Synthesis of 2 H-indazoles by the [3 + 2] dipolar cycloaddition of sydnones with arynes

Article abstract of DOI:10.1021/jo201605v

A rapid and efficient synthesis of 2H-indazoles has been developed using a [3 + 2] dipolar cycloaddition of sydnones and arynes. A series of 2H-indazoles have been prepared in good to excellent yields using this protocol, and subsequent Pd-catalyzed coupl

Full text of DOI:10.1021/jo201605v

Article
pubs.acs.org/joc
Synthesis of 2H-Indazoles by the [3 + 2] Dipolar Cycloaddition of
Sydnones with Arynes
Yuesi Fang,† Chunrui Wu,*,‡ Richard C. Larock,*,† and Feng Shi*,‡
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
‡Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng,
Henan 475004, China PR
S
* Supporting Information
ABSTRACT: A rapid and efficient synthesis of 2H-indazoles has
been developed using a [3 + 2] dipolar cycloaddition of sydnones and
arynes. A series of 2H-indazoles have been prepared in good to
excellent yields using this protocol, and subsequent Pd-catalyzed
coupling reactions can be applied to the halogenated products to generate a structurally diverse library of indazoles.
arynes and readily accessible sydnones (eq 3).11 This chemistry,
which offers very mild reaction conditions, high yields, and no
INTRODUCTION
■
The synthesis of heterocyclic compounds has attracted
significant attention for decades. Among the various hetero-
cycles, the indazole system has received significant attention
due to its diverse bioactivity.1 Although a number of methods
for the preparation of indazoles are known, most methods
target 1H-indazoles. Those focused on the selective and
efficient preparation of 2H-indazoles, which also appear to
have pharmaceutical promise,2 remain limited. Recently,
significant efforts have been devoted to the development of
synthetic routes toward 2H-indazoles,3 as highlighted by the
elegant chemistry developed by Halland (eq 1)3a and Song (eq
contamination by 1H-indazoles, presumably involves an initial
[3 + 2] cycloaddition to afford a bicyclic adduct, followed by
spontaneous extrusion of a molecule of CO2 in a retro-[4 + 2]
fashion. Herein, we wish to report the full details on this project
and demonstrate its potential application to the construction of
a small library utilizing palladium-catalyzed cross-couplings of
halogenated 2H-indazoles prepared by our methodology.
RESULTS AND DISCUSSION
■
Preparation of the Sydnones. Sydnones are readily
prepared from the corresponding amino acids12 by a sequence
which involves N-nitrosation/cyclodehydration. Three different
protocols, namely protocol 1A [1.5 equiv of NaNO2, 0 °C, 1 h,
then acidify], protocol 1B [2.0 equiv of NaNO2, HCl, then 0
°C, 1 h], and protocol 1C [1.5 equiv of i-amyl nitrite, dimethyl
ether (DME), rt, 2 d] have been used in the nitrosation step,
and two other protocols, namely 2A [Ac2O as solvent, 110 °C,
2 h] and 2B [2 equiv of trifluoroacetic anhydride (TFAA),
Et2O, rt, 2 h], have been used for the cyclodehydration step. A
variety of sydnones have been synthesized starting from readily
available amino acids (Scheme 1, see the Experimental Section
for details). However, preparation of some sydnones, especially
those with an alkyl group at the C-4 position have not been
successful.
2).3b However, it should be noted that most of these methods
still have significant limitations. Thus, new routes are still
desirable.
Our two groups have extensive ongoing research programs in
aryne chemistry directed toward biologically important hetero-
cycles, including approaches involving Pd-catalyzed annulation
reactions,4 electrophilic and nucleophilic reactions,5 inter- or
intramolecular annulation reactions,6 and insertion reactions.7
Aryne dipolar cycloadditions have provided synthetically useful
methods for the synthesis of benzotriazoles,8 indazoles,9 and
benzisoxazoles10 by reactions with azides, diazo compounds,
and nitrile oxides, respectively.
Sydnones not readily derived from amino acids can be
accessed by further functionalization of preformed monosub-
stituted sydnones. Thus, arylation and vinylation at the C-4
For the synthesis of 2H-indazoles, we have previously
communicated a [3 + 2] cycloaddition approach involving
Received: August 1, 2011
Published: October 4, 2011
© 2011 American Chemical Society
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a
Scheme 1. Synthesis of Sydnones
Table 1. Reaction Optimization
b
1a
fluoride source
(equiv)
T (°C/time
yield
(%)
position of sydnones can be achieved from monosubstituted
sydnones by Pd-catalyzed cross-coupling with aryl or vinylic
halides using literature procedures (eq 4).13 Alkynylation at the
entry (equiv)
solvent
h)
c
1
2
3
4
5
6
1.5
1.5
1.5
1.5
1.2
1.2
CsF (2.5)
MeCN
THF
rt, 36
70, 24
rt, 12
rt, 12
rt, 12
rt, 12
69
90
CsF (2.5)
d
d
d
f
e
TBAF (2.5)
TBAF (2.5)
TBAF (1.5)
TBAF (1.5)
MeCN
THF
95
94
98
97
THF
THF
a
All reactions were carried out on a 0.4 mmol scale at 0.1 M
b
c
concentration. Isolated yield. Incomplete conversion of 2a even after
d
e
2 days. Solid anhydrous TBAF was used. The product is significantly
yellow, although no apparent impurity was detected by 1H NMR
f
spectroscopy. A THF solution of TBAF (1 M) was used.
This sydnone-aryne cycloaddition appears to represent one of
the best approaches to 2H-indazoles in terms of efficiency and
yield. The reaction conditions reported in Table 1, entries 5
and 6, which employ the same stoichiometry and concen-
tration, but use of either solid TBAF or a THF solution of
TBAF afford similar results. Thus, the procedures reported in
entries 5 and 6 have been chosen as our standard reaction
conditions for our study of additional substrates.
Scope and Limitations. The scope and limitations of our
approach to 2H-indazoles have been tested, first using a range
of structurally diverse sydnones (Table 2). For monosub-
stituted sydnones with an aryl group, the reaction smoothly
afforded excellent yields of the corresponding 2H-indazoles
(entries 1−6), with a variety of functional groups tolerated,
including halogens (entries 2 and 3) and alkyl (entry 4), ether
(entry 5), and acetal (entry 6) groups. However, the electron
deficient N-(4-nitrophenyl)sydnone 2g (entry 7) was found to
be unreactive. Even with the addition of a second batch of 1.2
equiv of 1a after the first 1.2 equiv of 1a was consumed, 2g
remained unreacted. N-Alkylsydnones (entries 8 and 9) also
worked well under our reaction conditions, but in somewhat
lower yields.
With substitution in the C-4 position of the sydnone, we have
observed limited success with alkyl groups. Except for the
proline-derived sydnone 2j (entry 10), which has the 3- and 4-
substitution tethered into a ring, other sydnones were found
unstable under our reaction conditions and afforded a fairly
complex reaction mixture in the end. For example, sydnone 2k
derived from leucine (entry 11) afforded only a 23% yield with
∼10% recovery of the sydnone under our standard conditions,
and 1.6 equiv of 1a and 2.4 equiv of TBAF had to be employed
for the full conversion of 2k. On the other hand, sydnones with
sp2- or sp- carbon units in the C-4 position, including a vinyl
group (entry 12), different aryl groups varying in their
electronics (entries 13−16), different heterocyclic groups
(entries 17 and 18), and an alkynyl group (entry 19) were all
tolerated, and the desired products were obtained in good to
excellent yields, although in some cases (entries 18 and 19),
incomplete conversion was observed. Successful substitution at
the C-4 position of the sydnone has been extended to halogens,
as illustrated in sydnones 2t and 2u (entries 20 and 21), where
88% and 90% yields have been obtained. However, substitution
of other electron-withdrawing groups at the C-4 position has
not been tolerated. For example, 4-acetylsydnone 2v was found
to be unreactive with benzyne under our standard conditions
C-4 position can be performed using the same protocol or by
oxidative coupling with terminal alkynes (eq 5).14 Mono-
substituted sydnones can also be iodinated15 or acylated16 at
the C-4 position by reacting sydnones with ICl buffered with
NaOAc/AcOH (eq 6) or acetic anhydride combined with NBS
(eq 7), respectively.
Reaction Optimization. The reaction of o-
(trimethylsilyl)phenyl triflate (1a) and N-phenylsydnone (2a)
was investigated as the model reaction for optimization (Table
1). In the beginning, we found that using CsF in acetonitrile
only afforded a 69% yield of 3aa with incomplete conversion of
2a, even upon a prolonged reaction time (entry 1). Running
the reaction in tetrahydrofuran (THF) led to complete
conversion with a much improved 90% yield (entry 2). We
quickly found that better results and shorter reaction times
could be realized by changing the fluoride source from CsF to
tetra-n-butylammonium fluoride (TBAF; entries 3 and 4). With
this change, THF and acetonitrile exhibited no apparent
difference in yields. However, THF is slightly preferred,
because it appeared to afford a pure product (white vs yellow
in acetonitrile). In addition, when using THF as the solvent, the
loadings of both 1a and fluoride could be reduced while
maintaining a near quantitative yield (entries 5 and 6). The
reaction provides a clean, spot-to-spot transformation with
perhaps only a trace of the starting material; no other spots
were observed on thin layer chromatography (TLC) analysis.
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a
Table 2. Synthesis of 2H-Indazoles from Benzyne and Sydnones
a
b
c
All reactions were carried out on approximately 0.4 mmol of sydnone at a concentration of 0.1 M. Isolated yield. A trace amount of product was
d
e
detected by GC-MS. Substrate 2g was still unreactive upon heating. This reaction was performed with 1.6 equiv of 1a and 2.4 equiv of TBAF. The
reaction afforded a 52% yield of pure 3aq, together with another fraction of impure 3aq (32% by weight, approximately 80−85% purity) that was
very hard to purify. With 15% recovery of 2r. With 19% recovery of 2s. With total recovery of 2v, 1a was consumed. Substrate 2v was still
f
g
h
unreactive upon heating.
