Does a chiral alcohol really racemize when its OH group is protected with Boyer's reaction?

Article abstract of DOI:10.1002/chir.20710

Chiral reactants have been employed for assessing the real stereochemistry of the BiBr₃-catalyzed synthesis of benzylic ethers, a very useful reaction for protecting alcoholic groups. The results of this investigation are in clear contrast with the conclusions of previous studies (Boyer et al., Tetrahedron 2001;57:1917-1921). Indeed, chiral GC-MS analysis of the ethereal products gives unequivocal evidence of the complete racemization of the benzylic moiety and the complete retention of configuration of the protected alcoholic substrate. Such findings make BiBr₃ a powerful and stereochemically preservative catalyst for benzylation of chiral alcohols, and a potential candidate for orthogonal protecting group strategies applicable to polyhydroxy compounds.

Full text of DOI:10.1002/chir.20710

CHIRALITY 22:88–91 (2010)
Does a Chiral Alcohol Really Racemize when Its OH Group
Is Protected with Boyer’s Reaction?
CATERINA FRASCHETTI, MAURIZIO SPERANZA, AND ANTONELLO FILIPPI*
Dipartimento di Chimica e Tecnologie del Farmaco, Universit a` di Roma ‘‘La Sapienza’’, Rome, Italy
ABSTRACT
Chiral reactants have been employed for assessing the real stereochem-
istry of the BiBr -catalyzed synthesis of benzylic ethers, a very useful reaction for pro-
3
tecting alcoholic groups. The results of this investigation are in clear contrast with the
conclusions of previous studies (Boyer et al., Tetrahedron 2001;57:1917–1921). Indeed,
chiral GC-MS analysis of the ethereal products gives unequivocal evidence of the com-
plete racemization of the benzylic moiety and the complete retention of configuration of
the protected alcoholic substrate. Such findings make BiBr a powerful and stereo-
3
chemically preservative catalyst for benzylation of chiral alcohols, and a potential candi-
date for orthogonal protecting group strategies applicable to polyhydroxy compounds.
Chirality 22:88–91, 2010. VV C 2009 Wiley-Liss, Inc.
KEY WORDS: bismuth bromide; chiral alcohols; configuration determination;
heterogeneous catalysis; benzylic ethers; protecting groups
INTRODUCTION
(S)- or rac-2-butanol, (S)- or rac-2-octanol) and by monitor-
ing the reaction by standard GC analysis and optical rota-
tion measurements. On these grounds, they concluded
Benzyl groups are frequently used as protecting agents
of hydroxyl functions in multistep organic syntheses. The
reaction of the alcoholic substrate with benzyl bromide
and a strong base, such as sodium hydride, is the most
8
that the aliphatic R moiety in the BnOR product is com-
pletely (ROH 5 1-phenylethanol, 2-octanol) or almost
completely (ROH 5 2-butanol) racemized, whereas the
configuration of the benzylic carbon atom of Bn is com-
pletely retained (Table 1 in Ref. 8). The loss of stereo-
chemical integrity of the C ꢀꢀ O bond of ROH deprives
Boyer’s reaction of any real synthetic application and ben-
zyl alcohols of any use as protecting reactant in multistep
procedures involving chiral alcohols. Indeed, to the best of
our knowledge, the reaction has never been reported in lit-
1
common method to obtain benzyl ethers. Alcohols sensi-
tive to basic conditions can be treated with a benzyl imi-
date (e.g., trichloroacetimidate) in the presence of trifluor-
2
omethanesulfonic acid. A recent study employs a benzyl
3
pyridinium salt as a benzyl donor for alcohols.
The success of benzyl ethers as protective synthetic
intermediates of alcoholic groups mainly lies in their apti-
tude to release the benzyl moiety under the action of dif-
ferent reagents, which can be chosen depending on the
7
,8
erature after Boyer’s work.
4
sensitivity of the molecule to reaction conditions. The
presence of suitable functional groups on the phenyl ring
of benzylic reagents can modulate their protecting/depro-
tecting features toward different OH groups and, there-
RESULTS AND DISCUSSION
The above stereochemical pattern is completely
fore, enhance their applicability as orthogonal protecting reversed by our results. Indeed, in the course of a study
5
groups for polyhydroxy compounds. However, it would on the gas-phase behavior of protonated chiral ethers, we
be highly desirable to obtain benzyl ethers (BnOR) from had to synthesize small amounts of diastereoisomeric 1-(2-
alcoholic substrates (ROH) by using the corresponding butyloxy)ethylbenzenes (2). Strictly following Boyer’s pro-
7
benzyl alcohols (BnOH), which are the most convenient cedure, (1)-(R)-1-phenylethanol (1 ; FLUKA R/S > 99/1
R
6
sources of benzyl groups. To this end, Boyer et al. pro- –1.25 mmol in 2 ml of CCl ) was added to a stirred
4
posed BiBr as a catalyst for a very simple and efficient solution of (2)-(R)-2-butanol (ALDRICH R/Sꢁ92/8 –1.25
3
7
etherification reaction (eq. 1), specific for benzylic alco- mmol) and BiBr (ALDRICH ꢂ98% –1.25 mmol) in 3 ml of
3
hols and occurring under mild conditions (room tempera-
ture (RT) and CCl as a neutral solvent).
4
Contract grant sponsor: Ministero dell’Istruzione dell’Universit a` e della
BiBr3
BnOH þ ROH ꢀꢀꢀꢀꢀꢀꢀ! BnOR
CCl4 RT
Ricerca (MIUR, PRIN), Consiglio Nazionale delle Ricerche (CNR).
ð1Þ *Correspondence to: Antonello Filippi, Dipartimento di Chimica e Tecno-
logie del Farmaco, Universit a` di Roma ‘‘La Sapienza’’, P.le A. Moro, 5,
0
0185 Rome, Italy. E-mail: antonello.filippi@uniroma1.it
Received for publication 10 September 2008; Accepted 6 February 2009
DOI: 10.1002/chir.20710
Published online 19 May 2009 in Wiley InterScience
Boyer et al. investigated the stereochemistry of eq. 1 by
using several mixtures of enantiopure and racemic alco-
hols (BnOH 5 (R)- or rac-1-phenylethanol (1); ROH 5 (www.interscience.wiley.com).
VV C 2009 Wiley-Liss, Inc.

