Rhodium(III)-Catalyzed C-H Activation of Nitrones and Annulative Coupling with Nitroalkenes

Article abstract of DOI:10.1021/acs.joc.7b01574

Rh(III)-catalyzed synthesis of nitro-functionalized indenes has been realized via C-H activation of arylnitrones and annulation with nitroolefins. The reaction proceeded in moderate to high yields with good functional group tolerance under ambient atmosph

Full text of DOI:10.1021/acs.joc.7b01574

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Note
Rhodium(III)-Catalyzed C-H Activation of Nitrones
and Annulative Coupling with Nitroalkenes
Dachang Bai, Qingqian Jia, Teng Xu, Qiuqiu Zhang, Fen Wu,
Chaorui Ma, Bingxian Liu, Junbiao Chang, and Xingwei Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01574 • Publication Date (Web): 17 Aug 2017
Downloaded from http://pubs.acs.org on August 17, 2017
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Rhodium(III)ꢀCatalyzed CꢀH Activation of Nitrones and Annulative Coupling with
Nitroalkenes
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Dachang Bai,† Qingqian Jia,† Teng Xu, † Qiuqiu Zhang,† Fen Wu,† Chaorui Ma,† Bingxian Liu,†
Junbiao Chang,*,† Xingwei Li*,†,‡
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†Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of
Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
‡Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
Abstract: Rh(III)ꢀcatalyzed synthesis of nitroꢀfunctionalized indenes has been realized via CꢀH
activation of arylnitrones and annulation with nitroolefins. The reaction proceeded in moderate
to high yields with good functional group tolerance under ambient atmosphere.
Transition metalꢀcatalyzed CꢀH bond activation has proven to be a powerful strategy for the stepꢀ
economical construction of CꢀC bonds and has become an increasingly important tool in organic
syntheses.1 In particular, Rh(III)ꢀcatalyzed systems have stood out with high efficiency, good
selectivity, functional group compatibility, and diverse synthetic applicability.2 In these systems,
a directing group is almost inevitably required to ensure activity and selectivity of the CꢀH bond.
Importantly, the development of mild, straightforward, and ecoꢀfriendly processes assisted by a
multifunctional directing group is especially attractive, which allows realization of molecular
diversity and synthetic versatility.3 A variety of nitrogen and oxygen directing group such as
amide, imine, ester, and ketone have been developed.2,4 However, benzaldehydes are generally
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challenging as arene substrates because of the low ligating ability of the aldehyde oxygen and
related competitive side reactions.5 Instead, they are often viable as a coupling partner.6 A
strategy to enhance the directing effect of aldehyde carbonyl is to convert it to an imine,7
hydrazine,8 nitrone,9 or azomethine imine,10 which has exhibited high reactivity although lower
electrophilicity in the coupling with alkynes, alkenes, and diazo compounds. Among these
electrophilic DGs, imines have shown unique reactivity, and many [3+2] annulative coupling
reactions with alkynes,7aꢀd and alkylation/olefination with alkenes have been reported.7eꢀ7f
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As a special imine, nitrones have played a vital role in CꢀH activation reactions due to the polar
nature of N−O bond and the electrophilicity of the imine moiety.9 [3+2] and even [3+3]
annulative coupling systems have been developed using nitrone as an efficient directing group.
Although coupling of nitrones with olefins has been reported, the reaction is generally limited to
olefination using a terminal olefin.9c, 9g On the other hand, although disubstituted activated
olefins have been employed as a coupling partner,11 applications of substituted nitroalkenes still
lag behind. Very recently, Ellman reported Rh(III)ꢀcatalyzed C−H activation of benzamides and
insertion into nitroalkenes.12 In only one example, the authors reported synthesis of a nitroindene
using acetophenone as a substrate. To further apply nitroalkenes in useful cyclization reactions,
we now report Rh(III)ꢀcatalyzed efficient synthesis of nitroindenes via CꢀH activation of
arylnitrones under operationally simple conditions.
We commenced our studies by examining the reaction parameters of the coupling of Nꢀtertꢀ
butylꢀαꢀphenylnitrone (1a) with (E)ꢀ2ꢀnitroethenylbenzene (2a, Table 1). Our initial attempts
using a Rh(III) catalyst in CF3CH2OH afforded the [3+2] addition product 3a in 21% yield at
o
120 C (entry 1). Increasing the amount of AgSbF6 improved the yield to 46% (entry 2), while
addition of PivOH and AgOAc significantly decreased the catalytic efficiency, and bases such as
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CsOAc, K2CO3, and Cu(OAc)2 also inhibited the reaction (entries 3ꢀ7). To our delight, using two
equiv of 1a boosted the yield to 82% (entry 8), and this reaction even occurred efficiently under
ambient air (entry 9). The reaction was sensitive to the solvent, and the yield of 3a drastically
decreased when DCE, THF, HFIP or dioxane was used (entries 10ꢀ15). The product was
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o
o
obtained in 83% yield at 80 C, but further decreased the temperature to 60 C resulted in lower
yield (entries 16ꢀ17). Decreasing the catalyst loading to 2.5 mol % also significantly reduced the
yield (entry 18). Our control experiments confirmed that both the rhodium(III) catalyst and
AgSbF6 were necessary (entries 19ꢀ20). Further studies revealed other Rh catalysts, such as
Cp*Rh(CH3CN)3(SbF6)2, [RhCl(cod)]2, and RhCl(PPh3)3 were totally ineffective for the
annulation reaction (entries 21, 23 and 24), and only 19% yield was obtained for
Cp*Rh(CH3CN)3(SbF6)2/AgSbF6 (entry 22). With Nꢀphenyl nitrone (1a`), only starting material
was recovered (entry 25), and Nꢀbenzyl nitrone (1a``) afforded the product in 17% yield (entry
26). Furthermore, no product was observed when benzaldehyde was used instead of the
arylnitrone.
