Rhodium-Catalyzed ortho-Amidations in the Preparation of Thiadiazine 1-Oxides

Article abstract of DOI:10.1002/chem.201602550

Rhodium-catalyzed ortho-amidations of sulfoximines lead to key intermediates for the preparation of thiadiazine 1-oxides. Following a straightforward protocol, a variety of synthetically valuable compounds can be obtained, thus circumventing common multis

Full text of DOI:10.1002/chem.201602550

DOI: 10.1002/chem.201602550
Communication
&
Amidation
Rhodium-Catalyzed ortho-Amidations in the Preparation of
Thiadiazine 1-Oxides
Ying Cheng, Wanrong Dong, Han Wang, and Carsten Bolm*[a]
easing access to such interesting compounds and being in-
Abstract: Rhodium-catalyzed ortho-amidations of sulfox-
spired by our previous work in this area,[10] we wondered
imines lead to key intermediates for the preparation of
about an alternative strategy starting from readily available,
thiadiazine 1-oxides. Following a straightforward protocol,
commercial sulfoximines 5. Selective introduction of an amino
a variety of synthetically valuable compounds can be ob-
group in the ortho position of the sulfoximidoyl substituent by
tained, thus circumventing common multistep approaches
metal-catalyzed directed CÀH bond functionalization[11] would
towards potentially bioactive products.
lead to key intermediates 4, which could further be modified
to provide straightforward access to range of target products
1.[12] The success of this approach is described here.
On the basis of the work by Chang,[13] Glorius,[14] and
The first derivatives of thiadiazine 1-oxides were reported by
Wagner and Reinçhl as early as 1964.[1] A few years later, Wil-
others[15] we decided to focus on directed CÀH bond amid-
liams and Cram,[2] as well as industrial colleagues at Beiers-
dorf[3] and Gçdecke,[4] developed new synthetic strategies to-
wards such compounds. Those preparative investigations were
the basis for numerous bioactivity studies that revealed inter-
esting properties of thiadiazine 1-oxide derivatives 1 useful for
medical applications.[5,6] For example, NSC 287474 (2) was
found to be a potential reverse transcriptase inhibitor for the
protection of lymphocytes against HIV,[7] and in animal tests
thiadiazine 1-oxide 3 revealed equipotent blood-pressure-low-
ering activity as the commercial antihypertensive drug Prazosin
(Scheme 1).[8]
ations under rhodium catalysis.[16] S-Methyl-S-phenyl-sulfox-
imine (5a) and tert-butyl(2,4,6-trichlorobenzoyl)oxycarbamate
(6a) were chosen as representative substrates. The catalytic
system of [Cp*Rh(MeCN)3(SbF6)2] and NaOAc in 1,2-DCE at
1008C for 12 h provided the desired product 4aa in 55% yield
(Table 1, entry 1). Using tert-amylOH or acetonitrile as solvent
Table 1. Optimization of the amidation conditions.[a]
Commonly, thiadiazine-1-oxides 1 are prepared by multiple-
step syntheses starting from N-protected 2-thio-substituted
anilines or ortho-nitroaryl thioethers.[1–4,9] With the goal of
Entry
5a/6a ratio
Solvent
Yield of 4aa [%]
1
2
3
4
5
6
7
1:1.2
1:1.2
1:1.2
1:2
1.2:1
2:1
1,2-DCE
tert-AmylOH
MeCN
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
55
36
30
36
64
71
81
3:1
[a] Reaction conditions: Stirring of sulfoximine 5a, oxycarbamate 6a,
[Cp*Rh(MeCN)3](SbF6)2] (5 mol%), NaOAc (1.2 equiv) in the given solvent
at 1008C under argon for 12 h. DCE=1,2-dichloroethane.
gave 4aa in lower yields (Table 1, entries 2 and 3). Also increas-
ing the amount of 6a decreased the yield of 4aa (36%;
Table 1, entry 4). Assuming that the latter result was due to
partial substrate decomposition, the sulfoximine-to-oxycarba-
mate was varied. Supporting our hypothesis, the yield of 4aa
raised to 64% and 71% when 1.2 equiv and 2.0 equiv, respec-
tively, of 5a was applied (Table 1, entries 5 and 6). Finally, the
best result was achieved with 3.0 equiv of 5a providing 4aa in
81% yield (Table 1, entry 7).
