One-pot, three-component synthesis of novel 4-phenyl-2-[3-(alkynyl/alkenyl/ aryl)phenyl]pyrimidine libraries via michael addition, cyclization, and C-C coupling reactions: A new MCR strategy

Article abstract of DOI:10.1055/s-0032-1316814

Privileged medicinal scaffolds based on the structures of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines have been synthesized via a single-step, three-component reaction of 3-(dimethylamino)-1- phenylprop-2-en-1-one (enaminone), 3-bromobenzimidamide hydrochloride, and various alkynes/alkenes/arylboronic acids. The mechanism of this multi-component reaction (MCR) involves a Michael addition, cyclization, isomerization, and dehydration, followed by Sonogashira, Heck or Suzuki coupling. This new MCR strategy afforded a new compound library based on pyrimidine framework. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316814

PAPER
▌75
pOapnere-Pot, Three-Component Synthesis of Novel 4-Phenyl-2-[3-(alkynyl/
alkenyl/aryl)phenyl]pyrimidine Libraries via Michael Addition,
Cyclization, and C–C Coupling Reactions: A New MCR Strategy
A New MCR Strategy
L. Srinivasula Reddy,a,b T. Ram Reddy,b N. C. Gangi Reddy,*c Reddy Bodireddy Mohan,c Y. Lingappaa
a
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
b
Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad 500 049, Andhra Pradesh, India
c
Department of Chemistry, School of Physical Sciences, Yogi Vemana University, Kadapa 516 003, Andhra Pradesh, India
E-mail: ncgreddy@yogivemanauniversity.ac.in
Received: 11.10.2012; Accepted: 30.10.2012
rivatives.18 In addition to reports about the variation of es-
tablished protocols, new methods18 were also described
on the union of amine and carbonyl-containing fragments
and N-vinyl, N-aryl amides and nitriles to gather the im-
Abstract: Privileged medicinal scaffolds based on the structures of
4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimi-
dines have been synthesized via a single-step, three-component
reaction of 3-(dimethylamino)-1-phenylprop-2-en-1-one (enami-
none), 3-bromobenzimidamide hydrochloride, and various al- perative pyrimidine substructures. Additionally, the ad-
kynes/alkenes/arylboronic acids. The mechanism of this multi-
component reaction (MCR) involves a Michael addition, cycliza-
tion, isomerization, and dehydration, followed by Sonogashira,
plementary access to substituted azaheterocycles.19 How-
Heck or Suzuki coupling. This new MCR strategy afforded a new
compound library based on pyrimidine framework.
vancement of transition metal-catalyzed methodologies
for cross-coupling of activated azaheterocycles offer com-
ever, literature studies reveal that, none has been reported
on the synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/
Key words: multi-component reactions (MCRs), Michael addition,
aryl)phenyl]-substituted pyrimidine derivatives from en-
Pd catalyst, C–C coupling reactions
aminone, 3-bromobenzimidamide hydrochloride, and
various alkynes/alkenes/arylboronic acids via a single
step, one-pot multi-component reaction. Multi-compo-
The synthesis of ‘privileged medicinal scaffolds’ is highly
nent reactions (MCRs) are powerful strategies for the
important as these compounds often act as ligands for a
quick synthesis of diverse and complex organic molecules
number of functionally and structurally diverse biological
of potential interest particularly in the area of material sci-
receptors and further serve as a platform for developing
ence and drug discovery.20 MCRs have attracted much at-
pharmaceutical agents for diverse applications.1 For in-
tention owing to their excellent synthetic efficiency,
stance, pyrimidine and its derivatives are considered as
intrinsic atom economy, high selectivity, procedural sim-
‘privileged scaffold’ due to their potential biological ac-
plicity, and environmental friendliness.20a,21 As a result,
tivities such as antihypertensive,2 antipyretic,3 antibacteri-
the search and discovery of new MCR have attained sig-
al,4–6 antifungal,7,8 anticancer,9,10 anti-inflammatory,11,12
nificant value.22
and cardio-protective activities.13 The structural features
of pyrimidines are also found in some pesticides,14 herbi-
cides, and plant growth regulators.15 Consequently, meth-
odologies for the synthesis of novel pyrimidines or
pyrimidine-fused compounds are of particular interest in
the medicinal and agrochemical research areas.16,17
Herein we report a new MCR strategy for the synthesis of
4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted
pyrimidine derivatives from the reaction of enaminone 1,
3-bromobenzimidamide hydrochloride (2), and various
alkynes 3, alkenes 5 or arylboronic acids 7 in the presence
of K2CO3 and Pd catalyst in DMF (Scheme 1).
