Unexpected synthesis of 1,3,5-triarly-1,5-diketones from aryl ketones via di-enamine mechanism

Article abstract of DOI:10.1016/j.tet.2014.10.009

An unexpected reaction of aryl ketone with acetohydrazone of aromatic aldehyde via 1,2-di-enamine/di-iminium mechanism was discovered, leading to efficient synthesis of 1,3,5-triaryl-1,5-diketones in good to excellent yields.

Full text of DOI:10.1016/j.tet.2014.10.009

Tetrahedron 70 (2014) 9240e9244
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unexpected synthesis of 1,3,5-triarly-1,5-diketones from aryl
ketones via di-enamine mechanism
,
a,
Bin Liu a, Junfeng Wang b, Yi Pang b, Zemei Ge a , Runtao Li
*
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
b Department of Chemistry, University of Akron, Akron, OH 44325, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2014
Received in revised form 25 September 2014
Accepted 4 October 2014
Available online 13 October 2014
An unexpected reaction of aryl ketone with acetohydrazone of aromatic aldehyde via 1,2-di-enamine/di-
iminium mechanism was discovered, leading to efficient synthesis of 1,3,5-triaryl-1,5-diketones in good
to excellent yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aromatic aldehyde
Aryl ketone
Synthesis
1,3,5-Triaryl-1,5-diketones
Di-enamine mechanism
1. Introduction
Michael addition is one of the most efficacious methods for the
synthesis of this kind of compounds.3 Even though, there have been
1,5-Diketones are extremely important synthetic intermediates
and desirable starting materials for generating many heterocyclic
and polyfunctional compounds.1,2 Such as, the functionalized chiral
cyclohexenones (A)1d and 2,4,6-triarylpyridine (B) as precursors of
DNA binding ligands2d were all obtained from the corresponding
1,3,5-triaryl-1,5-diketones (Scheme 1).
few reports on the preparation of 1,3,5-triphenyl-1,5-dikeones
through the Michael addition of aryl ketones to chalcones,4 due
to the low reactivity and high steric hindrance for both substrates.
Moreover, the harsh reaction conditions, such as the use of exces-
sive strong base, always led to the lower yields and the limited
substrate scope. Thus it is challenging and highly desirable to de-
velop a mild efficient strategy for the preparation of this kind of
compounds. We disclose here an unexpected transformation of aryl
ketones for the synthesis of 1,3,5-triphenylpentane-1,5-dione de-
rivatives catalyzed by 1,2-primary diamine via a synergetic di-
enamine mechanism (Scheme 2).
Scheme 2. Unexpected synthesis of 1,5-diketones from aryl ketones.
Scheme 1. Application of 1,5-diketones.
The Mannich type reactions of acetohydrazone of aromatic al-
dehyde 1a and aryl ketones 2a were initially designed (Scheme 2),
based on recent papers5 and our discovery that 1,2-primary amine
catalysts could efficiently activate chalcones6a,b furanones6c and
aryl ketones6d (Scheme 3). The model reaction of 1a and 2a was
* Corresponding authors. E-mail addresses: lirt@mail.bjmu.edu.cn, lirt@bjmu.
edu.cn (R. Li).
http://dx.doi.org/10.1016/j.tet.2014.10.009
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

B. Liu et al. / Tetrahedron 70 (2014) 9240e9244
9241
(entry 1, cat. 1) could catalyze the reaction, indicating the syn-
ergetic catalytic mechanism. Subsequently, the reaction was fur-
ther explored in MeOH with ethylenediamine as the catalyst. The
yield of 3a was slightly improved to 20% with 100% loading of
catalyst at 50 ꢀC (entry 8). Inspired by our previous discovery7
that TEA might improve the catalytic efficiency in the enamine/
iminum mechanism, 1 equiv of TEA was added in the system, and
we were delight to find that the yield of 3a was significantly
improved to 64% (entry 9). Moreover, the reaction did not pro-
ceed in the absence of ethylenediamine (entry 10), which could
confirm the catalytic action of ethylenediamine. Subsequently,
the acid additive was further examined as well, and interestingly,
mostly reported strong acid CF3COOH (III) did not work well in
this case. The benzoic acids V and VI turned out to be the best
additives.
Scheme 3. Efficient 1,2-diamine catalyzed reactions of ketones.