Table 1. Control Reactions a
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R
[Cp*RhCl2]2/AgSbF6
NO2
NO2
N
O
Ph
solvent, temp
Ph
6
1
2a
3a
7
8
9
entry
1c
R
catalyst (mol %)
solvent
T (ºC) yieldb (%)
additive
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
Bu (
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
[Cp*RhCl2]2(5.0)/ AgSbF6(20)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2 (5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2 (5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
[Cp*RhCl2]2(2.5)/ AgSbF6(20)
[Cp*RhCl2]2(5.0)/--
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
DCE
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
80
21
46
31
trace
trace
trace
20
82
80
17
6
--
10
11
12
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2c
--
3c
PivOH
4c
CsOAc
5c
K2CO3
6c
Cu(OAc)2
7c
AgOAc
8d
--
--
--
--
--
--
--
--
--
--
--
--
--
--
9d
10d
11d
12d
13d
14d
15d
16d
17d
18d
19d
20d
21d
22d
23d
24d
25d
26d
THF
HFIP
28
16
trace
trace
83
75
56
--
Dioxane
Toluene
EtOH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
60
120
120
120
80
--/AgSbF6(40)
--
Cp*Rh(CH3CN)3(SbF6)2(10.0)/--
--
Cp*Rh(CH3CN)3(SbF6)2(10.0)/AgSbF6(40)
[RhCl(cod)]2(5.0)/ AgSbF6(40)
RhCl(PPh3)3(10.0)/ AgSbF6(40)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
80
19
--
--
--
--
--
--
80
80
--
1a'
Ph (
80
--
1a''
Bn (
)
[Cp*RhCl2]2(5.0)/ AgSbF6(40)
80
17
aReaction conditions: 2a (0.2 mmol), additive (1.0 equiv), solvent (2.0 mL), 24h, entries 1ꢀ8
under the argon, entries 9ꢀ26 under the air. bisolated yields. c1a (0.2 mmol). d1 (0.4 mmol).
With the optimized conditions in hand, we first examined the scope of the nitroalkene (Scheme
1). A variety of alkyl and arylꢀsubstituted nitroalkenes proved to be effective coupling partners
under the standard conditions.13 Aliphatic nitroalkenes afforded products 3b-3d in good to high
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yields, and 3b was isolated in 91% yields when a 4.0 mmol scale reaction was carried out.
Introduction of various electronꢀdonating, ꢀwithdrawing or halogen groups (3eꢀ3i) into the para
position of the aromatic βꢀnitrostyrenes ring was fully tolerated (30ꢀ71%). The reaction
efficiency is related to the electronic effect of the para substituent, electronꢀrich groups on the
aromatic ring gave products (3e and 3f) in moderate yield, probably due to the lower activity of
the nitroalkenes bearing electronꢀrich substituents. While the electronꢀwithdrawing group
afforded the nitroindene product (3g) in 33% yield, accompanying by the formation of multiple
unassigned products. Methyl group at the meta or ortho position was also tolerated, as in the
formation of desired products 3j and 3k in moderate yields.
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Scheme 1. Scope of Nitroalkenes.a
aReaction conditions: [Cp*RhCl2]2 (5.0 mol %), AgSbF6 (40 mol%), 1a (0.4 mmol), 2 (0.2
mmol), CF3CH2OH (2.0 mL), 24h, air, isolated yields. b4.0 mmol of 1a was used.
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We next explored the scope of the aryl nitrone substrate with nitroalkenes 2b and 2c (Scheme 2).
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t
Nitrones bearing Meꢀ, Buꢀ and MeOꢀ and halogens at para position coupled with 2b to afford
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the nitroindene in moderate to good yields (3lꢀ3q). Products 3r and 3s were obtained in 80% and
38% yields for meta Meꢀ and Clꢀsubstituted nitrone, respectively. Introduction of an ortho
methyl group is wellꢀtolerated (3t), although coupling of ortho Fꢀ, Brꢀ and Clꢀsubstituted
nitrones afforded relatively lower yields (3u-3x). With nitroalkene 2c being a coupling partner,
products 3y and 3z were also obtained in comparable yield.
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Scheme 2. Scope of Arylnitrons.a
aReaction conditions: [Cp*RhCl2]2 (5.0 mol %), AgSbF6 (40 mol%), 1 (0.4 mmol), 2 (0.2 mmol),
CF3CH2OH (2.0 mL), 24h, air, isolated yields.
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To demonstrate the synthetic utility of the annulated products, a derivatization reaction has been
carried out. The nitroindene was reduced by H2 in the presence of RaneyꢀNi,14 affording ketone 4
in 44% yield (Scheme 3, eq 1).
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Scheme 3. Derivatization Reactions.
