Rh(II)-Catalyzed Denitrogenative Transannulation of N-Sulfonyl-1,2,3-Triazolyl Cyclohexadienones for the Synthesis of Benzofurans and Cyclopropa[ cd]indole-carbaldehydes

Article abstract of DOI:10.1021/acs.joc.9b01924

A rhodium-catalyzed intramolecular denitrogenative transannulation of N-sulfonyl-1,2,3-Triazole-Tethered cyclohexadienones has been achieved for the synthesis of benzofurans and cyclopropa[cd]indole-carbaldehydes in an operationally simple procedure. Rema

Full text of DOI:10.1021/acs.joc.9b01924

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Note
Rh(II)-Catalyzed Denitrogenative Transannulation of N-
Sulfonyl-1,2,3-triazolyl Cyclohexadienones for the Synthesis
of Benzofurans and Cyclopropa[cd]indole-carbaldehydes
Chandra Mouleeswara Rao Volla, Geetanjali S. Sontakke, and Kuntal Pal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01924 • Publication Date (Web): 30 Aug 2019
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Rh(II)-Catalyzed Denitrogenative Transannulation of N-Sulfonyl-1,2,3-triazolyl
Cyclohexadienones for the Synthesis of Benzofurans and Cyclopropa[cd]indole-carbaldehydes
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Geetanjali S. Sontakke, Kuntal Pal and Chandra M. R. Volla*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India
Chandra.volla@chem.iitb.ac.in
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RECEIVED DATE
Ts
N
R
X = O
O
O
O
22 examples
Rh(II)
Ts
N
N
-N2
R
X
O
N
N
R
X
Ts
O
X = NTs
R
N
One-pot cascade protocol
Mild reaction conditions
Ts
Good functional group tolerance
3 examples
Abstract: A rhodium-catalyzed intramolecular denitrogenative transannulation of N-sulfonyl-1,2,3-triazole tethered
cyclohexadienones has been achieved for the synthesis of benzofurans and cyclopropa[cd]indole-carbaldehydes in an
operationally simple procedure. Remarkably, the reaction pathway is fully dependent on the linker heteroatom (O or N)
present between the cyclohexadienone unit and triazole moiety. In the case of O-linked triazoles, a cascade sequence
consisting of intramolecular cyclopropanation and rearrangement takes place leading to the formation of benzofurans, while
in case of N-linked triazoles, cyclopropa[cd]indole-carbaldehydes were isolated exclusively.
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Benzofurans are one of the most common oxygen-containing
structural motifs found in many natural products, drugs and
display potent biological activities such as antibacterial,
antifungal, anti-inflammatory and antidiabetic.1 A number of
benzofuran derived drugs such as dronedarone, amiodarone and
benzbromarone are clinically approved for treating various
diseases (Figure 1).2 Also, certain benzofuran derivatives are
studied as imaging agents for detecting aggregates of beta-
amyloid (Aβ) peptides, useful for treating Alzheimer's disease.3
The extraordinary biological and pharmacological activities of
benzofurans have drawn significant attention from the synthetic
community to develop effective and concise approaches for
accessing these skeletons.4 Though, various transition-metal
catalyzed as well as acid and base mediated strategies are
available to synthesize benzofurans, they often suffer from
various disadvantages like complex reaction conditions, low
substrate scope and limited functional-group tolerance. Therefore,
development of an operationally simple and step-economical
method to access these heterocycles is highly desirable.
tool for accessing various oxygen- and nitrogen-containing
heterocycles.5 The highly reactive rhodium azavinyl carbenes
derived via Rh(II)-catalyzed denitrogenative ring-opening of N-
sulfonyl-1,2,3-triazoles readily undergo
a
variety of
transformations including transannulations,6 cycloadditions,7 X–H
bond insertion8 (X = carbon or heteroatoms), and other reactions.9
The versatility of Rh azavinyl carbenes and importance of
benzofurans prompted various groups to study ring-opening of
triazoles as an efficient strategy for the construction of these
building blocks (Scheme 1).
Scheme 1. Overview of the work.
(a) Synthetic routes to benzofurans from N-sulfonyl-1,2,3-triazoles:
N
N
N
Ts
R
O
R1
1. Rh(II)
2. Pd/C
(B)
N
N
O
(A)
(C)
N
Ts
Br
O
Rh(II)/Cu(I)
N
CHO
Rh(II)
O
R
R
OH
Br
O
OH
HO
O2
N
N
R1
heat
O
OH
OMe
H
H
O
N
O
N N
O
MeO
OMe
Ts
O
O
CRA-024781
XH-14
Benzbromarone
Rh(II)/Yb(III)
O2
(D)
I
O
O
O
NH
O
SO2Me
HN
N(nBu)2
O
O
NEt2
N
F
N
I
HO
O
N
N
Ts
O
OH
R1
SO2Me
R
+
HCV-796
Amiodarone
Dronedarone
(b) This work:
Figure 1. Some benzofuran based bioactive compounds.
O
Ts
N
O
R
Recently, Rh(II)-catalyzed ring-opening of N-sulfonyl-1,2,3-
triazoles have gained a lot of attention and emerged as a powerful
Ts
Rh(II)
N
N
R
O
-N2, -H2O
N
O
O
R
N
via
Ts
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In 2015, Shi and co-workers established a simple methodology
We initiated our studies using cyclohexa-2,5-dien-1-one 1a as
for the synthesis of 2-aminobenzofurans from N-propargyl
phenol-derived triazoles by a tandem sequence consisting of
Friedel–Crafts type intramolecular nucleophilic addition to
carbenoids followed by a temperature assisted ring rearrangement
(Scheme 1a, Path A).10 Chen and co-workers disclosed
intramolecular sp3 C–H insertion with ꢀ-imino rhodium carbenes
a model substrate and treated with 2 mol% of Rh(II)-catalyst in
1,2-DCE at 100 oC. We were pleased to observe the clean
formation of 3-imino benzofuran 2a in 74% NMR yield using
catalytic amount of Rh2(Oct)4 after 1 h. Intrigued by this result,
different rhodium catalysts were tested to improve the yield of the
transannulated product 2a. While Rh2(OAc)4 displayed similar
reactivity (72 % NMR yield), Rh2(esp)2 was found to be less
efficient for this transformation (entries 2-3). Only traces of 2a
was detected when Rh2(TFA)4 was used as a catalyst (Table 1,
entry 4). As expected, the reaction was not proceeding in the
absence of catalyst, indicating that rhodium salt was crucial for
the sequence (Table 1, entry 5). Interestingly, by lowering the
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for the construction of benzofuran derivatives (Path B).11
A
similar but step-economic approach to access benzofurans was
reported by Kang and co-workers through Rh(II) and Cu(I)
catalyzed sequential sp3 C–H insertion and aerobic oxidation
(Path C).12 A Rh(II)-catalyzed O-H insertion followed by Yb(III)-
catalyzed cyclization and oxidation sequence of triazoles and
phenols was reported by Anbarasan and co-workers for the
synthesis of benzo/naphthofurans.13 Despite these efficient
methods, development of novel synthetic methods for the
construction of benzofurans are still desirable14 and herein, we
report a new protocol to prepare benzofurans via a Rh(II)-
catalyzed denitrogenative cascade process.
o
temperature to 90 C (entry 6), the yield of 2a was increased to
81% and other solvents like toluene, dichloromethane and
chloroform were screened (Table 1, entries 7−9). Satisfyingly, the
yield was further improved to 86% when chloroform was used as
a solvent and the benzofuran 2a was isolated in 80%. The yield of
2a was decreased to 56% when the reaction was carried out at 70
oC (entry 10). As imines were unstable for long time at room
temperature, we intended to reduce the imine in situ for
evaluating the scope of this current protocol. Using optimized
conditions in entry 9, 2 equiv. of NaCNBH3 was added at the end
of the reaction to isolate 3a in 84% yield (Scheme 2). Thereafter,
all the imines were reduced in one-pot by following the same
procedure.
In the past few years, transition-metal or organo-catalyzed
cascade cyclizations of alkyne tethered-cyclohexadienones via C-
H bond activations and/or carbocyclizations have appeared as a
useful
route
for
the
synthesis
of
functionalized
hydrobenzofurans.15 In 2017, Chegondi’s group developed a
copper-catalyzed three component coupling reaction for the
construction of cis-hydrobenzofurans by reacting alkynyl-
cyclohexadienones with tosyl azide and alcohols.16 At the same
time, Sun and co-workers described a one-pot protocol to access
fused tricyclic compounds by using diazoesters and
cyclohexadienone-tethered terminal alkynes as starting
materials.17 These reactions proceeded through the in situ
formation of tetrasubstituted allenoates followed by an anion
prompted annulation, and oxidative aromatization. These reports
on the cascade cyclizations with cyclohexadienones and our
continuous efforts18 on Rh(II)-catalyzed transannulation reactions,
encouraged us to synthesize cyclohexadienone-linked N-sulfonyl-
1,2,3-triazoles and explore their reactivity in the intramolecular
Rh-catalyzed denitrogenative process.
Scheme 2. In situ reduction of the imine.
O
Ts
NH
Me
Rh2(Oct)4 (2 mol %)
N
CHCl3, 90 oC, 1h
Me
O
O
N
then NaCNBH3 (2 equiv.)
N
Ts
3a, 84%
With the optimized one-pot reaction conditions for the
preparation of 3a in hand, we investigated the substrate scope for
a range of triazolyl-cyclohexadienones 1 (Table 2). Similar to
methyl group, other primary alkyls like ethyl, n-propyl and n-
butyl substituents on the cyclohexadienone moiety were well
tolerated and delivered the corresponding 5-substituted
benzofurans 3b−3d in good yields (75−82%). Notably, by
increasing the bulkiness of R1 substituent (iPr, sBu and tBu) at the
quaternary carbon center, the yields of the corresponding products
3e-3g gradually decreased from 70% to 61% indicating the steric
hindrance for the intramolecular cyclization. We were delighted
to observe that sensitive functional groups like ether (3h),
silyloxy ether (3i), protected amine (3j) on R1 were well tolerated
in the reaction (67−76%). In addition, halogens such as Br and I
on R1 furnished the related products 3k and 3l in 75% and 72%
yields respectively. Furthermore, benzyl and phenyl substituted
cyclohexadienone-tethered triazoles were found to be suitable
substrates for this process. To our delight, triazoles with various
sulfonyl protected groups proceeded equally well to deliver the
benzofurans 3o-3t in similar yields (74-82%). Interestingly, when
tetrahydronapthalenone derivative 1u was used, a mixture of 1:0.9
3u and 3u’ was isolated in 75% yield. Similarly, 3-methyl
substituted triazole 1v led to a 1:1 mixture of 3v and 3v’ in 72%
yield.
Table 1. Optimization of the reaction conditions[a]
O
Ts
N
Me
Rh(II)-Cat. (2 mol %)
temp, solvent, 1 h
N
Me
O
O
N
N
2a
1a
Ts
entry
Rh(II)-cat.
Rh2(Oct)4
Rh2(OAc)4
Rh2(esp)2
Rh2(TFA)4
-
temp (oC)
100
100
100
100
100
90
solvent
DCE
DCE
DCE
DCE
DCE
DCE
yield (%)[b]
74 (71)[c]
1
2
72
3
63
4
<5
5
0
81
6
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
7
90
Toluene
DCM
76
8
80
79
86 (80)[c]
9
90
CHCl3
CHCl3
10
70
56
Reaction conditions: [a] 0.1 mmol of triazole 1a, 2 mol % Rh-
catalyst in 1 mL solvent. [b] NMR yield was taken by using 0.1
mmol of 1,3,5-trimethoxybenzene as an internal standard. [c]
Yield of the product in parenthesis for 0.2 mmol triazole 1a.
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carbaldehyde 5a. To generalize this finding, n-Bu and Ph-
Table 2. Substrate scope of the benzofurans.
O
substituted triazoles were tested and the corresponding tricyclic
aldehydes 5b and 5c were isolated in 88% and 91% respectively.
Protecting group on nitrogen was found to be crucial as N-Boc
linked triazole was inefficient for this transformation and failed to
deliver the aldehyde 5d.
