Base-promoted ring contraction of eight-membered cyclic acyloins and their ethers to Cs-symmetric α-ketols

Article abstract of DOI:10.1055/s-2003-41003

In the presence of potassium hexamethyldisilazide and 18-crown-6 in THF at room temperature, 2-benzyloxycyclooctanone and its Δ ⁵-unsaturated congener undergo a two-stage rearrangement to give symmetrical seven-membered ring products. The pathw

Full text of DOI:10.1055/s-2003-41003

1872
SHORT PAPER
Base-Promoted Ring Contraction of Eight-Membered Cyclic Acyloins and
their Ethers to Cs-Symmetric -Ketols
R
ing Con
v
traction of
E
a
ight-Mem
b
n
ered
C
yclic Acylo
V
ins and their
E
the
r
i
s
to -K
l
etols otijevic, Jiong Yang, David Hilmey, Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
Fax +1(614)2921685; E-mail: paquette.1@osu.edu
Received 22 April 2003
Abstract: In the presence of potassium hexamethyldisilazide and
18-crown-6 in THF at room temperature, 2-benzyloxycyclo-
octanone and its 5-unsaturated congener undergo a two-stage re-
arrangement to give symmetrical seven-membered ring products.
The pathway consists of the sequential operation of an O C 1,2-
Scheme 2
shift and an -ketol rearrangement. The greater thermodynamic sta-
bility of the cycloheptane or cycloheptene generated in this fashion
is substantiated by MM3 calculations.
out experimentally. The preparation of 5 required re-
course to acidic trichloroacetimidate technology2
(Scheme 3).1 In turn, 5 was recovered without noticeable
chemical change following treatment with NaH in DMF,
LDA in THF, or KN(SiMe3)2 in THF at room temperature
for prolonged periods of time. Base-promoted 1,2-shifts
of the type 5 6 in -benzyloxy ketones are known to op-
erate under comparable conditions,3 and the recalcitrance
of 5 prompted further exploration of its potential for rear-
rangement. This aspect of medium-ring chemistry forms
the subject of the present report.
Key words: ring contractions, ketones, rearrangements, carbocy-
cles, isomerizations
In a recent study,1 2-hydroxycyclooctanone (1) and 2-hy-
droxy-5-cyclooctenone (3) were found to react with acti-
vated halides under basic conditions (NaH, DMF, –15 °C)
to afford in highly chemoselective fashion the products of
C-alkylation (2) and their alkoxide isomers 4, respectively
(Schemes 1 and 2). The causative factor underlying the
clean demarcation of this pair of kinetically controlled
substitution reactions is considered to reside in the inabil-
ity of the unsaturated reactant 3 to attain a conformation
conducive to ready proton abstraction at C-2. The same
impedance to proper stereoelectronic alignment of this
key -hydrogen is not present in the more flexible saturat-
ed system.
When the reactivity of potassium hexamethyldisilazide
was boosted by the co-addition of an equivalent amount of
18-crown-6, 5 underwent efficient conversion to the sym-
metrical ring-contracted isomer 7 over 10 minutes As
well, it was shown independently that analogous exposure
of 6 to these conditions likewise resulted in smooth con-
version to 7 (Scheme 4). The formation of 7 can therefore
be logically ascribed to the operation of an -ketol rear-
rangement.4
To expand our view of this ring contraction process, our
attention was turned to 8 in order to assess possible long-
range effects of its double bond. We were amazed to see
that the conversion of 8 to 9 in the presence of 18-crown-
6 required a minimum of 8 hours (Scheme 5).5 Proof of
structure was gained from the very evident symmetry of 9
and its catalytic hydrogenation to deliver 7. The identical
transformation took place with equally modest efficiency
Scheme 1
This conclusion was supported by MM3 calculations of
the respective ground states and the execution of proper
control experiments. Thus, the possibility that the alkyla-
tion of 1 is the end result of a facile O C shift was ruled
Scheme 3
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 07 08 2003.
