Tuning selectivity of anionic cyclizations: Competition between 5-exo and 6-endo-dig closures of hydrazides of o-acetylenyl benzoic acids and based-catalyzed fragmentation/recyclization of the initial 5-exo-dig products

Article abstract of DOI:10.1021/jo901551g

(Chemical Equation Presented) Depending on the reaction conditions and the nature of substituents at the triple bond, anionic cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three alternative paths, each of which

Full text of DOI:10.1021/jo901551g

pubs.acs.org/joc
Tuning Selectivity of Anionic Cyclizations: Competition between
5-Exo and 6-Endo-Dig Closures of Hydrazides of o-Acetylenyl Benzoic
Acids and Based-Catalyzed Fragmentation/Recyclization of the Initial
5-Exo-Dig Products
Sergey F. Vasilevsky,*,† Tat’yana F. Mikhailovskaya,† Victor I. Mamatyuk,‡
Georgy E. Salnikov,‡ Georgy A. Bogdanchikov,†,§ Mariappan Manoharan,^ and
Igor V. Alabugin*,z
†Institute of Chemical Kinetics and Combustion, Novosibirsk 630090, Russian Federation, ‡N. N. Vorozhtsov
Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090,
Novosibirsk, Russian Federation, §Institute of Computational Mathematics and Mathematical Geophysics,
Novosibirsk 630090, Russian Federation, ^School of Science, Engineering and Mathematics,
Bethune-Cookman University, Daytona Beach, Florida 32114, and zDepartment of Chemistry and
Biochemistry, Florida State University, Tallahassee, Florida 32306
vasilev@kinetics.nsc.ru; alabugin@chem.fsu.edu
Received July 17, 2009
Depending on the reaction conditions and the nature of substituents at the triple bond, anionic
cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three
alternative paths, each of which provides efficient access to a different class of nitrogen heterocycles.
The competition between 5-exo and 6-endo cyclizations of the “internal” nitrogen nucleophile is
controlled by the nature of alkyne substituents under the kinetic control conditions. In the presence of
KOH, the initially formed 5-exo products undergo a new rearrangement that involves a ring-opening
followed by recyclization to the formal 6-exo-products and rendered irreversible by a prototropic
isomerization. DFT computations provide insight into the nature of factors controlling relative rates
of 5-exo, 6-endo, and 6-exo cyclization paths, ascertain the feasibility of direct 6-exo closure and
relative stability for the anionic precursor for this process, provide, for the first time, the benchmark
data for several classes of anionic nitrogen cyclizations, and dissect stereoelectronic effects control-
ling relative stability of cyclic anionic intermediates and influencing reaction stereoselectivity. We
show that the stability gain due transformation of a weak π-bond into a stronger σ-bond (the usual
driving force for the cyclizations of alkynes) is offset in this case by the transformation of a stable
nitrogen anion into an inherently less stable carbanionic center. As a result, the cyclizations are much
more sensitive to external conditions and substituents than similar cyclizations of neutral species.
However, the exothermicity of such anionic cyclizations is increased dramatically upon prototropic
isomerization of the initially formed carbanions into the more stable N-anions. Such tautomeriza-
tions are likely to play the key role in driving such cyclizations to completion but may also prevent
future applications of such processes as the first step in domino cyclization processes.
8106 J. Org. Chem. 2009, 74, 8106–8117
Published on Web 09/25/2009
DOI: 10.1021/jo901551g
2009 American Chemical Society
r

Vasilevsky et al.
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SCHEME 1. Two Levels of Selectivity in Cyclizations of Alkynes Promoted by Bifunctional Reagents
Introduction
either 5-exo-dig (“internal carbon attack”) or 6-endo-dig
(“external carbon attack”) cyclizations (Scheme 1). In a
similar manner, external (“amine”) nitrogen can participate
in either 6-exo- or 7-endo-dig cyclizations. All of these
cyclizations are allowed by the Baldwin rules,8 and thus the
competition between these processes needs to be understood
and controlled for achieving high selectivity in practical
applications.9
In addition, the competition between the four possible
cyclization routes should provide valuable fundamental
information about the relative efficiency of these common
transformations of anionic nitrogen nucleophiles. Current
literature regarding cyclizations of hydrazides of vic-acety-
lenylbenzoic acid is limited to only two examples,10,11 and
thus cannot paint the full picture of basic heterocyclization
trends.
Our recent communication reported cyclizations of two
hydrazides of o-acetylenyl benzoic acids bearing p-methoxy-
phenyl and 1,5-dimethylpyrazol-4-yl substituents at the al-
kyne moiety (Scheme 2). Although we observed the
5-exo-dig cyclization with the formation of (Z)-2-amino-
3-(4-methoxybenzylidene)isoindolin-1-one (67%) in the first
case, cyclization of the pyrazolyl derivative unexpectedly
yielded the product of a formal 6-exo-dig cyclization, 4-((1,5-
dimethyl-1H-pyrazol-4-yl)methyl)phthalazin-1(2H)-one, in
70% yield.12
Diverse chemistry and broad synthetic potential of poly-
functional arylacetylenes continues to draw the attention of
organic and medicinal chemists.1 When the functional
groups are positioned in the direct vicinity of the alkyne
moiety, such compounds serve as convenient building blocks
for the preparation of condensed heterocycles with a large
scope of biological activity. From the fundamental per-
spective, these molecules lend themselves for investigation
of internal and external factors controlling cyclization
processes (structure of substrate, electronic and spatial
parameters, etc.)2,3 as well as convenient structural plat-
forms for the design of molecular systems with controlled
reactivity.4
Cyclizations of hydrazides of o-acetylenyl pyrazolcar-
bonic acids illustrate how the multifunctional character of
these substrates such as the different reactivity of the R- and
β-atoms in the triple bond and two nucleophilic centers
(“amine” and “amide” nitrogen atoms) in the hydrazide
moiety can be translated in the multichannel character
of their transformations.5,6,7 In particular, attack of the
internal (“amide”) nitrogen at the triple bond can lead to
(1) Acetylene Chemistry: Chemistry, Biology and Material Science;
Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim,
Germany, 2005.
According to our earlier observations,10,11 formation of
the diazinone ring for the related compounds occurred only
in the presence of CuCl and only under the neutral condi-
tions where the “amine” nitrogen atom behaves as a stronger
nucleophile than the “amide” nitrogen atom. This transfor-
mation can be formally described as the result of 6-exo attack
at the R-acetylenic carbon by the “amine” nitrogen with the
following prototropic isomerization. This process would be
unusual because, in the presence of KOH, the “amine”
nitrogen is a weaker nucleophile than the N-anion formed
via deprotonation at the “amide” nitrogen, and thus direct
participation of the “amine” nitrogen in the diazinone
formation is unlikely. An alternative scenario that includes
(2) Sakamoto, T.; Kondo, Y.; Yamanaka, M. Heterocycles 1988, 27,
2225.
(3) Vasilevsky, S. F.; Tretyakov, E. V.; Elguero, J. Adv. Heterocycl. Chem.
