Chemo-, regio-, and stereoselective n-alkenylation of pyrazoles/ benzpyrazoles using activated and unactivated alkynes

Article abstract of DOI:10.1021/acs.joc.7b01746

Transition-metal-free chemo-, regio-, and stereoselective synthesis of (Z) and (E) styryl pyrazoles and benzpyrazoles by the addition of N-heterocycles onto functionalized terminal and internal alkynes using a super basic solution of KOH/DMSO has been described. The stereochemical outcome of the reaction was governed by time and quantity of the base. The reaction of pyrazoles and benzpyrazoles onto alkynes takes place chemoselectively without affecting the free -NH2 group of pyrazoles and -OH group of alkynes. The designed protocol was well implemented on alkynes bearing long alkyl chain, an alicyclic ring, hydroxy, ether, and ester functionality, which offer the N-alkenylated products in good yields. This developed methodology also provides easy access for the synthesis of bis-vinylated heterocycles. The presence of free -NH₂, -OH, -COOR, and halo group in styryl pyrazoles, could be further utilized for synthetic elaboration, which is advantageous for biological evaluation. For the first time, we have disclosed the base-mediated conversion of (Z)-styryl pyrazoles to (E)-styryl pyrazoles in KOH/DMSO system. The cis-rans isomerization was supported by the control experiments and deuterium labeling studies.

Full text of DOI:10.1021/acs.joc.7b01746

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Article
Chemo-, Regio- and Stereoselective N-alkenylation of Pyrazoles/
Benzpyrazoles using Activated and Unactivated Alkynes
Vineeta Garg, Pradeep Kumar, and Akhilesh K. Verma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01746 • Publication Date (Web): 01 Sep 2017
Downloaded from http://pubs.acs.org on September 1, 2017
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Chemo_, Regio_ and Stereoselective N_alkenylation of
Pyrazoles/Benzpyrazoles using Activated and Unactivated
Alkynes
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Vineeta Garg, Pradeep Kumar and Akhilesh K. Verma*
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry,
University of Delhi, Delhi–110007, India
Email: averma@acbr.du.ac.in
ABSTRACT: Transition_metal_free chemo_, regio_ and stereoselective synthesis of (Z) and (E)
styryl pyrazoles and benzpyrazoles by the addition of N−heterocycles onto functionalized
terminal and internal alkynes using a super basic solution of KOH/DMSO has been described.
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The stereochemical outcome of the reaction was governed by time and quantity of the base. The
reaction of pyrazoles and benzpyrazoles onto alkynes takes place chemoselectively without
affecting the free –NH2 group of pyrazoles and –OH group of alkynes. The designed protocol
was well implemented on alkynes bearing long alkyl chain, an alicyclic ring, hydroxy, ether, and
ester functionality; offer the N_alkenylated products in good yields. This developed methodology
also provides easy access for the synthesis of bis_vinylated heterocycles. The presence of free –
NH2, –OH, −COOR and halo group in styryl pyrazoles, could be further utilized for synthetic
elaboration, which is advantageous for biological evaluation. For the first time, we have
disclosed the base-mediated conversion of (Z)-styryl pyrazoles to (E) styryl pyrazoles in
KOH/DMSO system. The cis–trans isomerization was supported by the control experiments and
deuterium labeling studies.
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INTRODUCTION
Heterocycles containing potential C–N bonds have an enormous impact on organic and
medicinal chemistry.1 In particular; alkylated pyrazoles have gained widespread interest of the
researchers over the past decade due to their vast biological significance like SR144528 (I) is a
potent and highly selective CB₂ receptor inverse agonist, MK−0893 (II) as a potent glucagon
receptor inhibitor, ruxolitinib (III) as a JAK 1/2 kinase inhibitor and 3−flourophenyl urea
derivative of pyrazole (IV) showed a good inhibition of neutrophils chemotaxis (Figure 1).2 A
broad range of pharmaceutically active ingredients like celecoxib, deracoxib, phenylbutazone,
oxyphenbutazone, feprazone, and kebuzone, possess pyrazole as a core nucleus with reduced
ulcer genic side effects.3 Pyrazoles motif act as an effective analgesic,4 antitubercular,5
anticancer,6 antibacterial,7 sodium channel blocker,8 anti–influenza,9 antioxidant and
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antimicrobial10 agent. Significantly, pyrazole analogs are well exploited for biological systems
due to their excellent stability and therefore used as a urease inhibitors,11 monoamine oxidase,12
and cannabinoid receptor antagonists.13 In 2009, Vukicevic and co−workers reported the
antimicrobial properties of ferrocene unit containing pyrazoles.14 Further, the pyrazole–
thiadiazole hybrids are known for selective cyclooxygenase–2 (COX–2) inhibitors due to their
ability to form hydrogen bonds and a π–cation interaction with cyclooxygenase–2 (COX–2)
enzyme effectively.15
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Figure 1. Biologically active compounds possessing N−substituted pyrazole.
Owing to the biological importance of pyrazoles analogs,15 their synthesis has been extensively
studied by various scientists.16 However; metal−free approach for the synthesis of vinylated
pyrazole under mild reaction condition remains elusive. A literature survey revealed that vinyl
group is widely used for the preparation of polymeric dyes, catalysis and act as synthetic
intermediates in various organic reactions.17 The transition–metal–catalyzed inter or
intramolecular hydroamination on alkynes, has been explored by Knochel,18 Bergmann,19
Doye,20 Beller,21 Yamamoto,22 Kondo,23 Ackermann24 and other25 for the synthesis of N–
heterocycles. However, the metal–catalyzed coupling reactions of vinyl halides and vinyl boronic
acids with azoles provide alternative methods for the synthesis of vinylated N–heterocycles
(Scheme 1, i). 26
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Scheme 1. Synthesis of N-Styryl Pyrazoles/Azoles
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In 2008, Tsuchimoto and co–workers reported the silver and zinc−catalyzed addition of N–H of
pyrazoles onto alkynes using high catalyst loading (Scheme 1, ii).27 Recently, Bhattacharjee28
and fellow workers use ruthenium complexes [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] and
[Ru(dppp)2(PPh3)(CH3CN)Cl][BPh4] for the generation of E and Z isomer respectively (Scheme
1, iii). Metal–free hydroamination has been explored by Trofimov,29 and our group30 using super
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basic system (KOH/DMSO). However, the synthesis of N–alkenylated pyrazoles in regio–,
chemo– and stereo–selective fashion with aliphatic as well as aromatic alkynes under metal–free
condition is challenging.
