Umpolung Strategy with 2-Aminothiophenols: Access to 2-Arylbenzothiazine Derivatives from Alkyl Aryl Ketones

Article abstract of DOI:10.1002/adsc.202000964

Strong Br?nsted acids were found to catalyze the oxidative condensation of 2-aminothiophenols with aryl alkyl ketones in DMSO to provide a wide range of complex 2-arylbenzothiazines. With acetophenones, dimeric 2-arylbenzothiazines were formed. On the other hand, the reaction with propiophenones resulted in 2:1 adducts whereas 1:1 adducts were produced with isobutyrophenones, benzoylacetonitrile and ethyl benzoylacetate. (Figure presented.).

Full text of DOI:10.1002/adsc.202000964

Title: Umpolung Strategy for Oxidative Functionalization with 2-
Aminothiophenols: Access to Complex 2-Arylbenzothiazine
Derivatives from Simple Alkyl Aryl Ketones
Authors: Thanh Binh Nguyen and pascal retailleau
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000964
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10.1002/adsc.202000964
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Umpolung Strategy with 2-Aminothiophenols: Access to 2-
Arylbenzothiazine Derivatives from Alkyl Aryl Ketones
Thanh Binh Nguyen,*,a and Pascal Retailleaua
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1
avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: thanh-binh.nguyen@cnrs.fr
Received: (will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
difficulty in controlling regiochemistry of the reactions.
Abstract. Strong Brønsted acids were found to catalyze the
oxidative condensation of 2-aminothiophenols with aryl To overcome this drawback, the transformation could
alkyl ketones in DMSO to provide a wide range of complex
2-arylbenzothiazines. With acetophenones, dimeric 2-
arylbenzothiazines were formed. On the other hand, the
reaction with propiophenones resulted in 2:1 adducts
whereas 1:1 adducts were produced with isobutyrophenones,
benzoylacetonitrile and ethyl benzoylacetate.
be performed in a stepwise manner in which the
nitrogen or sulfur terminus is temporarily masked or
protected and then released later for cyclization. Such
a process requires however additional operations of
protection/deprotection and thus lower the efficiency
of the global transformation.
Keywords: sulfur; 1,4-benzothiazines; DMSO; redox
condensation
Among nitrogen and sulfur heterocycles, 1,4-
benzothiazines[1] constitute an important motif that is
widely present in natural products and bioactive
molecules as dimeric and other oligomeric forms.[2]
For example, pheomelanins are polymeric structures of
melanin pigments in mammalian hair and chicken
feathers.[3] Trichochromes are produced from the same
sources, of lower molecular weight and usually yellow,
red or violet. All these structures contain multiple 1,4-
benzothiazines motifs.
Scheme 1. Umpolung Approach to 1,4-Benzothiazine
In this context, the development of new conditions
allowing direct access to original 2-aryl-1,4-
benzothiazine motif from 2-aminothiophenols and aryl
alkyl ketones would be highly desirable.[5] Taking
advantage of the facile oxidation of the thiols into the
corresponding disulfide and the acid-catalyzed
condensation of an amino group with a ketone group,
we suggest here the use of 2-aminothiophenols 1 for
direct oxidative functionalization of readily available
enolizable ketones via an in-situ and easily reversal of
polarity of 1 from a 1,2-bis-nucleophile to 1,2-
nucleophile/electrophile.
Figure 1. Selected Natural 1,4-Benzothiazines
We recently reported the reaction of 2-
aminothiophenol with ,’-enolizable ketones such as
cycloalkanones or dialkyl ketones to provide
spirobis(1,4-benzothiazines) A (Scheme 2). The
reaction was efficiently catalyzed by a strong Brønsted
acid such as TFA and required only DMSO as an
oxidant in near stoichiometric amounts.[6] We were
eager to investigate the behavior of -enolizable
The synthesis of 1,4-benzothiazine derivatives was
based mainly on non-redox condensation reactions of
o-aminothiophenols, which act as a bis-nucleophile,
with a 1,2-bis-electrophile.[4] Since both thiol SH and
amino NH2 groups could act as a nucleophile, a
frequently encountered issue of this approach is
1
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10.1002/adsc.202000964
Advanced Synthesis & Catalysis
ketones under the similar reaction conditions. 10), lower the DMSO amount to only 2 equiv (entry 9)
Gratifyingly, the reaction conditions applied to enhanced significantly the reaction. This improvement
acetophenone 2a led to dimeric 1,4-benzothiazine 3aa could be explained by an increase in the concentrations
as a yellow solid that precipitated out of the reaction of both starting materials and catalyst and favored the
mixture and readily isolable by a simple filtration in a dimerization of the monomeric intermediate 7a to 3aa.
moderate yield (60%).