(entry 22), leading to complete recovery of the starting
sydnone. The adverse effect of electron-withdrawing groups has
also been observed in entry 13, where a lower yield was
obtained.
Next, a variety of different aryne precursors have been tested
under our optimized reaction conditions (Table 3). As can be
seen, excellent yields can be achieved regardless of the aryne
structure. Symmetrical aryne precursors 1b and 1c have been
converted to the corresponding 2H-indazoles 3ba (entry 1) and
3ca (entry 2), respectively in almost quantitative yields.
Unsymmetrical aryne precursor 1d, which is neither electroni-
cally nor sterically biased, afforded mixtures of two possible
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a
Table 3. Reaction with Other Aryne Precursors
a
b
c
All reactions were carried out on 0.4 mmol of sydnone at a concentration of 0.1 M. Isolated yield. A 1:1 mixture of the 5-Me isomer and the 6-Me
d
e
isomer was obtained. An inseparable 0.8:1 mixture of two isomers (5-MeO and 6-MeO) was obtained. The major isomer was not identified. A
0.7:1 mixture of two inseparable isomers (4-Me and 7-Me) was obtained. The major isomer was not identified. A 1:1 mixture of 3ga and 3ga′ was
obtained. All sydnone starting material was recovered when precursor 1h was consumed. See the Supporting Information for the structure
assignment. The structures were assigned based on the polarity and H NMR coupling pattern of the two isomers obtained from entry 6.
f
g
h
i
1
regioisomers in nearly equal amounts (entry 3). Unsymmetrical
aryne precursor 1e, which is partially biased electronically, led
to an inseparable mixture of two isomers in a 1: 0.8 ratio (entry
4). Unsymmetrical aryne precursor 1f, which is slightly biased
by sterics, led to an inseparable mixture of two isomers in a 1:
0.7 ratio (entry 5). An unsymmetrical naphthalyne precursor 1g
was also reactive and led to an inseparable mixture of two
isomers in equal amounts (entry 6). However, 2,3-pyridyne
precursor 1h17 proved unsuccessful using our standard reaction
conditions. We observed that all sydnone starting material was
recovered when compound 1h was consumed (entry 7).
An interesting observation was made when we carried out
the reaction using the unsymmetrical aryne precursor 1i, which
is both sterically and electronically biased. While we isolated
two products, we were only able to assign one as the 4-MeO
isomer (3ia) (33% yield) through extensive NMR spectro-
scopic analysis and comparison with literature values.11,18 We
were unable to identify the other product. While HRMS
suggested the identity as the desired regioisomeric product, the
presence of extra aromatic protons, as well as two aliphatic
1
methyl groups in the H NMR spectrum, clearly suggested
otherwise. It was not until we reacted 1i with another sydnone
2d that we realized what had happened. In the latter reaction,
we again obtained two products. One was the desired 4-MeO
isomer (3id) in a 44% yield, and the other product was again
unidentified. However, we were able to observe exactly the
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Scheme 2. Regioselectivity in the Cycloaddition Reaction and Proposed Mechanism for the Formation of m-Anisidine
same extra aromatic protons and exactly the same extra methyl
signals that were observed in the previously unidentified
product, but here the integration no longer involved integers.
That clearly suggested that these “unidentified” products were
in fact mixtures of two compounds. The mixture obtained from
1i and 2a involved approximately a 1:1 ratio of two products.
Therefore, the HRMS information was correct. The “un-
identified” product from 1i and 2a actually contained the 7-
MeO isomer 3ia′. The other component in the mixture was
computational chemists long ago realized that despite the
enolate nature and the observed nucleophilic reactivity of C-4,
the N-2 position actually carries a significant negative charge20
and may serve as the nucleophile in the aryne reaction.
Although the charge distribution of sydnones has been
controversial,21 experimental results involving the cycloaddition
of sydnones with unsymmetrical alkynes have clearly suggested
that both N-2 and C-4 can react as the nucleophilic site.22
Moreover, the molecular orbital analysis of sydnones indicates
that the LUMO of sydnones has very similar coefficients for N-
2 and C-4,23 rendering the N-2 and C-4 positions of a sydnone
similar in reactivity. All these literature results support the
formation of both isomers 3ia and 3ia′ through cycloaddition,
and the side-product, m-anisidine, appears to arise from a
separate path during the formation of isomer 3ia. Possibly, due
to steric hindrance of the methoxy group, the [3 + 2]
cycloaddition to form 3ia is partially disrupted and therefore
occurs stepwise, which stops at betaine D.24 The addition of
water may lead to the formation of E, which is attacked by
hydroxide to form a ring-opened intermediate F. Intermediate
F can further decompose to nitroso compound G, which is then
reduced to m-anisidine.
1
later attributed to m-anisidine based on H NMR spectral
analysis and comparison with literature values. The existence of
m-anisidine was also confirmed by GC-MS. Thus, by stirring
this “unidentified” product with an excess of acetic anhydride
and pyridine, followed by a regular workup and silica gel
chromatography, the pure 7-MeO isomer (3ia′) could be
1
obtained in a 40% yield. The H NMR spectral data now
matched the literature values.18 Similarly, compound 3id′, the
7-MeO isomer from the reaction of 1i and 2d, could be isolated
pure in about a 42% yield.
The regioselectivity in this cycloaddition, especially with the
aryne derived from 1i, can be explained as shown in Scheme 2.
For a sydnone, there are three resonance structures (A, B, and
C, Scheme 2), and cycloaddition with the aryne should arise
from the latter two. Since the aryne derived from 1i is known to
be attacked preferentially by nucleophiles at the meta position
(with respect to the OMe group) for both electronic and steric
reasons,19 resonance structure B should lead to formation of
the 7-OMe regioisomer 3ia′, while resonance structure C
should lead to formation of the 4-OMe regioisomer 3ia. While
we typically draw the structure of sydnones as either A or B,
Mechanistic Investigation. To gain further insight into
this reaction, we conducted a brief Density Functional Theory
and ab initio calculation of the reaction path using Gaussian 09.
Geometry optimizations were performed with hybrid B3LYP
functions in conjunction with the 6-31G(d) basis set. Higher-
level relative energies were computed at the MP2/6-311+G-
(d,p) level based on the B3LYP/6-31G(d) optimized geo-
metries. The schematic potential energy surface of the reaction
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Figure 1. Schematic potential energy surface with zero-point energy (ZPE) corrections at the MP2/6-311+G(d,p) level (units in kilojoules per
mole). The values in parentheses are those obtained at the B3LYP/6-31G(d) level. The energy of the reactants is set to zero as a reference.
with zero-point energy corrections is plotted in Figure 1. As can
be seen, the initial [3 + 2] cycloaddition is an exothermic step.
A subsequent retro-[4 + 2] reaction is again exothermic. Since
we were not able to find the transition states of these
cycloaddition and cycloreversion processes, a relatively smooth
potential energy surface may exist.
Elaboration of 2H-Indazoles. As our approach to 2H-
indazoles tolerates halogen substituents, those halogen atoms
offer an ideal site for further elaboration by subsequent Pd-
catalyzed cross-couplings. Such a strategy can quickly afford a
library of structurally diverse, highly functionalized 2H-
indazoles. In this regard, we have demonstrated the feasibility
of such elaborations by converting 3at to the corresponding 3-
aryl- and 3-(1-alkynyl)-2H-indazoles using Suzuki−Miyaura25
and Sonogashira26 reactions, respectively (Scheme 3).27 By
our direct new synthesis of alkynylsydnones14 is unable to
prepare indazoles like 5at, and, therefore, the route described in
Scheme 3 provides an effective route toward such compounds.
CONCLUSIONS
■
This work affords an efficient, new, synthetic route to 2H-
indazoles by the [3 + 2] cycloaddition of arynes and sydnones.
The reaction is applicable to a variety of sydnones and silylaryl
triflates and affords the corresponding cycloadducts in
moderate to excellent yields. Compared with literature
protocols, our approach offers very mild reaction conditions,
high yields, and no contamination by 1H-indazoles. The
resulting halogen-substituted 2H-indazoles are readily elabo-
rated to more complex products using known organopalladium
chemistry. Thus, the versatility of the cycloaddition and the
tolerance of halogen make this methodology ideal for
pharmaceutical chemistry.
Scheme 3. Suzuki−Miyaura and Sonogashira Coupling of
2H-Indazoles
EXPERIMENTAL SECTION
■
General Information. All reagents purchased from commercial
sources were used as received. The solvents THF and MeCN were
distilled over Na/benzophenone and CaH2, respectively. The aryne
precursors were used as received; those not commercially available
were prepared according to literature procedures.29,17 The sydnones
were prepared as outlined below. The silica gel for column
chromatography was supplied as 300−400 mesh or 230−400
mesh.30 Powdered CsF was used as received and stored in a
desiccator. TBAF (either 1 M in THF solution or anhydrous solid)
was used as received. The solid TBAF was stored in a desiccator as
well.
1
All melting points were measured and are uncorrected. The H and
13C NMR spectra were recorded and are referenced to the residual
1
solvent signals (7.26 ppm for H in CDCl3 and 77.2 ppm for 13C in
modifying the structure of the sydnones and arynes,28 this
approach can be easily exploited to provide more derivatives for
potential biological activity screening. It should be noted that
CDCl3).
All aryne cycloaddition reactions were carried out in oven-dried
glassware and were magnetically stirred. A nitrogen atmosphere was
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not used, except that a balloon of nitrogen was attached to the reaction
flask for the ventilation of CO2.
3-(4-Methoxyphenyl)sydnone (2e). The corresponding amino
acid was prepared from 4-methoxylaniline following route 1 in a 50%
overall yield. Sydnone 2e was synthesized from this amino acid
following protocol 1 as an off-white solid (78% overall yield): 1H
NMR (400 MHz, CDCl3) δ 7.65 (d, J = 9.2 Hz, 2 H), 7.08 (d, J = 8.8
Hz, 2 H), 6.64 (s, 1 H), 3.91 (s, 3 H).
