One-pot four-component reaction for the generation of pyrazoles and pyrimidines

Article abstract of DOI:10.1055/s-2007-1000839

The palladium-catalysed four-component coupling of a halide, terminal alkyne, molybdenum hexacarbonyl and either a hydrazine or amidine has been shown to be an efficient method for the construction of highly substituted pyrazoles and pyrimidines, respectively, in a one-pot process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000839

100
LETTER
One-Pot Four-Component Reaction for the Generation of Pyrazoles and
Pyrimidines
One-Pot
F
e
our-Compo
f
nent Re
a
ction fo
r
r
G
enera
e
tion of Pyr
y
azoles and Pyrimid
P
ines . Stonehouse,*a Dmitriy S. Chekmarev,b Natalya V. Ivanova,b Stuart Lang,a Garry Pairaudeau,a Neal Smith,a
Michael J. Stocks,a Sergey I. Sviridov,b Lyubov M. Utkinab
a
AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, LE11 5RH, UK
Fax +44(1509)645567; E-mail: jeffrey.stonehouse@astrazeneca.com
ChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russia
b
Received 27 September 2007
R2
R1
PdCl2(PPh3)2
Abstract: The palladium-catalysed four-component coupling of a
OH
I
NH
H2N
Ar
halide, terminal alkyne, molybdenum hexacarbonyl and either a hy-
drazine or amidine has been shown to be an efficient method for the
construction of highly substituted pyrazoles and pyrimidines, re-
spectively, in a one-pot process.
+
+
H2N
CO (gas), DMF–H2O
R2
N
O
N
N
Key words: carbonylations, combinatorial chemistry, heterocy-
cles, multicomponent reactions, palladium
R1
R1
Ar
Ar
Scheme 1 Mori’s four-component coupling reaction to generate py-
razoles and isoxazoles. N.B. When R2 = Ph, no product was formed
The search for novel compounds with beneficial therapeu-
tic effects is at the forefront of medicinal chemistry re-
search. With this in mind, developing procedures for the
efficient generation of small heterocyclic organic mole-
cules is of paramount importance in identifying the next
generation of drug candidates.
ideally suited to parallel synthesis, due to its toxicity and
incompatibility with plate-based techniques.
A study of the recent literature revealed several examples
of the use of molybdenum hexacarbonyl as a replacement
for carbon monoxide gas in palladium-catalysed reac-
tions. This reagent has shown utility in the synthesis of es-
ters,13 amides14 and acyl sulfonamides.15 We describe here
the use of molybdenum hexacarbonyl as a replacement for
carbon monoxide in the one-pot palladium-catalysed
four-component synthesis of highly substituted pyrazoles
1, 4 and pyrimidines 5.16
Multicomponent processes, such as the Biginelli,1 Passe-
rini,2 and Ugi3 reactions are well-established methods for
the synthesis of molecules of considerable complexity and
containing multiple sites of diversity in a single step. The
benefits of developing methods for carrying out complex
sequences in one pot include: saving time in purification,
reducing the cost of reagents and solvent, and the removal
of the need to isolate often unstable intermediates. The at-
traction of this type of reaction has led to the publication
of a number of tandem, cascade, domino and telescoped
processes,4 as well as multicomponent reactions.5 Many
of the recently published multicomponent reactions em-
ploy catalysis. Examples of this are based on metals such
as Cu,6 Ni,7 Pd8 or Rh,9 in addition to organocatalysts,10
which are often used to promote enantioselectivity.11
Reaction of a range of terminal alkynes with iodobenzene
in this four-component coupling reaction was investigated
first. We were encouraged to find that these reactions pro-
ceeded well, with acceptable yields observed in most cas-
es (Table 1). The only problematic alkyne was ethyl
propiolate (Table 1, entry 4), which gave no detectable
product.
Further examination of the reaction, by variation of the
aryl halide, showed that the efficiency of the process was
reduced when the halogen was changed from iodine to
bromine, with no reaction observed when chlorobenzene
was used (Table 2, entries 1–3). In this case, the only
product detected (Table 2, entry 3) was 1,3,5-triphenyl-
benzene, which was formed as a result of the trimerisation
of phenylacetylene.17 Using phenyl triflate as a pseudo ha-
lide resulted in trace amounts of the desired product
(Table 2, entry 4), observed by LCMS.
