Studies of the generation and pericyclic behavior of cyclic pentadienyl carbanions. Alkylation reactions as an efficient route to functionalized cis-bicyclo[3.3.0]octenes

Article abstract of DOI:10.1021/ja063243l

Carbolithiation has been studied with alkyllithium reagents in a series of six- through nine-membered 3-methylene-1,4-cycloalkadienes, efficiently producing the corresponding cyclic pentadienyl carbanions. These pentadienyl anions display unique reactivit

Full text of DOI:10.1021/ja063243l

Published on Web 08/29/2006
Studies of the Generation and Pericyclic Behavior of Cyclic
Pentadienyl Carbanions. Alkylation Reactions as an Efficient
Route to Functionalized cis-Bicyclo[3.3.0]octenes
David R. Williams,* Jonathan T. Reeves, Partha P. Nag, William H. Pitcock, Jr., and
Mu-Hyun Baik*
Contribution from the Department of Chemistry & School of Informatics, Indiana UniVersity,
Bloomington, Indiana 47405-7102
Received May 9, 2006; E-mail: williamd@indiana.edu; mbaik@indiana.edu
Abstract: Carbolithiation has been studied with alkyllithium reagents in a series of six- through nine-
membered 3-methylene-1,4-cycloalkadienes, efficiently producing the corresponding cyclic pentadienyl
carbanions. These pentadienyl anions display unique reactivity, depending on ring size. Cyclooctadienyl
anions readily undergo disrotatory electrocyclization to cis-bicyclo[3.3.0]octenyl systems, which are trapped
with a variety of electrophiles to stereoselectively provide functionalized cis-bicyclo[3.3.0]octenes. The
carbolithiation and electrocyclization processes are examined using low-temperature 1H NMR experiments.
An expedient synthesis of a linear triquinane illustrates this methodology. Electrocyclization of the
corresponding cyclononadienyl anion requires unusually high temperatures (120 °C), and computational
studies provide insights into this change in reactivity. Cycloheptadienyl and cyclohexadienyl anions,
generated via carbolithiation, provide functionalized cycloheptadienes and cyclohexadienes upon electrophilic
capture. Trapping experiments reveal that the cycloheptadienyl anions are transformed to heptatrienyl anions.
A series of experiments have been designed to explore evidence for the feasibility of equilibration of open
and closed anionic systems, and these studies report the first isolation of a cis-bicyclo[3.1.0]hexene derived
from electrocyclization of a cyclohexadienyl carbanion.
treatise.4 Their conclusions regarding electrocyclic reactions
predicted that charged species should behave in analogous
Introduction
Thermal and photochemical electrocyclizations have played
a prominent role in our understanding of both synthetic and
physical organic chemistry.1 An early example of thermal
electrocyclization, or “valence tautomerism”, of 1,3,5-cyclo-
octatriene to cis-bicyclo[4.2.0]octa-2,4-diene was first disclosed
by Cope2 in 1950, and the dynamics of the equilibrium were
subsequently explored by Winstein.3 The conservation of orbital
symmetry and the stereospecific nature of the electrocyclization
were significant components of the Woodward and Hoffmann
fashion as the corresponding isoelectronic neutral system.4a
A
pioneering report by Bates and co-workers in 1969 confirmed
this prediction for the anionic equivalent of cyclooctatriene, with
the observation of the disrotatory conversion of cyclooctadi-
enyllithium to cis-bicyclo[3.3.0]octenyllithium.5 Since this
discovery, surprisingly few reports of electrocyclic ring closures
of pentadienyl anions have appeared. The low-yield conversion
of 1,5-diphenylpentadienyl anion to isomeric diphenylcyclo-
pentenes under harsh reaction conditions was disclosed and
remains the only example, to date, of an acyclic, all-carbon
pentadienyl anion electrocyclization.6 Additional reports have
described attempts at cyclization of cyclic7 and acyclic8 pen-
tadienyl anions. In the context of studies toward new strategies
for natural product total synthesis, we proposed to investigate
the nature of this anionic electrocyclic ring closure in a cascade
reaction in which the requisite pentadienyl system is generated
through the initial carbolithiation9 of triene 1 (Figure 1), inspired
by the well-known addition of organometallic reagents to the
6-position of fulvenes to give cyclopentadienyl anions (Eq. 1).10
(1) (a) Lehr, R. E.; Marchand, A. P. Orbital Symmetry: A Problem SolVing
Approach; Academic: New York, 1972. (b) Gill, G. B.; Willis, M. R.
Pericyclic Reactions; Chapman and Hall: London, 1974. (c) Fleming, I.
Frontier Orbitals and Organic Chemical Reactions; Wiley & Sons:
Chichester, U.K., 1976; Chapter 4. (d) Pericyclic Reactions; Lehr, R. E.,
Marchand, A. P., Eds.; Academic: New York, 1977; Vol 1. (e) Pericyclic
Reactions; Lehr, R. E., Marchand, A. P., Eds.; Academic: New York, 1977;
Vol 2. (f) Gilchrist, T. L.; Storr, R. C. Organic Reactions and Orbital
Symmetry, 2nd ed.; Cambridge University Press: Cambridge, U.K., 1979;
Chapter 3. (g) Desimoni, G.; Tacconi, G.; Barco, A.; Pollini, G. P. Natural
Products Synthesis Through Pericyclic Reactions; American Chemical
Society: Washington, DC, 1983. (h) ComprehensiVe Organic Synthesis:
SelectiVity, Strategy and Efficiency in Modern Organic Chemistry; Paquette,
L. A., Ed.; Pergamon: Oxford, U.K., 1992; Vol. 5, pp 675-784. (i)
Fleming, I. Pericyclic Reactions; Oxford University Press: New York, 1999;
Vol. 67, Chapter 4. (j) Sankararaman, S. Pericyclic ReactionssA Text-
book: Reactions, Applications and Theory; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim, 2005.
(4) (a) Woodward, R. B.; Hoffmann, R. H. J. Am. Chem. Soc. 1965, 87, 395-
397. (b) Woodward, R. B.; Hoffmann, R. H. The ConserVation of Orbital
Symmetry; Academic Press: Weinheim, Germany, 1971.
