Synthesis of 2,3-Disubstituted Indoles and Benzofurans by the Tandem Reaction of Rhodium(II)-Catalyzed Intramolecular C-H Insertion and Oxygen-Mediated Oxidation

Article abstract of DOI:10.1021/acs.joc.6b00611

A highly effective and straightforward method to construct a wide range of functionalized 2,3-disubstituted indoles has been developed. The method involves the tandem reaction of rhodium(II)-catalyzed denitrogenative annulation of triazole-based benzyl an

Full text of DOI:10.1021/acs.joc.6b00611

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Article
Synthesis of 2,3-Disubstituted Indoles and Benzofurans
by the Tandem Reaction of Rhodium(II)-Catalyzed
Intramolecular C–H Insertion and Oxygen-Mediated Oxidation
Hong-Juan Shen, Jun-Kai Fu, Hao Yuan, Jianxian Gong, and Zhen Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00611 • Publication Date (Web): 12 May 2016
Downloaded from http://pubs.acs.org on May 13, 2016
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Synthesis of 2,3ꢀDisubstituted Indoles and Benzofurans
by the Tandem Reaction of Rhodium(II)ꢀCatalyzed
Intramolecular C–H Insertion and OxygenꢀMediated
Oxidation
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HongꢀJuan Shen, JunꢀKai Fu, Hao Yuan, Jianxian Gong,* and Zhen Yang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen, China, 518055
gongjx@pku.edu.cn, zyang@pku.edu.cn
RECEIVED DATE
TsN
TsN
N
N
NTs
Rh(II)
O2
R1
R3
R1
R3
R1
C-H
insertion
N
N
R2
N
R2
R3
R2
ABSTRACT: A highly effective and straightforward method to construct a wide range of
functionalized 2,3ꢀdisubstituted indoles has been developed. The method involves the tandem reaction
of rhodium(II)ꢀcatalyzed denitrogenative annulation of triazoleꢀbased benzyl anilines and
oxygenꢀmediated oxidative aromatization. The developed method can also be used to synthesize
2,3ꢀdisubstituted benzofurans by replacing the benzyl anilines with benzyl phenols.
Introduction
2,3ꢀDisubstituted indoles are ubiquitous in biologically active natural products and medicinal
agents, and they are an important class of heterocycles.1 Therefore, development of practical and
efficient procedures to prepare functionalized indoles has long been an area of intensive research.2
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Among the reported methods,3 transitionꢀmetalꢀcatalyzed C–H insertion of metal carbene followed by
oxidation with DDQ or chloranil provides a novel pathway to prepare functionalized 2,3ꢀdisubstituted
indoles (eq 1, Figure 1).4
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Figure 1. Synthesis of heterocycles utilizing Rh(II) azavinyl carbene.
In this context, Nꢀsulfonyl 1,2,3ꢀtriazole can be regarded as a masked diazo compound.5 Upon
treatment with a Rh(ΙΙ) catalyst, Nꢀsulfonyl 1,2,3ꢀtriazole transforms to Rh(ΙΙ) azavinyl carbene,6
which allows Nꢀsulfonyl triazole to be
a
surrogate of the diazo compound in
Rh(II)ꢀcarbenoidꢀpromoted reactions, such as cyclopropanation,7 transannulation,8 C–H insertion,9
dehydrogenative rearrangement,10 and other rhodium carbeneꢀbased reactions.11
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Recently, Lin and coꢀworkers developed a simple approach12 to synthesize 3ꢀindolylimines
from Nꢀpropargyl anilineꢀderived triazoles by a tandem reaction involving Rh(II)ꢀcatalyzed
denitrogenative annulation of the substituted triazole followed by an intramolecular Friedel–Crafts
reaction (eq 2, Figure 1).
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We recently developed synthetic methods to construct core heterocycles in complex natural
products using Rh(ΙΙ)ꢀcatalyzed annulation of substituted triazoles as the key step, and the developed
chemistry allows construction of the core structures of oxaspirocycles13 (eq 3, Figure 1),
dihydroisobenzofurans, and indanones14 (eq 4, Figure 1).
[Rh]
TsN
N
NTs
N
intramolecular
C-H insertion
[Rh]
H
Ph
NTs
Ph
[RhII]
-N2
N
N
N
Ph
H
R1
R1
R1
B
A
C
- [RhII]
TsHN
NTs
Ph
NTs
Ph
[1,3]-
H shift
Ph
aromatization
O2
N
X
N
D
F
E
R1
R1
Figure 2. Rational proposal for the synthesis of 2,3ꢀdisubstituted indoles via
Rhꢀcatalyzed Nꢀsulfonylꢀ1,2,3ꢀtriazoleꢀbased anilines.
Based on our previous experience in Rhꢀcatalyzed denitrogenative annulation of substituted
triazoles, we wanted to apply this chemistry to synthesize 2,3ꢀdisusbtittued indoles. We envisioned that
triazoleꢀbased Nꢀbenzyl aniline A (Figure 2) might undergo Rhꢀcatalyzed denitrogenation to form
Rh(ΙΙ) azavinyl carbene B. B could then undergo sequential intramolecular C–H insertion and a
1,3ꢀhydrogen shift through transition state C15a, b and intermediate D to give intermediate E, followed
by oxygenꢀmediated oxidative aromatization to give 2,3ꢀdisubstituted indole F.
Herein, we report our recent results for the synthesis of 2,3ꢀdisubstituted indoles from
NꢀbenzylꢀNꢀ(2ꢀ(Nꢀsulfonylꢀ1,2,3ꢀtriazoleꢀ4ꢀyl)ꢀphenyl) acetamide by the tandem reaction of
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Rhꢀcatalyzed denitrogenative annulation and oxygenꢀmediated oxidation.16 The developed chemistry
provides an alternative way to synthesize this important scaffold.
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RESULTS AND DISCUSSION
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Our research began with evaluation of the substrate NꢀbenzylꢀNꢀ(2ꢀ(Nꢀsulfonylꢀ1,2,3ꢀtriazole
ꢀ4ꢀyl)ꢀphenyl) acetamide (1a) in the Rhꢀcatalyzed tandem reaction. Initially, 1a was treated with
Rh2(Oct)4 (5 mol %) in 1,2ꢀdichloroethane (DCE) at room temperature for 2 h, however, no desired
product 2a was obtained, and starting material 1a was recovered (entry 1 in Table 1). We then carried
out the reaction at a higher temperature (70 °C) for 2 h, under these conditions product 2a was
obtained in 30% yield, in addition to a hydrolyzed product 3a in 50% yield11a (entry 2). We later found
out that the yield of 2a could be improved up to 42% in the presence of oxygen under the conditions
listed in entry 2 (entry 3).
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To improve the yield, we then carried out a systematic evaluation of the effects of reaction
parameters on the outcomes of the annulation. In the event, when the reaction was performed in
dichloromethane (DCM) at 40 oC in the presence of 4Å MS,11a only a trace amount of product 2a was
obtained because of the lower reaction temperature (entry 4). On the other hand, when the reaction was
o
carried out at 70 C in the presence of 4Å MS in DCE and CHCl3, the corresponding product 2a was
formed in 50% and 54%, respectively, and product 3a could not be observed (entries 5 and 6). We then
changed the catalyst from Rh2(Oct)4 to Rh2(OAc)4 or Rh2(TFA)4, and run the reactions in CHCl3,
however, product 2a were obtained in 0% and 20%, respectively (entries 7 and 8), indicating Rh2(Oct)4
is an effective catalyst for this reaction. We therefore selected Rh2(Oct)4 as a catalyst, and ran the
o
reaction in the solvents of DCE and CHCl3 at 100 C in a sealed tube, as expected product 2a was
obtained in 75% and 80% yields, respectively (entries 9 and 10). We finally performed the reaction at
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120 °C in toluene for 1 h under N2, and then at 90 °C for another 1 h in the presence of O2,17 to our
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delight, the desired product 2a could be obtained in 89% yield (entry 11).
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Table 1. Conditions for the Rhꢀcatalyzed annulation of 1a for the syntheses
2,3ꢀdisubstituted indole 2aa
of
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Entrya
Catalyst
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(OAc)4
Rh2(OCOCF3)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Additive Solvent
Temperature Time Yield of 2a / 3ab
1
2
ꢀ
DCE
DCE
rt
2 h
2 h
0
ꢀ
70 oC
70 oC
40 oC
70 oC
70 oC
70 oC
70 oC
100 oC
100 oC
30%/50%
42%/45%
trace
3
ꢀ
DCE
2 hc
2 hc
2 hc
2 hc
2 hc
2 hc
2 h c
2 h c
4
4ÅMS
4ÅMS
4ÅMS
4ÅMS
4ÅMS
4ÅMS
4ÅMS
4ÅMS
DCM
DCE
5
50%/0
54%/0
0
6
CHCl3
CHCl3
toluene
DCE
7
8
20%/0
75%/0
80%/0
89%/0
9
10
11
CHCl3
toluene
120 oCꢀ90oC 2 hd
aReaction agents and conditions: 1a (90 mg, 0.2 mmol), solvent (0.025 M for substrate), catalyst (5
b
c
mol%), 4Å MS (180 mg, 200 wt. %, powder) unless otherwise noted; Yield of isolated product; The
mixture was carried out under an oxygen atmosphere; dThe reaction was carried out under a nitrogen
atmosphere for 1 h, then under an oxygen atmosphere at 90 oC for another 1 h.