With the optimized reaction conditions, the structural di-
versity of the substrates in this reaction was examined. As shown
in Table 2, most of the reactions gave the desired products 3 in
good to excellent yields with this catalytic system. The electronic
property and position of the substituents on the aromatic ring of
substrates 1 do not significantly influence the reaction, except for
the strong electron-donating group (eMeO, entry 5) and strong
electron-withdrawing group (eCO2Me, entry 6). Even the aceto-
hydrazone from cinnamaldehyde (1k) could still be efficiently
transformed into 3k in 86% yield (Table 2, entry 11). On the con-
trary, the electronic property of substituents on aryl ketones 2
showed apparent effect in the reaction. This further implied that
aryl ketones might be activated via enamine mechanism to func-
tion as Mannich donors. From the results of entries 14e17 and
19e21, we can see that mild electronic property of the sub-
stituents on the aromatic ring of aryl ketones 2 could improve the
synthesis of 3 to excellent yield (Table 2, entry 21, 94% yield).
However the strong electron withdrawing or electron donating
groups on the aryl ring of aryl ketones 2 are unfavorable for the
reactions (Table 2, entries 17 and 19). Moreover, this method is
also suitable for the heterocyclic substrates (Table 2, entries 12, 13
and 18).
first carried out using our reported method6b at room temperature
in MeOH with ethylenediamineeHOAc (1:2) as the catalyst. How-
ever, no desired product 4a was observed in the reaction, and much
to our surprise product 3a was separated in about 12% yield
(Table 1, entry 1). The interesting discovery encouraged us to fur-
ther develop this reaction into an efficient method for the synthesis
of 1,3,5-triphenyl-1,5-dikeones.
Table 1
Optimization of the reaction conditionsa
Entry
Solvent
Catalyst
Additives IeVI
Yield (3a) (%)
1
2
3
4
MeOH
DCM
Toluene
THF
1
1
1
1
I
I
I
I
12
Trace
n.r.
n.r.
10
5
EtOH
1
I
6
7
8
9
10
11
12
13
14
15
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2
3
1
I
I
I
I
n.r.
n.r.
20
64
n.r.
67
39
60
73
72
Table 2
Substrate scope of 1,2-diamine catalyzed reaction between aryl methyl ketones and
N-acetyl aromatic aldehyde hydrazone
1þTEA
TEA
1þTEA
1þTEA
1þTEA
1þTEA
1þTEA
I
II
III
IV
V
VI
Additives IeVI.
Entry
Ar1
Ar2
Yield (%)
1
2
3
4
5
6
7
8
4-MePh
Ph
4-ClPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
73(3a)
89(3b)
80(3c)
84(3d)
68(3e)
45(3f)
81(3g)
83(3h)
70(3i)
81(3j)
86(3k)
62(3l)
54(3m)
80(3n)
61(3o)
54(3p)
54(3q)
66(3r)
52(3s)
77(3t)
94(3u)
4-FPh
4-MeOPh
4-CO2MePh
2-BrPh
a
Entries 1e5: the loading of catalyst was 30 mol %; Entries 6e15: the loading of
catalyst was 100 mol % and reactions were carried out at 50 ꢀC.
3-ClPh
9
3,4-(OCH2O)Ph
3,4-dichloro
PhCH]CH
3-Indole
2-Pyrrole
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-ClPh
2. Result and discussion
10
11
12
13
14
15
16
17
18
19
20
21
To improve the yield, the model reaction was tested in dif-
ferent solvents, and the effect of different solvents on this re-
action revealed that the reaction could only proceed in protic
polar solvents such as MeOH/EtOH (Table 1, entries 1 and 5),
which is consistent with our previous discovery.6 Then the cat-
alytic efficiency of different catalysts was examined in MeOH
with additive I (Table 1, entries 1, 6 and 7). Interestingly, simple
primary amine (entry 6, cat. 2) and secondary amine (entry 7, cat.
