One-pot synthesis of 1,4-disubstituted pyrazoles from arylglycines via copper-catalyzed sydnone-alkyne cycloaddition reaction

Article abstract of DOI:10.1021/jo501420r

A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.

Full text of DOI:10.1021/jo501420r

Note
pubs.acs.org/joc
One-Pot Synthesis of 1,4-Disubstituted Pyrazoles from Arylglycines
via Copper-Catalyzed Sydnone−Alkyne Cycloaddition Reaction
Simon Specklin, Elodie Decuypere, Lucie Plougastel, Soifia Aliani, and Frederic Taran*
́
́
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette, F-91191, France
S
* Supporting Information
ABSTRACT: A robust method for constructing 1,4-pyrazoles
from arylglycines was developed using the copper-catalyzed
sydnone−alkyne cycloaddition reaction. The procedure offers
a straightforward and general route to the pyrazole heterocycle
through a three-step one-pot procedure.
yrazoles are small, “drug-like” heterocycles representing an
ditions,...), it requires a prior preparation of sydnone substrates.
P
important building block in medicinal chemistry.1 Despite
To improve the potential of this reaction, we propose in this
contribution a one-pot protocol that allows the use of
arylglycines as readily available substrates to form 1,4-pyrazoles
in high yields.
the numerous available methods,2 there is still an ongoing
search for simple and straightforward routes to polysubstituted
pyrazoles.3 Among them, the 1,3-dipolar cycloaddition reaction
of sydnones with alkynes appeared as a marginal, but attractive,
alternative approach to construct pyrazoles.4 This reaction has
been more particularly successfully exploited with alkyne
boronates giving rise to a regiocontrolled formation of pyrazole
boronic esters.5 However, besides this nice example, this
reaction is globally limited to electron-deficient alkynes, suffers
from a lack of regioselectivity, and usually requires harsh
conditions, especially elevated temperatures, therefore, reduc-
ing its attractiveness.
We recently described that Cu(I) salts complexed with
phenanthroline-based ligands, such as the commercially
available sulfonated bathophenanthroline (BPDS), are efficient
catalysts for cycloaddition reactions involving N-aryl sydnones
and terminal alkynes affording pure 1,4-pyrazoles under mild
conditions and with a total regiocontrol (Scheme 1).6 Reaction
Sydnones constitute a well-defined class of mesoionic
compounds useful for heterocyclic chemistry and displaying
several biological activities.7 The original method of prepara-
tion8 by cyclodehydration of an N-alkyl or aryl N-nitroso-α-
amino acid is still the only general route to sydnones. Classical
syntheses, therefore, involve two steps: (i) nitrosylation of
amino acids, generally carried out by sodium nitrite in aqueous
acidic conditions or using isoamyl nitrite,9 and (ii) cyclization
with acetic or trifluoroacetic anhydride.10 To avoid manipu-
lation of toxic nitrosamines, one-pot processes have been more
recently developed but require dibromo-dimethylhydantoin11
or N-dichloro-DABCO12 as electrophilic additives.
Our first goal in this project was, therefore, to optimize a
one-pot procedure yielding sydnone crudes that can be directly
used in the CuSAC reaction without purification. We first
investigated the cyclization step by testing a series of conditions
listed in Table 1.
Scheme 1. Cu-Catalyzed Sydnone−Alkyne Cycloaddition
Reaction (CuSAC)
N-p-Tolyl-glycine, used as model substrate, was first
nitrosylated by isopentyl nitrite to afford 2a in quantitative
isolated yield. This nitrosylation procedure was preferred to the
classical one using sodium nitrite in order to avoid the need to
remove water. 1,1′-Carbonyldiimidazole (CDI) was found to be
the best reagent, allowing quantitative formation of sydnone 3a
from 2a; dicyclohexyl carbodiimide (DCC) and trifluoroacetic
anhydride (TFAA) were also found to be quite efficient (Table
1, entries 5−7). We then evaluated these three cyclization
reagents for the one-pot formation of 3a from 1a. Direct
addition of CDI, DCC, or TFAA to the crude nitrosylation
reaction of 1a with isopentyl nitrite led to the desired sydnone
3a in only moderate yields (entries 1−3, Table 2). Hypothesiz-
ing that 3-methyl-butanol released from the nitrosylation step
may react with the cyclization reagents, we tested tert-butyl
conditions are quite similar to those of the well-known Cu-
catalyzed azide−alkyne cycloaddition reaction (CuAAC): a
number of Cu(I) sources can be used directly in various organic
solvents, but the reaction is better run in pure water or in
t‑BuOH/water mixtures using in situ reduction of Cu(II) salts
by sodium ascorbate.
While this Cu-catalyzed sydnone−alkyne cycloaddition
reaction (CuSAC) has shown many practical advantages
(broad substrate tolerance, high regioselectivity, mild con-
Received: June 26, 2014
Published: July 23, 2014
© 2014 American Chemical Society
7772
dx.doi.org/10.1021/jo501420r | J. Org. Chem. 2014, 79, 7772−7777

The Journal of Organic Chemistry
Note
a
Table 1. Optimization of the Cyclization Step
Table 3. Optimization of the One-Pot Pyrazole Formation
from Arylglycine 1a
a
b
entry
cyclization reagent
3a (%)
1
2
3
4
5
6
7
AcCl/Et3N
SOCl2/Et3N
PyBOP/Et3N
HBTU/Et3N
DCC
0
0
conditions
b
entry
cyclization
CuSAC
4a (%)
59
76
92
87
>99
1
2
3
CDI, THF, 60 °C
DCC, THF, 60 °C
TFAA, THF, 25 °C
DCC, neat, 60 °C
TFAA neat, 25 °C
THF/H2O, 60 °C
THF/H2O, 60 °C
THF/H2O, 60 °C
t-BuOH/H2O, 60 °C
t-BuOH/H2O, 60 °C
6
41
60
68
72
TFAA
c
4
c
CDI
5
a
Reactions were performed on a 1 mmol scale at a concentration of
a
b
1
Reactions were performed with 1 equiv. of 1a, 1.1 equiv. of t-BuONO
and cyclization reagent, 1 equiv. of TEA, 2 equiv. of Na asc., and 1
equiv. of alkyne in a (1:1) organo−aqueous solvent. Isolated yields.
2.5 equiv. of cyclization reagent and TEA were used in these cases.
0.5 M. Yields calculated by H NMR using 1,3,5-trimethoxybenzene
as internal standard.
b
c
a
Table 2. Optimization of the One-Pot Sydnone Formation
Scheme 2. Reaction Scope
b
entry
R
cyclization reagent
3a (%)
1
2
3
4
5
6
(CH3)2CH(CH2)2−
(CH3)2CH(CH2)2−
(CH3)2CH(CH2)2−
(CH3)3C−
(CH3)3C−
(CH3)3C−
DCC
TFAA
CDI
49
36
22
71
84
92
DCC
TFAA
CDI
a
Reactions were performed on a 1 mmol scale using 1.1 equiv. of
nitrosylation and cyclization agents at a concentration of 0.5 M.
b
Yields calculated by 1H NMR using 1,3,5-trimethoxybenzene as
internal standard.
nitrite as a more hindered reactant and obtained 3a in good
yields (entries 4−6, Table 2).
