Opening of diaryl epoxides: Ortho-fluorophenyl and 2-pyridyl epoxides

Article abstract of DOI:10.1002/1099-0690(200204)2002:8<1439::AID-EJOC1439>3.0.CO;2-0

Opening of epoxides with LiAlH₄, MgBr₂·2OEt₂ (solution in Et₂O), MgBr₂·OEt₂ (suspension in Et₂O), and NaBr/Amberlyst-15 has been studied. While 2-pyridyl epoxide 1 opens with complete regioselectivity, ortho-fluorophenyl epoxide 2 does not, but affords mixtures. Moreover, while the anti isomer (100-80%) is in all cases the major product with epoxide 1, epoxide 2 affords the anti isomer as major product with MgBr₂ and the syn isomer as major product with NaBr/Amberlyst-15. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200204)2002:8<1439::AID-EJOC1439>3.0.CO;2-0

FULL PAPER
Opening of Diaryl Epoxides: ortho-Fluorophenyl and 2-Pyridyl Epoxides
[a]
[a]
[a]
[a]
´
Arlette Solladie-Cavallo,* Paolo Lupattelli, Claire Marsol, Thomas Isarno,
Carlo Bonini,*[b] Leonilde Caruso,[a] and Angelica Maiorella[a]
Keywords: Epoxides / Asymmetric synthesis / Ring opening
Opening of epoxides with LiAlH4, MgBr2·2OEt2 (solution in
Et2O), MgBr2·OEt2 (suspension in Et2O), and NaBr/Amber-
1, epoxide 2 affords the anti isomer as major product with
MgBr2 and the syn isomer as major product with NaBr/Am-
lyst-15 has been studied. While 2-pyridyl epoxide 1 opens berlyst-15.
with complete regioselectivity, ortho-fluorophenyl epoxide 2
does not, but affords mixtures. Moreover, while the anti iso-
(
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
mer (100−80%) is in all cases the major product with epoxide 2002)
Introduction
nitrogen), were also studied; the reagents used were: pre-
pared MgBr2·2OEt2 (ഠ 4  solution in Et2O),[5] the com-
mercially available and crystalline MgBr2·OEt2 (as a sus-
pension in Et2O),[6,7] and NaBr/Amberlyst-15 (as a suspen-
sion in acetone).[7]
It should be noted that, while the magnesium atom is
involved in the reaction during both MgBr2 openings
(either with prepared MgBr2·2OEt2 or with commercial
MgBr2·OEt2, making an aqueous workup necessary (to
generate the hydroxyl group), the bromohydrin is formed
directly during NaBr/amberlyst-15 opening (sodium is
trapped by the resin, proton is provided) and no workup
is necessary. One could therefore say that, overall, HBr is
provided to the substrate; this is denoted below as ‘HBr’,
rather than NaBr/amberlyst-15.
During investigation of a short route towards type I
chiral aromatic alcohols[1] possessing an extra heteroatom,
and as an application of our asymmetric synthesis of trans
diaromatic epoxides (which has been shown to give almost
total enantioselectivities),[2] opening of trans diaryl epoxides
was considered.
Here we present the opening of racemic trans-2-pyridyl
epoxide 1,[3] and also of racemic trans-ortho-fluorophenyl
epoxide 2,[4] in order to prepare type II ligands that have
not yet been studied.
All the isomer ratios were determined on unpurified
crude reaction products (to avoid enrichment). All isomers
were fully characterised, either after isolation or on mix-
tures, as described below.
Results
Opening of the trans Phenyl-2-pyridyloxirane 1
The trans epoxide 1 has already been shown[3] to be re-
gioselectively opened by LiAlH4, to give the pyridyl alcohol
3 as the sole product (Scheme 1).
LiAlH4, which had provided fully regioselective opening
of epoxide 1,[3] was tested on epoxide 2. Metal bromides,
for production of halohydrins (in which the halogen can
be easily replaced by important functional groups such as
[a]
´ ´
´
´
Laboratoire de Stereochimie Organometallique associe au
´
CNRS, ECPM/Universite L. Pasteur,
25 rue Becquerel, 67087 Strasbourg, France
Fax: (internat.) ϩ 33Ϫ3 90 24 27 06
E-Mail: cavallo@chimie.u-strasbg.fr
[b]
`
Dipartimento di Chimica, Universita degli Studi della
Basilicata
Via Nazario Sauro 85, 85100 Potenza, Italy
Scheme 1
Eur. J. Org. Chem. 2002, 1439Ϫ1444
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0408Ϫ1439 $ 20.00ϩ.50/0
1439

´
A. Solladie-Cavallo, C. Bonini et al.
FULL PAPER
Two pairs of regioisomers, 4I/4II and 5I/5II, would, in
Interestingly, ‘HBr’ also provided 4 as the only re-
principle, be expected upon cleavage of 1 with bromide re- gioisomer, but with a lower diastereoselectivity than seen
agents (Scheme 2).
with MgBr2.
