Strain control in nucleophilic cyclizations:reversal of exo-selectivity in cyclizations ofhydrazides of acetylenyl carboxylic acids byannealing to a pyrazole scaffold†

Sergei F. Vasilevskya, Brian Goldb, Tatyana F. Mikhailovskayaa andIgor V. Alabuginb*

Independent of the nature of alkyne substitution, hydrazides of 4-arylethynyl-5-carboxylic acid annealed at thepyrazole scaffold undergo a regioselective base-catalyzed 6-endo-dig cyclization with the formation of pyrazolo[3,4-c]pyridine-7-ones. This behavior contrasts the observation of selective 5-exo closures in the analogousbenzannelated systems and illustrates selective destabilization of the reaction path leading to the formation of asmaller ring. Computational analysis also reveals an important role of prototropic equilibria in rendering the overallcyclization feasible in the strained heterocyclic systems. The switch to the formation of a larger cycle suggests thatstrategic incorporation of strain can be used as a tool for the efficient control of regiochemistry of nucleophiliccyclizations. Copyright © 2012 John Wiley & Sons, Ltd.Supporting information may be found in the online version of this paper.

Keywords: alkyne cyclizations; Baldwin rules; strain; 5-exo; 6-endo

INTRODUCTION

Diverse transformations of polyfunctional arylacetylenes areappealing from both the applied and fundamental points ofview.[1] Cyclizations of vicinally substituted acetylenyl arenes andheteroarenes provide direct synthetic route towards condensedheterocycles with many promising features in drug design.[2,3]

Additionally, such cyclizations continue to assist in developing andtesting the general rules for the formation of cyclic structures.[4–9]

Bifunctional nucleophiles are particularly interesting becausethe selectivity of intramolecular attack at the triple bond is sensi-tive to the variations in the nature of the alkyne substituents andreaction conditions. For example, hydrazides of vic-acetylenylbenzoic acids[10–12] can yield benzopyrrolidones, benzopyrida-zones or benzodiazinones – three promising biologically activetypes of annealed heterocycles with a wide spectrum of pharma-cological activity.[13–15] The multichannel reactivity originatesfrom the presence of two nucleophilic centers of different nature(the amide and the amine nitrogens[16,17]) and the possibility ofselective targeting a-acetylenic and b-acetylenic carbons (Fig. 1).

Previously, we have carried out systematic studies of cycloi-somerizations of vicinal hydrazides of acetylenyl benzoic[18,19]

and pyrazolcarboxylic acids[20,21] and found that, under catalysisby Cu salts, the reaction is sensitive to the structure of the alkyne.For the purely anionic cyclizations of benzoic hydrazides, thecompetition between 5-exo and 6-endo cyclizations of the “inter-nal” nitrogen nucleophile is controlled by the nature of alkynesubstituents. Alkyl substituents at the alkyne terminus favor the6-endo-dig closure whereas aryl groups direct the cyclization downthe 5-exo-dig path. These observations motivated us to compare thefeatures of base-catalyzed cycloisomerization of acetylenyl benzoic

acids with analogous derivatives of pyrazolcarboxylic acids, whereannealing the reacting system at a smaller core could provide anadditional factor to control the 5-exo/6-endo competition.

Discussion of experimental results

Most of the necessary methyl ethers of vic-acetylenyl pyrazolyl-carboxylic acids 1a, 1c–e were prepared from the Sonogashiracoupling of respective 4-iodo 1H-pyrazols with terminal alkynes[“Method A”, Pd(PPh3)2Cl2, CuI, Et3N] in 52%–89% yields.[22] Thep-OMePh derivative 1b was prepared via Cu acetylide synthesis(“Method B”).[23] Reaction of the starting 4-iodo pyrazolyl esterwith Cu acetylide in pyridine required reflux for 3 h under argonatmosphere and afforded the respective alkyne 1b in 58%(Fig. 2).

* Correspondence to: I. V. Alabugin, Department of Chemistry and Biochemistry,Florida State University, Tallahassee, FL 32306, USA.E-mail: alabugin@chem.fsu.edu

† This article is published in Journal of Physical Organic Chemistry as a specialissue on 11th Latin American Conference on Physical Organic Chemistry,edited by Eusebio Juaristi (Centro de Investigacion y de Estudios Avanzadosdel Instituto Politecnico Nacional, Quimica, Apartado Postal 14-740, Mexico,Mexico, 07000).

a S. F. Vasilevsky, T. F. MikhailovskayaInstitute of Chemical Kinetics and Combustion, Novosibirsk 630090, RussianFederation

b B. Gold, I. V. AlabuginDepartment of Chemistry and Biochemistry, Florida State University, Tallahassee,FL, 32306, USA