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Inspired by our previous reports on hydroamination,30 herein, we have described a facile
and versatile protocol for the construction of functionalized (E) and (Z) vinylated pyrazoles and
benzpyrazoles with activated and unactivated alkynes in KOH/DMSO system (Scheme 1, iv).
RESULTS AND DISCUSSION
To identify the optimal reaction conditions, we initiated the reaction of pyrazole (1a)
with phenyl acetylene (2a) using our reported conditions30d that is 0.2 equiv of KOH in
DMSO at 120 °C for 30 min, afforded the (Z)−1-styryl-1H-pyrazole (3a) in 58% yield (Table
1, entry 1). Increasing the amount of base from 0.2 to 0.5 equiv, provided the (Z)−styryl
product 3a in 74% yield (entry 2), however; further increasing the amount of base, decreases
the yield of (Z)−styryl product (entry 3). Thus, 0.5 equiv of the base in 30 min was found to be
efficient for obtaining (Z)−styryl product. When the reaction was allowed to stir for 24 h using
0.5 equiv of a base mixture of stereoisomers (Z:E::70:30) was obtained in 70% yield (entry 4).
Increase in the amount of base from 0.5 equiv to 1.0 equiv led to the formation of E isomer in
the ratio (Z:E::40:60) (entry 5). Further, to obtain the E_selective product we increase the
amount of base from 1.0 to 1.5 and then to 2.0 equiv, interestingly we obtained (E)−styryl
product 4a (Z:E::0:100) exclusively in 68% yield (entries 6 and 7). The lower yield was
obtained with other bases such as NaOH, CsOH.H2O, KOtBu, and K3PO4 in DMSO (entries 8–
11). An organic base such as Et3N was found to be ineffective for the reaction (entry 12). The
above results confirmed that the reaction time, as well as the amount of base, was important to
control the stereoselectivity of the reaction.
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Table 1. Optimization of the Reaction Conditionsa
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entry alkyne
base (equiv)
KOH (0.2)
KOH (0.5)
KOH (1.0)
KOH (0.5)
KOH (1.0)
KOH (1.5)
KOH (2.0)
NaOH (0.5)
CsOH.H2O (0.5)
KOtBu (0.5)
K3PO4(0.5)
Et3N (0.5)
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
time (h)/T °C
0.5 / 120
0.5 / 120
0.5 / 120
24 / 120
24 / 120
24 / 120
24 / 120
0.5 / 120
0.5 / 120
0.5 / 120
0.5 / 120
0.5 / 120
yield (%), 3a/4a (Z:E) b
58 (100:00)
74 (100:00)
72 (100:00)
70 (70:30)
130d
2a
2c
2a
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2a
2a
2a
2a
2a
2a
2a
2a
2a
5
68 (40:60)
6
68 (10:90)
7 c
8
68 (00:100)
69 (100:00)
62 (100:00)
60 (100:00)
68 (100:00)
NR
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12
aReactions were performed using pyrazole 1a (0.5 mmol), alkyne 2a (1.0 mmol) in 2.0 mL of
b
c
solvent. Sterioisomeric ratio. Optimized reaction conditions for the formation of Z−styryl
pyrazole 3a and E−styryl pyrazole 4a respectively.
After optimizing the reaction condition, we explored the scope of substituted pyrazoles
1a-h and alkynes 2a–m for the synthesis of (Z)-styryl pyrazoles 3a–p exclusively in good
yields (Table 2, entries 1-16). The reaction of pyrazole 1a with phenylacetylene 2a provided
the desired product 3a in 74% yield (entry 1). When electron_releasing group containing
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alkynes 2b–g were used, the desired (Z)-styryl products 3b–g were obtained in 67–72% yields
(entries 2–7). The reaction of hetero alkyne 2h was also successful in providing the desired
product 3h in good yield (entry 8). Interestingly, 2-ethynylphenylmethanol 2i bearing primary
alcoholic group afforded the product 3i in 65 % yield, without affecting the free –OH group
(entry 9).
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The designed methodology was well tolerated for substituted pyrazole having -CH3
and -NH2 functionality, and afforded the desired products 3j–k chemoselectively in good yield
without affecting free -NH2 group (entries 10-11). Significantly, electron-withdrawing and
halogen substituted pyrazoles having –CF3, –NO2 and –Br group afforded the hydroaminated
products 3l–n in 68-70% yields (entries 12-14). The sterically hindered pyrazoles were also
reacted smoothly with substituted terminal alkynes 2m, 2b and provided the corresponding
hydroaminated products 3o and 3p in good yields (entries 15-16).
Table 2. Synthesis of Z-Styryl Pyrazolesa
entry
1
pyrazoles
alkyne 2
(Z) product 3
yield (%)b
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2d
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1a
2e
2f
1a
1a
1a
1a
2g
3g
3h
3i
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2i
10c
11c
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3k
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3l
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1e
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3m
3n
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16c
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2a
2m
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1f
1g
1h
3o
3p
aThe reactions were performed using pyrazoles 1 (0.5 mmol), 1.0 mmol of alkynes 2, 0.5
equiv of KOH in 2.0 mL of DMSO at 120 oC for 0.5 h. b Isolated yields. c Reaction run for 4 h.
