Diastereoselective bromination of compounds bearing a cyclohex-3-enol moiety: Application to the enantioselective synthesis of (1R)-cis-deltamethrinic acid

Article abstract of DOI:10.1021/jo8022507

(Chemical Equation Presented) (1R)-cis-Chrysanthemic acid has been prepared in a few steps with complete control of the relative and absolute stereochemistry. Some mechanistic aspect of the addition of bromine to the C,C double bond of 2,2,5,5-tetramethylcyclohex-3-enol is disclosed.

Full text of DOI:10.1021/jo8022507

SCHEME 1
SCHEME 2
Diastereoselective Bromination of Compounds
Bearing a Cyclohex-3-enol Moiety: Application to
the Enantioselective Synthesis of
(1R)-cis-Deltamethrinic Acid†
Alain Krief,* Stephane Jeanmart,‡ and Adrian Kremer
a Laboratoire de Chimie Organique de Synthe`se, Faculte´s
UniVersitaires N.-D. de la Paix, 61 rue de Bruxelles, Namur,
B-5000, Belgium
alain.krief@fundp.ac.be
ReceiVed October 8, 2008
the lack of enantioselective methods for trans-Vic-dibromination
of C,C double bonds.3
For that reason, we developed the strategy disclosed in
Scheme 2, which instead involves the diastereoselective Vic-
dibromination of the C,C double bond of the (1S) homoallyl
alcohol 4′ expecting to take advantage of the directing effect4
of its hydroxyl group.
Enantioselective reduction of 2,2,5,5-tetramethylcyclohex-3-
enone 2 using (-)-B-chlorodiisopinocampheylborane5-7 (1.05
equiv, neat, 25 °C, 48 h) and quenching with diethanolamine (2.2
equiv) in anhydrous ether provides 1(S)-2,2,5,5-tetramethylcyclo-
hex-3-enol 4′ in 85% yield, with very high stereocontrol (ee
>97%,8,9 Scheme 3).
(1R)-cis-Chrysanthemic acid has been prepared in a few steps
with complete control of the relative and absolute stereo-
chemistry. Some mechanistic aspect of the addition of
bromine to the C,C double bond of 2,2,5,5-tetramethylcy-
clohex-3-enol is disclosed.
Vic-Dibromination of the resulting homoallyl alcohol 4a′ proved
to be highly stereoselective (1 equiv of Br2, -95 °C, 0.33 h,
CH2Cl2) and leads to 3(R),4(R)-dibromo-2,2,5,5-tetramethyl-cy-
A few years ago, we described that the synthesis of (d,l)-
cis-chrysanthemic acid 1 can be achieved in a few steps from
2,2,5,5-tetramethylcyclohex-3-enone 2. These involve the Vic-
dibromination of 2 using elemental bromine followed by reaction
with potassium hydroxide in DMSO which effect a cascade
cyclopropane formation and fragmentation reaction (Scheme 1).1
This paper reports extension of our previous work to the
enantioselective synthesis of (1R)-cis-chrysanthemic acid 1′ and
of the related deltamethrinic acid 1Br′ precursor of deltamethrin
the most active commercially available insecticide (Scheme 3).2
In fact, the planned transformation was not straightforward due to
(4) Hoveyda, A. H. Chem. ReV. 1993, 93, 1307.
(5) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem.
Soc. 1988, 110, 1539.
(6) In addition to (-)-B-chlorodiisopinocampheylborane A,5 other reducing
agents have been tested unsuccessfully, such as (a) (R)-alpine-borane B,7a (b)
modified aluminum hydride C,7b,c (THF, 20 °C, 96 h, 0%), and (c) Corey’s
oxazaborolidine D7d,e complexed with borane (cat. 10d, BH3,-78 °C, 0% yield).
The later reagent reacts, however, at higher temperature with 2 but leads to a
mixture of compounds resulting from the reduction of both the C,C and C,O
double bonds of 2.
† Dedicated to the memory of Al Meyers for his excellence in chemistry and
his acute sense of humor.
‡ Present address: Syngenta, Jealott’s Hill International Research Centre,
Bracknell, Berkshire RG42 6EY, UK.
(1) Krief, A.; Lorvelec, G.; Jeanmart, S. Tetrahedron Lett. 2000, 41, 3871.