We next investigated the substrate scope of this Rh(II)ꢀcatalyzed annulation reaction. To this
end, substrates 1b–1n were synthesized (see Experimental Section for details), and annulated under the
optimized reaction conditions listed in entry 12 in Table 1. The results are listed in Figure 3.
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Figure 3. Rh(ΙΙ)ꢀcatalyzed denitrogenative annulation with different substituents on
the aniline aromatic ring.a
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aIsolated yield. bReaction time 5 h. cReaction time 4 h.
From the results, we can make the following observations: (1) When the nitrogen atom of
aniline in the substrate is protected as its acetamide, both electronꢀrich and electronꢀdeficient substrates
can smoothly undergo Rhꢀcatalyzed denitrogenative annulation to give the corresponding products 2a–
2k in good to excellent yields (Figure 3). In addition, the substitution pattern did not greatly change the
product yield (2e vs. 2f and 2g vs. 2h). (2) When the nitrogen atom of the aniline in substrates 1l and
1m is protected with Ts and Me groups, respectively, the corresponding annulation proceeds to give
the desired annulated products 2l and 2m in good yields. (3) When the nitrogen atom of the aniline is
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protected with two Me groups, the resultant substrate can also undergo the desired reaction to give
annulated product 2n in 78% yield.
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We then investigated the effect of substituents on the benzyl ring on Rhꢀcatalyzed annulation.
Substrates 4a–4q were prepared (see Experimental Section form details) and then annulated under the
optimized conditions. The results are shown in Figure 4. Accordingly, when the benzyl ring contained
an alkyl substituent, such as a methyl or tertiary butyl group (4a–4d), annulation gave the
corresponding products 5a–5d in good yields (86%–90%). In contrast, when the benzyl ring contained
electronꢀdonating substituents (one or two methoxyl groups, 4e–4g), annulation gave low yields of
products 5e–5g (60%–70%), indicating that electronꢀdonating groups are unfavorable for annulation.
Presumably, the electronꢀrich benzyl ring could result in some unexpected side reactions in the
presence of Rh(ΙΙ) azavinyl carbene.15 When the benzene ring of the substrate contained an
electronꢀwithdrawing substituent (Cl, F, or CF3, 5h–5m and 5p) annulation proceeded smoothly to
give the corresponding products in good yields. It should be mentioned that when
electronꢀwithdrawing groups were located at the Cꢀ2 position (5h, 5n, and 5o), relatively low yields
were obtained because of steric hindrance, which prevents formation of transition state C.
Interestingly, the naphthalene ring was also suitable for this reaction sequence and gave the desired
annulated product 5q in 81% yield.
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Figure 4. Rh(ΙΙ)ꢀcatalyzed denitrogenative annulation with different substituents on
the benzyl aromatic ring.a
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aIsolated yield.
To increase the reaction scope, we used this methodology to synthesize 2,3ꢀdisubstituted
benzofurans by replacing the benzyl anilines in the triazoleꢀbased substrates with benzyl phenols.
Substrates 6a–6h were synthesized (see Experimental Section for details) and then subjected to the
optimized Rhꢀcatalyzed annulation reaction conditions. The results are listed in Figure 5. As expected,
all of the selected substrates smoothly underwent annulation to give 2ꢀ3ꢀdisubstituted benzofurans 7a–
7h in good to acceptable yields (48%–80%). Interestingly, all of the reactions needed to be carried out
for 6 h, indicating that formation of benzofurans is more difficult than the corresponding indoles.
Figure 5. Sequential Rh(ΙΙ)ꢀcatalyzed C–H insertion and oxidation to produce
2,3ꢀdisubstituted benzofurans.a
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aIsolated yield.
CONCLUSIONS
In summary, we have developed a simple method to synthesize structurally diverse
2,3ꢀdisubstituted indoles by a tandem reaction involving Rhꢀcatalyzed denitrogenative annulation of
triazoleꢀbased benzyl anilines and oxygenꢀmediated oxidative aromatization. This method can also
synthesize certain types of 2,3ꢀdisubstituted benzofurans.
EXPERIMENTAL SECTION
General Experimental Information. All of the reactions were performed under an argon atmosphere
with dry solvents under anhydrous conditions. Unless otherwise specified, all of the reagents and
starting materials were purchased from commercial sources and used as received. The chromatography
solvents were technical grade and distilled prior to use. Flash chromatography was performed using
200−300 mesh silica gel with the indicated solvent system according to standard techniques. Analytical
thinꢀlayer chromatography (TLC) was performed on precoated, glassꢀbacked silica gel plates. The
1
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developed chromatograms were visualized by UV absorbance (254 nm). The H and C NMR data
were recorded on 400 MHz NMR and 500 MHz NMR spectrometers, unless otherwise specified. The
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following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, b = broad. HRMS (ESI) analysis with a quadrupole timeꢀofꢀflight mass
spectrometer yielded ion mass/charge (m/z) ratios in atomic mass units. IR spectra were measured as
dry films (KBr), and peaks are reported in terms of wavenumber (cm−1).
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General procedure for the synthesis of triazole substrates 1a-1n, 4a-4q:
To a stirred solution of 2ꢀiodoaniline (1.0 g, 4.6 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was sequentially
added pyridine (0.7 mL, 6.8 mmol, 1.5 equiv) and acetic anhydride (0.6 mL, 6.9 mmol, 1.51 equiv) in
a dropwise manner at 0˚C under argon, and the mixture was then allowed to warm to room
temperature, and stirred for 1h. The reaction was worked up by addition of water (10 mL), and the
mixture was extracted with CH2Cl2 (10 mL x 3). Combined organic layers were washed with brine (10
mL) and dried over Na2SO4. The solvent was filtered off, and the filtrate was concentrated under
vacuum. The residue was purified by a flash column chromatography on silica gel (PE: EA = 4:1) to
give Nꢀ(2ꢀiodophenyl)acetamide 1-1 (1.06 g, 4.05 mmol) 18 in 88% yield as a crystalline solid. H
1
NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.75 (s, 1H), 7.50 (s, 1H), 7.31 (m, 1H), 6.83 (m, 1H), 2.22
(d, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 138.8, 138.2, 129.2, 126.1, 122.5, 24.7 ppm;
IR νmax (film): 3065, 3035, 2929, 2864, 2758, 1684, 1598, 1483, 1458, 1454, 1285, 1239, 1161, 1103,
1005, 758, 737, 696, 658 cmꢀ1; HRMS (ESI) m/z calcd for C8H9INO [M+H]+: 261.9729; found:
261.9721.
To a flame dried roundꢀbottom flask containing Nꢀ(2ꢀiodophenyl)acetamide 1-1 (2.0 g, 7.66 mmol,
1.0 equiv) was added Pd(Ph3P)2Cl2 (105 mg, 0.15 mmol, 0.02 equiv.) and CuI (15 mg, 0.08 mmol,
0.01 equiv), and degassed with argon for 3 times. To this flask was added dried THF (25 mL, 0.3 M
for substrate), Et3N (4.3 mL, 30.6 mmol, 4.0 equiv) and (trimethylsilyl)acetylene (1.6 mL, 11.5 mmol,
1.5 equiv.), and the resultant reaction mixture was then stirred at 50 °C for 16 h. After cooled to
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ambient temperature, the mixture was filtered off through a celite pad, and the filtrate was concentrated
under vacuum. The residue was purified by a flash column chromatography on silica gel (PE: EA =
16:1) to give Nꢀ(2ꢀ((trimethylsilyl)ethynyl)phenyl)ꢀ acetamide 1-213 (1.51 g, 6.51 mmol) in 85% yield
as a yellow viscous liquid. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.40
(dd, J = 7.6, 1.2 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.01 (m, 1H), 2.21 (s, 3H), 0.30 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 168.0, 139.5, 131.4, 129.9, 123.1, 118.9, 111.5, 102.2, 100.3, 24.8, ꢀ0.1 ppm; IR νmax
(film): 3064, 3042, 2915, 2814, 2766, 1572, 1435, 1368, 1324, 1319, 1161, 1153, 789, 765, 688, 628
cmꢀ1; HRMS (ESI) m/z calcd for C13H18NOSi [M+H]+: 232.1158; found: 232.1153.