These vast applications have inspired the development of
a number of methods for the preparation of pyrimidine de-
O
NH
Z
Ph
Br
Me
Me
PdCl2(PPh3)2, DMF, K2CO3
N
N
NH2
·HCl
N
+
R
3, CuI or
1
2
Z = alkynyl (4) or
alkenyl (6) or
aryl (8)
or
5
R
ArB(OH)2
7
Scheme 1 One-pot three-component synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines
SYNTHESIS 2013, 45, 0075–0084
Advanced online publication: 27.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316814; Art ID: SS-2012-N0802-OP
© Georg Thieme Verlag Stuttgart · New York

76
L. S. Reddy et al.
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In the present study, our initial objective was to identify ence of K2CO3 in DMF within 2.5 hours (Table 1, entry
well-suited reaction conditions for MCR besides seeking 11). When K2CO3 was replaced with an organic base such
an appropriate Pd catalyst, solvent, and base for the con- as Et3N, a lower yield (60%) of the product 4a was noticed
struction of pyrimidine scaffold followed by Sonogashira/ within 10 hours in the presence of the same catalyst and
Heck/Suzuki coupling in a single step operation. We solvent (Table 1, entry 12). The same catalyst with K2CO3
choose to assess the pyrimidine formation/Sonogashira in other solvents like DMSO and 1,4-dioxane gave mod-
coupling initially for this purpose. Accordingly, few pal- erate yields of the product 4a (Table 1, entries 13, 14). The
ladium catalysts, solvents, and bases were examined to reaction did not proceed in the absence of Pd catalyst (Ta-
determine the effect on the course of MCR of enaminone ble 1, entry 15).
1, 3-bromobenzimidamide hydrochloride (2), and prop-2-
yn-1-ol (3a) in the presence of CuI (Table 1) as a model
reaction. Initially, the reaction carried out by using 10%
With the help of optimized reaction conditions, the further
scope and generality of this process for pyrimidine forma-
tion and Sonogashira coupling were examined and the re-
Pd/C catalyst with K2CO3 in DMF at 100 °C for 24 hours
sults obtained are presented in Table 2.
afforded the product 4a in 10% yield (Table 1, entry 1).
Encouraged by these results, the possibilities of the con-
Later, optimization of the reaction conditions was scruti-
struction of pyrimidine scaffold and Heck coupling in a
nized to increase the yield of the product. Towards this di-
single step were examined. Initially, a reaction was car-
ried out using enaminone 1, 3-bromobenzimidamide hy-
drochloride (2), and methyl acrylate (5a) in the presence
rection, a variety of Pd catalysts, solvents, and bases were
also examined. The catalysts and solvents, which provid-
ed poor to moderate yields, are listed in Table 1 (Table 1,
of PdCl2(PPh3)2 and K2CO3 in DMF at 80–85 °C. The re-
entries 2–10). In contrast, the palladium catalyst,
action proceeded smoothly to give the corresponding
PdCl2(PPh3)2, is the only catalyst, which afforded the
product 6a in 83% yield. Other alkenes were examined
highest yield (80%) of the desired product 4a in the pres-
Table 1 Optimization of the Reaction Conditions for the Formation of 3-[3-(4-phenylpyrimidin-2-yl)phenyl]prop-2-yn-1-ola
OH
Pd catalyst, solvent, base
O
NH
OH
Ph
CuI,
Br
Me
Me
N
N
NH2
3a
N
·HCl
4a
1
2
Entry
Catalyst
Solvent
Base
Time (h)
Yield (%)b
1
2
10% Pd/C
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
24
24
24
24
14
20
20
07
10
10
2.5
10
07
07
24
10
40
30
25
55
40
42
55
50
45
80
60
65
60
0
20% Pd(OH)2
20% Pd(OH)2
20% Pd(OH)2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)4
DMF
3
DMSO
1,4-dioxane
DMF
4
5
6
DMSO
1,4-dioxane
DMF
7
8
9
Pd(PPh3)4
DMSO
1,4-dioxane
DMF
10
11
12
13
14
15
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
–
DMF
DMSO
1,4-dioxane
DMF
K2CO3
K2CO3
K2CO3
a The reaction was carried out using 1 (0.41 g, 2.339 mmol), 2 (0.5 g, 2.123 mmol), Pd catalyst (0.0712 mmol), base (1.02 g, 7.380 mmol), CuI
(0.04 g, 0.21 mmol), and prop-2-yn-1-ol (0.128 g, 2.282 mmol) in a solvent (2.5 mL) at 70–75 °C.
b Isolated yield.
Synthesis 2013, 45, 75–84
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A New MCR Strategy
77
Table 2 Synthesis of 4-Phenyl-2-[3-(alkynyl)phenyl]pyrimidines 4 via Sonogashira Coupling MCRa
R
DMF, K2CO3
O
NH
Ph
R
PdCl2(PPh3)2, CuI,
Br
Me
Me
N
N
NH2
·HCl
3
N
+
1
2
4
Rfc
Entry
Alkyne
Product
Time (h)
Yield (%)b
HO
OH
Ph
1
2.5
80
0.3
N
N
3a
4a
HO
OH
Ph
2
3
4
3.0
4.0
3.4
78
70
80
0.2
N
N
3b
4b
OH
HO
Ph
0.22
N
N
3c
4c
HO
HO
Ph
0.4
N
N
3d
4d
Ph
5
6
3.0
3.2
83
85
0.8
N
N
3e
4e
Ph
0.85
N
N
3f
4f
a All the reactions were carried out using 1 (2.339 mmol), 2 (2.123 mmol), CuI (0.21 mmol), terminal alkyne derivatives 3a–f (2.282 mmol),
DMF (2.5 mL), PdCl2(PPh3)2 (50 mg, 0.0712 mmol), K2CO3 (7.380 mmol) at 70–75 °C.
b Isolated yield.
c Retention factor; eluent: 10% EtOAc in PE.
