Domino Reactions Containing Different Types of Heck Reactions for Selective 3,3- and 1,3-Diarylations of Propenol with Aryl Halides by Triple Catalysis

Article abstract of DOI:10.1021/acs.joc.5b01650

A new domino Heck-isomerization/Saegusa/Heck reaction of propenol with aryl iodides has been developed for the synthesis of 3,3-diaryl propenals by triple transition-metal catalysis. Moreover, we also developed the domino Heck-isomerization/Heck-type reaction of propenol with aryl iodides for the synthesis of 1,3-diaryl propanones by double transition-metal catalysis and the mediation of secondary amine or triple transition metal catalysis and aminocatalysis.

Full text of DOI:10.1021/acs.joc.5b01650

Note
pubs.acs.org/joc
Domino Reactions Containing Different Types of Heck Reactions for
Selective 3,3- and 1,3-Diarylations of Propenol with Aryl Halides by
Triple Catalysis
Zhi-Qiang Zhu,† Jian-Shi He,‡ Hai-Jun Wang,§ and Zhi-Zhen Huang*,†,∥
†Department of Chemistry, Zhejiang University, Hangzhou 310028, China
‡Jiangsu Coben Pharmaceutical Co., Ltd, Qidong, Jiangsu 310004, P. R. China
§College of Pharmaceutical Sciences, Qiqihar Medical University, Qiqihar 161006, P. R. China
∥State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A new domino Heck-isomerization/Saegusa/
Heck reaction of propenol with aryl iodides has been
developed for the synthesis of 3,3-diaryl propenals by triple
transition-metal catalysis. Moreover, we also developed the
domino Heck-isomerization/Heck-type reaction of propenol
with aryl iodides for the synthesis of 1,3-diaryl propanones by
double transition-metal catalysis and the mediation of
secondary amine or triple transition metal catalysis and
aminocatalysis.
domino reaction can form two or more bonds in one
unexpectedly obtained 1,3-diphenyl propanone. In 2011, Xiao
Areaction and need not isolate intermediates, change and co-workers reported that under the catalysis of palladium
complex and using Cy2NMe and K2CO3 as a base and additive,
respectively, the Heck-isomerization reaction of propenol with
aryl bromides was performed to generate 3-aryl propanals in
situ.7 Then, a second molecule of aryl bromides and equivalent
pyrrolidine were added to perform a Heck-type arylation of the
formed 3-aryl propanals to give 1,3-diaryl propanones under
palladium catalysis via enamine intermediates. 1,3-Diaryl
propanones have many biological activities, such as anti-
bacterial, anticancer, and antioxidant activities,8 and have been
widely applied in natural product synthesis and drug discovery.9
Considering that this is a two-step reaction, and as the
continuation of our investigation on a domino reaction based
on Heck reactions by a combination of transition metal
catalysis and aminocatalysis,10 we embarked on an investigation
about a domino Heck-isomerization/Heck-type reaction for the
synthesis of 1,3-diaryl propanones by triple transition-metal
catalysis and aminocatalysis.
Initially, iodobenzene 1a and propenol 2 were chosen as
model substrates to explore and optimize the domino Heck-
isomerization/Saegusa/Heck reaction. When the reaction was
performed in the presence of 5 mol % Pd(OAc)2 and 2.5 equiv
of Cy2NMe in DMF at 110 °C, we found that desired 3,3-
diphenyl propenal 3a was formed in ∼7% yield (entry 1, Table
1). After various bases were examined in the reaction, Na2CO3
was found to be most efficient for the reaction, increasing the
yield of 3a to 64% (compare entries 1−4 with entry 5, Table 1;
reaction conditions, or add reagents or catalysts during the
reaction. Moreover, domino reactions can decrease the amount
of solvents, reagents, energy, labor, and so forth dramatically,
and have great potential to be used in the synthesis of natural
products and pharmaceuticals, especially in the chemical
industry.1 It is well-known that Heck reactions are very
important and classic transition metal-catalyzed coupling
reactions for the formation of carbon−carbon bonds mainly
through arylation of alkenes.2 Among them, there are some
reports on the synthesis of 3,3-diaryl propenals through Heck
reactions from 3-aryl propenals.3 In 2001, Strauss and co-
workers revealed that when they performed the reaction of
propenol with excess phenyl iodide under palladium catalysis,
complex mixtures of 3-phenylpropanal, 3-phenylpropenal, 3,3-
diphenylpropenal, 3,3-diphenylpropanal, 2,3-diphenylpropenol,
and 2,3-diphenylpropanal were observed.4 In 2010, Li et al.
developed a domino Heck-isomerization/Saegusa reaction of
aryl iodides with propenol for the synthesis of 3-aryl propenals
via 3-aryl propanal intermediates.5 Because 3-aryl propenal
retains a 3-olefinic hydrogen, it may continue to perform Heck
reactions in a domino pathway, giving 3,3-diaryl propenals,
which have been widely applied in the synthesis of biologically
active compounds.6 Thus, we carried out the investigation on
the domino Heck-isomerization/Saegusa/Heck reaction of allyl
alcohol with aryl halides for the synthesis of 3,3-diaryl
propenals by triple transition-metal catalysis.
