Strain control in nucleophilic cyclizations: Reversal of exo-selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

Article abstract of DOI:10.1002/poc.2990

Independent of the nature of alkyne substitution, hydrazides of 4-arylethynyl-5-carboxylic acid annealed at the pyrazole 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 analogous benzannelated systems and illustrates selective destabilization of the reaction path leading to the formation of a smaller ring. Computational analysis also reveals an important role of prototropic equilibria in rendering the overall cyclization feasible in the strained heterocyclic systems. The switch to the formation of a larger cycle suggests that strategic incorporation of strain can be used as a tool for the efficient control of regiochemistry of nucleophilic cyclizations. Copyright

Full text of DOI:10.1002/poc.2990

Special Issue Paper
Received: 16 April 2012,
Revised: 28 May 2012,
Accepted: 30 May 2012,
Published online in Wiley Online Library:
(wileyonlinelibrary.com) DOI: 10.1002/poc.2990
Strain control in nucleophilic cyclizations:
reversal of exo-selectivity in cyclizations of
hydrazides of acetylenyl carboxylic acids by
annealing to a pyrazole scaffold†
Sergei F. Vasilevskya, Brian Goldb, Tatyana F. Mikhailovskayaa and
Igor V. Alabuginb*
Independent of the nature of alkyne substitution, hydrazides of 4-arylethynyl-5-carboxylic acid annealed at the
pyrazole 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 analogous
benzannelated systems and illustrates selective destabilization of the reaction path leading to the formation of a
smaller ring. Computational analysis also reveals an important role of prototropic equilibria in rendering the overall
cyclization feasible in the strained heterocyclic systems. The switch to the formation of a larger cycle suggests that
strategic incorporation of strain can be used as a tool for the efficient control of regiochemistry of nucleophilic
cyclizations. 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
acids with analogous derivatives of pyrazolcarboxylic acids, where
annealing the reacting system at a smaller core could provide an
INTRODUCTION
Diverse transformations of polyfunctional arylacetylenes are
appealing from both the applied and fundamental points of
view.[1] Cyclizations of vicinally substituted acetylenyl arenes and
heteroarenes provide direct synthetic route towards condensed
heterocycles with many promising features in drug design.[2,3]
Additionally, such cyclizations continue to assist in developing and
testing the general rules for the formation of cyclic structures.[4–9]
Bifunctional nucleophiles are particularly interesting because
the selectivity of intramolecular attack at the triple bond is sensi-
tive to the variations in the nature of the alkyne substituents and
reaction conditions. For example, hydrazides of vic-acetylenyl
benzoic acids[10–12] can yield benzopyrrolidones, benzopyrida-
zones or benzodiazinones – three promising biologically active
types of annealed heterocycles with a wide spectrum of pharma-
cological activity.[13–15] The multichannel reactivity originates
from the presence of two nucleophilic centers of different nature
(the amide and the amine nitrogens[16,17]) and the possibility of
selective 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 catalysis
by Cu salts, the reaction is sensitive to the structure of the alkyne.
For the purely anionic cyclizations of benzoic hydrazides, the
competition between 5-exo and 6-endo cyclizations of the “inter-
nal” nitrogen nucleophile is controlled by the nature of alkyne
substituents. Alkyl substituents at the alkyne terminus favor the
6-endo-dig closure whereas aryl groups direct the cyclization down
the 5-exo-dig path. These observations motivated us to compare the
features of base-catalyzed cycloisomerization of acetylenyl benzoic
additional 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 Sonogashira
coupling of respective 4-iodo 1H-pyrazols with terminal alkynes
[“Method A”, Pd(PPh3)2Cl2, CuI, Et3N] in 52%–89% yields.[22] The
p-OMePh derivative 1b was prepared via Cu acetylide synthesis
(“Method B”).[23] Reaction of the starting 4-iodo pyrazolyl ester
with Cu acetylide in pyridine required reflux for 3 h under argon
atmosphere 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 special
issue on 11th Latin American Conference on Physical Organic Chemistry, edi-
ted by Prof. Eusebio Juaristi, Centro de Investigacion y de Estudios Avanzados
del Instituto Politecnico Nacional Quimica Apartado Postal 14-740, Mexico
07000, Mexico.
a S. F. Vasilevsky, T. F. Mikhailovskaya
Institute of Chemical Kinetics and Combustion, Novosibirsk 630090, Russian
Federation
b B. Gold, I. V. Alabugin
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
FL, 32306, USA
J. Phys. Org. Chem. 2012
Copyright © 2012 John Wiley & Sons, Ltd.