(2) (a) Cope, A. C.; Hochstein, F. A. J. Am. Chem. Soc. 1950, 72, 2515-
2520. (b) Cope, A. C.; Haven, A. C.; Ramp, F. L.; Trumbull, E. R. J. Am.
Chem. Soc. 1952, 74, 4867-4871.
(3) (a) Glass, D. S.; Zirner, J.; Winstein, S. Proc. Chem. Soc. 1963, 276-277.
(b) Glass, D. S.; Watthey, J. W. H.; Winstein, S. Tetrahedron Lett. 1965,
6, 377-388.
(5) Bates, R. B.; McCombs, D. A. Tetrahedron Lett. 1969, 12, 977-978.
(6) Shoppee, C. W.; Henderson, G. N. Chem. Commun. 1974, 561-562.
(7) Bates, R. B.; Deines, W. H.; McCombs, D. A.; Potter, D. E. J. Am. Chem.
Soc. 1969, 91, 4608.
(8) Hunter, D. H.; Sim, S. K.; Steiner, R. P. Can. J. Chem. 1977, 55, 1229.
9
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A R T I C L E S
Williams et al.
Figure 1. Concept for the carbolithiation/electrocyclization/alkylation cascade.
Disrotatory ring closure of the cyclooctadienyl anion 2 to the
cis-bicyclo[3.3.0]octenyl anion 3 and subsequent electrophilic
capture of 3 would stereoselectively provide the functionalized
cis-bicyclo[3.3.0]octene 4. This reaction cascade would allow
formation of three C-C bonds and three stereogenic sites in a
single operation from simple starting materials. The variation
of three reaction components would potentially allow for
substantial diversity in product structures. In this account, we
report the successful realization of this process, its scope with
respect to organolithium reagents and electrophile participation,
proton NMR analysis of the reaction, and its application for
preparation of a linear triquinane.11 Our investigations describe
the unique reactivity observed upon the extension of this concept
to six-, seven-, and nine-membered ring substrates.
with warming to 22 °C over 1-2 h resulted in complete
carbolithiation and electrocyclic ring closure. Quenching of the
resultant cis-bicyclo[3.3.0]octenyl anion at -78 °C with a
solution of electrophile in THF or Et2O led to the isolation of
products. The scope of the reaction was explored as summarized
in Table 1. Typical examples of primary, secondary, and tertiary
alkyllithium reagents proved to be uniformly effective for the
generation of pentadienyl anions, and a wide variety of
electrophiles were used as quenching agents. Phenyl-, allyl-,
methyl-, and vinyllithium species and Grignard reagents failed
to provide for carbometalation. The generation of secondary
and primary alkyllithium reagents from the corresponding alkyl
iodides by lithium/halogen exchange with tert-butyllithium
(entries 8 and 11) demonstrates the possibility for broader
applications of this reaction component and the compatibility
of base-stable functionality. The nucleophilicity of the inter-
mediate bicyclic allyllithium species 3 (Figure 1) enabled
efficient trapping with a range of electrophiles. Alkylation
reactions with ketones, aldehydes, and CO2 (entries 1-3 and
7-11) led to formation of a new C-C bond, while heteroatomic
electrophiles (entries 4-6) introduced allylic sulfide, alcohol,
and silane moieties. Transmetalation of the intermediate cis-
bicyclo[3.3.0]octenyllithium species 3 using a THF solution of
CuCN‚2LiCl was also possible.15 The resultant allylcuprates
efficiently engaged in C-C bond-forming conjugate additions
with R,â-unsaturated ketones and esters in the presence of
TMSCl (entries 12 and 13), acylations with acid chlorides (entry
14), and alkylation reactions with alkyl iodide and epoxide
electrophiles (entries 15 and 16). The relative stereochemistry
of the products was established by 1H NMR, COSY, and
NOESY data. The C-3 allylic methine hydrogen HC of the major
products (see 4, Figure 1) consistently appears as a broadened
singlet upon saturation of vicinal exocyclic neighboring hydro-
gens. This observation is indicative of the small coupling
constant (JBC < 2 Hz) which is anticipated from the Karplus
correlation of a dihedral angle (HB-C-C-HC) approximating
106°. The analyses of 2D-NOESY spectra confirmed all
assignments and revealed the expected through-space correla-
tions of the cis hydrogens for the ring fusion of the bicyclic
system. Electrophilic trapping of the allyl carbanions from the
more accessible convex face of the cis-bicyclo[3.3.0]octenyl
system was evident since through-space correlations were
observed as cross-peaks between the bridgehead methine
hydrogens and methyl, aryl, or methylene hydrogens of C-3
substituents. In all cases, our major isomers did not display
through-space NOESY correlations of the hydrogens of the cis
Results and Discussion
The triene 1 was prepared by Wittig methylenation (Ph3Pd
CH2, Et2O, -78 °C; 67%) of 2,7-cyclooctadienone,11 which in
turn was accessible in one step by o-iodoxybenzoic acid (IBX)
oxidation of cyclooctanone.12 For large-scale preparations, the
use of a 3-fold excess of IBX became impractical, and the more
economical albeit longer procedure of Garbisch13 was preferred.
This three-step sequence involved dibromination of the cyclic
ketal, dehydrobromination, and acid-catalyzed hydrolysis to
yield the cross-conjugated dienone for subsequent methylena-
tion. With the cyclic triene in hand, an initial screening of
reaction conditions for the addition of secondary and tertiary
alkyllithium reagents revealed that Et2O was the optimal solvent,
providing for rapid carbolithiation. Reactions of primary alkyl-
lithium reagents required hydrocarbon solvents, typically hex-
anes, as well as an equivalent of diamine ligand, such as
TMEDA or (-)-sparteine, to effect carbolithiation.14 Typical
experimental conditions involve dropwise introduction of a slight
excess (10 mol %) of organolithium reagent into a solution
(∼0.15 M) of triene 1 at -78 °C. Stirring of the reaction mixture
(9) (a) Wakefield, B. J. Organolithium Methods; Academic Press: London,
1988. (b) Lithium Chemistry: A Theoretical and Experimental OVerView;
Sapse, A. M., Schleyer, P. v. R., Eds.; John Wiley & Sons: New York,
1995. (c) Gray, M.; Tinkel, M.; Sniekus, V. In ComprehensiVe Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
McKillop, A., Eds.; Pergamon: Oxford, 1995; Vol. 11, pp 1-92. (d)
Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon Press:
Oxford, U.K., 2002; pp 273-335. (e) Organolithiums in StereoselectiVe
Synthesis; Hodgson, D. M., Ed.; Springer: Berlin, 2003. (f) The Chemistry
of Organolithium Compounds; Rapopport, Z., Marek, I., Eds.; John Wiley
& Sons: Chichester, 2004.
