Stereochemical issues on the fragmentation of non-enolisable β-heterosubstituted-cyclopentanones with wet and anhydrous potassium hydroxide

Article abstract of DOI:10.1016/j.tetlet.2010.03.119

Tandem Haller-Bauer-scission/Grob-fragmentation reaction of cyclopentanone bearing a leaving group in β-position involves antiperiplanar arrangements which can be also achieved from epimeric derivatives, probably due to the high flexibility of the five-membered ring. We have observed that epimeric compounds react at different rates if the leaving group is a halogen and leads to very different types of compounds when it is a mesyl group.

Full text of DOI:10.1016/j.tetlet.2010.03.119

Tetrahedron Letters 51 (2010) 3045–3049
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereochemical issues on the fragmentation of non-enolisable
b-heterosubstituted-cyclopentanones with wet and anhydrous potassium
hydroxide
*
Alain Krief , Adrian Kremer
Department of Chemistry, Facultés Universitaires N.-D. de la Paix, 61 Rue de Bruxelles, Namur B-5000, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Tandem Haller–Bauer-scission/Grob-fragmentation reaction of cyclopentanone bearing a leaving group in
b-position involves antiperiplanar arrangements which can be also achieved from epimeric derivatives,
probably due to the high flexibility of the five-membered ring. We have observed that epimeric com-
pounds react at different rates if the leaving group is a halogen and leads to very different types of com-
pounds when it is a mesyl group.
Received 18 February 2010
Revised 29 March 2010
Accepted 30 March 2010
Available online 3 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fragmentation
Hydroxide ion
Wet potassium hydroxide
Anhydrous potassium hydroxide
Vinyl cyclopropane carboxylic acid
Several years ago we devised1 an original route to cis-chrysan-
themic acid 1a, which takes advantage of the tandem Haller–Bau-
er-scission2/Grob-fragmentation3 reaction performed in aqueous
DMSO with potassium hydroxide on the exo-b-keto-mesylate 4a.
We were surprised 20 years later to be unable to reproduce4 the
yield we originally reported for the last step. We got instead a poly-
meric material resulting from competing attack of the hydroxide
ion onto the sulfur atom of the mesylate (6 equiv KOH, DMSO–
H2O (4:1) ‘WPH’, 70 °C; Method A;1,4,5 6% instead of 80%1 yield).4
We however found that the desired transformation can be
achieved, in almost quantitative yield and under very mild condi-
haves like 4a which also bears an endo-methyl group on the cyclo-
propane ring since 1b is obtained in very poor yield if the reaction
is instead carried out with ‘WPH’ (Method A, compare to Methods
B and C; Scheme 2, Table 1, entry b, compare to entry a).7a,b
‘APH’ however reacts sluggishly with the related exo-b-keto-
mesylates 4c and 4d both of which miss the methyl group in
endo-4-position. These reactions lead to desmethyl-1c and didesm-
ethyl-1d cis-chrysanthemic acids in extremely poor yields besides
large quantities of polymeric material whatever THF or DMSO is
used as the solvent (Table 1; entries c and d; Methods B and C).
We have surprisingly observed, in control experiments, that
‘WPH’ in DMSO behaves similarly but delivers 1c and 1d in
slightly better yields after acidic work-up (Table 1; entries c and
d; Method A).8
We however found that the synthesis of desmethyl-1c and
didesmethyl-1d cis-chrysanthemic acids can be efficiently
achieved by ‘APH’ using instead their epimeric endo-b-keto-mesy-
lates 6c and 6d as starting materials (Table 1, entries e and f, Meth-
ods B and C; compare to entries c and d). In such case ‘WPH’7a,c is
also able to achieve the same transformation but it requires higher
temperature, longer time, and delivers 1c and 1d in poorer yields
(40 °C instead of 20 °C, Table 1, entries e and f, compare Method
A to Methods B and C).
