Palladium Catalyzed Arylation and Benzylation of Nitroarenes Using Aryl Sulfonates and Benzyl Acetates

Article abstract of DOI:10.1021/acs.joc.7b00550

Pd-catalyzed arylation or benzylation of nitroazoles using aryl sulfonates or benzyl acetates is described. Electronically varied aryl tosylates and mesylates, as well as benzyl acetates, afford the arylated and benzylated products. Arylation of nitrobenz

Full text of DOI:10.1021/acs.joc.7b00550

Note
pubs.acs.org/joc
Palladium Catalyzed Arylation and Benzylation of Nitroarenes Using
Aryl Sulfonates and Benzyl Acetates
Zubaoyi Yi, Yodit Aschenaki,† Ryan Daley,† Stephen Davick,† Abigail Schnaith,† Rylee Wander,†
and Dipannita Kalyani*
St. Olaf College, 1520 St. Olaf Avenue, Northfield, Minnesota 55057, United States
S
* Supporting Information
ABSTRACT: Pd-catalyzed arylation or benzylation of nitroazoles using
aryl sulfonates or benzyl acetates is described. Electronically varied aryl
tosylates and mesylates, as well as benzyl acetates, afford the arylated and
benzylated products. Arylation of nitrobenzene is also reported. The
relative rate for the arylation of halides is greater than that of tosylates
using the reported reaction parameters. These studies enhance the scope
of electrophiles for nitroarene arylations and benzylations, which was
hitherto limited to the use of halide electrophiles.
itroarenes are important building blocks for the synthesis
different catalyst/ligand combinations than are used with
halides, thereby presenting an opportunity to engage the C−
X (X = halide) and C−O electrophiles at different stages in the
context of multistep synthesis.10,11 As part of our program on
transition metal catalyzed functionalizations using C−O
electrophiles,12 we report herein the first general method for
the direct arylation and benzylation of nitropyrazoles and
nitroimidazoles using aryl sulfonates11,13,14 and benzyl acetates
(Schemes 1b−3b). A brief scope for the arylation of
nitrobenzene is also described (Scheme 4b). Notably, function-
alized pyrazoles, imidazoles, and nitrobenzene derivatives find
applications in the synthesis of pharmaceuticals, agrochemicals,
or ligands for transition metals.1,9,4c
N
of pharmaceuticals, agrochemicals, polymers, and fine
chemicals.1,2 Many nitroarenes are readily available at low cost
via nitration of arenes.2 Reduction of the nitro group serves as a
versatile handle for structural elaboration through cross-
coupling and functional group transformation of the resulting
amino group.3 In lieu of these applications of nitroarenes, a few
reports have detailed the arylation of nitroazoles (Schemes 1a
Scheme 1. Literature Precedent and Present Study
Our studies commenced with the optimization of the
arylation of nitropyrazole 1 using 2-naphthyl tosylate. As
shown in Table 1, product 1a can be obtained in the presence
of Pd(OAc)2 with XPhos or SPhos as ligands (entries 4 and 5).
In contrast to the analogous reaction with halide electrophiles4
the use of PPh3 does not lead to 1a. Additionally, the bidentate
dcype ligand, which is effective for arylations of arenes using
tosylates and mesylates,12a,c does not promote the arylation of
nitropyrazole (entry 6). Substrate 1 has two distinct C−H
bonds (Ha and Hb) that can undergo arylation. Consistent with
previous reports on arylation using aryl halides4 product 1a is
derived via the preferential arylation of the more acidic C−Ha
bond.15 Unlike arylations using aryl bromides,4 transformations
using aryl tosylates do not require copper(I) additives.
Carbonate bases are effective at promoting the transformation
(entries 4 and 7). Increasing the temperature leads to
diminished yield of 1a. Notably, 5−10% of diarylation product
(1aa) is formed via functionalization of both C−Ha and C−Hb
regardless of the temperature (entries 4, 5, 7, and 8).16 No
product is obtained in the absence of the Pd(OAc)2 or the
and 2a)4 and nitrobenzene derivatives (Scheme 4a)2,5 using
halide electrophiles.6−8 The allylation and benzylation of
nitroazoles using allyl acetate and benzyl chloride, respectively,
has also been realized (Scheme 3a).9 Recently there have been
increasing reports on the use of C−O electrophiles in place of
halides for C−C bond formations.8,10,11 The use of C−O
electrophiles instead of halides presents several advantages
including: (i) the availability of alcohols from natural sources,
(ii) ready access of various ortho-substituted phenol derivatives
using directed ortho-metalation, and (iii) requirement for
Received: March 7, 2017
© XXXX American Chemical Society
A
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products are obtained in good to excellent yields using
electronically varied aromatic tosylates. Furthermore, pyrazole
substrates bearing various N-alkyl (N-butyl (1a−1g), N-Me (2c
and 2h), and N-CH2CH2Ph (3i)) or N-aryl groups (4a)
undergo arylation to afford the corresponding products in good
yields.17
Heterocylic tosylates also couple with nitropyrazoles under
the optimal conditions. For example, the use of tosylated
pyridine, quinoline, and quinoxaline affords products 1j (and
5j), 1k, and 1l, respectively in good yields (Scheme 3).
Furthermore, 1m bearing a π-rich heterocycle is also obtained
in good yield.18
Table 1. Optimization of Nitropyrazole Arylation
a
entry
ligand
base
T (°C)
GC yield (%)
1
2
3
4
5
6
7
8
PCy3HBF4
PtBu3HBF4
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
80
80
80
80
80
80
80
120
80
80
0
0
0
X-Phos
S-Phos
dcype
89
88
0
a
Scheme 3. Heteroarylation of Nitropyrazoles
X-Phos
X-Phos
X-Phos
none
87
56
0
Cs2CO3
Cs2CO3
Cs2CO3
b
9
10
0
a
Calibrated GC yields against hexadecane as the internal standard.
Reaction without Pd(OAc)2 catalyst.
b
ligand (entries 9 and 10). However, comparable yields of 1a are
obtained with or without CsOPiv (Scheme 2). Importantly, use
of N-methyl pyrazole in these arylations affords only trace
product, suggesting the importance of the nitro group for
efficiency of arylations using nitroazoles.
Scheme 2 depicts the scope of nitropyrazole arylation with
respect to the substrate and the electrophile. The optimal
temperature for these transformations (80 °C versus 120 °C)
varied based on the nature of the aryl tosylate. Arylated
a
Reaction conditions: Azole (1.0 equiv), tosylate (1.05−1.1 equiv),
Pd(OAc)2 (0.1 equiv), XPhos (0.3 equiv), Cs2CO3 (1.5 equiv),
CsOPiv (1.1 equiv), p-xylene (or toluene), 120 °C. Conducted at 80
°C. General conditions but with Pd(OAc)2 (0.15 equiv), XPhos (0.45
equiv).
b
c
The reaction conditions for pyrazole arylations are also
effective for arylation of nitroimidazoles, with a similar substrate
scope (Scheme 4). The higher yields for imidazole arylations
are in part due to the absence of diarylation because these
substrates contain only one acidic C−H bond.
Scheme 2. Scope of Nitropyrazole Arylations
Scheme 4. Scope of Nitroimidazole Arylations
a
Reaction set up outside the glovebox under inert atmosphere.
A sequential tosylation/arylation protocol enhances the step
economy of these arylations (Scheme 5).12 Tosylation of the
phenol derivative affords a solution of the corresponding
tosylate, which is employed directly in the subsequent Pd-
catalyzed arylations without purification of the intermediate
tosylate. Pyrazole and imidazole substrates undergo sequential
a
b
c
Conducted at 80 °C. Without CsOPiv. Reaction set up outside the
d
e
glovebox under inert atmosphere. p-Xylene used as solvent. 1.1
equiv of azole and 1.0 equiv of tosylate used. General conditions with
Pd(OAc)2 (0.15 equiv) and XPhos (0.45 equiv). NMR yield against
1,4-dinitrobenzene as the standard.
f
g
B
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Scheme 5. Sequential Tosylation/Arylation
Scheme 7. Scope for Benzylation of Nitroazoles
a
tosylation/arylation to afford products (1a, 1j, and 6a) in yields
comparable to those obtained using preformed tosylates
(Schemes 2−4).
Reaction set up outside the glovebox under inert atmosphere using
b
toluene as solvent. CsOPiv (1.1 equiv) added and toluene used as
solvent. Conducted at 120 °C.
c
We next investigated the use of the more atom economical
mesylates in these reactions.14 As shown in Scheme 6, both
nitropyrazole (1a, 4a, 1p, 1f, 1n) and nitroimidazoles (6a and
6c) are amenable to arylation with aromatic mesylates to afford
the products in modest to good yields. Yields are generally
higher with electron-neutral and electron-rich mesylates than
with electron-deficient mesylates in part due to hydrolysis of
the latter under the reaction conditions.
Scheme 8. Mono- and Diarylation of Halotosylates
Scheme 6. Arylation of Nitroazoles Using Mesylates
Br) bond (Scheme 8a).21 When the same reactions were
conducted in the presence of excess azole, diarylated product
1v resulting from the sequential functionalization of the C−X
and the C−OTs bonds is obtained in good yields (Scheme 8b).
Similarly, and as expected, the arylation of azole 2 with m-
chlorobenzyl acetate leads to 2w via preferential cleavage of the
more reactive C−Cl bond (Scheme 9a). However, use of excess
azole results in product 2x via sequential arylation and
benzylation reactions (Scheme 9b). These results demonstrate
the distinct reactivity of halides versus tosylates and benzyl
acetates and support the potential for engaging these
a
b
Conducted at 80 °C. Reaction set up outside the glovebox under
c
inert atmosphere. NMR yield against 1,4-dinitrobenzene as the
standard.
Scheme 9. Sequential Arylation and Benzylations
By employing benzyl acetates instead of aryl sulfonates,
pyrazoles and imidazoles can be benzylated in good yields
under otherwise similar reaction conditions (Scheme 7).19,20
Substituted benzyl acetates bearing electron-donating and
electron-withdrawing groups are compatible with these trans-
formations (2s and 2t). As observed for arylations described
above, good yields of benzylated products are obtained using X-
Phos as the ligand. Notably, previous reports on benzylation of
nitroazoles were limited to the use of benzyl chlorides; the use
of benzyl acetate with the Pd(OAc)2/PPh3 catalyst combina-
tion was reported to give 0% yield of the desired product for
the benzylation of N-benzylnitropyrazole.9
We next explored these nitroazole arylations using electro-
philes containing two different leaving groups (Scheme 8). For
example the reaction of (1) with m-haloaryl tosylate affords
product 1u via selective functionalization of the C−X (X = Cl,
C
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Note
Data were acquired on either a VG 70-VSE (EI+) or TOF (ES+)
instrument.
electrophiles selectively at different stages in a multistep
synthetic sequence. Furthermore, the result of the reaction in
Scheme 9a is orthogonal to that reported previously using meta-
chloro benzyl choride.9 As shown in Scheme 9c, the benzylated
product (2y) is obtained preferentially for the arylation of azole
2 using meta-chloro benzyl chloride.
