Novel synthesis of (d,l)-cis-chrysanthemic acid involving α,α′-dibromination of 2,2,5,5-tetramethylcyclohexane-1,3-dione: application to the enantioselective synthesis of (1R)-cis-chrysanthemic acid

Article abstract of DOI:10.1016/j.tetlet.2009.03.001

cis-Chrysanthemic acid has been prepared in a few steps from dimethyldimedone via dibromination at alpha positions of each carbonyl carbons. The trans-dibromide which is almost exclusively formed has been isomerized to its cis-stereoisomer by highly chemoselective tandem H/K-K/H exchanges involving potassium bases at low temperature (<-40 °C). Carbocyclization of the potassium enolate intermediate takes place at around -30 °C and provide the bicyclo[3.1.0]-hexane skeleton. Lithiated bases behave differently and mainly lead to Br/M rather than to H/M exchange. We have been unsuccessful in using state of the art enantioselective metallation reactions to achieve the enantioselective synthesis of (1R)-cis-chrysanthemic acid using the disclosed strategy. This therefore still remains challenge.

Full text of DOI:10.1016/j.tetlet.2009.03.001

Tetrahedron Letters 50 (2009) 2398–2401
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of (d,l)-cis-chrysanthemic acid involving a,
a0-dibromination
of 2,2,5,5-tetramethylcyclohexane-1,3-dione: application to the
enantioselective synthesis of (1R)-cis-chrysanthemic acid
z
*
Alain Krief , Willy Dumont , Adrian Kremer
Laboratoire de Chimie Organique de Synthèse, 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:
cis-Chrysanthemic acid has been prepared in a few steps from dimethyldimedone via dibromination at
alpha positions of each carbonyl carbons. The trans-dibromide which is almost exclusively formed has
been isomerized to its cis-stereoisomer by highly chemoselective tandem H/K–K/H exchanges involving
potassium bases at low temperature (<ꢀ40 °C). Carbocyclization of the potassium enolate intermediate
takes place at around ꢀ30 °C and provide the bicyclo[3.1.0]-hexane skeleton. Lithiated bases behave dif-
ferently and mainly lead to Br/M rather than to H/M exchange. We have been unsuccessful in using state
of the art enantioselective metallation reactions to achieve the enantioselective synthesis of (1R)-cis-
chrysanthemic acid using the disclosed strategy. This therefore still remains challenge.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 January 2009
Revised 20 February 2009
Accepted 2 March 2009
Available online 5 March 2009
Dedicated to Professor Heinz Viehe at the
occasion of its 80th birthday
Keywords:
Pyrethroids
Ketone halogenation
Carbocyclization
Br–M exchange
H–M exchange
Isomerization
We report a new synthetic route to cis-chrysanthemic 1 which
71% yield) and achieves the formal synthesis of (d,l)-cis-chrysan-
themic acid 1 (Scheme 1).4,9
takes advantage of the efficient transformation of dimethyldime-
done 2 to the corresponding trans-
a,
a0-dibromide 3trans on reac-
This approach offers the advantage over the former one4,9a
which also produces 6, to avoid the use of mono-brominated dim-
ethyldimedone 9 which cannot be achieved selectively from 2 and
requires tedious separation from the mixture of unreacted dimeth-
yldimedone 2 and its dibrominated homolog 3.9 It also offers the
possibility to reach scalemic (1R)-cis-chrysanthemic acid by, for
example, promoting the enantioselective carbocyclization of 3 to
scalemic 4.
tion with 2 equiv of bromine (2 mol equiv Br2, CCl4, 0 °C, 1 h, 93%
yield, Scheme 1).1,2
Easy cyclization of 3trans to the bicyclic-diketone 4 bearing a
bromine atom at a bridgehead was achieved by potassium hydrox-
ide (1.3 equiv solid KOH, THF, 20 °C, 4 h).3 Regio- and diastereose-
lective reduction using sodium borohydride and cerium trichloride
is reminiscent to the reduction of a related compound bearing a tri-
methylsilyl group instead of bromine at bridgehead.4 It selectively
occurs on the carbonyl away from the bromine atom and by the
concave face leading to 5 possessing an exo-hydroxyl group.5
The Br/H exchange at bridgehead of 5 is not, as we expected, as
For that purpose we carefully studied the reactivity of 3trans to-
ward bases including chiral ones. The behavior of 3trans toward
bases was almost unknown when we started this work.10 We have
found that metallation occurs efficiently in THF (Scheme 2) with
bases containing sodium and potassium counter ions including
hydroxides (Table 1, entries 2,3), alkoxides (Table 1, entry 6), and
amides (Table 1, entries 5,7,8). Potassium carbonate suspended in
hot THF however is not strong enough to achieve metallation (Ta-
ble 1, entry 1).