Opening of the trans 2-Fluorophenyl(phenyl)oxirane 2
Ring-opening of fluoro epoxide 2 with LiAlH4 in Et2O
(Scheme 3) gave a mixture of the two possible regioisomers,
6 and 7, in 68:32 ratio.
Two pairs of regioisomers, 8I/8II and 9I/9II, would also
be expected upon cleavage of epoxide 2 by bromine re-
agents, Scheme 4.
Scheme 2
As shown in Table 1, formation of a single regioisomer
Ϫ 4 Ϫ was observed in all cases (with either MgBr2 or
‘HBr’), in diastereomeric ratios ranging from 80:20 to
Ͼ 98:2. When freshly prepared (a few minutes)
MgBr2·2(OEt2) (ഠ 4  ethereal solution) was used, only
one diastereomer Ϫ 4I (Ͼ 98%) Ϫ was obtained, in almost
quantitative yield (Table 1, entry 1), while MgBr2·OEt2 pro-
vided a small amount of diastereomer II (4II, 8%). It is
worth noting that use of older solutions of MgBr2·2(OEt2)
(one day) resulted in a slower reaction and an almost equi-
molar mixture of 4I and 4II (56:44), but that 5 was never
observed.
Scheme 4
As shown in Table 2 (lines 1 and 2), MgBr2 Ϫ either pre-
pared [MgBr2·2(OEt2), ഠ 4  solution in Et2O] or commer-
cial [MgBr2·1(OEt2) suspension] Ϫ provided the two anti
isomers 8I and 9I (out of the four possible isomers) in the
ratio ഠ 4:1 in favour of the regioisomer 8I. On the other
hand, ‘HBr’-opening gave, in quantitative yield, a mixture
of all four isomers, with the syn bromohydrin 8II as the
major compound, Table 2 (line 3).
Scheme 3
Table 1. Opening of trans-phenyl-2-pyridylepoxide 1
Bromide
Conv.[a]
(%)
Product ratios[a]
Regioselectivity
4/5
Reaction condition
4I
4II
5I
5II
MgBr2·2(Et2O)[b]
MgBr2·1(Et2O)[d]
NaBr/Amberlyst-15
quant.
90
87
Ͼ98[c]
92
80
Ϫ
8
20
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
100:0
100:0
100:0
Et2O, 0 °C; 1 h
Et2O, 0 °C Ǟ 20 °C; 18 h
acetone, 25 °C; 48 h
1
[a] Determined by H NMR spectroscopy of the crude product of the reaction. [b] 3  solution in Et2O, freshly prepared from of Mg and
[d]
1,2-dibromoethane in diethyl ether.[5] [c] Isolated yield. Commercial (Aldrich).
Table 2. Bromide cleavage of trans-2-fluorophenyl-phenylepoxide 2
Bromide
Conv.[a]
(%)
Product ratios[a]
Regioselectivity
8/9
Reaction condition
8I
8II
9I
9II
MgBr2·2 (Et2O)[b]
MgBr2·1 (Et2O)[c]
NaBr/Amberlyst-15
98
83
quant.
84
82
13
Ϫ
Ϫ
62
16
18
10
Ϫ
Ϫ
15
84:16
82:18
75:25
Et2O, 0 °C Ǟ 20 °C; 18 h
Et2O, 0 °C; 3 h
acetone, 25 °C; 12 h
[a]
1
[b]
Determined by H NMR spectroscopy of the crude product of the reaction.
3  solution in Et2O, freshly prepared from Mg and
Eur. J. Org. Chem. 2002, 1439Ϫ1444
1,2-dibromoethane in diethyl ether.[5] [c] Commercial (Aldrich).