Cesium pivalate, 2-naphthol, and 3-pyridyl phenol were obtained
from Aldrich and used as received. Pd(OAc)2 and XPhos were
obtained from Strem chemical and used as received. Cesium carbonate
was obtained from Acros and used as received. K2CO3 was obtained
from JT Baker and used as received. The azoles,4 tosylates,12a
mesylates,12c and benzyl acetates were prepared using literature
procedures. Anhydrous p-xylene was obtained from Aldrich and used
as received. Toluene was purified using a Glass Contour solvent
purification system column composed of neutral alumina and a copper
catalyst. Other solvents were obtained from Fisher Chemical or VWR
Chemical and used without further purification. Flash chromatography
was performed on EM Science silica gel 60 (0.040−0.063 mm particle
size, 230−400 mesh), and thin layer chromatography was performed
Having explored the arylations and benzylations of
heteroaromatic nitroarenes with C−O electrophiles, we briefly
examined the use of significantly less acidic nitrobenzene as a
substrate for arylations using tosylates. K3PO4 is a more
effective base (63% yield of 8a) than Cs2CO3 (40% yield of 8a)
for arylation of nitrobenzene. Furthermore, CsOPiv is a
necessary additive for these arylations to afford the products
in significant yields. As shown in Scheme 10, electron-neutral
(8a) and electron-rich aryl tosylates (8d, 8p, 8f and 8e) can be
used to afford the ortho-arylated products. The site-selectivity
for the arylation of the ortho C−H bond clearly implicates the
directing effect of the nitro group (either as a directing ligand
and/or enhancing the acidity of the ortho C−H bond) and is
consistent with previous reports using aryl halides.2,5 Unlike the
azole reactions, an excess of the substrate (10 equiv of
nitrobenzene) and a higher temperature is required for these
arylations.2,5
on Analtech TLC plates precoated with silica gel 60 F254
.
General Procedures for Arylations. General Procedure A for
Azole Arylations Using Solid Electrophile. Substrate, electrophile
(tosylate or mesylate), and Pd(OAc)2 were weighed into a 20 mL
scintillation vial. The vial was taken into the glovebox, and XPhos, base
(Cs2CO3 or K2CO3), CsOPiv, and solvent (toluene or xylene) were
added. The vial was sealed with a Teflon lined cap and taken out of the
glovebox, and the reaction mixture was allowed to stir at the indicated
temperature for the indicated time. The reaction mixture was cooled to
room temperature and filtered through a 1.5 in. plug of silica gel,
eluting with EtOAc (100 mL). The filtrate was concentrated and
chromatographed on a silica gel column to afford the product.
General Procedure B for Azole Arylations Using a Liquid
Electrophile. Substrate and Pd(OAc)2 were weighed into a 20 mL
scintillation vial. The vial was taken into the glovebox, and XPhos, base
(Cs2CO3 or K2CO3), CsOPiv, and a solution of the electrophile in the
specified solvent (toluene or xylene) were added. The vial was sealed
with a Teflon lined cap and taken out of the glovebox, and the reaction
mixture was allowed to stir at the indicated temperature for the
indicated time. The reaction mixture was cooled to room temperature
and filtered through a 1.5 in. plug of silica gel, eluting with EtOAc (100
mL). The filtrate was concentrated and chromatographed on a silica
gel column to afford the product.
Scheme 10. Arylation of Nitrobenzene Using Tosylates
General Procedure C for Sequential Tosylation/Arylation. A
phenol derivative and tosyl chloride were weighed into a scintillation
vial. The vial was taken into the glovebox, and Cs2CO3 and toluene
were added to it. The vial was sealed with a Teflon lined cap, taken out
of the glovebox, and stirred at 120 °C for 3 h. The reaction vial was
cooled to rt and was taken into the glovebox. The tosylate solution was
added to a vial containing azole, Pd(OAc)2, XPhos, Cs2CO3, and
CsOPiv. The vial was sealed with a Teflon lined cap and taken out of
the glovebox, and the reaction mixture was allowed to stir at the
indicated temperature for the indicated time. The reaction mixture was
cooled to room temperature and filtered through a 1.5 in. plug of silica
gel, eluting with EtOAc (100 mL). The filtrate was concentrated and
chromatographed on a silica gel column to afford the product.
General Procedure D for Azole Benzylations. Substrate and
Pd(OAc)2 were weighed into a 20 mL scintillation vial. The vial was
taken into the glovebox, and XPhos, Cs2CO3, CsOPiv (if added), and a
solution of the acetate in the specified solvent (toluene or xylene) were
added. The vial was sealed with a Teflon lined cap and taken out of the
glovebox, and the reaction mixture was allowed to stir at the indicated
temperature for the indicated time. The reaction mixture was cooled to
room temperature and filtered through a 1.5 in. plug of silica gel,
eluting with EtOAc (100 mL). The filtrate was concentrated and
chromatographed on a silica gel column to afford the product.
General Procedure E for Nitrobenzene Arylations. Pd(OAc)2 and
tosylate was weighed into a 20 mL scintillation vial. The vial was taken
into the glovebox and XPhos, K3PO4, and CsOPiv were added. Xylene
and nitrobenzene were added sequentially, the vial was sealed with a
Teflon lined cap and taken out of the glovebox, and the reaction
mixture was allowed to stir at the indicated temperature for the
indicated time. The reaction mixture was cooled to room temperature
and filtered through a 1.5 in. plug of silica gel, eluting with EtOAc (100
In summary, this manuscript describes the first report for the
arylation and benzylation of nitroazoles using aryl sulfonates
(tosylates and mesylates) and benzyl acetates, respectively. The
products are obtained in good to excellent yields with
electronically varied C−O electrophiles. The selective function-
alization of halides in the presence of tosylates or benzyl
acetates make these arylations amenable to sequential arylations
and benzylations in the context of multistep synthesis. The
arylations using the more challenging nitrobenzene substrate
also afford the desired biaryls albeit in lower yields than the
corresponding azoles.
EXPERIMENTAL METHODS
■
Materials and Methods. NMR spectra were obtained on a Bruker
1
1
400 (399.96 MHz for H; 100.57 MHz for 13C) spectrometer. H
NMR chemical shifts are reported in parts per million (ppm) relative
to TMS, with the residual solvent peak used as an internal reference.
Multiplicities are reported as follows: singlet (s), doublet (d), doublet
of doublets (dd), triplet of doublets (td), triplet (t), doublet of triplets
(dt), triplet of triplets (tt), multiplet (m), and broad resonance (br).
IR spectra were obtained on a Thermo scientific Nicolet iS5 iD5 ATR
spectrometer. Melting points were obtained on a Thomas-Hoover
melting point apparatus. HRMS data were obtained from the
University of Illinois Urbana−Champaign Mass Spectrometry Lab.
D
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Note
mL). The filtrate was concentrated and chromatographed on a silica
gel column to afford the product.
ethyl acetate) yielded product 1b as a yellow oil (77.4 mg, 60% yield).
1H NMR (CDCl3): δ 8.20 (s, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.25 (d, J
= 8.3 Hz, 2H), 3.95 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.78−1.71 (m,
2H), 1.25−1.16 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 13C NMR (DMSO-
d6): δ 141.3, 139.8, 136.1, 132.3, 129.7, 129.3, 123.6, 49.4, 30.9, 21.0,
18.9, 13.2. The spectroscopic data are consistent with those previously
reported in the literature.4b
General Procedure F for Azole Arylations Using Solid Electro-
phile. Substrate, electrophile (tosylate or mesylate), Pd(OAc)2, XPhos,
base (Cs2CO3 or K2CO3), and CsOPiv were weighed into a 20 mL
scintillation vial. The vial was sealed with a Teflon lined cap having a
septum. The headspace of the vial was purged with nitrogen.
Anhydrous toluene was added, and the reaction mixture was allowed
to stir at the indicated temperature for the indicated time. The reaction
mixture was cooled to room temperature and filtered through a 1.5 in.
plug of silica gel, eluting with EtOAc (100 mL). The filtrate was
concentrated and chromatographed on a silica gel column to afford the
product.
General Procedure G for Azole Benzylations. Substrate, Pd(OAc)2,
XPhos, and Cs2CO3 were weighed into a 20 mL scintillation vial. The
vial was sealed with a Teflon lined cap having a septum. The headspace
of the vial was purged with nitrogen. A toluene solution of the acetate
was added, and the reaction mixture was allowed to stir at the
indicated temperature for the indicated time. The reaction mixture was
cooled to room temperature and filtered through a 1.5 in. plug of silica
gel, eluting with EtOAc (100 mL). The filtrate was concentrated and
chromatographed on a silica gel column to afford the product.
Synthesis and Characterization of Substrates. 1-Methyl-1H-
indol-5-yl 4-methylbenzene-1-sulfonate22 1H NMR (CDCl3). δ 7.70
(d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 2.3 Hz, 1H),
7.17 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 3.1 Hz, 1H), 6.83 (dd, J = 8.8, 2.4
Hz, 1H), 6.41 (dd, J = 3.1, 0.9 Hz, 1H), 3.77 (s, 3H), 2.44 (s, 3H). 13C
NMR (CDCl3): δ 144.9, 143.2, 135.0, 132.6, 130.4, 129.5, 128.5,
128.3, 116.1, 114.0, 109.5, 101.3, 32.9, 29.6. IR (neat): 2924, 1486,
1337, 1237, 1215, 1189, 1086, 839, 816, 771, 756, 741, 734, 708, 698,
657 cm−1. Mp = 135−137 °C. HRMS: [EI+, M+] calcd for
C16H15NO3S, 301.0773; found, 301.0766.
Product Synthesis and Characterization (Scheme 2). 1-Butyl-
5-(naphthalen-2-yl)-4-nitro-1H-pyrazole (1a). Following general
procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), 2-naphthyl tosylate
(149 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol,
0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244
mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv),
and anhydrous toluene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 80 °C for
16 h. Chromatography on a silica gel column using 95/5 hexanes/
EtOAc (Rf = 0.18 in 95% hexanes/5% ethyl acetate) yielded product
1a as a yellow oil (122.8 mg, 83% yield). 1H NMR (CDCl3): δ 8.26 (s,
1H), 8.00 (d, J = 8.5 Hz, 1H), 7.95−7.90 (m, 2H), 7.87 (s, 1H), 7.64−
7.57 (m, 2H), 7.43 (dd, J = 8.5, 1.7 Hz, 1H), 4.00 (t, J = 7.3 Hz, 2H),
1.80−1.73 (m, 2H), 1.25−1.15 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H). 13C
NMR (CDCl3): δ 141.4, 136.4, 133.7, 133.1, 132.8, 129.7, 128.7,
128.4, 128.0, 127.6, 127.0, 126.3, 124.1, 50.1, 31.8, 19.5, 13.4. IR
(neat): 2959, 2932, 1555, 1505, 1471, 1400, 1320, 828 cm−1. HRMS:
[TOF, ES+, M+H] calcd for C17H17N3O2, 296.1399; found, 296.1402.
