Intramolecular proton transfer

Article abstract of DOI:10.1021/ol026251p

(Matrix presented) Reversal of the normal kinetic protonation stereochemistry results as a consequence of intramolecular delivery.

Full text of DOI:10.1021/ol026251p

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2593-2595
Intramolecular Proton Transfer
Howard E. Zimmerman* and Pengfei Wang
Chemistry Department, UniVersity of Wisconsin, Madison, Wisconsin 53706
zimmerman@chem.wisc.edu
Received May 28, 2002
ABSTRACT
Reversal of the normal kinetic protonation stereochemistry results as a consequence of intramolecular delivery.
A very large number of organic reactions proceed via enols
and enolates that then tautomerize to carbonyl products. In
1956 it was recognized that prediction of the stereochemistry
of kinetic protonation of these intermediates would permit
prediction of the stereochemistry of the overall reactions. It
was proposed1 that in the highly exothermic process, the
protonation transition step has an R-carbon that is close to
sp2 hybridized with the consequence that the protonation
process occurs from the less hindered face of the enolic
system. Generally this leads to the less stable of two
diastereomers. Since that time we have published a series
of papers generalizing and exemplifying the phenomenon.2
One typical example is shown in eq 1.
Precursors used to generate these enols were the corre-
sponding tert-butyldimethyl silyl enol ethers, which reacted
smoothly with tetrabutylammonium fluoride to generate the
enols.4 In the case of the endo-phenyl stereoisomer 3, with
acetic acid as the proton donor, the reaction proceeded as in
eq 2 with the usual less hindered approach stereochemistry
preferred with a 7.3:1 selectivity independent of the acetic
acid concentration.
Conversely, the reaction of the endo-pyridyl diastereomer
afforded varying extents of intramolecular proton transfer
depending on the concentration of the proton donor em-
ployed.
Recently the question arose whether the stereochemistry
could be reversed by intramolecular delivery of the proton
to the more hindered face of the enolic system, and one
example was uncovered.3 It now appears that the phenom-
enon is general, and we report an example in a new molecular
system, utilizing the exo and endo 2-pyridyl enols 3 and 4.
(1) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549-557.
(2) (a) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-268. (b)
Zimmerman, H. E.; Linder, L. W. J. Org. Chem. 1985, 48, 1637-1646.
(3) Zimmerman, H. E.; Ignatchenko, A. J. Org. Chem. 1999, 64, 6635-
6645.
10.1021/ol026251p CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/25/2002

While acetic acid is known to cluster, these species are
rapidly equilibrated.5 It is posible that for intermolecular
protonation, one acetic acid molecule separates from the
cluster and delivers the proton. This, however, is irrelevant.
We know only from n - m that one extra acetic acid
molecule is involved in the intramolecular process. If it is
an aggregate in the inter mode, it is the same aggregate plus
one HOAc molecule in the intra mode. For simplicity of
discussion we will assume intermolecular protonation to
involve one acetic acid molecule. With n - m being unity,
we then conclude that the intramolecular proton-transfer
process involves two acetic acid molecules.
Dramatic contrasts were encountered (a) with less acidic
proton donors and (b) with hydrochloric acid as the donor.
In the case of phenol and the endo-pyridyl isomer 4 we found
that the less hindered protonation resulted, giving a prefer-
ence of 5.7:1, the same stereochemistry as in the case of the
endo-phenyl isomer 3, which however afforded a preference
of 19:1.Thus there seems to be minor intramolecular proto-
nation. Nevertheless, the pyridyl group is acting primarily
sterically.
Figure 1. Regioselectivity of enol 4 with HOAc.
Strikingly, in these endo pyridyl acetic acid runs the major
process is intramolecular protonation to afford diastereomer
12 as long as the acid concentration was at least 0.17 M.
Note eq 3. We note that here, as in all cases in the present
study where thermodynamic products resulted, control runs
established that the reaction was kinetic and equilibration
was not occurring.
In the case of triethylammonium chloride, another weak
acid, the endo-pyridyl diastereomer 4 afforded a ratio of 3:1
while the endo-phenyl isomer 3 gave a 9:1 ratio. Thus, again,
the weak acid was unable to efficiently protonate the pyridine
nitrogen, and the less hindered approach was observed with
both diastereomeric enols. The stereochemistry is indepen-
dent of these donor concentrations, both for this case and
that of the phenol protonation, and m equals n.
A remarkable result was encountered in the hydrochloric
acid protonation of enol 4. With or without fluoride (in this
case, fluoride proved unnecessary) there was again a
dependence of the stereochemistry on the concentration of
proton donor. However, in contrast to the acetic acid
example, the slope of the n - m plot was reversed (note
Figure 2) with a slope of close to -1 (i.e., -0.96) and an
intercept of -0.92.
It has been noted3 that the ratio of intra- to intermolecular
proton-transfer products is given by eq 4. Here Pint and Pext
are the products resulting from intra- and intermolecular
proton transfer. The k’s are the rate constants and [HA] is
the proton donor concentration; n and m are the number of
proton donor molecules required in the intra- and intermo-
lecular reactions, respectively:
Pint
Pext
kint
kext
With HCl as the donor, protonation of enol 3 led
exclusively via the less hindered approach to ketone 7.
It is clear that the stereochemistry of enols 3 and 4 is varied
and complex depending on which diastereomer is employed
and what proton donor is involved. The pattern is outlined
in Table 1.
log
) (n - m) log[HA] + log
(4)
(
)
(
)
The data obtained are plotted in Figure 1. The slope n -
m is 1.2, or within reasonable experimental error of unity.
We note that the slope of the plot only gives the difference
in the reaction orders for the two processes.
The first and most striking point to be made is that
intramolecular proton delivery now promises to be a general
(4) (a) A 15-step synthesis was employed to obtain the silyl enol ethers
and will be described in our full publication. (b) In a typical run, 4.0 mg of
the silyl enol ether in 0.40 mL of acetonitrile was treated with 2 equiv of
acetic acid and 2 equiv of tetrabutylammonium fluoride (1.0 M in THF).
After 4 h, the reaction was 90% complete, and the ketonized diastereomers
were analyzed by proton NMR.
(5) (a) Smirnov, S. N.; Golubev, N. S.; Denisov, G. S., Bendict, H.;
Schah-Mohammdei, P.; Limbach, H.-H. J. Am. Chem. Soc. 1996, 118,
4094-4101. (b) 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.
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Org. Lett., Vol. 4, No. 15, 2002

