Geminal acylation of α-heterosubstituted cyclohexanones and their ketals

Article abstract of DOI:10.1139/V10-097

Geminal acylation of derivatives of cyclohexanone with Br, Cl, F, and OCH₃ in the α position, and of their corresponding dimethyl ketals, could not be accomplished to a significant extent following published procedures. The transformation was a

Full text of DOI:10.1139/V10-097

1118
Geminal acylation of a-heterosubstituted
cyclohexanones and their ketals
Ian R. Pottie, Sheldon N. Crane, Anna Lee Gosse, David O. Miller, and
D. Jean Burnell
Abstract: Geminal acylation of derivatives of cyclohexanone with Br, Cl, F, and OCH3 in the a position, and of their cor-
responding dimethyl ketals, could not be accomplished to a significant extent following published procedures. The trans-
formation was accomplished in two steps. The initial BF3ÁEt2O-mediated reaction with 1,2-
bis(trimethylsilyloxy)cyclobutene gave a cyclobutanone product as a mixture of diastereomers. Only with 2-chlorocyclo-
hexanone did this occur with good diastereoselectivity. Then, pinacol rearrangement of the diastereomeric mixture medi-
ated by Amberlyst-15 in benzene provided the heterosubstituted spirocyclic diketone.
Key words: diastereoselectivity, Mukaiyama aldol, geminal acylation, spirocyclic diketone.
´
´
´
´
´
Resume : L’acylation geminale de derives de la cyclohexanone portant des substituants Br, Cl, F et OCH3 en position a
´
´
ˆ
´
´
´
ainsi que celle des dimethylcetals correspondants ne peut pas etre realisee avec des rendements significatifs par les metho-
´
`
´
`
´
´
des rapportees jusqu’a maintenant. On a reussi a effectuer cette transformation en deux etapes. La reaction initiale cataly-
´
´
`
`
`
see par le BF3ÁEt2O avec le 1,2-bis(trimethylsilyloxy)cyclobutene conduit a un produit a base de cyclobutanone, sous la
´
´
´
`
´
´
´
´
´
forme de melange de diastereoisomeres. Cette transformation ne s’est effectuee avec une bonne diastereoselectivite qu’a-
´
´ ´
`
´
vec la 2-chlorocyclohexanone. La transposition pinacolique du melange diastereoisomere catalysee par l’Amberlyst-15
´ ´
`
`
´
´
dans le benzene conduit alors a une dicetone spirocyclique heterosubstituee.
´
´
´
´
´
´
´
Mots-cles : diastereoselectivite, aldol de Mukaiyama, acylation geminale, dicetone spirocyclique.
Introduction
Scheme 1. Geminal acylation in two steps with the diethyl ketal of
cyclohexanone.1
The geminal acylation of ketones and their ketals with
1,2-bis(trimethylsilyloxy)cyclobutene (1) is
a powerful
method for generating 2,2-disubstituted 1,3-cyclopentane-
dione systems in high yield. Kuwajima and co-workers1 in-
troduced this transformation as
a two-step procedure
(Scheme 1). First, a BF3ÁEt2O-mediated Mukaiyama aldol
between a ketal and 12,3 affords a cyclobutanone, e.g., 2.
Then, pinacol rearrangement of 2 is effected by treatment
with trifluoroacetic acid (TFA), generating a 1,3-diketone
such as 3.
The process can be carried out, generally in excellent
yield, in one pot by the use of a large excess of BF3ÁEt2O.4–7
Geminal acylation of ketones is facilitated by the addition of
a small amount of water to the reaction medium after forma-
tion of the cyclobutanone intermediate.8 Methyl-substituted
versions of 1 can also be used for this reaction.9,10 Geminal
acylation has appeared as a key process in many synthetic
and methodological endeavors.11–13 Substitution by alkyl
groups a to the ketone, or ketal, reduces the yield of the
geminal acylation. For instance, the ethylene ketal of cyclo-
hexanone was geminally acylated in 96% yield using the
one-pot procedure,13 but the ketal of 2-methylcyclohexanone
gave only a 30% yield of the geminal acylation product.7 In
a similar way, yields with ketones were lower when the a
position was more substituted. The geminal acylation of cy-
clohexanone gave the diketone product in 94% yield, but
Received 8 January 2010. Accepted 9 February 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 28 October
2010.
This article is part of a Special Issue dedicated to Professor R. J. Boyd.
I.R. Pottie. Department of Chemistry and Physics, Mount Saint Vincent University, Halifax, NS B3M 2J6, Canada.
