A Route to Triazole-Fused Sultams via Metal-Free Base-Mediated Cyclization of Sulfonamide-Tethered 5-Iodotriazoles

Article abstract of DOI:10.1021/acs.joc.0c00520

An efficient direct approach to triazole-fused sultams has been developed. The key step of the proposed strategy is base-mediated cyclization of sulfonamide-tethered 5-iodo-1,2,3-triazoles which are readily available via an improved protocol for Cu-cataly

Full text of DOI:10.1021/acs.joc.0c00520

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Article
A route to triazole-fused sultams via metal-free base-
mediated cyclization of sulfonamide-tethered 5-iodotriazoles
Stepan Spartakovich Tatevosyan, Yury Nikolaevich Kotovshchikov, Gennadij Vladimirovich Latyshev, Dmitry
Alexandrovich Erzunov, Darina Vadimovna Sokolova, Irina P. Beletskaya, and Nikolay Vadimovich Lukashev
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00520 • Publication Date (Web): 21 May 2020
Downloaded from pubs.acs.org on May 22, 2020
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Page 1 of 33
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A route to triazole-fused sultams via metal-free base-
mediated cyclization of sulfonamide-tethered 5-
iodotriazoles
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Stepan S. Tatevosyan,a Yury N. Kotovshchikov,a Gennadij V. Latyshev,a,* Dmitry A. Erzunov,a Darina
V. Sokolova,b,c Irina P. Beletskaya,a and Nikolay V. Lukasheva
latyshev@org.chem.msu.ru
a Chemistry Department, M. V. Lomonosov Moscow State University, 1/3 Leninskiye Gory, Moscow 119991, Russia.
b Peoples' Friendship University of Russia, 6 Miklukho-Maklaya str., Moscow 117198, Russia.
c N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse,
Moscow 115478, Russia.
ABSTRACT: An efficient direct approach to triazole-fused sultams has been developed. The key step of the proposed strategy is
base-mediated cyclization of sulfonamide-tethered 5-iodo-1,2,3-triazoles which are readily available via an improved protocol for
Cu-catalyzed 1,3-dipolar cycloaddition. The annulation of the sultam fragment to the triazole ring proceeds smoothly under
transition metal-free conditions in the presence of Cs2CO3 in dioxane at 100 °C and affords fused heterocycles in high yields up to
99%. A favorability of SNAr-like mechanism for the cyclization was supported by DFT calculations. An applicability of the
developed procedure to modification of natural compounds was demonstrated by a preparation of a deoxycholic acid derivative.
H
O
S
O O
S
N
SO3H
R
R
TM-free
N
O
N
Cs2CO3
dioxane
100 °C
N3
R
R
N
N
N
N
N
I
I
R
SNAr in unactivated triazoles
23 examples (up to 99%)
DFT
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INTRODUCTION
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The discovery of Cu-catalyzed azide-alkyne cycloaddition1 provided the efficient route not only to 1,4-disubstituted 1,2,3-
triazoles, but also to some of their 5-elementosubstituted derivatives.2 Among them, 5-iodotriazoles3 are of special significance due
to the ease of further functionalization via metal-catalyzed substitution reactions (Scheme 1). These compounds were extensively
used in various Pd-catalyzed processes including Suzuki,4,5,6,7 Stille,7,8,9 Heck,4,10,11 Sonogashira,4,6,10,12 and carbonylation13 reactions.
Cu-catalyzed post-Ullmann chemistry was used to replace iodine atom by S-,14 ,15 O-14 and N-nucleophiles.16
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Scheme 1. Functionalization of 5-iodotriazoles
2-step substitution
F-, w
or
N
N
R2
R2
N
R2
N
N
N
N
N
N
Nu
AgF
R1
I
R1
N
F
R1
Nu
Pd
R2
R2
Cu
N
N
N
N
N
R1
N
Ar
N
R2
R
R1
N
R2
N
N
N
R2
N
N
N
CO2R
R1
X R
R1
X: O, S, N
R1
R
Scheme 2. Proposed approach to triazole-fused sultams
Proposed approach:
Model system in this work:
N
R2
N
N
I
N
N
Nu-
N
I
R
N
N
S
R2
N
- I-
O
N
R1
N
S
R1
N
N
N
O
O
O
1
2
H
Nu
R
O
Bn
O
H
O
O
O
O
O
N
S
N
N
S
N
H
N
N
Cl
S
OMe
O
O
O
O
Calpain I inhibitor
(anti-neurodegenerative)
AMPA modulator
Anticancer
OH
O
O
O
Cl
S
S
S
N
N
N
N
O
H
NH
N
N
S
I
S
O
O
O
O
Anti-inflammatory
Anti-HIV
Non-catalyzed substitution of iodine seems to be an attractive approach to the functionalized triazoles. However, this area of
triazole reactivity is poorly understood. In general, 5-iodotriazoles were considered as almost inert in nucleophilic substitution. The
notable exception is iodine to fluorine exchange under harsh conditions17 or in the presence of stoichiometric amounts of AgF18
(Scheme 1). Higher reactivity of 5-fluorotriazoles towards strong nucleophiles allows to implement two-step substitution protocol.
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The decreased loss of entropy in intramolecular reaction will significantly facilitate nucleophilic substitution. Recently we have
developed the approach to benzoxazoles from 2-(iodotriazolyl)phenols which should include the substitution step.19 We suppose
that this process is general and can be applied to other nucleophiles affording various fused triazoles.
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To verify this hypothesis cyclization of triazole-containing sulfonamides 1 was investigated (Scheme 2). This reaction should
provide a convenient approach to triazole-fused sultams 2 which can only be obtained by rather sophisticated method.20 Sultam
fragment is present in various compounds possessing a wide range of biological activity,21 including anti-malarial,22 anti-
inflammatory,23 anti-HIV,24 and anticancer25 effects.
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RESULTS AND DISCUSSION
Wide range of 2-azidobenzenesulfonamides 3 was synthesized from commercially available orthanilic acid by high-yielding
three-step procedure. The standard conditions3 for the cycloaddition of azides 3 to iodoalkynes, employing CuI and tris{[1-(tert-
butyl)-1H-1,2,3-triazol-4-yl]methyl}amine (TTTA), turned out to be inefficient leading to recovery of unreacted azide. It was found
that addition of catalytic amount of Cu powder afforded 1 in generally good to high yields. Only in some cases the product was
contaminated by aminobenzenesulfonamide due to the azide to amine reduction. The beneficial effect of Cu powder is probably
associated with reduction of Cu(II) species formed by oxidation of the Cu(I) catalyst by admixtures in iodoalkynes or by traces of
oxygen. The addition of stoichiometric amounts of Cu appeared inefficient and afforded a complex mixture of products.
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Scheme 3. Scope of various 4-substituted sulfonamide-tethered 5-iodotriazoles
3
4
5
6
7
8
9
I
R
4
( )
I
R
N3
N
O
N
N
O
10% CuI, 10% TTTA
20% Cu, THF, 50 °C
S
S
HN
O
O
O
HN
3a
1
I
I
I
Bu
10
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N
N
N
N
N
N
N
N
N
O
O
S
HN
O
S
S
HN
O
O
HN
1a
1b
1c
, 75%
I
, 50%
I
, 79%
I
OH
HO
N
N
N
N
N
N
N
N
N
O
O
O
S
S
HN
S
HN
O
O
O
HN
1d
1e
1f
, 73%
, 84%
, 10%
MeO
CO2Me
OMe
I
I
I
Ph
N
N
N
O
N
N
N
N
N
N
O
O
S
S
S
HN
O
O
O
HN
HN
1h
1g
1i
, 85%
, 75%
, 61%
Series of benzenesulfonamides 1 was prepared under the optimized conditions by varying the substituents in the triazole ring
and at the sulfonamide nitrogen atom (Schemes 3 and 4).
Iodoalkynes bearing alkyl and vinyl substituents afforded iodotriazoles in good yields (up to 84%). The presence of free
hydroxyl groups was tolerated. Even labile cyclopropyl-containing iodoalkyne gave cycloaddition product in rather high yield (1c,
79%). Significantly diminished yield was observed only for sterically demanding iodo(tert-butyl)acetylene (1f, 10%). Good to high
yields were achieved for arylalkynes (1g-i, 61-85%) with both electron-donating (OMe) and electron-withdrawing (CO2Me)
groups.
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Scheme 4. Scope of various N-substituted sulfonamide-tethered 5-iodotriazoles
3
4
5
6
7
8
I
Bu
R
NH
N3 O
I
Bu
N
O
N
S
N
R
10% CuI, 10% TTTA
20% Cu, THF, 50 °C
O
S
HN
O
3b-m
1
9
I
I
I
Bu
Bu
Bu
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11
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N
O
N
O
N
N
N
N
N
N
N
O
S
OMe
S
S
O
O
O
HN
HN
HN
CO2Et
1j
1k
1l
, 44%
, 52%
I
, 62%
I
I
Bu
Bu
Bu
N
O
N
N
N
N
N
N
N
N
O
O
S
HN
S
S
O
O
O
HN
NH2
HN O
Ph
1o
, 91%
HN
1n
, 54%
1m
, 18%
O
S
Bu
I
HN
O
N
N
O
N
Bu
I
N
N
N
I
N
N
N
NH
Bu
O
N
O
S
S
HN
1q
O
O
1p
, 59%
, 43%
I
Bu
I
I
Bu
Bu
N
N
N
N
O
N
O
N
N
S
HN
N
N
O
O
S
S
O
O
HN
O
HN
1r
, 70%
1s
, 54%
1t
, 76%
I
I
I
Bu
Ph
n OH
N
N
N
N
N
N
N
N
N
O
O
O
S
S
HN
S
O
O
O
HN
HN
1u
1v
, n=1, 53%
, n=2, 85%
1w
1x
, 86%
, 85%
The reaction tolerates various substituents at the sulfonamide nitrogen (Scheme 4). N-Alkylsulfonamides afforded iodotriazoles
in good to excellent yields (52-91%). The presence of ester (1k) as well as unprotected amino group (1n) was tolerated. Rather high
yields were achieved for compounds bearing various heterocyclic moieties, including electrophile-sensitive indole (1o, 91%) and
furan (1r, 70%). Reaction with N-p-tolylsulfonamide was accompanied by excessive azide reduction giving the product 1l only in
moderate yield (44%). A sharp decrease in yield occurred for hydroxylamine-containing sulfonamide 1m due to probable reductive
cleavage of N-O bond. In contrast, this side process wasn’t observed for isoxazole-containing sulfonamide 1q.
The steric hindrance at nucleophilic center can significantly influence the subsequent cyclization step. To evaluate this effect we
have prepared a number of benzenesulfonamides 1s-x bearing bulky groups attached to the nitrogen atom. Sulfonamides with
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cyclohexyl (1s), adamantyl (1t), and tert-butyl (1u-x) moieties were obtained in moderate to rather high yields up to 86%. Unlike
the detrimental effect of tert-butyl group on the formation of 1f, sterically demanding substituents at sulfonamide N didn’t
significantly influence the CuIAAC reaction. In fact, the yield with bulky N-substituents was even slightly higher than the average
one. Thus, the optimized cycloaddition protocol appeared quite robust. However, the reduction of azide by Cu powder led to the
formation of inseparable admixture of 2-aminobenzenesulfonamide in some cases (most notably for 1b,c,f,j).
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With a number of benzenesulfonamides 1a-x in hand, we explored the intramolecular nucleophilic substitution. Compound 1a
was used as a model substrate for base-mediated cyclization. A brief optimization of reaction conditions was carried out at 100 °C
using a twofold excess of base (Table 1).
Table 1. Optimization of cyclization conditionsa
I
N
Bu
N
N
Bu
N
O
base, solvent
100 °C, 2 h
N
N
N
S
R
S
O O
R
O
NH
1a
1w
R: Me,
R: t-Bu,
2a,w
Entry
R
Solvent
Dioxane
Dioxane
Dioxane
DMSO
Base
Yield, % b
0
1
2
3
4
5
6
Me
Li2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Me
16
Me
95 (95)
86
Me
t-Bu
t-Bu
DMSO
traces
(69)
Dioxane
a Reaction run on a 0.1 mmol scale; b according to 1H NMR, isolated yield in parentheses.
Intramolecular nucleophilic substitution in sulfonamide 1a proceeded smoothly with Cs2CO3 in dioxane and reached completion
in 2 h. The anticipated sultam 2a was formed in almost quantitative yield (entry 3, Table 1). The reaction with K2CO3 in dioxane
was much slower (entry 2), whereas only the unchanged starting material was recovered with Li2CO3 (entry 1). The complete
conversion of 1a was observed with K2CO3 in DMSO, though the product was contaminated by small amounts of unidentified
impurities. However, the cyclization of N-tert-butyl containing sulfonamide 1w in DMSO (entry 5) afforded complex mixture of
products, while 69% isolated yield of 2w was obtained in dioxane. Thus, the Cs2CO3/dioxane system was chosen for the cyclization
of sulfonamides 1.
