A base-promoted cascade reaction of α,β-unsaturated: N -tosylhydrazones with o -hydroxybenzyl alcohols: Highly regioselective synthesis of N-sec -alkylpyrazoles

Article abstract of DOI:10.1039/c9ob01780a

An efficient method for the synthesis of N-sec-alkylpyrazoles through a base-promoted cascade cyclization/Michael addition reaction of α,β-unsaturated N-tosylhydrazones with ortho-hydroxybenzyl alcohols has been developed. The desired products containing di- or triaryl groups at the same carbon atom were afforded in good to excellent yields with excellent regioselectivities (>20:1). Moreover, a three-component reaction of ortho-hydroxybenzyl alcohols, α,β-unsaturated N-tosylhydrazones and saturated N-tosylhydrazones also took place to afford pyrazoles in good yields. This reaction offers a new route to triarylmethanes with a simple operation and is applicable for large-scale synthesis.

Full text of DOI:10.1039/c9ob01780a

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10.1039/C9OB01780A.
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DOI: 10.1039/C9OB01780A
ARTICLE
Base-Promoted Cascade Reaction of α,β-Unsaturated N-
Tosylhydrazones with o-Hydroxybenzyl Alcohols: Highly
Regioselective Synthesis of N-sec-Alkylpyrazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Lian-Mei Chen,*a Juan Zhao,‡b An-Jie Xia,‡b Xiao-Qiang Guo,a Ya Gan,a Chuang Zhou,a Zai-Jun Yang,b
DOI: 10.1039/x0xx00000x
Jun Yangb and Tai-Ran Kang*ab
An efficient method for the synthesis of N-sec-alkyl pyrazoles through a base-promoted cascade cyclization/Michael
addition reaction of α,β-unsaturated N-tosylhydrazones with ortho-hydroxybenzyl alcohols, has been developed. The
desired products containing di- or triaryl groups at the same carbon atom were afforded in good to excellent yields with
excellent regioselectivities (>20:1). Moreover,
a three-component reaction of ortho-hydroxybenzyl alcohols, α,β-
unsaturated N-tosylhydrazones and saturated N-tosylhydrazones also took place to afford pyrazoles in good yields. This
reaction offers a new route to triarylmethanes with a simple operation and is applicable for the large-scale synthesis.
their medicinal values, they have been utilized for ligands and
dyes.1,5 Due to their biological activities and applications,
developing an efficient method is important for the synthesis
Introduction
Functionalized pyrazoles have been received increasing
attention in chemical, pharmaceutical, and material science.1
of N-sec-alkylpyrazoles.
Many approaches for the synthesis of functionalized pyrazoles
have been developed.5 The (3+2)-cycloaddition of diazo
compounds with alkenes or alkynes for constructing pyrazole
rings is a classic strategy.5c-d For example, the alkyl and aryl
diazomethanes formed in situ from N-tosylhydrazones6 were
widely used to react with electron-deficient olefins or terminal
alkynes to give pyrazole derivatives.7 The cyclization
condensation of hydrazines with 1,3-dicarbonyl compounds
represents another successful type of reaction to deliver
HN
O
O
NH
N
H
N
N
N
OH
Cl
O
S
N
F
O
O
N
F
F
O
Cl
MK-0893
GNE-4997
F
O
NH
N
H
N
O
pyrazoles.8 The oxidative cyclization of
α,β-alkenic N-
N
O
O
AcHN
tosylhydrazones (Scheme 1a) 9 and electrophilic cyclization of
α,β-alkynic hydrazones (Scheme 1b),10 has also been
developed to give functionalized pyrazoles. Other approaches
for the synthesis of N-sec-alkylpyrazoles include the
substitution reactions of pyrazoles with secondary alkyl
electrophile (such as alkyl halides),11a aza-Michael reaction of
pyrazole with various α,β-unsaturated ketones,11b as well as
rhodium-catalysed cross-coupling of pyrazoles with alkynes or
N
N
N
N
N
GNE-9822
PDE4
Figure 1. Some examples of biologically active N-sec-alkylated pyrazoles
Among these families, the N-sec-alkylated pyrazoles possess
various prominent biological and pharmacological activities,2-4
such as the glucagon receptor antagonist (MK-0893),2 the IKT
inhibiters (GNE-4997, GNE-9822)3 and the potent
Phosphodiesterase 4 (PDE4) inhibitors [4] (Figure 1). Apart from
allenes,12a,b
and
gold-catalyzed
cross-coupling
of
aryldiazoacetate with styryldiazoacetate.12c However, these
above approaches are usually suffered from poor
regioselectivity. Therefore, developing an efficient approach
for the synthesis of N-arylpyrazoles from easily available
starting materials with a simple operation is still highly
desirable.
a. College of Pharmacy and Biological Engineering, Chengdu University, Chengdu
City, 610106, P. R. of China. E-mail: chenlianmei845@163.com;
kangtairan@sina.com
b. Collaborative Innovation Center of Tissue Repair Material of Sichuan Province,
College of Chemistry & Chemical Engineering, China West Normal University,
Nanchong City, Sichuan, 637002, P. R. of China.
N-Tosylhydrazones have been employed as precursors of diazo
for the formation of C-C, C-N, C-B, C-O and C-Si bonds by
Barluenga,13 Valdés,14 Wang15 and Jiang.16 The reductive
coupling of N-tosylhydrazones with alcohols or phenols giving
ethers was reported by Barluenga and coworkers (Scheme
‡ These authors contributed equally to this work.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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1c).13c ortho-Quinone methides (o-QMs) generated in situ from
o-hydroxybenzyl alcohols, as a class of versatile building
blocks,17 have wide applications in conjugate addition and
cycloaddition reaction.18 We envisioned that an approach
could be developed for constructing N-sec-alkylpyrazoles from
α,β-unsaturated N-tosylhydrazones and o-hydroxybenzyl
alcohols via a cyclization/conjugate addition cascade reaction
(Scheme 1d). Moreover, if the one-pot reaction between α,β-
unsaturated N-tosylhydrazone, ortho-hydroxybenzyl alcohol
and saturated N-tosylhydrazone was conducted, the desired
product containing both pyrazole and ether group might be
obtained (Scheme 1e).
Results and discussion
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DOI: 10.1039/C9OB01780A
We started our investigations with the model reaction of α,β-
unsaturated N-tosylhydrazone 1a and ortho-hydroxybenzyl
alcohol 2a. The reaction of 1a (1.1 equiv) and 2a (1.0 equiv) in
the presence of Cs2CO3 (3.0 equiv) in 1,4-dioxane was first
attempted at 60 oC for 12 hours, giving the N-alkyl pyrazole 3a
as major isomer (3a/3a’>20:1, determined by 1H NMR
spectroscopy on the crude reaction mixture, see the SI for
details) in 70% yield (Table 1, entry 1). Both K2CO3 and Na2CO3
could furnish the desired product in 68% and 55% yields in 1,4-
dioxane (entries 2 and 3). Use of other solvents, such as THF,
toluene and 1, 2-dichloroethane were found to be inferior
(entries 4-6). Very interestingly, when the reaction
temperature was increased to 90 °C, the best yield of 3a could
be obtained in 92% yield and with >20:1 regioselectivity only
for 4 hours (entry 7). It is noted that this reaction proceeded
simply by heating both α,β-unsaturated N-tosylhydrazones and
ortho-hydroxybenzyl alcohols in 1,4-dioxane to provide the
valuable triarylmethanes.20
Previous works
R4
N
R1
NNHR4
Oxidative
cyclization
(a)
(b)
N
R1
R3
R2
R1
R2
R3
R3
NNHR3
R2
Electrophilic
cyclization
N
N
Table 1. Optimization of reaction conditions
R1
R2
Ph
OH
Ph
Ph
NNHTs
+
N
R1
O
R3
N
N
N
base (3 equiv)
Ph
+
OH
Ph
solvent, temp.