(2) (a) Tessier, J. Chem. Ind. (London) 1984, 199. (b) Krief, A. In
Stereocontrolled Organic Synthesis. A “Chemistry for the 21th Century”
Monograph; Trost, B. M., Ed.; International Union of Pure and Applied
Chemistry, Blackwell Scientific: Oxford, 1994; p 337, and references cited
therein. (c) Naumann, F. In Chemistry of Plant Protection; Bowers, W. S., Ebing,
W., Martin, D., Wegler, R., Eds.; Springer-Verlag: Berlin, 1990.
(3) (a) For examples of asymmetric bromination, see: Berti, G.; Marsili, A.
Tetrahedron 1966, 22, 2977. (b) Tanaka, K.; Shiraishi, R.; Toda, F. J. Chem.
Soc., Perkin Trans. 1 1999, 21, 3069. (c) Sakuraba, H.; Kaneko, T.; Nagashima,
R. Kenkyu Hokoku - Kanto Gakuin Daigaku Kogakubu 1999, 43, 35. (d) Chem.
Abstr. 1999, 133, 30374.
(7) (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A.
J. Am. Chem. Soc. 1980, 102, 867. (b) Brown, H. C.; Pai, G. G. J. Org. Chem.
1985, 50, 1384. (c) Vigneron, J. P. Jacquet, I. Tetrahedron 1976, 32, 939. (d)
Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem.
Soc. 1987, 109, 7925. (e) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem.
1988, 53, 2861.
(8) [R]20D-64.1 (c 1.0, CHCl3).
(9) (a) Enantiomeric excess has been determined on the corresponding
Mosher’s ester by 1H NMR. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1973, 95, 512.
10.1021/jo8022507 CCC: $40.75
Published on Web 11/13/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9795–9797 9795

SCHEME 3
SCHEME 5
SCHEME 4
TABLE 1
entry
4
R
T (°C)
de (%)
SCHEME 6
a
b
c
d
e
f
g
h
i
4a′
4a′
4a′
4b
4b
4c
H
H
H
-95
-78
0
97
90
76
CHdO
CHdO
-78
84.2
64.6
76.9
61.5
76.0
73.2
60.6
82.8
62.4
0
MeCdO
MeCdO
t-BuCdO
t-BuCdO
t-BuCdO
SiMe3
-78
0
-95
-78
0
4c
4d
4d
4d
4e
j
k
l
-78
4e
SiMe3
0
d,f,i,k). We have not been able to determine why the stereo-
control is poorer with 4b-d possessing carboxy groups which
have a higher propensity to lie in equatorial position than the
hydroxyl group.
The selective formation of 5a′ over 5a′′ could be rationalized
by assuming the attack of the bromide ion at C-4 of the
bromiranium 7a or at C-3 of its diastereoisomers 8a so that it
leads to a chair (Scheme 5, entries a,b) rather than a twisted
boat transition state (Scheme 5, entries c,d).14
clohexan-1(S)-ol 5a′ in high yield and with very high stereocontrol
(95% yield; de 97%, Scheme 3).
The relative and absolute stereochemistry of the 5a′ has been
deducted from the DRX10 of its acetate 5c′ (9 equiv of Ac2O, 9
equiv of Pyr, 0.1 equiv of DMAP, CH2Cl2, 0-20 °C, 36 h; 92%
yield).
The synthesis of scalemic (1R)-cis-chrysanthemic acid 1′ was
readily achieved from that stage by oxidation to the scalemic
3(R),4(R)-dibromo-2,2,5,5-tetramethylcyclohexanone 3′ (PDC,11
CH2Cl2, 20 °C, 0.33 h, 88% yield) followed by reaction with the
Gassman reagent12 (t-BuOK/H2O: 7.6/2.3, THF, 20 °C, 0.5 h) and
acid hydrolysis of the resulting potassium carboxylate (86% yield
in 1′, ee >98%, Scheme 3).
Dibromation of related 4-trideuteromethoxy- 9a, 4-acetoxy-
9b, and 4-trifluoromethylcyclohexenes 9c was carried out 25
years ago15 (CHCl3, 0 °C) and produces the corresponding
dibromides in quantitative yields but as a 65/35, 60/40, and 60/
40 mixture of 10′/10′′ diastereoisomers, respectively (Scheme
6).
The reaction involving the Gassman reagent12 is remarkable
since it sequentially allows the formation of the [3.1.0] bicyclic
skeleton by intramolecular substitution leading to 6′ and the high-
yielding Grob-type fragmentation reaction1,13 leading to the potas-
sium chrysanthemate.
Related results have been also reported16 on the dibromation
of tert-butyl N-(cyclohex-3-enyl)carbamate 11a and N-(cyclo-
hex-3-enyl)trifluoroacetamide 11b with bromine in methylene
dichloride (-78 °C) and produce 12 in about 90% yields and
in 83/17 and 77/23 ratios of 12′/12′′ diastereoisomers, respec-
tively (Scheme 6).