We then evaluated the compatibility of this one-pot sydnone
synthesis with the CuSAC reaction. The use of CDI was found
to be prejudicial to the copper catalysis. The procedure
involving TFAA was the most suitable for the CuSAC reaction,
and yields were finally improved by avoiding the use of THF as
solvent (Table 3). The nitrosylation and cyclization steps are
thus better run under neat conditions allowing the use of the
preferred t-BuOH/H2O mixture for the CuSAC step.
The scope of this one-pot procedure was then investigated
(Scheme 2). Various electron-rich or electron-poor N-aryl
sydnones successfully participated in this transformation.
Tolerance for variations in the acetylene component was
particularly excellent and revealed the lack of functional group
interference of the CuSAC reaction. In all cases, the 1,4-
pyrazole was the only product formed; no trace of a 1,3-
regioisomer was detected.
EXPERIMENTAL SECTION
■
General Experimental Details. Solvents were dried by standard
procedures prior to use. Purifications of reactions products were
carried out by column chromatography using silica gel (40−63 μm).
Analytical thin layer chromatographies were performed on silica gel
60-F plates. Visualization was accomplished with UV light and
phosphomolybdic acid. Infrared spectra (IR) are reported as
wavelength numbers (cm−1). Infrared spectra for liquid products
were obtained as a thin film on a NaCl disk, and spectra for solid
products were collected by preparing a KBr pellet containing the title
In conclusion, the one-pot process described here provides
1,4-disubstituted pyrazoles from readily available arylglycines in
good yields and perfect regioselectivity. The procedure is
experimentally simple and exhibits a broad scope; we, therefore,
believe it should be a useful addition to other pyrazole synthetic
routes.
1
compound. H NMR (400 MHz) and 13C NMR (100 MHz) were
measured on a 400 MHz spectrometer. Chemical shifts are reported in
parts per million (ppm, δ) downfield from residual solvent peaks, and
coupling constants are reported as hertz (Hz). Splitting patterns are
designated as singlet (s), broad singlet (br. s.), doublet (d), triplet
7773
dx.doi.org/10.1021/jo501420r | J. Org. Chem. 2014, 79, 7772−7777

The Journal of Organic Chemistry
Note
(t),.... Splitting patterns that could not be interpreted or easily
visualized are designated as multiplet (m). Electrospray mass spectra
were obtained using an ESI/TOF mass spectrometer. Unless
otherwise noted, all commercially available reagents and solvents
were used without further purification. N-Phenyl-glycine 1b was
purchased from a commercial supplier.
resulting precipitate was filtered, washed with water, and dried to
afford 11.9 g (60.7 mmol, 61%) of glycine 1e as a yellow solid; H
1
NMR (400 MHz, DMSO-d6) δ 12.80 (br. s, 1H), 8.00 (d, J = 9.2 Hz,
2H), 7.44 (t, J = 6.1 Hz, 1H), 6.66 (d, J = 9.2 Hz, 2H), 3.98 (d, J = 6.1
Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 171.5, 154.3, 136.4,
126.1 (2C), 111.3 (2C), 44.1; IR (KBr, cm−1) 3364, 3099, 1737, 1601,
1532, 1495, 1466, 1438, 1407, 1362, 1291, 1180, 1143, 1111, 993, 916,
843; LCMS (ESI) m/z 197 [M + H]+; HRMS(ESI) m/z calcd for
C8H7N2O4 (M − H−): 195.0406; found: 195.0406; mp. 224−226 °C.
2-((4-Cyanophenyl)amino)acetic Acid (1f).14 To a suspension
of 4-aminobenzonitrile (1.77 g, 15 mmol) in water (40 mL) was added
chloroacetic acid (2.84 g, 30 mmol). The mixture was refluxed
overnight, and the resulting precipitate was filtered. The solid was
dissolved in an aqueous solution of 6 M NaOH, and the resulting
solution was washed with EtOAc. The organic layer was extracted with
a solution of 6 M NaOH, and the combined aqueous extracts were
acidified at 0 °C to pH 2 with a HCl solution. The resulting precipitate
was filtered, washed with water, and dried to afford 1.25 g (7.11 mmol,
47%) of glycine 1f as a beige solid; 1H NMR (400 MHz, DMSO-d6) δ
12.7 (br s, 1H), 7.46 (d, J = 8.9 Hz, 2H), 6.89 (t, J = 5.5 Hz, 1H), 6.64
(d, J = 8.9 Hz, 2H), 3.90 (d, J = 5.5 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 171.8, 151.9, 133.3 (2C), 120.5, 112.2 (2C), 96.4, 43.9;
IR (KBr, cm−1) 3379, 3028, 2217, 1730, 1600, 1530, 1442, 1408, 1341,
1261, 1201, 1167, 1142, 956, 911, 849, 825, 731, 640; LCMS (ESI) m/
z 177 [M + H]+; mp. 240−243 °C.
4-((Carboxymethyl)amino)benzoic Acid (1g). To a solution of
sodium chloroacetate (2.33 g, 20.0 mmol) in water (20 mL) was
added 4-aminobenzoic acid (2.74 g, 20.0 mmol). The resulting mixture
was stirred at reflux for 10 h. After cooling to room temperature, the
precipitate was filtered, washed with water, and purified by
recrystallization from ethanol to afford 2.50 g (12.8 mmol, 64%) of
glycine 1g as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d,
J = 8.7 Hz, 2H), 6.66 (br. s., 1H), 6.57 (d, J = 8.7 Hz, 2H), 3.87 (s,
2H); 13C NMR (100 MHz, DMSO-d6) δ 172.1, 167.5, 152.1, 131.0,
117.6 (2C), 111.2 (2C), 44.1; IR (KBr, cm−1) 3427, 2544, 1703, 1598,
1527, 1410, 1334, 1319, 1280, 1246, 1188, 1152, 1126, 979, 953, 931,
839, 771, 691, 625; LCMS (ESI) m/z 196 [M + H]+; HRMS(ESI) m/
z calcd for C9H8NO4 (M − H−): 194.0453; found: 194.0449; mp.
258−261 °C.
2-((4-Trifluoromethylphenyl)amino)acetic Acid (1h). To a
solution of p-trifluoromethylaniline (322 mg, 2.00 mmol) in MeOH
(25.0 mL) at 0 °C were added NaOAc (328 mg, 4.00 mmol), glacial
acetic acid (0.460 mL, 8.00 mmol), glyoxylic acid monohydrate (276
mg, 3.00 mmol), and NaCNBH3 (126 mg, 2.00 mmol). The solution
was warmed slowly to rt over 2 h. The mixture was filtered through a
plug of Celite and washed with a solution of 1% acetic acid in EtOAc.
Brine was added, and the aqueous layer was extracted twice with
EtOAc. The organic layers were combined, dried over MgSO4, and
concentrated under vacuum. The crude product was purified by
recrystallization from a mixture of ethanol/water 8/2 to afford 130 mg
(0.59 mmol, 30%) of glycine 1h as a beige solid; 1H NMR (400 MHz,
DMSO-d6) δ 7.38 (d, J = 8.5 Hz, 2H), 6.72−6.57 (m, 3H), 3.87 (s,
2H), 3.59−3.14 (br. s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 172.1,
151.3, 126.2 (2C), 125.3 (q, J = 267 Hz), 115.8 (q, J = 32 Hz), 111.6
(2C), 44.1; IR (KBr, cm−1) 3421, 2899, 1901, 1731, 1616, 1585, 1538,
1491, 1441, 1412, 1319, 1281, 1242, 1188, 1164, 1151, 1110, 1062,
1005, 926, 825; LCMS (ESI) m/z 220 [M + H]+; HRMS(ESI) m/z
calcd for C9H7NO2F3 (M − H−): 218.0429; found: 218.0427; mp.