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To a stirred solution of Nꢀ(2ꢀ((trimethylsilyl)ethynyl)phenyl)acetamide 1-2 (2.74 g, 11.1 mmol, 1.0
equiv) in THF (60 mL) was added NaH (666 mg, 16.65 mmol, 1.5 equiv, 60% w/w) at 0 °C, and the
resultant reaction mixture was allowed to warm up to room temperature, and stirred for 30 min. To this
solution was added benzyl bromide (1.23 mL, 14.43mmol, 1.3 equiv) and tetrabutyl ammonium iodide
(408 mg, 1.11 mmol, 0.1 equiv) at room temperature, and the mixture was stirred at the same
temperature for 3h. The reaction mixture was quenched by addition of a saturated aqueous solution of
ammonium chloride, and the mixture was extracted with ethyl acetate (2 x 30 mL), and the combined
extracts were dried over Na2SO4. The extract was filtered off, and the filtrate as concentrated under
vacuum. The residue was purified by a flash column chromatography on silica gel (PE: EA = 8:1)
afforded NꢀbenzylꢀNꢀ(2ꢀ(1ꢀtosylꢀ1Hꢀ triazolꢀ4ꢀyl)phenyl)acetamide 1-3 13 (2.07 g, 8.33 mmol) in 75%
yield as a white oil. 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 7.2 Hz, 1H), 7.21 (m, 7H), 6.76 (d, J =
7.4 Hz, 1H), 5.51 (d, J = 14.3 Hz, 1H), 4.23 (d, J = 14.3 Hz, 1H), 3.25 (s, 1H), 1.84 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 170.3, 144.3, 137.2, 133.9, 129.7, 129.5, 129.1, 128.3, 128.1, 127.4, 121.8, 82.8,
79.4, 51.7, 22.4 ppm; IR νmax (film): 3258, 3223,3046, 3030, 1648, 1486, 1448, 1387, 1358, 1289,
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1261, 1216, 1070, 749, 703 cmꢀ1; HRMS (ESI) m/z calcd for C17H15NNaO [M+Na]+: 272.1051; found:
272.1045.
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Following the procedure published by Fokin19: To a solution of NꢀbenzylꢀNꢀ(2ꢀ(1ꢀtosylꢀ1Hꢀtriazꢀ
olꢀ4ꢀyl)phenyl)acetamide 1-3 (2.0 g, 8.03 mmol, 1.0 equiv) in dry toluene (80 mL) was added
copper(I) thiopheneꢀ2ꢀcarboxylate (CuTC, 152 mg, 0.80 mmol, 0.1 equiv), followed by addition of
tosyl azide (1.24 mL, 8.03 mmol, 1.0 equiv) in a dropwise manner at ambient temperature. The
reaction mixture was then stirred at the same temperatue for 3 h. The reaction mixture was was worked
up by addition of a saturated aqueous solution of ammonium chloride (60 mL), and then extracted with
ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine, and dried over
Na2SO4. The extract was filtered off, and the residue was concentrated under vacuum, and the residue
was purified by a flash column chromatography on silica gel (PE: EA = 4:1) to give
NꢀbenzylꢀNꢀ(2ꢀ(1ꢀtosylꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl)phenyl)acetamide 1a (3.04 g, 6.83 mmol) in 85% yield
as an orange solid; m p 101ꢀ102 oC; 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.84 (m, 4H), 7.29 (m, 3H),
7.21 (td, J = 7.7, 1.4 Hz, 1H), 7.07 – 6.95 (m, 5H), 6.84 (d, J = 7.2 Hz, 1H), 5.07 (d, J = 14.0 Hz, 1H),
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4.18 (d, J = 14.0 Hz, 1H), 2.31 (s, 3H), 1.62 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.4, 147.6,
143.4, 139.4, 136.4, 132.8, 130.5, 130.2, 129.8, 129.2, 128.8, 128.5, 128.3, 127.6, 127.6, 120.7, 51.9,
22.5, 21.7 ppm; IR νmax (film): 3142, 3085, 3064, 2925, 1662, 1392, 1195, 1176, 989, 763, 751, 701,
672, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C24H22N4NaO3S [M+Na]+: 469.1310; found: 469.1301.
Synthesis of N-benzyl-N-(5-methyl-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1b): 1b (1.5
g) was obtained in 90% yield as a yellow solid; m p 95ꢀ96 oC; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J
= 8.3 Hz, 2H), 7.79 – 7.70 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 7.9 Hz, 1H), 7.01 – 6.90 (m,
5H), 6.64 (s, 1H), 4.95 (d, J = 14.0 Hz, 1H), 4.21 (d, J = 14 Hz, 1H), 2.25 (s, 3H), 2.10 (s, 3H), 1.57 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 147.4, 143.6, 140.6, 139.3, 136.5, 132.9, 130.5, 130.5,
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129.6, 129.5, 129.2, 128.5, 128.2, 127.5, 124.7, 120.3, 52.0, 22.4, 21.7, 20.9 ppm; IR νmax (film):
3152, 3005, 2929, 2900, 1652, 1492, 1165, 1186, 969, 768, 741, 700, 692, 588, 543 cmꢀ1; HRMS (ESI)
m/z calcd for C25H25N4O3S [M+H]+: 461.1647; found: 461.1642.
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Synthesis of N-benzyl-N-(4-methyl-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1c): 1c (1.0
g) was obtained in 91% yield as an orange solid; m p 89ꢀ90 oC; 1H NMR (400 MHz, CDCl3) δ 8.01 (d,
J = 8.4 Hz, 2H), 7.91 (d, J = 1.2 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.23 – 7.14 (m, 3H),
7.14 – 7.06 (m, 3H), 6.76 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 13.6 Hz, 1H), 4.19 (d, J = 13.6 Hz, 1H), 2.45
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(s, 3H), 2.39 (s, 3H), 1.71 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.7, 147.4, 143.4, 138.9, 136.8,
136.5, 133.0, 130.8, 130.5, 130.2, 129.9, 129.4, 128.7, 128.4, 127.7, 127.2, 120.4, 51.9, 22.4, 21.8,
21.1 ppm; IR νmax (film): 3036, 3011, 2928, 2925, 2858, 1659, 1654, 1394, 1194, 1179, 989, 814,
750, 702, 672, 583, 542 cmꢀ1; HRMS (ESI) m/z calcd for C25H25N4O3S [M+H]+: 461.1647; found:
461.1641.
Synthesis of N-benzyl-N-(4-methoxy-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1d): 1d
1
(1.05 g) was obtained in 85% yield as orange solid; m p 100ꢀ101 oC; H NMR (400 MHz, CDCl3) δ
7.97 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.20 – 7.10
(m, 3H), 7.08 (m, 2H), 6.78 (m, 2H), 5.19 (d, J = 13.8 Hz, 1H), 4.16 (d, J = 13.8 Hz, 1H), 3.79 (s, 3H),
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2.41 (s, 3H), 1.70 (s, 3H); C NMR (100 MHz, CDCl3) δ 171.0, 159.3, 147.6, 143.2, 136.5, 132.8,
132.1, 131.3, 130.5, 129.4, 128.6, 128.5, 128.4, 127.7, 120.6, 116.0, 113.9, 55.6, 52.0, 22.4, 21.8 ppm;
IR νmax (film): 3148, 3088, 3064, 2961, 2934, 2839, 1654, 1594, 1503, 1494, 1395, 1327, 1291, 1195,
1777, 1093, 996, 968, 814, 746, 702, 671, 589, 543 cmꢀ1; HRMS (ESI) m/z calcd for C25H24N4NaO4S
[M+Na]+: 499.1416; found: 499.1412.
Synthesis of N-benzyl-N-(5-chloro-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1e): 1e (2.0
g) was obtained in 90% yield as an orange solid; m p 99ꢀ100 o C; 1H NMR (400 MHz, CDCl3) δ 8.06 –
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8.00 (m, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.83 (s, 1H), 7.40 (d, J = 8.0 Hz, 3H), 7.23 – 7.14 (m, 3H), 7.08
(d, J = 7.2 Hz, 2H), 6.93 (d, J = 2.0 Hz, 1H), 5.11 (d, J = 13.9 Hz, 1H), 4.33 (d, J = 13.9 Hz, 1H), 2.43
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(s, 3H), 1.72 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.1, 147.6, 142.4, 140.3, 135.9, 135.4, 132.8,
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130.8, 130.6, 130.2, 129.3, 129.2, 128.7, 128.6, 128.0, 126.6, 120.6, 52.0, 22.5, 21.9 ppm; IR νmax
(film): 3391, 3146, 3088, 3064, 3031, 2927, 1665, 1653, 1595, 1572, 1394, 1324, 1282, 1196, 1177,
1158, 1086, 990, 813, 763, 737, 702, 671, 594, 542 cmꢀ1; HRMS (ESI) m/z calcd for
C24H21ClN4NaO3S [M+Na]+: 503.0921; found: 503.0916.
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Synthesis of N-benzyl-N-(4-chloro-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1f): 1f (2.5
g) was obtained in 88% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 2.4 Hz, 1H),
7.96 (d, J = 8.4 Hz, 2H), 7.92 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 –
7.11 (m, 3H), 7.05 (d, J = 7.2 Hz, 2H), 6.82 (d, J = 8.8 Hz, 1H), 5.16 (d, J = 13.9 Hz, 1H), 4.20 (d, J =
13
13.9 Hz, 1H), 2.41 (s, 3H), 1.70 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.3, 147.7, 142.2, 137.8,
136.1, 134.7, 132.7, 131.6, 130.6, 130.1, 129.5, 129.4, 129.3, 128.7, 128.5, 127.8, 121.1, 51.8, 22.5,
21.8 ppm; IR νmax (film): 3290, 3140, 3076, 3044, 3011, 2900, 1643, 1600, 1590, 1562, 1304, 1298,
1280, 1096, 1160, 11543, 1076, 980, 816, 735, 678, 588, 560 cmꢀ1; HRMS (ESI) m/z calcd for
C24H22ClN4O3S [M+H]+: 481.1101; found: 481.1096.
