Regioselective SN2 opening of α,β-ethylenic epoxides by RLi-BF3 combination

Article abstract of DOI:10.1039/b005472k

Organolithium reagents effect a regioselective S_N2 nucleophilic cleavage of α,β-ethylenic epoxides only when BF₃·Et₂O is added. The reaction works with a variety of RLi reagents and with cyclic as well as acyclic epoxides. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b005472k

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Regioselective S 2 opening of ꢀ,ꢁ-ethylenic epoxides by RLi–BF
N
3
combination
a
b
b
b
Alexandre Alexakis,* Emmanuel Vrancken, Pierre Mangeney and Fabrice Chemla
1
a
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, Genève 4,
CH-1211. E-mail: alexandre.alexakis@chiorg.unige.ch; Tel. ϩ 41 22 702 65 22;
Fax (int.) ϩ 41 22 328 73 96
b
Laboratoire de Chimie des Organoéléments, UMR 7611, Université Pierre et Marie Curie,
4
place Jussieu, 75252 Paris Cedex 05 France
Received (in Cambridge, UK) 7th July 2000, Accepted 18th September 2000
First published as an Advance Article on the web 2nd October 2000
Organolithium reagents effect a regioselective S 2 nucleo-
philiccleavageofꢀ,ꢁ-ethylenicepoxidesonlywhenBF ؒEt O
is added. The reaction works with a variety of RLi reagents
and with cyclic as well as acyclic epoxides.
anti-process is involved, was checked by hydrogenation of the
double bond and comparison with authentic samples of trans-
N
3
2
2-butylcyclohexanol 2. It should be pointed out that no product
1
arising from an S 2Јprocess is detected by H NMR analysis of
N
the crude product (Scheme 2).
α,β-Ethylenic epoxides, particularly the cyclic ones, are versatile
synthons in organic synthesis. The problem with these com-
pounds concerns the regioselectivity of the nucleophilic ring
opening, via an S 2 or an S 2Ј process (Scheme 1).
N
N
Scheme 2
The results obtained with other organolithium reagents
are shown in Scheme 3. The reaction appears to be quite
Scheme 1
Among carbon nucleophiles, organocopper reagents are
known for their smooth and stereoselective reaction, where
both the S 2 and the S 2Ј are anti processes. The regioselectiv-
N
N
ity using acyclic α,β-ethylenic epoxides has been extensively
studied by several authors, and depends strongly on steric fac-
1
tors. However, in cyclic compounds, such as cyclohexa-1,3-
diene oxide, the difference in steric bias toward attack at C2 and
C4 is minimised. Although lithium organocuprate reagents
give excellent stereoselectivity and yield, the regioselectivity on
1,2
this epoxide is poor. A breakthrough in this area was the
discovery by Marino that cyanocopper derivatives RCuCNLi
3
afford regioselectively the S 2Ј product. Several synthetic
N
applications have taken advantage of this excellent regio-
4,5
control.
On the other hand, there are only scarce reports of a selective
Scheme 3
2,6,7
SN2 ring opening.
It might be predicted that a harder
nucleophile should have a preference for the S 2 process,
general with a variety of structural types of R groups. The
N
whereas a soft nucleophile (such as a copper reagent) would
prefer a softer center, such as C4. Indeed, we have shown that a
reaction with Grignard reagents suffers from the competitive
10
formation of the 1,2-halohydrin. This process is minimised
when R–MgCl is used instead of R–MgBr or R–MgI. This
1,2-halohydrin is easily removed from the crude reaction
mixture by an aqueous NaOH washing, during the workup.
The reactivity of cycloocta-1,3-diene oxide follows the
same trend (Scheme 4), although the reaction has to be per-
formed at a slightly higher temperature (Ϫ75 ЊC) in order to
achieve goods yields. The reaction works well with moderately
basic RLi, but not with strongly basic ones, such as n-BuLi or
s-BuLi. Again, when Grignards reagents are used, the form-
ation of a small amount of halohydrin is observed.
8
strong Lewis acid, BF ؒEt O, promotes the reaction of RLi
3
2
and Grignard reagents at the propargylic position of an
9
α,β-acetylenic epoxide (S 2). In a similar manner, we demon-
N
strate in this communication that the use of BF ؒEt O allows
3
2
regioselective attack at the C2 position by RLi and RMgCl
reagents on cyclic and acyclic α,β-ethylenic epoxides.
As representative epoxides we chose cyclohexa-1,3-diene
oxide and cycloocta-1,3-diene oxide. When cyclohexadiene
oxide is reacted with n-BuLi, only degradation products are
observed, slowly at Ϫ78 ЊC, but quickly at 0 ЊC. However, the
nucleophilic opening occurs when BF ؒEt O is added to the
The case of cyclopentadiene oxide was extensively studied.
