Cobalt(II) catalyzed C(sp)-H bond functionalization of alkynes with phenyl hydrazines: Facile access to diaryl 1,2-diketones

Article abstract of DOI:10.1039/c5ob00419e

A cobalt acetylacetonate catalyzed oxidative diketonation of alkynes via C(sp)-H bond functionalization has been described. The reaction involves a free-radical mechanism, wherein the phenyl radical formed from phenyl hydrazine couples with Co(ii) activated alkyne to produce 1,2-diketones. The reaction proceeds at room temperature in DMF with the use of Ag₂O/air as the oxidizing system. The utility of the protocol for the synthesis of a series of imidazoles including a potent platelet aggregation inhibitor trifenagrel has been demonstrated.

Full text of DOI:10.1039/c5ob00419e

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Paper
Cobalt (II) catalyzed C(sp)-H bond functionalization of alkynes with
phenyl hydrazines: A facile access to diaryl 1,2-diketones†‡
Jaideep B. Bharate,a,b Sheenu Abbat,c Rohit Sharma,a,b Prasad V. Bharatam,c* Ram A. Vishwakarma,a,b*
and Sandip B. Bharatea,b,
*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: XXX
A cobalt acetylacetonate catalyzed oxidative diketonation of alkynes via C(sp)-H bond functionalization has been described. The
reaction involves a free-radical mechanism, wherein the phenyl radical formed from phenyl hydrazine couples with Co(II)
activated alkyne to produce 1,2-diketones. The reaction proceeds at room temperature in DMF with the use of Ag2O/air as
10 oxidizing system. The utility of the protocol for synthesis of a series of imidazoles including a potent platelet aggregation inhibitor
trifenagrel has been demonstrated.
Introduction1
Literature reports
O
O
R2
N
N
N
R1
R
R2
Diaryl 1,2-diketones are privileged building blocks for the
15 synthesis of biologically active heterocycles including
imidazoles, quinoxalines and indolone-N-oxides.1-4 1,2-Diketones
are also precursors for the synthesis of N-heterocyclic carbenes
which are used as ligands in organometallic chemistry and
catalysis.5 Because of their importance in medicinal and
20 organometallic chemistry, 1,2-diketones are attractive
chemotypes to synthetic chemists.6 Numerous methods are
available for their synthesis (Scheme 1) including (a) radical
coupling of phenyl hydrazine with styrene in the presence of
copper triflate/ ferric nitrate,7 (b) AlCl3-catalyzed cross-coupling
25 of α-oxo acid chloride with organostannane compound at –30
°C),8 (c) Ru-catalyzed oxidation of stilbenes,9 (d) coupling of
iodobenzene with phenyl propiolic acid in the presence of CuI/
R1
FeCl3,
TBN
SmI2
(h)
O
PdBr2
CuBr2
O2
(g)
(f)
O
R2
R1
l
C
)
y
O
(a)
p
C
b
i
(
L
u
R
NH2
+
Cu(OTf)2
Fe(NO3)3
HN
O
X
(e)
X= halo, OH
O2
R2
R1
O
R2
R1
I
(d)
O
R1
[Ru(cymene)Cl2]2,
Bu4NI, TBHP
(b)
(c)
Cl
R1
+
O
HO2C
R2
PhSnnBu3
+
R2
R1
This work
O
H
N
R2
R2
10 mol%
Co(acac)2
Atmospheric air
Ag2O
NH2
R1
+
R1
O
Cu(OTf)2,10
(e)
Ru(bpy)2Cl2,9
VOCl3,11
Fe3O4,12
Bi(NO3)3/Cu(OAc)213 catalyzed oxidation of α-halo or α-hydroxy
30 ketones, (f) conversion of 1,3-diketones to 1,2-diketones in the
presence of Lewis acid (FeCl3) and TBN or I2/DMSO,14, 15 (g)
Scheme 1. Literature methods and our new method for preparation of 1,2-
40 diketones
16-19
23
PdBr2/ CuBr2,
PdCl2,20 CuI,21 Ru,22 or KMnO4 catalyzed
Although several methods are reported, most of them have one or
other drawback such as: (a) expensive metal catalysts,9, 11, 13, 16-19
(b) prior synthesis of starting materials (phenyl propiolic acids
Wacker-type oxidation of internal alkynes, (h) SmI2 catalyzed
25
transformation of N-acylbenzotriazoles to 1,2-diketones.24,
16-19, 23
11, 13
35 Additionally, few metal-free synthesis of 1,2-diketones have also 45 and diphenyl alkynes,10,
α-haloketones,9,
and 1,3-
been reported.26, 27
diketones14, 15) is required, and (c) many involve vigorous and
harsh reaction conditions. In this context, we thought of
exploiting terminal alkynes towards the synthesis of diaryl 1,2-
diketones via transition metal catalyzed C(sp)-H bond
50 functionalization.
a
Medicinal Chemistry Division, CSIR-Indian Institute of Integrative
Medicine (CSIR), Canal Road, Jammu-180001, India. Fax: +91-191-
2586333;; Tel: +91-191- 2585006;; *E-mail: sbharate@iiim.ac.in
(SBB); ram@iiim.ac.in (RAV).
Transition metal-catalyzed coupling of sp C−H bond of alkynes is
perhaps one of the most synthetically useful C−H bond
functionalization reactions.28-32 Among various transition metal-
catalyzed C-H bond functionalizations, cobalt-mediated C−H
55 bond functionalization has met with recent success for C-C bond
formation reactions.32 Herein, we employed the strategy to utilize
a phenyl hydrazine as a phenyl radical source,33-38 for coupling
with activated C−H of phenyl acetylene to yield diphenyl 1,2-
bAcademy of Scientific & Innovative Research (AcSIR), CSIR-Indian
Institute of Integrative Medicine, Canal Road, Jammu-180001, India
c
Departments of Pharmacoinformatics and Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research (NIPER),
SAS Nagar, Punjab-160062, India. *E-mail: pvbharatam@niper.ac.in
† IIIM Publication number IIIM/1714/2014
‡Electronic supplementary information (ESI) available for experimental
details. See DOI: XXX
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Table 1. Optimization studiesa
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O
H
N
N
NH2
+
N
+
View Article Online
DOI: 10.1039/C5OB00419E
O
+
5a
Temp.