(10) (a) Neuenschwander, M. In Chemistry of Double-Bonded Functional
Groups; Patai, S., Ed.; John Wiley: Chichester, U.K., 1989; Chapter 16.
(b) Hafner, K. Pure Appl. Chem. 1990, 62, 531-540.
(11) Williams, D. R.; Reeves, J. T. J. Am. Chem. Soc. 2004, 126, 3434-3435.
(12) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. J. Am. Chem.
Soc. 2002, 124, 2245-2258.
(13) Garbisch, E. W. J. Org. Chem. 1965, 30, 2109-2120.
(14) Norsikian, S.; Baudry, M.; Normant, J. F. Tetrahedron Lett. 2000, 41,
6575-6578.
(15) (a) Lipshutz, B. H.; Ung, C.; Elworthy, T. R.; Reuter, D. C. Tetrahedron
Lett. 1990, 31, 4539-4542. (b) Lipshutz, B. H.; Ellsworth, E. L.; Dimock,
S. H.; Smith, R. A. J. J. Am. Chem. Soc. 1990, 112, 4404-4410.
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Efficient Route to Functionalized cis-Bicyclo[3.3.0]octenes
A R T I C L E S
Table 1. Scope of the Cascade Carbolithiation/Electrocyclization/Alkylation Reaction of 1a
a Reactions conducted with 1 in Et2O (entries 1-7, 12-16) or hexanes/1 equiv of (-)-sparteine (entries 8-11). b Isolated yields after purification.
c Diastereomeric ratios determined from 1H NMR data of crude product mixtures and refer to the exo (major):endo (minor) ratio of the C-3 substituent with
respect to the cis-bicyclo[3.3.0]octene. d Diastereoselectivity (dr) as measured at the exocyclic stereogenic center in compounds 6, 7, 14, and 16. e Generated
from the corresponding iodides by treatment with t-BuLi (2.2 equiv) and cannulation away from precipitated LiI. f Enantiomeric excesses of 9 and 16% were
determined by Mosher ester analysis of each diastereomeric alcohol. g A solution of CuCN (1 equiv) and LiCl (2 equiv) in THF was added prior to the
electrophile.
ring fusion and the adjacent trans C-3 allylic hydrogen. In
examples where a fourth exocyclic stereogenic site was formed
in the alkylation step (entries 2, 3, 10, and 12), moderate
stereoselectivity was observed. Our initial studies to provoke
asymmetric induction in the alkylation reactions of the meso
allyl anion 3 employed the use of (-)-sparteine as a diamine
additive (entry 10). However, low levels of chiral induction were
observed for each of the purified diastereomeric alcohols 14
(9-16% ee).
signals at δ 3.03 (Hc) and 2.79 (Hd), and a singlet at δ 1.66
ppm (Ha). A new species, the cis-bicyclo[3.3.0]octenyl anion
22, begins to form at -35 °C at the expense of 21, with the
appearance of a new peak at δ 2.50, and is further characterized
by three singlets at δ 2.88 (Hc), δ 2.50 (Hb), and δ 1.85 ppm
(Ha), respectively. On warming to +5 °C, signals assigned to
cyclooctadienyl 21 are no longer apparent, and 22 is observed
as the major species.
The extraordinarily facile carbolithiation of 1 at -78 °C is
striking, since carbolithiations of terminal dienes generally
require temperatures of 0 °C or higher.9b,c Furthermore, the
temperature necessary for electrocyclization is notably lower
than that observed by Bates and co-workers for the conversion
of cyclooctadienyllithium to cis-bicyclo[3.3.0]octenyllithium in
THF (t1/2 ) 80 min at 35 °C).5 Our DFT calculations16 are
consistent with these experimental observations and predict the
free energy of activation for the cyclization to be 31.96 kcal/
The relative reactivity of the carbolithiation and electrocyclic
1
reactions was investigated by H NMR spectroscopy (Figure
2). Thus, a solution of 1 in Et2O-d10 was treated at -78 °C
with 1.1 equiv of tert-butyllithium in pentane, and the resultant
1
solution was observed by 400 MHz H NMR spectroscopy as
the probe temperature was gradually raised to 25 °C. Carbo-
lithiation was complete within minutes at -78 °C, as evidenced
by the absence of signals due to triene 1 and the appearance of
signals due to cyclooctadienyl anion 21. Carbanion 21 is
characterized by a doublet at δ 5.69 (Hb, J ) 9.2 Hz), broad
(16) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules;
Oxford University Press: New York, 1989.
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A R T I C L E S
Williams et al.
Figure 2. 1H NMR spectra (400 MHz) of cyclooctadienyl anion 21 (A, at -35 °C) and cis-bicyclo[3.3.0]octenyl anion 22 (B, at +5 °C).
Figure 3. Comparisons of activation energies, Gibbs free energies, and bonding distances calculated for the electrocyclization of cyclooctadienyllithium
and its n-pentyl derivative.
mol (at 298.15 K) in the case of the cyclooctadienyl ion 23,
whereas 26.3 kcal/mol is predicted for the n-pentyl-substituted
analogue 24. Thus, substitution of the eight-membered ring with
an alkyl group at C-3 leads to a 4- to 5-fold increase of the rate
of electrocyclization. Figure 3 illustrates the computational
results for generated structures of the reactants, transition states,
and the bicyclic allyl anions. The energy components of these
calculations are enumerated in Table S1 (Supporting Informa-
tion) and describe an energy difference that is mainly electronic
in nature. These findings are summarized by the following
discussion. The consideration of purely electronic contributions
for the cyclizations of cyclooctadienyl ion 23 and n-pentyl
formation. This exercise reveals substantial similiarities in the
transition states and bicyclo[3.3.0] species, with a small dif-
ferential in the respective ground states (Figure 3).
