Copper-mediated one-pot access to benzo[b][1,4]thiazines from 2-N-sulfonylaminoaryl disulfides

Article abstract of DOI:10.1002/ejoc.201200023

2-N-Sulfonylaminoaryl disulfides can be converted into the corresponding benzo[b][1,4]thiazines in one pot when reacted with an electron-rich alkene in the presence of a base and a substoichiometric amount of a copper salt. Depending upon the reaction con

Full text of DOI:10.1002/ejoc.201200023

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200023
Copper-Mediated One-Pot Access to Benzo[b][1,4]thiazines from
2-N-Sulfonylaminoaryl Disulfides
Caterina Viglianisi,*[a] Paola Bonaccorsi,[b] Lavinia Simone,[a] Lucia Nassini,[a] and
Stefano Menichetti*[a]
Dedicated to Professor Gianfranco Scorrano on the occasion of his retirement
Keywords: Synthetic methods / Disulfides / Sulfur heterocycles / Copper / Cycloaddition
2-N-Sulfonylaminoaryl disulfides can be converted into the
amounts of the corresponding benzo[b][1,4]thiazine S-oxides
corresponding benzo[b][1,4]thiazines in one pot when re- that are not the result of a post-oxidation reaction. The over-
acted with an electron-rich alkene in the presence of a base
and a substoichiometric amount of a copper salt. Depending
upon the reaction conditions, and in particular the copper
salt used, we observed the concurrent formation of variable
all procedure can provide simple access to benzo[b]thiazines
or thiazine S,S-dioxides by sequential reduction or oxidation
of the crude reaction mixtures.
Introduction
Benzo[b][1,4]thiazine are valuable heterocyclic systems
with wide applications in medicinal chemistry.[1] A few
years ago, we reported an original hetero-Diels–Alder ap-
proach for the synthesis of these compounds based on the
generation of transient o-iminothioquinones 1, which react
with electron-rich alkenes, in an inverse electron-demand
[4+2] cycloaddition, to afford benzothiazine derivatives 2
(Scheme 1).[2]
The key step of this synthetic sequence is a base-pro-
moted 1,4-elimination at sulfur of the phthalimide anion
from 2-N-sulfonylthiophthalimides 3, which, in turn, can be
prepared by SEAr of properly substituted N-tosylaniline 4
Scheme 1. Generation of ortho-iminothioquinones from 2-N-sulf-
onylthiophthalimides and inverse-electron-demand hetero-Diels–
Alder reaction (IEDDAR) mediated access to 1,4-benzo[b]thiaz-
ines.
with phthalimidesulfenyl chloride (PhtNSCl, Pht
=
phthaloyl). Indeed, the introduction of the sulfur, pre-
armed with a suitable leaving group (i.e., the PhtN residue),
by SEAr requires a properly substituted and very nucleo-
philic aromatic ring, limiting the applicability of this pro-
cedure. In fact, only 3-alkoxy or, much better, 3,5-dialkoxy-
N-sulfonyl anilines 4 can be successfully used (Scheme 1).[2]
Recently, we demonstrated that benzo[b][1,4]selenazines 5
can be obtained via o-iminoselenoquinones 6, which, in
turn, are generated by 1,4-elimination at selenium from 2-
Scheme 2.[3] This procedure requires that one of the sub-
units of diselenide 7 acts as a leaving group (i.e., selenolate
ion 8), whereas the second subunit is transformed into tran-
sient o-iminoselenoquinone 6, which is trapped as an elec-
tron-poor diene.
The use of a Lewis acid, like Cu(OTf)2, is mandatory for
the success of the reaction, as it promotes cleavage of the
Se–Se bond. Moreover, this method is particularly effi-
cacious, as selenolate ion 8 that acted as a leaving group is
oxidized by molecular oxygen to regenerate starting diselen-
ide 7, which can thus be completely converted into product
5.[3] The procedure described in Scheme 2 for the generation
of o-iminoselenoquinones from N-tosylaminoaryl diselen-
ides appears quite general and does not require any particu-
N-sulfonylaminoaryl diselenides
7
as reported in
[a] Dipartimento di Chimica “Ugo Schiff”,
Polo Scientifico e Tecnologico Università di Firenze,
Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
[b] Dipartimento di Chimica Organica e Biologica,
Università di Messina,
Viale F. Stagno D’Alcontres 31, 98166 Messina, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200023.