Scheme 5. Scope of sulfonamide cyclization
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I
R1
N
N
R1
N
N
N
N
Cs2CO3
dioxane
100 °C, 4 h
N
N
N
N
N
N
N
N
N
O
N
S
O O
R2
N
N
N
Bu
S
OH
O
N
HN R2
S
2
N
1
N
N
S
O O
S
S
O O
O O
2a
2c
, 96%
2b
, 90%
Ph
, 98%
O O
2d
, 90%
8
9
N
N
N
N
N
CO2Me
O
O
N
N
N
N
N
N
N
OH
N
N
N
N
N
N
Bu
N
10
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N
N
N
N
S
O O
S
N
S
S
O O
S
S
O O
O O
O O
O O
2e
, 93%
2f
2g
2h
2i
, 87%
, 78%
, 86%
, 96%
O
2j
, 87%
O
S
N
N
N
N
N
N
N
N
N
O
Bu
N
N
N
Bu
N
N
Bu
Bu
N
Bu
N
N
N
S
N
N
N
N
S
S
O O
S
S
N
N
Bu
O
O O
N
O O
O O
2q
CO2Et
NH
O
O
2o
2k
, 83%
2p
, 61%
, 24%
2l
, 86%
, 92%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
OH
N
Bu
O
N
N
Bu
N
Ph
Bu
Bu
n
N
S
O O
N
N
N
N
N
S
S
S
S
S
O O
O O
2w
O O
, n=1, 51%
, n=2, 56%
O O
2x
O O
2u
2v
, 69%
(67% [2 mmol scale])
2s
2r
, 94%
2t
, 85%
, 94%
, 45%
Sultams 2 were obtained in good to high yields regardless of the electronic effects of substituents in the triazole ring and at the
sulfonamide N (Scheme 5). Although cyclization benefits from substituents capable to stabilize sulfonamide anion (2l, 86%) or
negatively charged intermediates (2h, 96%), the yields were also high even for aliphatic groups. Additional acidic functionalities,
such as OH-groups (2d,e) and NH of indole (2o), didn’t influence the yield substantially. Steric effect of substituents wasn’t
noticeable for secondary alkyl (2c,s) and even adamantyl (2t) moieties. However, the presence of tert-butyl groups in the triazole
ring (2f, 78%) and especially attached to the nucleophile led to diminished yields (2u-x, down to 45%).
Glycine-derived sulfonamide 1k was not compatible with basic conditions affording low yield of sultam 2k (24%) accompanied
by numerous condensation byproducts. Surprisingly, a complex mixture of products was obtained in cyclization of 1m and 1n.
Formation of benzyl alcohol and benzaldehyde in the case of 1m indicated the cleavage of hydroxylamine moiety. Nevertheless,
excellent yields were achieved for sultams bearing various heterocyclic units, namely indole (2o, 83%), isoxazole (2q, 92%), and
furan (2r, 94%). Cyclization can even be performed twice giving ethylene-linked bis-sultam 2p in 61% yield.
Cytotoxic effect of triazole-fused sultams 2c,e,o was evaluated against ovarian (SKOV-3) and breast (MCF-7) cancer cell lines.
While 2c and 2e appeared almost inactive (IC50 > 50 µM), moderate activity against both SKOV-3 (IC50 = 19 µM) and MCF-7 (IC50
= 9 µM) was observed for 2o.
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To demonstrate the utility of the developed protocol in derivatization of polyfunctional natural compounds, we have prepared
azidobenzenesulfonamide 3n26 from deoxycholic acid which is an important member of bile acid group (Scheme 6). Azide 3n was
converted to the corresponding iodotriazole 1y, which smoothly underwent a cyclization under the standard conditions, furnishing
triazole-fused sultam 2y bearing steroidal moiety in almost quantitative yield (99%).
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9
Scheme 6. Synthesis of steroid-containing sultam
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OH
H
O
S
N
3n
H
O
N3
4a
H
H
10% CuI, 10% TTTA
20% Cu, THF, 50 °C
HO
H
Bu
Cs2CO3
dioxane
100 °C
N
N
N
NH
N
O
O
S
S
H
H
O
N
O
N
N
1y
2y
, 59%
, 99%
Bu
I
Thus, our approach to annulated triazoles, incorporating a sulfonamide fragment, turned out to be quite general and applicable
to substrates with various steric and electronic features.
Mechanistic aspects of the reaction were studied by DFT (B3LYP/ma-SVP/dioxane (SMD)) on a model substrate I-1. The
transformation of I-1 to sultam I-4 can proceed through nucleophilic substitution of iodine either in triazole (Scheme 7, path A, I-1
→ I-1' → I-4) or in tautomeric diazo form. The latter path is believed to operate in iodine to fluorine exchange in 5-iodo-1,2,3-
triazoles.17 The key intermediate I-2' can be produced in different order of deprotonation and ring-opening events, constituting
paths B (I-1 → I-1' → I-2' → I-3 → I4) and C (I-1 → I-2 → I-2' → I-3 → I-4).
Scheme 7. Possible cyclization mechanisms
O O
S
O O
S
O O
S
SNAr
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B
path
path
NH
N
N
N
N
N
N
N
N
N
I-4
I-1
I-1'
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N
I
I
BH
C
path
B-
O
O
O O
S
O
O
S
S
AdN-E
N
N
N
H
N
N
N
I-2
I-2'
I-3
N2
N2
N2
I
I
The structure of all intermediates and transition states for paths A and B starting from I-1' was located and optimized (Scheme
8). Triazole ring-opening in I-1' (path B) proceeds with rather high barrier (∆G≠ = 25.7 kcal/mol) affording unstable I-2'. The C–I
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bond in I-2' is substantially elongated (2.33 Å), justifying facile (∆G≠ = 3.8 kcal/mol) substitution of iodide. Cyclization of diazo
tautomer I-3 to final sultam I-4 has low activation energy (∆G≠ = 12.3 kcal/mol).
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Scheme 8. Free energy profiles for paths A and B
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
8
9
TS1B
25.7
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B
TS1A
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TS2B
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
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I-2'
13.0

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0.0
TS3B
-26.3

I-3
-38.6
I-4
-49.5
Formation of C–N bond through direct nucleophilic substitution in the triazole ring (SNAr) (path A) takes place simultaneously
with C–I bond breaking. We were unable to locate intermediate Meisenheimer complex, typical for classic SNAr mechanism. Since
B3LYP functional is known to predict a synchronous mechanism for reactions of anionic species,27 we confirmed the absence of the
intermediate by the second-order Möller-Plesset perturbation theory (RI-MP2/def2-TZVP/dioxane (SMD)). Since the barrier for
aromatic nucleophilic substitution is significantly lower (∆G≠ = 19.2 kcal/mol) than the barrier for the triazole ring-opening, path A
seems to be preferred for sulfonamide anions.
Path C is conceptually similar to path B but contains a different sequence of deprotonation and ring-opening events. Due to the
intrinsic problems with correct description of acidity by QM methods, the direct comparison of paths A and C was initially
attempted for equimolar mixture of I-1 and I-1' (Scheme 9, ∆Gd = 0). The transformation of uncharged I-1 into diazo form I-2 is
less endergonic (ΔG = 9.9 kcal/mol) and proceeds much easier than the same step for electron-rich anion I-1'. However, this barrier
(∆G≠ = 21.5 kcal/mol) is still higher than the barrier for nucleophilic substitution in I-1' (19.2 kcal/mol). Thus, there is a distinct
preference for the path A (SNAr mechanism) over paths B and C.
Scheme 9. Free energies of major intermediates and transition states along paths A and Ca
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
O O
S
N
N
O O
S
A
path
N
NHMe
G

N
G
d
I
19.2
N
N
N
S
N
N
N
N
I-1
I-1'
TS1A
O O
0.0
I
I
Gd
19.2+Gd
G
21.5
C
path

O O
S
O O
S
O O
9
S
N
N
N
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I-4
H
H
G

d
N
N
N
N
TS1C
I-2
I
I-2'
I
9.9+Gd
N
N2
N2
I
21.5
9.9
a Free energies in kcal/mol
The situation may be significantly altered by the basicity of the medium. The stronger base (ΔGd < 0) will shift the equilibrium
towards deprotonated sulfonamide I-1', effectively lowering the energy levels of all anionic intermediates and TSs and favoring
path A. However, for a weak base (ΔGd > 0) the contribution of deprotonation step to the apparent activation energy can be
decisive. The energy levels of all anionic intermediates will be increased, and TS1A (path A, ΔG = 19.2+ΔGd) can even become the
highest point on the PES (see SI, scheme S1).
Thus, in case of weak bases (strongly endergonic deprotonation step) the competition between mechanisms A and C is possible.
If a concentration of anion in the reaction mixture is fairly high, intramolecular nucleophilic substitution proceeds according to the
SNAr mechanism. This path is believed to operate in 1 due to rather high acidity of sulfonamide group.
CONCLUSION
In conclusion, intramolecular cyclization of nucleophile-tethered 5-iodotriazoles was proposed as a convenient route to fused
triazoles. To demonstrate the feasibility of this concept we have developed an efficient approach to triazole-fused sultams. It
comprises a modified CuIAAC protocol and base-mediated cyclization under catalyst-free conditions. The addition of
substoichiometric amounts of Cu powder was found to substantially increase the yields of [3+2]-cycloaddition. The subsequent
cyclization proceeded smoothly in the presence of Cs2CO3 in dioxane at 100 °C, affording sultams in up to 99% yield. According to
DFT analysis of possible reaction pathways, iodine substitution in non-activated triazoles should occur via SNAr-like mechanism.
Bearing in mind rather low nucleophilicity of sulfonamides, we believe that the reaction can be expanded on a broad range of other
nucleophiles furnishing various types of triazole-fused heterocycles.
EXPERIMENTAL SECTION
General Information
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NMR spectra were recorded with Bruker Avance 400, Agilent 400MR (1H 400 MHz, 13C 100.6 MHz), Bruker Avance 600 (1H
600 MHz, 13C 150 MHz), and Bruker AC200 (1H 200 MHz) spectrometers at ambient temperature. Chemical shifts are presented in
ppm (δ scale) and referenced to hexamethyldisiloxane (δ = 0.05 ppm) or tetramethylsilane (δ = 0 ppm) in the 1H NMR spectra and
to the solvent signal in the 13C{1H} NMR spectra. For compounds with low solubility in CDCl3 a few drops of CD3OD or DMSO-
d6 were added to NMR samples. MALDI-TOF spectra were recorded with a Bruker Daltonics UltraFlex instrument in a dithranol
or a cinnamic acid matrix using PEG 300, PEG 400 or PEG 600 as the internal standard. ESI-TOF spectra were recorded with a
Thermo Scientific Orbitrap Elite instrument. Column chromatography was carried out on Macherey–Nagel silica gel 60 (0.040–
0.063 mm). Iodoalkynes 4 were prepared according to the reported general procedure.28
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DFT calculations
The calculations were performed using ORCA 4.2.0 program package.29 DFT calculations were performed at B3LYP30,31/ma-
SVP32,33/SMD34 (dioxane) level of theory employing def2-ECP pseudopotential for iodine.35 RIJCOSX36 approximation was used to
speed up the calculations. Thermodynamic properties were calculated for ideal gas at 298.15 K using QRRHO approach37 for
vibrational entropy correction. The nature of optimized intermediates and transition states was verified by frequency analysis. IRC
calculations were performed to verify the connectivity of the PES. CYLView38 was used to visualize structure of the intermediates.
Experimental procedures
Sodium 2-azidobenzenesulfonate
2-Aminobenzenesulfonic acid (11.57 g, 66 mmol) and 15 mL of 10% H2SO4 were mixed in H2O (45 mL). The reaction mixture was
cooled to 0 °C, and NaNO2 (6.0 g, 87 mmol) in H2O (30 mL) was added. After stirring for 0.5 h, NaN3 (8.6 g, 133 mmol) in H2O
(30 mL) was added. The reaction mixture was stirred at room temperature for 15 h, evaporated under reduced pressure to half the
volume and placed in a refrigerator. The precipitate formed was filtered off and dried in a vacuum desiccator over P2O5. Though the
compound was described earlier as 2-azidobenzenesulfonic acid,39 the neutral pH of the aqueous solution is consistent with sodium
salt structure. Yield 12.881 g (88%). Beige powder; mp 220 °C (dec.); 1H NMR (400 MHz, DMSO-d6): δ 7.76 (dd, J = 7.9, 1.6 Hz,
1H), 7.38 (td, J = 8.0, 1.6 Hz, 1H), 7.20 (dd, J = 8.0, 1.1 Hz, 1H), 7.13 (td, J = 7.9, 1.1 Hz, 1H).
