Control of the Stereochemistry of Kinetic Protonation: Intramolecular Proton Delivery

Article abstract of DOI:10.1021/jo990323h

Four decades ago, we noted that for delocalized carbanions and enols the protonation transition state is close to sp² hybridized and that, as a consequence, under kinetic control protonation takes place from the less hindered approach, most often with formation of the less stable of two possible stereoisomers. The initial report was followed by an extensive series of examples. Nevertheless, a major question remained, namely whether it was possible to deliver the proton to the more hindered face of such a species using intramolecular proton transfer. To this end, silyl ether precursors to the enols of 3-benzoyl-endo-6-phenyl-exo-6-pyridylbicyclo[3.1.0]hexane and its endo-6-pyridyl-exo-6-phenyl stereoisomer were synthesized. The corresponding enols were generated with fluoride anion. The endo-phenyl enol stereoisomers, on kinetic protonation, led stereoselectively to the endo-3-benzoyl product resulting from the less hindered protonation. In stark contrast, the endo-6-pyridyl enol isomer led stereoselectively to the exo-3-benzoyl ketone by intramolecular proton delivery. However, the kinetic orders of the stereochemistries differ; the intramolecular process requires additional proton donor molecules. The log of the ratio of the two stereochemistries is linear with the log of the proton donor concentration with the slope giving the difference in kinetic orders. An aromatic cyclic 14 electron Hueckel transition state is proposed. Additionally, the roles of acyl, nitro and cyano delocalizing groups were analyzed with ab initio computations.

Full text of DOI:10.1021/jo990323h

J . Org. Chem. 1999, 64, 6635-6645
6635
Con tr ol of th e Ster eoch em istr y of Kin etic P r oton a tion :
In tr a m olecu la r P r oton Deliver y1,2
Howard E. Zimmerman* and Alexey Ignatchenko†
Chemistry Department, University of Wisconsin, Madison, Wisconsin 53706
Received February 22, 1999
Four decades ago, we noted that for delocalized carbanions and enols the protonation transition
state is close to sp2 hybridized and that, as a consequence, under kinetic control protonation takes
place from the less hindered approach, most often with formation of the less stable of two possible
stereoisomers. The initial report was followed by an extensive series of examples. Nevertheless, a
major question remained, namely whether it was possible to deliver the proton to the more hindered
face of such a species using intramolecular proton transfer. To this end, silyl ether precursors to
the enols of 3-benzoyl-endo-6-phenyl-exo-6-pyridylbicyclo[3.1.0]hexane and its endo-6-pyridyl-exo-
6-phenyl stereoisomer were synthesized. The corresponding enols were generated with fluoride
anion. The endo-phenyl enol stereoisomers, on kinetic protonation, led stereoselectively to the endo-
3-benzoyl product resulting from the less hindered protonation. In stark contrast, the endo-6-pyridyl
enol isomer led stereoselectively to the exo-3-benzoyl ketone by intramolecular proton delivery.
However, the kinetic orders of the stereochemistries differ; the intramolecular process requires
additional proton donor molecules. The log of the ratio of the two stereochemistries is linear with
the log of the proton donor concentration with the slope giving the difference in kinetic orders. An
aromatic cyclic 14 electron Hu¨ckel transition state is proposed. Additionally, the roles of acyl, nitro
and cyano delocalizing groups were analyzed with ab initio computations.
In tr od u ction
A very large number of organic reactions proceed by
way of transient delocalized carbanions and enolic inter-
mediates. Knowing the stereochemistry of protonation of
these species then is tantamount to knowing the stereo-
chemistry of the organic reactions. It was in 1955 that
one of us suggested that the R-carbon in the transition
state for ketonization of enols is close to sp2 hybridized
with the consequence that protonation occurs from the
less hindered side of the enolate π-bond.3 Most often, the
less hindered approach of a proton donor leads to the less
stable of two diastereomers. One example is depicted in
eq 1.
In this case, the enolate of 5 is generated by reaction of
methyllithium with enol acetate 4. The less hindered
approach of the proton donor, ammonium cation, leads
to the less stable of two stereoisomers.5 Spanning the four
decades we have reported a rather large number of
examples of the phenomenon.3-16 This has included both
enolates and other delocalized carbanions and a variety
of reactions. Additionally, the literature has provided
(5) Zimmerman, H. E.; Linder, L. W. J . Org. Chem. 1985, 48, 1637-
1646.
(6) Zimmerman, H. E. J . Amer. Chem. Soc. 1956, 78, 1168-1173.
(7) (a) For sulfone-stabilized carbanions the protonation transition
state has been shown to be closer to sp3 hybridized. Zimmerman, H.
E.; Thyagarajan, B. S. J . Am. Chem. Soc. 1960, 82, 2505-2511. (b)
Zimmerman, H. E.; Thyagarajan, B. S. J . Am. Chem. Soc. 1958, 80,
3060-3064.
Here the enolate of 2, generated from the cuprate
addition to benzoylcyclohexene 1, was protonated with
ammonium cation to give the less stable of two stereo-
isomers (i.e., 3).3 That the concept applies to other
delocalized carbanions was also demonstrated.4 A more
recent example is outlined in eq 2.
(8) Zimmerman, H. E.; Giallombardo, H. J . J . Am. Chem. Soc. 1956,
78, 6259-6263.
(9) Zimmerman, H. E. J . Am. Chem. Soc. 1957, 79, 6554-6558.
(10) Zimmerman, H. E.; Cutshall, T. W. J . Am. Chem. Soc. 1958,
80, 2893-2896.
(11) Zimmerman, H. E.; Chang, W.-H. J . Am. Chem. Soc. 1959, 81,
3634-3643.
† Present address: Eastman Chemical Co., P.O. Box 7444, Longview,
TX 75607.
(12) Zimmerman, H. E.; Mais, A. J . Am. Chem. Soc. 1959, 81, 3644-
(1) (a) This is paper 252 of the general series. (b) For a preliminary
report of the present study, see: Zimmerman, H. E.; Ignatchenko, A.
J . Am. Chem. Soc. 1998, 120, 12992-12993.
3651.
(13) Zimmerman, H. E.; Cutshall, T. W. J . Am. Chem. Soc. 1959,
81, 4305-4308.
(2) Paper 249, see Zimmerman, H. E. J . Phys. Chem. A 1998, 102,
5616-5621. For paper 250, see: Zimmerman, H. E.; Sebek, P.; Zhu,
Z. J . Am. Chem. Soc. 1998, 98, 8549-8550.
(14) Zimmerman, H. E. Base-Catalyzed Rearrangements. In Mo-
lecular Rearrangements; DeMayo, P., Ed. Interscience: New York,
1963; Chapter 6, pp 345-406.
(3) Zimmerman, H. E. J . Org. Chem. 1955, 20, 549-557.
(4) Zimmerman, H. E.; Nevins, T. E. J . Am. Chem. Soc. 1957, 79,
6559-6561.
(15) Zimmerman, H. E.; Mariano, P. S. J . Am. Chem. Soc. 1968,
90, 6091-6096.
(16) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-268.
10.1021/jo990323h CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/06/1999

6636 J . Org. Chem., Vol. 64, No. 18, 1999
Zimmerman and Ignatchenko
support for the concept,17 and we have reviewed the
literature as well.16
Sch em e 1. Syn th esis of Keton es a n d En ol
P r ecu r sor s
Thus, the phenomenon has been of consequence to
synthetic organic chemistry while being of interest
mechanistically as an example of kinetic control. With
this background it was of interest to determine if the
converse stereochemistry might be obtained by intramo-
lecular delivery of the proton. For this study, the two
enols 7-Exo and 7-En d o
were selected with the idea that the endo pyridyl group
in 7-En d o might selectively deliver a proton to the
hindered face of the enolic π-bond.
Resu lts
The synthesis of the corresponding ketones and of
precursors to the enols is illustrated in Scheme 1. In these
synthetic efforts we encountered a number of intriguing
results.
The initial step involved the addition of phenyl-2-
pyridylcarbene18 to cyclopentadiene with the objective of
formation of the endo and exo stereoisomers of 6-(2-
pyridyl)-6-phenylbicyclo[3.1.0]hex-2-ene. The carbene was
generated photochemically from triazole 9. It was ob-
served that the exo-2-pyridyl-endo-phenyl stereoisomer
(10-Exo) was formed stereoselectively with the exo-
pyridyl to endo-pyridyl isomers being formed in a ratio
of 4:1. The source of this selectivity is discussed below
in the Interpretative Section. However, because the endo-
pyridyl stereoisomers were formed in lesser quantities
and yet were required for intramolecular proton-transfer
experiments, a means of converting an endo-phenyl series
compound to its endo-pyridyl counterpart was desired.
This was found in the acetone sensitized equilibration
of the endo and exo stereoisomers of 3-cyano-6-(2-py-
ridyl)-6-phenylbicyclo[3.1.0]hexane (i.e., 14-En d o and 14-
Exo). Interestingly, again there was a preference for the
exo-pyridyl stereoisomer, here in a 10:1 ratio. This point
is also discussed below in the Interpretative Section.
The synthesis was designed to avoid several pitfalls.
For example, the endo-3-cyano reactants, 14-Exo and 14-
En d o, were converted to the corresponding benzoyl
ketones 17-Exo and 17-En d o by first converting these
to the corresponding aldehydes 15-E xo and 15-E n d o,
conversion to the alcohols 16-Exo and 16-En d o and,
thence, to the desired ketones 17-Exo and 17-En d o.
While this seems to be an indirect route, the direct
conversion of the nitriles to the desired ketones proceeded
with extensive epimerization of the cyano and keto
groups. When this epimerization was desired, it was
accomplished with sodium ethoxide to afford the exo-
ketones 18-En d o and 18-Exo.
Although the mode of synthesis, the spectral data, and
the equilibration of the endo-benzoyl (17-En d o and 17-
Exo) to exo-benzoyl (18-En d o and 18-Exo) ketones,
respectively, provided evidence for the validity of the
stereochemical assignments; nevertheless, X-ray struc-
tures were obtained for a strategically selected series of
compounds, namely 10-Exo, 12-Exo,14-En do, 14-Exo,17-
En d o, 18-Exo, and 22-Exo.