Synthesis of N-benzyl-N-(3-chloro-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1g): 1g (1.5
g) was obtained in 92% yield as an orange solid; m p 114ꢀ115 oC; 1H NMR (400 MHz, CDCl3) δ 7.98
(d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.48 (dd, J = 8.0, 0.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.31 (t, J =
8.0 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.4 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 6.92 (dd, J =
13
8.0, 0.8 Hz, 1H), 4.73 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H), 2.46 (s, 3H), 1.91 (s, 3H); C
NMR (100 MHz, CDCl3) δ 170.4, 147.6, 143.3, 140.3, 136.4, 135.2, 132.9, 130.9, 130.5, 130.0, 129.1,
129.0, 128.6, 128.4, 128.0, 127.6, 123.6, 52.4, 23.0, 21.8 ppm; IR νmax (film): 3149, 3065, 2954, 2926,
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1669, 1452, 1392, 1343, 1195, 1176, 998, 965, 766, 701, 670, 590, 537 cmꢀ1; HRMS (ESI) m/z calcd
for C24H22ClN4O3S [M+H]+: 481.1101; found: 481.1098.
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Synthesis of N-benzyl-N-(2-chloro-6-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1h): 1h (1.1
g) was obtained in 88% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H),
7.81 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.42 – 7.36(m, 3H), 7.08 (t, J = 7.4 Hz, 1H), 6.95 (t,
J = 7.6 Hz, 2H), 6.88 (d, J = 11.6 Hz, 2H), 5.17 (d, J = 13.8 Hz, 1H), 4.24 (d, J = 13.8 Hz, 1H), 2.46 (s,
3H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 147.5, 142.8, 136.8, 135.2, 134.9, 132.9,
131.2, 131.0, 130.5, 129.9, 129.7, 128.8, 128.4, 128.1, 127.8, 120.9, 51.2, 22.3, 21.8 ppm; IR νmax
(film): 3156, 3105, 2854, 2726, 1696, 1466, 1460, 1366, 1295, 1186, 996, 968, 765, 703, 660, 580, 557
cmꢀ1; HRMS (ESI) m/z calcd for C24H22ClN4O3S [M+H]+: 481.1101; found: 481.1096.
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Synthesis of N-benzyl-N-(5-fluoro-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1i): 1i (1.04
g) was obtained in 82% yield as an orange solid; m p 110ꢀ111 oC; 1H NMR (400 MHz, CDCl3) δ 8.09
(dd, J = 8.8, 6.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.24 – 7.12
(m, 4H), 7.10 (dd, J = 7.6, 1.2 Hz, 2H), 6.64 (dd, J = 8.9, 2.6 Hz, 1H), 5.19 (d, J = 13.9 Hz, 1H), 4.25
(d, J = 13.9 Hz, 1H), 2.45 (s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 162.8 (d, 1JCꢀF
=
251.3 Hz), 147.6, 142.5, 140.9, 140.8, 136.0, 132.9, 131.4, 131.3, 130.5, 129.3, 128.7, 128.6, 128.0,
124.3, 124.3, 120.3, 117.4, 117.2, 116.4, 116.2, 51.9, 22.4, 21.8 ppm; IR νmax (film):3356, 3308, 3147,
2926, 2852, 1663, 1593, 1431, 1392, 1293, 1202, 1179, 990, 813, 747, 703, 672, 625, 584, 542 cmꢀ1;
HRMS (ESI) m/z calcd for C24H22FN4O3S [M+H]+: 465.1397; found: 465.1390.
Synthesis of N-benzyl-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)-4-(trifluoromethyl)phenyl)acet-
o
amide (1j): 1j (900 mg) was obtained in 92% yield as an orange solid; m p 79ꢀ80 C; 1H NMR (400
MHz, CDCl3) δ 8.38 (s, 1H), 8.08 – 7.90 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H),
7.23 – 7.14 (m, 3H), 7.07–7.10 (m, 3H), 5.22 (dd, J = 14.0, 1.2 Hz, 1H), 4.27 (d, J = 14.0 Hz, 1H),
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2.44 (s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 147.8, 142.3, 142.0, 136.0, 132.6,
131.1, 130.6, 129.3, 128.9, 128.7, 128.6, 128.0, 127.6, 127.4, 127.0, 126.9, 126.8, 126.3, 123.3 (q, 1JCꢀF
= 271.1 Hz), 121.2, 51.9, 22.5, 21.8 ppm; IR νmax (film): 3395, 3150, 3090, 3065, 2929, 1668, 1653,
1594, 1394, 1339, 1306, 1266, 1196, 1174, 1131, 1083, 1027, 997, 914, 815, 755, 736, 720, 702, 672,
588, 542 cmꢀ1; HRMS (ESI) m/z calcd for C25H22F3N4O3S [M+H]+: 515.1365; found: 515.1357.
Synthesis of N-benzyl-N-(4-nitro-2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (1k): 1k (1.2 g)
was obtained in 86% yield as an orange solid; m p 143ꢀ144 oC; 1H NMR (400 MHz, CDCl3) δ 8.93 (d,
J = 2.4 Hz, 1H), 8.14 (dd, J = 8.8, 2.4 Hz, 1H), 8.06 – 7.91 (m, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.26 –
7.16 (m, 3H), 7.07 –7.11 (m, 3H), 5.24 (d, J = 14.0 Hz, 1H), 4.30 (d, J = 14.0 Hz, 1H), 2.46 (s, 3H),
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1.75 (s, 3H); C NMR (100 MHz, CDCl3) δ 169.6, 147.9, 147.5, 144.5, 141.4, 135.7, 132.5, 131.7,
130.6, 129.8, 129.3, 128.8, 128.7, 128.2, 125.0, 124.6, 121.4, 51.9, 22.6, 21.9 ppm; IR νmax (film):
3418, 3364, 3334, 3238, 2925, 2854, 2700, 1786, 1616, 1275, 1261, 1177, 1125, 1036, 1011, 763, 749,
683, 569 cmꢀ1; HRMS (ESI) m/z calcd for C24H22N5O5S [M+H]+: 492.1342; found: 492.1334.
Synthesis of N-benzyl-4-methyl-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)benzenesulfon-
amide (1l): 1l (1.0 g) was obtained in 80% yield except that tosyl chloride20 was used to replace the
acetic anhydride as an orange solid; m p 119ꢀ120 oC; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.04
(d, J = 8.3 Hz, 2H), 7.94 (d, J = 6.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.34 (t,
J = 8.9 Hz, 3H), 7.25 (dd, J = 10.8, 3.6 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.90 (t, J = 7.6 Hz, 2H), 6.76
(dd, J = 14.8, 7.6 Hz, 3H), 5.04 (d, J = 12.9 Hz, 1H), 4.20 – 4.04 (m, 1H), 2.47 (s, 3H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 147.2, 144.3, 143.3, 136.5, 135.3, 133.9, 133.5, 131.8, 130.4, 129.8,
129.3, 129.3, 129.0, 128.6, 128.5, 128.2, 128.1, 128.1, 123.1, 56.7, 21.8, 21.6 ppm; IR νmax (film):
3031, 3010, 2924, 2870, 1595, 1442, 1393, 1345, 1195, 1176, 1163, 1091, 1042, 987, 862, 814, 763,
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751, 727, 672, 591, 561, 543 cmꢀ1; HRMS (ESI) m/z calcd for C29H26N4O4S2 [M+H]+: 559.1474;
found: 559.1468.
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Synthesis of N-benzyl-N-methyl-2-(1-tosyl-1H-1,2,3-triazol-4-yl)aniline (1m): 1m (1.0 g) was
obtained in 91% yield except that methylation21 reaction was used instead of acylation reaction as a
yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.22 (dd, J = 7.6, 1.5 Hz, 1H), 7.97 (d, J = 8.4
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Hz, 2H), 7.32 (m, 6H), 7.19 (m, 4H), 4.05 (s, 2H), 2.53 (s, 3H), 2.43 (s, 3H); C NMR (100 MHz,
CDCl3) δ 150.9, 147.1, 144.7, 137.6, 133.4, 130.4, 129.6, 129.1, 128.9, 128.5, 128.4, 127.3, 124.3,
124.1, 122.1, 121.5, 60.5, 41.8, 21.8 ppm; IR νmax (film):3174, 3063, 2921, 2848, 2799, 1595, 1489,
1392, 1194, 1174, 1090, 983, 813, 701, 674, 591, 542 cmꢀ1; HRMS (ESI) m/z calcd for C23H23N4O2S
[M+H]+: 419.1542; found: 419.1538.
Synthesis of N,N-dimethyl-2-(1-tosyl-1H-1,2,3-triazol-4-yl)aniline (1n): 1n (1.16 g) was obtained in
86% yield expect for acylation21 as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.18 (d, J
= 7.6 Hz, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.18 (d, J =
8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 2.63 (s, 6H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.7,
147.2, 144.8, 133.3, 130.4, 129.6, 128.9, 128.5, 123.5, 123.5, 121.9, 119.6, 44.3, 21.8 ppm; IR νmax
(film): 3165, 3033, 2925, 2923, 2789, 1492, 1391, 1200, 1175, 983, 673, 592, 542 cmꢀ1; HRMS (ESI)
m/z calcd for C17H19N4O2S [M+H]+: 343.1229; found: 343.1222.