Eur. J. Org. Chem. 2012, 1707–1711
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Viglianisi, P. Bonaccorsi, L. Simone, L. Nassini, S. Menichetti
SHORT COMMUNICATION
Scheme 2. Generation of ortho-iminoselenoquinone from 2-N-sulf-
onylaminoaryl diselenides and IEDDAR-mediated access to 1,4-
benzo[b]selenazines.
Scheme 3. Reagents and conditions: (a) Cu(OTf)2 (0.2 equiv.), Et3N
(1 equiv.), p-methoxystyrene (10, 2 equiv.), CHCl3, 60 °C, 30 h.
lar substitution on the aromatic ring. Consequently, we de-
cided to study its applicability to easily available N-tosyl-
aminoaryl disulfides, like 9a or 9b, that, bearing no substi-
tuents on the aromatic ring or bearing an electron-with-
drawing group on the aromatic ring, would allow the prepa-
ration of benzo[b][1,4]thiazines not accessible through the
procedure depicted in Scheme 1.
Results and Discussion
When disulfides 9a and 9b[4] were subjected to the reac-
tion conditions that we found effective for diselenides, that
is, chloroform, 60 °C, in the presence of Cu(OTf)2
(0.2 equiv.), Et3N (1 equiv.), and p-methoxystyrene (10,
2 equiv.) as a suitable dienophile, we witnessed the complete
consumption of the starting material in 30 h and the forma-
tion of moderate yields[5] of expected benzo[b][1,4]thiazines
11a and 11b (Scheme 3). However, inspection of the crude
material revealed the presence of minor amounts of totally
Scheme 4. Reagents and conditions: (a) Cu(OTf)2 (0.2 equiv.), Et3N
(1 equiv.), CHCl3, 60 °C, 30 h; (b) m-CPBA (1.0 equiv.), CH2Cl2,
0 °C, 0.3 h.
unexpected benzo[b]thiazine S-oxides 12a and 12b as single in Table 1. Entries 2 and 3 show the results depicted in
trans stereoisomers, which could be isolated by flash Scheme 3. The presence of a copper salt,[6,7] in a substoi-
chromatography. Thus, under identical reaction conditions, chiometric amount,[8] is mandatory for this reaction, for
disulfides are consumed even faster than diselenides but without copper no thiazine is formed and the disulfide can
their transformation into benzo[b]thiazines is less efficient. be completely recovered after 30 h at 60 °C (Table 1, En-
Moreover, in this case, we isolated a chalcogen oxidized by- try 1). On the other hand, the presence of 1 equiv. of Et3N
product that has never been obtained in the reaction of di- is similarly essential, as without it (Table 1, Entry 4) or with
selenides (compare Schemes 2 and 3).
only 0.5 equiv. of base (Table 1, Entry 5) we observed exten-
First of all, we verified if thiazine S-oxides 12 were sim- sive decomposition of styrene 10, probably due to its Lewis
ply the result of a post-oxidation process occurring on sulf- acid assisted polymerization. Clearly, this phenomenon pre-
ides 11 under the reaction conditions used for their forma- vented the definitive demonstration that the base is also re-
tion. Thus, 11a and 11b were kept in chloroform at 60 °C quired for the formation of the thiazine ring, but previous
in the presence of Cu(OTf)2 (0.2 equiv.) and Et3N (1 equiv.) results obtained in the generation of o-thioquinones[9] and
in air for 30 h without observing the formation of any oxid- o-iminothioquinones,[2] as well as other observations col-
ized thiazine (Scheme 4). On the other hand, 11a and 11b lected in this study,[10] strongly support that deprotonation
could be easily oxidized with m-CPBA (1 equiv.) in DCM at the NHTs residue (vide infra) is a necessary step in the
at 0 °C to afford thiazine S-oxides 12a and 12b as a roughly pathway to benzo[b]thiazines. Molecular oxygen seems to
1:1 mixture of trans/cis stereoisomers, which after isolation play a role in these reactions as well,[3,7] because when the
provided further confirmation of the attribution of the reaction was carried out under a positive nitrogen atmo-
structure of derivatives trans-12 obtained in the reaction de- sphere roughly half of sulfide 9a was recovered after 30 h
picted in Scheme 3.
at 60 °C (Table 1, Entry 6). On the other hand, working un-
With this evidence in hand, we started a study directed der an oxygen atmosphere disulfide 9a was completely con-
towards the optimization of the procedure as summarized sumed after 30 h, but overall yields and the ratio of 11/12
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Copper-Mediated One-Pot Access to Benzo[b][1,4]thiazines
Table 1. One-pot copper-mediated formation of benzo[b]thiazine systems 11 and 12 from 2-N-sulfonylaminoaryl disulfides 9.
