Construction of Multi-Substituted Benzenes via NHC-Catalyzed Reactions of Carboxylic Esters

Article abstract of DOI:10.1002/cjoc.201700773

A carbene-catalyzed ester activation reaction for the synthesis of multi-substituted benzenes is developed. Tetra-substituted benzene compounds are efficiently synthesized through this methodology. Compared with aldehyde substrates used in previous reports, the ester substrates used here are much more readily available and inexpensive. In addition, the TEMPO oxidant used here is more inexpensive than the quinones commonly used in related carbene-catalyzed reactions.

Full text of DOI:10.1002/cjoc.201700773

Cite this paper: Wu, J.; Mou, C.; Chi, Y. R. Chin. J. Chem. 2018, 36, 333－337.
Concise Report
DOI: 10.1002/cjoc.201700773
Construction of Multi‐Substituted Benzenes via NHC‐Catalyzed Reactions
of Carboxylic Esters
Jichang Wu,a Chengli Mou,*,b and Yonggui Robin Chi*,a
ABSTRACT A carbene‐catalyzed ester activation reaction for the synthesis of multi‐substituted benzenes is developed. Tetra‐substituted benzene com‐
pounds are efficiently synthesized through this methodology. Compared with aldehyde substrates used in previous reports, the ester substrates used here
are much more readily available and inexpensive. In addition, the TEMPO oxidant used here is more inexpensive than the quinones commonly used in
related carbene‐catalyzed reactions.
KEYWORDS N‐heterocyclic carbene, carboxylic ester, benzene synthesis, organocatalysis, TEMPO oxidation
Introduction
a) NHC-catalyzed reactions for benzene synthesis:
Substituted benzenes are frequently found in both natural
O
O
OH
O
products and pharmaceuticals.[1] More than 70% of the best sold
human medicines contain at least one benzene ring in their struc‐
tures.[2] Therefore, the synthesis of substituted benzenes is im‐
portant. Traditionally, benzene rings with different substituents
were prepared through electrophilic substitutions on the benzene
structures[3] or transition metal‐catalyzed cross coupling reactions
using halogenated benzenes.[4] The direct construction of the
benzene rings through transition metal catalysis was disclosed
more than 50 years ago.[5] Various excellent methodologies have
been developed within this field including the transition metal
catalyzed [2＋2＋2] and [4＋2] reactions.[6] However, the con‐
struction of benzene rings through organocatalytic reactions has
been much less developed.[7] Therefore, developing a range of
organocatalytic methodologies that are complimentary to each
other to provide multiple strategies in the synthesis of substituted
benzenes is important.
We are interested in constructing various aromatic rings
through metal‐free organocatalytic reactions.[8] We have previ‐
ously reported the N‐heterocyclic carbene (abbreviated as NHC or
carbene) catalyzed [3＋3] oxidative reaction for the synthesis of
multi‐substituted benzene compounds.[9] β‐Methyl substituted
α,β‐unsaturated aldehydes were used to react with oxadienes to
afford 2,4,6‐tri‐substituted acetophenones in moderate to good
yields. The activation of the δ‐carbons on rationally designed vi‐
nylogous enals has also been developed to synthesize a variety of
multi‐substituted benzene molecules.[10] However, as a technical
note, the aldehyde substrates used in these methods are routinely
prepared from corresponding esters through a sequential reduc‐
tion/oxidation process (Figure 1a, right part). Therefore, the direct
activation of ester substrates in the benzene synthesis is interest‐
ing.[11] Herein, we report the construction of substituted benzene
rings through NHC catalytic reactions using β‐methyl substituted
α,β‐unsaturated esters as the starting materials (Figure 1a, left
part). Mechanistically, the α,β‐unsaturated carboxylic ester 1 is
initially attacked by the carbene catalyst and gives the acyl azoli‐
um intermediate I, which could react with oxadiene 2 through
Michael addition/enolization processs to form intermediate II.
Intermediate II then goes through an intramolecular aldol reaction
to form intermediate III, which leads to IV through lactone for‐
mation and liberates the NHC catalyst. Decarboxylation of IV de‐
livers intermediate V, which finally afford the benzene product 3
through an additional oxidation step (Figure 1b).
NHC
reduction
oxidation
NHC
OR
H
Ph
Ph
Ph
Ph
NHC
O
O
O
O
O
O
O
Ph
a, b, c, d
Ph
oxidation
NHC
NHC
a, b, c, d
Ph
Ph
Ph
Ph
this work
our previous work
a. Michael addition
b. Aldol reaction
c. de-carboxylation
d. oxidation
 0 reduction step
1 oxidation step
 1 reduction step
 3 oxidation steps

b) postulated reaction pathway:
O
N
O
O
O
N
NHC
OAr
+
oxidant
R
R
R'
O
R'
Ar = 4-NO2C6H4
2
3
1
[O]
NHC
"redox economy"
- H
O
NHC
V
R
O
R'
O
R
- CO2
I
O
NHC
NHC
O
O
Michael
addition
O
2
R
aldol
lactone
formation
- NHC
R
reaction
proton
O
R'
O
R
R'
transfer
R'
IV
III
II
O
Figure 1 NHC‐catalyzed ester activation for benzene synthesis.
Results and Discussion
The β‐methyl substituted α,β‐unsaturated ester 1a was cho‐
sen as the model substrate to react with oxadiene 2a. The substi‐
tuted benzene product 3a could be afforded in 28% yield with air
as the oxidant with the use of NHC pre‐catalyst A (Table 1, Entry 1).