141−143 °C.
2-((3-Iodophenyl)amino)acetic Acid (1i). To a solution of m-
iodoaniline (2.28 g, 10.4 mmol) in MeOH (120 mL) at 0 °C were
added NaOAc (1.71 g, 20.8 mmol), glacial acetic acid (2.38 mL, 41.6
mmol), glyoxylic acid monohydrate (1.44 g, 15.6 mmol), and
NaCNBH3 (654 mg, 10.4 mmol). The solution was warmed slowly
to rt over 2 h. The mixture was filtered through a plug of Celite and
washed with a solution of 1% acetic acid in EtOAc. Brine was added,
and the aqueous layer was extracted twice with EtOAc. The organic
layers were combined, dried over MgSO4, and concentrated under
vacuum. The crude product was purified by recrystallization from a
mixture of ethanol/water 8/2 to afford 2.39 g (8.6 mmol, 83%) of
2-((4-Methylphenyl)amino)acetic Acid (1a).13 To a suspension
of p-toluidine (16.1 g, 150 mmol) and sodium acetate (14.8 g, 180
mmol) in ethanol (50 mL) was added ethyl chloroacetate (22.1 g, 180
mmol). The mixture was refluxed for 7 h, left overnight at room
temperature, and poured into crushed ice. The formed precipitate was
filtrated and dried. To the intermediate ester in water (75 mL) was
added sodium hydroxide (6.58 g, 165 mmol), and the mixture was
refluxed for 30 min. After cooling, the reaction mixture was acidified to
pH 2 by dropwise addition of a 4 M solution of HCl. The resulting
precipitate was filtered, washed with water, and purified by
recrystallization from a mixture ethanol/water 8/2 to afford 10.5 g
(63.6 mmol, 42%) of glycine 1a as a beige solid; 1H NMR (400 MHz,
DMSO-d6) δ 6.87 (d, J = 8.4 Hz, 2H), 6.44 (d, J = 8.4 Hz, 2H), 3.72
(s, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 173.2, 146.3,
129.7 (2C), 124.9, 112.6 (2C), 45.3, 20.5; IR (KBr, cm−1) 2968, 2076,
2021, 1906, 1202, 1321, 1273, 1240, 1191, 1173, 1108, 1035, 1022,
1000, 981, 944, 903, 877, 864, 820; LCMS (ESI) m/z 166 [M + H]+,
120 [M − CO2 + H]+; mp. 119−121 °C.
2-((4-Methoxyphenyl)amino)acetic Acid (1c).13 To a suspen-
sion of p-anisidine (18.5 g, 150 mmol) and sodium acetate (14.8 g, 180
mmol) in ethanol (50 mL) was added ethyl chloroacetate (22.1 g, 180
mmol). The mixture was refluxed for 7 h, left overnight at room
temperature, and poured into crushed ice. The formed precipitate was
filtrated and dried. To the intermediate ester in water (75 mL) was
added sodium hydroxide (6.58 g, 165 mmol), and the mixture was
refluxed for 30 min. After cooling, the reaction mixture was acidified to
pH 2 by dropwise addition of a 4 M solution of HCl. The resulting
precipitate was filtered, washed with water, and purified by
recrystallization from a mixture ethanol/water 8/2 to afford 15.4 g
(85.1 mmol, 57%) of glycine 1c as a beige solid; 1H NMR (400 MHz,
DMSO-d6) δ 6.71 (m, 2H), 6.51 (m, 2H), 3.73 (s, 2H), 3.63 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 173.3, 151.4, 142.8, 114.9 (2C),
113.5 (2C), 55.7, 45.8; IR (KBr, cm−1) 2957, 1561, 1394, 1314, 1259,
1234, 1194, 1181, 1169, 1104, 1032, 1005, 989, 885, 869, 835, 8917,
803; LCMS (ESI) m/z 182 [M + H]+, 136 [M − CO2 + H]+; mp.
151−153 °C.
2-((4-Iodophenyl)amino)acetic Acid (1d). To a solution of p-
iodoaniline (3.29 g, 45.0 mmol) in MeOH (170 mL) at 0 °C were
added NaOAc (2.46 g, 30.0 mmol), glacial acetic acid (3.43 mL, 60.0
mmol), glyoxylic acid monohydrate (2.07 g, 22.5 mmol), and
NaBH3CN (0.942 g, 15.0 mmol). The solution was warmed slowly
to rt over 2 h. The mixture was filtered through a plug of Celite and
washed with a solution of 1% acetic acid in EtOAc. Brine was added,
and the aqueous layer was extracted twice with EtOAc. The organic
layers were combined, dried over MgSO4, and concentrated. The
crude product was purified by recrystallization from a mixture of
ethanol/water 8/2 to afford 2.121 g (7.66 mmol, 51%) of glycine 1d as
1
a beige solid; H NMR (400 MHz, DMSO-d6) δ 12.55 (br. s, 1H),
7.32 (d, J = 8.6 Hz, 2H), 6.12 (br. s, 1H), 6.39 (d, J = 8.6 Hz, 2H),
3.77 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 172.3, 148.0, 137.0,
114.8, 76.7, 44.4; IR (KBr, cm−1) 3417, 2883, 1873, 1715, 1589, 1505,
1435, 1392, 1349, 1316, 1292, 1270, 1234, 1181, 1145, 1113, 1059,
993, 914, 810; LCMS (ESI) m/z 278 [M + H]+; HRMS(ESI) m/z
calcd for C8H9NO2I (M + H+): 277.9678; found: 277.9673; mp. 119−
121 °C.
2-((4-Nitrophenyl)amino)acetic Acid (1e). To a suspension of
4-nitroaniline (13.8 g, 100 mmol) in water (100 mL) was added
chloroacetic acid (18.9 g, 200 mmol). The mixture was refluxed
overnight, and the resulting precipitate was filtered and successively
washed with water and with a mixture of hexane/diethyl ether. The
solid was dissolved in an aqueous solution of 6 M NaOH, and the
resulting solution was washed with EtOAc. The organic layer was
extracted with a solution of 6 M NaOH, and the combined aqueous
extracts were acidified at 0 °C to pH 2 with a HCl solution. The
7774
dx.doi.org/10.1021/jo501420r | J. Org. Chem. 2014, 79, 7772−7777

The Journal of Organic Chemistry
Note
1
glycine 1i as a beige solid; H NMR (400 MHz, DMSO-d6) δ 6.91−
(NaCl, cm−1) 3085, 3061, 3027, 2923, 2859, 1720, 1613, 1568, 1519,
1496, 1454, 1426, 1398, 1333, 1317, 1250, 1219, 1178, 1155, 1118,
1108, 1075, 1040, 1018, 955, 855, 814, 750, 719, 698; LCMS (ESI) m/
z 263 [M + H]+; HRMS(ESI) m/z calcd for C18H19N2 (M + H+):
263.1548; found: 263.1539; mp. 41−43 °C.