We next performed several experiments to gain mechanistic insight (Scheme 4). A kinetic
isotope effect (KIE) value of 5.7 was obtained for the competitive coupling of a mixture of 1a
and 1a-d5 with 2c at a low conversion under the standard conditions (Scheme 4, eq 2). This result
indicated that cleavage of the CꢀH bond activation was likely involved in the turnoverꢀlimiting
step. Moreover, H/D exchange between nitrone 1a and D2O was performed, and the nitrone
starting material was recovered with 40% deuteration at the ortho positions, indicating
reversibility of CꢀH activation in the absence of the nitroalkene (Scheme 4, eq 3). When D2O
was added into the reaction of 1a with 2c, no H/D exchanged at the ortho position of the
nitroindene product, indicative of irreversibility of the CꢀH under the catalytic conditions. In
addition, H/D exchanged was observed at the acidic methylene position of the indene (Scheme 4,
eq 4). When an equimolar mixture of 1p and 1n was allowed to competitively couple with olefin
2b, two nitroindene were obtained in 23% and 49% yield, where the electronꢀrich nitrone reacted
preferentially (Scheme 4, eq 5). In another competitive reaction using two electronically different
olefins 2a and 2f, the products 3a and 3f were obtained in 1.5:1 ratio, where the electronꢀpoor
olefin only exhibited slightly higher reactivity (Scheme 4, eq 6).
Scheme 4. Mechanistic Studies
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5
tBu
N
O
[Cp*RhCl2]2 (5.0 mol %)
AgSbF6 (40 mol%)
1a
NO2
KIE = 5.7
(eq 2)
6
7
8
CF3CH2OH, rt, 3 min
tBu
5%
N
2c
D5
O
9
1a-d5
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11
12
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40% D
tBu
H/D
[Cp*RhCl2]2 (5.0 mol %)
AgSbF6 (40 mol%)
tBu
tBu
(eq 3)
N
N
O
CF3CH2OH, 6.0 eq D2O, 80 ºC
95%
O
40% D
H/D
1a
15% D
N
O
100% H
H
1
H/D
H/D
[Cp*RhCl2]2 (5.0 mol %)
AgSbF6 (40 mol%)
1a
7
NO2
+
CF3CH2OH, 6.0 eq D2O, 80 ºC
36%
(eq 4)
NO2
2c
3c'
tBu
tBu
N
NO2
N
[Cp*RhCl2]2 (5.0 mol %)
O
O
AgSbF6 (40 mol%)
NO2
NO2
(eq 5)
+
+
+
Cl
MeO
CF3CH2OH, 80 ºC
Ph
Cl
Ph
Ph
OMe
3p
23%
3n
49%
1p
1n
2b
tBu
NO2
NO2
[Cp*RhCl2]2 (5.0 mol %)
AgSbF6 (40 mol%)
N
NO2
O
NO2
(eq 6)
+
+
CF3CH2OH, 80 ºC, 24 h
+
OMe
2f
OMe
3a
46%
3f
30%
1a
2a
On the basis of our preliminary experiments and related literature reports, a proposed mechanism
is given in Scheme 5. An active catalyst [Cp*RhX2] (X = SbF6) was generated via halide
abstraction. CꢀH activation of 1a produced an rhodacyclic intermediate A, and coordination of
the nitroalkene 2a provides an olefin intermediate B, which undergoes migratory insertion to
provide a Rh(III) alkyl species C. Protonolysis of C affords an alkylated nitrone intermediate D
and regenerates the active rhodium species. The nitrone species D is proposed to undergo
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intramolecular Henryꢀtype reaction to release the BuNHOH afforded nitroindene E, which
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eventually isomerizes to the thermodynamically more stable product 3a.
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Scheme 5. Proposed Mechanism
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In summary, we have demonstrated an easy handling approach to access nitroindenes through
Rh(III)ꢀcatalyzed CꢀH activation/annulation of arylnitrons with nitroalkenes. This reaction
occurred smoothly under air atmosphere. The scope of the arylnitrone and nitroalkene substrates
have been defined, and good functional groups tolerance has been achieved. Mechanistic studies
have been performed using H/D exchange and competition experiments. Further studies on the
synthesis of other carbocycles via CꢀH activation and functionalization are underway in our
laboratories.
EXPERIMENTAL SECTION
General Information: All chemicals were obtained from commercial sources and were used as
received unless otherwise noted. All the reactions were carried out under argon atmosphere using
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standard Schlenk technique. The H NMR spectra were recorded on a 400 MHz or 600 MHz
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NMR spectrometer. The 13C NMR spectra were recorded at 100 MHz or 150 MHz. The 19F
NMR spectra were recorded at 565 MHz. Chemical shifts were expressed in parts per million (δ)
down field from the internal standard tetramethylsilane, and were reported as s (singlet), d
(doublet), t (triplet), dd (doublet of doublet), dt (doublet of triplet), m (multiplet), brs (broad
singlet), etc. The residual solvent signals were used as references and the chemical shifts were
converted to the TMS scale. High resolution mass spectra were obtained on an Agilent QꢀTOF
6540 spectrometer. Column chromatography was performed on silica gel (300ꢀ400 mesh) using
petroleum ether (PE)/dichloromathane (DCM). Thin layer chromatography was performed on
preꢀcoated glassback plates and visualized with UV light at 254 nm. Flash column
chromatography was performed on silica gel. The arylnitrone 1a was purchased from
commercial sources, other arylnitrones were prepared by using literature procedures.15 The
nitroalkenes were prepared according the literature report. 12
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General procedure for Rhodium(III)-Catalyzed C-H Activation/annulation of Arylnitrons
with Nitroalkenes: Arylnitrone (0.400 mmol, 2.00 equiv) and nitroalkene (0.200 mmol, 1.00
equiv), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv), AgSbF6 (27.5 mg, 0.080 mmol, 0.200
equiv) in CF3CH2OH (2.0 mL) were charged into a 50 mL pressure tube under the air
atmosphere. The tube was then sealed and placed in a preheated oil bath at 80 °C. After the
reaction was complete, the reaction vial was removed from the oil bath and cooled to ambient
temperature. The reaction mixture was filtered through a pad of celite eluting with ethyl acetate,
concentrated and purified by silica gel chromatography (PE : DCM = 2:1) to give the indicated
product.
