Stereoelectronic effects in the DIBAL reduction of aryl-1,2-ethanediol benzylidene acetals

Article abstract of DOI:10.1016/S0040-4039(01)01466-6

Reduction of benzylidene acetal 8 with DIBAL-H selectively gave 4 in 89% yield. 1-Aryl-1,2-diol benzylidene acetals display unusual regioselectivity with electron withdrawing groups on the aryl group.

Full text of DOI:10.1016/S0040-4039(01)01466-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7011–7014
Stereoelectronic effects in the DIBAL reduction of
aryl-1,2-ethanediol benzylidene acetals
Donald R. Gauthier, Jr.,* Ronald H. Szumigala, Jr., Joseph D. Armstrong, III and R. P. Volante
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 3 July 2001; revised 6 August 2001; accepted 8 August 2001
Abstract—Reduction of benzylidene acetal 8 with DIBAL-H selectively gave 4 in 89% yield. 1-Aryl-1,2-diol benzylidene acetals
display unusual regioselectivity with electron withdrawing groups on the aryl group. © 2001 Elsevier Science Ltd. All rights
reserved.
tions (NaH, BnBr, DMF or Bn-trichloroacetimidate,
TMSOTf, THF) did not yield the desired secondary
alcohol 4 with satisfactory yield or regioselectivity (Eq.
(2)). Epoxide opening of 3,5-bis(trifluoromethyl)phenyl
styrene oxide (7) with BnOH afforded a respectable
yield and ratio of the desired product (88%, 10:1, 4/5,
Eq. (3)). However, asymmetric epoxidation2 of 3,5-
bis(trifluoromethyl)phenyl styrene gave (S)-7 in only
80% ee.3 The benzylidene acetal 8 (1:1 cis/trans mix-
ture), prepared in 90% yield from (S)-diol 2,
PhCH(OMe)2 and cat. pTsOH in toluene, was reduced
with DIBAL-H4 (2.5 equiv., 0°C) to provide a favor-
able 17:1 ratio (4/5) of alcohol products (Eq. (4)).5
Desired regioisomer (S)-4 was isolated by chromatogra-
phy in 89% yield as a low melting solid (mp 5–7°C).6 In
expectation of preparing a higher melting crystalline
analogue, we prepared p-methoxybenzyl and 4-bromo-
benzyl protected alcohols 11 and 13 via the respec-
tive benzylidene intermediates 9 and 10 (Eq. (5)). The
DIBAL-H reduction was faster with 9 (0.5 h) and
slower with 10 (3 h) compared to unsubstituted benzyl-
idene 8, however, the regioselective outcome was unper-
turbed. To our satisfaction, the bromobenzyl-protected
diol 13 was isolated as a crystalline solid,7 thus provid-
ing a means to eliminate chromatographic purification.
As part of our NK-1 receptor antagonist program, we
required primary protected (S)-1-(3,5-bis(trifluoro-
methyl)phenyl)-1,2-ethanediol 3 (Eq. (1)). In this com-
munication, a synthesis of crystalline (S)-1-(3,5-bis(tri-
fluoromethyl)phenyl)-2-(4-bromobenzyloxy)-1-ethanol
(13) from 2 and a study on the stereoelectronic influ-
ence of benzylidene acetal reduction are described. A
plausible mechanistic rational to explain the unusual
regioselectivity of the benzylidene acetal reduction is
proposed.
OH
OH
F3C
F3C
OH F3C
OP
2
3
1
CF3
CF3
CF3
(1)
(S)-1-(3,5-Bis(trifluoromethyl)phenyl)-1,2-ethanediol (2,
99% ee) was prepared via Sharpless asymmetric dihy-
droxylation of 3,5-bis(trifluoromethyl)phenyl styrene.1
t-Butyldimethylsilyl protection (3, P=TBS) was
achieved under standard conditions (TBS-Cl, imidazole,
DMF, 95%), however, a crystalline intermediate was
desired. Several approaches to benzyl protected 3 were
explored. Unfortunately, standard benzylation condi-
OH
OH
OBn
OBn
F3C
OH
F3C
OBn F3C
OH
F3C
OBn
BnBr, NaH
DMF, 0 °C
+
+
(2)
2
4
5
6
10%
CF3
CF3
CF3
CF3
35%
17%
* Corresponding author. Tel.: 732-594-4672; fax: 732-594-1499; e-mail: donald gauthier@merck.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01466-6