easy as for other
functional group adds to the difficulties. For example, Zn in acetic
acid which usually reduces
-halogeno-ketones to ketones6,7 re-
acts with 5 but leads to an intractable mixture of unidentified com-
pounds. Tributyltin hydride8 however reduces
to very
a-bromo-ketones and the presence of the aldol
a
5
6
efficiently (1.1 equiv Bu3SnH, 0.1 equiv AIBN, benzene, reflux, 4 h,
The reaction already takes place at ꢀ78 °C with sodium and
potassium hexamethyldisilazide (NaHMDS or KHMDS) or potassium
t-butoxide (t-BuOK) but cyclization of 3trans to 4 does not occur even
after standing for 2 hours at that temperature since the reaction
leads after acidification to the isomerized cis-dibromodiketone 3cis
* Corresponding author. Tel.: +32 0 81 72 45 39; fax: +32 0 81 72 45 36.
E-mail address: alain.krief@fundp.ac.be (A. Krief).
z
Deceased on the 17th September 2008.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.001

A. Krief et al. / Tetrahedron Letters 50 (2009) 2398–2401
2399
Br
O
O
O
O
O
(i) 1.3 eq. KOH,
THF, 20°C, 4 h
(ii) aq. NH4Cl
2 eq. Br2, CCl4,
0 °C, 1 h
Br
Br
O
93 %
92 %
2
3trans
4
1 mol. eq. NaBH4/
1 mol. eq. CeCl3,
MeOH, -78°C, 0.3 h
93 %
Br
O
O
O
OH
OH
OH
1.1 eq. Bu3SnH , 0.1
AIBN, benzene,
reflux, 4 h
71 %
1
6
5
Scheme 1.
in almost quantitative yield and extremely high diastereoisomeric
ratio (Scheme 2, Table 1, entries 5,6).11
the orbital during the whole process. In conjunction with this
hypothesis we found that 3cis is less prone to Br/li exchange when
reacted with LDA (3trans/3cis/9/10: 22/47/27/4, compare to Table 1,
entry 11).
Rationalization of these results is highly speculative and, for
example, they are not in agreement with Pearson’s theory.14
Furthermore only few reports deal with Br/Li prevailing over
Raising the temperature to 20 °C before acidification leads to
the bicyclic-diketone 4 bearing a bromine atom at bridgehead in
very good yield (Scheme 2, Table 1, entry 7). Cyclization also occurs
by reacting at room temperature 3cis dissolved in THF with sodium
hexamethyldisilazide or potassium or sodium hydroxide.
Lithium reagents especially lithium hydroxide and lithium
diisopropylamide (LDA) behave differently. Thus lithium hexa-
methyl disilazide (LiHMDS) in THF does not metallate 3trans, even
at room temperature, as efficiently as its potassium analog (com-
pare remaining 3trans, Table 1, entries 7,9) under these conditions,
cyclization of the enolate 7Li is not taking place to a reasonable ex-
tent (compare amount of 4 produced, Table 1, entries 7,9).
Reactions involving 3trans and LiOH and LDA are even more puz-
zling since Br/Li exchange which produces 8 is now favorably com-
peting with H/Li exchange leading to 7 since 9 is produced, in
substantial amounts, after acidification besides the epimerized di-
bromo-diketone 3cis (Table 1, entries 4,10,11).12,13 It is interesting
to notice that neither 7Li nor 8Li is prone to transannular alkylation
even under forcing conditions (Table 1, compare entries 11 to 10).