3) did not show any catalytic effect. Only 1,2-primary diamine
Ph
4-FPh
4-BrPh
4-MeOPh
4-NO2Ph
2-Thiophene
4-MeOPh
4-BrPh
4-MePh
4-ClPh
4-ClPh

9242
B. Liu et al. / Tetrahedron 70 (2014) 9240e9244
The novel mechanism was proposed based on the fact that the
4. Experimental section
4.1. General information
interesting direct transformation of aryl ketones could only be
catalyzed by 1,2-primary diamine (Scheme 4). The aryl ketones
might be activated via di-enamine intermediate 5, which further
reacted with 1a to form 6, and the transformation of 6 to 7 might be
a synergetic process.8 Fortunately, the key intermediate 7c was
separated and characterized by 1H NMR and Mass spectra (MW
366.67), which was found to be easily converted to 3a catalyzed by
acid (See Supplementary data). Furthermore, acetohydrazone of
aryl ketone 9 could not react with substrate 1a and aromatic al-
dehyde under the same catalytic conditions, further confirming the
enamine activation of aryl ketones (Scheme 5, (1)). The reaction of
aryl ketone and aryl aldehyde led to chalcone 10 instead of 3a
(Scheme 5, (2)), which ruled out the chalcone pathway. This also
tells us that the cleavage of the acetylhydrazide in 6 to 7 might also
proceed via a synergetic pathway. The preformed acetylhydrazone
1a is also essential in this reaction, because the three component
reaction of aryl acetone 2a, 4-methylbenzaldehyde and acetohy-
drazide could not be catalyzed to afford 3a (Scheme 5, (2)).
All chemicals were purchased from commercial sources without
further purification. All of the reactions were monitored by thin
layer chromatography (TLC) on GF254 silica gel plates. 1H NMR
spectra and 13C NMR spectra were recorded on a Bruker AVANCE III
400 (400 MHz) spectrometer in needful D-reagents with tetrame-
thylsilane (TMS) as an internal reference. NMR chemical shifts are
reported as values (parts per million) relative to internal tetrame-
thylsilane and splitting patterns are designated as: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet. HRMS of additional
products were carried out on Brucker Apex IV FTMS. Melting points
were measured on X5A made by Beijing Fukai Company, China.
4.2. General procedure of the synthesis of the products 3
A
mixture of p-tolualdehyde (0.5 mmol), acethydrazine
(0.5 mmol) in CH3OH (5 mL) was stirred at 50 ꢀC for 4 h (1 was
formed). Then 1,2-diamine (0.5 mmol), 2,6-difluorobenzoic acids
(1 mmol), TEA (0.5 mmol) and acetophenone (2, 2 mmol) were added
and the reaction was continued for another 72 h. After cooling, AcOH
(2 mL) was added and the resulting mixture was allowed to stir at
room temperature for 4 h. The solvent was evaporated under vacuum
and the residue was diluted with EtOAc (15 mL), and washed with
brine, dried over anhydrous Na2SO4, and concentrated at reduced
pressure. The crude product was further purified by column chro-
matography on silica gel (PEeEtOAc¼20:1) to get the final product 3.
4.2.1. 1,5-Diphenyl-3-(p-tolyl)pentane-1,5-dione (3a). White solid;
yield 73%, mp: 99.9e101.2 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.94 (d,
J¼7.4 Hz, 4H), 7.53 (t, J¼7.4 Hz, 2H), 7.43 (t, J¼7.6 Hz, 4H), 7.16 (d,
J¼7.9 Hz, 2H), 7.07 (d, J¼7.9 Hz, 2H), 4.14e3.94 (m, 1H), 3.47 (dd,
J¼16.6, 7.0 Hz, 2H), 3.32 (dd, J¼16.6, 7.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3)
d 198.7, 140.8, 137.0, 136.2, 133.1, 129.3, 128.6, 128.2, 127.3,
45.1, 36.9, 21.0; HRMS calcd for C24H23Oþ2 [MþH]þ 343.1706, found:
Scheme 4. Proposed synergistic mechanism.
343.1693.
4.2.2. 1,3,5-Triphenylpentane-1,5-dione (3b). Pale solid; yield 89%,
mp: 97.1e98.6 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.01e7.91 (m, 4H),
7.60e7.52 (m, 2H), 7.49e7.40 (m, 5H), 7.27 (dd, J¼6.7, 4.0 Hz, 4H),
4.06 (dd, J¼14.0, 7.0 Hz, 1H), 3.50 (dd, J¼16.6, 7.0 Hz, 2H), 3.36 (dd,
J¼16.6, 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 198.8, 143.8, 136.9,
133.1, 128.6, 128.2, 127.5, 126.7, 112.2, 44.9, 37.3; HRMS calcd. For
C
23H21Oþ2 [MþH]þ 329.1541, found: 329.1536.