Synthesis of N-(2-methylbenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4a): 4a
(2.65 g) was obtained in 95% yield as an orange solid; m p 136ꢀ137 oC; 1H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.40 (m, 3H), 7.32 (td, J = 7.6, 1.6 Hz,
1H), 7.08 (m, 1H), 6.99 – 6.87 (m, 4H), 5.04 (d, J = 14.0 Hz, 1H), 4.56 (d, J = 14.0 Hz, 1H), 2.46 (s,
3H), 1.98 (s, 3H), 1.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 147.5, 143.4, 139.3, 137.0,
134.2, 133.0, 130.6, 130.5, 130.2, 130.2, 129.8, 128.8, 128.7, 128.2, 127.8, 125.8, 120.4, 48.7, 22.7,
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21.8, 19.0 ppm; IR νmax (film): 3144, 3064, 2954, 2926, 2861, 1660, 1653, 1444, 1393, 1349, 1176,
1096, 989, 759, 739, 672, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C25H25N4O3S [M+H]+: 461.1647;
found: 461.1645.
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Synthesis of N-(3-methylbenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4b): 4b
(3.12 g) was obtained in 89% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz,
1H), 7.93 (d, J = 8.0 Hz, 2H), 7.86 (s, 1H), 7.36 (t, J = 7.6 Hz, 3H), 7.27 (t, J = 7.2 Hz, 1H), 6.89 –
7.00 (m, 3H), 6.90 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 6.4 Hz, 1H), 5.12 (d, J = 14.0 Hz, 1H), 4.19 (d, J =
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14.0 Hz, 1H), 2.37 (s, 3H), 2.18 (s, 3H), 1.65 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.4, 147.5,
143.4, 139.5, 138.2, 136.4, 132.9, 130.6, 130.2, 130.1, 129.8, 128.9, 128.6, 128.5, 128.3, 127.7, 126.3,
120.7, 52.0, 22.5, 21.8, 21.3 ppm; IR νmax (film): 3142, 3092, 3063, 2925, 2868, 1661, 1594, 1443,
1393, 1199, 1176, 1096, 989, 760, 672, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C25H24N4NaO3S
[M+Na]+: 483.1467; found: 483.1458.
Synthesis of N-(4-methylbenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4c): 4c
(1.02 g) was obtained in 86% yield as an orange solid; m p 114ꢀ115 oC; 1H NMR (400 MHz, CDCl3) δ
8.08 (dd, J = 8.0, 1.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.45 – 7.36 (m, 3H), 7.32 (td, J =
7.6, 1.2 Hz, 1H), 6.98 (s, 4H), 6.91 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 13.8 Hz, 1H), 4.24 (d, J = 13.8 Hz,
1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 147.5, 143.3, 139.4,
137.5, 133.3, 133.0, 130.5, 130.2, 130.2, 129.8, 129.3, 129.1, 128.8, 128.6, 127.7, 120.6, 51.7, 22.5,
21.8, 21.1 ppm; IR νmax (film): 3242, 3098, 3066, 2900, 2878, 1761, 1694, 1543, 1496, 1299, 1076,
1026, 999, 780, 682, 598, 541 cmꢀ1; HRMS (ESI) m/z calcd for C25H25N4O3S [M+H]+: 461.1647;
found: 461.1644.
Synthesis of N-(4-tert-butylbenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4d): 4d
o
(2.0 g) was obtained in 90% yield as an orange solid; m p 101ꢀ102 C; 1H NMR (400 MHz, CDCl3) δ
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8.12 (dd, J = 7.6, 0.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.38 –7.43 (m, 3H), 7.33 (m, 1H),
7.21 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H), 5.17 (d, J = 14.0 Hz, 1H),
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4.21 (d, J = 14.0 Hz, 1H), 2.43 (s, 3H), 1.67 (s, 3H), 1.26 (s, 9H); C NMR (100 MHz, CDCl3) δ
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170.4, 150.7, 147.5, 143.3, 139.5, 133.3, 133.0, 130.6, 130.2, 130.2, 129.8, 129.1, 128.9, 128.7, 127.7,
125.4, 120.7, 51.7, 34.5, 31.3, 22.5, 21.9 ppm; IR νmax (film): 3144, 2962, 2933, 2868, 1662, 1394,
1195, 1176, 1096, 989, 813, 762, 672, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C28H31N4O3S
[M+H]+: 503.2117; found: 503.2111.
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Synthesis of N-(3-methoxybenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4e): 4e
(1.06 g) was obtained in 87% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz,
1H), 7.99 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.39 – 7.45 (m, 3H), 7.33 – 7.36 (m, 1H), 7.09 (t, J = 7.8
Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.77 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 (s, 1H), 6.66 (d, J = 7.6 Hz, 1H),
5.16 (d, J = 13.9 Hz, 1H), 4.25 (d, J = 13.9 Hz, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 1.69 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.4, 159.5, 147.5, 143.3, 139.5, 137.9, 132.8, 130.5, 130.2, 130.1, 129.8, 129.4,
128.9, 128.6, 127.7, 121.5, 120.6, 114.6, 113.5, 55.1, 52.0, 22.4, 21.8 ppm; IR νmax (film): 3000, 2954,
2852, 2839, 2795, 1738, 1161, 1513, 1318, 1248, 1212, 1176, 1123, 1033, 1009, 966, 816, 764, 682,
568 cmꢀ1; HRMS (ESI) m/z calcd for C25H24N4NaO4S [M+Na]+: 499.1416; found: 499.1409.
Synthesis of N-(4-methoxybenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4f): 4f
(1.09 g) was obtained in 85% yield as a yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.5 Hz,
1H), 7.95 (d, J = 7.5 Hz, 2H), 7.79 (s, 1H), 7.36 – 7.41 (m, 3H), 7.31 (t, J = 7.5 Hz, 1H), 7.00 (d, J =
8.0 Hz, 2H), 6.90 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 8.0 Hz, 2H), 5.04 (d, J = 13.9 Hz, 1H), 4.28 (d, J =
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13.9 Hz, 1H), 3.73 (s, 3H), 2.41 (s, 3H), 1.66 (s, 3H); C NMR (125 MHz, CDCl3) δ 170.3, 159.1,
147.4, 143.2, 139.4, 132.9, 130.7, 130.5, 130.1, 129.7, 128.7, 128.6, 128.5, 127.8, 120.5, 113.8, 55.1,
51.4, 22.4, 21.7 ppm; IR νmax (film): 3011, 2900, 2868, 2855, 2800, 1768, 1666, 1613, 1436, 1348,
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1238, 1216, 1166, 1133, 1008, 968, 818, 766, 688, 566 cmꢀ1; HRMS (ESI) m/z calcd for
C25H24N4NaO4S [M+Na]+: 499.1416; found: 499.1408.
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Synthesis of N-(3,5-dimethoxybenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetami-
de(4g): 4g (2.01 g) was obtained in 84% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J
= 7.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.47 – 7.18 (m, 4H), 6.98 (d, J = 7.6 Hz, 1H),
6.36 – 6.13 (m, 3H), 5.01 (d, J = 13.9 Hz, 1H), 4.26 (d, J = 13.9 Hz, 1H), 3.61 (s, 6H), 2.37 (s, 3H),
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1.62 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.3, 160.8, 147.5, 143.4, 139.6, 138.6, 132.9, 130.5,
130.3, 130.0, 129.8, 128.9, 128.6, 127.8, 120.7, 107.1, 100.0, 55.2, 52.3, 22.4, 21.8 ppm; IR νmax (film):
3109, 2933, 2900, 2888, 2816, 1868, 1766, 1656, 1488, 1348, 1338, 1266, 1188, 1133, 1009, 966, 816,
768, 698, 666 cmꢀ1; HRMS (ESI) m/z calcd for C26H26N4NaO5S [M+Na]+: 529.1522; found: 529.1517.
Synthesis of N-(2-chlorobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4h): 4h
(1.08 g) was obtained in 95% yield as an orange solid; m p 118ꢀ119 oC; 1H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 8.8 Hz, 3H), 7.21 – 7.25 (m,
2H), 6.98 – 7.03 (m, 3H), 6.93 (d, J = 8.0 Hz, 1H), 5.15 (d, J = 14.4 Hz, 1H), 4.47 (d, J = 14.4 Hz, 1H),
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2.36 (s, 3H), 1.75 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.8, 147.6, 143.6, 139.3, 134.0, 133.9,
132.8, 131.4, 130.6, 130.3, 130.1, 129.9, 129.2, 129.1, 129.0, 128.6, 127.8, 126.9, 120.7, 48.5, 22.6,
21.8 ppm; IR νmax (film): 3629, 3387, 3322, 3287, 2959, 2926, 2855, 2468, 1662, 1394, 1267, 1199,
1175, 988, 749, 672, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C24H21ClN4NaO3S [M+Na]+: 503.0921;
found: 503.0914.
