Structure-selectivity relationship in ruthenium-catalyzed regio- and stereoselective addition of alkynes to pyrazoles: An experimental and theoretical investigation

Article abstract of DOI:10.1021/jo502151z

Ruthenium(II) complexes, [Ru(dppe)(PPh₃)(CH₃CN)₂Cl][BPh₄] {dppe = diphenylphosphinoethane} (1) and [Ru(dppp)₂(CH₃CN)Cl][BPh₄] (2) {dppp = diphenylphosphinopropane}, are efficient catalysts for vinylation of pyrazoles by alkynes. While the 1-catalyzed reaction is trans-selective, the corresponding 2-catalyzed reaction is cis-selective. The experimental results have been rationalized by density functional theory calculations.

Full text of DOI:10.1021/jo502151z

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Article
Structure – Selectivity Relationship in Ruthenium Catalyzed
Regio- and Stereoselective Addition of Alkynes to
Pyrazoles: An Experimental and Theoretical Investigation
Uttam Kumar Das, Subhajit Mandal, Anakuthil Anoop, and Manish Bhattacharjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502151z • Publication Date (Web): 13 Oct 2014
Downloaded from http://pubs.acs.org on October 18, 2014
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Structure – Selectivity Relationship in Ruthenium
Catalyzed Regioꢀ and Stereoselective Addition of
Alkynes to Pyrazoles: An Experimental and Theoretical
Investigation
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Uttam Kumar Das, Subhajit Mandal, Anakuthil Anoop* and Manish Bhattacharjee*
Department of Chemistry, Indian Institute of Technology Kharagpur 721 302, India
mxb@.iitkgp.ac.in
anoop@chem.iitkgp.ernet.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
The ruthenium(II) complexes, [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] {dppe = diphenylphosphinoethane}
(1) and [Ru(dppp)2(CH3CN)Cl][BPh4] (2) {dppp = diphenylphosphinopropane} are efficient catalysts
for vinylation of pyrazoles by alkynes. While 1 catalyzed reaction is trans selective, the corresponding 2
catalyzed reaction is cis selective. The experimental results have been rationalized by density functional
theoretical (DFT) calculations.
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Introduction
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NꢀVinyl azoles have attracted great attention over last few years because of their use in the synthesis of
polymeric materials which show catalytic as well as photorefractive properties.1 Some of the compounds
also show antifungal activities.2 It has been shown in literature that palladium3 and mercury4 complexes
can catalyze vinyation of azoles by vinyl bromide. However, both the methods require extreme
conditions. More recently, coupling of vinyl bromide/iodide and amines mediated by copper(I) in the
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presence of ligands and large amount of bases like Cs2CO3 have been developed and the same method
has been used for vinylation of azoles.1a,1d,6 Most of these methods either require harsh conditions or a
long reaction time. Moreover, some of these methods require high catalyst loading. A recent report deals
with copper(I) catalyzed reactions with only 5 mol% catalyst loading, but in most of the cases only vinyl
iodide was found to be effective.7 Moreover, in almost all the reported methods only Eꢀvinyl products
were obtained. It may be noted that coupling of vinyl bromide/iodide with amines is not an atom
economical and environment friendly and economical method as large amount of alkali halide is
produced and vinyl halides are expansive.
It was reported that Ru3(CO)10 can catalyze vinylation of azoles by alkynes, however, mixture of
products were obtained.8
In a recent report, the authors have found that Ag(NO3)/Ag(OTf) can catalyze single and double
addition of pyrazole to alkynes. However, for single addition the catalyst loading is high and the reaction
conditions are harsh (130 °C, PhCl).9
Azole addition to terminal alkynes is one types of hydramination that affords a numbers of possible
products. Selectivity of the reaction is a central issue. Gooßen and coꢀworkers reported that
[(cod)Ru(met)2] affords Eꢀenamides from terminal alkynes and secondary amides in presence of triꢀ
nbutylphosphine (P(nꢀBu)3) ligand, but the stereoselectivity changes to corresponding Zꢀenamides when
a bulkier ligand such as bisꢀ(dicyclohexylphosphino)methane (dcypm) is used.10
Often, nature of substrate determines the regioꢀ and stereoselectivity of a reaction. Control of regioꢀ
and stereoselectivity by the nature of catalyst is not very common. So, catalyst – controlled product
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stereoselectivity is a challenge. Thus, selectivity is one of the challenging aspects in the addition reaction
of terminal alkynes. We have been interested in the synthesis and catalytic activities of ruthenium
phosphine complexes with hemilabile ligands, such that coordinatively unsaturated species can be
generated in solution.11 Recently, in a preliminary communication, we have reported synthesis and
structure of [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] {dppe = diphenylphosphinoethane} (1) and it and
showed that 1 can catalyze addition of terminal alkynes to azoles in highly regiospecific as well
stereoselective manner and primarily Eꢀaddition products were obtained.12 In another recent report we
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have described synthesis and structure of [Ru(dppp)2(CH3CN)Cl][BPh4] {dppp
=
diphenylphosphinopropane} (2), which can catalyze oxidative coupling of terminal alkynes in the
presence of catalytic amount of Ag(NO3).13 We were interested in exploring this catalyst – structure
dependent stereospecificity of the reaction so that, Zꢀaddition product can be obtained.
Herein we report the structure – selectivity relationship in the vinylation of pyrazoles by alkynes
catalyzed by [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] {dppe = diphenylphosphinoethane} (1) and
[Ru(dppp)2(CH3CN)Cl][BPh4] {dppp = diphenylphosphinopropane} (2). Details of the 1 catalyzed
reaction have been described here. In addition the experimental results have been rationalized by
theoretical investigations on 1 and 2 catalyzed vinylation of pyrazoles by alkynes.
Results and Discussion
The reaction between 3,5−dimethylpyrazole 3a and phenyl acetylene 4a in toluene in the presence of 1
mol% of ruthenium compound was chosen as a model reaction. A number of ruthenium compounds
were tested for their efficacy as catalyst for the reaction (Table 1). While RuCl3⋅3H2O and
[Ru(CO)4Cl2]2 was found to be inactive (entries 1ꢀ2), Ru(PPh3)3Cl2 and [Ru(PPh3)2(CH3CN)3Cl][BPh4]
was found to be poorly active (entries 3ꢀ4). Somewhat better catalytic activity was observed in the cases
of the combination of bidentate phosphine ligands and Ru(PPh3)3Cl2, which afforded a low yield of 3,5ꢀ
dimethylꢀ1ꢀstyryl pyrazole in mixture of E/Z isomers (Table 1, entry 4, 5 and 6). The complex,
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Table 1 Catalyst screening for the reaction of 3,5–dimethylpyrazole with phenylacetylenea
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Entry
Catalyst
Time(h)
24
Yield(%)b
E/Zc
ꢀ
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2
trace
nr
RuCl3⋅3H2O + PPh3
[Ru(CO)3Cl2]2
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Ru(PPh3)3Cl2
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Mixture
(1:1)
(2:3)
(1:4)
(3:2)
(1:2)
(99:1)
(1:99)
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Ru(PPh3)3Cl2 + dppe
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Ru(PPh3)3Cl2 + (1:1) dppp
Ru(PPh3)3Cl2 + (1:2) dppp
[Ru(PPh3)2(CH3CN)3Cl][BPh4]
[Ru(dppe)2(CH3CN)Cl][BPh4]
[Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4]
[Ru(dppp)2(CH3CN)Cl][BPh4]
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aReaction conditions: phenylacetylene (1.5 mmol), 3,5ꢀdimethylpyrazole (1.0 mmol), Catalyst (1 mol %) in toluene (5.0 ml)
at 90 OC. Isolated, cNMR spectroscopy.
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[Ru(dppe)2(CH3CN)Cl][BPh4] was found to be active with better efficiency (entry 8). However, the
complexes [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4] (1) and [Ru(dppp)2(CH3CN)Cl][BPh4] (2) were found
to be highly efficient. Whereas reaction in the presence of 1 produced Eꢀ3,5ꢀdimethylꢀ1ꢀstyryl pyrazole
(E/Z = 99:1), reaction carried out in the presence of 2 afforded Zꢀ3,5ꢀdimethylꢀ1ꢀstyryl pyrazole (E/Z =
1:99) in very high yield with high selectivity (entries 9 and 10). In the absence of ruthenium compounds,
no product could be isolated. Also, reaction carried out in the presence of the Brønsted acid, triflic acid
failed to give any product. These studies indicate that the reaction is catalyzed by ruthenium(II)
complexes.