4.2.3. 3-(4-Chlorophenyl)-1,5-diphenylpentane-1,5-dione
(3c). White solid; yield 80%, mp: 93.8e94.3 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
7.93 (dd, J¼5.2, 3.3 Hz, 4H), 7.51 (m, 6H), 7.23 (m, 4H), 4.05
Scheme 5. Further verified experiments for the proposed synergistic mechanism.
(dd, J¼14.0, 7.0 Hz, 1H), 3.49 (dd, J¼16.8, 6.8 Hz, 2H), 3.33 (dd,
J¼16.8, 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 198.3, 142.3, 136.8,
3. Conclusion
133.2, 132.4, 128.9, 128.7, 128.6, 128.1, 44.7, 36.6; HRMS calcd for
C
23H20ClOþ2 [MþH]þ 363.1145, found: 363.1146.
In summary, an interesting reaction of aryl ketone and aceto-
hydrazone catalyzed by 1,2-primary diamine was discovered. After
careful optimization of the reaction conditions, it was found to be
an efficient method for the synthesis of 1,3,5-triaryl-1,5-diketones
directly from aryl ketones. Importantly, the mild reaction condi-
tions allow the synthesis of a variety of 1,3,5-triaryl-1,5-diketones
from a wide range of substrates. The novel synergetic mechanism
was rationally proposed and confirmed by the capture of key in-
termediate 7. We anticipate that this novel and mild reaction of aryl
ketones could be further employed in achieving biologically im-
portant molecules in organic chemistry and medicinal chemistry in
the future.
4.2.4. 3-(4-Fluorophenyl)-1,5-diphenylpentane-1,5-dione (3d). Pale
yellow solid; yield 84%, mp: 66.3e67.4 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
7.94 (dd, J¼5.2, 3.3 Hz, 4H), 7.55 (ddd, J¼6.8, 4.0, 1.2 Hz,
2H), 7.44 (dd, J¼10.5, 4.7 Hz, 4H), 7.31e7.19 (m, 1H), 7.04e6.88 (m,
3H), 4.07 (p, J¼7.0 Hz, 1H), 3.49 (dd, J¼16.7, 6.8 Hz, 2H), 3.32 (dd,
J¼16.7, 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 198.6, 139.4, 136.8,
133.2, 129.0, 129.0, 128.7, 128.2, 115.5, 115.3, 112.4, 112.2, 45.0, 36.6;
HRMS calcd. For C23H20FOþ2 [MþH]þ 347.1446, found: 347.1442.
4.2.5. 3-(4-Methoxyphenyl)-1,5-diphenylpentane-1,5-dione
(3e). White solid; yield 68%, mp: 70.9e71.7 ꢀC. 1H NMR (400 MHz,

B. Liu et al. / Tetrahedron 70 (2014) 9240e9244
9243
CDCl3)
d
8.02e7.86 (m, 4H), 7.60e7.49 (m, 2H), 7.43 (dd, J¼10.5,
d
8.04 (Br, 1H), 7.99e7.92 (m, 4H), 7.63 (d, J¼7.9 Hz, 1H), 7.52 (t,
4.7 Hz, 4H), 7.19 (d, J¼8.7 Hz, 2H), 6.80 (d, J¼8.7 Hz, 2H), 4.02 (p,
J¼7.4 Hz, 2H), 7.42 (t, J¼7.6 Hz, 4H), 7.31 (d, J¼8.1 Hz, 1H), 7.20e7.12
(m, 1H), 7.12e7.04 (m, 2H), 4.40 (p, J¼6.9 Hz, 1H), 3.62 (dd, J¼16.5,
7.0 Hz, 2H), 3.49 (dd, J¼16.5, 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
J¼7.0 Hz, 1H), 3.75 (s, 3H), 3.47 (dd, J¼16.5, 6.9 Hz, 2H), 3.31 (dd,
J¼16.5, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 198.8, 158.2, 137.0,
135.8, 133.1, 128.6, 128.4, 128.2, 114.0, 55.2, 45.2, 36.6; HRMS calcd
d 199.4, 137.0, 136.5, 133.0, 128.6, 128.2, 126.2, 122.0, 121.8, 119.4,
for C24H23Oþ3 [MþH]þ 359.1640, found: 359.1642.