6.81 (m, 3H), 6.55 (dt, J = 7.1 Hz, J = 2.4 Hz, 1H), 3.75 (s, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 210.0, 187.6, 168.5, 162.2, 158.0,
149.2, 133.1, 82.0; IR (KBr, cm−1) 3384, 2865, 1915, 1802, 1725,
1588, 1570, 1512, 1494, 1477, 1435, 1386, 1343, 1320, 1304, 1263,
1234, 1173, 1146, 1086, 1063, 1005, 983, 961, 912, 870, 859, 845;
LCMS (ESI) m/z 278 [M + H]+; HRMS(ESI) m/z calcd for
C8H9NO2I (M + H+): 277.9678; found: 277.9684; mp. 125−127 °C.
2-(Naphthalen-1-ylamino)acetic Acid (1j).15 To a solution of 1-
naphthalenamine (286 mg, 2.00 mmol) in MeOH (25 mL) at 0 °C
were added NaOAc (328 mg, 4.00 mmol), glacial acetic acid (0.46 mL,
8.00 mmol), glyoxylic acid monohydrate (276 mg, 3.00 mmol), and
NaBH3CN (126 mg, 2.00 mmol). The solution was warmed slowly to
rt over 2 h. The mixture was filtered through a plug of Celite and
washed with a solution of 1% acetic acid in EtOAc. Brine was added,
and the aqueous layer was extracted twice with EtOAc. The organic
layers were combined, dried over MgSO4, and concentrated. The
crude product was purified by recrystallization from a mixture of
ethanol/water 8/2 to afford 155 mg (0.77 mmol, 39%) of glycine 1j as
a beige solid; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J = 7.3 Hz, J
= 2.0 Hz, 1H), 7.77 (dd, J = 9.3 Hz, J = 2.2 Hz, 1H), 7.44 (m, 2H),
7.27 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 7.3 Hz,
1H), 3.98 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 172.6, 143.6,
134.0, 128.0, 126.6, 125.7, 124.2, 122.9, 121.4, 116.0, 103.0, 44.9; IR
(KBr, cm−1) 3402, 2572, 1723, 1622, 1583, 1520, 1481, 1463, 1452,
1434, 1417, 1404, 1372, 1340, 1286, 1259, 1212, 1171, 1141, 1092,
1039, 1016, 995, 975, 915, 880,867, 850; LCMS (ESI) m/z 202 [M +
H]+; mp. 201−203 °C.
2-((2-(Methoxycarbonyl)thiophen-3-yl)amino)acetic Acid
(1k). To a solution of methyl 3-amino-2-thiophenecarboxylate (472
mg, 3 mmol) in MeOH (34 mL) at 0 °C were added sodium acetate
(492 mg, 6 mmol), glacial acetic acid (686 μL, 12 mmol), glyoxylic
acid monohydrate (414 mg, 4.5 mmol), and sodium cyanoborohydride
(189 mg, 3 mmol). The solution was warmed slowly to room
temperature overnight, and the mixture was then filtered through a
plug of silica gel and washed with 1% glacial acetic acid in ethyl acetate.
The solution was washed with brine, dried over magnesium sulfate,
and concentrated. The crude product was purified by recrystallyzation
in ethyl acetate and heptane to afford 348 mg (1.6 mmol, 54%) of
glycine 1k as a white powder; 1H NMR (400 MHz, DMSO-d6) δ 7.66
(d, J = 5.1 Hz, 1H), 7.07 (t, J = 5.5 Hz, 1H), 6.73 (d, J = 5.1 Hz, 1H),
4.00 (d, J = 5.5 Hz, 2H), 3.70 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 171.9, 164.1, 155.3, 133.1, 177.4, 97.4, 50.9, 46.4; IR (KBr, cm−1)
3370, 3099, 2950, 1718, 1663, 1569, 1453, 1439, 1425, 1389, 1293,
1256, 1234, 1162, 1105, 1085, 908, 881, 840, 775, 735, 678, 655, 626;
LCMS (ESI) m/z 216 [M + H]+; HRMS(ESI) m/z calcd for
C8H10NO4S (M + H+): 216.0331; found: 216.0331; mp. 162−165 °C.
General Procedure for the Synthesis of Pyrazoles from
Arylglycines. To the neat stirred glycine (0.2 mmol) was added t-
butylnitrite (90 wt %, 29 μL, 0.22 mmol), and the mixture was
vigorously stirred for 30 min. Trifluoroacetic anhydride (70 μL, 0.5
mmol) was then added, and the mixture was further stirred for 30 min.
To the reaction mixture were then successively added t-BuOH (1 mL),
Et3N (167 μL), a solution of bathophenanthrolinedisulfonic acid
disodium salt hydrate (24 mg, 40 μmol) in water (0.5 mL), a solution
of copper(II) sulfate pentahydrate (10 mg, 40 μmol) in water (0.5
mL), alkyne (0.2 mmol), and sodium ascorbate (79 mg, 0.4 mmol).
The mixture was stirred at 60 °C for 16 h, and a 0.05 M solution of
HEDTA was added. The mixture was extracted with CH2Cl2, and the
combined organic phases were dried over MgSO4 and concentrated.
The residue was then purified by flash chromatography, yielding the
corresponding pyrazoles.
4-Phenethyl-1-phenyl-1H-pyrazole (4b).6 According to the general
procedure, reaction of glycine 1b with 4-phenyl-1-butyne, followed by
flash chromatography (SiO2, heptane/EtOAc 90:10), afforded
1
pyrazole 4b (42.0 mg, 0.17 mmol, 85%) as a beige solid; H NMR
(400 MHz, CDCl3) δ 7.67−7.60 (m, 3H), 7.54 (s, 1H), 7.43 (m, 2H),
7.34−7.27 (m, 2H), 7.25−7.19 (m, 3H), 2.91 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 141.6, 141.0, 140.3, 129.5 (2C), 128.6 (2C),
128.5 (2C), 126.2, 125.1, 123.1, 118.9 (2C), 37.2, 26.3; IR (NaCl,
cm−1) 3083, 3026, 2922, 2852, 1597, 1568, 1495, 1463, 1453, 1408,
1257, 1212, 1177, 1160, 1074, 1045, 1027, 1006, 955, 902, 842, 828,
751, 718, 696, 650; LCMS (ESI) m/z 263 [M + H]+; mp. 47−49 °C.
1-(p-Methoxyphenyl)-4-phenethyl-1H-pyrazole (4c). According to
the general procedure, reaction of glycine 1c with 4-phenyl-1-butyne,
followed by flash chromatography (SiO2, heptane/EtOAc 95:5),
1
afforded pyrazole 4c (38.2 mg, 0.14 mmol, 69%) as a beige solid; H
NMR (400 MHz, CDCl3) δ 7.57−7.49 (m, 4H), 7.35−7.28 (m, 2H),
7.25−7.19 (m, 3H), 6.95 (m, 2H), 3.84 (s, 3H), 2.89 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 158.1, 141.7, 140.4, 134.2, 128.6 (2C),
128.5 (2C), 126.2, 125.2, 122.7, 120.5 (2C), 114.5 (2C), 55.7, 37.3,
26.3; IR (NaCl, cm−1) 2914, 2854, 1597, 1561, 1513, 1494, 1453,
1445, 1392, 1317, 1302, 1244, 1189, 1172, 1151, 1106, 1041, 1023,
952, 923, 906, 859, 849, 810, 831, 798, 768, 745, 710, 654, 636, 624,
609; LCMS (ESI) m/z 279 [M + H]+; HRMS(ESI) m/z calcd for
C18H19N2O (M + H+): 279.1497; found: 279.1494; mp. 47−49 °C.