3-(3,4-Methylenedioxyphenyl)sydnone (2f). The correspond-
ing amino acid was prepared from 3,4-methylenedioxyaniline following
route 1 in a 60% overall yield. Sydnone 2f was synthesized from this
amino acid following protocol 1 as a brown solid (27% overall yield):
1H NMR (400 MHz, CDCl3) δ 7.25−7.15 (m, 2 H), 6.96 (d, J = 8.3
Hz, 1 H), 6.64 (s, 1 H), 6.14 (s, 2 H).
Computational Methods. All electronic structure calculations
involved in this work utilized the Gaussian 09 program package.31 The
geometries and frequencies of all the stationary points (including
reactants, intermediates, and products) were calculated by Becke’s
three-parameter nonlocal-exchange functional with the nonlocal
correlation functional of Lee−Yang−Parr (B3LYP) using the 6-
31G(d) basis set. To get more reliable reaction energies, single-point
corrections were performed by restricted or unrestricted second-order
Møller−Plesset perturbation theory (MP2) with the 6-311+G(d,p)
basis set using the B3LYP optimized geometries.
3-(4-Nitrophenyl)sydnone (2g). To 0.75 g of glycine (10 mmol)
was added 10 mL of tetrabutylammonium hydroxide in methanol (1
M, 10 mmol, 1.0 equiv); the solvent was removed under vacuum, and
the residue was dissolved in 20 mL of DMSO. p-Fluoronitrobenzene
(1.55 g, 11 mmol, 1.1 equiv) and 1.51 g of K2CO3 (11 mmol, 1.1
equiv) were added, and the mixture was allowed to react under gentle
warming (45 °C) with stirring until completion (monitored by TLC).
The mixture was then poured into cold water, acidified with HCl, and
extracted with ethyl acetate. The combined organic layers were
evaporated under vacuum and the residue was purified by column
chromatography (5:1 petroleum ether/EtOAc) to afford 1.2 g (65%
yield) of the desired amino acid as a yellow solid.33 Sydnone 2g was
then synthesized from this amino acid following protocol 1 as an off-
Preparation of the Sydnones. All the sydnones were prepared
as follows. Due to long T1 relaxation times, the acquisition of 13C
NMR spectra for many sydnones could not be achieved, even after an
overnight acquisition of 8000 scans on a 400 MHz instrument.
3-Phenylsydnone (2a).12a To a suspension of 5.00 g of N-
phenylglycine (33 mmol) in 60 mL of water at 0 °C was added
dropwise a solution of 3.50 g of NaNO2 (51 mmol, 1.5 equiv) in 20
mL of water. The mixture was stirred at 0 °C for an additional 20 min,
and the resultant clear red solution was filtered while cold. A scoop of
activated charcoal (ca. 200−300 mg) was added, and the mixture was
stirred for a few minutes before being filtered again. The intermediate
N-nitroso-N-phenylglycine was precipitated from the filtrate by the
addition of 10 mL of concentrated HCl and was then collected by
filtration. It was washed with cold water and dried overnight under a
high vacuum. The resulting solid was then dissolved in 25 mL of acetic
anhydride and the mixture was heated to 100 °C for 1.5 h. After being
cooled to room temperature, the resulting mixture was poured into
300 mL of ice water. A yellow solid formed, which was triturated by
stirring for a few minutes in this cold water. The solid was filtered,
washed thoroughly with water until no smell of acetic acid remained,
and dried under a high vacuum overnight to afford 3.37 g of product
(63% yield) as off-white crystals. This representative procedure for
preparing sydnones from the corresponding amino acid is identified as
protocol 1: 1H NMR (400 MHz, CDCl3) δ 7.77−7.58 (m, 5 H), 6.75
(s, 1 H).
1
white solid (36% overall yield): H NMR (400 MHz, CDCl3) δ 8.52
(d, J = 8.8 Hz, 2 H), 7,98 (d, J = 8.8 Hz, 2 H), 6.84 (s, 1 H).
3-Methylsydnone (2h). To an ice-cold solution of 6.7 mL of
conc HCl and 3.56 g of sarcosine (40 mmol) in 10 mL of water was
added a saturated solution of 5.52 g of NaNO2 (80 mmol) in water.
The mixture was stirred at 0 °C for 1 h and then extracted with ethyl
acetate three times. The combined organic layers were concentrated
under a vacuum to obtain N-nitroso-N-methylglycine as a yellow oil.
The resulting oil was dissolved in 4 mL of dry ether and charged
dropwise with ∼500 μL of trifluoroacetic anhydride (3.6 mmol, 1.8
equiv) at 0 °C. The reaction was stirred at 0 °C for a few minutes and
gradually warmed to room temperature and stirred for another 1 h.
The solvents were evaporated, and the residue was dissolved in EtOAc.
Solid NaHCO3 was added to neutralize the excess acid and was
removed by filtration. The EtOAc was evaporated and the residue was
purified by chromatography (2:1 petroleum ether/EtOAc) to yield
300 mg of the desired sydnone (8% overall yield) as a yellow oil. This
representative precedure for preparing sydnones from the correspond-
ing amino acid is identified as protocol 2: 1H NMR (400 MHz,
CDCl3) δ 6.32 (s, 1 H), 4.07 (s, 3 H).
3-(4-Chlorophenyl)sydnone (2b). A mixture of 5.10 g of 4-
chloroaniline (40 mmol), 5.14 mL of ethyl chloroacetate (48 mmol,
1.2 equiv), and 6.53 g of NaOAc·3H2O (48 mmol, 1.2 equiv) in 10 mL
of ethanol was refluxed in a 100 °C oil bath overnight. After being
cooled to room temperature, the mixture was poured into ice water,
and the precipitate was filtered and dried. The crude product, N-(4-
chlorophenyl)glycine ethyl ester, after crystallization from ethanol
(4.01 g, 47% yield), was an off-white solid. It is strongly suggested that
this intermediate be purified, either through recrystallization or
column chromatography. The resulting ester (3.00 g, 14 mmol) was
stirred with 1.01 g of LiOH (3.0 equiv) in 30 mL of THF/water (1:1)
at 0 °C. After 2 h at 0 °C, the reaction mixture was gradually warmed
up to room temperature, where the pH was adjusted to 3−4 with
concentrated HCl. The precipitate was filtered and dried to afford 2.53
g of N-(4-chlorophenyl)glycine (98% yield) as an off-white solid (62%
overall yield). This representative procedure for preparing an amino
acid is identified as route 1.32 Sydnone 2b was then synthesized as an
off-white solid (72% overall yield) from the resulting amino acid
3-Benzylsydnone (2i). This sydnone was synthesized from N-
benzylglycine as a white solid (39% overall yield) following protocol
2: 1H NMR (400 MHz, CDCl3) δ 7.45 (overlap, 3 H), 7.39 (overlap, 2
H), 6.21 (s, 1 H), 5.36 (s, 2 H).
3,4-Cyclopenta[c]sydnone (2j). This sydnone was prepared
according to a literature procedure34 as a brown oil (∼11% overall
yield).
3-(4-Chlorophenyl)-4-(isobutyl)-sydnone (2k). To a round-
bottom flask equipped with a stir bar was added 1.32 g of L-leucine (10
mmol), followed by 190 mg of CuI (1 mmol, 10 mol %), 3.04 g of
anhydrous K2CO3 (22 mmol, 2.2 equiv), 2.87 g of 4-bromochlor-
obenzene (15 mmol, 1.5 equiv), and 9 mL of undistilled dimethyl
sulfoxide (DMSO). The reaction system was flushed with nitrogen.
The flask was sealed with a Teflon stopper and placed in a 70 °C oil
bath. The suspension was vigorously stirred. After 15 h, the stirring
was found to be difficult, and another 4 mL of DMSO was added. The
reaction was stopped at 40 h when the color changed from a purple-
brown to blue. The reaction was poured into ice water and
concentrated HCl was added until the pH reached 3−4. The
precipitate was filtered, washed thoroughly with cold water (slightly
acidified by HCl to pH ∼4), and dried under a high vacuum to yield
2.6 g of crude N-(4-chlorophenyl)leucine as a slightly green solid
(yield >100%).12f,g It should be noted that this method did not work
for Met or Thr. This crude amino acid was used in the next step
without further purification.
1
following protocol 1: H NMR (400 MHz, CDCl3) δ 7.74−7.67 (m,
2H), 7.64−7.56 (m, 2H), 6.79 (s, 1H).
3-(4-Bromophenyl)sydnone (2c). The corresponding amino
acid was prepared from 4-bromoaniline following route 1 in a 65%
overall yield. Sydnone 2c was synthesized from this amino acid
1
following protocol 1 as an off-white solid (50% overall yield): H
NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.8
Hz, 2 H), 6.73 (s, 1 H).
3-(4-Methylphenyl)sydnone (2d). The corresponding amino
acid was prepared from 4-methylaniline following Route 1 in a 53%
overall yield. Sydnone 2d was synthesized from this amino acid
following Protocol 1 as an off-white to cream solid (60% overall
yield): 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2 H), 7.42
(d, J = 8.2 Hz, 2 H), 6.72 (s, 1 H), 2.49 (s, 3 H).
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To a solution of 500 mg (∼2 mmol considering possible impurities)
of crude N-(4-chlorophenyl)leucine in 3 mL of undistilled DME was
added dropwise ∼400 μL of isoamyl nitrite (3 mmol, 1.5 equiv) at
room temperature. The mixture was allowed to stir for 2 d before the
solvent was removed under reduced pressure. The solid was triturated
with petroleum ether and filtered. The cake was washed with
petroleum ether and air-dried. The solid was dissolved in 4 mL of dry
ether and was charged dropwise with ∼500 μL of trifluoroacetic
anhydride (3.6 mmol, 1.8 equiv) at 0 °C. The reaction was stirred at 0
°C for a few minutes and gradually warmed to room temperature and
stirred for another 1 h. The solvents were evaporated, and the residue
was dissolved in EtOAc. The excess acid present was neutralized by
the addition of solid NaHCO3, which was then removed by filtration.