Scheme 1. General structure of thiadiazine 1-oxides 1 and two bioactive de-
rivatives 2 and 3; envisaged syntheses of 1 via 4 starting from sulfoximines
5.
[a] Y. Cheng, Dr. W. Dong, H. Wang, Prof. Dr. C. Bolm
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
A screening of other NH-Boc oxycarbamates (Boc=tert-bu-
toxycarbonyl) with different aryl substituents (see Supporting
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602550.
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Information, Table S1) showed that 6a was the amidating
agent of choice, leading to the highest yields of 4aa.
With the optimal conditions in hand, the substrate scope
was evaluated (Scheme 2).[17] S-Aryl-S-methyl sulfoximines with
various substituents on the aromatic ring reacted smoothly in
the rhodium-catalyzed amidation reaction with tert-butyl(2,4,6-
trichlorobenzoyl)oxycarbamate (6a) affording the correspond-
ing ortho-amidation products (4aa–4ma) in good to moderate
yields (44–83%).
The subsequent investigations focused on converting the
catalytically prepared ortho-NHBoc aryl sulfoximines 4 into
thiadiazine 1-oxide derivatives 1 (Scheme 3). Cleavage of the
Boc group of sulfoximines 4aa and 4sa provided ortho-amino-
substituted sulfoximines 7a and 7b in yields of 90 and 80%,
Scheme 3. Syntheses of thiadiazine 1-oxide derivatives.
respectively (Scheme 3). Subsequent reactions of those prod-
ucts with carbon disulfide at 1708C for 24 h led to cyclizations
forming thiadiazine 1-oxide 8 in 90% yield and NSC 287474 (2)
in 89% yield. Thiadiazine 1-oxides 9 (22%) and 10 (88%) were
then obtained by treatment of 7a with DMF at 1708C for 24 h
and the reaction of 7a with methyl iodide under basic condi-
tions at 808C for 20 h.[18]
Heteroaromatic thioether 10 was recognized as a valuable
intermediate for Liebeskind–Srogl-type cross-coupling reac-
tions[19] with boronic acids to allow further extension of the
molecular diversity of the thiadiazine 1-oxide derivatives
(Scheme 3). Using a catalyst system consisting of tris(dibenzyl-
ideneacetone)dipalladium(0) [Pd2dba3], TFP [tri(2-furyl)phos-
phine], and CuTC (TC=thiophene-2-carboxylate) in THF at
508C for 24 h gave cross-coupling products 11 a–e in yields
ranging from 58 to 73%. It was also noted that reactive func-
tional groups such as bromo and nitro substituents at the aryl
boronic acids were tolerated, allowing for potential additional
structural modifications at later synthetic stages.
Scheme 2. Rhodium-catalyzed ortho-amidation [performed at 1008C, except
for catalyzes leading to 4ai–4am (608C)]; common scale: 0.6 mmol with re-
spect to sulfoximines 5. The result of a 1.5 mmol scale experiment for 4aa is
shown in parentheses.
para-Halo-substituted products 4da and 4ea showed the
best results (82 and 83% yield, respectively). The lowest yield
(44%) was observed in the formation of 4ja having a para-
nitro-substituent. It was noted that meta-substituted (5k and
5l) and 2-naphthyl sulfoximines (5m) showed an exclusive site
selectivity, providing single regioisomeric products (4ka–4ma)
in good yields (63–71%). Also, the reactions of S-phenyl sulfox-
imines with other S-alkyl substituents (other than methyl) pro-
ceeded well, giving 4na–4ra in yields ranging from 56 to 81%.
With diphenyl sulfoximine 5s, only mono-amidation to give
4sa (in 69% yield) was observed. Furthermore, S-aryl-S-benzyl
sulfoximines 4ta–4va were formed in good yields (70–78%).
