A chelation effect on the pathway between intramolecular hydrodimerization and pinacol coupling

Article abstract of DOI:10.1021/ol0502026

(Chemical Equation Presented) Depending upon the reaction conditions, the reductive cyclization affords either the pinacol or normal hydrodimerization- type products. This selectivity is highly dependent upon the substitution at the β-position of the enon

Full text of DOI:10.1021/ol0502026

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1553-1555
A Chelation Effect on the Pathway
between Intramolecular
Hydrodimerization and Pinacol Coupling
Scott T. Handy* and Duncan Omune
Department of Chemistry, State UniVersity of New York at Binghamton,
Binghamton, New York 13902-6000
shandy@binghamton.edu
Received January 31, 2005
ABSTRACT
Depending upon the reaction conditions, the reductive cyclization affords either the pinacol or normal hydrodimerization-type products. This
selectivity is highly dependent upon the substitution at the -position of the enones.
â
The hydrodimerization reaction is a very powerful reaction
that has been extensively studied over the years.1 One
particular variant of this reaction, the intramolecular hy-
drodimerization reaction, has received much less attention,
despite its considerable synthetic potential.2 Recently, we
have begun a more thorough investigation of this reaction
with the intent of understanding the effect of variables such
as â-substitution, tether length, mixed enone/enoate systems,
and the reaction conditions. Rather surprisingly, the studies
of compounds with a one-carbon tether (such as substrate
1), originally viewed as a potential route to linear triquinanes
and other five-member-ring-containing materials, displayed
very different behaviors depending upon the reaction condi-
tions. This effect and its potential implications are the focus
of this communication.
mainly 3. However, when the reaction was quenched after
only 2 h, ketone 2 could be reliably obtained in 90% yield.
Scheme 1. Synthesis of Cyclization Substrates
The preparation of 1 began with the synthesis of known
ketone 2 by the condensation of 1,3-cyclohexanedione with
paraformaldehyde in the presence of boron trifluoride-
etherate.3 Reaction time proved to be an important variable
in this reaction, since longer reaction times (4 h) afforded
(1) Nielsen, M. F.; Utley, J. H. P. Reductive Coupling. In Organic
Electrochemistry, 4th ed.; Lund, H., Hammerich, O., Eds.; Marcel Dekker:
New York, 2001; pp 795-882.
(2) Little, R. D.; Schwaebe, M. K. Topics Curr. Chem. 1997, 185, 1-48.
(3) Smith, A. B.; Dorsey, B. D.; Ohba, M.; Lupo, A. T.; Malamas, M.
S. J. Org. Chem. 1988, 53, 4314-4325.
10.1021/ol0502026 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/16/2005

At this point, treatment with titanium tetrachloride served
to form compound 4 in essentially quantitative yield.
From compound 4, three different cyclization substrates
were prepared. For the simple, â-unsubstituted compound
1, treatment with excess lithium aluminum hydride, followed
by acidic hydrolysis of the intermediate diol, afforded the
desired compound 1 in 52% yield. The dimethyl substrate 5
was prepared in similar fashion by adding an excess of
methyllithium, followed by acidic hydrolysis. Finally, the
monomethyl substrate 6 was prepared by addition first of 1
equiv of DIBAL-H, then 1 equiv of methyllithium, and
finally acidic hydrolysis. This sequence afforded compound
6 in a reasonable 55% yield overall.
trans, since it is not readily cleaved to afford the starting
materials 5 and 6 by treatment with sodium periodate.
Since nonelectrochemical conditions are also known to
promote the reductive cyclization reaction, we chose to
investigate one of these alternatives and determine what
effect it had on the cyclization and product outcome of these
reactions.7 Our choice was the use of samarium diiodide.
Treatment of substrate 1 with 3 equiv of samarium diiodide
at room temperature in THF under argon afforded the
anticipated cyclization product 7 in 25% yield. Again, the
product was isolated as a single isomer, the same as under
the electrochemical conditions. Interestingly, treatment of 5
and 6 under these samarium diiodide conditions also afforded
the reductive cyclization products 10 and 11 as single
isomers, with none of the pinacol product being detected.
The stereochemistry of product 11 is assigned as cis/anti/cis
on the basis of the stereochemistry of product 7 and the fact
that product 11 is symmetrical (only eight signals observed
in the 13C NMR spectrum and only one methyl signal
With these three compounds in hand, the reductive
cyclization was first explored under electrochemical condi-
tions (Scheme 2). Subjection of compound 1 to a constant
Scheme 2. Electrochemical Cyclizations
1
observed in the H NMR spectrum). Further evidence for
the cis ring fusion comes from the observation of an NOE
between the ring fusion methyl and the ring fusion proton.
The cis/anti/cis arrangement of product 10 is assigned by
analogy with the outcome of the other two cyclizations.
While these results clearly indicated that reductive cy-
clizations can be achieved on these shorter tether compounds,
they also raised the question as to why the electrochemical
conditions were leading to pinacol and the samarium diiodide
conditions to reductive cyclization. This question is even
more perplexing, since no similar difference was observed
in the cyclization of a compound related to 5 but with two
carbons in the tether between the two enones.8 In examining
these systems, one possible hypothesis is that chelation and
steric effects play the determining factor. Assuming that the
reductive cyclization of these compounds is proceeding via
a one-electron reduction of each enone to a radical anion,
followed by radical/radical coupling (the most commonly
postulated mechanism for such reactions), then the situation
outlined in Scheme 4 could help to explain the observed
results.1
current of 200 mA for 1 h using a sacrificial tin anode and
a platinum cathode in aqueous acetonitrile with tetraethyl-
ammonium chloride as the supporting electrolyte afforded
the anticipated cyclization product 7 in 73% yield as a single
isomer.4 The stereochemistry of this product was confirmed
to be cis/anti/cis by double Wolff-Kishner reduction to
afford the known perhydrofluorene compound.5
When there is no hindrance at the â-position, then the
reaction proceeds via the normal reductive cyclization
Interestingly, the reductive cyclizations of substrates 5 and
6 did not follow the same pattern. Both of these compounds
afforded only the pinacol-type products 8 and 9 under
electrochemical conditions. Although somewhat surprising,
this is not unprecedented, since steric hindrance at the
â-position is known to favor the pinacol product in the
intermolecular hydrodimerization of cyclic enones.6 The
stereochemistry of the pinacol products is assigned as being
Scheme 3. Samarium Diiodide Cyclizations
(4) Conditions were adapted from those reported by Kise and co-workers.
Kise, N.; Iitaka, S.; Iwasaki, K.; Ueda, N. J. Org. Chem. 2002, 67, 8305-
8315.
(5) Meusinger, R.; Rohloff, J.; Schumann, F.; Herzschuh, R. J. Prakt.
Chem./Chem.-Ztg. 1997, 339, 128-134.
(6) In addition to ref 1, for a specific example, see: Tissot, P.; Surbeck,
J.-P.; Guelacar, F. O.; Margaretha, P. HelV. Chim. Acta 1977, 60, 1472-
1477.
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Org. Lett., Vol. 7, No. 8, 2005