The net decrease in activation energy for the electrocyclic
ring closure, which is observed upon alkyl substitution in this
system, may be attributed to a destabilization of the ground state
or lowering of the energy of the transition state. To evaluate
these possibilities, we have calculated the homolytic C3-C and
C3-H bond dissociation energies for both the ground- and
transition-state species. In the starting cyclooctadienyl anion 24,
the bond dissociation energy of the alkyl substituent (C3-C) is
98.61 kcal/mol, whereas the C3-H bond dissociation energy
in 23 is 111.80 kcal/mol. For the transition states 23-TS and
24-TS, homolytic bond dissociation energies are 128.47 (C3-
H) and 121.18 kcal/mol (C3-C), respectively. These calculations
indicate that the n-pentyl substituent destabilizes both the ground
and the transition state by -13.2 and -7.3 kcal/mol, respec-
tively, compared to the parent cyclooctadienyl system. However,
the presence of the inductively donating n-pentyl group has a
more significant effect in the ground state than in the transition
state. Our computational thermodynamic driving force for the
solution-phase cyclization is -6.05 kcal/mol, suggesting a highly
favored overall conversion. Indeed, these insights effectively
corroborate our previous observations stemming from the low-
temperature NMR studies.
q
derivative 24 reveal free energies of activation (Ea ) of 34.2
and 28.3 kcal/mol, respectively. The inclusion of entropy and
solvation terms to account for the role of lithium cation in ether
affect each case in a similar fashion, without changing the
overall results. Transition state 23-TS (R ) H) lies 31.96 kcal/
mol above the ground state of the cyclooctadienyl system 23,
whereas 24-TS (R ) n-pentyl) requires 26.30 kcal/mol. The
overall change in Gibbs free energy (∆G°) for conversions to
the respective allyllithium species reflects a favorable situation
for the n-pentyl case 26 (∆G° ) -6.05 kcal/mol) but a more
difficult transformation for the unsubstituted cyclooctadienyl 25
(∆G° ) +1.31 kcal/mol). We also have calculated distances
(r) between the termini C1 and C5 which progress to bond
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Efficient Route to Functionalized cis-Bicyclo[3.3.0]octenes
A R T I C L E S
energy of 1.43 kcal/mol. Electrophilic capture of this intermedi-
ate upon addition of CO2 furnishes the carboxylate anion 34a.
Lithium coordination changes the reaction energy profile
considerably, as highlighted by the solid line in Figure 6 and
further enumerated in Table 2. The ion-pairing energy of the
lithiated carbanion 24 in the ground state is computed to be
-17.55 kcal/mol but decreases to -15.42 kcal/mol in the
transition state. As a result, the activation energy, when one
considers lithium cation coordination, increases to 26.3 kcal/
mol (24-TS). The bicyclo[3.3.0]octenyllithium intermediate 26
is stabilized by 7.48 kcal/mol as compared to the non-lithiated
system 26a, resulting in a relative free energy of -6.05 kcal/
mol.
Figure 4. Expedient synthesis of linear triquinane 29. Conditions: (a)
n-BuLi, (-)-sparteine, hexanes, -78 °C to room temperature, 1 h; CuCN‚
2LiCl, THF, -78 °C; ethyl acrylate, TMSCl, -78 °C to room temperature;
(b) LiOH, THF/H2O; (c) N-(phenylselenyl)phthalimide, n-Bu3P, THF; (d)
n-Bu3SnH, AIBN, PhH, reflux.
The synthetic potential of the carbolithiation/electrocycliza-
tion/alkylation cascade was demonstrated by the preparation of
linear triquinane 29 (Figure 4).11 Carbolithiation with n-BuLi
in the presence of (-)-sparteine, followed by transmetalation
with CuCN and treatment with ethyl acrylate/TMSCl, furnished
ester 27 in 70% yield (C-3; dr ) 8.4:1). Two-step conversion
to phenylselenyl ester17 28 and subsequent acyl radical cycliza-
tion18 furnished the triquinane 29 in excellent overall yield.
Our fundamental studies of the scope and utility of the
carbolithiation/electrocyclization/alkylation cascade for cyclo-
octadienyl anions subsequently led us to examine the reaction
course for both larger and smaller ring systems. Fraenkel and
co-workers had reported the addition of alkyllithium reagents
to substituted 4-methylene-2,5-cyclohexadienes and had detailed
studies of ion-pairing of the resulting conjugated carbanions via
NMR.19 Bates and McCulloch had observed the thermal (120
°C) electrocyclization of cyclononadienyllithium and subsequent
formation of a mixture of bicyclo[4.3.0]nonenes.1e,20 In view
of this precedent, the application of our reaction process to the
cyclononadienyl anion appeared feasible. In the event, treatment
of 3-methylene-1,4-cyclononadiene21 30 (Figure 5) with n-BuLi
in hexanes/TMEDA at -78 °C and subsequent warming to
100-120 °C led to low yields of cis-bicyclo[4.3.0]nonene 33
(31%) upon quenching at -78 °C, as well as a complex mixture
of unidentified hydrocarbons. While experiments indicated that
carbolithiation to 31 occurred rapidly at -78 °C, cyclization to
32 required heating. The addition of various electrophiles upon
recooling to -78 °C provided none of the expected alkylation
products, suggesting facile proton abstraction at the elevated
temperatures necessary for cyclization to 32.
The reason for increased ground-state stabilization in lithiated
24 lies in the compact ion-contact geometry facilitated by the
transannular distance of the terminal sp2 carbons. Streitwieser
has shown that pentadienyllithium systems prefer a U-shaped
structure, with the lithium cation η5-bound to the pentadienyl
anion.22 Our calculations indicate an optimized distance of 3.21
Å between these two π-termini. Analysis of the ground state of
the eight-membered anion 24 shows a distance of 3.38 Å
between the carbon atoms, which approximates the optimum
distance anticipated for the unsubstituted system. At this
distance, ion-pairing effects are maximized between the lithium
cation and the π system. This effect is less pronounced in the
transition state 24-TS, due to the fact that σ bond formation
decreases accessible charge and consequently leads to a decrease
of ion-pairing energy.