R3
NH
R2
Rh2(Oct)4 (2 mol %)
R1
R2
N
R1
O
CHCl3, 90 oC, 1h
N
O
then NaCNBH3 (2 equiv.)
1
N
R3
3
Ts
Ts
Ts
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NH
NH
NH
Table 3. Substrate scope of the tricyclic aldehydes.
Me
Me
O
Me
O
O
O
O
O
Rh2(Oct)4 (2 mol %)
3c, 82%
3b, 81%
3a, 84%
H
Ts
NH
Ts
NH
Ts
NH
N
R1
N
R2
CHCl3, 90 oC, 1h
N
Me
Me
R1
N
5 R2
N
4
Me
Me
Ts
Me
O
O
O
O
O
O
O
O
O
O
3f, 68%
O
3e, 70%
3d, 75%
Ts
NH
Ts
NH
Ts
NH
H
H
H
H
Me
Me
Me
MeO
TBSO
N
N
N
N
Me
Me
Ph
Me
Ts
Ts
5a, 93%
Boc
5d, 0%
Ts
5c, 91%
O
O
O
5b, 88%
3g, 61%
3h, 71%
3i, 76%
Ts
NH
Ts
NH
Ts
NH
H
N
In order to improve the efficacy of the transformation, a gram-
scale reaction was performed with 1.0 g of 1a using only 0.5
mol% of Rh2(Oct)4 and after 3h at 90 oC, 0.70 g of benzofuran 2a
was isolated in 80% (Scheme 3a). Furthermore, a one-pot reaction
of alkyne 6a and tosyl azide 7 was carried out to synthesize the
benzofuran derivative 2a by combining the Cu(I)-catalyzed
azide−alkyne cycloaddition and Rh(II)-catalyzed denitrogenative
transannulation reaction together in a single step (Scheme 3b).
Pleasingly, the yield of one-pot process was comparable with the
stepwise pathway. The synthetic utility of this protocol was
illustrated by hydrolyzing the imine 2a to 5-methylbenzofuran-3-
carbaldehyde 8 (88% yield) followed by reduction to isolate
synthetically useful (5-methylbenzofuran-3-yl)methanol 9 in 96%
yield (Scheme 3c).
Br
I
Boc
O
O
O
3l, 72%
3j, 67%
3k, 75%
Ts
NH
Ts
NH
O
O
3m, 65%
3n, 73%
Me
t-Bu
Me
Me
O
O
O
S
O
S
NH
S
O
O
NH
NH
Me
Me
Me
O
O
O
3o, 82%
3p,74%
3q, 80%
Scheme 3: Gram-scale synthesis, one-pot protocol and
functionalizations.
OMe
Br
Ph
(a) Gram-scale synthesis
O
O
O
S
NH
S
S
NH
O
O
O
O
Ts
NH
N
Me
Me
Me
Me
Rh2(Oct)4 (0.5 mol %)
N
CHCl3, 90 oC, 3h
O
3r, 82%
O
O
O
Me
O
O
N
3t, 75%
3s, 75%
N
1a, 1.0 g
2a, 0.70 g, 80%
Ts
Ts
NH
(b) One-pot synthesis
Ts
NH
Ts
N
O
CuTc (5 mol %)
Rh2(Oct)4 (2 mol %)
SO2N3
Me
N
+
O
1u
O
N
+
O
O
CHCl3, rt, 1h
then 90 oC, 1h
N
Ts
O
Me
7, (1.2 equiv.)
Me
O
3u:3u', 75% (1:0.9)
2a, 75%
6a
Ts
NH
Ts
NH
(c) Functionalizations
Me
Ts
Me
Me
Me
Me
N
OH
N
O
O
+
Me
N
Me
Me
Me
K2CO3 (4 equiv.)
MeOH/H2O, rt, 0.5h
NaBH4 (1 equiv.)
O
N
O
1v
Ts
MeOH, rt, 1h
O
O
3v:3v', 72% (1:1)
O
9, 96%
8, 88%
2a
Next, we sought to investigate the scope of N-tethered triazolyl-
cyclohexadienones in the denitrogenative transannulation
In order to gain some insights on the reaction mechanism, the
reactivity of 2,6-di-tert-butyl-substituted-cyclohexadienone 1w
was tested under the standard conditions and as expected, no
product formation was observed in 1H-NMR of the crude reaction
mixture, indicating the importance of the proton at the 2nd position
of cyclohexadienone (Scheme 4a). The formation of tricyclic
aldehyde 5 in the case of N-tethered triazoles 4 (Table 3)
4
reactions (Table 3). Interestingly, while using N-tethered triazole
4a, fused tricyclic aldehyde 5a was obtained exclusively in 93%
yield upon treating with 2 mol% Rh2(Oct)4 in CHCl3 at 90 oC. An
intramolecular cyclopropanation of in situ generated α-imino
rhodium carbene with cyclohexadienone followed by imine
hydrolysis led to the formation of tricyclic cyclopropa[cd]indole-
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conveyed substantial synthetic importance to the developed
elimination generates the 3-imino benzofuran 2. If the linker was
methodology and also provided basic information about the
intermediate of reaction mechanism. This inspired us to conduct a
1H NMR study with O-tethered triazole 1 to find more details
about the reaction mechanism (Scheme 4b). When 1a was heated
to 40 oC under the standard conditions, around 30% of fused
tricyclic imine Int. B (vide infra: Scheme 5) was observed after
20 mins and no 2a was detected at this temperature. Continuing
the reaction to 90 mins led to the full conversion of 1a into Int. B.
nitrogen, the imine intermediate (Int. B) undergoes hydrolysis to
afford cyclopropanecarbaldehyde 5. In the case of N-linker,
hydrolysis of imines seems to be faster leading to carbaldehydes
5. In the case of O-linker, ring-opening and intramolecular
nucleophilic addition might be favored because of the more
nucleophiilc nature of oxygen.
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Scheme 5: Proposed mechanism.
o
o
1
O
O
At this point, temperature was raised from 40 C to 90 C and H
NMR indicated the conversion of Int. B into imine 2a at this
temperature. Around 52% of 2a was detected after 30 mins. The
imine intermediate (Int. B) was sensitive and attempted isolation
led to its hydrolysis to afford cyclopropa[cd]benzofuran-
carbaldehyde 10 in 45% (Scheme 4c). The NMR study clearly
indicates that tricyclic imine intermediate Int. B forms at low
H
N
R
5
Ts
H2O
-TsNH2
X = NTs
O
O
O
o
H
temperature (40 C) and on heating undergoes rearrangement to
Ts
Rh(II)
-N2
cyclopropanation
deliver the benzofurans 2.
N
[Rh]
- Rh(II)
N
R
X
R
X
N
R
X
1
A
N
Ts
N
Scheme 4: Mechanistic studies.
B
Ts
X = O
(a)
t-Bu
O
H
Ts
N
t-Bu
HO
O
O
HO
Rh2(Oct)4 (2 mol %)
R
No reaction
N
- H2O
CHCl3, 90 oC, 1h
Me
O
N
N
Ts
N
O
N
1w
Ts
D
2
Ts
C
R
R
(b)
In summary, we have successfully established a Rh(II)-
catalyzed highly efficient and step-economical methodology for
the synthesis of functionalized benzofurans and fused tricyclic
aldehydes from easily preparable N-sulfonyl-1,2,3-triazole
tethered cyclohexadienones. Remarkably, the reactivity pattern of
the substrates fully depends on the connecter atom (O or N atom)
present at the quaternary carbon center of cyclohexa-2,5- dienone
moiety. 5-Substituted benzofurans were formed when the
connecter atom was oxygen, while cyclopropa[cd]indole-
carbaldehydes were observed in case of nitrogen. A diverse range
of benzofurans were isolated in good to excellent yields.
Furthermore, the successive transformations can be easily carried
out in a one pot Cu(I)/Rh(II) process starting from the alkynyl-
cyclohexadienones and tosyl azide. A gram-scale synthesis of 2a
also amplified the impact of this protocol.
2a
52% 2a w.r.t. Int. B
at 90 oC after 2 h
Only Int. B at 40 o
C
after 1.5 h
~30% Int. B w. r. t. 1a at
40 oC after 20 min
1a
EXPERIMENTAL SECTION
Materials and methods:
1a
All reactions were carried out under nitrogen atmosphere in screw
cap reaction tubes and the workups were performed under air. All
the solvents used for the reactions were dried by following the
reported procedures. Reactions were monitored using thin-layer
chromatography (SiO2). A gradient elution using petroleum ether
and ethyl acetate was performed based on Merck aluminium TLC
sheets (silica gel 60F254). TLC plates were visualized with UV
light (254 nm) or KMnO4 stain or Vanillin stain or 2,4-DNP stain.
For column chromatography, silica gel (100–200 mesh) from SRL
Co. was used. NMR studies were performed on Bruker Advance
DPX at 400 MHz (1H) or 500 MHz (1H) and at 100 MHz (13C) or
125 MHz (13C), respectively. Chemical shifts (δ) are reported in
ppm, using the residual solvent peak in CDCl3 (δH = 7.26 and δC
= 77.16) ppm as internal standards, and coupling constants (J) are
given in Hz. HRMS were recorded on Bruker MaXis impact mass
spectrometer using ESI-TOF techniques.
2a
(c)
O
O
O
Rh2(Oct)4 (2 mol %)
H
N
CHCl3, 40 oC, 2h
Me
O
1a
N
O
Me
10, 45%
N
Ts
Based on these control studies and previous literature reports, the
proposed mechanism of this reaction is illustrated in Scheme 5.
Intramolecular cyclopropanation of Rh-azavinyl carbene
intermediate A with the olefin leads to the formation of fused
tricyclic imine Int. B. In case of O-linker, the intermediate B
undergoes cyclopropane ring-opening and proton transfer to form
the alcohol intermediate C. Subsequent intramolecular
nucleophilic addition to the carbonyl group followed by water
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Alkynyl-cyclohexadienone 6a was prepared following the
4-(sec-butyl)-4-((1-tosyl-1H-1,2,3-triazol-4-yl) methoxy)cycloh
reported procedure.19
exa-2,5-dienone (1f): White semi-solid, 0.30 Rf in
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EtOAc:Hexane (1:4), 181 mg, 90% yield. H NMR (400 MHz,
(a) General procedure for the synthesis of N-sulfonyl-1,2,3-
triazolyl O-tethered cyclohexa-2,5-dienones (1).
CDCl3): δ 8.06 (s, 1H), 7.97 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.5
Hz, 2H), 6.74 (d, J = 10.1 Hz, 2H), 6.38 (t, J = 8.7 Hz, 2H), 4.47
(s, 2H), 2.42 (s, 3H), 1.80 – 1.66 (m, 2H), 1.30 – 1.19 (m, 1H),
0.89 (s, 3H), 0.87 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ
185.4, 149.5, 149.1, 147.5, 132.6, 132.2, 130.5, 128.8, 122.1,
79.0, 58.8, 43.5, 23.8, 21.9, 13.4, 12.5. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C20H23N3NaO4S 424.1301; Found 424.1299.
4-(tert-butyl)-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)cycloh
exa-2,5-dienone (1g): White semi-solid 0.29 Rf in EtOAc:Hexane
(1:4), 158 mg, 79% yield. 1H NMR (400 MHz, CDCl3): δ 8.05 (s,
1H), 8.00 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.92 (d, J
= 10.3 Hz, 2H), 6.41 (d, J = 10.3 Hz, 2H), 4.48 (s, 2H), 2.45 (s,
3H), 1.02 (s, 9H). 13C {1H} NMR (100 MHz, CDCl3): δ 184.8,
149.5, 147.6, 145.7, 133.0, 132.7, 130.6, 128.9, 121.8, 80.3, 59.3,
39.7, 25.8, 22.0. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C20H23N3NaO4S 424.1301; Found 424.1307.
In a 50 mL round bottom flask equipped with a magnetic stirrer
bar, O-tethered alkynyl-cyclohexa-2,5-dienone (0.5 mmol, 1.0
equiv.), TsN3 (99 mg, 0.5 mmol, 1.0 equiv.) and CuTc (4.8 mg,
0.025 mmol, 5 mol %) in toluene (10 mL) were placed. The
resulting mixture was stirred for 1-2 h at room temperature. After
completion, the reaction was quenched with saturated aq. NH4Cl
solution, and extracted with EtOAc, the combined organic phases
were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The resulting residue was purified by
recrystallization (Hexane/DCM 19:1) to give the desired product.
