A simple copper-catalysed tandem cyclisation of ynamides leading to triazolo-1,2,4-benzothiadiazine-1,1-dioxides in PEG-400 medium

Article abstract of DOI:10.1039/c4ra03503h

An efficient one-pot approach for the synthesis of fused triazolo 1,2,4-benzothiadiazine-1,1-dioxide derivatives from functionalised ynamides and sodium azide in the presence of CuI using PEG-400 as the medium is described. The cyclisation process involves intermolecular C-N bond formation and subsequent cycloaddition between ynamide and azide. Thus three new C-N bonds are formed in a single step. It is also demonstrated that the triazole ring in triazolo-1,2,4-benzothiadiazine-1,1-dioxide can be readily decyclised in the presence of glacial acetic acid with the elimination of molecular nitrogen.

Full text of DOI:10.1039/c4ra03503h

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A simple copper-catalysed tandem cyclisation of
ynamides leading to triazolo-1,2,4-
benzothiadiazine-1,1-dioxides in PEG-400
medium†
Cite this: RSC Adv., 2014, 4, 28359
*
Alla Siva Reddy, M. Nagarjuna Reddy and K. C. Kumara Swamy
An efficient one-pot approach for the synthesis of fused triazolo 1,2,4-benzothiadiazine-1,1-dioxide
derivatives from functionalised ynamides and sodium azide in the presence of CuI using PEG-400 as the
medium is described. The cyclisation process involves intermolecular C–N bond formation and
subsequent cycloaddition between ynamide and azide. Thus three new C–N bonds are formed in a
single step. It is also demonstrated that the triazole ring in triazolo-1,2,4-benzothiadiazine-1,1-dioxide
can be readily decyclised in the presence of glacial acetic acid with the elimination of molecular nitrogen.
Received 17th April 2014
Accepted 11th June 2014
DOI: 10.1039/c4ra03503h
www.rsc.org/advances
Introduction
Alkynes have been extensively used in many organic trans-
formations to synthesise important molecules and natural
products.1 Heteroatom substituted alkynes, especially ynamides
(N-substituted alkynes) have drawn prominent attention from a
synthetic perspective due to their high reactivity.2 These
precursors are utilized in both electrophilic and nucleophilic
reactions.3 They also act as surrogates of allenes. Over the last
few years, a rapid expansion in the cycloaddition reactions of
ynamides has taken place.4 However, there is still enormous
scope to explore reactions of functionalised ynamides in
cycloaddition and cyclisation reactions.
Benzosultams display a signicant role in drug discovery
because of their diverse medicinal uses.5,6 Recently, much
interest has been directed towards sultams such as 1,2,4-ben-
zothiadiazine-1,1-dioxides and triazolothiadiazepine 1,1-diox-
ides because of their wide range of biological activities.7,8
Majumdar's group reported the synthesis of tri-
azolothiadiazepine 1,1-dioxides by basic alumina supported
azide–alkyne cycloaddition whereas Sun's group reported the
synthesis of triazoloquinazolinones9a via copper catalysed
tandem click and intramolecular C–H amidation.9b It should be
noted that 1,2,3-triazole moiety is also important in synthetic,
medicinal as well as materials chemistry.10–12 In this context, we
envisioned that compounds having both 1,2,3-triazole and
Fig. 1 Examples of pharmaceutically useful sultams and triazoles.
sultam moieties will have utility in medicinal chemistry.
Representative examples are shown in Fig. 1.13 To the best of our
knowledge, formation of benzosultam fused triazoles directly
from ynamide is not reported. In continuation to our studies on
[Cu]-catalysed synthesis of fused triazoles,14 we report herein a
simple route for benzosultam fused triazoles from ynamides
using PEG-400 as a solvent in this work.
School of Chemistry, University of Hyderabad, Hyderabad 500 046, A. P., India.
E-mail: kckssc@yahoo.com; kckssc@uohyd.ac.in; Fax: +91-40-23012460; Tel: +91-
40-23134856
Results and discussion
The precursors used in the present study are N-alkynyl 2-halo-
benzenesulfonamides. These were prepared using 2-halo-ben-
zenesulfonamides 1a–i and the corresponding bromo-alkynes
2a–g following a literature method.15 However, all these
† Electronic supplementary information (ESI) available: Details on the synthesis
of precursors 3a–p, 1H and 13C NMR spectra and CIF les. CCDC
992617–992619. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra03503h
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Table 1 Optimization of the catalytic system for the synthesis of tri-
azolo 1,2,4-benzothiadiazine 1,1-dioxide 4 (cf. Scheme 1)a
compounds 3a–p (Fig. 2) are new. These substrates readily
undergo hydrolysis at room temperature but can be stored at
low temperature. Details of their synthesis are given in the ESI.†
Initially, we performed the reaction between N-alkynyl-2-
iodo-benzenesulfonamide 3a and sodium azide in the presence
of CuI (10 mol%) and L-proline (20 mol%) in DMF solvent at 100
ꢀC for 12 h. To our delight, we got the desired benzosultam
fused 1,2,3-triazole product 4 in 64% isolated yield. This reac-
tion proceeds via intermolecular C–N bond formation followed
by cycloaddition between alkyne and azide. Our next step was
directed towards screening various reaction parameters to
improve the yield of the product and the details are given in
Table 1.