2-Azidobenzenesulfonyl chloride (5)
The suspension of sodium 2-azidobenzenesulfonate (1.50 g, 6.8 mmol) in POCl3 (7.5 mL) was stirred under refluxed for 8 h. Then
excess of POCl3 was evaporated at 40 °C under reduced pressure. Ice water (100 mL) was added to the residue, and the obtained
mixture was stirred for 15 min until complete hydrolysis of POCl3 residue (Caution: reaction is highly exothermic). The product
was extracted with CH2Cl2 (100 mL). The organic layer was dried with anhydrous Na2SO4, and the solvent was evaporated in
vacuo. The residue was used in the preparation of sulfonamides 3 without further purification. Yield 1.051 g (71%). Dark powder.
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1H NMR (200 MHz, CDCl3): δ 8.05 (dd, J = 8.1, 1.5 Hz, 1H), 7.76 (td, J = 8.1, 1.5 Hz, 1H), 7.42 (dd, J = 8.1, 1.0 Hz, 1H), 7.33 (td,
J = 8.1, 1.0 Hz, 1H). Spectral data were consistent with literature.40
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General procedure for the preparation of 2-azidobenzenesulfonamides
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Primary amine (1.8 mmol) was added to a solution of 5 (1.5 mmol) and Et3N (3.0 mmol) in THF (3.0 mL). The reaction mixture
was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL), and washed with water (50 mL). The organic layer
was dried with anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue was purified by column
chromatography.
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2-Azido-N-methylbenzenesulfonamide (3a)
Prepared from 5 (1.04 g. 4.8 mmol) and 40% aq. solution of CH3NH2 (1.7 mL, 12.0 mmol) according to the general procedure
without addition of Et3N; eluent: CH2Cl2–MeOH = 100:1. Yield 895 mg (88%). Pale yellow powder; mp 150–152 °C (lit.39 136–
138 °C); 1H NMR (600 MHz, CDCl3): δ 8.00 (dd, J = 7.8, 1.3 Hz, 1H), 7.62 (td, J = 7.8, 1.3 Hz, 1H), 7.32-7.27 (m, 2H), 4.99 (br q,
J = 5.4 Hz, 1H), 2.62 (d, J = 5.4 Hz, 3H).
2-Azido-N-(2-methoxyethyl)benzenesulfonamide (3b)
Prepared from 5 (261.1 mg, 1.2 mmol) and 2-methoxyethanamine (115.5 μL, 1.44 mmol) according to the general procedure;
1
eluent: CH2Cl2–MeOH = 100:1. Yield 277 mg (90%). Brown oil; H NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 7.8, 1.5 Hz, 1H),
7.61 (td, J = 8.0, 1.5 Hz, 1H), 7.31 (dd, J = 8.0, 1.1 Hz, 1H), 7.27 (td, J = 7.8, 1.1 Hz, 1H), 5.51 (t, J = 5.7 Hz, 1H), 3.38 (t, J = 5.7
Hz, 2H), 3.27 (s, 3H), 3.09 (q, J = 5.7 Hz, 2H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 137.7 (Cquat), 134.0, 130.4, 129.8 (Cquat),
124.7, 119.3, 70.2, 58.7, 45.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H13N4O3S 257.0703; Found 257.0703. Spectral data
were consistent with literature.41
Ethyl N-[(2-azidophenyl)sulfonyl]glycinate (3c)
Prepared from 5 (261.1 mg, 1.2 mmol) and ethyl glycinate hydrochloride (201.0 mg, 1.44 mmol) according to the general
procedure; eluent: CH2Cl2–MeOH = 100:1. Yield 200 mg (59%). Dark brown oil; 1H NMR (400 MHz, CDCl3): δ 7.94 (dd, J = 8.0,
1.4 Hz, 1H), 7.61 (td, J = 7.6, 1.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 5.67 (t, J = 5.4 Hz, 1H), 4.08 (q, J =
7.2 Hz, 2H), 3.82 (d, J = 5.4 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 168.6 (Cquat), 138.2 (Cquat),
134.1, 130.3, 129.3 (Cquat), 124.6, 119.5, 61.8, 44.5, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H13N4O4S 285.0652;
Found 285.0652.
2-Azido-N-(4-methylphenyl)benzenesulfonamide (3d)
Prepared from 5 (261.1 mg, 1.2 mmol) and 4-methylaniline (154 mg, 1.44 mmol) according to the general procedure; eluent:
CH2Cl2. Yield 278 mg (80%). Pale orange powder; mp 149–151 °C (lit.39 138–140 °C); 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J
= 7.8, 1.3 Hz, 1H), 7.54 (td, J = 7.8, 1.3 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 7.00 (s, 4H), 2.23
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(s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 137.6 (Cquat), 135.4 (Cquat), 134.2, 133.4 (Cquat), 131.2, 129.8 (2C), 128.6 (Cquat),
124.7, 121.8 (2C), 119.3, 20.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13N4O2S 289.0754; Found 289.0754.
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2-Azido-N-(benzyloxy)benzenesulfonamide (3e)
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Prepared from 5 (261.1 mg, 1.2 mmol) and O-benzylhydroxylamine (174.5 mg, 1.44 mmol) according to the general procedure;
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eluent: CH2Cl2. Yield 320 mg (88%). Pale yellow crystals; mp 133–135 °C; H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 7.7 Hz,
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1H), 7.83 (s, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.32-7.28 (m, 7H), 4.98 (s, 2H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 137.8 (Cquat),
135.1 (Cquat), 135.0, 132.1, 129.4 (2C), 128.7, 128.4 (2C), 126.9 (Cquat), 125.0, 119.3, 79.4; HRMS (MALDI-TOF, dithranol) m/z:
[M + H]+ Calcd for C13H13N4O3S 305.0703; Found 305.0705.
N-(2-Aminobenzyl)-2-azidobenzenesulfonamide (3f)
Prepared from 5 (261.1 mg, 1.2 mmol) and 2-(aminomethyl)aniline (176 mg, 1.44 mmol) according to the general procedure;
eluent: hexanes–EtOAc = 1:1. Yield 200 mg (55%). Dark brown powder; mp 147–148 °C; 1H NMR (400 MHz, CDCl3/CD3OD): δ
7.96 (dd, J = 7.9, 1.4 Hz, 1H), 7.58 (td, J = 7.8, 1.5 Hz, 1H), 7.25 (td, J = 7.7, 1.0 Hz, 1H), 7.21 (dd, J = 8.0, 0.7 Hz, 1H), 7.05 (td, J
= 7.7, 1.5 Hz, 1H), 6.81 (dd, J = 7.5, 1.3 Hz, 1H), 6.67 (dd, J = 8.0, 0.9 Hz, 1H), 6.56 (td, J = 7.4, 1.1 Hz, 1H), 6.17 (m, 1H), 3.99
(br s, 2H), 3.68 (br s, 2H); 13C{1H} NMR (100.6 MHz, CDCl3/CD3OD): δ 145.2 (Cquat), 137.7 (Cquat), 134.1, 130.6, 130.0, 129.4,
129.2 (Cquat), 124.7, 120.6 (Cquat), 119.4, 118.3, 116.1, 44.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H14N5O2S 304.0863;
Found 304.0866.
2-Azido-N-[2-(1H-indol-3-yl)ethyl]benzenesulfonamide (3g)
Prepared from 5 (261.1 mg, 1.2 mmol) and 2-(1H-indol-3-yl)ethanamine (273.9 mg, 1.71 mmol) according to the general
1
procedure; eluent: CH2Cl2. Yield 352 mg (86%). Brown oil; H NMR (600 MHz, CDCl3): δ 8.16 (br s, 1H), 7.92 (dd, J = 7.8, 1.4
Hz, 1H), 7.45 (td, J = 7.8, 1.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.20-7.15 (m, 2H), 7.04 (d, J = 2.3 Hz,
1H), 6.97 (td, J = 8.1, 0.8 Hz, 1H), 6.84 (dd, J = 8.1, 0.8 Hz, 1H), 4.92 (t, J = 5.7 Hz, 1H), 3.20 (m, 2H), 2.97 (t, J = 6.2 Hz, 2H);
13C{1H} NMR (100.6 MHz, CDCl3): δ 137.2 (Cquat), 136.4 (Cquat), 133.8, 130.6, 128.5 (Cquat), 126.6 (Cquat), 124.4, 123.1, 122.3,
119.6, 118.9, 118.2, 111.4, 111.1 (Cquat), 43.0, 24.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H16N5O2S 342.1019; Found
342.1019.
N,N'-Ethane-1,2-diylbis(2-azidobenzenesulfonamide) (3h)
Prepared from 5 (326.4 mg, 1.5 mmol) and ethylenediamine (50 μL, 0.75 mmol) according to the general procedure; eluent:
CH2Cl2–MeOH
=
50:1. Yield 255 mg (80%). Beige powder; mp 180–182 °C; 1H NMR (400 MHz, DMSO-
d6/CD3OD/CDCl3/CCl4): δ 7.83 (dd, J = 7.9, 1.2 Hz, 2H), 7.65 (td, J = 7.7, 1.3 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.6
Hz, 2H), 2.89 (s, 4H); 13C{1H} NMR (100.6 MHz, DMSO-d6/CD3OD/CDCl3/CCl4): δ 137.3 (2Cquat), 133.7 (2C), 129.8 (2C), 126.8
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(2Cquat), 124.3 (2C), 119.8 (2C), 42.1 (2C); HRMS (MALDI-TOF, dithranol) m/z: [M + Na]+ Calcd for C14H14N8O4S2Na 445.0472;
Found 445.0473.
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2-Azido-N-[2-(3,5-dimethylisoxazol-4-yl)ethyl]benzenesulfonamide (3i)
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Prepared from 5 (261.1 mg, 1.2 mmol) and 2-(3,5-dimethylisoxazol-4-yl)ethanamine (201.6 mg, 1.44 mmol) according to the
general procedure; eluent: CH2Cl2–MeOH = 50:1. Yield 256 mg (66%). Pale yellow crystals; mp 126–128 °C; 1H NMR (400 MHz,
CDCl3): δ 7.97 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (td, J = 7.8, 1.5 Hz, 1H), 7.30-7.25 (m, 2H), 5.21 (t, J = 6.0 Hz, 1H), 2.99 (m, 2H),
2.56 (t, J = 6.9 Hz, 2H), 2.31 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 165.9 (Cquat), 159.0 (Cquat), 137.1 (Cquat),
133.8, 130.2, 129.0 (Cquat), 124.4, 119.0, 109.4 (Cquat), 42.2, 22.6, 10.6, 9.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd
for C13H16N5O3S 322.0968; Found 322.0967.
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2-Azido-N-(2-furylmethyl)benzenesulfonamide (3j)
Prepared from 5 (326.4 mg, 1.5 mmol) and (2-furylmethyl)amine (166 μL, 1.8 mmol) according to the general procedure; eluent:
1
CH2Cl2. Yield 363 mg (87%). Pale yellow powder; mp 92–94 °C; H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 7.7, 1.4 Hz, 1H),
7.53 (td, J = 7.7, 1.4 Hz, 1H), 7.22 (td, J = 7.7, 1.4 Hz, 1H), 7.19-7.15 (m, 2H), 6.09 (dd, J = 3.0, 1.3 Hz, 1H), 5.91 (d, J = 3.0 Hz,
1H), 5.50 (t, J = 6.3 Hz, 1H), 4.18 (d, J = 6.3 Hz, 2H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 149.2 (Cquat), 142.3, 137.5 (Cquat),
133.7, 130.3, 129.9 (Cquat), 124.6, 119.1, 110.2, 108.3, 40.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H11N4O3S 279.0546;
Found 279.0546.
2-Azido-N-cyclohexylbenzenesulfonamide (3k)
Prepared from 5 (326.4 mg, 1.5 mmol) and cyclohexylamine (206 μL, 1.8 mmol) according to the general procedure; eluent:
1
CH2Cl2. Yield 350 mg (83%). Light yellow oil; H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H),
7.31-7.25 (m, 2H), 4.97 (d, J = 6.9 Hz, 1H), 3.12 (m, 1H), 1.75 (m, 2H), 1.63 (m, 2H), 1.52 (m, 1H), 1.30-1.08 (m, 5H); 13C{1H}
NMR (100.6 MHz, CDCl3): δ 137.4 (Cquat), 133.7, 131.6 (Cquat), 130.1, 124.8, 119.4, 53.0, 33.6 (2C), 25.1, 24.5 (2C); HRMS
(MALDI-TOF, dithranol) m/z: [M + Na]+ Calcd for C12H16N4O2SNa 303.0886; Found 303.0887.
