Isomerisation of 2,2-dimethyl dimedone to (D,L) cis-chrysanthemic acid

Article abstract of DOI:10.1016/S0040-4039(00)00542-6

(D,L) cis-Chrysanthemic acid has been obtained in four steps from 2,2- dimethyl dimedone which involves Bamford-Stevens olefination and tandem cyclization-Grob fragmentation reactions. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00542-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3871–3874
Isomerisation of 2,2-dimethyl dimedone to (D,L)
cis-chrysanthemic acid†
Alain Krief,a,∗ Guillaume Lorvelec a and Stephane Jeanmart a,b
aLaboratoire de Chimie Organique de Synthèse, Department of Chemistry, Facultés Universitaires Notre-Dame de la Paix,
61 rue de Bruxelles, B-5000 Namur, Belgium
bFonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture, 5 Rue d’Egmont, B-1000 Bruxelles, Belgium
Received 18 February 2000; accepted 31 March 2000
Abstract
(D,L) cis-Chrysanthemic acid has been obtained in four steps from 2,2-dimethyl dimedone which involves
Bamford–Stevens olefination and tandem cyclization–Grob fragmentation reactions. © 2000 Published by Elsevier
Science Ltd. All rights reserved.
Keywords: Bamford–Stevens reaction; cyclopropanes; hydrazones; olefin bromination.
Some time ago, we showed that 2,2-dimethyl dimedone 1a can be transformed in a few steps into chry-
santhemic acid 5a (Scheme 1).1,2 This transformation involves the production of the bicyclo[3.1.0]hexane
dione 2a and its exo-β-ketosulfonate 4aexo which is then subjected to Grob fragmentation.1,3 The key
step of this transformation is indubitably the formation of the β-ketoalcohol 3aexo which required the
stereoselective reduction of the dione 2a by its more hindered face.
Scheme 1. Previous synthesis of cis-chrysanthemic acid from dimethyl dimedone. (i) t-BuOK, Br2, THF–pentane; (ii)
NaBH4–CeCl3, ethanol; (iii) Ts–Cl, Pyr., CH2Cl2; (iv) KOH, DMSO–H2O
We show in this paper our results concerning the synthesis of chrysanthemic acid 5a (R1, R2=Me)
as well as its analogues 5b (R1=H, R2=Me) and 5c (R1, R2=H) from cyclohexanediones 1a–c through
β-keto-olefins 7a–c and bicyclic ketones 9a–c according to the strategy disclosed in Scheme 2.
∗
†
Corresponding author. Fax: +32 81724536.
Dedicated with great appreciation to Prof. Pierre Sinay on the occasion of his 62nd birthday.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00542-6
tetl 16821

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Scheme 2. Novel synthesis of cis-chrysanthemic acid and homologues from dimedones
The transformation of 1a to 8a, using the Bamford–Stevens reaction,4 was known to occur in very
poor yield (<20%)5,6 due to the concomitant formation of bis-tosylhydrazone, besides the desired β-
ketohydrazone 6a from 1a and N-tosylhydrazine.7 Careful investigation of this reaction shows that the
β-ketohydrazone 6a is in equilibrium with the bis-tosylhydrazone and the β-diketone 1a.8 We have found
that 6a can be chemoselectively obtained by performing the reaction in ethanol taking advantage of its
insolubility in this solvent (1 equiv. TsNHNH2, EtOH, 20°C, 4 h, 84% yield, Scheme 3). The synthesis of
the β-keto-olefin 7a was then achieved in very good yield using the Bamford–Stevens reaction (5 equiv.
HOCH2CH2ONa, ethyleneglycol, 180°C, 0.5 h, 80% yield). Bromination of the C,C double bond was
chemoselectively performed with bromine in the presence of acetamide as an acid scavenger9 (1 equiv.
Br2, 0.1 equiv. AcNH2, CCl4, 0°C, 98% yield) and transformation of the resulting 8a to 5a was achieved
in a single step using the conditions we previously set up1 for the transformation of 4a to 5a (6 equiv.
KOH, DMSO:H2O (4:1), 70°C, 2 h, 87%).
Scheme 3. Synthesis of cis-chrysanthemic acid and lower homologues. R1, R2=Me: (i) 1 equiv. TsNHNH2, EtOH, 20°C, 4 h,
6a: 84% yield; (ii) 5 equiv. HOCH2CH2ONa, ethyleneglycol, 180°C, 0.5 h, 7a: 80% yield; (iii) 1 equiv. Br2, 0.1 equiv. AcNH2,
CCl4, 0°C, 8a: 98% yield (iv+v) 6 equiv. KOH, DMSO:H2O (4:1), 70°C, 2 h, 5a: 87% yield. R1=H, R2=Me; R1, R2=H: (i+ii)
1 equiv. TsNHNH2, THF, 20°C, 4 h, then 5 equiv. HOCH2CH2ONa, ethyleneglycol, 180°C, 0.5 h, 7b and 7c: 30% yield each;
(iii) 1 equiv. Br2, CH2Cl2, −78°C, 8b: 74% yield, 8c: 81% yield; (iv) 1 equiv. LDA, THF, −78°C, 1 h, 9b: 74% yield, 9c: 91%
yield; (v) 6 equiv. KOH, DMSO:H2O (4:1), 70°C, 2 h, 5b: 94% yield, 5c: 83% yield
We have proved, in separate experiments, using lithium diisopropylamide or potassium t-butoxide,
that the first step of the reaction 8a to 9a involves the stereoselective synthesis of the bicyclic exo-β-
bromoketone 9aexo (1 equiv. LDA, THF, −78°C, 1 h, 86% yield or 2 equiv. t-BuOK, 23°C, 2 h, 94%
yield). It is interesting to notice that we have not previously been able to obtain compound 9aexo from
3aendo and that, for example CBr4–PPh3 (2 equiv. CBr4, 4 equiv. PPh3, CH2Cl2, 20°C, 20 h)10a and its
exo-stereoisomer 9aexo has been produced along with some exo-isopropylidene cyclopentenone 10 when
3aexo was used instead (Scheme 4).10b
The synthesis of desmethyl or didesmethyl derivatives 5b and 5c from the related cyclohexadiones 1b11
and 1c was achieved according the same strategy but some differences were noticed. We have not been
able to find a solvent in which the β-ketohydrazones 6b,c could selectively precipitate. Since separation
of the mixture of the three products (1, 6 and the bis-tosylhydrazones) could not be achieved efficiently,