When exploring the domino Heck-isomerization/Saegusa/
Heck reaction of propenol with phenyl iodide in the presence
of palladium catalyst and secondary amine, we once
Received: July 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01650
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of the Domino Reaction Conditions
for the Synthesis of 3,3-Diphenyl Propenal 3a
Table 2. Domino Heck-Isomerization/Saegusa/Heck
Reaction for the Synthesis of 3,3-Diaryl Propenals 3a−l
a
a
entry
catalyst
base
solvent
T (°C) yield (%)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cy2NMe
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO
DMF
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
100
120
7
trace
42
K2CO3
NaHCO3
Na2CO3
Et2NH
47
64
b
6
0
7
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
37
8
Pd(PPh3)4
Pd(dba)3
Rh(PPh3)3Cl
35
9
43
10
11
12
13
14
15
trace
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
56
10
59
61
a
1a (1.25 mmol), 2a (0.5 mmol), catalyst (5 mol %), base (1.25
b
mmol), solvent (2 mL), at 110 °C under air for 24 h. Yield of 4a was
11%.
also see the Supporting Information (SI)). Interestingly, when
Et2NH was used instead of the above bases, 1,3-diphenyl
propanone 4a was obtained in an 11% yield without
observation of expected 3a (entry 6, Table 1). Then, various
transition-metal catalysts were screened for 3a, and the
experiment indicated that Pd(OAc)2 was the best transition-
metal catalyst among them (compare entries 7−10 with entry
5, Table 1; also see SI). In the absence of a palladium catalyst,
no reaction occurred (entry 11, Table 1). Various solvents in
this reaction were also examined. DMF was proved to be best
in the yield of 3a as compared to DMA, NMP, and DMSO
(compare entries 12−13 with entry 5, Table 1). No desired
product 3a was observed in other solvents, such as toluene,
MeCN, THF, and DCE (see SI). The effect of temperature on
this reaction was also studied, and lower yields of 3a were
obtained no matter whether the temperature was elevated or
reduced (entries 14−15 with entry 5, Table 1; also see SI).
After the reaction conditions were screened, it could be
concluded that the optimized reaction should be performed
under the catalysis of 5 mol % Pd(OAc)2 using 2.5 equiv of
Na2CO3 as a base in DMF at 110 °C. As shown in Table 2,
various aryl iodides 1a−l were able to undergo the domino
Heck-isomerization/Saegusa/Heck reaction smoothly with
propenol 2 to give desired 3,3-diaryl propenals 3a−l in the
yields of 40−71% under the optimized conditions. The
experimental results also demonstrated that the functional
groups connected to the benzene rings in substituted phenyl
iodides 1b−j had an effect on the yields of desired products
3b−j. The electron-donating groups on the benzene rings of
phenyl iodides 1b−h were more beneficial to the domino
reaction as compared to the electron-withdrawing groups on
the benzene rings of phenyl iodides 1i−j. Furthermore, the aryl
iodides, other than substituted phenyl iodides, 1-naphthalenyl
iodide 1k, or 3-thienyl iodide 1l, could also undergo the
domino reaction to give the corresponding 3,3-diaryl propenals
a
Reaction conditions: the mixture of 1 (1.25 mmol), 2 (0.5 mmol),
Pd(OAc)2 (5 mol %), and Na2CO3 (1.25 mmol) was stirred in DMF
(2 mL) at 110 °C under air for 24 h.
3k−l expediently. It is noteworthy that the domino reaction
tolerates a range of functional groups, such as fluoro, chloro,
methoxy, tert-butyl, ethyl, and methyl groups. When but-3-en-2-
ol was employed instead of propenol 2, its domino reaction
with phenyl iodide 1a was able to occur as well, but only 23%
yield of desired product 3m, 4,4-diphenylbut-3-en-2-one, was
achieved (see SI).
The possible mechanism for the domino Heck-isomer-
ization/Saegusa/Heck reaction is depicted in Scheme 1.