© Georg Thieme Verlag Stuttgart · New York
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78
L. S. Reddy et al.
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and the results obtained are presented in Table 3. All reac- all the prepared alkenes were confirmed as E-isomers
tions required 5–7 hours for completion and to provide the (J = 16.8–16.0 Hz).
1
desired alkene derivatives 6a–f. Based on H NMR data
Table 3 Synthesis of (E)-4-Phenyl-2-[3-(alkenyl)phenyl]pyrimidines 6 via Heck Coupling MCRa
R
DMF, K2CO3
O
NH
PdCl2(PPh3)2,
Ph
Br
Me
Me
5
R
NH2
·HCl
N
N
N
1
6
2
Rfc
Entry
Alkene
Product
Time (h)
Yield (%)b
MeO
O
OMe
Ph
1
5.0
83
0.2
N
N
O
5a
6a
EtO
O
OEt
Ph
2
3
N
5.4
6.0
78
80
0.25
O
5b
N
6b
t-BuO
O
Ot-Bu
Ph
O
0.4
N
N
5c
6c
O
Ph
4
5
6.3
6.0
78
81
0.1
0.1
N
N
O
5d
6d
CN
Ph
CN
N
N
5e
6e
H2N
O
NH2
Ph
N
N
6
7.0
73
0.1
O
5f
6f
a All the reactions were carried out using 1 (2.339 mmol), 2 (2.123 mmol), PdCl2(PPh3)2 (50 mg, 0.0712 mmol), alkene derivatives 5a–f (2.555
mmol), K2CO3 (7.380 mmol) in DMF (2.5 mL) at 80–85 °C.
b Isolated yield.
c Retention factor; eluent: 15% EtOAc in PE.
Synthesis 2013, 45, 75–84
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A New MCR Strategy
79
Table 4 Synthesis of 2-(Biphenyl-3-yl)-4-phenylpyrimidines 8 via Suzuki Coupling MCRa
O
NH
DMF, K2CO3
Ar
Ph
Br
Me
Me
PdCl2(PPh3)2, ArB(OH)2
7
NH2
·HCl
N
+
N
N
1
8
2
Rfc
Entry
Arylboronic acid
Product
Time (h)
Yield (%)b
NC
NC
B(OH)2
F
Ph
1
2.0
90
0.3
N
N
F
7a
8a
OMe
B(OH)2
Ph
2
2.6
85
0.4
N
N
MeO
7b
8b
B(OH)2
OMe
Ph
N
N
3
4
2.3
3.5
80
74
0.4
0.2
OMe
7c
8c
B(OH)2
Ph
OH
N
N
HO
7d
8d
CF3
B(OH)2
Ph
5
2.0
85
0.4
N
N
F3C
7e
8e
Cl
B(OH)2
Ph
6
3.2
75
0.45
N
N
Cl
7f
8f
© Georg Thieme Verlag Stuttgart · New York
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L. S. Reddy et al.
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Table 4 Synthesis of 2-(Biphenyl-3-yl)-4-phenylpyrimidines 8 via Suzuki Coupling MCRa (continued)
O
NH
DMF, K2CO3
Ar
Ph
Br
Me
Me
PdCl2(PPh3)2, ArB(OH)2
7
NH2
·HCl
N
+
N
N
1
8
2
Rfc
Entry
Arylboronic acid
Product
Time (h)
Yield (%)b
N
OMe
B(OH)2
Ph
N
N
7
8
3.5
3.3
78
0.4
0.5
MeO
N
7g
8g
Cl
B(OH)2
Cl
Ph
Cl
76
N
N
Cl
7h
8h
a All the reactions were carried out using 1 (2.339 mmol), 2 (2.123 mmol), PdCl2(PPh3)2 (50 mg, 0.0712 mmol), K2CO3 (7.380 mmol), DMF
(2.5 mL), arylboronic acids 7a–h (2.546 mmol) at 80–85 °C.
b Isolated yield.
c Retention factor; eluent: 15% EtOAc in PE.
The possibilities for the formation of pyrimidine ring fol- short reaction time, easy isolation of products, simple con-
lowed by Suzuki coupling in a single step were also exam- struction of substituted pyrimidine moiety, and subse-
ined. Initially, the reaction was carried out using quent C–C couplings for the structural elaboration of
enaminone 1, 3-bromobenzimidamide hydrochloride (2), pyrimidine framework in one pot.
and 3-cyano-5-fluorophenylboronic acid (7a) in the pres-
ence of PdCl2(PPh3)2 and K2CO3 in DMF at 80–85 °C.
Melting points were determined using a melting point apparatus and
are uncorrected. 1H NMR and 13C NMR spectra were recorded on a
Varian 400 MHz spectrometer. Chemical shifts are expressed in
parts per million (ppm) and coupling constants in hertz (Hz). Stan-
dard abbreviations were used to describe the splitting pattern. High-
resolution mass spectra (HRMS) were recorded on a Waters LCT
Premier XE mass spectrometer equipped with electrospray ioniza-
tion (ESI) source. TLC was performed on 0.25 mm Merck silica gel
plates and visualized with UV light. Column chromatography was
performed on silica gel. Enaminone 1 and 3-bromobenzimidamide
hydrochloride (2) were prepared according to the known
procedure23,24 and other chemicals and solvents were purchased
from Sigma Aldrich and Merck and used directly. Petroleum ether
(PE) used refers to the fraction boiling at 60–80 °C.
