Cu-Mediated Sulfonyl Radical-Enabled 5- exo-trig Cyclization of Alkenyl Aldehydes: Access to Sulfonylmethyl 1 H -Indenes

Article abstract of DOI:10.1021/acs.joc.8b00341

An efficient method for the construction of sulfonylmethyl 1H-indenes via Cu(I)-mediated sulfonyl radical-enabled 5-exo-trig cyclization of alkenyl aldehydes has been developed for the first time. Mechanistic studies indicated that a radical addition-cycl

Full text of DOI:10.1021/acs.joc.8b00341

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Cu-Mediated Sulfonyl Radical-Enabled 5-exo-trig Cyclization
of Alkenyl Aldehydes: Access to Sulfonylmethyl 1H-Indenes
Jiabin Ni, Yu Xue, Liping Sun, and Ao Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00341 • Publication Date (Web): 28 Mar 2018
Downloaded from http://pubs.acs.org on March 28, 2018
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Cu-Mediated Sulfonyl Radical-Enabled 5-exo-trig
Cyclization of Alkenyl Aldehydes: Access to
Sulfonylmethyl 1H-Indenes
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⊥
⊥
Jiabin Ni,†,‡,#,§ Yu Xue,†,‡, ,§ Liping Sun,*, and Ao Zhang*,†,‡,#
†CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese
Academy of Sciences, Shanghai 201203, China
‡State key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese
Academy of Sciences, Shanghai 201203, China
#University of Chinese Academy of Sciences, Beijing 100049, China
⊥Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
ABSTRACT: An efficient method for the construction of sulfonylmethyl 1Hꢀindenes via Cu(I)ꢀmediated
sulfonyl radicalꢀenabled 5ꢀexoꢀtrig cyclization of alkenyl aldehydes has been developed for the first time.
Mechanistic studies indicated that a radical additionꢀcyclizationꢀelimination (RACE) process might be
involved. The reaction features relatively broad substrate scope, good annulation efficiency and various
functional group tolerance.
INTRODUCTION
Indene derivatives are important cyclic compounds that serve as building blocks for natural products1 and
pharmaceutical compounds2 possessing interesting biological activities, as well as many functional
materials3 (Figure 1). They can also be used as valuable ligands for indenyl metal complexes, which are
widely utilized in various catalytic reactions4. Due to their importance and usefulness, various synthetic
approaches have been developed to construct indene derivatives including intramolecular5 and
intermolecular6 cyclization reactions. In spite of this progress, there is still a need to develop new methods
that can expand the structural scope with wide functionality and use inexpensive catalysts through simple
synthetic manipulations.
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Figure 1. Selected examples of important indenes and sulfones
Meanwhile, sulfonylꢀcontaining compounds are of great importance in functional transformation of many
pharmaceuticals, agrochemicals and materials7, especially for aryl alkyl sulfones8 (Figure 1), however,
available methods to easily accessing alkyl sulfone are limited.9
Recently, Zhu and coworkers10 developed a tandem radical additionꢀcyclizationꢀoxidation (RACO)
reaction process to realize acylalkylation of inactivated alkenes. In this strategy, formation of a nucleophilic
carbon radical favors the intramolecular addition to aldehydes, and subsequent oxidation facilitated a series
of substituted indanones (Scheme 1a).
Scheme 1. Radical initiated cascade reaction of alkenyl aldehydes.
By taking advantage of the powerful radical chemistry11 and in view of the success in using a sulfonyl
radical to attack CꢀC unsaturated bonds to achieve sulfones,12,13 we envisioned that using a sulfonyl radical
other than the alkyl carbon radicals in Zhu’s work would convert the same alkenyl substrates to
acylsulfonylated products I (sulfonylmethyl indenones, Scheme 1b) through a similar RACO cascade
process. Surprisingly, treatment of sulfonyl hydrazide, the sulfonyl radical precursor,12c with
2ꢀallylbenzaldehyde under CuBr/DTBP catalyst/oxidant system14 did not generate the desired I, instead, an
eliminated product II (sulfonylmethyl indene) was obtained as the major product. Herein, we reported
optimization of the reaction condition, exploration of the substrate scope and limitation as well the
discussion of the possible reaction mechanism (RACE cascade reaction).
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RESULTS AND DISCUSSION
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Initially, we commenced the reaction with 2ꢀallyl benzaldehyde (1a) and pꢀtoluenesulfonyl hydrazide (2a)
as model substrates (Table 1). To our delight, product 3a was obtained in 30% yield with CuI as the catalyst,
diꢀtertꢀbutyl peroxide (DTBP) as the oxidant and acetonitrile as the solvent (entry 1). Then effects of copper
salts were investigated, which elected CuBr as the most efficient catalyst, giving 3a in 51% yield (entries
2ꢀ7). Next, an array of different oxidants, such as tertꢀbutyl hydroperoxide (TBHP), tertꢀbutyl
peroxybenzoate (TBPB) and dicumyl peroxide (DCP), were examined and the results were no better than the
case of DTBP (entries 2, 8ꢀ10). In addition, employment of other solvents such as toluene, DMSO, DMF and
1,4ꢀdioxane provided inferior results (entries 11ꢀ14). Further, increasing the loading of CuBr to 50 mol%
slightly promoted the yield (entry 17). From these results, the optimum reaction condition was determined as
those in entry 17.