Special Issue Article

Received: 16 April 2012, Revised: 28 May 2012, Accepted: 30 May 2012, Published online in Wiley Online Library: 4 July 2012

(wileyonlinelibrary.com) DOI: 10.1002/poc.2990

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Heating of methyl esters 1a–e and 80% NH2NH2�H2O inethanol provided hydrazides 2a–e in 73%–89% (Fig. 3). Thenitro-substituted ester 1e was the most reactive, affording thehydrazide in 78% yield after 20min.The clean transformation of esters into acyclic hydrazides

under these conditions contrasted the behavior of analogous

compounds with the benzene core where the formation ofhydrazides was accompanied by their cyclizations. This observa-tion suggests that annealing hydrazides to a smaller cycleincreases activation barriers for their cyclizations.

The structures of hydrazides 2a–e were determined unambig-uously from their analytical and spectral analysis. For example, theinfrared (IR) spectra display the characteristic frequencies of disub-stituted alkynemoiety at 2200–2230 cm–1 along with the character-istic hydrazide NH-group and NH2-group peaks at 3315–3425 cm–1.

The heterocyclization of the pyrazolyl hydrazides 2a–e wascarried out in hot ethanol in the presence of KOH (Fig. 4). The re-action was complete in 2–7 h. Alkynes with acceptor substitutionwere slightly more reactive but, in every case, the reaction led tothe formation of the 6-endo-dig products, N-amino lactams 3a–e(56%–78%). Even in the case of p-nitro substituted substrate 2b,only the 6-endo product was observed in the 89% yield.

The 1H NMR chemical shifts of exo and endomethine protons areclose, rendering the distinction between the 5-membered and6-membered lactams difficult. However, it is known from the litera-ture that increased strain in the smaller 5-membered cycle leads toa 30–35cm–1 blue shift in the IR-vC=O frequencies.

[24] As a result, thesefrequencies for d-N-aminolactams are in the region of 1650–1680cm–1,whereas for g-N-aminolactams they reach 1695–1700 cm–1.

We have recently confirmed the reliability of this IR-criterionfor the assignment of ring size by comparing its predictions withthe data of multidimensional nuclear magnetic resonance (NMR)analysis.[11] The results were identical. Because for all pyrazolo-pyridines 3a–e, the valence vibrations of the carbonyl group liewithin 1653–1674 cm–1, they can be unambiguously assignedas d-N-aminolactams.

DESCRIPTION OF COMPUTATIONALAPPROACH

Calculations were performed by using GAUSSIAN 03 software[25] withgeometries and energies obtained at the Becke, three-parameter,Lee–Yang–Parr (B3LYP)/6-31G(d,p) level of theory. All stationarypoint geometries for the anionic cyclizations were optimized atthe B3LYP/6-31G(d,p) level. Reactants, products, and intermediateswere confirmed as minima and the transition state structures wereconfirmed as saddle points with a single imaginary frequencythrough frequency calculations. See supporting information forcoordinates, total energies, and imaginary frequencies (for transi-tion state structures) of optimized structures. The solvation effectswere tested by single point energy calculations with the conductorpolarized continuum model (CPCM) at the self-consistent reactionfield (SCRF)-B3LYP/6-31G(d,p) level in ethanol at the respectivegas phase geometries. Energies of hyperconjugative interactionswere calculated by using the natural bond orbital (NBO)[26] methodimplemented in GAUSSIAN.

Figure 1. The multichannel reactivity of hydrazides of vic-acetylenylbenzoic acids

Figure 2. Two approaches to pyrazolyl alkynes

Figure 3. Conversion of esters into hydrazides

Figure 4. Regioselectivity of base-catalyzed cyclizations of alkynyl hydrazides with pyrazolyl core

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Discussion of computational resultsBoth 5-exo and 6-endo-dig cyclizations are stereoelectronicallyfavorable according to the Baldwin rules.[4–6] Although5-exo-dig closures are generally preferred in anionic alkynecyclizations,[7–9] their competition can be perturbed by exter-nal factors.[27] For the cyclization of benzannelated hydrazides,the difference between the two directions is small in the caseof alkyl-substituted alkynes where the selectivity just barelyfavors the formation of 6-endo products. The ~12–14 kcal/molgreater thermodynamic stability of 6-endo-dig products incomparison to the 5-exo products translates into preferentialstabilization of the 6-endo barrier, which is large enough tooverride the intrinsic 5-exo preference.[28–39] However, thedifference is relatively small and the 5-exo preference canbe restored when an aromatic substituent is introduced atthe acetylenic terminus.