Procedure without the Glovebox. Following general procedure F,
1 (84.6 mg, 0.500 mmol, 1.0 equiv), 2-naphthyl tosylate (149 mg,
0.500 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv),
XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750
mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 80 °C for 16 h.
Chromatography on a silica gel column using 95/5 hexanes/EtOAc
(Rf = 0.18 in 95% hexanes/5% ethyl acetate) yielded product 1a as a
yellow oil (131 mg, 89% yield). The spectroscopic data of the product
were identical to those described above.
1-Butyl-5-(3-methoxyphenyl)-4-nitro-1H-pyrazole (1c). Following
general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), meta-
methoxyphenyl tosylate (153 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 93/7 hexanes/EtOAc (Rf = 0.19 in 93% hexanes/7%
1
EtOAc) yielded product 1c as a yellow oil (83.0 mg, 60% yield). H
NMR (CDCl3): δ 8.18 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.08−7.05
(m, 1H), 6.92 (dt, J = 7.6, 1.4 Hz, 1H), 6.88−6.87 (m, 1H), 3.94 (t, J =
7.2 Hz, 2H), 3.83 (s, 3H), 1.78−1.71 (m, 2H), 1.25−1.16 (m, 2H),
0.82 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3): δ 159.6, 141.1, 136.3,
132.8, 129.9, 127.8, 121.7, 115.7, 115.2, 55.4, 50.0, 31.7, 19.5, 13.4. IR
(neat): 1582, 1556, 1497, 1465, 1434, 1358, 1318, 1286, 1252, 1216,
1177, 1156, 1047, 1031, 855, 815, 786, 770, 743, 692 cm−1. HRMS:
[TOF, ES+, M+H] calcd for C14H17N3O3, 276.1348 found, 276.1347.
1-Butyl-5-(7-methoxynaphthalen-2-yl)-4-nitro-1H-pyrazole (1d).
Following general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), 7-
methoxynaphthyl tosylate (164 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 80 °C for 16 h. Chromatography on a silica gel
column using 85/15 hexanes/EtOAc (Rf = 0.21 in 85% hexanes/15%
EtOAc) yielded product 1d as a yellow solid (153 mg, 94% yield), mp
= 84.7 °C. 1H NMR (CDCl3): δ 8.25 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H),
7.83 (d, J = 9.0 Hz, 1H), 7.76 (s, 1H), 7.28−7.25 (m, 2H), 7.17 (d, J =
2.4 Hz, 1H), 4.00 (t, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.80−1.73 (m,
2H), 1.25−1.15 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(CDCl3): δ 158.4, 141.6, 136.4, 134.1, 133.0, 129.4, 129.2, 128.43,
128.39, 124.5, 123.9, 120.6, 106.1, 55.4, 50.1, 31.8, 19.5, 13.4. IR
(neat): 3138, 2976, 2958, 2926, 1607, 1509, 1496, 1466, 1437, 1397,
1367, 1335, 1244, 1229, 1216, 1176, 1028, 901, 850, 836, 828 cm−1.
HRMS: [TOF, ES+, M+H] calcd for C18H19N3O3, 326.1505; found,
326.1505.
5-(2H-1,3-Benzodioxol-5-yl)-1-butyl-4-nitro-1H-pyrazole (1e).
Following general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv),
sesamol tosylate (161 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2
mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous xylene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 80 °C for 16 h. Chromatography on a silica gel
column using 90/10 hexanes/EtOAc (Rf = 0.16 in 90% hexanes/10%
ethyl acetate) yielded product 1e as an off white solid (105 mg, 73%
yield), mp = 63.4 °C. 1H NMR (CDCl3): δ 8.18 (s, 1H), 6.95 (d, J =
8.5 Hz, 1H), 6.82 (dd, J = 6.4, 1.8 Hz, 2H), 6.08 (s, 2H), 3.96 (t, J =
7.3 Hz, 2H), 1.79−1.71 (m, 2H), 1.27−1.17 (m, 2H), 0.85 (t, J = 7.4
Hz, 3H). 13C NMR (CDCl3): δ 149.2, 148.0, 140.9, 136.2, 132.8,
123.7, 119.6, 109.9, 108.6, 101.7, 49.9, 31.7, 19.5, 13.4. IR (thin film,
CH2Cl2): 2963, 2932, 1508, 1497, 1484, 1465, 1397, 1343, 1318, 1243,
1221, 1034, 976, 864, 826, 810, 763 cm−1. HRMS: [TOF, ES+, M+H]
calcd for C14H15N3O4, 290.1141; found, 290.1142.
1-Butyl-5-(4-methylphenyl)-4-nitro-1H-pyrazole (1b). Following
general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), para-
methylphenyl tosylate (138 mg, 0.525 mmol, 1.05 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 93/7 hexanes/EtOAc (Rf = 0.23 in 93% hexanes/7%
1-Butyl-4-nitro-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole (1f). Fol-
lowing general procedure A, 1 (93.1 mg, 0.550 mmol, 1.1 equiv), 3,4,5-
trimethoxyphenyl tosylate (169 mg, 0.500 mmol, 1.0 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg,
0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv),
CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous xylene (1.0
mL) were combined in a 20 mL scintillation vial. The reaction mixture
E
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The Journal of Organic Chemistry
Note
was allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 80/15/5 hexanes/CH2Cl2/acetone (Rf = 0.13 in 80%
hexanes/15% CH2Cl2/5% acetone) yielded product 1f as a yellow oil
(121 mg, 72% yield). 1H NMR (CDCl3): δ 8.20 (s, 1H), 6.55 (s, 2H),
3.97 (t, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.87 (s, 6H), 1.82−1.74 (m,
2H), 1.29−1.20 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3):
δ 153.5, 141.2, 139.44, 139.42, 136.3, 132.7, 121.7, 106.89, 106.86,
60.9, 56.3, 50.1, 31.9, 19.6, 13.5. IR (thin film, CH2Cl2): 2959, 2936,
1584, 1557, 1505, 1463, 1400, 1341, 1302, 1239, 1124, 1002, 840
cm−1. HRMS: [TOF, ES+, M+H] calcd for C16H21N3O5, 336.1559;
found, 336.1558.
= 7.8 Hz, 1H), 7.26−7.19 (m, 3H), 7.02 (s, 1H), 6.94 (d, J = 7.8 Hz,
1H), 6.79 (d, J = 6.6 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 3.14 (t, J = 6.5
Hz, 2H). 13C{1H} NMR (CDCl3): δ 140.5, 136.8, 136.7, 133.0, 132.9,
131.1 (J = 33 Hz), 129.1, 128.9, 128.6, 127.2, 127.1, 126.9 (J = 3.6
Hz), 126.4 (J = 3.8 Hz), 123.4 (J = 271 Hz), 51.6, 35.8. The
spectroscopic data are consistent with those previously reported in the
literature.4b
1-(4-Methylphenyl)-5-(naphthalen-2-yl)-4-nitro-1H-pyrazole
(4a). Following general procedure A, 1-(4-methylphenyl)-4-nitro-1H-
pyrazole (4) (50.8 mg, 0.250 mmol, 1.0 equiv), 2-naphthyl tosylate
(74.6 mg, 0.250 mmol, 1.0 equiv), Pd(OAc)2 (5.6 mg, 0.025 mmol,
0.10 equiv), XPhos (35.8 mg, 0.075 mmol, 0.30 equiv), Cs2CO3 (122
mg, 0.375 mmol, 1.5 equiv), CsOPiv (64.4 mg, 0.275 mmol, 1.1
equiv), and anhydrous toluene (0.5 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 80 °C for
16 h. The reaction was filtered through a 1-in. pad of silica gel eluting
with EtOAc (100 mL). The filtrate was concentrated. 1H NMR
spectroscopic analysis of the crude product against 1,4-dinitrobenzene
as the standard showed >99% yield of 4a.
1-Butyl-5-(2-methylphenyl)-4-nitro-1H-pyrazole (1g). Following
general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), ortho-tolyl
tosylate (144 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2 (16.8 mg, 0.075
mmol, 0.15 equiv), XPhos (107 mg, 0.225 mmol, 0.45 equiv), Cs2CO3
(244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1
equiv), and anhydrous toluene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 120 °C for
16 h. Chromatography on a silica gel column using 95/5 hexanes/
EtOAc (Rf = 0.18 in 95% hexanes/5% EtOAc) yielded product 1g as a
1-Butyl-3,5-bis(naphthalen-2-yl)-4-nitro-1H-pyrazole (1aa). Fol-
lowing general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), 2-
naphthyl tosylate (298 mg, 1.00 mmol, 2.0 equiv), Pd(OAc)2 (22.5
mg, 0.10 mmol, 0.20 equiv), XPhos (143 mg, 0.30 mmol, 0.60 equiv),
Cs2CO3 (489 mg, 1.50 mmol, 3.0 equiv), CsOPiv (129 mg, 0.550
mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) were combined in
a 20 mL scintillation vial. The reaction mixture was allowed to stir at
120 °C for 16 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.15 in 95% hexanes/5% ethyl acetate) yielded
product 1aa as a light yellow solid (159 mg, 76% yield). Mp = 137−
1
yellow oil (54.7 mg, 42% yield). H NMR (CDCl3): δ 8.23 (s, 1H),
7.45 (td, J = 7.6, 1.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5
Hz, 1H), 7.17 (dd, J = 7.7, 1.4 Hz, 1H), 3.93−3.75 (m, 2H), 2.12 (s,
3H), 1.76−1.68 (m, 2H), 1.25−1.16 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3): δ 140.9, 137.7, 136.2, 133.3, 130.5, 130.4, 129.3,
126.5, 126.1, 49.8, 31.5, 19.5, 19.4, 13.4. IR (neat): 2958, 2873, 1557,
1504, 1486, 1458, 1400, 1322, 828, 762, 730 cm−1. HRMS: [EI+, M+]
calcd for C14H17N3O2, 259.1321; found, 259.1316.
5-(4-Methoxyphenyl)-1-methyl-4-nitro-1H-pyrazole (2h). Follow-
ing general procedure A, 1-methyl-4-nitro-1H-pyrazole (2) (63.6 mg,
0.500 mmol, 1.0 equiv), para-methoxyphenyl tosylate (146 mg, 0.525
mmol, 1.05 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv),
XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750
mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 16 h.
Chromatography on a silica gel column using 85/10/5 hexanes/
CH2Cl2/acetone (Rf = 0.28 in 85% hexanes/10% methylene chloride/
5% acetone) yielded product 2h as a light yellow solid (89.4 mg, 77%
1
140 °C. H NMR (CDCl3): δ 8.24 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H),
7.97−7.88 (m, 6H), 7.81 (dd, J = 8.6, 1.7 Hz, 1H), 7.66−7.59 (m,
2H), 7.56−7.50 (m, 3H), 4.06 (t, J = 7.4 Hz, 2H), 1.89−1.81 (m, 2H),
1.29−1.24 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3): δ
147.3, 142.9, 133.6, 133.5, 133.0, 132.8, 130.7, 129.6, 128.7, 128.6,
128.5, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 126.9, 126.6, 126.5,
126.3, 126.2, 124.6, 50.2, 31.9, 19.6, 13.5. IR (neat): 2927, 1553, 1498,
1456, 1418, 1356, 926, 776, 766 cm−1. HRMS: [EI+, M+] calcd for
C27H23N3O2, 421.1790; found, 421.1789.