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Table 1. Optimization of Reaction Conditionsa
entry
1
Catalyst (mol%)
CuI (20)
oxidant
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHPc
TBPB
DCP
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhMe
yield[%]b
30
2
CuBr (20)
51
3
CuCl (20)
17
4
CuOAc (20)
Cu(MeCN)4PF6 (20)
CuSO4 (20)
Cu(OAc)2 (20)
CuBr (20)
6
5
11
6
13
7
Trace
30
8
9
CuBr (20)
39
10
11
12
13
14
15
16
17
18
CuBr (20)
25
CuBr (20)
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
20
CuBr (20)
DMSO
DMF
21
CuBr (20)
13
CuBr (20)
1,4ꢀdioxane
MeCN
MeCN
MeCN
MeCN
17
CuBr (30)
50
CuBr (40)
48
56 (57d,e
)
CuBr (50)
CuBr (60)
52
aReactions were carried out by using 1a (0.10 mmol), 2a (0.20 mmol), Catalyst, Oxidant (0.30 mmol),
o
b
1
solvent (0.5 ml), 100 C, N2, 2h. The yield was determined by H NMR using CH2Br2 as the internal
c
d
e
standard. TBHP (5.5 M in nonane). Isolated yield. 1.0 mmol scale. DTBP: Diꢀtertꢀbutyl peroxide. TBHP:
tertꢀButyl hydroperoxide. TBPB: tertꢀButyl peroxybenzoate. DCP: Dicumyl peroxide.
With the optimized reaction conditions in hand, we evaluated its versatility and limitation in the
Cu(I)ꢀmediated sulfonyl radicalꢀenabled 5ꢀexoꢀtrig cyclization of various alkenyl aldehydes. As illustrated in
Scheme 2, all the reactions went through smoothly and the sulfonated products 3 were obtained in moderate
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yields. The orthoꢀsubstituted aldehydes 1b and 1c were converted into the corresponding products 3b and 3c
in 53% and 34% yield, respectively, implying that the electronic property rather than steric hindrance of the
substituent near the aldehyde group has more impact on the reaction. Substrates 1dꢀk bearing the
electronꢀdonating groups such as MeOꢀ, BnOꢀ, and Meꢀ, or electronꢀwithdrawing groups such as Fꢀ, and Clꢀ,
showed good compatibility, and the corresponding products 3d−k were obtained in 30−57% yields. In
general, substrates having electronꢀdonating substituents went through at higher reactivity, indicating that the
electronic effect of the aldehyde group in substrates has a significant correlation with the reaction efficiency.
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Scheme 2. Substrates Scope for Synthesis of 3a,b
aReactions were carried out by using 1 (0.1 mmol), 2 (0.2 mmol), CuBr (0.05 mmol, 50 mol %), DTBP (0.6
mmol), MeCN (0.5 mL), 100 °C, N2, 2 h. bIsolated yield.
In the meantime, sulfonyl hydrazides bearing different substituents were examined as well.
i
t
Benzenesulfonhydrazide and derivatives with MeOꢀ, Prꢀ, and Buꢀ substituents at the paraꢀposition went
through the reaction smoothly and gave desired products 3lꢀ3o in 32ꢀ46% yields. Halide substituents, such as
Cl and Br, tolerated the standard reaction conditions, thus providing possible access for further functional
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transformations (3pꢀq). However, the yield dropped to 28 % in the case of sulfonyl hydrazide bearing a
bulky biphenyl group (3r).15 Sulfonyl hydrazides with substituents such as Meꢀ or Brꢀ, at the metaꢀposition
also reacted smoothly with substrate 1a and provided corresponding products 3sꢀt in moderate yields. In
addition, naphthaleneꢀ1ꢀsulfonohydrazide also showed good reactivity, giving product 3u in 51% yield.
8
9
More appealingly, the scope of this reaction was not restricted to alkenyl aldehydes as the substrates.
Indeed, 1ꢀ(2ꢀallylphenyl)ethanꢀ1ꢀone 4 was found also suitable for this cascade reaction (Scheme 3), thus
providing disubstituted indenes 5aꢀd, although the yields were relatively lower (31ꢀ38%).
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Scheme 3. Substrates Scope for Synthesis 5a,b
aReactions were carried out by using 4 (0.1 mmol), 2 (0.2 mmol), CuBr (0.05 mmol, 50 mol %), DTBP (0.6
mmol), MeCN (0.5 mL), 100 °C, N2, 2 h. bIsolated yield.
To gain some insights into the reaction mechanism, a series of control experiments were performed
(Scheme 4). First, radical scavenger experiments were implemented. We found that radical scavengers, such
as 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and 1,4ꢀbenzoquinone (BQ), significantly suppressed the
reaction progress, confirming that the proposed radical process is indeed involved (Scheme 4a). During
optimization of reaction conditions, we found that the reaction failed to proceed without either DTBP or
CuBr, and the major byproduct sulfonohydrazone 6 could be isolated in 64ꢀ67% yield (Scheme 4b). This
result suggested that the copper salt and the oxidant DTBP are indispensable for the reaction; otherwise, the
reaction process would stop at the formation of sulfonohydrazone 6. To provide further support for the
reaction pathway, we stopped the reaction at an early stage and found 1a could be completely transformed to
6 (Scheme 4c). Subsequent treatment of 6 with 2a under standard conditions gave the desired product 3a in
42% yield (Scheme 4d), suggesting that the reaction might involve the in situ formation of sulfonohydrazone
6. Sulfonohydrazone 6 was found to proceed alone the cascade reaction very sluggishly under the standard
conditions without addition of 2a, leading to 3a in 10% yield (Scheme 4e), indicating the Ts radical to attack
the terminal vinyl carbon was primarily from another equivalent of 2a, not from the intermediate 6.