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4-methyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)Cyclohexa-
2,5-dienone (1a): White solid, 0.30 Rf in EtOAc:Hexane (1:4),
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174 mg, 97% yield. H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H),
7.97 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 6.81 (d, J = 9.5
Hz, 2H), 6.30 (d, J = 9.5 Hz, 2H), 4.46 (s, 2H), 2.43 (s, 3H), 1.46
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 184.9, 150.8, 147.6,
132.9, 130.7, 130.6, 128.8, 127.6, 122.4, 73.2, 59.1, 26.3, 21.9.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H18N3O4S
360.1012; Found 360.1009.
4-(2-methoxyethyl)-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)
cyclohexa-2,5-dienone (1h): White semi-solid, 0.22 Rf in
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EtOAc:Hexane (1:4), 181 mg, 90% yield. H NMR (500 MHz,
CDCl3): δ 8.07 (s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3
Hz, 2H), 6.82 (d, J = 10.2 Hz, 2H), 6.31 (d, J = 12.1 Hz, 2H), 4.46
(s, 2H), 3.39 (t, J = 6.2 Hz, 2H), 3.20 (s, 3H), 2.41 (s, 3H), 2.00 (t,
J = 6.2 Hz, 2H). 13C {1H} NMR (125 MHz, CDCl3): δ 185.1,
149.9, 147.5, 132.9, 131.1, 130.5, 128.7, 127.5, 122.3, 74.8, 67.2,
58.7, 58.5, 39.5, 21.8. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C19H21N3NaO5S 426.1094; Found 426.1094.
4-ethyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)Cyclohexa-2,5-
dienone (1b): White semi-solid, 0.31 Rf in EtOAc:Hexane (1:4),
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173 mg, 93% yield. H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H),
7.96 (d, J = 6.6 Hz, 2H), 7.36 (d, J = 6.3 Hz, 2H), 6.75 (d, J = 8.6
Hz, 2H), 6.36 (d, J = 8.8 Hz, 2H), 4.48 (s, 2H), 2.42 (s, 3H), 1.79
(q, J = 6.3 Hz, 2H), 0.81 (t, J = 6.3 Hz, 3H). 13C {1H} NMR (100
MHz, CDCl3): δ 185.2, 150.1, 147.6, 145.0, 132.9, 131.9, 130.5,
128.8, 122.3, 76.9, 59.0, 32.3, 21.9, 7.9. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C18H19N3NaO4S 396.0988; Found 396.0990.
4-propyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy) cyclohexa-
2,5-dienone (1c): Yellow semi-solid, 0.35 Rf in EtOAc:Hexane
(1:4), 182 mg, 94% yield. 1H NMR (400 MHz, CDCl3): δ 8.07 (s,
1H), 7.93 (d, J = 6.8 Hz, 2H), 7.34 (d, J = 6.7 Hz, 2H), 6.76 (d, J
= 9.1 Hz, 2H), 6.31 (d, J = 8.9 Hz, 2H), 4.45 (s, 2H), 2.39 (s, 3H),
1.70 (t, J = 9.2 Hz, 2H), 1.24 – 1.19 (m, 2H), 0.83 (t, J = 6.8 Hz,
3H). 13C {1H} NMR (100 MHz, CDCl3): δ 185.2, 150.3, 147.5,
145.0, 132.8, 131.5, 130.5, 128.7, 122.2, 76.3, 58.7, 41.4, 21.8,
16.8, 14.2. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C19H21N3NaO4S 410.1144; Found 410.1139.
4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((1-tosyl-1H-1,2,3-
triazol-4-yl)methoxy) cyclohexa-2,5-dienone (1i): Yellow semi-
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solid, 0.28 Rf in EtOAc:Hexane (1:4), 231 mg, 92% yield. H
NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H),
7.37 (d, J = 7.6 Hz, 2H), 6.85 (d, J = 9.8 Hz, 2H), 6.32 (d, J =
15.3 Hz, 2H), 4.47 (s, 2H), 3.67 (t, J = 5.7 Hz, 3H), 2.43 (s, 3H),
1.98 (t, J = 5.7 Hz, 2H), 0.83 (s, 9H), -0.02 (s, 6H). 13C {1H}
NMR (100 MHz, CDCl3): δ 185.3, 150.2, 147.6, 145.0, 133.0,
131.0, 130.6, 128.8, 127.6, 122.2, 75.0, 58.7, 57.9, 42.9, 25.9,
21.9, 18.2, -5.4. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C24H33N3NaO5SSi 526.1802; Found 526.1797.
tert-butyl (2-(4-oxo-1-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)
cyclohexa-2,5-dien-1-yl)ethyl)carbamate (1j): Yellow semi-solid,
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0.17 Rf in EtOAc:Hexane (1:4), 212 mg, 87% yield. H NMR
(400 MHz, CDCl3): δ 8.07 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.30
(d, J = 8.1 Hz, 2H), 6.77 (d, J = 10.1 Hz, 2H), 6.27 (d, J = 10.0
Hz, 2H), 4.95 (t, J = 8.0 Hz, 1H), 4.40 (s, 2H), 2.35 (s, 3H), 1.90
(q, J = 7.2 Hz, 2H), 1.31 (s, 9H), 1.14 (t, J = 7.2 Hz, 2H). 13C
{1H} NMR (100 MHz, CDCl3): δ 184.6, 155.6, 149.2, 147.4,
144.7, 132.6, 131.4, 130.4, 128.5, 122.3, 79.1, 74.9, 58.6, 39.4,
35.6, 28.2, 21.7. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C23H28N4NaO6S 511.1621; found 511.1615.
4-butyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy) cyclohexa2,5-
dienone (1d): Yellow semi-solid, 0.33 Rf in EtOAc:Hexane (1:4),
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181 mg, 90% yield. H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H),
7.97 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 6.77 (d, J = 9.6
Hz, 2H), 6.34 (d, J = 9.4 Hz, 2H), 4.48 (s, 2H), 2.42 (s, 3H), 1.76
(t, J = 7.5 Hz, 2H), 1.28 – 1.19 (m, 4H), 0.84 (t, J = 5.7 Hz, 3H).
13C {1H} NMR (100 MHz, CDCl3): δ 185.2, 150.3, 147.5, 145.1,
133.1, 131.7, 130.5, 128.8, 122.2, 76.4, 58.9, 39.2, 25.6, 22.9,
21.9, 13.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C20H24N3O4S 402.1482; Found 402.1485.
4-(2-bromoethyl)-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)
cyclohexa-2,5-dienone (1k): White semi-solid, 0.30 Rf in
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EtOAc:Hexane (1:4), 206 mg, 91% yield. H NMR (400 MHz,
4-isopropyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)cyclohex
a-2,5-dienone (1e): White solid, 0.32 Rf in EtOAc:Hexane (1:4),
CDCl3): δ 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.9
Hz, 2H), 6.83 (d, J = 9.9 Hz, 2H), 6.41 (d, J = 10.0 Hz, 2H), 4.48
(s, 2H), 3.33 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H), 2.35 (t, J = 8.0 Hz,
2H). 13C {1H} NMR (125 MHz, CDCl3): δ 184.6, 148.6, 147.7,
132.9, 132.2, 130.6, 128.9, 122.40, 122.37, 75.5, 58.9, 42.9, 25.4,
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180 mg, 93% yield. H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H),
7.97 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.7 Hz, 2H), 6.76 (d, J = 9.8
Hz, 2H), 6.40 (d, J = 9.8 Hz, 2H), 4.47 (s, 2H), 2.43 (s, 3H), 2.06
– 1.97 (m, 1H), 0.93 (s, 3H), 0.91 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3): δ 185.3, 149.2, 147.5, 132.9, 132.5, 130.5, 128.8,
78.9, 59.0, 36.6, 21.9, 17.1. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C19H21N3NaO4S 410.1144; Found 410.1146.
22.0. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for
C18H18BrN3NaO4S 474.0093; found 474.0090.
4-(2-iodoethyl)-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)
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cyclohexa-2,5-dienone (1l): White solid, 0.31 Rf in
EtOAc:Hexane (1:4), 239 mg, 96% yield H NMR (400 MHz,
115.2, 73.2, 59.1, 56.1, 26.4. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C17H18N3O5S 376.0961; Found 376.0961.
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CDCl3): δ 8.08 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.1
Hz, 2H), 6.79 (t, J = 11.2 Hz, 2H), 6.41 (d, J = 10.2 Hz, 2H), 4.47
(s, 2H), 3.06 (t, J = 8.0 Hz, 2H), 2.44 (s, 3H), 2.37 (t, J = 8.0 Hz,
2H). 13C {1H} NMR (100 MHz, CDCl3): δ 184.6, 148.6, 147.7,
144.5, 132.8, 132.3, 130.6, 128.8, 122.4, 76.6, 58.9, 44.1, 22.0,
4-((1-((4-bromophenyl)sulfonyl)-1H-1,2,3-triazol-4-yl)meth
oxy)-4-methylcyclohexa-2,5-dienone (1s): White solid, 0.32 Rf in
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EtOAc:Hexane (1:4), 193 mg, 91% yield. H NMR (400 MHz,
CDCl3): δ 8.08 (s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7
Hz, 2H), 6.82 (d, J = 10.1 Hz, 2H), 6.33 (d, J = 10.1 Hz, 2H), 4.48
(s, 2H), 1.48 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 184.9,
150.7, 145.2, 135.0, 133.4, 131.8, 130.9, 130.2, 122.4, 73.3, 59.1,
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-4.4. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for
C18H18IN3NaO4S 521.9954; Found 521.9956.
4-benzyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)cyclohexa-
2,5-dienone (1m): White semi-solid, 0.35 Rf in EtOAc:Hexane
(1:4), 197 mg, 91% yield. 1H NMR (400 MHz, CDCl3): δ 8.01 (s,
1H), 7.98 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.26 –
7.22 (m, 3H), 7.16 – 7.11 (m, 2H), 6.76 (d, J = 10.2 Hz, 2H), 6.28
(d, J = 10.2 Hz, 2H), 4.48 (s, 2H), 3.04 (s, 2H), 2.44 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3): δ 184.8, 149.5, 147.5, 145.3,
134.4, 133.0, 131.6, 130.8, 130.5, 128.8, 128.1, 127.3, 122.2,
76.0, 59.2, 46.2, 21.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
C23H22N3O4S 436.1325; Found 436.1325.
26.4. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for
C16H14BrN3NaO4S 445.9780; Found 445.9778.
4-((1-([1,1'-biphenyl]-4-ylsulfonyl)-1H-1,2,3-triazol-4-yl)meth
oxy)-4-methylcyclohexa-2,5-dienone (1t): White solid, 0.31 Rf in
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EtOAc:Hexane (1:4), 179 mg, 85% yield. H NMR (400 MHz,
CDCl3): δ 8.16 (d, J = 8.6 Hz, 2H), 8.13 (s, 1H), 7.77 (d, J = 8.6
Hz, 2H), 7.57 (dd, J = 8.0, 1.3 Hz, 2H), 7.52 – 7.42 (m, 3H), 6.83
(d, J = 10.2 Hz, 2H), 6.34 (d, J = 10.2 Hz, 2H), 4.49 (s, 2H), 1.47
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 184.9, 150.8, 149.0,
145.0, 138.5, 134.3, 130.8, 129.4, 129.3, 128.5, 127.5, 122.4,
73.3, 59.1, 26.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H20N3O4S 422.1169; Found 422.1165.