Synthesis of N-(3-chlorobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4i): 4i (1.08
g) was obtained in 87% yield as an orange solid; m p 129ꢀ130 oC; 1H NMR (400 MHz, CDCl3) δ 8.07
(dd, J = 8.0, 1.2 Hz, 1H), 8.04 – 7.95 (m, 3H), 7.47 – 7.37 (m, 3H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.17
(d, J = 8.4 Hz, 1H), 7.08 – 7.12 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 5.27 (d, J =
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14.4 Hz, 1H), 4.01 (d, J = 14.4 Hz, 1H), 2.44 (s, 3H), 1.73 (s, 3H); C NMR (100 MHz, CDCl3) δ
170.7, 147.6, 143.3, 139.2, 138.6, 134.2, 132.8, 130.6, 130.3, 130.3, 130.0, 129.7, 129.3, 129.1, 128.7,
127.9, 127.5, 120.5, 51.4, 22.5, 21.9 ppm; IR νmax (film): 3149, 3092, 3064, 2927, 2855, 2588, 2285,
1661, 1594, 1490, 1442, 1393, 1349, 1291, 1195, 1176, 1095, 990, 813, 761, 701, 673, 589, 542 cmꢀ1;
HRMS (ESI) m/z calcd for C24H21ClN4NaO3S [M+Na]+: 503.0921; found: 503.0911.
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Synthesis of N-(4-chlorobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4j): 4j
(1.09 g) was obtained in 91% yield as an orange solid; m p 136ꢀ138 oC; 1H NMR (400 MHz, CDCl3) δ
7.95 – 7.97 (m, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.31 – 7.35 (m, 3H), 7.30 – 7.20 (m, 1H), 7.02 (d, J =
8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.87 – 6.79 (m, 1H), 5.11 (d, J = 14.0 Hz, 1H), 4.09 (d, J = 14.0
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Hz, 1H), 2.34 (s, 3H), 1.66 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.6, 147.6, 143.3, 139.2, 135.1,
133.3, 132.7, 130.7, 130.6, 130.3, 130.2, 129.9, 129.0, 128.6, 128.4, 127.5, 120.7, 51.2, 22.4, 21.8 ppm;
IR νmax (film): 3064, 2954, 2924, 2854, 2361, 2325, 1700, 1391, 1347, 1296, 1195, 1176, 1096, 990,
761, 672, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C24H22ClN4O3S [M+H]+: 481.1101; found:
481.1095.
Synthesis of N-(2-fluorobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4k): 4k
(2.01 g) was obtained in 87% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.09 – 7.90 (m, 4H),
7.39 (d, J = 8.0 Hz, 3H), 7.31 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.13 (dd, J = 13.2, 6.4 Hz,
1H), 6.94 (dd, J = 12.4, 7.2 Hz, 2H), 6.75 (t, J = 9.0 Hz, 1H), 5.09 (d, J = 14.2 Hz, 1H), 4.47 (d, J =
14.2 Hz, 1H), 2.42 (s, 3H), 1.75 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.8, 160.9 (d, 1JCꢀF = 245.8
13
Hz), 147.6, 143.4, 139.3, 132.9, 131,9, 131.8, 130.6, 130.2, 130.0, 129.98, 129.7, 129.6, 129.0, 128.7,
127.7, 124.2, 124.2, 123.3, 123.3, 120.6, 115.2, 114.9, 44.8, 44.8, 22.6, 21.8 ppm; IR νmax (film): 3627,
3357, 3318, 2920, 2849, 2257, 1661, 1647, 1492, 1393, 1195, 1176, 990, 759, 672, 589, 542 cmꢀ1;
HRMS (ESI) m/z calcd for C24H21FN4NaO3S [M+Na]+: 487.1216; found: 487.1210.
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Synthesis of N-(3-fluorobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4l): 4l (2.01
g) was obtained in 85% yield as an orange solid; m p 116ꢀ117 oC; 1H NMR (400 MHz, CDCl3) δ 8.07 –
8.00 (m, 1H), 8.00 – 7.92 (m, 3H), 7.37 – 7.41 (m, 3H), 7.26 – 7.30 (m, 1H), 7.15 – 7.04 (m, 1H), 6.85
(m, 4H), 5.22 (d, J = 14.1 Hz, 1H), 4.07 (d, J = 14.1 Hz, 1H), 2.40 (s, 3H), 1.71 (s, 3H); 13C NMR (100
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MHz, CDCl3) δ 170.7, 162.5 (d, JCꢀF = 245.0 Hz) , 147.6, 143.4, 139.3, 139.1, 139.0, 132.8, 130.6,
130.3, 130.2, 130.0, 129.9, 129.9, 129.5, 129.1, 128.6, 127.5, 126.3, 124.9, 124.9, 120.6, 116.2, 115.9,
114.7, 114.5, 51.5, 22.4, 21.8 ppm; IR νmax (film): 3147, 3064, 3037, 2927, 2853, 1660, 1653, 1466,
1393,1348, 1295, 1200, 1176, 990, 761, 672, 588, 542 cmꢀ1; HRMS (ESI) m/z calcd for C24H22FN4O3S
[M+H]+: 465.1397; found: 465.1392.
Synthesis of N-(4-fluorobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4m): 4m
(1.08 g) was obtained in 86% yield as an orange solid; m p 98ꢀ99 C; 1H NMR (400 MHz, CDCl3) δ
o
7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.92 (t, J = 4.2 Hz, 3H), 7.35 (t, J = 8.0 Hz, 3H), 7.27 (ddd, J = 7.6, 6.4,
1.2 Hz, 1H), 7.00 (dd, J = 8.8, 5.6 Hz, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.74 (t, J = 8.6 Hz, 2H), 5.07 (d, J
= 14.0 Hz, 1H), 4.17 (d, J = 14.0 Hz, 1H), 2.36 (s, 3H), 1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.5, 162.1 (d, 1JCꢀF = 244.7 Hz), 147.6, 143.3, 139.2, 132.7, 132.5, 132.4, 131.1, 131.0, 130.6, 130.2,
130.2, 129.8, 128.9, 128.6, 127.6, 120.6, 115.2, 115.0, 51.2, 22.5, 21.7 ppm; IR νmax (film): 3166, 3064,
3044, 2928, 2866, 1666, 1653, 1638, 1468, 1399, 1368, 1296, 1200, 1166, 990, 766, 672, 589, 556,
542 cmꢀ1; HRMS (ESI) m/z calcd for C24H22FN4O3S [M+H]+: 465.1397; found: 465.1390.
Synthesis of N-(2-iodobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4n): 4n (1.08
g) was obtained in 81% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.11 – 7.85 (m, 4H), 7.67
– 7.51 (m, 1H), 7.47 – 7.33 (m, 4H), 7.30 (dd, J = 7.6, 1.4 Hz, 1H), 7.25 – 7.13 (m, 1H), 6.98 – 6.74
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(m, 2H), 5.31 (dd, J = 14.4, 6.4 Hz, 1H), 4.37 (d, J = 14.4 Hz, 1H), 2.44 (s, 3H), 1.81 (s, 3H).; C
NMR (100 MHz, CDCl3) δ 170.9, 147.5, 143.6, 139.2, 139.1, 132.9, 130.8, 130.5, 130.5, 130.3, 130.0,
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129.3, 129.0, 128.7, 128.6, 128.0, 120.6, 100.1, 55.1, 22.5, 21.9 ppm; IR νmax (film): 3122, 3068, 2966,
1665, 1660, 1651, 1396, 1390, 1349, 1328, 1302, 1198, 1176, 1166, 1126, 1096, 1073, 990, 813, 766,
705, 671, 589, 542 cmꢀ1; HRMS (ESI) m/z calcd for C24H22IN4O3S [M+H]+: 573.0451; found:
573.0451.
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Synthesis of N-(2-cyanobenzyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)acetamide (4o): 4o (980
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mg) was obtained in 85% yield as an orange solid; m p 116ꢀ127 C; 1H NMR (400 MHz, CDCl3) δ
8.08 – 7.92 (m, 3H), 7.85 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.45 – 7.30 (m, 6H), 7.27 –
7.24 (m, 1H), 6.92 (d, J = 11.2 Hz, 1H), 5.25 (d, J = 14.6 Hz, 1H), 4.52 (d, J = 14.6 Hz, 1H), 2.42 (s,
3H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 147.6, 143.7, 140.0, 138.9, 133.0, 132.7,
132.3, 130.7, 130.6, 130.3, 130.3, 129.3, 128.7, 128.2, 127.8, 120.8, 116.8, 112.5, 49.3, 22.5, 21.8 ppm;
IR νmax (film): 3096, 3088, 2968, 1666, 1660, 1651, 1496, 1396, 1369, 1326, 1312, 1198, 1186, 1166,
1128, 1074, 998, 816, 766, 676, 588, 541 cmꢀ1; HRMS (ESI) m/z calcd for C25H22N5O3S [M+H]+:
472.1443; found: 472.1438.
Synthesis of N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)ace-
tamide (4p): 4p (1.26 g) was obtained in 86% yield as a yellow oil; 1H NMR (400 MHz, CDCl3) δ
8.07 (d, J = 8.0 Hz, 1H), 8.05 – 7.95 (m, 3H), 7.47 – 7.36 (m, 5H), 7.35 – 7.27 (m, 3H), 6.90 – 6.68 (m,
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1H), 5.35 (d, J = 14.4 Hz, 1H), 4.09 (d, J = 14.4 Hz, 1H), 2.45 (s, 3H), 1.77 (s, 3H); C NMR (100
MHz, CDCl3) δ 170.8, 147.7, 143.4, 139.1, 137.6, 132.8, 130.7, 130.7, 130.6, 130.4, 130.4, 130.3,
130.1, 130.0, 129.2, 129.0, 128.8, 127.5, 126.0, 126.0, 125.9, 125.9, 125.9, 124.9 (q, 1JCꢀF = 269.3 Hz),
124.5, 124.5, 124.5, 124.1, 120.5, 51.4, 22.5, 21.8 ppm; IR νmax (film): 3067, 2828, 1663, 1660, 1650,
1395, 1392, 1349, 1329, 1303, 1196, 1176, 1166, 1124, 1098, 1074, 990, 813, 762, 703, 671, 589, 543
cmꢀ1; HRMS (ESI) m/z calcd for C25H21F3N4NaO3S [M+Na]+: 537.1184; found: 537.1197.