N-1-Adamantyl-2-azidobenzenesulfonamide (3l)
Prepared from 5 (261.1 mg, 1.2 mmol) and 1-adamantylamine (217.7 mg, 1.44 mmol) according to the general procedure; eluent:
1
CH2Cl2. Yield 330 mg (83%). Pale yellow powder; mp > 201 °C (dec.); H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H,),
7.58 (t, J = 7.6 Hz, 1H), 7.30-7.24 (m, 2H), 4.96 (s, 1H), 2.00 (m, 3H), 1.77 (m, 6H), 1.58 (m, 6H); 13C{1H} NMR (100.6 MHz,
CDCl3): δ 136.9 (Cquat), 133.9 (Cquat), 133.0, 129.0, 124.6, 119.0, 54.9 (Cquat), 42.6 (3C), 35.4 (3C), 29.1 (3C); HRMS (MALDI-
TOF, dithranol) m/z: [M + K]+ Calcd for C16H20N4O2SK 371.0939; Found 371.0901.
2-Azido-N-tert-butylbenzenesulfonamide (3m)
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Prepared from 5 (99.6 mg. 0.5 mmol) and tert-butylamine (158 μL, 1.5 mmol) according to the general procedure without addition
of Et3N; eluent: CH2Cl2. Yield 122 mg (96%); mp 162–164 °C; 1H NMR (400 MHz, CDCl3): δ 8.00 (dd, J = 7.8, 1.4 Hz, 1H), 7.58
(td, J = 7.8, 1.4 Hz, 1H), 7.28-7.24 (m, 2H), 4.98 (br s, 1H), 1.21 (s, 9H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 137.2 (Cquat), 133.6
(Cquat), 133.4, 129.5, 124.9, 119.3, 54.7 (Cquat), 30.0 (3C); HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C10H15N4O2S
255.0910; Found 255.0912.
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2-Azido-N-[(3α,5β,12α)-3,12-dihydroxycholan-24-yl]benzenesulfonamide (3n)
Prepared from 5 (261.1 mg, 1.2 mmol) and (3α,5β,12α)-24-aminocholane-3,12-diol26 (542.3 mg, 1.44 mmol) according to the
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general procedure; eluent: CH2Cl2–MeOH = 15:1. Yield 592 mg (88%). Beige powder; mp 124–125 °C; H NMR (400 MHz,
CDCl3): δ 7.98 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.32-7.25 (m, 2H), 5.12 (t, J = 6.0 Hz, 1H), 3.95 (m, 1H), 3.60 (tt, J =
11.0, 4.9 Hz, 1H), 2.86 (m, 2H), 2.05-0.93 (m, 28H), 0.90 (m, 6H), 0.64 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 137.1
(Cquat), 135.5, 130.3, 129.6 (Cquat), 124.5, 118.9, 72.7, 71.3, 47.8, 46.9, 46.0, 43.5, 41.6, 36.0, 35.6, 34.83, 34.78, 33.7, 33.2, 32.2,
30.0, 28.2, 27.2, 26.7, 25.8, 25.7, 23.2, 22.7, 17.1, 12.3; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C30H47N4O4S
559.3313; Found 559.3311.
General procedure for the preparation of iodotriazoles
2-Azidobenzenesulfonamide 3 (1.0 mmol), 1-iodoalkyne 4 (1.1 mmol), CuI (19.1 mg, 0.100 mmol, 10 mol%), Cu powder (12.7
mg, 0.200 mmol, 20 mol%), and tris[(1-tert-butyl-1H-1,2,3-triazol-4-yl)methyl]amine (TTTA) (42.8 mg, 0.100 mmol, 10 mol%)
were mixed under an Ar atmosphere in THF (1 mL). The reaction mixture was stirred at 50 °C in a dry block overnight or for
several days (TLC control), then diluted with CH2Cl2 (50 mL), washed with EDTA solution (50 mL) and water (50 mL). The
organic layer was dried with anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue was purified by column
chromatography.
2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-methylbenzenesulfonamide (1a)
Prepared from 3a (212.2 mg, 1.0 mmol) and 1-iodohex-1-yne (150 μL, 1.1 mmol) according to the general procedure; eluent:
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hexanes–EtOAc = 1:1. Yield 315 mg (75%). Pale yellow powder; mp 122–124 °C; H NMR (400 MHz, CDCl3): δ 8.19 (dd, J =
7.6, 1.6 Hz, 1H), 7.80 (td, J = 7.6, 1.6 Hz, 1H), 7.75 (td, J = 7.6, 1.4 Hz, 1H), 7.43 (dd, J = 7.6, 1.4 Hz, 1H), 5.05 (q, J = 5.3 Hz,
1H), 2.77 (t, J = 7.8 Hz, 2H), 2.68 (d, J = 5.3 Hz, 3H), 1.77 (quint, J = 7.7 Hz, 2H), 1.44 (sext, J = 7.6 Hz, 2H), 1.77 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.8 (Cquat), 135.6 (Cquat), 134.3 (Cquat), 133.3, 131.2, 130.8, 130.3, 83.0 (Cquat), 30.9,
29.6, 25.8, 22.1, 13.8; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C13H18IN4O2S 421.0190; Found 421.0189.
2-[4-(Cyclohex-1-en-1-yl)-5-iodo-1H-1,2,3-triazol-1-yl]-N-methylbenzenesulfonamide (1b)
Prepared from 3a (212.2 mg, 1.0 mmol) and 1-(iodoethynyl)cyclohexene (145 μL, 1.1 mmol) according to the general procedure;
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eluent: hexanes–EtOAc = 2:1. Yield 264 mg (50% assuming purity 85%). Light brown crystals; mp 174–176 °C; H NMR (400
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MHz, CDCl3): δ 8.19 (d, J = 7.7 Hz, 1H), 7.82-7.33 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 6.61 (m, 1H), 5.00 (q, J = 5.2 Hz, 1H), 2.67
(d, J = 5.2 Hz, 3H), 2.64-2.60 (m, 2H), 2.26-2.23 (m, 2H), 1.82-1.77 (m, 2H), 1.72-1.66 (m, 2H); 13C{1H} NMR (100.6 MHz,
CDCl3) δ 151.6 (Cquat), 135.7 (Cquat), 134.1 (Cquat), 133.2, 131.2, 130.9, 130.7, 129.5, 127.3 (Cquat), 79.6 (Cquat), 29.6, 27.1, 25.4,
22.5, 21.8; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C15H18IN4O2S 445.0190; Found 445.0190.
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Prepared from 3a (159.2 mg, 0.75 mmol) and (iodoethynyl)cyclopropane (90 μL, 0.75 mmol) according to the general procedure;
eluent: hexanes–EtOAc = 2:1. Yield 252 mg (79% assuming purity 95%). Pale yellow powder; 1H NMR (400 MHz,
CDCl3/CD3OD): δ 8.17 (dd, J = 7.5, 1.6 Hz, 1H), 7.84-7.75 (m, 2H), 7.45 (dd, J = 7.5, 1.3 Hz, 1H), 5.38 (q, J = 5.1 Hz, 1H), 2.66
(br s, 3H), 1.91 (m, 1H), 1.12-1.04 (m, 4H); 13C{1H} NMR (100.6 MHz, CDCl3/CD3OD): δ 153.8 (Cquat), 135.5 (Cquat), 134.0
(Cquat), 133.5, 131.2, 131.1, 130.5, 83.0 (Cquat), 29.4, 7.8, 7.4 (2C); HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for
C12H14IN4O2S 404.9877; Found 404.9878.
2-[4-(Hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl]-N-methylbenzenesulfonamide (1d)
Prepared from 3a (212.2 mg, 1.0 mmol) and 3-iodoprop-2-yn-1-ol (125 mg, 1.1 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 1:6. Yield 286 mg (73%). White powder; mp 159–161 °C; 1H NMR (400 MHz, CDCl3/CD3OD): δ 8.10 (d, J =
7.6 Hz, 1H), 7.77-7.70 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 5.45 (m, 1H), 4.69 (s, 2H), 2.57 (br s, 3H); 13C{1H} NMR (100.6 MHz,
CDCl3/CD3OD): δ 152.9 (Cquat), 135.7 (Cquat), 133.9 (Cquat), 133.7, 131.4, 131.3, 130.6, 84.8 (Cquat), 56.0, 29.3; HRMS (MALDI-
TOF, dithranol) m/z: [M + H]+ Calcd for C10H12IN4O3S 394.9669; Found 394.9669.
2-[4-(Hydroxyethyl)-5-iodo-1H-1,2,3-triazol-1-yl]-N-methylbenzenesulfonamide (1e)
Prepared from 3a (212.2 mg, 1.0 mmol) and 3-iodobut-2-yn-1-ol (125 μL, 1.1 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 1:6. Yield 341 mg (84%). Yellow powder; mp 158–160 °C; 1H NMR (400 MHz, CDCl3/CD3OD): δ 8.18 (dd, J =
7.6, 1.6 Hz, 1H), 7.82 (m, 2H), 7.48 (dd, J = 7.6, 1.3 Hz, 1H), 5.64 (m, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H), 2.67
(br s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3/CD3OD): δ 150.2 (Cquat), 135.7 (Cquat), 134.2 (Cquat), 133.8, 131.4, 131.4, 130.7, 84.9
(Cquat), 60.9, 29.7, 29.4; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C11H14IN4O3S 408.9826; Found 408.9822.
2-(4-tert-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-methylbenzenesulfonamide (1f)
Prepared from 3a (212.2 mg, 1.0 mmol) and 1-iodo-3,3-dimethylbut-1-yne (151 μL, 1.1 mmol) according to the general procedure;
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eluent: hexanes–EtOAc = 2:1. Yield 50 mg (10% assuming purity 85%). Orange powder; H NMR (400 MHz, CDCl3/CD3OD): δ
8.16 (dd, J = 7.6, 1.6 Hz, 1H), 7.84 (m, 2H), 7.50 (dd, J = 7.6, 1.4 Hz, 1H), 4.67 (q, J = 5.3 Hz, 1H), 2.64 (d, J = 5.3 Hz, 3H), 1.55
(s, 9H); 13C{1H} NMR (100.6 MHz, CDCl3/CD3OD): δ 158.0 (Cquat), 136.6 (Cquat), 135.1 (Cquat), 134.2, 132.0, 131.7, 131.6, 81.2
(Cquat), 32.5(Cquat), 29.9 (3C), 29.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C13H18IN4O2S 421.0190; Found
421.0189.
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2-[4-(3,4-Dimethoxyphenyl)-5-iodo-1H-1,2,3-triazol-1-yl]-N-methylbenzenesulfonamide (1g)
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Prepared from 3a (212.2 mg, 1.0 mmol) and 4-(iodoethynyl)-1,2-dimethoxybenzene (316.8 mg, 1.1 mmol) according to the general
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procedure; eluent: CH2Cl2–MeOH = 20:1. Yield 425 mg (85%). White powder; mp 196–197 °C; H NMR (400 MHz, CDCl3): δ
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8.23 (dd, J = 7.6, 1.2 Hz, 1H), 7.85-7.77 (m, 2H), 7.62 (dd, J = 8.3, 1.7 Hz, 1H), 7.58 (m, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.00 (d, J =
8.3 Hz, 1H), 5.01 (q, J = 5.3 Hz, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.71 (d, J = 5.3 Hz, 3H); 13C{1H} NMR (100.6 MHz, DMSO-
d6/CCl4): δ 148.9 (Cquat), 148.6 (Cquat), 147.7 (Cquat), 136.8 (Cquat), 134.2 (Cquat), 133.4, 131.7, 131.1, 129.7, 122.8 (Cquat), 119.2
(Cquat), 111.7, 110.3, 84.8 (Cquat), 55.5, 55.4, 28.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C17H18IN4O4S
501.0088; Found 501.0089.
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Methyl 3-{5-iodo-1-[2-(methylsulfamoyl)phenyl]-1H-1,2,3-triazol-4-yl}benzoate (1h)
Prepared from 3a (180.5 mg, 0.85 mmol) and methyl 3-(iodoethynyl)benzoate (267.4 mg, 0.94 mmol) according to the general
procedure; eluent: CH2Cl2–MeOH = 75:1. Yield 375 mg (75%). White foam; mp 86–88 °C; 1H NMR (400 MHz, CDCl3): δ 8.74 (t,
J = 1.7 Hz, 1H), 8.25-8.22 (m, 2H), 8.12 (d, J = 7.8 Hz, 1H), 7.84 (td, J = 7.6, J = 1.6 Hz, 1H), 7.80 (td, J = 7.7, 1.4 Hz, 1H), 7.59
(t, J = 7.6 Hz, 1H), 7.52 (dd, J = 7.6 Hz, J = 1.4 Hz), 4.96 (q, J = 5.2 Hz, 1H), 3.96 (s, 3H), 2.71 (d, J = 5.2 Hz, 3H); 13C{1H} NMR
(100.6 MHz, CDCl3): δ 166.7 (Cquat), 149.6 (Cquat), 135.9 (Cquat), 134.0 (Cquat), 133.4, 131.9, 131.4, 131.2, 130.7, 130.0, 128.8,
128.7, 81.6 (Cquat), 52.3, 29.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C17H16IN4O4S 498.9931; Found 498.9931.