The EtOAc was evaporated and the residue was purified by
chromatography (3:1 petroleum ether/EtOAc) to yield 130 mg of
the desired sydnone (26% overall yield) as a light brown oil: 1H NMR
(400 MHz, CDCl3) δ 7.62 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.7 Hz, 2
H), 2.37 (d, J = 7.4 Hz, 2 H), 1.88 (dt, J = 13.6, 6.8 Hz, 1 H), 0.80 (d, J
= 6.6 Hz, 6 H).
mmol) in 3 mL of toluene was added over 6 h using a syringe pump
while the reaction was stirred open to the air. The reaction was
allowed to stir for an additional 2 h after the addition, and then EtOAc
and water were added. The layers were separated and the EtOAc was
washed with brine, dried over MgSO4, filtered, and evaporated. The
residue was purified by column chromatography (petroleum ether/
EtOAc) to afford 82 mg of 2s as a yellow solid (69% yield): 1H NMR
(400 MHz, CDCl3) δ 7.87−7.81 (m, 2 H), 7.67−7.61 (m, 2 H), 7.44−
7.31 (m, 5 H).
4-Iodo-3-phenylsydnone (2t).15 To a solution of 243 mg of
sydnone 2a (1.5 mmol) in 2.5 mL of acetic acid was added 185 mg of
NaOAc (2.25 mmol, 1.5 equiv.), followed by a solution of 366 mg of
ICl (2.25 mmol, 1.5 equiv.) in 1.5 mL of acetic acid. The mixture was
allowed to stir for 3 h, then quenched with water and the solid was
collected by filtration. The cake was washed with drops of cold ethanol
and dried under vacuum to afford 272 mg of product (63%) as a
brown solid. This representative procedure for preparing functional-
ized sydnones is identified as protocol 4: 1H NMR (400 MHz,
CDCl3) δ 7.73 (t, J = 7.2 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 2 H), 7.60 (d, J
= 7.6 Hz, 2 H).
3-(4-Chlorophenyl)-4-(4-methoxyphenyl)sydnone (2o).13
To a mixture of 197 mg of N-(4-chlorophenyl)sydnone (1.0 mmol),
351 mg of 4-iodoanisole (1.5 mmol, 1.5 equiv), 11 mg of Pd(OAc)2
(0.05 mmol, 5 mol %), 26 mg of PPh3 (0.1 mmol, 10 mol %), and 276
mg of anhydrous K2CO3 in a 10 mL round-bottom flask was added 2
mL of undistilled DMF. The flask was fitted with an air condenser and
placed in a 120 °C oil bath overnight, during which time the reaction
mixture was stirred open to the air. The mixture was cooled to room
temperature, poured into 30 mL of water, and extracted three times
with EtOAc. The combined extracts were washed once with brine,
dried over MgSO4, filtered, and evaporated. The residue was purified
by column chromatography (petroleum ether/EtOAc) to afford 145
mg of 2o as a yellow solid (48% yield). This representative procedure
3-(4-Bromophenyl)-4-iodosydnone (2u). This sydnone was
prepared from sydnone 2c as a brown solid (60% yield) following
protocol 4: mp 160−162 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d,
J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H); LRMS (ESI) 367 (M + H);
HRMS (ESI) calcd for C8H5BrIN2O2 (M + H) 366.8574, found
366.8574.
4-Acetyl-3-phenylsydnone (2v).16 To a solution of 0.81 g of
sydnone 2a (5 mmol) in 5 mL of acetic anhydride was added 0.89 g of
NBS (5 mmol). The mixture was allowed to stir for 4 h, poured into
20 mL of ice water, and extracted by EtOAc. The combined organic
layers were washed with saturated NaHCO3 solution, dried over
Na2SO4, and evaporated under vacuum. The residue was purified by
column chromatography (5:1 petroleum ether/EtOAc) to afford 529
1
for preparing functionalized sydnones is identified as protocol 3: H
1
NMR (400 MHz, CDCl3) δ 7.57−7.51 (m, 2 H), 7.47−7.40 (m, 2 H),
mg of product (52% yield) as colorless crystals: H NMR (400 MHz,
7.24−7.17 (m, 2 H), 6.87−6.79 (m, 2 H), 3.79 (s, 3 H).
CDCl3) δ 7.83 (d, J = 7.6 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.23 (d, J
= 7.6 Hz, 1 H).
3-Phenyl-4-vinylsydnone (2l). This sydnone was prepared from
sydnone 2a and vinyl bromide as a brown solid (40% yield) following
General Procedure for the Synthesis of 2H-Indazoles. To an
oven-dried 10 mL round-bottom flask equipped with a stir bar were
added 140 mg of benzyne precursor (∼0.48 mmol, ∼1.2 equiv) and
0.4 mmol of sydnone. THF (4 mL) was added, and the mixture was
stirred until all solid dissolved. To this solution was added TBAF
(∼160 mg of solid or ∼630 μL of 1M THF solution, ∼1.6 equiv) in
one portion. The flask was sealed with a septum, and a nitrogen
balloon was attached. The reaction mixture was stirred at room
temperature overnight. Upon completion, the reaction mixture was
poured into saturated NaHCO3 and extracted three times with EtOAc.
The combined extracts were washed once with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by column
chromatography (petroleum ether/EtOAc) to afford the 2H-indazole.
2-Phenyl-2H-indazole (3aa). Following the general procedure,
this product was isolated as a white solid: mp 79−81 °C (lit35 81−82
°C); Rf = 0.45 (6:1 petroleum ether/EtOAc);36 1H NMR (400 MHz,
CDCl3) δ 8.41 (s, 1 H), 7.92−7.89 (m, 2 H), 7.81 (dd, J = 8.8, 0.9 Hz,
1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.56−7.50 (m, 2 H), 7.43−7.38 (m, 1
H), 7.34 (ddd, J = 8.8, 6.6, 1.1 Hz, 1 H), 7.12 (ddd, J = 8.4, 6.6, 0.8
Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 149.7, 140.5, 129.5, 127.9,
126.8, 122.7, 122.4, 120.9, 120.40, 120.37, 117.9; LRMS (ESI): 217
(M + Na), 195 (M + H); HRMS (ESI): calcd for C13H11N2 (M + H)
195.0917, found 195.0916.
1
protocol 3: H NMR (300 MHz, CDCl3) δ 7.79−7.60 (m, 3 H),
7.59−7.50 (m, 2 H), 6.40−6.16 (m, 2 H), 5.41 (d, J = 10.6 Hz, 1 H).
4-(4-Acetylphenyl)-3-phenylsydnone (2m). This sydnone was
prepared from sydnone 2a and 4-bromoacetophenone as a yellow solid
1
(30% yield) following protocol 3: H NMR (300 MHz, CDCl3) δ
7.83 (d, J = 7.7 Hz, 2 H), 7.76−7.56 (m, 3 H), 7.54−7.44 (m, 2 H),
7.43−7.33 (m, 2 H), 2.54 (s, 3 H).
4-(4-Methoxyphenyl)-3-phenylsydnone (2n). This sydnone
was prepared from sydnone 2a and 4-iodoanisole as a yellow solid
1
(46% yield) following protocol 3: H NMR (400 MHz, CDCl3) δ
7.66 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.2 Hz, 2 H), 7.48 (d, J = 7.6 Hz,
2 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 3.78 (s, 3 H).
3,4-Bis(4-chlorophenyl)sydnone (2p). This sydnone was pre-
pared from sydnone 2b and 4-bromochlorobenzene as a brown solid
1
(44% yield) following protocol 3: H NMR (400 MHz, CDCl3) δ
7.60−7.55 (m, 2 H), 7.47−7.42 (m, 2 H), 7.31−7.27 (m, 2 H), 7.24
7.20 (m, 2 H).
3-(4-Chlorophenyl)-4-(2-thiophenyl)sydnone (2q). This syd-
none was prepared from sydnone 2b and 2-iodothiophene as a brown
solid (50% yield) following protocol 3: 1H NMR (400 MHz, CDCl3)
δ 7.65 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 3.7
Hz, 1 H), 7.28 (d, J = 5.0 Hz, 1 H), 7.02 (t, J = 4.5 Hz, 1 H).
3-(4-Chlorophenyl)-4-(2-pyridyl)sydnone (2r). This sydnone
was prepared from sydnone 2b and 2-bromopyridine as a brown solid
2-(4-Chlorophenyl)-2H-indazole (3ab). White solid: mp 141−
143 °C; Rf = 0.50 (6:1 petroleum ether/EtOAc);36 1H NMR (400 MHz,
CDCl3) δ 8.39 (s, 1 H), 7.89−7.84 (m, 2 H), 7.77 (d, J = 8.8 Hz, 1 H),
7.71 (d, J = 8.5 Hz, 1 H), 7.53−7.48 (m, 2 H), 7.33 (ddd, J = 8.6, 6.6,
0.8 Hz, 1 H), 7.17−7.09 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ
149.8, 138.9, 133.5, 129.7, 127.1, 122.8, 122.7, 122.0, 120.35, 122.30,
117.8; LRMS (ESI) 251 (M + Na), 229 (M + H); HRMS (ESI) calcd
for C13H10ClN2 (M + H) 229.0527, found 229.0525.
1
(60% yield) following protocol 3: H NMR (400 MHz, CDCl3) δ
8.25 (d, J = 4.6 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.75 (t, J = 7.8 Hz,
1 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H), 7.13 (dd, J =
7.4, 4.9 Hz, 1 H).
3-(4-Chlorophenyl)-4-(phenylethynyl)sydnone (2s).14 A sol-
ution of 79 mg of sydnone 2b (0.4 mmol) in 2 mL of toluene was
charged with 4.5 mg of Pd(OAc)2 (5 mol %), 6.8 mg of CuCl2·2H2O
(10 mol %), and 186 mg of Ag2O (2.0 equiv), and then heated to 75
°C in an open flask. A solution of 88 μL of phenylacetylene (0.6
2-(4-Bromophenyl)-2H-indazole (3ac). Yellow solid: mp 146−
148 °C; Rf = 0.38 (5:1 petroleum ether/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 8.36 (s, 1 H), 7.79−7.75 (m, 3 H), 7.68 (d, J = 8.4 Hz, 1 H),
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7.63 (d, J = 9.2 Hz, 2 H), 7.32 (dd, J = 7.6, 6.8 Hz, 1 H), 7.11 (t, J =
7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 150.1, 139.7, 132.8,
127.3, 123.1, 122.9, 122.4, 121.6, 120.6, 120.4, 118.1; LRMS (ESI) 273
(M + H); HRMS (ESI) calcd for C13H10BrN2 (M + H) 273.0022,
found 273.0030.