S.N. Crane, A.L. Gosse, and D.O. Miller. Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X7,
Canada.
D.J. Burnell.1 Department of Chemistry, Dalhousie University, Halifax, NS B3H 4J3, Canada.
1Corresponding author (e-mail: jean.burnell@dal.ca).
Can. J. Chem. 88: 1118–1124 (2010)
doi:10.1139/V10-097
Published by NRC Research Press

Pottie et al.
1119
under very similar conditions 2-methylcyclohexanone pro-
vided the diketone in only 62% yield.8 Differing degrees of
a substitution has allowed selective geminal acylation to
take place.8,13 The reason for the attenuation of the yields
has been presumed to be steric hindrance.
It was thought that a substitution by a heteroatom might
be better tolerated than a substitution by an alkyl group be-
cause the former might have a smaller steric effect. The
products of geminal acylations with a-substituted ketones or
ketals would possess functionality that might be useful for
further synthetic manipulation. The results of our experi-
ments with a-substituted cyclohexanones and their corre-
sponding dimethyl ketals are presented here.
reomer 11a separated from the others during chromatogra-
phy. (The diastereomeric mixtures 9, 10, 13, and 14 could
not be separated by flash chromatography.) It was fortuitous
that both 11a and 12a provided crystals that allowed analy-
sis by X-ray crystallography. This analysis revealed that
these major diastereomers had the same basic structure
(Figs. 1 and 2).
Diastereoselective additions of nucleophiles, such as hy-
dride, organomagnesium reagents, and organolithium re-
agents, to a-heterosubstituted cyclohexanones have been
noted a number of times.14–16 The selectivity has been ra-
tionalized in terms of Felkin–Anh control15 and electrostatic
interactions.14,17 Previous studies involved products that
were predominantly the result of addition to the face of the
carbonyl anti to the heteroatom. However, in both 11a and
12a, the position of the cyclobutanone moiety relative to
the halogen was cis with respect to the cyclohexane ring,
which implied that the Mukaiyama aldol reaction preferen-
tially occurred on the face of the ketone syn to the halogen.
Previous work with conformationally locked cyclohexanones
indicated that addition of hydride was predominantly axial,
and the rate of anti addition to the carbonyl was faster
when the a-heteroatom was axial.14 In other words, the dia-
stereoselectivity of additions of smaller nucleophiles to a-
substituted cyclohexanones arises from axial addition to the
carbonyl when the a-substituent is axial and anti to the in-
coming nucleophile. NMR studies have shown that the cy-
clohexanone conformer with the a-halogen in an axial
position is either the major conformer or at least similar in
energy to the conformer with an equatorial halogen.15,18
Results and discussion
The dimethyl ketals of 2-bromo-, 2-chloro-, 2-fluoro-, and
2-methoxycyclohexanone were subjected to the conditions
previously used by Kuwajima and co-workers1 for the two-
step geminal acylation of the ketal of cyclohexanone. Gemi-
nally acylated product was not detected from any of these
ketals. The same ketals were treated with an excess of 1
and a large excess of BF3ÁEt2O. These conditions would
have geminally acylated the ketal of cyclohexanone in high
yield,4,7 but, once again, no geminally acylated product was
obtained.
The procedure developed by Kuwajima and co-workers
was used with the four a-substituted ketones, but only two
gave geminally acylated products: 4 in 7% yield from the
2-bromocyclohexanone and 5 in 10% yield from the 2-
methoxycyclohexanone. Conditions had been developed spe-
cifically for the geminal acylation of ketones in one pot.8
When these conditions were applied to the four a-substituted
ketones, only two yielded a detectable amount of a
geminally acylated product: 4 in 24% yield from the 2-
bromocyclohexanone and 6 in 4% yield from the 2-chloro-
cyclohexanone.
TLC analysis of the reactions of the ketals and of the ke-
tones indicated that the starting compounds were consumed
fairly rapidly. 13C NMR spectra of the resulting material in-
cluded clusters of resonances between d 90 and 100 ppm.
Chemical shifts in this region have been seen for the carbi-
nolic carbon of a cyclobutane intermediate,1,8,9 and it was
surmised that as a result of these attempted geminal acyla-
tions, the Mukaiyama aldol reactions had taken place to
give cyclobutanone derivatives (7–14), but the pinacol rear-
rangements had failed. The products from the ketals 7–10
were mixtures with silylated alcohol functions, but product
ratios could not be determined owing to partial desilylation.