2-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)-N-methylbenzenesulfonamide (1i)
Prepared from 3a (212.2 mg, 1.0 mmol) and (iodoethynyl)benzene (148 μL, 1.1 mmol) according to the general procedure; eluent:
CH2Cl2–MeOH = 100:1. Yield 267 mg (61%). Yellow powder; mp 181–183 °C; 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.5 Hz,
1H), 8.04 (d, J = 7.2 Hz, 2H), 7.88-7.77 (m, 2H), 7.53-7.49 (m, 3H), 7.45 (m, 1H), 4.98 (q, J = 5.2 Hz, 1H), 2.71 (d, J = 5.2 Hz,
3H); 13C{1H} NMR (100.6 MHz, DMSO-d6/CCl4): δ 147.8 (Cquat), 140.9 (Cquat), 134. 1 (Cquat), 133.4 (Cquat), 131.7, 131.0, 130.4
(Cquat), 129.7, 128.5 (2C), 128.2, 126.7 (2C), 85.7 (Cquat), 28.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for
C15H14IN4O2S 440.9877; Found 440.9877.
2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-(2-methoxyethyl)benzenesulfonamide (1j)
Prepared from 3b (179.4 mg, 0.7 mmol) and 1-iodohex-1-yne (105 μL, 0.77 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 2:1. Yield 197 mg (52% assuming purity 86%). Green powder; 1H NMR (600 MHz, CDCl3): δ 8.17 (d, J = 7.6
Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 5.45 (t, J = 5.4 Hz, 1H), 3.43 (m, 2H), 3.26 (s,
3H), 3.16 (br s, 2H), 2.77 (t, J = 7.6 Hz, 2H), 1.77 (m, 2H), 1.44 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ 152.7 (Cquat), 137.0 (Cquat), 134.2 (Cquat), 133.1, 130.8, 130.7, 130.3, 82.8 (Cquat), 70.6, 58.8, 43.4, 30.9, 25.9, 22.1, 13.8;
HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C15H22IN4O3S 465.0452; Found 465.0450.
Ethyl N-{[2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)phenyl]sulfonyl}glycinate (1k)
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Prepared from 3c (170.6 mg, 0.6 mmol) and 1-iodohex-1-yne (90 μL, 0.66 mmol) according to the general procedure; eluent:
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hexanes–EtOAc = 2:1. Yield 199 mg (62% assuming purity 93%). Light yellow oil; H NMR (600 MHz, CDCl3): δ 8.13 (dd, J =
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7.6, 1.4 Hz, 1H), 7.78 (td, J = 7.6, 1.4 Hz, 1H), 7.72 (td, J = 7.7, 1.4 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 5.86 (br t, J = 4.3 Hz, 1H),
4.07 (m, 2H), 3.85 (d, J = 4.3 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 1.77 (m, 2H), 1.44 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H), 0.98 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 168.2 (Cquat), 152.7 (Cquat), 137.1 (Cquat), 134.2 (Cquat), 133.3 (Cquat), 130.8, 130.3,
130.2, 82.6 (Cquat), 61.6, 44.9, 30.9, 25.8, 22.1, 14.0, 13.8; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C16H22IN4O4S
493.0401; Found 493.0403.
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2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-(4-methylphenyl)benzenesulfonamide (1l)
Prepared from 3d (278 mg, 0.9 mmol) and 1-iodohex-1-yne (136 μL, 1.0 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 2:1. Yield 216 mg (44% assuming purity 92%). Orange crystals; 1H NMR (600 MHz, CDCl3): δ 7.77 (d, J = 7.6
Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.19 (br s, 1H), 7.11 (m, 2H), 7.01 (m, 2H),
2.80 (t, J = 7.4 Hz, 2H), 2.26 (s, 3H), 1.80 (quint, J = 7.4 Hz, 2H), 1.45 (sext, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (150 MHz, CDCl3): δ 152.9 (Cquat), 136.1 (Cquat), 135.7 (Cquat), 134.1 (Cquat), 133.4 (Cquat), 133.3, 131.3, 130.6, 130.0, 129.7
(2C), 123.6 (2C), 83.0 (Cquat), 30.8, 25.8, 22.1, 20.8, 13.8; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C19H22IN4O2S
497.0503; Found 497.0499.
N-(Benzyloxy)-2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)benzenesulfonamide (1m)
Prepared from 3e (304 mg, 1.0 mmol) and 1-iodohex-1-yne (143 μL, 1.05 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 4:1. Yield 94 mg (18%). Pale yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.8, 1H), 8.26 (s, 1H), 7.82
(t, J = 7.7, 1H), 7.75 (t, J = 7.6, 1H), 7.45 (d, J = 7.7, 1H), 7.38-7.31 (m, 5H), 5.01 (br s, 2H), 2.75 (t, J = 7.7 Hz, 2H), 1.75 (m, 2H),
1.41 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 153.1 (Cquat), 135.1 (Cquat), 134.4 (Cquat), 134.2, 133.6
(Cquat), 133.4, 130.8, 130.0, 129.3 (2C), 128.6, 128.5 (2C), 82.5 (Cquat), 79.4, 30.8, 25.8, 22.1, 13.8; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C19H22IN4O3S 513.0452; Found 513.0452.
N-(2-Aminobenzyl)-2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)benzenesulfonamide (1n)
Prepared from 3f (303 mg, 1.0 mmol) and 1-iodohex-1-yne (143 μL, 1.05 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 2:1. Yield 276 mg (54%). Brown foam; mp 68–71 °C; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.7 Hz, 1H),
7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.7, 0.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.07 (td, J = 7.7, 1.1 Hz, 1H), 6.97 (d, J = 7.3
Hz, 1H), 6.65-6.60 (m, 2H), 5.39 (t, J = 6.3 Hz, 1H), 4.05 (br s, 4H), 2.73 (t, J = 7.6 Hz, 2H), 1.73 (m, 2H), 1.40 (m, 2H), 0.95 (t, J
= 7.3 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.7 (Cquat), 145.6 (Cquat), 135.9 (Cquat), 134.1 (Cquat), 133.4, 131.1, 130.9,
130.5, 130.2, 129.5, 119.3 (Cquat), 118.2, 116.1, 83.1 (Cquat), 45.5, 30.8, 25.7, 22.0, 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H23IN5O2S 512.0612; Found 512.0611.
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N-[2-(1H-Indol-3-yl)ethyl]-2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)benzenesulfonamide (1o)
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Prepared from 3g (307.3 mg, 0.9 mmol) and 1-iodohex-1-yne (136 μL, 1.0 mmol) according to the general procedure; eluent:
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hexanes–EtOAc = 2:1. Yield 450 mg (91%). Light yellow foam; mp 84–87 °C; H NMR (400 MHz, CDCl3): δ 8.12 (dd, J = 7.7,
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1.6 Hz, 1H), 8.02 (br s, 1H), 7.73-7.63 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H),
7.16 (t, J = 7.6 Hz, 1H), 7.08-7.04 (m, 2H), 5.23 (t, J = 5.9 Hz, 1H), 3.31 (m, 2H), 2.97 (m, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.76 (m,
2H), 1.43 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.6 (Cquat), 136.7 (Cquat), 136.3 (Cquat), 133.9
(Cquat), 133.0, 130.8, 130.5, 130.1, 126.9 (Cquat), 122.6, 121.9, 119.3, 118.4, 111.6 (Cquat), 111.2, 83.0 (Cquat), 44.0, 30.9, 25.8, 25.6,
22.1, 13.8; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C22H25IN5O2S 550.0768; Found 550.0764.
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N,N'-Ethane-1,2-diylbis[2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)benzenesulfonamide] (1p)
Prepared from 3h (169 mg, 0.4 mmol) and 1-iodohex-1-yne (114 μL, 0.84 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 1:1. Yield 199 mg (59%). Colorless oil; 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 7.6, 1.3 Hz, 2H), 7.79-7.71
(m, 4H), 7.41 (dd, J = 7.5, 1.2 Hz, 2H), 5.47 (br t, J = 5.8 Hz, 2H), 3.10 (br s, 4H), 2.75 (t, J = 7.6 Hz, 4H), 1.75 (m, 4H), 1.42 (m,
4H), 0.97 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.7 (Cquat), 136.6 (Cquat), 134.0 (Cquat), 133.4, 131.1, 130.8,
130.4, 83.0 (Cquat), 43.2, 30.9, 25.8, 22.2, 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H33I2N8O4S2 839.0150; Found
839.0150.
2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-[2-(3,5-dimethylisoxazol-4-yl)ethyl]benzenesulfonamide (1q)
Prepared from 3i (256.8 mg, 0.8 mmol) and 1-iodohex-1-yne (114 μL, 0.84 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 1:1. Yield 228 mg (43%). Light yellow foam; mp 184–185 °C; 1H NMR (600 MHz, CDCl3): δ 8.13 (dd, J = 7.7,
1.5 Hz, 1H), 7.82-7.72 (m, 2H), 7.44 (dd, J = 7.6, 1.1 Hz, 1H), 5.39 (t, J = 6.1 Hz, 1H), 3.05 (m, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.53
(t, J = 7.3, 2H), 2.27 (s, 3H), 2.15 (s, 3H), 1.76 (m, 2H), 1.43 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ
166.0 (Cquat), 159.2 (Cquat), 152.7 (Cquat), 136.7 (Cquat), 134.0 (Cquat), 133.3, 130.9, 130.4, 130.3, 109.8 (Cquat), 83.1 (Cquat), 43.0, 30.8,
25.7, 23.1, 22.0, 13.8, 10.9, 10.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H25IN5O3S 530.0717; Found 530.0717.
2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-(2-furylmethyl)benzenesulfonamide (1r)
Prepared from 3j (278 mg, 1.0 mmol) and 1-iodohex-1-yne (150 μL, 1.1 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 3:1. Yield 340 mg (70%). Orange crystals; mp 111–113 °C; 1H NMR (600 MHz, CDCl3): δ 8.10 (dd, J = 7.8, 1.4
Hz, 1H), 7.73 (td, J = 7.8, 1.4 Hz, 1H), 7.66 (td, J = 7.8, 1.4 Hz, 1H), 7.40 (dd, J = 7.8, 1.4 Hz, 1H), 7.16 (m, 1H), 6.17-6.15 (m,
2H), 5.72 (t, J = 6.1 Hz, 1H), 4.23 (d, J = 6.1 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 1.76 (quint, J = 7.5 Hz, 2H), 1.43 (sext, J = 7.4 Hz,
2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 152.8 (Cquat), 149.2 (Cquat), 142.4, 136.9 (Cquat), 134.0 (Cquat),
133.0, 130.7, 130.6, 130.0, 110.2, 108.4, 82.8 (Cquat), 40.6, 30.8, 25.8, 22.1, 13.8; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+
Calcd for C17H20IN4O3S 487.0295; Found 487.0279.
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Prepared from 3k (280 mg, 1.0 mmol) and 1-iodohex-1-yne (143 μL, 1.05 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 4:1. Yield 262 mg (54%). Orange crystals; mp 124–126 °C; 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 7.4, 1.7
Hz, 1H), 7.75 (m, 2H), 7.41 (d, J = 7.6, 1.7 Hz, 1H), 5.09 (d, J = 7.2, 1H), 3.20 (m, 1H), 2.76 (t, J = 7.6, 2H), 1.77 (m, 2H), 1.75-
1.54 (m, 3H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35-1.06 (m, 5H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.6
(Cquat), 138.5 (Cquat), 134.0 (Cquat), 132.9, 130.9, 130.3, 130.2, 83.0 (Cquat), 53.6, 30.9, 25.8, 25.1 (2C), 24.5 (2C), 22.1, 13.8; HRMS
(MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C18H26IN4O2S 489.0816; Found 489.0816.
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N-1-Adamantyl-2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)benzenesulfonamide (1t)
Prepared from 3l (265.6 mg, 0.8 mmol) and 1-iodohex-1-yne (114 μL, 0.84 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 4:1. Yield 330 mg (76%). Colorless foam; mp 147–148 °C; 1H NMR (400 MHz, CDCl3): δ 8.25 (m, 1H), 7.76-
7.70 (m, 2H), 7.36 (m, 1H), 4.91 (s, 1H), 2.76 (t, J = 7.6 Hz, 2H), 2.01 (m, 3H), 1.86 (m, 6H), 1.77 (m, 2H), 1.59 (m, 6H), 1.43 (m,
2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.5 (Cquat), 141.1 (Cquat), 133.9 (Cquat), 132.6, 130.9, 130.1,
129.9, 83.4 (Cquat), 56.1 (Cquat), 42.8 (3C), 35.8 (3C), 30.9, 29.5 (3C), 25.8, 22.1, 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H30IN4O2S 541.1129; Found 541.1116.