Br/Li exchange is not unexpected since 3trans possesses in
H/Li exchange in a-bromo-ketones, especially when metal
hydroxides or metal amides15 are used. It however prevails
with reagents such as metal selenolates and tellurolates pos-
sessing a softer reacting species with
a
-iodoketones.16 Further-
more it is surprising that the Br/M exchange observed with
LDA and LiOH is not observed when lithium hexamethyldisilaz-
ide is used instead.
With these results in hand we performed the reaction of chiral
bases possessing potassium or ammonium counterions (Fig. 1)
with the prochiral dibromodiketone 3cis (Scheme 3).
Sodium and potassium (1S,2R)-2-(dibutylamino)-1-phenylpro-
pan-1-olate 11 (Fig. 1) the Soai base17 which was also exploited
in the Duhamels group18 effectively reacts with 3cis and leads to
the desired compound 4 in 81% yield but as a racemate (1.3 equiv
11K, THF, 0 °C, 1 h). Performing the reaction at lower temperature
(ꢀ40 °C) dramatically lowers the yield but still leads to the race-
mate (29%, ee 0%).
a
- and a0-position one axial hydrogen and one axial bromine
atom well suited to deliver an enolate by constant overlapping of
Br
O
O
O
O
O
O
M
+
Br
Br
Br
Br
O
4
7
8
O
O
3cis
1.3 eq BM
THF
Br
Br
O
O
M
O
O
3trans
+
Br
O
Br
9
10
Scheme 2.

2400
A. Krief et al. / Tetrahedron Letters 50 (2009) 2398–2401
Table 1
BM
Conditions
3trans
3cis
4
9
1
2
3
4
5
6
7
8
9
K2CO3
KOH
NaOH
LiOH
KHMDS
t-BuOK
KHMDS
NaHMDS
LiHMDS
LDA
(i) 80 °C, 4 h, (ii) aq HCl
(i) 20 °C, 4 h, (ii) aq NH4Cl
(i) 20 °C, 4 h, (ii) aq NH4Cl
(i) 20 °C, 4 h, (ii) aq NH4Cl
(i) ꢀ78 °C, 2 h (ii) aq NH4Cl, ꢀ78 °C
(i) ꢀ78 °C, 2 h, (ii) aq NH4Cl, ꢀ78 °C
(i) ꢀ78 °C, 2 h, (ii) ꢀ78 to 20 °C, 2 h, (iii) aq NH4Cl
(i) ꢀ78 °C, 2 h, (ii) ꢀ78 to 20 °C, 2 h, (iii) aq NH4Cl
(i) ꢀ78 °C, 2 h, (ii) ꢀ78 to 20 °C, 2 h, (iii) aq NH4Cl
(i) ꢀ78 °C, 1 h, (ii) HCl, MeOH, ꢀ78 °C
(i) ꢀ78 °C, 2 h, (ii) ꢀ78 to 20 °C, 2 h, (iii) aq NH4Cl
95
92
88
30
22
02
02
04
14
53
26
22
20
98
98
04
12
42
22
16
28
93
74
05
10
11
52
55
LDA
02
Br-
Br-
N+
O
N+
H
F
H
Ph
Me
F
O
(S)
(R)
F
N
N
n-Bu
MO
N
n-Bu
11M; M=Na, K
12
13
Br-
N+
O
R
Br-
N+
Br-
N+
N
O
R
N
15: R=2-naphthalenyl
16: R=3,4,5-F3-Ph
14
Figure 1.
We have determined that 40 is the major enantiomer obtained
in the above alkylative annelation by transforming it to (1R)-cis-
chrysanthemic acid25 10 using the set of reactions described in
Scheme 1 for the racemate.4
Since we have observed similar results (yield and ee’s) when
performing the reaction, under similar conditions, on the trans-
diastereoisomer 3trans, we suspect that a complex process involv-
ing a series of epimerizations is taking place prior annelation
leading to 4.
Br
O
O
O
O
Br
B*M
+
Br
Br
O
O
3cis
4'
4"
Scheme 3.
Acknowledgment
We also carried out the reaction which involves potassium
hydroxide (Scheme 1) in the presence of scalemic ammonium salts
derived from chinconidia alkaloids19–22 such as 12–14 (Fig. 1) or
from binaphthyls22,23 15 and 16 (Fig. 1).