Scheme 4. Mechanistic Studies
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O
Ts
standard conditions
TsNHNH2
+
+
H
H
(a)
(b)
2a
TEMPO or BQ
3a, 0%
1a
O
NHTs
H
N
Ts
TsNHNH2
2a
+
3a, 0%
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6
1a
yield of 3a
yield of 6
Standard conditions:
57%
Trace
67%
NO DTBP:
NO CuBr:
0
0
64%
O
standard conditions
5 minutes
Yield of 3a: 0%
Yield of 6:
No observation of 1a
TsNHNH2
2a
+
H
(c)
(d)
76%
1a
6
Ts
standard conditions
TsNHNH2
2a
+
3a, 42%
Ts
standard conditions
6
without TsNHNH2
(e)
3a, 10%
Based on the experiments above and the literature reports,10,13f,14 a proposed mechanism for the current
Cu(I)ꢀmediated sulfonyl radicalꢀenabled cyclization of alkenyl aldehydes is proposed. As shown in Scheme
5, the first step involves formation of sulfonohydrazone 6 from 2ꢀallyl benzaldehyde 1 and sulfonyl
hydrazide 2. In the meantime, sulfonyl radical is formed in situ from the oxidative decomposition of sulfonyl
hydrazide 2 mediated by copper salt and DTBP14, which then attacks the terminal vinyl carbon of substrate 1
to give the nucleophilic alkyl radical Intꢀ1. Subsequent intramolecular 5ꢀexoꢀtrig cyclization and
Hꢀabstraction give the intermediate Intꢀ3, which is then converted to the radical species Intꢀ4 by releasing
the sulfonyl radical and N2.13f Finally, indene 3 is formed from the intermediate Intꢀ4 through a copper
(II)ꢀmediated single electron transfer oxidation to generate a carbocation species, which then undergoes
elimination process via βꢀHꢀabstraction by tBuOꢀ.16 It should be mentioned that the overall moderate yield of
the reaction is likely due to the high reactivity of the alkenyl aldehyde substrates and the incomplete
conversion of the sulfonohydrazone intermediates.
Scheme 5. Proposed Reaction Mechanism
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In conclusion, we have reported a novel and efficient approach to prepare 2ꢀsulfonylmethyl 1Hꢀindene
derivatives via Cu(I)ꢀmediated sulfonyl radicalꢀenabled 5ꢀexoꢀtrig cyclization strategy. The transformation
possesses a relatively broad substrate scope with good functional group compatibility, thus leading to
vinylsulfonylation of inactivated alkenes to yield various sulfonylmethyl indenes. Mechanism study
indicates that the reaction may occur through
additionꢀcyclizationꢀelimination process (RACE).
a tandem cascade process involving radical
EXPERIMENTAL SECTION
General Information. All reactions were performed in flameꢀdried glassware using sealed tubes or
Schleck tubes. Liquids and solutions were transferred with syringes. All solvents and chemical reagents were
1
obtained from commercial sources and used without further purification. H and 13C NMR spectra were
recorded with tetramethylsilane as an internal reference. Lowꢀ and highꢀresolution mass spectra were
recorded on EIꢀTOF (electrospray ionization/timeꢀofꢀflight). Flash column chromatography on silica gel
(200−300 mesh) was used for the routine purification of reaction products. The column output was
monitored by TLC on silica gel (100−200 mesh) precoated on glass plates (15 × 50 mm), and spots were
visualized by UV light at 254 nM. General procedure for the preparation of starting materials 1 and 4 was
according to the literature procedures.10,17 Starting materials arylsulfonyl hydrazides were prepared
according to the literature procedures.18
General Procedure for Synthesis of Sulfonylmethyl 1HꢀIndenes. Example for the Synthesis of 3a. To
an ovenꢀdried 10 mL sealed tube was added substrate 1a (14.6 mg, 0.10 mmol),
4ꢀmethylbenzenesulfonohydrazide 2a (37.2 mg, 0.20 mmol), CuBr (7.2 mg, 0.050 mmol), DTBP (55 ꢁL,
0.30 mmol) and acetonitrile (0.5 mL) under a nitrogen atmosphere. The mixture was stirred for 2 h at 100
oC. The mixture was then cooled to room temperature, diluted with DCM, filtered through a celite pad, and
concentrated in vacuo. The residue was purified by preparative thinꢀlayer chromatography (eluent: PE/DCM
= 2/3), to afford the desired product 3a.