The absence of any pinacol products in the two-carbon
tether compound related to 5 can also be explained using
this rationale, since attempts to form a tin-chelated interme-
diate would require the formation of an even larger nine-
member chelate. Entropic considerations now favor the more
typical reductive cyclization product.
Scheme 4. Mechanistic Rationale
On the basis of this mechanistic rationale, it was expected
that reductive cyclizations with metals capable of chelation
should favor the pinacol pathway for compounds 5 and 6,
while metals incapable of chelation should favor the reductive
cyclization pathway. To test this hypothesis, a reductive
cyclization of 5 was performed using magnesium metal in
MeOH (Scheme 5). On the basis of the previous rationale,
Scheme 5. Cyclization Using Magnesium in Methanol
manifold. As this hindrance becomes an issue, however, then
chelation to form intermediate 12 can occur.9 This will be
particularly facile under the sacrificial anode conditions, since
Lewis acidic tin(II) and/or tin(IV) salts will be generated.
These salts can then coordinate to the two carbonyls and
form an eight-member chelate that favors reaction at the
carbonyls to form the pinacol products.
For the samarium diiodide conditions, chelation plays less
of a role since each one of the enones must be reduced by
one molecule of samarium diiodide to form a samarium(III)
enolate and the â-radical. Assuming that radical/radical
coupling proceeds faster than any reorganization of the
coordination sphere of the samarium ions, then no cyclic
chelate would result and the hydrodimerization product
would be formed. Indeed, in this case the steric hindrance
at the carbonyl is now increased due to the samarium ion
and its ligands (such as HMPA and THF), thereby further
favoring reaction at the â-position.
it was anticipated that this reaction should afford the pinacol
product 8. Indeed, this was the sole reaction product, isolated
in 78% yield, and was identical to that obtained using the
electrochemical conditions.
In conclusion, we have noted that tethered bis-enones with
one-carbon tethers can successfully undergo the reductive
cyclization. Choice of reaction conditions is important in
these cases to avoid a competing pinacol process, which is
rationalized on the basis of a metal-chelated intermediate
coupled with steric hindrance to cyclization at the â-position.
Further studies of this reaction, the mechanism, and synthetic
applications are in progress and will be reported in due
course.
(7) Photochemical: Pandey, G.; Hajra, S.; Ghorai, M. K.; Kumar, K. R.
J. Am. Chem. Soc. 1997, 119, 8777-8787. Pandey, G.; Ghorai, M. K.;
Hajra, S. Tetrahedron Lett. 1998, 39, 1831-1834. Pandey, G.; Chorai, M.
K.; Hajra, S. Tetrahedron Lett. 1998, 39, 8341-8344. Tin Hydride: Enholm,
E. J.; Kinter, K. S. J. Org. Chem. 1995, 60, 4850-4855. Samarium
Diiodide: Cabrera, A.; Lagadec R. L.; Sharma, P.; Arias. J. L.; Toscano,
R. A.; Velasco, L.; Gavino, R.; Alvarez, C.; Salmon, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 3609-3617.
Acknowledgment. The authors thank the State University
of New York at Binghamton and the Research Foundation
for financial support of this work.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Mandell, L.; Daley, R. F.; Day, Jr., R. A. J. Org. Chem. 1976, 26,
4087-4089. Handy, S. T.; Omune, D. Unpublished results.
(9) Chelation has been implicated in the selectivity of prior hydrodimer-
ization reactions, particularly those done in protic solvents. For an example,
see: Tissot, P.; Surbeck, J.-P.; Guelacar, F. O.; Margaretha, P. HelV. Chim.
Acta 1981, 64, 1570-1574.
OL0502026
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