Initially, under the catalysis of palladium(0), which is reduced
from Pd(OAc)2 by propenol, and so forth,2a aryl iodide 1, and
propenol 2 perform a Heck-isomerization reaction in the first
catalytic cycle to give the tautomer 7a of 3-aryl propanal.11
Then, 7a undergoes the Saegusa oxidative reaction to afford 3-
aryl propenal 9 by the catalysis of Pd(OAc)2 using air as an
oxidant in the second catalytic cycle.12 Finally, 9 undergoes a
Heck reaction with another molecular aryl iodide 1 by
palladium catalysis in the third catalytic cycle, giving desired
3,3-diaryl propenals 3.2d
As mentioned above, when we employed Et2NH instead of
Na2CO3 in the reaction of phenyl iodide with propenol 2 under
the catalysis of Pd(OAc)2, 1,3-diphenyl propanone 4a instead
of 3a was obtained (entry 6, Table 1). Then, iodobenzene 1a
and propenol 2 were chosen as model substrates to optimize
the domino Heck-isomerization/Heck-type reaction under the
catalysis of transition-metal and the mediation of secondary
amine (see SI). After optimization, it can be concluded that the
domino reaction should be performed under the catalysis of
Pd(OAc)2 (2 mol %) and the mediation of pyrrolidine (1.0
B
DOI: 10.1021/acs.joc.5b01650
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Possible Mechanism for the Domino Heck-Isomerization/Saegusa/Heck Reaction
Table 3. Domino Heck-Isomerization/Heck-Type Reaction for the Synthesis of 1,3-Diaryl Propanones 4a−o
a
Reaction conditions A: 1 (1.05 mmol), 2 (0.5 mmol), Pd(OAc)2 (2 mol %), K2CO3 (1.25 mmol), and pyrrolidine (0.5 mmol) was stirred in DMF
b
(2 mL) at 110 °C under nitrogen for 24 h. Reaction conditions B are the same as A except pyrrolidine is at 0.15 mmol.
Scheme 2. Possible Mechanism for the Domino Heck-Isomerization/Heck-Type Reaction
equiv) using K2CO3 (2.5 equiv) as a base in DMF at 110 °C,
leading to the desired 1,3-diphenyl propanone 4a in 70% yield.
As shown in Table 3, a series of aryl iodides 1a−o were able to
undergo the domino Heck-isomerization/Heck-type reaction
smoothly with propenol 2 to give desired 1,3-diaryl propanones
4a−o in yields of 41−80% under the optimized conditions. Our
experiment also indicated that the domino reaction was
sensitive to the functional groups connected to the benzene
rings in substituted phenyl iodides 1b−j and 1n−o. The
electron-donating groups on benzene rings of aryl iodides 1b−
h and 1o were more beneficial to the domino reaction as
compared to the electron-withdrawing groups on benzene rings
of aryl iodides 1i−j and 1n. In addition, the aryl iodides bearing
other aromatic rings than benzene, 1-naphthalenyl iodide 1k, 3-
thienyl iodide 1l, and 1-methyl-1H-indol-5-yl iodide 1m could
also undergo the domino reaction readily to furnish desired 1,3-
diaryl propanones 4k−m. The domino reaction for 1,3-diaryl
propanones 4 under the palladium catalysis and mediated by
pyrrolidine also tolerates a variety of functional groups, such as
fluoro, chloro, methoxy, hydroxymethyl, tert-butyl, ethyl, and
methyl groups. Furthermore, when the amount of pyrrolidine
was decreased to 30 mol %, the domino reaction of propenol 2
C
DOI: 10.1021/acs.joc.5b01650
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
NMR (100 MHz, CDCl3) δ 193.6, 162.0, 161.7, 160.8, 132.5, 130.5,
129.2, 125.5, 114.0, 113.7, 55.4, 55.4; MS (EI) m/z 268 (M+), 237,
165, 132, 77.
with aryl iodides 1b−f also performed smoothly to give desired
1,3-diaryl propanones 4b−f under optimized conditions, albeit
in slightly lower yields.13 Compared with the literature method
by Xiao,7 this is a domino reaction and only uses K2CO3 and an
equivalent or catalytic amount of pyrrolidine rather than a two-
step reaction and using Cy2NMe, K2CO3, and an equivalent
amount of pyrrolidine, respectively.
Therefore, the domino Heck-isomerization/Heck-type re-
action for 1,3-diaryl propanone 4 may be performed by triple
catalysis, which is the relay catalysis of palladium and
pyrrolidine, and another palladium catalysis inserted into the
aminocatalysis (Scheme 2). The possible mechanism of the
domino reaction for 4 is as follows. Initially, aryl iodide 1 and
propenol 2 undergo a Heck-isomerization reaction in the first
catalytic cycle to give 3-aryl propanal 7b.11 Then, enamine 11
resulted from the reaction of 3-aryl propanal 7b with
pyrrolidine undergoes the Heck-type reaction with another
molecular aryl iodide 1 to generate the corresponding 1-
arylated enamine 13 under palladium catalysis.14 Finally,
hydrolysis of 13 led to the desired 1,3-diaryl propanone 4
with regenerating pyrrolidine as an organocatalyst.