Product Synthesis and Characterization (Scheme 3). 3-(1-
Butyl-4-nitro-1H-pyrazol-5-yl)pyridine (1j). Following general proce-
dure A, 1 (120 mg, 0.710 mmol, 1.0 equiv), 3-pyridyl tosylate (187
mg, 0.750 mmol, 1.05 equiv), Pd(OAc)2 (15.9 mg, 0.071 mmol, 0.10
equiv), XPhos (101 mg, 0.213 mmol, 0.30 equiv), Cs2CO3 (347 mg,
1.065 mmol, 1.5 equiv), CsOPiv (183 mg, 0.781 mmol, 1.1 equiv), and
anhydrous xylene (1.42 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 24 h.
Chromatography on a silica gel column using 60/40 hexanes/EtOAc
(Rf = 0.27 in 60% hexanes/40% EtOAc) yielded product 1j as a yellow
1
yield). H NMR (CDCl3): δ 8.19 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H),
7.05 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H), 3.75 (s, 3H). The spectroscopic
data are consistent with those previously reported in the literature.4b
5-(3-Methoxyphenyl)-1-methyl-4-nitro-1H-pyrazole (2c). Follow-
ing general procedure A, 2 (63.6 mg, 0.500 mmol, 1.0 equiv), meta-
methoxyphenyl tosylate (153.1 mg, 0.55 mmol, 1.1 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 80 °C for 16 h. Chromatography on a silica gel
column using 80% hexanes/20% EtOAc (Rf = 0.20 in 80% hexanes/
20% EtOAc) yielded product 2c as a yellow solid (104 mg, 89% yield).
1H NMR (CDCl3): δ 8.19 (s, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.08 (dd, J
= 8.4, 2.6 Hz, 1H), 6.95 (dt, J = 7.6, 1.2 Hz, 1H), 6.90 (t, J = 2.1 Hz,
1H), 3.85 (s, 3H), 3.74 (s, 3H). 13C{1H} NMR (CDCl3): δ 159.6,
141.2, 136.2, 132.9, 129.9, 127.6, 121.7, 115.8, 115.2, 55.4, 37.9. The
spectroscopic data are consistent with those previously reported in the
literature.4b
4-Nitro-1-(2-phenylethyl)-5-[3-(trifluoromethyl)phenyl]-1H-pyra-
zole (3i). Following general procedure A, 4-nitro-1-(2-phenylethyl)-
1H-pyrazole (3) (109 mg, 0.500 mmol, 1.0 equiv), meta-trifluoro-
methylphenyl tosylate (174 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 85/15 hexanes/EtOAc (Rf = 0.21 in 85% hexanes/15%
EtOAc) yielded product 3i as a light yellow solid (115 mg, 64% yield).
1H NMR (CDCl3): δ 8.30 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.48 (t, J
1
oil (119 mg, 68% yield). H NMR (CDCl3): δ 8.80 (d, J = 4.9 Hz,
1H), 8.64 (s, 1H), 8.24 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.52−7.49
(m, 1H), 3.97 (t, J = 7.3 Hz, 2H), 1.81−1.73 (m, 2H), 1.26−1.17 (m,
2H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3): δ 151.3, 149.8,
137.9, 137.6, 136.5, 133.5, 123.5, 123.3, 50.3, 31.8, 19.5, 13.4. IR
(neat): 1502, 1477, 1460, 1398, 1322, 830, 761, 711 cm−1. HRMS:
[TOF, ES+, M+H] calcd for C12H14N4O2, 247.1195; found, 247.1195.
6-(1-Butyl-4-nitro-1H-pyrazol-5-yl)quinoline (1k). Following gen-
eral procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), 6-quinolyl
tosylate (157 mg, 0.525 mmol, 1.05 equiv), Pd(OAc)2 (11.2 mg, 0.05
mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3
(244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1
equiv), and anhydrous xylene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 80 °C for
24 h. Chromatography on a silica gel column using 50/50 hexanes/
EtOAc (Rf = 0.27 in 50% hexanes/50% EtOAc) yielded product 1k as
a yellow solid (93 mg, 63% yield). Mp = 80−83 °C. 1H NMR
(CDCl3): δ 9.06 (dd, J = 4.3, 1.7 Hz, 1H), 8.29−8.23 (m, 3H), 7.89
(d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.7, 2.0 Hz, 1H), 7.53 (dd, J = 8.3,
4.2 Hz, 1H), 4.00 (t, J = 7.2 Hz, 2H), 1.81−1.73 (m, 2H), 1.25−1.16
(m, 2H), 0.81 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3): δ 152.0, 148.3,
140.5, 136.4, 133.2, 130.4, 129.9, 129.8, 127.8, 124.9, 122.1, 50.2, 31.7,
F
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Note
19.5, 13.4 two carbon peaks are overlapping. IR (neat): 1556, 1502,
1470, 1401, 1374, 1329, 1310, 915, 861, 843, 825, 813, 776, 769, 759,
598 cm−1. HRMS: [TOF, ES+, M+H] calcd for C16H16N4O2,
297.1352; found, 297.1357.
column using 42/55/3 hexanes/EtOAc/acetone (Rf = 0.30 in 42%
hexanes/55% EtOAc/3% acetone) yielded product 6a as a yellow solid
1
(165 mg, 93% yield). Mp = 128−131 °C. H NMR (CDCl3): δ 7.89
(t, J = 8.2 Hz, 2H), 7.77 (s, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.58−7.50
(m, 2H), 7.37 (dd, J = 8.9, 1.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 2H), 6.78
(d, J = 7.9 Hz, 2H), 4.97 (s, 2H), 2.41 (s, 3H), 2.33 (s, 3H). 13C NMR
(CDCl3): 144.3, 143.3, 137.9, 133.4, 133.0, 132.5, 131.6, 129.9, 129.6,
128.4, 128.2, 127.7, 127.3, 126.8, 126.6, 125.7, 124.4, 47.8, 20.9, 13.7.
δ. IR (neat): 1569, 1534, 1506, 1433, 1400, 1384, 1356, 1329, 1310,
1287, 1274, 1236, 1227, 1197, 1184, 1144, 1123, 1110, 1036, 1019,
938, 923, 870, 840, 830, 813, 801, 772, 765, 750, 716, 694, 663, 630,
613, 577, 567, 555 cm−1. HRMS: [TOF, ES+, M+H] calcd for
C22H19N3O2, 358.1556; found, 358.1553.
2-(1-Butyl-4-nitro-1H-pyrazol-5-yl)quinoxaline (1l). Following
general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv),
quinoxalin-2-yl 4-methylbenzene-1-sulfonate (157 mg, 0.525 mmol,
1.05 equiv), Pd(OAc)2 (16.8 mg, 0.075 mmol, 0.15 equiv), XPhos
(107 mg, 0.225 mmol, 0.45 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5
equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous
xylene (1.0 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 80 °C for 24 h.
Chromatography on a silica gel column using 85/15 hexanes/EtOAc
(Rf = 0.20 in 85% hexanes/15% EtOAc) yielded product 1l as a yellow
solid (92 mg, 62% yield). Mp = 43−46 °C. 1H NMR (CDCl3): δ 9.09
(s, 1H), 8.28 (s, 1H), 8.24 (dd, J = 8.0, 1.8 Hz, 1H), 8.17 (dd, J = 7.9,
1.9 Hz, 1H), 7.95−7.87 (m, 2H), 4.24 (t, J = 7.4 Hz, 2H), 1.88−1.80
(m, 2H), 1.30−1.21 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3): δ 146.2, 142.1, 141.9, 141.6, 136.5, 136.1, 133.8, 131.7,
130.9, 129.55, 129.54, 51.1, 31.9, 19.5, 13.4. IR (neat): 1537, 1508,
1492, 1478, 1461, 1452, 1402, 1388, 1368, 1335, 1315, 1271, 1225,
1197, 1131, 1049, 980, 964, 954, 923, 850, 825, 799, 757, 747, 731,
623, 589 cm−1. HRMS: [TOF, ES+, M+H] calcd for C15H15N5O2,
298.1304; found, 298.1295.
5-(1-Butyl-4-nitro-1H-pyrazol-5-yl)-1-methyl-1H-indole (1m). Fol-
lowing general procedure A, 1 (42.3 mg, 0.25 mmol, 1.0 equiv), 1-
methyl-1H-indol-5-yl 4-methylbenzene-1-sulfonate (83.3 mg, 0.275
mmol, 1.1 equiv), Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.10 equiv), XPhos
(35.6 mg, 0.075 mmol, 0.30 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5
equiv), CsOPiv (64.4 mg, 0.275 mmol, 1.1 equiv), and anhydrous
toluene (0.5 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 120 °C for 16 h.
Chromatography on a silica gel column using 80/20 hexanes/EtOAc
(Rf = 0.23 in 80% hexanes/20% EtOAc) yielded product 1m as a
viscous yellow oil (63.7 mg, 85% yield). 1H NMR (CDCl3): δ 8.23 (s,
1H), 7.62 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.4, 1.7 Hz,
1H), 7.16 (d, J = 3.3 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 3.98 (t, J = 7.3
Hz, 2H), 3.86 (s, 3H), 1.79−1.72 (m, 2H), 1.24−1.15 (m, 2H), 0.81
(t, J = 7.3 Hz, 3H). 13C NMR (CDCl3): δ 142.9, 137.1, 136.4, 132.8,
130.2, 128.3, 122.7, 122.5, 117.2, 109.7, 101.7, 49.9, 33.0, 31.8, 19.6,
13.5. IR (neat): 2958, 1734, 1555, 1502, 1459, 1398, 1372, 1337, 1318,
1285, 1242, 1177, 1045, 828, 803, 761, 724 cm−1. HRMS: [EI+, M+]
calcd for C16H18N4O2, 298.1429; found, 298.1424.
Procedure without the Glovebox. Following general procedure F,
6 (116 mg, 0.500 mmol, 1.0 equiv), 2-naphthyl tosylate (167 mg,
0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv),
XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690
mmol, 1.4 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.30 in 42% hexanes/55% EtOAc/3% acetone)
yielded product 6a as a yellow solid (164 mg, 92% yield).