(17) (a) Adam, W.; Nava-Salgado, V. O. J . Org. Chem. 1995, 60,
578-584. (b) Compagnone, R. S.; Rapoport, H. J . Org. Chem. 1986,
51, 1713-1719. (c) Hirai, H.; Sawada, K.; Aratani, M.; Hashimoto, M.
Tetrahedron Lett. 1985, 26, 1739-1742. (d) Kametani, T.; Tsubuki,
M.; Higurashi, K.; Honda, T. J . Org. Chem. 1986, 51, 2932-2939. (e)
Williams, T. W.; Crumbie, R.; Mosher, H. S. J . Org. Chem. 1985, 50,
91-97. (f) Fleming, I.; Lewis, J . J . Chem. Soc., Chem. Commun. 1985,
149-151. (g) Grieco, P. A.; Majetich, G. F.; Ohfune, Y. J . Am. Chem.
Soc. 1981, 104, 4226-4233. (h) Gillissen, H. M. J .; Buck, H. M. J . Org.
Chem. 1982, 47, 5214-5132. (i) Krause, N. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1764-1765. (j) Baker, W. R.; Pratt, J . K. Tetrahedron
1993, 49, 8739-8856. (k) Kno¨lker, H.-J .; Ecker, A.; Struwe, P.;
Steinmeyer, A.; Mu¨ller, G.; Neef, G. Tetrahedron 1997, 53, 91-108.
(l) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461-462.
(m) Tamura, R.; Watanabe, K.; Ono, N.; Yamamoto, Y. J . Org. Chem.
1992, 57, 4895-4899. (n) Rehders, F.; Hoppe, D. Synthesis 1992, 859-
861.
One mode of enol generation used in our past research
was the treatment of R-bromoketones with dilute hydri-
odic acid in acetone.3,5,6,8,10,11 That this proceeds via the
enol to give the corresponding debrominated ketone was
noted to be clear from consideration of microscopic
reversibility. The reaction of a ketone with a halogen is
well known to proceed via an enolic intermediate to afford
(18) (a) Cf. the extensive work of Wentrup on pyridyl-substituted
carbenes with evidence for a tautomeric relationship between 2-py-
ridylcarbenes and the isomeric triazopyridines: Wentrup, C. Helv.
Chim. Acta 1978, 61, 1755-1763. (b) Mayor, C.; Wentrup, C. J . Am.
Chem. Soc. 1975, 97, 7467-7480.

Control of the Stereoselectivity of Kinetic Protonation
J . Org. Chem., Vol. 64, No. 18, 1999 6637
Sch em e 2. Hyd r iod ic Acid Debr om in a tion a s a
Mod e of En ol Gen er a tion
Sch em e 3. En ol Gen er a tion fr om th e Silyl En ol
Eth er s With F lu or id e
a haloketone and hydrogen halide. The present reaction
with HI and bromoketone, in leading to dehalogenated
product plus iodine, is mechanistically the microscopic
reverse, except that here the use of iodine has reversed
the thermodynamics in favor of ketone and halogen. One
example9 is shown in Scheme 2. Here it has been shown
that the same product distribution resulted from enol
generation from either of the two stereoisomeric â-bromo-
ketones 19a and 19b and that the enol 20 protonated
stereoselectively to afford the less stable, cis isomer 21a
with 21b being minor.
of the endo-phenyl stereoisomer (23-Exo), only one
protonation product was formed, namely 17-Exo. Runs
were made with tetrabutylammonium fluoride in THF
with ammonium chloride as the proton donor in one case
and acetic acid in the other. We note that protonation in
both cases results from the less hindered approach to the
R-carbon of the enol. Details are given in Table 1 of the
Supporting Information. Also note Scheme 3.
In the present study, bromination of exo-pyridyl ketone
17-Exo proceeded smoothly to afford the corresponding
bromoketone 22-Exo. Note eq 3.
However, kinetic protonation in the endo-pyridyl sys-
tem led to results that were dependent on choice and
concentration of proton donor. Thus, treatment of the
endo-pyridylsilyl enol ether 23-En d o with tetrabutylam-
monium fluoride and ammonium chloride in THF led to
the same preference for intermolecular protonation ob-
served with the exo-pyridyl stereoisomer 23-Exo. In
contrast, under conditions used with the exo-pyridyl
stereoisomer (8.6%, 1.44 M acetic acid in THF), proto-
nation of the R-carbon of the endo-pyridyl isomer 23-
En d o occurred preferentially from the more hindered
approach to afford benzoyl ketone 18-En d o; the ratio of
intramolecular to intermolecular protonation (i.e., 18-
En d o/17-en d o) was 97.0:3.0 as determined by quantita-
tive HPLC analysis. Isolation and NMR analysis con-
firmed the identities of the protonation products. Formic
acid in THF led, again, to a similar stereoisomer ratio
favoring intramolecular protonation and formation of 18-
En d o. However, with decreasing concentrations of acetic
acid, the preference for endo protonation slowly dimin-
ished until with 1.86% (0.31 M) acetic acid in THF a ratio
of 4:1 endo/exo protonation resulted, and with 0.5% (0.08
M) acetic acid a ratio of 1:2.4 resulted with exo protona-
tion now being preferred. A similar trend was encoun-
tered in solvents DMSO and isopropanol as well as with
formic acid in THF.
Treatment with dilute hydriodic acid in acetone, mildly
acidic enough so that the debrominated ketones were
unequilibrated, led cleanly to 3-endo-benzoyl-6-endo-
phenyl-6-exo-pyridylbicyclo[3.1.0]hexane (17-Exo), the
product of protonation from the less hindered side of the
exocyclic enolic π-bond. Note eq 4.
In contrast, attempted bromination of the endo-pyridyl
ketone 17-En d o did not afford the desired R-bromoketone
in appreciable yield, and the chemistry of this isomer was
not pursued.
More practical enol precursors were found to be the
silyl enol ethers 23-Exo and 23-En d o of enols 7-Exo and
7-En d o. The enols were generated smoothly on treat-
ment19 with tetrabutylammonium fluoride. In the case
An important point is that control runs established
that the rate of equilibration of the endo-benzoyl (17) to
exo-benzoyl (18) stereoisomers was very slow and not
observed appreciably under conditions of enol ketoniza-
tion. Thus, the stereochemical results reported above are,
indeed, kinetic.
(19) (a) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181-
187. (b) Kuwajima, I.; Nakamura, E. J . Am. Chem. Soc. 1975, 97,
3257-3258.

6638 J . Org. Chem., Vol. 64, No. 18, 1999
Zimmerman and Ignatchenko
If we consider the partition between the two stereo-
chemical ketonization processes shown in eq 5, we can
see that the ratio of rates of formation of the two ketones
of the endo-pyridyl series, exo-benzoyl ketone 18 and
endo-benzoyl ketone 17, should be independent of (e.g.)
acetic acid concentration if both of the processes are same
order in the acid. For formation of the exo-benzoyl ketone
(i.e., 18), the intramolecular protonation
product, to be enhanced by increasing acid concentration,
this reaction must be of higher kinetic order in the acid.
“Differential plots” were employed to check this conclu-
sion. Equations 6a,b give the rates of formation of the
two stereoisomeric ketonization products as νext for the
external protonation (order m) and νint for the higher
order (n) intramolecular ketonization; kext and kint are the
corresponding rate constants. In eq 7, Pint and Pext
represent the amounts of the two stereoisomers at any
given time, and Pint/Pext gives the product ratio during
the ketonization reaction. Integration to complete reac-
tion affords, in logarithmic form, eq 8b. This reveals that
a plot of the log of the ratio of stereoisomers obtained in
several runs against the log of the proton donor (H-A)
concentration should afford a slope n - m, which is the
difference in H-A reaction orders for the two stereoiso-
meric protonation processes, intramolecular and inter-
molecular. A slope of zero would signify the same
dependence on proton donor concentration for internal
and external protonations, while a positive slope signifies
a greater order for intramolecular protonation as has
been suggested above. The differential plots are given in
Figure 1. The similarity of the acetic and formic acid runs
in THF is of interest, and Figure 1e plots these together.
F igu r e 1. Differential plots: (a) acetic acid-THF; (b) acetic
acid-isopropyl alcohol; (c) formic acid-THF; (d) acetic acid-
DMSO; (e) acetic and formic acids in THF. Note: The
intercepts are calculated for an abscissa of zero.
The experimental details of the kinetics are given in
the Supporting Information (note Table 1). Also note the
Experimental Section for further details on the stereo-
chemistry and kinetic runs including control experi-
ments.
Com p u ta tion a l Resu lts
Finally, it seemed worthwhile to ascertain the extent
and nature of electron delocalization in enolates, nitro-
nates, and cyano-stabilized carbanions. For this, we used
Gaussian94 and Gaussian9820a along with Weinhold
NBO Analysis20b applied to nine systemssthree enolates
(24, 27, and 30), three nitronates (25, 28, and 31), and
three cyano-stabilized carbanions (26, 29, and 32); see
Figure 2. The salient features of these computations are
given in Table 1, which includes the R-carbon electron
density, the electron density on the heteroatoms in each
case, the deformation angle at the R-carbon, and the
molecular energy.21 The deformation angle is defined in
νext ) dPext/dt ) kext[H-A]m[Enol]
νint ) dPint/dt ) kint[H-A]n[Enol]
dPint/dPext ) (kint/kext)[H-A]n-m
Pint/Pext ) (kint/kext)[H-A]n-m
(6a)
(6b)
(7)
(8a)
log(Pint/Pext) ) (n - m) log[H-A] + log(kint/kext) (8b)
The average slope for THF runs (Figure 1a-d) is 1.17,
while in DMSO (Figure 1d) the slope is 2.1. If either
stereochemistry were a mixture of two kinetic orders,
there would not be the observed linearity. Also, the
intercepts of the plots of Figure 1 give, in principle, the
ratio of rate constants (kint/kext). Excluding DMSO, these
intercepts were in the range of 0.93-1.17 corresponding
to a rate ratio of 10. The slope in three of the solvents
gives a difference (n - m) of unity. If external protonation
is a simple process and first order in proton donor, then
the external protonation in the three solvents is second
order.