No or trace product could be observed when using B, C or D as
the NHC pre‐catalysts (Entry 2). The product yield could be dra‐
a Laboratory Breeding Base of Green Pesticide and Agricultural Bioengi‐
neering, Key Laboratory of Green Pesticide and Agricultural Bioengi‐
neering Ministry of Education, Guizhou University, Huaxi District, Gui‐
yang, Guizhou 550025, China
b School of Pharmacy, Guiyang College of Traditional Chinese Medicine,
Huaxi District, Guiyang, Guizhou 550025, China
*E‐mail: robinchi@ntu.edu.sg, mouchengli_h@163.com
Chin. J. Chem. 2018, 36, 333－337
© 2018 SIOC, CAS, Shanghai, & WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
333

Wu, Mou & Chi
Concise Report
matically increased when oxidant 4[12] was added into the catalytic
system (Entry 3). A variety of oxidants were then examined for
this catalytic process (Entries 3 to 6). The radical oxidant TEMPO
Table 2 Substrate scopea
A (30 mol%)
O
O
O
O
Cs2CO3 (200 mol%)
OAr
R'
5 (200 mol%)
5
[13] could give the benzene product 3a in 75% yield (Entry 4). The
R'
+
THF
RT, 15 h
Ar'
Ar'
R
substituted benzene 3a could also be afforded with phenazine 6
or MnO2 as the oxidants, although the product yields were slightly
lower. The yield of 3a could be further improved to 86% when 2
equiv. of the TEMPO 5 was applied as the oxidative additive (Entry
7). We then decided to use 2 equiv. of 5 as the oxidant in the fol‐
lowing examinations of different bases and solvents (Entries 8 to
11). Switching the base additives from Cs2CO3 to other organic/
inorganic bases led to drops of the product yields (e.g., Entries 8
to 9). A variety of organic solvents could be used for this trans‐
formation (e.g., Entries 10 to 11), but the product yields did not
show further improvements comparing with the reaction using
THF as the solvent (Entry 7). It is worth noting that the radical
oxidant TEMPO 5 ($ 20/g, TCI) used in this methodology is less
expensive than the oxidant 4 ($ 146/g, TCI) used in our previous
aldehyde activation approaches.[9,10]
R
Ar = 4-NO2C6H4
1
2
3
O
O
O
Ph
Ph
Ph
Ph
H3C
H3CO
3b, 84%
3c, 90%
3a, 86%
O
O
O
OCH3
H3C
H3CO
Ph
Ph
Ph
O
3d, 77%
3e, 85%
3f, 81%
3i, 60%
O
O
Table 1 Condition optimizationa
O
NHC
base
oxidant
O
Ph
Ph
Ph
O
O
OAr
F
Br
Cl
Cl
3g, 59%
3h, 63%
+
solvent
RT, 15 h
Ph
Ph
Ph
O
Ph
O
O
Ar = 4-NO2C6H4
Cl
F
1a
2a
3a
tBu
tBu
tBu
tBu
Ph
O
Ph
Ph
oxidant:
NHC:
N
O
O
3l, 63%
3j, 57%
3k, 65%
N
Mes
N
Mes
Ph
N
N
N
O
O
Mes
Cl
Cl
4
A
B
O
N
F
O
S
N
N
N
Ph
Ph
Ph
N
Mes
N
N
N
3m, 73%
3n, 95%
3o, 85%
BF4
BF4
5
6
C
D
O
O
O
Entry
Cat.
Base
Oxidant
Solvent
Yieldb/%
28
Ph
Ph
Ph
Ph
c
1
2
3
4
5
A
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
—
—
4
THF
THF
THF
THF
THF
THF
THF
THF
THF
c
F
CH3
B
/
C
/
D
＜5
3p, 82%
3q, 77%
3r, 70%
A
A
A
A
A
A
A
A
A
69
75
62
52
86
44
0
O
O
O
5
6
Br
6
MnO2
Ph
Ph
7d
8d
9d
10d
11d
5
5
5
5
5
Cl
3s, 62%
3t, 58%
3u, 70%
TEA
Cs2CO3
Cs2CO3
O
O
O
CH2Cl2
CH3CN
70
68
Ph
S
a 1.0 equiv. 1a (0.1 mmol), 1.0 equiv. 2a, 30 mol% NHC, 200 mol% base, 1.0
equiv. oxidant, 1.2 mL THF, r.t., 15 h. b Yields were isolated yields via SiO2
column chromatography. c Under air. d 2.0 equiv. oxidant 5 was used.
Ph
Ph
Ph
Ph
3v, 70%
3w, 48%
3x, 56%
a Reactions were carried out under conditions as stated in Table 1, Entry 7.
The product yields indicated isolated yields after column chromatography.
With an optimized reaction condition in hand, we then tested
the scope of this benzene constructing process using substrates
with different substitution patterns (Table 2). Electron donating
substitutents were well torlerated on each position of the β‐
benzene rings of the ester substrates 1, with the corresponding
tetra‐substituted benzene products afforded in good isolated
yields (3b to 3f). Electron withdrawing groups also worked well in
this transformation, although the product yields were slightly
lower (3g to 3m). The substituted benzene rings on substrates 1
could even be switched to a variety of hetero aromatic groups (3n
to 3o) or a napthyl group (3p) and the products could be isolated
in good to excellent yields. However, no products could be
observed when the β‐aryl groups on the ester substrates 1 were
replaced with alkyl groups. This might be because that the C—H
bond on the β‐dialkyl ester is not sufficiently acidic to be activated
by the NHC catalyst to react with the oxadiene substrates. Substit‐
uents with different electronic properties could also be installed
on the β‐benzene rings of the oxadiene substrates 2, with all the
products afforded in moderate to good isolated yields (3q to 3u).