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2ꢀ(Tosylmethyl)ꢀ1Hꢀindene (3a). White solid, yield: 57 % (16.2 mg); mp 173ꢀ174 C. H NMR (300
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MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 7.0 Hz, 1H), 7.31 – 7.26 (m, 3H), 7.25 – 7.16 (m, 2H),
6.58 (s, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.43 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 144.7, 144.0, 143.7,
135.4, 135.2, 134.3, 129.7, 128.4, 126.4, 125.3, 123.7, 121.2, 59.0, 41.5, 21.6; Ms (EI): m/z = 284 [M]+;
HRMS (EI): m/z [M]+ Calcd for C17H16O2S, 284.0866; Found, 284.0874.
o
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4ꢀMethoxyꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3b). White solid, yield: 53 % (16.8 mg); mp 90ꢀ91 C. H NMR
(300 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.20 – 7.13 (m, 1H), 7.04 (d, J = 7.5
Hz, 1H), 6.78 – 6.72 (m, 2H), 4.23 (s, 2H), 3.82 (s, 3H), 3.53 (s, 2H), 2.42 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 153.1, 146.0, 144.7, 135.5, 132.5, 132.2, 131.6, 129.7, 128.3, 126.7, 116.6, 108.4, 59.1, 55.4, 41.8,
21.6; Ms (EI): m/z = 314 [M]+; HRMS (EI): m/z [M]+ Calcd for C18H18O3S, 314.0971; Found, 314.0970.
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4ꢀFluoroꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3c). White solid, yield: 34 % (10.3 mg); mp 135ꢀ136 C. H NMR
(300 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.23 – 7.13 (m, 2H), 6.94 (t, J = 8.7
Hz, 1H), 6.66 (s, 1H), 4.24 (s, 2H), 3.61 (s, 2H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 156.1 (d, J =
249.4 Hz), 147.0 (d, J = 5.5 Hz), 144.9, 135.3, 134.5, 130.8 (d, J = 16.3 Hz), 129.8, 129.7, 128.3, 126.9 (d, J
= 6.7 Hz), 119.6 (d, J = 3.2 Hz), 113.0 (d, J = 19.6 Hz), 58.9, 41.9, 21.6; Ms (EI): m/z = 302 [M]+; HRMS
(EI): m/z [M]+ Calcd for C17H15FO2S, 302.0771; Found, 302.0769.
5ꢀMethoxyꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3d). White solid, yield: 51 % (16.0 mg); mp 144ꢀ145 oC. 1H NMR
(300 MHz, CDCl3) δ 7.67 (d, J = 8.3 Hz, 2H), 7.32 – 7.25 (m, 3H), 6.84 (d, J = 2.3 Hz, 1H), 6.76 (dd, J =
8.2, 2.4 Hz, 1H), 6.53 (s, 1H), 4.23 (s, 2H), 3.80 (s, 3H), 3.43 (s, 2H), 2.43 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 158.8, 145.0, 144.7, 136.1, 135.7, 135.4, 135.1, 129.7, 128.4, 124.1, 111.4, 106.7, 59.0, 55.4, 40.8,
21.6; Ms (EI): m/z = 314 [M]+; HRMS (EI): m/z [M]+ Calcd for C18H18O3S, 314.0971; Found, 314.0969.
o
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5ꢀ(Benzyloxy)ꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3e). White solid, yield: 47 % (18.2 mg); mp 143ꢀ144 C. H
NMR (300 MHz, CDCl3) δ 7.67 (d, J = 8.3 Hz, 2H), 7.46 – 7.31 (m, 5H), 7.31 – 7.26 (m, 3H), 6.91 (d, J =
2.2 Hz, 1H), 6.83 (dd, J = 8.2, 2.4 Hz, 1H), 6.52 (s, 1H), 5.06 (s, 2H), 4.22 (s, 2H), 3.43 (s, 2H), 2.43 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 158.1, 145.0, 144.7, 137.2, 136.4, 135.7, 135.4, 135.1, 129.7, 128.5, 128.4,
127.9, 127.4, 124.1, 112.3, 107.8, 70.3, 59.0, 40.8, 21.6; Ms (EI): m/z = 390 [M]+; HRMS (EI): m/z [M]+
Calcd for C24H22O3S, 390.1284; Found, 390.1294.
o
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5ꢀFluoroꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3f). White solid, yield: 30 % (9.0 mg); mp 175ꢀ176 C. H NMR
(300 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.36 – 7.27 (m, 3H), 7.00 – 6.83 (m, 2H), 6.53 (s, 1H), 4.23 (s,
2H), 3.49 (s, 2H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 162.2 (d, J = 242.7 Hz), 145.3 (d, J = 9.3 Hz),
144.9, 139.2 (d, J = 2.1 Hz), 136.8, 135.4, 134.5 (d, J = 3.1 Hz), 129.8, 128.4, 124.4 (d, J = 9.1 Hz), 112.1 (d,
J = 23.1 Hz), 108.2 (d, J = 23.2 Hz), 58.9, 40.9, 21.6; Ms (EI): m/z = 302 [M]+; HRMS (EI): m/z [M]+ Calcd
for C17H15FO2S, 302.0771; Found, 302.0767.