The reaction proceeded smoothly and afforded the corre-
sponding product 8a in 90% yield. Different types of bo-
ronic acids were examined and the obtained results are
summarized in Table 4. All the reactions were completed
within 2–3.5 hours and afforded the desired products
8a–h.
The plausible mechanism of MCR may proceed via a
base-catalyzed Michael addition of 3-bromobenzimidam-
ide hydrochloride (2) to the enaminone 1 to form the in-
termediate 9. This intermediate sequentially undergoes
cyclization, isomerization, and dehydration to give 2-(3-
bromophenyl)-4-phenylpyrimidine (10), followed by
Sonogashira, Heck or Suzuki coupling to afford the 4-
phenyl-2-(3-alkynyl/alkenyl/aryl)phenyl-substituted py-
rimidines 4, 6, and 8 as shown in Scheme 2.
3-[3-(4-Phenylpyrimidin-2-yl)phenyl]prop-2-yn-1-ol (4a); Typ-
ical Procedure
In a 25 mL round-bottomed flask were charged enaminone 1 (0.41
g, 2.339 mmol), 3-bromobenzimidamide hydrochloride (2; 0.5 g,
2.123 mmol), DMF (2.5 mL), K2CO3 (1.02 g, 7.380 mmol),
PdCl2(PPh3)2 (50 mg, 0.0712 mmol), CuI (0.04 g, 0.21 mmol) and
prop-1-yn-3-ol (3a; 0.128 g, 2.282 mmol) at r.t. Then, the reaction
mixture was stirred at 70–75 °C for 2.5 h and the reaction was mon-
itored by TLC (10% EtOAc in PE). After completion of the reac-
tion, the mixture was concentrated under vacuum and the obtained
crude product 4a was purified by column chromatography on silica
gel (230–400 mesh) using EtOAc–PE (10% EtOAc–PE); yield: 486
mg (80%); off-white solid; mp 95.1–97.4 °C.
In conclusion, we have developed a new MCR strategy for
the synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phe-
nyl]-substituted pyrimidines in high yields from enami-
none 1, 3-bromobenzimidamide hydrochloride (2), and
various alkynes/alkenes/arylboronic acids via a Michael
addition, cyclization, isomerization, dehydration, and fol-
lowed by Sonogashira/Heck/Suzuki coupling in a single
pot. This MCR strategy offers several advantages like
Synthesis 2013, 45, 75–84
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A New MCR Strategy
81
Br
Br
Br
base
H
N
H2N
H+
H2N
N
N
Michael addition
– H+
O
H2N
Me
Me
N
Me
Me
O
N
H2N
N
O
Me
N
–
O
Me
Br
N
Me
1
Me
2
9
– H+
cyclization
Br
Z
Br
Br
in situ
N
N
dehydration
– H2O
N
N
N
N
H
isomerization
Me
PdCl2(PPh3)2
3, CuI or
H
N
N
H
HO
R
–
N
Me
Me
or
Me
N
H
5
R
H
O
H
Z = alkynyl (4) or
alkenyl (6) or
aryl (8)
ArB(OH)2
7
10
H+
Scheme 2 Plausible mechanism for the formation of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines
1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 4.8 Hz, 1 Harom), 8.55
(d, J = 8.4 Hz, 2 Harom), 8.21–8.20 (m, 2 Harom), 7.60–7.25 (m, 6
Harom), 4.53 (s, 2 H, OCH2), 1.97 (br, 1 H, OH).
13C NMR (400 MHz, CDCl3): δ = 163.9, 163.7, 157.7, 137.6, 136.6,
131.8 (2 C), 131.0, 128.9 (2 C), 128.1 (2 C), 127.1 (2 C), 124.8,
114.6, 89.1, 85.5, 51.5.
HRMS (ESI): m/z (M + H)+ calcd for C21H19N2O: 315.1497; found:
315.1486.
5-[3-(4-Phenylpyrimidin-2-yl)phenyl]pent-4-yn-1-ol (4d)
Purification by column chromatography (15% EtOAc–PE) gave 4d
as an off-white solid; yield: 533 mg (80%); mp 94.3–96.6 °C.
1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 5.6 Hz, 1 Harom), 8.52
(d, J = 8.4 Hz, 2 Harom H), 8.23–8.20 (m, 2 Harom), 7.60 (d, J = 5.2
Hz, 1 Harom), 7.55–7.52 (m, 5 Harom), 3.85 (t, J = 6.4 Hz, 2 H, OCH2),
2.61 (t, J = 6.8 Hz, 2 H, CH2), 1.90 (quint, J = 6.4 Hz, 2 H, CH2).
13C NMR (400 MHz, CDCl3): δ = 163.8, 157.8, 137.7, 136.7, 131.8
(2 C), 131.0, 128.9 (2 C), 128.1 (2 C), 127.2 (2 C), 124.8, 114.6,
85.6, 51.6, 31.9, 14.1.
HRMS (ESI): m/z (M + H)+ calcd for C19H15N2O: 287.1184; found:
287.1173.