1a
4a
3a
2a
Entry
Oxidant (mol%)
Catalyst (mol%)
Solvent
Time (h)
3a yieldb
1
2
3
4
5
6
7
8
Air
Air
Air
O2
O2
noned
Air, K2S2O8 (50)
Air, Na2S2O8 (50)
Air, BQ (50)
Air, MnO2 (50)
Air, PhI(OAc)2 (50)
Air, AgOAc (50)
Air, Ag2CO3 (50)
Air, Ag2O (50)
O2, Ag2O (50)
Air, Ag2O (10)
Air, Ag2O (10)
Air
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
DMFc
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
0.5
8
8
0.5
8
8
8
8
8
8
8
8
8
8
8
0.5
8
8
8
20
5
25
16
23
tracese
5
5
9
35
32
30
30
20
38
38
35
40f
0
0
0
0
50
58
64
70g
35
68
10
11
12
13
14
15
16
17
18g
19
20
21
22
23
24
25h
26
27
CuCl2 (10)
CuBr (10)
CuI (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10), Fe(NO3)3 (10), DABCO (3 equiv.)
Co(acetate) (10)
Co(acac)2 (10)
Air
Air
Air
Air
Air
Air
8
8
8
8
rt
rt
rt
70
8
Air, Ag2O (10)
Air, Ag2O (10)
Air, Ag2O (10)
Co(acac)2 (10)
Co(acac)2 (10)
Co(acac)2 (10)
8
8
8
DMF: H2O (9:1) rt
a1a (1.0 mmol), 2a (1.2 mmol) and oxidizing agent and/ or catalyst (wherever mentioned) in a mentioned solvent at rt; Isolated yields after silica gel
column chromatography; creaction does not proceed in other solvents such as ACN, DCE, dioxane, ethanol, methanol, toluene and NMP; dreaction under
N2 atmosphere; e 1.3% yield, determined by GCMS; f under this reaction condition, we have also isolated side products azobenzene 4a (14%) and stilbene
5a (13%); g Reactions does not proceed in presence of iron acetate, iron bromide, gold chloride and palladium acetate catalysts (10 mol%), under air,
DMF, rt, 8 h reaction condition; h bold entry indicates optimized reaction condition for synthesis of 1,2-diketones; BQ: benzoquinone.
b
diaryl ketones. To the best of our knowledge, there has been no 25 reaction. Next, we investigated the reaction in the presence of
previous report on the direct synthesis of 1,2-diketones from
terminal alkynes and phenyl hydrazines. In the present
communication, we report Co(acac)2 catalyzed synthesis of diaryl
1,2-diketones using atmospheric oxygen and Ag2O as a mixed
various oxidants such as K2S2O8, Na2S2O8, benzoquinone, MnO2,
PhI(OAc)2 and silver catalysts AgOAc, Ag2CO3 and Ag2O in
DMF (entries 7-17). Reactions performed in the presence of
benzoquinone, MnO2, PhI(OAc)2, AgOAc and Ag2O showed
5
oxidizing system (Scheme 1). The developed method showed 30 formation of diphenyl 1,2-diketone 3a in 30-40% yield. The 10
good substrate scope for variety of substituted phenyl hydrazines
and phenyl acetylenes.
mol% of Ag2O was found to be optimal for efficient formation of
desired product (entry 17). We further made attempts to improve
the product yield beyond 40% under catalyst and oxidant free
reaction conditions, by varying the relative equivalents of both
35 the substrates; however all such attempts were unsuccessful.
The study was initiated with the preliminary reaction of phenyl
10 hydrazine 1a with phenylacetylene 2a in an open air atmosphere
using various solvents. Among various solvents investigated,
DMF was the best solvent for this reaction. Reaction of 1a with
2a in DMF at room temperature for 30 min led to the formation
of diphenyl 1,2-diketone 3a in 20% yield (Table 1, entry 1).
15 Intriguingly, this result does not involve the use of any metal
Next, we tried to improve the reaction yield by using various
catalysts such as iron acetate, iron bromide, gold chloride and
palladium acetate, Cu-based catalysts CuCl2, CuBr, CuI,
Cu(OTf)2, Co(acetate) and Co(acac)2 (entries 18-21 and 23-24).
catalysts or oxidizing agent; however, the poor yields warranted 40 The copper triflate/ ferric nitrate,7 which was used earlier for the
optimization of the reaction conditions. When the open air
catalyst-free reaction was continued further for 8 h, the desired
product was formed in 25% yield (entry 3). When the reaction
20 was performed with molecular oxygen, the desired product 3a
synthesis of 1,2-diketones from phenyl hydrazines and styrenes,
was also investigated for our reaction. Under this condition (entry
22), desired 1,2-diketone 3a was formed in 50% yield. However,
with the use of only copper triflate, it did not led to the product
was formed in similar yields to that of atmospheric air (entries 1 45 formation (entry 21). Among various catalysts attempted,
and 3 versus 4-5). Interestingly, under N2 atmosphere in dry
DMF, only trace amount of product was formed (1.3%, entry 6),
which indicated the role of oxygen for the progress of the
Co(acac)2 in the presence of Ag2O provided best results (70%
yield of 3a) (entry 25). When the entry 25 condition, was
attempted under heating (70 °C), the product yield was decreased
2
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24
25
26
27
28
29
30
31
p-tBu
p-F
p-I
p-Br
p-F
p-CN
m-NO2
H
-Ph(p-Me)
-Ph(p-OMe)
-Ph(p-OMe)
-thiophen-3-yl
-naphthalen-1-yl
-Ph
3t
3u
3v
3w
3x
3y
63
66
from 70 to 35% (entry 25 versus 26). Next, in order to check
whether addition of water as an additional oxygen source results
in the improvement of product yield, reaction was performed in
the mixture of DMF and water. Reaction in DMF: water (9:1) led
to the formation of equivalent yield of the desired product 3a to
that of optimized condition (entry 27 versus 25). Thus, we used
entry 25 as an optimized reaction for further experiments.