Notably, the aryl groups on substrates 2 could be replaced with
334
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© 2018 SIOC, CAS, Shanghai, & WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2018, 36, 333－337

Construction of Multi‐Substituted Benzenes
Chin. J. Chem.
either a hetero aromatic thiophenyl group (3v) or even an aliphat‐
ic alkene group with a conjugated double bond installed next to
the β‐position of oxadiene substrate (3w). One of the methyl
groups attached to the ketone moieties of the substrate 2 could
be replaced with an aromatic benzene substituent, although the
corresponding product could only be afforded in moderate yield
under the current catalyic reaction condition (3x).
reduced pressure to afford the desired α,β‐unsaturated acid S3,
which was used in the next reaction without further purification.
To a 50 mL round bottom flask containing α,β‐unsaturated acids
S3 (10 mmol) and EtOAc (15 mL) was successively added 4‐nitro‐
phenol (11 mmol), DCC (11 mmol) and DMAP (0.4 mmol), and the
reaction mixture was stirred at room temperature for 12 h. After
completion of the reaction, the precipitate was filtered and the
filtrate was concentrated under reduced pressure. The resulting
residue was subjected to flash chromatography [V(hexanes)/
V(EtOAc)＝5/1] to give substrate 1.
Conclusions
In summary, we have developed a carbene catalyzed ester ac‐
tivation reaction for the construction of substituted benzene rings.
2,4,6‐Tri‐substituted acetophenones (tetra‐substituted benzenes)
could be efficiently synthesized in up to 95% isolated yields through
this strategy. This newly developed methodology processes certain
advantages over the previous aldehyde activation approaches
because the ester substrates used here are easily prepared and
inexpensive. Moreover, the TEMPO oxidant used in this method is
much more inexpensive than the quinone oxidant 4 that has been
frequently used in the aldehyde oxidative activations. Further
investigations on the synthesis of multi‐substituted aromatic com‐
pounds through organocatalytic reactions are currently in pro‐
gress in our laboratory.
General procedure for the preparation of substrates 2
AlCl3 (0.2 mmol) was added to a solution of the β‐diketone
(1.0 mmol) in DCM (2 mL) and the mixture was stirred at room
temperature for 5 min. Then the aldehyde (1.0 mmol) was added
and the resulting system was stirred at room temperature until
the reaction was complete (determined by TLC). Then the reaction
was quenched with saturated NaHCO3 solution. After extraction
with DCM (10 mL×3), the organic phase was collected and dried
over Na2SO4. The solvent was removed under reduced pressure,
and the crude mixture was purified by silica gel column chroma‐
tography.
1‐(5'‐Methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone (3a). Light
yellow oil, 86% yield. 1H NMR (500 MHz, CDCl3) δ: 7.64—7.62 (m,
2H), 7.38—7.64 (m, 10H), 2.41 (s, 3H), 1.98 (s, 3H); 13C NMR (126
MHz, CDCl3) δ: 207.69, 141.96, 140.68, 140.43, 139.49, 134.67,
129.23, 129.22, 129.21, 129.08, 128.91, 128.55, 128.09, 127.99,
Experimental
General information
＋
127.43, 126.41, 32.38, 20.02; HRMS (ESI) calcd for C21H19O [M＋H] :
287.1430, found 287.1431.
Commercially available materials purchased from Alfa Aesar
or Sigma‐Aldrich were used as received. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Bruker (500 or
400 MHz) spectrometer. Chemical shifts were recorded (δ) relative
1‐(4,5'‐Dimethyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone (3b).
1
Light yellow powder, 84% yield; m.p.: 143—144 °C. H NMR (500
1
MHz, CDCl3) δ: 7.54—7.52 (m, 2H), 7.44—7.39 (m, 7H), 2.41 (s,
3H), 2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 207.66,
141.68, 140.56, 139.95, 139.28, 137.65, 137.30, 134.47, 129.57,
128.99, 128.67, 128.13, 127.82, 127.02, 125.99, 32.19, 21.14,
to tetramethylsilane (δ 0.00) or chloroform (δ 7.26, singlet). H
NMR splitting patterns are designated as singlet (s), doublet (d),
triplet (t), quartet (q), dd (doublet of doublets), m (multiplets), etc.
All first‐order splitting patterns were assigned on the basis of the
appearance of the multiplet. Splitting patterns that could not be
easily interpreted are designated as multiplet (m) or broad (br).
Carbon nuclear magnetic resonance (13C NMR) spectra were
recorded on a Bruker (126 MHz) (101 MHz) spectrometer. High
resolution mass spectral analysis (HRMS) was performed on
Thermo Fisher Q Exactive mass spectrometer. Analytical thin‐layer
chromatography (TLC) was carried out on pre‐coated silica gel
plate (0.2 mm thickness). Melting Point (m.p.): Melting points
were measured on a Beijing Tech XT‐4 micro melting point appa‐
ratus and are uncorrected. Visualization was performed using a
UV lamp.