119.0, 118.2, 111.4, 44.3, 29.1; HRMS calcd. For C25H22NOþ2 [MþH]þ
368.1646, found: 368.1645.
4.2.6. Methyl
(3f). Pale yellow solid; yield 45%, mp: 95.7e96.4 ꢀC. 1H NMR
(400 MHz, CDCl3)
4-(1,5-dioxo-1,5-diphenylpentan-3-yl)benzoate
4.2.13. 1,5-Diphenyl-3-(1H-pyrrol-2-yl)pentane-1,5-dione
d
8.00e7.87 (m, 6H), 7.55 (dd, J¼10.5, 4.3 Hz, 2H),
(3m). Yellow solid; yield 54%, mp: 41.7 ꢀC. 1H NMR (400 MHz,
7.45 (t, J¼7.6 Hz, 4H), 7.37 (d, J¼8.3 Hz, 2H), 4.14 (p, J¼7.0 Hz, 1H),
3.88 (s, 3H), 3.52 (dd, J¼16.9, 6.8 Hz, 2H), 3.37 (dd, J¼17.0, 7.2 Hz,
CDCl3)
d
8.01e7.92 (m, 4H), 7.56 (t, J¼7.4 Hz, 2H), 7.45 (t, J¼7.6 Hz,
5H), 6.68 (dd, J¼4.1, 2.6 Hz,1H), 6.09 (dd, J¼5.8, 2.8 Hz,1H), 5.98 (br,
2H); 13C NMR (100 MHz, CDCl3)
d 198.1, 166.9, 149.3, 136.8, 133.3,
1H), 4.15 (p, J¼6.5 Hz, 1H), 3.50 (d, J¼6.5 Hz, 4H); 13C NMR
130.0, 128.7, 128.6, 128.1, 127.6, 52.0, 44.5, 37.0; HRMS calcd. For
(100 MHz, CDCl3) d 199.7, 136.8, 135.0, 133.4, 128.7, 128.1, 116.9,
C
25H23Oþ4 [MþH]þ 387.1590, found: 387.1591.
107.6, 103.8, 43.7, 28.9; HRMS calcd. For C21H20NOþ2 [MþH]þ
318.1484, found: 318.1489.
4.2.7. 3-(2-Bromophenyl)-1,5-diphenylpentane-1,5-dione
(3g). White solid; yield 81%, mp: 87.0e89.1 ꢀC. 1H NMR (400 MHz,
4.2.14. 1,5-Bis(4-fluorophenyl)-3-(p-tolyl)pentane-1,5-dione
(3n). Colorless oil; yield 80%, 1H NMR (400 MHz, CDCl3)
CDCl3)
d
8.02e7.94 (m, 4H), 7.55 (ddt, J¼6.7, 3.4, 1.2 Hz, 3H), 7.44
(dd, J¼10.5, 4.7 Hz, 4H), 7.33 (dd, J¼7.8, 1.6 Hz, 1H), 7.30e7.19 (m,
1H), 7.04 (td, J¼7.9, 1.7 Hz, 1H), 4.53 (p, J¼7.0 Hz, 1H), 3.53 (dd,
J¼16.9, 7.2 Hz, 2H), 3.44 (dd, J¼16.9, 6.7 Hz, 2H); 13C NMR
d
8.07e7.95 (m, 4H), 7.15e7.05 (m, 8H), 3.98 (p, J¼7.0 Hz, 1H), 3.45
(dd, J¼16.5, 7.0 Hz, 2H), 3.28 (dd, J¼16.5, 7.0 Hz, 2H), 2.28 (s, 3H);
13C NMR (100 MHz, CDCl3)
197.2, 167.0, 164.5, 140.4, 136.4, 133.3,
d
(100 MHz, CDCl3)
d
198.4, 142.5, 136.8, 133.4, 133.2, 128.6, 128.2,
133.3, 130.9, 130.8, 129.4, 127.2, 115.8, 115.6, 44.9, 37.0, 21.0; HRMS
128.2, 128.1, 127.7, 124.5, 43.2, 36.3; HRMS calcd. For C23H20BrO2þ
calcd. For C24H21F2Oþ2 [MþH]þ 379.1510, found: 379.1504.