S. F. VASILEVSKY ET AL.
compounds with the benzene core where the formation of
hydrazides was accompanied by their cyclizations. This observa-
tion suggests that annealing hydrazides to a smaller cycle
increases activation barriers for their cyclizations.
The structures of hydrazides 2a–e were determined unambig-
uously from their analytical and spectral analysis. For example, the
infrared (IR) spectra display the characteristic frequencies of disub-
stituted alkyne moiety 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 was
carried out in hot ethanol in the presence of KOH (Fig. 4). The re-
action was complete in 2–7 h. Alkynes with acceptor substitution
were slightly more reactive but, in every case, the reaction led to
the 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 1 H NMR chemical shifts of exo and endo methine protons are
close, rendering the distinction between the 5-membered and
6-membered lactams difficult. However, it is known from the litera-
ture that increased strain in the smaller 5-membered cycle leads to
a 30–35 cm–1 blue shift in the IR-vC=O frequencies.[24] As a result, these
frequencies for d-N-aminolactams are in the region of 1650–1680 cm–1,
whereas for g-N-aminolactams they reach 1695–1700 cm–1.
We have recently confirmed the reliability of this IR-criterion
for the assignment of ring size by comparing its predictions with
the 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 lie
within 1653–1674 cm–1, they can be unambiguously assigned
as d-N-aminolactams.
Figure 1. The multichannel reactivity of hydrazides of vic-acetylenyl
benzoic acids
Figure 2. Two approaches to pyrazolyl alkynes
DESCRIPTION OF COMPUTATIONAL
APPROACH
Calculations were performed by using GAUSSIAN 03 software[25] with
geometries and energies obtained at the Becke, three-parameter,
Lee–Yang–Parr (B3LYP)/6-31G(d,p) level of theory. All stationary
point geometries for the anionic cyclizations were optimized at
the B3LYP/6-31G(d,p) level. Reactants, products, and intermediates
were confirmed as minima and the transition state structures were
confirmed as saddle points with a single imaginary frequency
through frequency calculations. See supporting information for
coordinates, total energies, and imaginary frequencies (for transi-
tion state structures) of optimized structures. The solvation effects
were tested by single point energy calculations with the conductor
polarized continuum model (CPCM) at the self-consistent reaction
field (SCRF)-B3LYP/6-31G(d,p) level in ethanol at the respective
gas phase geometries. Energies of hyperconjugative interactions
were calculated by using the natural bond orbital (NBO)[26] method
implemented in GAUSSIAN.
Figure 3. Conversion of esters into hydrazides
Heating of methyl esters 1a–e and 80% NH2NH2ꢀH2O in
ethanol provided hydrazides 2a–e in 73%–89% (Fig. 3). The
nitro-substituted ester 1e was the most reactive, affording the
hydrazide in 78% yield after 20 min.
The clean transformation of esters into acyclic hydrazides
under these conditions contrasted the behavior of analogous
Figure 4. Regioselectivity of base-catalyzed cyclizations of alkynyl hydrazides with pyrazolyl core
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STRAIN CONTROL IN NUCLEOPHILIC CYCLIZATIONS
Discussion of computational results
cycles, whereas the 6-endo cyclization leads to a system that
combines a five-membered and a six-membered cycle. To test
this hypothesis, we carried out density functional theory
analysis of potential energy surfaces for the two cyclization
directions of acetylenic hydrazides with benzene and pyrazolyl
cores.
The results are summarized in Fig. 5. The barriers for the two
cyclizations of benzannelated hydrazide anions presented in this
work (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 analogous
cyclization of the parent N-centered anion formed by deprotonation
of an amine (12–14 kcal/mol vs. 18–19 kcal/mol for the gas
phase 5-exo and 6-endo-dig barrier, respectively, at B3LYP and
M05-2X/6-31 +G(d,p) levels of theory),[7–9] even though the
hydrazide cyclizations are less exothermic.[4,40–44] The relatively
low 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 not
change upon introduction of solvation (CPCM, ethanol) in the
computational model. The main effect of solvation is in
rendering both cyclizations less thermodynamically favorable.