The exclusive formation of 5-exo products from Ar-substitutedalkynes annealed at the benzene core renders the observedswitch to 6-endo products in the pyrazolyl-based substratesintriguing. A possible reason for the observed change in selec-tivity in pyrazolyl hydrazides is the greater strain in the 5-exotransition state, which originates from a larger angle betweenthe interacting groups in pyrazolyl acetylenes. The 5-exoclosure leads to a condensed system of two five-membered

cycles, whereas the 6-endo cyclization leads to a system thatcombines a five-membered and a six-membered cycle. To testthis hypothesis, we carried out density functional theoryanalysis of potential energy surfaces for the two cyclizationdirections of acetylenic hydrazides with benzene and pyrazolylcores.The results are summarized in Fig. 5. The barriers for the two

cyclizations of benzannelated hydrazide anions presented in thiswork (7.0 (5-exo) vs. 14.7 (6-endo) kcal/mol at the B3LYP/6-31G(d,p)level of theory) are slightly lower than the barriers for the analogouscyclization of the parent N-centered anion formed by deprotonationof an amine (12–14 kcal/mol vs. 18–19 kcal/mol for the gasphase 5-exo and 6-endo-dig barrier, respectively, at B3LYP andM05-2X/6-31 +G(d,p) levels of theory),[7–9] even though thehydrazide cyclizations are less exothermic.[4,40–44] The relativelylow barriers suggest greater nucleophilicity of hydrazides(the a-effect).Importantly, the 5-exo-dig closure is preferred both kinetically

and thermodynamically for the benzannelated hydrazide anion.The ~8 kcal/mol 5-exo preference in the gas phase does notchange upon introduction of solvation (CPCM, ethanol) in thecomputational model. The main effect of solvation is inrendering both cyclizations less thermodynamically favorable.Although the 6-endo-dig closure becomes essentially thermoneutral

Figure 5. Comparison of 5-exo and 6-endo cyclization and reaction energies for the benzannelated (top) and pyrazolyl-annelated (bottom) acetylenichydrazides. Energy profiles in the gas phase in the gas phase and with inclusion of solvation (CPCM, EtOH, dashed lines) at the B3LYP/6-31G(d,p) level oftheory. The difference between 5-exo and 6-endo barriers are shown with the blue arrow

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with the driving force ΔGrxn of ~0.0 kcal/mol whereas the5-exo-product is still ~11 kcal/mol more stable than theacyclic hydrazide anion, both cyclic carbanions can be protonatedunder the reaction conditions rendering the overall processirreversible.Although the change from a six-membered (benzene) to the

five-membered (pyrazole) core imposes a dramatic deceleratingeffect on both 5-exo and 6-endo cyclizations, as expected fromthe strain hypothesis, the 5-exo-TS and product are destabilizedto a much greater extent. Now, the calculated cyclization barriersfor the both competing cyclization of pyrazolyl reactants are inthe order of 20 kcal/mol and both cyclizations are moderatelyendergonic. Similar effects of strain on the exo/endo selectivityhave been reported for 4-exo/5-endo[45–47] and 5-exo/6-endo[27]

radical cyclizations of alkynes. However, the exo-preference iseven more pronounced for anionic cyclizations, so this switchin selectivity is more impressive.In a good agreement with the experimental observation, the

6-endo-dig cyclization is calculated to be the lower energy path(Fig. 5). The difference is small in the gas phase (~0.6 kcal/mol)but increases to 2.1 kcal/mol once solvation is introduced.Because the cyclizations are endergonic and thus, the equilib-rium concentrations of the cyclized products should be low, bothcyclic carbanions need to quickly be trapped by either anintramolecular or an intermolecular proton transfer.Because multiple mechanisms are possible for this step we

have not calculated the barriers for the proton transfer. Impor-tantly, even after the transformation of a cyclic carbanion tothe respective N-centered anion, the 5-exo-products remainless stable than the starting acyclic anion. Even if 5-exo-digcyclization were faster, one would expect the formation of thefive-membered products to be reversible.Indeed, the exclusive formation of 6-endo-products from the

p-nitro substituted alkyne suggests that the reaction doesproceed under thermodynamic control. In this case, the 5-exo-TSis calculated to be lower and the 5-exo-product should beformed faster. However, the stabilizing effect of the nitro-groupat the 5-exo-TS and product does not extend to the N-anion prod-uct of the prototropic rearrangement of the initially formed cycliccarbanion (Fig. 6). As a result, the 5-exo-product remains less stable

than the reactant and is not accumulated under the reaction con-ditions. Under thermodynamic control, only the 6-endo productaccumulates in a high yield.[48]

Strain in the cyclization transition states

The 6-endo-dig product benefits from slightly larger aromaticstabilization[11] whereas the 5-exo-dig cyclization benefits fromdelocalization of the developing carbanion to the terminal arylring and H-bonding between the anion and the NH2 of hydra-zide. These factors are balanced in favor of 5-exo closure in thecase of the benzene scaffold but the inherent strain introducedupon the fusion of the second five-membered ring at thepyrazole core tips the balance in favor of the 6-endo productfor the heterocyclic substrates. To evaluate the effect of strain,we have analyzed transition state geometries for the competingcyclization pathways in more detail (Fig. 6).