1-(p-Iodophenyl)-4-phenethyl-1H-pyrazole (4d). According to the
general procedure, reaction of glycine 1d with 4-phenyl-1-butyne,
followed by flash chromatography (SiO2, heptane/EtOAc 95:5),
afforded pyrazole 4d (58.6 mg, 0.16 mmol, 78%) as a yellow solid; 1H
NMR (400 MHz, CDCl3) δ 7.73 (m, 2H), 7.58 (s, 1H), 7.53 (s, 1H),
7.40 (m, 2H), 7.34−7.28 (m, 2H), 7.25−7.18 (m, 3H), 2.89 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 141.4, 140.0, 138.4 (2C), 128.6 (2C),
128.5 (2C), 126.2, 124.8, 123.5, 120.5 (2C), 90.0, 37.1, 26.2; IR
(NaCl, cm−1) 3110, 3096, 3023, 3000, 2939, 2916, 2854, 1949, 1898,
1585, 1493, 1450, 1421, 1396, 1309, 1219, 1188, 1112, 1095, 1061,
1074, 1010, 985, 952, 909, 854, 829, 816, 804, 753, 729, 702; LCMS
(ESI) m/z 375 [M + H]+; HRMS(ESI) m/z calcd for C17H16N2I (M +
H+): 375.0358; found: 375.0344; mp. 79−81 °C.
1-(p-Nitrophenyl)-4-phenethyl-1H-pyrazole (4e). According to the
general procedure, reaction of glycine 1e with 4-phenyl-1-butyne,
followed by flash chromatography (SiO2, heptane/EtOAc 95:5 to
85:15), afforded pyrazole 4e (40.2 mg, 0.14 mmol, 69%) as a yellow
1
solid; H NMR (400 MHz, CDCl3) δ 8.31 (m, 2H), 7.79 (m, 2H),
7.69 (s, 1H), 7.58 (s, 1H), 7.35−7.28 (m, 2H), 7.26−7.18 (m, 3H),
2.91 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 145.2, 144.5, 143.1,
141.2, 128.62 (2C), 128.60 (2C), 126.4, 125.5 (2C), 125.1, 124.9,
118.2 (2C), 36.9, 26.1; IR (NaCl, cm−1) 3125, 3093, 3028, 2934, 2856,
2364, 1611, 1600, 1514, 1452, 1395, 1341, 1308, 1223, 1155, 1113,
1075, 1035, 1013, 947, 910, 866, 847, 825, 795, 748, 739, 708, 698,
684; LCMS (ESI) m/z 294 [M + H]+; HRMS(ESI) m/z calcd for
C17H16N3O2 (M + H+): 294.1243; found: 294.1232; mp. 130−133 °C.
p-(4-Phenethyl-1H-pyrazol-1-yl)benzonitrile (4f). According to the
general procedure, reaction of glycine 1f with 4-phenyl-1-butyne,
followed by flash chromatography (SiO2, heptane/EtOAc 95:5 to
90:10), afforded pyrazole 4f (50.5 mg, 0.18 mmol, 92%) as a white
solid; 1H NMR (400 MHz, CDCl3) δ 7.73 (m, 4H), 7.65 (s, 1H, 7.65
(s, 1H), 7.34−7.28 (m, 2H), 7.26−7.17 (m, 3H), 2.90 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 142.9, 142.5, 141.0, 133.6 (2C), 128.5
(2C), 128.4 (2C), 126.2, 124.7, 124.4, 118.5, 118.4, 109.0, 36.8, 26.0;
IR (NaCl, cm−1) 3120, 3083, 3063, 3030, 2935, 2227, 1719, 1608,
1518, 1497, 1454, 1430, 1377, 1320, 1226, 1181, 1158, 1111, 1079,
1021, 948, 872, 860, 827, 771, 727, 711, 695, 655; LCMS (ESI) m/z
274 [M + H]+; HRMS(ESI) m/z calcd for C18H16N3 (M + H+):
274.1344; found: 274.1338; mp. 92−95 °C.
4-Phenethyl-1-(p-tolyl)-1H-pyrazole (4a). According to the general
procedure, reaction of glycine 1a with 4-phenyl-1-butyne, followed by
flash chromatography (SiO2, heptane/EtOAc 90:10), afforded
1
pyrazole 4a (37.9 mg, 0.14 mmol, 72%) as a yellow solid; H NMR
(400 MHz, CDCl3) δ 7.59 (s, 1H), 7.54−7.48 (m, 3H), 7.34−7.28 (m,
2H), 7.25−7.19 (m, 5H), 2.90 (m, 4H), 2.38 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 141.7, 140.7, 138.1, 136.0, 130.0 (2C), 128.6 (2C),
128.5 (2C), 126.2, 125.0, 122.9, 118.9 (2C), 37.3, 26.3, 21.0; IR
p-(4-Phenethyl-1H-pyrazol-1-yl)benzoic Acid (4g).6 According to
the general procedure using a larger amount of trifluoroacetic
7775
dx.doi.org/10.1021/jo501420r | J. Org. Chem. 2014, 79, 7772−7777

The Journal of Organic Chemistry
Note
1
anhydride (111 μL, 0.80 mmol) and Et3N (279 μL, 2.00 mmol),
reaction of glycine 1g with 4-phenyl-1-butyne, followed by flash
chromatography (SiO2, heptane/EtOAc 8:2 to 6:4 with 1% AcOH),
afforded pyrazole 4g (49.5 mg, 0.17 mmol, 85%) as a yellow solid; 1H
NMR (400 MHz, acetone-d6) δ 8.23 (s, 1H), 8.12 (m, 2H), 7.93 (m,
2H), 7.59 (s, 1H), 7.31−7.23 (m, 4H), 7.21−7.15 (m, 1H), 2.92 (m,
4H); 13C NMR (100 MHz, acetone-d6) δ 167.0, 144.4, 142.7, 142.5,
132.0 (2C), 129.3 (2C), 129.1 (2C), 128.3, 126.8, 126.2, 125.0, 118.3
(2C), 37.5, 26.8; IR (NaCl, cm−1) 2927, 2546, 1673, 1605, 1567, 1519,
1496, 1425, 1391, 1315, 1288, 1206, 1178, 1132, 1116, 1132, 1076,
1028, 948, 855, 838, 810, 800, 769, 742, 721, 692, 650; LCMS (ESI)
m/z 293 [M + H]+; mp. 187−190 °C.
pyrazole 4l (37.0 mg, 0.17 mmol, 84%) as a yellow solid; H NMR
(400 MHz, CDCl3) δ 8.17 (s, 1H), 8.02 (s, 1H), 7.75 (d, J = 7.9 Hz,
2H), 7.57 (d, J = 7.3 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.3
Hz, 2H), 7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.2, 139.0,
132.2, 129.7 (2C), 129.2 (2C), 127.1, 126.8, 125.9 (2C), 125.2, 123.5,
119.3 (2C); IR (KBr, cm−1) 3038, 1595, 1504, 1464, 1400, 1389,
1362, 1324, 1295, 1257, 1238, 1190, 1171, 1143, 1095, 1086, 1074,
1033, 1014, 954, 902, 863, 845, 801; LCMS (ESI) m/z 221 [M + H]+;
mp. 93−95 °C.