4-[3-(4-Phenylpyrimidin-2-yl)phenyl]but-3-yn-1-ol (4b)
Purification by column chromatography (15% EtOAc–PE) gave 4b
as an off-white solid; yield: 497 mg (78%); mp 94.2–96.3 °C.
1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 5.6 Hz, 1 Harom), 8.53
(d, J = 8.4 Hz, 2 Harom), 8.23–8.20 (m, 2 Harom), 7.60 (d, J = 5.2 Hz,
1 Harom), 7.55–7.53 (m, 5 Harom), 3.86 (t, J = 6.4 Hz, 2 H, OCH2),
2.60 (t, J = 6.8 Hz, 2 H, CH2).
13C NMR (400 MHz, CDCl3): δ = 163.9, 163.8, 157.7, 136.9, 136.8,
131.7 (2 C), 130.9, 128.9 (2 C), 128.0 (2 C), 127.1 (2 C), 126.0,
114.5, 91.4, 81.7, 61.7, 16.0.
HRMS (ESI): m/z (M + H)+ calcd for C21H19N2O: 315.1497; found:
315.1482.
2-[3-(Hex-1-ynyl)phenyl]-4-phenylpyrimidine (4e)
Purification by column chromatography (10% EtOAc–PE) gave 4e
as an off-white solid; yield: 550 mg (83%); mp 109.4–111.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.82 (d, J = 5.6 Hz, 1 Harom), 8.51
(d, J = 8.4 Hz, 2 Harom), 8.23–8.20 (m, 2 Harom), 7.59 (d, J = 5.2 Hz,
1 Harom), 7.55–7.52 (m, 5 Harom), 2.46 (t, J = 6.8 Hz, 2 H, CH2),
1.64–1.48 (m, 4 H, 2 CH2), 0.98 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (400 MHz, CDCl3): δ = 162.9, 162.8, 156.7, 135.8, 135.7,
130.6 (2 C), 129.9, 127.8 (2 C), 127.0 (2 C), 126.1 (2 C), 125.4,
113.4, 91.5, 79.6, 29.7, 21.0, 18.2, 12.6.
HRMS (ESI): m/z (M + H)+ calcd for C20H17N2O: 301.1341; found:
301.1347.
2-Methyl-4-[3-(5-phenylpyrimidin-2-yl)phenyl]but-3-yn-2-ol
(4c)
Purification by column chromatography (20% EtOAc–PE) gave 4c
as an off-white solid; yield: 467 mg (70%); mp 95.3–97.7 °C.
1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 5.6 Hz, 1 Harom), 8.54
(d, J = 8.8 Hz, 2 Harom), 8.23–8.21 (m, 2 Harom), 7.61 (d, J = 4.8 Hz,
1 Harom), 7.62–7.54 (m, 5 Harom), 1.50 [6 H, C(CH3)2].
13C NMR (400 MHz, CDCl3): δ = 163.9, 163.8, 157.8, 137.4, 136.7,
131.8 (2 C), 131.0, 128.9 (2 C), 128.1 (2 C), 127.2 (2 C), 125.0,
114.6, 83.9, 66.3, 31.4, 31.0 (2 C).
HRMS (ESI): m/z (M + H)+ calcd for C22H21N2: 313.1705; found:
313.1693.
2-[3-(Oct-1-ynyl)phenyl]-4-phenylpyrimidine (4f)
Purification by column chromatography (10% EtOAc–PE) gave 4f
as an off-white solid; yield: 614 mg (85%); mp 113.2–115.4 °C.
© Georg Thieme Verlag Stuttgart · New York
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82
L. S. Reddy et al.
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1H NMR (400 MHz, CDCl3): δ = 8.82 (d, J = 5.6 Hz, 1 Harom), 8.51
(d, J = 8.4 Hz, 2 Harom), 8.23–8.20 (m, 2 Harom), 7.59 (d, J = 5.6 Hz,
1 Harom), 7.54–7.52 (m, 5 Harom), 2.45 (t, J = 7.2 Hz, 2 H, CH2),
1.67–1.44 (m, 4 H, 2 CH2), 1.35–1.33 (m, 4 H, 2 CH2), 0.93 (t,
J = 6.8 Hz, 3 H, CH3).
13C NMR (400 MHz, CDCl3): δ = 164.0, 163.8, 157.7, 136.8, 136.7,
131.6 (2 C), 130.9, 128.8 (2 C), 128.0 (2 C), 127.1 (2 C), 126.4,
114.4, 92.6, 80.6, 31.3, 28.67, 28.63, 22.5, 19.5, 14.0
1H NMR (400 MHz, CDCl3): δ = 8.85 (d, J = 5.6 Hz, 1 Harom), 8.62
(d, J = 8.4 Hz, 2 Harom), 8.24–8.21 (m, 2 Harom), 7.70 (d, J = 8.4 Hz,
1 Harom), 7.63–7.61 (m, 1 Harom), 7.57–7.53 (m, 3 Harom and trans H),
6.83 (d, J = 16.0 Hz, 1 H, trans H), 2.42 (s, 3 H, CH3).
13C NMR (400 MHz, CDCl3): δ = 198.1, 163.7, 163.5, 157.7, 142.6,
139.6, 136.5, 136.3, 131.0, 128.8 (2 C), 128.6 (2 C), 128.3 (2 C),
127.7, 127.0 (2 C), 114.7, 27.4.