5-(3-Methoxyphenyl)-2-methyl-1-[(4-methylphenyl)methyl]-4-
nitro-1H-imidazole (6c). Following general procedure A, 6 (116 mg,
0.500 mmol, 1.0 equiv), meta-methoxyphenyl tosylate (150 mg, 0.540
mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv), XPhos
(71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690 mmol, 1.4
equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous
toluene (1.0 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.13 in 42% hexanes/55% EtOAc/3% acetone)
1
yielded product 6c as a light yellow solid (130 mg, 77% yield). H
NMR (CDCl3): δ 7.34 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H),
7.01−6.98 (m, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.79−6.77 (m, 3H), 4.92
(s, 2H), 3.69 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H). 13C NMR (CDCl3):
159.4, 144.1, 143.0, 137.9, 132.8, 131.7, 129.7, 129.6, 128.2, 125.6,
122.1, 115.8, 115.2, 55.0, 47.8, 20.9, 13.6.4c
5-(4-Methoxyphenyl)-2-methyl-1-[(4-methylphenyl)methyl]-4-
nitro-1H-imidazole (6h). Following general procedure A, 6 (116 mg,
0.500 mmol, 1.0 equiv), para-methoxyphenyl tosylate (209 mg, 0.750
mmol, 1.5 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv), XPhos
(71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690 mmol, 1.4
equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous
toluene (1.0 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.28 in 42% hexanes/55% EtOAc/3% acetone)
3-{1-[(4-Methylphenyl)methyl]-4-nitro-1H-pyrazol-5-yl}pyridine
(5j). Following general procedure A, 1-[(4-methylphenyl)methyl]-4-
nitro-1H-pyrazole (5) (109 mg, 0.500 mmol, 1.0 equiv), 3-pyridyl
tosylate (131 mg, 0.525 mmol, 1.05 equiv), Pd(OAc)2 (11.2 mg, 0.05
mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3
(244 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1
equiv), and anhydrous xylene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 120 °C for
24 h. Chromatography on a silica gel column using 60/40 hexanes/
EtOAc (Rf = 0.18 in 60% hexanes/40% EtOAc) yielded product 5j as a
1
yielded product 6h as a yellow solid (153 mg, 91% yield). H NMR
(CDCl3): δ 7.22 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.94 (d,
J = 8.8 Hz, 2H), 6.78 (d, J = 7.9 Hz, 2H), 4.92 (s, 2H), 3.83 (s, 3H),
2.35 (s, 3H), 2.33 (s, 3H). 13C NMR (CDCl3): 160.7, 144.0, 143.1,
137.9, 133.1, 131.7, 131.5, 129.7, 125.6, 118.8, 114.1, 55.2, 47.7, 21.0,
13.7.4c
1
yellow solid (117 mg, 80% yield). H NMR (CDCl3): δ 8.77 (d, J =
5.0 Hz, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.61 (dt, J = 7.9, 2.0 Hz, 1H),
7.43 (dd, J = 7.8, 4.9 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 8.0
Hz, 2H), 5.15 (s, 2H), 2.31 (s, 3H). 13C NMR (CDCl3): δ 151.3,
149.9, 138.5, 138.2, 137.6, 136.6, 133.9, 131.7, 129.6, 127.3, 123.3,
123.2, 54.4, 21.1. The spectroscopic data are consistent with those
previously reported in the literature.4b
Product Synthesis and Characterization (Scheme 4). 2-
Methyl-1-[(4-methylphenyl)methyl]-5-(naphthalen-2-yl)-4-nitro-
1H-imidazole (6a). Following general procedure A, 2-methyl-1-[(4-
methylphenyl)methyl]-4-nitro-1H-imidazole (6) (116 mg, 0.500
mmol, 1.0 equiv), 2-naphthyl tosylate (167 mg, 0.550 mmol, 1.1
equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv), XPhos (71.5 mg,
0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690 mmol, 1.4 equiv),
CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0
mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 120 °C for 14 h. Chromatography on a silica gel
2-Methyl-1-[(4-methylphenyl)methyl]-4-nitro-5-[3-(trifluoro-
methyl)phenyl]-1H-imidazole (6i). Following general procedure A, 6
(116 mg, 0.500 mmol, 1.0 equiv), meta-trifluoromethylphenyl tosylate
(174 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.005 mmol,
0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224
mg, 0.690 mmol, 1.4 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv),
and anhydrous toluene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 120 °C for
14 h. Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.30 in 42% hexanes/55% EtOAc/3% acetone)
1
yielded product 6i as a light yellow solid (160 mg, 84% yield). H
NMR (CDCl3): δ 7.72 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H),
7.46 (d, J = 6.2 Hz, 1H), 7.46 (s, 1H), 7.12 (d, J = 7.8 Hz, 2H), 6.72
(d, J = 7.8 Hz, 2H), 4.91 (s, 2H), 2.45 (s, 3H), 2.33 (s, 3H). 13C NMR
(CDCl3): 144.7, 143.4, 138.3, 133.4, 131.2, 130.97, 130.96 (J = 33
G
DOI: 10.1021/acs.joc.7b00550
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The Journal of Organic Chemistry
Note
Hz), 129.7, 129.2, 128.1, 127.1 (J = 3.7 Hz), 126.6 (J = 3.6 Hz), 125.6,
123.4 (J = 271 Hz), 48.1, 20.9, 13.6.4c
EtOAc/acetone (Rf = 0.29 in 40% hexanes/55% EtOAc/5% acetone)
yielded product 7i as a cream solid (186 mg, 94% yield). H NMR
1
2-Methyl-1-[(4-methylphenyl)methyl]-4-nitro-5-[4-(trifluoro-
methyl)phenyl]-1H-imidazole (6n). Following general procedure A, 6
(116 mg, 0.500 mmol, 1.0 equiv), para-trifluoromethylphenyl tosylate
(174 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol,
0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224
mg, 0.689 mmol, 1.4 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv),
and anhydrous toluene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 120 °C for
14 h. Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.28 in 42% hexanes/55% EtOAc/3% acetone)
yielded product 6n as a yellow solid (176 mg, 94% yield). Mp = 131−
134 °C. 1H NMR (CDCl3): δ 7.68 (d, J = 7.7 Hz, 2H), 7.40 (d, J = 8.3
Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.74 (d, J = 7.8 Hz, 2H), 4.91 (s,
2H), 2.41 (s, 3H), 2.33 (s, 3H). 13C NMR (CDCl3): δ 144.8, 143.3,
138.2, 131.7 (q, J = 33 Hz), 131.17, 131.16, 130.89, 130.88, 130.6,
129.8, 125.5 (m), 123.5 (q, J = 271 Hz), 47.9, 20.9, 13.6. IR (neat):
1513, 1493, 1402, 1385, 1320, 1294, 1258, 1166, 1108, 1066, 1027,
1007, 859, 809, 781, 752, 723, 698, 673, 619 cm−1. HRMS: [TOF, ES
+, M+H] calcd for C19H16F3N3O2, 376.1273; found, 376.1262.
2-{2-Methyl-1-[(4-methylphenyl)methyl]-4-nitro-1H-imidazol-5-
yl}quinoline (6o). Following general procedure A, 6 (116 mg, 0.500
mmol, 1.0 equiv), 2-quinolyl tosylate (299 mg, 1.00 mmol, 2.0 equiv),
Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150
mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690 mmol, 1.4 equiv), CsOPiv
(129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 14 h. Chromatography on a silica gel
column using 42/55/3 hexanes/EtOAc/acetone (Rf = 0.28 in 42%
hexanes/55% EtOAc/3% acetone) yielded product 6o as a light yellow
(CDCl3): δ 7.77 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.58 (s,
1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26−7.18 (m, 3H), 6.95 (d, J = 7.3 Hz,
2H), 3.71−3.67 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.88−
1.81 (m, 2H). 13C NMR (CDCl3): 143.9, 143.2, 139.1, 133.4, 131.1 (J
= 33 Hz), 130.2, 129.4, 128.5, 128.3, 127.7, 126.6 (J = 4.2 Hz), 126.5
(J = 3.6 Hz), 126.3, 123.4 (J = 271 Hz), 44.0, 32.2, 31.1, 13.2. The
spectroscopic data are consistent with those previously reported in the
literature.4c
Product Synthesis and Characterization (Scheme 5). 1-Butyl-
5-(naphthalen-2-yl)-4-nitro-1H-pyrazole (1a). Following general
procedure C, 2-naphthol (79.3 mg, 0.550 mmol, 1.1 equiv), para-
toluenesulfonyl chloride (107 mg, 0.560 mmol, 1.12 equiv), Cs2CO3
(269 mg, 0.825 mmol, 1.6 equiv), and anhydrous toluene (2.0 mL)
were combined in a 20 mL scintillation vial for step 1. For step 2, the
reaction mixture from step 1 was combined with 1 (84.6 mg, 0.500
mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv), XPhos
(71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.550 mmol, 1.5
equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous
toluene (1.0 mL) in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 80 °C for 24 h. Chromatography on a silica gel
column using 85/15 hexanes/EtOAc (Rf = 0.34 in 85% hexanes/15%
EtOAc) yielded product 1a as a yellow oil (146 mg, 99% yield). The
spectroscopic data are consistent with those of the product isolated
using 2-naphthyl tosylate.
3-(1-Butyl-4-nitro-1H-pyrazol-5-yl)pyridine (1j). Following general
procedure C, 3-hydroxy pyridine (52.3 mg, 0.550 mmol, 1.1 equiv),
para-toluenesulfonyl chloride (107 mg, 0.560 mmol, 1.12 equiv),
Cs2CO3 (269 mg, 0.8250 mmol, 1.6 equiv), and anhydrous toluene
(2.0 mL) were combined in a 20 mL scintillation vial for step 1. For
step 2, the reaction mixture from step 1 was combined with 1 (84.6
mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10
equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg,
0.550 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 120 °C for 24 h. Chromatography on a
silica gel column using 40/60 hexanes/EtOAc (Rf = 0.15 in 40%
hexanes/60% EtOAc) yielded product 1j as a yellow oil (94.1 mg, 76%
yield). The spectroscopic data are consistent with those of the product
isolated using 3-pyridyl tosylate.
2-Methyl-1-[(4-methylphenyl)methyl]-5-(naphthalen-2-yl)-4-
nitro-1H-imidazole (6a). Following general procedure C, 2-naphthol
(79.3 mg, 0.550 mmol, 1.1 equiv), para-toluenesulfonyl chloride (107
mg, 0.560 mmol, 1.12 equiv), Cs2CO3 (269 mg, 0.8250 mmol, 1.6
equiv), and anhydrous toluene (2.0 mL) were combined in a 20 mL
scintillation vial for step 1. For step 2, the reaction mixture from step 1
was combined with 6 (116 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2
(11.2 mg, 0.05 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.550 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL) in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 120 °C for
14 h. Chromatography on a Biotage purification system silica gel
column using 45/55 hexanes/EtOAc (Rf = 0.36 in 45% hexanes/55%
EtOAc) yielded product 6a as a yellow solid (176 mg, 98% yield). The
spectroscopic data are consistent with those of the product isolated
using 2-naphthyl tosylate.