1-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-[1,1'-biphenyl]-
4(1H)-one (1n): White solid, 0.31 Rf in EtOAc:Hexane (1:4), 200
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mg, 95% yield. H NMR (500 MHz, CDCl3): δ 8.16 (s, 1H), 8.01
4a-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-5,6,7,8-tetrahydro
naphthalen-2(4aH)-one (1u): White solid, 0.21 Rf in
(d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.4 Hz, 2H), 7.41 – 7.33 (m, 5H),
6.87 (d, J = 9.8 Hz, 2H), 6.42 (d, J = 9.8 Hz, 2H), 4.74 (s, 2H),
2.46 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 185.3, 149.5,
147.6, 137.7, 132.9, 130.6, 130.3, 129.0, 128.8, 128.7, 127.6,
125.8, 122.4, 76.8, 58.8, 21.9. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C22H20N3O4S 422.1169; Found 422.1169.
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EtOAc:Hexane (1:4), 170 mg, 85% yield. H NMR (500 MHz,
CDCl3): δ 8.07 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0
Hz, 2H), 6.72 (d, J = 10.0 Hz, 1H), 6.32 (d, J = 9.9 Hz, 1H), 6.23
(s, 1H), 4.35 (d, J = 11.9 Hz, 1H), 4.23 (d, J = 12.0 Hz, 1H), 2.48
– 2.42 (m, 4H), 2.35 (d, J = 12.3 Hz, 1H), 2.17 (d, J = 13.6 Hz,
1H), 2.00 (d, J = 11.8 Hz, 1H), 1.89 (d, J = 13.4 Hz, 1H), 1.60 (d,
J = 12.9 Hz, 1H), 1.24 (s, 1H), 0.86 (t, J = 6.9 Hz, 1H). 13C {1H}
NMR (125 MHz, CDCl3): δ 185.9, 162.3, 150.4, 147.6, 133.0,
131.2, 130.6, 128.9, 126.9, 122.2, 74.3, 57.9, 39.3, 32.6, 28.1,
21.9, 20.4. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C20H21N3NaO4S 422.1145; Found 422.1147.
3,4-dimethyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy) cycloh
exa-2,5-dienone (1v): White solid, 0.31 Rf in EtOAc:Hexane
(1:4), 168 mg, 90% yield. 1H NMR (400 MHz, CDCl3): δ 8.06 (s,
1H), 7.97 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 6.9 Hz, 2H), 6.81 (d, J
= 9.7 Hz, 1H), 6.29 (d, J = 9.6 Hz, 1H), 6.20 (s, 1H), 4.37 (d, J =
11.7 Hz, 1H), 4.21 (d, J = 11.7 Hz, 1H), 2.43 (s, 3H), 2.01 (s, 3H),
1.39 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 185.3, 159.7,
151.2, 147.6, 144.5, 132.9, 130.5, 130.4, 129.4, 128.8, 122.3,
75.1, 58.6, 25.6, 21.9, 18.0. HRMS (ESI-TOF) m/z: [M+K]+
Calcd for C18H19KN3O4S 412.0728; Found 412.0725.
4-methyl-4-((1-(phenylsulfonyl)-1H-1,2,3-triazol-4-yl)metho
xy)cyclohexa-2,5-dienone (1o): White solid, 0.35 Rf in
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EtOAc:Hexane (1:4), 150 mg, 87% yield. H NMR (400 MHz,
CDCl3): δ 8.16 – 8.05 (m, 3H), 7.72 (t, J = 7.4 Hz, 1H), 7.59 (t, J
= 7.7 Hz, 2H), 6.82 (d, J = 10.0 Hz, 2H), 6.31 (d, J = 10.0 Hz,
2H), 4.47 (s, 2H), 1.43 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3)
δ 185.0, 150.9, 145.0, 136.0, 135.9, 130.7, 130.0, 128.8, 122.5,
73.2, 59.0, 26.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H16N3O4S 346.0856; Found 346.0861.
4-((1-(mesitylsulfonyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-meth
ylcyclohexa-2,5-dienone (1p): White solid, 0.35 Rf in
EtOAc:Hexane (1:4), 174 mg, 90% yield.1H NMR (400 MHz,
CDCl3): δ 8.13 (s, 1H), 7.02 (s, 2H), 6.84 (d, J = 10.1 Hz, 2H),
6.33 (d, J = 10.0 Hz, 2H), 4.50 (s, 2H), 2.66 (s, 6H), 2.32 (s, 3H),
1.48 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 184.9, 150.9,
146.4, 142.1, 132.8, 130.8, 73.3, 59.2, 26.4, 23.3, 21.4. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C19H21N3NaO4S 410.1144;
Found 410.1148.
2,6-di-tert-butyl-4-methyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)m
ethoxy)cyclohexa-2,5-dienone (1w): White solid, 0.35 Rf in
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4-((1-((4-(tert-butyl)phenyl)sulfonyl)-1H-1,2,3-triazol-4-
yl)methoxy)-4-methylcyclohexa-2,5-dienone (1q): White semi-
EtOAc:Hexane (1:4), 211 mg, 90% yield. H NMR (500 MHz,
CDCl3): δ 8.07 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2
Hz, 2H), 6.44 (s, 2H), 4.39 (s, 2H), 2.43 (s, 3H), 1.39 (s, 3H), 1.19
(s, 18H). 13C {1H} NMR (125 MHz, CDCl3): δ 185.8, 149.2,
147.5, 141.7, 133.0, 130.5, 130.4, 128.8, 122.0, 73.1, 58.4, 35.0,
29.6, 27.3, 21.9. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C25H33N3NaO4S 494.2083; Found 494.2091.
1
solid, 0.31 Rf in EtOAc:Hexane (1:4), 170 mg, 85% yield. H
NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H),
7.59 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 10.2 Hz, 2H), 6.32 (d, J =
9.9 Hz, 2H), 4.48 (s, 2H), 1.47 (s, 3H), 1.32 (s, 9H). 13C {1H}
NMR (100 MHz, CDCl3): δ 184.9, 160.4, 150.8, 144.9, 132.9,
130.8, 128.8, 127.1, 122.4, 73.3, 59.1, 35.7, 31.0, 26.4. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for
Found 402.1479.
C20H24N3O4S 402.1482;
(b) General procedure for the synthesis of N-sulfonyl-1,2,3-
triazolyl N-tethered cyclohexa-2,5-dienones (4).
4-((1-((4-methoxyphenyl)sulfonyl)-1H-1,2,3-triazol-4-yl)meth
In a 50 mL round bottom flask equipped with a magnetic stirrer
bar, N-tethered alkynyl-cyclohexa-2,5-dienone (0.5 mmol, 1.0
equiv.), TsN3 (99 mg, 0.5 mmol, 1.0 equiv.) and CuTc (4.8 mg,
0.025 mmol, 5 mol %) in toluene (10 mL) were placed. The
resulting mixture was stirred for 1-2 h at room temperature. After
completion, the reaction was quenched with saturated aq. NH4Cl
solution, and extracted with EtOAc, the combined organic phases
oxy)-4-methylcyclohexa-2,5-dienone (1r): White solid, 0.25 Rf in
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EtOAc:Hexane (1:4), 173 mg, 92% yield. H NMR (500 MHz,
CDCl3): δ 8.09 (s, 1H), 8.05 (d, J = 6.9 Hz, 2H), 7.04 (d, J = 7.9
Hz, 2H), 6.85 (d, J = 9.7 Hz, 2H), 6.34 (d, J = 8.8 Hz, 2H), 4.49
(s, 2H), 3.90 (s, 3H), 1.49 (s, 3H). 13C {1H} NMR (125 MHz,
CDCl3): δ 185.0, 165.6, 150.9, 144.8, 131.4, 130.8, 126.8, 122.2,
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were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The resulting residue was purified by
recrystallization (Hexane/DCM 19:1) to give the desired product.
21.8, 21.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H16NO3S 314.0845; Found 314.0849.
4-methyl-N-((5-methylbenzofuran-3-yl)methyl)benzenesulfona
mide (3a): White solid, 0.45 Rf in EtOAc:Hexane (1:4), 53 mg,
84% yield, mp = 140-142 oC. 1H NMR (400 MHz, CDCl3): δ 7.76
(d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 7.31 – 7.26 (m, 3H), 7.14 (s,
1H), 7.08 (dd, J = 8.4, 1.6 Hz, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.22
(d, J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.39 (s, 3H). 13C {1H} NMR
(100 MHz, CDCl3): δ 154.0, 143.8, 143.1, 136.7, 132.5, 129.8,
127.4, 126.4, 126.2, 119.5, 115.7, 111.2, 37.5, 21.7, 21.4. HRMS
(ESI-TOF) m/z: [M+K]+ Calcd for C17H17KNO3S 354.0561;
Found 354.0563.
N-((5-ethylbenzofuran-3-yl)methyl)-4-methylbenzenesulfona
mide (3b): Off-white solid, 0.51 Rf in EtOAc:Hexane (1:4), 53
mg, 81% yield, mp = 120-122 oC. 1H NMR (400 MHz, CDCl3): δ
7.76 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.35 – 7.26 (m, 3H), 7.15
(s, 1H), 7.12 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 4.73 (t, J = 5.5 Hz, 1H),
4.24 (d, J = 5.8 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.43 (s, 3H),
1.24 (t, J = 7.6 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3):
δ154.2, 143.8, 143.2, 139.2, 136.8, 129.9, 127.4, 126.4, 125.2,
118.3, 115.8, 111.4, 37.6, 28.9, 21.7, 16.5. HRMS (ESI-TOF)
m/z: [M+K]+ Calcd for C18H19KNO3S 368.0717; Found
368.0710.
4-methyl-N-((5-propylbenzofuran-3-yl)methyl)benzenesulfona
mide (3c). Off-white solid, 0.50 Rf in EtOAc:Hexane (1:4), 56
mg, 82% yield, mp = 107-109 oC. 1H NMR (400 MHz, CDCl3): δ
7.77 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H), 7.31 (t, J = 8.9 Hz, 3H),
7.13 (s, 1H), 7.10 (dd, J = 8.4, 1.5 Hz, 1H), 4.62 (s, 1H), 4.25 (d,
J = 5.6 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 2.43 (s, 3H), 1.65 – 1.62
(m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C {1H} NMR (100 MHz,
CDCl3): δ 154.2, 143.8, 143.2, 137.6, 136.8, 129.9, 127.4, 126.3,
125.7, 118.9, 115.7, 111.3, 38.1, 37.6, 25.3, 21.7, 14.0. HRMS
(ESI-TOF) m/z: [M+K]+ Calcd for C19H21KNO3S 382.0873;
Found 382.0871.
4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)-N-((1-
tosyl-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide
(4a):
White solid, 0.32 Rf in EtOAc:Hexane (1:4), 244 mg, 95% yield.
1H NMR (500 MHz, CDCl3): δ 8.24 (s, 1H), 8.00 (d, J = 8.2 Hz,
2H), 7.51 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.20 (d, J
= 8.0 Hz, 2H), 6.89 (d, J = 10.0 Hz, 2H), 6.09 (d, J = 10.0 Hz,
2H), 4.59 (s, 2H), 2.46 (s, 3H), 2.40 (s, 3H), 1.51 (s, 3H). 13C
{1H} NMR (125 MHz, CDCl3): δ 184.3, 150.8, 147.6, 144.3,
138.8, 133.1, 130.7, 130.6, 130.0, 128.9, 128.4, 127.4, 123.9,
60.6, 42.1, 26.2, 22.0, 21.7. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C24H25N4O5S2 513.1260; Found 513.1253.
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N-(1-butyl-4-oxocyclohexa-2,5-dien-1-yl)-4-methyl-N-((1-tosyl-
1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (4b): White
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solid, 0.33 Rf in EtOAc:Hexane (1:4), 250 mg, 90% yield. H
NMR (500 MHz, CDCl3): δ 8.27 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H),
7.49 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.9
Hz, 2H), 6.80 (d, J = 10.0 Hz, 2H), 6.14 (d, J = 9.9 Hz, 2H), 4.62
(s, 2H), 2.46 (s, 3H), 2.40 (s, 3H), 1.90 – 1.83 (m, 2H), 1.10 –
1.03 (m, 2H), 0.93 – 0.88 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H). 13
C
{1H} NMR (125 MHz, CDCl3): δ 184.8, 148.9, 147.6, 144.3,
138.7, 133.1, 130.6, 129.84, 129.82, 128.9, 127.5, 124.0, 64.5,
41.8, 36.7, 26.1, 22.5, 22.0, 21.7, 13.7. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C27H30N4NaO5S2 577.1549; Found 577.1551.
