Neighboring group participation in a regio- and stereoselective chlorination of a bicyclo[2.2.2]octanone

Article abstract of DOI:10.1021/jo9607370

The zinc chloride-mediated acetylation of the optically active silyl enol ether 2a gave the β-diketone 3a (48%) together with the regio- and stereoselectively chlorinated compound 4 (27%). The yield of 4 increased to 70% by starting from the O-acetyl derivative 2c. The chlorination most likely occurs via neighboring group participation by the endo acetoxy group.

Full text of DOI:10.1021/jo9607370

J . Org. Chem. 1996, 61, 6947-6951
6947
Neigh bor in g Gr ou p P a r ticip a tion in a Regio- a n d Ster eoselective
Ch lor in a tion of a Bicyclo[2.2.2]octa n on e
Fredrik Almqvist and Torbjo¨rn Frejd*
Organic Chemistry 1, Department of Chemistry, Lund University, P. O. Box 124, S-221 00 Lund, Sweden
Received April 23, 1996X
The zinc chloride-mediated acetylation of the optically active silyl enol ether 2a gave the â-diketone
3a (48%) together with the regio- and stereoselectively chlorinated compound 4 (27%). The yield
of 4 increased to 70% by starting from the O-acetyl derivative 2c. The chlorination most likely
occurs via neighboring group participation by the endo acetoxy group.
Sch em e 1a
Optically active bicyclo[2.2.2]octane derivatives have
attracted attention as rigid templates for regio- and
stereocontrolled transformations toward natural prod-
ucts.1-3 Several other synthetic applications of optically
active bicyclo[2.2.2]octane derivatives have been re-
ported,4-8 and very recently racemic analogs were used
in combinatorial chemistry.9 We would also like to point
out the use of a racemic bicyclo[2.2.2]octane derivative
for the intentional construction of taxanes.10 Our initial
aim was to prepare optically active bicyclo[2.2.2]octane
derivatives, e.g. â-diketones 3 (Scheme 2), for further
development into ligands for asymmetric synthesis.11
During this work we encountered an unexpected stereo-
and regioselective chlorination during acetylation at-
tempts of the bicyclo[2.2.2]octane enol ethers 2a -c,
which is reported here as well as its probable mechanism.
Our attempts to acetylate directly the enolate of ketone
1b (Scheme 1), generated by LDA treatment, using
acetylating agents such as acetyl chloride or N-acetyl-
imidazole were unsuccessful; only starting material was
recovered. This sluggishness was also observed for
another class of reagents namely, diphenyl disulfide and
phenylsulfenyl chloride, with the same ketone enolate.12
Silyl enol ethers seem to be better choices for synthesis
of 1,3-diketones but still O-acylation may be the major
reaction.13 In order to avoid this complication, Rathke
et al.14 recommended a zinc chloride/acetyl chloride
mixture for C-acetylation of silyl enol ethers. These
conditions were reported to give good yields of 1,3-
diketones with formation of only minor amounts of the
O-acetylated product. We applied these and other condi-
tions to the TMS-enol ethers 2a -d , prepared according
a
(a) TBDMSCl, imidazole, DMF, 97%; (b) p-methoxybenzyl
trichloroacetimidate, BF3‚OEt2, 0 °C to rt, 87%; (c) Ac2O, pyr, 95%;
(d) MeI, Ag2O, MeCN, reflux, 81%; (e) LDA, TMSCl, -72 °C, >90%;
(f) LiBr, TMSCl, NEt3, -20 to +40 °C, 84%.
to Scheme 1, and our experiments are shown in Table 1
and Scheme 2.
Resu lts a n d Discu ssion
Treatment of 2a with the zinc chloride/acetyl chloride
mixture gave 3a as the major product (entry 1). This
was the desired product although the protecting group
at O-6 was exchanged for an acetyl group. Also some
1d was isolated. Since chlorination has not been reported
previously with this reagent mixture, we were surprised
to find that chloro enone 4 was formed in considerable
amounts (27%). When the zinc chloride was used directly
as delivered (i.e. without drying), the only product was
1d (entry 2). In order to circumvent the chlorination,
we tried other Lewis acids containing no halogens. Zinc
tosylate gave only 1d (entry 3) without any C-acetylated
product. C-acetylation did occur, albeit with the TBDMS
group exchanged for an acetyl group, by application of
the zinc triflate/acetyl chloride mixture (entry 4). But
here also a trace of the chlorinated derivative 4 was
detected together with a substantial amount of 1d .