＋
19.82; HRMS (ESI) calcd for C22H21O [M＋H] : 301.1587, found
301.1586.
1‐(4‐Methoxy‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3c). Light yellow oil, 90% yield. 1H NMR (500 MHz, CDCl3) δ:
7.58—7.56 (m, 2H), 7.43—7.39 (m, 7H), 7.00—6.98 (m, 2H), 3.86
(s, 3H), 2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ:
199.90, 141.87, 140.63, 140.36, 140.31, 137.67, 137.57, 135.88,
133.14, 129.39, 129.21, 128.90, 128.32, 128.10, 128.06, 127.77,
127.29, 127.25, 126.22, 19.95; HRMS (ESI) calcd for C22H20O2
＋
Na[M＋Na] : 339.1356, found 339.1361.
1‐(2‐Methoxy‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3d). Light yellow oil, 77% yield. 1H NMR (500 MHz, CDCl3) δ:
7.45—7.30 (m, 9H), 7.07—6.95 (m, 2H), 3.84 (s, 3H), 2.37 (s, 3H),
1.96 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 207.85, 156.56, 140.75,
139.98, 139.27, 138.52, 133.67, 130.95, 130.79, 129.79, 129.57,
129.15, 128.67, 127.73, 120.99, 117.38, 111.31, 55.71, 32.26,
General procedure for the preparation of substrates 1
To a 100 mL round bottom flask containing NaH (46 mmol, 60%
mineral dispersion) and anhydrous THF (92 mL) at 0 °C, was added
triethyl phosphonoacetate (49.6 mmol) dropwise via an addition
funnel. The reaction mixture was gradually warmed to r.t., fol‐
lowed by a dropwise addition of the ketone solution (20 mmol, in
46 mL anhydrous THF). The reaction mixture was stirred for 12 h,
and then quenched with water. The organic layer was separated,
and the aqueous layer was extracted with diethyl ether (50 mL×
2). The combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude residue was
subjected to flash chromatography [V(hexanes)/V(EtOAc)＝95/5]
to afford the corresponding α,β‐unsaturated ester S2. To a 100 mL
round bottom flask was added α,β‐unsaturated ester S2 (15
mmol), 0.5 N aqueous KOH (42 mL) and the reaction mixture was
stirred at 100 °C until the oil layer disappeared. After cooling to rt,
1 mol/L aqueous HCl solution (200 mL) was carefully added and
the reaction mixture was extracted with diethyl ether (100 mL×
3). The combined organic layers were washed with brine (200 mL),
dried over Na2SO4 and filtered, the solvent was removed under
＋
19.85; HRMS (ESI) calcd for C22H21O2 [M＋H] : 317.1536, found
317.1528.
1‐(3,5'‐Dimethyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone (3e).
1
Light yellow oil, 85% yield. H NMR (400 MHz, CDCl3) δ: 7.43 (t,
J＝3.8 Hz, 4H), 7.42—7.37 (m, 5H), 7.33 (t, J＝7.8 Hz, 1H), 7.21—
7.17 (m, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (101
MHz, CDCl3) δ: 207.64, 141.92, 140.56, 140.22, 140.16, 139.28,
138.50, 134.45, 129.03, 128.78, 128.69, 128.53, 128.37, 127.99,
127.85, 126.24, 124.33, 32.19, 21.54, 19.81; HRMS (ESI) calcd for
＋
C22H21O [M＋H] : 301.1587, found 301.1587.
1‐(3‐Methoxy‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3f). Light yellow oil, 81% yield. 1H NMR (500 MHz, CDCl3) δ: 7.43
(dd, J＝6.8, 3.7 Hz, 3H), 7.42—7.38 (m, 4H), 7.38—7.34 (m, 1H),
7.23—7.18 (m, 1H), 7.16—7.12 (m, 1H), 6.93—6.91 (m, 1H), 3.86
(s, 3H), 2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (126 MHz, CDCl3) δ:
207.62, 160.11, 141.84, 141.74, 140.54, 140.46, 139.36, 134.57,
Chin. J. Chem. 2018, 36, 333－337
© 2018 SIOC, CAS, Shanghai, & WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley‐vch.de
335

Wu, Mou & Chi
Concise Report
129.96, 129.10, 128.78, 128.48, 127.96, 126.34, 119.79, 113.28,
113.03, 55.45, 32.24, 19.88; HRMS (ESI) calcd for C22H21O2 [M＋H] :
140.23, 139.47, 134.69, 131.30, 129.02, 128.77, 128.00, 124.80,
122.82, 111.89, 106.18, 32.20, 19.87; HRMS (ESI) calcd for
＋
＋
317.1536, found 317.1528.
C19H17O2 [M＋H] : 277.1223, found 277.1223.