1440

Opening of Diaryl Epoxides: ortho-Fluorophenyl and 2-Pyridyl Epoxides
FULL PAPER
Characterisation of the Bromohydrins 4I and 4II
that the structure of the major regioisomer obtained from
epoxide 2 was 6. As a consequence, structure 7 was assigned
to the minor regioisomer, consistently with the absence of
the CH(OH) signal at δ ϭ 5.0 and with the presence of an
The structure 4 was assigned to the major isomer I by
long-range 1H/13C NMR correlation, which identified a
correlation between the pyridyl ring C2 carbon[8] and the
proton at C6 (Figure 1), assigned to CH(OH) from the pres-
ence of a coupling constant with the OH proton (dd). No
correlation was observed with the proton at C7 assigned to
CHBr (d).
2
AB system at δ ϭ 3.09 (d, J ϭ 12.0 Hz) and δ ϭ 3.15 (d,
2J ϭ 12.0 Hz).
Characterisation of Bromohydrins 8I, 8II, 9I, and 9II
The structure of the major isomer (Table 2, entries 1 and
2) obtained from MgBr2-opening of epoxide 2 was assigned
1
as 8 by comparison of the H NMR spectrum of the 84:16
mixture (d, δ ϭ 5.12: CHBr; dd, δ ϭ 5.40: CHOH[11]) to
that of the mixture obtained on opening epoxide 10 (deuter-
ated at C8)[10] with prepared MgBr2·2(OEt2) (Scheme 6).
1
The H NMR spectrum of the major isomer obtained from
epoxide 10 exhibited a broad singlet at δ ϭ 5.45 (corres-
ponding to the δ ϭ 5.40 signal observed in the major isomer
obtained from epoxide 2 and assigned to CHOH) and no
signal at δ ഠ 5.12 (where the CHBr signal would be ex-
pected). Structure 13 was thus assigned to the major isomer
obtained from 10 and, as a consequence, structure 8 to the
major isomer obtained from 2.
Figure 1. NMR data used for the assignment of the structure of 4I
and 4II
In the case of the minor isomer II, a correlation was ob-
served between the pyridyl ring C1 carbon and the proton
at C6 (br. d), while no correlation was found between C1
and the proton at C7 (d).
The two isomers obtained were thus both assigned as
structure 4, showing that regioisomer 5 was not formed.
The stereochemistry was determined by alkaline ring-clos-
ure.[9] A 4:1 mixture of 4I/4II gave a 4:1 trans/cis mixture
of the corresponding pyridyl epoxide, indicating that the
major 4I isomer was anti, as shown in Scheme 2, and 4II
was syn.
Scheme 6
LiAlH4 reduction of the above 84:16 mixture (in which
the major isomer (84%) was assigned the structure 8) af-
forded both regioisomers 6 (corresponding to 8) and 7 (cor-
responding to 9) in ഠ 4:1 ratio. It could thus be concluded
that the minor isomer was the regioisomer 9. A GC-MS
analysis confirmed the regiochemistry, allowing us to assign
the structure 8 to the major isomer (main peak: m/z ϭ 125,
T1) and the structure 9 to the minor product (main peak:
m/z ϭ 107, T2). The anti stereochemistries of both 8 and 9
were then determined by alkaline ring-closure[9] of the 82:18
mixture of 8 and 9, which gave only the trans fluoro epoxide
2 (Ͼ 95%, NMR) as the crude product. Both isomers, major
and minor, were thus assigned as anti: 8I and 9I (Scheme 3).
The major isomer obtained with ‘HBr’ (Table 2, line 3)
Characterisation of Alcohols 6 and 7
The structure 6 was assigned to the major (68%) re-
gioisomer (and 7 to the minor one) by comparison of the
1H NMR spectra of mixtures obtained by LiAlH4 reduction
either from epoxide 2 or from epoxide 10 monodeuterated
at C8[10] (Scheme 5).
1
was assigned structure 8 by long-range H/13C NMR cor-
Scheme 5
relation, which revealed, for this isomer, a correlation be-
tween the phenyl ring C9[12] (Scheme 4) and proton CHBr
at C8. This isomer, being different from 8I (different NMR
spectra), could therefore only be syn (8II), which was also
confirmed by GC-MS analysis (main peak: m/z ϭ 125, T1)
and by alkaline ring-closure.[9] The 13:62:10:15 mixture of
bromohydrins gave ഠ3:1 cis/trans mixture of the corres-
ponding fluoro epoxide.