When we examine the observations of Figure 5, the non-
lithiated nine-membered carbanion 31a follows an analogous
pathway (Figure 7) and displays an activation energy of 30.3
kcal/mol (31a-TS), leading to the 5,6-bicyclic non-lithiated
intermediate 32a (5.6 kcal/mol). Lithium coordination accounts
for a slight decrease in the activation barrier to 29.0 kcal/mol
(31-TS), whereas the bicyclic intermediate 32 is stabilized by
nearly 16 kcal/mol, resulting in a relative free energy of -10.4
kcal/mol. For comparison, the calculations evaluated hypotheti-
cal reactions with CO2, leading to the lithium carboxylate 35,
and the energy components are also enumerated in companion
Table 3. At a rate-determining activation barrier of 29.0 kcal/
mol, elevated temperature is required, as the cyclization of the
nine-membered pentadienyl system is approximately 1000 times
slower than that of the eight-membered ring. As before, lithium
coordination has a pronounced effect on the energy profile. The
stabilization of the transition state by ion-pairing in the nine-
membered system is essentially identical to that observed in
the eight-membered system. Interestingly, ion-pairing does not
stabilize the ground state to the same degree as in the eight-
membered analogue, and it destabilizes the ground state relative
to the transition state by 1.2 kcal/mol. The computed transan-
nular distance of the π-termini in lithiated 31 is 3.59 Å, deviating
from the optimal distance of 3.21 Å. The ion-pairing energy
for the ground state of the nine-membered system is 4.4 kcal/
mol less than that of the eight-membered ring.
To understand the physical basis of the different kinetic
behavior of the eight- and nine-membered substrates in more
detail, we employed computational methods based on density
functional theory.16 Cyclization reactions were considered
without and with ion-pairing, to separate purely electronic effects
of the cyclization from the perturbation introduced by the
formation of the allyllithium complex. The reaction energy
profile (Figure 6) of the non-lithiated eight-membered carbanion
24a, with a rate-determining activation barrier of 24.17 kcal/
mol (24a-TS), leads to the bicyclic intermediate 26a (broken
line), which is computed to be slightly higher in energy than
the starting cyclopentadienyl species 24a, with a relative free
(17) Grieco, P. A.; Jaw, J. Y.; Claremon, D. A.; Nicolaou, K. C. J. Org. Chem.
1981, 46, 1215-1217.
(18) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429.
(19) (a) Hallden-Abberton, M.; Engelman, C.; Fraenkel, G. J. Org. Chem. 1981,
46, 538-546. (b) Fraenkel, G.; Hallden-Abberton, M. P. J. Am. Chem.
Soc. 1981, 103, 5657-5664.
The experimental observations and the activation barriers for
reactions of the eight- and nine-membered carbocycles offer a
stark contrast. The barrier for cyclization of the nine-membered
anion is approximately 5 kcal/mol higher than that of the eight-
membered system. While ion-pairing is important, it does not
(20) McCulloch, C. S. Synthesis and Rearrangement of Cyclononadienyllithium.
M.S. Thesis, University of Arizona, 1978.
(21) (a) Mehta, G. Org. Prep. Proceed. Int. 1970, 2, 245-248. (b) Billups, W.
E.; Baker, B. A.; Chow, W. Y.; Leavell, K. H.; Lewis, E. S. J. Org. Chem.
1975, 40, 1702-1704.
9
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A R T I C L E S
Williams et al.
Figure 5. Carbolithiation studies of triene 30.
Table 2. Energy Components for the Reaction Profile of Non-lithiated and Lithiated Species with Corresponding ∆∆G Values (kcal/mol)
species
∆H
−T
∆S
∆G(GP)
∆G(Solv)
∆G(Sol)
∆∆G(Sol)
24a
24a-TS
26a
34a
24
24-TS
26
-318 434.99
-318 412.52
-318 433.51
-436 837.49
-323 165.83
-323 138.07
-323 166.18
-441 567.68
-4 571.41
36.32
35.10
35.27
39.54
37.18
35.70
36.77
41.05
9.48
-318 471.31
-318 447.63
-318 468.78
-436 877.03
-323 203.01
-323 173.77
-323 202.96
-441 608.73
-4 580.89
-37.05
-36.56
-38.15
-45.84
-8.79
-318 508.36
-318 484.19
-318 506.93
-436 922.87
-323 211.80
-323 185.50
-323 217.86
-441 634.26
-4 685.90
0.00
24.17
1.43
-45.05
0.00
-11.73
-14.90
-25.53
-105.01
-1.94
26.30
-6.05
-53.00
34
Li+
CO2
-118 352.27
-159.43
15.25
-8.61
-8.88
-118 367.52
-150.82
-118 369.46
-17.55
24a + Li+ f 24
133.27
129.84
0.00
2.13
24a-TS + Li+ f 24-TS
-154.14
-145.26
-15.42
Figure 6. Comparison of energy profiles for non-lithiated 24a and lithiated
cyclooctadienyl 24 pathways.
Figure 7. Comparison of energy profiles for non-lithiated 31a and lithiated
cyclononadienyl 31 pathways.
change the trend. Our analysis of 31-TS recognizes strain in
the transition state.
As shown in Figure 7, cyclization provides a planar, five-
membered allylic system with a boat-like conformation for the
newly formed cyclohexane. While this conformation is strained
and less favored than the complementary chair-like conformer,
it is required to facilitate the thermal disrotatory ring closure.
Thus, substituents located on the π-termini of the pentadienyl
system develop eclipsed interactions in the transition state for
electrocyclization. This additional factor in the formation of the
six-membered ring is alleviated in the cyclopentanyl case (Figure
3 for 24-TS), which adopts an envelope conformation.
Our evaluation of six- and seven-membered ring substrates
recognized the favorable planar orbital alignment of the starting
trienes and transannular distances of reacting termini facilitating
cyclization. However, we reasoned that the substantial ring strain
introduced in the electrocyclic process would favor the conju-
gated pentadienyl carbanion. Thus, issues of reactivity of these
trienes were examined to evaluate the synthetic utility of the
reaction and to probe the possibility of an electrocyclic
equilibrium of opened and closed anions. The subjection of
3-methylene-1,4-cycloheptadiene23 36 to conditions optimized
for the eight-membered ring substrates resulted in smooth
carbolithiation and, after electrophilic trapping, gave exclusively
the 1,3-cycloheptadienes 39 (Figure 8).