4-methyl-N-(4-oxo-1,4-dihydro-[1,1'-biphenyl]-1-yl)-N-((1-tosyl-
1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (4c): White
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solid, 0.31 Rf in EtOAc:Hexane (1:4), 267 mg, 93% yield. H
NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H),
7.41 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 10.2 Hz, 2H), 7.27 – 7.21
(m, 5H), 7.13 (t, J = 7.6 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.08
(d, J = 10.1 Hz, 2H), 4.54 (s, 2H), 2.46 (s, 3H), 2.37 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3): δ 184.5, 147.6, 147.4, 144.4,
137.5, 137.1, 133.3, 130.7, 129.6, 129.3, 129.2, 129.1, 128.9,
128.4, 128.1, 127.9, 127.2, 65.3, 42.7, 22.0, 21.7. HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C29H26N4NaO5S2 597.1236; Found
597.1239.
N-((5-butylbenzofuran-3-yl)methyl)-4-methylbenzenesulfona
mide (3d): Off-white solid, 0.55 Rf in EtOAc:Hexane (1:4), 54
o
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mg, 75% yield, mp = 93-95 C. H NMR (400 MHz, CDCl3): δ
7.76 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.34 – 7.26 (m, 3H), 7.15
(s, 1H), 7.10 (dd, J = 8.4, 1.2 Hz, 1H), 4.72 (s, 1H), 4.24 (d, J =
5.8 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H), 2.43 (s, 3H), 1.62 – 1.57 (m,
2H), 1.41 – 1.31 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C {1H} NMR
(100 MHz, CDCl3): δ 154.2, 143.8, 143.1, 137.8, 136.8, 129.9,
127.4, 126.4, 125.7, 118.9, 115.8, 111.2, 37.6, 35.7, 34.5, 22.5,
21.7, 14.1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C20H23NNaO3S 380.1290; Found 380.1295.
(c) General procedure for the synthesis of benzofurans:
The substituted N-sulfonyl 1,2,3-triazolyl O-tethered cyclohexa-
2,5-dienone 1, (0.2 mmol, 1.0 equiv.) and Rh2(Oct)4 (3.1 mg,
0.004 mmol, 2 mol %) were taken into an oven-dried screw cap
reaction tube equipped with a stir bar. The tube was evacuated
and refilled with nitrogen three times. Then, chloroform (2 mL)
N-((5-isopropylbenzofuran-3-yl)methyl)-4-methylbenzenesulf
onamide (3e): Off-white solid, 0.52 Rf in EtOAc:Hexane (1:4),
48 mg, 70% yield, mp = 123-125 oC. 1H NMR (400 MHz,
CDCl3): δ 7.76 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.5
Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.20 (s, 1H), 7.16 (dd, J = 8.5,
1.5 Hz, 1H), 4.80 (t, J = 5.7 Hz, 1H), 4.25 (d, J = 5.6 Hz, 2H),
2.99 – 2.90 (m, 1H), 2.42 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3): δ 154.2, 143.9, 143.7, 143.2,
136.8, 129.8, 127.3, 126.3, 123.8, 116.8, 115.9, 111.4, 37.6, 34.3,
24.6, 21.6. HRMS (ESI-TOF) m/z: [M+K]+ Calcd for
C19H21KNO3S 382.0873; Found 382.0877.
N-((5-(sec-butyl)benzofuran-3-yl)methyl)-4-methylbenzene
sulfonamide (3f): White solid, 0.51 Rf in EtOAc:Hexane (1:4),
48 mg, 68% yield, mp = 87-89 oC. 1H NMR (400 MHz, CDCl3): δ
7.76 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H),
7.26 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.11 (dd, J = 8.5, 2.0 Hz,
1H), 4.93 (s, 1H), 4.25 (d, J = 5.5 Hz, 2H), 2.67 – 2.59 (m, 1H),
2.41 (s, 3H), 1.62 – 1.56 (m, 2H), 1.24 (d, J = 6.9 Hz, 3H), 0.81
o
was added via syringe. The reaction mixture was heated to 90 C
for 1 h using an oil bath. After that NaCNBH3 (0.4 mmol, 2.0
equiv., 25.13 mg) was added to the reaction mixture and further
stirred at room temperature for 1-2h. The resulting mixture was
cooled, evaporated under reduced pressure and the residue was
purified by column chromatography (EtOAc/Hex 1:4) to afford
the respective product.
(E)-4-methyl-N-((5-methylbenzofuran-3-
yl)methylene)benzenesulfonamide (2a): White solid, 0.65 Rf in
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EtOAc:Hexane (1:4), 50 mg, 80% yield, mp = 157-159 C. H
NMR (500 MHz, CDCl3): δ 9.17 (s, 1H), 8.24 (s, 1H), 7.96 (s,
1H), 7.91 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.35 (d, J
= 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H), 2.43 (s, 3H).
13C {1H} NMR (125 MHz, CDCl3): δ 162.3, 156.3, 154.9, 144.6,
135.6, 135.0, 130.0, 128.1, 128.0, 123.2, 123.1, 118.7, 111.3,
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(t, J = 7.3 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 154.2,
143.7, 143.1, 142.7, 136.8, 129.8, 127.3, 126.3, 124.1, 117.5,
115.8, 111.3, 41.8, 37.5, 31.6, 22.5, 21.6, 12.5. HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C20H23NNaO3S 380.1290; Found
380.1293.
N-((5-(tert-butyl)benzofuran-3-yl)methyl)-4-methylbenzenesul
fonamide (3g): White semi-solid, 0.45 Rf in EtOAc:Hexane (1:4),
44 mg, 61% yield. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.1
Hz, 2H), 7.41 (d, J = 3.9 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.25
(dd, J = 6.5, 2.4 Hz, 2H), 4.91 (bs, 1H), 4.26 (d, J = 5.9 Hz, 2H),
2.41 (s, 3H), 1.34 (s, 9H). 13C {1H} NMR (100 MHz, CDCl3): δ
153.8, 146.1, 143.7, 143.2, 136.8, 129.8, 127.3, 126.0, 122.9,
116.0, 115.7, 111.0, 37.5, 34.9, 31.9, 21.6. HRMS (ESI-TOF)
m/z: [M+K]+ Calcd for C20H23KNO3S 396.1030; Found
396.1036.
sulfonamide (3l): Off-white solid, 0.42 Rf in EtOAc:Hexane
o
(1:4), 65 mg, 72% yield, mp = 117-119 C. 1H NMR (400 MHz,
CDCl3): δ 7.76 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J = 8.4
Hz, 1H), 7.31 – 7.27 (m, 2H), 7.17 (d, J = 1.0 Hz, 1H), 7.10 (dd, J
= 8.4, 1.6 Hz, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.24 (d, J = 6.0 Hz,
2H), 3.33 (t, J = 7.8 Hz, 2H), 3.18 (t, J = 7.7 Hz, 2H), 2.44 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3): δ 154.7, 143.9, 143.6,
136.7, 135.6, 129.9, 127.4, 126.7, 125.4, 119.3, 115.9, 111.7,
40.3, 37.5, 21.7, 6.3. HRMS (ESI-TOF) m/z: [M+K]+ Calcd for
C18H18IKNO3S 493.9683; Found 493.9696.
N-((5-benzylbenzofuran-3-yl)methyl)-4-methylbenzenesulfo
namide (3m): White solid, 0.41 Rf in EtOAc:Hexane (1:4), 51
mg, 65% yield, mp = 125-127 oC. 1H NMR (400 MHz, CDCl3): δ
7.73 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H), 7.33 – 7.27 (m, 3H), 7.24 –
7.17 (m, 6H), 7.10 (dd, J = 8.5, 1.6 Hz, 1H), 4.75 (t, J = 6.4 Hz,
1H), 4.23 (d, J = 4.9 Hz, 2H), 4.01 (s, 2H), 2.37 (s, 3H). 13C {1H}
NMR (100 MHz, CDCl3): δ 154.4, 143.8, 143.4, 141.6, 136.7,
136.0, 129.8, 128.9, 128.6, 127.4, 126.6, 126.3, 126.2, 119.6,
115.9, 111.6, 41.9, 37.5, 21.6. HRMS (ESI-TOF) m/z: [M+Na]+
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N-((5-(2-methoxyethyl)benzofuran-3-yl)methyl)-4-methylben
Zenesulfonamide (3h): White solid, 0.42 Rf in EtOAc:Hexane
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(1:4), 51 mg, 71% yield, mp = 93-95 C H NMR (400 MHz,
CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.4
Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.22 (s, 1H), 7.14 (dd, J = 8.4,
1.4 Hz, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.23 (d, J = 5.9 Hz, 2H),
3.59 (t, J = 7.0 Hz, 2H), 3.35 (s, 3H), 2.91 (t, J = 7.0 Hz, 2H),
2.42 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 154.4, 143.8,
143.2, 136.8, 133.8, 129.8, 127.3, 126.5, 126.0, 119.6, 115.9,
111.4, 74.1, 58.8, 37.5, 36.1, 21.6. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C19H21NNaO4S 382.1083; Found 382.1082.
N-((5-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-3-yl)
methyl)-4-methylbenzenesulfonamide (3i): White solid, 0.50 Rf
Calcd for C23H21NNaO3S 414.1134; Found 414.1112.
4-methyl-N-((5-phenylbenzofuran-3-yl)methyl)benzenesulfo
namide (3n): Off-white solid, 0.45 Rf in EtOAc:Hexane (1:4), 55
mg, 73% yield, mp = 137-139 oC. 1H NMR (500 MHz, CDCl3): δ
7.74 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 1.4 Hz, 1H), 7.56 (dd, J =
8.1, 1.0 Hz, 2H), 7.50 (dd, J = 8.6, 1.8 Hz, 1H), 7.48 – 7.43 (m,
4H), 7.37 – 7.34 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 5.02 (t, J = 5.9
Hz, 1H), 4.28 (dd, J = 5.9, 0.5 Hz, 2H), 2.36 (s, 3H). 13C {1H}
NMR (125 MHz, CDCl3): δ 155.1, 143.74, 143.70, 141.4, 136.72,
136.65, 129.8, 128.9, 127.6, 127.3, 127.2, 126.9, 124.6, 118.2,
116.3, 111.8, 37.5, 21.6. HRMS (ESI-TOF) m/z: [M+K]+ Calcd
for C22H19KNO3S 416.0717; Found = 416.0724.
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in EtOAc:Hexane (1:4), 70 mg, 76% yield, mp = 92-94 C H
NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H),
7.32 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.1 Hz 2H), 7.16 (s, 1H),
7.13 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 4.77 (t, J = 5.7 Hz, 1H), 4.23
(d, J = 5.8 Hz, 2H), 3.78 (t, J = 7.0 Hz, 2H), 2.84 (t, J = 7.0 Hz,
2H), 2.43 (s, 3H), 0.87 (s, 9H), -0.02 (s, 6H). 13C {1H} NMR (100
MHz, CDCl3): δ 154.4, 143.8, 143.2, 136.8, 134.0, 129.9, 127.4,
126.4, 126.3, 119.8, 115.8, 111.2, 65.0, 39.5, 37.5, 26.1, 21.7,
18.4, -5.2. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C24H33NNaO4SSi 482.1792; Found 482.1812.
N-((5-methylbenzofuran-3-yl)methyl)benzenesulfonamide (3o):
White semi-solid, 0.50 Rf in EtOAc:Hexane (1:4), 49 mg, 82%
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yield. H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 7.3 Hz, 2H),
7.60 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.39 (s, 1H),
7.30 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J = 8.4, 1.5 Hz,
1H), 4.64 (t, J = 5.4 Hz, 1H), 4.26 (d, J = 5.8 Hz, 2H), 2.39 (s,
2H). 13C {1H} NMR (125 MHz, CDCl3): δ 154.1, 143.2, 139.8,
133.0, 132.6, 129.3, 127.3, 126.4, 126.3, 119.4, 115.6, 111.3,
37.6, 21.4. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C16H15NNaO3S 324.0664; Found 324.0657.