In the 1H NMR, the ABX system of the major re-
gioisomer obtained from epoxide 2 showed the CH(OH)
signal (X part) at δ ϭ 5.29[11] (after D2O exchange: dd, 3J ϭ
7.5 and 5 Hz) and the CH2 signals (AB part) at δ ϭ 3.15
2
3
2
(dd, J ϭ 12.0, J ϭ 5.0 Hz) and δ ϭ 2.95 (dd, J ϭ 12.0,
3J ϭ 7.5 Hz), while in the 1H NMR of the major re-
gioisomer obtained from epoxide 10, the AX system exhib-
3
ited a signal at δ ϭ 5.28 (d, J ϭ 4.0 Hz, after D2O ex-
change), which was assigned to CH(OH), and one at δ ϭ
3
3.15 (d, J ϭ 4.0 Hz), assigned to CH(D). It was thus con-
cluded that the hydroxyl group was at C7 (Scheme 5), and
Eur. J. Org. Chem. 2002, 1439Ϫ1444
1441

´
A. Solladie-Cavallo, C. Bonini et al.
FULL PAPER
Discussion and Conclusion
Diastereoselectivity
The diastereoselectivities observed for β- and α-opening
are listed in Table 3.
Regioselectivity
As shown in Figure 2 (Tables 1 and 2), while the 2-pyridyl
epoxide 1 opened with complete regioselectivity, the ortho-
fluorophenyl epoxide 2 did not, but afforded mixtures with
all three reagents used: LiAlH4, MgBr2, and ‘HBr’.
Table 3. Diastereoselectivities obtained for α- and β-opening of ep-
oxides 1 and 2
Compound
Bromide
β-Opening
anti I/syn II
α-Opening
anti I/syn II
MgBr2
MgBr2
‘HBr’
MgBr2
MgBr2
‘HBr’
100:0
92:8
80:20
100:0
100:0
17:83
Ϫ
Ϫ
Ϫ
100:0
100:0
40:60
4
8
The obtainment of the anti isomer corresponds to an SN2
reaction at the centre undergoing substitution, in agreement
with previous results,[6aϪ6c] and so the results obtained with
MgBr2 (Table 3, lines 1, 2, 4, 5) are not surprising.
The results observed in the case of epoxide 2 for ‘HBr’
opening (NaBr/Amberlyst-15), in which the syn[15] isomers
8II and 9II were major products (Table 3, line 6), can be
compared to literature results[16] in which mainly syn iso-
mers (explained by frontal approach)[16] were obtained
through opening of trans and/or cis stilbene oxide with dry
HCl in benzene. The obtaining of the syn isomer as the
major product thus suggests the same kind of approach for
NaBr/amberlyst-15-opening (‘HBr’ addition) of epoxide 2.
The results observed with epoxide 1 for ‘HBr’-opening,
in which the anti isomer was the major product, may be
compared to HBr delivery from grafted phosphonium
salts,[17] which gave a 1:1 mixture of trans/cis addition with
stilbene, and also to previous results with NaBr/Amberlyst-
15 and functionalised epoxides, which provided trans iso-
mers.[7]
Figure 2. Regioselectivity of ring opening
Although participation of a neighbouring fluorine atom
has been observed during opening of epoxides with organ-
oaluminium reagents,[13] such assistance is not strong
enough in the case of epoxide 2 and MgBr2. It also appears
that, although the bite angle[14] is more favourable in the
case of epoxide 2 (six-membered ring) than in epoxide 1
(five-membered ring) for small cations such as magnesium
(Figure 3), the complexing ability of fluorine when attached
to a carbon is not enough to provide full regioselectivity,
while the complexing ability of nitrogen is enough to over-
come the effect of the bite angle and direct the approach
of the reagent (through formation of a five-membered Mg-
chelate), resulting in complete regioselectivity in the case of
epoxide 1 (100% β-opening). A directed approach through
Mg-chelation has also been postulated with functionalized
epoxides.[6,7d]
Other studies to provide more insight into NaBr/resin re-
agents are underway.
Experimental Section
General: 1D and 2D 1H and 13C NMR spectra (pulse programmes:
coloc for long range and hxco for direct) were recorded on a Bruker
Avance 400 with C6D6 or CDCl3 as solvents. Chemical shifts (δ)
are given in ppm downfield from TMS as internal standard. TLC
was performed on Merck glass plates with 60 F254 silica gel. Merck
silica gel was used for chromatographic purification. MS spectra
were recorded on a Hewlett Packard 6890 chromatograph equipped
with a HP 5973 mass detector. Crystalline MgBr2:1(OEt2) and Am-
berlyst-15 were purchased from Aldrich.