1‐(4‐Fluoro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3g). Light yellow oil, 59% yield. 1H NMR (500 MHz, CDCl3) δ:
7.60—7.57 (m, 2H), 7.43—7.39 (m, 7H), 7.16—7.12(m, 2H), 2.40
(s, 3H), 1.96 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 207.47, 162.82
(d, Jcf＝247.2 Hz), 140.84, 140.45, 140.34, 139.48, 136.46, 134.69,
129.07, 128.87 (d, Jcf＝8.1 Hz), 128.78, 128.27, 128.00, 126.14,
1‐(3‐Methyl‐5‐(thiophen‐2‐yl)‐[1,1'‐biphenyl]‐2‐yl)ethanone
(3o). Light yellow oil, 85% yield. 1H NMR (400 MHz, CDCl3) δ:
7.49—7.42 (m, 3H), 7.42—7.35 (m, 5H), 7.32 (dd, J＝5.1, 1.1 Hz,
1H), 7.10 (dd, J＝5.1, 3.6 Hz, 1H), 2.37 (s, 3H), 1.94 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ: 207.23, 143.30, 140.35, 140.24, 139.56,
134.90, 134.83, 128.97, 128.74, 128.15, 128.00, 126.97, 125.53,
115.83 (d, Jcf＝21.4 Hz), 32.20, 19.84; 19F NMR (471 MHz, CDCl3) δ: 124.84, 123.84, 32.12, 19.75; HRMS (ESI) calcd for C19H17OS [M＋
＋
＋
–114.75; HRMS (ESI) calcd for C21H18OF [M＋H] : 305.1336, found
305.1338.
H] : 293.0995, found 293.0992.
1‐(3‐Methyl‐5‐(naphthalen‐2‐yl)‐[1,1'‐biphenyl]‐2‐yl)ethan‐
one (3p). Light yellow powder, 82% yield; m.p.: 110—111 °C. H
NMR (400 MHz, CDCl3) δ: 8.09 (d, J＝1.4 Hz, 1H), 7.97—7.85 (m,
3H), 7.78 (dd, J＝8.5, 1.9 Hz, 1H), 7.59 (dd, J＝3.5, 0.5 Hz, 2H),
7.56—7.47 (m, 2H), 7.46—7.41 (m, 5H), 2.44 (s, 3H), 1.99 (s, 3H);
13C NMR (101 MHz, CDCl3) δ: 207.56, 141.66, 140.51, 140.31,
139.45, 137.52, 134.65, 133.64, 132.86, 129.06, 128.73, 128.58,
128.26, 127.92, 127.69, 126.46, 126.22, 126.07, 125.37, 32.20,
1
1‐(4‐Bromo‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3h). Light yellow powder, 63% yield; m.p.: 176—177 °C. 1H NMR
(500 MHz, CDCl3) δ: 7.61—7.55 (m, 2H), 7.51—7.47 (m, 2H),
7.45—7.37 (m, 7H), 2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ: 207.53, 140.60, 140.32, 139.54, 139.21, 134.81, 132.07,
129.06, 128.87, 128.83, 128.18, 128.07, 126.06, 122.19, 32.23,
＋
19.89; HRMS (ESI) calcd for C21H18OBr [M＋H] : 365.0536, found
＋
365.0642.
19.86; HRMS (ESI) calcd for C25H21O [M＋H] : 337.1587, found
337.15
1‐(4‐Chloro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3i). Light yellow powder, 60% yield; m.p.: 159—160 °C. H NMR
(500 MHz, CDCl3) δ: 7.57—7.54 (m, 2H), 7.44—7.42 (m, 2H),
7.42—7.39 (m, 7H), 2.40 (s, 3H), 1.96 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ: 207.39, 140.57, 140.37, 139.53, 138.76, 134.76, 134.01,
129.10, 129.06, 128.79, 128.51, 128.21, 128.03, 126.10, 32.18,
1
1‐(2''‐Fluoro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3q). Light yellow oil, 77% yield. 1H NMR (500 MHz, CDCl3) δ: 7.62
(dd, J＝8.3, 1.2 Hz, 2H), 7.49—7.44 (m, 4H), 7.39—7.37 (m, 2H),
7.30 (td, J＝7.5, 1.7 Hz, 1H), 7.23—7.14 (m, 2H), 2.43 (s, 3H), 2.09
(s, 2H); 13C NMR (126 MHz, CDCl3) δ: 206.48, 159.47 (d, J＝246.8
Hz), 141.69, 140.94, 140.13, 134.61, 132.88, 132.06, 130.06 (d,
J＝8.1 Hz), 129.03 (d, J＝25.5 Hz), 127.89, 127.79, 127.24 (d, J＝
20.9 Hz), 124.40, 124.37, 116.02 (d, J＝22.1 Hz), 31.78, 20.03; 19F
NMR (471 MHz, CDCl3) δ: –114.97; HRMS (ESI) calcd for C21H18OF
＋
19.84; HRMS (ESI) calcd for C21H18OCl [M＋H] : 321.1041, found
321.1040.
1‐(2‐Chloro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3j). Light yellow oil, 57% yield. 1H NMR (400 MHz, CDCl3) δ:
7.51—7.47 (m, 1H), 7.42—7.34 (m, 6H), 7.34—7.29 (m, 4H), 2.38
(s, 3H), 1.99 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 207.68, 140.48,
140.24, 139.93, 139.61, 138.47, 133.79, 132.43, 131.34, 130.57,
130.07, 129.04, 128.88, 128.67, 128.54, 127.85, 126.93, 32.17,
＋
[M＋H] : 305.1336, found 305.1328.
1‐(4'',5'‐Dimethyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone (3r).
1
Light yellow oil, 70% yield. H NMR (500 MHz, CDCl3) δ: 7.64—
7.58 (m, 2H), 7.48—7.40 (m, 4H), 7.36 (td, J＝7.1, 3.2 Hz, 1H),
7.29 (d, J＝8.0 Hz, 2H), 7.22 (d, J＝7.9 Hz, 2H), 2.39 (s, 3H), 2.38 (s,
3H), 1.97 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 207.81, 141.83,
140.41, 140.28, 139.40, 137.80, 137.64, 134.54, 129.49, 128.96,
128.93, 128.23, 127.81, 127.30, 126.31, 32.28, 21.29, 19.90;
＋
19.70; HRMS (ESI) calcd for C21H18OCl [M＋H] : 321.1041, found
321.1028.