219 (M − H); HRMS (EI) calcd for C15H12N2 (M) 220.1000, found
220.0990.
3-(4-Acetylphenyl)-2-phenyl-2H-indazole (3am). Yellow
solid: mp 135−137 °C (lit18 136−138 °C); Rf = 0.36 (2:1 hexanes/
1
EtOAc); H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 2 H),
2-(4-Tolyl)-2H-indazole (3ad). White solid: mp 101−103 °C; Rf
= 0.44 (6:1 petroleum ether/EtOAc);36 1H NMR (400 MHz, CDCl3) δ
8.37 (d, J = 0.9 Hz, 1 H), 7.83−7.76 (m, 3 H), 7.71 (dt, J = 8.5, 1.0 Hz,
1 H), 7.38−7.29 (m, 3 H), 7.11 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H), 2.43
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 149.6, 138.3, 137.9, 130.1,
126.6, 122.7, 122.3, 120.8, 120.30, 120.28, 117.9, 21.0; LRMS (ESI)
231 (M + Na), 209 (M + H); HRMS (ESI) calcd for C14H13N2 (M +
H) 209.1073, found 209.1072.
7.82 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.47−7.36 (m, 8
H), 7.18 (t, J = 7.6 Hz, 1 H), 2.61 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 197.3, 149.0, 139.9, 136.2, 134.4, 133.9, 129.6, 129.1, 128.6,
128.6, 127.1, 125.9, 123.2, 121.8, 120.0, 117.9, 26.6; LRMS (EI) 312
(M); HRMS (EI) calcd for C21H16N2O (M) 312.1263, found
312.1262.
3-(4-Methoxyphenyl)-2-phenyl-2H-indazole (3an). Yellow
1
solid: mp 103−105 °C; Rf = 0.52 (2:1 hexanes/EtOAc); H NMR
2-(4-Methoxyphenyl)-2H-indazole (3ae). Yellow solid: mp
130−132 °C; Rf = 0.25 (5:1 petroleum ether/EtOAc); 1H NMR
(400 MHz, CDCl3) δ 8.30 (s, 1 H), 7.79 (d, J = 8.8 Hz, 3 H), 7.69 (d,
J = 8.4 Hz, 1 H), 7.31 (dd, J = 7.6, 7.2 Hz, 1 H), 7.10 (t, J = 7.4 Hz, 1
H), 7.01 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 159.4, 149.7, 134.3, 126.7, 122.8, 122.6, 122.4, 120.5, 120.4,
117.9, 114.8, 55.8; LRMS (ESI) 257 (M + Na), 225 (M + H); HRMS
(ESI) calcd for C14H13N2O (M + H) 225.1022, found 225.1026.
2-(3,4-Methylenedioxyphenyl)-2H-indazole (3af). Pale white
solid: mp 117−118 °C; Rf = 0.31 (6:1 petroleum ether/EtOAc);36 1H
NMR (400 MHz, CDCl3) δ 8.29 (s, 1 H), 7.77 (dd, J = 8.8, 0.9 Hz, 1
H), 7.69 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 2.2 Hz, 1 H), 7.35−7.29 (m,
2 H), 7.11 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H),
6.07 (s, 2 H); 13C NMR (100 MHz, CDCl3) δ 149.1, 148.4, 147.3,
135.2, 126.7, 125.6, 122.3, 120.5, 120.2, 117.7, 114.4, 108.4, 103.1,
101.9; LRMS (ESI) 261 (M + Na), 239 (M + H); HRMS (ESI) calcd
for C14H11O2N2 (M + H) 239.0815, found 239.0812.
(400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1 H); 7.69 (d, J = 8.4 Hz, 1
H), 7.39 (d, J = 2.4 Hz, 2 H), 7.38−7.33 (m, 4 H), 7.27 (d, J = 8.8 Hz,
2 H), 7.12 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2 H); 3.82 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 159.7, 149.0, 140.4, 135.5, 131.1,
129.1, 128.3, 127.1, 126.1, 122.4, 122.2, 121.7, 120.8, 117.8, 114.4,
55.4; LRMS (EI) 300 (M); HRMS (EI) calcd for C20H16N2O (M)
300.1263, found 300.1272.
2-(4-Chlorophenyl)-3-(4-methoxyphenyl)-2H-indazole
(3ao). Slightly brown solid: mp 122−124 °C; Rf = 0.39 (6:1 petroleum
ether/EtOAc);36 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1
H), 7.68 (d, J = 8.5 Hz, 1 H), 7.42−7.33 (m, 5 H), 7.30−7.26 (m, 2
H), 7.13 (ddd, J = 8.4, 6.6, 0.7 Hz, 1 H), 6.99−6.91 (m, 2 H), 3.86 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.7, 149.0, 138.8, 135.4,
133.9, 130.9, 129.2, 127.2, 127.1, 122.4, 121.8, 121.7, 120.6, 117.6,
114.4, 55.3; LRMS (ESI) 357 (M + Na), 335 (M + H); HRMS (ESI)
calcd for C20H16ClN2O (M + H) 335.0946, found 335.0942.
2,3-Bis(4-chlorophenyl)-2H-indazole (3ap). Pale white solid:
mp 126−129 °C; Rf = 0.52 (6:1 petroleum ether/EtOAc);36 1H NMR
(400 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1
H), 7.43−7.35 (m, 7 H), 7.32−7.27 (m, 2 H), 7.17 (ddd, J = 8.5, 6.6,
0.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 149.1, 138.4, 134.7,
134.3, 134.1, 130.8, 129.35, 129.29, 128.0, 127.4, 127.1, 123.1, 121.8,
120.1, 117.8; LRMS (ESI) 361 (M + Na), 339 (M + H); HRMS (ESI)
calcd for C19H13Cl2N2 (M + H) 339.0450, found 339.0448.
2-Methyl-2H-indazole (3ah). Yellow oil: Rf = 0.21 (2:1
1
petroleum ether/EtOAc); H NMR (400 MHz, CDCl3) δ 7.88 (s, 1
H), 7.70 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.28 (t, J = 7.2
Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 4.21 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 149.2, 126.0, 123.7, 122.3, 121.8, 120.1, 117.4, 40.5;
LRMS (APCI) 133 (M + H); HRMS (APCI) calcd for C8H9N2 (M +
H) 133.0760, found 133.0762.
2-Benzyl-2H-indazole (3ai). Yellow oil: Rf = 0.31 (5:1 petroleum
ether/EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1 H), 7.73 (dd,
J = 8.7, 0.9 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.34−7.30 (m, 3 H),
2-(4-Chlorophenyl)-3-(2-thiophenyl)-2H-indazole (3aq). Yel-
low solid: mp 99−101 °C; Rf = 0.49 (6:1 petroleum ether/EtOAc).36
The product spot overlapped with a highly fluorescent spot that
immediately follows the product spot. Performing column chromatog-
raphy with 8:1:0.4 petroleum ether/CH2Cl2/EtOAc offers some help
7.27−7.23 (m, 3 H), 7.06 (dd, J = 8.1, 7.5 Hz, 1 H), 5.57 (s, 2 H); 13
C
NMR (100 MHz, CDCl3) δ 149.0, 135.9, 129.1, 128.5, 128.1, 126.2,
123.0, 122.2, 121.9, 120.3, 117.7, 57.6; LRMS (APCI) 209 (M + H);
HRMS (APCI) calcd for C14H13N2 (M + H) 209.1073, found
209.1078.
2,3-Dihydro-1H-pyrrolo[1,2-b]indazole (3aj). Off-white solid:
mp 99−100 °C; Rf = 0.31 (1:1 CH2Cl2/EtOAc);36 1H NMR (400
MHz, CDCl3) δ 7.67 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 8.3 Hz, 1 H),
7.26 (t, J = 7.6 Hz, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 4.42 (t, J = 7.3 Hz, 2
H), 3.18 (t, J = 7.2 Hz, 2 H), 2.84−2.63 (m, 2 H); 13C NMR (100
MHz, CDCl3) δ 153.5, 138.8, 125.5, 120.3, 119.8, 117.6, 116.1, 48.9,
25.7, 23.0; LRMS (ESI) 181 (M + Na), 159 (M + H); HRMS (ESI)
calcd for C10H11N2 (M + H) 159.0917, found 159.0915.
1
in separation and purification of the desired product: H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H),
7.49−7.35 (m, 6 H), 7.19 (ddd, J = 8.4, 6.6, 0.8 Hz, 1 H), 7.10 (dd, J =
5.1, 3.6 Hz, 1 H), 7.03 (dd, J = 3.6, 1.1 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 148.9, 138.4, 134.7, 129.9, 129.6, 129.3, 128.4, 127.69,
127.65, 127.5, 127.3, 123.0, 121.9, 120.5, 117.7; LRMS (ESI) 333 (M
+ Na), 311 (M + H); HRMS (ESI) calcd for C17H12ClSN2 (M + H)
311.0404, found 311.0404. The contaminant (the fluorescent spot)
shows a series of nonoverlapped signals as follows: 7.87 (d, J = 8.5
Hz), 7.50 (apparent t, J = 9.0 Hz), 7.13 (d, J = 3.8 Hz), 6.88 (d, J = 3.8
Hz).
2-(4-Chlorophenyl)-3-isobutyl-2H-indazole (3ak). Slightly or-
ange solid: mp 77−79 °C; Rf = 0.47 (6:1 petroleum ether/EtOAc);36 1H
NMR (400 MHz, CDCl3) δ 7.72−7.68 (m, 1 H), 7.65 (dt, J = 8.5, 1.0
Hz, 1 H), 7.55−7.44 (m, 4 H), 7.33 (ddd, J = 8.8, 6.6, 1.1 Hz, 1 H),
7.08 (ddd, J = 8.5, 6.6, 0.8 Hz, 1 H), 2.91 (d, J = 7.4 Hz, 2 H), 2.04−
1.89 (m, 1 H), 0.83 (d, J = 6.6 Hz, 6 H); 13C NMR (100 MHz,
CDCl3) δ 148.6, 138.7, 136.3, 134.8, 129.3, 127.6, 126.8, 121.5, 121.1,
120.4, 117.5, 34.1, 29.2, 22.5; LRMS (ESI) 307 (M + Na), 285 (M +
H); HRMS (ESI) calcd for C17H18ClN2 (M + H) 285.1153, found
285.1151.