In conclusion, a new domino Heck-isomerization/Saegusa/
Heck reaction of propenol with aryl iodides has been developed
for the synthesis of 3,3-diaryl propenals by triple transition-
metal catalysis. Moreover, we also developed the domino Heck-
isomerization/Heck-type reaction of propenol with aryl iodides
for the synthesis of 1,3-diaryl propanones by double transition-
metal catalysis and the mediation of secondary amine or triple
transition metal catalysis and aminocatalysis. These domino
reactions tolerate a range of functional groups, such as fluoro,
chloro, methoxy, tert-butyl, ethyl, and methyl groups to afford
3,3-diaryl propenals or 1,3-diaryl propanones in satisfactory
yields. The novel domino reactions may have potential
applications in natural product synthesis and drug discovery
in the future.
3,3-Bis(4-ethylphenyl)propenal (3d). Yield 67% (88.5 mg); light
1
yellow oil; H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 7.6 Hz, 1H),
7.30−7.19 (m, 8H), 6.56 (d, J = 8.0 Hz, 1H), 2.73 (q, J = 7.6 Hz, 2H),
2.68 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H), 1.25 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.8, 162.6, 147.2, 145.9,
137.4, 134.2, 130.9, 128.9, 128.1, 127.8, 126.5, 28.7, 28.7, 15.4, 15.3;
HRMS (EI-TOF) m/z calcd for C19H20O 264.1514, found 264.1516.
3,3-Bis(4-tert-butylphenyl)propenal (3e). Yield 68% (108.8 mg);
1
light yellow solid; mp 111−112 °C; H NMR (400 MHz, CDCl3) δ
9.52 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4
Hz, 1H), 1.37 (s, 9H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 193.9, 162.4, 154.0, 152.7, 137.0, 133.8, 130.7, 128.6, 126.6,
125.6, 125.2, 34.9, 34.8, 31.3, 31.2; HRMS (EI-TOF) m/z calcd for
C23H28O 320.2140, found 320.2141.
3,3-Bis(3,5-dimethylphenyl)propenal (3f). Yield 69% (91.1 mg);
1
light yellow solid; mp 112−113 °C; H NMR (400 MHz, CDCl3) δ
9.50 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 6.97 (s, 2H), 6.90
(s, 2H), 6.51 (d, J = 8.4 Hz, 1H), 2.35 (s, 6H), 2.30 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.9, 163.3, 140.0, 138.1, 137.8, 136.8,
132.2, 131.0, 128.5, 127.1, 126.6, 21.3; HRMS (EI-TOF) m/z calcd for
C19H20O 264.1514, found 264.1516.
3,3-Bis(3,4-dimethoxyphenyl)propenal (3g). Yield 71% (116.4
mg); light yellow solid; mp 129−131 °C (lit.6a 129−130 °C); H
1
NMR (400 MHz, CDCl3) δ 9.51 (d, J = 8.0 Hz, 1H), 6.95−6.92 (m,
4H), 6.85 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H), 6.52 (d, J = 8.0 Hz, 1H),
3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 193.5, 162.0, 151.3, 150.3, 148.9, 148.6, 132.4, 129.3, 125.7,
124.4, 122.9, 113.7, 111.2, 110.7, 110.5, 56.0,56.0, 56.0; MS (EI) m/z
328 (M+), 285, 165, 139, 77.
3,3-Bis(3-methoxyphenyl)propenal (3h).6a Yield 60% (80.4 mg);
1
light yellow oil; H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 8.0 Hz,
1H), 7.35 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.4
Hz, J = 2.0 Hz, 1H), 6.98−6.90 (m, 4H), 6.82 (s, 1H), 3.81 (s, 3H),
3.79 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 161.8, 159.7,
159.4, 140.9, 137.9, 129.6, 129.4, 127.4, 123.2, 121.2, 116.1, 116.0,
115.0, 114.1, 55.4, 55.4; MS (EI) m/z 268 (M+), 237, 165, 132, 77.