The products from the ketones 11–14 were obtained with al-
cohol functions only. NMR signals were discerned for at
least three of the four possible diastereomers of 11–14, and
the proportions of these diastereomers (Table 1) were esti-
mated by integration of the NMR spectra of the crude mix-
tures of diastereomers.
In contrast with the reactions of hydride and many orga-
nometallics, the initial step of the geminal acylation of cy-
clohexanone or its ketal gives mainly the product of
equatorial addition.1,8 If that mode of addition is still the
case with the a-heterosubstituted cyclohexanones, what is
intriguing is that the relative stereochemistry observed with
11a and 12a must have arisen by addition of 1 syn to the a-
heteroatom, but with the conformation of the cyclohexanone
having the heteroatom in an axial position. It has been ac-
cepted for a long time that equatorial additions to cyclohex-
anones by larger nucleophiles are due to larger steric
interactions in the transition state for axial addition.19 On
the other hand, the axial disposition of the heteroatom is
likely due to stabilization of the intermediate carbocation
(e.g., 16). Thus, a plausible reason for the generally low
stereoselectivity of the addition reactions summarized in Ta-
ble 1, relative to additions of smaller nucleophiles,13–15
would be that the axial heteroatom would retard attack by
1, since this larger nucleophile would be adding equatori-
ally, which would be syn to the heteroatom, making other
modes of reaction competitive in rate.
Only 2-chlorocyclohexanone showed good stereoselectiv-
ity (80% of one diastereomer by NMR), and a tiny amount
of the major diastereomer 12a was isolated by repeated flash
chromatography. 2-Bromocyclohexanone had reacted with
modest stereoselectivity (the ratio of diastereomers was
only 3:1:1:1), and a very small amount of the major diaste-
Published by NRC Research Press

1120
Can. J. Chem. Vol. 88, 2010
Table 1. Results of the two-step geminal acylation of a-heterosubstituted cyclohexanones and their ketals.
Published by NRC Research Press

Pottie et al.
1121
Scheme 2.
Fig. 1. X-ray crystal structure of 11a.
Fig. 2. X-ray crystal structure of 12a.
Amberlyst-15, which is a resin with sulfonic acid sites, was
chosen as the acid. Amberlyst-15 had proven to be an excel-
lent catalyst for the rearrangement of cyclobutanone inter-
mediates generated from aldehydes.21 It was gratifying that
the desired spirocyclic 1,3-diketone (6) was obtained in
95% yield. The use of p-TsOH in the place of Amberlyst-
15 gave no rearranged product, just intractable material.
This dramatic difference in the result was evidence that the
macroreticular structure of the resin, and not just its acidity,
plays an important role in promoting the rearrangement of
the cyclobutanone. This may be related to pinacol rearrange-
ments mediated by acidic agents in other porous structures,
e.g., iron(III)-substituted molecular sieves.22
The procedure using Amberlyst-15 was carried out with
all of the cyclobutanone derivatives in Table 1. The cyclo-
butanones derived from ketones (11–14) rearranged within
an hour in benzene under reflux. The halogenated com-
pounds 11–13 provided the 1,3-diketones 4, 6, and 15 in ex-
cellent yield. The methoxy derivative 5 was obtained in
modest yield from 14. Diketone 5 was accompanied by a
significant amount of by-product, which was difficult to sep-
1
arate. It appeared by H NMR spectroscopic analysis to be
17. (Its diagnostic NMR signals were a multiplet at
d 6.98 ppm, a singlet at d 3.71 ppm, and triplets at d 3.00
and 2.64 ppm.) It was likely that 17 was produced from 5
(Scheme 2). Acid-catalyzed elimination of methanol might
be accompanied by ring-opening and generation of the acy-
lium ion 18, which would then capture the evolved methanol
to provide 17.
The reactions of the cyclobutanones derived from the ke-
tals (7–10) were sluggish, requiring 48 h to consume the
starting materials in benzene under reflux. The 1,3-diketones
4, 6, and 15 were isolated in poorer yield than from 11–13,
and the methoxycyclobutanone 10 gave none of the 1,3-
diketone 5. The reason for the slower reaction was the pres-
ence of the TMS group, because desilylation of 8 with
TBAF followed immediately by treatment with Amberlyst-
15 in benzene gave 6 in 88% yield.