After obtaining the selective Z-styryl product, we extended the scope of the developed
chemistry for the stereoselective synthesis of (E)-styryl pyrazoles 4a–g in good yields (Scheme
2). The reaction of pyrazole 1a with substituted alkynes 2a–b and 2n–p in the presence of 2.0
o
equiv KOH in DMSO at 120 C for 24 h gave the E-styryl products 4a–e in 65-70% yield.
Electron withdrawing aryl alkynes such as 1-ethynyl-4-(trifluoromethyl)benzene 2q and 1-
ethynyl-4-nitrobenzene 2r provided the desired E-styryl product 4h-i in moderate yield with
excellent selectivity.
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Scheme 2. Synthesis of E-Styryl Pyrazolesa
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4a, 68%
4b, 70%
4c, 65%b
4d, 68%
4e, 66%
4i, 50% c
4f, 64%
4g, 62%
4h, 45% c
aThe reactions were performed using pyrazoles 1 (0.5 mmol), 1 mmol of alkynes 2, 2.0 equiv of KOH
in 2.0 mL of DMSO at 120 oC for 24 h. bReaction completed in 6 h.cReaction run for 0.5 h with 50%
recovery of starting substrate.
In past decades hydroamination reactions on aliphatic alkynes have been reported using
expensive metal catalyst.27-28 Therefore, we examined the developed strategy for aliphatic
alkynes 2aa–ak bearing long chain, an alicyclic ring, hydroxyl, ether, and ester group were
utilized for the synthesis of N-alkenylated pyrazoles 5a–m in 40-69% yields (Table 3). The
reaction with aliphatic alkyne 2aa and 2ab provided the (Z)-vinylated products 5a–b in good
yields (entries 1-2). Interestingly, when a primary alcoholic group containing alkynes 2ac–ad
were employed under standard reaction conditions, the reaction gave the hydroaminated products
5c–d in fair yields instead of hydroxylation on primary alcohol (entries 3-4). However, the
reaction with 1-ethynylcyclopentanol 2ae and 1-ethynylcyclohexanol 2af afforded the
corresponding products 5e and 5f in 55% and 60% yields, respectively (entries 5 and 6).
Similarly, methyl and phenyl propargyl ether 2ag–ah were also found compatible to provide the
Z-alkenylated products 5g and 5h in good yields (entries 7-8). Substituted pyrazoles having
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electron-withdrawing group were also successful in providing the hydroaminated products 5i–j
in 59-69% yield (entries 9-10). 4-Bromo-1H-pyrazole (1f) gave the fruitful yield of desired
products 5k–l with 1-hexyne 2ai and 1-pentynol 2aj (entries 12-13). Surprisingly, the reaction of
ethyl propiolate 2ak with pyrazole 1a provided the hydroaminated product 5m in 66% yield with
absolute E_stereoselectivity (entry 14). The formation of N-alkenylated products reveals the
efficacy, functional group tolerance and chemoselective behavior of designed protocol.
Table 3. Scope of Aliphatic Alkynesa
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entry
pyrazoles
alkyne 2a
product 5
yield (%) b
62
2aa
2ab
5a
5b
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1a
1a
2
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3
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68
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2ac
2ad
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2ae
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2af
2ag
2ah
5f
5g
5h
5i
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69
1a
1a
1d
2ac
2ab
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5j
1d
1f
2ai
5k
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66
1f
2aj
5l
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1a
2ak
5m
aThe reactions were performed using 1a-c (0.5 mmol), alkyne 2 (1.0 mmol), and 1.0 equiv of
KOH in 2.0 mL of DMSO at 120 oC for 5 h. b Isolated yields. cReaction completed in 0.5 h.
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Scheme 3. Scope of Internal Alkynesa
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7a, 70%
7e, 70%
7b, 68%
7f, 62%
7c, 65%b
7d, 71% b
7g, 72%
7h, 65% b
7i, 69%
7j, 65%
7k, 63%
aThe reactions were performed using pyrazoles 1 (0.5 mmol), alkynes 2 (0.5 mmol), 1.5
equiv of KOH in 2.0 mL of DMSO at 120 oC for 24 h. bReaction completed in 3 h.
We next examined the scope and efficacy of the reaction by employing a wide range of
substituted symmetrical and unsymmetrical internal alkynes 6a−h with pyrazoles 1 to synthesize
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corresponding hydroaminated product 7 in regioselective manner (Scheme 3). Nucleophilic
addition of pyrazole 1a provided the desired product 7a with diphenylacetylene 6a in good
yields. However, 1,2-di-p-tolylethyne 6b and 1-methyl-3-(p-tolylethynyl)benzene 6c afforded the
hydroaminated products 7b-c in 65-68% yields. It was observed that alkyne 6d reacted more
promptly with 1a and gave the desired product 7d in 71% yield. Electron-withdrawing group
containing alkyne 6e yielded the addition product 7e in 70% yield whereas electron-rich alkyne
6f afforded the desired product 7f in 62% yield. Aryl alkyl internal alkynes, prop-1-yn-1-
ylbenzene 6g and 3-phenylprop-2-yn-1-ol 6h, gave the N-alkenylated products 7g and 7h in good
yields. Similarly, commendable results were obtained when the reaction of 3-methyl pyrazole 1b
with alkyne 6g was performed. The reaction of trifluoromethane substituted pyrazoles 1d with
alkyne 6a leads to the formation of desired product 7j in 65% yield whereas bromo substituted
pyrazoles 1f gave the product 7k in 63% yield. The regioselectivity of the reaction was
recognized by chemical shifts, coupling constants (JH-H), and NOESY studies (see SI).