3,3-Bis(4-fluorophenyl)propenal (3i). Yield 43% (52.4 mg); light
yellow solid; mp 58−60 °C (lit.6a 58−59.5 °C); 1H NMR (400 MHz,
CDCl3) δ 9.50 (d, J = 8.0 Hz, 1H), 7.36−7.27 (m, 4H), 7.17 (d, J = 8.4
Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 192.9, 165.2 (d, JC−F = 69.3 Hz), 162.7 (d,
JC−F = 67.6 Hz), 159.8, 135.7 (d, JC−F = 2.6 Hz), 132.6 (d, JC−F = 9.1
Hz), 132.5 (d, JC−F = 3.5 Hz), 130.7 (d, JC−F = 8.3 Hz), 127.4, 115.9
(d, JC−F = 16.1 Hz), 115.7 (d, JC−F = 16.5 Hz); MS (EI) m/z 244
(M+), 214, 149, 120, 96.
EXPERIMENTAL SECTION
■
General Procedure for the Domino Heck-Isomerization/
Saegusa/Heck Reaction between Aryl Iodides 1 and Propenol
2. The reaction mixture of Pd(OAc)2 (5.6 mg, 0.025 mmol), Na2CO3
(132.5 mg, 1.25 mmol), aryl iodide 1 (1.25 mmol), and propenol 2
(29.04 mg, 0.5 mmol) in DMF (2 mL) was stirred at 110 °C under air
for 24 h. After cooling to room temperature, the mixture was diluted
with EtOAc (15 mL) and washed with water and brine, respectively.
The organic layer was dried over Na2SO4 and then concentrated in
vacuo. The residue was subjected to flash column chromatography
(silica gel, petroleum ether/ethyl acetate as an eluent) to give desired
3,3-diaryl propenals 3.
3,3-Bis(4-chlorophenyl)propenal (3j).6a Yield 41% (77.0 mg); light
1
yellow oil; H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 8.0 Hz, 1H),
3,3-Diphenylpropenal (3a).6a Yield 64% (66.5 mg); light yellow
7.45 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.4 Hz,
2H), 7.24 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 192.6, 159.3, 137.8, 137.0, 136.1, 134.6, 132.0,
129.8, 129.1, 128.9, 127.7; MS (EI) m/z 276 (M+), 178, 165, 136, 111.
3,3-Di(naphthalen-1-yl)propenal (3k). Yield 40% (61.6 mg); light
1
oil; H NMR (400 MHz, CDCl3) δ 9.53 (d, J = 8.0 Hz, 1H), 7.47−
7.40 (m, 4H), 7.38−7.29 (m, 6H), 6.60 (d, J = 8.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.5, 162.2, 139.8, 136.7, 130.8, 130.5,
129.5, 128.7, 128.6, 128.4, 127.3; MS (EI) m/z 208 (M+), 178, 165,
102, 77.
1
yellow solid; mp 110−112 °C; H NMR (400 MHz, CDCl3) δ 9.53
(d, J = 8.0 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.96−7.83 (m, 5H),
7.59−7.53 (m, 4H), 7.45 (t, J = 7.4 Hz, 1H), 7.36−7.30 (m, 2H),
7.25−7.23 (m, 1H), 6.78 (d, J = 8.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 193.0, 159.9, 138.5, 135.5, 134.3, 134.2, 133.8, 132.1,
130.4, 130.2, 129.9, 129.5, 129.0, 128.6, 127.6, 127.3, 127.2, 126.4,
126.3, 125.6, 125.0, 125.0, 124.9; HRMS (EI-TOF) m/z calcd for
C23H16O 308.1201, found 308.1206.
3,3-Bis(4-methylphenyl)propenal (3b). Yield 67% (79.1 mg); light
yellow solid; mp 93−94 °C (lit.6a 93−94 °C); H NMR (400 MHz,
1
CDCl3) δ 9.52 (d, J = 8.0 Hz, 1H), 7.26−7.23 (m, 4H), 7.19−7.16 (m,
4H), 6.55 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H), 2.37 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.6, 162.5, 140.9, 139.6, 137.2, 134.0,
130.8, 129.3, 129.0, 128.8, 126.5, 21.4; MS (EI) m/z 236 (M+), 178,
165, 115, 91.
3,3-Di(thiophen-3-yl)propenal (3l). Yield 46% (50.6 mg); light
3,3-Bis(4-methoxyphenyl)propenal (3c). Yield 66% (88.4 mg);
1
light yellow solid; mp 56−57 °C (lit.6a 56−57 °C); H NMR (400
1
yellow oil; H NMR (400 MHz, CDCl3) δ 9.64 (d, J = 8.0 Hz, 1H),
7.45−7.43 (m, 2H), 7.40−7.38 (m, 1H), 7.34−7.33 (m, 1H), 7.29 (dd,
J = 5.2 Hz, J = 1.2 Hz, 1H), 7.14 (dd, J = 4.8 Hz, J = 1.2 Hz, 1H), 6.55
(d, J = 8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 150.4,
MHz, CDCl3), δ 9.27 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H),
7.02 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz,
2H), 6.28 (d, J = 8.0 Hz, 1H), 3.66 (s, 3H), 3.63 (s, 3H); 13C{1H}
D
DOI: 10.1021/acs.joc.5b01650
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
141.6, 136.8, 129.4, 128,8, 127.7, 126.9, 126,5 126,2, 126,2; HRMS
(EI-TOF) m/z calcd for C11H8OS2 220.0017, found 220.0013.