The success of the two-step process from ketones
prompted us to re-examine the reactions of two a-substituted
substrates that had given only modest yields of 1,3-diketones
previously. 2-Methylcyclohexanone and 3-methylbutanone
had given 19 and 20 in yields of 62% and 52%, respec-
tively, using the one-pot, two-step method using excess
BF3ÁEt2O to effect the rearrangement.8 In contrast, using the
When some cyclobutanone compounds were maintained
in warm TFA, very little, if any, rearrangement took place,
but the starting compound was steadily consumed, and
some material that was insoluble in common organic
solvents was produced. The formation of a spirocyclic 1,3-
diketone from the cyclobutanone might take place in a step-
wise fashion, by initial generation of an intermediate tertiary
carbocation followed by rearrangement, or by a concerted
mechanism in which carbon–carbon bond reorganization ac-
companies the loss of the oxygen. TFA, being a polar me-
dium, should stabilize a discreet carbocation. However,
calculations by Nakamura and Osamura20 suggested that as
a carbocation is stabilized, the energy required for carbon–
carbon bond reorganization increases. This would likely
make other reaction pathways (leading to decomposition)
more competitive. It was hypothesized that performing the
rearrangement in a nonpolar medium would create a more
favorable situation for a concerted process to occur instead
of other more destructive reaction pathways.
To this end, benzene was chosen as the solvent and
Published by NRC Research Press

1122
Can. J. Chem. Vol. 88, 2010
same two-step procedure involving Amberlyst-15 that was
used to produce the spirocyclic 1,3-diketones in Table 1, 19
and 20 were prepared in 84% and 80% yield, respectively,
from the ketones.
cooled to rt, and the Amberlyst-15 was removed by gravity
filtration. The filtrate was concentrated under reduced pres-
sure, and flash chromatography afforded the 1,3-diketone.
Characterization data for the 1,3-diketones 4, 5, 6, and 15
and the cyclobutanone intermediates 11a and 12a are given
in the following. Data for 19 and 20 were consistent with
published data.7
6-Bromospiro[4.5]decane-1,4-dione (4)
Solid, mp 56–58 8C. IR (Nujol, cm–1): 1728, 1460, 1377,
1
1311, 1178, 986, 696. H NMR (500 MHz) d: 4.12 (dd, J =
12.7, 4.7 Hz, 1H), 2.81–2.73 (m, 4H), 2.54 (dq, J = 13.1,
4.1 Hz, 1H), 2.13 (m, 1H), 1.86 (m, 1H), 1.80–1.73 (m,
2H), 1.59 (m, 1H), 1.51 (m, 1H), 1.40 (m, 1H). 13C NMR
(125 MHz) d: 214.2 (0), 213.1 (0), 59.3 (0), 49.4 (1), 35.5
(2), 34.8 (2), 32.9 (2), 31.7 (2), 26.7 (2), 18.9 (2). GC–MS:
246 (M+2, 2), 244 (M+, 2), 166 (11), 165 (100), 164 (8), 147
(4), 123 (15), 109 (14), 95 (7). HRMS (EI) calcd. for
C10H13BrO2: 244.0099; found: 244.0098.
In summary, a two-step procedure has been developed for
the geminal acylation of an a-heterosubstituted cyclohexa-
none. The first step is the BF3ÁEt2O-mediated addition of 1
to the ketone to give a cyclobutanone intermediate, and the
second is the rearrangement of the cyclobutanone in benzene
with Amberlyst-15. The process works less well with the
corresponding ketal. Following the same procedure, yields
of geminally acylated products from ketones substituted in
the a position with alkyl groups are improved over the older
one-pot, two-step procedure. It is expected that the proce-
dure will be widely applicable for the geminal acylation of
other cyclic and acyclic ketones with a substitution.
6-Methoxyspiro[4.5]decane-1,4-dione (5)
1
Yellow oil. H NMR (500 MHz) d: 3.44 (dd, J = 11.7,
4.5 Hz, 1H), 3.20 (s, 3H), 2.73–2.63 (m, 4H), 1.97 (m, 1H),
1.88 (m, 1H), 1.83–1.75 (m, 2H), 1.59 (m, 1H), 1.50–1.44
(m, 2H), 1.30–1.24 (m, 2H). 13C NMR (125 MHz) d: 217.8
(0), 215.9 (0), 83.8 (1), 59.4 (0), 56.9 (3), 36.5 (2), 35.9 (2),
30.1 (2), 24.9 (2), 23.8 (2), 19.9 (2). GC–MS: 196 (M+, 64),
182 (25), 181 (100), 165 (53), 164 (80), 163 (54), 141 (51),
138 (58), 136 (58), 125 (68), 112 (96). HRMS (EI) calcd.
for C11H16O3: 196.1099; found: 196.1092.