We thank Professor A. Luxen (ULG, Belgium) for providing us
some of the chiral ammonium salts used in this work.
As expected all those catalysts allow the synthesis of 4 in good
yield but we found that under these conditions the enantioselec-
tivity of the reaction is extremely poor [(a) 12 (0.1 equiv, CsOH.-
H2O, CH2Cl2, 0 °C, 6 h, 82% yield, ee: 11%; or ꢀ40 °C, under
similar conditions, 23% yield, ee: 14%); (b) 13 (0.1 equiv, 50% aq
KOH, CHCl3–toluene, 0 °C, 6 h, 42% yield, ee: <2%); (c) 14 (0.1 equiv,
50% aq KOH, CHCl3–toluene, 0 °C, 6 h, 86% yield, ee: 5%); (d) 15
(0.01 equiv, 0 °C, 6 h, 50% aq KOH, toluene, 60% yield, ee: <1%)].
Best enantioselectivity, although extremely modest according
to usual standards, has been however obtained using Binap-de-
rived chiral catalyst 16 (0.01 equiv 16, 50% aq KOH, toluene, 0 °C,
6 h, 75% yield, ee: 26%).24
References and notes
1. Theobald, D. W. Tetrahedron 1978, 34, 1567–1569.
2. trans-4,6-Dibromo-2,2,5,5-tetramethylcyclohexane-1,3-dione 3trans
. Into a
500 mL round-bottomed two-necked flask, was added dropwise, at 0 °C, a
solution of bromine (32.0 g, 0.2 mol) in CCl4 (150 mL) to a stirred solution of
2,2,5,5-tetramethylcyclohexane-1,3-dione 2 (16.8 g, 0.1 mol) in CCl4 (200 mL).
After 1 h at 0 °C, 20 mL of satd aq K2CO3 and 20 mL of satd aq Na2S2O5 were
added. The organic layer was decanted, dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude product was crystallized from
CH2Cl2–pentane to furnish 30.5 g (93%) of trans-4,6-dibromo-2,2,5,5-
tetramethylcyclohexane-1,3-dione 3trans as
NMR (400 MHz, CDCl3) d 4.99 (s, 2H), 1.53 (s, 6H), 1.23 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 202.7, 60.5, 58.8, 38.6, 26.3, 24.8; IR (KBr):
(cmꢀ1) 2985,
a
white solid: mp 109 °C; 1H
m

A. Krief et al. / Tetrahedron Letters 50 (2009) 2398–2401
2401
2937, 1731, 1703, 1461, 1386, 1295, 1214, 1096, 1045, 1001, 914, 821, 727,
671, 635; EIMS m/z 247, 245, 177, 175, 149, 147, 137, 125, 122, 107.
3. 1-Bromo-3,3,6,6-tetramethylbicyclo[3.1.0]hexane-2,4-dione 4. Into a 100 mL
round-bottomed two-necked flask under Ar, was added solid KOH
dry THF (75 mL) maintained at ꢀ78 °C. After 2 h at ꢀ78 °C, and usual work-up,
the crude product is crystallized from CH2Cl2–pentane to furnish 6.13 g (94%)
of cis-4,6-dibromo-2,2,5,5-tetramethylcyclohexane-1,3-dione 3cis as a white
solid: mp 147 °C; 1H NMR,13C NMR, and EIMS agree with the published ones.1
12. Reaction of cis-4,6-dibromo-2,2,5,5-tetramethylcyclohexane-1,3-dione 3cis
with LDA at ꢀ78 °C. LDA (0.5 M in dry THF, 2.6 mL, 1.3 mmol) is added
(730 mg, 13 mmol) to
a stirred solution of trans-4,6-dibromo-2,2,5,5-
tetramethylcyclohexane-1,3-dione 3trans (3.26 g, 10 mmol) in dry THF
(50 mL) and the reaction mixture was stirred at rt. After 4 h, the reaction
mixture was quenched with satd aq NH4Cl (20 mL) and extracted with ether
(4 ꢁ 30 mL). The combined organic extracts were washed with water (5 mL)
and brine (5 mL), dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by column chromatography
(pentane/ether: 90:10) to furnish 2.25 g (92%) of 1-bromo-3,3,6,6-