View A6rt5icle Online
63
DOI: 10.1039/C5OB00419E
68
0
0
5
-Ph
-pyridin-2-yl
3z
3aa
0
aReagents and conditions: 1 (1.0 mmol), 2 (1.2 mmol), Co(acac)2/Ag2O
b
(10 mol% each), DMF, rt, 8 h. Isolated yields after silica gel column
chromatography.
With the optimized reaction condition in hand, we explored the
utility of this approach for oxidative coupling of various
10 substituted phenyl hydrazines with phenylacetylene. As shown in
Table 2, various substituted phenyl hydrazines were well
tolerated in the reaction. The phenyl hydrazines substituted with
various electron-withdrawing groups such as F, Cl, Br, I, CF3
(entries 2, 5, 12, 13, 15) as well as electron-donating groups such
15 as OCF3, t-Bu groups (entries 3 and 10) gave corresponding 1,2-
diketones in good yields. In order to check whether the reaction
works with –CN, -NO2 substituents on aromatic rings, the
reaction between 4-cyano phenyl hydrazine and 3-nitro phenyl
hydrazine with phenylacetylene was attempted, however desired
20 products were not obtained (entries 29-30 in Table 2). The
phenylacetylenes substituted with various electron-donating
groups (e.g. methyl, ethyl, propyl, OMe, acetylene, tert-butyl;
entries 6-9 and 21-26), as well as electron withdrawing groups
(e.g. F, Cl, Br; entries 11, 14, 16), participated well in the
25 reaction. Reaction of 2-ethynylpyridine (entry 31) was also
attempted, however the product was not formed. However, the
reaction was also well tolerated for thiophene heterocycle (entries
17 and 27), bicyclic (entries 18 and 28), tricyclic (entry 19) and
biphenyl (entry 20) acetylenes, producing desired products in
30 good yields All our attempts with aliphatic alkynes such as 1-
hexyne, 1-heptyne, 1-octyne failed to give desired 1,2-diketones;
wherein primarily the azobenzene 4a and styryl products were
formed.
40 The possibility of free-radical mechanism was investigated by
performing reaction in the presence of free-radical quencher
TEMPO. Reaction performed in the presence of TEMPO
produced trace amounts of product 3a, which indicated that the
reaction involves free-radical mechanism. As confirmed by
45 TEMPO experiment and quantum chemical calculations (details
provided in section S6 of ESI), the reaction pathway possibly
involves a radical mechanism. The reaction mechanism showing
key possible reaction intermediates is depicted in Scheme 2.
O
H
N
Co(acac)2
Ag2O, DMF
NH2
Ph
rt, 8 h
O
2a
Co(acac)2
1a
3a
3O2
.
2.Ag2O
.
4.AgOH
OOH
N2
.
OOH
Co
3.OOH
OOH
OOH
Co
.
+
.
III
IVb
V
50 Scheme 2. Plausible reaction mechanism
Next, utility of the protocol for the synthesis of imidazoles was
investigated. The treatment of 1,2-diketone 3a with aldehydes 6a-
c in acetic acid produced imidazoles 7a-c in 60-70% yields
55 (Scheme 3, route A). It is noteworthy to mention that the one-pot
synthesis of 2,4,5-trisubstituted imidazoles 7a-c directly from
phenylacetylene 2a and phenyl hydrazine 1a was also successful
(Scheme 3, route B).
35 Table 2. Substrate scope for the synthesis of diaryl 1,2-diketonesa
O
H
N
Ar
Co(acac)2/Ag2O
NH2
Ar
+
R
R
O
DMF/ rt, 8 h
air atm
3a-i
1
2
Entry
1
2
3
4
5
6
7
8
R
Ar
Product
3a
3b
3c
3d
3e
3f
3g
% yieldb
H
p-CF3
p-OCF3
m-CF3
p-I
H
H
H
H
p-tBu
H
p-F
p-Cl
H
p-Br
H
H
-Ph
-Ph
-Ph
-Ph
-Ph
-Ph(p-Me)
-Ph(p-C≡CH)
70
65
68
68
72
70
64
60
68
70
68
70
62
67
68
66
62
72
64
64
62
65
68
H
N
7a:
R =
NH2
R-CHO
+
+
Route B
b
1a
2a
6a-c
7b:
7c:
R =
H
N
O
a
+
R-CHO
R
-Ph(p-CH2CH2CH3) 3h
Route A
N
R =
9
-Ph(p-tBu)
-Ph
-Ph(p-F)
-Ph
-Ph
3i
3i
3j
3j
3k
3k
3l
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3a
6a-c
7a-c
60
Scheme 3. Synthesis of imidazoles 7a-c. Reagents and conditions: (a).
AcOH, NH4OAc, 120 °C, 2 h, 60-70%; (b) Co(acac)2, Ag2O/DMF, air
atm, AcOH, NH4OAc, 120 °C, 2 h, 55-65%.
-Ph(p-Cl)
-Ph
-Ph(p-Br)
-thiophen-3-yl
-naphthalen-1-yl
-anthracen-10-yl
-Ph(p-Ph)
-Ph(p-OMe)
-Ph(p-Me)
-Ph(p-Et)
3l
3m
3n
3o
3p
3q
3r
3s
65 Trifenagrel (8), a 2,4,5-triaryl imidazole is a potent platelet
aggregation inhibitor.39 The present method was utilized for the
synthesis of this inhibitor as depicted in Scheme 4. It is
noteworthy to mention that we could prepare imidazole 7d using
a one-pot manner directly from precursors 1a, 2a and 6d.