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5ꢀChloroꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3g). White solid, yield: 32 % (10.2 mg); mp 192ꢀ193 C. H NMR
(300 MHz, CDCl3) δ 7.67 (d, J = 8.1 Hz, 2H), 7.35 – 7.29 (m, 3H), 7.26 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H),
6.50 (s, 1H), 4.23 (s, 2H), 3.51 (s, 2H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 145.3, 144.9, 142.1,
136.5, 135.3, 134.2, 132.4, 129.8, 128.4, 125.3, 124.6, 121.4, 58.9, 41.1, 21.6; Ms (EI): m/z = 318 [M]+;
HRMS (EI): m/z [M]+ Calcd for C17H15ClO2S, 318.0476; Found, 318.0470.
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6ꢀMethylꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3h). White solid, yield: 52 % (15.6 mg); mp 151ꢀ152 C. H NMR
(300 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H),
7.06 (d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 4.23 (s, 2H), 3.47 (s, 2H), 2.43 (s, 3H), 2.38 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 144.7, 144.3, 141.1, 135.4, 135.1, 135.0, 133.2, 129.6, 128.4, 127.2, 124.6, 120.8, 59.0, 41.2,
21.6, 21.5; Ms (EI): m/z = 298 [M]+; HRMS (EI): m/z [M]+ Calcd for C18H18O2S, 298.1022; Found,
298.1023.
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6ꢀFluoroꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3i). White solid, yield: 41 % (12.4 mg); mp 174ꢀ175 C. H NMR
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(300 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 8.3, 5.1 Hz, 1H), 7.12
(d, J = 8.7 Hz, 1H), 6.99 – 6.90 (m, 1H), 6.55 (s, 1H), 4.21 (s, 2H), 3.50 (s, 2H), 2.43 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 161.6 (d, J = 244.4 Hz), 146.0 (d, J = 8.8 Hz), 144.8, 139.7 (d, J = 2.0 Hz), 135.5, 134.4,
133.9 (d, J = 3.9 Hz), 129.7, 128.3, 121.8 (d, J = 8.8 Hz), 113.5 (d, J = 23.1 Hz), 111.4 (d, J = 23.4 Hz), 58.8,
41.6 (d, J = 2.0 Hz), 21.6; Ms (EI): m/z = 302 [M]+; HRMS (EI): m/z [M]+ Calcd for C17H15FO2S, 302.0771;
Found, 302.0772.
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6ꢀChloroꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (3j). White solid, yield: 31 % (10.0 mg); mp 193ꢀ194 C. H NMR
(300 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.39 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.23 – 7.17 (m, 2H),
6.56 (s, 1H), 4.22 (s, 2H), 3.50 (s, 2H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 145.5, 144.9, 142.2,
135.4, 134.8, 134.4, 131.5, 129.8, 128.3, 126.7, 124.1, 121.9, 58.8, 41.4, 21.6; Ms (EI): m/z = 318 [M]+;
HRMS (EI): m/z [M]+ Calcd for C17H15ClO2S, 318.0476; Found, 318.0480.
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6ꢀ(Tosylmethyl)ꢀ5Hꢀindeno[5,6ꢀd][1,3]dioxole (3k). White solid, yield: 57 % (18.8 mg); mp 177ꢀ178 C.
1H NMR (300 MHz, CDCl3) δ 7.68 (t, J = 6.7 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.91 (s, 1H), 6.76 (s, 1H),
6.46 (s, 1H), 5.95 (s, 2H), 4.19 (s, 2H), 3.41 (s, 2H), 2.43 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 146.6,
146.3, 144.7, 138.0, 137.4, 135.5, 134.8, 132.8, 129.6, 128.4, 105.1, 102.0, 100.9, 59.0, 41.3, 21.6; Ms (EI):
m/z = 328 [M]+; HRMS (EI): m/z [M]+ Calcd for C18H16O4S, 328.0764; Found, 328.0774.
2ꢀ((Phenylsulfonyl)methyl)ꢀ1Hꢀindene (3l). White solid, yield: 46 % (13.2 mg); mp 137ꢀ138 oC. 1H NMR
(300 MHz, CDCl3) δ 7.85 – 7.77 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 6.8
Hz, 1H), 7.31 – 7.27 (m, 1H), 7.25 – 7.17 (m, 2H), 6.56 (s, 1H), 4.27 (s, 2H), 3.52 (s, 2H); 13C NMR (126
MHz, CDCl3) δ 144.0, 143.7, 138.3, 135.3, 134.1, 133.8, 129.1, 128.4, 126.5, 125.4, 123.7, 121.3, 58.9, 41.5;
Ms (EI): m/z = 270 [M]+; HRMS (EI): m/z [M]+ Calcd for C16H14O2S, 270.0709; Found, 270.0703.
2ꢀ(((4ꢀMethoxyphenyl)sulfonyl)methyl)ꢀ1Hꢀindene (3m). White solid, yield: 32 % (10.0 mg); mp 123ꢀ124
oC. 1H NMR (300 MHz, CDCl3) δ 7.74 – 7.67 (m, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.26 –
7.15 (m, 2H), 6.98 – 6.91 (m, 2H), 6.57 (s, 1H), 4.24 (s, 2H), 3.86 (s, 3H), 3.51 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 163.8, 144.0, 143.7, 135.1, 134.6, 130.6, 129.9, 126.4, 125.3, 123.7, 121.2, 114.2, 59.1, 55.6, 41.5;
Ms (EI): m/z = 300 [M]+; HRMS (EI): m/z [M]+ Calcd for C17H16O3S, 300.0815; Found, 300.0818.