tetramethylbicyclo[3.1.0]hexane-2,4-dione 4 as a colorless liquid: 1H NMR
(400 MHz, CDCl3) d 2.50 (s, 1H), 1.49 (s, 3H), 1.31 (s, 3H), 1.15 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 207.9, 206.8, 55.5, 47.4, 46.4, 33.2, 26.6, 25.2, 18.8, 15.7; IR
dropwise to
a stirred solution of cis-4,6-dibromo-2,2,5,5-tetramethyl-
cyclohexane-1,3-dione 3cis (326 mg, 1 mmol) in dry THF (5 mL) maintained
at ꢀ78 °C. The solution is stirred at ꢀ78 °C for an additional hour. After usual
work-up we obtained 284 mg (100%) of
a mixture of trans-4,6-dibromo-
2,2,5,5-tetramethylcyclohexane-1,3-dione 3trans
, cis-4,6-dibromo-2,2,5,5-
tetramethylcyclohexane-1,3-dione 3cis and 4-bromo-2,2,5,5-tetramethylcy-
,
clohexane-1,3-dione 9 in a 26:22:52 ratio, respectively. Spectral properties
(1H NMR,13C NMR, and EIMS) of the two dibromides 3trans and 3cis and 9 (mp
117 °C) agree with the published ones.1,9
(film):
m
(cmꢀ1) 2976, 2934, 2873, 1762, 1726, 1462, 1382, 1288, 1110, 1073,
13. The different products resulting from the reaction of dibromides 3trans or 3cis
863, 833, 759; EIMS m/z 246, 244, 203, 201, 176, 174, 161, 159, 109, 95, 70, 67,
55, 51, 42. Anal. Calcd for C10H13BrO2: C, 49.00; H, 5.35. Found: C, 48.82; H,
5.50.
with bases were quantified by 1H NMR.
14. (a) Pearson, R. G. J. Chem. Edu. 1987, 64, 561–567; (b) Pearson, R. G. J. Am. Chem.
Soc. 1963, 85, 3533–3539.
4. Krief, A.; Kremer, A. Synlett 2007, 607–610.
15. Dubois, J. E.; Lion, C.; Dugast, J. Y. Tetrahedron Lett. 1983, 24, 4207–4208.
16. Sheshadri, R.; Pegg, W. J.; Israel, M. J. Org. Chem. 1981, 46, 2596–2598.
17. Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. J. Chem. Soc., Chem. Commun.
1987, 1690–1691.
18. (a) Vadecard, J.; Plaquevent, J.-C.; Duhamel, L.; Duhamel, P.; Toupet, L. J. Org.
Chem. 1994, 59, 2285–2286; (b) Vadecard, J.; Plaquevent, J.-C.; Duhamel, L.;
Duhamel, P. J. Chem. Soc., Chem. Commun. 1987, 116–117.
19. O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353–2355.
20. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–12415.
21. (a) Jew, S.-S.; Yoo, M.-S.; Jeong, B.-S.; Park Il, Y.; Park, H.-G. Org. Lett. 2002, 4,
4245–4248; (b) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee,
Y.-J.; Kim, M.-J.; Jew, S.-S. Angew. Chem., Int. Ed. 2002, 41, 3036–3038.
22. Lemaire, C.; Gillet, S.; Guillouet, S.; Plenevaux, A.; Aerts, J.; Luxen, A. Eur. J. Org
Chem. 2004, 2899–2904.
5. 1-Bromo-4-exo-hydroxy-3,3,6,6-tetramethylbicyclo[3.1.0]hexan-2-one
Into 50 mL round-bottomed two-necked flask under Ar, was added
CeCl3.7H2O (1.12 g, 3 mmol) to stirred solution of 1-bromo-3,3,6,6-
tetramethylbicyclo[3.1.0]hexane-2,4-dione (735 mg, 3 mmol) in MeOH
5.
a
a
4
(20 ml). After complete dissolution of cerium salt, the solution was cooled to
ꢀ78 °C before NaBH4 (114 mg, 3 mmol) was added in one portion. After 0.3 h at
ꢀ78 °C, the reaction mixture was quenched with aq HCl (10%, 15 mL), allowed
to warm to room temperature, and extracted with ether (4 ꢁ 25 mL). The
combined organic extracts were washed with water (2 ꢁ 5 mL) and brine
(5 mL), dried over MgSO4, filtered, and evaporated under reduced pressure.