1‐(2‐Fluoro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3k). Light yellow oil, 65% yield. 1H NMR (400 MHz, CDCl3) δ: 7.46
(td, J＝7.7, 1.8 Hz, 1H), 7.43—7.30 (m, 8H), 7.24—7.13 (m, 2H),
2.39 (s, 3H), 1.97 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 206.47,
＋
HRMS (ESI) calcd for C22H21O [M＋H] : 301.1587, found 301.1586.
1‐(4''‐Chloro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
160.00, 157.53, 139.55, 139.23, 137.87, 135.37, 133.07, 129.69 (d, (3s). Light yellow oil, 62% yield. 1H NMR (400 MHz, CDCl3) δ: 7.61
J＝3.3 Hz), 129.13 (d, J＝2.9 Hz), 128.39 (d, J＝8.3 Hz), 128.00,
127.64, 127.21, 127.08, 127.01 (d, J＝2.8 Hz), 126.83, 123.41 (d,
J＝3.7 Hz), 115.15 (d, J＝22.7 Hz), 31.09, 18.69; 19F NMR (376
(dd, J＝8.3, 1.3 Hz, 2H), 7.52—7.42 (m, 3H), 7.42—7.31 (m, 6H),
2.39 (s, 3H), 2.00 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 207.35,
141.94, 140.22, 140.07, 138.89, 137.89, 134.59, 134.16, 130.31,
128.91, 128.90, 128.68, 127.88, 127.21, 126.09, 32.31, 19.74;
＋
MHz, CDCl3) δ: –117.61; HRMS (ESI) calcd for C21H18OF [M＋H] :
＋
305.1336, found 305.1332.
HRMS (ESI) calcd for C21H18OCl [M ＋H] : 321.1041, found
321.1039.
1‐(3‐Chloro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3l). Light yellow oil, 63% yield. 1H NMR (400 MHz, CDCl3) δ: 7.60
(t, J＝1.6 Hz, 1H), 7.49 (dt, J＝7.3, 1.7 Hz, 1H), 7.45—7.32 (m, 9H),
2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 207.38,
142.08, 140.77, 140.32, 140.21, 139.46, 134.79, 134.72, 130.10,
129.00, 128.75, 128.28, 128.00, 127.78, 127.34, 126.18, 125.37,
1‐(3''‐Bromo‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3t). Light yellow oil, 58% yield. 1H NMR (400 MHz, CDCl3) δ: 7.61
(dt, J＝3.7, 1.5 Hz, 3H), 7.56—7.50 (m, 1H), 7.50—7.42 (m, 3H),
7.39 (dd, J＝4.4, 2.8 Hz, 2H), 7.35—7.27 (m, 2H), 2.39 (s, 3H), 2.02
(s, 3H); 13C NMR (101 MHz, CDCl3) δ: 207.11, 142.53, 141.96,
140.15, 139.99, 137.61, 134.66, 131.78, 130.96, 130.15, 128.91,
128.88, 127.91, 127.83, 127.22, 126.12, 122.81, 32.35, 19.79;
＋
32.13, 19.78; HRMS (ESI) calcd for C21H18OCl [M＋H] : 321.1041,
found 321.1032.
＋
1‐(3‐Fluoro‐5'‐methyl‐[1,1':3',1''‐terphenyl]‐4'‐yl)ethanone
(3m). Light yellow oil, 73% yield. H NMR (500 MHz, CDCl3) δ:
HRMS (ESI) calcd for C21H18OBr [M＋H] : 365.0536, found
365.0532.
1
7.48—7.36 (m, 9H), 7.35—7.28 (m, 1H), 7.12—7.02 (m, 1H), 2.39
(s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 162.16 (d, J＝
246.0 Hz), 141.47 (d, J＝7.6 Hz), 129.31 (d, J＝8.4 Hz), 113.53 (d,
J＝21.2 Hz), 113.08 (d, J＝22.1 Hz); 19F NMR (471 MHz, CDCl3) δ:
–112.68; HRMS (ESI) calcd for C21H18OF [M＋H] : 305.1336, found
305.1349.
1‐(3‐methyl‐5‐(naphthalen‐2‐yl)‐[1,1'‐biphenyl]‐4‐yl)ethanone
(3u). Light yellow powder, 70% yield; m.p.: 100—101 °C. H NMR
(400 MHz, CDCl3) δ: 8.03—7.83 (m, 4H), 7.69—7.62 (m, 2H),
7.58—7.50 (m, 4H), 7.49—7.44 (m, 3H), 7.39 (dt, J＝9.4, 4.3 Hz,
1H), 2.43 (s, 3H), 1.95 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 207.62,
141.87, 140.43, 140.26, 139.24, 137.92, 134.67, 133.27, 132.69,
1
＋
1‐(5‐(Furan‐2‐yl)‐3‐methyl‐[1,1'‐biphenyl]‐2‐yl)ethanone (3n). 128.90, 128.49, 128.46, 128.29, 128.13, 127.82, 127.74, 127.26,
1
Light yellow oil, 95% yield. H NMR (500 MHz, CDCl3) δ: 7.52 (d,
J＝5.6 Hz, 2H), 7.48 (d, J＝1.0 Hz, 1H), 7.42—7.38 (m, 5H), 6.71 (d, C25H21O [M＋H] : 337.1587, found 337.1587.