(20) (a) Gaussian 94, Revision D, and Gaussian 98, Revision A.6:
Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A., J r.;
Stratmann, R. E.; Burant, J . C.; Millam, J . M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, C.; Ochter-
ski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski,
J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challo-
combe, M.; Gill, P. M. W.; J ohnson, B.; Chen, W.; Wong, M. W.; Andres,
J . L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J . A.
Gaussian, Inc., Pittsburgh, PA, 1998. (b) Reed, A.; Curtiss, L. A.;
Weinhold, F. Chem. Rev. 1988, 88, 899-926.

Control of the Stereoselectivity of Kinetic Protonation
J . Org. Chem., Vol. 64, No. 18, 1999 6639
Ta ble 1. Som e Sa lien t F ea tu r e of th e Geom etr y-Op tim ized Deloca lized System s
R-carbon
deformation
angle (deg)
B3LYP
molecule
enolate 24
nitronate 25
cyano anion 26
dimethyl enolate 27
dimethyl nitronate 28
dimethyl nitrile 29
cyclohexyl enolate 30
cyclohexyl nitronate 31
cyclohexyl nitrile 32
density
heterodensity
energya,b
1.4442
1.4557
1.6893
1.3431
1.2430
1.4917
1.3430
1.3527
1.5312
1.6327
1.6501c
1.3635
1.6323
1.7158c
1.4105
1.6334
1.6470c
1.3708
179.4755
180.0000
141.9151
179.0648
179.9315
178.9583
177.2824
179.9287
164.6802
-153.2072
-244.4060
-132.1225
-231.8476
-323.0464
-210.7549
-348.5882
-439.7861
-327.4971
a
b
6-31G* basis. Hartrees. c For each oxygen.
First, ketonization of the endo-phenyl enol 7-Exo to
give the less stable endo-benzoyl stereoisomeric ketone
17-Exo showed complete stereoselectivity within HPLC
experimental error; this corresponds to a selectivity of
over 1000:1. Inspection of molecular models shows the
endo lobe of the R-carbon p-orbital to be severely blocked
by the C-6 endo-phenyl group. The stereoselectivity
seems to be of the same order as that observed for the
tricyclic system 5 we studied earlier.5 Control by steric
accessibility to the R-carbon is a phenomenon we origi-
nally reported in 1955. The theory depends on the
protonation transition state being an early one with the
R-carbon still being close to sp2 hybridized. Not only
ketone enolates and enols are subject to this control but
other delocalized species such aci-nitro anions.4,15 The
principle has been discussed, and many examples have
been given in a long series of our articles3-16 including a
reasonably comprehensive review.16 Still, the literature
contains examples where the mechanistic basis for
preferential formation of less stable protonation products
has not been recognized.
F igu r e 2. Six-electron delocalized systems.
Nevertheless, there is a second factor to be considered,
a stereoelectronic one. In very early work, Corey22 has
noted that for cases where the C-H bond of the proto-
nated product may or may not overlap with the product
carbonyl π-system, there is an energetic preference for
that stereochemistry in which the developing R C-H
bond remains in conjugation with the carbonyl group.
Typical examples are found in endocyclic six-membered
ring enols where there is a preference for axial protona-
tion.22,23 More recently, an interesting case has been
reported by Stork.24
F igu r e 3. Deformation angle θ. D is the delocalizing group.
X is a “ghost atom” (see text).
Figure 3, where atom D is a delocalizing group (acyl,
nitro, or cyano), A and B are substituents (H, Me, or
methylene), and X is a “ghost atom”, placed in the
A-B-C plane midway between A and B. This permits
simple evaluation of the deformation angle θ.
Also, it seemed important to determine the energetic
consequences of deforming the delocalizing group in the
unsubstituted molecules 24, 25, and 26. For a 40°
deformation from planarity, the enolate energy rose 2.57
kcal/mol, the nitro energy rose 1.50 kcal/mol, while the
cyano-substituted anion rose only 0.6 kcal/mol when
forced into planarity.
Overlap is not a factor in the case of exocyclic enols,
since with either approach there is usually continued
overlap between the R-carbon p-orbital and the carbonyl
group as the molecule proceeds to ketone product.
Nevertheless, the relative energetic importance of the two
controlling factors is one we are presently studying.
Discu ssion
There are several points to be discussed, namely (a)
the stereochemistry of kinetic protonation of the endo-
phenyl enol, (b) the stereochemistry of protonation of the
endo-pyridyl enol, (c) the preferential formation of the
exo-pyridyl bicyclic in the cyclopentadiene-carbene cy-
cloaddition, (d) the triplet steady-state equilibration of
the endo- and exo-pyridyl bicyclics favoring the exo-
pyridyl stereoisomer, and (e) the computational results.
We turn now to the second, and perhaps more novel,
result of interest, namely the stereochemistry of proto-
nation of the endo-pyridyl enol. With a weakly acidic
proton donor such as ammonium, the normal external
proton attack from the less hindered side of the π-system
is observed. With the ca. 10 pKa of ammonium and the
ca. 5 pKa of pyridinium (aqueous values), proton transfer
from ammonium to the pyridyl nitrogen is quite energeti-
(21) (a) Extensive and very pretty computations have been carried
out by Wiberg on carbanions with and without delocalizing groups.21b
At the time of computation we were unaware of these. However, it is
of interest to compare the results, where comparable systems are
considered. These are qualitatively similar despite different compu-
tational methods and basis orbitals. (b) Wiberg, K. B.; Castejon, H. J .
Org. Chem. 1995, 60, 6327-6334.
(22) Corey, E. J .; Sneen, R. A. J . Am. Chem. Soc. 1956, 78, 6269-
6278.
(23) For example, see: Shea, K. J .; Wada, E. J . Am. Chem. Soc.
1982, 104, 5715-5729.
(24) Stork, G. E.; Manabe, K.; Longbin, L. J . Am. Chem. Soc. 1998,
120, 1337-1338.

6640 J . Org. Chem., Vol. 64, No. 18, 1999
Zimmerman and Ignatchenko
Sch em e 4. Mech a n ism for P r oton a tion of th e
en d o-P yr id yl En ol
F igu r e 4. Geometry vs delocalization for the cyano-stabilized
anions.
Releva n ce of th e Com p u ta tion a l Asp ects
The different geometries of the cyano-substituted
anions from those of the enolates and nitronates were
intriguing in view of the similarity of the stereochemistry
of kinetic protonation in all three cases (vide infra).
Further, the planarity of the dimethyl cyano methide 29
contrasts with the partial pyramidalization of the sim-
plest cyano member 26 and the cyanocyclohexyl anion
32.
cally unfavorable and uninvolved. Thus, the preferred
stereochemistry is the same as that in the endo-phenyl
case.
However, with acetic acid present (pKa 4.7), one
anticipates the presence of the protonated endo-pyridyl
moiety. Molecular modeling shows that the endo-pyridyl
proton may approach within 1.6 Å of the R-carbon and
thus transfer the proton intramolecularly.
Three effects are involved in delocalized carbanions.
Delocalization favors planarity as does relief of steric
interactions incurred on pyramidalization. But with weak
delocalization, maximizing s-weighting of the electron
pair trends towards sp3 hybridization with resulting loss
of planarity. All three systemssenolate, nitronate, and
cyano anionsreveal shallow minima and small energy
changes on deformation. In the case of the enolates and
nitronates, planarization dominates. The balance of
effects is closer in the cyano anion situation with only
0.6 kcal/mol separating the deformed and planar confor-
mations. Figure 4 shows the weak dependence of delo-
calization on the deformation angle for the parent cyano
anion case. Slight pyramidalization dominates for two of
the three cyano anions. However, steric repulsive forces
in the dimethyl cyanomethide anion lead to the observed
planarization. Van der Waals forces along with the
electronic preference lead to the cyclohexyl cyanomethide
anion being slightly deformed from planarity. Neverthe-
less, the approach to planarity accounts for kinetic
protonation occurring from the less hindered side of the
π anionic system as experimentally observed.31 Hence,
for all systemssenolate, nitronate, and cyanoskinetic
protonation is similar.
We must take into account the observation of pyri-
dine-acetic acid clusters25 as well as the finding that
equilibration of such clusters is a rapid process as noted
from NMR.26 But, ketonization of enols is slow by
comparison.27 Hence, we can conclude from the linearity
of the kinetic plots either that any clustering is constant
as the proton donor concentration is varied or, more
simply, that acid molecules bound in clusters to the
pyridyl groups are released prior to transition state
formation.
One initially puzzling point was the mechanistic source
of the difference in the internal and external protonation
processes. We see from the kinetics that the endo-pyridyl
enol 7-En d o utilizes one more (e.g.) acetic acid molecule
than the exo-pyridyl enol 7-Exo. While the role of the
acetic acid is subject to some conjecture, we do know that
enolates protonate more rapidly than their enol conjugate
acids28 just as nitronates protonate more rapidly than
their aci-nitro conjugate acids.4,15
A reasonable possibility is depicted in Scheme 4 where
the role of the second acetic acid molecule is to hydrogen
bond to the acetate of the ion pair with migration of the
negative charge from acetate to this second acetic acid
and thus provide a species able to convert the enol to
enolate. In contrast, the exo-pyridyl isomer has geometry
not permitting such a mechanism, and with ammonium
cation as the proton source, neither isomer can partake
of this process.
Ad d ition a l Asp ects
One interesting aspect of the present study is not
related to the stereochemistry of protonation but, instead,
derives from two steps of the synthesis as noted in the
Results.
Thus, in the initial reaction of phenyl pyridyl carbene
there was a preference for formation of the exo-pyridyl
(10-Exo) relative to the endo-pyridyl (10-En d o) stereo-
A final point of interest is that the cyclic transition
state is an aromatic one with 14 delocalized electrons and
no enforced orbital phase inversions.29
(25) Akiyama, Y.; Wakisaka, A.; Mizukami, F.; Sakaguchik, K. J .