2002, 82, 1. Vasilevsky, S. F.; Baranov, D. S.; Mamatyuk, V. I.; Gatilov,
Y. V.; Alabugin, I. V. J. Org. Chem. 2009, 74, 6143.
(4) Zeidan, T. A.; Manoharan, M.; Alabugin, I. V. J. Org. Chem. 2006, 71,
954. Zeidan, T.; Kovalenko, S. V.; Manoharan, M.; Alabugin, I. V. J. Org.
Chem. 2006, 71, 962. Alabugin, I. V.; Manoharan, M. J. Phys. Chem. A 2003,
107, 3363. Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett.
2002, 4, 1119. Alabugin, I. V.; Gilmore, K.; Patil, S.; Manoharan, M.;
Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J. Am. Chem. Soc. 2008, 30,
11535.
(5) Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. J. Heterocycl.
Chem. 2002, 39, 1229.
(6) Vasilevsky, S. F.; Mshvidobadze, E. V.; Mamatyuk, V. I.; Romanenko,
G .V.; Elguero, J. Tetrahedron. Lett. 2005, 46, 4457.
(7) For a recent interesting example of multifunctional reactivity of
hydrazides, see: Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Gorelsky, S. I.;
Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc., 2009, 131, 8740.
(8) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. See also:
Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem.
Commun. 1980, 482-483. For a useful mnemonics for Baldwin rules, see:
Juaristi, E.; Cuevas, G. Rev. Soc. Quim. Mex. 1992, 36, 48.
(9) For the general analysis of factors responsible for a similar 5-exo-/
6-endo competition in radical cyclizations, see: Alabugin I. V.; Manoharan,
M. J. Am. Chem. Soc. 2005, 127, 12583.
(10) Vasilevsky, S. F.; Pozdnyakov, A. V.; Shvartsberg, M. S. Izv. Akad.
Nauk SSSR, Ser. Khim. 1985, 6, 1367.
(11) Vasilevsky, S. F.; Pozdnyakov, A. V.; Shvartsberg, M. S. Izv. Sib.
Otd. Akad. Nauk SSSR, Ser. Khim. 1985, 5, 83.
(12) Vasilevsky, S. F.; Mikhailovskaya, T. F. Chem. Heterocycl. Compd.
2009, 1, 67.
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SCHEME 2. Two Previously Observed Pathways for the Cyclization of the o-Acetylenyl Benzoic Acid Hydrazides
SCHEME 3. Cross-Coupling of Methyl Ester of o-Iodobenzoic
Acid with Terminal Alkynes
a rearrangement of an initially formed product seems more
plausible than the direct 6-exo closure.
All of the above, along with the large effect of substituents
on the observed selectivity,6 motivated us to carry out
a systematic study of such cyclizations using a broader
selection of substituents. This study should also be of
practical value because the cyclization pathways will pro-
duce medicinally interesting compounds with a promising
spectrum of biological activity. For example, 4-hetaryl-
1(2H)-phthalazinones proved to be effective antiasthmatic
and bronchodilating agents13,14 whereas benzopyridazi-
nones display promising properties as melanin-concentrat-
ing hormone antagonists for treatment of anorexia, obesity,
and diabetes.15
substituent could the intermediate acetylenyl hydrazide 4d
be isolated (in 80% yield). Interestingly, the yield of the 5-exo
product increased for the acceptor aryl substituents in accord
with the buildup of negative charge at the benzylic carbon in
the TS for the ring closure step.
Results and Discussion
Although chemical shifts of the endo- and exo-methyne
hydrogens in the 1D 1H NMR spectra of the γ- and
δ-N-aminolactames are similar, the isoindolinone structure
of the products can be unambiguosly determined by using
2D 1H-1H correlations with double quantum filter
(COSYDQF), one bond (HSQC), and long-range (HMBC)
inverse 13C-1H correlations. As an example, the signal
assignments for the methoxy-derivative 3a are given in the
SI. The 5- and 6-membered condensed cycles can also be
conveniently distinguished from the observed differences in
the IR frequencies for the CO groups. The increase in strain
upon the transition from a six- to a five-membered cycle
Sonogashira cross-coupling of terminal alkynes with ap-
propriately substituted aromatic halides continues to be a
highly convenient method for the preparation of aryl- and
hetaryl-acetylenes with ortho-substituents.16,17 Thus, the
starting materials for this study—esters of o-acetylenylben-
zoic acids 1a-e—were prepared through the reaction of the
methyl ester of o-iodobenzoic acid with the appropriate
alkynes 2a-e under Cu-Pd catalysis in the Pd(PPh3)2Cl2/
CuI/NEt3 system in 67-97% yields (Scheme 3).
Heating ethynylbenzoates 1a-d with hydrazine hydrate in
ethanol led directly to the cyclization products 3a-c
(67-90%) without the intermediate accumulation of hydra-
zides 4a-c (Scheme 4). Only in the case of the n-butyl
caused increase of ν(CO) by 30-35 cm .
-1 18 It is known that,
in δ-lactams, the valence stretch frequency of the CO-group,
ν(CO), is ca. 1660-1680 cm-1, whereas in γ-lactams this
frequency exceeds 1695-1700 cm-1. The observed ν(CO)
value of 1706-1716 cm-1 in isolated lactams 3a-c is fully
consistent with the assigned γ-N-aminolactam structure.
Use of the nuclear Overhauser effect has also allowed us to
determine for the first time the stereochemistry of the
exocyclic C3dC8 double bond in the condensed 5-membered
N-aminolactams 3a-c. Reliable information related to the
spatial structure of these compounds was not available
before.10,11 In particular, the 2D NOESY spectrum clearly
(13) Yamaguchi, M.; Koga, T.; Kamei, K.; Akima, M.; Maruyama, N.;
Kuroki, T.; Hamana, M.; Ohi, N. Chem. Pharm. Bull. 1994, 42, 1850.
(14) Yamaguchi, M.; Kamei, K.; Koga, T.; Akima, M.; Kuroki, T.; Ohi,
N. J. Med. Chem. 1993, 36, 4052.
(15) (a) Dyck, B.; Markison, S.; Zhao, L.; Tamiya, J.; Grey, J.;Rowbottom,
M. W.; Zhang, M.; Vickers, T.; Sorensen, K.; Norton, C.; Wen, J.; Heise, C. E.;
Saunders, J.; Conlon, P.; Madan, A.; Schwarz, D.; Goodfellow, V. S. J. Med.
Chem. 2006, 49, 3753. (b) Sotelo, E.; Coelho, A.; Ravina, E. Tetrahedron Lett.
2001, 42, 8633. Frank, H.; Heinisch, G.; Pharmacologically active pyridazines.
In: Ellis, G.P.; West, G.B.; , Editors, Progress in Medicinal Chemistry; Elsevier:
Amsterdam, The Netherlands, 1990; p 1.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. A. Tetrahedron Lett.
1975, 50, 4467.
(17) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application of
Transition Metal Catalysts in Organic Synthesis; Springer-Verlag: New York,
1998; p 335.
(18) Vasilevsky, S. F.; Shvartsberg, M. S. Izv Akad. Nauk SSSR, Ser.
Khim. 1990, 9, 2089.