Experimental
General
All reactions were performed under N2. BF3ÁEt2O was dis-
tilled before use. CH2Cl2 and benzene were distilled from
calcium hydride before use. Flash chromatography used
230–400 mesh silica gel, starting with 20% ethyl
acetate – hexane mixtures with an increasing portion of ethyl
acetate as the eluting solvent. 1H NMR spectra were re-
corded in CDCl3. Chemical shifts are relative to internal
TMS. 13C NMR chemical shifts are relative to the CDCl3
solvent (d 77.0 ppm). Each 13C NMR chemical shift is fol-
lowed by a number in parentheses that represents the num-
ber of attached protons as determined by DEPT
experiments. Compound 1 was prepared by the method of
Bloomfield and Nelke.3 2-Chloro-, 2-methoxy-, and 2-
methyl-cyclohexanone and 3-methylbutanone were pur-
chased (Sigma-Aldrich). 2-Bromo- and 2-fluorocyclohexa-
none were prepared by oxidation of the corresponding
alcohols23 with pyridinium chlorochromate. Ketals24 were
formed by treatment of the ketones with methanol–trimethyl-
orthoformate (1:1) with some p-TsOH.
6-Chlorospiro[4.5]decane-1,4-dione (6)
1
Solid, mp 42–46 8C. H NMR (500 MHz) d: 4.08 (dd, J =
12.5, 4.7 Hz, 1H), 2.82–2.72 (m, 4H), 2.38 (m, 1H), 2.01
(m, 1H), 1.91 (m, 1H), 1.78–1.71 (m, 2H), 1.56–1.46 (m,
2H), 1.38 (m, 1H). 13C NMR (125 MHz) d: 214.4 (0), 213.1
(0), 59.4 (0), 59.1 (1), 35.9 (2), 35.2 (2), 32.2 (2), 31.0 (2),
25.6 (2), 18.9 (2). GC–MS: 202 (M+2, 2), 200 (M+, 5), 166
(11), 165 (100), 164 (28), 147 (9), 137 (6), 123 (24), 109
(34). HRMS (EI) calcd. for C10H13ClO2: 200.0604; found:
200.0598.
6-Fluorospiro[4.5]decane-1,4-dione (15)
Solid, mp 62–63 8C. IR (Nujol, cm–1): 1721, 1456, 1377,
1
1307, 1182, 1020, 963. H NMR (500 MHz) d: 4.70 (ddd,
J = 4.8, 11.8, 47.4 Hz, 1H), 2.80–2.70 (m, 4H), 2.15 (m,
1H), 1.97–1.89 (m, 2H), 1.78–1.65 (m, 2H), 1.51–1.45 (m,
2H), 1.32 (m, 1H). 13C NMR (125 MHz) d: 215.0 (0), 213.4
(0), 94.2 (1, d, J = 175.4 Hz), 58.9 (0, d, J = 20.0 Hz), 35.8
(2, d, J = 70.7 Hz), 30.2 (2, d, J = 5.7 Hz), 26.8 (2, d, J =
18.0 Hz), 23.1 (2, d, J = 11.5 Hz), 19.2 (2). GC–MS: 184
(M+, 80), 164 (49), 155 (18), 129 (18), 109 (96), 103 (23),
81 (100). HRMS (EI) calcd. for C10H13FO2: 184.0900;
found: 184.0904.
General procedure for geminal acylation
To a solution of the ketone or ketal (1.0 mmol) in CH2Cl2
(8 mL) at –78 8C was added BF3ÁEt2O (1.5 mmol) and then
1 (3.0 mmol) dropwise. The mixture was warmed slowly to
room temperature (rt) and then stirred until TLC indicated
that the starting ketone or ketal was consumed. The mixture
was concentrated under reduced pressure. Flash chromatog-
raphy was used to remove unreacted and decomposed 1
from the mixture of cyclobutanone products. The cyclobuta-
none mixture was dissolved in benzene (25 mL). Amberlyst-
15 (0.25 g) was added to this solution, and the resulting
mixture was heated under reflux. When TLC indicated that
the cyclobutanones had been consumed, the mixture was
(1’R*,2R*,2’S*)-2-(2-Bromo-1-hydroxycyclohexyl)-2-
hydroxycyclobutanone (11a)
Solid. IR (Nujol, cm–1): 3389 (sharp), 1776, 1737, 1462,
1
1377. H NMR (300 MHz) d: 4.40 (narrow m, 1H), 3.25
(ddd, J = 8.6, 12.4, 17.4 Hz, 1H), 3.23 (s, OH), 2.93 (ddd,
J = 6.9, 10.8, 17.4 Hz, 1H), 2.70 (m, 1H), 2.45 (s, OH),
Published by NRC Research Press

Pottie et al.