A recent report by Mori and co-workers12 described a pal-
ladium-based four-component method for the preparation
of pyrazoles and isoxazoles from an aryl halide, terminal
alkyne, carbon monoxide and either hydrazine or hydrox-
ylamine (Scheme 1). The authors showed that this reac-
tion worked well with a range of substrates although there
were limitations, notably the failure of the reaction with
phenylhydrazines.
Another limitation of this method, for our needs, was the
use of gaseous carbon monoxide as a reagent which is not
Substitution of the aryl halide had little effect on reaction
yield (Table 2, entries 1, 5, and 6), and heteroaryl halides,
such as 3-iodopyridine, also reacted well (Table 2, entry
7), thus demonstrating the utility of this reaction se-
quence. However, when benzyl bromide was used, none
of the expected pyrazole was obtained (Table 2, entry 8).
Analysis of the reaction mixture by LCMS showed that
the in situ generated, highly enolisable ketone intermedi-
ate (Scheme 2, intermediate 2, R1 = Bn, R2 = Ph) had re-
SYNLETT 2008, No. 1, pp 0100–0104
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000839; Art ID: D30607ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Four-Component Reaction for Generation of Pyrazoles and Pyrimidines
101
Table 1 Four-Component Coupling of Iodobenzene, Molybdenum
Hexacarbonyl, Hydrazine Hydrate and Various Alkynes to Form
Pyrazines 1
O
Mo(CO)6, Pd(OAc)2
X
R1
R1
+
R2
CuI, Pt-Bu3, Cs2CO3
N2H4⋅H2O
Mo(CO)6, Pd(OAc)2
N
NH
R2
toluene–MeCN
80 °C, 18 h
I
2
R
+
R
CuI, Pt-Bu3, Cs2CO3
toluene–MeCN
80 °C, 18 h
1
where
N2H4⋅H2O
O
R1 = Bn
R2 = Ph
Ph
Entry
R
Product
1a
Yield (%)a
N
NH
R2
1
2
3
4
5
6
7
8
Ph
53
50
39
0
Ph
R1
Ph
3-thiophene
1b
1
3
(tetrahydropyranyl)OCH2
1c
Scheme 2 Reaction mechanism via ynone intermediate 2
EtO2C
p-MeOPh
p-ClPh
3-pyridyl
Bn
–
Indeed, in the absence of hydrazine, the ynone 2a was ob-
served as the major product in 60% yield (Scheme 3).
1d
69
56
99
56
1e
O
Mo(CO)6, Pd(OAc)2
I
1f
Ph
Ph
+
Ph
CuI, Pt-Bu3, Cs2CO3
Ph
1g
2a
a Isolated yield.
60% yield
Scheme 3 Reaction without added hydrazine
acted with a second molecule of benzyl bromide to form
ynone 3.
Further investigation of the process showed that the reac-
tion worked well using monosubstituted hydrazines
(Table 3, entries 1–3). It was especially pleasing to see
that phenylhydrazine reacted well under our conditions
(Table 3, entries 2 and 3) in contrast to Mori’s work, using
carbon monoxide gas, where phenylhydrazine does not re-
act. When 3-ethynylpyridine was used (Table 3, entry 3),
a regioisomeric mixture was formed as this reaction was
carried out at elevated temperatures, which did not lend it-
self to the selective formation of one regioisomer.
The four-component coupling reaction proceeds via an in-
termediate ynone 2, formed by a carbonylative Sonogash-
ira reaction18 followed by a subsequent cyclocondensation
with hydrazine to form the pyrazole 1 (Scheme 2).
Table 2 Four-Component Coupling of Phenylacetylene, Molybde-
num Hexacarbonyl, Hydrazine Hydrate and Various Halides to Form
Pyrazoles 1
A further extension of the reaction showed that other nu-
cleophiles could be used in this four-component process,
thus allowing us to synthesise alternative ring systems.
Amidines were shown to afford trisubstituted pyrimidines
in good yield, as were N,N-disubstituted guanidines
(Table 3, entries 6–10). Unfortunately, the use of urea
gave none of the desired product and changing the nucleo-
phile to guanidine provided only trace amounts of prod-
uct, as detected by LCMS (Table 3, entries 4 and 5).
N2H4⋅H2O
Mo(CO)6, Pd(OAc)2
N
NH
X
+
R
R
CuI, Pt-Bu3, Cs2CO3
toluene–MeCN
80 °C, 18 h
1
Entry
R
X
I
Product
Yield (%)a
1
2
3
4
5
6
7
8
Ph
1a
1a
–
53
34
0
Ph
Br
Cl
OTf
I
These results have led us to conclude that urea and guani-
dine are not reactive enough to participate in the reaction
sequence due to their ability to delocalise their electron
density.