On treatment of 2a with acetyl chloride in the presence
of the strong Lewis acids TiCl4 and SnCl4 (entries 5 and
6) only deprotection of the TBDMS-ether and restoration
of the keto function occurred. It is likely that the keto
group was restored during the aqueous workup. With
the milder Lewis acids, silver triflate and MgCl2, the
OTBDMS-protecting group survived but C-acetylated or
-chlorinated products were not detected in any of these
cases (entries 7, 8). It should be mentioned that the most
substituted TMS-enol ether of 2-methylcyclohexanone
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Mori, K. Synlett 1995, 1097-1109.
(2) Paquette, L. A.; Tsui, H.-C. Synlett 1996, 129-130.
(3) Paquette, L. A.; Tsui, H.-C. J . Org. Chem. 1996, 61, 142-145.
(4) Waldmann, H.; Weigerding, M.; Dreisbach, C.; Wandrey, C. Helv.
Chim. Acta 1994, 77, 2111-2116.
(5) Be´langer, P. C.; Dufresne, C. Can. J . Chem. 1986, 64, 1514-
1520.
(6) Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J .; Ziller, J . W.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2386-2388.
(7) Seebach, D.; J aeschke, G.; Wang, Y. M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2395-2396.
(8) Almqvist, F.; Frejd, T. Tetrahedron Asymmetry 1995, 6, 957-
960.
(9) Ley, S. V.; Mynett, D. M.; Koot, W.-J . Synlett 1995, 1017-1020.
(10) Martin, S. F.; White, J . B.; Wagner, R. J . Org. Chem. 1982, 47,
3190-3192.
(11) Almqvist, F.; Torstensson, L.; Gudmundsson, A.; Frejd, T. To
be published.
(12) Almqvist, F.; Ekman, N.; Frejd, T. J . Org. Chem. 1996, 61,
3794-3798.
(13) Rasmussen, J . K. Synthesis 1977, 91-110.
(14) Tirpak, R. E.; Rathke, M. W. J . Org. Chem. 1982, 47, 5099-
5102.
S0022-3263(96)00737-2 CCC: $12.00 © 1996 American Chemical Society

6948 J . Org. Chem., Vol. 61, No. 20, 1996
Almqvist and Frejd
Ta ble 1. Resu lts of th e Lew is Acid -Acetyl Ch lor id e Tr ea tm en t of 2a -d
Isolated yields (%)
entry
silyl enol ether
MX
conditions
3
4
1
a
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2c
2d
2b
ZnCl2
ZnCl2
0 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
-72 °C f rt
-72 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
3a 48
-
27
-
1d 16
1d 78
1d 74
1d 38
1a 74
1a 68
1b 70, 1a 10
1b 64, 1a 12
1d 24
b
Zn(tosylate)2
Zn(OTf)2
TiCl4
-
-
3a 50
-
traces
-
SnCl4
-
-
AgOTf
-
-
MgCl2
-
-
a
ZnCl2
ZnCl2
ZnCl2
3a 2
3b 13
3a 44
70
-
a
10
11
1e 27
1d 11
a
21
a
b
Dried (see Experimental Section). The commercial quality was used as delivered.
Sch em e 2
Sch em e 3
Sch em e 4. Ten ta tive Mech a n ism Sh ow in g th e
Neigh bor in g Gr ou p P a r ticip a tion of th e 6-OAc
Gr ou p
was reported to give a very high yield of the 1,3-diketone
on treatment with TiCl4/acetyl chloride.15,16
The PMB-ether 2b (entry 11) behaved essentially as
the TBDMS-ether in entry 1. Both gave exchange of the
protecting groups and very similar product distributions.
On the other hand, the methyl ether derivative 2d did
not result in any chlorinated compounds (entry 10) at
the expected interval of retention times as judged by GC-
mass spectroscopy. For unknown reasons, 2d gave a
large number of products of which only 3b and 1e were
isolated. Since the protecting group at O-6 was ex-
changed in several reactions, we simply applied com-
pound 2c, having an O-6 acetyl group already in place,
as a substrate. This gave, on treatment with the dry
ZnCl2/acetyl chloride mixture, a quite high yield of 4
(70%) and a small amount of 1d (entry 9).