1
solid (174 mg, 97% yield). Mp = 137−139 °C. H NMR (CDCl3): δ
8.21 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.3 Hz,
1H), 7.77 (t, J = 7.3 Hz, 1H), 7.65−7.61 (m, 2H), 7.00 (d, J = 7.8 Hz,
2H), 6.78 (d, J = 7.7 Hz, 2H), 5.30 (s, 2H), 2.46 (s, 3H), 2.27 (s, 3H).
13C NMR (CDCl3): δ 147.4, 147.3, 145.1, 143.6, 137.7, 136.3, 131.5,
130.8, 130.0, 129.29, 129.26, 127.7, 127.6, 127.3, 126.3, 123.9, 48.2,
20.8, 13.7. IR (neat): 2921, 1495, 1402, 1389, 1334, 1304, 1292, 868,
842, 831, 815, 808, 792, 773, 768, 757 cm−1. HRMS: [EI+, M+] calcd
for C21H18N4O2, 358.1429; found, 358.1422.
5-(3-Methoxyphenyl)-2-methyl-4-nitro-1-(3-phenylpropyl)-1H-
imidazole (7c). Following general procedure A, 2-methyl-4-nitro-1-(3-
phenylpropyl)-1H-imidazole (7) (124 mg, 0.506 mmol, 1.0 equiv),
meta-methoxyphenyl tosylate (150 mg, 0.540 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150
mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690 mmol, 1.4 equiv), CsOPiv
(129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 14 h. Chromatography on a silica gel
column using 40/55/5 hexanes/EtOAc/acetone (Rf = 0.29 in 40%
hexanes/55% EtOAc/5% acetone) yielded product 7c as a light yellow
solid (178 mg, >99% yield). Mp = 113−114 °C. 1H NMR (CDCl3): δ
7.39 (t, J = 8.0 Hz, 1H), 7.26−7.17 (m, 3H), 7.04 (dd, J = 8.2, 2.6 Hz,
1H), 6.99−6.97 (m, 2H), 6.89 (d, J = 7.4 Hz, 1H), 6.83 (t, J = 2.2 Hz,
1H), 3.82 (s, 3H), 3.74−3.70 (m, 2H), 2.50 (t, J = 7.4 Hz, 2H), 2.39
(s, 3H), 1.89−1.82 (m, 2H). 13C NMR (CDCl3): δ 159.5, 143.3,
143.0, 139.4, 132.0, 129.9, 128.51, 128.46, 127.9, 126.3, 121.9, 115.37,
115.34, 55.2, 44.0, 32.3, 31.0, 13.3. IR (neat): 1604, 1588, 1566, 1535,
1496, 1447, 1403, 1381, 1329, 1300, 1280, 1261, 1249, 1222, 1044,
1023, 904, 849, 837, 822, 800, 747, 695 cm−1. HRMS: [TOF, ES+, M
+H] calcd for C20H21N3O3, 352.1661; found, 352.1665.
2-Methyl-4-nitro-1-(3-phenylpropyl)-5-[3-(trifluoromethyl)-
phenyl]-1H-imidazole (7i). Following general procedure A, 7 (124
mg, 0.506 mmol, 1.0 equiv), meta-trifluoromethylphenyl tosylate (174
mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.10
equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg,
0.690 mmol, 1.4 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 40/55/5 hexanes/
Product Synthesis and Characterization (Scheme 6). 1-Butyl-
5-(naphthalen-2-yl)-4-nitro-1H-pyrazole (1a). Following general
procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), 2-naphthyl mesylate
(124 mg, 0.556 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol,
0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244
mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv),
and anhydrous toluene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 80 °C for
16 h. Chromatography on a silica gel column using 95/5 hexanes/
EtOAc (Rf = 0.24 in 95% hexanes/5% ethyl acetate) yielded product
1a as a yellow oil (148 mg, > 99% yield). The spectroscopic data are
consistent with those of the product isolated using 2-naphthyl tosylate.
H
DOI: 10.1021/acs.joc.7b00550
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The Journal of Organic Chemistry
Note
Procedure outside the Glovebox. Following general procedure F, 1
(42.3 mg, 0.250 mmol, 1.0 equiv), 2-naphthyl mesylate (61.1 mg,
0.275 mmol, 1.1 equiv), Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.10 equiv),
XPhos (35.8 mg, 0.075 mmol, 0.30 equiv), Cs2CO3 (122 mg, 0.375
mmol, 1.5 equiv), CsOPiv (64.4 mg, 0.275 mmol, 1.1 equiv), and
anhydrous toluene (0.5 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 80 °C for 16 h. The
reaction was filtered through a 1-in. pad of silica gel eluting with
EtOAc (100 mL). The filtrate was concentrated. 1H NMR
spectroscopic analysis of the crude product against 1,4-dinitrobenzene
as the standard showed 30% yield of the desired product and 70% of
azole 1.
NMR (CDCl3): δ 8.23 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.52 (d, J =
8.1 Hz, 2H), 3.94 (t, J = 7.2 Hz, 2H), 1.79−1.72 (m, 2H), 1.27−1.16
(m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3): δ 139.7, 136.4,
133.1, 132.3 (q, J = 33 Hz), 130.5, 130.3, 125.8 (q, J = 3.7 Hz), 123.6
(q, J = 271 Hz), 50.3, 31.8, 19.5, 13.4. IR (neat): 2962, 1567, 1514,
1498, 1461, 1400, 1320, 1166, 1125, 1109, 1066, 1025, 847, 826, 762
cm−1. HRMS: [TOF, ES+, M+H] calcd for C14H14F3N3O2, 314.1116;
found, 314.1115.
2-Methyl-1-[(4-methylphenyl)methyl]-5-(naphthalen-2-yl)-4-
nitro-1H-imidazole (6a). Following general procedure A, 6 (116 mg,
0.500 mmol, 1.0 equiv), 2-naphthyl mesylate (122 mg, 0.550 mmol,
1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5
mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690 mmol, 1.4
equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous
toluene (1.0 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.28 in 42% hexanes/55% EtOAc/3% acetone)
yielded product 6a as a light yellow solid (176 mg, 98% yield). The
spectroscopic data are consistent with those of the product isolated
using 2-naphthyl tosylate.
5-(3-Methoxyphenyl)-2-methyl-1-[(4-methylphenyl)methyl]-4-
nitro-1H-imidazole (6c). Following general procedure B, 6 (116 mg,
0.500 mmol, 1.0 equiv), meta-methoxyphenyl mesylate (111 mg, 0.550
mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv),
XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (224 mg, 0.690
mmol, 1.4 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 42/55/3 hexanes/
EtOAc/acetone (Rf = 0.28 in 42% hexanes/55% EtOAc/3% acetone)
yielded product 6c as a light yellow solid (153 mg, 91% yield). The
spectroscopic data are consistent with those of the product isolated
using 3-methoxy phenyl tosylate.
1-(4-Methylphenyl)-5-(naphthalen-2-yl)-4-nitro-1H-pyrazole
(4a). Following general procedure A, 4 (50.8 mg, 0.25 mmol, 1.0
equiv), 2-naphthyl mesylate (61.1 mg, 0.275 mmol, 1.1 equiv),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.10 equiv), XPhos (35.8 mg, 0.075
mmol, 0.30 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5 equiv), CsOPiv
(64.4 mg, 0.275 mmol, 1.1 equiv), and anhydrous toluene (0.5 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 80 °C for 16 h. Chromatography on a silica gel
column using 95/5 hexanes/EtOAc (Rf = 0.15 in 95% hexanes/5%
ethyl acetate) yielded product 4a as a light yellow solid (79.5 mg, 97%
1
yield). Mp = 129−134 °C H NMR (CDCl3): δ 8.43 (s, 1H), 7.87−
7.83 (m, 3H), 7.79 (d, J = 7.8 Hz, 1H), 7.59−7.50 (m, 2H), 7.33 (dd, J
= 8.6, 1.7 Hz, 1H), 7.12−7.05 (m, 4H), 2.29 (s, 3H). 13C NMR
(CDCl3): δ 140.8, 138.9, 137.4, 136.1, 134.0, 133.5, 132.6, 130.8,
129.7, 128.5, 128.3, 127.8, 127.6, 126.71, 126.65, 125.0, 123.8, 21.0. IR
(thin film, CH2Cl2): 2923, 1549, 1512, 1499, 1393, 1318, 821 cm−1.
HRMS: [EI+, M+] calcd for C20H15N3O2, 329.1164; found, 329.1161.
1-Butyl-5-(3,4-dimethoxyphenyl)-4-nitro-1H-pyrazole (1p). Fol-
lowing general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv),
3,4-dimethoxyphenyl mesylate (128 mg, 0.550 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150
mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv
(129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 85/15 hexanes/EtOAc (Rf = 0.18 in 85% hexanes/15%
ethyl acetate) yielded product 1p as a viscous yellow oil (97.0 mg, 64%
Product Synthesis and Characterization (Scheme 7). 5-
Benzyl-1-methyl-4-nitro-1H-pyrazole (2q). Following general proce-
dure D, 2 (63.6 mg, 0.500 mmol, 1.0 equiv), benzyl acetate (82.6 mg,
0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv),
XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750
mmol, 1.5 equiv), and anhydrous xylene (1.0 mL) were combined in a
20 mL scintillation vial. The reaction mixture was allowed to stir at 80
°C for 16 h. Chromatography on a silica gel column using 55/45
hexanes/EtOAc (Rf = 0.45 in 55% hexanes/45% EtOAc) yielded
1
yield). H NMR (CDCl3): δ 8.20 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H),
6.93 (dd, J = 8.2, 2.0 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 3.97 (t, J = 7.2
Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 1.80−1.72 (m, 2H), 1.27−1.18
(m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3): δ 150.5, 149.1,
141.2, 136.4, 132.7, 122.5, 118.6, 112.6, 111.1, 56.1, 55.9, 50.0, 31.8,
19.6, 13.5. IR (thin film, CH2Cl2): 2958, 2934, 1508, 1463, 1398,
1320, 1262, 1249, 1218, 1174, 1140, 1023, 857, 826, 759 cm−1.
HRMS: [TOF, ES+, M+H] calcd for C15H19N3O4, 306.1454; found,
306.1454.
1-Butyl-4-nitro-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole (1f). Fol-
lowing general procedure A, 1 (84.6 mg, 0.500 mmol, 1.0 equiv), 3,4,5-
trimethoxyphenyl mesylate (144 mg, 0.550 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg,
0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv),
CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0
mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 80/20 hexanes/EtOAc (Rf = 0.20 in 80% hexanes/20%
EtOAc) yielded product 1f as a yellow oil (111 mg, 66% yield). The
spectroscopic data are consistent with those of the product isolated
using 3,4,5-trimethoxyphenyl tosylate.