2,4,6-trimethyl-N-((5-methylbenzofuran-3-yl)methyl)benzene
sulfonamide (3p): White solid, 0.45 Rf in EtOAc:Hexane (1:4),
51 mg, 74% yield, mp = 121-123 oC. 1H NMR (500 MHz,
CDCl3): δ 7.39 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 6.1
Hz, 2H), 6.94 (s, 2H), 4.80 (t, J = 5.0 Hz, 1H), 4.18 (d, J = 5.6 Hz,
2H), 2.63 (s, 6H), 2.38 (s, 3H), 2.30 (s, 3H). 13C {1H} NMR (125
MHz, CDCl3): δ 154.0, 143.1, 142.5, 139.3, 133.4, 132.4, 132.1,
126.5, 126.1, 119.3, 115.8, 111.1, 36.9, 23.1, 21.3, 21.0. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C19H21NNaO3S 366.1134;
Found 366.1126.
4-(tert-butyl)-N-((5-methylbenzofuran-3-yl)methyl)benzene
sulfonamide (3q): White solid, 0.47 Rf in EtOAc:Hexane (1:4),
57 mg, 80% yield, mp = 88-90 oC. 1H NMR (500 MHz, CDCl3): δ
7.76 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.37 (s, 1H),
7.27 (d, J = 8.4 Hz, 1H), 7.26 – 7.24 (m, 1H), 7.07 (dd, J = 8.4,
1.6 Hz, 1H), 5.16 (t, J = 5.9 Hz, 1H), 4.23 (d, J = 5.5 Hz, 2H),
2.38 (s, 3H), 1.33 (s, 9H). 13C {1H} NMR (125 MHz, CDCl3): δ
156.6, 153.9, 143.1, 136.6, 132.4, 127.1, 126.5, 126.10, 126.08,
119.6, 115.7, 111.1, 37.5, 35.2, 31.2, 21.4. HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C20H23NNaO3S 380.1290; Found
380.1301.
tert-butyl (2-(3-((4-methylphenylsulfonamido)methyl)benzo
furan-5-yl)ethyl)carbamate (3j): White solid, 0.45 Rf in
o
1
EtOAc:Hexane (1:4), 60 mg, 67% yield, mp = 111-113 C. H
NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.3 Hz, 2H), 7.42 (s, 1H),
7.32 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 8.0 Hz ,2H), 7.21 (s, 1H),
7.09 (dd, J = 8.4 1.7 Hz, 1H), 5.13 (t, J = 7.0 Hz, 1H), 4.60 (s,
1H), 4.21 (d, J = 7.9 Hz, 2H), 3.39 – 3.29 (m, 2H), 2.81 (t, J = 7.0
Hz, 2H), 2.41 (s, 3H), 1.41 (s, 9H). 13C {1H} NMR (125 MHz,
CDCl3): δ 156.1, 154.5, 143.7, 143.4, 136.8, 133.7, 129.8, 127.3,
126.7, 125.8, 119.6, 115.9, 111.6, 79.5, 42.3, 37.5, 36.2, 28.5,
21.6. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H28N2NaO5S
467.1611; Found 467.1618.
N-((5-(2-bromoethyl)benzofuran-3-yl)methyl)-4-methylbenze
nesulfonamide (3k): Off-white solid, 0.43 Rf in EtOAc:Hexane
o
(1:4), 61 mg, 75% yield, mp = 118-120 C. 1H NMR (500 MHz,
CDCl3): δ 7.74 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H), 7.33 (d, J = 8.4
Hz, 1H), 7.25 (d, J = 5.5 Hz, 2H), 7.19 (s, 1H), 7.10 (dd, J = 8.4,
1.6 Hz, 1H), 5.18 (t, J = 5.9 Hz, 1H), 4.22 (d, J = 5.9 Hz, 2H),
3.53 (t, J = 7.6 Hz, 2H), 3.16 (t, J = 7.6 Hz, 2H), 2.41 (s, 3H). 13
C
{1H} NMR (125 MHz, CDCl3): δ 154.6, 143.8, 143.5, 136.7,
133.7, 129.8, 127.2, 126.7, 125.6, 119.6, 115.9, 111.6, 39.3, 37.4,
33.5, 21.6. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C18H18BrNNaO3S 430.0082; Found 430.0086.
N-((5-(2-iodoethyl)benzofuran-3-yl)methyl)-4-methylbenzene
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4-methoxy-N-((5-methylbenzofuran-3-yl)methyl)benzenesulfo
(d)
General
procedure
for
the
synthesis
of
namide (3r): White solid, 0.40 Rf in EtOAc:Hexane (1:4), 54 mg,
82% yield, mp = 177-179 oC. 1H NMR (400 MHz, CDCl3): δ 7.81
(d, J = 8.6 Hz, 2H), 7.40 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.14 (s,
1H), 7.09 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 4.63 (t, J =
4.0 Hz, 1H), 4.22 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 2.39 (s, 3H).
13C {1H} NMR (125 MHz, CDCl3): δ 163.2, 154.1, 143.2, 132.6,
131.3, 129.5, 126.5, 126.2, 119.5, 115.7, 114.4, 111.2, 55.8, 37.6,
21.4. HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C17H17KNO4S
370.0509; Found 370.0516.
4-bromo-N-((5-methylbenzofuran-3-yl)methyl)benzenesulfo
namide (3s): White semi-solid, 0.45 Rf in EtOAc:Hexane (1:4),
57 mg, 75% yield. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.6
Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.43 (s, 1H), 7.31 (d, J = 9.0
Hz, 1H), 7.11 (d, J = 7.1 Hz, 2H), 4.70 (t, J = 5.2 Hz, 1H), 4.27
(d, J = 5.7 Hz, 2H), 2.40 (s, 3H). 13C {1H} NMR (125 MHz,
CDCl3): δ 154.1, 143.3, 139.0, 132.7, 132.5, 128.8, 128.0, 126.4,
126.3, 119.4, 115.4, 111.4, 37.7, 21.4. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C16H14BrNNaO3S 401.9769; Found 401.9780
N-((5-methylbenzofuran-3-yl)methyl)-[1,1'-biphenyl]-4-
sulfonamide (3t): White solid, 0.46 Rf in EtOAc:Hexane (1:4),
57 mg, 75% yield, mp = 140-142 oC. 1H NMR (500 MHz,
CDCl3): δ 7.93 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.60
(d, J = 7.1 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.3 Hz,
2H), 7.29 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.08 (dd, J = 8.4, 1.5
Hz, 1H), 4.72 (t, J = 5.8 Hz, 1H), 4.30 (d, J = 5.2 Hz, 2H), 2.38 (s,
3H). .13C {1H} NMR (125 MHz, CDCl3): δ 154.1, 146.0, 143.2,
139.4, 138.3, 132.6, 129.2, 128.7, 127.8, 127.5, 126.4, 126.3,
119.5, 115.6, 111.3, 37.7, 21.4. HRMS (ESI-TOF) m/z: [M+K]+
Calcd C22H19KNO3S 416.0717; Found 416.0721.
Cyclopropa[cd]indole-carbaldehyde:
The substituted N-sulfonyl 1,2,3-triazolyl N-tethered cyclohexa-
2,5-dienone 4 (0.2 mmol, 1.0 equiv.) and Rh2(Oct)4 (3.1 mg,
0.004 mmol, 2 mol%) in CHCl3 (2 mL) under nitrogen
atmosphere were charged to a reaction tube and the resulting
o
reaction mixture was heated at 90 C for 1h using an oil bath.
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After completion of the reaction, the mixture was cooled and
evaporated under reduced pressure. The residue was purified by
column chromatography (EtOAc/Hex 1:4) to afford the respective
product.
5a-methyl-3-oxo-1-tosyl-2,2a,2a1,2b,3,5a-hexahydro-1H-
cyclopropa[cd]indole-2a-carbaldehyde (5a): White solid, 0.55 Rf
o
1
in EtOAc:Hexane (1:4), 62 mg, 93% yield, mp = 109-111 C. H
NMR (500 MHz, CDCl3): δ 8.97 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.0 Hz, 2H), 6.73 (dd, J = 10.1, 0.7 Hz, 1H), 6.02 (dd,
J = 10.2, 1.0 Hz, 1H), 4.35 (d, J = 11.7 Hz, 1H), 3.11 (d, J = 11.7
Hz, 1H), 2.79 (dd, J = 7.8, 0.7 Hz, 1H), 2.67 (dd, J = 7.8, 0.9 Hz,
1H), 2.43 (s, 3H), 1.94 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3): δ 193.8, 189.3, 147.4, 144.4, 136.9, 130.0, 128.3, 127.5,
62.4, 46.1, 45.4, 43.7, 36.2, 25.3, 21.7. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd. for C17H17NNaO4S 354.0770; Found 354.0775.
5a-butyl-3-oxo-1-tosyl-2,2a,2a1,2b,3,5a-hexahydro-1H-
cyclopropa[cd]indole-2a-carbaldehyde (5b): White solid, 0.61 Rf
in EtOAc:Hexane (1:4), 66 mg, 88% yield. H NMR (500 MHz,
1
CDCl3): δ 8.99 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0
Hz, 2H), 6.70 (d, J = 10.2 Hz, 1H), 6.03 (d, J = 10.1 Hz, 1H), 4.33
(d, J = 11.6 Hz, 1H), 3.11 (d, J = 11.6 Hz, 1H), 2.85 (d, J = 7.8
Hz, 1H), 2.67 (d, J = 7.8 Hz, 1H), 2.42 (s, 4H), 2.15 – 2.08 (m,
1H), 1.47 – 1.35 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H). 13C {1H} NMR
(125 MHz, CDCl3): δ 194.0, 189.6, 147.6, 144.4, 136.8, 129.9,
129.0, 127.6, 66.2, 45.9, 45.6, 41.8, 36.8, 36.2, 27.1, 23.0, 21.7,
14.1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H23NNaO4S
396.1240; Found 396.1240.
4-methyl-N-((5,6,7,8-tetrahydronaphtho[2,3-b]furan-3-
yl)methyl)benzenesulfonamide: 4-methyl-N-((6,7,8,9-tetrahy
dronaphtho[2,1-b]furan-1-yl)methyl)benzenesulfonamide
(Regioisomers (1:0.9 ratio)) (3u): White solid, 0.41 Rf in
o
1
EtOAc:Hexane (1:4), 53 mg, 75% yield, mp = 127-129 C. H
NMR (400 MHz, CDCl3): δ 7.78 – 7.72 (m, 4H), 7.33 (d, J = 10.5
Hz, 2H), 7.31 – 7.26 (m, 4H), 7.15 (d, J = 8.4 Hz, 1H), 7.11 (s,
1H), 7.00 (s, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.71 (t, J = 5.8 Hz,
1H), 4.65 (t, J = 5.6 Hz, 1H), 4.28 (dd, J = 5.7, 0.6 Hz, 2H), 4.20
(dd, J = 5.9, 0.7 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.86 (t, J = 8.0
Hz, 2H), 2.82 – 2.76 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H), 1.83 –
1.74 (m, 8H). 13C {1H} NMR (100 MHz, CDCl3): δ 154.32,
154.27, 143.8, 143.74, 143.71, 142.5, 136.7, 136.6, 134.8, 132.3,
131.5, 130.3, 129.84, 129.82, 127.4, 127.3, 126.7, 124.6, 124.3,
119.1, 116.4, 115.4, 111.1, 109.1, 38.9, 37.6, 30.2, 29.7, 26.5,
23.5, 23.3, 23.1, 23.0, 21.7. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C20H21NNaO3S 378.1134; Found 378.1149.
3-oxo-5a-phenyl-1-tosyl-2,2a,2a1,2b,3,5a-hexahydro-1H-
cyclopropa[cd]indole-2a-carbaldehyde (5c): White solid, 0.32 Rf
in EtOAc:Hexane (1:4), 71 mg, 91% yield. H NMR (400 MHz,
1
CDCl3): δ 8.89 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.46 – 7.33 (m,
6H), 7.27 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 10.3 Hz, 1H), 4.44 (d, J
= 11.4 Hz, 1H), 3.31 (d, J = 11.4 Hz, 1H), 2.86 (d, J = 7.8 Hz,
1H), 2.65 (d, J = 7.8 Hz, 1H), 2.42 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3): δ 193.4, 189.2, 145.2, 144.5, 140.9, 135.9, 129.8,
129.7, 129.0, 128.7, 127.8, 125.7, 67.5, 47.1, 45.5, 45.0, 35.7,
21.7. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H19NNaO4S
416.0927; Found 416.0924.