OH
OH
Ph
R2 R4
or
R3 R4
or
OH
NNHTs
3a
1a
2a
Metal-free
3a'
+
(c)
R1 R2
entrya
base
solvent/temp(°C)
3a yield
(%)b
70
68
55
62
48
23
92
3a/3a’ c
R1
O
OH
R2
1
2
3
4
5
Cs2CO3
K2CO3
1,4-dioxane/60
1,4-dioxane/60
1,4-dioxane/60
THF/60
Toluene/60
(CH2Cl)2/60
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
This work
R1
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
R2
OH
N
N
NNHTs
(d)
base
R3
+
R1
R2
6
7[d]
R3
R2
OH
1,4-dioxane/90
OH
R1
(e)
aReaction conditions: α,β-unsaturated N-tosylhydrazone 1a (0.22 mmol, 1.1
equiv), ortho-hydroxybenzyl alcohol 2a (0.2 mmol, 1 equiv), base (0.6
NNHTs
R4 R5
NNHTs
R2
N
OH
R3
N
mmol, 3.0 equiv) in 1 mL solvent for 12 hours. bIsolated yield. Determined
c
R1
by 1H NMR analysis of the crude reaction mixture. dFor 4 hours.
R3
one-pot
OH
O
R4
With the established conditions in hand (Table 1, entry 7), a
variety of α,β-unsaturated N-tosylhydrazones 1 derived from
enals (or enones) and ortho-hydroxybenzyl alcohols 2a were
subjected to the cascade reaction (Scheme 2). The electronic
R5
Scheme 1. Some strategies for the synthesis of N-substituted pyrazoles or ethers
using N-toshydrazones.
Despite using o-QM intermediates as substrates in conjugate effects of different substituents on the aromatic ring of α,β-
addition and cyclization reaction has been well-established to unsaturated N-tosylhydrazones were evaluated. In fact, the
date, the use of α,β-unsaturated diazo for constructing presence of both electron-donating and electron-withdrawing
pyrazole rings at the benzylic position of o-QM intermediates groups at the ortho, meta, and para positions afforded the
has not been established yet.17,18 Continuing with our interests corresponding products 3b-i in good to excellent yields and
in diazo chemistry,19 herein, we report a metal-free reaction of with >20:1 regioselectivity. The heteroaromatic substituents,
α,β-unsaturated diazo with o-QM intermediates to provide a such as thiophen-2-yl α,β-unsaturated N-tosylhydrazone,
promising route to N-sec-alkylpyrazoles. Very interestingly, the provided the expected product 3j in 91% yield and with 8:1
desired products contain three or two (hetero)aryl ring at the regioselectivity. The N-Boc-protected 2-methyl-3-indolyl α,β-
same carbon atom (triarylmethanes and 1,1-diarylalkanes), unsaturated N-tosylhydrazone could give the expected
which are found in various biologically active compounds.20 product 3k in 95% yield with >20:1 regioselectivity (entry 11).
Thus, this strategy offers a new route to triarylmethanes.
However, no desired products were detected by using the α,β-
unsaturated N-tosylhydrazones derived from (E)-but-2-enal
2 | J. Name., 2012, 00, 1-3
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and (E)-5-methylhexa-2,4-dienal as substrates, which may be R2, such as aromatic (2k-m), hydrogen (2n) and VaielwipAhrtaictleicOn(l2inoe
due to their instability of alkyl diazo intermediates at 90 oC. To and 2p) group, were studied. Obviously,DwOhI:e10n.1t0h3e9/aCr9yOlBg0r1o7u80pAs
our delight, when R2 was methyl group, the corresponding served as competent R2 substituents of ortho-hydroxybenzyl
product 3l was afforded in 90% yield with >20:1 alcohols 2, the desired products 4k-m were obtained in
regioselectivity. However, when R2 was phenyl, it failed to excellent yields. Notably, substrates 2n-p bearing H, ethyl or
obtain the desired product because the corresponding 3,5- cyclopropyl group could also successfully take part in the
diphenyl-1H-pyrazole intermediate was difficult to react with reaction to give the corresponding products 4n-p in 88%, 96%
the o-QM intermediate for its larger steric hindrance in the and 90% yield, respectively. It is noted that these reactions (as
step of aza-Michael addition.
shown Scheme 3) provided the desired products in excellent
regioselectivity (>20:1). The structure of 4l was confirmed by
X-ray crystal structure analysis (Scheme 2, see the SI for
details).21
Scheme 2. Substrate scope of α,β-unsaturated N-tosylhydrazones 1a
Ph
R1
OH Ph
OH Ph
NNHTs
Cs CO
OH
N
2
3
R1
N
N
N
+
R1
R2
+
Scheme 3. Substrate scope of ortho-hydroxybenzyl alcohols 2a
Dioxane
90 o
OH
R2
3
C
R2
2a
3'
OH R2
1
R2
N
Cs2CO3 (3 equiv)
N
OH
Ph
R1
R1
c
Ph
b 3a/3a
NNHTs +
1, 4-dioxane, 90 o
C
3a
R = H, , 92% yield,
' > 20:1
3b/3b
' > 20:1
OH Ph
OH
4
1a
3b
R = Br, , 97% yield,
2
N
N
R
N
3c
R = CF3, , 93% yield,
3c/3c
' > 20:1
3d/3d
' > 20:1
OH Ph
OH Ph
3d
R = Me, , 95% yield,
R1 = Cl, , 93%
1
H
R1 = F, , 94%
b
4d
4a
N
N
N
3e
3e/3e
N
R = MeO, , 94% yield,
' > 20:1
R1 = Br, , 93%
Ph
4e
Ph
R
= Me, , 95%
4b
OH Ph
R1 = OMe, , 96%
R1 = Me, , 96%
R1
4f
4c
R1
3f
R = Cl, , 94% yield,
3f/3f
' > 20:1
N
N
OH Ph
N
OH
3g
R = Me, , 92% yield,
3g/3g
' > 20:1
R1 = Me, R3 = H,
O
O
R1
H
R
N
4i
, 92%
Ph
4g
, 98%
N
Ph
N
R1 = R3 = tBu,
OH Ph
Ph
3h
R = Cl, , 95% yield,
3h/3h
4h, 95%
' > 20:1
R3
OH Ph
N
N
R4
R4 = Me, R3 = R5 = H,
4k
3i
3i/3i
R = MeO, , 91% yield,
' > 20:1
R3
R5
N
, 96%
R4 = OMe, R3 = R5 = H,
4l
4j
, 88%
N
H
N
R
Ph
Ph
OH
Ph
OH
, 94%
R4 = R3 = R5 = F
OH Ph
N
Ph
N
N
4m
, 90%
N
S
NBoc
OH R2
H
H
N
N
3j
3j/3j
3k
3k/3k
, 95% yield, ' > 20:1
, 91% yield,
' = 8:1
4l
CCDC 1582529
R2 = H, , 88%
OH Ph
4n
OH Ph
N
R2 = Ethyl, , 96%
4o
N
N
R2 = Cyclopropyl, , 90%
N
4p
trace
trace
H
aReaction conditions: α,β-unsaturated N-Tosylhydrazone 1a (0.22 mmol, 1.1
H
equiv), ortho-hydroxybenzyl alcohol
2 (0.2 mmol, 1.0 equiv), Cs2CO3 (0.6
OH Ph
OH Ph
mmmol, 3.0 equiv) in 1 mL 1,4-dioxane for 4-8 h. bIsolated yield.