70 Treatment of phenyl hydrazine 1a, phenylacetylene 2a and 2-
H
H
H
p-OCF3
p-CF3
p-CF3
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1
Benzil (3a):7 Yellow solid; m.p. 94-96 °C; H NMR (CDCl3,
formyl phenol 6d in one-pot in presence of the Co(II)/Ag2O/air
catalytic system and NH4OAc/ AcOH produced imidazole 7d.
400 MHz): δ 7.99 (d, J = 8.0 Hz, 4H), 7.66 (t, J = 8.0 Hz, 2H),
View Article Online
7.52 (t, J = 8.0 Hz, 4H); 13C NMR (CDCl3,100 MHz): δ 194.6,
Treatment
of
intermediate
7d
with
2-chloro-N,N-
DOI: 10.1039/C5OB00419E
dimethylethanamine (9) in the presence of K2CO3 produced
trifenagrel (8) in 70% yield.
135.0, 133.0, 129.9, 129.1; IR (CHCl3): νmax 3438, 2923, 1725,
55 1682, 1596, 1581, 1449 cm-1; GC-MS: m/z (EI) 210 (M+, 7), 105
(100), 77 (64), 51 (17).
5
H
N
OHC
NH2
H
N
N
H
N
HO
Cl
1-Phenyl-2-(4-(trifluoromethyl) phenyl) ethane-1,2-dione
1
1a
2a
6d
9
N
(3b):7 Brown sticky solid; H NMR (CDCl3, 400 MHz): δ 8.12
N
b
a
O
+
HO
(d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz,
60 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 2H); 13C NMR
7d
Trifenagrel (8)
N
2
Scheme 4. Synthesis of trifenagrel (8). Reagents and conditions: (a). 10
mol% Co(acac)2, 10 mol% Ag2O/DMF, air atm, AcOH, NH4OAc, 120 °C,
2 h, 55%; (b) K2CO3, rt, 6 h, 70%.
(CDCl3, 100 MHz): δ 193.5, 193.1, 136.0 (t, JCF = 32.69 Hz),
135.6, 135.3, 132.6, 130.3, 130.0, 129.2, 126.2; 19F NMR (376.5
MHz, CDCl3): δ -63.36 (s, 3F); IR (CHCl3): νmax 3435, 2922,
1737, 1674, 1596, 1450 cm-1; GC-MS: m/z (EI) 278 (M+, 1), 173
65 (16), 145 (22), 125 (5), 105 (100), 77 (31), 51 (6).
10
Conclusion
1-Phenyl-2-(4-(trifluoromethoxy) phenyl) ethane-1,2-dione
(3c):7 Brown sticky oil; 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J
= 8.0 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H),
7.53 (t, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H); 13C NMR
70 (CDCl3, 100 MHz): δ 193.8, 192.7, 153.9, 135.2, 132.7, 132.1,
In summary, we have successfully developed new cobalt (II)
catalyzed synthesis of 1,2-diketones using air/Ag2O as a mixed
oxidizing system. This is the first report on the synthesis of 1,2-
15 diketones from terminal alkynes. Developed method is
operationally simple and could be used efficiently for the
preparation of variety of biologically important heterocycles as
demonstrated by the synthesis of trifenagrel. This protocol may
serve as an excellent method for C−H activation of terminal
20 alkynes to study its scope in other reactions.
1
130.0, 129.1, 128.8 (t, JCF = 32.69 Hz), 120.7 ; 19F NMR (376.5
MHz, CDCl3): δ -57.54 (s, 3F); IR (CHCl3): νmax 3437, 1674,
1599, 1259, 1211, 1167 cm-1; GC-MS: m/z (EI) 294 (M+, 2), 189
(55), 105 (100), 95 (9), 77 (26), 63 (7), 50 (3).
75
1-Phenyl-2-(3-(trifluoromethyl) phenyl) ethane-1,2-dione
1
(3d):7 Brown sticky solid; H NMR (CDCl3, 400 MHz): δ 8.28
Experimental section
(s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.92
(d, J = 8.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.54 (t, J = 8.0 Hz, 2H);
13C NMR (CDCl3, 100 MHz): δ 193.3, 192.6, 135.3, 133.6,
General. All chemicals were obtained from Sigma-Aldrich
1
Company and used as received. H, 13C and DEPT NMR spectra
2
80 133.2, 132.6, 132.0 (t, JCF = 41.50 Hz), 131.2, 130.0, 129.7,
129.2, 126.5; 19F NMR (376.5 MHz, CDCl3): δ -62.93 (s, 3F); IR
(CHCl3): νmax 3438, 2924, 1686, 1674, 1611, 1556, 1450 cm-1;
GC-MS: m/z (EI) 278 (M+ 1), 259 (4), 173 (18), 145 (19), 125
(4), 105 (10), 95 (1), 77 (7), 51 (1).
25 were recorded on Brucker-Avance DPX FT-NMR 500 and 400
MHz instruments. Chemical data for protons are reported in parts
per million (ppm) downfield from tetramethylsilane and are
referenced to the residual proton in the NMR solvent (CDCl3,
7.26 ppm). Carbon nuclear magnetic resonance spectra (13C
30 NMR) were recorded at 125 MHz or 100 MHz: chemical data for
carbons are reported in parts per million (ppm, δ scale) downfield
from tetramethylsilane and are referenced to the carbon resonance
of the solvent (CDCl3, 77 ppm). ESI-MS and HR-ESIMS spectra
were recorded on Agilent 1100 LC-Q-TOF and HRMS-6540-
35 UHD machines. IR spectra were recorded on Perkin-Elmer IR
spectrophotometer. Melting points were recorded on digital
melting point apparatus.