7012
D. R. Gauthier, Jr. et al. / Tetrahedron Letters 42 (2001) 7011–7014
O
The reduction of benzylidene acetals to give mono
F3C
BnOH, NaOtBu
benzyl protected diols is a valu-able reaction for the
selective functionalization of organic intermediates.8
Benzylidene acetals are generally reduced at the less
sterically hindered oxygen, yielding the more hindered
alcohol protected as the benzyl ether.9 The unusual
4 + 5
(10 : 1)
7
88 %, 60 °C
CF3
(3)
Ph
O
4 / 5 (time, yield of 4)
8a/b (~1:1 mix)
8a (trans)
8b (cis)
DIBAL-H (2.5 eq)
17 : 1 (2 h, 89%)
100 : 1 (1 h 96%)
9 : 1 (0.5 h, 84%)
O
F3C
(4)
toluene, 0 °C
CF3
R
R
R
OH
O
DIBAL-H (2.5 eq)
F3C
O
F3C
OH
+
O
(5)
O
F3C
toluene, 0 °C
CF3
CF3
9 (R = OMe)
10 (R = Br)
0.15 h, 87 %
18 h, 85 %
11 (R = OMe)
13 (R = Br)
12 (R = OMe)
14 (R = Br)
CF3
19 : 1
19 : 1
Table 1. DIBAL-H (2.5 equiv.) reduction of acetals 15a–h
in toluene at 0°C
regioselectivity in the reduction of 8, 9 and 10 with the
secondary alcohol being the major product, prompted
us to explore the electronic effects of aryl group substi-
Ph
tution in this reaction.10
A series of 1-aryl-1,2-
OH
OBn
O
ethanediols11 was converted to the benzylidene acetals
OBn
OH
O
+
15a–h (PhCH(OMe)2, pTsOH in toluene, 23°C) and
then reduced with DIBAL-H at 0°C (Table 1).12
A
R
R
R
17a-h
15a-h
trend is observed as selectivity for 16 diminishes with
attenuated electron withdrawing capacity of the aryl
substituent. Electron donating groups (15g and 15h,
entries 7 and 8, Table 1) affected only slight preference
for 17, the anticipated product based upon sterics.
16a-h
Entry
15a
R
Ratio 16:17b
Yield (%)c
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Perfluoro
3-CF3
4-F
4-Cl
4-Br
H
3-Me
4-MeO
8.2:1
3.9:1
2.0:1
2.6:1
2.5:1
1.3:1
1:1.1
1:3
70
95
87
78
83
90
78
83
Lewis acid-mediated nucleophilic additions to acetals
have been the focus of significant research effort and
several mechanistic investigations have been recently
conducted.13 A plausible mechanistic rational for the
regioselectivity in 8 is outlined in Scheme 1. Lewis acid
complex A1 may be considered higher in energy than B1
with an electron withdrawing aryl group (Ar). DIBAL
is associated with the less hindered oxygen in complex
B1. Thus, the A1/B1 equilibrium should favor B1 both
kinetically and thermodynamically. However, the A1/B1
g
h
a The purified acetals were isolated as
a ꢀ1:1 mixture of
diastereomers.
b Ratios were determined by 1H NMR of the crude reaction mixtures.
c Combined unoptimized yield of 16 and 17 after chromatography.
R
R
Ph
O
Ph
Ph
H
Ph
O
H
Ph
Al
O
Al
O
O
O
R
H
H
R
O
16
17
O
Al
R
Al R
O
R
Ar
Ar
O
Ar
R
Ar
Ar
A2
A1
B1
B2
15
Scheme 1.