From the above experiments it is obvious that the
acetyl group at O-6 is necessary for an efficient conver-
sion into the chloro enone 4. It also seems necessary to
maintain a high chloride concentration since neither zinc
triflate nor zinc tosylate gave much chlorinated product,
despite the presence of acetyl chloride. In some of the
reactions of 2a we observed that some of the C-acetylated
product was formed, which still carried the O-TBDMS
group. Thus, it seems possible that the C-acetylation is
competing with the deprotective acetylation at O-6 (un-
less the O-6 carries an acetyl group already). The next
event should be the chlorination of some intermediate,
which is likely to be a zinc enolate of the 1,3-diketone.
Acetyl group participation is indicated from the experi-
ment in entry 10, which does not result in any chlorina-
tion but does give some C-acetylation, and the high yield
when the O-6 acetate is present from the beginning (entry
9). Moreover, compound 5, lacking a participating group,
gives only the O-acetyl enolate 6 (Scheme 3) in good yield.
On the basis of these observations, we propose the
mechanism shown in Scheme 4. Thus, the C- and O-6
acetylated primary intermediate forms a zinc enolate
(possibly a chelate), which is triggered to lose a chloride
ion by participation of the endo-positioned acetoxy group
(A f B). It is then possible that the chloride migrates
to the exo-methylene carbon without becoming entirely
free (B f C). During this migration, the acetoxy group
at C-6 is restored to give C, which then decomposes to
give 4. Whether the stereoselectivity originates from
kinetic or thermodynamic control is unclear. A mixutre
of the (E)- and (Z)-isomers may be formed initially which
then equilibrates to give only the (E)-derivative under
the reaction conditions. We have not been able to
validate this since the (Z)-derivatives were not available,
and the literature does not seem to give any leads.
However, ab initio (STO-3G) calculations17 confirmed
that the (E)-isomer is 4.4 kcal/mol lower in energy than
the (Z)-isomer and thus would dominate under thermo-
dynamic control. It should be noted that in all cases
where there is a hetero substituent at the exo-methylene
position (4, 6, 8,10) the (E)-configuration is obtained
except for OH, which stabilizes the (Z)-configuration via
hydrogen bonding (3a -c, 9).
Structural proof for 4 was obtained from its spectro-
scopic data. The presence of one chlorine atom as well
as the absence of the TBDMS group was obvious from
its mass spectrum. The 1H NMR data show a large
downfield shift of H-4 in 4 as compared with H-4 in 3a
(15) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic
Press: London, 1988.
(16) Fleming, I.; Iqbal, J .; Krebs, E.-P. Tetrahedron 1983, 39, 841-
846.
(17) SPARTAN 4.1, Hehre, W. J .; Huang, W. W., Wavefunction, Inc.,
Irvine, CA, 1995.

Chlorination of a Bicyclo[2.2.2]octanone
J . Org. Chem., Vol. 61, No. 20, 1996 6949
Sch em e 5a
In conclusion, we found that the use of the ZnCl2/acetyl
chloride mixture in the case of 2c gave the chlorinated
product 4 in high yield (70%). Also 2a gave a consider-
able amount of 4 with this reagent. The mechanism of
the chlorination most likely occurs via neighboring group
participation by the endo acetoxy group. The chlorination
could be avoided by the use of zinc triflate/acetyl chloride,
which is the reagent of choice for the direct synthesis of
3a from silyl enol ether 2a . Compound 4 can be trans-
formed into various optically active compounds such as
7, 8, 9, 10, and 3c, suitable for further development.
Exp er im en ta l Section
Gen er a l. GC analyses were performed with a SPB-5
(Supelco) capillary column (30 m, 0.25 mm i.d., 0.25 µm
stationary phase). NMR spectra were recorded at 300 or 400
MHz using CDCl3 (CHCl3 δ 7.26 (1H) and 77.0 (13C)) as solvent.
Chromatographic separations were performed on Matrex
Amicon normal phase silica gel 60 (0.035-0.070 mm), and for
TLC we used Merck precoated plates (silica gel 60 F-254, 0.25
mm). All solvents were dried and distilled according to
standard procedures,21 and the reactions were performed in
septum-capped, oven-dried flasks under an atmospheric pres-
sure of argon. Organic extracts were dried using Na2SO4
throughout. Optical rotations were measured at rt at the
sodium D-line.
Dry ZnCl2 was prepared as follows: ZnCl2 was added to a
flame-dried, weighed roundbottomed flask followed by SOCl2.
The mixture was heated at reflux temperature for 4 h, and
then the SOCl2 was evaporated at reduced pressure under
argon. The flask was placed in a desiccator over KOH pellets
and kept at reduced pressure overnight. The flask was
weighed and the amount of dry ZnCl2 was determined.