2ꢀ(((4ꢀIsopropylphenyl)sulfonyl)methyl)ꢀ1Hꢀindene (3n). White solid, yield: 42 % (13.8 mg); mp 110ꢀ111
oC. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 6.9 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H),
7.31 – 7.27 (m, 1H), 7.25 – 7.16 (m, 2H), 6.60 (s, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.98 (hept, J = 6.9 Hz, 1H),
1.26 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 155.5, 144.0, 143.8, 135.8, 135.2, 134.3, 128.5,
127.2, 126.4, 125.3, 123.7, 121.2, 59.0, 41.5, 34.2, 23.6; Ms (EI): m/z = 312 [M]+; HRMS (EI): m/z [M]+
Calcd for C19H20O2S, 312.1179; Found, 312.1176.
2ꢀ(((4ꢀ(tertꢀButyl)phenyl)sulfonyl)methyl)ꢀ1Hꢀindene (3o). White solid, yield: 44 % (14.8 mg); mp
156ꢀ157 oC. 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.0
Hz, 1H), 7.31 – 7.27 (m, 1H), 7.26 – 7.16 (m, 2H), 6.61 (s, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 1.33 (s, 9H); 13
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NMR (126 MHz, CDCl3) δ 157.7, 144.0, 143.8, 135.5, 135.2, 134.3, 128.2, 126.4, 126.1, 125.3, 123.6, 121.2,
59.0, 41.5, 35.2, 31.0; Ms (EI): m/z = 326 [M]+; HRMS (EI): m/z [M]+ Calcd for C20H22O2S, 326.1335;
Found, 326.1332.
2ꢀ(((4ꢀChlorophenyl)sulfonyl)methyl)ꢀ1Hꢀindene (3p). White solid, yield: 45 % (14.2 mg); mp 131ꢀ132
oC. 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 7.1 Hz, 2H), 7.51 – 7.41 (m, 3H), 7.32 – 7.28 (m, 1H), 7.26 –
7.17 (m, 2H), 6.57 (s, 1H), 4.26 (s, 2H), 3.54 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 143.9, 143.5, 140.6,
136.7, 135.6, 133.8, 129.9, 129.4, 126.5, 125.5, 123.7, 121.4, 59.0, 41.5; Ms (EI): m/z = 304 [M]+; HRMS
(EI): m/z [M]+ Calcd for C16H13ClO2S, 304.0319; Found, 304.0323.
2ꢀ(((4ꢀBromophenyl)sulfonyl)methyl)ꢀ1Hꢀindene (3q). White solid, yield: 48 % (17.3 mg); mp 139ꢀ140
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oC. 1H NMR (300 MHz, CDCl3) δ 7.65 (s, 4H), 7.44 (d, J = 6.9 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.27 – 7.18 (m,
2H), 6.58 (s, 1H), 4.26 (s, 2H), 3.54 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 143.9, 143.5, 137.3, 135.6,
133.7, 132.4, 129.9, 129.2, 126.5, 125.5, 123.7, 121.4, 58.9, 41.5; Ms (EI): m/z = 348 [M]+; HRMS (EI): m/z
[M]+ Calcd for C16H13BrO2S, 347.9814; Found, 347.9811.
2ꢀ(([1,1'ꢀBiphenyl]ꢀ4ꢀylsulfonyl)methyl)ꢀ1Hꢀindene (3r). White solid, yield: 28 % (10 mg); mp 219ꢀ220
oC. 1H NMR (300 MHz, CDCl3) δ 7.91 – 7.83 (m, 2H), 7.75 – 7.68 (m, 2H), 7.64 – 7.58 (m, 2H), 7.53 – 7.41
(m, 4H), 7.32 – 7.18 (m, 3H), 6.63 (s, 1H), 4.31 (s, 2H), 3.56 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 146.7,
144.0, 143.7, 139.0, 136.9, 135.4, 134.2, 129.1, 128.9, 128.7, 127.6, 127.4, 126.5, 125.4, 123.7, 121.3, 59.0,
41.5; Ms (EI): m/z = 346 [M]+; HRMS (EI): m/z [M]+ Calcd for C22H18O2S, 346.1022; Found, 346.1026.
2ꢀ((mꢀTolylsulfonyl)methyl)ꢀ1Hꢀindene (3s). White solid, yield: 43 % (12.9 mg); mp 121ꢀ122 oC. 1H
NMR (300 MHz, CDCl3) δ 7.66 – 7.55 (m, 2H), 7.45 – 7.34 (m, 3H), 7.31 – 7.27 (m, 1H), 7.26 – 7.15 (m,
2H), 6.60 (s, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.38 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 144.0, 143.7, 139.4,
138.2, 135.3, 134.5, 134.1, 128.9, 128.6, 126.4, 125.5, 125.3, 123.6, 121.2, 58.9, 41.5, 21.2; Ms (EI): m/z =
284 [M]+; HRMS (EI): m/z [M]+ Calcd for C17H16O2S, 284.0866; Found, 284.0863.
2ꢀ(((3ꢀBromophenyl)sulfonyl)methyl)ꢀ1Hꢀindene (3t). White solid, yield: 40 % (14.7 mg); mp 154ꢀ155 oC.