No products were observed from alkylation of the cis-bicyclo-
[3.2.0]heptenyl 38 or trapping of cycloheptadienyl anion 37 at
the central carbon. The scope of the reaction was examined with
respect to the reactivity of alkyllithium reagents and various
electrophiles (Table 4). Application of the solvent systems
optimized for the cases of the eight-membered ring triene
allowed efficient carbolithiations with primary, secondary, and
tertiary alkyllithium reagents. As before, carbolithiation was
(23) Billups, W. E.; Chow, W. Y.; Leavell, K. H.; Lewis, E. S. J. Org. Chem.
1974, 39, 274-275.
(22) Streitwieser, A.; Pratt, L. M. J. Org. Chem. 2000, 65, 290-294.
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12344 J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006

Efficient Route to Functionalized cis-Bicyclo[3.3.0]octenes
A R T I C L E S
Table 3. Energy Components for the Reaction Profile of Non-lithiated and Lithiated Cyclononadienyl Species with Corresponding ∆∆G
Values (kcal/mol)
species
∆H
−T
∆S
∆G(GP)
∆G(Solv)
∆G(Sol)
∆∆G(Sol)
31a
31a-TS
32a
35a
31
31-TS
32
-343 074.62
-343 044.74
-343 068.04
-461 474.38
-347 799.15
-347 771.11
-347 805.26
-466 211.27
-4 571.41
38.12
37.01
37.21
42.20
38.83
37.74
36.55
42.66
9.48
-343 112.75
-343 081.75
-343 105.25
-461 516.58
-347 837.98
-347 808.84
-347 841.81
-466 253.93
-4 580.89
-35.22
-35.95
-37.13
-45.69
-9.07
-343 147.97
-343 117.70
-343 142.38
-461 562.27
-347 847.05
-347 818.02
-347 857.41
-466 279.27
-4 685.90
0.00
30.27
5.58
-44.84
0.00
-9.18
29.02
-10.37
-62.77
-15.60
-25.34
-105.01
-1.94
131.16
131.78
35
Li+
CO2
-118 352.27
-153.12
15.25
-8.77
-8.75
-118 367.52
-144.35
-118 369.46
-13.19
31a + Li+ f 31
0.00
-1.24
31a-TS + Li+ f 31-TS
-154.96
-146.21
-14.43
Table 4. Scope of the Carbolithiation/Alkylation of Triene 36a
a Reaction conducted in Et2O (entries 2, 4-6) or hexanes/1 equiv of (-)-sparteine (entries 1 and 3). b Isolated yields after purification. c Isolated as an
inseparable 1:1 mixture of diastereomers.
Figure 8. Carbolithiation and alkylation of triene 36.
complete within minutes at -78 °C. Alkylation of cyclohep-
tadienyl carbanions proved feasible, making this an efficient
route for rapid preparation of functionalized 1,3-cyclohepta-
dienes.
Investigations in the six-membered series employed 6,6-
Figure 9. Carbolithiation and alkylation of triene 46.
dimethyl-3-methylene-1,4-cyclohexadiene 46, which was pre-
pared as described by Zimmerman and co-workers.24 Subjection
of 46 to the usual conditions for carbolithiation and subsequent
trapping with electrophiles furnished functionalized 1,3- or 1,4-
cyclohexadienes 49 and 50 as major products (Figure 9). As
with the seven-membered derivatives, no products deriving from
electrocyclization of the cyclohexadienyl anion 47 were ob-
served. Alkylation at the central carbon of the pentadienyl
carbanion led to 50 as a result of significant steric hindrance
imposed by the gem-dimethyl group.
Examples are summarized in Table 5. Carbolithiation of 46
with primary, secondary, and tertiary alkyllithium reagents
proved facile at -78 °C. However, alkylations of the cyclo-
hexadienyl anions were slower than those observed for the
cycloheptadienyl cases in Table 4.
The absence of products derived from electrocyclization in
the six- and seven-membered ring substrates indicated that these
cyclic pentadienyl anions may not support an equilibrium with
ring-closed species due to prohibitive strain energy, despite
formation of a new carbon-carbon single bond. Experiments
were designed in which cis-bicyclic allyl intermediates could
be trapped via elimination processes to test the possibility of
equilibration. Seven-membered triene 57, containing the gem-
diphenyl substitution, was prepared in two steps25a from 4,4-
diphenylcycloheptanone.25b-d The seven-membered triene 57
was subjected to carbolithiation with t-BuLi at -78 °C, and
(25) (a) See Supporting Information. (b) Zimmerman, H. E.; Keese, R.; Nasielski,
J.; Swenton, J. S. J. Am. Chem. Soc. 1966, 88, 4895-4904. (c) Bordwell,
F. G.; Wellman, K. M. J. Org. Chem. 1963, 28, 2544-2550. (d) Bunce,
R. A.; Taylor, V. L.; Holt, E. M. J. Photochem. Photobiol., A 1991, 57,
317-329.
(24) Zimmerman, H. E.; Hackett, P.; Juers, D. F.; McCall, J. M.; Schro¨der, B.
J. Am. Chem. Soc. 1973, 95, 3653-3662.
9
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A R T I C L E S
Williams et al.
Table 5. Scope of the Carbolithiation/Alkylation of Triene 46a
a Reaction conducted in Et2O (entries 1, 2, 4 and 5) or hexanes/1 equiv (-)-sparteine (entries 3 and 6). b Isolated yields after purification. c Isolated as
a separable 3.3:1 mixture of diastereomers.
Figure 11. Preparation of R-methoxymethyl trienes 61 and 63. Condi-
tions: (a) (CH2O)n, imidazole, THF/1 M aqueous NaHCO3, 64%, brsm;
(b) Me3OBF4, proton sponge, CH2Cl2, 0 °C to room temperature, 69%; (c)
i. LDA, THF, -78 °C; PhSeBr, -78 °C to room temperature; ii. 30%
aqueous H2O2, pyridine, CH2Cl2, 56%; (d) n-BuLi, Ph3PCH3Br, Et2O, -78
Figure 10. Result of carbolithiation of triene 57. Conditions: (a) t-BuLi,
Et2O, -78 °C to room temperature, 12 h; 50%.
