-150 °C.
IR (KBr) 3350-3150, 1650, 1315, 1170, 770 cm-1 1H NMR
;
(CDCl3) δ 1.79 (m, 4H), 2.40 (m, 2H), 2.50 (m, 2H), 6.98 (br s,
1H), 7.25-7.89 (m, 4H); 13C NMR (CDCl3) δ 22.1, 22.2, 24.5,
29.2, 111.9, 121.2, 123.0, 126.5, 131.8, 131.9, 134.4, 134.8; MS
(70 eV) m/z (rel intensity) 235 (100), 221 (20), 207 (40), 170
(52), 89 (25); HRMS calcd for C12H13NO2S: 235.0667, found
235.0678. Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57; N,
5.95. Found: C, 61.30; H, 5.60; N, 5.91.
(()-8,9,10,11-Tetrahydro-11a-hydroxy-7H-cycloocta[c]-
[1,2]-benzothiazine 5,5-Dioxide (29). The residue was
extracted with 400 mL of refluxing hexane. The hexane
solution was decanted and concentrated to an oil containing
mostly cyclooctanone. The solid residue remaining from the
hexane extraction was partitioned between water and CH2Cl2.
The CH2Cl2 solution was separated, dried over Na2SO4,
filtered, and concentrated to yield 3.03 g of an immobile oil.
The oil was dissolved in 120 mL of 80% 2-propanol, 6.55 g (10.6
mmol) of 80% magnesium monoperoxyphthalate hexahydrate
was added, and the solution was stirred at room temperature
for 4 h and then heated at 40 °C for 4h in an oil bath. The
solution was cooled, 3 g of sodium thiosulfate was added, and
the solvent was remove in vacuo. The residue was partitioned
between 5% NaHCO3 and CH2Cl2. The CH2Cl2 extract was
dried over Na2SO4, filtered, and concentrated to yield 2.40 g
of a yellow solid. Flash chromatography of this solid with
hexanes-EtOAc (6:4) and recrystallization from CCl4 gave 1.04
g (35%) of pure 29, mp 182-185 °C. Concentration of mother
liquor and recrystallization from toluene afforded another 0.88
g (30%) of 29, mp 180-183 °C. An X-ray crystal structure was
determined from the crystals of 29 that separated from CCl4.
Reaction of N,N-Dideuterio-2-iodobenzenesulfon-
amide with 2,4-Dimethyl-3-pentanone Enolate in Liquid
ND3. 2-Iodobenzenesulfonyl chloride29,31 (0.40 g, 1.32 mmol)
was added to a stirred solution of the enolate prepared from
7.0 mmol of KND2 and 2,4-dimethyl-3-pentanone (0.50 g, 4.38
mmol) in 50 mL of liquid ND3 and the resulting reaction
mixture was irradiated for 30 min. Excess MeOD was then
added and the solution was poured into a beaker containing 3
g of NH4Cl. The ND3 was evaporated and the residue was
treated as previously described. The benzenesulfonamide thus
obtained analyzed 95% d0 and 5% d1. Two weak resonances
2
were present in the H NMR spectrum at δ 7.96 and δ 7.6432
in a ratio of intensities of 2:1, respectively.
IR (KBr) 3600-3400, 2970, 1625, 1325, 1175, 765 cm-1 1H
;
Reaction of N,N-Dideuterio-2-iodobenzenesulfon-
amide with the Enolate from 2,4-Dideuterio-2,4-dimeth-
yl-3-pentanone in Liquid ND3. To a stirred solution of 6.40
mmol of KND2 in 50 mL of liquid ND3 was added 2,4-
dideuterio-2,4-dimethyl-3-pentanone (0.50 g, 4.38 mmol) fol-
lowed by 2-iodobenzenesulfonyl chloride (0.33 g, 1.09 mmol)
and the mixture was irradiated for 45 min. MeOD was then
added and the resulting solution was poured onto 3 g of NH4Cl
contained in a beaker. Evaporation of the ND3 yielded a solid
residue, which was treated as before to obtain benzenesulfon-
amide that was 94% d0 and 6% d1 by mass spectral analysis.
The 2H NMR spectrum consisted of two weak resonances at δ
7.96 and δ 7.64 in a ratio of 3:1.