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Scheme 4. Synthesis of endo β-bromoketone 9aendo
we decided to perform the Bamford–Stevens reaction directly on the crude product obtained from the
reaction of the cyclohexadiones 1b,c with tosylhydrazine (i) 1 equiv. TsNHNH2, THF, 20°C, 4 h; (ii) 5
equiv. HOCH2CH2ONa, ethyleneglycol, 180°C, 0.5 h, 30% yield each) thus accepting the modest overall
yield in 7b,c.
Bromination of 7b and 7c using the conditions already used for the higher homologue 7a was
not successful since the tribromides 11b,c involving competing bromination alpha to the ketone were
produced besides the starting materials 7b,c and the desired dibromides 8b–c, and increasing the amount
of bromine in order to completely remove 7b,c led to the formation of 11b–c in very good yields (Scheme
5).
Scheme 5. Synthesis of tribromocyclohexanones 7b,c
We nevertheless found that the synthesis of the dibromides 8b,c could be chemoselectively achieved
by performing the reaction of bromine on 7b,c at low temperature without any additive (1 equiv. Br2,
CH2Cl2, −78°C; 8b and 8c in 74 and 81% yield, respectively, Scheme 3).12 Under the same conditions
8a was quantitatively formed from 7a. The formation of the single stereoisomer 8b from 7b is worthwhile
to note.
Reaction of 8b and 8c with potassium hydroxide using the conditions already used for the transfor-
mation of the higher homologue 8a to 5a did not lead to the desired derivatives 5b and 5c but instead
produce the lactones 12b,c resulting from the Grob fragmentation1,3 without prior cyclization to 9b,c
(Scheme 6). The more efficient cyclization of 9a can therefore be accounted for by the Thorpe–Ingold
effect.
Scheme 6. Reaction of dibromocyclohexanones 8b,c with potassium hydoxide.
Anyhow, the desired transformation can be achieved in two steps involving first the synthesis of the
cyclopropane ring leading to the bicyclic exo-β-bromoketones 9b,c (1 equiv. LDA, THF, −78°C, 1 h,
9b,c in 74 and 91% yield, respectively, Scheme 3) and their further reaction with potassium hydroxide in
DMSO for achieving the Grob fragmentation reaction (6 equiv. KOH, DMSO:H2O (4:1), 70°C, 2 h, 5b
and 5c in 94 and 83% yield, respectively, Scheme 3).

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Finally, we have described a short, efficient and stereoselective synthesis of cis-chrysanthemic acid
from easily available dimethyl dimedone and very simple reagents. Although the strategy used applies
to the synthesis of lower homologues bearing one or even no methyl group on the cyclopropane ring, the
individual reactions used in the case of chrysanthemic acid can no longer be applied.
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