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SCHEME 4. Interaction of Methyl o-Acetylenylbenzoates with Hydrazine
SCHEME 5. Divergent Synthesis of Two Classes of Six-Membered Nitrogen Heterocycles from o-Alkynyl Hydrazides 4d,e
TABLE 1. Comparison of Experimental and Calculated (GIAO-B3LYP/
6-311þG** and GIAO-mPW1PW91/6-31G** levels (in parentheses) on
B3LYP/6-31þG** geometry) Chemical Shifts of H4 and H8 for E- and
Z-Forms of 3aa
SCHEME 6. Base-Catalyzed Rearrangement of N-Amino
Lactams into Benzopyridazinones
atom experiment calculation for Z-isomer calculation for E-isomer
H-4
H-8
7.69
6.65
7.81 (7.77)
6.63 (6.36)
8.45 (8.28)
7.27 (7.26)
aSee Scheme 4 for the atom numbering scheme.
displayed cross-peaks between H4-H8 and H11,13-OCH3
protons. The respective cross-peaks can only be explained
by substantial Overhauser effect as the result of spatial
proximity of these protons, which is only possible for
H4 and H8 protons in the Z-configuration. This is an inter-
esting observation because the observed Z-isomer is ex-
pected to be less stable than the nonobserved E-isomer
(vide infra).
The spatial structure of lactam 3a was additionally con-
firmed by the DFT calculation of proton NMR chemical
shifts (Table 1). The mPW1PW91 functional with polariza-
tion basis set (e.g., 6-31G*) was used extensively for repro-
ducing experimental 1H and 13C NMR data19 although
NMR computations often required a higher basis set. Thus,
NMR results were obtained from both mPW1PW91 and
B3LYP computations as shown in Table 1. Not only are the
differences in the chemical shifts of these protons calculated
for the E- and Z-configurations significant, but the experi-
mental data agree much better with the calculated data for
the Z-configuration. As a result, we conclude that quantum-
mechanical calculations in these systems reliably confirm
stereochemical assigments of 3a and agree fully with the
NOESY spectra.
Because reaction of the butyl derivative 1d with hydrazine
stopped at the stage of an open hydrazide 4d, we repeated
this experiment using a stronger base—KOH. The result
was unexpected—for the first time for these benzoic acid
derivatives, a six-membered N-amino lactam 5d was formed
via a 6-endo cyclization (75%). Note that this product
is structurally different from the formal 6-exo-product 6
observed for the cyclization of a hetaryl-substituted acety-
lene 4e (Scheme 5).
(19) Selected references discussing NMR computations at the
MPW1PW91 level: Rychnovsky, S. D. Org. Lett. 2006, 8, 2895. Cimino,
P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson.
Chem. 2004, 42, S26. Wojciech, M.; Barbara, R. Magn. Reson. Chem. 2004,
42, 459. Yang, J.; Huang, S.-X.; Zhao, Q.-S. J. Phys. Chem. A 2008, 112,
12132. For a general discussion, see also: Tuttle, T.; Kraka E.; Wu, A.;
Cremer, D. J. Am. Chem. Soc. 2004, 126, 5093.
To test whether the formation of diazinone 6 proceeds
through a rearrangement, we refluxed other N-amino lac-
tams 3a-c in ethanol in the presence of KOH (Scheme 6).
Under these conditions, both lactams 3a,b were converted
into the analogous benzopyridazinones 6a,b in 65% and
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SCHEME 7. Suggested Mechanism for the Base-Catalyzed Rearrangement of N-Amino Lactams 3 into Benzopyridazinones 6
JOCArticle
75% yields, respectively. Only lactam 3c with a strong
acceptor nitro substituent did not undergo recyclization even
under more prolonged heating with KOH.
We also considered the two intramolecular versions of this
mechanism where exocyclic nitrogen serves as a nucleophile.
These mechanisms, as shown in Scheme 7, are disfavored by
high strain in the tricyclic aziridine intermediates, both of
which do not correspond to a local energy minima at the
B3LYP/6-31þG(d,p) potential energy surface (vide infra).
Moreover, the intramolecular path 2 is further disfavored by
the experimentally observed absence of rearrangement for
R = p-NO2. On the basis of these considerations, the inter-
molecular version of the process presents itself as a more
likely scenario. In any case, independent of the exact
mechanism, such recyclization of γ-N-amino lactams into
benzodiazinones under treatment with KOH is a previously
unknown rearrangement.
We believe that such an isomerization can serve as a con-
venient synthetic approach toward pharmacologically impor-
tant phthalazinones,21-23 because the current literature methods
require multistep procedures which involve either organometal-
lic reagents, anhydrous media and high temperatures (up to
200 ꢀC), or highly reactive chemicals such as SOCl2.13
Proposed mechanisms for the rearrangement are out-
lined in Scheme 7. At the first step, the highly polarized
carbonyl group is attacked by an external nucleophile.
Subsequent collapse of the tetrahedral intermediate with
concomitant cleavage of the C-N bond not only opens the
cycle but also transforms the hydrazide moiety into con-
jugated base of a vinyl hydrazine. Unlike the hydrazide
reactant, the hydrazine intermediate should have a rela-
tively small difference in basicity between the internal and
external nitrogen atoms.20 Similar stability of the two
conjugate nitrogen bases should enable their equlibration
through proton transfer to the internal nitrogen atom.
6-Exo-trig attack of the terminal nitrogen anion at the
carbonyl moiety furnishes the cyclic framework of the
final product. Expulsion of the external nucleophile from
the second tetrahedral intermediate followed by another
prototropic isomerization affords the final product 6
(Scheme 7).
It is worth noting that cyclization of all positional
isomers of hydrazides of o-acetylenyl pyrazolcarboxylic
acids under basic conditions always led to 6-membered
N-amino lactams.5,24 These differences in the direction
The equilibrium between the two conjugate bases of
opened vinyl hydrazine is likely to be important for the
success of recyclization. In particular, this equilibrium
provides a simple explanation of why the p-nitro substitu-
tion stops the rearrangement. An acceptor substituent will shift
the equilibrium away from the external anion and disfavor all
reactions which originate from this intermediate.
(21) Loh, V. M. Jr.; Cockcroft, X. L.; Dillon, K. J.; Dixson, L.;
Drzewiecki, J.; Eversley, P. J.; Gomez, S.; Hoare, J.; Kerrigan, F.; Matthews,
I. T. W.; Menear, K. A.; Martin, N. M. B.; Newton, R. F.; Paul, J.; Smith,
G. C. M.; Vile, J.; Whittle, A. J. Bioorg. Med. Chem. Lett. 2005, 15, 2235.
(22) Cockcroft, X. L.; Dillon, K. J.; Dixson, L.; Drzewiecki, J.; Kerrigan,
F.; Loh, V. M. Jr.; Martin, N. M. B.; Menear, K. A.; Smith, G. C. M. Bioorg.
Med. Chem. Lett. 2006, 16, 1040.
(23) del Olmo, E.; Barmoza, B.; Ybarra, M. I.; Lopez-Perez, J. L.;
Carron, R.; Sevilla, M. A.; Boselli, C.; San Feliciano, A. Bioorg. Med. Chem.
Lett. 2006, 16, 2786.