N
N
N
N
Ph
Ph
Ph
Ph
3l
3l/3l
trace
, 90% yield,
' > 20:1
NNHTs
N
Ph
OH
OH
N
Ph
aReaction conditions: α,β-unsaturated N-tosylhydrazones 1 (0.22 mmol, 1.1
equiv), ortho-hydroxybenzyl alcohol 2a (0.2 mmol, 1.0 equiv), Cs2CO3 (0.6
Ph
110 oC
O
Cs2CO3
1,4-dioxane
mmol, 3.0 equiv) in 1 mL 1,4-dioxane for 4-8 h. bIsolated yield. Determined
c
Ph
5
by 1H NMR analysis of the crude reaction mixture.
2a
NNHTs
, 85% yield
Ph
90 oC
+
NNHTs
Next, we explored the scope of ortho-hydroxybenzyl alcohols 2
with different substitution patterns as shown in Scheme 3.
Firstly, a variety of substituted groups on the phenol moiety
were employed as the substrates 2a-i, giving the
corresponding products 4a-j in excellent yields (92-98%). Both
N
N
Ph
Ph
1a
110 oC
O
6
, 80% yield
t
electron-rich groups (Me, MeO, Bu) and electron-poor groups
Scheme 4. Three-component reaction of α,β-unsaturated N-tosylhydrazone,
ortho-hydroxybenzyl alcohols and saturated N-tosylhydrazones.
(F, Cl, Br) were proved to be suitable substrates. The reaction
also worked well with 1-naphthyl ortho-hydroxybenzyl
alcohols, albeit affording the expected N-alkyl pyrazole 4j with
slightly diminished yield (88%). Then, the different substituents
We investigated whether the reactions could be carried out in
a
one-pot fashion by mixing of α,β-unsaturated N-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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tosylhydrazones, ortho-hydroxybenzyl alcohols with saturated pyrazole as a major product in >95% yield under standard
View Article Online
DOI: 10.1039/C9OB01780A
N-tosylhydrazones (Scheme 4). It was possible by heating α,β- conditions, and the isomer product 5-phenyl-1H-pyrazole was
unsaturated N-tosylhydrazone and ortho-hydroxybenzyl observed in trace (< 5% yield) on the 1H NMR spectroscopy of
alcohol at 90 oC prior to the addition of 4-methyl-N'-(1- the crude reaction mixture (Scheme 6 a, see the SI for details).
phenylethylidene)benzene-sulfonohydrazide
and
N'- The C-O bond-forming reaction between α, β-unsaturated N-
cyclohexylidene-4-methylbenzene-sulfonohydrazide, and then tosylhydrazone 1a and phenol (or alcohol) didn’t occur
the desired products 5 and 6 were afforded in 85% and 80% (Scheme 6 b and c). It indicated that the α,β-unsaturated
yields by heating at 110 oC, respectively (see the SI for details). carbene didn’t form. The other side product 2-
We attempted the scaled-up synthesis pyrazoles for practical (phenyl(tosyl)methyl)phenol (Scheme 6 d) was observed in
purposes. The reaction using 5.5 mmol of 1a provided the trace on the TLC under standard conditions because it is also
products 3a (1.47g, 90% yield) and 4l (1.62g, 91% yield), easily transformed to ortho-Quinone methides intermediate
respectively, without any significant decrease in its efficiency under basic condition.
(Scheme 5 a, see the SI for details). Since 3a has a hydroxyl Based on the previous works19c and our experimental
functionality, we conducted some transformations to explore observations,
a plausible mechanism was proposed as
the versatility of the method (Scheme 5 b). 3a was converted illustrated in Figure 2. The α, β-unsaturated diazo substrate A
to the corresponding triflate ester 7 in 95% yield by treating is generated in situ from α, β-unsaturated N-tosylhydrazone 1a
with trifluoromethanesulfonic acid anhydride and 2,6- by treating with Cs2CO3. Then the 3-Phenyl-3H-pyrazole B is
dimethylpyridine. Then, an intramolecular aryl sulflate-arene formed via an intermolecular cyclization. The major
coupling mediated by Pd(PPh3)2Cl2 was employed as a key step intermediate 3-phenyl-1H-pyrazole
C
and the minor
in the synthesis of 3-phenyl-1-(9H-xanthen-9-yl)-1H-pyrazole 8 intermediate 5-phenyl-1H-pyrazole C’ are easily formed from B
in 60% yield. Oxidation of 3a with PhI(OAc)2 in MeOH afforded through proton transfer tautomerization. The 3-phenyl-1H-
the cyclohexadienone 9 in 66% yield.
pyrazole C is a major intermediate due to its larger conjugation
than that of C’.19c The o-QM intermediate is formed in situ
from ortho-hydroxybenzyl alcohols. The following aza-Michael
addition reaction of C (C’) with o-QM intermediate provides
the final product 3a or 3a’.
(a) Gram-scale experiments
Ph
R
N
N
NNHTs
Cs2CO3 (3 equiv)
OH
Ph
H
+
1, 4-dioxane, 90 o
C
OH
OH
N
R
N
NNHTs
base
N
3a
R = H
1.47 g (90%)
4l
Ph
5.5 mmol
5 mmol
cyclization
N
= MeO 1.62 g (91%)
H
(b) Some transformations
Ph
Ph
N
-H+, -Ts-
B
A
Ph
Ph
2,6-dimethylpyridine
(1.5 eqiv.)
triflic anhydide
(1.2 eqiv. in DCM)
DCM, Ar, -30oC
H
N
N
Pd(PPh3)2Cl2 (10%)
LiCl (3 eqiv), DBU (1.2 eqiv)
N
N
Ph
Ph
N
N
O
NH
proton transfer
+
DMF, Ar, 145 o
60% yield
C
3a
Ph
C',
minor
C,
major
95% yield
OTf
Ph
N
N
N
8
7
PhI(OAc)2
MeOH, 0oC
Ph
OMe
OMe
N
Ph
O
OH
, major
N
OH
3a
Ph
C
C'
base
or
66% yield
3a
Ph
O
base
9
Ph
Michael addition
OH
N
Scheme 5. Gram-scale experiments and synthetic utility.
o-QM
Ph
OH
3a'
H
N
N
standard
conditions
NH
NNHTs
, minor
N
+
(a)
Ph
Ph
Ph
>95% yield
major
trace
minor
Figure 2. Proposed mechanism for this cascade reaction.
OH
NNHTs
NNHTs
standard
conditions
O
(b)
(c)
Ph
Ph
+
+
Ph
Ph
not observed
OH
Experimental
O
Ph
standard
conditions
Ph
1
General information. H NMR spectra were determined on a
400 MHz spectrometer in CDCl3 solution. Chemical shifts are
expressed in parts per million (δ), and the signals were
reported as s (singlet), d (doublet), t (triplet), m (multiplet),
and coupling constants J were given in Hz. 13C NMR spectra
were recorded at 100 MHz in CDCl3 solution. Chemical shifts
are expressed in parts per million (δ) and are referenced to
CDCl3 (δ = 77.16) as an internal standard. TLC was done on
silica gel coated glass slide (Silica gel G for TLC). Silica gel (60-
120 mesh) was used for column chromatography. Petroleum
not observed
Ts
standard
conditions
OH
NNHTs
(d)
+
OH
Ph
H
< 5% yield
OH
Scheme 6. Some complementary experiments.