126.96, 126.61, 126.56, 126.46, 32.30, 19.87; HRMS (ESI) calcd for
＋
J＝3.3 Hz, 1H), 6.49 (dd, J＝3.1, 1.7 Hz, 1H), 2.36 (s, 3H), 1.93 (s,
1‐(3‐Methyl‐5‐(thiophen‐2‐yl)‐[1,1'‐biphenyl]‐4‐yl)ethanone
3H); 13C NMR (126 MHz, CDCl3) δ: 207.41, 153.19, 142.66, 140.43,
(3v). Light yellow oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ: 7.60
336
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© 2018 SIOC, CAS, Shanghai, & WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2018, 36, 333－337

Construction of Multi‐Substituted Benzenes
Chin. J. Chem.
(d, J＝7.9 Hz, 2H), 7.52 (s, 1H), 7.48—7.33 (m, 3H), 7.11—6.99 (m,
2H), 2.37 (s, 3H), 2.14 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 207.53,
141.97, 141.43, 140.32, 140.08, 134.59, 131.50, 128.96, 127.95,
127.86, 127.30, 126.62, 126.56, 125.25, 122.65, 31.87, 19.73;
Scherkenbeck, J. Bioorg. Med. Chem. 2016, 24, 873; (f) Liu, C.; Zhang,
M.; Zhang, Z.; Zhang, S. B.; Yang, S.; Zhang, A.; Yin, L.; Swarts, S.;
Vidyasagar, S.; Zhang, L.; Okunieff, P. Bioorg. Med. Chem. 2016, 24,
4263; (g) Sunke, R.; Nallapati, S. B.; Kumar, J. S.; Kumarb, K. S.; Pal, M.
Org. Biomol. Chem. 2017, 15, 4042.
＋
HRMS (ESI) calcd for C19H17OS [M ＋H] : 293.0995, found
293.0990.
[4] (a) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901; (b) Bonesi, S.
M.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2008, 47, 10022; (c)
Yu, D. G.; Yu, M.; Guan, B. T.; Li, B. J.; Zheng, Y.; Wu, Z. H.; Shi, Z. J.
Org. Lett. 2009, 11, 3374; (d) Ciana, C. L.; Phipps, R. J.; Brandt, J. R.;
Meyer, F. M.; Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 458; (e)
Gustafson, J. L.; Lim, D.; Barrett, K. T.; Miller, S. J. Angew. Chem. Int.
Ed. 2011, 50, 5125; (f) Rahimi, A.; Namyslo, J. C.; Drafz, M. H. H.;
Halm, J.; Hubner, E.; Nieger, M.; Rautzenberg, N.; Schmidt, A. J. Org.
Chem. 2011, 76, 7316; (g) Zhao, F.; Zhang, Y. F.; Wen, J.; Yu, D. G.;
Wei, J. B.; Xi, Z.; Shi, Z. J. Org. Lett. 2013, 15, 3230.
(E)‐1‐(3‐Methyl‐5‐(pent‐1‐en‐1‐yl)‐[1,1'‐biphenyl]‐4‐yl)etha‐
none (3w). Light yellow oil, 48% yield. 1H NMR (400 MHz, CDCl3) δ:
7.62—7.53 (m, 2H), 7.50—7.41 (m, 3H), 7.37 (d, J＝7.3 Hz, 1H),
7.28 (d, J＝0.7 Hz, 1H), 6.39 (dd, J＝23.0, 13.5 Hz, 1H), 6.19 (dt,
J＝15.6, 6.9 Hz, 1H), 2.49 (s, 3H), 2.31 (s, 3H), 2.19 (dd, J＝14.6,
7.0 Hz, 2H), 1.49 (dd, J＝14.7, 7.3 Hz, 2H), 0.95 (t, J＝7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ: 208.34, 141.68, 140.65, 139.69,
135.09, 134.49, 133.21, 128.78, 127.74, 127.59, 127.19, 126.91,
122.58, 35.34, 32.76, 22.37, 19.31, 13.72; HRMS (ESI) calcd for
＋
C20H23O [M＋H] : 279.1743, found 279.1743.
[5] Reppe, W.; Schlichting, O.; Klager, K.; Klager, K.; Toepel, T. Justus
Liebigs Ann. Chem. 1948, 560, 1.
[6] (a) Domínguez, G.; Pérez‐Castells, J. Chem. Soc. Rev. 2011, 40, 3430;
(b) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P.
Nature 2012, 490, 208.
1‐(5'‐Phenyl‐[1,1':3',1''‐terphenyl]‐2'‐yl)ethanone (3x). Light
yellow oil, 56% yield. 1H NMR(400 MHz, CDCl3) δ: 7.74—7.60 (m,
3H), 7.59—7.45 (m, 4H), 7.41 (dd, J＝7.2, 1.8 Hz, 2H), 7.34—7.27
(m, 3H), 7.23—7.10 (m, 3H), 2.33 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ: 199.90, 141.87, 140.63, 140.36, 140.31, 137.67, 137.57,
135.88, 133.14, 129.39, 129.21, 128.90, 128.32, 128.10, 128.06,
127.77, 127.29, 127.25, 126.22, 19.95; HRMS (ESI) calcd for
[7] For selected examples see: (a) Song, X.; Zhang, X.; Zhang, S.; Li, H.;
Wang, W. Chem. – Eur. J. 2012, 18, 9770; (b) Candish, L.; Levensa, A.;
Lupton, D. W. Chem. Sci. 2015, 6, 2366; (c) Jia, Q.; Wang, J. Org. Lett.