We next examined the optimum concentration of catalyst required for the highest conversion. We
found that in a 1 catalyzed reaction 0.5 mol% catalyst loading is sufficient. However, in a 2 catalyzed
reaction, for optimum conversion, 1 mol% catalyst loading is required. No further improvement in
conversion was observed when higher catalyst loading was used. Thus, in subsequent reactions, 0.5
mol% of 1 and 1 mol% of 2 were used, respectively.
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We then proceeded to examine the effect of solvent and temperature on the reaction. To begin with,
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2
the reaction was carried out for 24 hrs. at room temperature in toluene. However, we could not detect
any product formation. Gradually the temperature was raised to 70 °C, and the product could be isolated
in 70% yield in 10 hrs. At 80 °C in 15 hrs, the conversion was found to be 85%. Interestingly, when the
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reaction temperature was raised to 90 °C, the conversion was found to be 95% in 8 hrs. With further
increase in reaction temperature, the conversion did not improve.
The reaction in DCM or acetonitrile failed to give any product. Reaction at 80 °C in DMF and
dichloroethane (DCE) led to the formation of Zꢀ3,5ꢀdimethylꢀ1ꢀstyryl pyrazole, the conversions being
15% and 45%, respectively (Table 2).
After optimizing the reaction conditions, we examined the reaction of various pyrazoles with different
terminal alkynes in toluene in presence of 0.5 mol% 1 at 90 °C and 1 mol% of 2 at 100 °C. For
convenience, the pyrazole/alkyne ratio was kept at 1:1.5 and the corresponding vinyl products were
Table 2 Solvent and temperature effect on reactions of 3,5ꢀdimethylpyrazole with phenylacetylene
catalyzed by 2a
Entry
Solvent
Toluene
DCM
Temp(°C)
Time(h)
Conversion (%)b
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Acetonitrile
DMF
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DCE
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70
85
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95
Toluene
Toluene
Toluene
Toluene
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aReaction conditions: phenylacetylene (1.5 mmol), 3,5ꢀdimethylpyrazole (1.0 mmol), 2 (1 mol %) in solvent (5.0 ml).
bIsolated
isolated in moderate to good yields. The products were characterized by 1H and 13C NMR spectroscopy
and mass spectrometry. The results are given in Table 3 and Table 4, respectively.
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The reaction of pyrazole and its derivatives with terminal alkynes bearing both aliphatic and aromatic
substituents, catalyzed by 1, (Table 3) (Scheme 1) afforded exclusively E – N – vinylꢀ pyrazoles in most
of the cases. However, the reaction of pyrazole (3a) with phenylacetylene (4a) afforded 1ꢀstyryl pyrazole
(5a) as mixture of product (E/Z ratio = 19:1). In the reactions of 3,5ꢀdimethylpyrazole (3c), 3,4,5ꢀ
trimethylpyrazole (3d) and 3ꢀmethylꢀ5ꢀphenylpyrazole (3e) with 1ꢀhexyne (4e), mixture of E and Z
products were obtained (Table 3; 5d, 5i, 5j), the E product being the major product. Similarly, the
reaction of 2ꢀbutꢀ3ꢀynylꢀisoindoleꢀ1,3ꢀdione (4i) with 3,5ꢀdiphenylpyrazole (3c) afforded a mixture of E
and Z 2ꢀ[4ꢀ(3,5ꢀdiphenylꢀpyrazolꢀ1ꢀyl)ꢀbutꢀ3ꢀenyl]ꢀisoindoleꢀ1,3ꢀdione (5m). The major product was the
E product.
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Table 3 Vinylation of pyrazoles catalyzed by 1a
a Reaction conditions: alkyne (1.5 mmol), azole (1.0 mmol), 1 (0.5 mol%), toluene (5.0 mL), T=100 °C.
Yield: Isolated. E/Z: from NMR spectroscopy
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The reaction is highly regiospecific, as shown by the reactions of 3ꢀmethylꢀ5ꢀphenylpyrazole (3e) with
1ꢀhexyne (4e) and 2ꢀbutꢀ3ꢀynylꢀisoindoleꢀ1,3ꢀdione (4i), which afford 1ꢀhexꢀ1ꢀenylꢀ3ꢀmethylꢀ5ꢀphenylꢀ
pyrazole (5j) and 2ꢀ[4ꢀ(3ꢀmethylꢀ5ꢀphenylꢀpyrazolꢀ1ꢀyl)ꢀbutꢀ3ꢀenyl)ꢀisoindoleꢀ1,3ꢀdione (5k),
respectively. The substitution takes place specifically at the nitrogen adjacent to the phenyl group. The
regiospecifity of the substitution products were confirmed by NOESY measurements (electronic
supplementary information). The NOESY of 5j and 5k show the interaction between the vinyl proton
and the phenyl proton. No interaction was observed between the vinyl proton and the methyl proton.
It may be noted that, one of the products, namely E ꢀ 2ꢀ[5ꢀ(3,5ꢀdimethylꢀpyrazolꢀ1ꢀyl)pentꢀ4ꢀenꢀ1ꢀyl]ꢀ
isoindoleꢀ1,3ꢀdione (5f), has been characterized by single crystal Xꢀray crystallography.12 The Xꢀray
structure confirms the E geometry of the compound.
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Scheme 1. stereoꢀ and regioselective vinylation of pyrazoles catalyzed by 1 and 2.
In contrast, when 2 was used as catalyst instead of 1, the stereoslectivity was found be opposite
to that observed in the reaction catalyzed by 1 (Scheme 1). The major product was found to be Z–
isomer (Table 4). In most of the cases, the reaction afforded exclusively Z isomer, except in the cases of
the reaction of pyrazole (3a) and 3,5ꢀdimethylpyrazole (3c) with 1ꢀhexyne (4e) and with 1ꢀoctyne (4f),
which afforded 1ꢀhexꢀ1ꢀenylꢀpyrazole (E/Z ratio = 1:2) (Table 4, 6d) and 1ꢀoctꢀ1ꢀenylꢀpyrazole (E/Z
ratio = 1:4) (Table 4, 6e), and 3,5ꢀdimthylꢀ1ꢀhexꢀ1ꢀenylꢀpyrazole (6n) (E/Z ratio = 1:2) and 3,5ꢀdimthylꢀ
1ꢀoctꢀ1ꢀenylꢀpyrazole (6o) (E/Z ratio = 2:3), respectively (Table 4). Similarly, reaction of 3,5ꢀ ꢀ
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diphenyl pyrazole (3e) with 1ꢀhexyne (4e) afforded a 1:3 mixture (E/Z) of 3,5ꢀdiphenylꢀ1ꢀhexꢀ1ꢀenylꢀ
pyrazole (6u). Thus the results show that, there is effect of functional group, attached to the alkyne, on
the stereoslectivity of the reactions.
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Table 4 Vinylation of pyrazoles catalyzed by 2a
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aReaction conditions: alkyne (1.5 mmol), pyrazole (1.0 mmol), 2 (1 mol %), toluene (5.0 mL), T= 90
°C. Yield: Isolated. E/Z: from NMR spectroscopy.