Chem. Soc., Perkin Trans. 2 1998, 95-99.
(30) (a) Takano, S. Chem. Lett. 1982, 733-736. (b) Takano, S.; Kudo,
J .; Takahashi, M.; Ogasawara, K. Tetrahedron Lett. 1986, 2405-2408.
(c) Takano, S.; Uchida, W.; Hatakeyama, S.; Ogaswara, K. Chem. Lett.
1982, 733-736. (d) Takano, S.; Goto, E.; Ogasawara, K. Tetrahedron
Lett. 1982, 5567-5569. (e) Takano, S.; Yamada, S.; Numata, H.;
Hatakeyama, S.; Ogasawara, K. Heterocycles 1983, 20, 2159-2162. (f)
Takano, S.; Tanaka, M.; Seo, M.; Hirama, M.; Ogasawara, K. J . Org.
Chem. 1985, 50, 931-936.
(26) Golubev, N. S.; Smirnov, S. N., Gindin, V. A.; Denisov, G. S.;
Benedict, H.; Limbach, H.-H. J . Am. Chem. Soc. 1994, 116, 12055-
12056.
(27) Andraos, J .; Kresge, A. J .; Obraztsov, P. A. J . Phys. Org. Chem.
1992, 5, 322-326.
(28) (a) Reference 14. (b) Malhotra, S. K.; Ringold, H. J . J . Am.
Chem. Soc. 1965, 87, 3228-3236. (c) Paufler, R. M., Ph.D. Thesis,
Northwestern University, 1960.
(31) Gerlach, U.; Haubenreich, T.; Hu¨nig, S.; Keita, Y. Chem. Ber.
1993, 126, 1205-1215. Note also ref 30.
(29) Zimmerman, H. E. J . Am. Chem. Soc. 1966, 88, 1564-1565.

Control of the Stereoselectivity of Kinetic Protonation
J . Org. Chem., Vol. 64, No. 18, 1999 6641
Sch em e 5. F ou r Sp ecies in th e Ad d ition of
P h en yl P yr id yl Ca r ben e to Cyclop en ta d ien e
yet in view of the utility in obtaining desired stereochem-
istry it is not surprising that the concept has been
rediscovered30-32 several times and that many recent
publications cite only the rediscoveries. However, now the
concept is accepted but its source sometimes goes unrec-
ognized.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were performed under
an atmosphere of dry nitrogen. Column chromatography was
performed on silica gel (Matheson, Coleman and Bell, grade
62, 60-200 mesh) mixed with Sylvania 2282 phosphor and
slurry packed into quartz columns to allow monitoring with a
1
hand-held UV lamp. Melting points are uncorrected. H and
13C NMR spectra were recorded at 300 and 75 MHz, respec-
tively, using CDCl3 as solvent and are reported in ppm
downfield from tetramethylsilane. Solvents were dried follow-
ing standard methods.
isomer. Similarly, in the acetone-sensitized equilibration
of the cyano-bicyclics 14-Exo and 14-En d o the steady-
state ratio favored the former (i.e., 14-Exo). While this
was a synthetic impediment it proved to be theoretically
interesting. Thus, Scheme 5 depicts the addition of the
pyridyl phenyl carbene to the cyclopentadiene ring with
four of the most reasonable alternative stereochemical
geometries. These pictures show one σ bond forming more
rapidly than the other as would result from a triplet
addition. This must be followed, or accompanied, by
intersystem crossing to give So to permit the final three-
membered ring to form. Each aromatic ring is either close
to perpendicular to the five ring or twisted 90° from this.
Species A and B exhibit severe steric interactions be-
tween the perpendicular endo-aryl group and the five-
membered ring and seem unlikely to be utilized. In
comparing species C and D, we note that the electron-
rich nonbonded benzylic orbital in D is orthogonal to the
endo-pyridyl ring while in C it overlaps with the exo-
pyridyl π-system. Since delocalization by a pyridyl ring
is more effective than ordinary benzylic resonance, we
conclude that species C is preferred, which is in accord
with the preferential formation of the exo-pyridyl stereo-
isomer. Also, having the odd electron delocalized into the
pyridyl ring should enhance the spin-orbit coupling
required for three-membered ring closure.
Gen er a l P r oced u r e for X-r a y Cr ysta llogr a p h y An a ly-
sis. X-ray diffraction data were collected on a Siemens P4/
CCD diffractometer for single crystals of each compound.
Lorentz and polarization corrections were applied, and each
structure was solved under the appropriate space group
symmetry by direct methods using Shelx86 or SHELXTL.33
Hydrogen atom positions were calculated and refined with a
rigid model. Full-matrix least-square refinement on F2 was
carried out employing anisotropic displacement parameters for
all non-hydrogen atoms and isotropic displacement parameters
for all hydrogen atoms. The coordinates for all compounds
studied by X-ray crystallography were deposited with the
Cambridge Crystallographic Data Centre. The coordinates can
be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
U.K.
2-Ben zoylp yr id in e. A modified procedure of Glover and
J ones was used.34 From 2-cyanopyridine (20.8 g, 0.20 mol)
there was obtained 28.9 g (79%) of product. An analytical
sample distilled under vacuum (bp 145-146 °C at 3 mmHg)
(lit.34 bp 107 °C/0.1 mmHg).
2-Ben zoylp yr id in e Hyd r a zon e. This was prepared by a
modification of the method of Boyer, Borgers, and Wolford.35
From 18.3 g (0.1 mol) of 2-benzoylpyridine there was obtained
15.26 g (78%) of colorless needles of the hydrazone, mp 96-
104 °C. An analytical sample was distilled: bp 160-170 °C/
0.35 mmHg; mp 108-110 °C from EtOAc (lit.35 mp 106-108
°C).
4-P h en yl[1,2,3]tr iazolo[1,5-a ]pyr idin e. Starting with 7.63
g (38.7 mmol) of 2-benzoylpyridine hydrazone, 5.66 g (75%) of
pure product was obtained as colorless prisms: mp 111-112
°C (lit.35 mp 113-115 °C).
Ir r a d ia tion of 4-P h en yl[1,2,3ltr ia zolo[1,5-a ]p yr id in e.
In a typical run, 2.00 g (9.95 mmol) of the triazole in 350 mL
of cyclopentadiene was photolyzed in an immersion well
apparatus with a 0.25 N copper sulfate filter using a 400 W
lamp for 16 h. The solution was concentrated in vacuo,
removing excess cyclopentadiene and dicyclopentadiene. The
dark oily residue was chromatographed on a 4.5 × 50 cm silica
gel column with hexane-ethyl acetate gradient elution to yield
In the case of the photochemical triplet equilibration
of the cyano-bicyclics 14-Exo and 14-En d o we are
dealing with a steady state. Either (i) sensitized triplet
energy transfer to the endo-pyridyl isomer is more
efficient than to the exo-pyridyl counterpart, (ii) the
triplet of the 14-En d o stereoisomer undergoes three-ring
opening more readily than the 14-Exo counterpart, (iii)
the open triplet diradical intersystem crosses to So and
closes more rapidly with the pyridyl in the exo conforma-
tion, or (iv) some of all of the preceding are factors.
(32) (a) Relatively recently, the phenomenon has been reported
anew32b with the same comment that countless syntheses proceed via
formal carbanions as enolates which in the final step are protonated
to give less stable isomers. The mechanistic analysis followed that in
our publications. But it was stated that there had been hardly any
systematic study of the stereochemistry of protonation. No reference
was made to the earlier studies except for listing of our review. (b)
Hu¨nig, S. In Houben-Weyl, Methods of Organic Chemistry, Protonation
of Carbanions and Polar Double Bonds; Helmchen, G., Hoffmann, R.
W., Mulzer, J ., Schaumann, E., Eds.; G. Thieme Verlag: Stuttgart,
1996; Vol. E21D 7, pp 3851-3911.
Con clu sion
The stereochemistry of kinetic protonation of enols,
enolates, and other delocalized species has been an area
of special interest and value. The number of reactions
proceeding by way of these transient species is quite
large, and hence, an understanding of the stereochem-
istry of this mechanistic step permits one to understand
the stereochemistry of the overall reactions. Curiously,
in 1956, our initial suggestion of this phenomenon of the
near-planar delocalized species preferentially giving rise
to the less stable of two stereoisomers by the less
hindered protonation was not immediately accepted, and
(33) Sheldrick, G. M. 1994. SHELXTL Version 5 Reference Manual.
Siemens Analytical X-ray Instruments, 6300 Enterprise Dr., Madison,
WI 53719-1173.
(34) Glover, E. E.; J ones, G. J . Chem. Soc. 1959, 1686-1691.
(35) Boyer, J . H.; Borgers, R.; Wolford, L. T. J . Am. Chem. Soc. 1957,
79, 678-680.
(36) Bank, S.; Gernon, M. J . Org. Chem. 1987, 52, 5105-5111.

6642 J . Org. Chem., Vol. 64, No. 18, 1999
Zimmerman and Ignatchenko
four main fractions: (1) 6-exo-(pyridyl-2)-6-endo-phenylbicyclo-
[3.1.0]hex-2-ene 10-Exo as colorless prisms: 0.67 g (28%); mp
96-97 °C (from hexane-ether); TLC Rf 0.85 (hexane-ethyl
acetate 10:1); 1H NMR δ 2.08 (dq, J ) 18.0, 2.4 Hz, 1H), 2.61
(sym m, 1H), 2.65-2.82 (br m, 2H), 5.14 (sym m, 1H), 5.77
(sym m, 1H), 6.52 (dt, J ) 8.1, 0.9 Hz, 1H), 6.87 (ddd, J ) 7.5,
4.8, 1.2 Hz, 1H), 7.09-7.28 (br m, 6 H), 8.41 (ddd, J ) 4.8,
1.8, 0.9 Hz, 1H); 13C NMR δ 33.5, 34.7, 40.5, 42.7, 119.9, 122.1,
126.4, 128.0, 131.3, 132.0, 133.3, 136.5, 148.7, 164.4. Anal.
Calcd for C17H15N: C, 87.52; H, 6.48; N, 6.00. Found: C, 87.71;
H, 6.59; N, 5.96. This structure was also confirmed by X-ray
analysis.