After synthesizing the library of N-styryl pyrazoles from differently substituted aromatic
and aliphatic alkynes with pyrazoles in good yields, further efforts were carried out to explore
the benzpyrazoles in the reaction. The benzpyrazoles 1k-l, having –Br functionality reacted with
terminal and internal alkynes and gave the (Z)-5/6-bromo-1-styryl-1H-indazoles 8a-g in good
yield (Scheme 4). The addition of 5-bromobenzpyrazoles 1k on alkyne 2a provided the product
8a in 65% yield. However, alkyne 2b and 2n afforded the corresponding Z-addition products 8b-
c in 63-67% yield. Alkyne 2h containing thienyl ring gave the desired product 8d in 60% yield.
Similarly, the reaction of 6 bromo-1H-indazoles 1l afforded the hydroaminated products 8e and
8f with alkynes 2a and 2c in 62% and 60% yields respectively. Reactions of internal alkynes 6a
with 1k provided the styryl products 8g in good yield using 2.0 equiv of KOH at 120 °C for 36 h.
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Scheme 4. Synthesis of (Z)-5/6-bromo-1-styryl-1H-indazolesa
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aThe reactions were performed using benzpyrazoles 1 (0.5 mmol), alkynes 2 (1.0 mmol), 1 equiv
o
b
of KOH in 2.0 mL of DMSO at 120 C for 8 h. benzpyrazole 1l (0.5 mmol), alkynes 2 (0.5
mmol), 2.0 equiv of KOH for 36 h.
Encouraged by above results, we explore 1, 3 and 1, 4 diethynyl benzene 2r and 2s for
the synthesis of bis-vinylated N-heterocycles compound 9a-e (Scheme 5, a). The reaction was
carried out by using 1.0 equiv of KOH at 120 oC with 4-iodo-1H-pyrazole 1m for 0.5 h, provided
the bis hydroaminated product 9a in 58% yield. The reaction was also compatible with
benzpyrazoles to synthesize the 1,4-bis((Z)-2-(6-bromo-1H-indazol-1-yl)vinyl)benzene 9b in 2 h
(Scheme 5, b). The reaction of triazole 1n with alkynes 2r along with pyrazole 1a furnish the 1-
((Z)-3-((Z)-2-(1H-pyrazol-1-yl)vinyl)styryl)-1H-1,2,4-triazole 9c in 59% yields (Scheme 5, c).
Similarly, indole 1o and pyrazole 1a with alkyne 2s gave the bis-hydrominated product 9d in
good yield. Further, we elaborate the scope of reaction with 1,4-bis(4-methoxyphenyl)buta-1,3-
diyne 2t and 1a; we obtained the hydroaminated product 9e in 48% yield selectively (Scheme 5,
e).
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Scheme 5. Hydroamination on Dialkynes
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(a) The reactions were performed using pyrazole 1m (0.5 mmol), 0.25 mmol of the alkyne 2r,
1.0 equiv of KOH in 2.0 mL of DMSO at 120 oC for 0.5 h. (b) Benzpyrazole 1l (0.5 mmol), 0.25
mmol of the alkyne 2s, 1.0 equiv of KOH in 2.0 mL of DMSO at 120 oC for 2 h. (c) Pyrazole 1a
(0.5 mmol) along with triazole 1n (0.5 mmol), 0.25 mmol of the alkyne 2r, 1.0 equiv of KOH in
2.0 mL of DMSO at 120 oC for 2 h. (d) Pyrazole 1a (0.5 mmol) along with indole 1o (0.5 mmol),
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0.25 mmol of the alkyne 2s, 1.0 equiv of KOH in 2.0 mL of DMSO at 120 C for 2 h. (e)
Pyrazole 1a (0.5 mmol), 0.25 mmol of the alkyne 2t, 0.5 equiv of KOH in 2.0 mL of DMSO at
120 oC for 0.5 h.
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Inspired by our previously reported mechanistic studies of hydrophenoxylation31a and
hydrothiolation31b using KOH/DMSO system. Further, we explore the cis to trans isomerization
in hydroamination. The reaction in deuterated DMSO-d6 furnished deuterium labeled at styryl
position in compounds 10a-d indicates the source of the styryl proton was solvent (Scheme 6A).
Similarly, no reaction occurs when the reaction is carried out with isolated (Z)-isomer 3a using
KOH/Toluene system for 36 h (Scheme 6B). These experiments confirmed that the source of
styryl proton is DMSO, and experiment 6B suggested the exchange of proton was facilitating in
KOH/DMSO system.
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Further studies were focused on to understand the involvement of our catalyst system in
cis to trans isomerization by performing the reaction in DMSO without KOH, the starting
material remains unchanged (scheme 6C). This control experiment confirmed the presence of
KOH/DMSO catalytic system is crucial for the reaction, probably the KOH functioning as an
initiator in the scrambling of DMSO. The compound 3a was treated with KOH/DMSO system;
the E_product 4a was obtained in 68% in 24 h (Scheme 6D, i). Next reaction was performed in
KOH/DMSO-d6, and the product 10e was achieved with deuterium-labeled at styryl position
(scheme 6D, ii). Further running the reaction for more time from 20 h to 24, 30 and 40 h in
KOH/DMSO-d6 provided the deuterated compounds 10f-h in different deuterium percentage up
to 100% (scheme 6C, iii-v). The Comparative 1H NMR spectrum studies of cis_trans conversion
in DMSO/DMSO−d6 with various reaction intervals are shown in Figure 2.