N-tert-Butyl-2-[4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl]benzenesulfonamide (1u)
Prepared from 3m (254.3 mg, 1.0 mmol) and 3-iodoprop-2-yn-1-ol (200 mg, 1.1 mmol) according to the general procedure; eluent:
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hexanes–EtOAc = 1:1. Yield 244 mg (53% assuming purity 94%). White powder; mp 89–91 °C; H NMR (400 MHz, CDCl3): δ
8.26 (m, 1H), 7.76-7.73 (m, 2H), 7.35 (m, 1H), 5.68 (s, 1H), 4.74 (s, 2H), 3.34 (br s, 1H), 1.27 (s, 9H); 13C{1H} NMR (100.6 MHz,
CDCl3): δ 150.9 (Cquat), 140.6 (Cquat), 133.6 (Cquat), 132.9, 131.2, 130.4, 130.3, 84.4 (Cquat), 56.2, 55.4 (Cquat), 30.1 (3C); HRMS
(MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C13H18IN4O3S 437.0139; Found 437.0137.
N-tert-Butyl-2-[4-(2-hydroxyethyl)-5-iodo-1H-1,2,3-triazol-1-yl]benzenesulfonamide (1v)
Prepared from 3m (254.3 mg, 1.0 mmol) and 3-iodobut-2-yn-1-ol (214.5 mg, 1.1 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 1:2. Yield 381 mg (85%). White foam; mp 134–136 °C; 1H NMR (600 MHz, CDCl3): δ 8.25 (d, J = 7.7 Hz, 1H),
7.77-7.72 (m, 2H), 7.41 (d, J = 7.7 Hz, 1H), 5.02 (s, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.01 (t, J = 6.1 Hz, 2H), 2.66 (br s, 1H), 1.27 (s,
9H); 13C{1H} NMR (150 MHz, CDCl3): δ 150.2 (Cquat), 140.5 (Cquat), 133.8 (Cquat), 132.8, 131.1, 130.2, 130.1, 84.6 (Cquat), 61.2,
55.6 (Cquat), 30.0 (3C), 29.4; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C14H20IN4O3S 451.0295; Found 451.0318.
N-tert-Butyl-2-(4-butyl-5-iodo-1H-1,2,3-triazol-1-yl)benzenesulfonamide (1w)
Prepared from 3m (254.3 mg, 1.0 mmol) and 1-iodohex-1-yne (150 μL, 1.1 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 3:1. Yield 394 mg (85%). White crystalline powder; mp 119–121 °C; 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J
= 7.5, 1.9 Hz, 1H), 7.76-7.70 (m, 2H), 7.37 (dd, J = 7.6, 1.4 Hz, 1H), 5.02 (s, 1H), 2.76 (t, J = 7.5 Hz, 2H), 1.77 (quint, J = 7.5 Hz,
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2H), 1.43 (sext, J = 7.5 Hz, 2H), 1.27 (s, 9H), 0.98 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.6 (Cquat), 140.6
(Cquat), 134.0 (Cquat), 132.7, 131.0, 130.2, 130.1, 83.4 (Cquat), 55.5 (Cquat), 30.9, 30.0 (3C), 25.9, 22.2, 13.8; HRMS (MALDI-TOF,
dithranol) m/z: [M + H]+ Calcd for C16H24IN4O2S 463.0659; Found 463.0659.
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N-tert-Butyl-2-(5-iodo-4-phenyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide (1x)
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Prepared from 3m (254.3 mg, 1.0 mmol) and (iodoethynyl)benzene (148 μL, 1.1 mmol) according to the general procedure; eluent:
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CH2Cl2–MeOH = 100:1. Yield 414 mg (86%). Light yellow powder; mp 189–191 °C; H NMR (400 MHz, DMSO-d6/CCl4): δ
8.21(m, 1H), 8.05 (d, J = 7.5 Hz, 2H), 7.87-7.83 (m, 2H), 7.55-7.49 (m, 3H), 7.42 (t, J = 7.5 Hz, 1H), 7.23 (s, 1H), 1.18 (s, 9H);
13C{1H} NMR (100.6 MHz, DMSO-d6/CCl4): δ 147.8 (Cquat), 141.0 (Cquat), 133.5 (Cquat), 132.6, 131.1, 130.6, 130.4 (Cquat), 129.4,
128.3 (2C), 128.0, 126.7 (2C), 85.0 (Cquat), 54.0 (Cquat), 29.6 (3C); HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for
C18H20IN4O2S 483.0346; Found 483.0345.
2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-[(3α,5β,12α)-3,12-dihydroxycholan-24-yl]benzenesulfonamide (1y)
Prepared from 3n (558 mg, 1.0 mmol) and 1-iodohex-1-yne (143 μL, 1.05 mmol) according to the general procedure; eluent:
hexanes–EtOAc = 1:2. Yield 450 mg (59%). Colorless foam; mp 105–107 °C (Ether); 1H NMR (400 MHz, CDCl3): δ 8.18 (dd, J =
7.5, 1.2 Hz, 1H), 7.80-7.71 (m, 2H), 7.43 (d, J = 7.4 Hz, 1H), 5.16 (t, J = 5.9 Hz, 1H), 3.94 (m, 1H), 3.59 (tt, J = 11.0, 4.8 Hz, 1H),
2.93 (m, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.89-1.68 (m, 6H), 1.77 (m, 2H), 1.68-1.20 (m, 21H), 1.20-1.08 (m, 2H), 0.98 (t, J = 7.4 Hz,
3H), 0.93-0.82 (m, 6H), 0.63 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 152.6 (Cquat), 136.9 (Cquat), 134.1 (Cquat), 133.0, 130.8,
130.7, 130.2, 83.0 (Cquat), 73.0, 71.6, 48.1, 47.3, 46.4, 44.2, 42.0, 36.3, 35.9, 35.2, 35.1, 34.0, 33.5, 32.6, 30.8, 30.4, 28.5, 27.4,
27.1, 26.2, 26.1, 25.8, 23.6, 23.1, 22.1, 17.4, 13.8, 12.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C36H56IN4O4S 767.3061;
Found 767.3060.
General procedure for the preparation of triazole-fused sultams 2
In a vial with a screw cap iodotriazole 1 (0.25 mmol) and Cs2CO3 (167 mg, 0.5 mmol, 2 equiv) were mixed under an Ar atmosphere
in dioxane (2 mL). The reaction mixture was stirred at 100 °C in a dry block for 4 h, then diluted with CH2Cl2 (40 mL), washed
with water (20 mL). The organic layer was dried with anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue
was purified by column chromatography.
3-Butyl-4-methyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2a)
Prepared from 1a (105 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 2:1. Yield 70 mg (96%).
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White solid; mp 68–71 °C; H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 7.8 Hz,
1H), 7.62 (t, J = 8.0 Hz, 1H), 3.28 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 1.80 (quint, J = 7.6 Hz, 2H), 1.46 (sext, J = 7.4 Hz, 2H), 0.98 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 138.9 (Cquat), 134.4, 133.4 (Cquat), 131.7 (Cquat), 128.4, 124.4, 124.2 (Cquat),
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118.5, 37.7, 30.8, 24.3, 22.2, 13.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C13H17N4O2S 293.1067; Found
293.1063.
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Prepared from 1b (130.7 mg, containing 0.25 mmol of pure 1b) according to the general procedure; eluent: CH2Cl2. Yield 77.5 mg
(98%). White crystals; mp 148–151 °C; 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.84 (t, J
= 8.3 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 6.53 (m, 1H), 3.16 (s, 3H), 2.61 (m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.72 (m, 2H); 13C{1H}
NMR (100.6 MHz, CDCl3): δ 140.0 (Cquat), 134.5, 131.7 (Cquat), 129.1, 128.6, 127.9 (Cquat), 126.8 (Cquat), 124.9, 123.9 (Cquat), 118.7,
38.0, 26.0, 25.5, 22.4, 21.9; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C15H17N4O2S 317.1067; Found 317.1067.
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3-Cyclopropyl-4-methyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2c)
Prepared from 1c (106.3 mg, containing 0.25 mmol of pure 1c) according to the general procedure; eluent: hexanes–EtOAc = 2:1.
Yield 62 mg (90%). Light orange oil; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.0 Hz, 1H), 7.96 (dd, J = 7.8, 1.0 Hz, 1H), 7.83
(td, J = 7.8, 1.1 Hz, 1H), 7.62 (td, J = 8.0, 1.1 Hz, 1H), 3.40 (s, 3H), 1.96 (tt, J = 8.3, 5.1 Hz, 1H), 1.15-1.04 (m, 4H); 13C{1H}
NMR (100.6 MHz, CDCl3): δ 139.3 (Cquat), 134.4, 133.7 (Cquat), 131.7 (Cquat), 128.4, 124.3 (Cquat), 124.2, 118.3, 37.2, 7.19 (2C),
5.5; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C12H13N4O2S 277.0754; Found 277.0762.
(4-Methyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-3-yl)methanol (2d)
Prepared from 1d (98.5 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 1:4. Yield 60 mg (90%).
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White powder; mp 202–204 °C H NMR (600 MHz, DMSO-d6/CCl4): δ 8.31 (dd, J = 7.9, 1.2 Hz, 1H), 8.05 (dd, J = 7.9, 1.2 Hz,
1H), 8.00 (td, J = 7.8, 1.2 Hz, 1H), 7.78 (td, J = 7.8, 1.2 Hz, 1H), 5.51 (br s, 1H), 4.71 (s, 2H), 3.48 (s, 3H); 13C{1H} NMR (150
MHz, DMSO-d6/CCl4): δ 136.5 (Cquat), 135.1, 134.2 (Cquat), 131.0 (Cquat), 129.2, 123.8 (Cquat), 123.6, 118.2, 53.8, 35.5; HRMS
(MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C10H11N4O3S 267.0547; Found 267.0547.
2-(4-Methyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-3-yl)ethanol (2e)
Prepared from 1e (102 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 1:5. Yield 65 mg (93%).
White powder; mp 173–175 °C; 1H NMR (400 MHz, DMSO-d6/CCl4): δ 8.30 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.01 (t,
J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 4.89 (t, J = 5.8 Hz, 1H), 3.77 (q, J = 5.8 Hz, 2H), 3.22 (s, 3H), 2.93 (t, J = 5.8 Hz, 2H);
13C{1H} NMR (100.6 MHz, DMSO-d6/CCl4): δ 136.2 (Cquat), 135.4, 134.3 (Cquat), 131.1 (Cquat), 129.4, 124.3, 123.6 (Cquat), 118.4,
59.8, 37.6, 27.9; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C11H13N4O3S 281.0703; Found 281.0705.
3-tert-Butyl-4-methyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2f)
Prepared from 1f (28.2 mg, containing 0.057 mmol of pure 1f) according to the general procedure; eluent: hexanes–EtOAc = 3:1.
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Yield 13 mg (78%). Colorless oil; H NMR (400 MHz, CDCl3): δ 8.28 (dd, J = 8.3, 0.6 Hz, 1H), 7.96 (dd, J = 7.8, 1.4 Hz, 1H),
7.84 (td, J = 7.9, 1.4 Hz, 1H), 7.63 (td, J = 7.7, 1.1 Hz, 1H), 3.10 (s, 3H), 1.51 (s, 9H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 138.2
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(Cquat), 134.7, 133.0 (Cquat), 131.8 (Cquat), 128.7, 125.7, 123.5 (Cquat), 118.8, 41.3, 31.7 (Cquat), 29.6 (3C); HRMS (MALDI-TOF,
dithranol) m/z: [M + H]+ Calcd for C13H17N4O2S 293.1067; Found 293.1057.
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Prepared from 1g (125 mg, 0.25 mmol) according to the general procedure; eluent: CH2Cl2–MeOH = 200:1. Yield 80 mg (86%).
White powder; mp 186–187 °C; 1H NMR (600 MHz, CDCl3): δ 8.37 (d, J = 8.1 Hz, 1H), 8.00 (dd, J = 8.0, 1.0 Hz, 1H), 7.87 (td, J
= 7.9, 1.3 Hz, 1H), 7.66 (td, J = 7.7, 0.9 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.3, 1.9 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H),
4.00 (s, 3H), 3.96 (s, 3H), 3.17 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 149.8 (Cquat), 149.4 (Cquat), 138.1 (Cquat), 134.6, 132.1
(Cquat), 131.7 (Cquat), 128.8, 124.9, 123.9 (Cquat), 121.2 (Cquat), 119.2, 118.6, 111.4, 109.5, 56.1, 56.0, 37.9; HRMS (MALDI-TOF,
dithranol) m/z: [M + H]+ Calcd for C17H17N4O4S 373.0965; Found 373.0965.
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Methyl 3-(4-methyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-3-yl)benzoate (2h)
Prepared from 1h (124.5 mg, 0.25 mmol) according to the general procedure; eluent: CH2Cl2–MeOH = 200:1. Yield 89 mg (96%).