D. R. Gauthier, Jr. et al. / Tetrahedron Letters 42 (2001) 7011–7014
7013
H
H
H
H
O
O
O
O
H
AlHR2
Ph
AlHR2
Ph
AlHR2
Ph
O
8a (trans)
O
O
AlHR2
Ph
O
Ar
Ar
Ar
Ar
1 h
H
H
H
A2 (trans)
A1 (trans)
B2 (trans)
B1 (trans)
(100 : 1)
4 : 5
5
4
(9 : 1)
0.5 h
8b (cis)
H
H
H
H
O
H
H
H
H
Ph
AlHR2
Ph
AlHR2
Ph
Ph
AlHR2
O
O
O
O
O
O
Ar
O
Ar
Ar
Ar
AlHR2
A2 (cis)
A1 (cis)
B2 (cis)
B1 (cis)
Scheme 2.
ratio appears to be less important in determining the
product outcome.14 Oxocarbenium ion B2 is destablized
with electron withdrawing groups compared with A2.
Thus, the product-determining factor in the reaction
pathway depends on the relative stabilities of oxocarbe-
nium ions A2/B2.15
Acknowledgements
The authors thank Ms. Lisa DiMichele for NOE experi-
ments on 8a and 8b.
The cis and trans benzylidene acetals 8a and 8b (Eq.
(4)) were separated by column chromatography,
assigned by 1H NMR difference NOE, and subse-
quently each isomer was reduced. Interestingly, the
trans diastereomer was reduced slower (1 h versus 0.5
h) and with enhanced regioselectivity (100:1 versus
9:1).16 A model is illustrated in Scheme 2 to explain the
difference in rate and selectivity. Isomers 8a/8b proceed
through diastereomeric Lewis acid complexes A1
(trans)/A1 (cis) and B1 (trans)/B1 (cis), respectively.
These Lewis acid complexes generate the E-oxocarbe-
nium ion pairs A2 (trans)/A2 (cis) and B2 (trans)/B2
(cis), which ultimately yield products 4 and 5, respec-
tively. The slower reduction rate observed for 8a can be
attributed to the increased steric demand of the coordi-
nated DIBAL. The trans Ar and Ph groups dictate a
more congested psuedo-axial/equatorial relationship in
complexes A1 (trans) and B1 (trans). The enhanced
regioselectivity observed for 8a may be due to the
non-bonded interactions that impede the CꢀO bond
shortening17 of the incipient E-oxocarbenium ion B2
(trans). These non-bonded interactions are absent in the
formation of other E-oxocarbenium ions.
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1
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J=9.6, 3.6 Hz, 1H), 3.52 (dd, J=9.6, 8.2 Hz, 1H), 3.13
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procedure to make (S)-1-(3,5-bis(trifluoromethyl)-
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1-(3,5-Bis(trifluoromethyl)phenyl)-1,2-ethanediol (2) via
reduction of benzylidene acetal 10. In this work, we
report that the electronic nature of aryl-1,2-ethanediols
affects the selectivity of the reduction in that opposite
regioselectivities dominate with electron withdrawing
aryl groups.
126.4, 124.7, (CF3C6 : 122.0, 121.6), 74.9, 73.6, 71.6. The %
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pTsOH (0.10 g, 0.5 mmol) in toluene (30 mL) was aged
for 1 h at 60°C. The solution was concentrated in vacuo
(40°C, 50 mmHg) and flushed with one volume of tolu-

7014
D. R. Gauthier, Jr. et al. / Tetrahedron Letters 42 (2001) 7011–7014
ene. The resulting solution was washed with 10% aq.
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NaHSO3 (3×30 mL) and saturated brine (15 mL). The
solution was azeotropically dried by flushing with one
volume of toluene. The solution of 10 (ca. 1:1 mixture of
acetal diastereomers) was cooled to 0°C and added 1.0 M
DIBAL-H in toluene (25 mL, 25.0 mmol). The solution
was aged 18 h at 0°C. The reaction was washed with 10%
NaOH (25 mL) and saturated brine (15 mL). The solu-
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from hexanes (10 mL/g) yielding 3.10 g (70%) of a white
1
solid (mp=74–75°C). H NMR (CDCl3): l 7.83 (s, 2H),
7.80 (s, 1H), 7.47 (d, J=2.1 Hz, 2H), 7.16 (d, J=2.1 Hz,
2H), 5.00 (m, 1H), 4.53 (s, 2H), 3.67 (dd, J=2.4, 0.9 Hz,
1H), 3.48 (t, J=2.2 Hz, 1H), 2.94 (d, J=0.9 Hz, 1H). 13C
NMR (CDCl3): l 142.9, 136.2, (CF3: 131.9, 131.7, 131.5),
129.4, 126.4, 124.6, (CF3C
72.8, 71.7.
6 : 122.0, 121.9, 121.8), 74.9,
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15. Reduction may also occur through intimate ion pairs
precluding the formation of solvent separated oxocarbe-
nium ions A2/B2 (see Ref. 13). However, the overall
electronic consequence is analogous.
R
Ph
O
Ph
O
H
Al
O
H
O
R
B1
17
A1
16
Al
R
R
Ar
Ar
16. Epimerization of 8a or 8b did not occur during the
reaction. Reaction progress and product ratios were
determined by HPLC.
17. Mori, A.; Fujiwara, J.; Maruoka, K.; Yamamoto, H. J.
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12. All new compounds were fully characterised.