Ph
Ph
1a
1d
1e
1f
–
traceb
54
54
52
0
p-MeOPh
p-ClPh
3-pyridyl
Bn
In conclusion, we have shown that molybdenum hexacar-
bonyl can be successfully used as an alternative to gas-
eous carbon monoxide for the generation of pyrazoles and
pyrimidines using a wide range of halides, alkynes and
nucleophiles by an efficient four-component process. This
method has been used for the generation of compound li-
braries that are currently being evaluated in order to iden-
tify potential new drug candidates.
I
I
Br
a Isolated yield.
b Observed by LCMS.
Synlett 2008, No. 1, 100–104 © Thieme Stuttgart · New York

102
J. P. Stonehouse et al.
LETTER
Table 3 Formation of Substituted Pyrazoles 1, 4 and Pyrimidines 5 from Hydrazines and Amidines, Respectively
R2
R2
N
N
N
N
I
H
Mo(CO)6, Pd(OAc)2
N
R1
R1
R2
+
+
H2N
R1
CuI, Pt-Bu3, Cs2CO3
toluene–MeCN
80 °C, 18 h
1
4
Entry
R1
Ph
Ph
R2
Product
1h
Yield (%)a
1
2
3
Me
Ph
Ph
63
1i
47
3-pyridyl
1j/4j
20/27
R2
R2
N
N
I
Mo(CO)6, Pd(OAc)2
+
+
R1
R1
HN
NH2
CuI, Pt-Bu3, Cs2CO3
toluene–MeCN
80 °C, 18 h
5
Entry
R1
R2
Product
–
Yield (%)a
4
5
Ph
OH
NH2
Meb
Meb
Phb
Phb
0
b
Ph
5a
tracec
49
6
Ph
5b
7
3-pyridyl
Ph
5c
50
8
5d
74
9
3-pyridyl
Ph
5e
40
10
4-morpholinyld
5f
80
a Isolated yield.
b HCl salt of amidine.
c Observed by LCMS.
d HBr salt of guanidine.
(6) For some recent examples, see: (a) Côté, A.; Charette, A. B.
J. Org. Chem. 2005, 70, 10864. (b) Cui, S.-L.; Lin, X.-F.;
Wang, Y.-G. Org. Lett. 2006, 8, 4517. (c) Xu, X.; Cheng,
D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585.
(7) For some recent examples, see: (a) Kimura, M.; Kojima, K.;
Tatsuyama, Y.; Tamaru, Y. J. Am. Chem. Soc. 2006, 128,
6332. (b) El Douhaibi, A. S.; Lozanov, M.; Montgomery, J.
Tetrahedron 2006, 62, 11460.
(8) For some recent examples, see: (a) Siamaki, A. R.;
Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128, 6332.
(b) Dhawan, R.; Dghaym, R. D.; St. Cyr, D. J.; Arndtsen, B.
A. Org. Lett. 2006, 8, 3927. (c) Mitsudo, K.; Thansandote,
P.; Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett.
2006, 8, 3939.
Acknowledgment
We would like to thank James Russell and Robert Jewell for com-
pound purification work.
References and Notes
(1) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(2) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
(b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181.
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I. Angew. Chem. Int. Ed.
1962, 1, 8.
(4) For a general review, see: (a) Bunce, R. A. Tetrahedron
1995, 51, 13103. (b) Tietze, L. F. Pure Appl. Chem. 2004,
76, 1967. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem. Int. Ed. 2006, 45, 7134.
(5) For some recent examples, see: (a) Ghosh, A. K.; Kulkarni,
S.; Xu, C.-H.; Fanwick, P. E. Org. Lett. 2006, 8, 4509.
(b) Paravidino, M.; Bon, R. S.; Scheffelaar, R.; Vugts, D. J.;
Znabet, A.; Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.;
Spek, A. L.; Groen, M. B.; Orru, R. V. A. Org. Lett. 2006, 8,
5369. (c) Ma, C.; Ding, H.; Zhang, Y.; Bian, M. Angew.
Chem. Int. Ed. 2006, 45, 7793.
(9) For some recent examples, see: (a) Schmidt, A. M.;
Eilbracht, P. J. Org. Chem. 2005, 70, 5528. (b) Galliford,
C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72, 1811.