The following products were obtained under air atmosphere procedure.
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2ꢀnitroꢀ3ꢀphenylꢀ1Hꢀindene (3a); a yellow solid (mp = 104ꢀ106 °C); (39 mg, 83% yield); H
NMR (600 MHz, CDCl3): δ 7.58–7.41 (m, 7H), 7.36 (m, 2H), 4.16 (s, 2H). 13C NMR (151 MHz,
CDCl3): δ 148.4, 146.8, 142.4, 140.2, 131.4, 130.1, 129.3, 128.8, 128.5, 127.8, 124.8, 124.5, 38.0.
HRMS (ESI): [M + Na]+ calculated for C15H11NNaO2: 260.0682, found:260.0685.
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2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3b); a yellow solid (mp = 68ꢀ71°C); (47 mg, 88% yield); H
NMR (600 MHz, CDCl3):δ 7.56 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 7.2 Hz,
1H), 7.42 (d, J = 7.4 Hz, 1H), 7.30 (m, 2H), 7.24ꢀ7.18 (m, 1H), 4.00 (s, 2H), 3.47ꢀ3.33 (t, J = 8.2
Hz, 2H), 3.07ꢀ2.91 (t, J = 8.2 Hz, 1H, 2H).13C NMR (151 MHz, CDCl3): δ 151.2, 147.4, 141.6,
140.8, 140.3, 130.1, 128.6, 128.5, 127.6, 126.5, 124.5, 122.9, 37.4, 34.5, 28.8. HRMS (ESI): [M
+ Na]+ calculated for C17H15NNaO2: 288.0995, found:288.1002.
3ꢀisobutylꢀ2ꢀnitroꢀ1Hꢀindene (3c); a yellow solid (mp = 49ꢀ52 °C); (31 mg, 72% yield); 1H NMR
(600 MHz, CDCl3): δ 7.61 (d, J = 7.4 Hz, 1H), 7.55–7.38 (m, 3H), 4.02 (s, 2H), 3.06 (d, J = 7.0
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Hz, 2H), 2.25–2.10 (m, 1H), 1.02 (d, J = 6.1 Hz, 6H). C NMR (151 MHz, CDCl3): δ 151.8,
147.7, 142.6, 140.3, 130.1, 127.6, 124.5, 123.6, 37.6, 35.1, 29.3, 23.16. HRMS (ESI): [M+Na]+
calculated for C13H15NNaO2: 240.0995, found:240.1003.
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3ꢀcyclohexylꢀ2ꢀnitroꢀ1Hꢀindene (3d); yellow solid (mp = 66ꢀ68 °C); (21 mg, 43% yield); H
NMR (600 MHz, CDCl3): δ 7.91 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.1 Hz, 1H), 7.44 (d, J = 6.9
Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H), 4.09 (s, 2H), 3.96–3.86 (m, 1H), 2.00 (dd, J = 25.0, 12.5 Hz,
2H), 1.86ꢀ1.81 (m, 5H), 1.52ꢀ1.31 (m, 3H). 13C NMR (151 MHz, CDCl3): δ 155.0, 146.9, 141.1,
140.8, 129.4, 127.1, 125.6, 124.7, 38.0, 37.7, 30.1, 26.5, 26.2. HRMS (ESI): [M+Na]+ calculated
for C15H17NNaO2: 266.1151, found:266.1154.
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2ꢀnitroꢀ3ꢀ(pꢀtolyl)ꢀ1Hꢀindene (3e); a yellow oil; (26 mg, 52% yield); H NMR (600 MHz,
CDCl3): δ 7.56 (d, J = 7.3 Hz, 1H), 7.49 (s, 1H), 7.37 (m, 4H), 7.33 (d, J = 7.4 Hz, 1H), 4.17 (s,
2H), 2.46 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 148.6, 146.5, 142.6, 140.2, 139.6, 130.1,
129.3, 128.9, 128.4, 127.8, 124.9, 124.5, 38.0, 21.7. HRMS (ESI): [M + Na]+ calculated for
C16H13NNaO2: 274.0838, found:274.0838.
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3ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀnitroꢀ1Hꢀindene (3f); a yellow solid (mp = 141ꢀ142°C); (27 mg, 50%
yield); 1H NMR (600 MHz, CDCl3): δ 7.56 (d, J = 7.4 Hz, 1H), 7.51–7.42 (m, 3H), 7.40 (m, 2H),
7.05 (d, J = 8.1 Hz, 2H), 4.17 (s, 2H), 3.90 (s, 3H).13C NMR: (151 MHz, CDCl3): δ 160.6, 148.3,
146.3, 142.6, 140.3, 130.8, 130.1, 127.7, 125.0, 124.5, 123.3, 114.0, 55.5, 38.1. HRMS (ESI):
[M + Na]+ calculated for C16H13NNaO3: 290.0788, found:290.0791.
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2ꢀnitroꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀindene (3g); a yellow oil; (15 mg, 24% yield); H
NMR (600 MHz, CDCl3): δ 7.79 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 9.0 Hz, 3H), 7.52 (m, 1H), 7.40
(d, J = 6.2 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 4.21 (s, 2H). 19F NMR (565 MHz, CDCl3):δ ꢀ63.53.