2-(4-Chlorophenyl)-3-(2-pyridyl)-2H-indazole (3ar). Slightly
brown solid: mp 137−139 °C; Rf = 0.25 (6:1 petroleum ether/
EtOAc);36 1H NMR (400 MHz, CDCl3) δ 8.71−8.67 (m, 1 H), 7.93
(d, J = 8.5 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.71 (td, J = 7.8, 1.8 Hz,
1 H), 7.44−7.36 (m, 5 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.29−7.24 (m, 1
H), 7.21 (ddd, J = 8.5, 6.6, 0.7 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 150.2, 149.2, 149.1, 139.1, 136.5, 134.3, 134.1, 129.2, 127.3,
127.1, 124.6, 123.6, 122.6, 122.3, 120.7, 117.8; LRMS (ESI) 328 (M +
Na), 306 (M + H); HRMS (ESI) calcd for C18H13ClN3 (M + H)
306.0793, found 306.0790.
2-(4-Chlorophenyl)-3-phenylethynyl-2H-indazole (3as). Yel-
low solid: mp 141−144 °C; Rf = 0.50 (6:1 petroleum ether/EtOAc).36
The product spot overlapped with some spots that have a long
wavelength UV absorption. Performing column chromatography with
8:1:0.4 petroleum ether/CH2Cl2/EtOAc offers some help in
separation and purification of the desired product. The impurities
do not show more than minimum contamination by 1H NMR
2-Phenyl-3-vinyl-2H-indazole (3al). Yellow gel: Rf = 0.18 (5:1
1
hexanes ether/EtOAc); H NMR (400 MHz, CDCl3) δ 7.92 (d, J =
8.5 Hz, 1 H), 7.79 (d, J = 8.7 Hz, 1 H), 7.64−7.48 (m, 5 H), 7.43−
7.34 (m, 2 H), 7.23−7.15 (m, 1 H), 6.81 (dd, J = 17.8, 11.6 Hz, 1 H),
6.04 (dd, J = 17.8, 0.8 Hz, 1 H), 5.53 (dd, J = 11.6, 0.9 Hz, 1 H); 13
C
NMR (100 MHz, CDCl3) δ 148.8, 139.6, 133.2, 129.1, 128.8, 126.7,
126.2, 124.9, 122.7, 120.6, 120.3, 118.0, 117.7; LRMS (EI) 220 (M),
8848
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1
spectroscopy: H NMR (400 MHz, CDCl3) δ 8.01−7.95 (m, 2 H),
127.89, 127.4, 125.8, 124.3, 122.9, 122.7, 121.7, 121.3, 121.1, 120.9,
119.7, 117.9, 115.4, 19.3, 17.3; LRMS (ESI) 209 (M + H); HRMS
(ESI) calcd for C14H13N2 (M + H) 209.1073, found 209.1078.
2-Phenyl-2H-benzo[g]indazole and 2-Phenyl-2H-benzo[e]-
indazole (3ga + 3ga′). Yellow gel: Rf = 0.42 (5:1 hexanes/
EtOAc); 1H NMR (400 MHz, CDCl3, mixture of isomers, two sets of
signals) δ 8.74 (d, J = 8.0 Hz, 1 H), 8.71 (s, 1 H), 8.33 (s, 1 H), 8.12
(d, J = 7.6 Hz, 1 H), 7.93 (t, J = 7.2 Hz, 4 H), 7.83 (d, J = 8.0 Hz, 2
H), 7.74 (d, J = 9.2 Hz, 1 H), 7.62 (m, 2 H), 7.52 (m, 8 H), 7.38 (m, 3
H); 13C NMR (100 MHz, CDCl3, mixture of isomers) δ 148.9, 147.7,
140.7, 140.6, 132.9, 130.6, 129.72, 129.69, 129.3, 129.1, 128.6, 127.6,
127.5, 127.4, 127.2, 127.1, 126.9, 125.8, 125.6, 124.7, 123.6, 122.8,
121.2, 120.6, 120.5, 120.2, 120.0, 118.5, 117.9, 117.5; LRMS (ESI) 245
(M + H); HRMS (ESI) calcd for C17H13N2 (M + H) 245.1073, found
245.1064.
4-Methoxy-2-phenyl-2H-indazole (3ia). Following the general
procedure, this product was isolated as a white gel by collecting the
first spot: Rf = 0.24 (5:1 hexanes/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 8.48 (s, 1 H), 7.89 (d, J = 8.1 Hz, 2 H), 7.51 (t, J = 7.7 Hz, 2
H), 7.44−7.33 (m, 2 H), 7.31−7.18 (m, 1 H), 6.35 (d, J = 7.3 Hz, 1
H), 3.96 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 153.4, 151.2, 140.4,
129.5, 127.70, 127.65, 120.7, 119.0, 116.8, 110.3, 98.8, 55.2; LRMS
(EI) 224 (M), 209 (M-Me); HRMS (EI) calcd for C14H12N2O (M)
224.0950, found 224.0950. The 2D NMR spectra and the analysis are
included in the Supporting Information (SI).
7.87−7.78 (m, 2 H), 7.58−7.49 (m, 4 H), 7.43−7.36 (m, 4 H), 7.25−
7.21 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 148.7, 138.6, 134.3,
131.3, 129.19, 129.14, 128.6, 127.6, 125.6, 125.5, 123.5, 121.9, 120.2,
118.2, 100.7, 77.7 (one overlapped signal); LRMS (ESI) 329 (M + H);
HRMS (ESI) calcd for C21H14ClN2 (M + H) 329.0840, found
329.0837.
3-Iodo-2-phenyl-2H-indazole (3at). Off-white solid: mp 104−
105 °C; Rf = 0.42 (5:1 petroleum ether/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 8.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 2 H), 7.50 (m,
4 H), 7.36 (dd, J = 7.6, 6.8 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ 150.1, 140.6, 129.4, 129.1, 128.4, 127.7,
126.8, 123.3, 121.2, 118.4, 76.2; LRMS (ESI) 321 (M + H); HRMS
(ESI) calcd for C13H10IN2 (M + H) 320.9883, found 320.9884.
2-(4-Bromophenyl)-3-iodo-2H-indazole (3au). Yellow solid:
1
mp 159−161 °C; Rf = 0.38 (5:1 petroleum ether/EtOAc); H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 2
H), 7.54 (d, J = 8.8 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.4
Hz, 1 H), 7.18 (t, J = 7.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
150.4, 139.6, 132.5, 132.4, 128.7, 128.4, 128.0, 123.6, 121.3, 118.5,
76.0; LRMS (ESI) 399 (M + H); HRMS (ESI) calcd for C13H9BrIN2
(M + H) 398.8988, found 398.8988.
5,6-Dimethyl-2-phenyl-2H-indazole (3ba). White solid: mp
133−135 °C; Rf = 0.24 (5:1 hexanes/EtOAc); H NMR (400 MHz,
1
CDCl3) δ 8.21 (s, 1 H), 7.87 (d, J = 7.8 Hz, 2 H), 7.56 (s, 1 H), 7.49
(t, J = 7.8 Hz, 2 H), 7.40 (s, 2 H), 7.36 (t, J = 7.4 Hz, 1 H), 2.39 (s, 3
H), 2.34 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 149.6, 140.5, 137.2,
132.3, 129.4, 127.3, 121.8, 120.5, 119.0, 118.6, 116.5, 21.1, 20.5; LRMS
(EI) 222 (M), 207 (M − Me); HRMS (EI) calcd for C15H14N2 (M)
222.1157, found 222.1155.
7-Methoxy-2-phenyl-2H-indazole (3ia′). The second spot of
the aforementioned column chromatography afforded a yellow gel: Rf
= 0.12 (5:1 hexanes/EtOAc). This material was stirred with 1 mL of
Ac2O and 1 mL of pyridine at room temperature for 30 min. Then the
volatiles were evaporated under a vacuum, and the product was
5,6-Dimethoxy-2-phenyl-2H-indazole (3ca). White solid: mp
1
purified by column chromatography: H NMR (400 MHz, CDCl3) δ
147−148 °C (lit37 149−150 °C); Rf = 0.26 (2:1 hexanes/EtOAc); H
1
8.36 (s, 1 H), 7.93 (d, J = 8.0 Hz, 2 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.37
(t, J = 7.4 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 7.02 (dd, J = 8.4, 0.8 Hz,
1 H), 6.58 (d, J = 7.2 Hz, 1 H), 4.04 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 150.6, 143.5, 140.5, 129.6, 128.0, 124.5, 123.3, 121.2, 120.8,
112.5, 103.3, 55.7; LRMS (ESI) 225 (M + H), 247 (M + Na), 471
(2M + Na); HRMS (ESI) calcd for C14H13N2O (M + H) 225.1022,
NMR (400 MHz, CDCl3) δ 8.21 (s, 1 H), 7.84 (d, J = 7.7 Hz, 2 H),
7.49 (t, J = 7.9 Hz, 2 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.06 (s, 1 H), 6.89
(s, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
152.0, 148.4, 146.6, 140.5, 129.5, 127.0, 120.0, 119.1, 117.4, 96.9, 95.8,
55.9; LRMS (EI) 254 (M); HRMS (EI) calcd for C15H14N2O2 (M)
254.1055, found 254.1059.