Synthesis of N-(naphthalen-1-ylmethyl)-N-(2-(1-tosyl-1H-1,2,3-triazol-4-yl)phenyl)aceta-
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mide (4q): 4q (1.07 g) was obtained in 87% yield as an orange solid; m p 99ꢀ100 C; 1H NMR (400
MHz, CDCl3) δ 8.13 (dd, J = 8.0, 1.2 Hz, 1H), 7.99 – 7.84 (m, 3H), 7.85 – 7.76 (m, 1H), 7.73 – 7.69
(m, 2H), 7.52 (s, 1H), 7.49 – 7.40 (m, 3H), 7.40 – 7.32 (m, 3H), 7.28 – 7.21 (m, 1H), 6.90 – 6.76 (m,
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1H), 5.52 (d, J = 13.9 Hz, 1H), 4.26 (d, J = 13.9 Hz, 1H), 2.43 (s, 3H), 1.76 (s, 3H); C NMR (100
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MHz, CDCl3) δ 170.7, 147.5, 143.3, 139.3, 134.1, 133.1, 132.9, 132.8, 130.5, 130.3, 130.1, 129.8,
128.9, 128.7, 128.3, 128.3, 127.9, 127.7, 127.6, 127.2, 126.1, 126.0, 120.5, 52.0, 22.5, 21.8 ppm; IR
νmax (film): 3147, 3058, 3030, 2925, 2849, 1661, 1394, 1289, 1195, 1176, 1096, 990, 813, 761, 670,
588, 542 cmꢀ1; HRMS (ESI) m/z calcd for C28H25N4O3S [M+H]+: 497.1647; found: 497.1644.
General procedure for the synthesis of triazole substrates 6a-6h:
To a stirred solution of commercial available compound salicylaldehyde (1.50 g, 12.30 mmol, 1.0
equiv) in THF (60 mL) at 0 °C was added NaH (798 mg, 19.96 mmol, 1.5 equiv, 60% w/w). The
reaction mixture was allowed to warm up to ambient temperature, and stirred for 30 min. Benzyl
bromide (1.36 mL, 15.99 mmol, 1.3 equiv) was added, followed by the addition of tetrabutyl
ammonium iodide (452 mg, 1.23 mmol, 0.1 equiv). Upon TLC showed complete consumption of the
starting material (about 3 h), the reaction was quenched with saturated aqueous ammonium chloride,
extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash column chromatography (PE: EA = 16:1) afforded 2ꢀ(benzyloxy)benzaldehyde 6-113 (1.96 g,
9.23 mmol) in 75% yield as a white oil. 1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 7.89 (dd, J = 7.6,
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1.6 Hz, 1H), 7.57 – 7.50 (m, 1H), 7.48 – 7.36 (m, 5H), 7.10 – 7.01 (m, 2H), 5.18 (s, 2H); C NMR
(100 MHz, CDCl3) δ 189.7, 161.1, 136.1, 136.0, 128.8, 128.4, 128.3, 127.3, 125.2, 121.0, 113.1, 70.5
ppm; IR νmax (film): 3358, 3266, 3146, 3030, 1666, 1586, 1448, 1386, 1368, 1289, 1266, 1226, 1076,
766, 749, 703, 566, 541 cmꢀ1; HRMS (ESI) m/z calcd for C14H12NaO2 [M+Na]+: 235.0735; found:
235.0730.
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To a flame dried roundꢀbottom flask containing CBr4 (6.12g, 18.46 mmol, 2.0 equiv) and PPh3 (9.68g,
36.92 mmol, 4.0 equiv) in DCM (150 mL) was added 2ꢀ(benzyloxy)benzaldehyde 6-1 (1.96 g, 9.23
mmol, 1.0 equiv). The reaction mixture was stirred at 0 °C for 1 h and TLC showed the starting
2ꢀ(benzyloxy)benzaldehyde 6-1 was completely consumed. Then nꢀhexane was added to the reaction
mixture until solid was completely precipitated. The mixture was filtered through celite, and the filtrate
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was concentrated in vacuo. Further purification by flash column chromatography (PE: EA = 30:1) gave
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desired 1ꢀ(benzyloxy)ꢀ2ꢀ(2,2ꢀdibromovinyl)benzene 6-2 (2.87 g, 7.85 mmol) in 85% yield
as a
yellow viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.72 (s, 1H), 7.48 –
7.42 (m, 4H), 7.40 – 7.31 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 155.8, 136.8, 133.0, 130.0, 129.3, 128.7, 128.0, 127.2, 125.0, 120.6, 112.4,
89.9, 70.4 ppm; IR νmax (film): 3460, 3322, 3214, 3166, 3030, 1666, 1586, 1445, 1366, 1332, 1286,
1267, 1216, 1076, 766, 749, 703, 566, 541 cmꢀ1; HRMS (ESI) m/z calcd for C15H12Br2NaO [M+Na]+:
388.9153; found: 388.9156.
To a stirred solution of 1ꢀ(benzyloxy)ꢀ2ꢀ(2,2ꢀdibromovinyl)benzene 6-2 (2.87 g, 7.85 mmol, 1.0 equiv)
in THF (50 mL) at ꢀ78 °C was added CH3Li (12.27 mg, 19.63 mmol, 2.5 equiv. 1.6 M) dropwise
slowly. The reaction mixture was allowed to stir at ꢀ78 °C for 1 h. Upon TLC showed complete
consumption of the starting dibromide product 6-2, the reaction was quenched with saturated aqueous
ammonium chloride, extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated
in vacuo. Purification by flash column chromatography (PE: EA = 50:1) afforded
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1ꢀ(benzyloxy)ꢀ2ꢀethynylbenzene 6-3 (1.23 g, 5.89 mmol) in 75% yield as a colourless oil. 1H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.55 (t, J = 7.4 Hz, 2H), 7.48 (t,
J = 7.3 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H),
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3.56 (s, 1H); C NMR (100 MHz, CDCl3) δ 160.1, 137.1, 134.4, 130.5, 128.9, 128.1, 127.3, 121.1,
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112.9, 112.4, 82.3, 80.6, 70.4 ppm; IR νmax (film): 3268, 3266, 3146, 3030, 1668, 1466, 1458, 1386,
1368, 1287, 1265, 1215, 1060, 749, 703, 666, 541 cmꢀ1; HRMS (ESI) m/z calcd for C15H13O [M+H]+:
209.0966; found: 209.0961.
9
According to the procedure published by Professor Fokin19: To a solution of 1ꢀ(benzyloxy)ꢀ2ꢀethꢀ
ynylbenzene 6-3 (1.23 g, 5.91 mmol, 1.0 equiv) in dry toluene (60 mL) was added copper(I)
thiopheneꢀ2ꢀcarboxylate (CuTc, 112 mg, 0.59 mmol, 0.1 equiv). Then tosyl azide (0.91 mL, 5.91 mmol,
1.0 equiv) was added dropwise at ambient temperature, and the reaction mixture was allowed to stir for
3 h. The reaction was diluted with saturated aqueous ammonium chloride (60 mL), extracted twice
with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash column chromatography (PE: EA = 6:1)
to afford 4ꢀ(2ꢀ(benzyloxy)phenyl)ꢀ1ꢀtosylꢀ1Hꢀ1,2,3ꢀtriazole 6a (2.11 g, 5.20 mmol) in 88% yield as a
white solid; m p 118ꢀ119 oC; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 7.89
(d, J = 8.0 Hz, 2H), 7.47 (s, 5H), 7.33 (d, J = 7.6 Hz, 3H), 7.10 – 7.04 (m, 2H), 5.20 (s, 2H), 2.42 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 155.1, 147.0, 142.9, 136.4, 133.4, 130.3, 129.9, 128.8, 128.4,
128.0, 127.7, 122.4, 121.3, 118.0, 112.1, 70.7, 21.8 ppm; IR νmax (film): 3175, 2988, 2920, 2848, 2587,
1393, 1200, 1174, 985, 812, 752, 701, 670, 590, 539 cmꢀ1; HRMS (ESI) m/z calcd for C22H19N3NaO3S
[M+Na]+: 428.1045; found: 428.1039.