13C NMR (151 MHz, CDCl3): δ 147.6, 146.9, 141.9, 140.1, 135.3, 131.3 (q, J = 32.5 Hz), 130.5,
129.3, 128.1, 125.7, 125.6, 124.7, 124.5, 38.0. HRMS (ESI): [M+Na]+ calculated
forC16H10F3NaNO2:328.0556, found:328.0566.
3ꢀ(4ꢀfluorophenyl)ꢀ2ꢀnitroꢀ1Hꢀindene (3h); a yellow solid (mp = 178ꢀ180 °C); (26 mg, 52%
yield); 1H NMR (600 MHz, CDCl3): δ 7.57 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.47 (s,
2H), 7.39 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 8.2 Hz, 2H), 4.18 (s, 2H). 19F
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NMR (565 MHz, CDCl3): δ ꢀ111.93. C NMR (151 MHz, CDCl3): δ 163.3 (d, J = 249.5 Hz),
147.4, 147.0, 142.3, 140.1, 131.1, 131.0, 130.3, 127.9, 127.2, 124.7(d, J = 6.7 Hz, 1H), 115.8 (d,
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J = 21.8 Hz, 1H), 38.0. HRMS (ESI): [M + Na]+ calculated for C15H10FNaNO2: 278.0588,
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3ꢀ(4ꢀbromophenyl)ꢀ2ꢀnitroꢀ1Hꢀindene (3i); yellow solid (mp =110ꢀ113 °C); (33 mg, yield 52%);
1H NMR (600 MHz, CDCl3): δ 7.66 (d, J = 8.1 Hz, 2H), 7.54 (dd, J = 22.4, 7.4 Hz, 2H), 7.34 (m,
4H), 4.17 (s, 2H). 13C NMR (151 MHz, CDCl3): δ 147.2, 142.0, 140.1, 131.9, 130.6, 130.4,
130.3, 128.0, 124.7, 124.6, 123.8, 38.0. HRMS (EI) Calcd. for C15H10BrNO2 (M+): 314.9895;
Found: 314.9897.
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3ꢀ(3,5ꢀdimethylphenyl)ꢀ2ꢀnitroꢀ1Hꢀindene (3j); yellow solid (mp = 73ꢀ75 °C); (34 mg, 64%
yield); 1H NMR (600 MHz, CDCl3): δ 7.55 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 7.0 Hz, 1H), 7.35 (t,
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J = 10.1 Hz, 2H), 7.12 (s, 1H), 7.05 (s, 2H), 4.16 (s, 2H), 2.39 (s, 6H). C NMR (151 MHz,
CDCl3): δ 148.9, 146.6, 142.7, 140.2, 138.2, 131.4, 131.1, 130.0, 127.7, 126.3, 125.0, 124.5, 38.0,
21.5. HRMS (ESI): [M+Na]+ calculated for C17H15NNaO2: 288.0995, found:288.0997.
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2ꢀnitroꢀ3ꢀ(oꢀtolyl)ꢀ1Hꢀindene (3k); a yellow solid (mp = 111ꢀ114 °C); (29 mg, 58% yield); H
NMR (600 MHz, CDCl3): δ 7.56 (t, J = 14.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.42–7.28 (m,
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4H), 7.15 (dd, J = 20.1, 7.6 Hz, 2H), 4.21 (s, 2H), 2.16 (s, 3H). C NMR (151 MHz, CDCl3): δ
148.9, 147.7, 142.5, 140.2, 136.1, 131.6, 130.4, 130.2, 129.0, 127.9, 127.8, 126.0, 124.8, 124.5,
37.7, 19.8. HRMS (ESI): [M+Na]+ calculated for C16H13NNaO2: 274.0838, found:274.0839.
5ꢀmethylꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3l); a yellow solid (mp = 72ꢀ74°C); (47 mg, 85%
yield); 1H NMR (400 MHz, CDCl3): δ 7.38 (m, J = 7.6 Hz, 1H), 7.30 (m, 6H), 7.26ꢀ7.18 (m, 1H),
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3.95 (s, 2H), 3.47ꢀ3.32 (t, J = 8.0 Hz, 2H), 3.03ꢀ2.92 (t, J = 8.0Hz, 2H), 2.42 (s, 3H). C NMR
(101 MHz, CDCl3): δ 151.4, 147.6, 141.8, 141.0, 137.6, 137.5, 131.3, 128.7, 128.6, 126.5, 124.3,
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123.5, 37.1, 34.6, 28.9, 21.7. HRMS (ESI): [M + Na]+ calculated for C18H17NNaO2: 302.1151,
found:302.1152.
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5ꢀ(tertꢀbutyl)ꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3m); a yellow solid (mp = 91ꢀ93 °C); (52 mg, 81%
yield); 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 7.9 Hz, 1H), 7.47ꢀ7.40 (m, 2H), 7.29ꢀ7.25 (m,
4H), 7.21 (d, J = 6.6 Hz, 1H), 3.96 (s, 2H), 3.42 (t, J = 7.9 Hz, 2H), 3.01 (t, J = 7.9 Hz, 2H), 1.33
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(s, 9H). C NMR (101 MHz, CDCl3): δ 152.0, 151.1, 147.6, 141.6, 141.0, 137.6, 128.7, 128.6,
127.8, 126.5, 124.1, 119.6, 37.0, 35.0, 34.7, 31.6, 28.8. HRMS (ESI): [M + Na]+ calculated for
C21H23NNaO2: 344.1621, found:344.1621.
5ꢀmethoxyꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3n); a yellow solid (mp = 73ꢀ74 °C); (42 mg, 71%
yield); 1H NMR (600 MHz, CDCl3): δ 7.39 (d, J = 8.2 Hz, 1H), 7.29 (m, 4H), 7.22 (m, 1H), 7.02
(d, J = 8.2 Hz, 1H), 6.98 (s, 1H), 3.94 (s, 2H), 3.82 (s, 3H), 3.37 (t, J = 7.8 Hz, 2H), 2.97 (t, J =
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7.9 Hz, 2H). C NMR (151 MHz, CDCl3): δ 159.7, 151.2, 148.4, 143.0, 140.9, 132.5, 128.7,
128.6, 126.6, 125.3, 116.9, 107.8, 55.7, 36.8, 34.6, 28.9. HRMS (ESI): [M + Na]+ calculated for
C18H17NNaO3: 318.1101, found:318.1103.
5ꢀbromoꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3o);a yellow solid (mp = 90ꢀ92 °C); (38 mg, 56%
yield); 1H NMR (600 MHz, CDCl3): δ 7.58 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.34–7.18 (m, 5H),
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3.96 (s, 2H), 3.36 (t, J = 7.7 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H). C NMR (151 MHz, CDCl3): δ
149.9, 148.4, 143.7, 140.5, 138.7, 132.9, 128.7, 128.6, 126.7, 126.1, 126.0, 121.7, 37.2, 34.5,
28.8. HRMS (ESI): [M + Na]+ calculated for C17H14BrNNaO2: 366.0100, found:366.0099.
5ꢀchloroꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3p); a yellow solid (mp = 73ꢀ75 °C); (28 mg, 47%
yield); 1H NMR (600 MHz, CDCl3): δ 7.45 (s, 1H), 7.43 (s, 2H), 7.34–7.25 (m, 4H), 7.23 (d, J =
6.9 Hz, 1H), 3.98 (s, 2H), 3.36 (t, J = 7.8 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H). 13C NMR (151 MHz,
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CDCl3): δ 150.0, 148.5, 143.4, 140.5, 138.2, 133.9, 130.1, 128.7, 128.6, 126.7, 125.7, 123.1, 37.2,
34.5, 28.8. HRMS (ESI): [M + Na]+ calculated for C17H14ClNNaO2: 322.0605, found:322.0605.
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MHz, CDCl3): δ 7.45 (m, 1H), 7.33ꢀ7.25 (m, 5H), 7.23 (m, 1H), 7.18 (m, 1H), 3.98 (s, 2H), 3.36
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(t, J = 8.0 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H). F NMR (565 MHz, CDCl3): δ ꢀ114.27. C NMR
(151 MHz, CDCl3): δ 162.8 (d, J = 245.5 Hz), 150.2, 148.9, 143.6 (d, J = 8.6 Hz), 140.6, 135.6,
128.8, 128.6, 126.7, 125.9 (d, J = 8.7 Hz), 117.4(d, J = 23.2 Hz), 109.9 (d, J = 23.6 Hz), 37.0,
34.6, 29.0. HRMS (ESI): [M + Na]+ calculated for C17H14FNNaO2: 306.0901, found: 306.0906.
6ꢀmethylꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3r); a yellow solid (mp = 86ꢀ88°C); (45 mg, 80%
yield); 1H NMR (600 MHz, CDCl3): δ 7.44 (d, J = 7.8 Hz, 1H), 7.31 (m, 5H), 7.23 (m, 2H), 3.96
(s, 2H), 3.42 (t, J = 7.9 Hz, 2H), 3.01 (t, J = 7.9 Hz, 2H), 2.45 (s, 3H). 13C NMR (151 MHz,
CDCl3): δ 151.7, 146.7, 141.0, 141.0, 140.8, 139.1, 128.7, 128.6, 126.5, 125.4, 122.8, 77.4, 77.2,
77.0, 37.3, 34.6, 29.0, 22.1. HRMS (ESI): [M + H]+ calculated for C18H18NO2: 280.1338,
found:280.1336.
6ꢀchloroꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3s); a yellow solid (mp = 67ꢀ70 °C); (23 mg, 38%
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yield); H NMR (600 MHz, CDCl3):δ 7.50 (s, 1H), 7.40 (m, 2H), 7.28 (m, 4H), 7.22 (m, 1H),
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4.00 (s, 2H), 3.38 (t, J = 7.7 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H). C NMR (151 MHz, CDCl3): δ
150.5, 147.4, 141.7, 140.6, 140.3, 136.5, 128.7, 128.6, 128.2, 126.7, 125.1, 124.0, 77.4, 77.2,
77.0, 37.3, 34.6, 28.9. HRMS (ESI): [M + Na]+ calculated for C17H14ClNNaO2: 322.0605,
found:322.0607.
7ꢀmethylꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3t); a yellow solid (mp = 55ꢀ57°C); (55 mg, 98%
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yield). H NMR (600 MHz, CDCl3): δ 7.41 (d, J = 7.4 Hz, 1H), 7.36–7.26 (m, 6H), 7.22 (d, J =
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8.8 Hz, 1H), 3.87 (s, 2H), 3.36 (t, J = 7.7 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H). C
NMR (151 MHz, CDCl3): δ 151.7, 147.3, 141.4, 140.9, 139.2, 134.0, 131.4, 128.7, 128.6, 128.0,
126.5, 120.7, 36.5, 34.67, 29.0, 18.5. HRMS (ESI): [M + Na]+ calculated for C18H17NNaO2:
302.1151, found:302.1158.