[MþH]þ 407.0644, found: 407.0641.
4.2.15. 1,5-Bis(4-bromophenyl)-3-(p-tolyl)pentane-1,5-dione
4.2.8. 3-(3-Chlorophenyl)-1,5-diphenylpentane-1,5-dione
(3o). White solid; yield 61%, mp: 145.7e146.2 ꢀC. 1H NMR
(3h). Yellow solid; yield 83%, mp: 92.3e94.3 ꢀC. 1H NMR (400 MHz,
(400 MHz, CDCl3) d 7.83e7.75 (m, 4H), 7.59e7.53 (m, 4H), 7.10 (dd,
CDCl3)
d
8.02e7.87 (m, 4H), 7.55 (t, J¼7.4 Hz, 2H), 7.44 (t, J¼7.6 Hz,
J¼23.3, 8.1 Hz, 4H), 3.97 (t, J¼7.0 Hz, 1H), 3.43 (dd, J¼16.6, 7.0 Hz,
4H), 7.28 (s, 1H), 7.20 (d, J¼5.2 Hz, 2H), 7.15 (ddd, J¼9.2, 4.2, 2.0 Hz,
1H), 4.06 (p, J¼7.0 Hz, 1H), 3.49 (dd, J¼16.9, 6.8 Hz, 2H), 3.34 (dd,
2H), 3.26 (dd, J¼16.6, 7.0 Hz, 2H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 197.6, 140.3, 136.5, 135.6, 131.9, 129.7, 129.4, 128.3, 127.2,
J¼16.9, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
198.2, 146.0, 136.7,
44.9, 36.8, 21.0; HRMS calcd. For C24H21Br2O2þ [MþH]þ 498.9913,
134.3,133.3, 129.9,128.7,128.2,127.6, 126.9,126.0, 44.6, 36.7; HRMS
found: 498.9903.
calcd. For C23H20ClOþ2 [MþH]þ 363.1145, found: 363.1148.
4.2.16. 1,5-Bis(4-methoxyphenyl)-3-(p-tolyl)pentane-1,5-dione
4.2.9. 3-(Benzo[d][1,3]dioxol-5-yl)-1,5-diphenylpentane-1,5-dione
(3p). Colorless oil; yield 54%. 1H NMR (400 MHz, CDCl3)
d 8.01e7.86
(3i). Red solid; yield 70%, mp: 87.3e87.4 ꢀC. 1H NMR (400 MHz,
(m, 4H), 7.15 (d, J¼8.1 Hz, 2H), 7.07 (d, J¼7.9 Hz, 2H), 6.99e6.83 (m,
4H), 4.06e3.93 (m, 1H), 3.84 (s, 6H), 3.41 (dd, J¼16.2, 7.0 Hz, 2H),
3.24 (dd, J¼16.2, 7.1 Hz, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3)
CDCl3)
d
8.04e7.81 (m, 4H), 7.61e7.50 (m, 2H), 7.44 (t, J¼7.6 Hz, 4H),
6.84e6.63 (m, 3H), 5.88 (s, 2H), 3.99 (p, J¼7.0 Hz, 1H), 3.44 (dd,
J¼16.6, 6.9 Hz, 2H), 3.29 (dd, J¼16.6, 7.2 Hz, 2H); 13C NMR (100 MHz,
d
197.4, 163.4, 141.0, 136.1, 130.5, 130.1, 129.3, 127.3, 113.7, 55.5, 44.9,
CDCl3)
d
198.6, 147.7, 146.2, 137.7, 136.9, 133.1, 128.6, 128.2, 120.5,
37.4, 21.0; HRMS calcd. For C26H27Oþ4 [MþH]þ 403.1899, found:
108.3, 107.9, 100.9, 45.2, 37.1; HRMS calcd for C24H21Oþ4 [MþH]þ
403.1904.
373.1431, found: 373.1434.