(1R,4S,6S)-6-[(ter t-Bu tyldim eth ylsilyl)oxy]bicyclo[2.2.2]-
octa n -2-on e (1b) was prepared according to published pro-
cedures.12
a
(a) 1 M HCl:EtOH, 50 °C, 5 h, 91%; (b) 1 M HCl:EtOH, reflux,
14 h, 83%; (c) TBDMSCl, imidazole, DMF, 84%; (d) KOtBu, THF,
-50 °C, quant; (e) K2CO3, MeOH:H2O, quant.
(3.43 ppm versus 2.85 ppm), which indicates that the
chlorine atom and H-4 are positioned close in space. A
differential NOE experiment further confirmed this
observation. A strong NOE between the ethylidene
methyl protons and H-4 would be expected for the (Z)-
isomer but not for the corresponding (E)-isomer. The
experiment showed the H-4fH-5 and H-4fH-8 NOE
effects, but none was detected between H-4 and the
ethylidene methyl protons. The (E)-configuration of 6
was determined similarly.
â-Chloro-R,â-unsaturated ketones synthesized from
R-allenones and SnCl4 were reported to have the (E)-
configuration,18 in agreement with our results. Other
methods such as the sodium acetate-induced elimination
of HCl from R-(1,1-dichloroethyl)cyclohexanone gave a 77/
23 mixture of the (E)- and (Z)-products.19 Still, the (E)-
isomer dominated. On the other hand, treatment of
R-acetylcyclohexanone with oxalyl chloride was reported
to give the (Z)-isomer as the major product, together with
the isomer having the chlorine atom at the ring position.20
The structure of the (Z)-isomer was not rigorously proven,
however.
Thus, not many examples of exo-chloroethylidene
ketones or analogues appear to be reported in the
literature, despite their seemingly high potential as
reactive intermediates in organic synthesis. Examples
of some useful transformations are shown in Scheme 5.
Compound 4 could be almost quantitatively transformed
into the chiral allene 7 on treatment with potassium tert-
butylate. Hydrolysis of 7 in methanol/water was not
selective; the acetyl group was removed but methanol
added to the allenic moiety. On the other hand, the
acetyl group of 4 could be selectively removed under
hydrolytic conditions to give 8, and under more forcing
conditions also the vinylic chloride function was hydro-
lyzed to generate the nonprotected 9, the 6-OH group of
which could be selectively protected after acidic work up
to give 3c. Thus a host of optically active compounds
can be obtained by selective manipulation of the func-
tionalities of 4. Since the reactions used in this work do
not allow racemization, we assume that the optical
purities of all compounds are at least as high as the
starting material 1a (97% ee). Some obvious aspects of
this chemistry is now under active investigation in our
laboratories.
(1R,4S,6S)-6-[(p-Meth oxyben zyl)oxy]bicyclo[2.2.2]octan -
2-on e (1c). Hydroxy ketone (-)-1a 22,23 (610 mg, 4.35 mmol)
in CH2Cl2 (5.0 mL) was added to a solution of p-methoxybenzyl
trichloroacetimidate24 (1.84 g, 6.51 mmol) in cyclohexane (10.5
mL) followed by addition of BF3‚OEt2 (8 µL) at 0 °C. After 30
min the cooling bath was removed, and after 12 h the resultant
nonhomogenous mixture was filtered through a pad of Hyflo-
Supercel. The pad was rinsed several times with CH2Cl2:
cyclohexane 1:2, and the combined solution was washed with
aqueous saturated NaHCO3 and dried. Concentration at
reduced pressure followed by chromatography (SiO2, heptane:
EtOAc 70:30) gave 1c as an oil (987 mg, 87%): [R] -27° (c
1
0.7, CHCl3); IR (neat) 3020, 2930, 1715, 1605, 1505 cm-1; H
NMR (400 MHz, CDCl3) δ 7.21 (d, J ) 8.4 Hz, 2H) 6.85 (d, J
) 8.4 Hz, 2H) 4.52 (d, J ) 11.4 Hz, 1H) 4.34 (d, J ) 11.4 Hz,
1H) 3.87 (m, 1H) 3.79 (d, J ) 0.7 Hz, 3H) 2.72 (m, 1H) 2.35
(dm, J ) 18.2 Hz, 1H) 2.15-2.26 (m, 2H) 2.05 (m, 1H) 1.82
(m, 1H) 1.47-1.74 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
214.71, 159.09, 130.10, 129.27, 113.73, 75.01, 69.26, 55.23,
46.69, 44.40, 34.21, 27.63, 24.18, 19.90; HRCIMS (CH4) calcd
for C16H20O3 260.1412, observed 260.1411.