4,4-Diphenylbut-3-en-2-on (3m).15 Yield 23% (25.5 mg); yellow
MHz, CDCl3) δ 198.0, 153.3, 149.0, 148.9, 147.4, 134.1, 130.2, 122.7,
120.2, 111.9, 111.4, 110.2, 110.0, 56.1, 56.0, 55.9, 55.8, 40.2, 30.2; MS
(EI) m/z 330 (M+), 239, 165, 137, 97.
1,3-Bis(3-methoxyphenyl)propan-1-one (4h):21 Yield 61% (82.4
mg, method A); colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.52
(d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.21 (d, J =
7.6 Hz, 1H), 7.09 (dd, J = 8.4 Hz, J = 2.8 Hz, 1H), 6.83 (d, J = 7.6 Hz,
1H), 6.80 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H),
3.27 (t, J = 7.8 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 199.0, 159.9, 159.8, 142.9, 138.3, 129.6, 129.5, 120.8,
120.7, 119.6, 114.3, 112.3, 111.4, 55.4, 55.2, 40.5, 30.3; MS (EI) m/z
270 (M+), 239, 135, 107, 77.
1
oil; H NMR (400 MHz, CDCl3) δ 7.42−7.41 (m, 3H), 7.36−7.27
(m, 5H), 7.23−7.21 (m, 2H), 6.58 (s, 1H), 1.88 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 200.2, 154.0, 140.8, 139.0, 129.6, 129.5,
128.8, 128.5, 128.4, 127.7, 30.4; MS (EI) m/z 222 (M+), 207, 179,
149, 77.
General Procedure for the Domino Heck-Isomerization/
Heck-Type Reaction between Aryl Iodides 1 and Propenol 2.
The mixture of Pd(OAc)2 (2.3 mg, 0.01 mmol), K2CO3 (172.8 mg,
1.25 mmol), aryl iodide 1 (1.05 mmol), and propenol 2 (29.04 mg, 0.5
mmol) in DMF (2 mL) was stirred at 110 °C under nitrogen for 5
min, and then pyrrolidine (0.5 mmol, method A; 0.15 mmol, method
B) was added. The reaction mixture was stirred at 110 °C for 24 h.
After the reaction was finished, a similar workup to that for 3 led to
desired 1,3-diaryl propanones 4.
1,3-Bis(4-fluorophenyl)propan-1-one (4i).22 Yield 42% (51.6 mg,
1
method A); colorless liquid; H NMR (400 MHz, CDCl3) δ 7.99−
7.96 (m, 2H), 7.22−7.18 (m, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.97 (t, J =
8.8 Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 165.8 (d, JC−F = 253.0
Hz), 161.4 (d, JC−F = 242.5 Hz), 136.7 (d, JC−F = 2.7 Hz), 133.2 (d,
JC−F = 2.2 Hz), 130.7 (d, JC−F = 9.7 Hz), 129.8 (d, JC−F = 7.5 Hz),
115.7 (d, JC−F = 20.9 Hz), 115.3 (d, JC−F = 20.2 Hz), 40.4, 29.2; MS
(EI) m/z 246 (M+), 228, 123, 109, 95.
1,3-Diphenylpropan-1-one (4a). Yield 70% (73.5 mg, method A);
white solid; mp 69−71 °C (lit.16 70−70.5 °C); H NMR (400 MHz,
1
CDCl3) δ 7.95 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.0 Hz, 1H), 7.44 (t, J =
7.6 Hz, 2H), 7.41−7.24 (m, 4H), 7.20 (t, J = 6.8 Hz, 1H), 3.30 (t, J =
7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.2, 141.3, 136.9, 133.0, 128.6, 128.5, 128.4, 128.0, 126.1,
40.4, 30.1; MS (EI) m/z 210 (M+), 131, 105, 91, 77.
1,3-Bis(4-chlorophenyl)propan-1-one (4j).23 Yield 46% (63.59 mg,
method A); white solid; mp 70−72 °C; 1H NMR (400 MHz, CDCl3)
δ 7.88 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.4
Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 3.03 (t, J =
7.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 139.6, 139.5,
135.1, 132.0, 129.8, 129.4, 129.0, 128.7, 40.1, 29.3; MS (EI) m/z 278
(M+), 243, 139, 111, 75.