4-Pentyl-1-phenyl-1H-pyrazole (4m).16 According to the general
procedure, reaction of N-phenylglycine 1b with 1-heptyne, followed by
flash chromatography (SiO2, heptane/EtOAc 95:5), afforded pyrazole
1
4-Phenethyl-1-(p-(trifluoromethyl)phenyl)-1H-pyrazole (4h). Ac-
cording to the general procedure, reaction of glycine 1h with 4-phenyl-
1-butyne, followed by flash chromatography (SiO2, heptane/EtOAc
95:5 to 90:10), afforded pyrazole 4h (50.5 mg, 0.16 mmol, 80%) as a
yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.8 Hz, 2H),
7.69 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.56 (s, 1H)7.35−7.27 (m, 2H),
7.26−7.18 (m, 3H), 2.91 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
142.7, 142.1, 141.4, 128.7 (2C), 128.6 (2C), 127.9 (q, JC−F = 33.0 Hz),
126.8 (q, JC−F = 3.8 Hz, 2C), 126.3, 125.5, 124.1 (q, JC−F = 271.4 Hz),
124.0, 118.4 (2C), 37.1, 26.2; 19F NMR (376 MHz, CDCl3) δ −62.2
(s, 3F); IR (NaCl, cm−1) 2927, 1615, 1573, 1522, 1496, 1453, 1433,
1395, 1374, 1319, 1219, 1155, 1118, 1106, 1067, 1031, 1015, 948, 865,
842, 827, 807, 779, 756, 723, 700, 650; LCMS (ESI) m/z 317 [M +
H]+; HRMS(ESI) m/z calcd for C18H16N2F3 (M + H+): 317.1266;
found: 317.1254; mp. 92−94 °C.
4m (34.8 mg, 0.16 mmol, 82%) as a bright yellow oil; H NMR (400
MHz, CDCl3) δ 7.71 (s, 1H), 7.68−7.66 (m, 2H), 7.55 (s, 1H), 7.45−
7.41 (m, 2H), 7.26−7.23 (m, 1H), 2.53 (t, J = 7.6 Hz, 2H), 1.66−1.58
(m, 2H), 1.38−1.34 (m, 4H), 0.93−0.90 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 140.9, 140.2, 129.3 (2C), 125.9, 124.6, 124.0, 118.7
(2C), 31.4, 30.4, 24.1, 22.4, 14.0 ; IR (KBr, cm−1) 2955, 2856, 2926,
1600, 1571, 1503, 1463, 1395, 1328, 1251, 1211, 1176, 1072, 1012,
1042, 952, 901, 854, 788, 752, 688, 652; LCMS (ESI) m/z 215 [M +
H]+.
4-(2-Bromoethyl)-1-phenyl-1H-pyrazole (4n). According to the
general procedure using less Et3N (125 μL, 0.90 mmol), reaction of N-
phenylglycine 1b with 4-bromo-1-butyne, followed by flash
chromatography (SiO2, heptane/EtOAc 90:10 to 95:5), afforded
1
pyrazole 4n (22.8 mg, 0.09 mmol, 45%) as a yellow solid; H NMR
(400 MHz, CDCl3) δ 7.84 (s, 1H), 7.67 (m, 2H), 7.62 (s, 1H), 7.45
(m, 2H), 7.28 (m, 1H), 3.56 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 140.9, 140.2, 129.6 (2C), 126.5,
125.6, 120.6, 119.1 (2C), 33.0, 28.3; IR (KBr, cm−1) 2922, 2964, 1724,
1598, 1570, 1503, 1464, 1446, 1432, 1398, 1370, 1331, 1266, 1220,
1206, 1181, 1155, 1108, 1073, 1042, 1031, 1012, 952, 905, 855, 799,
750688, 651, 622; LCMS (ESI) m/z 251 [M(79Br) + H]+, 253
[M(81Br) + H]+ ; HRMS(ESI) m/z calcd for C11H12N2Br (M[79Br] +
H+): 251.0184; found: 251.0172; mp. 42−44 °C.
tert-Butyl N-((1-Phenyl-1H-pyrazol-4-yl)methyl)carbamate (4o).
According to the general procedure, reaction of N-phenylglycine 1b
with N-Boc-propargylamine, followed by flash chromatography (SiO2,
heptane/EtOAc 85:15), afforded pyrazole 4o (46.6 mg, 0.17 mmol,
1-(m-Iodophenyl)-4-phenethyl-1H-pyrazole (4i). According to the
general procedure, reaction of glycine 1i with 4-phenyl-1-butyne,
followed by flash chromatography (SiO2, heptane/EtOAc 95:5),
1
afforded pyrazole 4i (62.2 mg, 0.17 mmol, 83%) as a yellow oil; H
NMR (400 MHz, CDCl3) δ 8.04 (t, J = 1.9 Hz, 1H), 7.61−7.55 (m,
3H), 7.51 (s, 1H), 7.34−7.28 (m, 2H), 7.25−7.18 (m, 3H), 7.17 (t, J =
8.1 Hz, 1H), 2.89 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 141.6,
141.4, 141.2, 135.0, 130.9, 128.6 (2C), 128.5 (2C), 127.7, 126.3, 124.9,
123.6, 117.8, 94.5, 37.1, 26.2; IR (NaCl, cm−1) 3085, 3062, 3026,
2924, 2858, 1588, 1567, 1485, 1453, 1429, 1395, 1334, 1297, 1215,
1169, 1075, 1064, 1039, 1019, 993, 956, 907, 859, 778, 736, 700, 679;
LCMS (ESI) m/z 375 [M + H]+; HRMS(ESI) m/z calcd for
C17H16N2I (M + H+): 375.0358; found: 375.0344.
1
85%) as a white solid; H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H),
1-(Naphthalen-1-yl)-4-phenethyl-1H-pyrazole (4j). According to
the general procedure, reaction of glycine 1j with 4-phenyl-1-butyne,
followed by flash chromatography (SiO2, heptane/EtOAc 95:5 to
90:10), afforded pyrazole 4j (41.0 mg, 0.14 mmol, 69%) as a brown
oil; 1H NMR (400 MHz, CDCl3) δ 7.91 (td, J = 7.3 Hz and J = 2.3 Hz,
2H), 7.78 (d, J = 7.3 Hz, 1H), 7.67 (s, 1H), 7.57−7.48 (m, 4H), 7.46
(s, 1H), 7.36−7.29 (m, 2H), 7.27−7.20 (m, 3H), 2.97 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 141.7, 140.7, 137.6, 134.4, 130.1, 129.1,
128.75, 128.72 (2C), 128.5 (2C), 128.2, 127.2, 126.7, 126.2, 125.2,
123.4, 123.1, 121.9, 37.4, 26.3; IR (NaCl, cm−1) 3084, 3056, 3026,
2924, 2858, 1597, 1577, 1511, 1496, 1469, 1453, 1423, 1399, 1329,
1261, 1217, 1179, 1160, 1114, 1075, 1019, 860, 799, 772, 750, 717,
698; LCMS (ESI) m/z 299 [M + H]+; HRMS(ESI) m/z calcd for
C21H19N2 (M + H+): 299.1548; found: 299.1534.