The absence of ligand (L-proline) did not affect the yield of
the product (entry 1). Diethyl carbonate was ineffective and did
not furnish the desired product (entry 2). Water as a solvent led
to only 20% of 4 along with 36% of the hydrolysed product 5
(entry 3).16 Thus, hydrolysis was a major problem in water
medium. Surprisingly, in PEG-400 as a solvent compound 4 was
isolated in 65% yield (entry 4). Although all the solvents checked
had oxygen donors, PEG-400 has a combination of ether and
residual hydroxyl groups which may promote the reaction
better.17 This might be responsible for the improved yield of the
product. Later, we found that 5 mol% of CuI furnished similar
yield (entry 5). Further decreasing catalyst loading to 2 mol%
CuI, decreased the yield of the product (entry 6). The yield was
increased to 78% by using 2 equiv. of NaN3 instead of 1.2 equiv.
of NaN3 (entry 7). No reaction was observed in the absence of
CuI. Utilization of other copper salts did not improve yield of
the desired product. Decrease in the yield of the product was
Temp.
Entry CuX (mol%)
NaN3 (eq.) Solvent
(ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuI (2)
CuI (5)
CuCl (5)
CuSO4$5H2O(5) 2.0
CuCl2$2H2O(5)
CuBr (5)
CuI (5)
CuI (5)
CuI (5)
1.2
1.2
1.2
1.2
1.2
1.2
2.0
2.0
DMF
(EtO)2CO 100
H2O
100
64
0
100
100
100
100
100
100
100
100
100
100
80
20c
65
65
58
78
65
62
48
68
56d
72e
38
52
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
9
10
11
12
13
14
15
2.0
2.0
2.0
2.0
2.0
2.0
60
r.t.
CuI (5)
a
Ynamide (0.24 mmol), CuI (x mol%), NaN3, solvent (1 mL) in the
b
absence of L-proline for entries 1–15. Yield of the isolated product.
c
d
Hydrolysed product 5 was isolated (36%). Reaction was performed
e
in an open air. CuI (30 mol%), TMSN3 (2.5 eq.), DIPEA (3 eq.), DMF
(1 mL) were used.
observed when the reaction was performed in open air (entry
12). Lowering the reaction temperature also decreased the yield
of the product. The reaction proceeds at room temperature but
the yield was only 52% even aer longer reaction times (48 h)
(entry 15). It is interesting to note that Yao's conditions8a did
give decent yields (ca. 70%) but in view of the use of simple
NaN3, the environmentally friendly solvent PEG-400, and lesser
load of CuI, in this work we have chosen conditions shown in
entry 7 as the best.
With the optimized conditions (entry 7) in hand, we exam-
ined the scope of this [Cu]-catalysed one-pot reaction by
employing various N-alkynyl-2-iodo-benzenesulfonamides 3a–l
with sodium azide. Gratifyingly, the triazolo 1,2,4-benzothia-
diazine 1,1-dioxide derivatives (4, 6–15) were isolated in good to
excellent yields (Table 2). The structure of compound 4 was
conrmed by X-ray crystallography (Fig. 3). There was no
signicant effect on yields of the products by changing the
substituent on the benzene ring of 2-iodo-benzenesulfona-
mides. While changing the substituent on the nitrogen of
sulfonamide, we encountered a difficulty in the preparation of
ynamide 3h; however we did not nd any difficulty in the course
of cyclisation process. The triisopropylsilyl substituted ynamide
3j afforded the desired product 14 in 80% yield with the removal
of triisopropylsilyl group and the structure was conrmed by X-
Fig. 2 Ynamides used in the present study.
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Table 2 Synthesis of triazolo 1,2,4-benzothiadiazine 1,1-dioxides from N-alkynyl-2-iodo-benzene sulfonamides
Product
Yield (%)
Product
Yield (%)
4
78
10
72
6
84
11
48
7
70
12
64
8
78
13
62
9
78
14
80
15
72
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Scheme
1
One-pot [Cu]-catalysed reaction of ynamide 3a with
sodium azide to afford compound 4.
Fig. 3 ORTEP diagram for compound 4. Selected bond lengths [A˚]
with esds in parentheses: C(6)–N(1) 1.411(2), C(7)–N(1) 1.367(2), C(8)–
N(3) 1.377(2), S(1)–O(1) 1.4229(13), S(1)–O(2) 1.4201(15), S(1)–N(4)
1.6487(15).
Scheme 2 One-pot synthesis of fused triazoles 16–18 and 4 from
ynamides 3m–p.
Fig. 4 ORTEP diagram for compound 14. Selected bond lengths [A˚]
with esds in parentheses: C(1)–N(1) 1.403(2), C(7)–N(1) 1.348(3), C(8)–
N(3) 1.357(3), S(1)–O(1) 1.4188(18), S(1)–O(2) 1.4233(19), S(1)–N(4)
1.6491(18).
In a manner similar to above, N-alkynyl-2-bromo-benzene-
sulfonamides 3m–p were subjected to the tandem reaction
following optimized conditions. This procedure afforded the
desired cyclised products 16–18 and 4 in lower yields and
required longer reaction time (Scheme 2). This shows that aryl
bromides are less reactive than aryl iodides, which is in accor-
dance with the literature reports.14b
In continuation to above reactions, we made an attempt to
synthesise seven membered benzosultam fused triazole.