In both cases, one of the lone pairs of the nucleophilic nitrogenin the reactants is constrained via nN ! s*C–O and nN ! s*N–Hinteractions in the appropriate position for the attack at the alkynein-plane p-bond. As a result, geometry changes associatedwith thecyclization mostly involve in-plane bending.

In both reactants, the “1,5” distance (2.8 and 3.0 Å) is muchshorter than the “1,6-distance” (3.3 and 3.6 Å) indicating thatmore considerable alkyne bending should be required on routefrom the reactants to the 6-endo TSs (Fig. 7). However, the en-ergy cost for alkyne bending is relatively small[49–51] and thereis little change in the other angles of the starting material inreaching the 6-endo TS. The angles between the pyrazolyl coreand the two substituents (129 and 132 degrees for acetyleneand hydrazide, respectively) are increased significantly in com-parison with the same angles in the benzannelated substrate(123 and 127 degrees, respectively; Fig. 6). The greater anglesalso lead to the greater separation between the two reactingfunctionalities in the heterocyclic reactant.

As a consequence of these differences, significantly greaterrelative bending is required to reach the 5-exo TS in theheterocyclic reactant. Moreover, because the cyclization is endo-thermic, the TS adopts a late, product-like geometry. The shorterincipient C. . .N bonds together with the greater C–N distances in

Figure 6. Comparison of 5-exo and 6-endo cyclization and reaction energies for the benzannelated (left) and pyrazolyl-annelated (right) acetylenichydrazides with p-nitrophenyl substituent at the terminal alkyne position. Energy profiles in the gas phase in the gas phase and with inclusion of sol-vation (CPCM, EtOH, dashed lines) at the B3LYP/6-31G(d,p) level of theory. The difference between 5-exo and 6-endo barriers are shown with the bluearrow. The 5-exo-cyclization is favored kinetically but not thermodynamically

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the starting alkyne suggest greater strain and distortion in the5-exo TS for the pyrazole alkynes. Even the conjugative assistanceof a strongly accepting terminal Ar group (Ar=p-NO2) cannot over-come the effect of strain and bring back the 5-exo selectivity.

Negative hyperconjugation in 5-exo and 6-endo cyclizations

Because the carbanionic center is one of the strongest donors inorganic chemistry, negative hyperconjugation plays an impor-tant role in stabilizing the anionic species (Fig. 8).[52] To comparethe importance of this factor in the 5-exo/6-endo competition,we have quantified the key nC-!s*C–N hyperconjugativeinteractions in the respective products by NBO analysis (Table 1).It is likely that the same hyperconjugative effects are partially

manifested in the transition states for the two cyclizations.[53,54]

Interestingly, the hyperconjugative stabilization consistentlyfavors the 5-exo relative to the 6-endo products (25–27 kcal/molvs. 18–19 kcal/mol). The difference can be explained by the var-iations in hybridization of the carbanionic orbital in the 5-exoand 6-endo products (Table 1). To increase overlap with theterminal phenyl group, the anion in the 5-exo product adoptsa ~sp3.4 hybridization, whereas the 6-endo anion is very close tosp2 hybridization.[55–57] This difference allows the 5-exo anionto benefit simultaneously from conjugation with the terminalaryl and from the increased hyperconjugation with the antiperi-planar s*C–N acceptor orbital. It is also interesting that themagnitude of these interactions in the 6-endo product remainsrelatively constant, whereas the same interactions in the 5-exoproducts are noticeably increased for the product with the pyra-zolyl core.[58,59] However, even the increase in hyperconjugativeassistance in the pyrazolyl 5-exo product cannot fully compensa-tive for the destabilizing strain effect.