7.67−7.62 (m, 3H), 7.43 (m, 2H), 7.27 (m, 1H), 4.85 (br s, 1H), 4.24
(d, J = 5.8 Hz, 2H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.9, 140.6, 140.1, 129.5 (2C), 126.6, 125.8, 121.4, 119.1 (2C), 79.7,
35.2, 28.5 (3C); IR (KBr, cm−1) 3322, 2978, 1682, 1599, 1504, 1398,
1364, 1346, 1246, 1158, 1073, 1039, 1023, 949, 901, 870, 810, 782,
752, 707, 673, 650, 618; LCMS (ESI) m/z 274 [M + H]+;
HRMS(ESI) m/z calcd for C15H20N3O2 (M + H+): 274.1556;
found: 274.1544; mp. 78−81 °C.
5-tert-Butyl-3-(2,4-dichloro-5-((1-phenyl-1H-pyrazol-4-yl)-
methoxy)phenyl)-2,3-dihydro-1,3,4-oxadiazol-2-one (4p). Accord-
ing to the general procedure using less Et3N (125 μL, 0.90 mmol),
reaction of N-phenylglycine 1b with oxadiargyl, followed by flash
chromatography (SiO2, heptane/EtOAc 90:10 to 60:40), afforded
1
pyrazole 4p (83.4 mg, 0.18 mmol, 78%) as a beige solid; H NMR
(400 MHz, CDCl3) δ 8.06 (s, 1H), 7.79 (s, 1H), 7.70 (m, 2H), 7.54 (s,
1H), 7.46 (m, 2H), 7.30 (m, 1H), 7.18 (s, 1H), 5.13 (s, 2H), 1.38 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 163.7, 153.3, 152.3, 140.9,
140.0, 131.7, 131.5, 129.6 (2C), 126.9 (2C), 125.5, 123.7, 119.4 (2C),
117.9, 113.6, 63.3, 33.1, 27.2 (3C); IR (KBr, cm−1) 2973, 1768, 1618,
1600, 1568, 1504, 1489, 1429, 1407, 1395, 1356, 1339, 1324, 1283,
1248, 1225, 1142, 1125, 1092, 1125, 1092, 1037, 974, 954, 906, 875,
863, 832, 796, 755, 712, 688, 658, 666; LCMS (ESI) m/z 459 [M +
H]+; HRMS(ESI) m/z calcd for C22H21N4O3Cl2 (M + H+): 459.0991;
found: 459.0980; mp. 148−151 °C.
3-(4-Phenethyl-1H-pyrazol-1-yl)thiophene-2-carboxylic Acid (4k).
According to the general procedure, reaction of glycine 1k with 4-
phenyl-1-butyne, followed by flash chromatography (SiO2, heptane/
EtOAc 80:20 to 60:40), afforded pyrazole 4k (31.0 mg, 0.10 mmol,
1
50%) as a yellow oil; H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H),
7.50 (s, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.33−
7.27 (m, 2H), 7.25−7.18 (m, 3H), 3.85 (s, 3H), 2.90 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 161.5, 143.1, 141.7, 141.3, 130.7, 130.5,
128.6 (2C), 128.5 (2C), 126.7, 126.2, 122.2, 118.0, 52.4, 37.2, 26.3; IR
(NaCl, cm−1) 3088, 3062, 3026, 2949, 2858, 1715, 1574, 1545, 1496,
1455, 1438, 1421, 1398, 1264, 1235, 1210, 1110, 1085, 1071, 975, 955,
874, 774, 698; LCMS (ESI) m/z 313 [M + H]+; HRMS(ESI) m/z
calcd for C17H17N2O2S (M + H+): 313.1011; found: 313.1000.
1,4-Diphenyl-1H-pyrazole (4l).6 According to the general proce-
dure, reaction of N-phenylglycine 1b with phenylacetylene, followed
by flash chromatography (SiO2, heptane/EtOAc 90:10), afforded
2-(1-Phenyl-1H-pyrazol-4-yl)pyridine (4q).6 According to the
general procedure, reaction of N-phenylglycine 1b with 2-ethynylpyr-
idine, followed by flash chromatography (SiO2, heptane/EtOAc
70:30), afforded pyrazole 4q (30.7 mg, 0.14 mmol, 69%) as a white
1
powder; H NMR (400 MHz, CDCl3) δ 8.60−8.58 (m, 1H), 8.52 (s,
1H), 8.18 (s, 1H), 7.77−7.75 (m, 2H), 7.70 (td, J = 7.7 Hz, 1.9 Hz,
7776
dx.doi.org/10.1021/jo501420r | J. Org. Chem. 2014, 79, 7772−7777

The Journal of Organic Chemistry
Note
1H), 7.55 (br. d, J = 7.9 Hz, 1H), 7.49−7.44 (m, 2H), 7.31 (m, 1H),
7.15 (ddd, J = 7.5 Hz, 4.9 Hz, 1.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 151.3, 149.5, 139.8, 139.1, 136.8, 129.4, 126.8, 125.3, 125.0,
121.5, 119.8, 119.1; IR (KBr, cm−1) 3052, 1700, 1652, 1594, 1557,
1505, 1411, 1260, 1192, 1152, 1034, 962, 870, 778, 756, 717, 690;
LCMS (ESI) m/z 222 [M + H]+; mp. 86−88 °C.
Feltell, R. E.; Lewis, E. J.; MsMenamin, R. L.; Navarro, E. F.; O’Brien,
M. A.; O’Reilly, M.; Reule, M.; Saxty, G.; Seavers, L. A.; Smith, D.-M.;
Squires, M.; Trewartha, G.; Walker, M. T.; Woolford, A. J.-A. J. Med.
Chem. 2008, 51, 4986−4999. (d) Lamberth, C. Heterocycles 2007, 71,
1467−1502. (e) de Paulis, T.; Hemstapat, K.; Chen, Y.; Zhang, Y.;
Saleh, S.; Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.; Conn, P. J. J.
Med. Chem. 2006, 49, 3332−3344. (f) Bekhit, A. A.; Abdel-Aziem, T.
Bioorg. Med. Chem. 2004, 12, 1935−1945. (g) Tanitame, A.; Oyamada,
Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.; Ueda, T.; Terauchi, H.;
Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi, J.-I. Bioorg. Med. Chem.
2004, 12, 5515−5524.
Ethyl 1-Phenyl-1H-pyrazole-4-carboxylate (4r).6 According to the
general procedure, reaction of N-phenylglycine 1b with ethyl
propiolate, followed by flash chromatography (SiO2, heptane/EtOAc
95:5), afforded pyrazole 4r (22.1 mg, 0.10 mmol, 51%) as a white
1
solid; H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.09 (s, 1H),
7.71−7.68 (m, 2H), 7.49−7.45 (m, 2H), 7.37−7.32 (m, 1H), 4.34 (q, J
= 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 162.8, 142.1, 139.3, 129.9, 129.5, 127.5, 119.5, 116.9, 60.4, 14.3 ; IR
(KBr, cm−1) 2925, 2213, 1707, 1630, 1597, 1559, 1497, 1412, 1247,
1148, 1025, 996, 951, 908, 887, 853, 825, 768, 755, 686, 654; LCMS
(ESI) m/z 217 [M + H]+; mp. 88−91 °C.