Although the 6-endo-dig closure becomes essentially thermoneutral
Both 5-exo and 6-endo-dig cyclizations are stereoelectronically
favorable according to the Baldwin rules.[4–6] Although
5-exo-dig closures are generally preferred in anionic alkyne
cyclizations,[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 case
of alkyl-substituted alkynes where the selectivity just barely
favors the formation of 6-endo products. The ~12–14 kcal/mol
greater thermodynamic stability of 6-endo-dig products in
comparison to the 5-exo products translates into preferential
stabilization of the 6-endo barrier, which is large enough to
override the intrinsic 5-exo preference.[28–39] However, the
difference is relatively small and the 5-exo preference can
be restored when an aromatic substituent is introduced at
the acetylenic terminus.
The exclusive formation of 5-exo products from Ar-substituted
alkynes annealed at the benzene core renders the observed
switch to 6-endo products in the pyrazolyl-based substrates
intriguing. A possible reason for the observed change in selec-
tivity in pyrazolyl hydrazides is the greater strain in the 5-exo
transition state, which originates from a larger angle between
the interacting groups in pyrazolyl acetylenes. The 5-exo
closure leads to a condensed system of two five-membered
Figure 5. Comparison of 5-exo and 6-endo cyclization and reaction energies for the benzannelated (top) and pyrazolyl-annelated (bottom) acetylenic
hydrazides. 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 of
theory. The difference between 5-exo and 6-endo barriers are shown with the blue arrow
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S. F. VASILEVSKY ET AL.
with the driving force ΔGrxn of ~0.0 kcal/mol whereas the
5-exo-product is still ~11 kcal/mol more stable than the
acyclic hydrazide anion, both cyclic carbanions can be protonated
under the reaction conditions rendering the overall process
irreversible.
than the reactant and is not accumulated under the reaction con-
ditions. Under thermodynamic control, only the 6-endo product
accumulates in a high yield.[48]
Strain in the cyclization transition states
Although the change from a six-membered (benzene) to the
five-membered (pyrazole) core imposes a dramatic decelerating
effect on both 5-exo and 6-endo cyclizations, as expected from
the strain hypothesis, the 5-exo-TS and product are destabilized
to a much greater extent. Now, the calculated cyclization barriers
for the both competing cyclization of pyrazolyl reactants are in
the order of 20 kcal/mol and both cyclizations are moderately
endergonic. Similar effects of strain on the exo/endo selectivity
have been reported for 4-exo/5-endo[45–47] and 5-exo/6-endo[27]
radical cyclizations of alkynes. However, the exo-preference is
even more pronounced for anionic cyclizations, so this switch
in selectivity is more impressive.
The 6-endo-dig product benefits from slightly larger aromatic
stabilization[11] whereas the 5-exo-dig cyclization benefits from
delocalization of the developing carbanion to the terminal aryl
ring and H-bonding between the anion and the NH2 of hydra-
zide. These factors are balanced in favor of 5-exo closure in the
case of the benzene scaffold but the inherent strain introduced
upon the fusion of the second five-membered ring at the
pyrazole core tips the balance in favor of the 6-endo product
for the heterocyclic substrates. To evaluate the effect of strain,
we have analyzed transition state geometries for the competing
cyclization pathways in more detail (Fig. 6).
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, both
cyclic carbanions need to quickly be trapped by either an
intramolecular 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 to
the respective N-centered anion, the 5-exo-products remain
less stable than the starting acyclic anion. Even if 5-exo-dig
cyclization were faster, one would expect the formation of the
five-membered products to be reversible.
Indeed, the exclusive formation of 6-endo-products from the
p-nitro substituted alkyne suggests that the reaction does
proceed under thermodynamic control. In this case, the 5-exo-TS
is calculated to be lower and the 5-exo-product should be
formed faster. However, the stabilizing effect of the nitro-group
at the 5-exo-TS and product does not extend to the N-anion prod-
uct of the prototropic rearrangement of the initially formed cyclic
carbanion (Fig. 6). As a result, the 5-exo-product remains less stable
In both cases, one of the lone pairs of the nucleophilic nitrogen
in the reactants is constrained via nN ! s*C–O and nN ! s*N–H
interactions in the appropriate position for the attack at the alkyne
in-plane p-bond. As a result, geometry changes associated with the
cyclization mostly involve in-plane bending.