However, in reactions with alkyllithium reagents, mixtures of
several unidentified products are observed, even at low tem-
perature. This epoxide seems too sensitive to strongly basic or
Lewis acidic conditions. Only alkenyl- or alkynyl-lithium
3
2
10
reaction mixture at Ϫ78 ЊC. Running the reaction at Ϫ90 ЊC
improves the yield of 2-butylcyclohex-3-en-1-ol 1. The isolated
yield is good in toluene or Et O as solvents (75% and 77%
2
respectively), but much lower in THF (<25%). That a clean
3
352
J. Chem. Soc., Perkin Trans. 1, 2000, 3352–3353
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005472k

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Clearly, Tetrahedron, 1989, 45, 391; J. A. Marshall, J. D. Trometer,
B. E. Blough and T. D. Crute, Tetrahedron Lett., 1988, 29, 913.
C. B. Rose and C. W. Smith Jr., J. Chem. Soc., Chem. Commun.,
6
1
9
969, 248; M. Apparu and M. Barelle, Bull. Soc. Chim. Fr., 1977,
47; Y. Naruta and K. Maruyama, Chem. Lett., 1987, 963; I.
Mukerji, A. Wayda, G. Dabbagh and S. H. Bertz, Angew. Chem.,
Int. Ed. Engl., 1986, 25, 760; H. Ent, H. de Koning and W. N J.
Speckamp, J. Org. Chem., 1986, 51, 1687; A. J. Briggs and K. A. M.
Walker, J. Org. Chem., 1990, 55, 2962. For a SN ring opening process
with retention of configuration, see: N. Krause and D. Seebach,
Chem. Ber., 1988, 121, 1315.
7
8
E. J. Corey and H. A. Kirst, Tetrahedron Lett., 1968, 5041; G. Stork,
C. Kowalski and G. Garci, J. Am. Chem. Soc., 1975, 97, 3258;
G. Stork and M. Isobe, J. Am. Chem. Soc., 1975, 97, 4745; R. H.
Bradbury and K. M. Walker, J. Org. Chem., 1983, 48, 1741.
The use of BF ؒEt O for the nucleophilic opening of epoxide by RLi
3
2
reagents is already known. For examples with saturated epoxides
see: M. Yamaguchi and I. Hirao, Tetrahedron Lett., 1983, 24, 391;
M. J. Eis, J. E. Wrobel and B. Ganem, J. Am. Chem. Soc., 1984, 106,
Scheme 4
3
693.
reagents are known to undergo nucleophilic ring opening at the
C2 position.
9 N. Bernard, F. Chemla and J. F. Normant, Tetrahedron Lett., 1998,
6
3
9, 6715; N. Bernard, F. Chemla and J. F. Normant, Eur. J. Org.
Chem., 1999, 2067.
Finally, we extended the reaction to acyclic cases having the
same substitution pattern at C2 and C4, in order to have an
unbiased system. (Z,Z )- and (E,E )-dodeca-5,7-diene oxides
were chosen as representative substrates. Both react by a clean
1
0 R. W. Herr and C. R. Johnson, J. Am. Chem. Soc., 1970, 92, 4979;
H. Imogaï and M. Larchevêque, Tetrahedron: Asymmetry, 1997, 8,
9
65.
1
1 Typical procedure. trans-2-Butylcyclohex-3-en-1-ol:cyclohexa-1,3-
SN2 process in excellent yield, under the same experimental
diene oxide (192 mg, 2 mmol) in dry Et O (1 ml) was added dropwise
2
conditions as above, although the (E,E ) isomer has to be
to a stirred solution of n-butyllithium (1.6 M in hexane, 2.5 ml, 4
reacted at lower temperature. It is noteworthy that the Z double
bond retains its configuration. In addition, butadiene oxide,
despite being unsubstituted at the terminal ethylenic carbon,
mmol) in 12 ml of dry Et O at Ϫ95 ЊC, under a nitrogen atmosphere.
2
Then BF ؒEt O (0.38 ml, 1.5 mmol) in dry Et O (2 ml) was slowly
3
2
2
added (30 min) via a syringe pump in order to maintain the temper-
ature of the reaction mixture below Ϫ95 ЊC. After stirring for 5 min,
gives no trace of S 2Ј product. However, some product from
N
the reaction was quenched with MeOH (2.5 ml) and Et N (1.5 ml).
3
SN2 attack at the least substituted epoxide carbon is isolated in
The mixture was allowed to warm up to room temperature and was
poured into 5% aqueous H SO (10 ml). After standard work-up, the
1
6% yield (Scheme 5).
2
4
crude product was purified by column chromatography on silica gel
(
eluent pentane–Et O = 85:15) to afford 238 mg (77% yield) of
2
1
trans-2-butylcyclohex-3-en-1-ol as a colorless oil. H NMR (400
MHz, CDCl ) δ 0.91 (t, 3H), 1.21–2.1 (m, 12H), 3.59 (m, 1H), 5.55
3
1
3
(
3
m, 1H), 5.64 (m, 1H). C NMR 14.46, 23.42, 23.97, 29.17, 30.10,
3.07, 44.13, 71.48, 126.57, 129.30.