4.2.17. 1,5-Bis(4-nitrophenyl)-3-(p-tolyl)pentane-1,5-dione
4.2.10. 3-(3,4-Dichlorophenyl)-1,5-diphenylpentane-1,5-dione
(3q). Orange solid; yield 54%, mp: 128.3 ꢀC. 1H NMR (400 MHz,
(3j). White solid; yield 81%, mp: 108.1e108.7 ꢀC. 1H NMR
CDCl3)
d
8.35e8.24 (m, 4H), 8.15e8.00 (m, 4H), 7.12 (dd, J¼19.8,
(400 MHz, CDCl3)
d
8.02e7.89 (m, 4H), 7.63e7.52 (m, 2H), 7.44 (dd,
8.1 Hz, 4H), 4.00 (p, J¼6.9 Hz, 1H), 3.54 (dd, J¼16.9, 7.0 Hz, 2H), 3.38
J¼10.6, 4.7 Hz, 4H), 7.36 (d, J¼2.2 Hz, 1H), 7.29 (d, J¼8.4 Hz, 1H), 7.17
(dd, J¼8.4, 2.2 Hz, 1H), 4.49 (p, J¼6.9 Hz, 1H), 3.53 (dd, J¼17.0,
7.0 Hz, 2H), 3.43 (dd, J¼17.0, 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
(dd, J¼16.9, 6.8 Hz, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
197.1, 150.4, 141.2, 139.7, 136.9, 129.6, 129.2, 127.2, 123.9, 45.3, 36.6,
21.0; HRMS calcd for
433.1394.
C
24H21N2Oþ6 [MþH]þ 433.1397, found:
d
198.1, 139.5, 136.7, 134.4, 133.3, 132.8, 129.8, 129.4, 128.7, 128.1,
127.3, 42.8, 33.5; HRMS calcd for C23H19Cl2Oþ2 [MþH]þ 397.0762,
found: 397.0757.
4.2.18. 1,5-Di(thiophen-2-yl)-3-(p-tolyl)pentane-1,5-dione
(3r). Creamy white solid; yield 66%, mp: 92.8e93.4 ꢀC. 1H NMR
4.2.11. 1,5-Diphenyl-3-styrylpentane-1,5-dione (3k). Pale yellow
solid; yield 86%, mp: 58.6e59.1 ꢀC. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3) d 7.85e7.66 (m, 2H), 7.67e7.55 (m, 2H), 7.22e7.13
(m, 2H), 7.13e7.05 (m, 4H), 4.01 (p, J¼7.1 Hz, 1H), 3.41 (dd, J¼16.0,
d
8.06e7.96 (m, 4H), 7.61e7.52 (m, 2H), 7.46 (dd, J¼10.5, 4.7 Hz, 4H),
7.0 Hz, 2H), 3.25 (dd, J¼16.0, 7.2 Hz, 2H), 2.28 (s, 3H); 13C NMR
7.33e7.24 (m, 4H), 7.21e7.15 (m, 1H), 6.43 (d, J¼15.9 Hz, 1H), 6.29
(dd, J¼15.9, 8.1 Hz, 1H), 3.74e3.55 (m, 1H), 3.36 (dd, J¼16.5, 6.5 Hz,
2H), 3.20 (dd, J¼16.5, 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3) d 191.5, 144.3, 140.2, 136.4, 133.7, 132.2, 129.4,
128.2, 127.3, 45.5, 37.6, 21.0; HRMS calcd for C20H19O2Sþ2 [MþH]þ
355.0825, found: 355.0821.
d
198.9, 137.1, 137.0, 133.1, 131.9, 130.5, 128.7, 128.5, 128.2, 127.3,
126.3, 43.4, 35.1; HRMS calcd for C25H23Oþ2 [MþH]þ 355.1699,
4.2.19. 3-(4-Chlorophenyl)-1,5-bis(4-methoxyphenyl)pentane-1,5-
found: 355.1693.
dione (3s). Green solid; yield 52%, mp: 62.1e62.9 ꢀC. 1H NMR
(400 MHz, CDCl3)
d 8.13e7.75 (m, 4H), 7.22 (s, 4H), 7.05e6.75 (m,
4.2.12. 3-(1H-Indol-3-yl)-1,5-diphenylpentane-1,5-dione (3l). Red
solid; yield 62%, mp: 106.3e107.4 ꢀC. 1H NMR (400 MHz, CDCl3)
4H), 4.02 (p, J¼7.1 Hz, 1H), 3.85 (s, 6H), 3.42 (dd, J¼16.4, 6.8 Hz, 2H),
3.24 (dd, J¼16.4, 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 196.9,

9244
B. Liu et al. / Tetrahedron 70 (2014) 9240e9244
163.6, 142.5, 132.2, 130.4, 129.9, 128.9, 128.7, 113.8, 55.5, 44.5, 37.0;
Supplementary data
HRMS calcd for C25H24ClOþ4 [MþH]þ 423.1360, found: 423.1358.