6
tions, using ‘anhydrous’ potassium hydroxide ‘APH’ (mixture of
potassium hydroxide, potassium t-butoxide, and t-butanol) pre-
pared by the addition of water to an excess of potassium t-butoxide
in DMSO (Method B)4–6 or THF (Method C)4–6 ((i) 4a/t-BuOK/H2O
(1:7.6:2.3 ratio), 20 °C, <1 h, Scheme 1, entry a, Table 1, entry a).
We decided to extend these reactions to the synthesis of desm-
ethyl-1b, 1c and didesmethyl-1d cis-chrysanthemic acids from the
corresponding b-keto-mesylates bearing an exo-mesyloxy group 4
as well as their endo-stereoisomers 6 any time they were available
(Scheme 2).
We found that ‘APH’ efficiently transforms the exo-b-keto-mesy-
late 4b to the corresponding desmethyl cis-chrysanthemic acid 1b
especially if the reaction is performed in DMSO (Method B, compare
to Method C; Scheme 2, Table 1, entry b). We also found that 4b be-
Accordingly we have been able to propose two different strate-
gies to achieve the stereoselective synthesis of the whole set of cis-
vinyl cyclopropane carboxylic acids 1 differently substituted at C-6
on the cyclopropane ring from the 3,3-dimethylbicyclo[3.1.0]hex-
ane-2,4-diones 2, both of which use the efficiency of ‘APH’ to pro-
* Corresponding author. Tel.: +32 474 318181; fax: +32 81 724 536.
E-mail address: alain.krief@fundp.ac.be (A. Krief).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.119

3046
A. Krief, A. Kremer / Tetrahedron Letters 51 (2010) 3045–3049
Scheme 1. Reagents and conditions: (i) 1 equiv NaBH4, 1 equiv CeCl3ꢀ7H2O, ꢁ78 °C, 1.5 h; (ii) MsCl, NEt3, CH2Cl2, ꢁ10 °C, 1 h; (iii) t-BuOk–H2O (7.6–2.3), DMSO, 20 °C; (iv) aq
HCl.
Table 1
Reaction of 4-mesyloxy-3,3-dimethylbicyclo[3.1.0]hexan-2-ones 4 and 6 with potassium hydroxide
R1
R2
Leaving group
4/6
1%a (h) Method A5
1%a (h) Method B5
1%a (h) Method C5
a
b
c
d
e
f
Me
H
Me
H
Me
H
Me
Me
H
H
H
OMs
OMs
OMs
OMs
OMs
OMs
4a
4b
4c
4d
6c
6d
6 (6)
18 (6)
90 (0.4)
93 (0.5)
5 (0.5)
9 (0.5)
70 (0.3)
73 (0.3)
60 (0.3)
54 (0.5)
<5 (0.5)
3 (0.5)
90 (0.3)
76 (0.3)
14 (1.5)
21 (2)
55 (0.8)b
65 (0.8)b
H
a
The yields reported refer to isolated analytically pure compounds.
These reactions have been carried out at 40 °C.
b
Scheme 2.
mote the tandem Haller–Bauer-scission2/Grob-fragmentation3 reac-
tion reported above (Schemes 1 and 3).
nol at ꢁ78 °C or better with lithium triethyl borohydride in THF
at the same temperature.9
The synthesis of desmethyl cis-chrysanthemic acid 1b, as that of
cis-chrysanthemic acid 1a we already published,4 can only be
achieved from the exo-b-keto-mesylate 4b and ‘APH’, DMSO being
the best solvent. The synthesis of the mesylates requires the ster-
eoselective reduction of the diketone 2b possessing an endo-
methyl group at C-6, by its most hindered face. This has been effi-
ciently achieved using Luche’s reagent (NaBH4–CeCl3ꢀ7H2O, MeOH,
ꢁ78 °C, Scheme 1, entry b compare to entry a).9
All steps involved in the two strategies are not interchangeable.