In both reactants, the “1,5” distance (2.8 and 3.0 Å) is much
shorter than the “1,6-distance” (3.3 and 3.6 Å) indicating that
more considerable alkyne bending should be required on route
from the reactants to the 6-endo TSs (Fig. 7). However, the en-
ergy cost for alkyne bending is relatively small[49–51] and there
is little change in the other angles of the starting material in
reaching the 6-endo TS. The angles between the pyrazolyl core
and the two substituents (129 and 132 degrees for acetylene
and 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 angles
also lead to the greater separation between the two reacting
functionalities in the heterocyclic reactant.
As a consequence of these differences, significantly greater
relative bending is required to reach the 5-exo TS in the
heterocyclic reactant. Moreover, because the cyclization is endo-
thermic, the TS adopts a late, product-like geometry. The shorter
incipient 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) acetylenic
hydrazides 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 blue
arrow. The 5-exo-cyclization is favored kinetically but not thermodynamically
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STRAIN CONTROL IN NUCLEOPHILIC CYCLIZATIONS
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
manifested in the transition states for the two cyclizations.[53,54]
Interestingly, the hyperconjugative stabilization consistently
favors the 5-exo relative to the 6-endo products (25–27 kcal/mol
vs. 18–19 kcal/mol). The difference can be explained by the var-
iations in hybridization of the carbanionic orbital in the 5-exo
and 6-endo products (Table 1). To increase overlap with the
terminal phenyl group, the anion in the 5-exo product adopts
a ~sp3.4 hybridization, whereas the 6-endo anion is very close to
Figure 8. Stabilizing hyperconjugative nC-!s*C–N interaction in the
carbanionic products of 5-exo and 6-endo cyclizations
sp2 hybridization.[55–57] This difference allows the 5-exo anion
to benefit simultaneously from conjugation with the terminal
aryl and from the increased hyperconjugation with the antiperi-
planar s*C–N acceptor orbital. It is also interesting that the
magnitude of these interactions in the 6-endo product remains
relatively constant, whereas the same interactions in the 5-exo
products are noticeably increased for the product with the pyra-
zolyl core.[58,59] However, even the increase in hyperconjugative
assistance in the pyrazolyl 5-exo product cannot fully compensa-
tive for the destabilizing strain effect.
the starting alkyne suggest greater strain and distortion in the
5-exo TS for the pyrazole alkynes. Even the conjugative assistance
of 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 in
organic chemistry, negative hyperconjugation plays an impor-
tant role in stabilizing the anionic species (Fig. 8).[52] To compare
the importance of this factor in the 5-exo/6-endo competition,
we have quantified the key nC-!s*C–N hyperconjugative
interactions in the respective products by NBO analysis (Table 1).
It is likely that the same hyperconjugative effects are partially
Summary: two strategies for 5-exo to 6-endo switch in anionic
dig cyclizations
These findings reveal one more way to control the 5-exo/6-endo-dig
selectivity in cyclizations of acetylenic hydrazides (Fig. 9). Our earlier
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S. F. VASILEVSKY ET AL.
Table 1. Energies of the stabilizing hyperconjugative nC-!s*CN interaction in the carbanion cyclization products for both the
pyrazolyl and benzene cores (B3LYP/6-31G(d,p) level of theory). Fock matrix elements, Fij, and NBO energy differences, ΔE, for
the 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
Benzene
27.0
25.3
0.11/0.49
0.11/0.53
sp3.42
sp3.30
18.9
18.5
0.094/0.56
0.094/0.57
sp2.04
sp2.06
constants (J in Hz) were accurate to ꢂ 0.2 Hz. The multiplicity of signals
finding that alkyl groups provide less stabilization of the anion de-
veloped during the 5-exo cyclization, thus favoring the 6-endo
pathway, is complemented by the present disclosure that the same
switch in selectivity can also be accomplished by annealing
the reacting system to a more strained heterocyclic core without
sacrificing aryl substituents at the terminal alkyne carbon. Note
that in this case even the conjugative assistance of the terminal
para-nitrophenyl group cannot switch the selectivity back to the
5-exo-closure because selective strain destabilization switches
reaction from kinetic to thermodynamic control.