1123
Table 2. X-ray crystallographic data for 11a and 12a.
Crystal
Data
11a
12a
Empirical formula
Formula mass
Color, habit
Dimensions (mm)
Crystal system
Space group
Z
C10H15BrO3
263.13
C10H15ClO3
218.68
Colorless, irregular
0.40Â0.25Â0.25
Orthorhombic
Pbca (No. 61)
8
11.490(2)
22.733(5)
8.156(2)
Colorless, irregular
0.40Â0.30Â0.10
Orthorhombic
Pbca (No. 61)
8
11.440(5)
22.389(6)
8.122(7)
˚
a (A)
˚
b (A)
˚
c (A)
Collection ranges
–12£h£12; –25£k£25; –9£l£9
299(2)
2130.1(8)
0£h£12; 0£k£25; 0£l£9
299(2)
2080.4(20)
1.396
Temperature (K)
3
˚
V (A )
Calcd. density (g cm–3)
1.641
Absorption coefficient m (Cu Ka) (cm–1) 51.15
31.02
F(000)
1072
928
q range for data collection (8)
No. of reflections
3.89–59.97
3278
3.95–59.99
1612
No. of unique reflections
Reflection parameter
Maximum shift –error
Goodness-of-fit on F2
R1, [I > s(I)]
1583 (Rint = 0.0177)
12.37
0.001
1.037
1545 (Rint = 0.0215)
11.98
0.001
1.099
0.0365
0.0399
R indices (all reflections)
Largest diff. peak and hole (e A )
R = 0.0529, wR2 = 0.1153
0.32 and –0.83
R = 0.0572, wR2 = 0.1126
0.22 and –0.34
–3
˚
2.37–2.14 (m, 4H), 1.91 (d of narrow m, J = 15.0 Hz, 1H),
1.81–1.55 (m, 4H), 1.41 (br d, J = 13.8 Hz, 1H). 13C NMR
(75 MHz) d: 212.7 (0), 95.5 (0), 74.6 (0), 51.4 (1), 44.4 (2),
30.5 (2), 27.6 (2), 26.0 (2), 20.1 (2), 20.0 (2). GC–MS: no
M+, 182 (2), 164 (46), 139 (53), 125 (43), 112 (59), 111
(60), 81 (68), 79 (57), 55 (100).
ware package except for refinement, which was performed
using SHELXL-97.26
Supplementary data
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca). CCDC 760849 and
760850 contain the X-ray data in CIF format for this manu-
script. These data can be obtained, free of charge, via www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.
cam.ac.uk).
(1’R*,2R*,2’S*)-2-(2-Chloro-1-hydroxycyclohexyl)-2-
hydroxycyclobutanone (12a)
1
Solid, mp 126–128 8C. H NMR (300 MHz) d: 4.29 (br s,
1H), 3.42 (s, OH), 3.24 (m, 1H), 2.90 (m, 1H), 2.67 (m,
1H), 2.44 (s, OH), 2.35–1.94 (m, 4H), 1.82 (d of narrow m,
J = 17 Hz, 1H), 1.81–1.55 (m, 4H), 1.41 (br d, J = 12 Hz,
1H). 13C NMR (75 MHz) d: 211.8 (0), 94.2 (0), 74.6 (0),
60.2 (1), 46.1 (2), 31.7 (2), 29.1 (2), 27.2 (2), 21.9 (2), 21.0
(2). GC–MS: no M+, 183 (3), 165 (56), 133 (45), 109 (77),
81 (100), 79 (64), 55 (80), 43 (99).
Acknowledgement
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for financial support.
X-ray crystallography
References
Table 2 summarizes the crystallographic data for 11a and
12a. Diffraction data were acquired using a Rigaku AFC6S
diffractometer with graphite-monochromated Cu Ka radia-
(1) Shimada, J.; Hashimoto, K.; Kim, B. H.; Nakamura, E.;
Kuwajima, I. J. Am. Chem. Soc. 1984, 106 (6), 1759.
doi:10.1021/ja00318a035.
(2) Ru¨hlmann, K. Synthesis 1971, 1971 (05), 236. doi:10.1055/s-
1971-21707.