Figure 3. 5- and 6-membered chelates
Observation of 100% β-opening of pyridyl epoxide 1 with
‘HBr’ (NaBr/Amberlyst-15) is less straightforward, as it is
difficult to envisage such a strong role/chelation of sodium
under these conditions (surface of a resin providing Hϩ).
One could thus postulate a contribution of a carbenium ion
(or a partial plus-charge) that is more reactive when α to a
phenyl group than when α to a pyridyl group, which may
be due to formation of a ‘charged’ pyridinium ion (Hϩ pro-
vided by the resin), thus resulting in Br fixation only at the
β-position.
General Procedure for the Synthesis of Racemic Epoxides 1 and 2:[18]
NaOH (7.1 mL of. 50% aqueous solution) was added dropwise at
0 °C to a stirred solution of benzyldimethylsulfonium chloride (1.3
equiv., 10.5 mmol), 2-pyridinecarboxyaldehyde (for 1), or 2-fluoro-
benzaldehyde (for 2) (1 equiv.), and tetrabutylammonium hydro-
gensulfate (0.05 equiv.) in CH2Cl2 (15 mL). After 5 h, the organic
layer was separated and the aqueous phase was extracted with
CH2Cl2 (3 ϫ 10 mL). The organic phases were combined and dried
Such a driving force being absent in epoxide 2, α-opening
is also obtained with ‘HBr’.
1442
Eur. J. Org. Chem. 2002, 1439Ϫ1444

Opening of Diaryl Epoxides: ortho-Fluorophenyl and 2-Pyridyl Epoxides
FULL PAPER
with Na2SO4. After evaporation, the crude product was analysed
anti-2-Bromo-1-(o-fluorophenyl)-2-phenylethanol (8I) and anti-2-
Bromo-2-(o-fluorophenyl)-1-phenylethanol (9I): Characterisation by
by NMR and found to be a ഠ 7:3 mixture of trans/cis epoxide (as
1
1
seen on H NMR spectra).
1H NMR of the mixture: 8I/9I ϭ 4:1. H NMR (400 MHz, C6D6):
3
3
δ ϭ 4.96 (dd, J1 ϭ 6, J2 ϭ 5 Hz, 1 H, CHOH, 9I, 20%), 5.12 (d,
trans-2-Phenyl-1-(2-pyridyl)oxirane (1):[2b] This compound was ob-
3
3
3J ϭ 6.0 Hz, 1 H, CHBr, 8I, 80%), 5.40 (dd, J1 ϭ 6, J2 ϭ 5 Hz,
3
tained in a yield of 63% after chromatographic purification
1 H, CHOH, 8I, 80%), 5.50 (d, J ϭ 6.0 Hz, 1 H, CHBr, 9I, 20%),
1
(CHCl3/Et2O, 7:3). H NMR (CDCl3/TMS): δ ϭ 4.05 (br. s, 2 H),
6.6Ϫ7.2 (m, 9 H, CH arom., 8Iϩ9I). MS major: 8I (m/z,%): 296
[M ϩ 2]ϩ (1), 294 [Mϩ] (1), 125 (100). MS minor: 9I (m/z,%): 296
[M ϩ 2]ϩ (1), 294 [Mϩ] (1), 107 (100).
4
7.25 (m, 2 H), 7.35 (m, 5 H), 7.70 (td, 3J ϭ 7.0, J ϭ 2.0 Hz, 1 H),
8.60 (dd, 3J ϭ 5.0, 4J ϭ 2.0 Hz, 1 H). 13C NMR (CDCl3/TMS):
δ ϭ 61.8, 62.9, 120.2, 123.3, 125.8, 128.5, 128.6, 136.9, 149.6,
136.8, 156.4.