1,3-Bis(4-methylphenyl)propan-1-one (4b). Yield 57% (67.8 mg,
method B); white solid; mp 59−61 °C (lit.16 65−65.5 °C); H NMR
1
(400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.6 Hz,
2H), 7.14 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 3.24 (t, J = 7.8
Hz, 2H), 3.01 (t, J = 7.8 Hz, 2H), 2.39 (s, 3H), 2.31 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 199.0, 143.7, 138.3, 135.6, 134.5, 129.3,
129.2, 128.3, 128.2, 40.5, 29.8, 21.6, 21.0; MS (EI) m/z 238 (M+), 223,
105, 91, 77.
1,3-Di(naphthalen-1-yl)propan-1-one (4k). Yield 43% (66.7 mg,
method A); white solid; mp 76−78 °C (lit.24 76−77 °C); H NMR
1
(400 MHz, CDCl3) δ 8.63 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.0 Hz,
1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86−7.83 (m, 2H), 7.77 (d, J = 7.6 Hz,
1H), 7.71 (dd, J = 6.4 Hz, J = 2.4 Hz, 1H), 7.57 (td, J = 6.8 Hz, J = 1.2
Hz, 1H), 7.53−7.45 (m, 3H), 7.41−7.35 (m, 3H), 3.59 (t, J = 7.4 Hz,
2H), 3.48 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
203.5, 137.2, 135.8, 134.0, 134.0, 132.7,131.7, 130.2, 129.0, 128.5,
128.0, 127.6, 127.1, 126.5, 126.2, 126.1, 125.9, 125.7, 125.6, 124.4,
123.6, 43.0, 27.8; MS (EI) m/z 310 (M+), 182, 155, 127, 77.
1,3-Di(thiophen-3-yl)propan-1-one (4l).25 Yield 53% (58.8 mg,
method A); colorless liquid; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J
= 1.6 Hz, 1H), 7.53 (dd, J = 5.2 Hz, J = 0.8 Hz, 1H), 7.29−7.22 (m,
2H), 6.99−6.96 (m, 2H), 3.19 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.4 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 142.2, 141.4, 131.9,
128.2, 126.9, 126.5, 125.7, 120.6, 40.7, 24.6; MS (EI) m/z 222 (M+),
111, 97, 83, 39.
1,3-Bis(4-methoxyphenyl)propan-1-one (4c).17 Yield 67% (90.5
1
mg, method A); yield 53% (71.4 mg, method B); colorless liquid; H
NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4
Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 3.75 (s,
3H), 3.68 (s, 3H), 3.11 (t, J = 7.6 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 163.4, 158.0, 133.5, 130.3,
130.1, 129.4, 113.9, 113.7, 55.5, 55.3, 40.4, 29.5; MS (EI) m/z 270
(M+), 239, 135, 107, 77.
1,3-Bis(4-ethylphenyl)propan-1-one (4d). Yield 60% (79.8 mg,
method B); colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J
= 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.12
(d, J = 8.0 Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H), 3.02 (t, J = 7.8 Hz, 2H),
2.68 (q, J = 7.6 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz,
3H), 1.22 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
199.0, 150.0, 142.0, 138.6, 134.7, 128.4, 128.3, 128.1, 128.0, 40.5, 29.9,
29.0, 28.5, 15.7, 15.2; HRMS (EI-TOF) m/z calcd for C19H22O
266.1671, found 266.1674.
1,3-Bis(1-methyl-1H-indol-5-yl)propan-1-one (4m). Yield 55%
1
(86.9 mg, method A); white solid; mp 120−122 °C; H NMR (400
MHz, CDCl3) δ 8.31 (d, J = 0.8 Hz, 1H), 7.91 (dd, J = 8.4 Hz, J = 1.2
Hz, 1H), 7.51 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz,
1H), 7.15 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 7.00 (d, J = 3.2
Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H), 6.41 (d, J = 2.8 Hz, 1H), 3.76 (s,
3H), 3.73 (s, 3H), 3.41 (t, J = 7.8 Hz, 2H), 3.19 (t, J = 7.8 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 199.9, 139.1, 135.5, 132.5, 130.4,
129.2, 129.1, 128.8, 128.0, 122.8, 122.5, 121.8, 120.1, 109.2, 109.1,
103.0, 100.6, 41.5, 33.0, 32.9, 31.0; HRMS (EI-TOF) m/z calcd for
C21H20N2O 316.1576, found 316.1573.