The dibromination of the equatorial homoallyl alcohol 4a′ is
even more remarkable since the high stereocontrol reported above
is only observed when the reaction is performed at quite low
temperature (-95 °C, Schemes 4, Table 1, compare entry a to b,c),
and interestingly, dilution does not affect this stereocontrol.
We have also performed the bromination either of the
corresponding formiate 4b, acetate 4c, pivalate 4d, or trimeth-
ylsilyl derivative 4e (Table 1, entries d-l) but the results were
disappointing since we never reached the high stereoselectivity
observed from the free alcohol 4a (Table 1, compare entry b to
Those results are related to those reported in this work, but
diastereoselections are far poorer than we have observed from
the homoallyl alcohol 4a.
Preliminary results on the addition of hypobromous acid on
4 lead us to suspect that the addition of bromenium ion (Br+)
is not stereoselective and produces a 60/40 mixture of 7/8. We
will report in due course this work and its uses for another
synthesis of (1R)-cis-chrysanthemic acid 1′.
(10) Kremer, A.; Krief, A.; Wouters, J.; Norberg, B. Acta Crystallogr. E.
Manuscript in preparation.
(11) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(12) (a) Gassman, P. G.; Zalar, F. V. Tetrahedron Lett. 1964, 5, 3251. (b)
Gassman, P. G.; Zalar, F. V. Tetrahedron Lett. 1964, 5, 3031. (c) Gassman,
P. G.; Lumb, J. T.; Zalar, F. V. J. Am. Chem. Soc. 1967, 89, 946.
(13) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1.
(14) (a) Alt, G. H.; Barton, D. H. R. J. Chem. Soc. 1954, 4284. (b) Valls, J.;
Toromanoff, E. Bull. Soc. Chim. Fr. 1961, 758.
(15) Zefirov, N. S.; Samoshin, V. V.; Zemlyanova, T. G. Tetrahedron Lett.
1983, 24, 5133.
(16) Kupferer, P.; Vasella, A. HelV. Chim. Acta 2004, 87, 2764.
(17) Krief, A.; Kremer, A. Synlett 2007, 607.
9796 J. Org. Chem. Vol. 73, No. 24, 2008

The product was crystallized, without special care, by evaporation
of isopropyl alcohol solution over a period of 2 days for X-ray
diffraction analysis.
Experimental Section
2,2,5,5-Tetramethylcyclohex-3-enone 2 was prepared according
to the literature procedure.1
(3R,4R)-Dibromo-2,2,5,5-tetramethylcyclohexanone 3′. Into a 25
mL round-bottomed two-necked flask under Ar were added at 0 °C
PDC (1.13 g, 3 mmol) and powdered molecular sieves 4 Å (1.13 g)
mixed together with a stirred solution of (1S)-(3R,4R)-dibromo-2,2,5,5-
tetramethylcyclohexanol 5a′ (785 mg, 2.5 mmol) in dry CH2Cl2 (15
mL), and the reaction mixture was stirred at rt. After 0.33 h, the reaction
mixture was filtered through Celite, the Celite cake was washed with
CH2Cl2 (2 × 25 mL), and the filtrate was concentrated under reduced
pressure. The crude product was purified by column chromatography
(pentane/ether: 90/10) to furnish 886 mg (88%) of (3R,4R)-dibromo-
2,2,5,5-tetramethylcyclohexanone 3′ as a white solid: mp 104 °C; 1H
NMR (400 MHz, CDCl3) δ 4.44 (d, J ) 11.6 Hz, 1H), 4.25 (d, J )
11.6 Hz, 1H), 2.78 (d, J ) 14.0 Hz, 1H), 2.32 (d, J ) 14.0 Hz, 1H),
1.30 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 0.98 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 207.9, 66.8, 66.5, 52.7, 49.8, 40.4, 32.0, 23.9, 23.8,
21.2; IR (KBr) ν (cm-1) 2982, 2941, 2879, 1712, 1460, 1389, 1371,
1345, 1298, 1245, 1185, 1122, 1076, 945, 893, 856, 806, 733; EIMS
m/z 233, 231, 205, 203, 191, 189, 151, 149, 147, 123, 110, 109. Anal.
Calcd for C10H16Br2O: C, 38.49; H, 5.17. Found: C, 38.88; H, 4.95.