In summary, independent of the nature of alkyne substitution,
hydrazides of 4-arylethynyl-5-carboxylic acid annealed at
the pyrazole scaffoled undergo a base-catalyzed regioselective
6-endo-dig cyclization with the formation of pyrazolo[3,4-c]pyri-
dine-7-ones – the azole analogues of phthalazinone, compounds
that belong to a class with promising analgesic activity.[60] This
work illustrates how strain effects are capable of overriding the
usual 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.
in 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
(0.023 mol), Et3N (6 mL), CuI (20 mg), [Pd(PPh3)2]Cl2 (40 mg), and
2-methylbut-3-yn-2-ole 3.63 г g (0.043 mol) in toluene (40 mL) was kept
for 13 h under Ar atmosphere at 65ꢁC until iodide disappeared (TLC mon-
itoring, CH2Cl2, EtOAc). After cooling, the reaction mixture was filtered
through a layer of Al2O3 (2 ꢃ 2 cm), the solvent was evaporated under
reduced pressure, the residue was chromatographed on Al2O3 with
toluene as the eluent. The product was recrystallized from hexane to
afford 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
(CꢄC), HRMS, Found: m/z 222.0999 [M]+; C11H14N2O3. Calcd.:
M=222.1000. 1 H NMR (CDCl3, 400.13 MHz) 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.
EXPERIMENTAL SECTION
Methyl 4-[(6-amino-4-methylpyridin-3-yl)ethynyl]-1-methyl-
Melting points were determined with a Kofler apparatus. The IR-spectra
were recorded in KBr pellets on a “Vector-22” instrument. PdCl2(PPh3)2,
hexyn-1, Et3N, CuI (Aldrich) were commercially available reactants. All
the organic solvents were of analytical quality. Mass spectra (HRMS) were
measured on a «DFS», Thermo Electron Corporation. NMR spectra were
recorded on a “Bruker AV 300” spectrometer (300.13 (1 H) and 75.47
1H-pyrazole-5-carboxylate (1c)
1.0 g (81%, 12 h), m.p. 185–186 ꢁC (from EtOAc). HRMS, Found: m/z
270.1111 [M]+; C14H14N4O2. Calcd.: M = 270.1110. IR n/cm–1: 1713 (C=O),
2214 (CꢄC). 1 H NMR (CDCl3, 400.13 MHz) 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.
(
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 to
the residual signals of CHCl3 (dн 7.24 ppm and dc 76.90 ppm). Coupling
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/z
258.1111 [M]+; C13H14N4O4. Calcd.: M = 258.1109. IR n/cm–1: 1713 (C=O),
2226 (CꢄC). 1 H NMR (CDCl3, 400.13 MHz) d: 2.36 (3H, s, 50-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/z
285.0744 [M]+; C14H11N3O4. Calcd.: M = 285.0745. IR n/cm–1: 1720 (C=O),
2220 (CꢄC). 1 H NMR (CDCl3, 400.13 MHz) 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.
Figure 9. Two strategies for the 5-exo-dig ! 6-endo-dig switch in
anionic cyclizations
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J. Phys. Org. Chem. 2012

STRAIN CONTROL IN NUCLEOPHILIC CYCLIZATIONS
Methyl 4-[(4-methoxyphenyl)ethynyl]-1-methyl-1H-pyrazole-
5-carboxylate (1b)
Hydrazide 1-methyl-4-[(4-nitrophenyl)ethynyl]-1H-pyrazole-
5-carboxylic acid (2e)