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7ꢀfluoroꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3u); a yellow solid (mp = 80ꢀ81 °C); (31 mg, 54%
yield); 1H NMR (600 MHz, CDCl3): δ 7.43–7.37 (m, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.32–7.24 (m,
4H), 7.22 (t, J = 6.8 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 4.04 (s, 2H), 3.36 (t, J = 7.6 Hz, 2H), 2.96
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(t, J = 7.6 Hz, 2H). F NMR (565 MHz, CDCl3): δ ꢀ118.30. C NMR (151 MHz, CDCl3): δ
158.6 (d, J = 249.9 Hz), 150.4 (d, J = 2.4 Hz), 147.9, 144.6 (d, J = 6.1 Hz), 140.6, 129.8 (d, J =
6.9 Hz), 128.7, 128.6, 126.6, 125.6 (d, J = 18.4 Hz), 119.1 (d, J = 3.3 Hz), 117.0 (d, J = 20.2 Hz),
34.6, 34.3, 29.0. HRMS (ESI): [M + Na]+ calculated for C17H14FNNaO2: 306.0901,
found:306.0896.
7ꢀbromoꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3v); a yellow solid (mp = 129ꢀ131 °C); (38 mg, 55%
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yield); H NMR (600 MHz, CDCl3): δ 7.60 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.40–
7.14 (m, 6H), 3.99 (s, 2H), 3.36 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H). 13C NMR (151 MHz,
CDCl3): δ 150.5, 143.1, 140.7, 133.1, 129.5, 128.8, 128.6, 126.7, 122.1, 119.4, 39.1, 34.7, 29.1.
HRMS (ESI): [M + Na]+ calculated for C17H14BrNNaO2: 366.0100, found:366.0099.
7ꢀchloroꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3w); a yellow solid (mp = 121ꢀ123°C); (22 mg, 37%
1
yield). H NMR (600 MHz, CDCl3): δ 7.44 (t, J = 8.1 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.32ꢀ
7.24 (m, 5H), 7.22 (d, J = 6.7 Hz, 1H), 4.02 (s, 2H), 3.39 (t, J = 7.7 Hz, 2H), 2.97 (t, J = 7.7 Hz,
2H). 13C NMR (151 MHz, CDCl3): δ 150.5, 147.8, 143.2, 140.6, 138.2, 130.7, 130.1, 129.3,
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128.7, 128.6, 126.7, 121.5, 37.2, 34.7, 29.1. HRMS (ESI): [M + Na]+ calculated for
C17H14ClNNaO2: 322.0605, found:322.0600.
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6,7ꢀdichloroꢀ2ꢀnitroꢀ3ꢀphenethylꢀ1Hꢀindene (3x); a yellow solid (mp = 111ꢀ113 °C); (19 mg, 28%
yield). 1H NMR (600 MHz, CDCl3): δ 7.49 (d, J = 8.2 Hz, 1H), 7.34ꢀ7.14 (m, 6H), 4.04 (s, 2H),
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3.36 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H). C NMR (151 MHz, CDCl3): δ 150.0, 147.8,
141.3, 140.4, 140.0, 134.5, 130.2, 129.3, 128.8, 128.6, 126.7, 122.0, 37.9, 34.6, 29.0. HRMS
(ESI): [M + Na]+ calculated for C17H13Cl2NNaO2: 356.0216, found:356.0216.
3ꢀisobutylꢀ6ꢀmethylꢀ2ꢀnitroꢀ1Hꢀindene (3y); as a yellow solid (mp = 107ꢀ109°C); (29 mg, 63%
yield). 1H NMR (600 MHz, CDCl3): δ 7.49 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J = 7.8 Hz,
1H), 3.96 (s, 2H), 3.04 (d, J = 7.3 Hz, 2H), 2.45 (s, 3H), 2.26–2.05 (m, 1H), 1.01 (d, J = 6.7 Hz,
6H). 13C NMR (151 MHz, CDCl3): δ 152.2, 146.9, 140.8, 140.7, 140.0, 128.5, 125.2, 123.5, 37.4,
35.2, 29.3, 23.1, 22.0. HRMS (ESI): [M+Na]+ calculated for C14H17NNaO2: 254.1151,
found:254.1155.
1
6ꢀchloroꢀ3ꢀisobutylꢀ2ꢀnitroꢀ1Hꢀindene (3z); a yellow oil，(26 mg, 51% yield); H NMR (600
MHz, CDCl3): δ 7.53 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.41 (dd, J = 8.2, 1.6 Hz, 1H), 4.01 (s,
13
2H), 3.03 (d, J = 7.3 Hz, 2H), 2.14 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H). C NMR (151 MHz,
CDCl3): δ 150.9, 147.6, 141.7, 141.1, 136.3, 128.1, 125.0, 124.6, 37.5, 35.1, 29.3, 23.1. HRMS
(ESI): [M+Na]+calculated forC13H14ClNNaO2: 274.0605, found:274.0609.