Following optimized reaction conditions, we employed the
reaction between N-propargyl 2-iodo-benzenesulfonamide 19
and sodium azide (Scheme 3). Here, we were able to isolate the
expected product 20 in 30% yield. There were also other
byproducts that were not isolated. Thus it appears that for these
systems, conditions available in the literature8a were better.
To understand the reaction pathway, we performed the
reaction between phenyl iodide and ynamide with NaN3 in the
presence of [Cu]-catalyst. We observed the formation of phenyl
azide VI from phenyl iodide, but there was no reaction with
ynamide VII (Scheme 4a and b). Thus the azide is formed rst.
The other possibility involving cycloaddition between alkyne
ray crystallography (Fig. 4). On the other hand the bulkier 1-
bromo-2-biphenyl ethyne gave the corresponding ynamide 3k in
excellent yield, but unfortunately the cyclisation reaction was
not observed. This may be due to the steric effect caused by the
biphenyl moiety. Both alkyl and aryl alkynyl ynamides were
readily subjected to this one-pot protocol to obtain benzosultam
fused triazoles. Overall the reaction involves the formation of
three new C–N bonds.
Fig. 5 ORTEP diagram for compound 21. Selected bond lengths [A˚]
with esds in parentheses: C(8)–O(3) 1.224(5), C(7)–O(4) 1.435(5), C(7)–
C(8) 1.528(6), S(1)–O(1) 1.420(4), S(1)–O(2) 1.430(4), S(1)–N(1) 1.615(5). Scheme 3 Synthesis of triazolothiadiazepine 1,1-dioxide 20.
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acid 1,2,3-triazoles tend to undergo nitrogen elimination.19 We
employed benzosultam fused triazoles under this condition.
However, we isolated sulfonamides 21–24 in good yields
(Scheme 6). These were formed by the cleavage of sulfonamide
N–C bond along with nitrogen elimination from triazole moiety.
The products may have considerable interest for chemists as
they contain two functional groups amide and sulfonamide in a
single molecule. The structure of compound 21 was conrmed
by X-ray crystallography (Fig. 5). This type of cleavage followed
by acetic acid–water addition was not reported earlier in the
literature.
Scheme 4 Control experiments.
Conclusions
In conclusion, we have described a sequential one-pot reaction
to synthesise triazolo 1,2,4-benzothiadiazine 1,1-dioxide deriv-
atives from functionalised ynamides and sodium azide using
CuI as the catalyst using the solvent PEG-400. The reaction
involves intermolecular C–N bond formation followed by
cycloaddition between alkyne and azide. The main attractive
feature of this methodology is using low catalyst loadings of air
stable CuI and PEG-400, an eco-friendly solvent system.
Experimental section
The general experimental conditions and synthesis of the
precursors are described in the ESI.†
Synthesis of triazolo 1,2,4-benzothiadiazine 1,1-dioxide
derivatives (compounds 4–18) – representative procedure for
compound 4
Scheme 5 Plausible pathway for the formation of benzothiadiazines.
To an oven dried Schlenk tube was added 2-iodo-4,N-dimethyl-
N-phenylethynyl-benzenesulfonamide 3a (0.24 mmol), CuI (10
mol%), NaN3 (0.48 mmol) and PEG-400 (1 mL). The contents
ꢀ
and sodium azide followed by intramolecular C–N bond
formation catalysed by [Cu]8a,18 is not observed here. Thus, the
plausible catalytic cycle for the synthesis of triazolo 1,2,4-ben-
zothiadiazine 1,1-dioxide derivative is shown in Scheme 5. The
intermediate VIII is not isolated. Later, the [3 + 2] cycloaddition
between alkyne and azide affords the benzosultam fused
triazole.
were sealed under nitrogen atmosphere and heated at 100 C
(oil bath temperature) overnight. Aer completion of the reac-
tion as monitored by TLC, the crude reaction mixture was
cooled to r.t. The mixture was diluted with ethyl acetate (20 mL)
and washed with water. The aqueous layer was extracted twice
with ethyl acetate (20 mL). The combined organic layer was
washed with brine solution, dried over sodium sulfate and
concentrated in vacuum. The crude residue was then puried by
using silica gel column chromatography using hexane–ethyl
acetate (9 : 1) as the eluent to afford triazolo-1,2,4-benzothia-
diazine 1,1-dioxide 4. Compounds 5–17 were prepared following
same procedure and same molar quantities.
Later, we made an attempt to utilize the 1,2,3-triazoles syn-
thesised so far. We found that in the presence of glacial acetic
4,8-Dimethyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c]-
[1,2,4]thiadiazine 5,5-dioxide (4). White solid; yield 0.062 g
ꢀ
(78%); Mp 196 C; IR nmax (KBr): 2992, 1605, 1468, 1353, 1178,
1123, 992, 849, 679 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 2.60 (s,
3H, Ar-CH3), 3.15 (s, 3H, NCH3), 7.44–7.47 (m, 2H, Ar-H), 7.53 (t,
J ¼ 7.2 Hz, 2H, Ar-H), 7.88 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.03 (d, J ¼
7.2 Hz, 2H, Ar-H), 8.20 (s, 1H, Ar-H); 13C NMR (100 MHz, CDCl3):
d 22.0 (Ar-CH3), 38.1 (NCH3), 118.9, 121.2, 124.7, 126.4, 128.6,
129.1, 129.7, 131.6, 133.1, 138.0, 146.3; HRMS (ESI): calcd for
Scheme 6 Utilization of the benzosultam fused triazoles.