Finally, other oxycarbamates varying in the amido substituent
were used in the reaction with 5a. As those reagents (6i–6m)
degraded at 1008C, the catalyses were performed at 608C. As
a result, products 4ai–4am were obtained in yields ranging
from 51 to 78%.[17]
Finally, we demonstrated a selective derivatization of the
sulfur-bound NH group of NHBoc-containing sulfoximine 4aa
(Scheme 4). Treatment of 4aa in toluene with 1-(bromoethyn-
yl)-4-chlorobenzene (12) in the presence of Cu(OAc)2, 1,10-phe-
nanthroline and K2CO3 for 48 h at 608C[20] led to two products,
which were identified as N-alkynylated sulfoximine 13 (23%)
and thiadiazine 1-oxide 14 (51%). Based on the demonstrated
reactivity pattern of the former product type,[21] it is reasonable
to assume that the formation of heterocycle 14 proceeded via
13 by a regioselective intramolecular nucleophilic attack of the
triple bond by the NHBoc moiety of 13.
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Keywords: heterocycles · ortho-amidation · rhodium catalysis ·
sulfoximines · thiadiazine 1-oxides
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Scheme 4. Copper-catalyzed N-alkynylation of 4aa.
In summary, we developed a new access towards thiadiazine
1-oxides with rhodium(III)-catalyzed ortho-amidations of NH-
sulfoximines as the key transformation. As the starting materi-
als are readily available commercially, a variety of products can
now be obtained in a straightforward manner, leading to core
scaffolds for potentially bioactive molecules.
Experimental Section
General procedure for the rhodium-catalyzed amidation
A
5
Schlenk tube (25 mL) was charged with sulfoximine
(0.60 mmol), aroyloxycarbamat (0.20 mmol),
6
[Cp*Rh(MeCN)3(SbF6)2] (8.3 mg, 0.010 mmol), and NaOAc (19.7 mg,
0.24 mmol). Under an argon atmosphere, dry 1,2-dichloroethane
(1.0 mL) was added to the mixture by syringe, and stirring was
continued at 1008C for 12 h. Then, the mixture was cooled to
room temperature, diluted with dichloromethane (10 mL), and fil-
tered through a Celite pad. After washing with dichloromethane
(3ꢁ20 mL), the filtrate was concentrated, and the product was pu-
rified by flash column chromatography on silica gel with a mixture
of n-pentane and acetone as the eluent affording 4 as a pure prod-
uct. For additional experimental details, see the Supporting Infor-
mation.
General procedure for the palladium-catalyzed cross-cou-
pling
A Schlenk tube (25 mL) was charged with 1-methyl-3-(methylthio)-
benzo[e][1,2,4]thiadiazine 1-oxide (10, 45.2 mg, 0.20 mmol), the
boronic acid (0.22 mmol), [Pd2dba3] (7.3 mg, 0.0080 mmol), tri(2-fur-
yl)phosphine (7.4 mg, 0.032 mmol), and CuTC (49.7 mg,
0.26 mmol). Under an argon atmosphere, dry THF (2.0 mL) was
added to the mixture by syringe. After stirring at 508C for 24 h, the
mixture was cooled to room temperature, was washed with satu-
rated NaHCO3 solution, and extracted with EtOAc (3ꢁ10 mL). The
combined organic layers were dried over MgSO4, filtered and con-
centrated. The product was purified by flash column chromatogra-
phy on silica gel with n-pentane/acetone (20:1) as eluent, affording
11 as a pure product. For additional experimental details, see the
Supporting Information.
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Acknowledgements
Y.C., W.D., and H.W. thank the China Scholarship Council for
predoctoral stipends. We also thank Dr. Shunxi Dong (RWTH
Aachen University) for helpful discussions.
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Received: May 29, 2016
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Amidation
Y. Cheng, W. Dong, H. Wang, C. Bolm*
&& – &&
Rhodium-Catalyzed ortho-Amidations
in the Preparation of Thiadiazine 1-
Oxides
A channel to thiadiazine 1-oxides:
Rhodium-catalyzed ortho-amidations of
sulfoximines with aroyloxycarbamates
show a high functional group tolerance
and provide key intermediates for bio-
logically interesting thiadiazine 1-oxides.
Chem. Eur. J. 2016, 22, 1 – 5
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