Art Id.1437-210X,E;2003,0,12,1872,1874,ftx,en;M01303SS.pdf.
DOI: 10.1055/s-2003-41003
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Ring Contraction of Eight-Membered Cyclic Acyloins and their Ethers to -Ketols
1873
When the double bond is present, the disparity in steric
energy grows to 3.7 kcal/mol and favors 9 over 11. This
increased energy difference could be attributed to the ex-
istence of a favorable OH/C=O interaction in 9. A compa-
rable arrangement is present only in the 19th lowest
energy conformation of the cyclooctenone 11 relative to
its global minimum. Visual inspection of the three-dimen-
sional models shown in Figure 1 suggests that this state of
affairs is brought on by increased nonbonded steric com-
Scheme 4
when 11, obtained by the addition of benzylmagnesium pression between the eight-membered ring and benzyl
bromide to -diketone 10,6 was comparably processed.
substituent. This interaction is absent in 9.
On the basis of the experiments documented here, it is In conclusion, we have investigated the susceptibility of
clear that benzyl migration in keto ethers 5 and 8 sets the 2-oxygenated cyclooctanones and 5-unsaturated analogs
stage for base-induced -ketol rearrangement, the ring thereof to base-promoted structural isomerization. The
contraction constituting a means for generating tertiary - dominant themes consist of the initial O
hydroxy ketones having a cycloheptane or cycloheptene tion of 2-alkoxy derivatives and sequential operation of an
motif. Since the rearrangement in question is an equilibri- -ketol ring contraction. The protocol is likely to be of
C isomeriza-
um-based chemical change, our observations implicate general interest as a direct route to functionalized seven-
greater thermodynamic stability for the seven-membered membered ring compounds.
isomer of each -ketol pair. The results of MM3
calculations7 involving a Monte-Carlo search carried out
with the MacroModel 5.0 software package are compiled
THF was distilled from sodium benzophenone ketyl and DMF was
distilled from CaH2. Comercially available reagents were used as
in Figure 1. In the saturated series, cyclooctanone 6 is
seen to be less stable than cycloheptanol 7 by 1.9 kcal/mol
(Scheme 5). This difference in steric strain cannot be at-
tributed to selective intramolecular hydrogen bonding in
7. In fact, this interaction, if operative, would serve to
bring the two isomers closer in energy since it is present
in the global minimum of 6 but not of 7.
recieved. 1H NMR (Bruker, 300MHz) and 13C NMR (Bruker,
75MHz) spetra were recorded in CDCl3, and chemical shifts (delta)
are given in ppm relative to CHCl3 (7.23ppm). IR spectra were de-
termined on a Perkin–Elmer 1600 series FTIR. Column chromato-
graphy was performed with E. Merck silica gel (230–400 mesh)
using flash chromatography techniques. All reactions were per-
formed under a nitrogen atmosphere.
Rearrangement of 5, 6, 8 and 11 to 7 and 9; General Procedure
A solution of 5 (115 mg, 0.50 mmol) and 18-crown-6 (396 mg, 1.50
mmol, from 458 mg of the MeCN complex after 12 h under high
vacuum) in anhyd THF (10 mL) was treated dropwise with a solu-
tion of potassium hexamethyldisilazide in toluene (3 mL of 0.5 M,
1.50 mmol) and stirred at r.t. The progress of reaction was moni-
tored by TLC. After consumption of starting material (10 min for 5
and 6; 8 h for 8 and 11), H2O was carefully introduced and the mix-
ture was extracted with Et2O. The combined organic phases were
dried and evaporated. The residue was chromatographed [silica gel;
EtOAc (3%) in hexanes] to afford 7.
Yield: 105 mg (91%); colorless oil.
IR (neat): 3474, 1706 cm–1.
1H NMR (300 MHz, CDCl3): = 7.36–7.19 (m, 5 H), 3.98 (s, 2 H),
3.40 (s, 1 H), 2.00–1.59 (m, 12 H).
Scheme 5
Figure 1 The three lowest energy conformations of 5
Synthesis 2003, No. 12, 1872–1874 © Thieme Stuttgart · New York