(10) For a recent review, see: Enders, D.; Grondal, C.; Hüttl, M.
R. M. Angew. Chem. Int. Ed. 2007, 46, 1570.
(11) For a recent review, see: Ramón, D. J.; Yus, M. Angew.
Chem. Int. Ed. 2005, 44, 1602.
(12) Mohamed Ahmed, M. S.; Kobayashi, K.; Mori, A. Org. Lett.
2005, 7, 4487.
(13) Georgsson, J.; Hallberg, A.; Larhed, M. J. Comb. Chem.
2003, 5, 350.
Synlett 2008, No. 1, 100–104 © Thieme Stuttgart · New York

LETTER
One-Pot Four-Component Reaction for Generation of Pyrazoles and Pyrimidines
103
(14) (a) Lagerlund, O.; Larhed, M. J. Comb. Chem. 2006, 8, 4.
(b) Wu, X.; Wannberg, J.; Larhed, M. Tetrahedron 2006, 62,
4665. (c) Letavic, M. A.; Ly, K. S. Tetrahedron Lett. 2007,
48, 2339.
(15) Wu, X.; Roenn, R.; Gossas, T.; Larhed, M. J. Org. Chem.
2005, 70, 3094.
(lit. 58–59 °C). 1H NMR (400 MHz, CDCl3): d = 3.92 (s, 3
H, Me), 6.60 (s, 1 H, pyrazole ArH), 7.28–7.47 (m, 8 H,
ArH), 7.82–7.84 (m, 2 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 37.5, 103.2, 125.5, 127.6, 128.5, 128.6, 128.7,
128.7, 130.6, 133.4, 145.0, 150.5.
1,3,5-Triphenyl-1H-pyrazole (1i):25 mp 140–141 °C (lit.
141–142 °C). 1H NMR (400 MHz, CDCl3): d = 6.82 (s, 1 H,
pyrazole ArH), 7.28–7.44 (m, 13 H, ArH), 7.92 (d, J = 7.7
Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): d = 105.2,
125.3, 125.8, 127.4, 128.0, 128.3, 128.5, 128.6, 128.7,
128.9, 130.6, 133.0, 140.1, 144.4, 151.9.
(16) General Procedure: In a 25-mL 3-neck round-bottomed
flask were added halide (1.0 mmol), alkyne (1.5 mmol),
molybdenum hexacarbonyl (1.5 mmol), nucleophile (2.0
mmol), palladium acetate (0.05 mmol), copper iodide (0.02
mmol), tri-tert-butylphosphine (0.1 mmol) and cesium
carbonate (2.5 mmol, 5.0 mmol when nucleophile was used
as a salt) in toluene (2.5 mL) and MeCN (2.5 mL) and the
mixture was heated at 80 °C overnight. The solvent was
removed and the residue was dissolved in CH2Cl2 and
filtered through celite. This crude material was purified by
flash chromatography (gradient elution with PE and EtOAc)
and then by reverse-phase preparative HPLC on a Xbridge
C8 19 × 50 mm column (gradient elution with 95% of 0.3%
aq NH3 solution–5% MeCN to 5% of 0.3% aq NH3 solution–
95% MeCN).
3-(1,3-Diphenyl-1H-pyrazol-5-yl)pyridine (1j):26 mp 151–
152 °C (lit. 150 °C). 1H NMR (400 MHz, CDCl3): d = 6.86
(s, 1 H, pyrazole ArH), 7.26–7.37 (m, 11 H, ArH), 8.23 (ddd,
J = 2.0, 2.0, 8.0 Hz, 1 H, ArH), 8.58–8.62 (m, 1 H, ArH),
9.14 (br s, 1 H, ArH). 13C NMR (100 MHz, CDCl3): d =
105.1, 123.5, 125.3, 127.7, 128.5, 128.5, 128.7, 128.7,
128.9, 130.2, 132.9, 139.9, 144.7, 147.3, 149.0, 149.0.