(20) Note, however, that the equilibrium still should be shifted toward the
vinyl hydrazide anion and, thus, be unfavorable for the recyclization. This
notion may explain the absence of the rearrangement for X = p-NO2-Ph
where the initially formed hydrazide anion will be additionally stabilized by
the electron acceptor and, thus, the prototropic equilibrium will be even less
favorable for the rearrangement.
(24) Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. Heterocycles
2002, 57, 2255.
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SCHEME 8. Substituent Effects on the Relative Stabilities of Key Anionic Intermediates for R= Me and Ph at the B3LYP/6-31þG(d,p)
Levela
aAll values for the gas phase relative to the hydrazide anion, data for R = Ph are given in parentheses.
and feasibility of cycloisomerization stimulated us to
investigate this reaction and related processes through
a detailed quantum mechanical study. Computational
analysis was used to understand the nature of factors
controlling the relative rates of 5-exo, 6-endo, and 6-exo
cyclization paths, to ascertain the feasibility of direct
6-exo closure and relative stability of the anionic precursor
for this process, and to dissect stereoelectronic effects
controlling the relative stability of cyclic anionic inter-
mediates and reaction stereoselectivity. These results will
be used to validate our interpretation of experimental
findings and to benchmark the accuracy of computational
models for these types of anionic cyclizations.
Because the calculated activation barrier for the 5-exo
cyclization reaction of the neutral hydrazides was found to
be prohibitively large (∼50 kcal/mol), all calculations were
performed for the anionic form of the reagent. The relative
acidity of hydrazides suggests that this form is sufficiently
populated under the reaction conditions.30
Intrinsic and thermodynamic contributions to the reaction
barrier were separated by using Marcus theory.31 This
analysis allows one to compare inherent stereoelectronic
requirements of reactions with different thermodynamic
driving forces by comparing their intrinsic barriers separated
from the thermodynamic contribution. Intrinsic activation
energy, Eo, is determined from the following equation: Eo =
[Ea - 1/2ΔER þ (Ea2 - EaΔER)1/2]/2, where Ea = activation
energy and ΔER = reaction energy.
Computational Results. To rationalize the observed ex-
perimental results and gain a deeper insight into the nature of
electronic effects responsible for the formation of three
different families of heterocycles from the same common
class of precursors, we concentrated on several questions: (a)
relative stabilities of anions at the two adjacent nitrogen
atoms in hydrazides and vinyl hydrazines (thermodynamic
control), (b) relative barriers for the alternative cyclization
paths (kinetic control), and (c) relative stability of cyclic
intermediates and final products and its correlation with
hyperconjugative stereoelectronic effects (stereochemical
preferences).
Description of Computational Approach. Calculations were
performed by using Gaussian 03 software25 with geometries
and energies obtained at the B3LYP/6-31þG(d,p) level of
theory.26 All stationary point geometries for the anionic
cyclizations were optimized at the B3LYP/6-31þG** 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. The solvation effects were tested by
single point energy calculations with PCM model at the
SCRF-B3LYP/6-31þG** level in ethanol at the respective
gas phase geometries. Energies of hyperconjugative interac-
tions were calculated by using the Natural Bond Orbital
(NBO)27 method implemented in Gaussian. The Nucleus
Independent Chemical Shift (NICS) values were were eval-
Relative Stability of Acyclic Anions and Cyclic Anions.
As expected, the adjacent carbonyl group provides strong
˚
uated at 1 A above the center of the ring planes by using the
GIAO28 approach.
(30) Zhao, Y.; Bordwell, F. G.; Cheng, J. P.; Wang, D. J. Am. Chem. Soc.
1997, 119, 9125. Due to the presence of hydrazine in the reaction medium
All energies at T = 0 were calculated with the zero-
point vibration (ZPVE) and thermal correction (TCE)
energies.29 Solvation effects were calculated at the PCM-
SCRF B3LYP/6-31þG(d,p)//B3LYP/6-31þG(d,p) level,
using geometries and frequencies obtained from the gas
phase calculations.
(KB = [N2H5þ] [OH-]/[N2H4] = 10-5.9 at room temperature), the reaction
3
medium has substantial basic character (pH ∼11 at [N2H4] ≈ 1 M). National
Institute of Standards and Technology (NIST). Computational Chemistry
Comparison and Benchmark Data Base (CCCBDB): http://srdata.nist.gov/
cccbdb/.
(31) Marcus, R. A. Annu. Rev. Phys. Chem. 1964, 15, 155. Marcus, R. A.
J. Phys. Chem. 1968, 72, 891. Selected applications to different classes of
chemical reactions: Chen, M. Y.; Murdoch, J. R. J. Am. Chem. Soc. 1984, 106,
4735. Wolfe, S.; Mitchell, J.; Schlegel, H. B. J. Am. Chem. Soc. 1981, 103, 7694.
Newcomb, M.; Johnson, C. C.; Makek, M. B.; Varick, T. R. J. Am. Chem.
Soc. 1992, 114, 10915. Martinesker, A. A.; Johnson, C. C.; Horner, J. H.;
Newcomb, M. J. Am. Chem. Soc. 1994, 116, 9174. Guthrie, J. P.; Guo, J. N.
J. Am. Chem. Soc. 1996, 118, 11472. Guthrie, J. P. J. Am. Chem. Soc. 2000, 122,
5529. Lewis, F. D.; Kalgutkar, R. S.; Wu, Y.; Liu, X.; Liu, J.; Hayes, R. T.;
Miller, S. E.; Wasielewksi, M. R. J. Am. Chem. Soc. 2000, 122, 12346.
Newcomb, M.; Makek, M. B.; Glenn, A. G. J. Am. Chem. Soc. 1991, 113,
949. Yoo, H. Y.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 2877. Alabugin,
I. V.; Manoharan, M.;Breiner, B.; Lewis, F. J. Am. Chem. Soc. 2003, 125, 9329.
(25) Frish, M. J. et al., Gaussian 03, Revision E.01; Gaussian, Inc.,
Wallingford CT, 2004.
(26) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(27) The NBO 4.0 Program: Glendening, E. D.; Badenhoop, J. K.; Reed,
A. E.; Carpenter, J. E.; Weinhold, F. Theoretical Chemistry Institute,
University of Wisconsin, Madison, WI, 1996.
(28) Wolinski, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112,
8251.
(29) Hehre, W. J.; Ditchfield, R.; Radom, L.; Pople, J. A. J. Am. Chem.
Soc. 1970, 92, 4796.
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TABLE 2. Reaction Energies for the Anionic 5-Exo and 6-Endo Closures and Formal 5-Exo f 6-Endo Isomerization at the PCM-SCRF B3LYP/
6-31þG(d,p)//B3LYP/6-31þG(d,p) Level of Theorya
aThe data are given for T = 298.15 K, solvent = ethanol; all energies are in kcal/mol.
TABLE 3. Reaction Energies for the Formal 5-Exo and 6-Endo Closures and 5-Exo f 6-Endo Isomerization of the Neutral Hydrazides at the PCM-
SCRF B3LYP/6-31þG(d,p)//B3LYP/6-31þG(d,p) Level of Theorya
aThe data are given for T 298.15 K, solvent = ethanol; all energies are in kcal/mol.
stabilization to the anionic center, imparting larger stability
to the R-anion. The calculated ca. 14 kcal/mol difference in
stability does not depend strongly on the nature of substi-
tuent at the triple bond. As a result, all cyclizations of the less
stable β-anion have to carry an additional energy penalty
and, thus, are unlikely to be competitive unless their activa-
tion energies are sufficiently low to overcome this handicap
(vide infra) (Scheme 8).