To gain insight into the mechanism, some experiments were
carried out as shown in Scheme 6. The α,β-unsaturated N-
tosylhydrazone 1a was easily transformed to 3-phenyl-1H-
4 | J. Name., 2012, 00, 1-3
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ether refers to the fraction boiling in the range of 60-90 °C 1H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 155.8, 152.0, 138.9,
View Article Online
DOI: 10.1039/C9OB01780A
unless otherwise mentioned. All solvents were dried and 132.6, 131.2, 130.7, 129.2, 128.8, 128.7, 128.5, 128.3, 127.7,
distilled before use. Commercially available substrates were 126.3, 125.7, 120.0, 119.9, 102.6, 69.5. HRMS calcd for
freshly distilled before the reaction. Solvents, reagents and C22H18N2O [M+Na]+ 349.1317, found: 349.1315.
chemicals were commercially purchased. All reactions
involving moisture sensitive reactants were executed using 2-((3-(4-bromophenyl)-1H-pyrazol-1-yl)(phenyl)methyl)-
oven-dried glassware
phenol (3b): Rf = 0.37 (EtOAc/PE = 1:5), yield: 95%, yellow
solid. m.p. 170-171 °C. 1H NMR (400 MHz, CDCl3): δ (ppm)
General procedure for the synthesis of 2-(phenyl(3-phenyl- 10.62 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.61 (d, J = 8.6Hz, 2H),
1H-pyrazol-1-yl)methyl)phenol (3a): α,β-unsaturated N- 7.50 (d, J = 8.6Hz, 2H), 7.33-7.27 (m, 2H), 7.26-7.24 (m, 3H),
tosylhydrazones 1a (0.22 mmol), ortho-hydroxymethzyl 7.02-7.00 (m, 1H), 6.95-6.91 (m, 1H), 6.87-6.85 (m, 2H), 6.63
phenols 2a (0.2 mmol), Cs2CO3 (0.6 mmol) and 1,4-dioxane (1 (d, J = 2.4Hz, 1H), 6.45 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ
mL) were added into a tube. The mixture was stirred at 90 °C (ppm) 115.8, 151.0, 138.7, 132.8, 131.9, 131.3, 131.1, 130.9,
for 4 hours. After cooling to room temperature, the mixture 128.5, 127.9, 127.3, 126.2, 125.2, 122.3, 120.0, 119.9, 102.7,
was quenched with NH4Cl (2 mL, saturated aqueous solution) 69.7. HRMS calcd for C22H17BrN2O [M+Na]+ 427.0422, found:
and extracted with CH2Cl2 (3 × 2 mL). The combined organic 427.0420.
phase was dried over Na2SO4, and then organic solvents were
removed in vacuo. The residue was purified by flash column 2-(phenyl(3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-1-
chromatography on silica gel with ethyl acetate/petroleum yl)methyl)phenol (3c): Rf = 0.58 (EtOAc/PE = 1:5), yield: 93%,
ether (1:15-1:10, V/V) as the eluent to give the compounds 3a white solid. m.p. 178-179°C. 1H NMR (400 MHz, CDCl3): δ
(60mg, 92% yield) as white solid.
(ppm) 10.29 (s, 1H), 7.76 (d, J = 8.1Hz, 2H), 7.62 (s, 1H), 7.54 (d,
J = 8.1Hz, 2H), 7.20-7.18 (m, 4H), 7.14-7.11 (m, 1H), 6.89-6.87
Typical procedure for the synthesis of 3a on gram scale: α,β- (m, 1H), 6.84-6.81 (m, 3H), 6.61 (d, J = 2.4Hz, 1H), 6.47 (s, 1H).
unsaturated tosylhydrazones 1a (5.5 mmol), ortho- 13C NMR (CDCl3, 100 MHz): δ (ppm) 155.5, 150.6, 138.6, 135.6,
hydroxymethzyl phenols 2a (5 mmol), Cs2CO3 (15 mmol) were 132.9, 131.1, 130.8, 128.7, 128.6, 128.0, 126.8, 126.4, 126.0,
suspended in 1,4-dioxane (10 mL) in a flask. The resulting 125.8, 120.1, 119.6, 117.3, 103.2, 69.3. HRMS calcd for
solution was stirred at 90 °C for 4 hours. After cooling to room C23H17F3N2O [M+Na]+ 417.1191, found: 417.1192.
temperature, the mixture was quenched with NH4Cl (40 mL,
saturated aqueous solution) and extracted with CH2Cl2 (3 × 40 2-(phenyl(3-(p-tolyl)-1H-pyrazol-1-yl)methyl)phenol (3d): Rf =
mL). The combined organic phase was dried over Na2SO4, and 0.50 (EtOAc/PE = 1:5), yield: 95%, white solid. m.p. 161-163 °C.
then the solvent was removed in vacuo to give a residue. The 1H NMR (400 MHz, CDCl3): δ (ppm) 11.08 (s, 1H), 7.69-7.63 (m,
residue was purified by flash column chromatography 3H), 7.27-7.24 (m, 5H), 7.19-7.18 (m, 2H), 7.02-7.00 (m, 1H),
(EtOAc/hexane) to give the compounds 3a (1.47g, 90% yield).
6.93-6.90 (m, 1H), 6.87-6.85 (m, 2H), 6.62 (s, 1H), 6.42 (s, 1H),
2.35 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 156.0, 152.1,
Typical procedure of the three-component reaction for the 139.1, 138.2, 132.5, 131.3, 130.8, 129.4, 129.3, 128.5, 127.7,
synthesis of product 5: α,β-unsaturated tosylhydrazones 1 126.2, 125.7, 125.5, 120.0, 119.8, 102.4, 69.7, 21.3. HRMS
(0.11 mmol), ortho-hydroxymethzyl phenols 2 (0.1 mmol), calcd for C23H20N2O [M+Na]+ 363.1473, found: 363.1471.
Cs2CO3 (0.4 mmol) and 1,4-dioxane (0.5 mL) were added into a
tube. The mixture was stirred at 90 °C for 4 hours. Next, (E)-4- 2-((3-(4-methoxyphenyl)-1H-pyrazol-1-yl)(phenyl)methyl)-
methyl-N'-(1-phenylethylidene)benzenesulfonohydrazide (0.1 phenol (3e): Rf = 0.33 (EtOAc/PE = 1:5), yield: 92%, white solid.
1
mmol) was added. The system was heated at 110 oC with m.p. 180-183 °C. H NMR (400 MHz, CDCl3): δ (ppm) 11.12 (s,
stirring and refluxing. When the reaction was completed, the 1H), 7.68-7.66 (m, 3H), 7.37-7.35 (m, 2H), 7.25-7.24 (m, 3H),
reaction mixture was cooled to room temperature, and the 6.99 (d, J = 8.0Hz, 1H), 6.94-6.90 (m, 3H), 6.87-6.85 (m, 2H),
solvent was eliminated under reduced pressure. 2mL NaOH 6.57 (d, J = 2.0Hz, 1H), 6.41 (s, 1H), 3.80 (s, 3H). 13C NMR
solution (2M) and 2mL dichloromethane were added to the (CDCl3, 100 MHz): δ (ppm) 159.8, 155.9, 151.8, 139.1, 132.6,
residue. The aqueous phase was extracted three times with 131.3, 130.8, 128.7, 128.5, 127.1, 126.8, 126.2, 120.0, 119.9,
dichloromethane. The combined organic layer was washed 117.3, 114.2, 102.1, 69.6, 55.3. HRMS calcd for C23H20N2O2
with brine and dried over Na2SO4. The organic solvent was [M+Na]+ 379.1422, found: 379.1429
removed under reduced pressure. The residue was purified by
flash column chromatography (EtOAc/hexane) to give the 2-((3-(3-chlorophenyl)-1H-pyrazol-1-yl)(phenyl)methyl)phenol
compounds 5 (37mg, 85% yield) as white solid.
(3f): Rf = 0.50 (EtOAc/PE = 1:5), yield: 92%, yellow solid. m.p.