(3) Nelke, J. M. Organic Syntheses; Wiley: New York, 1988;
Collect. Vol. VI, pp 167–172.
(4) Wu, Y.-J.; Burnell, D. J. Tetrahedron Lett. 1988, 29 (35),
4369. doi:10.1016/S0040-4039(00)80497-9.
˚
tion (l = 1.541 78 A). An empirical absorption correction
was applied. The data were corrected for Lorentz and polar-
ization effects. The structures were solved by direct methods
and expanded using Fourier techniques. The non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were
refined using the riding model. Final cycles of full-matrix
least-squares refinement were applied. All calculations were
performed using the CrystalStructure25 crystallographic soft-
(5) Wu, Y.-J.; Burnell, D. J. Tetrahedron Lett. 1989, 30 (9),
1021. doi:10.1016/S0040-4039(01)80348-8.
Published by NRC Research Press

1124
(6) Pandey, B.; Khire, U. R.; Ayyangar, N. R. Synth. Commun.
1989, 19 (15), 2741. doi:10.1080/00397918908053069.
(7) Wu, Y.-J.; Strickland, D. W.; Jenkins, T. J.; Liu, P.-Y.;
Burnell, D. J. Can. J. Chem. 1993, 71 (9), 1311. doi:10.
1139/v93-169.
(8) Jenkins, T. J.; Burnell, D. J. J. Org. Chem. 1994, 59 (6),
1485. doi:10.1021/jo00085a041.
(9) Crane, S. N.; Jenkins, T. J.; Burnell, D. J. J. Org. Chem.
1997, 62 (25), 8722. doi:10.1021/jo971055v.
Can. J. Chem. Vol. 88, 2010
(13) Burnell, D. J.; Wu, Y.-J. Can. J. Chem. 1990, 68 (6), 804.
doi:10.1139/v90-128.
(14) Rosenberg, R. E.; Abel, R. L.; Drake, M. D.; Fox, D. J.;
Ignatz, A. K.; Kwiat, D. M.; Schaal, K. M.; Virkler, P. R. J.
Org. Chem. 2001, 66 (5), 1694. doi:10.1021/jo0011787.
PMID:11262115.
(15) Billings, S. B.; Woerpel, K. A. J. Org. Chem. 2006, 71 (14),
5171. doi:10.1021/jo060077r. PMID:16808503.
(16) (a) Additional examples: Cherest, M. Tetrahedron 1980, 36
(11), 1593. doi:10.1016/S0040-4020(01)83127-6.; (b) Angoh,
A. G.; Clive, D. L. J. J. Chem. Soc. Chem. Commun. 1985,
(14): 980 doi:10.1039/c39850000980.; (c) Chu, Y.; Colclough,
D.; Hotchkin, D.; Tuazon, M.; White, J. B. Tetrahedron
1997, 53 (42), 14235. doi:10.1016/S0040-4020(97)00952-6.;
(d) Dunet, G.; Mayer, P.; Knochel, P. Org. Lett. 2008, 10
(1), 117. doi:10.1021/ol702607t. PMID:18067308.
(17) Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116 (26), 11678.
doi:10.1021/ja00105a009.
(18) Yoshinaga, F.; Tormena, C. F.; Freitas, M. P.; Rittner, R.;
Abraham, R. J. J. Chem. Soc., Perkin Trans. 2 2002, (9):
1494. doi:10.1039/b204635k.
(19) Gung, B. W. Chem. Rev. 1999, 99 (5), 1377. doi:10.1021/
cr980365q. PMID:11749449.
(20) (a) Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115
(20), 9112. doi:10.1021/ja00073a029.; (b) See also: Helal,
M. R.; Abbas, K. A. Jordan J. Chem. 2009, 4, 251.
(21) Gao, F.; Burnell, D. J. J. Org. Chem. 2006, 71 (1), 356.
doi:10.1021/jo051683+. PMID:16388658.
(22) Hsien, M.; Sheu, H.-T.; Lee, T.; Cheng, S.; Lee, J.-F. J. Mol.
Catal. Chem. 2002, 181 (1-2), 189. doi:10.1016/S1381-
1169(01)00382-X.
(10) (a) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998, 63 (4),
1352. doi:10.1021/jo971867r.; (b) Crane, S. N.; Burnell, D.
J. J. Org. Chem. 1998, 63 (16), 5708. doi:10.1021/
jo9806308.