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Scheme 6. Deuterium Labeling and Control Experiments: Cis to Trans Isomerization
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entry
1H NMR spectrum studies
product
time/solvent
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Figure 2. H NMR Spectrum studies of cis to trans conversion and deuterium exchange in
DMSO/DMSO-d6. (i) Reaction in DMSO after 0.5 h. (ii) Reaction in DMSO after 24 h. (iii)
Reaction in DMSO-d6 after 6 h. (iv) Reaction in DMSO-d6 after 24 h. (v) Reaction in DMSO-d6
after 30 h. (vi) Reaction in DMSO-d6 after 40 h.
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Scheme 7. Plausible Mechanism
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In the illumination of preliminary experiments, we proposed the possible mechanistic
pathway for the synthesis of cis hydroaminated product 3a_d2 and their conversion to trans
isomer 10 via intermediate V. The formation of cis isomer was initiated by the attack of pyrazole
anion 1’ on alkyne 2-d1 to form alkenyl anion I (Scheme 7). Subsequently, kinetically stable Z-
enamines 3a_d2 changed into iminium ion II by the migration of pyrazole lone pair towards
adjacent carbon. The intermediate II converted into intermediate III which after deuterium
exchange generates trans isomer V. Further deuteration of intermediate V generated the
compound 10 via intermediate VI and VII. The above experiments concluded that initially, the
kinetic control leads to the formation of Z isomer but later on, the thermodynamic control
converts the Z_ to E_isomer.
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Scheme 8. Synthetic Transformation
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Having explored the variety of simple and substituted pyrazoles and benzpyrazoles with
aromatic and aliphatic alkynes, further we carried out synthetic transformation of our designed
N-vinylated pyrazoles (3a and 4a) through reduction of styryl bond using 10 mol % of Pd/C in
EtOAc:MeOH (4:1). Next, we diversified bromo handle compound 8c by palladium-catalyzed
Sonogashira coupling reaction (Scheme 8).
CONCLUSIONS
In summary, we have envisaged a versatile and efficient regio−, chemo− and
stereoselective synthetic approach to produce a broad range of functionalized (E) and (Z) styryl
pyrazole and benzpyrazole derivatives which can be used as precursors for the synthesis of
biologically active molecules. We also disclosed the implementation of aliphatic alkynes in
hydroamination using metal and ligand-free protocol. This method provides the simplest way for
the synthesis of symmetrical and unsymmetrical bis-vinylated heterocyclic compounds.
Deuterium labeling and control experiments demonstrate the role of KOH/DMSO catalytic
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system in the cis_trans isomerization, which was further supported by comparative H NMR
spectrum studies in DMSO/DMSO−d6.
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EXPERIMENTAL SECTION
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General Information and Method. All the reactions were performed in an oven˗dried
Schlenk flask under an argon atmosphere. Column chromatography was performed using silica
gel (mesh 100˗200). TLC analysis was performed on commercially prepared 60 F254 silica gel
plates. Visualization of spots on TLC plate was accomplished with UV light (254 nm) and
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staining over I2 chamber. H NMR (400 MHz) and C NMR (100 MHz) spectra were recorded
in CDCl3 and (CD3)2SO. Chemical shifts for carbons are reported in ppm from tetramethylsilane
and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublet, br s = broad singlet), coupling constants in Hertz, and integration. High−resolution mass
spectra were recorded with q−TOF electrospray mass spectrometer. All purchased chemicals
were used as received. All melting points are uncorrected.
General procedure for the synthesis of (Z)−styryl pyrazoles (3a–p): In an oven dried pressure
tube, to a solution of pyrazoles 1a–h (0.5 mmol) in DMSO, finely crushed KOH (0.5 equiv) and
alkynes 2a–m (1.0 mmol) were added under inert atmosphere. The resulting reaction mixture
was heated at 120 °C for 30 min. Progression of the reaction was monitored by TLC, while
noticing complete consumption of alkynes, reaction was brought to room temperature. The
reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL). Organic layer was
concentrated under reduced pressure. The crude material so obtained was purified by column
chromatography on silica gel mesh size 100–200 (hexane).
(Z)−1−Styryl−1H−pyrazole (3a). The product was obtained as yellow oil (62.9 mg, 74% yield),
1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.30–7.27 (m, 4H), 7.20–7.18 (m, 2H), 7.00 (d, J =
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9.7 Hz, 1H), 6.25 (d, J = 9.7 Hz, 1H), 6.19–6.18 (m, 1H); 13C NMR (100 MHz, CDCl3)  140.2,
134.3, 129.4, 128.61, 128.56, 127.8, 126.9, 118.9, 106.6; HRMS (ESI_TOF) m/z: (M+H)+ Calcd
for C11H11N2 171.0922; found 171.0915.
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(Z)−1−(4−Methylstyryl)−1H−pyrazole (3b). The product was obtained as a yellow semi–solid
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(66.2 mg, 72% yield), H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.245–7.240 (m, 1H), 7.02–
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6.96 (m, 4H), 6.86 (d, J = 9.1 Hz, 1H), 6.14–6.09 (m, 2H), 2.23 (s, 3H) ; C NMR (100 MHz,
CDCl3) δ 140.0, 137.6, 131.2, 129.4, 129.1, 128.4, 126.3, 119.3, 106.4, 21.1; HRMS (ESI_TOF)
m/z: (M+H)+ Calcd for C12H13N2 185.1079; found 185.1080.
(Z)−1−(4−Ethylstyryl)−1H−pyrazole (3c). The product was obtained as a pale yellow oil (69.3
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mg, 70% yield), H NMR (400 MHz, CDCl3) δ 7.484–7.482 (m, 1H), 7.246–7.240 (m, 1H),
7.03–6.98 (m, 4H), 6.85 (d, J = 9.7 Hz, 1H), 6.11 (d, J = 9.7 Hz, 1H), 6.08 (t, J = 1.8 Hz, 1H),
13
2.52 (q, J = 7.3 Hz, 2H), 1.12 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ 144.0, 140.0,
131.4, 129.4, 128.6, 128.0, 126.3, 119.4, 106.4, 28.5, 15.3; HRMS (ESI_TOF) m/z: (M+H)+
Calcd for C13H15N2 199.1235; found 199.1226.