Interestingly, the cyclic carbanions have relatively high
energy and several of the calculated ring closures are pre-
dicted to be endothermic. This finding contrasts sharply with
the high exothermicity of analogous cyclizations of carbon
centered reactive species32 where the gain in stability due to
the transformation of a relatively weak acetylenic π-bond
into a stronger σ-bond is not partially offset by the con-
comitant transformation of a relatively stable nitrogen anion
into a less stable carbanion. On the other hand, exothermi-
city of the anionic cyclizations is increased dramatically
upon prototropic isomerization of the initially formed car-
banions into N-anions. The computational data suggest that
such tautomerizations are likely to play the key role in
driving these cyclizations to completion.
Overall, the calculated energies suggest that the formal
6-exo product for R = Ph and 6-endo product for R = alkyl
are likely to be formed under thermodynamic control con-
ditions leading to the formation of the most stable product.
Substituent effects at the relative enthalphies for the forma-
tion of 5-exo and 6-endo products in their anionic form at
T = 298.15 K are given in Table 2. The calculated energetic
preference for the formation of six-membered cycles suggests
that the experimental preference for the formation of the
5-membered cycle for R = C6H4OCH3, C6H5, C6H4Br,
C6H4NO2 results from kinetic, rather from thermodynamic,
control. In accord with the experimental results, computa-
tions suggest that formation of the five-membered products
is most favorable for the aromatic substituents whereas
(32) See for example: Alabugin, I. V.; Manoharan, M. J. Am. Chem. Soc.
2005, 127, 95345. Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark,
R. J.; Alabugin, I. V. Org. Lett. 2004, 6, 2457. Also see refs 4 and 9.
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TABLE 4. Computed Activation and Reaction Energies for Competing Anionic Cyclizations of the Two CoNjugate Bases of Aryl Hydrazides at the
B3LYP/6-31þG** Levela
c
aZ-isomer is more stable than E-isomer by 6.1 (2.3) kcal/mol. bZ-isomer is more stable than E-isomer by 4.5 (3.0) kcal/mol. The Z-isomer of
protonated product is less stable than E-isomer by 0.2 (1.9) kcal/mol. dThe Z-isomer of protonated product (experimentally observed) is less stable than
E-isomer than E by 1.9 (2.7) kcal/mol. eComputed from PCM-SCRF solvation model. aR = methyl and phenyl (values in parentheses). Solvation effects
are estimated with single point PCM-SCRF B3LYP/6-31þG**//B3LYP/6-31þG** calculations. Eo corresponds to the intrinsic activation energy
obtained from the Marcus equation. See Figure 2 for the product structures.
R. In particular, as the acceptor properties increase in the
series R = C4H9 f C6H4OCH3 f C6H5 f C6H4Br f
C6H4NO2, the relative stability of the six-membered cycle
decreases. The analogous dependence, with the exception of
R = C4H9, is observed for the cycle formation: exothermi-
city for the five- and six-membered-ring formation increases
in the R = C6H4OCH3 f C6H5 f C6H4Br f C6H4NO2
series.
Higher stability of the 6-endo products can be explained
by greater aromaticity of the newly formed ring, as suggested
by the more negative Nucleus Independent Chemical Shift
(NICS) values in Figure 1. The NICS value at a distance of
˚
1 A from the ring centers (NICS(1) value) is a convenient
magnetic measure of aromaticity that generally correlates
with aromatic stabilization as well.33 Typically, more nega-
tive NICS found at the center of ring systems indicates the
presence of diatropic ring current and an aromatic system
whereas positive NICS indicates paramagnetic ring current
and antiaromaticity.
Kinetic Competition between 5-Exo-, 6-Endo-, and 6-Exo
Cyclizations. Potential energy surfaces for the three anionic
closures (5-exo, 6-endo, and 6-exo) for the parent aryl-
substituted hydrazide (R = Ph) are presented in Figure 2.
The 5-exo-dig closure is clearly kinetically favored in this
system. Interestingly, although the activation barrier is lower
for the formation of the Z-isomer of the cyclic anion B2
(corresponding to the experimentally observed Z-product),
the E-form of the cyclic anion B3 is slightly more stable in the
product (we will discuss the origin of this effect in the
following section). Because the 5-exo cyclization is 7-
10 kcal/mol exothermic, ring-opening of the 5-exo product
should be relatively slow, thus providing additional time
for the prototropic isomerization into a nitrogen-centered
anion B4 to occur. The 6-endo-dig cyclization has a notice-
ably higher barrier (∼15 kcal/mol) and should be kinetically
FIGURE 1. Nucleus independent chemical shift (NICS(1) in ppm)
data for the products of 5-exo-dig and 6-endo-dig cyclizations
computed at the B3LYP/6-311þG**// B3LYP/6-31þG** level.
formation of the six-membered product may be expected for
R = alkyl. As expected, the relative stability of the five-
membered cycle increases in parallel to the increase
of acceptor ability of substituent R (R = C4H9 f C6H4-
OCH3 f C6H5 f C6H4Br f C6H4NO2).
Again, all anionic cyclizations in Table 2 do not have the
strong thermodynamic driving force due to the unfavorable
transformation of a nitrogen anion into a less stable carba-
nion. Interestingly, inclusion of solvation further decreases
exothermicities of these cyclizations and even renders some
of them endothermic. The lower yield of the 5-exo cyclization
for R = p-OMe-Ph (67%) is consistent with the prediction
that this reaction is essentially thermoneutral, whereas the
higher yielding 5-exo cyclizations for R = p-Br-Ph, p-NO2-
Ph (∼90%) are predicted to be noticeably exothermic.
For the neutral acyclic starting materials and cyclized
products, the relative energies (Table 3) do not bear the
above energy penalty for the transformation of nitrogen
anions into carbanions. As a result, the relative trends in
stability for the neutral molecules more accurately reflect the
gain in stability due to the conversion of acetylenic π-bonds
into stronger C-N σ-bonds. Consequently, the stability of
the cyclic products relative to the acyclic starting materials
increases significantly in comparison to their anionic coun-
terparts in Table 2. Although formation of both five- and six-
membered cycles is exothermic, the 6-membered cycles are
more stable. The relative stability of cyclic compounds
correlates with the donor-acceptor properties of substituent
(33) For the details of NICS calculations, see: Schleyer, P. v. R.; Maerker,
C.; Dransfeld, A.; Jiao, H.; van Eikema Hommes, N. J. R. J. Am. Chem. Soc.
1996, 118, 6317. Schleyer, P. v. R.; Manoharan, M.; Wang, Z. X.; Kiran, B.;
Jiao, H.; Puchta, R.; van Eikema Hommes, N. J. R. Org. Lett. 2001, 3, 2465.