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Synthesis of 4-(2-(3-methylbenzyloxy)phenyl)-1-tosyl-1H-1,2,3-triazole (6b): 6b (1.25 g) was
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obtained in 78 % yield as a white solid; m p 103ꢀ104 C; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H),
8.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.41 – 7.30 (m, 5H), 7.26 (d, J = 7.2 Hz, 2H),
7.07 (dd, J = 12.8, 7.6 Hz, 2H), 5.17 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
155.2, 147.0, 142.9, 138.7, 136.3, 133.4, 130.3, 129.9, 129.2, 128.7, 128.4, 128.4, 128.0, 124.7, 122.5,
121.2, 118.0, 112.1, 70.7, 21.8, 21.5 ppm; IR νmax (film): 3472, 3334, 3176, 3063, 2922, 2588, 2126,
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1594, 1505, 1393, 1325, 1285, 1240, 1194, 1174, 1150, 1085, 1026, 989, 961, 810, 739, 700, 670, 591,
541 cmꢀ1; HRMS (ESI) m/z calcd for C23H22N3O3S [M+H]+: 420.1382; found: 420.1376.
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Synthesis of 4-(2-(4-methylbenzyloxy)phenyl)-1-tosyl-1H-1,2,3-triazole (6c): 6c (1.08 g) was
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obtained in 90 % yield as a white solid; m p 125ꢀ126 C; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H),
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8.33 (dd, J = 7.6, 1.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hz, 5H), 7.30 – 7.27 (m, 2H),
7.07 (dd, J = 14.2, 7.6 Hz, 2H), 5.17 (s, 2H), 2.44 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
155.2, 147.0, 142.9, 138.2, 133.4, 133.4, 130.3, 129.8, 129.5, 128.4, 128.0, 127.7, 122.4, 121.2, 118.1,
112.2, 70.6, 21.8, 21.3 ppm; IR νmax (film): 3355, 3176, 2956, 2900, 2869, 2853, 1742, 1456, 1377,
1287, 1245, 1194, 1175, 1088, 1016, 985, 850, 801, 667, 591 cmꢀ1; HRMS (ESI) m/z calcd for
C23H22N3O3S [M+H]+: 420.1382; found: 420.1376.
Synthesis of 4-(2-(4-tert-butylbenzyloxy)phenyl)-1-tosyl-1H-1,2,3-triazole (6d): 6d (985 mg) was
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obtained in 87 % yield as a white solid; m p 121ꢀ122 C; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H),
8.35 (dd, J = 8.0, 1.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz,
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2H), 7.36 – 7.32 (m, 3H), 7.08 (dd, J = 7.2, 4.4 Hz, 2H), 5.19 (s, 2H), 2.42 (s, 3H), 1.43 (s, 9H); C
NMR (100 MHz, CDCl3) δ 155.3, 151.6, 147.0, 143.0, 133.6, 133.4, 130.4, 129.9, 128.4, 128.0, 127.7,
125.8, 122.6, 121.2, 118.1, 112.2, 70.5, 34.7, 31.4, 21.8 ppm; IR νmax (film): 3175, 2962, 2869, 1500,
1488, 1394, 1246, 1195, 1175, 985, 813, 753, 701, 673, 590, 540 cmꢀ1; HRMS (ESI) m/z calcd for
C26H28N3O3S [M+H]+: 462.1851; found: 462.1847.
Synthesis of 4-(2-(4-methoxybenzyloxy)phenyl)-1-tosyl-1H-1,2,3-triazole (6e): 6e (2.62 g) was
obtained in 90 % yield as a white oil; 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.32 (dd, J = 8.0, 2.0
Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.43 – 7.36 (m, 2H), 7.34 – 7.32 (m, 3H), 7.11 – 7.03 (m, 2H), 7.03
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– 6.96 (m, 2H), 5.13 (s, 2H), 3.88 (s, 3H), 2.43 (s, 3H); C NMR (100 MHz, CDCl3) δ 159.8, 155.2,
147.0, 142.9, 133.4, 130.3, 129.8, 129.4, 128.5, 128.4, 128.0, 122.4, 121.2, 118.1, 114.2, 112.2, 70.5,
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55.4, 21.8 ppm; IR νmax (film): 3852, 3668, 3571, 3147, 2920, 2452, 1500, 1391, 1243, 1174, 986, 810,
753, 670, 589, 546 cmꢀ1; HRMS (ESI) m/z calcd for C23H22N3O4S [M+H]+: 436.1331; found:
436.1324.
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Synthesis of 4-(2-(3,5-dimethoxybenzyloxy)phenyl)-1-tosyl-1H-1,2,3-triazole (6f): 6f (1.85 g) was
obtained in 95 % yield as a white oil; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.33 (d, J = 7.2 Hz,
1H), 7.93 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 3H), 7.16 – 6.88 (m, 2H), 6.61 (s, 2H), 6.53 (s, 1H),
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5.13 (s, 2H), 3.84 (s, 6H), 2.43 (s, 3H); C NMR (100 MHz, CDCl3) δ 161.3, 155.1, 146.9, 142.9,
138.7, 133.4, 130.3, 129.8, 128.5, 128.1, 122.4, 121.3, 118.1, 112.1, 105.5, 100.2, 70.7, 55.4, 21.8 ppm;
IR νmax (film): 3866, 3768, 3591, 3222, 3167, 2929, 2452, 1600, 1500, 1396, 1244, 1176, 966, 810, 756,
677, 589, 546 cmꢀ1; HRMS (ESI) m/z calcd for C24H24N3O5S [M+H]+: 466.1437; found: 466.1427.
Synthesis of 4-(2-(benzyloxy)-5-methylphenyl)-1-tosyl-1H-1,2,3-triazole (6g): 6g (2.24 g) was
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obtained in 90 % yield as a white solid; m p 122ꢀ123 C; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H),
8.15 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.53 – 7.41 (m, 5H), 7.32 (d, J = 8.4 Hz, 2H), 7.12
(dd, J = 8.4, 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.16 (s, 2H), 2.41 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 153.2, 147.0, 143.1, 136.6, 133.4, 130.6, 130.4, 128.8, 128.4, 128.4, 128.4, 127.7,
122.4, 117.7, 112.2, 70.8, 21.8, 20.5 ppm; IR νmax (film): 3852, 3571, 3176, 3030, 2921, 2869, 2125,
1504, 1392, 1284, 1240, 1194, 1174, 989, 962, 810, 739, 700, 670, 590, 541 cmꢀ1; HRMS (ESI) m/z
calcd for C23H22N3O3S [M+H]+: 420.1382; found: 420.1379.
Synthesis of 4-(2-(benzyloxy)-5-chlorophenyl)-1-tosyl-1H-1,2,3-triazole (6h): 6h (2.65 g) was
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obtained in 85 % yield as a white solid; m p 169ꢀ170 C; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H),
8.30 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.51 – 7.40 (m, 5H), 7.34 (d, J = 8.4 Hz, 2H), 7.25
(d, J = 2.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
153.6, 147.1, 141.7, 135.9, 133.2, 130.4, 129.3, 128.9, 128.6, 128.5, 127.7, 127.7, 126.5, 122.8, 119.6,
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113.4, 71.1, 21.8 ppm; IR νmax (film): 3856, 3561, 3166, 3130, 2931, 2889, 2126, 1506, 1395, 1248,
1199, 1172, 990, 957, 809, 726, 674, 591, 539 cmꢀ1; HRMS (ESI) m/z calcd for C22H19ClN3O3S
[M+H]+: 440.0836; found: 440.0830.
9
General procedure for the synthesis of 2,3-disubstituted indoles 2a-2n, 5a-5q: To a solution of
triazole (0.20 mmol, 1.0 equiv) in dry toluene (8 mL) was added Rh2(Oct)4 (7.8 mg, 0.010 mmol, 0.05
equiv) and 4ÅMs (200 wt. %, powder) at room temperature. The resultant mixture was degassed with
nitrogen for 3 times, and then stirred under a balloon pressure of nitrogen at 120 °C for 1 h. The
reaction mixture was cooled down to RT and was degassed with oxygen for 3 times, and then stirred
under a balloon pressure of oxygen at 90 °C for another 1 h. The reaction was worked by removal of
the reaction solvent toluene under vacuum, and the residue was purified by a flash column
chromatography on silica gel to give the corresponding 2,3ꢀdisubstituted indoles.
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Synthesis of N-((1-acetyl-2-phenyl-1H-indol-3-yl)methylene)-4-methylbenzenesulfonam-
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ide (2a): 2a (74 mg) was obtained in 89% yield as a yellow solid; mp: 212ꢀ213 C; H NMR (400
MHz, CDCl3) δ 8.79 (s, 1H), 8.44 (d, J = 6.8 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.2 Hz,
2H), 7.62 – 7.56 (m, 3H), 7.48 – 7.40 (m, 4H), 7.32 (d, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.1, 164.2, 150.0, 144.1, 136.9, 135.9, 130.9, 130.3, 129.7, 129.6, 129.4,
127.7, 126.8, 125.4, 125.3, 122.8, 116.2, 115.4, 27.7, 21.6 ppm; IR νmax (film): 3418, 3386, 3364,
3244, 2923, 1645, 1568, 1449, 1331, 1275, 1153, 1085, 736, 705, 546, 541 cmꢀ1; HRMS (ESI) m/z
calcd for C24H20N2NaO3S [M+Na]+: 439.1092; found: 439.1084
Synthesis
of
N-((1-acetyl-6-methyl-2-phenyl-1H-indol-3-yl)methylene)-4-methylbenzene-
sulfonamide (2b): 2b (76 mg) was obtained in 88% yield as a yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.76 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.65 – 7.54 (m, 3H),
7.46 (d, J = 6.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H), 2.42 (s, 3H),
29
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