HRMS (ESI): m/z (M + H)+ calcd for C20H17N2O: 301.1341; found:
301.1349.
HRMS (ESI): m/z (M + H)+ calcd for C24H25N2: 341.2018; found:
341.2025.
(E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylonitrile (6e)
Purification by column chromatography (20% EtOAc–PE) gave 6e
as an off-white solid; yield: 487 mg (81%); mp 204.1–206.4 °C.
Methyl (E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylate (6a);
Typical Procedure
In a 25 mL round-bottomed flask were charged enaminone 1 (0.41
g, 2.339 mmol), 3-bromobenzimidamide hydrochloride (2; 0.5 g,
2.123 mmol), DMF (2.5 mL), K2CO3 (1.02 g, 7.380 mmol),
PdCl2(PPh3)2 (50 mg, 0.0712 mmol), and methyl acrylate (5a; 0.22
g, 2.555 mmol) at r.t. Then, the mixture was stirred at 80–85 °C for
4–5 h and the reaction was monitored by TLC (10% EtOAc in PE).
After completion of the reaction, the mixture was concentrated un-
der vacuum and the obtained crude product 6a was purified by col-
umn chromatography on silica gel (230–400 mesh) using 15%
EtOAc–PE; yield: 557 mg (83%); off-white solid; mp 153.2–
155.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.85 (d, J = 5.6 Hz, 1 Harom), 8.63
(d, J = 8.0 Hz, 2 Harom), 8.23–8.21 (m, 2 Harom), 7.64–7.54 (m, 6
Harom), 7.48 (d, J = 16.4 Hz, 1 H, trans H), 6.00 (d, J = 16.8 Hz, 1
H, trans H).
13C NMR (400 MHz, CDCl3): δ = 166.5, 162.9, 162.7, 158.6, 138.4,
138.0, 137.2, 136.1, 131.2, 129.0 (2 C), 128.3 (2 C), 127.9 (2 C),
127.1 (2 C), 123.5, 115.1.
HRMS (ESI): m/z (M + H)+ calcd for C19H14N3: 284.1188; found:
284.1181.
1H NMR (400 MHz, CDCl3): δ = 8.85 (d, J = 5.2 Hz, 1 Harom), 8.61
(d, J = 8.4 Hz, 2 Harom), 8.23–8.21 (m, 2 Harom), 7.79 (d, J = 16.4 Hz,
1 H, trans H), 7.68–7.54 (m, 6 Harom), 6.56 (d, J = 16.0 Hz, 1 H,
trans H), 3.83 (s, OCH3).
13C NMR (400 MHz, CDCl3): δ = 167.2, 163.8, 163.6, 157.7, 144.2,
139.4, 136.6, 136.3, 131.0, 128.8 (2 C), 128.6 (2 C), 128.1 (2 C),
127.1 (2 C), 118.5, 114.6, 51.6.
(E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylamide (6f)
Purification by column chromatography (25% EtOAc–PE) gave 6f
as an off-white solid; yield: 467 mg (73%); mp 195.3–197.6 °C.
1H NMR (400 MHz, CDCl3): δ = 8.98 (d, J = 5.2 Hz, 1 Harom), 8.57
(d, J = 8.0 Hz, 2 Harom), 8.37–8.36 (m, 2 Harom), 8.04 (d, J = 5.6 Hz,
1 Harom), 7.76 (d, J = 8.4 Hz, 2 Harom), 7.62–7.60 (m, 4 Harom), 7.19
(br, 1 H, NH),7.52 (d, J = 16.4 Hz, 1 H, trans H), 6.76 (d, J = 16 Hz,
1 H, trans H).
13C NMR (400 MHz, CDCl3): δ = 174.7, 162.9, 162.4, 158.2, 149.4,
147.8, 139.4, 135.9, 135.5, 130.9, 128.7 (2 C), 128.1, 127.7, 126.8
(2 C), 118.1, 115.0, 97.7.
HRMS (ESI): m/z (M + H)+ calcd for C19H16N3O: 302.1293; found:
302.1296.
HRMS (ESI): m/z (M + H)+ calcd for C20H17N2O2: 317.1290; found:
317.1287.
Ethyl (E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylate (6b)
Purification by column chromatography (15% EtOAc–PE) gave 6b
as an off-white solid; yield: 546 mg (78%); mp 106.5–108.7 °C.
1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 5.2 Hz, 1 Harom), 8.60
(d, J = 8.4 Hz, 2 Harom), 8.23–8.20 (m, 2 Harom), 7.76 (d, J = 16.4 Hz,
1 H, trans H), 7.67 (d, J = 8.4 Hz, 2 Harom), 7.62 (d, J = 4.8 Hz, 1
5-Fluoro-3′-(4-phenylpyrimidin-2-yl)biphenyl-3-carbonitrile
(8a); Typical Procedure
In a 25 mL round-bottomed flask were charged enaminone 1 (0.41
g, 2.339 mmol), 3-bromobenzimidamide hydrochloride (2; 0.5 g,
2.123 mmol), DMF (2.5 mL), K2CO3 (1.02 g, 7.380 mmol),
PdCl2(PPh3)2 (50 mg, 0.0712 mmol), and 3-cyano-5-fluorophenyl-
boronic acid (7a; 0.42 g, 2.546 mmol) at r.t. The reaction mixture
was then stirred at 80–85 °C for 2 h and the reaction was monitored
by TLC (15% EtOAc in PE). After completion of the reaction, the
mixture was concentrated under vacuum and the obtained crude
product 8a was purified by column chromatography on silica gel
(230–400 mesh) using 15% EtOAc–PE; yield: 671 mg (90%); off-
white solid; mp 152.5–154.6 °C.