2016, 18, 2212; (d) Zhang, C. L.; Ye, S. Org. Lett. 2016, 18, 6408; (e)
Zhang, C. L.; Gao, Z. H.; Liang, Z. Q.; Ye, S. Adv. Synth. Catal. 2016, 358,
2862; (f) Li, X.; Yu, H.; Huang, Y. Adv. Synth. Catal. 2017, 359, 1379.
[8] (a) Hao, L.; Chen, X.; Chen, S.; Jiang, K.; Torres, J.; Chi, Y. R. Org. Chem.
Front. 2014, 1, 148; (b) Mou, C.; Zhu, T.; Zheng, P.; Yang, S.; Song,
B.‐A.; Chi, Y. R. Adv. Synth. Catal. 2016, 358, 707; (c) Li, X.; Zhou, J.;
Zhuo, S. Chin. J. Org. Chem. 2016, 36, 1484; (d) Mou, C.; Wu, J.;
Huang, Z.; Sun, J.; Jin, Z.; Chi, Y. R. Chem. Commun. 2017, 53, 13359;
(e) Wang, A.; Xiao, Y.; Zhou, Y.; Xu, J.; Liu, H. Chin. J. Org. Chem. 2017,
37, 2590; (f) Ye, M.; Shen, P.; Duan, W.; Song, C.; Ma, Y. Chin. J. Org.
Chem. 2017, 37, 2919; (g) Yuan, H.; Chen, H.; Luo, Z.; Gao, Y.; Lu, H.
Chin. J. Org. Chem. 2017, 37, 2948.
＋
C26H21O [M＋H] : 349.1587, found 349.1577.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.201700773.
Acknowledgement
We acknowledge financial support by the National Natural
Science Foundation of China (No. 21472028), the National Key
Technologies R&D Program (No. 2014BAD23B01), the “Thousand
Talent Plan”, the 10 Talent Plan (Shicengci) of Guizhou Province,
Guizhou Province Returned Oversea Student Science and Technol‐
ogy Activity Program, and Guizhou University (China).
[9] Zhu, T.; Zheng, P.; Mou, C.; Yang, S.; Song, B.‐A.; Chi, Y. R. Nat.
Commun. 2014, 5, 5027.
[10] Zhu, T.; Mou, C.; Li, B.; Smetankova, M.; Song, B.‐A.; Chi, Y. R. J. Am.
Chem. Soc. 2015, 137, 5658.
References
[11] For comments on NHC catalyzed ester activation reactions, see: (a)
Bode, J. W. Nat. Chem. 2013, 5, 813; (b) Wang, L.; Xiao, J.; Loh, T. P.
ChemCatChem 2014, 6, 1183; (c) Chauhan, P.; Enders, D. Angew.
Chem. Int. Ed. 2014, 53, 1485.
[12] For pioneering studies on the application of 4 in NHC organocatalysis
see: (a) Sarkar, S. D.; Grimme, S.; Studer, A. J. Am. Chem. Soc. 2010,
132, 1190; (b) Sarkar, S. D.; Studer, A. Angew. Chem. Int. Ed. 2010, 49,
9266; (c) Sarkar, S. D.; Studer, A. Org. Lett. 2010, 12, 1992.
[13] For pioneering studies on the application of 5 in NHC organocatalysis
see: Maji, M. S.; Pfeifer, T.; Studer, A. Angew. Chem. Int. Ed. 2008, 47,
9547.
[1] (a) Turner, C. E.; Elsohly, M. A.; Boeren, E. G. J. Nat. Prod. 1980, 43,
169; (b) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith,
R. L. J. Med. Chem. 1986, 29, 852; (c) Naito, T.; Katsuhara, T.; Niitsu,
K.; Ikeya, Y.; Okada, M.; Mitsuhashi, H. Phytochemistry 1992, 31, 639;
(d) ElSohly, M. A.; Slade, D. Life Sci. 2005, 78, 539; (e) Ortar, G. Bioorg.
Med. Chem. Lett. 2013, 23, 5614;
[2] (a) MIDAS World Review (TM), January 2009—December 2009,
IMSHealth Incorporated; (b) McGrath, N. A.; Brichacek, M.;
Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348; (c) Baumann, M.;
Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7,
442.
Manuscript received: December 16, 2017
Manuscript revised: January 29, 2018
Manuscript accepted: January 29, 2018
Version of record online: XXXX, 2018
[3] (a) Calloway, N. O. Chem. Rev. 1935, 17, 327; (b) Illuminati, G.; Gilman,
H. J. Am. Chem. Soc. 1952, 74, 2896; (c) Pollak, A.; Stanovnik, B.;
Tisler, M. J. Org. Chem. 1966, 31, 4297; (d) Coates, W. J.; McKillop, A.
J. Org. Chem. 1990, 55, 5418; (e) Sivanathan, S.; Körber, F.;
Chin. J. Chem. 2018, 36, 333－337
© 2018 SIOC, CAS, Shanghai, & WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley‐vch.de
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