Methods utilizing basic conditions for the protection accord-
ing to standard procedures25 were unsuccessful.
(1R,4S,6S)-6-Acetoxybicyclo[2.2.2]octan -2-on e (1d). Ace-
tic anhydride (0.20 mL, 2.13 mmol) was added dropwise to a
solution of (-)-1a (100 mg, 0.71 mmol) in pyridine (3.0 mL) at
rt. The mixture was kept at this temperature for 8 h when
(20) Clark, R. D.; Heathcock, C. H. J . Org. Chem. 1976, 41, 636-
643.
(21) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1989.
(22) Almqvist, F.; Eklund, L.; Frejd, T. Synth. Commun. 1993,
1499-1505.
(23) Mori, K.; Nagano, E. Biocatalysis 1990, 3, 25-36.
(24) Audia, J . E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Dan-
ishefsky, S. J . J . Org. Chem. 1989, 54, 3738-3740.
(25) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; 2nd ed.; J ohn Wiley and Sons, Inc.: New York, 1991.
(18) Gras, J .-L.; Galle´dou, B. S. Bull. Soc. Chim. Fr. 1983, 3-4, II89-
II95.
(19) Blanco, L.; Mansouri, A. Tetrahedron Lett. 1988, 29, 3239-3242.

6950 J . Org. Chem., Vol. 61, No. 20, 1996
Almqvist and Frejd
aqueous saturated NaHCO3 (10.0 mL) was added, and the
resultant mixture was extracted with EtOAc. The combined
organic phase was washed in sequence with aqueous saturated
CuSO4 and brine and dried. Concentration at reduced pres-
sure and chromatography (SiO2, heptane:EtOAc 1:2) gave 1d
2a and dry ZnCl2 gave 3a (48%), 4 (27%), and 1d (16%).
For 3a : mp 84.5-85.5 °C; [R] -55° (c 9.9, CHCl3); IR (neat)
2960, 2880, 1740, 1650, 1610, 1245 cm-1; 1H NMR (400 MHz,
CDCl3) δ 14.24 (s, 1H) 5.06 (dm, J ) 9.2 Hz, 1H) 2.85 (m, 1H)
2.69 (m, 1H) 2.20 (ddd, J ) 14.0, 9.2, 2.6 Hz, 1H) 2.04 (s, 3H)
1.98 (s, 3H) 1.70 (m, 2H) 1.57 (m, 1H) 1.46 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 200.05, 174.59, 170.41, 112.54, 71.29,
44.89, 36.10, 29.38, 25.09, 21.13, 19.97, 18.78; HRCIMS (CH4)
calcd for C12H16O4 224.1049, observed 224.1047.
For 4: [R] -40° (c 3.9, CHCl3); IR (neat) 2930, 2860, 1730,
1695, 1600 1225 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.10 (dm,
J ) 9.5 Hz, 1H) 3.43 (m, 1H) 2.65 (d, J ) 0.8 Hz, 3H) 2.65 (m,
1H) 2.26 (m, 1H) 1.99 (d, J ) 1.0 Hz, 3H) 1.71-1.87 (m, 2H)
1.58-1.68 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 199.14,
170.19, 143.99, 134.77, 70.81, 48.40, 34.13, 33.33, 25.06, 23.18,
21.06, 19.73; HRCIMS (CH4) calcd for C12H15O3Cl 242.0710,
observed 242.0710.
as an oil (123 mg, 95%); [R] -30° (c 3.1, CHCl3) (lit.23 [R]20.0
D
-27.6° (c 1.4, CHCl3)); IR and NMR data were as reported.23
(1R,4S,6S)-6-Meth oxybicyclo[2.2.2]octa n -2-on e (1e). Io-
domethane (1.1 mL, 17.7 mmol) was added dropwise to a
solution of (-)-1a (200 mg, 1.43 mmol) in acetonitrile (2.5 mL)
under argon at rt. After 5 min Ag2O (460 mg, 1.98 mmol) was
added in portions, and the mixture was heated at reflux for
36 h and then filtered through a pad of Hyflo-Supercel. The
pad was washed with CH2Cl2, and the combined solution was
concentrated at reduced pressure. Chromatography (SiO2,
heptane:EtOAc 1:1) gave 1e as an oil (178 mg, 81%): [R] -26°
(c 1.9, CHCl3); IR (neat) 2940, 2870, 2820, 1725, 1100 cm-1
;
1H NMR (400 MHz, CDCl3) δ 3.67 (ddd, J ) 8.9, 3.7, 2.5 Hz,
1H) 3.26 (s, 3H) 2.65 (m, 1H) 2.27 (dm, J ) 18.3 Hz, 1H) 2.22
(m, 1H) 2.15 (dm, J ) 18.3 Hz, 1H) 2.04 (m, 1H) 1.80 (m, 1H)
1.45-1.68 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 214.39, 77.84,
55.67, 46.39, 44.31, 33.98, 27.56, 24.06, 19.78; HRCIMS (CH4)
calcd for C9H15O2 155.1072, observed 155.1075.