°C to reflux, 52%; (e) DMAP, THF, formalin, room temperature, 48 h,
59%, brsm; (f) Me3OBF4, proton sponge, 4 Å MS, CH2Cl2, 0 °C to room
temperature, 82%; (g) n-BuLi, Ph3PCH3Br, Et2O, -78 °C to room
temperature, 21%.
subsequent stirring at room temperature for 12 h gave triene
58 in 50% yield as a 1:1 mixture of E:Z olefin isomers (Figure
10). None of the cyclopentadiene product 59, derived from
fragmentation of the putative cis-bicyclo[3.2.0]heptenyl anion,
was observed.26
The formation of 58 can be rationalized as a thermal,
conrotatory opening of the cycloheptadienyl system, followed
by protonation to give the fully conjugated 58. Interestingly,
the low-temperature generation and electrocyclization of hep-
tatrienyl anions to cycloheptadienyl anions has been described
by Bates and co-workers.27 While their observations have shown
this conversion to be an extremely facile electrocyclization, our
reaction from 57 effectively proceeds in the reverse direction,
suggesting a reaction pathway that is impacted by the diphenyl
substitution.
A second approach, which was designed to establish the
possibility of an equilibrium of six- and seven-membered
pentadienyl carbanions with the corresponding cis-bicyclic allyl
species, proved more rewarding. We rationalized that â-elimina-
tion of an alkoxide leaving group could facilitate trapping of
strained bicyclic intermediates. To this end, the R-methoxy-
methyl trienes 61 and 63 were prepared as outlined in Figure
11. After some experimentation, it was found that the Morita-
Baylis-Hillman reaction of 4,4-dimethyl-2-cyclohexenone with
paraformaldehyde and imidazole in a mixture of THF and
aqueous NaHCO3 conveniently provided the hydroxymethyl
derivative 60 in good yield (64%).28 Methylation of the alcohol,
and oxidation followed by Wittig olefination, furnished the triene
61. Similarly, Morita-Baylis-Hillman reaction of cyclohep-
tadienone with formaldehyde and DMAP gave alcohol 62 in
59% yield.29 Methylation and Wittig olefination furnished the
seven-membered triene 63.
Studies of the carbolithiation of 61 proved most gratifying,
as the addition of t-BuLi occurred rapidly at -78 °C and
subsequent warming to 22 °C smoothly produced the cis-
bicyclo[3.1.0]hexene 66 in 53% isolated yield (Figure 12). The
formation of 66 suggests the equilibrium of 64 and 65 via
disrotatory processes which result in the trapping of the minor
contributor 65. While the deprotonation of cis-bicyclo[3.1.0]-
hexenes and subsequent electrocyclic opening to cyclohexadi-
enyl anions is known,30 this is the first example of the
(28) Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69, 555-558.
(29) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965-5966.
(30) (a) Atkinson, D. J.; Perkins, M. J.; Ward, P. Chem. Commun. 1969, 1390-
1391. (b) Sustmann, R.; Dern, H.-J. Chem. Ber. 1983, 116, 2958-2971.
(26) Staley, S. W.; Erdman, J. J. Am. Chem. Soc. 1970, 92, 3832-3833.
(27) Klo¨tgen, S.; Fro¨hlich, R.; Wu¨rthwein, E. U. Tetrahedron 1996, 52, 14801-
14812.
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12346 J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006

Efficient Route to Functionalized cis-Bicyclo[3.3.0]octenes
A R T I C L E S
alkyllithium reagent and electrophile. Trapping of putative cis-
bicyclo[3.2.0]heptenyl anion species has furnished products
resulting from the 8e- conrotatory electrocyclic opening of the
initial cycloheptadienyl anion. This process appears to predomi-
nate over 6e- electrocyclic closure to the cis-bicyclo[3.2.0]-
heptenyl anion. Successful trapping of a cis-bicyclo[3.1.0]-
hexenyl intermediate via â-elimination suggests the probability
of facile disrotatory processes for equilibration of cyclohexa-
dienyl and cis-bicyclo[3.1.0]hexenyl carbanions. The nature of
these reactions may find utility in strategies for organic
synthesis.
Computational Details
All calculations were carried out using density functional theory as
implemented in the Jaguar 6.0 suite31 of ab initio quantum chemistry
programs. Geometry optimizations were performed with the B3LYP32
functional and the 6-31G** basis set. Lithium was always represented
using the D95** basis.33 The energies of the optimized structures were
re-evaluated by additional single-point calculations on each optimized
geometry using Dunning’s correlation-consistent triple-ú basis set34 cc-
pVTZ++, which includes a double set of polarization functions and
diffuse functions. Vibrational frequency calculations based on analytical
second derivatives at the B3LYP/6-31G** level of theory were carried
out to derive the zero-point energy (ZPE) and entropy corrections at
room temperature utilizing unscaled frequencies. Vibrational calcula-
tions were also used to confirm proper convergence to local minima
or local maxima of the potential energy surface. Note that by “entropy”
here we refer specifically to the vibrational/rotational/translational
entropy of the solute(s); the entropy of the solvent is implicitly included
in the dielectric continuum model.
Solvation energies were evaluated by a self-consistent reaction field
(SCRF)35 approach based on accurate numerical solutions of the
Poisson-Boltzmann equation.36 In the results reported, solvation
calculations were carried out at the optimized gas-phase geometry,
employing the dielectric constant of ꢀ ) 4.2666 (diethyl ether). As is
the case for all continuum models, the solvation energies are subject
to empirical parametrization of the atomic radii that are used to generate
the solute surface. We employ the standard set of optimized radii in
Jaguar for H (1.150 Å), C (1.900 Å), O (1.600 Å), and Li (1.226 Å).