Summary: two strategies for 5-exo to 6-endo switch in anionicdig cyclizations

These findings reveal one more way to control the 5-exo/6-endo-digselectivity in cyclizations of acetylenic hydrazides (Fig. 9). Our earlier

Figure 7. Optimized geometries (B3LYP/6-31G(d,p)) of 5-exo and 6-endo cyclizations for the benzannelated (top) and pyrazolyl-annelated (bottom)acetylenic hydrazides. Bond lengths given in Ångstroms, angles in degrees

Figure 8. Stabilizing hyperconjugative nC-!s*C–N interaction in thecarbanionic products of 5-exo and 6-endo cyclizations

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finding that alkyl groups provide less stabilization of the anion de-veloped during the 5-exo cyclization, thus favoring the 6-endopathway, is complemented by the present disclosure that the sameswitch in selectivity can also be accomplished by annealingthe reacting system to a more strained heterocyclic core withoutsacrificing aryl substituents at the terminal alkyne carbon. Notethat in this case even the conjugative assistance of the terminalpara-nitrophenyl group cannot switch the selectivity back to the5-exo-closure because selective strain destabilization switchesreaction from kinetic to thermodynamic control.In summary, independent of the nature of alkyne substitution,

hydrazides of 4-arylethynyl-5-carboxylic acid annealed atthe pyrazole scaffoled undergo a base-catalyzed regioselective6-endo-dig cyclization with the formation of pyrazolo[3,4-c]pyri-dine-7-ones – the azole analogues of phthalazinone, compoundsthat belong to a class with promising analgesic activity.[60] Thiswork illustrates how strain effects are capable of overriding theusual 5-exo-dig preference in these nucleophilic cyclizations,suggesting that strategic incorporating of strain in fast exother-mic cyclizations can be used as a tool in the reaction design.

EXPERIMENTAL SECTION

Melting points were determined with a Kofler apparatus. The IR-spectrawere recorded in KBr pellets on a “Vector-22” instrument. PdCl2(PPh3)2,hexyn-1, Et3N, CuI (Aldrich) were commercially available reactants. Allthe organic solvents were of analytical quality. Mass spectra (HRMS) weremeasured on a «DFS», Thermo Electron Corporation. NMR spectra wererecorded on a “Bruker AV 300” spectrometer (300.13 (1 H) and 75.47(13 C) MHz) and on a “Bruker AV 400“ (400.13 (1 H) and 100.61 (13 C)mHz) at 25 �C. Chemical shifts were given in (d in ppm) relative tothe residual signals of CHCl3 (dн 7.24 ppm and dc 76.90 ppm). Coupling

constants (J in Hz) were accurate to� 0.2 Hz. The multiplicity of signalsin the 13 C NMR spectra was determined using J-modulation.

Representative procedure for Sonogashira couplings

A mixture of methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate 6 g(0.023mol), Et3N (6mL), CuI (20mg), [Pd(PPh3)2]Cl2 (40mg), and2-methylbut-3-yn-2-ole 3.63 г g (0.043mol) in toluene (40mL) was keptfor 13 h under Ar atmosphere at 65�C until iodide disappeared (TLC mon-itoring, CH2Cl2, EtOAc). After cooling, the reaction mixture was filteredthrough a layer of Al2O3 (2 � 2 cm), the solvent was evaporated underreduced pressure, the residue was chromatographed on Al2O3 withtoluene as the eluent. The product was recrystallized from hexane toafford the product.

Methyl 4-(3-hydroxy-3-methylbut-1-ynyl)-1-methyl-1H-pyrazole-5-carbo-xylate (1a)

3.84 g (77%), m.p. 94–95 �C (from C6H6). IR n/cm–1: 1728 (C=O), 2245(C�C), HRMS, Found: m/z 222.0999 [M]+; C11H14N2O3. Calcd.:M=222.1000. 1 H NMR (CDCl3, 400.13MHz) d: 1.52 (6H, s, (CH3)2); 2.56(1H, s, OH); 3.86 (3H, s, NCH3-Pz); 4.10 (3H, s, OCH3); 7.36 (1H, s, 3-H-Pz);13 C NMR d: 31.22; 40.15; 51.87; 65.42; 72.91; 98.20; 107.56; 132.94;140.96; 159.59.

Methyl 4-[(6-amino-4-methylpyridin-3-yl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylate (1c)

1.0 g (81%, 12 h), m.p. 185–186 �C (from EtOAc). HRMS, Found: m/z270.1111 [M]+; C14H14N4O2. Calcd.: M=270.1110. IR n/cm–1: 1713 (C=O),2214 (C�C). 1 H NMR (CDCl3, 400.13MHz) d: 2.38 (3H, s, CH3-Py); 3.49(3H, s, NCH3-Pz); 4.17 (3H, s, OCH3); 4.58 (2H, s, NH2-Py); 6.36 (1H, s,b-H-Py); 7.62 (1H, s, 3-H-Pz); 8.18 (1H, s, a-H-Py,); 13 C NMR d: 20.12;40.25; 51.96; 83.99; 90.12; 108.24; 108.44; 110.72; 132.19; 140.84;150.05; 151.36; 157.61; 159.80.