1H NMR (400 MHz, CDCl3): δ = 8.87 (d, J = 5.2 Hz, 1 Harom), 8.69
(d, J = 8.0 Hz, 2 Harom), 8.26–8.23 (m, 2 Harom), 7.76 (s, 1 Harom),
7.70 (d, J = 8.4 Hz, 2 Harom), 7.66 (d, J = 5.2 Hz, 2 Harom) 7.63–7.55
(m, 3 Harom), 7.37–7.35 (m, 1 Harom).
13C NMR (400 MHz, CDCl3): δ = 164.1, 163.7 (d, J = 34.4 Hz, Ar-
CF), 161.2, 157.7 (2 C), 144.4, 139.5, 139.5, 138.3, 136.5, 131.1 (2
C), 129.1, 128.9, 127.1 (2 C), 127.1, 126.75, 126.71, 119.0, 118.8,
115.3, 114.8.
H
arom), 7.56–7.53 (m, 3 Harom), 6.54 (d, J = 16.0 Hz, 1 H, trans H),
4.29 (q, J = 6.8 Hz, 2 H, OCH2), 1.36 (t, J = 6.8 Hz, 3 H, CH3).
13C NMR (400 MHz, CDCl3): δ = 166.7, 163.7, 163.6, 157.7, 143.8,
139.3, 136.6, 136.4, 130.9, 128.8 (2 C), 128.6 (2 C), 128.1 (2 C),
127.0 (2 C), 119.0, 114.6, 60.4, 14.2.
HRMS (ESI): m/z (M + H)+ calcd for C21H19N2O2: 331.1447; found:
331.1455.
tert-Butyl (E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylate
(6c)
Purification by column chromatography (15% EtOAc–PE) gave 6c
as an off-white solid; yield: 608 mg (80%); mp 94.8–97.1 °C.
1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 5.2 Hz, 1 Harom), 8.59
(d, J = 8.8 Hz, 2 Harom), 8.24–8.20 (m, 2 Harom), 7.68–7.53 (m, 7
Harom and trans H), 6.49 (d, J = 16.0 Hz, 1 H, trans H), 1.55 (s, 9 H,
t-C4H9).
13C NMR (400 MHz, CDCl3): δ = 166.1, 163.8, 163.8, 157.8 (2 C),
142.9, 139.1, 136.7, 131.0, 128.9 (2 C), 128.6 (2 C), 128.0 (2 C),
127.1 (2 C), 121.0, 114.6, 80.5, 28.1 (3 C).
HRMS (ESI): m/z (M + H)+ calcd for C23H23N2O2: 359.1760; found:
359.1761.
HRMS (ESI): m/z (M + H)+ calcd for C23H15FN3: 352.1250; found:
352.1255.
2-(4′-Methoxybiphenyl-3-yl)-4-phenylpyrimidine (8b)
Purification by column chromatography (10% EtOAc–PE) gave 8b
as an off-white solid; yield: 610 mg (85%); mp 159.2–161.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 5.6 Hz, 1 Harom), 8.63
(d, J = 8.4 Hz, 2 Harom), 8.26–8.23 (m, 2 Harom), 7.71 (d, J = 8.8 Hz,
(E)-4-[3-(4-Phenylpyrimidin-2-yl)phenyl]but-3-en-2-one (6d)
Purification by column chromatography (10% EtOAc–PE) gave 6d
as an off-white solid; yield: 497 mg (78%); mp 173.1–175.5 °C.
Synthesis 2013, 45, 75–84
© Georg Thieme Verlag Stuttgart · New York

PAPER
A New MCR Strategy
83
2 Harom), 7.65–7.62 (m, 2 Harom), 7.60 (d, J = 5.6 Hz, 2 Harom), 7.57–
7.54 (m, 2 Harom), 7.02 (d, J = 8.8 Hz 2 Harom), 3.87 (s, 3 H, OCH3).
7.61 (d, J = 5.6 Hz, 1 Harom), 7.56–7.54 (m, 3 Harom), 6.86 (d, J = 8.8
Hz, 1 Harom), 4.0 (s, 3 H, OCH3).
13C NMR (400 MHz, CDCl3): δ = 164.3, 163.8, 159.4, 157.7, 142.9,
136.8, 136.0, 132.9, 130.9, 128.8 (2 C), 128.7 (2 C), 128.1 (2 C),
127.1 (2 C), 126.6 (2 C), 116.0, 114.2 (2 C), 55.2.
13C NMR (400 MHz, CDCl3): δ = 164.0, 163.7, 163.6, 157.7 (2 C),
145.0 (2 C), 139.8, 137.2, 136.7, 130.8, 129.3, 128.8 (2 C), 128.8 (2
C), 127.0 (2 C), 126.4 (2 C), 114.3, 110.7, 53.4.