1,3-Bis(4-tert-butylphenyl)propan-1-one (4e).18 Yield 80% (128.8
mg, method A); yield 62% (99.8 mg, method B); white solid; mp 57−
58 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.37
(d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H),
3.19 (t, J = 7.6 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.24 (s, 9H), 1.22 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.1, 156.8, 148.9, 138.4,
134.4, 128.1, 128.0, 125.6, 125.4, 40.4, 35.1, 34.4, 31.5, 31.2, 29.7; MS
(EI) m/z 322 (M+), 265, 161, 91, 77.
1,3-Bis(3-chlorophenyl)propan-1-one (4n).26 Yield 41% (57.0 mg,
1,3-Bis(3,5-dimethylphenyl)propan-1-one (4f).19 Yield 61% (81.2
1
method A); light yellow liquid; H NMR (400 MHz, CDCl3) δ 7.91
1
mg, method B); white solid; mp 63−65 °C; H NMR (400 MHz,
(s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.39 (t, J =
8.0 Hz, 1H), 7.23−7.16 (m, 3H), 7.12 (d, J = 5.2 Hz, 1H), 3.26 (t, J =
7.4 Hz, 2H), 3.03 (t, J = 7.4 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.3, 143.0, 138.2, 135.0, 134.3, 133.1, 130.0, 129.8, 128.6,
128.2, 126.7, 126.5, 126.1, 40.1, 29.5; MS (EI) m/z 278 (M+), 243,
139, 111, 75.
CDCl3) δ 7.56 (s, 2H), 7.18 (s, 1H), 6.87 (s, 2H), 6.85 (s, 1H), 3.24
(t, J = 7.6 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.35 (s, 6H), 2.29 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 199.8, 141.4, 138.2, 138.0, 137.1,
134.6, 127.8, 126.3, 125.9, 40.8, 30.1, 21.3, 21.2; MS (EI) m/z 266
(M+), 133, 105, 91, 77.
1,3-Bis(3,4-dimethoxyphenyl)propan-1-one (4g). Yield 65%
(107.3 mg, method A); white solid; mp 87−89 °C (lit.20 88−90
°C); 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.8 Hz, J = 1.6 Hz,
1H), 7.53 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H),
6.79 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H),
3.24 (t, J = 7.6 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100
1,3-Bis(4-(hydroxymethyl)phenyl)propan-1-one (4o). Yield 62%
(83.7 mg, method A); white solid; mp 102−104 °C; H NMR (400
MHz, DMSO-d6) δ 7.94 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H),
7.24−7.20 (m, 4H), 5.35 (br s, 1H), 5.08 (br s, 1H), 4.57 (s, 2H), 4.44
(s, 2H), 3.33 (t, J = 7.4 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 199.3, 148.5, 140.5, 140.0, 135.6, 128.5,
1
E
DOI: 10.1021/acs.joc.5b01650
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
128.4, 127.0, 126.7, 63.2, 62.9, 40.4, 29.8; HRMS (EI-TOF) m/z calcd
for C17H18O3 270.1256, found 270.1262.
Chem. 2006, 14, 1710. (c) Kobori, M.; Shinmoto, H.; Tsushida, T.;
Shinohara, K. Cancer Lett. 1997, 119, 207. (d) Silva, D. H. S.; Davino,
S. C.; de Moraes Barros, S. B.; Yoshida, M. J. Nat. Prod. 1999, 62,
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(a) Siddaiah, V.; Rao, C. V.; Venkateswarlu, S.; Subbaraju, G. V.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01650.
■
S
1
́
(c) Thevenin, M.; Mouray, E.; Grellier, P.; Dubois, J. Eur. J. Org.
Optimization of reaction conditions and spectra of H
NMR, 13C NMR, MS, and HRMS for products (PDF)
Chem. 2014, 2014, 2986. (d) Xu, Z.; Ba, M.; Zhou, H.; Cao, Y.; Tang,
C.; Yang, Y.; He, R.; Liang, Y.; Zhang, X.; Li, Z.; Zhu, L.; Guo, Y.; Guo,
C. Eur. J. Med. Chem. 2014, 85, 27.
AUTHOR INFORMATION
Corresponding Author
*E-mail: huangzhizhen@zju.edu.cn.
■
(10) Guo, C.-S.; Du, Y.-H.; Huang, Z.-Z. Chem. Commun. 2011, 47,
3995.
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72, 2596.
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V.; Nacci, A.; Monopoli, A.; Ferola, V. J. Org. Chem. 2007,
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from MOST of China (973 program
2011CB808600) and National Natural Science Foundation of
China (No. 21372195) are gratefully acknowledged.
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DOI: 10.1021/acs.joc.5b01650
J. Org. Chem. XXXX, XXX, XXX−XXX