85
1-(4-Iodophenyl)-2-phenylethane-1,2-dione (3e):40 Yellow
solid; m.p. 79-80 °C; 1H NMR (CDCl3, 400 MHz): δ 7.97 (d, J =
8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.69-7.66 (m, 3H), 7.52 (t,
J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 193.9, 193.7,
138.4, 135.1, 132.8, 132.3, 131.0, 130.0, 129.1, 103.7; IR
90 (CHCl3): νmax 3437, 2924, 1671, 1581, 702 cm-1; GC-MS: m/z
(EI) 336 (M+ 7), 231 (69), 209 (8), 203 (15), 105 (100), 77 (54),
50 (16).
General procedure for synthesis of diaryl 1,2-diketones 3a-
x. To the mixture of phenyl hydrazine (1.0 equiv.) and phenyl
40 acetylene (1.2 equiv.) in dimethylformamide was added 10 mol%
of cobalt acetylacetanoate Co(acac)2, 10 mol% silver oxide
(Ag2O) and reaction was stirred at room temperature for 8 h.
After completion of the reaction (monitored by TLC), reaction
mixture was filtered using whatman filter paper and then was
45 extracted with ethyl acetate. The combined organic layers were
dried over anhydrous sodium sulphate and evaporated on vacuo
rotavapor to get crude product. The crude product was purified by
silica gel (#100-200) column chromatography using n-hexane and
ethyl acetate as an eluent to get pure products 3a-3x in 60-72%
50 yield.
1-Phenyl-2-(p-tolyl)ethane-1,2-dione (3f):7 Yellow solid; m.p.
0
1
94-96 C; H NMR (CDCl3, 400 MHz): δ 7.98 (d, J = 8.0 Hz,
95 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.51 (t, J =
8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ 194.8, 194.4, 146.3, 134.8, 133.1, 130.6,
130.1, 129.9, 129.8, 129.1, 22.0 ; IR (CHCl3): νmax 3436, 2923,
1726, 1671, 1450, 1216 cm-1; GC-MS: m/z (EI) 224 (M+ 5), 119
100 (100), 105 (22), 91 (28), 77 (19), 65 (12), 51 (7).
1-(4-Ethynylphenyl)-2-phenylethane-1,2-dione (3g): Yellow
1
sticky solid; H NMR (CDCl3, 400 MHz): δ 7.98-7.93 (m, 4H),
7.67 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 8.0
Hz, 2H), 3.32 (s, 1H); 13C NMR (CDCl3,100 MHz): δ 194.1,
105 193.6, 135.1, 132.8, 132.7, 130.0, 129.7, 129.1, 128.8, 128.5,
4
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82.5, 81.7; IR (CHCl3): νmax 3440, 2921, 1665, 1617, 1450 cm-1;
GC-MS: m/z (EI) 234 (M+ 6), 206 (32), 129 (100), 105 (88), 101
(35), 77 (50), 75 (22), 51 (17).
128.7, 127.1, 126.0, 124.4; IR (CHCl3): νmax 3443, 1633, 1452,
1120 cm-1; GC-MS: m/z (EI) 260 (M+ 6), 155 (100), 127 (54), 105
View Article Online
(15), 77 (29), 51 (9).
DOI: 10.1039/C5OB00419E
1-Phenyl-2-(4-propylphenyl) ethane-1,2-dione (3h): Yellow
1
sticky solid; H NMR (CDCl3, 400 MHz): δ 7.99-7.88 (m, 4H), 60 sticky solid; H NMR (CDCl3, 400 MHz): δ 9.30 (d, J = 8.0 Hz,
1-(Anthracen-9-yl)-2-phenylethane-1,2-dione (3o): Yellow
1
5
7.65 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0
Hz, 2H), 2.66 (t, J = 8.0 Hz, 2H), 1.70-1.59 (m, 2H), 0.95 (t, J =
8.0 Hz, 3H); 13C NMR (CDCl3,100 MHz): δ 194.8, 194.4, 150.9,
134.8, 130.8, 130.1, 129.9, 129.2, 129.0, 128.8, 38.3, 24.2, 13.8;
1H), 8.70 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 12.0 Hz, 1H), 8.16 (s,
1H), 8.02 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 12.0 Hz, 1H), 7.75-
7.69 (m, 3H), 7.60 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H),
7.47 (t, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 197.1,
10 IR (CHCl3): νmax 3439, 2923, 1721, 1668, 1604, 1450, 1049 cm-1; 65 194.5, 138.8, 134.8, 133.2, 131.0, 130.1, 129.5, 129.1, 128.4,
GC-MS: m/z (EI) 252 (M+, 2), 147 (100), 119 (4), 91 (18), 51 (5).
127.7, 127.4, 126.9, 122.8; IR (CHCl3): νmax 3443, 1757, 1633,
1453 cm-1; ESI-MS: m/z 311.10 [M+H+]; HRMS: m/z 311.1093
(ESI) calcd for C22H15O2 (311.1093).
1-(4-(Tert-butyl)phenyl)-2-phenylethane-1,2-dione
(3i):7
1
Yellow sticky solid; H NMR (CDCl3, 400 MHz): δ 7.99 (d, J =
8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H),
15 7.54-7.49 (m, 4H), 1.34 (s, 9H);13C NMR (CDCl3, 100 MHz): δ 70 Yellow solid, m.p. 103-105 °C; H NMR (CDCl3, 400 MHz): δ
1-([1,1'-Biphenyl]-4-yl)-2-phenylethane-1,2-dione
1
(3p):10
194.8, 194.3, 159.1, 134.8, 133.1, 130.5, 129.9, 130.0, 126.1,
31.0; IR (CHCl3): νmax 3449, 1733, 1669, 1598, 1217, 1177 cm-1;
GC-MS: m/z (EI) 266 (M+, 2), 161 (100), 146 (10), 105 (20), 77
(20), 51 (6).