The 2 catalyzed reaction is also, regiospecific as evidenced by the reaction of 3ꢀmethylꢀ1Hꢀ
pyrazole (3b) and 3ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrazole (3f) with phenylacetylene (4a), propꢀ2ꢀynyloxyꢀ
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benzene (4g) and 2ꢀpropꢀ2ꢀynylꢀisoindoleꢀ1,3ꢀdione (4i). The corresponding regiospecific products, 3ꢀ
methylꢀ1ꢀstyrylꢀ1Hꢀpyrazole (6i), 3ꢀmethylꢀ5ꢀphenylꢀ1ꢀstyrylꢀ1Hꢀpyrazole (6s), 3ꢀmethylꢀ1ꢀ(3ꢀphenoxyꢀ
propenyl)ꢀ5ꢀphenylꢀ1Hꢀpyrazole (6t) and 2ꢀ[3ꢀ(3ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrazolꢀ1ꢀyl)allyl)isoindolineꢀ
1,3ꢀdione (6z), respectively. The regiospecificity of the substitution reaction was confirmed from
NOESY spectra of 6i, 6s and 6t (electronic supplementary information), where we could not observe
any interaction between the methyl proton and the vinyl proton. However we could observe the
interaction between the phenyl proton and the vinyl proton in the NOESY spectra of 6s and 6t. Further,
one of the product, Zꢀ2ꢀ[3ꢀ(3ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrazolꢀ1ꢀyl)allyl)isoindolineꢀ1,3ꢀdione (6z), has
been structurally characterized.14 The ORTEP view of the product has been shown in figure 1. The
single crystal Xꢀray structure confirms the stereoselectivity and regiospecificity of the reaction.
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Figure 1. ORTEP view of Zꢀ2ꢀ[3ꢀ(3ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrazolꢀ1ꢀyl)allyl)isoindolineꢀ1,3ꢀdione (6z).
Hydrogen atoms have been omitted for clarity.
Having established the stereoselectivity and regioselectivity of 1 and 2 catalyzed substitution
reactions, we performed density functional theory (DFT) computations to gain some insight into the
possible mechanism of stereo and regioselective vinylation of pyrazoles catalyzed by the two cationic
ruthenium complexes, 1 and 2. We have optimized all the intermediates and transition states and
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computed the relative energies between the competing paths. A stable minimum was found for every
postulated intermediate within the catalytic cycle (Figure 2 and 4). The overall reaction mechanism is
similar, although there are minor variations between the reactions catalyzed by 1 and 2.
The catalytic cycle of 1 starts with the octahedral ruthenium(II) complex (1_a), where two
acetonitrile ligands occupy the axial positions [RuꢀN bond distances are 1.971 (AN1) and 1.964 Å
(AN2)] and the equatorial positions are occupied by two phosphorus atoms of the bidentate
diphenylphophinoethane (dppe) ligand (RuꢀP bond distances are 2.313 and 2.356 Å), and one
phosphorus atom of triphenylphosphine (RuꢀP bond distance is 2.389 Å) and a chloride (RuꢀCl bond
distance is 2.469 Å).
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Figure 2. Mechanism for the vinylation of pyrazole in presence of 1.
In the initial step of the reaction, the loss of one acetonitrile group (AN1) from the axial position
of the octahedral complex generates a square pyramidal structure (1_b), with the other having the
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remaining acetonitrile (AN2) group in the axial position. However, the coordinatively unsaturated
species having square pyramidal geometry can be obtained either by loss of the other axial acetonitrile
group (AN2) from the axial position or by loss of the equatorial PPh3 group. However, acetonitrile are
known to be more labile than the phosphine ligands.15 Furthermore, AN1 is more loosely bound to the
metal, as is evident from the longer RuꢀN bond distance of AN1 compared to that of AN2 in 1_a. The
square pyramidal structure generated from the loss of AN1 is more stable than those generated from the
loss of AN2 or the loss of PPh3. The two intermediates generated from the loss of AN2 and PPh3 are of
higher energy by 2.22 and 3.05 kcal/mol, respectively, than that generated by the loss of AN1.
Our attempts to locate the transition states for the square pyramidal intermediates generated by
the loss of AN1, AN2 and PPh3 failed as the energy of the fragments increases monotonously in the
relaxed surface scan. This prompted us to consider an alternative pathway; associative removal of AN1
with simultaneous addition of phenylacetylene. According to this pathway we have studied three
possibilities, loss of AN1, AN2 and PPh3 in assistance with phenylacetylene addition. Here, AN1 loss
has 17.19 kcal/mol of activation barrier. The AN2 and PPh3 loss has 19.68 and 23.37 kcal/mol of free
energy barriers. Therefore AN1 removal pathway is the most feasible among these three possibilities.
The geometries related with catalyst 1 are presented in Figure 3.
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Ruthenium is known to form strong πꢀcomplexes with alkynes.16ꢀ18 Uchimaru proposed a
mechanism for the ruthenium catalyzed hydroamination of terminal alkynes,19 in which a πꢀcoordinated
alkyne inserts into the RuꢀN bond of a ruthenium amine species. In another study, Caulton and coꢀ
workers20 investigated the pathways towards the formation of ruthenium vinylidene intermediate, and
have shown that πꢀcoordinated alkynes readily insert into RuꢀH bonds and form ruthenium vinyl
complexes. On further rearrangement the ruthenium vinyl species produces ruthenium vinylidene
complex. They have also proposed that for bulkier ruthenium complexes, instead of πꢀcomplex, the
vinylidine can be produced through an 1,2 hydrogen migration directly from the σꢀcomplex.
The addition of phenylacetylene can result in either a πꢀcomplex (1_c) or a σꢀcomplex (1_d).
Relaxed surface scans between the ruthenium center and the terminal carbon of phenylacetylene suggest
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the formation of πꢀcomplex, which is also thermodynamically more stable. This step is endothermic and
endergonic (ꢁrEtot = 6.16 kcal/mol, ꢁrG298 = 11.01 kcal/mol). In the πꢀcomplex ruthenium is coordinated
to phenylacetylene in η2 manner. The RuꢀC1 and RuꢀC2 bond distances in 1_c are 2.155 and 2.259 Å,
respectively (Figure 2). In the subsequent step the πꢀcomplex rearranges to the σꢀcomplex. Morokuma et
al. studied the insertion of acetylene with ruthenium(II) and showed that acetylene first forms a πꢀ
complex, which converts to σꢀcomplex and finally 1,2 hydrogen migration produces the metalꢀ
vinylidine complex.21 The slippage of πꢀcomplex to σꢀcomplex has an activation energy barrier of
ꢁ‡G298 = 8.05 kcal/mol. In 1_TS-c_d geometry the RuꢀC2 bond distances increase to 3.194 Å and Ruꢀ
H1 distance reduces markedly to 2.615 Å, whereas the RuꢀC1 bond distance remains almost unchanged
compared to 1_c. The RuꢀC1 and RuꢀH1 bond distance further shortens to 2.089 Å and 1.851 Å in 1_d,
indicating η2 coordination of phenylacetylene.
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In 1_d phenylacetylene is coordinated to the ruthenium center through the σꢀelectrons of the C1ꢀ
H1 bond. The reaction energy for this step is 5.74 kcal/mol. From the σꢀcomplex an 1,2 hydrogen
migration takes place from C1 to C2 atom to form the vinylidine complex (1_e). The hydrogen
migration step has small barrier of ꢁ‡G298 = 3.86 kcal/mol. In 1_TS-d_e the RuꢀC1 bond distances
further shortens to 1.971 Å, C2ꢀH1 distance shortens to 1.456 Å whereas the RuꢀH1 distance increase to
2.755 Å. Decrease in the RuꢀC1 distance indicates the formation rutheniumꢀvinylidine complex (1_e). In
1_e the RuꢀC1 distance further decreases to 1.825 Å. Moreover in 1_e the C1ꢀC2 bond distance
becomes 1.334 Å which was 1.268 Å in 1_c and 1.246 Å in 1_d. The rutheniumꢀvinylidine complex
(1_e) is thermodynamically stable intermediate and therefore this step provides additional
thermodynamic stability of ꢁrEtot = ꢀ19.77 kcal/mol and ꢁrG298 = ꢀ19.70 kcal/mol.
There are two possible orientation of the added pyrazole, proꢀcis (1_f-pro-cis) or proꢀtrans (1_f-
pro-trans) orientation. The species 1_f-pro-trans is more stable than 1_f-pro-cis by 4.26 kcal/mol
(Figure 4). In the following step antiꢀMarkovnikov addition of pyrazole nitrogen occurs to the
vinylidene carbon atom α to the ruthenium(II) centre. For pro-cis orientation, this addition step has a
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The Journal of Organic Chemistry
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Figure 3. Geometries of the intermediates and transition states for the vinylation of pyrazole in the
presence of 1. Hydrogen atoms are not shown for clarity. Selected distances and angles are presented in
angstrom and degree units respectively.