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FIGURE 2. Full potential energy surface for the competing 6-endo, 5-exo, and 6-exo anionic cyclizations of hydrazide anions A and B. All
energies of stationary point geometries are given relative to the most stable hydrazide anion (compound B in Scheme 8) at the B3LYP/
6-31þG** level.
disfavored compared to the 5-exo-dig cyclizations (Ea =
8-9 kcal/mol).
preference. Moreover, the 5-exo-dig cyclization is predicted
to be endothermic and readily reversible in this case, whereas
the 6-endo-dig closure is ∼10 kcal/mol exothermic.
The ∼15 kcal/mol barrier for 6-exo-dig cyclization of the
β-anion is comparable to the barrier for the 6-endo-dig
closure of the R-anion B. However, the lower stability of
the β-anion A raises the overall 6-exo cyclization barrier up
to ca. 29 kcal/mol (according to the Curtin-Hammett
principle). Since both 5-exo and 6-endo barriers for the R-
anion cyclizations are much lower, the formal 6-exo products
A1 and A2 described in Scheme 6 cannot be accessed directly
from the acyclic hydrazide anion under the kinetic control
conditions. Instead, the formal 6-exo products stem from an
alternative rearrangement path discussed earlier (Scheme 7).
Tautomerization of the 6-exo products into a nitrogen-
centered anion A3 provides the most stable structure on
the overall potential energy surface (∼36 kcal/mol lower
than the hydrazide R-anion B and ∼50 kcal/mol lower than
the β-anion A).
Activation energies summarized in Table 4 clearly show
that substituents at the alkyne moiety have a strong effect on
the competition between the 5-exo and 6-endo cyclization of
the R-anion. Decreased 5-exo-dig activation energies and
increased stability of the 5-exo products for R = Ph confirm
that the Ph group steers the cyclization selectively down the
5-exo path by providing benzylic stabilization to the anionic
center in the product. In contrast, the competition between
the 5-exo and 6-endo-dig closures is rather close for R = Me.
In this case, the values of cyclization barriers are within
1 kcal/mol of each other and thus both cyclizations can
proceed with comparable rates. Although the 5-exo cycliza-
tion has a 0.6 kcal/mol lower barrier than the 6-endo closure
in the gas phase, introduction of solvation reverses this subtle
Higher values for the computed activation barriers for both
cyclizations of alkyl-substituted alkynes are consistent with
our ability to isolate the hydrazide intermediate under the
conditions where aryl-substituted substrates undergo fast
5-exo closure (Scheme 4). Overall, computational results are
in excellent agreement with the experimental observations.
The above reactions of anionic nucleophiles are less
exothermic than the topologically similar cyclizations of
other reactive intermediates.34 To understand the role of
thermodynamic factors on the cyclization rates and to compare
intrinsic stereoelectronic factors involved in the three cycliza-
tions, we separated intrinsic barriers (Eo in Table 4) from the
variable thermodynamic contributions using Marcus theory.
We have used this approach in the past for the analysis of
radical cyclizations of alkynes.34 The present work provides the
first application of this approach to anionic cyclizations.
A more detailed comparison of calculated activation
barriers and their intrinsic components of 5-exo and 6-endo
anionic cyclization with the same parameters for the topo-
logically analogous cyclizations of vinyl radicals is given in
Scheme 9. Both anionic cyclizations are predicted to be much
slower than the radical processes despite the obvious simi-
larity in the cyclization patterns. Marcus dissection clearly
illustrates that the reason for the higher barriers for the
(34) (a) Alabugin, I. V.; Manoharan, M. J. Comput. Chem. 2007, 28, 373.
(b) Alabugin, I. V.; Manoharan, M. J. Org. Chem. 2004, 69, 9011. (c)
Alabugin, I. V.; Manoharan, M.; Zeidan, T. A. J. Am. Chem. Soc. 2003,
125, 14014. (d) Alabugin, I. V.; Zeidan, T. A. J. Am. Chem. Soc. 2002, 124,
3175. (e) Alabugin, I. V. J. Org. Chem. 2000, 65, 3910.
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SCHEME 9. Comparison of Total and Intrinsic Activation
Barriers (kcal/mol) for 5-Exo-Dig and 6-Endo-Dig Cyclizations
of N-Anions and C-Radicals
TABLE 5. Relative Energies of the Stereoisomers of the 5-Exo and 6-
Exo Anionic Cyclization Products B2/B3 and A1/A2 along with Energies
of Selected Hyperconjugative Interactions (B3LYP/6-31þG**) a
5-exo (Z)
5-exo (E)
6-exo (Z)
6-exo (E)
relative energy
E(nC-fσ*C-N
E(nC-fσ*C-C
E(nC-fσ*N-H
4.5 (3.0)
27.2 (24.8) 6.3 (7.9)
1.5 (2.8)
0.0 (0.0)
10.6 (11.6) 16.7 (13.9)
21.7 (21.5) 4.9 (7.8)
)
)
)
18.2 (17.1) 1.2 (2.4)
NA
18.3 (17.4)
NA
NA
11.2 (7.5)
aEnergies are given in kcal/mol, data for R=Ph are in parentheses,
structures are given in Scheme 10.
anionic cyclizations lies in their lower exothermicity. Once
the thermodynamic factors are removed, intrinsic barriers
for these two anionic cyclizations become slightly lower than
those for the radical counterparts. It is also interesting that,
independent of the type of reaction species (nitrogen anion
or carbon radical), the 5-exo-dig cyclization remains stereo-
electronically preferred to the 6-endo-dig ring closure as
evidenced by the lower intrinsic 5-exo barriers.
The Origin of Z-Stereoselectivity in the 5-Exo Cyclizations
and Competition of Stereoelectronic Hyperconjugative Effects
in Cyclized Carbanions. Our computational analysis yielded
several interesting observations regarding relative energies of
stereoisomeric anions formally corresponding to products of
5-exo and 6-exo-dig cyclizations. Although stereochemical
information is lost during the prototropic isomerization of
the formal 6-exo products into experimentally observed
benzopyridazinones 6, the 5-exo cyclization proceeds stereo-
selectively and affords only Z-isomer of the product. This
result is fully consistent with the lower calculated barrier for
the formation of the Z-isomer.
An unusual observation is that although the transition
state energy for the 5-exo-dig cyclization leading to the
Z-isomer is lower than that for the analogous cyclization
of the E-isomer, the relative stability of the two cyclized
anions is opposite to that of the transition states. Taking into
account our long-standing interest in hyperconjugative
stereoelectronic effects,34 we analyzed delocalizing hypercon-
jugative interactions in the key anionic species using Natural
Bond Orbital (NBO) analysis. Similar interactions which
FIGURE 3. Competion of nC- f σ*C-N vicinal hyperconjugation
in the Z-anionic product of the 5-exo-dig closure and C H-N
3 3 3
H-bonding and nC- f σ*C-C vicinal hyperconjugation in the
E-anion.
involve σ bonds manifest themselves in numerous stereoelec-
tronic effects controlling organic structure and reactivity.35,36
In particular, hyperconjugation influences conformational
equilibria,37,38 modifies reactivity,39 determines selectivity,40
and is enhanced dramatically in excited, radical, and ionic
species.41 In the following part, we will show that observed
stereoselectivity stems from an interesting interplay of hyper-
conjugative effects which are developed to a different extent at
the different stages of the cyclization process.