(2) 6-endo-(Pyridyl-2)-6-exo-phenylbicyclo[3.1.0]hex-2-ene (10-
En d o) as a yellow oil: 0.17 g (7%); TLC Rf 0.50 (hexane-ethyl
acetate 10:1); 1H NMR δ 2.38 (m, 2H), 2.65 (m, 2H), 5.12 (sym
m, 1H), 5.82 (dt, J ) 7.6, 2.1 Hz, 1H), 6.98-7.19 (m, 7H), 7.49
(dt, J ) 7.7, 1.9 Hz, 1H), 8.48 (ddd, J ) 4.9, 0.8 Hz, 1H); HRMS
m/z (M+) calcd for C17H15N 233.1204, obsd 233.1180.
from ethyl acetate to yield 6.16 g of colorless plates (86%): mp
167-169 °C; TLC Rf 0.60 (hexane-ethyl acetate 1:1); 1H NMR
δ 2.14 (m, 4H), 2.39 (t, J ) 1.2 Hz, 2H), 2.45 (s, 3H), 3.16
(quintet, J ) 7.6 Hz, 1H), 6.55 (dt, J ) 8.1, 1.1 Hz, 1H), 6.96
(ddd, J ) 7.5, 4.7, 1.2 Hz, 1H), 7.01-7.71 (m, 10H), 8.44 (ddd,
J ) 4.7, 2.0, 0.9 Hz, 1H). Anal. Calcd for C24H23NO3S: C, 71.08;
H, 5.72; N, 3.45. Found: C, 71.40; H, 5.93; N, 3.40.
3-en d o-Cya n o-6-exo-(p yr id yl-2)-6-en d o-p h en ylbicyclo-
[3.1.0]h exa n e (14-Exo). To a stirred suspension of sodium
cyanide (1.10 g, 22.5 mmol) in 20 mL of HMPA was added
3.04 g (7.5 mmol) of 3-exo-(p-toluenesulfonoxy)-6-exo-(pyridyl-
2)-6-endo-phenylbicyclo[3.1.0]hexane. The reaction mixture
was stirred at 70 °C for 4 days and poured into 25 mL of water.
The solid was filtered, air dried, and chromatographed on silica
gel using hexane-ethyl acetate gradient elution to give 0.31
g (16%) of 6-exo-(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]hex-2-
ene, 0.36 g (19%) of 3-exo-hydroxy-6-exo-(pyridyl-2)-6-endo-
phenylbicyclo[3.1.0]hexane, and 1.1 g (56%) of 3-endo-cyano-
6-exo-(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]hexane: mp 237-
238 °C; TLC Rf 0.45 (hexane-ethyl acetate 1:1); 1H NMR δ
2.05-2.14 (br m, 2H), 2.54-2.64 (br m, 4H), 3.11 (m, 1H), 6.58
(dt, J ) 8.1, 1.1 Hz, 1H), 6.99 (ddd, J ) 7.5, 4.8, 0.9 Hz, 1H),
7.01-7.56 (br m, 6H), 8.47 (dq, J ) 4.8, 1.1 Hz); 13C NMR
DEPT-135 δ 30.2 (1C, CH), 31.8 (2C, CH), 37.4 (2C, CH2), 41.4
(1C, -C-), 120.3 (1C, Py CH), 120.9 (1C, CN), 121.6, 128.2,
129.6, 132.8, 134.4 (1C, Ph -C-), 135.7, 148.7 (1C, Py CH),
163.5 (1C, Py -C-); IR (CCl4, cm-1) 2252.5. Anal. Calcd for
(3) 1,2-Di(pyridyl-2)-1,2-diphenylethane as colorless crys-
tals: 0.40 g (24%); mp 242-244 °C (lit.36 mp 242-244 °C); TLC
Rf 0.30 (hexane-ethyl acetate 10:1). The NMR spectrum is in
agreement with the literature data.36
(4) The fourth fraction was 0.37 g (19%) of the starting
4-phenyl[1.2.3]triazolo[1,5-a]pyridine: TLC Rf 0.20 (hexane-
ethyl acetate 10:1).
Hyd r obor a t ion of 6-exo-(P yr id yl-2)-6-en d o-p h en ylb i-
cyclo[3.1.0]h ex-2-en e (10-Exo). To a solution of 4.66 g (20
mmol) of 6-exo-(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]hex-2-ene
in 40 mL of dry tetrahydrofuran at 0 °C was added 10 mL of
diborane (1 M in THF, 10 mmol). The mixture was stirred at
0 °C for 1 h and then for 6 h under reflux. After the mixture
was cooled to -10 °C, 800 mg (20 mmol) of sodium hydroxide
solution in 10 mL of water, and then 6.0 mL of 30% hydrogen
peroxide (60 mmol) was added slowly with stirring. After being
stirred for 2 h at rt, the mixture was poured into 100 mL of
saturated ammonium chloride solution and methylene chloride
extracted (5 × 30 mL), and the combined organic layers were
washed with saturated sodium sulfate solution, dried over
sodium sulfate, and concentrated. The residue was chromato-
graphed on a 4.5 × 50 silica gel column with hexane-ethyl
acetate gradient elution to give two isomeric alcohols: (1)
3-exo-hydroxy-6-exo-(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]-
hexane (12-Exo) as large colorless needles: 2.91 g (58%); mp
124-125 °C (from ethyl acetate); TLC Rf 0.20 (hexane-ethyl
acetate 1:1); 1H NMR δ 1.86 (br s, 1H), 1.93 (sym m, 2H), 2.25
(dd, J ) 13.8, 7.5 Hz, 2H), 2.38 (dd, J ) 3.7, 1.5 Hz, 2H), 2.86
(quintet, J ) 7.2 Hz, 1H), 6.58 (dt, J ) 8.1 Hz, 1.1), 6.95 (ddd,
J ) 7.5, 4.8, 1.1 Hz, 1H), 7.25-7.45 (m, 6H), 8.44 (ddd, J )
4.8, 1.8 0.9 Hz, 1H); 13C NMR DEPT-135 δ 33.9 (CH), 36.7
(CH2), 38.0 (-C-), 72.1 (COH), 119.9 (CH), 121.7 (CH), 127.0
(CH), 129.0 (CH), 131.4 (CH), 135.5 (CH), 137.6 (-C-, Ph),
148.6 (CH, Pyr), 164.2 (-C-, Pyr); HRMS m/z (M+) Calcd for
C
18H16N2: C, 83.04; H, 6.20; N, 10.76. Found: C, 83.02; H,
6.18; N, 10.55. This structure was confirmed by X-ray analysis.
6-exo-P yr idyl-6-en do-ph en ylbicyclo[3.1.0]h exan -3-en do-
ca r boxa ld eh yd e (15-E xo). 3-endo-Cyano-6-exo-(2-pyridyl)-
6-endo-phenylbicyclo[3.1.0]hexane (0.05 g, 0.19 mmol) in tolu-
ene (10 mL) was stirred under nitrogen at -78 °C, and DIBAL
(0.30 mL of 1 M solution in hexane, 0.3 mmol, 1.58 equiv) was
slowly added via a syringe. The mixture was stirred for 1 h at
-78 °C and for 1 h more at -30 °C and poured into an
ammonium chloride and ice mixture. Acetic acid (10%, 5.0 mL)
was added. After being stirred for 30 min, the organic layer
was separated and the aqueous phase extracted with ethyl
acetate (3 × 10 mL). The extracts were washed with saturated
NaHCO3 and saturated NaCl and then dried (Na2SO4). Con-
centration afforded 50 mg of product aldehyde as a colorless
solid: mp 179-182 °C; TLC Rf 0.55 (hexane/ethyl acetate 1:1);
1H NMR δ 2.31-2.49 (m, 6H), 2.70-2.80 (m, 1H), 6.54 (dt, J )
8.1, 1.0 Hz, 1H), 6.97 (ddd, J ) 7.5, 4.8, 1.1 Hz, 1H), 7.25-
7.47 (m, 6H), 8.20 (s, 1H), 8.47 (ddd, J ) 4.8, 1.8, 0.9 Hz, 1H);
13C NMR 28.3, 36.8, 38.8, 52.3, 119.9, 121.2, 127.9, 129.1,
132.4, 135.1, 135.5, 148.6, 164.0, 202.5; IR (cm-1) 1717.2. Anal.
Calcd for C18H17NO: C, 82.11; H, 6.50; N, 5.32. Found: C,
81.76; H, 6.58; N, 5.21.