The original data of 1H NMR and 13C NMR of all products are
supplied. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.10.009. These data include MOL
files and InChiKeys of the most important compounds described in
this article.
4.2.20. 1,5-Bis(4-bromophenyl)-3-(4-chlorophenyl)pentane-1,5-
dione (3t). White solid; yield 77%, mp: 98.8e100.4 ꢀC. 1H NMR
(400 MHz, CDCl3) d 7.84e7.76 (m, 4H), 7.64e7.55 (m, 4H), 7.29e7.15
(m, 4H), 4.00 (p, J¼6.9 Hz, 1H), 3.44 (dd, J¼16.8, 6.8 Hz, 2H), 3.26
(dd, J¼16.8, 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 197.2, 141.9,
135.4, 132.6, 132.0, 129.6, 128.9128.8, 128.5, 44.6, 36.5; HRMS calcd.
References and notes
For C23H18Br2ClOþ2 [MþH]þ 518.9346, found: 518.9357.
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4.2.21. 3-(4-Chlorophenyl)-1,5-di-p-tolylpentane-1,5-dione
(3u). White solid; yield 94%, mp: 86.8e87.1 ꢀC. 1H NMR (400 MHz,
CDCl3)
1H), 3.44 (dd, J¼16.6, 6.8 Hz, 2H), 3.28 (dd, J¼16.6, 7.3 Hz, 2H), 2.39
(s, 6H); 13C NMR (100 MHz, CDCl3)
198.0, 144.1, 142.5, 134.3, 132.3,
d
7.83 (d, J¼8.2 Hz, 4H), 7.30e7.16 (m, 8H), 4.03 (p, J¼7.0 Hz,
d
129.3, 128.9, 128.7, 128.3, 44.7, 36.7, 21.7; HRMS calcd for
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C
25H24ClOþ2 [MþH]þ 391.1461, found: 391.1459.
4.3. Capture of key intermediate 7
A 10 mL tube was charged with p-tolualdehyde (0.5 mmol),
acethydrazide (0.5 mmol), CH3OH 5 mL and a stir bar. The reaction
was heated to 50 ꢀC for 4 h (1 was formed). Then 1,2-diamine
catalyst (0.5 mmol), 2,6-difluorobenzoic acids (1 mmol), TEA
(0.5 mmol) and acetophenone (2, 2 mmol) were added to the re-
action and the mixture was stirred at 50 ꢀC for 72 h. The resulting
mixture was allowed to cool down to room temperature. The
mixture was then purified by column chromatography on silica gel
(PEeEtOAc¼4:1) to get the intermediate 7c. 1H NMR (600 MHz,
CDCl3)
d
7.66e7.51 (m, 4H), 7.29 (t, J¼7.6 Hz, 4H), 7.23 (td, J¼7.2,
1.2 Hz, 2H), 7.04 (dd, J¼24.0, 8.0 Hz, 4H), 4.89 (t, 1H), 3.50 (dt, J¼9.2,
6.6 Hz, 1H), 3.15e2.92 (m, 2H), 2.94e2.82 (m, 2H), 2.35 (ddd,
J¼12.3, 5.6, 1.1 Hz, 1H), 2.23 (s, 3H), 2.13 (m, J¼8.2, 7.0 Hz, 1H); 13
C
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NMR (150 MHz, CDCl3)
d 145.5, 144.8, 142.3, 139.6, 135.7, 129.1,
128.3, 128.2, 127.8, 127.4, 127.3, 127.1, 125.9, 107.8, 80.6, 52.2, 44.2,
41.5, 38.7, 21.0. ESI calcd. For C26H26Nþ2 [MþH]þ 366.61, found:
366.67.
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Acknowledgements
This research was supported by the funds of the National Nat-
ural Science Foundation of China (No. 20972005, 81172915).
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