NBO analysis identified an extremely strong hyperconjuga-
tive nC- f σ*C-N interaction of anionic carbon orbital and
antiperiplanar acceptor C-N bond34d in the Z-isomer. The
analogous interaction between these orbitals is significantly
lower in the E-isomer due to the less favorable syn-arrangement
of the two interacting orbitals. Evidently, this interaction is
developed already in the TS providing a favorable stabilizing
(38) (a) Reed, A. E.; Weinhold, F. Isr. J. Chem. 1991, 31, 277. (b)
Goodman, L.; Pophristic, V.; Gu, H. J. Chem. Phys. 1999, 110, 4268. (c)
Goodman, L.; Pophristic, V.; Weinhold, F. Acc. Chem. Res. 1999, 32, 983. (d)
Schreiner, P. R. Angew. Chem., Int. Ed. 2002, 41, 3579. (e) Cramer, C. J.
THEOCHEM 1996, 370, 135.
(39) Baddeley, G. Tetrahedron Lett. 1973, 14, 1645. Chang, J.-W. A.;
Taira, K.; Urano, S.; Gorenstein, D. G. Tetrahedron 1987, 43, 479. Um, I. H.;
Chung, E. K.; Lee, S. M. Can. J. Chem. 1998, 76, 729. Deslongchamps, P.
Tetrahedron 1975, 31, 2463. Doddi, G.; Ercolani, G.; Mencarelli, P. J. Org.
Chem. 1992, 57, 4431. Roberts, B. P.; Steel, A. J. Tetrahedron Lett. 1993, 34,
5167. Sato, M.; Sunami, S.; Kaneko, C. Heterocycles 1995, 42, 861 and
references cited therein. Wagner, P. J.; Scheve, B. J. J. Am. Chem. Soc. 1977,
99, 1858. Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu, X.;
So, J. -H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 18. Borden, W. T.
J. Chem. Soc., Chem. Commun. 1998, 1919. Maier, M. E. Angew. Chem., Int.
Ed. 2000, 39, 2073. Kleinpeter, E.; Rolla, N.; Koch, A.; Taddei, F. J. Org.
Chem. 2006, 71, 4393.
(35) (a) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer-Verlag: Berlin, Germany, 1983. (b) The Anomeric
Effect and Associated Stereoelectronic Effects; Thatcher, G. R. J., Ed.; ACS
Symp. Ser. No. 539; American Chemical Society: Washington, DC, 1993. (c)
Juaristi, E.; Guevas, G. The Anomeric Effect; CRC Press: Boca Raton, FL, 1994.
(d) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev 1988, 88, 899. (e) Juaristi,
E.; Cuevas, G. Acc. Chem. Res. 2007, 40, 961.
(36) Cohen, T.;Lin, M.-T. J. Am. Chem. Soc. 1984, 106, 1130. Danishefsky,
S. J.; Langer, M. Org. Chem. 1985, 50, 3672. Rychnovsky, S. D.; Mickus, D. E.
Tetrahedron Lett. 1989, 30, 3011. Vedejs, E.; Dent, W. H. J. Am. Chem. Soc.
1989, 111, 6861. Juaristi, E.; Cuevas, G.; Vela, A. J. Am. Chem. Soc. 1994, 116,
5796. Salzner, U.;Schleyer, P. v.R.J. Org. Chem. 1994,59, 2138. Vedejs, E.; Dent,
W. H.;Kendall, J. T.;Oliver, P. A.J. Am. Chem. Soc. 1996, 118, 3556. Cuevas, G.;
Juaristi, E.; Vela, A. THEOCHEM 1997, 418, 231. Anderson, J. E.; Cai, J.;
Davies, A. G. J. Chem. Soc., Perkin Trans. 2 1997, 2633. Wiberg, K. B.; Hammer,
J. D.; Castejon, H.; Bailey, W. F.; DeLeon, E. L.; Jarret, R. M. J. Org. Chem.
1999, 64, 2085. Juaristi, E.; Rosquete-Pina, G. A.; Vazquez-Hernandez, M.;
Mota, A. J. Pure Appl. Chem 2003, 75, 589.
(40) Beckwith, A. L. J.; Duggan, P. J. Tetrahedron, 1998, 54, 6919 and the
examples cited therein.
(41) (a) Muller, N.; Mulliken, R. S. J. Am. Chem. Soc. 1958, 80, 3489. For
more recent examples, see: (b) Stability of R-sulfonyl carbanions: Raabe, G.;
Gais, H. J.; Fleischhauer, J. J. Am. Chem. Soc. 1996, 118, 4622. (c)
Carbocations: Rauk, A.; Sorensen, T. S.; Maerker, C.; Carneiro, J. W. d. M.;
Sieber, S.; Schleyer, P. v. R. J. Am. Chem. Soc. 1996, 118, 3761. (d) Kirchen,
R. P.; Ranganayakulu, K.; Sorensen, T. S. J. Am. Chem. Soc. 1987, 109, 7811.
(42) Keith, B.; Khalaf, D.; Ghadir, F. J. Chem. Soc., Perkin Trans. 1990,
1333.
(37) Juaristi, E., Ed. Conformational Behavior of Six-Membered Rings;
VCH Publishers: New York, 1995. See also: Romers, C.; Altona, C.; Buys,
H. R.; Havinga, E. Top. Stereochem. 1969, 4, 39. Zefirov, N. S.; Schechtman,
N. M. Usp. Khim. 1971, 40, 593. Juaristi, E.; Cuevas, G. Tetrahedron 1992, 48,
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SCHEME 10. Relative Stabilities in the Pairs of Stereoisomeric Cyclization Products at the B3LYP/6-31þG** Level
Energies are given in kcal/mol; data for R = Ph are in parentheses.
SCHEME 11. Summary of accessible reaction pathways with the most likely intermediates for the anionic transformations of hydrazides
of o-ethynyl substituted benzoic acids
interaction, which facilitates cyclization of the Z-isomer.
Although the competing nC- f σ*C-C interaction with
another vicinal antibonding orbital selectively stabilizes the
opposite E-isomer, the latter interaction is weaker because of
the weaker acceptor ability of σ*C-C orbitals in comparison
with that of σ*C-N orbitals34d (Table 5).
The last remaining question is why the E-product is
more stable despite the less favorable pattern of vicinal
hyperconjugative interactions. The effect responsible for
this switch in the relative stability has to develop relatively
late along the reaction coordinate (after the transition
state is passed) in order to explain the reversal of relative
stability of the TS and products for the two stereoisomers.
NBO analysis answers this question by detecting an in-
tramolecular H-bonding interaction between the anionic
carbon and an N-H bond of the exocyclic NH2 group.
This interaction only fully develops at the late reaction
stage in the E-conformer of the 5-exo-product (when the
anionic center and the N-H bond are brought closer in the
cyclization step) and thus is not capable of influencing the
E-transition state and perturbing kinetic competion between
the two isomers. Since we do not observe formation of the
more stable E-isomer, external protonation of the cyclic
carbanions should be faster than conversion between the
two stereoisomers. Taking into account that this reaction is
carried out in ethanol as a solvent, this scenario is plausible.