2d and dry ZnCl2 gave 3b (13%) and 1e (27%). For 3b: [R]
-36° (c 0.15, CHCl3); IR (neat) 2930, 2860, 1640, 1590, 1255
1
cm-1; H NMR (400 MHz, CDCl3) δ 14.27 (s, 1H) 3.66 (dm, J
) 9.4 Hz, 1H) 3.32 (s, 3H) 2.87 (m, 1H) 2.84 (m, 1H) 2.02-
2.10 (m, 1H) 2.03 (s, 3H) 1.71 (m, 1H) 1.42-1.76 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 201.17, 173.87, 112.67, 78.45, 55.94,
44.41, 36.12, 29.52, 25.72, 19.81, 18.68; HRCIMS (CH4) calcd
for C11H17O3 197.1177, observed 197.1177.
Methods utilizing basic conditions for the protection accord-
ing to standard procedures25 were unsuccessful.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e TMS-
En ol Eth er s 2a -d a n d 5. The silyl enol ethers 2a , 2b, 2d ,
and 5 were prepared according to a literature procedure12 in
over 90% yields. Silyl enol ether 2c was synthesized by
applying a method developed for the preparation of silyloxy
dienes as follows.26 TMSCl (0.52 mL, 4.10 mmol), 1d (748 mg,
4.10 mmol), and NEt3 (0.57 mL, 4.38 mmol) were added in
sequence to a solution of dry LiBr (714 mg, 8.22 mmol) in THF
(3 mL) at -20 °C. After 1 h at -20 °C, the temperature was
raised to 40 °C, and the mixture was kept at that temperature
for 48 h. The solvent was then removed at reduced pressure
and replaced with cold pentane. The resulting mixture was
filtered through Hyflo-Supercel, and then the solvent was
removed at reduced pressure to give an oil which was diluted
with heptane:EtOAc 3:1, and the solution was filtered through
a pad of silica. The solvent was removed at reduced pressure
to give 2c as a pale yellow oil (877 mg, 84%). Due to their
sensibility toward hydrolysis, all the TMS-enol ethers were
used directly in the next step without further purification. The
purity of the TMS-enol ethers was generally g90% according
to GC; NMR data were as reported for 2a 12 and 5.27
5 and dry ZnCl2 gave 6 (62%) as an oil: [R] +141° (c 1.40,
CHCl3); IR (neat) 2960, 2920, 2870, 1755, 1730, 1665, 1370,
1
1200, 1175 cm-1; H NMR (400 MHz, CDCl3) δ 2.59 (d, J )
4.2 Hz, 1H) 2.28 (s, 3H) 2.17 (s, 3H) 1.92 (m, 1H) 1.64 (m, 1H)
1.42 (m, 2H) 0.94 (s, 3H) 0.91 (s, 3H) 0.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.55, 168.06, 151.24, 130.21, 58.82,
47.95, 46.10, 30.31, 25.65, 20.86, 20.27, 18.30, 17.20, 9.35;
HRCIMS (CH4) calcd for C14H20O3 237.1491, observed 237.1490.
(1R,4S,6S)-6-Acetoxy-3-vin ylid en ebicyclo[2.2.2]octa n -
2-on e (7). Potassium tert-butoxide (180 mg, 1.61 mmol) was
added in one portion under a stream of argon to a solution of
4 (300 mg, 1.24 mmol) in THF (55 mL) at -50 °C. After 90
min at this temperature aqueous saturated NH4Cl was added
cautiously, and the mixture was extracted with EtOAc and
dried. Concentration at reduced pressure followed by chro-
matography (SiO2, heptane:EtOAc 70:30) gave 7 (255 mg,
100%): mp 131-132 °C; [R] -39° (c 0.7, CHCl3); IR (KBr) 2950,
2880, 1960, 1930, 1735, 1680, 1240 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.24 (s, 2H) 5.15 (dm, J ) 9.6 Hz, 1H) 2.86 (m, 1H)
2.69 (m, 1H) 2.30 (m, 1H) 2.00 (s, 3H) 1.62-1.92 (m, 5H); 13
C
NMR (100 MHz, CDCl3) δ 206.57, 200.23, 170.29, 106.88,
79.86, 70.74, 46.67, 34.89, 33.48, 24.08, 21.11, 19.62; HRMS
calcd for C12H14O3 206.0943, observed 206.0946.