3-en do-(P h en ylh ydr oxym eth yl)-6-exo-(pyr idyl-2)-6-en do-
p h en ylbicyclo[3.1.0]h exa n e (16-Exo). To the Grignard
reagent prepared from 10 mg (0.42 mmol) of magnesium
turnings and 45 mg (0.3 mmol) of phenyl bromide in 1.0 mL
of ether was added 53 mg (0.20 mmol) of 6-exo-(pyridyl-2)-6-
endo-phenylbicyclo[3.1.0]hexane-3-endo-carboxaldehyde in 0.50
mL of dry benzene with stirring at rt. Stirring was continued
at the same temperature for 2 h. The reaction mixture was
poured into 5.0 mL of cold saturated ammonium chloride
solution followed by ether extraction (3 × 5 mL), washing with
saturated sodium sulfate, drying (Na2SO4), and concentrating
in vacuo. The residue was recrystallized from ether-hexane
to give 37 mg (54%) of pure product as colorless microcrys-
tals: mp 136-137 °C; TLC Rf 0.50 (hexane-ethyl acetate 1:1);
1H NMR δ 1.25 (ddd, J ) 14.5, 8.1, 1.8 Hz, 1H), 1.62 (bs, 1H),
1.73-1.89 (m, 2H), 2.34-2.53 (m, 3H), 2.71-2.88 (m, 1H), 2.93
(d, J ) 9.3 Hz, 1H), 6.59 (dt, J ) 8.1, 1.1 Hz, 1H), 6.94 (ddd,
J ) 7.4, 4.8, 1.1 Hz, 1H), 6.98-7.01 (m, 2H), 7.16-7.36 (m,
6H), 7.40-7.46 (m, 1H), 7.52-7.57 (m, 2H), 8.45 (ddd, J ) 4.8,
1.8, 0.7 Hz, 1H); 13C NMR δ 30.1, 30.9, 37.7, 38.5 (2C), 42.5,
52.7, 119.9, 121.4, 126.5, 127.3, 127.5, 128.2, 129.0, 133.8,
135.5, 136.4, 144.1, 148.8, 164.5; IR (cm-1) 3241.4: HRMS m/z
(M+) calcd (M+) ) 341.1780, obsd 341.1782. Anal. Calcd for
C
17H17NO 251.1310, obsd 251.1301. Anal. Calcd for C17H17-
NO: C, 81.23; H, 6.82; N, 5.58. Found: C, 81.22; H, 6.86; N,
5.48. The structure was confirmed by X-ray. (2) 2-exo-hydroxy-
6-exo-(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]hexane (11-Exo)
as colorless microcrystals: 1.86 g (37%); mp 116-119 °C; TLC
1
Rf 0.15 (hexane-ethyl acetate 1:1); H NMR δ 0.36-0.49 (m,
1H), 1.40 (dd, J ) 14.7, 9.9 Hz, 1H), 1.80 (dd, J ) 13.6, 8.8
Hz, 1H), 2.12-2.31 (m, 1H), 2.46-2.55 (m, 2H), 4.30 (d, J )
5.1 Hz, 1H), 6.62 (d, J ) 8.1 Hz, 1H), 6.96-7.00 (m, 1H), 7.27-
7.41 (m, 6H), 8.47-8.48 (m, 1H); 13C NMR: 24.8, 33.6, 35.2,
38.2, 42.8, 74.7, 120.1, 121.9, 127.0, 128.9, 130.7, 135.6, 137.6,
148.7, 163.9; HRMS m/z (M+) calcd for C17H17NO 251.1310,
obsd 251.1301.
3-exo-(p -Tolu en esu lfon oxy)-6-exo-(p yr id yl-2)-6-en d o-
p h en ylbicyclo[3.1.0]h exa n e (13-Exo). 3-exo-Hydroxy-6-exo-
(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]hexane (4.43 g, 17.6
mmol) was dissolved in 25 mL of dry pyridine, and 5.05 g (26.5
mmol) of tosyl chloride was added while the pyridine solution
was stirred in an ice bath. After being stirred for 4 h, the
solution was placed in a refrigerator for 16 h. The pyridine
solution was slowly poured into a stirring solution prepared
from 12 mL of 12 M HCl and 40 g of crushed ice. The resulted
mixture was filtered, and the solid was dried and crystallized
C
24H23N2O: C, 84.42; H, 6.79; N, 4.10. Found: C, 84.09; H,
6.81; N, 4.20.

Control of the Stereoselectivity of Kinetic Protonation
J . Org. Chem., Vol. 64, No. 18, 1999 6643
3-en do-Ben zoyl-6-exo-(pyr idyl-2)-6-en do-ph en ylbicyclo-
[3.1.0]h exa n e (17-Exo). A solution of 34 mg (0.10 mmol)
3-endo-(phenylhydroxymethyl)-6-exo-(pyridyl-2)-6-endo-phenyl-
bicyclo[3.1.0]hexane in 1.0 mL of methylene chloride (1.0 mL)
was added to Collins reagent prepared from 0.12 g of chro-
mium trioxide and 2.0 mL of pyridine. The mixture was stirred
at rt for 30 min and then poured into 2.0 mL of saturated
sodium chloride solution and extracted with methylene chlo-
ride. Concentration afforded 34 mg of a colorless solid that
was recrystallized from ethyl acetate-hexane: mp 158-159
°C; TLC Rf 0.65 (hexane-ethyl acetate 1:1); 1H NMR δ 2.24-
2.32 (m, 2H), 2.46-2.57 (m, 4H), 3.94 (ddd, J ) 19.1, 10.5, 6.6
Hz, 1H), 6.52 (d, J ) 8.1 Hz, 1H), 6.95 (ddd, J ) 7.4, 4.8, 0.9
Hz, 1H), 7.18-7.21 (m, 2H), 7.23-7.53 (m, 9H), 8.46-8.48 (m,
1H); 13C NMR δ 30.0, 37.5, 41.9, 52.7, 119.9, 121.5, 127.2,
128.0, 128.2, 129.1, 132.0, 133.1, 135.2, 135.5, 137.2, 148.7,
164.4, 199.4; IR (cm-1) 1682.0. HRMS m/z calcd (M+) )
339.1623, obsd 339.1623. Anal. Calcd for C24H21NO: C, 84.92;
H, 6.24; N, 4.13. Found: C, 84.37; H, 5.96; N, 4.23.
3-exo-Ben zoyl-6-exo-(p yr id yl-2)-6-en d o-p h en ylbicyclo-
[3.1.0]h exa n e (18-Exo). Treatment of 3-endo-benzoyl-6-exo-
(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]hexane (34 mg, 0.10
mmol) with ethanolic sodium ethoxide, prepared from 230 mg
of sodium, for 20 h at rt gave 34 mg of product: mp 124-125
°C; TLC Rf 0.80 (hexane-ethyl acetate 1:1); 1H NMR δ 2.07-
2.24 (m, 3H), 2.38 (sym m, 2H), 2.51 (dd, J ) 3.5, 1.3 Hz, 2H),
6.68 (dt, J ) 8.1, 1.1 Hz, 1H), 6.98 (ddd, J ) 7.5, 4.8, 1.1 Hz,
1H), 7.31-7.41 (m, 2H), 7.43-7.57 (m, 9H), 8.49 (ddd, J ) 4.8,
2.0, 0.9 Hz, 1H); IR (cm-1) 1687.4; HRMS m/z (M+) calcd for
poured into 10 mL of saturated ammonium chloride solution,
prepared from distilled water, and ether extracted (3 × 10 mL).
Combined organic layers were washed with distilled water (10
mL) and dried over sodium sulfate. After concentration, the
residue was recrystallized from hexane to yield 61 mg (74%)
of colorless microcrystals: mp 105-106 °C; TLC Rf 0.95
1
(hexane-ethyl acetate 1:1); H NMR δ -0.15 (s, 9H), 2.37-
2.47 (m, 3H), 2.61-2.67 (m, 1H), 2.77-2.86 (m, 2H), 6.54 (d,
J ) 8.1 Hz, 1H), 6.82-6.86 (m, 2H), 6.92-6.96 (m, 1H), 7.09-
7.33 (m, 9H), 8.46-8.48 (m, 1H); 13C NMR δ 0.5, 31.2, 31.6,
34.3, 35.3, 37.6, 117.1, 119.7, 121.6, 121.7, 126.5, 126.6, 127.1,
128.0, 128.4, 131.1, 135.4, 136.2, 139.2, 148.6, 165.0; the IR
spectrum showed no carbonyl group signals; HRMS m/z (M+)
calcd for C27H29NOSi 411.2018, obsd 411.2010.
Con ver sion of 3-en d o-Cya n o-6-exo-(p yr id yl-2)-6-en d o-
p h en ylbicyclo[3.1.0]h exa n e in to 3-en d o-Cya n o-6-en d o-
(p yr id yl-2)-6-exo-p h en ylbicyclo[3.1.0]h exa n e by Ir r a d ia -
tion in Aceton e. A solution of 3-endo-cyano-6-exo-(pyridyl-
2)-6-endo-phenylbicyclo[3.1.0]hexane (3.0 g) in 3.0 L of acetone
was purged with vanadous ion purified nitrogen in a water-
jacketed photolysis flask for 15 min and then irradiated with
a 400 W mercury lamp for 2 h. The acetone was concentrated
in vacuo and the residue analyzed by NMR. Crystallization
from acetone recovered 2.30 g of the starting material. The
mother liquor was subjected to column chromatography using
a 2.5 × 35 cm silica gel column and a methylene chloride-
ethyl acetate-hexane (4:1:4) solution as an eluent. Two
fractions were collected: (1) 0.40 g of the starting material
and (2) 0.30 g of 3-endo-cyano-6-endo-(pyridyl-2)-6-exo-phenyl-
bicyclo[3.1.0]hexane (14-En d o) as a colorless solid: mp 182-
183 °C; TLC Rf 0.35 (hexane-ethyl acetate 1:1); 1H NMR δ
2.25-2.27 (m, 2H), 2.29-2.36 (m, 2H), 2.48-2.59 (m, 2H),
3.05-3.16 (m, 1H), 7.08-7.25 (m, 6H), 7.32 (ddd, 7.7, 1.1, 0.7
Hz, 1H), 7.70 (dt, J ) 7.7, 1.8 Hz, 1H), 8.71 (ddd, J ) 4.8, 1.8,
0.7 Hz, 1H); 13C NMR δ 29.4, 31.5, 34.9, 41.5, 121.1, 122.4,
C
24H21NO 339.1623, obsd 339.1610. This structure was con-
firmed by X-ray analysis.
Br om in a t ion of 3-en d o-Ben zoyl-6-exo-(p yr id yl-2)-6-
en d o-p h en ylbicyclo[3.1.0]h exa n e (17-Exo). Bromine (0.52
mL, 10 mmol) was diluted with acetic acid to 100 mL, and 2.2
mL (0.22 mmol) of this was added to a stirred solution of
3-endo-benzoyl-6-exo-(pyridyl-2)-6-endo-phenylbicyclo[3.1.0]-
hexane (68 mg, 0.20 mmol) in 0.25 mL of acetic acid (2.0 mL)
at rt. Hydrobromic acid (25 µL of 48%, 0.22 mmol) was added
via a microsyringe. Immediate decolorization was observed.
After 5 min, the reaction mixture was poured onto cracked
ice and extracted with methylene chloride (3 × 10 mL). The
organic layer was dried over sodium sulfate and concentrated
under vacuum, and the solid residue was recrystallized from
methylene chloride-hexane to yield 52 mg (62%) of 3-exo-
bromo-3-endo-benzoyl-6-exo-(pyridyl-2)-6-endo-phenylbicyclo-
[3.1.0]hexane 22-Exo as colorless microcrystals: mp 167-168
126.1, 126.7, 127.2, 128.2, 137.0, 145.1, 150.4, 156.6; IR (cm-1
)
2231.2; HRMS m/z (M+) calcd 260.1313, obsd 260.1324. Anal.