(Z)−1−(4−Butylstyryl)−1H−pyrazole (3d). The product was obtained as a pale yellow oil (80.2
1
mg, 71% yield), H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.356–7.351 (m, 1H), 7.12–7.07
(m, 4H), 6.96 (d, J = 9.1 Hz, 1H), 6.25–6.20 (m, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.58–1.55 (m,
2H), 1.38–1.34 (m, 2H), 0.94–0.90 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 142.8, 140.2, 131.5,
129.50, 128.62, 128.55, 126.4, 119.5, 106.5, 35.4, 33.4, 23.3, 13.9; HRMS (ESI_TOF) m/z:
(M+H)+ Calcd for C15H19N2 227.1548; found 227.1557.
(Z)−1−(4−Methoxystyryl)−1H−pyrazole (3e). The product was obtained as a brown oil (68.0
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mg, 68% yield), H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.287–7.281 (m, 1H), 7.02 (d, J =
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8.2 Hz, 2H), 6.84 (d, J = 10.8 Hz, 1H), 6.74 (d, J = 9.6 Hz, 2H), 6.15–6.13 (m, 2H), 3.72 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.2, 140.1, 130.0, 129.5, 126.5, 125.7, 119.8, 113.9, 106.4,
55.2. HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C12H13N2O 201.1028; found 201.1017.
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(Z)−1−(4−Phenoxystyryl)−1H−pyrazole (3f). The product was obtained as colorless oil (90.3
mg, 69% yield), 1H NMR (400 MHz, CDCl3)  7.594–7.591 (m, 1H), 7.378–7.372 (m, 1H), 7.33
(t, J = 8.3 Hz, 2H), 7.14–7.10 (m, 3H), 7.02 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 9.7 Hz, 1H), 6.91–
6.89 (m, 2H), 6.22–6.19 (m, 2H); 13C NMR (100 MHz, CDCl3)  157.1, 156.4, 140.2, 130.2,
129.7, 129.4, 128.8, 126.2, 123.6, 119.2, 118.9, 118.3, 106.6; HRMS (ESI_TOF) m/z: (M+H)+
Calcd for C17H15N2O 263.1184; found 263.1178.
(Z)−1−(2−(6−Methoxynaphthalen−2−yl)vinyl)−1H−pyrazole (3g). The product was obtained
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as a pale yellow solid (83.7 mg, 67% yield), mp 91–94 oC, H NMR (400 MHz, CDCl3) δ 7.66–
7.60 (m, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.55 (s, 2H) 7.277–7.271 (m, 1H), 7.12–7.10 (m, 1H),
7.06 (dd, J = 9.1 and 2.4 Hz, 1H), 7.029–7.024 (m, 1H), 6.98 (d, J = 9.7 Hz, 1H), 6.32 (d, J = 9.7
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Hz, 1H), 6.12–6.11 (m, 1H), 3.84 (s, 3H) ; C NMR (100 MHz, CDCl3) δ 158.1, 140.2, 134.0,
129.7, 129.5, 129.4, 128.8, 127.9, 127.0, 126.8, 126.6, 119.7, 119.2, 106.6, 105.7, 55.3; HRMS
(ESI_TOF) m/z: (M+Na)+ Calcd for C16H14N2ONa 273.1004; found 273.1006.
(Z)−1−(2−(Thiophen−3−yl)vinyl)−1H−pyrazole (3h). The product was obtained as a yellow
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semi–solid (59.8 mg, 68% yield), H NMR (400 MHz, CDCl3) δ 7.57–7.56 (m, 1H), 7.37–7.36
(m, 1H), 7.18–7.14 (m, 2H), 6.83 (d, J = 9.1 Hz, 1H), 6.73 (dd, J = 4.8 and 1.2 Hz, 1H), 6.22–
6.21 (m, 1H), 6.19 (d, J = 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.0, 134.0, 129.4,
127.8, 127.3, 126.0, 123.7, 119.1, 107.2; HRMS (ESI_TOF) m/z: (M+Na)+ Calcd for C9H8N2SNa
199.0306; found 199.0306.
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(Z)−(2−(2−(1H−Pyrazol−1−yl)vinyl)phenyl)methanol (3i). The product was obtained as yellow
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solid (65.0 mg, 65% yield), mp 91–94 C, H NMR (400 MHz, CDCl3) δ 7.50–7.49 (m, 2H),
7.34 (t, J = 6.8 Hz, 1H), 7.27–7.23 (m, 1H), 7.14–7.13 (m, 1H), 7.13–7.11 (m, 1H), 7.07 (d, J =
2.2 Hz, 1H), 6.31 (d, J = 9.9 Hz, 1H), 6.12 (t, J = 2.2 Hz, 1H), 4.61 (s, 2H), 2.52 (br s, 1H) ; 13C
NMR (100 MHz, CDCl3) δ 140.2, 138.9, 133.4, 129.2, 128.8, 128.22, 128.17, 127.9, 115.1,
107.0, 63.1; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C12H13N2O 201.1028; found 201.1024.
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(Z)−3−Methyl−1−styryl−1H−pyrazole (3j). The product was obtained as a yellow semi–solid
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(67.1 mg, 73% yield), H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.24–7.22 (m, 3H), 6.95–6.94
(m, 2H), 6.81 (d, J = 9.1 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 6.08 (s, 1H), 2.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 149.6, 134.7, 130.2, 128.9, 128.7, 128.6, 127.6, 117.4, 106.6, 13.5; HRMS
(ESI_TOF) m/z: (M+H)+ Calcd for C12H13N2 185.1079; found 185.1080.