Entry
Disulfide
Cu salt[a]
Atmosphere
T
[°C]
t
[h]
Consumption
Products
Yield of 11
Ratio of
of 9 [%][b]
[%][c]
11/12[b]
1
2
3
4
5
6
7
8
9a
9a
9b
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9a
9a
9b
9a
9b
–
air
air
air
air
air
N2
O2
air
air
air
air
air
air
air
air
air
air
air
air
60
60
60
60
60
60
60
60
60
r.t.
60
60
60
60
60
r.t.
r.t.
60
60
30
30
30
30
30
30
30
30
30
96
30
30
30
30
30
96
96
48
48
–
100
100
–
–
47
33
–
4:1
4:1
–
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
11a/12a
11b/12b
[d]
[e]
–
–
–
–
–
[f]
[e]
–
–
50
100
100
25
100
100
–
100
100
100
100
100
100
100
11a/12a
11a/12a
11a/12a
11a/12a
11a/12a
11a/12a
–
11a/12a
11b/12b
11a/12a
11a
18[b]
37
5:2
7:2
7:2
1:1
7:2
1:1
–
2:1
5:2
5:2
[g]
Cu(OTf)2[h]
Cu(OTf)2
Cu(OTf)2
CuSO4
36
9
10[b]
42
10
11
12
13
14
15
16
17
18
19
23[b]
–
CuO[i]
Cu(OAc)2
Cu(OAc)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
CuI
25[b]
18[b]
31
28
29
42
36
Ͼ50:1
Ͼ50:1
3:2
11b
11a/12a
11b/12b
CuI
3:2
1
[a] 0.2 equiv. [b] Estimated by H NMR spectroscopic analysis of the crude reaction mixture after workup. [c] Isolated yield after column
chromatography. [d] Without base. [e] Polymerization of alkene 10 was observed. [f] With 0.5 equiv. of Et3N. [g] With 1 equiv. of sodium
ascorbate. [h] With 0.2 equiv. of 2,2Ј-bipyridine. [i] CuO nanoparticles.
remained almost unchanged, indicating no tangible differ- Lewis acid thiazines 11a and 11b and their oxides 12a and
ences working under pure oxygen or air (Table 1, Entry 7). 12b were obtained, after 48 h at 60 °C, in roughly 1.5:1 ratio
Similarly, the reaction seems insensitive to the presence of and isolated in an overall yield of 70 and 60%, respectively
a reducing agent, as 1 equiv. of sodium ascorbate (Table 1, (Table 1, Entries 18 and 19), a result that, independent of
Entry 8), in fact did not affect the overall yield or the the sulfur oxidation state, represents so far the more pro-
amount of thiazine S-oxide formed. Using a chelating agent ductive one-pot transformation of disulfides
9 into
like 1,1Ј-bipyridine (Bipy; Table 1, Entry 9), which has been benzo[b][1,4]thiazine ring systems. In this light, we decided
reported to facilitate similar copper-catalyzed activations of to verify if it was possible to bypass, at least practically, the
disulfides,[7,11] we experienced a huge decrease in the reac- disadvantageous formation of a mixture of thiazines and
tion rate and about 75% of disulfide 9a was found to be thiazine S-oxides. In fact, on the crude reaction mixture
unreacted after 30 h at 60 °C. When the reaction described obtained by using the conditions of Table 1, Entry 18, we
in Scheme 2 was carried out at room temperature (Table 1, ran a reduction reaction with BH3·THF[12] and an over-
Entry 10), we observed a decrease in the reaction rate; the oxidation reaction with m-CPBA that allowed sulfide 11a
complete consumption of 9a was only observed after 96 h and sulfone 13a to be isolated in 64 and 54% overall yield,
and the yields and sulfide/sulfoxide ratio were similar to respectively (Scheme 5).
those obtained at 60 °C. Then, we studied the ability of dif-
ferent copper salts to promote the reaction. As shown in
Table 1 (Entries 11–19), independent of the copper salts
used, we were unable to isolate thiazine 11a in a yield higher
than those obtained with Cu(OTf)2 (47%; Table 1, Entry 2).