(11) (a) Parker, K. A.; Breault, G. A. Tetrahedron Lett. 1986, 27
(33), 3835. doi:10.1016/S0040-4039(00)83892-7.; (b) Saint-
Jalmes, L.; Lila, C.; Xu, J. Z.; Moreau, L.; Pfeiffer, B.; Eck,
G.; Pelsez, L.; Rolando, C.; Julia, M. Bull. Soc. Chim. Fr.
1993, 130, 447; (c) Wendt, J. A.; Gauvreau, P. J.; Bach, R.
D. J. Am. Chem. Soc. 1994, 116 (22), 9921. doi:10.1021/
ja00101a013.; (d) Balog, A.; Curran, D. P. J. Org. Chem.
1995, 60 (2), 337. doi:10.1021/jo00107a011.; (e) Balog, A.;
Geib, S. J.; Curran, D. P. J. Org. Chem. 1995, 60 (2), 345.
doi:10.1021/jo00107a012.; (f) Lin, X.; Kavash, R. W.; Mariano,
P. S. J. Org. Chem. 1996, 61 (21), 7335. doi:10.1021/
jo961179s. PMID:11667659.; (g) Kanada, R. M.; Taniguchi,
T.; Ogasawara, K. J. Chem. Soc. Chem. Commun. 1998, 1755;
(h) Chavan, S. P.; Kharul, R. K.; Kale, R. R.; Khobragade, D.
A. Tetrahedron 2003, 59 (15), 2737. doi:10.1016/S0040-
4020(03)00236-9.
(12) (a) Burnell, D. J.; Wu, Y.-J. Can. J. Chem. 1989, 67 (5), 816.
doi:10.1139/v89-125.; (b) Wu, Y.-J.; Zhu, Y.-Y.; Burnell, D.
J. J. Org. Chem. 1994, 59 (1), 104. doi:10.1021/
jo00080a018.; (c) Liu, P.-Y.; Burnell, D. J. J. Chem. Soc.
Chem. Commun. 1994, (10): 1183. doi:10.1039/
c39940001183.; (d) Zhu, Y.-Y.; Burnell, D. J. Tetrahedron
Asymmetry 1996, 7 (11), 3295. doi:10.1016/0957-4166(96)
00430-2.; (e) Liu, P.-Y.; Wu, Y.-J.; Burnell, D. J. Can. J.
Chem. 1997, 75 (6), 656. doi:10.1139/v97-080.; (f)
Blanchard, A. N.; Burnell, D. J. Tetrahedron Lett. 2001, 42
(29), 4779. doi:10.1016/S0040-4039(01)00852-8.; (g) Elliott,
C. E.; Miller, D. O.; Burnell, D. J. J. Chem. Soc., Perkin
Trans. 1 2002, 217; (h) Thornton, P. D.; Burnell, D. J. Org.
Lett. 2006, 8 (15), 3195. doi:10.1021/ol0609715. PMID:
16836364.; (i) Gao, F.; Burnell, D. J. Tetrahedron Lett.
2007, 48 (46), 8185. doi:10.1016/j.tetlet.2007.09.089.; (j)
Morrison, C. F.; Stamp, C. T. M.; Burnell, D. J. Tetrahedron
Lett. 2009, 50 (50), 7021. doi:10.1016/j.tetlet.2009.09.162.
¨
(23) Wolker, D.; Haufe, G. J. Org. Chem. 2002, 67 (9), 3015.
doi:10.1021/jo016331r. PMID:11975561.
(24) (a) Mursakulov, I. G.; Guseinov, M. M.; Kasumov, N. K.;
Zefirov, N. S.; Samoshin, V. V.; Chalenko, E. G. Tetrahe-
dron 1982, 38 (14), 2213. doi:10.1016/0040-4020(82)85169-
7.; (b) Mursakulov, I. G.; Samoshin, V. V.; Binnatov, R. V.;
Kasumov, N. K.; Povolotskii, M. I.; Zefirov, N. S. Zh. Orga-
nich. Khim. 1983, 19, 2527.
(25) (a) CrystalStructure 3.7.0 (Crystal Structure Analysis Pack-
age); Rigaku and Rigaku/MSC: The Woodlands, TX, 2000–
2005.; (b) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.;
Betteridge, P. W. CRYSTALS Issue 10; Chemical Crystallo-
graphy Laboratory, Oxford, UK, 1996.
¨
¨
(26) Sheldrick, G. M. SHELX97; University of Gottingen, Gottin-
gen, Germany, 1997.
Published by NRC Research Press