C
16H15N4O2S [M+ + H]: m/z 327.0915. Found: 327.0913. This
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compound was crystallized from ethyl acetate–hexane (2 : 1) 132.7, 138.2, 139.1, 146.3; HRMS (ESI): calcd for C17H17N4O2S
mixture at room temperature. X-ray structure was determined [M+ + H]: m/z 341.1072. Found: 341.1068.
for this compound.
3-Hexyl-4,8-dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]-
N-((2-Iodo-4-methylphenyl)sulfonyl)-N-methyl-2-phenyl- thiadiazine 5,5-dioxide (10). Gummy liquid; yield 0.058 g (72%);
acetamide (5). This compound was isolated when water was IR nmax(neat): 2926, 2860, 1605, 1468, 1364, 1184, 1123, 838, 679
used as solvent (Table 1, entry 3) along with the triazole 4 (20%). cmꢁ1; 1H NMR (400 MHz, CDCl3): d 0.90 (t, J ¼ 6.8 Hz, 3H), 1.32–
White solid; yield 0.038 g (36%); Mp 106 ꢀC; IR nmax (KBr): 2942, 1.43 (m, 6H, 3 CH2), 1.76–1.84 (m, 2H, CH2), 2.56 (s, 3H, Ar-CH3),
2909, 1704, 1578, 1457, 1336, 1161, 1073, 865, 766, 673 cmꢁ1; 1H 2.80 (t, J ¼ 8.0 Hz, 2H, CH2), 3.26 (s, 3H, NCH3), 7.41 (d, J ¼ 8.0
NMR (400 MHz, CDCl3): d 2.37 (s, 3H, Ar-CH3), 3.39 (s, 3H, Hz, 1H, Ar-H), 7.83 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.12 (s, 1H, Ar-H);
NCH3), 3.96 (s, 2H, CH2), 7.16 (d, J ¼ 7.2 Hz, 1H, Ar-H), 7.27–7.34 13C NMR (100 MHz, CDCl3): d 14.1, 22.0 (Ar-CH3), 22.6, 24.7,
(m, 4H, Ar-H), 7.88 (s, 1H, Ar-H), 8.17 (d, J ¼ 8.0 Hz, 1H, Ar-H); 28.8, 28.9, 31.5, 37.8 (NCH3), 118.7, 121.6, 124.4, 129.3, 131.7,
13C NMR (100 MHz, CDCl3): d 20.9 (Ar-CH3), 34.0 (NCH3), 43.3 133.6, 139.1, 146.1; HRMS (ESI): calcd for C16H23N4O2S [M+ + H]:
(CH2), 91.4 (CI), 127.3, 128.7, 129.3, 129.4, 132.8, 138.6, 143.1, m/z 335.1541. Found: 335.1544.
145.7, 171.3; HRMS (ESI): calcd for C16H17INO3S [M+ + H]: m/z
3-((Benzyloxy)methyl)-4,8-dimethyl-4H-benzo[e][1,2,3]tri-
azolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (11). White solid; yield
429.9974. Found: 429.9969.
8-(tert-Butyl)-4-methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo- 0.043 g (48%); Mp 106 ꢀC; IR nmax (KBr): 3063, 2860, 1605, 1479,
[5,1-c][1,2,4]thiadiazine 5,5-dioxide (6). White solid; yield 0.075 1359, 1310, 1173, 1068, 877, 745 cmꢁ1 1H NMR (400 MHz,
;
g (84%); Mp 152 ꢀC; IR nmax (KBr): 2970, 1600, 1458, 1364, 1189, CDCl3): d 2.44 (s, 3H, Ar-CH3), 3.38 (s, 3H, NCH3), 4.47 (s, 2H,
1129, 992, 833, 658, 641 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 1.45 OCH2), 4.58 (s, 2H, OCH2), 6.54 (s, 1H, Ar-H), 7.30–7.32 (m, 1H,
(s, 9H, C(CH3)3), 3.16 (s, 3H, NCH3), 7.44 (t, J ¼ 7.6 Hz, 1H, Ar-H), Ar-H), 7.34–7.38 (m, 4H, Ar-H), 7.43 (s, 1H, Ar-H), 7.84 (d, J ¼ 8.0
7.53 (t, J ¼ 7.6 Hz, 2H, Ar-H), 7.68 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.92 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): d 21.9 (Ar-CH3), 34.0
(d, J ¼ 8.4 Hz, 1H, Ar-H), 8.04 (d, J ¼ 8.4 Hz, 2H, Ar-H), 8.39 (s, (NCH3), 68.4 (OCH2), 71.7 (OCH2), 113.4, 122.1, 124.6, 127.9,
1H, Ar-H); 13C NMR (100 MHz, CDCl3): d 31.0 (C(CH3)3), 36.0 128.1, 128.2, 128.6, 133.1, 137.7, 142.8; HRMS (ESI): calcd for
(C(CH3)3), 38.1 (NCH3), 115.7, 121.1, 124.6, 126.2, 126.5, 128.6,
C
18H19N4O3S [M+ + H]: m/z 371.1178. Found: 371.1178.