133-135 °C. H NMR (400 MHz, CDCl3): δ (ppm) 10.45 (s, 1H),
1
2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol (3a): Rf
=
7.69-7.68 (m, 2H), 7.63-7.61 (m, 1H), 7.37-7.30 (m, 3H), 7.25-
0.46 (EtOAc/PE = 1:5), yield: 90%, white solid. m.p. 153-154 °C. 7.20 (m, 3H), 6.99-6.99 (m, 1H), 6.98 (d, J = 8.0Hz, 1H), 6.93-
1H NMR (400 MHz, CDCl3): δ (ppm) 11.01 (s, 1H), 7.79 (d, J = 6.90 (m, 3H), 6.62 (d, J = 2.2Hz, 1H), 6.49 (s, 1H). 13C NMR
7.5Hz, 2H), 7.73 (s, 1H), 7.43-7.40 (m, 2H), 7.36-7.27 (m, 6H), (CDCl3, 100 MHz): δ (ppm) 155.6, 150.7, 138.6, 134.7, 132.8,
7.03 (d, J = 8.1Hz, 1H), 6.91-6.90 (m, 3H), 6.69 (s, 1H), 6.50 (s, 131.2, 130.9, 130.1, 128.7, 128.6, 128.3, 127.9, 126.8, 126.4,
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Organic & Biomolecular Chemistry
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Journal Name
125.9, 123.9, 120.1, 117.3, 103.0, 69.5. HRMS calcd for 123.9, 123.1, 120.3, 119.9, 119.0, 115.4, 112.5,Vi1ew06Ar.t0ic,le8O4nl.in0e,
+
C22H17ClN2O [M+Na]+ 383.0927, found: 383.0927.
70.0, 28.3, 15.1. HRMS calcd for C30H29N3DOO3I:[1M0.+10N3a9]/C59O02B0.21178007A,
found: 502.2100.
2-(phenyl(3-(m-tolyl)-1H-pyrazol-1-yl)methyl)phenol (3g): Rf =
0.63 (EtOAc/PE = 1:5), yield: 90%, yellow solid. m.p. 128-130 °C. 2-((5-methyl-3-phenyl-1H-pyrazol-1-yl)(phenyl)methyl)phenol
1H NMR (400 MHz, CDCl3): δ (ppm) 10.98 (s, 1H), 7.71 (s, 1H), (3l): Rf = 0.50 (EtOAc/PE = 1:5), yield: 87%, white solid. m.p.
1
7.55 (d, J = 7.0Hz, 2H), 7.32-7.25 (m, 6H), 7.12 (d, J = 7.3Hz, 1H), 120-122 °C. H NMR (400 MHz, CDCl3): δ (ppm) 11.52 (s, 1H),
7.02 (d, J = 7.9Hz, 1H), 6.94-6.90 (m, 1H), 6.85 (d, J = 3.1Hz, 2H), 7.73-7.70 (m, 2H), 7.39-7.32 (m, 3H), 7.30-7.22 (m, 5H), 7.06-
6.64 (s, 1H), 6.42 (s, 1H), 2.37 (s, 3H). 13C NMR (CDCl3, 100 7.04 (m, 1H), 6.95-6.91 (m, 1H), 6.82-6.79 (m, 2H), 6.46-6.46
MHz): δ (ppm) 155.9, 152.1, 139.0, 138.4, 132.5, 131.9, 131.4, (m, 1H), 6.38 (s, 1H), 2.50 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
130.8, 129.1, 128.7, 128.5, 127.7, 126.4, 126.2, 125.4, 122.9, (ppm) 156.5, 150.2, 141.2, 139.2, 132.1, 131.8, 130.9, 128.7,
120.0, 119.8, 102.6, 69.7, 21.5. HRMS calcd for C23H20N2O 128.5, 128.2, 127.6, 126.0, 125.7, 125.3, 120.4, 119.7, 102.8,
[M+Na]+ 363.1473, found: 363.1475.
65.9, 11.4. HRMS calcd for C23H20N2O [M+Na]+ 363.1473, found:
363.1471.
2-((3-(2-chlorophenyl)-1H-pyrazol-1-yl)(phenyl)methyl)phenol
(3h): Rf = 0.50 (EtOAc/PE = 1:5), yield: 91%, yellow solid. m.p. 4-fluoro-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol
1
143-144 °C. H NMR (400 MHz, CDCl3): δ (ppm) 10.61 (s, 1H), (4a): Rf = 0.45 (EtOAc/PE = 1:5), yield: 93%, yellow solid. m.p.
1
7.90 (s, 1H), 7.74 (s, 1H), 7.38-7.30 (m, 5H), 7.28-7.25 (m, 4H), 176-178 °C. H NMR (400 MHz, CDCl3): δ (ppm) 10.74 (s, 1H),
6.89-6.84 (m, 3H), 6.46 (s, 1H), 5.98 (s, 1H). 13C NMR (CDCl3, 7.75 (m, 2H), 7.62 (s, 1H), 7.40-7.36 (m, 2H), 7.33-7.28 (m, 4H),
100 MHz): δ (ppm) 155.5, 149.5, 141.8, 138.9, 131.8, 131.4, 6.95-6.80 (m, 5H), 6.66 (d, J = 2.3Hz, 1H), 6.52 (s, 1H). 13C NMR
130.8, 130.5, 129.3, 128.7, 128.5, 128.2, 127.8, 127.0, 126.8, (CDCl3, 100 MHz): δ (ppm) 157.4, 155.0, 152.2, 151.6, 138.1,
126.2, 119.9, 117.3, 106.8, 69.7. HRMS calcd for C22H17ClN2O 132.6, 132.0, 128.8, 128.6, 128.4, 128.1, 126.7, 125.8, 120.2,
[M+Na]+ 383.0927, found: 383.0930.
116.8, 116.6, 102.8, 68.3. HRMS calcd for C22H17FN2O [M+Na]+
367.1223, found: 367.1220.
2-((3-(2-methoxyphenyl)-1H-pyrazol-1-yl)(phenyl)methyl)-
phenol (3i): Rf = 0.25 (EtOAc/PE = 1:5), yield: 88%, yellow solid. 4-bromo-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol
1
m.p. 140-143 °C. H NMR (400 MHz, CDCl3): δ (ppm) 11.27 (s, (4b): Rf = 0.52 (EtOAc/PE = 1:5), yield: 91%, yellow solid. m.p.
1
1H), 7.78 (d, J = 7.7Hz, 1H), 7.71 (d, J = 2.3Hz, 1H), 7.38-7.34 (m, 188-189 °C. H NMR (400 MHz, CDCl3): δ (ppm) 11.19 (s, 1H),
1H), 7.32-7.28 (m, 2H), 7.25-7.22 (m, 3H), 7.01 (d, J = 8.6Hz, 7.75-7.73 (m, 2H), 7.66 (m, 1H), 7.40-7.36 (m, 3H), 7.35-7.31
1H), 6.97-6.96 (m, 1H), 6.94-.91 (m, 1H), 6.88 (d, J = 2.4Hz, 1H), (m, 3H), 7.28-7.27 (m, 2H), 6.96-6.89 (m, 2H), 6.82-6.75 (m,
6.86-6.84 (m, 3H), 6.40 (s, 1H), 3.89 (s, 3H). 13C NMR (CDCl3, 1H), 6.66 (d, J = 2.3Hz, 1H), 6.45(s, 1H). 13C NMR (CDCl3, 100
100 MHz): δ (ppm) 156.8, 156.1, 148.9, 139.2, 131.6, 131.4, MHz): δ (ppm) 155.0, 152.2, 138.1, 133.3, 132.7, 130.7, 128.9,
130.8, 129.3, 128.7, 128.4, 127.7, 126.8, 126.2, 120.9, 120.2, 128.6, 128.1, 127.4, 126.8, 126.5, 125.8, 121.5, 119.2, 111.5,
119.8, 117.3, 111.4, 106.4, 69.8, 55.4. HRMS calcd for 102.9, 68.5. HRMS calcd for C22H17BrN2O [M+Na]+ 427.0422,
C23H20N2O2 [M+Na]+ 379.1422, found: 379.1419.
found: 427.0419.