White powder; mp 202–204 °C; 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.11
(d, J = 6.8 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.88 (t, J = 7.1 Hz, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.61 (t, J = 7.3 Hz), 3.97 (s, 3H),
3.19 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 161.5 (Cquat), 137.0 (Cquat), 134.7, 133.24 (Cquat), 131.6 (Cquat), 131.1 (Cquat),
130.6, 130.1, 129.2, 129.0, 128.9 (Cquat), 127.4, 124.8, 124.0 (Cquat), 118.7, 52.4, 38.2; HRMS (MALDI-TOF, dithranol) m/z: [M +
H]+ Calcd for C17H15N4O4S 371.0809; Found 371.0792.
4-Methyl-3-phenyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2i)
Prepared from 1i (110 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 2:1. Yield 68 mg (87%). Pale
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yellow powder; mp 193–195 °C (lit.20 190 °C); H NMR (600 MHz, CDCl3): δ 8.37 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H),
8.01 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.44 (t, J = 8.0 Hz, 1H), 3.17 (s,
3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 138.0 (Cquat), 134.6, 132.9 (Cquat), 131.7 (Cquat), 129.1, 129.1 (2C), 128.9, 128.5 (Cquat),
126.5 (2C), 124.8, 124.0 (Cquat), 118.7, 38.0; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C15H13N4O2S 313.0754;
Found 313.0751.
3-Butyl-4-(2-methoxyethyl)-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2j)
Prepared from 1j (135 mg, containing 0.25 mmol of pure 1k) according to the general procedure; eluent: hexanes–EtOAc = 3:2.
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Yield 73 mg (87%). Pale yellow crystals; mp 75–77 °C; H NMR (600 MHz, CDCl3): δ 8.28 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8
Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 3.89 (t, J = 5.1 Hz, 2H), 3.23 (t, J = 5.1 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H),
2.74 (s, 3H), 1.79 (quint, J = 7.6 Hz, 2H), 1.45 (sext, J = 7.5 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ
139.5 (Cquat), 133.8, 132.2 (Cquat), 132.1 (Cquat), 128.2, 126.4 (Cquat), 123.5, 118.4, 68.8, 58.2, 51.6, 30.3, 24.3, 22.3, 13.7; HRMS
(MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C15H21N4O3S 337.1329; Found 337.1329.
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Ethyl (3-butyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-4-yl)acetate (2k)
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Prepared from 1k (148.3 mg, containing 0.25 mmol of pure 1l) according to the general procedure; eluent: hexanes–EtOAc = 2:1.
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Yield 22 mg (24%). Pale yellow crystals; mp 92–94 °C; H NMR (600 MHz, CDCl3): δ 8.33 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.8
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Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 4.55 (s, 2H), 3.94 (q, J = 7.2 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.77
(quint, J = 7.6 Hz, 2H), 1.43 (sext, J = 7.6 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ 166.9 (Cquat), 138.2 (Cquat), 134.1, 132.2 (Cquat), 131.6 (Cquat), 128.2, 126.3 (Cquat), 123.0, 118.4, 62.1, 51.0, 30.4, 24.5,
22.3, 13.8, 13.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C16H21N4O4S 365.1278; Found 365.1284.
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3-Butyl-4-(4-methylphenyl)-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2l)
Prepared from 1l (134.9 mg, containing 0.25 mmol of pure 1l) according to the general procedure; eluent: hexanes–EtOAc = 3:1.
Yield 90 mg (86% assuming purity 88%). Orange oil; 1H NMR (600 MHz, CDCl3): δ 8.40 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz,
1H), 7.85 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.15 (m, 2H), 6.98 (m, 2H), 2.39 (t, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.48 (quint,
J = 7.5 Hz, 2H), 1.21 (sext, J = 7.4 Hz, 2H), 0.79 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 139.3 (Cquat), 138.9
(Cquat), 134.6, 132.9 (Cquat), 132.0 (Cquat), 130.2 (2C), 128.9 (Cquat), 128.5, 126.3 (2C), 125.1 (Cquat), 124.6, 118.7, 30.1, 23.9, 22.0,
21.0, 13.5; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C19H21N4O2S 369.1380; Found 369.1372.
3-Butyl-4-[2-(1H-indol-3-yl)ethyl]-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2o)
Prepared from 1o (137.4 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 2:1. Yield 87 mg (83%).
Light yellow foam; mp 125–127 °C; 1H NMR (600 MHz, CDCl3): δ 7.95 (d, J = 7.8 Hz, 1H), 7.92 (br s, 1H), 7.68 (d, J = 7.8 Hz,
1H), 7.56 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H),
7.01 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 1.9 Hz, 1H), 4.15 (t, J = 7.7 Hz, 2H), 2.85 (t, J = 7.7 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 1.74
(quint, J = 7.6 Hz, 2H), 1.42 (sext, J = 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 138.8 (Cquat),
135.8 (Cquat), 133.5, 131.7 (Cquat), 131.4 (Cquat), 127.9, 126.6 (Cquat), 125.6 (Cquat), 122.7, 122.3, 122.1, 119.7, 117.9, 111.09, 110.09
(Cquat), 51.3, 30.4, 24.5, 23.7, 22.3, 13.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C22H24N5O2S 422.1645; Found
422.1644.
4,4'-Ethane-1,2-diylbis(3-butyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine) 5,5,5',5'-tetraoxide (2p)
Prepared from 1p (107 mg, 0.128 mmol) according to the general procedure; eluent: hexanes–EtOAc = 1:1. Yield 49 mg (61%
assuming purity 92%). White crystalline powder; mp > 220 °C (dec., Ether); 1H NMR (400 MHz, CD3OD/CDCl3): δ 8.16 (d, J =
8.1 Hz, 2H), 7.88 (t, J = 7.8 Hz, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.64 (t, J = 7.7, 0.7 Hz, 2H), 4.07 (s, 4H), 2.64 (t, J = 7.7 Hz, 4H),
1.69 (m, 4H), 1.40 (m, 4H), 0.96 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (100.6 MHz, CD3OD/CDCl3): δ 136.8 (2Cquat), 134.8 (2C),
131.3 (2Cquat), 130.6 (2Cquat), 128.7 (2C), 124.6 (2Cquat), 123.0 (2C), 118.3 (2C), 48.0 (2C), 30.1 (2C), 24.2 (2C), 21.9 (2C), 13.3
(2C); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H31N8O4S2 583.1904; Found 583.1907.
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3-Butyl-4-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2q)
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Prepared from 1q (132.3 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 1:1. Yield 92 mg (92%).
Colorless oil; 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.61 (t, J =
7.6 Hz, 1H), 3.86 (t, J = 7.3 Hz, 2H), 2.75 (t, J = 7.7 Hz, 2H), 2.49 (t, J = 7.3 Hz, 2H), 2.07 (s, 3H), 2.02 (s, 3H), 1.80 (m, 2H), 1.46
(m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 166.0 (Cquat), 158.9 (Cquat), 138.5 (Cquat), 134.4, 131.6
(Cquat), 131.3 (Cquat), 128.7, 125.1 (Cquat), 123.3, 118.3, 108.4 (Cquat), 50.0, 30.5, 24.4, 22.2, 21.4, 13.7, 10.5, 9.8; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C19H24N5O3S 402.1594; Found 402.1589.
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3-Butyl-4-(furan-2-ylmethyl)-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2r)
Prepared from 1r (122 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 3:1. Yield 84 mg (94%).
White powder; mp 115–117 °C; 1H NMR (600 MHz, CDCl3): δ 8.09 (d, J = 7.8 Hz, 1H), 7.85 (dd, J = 7.6, 1.3 Hz, 1H), 7.69 (td, J
= 7.8, 1.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 6.90 (m, 1H), 5.98-5.95 (m, 2H), 4.74 (s, 2H), 2.74 (t, J = 7.6 Hz, 2H), 1.81 (quint, J =
7.6 Hz, 2H), 1.46 (sext, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 146.4 (Cquat), 143.1, 141.1
(Cquat), 134.0, 131.8 (Cquat), 131.7 (Cquat), 128.1, 125.7 (Cquat), 124.2, 118.3, 111.0, 110.3, 48.9, 30.3, 24.1, 22.3, 13.7; HRMS
(MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C17H19N4O3S 359.1172; Found 359.1173.
3-Butyl-4-cyclohexyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2s)
Prepared from 1s (122 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 2:1. Yield 85 mg (94%).
Colorless oil; 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 8.1 Hz, 1H), 7.93 (dd, J = 7.8, 1.0 Hz, 1H), 7.81 (td, J = 7.8, 1.2 Hz, 1H),
7.60 (td, J = 7.8, 0.7 Hz, 1H), 3.94 (m, 1H), 2.81 (t, J = 7.6 Hz, 2H), 1.84 (m, 2H), 1.75-1.64 (m, 4H), 1.59-1.51 (m, 1H), 1.44 (m,
2H), 1.29-1.13 (m, 5H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 142.8 (Cquat), 134.2, 132.0 (Cquat), 131.0
(Cquat), 128.5, 127.6 (Cquat), 124.0, 118.7, 64.9, 31.2 (2C), 30.3, 25.5 (2C), 24.8, 24.6, 22.2, 13.7; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C18H25N4O2S 361.1693; Found 361.1697.
4-(1-Adamantyl)-3-butyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2t)
Prepared from 1t (135 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 4:1. Yield 88 mg (85%). Pale
yellow solid; mp 163–165 °C; 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.8, 1.0 Hz, 1H), 7.80 (t, J = 7.8
Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 2.80 (m, Hz, 2H), 2.03 (m, 3H), 1.96-1.82 (m, 6H), 1.87 (m, 2H), 1.56 (m, 6H), 1.43 (m, 2H),
0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 144.5 (Cquat), 134.0, 132.3 (Cquat), 131.5 (Cquat), 129.5 (Cquat), 128.5,
124.0, 118.8, 68.2 (Cquat), 41.2 (3C), 35.4 (3C), 30.1 (3C), 29.8, 25.4, 22.2, 13.7; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+
Calcd for C22H29N4O2S 413.2006; Found 413.2022.
(4-tert-Butyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-3-yl)methanol (2u)
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Prepared from 1u (109.1 mg, containing 0.24 mmol of pure 1u) according to the general procedure; eluent: hexanes–EtOAc = 1:2.
Yield 37 mg (51%). White powder; mp 250 °C (dec.); 1H NMR (400 MHz, DMSO-d6/CCl4): δ 8.24 (d, J = 8.1 Hz, 1H), 8.00-7.94
(m, 2H), 7.75 (t, J = 7.7 Hz, 1H), 5.49 (br s, 1H), 4.62 (s, 2H), 1.28 (s, 9H); 13C{1H} NMR (100.6 MHz, DMSO-d6/CCl4): δ 142.9
(Cquat), 134.7, 132.0 (Cquat), 131.2 (Cquat), 129.3, 128.2 (Cquat), 123.8, 118.9, 66.1 (Cquat), 53.9, 28.8 (3C); HRMS (MALDI-TOF,
dithranol) m/z: [M + H]+ Calcd for C13H17N4O3S 309.1016; Found 309.1018.
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2-(4-tert-Butyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-3-yl)ethanol (2v)
Prepared from 1v (112.6 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 1:3. Yield 45 mg (56%).
Pale yellow crystals; mp 148–150 °C; 1H NMR (600 MHz, CDCl3): δ 8.23 (dd, J = 8.1, 1.3 Hz, 1H), 7.95 (dd, J = 7.8, 1.0 Hz, 1H),
7.84 (m, 1H), 7.63 (td, J = 7.8, 1.0 Hz, 1H), 4.14-3.98 (m, 2H), 3.14-2.98 (m, 2H), 2.88 (br s, 1H), 1.32 (s, 9H); 13C{1H} NMR (150
MHz, CD3OD/CDCl3): δ 142.3 (Cquat), 134.3, 132.9 (Cquat), 132.1 (Cquat), 129.03, 128.97 (Cquat), 124.4, 119.0, 67.0 (Cquat), 60.7, 29.2
(3C), 29.0; HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C14H19N4O3S 323.1172; Found 323.1172.
3-Butyl-4-tert-butyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2w)
Prepared from 1w (115.6 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 2:1. Yield 58 mg (69%).
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The reaction at 2 mmol of 1w afforded 451 mg (67%) of 2w. Colorless crystals; mp 120–122 °C; H NMR (400 MHz, CDCl3): δ
8.22 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 7.7, 1.1 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 2.79 (t, J = 7.5 Hz, 2H),
1.85 (quint, J = 7.5 Hz, 2H), 1.43 (sext, J = 7.5 Hz, 2H), 1.30 (s, 9H), 0.97 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3):
δ 144.3 (Cquat), 134.1, 132.2 (Cquat), 132.1 (Cquat), 128.9 (Cquat), 128.6, 124.2, 118.8, 66.7 (Cquat), 29.8, 29.2 (3C), 25.4, 22.2, 13.7;
HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C16H23N4O2S 335.1536; Found 335.1534.