protonation of pyridine by a trimer6 and intermolecular
protonation by the dimer would also account of the n - m
value of unity.
The case of protonation by phenol is particularly interest-
ing. Phenol with a pKa of ca. 10 is insufficiently acidic to
protonate the 2-pyridyl group (pKa conj acid ca. 5). Thus, in
contrast to the acetic acid ketonizations, the protonation
process is aware of pyridyl only as a sterically blocking group
equivalent to phenyl. As a consequence, protonation from
the less hindered face affords the same regioselectivity as
with a phenyl blocker.
The inverse slope observed with hydrochloric acid pro-
tonation, with more than an equivalent of the acid, clearly
results from complete pyridyl protonation by this strong acid.
Thus the intramolecular proton transfer is zero order in
concentrations of hydrochloric acid beyond the one equiva-
lent (i.e., n ) 0), while the intermolecular process is first
order in hydrochloric acid (m ) 1). Hence n - m is minus
unity as observed in Figure 2.
A further point of interest is the geometry of the endo-
pyridyl protonation process. Thus, it seems likely that the
initial pyridyl protonation occurs from a conformation in
which the pyridyl nitrogen is more accessible. This, then, is
followed by a twist and intramolecular protonation. The twist
is depicted in eq 6.
Figure 2. Regioselectivity of enol 4 with HCl.
phenomenon. Thus we have a second example of a 2-pyridyl
moiety being able to deliver a proton to the more hindered
face of an enolic π-bond just as in ordinary situations proton
donors prefer the less hindered enolic face under kinetic
conditions.
Table 1. Ratio of External to Intramolecular Protonationa
proton donor
diastereomer
HOAcb
phenol
Et3NHCl
HCl
endo phenyl
endo pyridyl
7.3:1
1:24
19:1
5.7:1
9:1
3:1
1:0
1:5.3c
a The ratio of products 7 to 8 for the enol 3 and 11 to 12 for the enol 4.
b Ratio given for 1.4 M HOAc. c For 0.022 M HCl.
With kinetic protonation of delocalized systems pervading
organic chemistry by virtue of their intermediacy in a very
large variety of reactions,7 it becomes critical to determine
in which situations protonation will occur externally and in
which cases it will proceed intramolecularly as in the present
study. We are proceeding to determine other modes of
intramolecular delivery.
A second conclusion, equally intriguing, derives from the
kinetic observation of a unity value for n - m. This value
signifies that one more acetic acid molecule is required for
the intramolecular protonation than for the intermolecular
process. The simplest assumption, as noted above, is that a
single acetic acid molecule is involved in the intermolecular
protonation. Hence two acetic acid molecules are required
for the intramolecular transfer. The first acetic acid molecule
is required to bond to nitrogen, generating incipient pyri-
dinium and acetate species. The acetate generated is distant
from the enolic hydroxyl but can interact with a second acetic
acid molecule to provide an acetate anion in proximity of
the enolic hydroxyl. It is known6 that ketonization of enols
occurs preferentially by protonation of the enolate rather than
the neutral enol. Thus the second acetate can be involved in
the enol to enolate conversion.
Acknowledgment. Support of this research by the
National Science Foundation is gratefully acknowledged with
special appreciation for its support of basic research.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL026251P
(7) The phenomenon has been proven of value in synthesis, often
unexpectedly. Interestingly, the concept has been rediscovered twice,8 and
it seems that the rediscoveries are often cited.
(8) (a) Gerlach, U.; Haubenreich, T.; Hu¨nig, S.; Keita, Y. Chem. Ber.
1993, 126, 1205-1215. (b) Takano, S.; Kudo, J.; Takahashi, N.; Ogasawara,
K. Tetrahedron Lett. 1986, 2405-2408. (c) Takano, S.; Uchida, W.;
Hatakeyama, S.; Ogaswara, K. Chem. Lett. 1982, 733-737. (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.; Tananka, M.; Seo, M.;
Hirama, M.; Ogasawara, K. J. Org. Chem. 1985, 50, 931-936. (g) Note
also: Hu¨nig, S. Protonation of Carbanions and Polar Double Bonds. Houben-
Weyl, Methods of Organic Chemistry; G. Thieme: Stuttgart, 1996; Vol.
E21D 7, pp 3851-3911.
If acetic acid aggregates are involved with an n-aggregate
for external protonation, then intramolecular proton transfer
must utilize an n + 1 aggregate. Thus, for example,
(6) (a) Base-Catalyzed Rearrangements. In Molecular Rearrangements;
Zimmerman, H. E., Ed.; P. DeMayo, Interscience: New York, 1963; Chapter
6, pp 345-406. (b) Malhotra, S. K.; Ringold, H. J. J. Am. Chem. Soc. 1965,
87, 3228-3236;
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