For 2b: 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.6 Hz,
2H) 6.86 (d, J ) 8.6 Hz, 2H) 5.17 (dd, J ) 7.3, 2.2 Hz, 1H)
4.51 (d, J ) 11.7 Hz, 1H) 4.40 (d, J ) 11.6 Hz, 1H) 3.80 (s,
3H) 3.65 (m, 1H) 2.69 (m, 1H) 2.53 (m, 1H) 1.78 (ddd, J )
13.0, 8.2, 2.4 Hz, 1H) 1.46 (m, 1H) 1.12-1.38 (m, 4H) 0.21 (s,
9H).
(1R,4S,6S)-(E)-3-(1-Ch lor oeth yliden e)-6-h ydr oxybicyclo-
[2.2.2]octa n -2-on e (8). Compound 4 (614 mg, 2.54 mmol) was
diluted with EtOH (14 mL) and 1 M HCl (43 mL). After 6 h
at 50 °C ice was added, and the mixture was extracted with
EtOAc. The combined organic phase was washed with satu-
rated aqueous NaHCO3 and dried. Concentration at reduced
pressure followed by chromatography (SiO2, heptane:EtOAc
1:2) gave 8 (462 mg, 91%): mp 83-84 °C; [R] -0.4° (c 7.7,
CHCl3); IR (KBr) 3420, 1690, 1600, 635 cm-1 1H NMR (400
MHz, CDCl3) δ 4.16 (dm, J ) 9.0 Hz, 1H) 3.38 (m, 1H) 2.81-
3.06 (s, 1H) 2.60 (d, J ) 1.2 Hz, 3H) 2.56 (m, 1H) 2.15 (m, 1H)
1.52-1.81 (m, 5H) 13C NMR (100 MHz, CDCl3) δ 201.33,
143.61, 135.09, 68.68, 52.14, 36.10, 33.42, 25.09, 23.22, 19.58;
HRCIMS (CH4) calcd for C10H12OCl 183.0576, observed
183.0577.
For 2c: 1H NMR (300 MHz, CDCl3) δ 5.1 (dd, J ) 7.2, 2.3
Hz, 1H) 4.88 (m, 1H) 2.53 (m, 1H) 1.97 (s, 3H) 1.89-1.99 (m,
1H) 1.40-1.50 (m, 2H) 1.12-1.36 (m, 3H) 0.19 (s, 9H).
For 2d : 1H NMR (400 MHz, CDCl3) δ 5.16 (dd, J ) 7.2, 2.3
Hz, 1H) 3.48 (m, 1H) 3.28 (s, 3H) 2.64 (m, 1H) 2.53 (m, 1H)
1.77 (dd, J ) 12.9, 7.9, 2.4 Hz, 1H) 1.46 (m, 1H) 1.14-1.38
(m, 4H) 0.19 (s, 9H).
Gen er a l P r oced u r e for th e Acetyla tion of th e TMS-
En ol Eth er s 2a -d a n d 5. Acetyl chloride (2.7 mmol) was
added to a slurry of Lewis acid (2.3 mmol) in CH2Cl2 (1.2 mL)
and diethyl ether (0.2 mL) at 0 °C (-72 °C when TiCl4 or SnCl4
were used). After 5 min the TMS-enol ether (1.0 mmol) was
added. The mixture was kept at 0 °C for 1 h and then allowed
to reach rt within 45 min. After 30 min at rt ice was added,
and then the mixture was extracted with CH2Cl2. The
combined organic phase was washed with saturated aqueous
NaHCO3 and dried. Concentration at reduced pressure gave
a crude oil which was purified by chromatography (SiO2,
heptane:EtOAc 70:30).
(1R ,4S ,6S )-(Z)-6-H yd r oxy-3-(1-h yd r oxye t h ylid e n e )-
bicyclo[2.2.2]octa n -2-on e (9). Compound 4 (218 mg, 0.90
mmol) was diluted with EtOH (5 mL) and 1 M HCl (15 mL).