A mixture of 2.5 g (0.009 mol) of methyl 4-iodo-1-methyl-1H-pyrazole-5-
carboxylate and 2.2 g (0.011 mol) of 4-(methoxyphenyl)ethynyl)copper
in 30 mL pyridine was refluxed for 3 h under argon atmosphere. The reac-
tion mixture was cooled, poured into aqueous ammonium hydroxide and
extracted with dichloromethane. The dichloromethane solution was
dried over sodium sulfate and filtered through alumina (0.5 ꢃ 1 cm),
and the solvent was evaporated under reduced pressure. The product
was 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 (CꢄC). 1 H NMR (CDCl3,
400.13 MHz) 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.
0.062 g (89%, 20 min), 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 (CꢄC), 3323, 3398 (NH, NH2). 1 H NMR (CDCl3, 400.13 MHz) 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 (1.4 mmol) hydrazide 2a and 0.078 g KOH was
refluxed in 5 mL EtOH for 7 h, until the disappearance of starting material
according TLC monitoring (EtOAc). The reaction mixture was cooled and
the precipitate was filtered off. The product was crystallized from EtOH to
afford the product.
Representative procedure for preparation of hydrazides
6-Amino-5-(2-hydroxyprop-2-yl)-1-methyl-1H-pyrazolo[3,4-c]
pyridin-7(6H)-one (3a)
Mixture of 2.27 g (12 mmol) methyl ester of ethynylpyrazol-carboxylic
acid (1a), 1.2 g (24 mmol) of 80% NH2NH2 ꢀH2O in 20 mL ethanol was
refluxed 7 h, until ether disappeared (TLC monitoring, EtOAc), cooled
and the precipitate was filtered off, product was crystallized from EtOH
to afford the product.
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, 400.13 MHz) 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.
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
(CꢄC), 3299, 3386 (NH, NH2). 1 H NMR (CDCl3, 400.13 MHz) 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.
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, 400.13 MHz) 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.
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 (CꢄC), 3366, 3450 (NH, NH2). 1 H NMR (CDCl3, 400.13 MHz) 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.
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, 400.13 MHz) 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
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 (CꢄC), 3315, 3423 (NH, NH2). 1 H NMR (CDCl3, 400.13 MHz) 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.
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, 400.13 MHz) 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.
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 (CꢄC), 3327, 3394 (NH, NH2). 1 H NMR (CDCl3, 400.13 MHz) 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.
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, 400.13 MHz) d: 4.41 (3H, s, NCH3); 4.82
J. Phys. Org. Chem. 2012
Copyright © 2012 John Wiley & Sons, Ltd.
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S. F. VASILEVSKY ET AL.
(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 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.
[25] M. J. Frish, et al., Gaussian 03, Revision E.01, Gaussian, Inc.,
Wallingford CT, 2004.
[26] The NBO 4.0 Program: E. D. Glendening, J. K. Badenhoop, A. E. Reed,
J. E. Carpenter, F. Weinhold, Theoretical Chemistry Institute, Univer-
sity of Wisconsin, Madison, WI, 1996.
[27] For the general analysis of factors responsible for a similar 5-exo-/
6-endo competition in radical cyclizations, see: I. V. Alabugin,
M. Manoharan, J. Am. Chem. Soc. 2005, 127, 12583.
[28] Connection between thermodynamic stabilization and reaction
barriers: R. A. Marcus, Annu. Rev. Phys. Chem. 1964, 15, 155.
[29] R. A. Marcus, J. Phys. Chem. 1968, 72, 891. Selected applications to
different classes of chemical reactions.
[30] M. Y. Chen, J. R. Murdoch, J. Am. Chem. Soc. 1984, 106, 4735.
[31] S. Wolfe, J. Mitchell, H. B. Schlegel, J. Am. Chem. Soc. 1981, 103, 7694.
[32] M. Newcomb, C. C. Johnson, M. B. Makek, T. R. Varick, J. Am. Chem.
Soc. 1992, 114, 10915.
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 the
National Science Foundation (to I.A.).
REFERENCES
[1] Acetylene Chemistry: Chemistry, Biology and Material Science, (Eds:
F. Diederich, P. J. Stang, R. R. Tykwinski), Wiley-VCH, Weinheim,
Germany, 2005.
[2] S. F. Vasilevsky, E. V. Tretyakov, J. Elguero, Adv. Het. Chem. 2002, 82, 1.
[3] W. R. Pitt, D. M. Parry, B. G. Perry, C. R. Groom, J. Med. Chem. 2009,
52, 2952.
[4] J. E. Baldwin, J. Chem. Soc., Chem. Comm. 1976, 18, 738.