We found that the reaction the reaction conducted
under an inert atmosphere led to practically the same
result (entry 11). The reaction could be performed with
2,2′-dithiodianiline B instead of 1a (entry 12). Finally,
we found that a weak acid such as HOAc was not
suitable as a catalyst for this reaction (entry 13).
Table 1. Optimization of the Reaction Conditions
Scheme 2. Oxidative Coupling of 2-Aminothiophenol with
Ketones
Previously, access to such dimeric 1,4-
benzothiazines was based mainly on the condensation
of
o-aminothiophenols
with
1,2-bis-
Entry[a] Catalyst (x mol %)
y
T (ºC) Yield (%)[b]
electrophiles.[7] Recently, 3aa analogues were
obtained via a reaction of 2,2′-dithiodianilines and
acetophenones in HOAc under aerobic conditions. One
of the major disadvantages of this method is the use of
AIBN.[8] This unstable initiator should be stored at low
temperature in the dark to avoid thermal and
photochemical decomposition and accidental
explosion. Moreover, the reactions were reported only
with 2,2′-dithiodianilines, which should be prepared
from their monomeric precursors 2-aminothiophenols
by an additional oxidation.
1
2
TFA (10)
-
4.5 80
4.5 80
4.5 100
4.5 80
4.5 80
4.5 80
4.5 80
4.5 100
2
2
2
2
2
3aa, 65
8, 30
3
-
3aa, 21
7a, 25[c]
7a, 56[c]
3aa, 51
3aa, 61
3aa, 42
3aa, 77
3aa, 28
3aa, 76
3aa, 73
3aa, 25
4
5
6
7
DBU (10)
CyNH2 (100)
FeCl3•6H2O (10)
PTSA
8
9
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
HOAc (10)
80
60
80
80
80
10
11[d]
12[b]e
13
Based on this serendipitous observation and the
above-mentioned literature precedent, we focused our
investigation on such a new reactivity and report here
interesting aspects of the reaction of 2-
aminothiophenols with alkyl aryl ketones in DMSO
catalyzed by a strong Brønsted acid. The initial
reaction conditions were applied to an equimolar
mixture of both starting materials and resulted in an
better yield (Table 1, entry 1). The important role of
TFA catalyst was further demonstrated. Indeed, when
the reaction was performed in the absence of TFA, the
reaction proceeded in an uncontrolled way, leading to
complex mixtures from which we could isolate 2-
phenylbenzothiazole 8 in low yield (22%). In this case,
the expected product 3aa was formed only in a trace
amount that could be detected by the characteristic 1H
NMR signal of the aliphatic C-H proton (entry 2). On
the other hand, the background reaction conditions
could result in higher yield (21%) of 3aa at a higher
temperature (100 ºC) (entry 3). When a base such as
DBU[5] or cyclohexylamine was used as a catalyst
(entry 4) or additive (entry 5), the reactions in both
cases stopped at the formation of monomer 3-phenyl-
2H-benzo[b][1,4]thiazine 7a.
[a] Conditions: 1a (1 mmol, 125 mg), acetophenone (1 mmol,
120 mg), additive or catalyst (x mol %), DMSO (y mmol)
[b]
under air.
Isolated yield unless otherwise noted.
[c]Determined by 1H NMR. [d] Reaction performed under an
Ar atmosphere. 2,2′-Dithiodianiline B (0.5 mmol) were
[e]
used in place of 1a.