(2) For reviews on pyrazole synthesis, see: (a) Fustero, S.; Sanchez-
Rosello, M.; Barrio, P.; Simon-Fuentes, A. Chem. Rev. 2011, 111,
6984−7034. (b) Dadiboyena, S.; Nefzi, A. Eur. J. Med. Chem. 2011, 46,
5258−5275.
(3) For recent examples, see: (a) Kong, Y.; Tang, M.; Wang, Y. Org.
́
Lett. 2014, 16, 576−579. (b) Schneider, Y.; Prevost, J.; Gobin, M.;
2-Methyl-4-oxo-3-((1-phenyl-1H-pyrazol-4-yl)methyl)cyclopent-
2-en-1-yl 2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-
carboxylate (4s). According to the general procedure using less
Et3N (125 μL, 0.90 mmol), reaction of N-phenylglycine 1b with
prallethrin, followed by flash chromatography (SiO2, heptane/EtOAc
90:10 to 60:40), afforded pyrazole 4s (65 mg, 0.16 mmol, 78%) in a
Legault, C. Y. Org. Lett. 2014, 16, 596−599. (c) Kumar, S. V.; Yadav, S.
K.; Raghava, B.; Saraiah, B.; Ila, H.; Rangappa, S.; Hazra, A. J. Org.
Chem. 2013, 78, 4960−4973.
(4) (a) Foster, R. S.; Jakobi, H.; Harrity, J. P. A. Tetrahedron Lett.
2011, 52, 1506−1508. (b) Harju, K.; Vesterinen, J.; Yli-Kauhaluoma, J.
Org. Lett. 2009, 11, 2219−2221. (c) Browne, D. L.; Taylor, J. B.; Plant,
A.; Harrity, J. P. A. J. Org. Chem. 2010, 75, 984−987. (d) Foster, R. S.;
Jakobi, H.; Harrity, J. P. A. Org. Lett. 2012, 14, 4858−4861. (e) Foster,
R. S.; Huang, J.; Vivat, J. F.; Browne, D. L.; Harrity, J. P. A. Org.
Biomol. Chem. 2009, 7, 4052−4056.
1
diastereomeric mixture (dr: 47/53) as a yellow oil; H NMR (400
MHz, CDCl3) minor diastereomer δ 7.76 (s, 1H), 7.63 (m, 2H), 7.52 (s,
1H), 7.42 (m, 2H), 7.25 (m, 1H), 5.77 (br d, J = 6.3 Hz, 1H), 4.90 (m,
1H), 3.46 (s, 2H), 2.90 (dd, J = 10.5 Hz and J = 6.2 Hz, 1H), 2.32 (dd,
J = 18.7 Hz and J = 2.1 Hz, 1H), 2.11−2.06 (m, 1H), 2.07 (s, 3H),
1.73−1.69 (m, 6H), 1.40 (d, J = 5.3 Hz, 1H), 1.29 (s, 3H), 1.15 (s,
3H); major diastereomer δ 7.76 (s, 1H), 7.63 (m, 2H), 7.52 (s, 1H),
7.42 (m, 2H), 7.25 (m, 1H), 5.68 (br d, J = 6.2 Hz, 1H), 4.90 (m, 1H),
3.46 (s, 2H), 2.90 (dd, J = 10.5 Hz and J = 6.3 Hz, 1H), 2.32 (dd, J =
18.7 Hz and J = 2.0 Hz, 1H), 2.11−2.06 (m, 1H), 2.10 (s, 3H), 1.73−
1.69 (m, 6H), 1.41 (d, J = 5.2 Hz, 1H), 1.26 (s, 3H), 1.14 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 204.04/203.99, 172.4, 165.4/165.3,
142.64/142.58, 140.9, 140.2, 136.10/136.07, 129.5 (2C), 126.4, 125.7,
120.90/120.82, 119.8, 119.0 (2C), 73.1/72.7, 42.2/41.8, 34.72/34.68,
33.4/33.2, 29.3, 25.7, 22.3/22.2, 20.7/20.5, 18.6, 18.1, 14.3/14.2 ; IR
(KBr, cm−1) 2923, 1709, 1655, 1599, 1504, 1413, 1396, 1379, 1339,
1281, 1234, 1192, 1149, 1113, 1075, 1040, 1011, 993, 952, 903, 855,
754, 689, 652; LCMS (ESI) m/z 419 [M + H]+; HRMS(ESI) m/z
calcd for C26H31N2O3 (M + H+): 419.2335; found: 419.2344.
(5) (a) Browne, D. L.; Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.;
Harrity, J. P. A. J. Am. Chem. Soc. 2009, 131, 7762−7769. (b) Browne,
D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed.
2007, 46, 8656−8658.
(6) Kolodych, S.; Rasolofonjatovo, E.; Chaumontet, M.; Nevers, M.-
C.; Crem
12060.
́
inon, C.; Taran, F. Angew. Chem., Int. Ed. 2013, 52, 12056−
(7) For a recent review on sydnones, see: Browne, D. L.; Harrity, J. P.
A. Tetrahedron 2010, 66, 553−568.
(8) Earl, J. C.; Mackney, A. W. J. Chem. Soc. 1935, 899−900.
(9) Applegate, J.; Turnbull, K. Synthesis 1988, 1011−1012.
(10) Baker, W.; Ollis, W. D.; Poole, V. D. J. Chem. Soc. 1950, 1542−
1551.
(11) Azarifar, D.; Ghasemnejad-Bosra, H. Synthesis 2006, 1123−
1126.
(12) Azarifar, D.; Ghasemnejad-Bosra, H.; Tajbaksh, M.; Habibzadeh,
S. Heterocycles 2007, 71, 1815−1819.
ASSOCIATED CONTENT
■
S
* Supporting Information
(13) Nithinchandra; Kalluraya, B.; Aamir, S.; Shabaraya, A. R. Eur. J.
Med. Chem. 2012, 54, 597−604.
1H and 13C NMR for all products and 19F NMR for compound
4h. This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Popovici-Muller, J.; Salituro, F. G.; Saunders, J. O.; Travins, J.;
Yan, S. (Agios Pharmaceuticals, Inc., USA). Patent WO 2012009678
A1, 2012.
(15) Hu, C.; Chen, Z.; Yang, G. Synth. Commun. 2004, 34, 219−224.
(16) Finar, I. L.; Lord, G. H. J. Chem. Soc. 1959, 1819−1823.
AUTHOR INFORMATION
Corresponding Author
*E-mail: frederic.taran@cea.fr.
■
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENTS
This work was supported by ANR (ClickScreen project) and by
the labex Charmmmat.
■
REFERENCES
■
(1) See, for example: (a) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.;
Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222−7228.
(b) Mowbray, C. E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes, M.;
Perros, M.; Tran, I.; Price, D. A.; Quinton, F. J.; Selby, M. D.; Stupple,
P. A.; Webster, R.; Wood, A. Bioorg. Med. Chem. Lett. 2009, 19, 5857−
5860. (c) Wyatt, P. G.; Woodhead, A. J.; Berdini, V.; Boulstridge, J. A.;
Carr, M. G.; Cross, D. M.; Davis, D. J.; Devine, L. A.; Early, T. R.;
7777
dx.doi.org/10.1021/jo501420r | J. Org. Chem. 2014, 79, 7772−7777