(Z)−1−(3−Aminostyryl)−1H−pyrazol−4−amine (3k). The product was obtained as a yellow
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semi–solid (65.0 mg, 65% yield), H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 2.2 Hz, 1H), 7.09–
7.05 (m, 1H), 6.69 (d, J = 9.9 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.56–6.54 (m, 2H), 5.93 (d, J =
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9.9 Hz, 1H), 5.55 (d, J = 3.0 Hz, 1H), 3.64 (br s, 4H); C NMR (100 MHz, CDCl3) δ 154.8,
146.5, 135.9, 131.1, 129.4, 126.4, 118.9, 115.6, 114.9, 114.2, 95.3; HRMS (ESI_TOF) m/z:
(M+H)+ Calcd for C11H13N4 201.1140; found 201.1135.
(Z)−1−(3−Methoxystyryl)−3−(trifluoromethyl)−1H−pyrazole (3l). The product was obtained as
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a yellow oil (91.1 mg, 68% yield), H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.19–7.15 (m,
1H), 6.91 (d, J = 9.1 Hz, 1H), 6.78 (dd, J = 8.5 and 2.4 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.60
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(s, 1H), 6.38–6.34 (m, 2H), 3.65 (s, 3H); C NMR (100 MHz, CDCl3) δ 159.8, 134.6, 131.3,
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130.0, 126.4, 122.4, 122.3, 121.0, 114.5, 113.4, 105.0, 55.1; HRMS (ESI_TOF) m/z: (M+H)+
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Calcd for C13H12F3N2O 269.0902; found 269.0909.
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(Z)−1−(3−Methylstyryl)−4−nitro−1H−pyrazole (3m). The product was obtained as a yellow
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semi–solid (80.1 mg, 70% yield), H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.91 (s, 1H), 7.16
(t, J = 8.3 Hz, 1H), 7.08–7.07 (m, 1H), 6.91 (s, 1H), 6.87–6.82 (m, 2H), 6.45 (d, J = 10.6 Hz,
1H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.0, 136.1, 136.0, 132.4, 129.8, 129.0,
128.9, 128.6, 125.5, 125.1, 124.5, 21.4; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C12H12N3O2
230.0930; found 230.0917.
(Z)−4−Bromo−1−styryl−1H−pyrazole (3n). The product was obtained as a yellow liquid (83.9
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mg, 68% yield), H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.29–7.21 (m, 4H) 7.13–7.11 (m,
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2H), 6.84 (d, J = 9.6 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H); C NMR (100 MHz, CDCl3) δ 140.8,
133.7, 129.4, 128.8, 128.5, 128.2, 126.5, 119.8, 94.6; HRMS (ESI_TOF) m/z: (M+H)+Calcd for
C11H10BrN2 249.0027; found 249.0051.
(Z)−5−Methyl−1−(4−(trifluoromethoxy)styryl)−1H−pyrazol−3−amine (3o). The product was
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obtained as a yellow semi–solid (101.8 mg, 72% yield), H NMR (400 MHz, CDCl3) δ 7.22 (d, J
= 9.5 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 9.1 Hz, 1H), 6.18 (d, J = 9.1 Hz, 1H), 5.48
(s, 1H), 3.70 (br s, 2H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.7, 148.3, 140.8, 133.2,
130.5, 124.1, 121.7, 121.3, 120.4, 95.0, 11.3; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for
C13H13F3N3O 284.1011; found 284.1006.
(Z)−3,5−Dimethyl−1−(4−methylstyryl)−1H−pyrazole (3p). The product was obtained as a
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yellow semi–solid (68.9 mg, 65% yield), H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.3 Hz, 2H),
6.84 (d, J = 7.6 Hz, 2H), 6.66 (d, J = 9.1 Hz, 1H), 6.40 (d, J = 9.1 Hz, 1H), 5.83 (s, 1H), 2.26 (s,
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6H), 1.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.2, 139.8, 138.0, 131.1, 129.0, 128.5,
127.7, 123.8, 105.7, 21.2, 13.6, 11.1; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C14H15N2
213.1392; found 213.1376.
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General procedure for the synthesis of (E)−styryl pyrazoles (4a–g): In an oven dried pressure
tube, to a solution of pyrazoles 1a and 1i–j (0.5 mmol) in DMSO, finely crushed KOH (2.0
equiv) and alkynes 2a–b, 2n–2p and 2q (1.0 mmol) were added under inert atmosphere. The
resulting reaction mixture was heated at 120 °C for 24 h. Progression of the reaction was
monitored by TLC, while noticing complete consumption of alkynes, reaction was brought to
room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and water (15
mL). Organic layer was concentrated under reduced pressure. The crude material so obtained
was purified by column chromatography on silica gel mesh size 100–200 (hexane).
(E)−1−Styryl−1H−pyrazole (4a). The product was obtained as a yellow semi–solid (57.8 mg,
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68% yield), H NMR (400 MHz, CDCl3) δ 7.60–7.59 (m, 2H), 7.44 (d, J = 14.5 Hz, 1H), 7.36–
7.34 (m, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.20–7.16 (m, 1H), 6.97 (d, J = 14.5 Hz, 1H), 6.33–6.32
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(m, 1H); C NMR (100 MHz, CDCl3) δ 141.1, 134.9, 128.8, 128.0, 127.5, 126.3, 126.1, 116.9,
107.3; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C11H11N2 171.0922; found 171.0915.