1
product 2q as a light yellow solid (106 mg, 97% yield). H NMR
(CDCl3): δ 8.13 (s, 1H), 7.34−7.24 (m, 3H), 7.13 (d, J = 7.5 Hz, 2H),
4.49 (s, 2H), 3.77 (s, 3H). 13C NMR (CDCl3): δ 140.7, 136.1, 134.8,
133.1, 129.0, 128.0, 127.3, 37.6, 29.9. The spectroscopic data are
consistent with those previously reported in the literature.9
Procedure outside the Glovebox. Following general procedure G,
2 (63.6 mg, 0.500 mmol, 1.0 equiv), benzyl acetate (82.6 mg, 0.550
mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv),
XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750
mmol, 1.5 equiv), and anhydrous toluene (1.0 mL) were combined in
a 20 mL scintillation vial. The reaction mixture was allowed to stir at
80 °C for 16 h. Chromatography on a silica gel column using 55/45
hexanes/EtOAc (Rf = 0.45 in 55% hexanes/45% EtOAc) yielded
product 2q as a light yellow solid (77.1 mg, 71% yield).
1-Methyl-5-[(4-methylphenyl)methyl]-4-nitro-1H-pyrazole (2r).
Following general procedure D, 2 (63.6 mg, 0.500 mmol, 1.0
equiv), para-methylbenzyl acetate (90.3 mg, 0.550 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150
mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 80 °C for 16 h.
Chromatography on a silica gel column using 80/20 hexanes/EtOAc
(Rf = 0.22 in 80% hexanes/20% EtOAc) yielded product 2r as a yellow
solid (86.1 mg, 74% yield). 1H NMR (CDCl3): δ 8.12 (s, 1H), 7.11 (d,
J = 7.9 Hz, 2H), 7.02 (d, J = 7.9 Hz, 2H), 4.44 (s, 2 H), 3.77 (s, 3H),
2.32 (s, 3H). 13C NMR (CDCl3): δ 140.9, 136.9, 136.1, 133.0, 131.6,
1-Butyl-4-nitro-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (1n).
Following general procedure B, 1 (84.6 mg, 0.500 mmol, 1.0 equiv),
para-trifluoromethylphenyl mesylate (132 mg, 0.550 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150
mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), CsOPiv
(129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 120 °C for 16 h. Chromatography on a silica gel
column using 90/10 hexanes/EtOAc (Rf = 0.18 in 90% hexanes/10%
1
EtOAc) yielded product 1n as a yellow oil (80 mg, 51% yield). H
I
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The Journal of Organic Chemistry
Note
129.6, 127.9, 37.5, 29.5, 20.9. The spectroscopic data are consistent
with those previously reported in the literature.9
(1u). Following general procedure A, 1 (42.3 mg, 0.25 mmol, 1.0
equiv), 3-chloro phenyl tosylate (106 mg, 0.375 mmol, 1.5 equiv),
Pd(OAc)2 (2.80 mg, 0.012 mmol, 0.05 equiv), XPhos (11.8 mg, 0.025
mmol, 0.10 equiv), K2CO3 (51.8 mg, 0.375 mmol, 1.5 equiv), and
anhydrous toluene (0.25 mL) were combined in a 4 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 24 h.
Chromatography on a silica gel column using 80/20 hexanes/EtOAc
(Rf = 0.28 in 80% hexanes/20% EtOAc) yielded product 1u as a
yellow oil (81.3 mg, 78% yield). 1H NMR (CDCl3): 8.18 (s, 1H), 7.72
(d, J = 8.3 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H),
7.27−7.25 (m, 1H), 7.21 (ddd, J = 8.3, 2.4, 1.1 Hz, 1H), 7.03 (t, J =
1.7 Hz, 1H), 3.88 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.74−1.67 (m,
2H), 1.23−1.15 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3):
δ 149.6, 145.8, 139.4, 136.1, 132.9, 131.7, 130.2, 129.9, 128.43, 128.38,
128.2, 124.3, 123.8, 50.1, 31.6, 21.6, 19.4, 13.3. IR (neat): 1557, 1505,
1481, 1463, 1400, 1374, 1324, 1257, 1192, 1180, 1147, 1120, 1091,
890, 828, 814, 804, 763, 748, 732, 689, 661 cm−1. HRMS: [EI+, M+]
calcd for C20H21N3O5S, 415.1202; found, 415.1206.
5-[(3-Fluorophenyl)methyl]-1-methyl-4-nitro-1H-pyrazole (2s).
Following general procedure D, 2 (63.6 mg, 0.500 mmol, 1.0
equiv), meta-fluorobenzyl acetate (92.5 mg, 0.550 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150
mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 80 °C for 16 h.
Chromatography on a silica gel column using 75/25 hexanes/EtOAc
(Rf = 0.20 in 75% hexanes/25% EtOAc) yielded product 2s as a light
yellow solid (84.8 mg, 72% yield). 1H NMR (CDCl3): δ 8.14 (s, 1H),
7.32−7.26 (m, 1H), 6.97 (t, J = 8.5 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H),
6.84 (d, J = 9.3 Hz, 1H), 4.49 (s, 2H), 3.79 (s, 3H). 13C NMR
(CDCl3): δ 163.0 (J = 246 Hz), 139.9, 137.1 (J = 7.4 Hz), 136.2,
133.2, 130.5 (J = 8.1 Hz), 123.7 (J = 2.9 Hz), 115.1 (J = 22 Hz), 114.3
(J = 21 Hz), 37.6, 29.6 (J = 2.1 Hz). The spectroscopic data are
consistent with those previously reported in the literature.9
5-[(3-Methoxyphenyl)methyl]-1-methyl-4-nitro-1H-pyrazole (2t).
Following general procedure D, 2 (63.6 mg, 0.500 mmol, 1.0 equiv),
meta-methoxybenzyl acetate (99.1 mg, 0.550 mmol, 1.1 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg,
0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv),
and anhydrous xylene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 80 °C
for 16 h. Chromatography on a silica gel column using 60/40 hexanes/
EtOAc (Rf = 0.35 in 60% hexanes/40% EtOAc) yielded product 2t as
3-(1-Butyl-4-nitro-1H-pyrazol-5-yl)phenyl 4-methylbenzene-1-
sulfonate (1u). Following general procedure A, 1 (42.3 mg, 0.25
mmol, 1.0 equiv), 3-bromo phenyl tosylate (123 mg, 0.375 mmol, 1.5
equiv), Pd(OAc)2 (2.80 mg, 0.012 mmol, 0.05 equiv), XPhos (11.8
mg, 0.025 mmol, 0.10 equiv), K2CO3 (51.8 mg, 0.375 mmol, 1.5
equiv), and anhydrous toluene (0.25 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 120 °C for
24 h. Chromatography on a silica gel column using 80/20 hexanes/
EtOAc (Rf = 0.28 in 80% hexanes/20% EtOAc) yielded product 1u as
a yellow oil (92.3 mg, 89% yield). The spectroscopic data are identical
to those of the product obtained using 3-chlorophenyl tosylate.
1-Butyl-5-[3-(1-butyl-4-nitro-1H-pyrazol-5-yl)phenyl]-4-nitro-1H-
pyrazole (1v). Following general procedure A, 1 (169 mg, 1.00 mmol,
2.0 equiv), 3-chloro phenyl tosylate (141 mg, 0.500 mmol, 1.0 equiv),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.05 equiv), XPhos (23.5 mg, 0.05
mmol, 0.10 equiv), K2CO3 (415 mg, 3.00 mmol, 6.0 equiv), and
anhydrous toluene (0.5 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 24 h.
Chromatography on a silica gel column using 80/20 hexanes/EtOAc
(Rf = 0.25 in 80% hexanes/20% EtOAc) yielded product 1v as a yellow
oil (165 mg, 80% yield). 1H NMR (CDCl3): 8.23 (s, 2H), 7.73 (t, J =
7.8 Hz, 1H), 7.56 (dd, J = 7.7, 1.7 Hz, 2H), 7.45 (t, J = 1.8 Hz, 1H),
4.05 (t, J = 7.3 Hz, 4H), 1.78−1.72 (m, 4H), 1.28−1.18 (m, 4H), 0.83
(t, J = 7.3 Hz, 6H). 13C NMR (CDCl3): δ 139.8, 136.3, 133.0, 131.6,
131.3, 129.4, 127.6, 50.4, 31.7, 19.5, 13.4. IR (neat): 1551, 1502, 1480,
1464, 1398, 1321, 1267, 1190, 910, 831, 807, 761, 730, 704 cm−1.
HRMS: [EI+, M+] calcd for C20H24N6O4, 412.1859; found, 412.1860.
1-Butyl-5-[3-(1-butyl-4-nitro-1H-pyrazol-5-yl)phenyl]-4-nitro-1H-
pyrazole (1v). Following general procedure A, 1 (169 mg, 1.00 mmol,
2.0 equiv), 3-bromo phenyl tosylate (164 mg, 0.500 mmol, 1.0 equiv),
Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.05 equiv), XPhos (23.5 mg, 0.05
mmol, 0.10 equiv), K2CO3 (415 mg, 3.00 mmol, 6.0 equiv), and
anhydrous toluene (0.5 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 24 h.
Chromatography on a silica gel column using 80/20 hexanes/EtOAc
(Rf = 0.25 in 80% hexanes/20% EtOAc) yielded product 1v as a yellow
oil (152 mg, 74% yield). The spectroscopic data are identical to those
of the product obtained using 3-chlorophenyl tosylate.
1
a yellow viscous oil (95.7 mg, 78% yield). H NMR (CDCl3): δ 8.12
(s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 8.0, 2.5 Hz, 1H), 6.70
(d, J = 7.7 Hz, 1H), 6.67 (t, J = 2.2 Hz, 1H), 4.46 (s, 2H), 3.77 (s,
6H). The spectroscopic data are consistent with those previously
reported in the literature.9
5-Benzyl-1-(4-methylphenyl)-4-nitro-1H-pyrazole (4q). Following
general procedure D, 4 (50.8 mg, 0.25 mmol, 1.0 equiv), benzyl
acetate (41.3 mg, 0.275 mmol, 1.1 equiv), Pd(OAc)2 (5.6 mg, 0.025
mmol, 0.10 equiv), XPhos (35.8 mg, 0.075 mmol, 0.30 equiv), Cs2CO3
(122 mg, 0.375 mmol, 1.5 equiv), CsOPiv (64.4 mg, 0.275 mmol, 1.1
equiv), and anhydrous toluene (0.5 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 80 °C for
16 h. Chromatography on a silica gel column using 90/10 hexanes/
EtOAc (Rf = 0.26 in 90% hexanes/10% EtOAc) yielded product 4q as
a clear viscous oil (39.1 mg, 53% yield). 1H NMR (CDCl3): δ 8.31 (s,
1H), 7.27−7.15 (m, 7H), 6.96 (dd, J = 7.6, 2.1 Hz, 2H), 4.42 (s, 2H),
2.42 (s, 3H). 13C NMR (CDCl3): δ 141.5, 140.1, 137.1, 135.8, 135.5,
133.8, 130.0, 128.7, 128.0, 127.0, 125.7, 30.6, 21.2. IR (neat): 2922,
1544, 1504, 1494, 1463, 1401, 1318, 1178, 829, 821, 804, 778, 757,
723, 712, 694 cm−1. HRMS: [EI+, M+] calcd for C17H15N3O2,
293.1164; found, 293.1162.