Calcd for C18H16N2: C, 83.04; H, 6.20; N, 10.76. Found: C,
83.02; H, 6.18; N, 10.55. This structure was confirmed by X-ray
analysis.
6-en d o-(P yr id yl-2)-6-exo-p h en ylbicyclo[3.1.0]h exa n e-3-
en d o-ca r boxa ld eh yd e (15-En d o). 3-endo-Cyano-6-endo-(py-
ridyl-2)-6-exo-phenylbicyclo[3.1.0]hexane (0.52 g, 1.98 mmol)
in toluene (100 mL) was stirred under nitrogen at -30 °C, and
DIBAL (3.6 mL of 1.0 M solution in toluene, 3.6 mmol, 1.8
equiv) was slowly added via syringe. The mixture was stirred
for 30 min at -30 °C and poured into an ammonium chloride
and ice mixture. Five mL of aqueous acetic acid (10%) was
added and the mixture stirred for 30 min. The aqueous phase
was extracted with ethyl acetate (3 × 20 mL), the combined
organic extracts were washed with saturated sodium bicarbon-
ate and saturated NaCl and dried over sodium sulfate,
concentrated in vacuo, and the residue was crystallized from
ethyl acetate to yield 0.40 g (76%) of colorless plates: mp 119-
121 °C; TLC Rf 0.25 (hexane-ethyl acetate 1:1); 1H NMR δ
2.17-2.22 (m, 2H), 2.34-2.45 (m, 2H), 2.56 (dd, J ) 14.3, 3.8
Hz, 2H), 2.81 (tt, J ) 12.1, 3.7 Hz, 1H), 7.07-7.22 (m, 6H),
7.28 (dt, J ) 7.7, 1.1 Hz, 1H), 7.63 (dt, J ) 7.4, 1.8 Hz, 1H),
8.37 (s, 1H), 8.61 (ddd, J ) 4.8, 1.8, 1.1 Hz, 1H); 13C NMR δ
27.6, 34.3, 39.7, 52.9, 122.3, 125.9, 126.8, 127.1, 128.2, 136.8,
145.6, 149.7, 157.4, 202.4 IR (cm-1) 1717.3; HRMS m/z (M+)
calcd for C18H17NO 263.1310, obsd 263.1313.
1
°C; TLC Rf 0.75 (hexane-ethyl acetate 1:1); H NMR δ 2.57
(d, J ) 16.5 Hz, 2H), 2.84 (t, J ) 2.9 Hz, 2H), 2.97-3.05 (m,
2H), 6.53 (dt, J ) 8.1, 1.1 Hz, 1H); 7.00 (ddd, J ) 7.7, 4.8, 1.1
Hz, 1H); 7.13-7.16 (m, 2H), 7.25-7.39 (m, 6H), 7.45-7.51 (m,
1H), 7.85-7.89 (m, 2H), 8.53 (ddd, J ) 4.8, 1.8, 0.7 Hz, 1H);
IR (cm-1) 1670.9. Anal. Calcd for C24H20BrNO: C, 68.91; H,
4.82; N, 3.35. Found: C, 68.77; H, 4.66; N, 3.69. This structure
was confirmed by X-ray analysis.
Debr om in a tion of 3-exo-br om o-3-en d o-ben zoyl-6-exo-
(p yr id yl-2)-6-en d o-p h en ylbicyclo[3.1.0]h exa n e w ith HI in
Aceton e. Hydriodic acid (1.82 mL of 47%, 10 mmol) was
diluted by acetone to 10 mL. The resulting solution (0.22 mL,
0.22 mmol) was added to the solution of the bromoketone (42
mg, 0.1 mmol) in acetone (2.0 mL) with stirring at rt. There
was an immediate color of iodine. After 5 min, water (5 mL)
was added. The mixture was extracted with methylene chloride
(3 × 5 mL). The organic layer was washed with saturated
sodium hydrogen sulfite, dried over sodium sulfate, and
concentrated under vacuum. The crude residue (40 mg) was
dissolved in deuteriochloroform and analyzed by NMR spec-
troscopy, which showed only the endo-benzoyl isomer.
3-[Tr im et h ylsilyloxy(p h en yl)m et h ylid en e]-6-exo-(p y-
r id yl-2)-6-en d o-p h en ylbicyclo[3.1.0]h exa n e (23-Exo). To
a solution of 68 mg (0.2 mmol) of 3-endo-benzoyl-6-exo-(pyridyl-
2)-6-endo-phenylbicyclo[3.1.0]hexane in 1.0 mL of dry THF at
-65 °C was added 0.4 mL of LDA (1 M in THF, 0.4 mmol).
The mixture was stirred at -65 °C for 20 min, and 0.050 mL
(0.40 mmol) of trimethylchlorosilane was added. After being
stirred for 20 min at ambient temperature, the mixture was
The mother liquor was subjected to silica gel chromatogra-
phy eluting with ethyl acetate-hexane (2:3) to yield 80 mg
(15%) of 6-endo-(pyridyl-2)-6-exo-phenylbicyclo[3.1.0]hexane-
3-exo-carboxaldehyde as colorless plates: mp 110-112 °C, TLC
1
Rf 0.40 (hexane-ethyl acetate 1:1); H NMR δ 1.06-1.16 (m,
1H), 2.13-2.20 (m, 6H), 7.08-7.26 (m, 6H), 7.33 (dt, J ) 7.7,
1.1 Hz, 1H), 7.65 (dt, J ) 7.7, 1.8 Hz, 1H), 8.63 (ddd, J ) 4.8,
1.8, 0.7 Hz, 1 H), 9.39 (d, J ) 2.2 Hz, 1H); 13C NMR δ 28.0,
33.2, 39.0, 49.5, 121.6, 124.9, 126.0, 127.3, 128.2, 136.8, 145.1,
150.1, 158.8, 201.7; HRMS m/z (M+) calcd 263.1310, obsd
263.1300. Anal. Calcd for C18H17NO: C, 82.11; H, 6.50; N, 5.32.
Found: C, 81.57; H, 6.45; N, 5.40.

6644 J . Org. Chem., Vol. 64, No. 18, 1999
Zimmerman and Ignatchenko
3-en d o-(P h en ylh yd r oxym et h yl)-6-en d o-(p yr id yl-2)-6-
exo-p h en ylbicyclo[3.1.0]h exa n e (16-En d o). To an ether
solution of phenylmagnesium bromide (1 M, 1.5 mL) was added
the solution of 6-endo-(pyridyl-2)-6-exo-phenylbicyclo[3.1.0]-
hexane-3-endo-carboxaldehyde (263 mg, 1 mmol) in 5.0 mL of
dry benzene with stirring at rt. Stirring was continued at the
same temperature for 2 h. The reaction mixture was poured
into 5 mL of cold saturated ammonium chloride solution
followed by ether extraction (3 × 5 mL). The combined ether
solution was washed with saturated sodium sulfate, dried (Na2-
S04), and concentrated in vacuo. The residue was recrystallized
from ether-hexane to give 276 mg (81%) of product as colorless
microcrystals: mp 144-145 °C; TLC Rf 0.20 (hexane-ethyl
1.1 Hz, 1H) IR showed no carbonyl group signals; HRMS m/z
(M+) calcd for C27H29NOSi 411.2018, obsd 411.1993.
En ol Gen er a tion fr om th e Silyl En ol Eth er s. In a
typical run, to 1.0 mg of the trimethylsilyloxy enol derivative
of the endo-pyridyl ketone in 5.0 µL of acetic acid and 500 µL
of THF there was added 5.0 µL of 1.0 M tetrabutylammonium
fluoride in THF. The reaction mixture was stirred at rt for 5
min. Then water-ether quenching and extraction afforded a
mixture of the endo- and exo-benzoyl products. The mixture
was analyzed as described above by HPLC to give the endo-
and exo-benzoyl isomers in a 2.5:97.5 ratio.
In a parallel run starting with the endo-phenyl silyl enol
ether and with the same conditions, a 98.4:1.6 ratio of endo-
benzoyl to exo-benzoyl products was obtained. In these acetic
acid runs, the concentration of acetic acid was varied as listed
in Table 1. Runs with DMSO replacing the THF and formic
acid replacing the acetic acid were done similarly. Additionally,
aqueous ammonium chloride runs were similarly performed
using THF as a cosolvent. The HPLC fractions from 20 runs
were combined and subjected to NMR analysis. Also, in larger
scale runs, NMR analysis was also employed.
(A) The residual material from 20 of the kinetic runs used
for HPLC analysis was combined and the resulting mixture
separated by column chromatography on silica gel, using
hexane-ethyl acetate 10:1 as an eluent. Two compounds thus
obtained were identified by 1H NMR analysis as the exo-
benzoyl and endo-benzoyl isomers and revealed only peaks
deriving from the endo- and exo-benzoyl epimers.
(B) To a solution of 17 mg of the endo-pyridyl enol ether
(0.05 mmol) in 8.50 mL of THF and 0.170 mL of acetic acid
was added tetrabutylammonium fluoride (1 M in THF, 0.085
mL) at rt. After 10 min, the standard workup and ether
extraction was done as described above. 1H NMR analysis
showed peaks at δ 3.90-4.02 characteristic for the proton at
position 3-exo of the endo-benzoyl isomer and δ 1.94-2.03
characteristic for the proton at position 3-endo of the exo-
benzoyl isomer that were used to give a 1:4.84 ratio (i.e., 17%:
83%) of endo-benzoyl to exo-benzoyl isomers. Less accurately,
the integration of the δ 8.75 vs 8.51 R-pyridyl proton peaks
gave the endo-benzoyl-exo-benzoyl ratio as 1:5.76 (i.e., 14%:
86%). Thus, the NMR analysis was comparable to the ratio
found by the HPLC method.