1
found 225.1024. This regioisomer matches the reported H and 13C
5-Methyl-2-phenyl-2H-indazole and 6-Methyl-2-phenyl-2H-
indazole (3da + 3da′). Slightly yellow solid: Rf = 0.26 (5:1 hexanes/
EtOAc); 1H NMR (400 MHz, CDCl3, mixture of isomers, two sets of
signals) δ 8.32 (s, 1 H), 8.27 (s, 1 H), 7.89 (s, 2 H), 7.87 (s, 2 H), 7.71
(d, J = 8.9 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.53−7.47 (m, 4 H),
7.55 (s, 1 H), 7.43 (s, 1 H), 7.41−7.34 (m, 2 H), 7.17 (d, J = 8.6 Hz, 1
H), 6.96 (d, J = 8.5 Hz, 1 H), 2.48 (s, 3 H), 2.43 (s, 3 H); 13C NMR
(100 MHz, CDCl3, mixture of isomers) δ 150.3, 148.7, 140.5, 136.7,
131.7, 129.8, 129.4, 127.6, 125.4, 123.0, 121.1, 120.73, 120.70, 120.1,
119.8, 119.4, 118.3, 117.5, 116.1, 22.3, 21.8 (some overlap); LRMS
(EI) 208 (M); HRMS (EI) calcd for C14H12N2 (M) 208.1000, found
208.1003.
5-Methoxy-2-phenyl-2H-indazole and 6-Methoxy-2-phenyl-
2H-indazole (3ea + 3ea′). Yellow solid: Rf = 0.25 (5:1 hexanes/
EtOAc); 1H NMR (400 MHz, CDCl3, mixture of isomers, two sets of
signals) δ 8.27 (s, 1H), 8.22 (s, 0.8 H), 7.84 (d, J = 8.4 Hz, 3.6 H),
7.68 (d, J = 9.2 Hz, 0.8 H), 7.53 (d, J = 9.2 Hz, 1 H), 7.48 (t, J = 7.8
Hz, 3.6 H), 7.36−7.32 (m, 1.8 H), 7.04−7.02 (m, 1.8 H), 6.86 (d, J =
2.0 Hz, 0.8 H), 6.80 (dd, J = 8.8, 1.6 Hz, 1 H), 3.87 (s, 3 H), 3.82 (s,
2.4 H); 13C NMR (100 MHz, CDCl3, mixture of isomers) δ 159.5,
155.6, 151.0, 146.9, 140.7, 140.6, 129.6, 127.6, 127.5, 122.9, 122.2,
121.4, 120.7, 120.53, 120.50, 119.46, 119.41, 118.7, 118.0, 96.4, 94.7,
55.5, 55.4 (one overlapped signal); LRMS (ESI) 225 (M + H); HRMS
(ESI) calcd for C14H13N2O (M + H) 225.1022, found 225.1022.
4-Methyl-2-phenyl-2H-indazole and 7-Methyl-2-phenyl-2H-
indazole (3fa + 3fa′). Yellow oil: Rf = 0.35 (5:1 hexanes/EtOAc);
1H NMR (400 MHz, CDCl3, mixture of isomers, two sets of signals) δ
NMR spectral data.18
4-Methoxy-2-(4-methylphenyl)-2H-indazole (3id). Following
the general procedure, this product was isolated as a white gel by
1
collecting the first spot: Rf = 0.30 (5:1 hexanes/EtOAc); H NMR
(400 MHz, CDCl3) δ 8.43 (s, 1 H), 7.76 (d, J = 7.6 Hz, 2 H), 7.36 (d,
J = 8.4 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 2 H), 7.24−7.20 (m, 1 H), 6.34
(d, J = 7.2 Hz, 1 H), 3.94 (s, 3 H), 2.40 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 153.6, 151.3, 138.3, 137.9, 130.2, 127.7, 120.8, 119.1,
116.9, 110.4, 98.9, 55.4, 21.2; LRMS (ESI) 239 (M + H); HRMS
(ESI) calcd for C15H15N2O (M + H) 239.1179, found 239.1179.
7-Methoxy-2-(4-methylphenyl)-2H-indazole (3id′). The sec-
ond spot of the aforementioned column chromatography afforded a
yellow gel: Rf = 0.22 (5:1 hexanes/EtOAc). This material was stirred
with 1 mL of Ac2O and 1 mL of pyridine at room temperature for 30
min. Then the volatiles were evaporated under vacuum, and the
1
product purified by column chromatography: H NMR (400 MHz,
CDCl3) δ 8.31 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.26 (t, J = 9.2 Hz, 3
H), 7.01 (t, J = 7.8 Hz, 1 H), 6.57 (d, J = 7.6 Hz, 1 H), 4.03 (s, 3 H),
2.39 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 150.5, 143.3, 138.3,
137.9, 130.0, 124.4, 123.1, 121.0, 120.6, 112.4, 103.1, 55.6, 21.2; LRMS
(ESI) 239 (M + H), 261 (M + Na); HRMS (ESI) calcd for
C15H14N2ONa (M + Na) 261.0998, found 261.0999.
Procedure for the Suzuki−Miyaura Coupling with Boronic
Acids. To a 4 dram vial were added the starting material 3at (∼0.4
mmol), the boronic acid (1.5 equiv), KOH (3.0 equiv), and Pd(PPh3)4
(5 mol %) in 20:5:1 toluene/ethanol/H2O (4 mL in total). The
solution was vigorously stirred for 5 min at room temperature, flushed
with argon and sealed, and then heated to 80 °C until TLC revealed
complete conversion of the starting material. Upon cooling to room
temperature, the resulting reaction mixture was diluted with water and
extracted with EtOAc. The combined organic layers were dried over
8.35 (s, 1 H), 8.32 (s, 0.7 H), 7.88 (dd, J = 8.4, 2.0 Hz, 3.4 H), 7.62 (d,
J = 8.8 Hz, 1 H), 7.52−7.46 (m, 4.1 H), 7.37−7.34 (m, 1.7 H), 7.23−
7.19 (m, 1 H), 7.07−6.98 (m, 1.4 H), 6.84 (d, J = 6.8 Hz, 1 H), 2.68
(s, 2.1 H), 2.54 (s, 3 H); 13C NMR (100 MHz, CDCl3, mixture of
isomers) δ 150.3, 150.0, 140.8, 140.7, 130.7, 129.7, 128.2, 127.93,
8849
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Article
MgSO4, concentrated, and purified by column chromatography to
afford the following product.
3-(3,4-Methylenedioxyphenyl)-2-phenyl-2H-indazole (4at).
(2) (a) Andreonati, S.; Sava, V.; Makan, S.; Kolodeev, G. Pharmazie
1999, 54, 99. (b) Paluchowska, M. H.; Duszynska, B.; Klodzinska, A.;
Tatarzynska, E. Pol. J. Pharmacol. 2000, 52, 209. (c) Saczewski, F.;
Saczewski, J.; Hudson, A. L.; Tyacke, R. J.; Nutt, D. J.; Man, J.; Tabin,
P. Eur. J. Pharm. Sci. 2003, 20, 201. (d) Angelis, M. D.; Stossi, F.;
Carlson, K. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2005, 48, 1132.
Following the general procedure, this product was isolated as a brown
1
solid: mp 154−156 °C; Rf = 0.31 (5:1 hexanes/EtOAc); H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1
H), 7.45 (d, J = 6.8 Hz, 2 H), 7.42−7.33 (m, 4 H), 7.12 (dd, J = 8.0,
7.2 Hz, 1 H), 6.87−6.81 (m, 2 H), 6.78 (s, 1 H), 5.98 (s, 2 H); 13C
NMR (100 MHz, CDCl3) δ 149.0, 148.1, 147.9, 140.2, 135.3, 129.2,
128.4, 127.2, 126.1, 124.0, 123.5, 122.5, 121.8, 120.6, 117.8, 110.0,
108.9, 101.5; LRMS (ESI) 315 (M + H); HRMS (ESI) calcd for
C20H15N2O2 (M + H) 315.1128, found 315.1125.
́
(3) (a) Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.;
Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48, 6879. (b) Song, J.
J.; Yee, N. K. Org. Lett. 2000, 2, 519. (c) Haag, B.; Peng, Z.; Knochel,
P. Org. Lett. 2009, 11, 4270. (d) Taher, A.; Ladwa, S.; Rajan, S. T.;
Weaver, G. W. Tetrahedron Lett. 2000, 41, 9893. (e) Varughese, D. J.;
Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 2006, 47, 6795. (f) Lee,
K. Y.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2005, 46, 5387.
(g) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett. 2011, 13, 3542.
(4) (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
15716. (b) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973. (c) Liu,
Z.; Larock, R. C. Org. Lett. 2004, 6, 3739. (d) Liu, Z.; Larock, R. C.
Tetrahedron 2007, 63, 347. (e) Henderson, J. L.; Edwards, A. S.;
Greaney, M. F. J. Am. Chem. Soc. 2006, 128, 7426. (f) Jayanth, T. T.;
Procedure for the Sonogashira Coupling with a Terminal
Alkyne. To a 4 dram vial was added the starting material 3at (∼0.4
mmol), the alkyne (1.2 equiv), PdCl2(PPh3)2 (3 mol %), CuI (3 mol
%), DMF (1.5 mL) and Et2NH (1.5 mL). The solution was stirred at
room temperature, flushed with argon and sealed, and then heated to
60 °C until TLC analysis revealed complete conversion of the starting
material. The solution was allowed to cool and diluted with EtOAc.
The combined organic layers were dried over MgSO4, concentrated,
and purified by column chromatography to afford the following
product.
3-(3-Methoxyprop-1-ynyl)-2-phenyl-2H-indazole (5at). Yel-
low oil: Rf = 0.25 (5:1 hexanes/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 7.6 Hz, 2 H), 7.78 (dd, J = 15.6, 8.8 Hz, 2 H),
7.53 (t, J = 7.8 Hz, 2 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1
H), 7.20 (t, J = 7.4 Hz, 1 H), 4.41 (s, 2 H), 3.43 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 148.7, 140.2, 129.2, 128.9, 127.5, 126.1, 124.7,
123.6, 120.2, 118.5, 117.7, 96.7, 75.4, 60.7, 58.0; LRMS (ESI) 263 (M
+ H); HRMS (ESI) calcd for C17H15N2O (M + H) 263.1179, found
263.1180.
Cheng, C.-H. Chem. Commun. 2006, 894. (g) Pena, D.; Per
́
ez, D.;
, E.; Castedo, L. Org. Lett. 1999, 1, 1555. (h) Radhakrishnan, K.