The optimized reaction conditions (Table 1, entry 9)
were next applied to a range of aryl methyl ketones
(Scheme 3). Functional groups such as alkyl, alkoxy,
halogen and cyano were compatible with the reaction
conditions, leading to the expected products 3ab-3am
in moderate to good yields. In most cases, the products
could be isolated by a simple trituration of the reaction
mixture with methanol. While good to excellent yields
were obtained with alkyl, alkoxy, fluoro, chloro and
cyano substituted acetophenones, the reactions were
less efficient with m- and p-bromo- acetophenones.
In some cases, while the products 3 are sparingly
soluble in common organic solvents such as
chloroform or DMSO, their solubility is significantly
enhanced by addition of TFA as exemplified by the
case of dimer product 3ad issued from p-
A Lewis acid such as FeCl3•6H2O or another
Brønsted acid PTSA showed also good catalytic effect
(entries
7
and 8). While changing reaction
methoxyacetophenone 2d. The H and 13C NMR
spectra of 3ad were recorded in CDCl3 and TFA and
1
temperatures reduced the yield of 3aa (entries 8 and
2
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10.1002/adsc.202000964
Advanced Synthesis & Catalysis
its crystals for X-ray crystallographic study were nor heteropropellane was formed. the reaction stopped
obtained as 3ad•2TFA salt from slow evaporation of at the formation of the corresponding benzothiazines
this salt in chloroform. Acetyl hetarenes derived from 7a-c in high yields by 1H NMR of the crude mixtures
thiophene, furan and benzofuran were shown to be (Scheme 4b) but their isolation by column
competent substrates, providing the expected product chromatography was shown to be problematic due to
3an, 3ao, 3bo and 3ap in excellent yields.
reactions with oxygen. Indeed, freshly purified
samples upon leaving under air turned from bright
yellow of benzothiazine 7a-c to dark brown mixtures
from which large and single crystals were separated
and determined as 2-phenylbenzothiazole 8 for all
these three cases.
Scheme 4. Reactions with Propiophenones and Homologues
On the other hand, -substituted alkyl phenyl
ketones
such
as
isobutyrophenone
and
benzoylcyclohexane were found to yield 3,3-dialkyl-
1,4-benzothiazines 7d,e, which were bench-stable and
could be isolated in high yields (Scheme 5).
Scheme 3. Reactions of 1a,b with Methyl Ketones 2a-q
As an -enolizable aliphatic methyl ketone,
pinacolone 2q reacted sluggishly, leading to the
desired product 3aq in a low yield, which could be
ascribed to the important steric hindrance of the t-butyl
group. The reactivity is ameliorated with a less
sterically demanding ketone such as methyl neopentyl
ketone 2r. In this case, although the ketone substrate
2r is ,’-enolizable, the isolated product 3ar was
issued from the oxidation that exclusively occurred at
the methyl ketone group.
The reaction was next extended to propiophenone
4a (Scheme 4a). To our surprise, while the
corresponding bis-1,4-benzothiazine was not formed,
we could isolate from the reaction mixture a white
solid which was identified as an original
heteropropellane 5a (22%). Based on this observation,
the molar ratio 1a:4a was adjusted to 2:1. Gratifyingly,
such a simple modification allowed us to increase the
yield of 5a up to 79%. This set of reaction conditions
were applied to p-substituted propiophenones 4b-d and
resulted in the expected heteropropellanes 5b-5d,
which were isolated in high yields by simple filtration
in all cases.
Scheme 5. Reactions with -Substituted Propiophenones
Based on these observations, we tentatively suggest
a mechanism (Scheme 6) for the formation of
benzothiazines 3, 5a-d and 7d-e as well as of
benzothiazole 8 from autoxidation of 7a-c. The first
step was the formation of disulfide B by oxidation of
1a with DMSO, confirmed by a control experiment.[11]
Disulfide B condensed next with ketone C to provide
imine- enamine D-E. Cyclization of E led to
benzothiazine 7 along with the extrusion of 1a, which
was recycled to disulfide B by DMSO (Scheme 6a).
Ketones 7 bear a small substituent (R = H or Me, 7H
or 7Me) were oxidized easily to sulfoxide by DMSO
(Scheme 6b). The rearrangement of sulfoxide F to
sulfonium J was promoted by acid via intermediates
G-I. Dimer 3aa was obtained by the condensation of J
(R = H) with 7a, which is the enamine form of 7 (R =
H).