We have been lucky that ‘APH’ allows the fragmentation of the
mesylates 4b as 4a since the related epimers 6b as 6a are thermally
unstable and decompose around ꢁ10 °C extremely rapidly. This
prevents their use for the synthesis of the corresponding cyclopro-
pane carboxylic acids 1b and 1a. We have been also extremely
lucky that ‘APH’ fragments efficiently the endo-keto-mesylates 6c
and 6d and not their epimers 4c and 4d which cannot be produced
stereoselectively from b-diketones 2c and 2d using the Luche’s re-
agent since it produces at best almost 1:1 epimeric mixtures of 4c/
6c and 4d/6d.9
The synthesis of desmethyl cis-chrysanthemic acid 1c and
didesmethyl cis-chrysanthemic acid 1d however is best achieved
on the reaction of ‘APH’ in THF with endo-mesylates 6c and 6d
(Method C, Scheme 3, entries a and b). The synthesis of the latter
requires the stereoselective reduction of the diones 2c and 2d pos-
sessing an endo-hydrogen at C-6, by their least hindered faces. It
has been efficiently achieved with sodium borohydride in metha-
The transformations reported above involve a stepwise mecha-
nism which implies addition of the hydroxide ion to the carbonyl
of 4 and 6 followed by the fragmentation of the resulting intermedi-
ate A (Scheme 4). The former step is expected to be better achieved
Scheme 3. Reagents and conditions: (i) 1 equiv LiBhEt3, THF, ꢁ78 to 20 °C, 0.3 h; (ii) MsCl, NEt3, CH2Cl2, ꢁ10 °C, 1 h; (iii) t-BuOK–H2O (7.6–2.3), THF, 20 °C; (iv) aq HCl.

A. Krief, A. Kremer / Tetrahedron Letters 51 (2010) 3045–3049
3047
Scheme 4. Reagents: (i) t-BuOK, t-BuOH from ‘APH’.
with ‘APH’ rather than with ‘WPH’ because it involves the more reac-
tive naked hydroxide ion and because the excess of potassium t-
butoxide present beside potassium hydroxide is able to promote
ing on the orientation of the mesyloxy group and the substitution
at carbon-6 on the cyclopropane ring fused to the flexible five-
membered ring.
the formation of the
a,a
-dialkoxides C6 more prone to release the
Apparently the conformation leading to the antiperiplanar
arrangement cited above can be achieved from 4a and 4b bearing
an endo-methyl group and an exo-mesyloxy group. However the
top face attack of the hydroxide ion could be hampered by the
presence of the ‘bulky’ mesyloxy group thus favoring competitive
attack on its sulfur atom which finally leads to polymeric material.4
The less ‘hindered’ and more reactive naked hydroxide ion from
‘APH’ and the formation of the dialkoxide C1 (R1, R2: Me for exam-
ple) which is expected to be more prone to fragment than A1 or B1
(R1, R2 = Me for example) might be responsible for the difference of
reactivity observed between ‘APH’ and ‘WPH’.
unfavorable electronic interactions by fragmentation than B.
Furthermore it is well documented that an antiperiplanar
arrangement of atoms and bonds usually favors smooth fragmen-
tation reactions.3,10 This could be apparently achieved from some
of the 4-oxobicyclo[3.1.0]hexan-2-yl methanesulfonates depend-
Figure 1.
Figure 2.

3048
A. Krief, A. Kremer / Tetrahedron Letters 51 (2010) 3045–3049
Scheme 5.
The difference of reactivity observed between the exo-mesy-
group and whether ‘AHP’ or even ‘WHP’ is used (Table 2, entries
a–c).13 This suggests that the impact of the mesyloxy group and
of its direction on the reactivity of b-keto-mesylates 4 and maybe
6 is far more important than the access to the antiperiplanar
arrangement.
An even better insight on the mechanism of these transforma-
tions arises from the reaction of potassium hydroxide toward the
couple of b-chloro-ketones 8aCl and 9aCl.
The exo-b-chloro-ketone 8aCl whose reaction with potassium
hydroxide is expected to easily proceed through an antiperiplanar
arrangement provides cis-chrysanthemic acid 1a in good yield
(Method A and C, Table 2, entry d) and at the same rate than that
of the related exo-b-bromo-ketone 8aBr (Table 2, compare entries c
and d) even as the leaving group ability of the chloride is much
poorer than that of the bromide.