129.1, 131.6, 133.1, 138.0, 159.5; HRMS (ESI): calcd for
4-Isopropyl-8-methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo-
[5,1-c][1,2,4]thiadiazine 5,5-dioxide (12). White solid; yield
C
19H20N4O2SNa [M+ + Na]: m/z 391.1205. Found: 391.1224.
8-Methoxy-4-methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1- 0.054 g (64%); Mp 154 ꢀC; IR nmax (KBr): 2981, 1605, 1468, 1370,
c][1,2,4]thiadiazine 5,5-dioxide (7). White solid; yield 0.056 g 1348, 1184, 1118, 986, 778, 674 cmꢁ1
;
1H NMR (400 MHz,
ꢀ
(70%); Mp 192 C; IR nmax (KBr): 3003, 2937, 2844, 1605, 1595, CDCl3): d 0.98 (d, J ¼ 6.8 Hz, 6H, (CH(CH3)2)), 2.59 (s, 3H, Ar-
1458, 1353, 1178, 981, 844, 773 cmꢁ1
;
1H NMR (400 MHz, CH3), 4.19 (m, 1H, NCH), 7.44 (d, J ¼ 7.2 Hz, 2H, Ar-H), 7.50 (t, J
CDCl3): d 3.15 (s, 3H, NCH3), 4.01 (s, 3H, Ar-OCH3), 7.14 (dd, J ¼ ¼ 7.2 Hz, 2H, Ar-H), 7.86 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.02 (d, J ¼ 7.2
8.8 and 2.4 Hz, 1H, Ar-H), 7.44 (t, J ¼ 7.2 Hz, 1H, Ar-H), 7.53 (t, J Hz, 2H, Ar-H), 8.16 (s, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): d
¼ 7.2 Hz, 2H, Ar-H), 7.83 (d, J ¼ 2.4 Hz, 1H, Ar-H), 7.90 (d, J ¼ 8.8 20.9 (CH(CH3)2), 22.0 (Ar-CH3), 59.1 (NCH), 119.0, 124.2, 124.3,
Hz, 1H, Ar-H), 8.03 (d, J ¼ 7.2 Hz, 2H, Ar-H); 13C NMR (100 MHz, 127.3, 128.9, 129.19, 129.21, 129.6, 130.8, 131.8, 141.2, 146.0;
CDCl3): d 38.1 (NCH3), 56.4 (Ar-OCH3), 102.9, 115.8, 115.9, HRMS (ESI): calcd for C18H19N4O2S [M+ + H]: m/z 355.1228.
126.5, 126.7, 128.6, 129.1, 133.4, 138.2, 164.4; HRMS (ESI): calcd Found: 355.1229.
for C16H15N4O3S [M+ + H]: m/z 343.0865. Found: 343.0864.
3-(3-Fluorophenyl)-4,8-dimethyl-4H-benzo[e][1,2,3]triazolo-
4-Methyl-3,8-diphenyl-4H-benzo[e][1,2,3]triazolo[5,1-c]- [5,1-c][1,2,4]thiadiazine 5,5-dioxide (13). White solid; yield
[1,2,4]thiadiazine 5,5-dioxide (8). White solid; yield 0.073 g 0.052 g (62%); Mp 206 ꢀC; IR nmax (KBr): 3079, 1600, 1463, 1364,
(78%); Mp 180 C; IR nmax (KBr): 3058, 1605, 1468, 1392, 1370, 1178, 1123, 893, 789, 734, 674 cmꢁ1; 1H NMR (400 MHz, CDCl3):
ꢀ
1178, 992, 827, 762 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 3.21 (s, d 2.60 (s, 3H, Ar-CH3), 3.16 (s, 3H, NCH3), 7.14 (dt, J ¼ 8.4 and 2.4
3H, NCH3), 7.43–7.49 (m, 1H, Ar-H), 7.51–7.58 (m, 5H, Ar-H), Hz, 1H, Ar-H), 7.47–7.53 (m, 2H, Ar-H), 7.75–7.78 (m, 1H, Ar-H),
7.72 (d, J ¼ 7.2 Hz, 2H, Ar-H), 7.86 (dd, J ¼ 8.4 and 1.2 Hz, 1H, Ar- 7.82 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.89 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.19
H), 8.04–8.07 (m, 3H, Ar-H), 8.59 (s, 1H, Ar-H); 13C NMR (100 (s, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): d 22.0 (Ar-CH3), 113.4
MHz, CDCl3): d 37.5 (NCH3), 116.3, 121.7, 125.9, 126.8, 126.9, (d, J ¼ 20 Hz), 116.0 (d, J ¼ 20 Hz), 118.9, 121.2, 122.0, 124.9,
127.9, 128.5, 128.8, 131.5, 132.5, 137.5, 147.5; HRMS (ESI): calcd 129.8, 130.6, 130.7, 130.8, 131.5, 133.5, 137.0, 146.4, 164.3 (d, J ¼
for C21H17N4O2S [M+ + H]: m/z 389.1072. Found: 389.1071.
240 Hz); HRMS (ESI): calcd for C16H15N4O2S [M+ + H]: m/z
4,8-Dimethyl-3-(p-tolyl)-4H-benzo[e][1,2,3]triazolo[5,1-c]- 345.0821. Found: 345.0821.