[5] See also: A. L. J. Beckwith, C. J. Easton, A. K. Serelis, J. Chem. Soc.,
Chem. Commun. 1980, 482-483.
[6] For a useful mnemonics for Baldwin rules, see: E. Juaristi, G. Cuevas,
Rev. Soc. Quim. Mex. 1992, 36, 48.
[33] A. A. Martinesker, C. C. Johnson, J. H. Horner, M. Newcomb, J. Am.
Chem. Soc. 1994, 116, 9174.
[34] J. P. Guthrie, J. N. Guo, J. Am. Chem. Soc. 1996, 118, 11472.
[35] J. P. Guthrie, J. Am. Chem. Soc. 2000, 122, 5529.
[36] F. D. Lewis, R. S. Kalgutkar, Y. Wu, X. Liu, J. Liu, R. T. Hayes, S. E. Miller,
M. R. Wasielewksi, J. Am. Chem. Soc. 2000, 122, 12346.
[37] M. Newcomb, M. B. Makek, A. G. Glenn, J. Am. Chem. Soc. 1991,
113, 949.
[38] H. Y. Yoo, K. N. Houk, J. Am. Chem. Soc. 1997, 119, 2877.
[39] I. V. Alabugin, M. Manoharan, B. Breiner, F. Lewis, J. Am. Chem. Soc.
2003, 125, 9329.
[7] Redefined rules for alkyne cyclizations: I. V. Alabugin, K. Gilmore,
M. Manoharan, J. Am. Chem. Soc. 2011, 133, 12608.
[8] K. Gilmore, I. V. Alabugin, Chem. Rev. 2011. 111, 6513.
[9] I. V. Alabugin, K. Gilmore, Unusual Radical Cyclizations. Encyclopedia
of Radicals in Chemistry, Biology and Materials, (Eds: C. Chatgilialoglu,
A. Studer), John Wiley & Sons Ltd, Chichester, UK, 2012, 693–728.
[10] S. F. Vasilevsky, T. F. Mikhailovskaya, Chem. Heterocycl. Compd. 2009,
1, 67.
[11] S. F. Vasilevsky, T. F. Mikhailovskaya, V. I. Mamatyuk, G. A. Bogdanchikov,
M. Manoharan, I. V. Alabugin, J. Org. Chem. 2009, 74, 8106.
[12] T. F. Mikhailovskaya, S. F. Vasilevsky, Izv. Akad. Nauk SSSR, Ser. Khim.
2010, 3, 618.
[13] V. M. Loh, Jr., X. L. Cockcroft, K. J. Dillon, L. Dixon, J. Drzewiecki, P. J.
Eversley, S. Gomez, J. Hoare, F. Kerrigan, I. T. W. Matthews, K. A.
Menear, N. M. B. Martin, R. F. Newton, J. Paul, G. C. M. Smith, J. Vile,
A. J. Whittlec, Bioorg. Med. Chem. Lett., 2005, 15, 2235.
[14] X. L. Cockcroft, K. J. Dillon, L. Dixon, J. Drzewiecki, F. Kerrigan,
V. M. Loh, Jr., N. M. B. Martin, K. A. Menear, G. C. M. Smith, Bioorg.
Med. Chem. Lett., 2006, 16, 1040.
[15] E. del Olmo, B. Barboza, M. I. Ybarra, J. L. Lopez-Perez, R. Carron,
M. A. Sevilla, C. Boselli, A. San Feliciano, Bioorg. Med. Chem. Lett.,
2006, 16, 2786.
[40] For a discussion of thermodynamic effect on activation energies of
alkyne cyclizations and separation of thermodynamic contributions
from intrinsic stereoelectronic factors, see: Ref. 17.
[41] I. V. Alabugin, M. Manoharan, J. Am. Chem. Soc. 2005, 127, 9534.
[42] C. W. Wu, J. J. Ho, J. Org. Chem. 2006, 71, 9595.
[43] Y.-Y. Yu, Y. Fu, M. Xie, L. Liu, Q.-X. Guo, J. Org. Chem. 2007, 72, 8025.
[44] When the bond stretching/forming PES for the starting material and
product are drastically different, significant deviations from simple
models are possible: S. Osuna, K. N. Houk, Chem. Eur. J. 2009, 15,
13219.