(E)−1−(4−Methylstyryl)−1H−pyrazole (4b). The product was obtained as a yellow semi–solid
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(64.4 mg, 70% yield), H NMR (400 MHz, CDCl3) δ 7.59–7.58 (m, 2H), 7.41 (d, J = 14.5 Hz,
1H), 7.25 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 6.95 (d, J = 14.5 Hz, 1H), 6.32–6.31 (m,
1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.9, 137.5, 132.1, 129.5, 127.8, 126.1,
125.7, 116.9, 107.1, 21.2; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C12H13N2 185.1079; found
185.1080.
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(E)−1−(4−Bromostyryl)−1H−pyrazole (4c). The product was obtained as a yellow semi–solid
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(80.2 mg, 65% yield), H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 2.2
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Hz, 1H), 7.50–7.47 (m, 2H), 7.44 (s, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 14.5 Hz, 1H),
6.40–6.39 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 141.3, 134.0, 131.9, 128.1, 127.6, 126.7,
121.2, 115.7, 107.5; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C11H10BrN2 249.0027; found
249.0051.
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(E)−1−(3,5−Dimethoxystyryl)−1H−pyrazole (4d). The product was obtained as a yellow oil
(78.2 mg, 68% yield), 1H NMR (400 MHz, CDCl3) δ 7.60–7.58 (m, 1H), 7.51 (s, 1H), 7.43 (d, J
= 14.5 Hz, 1H), 7.30–7.29 (m, 1H), 6.51–6.50 (m, 1H), 6.32–6.30 (m, 1H), 6.269–6.263 (m, 1H),
6.14–6.12 (m, 1H), 3.73 (s, 3H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 140.3,
136.1, 129.8, 127.2, 119.1, 106.3, 104.2, 100.3, 55.3; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for
C13H15N2O2 231.1134; found 231.1135.
(E)−1−(2−(Phenanthren−9−yl)vinyl)−1H−pyrazole (4e). The product was obtained as orange
needles (89.1 mg, 66% yield), mp 91–94 oC, 1H NMR (400 MHz, CDCl3)  8.65 (d, J = 7.7 Hz,
1H), 8.58 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.81–7.78 (m, 2H), 7.72 (d, J = 13.7 Hz,
1H), 7.666–7.660 (m, 2H), 7.63–7.61 (m, 1H), 7.59–7.58 (m, 1H), 7.56 (s, 1H), 7.54–7.51 (m,
1H), 7.48 (d, J = 14.2 Hz, 1H), 6.37–6.36 (m, 1H); 13C NMR (100 MHz, CDCl3)  141.3, 131.7,
131.4, 130.7, 130.4, 130.3, 128.6, 128.4, 126.9, 126.8, 126.73, 126.66, 124.8, 124.5, 123.1,
122.5, 114.8, 107.4; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C19H15N2 271.1235; found
271.1231.
(E)−4−Bromo−1−(4−(trifluoromethyl)styryl)−1H−pyrazole (4f). The product was obtained as
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a yellow solid (100.8 mg, 64% yield), mp: 90–92 °C, H NMR (400 MHz, CDCl3) δ 7.64 (s,
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1H), 7.56 (s, 1H), 7.53–7.51 (m, 2H), 7.42 (s, 1H), 7.41–7.40 (m, 1H), 7.38 (s, 1H), 6.94 (d, J =
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14.6 Hz, 1H); C NMR (100 MHz, CDCl3) δ 142.1, 138.2, 129.8, 129.5, 128.1, 127.6, 126.4,
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125.8 (q, J = 3.8 Hz, 1C), 116.1, 95.9; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C12H9BrF3N2
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316.9901; found 316.9897.
(E)−4−Bromo−3,5−dimethyl−1−(4−(trifluoromethyl)styryl)−1H−pyrazole (4g). The product
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was obtained as a yellow semi–solid (106.6 mg, 62% yield), H NMR (400 MHz, CDCl3) δ 7.51
(d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 13.7 Hz, 1H), 7.15 (d, J = 13.4 Hz, 1H),
2.30 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.2, 139.0, 137.6, 128.1, 127.6,
126.2, 125.7 (q, J = 3.9 Hz, 1C), 124.3, 115.7, 97.0, 12.5, 10.3; HRMS (ESI_TOF) m/z: (M+H)+
Calcd for C14H13BrF3N2 345.0214; found 345.0224.
(E)-1-(4-(Trifluoromethyl)styryl)-1H-pyrazole (4h). The product was obtained as a white solid
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(53.75 mg, 45% yield), mp: 100–102 °C, H NMR (400 MHz, CDCl3) δ 7.69–7.67 (m, 2H),
7.60–7.58 (m, 2H), 7.55–7.49 (m, 3H), 7.08 (d, J = 14.2 Hz, 1H), 6.42 (t, J = 1.83 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 141.6, 138.7, 129.4, 129.1, 128.4, 128.0, 126.2, 125.80–125.70 (m,
1C), 122.8, 115.3, 107.3; HRMS (ESI_TOF) m/z: (M+H)+ Calcd for C12H10F3N2 239.0796; found
239.0794.
(E)-1-(4-Nitrostyryl)-1H-pyrazole (4i). The product was obtained as a dark yellow solid (53.55
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mg, 50% yield), mp: 190–192 °C, H NMR (400 MHz, CDCl3) δ 8.22–8.20 (m, 2H), 7.718–
7.714 (m, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 14.2 Hz, 1H), 7.56–7.54 (m, 2H), 7.12 (d, J
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= 14.6 Hz, 1H), 6.45 (t, J = 1.83 Hz, 1H); C NMR (100 MHz, CDCl3) δ 146.8, 142.2, 142.0,
129.4, 128.8, 126.5, 124.3, 114.5, 108.2; HRMS (EI_TOF) m/z: (M)+Calcd for C11H9N3O2
215.0676; found 215.0676.
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