[1,2,4]thiadiazine 5,5-dioxide (9). White solid; yield 0.064 g
4,8-Dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadia-
ꢀ
(78%); Mp 190 C; IR nmax (KBr): 2926, 1595, 1463, 1353, 1178, zine 5,5-dioxide (14). White solid; yield 0.048 g (80%); Mp 172
1123, 986, 849, 822, 619 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 2.43 ꢀC; IR nmax (KBr): 3134, 1595, 1496, 1452, 1326, 1244, 1085, 975,
(s, 3H, Ar-CH3), 2.59 (s, 3H, Ar-CH3), 3.14 (s, 3H, NCH3), 7.33 (d, J 811, 685 cmꢁ1; H NMR (400 MHz, CDCl3): d 2.58 (s, 3H, Ar-
1
¼ 8.0 Hz, 2H, Ar-H), 7.45 (d, J ¼ 8.0 Hz, 1H, Ar-H), 7.87 (d, J ¼ 8.0 CH3), 3.47 (s, 3H, NCH3), 7.43–7.45 (m, 2H, Ar-H + triazole-CH),
Hz, 1H, Ar-H), 7.91 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.19 (s, 1H, Ar-H); 7.90 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.17 (s, 1H, Ar-H); 13C NMR (100
13C NMR (100 MHz, CDCl3): d 21.4 (Ar-CH3), 22.0 (Ar-CH3), 38.0 MHz, CDCl3): d 22.0 (Ar-CH3), 31.5 (NCH3), 118.3, 119.5, 121.3,
(NCH3), 118.9, 121.2, 124.7, 125.7, 126.4, 129.6, 129.8, 131.6, 123.4, 129.2, 131.5, 137.9, 146.4; HRMS (ESI): calcd for
C
16H15N4O2S [M+ + H]: m/z 251.0602. Found: 251.0601. This
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compound was crystallized from ethyl acetate–hexane (2 : 1) solution, dried over sodium sulfate and concentrated in vacuo.
mixture at room temperature. X-ray structure was determined The crude product was puried by using silica gel column
for this compound.
chromatography using hexane–ethyl acetate (4 : 1) as the eluent.
2-((5-Methyl-2-(N-methylsulfamoyl)phenyl)amino)-2-oxo-1-
4-Methyl-3-phenyl-4H-naphtho[1,2-e][1,2,3]triazolo[5,1-c]-
[1,2,4]thiadiazine 5,5-dioxide (15). White solid; yield 0.064 g phenylethyl acetate (21). White solid; yield 0.090 g (80%); Mp
ꢀ
(72%); Mp 184 C; IR nmax (KBr): 2921, 2855, 1595, 1447, 1353, 130 ꢀC; IR nmax (KBr): 3315, 2980, 1737, 1682, 1518, 1414, 1332,
1
1178, 1118, 811, 690, 559 cmꢁ1; H NMR (400 MHz, CDCl3): d 1244, 1173, 1068, 756, 663 cmꢁ1; 1H NMR (400 MHz, CDCl3): d
3.18 (s, 3H, NCH3), 7.47 (d, J ¼ 7.6 Hz, 1H, Ar-H), 7.56 (t, J ¼ 7.6 2.32 (s, 3H, COCH3), 2.39 (s, 3H, Ar-CH3), 2.51 (d, J ¼ 5.2 Hz, 3H,
Hz, 2H, Ar-H), 7.77–7.86 (m, 2H, Ar-H), 7.99–8.05 (m, 2H, Ar-H), NHCH3), 4.67 (qrt, J ¼ 5.2 Hz, 1H, SO2NH), 5.99 (s, 1H, Ar-CH),
8.12 (d, J ¼ 8.4 Hz, 1H, Ar-H), 9.66 (d, J ¼ 8.4 Hz, 1H, Ar-H); 13
C
7.07 (d, J ¼ 8.0 Hz, 1H, Ar-H), 7.44 (d, J ¼ 6.8 Hz, 3H, Ar-H), 7.57
NMR (100 MHz, CDCl3): d 37.9 (NCH3), 119.3, 122.2, 124.0, (d, J ¼ 6.4 Hz, 2H, Ar-H), 7.76 (d, J ¼ 8.0 Hz, 1H, Ar-H), 7.94 (s,
126.5, 127.4, 128.5, 128.6, 129.0, 129.1, 129.2, 129.6, 129.7, 1H, Ar-H), 9.63 (s, 1H, CONH); 13C NMR (100 MHz, CDCl3): d
130.3, 133.6, 136.7, 137.9; HRMS (ESI): calcd for C19H15N4O2S 21.2 (COCH3), 21.7 (Ar-CH3), 29.1 (NCH3), 76.7, 124.6, 124.8,
[M+ + H]: m/z 363.0915. Found: 363.0914.
125.6, 127.4, 129.0, 129.4, 129.7, 134.3, 134.4, 145.2, 167.1,
4-Methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]- 171.4; HRMS (ESI): calcd for C18H20N2O5SNa [M+ + Na]: m/z
thiadiazine 5,5-dioxide (16). White solid; yield 0.042 g (56%); 399.0991. Found: 399.1036. This compound was crystallized
ꢀ
Mp 190 C; IR nmax (KBr): 2997, 2931, 1589, 1485, 1370, 1255, from methanol at 4 ꢀC. X-ray structure was determined for this
1184, 986, 822, 778, 641 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 3.18 compound.