1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.79 – 7.74 (m, 1H), 7.71 (dd, J = 7.9, 0.6 Hz, 1H), 7.44 (d, J =
6.9 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.27 – 7.19 (m, 2H), 6.62 (s, 1H), 4.27 (s, 2H),
3.55 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 143.9, 143.5, 140.2, 136.9, 135.8, 133.5, 131.2, 130.5, 127.1,
126.5, 125.5, 123.7, 123.2, 121.4, 58.9, 41.5; Ms (EI): m/z = 348 [M]+; HRMS (EI): m/z [M]+ Calcd for
C16H13BrO2S, 347.9814; Found, 347.9805.
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1ꢀ(((1Hꢀindenꢀ2ꢀyl)methyl)sulfonyl)naphthalene (3u). White solid, yield: 51 % (17 mg); mp 148ꢀ149 C.
1H NMR (300 MHz, CDCl3) δ 8.81 (d, J = 8.6 Hz, 1H), 8.15 (dd, J = 7.4, 1.2 Hz, 1H), 8.11 (d, J = 8.3 Hz,
1H), 7.99 (d, J = 8.1 Hz, 1H), 7.72 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.52 – 7.46 (m, 1H),
7.37 (d, J = 6.3 Hz, 1H), 7.22 – 7.13 (m, 3H), 6.43 (s, 1H), 4.47 (s, 2H), 3.46 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 143.9, 143.7, 135.3, 135.2, 134.1, 134.0, 133.5, 131.2, 129.3, 129.0, 128.8, 127.0, 126.4, 125.3,
124.3, 124.0, 123.6, 121.2, 58.3, 41.5; Ms (EI): m/z = 320 [M]+; HRMS (EI): m/z [M]+ Calcd for C20H16O2S,
320.0866; Found, 320.0862.
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3ꢀMethylꢀ2ꢀ(tosylmethyl)ꢀ1Hꢀindene (5a). White solid, yield: 31 % (9.3 mg); mp 133ꢀ134 C. H NMR
(300 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.32 – 7.20 (m, 5H), 4.23 (s, 2H),
3.52 (s, 2H), 2.43 (s, 3H), 1.61 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 145.3, 144.7, 143.2, 141.5, 135.6,
129.7, 128.4, 127.2, 126.2, 125.5, 123.5, 119.3, 57.0, 41.1, 21.6, 10.0; Ms (EI): m/z = 298 [M]+; HRMS (EI):
m/z [M]+ Calcd for C18H18O2S, 298.1022; Found, 298.1008.
2ꢀ(((4ꢀIsopropylphenyl)sulfonyl)methyl)ꢀ3ꢀmethylꢀ1Hꢀindene (5b). White solid, yield: 38 % (12.4 mg);
mp 105ꢀ106 oC. 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 6.5 Hz, 1H), 7.34 – 7.26
(m, 3H), 7.25 – 7.19 (m, 2H), 4.22 (s, 2H), 3.52 (s, 2H), 2.97 (hept, J = 6.9 Hz, 1H), 1.58 (t, J = 2.0 Hz, 3H),
1.25 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 155.5, 145.3, 143.2, 141.5, 135.7, 128.6, 127.3,
127.2, 126.2, 125.5, 123.5, 119.3, 57.0, 41.1, 34.2, 23.6, 9.9; Ms (EI): m/z = 326 [M]+; HRMS (EI): m/z [M]+
Calcd for C20H22O2S, 326.1335; Found, 326.1327.
2ꢀ(((4ꢀ(tertꢀButyl)phenyl)sulfonyl)methyl)ꢀ3ꢀmethylꢀ1Hꢀindene (5c). White solid, yield: 36 % (12.2 mg);
mp 142ꢀ143 oC. 1H NMR (300 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.51 – 7.45 (m, 2H), 7.43 (d, J = 6.6 Hz,
1H), 7.32 – 7.27 (m, 1H), 7.25 – 7.20 (m, 2H), 4.22 (s, 2H), 3.53 (s, 2H), 1.57 (t, J = 2.1 Hz, 3H), 1.33 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 157.8, 145.3, 143.2, 141.5, 135.4, 128.3, 127.3, 126.2, 126.1, 125.5,
123.5, 119.3, 57.0, 41.1, 35.2, 31.0, 9.9; Ms (EI): m/z = 340 [M]+; HRMS (EI): m/z [M]+ Calcd for
C21H24O2S, 340.1492; Found, 340.1496.
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2ꢀ(((4ꢀChlorophenyl)sulfonyl)methyl)ꢀ3ꢀmethylꢀ1Hꢀindene (5d). White solid, yield: 32 % (10.2 mg); mp
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125ꢀ126 oC. H NMR (300 MHz, CDCl3) δ 7.72 – 7.67 (m, 2H), 7.49 – 7.42 (m, 3H), 7.34 – 7.28 (m, 1H),
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145.1, 143.1, 141.9, 140.6, 137.0, 129.9, 129.4, 126.6, 126.4, 125.7, 123.5, 119.5, 57.0, 41.1, 10.2; Ms (EI):
m/z = 318 [M]+; HRMS (EI): m/z [M]+ Calcd for C17H15ClO2S, 318.0476; Found, 318.0480.