3-(1,5-Diphenyl-1H-pyrazol-3-yl)pyridine (4j): mp 101–
103 °C. IR (CH2Cl2): 2366, 1595, 1498, 1421, 1026, 764,
707 cm–1. 1H NMR (400 MHz, CDCl3): d = 6.89 (s, 1 H,
pyrazole ArH), 7.24 (dd, J = 5.2, 8.0 Hz, 1 H, ArH), 7.32–
7.41 (m, 6 H, ArH), 7.43–7.46 (m, 2 H, ArH), 7.49–7.52 (m,
1 H, ArH), 7.91–7.93 (m, 2 H, ArH), 8.61 (d, J = 11.2 Hz, 2
H, ArH). 13C NMR (100 MHz, CDCl3): d = 105.6, 123.1,
125.4, 125.7, 126.7, 127.9, 128.2, 128.7, 128.9, 129.2,
132.6, 135.7, 139.6, 140.9, 149.3, 152.3. HRMS: m/z calcd
for C20H15N3: 298.1344; found: 298.1337.
3,5-Diphenyl-1H-pyrazole (1a):19 mp 201–202 °C (lit.
201–203 °C). 1H NMR (400 MHz, CDCl3): d = 6.81 (s, 1 H,
pyrazole ArH), 7.28–7.37 (m, 6 H, Ph ArH), 7.70–7.71 (m,
4 H, Ph ArH). 13C NMR (100 MHz, CDCl3): d = 100.1,
125.5, 125.6, 128.2, 128.8, 131.2.
3-Phenyl-5-(thiophen-3-yl)-1H-pyrazole (1b):20 mp 181–
183 °C (lit. 183 °C). 1H NMR (400 MHz, CDCl3): d = 6.68
(s, 1 H, pyrazole ArH), 7.27–7.39 (m, 5 H, ArH), 7.49 (dd,
2-Methyl-4,6-diphenylpyrimidine (5b):27 mp 90–91 °C
(lit. 90–92 °C). 1H NMR (400 MHz, CDCl3): d = 2.87 (s, 3
H, Me), 7.50–7.54 (m, 6 H, ArH), 7.88 (s, 1 H, pyrimidine
ArH), 8.11–8.14 (m, 4 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 26.5, 110.0, 127.2, 128.9, 130.7, 137.4, 164.7,
168.5.
2-Methyl-4-phenyl-6-(pyridin-3-yl)pyrimidine (5c): mp
136–137 °C. IR (CH2Cl2): 1590, 1568, 1527, 1355, 1026,
745, 707 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.88 (s, 3
H, Me), 7.45–7.49 (m, 1 H, ArH), 7.53–7.55 (m, 3 H, ArH),
7.92 (s, 1 H, pyrimidine ArH), 8.13–8.16 (m, 2 H, ArH), 8.46
(ddd, J = 2.0, 2.0, 8.0 Hz, 1 H, ArH), 8.75–8.76 (m, 1 H,
ArH), 9.32 (s, 1 H, ArH). 13C NMR (100 MHz, CDCl3): d =
26.4, 110.0, 123.7, 127.2, 129.0, 130.9, 133.1, 134.7, 137.1,
148.5, 151.4, 162.4, 165.2, 168.9. HRMS: m/z calcd for
C16H13N3: 248.1188; found: 248.1176.
J = 1.2, 2.8 Hz, 1 H, ArH), 7.65–7.71 (m, 2 H, ArH). 13
C
NMR (100 MHz, CDCl3): d = 100.2, 120.9, 125.6, 125.7,
126.3, 128.2, 128.8, 131.0, 132.9, 148.2, 169.1.
3-Phenyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1H-
pyrazole (1c):21 1H NMR (400 MHz, CDCl3): d = 1.50–1.65
(m, 4 H), 1.70–1.88 (m, 2 H), 3.53–3.58 (m, 1 H), 3.88–3.93
(m, 1 H), 4.63–4.81 (m, 3 H), 6.56 (s, 1 H, pyrazole ArH),
7.29 (t, J = 7.3 Hz, 1 H, ArH), 7.36 (dd, J = 7.0, 7.3 Hz, 1 H,
ArH), 7.72 (d, J = 7.0 Hz, 2 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 19.4, 25.3, 30.4, 61.1, 62.5, 98.2, 102.1, 125.6,
127.9, 128.7, 132.0.
5-(4-Methoxyphenyl)-3-phenyl-1H-pyrazole (1d):19 mp
166–168 °C (lit. 160–162 °C). 1H NMR (400 MHz, CDCl3):
d = 3.82 (s, 3 H, Me), 6.74 (s, 1 H, pyrazole ArH), 6.90 (d,
J = 8.8 Hz, 2 H, ArH), 7.31 (tt, J = 2.9, 7.1 Hz, 1 H, ArH),
7.36 (dd, J = 7.1, 7.5 Hz, 2 H, ArH), 7.63 (d, J = 8.8 Hz, 2 H,
ArH), 7.71 (dd, J = 2.8, 7.5 Hz, 2 H, ArH). 13C NMR (100
MHz, CDCl3): d = 55.3, 99.5, 104.4, 114.2, 123.9, 125.5,
126.9, 128.0, 131.5, 159.6.