Nevertheless, some of the results achieved deserve com-
ment.
Scheme 5. Reagents and conditions: (a) CuI (0.2 equiv.), Et3N
Under the reaction conditions indicated in Scheme 3, un-
(1 equiv.), p-methoxystyrene (10, 2 equiv.), CHCl3, 60 °C, 48 h;
satisfactory formation of thiazines 11 or 12 was ob-
served using CuSO4, CuO nanoparticles, Cu(OAc)2, and
(b) BH3·THF, 0 °C to r.t.; (c) m-CPBA, CH2Cl2, 0 °C to r.t., 0.5 h.
Cu(acac)2 (Table 1, Entries 11–17). However, by using Cu-
From the gathered data and boosted by the results ob-
(acac)2 and by running the reaction at room temperature, tained in the reactions of the corresponding diselenides,[3]
a
after 96 h we observed the complete consumption of disulf- mechanistic rationale, which is far from definitive, for the
ides 9a and 9b, and despite the fact that derivatives 11a and reactions occurring under the conditions described in
11b were isolated in quite poor yield (28 and 29%, respec- Scheme 3 and Table 1 can be postulated. Reasonably, de-
tively), for the first time evidence for the formation of protonation of the NHTs group by Et3N and activation of
thiazine S-oxides 12a and 12b was not detected by 1H the sulfur–sulfur bond by the copper salt occurs, as ex-
NMR spectroscopic analysis of the crude reaction mixtures pected, promoting 1,4-elimination at sulfur and generation
(Table 1, Entries 16 and 17). Finally, by using CuI as a of o-iminothioquinone 15 and elimination of thiolate 14
Eur. J. Org. Chem. 2012, 1707–1711
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1709

C. Viglianisi, P. Bonaccorsi, L. Simone, L. Nassini, S. Menichetti
SHORT COMMUNICATION
ion, as depicted in Scheme 6. o-Iminothione 15[2,13] reacts
as an electron-poor diene in an IEDDAR with 10 to give
benzo[b]thiazine 11a with complete control of the regioch-
emistry. This first half of the transformation occurs with
several copper salts and is almost quantitative with 9a and
Cu(OTf)2 (Table 1, Entry 2; 47% yield[5] of 11a). However,
in contrast with the behavior observed for the correspond-
ing selenolate ion,[3] thiolate ion 14 does not undergo clean
oxidation[14] (by molecular oxygen) to starting disulfide 9,
but probably gives rise to the formation of trans-thiazine S-
oxide 12. Actually, we do not possess any clear explanation
for the pathways leading to the formation of S-oxide 12,
but an ortho-iminothioquinone S-oxide[15] or an ortho-N-
(2ϫ30 mL), dried with anhydrous Na2SO4, and concentrated to
dryness. Purification by silica gel column chromatography (DCM/
petroleum ether, 3:1 followed by DCM/EtOAc, 3:1) afforded thi-
azine 11a (31 mg, 42% yield) and thiazine S-oxide trans-12a
(21 mg, 28% yield) as colorless oils.
3,4-Dihydro-3-(4-methoxyphenyl)-4-tosyl-2H-benzo[b]thiazine (11a):
1H NMR (200 MHz, CDCl3): δ = 7.75 (d, J = 7.8 Hz, 1 H), 7.45–
7.41 (m, 2 H), 7.33–7.28 (m, 2 H), 7.19–7.12 (m, 23 H), 7.08–7.05
(m, 2 H), 6.84–6.78 (m, 2 H), 5.69 (t, J = 6.5 Hz, 1 H), 3.75 (s, 3
H), 3.19 (dd, J = 13.3, 6.0 Hz, 1 H), 3.02 (dd, J = 13.3, 6.6 Hz, 1
H), 2.39 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 158.6,
143.5, 136.0, 134.0, 131.7, 131.4, 129.7, 129.2, 127.8, 127.5, 127.2,
126.2, 125.7, 113.8, 59.6, 55.2, 33.8, 21.6 ppm. IR (CDCl ): ν =
˜
3
3065, 3004, 2952, 2926, 2832, 2254, 1696, 1610, 1512, 1469, 1348,
tosylaminosulfenic acid are among the possible intermedi- 1249, 1163, 1086, 1034 cm–1. C22H21NO3S2 (411.53): calcd. C
ates that can be considered.[16]
64.21, H 5.14, N 3.40; found C 63.26, H 4.52, N 3.31.