syn-2-Bromo-1-(o-fluorophenyl)-2-phenylethanol (8II): Characteris-
ation as the major product of the mixture: 8I/8II/9I/9II ϭ
1
trans-1-(o-Fluorophenyl)-2-phenyloxirane (2):[10] This compound
was obtained in a yield of 51% after chromatographic purification
(hexane/CH2Cl2 7:3). 1H NMR (CDCl3/TMS): δ ϭ 3.9 (d, 3J ϭ
13:62:10:15. H NMR (400 MHz, C6D6), overlapping signals but:
4.95 (br. d, CHOH, 1 H, 9I, 10%), 5.11 (d, 3J ϭ 5.0 Hz, 1 H, CHBr,
3
3
8II, 62%), 5.14 (d, 1 H, CHBr, 8I, 13%), 5.23 (dd, J1 ϭ 5, J2 ϭ
3 Hz, 1 H, CHOH, 8II, 62%), 5.40 (dd, 1 H, CHOH, 8I, 13%), 5.2
(br. d, 1 H, CHOH, 9II, 15%), 5.50 (d,, 1 H CHBr, 9I, 10%), 5.76
(d, 1 H, CHBr, 9II, 15%). 13C NMR (100 MHz, C6D6), 8II: 63.1
3
2.0 Hz, 1 H), 4.3 (d, J ϭ 2.0 Hz, 1 H), 7.25 (m, 9 H). 13C NMR
(CDCl3/TMS): δ ϭ 57.15 (d, 3JC,F ϭ 6 Hz), 62.4, 115.4 (d, 3JC,F ϭ
2
20 Hz), 124.5 (d, JC,F ϭ 4 Hz), 124.7 (d, JC,F ϭ 12.5 Hz), 125.8,
2
(CHBr), 72.0 (CHOH), 115.2 (d, JC,F ϭ 22 Hz, C3H), 124.2
126.1 (d, JC,F ϭ 4 Hz), 128.7, 128.8, 129.7 (d, JC,F ϭ 8 Hz), 136.8,
2
3
1
(C5H), 126.0 (d, JC,F ϭ 22 Hz, C1), 127.2, 128.3 (d, JC,F
ϭ
161.6 (d, JC,F ϭ 245 Hz). C14H11FO (214.2): found C 78.60, H
4.5 Hz, C4H or C6H) 128.5, 128.6, 128.7, 128.7 (d, 3JC,F ϭ 4.5 Hz,
5.23; calcd. C 78.48, H 5.17.
1
C4H or C6H), 129.7, 138.8 (C9) 160.0 (d, JC,F ϭ 245 Hz, C2).
trans-(R,R)-[2-2H]-1-(o-Fluorophenyl)-2-phenyloxirane (10):[10] 1H
NMR (CDCl3/TMS): δ ϭ 4.3 (br. s, 1 H), 7.25 (m, 9 H).
MS: 8II (m/z,%): 296 [M ϩ 2]ϩ (1), 294 [Mϩ] (1), 125 (100).
Reduction of Epoxide 2: LiAlH4 (1  in diethyl ether, 1.5 equiv.) was
added dropwise and under argon to a solution of trans-2 (214 mg,
1 mmol, 1 equiv.) in anhydrous Et2O (5 mL). The mixture was
stirred at room temperature for 2 h and monitored by TLC. After
usual workup the organic layer was dried with Na2SO4, the solvent
was evaporated under vacuum, and the crude product was analysed
by NMR: 220 mg of a 68:32 mixture of 6 and 7 was obtained, with
a conversion of 88%.
General Procedure for Opening of Epoxides with MgBr2: Either
commercial MgBr2·Et2O or freshly prepared 4  MgBr2·2Et2O in
Et2O (4 equiv.)[3] was added at 0 °C, all at once, to a solution of
the desired epoxide (1 equiv.) in anhydrous Et2O (5 mL). The mix-
ture was stirred at the desired temperature, and the reaction was
monitored by TLC. After completion of the reaction, the mixture
was poured into ice (or into a saturated NH4Cl solution in H2O,
in the case of MgBr2·2Et2O) and the precipitate was filtered off.
The filtrate was washed with H2O and dried with Na2SO4, the solv-
ent was evaporated under vacuum, and the crude product was ana-
lysed by NMR.
1-(o-Fluorophenyl)-2-phenylethanol (6) and 2-(o-Fluorophenyl)-1-
1
phenylethanol (7): H NMR (400 MHz, CDCl3 ϩ 1 drop of D2O),
3
2
δ ϭ 2.96 (A part of ABX system, JAX ϭ 7.5, JAB ϭ 12 Hz, 1 H,
6, 68%), 3.06 (AB part of ABX system, 2 H, 7, 32%), 3.15 (B part
of ABX system, 3JBX ϭ 5, 2JAB ϭ 12 Hz, 1 H, 6, 68%), 5.0 (X part
General Procedure for Opening of Epoxides with NaBr/Amberlyst-
15: NaBr (2 equiv.) and Amberlyst-15 (1 equiv.)[7d] were added to
a cold (Ϫ30 °C), stirred solution of epoxide (1 equiv.) in acetone
(10 mL). The mixture was stirred at the desired temperature, and
the reaction was monitored by TLC, until completion. The mixture
was then filtered, and the filtrate was evaporated under vacuum.