8.06 (dd, J = 8.0 Hz, 4H), 7.75 (d, J = 8.0 Hz, 2H), 7.68-7.62 (m,
2H), 7.55-7.42 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ 194.6,
194.2, 147.7, 139.5, 134.9, 133.1, 131.7, 130.5, 130.0, 129.1,
128.7, 127.7, 127.4; IR (CHCl3): νmax 3443, 1639, 1449, 1321
75 cm-1; GC-MS: m/z (EI) 286 (M+ 2), 181 (100), 152 (41), 105 (14),
77 (21), 51 (7).
20
1-(4-Fluorophenyl)-2-phenylethane-1,2-dione: (3j):7 Brown
1
solid, m.p. 68-70 °C; H NMR (CDCl3, 400 MHz): δ 8.04 (dd, J
= 4.0 & 4.0 Hz, 2H), 7.98 (d, J = 4.0 Hz, 2H), 7.67 (t, J = 8.0 Hz,
1H), 7.52 (t, J = 8.0 Hz, 2H); 7.19 (t, J = 8.0 Hz, 2H); 13C NMR
1-(4-Methoxyphenyl)-2-(4-(trifluoromethoxy) phenyl) ethane-
1,2-dione (3q): Yellow sticky solid; 1H NMR (CDCl3, 400 MHz):
δ 8.06 (d, J = 12.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.34 (d, J =
1
(CDCl3, 100 MHz): δ 194.1, 192.7, 168.1, (d, JCF = 258 Hz),
2
25 135.1, 132.9, 132.8, 132.7, 130.0, 129.1, 116.5, (d, JCF = 22.13 80 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H); 13C NMR
Hz); 19F NMR (376.5 MHz, CDCl3): δ -101.18 (s, 1F); IR
(CHCl3): νmax 3440, 1657, 1643, 1633, 1452, 718 cm-1; GC-MS:
m/z (EI) 228 (M+, 6), 123 (60), 105 (100), 77 (50), 51 (15).
(CDCl3,100 MHz): δ 193.0, 192.4, 165.2, 153.7, 132.5, (d, 1JCF
=
55.33 Hz), 131.3, 125.8, 120.6, 114.5, 55.7 ; 19F NMR (376.5
MHz, CDCl3): δ -57.53 (s, 3F); IR (CHCl3): νmax 3437, 2925,
1726, 1667, 1599, 1424, 1260 cm-1; GC-MS: m/z (EI) 324 (M+,
85 1), 189 (10), 135 (100), 107 (7), 92 (13), 77 (16), 63 (8).
1-(4-Chlorophenyl)-2-phenylethane-1,2-dione (3k):7 Yellow
1
30 solid, m.p. 66-67°C; H NMR (CDCl3, 400 MHz): δ 7.98-7.92
(m, 4H), 7.67 (t, J = 8.0 Hz, 1H), 7.54-7.48 (m, 4H); 13C NMR
(CDCl3, 100 MHz): δ 193.9, 193.2, 141.9, 135.1, 131.3, 131.2,
130.0, 129.5, 129.4, 129.1; IR (CHCl3): νmax 3436, 2923, 1721,
1676, 1587, 1208, 837 cm-1; GC-MS: m/z (EI) 244 (M+, 2), 209
35 (4), 139 (41), 111 (20), 105 (100), 77 (50), 51 (13).
1-(P-Tolyl)-2-(4-(trifluoromethyl) phenyl) ethane-1,2-dione
(3r): Brown solid; m.p. 77-78 °C; 1H NMR (CDCl3, 400 MHz): δ
8.11 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.78 (d, J =
12.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H); 13C NMR
2
90 (CDCl3,100 MHz): δ 193.2, 193.1, 146.7, 136.0, (t, JCF = 15.0
Hz), 135.6, 130.3, 130.2, 130.1, 129.9, 126.1, 21.9; 19F NMR
(376.5 MHz, CDCl3): δ -63.35 (s, 1F ); IR (CHCl3): νmax 3436,
2924, 1677, 1664, 1605, 1117 cm-1; GC-MS: m/z (EI) 292 (M+,
1), 173 (9), 145 (17), 119 (100), 91 (40), 65 (17).
1-(4-Bromophenyl)-2-phenylethane-1,2-dione (3l):7 Yellow
solid, m.p. 86-88 °C; 1H NMR (CDCl3, 400 MHz): δ 7.98 (d, J =
8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 3H),
7.53 (t, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 193.8,
40 193.3, 135.1, 132.8, 132.5, 131.8, 131.3, 130.5, 130.0, 129.1; IR
(CHCl3): νmax 3443, 1633, 1456, 1420 cm-1; GC-MS: m/z (EI) 290
(M+, 2), 209 (5), 185 (24), 157 (10), 105 (100), 77 (52).
95
1-(4-Ethylphenyl)-2-(4-(trifluoromethyl) phenyl) ethane-1,2-
1
dione (3s): Brown sticky solid; H NMR (CDCl3, 400 MHz): δ
8.11 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0
Hz, 2H), 7.37 (d, J = 12.0 Hz, 2H), 2.77-2.71 (quartet, J = 8.0 Hz,
1-Phenyl-2-(thiophen-3-yl)ethane-1,2-dione (3m):41 Yellow
sticky solid; 1H NMR (CDCl3, 400 MHz): δ 8.22 (s, 1H), 8.02 (d,
45 J = 8.0 Hz, 2H), 7.68-7.64 (m, 2H), 7.51 (t, J = 8.0 Hz, 2H); 7.41
(s, 1H); 13C NMR (CDCl3, 100 MHz): δ 193.3, 187.3, 138.1,
137.0, 134.8, 132.8, 130.2, 129.0, 127.2, 127.1; IR (CHCl3): νmax
3435, 1737, 1617, 1577, 1465 cm-1; GC-MS: m/z (EI) 216 (M+,
18), 105 (99), 77 (71), 51 (21), (4).