(s, 3H, NCH3), 7.45 (t, J ¼ 7.6 Hz, 1H, Ar-H), 7.53 (t, J ¼ 7.6 Hz,
2-((5-(tert-Butyl)-2-(N-methylsulfamoyl)phenyl)amino)-2-
2H, Ar-H), 7.68 (t, J ¼ 8.0 Hz, 1H, Ar-H), 7.89 (t, J ¼ 8.0 Hz, 1H, oxo-1-phenylethyl acetate (22). Gummy liquid; yield 0.106 g
Ar-H), 8.01–8.04 (m, 3H, Ar-H), 8.39 (d, J ¼ 8.0 Hz, 1H, Ar-H); 13
C
(86%); IR nmax(neat): 3310, 2964, 1759, 1704, 1567, 1529, 1403,
NMR (100 MHz, CDCl3): d 38.1 (NCH3), 118.7, 124.0, 124.8, 1326, 1222, 1167, 1052, 838 cmꢁ1; 1H NMR (400 MHz, CDCl3): d
126.5, 128.5, 128.9, 129.1, 129.2, 131.7, 132.9, 134.7, 138.0; 1.32 (s, 9H, C(CH3)3), 2.32 (s, 3H, COCH3), 2.53 (d, J ¼ 5.6 Hz,
HRMS (ESI): calcd for C16H15N4O2S [M+ + H]: m/z 313.0759. 3H, NHCH3), 4.64 (qrt, J ¼ 5.6 Hz, 1H, SO2NH), 6.02 (s, 1H, Ar-
Found: 313.0757.
CH), 7.27 (s, 1H, Ar-H), 7.44 (d, J ¼ 7.6 Hz, 3H, Ar-H), 7.58 (d, J ¼
3-Hexyl-4-methyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thia- 7.6 Hz, 2H, Ar-H), 7.78 (d, J ¼ 8.4 Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-
diazine 5,5-dioxide (17). Gummy liquid; yield 0.040 g (52%); IR H), 9.74 (s, 1H, CONH); 13C NMR (100 MHz, CDCl3): d 21.2
nmax(neat): 2937, 2860, 1605, 1490, 1364, 1189, 1047, 849, 767 (COCH3), 29.2 (NCH3), 30.9 (C(CH3)3), 35.4 (C(CH3)3), 77.1,
cmꢁ1; 1H NMR (400 MHz, CDCl3): d 0.90 (t, J ¼ 6.8 Hz, 3H, CH3), 121.4, 121.8, 124.3, 127.4, 129.0, 129.4, 129.5, 134.4, 134.6,
1.33–1.43 (m, 6H, 3 CH2), 1.79–1.83 (m, 2H, CH2), 2.81 (t, J ¼ 7.8 158.2, 167.1, 171.3; HRMS (ESI): calcd for C21H26N2O5SNa [M+ +
Hz, 2H, CH2), 3.29 (s, 3H, NCH3), 7.63 (t, J ¼ 7.6 Hz, 1H, Ar-H), Na]: m/z 441.1460. Found: 441.1465.
7.84 (t, J ¼ 7.6 Hz, 1H, Ar-H), 7.97 (d, J ¼ 7.2 Hz, 1H, Ar-H), 8.31
2-((4-(N-Methylsulfamoyl)-[1,10-biphenyl]-3-yl)amino)-2-oxo-
(d, J ¼ 8.4 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): d 14.1, 1-phenylethyl acetate (23). Gummy liquid; yield 0.102 g (78%);
22.6, 24.7, 28.8, 28.9, 31.5, 37.8 (NCH3), 118.6, 124.3, 124.5, IR nmax(neat): 3315, 2921, 1759, 1699, 1567, 1414, 1321, 1222,
128.5, 131.8, 133.5, 134.5, 139.0; HRMS (ESI): calcd for 1162, 1074, 701 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 2.33 (s, 3H,
C
15H21N4O2S [M+ + H]: m/z 321.1385. Found: 321.1384.
COCH3), 2.56 (d, J ¼ 5.2 Hz, 3H, NHCH3), 4.87–4.88 (m, 1H,
4-Butyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thia- SO2NH), 6.05 (s, 1H, Ar-CH), 7.37–7.48 (m, 7H, Ar-H), 7.58–7.61
diazine 5,5-dioxide (18). White solid; yield 0.052 g (60%); Mp 92 (m, 4H, Ar-H), 7.93 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.42 (s, 1H, Ar-H),
ꢀC; IR nmax (KBr): 2953, 2860, 1595, 1474, 1359, 1249, 1189, 1118, 9.83 (s, 1H, CONH); 13C NMR (100 MHz, CDCl3): d 21.2 (COCH3),
981, 773, 636 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 0.60 (t, J ¼ 7.4 29.2 (NCH3), 76.8, 122.8, 123.1, 125.9, 127.4, 128.7, 128.98,
Hz, 3H, CH3), 0.90–1.16 (m, 4H, 2 CH2), 3.66 (t, J ¼ 8.0 Hz, 2H, 129.03, 129.4, 130.2, 134.4, 134.9, 138.7, 147.0, 167.3, 171.4;
CH2), 7.43–7.54 (m, 3H, Ar-H), 7.66 (t, J ¼ 7.6 Hz, 1H, Ar-H), 8.39 HRMS (ESI): calcd for C23H22N2O5SNa [M+ + Na]: m/z 461.1147.