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Figure 4. Free energy profile for the vinylation of pyrazole in the presence of 1. The values presented in
parentheses are ꢁG298 in gas phase and in braces are ꢁG298 in solvent toluene.
large barrier of ꢁ‡G298 = 46.21 kcal/mol. In this transition state structure (1_TS-f_g-cisoid) the C1ꢀN1
distance is 1.949 Å. However for the proꢀtrans orientation the activation barrier is relatively smaller,
ꢁ‡G298 = 29.09 kcal/mol (1_TS-f_g-transoid). The C1ꢀN1 bond distance is 1.893 Å in 1_TS-f_g-
transoid, which is significantly shorter than that in 1_TS-f_g-cisoid (1.949 Å). The enormous difference
between two activation barriers suggest that the pyrazole addition step is feasible only in proꢀtrans
orientation. Pyrazole addition step has the highest activation barrier in the whole reaction profile.
Moreover this step regulates the stereoselectivity of the products. Therefore the stereoselectivity
determining step is the slowest and rate determining step.
Pyrazole addition to the ruthenium vinylidene complex generates cationic pyrazole moieties
(1_g-cisoid and 1_g-transoid), which have energies close to the corresponding transition state energies.
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The Journal of Organic Chemistry
Removal of one proton each from 1_g-cisoid and 1_g-transoid geometry generates the corresponding
cis-precursor (1_h-cis-precursor) and trans-precursor (1_h-trans-precusor) structures. This step is
highly exergonic and exothermic for both the cis-precursor (ꢁrEtot = ꢀ78.43 kcal/mol, ꢁrG298 = ꢀ84.73
kcal/mol) and trans-precursor (ꢁrEtot = ꢀ68.54 kcal/mol, ꢁrG298 = ꢀ77.06 kcal/mol) orientations.
Additionally, the 1_h-trans-precursor is more stable than the 1_h-cis-precursor by ꢁrEtot = ꢀ13.35
kcal/mol and ꢁrG298 = ꢀ11.87 kcal/mol. Finally on protonolysis of 1_h-cis-precursor and 1_h-trans-
precusor produce the related cis and transꢀproduct, respectively. The free energy profile of the reaction
is shown in figure 4.
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Figure 5. Mechanism of vinylation of pyrazole in the presence of 2.
The catalytic cycle of [Ru(dppp)2(CH3CN)Cl][BPh4] (2) (Figure 5) catalyzed reaction starts with
octahedral ruthenium(II) complex (2_a), and [BPh4]ꢀ as the counter anion. In the octahedral complex
2_a, acetonitrile and chloride group occupies axial positions and two bidentate
diphenylphosphinopropane (dppp) ligands occupy equatorial positions, as observed from the crystal
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structure.13 In the initial step of the reaction, removal of acetonitile group produces a distorted trigonalꢀ
bipyramidal (TBP) geometry (2_b), as seen in the crystal structure.13 As the geometry and the existence
of this intermediate is proved by the crystal structure, we have not attempted to find the transition state
for the removal of acetonitrile.
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In the TBP structure one phosphorus from each bidentate ligand occupies the axial positions, the
other two phosphorus and chlorine occupy the equatorial positions. The axial RuꢀP bond distances
(2.395 Å and 2.390 Å) [experimentally observed bond distances are 2.429 Å and 2.416 Å] are larger
than the equatorial RuꢀP bond distances (2.224 and 2.261 Å) [experimentally observed bond distances
are 2.263 Å and 2.280 Å]. Removal of acetonitrile is endothermic (ꢁrG298 = 3.71 kcal/mol; ꢁrEtot =
12.44 kcal/mol), due to the generation of a coordinatively unsaturated species. The endothermicity
justifies the high temperature reaction condition to gain the required reaction energy.
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Addition of an alkyne to the TBP intermediate (2_b) can result either in a πꢀcomplex (2_c) or a
σꢀcomplex (2_d) formation. Our result shows that for 2 the σꢀcomplex is thermodynamically more
favored than the πꢀcomplex by 7.37 kcal/mol. This is in contrast to the 1_c/d where πꢀcomplex is more
stable. In the σꢀcomplex phenylacetylene is coordinated to the ruthenium center in η2 manner with the σꢀ
electrons of C1ꢀH1 bond of phenylacetylene. The C1ꢀC2, RuꢀC1 and RuꢀH1 distances in 2_d are 1.247
Å, 2.036 Å and 1.754 Å, respectively. In the πꢀcomplex (2_c) phenylacetylene is coordinated to the
ruthenium center in η2 fashion. The relaxed surface scans also suggest the occurrence of σꢀcomplex
instead of πꢀcomplex. Additionally, from the thermodynamic stand point the appearance of πꢀcomplex in
the reaction profile is less probable. The more stabilization of σꢀcomplex can be attributed to the less
steric interaction on phenylacetylene in σꢀcomplex compared to that in πꢀcomplex, by the large phenyl
rings of phosphine ligands. Hence the relevant σꢀcomplex readily forms instead of the πꢀcomplex. The
σꢀcomplex is formed from 2_b via an activation barrier of 24.47 kcal/mol. In 2_TS-b_d geometry the
Ruꢀ C1 and RuꢀH1 distances are 2.581 and 2.262 Å, whereas the RuꢀC2 distance is 3.683 Å, which is
distinctly longer than RuꢀC1 distance.
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The Journal of Organic Chemistry
The σꢀcomplex can undergo a 1,2ꢀhydrogen migration to form the ruthenium vinylidene complex
1
2
(2_e). This 1,2ꢀhydrogen migration step goes via a small activation barrier of 6.03 kcal/mol. In the
2_TS-d_e structure the RuꢀC1 bond distance again decreases to 1.957 Å and C1ꢀC2 distance increases
to 1.281 Å compared to the distances in 2_d. In 2_e C1ꢀC2 distance increases further to 1.341 Å and
RuꢀC1 distance decreases to 1.804 Å. The vinylidene complex (2_e) is a thermodynamically stable
intermediate. Also the reaction energy suggest that 2_e is more stable than 2_d by ꢁrEtot = 8.17 kcal/mol
and ꢁrG298 = 4.30 kcal/mol. Therefore this rearrangement is thermodynamically feasible. All the related
geometries of catalyst 2 are given in figure 6.
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Addition of pyrazole to the ruthenium vinylidene complex occurs via an intermediate adduct 2_f,
in which pyrazole is nonꢀcovalently bound with ruthenium vinylidene complex (2_e). Among the
various possible orientations by which pyrazole can approach the metal center, two adducts were
characterized (2_f-pro-cis and 2_f-pro-trans). Pyrazole bound complex 2_f is more stable than 2_e by
ꢁrEtot = ꢀ28.50 kcal molꢀ1 and ꢁrG298 = ꢀ18.46 kcal molꢀ1 for the related pro-cisꢀorientation (2_f-pro-cis)
and by ꢁrEtot = ꢀ15.62 kcal molꢀ1 and ꢁrG298 = ꢀ5.53 kcal molꢀ1 for the pro-transꢀorientation (2_f-pro-
trans). The 2_f-pro-cis species is more stable than 2_f-pro-trans by 10.09 kcal/mol. Stereoselection is
initiated at this complex.
In the subsequent step N(H) center of pyrazole attacks the carbon atom α to the ruthenium(II)
center in antiꢀMarkovnikov's fashion to generate 2_g in cisoid and transoid forms. For the pro-cis
orientation, the addition of pyrazole to the vinylidine carbon occurs with an activation barrier of ꢁ‡G298
= 42.26 kcal/mol and ꢁ‡Etot = 38.27 kcal/mol. In 2_TS-f_g-cisoid structure the C1ꢀN1 distance is 1.813
Å. However for the related pro-trans orientation the addition step demands a large barrier of ꢁ‡G298
=
62.36 kcal/mol and ꢁ‡Etot = 57.31 kcal/mol. In 2_TS-f_g-transoid geometry the C1ꢀN1 distance is 1.928
Å, which is notably longer than the 2_TS-f_g-cisoid geometry.