2H), 1.27 (t, J = 4.0 Hz, 3H); 13C NMR (CDCl3,100 MHz): δ
2
100 193.3, 193.2, 152.8, 135.9, (t, JCF = 17.1 Hz), 135.6, 130.4,
130.3, 130.2, 128.7, 126.0, 124.7, 29.2, 15.0; 19F NMR (376.5
MHz, CDCl3): δ -63.35 (s, 3F); IR (CHCl3): νmax 3437, 2925,
1672, 1604, 1325, 1068 cm-1.
1-(4-(Tert-butyl) phenyl)-2-(p-tolyl)ethane-1,2-dione
(3t):
105 Brown sticky solid; 1H NMR (CDCl3, 400 MHz): δ 7.91-7.85 (m,
4H), 7.54 (t, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 2.45 (s,
3H), 1.35 (s, 9H); 13C NMR (CDCl3,100 MHz): δ 193.4, 157.7,
144.9, 129.5, 129.3, 128.9, 128.7, 128.5, 124.8, 121.2, 30.1, 28.5,
20.8; IR (CHCl3): νmax 1725, 1671, 1604, 1542, 1463, 1410 cm-1;
50
1-(Naphthalen-1-yl)-2-phenylethane-1,2-dione (3n):42 Yellow
solid, m.p. 100-102 °C; 1H NMR (CDCl3, 400 MHz): δ 9.32 (d, J
= 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H),
7.96 (dd, J = 8.0 & 8.0 Hz, 2H); 7.75 (t, J = 8.0 Hz, 1H), 7.68-
7.62 (m, 2H), 7.54-7.48 (m, 3H); 13C NMR (CDCl3, 100 MHz):
55 197.2, 194.8, 136.0, 135.0, 134.7, 130.0, 129.5, 129.0, 128.8,
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GC-MS: m/z (EI) 280 (M+4), 161 (100), 146 (9), 119 (48), 91
were dried over anhydrous sodium sulphate and evaporated on
vacuo rotavapor to get crude product. The crude product was
(28), 65 (10).
purified by silica gel (#100-200) column chromatogrVaipewhyArtuicsleinOgnline
DOI: 10.1039/C5OB00419E
n-hexane and ethyl acetate as an eluent to get pure product 7a-d
1-(4-Fluorophenyl)-2-(4-methoxyphenyl)
ethane-1,2-dione
(3u):43 Yellow solid, m.p. 68-70 °C; 1H NMR (CDCl3, 400
MHz): δ 8.03-7.94 (m, 4H), 7.18 (t, J = 8.0 Hz, 2H), 7.00 (d, J =
8.0 Hz, 2H), 3.89 (s, 3H); 13C NMR (CDCl3,100 MHz): δ 193.0,
60 in 55-65% yield.
5
2,4,5-Triphenyl-1H-imidazole (7a):1 White solid; m.p. 274-
276 °C; 1H NMR (DMSO-d6, 400 MHz): δ 12.71 (s, 1H), 8.11 (d,
J = 8.0 Hz, 2H), 7.56-7.23 (m, 13H); 13C NMR (DMSO-d6,100
MHz): δ 145.0, 134.6, 130.5, 129.8, 128.1, 127.9, 127.7, 127.6,
65 127.2, 126.5, 126.0, 124.6; IR (CHCl3): νmax 3417, 1658, 1644,
1633, 1503, 1460 cm-1; ESI-MS: m/z 297.00 [M+H+]; HRMS:
m/z 297.1417 (ESI) calcd for C21H17N2 (297.1417).
1
192.6, 168.0 (d, JCF = 257 Hz), 165.1, 132.8, 132.7, 132.4,
2
116.4, (d, JCF = 22.13 Hz),114.4, 55.6; 19F NMR (376.5 MHz,
CDCl3): δ -101.64 (s, 1F); IR (CHCl3): νmax 3440, 1650, 1643,
10 1633, 1599, 749 cm-1.
1-(4-Iodophenyl)-2-(4-methoxyphenyl) ethane-1,2-dione (3v):
1
Yellow sticky solid; H NMR (CDCl3, 400 MHz): δ 7.94-7.87
(m, 4H), 7.69 (d, J = 12.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 3.89
(s, 3H); 13C NMR (CDCl3, 100 MHz): δ 193.7, 192.0, 134.5,
2-(Naphthalen-1-yl)-4,5-diphenyl-1H-imidazole (7b):44 Brown
solid, m.p. 220-222 °C; 1H NMR (DMSO-d6, 400 MHz): δ 12.88,
15 132.2, 130.5, 130.2, 129.7, 128.9, 128.6, 127.4, 126.8, 49.6; IR 70 (s, 1H), 8.63 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.03-7.94 (m, 4H),
(CHCl3): νmax 3441, 1733, 1675, 1593, 1018 cm-1.
7.58-7.34 (m, 11H); 13C NMR (DMSO-d6, 100 MHz): δ 145.5,
133.0, 132.7, 128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.1,
126.7, 126.3, 123.7, 123.5; IR (CHCl3): νmax 3357, 1652, 1600,
1502, 1446 cm-1; ESI-MS: m/z 347.00 [M+H]+; HRMS: m/z
75 347.9528 (ESI) calcd for C25H18N2 (347.9528).
1-(4-Bromophenyl)-2-(thiophen-3-yl)ethane-1,2-dione
(3w):
1
Pale yellow sticky solid; H NMR (CDCl3, 400 MHz): δ 8.24 (s,
1H), 7.90 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 3H), 7.42 (s,
20 1H); 13C NMR (CDCl3, 100 MHz): δ 192.0, 186.4, 137.8, 137.3,
132.4, 131.5, 130.5, 127.3, 127.2; IR (CHCl3): νmax 3443, 1633,
2-(Anthracen-9-yl)-4,5-diphenyl-1H-imidazole (7c):45 Brown
1449, 1417, 748 cm-1; GC-MS: m/z (EI) 294 (M+ 3), 185 (24),
solid, m.p.166-168 °C; H NMR (DMSO, 400 MHz): δ 12.96 (s,
1
,
111 (100), 76 (11), 50 (7).