(d, J ¼ 8.4 Hz, 1H, Ar-H), 7.87 (t, J ¼ 8.0 Hz, 1H, Ar-H), 7.97–8.01 Found: 461.1150.
(m, 3H, Ar-H); 13C NMR (100 MHz, CDCl3): d 13.2, 19.4, 29.1,
2-((5-Methyl-2-(N-methylsulfamoyl)phenyl)amino)-2-oxoethyl
51.3, 118.7, 123.9, 126.1, 126.9, 128.7, 128.9, 129.0, 129.2, 131.6, acetate (24). White solid; yield 0.082 g (90%); Mp 110 ꢀC; IR nmax
131.7, 134.5, 138.2; HRMS (ESI): calcd for C16H15N4O2S [M+ + H]: (KBr): 3271, 1753, 1688, 1589, 1419, 1321, 1244, 1140, 827, 767
m/z 355.1228. Found: 355.1228.
cmꢁ1; 1H NMR (400 MHz, CDCl3): d 2.29 (s, 3H, Ar-CH3), 2.43 (s,
3H, COCH3), 2.56 (d, J ¼ 5.2 Hz, 3H, NHCH3), 4.69 (s, 2H,
COCH2O), 4.82–4.83 (m, 1H, SO2NH), 7.07 (d, J ¼ 8.0 Hz, 1H, Ar-
H), 7.75 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.13 (s, 1H, Ar-H), 9.66 (s, 1H,
General procedure for the synthesis of esters 21–24
To an oven dried Schlenk vessel was added triazolo-1,2,4-ben- CONH); 13C NMR (100 MHz, CDCl3): d 20.9 (COCH3), 21.8 (Ar-
zothiadiazine 1,1-dioxide (4, 6, 8 or 14; 0.3 mmol) and glacial CH3), 29.1 (NCH3), 63.4, 77.1, 123.9, 124.0, 125.4, 129.7, 134.3,
acetic acid (2 mL). Then the vessel was stoppered and heated 145.3, 165.9, 171.5; HRMS (ESI): calcd for C12H16N2O5SNa [M+ +
under reux for 3 days. Aer completion of reaction (tlc), the Na]: m/z 323.0678. Found: 323.0677.
reaction mixture was quenched with saturated sodium bicar-
Single crystal X-ray data were collected on a Bruker AXS-
˚
bonate solution (30 mL) and extracted twice with ethyl acetate SMART or OXFORD diffractometer using Mo-Ka (l ¼ 0.71073 A)
(20 mL). The combined organic layers were washed with brine radiation. The structures were solved by direct methods and
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rened by full-matrix least squares method using standard
procedures.20 Absorption corrections were done using SADABS
program, where applicable. In general, all non-hydrogen atoms
were rened anisotropically; hydrogen atoms were xed by
geometry or located by a Difference Fourier map and rened
isotropically.
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Crystal data
4,8-Dimethyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]-
thiadiazine 5,5-dioxide (4). C16H14N4O2S, M ¼ 326.37, triclinic,
˚
ꢀ
space group P1, a ¼ 7.1492(7), b ¼ 7.7691(8), c ¼ 14.105(2) A, a ¼
3
ꢀ
˚
97.012(10), b ¼ 102.997(10), g ¼ 98.628(8) , V ¼ 744.79(15) A , Z
¼ 2, m ¼ 0.233 mmꢁ1, data/restraints/parameters: 3024/0/210, R
indices (I > 2s(I)): R1 ¼ 0.0405, wR2 (all data) ¼ 0.1171.†
4,8-Dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thia-
diazine 5,5-dioxide (14). C10H10N4O2S, M ¼ 250.28, monoclinic,
˚
space group P21/c, a ¼ 8.0936(11), b ¼ 21.469(3), c ¼ 6.2322(8) A,
b ¼ 95.001(11) , V ¼ 1078.8(2) A , Z ¼ 4, m ¼ 0.295 mmꢁ1, data/
3
ꢀ
˚
restraints/parameters: 2203/0/156, R indices (I > 2s(I)): R1
0.0442, wR2 (all data) ¼ 0.1167.†
¼
2-((5-Methyl-2-(N-methylsulfamoyl)phenyl)amino)-2-oxo-1-
phenylethyl acetate (21). C18H20N2O5S, M ¼ 376.43, monoclinic,
space group P21/c, a ¼ 10.3978(17), b ¼ 19.4530(4), c ¼
3
ꢀ
˚
˚
9.6211(19) A, b ¼ 97.179(16) , V ¼ 1930.7(6) A , Z ¼ 4, m ¼ 1.754
mmꢁ1, data/restraints/parameters: 3614/0/238, R indices (I >
2s(I)): R1 ¼ 0.0622, wR2 (all data) ¼ 0.2664.†
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Acknowledgements
We thank Department of Science and Technology (DST, New
Delhi) for nancial support and Single Crystal X-ray diffrac-
tometer facility, and the University Grants Commission (UGC,
New Delhi) for equipment under UPE and CAS programs. ASR
and MNR thank Council of Scientic and Industrial Research
(CSIR, New Delhi) for fellowship. KCK thanks DST for the J. C.
Bose fellowship.
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