HRMS (ESI): m/z (M + H)+ calcd for C23H19N2O: 339.1497; found:
HRMS (ESI): m/z (M + H)+ calcd for C22H18N3O: 340.1450; found:
339.1506.
340.1461.
2-(3′-Methoxybiphenyl-3-yl)-4-phenylpyrimidine (8c)
Purification by column chromatography (10% EtOAc–PE) gave 8c
as an off-white solid; yield: 574 mg (80%); mp 158.2–160.5 °C.
2-(3′,4′-Dichlorobiphenyl-3-yl)-4-phenylpyrimidine (8h)
Purification by column chromatography (10% EtOAc–PE) gave 8h
as an off-white solid; yield: 606 mg (76%); mp 121.3–123.7 °C.
1H NMR (400 MHz, CDCl3): δ = 8.85 (d, J = 5.2 Hz, 1 Harom), 8.65
(d, J = 8.8 Hz, 2 Harom), 8.26–8.23 (m, 2 Harom), 7.75 (d, J = 8.0 Hz,
2 Harom), 7.61 (d, J = 5.6 Hz, 1 Harom), 7.56–7.54 (m, 3 Harom), 7.39
(t, J = 8.0 Hz, 1 Harom), 7.29–7.21 (m, 3 Harom), 3.89 (s, 3 H, OCH3).
1H NMR (400 MHz, CDCl3): δ = 8.86 (d, J = 5.2 Hz, 1 Harom), 8.66
(d, J = 8.4 Hz, 2 Harom), 8.26–8.23 (m, 2 Harom), 7.76 (d, J = 2.0 Hz,
1 Harom), 7.69 (d, J = 8.4 Hz, 2 Harom), 7.64 (d, J = 5.2 Hz, 1 Harom),
7.56–7.51 (m, 5 Harom).
13C NMR (400 MHz, CDCl3): δ = 164.2, 163.8, 159.9, 157.8 (2C),
143.1, 142.1, 136.9, 130.9, 129.8, 128.9 (2 C), 128.7 (2 C), 127.2 (2
C), 127.1 (2 C), 119.6, 114.4, 113.0, 112.8, 55.3.
13C NMR (400 MHz, CDCl3): δ = 164.1, 163.9, 157.6 (2 C), 155.3,
140.7, 140.5, 137.4, 136.6, 132.9, 131.7, 131.1, 130.7, 130.7 (2 C),
128.9, 128.9, 128.9, 127.2, 127.0, 126.3 (2 C).
HRMS (ESI): m/z (M + H)+ calcd for C23H19N2O: 339.1497; found:
HRMS (ESI): m/z (M + H)+ calcd for C22H15Cl2N2: 377.0612;
339.1503
found: 377.0624.
[3′-(4-Phenylpyrimidin-2-yl)biphenyl-3-yl]methanol (8d)
Purification by column chromatography (20% EtOAc–PE) gave 8d
as an off-white solid; yield: 531 mg (74%); mp 123.1–125.7 °C.
1H NMR (400 MHz, CDCl3): δ = 8.85 (d, J = 5.6 Hz, 1 Harom), 8.66
(d, J = 8.8 Hz, 2 Harom), 8.27–8.24 (m, 2 Harom), 7.77 (d, J = 8.8 Hz,
2 Harom), 7.70 (s, 1 Harom), 7.64–7.61 (m, 2 Harom), 7.58–7.56 (m, 3
Acknowledgment
The authors thank Dr. A. K. Roy, Dr. K. V. Raghu, Dr. V. Dahanu-
kar, and the analytical group of Dr. Reddy’s Laboratories, Hydera-
bad, India for spectral data, and CSIR, Human Resources
Development Group, Govt. of India, New Delhi for providing fi-
nancial assistance [No. 01(2391)/10/EMR-II].
Harom), 7.48 (t, J = 7.6 Hz, 1 Harom), 7.39 (d, J = 7.6 Hz, 1 Harom),
4.80 (s, 2 H, OCH2).
13C NMR (400 MHz, CDCl3): δ = 163.9, 163.5, 157.3 (2 C), 142.7,
141.1, 140.4, 136.4, 136.3, 130.6 (2 C), 128.6, 128.5, 128.3, 126.8
(2 C), 126.0 (2 C), 125.8, 125.3 (2 C), 114.1, 64.8.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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HRMS (ESI): m/z (M + H)+ calcd for C23H19N2O: 339.1497; found:
339.1504.
References
4-Phenyl-2-[4′-(trifluoromethyl)biphenyl-3-yl]pyrimidine (8e)
Purification by column chromatography (15% EtOAc–PE) gave 8e
as an off-white solid; yield: 679 mg (85%); mp 188.1–190.3 °C.
1H NMR (400 MHz, CDCl3): δ = 8.88 (d, J = 5.2 Hz, 1 Harom), 8.70
(d, J = 8.4 Hz, 2 Harom), 8.27–8.25 (m, 2 Harom), 7.81–7.73 (m, 6
Harom), 7.65 (d, J = 5.6 Hz, 1 Harom), 7.59–7.56 (m, 3 Harom).
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141.7, 137.7, 136.8, 131.0 (2 C), 128.9 (2 C), 128.9 (2 C), 127.4 (2
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