The epimeric endo-b-chloro-ketone 9aCl, whose reaction with
potassium hydroxide is not expected to achieve so easily the anti-
periplanar arrangement, leads to a polymeric material on reaction
with ‘WPH’ at 70 °C (Method A, Table 2, entry e). It reacts extre-
mely slowly with ‘APH’ to produce cis-chrysanthemic acid 1a in
poor yield if the reaction is carried out at 20 °C (Method C, Table
2, entry e) and in much better yield if it is instead performed at
60 °C for quite a long time (Method C, Table 2, entry f).
lates 4a and 4b bearing the endo-methyl group and their related
regioisomers 4c and 4d missing it (Table 1, compare entries c
and d to a and b) could be related to the change of preferred con-
formation in the transition state due to the flexibility of the five-
membered ring. This not only brings the mesyloxy group in axial
position which favors, as described above for 4a and 4b, the forma-
tion of polymeric material but also at the same time does not favor
the antiperiplanar arrangement suitable for fragmentation. There-
fore both ‘WPH’ and ‘APH’ behave similarly and do not allow the
fragmentation reaction leading to 1c and 1d, respectively (Table
1, entries c and d).
X-ray crystallographic data of the two isomeric di-exo-acetoxy-
camphenoates possessing the endo-methyl group 7b or missing it
7c (Fig. 1),11 which could be related to the transition states of the
two type of reactions described above, clearly show that the anti-
periplanar arrangement present in the former is no longer present
in the latter. These results tend to support the hypotheses pre-
sented above.
Finally the successful synthesis of desmethyl-1c and didesm-
ethyl-1d cis-chrysanthemic acids 1c and 1d from keto-mesylates
epimers 6c and 6d both missing the endo-methyl group on the
cyclopropane ring and bearing an endo-mesyloxy group could ac-
count from the conformation of the starting material in which
the mesyloxy group lies in equatorial position (see X-ray data12
for 6d, Fig. 2). It allows, at the same time, the top face attack of
any type of hydroxide ion on to its carbonyl group, avoiding the
competing attack on the sulfur atom of the mesyloxy group and fa-
vors the achievement of the antiperiplanar arrangement in the
transition state of the fragmentation step.
In order to delineate the role of each of the factors reported
above, we have carried out the reaction of ‘AHP’ toward the related
b-keto-halides 8 and 9 (Scheme 5) missing the mesyloxy group
present on the related b-keto-mesylates 4 and 6, which is particu-
larly ‘bulky’ and possesses an extra electrophilic site on sulfur.
We found that the fragmentation is efficiently achieved from all
the exo-b-keto-bromides 8Br possessing or not the endo-methyl
In conclusion cyclopentanones 4, 6, 8, and 9 fused in a0,b0-posi-
tion to a cyclopropane ring and bearing a leaving group in b-posi-
tion react with potassium hydroxide to produce vinylcyclopropane
carboxylates 1 by fragmentation reaction. This reaction is best
achieved with those compounds bearing an exo-halogen atom 8.
This has been rationalized by assuming an access to a periplanar
arrangement of those atoms and bonds involved in the process fa-
vored by the flexibility of the cyclopentane skeleton.14
In the related mesylates 4 and 6, the formation of polymers often
compete in those derivatives bearing this group in exo-position due
to competing attack of the hydroxide ion on its sulfur atom leading
then to a retroaldol fragmentation reaction if the nucleophile is not
strong enoughortheantiperiplanararrangementisdifficulttoreach.4
Thus ‘APH’ proved to be the reagent of choice owing the nucleophilic-
Table 2
Reaction of some 4-halogeno-3,3-dimethylbicyclo[3.1.0]hexan-2-ones 8 and 9 with potassium hydroxide
R1
R2
Leaving group
8/9
1%a (h) Method A
1a% (h) Method B
1a% (h) Method C
a
b
c
d
e
f
Me
H
Me
Me
Me
Me
H
H
Me
Me
Me
Me
Br
Br
Br
Cl
Cl
Cl
8cBr
8dBr
8aBr
8aCl
9aCl
9aCl
95 (0.3)13
83 (0.3)13
87 (0.8)4,13
75 (0.8)
0 (3.5)
—
—
95 (0.3)
86 (0.3)
94 (0.5)4
91 (0.5)
22 (216)b
72 (72)c,d
53 (0.3)4
—
—
—
—
a
b
c
The yields reported refer to isolated analytically pure compounds.