2-(phenyl(3-(thiophen-2-yl)-1H-pyrazol-1-yl)methyl)phenol
4-methyl-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol
(3j): Rf = 0.37 (EtOAc/PE = 1:5), yield: 88%, white solid. m.p. (4c): Rf = 0.37 (EtOAc/PE = 1:5), yield: 95%, yellow solid. m.p.
1
83-85 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.38 (s, 1H), 7.92 123-125 °C. H NMR (400 MHz, CDCl3): δ (ppm) 10.62 (s, 1H),
(s, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.38-7.37 (m, 1H), 7.36-7.34 (m, 7.67-7.65 (m, 2H), 7.60 (d, J = 2.3Hz, 1H), 7.30-7.27 (m, 2H),
1H), 7.27-7.27 (m, 1H), 7.25-7.25 (m, 2H), 7.18-7.16 (m, 2H), 7.22 (d, J = 7.3Hz, 1H), 7.18-7.14 (m, 3H), 7.01-6.97 (m, 2H),
7.03-7.01 (m, 1H), 6.97-6.95 (m, 1H), 6.91-6.90 (m, 2H), 6.52 6.83-6.79 (m, 3H), 6.55 (d, J = 2.3Hz, 1H), 6.30 (s, 1H), 2.22 (s,
(d, J = 2.4Hz, 1H), 6.50 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 3H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 153.4, 152.0, 139.1,
(ppm) 155.7, 138.7, 135.3, 132.5, 130.7, 128.7, 128.5, 128.3, 132.6, 132.1, 131.8, 131.3, 129.1, 128.8, 128.5, 128.3, 127.8,
128.2, 127.9, 127.6, 126.8, 126.5, 124.4, 119.7, 117.3, 102.7, 126.3, 125.8, 125.1, 119.8, 102.6, 69.7, 20.4. HRMS calcd for
69.1. HRMS calcd for C20H16N2OS [M+Na]+ 355.0881, found: C23H20N2O [M+Na]+ 363.1473, found: 363.1472.
355.0880.
5-chloro-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol
tert-butyl3-(1-((2-hydroxyphenyl)(phenyl)methyl)-1H-pyrazol- (4d): Rf = 0.46 (EtOAc/PE = 1:5), yield: 91%, white solid. m.p.
1
3-yl)-2-methyl-1H-indole-1-carboxylate (3k): Rf
=
0.55 172-173 °C. H NMR (400 MHz, CDCl3): δ (ppm) 11.40 (s, 1H),
1
(EtOAc/PE = 1:5), yield: 94%, yellow solid. m.p. 185-186 °C. H 7.75-7.73 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H ), 7.40-7.39 (m, 2H),
NMR (400 MHz, CDCl3): δ (ppm) 10.84 (s, 1H), 8.13 (d, J = 8.1Hz, 7.33-7.31 (m, 1H), 7.30-7.26 (m, 3H), 7.25 (s, 1H), 6.93-6.87 (m,
1H), 7.85 (s, 1H), 7.62 (d, J = 7.3Hz, 1H), 7.33-7.27 (m, 5H), 4H), 6.66 (d, J = 2.3 Hz, 1H), 6.48 (s, 1H). 13C NMR (CDCl3, 100
7.23-7.18 (m, 2H), 7.01-6.93 (m, 2H), 6.85 (d, J = 7.0Hz, 2H), MHz): δ (ppm) 156.7, 152.1, 138.3, 135.8, 132.6, 131.8, 131.6,
6.59 (s, 1H), 6.46 (s, 1H), 2.68 (s, 3H), 1.68 (s, 9H). 13C NMR 128.8, 128.6, 128.5, 128.1, 126.4, 125.8, 124.1, 120.0, 119.9,
(CDCl3, 100 MHz): δ (ppm) 156.0, 150.7, 146.3, 145.6, 139.3, 102.8, 68.7. HRMS calcd for C22H17ClN2O [M+Na]+ 383.0927,
136.0, 135.7, 132.0, 131.5, 130.9, 128.5, 127.8, 126.1, 125.5, found: 383.0929.
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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3-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)naphthalen-2-ol
View Article Online
DOI: 10.1039/C9OB01780A
5-methyl-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol
(4j): Rf = 0.58 (EtOAc/PE = 1:5), yield: 86%, white solid. m.p.
1
(4e): Rf = 0.45 (EtOAc/PE = 1:5), yield: 94%, yellow solid. m.p. 174-176°C. H NMR (400 MHz, CDCl3): δ (ppm) 11.53 (s, 1H),
143-145 °C. H NMR (400 MHz, CDCl3): δ (ppm) 10.85 (s, 1H), 8.05 (d, J = 8.7Hz, 1H), 7.81-7.75 (m, 3H), 7.71-7.69 (m, 2H),
1
7.74 (d, J = 7.3Hz, 2H), 7.63-7.62 (m, 1H), 7.37-7.34 (m, 2H), 7.51-7.42 (m, 2H), 7.34-7.29 (m, 3H), 7.26-7.25 (m, 1H), 7.22-
7.30-7.22 (m, 4H), 7.07 (d, J = 7.6Hz, 1H), 6.89-6.88 (m, 2H), 7.20 (m, 1H), 7.17-7.15 (m, 3H), 6.75-6.74 (m, 2H), 6.61 (s, 1H).
6.78 (s, 1H), 6.71-6.70 (m, 1H), 6.61 (d, J = 2.3Hz, 1H), 6.44 (s, 13C NMR (CDCl3, 100 MHz): δ (ppm) 154.2, 151.0, 138.4, 132.1,
1H), 2.27 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 155.6, 132.0, 131.0, 130.1, 128.3, 128.0, 127.7, 127.4, 127.4, 126.5,
152.0, 140.9, 139.2, 132.5, 132.2, 130.9, 128.8, 128.5, 128.3, 126.3, 124.9, 124.8, 122.0, 121.3, 119.3, 116.2, 101.6, 60.5.
127.8, 126.4, 125.8, 122.6, 120.6, 120.3, 102.6, 69.1, 21.2. HRMS calcd for C26H20N2O [M+Na]+ 399.1473, found: 399.1475.
HRMS calcd for C23H20N2O [M+Na]+ 363.1473, found: 363.1475.
2-((3-phenyl-1H-pyrazol-1-yl)(p-tolyl)methyl)phenol (4k): Rf =
5-methoxy-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)-
0.25 (EtOAc/PE = 1:5), yield: 96%, white solid. m.p. 181-182°C.
phenol (4f): Rf = 0.40 (EtOAc/PE = 1:5), yield: 96%, yellow solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.89 (s, 1H), 7.78-7.75 (m,
1
m.p. 124-125 °C. H NMR (400 MHz, CDCl3): δ (ppm) 11.19 (s, 2H), 7.73 (d, J = 2.4Hz, 1H), 7.41-7.37 (m, 2H), 7.33-7.31 (m,
1H), 7.76-7.72 (m, 3H), 7.40-7.36 (m, 2H), 7.32 (d, J = 7.3Hz, 1H), 7.25-7.19 (m, 4H), 7.14 (d, J = 6.4Hz, 1H), 6.86-6.82 (m,
1H), 7.26-7.24 (m, 2H), 7.18-7.16 (d, J = 8.1Hz, 2H), 6.86-6.84 3H), 6.66 (d, J = 2.4Hz, 1H), 6.40 (s, 1H), 2.27 (s, 3H). 13C NMR
(m, 2H), 6.65 (d, J = 2.4Hz, 1H), 6.59 (d, J = 2.5Hz, 1H), 6.50- (CDCl3, 100 MHz): δ (ppm) 154.1, 151.9, 139.2, 132.6, 132.2,
6.47 (m, 1H), 6.36 (s, 1H), 3.78 (s, 3H). 13C NMR (CDCl3, 100 132.1, 132.0, 129.2, 128.7, 128.4, 128.3, 127.6, 126.0, 125.7,
MHz): δ (ppm) 161.8, 157.2, 151.9, 139.4, 132.5, 132.1, 132.0, 124.9, 119.4, 102.5, 70.0, 16.6. HRMS calcd for C23H20N2O
128.8, 128.4, 128.3, 127.7, 126.1, 125.8, 117.9, 106.1, 104.9, [M+Na]+ 363.1473, found: 363.1469.