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1 mmolꢀscale synthesis of 3a. To an ovenꢀdried 25 mL sealed tube was added substrate 1a (146.2 mg, 1.0
mmol), 4ꢀmethylbenzenesulfonohydrazide 2a (372.4 mg, 2.0 mmol), CuBr (71.7 mg, 0.50 mmol), DTBP
(551 ꢁL, 3.0 mmol) and acetonitrile (2.0 mL) under a nitrogen atmosphere. The mixture was stirred for 2 h at
100 ⁰C. The mixture was then cooled to room temperature, diluted with DCM, filtered through a celite pad,
and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA
= 5/1), to afford 161.2 mg (57%) of the desired product 3a.
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Radical Trapping Experiments (Scheme 4a). To an ovenꢀdried 10 mL sealed tube was added substrate
1a (14.6 mg, 0.10 mmol), 4ꢀmethylbenzenesulfonohydrazide 2a (37.2 mg, 0.20 mmol), CuBr (7.2 mg, 0.050
mmol), TEMPO (46.9 mg, 3.0 equiv) or 1,4ꢀbenzoquinone (32.4 mg, 3.0 equiv), DTBP (55 ꢁL, 0.30 mmol)
and acetonitrile (0.5 mL) under a nitrogen atmosphere. The mixture was stirred for 2 h at 100 ⁰C. The
mixture was then cooled to room temperature, diluted with DCM, filtered through a celite pad, and
concentrated in vacuo. The yield of product 3a was based on 1H NMR analysis of the crude product.
Control Experiment 1 (Scheme 4b). To an ovenꢀdried 10 mL sealed tube was added oꢀallylbenzaldehyde
tosylhydrazone 6 (31.4 mg, 0.10 mmol), 4ꢀmethylbenzenesulfonohydrazide 2a (37.2 mg, 0.20 mmol), CuBr
(7.2 mg, 0.050 mmol) and acetonitrile (0.5 mL) under a nitrogen atmosphere. The mixture was stirred for 2 h
at 100 oC. The mixture was then cooled to room temperature, diluted with DCM, filtered through a celite pad,
and concentrated in vacuo. The residue was purified by preparative thinꢀlayer chromatography (eluent:
PE/DCM = 2/3), to afford the oꢀallylbenzaldehyde tosylhydrazone 6 (21 mg, 67 %). Thus the reactions were
repeated in the absence of CuBr, affording 20 mg of the oꢀallylbenzaldehyde tosylhydrazone 6 in 64% yield.
Control Experiment 2 (Scheme 4c). To an ovenꢀdried 10 mL sealed tube was added 1a (14.6 mg, 0.10
mmol), 4ꢀmethylbenzenesulfonohydrazide 2a (37.2 mg, 0.20 mmol), CuBr (7.2 mg, 0.050 mmol), DTBP (55
ꢁL, 0.30 mmol) and acetonitrile (0.5 mL) under a nitrogen atmosphere. The mixture was stirred for 5 min at
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100 C. The mixture was then cooled to room temperature, diluted with DCM, filtered through a celite pad,
and concentrated in vacuo. The residue was purified by preparative thinꢀlayer chromatography (eluent:
PE/DCM = 2/3), to afford the oꢀallylbenzaldehyde tosylhydrazone 6 (23.9 mg, 76 %).
Control Experiment 3 (Scheme 4d). To an ovenꢀdried 10 mL sealed tube was added oꢀallylbenzaldehyde
tosylhydrazone 6 (31.4 mg, 0.10 mmol), 4ꢀmethylbenzenesulfonohydrazide 2a (37.2 mg, 0.20 mmol), CuBr
(7.2 mg, 0.050 mmol), DTBP (55 ꢁL, 0.30 mmol) and acetonitrile (0.5 mL) under a nitrogen atmosphere.
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The mixture was stirred for 2 h at 100 C. The mixture was then cooled to room temperature, diluted with
DCM, filtered through a celite pad, and concentrated in vacuo. The residue was purified by preparative
thinꢀlayer chromatography (eluent: PE/DCM = 2/3), to afford the desired product 3a (12 mg, 42 %).
Control Experiment 4 (Scheme 4c). To an ovenꢀdried 10 mL sealed tube was added oꢀallylbenzaldehyde
tosylhydrazone 6 (31.4 mg, 0.10 mmol), CuBr (7.2 mg, 0.050 mmol), DTBP (55 ꢁL, 0.30 mmol) and
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acetonitrile (0.5 mL) under a nitrogen atmosphere. The mixture was stirred for 2 h at 100 C. The mixture
was then cooled to room temperature, diluted with DCM, filtered through a celite pad, and concentrated in
vacuo. The residue was purified by preparative thinꢀlayer chromatography (eluent: PE/DCM = 2/3), to afford
the desired product 3a (2.9 mg, 10 %).
ASSOCIATED CONTENT
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Supporting Information
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Copies of H NMR and 13C NMR spectra for new compounds and Xꢀray crystallography data for compound 3l.
This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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* Email: chslp@cpu.edu.cn
* Email: aozhang@simm.ac.cn
Author Contributions
§ These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the International Cooperative Program (GJHZ1622 2060899) and Key Program of the
Frontier Science (QYZDJꢀSSWꢀSMC002) of the Chinese Academy of Sciences. Grants from National Natural
Science Foundation of China (81773565,81430080,) and the Shanghai Commission of Science and Technology
(16XD1404600).
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