The crude product was purified by column chromatography (pentane/
ether: 60:40) to furnish 689 mg (93%) of 1-bromo-4-exo-hydroxy-3,3,6,6-
tetramethylbicyclo[3.1.0]hexan-2-one
5 as a
colorless liquid: 1H NMR
(400 MHz, CDCl3) d 3.89 (s, 1H), 1.93 (br, 1H), 1.82 (s, 1H), 1.38 (s, 3H), 1.19
23. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519–6520; (b)
Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122,
5228–5229; (c) Maruoka, K. J. Fluorine Chem. 2001, 112, 95–99.
(s, 3H), 1.10 (s, 3H), 0.99 (s, 3H); 13C NMR (100 MHz, CDCl3) d 211.2, 74.4, 54.8,
47.8, 43.4, 27.9, 26.7, 21.6, 19.6, 17.0; IR (film):
m
(cmꢀ1) 3359, 2970, 2931,
1739, 1456, 1381, 1356, 1241, 1135, 1108, 1048, 963, 843, 808, 663; EIMS m/z
248, 246, 205, 203, 176, 174, 167, 159, 121, 107, 95, 67, 57, 41. Anal. Calcd for
C10H15BrO2: C, 48.60; H, 6.12. Found: C, 48.36; H, 6.15.
24. Enantioselective cyclization of cis-4,6-dibromo-2,2,5,5-tetramethylcyclo-
hexane-1,3-dione 3cis. KOH (50%, aq solution, 2 mL) is added to a stirred
toluene solution (6 mL) of (S,S)-3,4,5-trifluorophenyl-NAS bromide 16 (9.1 mg,
0.01 mmol) and cis-4,6-dibromo-2,2,5,5-tetramethylcyclohexane-1,3-dione
3cis (326 mg, 1 mmol) maintained at 0 °C. This solution is further stirred for
an additional 6 h. The crude product, obtained after usual work-up is purified
by column chromatography (pentane/ether: 90:10) to furnish 184 mg (75%) of
4. The 40/400 ratio is determined by chiral HPLC ([column: DAICEL CHIRALPAK
OD-H; solvent: hexane/i-propanol = 99.5/0.5; flow rate: 0.8 mL/min; detection:
217 nm]. We observe two distinct peaks on the chromatogram at 22.8 and
25.3 min in a 62:36 ratio. Structural assignment relies on the observation that
the major (S,S)-enantiomer 40 leads to the major (1R)-cis enantiomer of
chrysanthemic acid 10.
6. Lardon, A.; Reichstein, T. Helv. Chim. Acta 1943, 26, 705–715.
7. Bertrand, M.; Gil, G.; Junino, A.; Maurin, R. Tetrahedron 1985, 41, 2759–2764.
8. Ng, W.; Wege, D. Tetrahedron Lett. 1996, 37, 6797–6798.
9. (a) Krief, A.; Surleraux, D.; Frauenrath, H. Tetrahedron Lett. 1988, 29, 6157–
6160; (b) Nozaki, H.; Okada, T. Bull. Chem. Soc. Jpn. 1970, 43, 2908–2911.
10. Theobald reported1 30 years ago that the trans-dibromide 3trans resulting from
the dibromination of
2 by bromine in acetic acid containing trace of
hydrobromic acid, produces after being refluxed in pyridine for 3 h, the cis-
stereoisomer 3cis in 10–15% yield.
11. cis-4,6-Dibromo-2,2,5,5-tetramethylcyclohexane-1,3-dione 3cis. KHMDS (0.5 M
in toluene, 44 mL, 22 mmol) is added to
a
stirred solution of trans-4,6-
25.
½
a 2D0
ꢂ
+21.7 (c 1.75, CHCl3); for (1R)-cis-chrysanthemic acid 10: lit.4: ½a D20
ꢂ
+83.0
dibromo-2,2,5,5-tetramethylcyclohexane-1,3-dione 3trans (6.52 g, 20 mmol) in
(c 1.75, CHCl3).