The energy components have been computed following the standard
protocol. The free energy in the solution phase, G(sol), was calculated
as follows:
Figure 12. Results of carbolithiations of trienes 61 and 63. Conditions:
(a) t-BuLi, Et2O, -78 °C to room temperature, 15 h; 53%; (b) t-BuLi, Et2O,
-78 °C to room temperature, 16 h; 78%.
electrocyclization of a cyclohexadienyl anion in which the
product cis-bicyclo[3.1.0]hexene has been isolated.
Subjection of 63 to carbolithiation with t-BuLi at -78 °C
and subsequent stirring at 22 °C for 16 h provided tetraene 68
in 78% yield (Figure 12). None of the desired cis-bicyclo[3.2.0]-
heptene 67 was observed. Once again, the formation of the
cycloheptadienyl anion and the ring-opened heptatrienyl system
accounts for the elimination to 68.27 The extent to which
cycloheptadienyl carbanions are in equilibrium with cis-bicyclo-
[3.2.0]heptenyl anions is obscured by this dominant pathway.
Conclusion
The carbolithiation of six- through nine-membered 3-meth-
ylene-1,4-cycloalkadienes has been investigated and shown to
be an exceptionally facile and general process. Primary, second-
ary, and tertiary organolithium reagents may be employed for
carbolithiation of cyclic trienes with uniform efficiency, generat-
ing cyclic pentadienyl carbanions. The six-electron pentadienyl
systems display unique reactivity as a function of ring size.
Cyclooctadienyl anions undergo efficient thermal, disrotatory
electrocyclization on warming to 22 °C to provide cis-bicyclo-
[3.3.0]octenyl anions. The latter species react efficiently with a
variety of electrophiles in a stereoselective manner, thus
providing one-step access to a diverse array of substituted cis-
bicyclo[3.3.0]octenes. Transmetalation of the allyllithium in-
termediates with copper cyanide results in modification of
reactivity as organocopper species, which permits expanded
possibilities for electrophilic trapping. The potential for further
derivatization of the product cis-bicyclo[3.3.0]octenes is dem-
onstrated by the expedient stereoselective preparation of a linear
triquinane. Electrocyclization of the cyclononadienyl system
proved much less favorable and required 120 °C to effect
significant formation of the cis-bicyclo[4.3.0]nonenyl anion. This
species was protonated in situ, precluding its direct function-
alization through electrophilic capture. Cycloheptadienyl anions
undergo alkylations to provide exclusively 1,3-cycloheptadiene
products in good yields, demonstrating a useful entry to
functionalized 1,3-cycloheptadienes. Intermediate carbanions of
the 6,6-dimethylcyclohexadienyl system yield alkylations which
provide six-membered ring products, although the regioselec-
tivity of electrophilic attack is dependent on the nature of the
G(sol) ) G(gas) + Gsolv
(1)
G(gas) ) H(gas) - TS(gas)
H(gas) ) H(SCF) + ZPE
(2)
(3)
where G(gas) is the free energy in the gas phase, Gsolv is the free energy
of solvation as computed using the continuum solvation model, H(gas)
is the enthalpy in the gas phase, T is the temperature (298.15 K), S(gas)
is the entropy in the gas phase, H(SCF) is the self-consistent field
(31) Jaguar 6.0; Schro¨dinger, Inc.: Portland, OR, 2003.
(32) (a) Becke, A. D. Phys. ReV. A 1988, 38, 3098-3100. (b) Becke, A. D. J.
Chem. Phys. 1993, 98, 5648-5652. (c) Lee, C. T.; Yang, W. T.; Parr, R.
G. Phys. ReV. B 1988, 37, 785-789.
(33) Dunning, T. H., Jr.; Hay, P. J. In Modern Theoretical Chemistry: Methods
of Electronic Structure Theory; Schaefer, H. F., III, Ed.; Plenum: New
York, 1977; Vol. 3, Chapter 1.
(34) Dunning, T. H. J. Chem. Phys. 1989, 90, 1007-1023.
(35) (a) Marten, B.; Kim, K.; Cortis, C.; Friesner, R. A.; Murphy, R. B.;
Ringnalda, M. N.; Sitkoff, D.; Honig, B. J. Phys. Chem. 1996, 100, 11775-
11788. (b) Friesner, R. A.; Murphy, R. B.; Beachy, M. D.; Ringnalda, M.
N.; Pollard, W. T.; Dunietz, B. D.; Cao, Y. X. J. Phys. Chem. A 1999,
103, 1913-1928. (c) Edinger, S. R.; Cortis, C.; Shenkin, P. S.; Friesner,
R. A. J. Phys. Chem. B 1997, 101, 1190-1197.
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J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006 12347

A R T I C L E S
Williams et al.
energy, i.e., “raw” electronic energy as computed from the SCF
procedure, and ZPE is the zero-point energy.
Service Award (GM-068318, J.T.R.) for support of experimental
investigations. M.-H.B. acknowledges the support from the
National Institutes of Health (HG-003894) and the National
Science Foundation (0116050) for computational studies. Pro-
fessor Robert B. Bates (University of Arizona) is thanked for
helpful discussions.
To locate transition states, the potential energy surface was first
explored approximately using the linear synchronous transit (LST)
method,37 followed by a quadratic synchronous transit (QST)38 search
using the LST transition state as an initial guess. In QST, the initial
part of the transition-state search is restricted to a circular curve
connecting the reactant, the initial transition-state guess, and the product,
followed by a search along the Hessian eigenvector that is most similar
to the tangent of this curve. In certain cases (i.e., when structures were
very similar), the QST-optimized transition states were refined by an
unrestricted transition-state search.
Supporting Information Available: Full experimental details,
characterization data, 1H and 13C NMR spectra of all new
compounds, a tabulation of spectra from variable low-temper-
ature NMR studies of 2 to 3, Cartesian coordinates of computed
structures, vibrational frequencies, and energy components. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully ackowledge the National
Institutes of Health (GM-41560) and the National Research
(36) Rashin, A. A.; Honig, B. J. Phys. Chem. 1985, 89, 5588-5593.
(37) Halgren, T. A.; Lipscomb, W. N. Chem. Phys. Lett. 1977, 49, 225-232.
(38) Peng, C. Y.; Schlegel, H. B. Isr. J. Chem. 1993, 33, 449-454.
JA063243L
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12348 J. AM. CHEM. SOC. VOL. 128, NO. 37, 2006