75% of 9aCl recovered.
Reaction carried out at 60 °C.
d
15% of 9aCl recovered.

A. Krief, A. Kremer / Tetrahedron Letters 51 (2010) 3045–3049
3049
6. (a) Gassman, P. G.; Zalar, F. V. Tetrahedron Lett. 1964, 5, 3031–3034; (b) Swan,
G. A. J. Chem. Soc. 1948, 1408–1412.
ity of the naked hydroxide ion and the aptitude fragmentation of the
dialkoxide intermediates C to fragment (Scheme 4).6a
7. (a) Krief, A.; Surleraux, D.; Robson, M. J. Synlett 1991, 276–278; (b) The yield of
1b resulting from the fragmentation reaction of 4b using ‘WPH’ is much poorer
than the one reported in Ref. 7a; (c) These results are in accordance with those
reported using ‘WPH’ in Ref. 7a. However the statement that the exo-mesylate
4d is more reactive toward ‘WPH’ than is endo-isomer 6d is wrong.7a
8. Original work.
References and notes
1. (a) Krief, A.; Surleraux, D.; Frauenrath, H. Tetrahedron Lett. 1988, 29, 6157–6160;
(b) Krief, A.; Surleraux, D.; Ropson, N. Tetrahedron: Asymmetry 1993, 4, 289–292.
2. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399–1422.
3. (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1–15; (b) Grob,
C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535–546.
9. (a) The proof of structure of those compounds have already been published9b
;
(b) Krief, A.; Surleraux, D. Synlett 1991, 273–275.
10. (a) Wharton, P. S.; Hiegel, G. A. J. Org. Chem. 1965, 30, 3254–3257; (b) Zurflüh,
R.; Wall, E. N.; Sidall, J. B.; Edwards, J. A. J. Am. Chem. Soc. 1968, 90, 6224–6225;
(c) Heathcock, C. H.; Badger, R. A. J. Org. Chem. 1972, 37, 234–238.
11. (a) Ollevier, T. PhD Thesis, FUNDP-Namur, Belgium, 1998; (b) Krief, A.; Ollevier,
T.; Swinnen, D.; Norberg, B.; Baudoux, G.; Evrard, G. Acta Crystallogr., Sect. C
1998, 54, 392–398.
4. Krief, A.; Kremer, A. Synlett 2007, 607–610.
5. Method A: 4 or 6 (1 mmol, neat) is added to a solution of potassium hydroxide
(6 mmol) in DMSO–water mixture (4:1, 3 mL) at 70 °C and stirred at the
temperature for the time required (Table 1). Acidification and usual work-up
lead to 1 (Table 1); Method B: 4 or 6 (1 mmol, neat) is added at room
temperature to a slurry resulting from the addition of water (2.3 mmol) to a
solution of t-BuOK (7.6 mmol) in dry DMSO (4 mL). After the time required
(Table 1), acidification and usual work-up, 1 is produced (Table 1); Method C: A
solution of 4 or 6 (1 mmol) in THF (4 mL) is added at room temperature to a
suspension resulting from the addition of water (2.3 mmol) to a solution of t-
BuOK (7.6 mmol) in dry THF (8 mL). After the time required (Table 1),
acidification and usual work-up, 1 is produced (Table 1).
12. Kremer, A.; Norberg, B.; Krief, A.; Wouters, J. Acta Crystallogr., Sect. E 2010, 66,
o948.
13. Krief, A.; Lorvelec, G.; Jeanmart, S. Tetrahedron Lett. 2000, 41, 3871–3874.
14. Most of the reactions involving ‘Grob-type fragmentation reaction’ so far
reported have been carried out on rigid six-membered cyclic derivatives2,3,10
where change in the stereochemistry of one of the group involved in the
process changes, in an expected manner, the outcome of the reaction.