[45] Ref. 41. Additional information on 4-exo/5-endo competition.
[46] I. V. Alabugin, V. I. Timokhin, J. N. Abrams, M. Manoharan, I.
Ghiviriga, R. Abrams, J. Am. Chem. Soc., 2008, 130, 10984.
[47] K. Gilmore, M. Manoharan, J. Wu, P. V. R. Schleyer, I. V. Alabugin, J.
Am. Chem. Soc. 2012, 134, 10584.
[48] Note that Baldwin rules are not applicable to reactions under
thermodynamic control.
[49] P. R. Schreiner, J. Am. Chem. Soc. 1998, 120, 4184.
[50] I. V. Alabugin, M. Manoharan, J. Phys. Chem. A 2003, 107, 3363.
[51] R. D. Bach, J. Am. Chem. Soc. 2009, 131, 5233.
[52] I. V. Alabugin, K. Gilmore, P. Peterson, Hyperconjugation. WIREs
Comput. Mol. Sci. 2011, 1, 109.
[16] Formation of the 6-exo products for these compounds occurs only
in the presence of CuCl and only under the neutral conditions
where the “amine” nitrogen atom behaves as a stronger nucleo-
phile than the “amide” nitrogen atom. See ref. 9 for further details.
[17] For an interesting recent example of multifunctional reactivity of
hydrazides, see: J.-G. Roveda, C. Clavette, A. D. Hunt, S. I. Gorelsky,
C. J. Whipp, A. M. Beauchemin, J. Am. Chem. Soc. 2009, 131, 8740.
[18] S. F. Vasilevsky, A. V. Pozdnyakov, M. S. Shvartsberg, Izv. Akad. Nauk
SSSR, Ser. Khim. 1985, 6, 1367.
[19] S. F. Vasilevsky, A. V. Pozdnyakov, M. S. Shvartsberg, Izv. Sib.Otd.
Akad. Nauk SSSR, Ser. Khim. 1985, 5, 83.
[20] S. F. Vasilevsky, E. V. Mshvidobadze, J. Elguero, J. Het. Chem., 2002,
39, 1229.
[53] For the use of hyperconjugative assistance for selective transition
state stabilization, see: B. Gold, N. Schevchenko, N. Bonus, G. B.
Dudley, I. V. Alabugin, J. Org. Chem. 2012, 77, 75.
[54] B. Gold, G. B. Dudley, I. V. Alabugin, J. Am. Chem. Soc. 2012, Under
Review.
[55] For expanded further discussion of rehybridization effects in organic
chemistry, see: General effects: I. V. Alabugin, M. Manoharan, J. Comp.
Chem. 2007, 28, 373.
[56] hybridization of non-bonding orbitals: I. V. Alabugin, M. Manoharan,
T. A. Zeidan, J. Am. Chem. Soc. 2003, 125, 14014.
[57] An interesting recent example: M. G. Song, R. S. Sheridan, J. Phys.
Org. Chem. 2011, 24, 889.
[58] Analysis of the Fij/ΔE terms suggests that increased hyperconjuga-
tion in the strained cycle is due to the lower energy gap between
the donor and the acceptor. For an extended discussion of this
parameter in hyperconjugative interactions, see: I. V. Alabugin,
T. A. Zeidan, J. Am. Chem. Soc. 2002, 124, 3175.
[21] S. F. Vasilevsky, E. V. Mshvidobadze, V. I. Mamatyuk, G. V. Romanenko,
J. Elguero, Tetrahedron Lett. 2005, 46, 4457.
[22] K. Sonogashira, Y. Tohda, N. A. Hagihara, Tetrahedron Lett. 1975, 50,
4457.
[23] C. E. Castro, E. J. Gaughan, D. C. Owsley, J. Org. Chem., 1966, 31, 4071.
[24] S. F. Vasilevsky, M. S. Shvartsberg, Izv Akad. Nauk SSSR, Ser. Khim.
1990, 9, 2089.
[59] I. V. Alabugin, M. Manoharan, J. Org. Chem. 2004, 69, 9011.
[60] W. Pakulska, Z. Malinowski, A. K. Szczesniak, E. Czarnecka, J. Epsztajn,
Arch. Pharm. Chem. Life Sci., 2009, 342, 41.
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