An a lysis of Kin etic P r oton a tion Ru n s. The ratio of the
endo to the exo product was determined by HPLC using a
Zorbax silica gel column, 6 nm, 0.46 cm × 25 cm with a flow
rate 1.0 mL/min of hexane-ethyl acetate (4:1) eluent. UV
monitoring was at 254 nm and in some runs at 270 nm.
Automatic integration was followed by correction for the
differing absorbtivities at these wavelengths. The correction
at 254 nm was 1.20:1 for the endo-benzoyl-exo-benzoyl ratio
in the case of the 3-benzoyl-6-endo-pyridyl-6-exo-phenylbicyclo-
[3.1.0]hexanes. A larger correction was observed at 270 nm,
and thus, data at 250 nm was used.
Stability of 3-en do-Ben zoyl-6-en do-pyr idyl-6-exo-ph en yl-
bicyclo[3.1.0]h exa n e u n d er P r oton a tion Con d ition s. (a)
The endo-pyridyl-endo-benzoylbicyclic ketone (4.0 mg, 0.0118
mmol) was dissolved in 2.0 mL of THF and 0.20 mL of AcOH.
The resulting solution was sealed under nitrogen atmosphere
and left at rt for kinetic measurements. Small portions of this
solution (0.2 mL) were taken with 2.0 mL of ether and 2.0 mL
of water at the end of 2, 20, 30, and 60 h. The water layer was
extracted with ether (2 × 2 mL). The combined ether solution
was washed with water, dried over sodium sulfate, and
concentrated under vacuo. The residue was analyzed by HPLC,
as described earlier. The results are summarized in Table 2a.
(b) 3-endo-Benzoyl-6-endo-pyridyl-6-exo-phenylbicyclo[3.1.0]-
hexane (4.0 mg, 0.0118 mmol) was dissolved in 2.0 mL of
AcOH, and 0.080 mL of tetrabutylammonium fluoride solution
(1 M in THF) was added. The resulting solution was sealed
under nitrogen atmosphere and left at rt for kinetic measure-
ments. Small portions of this solution (0.20 mL) were taken
with 2.0 mL of ether and 2.0 mL of water at the end of 5 min,
30 min, 6 h, 16 h, and 27 h. The water layer was ether
extracted (3 × 2 mL). The combined extracts were washed with
water (3 × 2 mL), dried over sodium sulfate, and concentrated
1
acetate 1:1); H NMR δ 1.44 (ddd, J ) 14.3, 9.2, 2.2 Hz, 1H),
1.73-1.90 (m, 2H), 2.02 (s, 1H), 2.10 (dt, J ) 7.4, 2.2 Hz, 1H),
2.22 (dt, J ) 7.4, 1.8 Hz, 1H), 2.32-2.42 (m, 1H), 2.78
(sextuplet, J ) 9.2 Hz, 1H), 3.04 (d, J ) 9.2 Hz, 1H), 7.01 (dd,
J ) 7.7, 1.8 Hz, 1H), 7.04-7.25 (m, 9H), 7.29 (d, J ) 7.7 Hz,
1H), 7.69 (dt, J ) 7.7 Hz, 1.8, 1H), 8.69 (ddd, J ) 5.9, 1.8, 0.7
Hz, 1H); 13C NMR δ 29.5, 30.4 (1C), 35.1 (1C), 35.4 (1C), 43.6
(1C), 53.9 (1C), 77.5 (1C), 121.5 (1C), 125.7 (1C), 126.3 (2C),
127.3 (2C), 127.4 (1C), 127.9 (1C), 128.1 (4C), 136.5 (1C), 143.9
(1C), 146.1 (1C), 149.8 (1C), 158.8 (1C); IR (cm-1) 3232.8;
HRMS m/z (M+) calcd for C24H23NO 341.1780, obsd 341.1807.
3-en do-Ben zoyl-6-en do-(pyr idyl-2)-6-exo-ph en ylbicyclo-
[3.1.0]h exa n e (17-En d o). A solution of 340 mg of (1 mmol)
3-endo-(phenylhydroxymethyl)-6-endo-(pyridyl-2)-6-exo-phenyl-
bicyclo[3.1.0]hexane in methylene chloride (10 mL) was added
to Collins reagent prepared from 1.0 g of chromium trioxide
and 5.0 mL of pyridine. The mixture was stirred at rt for 30
min. It was poured into 2 mL of saturated sodium chloride
solution in water and extracted with methylene chloride.
Concentration in vacuo gave 340 mg of a colorless solid that
was crystallized from ethyl acetate-hexane: mp 170-171 °C;
1
TLC Rf 0.55 (hexane-ethyl acetate 1:1); H NMR δ 2.24 (t, J
) 2.2 Hz, 2H), 2.47-2.51 (m, 4H), 3.90-4.02 (m, 1H), 7.06-
7.21 (m, 6H), 7.27 (dt, J ) 7.7, 1.1 Hz, 1H), 7.31-7.37 (m, 2H),
7.41-7.46 (m, 1H), 7.52-7.55 (m, 2H), 7.63 (dt, J ) 7.7, 1.8
Hz, 1H), 8.51 (ddd, J ) 4.8, 1.8, 1.1 Hz, 1H); 13C NMR 29.7,
34.9, 42.3, 52.3, 121.5, 125.7, 127.2, 127.3, 128.0, 128.1, 128.2,
132.1, 136.6, 136.8, 146.1, 149.9, 157.6, 199.3; IR (cm-1) 1686.7;
HRMS m/z (M+) calcd for C24H21NO 339.1623, obsd 339.1616.
This structure was confirmed by X-ray analysis.
Treatment of 21 mg of this material with ethanolic sodium
ethoxide, prepared from 1.0 mL of ethanol and 23 mg (1.0
mmol) of sodium, for 20 h at rt gave 17 mg of 3-exo-benzoyl-
6-endo-(pyridyl-2)-6-exo-phenylbicyclo[3.1.0]hexane (18-En d o):
1
mp 149-150 °C; TLC Rf 0.70 (hexane-ethyl acetate 1:1); H
NMR δ 1.94-2.03 (m, 1H), 2.25 (t, J ) 1.5 Hz, 2H), 2.29-2.44
(m, 4H), 7.09-7.27 (m, 6H), 7.31-7.37 (m, 2H), 7.42-7.50 (m,
2H), 7.52-7.57 (m, 2H), 7.74 (dt, J ) 7.4, 1.8 Hz, 1H), 8.75
(ddd, J ) 4.8, 1.8, 1.1 Hz, 1H); 13C NMR δ 31.1, 33.0, 38.5,
44.2, 121.6, 125.1, 125.9, 127.4, 128.1, 128.2, 128.3, 132.8,
136.5, 136.8, 145.2, 150.0, 159.7, 200.4; IR (cm-1) 1680.4;
HRMS m/z (M+) calcd for C24H21NO 339.1623, obsd 339.1625.
3-[Tr im eth ylsilyloxy(p h en yl)m eth ylid en e]-6-en d o-(p y-
r id yl-2)-6-exo-p h en ylbicyclo[3.1.0]h exa n e (23-En d o). To
a solution of 68 mg (0.2 mmol) of 3-endo-benzoyl-6-endo-
(pyridyl-2)-6-exo-phenylbicyclo[3.1.0]hexane in 1.0 mL of dry
THF at -65 °C was added 0.40 mL of LDA (1 M in THF, 0.4
mmol). The mixture was stirred at -65 °C for 20 min, and
0.050 mL (0.4 mmol) of trimethylchlorosilane was added. After
being stirred for 20 min at ambient temperature, the mixture
was poured into 10 mL of saturated ammonium chloride
solution, prepared from distilled water, and ether extracted
(3 × l0 mL). The combined organic layers were washed with
distilled water (10 mL) and dried over sodium sulfate. After
solvent concentration, the residue was crystallized from hex-
ane to yield 53 mg (64%) of colorless microcrystals: mp 78-
79 °C; TLC Rf 0.80 (hexane-ethyl acetate 1:1); 1H NMR δ
-0.12 (s, 9H); 2.12 (dd, J ) 3.0, 2.2 Hz, 2H); 2.54-2.60 (m,
1H) overlapped with 2.63 (dd, J ) 16.5, 1.5 Hz, 1H); 2.79 (dd,
J ) 6.2, 2.6 Hz, 1H); 3.03 (dd, J ) 16.5, 1.5 Hz; 1H); 6.84-
6.88 (m, 2H); 7.00 (ddd, J ) 7.4, 4.8, 1.1 Hz, 1H); 7.05-7.21
(m, 9H); 7.44 (dt, J ) 7.7, 1.8 Hz, 1H); 8.40 (ddd, J ) 4.8, 1.8,

Control of the Stereoselectivity of Kinetic Protonation
J . Org. Chem., Vol. 64, No. 18, 1999 6645
Ta ble 2. Equ ilibr a tion Ru n sa
Ack n ow led gm en t. Support of this research by the
National Science Foundation is gratefully acknowledged
with special appreciation for its support of basic re-
search. Also, we wish to acknowledge helpful discussions
with and advice from Dr. Douglas Powell regarding
X-ray diffractometry.
(a) without added fluoride
(b) with added fluoride
time, h
exo-endo ratio
time
exo-endo ratio
2
20
30
60
1.1:98.9
2.1:97.9
2.4:97.6
3.1:96.9
5 min
30 min
6 h
4.1:95.9
8.4:91.6
15.2:84.8
31.2:68.8
46.3:53.7
16 h
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures for 2-benzoylpyridine, 2-benzoylpyridine
hydrazone (8), and 4-phenyl[1.2.3]triazolo[1,5-a]pyridine (9)
are given. Also, Table 1 gives kinetic data with product ratios
in various solvents as a function of proton donor concentration.
This material is available free of charge via the Internet at
http://pubs.acs.org.
27 h
The concentration of bicyclic was 5.4 × 10-3 M.
a
in vacuo. The residue was analyzed by HPLC, as described
earlier. The results with added fluoride are summarized in
Table 2b. The concentrations employed were 3.8 × 10-2 M Bu4-
NF, 16.8 M AcOH, and 5.4 × 10-3 M of reactant bicyclic ketone.
J O990323H