Methyl 4-[(1,5-dimethyl-1H-pyrazol-4-yl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylate (1d)

0.25 g (52%, 12 h), m.p. 153–154 �C (from EtOAc). HRMS, Found: m/z258.1111 [M]+; C13H14N4O4. Calcd.: M= 258.1109. IR n/cm–1: 1713 (C=O),2226 (C�C). 1 H NMR (CDCl3, 400.13MHz) d: 2.36 (3H, s, 5

0-CH3-Pz

´); 3.77(3H, s, N-CH3-Pz

´); 3.92 (3H, s, NCH3-Pz); 4.14 (3H, s, OCH3); 7.29 (1H, s,30-H-Pz0); 7.76 (1H, s, 3-H-Pz). 13 C NMR d: 10.00; 36.48; 40.25; 51.91;81.90; 85.51; 102.33; 108.69; 132.18; 140.21; 140.77; 141.40; 159.81.

Methyl 4-[(4-nitrophenyl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylate (1e)

1.27 g (89%, 6h), m.p. 154–155 �C (from EtOAc). HRMS, Found: m/z285.0744 [M]+; C14H11N3O4. Calcd.: M=285.0745. IR n/cm–1: 1720 (C=O),2220 (C�C). 1 H NMR (CDCl3, 400.13MHz) d: 3.98 (3H, s, NCH3-Pz); 4.21(3H, s, OCH3); 7.64 (2H, d, H-o,o´, J=8); 7.69 (1H, s, 3-H-Pz); 8.23 (2H, d,H-m,m0 , J=8). 13 C NMR d: 40.41; 52.25; 85.84; 99.29; 113.82; 123.58;128.24; 130.14; 131.96; 138.10; 141.31; 160.39.

Table 1. Energies of the stabilizing hyperconjugative nC-!s*CN interaction in the carbanion cyclization products for both thepyrazolyl and benzene cores (B3LYP/6-31G(d,p) level of theory). Fock matrix elements, Fij, and NBO energy differences, ΔE, forthe carbon lone pair and s*C–N orbitals are given in a.u.

5-exo 6-endo

Core E, kcal/mol Fij/ΔE Carbanion hybridization E, kcal/mol Fij/ΔE Carbanion hybridization

Pyrazole 27.0 0.11/0.49 sp3.42 18.9 0.094/0.56 sp2.04

Benzene 25.3 0.11/0.53 sp3.30 18.5 0.094/0.57 sp2.06

Figure 9. Two strategies for the 5-exo-dig ! 6-endo-dig switch inanionic cyclizations

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Methyl 4-[(4-methoxyphenyl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylate (1b)

A mixture of 2.5 g (0.009mol) of methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate and 2.2 g (0.011mol) of 4-(methoxyphenyl)ethynyl)copperin 30mL pyridine was refluxed for 3 h under argon atmosphere. The reac-tion mixture was cooled, poured into aqueous ammonium hydroxide andextracted with dichloromethane. The dichloromethane solution wasdried over sodium sulfate and filtered through alumina (0.5 � 1 cm),and the solvent was evaporated under reduced pressure. The productwas crystallized from benzene to yield 1.44 g (58%) of compound 1b,m.p. 94–95 �C. HRMS, Found: m/z 270.1111 [M]+; C15H14N2O3. Calcd.:M=270.1110. IR n/cm–1: 1721 (C=O), 2226 (C�C). 1 H NMR (CDCl3,400.13MHz) d: 3.83 (3H, s, NCH3-Pz); 3.97 (3H, s, Ph-OCH3); 4.18 (3H, s,OCH3); 7.19 (2H, d, H- m,m0, J=9); 7.48 (2H, d, H-o,o0 , J=9); 7.62 (1H, s,3-H-Pz). 13 C NMR d: 31.12; 40.18; 51.89; 65.44; 72.93; 98.19; 103.32;107.55; 113. 58; 114.00; 132.94; 140.97; 159.60.

Representative procedure for preparation of hydrazides

Mixture of 2.27 g (12mmol) methyl ester of ethynylpyrazol-carboxylicacid (1a), 1.2 g (24mmol) of 80% NH2NH2 �H2O in 20mL ethanol wasrefluxed 7 h, until ether disappeared (TLC monitoring, EtOAc), cooledand the precipitate was filtered off, product was crystallized from EtOHto afford the product.

Hydrazide 4-(3-hydroxy-3-methylbut-1-ynyl)-1-methyl-1H-pyrazole-5-carbo-xylic acid (2a)

1.78 g (78%), m.p. 123–124 �C (from EtOH). HRMS, Found: m/z: 222.1011[M]+; C10H14N4O2. Calcd.: M=222.1024. IR n/cm–1: 1682 (C=O), 2228(C�C), 3299, 3386 (NH, NH2).