1H), 8.81 (s, 1H), 8.22 (d, J = 12.0 Hz, 2H), 7.96 (d, J = 8.0 Hz,
2H), 7.69 (d, J = 8.0 Hz, 2H), 7.58 (t, J = 4.0 Hz, 6H), 7.45 (t, J =
80 4.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 3H), 7.27 (t, J = 4.0 Hz, 1H);
13C NMR (DMSO,100 MHz): δ 143.3, 136.9, 135.4, 131.1,
130.9, 130.8, 128.7, 128.4, 128.2, 127.9, 127.3, 126.6, 126.0,
125.5; IR (CHCl3): νmax 3391, 1666, 1602, 1533, 1483, 1444,
1266 cm-1; ESI-MS: m/z 397.00 [M+H]+; HRMS: m/z 397.1709
85 (ESI) calcd for C29H21N2 (397.1709).
1-(4-Fluorophenyl)-2-(naphthalen-1-yl)ethane-1,2-dione
1
25 (3x):19 Pale yellow solid; m.p. 68-70 °C; H NMR (CDCl3, 400
MHz): δ 9.29 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.07
(t, J = 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz,
1H), 7.76 (t, J = 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.51 (t, J =
8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100
1
30 MHz): δ 196.7, 192.9, 168.0, (d, JCF = 258 Hz), 136.1, 135.1,
134.1, 132.9, 132.8, 129.5, 128.9, 127.2, 125.9, 124.4, 116.5, (d,
2JCF = 22.13 Hz); 19F NMR (376.5 MHz, CDCl3): δ -101.64 (s,
1F); IR (CHCl3): νmax 3444, 1667, 1650, 1597, 1411, 776, cm-1;
GC-MS: m/z (EI) 278 (M+ 5), 155 (100), 127 (62), 95 (17), 75
35 (16), 50 (3).
Procedure for synthesis of trifenagrel (8): To the mixture of
phenyl hydrazine (1a, 1.0 equiv.) and phenylacetylene (2a, 1.2
equiv.) in DMF was added 10 mol% of cobalt acetylacetanoate
and 10 mol% silver oxide. Reaction mixture was then stirred at
90 room temperature for 8 h. Salicyladehyde (6d, 1 equiv.),
ammonium acetate and acetic acid (2 mL) was added to the
reaction mixture and it was refluxed at 100 °C for 3 h. After
completion of the reaction (monitored by TLC), reaction mixture
was filtered, and filtrate was extracted with ethyl acetate and the
95 combined organic layers were dried over anhydrous sodium
sulphate. Solvent was evaporated on vacuo rotavapor to get the
crude product. The crude product was purified by silica gel
(#100-200) column chromatography using n-hexane-EtOAc as an
eluent to get imidazole 7d in 55% yield. Compound 7d (1 equiv.)
100 was then treated with 2-chloro-N,N-dimethylethanamine (1.5
equiv.) in presence of K2CO3 (2 equiv.) in dry acetone for 6 h at
room temparature, resulting in formation of trifenagrel (8) in 70%
yield.
General procedure for synthesis of imidazoles 7a-c from
1,2-diketones. Benzil (0.2 equiv.), benzaldehyde (0.2 equiv.),
and ammonium acetate (2.0 equiv.) were mixed together and
were dissolved in 1.0 mL of AcOH in a round bottom flask
40 containing a magnetic stir bar. Reaction mixture was then
refluxed at 100 °C for 3 h. Then, concentrated NH4OH solution
was added to the reaction mixture at 0 °C, which resulted in
formation of a white precipitate which was collected by filtration
and washed with H2O. The solid was dried in a vacuum oven for
45 18 h at 50 °C to afford as imidazoles 7a-c bright white solids.
General one-pot procedure for synthesis of imidazoles 7a-c
from phenylacetylenes. To the mixture of phenyl hydrazine (1.0
equiv.) and phenylacetylene (1.2 equiv.) in DMF was added 10
mol% of cobalt acetylacetanoate and 10 mol% silver oxide.
50 Reaction mixture was stirred at room temperature for 8 h.
Aldehyde (1 equiv.), ammonium acetate (2 equiv.) and acetic acid
(2 ml) were then added to the reaction mixture and it was
refluxed at 100 °C for 3 h. After completion of the reaction
(monitored by TLC), reaction mixture was filtered, and filtrate
55 was extracted with ethyl acetate. The combined organic layers
2-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (7d):46 Yellow solid;
105 m.p. 170-172 °C; 1H NMR (acetone-d6, 400 MHz): δ 8.00 (d, J =
8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 4H), 7.43-7.28 (m, 7H), 7.03 (d,
J = 8.0 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H); 13C NMR (acetone-d6,
100 MHz): δ 158.5, 147.3, 131.0, 129.5, 128.8, 128.5, 125.8,
119.7, 118.0, 113.9; IR (CHCl3): νmax 3436, 1629, 1604, 1488,
110 1444 cm-1; ESI-MS: m/z 313.10 [M+H]+; HRMS: m/z 313.1350
(ESI) calcd for C21H16N2O (313.1350).
6
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Trifenagrel (8).1 White solid; m.p. 132-134 °C 1H NMR
(CDCl3, 400 MHz): δ 12.33 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H),
7.75-7.40 (m, 4H), 7.35-7.20 (m, 7H), 7.13 (t, J = 8.0 Hz, 1H),
7.01 (d, J = 8.0 Hz, 1H), 4.22 (t, J = 4.0 Hz, 2H), 2.66 (t, J = 4.0
Hz, 2H), 1.97 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 155.1,
143.7, 129.0, 128.9, 128.3, 127.1, 124.0, 123.5, 122.2, 120.3,
115.9, 113.6, 65.7, 58.1, 44.5; IR (CHCl3): νmax 3225, 2923,
1603, 1587, 1481, 1465, 1261, 765 cm-1; ESI-MS: m/z 384.2070
[M+H]+.
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