Conclusion
In summary, cyclizations of hydrazides of o-acetylenyl
benzoic acids under basic conditions can be directed along
three alternative paths depending on the external factors
and the nature of substituents at the acetylenic moiety.
Alkyl substituents at the alkyne terminus favor the 6-endo-
dig closure whereas aryl groups greatly fascilitate the alter-
native 5-exo-dig path. Synthetic utility of these processes is
amplified by rearrangement of the initial 5-exo-dig cyclization
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Vasilevsky et al.
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products into diazinone products of a formal 6-exo-dig cycli-
zation via the less reactive external nitrogen participation. The
latter process proceeds in an indirect way, through a sequence
of nucleophilic attack, ring-opening, and recyclization which
is negotiated through several proton shifts, ultimately leading
to the most stable of tautomeric anions as a thermodynamic
sink. The most likely reaction intermediates identified by the
DFT analysis of potential energy surfaces for the competiting
rearrangements are summarized in Scheme 11. Trends dis-
covered in this work allow selective transformation of a
common precursor into benzopyrrolidones, benzopyrida-
zones, or benzodiazinones—three promising biologically
active classes of annealed heterocycles.
Finally, NBO analysis reveals that stereoelectronic hyper-
conjugative σC- f σ*C-N interactions efficiently control
stereoselectivity of 5-exo-dig cyclization providing a kine-
tically favorable pathway to the thermodynamically unfa-
vorable Z-isomer. Intramolecular H-bonding selectivily
stabilizes the E-isomer of the product but develops at the
later reaction stage, after the TS.
The reaction mixture was dried in vacuum, redissolved in
benzene, and filtered through Al2O3 (2.5 ꢀ 2 cm). After
removal of benzene under vacuum, the product was crystallized
from EtOH to afford 30 mg (75%) of 5d: mp 75-76 ꢀC (from
EtOH); IR ν/cm-1 1645 (CdO); HRMS, found m/z 216.1254
1
[M]þ; C13H16N2O calcd M = 216.1257; H NMR (CDCl3,
400.13 MHz) δ 0.96(3H, t, Me, J = 7.2 Hz), 1.43-1.76 (4H, m,
H-10, H-11), 2.83 (2H, t, H-9, J = 7.6 Hz), 4.95 (2H, s, NH2),
6.33 (1H, s, dCH), 7.46-7.60 (3H, m, H-5, H-6, H-7), 8.34
(1H, d, H-8, J = 8 Hz); 13C NMR δ 13.7 (C-13), 22.2 (C-12),
30.4 (C-11), 32.0 (C-10), 103.7 (C-4), 123.3 (C-3), 125.2 (C-6),
125.5 (C-7), 127.3 (C-5), 131.9 (C-8), 136.2 (C-5a), 144.6
(C-8a), 162.2 (C-1). Anal. Calcd for C13H16N2O: C 72.19;
H 7.46; N 12.95. Found: C 72.12; H 7.46; N 12.63.
4-(4-Methoxybenzyl)phthalazin-1(2H)-one, 6a. A mixture of
2 mmol of isoindolinone 3a and 2 mmol of KOH was refluxed in
5 mL of EtOH (TLC control, EtOAc) for 2 h.
Experimental Section
(Z)-N-Amino-3-(4-nitrobenzylidene)isoindolin-1-one, 3c.
A
mixture of 2.8 mmol of methyl ethynylbenzoate (1c)42 and
4.2 mmol of 80% NH2NH2 H2O were refluxed in 5 mL of
3
The reaction mixture was dried under vacuum, redissolved in
benzene, and filtered through Al2O3 (2.5 ꢀ 2 cm). After
removal of benzene under vacuum, the product was crystallized
from EtOH. Compound 6a (3 h, 70%): mp 193.5-194.5 ꢀC
(from C2H5OH); IR ν/cm-1 1665 (CdO); HRMS, found m/z
266.1052 [M]þ; C16H14N2O2 calcd M = 266.1050; 1H NMR
(CDCl3, 300.13 MHz) δ 3.74 (3H, s, OCH3), 4.22 (2H, s, CH2),
6.80 (2H, d, H-12, H-14, J = 8.4 Hz), 7.17 (2H, d, H-11, H-15,
J = 8.4 Hz), 7.71-7.76 (3H, m, H-5, H-6, H-7), 8.45 (1H, d, H-
8, J = 9.6 Hz), 10.58 (1H, s, NH); 13C NMR δ 37.9 (C-9), 55.1
(C-OMe), 114.0 (C-12, C-14), 122.9 (C-8a), 125.3 (C-5), 126.8
(C-8), 128.2 (C-10), 129.3 (C-11, C-15), 129.6 (C-4a), 131.1
(C-7), 133.3 (C-6), 146.5 (C-4), 158.2 (C-13), 160.4 (C-1). Anal.
Calcd for C16H14N2O2: C 72.16; H 5.30; N 10.52. Found:
C 72.25; H 5.27; N 10.58.
ethanol for 7 h until full disappearance of the ester (TLC
monitoring, CH2Cl2, EtOAc).
The reaction mixture was cooled and the precipitate was
filtered off. Recrystallization from EtOH afforded com-
pound 3c (90%), mp 246-246.5 ꢀC (from C2H5OH): IR
ν/cm-1 1716 (CdO); HRMS, found m/z 281.0802 [M]þ;
C15H11N3O3 calcd M = 281.0800; 1H NMR (CDCl3,
400.13 MHz) δ 4.31 (2H, s, NH2), 7.02 (1H, s, dCH),
7.39-7.48 (3H, m, H-4,5,6), 7.66 (2H, d, H-10, 14, J =
8.4 Hz), 7.86 (1H, d, H-3, J = 7.6 Hz), 8.29 (2H, d, H-11,
H-13, J = 8.4 Hz); 13C NMR δ 108.9 (C-8), 122.5 (C-4), 123.3
(C-7), 123.7 (C-10,14), 128.4 (C-3), 129.8 (C-6), 129.9 (C-11,
C-13), 130.1 (C-5), 132.3 (C-3a), 137.4 (C-7a), 142.3 (C-9),
146.6 (C-12), 165.1 (C-1). Anal. Calcd for C15H11N3O3:
C 64.05; H 3.94; N 14. Found: C 63.89; H 3.61; N 14.99.
N-Amino-3-butylisoquinolin-1-one, 5d. A mixture of 40 mg
(1.9 mmol) hydrazide 4d and 10 mg (1.9 mmol) of KOH was
refluxed in 5 mL of EtOH until full disappearance of the
hydrazide (2 h, TLC control, EtOAc).
Acknowledgment. This work was supported by a grant
from RFBR 07-03-00048-a, an Interdisciplinary grant from
SB of the Russian Academy of Sciences No. 93 (2009-2011),
an Intergrational grant from the Russian Academy of
Sciences 5.9.3. (2009-2011), and the Chemical Service Center
of SB RAS. I.A. is grateful to the National Science Founda-
tion (CHE-0848686) and to the donors of Petroleum
Research Fund, administered by the American Chemical
Society (Award no. 47590-AC4) for partial support of his
research at FSU.
Supporting Information Available: Full experimental de-
tails, NMR assignments, geometries and energies of calculated
intermediates, and full reference 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 21, 2009 8117