(1R)-cis-Chrysanthemic Acid 1′ with the Gassman Reagent. Into
a 25 mL round-bottomed two-necked flask under Ar was added water
(21 mg, 1.15 mmol) to a stirred solution of freshly sublimed potassium
tert-butoxide (426 mg, 3.8 mmol) in dry THF (4 mL), and the reaction
mixture was stirred at rt. After 10 min, a solution of (3R,4R)-dibromo-
2,2,5,5-tetramethylcyclohexanone 3′ (156 mg, 0.5 mmol) in dry THF
(2 mL) was added dropwise. A yellow coloration appeared, and the
reaction was monitored by TLC (pentane/ether: 80/20). After 0.5 h at
rt, ice (8 mL) was added and the reaction mixture acidified to pH 2
with aq HCl (10%) (discoloration) and extracted with ether (4 × 15
mL). The combined organic extracts were washed with water (2 × 5
mL), dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by column chromatography
(pentane/ether: 80/20) to furnish 72 mg (86%) of (1R)-cis-chrysan-
themic acid 1′ as a white solid: mp 108 °C; [R]20D +82.3 (c 1.0, CHCl3)
(lit.17 [R]20D +83.0 (c 1.75, CHCl3); 1H NMR (400 MHz, CDCl3) δ
9.85 (broad, 1H), 5.36 (dt, J ) 8.8, 1.3 Hz, 1H), 1.96 (dd, J 8.5, 8.6
Hz, 1H), 1.74 (s, 3H), 1.69 (s, 3H), 1.64 (d, J ) 9.1 Hz, 1H), 1.24 (s,
3H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.1, 135.2, 117.9,
33.1, 30.9, 28.8, 27.4, 25.9, 18.2, 14.7; IR (KBr) ν (cm-1) 3037, 2928,
2559, 1693, 1438, 1394, 1376, 1326, 1305, 1229, 1148, 1120, 1090,
1061, 1004, 979, 940, 852, 838, 786, 718.
(S)-2,2,5,5-Tetramethylcyclohex-3-enol 4a′. Into a 25 mL round-
bottomed two-necked flask under a bell of Ar were added 2,2,5,5-
tetramethylcyclohex-3-enone 2 (3.040 g, 20 mmol) and (-)-Ipc2BCl
(6.74 g, 21 mmol), and the solution was stirred at rt. After 3 days,
liberated R-pinene was removed by vacuum (0.1 mmHg) at 40 °C.
Dry ether (70 mL) was added followed by diethanolamine (4.62 g, 44
mmol) and the solution stirred for 2 h at rt. The white precipitate that
appeared was filtered through a Bu¨chner funnel, and the filter cake
was washed with dry ether (4 × 25 mL). The filtrate was concentrated
under reduced pressure. The crude product was purified by column
chromatography (pentane/ether: 95/5) to furnish 2.61 g (85%) of (S)-
2,2,5,5-tetramethylcyclohex-3-enol 4a′ as a white solid with an odor
close to that of menthol: mp 47 °C; [R]20D -64.1 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 5.23 (s, 2H), 3.67 (dd, J ) 11.2, 4.8 Hz,
1H), 1.58 (m, 2H), 1.38 (broad, 1H), 1.08 (s, 3H), 1.02 (s, 3H), 1.01
(s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 134.8, 133.9,
73.6, 42.1, 36.9, 34.6, 31.0, 29.4, 27.6, 21.3; IR (KBr): ν (cm-1) 3372,
3005, 2959, 2931, 2868, 1469, 1361, 1185, 1076, 1041, 912, 764, 736.
(1S)-(3R,4R)-Dibromo-2,2,5,5-tetramethylcyclohexanol 5a′. Into
a 50 mL round-bottomed two-necked flask under Ar was added
dropwise, at -95 °C, a solution of bromine (480 mg, 3 mmol) in dry
CH2Cl2 (12 mL) to a stirred solution of (S)-2,2,5,5-tetramethylcyclohex-
3-enol 4a′ (462 mg, 3 mmol) in dry CH2Cl2 (18 mL). After 0.25 h at
-95 °C, 10 mL of satd aq Na2S2O5 was added, and the reaction
mixture was allowed to warm to room temperature and diluted with
CH2Cl2 (100 mL). The organic layer was decanted, dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude product
was purified by column chromatography (pentane/ether: 90/10) to
furnish 895 mg (95%) of (1S)-(3R,4R)-dibromo-2,2,5,5-tetramethyl-
cyclohexanol 5a′ as a white solid: mp 119 °C; [R]20 -48.9 (c 1.4,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 4.61 (d, J ) 11.6 Hz, 1H),
4.30 (d, J ) 11.6 Hz, 1H), 3.78 (dd, J ) 3.0, 2.8 Hz, 1H), 1.88 (m,
2H), 1.56 (s, 1H), 1.32 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H), 1.10 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 75.9, 69.5, 66.0, 43.9, 41.0, 39.0,
33.3, 28.0, 25.4, 21.5; IR (KBr) ν (cm-1) 3576, 2973, 2932, 2881,
1464, 1452, 1391, 1367, 1347, 1288, 1245, 1205, 1166, 1114, 1079,
1048, 1014, 998, 933, 916, 881; EIMS m/z 235, 233, 153, 135, 111,
95, 69, 55. Anal. Calcd for C10H18Br2O: C, 38.24; H 5.78. Found: C,
38.64; H, 4.78.