5-[(3-methoxyphenyl)methyl]-2-methyl-1-[(4-methylphenyl)-
methyl]-4-nitro-1H-imidazole (6t). Following general procedure D, 6
(115.6 mg, 0.500 mmol, 1.0 equiv), meta-methoxybenzyl acetate (99.1
mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10
equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), Cs2CO3 (244 mg,
0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and
anhydrous toluene (1.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 120 °C for 14 h.
Chromatography on a silica gel column using 12/30/58 acetone/
CH2Cl2/hexanes (Rf = 0.36 in 12% acetone/30% CH2Cl2/58%
Product Synthesis and Characterization (Scheme 9). [3-(1-
Methyl-4-nitro-1H-pyrazol-5-yl)phenyl]methyl Acetate (2w). Fol-
lowing general procedure D, 2 (63.6 mg, 0.50 mmol, 1.0 equiv), 3-
chloro benzyl acetate (101 mg, 0.550 mmol, 1.1 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and anhydrous
xylene (1.0 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 80 °C for 24 h.
Chromatography on a silica gel column using 65/35 hexanes/EtOAc
(Rf = 0.25 in 65% hexanes/35% EtOAc) yielded product 2w as a white
1
hexanes) yielded product 6t as a viscous oil (88.0 mg, 50% yield). H
NMR (CDCl3): δ 7.19 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H),
6.77 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 7.8 Hz,
1H), 6.64 (t, J = 2.1 Hz, 1H), 4.93 (s, 2H), 4.34 (s, 2H), 3.75 (s, 3H),
2.35 (s, 3H), 2.34 (s, 3H). 13C NMR (CDCl3): δ 160.0, 144.2, 144.0,
138.2, 137.2, 132.1, 130.8, 129.92, 129.89, 125.5, 120.3, 114.0, 112.2,
55.2, 47.6, 30.0, 21.0, 13.5. IR (neat): 1599, 1584, 1567, 1540, 1488,
1455, 1435, 1406, 1386, 1338, 1281, 1257, 1161, 1145, 1043, 858, 792,
764, 740, 690 cm−1. HRMS: [TOF, ES+, M+H] calcd for
C20H21N3O3, 352.1661; found, 352.1657.
1
solid (114 mg, 82% yield). Mp = 102−105 °C. H NMR (CDCl3):
8.20 (s, 1H), 7.55−7.54 (m, 2H), 7.40 (s, 1H), 7.37−7.35 (m, 1H),
5.18 (s, 2H), 3.75 (s, 3H), 2.13 (s, 3H). 13C NMR (CDCl3): δ 170.6,
140.9, 136.9, 136.3, 132.9, 130.0, 129.4, 129.3, 129.0, 126.8, 65.4, 38.0,
Product Synthesis and Characterization (Scheme 8). 3-(1-
Butyl-4-nitro-1H-pyrazol-5-yl)phenyl 4-methylbenzene-1-sulfonate
J
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The Journal of Organic Chemistry
Note
20.9. IR (neat): 1732, 1499, 1469, 1406, 1381, 1360, 1328, 1288, 1195,
1178, 1029, 893, 825, 800, 762, 682, 644, 621, 605, 582 cm−1. HRMS:
[TOF, ES+, M+H] calcd for C13H14N3O4, 276.0984; found, 276.0989.
1-Methyl-5-{3-[(1-methyl-4-nitro-1H-pyrazol-5-yl)methyl]-
phenyl}-4-nitro-1H-pyrazole (2x). Following general procedure D, 2
(63.6 mg, 0.50 mmol, 2.0 equiv), 3-chloro benzyl acetate (46.2 mg,
0.25 mmol, 1.0 equiv), Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.10 equiv),
XPhos (35.3 mg, 0.075 mmol, 0.30 equiv), Cs2CO3 (244 mg, 0.750
mmol, 3.0 equiv), and anhydrous xylene (0.5 mL) were combined in a
20 mL scintillation vial. The reaction mixture was allowed to stir at 80
°C for 24 h. Chromatography on a silica gel column using 100%
diethyl ether (Rf = 0.30 in 100% diethyl ether) yielded product 2x as
111.1, 55.90, 55.86. The spectroscopic data are consistent with those
previously reported in the literature.24
1,2,3-Trimethoxy-5-(2-nitrophenyl)benzene (8f). Following gen-
eral procedure E, nitrobenzene (616 mg, 5.00 mmol, 10 equiv), 3,4,5-
trimethoxyphenyl tosylate (169 mg, 0.500 mmol, 1.0 equiv),
Pd(OAc)2 (11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg,
0.150 mmol, 0.30 equiv), K3PO4 (159 mg, 0.750 mmol, 1.5 equiv),
CsOPiv (129 mg, 0.550 mmol, 1.1 equiv), and anhydrous toluene (1.0
mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 24 h. Chromatography on a silica gel
column using 80/20 hexanes/EtOAc (Rf = 0.30 in 80% hexanes/20%
1
EtOAc) yielded product 8f as a yellow solid (63 mg, 44% yield). H
1
NMR (CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H),
7.50−7.45 (m, 2H), 6.52 (s, 2H), 3.89 (s, 3H), 3.86 (s, 6H). 13C NMR
(CDCl3): δ 153.3, 149.4, 137.9, 135.9, 132.6, 132.0, 131.6, 128.1,
123.7, 105.0, 60.8, 56.1. HRMS: [TOF, ES+, M+H] calcd for
C15H15NO5, 290.1028; found, 290.1030.
an off white solid (60.0 mg, 70% yield). Mp = 70−72 °C. H NMR
(CDCl3): 8.19 (s, 1H), 8.14 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34−
7.29 (m, 2H), 7.21−7.20 (m, 1H), 4.57 (s, 2H), 3.84 (s, 3H), 3.73 (s,
3H). 13C NMR (CDCl3): δ 140.6, 139.8, 136.3, 136.2, 135.7, 133.2,
132.9, 130.0, 129.7, 129.5, 128.5, 127.2, 38.1, 37.7, 29.8. IR (neat):
1552, 1497, 1432, 1404, 1317, 1193, 870, 832, 786, 772, 764, 752
cm−1. HRMS: [EI+, M+] calcd for C15H14N6O4, 342.1077; found,
342.1075.
5-(2-Nitrophenyl)-2H-1,3-benzodioxole (8e). Following general
procedure E, nitrobenzene (616 mg, 5.00 mmol, 10 equiv), sesimol
tosylate (146 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.050
mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), K3PO4
(159 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1
equiv), and anhydrous xylene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 140 °C for
24 h. Chromatography on a silica gel column using 97/3 hexanes/
EtOAc (Rf = 0.26 in 97% hexanes/3% EtOAc) yielded product 8e as a
Product Synthesis and Characterization (Scheme 10). 2-(2-
Nitrophenyl)naphthalene (8a). Following general procedure E,
nitrobenzene (616 mg, 5.00 mmol, 10 equiv), 2-naphthyl tosylate
(149 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol,
0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30 equiv), K3PO4 (159
mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg, 0.550 mmol, 1.1 equiv),
and anhydrous xylene (1.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 140 °C
for 24 h. Chromatography on a silica gel column using 97/3 hexanes/
EtOAc (Rf = 0.12 in 97% hexanes/3% EtOAc) yielded product 8a as a
1
dark orange solid (60.4 mg, 50% yield). H NMR (CDCl3): δ 7.80
(dd, J = 8.1, 1.3 Hz, 1H), 7.59 (td, J = 7.6, 1.3 Hz, 1H), 7.45 (td, J =
7.8, 1.4 Hz, 1H), 7.42 (dd, J = 7.8, 1.4 Hz, 1H), 6.86 (d, J = 7.8 Hz,
1H), 6.80−6.76 (m, 2H), 6.02 (s, 2H). The spectroscopic data are
consistent with those previously reported in the literature.25
1
yellow solid (78 mg, 63% yield). H NMR (CDCl3): 7.94−7.85 (m,
4H), 7.82 (s, 1H), 7.66 (td, J = 7.6, 1.4 Hz, 1H), 7.56−7.50 (m, 4H),
7.41 (dd, J = 8.5, 1.9 Hz, 1H). 13C NMR (CDCl3): δ 149.3, 136.4,
134.9, 133.2, 132.8, 132.4, 132.3, 128.3, 128.2, 128.1, 127.7, 126.9,
126.5, 125.7, 124.2. The spectroscopic data are consistent with those
previously reported in the literature.23
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00550.
■
S
2-Methoxy-7-(2-nitrophenyl)naphthalene (8d). Following general
procedure E, nitrobenzene (616 mg, 5.00 mmol, 10 equiv), 7-
methoxynaphthyl tosylate (164 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), K3PO4 (159 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous xylene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 140 °C for 24 h. Chromatography on a silica gel
column using 93/7 hexanes/EtOAc (Rf = 0.31 in 93% hexanes/7%
NMR spectra of all isolated products and new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: kalyani@stolaf.edu.
ORCID
■
1
EtOAc) yielded product 8d as a yellow oil (80 mg, 58% yield). H
Dipannita Kalyani: 0000-0003-4349-8016
NMR (CDCl3): 7.90 (dd, J = 8.1, 1.3 Hz, 1H), 7.81 (d, J = 8.4 Hz,
1H), 7.77 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.65 (td, J =
7.6, 1.4 Hz, 1H), 7.55−7.49 (m, 2H), 7.27 (dd, J = 8.4, 1.8 Hz, 1H),
7.19 (dd, J = 8.9, 2.5 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H).
13C{1H} NMR (CDCl3): δ 158.1, 149.3, 136.4, 135.4, 134.4, 132.3,
132.1, 129.2, 128.3, 128.09, 128.06, 125.8, 124.1, 123.4, 119.4, 106.0,
55.3. HRMS: [TOF, ES+, M+H] calcd for C17H13NO3, 280.0974;
found, 280.0971. IR (thin film, CH2Cl2): 3002, 1630, 1610, 1519,
1460, 1391, 1350, 1237, 1212, 1174, 1125, 1024, 838, 742 cm−1.
1,2-Dimethoxy-4-(2-nitrophenyl)benzene (8p). Following general
procedure E, nitrobenzene (616 mg, 5.00 mmol, 10 equiv), 3,4-
dimethoxyphenyl tosylate (154 mg, 0.500 mmol, 1.0 equiv), Pd(OAc)2
(11.2 mg, 0.050 mmol, 0.10 equiv), XPhos (71.5 mg, 0.150 mmol, 0.30
equiv), K3PO4 (159 mg, 0.750 mmol, 1.5 equiv), CsOPiv (129 mg,
0.550 mmol, 1.1 equiv), and anhydrous xylene (1.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 140 °C for 24 h. Chromatography on a silica gel
column using 88/12 hexanes/EtOAc (Rf = 0.24 in 88% hexanes/12%
Author Contributions
†Y.A., R.D., S.D., A.S., R.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Institutes of Health
(R15 GM107892) and St. Olaf College. The authors also thank
Emily Reeves for isolating a few catalysis products.
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