Derivatization Reactions:
1-hydroxy-1-phenyl-1,3-dihydro-2H-inden-2-one (4): 3a (125.0 mg, 0.53 mmol) was dissolved
in methanol (2.0 mL) and RaneyꢀNi (30 mg) was added, The reaction vessel was then
pressurized with hydrogen at 1 atm and vigorously stirred at room temperature. After complete
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conversion (TLC), The heterogeneous mixture was then filtered through a bed of celite and the
celite subsequently washed with CH2Cl2, The filtrate was concentrated (rotary evaporator) to
remove the solvent, concentrated and purified by silica gel chromatography (PE :EA = 2:1) to
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give the product 4 (50.9 mg, yield 44%); (mp = 100ꢀ103 °C). H NMR (600 MHz, Acetone): δ
7.47 (d, J = 7.0 Hz, 1H), 7.46ꢀ7.36 (m, 2H), 7.36ꢀ7.28 (m, 5H), 7.28ꢀ7.22 (m, 1H), 5.46 (s, 1H),
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3.73 (d, J = 21.8 Hz, 1H), 3.54 (d, J = 21.9 Hz, 1H). C NMR (151 MHz, Acetone): δ 214.00,
145.8, 142.8, 137.7, 129.9, 129.1, 129.0, 128.4, 127.00, 126.5, 125.9, 82.8, 40.9. HRMS (ESI):
[M+Na]+calculated for C15H12NaO2: 247.0730, found: 247.0739.
KIE measurements of reaction for 3c:
An equimolar mixture of 1a (36.0 mg, 0.2mmol) and 1a-d5 (37.0 mg, 0.2 mmol), 2c (26.0 mg,
0.2 mmol), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv), AgSbF6 (27.5 mg, 0.080 mmol,
0.200 equiv) in CF3CH2OH (2.0 mL) were charged into a pressure tube under the air atmosphere.
The reaction mixture was stirred at room temperature for 3 min. then filtered through a 0.5 inch
plug of silica gel (eluting with EtOAc) to remove the solid and the residue was purified by silica
gel chromatography,using PE/EA (10:1) to afford the mixed product 3c. KIE value (kH/kD = 5.7)
was determined on the basis of 1HNMR analysis.
H/D exchange:
For 1a: Arylnitron 1a (69.0 mg, 0.400 mmol, 2.00 equiv), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol,
0.050 equiv), AgSbF6 (27.5 mg, 0.080 mmol, 0.200 equiv) and D2O (22 mg, 1.20 mol) in
CF3CH2OH (2.0 mL) were charged into a 50 mL pressure tube under the air atmosphere. The
tube was then sealed and placed in a preheated oil bath at 80 °C for 24 h, then reaction vial was
removed from the oil bath and cooled to ambient temperature. The reaction mixture was filtered
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through a pad of celite eluting with ethyl acetate, concentrated and purified by silica gel
chromatography (PE : DCM = 1:2) to give the product. H/D exchange at the 2ꢀposition was
detected on the basis of 1H NMR analysis.
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For 3c’: Arylnitron 1a (69.0 mg, 0.400 mmol, 2.00 equiv) and nitroalkene 2c (26.0 mg, 0.200
mmol, 1.00 equiv), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv), AgSbF6 (27.5 mg, 0.080
mmol, 0.200 equiv) and D2O (22 mg, 1.2 mol) in CF3CH2OH (2.0 mL) were charged into a 50
mL pressure tube under the air atmosphere. The tube was then sealed and placed in a preheated
oil bath at 80 °C under the air for 3 min. then reaction vial was removed from the oil bath and
cooled to ambient temperature. The reaction mixture was filtered through a pad of celite eluting
with ethyl acetate, concentrated and purified by silica gel chromatography (PE : DCM = 2:1) to
give the product. For the product 3c’, only H/D exchange at the 7ꢀposition was detected, no H/D
exchange at the 2ꢀposition was detected on the basis of 1H NMR analysis.
Competitive Experiment:
For 3p/3n: An equimolar mixture of 1p (42.2 mg, 0.2 mmol), 1n (41.4 mg, 0.2 mmol), 2b (36.0
mg, 0.2 mmol), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv), AgSbF6 (27.5 mg, 0.080 mmol,
0.200 equiv) in CF3CH2OH (2.0 mL) were charged into a pressure tube under the air atmosphere.
The reaction mixture was stirred at room temperature for 24h. then filtered through a 0.5 inch
plug of silica gel (eluting with EtOAc) to remove the solid and the residue was purified by silica
gel chromatography, using PE/EA (10:1) to afford the mixed product. The yield ratio (3p/3n=
1:2.1) was determined on the basis of 1H NMR analysis.
For 3a/3f: An equimolar mixture of 1a (35.0 mg, 0.2 mmol), 2a (30.0 mg, 0.2 mmol), 2b (36.0
mg, 0.2 mmol), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv), AgSbF6 (27.5 mg, 0.080 mmol,
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0.200 equiv) in CF3CH2OH (2.0 mL) were charged into a pressure tube under the air atmosphere.
The reaction mixture was stirred at room temperature for 24h. then filtered through a 0.5 inch
plug of silica gel (eluting with EtOAc) to remove the solid and the residue was purified by silica
gel chromatography, using PE/EA (10:1) to afford the mixed product. The yield ratio (3a/3f =
1.5:1) was determined on the basis of 1H NMR analysis.
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AUTHOR INFORMATION
Corresponding Author
xwli@dicp.ac.cn
changjunbiao@zzu.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The NSFC (Nos. 21525208 and 21472186), research fund from Henan Normal University
(5101034011009)
Supporting Information
Copies of 1H NMR and 13C NMR spectra for all new compounds, deuteriumꢀlabelling
experiments, competitive experiment, This material is available free of charge via the Internet at
http://pubs.acs.org.
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