With butyrophenone 6a, valerophenone 6b and
hexyl phenyl ketone 6c, neither bis-1,4-benzothiazine
3
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10.1002/adsc.202000964
Advanced Synthesis & Catalysis
When R = Me, the similar condensation is hindered. remained unchanged, 2-aminothiophenol 1a was
As a result, a reaction of J with an additional molecule oxidized mainly into B.
of 1a would provide sulfonium M, which underwent a
Benzothiazines bearing larger R groups (Et, n-Pr, n-
cyclization by the mercapto group from the less Bu) were more stable against oxidation by DMSO but
hindered face to give 5a as a single diastereomer.
not air-stable, being oxidized by O2 to ketone H. In this
case, the transformation of H to sulfonium K was
hindered by the larger R group. Instead, cyclization of
H to benzothiazoline L occurred easily. Elimination of
RCHO from L yielded 8.[9] The autoxidation of
benzothiazines 7d,e is totally inhibited by the two R
groups.
The presence of sulfonium J (R = H) could be
confirmed by trapping experiments with anilines 9a,b,
providing imine 10a,b in moderate yields (Scheme 7).
Previously, similar reactions were reported to involve
both O2/DMSO oxidant and KI catalyst at 120 °C.[10]
a. formation of benzothiazine derivatives 7:
R
R
Ph
H2N
Ph
O
DMSO
S
N
C
S
1a
S
H+
-H2O
NH2
S
NH2
B
D
DMSO
H+
R
SH
S
R
Ph
+
HN
S
NH2
N
Ph
S
NH2
1a
7
E
b. Evolution of benzothiazines
Me
O-
S+
S+
-O
S
S
R
Me
O
R
R
R = H, Me
H
N
Ph
N
N
Ph
Ph
or O2
7
G
F
R = Et, n-Pr, n-Bu
R = H
S
N
H
Ph
7a
OH
R
S+
R
SH
S
H+
H+
R = H, Me
O
R = H
R
3aa
-H2O
+7a
N
Ph
N
Ph
N
Ph
J
I
H
Scheme 7. Three-component Access to 10a,b via J
R = Me
+1a
DMSO
-Me2S
S+
Me SH
R = Et,
n-Pr,n-Bu
Finally, we observed that benzothiazines 7 could be
stabilized against oxidation by an electron
withdrawing group (R = CN or CO2Et) installed next
to the sulfur atom (Scheme 8). The reaction of 1a with
ketone 11a,b resulted in 12a,b as orange air-stable
solids.
5a
N
N
H
H
Ph
M
R
S+
R
Ph
S
S
Ph
O
Ph
N
N
H
N
8
L
K
control experiments with an acid scavenger (1 equiv):
DMSO, (3 equiv)
80 ºC, 16 h
+
1a
2a
B
+
unchanged 2a
pyridine or
N-methylpiperidine
(1 equiv)
Scheme 8. Reaction with Ketones 11a,b Bearing an EWG
Scheme 6. Proposed reaction pathways
In conclusion, we have developed a simple method
for functionalization of aryl alkyl ketones with o-
aminothiophenols to provide a wide range of 2-
arylbenzothiazines. The method is highlighted by the
use of TFA as an acid catalyst and DMSO in near
stoichiometric amount as an oxidant. Although 1,4-
benzothiazines 7 are common reaction intermediates,
the final reaction outcomes were determined by the
size and electronic effect of the alkyl group of the
ketones. The results presented here confirm that
complex structures could be built from simple starting
materials under simple conditions. Further study on the
mechanism as well as the reaction scopes are ongoing
in our laboratory.