1874
I. Vilotijevic et al.
SHORT PAPER
Figure 2 The three lowest energy conformations of 6
13C NMR (75 MHz, CDCl3): = 212.1, 133.9, 129.5 (2 C), 128.6 (2
C), 127.0, 81.3, 42.6, 37.8 (2 C), 29.1 (2 C), 23.1 (2 C)
13C NMR (75 MHz, CDCl3): = 216.8, 135.5, 131.0, 130.5, 130.4,
128.5 (2 C), 127.1 (2 C), 82.3, 46.4, 42.8, 37.4, 22.0, 21.9.
ES HRMS: m/z calcd for C15H20O2Na (M + Na)+: 255.1355; found:
ES HRMS: m/z calcd for C15H18O2Na (M + Na)+: 253.1199; found:
255.1360.
253.1208.
Compound 9
Hydrogenation of 9
Colorless oil.
IR (neat) 3464, 1706 cm–1.
1H NMR (300 MHz, CDCl3): = 7.36–7.18 (m, 5 H), 5.87–5.84 (m,
2 H), 3.89 (s, 2 H), 3.41 (br s, 1 H), 2.61–2.52 (m, 2 H), 2.16–2.08
(m, 2 H), 1.97–1.88 (m, 2 H), 1.62–1.55 (m, 2 H).
13C NMR (75 MHz, CDCl3): = 211.2, 133.7, 132.1, 129.5 (2 C),
128.6 (2 C), 127.1 (2 C), 81.2, 42.7, 35.2 (2 C), 22.8 (2 C).
A solution of 9 (10 mg, 0.043 mmol) in anhyd EtOH (1 mL) was
treated with 10% palladium on charcoal (4 mg). Hydrogen gas was
bubbled through this solution for 10 min and the reaction mixture
was left to stir at r.t. Additional hydrogen was introduced every 4 h.
After 4 days, the catalyst was removed by filtration through a pad
of silica gel, which was rinsed in turn with EtOH. The solvent was
removed under vacuum and the residue was chromatographed [sili-
ca gel; EtOAc (3%) in hexanes] giving 9 (8.2 mg), and 7 (1.5 mg,
15%; 83% based on recovered starting material), spectroscopically
identical with the sample generated above.
ES HRMS: m/z calcd for C15H18O2Na (M + Na)+: 253.1199; found:
253.1206.
2-Benzyl-5-cycloocten-2-ol (11)
References
A solution of benzylmagnesium bromide in Et2O (0.65 mL of 0.5
M, 0.33 mmol) was added slowly to a solution of 106 (45 mg, 0.33
mmol) in anhyd Et2O (2.5 mL). The reaction mixture was stirred at
r.t. for 2 days and quenched with H2O. The separated aq phase was
extracted with Et2O and the combined organic solutions were dried
and concentrated. Chromatography of the residue [silica gel; EtOAc
(5%) in hexanes] gave 11.
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Lett. 2003, 5, 463.
(2) (a) Overman, L. E. Acc. Chem. Res. 1980, 13, 218; and
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(5) Several by-products are also generated under these longer-
term conditions. These proved to be difficult to separate and
have not been characterized.
(6) Kowar, T. R.; LeGoff, E. J. Org. Chem. 1976, 41, 3760.
(7) Allinger, N. L.; Yuh, Y. H.; Lii, J.-H. J. Am. Chem. Soc.
1989, 111, 8551.
Yield: 60 mg (80%); white crystals; mp 102–103 C.
IR (CHCl3) 3363, 1690 cm–1.
1H NMR (300 MHz, CDCl3): = 7.33–7.14 (m, 5 H), 5.72–5.67 (m,
2 H), 3.21 (d, J = 13.4 Hz, 1 H), 2.91–2.78 (m, 2 H), 2.78 (d,
J = 13.4 Hz, 1 H), 2.60 (br s, 1 H), 2.58–2.17 (m, 3 H), 2.06–1.96
(m, 1 H), 1.93–1.82 (m, 1 H), 1.66–1.55 (m, 1 H).
Synthesis 2003, No. 12, 1872–1874 © Thieme Stuttgart · New York