(e) Gram-scale synthesis:
N-((5,6-dimethylbenzofuran-3-yl)methyl)-4-methylbenzene
sulfonamide: N-((4,5-dimethylbenzofuran-3-yl)methyl)-4-met
hylbenzenesulfonamide (Regioisomers (1:1 ratio)) (3v): White
In a 50 mL round bottom flask equipped with magnetic stirring
bar, was added 1a (1.0 g, 2.78 mmol, 1.0 equiv.), Rh2(Oct)4 (10.8
mg, 0.014 mmol, 0.5 mol%), followed by CHCl3 (20 mL). The
1
semi-solid, 0.45 Rf in EtOAc:Hexane (1:4), 47 mg, 72% yield. H
o
reaction mixture was heated at 90 C for 3h (In oil bath). After
NMR (400 MHz, CDCl3): δ 7.74 (t, J = 7.4 Hz, 3H), 7.33 (d, J =
6.4 Hz, 2H), 7.26 (t, J = 6.7 Hz, 3H), 7.19 (s, 1H), 7.14 (d, J = 8.4
Hz, 1H), 7.10 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.86 (t, J = 5.7 Hz,
1H), 4.81 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 5.7 Hz, 2H), 4.19 (d, J =
5.9 Hz, 2H), 2.41 (d, J = 5.0 Hz, 9H), 2.31 (d, J = 6.6 Hz, 6H),
2.27 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 154.7, 154.6,
143.9, 143.74, 143.68, 142.3, 136.8, 136.6, 134.1, 131.6, 130.9,
129.80, 129.78, 129.3, 127.33, 127.29, 127.1, 125.2, 124.2, 119.7,
116.2, 115.6, 112.0, 108.8, 39.0, 37.6, 21.6, 20.5, 20.0, 19.6, 15.7.
HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C18H19KNO3S
368.0717; Found 368.0724.
completion of the reaction, the resulting mixture was cooled,
evaporated under reduced pressure and the residue was purified
by column chromatography (EtOAc/Hex 1:4) to afford the
respective product 2a with 80% yield (0.7 g).
(f) One-pot synthesis:
6a (32.4 mg, 0.2 mmol, 1.0 equiv.), 7 (47.3 mg, 0.24 mmol, 1.2
equiv.), CuTc (2 mg, 0.01 mmol, 5 mol%), Rh2(Oct)4 (3.1 mg,
0.004 mmol, 2 mol%) and 5 mL CHCl3 were charged to an oven-
dried reaction tube equipped with a stir bar. The reaction mixture
o
was stirred at room temperature for 1h and then heated at 90 C
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for another 1h using an oil bath. The resulting mixture was
SUPPORTING INFORMATION
cooled, evaporated under reduced pressure and the residue was
purified by column chromatography (EtOAc/Hex 1:4) to afford
the respective product 2a (47 mg, 75% yield).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: Copies of H and 13C NMR
1
spectra of all the compounds.
(g) Functionalizations:
Synthesis of 8: To a solution of 2a (126 mg, 0.4 mmol. 1.0
equiv.) in MeOH (10 mL) was added K2CO3 (220 mg, 1.6 mmol,
4.0 equiv.) and H2O (288 mg, 16.0 mmol, 40.0 equiv.), the
resulting reaction mixture was allowed to stir at room temperature
till the complete consumption of starting material (appox. 30
mins.). Filter the reaction mixture to get the crude product 8 as
white solid (56 mg, 88% yield).
ACKNOWLEDGEMENTS
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The activity was generously supported by Department of Science
and Technology, India (TMD/CERI/BEE/2016/098(G)). G.S.S
and K.P. would like to thank CSIR, India for the fellowships.
REFERENCES
5-methylbenzofuran-3-carbaldehyde (8): White solid, 0.85 Rf in
1. (a) Chand, K.; Rajeshwari; Hiremathad, A.; Singh, M.;
Santos, M. A.; Keri, R. S. A Review on Antioxidant Potential
of Bioactive Heterocycle Benzofuran: Natural and Synthetic
Derivatives. Pharmacological Reports 2017, 69, 281–295. (b)
Naik, R.; Harmalkar, D. S.; Xu, X.; Jang, K.; Lee, K.
Bioactive Benzofuran Derivatives: Moracins A–Z in
Medicinal Chemistry. Eur. J. Med. Chem. 2015, 90, 379–393.
2. (a) Saleeb, M.; Mojica, S.; Eriksson, A. U.; Andersson, C. D.;
Gylfe, Å.; Elofsson, M. Natural Product Inspired Library
Synthesis-Identification of 2,3-Diarylbenzofuran and 2,3-
Dihydrobenzofuran Based Inhibitors of Chlamydia
Trachomatis. Eur. J. Med. Chem. 2018, 143, 1077–1089. (b)
Heravi, M. M.; Zadsirjan, V.; Hamidi, H.; Amiri, P. H. T.
Total Synthesis of Natural Products Containing Benzofuran
Rings. RSC Adv. 2017, 7, 24470–24521.
3. Goyal, D.; Kaur, A.; Goyal, B. Benzofuran and Indole:
Promising Scaffolds for Drug Development in Alzheimer’s
Disease. ChemMedChem 2018, 13, 1275–1299.
4. (a) Porcu, S.; Demuro, S.; Luridiana, A.; Cocco, A.; Frongia,
A.; Aitken, D. J.; Charnay-Pouget, F.; Guillot, R.; Sarais, G.;
Secci, F. Brønsted Acid Mediated Cascade Reaction to
Access 3-(2-Bromoethyl)Benzofurans. Org. Lett. 2018, 20,
7699–7702. (b) Yang, D.; Zhu, Y.; Yang, N.; Jiang, Q.; Liu,
R. One-Step Synthesis of Substituted Benzofurans from
1
EtOAc:Heaxane (1:4), 28 mg, 88% yield. H NMR (400 MHz,
CDCl3): δ 10.14 (s, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.41 (d, J =
8.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 2.47 (s, 3H). 13C {1H}
NMR (100 MHz, CDCl3): δ 185.0, 155.7, 154.6, 134.8, 127.6,
123.6, 123.0, 122.4, 111.2, 21.4. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C10H8NaO2 183.0416; Found 183.0420.
Synthesis of 9: The solution of 8 (32 mg, 0.2 mmol, 1.0 equiv.) in
MeOH (5 mL) was allowed to cool at 0 oC with constant swirling
then NaBH4 (8 mg, 0.2 mmol, 1.0 equiv.) was added portion wise
and stirred for 1h at the same temperature. After the completion
of the reaction, the reaction mixture was quenched with saturated
aq. NH4Cl solution, extracted with EtOAc, dried over Na2SO4 and
the combined organic phases were evaporated under vaccuo. The
crude product was purified by column chromatography
(EtOAc/Hex 1:4) to give 9 as white solid (31 mg, 96% yield).
(5-methylbenzofuran-3-yl)methanol (9): White solid, 0.35 Rf in
1
EtOAc:Heaxane (1:4), 31 mg, 96% yield. H NMR (400 MHz,
CDCl3): δ 7.56 (s, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H),
7.13 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 0.6 Hz, 2H), 2.46 (s, 3H),
1.80 (s, 1H). 13C {1H} NMR (100 MHz, CDCl3): δ 154.2, 142.6,
132.4, 126.9, 126.0, 120.2, 119.8, 111.2, 56.1, 21.4. HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C10H10NaO2 185.0573; Found
185.0577.
Ortho-Alkenylphenols
via
Palladium-Catalyzed
C-H
(h) Control experiment:
Functionalization. Adv. Synth. Catal. 2016, 358, 1731–1735.
(c) Deng, G.; Li, M.; Yu, K.; Liu, C.; Liu, Z.; Duan, S.; Chen,
W.; Yang, X.; Zhang, H.; Walsh, P. J. Synthesis of
Reaction of 4-methyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)metho
xy) Cyclohexa-2,5-dienone at 40 oC
1a (72 mg, 0.2 mmol, 1.0 equiv.) and Rh2(Oct)4 (3.1 mg, 0.004
mmol, 2 mol%) in CHCl3 (2 mL) were added to a reaction tube
under nitrogen. The resulting reaction mixture was heated at 40
oC for 2h using an oil bath. The resulting mixture was cooled, the
solvent was evaporated under reduced pressure and purified by
column chromatography (EtOAc/Hex 1:4) to afford the respective
product 10 as white solid (16 mg, 45% yield).
Benzofuran
Derivatives
through
Cascade
Radical
Cyclization/Intermolecular Coupling of 2-Azaallyls. Angew.
Chem. Int. Ed. 2019, 58, 2826–2830. (d) Nagamochi, M.;
Fang, Y.-Q.; Lautens, M. A General and Practical Method of
Alkynyl Indole and Benzofuran Synthesis via Tandem Cu-
and Pd-Catalyzed Cross-Couplings. Org. Lett. 2007, 9, 2955–
2958.
5a-methyl-3-oxo-2,2a,2a1,2b,3,5a-hexahydrocyclopropa[cd]
benzofuran-2a-carbaldehyde (10): White solid, 0.30 Rf in
5. For reviews on Rh-AVC, see: (a) Chattopadhyay, B.;
Gevorgyan, V. Transition-Metal-Catalyzed Denitrogenative
1
EtOAc:Hexane (1:4), 16 mg, 45% yield, mp = 85-87 oC H NMR
Transannulation:
Converting
Triazoles
into
Other
(500 MHz, CDCl3): δ 9.11 (s, 1H), 6.34 (d, J = 10.1 Hz, 1H), 6.14
(d, J = 10.1 Hz, 1H), 4.68 (d, J = 10.9 Hz, 1H), 3.50 (d, J = 10.9
Hz, 1H), 2.92 (d, J = 7.7 Hz, 1H), 2.86 (d, J = 7.6 Hz, 1H), 1.64
(s, 3H). 13C {1H} NMR (125 MHz, CDCl3): δ 194.2, 190.7, 145.3,
128.8, 76.9, 62.8, 55.6, 43.2, 38.9, 25.1. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C10H11O3 179.0702; Found 179.0699.
Heterocyclic Systems. Angew. Chem. Int. Ed. 2011, 51, 862–
872. (b) Gulevich, A. V.; Gevorgyan, V. Versatile Reactivity
of Rhodium-Iminocarbenes Derived from N-Sulfonyl
Triazoles. Angew. Chem. Int. Ed. 2013, 52, 1371–1373. (c)
Davies, H. M. L.; Alford, J. S. Reactions of Metallocarbenes
Derived from N-Sulfonyl-1,2,3-Triazoles. Chem. Soc. Rev.
2014, 43, 5151. (d) Anbarasan, P.; Yadagiri, D.; Rajasekar, S.
Recent
Advances
in
Transition-Metal-Catalyzed
Denitrogenative Transformations of 1,2,3-Triazoles and
Related Compounds. Synthesis 2014, 46, 3004–3023. (e)
Jiang, Y.; Sun, R.; Tang, X.-Y.; Shi, M. Recent Advances in
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
the Synthesis of Heterocycles and Related Substances Based
17, 1830-1833. (d) Miura, T.; Nakamura, T.; Miyakawa, S.;
Murakami, M. A syn-Selective Aza-Aldol Reaction of Boron
Aza-Enolates Generated from N-Sulfonyl-1,2,3-Triazoles and
9-BBN-H. Angew. Chem. Int. Ed. 2016, 55, 8732-8735. (e)
Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.; Fokin,
V. V. Stereoselective 1,3-Insertions of Rhodium(II) Azavinyl
Carbenes. J. Am. Chem. Soc. 2014, 136, 195-202. (f) Kahar,
N. M.; Nabar, K. U.; Jadhav, P. P.; Dawande, S. G.
on α-Imino Rhodium Carbene Complexes Derived from N-
Sulfonyl-1,2,3-triazoles. Chem. Eur. J. 2016, 22, 17910-
17924.