trans-2-Methylcyclooct-3-en-1-ol: cycloocta-1,3-diene oxide (250
mg, 2 mmol) in dry Et O (1 ml) was added dropwise to a stirred
2
solution of methyllithium (2 M in ether, 3 ml, 6 mmol) in 12 ml of
dry Et O at Ϫ75 ЊC, under a nitrogen atmosphere. Then BF ؒEt O
2
3
2
(
0.38 ml, 1.5 mmol) in dry Et O (2 ml) was slowly added (30 min) via
2
a syringe pump in order to maintain the temperature of the reaction
mixture below Ϫ75 ЊC. After stirring for 5 min, the reaction was
quenched with MeOH (2.5 ml) and Et N (1.5 ml). The mixture was
3
allowed to warm up to room temperature and poured into 5% aque-
ous H SO (10 ml). After standard work-up, the crude product was
2
4
purified by column chromatography on silica gel (eluent pentane–
Et O = 80:20) to afford 202 mg (72% yield) of trans-2-methyl-
2
cyclooct-3-en-1-ol as a colorless oil. Anal. calcd. for C H O: C,
9
16
7
2
7.09, H, 11.50. Found: C, 77.05, H, 11.56%. IR (film): 3369, 3009,
Ϫ1 1
928, 1760, 1459, 1009 cm . H NMR (400 MHz, CDCl ) δ 1.12 (d,
3
J = 6.4 Hz, 3H, H9), 1.25–2.60 (m, 10H, H2, H5–H8, and OH), 3.39
Scheme 5
(
m, 1H, H1), 5.25 (ddd, J = 1.5, 8.9, 10.5 Hz, 1H, H3), 5.64 (m, 1H,
1
3
H4). C NMR (100 MHz, CDCl ) δ 18.2, 21.7, 27.1, 28.7, 29.6, 34.8,
3
In conclusion, these results demonstrate that a regioselective
S 2 opening of α,β-ethylenic epoxides is indeed possible under
strictly controlled experimental conditions. The scope and
limitations of this methodology are presently under investi-
gation.
3
6.9, 77.1, 130.0, 134.6.
(Z)-trans-6-Butyloct-5-en-7-ol: (Z,Z)-dodeca-5,7-diene oxide (364
N
11
mg, 2 mmol) in dry Et O (1 ml) was added dropwise to a stirred
solution of n-butyllithium (1.6 M in hexane, 2.5 ml, 4 mmol) in 12
ml of dry Et O at Ϫ90 ЊC, under nitrogen atmosphere. Then
BF ؒEt O (0.38 ml, 1.5 mmol) in dry Et O (2 ml) was slowly added
2
2
3
2
2
(
30 min) via a syringe pump in order to maintain the temperature of
the reaction mixture below Ϫ90 ЊC. After stirring for 5 min, the
Notes and references
reaction was quenched with MeOH (2.5 ml) and Et N (1.5 ml). The
3
1
For a comprehensive review on S 2Ј additions of organocopper
mixture was allowed to warm up to room temperature and poured
into 5% aqueous H SO (10 ml). After standard work-up, the crude
product was purified by column chromatography on silica gel
N
reagents to vinyloxiranes see: J. A. Marshall, Chem. Rev., 1989, 89,
2
4
1
503.
2
3
J. Staroscik and B. Rickborn, J. Am. Chem. Soc., 1971, 93, 3046.
(a) J. P. Marino and D. P. Floyd, Tetrahedron Lett., 1979, 675; (b) J. P.
Marino, R. Fernàndez de la Pradilla and E. Laborde, J. Org. Chem.,
(eluent pentane–Et O = 95:5) to afford 432 mg (92% yield) of
2
(Z)-trans-6-butyloct-5-en-7-ol as a colorless oil. Anal. calcd. for
C H O: C, 79.93, H, 13.42. Found: C, 79.91, H, 13.30%. IR (film):
1
0
18
Ϫ1
1
1
987, 52, 4898 and references therein.
A. Alexakis, C. Cahiez and J. F. Normant, Tetrahedron Lett., 1978,
027; J. P. Marino and H. Abe, J. Am. Chem. Soc., 1981, 103, 2907;
3400, 2985, 1400, 1050, 750 cm . H NMR (400 MHz, CDCl ) δ
3
4
5
0.90 (m, 12H, H1, H12 and H16), 1.15–1.45 (m, 15H, H2–H4, H10,
H11, H13-H15 and OH), 2.06 (m, 2H, H9), 2.51 (m, 1H, H6), 3.32
(m, 1H, H5), 5.10 (dd, J = 10.7, 10.7 Hz, 1H, H7), 5.53 (dt, J = 7.4,
2
J. P. Marino and M. G. Kelly, J. Org. Chem., 1981, 46, 4389.
J. A. Marshall, J. D. Trometer, B. E. Blough and T. D. Crute, J. Org.
Chem., 1988, 53, 4274; J. A. Marshall, J. D. Trometer and D. G.
1
3
10.7 Hz, 1H, H8). C NMR (100 MHz, CDCl ) δ 14.3, 14.4, 22.8,
3
23.1, 23.2, 27.9, 28.6, 29.9, 31.0, 32.3, 34.1, 44.1, 75.5, 130.7, 133.0.
J. Chem. Soc., Perkin Trans. 1, 2000, 3352–3353
3353