One of the possible reason for the formation of 3aa
without any added acid catalyst is that the reaction is
autocatatalyzed by the acidic thiol function of 2-
aminothiophenol 1a (pKa = 6.59)[12] as well as by other
oxygenated acidic species generated from oxidation of
the thiol function of 1a by DMSO such as sulfinic and
sulfonic acids. To confirm this hypothesis, we
performed control experiments in the presence of an
organic base (1 equiv.) such as pyridine or N-
methylpiperidine. Under the same conditions of
heating (DMSO (3 equiv), 80 ºC, 16 h). Such bases
prevented the formation of 3aa. While acetophenone
4
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10.1002/adsc.202000964
Advanced Synthesis & Catalysis
Experimental Section
[5] For a recent example of oxidative condensation of 2-
aminothiophenols with enolizable ketones at 110 ºC, see:
Y. Lin, G. Lu, R. Wang, W. Yi, Org. Lett. 2016, 18, 6424.
General procedure for the synthesis of 3 from 2-
aminothiophenols 1 and methyl ketone 2 (Table 1 and
Scheme 3)
[6] T. B. Nguyen, P. Retailleau, Adv. Synth. Catal. 2020,
DOI: 10.1002/adsc.202000535.
A mixture of 2-aminothiophenol 1 (1 mmol), acetophenone
2 (1 mmol), TFA (0.1 mmol, 11 mg) in DMSO (2 mmol,
0.15 mL) was stirred in a 7-mL tube closed with a rubber
septum at 80 ºC for 16 h. After being cooled to room
temperature, the crude reaction mixture was purified as
indicated for each compound, by trituration or
chromatography on silica gel column.
[7] For selected examples, see: a) from dibenzoylacetylene:
M. I. Ansari, R. Shankar, M. K. Hussain, R. Kant, P. R.
Maulik, K. R. Kumar, Hajela, K. J. Heterocyclic Chem.,
2011, 48, 1336. from α,α-dibromoacetophenones,
Prakash, O. Sharma, N. Pannu, K. Synth. Commun. 2007,
37, 1995. From 3-phenyl-5(4H)-isoxazolone: M. H. Rao ,
A. P. R. Reddy, V. Veeranagaiah, Synth. Commun. 1991,
21, 1715.
Products 7d,e and 12a,b were synthesized in the same
manner with DMSO (4.5 mmol, 0.32 mL). In these cases,
the products were purified by chromatography on silica gel
column.
[8] X. Huang, N. Rong, P. Li, G. Shen, Q. Li, N. Xin, C. Cui,
J. Cui, B. Yang, D. Li, C. Zhao, J. Dou, B. Wang, Org.
Lett. 2018, 20, 3332.
Representative procedure for the synthesis of
heteropropellanes 5 from 2-aminothiophenol 1a and
propiophenone 4
[9] J. D. Charrier, C. Landreau, D. Deniaud, F. Reliquet, A.
Reliquet, J. C. Meslin, Tetrahedron 2001, 57, 4195.
A mixture of 2-aminothiophenol 1a (2 mmol, 250 mg),
propiophenone 4a (1 mmol, 134 mg), TFA (0.1 mmol, 11
mg) in DMSO (4.5 mmol, 0.32 mL) was stirred in a 7-mL
tube closed with a rubber septum at 80 ºC for 16 h. After
being cooled to room temperature, the crude reaction
mixture was purified as by trituration and filtration with cold
methanol (0-4 ºC) to provide heteropropellane 5a as a white
solid.
[10] J. Zhao, Z. Luo, J. Xu, Adv. Synth. Catal. 2020, 362,
1988.
[11] W. E. Fristad, J. R. Peterson, Synth. Commun. 1985, 15,
1.
[12] R. Fujiki, Y. Kasai, Y. Seno, T. Matsui, T. Shigeta,N.
Yoshida, H. Nakano, Phys. Chem. Chem. Phys. 2018, 20,
27272.
CCDC 2016315-2016319; 2016321-2016322 and 2031498-
2031499 contain the supplementary crystallographic data
for 3ad•2TFA, 3ah, 3ai, 3aq, 3ar, 7d, 7e, 5a and 12a
respectively in this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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5
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10.1002/adsc.202000964
Advanced Synthesis & Catalysis
COMMUNICATION
Umpolung Strategy with 2-Aminothiophenols:
Access to 2-Arylbenzothiazine Derivatives from
Alkyl Aryl Ketones
Adv. Synth. Catal. Year, Volume, Page – Page
Thanh Binh Nguyen,*,a and Pascal Retailleaua
6
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