NMR (CDCl3) δ 1.23-2.15 (m, 10H), 2.54 (m, 1H), 3.24 (s, 1H),
3.41 (m, 1H), 7.36-7.73 (m, 4H); 13C NMR (CDCl3) δ 21.8, 25.1,
27.7, 28.0, 36.1, 46.2, 71.8, 124.2, 125.3, 128.5, 131.9, 132.8,
197.9; MS (CI mode) m/z (rel intensity) 280 (30), 264 (100),
262 (42). Anal. Calcd for C14H17NO3S; C, 60.18; H, 6.13; N,
5.01. Found: C, 60.15; H, 6.09; N, 4.95.
Reaction of 1a with the Enolate Derived from tert-
Butyl Acetate. To a stirred solution of KNH2 prepared by the
addition of potassium (1.26 g, 32.6 mmol) to 400 mL of liquid
NH3 was added tert-butyl acetate (3.16 g, 27.3 mmol) and 1a
(1.63 g, 5.76 mmol). The heterogeneous mixture was irradiated
for 2 h and then poured onto excess NH4Cl in a beaker.
Evaporation of the NH3 yielded a solid residue to which was
added 100 mL of 1 M HCl and the resulting cloudy solution
was extracted with CHCl3. The CHCl3 extract was dried over
Na2SO4 and concentrated to give 1.19 g of a 1:1 solid mixture
1,2,3,4-Tetrahydrocyclopenta[c][1,2]benzothiazine 5,5-
Dioxide (26). The solid residue remaining after evaporation
of NH3 was dissolved in water and 1 g of sodium thiosulfate
was added to discharge the iodine color. This solution was then
acidified to pH 3 with 5% HCl and extracted with CHCl3. The
CHCl3 extracts were combined, dried over anhydrous Na2SO4,
filtered, and concentrated to a brown oil, which was chromato-
graphed using hexanes-EtOAc (6:4). A yellow oil was obtained
that crystallized from CCl4 to give 1.06 g (45%) of 26 as a
colorless solid, mp 184-187 °C. An analytical sample was
prepared by recrystallization from toluene, mp 186.5-188 °C.
1
of 1a/benzenesulfonamide by H NMR.
Reaction of 1a with the Enolate Derived from Ethyl
Phenylacetate. Ethyl phenylacetate (2.32 g, 14.1 mmol) was
added to a solution of 17.6 mmol of KNH2 in 300 mL of liquid
NH3 followed by the addition of 1a (1.00 g, 3.53 mmol). The
heterogeneous mixture was irradiated for 1 h and quenched
with NH4Cl, and the NH3 was evaporated. The residue was
washed with 50 mL of hexanes-ether (4:1) to remove unre-
acted ester and then dissolved in 100 mL of H2O containing 1
g of sodium thiosulfate and the solution was acidified to pH 3
with 2 M HCl and extracted with CHCl3. The CHCl3 extracts
were dried over MgSO4 and concentrated to give 0.48 g (87%)
of crude benzenesulfonamide containing unreacted 1a.
Preparation of Methyl R-(2-Sulfamoylphenyl)phenyl-
acetate (32) by the Reaction of 1a with the Anion
Derived from 2-Benzyl-4,4-dimethyl-2-oxazoline (30). To
a stirred solution of 52.6 mmol of KNH2 in 800 mL of NH3
was added the oxazoline (8.00 g, 42.4 mmol) and 1a (4.00 g,
1
IR (KBr) 3175, 1660, 1305, 1160, 785 cm-1; H NMR (CDCl3)
δ 2.13 (m, 2H), 2.72-2.88 (m, 4H), 7.00 (br s, 1H), 7.28-7.92
(m, 4H); 13C NMR (CDCl3) δ 20.5, 29.1, 33.4, 115.6, 122.0,
123.7, 130.1, 132.1, 132.2, 138.4; MS (70 eV) m/z (rel intensity)
221 (100), 204 (12), 156 (35), 129 (20), 77 (8). Anal. Calcd for
C11H11NO2S: C, 59.70; H, 5.01; N, 6.33. Found: C, 59.61; H,
5.02; N, 6.31. Further elution gave 0.17 g (10%) of benzene-
sulfonamide, mp 149-152 °C.
7,8,9,10-Tetrahydro-6H-dibenzo[c,e][1,2]thiazine 5,5-
Dioxide (27). The residue, which was still moist with liquid
NH3, was partitioned between water and CHCl3. The CHCl3
solution was dried over MgSO4, filtered, and concentrated to
an oil that was chromatographed using hexanes-EtOAc (6:4)
(32) The source of the small amount of aryl deuterium at δ 7.64
and its position on the sulfonamide ring were not determined.