1 H NMR (CDCl3, 400.13MHz) d: 1.63 (6H, s,(CH3)2); 3.82 (1H, s, OH); 4.18 (3H, s, NCH3-Pz); 5.09 (2H, s, NHNH2), 7.49(1H, s, 3-H-Pz); 8.39 (1H, s, NHNH2).

13 C NMR d: 31.22; 40.15; 51.87;65.42; 72.91; 98.20; 132.94; 140.96; 159.59.

Hydrazide 4-[(4-methoxyphenyl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylic acid (2b)

0.28 g (89%, 3h), m.p. 138–139 �C (from EtOH). HRMS, Found: m/z:270.1229 [M]+; C13H14N6O. Calcd.: M=270.1223. IR n/cm–1: 1674 (C=O),2208 (C�C), 3366, 3450 (NH, NH2).

1 H NMR (CDCl3, 400.13MHz) d: 3.88(3H, s, NCH3); 4.27 (3H, s, Ph-OCH3); 4.61 (2H, s, NHNH2); 6.92 (2H, d,H-m,m0, J=9); 7.52 (2H, d, H- o,o0, J=9); 7.67 (1H, s, 3-H-Pz), 8.62 (1H, s,NHNH2).

13 C NMR d: 40.35; 55.25; 78.38; 81.09; 95.72; 103.41; 113.82;114.13; 132.92; 135.94; 140.42; 160.12.

Hydrazide 4-[(6-amino-4-methylpyrid-3-yl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylic acid (2c)

0.072 g (73%, 2 h), m.p. 235–236 �C (from EtOH). HRMS, Found: m/z:270.1229 [M]+; C13H14N6O. Calcd.: M=270.1223. IR n/cm–1: 1672 (C=O),2204 (C�C), 3315, 3423 (NH, NH2).

1 H NMR (CDCl3, 400.13MHz) d: 2.24(3H, s, CH3-Py); 3.97 (3H, s, NCH3-Pz); 4.54 (2H, s, CONHNH2); 6.06 (2H, s,NH2-Py); 6.31 (1H, s, b-H-Py); 7.55 (1H, s, 3-H-Pz); 7.99 (1H, s, a-H-Py);9.23 (1H, s, NHNH2).

13 C NMR d: 20.28; 39.07; 83.17; 90.83; 103.61;107.78; 108.00; 136.08; 140.00; 148.76; 151.39; 158.79; 159.54.

Hydrazide 4-[(1,5-dimethyl-1H-pyrazol-4-yl)ethynyl]-1-methyl-1H-pyrazole-5-carboxylic acid (2d)

0.038 g (76%, 6 h), m.p. 159–160 �C (from EtOH). HRMS, Found: m/z:258.1224 [M]+; C12H14N6O. Calcd.: M=258.1220. IR n/cm–1: 1668 (C=O),2216 (C�C), 3327, 3394 (NH, NH2).

1 H NMR (CDCl3, 400.13MHz) d: 2.35(3H, s, 50-CH3-Pz0); 3.79 (3H, s, NCH3-Pz0); 4.04 (2H, s, NHNH2); 4.21 (3H,s, NCH3-Pz); 7.54 (1H, s, 30-H-Pz0); 7.57 (1H, s, 3-H-Pz); 8.46 (1H, s, NHNH2).13 C NMR d: 10.17; 36.57; 40.35; 81.49; 87.82; 101.12; 103.59; 133.39;140.40; 141.77; 151.44; 160.00.

Hydrazide 1-methyl-4-[(4-nitrophenyl)ethynyl]-1H-pyrazole-5-carboxylic acid (2e)

0.062 g (89%, 20min), m.p. 212–213 �C (from EtOAc). HRMS, Found: m/z:285.0856 [M]+; C13H11N5O3. Calcd.: M=285.0855. IR n/cm–1: 1685 (C=O),2216 (C�C), 3323, 3398 (NH, NH2).

1 H NMR (CDCl3, 400.13MHz) d: 4.11(2H, s, NHNH2); 4.25 (3H, s, NCH3-Pz); 7.65 (1H, s, 3-H-Pz); 7.68 (2H, d,H-o,o0 , J=8); 8.25 (2H, d, H-m,m0 , J=8), 8.28 (1H, s, NHNH2).

13 C NMR d:40.36; 84.84; 93.48; 101.91; 123.76; 128.69; 132.01; 134.43; 140.94;147.30; 159.62.

Representative procedure for cyclizations

The mixture of 0.3 g (1.4mmol) hydrazide 2a and 0.078 g KOH wasrefluxed in 5mL EtOH for 7 h, until the disappearance of starting materialaccording TLC monitoring (EtOAc). The reaction mixture was cooled andthe precipitate was filtered off. The product was crystallized from EtOH toafford the product.