The large difference between the two activation barriers justifies the stereospecific production of
cisoidꢀgeometry. The energetic at this step is also stereogenic towards the selective formation of cisoidꢀ
intermediate. The 2_g_cisoid species is more stable than 2_g_transoid by 26.64 kcal/mol (ꢁrG298) .
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Figure 6. Geometries of the intermediates and transition states for the vinylation of pyrazole in the
presence of 2. Hydrogen atoms are not shown for clarity Selected distances and angles are presented in
angstrom and degree units respectively.
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The Journal of Organic Chemistry
In the following step removal of one proton produces the related cisꢀ (2_h_cis-precursor) and
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transꢀprecursors (2_g_trans-precursor). This step is highly exothermic and exergonic for both the cisꢀ
(ꢁrEtot = ꢀ80.93 kcal/mol and ꢁrG298 = ꢀ85.53 kcal/mol) and transꢀprecursor geometry (ꢁrEtot = ꢀ87.64
kcal/mol and ꢁrG298 = ꢀ94.79 kcal/mol). Between the 2_h geometries 2_h_cis-precursor is more stable
than 2_h_trans-precursor by 17.48 kcal/mol, making cisꢀ as the obvious choice for the product
stereochemistry. Free energy profile for the catalytic cycle is shown in Figure 7. The large energy
differences between 2_TS-f_g-cisoid and 2_TS-f_g-transoid translate to the selectivity for the cis
isomeric product. On protonolysis 2_h_cis-precursor produces cis (Z) and 2_h_trans-precursor
produces trans (E) products.
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It is clear form the optimized geometry of the ruthenium species 1_e that, it has a sterically less
hindered reaction site and the trans substituent of the alkenyl group can be easily accommodated, thus
leading to the formation of trans alkenyl product, that is also thermodynamically more favorable than
the corresponding cis alkenyl product. In contrast, the optimized geometry of the ruthenium species, 2_e
shows that the reaction site is surrounded by four PPh2 groups and prevents the formation of trans
alkenyl product leading to the formation of the cis alkenyl product which is thermodynamically less
stable, with respect to the olefin geometry.
Conclusion
In conclusion, it has been shown that, the ruthenium complexes, [Ru(dppe)(PPh3)(CH3CN)2Cl][BPh4]
(1) and [Ru(dppp)2(NCCH3)Cl][BPh4] (2) are efficient catalysts for regioꢀ and stereoselective addition
of pyrazoles to alkynes and the stereoselectivity is dependent upon the ligand environment around the
ruthenium center.
Experimental
1
Solvents and reagents used were reagent grade products. H, 13C NMR and NOESY spectra were
recorded on 400 and 200 MHz (1H frequency) spectrometers. HRMS of the newly synthesized
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compounds were recorded on TOF MS in ESI+ mode in methanol water mixture. The complexes 1 and
2 have been synthesized by the procedure reported form this laboratory.12, 13
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Figure 7. Energy profile for the vinylation of pyrazole in the presence of 2. The values presented in
parentheses are ꢁG298 in gas phase and in braces are ꢁG298 in solvent toluene.
Single crystal data collection and refinements
Single crystal Xꢀray data of 2ꢀ[3ꢀ(3ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrazolꢀ1ꢀyl)allyl)isoindolineꢀ1,3ꢀdione (6z).
were collected on single crystal Xꢀray diffractometer that uses graphite monochromated Mo Kα
radiation (λ = 0.71073 Å). The structure was solved by direct method and refined by least square
method on F2 employing WinGx22a package and the relevant programs (SHELXꢀ9723 and ORTEPꢀ322b)
implemented therein. Nonꢀhydrogen atoms were refined anisotropically and hydrogen atoms on Cꢀatoms
were fixed at calculated positions and refined using a riding model.
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The Journal of Organic Chemistry
Computational Details
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All the computations were performed with Turbomole V6.524 software package. All optimizations of the
ground state geometries were done in the gas phase using the Density Functional Theory (DFT) method
BP8625,26 with Resolution of the Identity (RI27) approximation. The def2ꢀSVP28 basis set and the
corresponding auxiliary basis set was used for all the calculations. Restricted approach was used in the
computational analysis for the closed shell structures. For ruthenium atoms the effective core potential29
were taken into account. Grimme’s empirical dispersion correction D330 with BJ31 (D3ꢀBJ) was
included in all calculations. The natures of the stationary points were characterized by vibrational
frequency calculation. All the ꢁG values are calculated at 298 K temperature. Single point calculations
were done with B3LYP32(D3ꢀBJ)/def2ꢀSVP level of theory on BP86 optimized geometries. Solvent
effects by the solvent toluene (ε = 2.38) were considered by single point calculations at BP86(RI,D3ꢀ
BJ)/def2ꢀSVP level with the COSMO33 (the conductorꢀlike screening model).
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[Ru(dppe)2(CH3CN)Cl][BPh4] (1) and [Ru(dppp)2(CH3CN)Cl] [BPh4] (2) catalyzed reaction of
alkynes with pyrazole
The alkyne (1.0 mmol) and either 1 or 2 (0.005 mmol), and toluene (5 cm3) was taken in a round
bottomed flask fitted with a refluxing condenser along with a stirring bar. To this was added pyrazole (1
mmol) and the reaction solution was heated in an oil bath for 5 to 8 hours. The reaction solution was
cooled to room temperature and solvent and other volatile components were removed under vacuum.
The resulting products were purified by column chromatography using silica gel 60–120 and 100–200
mesh using a mixture of hexane and ethyl acetate (2%) as eluent. Structural assignments of the products
were made on the basis 1D and 2D NMR techniques. The spectra are given in electronic supplementary
information. The single crystal Xꢀray structure of one of the products, namely, Eꢀ 2ꢀ[5ꢀ(3,5ꢀdimethylꢀ
pyrazolꢀ1ꢀyl)pentꢀ4ꢀenꢀ1ꢀyl]ꢀisoindoleꢀ1,3ꢀdione (5f) has been has been determined and reported in our
earlier recent communication.12
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(Z)-1-Styryl-1H-pyrazole (6a): A pale yellow oil, 98% yield (0.167 gm) .1H NMR (200 MHz, CDCl3,
ppm) δ 6.17 (t, J = 2.0 Hz, 1H), 6. 22 (d, J = 9.8 Hz, 1H), 6.98(d, J = 9.8 1H), 7.16 (d, J = 1.6Hz, 1H),
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7.18ꢀ7.20 (m, 2H), 7.24ꢀ7.29 (m, 3H), 7.58 (d, J =1.4 Hz,1H); C NMR (50 MHz, CDCl3, ppm) δ
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106.7, 119.0, 127.0, 127.9, 128.6, 128.7, 129.5, 134.4, 140.3. HRMS (ESI) Calcd for C11H11N2: [M+H]
+, 171.0917. Found: 171.0910.
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(Z)-1-[2-(4-Fluoro-phenyl)-vinyl]-1H-pyrazole (6b): A pale yellow oil, 95% yield (0.179 gm). H
NMR (200 MHz, CDCl3, ppm) δ 6.20ꢀ6.24 (m, 2H), 6.95ꢀ7.03 (m, 3H), 7.13ꢀ7.20 (m, 2H), 7.29 (d, J =
13
2.2 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H); C NMR (50 MHz, CDCl3, ppm) δ 106.9, 115.5, 116.0, 118.7,
127.0, 129.6, 130.6, 130.7, 140.5, 159.9, 164.8. HRMS (ESI) Calcd for C11H10FN2: [M+H] +, 189.0823.
Found: 189.0828.
(Z)-1-[2-(4-Methoxy-phenyl)-vinyl]-1H-pyrazole (6c): A pale yellow oil, 95% yield (0.192 gm).1H
NMR (400 MHz, CDCl3, ppm) δ 3.79 (s, 3H), 6.20ꢀ6.23 (m, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.90 (d, J =
13
9.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 2.4 Hz 1H), 7.59 (s, 1H); C NMR (100 MHz,
CDCl3, ppm) δ 55.4, 106.7, 114.2, 120.1, 125.9, 127.6 129.7, 130.2, 140.3, 159.4. HRMS (ESI) Calcd
for C12H13N2O: [M+H] +, 201.1028. Found: 201.1030.