After 14 h at reflux ice was added, and the mixture was
extracted with EtOAc. The combined organic phase was
washed with saturated aqueous NaHCO3 and dried. Concen-
tration at reduced pressure followed by chromatography (SiO2,
heptane:EtOAc 1:3) gave 9 (136 mg, 83%): mp 137-143 °C;
[R] -24° (c 0.3, CHCl3); IR (KBr) 3400, 1630, 1585, 705 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.18 (dm, J ) 8.7 Hz, 1H) 2.85
(m, 1H) 2.63 (m, 1H) 2.15 (ddd, J ) 13.7, 8.9, 2.6 Hz, 1H) 2.04
(s, 3H) 1.39-1.91 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
(26) Hansson, L.; Carlson, R. Acta Chem. Scand. 1989, 43, 188-
192.
(27) J oshi, G. C.; Pande, L. M. Synthesis 1975, 450-451.

Chlorination of a Bicyclo[2.2.2]octanone
J . Org. Chem., Vol. 61, No. 20, 1996 6951
201.21, 174.44, 112.70, 69.43, 48.83, 38.31, 29.42, 25.15, 19.90,
15.91; HRCIMS (CH4) calcd for C10H15O3 183.1021, observed
183.1023.
to approximately 1 mL, and brine was added. The mixture
was extracted with EtOAc and dried. Concentration at
reduced pressure followed by chromatography (SiO2, EtOAc)
gave 10 (26 mg, quant): mp 184-186 °C; [R] -0.4° (c 0.1,
CHCl3); IR (KBr) 3360, 1650, 1570 cm-1 1H NMR (400 MHz,
CDCl3) δ 4.14 (dm, J ) 8.9 Hz, 1H) 3.72 (s, 3H) 3.31 (m, 1H)
2.49 (s, 3H) 2.49 (m, 1H) 2.29 (s, 1H) 2.08 (ddd, J ) 14.0, 9.1,
2.7 Hz) 1.72 (m, 1H) 1.59 (m, 1H) 1.40-49 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 202.80, 162.38, 117.87, 69.62, 54.35, 52.36,
37.28, 27.45, 24.29, 20.24, 14.31; HRCIMS (CH4) calcd for
C11H17O3 197.1178, observed 197.1180.
(1R ,4S ,6S )-(Z )-3-(1-H y d r o x y e t h y li d e n e )-6-[(t er t -
bu tyld im eth ylsilyl)oxy]bicyclo[2.2.2]octa n -2-on e (3c). A
solution of 9 (79 mg, 0.43 mmol), imidazole (88 mg, 1.29 mmol),
and TBDMSCl (131 mg, 0.87 mmol) in DMF (1 mL) was kept
at rt for 12 h. A mixture of diethyl ether and EtOAc (1:1) was
then added, and the mixture was washed in sequence with
water, cold 1.5 M HCl (several times), saturated aqueous
NaHCO3, and water. The organic phase was dried, the solvent
was removed at reduced pressure, and the residue was
chromatographed (SiO2, heptane:EtOAc 85:15) to give 3c (107
mg, 84%): [R] -36° (c 1.3, CHCl3); IR (KBr) 1705, 1640, 1605,
1250, 1095 cm-1 1H NMR (400 MHz, CDCl3) δ 14.31 (s, 1H)
4.07 (dm, J ) 8.7 Hz, 1H) 2.78 (m, 1H) 2.52 (m, 1H) 2.06 (ddd,
J ) 13.2, 8.7, 2.6 Hz, 1H) 2.02 (s, 3H) 1.36-1.69 (m, 5H) 0.84
(s, 9H) 0.04 (s, 3H) 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.54, 173.16, 112.76, 69.90, 48.88, 39.60, 29.54, 25.74, 25.34,
20.00, 18.62, 18.01, -4.67, -4.82; HRCIMS (CH4) calcd for
C16H29O3Si 297.1886, observed 297.1891.
Ack n ow led gm en t. We thank the Swedish Natural
Science Research Council for generous economic sup-
port.
Su p p or t in g In for m a t ion Ava ila b le: Copies of the 13C
NMR spectra for those compounds for which elemental analy-
sis data are given as HRMS data (11 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of this journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(1R ,4S ,6S )-(E )-6-H yd r oxy-3-(1-m e t h oxye t h ylid e n e )-
bicyclo[2.2.2]octa n -2-on e (10). K2CO3 (84 mg, 0.61 mmol)
was added to a solution of 7 (29 mg, 0.11 mmol) in MeOH and
water (6 mL, 9:1). After 2 h at rt the mixture was concentrated
J O9607370