The residue was dissolved in EtOAc, and the resulting organic layer
was dried with Na2SO4, the solvent was evaporated under vacuum,
and the crude product was analysed by NMR.
3
3
of ABX system, dd, J ϭ 7.5, J ϭ 5.0 Hz, 1 H, 7, 32%), 5.25 (X
3
3
part of ABX system, dd, J ϭ 7.5, J ϭ 5.0 Hz, 1 H, 6, 68%), 7.3
(m, H arom). C14H13FO (216.3): found C 77.51, H 6.11; calcd. C
77.75, H 6.05.
[1]
Pyridyl alcohols have numerous applications as chiral ligands
or as resolving agents. See: [1a] J. M. Hawkins, K. B. Sharpless,
[1b]
Tetrahedron Lett. 1987, 28, 2825.
H. Gärtner, U. Salz, C.
[1c]
Rüchardt, Angew. Chem. Int. Ed. Engl. 1984, 23, 162.
E.
[1d]
1H
NMR
Macedo, C. Moberg, Tetrahedron: Asymm. 1995, 6, 549.
anti-2-Bromo-2-phenyl-1-(2-pyridyl)ethanol
(4I):
K. Nordström, E. Macedo, C. Moberg, J. Org. Chem. 1997,
62, 1604.
3
(400 MHz, C6D6): δ ϭ 4.15 (br. d, 1 H, OH), 5.21 (dd, JH,OH
ϭ
3
3
8, JH,H ϭ 6 Hz, 1 H, CHOH), 5.31 (d, J ϭ 6.0 Hz, 1 H, CHBr)
6.47 (m, 1 H, C4H), 6.8Ϫ7.0 (m, 6 H), 7.26 (ഠd, 3J ϭ 5.0 Hz, 2
H), 8.18 (ഠd, 3J ϭ 4.0 Hz, C5H). 13C NMR (100 MHz, C6D6):
δ ϭ 58.7 (CHBr), 77.4 (CHOH), 122.7/122.8 (C2H and C4H, pyri-
dyl), 128.3/128.4/129.3 (CH, phenyl), 136.0 (C3H, pyridyl), 138.7
(C8, phenyl), 148.6 (C5H, pyridyl), 159.0 (C1, pyridyl).
[2] [2a]
´
A. Solladie-Cavallo, A. Diep-Vohuule, J. Org. Chem. 1995,
[2b]
´
60, 3494.
A. Solladie-Cavallo, A. Diep-Vohuule, V. Sunjic,
V. Vinkovic, Tetrahedron: Asymm 1996, 7, 1783. [2c] A. Solladie-
´
´
Cavallo, L. Bouerat, M. Roje, Tetrahedron Lett. 2000, 41, 7309.
[3]
The (R,R)-epoxide 1 can be obtained with up to 99.2% ee. by
´
the chiral sulfonium method; see: A. Solladie-Cavallo, M. Roje,
T. Isarno, V. Sunjic, V. Vinkovic, Eur. J. Org. Chem. 2000, 1077.
Obtainment of pyridyl epoxide 1 by classical epoxidation
methods is not possible because of oxidation of the pyridyl
group.
The (R,R)-epoxide 2 can be obtained with up to 99.9% ee by
the chiral sulfonium method (cf. ref.[2b]).
J. Guillermet, A. Novak, J. Chim. Phys. 1970, 67, 982Ϫ992.
Preparation of MgBr2 from Mg and BrCH2ϪCH2Br in Et2O
provides an Et2O solution of MgBr2 composed of two limpid
layers: the lower one being ഠ 4  and providing, upon cooling,
crystals with MgBr2·2(OEt2) composition.
syn-2-Bromo-2-phenyl-1-(2-pyridyl)ethanol (4II): Characterisation
in the mixture: 4I/4II ϭ 4:1. 1H NMR (400 MHz, C6D6), over-
lapped with 4I signals but: δ ϭ 4.95 (br. d, 3J ϭ 4.0 Hz, 1 H,
[4]
[5]
3
CHOH), 5.37 (d, J ϭ 4.0 Hz, 1 H, CHBr). 13C NMR (100 MHz,
C6D6): overlapped with 4I but: δ ϭ 61.5 (CHBr), 76.5 (CHOH),
121.8 (C2H, pyridyl), 136.2 (C3H, pyridyl), 140.0 (C8, phenyl),
148.4 (C5H, pyridyl), 159.1 (C1, pyridyl). C14H12BrFO (295.2):
found C 57.04, H 4.11, calcd. C 56.94, H 4.06. C13H12BrNO
(278.1): found C 56.04, H 4.41; calcd: calcd. C 56.13, H 4.34.