(Z)-1-Hex-1-enyl-1H-pyrazole (6d): A colorless oil, 87% yield (E/Z mixture 0.131 gm). 1H NMR (400
MHz, CDCl3, ppm) δ 0.85ꢀ0.97 (m, 3H), 1.13ꢀ1.38 (m, 2H), 1.41ꢀ1.57 (m, 2H), 2.40 (quint, J = 7.2 Hz,
2H), 5.22 (dt, J = 9.2, 7.2 Hz, 1H), 6.31 (m, 1H), 6.76 (d, J = 9.6 Hz), 7.52 (d, J = 1.2 Hz, 1H), 7.60 (s,
1H); 13C NMR (50 MHz, CDCl3, ppm) δ 14.2, 22.5, 27.0, 31.9, 106.2, 121.6, 126.1, 129.9, 140.1.
HRMS (ESI) Calcd for C9H15N2: [M+H] +, 151.1165. Found: 151.1153.
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(E)-1-Hex-1-enyl-1H-pyrazole (6d): A colorless oil, 87% yield. H NMR (400 MHz, CDCl3, ppm) δ
0.85ꢀ0.97 (m, 3H), 1.13ꢀ1.38(m, 2H), 1.41ꢀ1.57 (m, 2H), 2.14 (quint, J = 7.2 Hz, 2H), 6.04 (dt, J = 14.0,
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7.2 Hz, 1H), 6.30 (m, 1H), 6.83 (d, J = 14.0 Hz), 7.54 (d, J = 1.0 Hz, 1H), 7.56 (s, 1H); C NMR (50
MHz, CDCl3, ppm) δ 14.2, 22.3, 27.0, 31.7, 106.6, 118.4, 127.2, 129.9, 140.3. HRMS (ESI) Calcd for
C9H15N2: [M+H] +, 151.1165. Found: 151.1153.
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(Z)-1-Oct-1-enyl-1H-pyrazole (6e): A colorless oil, 85% yield (E/Z mixture 0.151 gm).1H NMR (200
MHz, CDCl3, ppm) δ 0.84ꢀ 0.90 (m, 3H), 1.25ꢀ1.49 (m, 8H), 2.36 (q, J = 7.0 Hz, 2H), 5.18 (dt, J = 9.2 ,
7.2 Hz, 1H), 6.31 (t, J = 2.2 Hz, 1H), 6.75 (d, J = 9.6, Hz, 1H), 7.51 (m, 1H), 7.59 (s, 1H); 13C NMR (50
MHz, CDCl3) δ 14.2, 22.7, 27.3, 29.0, 29.7, 31.8, 106.1, 121.6, 126.0, 129.9, 140.1. HRMS (ESI) Calcd
for C11H19N2: [M+H] +, 179.1549. Found: 179.1541.
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(E)-1-Oct-1-enyl-1H-pyrazole (6e): A colorless oil, 85% yield.1H NMR (200 MHz, CDCl3, ppm) δ
0.84ꢀ.090 (m, 3H), 1.25ꢀ1.49 (m, 8H), 2.10 (q, J = 6.8 Hz, 2H), 5.99 (dt, J = 7.4 , 7.0 Hz, 1H), 6.29 (t, J
= 2.2 Hz, 1H), 6.80 (d, J = 16.6 Hz, 1H), 7.51 (m, 1H), 7.58 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 14.2,
22.7, 27.3, 29.7, 29.5, 31.8, 106.5, 118.4, 127.1, 129.9, 140.3.
(Z)-1-(3-Phenoxy-propenyl)-1H-pyrazole (6f): A pale yellow oil, 90% yield (0.2 gm).1H NMR (200
MHz, CDCl3, ppm) δ 5.17 (dd, J = 5.6, 1.8 Hz, 2H), 5.44 (dt, J = 9.6, 5.6 Hz, 1H), 6.36 (t, J = 2.0 Hz,
1H), 6.83 (d, J = 9.6 Hz, 1H), 6.92ꢀ6.99 (m, 3H), 7.25ꢀ7.33(m, 2H), 7.55 (d, J = 2.2 Hz, 1H), 7.69 (s,
13
1H); C NMR (50 MHz, CDCl3) δ 64.7, 106.9, 114.9, 115.3, 121.0, 126.1, 129.6, 130.5, 141.5, 158.5.
HRMS (ESI) Calcd for C12H13N2O: [M+H] +, 201.1028. Found: 201.1030.
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(Z)-2-(3-Pyrazol-1-yl-allyl)-isoindole-1,3-dione (6g). A white solid, 87% yield (0.22 gm). H NMR
(400 MHz, CDCl3) δ 4.95 (dd, J = 6.0, 1.6 Hz, 2H), 5.14 (dt, J = 9.6, 1.6 Hz, 1H), 6.36 (t, J = 2.0 Hz,
1H), 6.77 (dt, J = 9.6, 5.6, Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.70ꢀ7.73(m, 2H), 7.83ꢀ7.85
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(m, 2H); C NMR (100 MHz, CDCl3) δ 36.0, 106.1, 113.7, 123.5, 126.6, 130.7, 133.0, 134.2, 141.4,
168.2. HRMS (ESI) Calcd for C14H12N3O2: [M+H]+, 254.0924. Found: 254.0922.
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(Z)-2-(5-Pyrazol-1-yl-pent-4-enyl)-isoindole-1,3-dione (6h). A white solid, 83% yield (0.233 gm). H
NMR (200 MHz, CDCl3) δ 1.78 (quint, J = 7.4 Hz, 2H), 2.51 (q, J = 7.4 Hz, 2H), 3.68 (t, J = 7.4 Hz,
2H), 5.18 (dt, J = 8.8, 7.4 Hz, 1H), 6.28 (s, 1H), 6.72 (dd, J = 9.2, 8.4 Hz, 1H), 7.47(m, 2H), 7.66ꢀ7.69
(m, 2H), 7.71–7.77 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 24.5, 28.4, 37.5, 106.1, 119.1, 123.2, 126.3,
+
130.0, 132.1, 133.9, 140.2, 168.4. HRMS (ESI) Calcd for C16H16N3O2: [M+H] , 282.1237. Found:
282.1235.
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(Z)-3-Methyl-1-styryl-1H-pyrazole (6i): A colorless oil, 92% yield (0.17 gm). H NMR (400 MHz,
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CDCl3) δ 2.30 (s, 3H), 5.96 (d, J = 2.0 Hz, 1H), 6.14(d, J = 9.6 Hz, 1H), 6.93(d, J = 9.6 Hz, 1H), 7.18(d,
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J = 2.0 Hz, 1H) 7.21ꢀ7.32 (m, 5H) ; C NMR (100 MHz, CDCl3) δ 13.6,106.7, 117.6, 127.0, 127.8,
128.7, 128.8, 130.3, 134.8, 149.7. HRMS (ESI) Calcd for C12H13N2: [M+H]+, 185.1073. Found:
185.1090.
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(Z)-3,5-Dimethyl-1-styryl-1H-pyrazole (6j): A white Solid, 95% yield (0.168 gm). H NMR (200
MHz, CDCl3, ppm) δ 1.89 (s, 3H), 2.27 (s, 3H), 5.8 (s, 1H), 6.42 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8
Hz, 1H), 6.95ꢀ7.00 (m, 2H), 7.19ꢀ7.22 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 11.2, 13.6, 105.9, 124.6,
127.4, 128.1, 128.3, 128.7, 134.2, 139.9, 149.5. HRMS (ESI) Calcd for C13H15N2: [M+H] +, 199.1230.
Found: 199.1236.