(33) Sheldrick, G. M. SHELXTL NT, version 6.12; Bruker Analytical
X-ray Systems: Inc. Madison, WI, 2001.
(31) Chau, M. M.; Kice, J. L. J. Org. Chem. 1977, 42, 3265-3270.
9154 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of 2H-1,2-Benzothiazine 1,1-Dioxides
14.1 mmol). The slightly heterogeneous mixture was irradiated
for 30 min, producing a homogeneous green solution. The
residue obtained after quenching the reaction with NH4Cl was
suspended in a solution containing 1 g of sodium thiosulfate
in 100 mL of H2O. The mixture was acidified to pH 3 and was
extracted with CH2Cl2. The CH2Cl2 solution was dried over
Na2SO4, filtered, and concentrated to an oil that was chro-
matographed using hexanes-EtOAc (7:3) to give the recovered
oxazoline, benzenesulfonamide (0.61 g, 27%) and 2.49 g of a
mixture of substitution products resulting from opening of the
oxazoline ring. This mixture was treated with refluxing
methanolic HCl overnight and concentrated, and the oily
residue was chromatographed with CH2Cl2-CH3CN (9:1) to
afford 1.04 g (25%) of 32 as a colorless oil that solidified on
standing. An analytical sample was obtained by recrystalli-
zation from CH2Cl2-hexane as white needles, mp 99-101 °C.
IR (KBr) 3370, 3280, 1745, 1350, 1175 cm-1; 1H NMR (CDCl3)
δ 3.75 (s, 3H), 4.80 (br s, 2H), 6.18 (s, 1H) 7.26-8.10 (m, 9H);
13C NMR (CDCl3) δ 52.5, 127.6, 128.6, 128.9, 131.6, 132.8,
136.9, 137.5, 140.3, 172.9; MS (CI mode), m/z (rel intensity)
306 (15), 289 (100), 274 (20), 246 (30), 225 (25). Anal. Calcd
for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59. Found: C, 58.95;
H, 4.97; N, 4.58.
concentrated. The resulting oil was dissolved in 1 mL of ether.
The dropwise addition of hexane to the ethereal solution
caused crystallization of 0.19 g of 3 (R ) Ph), mp 198-200°C.
Recrystallization from ether-hexane provided pure 3 (R ) Ph)
1
as colorless crystals, 0.15 g (56%), mp 200-201°C. H NMR
(CDCl3) δ 4.59 (br s, 1H), 6.02 (s, 1H), 7.14 (m, 2H), 7.36 (m,
3H), 7.69 (t, 1H), 7.85 (t, 1H), 7.98 (d, 1H), 8.16 (d, 1H); 13C
NMR (CDCl3) δ 48.6, 123.3, 128.4, 128.7, 129.0, 129.5, 132.4,
133.8, 137.2, 170.3. Anal. Calcd for C14H11NO3S: C, 61.52; H,
4.06; N, 5.13. Found: C, 61.39; H, 4.11; N, 5.20.
Acknowledgment. We are pleased to acknowledge
generous financial support from the Harvey W. Peters
Research Center for Parkinson’s Disease and Disorders
of the Central Nervous System Foundation, from the
National Science Foundation, Grant CHE-8513216,
from the National Institutes of Health through STTR
Grant 442730 and from Virginia’s Center for Innovative
Technology, Grant B10-99-006. We also gratefully ac-
knowledge National Science Foundation Grant CHE-
0131128 for funding the purchase of the XCalibur2
Single Crystal Diffractometer and Dr. Carla Slebodnick
for determining the X-ray structure of 29.
4-Phenyl-3,4-dihydro-1,2-benzothiazin-3(2H)-one 1,1-
Dioxide (3, R ) Ph). To a slurry of NaH (0.12 g of a 60%
dispersion in mineral oil, 3.0 mmol) in 10 mL of THF was
added dropwise a solution of 32 (0.30 g, 0.98 mmol) in 20 mL
of THF. The resulting solution was stirred for 3 h and cooled
to 0°C and 2 M HCl was added cautiously dropwise until pH
1 was achieved. The THF solution was separated and concen-
trated on a rotary evaporator to a pale yellow oil that was
dissolved in CH2Cl2, washed with water, dried (MgSO4), and
Supporting Information Available: X-ray crystallo-
graphic data file in CIF format and ORTEP plot for 29. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050964E
J. Org. Chem, Vol. 70, No. 23, 2005 9155