8
9
6. For transannulation: (a) Horneff, T.; Chuprakov, S.;
Chernyak, N.; Gevorgyan, V.; Fokin, V. V. Rhodium-
Catalyzed Transannulation of 1,2,3-Triazoles with Nitriles. J.
Am. Chem. Soc. 2008, 130, 14972–14974. (b) Chattopadhyay,
B.; Gevorgyan, V. Rh-Catalyzed Transannulation of N-Tosyl-
1,2,3-Triazoles with Terminal Alkynes. Org. Lett. 2011, 13,
3746-3749. (c) Schultz, E. E.; Sarpong, R. Application of In
Situ-Generated Rh-Bound Trimethylenemethane Variants to
the Synthesis of 3,4-Fused Pyrroles. J. Am. Chem. Soc. 2013,
135, 4696-4699. (d) Spangler, J. E.; Davies, H. M. L.
Catalytic Asymmetric Synthesis of Pyrroloindolines via a
Rhodium(II)-Catalyzed Annulation of Indoles. J. Am. Chem.
Soc. 2013, 135, 6802-6805. (e) Chuprakov, S.; Kwok, S. W.;
Fokin, V. V. Transannulation of 1-sulfonyl-1,2,3-triazoles
with heterocumulenes. J. Am. Chem. Soc. 2013, 135, 4652-
4655. (f) Yang, J.-M.; Zhu, C.-Z.; Tang, X.-Y.; Shi, M.
Rhodium(II)-Catalyzed Intramolecular Annulation of 1-
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
Rhodium(II)-Catalyzed
Highly
Stereoselective
C3
Functionalization of Indolizines with N-Sulfonyl-1,2,3-
Triazoles. Asian J. Org. Chem. 2018, 8, 79–82.
9. Insertion followed by rearrangement: (a) Miura, T.; Tanaka,
T.; Biyajima, T.; Yada, A.; Murakami, M. One-pot procedure
for the introduction of three different bonds onto terminal
alkynes through N-sulfonyl-1,2,3-triazole intermediates.
Angew. Chem. Int. Ed. 2013, 52, 3883-3886. (b) Jung, D. J.;
Jeon, H. J.; Lee, J. H.; Lee, S. CuI/RhII-Catalyzed Tandem
Convergent Multicomponent Reaction for the Regio- and
Stereocontrolled Synthesis of γ-Oxo-β-amino Esters. Org.
Lett. 2015, 17, 3498-3501. (c) Mi, P.; Kumar, R. K.; Liao, P.;
Bi, X. Tandem O–H Insertion/[1,3]-Alkyl Shift of Rhodium
Azavinyl Carbenoids with Benzylic Alcohols: A Route To
Convert C–OH Bonds into C–C Bonds. Org. Lett. 2016, 18,
4998-5001. (d) Miura, T.; Biyajama, T.; Fujii, T.; Murakami,
M. Synthesis of α-Amino Ketones from Terminal Alkynes via
Rhodium-Catalyzed Denitrogenative Hydration of N-
Sulfonyl-1,2,3-triazoles. J. Am. Chem. Soc. 2012, 134, 194-
196. (e) Pal, K.; Shukla, R. K.; Volla, C. M. R. Rh(II)-
Catalyzed Denitrogenative Reaction of N-Sulfonyl-1,2,3-
triazoles with Isatins for the Construction of Indigoids. Org.
Lett. 2017, 19, 5764-5767. (f) Pal, K.; Hoque, A.; Volla, C.
M. R. Rh-Catalyzed Denitrogenative Reaction of N-Sulfonyl-
Sulfonyl-1,2,3-Triazoles with Pyrrole and Indole Rings:
Facile Synthesis of N-Bridgehead Azepine Skeletons. Angew.
Chem. Int. Ed. 2014, 53, 5142-5146. (g) Miura, T.;
Funakoshi, Y.; Fujimoto, Y.; Nakahashi, J.; Murakami, M.
Facile Synthesis of 2,5-Disubstituted Thiazoles from
Terminal Alkynes, Sulfonyl Azides, and Thionoesters. Org.
Lett. 2015, 17, 2454-2457. (h) Yadagiri, D.; Reddy, A. C. S.;
Anbarasan, P. Rhodium Catalyzed Diastereoselective
Synthesis of 2,2,3,3-Tetrasubstituted Indolines from N-
Sulfonyl-1,2,3-Triazoles and Ortho-Vinylanilines. Chem.
Sci. 2016, 7, 5934–5938.
1,2,3-triazoles with Isatoic Anhydrides and Oxadiazolones.
Chem. - Eur. J. 2018, 24, 2558-2564.
7. Cycloaddition reactions: (a) Chuprakov, S.; Kwok, S. W.;
Zhang, L.; Lercher, L.; Fokin, V. V. Rhodium-Catalyzed
Enantioselective Cyclopropanation of Olefins with N-
Sulfonyl 1,2,3-Triazoles. J. Am. Chem. Soc. 2009, 131,
18034-18035. (b) Grimster, N.; Zhang, L.; Fokin, V. V.
Synthesis and Reactivity of Rhodium(II) N-Triflyl Azavinyl
Carbenes. J. Am. Chem. Soc. 2010, 132, 2510-2511. (c)
Alford, J. S.; Davies, H. M. L. Expanding the Scope of
Donor/Acceptor Carbenes to N-Phthalimido Donor Groups:
Diastereoselective Synthesis of 1-Cyclopropane α-Amino
Acids. Org. Lett. 2012, 14, 6020-6023. (d) Miura, T.; Hiraga,
K.; Biyajima, T.; Nakamuro, T.; Murakami, M.
Regiocontrolled Synthesis of Polysubstituted Pyrroles
Starting from Terminal Alkynes, Sulfonyl Azides, and
Allenes. Org. Lett. 2013, 15, 3298-3301. (e) Wang, Y.; Lei,
X.; Tang, Y. Rh(II)-Catalyzed Cycloadditions of 1-Tosyl
1,2,3-Triazoles with 2H-Azirines: Switchable Reactivity of
Rh-Azavinylcarbene as [2C]- or Aza-[3C]-Synthon. Chem.
Commun. 2015, 51, 4507–4510. (f) Miura, T.; Nakamuro, T.;
Liang, C.-J.; Murakami, M. Synthesis of trans-Cycloalkenes
via Enantioselective Cyclopropanation and Skeletal
Rearrangement. J. Am. Chem. Soc. 2014, 136, 15905-15908.
8. Insertion reactions: (a) Park, S.; Yong, W. S.; Kim, S.; Lee, P.
H. Diastereoselective N-Sulfonylaminoalkenylation of
Azulenes from Terminal Alkynes and Azides via N-Sulfonyl-
1,2,3-triazoles. Org. Lett. 2014, 16, 4468-4471. (b) Yadagiri,
D.; Anbarasan, P. Rhodium Catalyzed Direct Arylation of α-
Diazoimines. Org. Lett. 2014, 16, 2510-2513. (c) Lee, D. J.;
Yoo, E. J. Efficient synthesis of C-N-coupled heterobiaryls by
sequential N-H functionalization reactions. Org. Lett. 2015,
10. Tang, X.-Y.; Zhang, Y.-S.; He, L.; Wei, Y.; Shi, M.
Intramolecular Annulation of Aromatic Rings with N-
Sulfonyl 1,2,3-Triazoles: Divergent Synthesis of 3-
Methylene-2,3-Dihydrobenzofurans and 3-Methylene-2,3-
Dihydroindoles. Chem. Commun. 2015, 51, 133–136.
11. Ma, X.; Wu, F.; Yi, X.; Wang, H.; Chen, W. One-Pot
Synthesis of 2,3-Disubstituted Dihydrobenzofurans and
Benzofurans via Rhodium-Catalyzed Intramolecular C–H
Insertion Reaction. Chem. Commun. 2015, 51, 6862–6865.
12. Li, L.; Xia, X.-H.; Wang, Y.; Bora, P. P.; Kang, Q. Synthesis
of Benzofurans via Tandem Rhodium-Catalyzed C(sp3)-H
Insertion and Copper-Catalyzed Dehydrogenation. Adv. Synth.
Catal. 2015, 357, 2089–2097.
13. Kaladevi, S.; Kamalraj, M.; Altia, M.; Rajasekar, S.;
Anbarasan, P. Cascade Rh(II) and Yb(III) Catalyzed
Synthesis of Substituted Naphthofurans via Transannulation
of N-Sulfonyl-1,2,3-Triazoles with β-Naphthols. Chem.
Commun. 2019, 55, 4507–4510.
14. (a) Zhu, C.-Z.; Wei, Y.; Shi, M. Rhodium(II)-Catalyzed
Intramolecular Transannulation of 4-Methoxycyclohexa-2,5-
dienone Tethered 1-Sulfonyl-1,2,3-triazoles: Synthesis of
Azaspiro[5.5]undecane Derivatives. Adv. Synth. Catal. 2019,
361, 3430-3435. (b) Zhu, C.-Z.; Wei, Y.; Shi, M.
Rhodium(II)-catalyzed Divergent Intramolecular Tandem
Cyclization of N- or O-tethered Cyclohexa-2,5-dienones with
1-Sulfonyl-1,2,3-triazole: Synthesis of Cyclopropa[cd]indole
and benzofuran derivatives. Org. Chem. Front. 2019, 6, 2884-
2891.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 12
1
2
3
4
5
15. (a) Fukui, Y.; Liu, P.; Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.;
Lin, G.-Q. Tunable Arylative Cyclization of 1,6-Enynes
Triggered by Rhodium(III)-Catalyzed C–H Activation. J. Am.
Chem. Soc. 2014, 136, 15607–15614. (b) Gollapelli, K. K.;
Donikela, S.; Manjula, N.; Chegondi, R. Rhodium-Catalyzed
Highly Regio- and Enantioselective Reductive Cyclization of
Alkyne-Tethered Cyclohexadienones. ACS Catal. 2018, 8,
1440–1447. (c) Keilitz, J.; Newman, S. G.; Lautens, M.
Enantioselective Rh-Catalyzed Domino Transformations of
Alkynylcyclohexadienones with Organoboron Reagents. Org.
Lett. 2013, 15, 1148–1151. (d) Takenaka, K.; Mohanta, S. C.;
Sasai, H. Palladium Enolate Umpolung: Cyclative
Diacetoxylation of Alkynyl Cyclohexadienones Promoted by
a Pd/SPRIX Catalyst. Angew. Chem. Int. Ed. 2014, 53, 4675–
4679. (e) Wu, W.; Chen, T.; Chen, J.; Han, X. Cationic
Palladium(II)-Catalyzed Reductive Cyclization of Alkynyl
Cyclohexadienones. J. Org. Chem. 2017, 83, 1033–1040.
16. Anugu, R. R.; Chegondi, R. Tunable Diastereoselective
Desymmetrization of Cyclohexadienones Triggered by
Copper-Catalyzed Three-Component Coupling Reaction. J.
Org. Chem. 2017, 82, 6786–6794.
6
7
8
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
17. Xu, G.; Liu, K.; Sun, J. Divergent Synthesis of Fused
Tricyclic Compounds via a Tandem Reaction from Alkynyl-
Cyclohexadienones and Diazoesters. Org. Lett. 2017, 19,
6440–6443.
18. (a) Pal, K.; Volla, C. M. R. Rhodium-Catalyzed
Denitrogenative
Transannulation
of
1,2,3-Triazolyl-
Carbamates: Efficient Access to 4-Aminooxazolidinones.
Org. Chem. Front. 2017, 4, 1380–1384. (b) Pal, K.; Sontakke,
G. S.; Volla, C. M. R. Rh(II)-Catalyzed Highly
Diastereoselective Cascade Transannulation of N-Sulfonyl-
1,2,3-Triazoles
and
Vinyl
Benzoxazinanones. Org.
Lett. 2019, 21, 3716–3720.
19. Kumar, R.; Hoshimoto, Y.; Tamai, E.; Ohashi, M.; Ogoshi, S.
Two-step Synthesis of Chiral Fused Tricyclic Scaffolds from
Phenols via Desymmetrization on Nickel. Nat Commun. 2017,
8, 32.
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