4-tert-Butyl-3-phenyl-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazine 5,5-dioxide (2x)
Prepared from 1x (120.6 mg, 0.25 mmol) according to the general procedure; eluent: CH2Cl2–MeOH = 100:1. Yield 40 mg (45%).
Beige crystals; 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.3 Hz, 2H), 7.97 (d, J = 7.6 Hz, 1H), 7.84 (t, J
= 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.2 Hz, 2H), 7.43 (m, 1H), 1.23 (s, 9H); 13C{1H} NMR (100.6 MHz, CDCl3): δ
142.6 (Cquat), 134.2, 132.0 (Cquat), 131.4 (Cquat), 129.8 (Cquat), 129.1, 128.99, 128.95 (2C), 128.6 (Cquat), 127.0 (2C), 124.3, 118.9,
67.9 (Cquat), 20.1 (3C); HRMS (MALDI-TOF, dithranol) m/z: [M + H]+ Calcd for C18H19N4O2S 355.1223; Found 355.1223.
(3α,5β,12α)-24-(4-Butyl-5,5-dioxido-4H-[1,2,3]triazolo[5,1-c][1,2,4]benzothiadiazin-3-yl)cholane-3,12-diol (2y)
Prepared from 1y (191.7 mg, 0.25 mmol) according to the general procedure; eluent: hexanes–EtOAc = 1:2. Yield 159 mg (99%).
Colorless oil; 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.62 (t, J =
7.7 Hz, 1H), 3.89 (m, 1H), 3.69 (m, 2H), 3.61 (tt, J = 11.0, 4.7 Hz, 1H), 2.82 (br s, 2H), 2.78 (t, J = 7.6 Hz, 2H), 1.87-0.73 (m,
30H), 0.97 (t, J = 7.3 Hz, 3H), 0.89 (s, 3H), 0.77 (d, J = 6.4 Hz, 3H), 0.58 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 138.6
(Cquat), 134.1, 131.9 (Cquat), 131.5 (Cquat), 128.3, 125.7 (Cquat), 123.5, 118.5, 72.7, 71.3, 51.8, 47.9, 47.0, 46.1, 41.8, 36.1, 35.7, 35.0,
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The Journal of Organic Chemistry
34.9, 33.9, 33.3, 32.2, 30.4, 30.1, 28.5, 27.2, 26.9, 25.9, 24.9, 24.4, 23.4, 22.9, 22.1, 17.0, 13.6, 12.4; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C36H55N4O4S 639.3939; Found 639.3926.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the Internet.
1H and 13C{1H} NMR spectra, details of DFT calculations (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: latyshev@org.chem.msu.ru.
ACKNOWLEDGMENT
This work was supported by the Russian Foundation for Basic Research (Grant No. 18-33-01024-mol_a) and the M. V. Lomonosov
Moscow State University Program of Development. I. P. Beletskaya is grateful to the Russian Science Foundation (Grant No. 19-13-
00223). The authors would like to acknowledge Thermo Fisher Scientific, Inc., MS Analytica (Moscow, Russia), and Prof. A. Makarov
(Thermo Fisher Scientific, Inc.) personally for providing mass spectrometry equipment for this work.
REFERENCES
(1) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific
Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67, 3057-3064. (b)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition Process: Copper(I)-
Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596-2599.
(2) (a) Yamada, M.; Matsumura, M.; Murata, Y.; Kawahata, M.; Saito, K.; Kakusawa, N.; Yamaguchi, K.; Yasuike, S.
Synthesis of 5-organostibano-1H-1,2,3-triazoles by Cu-catalyzed azide-alkyne cycloaddition and their application in the
acyl-induced deantimonation for the preparation of fully substituted 5-acyl-1,2,3-triazoles. Tetrahedron 2017, 73, 2614-
2622. (b) Li, L.; Hao, G.; Zhu, A.; Fan, X.; Zhang, G.; Zhang, L. A Copper(I)‐Catalyzed Three‐Component Domino Process:
Assembly of Complex 1,2,3‐Triazolyl‐5‐Phosphonates from Azides, Alkynes, and H‐Phosphates. Chem. Eur. J. 2013, 19,
14403-14406. (c) Worrell, B. T.; Ellery, S. P.; Fokin, V. V. Copper(I)-Catalyzed Cycloaddition of Bismuth(III) Acetylides
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
6
7
8
with Organic Azides: Synthesis of Stable Triazole Anion Equivalents. Angew. Chem. Int. Ed. 2013, 52, 13037-13041. (d)
Wang, W.; Peng, X.; Wei, F.; Tung, C-H.; Xu, Z. Copper(I)‐Catalyzed Interrupted Click Reaction: Synthesis of Diverse
5‐Hetero‐Functionalized Triazoles. Angew. Chem. Int. Ed. 2016, 55, 649-653. (e) Malnuit, V.; Duca, M.; Manout, A.;
Bougrin, K.; Benhida, R. Tandem Azide-Alkyne 1,3-Dipolar Cycloaddition/Electrophilic Addition: A Concise Three-
Component Route to 4,5-Disubstituted Triazolyl-Nucleosides. Synlett 2009, 2123-2128. (f) Stefani, H. A.; Vasconcelos, S.
N. S.; Manarin, F.; Leal, D. M.; Souza, F. B.; Madureira, L. S.; Zukerman-Schpector, J.; Eberlin, M. N.; Godoi, M. N.; De
Souza Galaverna, R. Synthesis of 5-organotellanyl-1H-1,2,3-triazoles: Functionalization of the 5-position scaffold by the
Sonogashira cross-coupling reaction. Eur. J. Org. Chem. 2013, 3780-3785. (g) Stefani, H. A.; Silva, N. C. S.; Vasconcelos,
S. N. S.; Manarin, F.; Souza, F. B. Functionalization of 5-telluro-1,2,3-triazoles: Te/Li exchange and Suzuki-Miyaura cross-
coupling reaction. Tetrahedron Lett. 2013, 54, 2809-2812. (h) Yamada, M.; Matsumura, M.; Uchida, Y.; Kawahata, M.;
Murata, Y.; Kakusawa, N.; Yamaguchi, K.; Yasuike, S. Copper-catalyzed [3+2] cycloaddition of (phenylethynyl)di-p-
tolylstibane with organic azides. Beilstein J. Org. Chem. 2016, 12, 1309-1313.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) Hein, J. E.; Tripp J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin V. V. Copper(I)-Catalyzed Cycloaddition of Organic
Azides and 1-Iodoalkynes. Angew. Chem. Int. Ed. 2009, 48, 8018-8021.
(4) Deng, J.; Wu, Y-M.; Chen, Q-Y. Cross-coupling Reaction of Iodo-1,2,3-triazoles Catalyzed by Palladium. Synthesis
2005, 16, 2730-2738.
(5) (a) Diner, P.; Andersson, T.; Kjellen, J.; Elbing, K.; Hohmann, S.; Grotli, M. Short Cut to 1,2,3-Triazole-based P38 MAP
Kinase Inhibitors via [3+2]-Cycloaddition Chemistry. New J. Chem. 2009, 33, 1010-1016. (b) Wang, D.; Chen, S.; Chen, B.
“Green” Synthesis of 1,4-Disubstituted 5-Iodo-1,2,3-triazoles under Neat Conditions, and an Efficient Approach of
Construction of 1,4,5-Trisubstituted 1,2,3-Triazoles in One Pot. Tetrahedron Lett. 2014, 55, 7026-7028. (c) Ahmed, N.;
Konduru, N. K.; Ahmad, S.; Owais, M. Design, Synthesis and Antiproliferative Activity of Functionalized Flavone-triazole-
tetrahydropyran Conjugates Against Human Cancer Cell Lines. Eur. J. Med. Chem. 2014, 82, 552-564. (d) Yousuf, M.;
Mukherjee, D.; Dey, S.; Pal, C.; Adhikari, S. Antileishmanial Ferrocenylquinoline Derivatives: Synthesis and Biological
Evaluation Against Eishmania Donovani. Eur. J. Med. Chem. 2016, 124, 468-479.
(6) (a) Goyard, D.; Chajistamatiou, A. S.; Sotiropoulou, A. I.; Chrysina, E. D.; Praly, J.-P.; Vidal, S. Efficient
Atropodiastereoselective Access to 5,5′-Bis-1,2,3-triazoles: Studies on 1-Glucosylated 5-Halogeno 1,2,3-Triazoles and Their
5-Substituted Derivatives as Glycogen Phosphorylase Inhibitors. Chem. Eur. J. 2014, 20, 5423-5432. (b) Fehr, K.; Gömöry,
G.; Skoda-Földes, R. A Modular Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles with Ferrocene Moieties. Monatsh. Chem.
2015, 146, 1455-1463. (c) Govdi, A. I.; Danilkina, N. A.; Ponomarev, A. V.; Balova, I. A. 1-Iodobuta-1,3-diynes in Copper-
ACS Paragon Plus Environment

Page 29 of 33
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Catalyzed Azide-Alkyne Cycloaddition: A One-Step Route to 4-Ethynyl-5-iodo-1,2,3-triazoles. J. Org. Chem. 2019, 84,
2
3
4
1925-1940.
5
6
7
8
(7). (a) Thiery, E.; You, V.; Mora, A-S.; Abarbri, M. Synthesis of 5-Substituted 1,2,3-Triazolyl-4-phosphonate through
Cross-coupling Reactions of 5-Iodo-1,2,3-triazolyl-4-phosphonate. Eur. J. Org. Chem. 2016, 529-534. (b) Gribanov, P. S.;
Chesnokov, G. A.; Dzhevakov, P. B.; Kirilenko, N. Yu.; Rzhevskiy, S. A.; Ageshina, A. A.; Topchiy, M. A.; Bermeshev, M.
V.; Asachenko, A. F.; Nechaev, M. S. Solvent-free Suzuki and Stille Cross-coupling Reactions of 4- and 5-Halo-1,2,3-
triazoles. Mendeleev Commun. 2019, 29, 147-149.
9
10
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12
13
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15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8) (a) Malnuit, V.; Duca, M.; Manout, A.; Bougrin, K.; Benhida, R. Tandem Azide-Alkyne 1,3-dipolar
Cycloaddition/Electrophilic Addition: A Concise Three-component Route to 4,5-Disubstituted Triazolyl-nucleosides. Synlett
2009, 13, 2123-2128. (b) Ostrowski, T.; Januszczyk, P.; Cieslak, M.; Kazmierczak-Baranska, J.; Nawrot, B.; Bartoszak-
Adamska, E.; Zeidler, J. 5-Ethynyl-1-β-d-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic Acid Amide (ETCAR) and Its
Analogues: Synthesis and Cytotoxic Properties. Bioorg. Med. Chem. 2011, 19, 4386-4398. (c) Amdouni, H.; Robert, G.;
Driowya, M.; Furstoss, N.; Métier, C.; Dubois, A.; Dufies, M.; Zerhouni, M.; Orange, F.; Lacas-Gervais, S.; Bougrin, K.;
Martin, A. R.; Auberger, P.; Benhida, R. In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl)-
4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid
Malignancies. J. Med. Chem. 2017, 60, 1523-1533.
(9) Carcenac, Y.; David-Quillot, F.; Abarbri, M.; Duchêne, A.; Thibonnet, J. Palladium-catalyzed Cross-coupling of 1,4-
Disubstituted 5-Iodo-1,2,3-triazoles with Organotin Reagents. Synthesis 2013, 45, 633-638.
(10) (a) Panteleev, J.; Geyer, K.; Aguilar-Aguilar, A.; Wang, L.; Lautens, M. C-H Bond Functionalization in the Synthesis of
Fused 1,2,3-Triazoles. Org. Lett. 2010, 12, 5092-5095. (b) Schulman, J. M.; Friedman, A. A.; Panteleev, J.; Lautens, M.
Synthesis of 1,2,3-Triazole-fused Heterocycles via Pd-Catalyzed Cyclization of 5-Iodotriazoles. Chem. Commun. 2012, 48,
55-57. (c) Morgen, M.; Jöst, C.; Malz, M.; Janowski, R.; Niessing, D.; Klein, C. D.; Gunkel, N.; Miller, A. K.
Spiroepoxytriazoles Are Fumagillin-like Irreversible Inhibitors of MetAP2 with Potent Cellular Activity. ACS Chem. Biol.
2016, 11, 1001-1011.
(11) Irastorza, A.; Aizpurua, J. M.; Correa, A. Triazole-Directed Pd-Catalyzed C(sp2)-H Oxygenation of Arenes and
Alkenes. Org. Lett. 2016, 18, 1080-1083.
(12) (a) Joubert, Nicolas; Schinazi, Raymond F.; Agrofoglio, Luigi A. Efficient Pd(0)-Catalyzed Synthesis of 1,2,3-Triazolo-
3′-deoxycarbanucleosides and Their Analogues. Tetrahedron 2005, 61, 11744-11750. (b) Wu, Y-M.; Deng, J.; Chen, Q-Y.
ACS Paragon Plus Environment