102.5, 69.3, 55.3. HRMS calcd for C23H20N2O2 [M+Na]+
379.1422, found: 379.1425.
2-((4-methoxyphenyl)(3-phenyl-1H-pyrazol-1-yl)methyl)-
phenol (4l): Rf = 0.50 (EtOAc/PE = 1:5), yield: 94%, white solid.
1
2-methyl-6-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol
m.p. 180-184°C. H NMR (400 MHz, CDCl3): δ (ppm) 10.89 (s,
(4g): Rf = 0.72 (EtOAc/PE = 1:5), yield: 97%, white solid. m.p. 1H), 7.68-7.62 (m, 3H), 7.32-7.28 (m, 2H), 7.24-7.20 (m, 2H),
1
178-179°C. H NMR (400 MHz, CDCl3): δ (ppm) 10.90 (s, 1H), 7.18-7.13 (m, 1H), 6.92 (d, J = 7.9Hz, 1H), 6.85-6.81 (m, 1H),
7.77-7.71 (m, 3H), 7.41-7.29 (m, 3H), 7.24-7.12 (m, 5H), 6.85- 6.75-6.69 (m, 4H), 6.56 (d, J = 2.3Hz, 1H), 6.34 (s, 1H), 3.67 (s,
6.82 (m, 3H), 6.65 (d, J = 2.1Hz, 1H), 6.39 (s, 1H), 2.27 (s, 3H). 3H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 159.1, 155.9, 151.9,
13C NMR (CDCl3, 100 MHz): δ (ppm) 154.1, 152.0, 139.2, 132.6, 132.5, 132.1, 131.1, 130.9, 130.7, 128.8, 128.3, 127.6, 125.8,
132.2, 132.0, 129.2, 128.9, 128.8, 128.4, 128.3, 127.7, 126.1, 125.5, 119.9, 119.8, 113.9, 102.5, 69.3, 55.3. HRMS calcd for
125.8, 125.0, 119.4, 102.6, 70.0, 16.6. HRMS calcd for C23H20N2O2 [M+Na]+ 379.1422, found: 379.1420.
C23H20N2O [M+Na]+ 363.1473, found: 363.1472.
2-((3-phenyl-1H-pyrazol-1-yl)(3,4,5-trifluorophenyl)methyl)-
2,4-di-tert-butyl-6-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)-
phenol (4m): Rf = 0.38 (EtOAc/PE = 1:5), yield: 89%, yellow
phenol (4h): Rf = 0.38 (EtOAc/PE = 1:30), yield: 95%, yellow solid. m.p. 200-203°C. 1H NMR (400 MHz, CDCl3): δ (ppm)
solid. m.p. 144-145°C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.78 (s, 1H), 7.68-7.62 (m, 3H), 7.34-7.30 (m, 2H), 7.27-7.22
10.86 (s, 1H), 7.75-7.73 (m, 3H), 7.40-7.34 (m, 3H), 7.29-7.19 (m, 2H), 7.16-7.12 (m, 1H), 6.93 (d, J = 8.3Hz, 1H), 6.87-6.83 (m,
(m, 4H), 7.14 (d, J = 1.8Hz, 1H), 6.83-6.82 (m, 2H), 6.64-6.63 (m, 1H), 6.60 (d, J = 2.3Hz, 1H), 6.40-6.36 (m, 2H), 6.24 (s, 1H). 13C
1H), 6.36 (s, 1H), 1.43 (s, 9H), 1.33 (s, 9H). 13C NMR (CDCl3, 100 NMR (CDCl3, 100 MHz): δ (ppm) 155.6, 152.7, 152.4, 149.9,
MHz): δ (ppm) 152.6, 151.8, 141.5, 139.6, 139.5, 132.7, 132.3, 135.6, 132.7, 131.6, 131.5, 131.1, 128.8, 128.6, 125.8, 124.2,
128.8, 128.3, 128.2, 127.6, 126.5, 126.1, 125.7, 125.4, 125.2, 120.3, 110.9, 110.7, 103.1, 68.3. HRMS calcd for C22H15F3N2O
102.5, 70.9, 31.8, 29.9. HRMS calcd for C30H34N2O2 [M+Na]+ [M+Na]+ 403.1034, found: 403.1038.
461.2569, found: 461.2571.
2-((3-phenyl-1H-pyrazol-1-yl)methyl)phenol (4n): Rf = 0.45
1
6-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)benzo[d][1,3]-
(EtOAc/PE = 1:5), yield: 86%, yellow semisolid. H NMR (400
dioxol-5-ol (4i): Rf = 0.30 (EtOAc/PE = 1:5), yield: 90%, yellow MHz, CDCl3): δ (ppm) 10.52 (s, 1H), 7.70-7.68 (m, 2H), 7.43 (d, J
solid. m.p. 163-165°C. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.4Hz, 1H), 7.35-7.31 (m, 2H), 7.27-7.19 (m, 2H), 7.17-7.12
10.70 (s, 1H), 7.75 (d, J = 7.5Hz, 2H), 7.66 (d, J = 2.2Hz, 1H), (m, 1H), 6.97-6.94 (m, 1H), 6.82-6.78 (m, 1H), 6.46 (d, J = 2.4Hz,
7.40-7.37 (m, 2H), 7.33-7.26 (m, 5H), 6.92-6.90 (m, 2H), 6.70 (s, 1H), 5.17 (s, 2H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 155.7,
1H), 6.65 (d, J = 2.2Hz, 1H), 6.52 (s, 1H), 5.94 (s, 1H), 5.89 (s, 150.6, 131.1, 129.9, 129.6, 129.1, 127.7, 127.2, 124.6, 122.2,
1H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 152.0, 151.3, 149.0, 119.2, 118.0, 101.7, 52.7. HRMS calcd for C16H14N2O [M+Na]+
140.9, 139.0, 132.4, 132.1, 128.8, 128.5, 128.3, 127.8, 126.3, 273.1004, found: 273.1001.
125.8, 117.2, 109.9, 102.6, 101.7, 101.3, 68.9. HRMS calcd for
C23H18N2O3 [M+Na]+ 393.1215, found: 393.1214.