(Z)-1-[2-(4-Fluoro-phenyl)-vinyl]-3,5-dimethyl-1H-pyrazole(6k): A orange oil, 94% yield (0.203
1
gm). H NMR (200 MHz, CDCl3, ppm) δ 1.39 (s, 3H), 2.25 (s, 3H), 5.85 (s, 1H), 6.36 (d, J = 9.0 Hz,
1H), 6.67 (d, J = 9.0 Hz, 1H), 6.85ꢀ7.01 (m, 4H); 13C NMR (50 MHz, CDCl3, ppm) δ 11.2, 13.7, 106.2,
115.2, 115.6, 124.3, 130.4, 130.7, 130.8, 139.9, 149.7. HRMS (ESI) Calcd for C13H14FN2: [M+H]+,
217.1136 Found: 217.1135.
(Z)-1-[2-(4-Methoxy-phenyl)-vinyl]-3,5-dimethyl-1H-pyrazole (6l): A yellow solid, 95% yield (0.216
gm). 1H NMR (400 MHz, CDCl3, ppm) δ 1.93 (s, 3H), 2.27 (s, 3H), 3.76 (s, 3H), 5.85 (s, 1H), 6.38 (d, J
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= 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H): C
NMR(100 MHz, CDCl3, ppm) δ 11.3, 13.8, 55.3, 106.0, 114.0, 123.0, 126.9, 127.9, 13.4, 140.1, 149.5,
159.6. HRMS (ESI) Calcd for C14H17N2O: [M+H]+, 229.1335. Found: 229.1336.
(Z)ꢀ1-(2-Cyclohexyl-vinyl)-3,5-dimethyl-1H-pyrazole (6m): A colorless oil, 82% yield (0.176 gm). 1H
NMR (400 MHz, CDCl3, ppm) δ 1.61ꢀ1.81(m, 9H), 2.19 (s, 3H), 2.24 (s, 3H), 2.81(m 1H), 5.16 (t, J =
9.2 Hz, 1H), 5.82(s, 1H), 6.35(d, J = 8.8 Hz, 1H); 13C NMR(100 MHz, CDCl3, ppm) δ 11.4, 13.8, 25.8,
26.2, 33.0, 35.6, 105.2, 121.3, 1310.3, 138.3, 149.3. HRMS (ESI) Calcd for C13H21N2: [M+H]+,
205.1705. Found: 205.1705.
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(Z)-1-Hex-1-enyl-3,5-dimethyl-1H-pyrazole (6n): A colorless oil, 81% yield (E/Z mixture 0.144 gm).
1H NMR (400 MHz, CDCl3, ppm) δ 0.83ꢀ0.90 (m , 3H). 1.27ꢀ1.46 (m, 4H), 2.21 (s, 6H), 2.35 (q, J = 7.2
Hz, 2H), 5.31 (q, J = 7.6 Hz, 1H), 5.79 (s, 1H), 6.44 (d, J = 9.2 Hz, 1H); 13C NMR(100 MHz, CDCl3,
ppm) δ 11.3, 13.7, 22.3, 26.7, 31.6, 105.1, 123.1, 125.8, 139.6, 148.5. HRMS (ESI) Calcd for C11H19N2:
[M+H]+, 179.1543. Found: 179.1550.
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(E)-1-Hex-1-enyl-3, 5-dimethyl-1H-pyrazole (6n): A colorless oil, 81% yield. H NMR (400 MHz,
CDCl3, ppm) δ 0.83ꢀ0.90 (m, 3H). 1.27ꢀ1.46 (m, 4H), 2.11ꢀ2.21 (m, 2H), 2.16 (s, 6H), 5.79 (s, 1H),
6.08ꢀ6.16 (m, 1H), 6.59(d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ11.0, 13.6, 22.2, 30.0,
31.8, 106.1, 118.4, 123.4, 138.4, 149.1. HRMS (ESI) Calcd for C11H19N2: [M+H] +, 179.1543. Found:
179.1550.
(Z)-3, 5-Dimethyl-1-oct-1-enyl-1H-pyrazole (6o). A colorless oil, 80% yield (E/Z mixture 0.165 gm).
1H NMR (200 MHz, CDCl3) δ 0.86ꢀ 0.87 (m, 3H), 1.25ꢀ1.41 (m, 8H), 2.20 (s, 6H), 2.34 (q, J = 6.6 Hz,
2H), 5.30 (dt, J = 8.6, 7.4 Hz, 1H), 5.82 (s, 1H), 6.45 (d, J = 8.8 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ
11.4, 13.8, 14.2, 22.7, 27.1, 29.0, 29.5, 31.8, 105.2, 123.1, 125.9, 139.7, 148.6. HRMS (ESI) Calcd for
C13H23N2: [M+H] +, 207.1856. Found: m/z 207.1860.
(E)-3, 5-Dimethyl-1-oct-1-enyl-1H-pyrazole (6o). A colorless oil, 1H NMR (200 MHz, CDCl3) δ 0.86ꢀ
0.87 (m, 3H), 1.25ꢀ1.41 (m, 8H), 2.1(m, 2H) 2.18 (s, 6H), 5.82 (s, 1H), 6.07 (m, 1H), 6.59 (d, J = 13.8
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Hz, 1H); C NMR (50 MHz, CDCl3) δ 11.2, 13.8, 14.2, 22.7, 27.1, 29.0, 29.8, 31.9, 106.2, 123.5,
125.9, 138.5, 149.2. HRMS (ESI) Calcd for C13H23N2: [M+H] +, 207.1856. Found: m/z 207.1860.
(Z)-3,5-Dimethyl-1-(3-phenoxy-propenyl)-1H-pyrazole(6p): A pale yellow oil, 80% yield (0.231 gm).
1H NMR (200 MHz, CDCl3, ppm) δ 2.18 (s, 6H), 5.14(dd, J = 7.6, 1.2 Hz, 2H), 5.25 (dt, J = 9.2,
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7.41H), 5.80 (s, 1H), 6.52 (d, J = 9.4 Hz, 1H), 6.81ꢀ6.95 (m, 3H), 7.15ꢀ7.27(m, 2H); C NMR (50
MHz, CDCl3) δ11.3, 13.9, 65.1, 106.4, 115.0, 115.1, 120.7, 122.6, 129.6, 140.0, 149.9, 158.7 HRMS
(ESI) Calcd for C14H17N2O : [M+H]+, 229.1335. Found: 229.1338.
(Z)- 3, 5-Dimethyl-1-[2-(4-phenoxy-phenyl)-vinyl]-1H-pyrazole (6q): Yellow oil, 86% yield (0.25
gm). 1H NMR (200 MHz,CDCl3, ppm) δ 1.98 (s, 3H), 2.26 (s, 3H), 5.86 (s, 1H), 6.38 (d, J = 9.0 Hz,
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1H), 6.69(d, J = 9.0Hz, 1H), 6.82ꢀ6.86 (m, 2H), 6.94ꢀ7.11(m, 4H), 7.297.37 (m, 3H); C NMR (50
MHz, CDCl3, ppm) δ 11.2, 13.6, 105.9, 118.2, 119.3,123.6, 126.9, 129.0, 129.8, 130.4, 139.8, 149.4,
156.6, 157.3 . HRMS (ESI) Calcd for C19H19N2O : [M+H]+, 291.1492. Found: 291.1490.
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(Z)-3,4,5-Trimethyl-1-styryl-1H-pyrazole (6r): A colorless oil, 92% yield (0.195 gm). H NMR (200
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MHz, CDCl3, ppm) δ 1.82 (s, 3H), 1.88 (s, 3H), 2.21 (s, 3H), 6.35 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 9.0
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Hz, 1H), 6.97ꢀ7.02 (m, 2H), 7.16ꢀ7.21 (m, 3H); C NMR (50 MHz, CDCl3, ppm) δ 8.2, 10.0, 12.1,
112.6, 124.9, 126.4, 128.0, 128.4, 128.9, 134.6, 136.7, 148.6. HRMS (ESI) Calcd for C14H17N2 :
[M+H]+, 213.1386. Found: 213.1391.
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(Z)-3-Methyl-5-phenyl-1-styryl-1H-pyrazole (6s): Yellow oil, 86% yield (0.224 gm). H NMR (400
MHz, CDCl3, ppm) δ 2.34 (s, 3H), 6.19 (s, 1H), 6.32 (d, J = 8.8 Hz,1H), 6.75 (d, J = 8.8 Hz, 1H), 6.91ꢀ
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6.93 (m, 2H), 7.12ꢀ7.15 (m, 3H), 7.26ꢀ7.27 (m, 5H); C NMR (100 MHz, CDCl3, ppm) δ 13.8, 106.6,
125.1, 127.0, 127.9, 128.1, 128.2, 128.3, 128.4, 129.1, 130.3, 134.1, 144.8, 149.7. HRMS (ESI) Calcd
for C18H17N2 : [M+H]+, 261.1386. Found: 261.1389.