6-Amino-5-(2-hydroxyprop-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one (3a)

0.23 g (78%), white crystals m.p.169–170 �C (from EtOH). HRMS, Found:m/z: 222.1111 [M]+; C10H14N4O2. Calcd.: M=222.1108. IR n/cm–1: 1662(C=O), 3419 (NNH2).

1 H NMR (CDCl3, 400.13MHz) d: 1.62 (6H, s, (CH3)2);4.27 (3H, s, NCH3-Pz); 5.23 (1H, s, OH); 6.24 (2H, s, NNH2); 6.45 (1H, s,=CH); 7.64 (1H, s, 3-H-Pz). 13 C NMR d: 29.77; 38.12; 71.56; 95.43; 124.50;128.11; 132.76; 144.79; 155.23.

6-Amino-5-(4-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one (3b)

0.08 g (57%, 7 h), m.p. 172–173 �C (from EtOH). HRMS, Found: m/z:270.1115 [M]+; C14H14N4O2. Calcd.: M=270.1116. IR n/cm–1: 1674 (C=O),3445 (NNH2).

1 H NMR (CDCl3, 400.13MHz) d: 3.83 (3H, s, NCH3-Pz); 4.40(3H, s, Ph-OCH3); 4.96 (2H, s, NNH2); 6.43 (1H, s, =CH), 7.72 (1H, s, 3-H-Pz); 6.49 (2H, d, H-m,m0 , J=9); 7.38 (2H, d, H-o,o0, J=9). 13 C NMR d: 40.35;55.25; 78.38; 81.09; 95.72; 103.41; 113.82; 114.13; 132.92; 135.94; 140.42;160.12.

6-Amino-5-(6-amino-4-methylpyrid-3-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one (3c)

0.03 g (56%, 6 h), m.p. 256–257 �C (from EtOH). HRMS, Found: m/z:270.1224 [M]+; C13H14N6O. Calcd.: M=270.1221. IR n/cm–1: 1653 (C=O),3150 (NH2-Py); 3385 (NNH2).

1 H NMR (CDCl3, 400.13MHz) d: 2.12 (3H, s,CH3-Py); 4.42 (3H, s, NCH3-Pz); 4.56 (2H, s, NNH2); 5.09 (2H, s, NH2-Py);6.40 (1H, s, =CH); 6.42 (1H, s, b-H-Py); 7.76 (1H, s, 3-H-Pz); 8.26 (1H, s,a-H-Py). 13 C NMR d: 20.28; 39.07; 83.17; 90.83; 103.61; 107.78; 108.00;136.08; 140.00; 148.76; 151.39; 158.79; 159.54

6-Amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one (3d)

0.02 г (76%, 5 h), m.p. 201.7–202.8 �C (from EtOH). HRMS, Found: m/z:258.1224 [M]+; C12H14N6O. Calcd.: M= 258.1221. IR n/cm–1: 1657 (C=O),3437 (NNH2).

1 H NMR (CDCl3, 400.13MHz) d: 2.28 (3H, s, 50-CH3Pz0); 3.86(3H, s, NCH3-Pz0); 4.41 (3H, s, NCH3-Pz,); 5.09 (2H, s, NNH2); 6.38 (1H, s,=CH); 7.56 (1H, s, 30-H-Pz0); 7.72 (1H, s, 3-H-Pz). 13 C NMR d: 18.31; 36.50;38.19; 100.63; 113.80; 124.50; 128.60; 132.26; 132.64; 137.87; 138.71;153.26.

6-Amino-1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one (3e)

0.01 g (77%, 2 h), m.p. 231–232 �C (from EtOH). HRMS, Found: m/z:285.0856 [M]+; C13H11N5O3. Calcd.: M=285.0855. IR n/cm–1: 1661 (C=O),3443 (NNH2).

1 H NMR (CDCl3, 400.13MHz) d: 4.41 (3H, s, NCH3); 4.82

S. F. VASILEVSKY ET AL.

wileyonlinelibrary.com/journal/poc Copyright © 2012 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2012, 25 998–1005

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(2H, s, NNH2); 6.51 (1H, s, =CH); 7.66 (2H, d, H-o,o0 , J=8); 7.77 (1H, s, 3-H-Pz);8.29 (2H, d, H-m,m0, J=8). NMR 13C NMR d: 40.36; 84.84; 93.48; 101.91;123.76; 128.69; 132.01; 134.43; 140.94; 147.30; 159.62.

Acknowledgements

This work was supported by the grant of RFBR 10-03-00257,grant of SB of the Russian Academy of Sciences No. 51 (2012–2014) and grant of the Russian Academy of Sciences 5.9.3.(2009–2012) (both to S.F.) and by Grant CHE-0848686 of theNational Science Foundation (to I.A.).

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