2-(1-(3-phenyl-1H-pyrazol-1-yl)propyl)phenol (4o): Rf = 0.37
(EtOAc/PE = 1:5), yield: 96%, white semisolid. H NMR (400
1
MHz, CDCl3): δ (ppm) 11.49 (s, 1H), 7.77 (d, J = 7.6Hz, 2H), 7.50
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J. Name., 2013, 00, 1-3 | 7
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(d, J = 2.2Hz, 1H), 7.42-7.38 (m, 2H), 7.33-7.30 (m, 1H), 7.25- 3-phenyl-1-(9H-xanthen-9-yl)-1H-pyrazole (8): Rf
=
0.87
View Article Online
1
7.20 (m, 1H), 7.11 (d, J = 7.3Hz, 1H), 7.01 (d, J = 8.2Hz, 1H), (EtOAc/PE = 1:5), yield: 40%, yellow soliDdO. Im: 1.0p.1.01393/1C-91O3B20°1C7.80HA
6.84-6.81 (m, 1H), 6.52 (d, J = 2.2Hz, 1H), 5.08-5.04 (m, 1H), NMR (400 MHz, CDCl3): δ (ppm) 7.86-7.84 (m, 2H), 7.66-7.64
2.56-2.47 (m, 1H), 2.25-2.16 (m, 1H), 0.92-0.88 (m, 3H). 13C (m, 1H), 7.42-7.40 (m, 1H), 7.39-7.36 (m, 2H), 7.35-7.33 (m,
NMR (CDCl3, 100 MHz): δ (ppm) 155.9, 151.3, 132.2, 131.2, 2H), 7.32-7.26 (m, 4H), 7.18-7.16 (m, 2H), 6.76 (s, 1H), 6.19 (s,
130.1, 129.8, 128.8, 128.2, 125.9, 125.7, 119.8, 119.7, 102.2, 1H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 156.6, 147.1, 145.8,
67.7, 35.6, 13.5. HRMS calcd for C18H18N2O [M+Na]+ 301.1317, 137.8, 134.0, 129.8, 129.1, 128.6, 128.5, 127.7, 127.3, 125.7,
found: 301.1320.
124.0, 120.5, 93.7, 67.2. HRMS calcd for C22H16N2O [M+Na]+
324.1263, found: 324.1265.
2-(cyclopropyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenol (4p):
Rf = 0.15 (EtOAc/PE = 1:5), yield: 90%, yellow solid. m.p. 151- 4,4-dimethoxy-2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)-
152°C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.36 (s, 1H), 7.69 (d, cyclohexa-2,5-dien-1-one (9): Rf = 0.65 (EtOAc/PE = 1:10), yield:
J = 7.6Hz, 2H), 7.43 (s, 1H), 7.33-7.30 (m, 2H), 7.24-7.21 (m, 66%, colorless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.82-7.80
1H), 7.14-7.10 (m, 1H), 7.05 (d, J = 7.5Hz, 1H), 6.91 (d, J = 7.9Hz, (m, 2H), 7.42-7.37 (m, 5H), 7.35-7.33 (m, 2H), 7.31-7.29 (m,
1H), 6.78-6.74 (m, 1H), 6.47 (s, 1H), 4.26 (d, J = 10.0Hz, 1H), 2H), 6.86-6.85 (m, 1H), 6.77 (s, 1H), 6.58 (d, J = 2.4Hz, 1H),
2.03 (s, 1H), 0.64 (d, J = 4.0Hz, 2H), 0.31 (s, 2H). 13C NMR (CDCl3, 6.43-6.42 (m, 1H), 6.33-6.31 (m, 1H), 3.37 (s, 3H), 3.33 (s, 3H).
100 MHz): δ (ppm) 155.8, 151.2, 132.2, 130.2, 130.1, 128.9, 13C NMR (CDCl3, 100 MHz): δ (ppm) 183.4, 151.9, 143.3, 142.2,
128.8, 128.2, 126.3, 125.7, 119.8, 119.4, 102.3, 71.1, 14.4, 5.64, 139.5, 137.1, 133.5, 131.4, 130.0, 128.9, 128.6, 128.5, 128.1,
5.42. HRMS calcd for C19H18N2O [M+Na]+ 313.1317, found: 127.6, 125.6, 102.9, 93.3, 62.8, 50.8, 50.4. HRMS calcd for
313.1320.
C24H22N2O3 [M+Na]+ 409.4408, found: 409.4410.
3-phenyl-1-(phenyl(2-(1-phenylethoxy)phenyl)methyl)-1H-
pyrazole (5): Rf = 0.78 (EtOAc/PE = 1:10), yield: 85%, white
solid. m.p. 126-128°C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.78-
7.75 (m, 2H), 7.73-7.72 (m, 1H), 7.44-7.41 (m, 2H), 7.40-7.38
(m, 2H), 7.34-7.31 (m, 2H), 7.30-7.27 (m, 3H), 7.25 (s, 1H),
7.20-7.18 (m, 2H), 7.16-7.15 (m, 1H), 7.04-7.02 (m, 1H), 6.96-
6.92 (m, 1H), 6.89-6.87 (m, 2H), 6.67 (d, J=2.4 Hz, 1H), 6.46 (s,
1H), 2.40 (s, 1H), 1.77 (d, J=7.16 Hz, 3H). 13C NMR (CDCl3, 100
MHz): δ (ppm) 155.9, 152.0, 139.0, 132.6, 132.1, 131.3, 130.8,
129.4, 129.3, 129.3, 128.8, 128.7, 128.5, 128.4, 128.3, 127.8,
126.3, 125.8, 125.4, 119.9, 102.6, 69.6, 66.1, 22.7. HRMS calcd
for C30H26N2O [M+Na]+ 430.5510, found: 430.5511.
Conclusions
We have successfully developed a cascade reaction between
α,β-unsaturated N-tosylhydrazone and ortho-hydroxybenzyl
alcohol to directly access carbon-nitrogen (C-N) linked N-sec-
alkylpyrazoles containing three or two (hetero)aryl ring at the
same carbon atom (triarylmethanes and 1,1-diarylalkanes). A
broad range of ortho-hydroxybenzyl alcohols reagents and α,β-
unsaturated N-tosylhydrazone compounds were tolerated. The
reaction proceeds under metal-free conditions, giving highly
functionalized pyrazoles in excellent yield and regioselectivity.
The procedure is operationally simple and applicable to large-
scale synthesis. We believe that this protocol may become a
useful tool in organic synthesis.
1-((2-(cyclohexyloxy)phenyl)(phenyl)methyl)-3-phenyl-1H-
pyrazole (6): Rf = 0.64 (EtOAc/PE = 1:10), yield: 60%, white
solid. m.p. 121-123°C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.75-
7.73 (m, 2H), 7.30-7.28 (m, 2H), 7.23-7.21 (m, 1H), 7.21-7.20
(m, 2H), 7.19-7.19 (m, 1H), 7.17-7.17 (m, 1H), 7.16-7.15 (m,
1H), 7.10 (s, 1H), 7.06-7.04 (m, 2H), 6.80-6.78 (m, 1H), 6.77-
6.75 (m, 1H), 6.71-6.69 (m, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.23-
4.17 (m, 1H), 1.21-1.14 (m, 10H). 13C NMR (CDCl3, 100 MHz): δ
(ppm) 154.0, 150.4, 138.9, 132.9, 129.8, 128.1, 128.0, 127.4,
127.3, 127.2, 126.5, 126.3, 124.7, 118.8, 111.3, 101.2, 63.4,
30.1, 30.1, 28.7, 24.5, 21.8. HRMS calcd for C28H28N2O [M+Na]+
431.2099, found: 431.2097.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (NO. 21672172), and the project
of Youth Science and Technology Innovation Team of Sichuan
Province (NO. 2017TD0008), and the Education Department of
Sichuan Province (NO. 15CZ0016).
2-(phenyl(3-phenyl-1H-pyrazol-1-yl)methyl)phenyl trifluoro-
methanesulfonate (7): Rf = 0.80 (EtOAc/PE = 1:5), yield: 100%,
white oil.1H NMR (400 MHz, CDCl3): δ (ppm) 7.73-7.71 (m, 2H),
7.37-7.18(m, 11H), 7.10-7.08 (m, 2H), 7.00 (m, 1H), 6.51 (d, J =
2.4Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 152.3, 147.0,
137.5, 133.4, 132.9, 131.3, 130.5, 130.0, 128.9, 128.6, 128.6,
128.5, 128.4, 127.7, 125.8, 121.2, 116.8, 103.0, 63.8. HRMS
calcd for C23H17F3N2O3S [M+Na]+ 481.0810, found: 481.0809.
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