Eur. J. Org. Chem. 2002, 1439Ϫ1444
1443

´
A. Solladie-Cavallo, C. Bonini et al.
FULL PAPER
[6] [6a]
[11]
[12]
G. Righi, G. Rumboldt, C. Bonini, J. Org. Chem. 1996, 61,
The CH(OH) signals were assigned, in all cases, from the pres-
ence of a 3JHϪOH coupling constant (resulting in an extra split-
ting or in broadening), which disappears upon addition of
D2O.
[6b]
3557.
G. Righi, A. Chionne, C. Bonini, Eur. J. Org. Chem.
[6c]
2000, 3127.
G. Righi, G. Pescatore, F. Bonadies, C. Bonini,
Tetrahedron 2001, 57, 5649. For the use of MgI2 see: C. Bonini,
C. Federici, L. Rossi, G. Righi, J. Org. Chem. 1995, 60, 4803.
The phenyl C9 (cf. Scheme 4 for numbering) was assigned by
direct H/13C NMR experiments and comparison with spectra
1
[7]
[7a]
For the use of NaI/Amberlyst-15 see:
C. Bonini, C. Giuli-
[7b]
of known compounds: Carbon-13 Nuclear Magnetic Resonance
for Organic Chemists, (Ed.: Levy and Nelson, Wiley Intersci-
ence, New York, 1972.
K. Maruoka, T. Ooi, Chem. Eur. J. 1999, 5, 829Ϫ833.
T. Ooi, N. Kagoshima, K. Maruoka, J. Am. Chem. Soc. 1997,
119, 5754Ϫ5755.
ano, G. Righi, L. Rossi, Synth. Comm. 1992, 22, 1861.
G.
Righi, G. Rumboldt, C. Bonini, Tetrahedron 1995, 51, 13401.
[7c]
C. Bonini, L. Chiummiento, C. Federici, M. Funicello, G.
[13] [13a]
[13b]
Righi, L. Rossi, Tetrahedron Lett. 1994, 35, 797. [7d] C. Bonini,
G. Righi, Synthesis 1994, 225.
[8]
[9]
The pyridyl C2 was assigned by direct 1H/13C NMR correla-
tion experiments and reference to Carbon-13 Nuclear Magnetic
Resonance for Organic Chemists, (Ed.: Levy and Nelson, Wiley
Interscience, NY, 1972.
[14]
[15]
R. D. Hancock, Acc. Chem. Res. 1990, 23, 253Ϫ257, and: J.
Chem. Educ. 1992, 69, 615Ϫ621.
However, the obtainment of the syn isomer implies a retention
at the opening-centre and could come either from a ‘front’
mechanism, from a double SN2 (due to Br exchange after open-
ing) or from an SN1.
G. Berti, F. Bottari, P. L. Ferrarini, B. Macchia, J. Org. Chem.
1965, 30, 4091.
The mixture of bromohydrins was stirred at room temperature
in anhydrous THF, in the presence of 1 equiv. of NaH, until
disappearance of starting material. The crude product was
neutralised with sat. sol. NH4Cl in ice, extracted with Et2O,
[16]
[17]
[18]
1
and analysed by H NMR.
C. A. M. Afonso, N. M. L. Vieira, W. B. Motherwell, Synlett
2000, 382.
[10]
T. Isarno, PhD Dissertation, Strasbourg, February 2000. Deu-
2
terated (80% H) (R,R)-epoxide 10 was synthesized in ഠ 50%
T. Durst, E. Agkun, M. B. Glinski, K. L. Dhawan, J. Org.
Chem. 1981, 46, 2730Ϫ2734.
yield, from 2-fluorobenzaldehyde and a chiral deuterated
benzyl sulfonium salt as described in ref. [3].
Received December 7, 2001
[O01579]
1444
Eur. J. Org. Chem. 2002, 1439Ϫ1444