2,4,6-Triphenylpyrimidine (5d):28 mp 184–185 °C (lit.
184–186 °C). 1H NMR (400 MHz, CDCl3): d = 7.51–7.59
(m, 9 H, ArH), 8.03 (s, 1 H, pyrimidine ArH), 8.28–8.31 (m,
4 H, ArH), 8.72–8.77 (m, 2 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 110.3, 127.3, 128.4, 128.4, 128.9, 130.6, 130.7,
137.5, 138.1, 164.5, 164.7.
2,4-Diphenyl-6-(pyridin-3-yl)pyrimidine (5e): mp 159–
161 °C. IR (CH2Cl2): 2833, 1562, 1542, 1492, 1443, 1261,
1114, 985, 757, 707 cm–1. 1H NMR (400 MHz, CDCl3): d =
7.51–7.61 (m, 8 H, ArH), 8.04 (s, 1 H, pyrimidine ArH),
8.29–8.32 (m, 2 H, ArH), 8.60–8.63 (m, 1 H, ArH), 8.71–
8.75 (m, 2 H, ArH), 8.76–8.79 (m, 1 H, ArH). 13C NMR (100
MHz, CDCl3): d = 110.3, 127.2, 127.3, 128.4, 128.5, 129.0,
130.9, 131.0, 134.6, 134.7, 137.1, 137.7, 148.6, 151.5,
162.4, 164.7, 163.1. HRMS: m/z calcd for C21H15N3:
310.1344; found: 310.1329.
5-(4-Chlorophenyl)-3-phenyl-1H-pyrazole (1e):22 mp
216–218 °C (lit. 215–217 °C). 1H NMR (400 MHz,
CD3OD): d = 6.98 (s, 1 H, pyrazole ArH), 7.33 (t, J = 7.2 Hz,
1 H, ArH), 7.40–7.44 (m, 4 H, ArH), 7.75–7.78 (m, 4 H,
ArH).
3-(3-Phenyl-1H-pyrazol-5-yl)pyridine (1f):19 mp 187–
189 °C (lit. 187–189 °C). 1H NMR (400 MHz, CDCl3): d =
6.85 (s, 1 H, pyrazole ArH), 7.34–7.48 (m, 4 H, ArH), 7.67
(d, J = 7.2 Hz, 2 H, ArH), 8.10 (d, J = 7.6 Hz, 1 H, ArH), 8.60
(br s, 1 H, ArH), 9.05 (br s, 1 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 101.4, 125.5, 125.5, 126.7, 126.8, 129.6, 129.6,
130.1, 135.0, 147.3, 149.2, 149.3.
5-Benzyl-3-phenyl-1H-pyrazole (1g):23 mp 187–189 °C
(lit. 187–189 °C). 1H NMR (400 MHz, CDCl3): d = 3.96 (s,
2 H, CH2), 6.32 (s, 1 H, pyrazole ArH), 7.20–7.34 (m, 8 H,
ArH), 7.65 (d, J = 7.2 Hz, 2 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 33.1, 102.0, 125.6, 126.6, 127.9, 128.6, 128.7,
128.7, 132.0, 138.5.
4-(4,6-Diphenylpyrimidin-2-yl)morpholine (5f): mp 172–
174 °C. 1H NMR (400 MHz, CDCl3): d = 3.84 (t, J = 4.8 Hz,
4 H, CH2), 4.02 (t, J = 4.8 Hz, 4 H, CH2), 7.32–7.35 (m, 2 H,
ArH), 7.44 (s, 1 H, pyrimidine ArH), 7.47–7.50 (m, 4 H,
ArH), 8.10–8.13 (m, 4 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 44.4, 67.0, 102.3, 127.1, 128.6, 130.3, 131.5,
1-Methyl-3,5-diphenyl-1H-pyrazole (1h):24 mp 58–60 °C
Synlett 2008, No. 1, 100–104 © Thieme Stuttgart · New York

104
J. P. Stonehouse et al.
LETTER
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Synlett 2008, No. 1, 100–104 © Thieme Stuttgart · New York

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