(Z)-3-Methyl-1-(3-phenoxy-propenyl)-5-phenyl-1H-pyrazole (6t): Yellow oil, 80% yield (0.232 gm).
1H NMR (400 MHz, CDCl3, ppm) δ 2.36 (s, 3H), 5.24 (dd, J = 5.2, 1.6 Hz, 2H), 5.37 (dt,J = 9.2, 5.6
Hz,1H), 6.19 (s, 1H), 6.67 (dt, J = 9.2, 2.0 Hz, 1H), 6.92ꢀ 6.99 (m, 3H), 7.28ꢀ7.20 (m, 2H), 7.39 –7.46
(m, 5H); 13C NMR (50 MHz, CDCl3, ppm) δ 14.0, 65.1, 106.9, 114.9, 115.9, 120.8, 124.3, 128.8, 129.2,
129.6, 145.1, 150.2, 158.7. HRMS (ESI) Calcd for C19H19N2O : [M+H]+, 291.1492. Found: 291.1497.
(Z)-1-Hex-1-enyl-3,5-diphenyl-1H-pyrazole (6u): pale yellow oil, 77% yield ( E/Z mixture 0.156 gm).
1H NMR (400 MHz, CDCl3, ppm) δ 0.88ꢀ 0.93 (m, 3H), 1.39ꢀ1.47 (m,4H), 2.50 (q, J = 7.2 Hz, 2H),
5.36 (dt, J = 8.8, 7.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 7.38ꢀ7.52 (m, 8H), 7.78 (d, J =7.6,
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2H); C NMR (100 MHz, CDCl3, ppm) δ 14.1, 22.7, 27.2, 31.6, 103.4, 124.2, 125.6, 125.8, 126.0,
128.0, 128.7, 129.1, 129.5, 130.6, 133.4, 145.2, 151.3. HRMS (ESI) Calcd for C21H23N2 : [M+H]+,
303.1856. Found: 303.1860.
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CDCl3, ppm) δ 0.88ꢀ 0.93 (m, 3H), 1.39ꢀ1.47 (m,4H), 2.13 (q, J = 6.8 Hz, 2H), 6.40 (m, 1H), 6.70 (s,
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1H), 6.77 (d, J = 14.0 Hz, 1H), 7.31ꢀ7.34 (m, 8H), 7.73 (d, J =7.6, 2H); C NMR (100 MHz, CDCl3,
ppm) δ 14.1, 22.4, 30.0, 31.8, 104.4, 120.6, 124.6, 125.8, 126.0, 128.7, 128.9, 129.1, 129.5, 130.6,
133.4, 145.2, 151.3. ESIꢀMS [M+H] + m/z, calculated for C21H23N2: 303.1856. Found: 303.1860.
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7.19 (m, 3H), 7.29ꢀ7.45 (m, 8H), 7.81ꢀ7.85 (m, 2H); δ C NMR (50 MHz, CDCl3, ppm ) δ 104.1,
124.9, 125.9, 126.8, 128.0, 128.2, 128.5, 128.7, 128.8, 129.2, 130.2, 133.1, 134.2, 145.5, 152.0. HRMS
(ESI) Calcd for C23H19N2 : [M+H]+, 323.1543. Found: 323.1550.
(Z)-2-[5-(3,5-Dimethyl-pyrazol-1-yl)-pent-4-enyl]-isoindole-1,3-dione (6w): White solid, 85% yield
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(0.263 gm). H NMR (400 MHz, CDCl3, ppm) δ 1.78ꢀ1.86 (m, 2H), 2.12 (s, 3H), 2.18 (s, 3H), 2.53
(quint, J = 7.6 Hz, 2H), 3.67 (t, J = 7.6 Hz, 2H), 5.25 (dt, J = 8.8, 7.6 Hz, 1H), 5.76 (s, 1H), 6.47 (d, J =
9.2 Hz, 1H), 7.66ꢀ7.68 (m, 2H), 7.79ꢀ7.81 (m, 2H); δ13C NMR (50 MHz, CDCl3, ppm ) δ 11.4, 13.7,
24.4, 28.3, 37.7, 105.5, 121.5, 123.3, 123.5, 132.3, 133.9, 139.8, 148.9, 168.5. HRMS (ESI) Calcd for
C18H20N3O2 : [M+H]+, 310.1550. Found: 310.1557.
(Z)-2-[5-(3,4,5-Trimethyl-pyrazol-1-yl)-pent-4-enyl]-isoindole-1,3-dione (6x): White solid, 80%
yield (0.258 gm). 1H NMR (200 MHz, CDCl3, ppm) δ 1.78 (m, 2H), 1.86 (s, 3H), 2.07 (s, 3H), 2.10 (s,
3H), 2.53 (quint, J = 7.4 Hz, 2H), 3.65 (t, J = 7.4 Hz, 2H), 5.16 (dt, J = 9.0,7.4Hz, 1H), 6.47 (d, J = 9.0
Hz, 1H), 7.65ꢀ7.72(m, 2H), 7.76ꢀ7.82 (m, 2H); 13C NMR (50 MHz, CDCl3, ppm ) δ 7.9. 9.6. 11.9, 24.3,
28.1, 37.5, 120.3, 123.0, 123.5, 132.1, 133.7, 136.1, 147.8, 168.3. HRMS (ESI) Calcd for C19H22N3O2 :
[M+H]+, 324.1707. Found: 324.1713.
(Z)-2-[3-(3,5-Dimethyl-pyrazol-1-yl)-allyl]-isoindole-1,3-dione (6y): White solid, 81% yield (0.228
gm). 1H NMR (400 MHz, CDCl3, ppm) δ 2.24 (s, 3H), 2.25 (s, 3H), 4.99 (dd, J = 5.6, 1.6 Hz, 2H), 5.06
(dt, J = 9.2, 5.2 Hz, 1H), 5.85 (s, 1H), 6.56 (dt, J = 9.2, 1.6 Hz, 1H), 7.69ꢀ7.17 (m, 2H), 7.83ꢀ7.87 (m,
13
2H); C NMR (100 MHz, CDCl3, ppm ) δ 11.3,13.9, 36.3, 106.3, 113.3, 123.4, 132.4, 134.0, 139.9,
149.8, 168.3. HRMS (ESI) Calcd for C16H16N3O2: [M+H]+, 282.1237. Found: 282.1241.
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(Z)ꢀ2-[3-(3,5-Dimethyl-pyrazol-1-yl)-allyl]-isoindole-1,3-dione (6z): White crystalline solid, 78%
yield (0.267 gm). 1H NMR (400 MHz, CDCl3, ppm) δ 2.35 (s, 3H), 5.03 (dd, J = 6.0, 1.6 Hz, 2H), 5.10
(dt,J = 8.8, 5.2 Hz, 1H), 6.18 (s, 1H), 6.61 (dt, J = 8.8, 1.6 Hz, 1H),7.38ꢀ7.43 (m, 5H), 7.70ꢀ7.73 (m,
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2H), 7.84ꢀ7.87 (m, 2H); C NMR (100 MHz, CDCl3, ppm ) δ 14.0, 36.4, 106.8, 114.3, 123.4, 125.2,
9
128.8, 129.3, 130.3, 132.4, 134.1, 145.0, 149.9, 168.3. HRMS (ESI) Calcd for C21H18N3O2: [M+H]+,
344.1394. Found: 344.1389.
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Acknowledgment We thank Department of Science & Technology, Government of India, New Delhi
for single crystal Xꢀray, NMR and HPC facilities and SERB, Government of India, New Delhi for
financial support. UKD thanks Council of Scientific & Industrial Research, New Delhi for fellowship.
SM thanks University Grant Commission (UGC) for the fellowship. We thank reviewers for their
helpful comments.
Author Contributions: M.B. and A. A. defined the research problem; U. K. D. performed the
experimental work. S.M. performed the computational studies under the supervision of A. A. All
authors discussed the results and contributed on the manuscript.
Supporting Information Available: ORTEP view of 6z, cif file, 1H and 13C NMR spectra and NOESY
spectra and details of the results of the theoretical calculations. This material is available free of charge
via the Internet at http://pubs.acs.org.
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