V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 7533.
̃
Guitian
́
(i) Pena, D.; Per
121, 5827.
́
ez, D.; Guitian
́
, E.; Castedo, L. J. Am. Chem. Soc. 1999,
̃
(5) (a) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem.
Commun. 2001, 1880. (b) Yoshida, H.; Shirakawa, E.; Honda, Y.;
Hiyama, T. Angew. Chem., Int. Ed. Engl. 2002, 41, 3247. (c) Liu, Z.;
Larock, R. C. Org. Lett. 2003, 5, 4673. (d) Liu, Z.; Larock, R. C. Org.
Lett. 2004, 6, 99. (e) Jeganmohan, M.; Cheng, C.-H. Synthesis 2005,
1693. (f) Bhuvaneswari, S.; Jeganmohan, M.; Yang, M. C.; Cheng, C.
H. Chem. Commun. 2008, 2158.
(6) (a) Raminelli, C.; Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71,
4689. (b) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.;
Hsung, R. P. Org. Lett. 2009, 11, 3430. (c) Allan, K. M.; Stoltz, B. M. J.
Am. Chem. Soc. 2008, 130, 17270. (d) Gilmore, C. D.; Allan, K. M.;
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed computational results and full 1H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
́ ́
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558. (e) Perez, D.; Guitian,
E.; Castedo, L. J. Org. Chem. 1992, 57, 5911. (f) Matsumoto, T.;
Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568. (g) Hosoya,
T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994,
116, 1004. (h) Hussain, H.; Kianmehr, E.; Durst, T. Tetrahedron Lett.
2001, 42, 2245. (I) Soorukram, D.; Qu, T.; Barrett, A. G. M. Org. Lett.
2008, 10, 3833.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cwu@henu.edu.cn; larock@iastate.edu; fshi@henu.
edu.cn.
(7) (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112.
(b) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
(8) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2409.
(9) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C. J.
Org. Chem. 2008, 73, 219.
(10) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180.
(11) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12,
2234.
(12) (a) Thoman, C. J.; Voaden, D. J. Org. Synth. 1965, 45, 96.
(b) Baker, W.; Ollis, W. D.; Poole, V. D. J. Chem. Soc. 1950, 1542.
(c) Applegate, J.; Turnbull, K. Synthesis 1988, 1011. (d) Azarifar, D.;
Ghasemnejad-Borsa, H. Synthesis 2006, 1123. (e) Azarifar, D.;
Ghasemnejad-Borsa, H.; Tajbaksh, M.; Habibzadeh, S. Heterocycles
2007, 71, 1815. (f) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(g) Browne, D. L.; Vivat, J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J.
P. A J. Am. Chem. Soc. 2009, 131, 7762.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM070620 and
GM079593 to R.C.L.), the National Institutes of Health Center
for Chemical Methodology and Library Development at
University of Kansas (P50 GM069663 to R.C.L.), the National
Natural Science Foundation of China (No. 21002021 to F.S.),
and the Key Project of the Chinese Ministry of Education (No.
210127 to F.S.) for their generous financial support and the
State Key Laboratory of Physical Chemistry of Solid Surfaces
(Xiamen University) for providing computational resources.
We also thank Mr. Donald C. Rogness (Iowa State University)
for his help in preparation of the benzyne precursors and Mr.
Yong Wang (Henan University), Dr. Jiang Zhou (Peking
University), Mr. Shu-Lun Tang, and Dr. Kermal Harrata (both
Iowa State University) for their help in the spectroscopic
analysis.
(13) Rodriguez, A.; Fennessy, R. V.; Moran, W. J. Tetrahedron Lett.
2009, 50, 3942.
(14) Wu, C.; Li, P.; Fang, Y.; Zhao, J.; Xue, W.; Li, Y.; Larock, R. C.;
Shi, F. Tetrahedron Lett. 2011, 52, 3797.
(15) Browne, D. L.; Taylor, A. P.; Harrity, J. P. J. Org. Chem. 2010,
REFERENCES
■
(1) (a) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem.
2008, 4073. (b) Clutterbuck, L. A.; Posada, C. G.; Visintin, C.; Riddal,
D. R.; Lancaster, B.; Gane, P. J.; Garthwaite, J.; Selwood, D. L. J. Med.
Chem. 2009, 52, 2694.
75, 984.
(16) Ghasemnejad-Bosra, H.; Haghdadi, M.; Gholampour-Azizi, I.
Heterocycles 2008, 75, 391.
8850
dx.doi.org/10.1021/jo201605v|J. Org. Chem. 2011, 76, 8840−8851

The Journal of Organic Chemistry
Article
(17) (a) Effenberger, F.; Daub, W. Chem. Ber 1991, 124, 2119.
(b) Walters, M.; Shay, J. Synth. Commun. 1997, 27, 3573.
(18) Ohnmacht, S. A.; Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010,
12, 224.
(19) Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, England, 1991; Vol. 4, pp
483−515.
(20) (a) Hill, R.; Sutton, L. E.; Longuet-Higgins, C. J. Chem. Phys.
1949, 46, 244. (b) Orgel, L. E.; Cotterell, T. L.; Dick, W.; Sutton, L. E.
Trans. Faraday Soc. 1951, 47, 113.
(33) Meo, P. L.; D’Anna, F.; Riela, S.; Gruttadauria, M.; Noto, R.
Org. Biomol. Chem. 2003, 1, 1584.
(34) (a) Ranganathan, D.; Bamezai, S. Tetrahedron Lett. 1983, 24,
1067. (b) Nikitenko, A. A.; Winkley, M. W.; Zeldis, J.; Kremer, K.;
Chan, A. W.-Y.; Strong, H.; Jennings, M.; Jirkovsky, I.; Blum, D.;
Khafizova, G.; Grosu, G. T.; Venkatesan, A. M. Org. Process Res. Dev.
2006, 10, 712.
(35) Cadogan, J. I. G.; Mackie, R. K. Org. Synth. 1968, 48, 113.
(36) The italicized Rf values were obtained using the 300−400 mesh
silica gel. The rest of the Rf values were obtained using the 230−400
mesh silica gel. These two types of silica gels behave quite differently.
(37) Ina, S.; Inoue, S.; Noguchi, I. Yakugaku Zasshi: J. Pharm. Soc.
Jpn. 1975, 95, 1245.
(21) Fan, J.; Wang, Y.; Ueng, C. J. Phys. Chem. 1993, 97, 8193.
(22) For regioselectivities in favor of C-4 reacting as the nucleophilic
site, see: (a) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M.
J. Org. Chem. 1982, 47, 786. (b) Chang, E.; Wong, F. F.; Chen, T.;
Chiang, K.; Yeh, M. Heterocycles 2006, 68, 1007. (c) Farina, F.;
̃
́ ́
́
Fernandez, P.; Fraile, M. T.; Martin, M. V.; Martin, M. R. Heterocycles
1989, 29, 967. (d) Harju, K.; Vesterinen, J.; Yli-Kauhaluoma, J. Org.
Lett. 2009, 11, 2219. For regioselectivities in favor of N-2 reacting as
the nucleophilic site, see: (e) Hegde, J. C.; Rai, G.; Puranik, V. G.;
Kalluraya, B. Synth. Commun. 2006, 36, 1285. (f) Croce, P. D.; Rosa,
C. L.; Zecchi, G. J. Chem. Soc., Perkin Trans. 1 1985, 2621.
(23) (a) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M. J.
Org. Chem. 1982, 47, 786. (b) Houk, K. N; Sims, J.; Duke, R. E.;
Strozier, R. W.; George, J. K. J. Am. Chem. Soc. 1973, 95, 7287.
(24) The reaction between resonance structure C and aryne leads to
a closer approximity between the carbonyl group of the sydnone and
the OMe group of the aryne. Such steric repulsion does not exist if
resonance structure B is reacting.
(25) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(26) (a) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(b) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.
(27) Cho, C.; Neuenswander, B.; Lushington, G. H.; Larock, R. C. J.
Comb. Chem. 2008, 10, 941.
(28) For an improved synthesis of aryne precursors bearing diverse
functional groups, see: (a) Kirkham, J. D.; Delaney, P. M.; Ellames, G.
J.; Rowb, E. C.; Harrity, J. P. A Chem. Commun. 2010, 46, 5154.
(b) Crossley, J. A.; Kirkham, J. D.; Browne, D. L.; Harrity, J. P. A
Tetrahedron Lett. 2010, 51, 6608.
(29) (a) Pena, D.; Per
Soc. 1999, 121, 5827. (b) Pena, D.; Perez, D.; Guitian
J. Org. Chem. 2000, 65, 6944. (c) Yoshida, H.; Sugiura, S.; Kunai, A.
Org. Lett. 2002, 4, 2767. (d) Liu, Z.; Zhang, X.; Larock, R. C. J. Am.
́
ez, D.; Guitian
́
, E.; Castedo, L. J. Am. Chem.
̃
́
́
, E.; Castedo, L.
̃
Chem. Soc. 2005, 127, 15716. (e) Pena, D.; Escudero, S.; Per
́
ez, D.;
̃
Guitian
́
, E.; Castedo, L. Angew. Chem., Int. Ed. Engl. 1998, 37, 2659.
(f) Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. J. Am.
Chem. Soc. 2003, 125, 6638. (g) Himeshima, Y.; Sonoda, T.;
Kobayashi, H. Chem. Lett. 1983, 1211. (h) Pena, D.; Cobas, A.;
̃
́
Perez, D.; Guitian, E. Synthesis 2002, 1454.
(30) These two types of silica gel are noticeably different. We have
observed that much higher Rf values are obtained using the 300−400
mesh silica gel.
(31) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
̈
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
revision A.1; Gaussian, Inc., Wallingford CT, 2009.
(32) Rai, N. S.; Kalluraya, B.; Lingappa, B.; Shenoy, S.; Puranic, V. G.
Eur. J. Med. Chem. 2008, 43, 1715.
8851
dx.doi.org/10.1021/jo201605v|J. Org. Chem. 2011, 76, 8840−8851