trans-3,4-Dihydro-3-(4-methoxyphenyl)-4-tosyl-2H-benzo[b]thiazine
1
1-Oxide (trans-12a): H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J
= 8.0, 1.0 Hz, 1 H), 7.67 (dd, J = 8.0, 1.6 Hz, 1 H), 7.59 (td, J =
8.0, 1.6 Hz, 1 H), 7.51 (td, J = 8.0, 1.0 Hz, 1 H), 7.37–7.33 (m, 2
H), 7.22–7.17 (m, 4 H), 6.88–6.84 (m, 2 H), 5.42 (dd, J = 11.6,
7.2 Hz, 1 H), 3.84 (dd, J = 12.0, 7.2 Hz, 1 H), 3.79 (s, 3 H), 2.94
(t, J = 11.8 Hz, 1 H) 2.40 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.4, 144.6, 143.3, 134.9, 132.2, 132.0, 131.3, 129.8,
129.7, 127.9, 127.6, 127.1, 123.5, 114.4, 60.4, 55.3, 54.9, 21.6 ppm.
C22H21NO4S2 (427.53): calcd. C 61.80, H 4.95, N 3.28; found C
62.17, H 4.77, N 3.00.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental conditions, isolation of thiazine 11b and
thiazine S-oxide 12b using Cu(OTf)2 as catalyst, m-CPBA oxi-
dation of thiazines 11a and 11b, isolation of pure 11a and 13a by
consecutive reduction or oxidation, and copies of the 1H NMR
Scheme 6. Possible mechanism for the formation of derivatives 11
(and 12).
and 13C NMR spectra of thiazine systems.
Acknowledgments
Conclusions
Fondazione Cassa di Risparmio delle Provincie Lombarde (CARI-
PLO) is acknowledged for a grant to C. V.
In this communication we described the one-pot copper-
catalyzed transformation of 2-N-tosylaminoaryldisulfides
into a mixture of benzo[b]thiazines and benzo[b]thiazine S-
oxides. The isolation of pure thiazines or thiazine S,S-diox-
ides can be achieved by sequential reduction or oxidation
of the crude reaction mixtures, transforming the overall
procedure into a simple method that can be used to access
this interesting class of heterocyclic derivatives from easily
available starting materials. Investigation of the actual
mechanism(s) in operation in this novel procedure, its opti-
mization, as well as its potential applications are under in-
vestigation.
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Experimental Section
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commercially available 2-aminothiophenols by I2/NaOH oxi-
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(vide infra) was similarly prepared by acetylation of 2-aminodi-
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[5] Yields of thiazine derivatives 11 (and 12) reported in Scheme 3
and Table 1 (vide infra) were calculated by considering the po-
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disulfides 9.
Representative Procedure for the Transformation of Disulfide 9a into
Thiazine 11a and Thiazine S-Oxide 12a by Using CuI: In a reaction
vial, to a solution of disulfide 9a (50 mg, 0.09 mmol) in dry CHCl3
(1 mL) was sequentially added CuI (3.42 mg, 0.018 mmol), styrene
10 (24 mg, 0.18 mmol), and Et3N (9 mg, 0.09 mmol), and the mix-
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ide 9a, as monitored by TLC (48 h). Then, the crude reaction mix-
ture was diluted with DCM (40 mL), washed with saturated NH4Cl
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Copper-Mediated One-Pot Access to Benzo[b][1,4]thiazines
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[16] Probably, the transformation into thiazine S-oxide 12 is not the
only process occurring from thiolate 14. In fact, whereas the
yields of sulfides 11 were, in some case, near the limit of 50%
allowed for the transformation of one half of the amount of
disulfides 9,[5] the recovery of sulfoxides 12 was, depending on
the conditions used, in the range 0–28%, indicating an evident
loss of the aminoarylsulfenyl units from thiolate 14.
Received: January 9, 2012
[10] As a matter of fact, using 2-N-acetylaminoaryl disulfide (9c)
as starting material under the reaction conditions depicted in
Scheme 3, we observed neither polymerization of 10 nor for-
mation of the corresponding N-acetylated thiazine (11c) or
thiazine S-oxides (12c). Thus, reasonably, Et3N is actually able
to prevent the LA-induced polymerization of electron-rich al-
kene 10, yet not basic enough to deprotonate the NHAc group,
Published Online: February 17, 2012
Eur. J. Org. Chem. 2012, 1707–1711
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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