(1R)-cis-Chrysanthemic Acid 1′ with KOH in DMSO/Water
Mixture. Into a 25 mL round-bottomed two-necked flask under Ar,was
added (3R,4R)-dibromo-2,2,5,5-tetramethylcyclohexanone 3′ (156 mg,
0.5 mmol) to a stirred solution of potassium hydroxide (168 mg, 3
mmol) in a mixture of dimethyl sulfoxide and water (4:1, 2 mL). The
reaction mixture was then heated to 70 °C for 2.5 h. The reaction was
monitored by TLC (pentane/ether: 80/20). The reaction was hydrolyzed
to pH 2 with aq HCl (10%) and extracted with ether (4 × 15 mL).
The combined organic extracts were washed with water (2 × 5 mL),
dried over MgSO4, filtered, and evaporated under reduced pressure.
The crude product was purified by column chromatography (pentane/
ether: 80/20) to furnish 69 mg (82%) of (1R)-cis-chrysanthemic acid
1′ as a white solid. Spectral properties were identical with those already
reported.
(1S)-Acetoxy-(3R,4R)-dibromo-2,2,5,5-tetramethylcyclohexane
5c′. Into a 25 mL round-bottomed two-necked flask under Ar were
added dry pyridine (240 mg, 3 mmol) and DMAP (4 mg, 0.04 mmol)
to a stirred solution of (1S)-(3R,4R)-dibromo-2,2,5,5-tetramethylcy-
clohexanol 5a′ (105 mg, 0.33 mmol) in dry CH2Cl2 (3 mL). The
solution was cooled to 0 °C before freshly distilled acetic anhydride
(306 mg, 3 mmol) diluted with 2 mL of dry CH2Cl2 was added
dropwise. After 36 h at room temperature, the reaction mixture was
quenched with aq HCl (10%, 3 mL) and extracted with CH2Cl2 (3 ×
10 mL). The combined organic extracts were washed with an aq satd
solution of NaHCO3 (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: 95/5) to
furnish 108 mg (92%) of (1S)-acetoxy-(3R,4R)-dibromo-2,2,5,5-
tetramethylcyclohexane 5c′ as a white solid: mp 121 °C; [R]20D -52.3
Acknowledgment. S.J. thanks the FRIA for financial support.
1
(c 1.6, CHCl3); H NMR (400 MHz, CDCl3) δ 4.90 (t, ) 3.0 Hz,
1H), 4.54 (d, J ) 11.7 Hz, 1H), 4.30 (d, J ) 11.7 Hz, 1H), 2.08 (s,
3H), 1.96 (d, J ) 3.2 Hz, 1H), 1.91 (d, J ) 3.2 Hz, 1H), 1.22 (s, 3H),
1.18 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.0, 76.8, 68.6, 65.4, 42.8, 38.9, 38.3, 33.1, 27.7, 25.0, 21.5, 21.1;
IR (KBr) ν (cm-1) 2989, 2973, 2940, 2879, 1735, 1464, 1451, 1432,
1393, 1373, 1351, 1240, 1198, 1163, 1076, 1060, 1022, 994; EIMS
m/z 217, 215, 153, 149, 147, 136, 135, 121, 120, 119, 107. Anal. Calcd
for C12H20Br2O2: C, 40.48; H, 5.66. Found: C, 41.16; H, 5.69.
Supporting Information Available: NMR spectra (1H and
13C) for compounds 4a′, 5a′, 5c′, 3′. and 1′. Experimental
procedures, characterizations, and NMR spectra (1H) for
compounds 4b-e and relative bromine adducts 5b, 5d, and 5e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8022507
J. Org. Chem. Vol. 73, No. 24, 2008 9797