PROTECTION OF CHIRAL ALCOHOL
89
TABLE 1. GC-MS monitoring of the reaction using 1-phenylethanol and 2-butanol
a
a
Alcoholic reagents
Entry Time (min)
1
R
(%)
1
S
(%)
1
total (a.u.)
2
SR (%)
2
RS (%)
2
RR (%)
2
SS (%)
2total (a.u.)
R-1-Phenylethanol (1
R
)
1
2
3
4
<1
25
49.9
48.8
50.4
51.6
50.1
51.2
49.6
48.4
460
47.2
52.8
290
830
290
790
9
9
3.8
3.1
6.2
6.9
93.8
93.1
8.0
6.2
6.9
2
-Butanol (R:Sꢁ 92:8)
20
300
22
47.7
43.9
51.2
52.3
R-1-Phenylethanol (1
R
)
<1
25
56.1
48.8
8
7
.9
.3
91.1
92.7
92.0
93.3
2
-Butanol (R:Sꢁ 8:92)
6.7
S-1-Phenylethanol (1
S
)
5
6
<1
6.3
93.7
52.3
590
10
46.2
49.4
53.8
50.6
30
b
b
1
00.0
n.d.
100.0
93.0
n.d.
2
-Butanol (R:Sꢁ 92:8)
25
47.7
800
9
3.0
7.0
7.0
R-1-Phenylethanol (1
rac-2-Butanol
R
)
7
8
<1
69.3
50.2
30.7
49.8
770
15
50.8
48.9
49.2
51.1
980
910
4
5
8.0
1.1
52.0
48.9
51.5
49.6
48.5
50.4
25
The GC signals of the diastereomeric ethers 2 have been assigned by comparison with authentic standard compounds.* Uncertainty ca. 5%.
a
GC peak area (Arbitrary Units).
Not detectable.
b
Scheme 1. Expected vs. found stereochemical results for entries 1 and 2 in Table 1.
CCl4 at RT. Surprisingly enough, we did not find the amount of the (S)-1-((R)-2-butyloxy)ethylbenzene (2SR
)
expected almost equimolar mixture of the (R)-1-((R)-2- diastereoisomer (right side of Scheme 1), instead of the
butyloxy)ethylbenzene (2RR) and (R)-1-((S)-2-butyloxy) expected (R)-1-((S)-2-butyloxy)ethylbenzene (2RS) one.
ethylbenzene (2RS
Scheme 1).*
)
diastereoisomers (left side of
It is worth noting that the yield ratios 2RR/2RSꢁ2SR/
8
2SS closely resemble that of the starting 2-butanol even af-
Indeed, after the complete addition of the 1 reactant to ter 25 min reaction time, when the racemic benzylic alco-
R
BiBr /ROH, a small sample of the reaction mixture was hol 1 has almost completely reacted (Fig. 2 and entry 2 in
3
analyzed by GC-MS using a chiral column (CHROMPACK Table 1).
y
CP-Chirasil-Dex CB, L 25 m, ID 0.25 mm, d 0.25 lm).
The procedure was repeated by using (1)-(S)-2-butanol
f
The analysis revealed that, after less than 1 min, the 1R (ALDRICH R/Sꢁ8/92). The results, summarized in
reactant was completely racemized (1R and 1S in Fig. 1 entries 3 and 4 of Table 1, fully conform to those reported
and entry 1 in Table 1). At the same time, the predominant in entries 1 and 2, the only obvious differences being the
formation of 2RR was accompanied by an equimolar consequence of the opposite configuration of the starting
2
-butanol (i.e., 2RR/2RSꢁ2SR/2SSꢁ8:92).*
Of course, when the (S)-enantiomer of 1-phenylethanol
(
1S; FLUKA S/R>99/1) and the (2)-(R)-2-butanol (R/
*
For ethers 2XY and 3XY, the X label refers to the chirality of the benzylic
carbon atom, whereas the Y one indicates the stereochemistry of the 2- Sꢁ92/8) are used as reagents (entries 5 and 6 in Table 1),
alkyl moiety.
the stereochemical results for products 2 closely resemble
y
Twenty microliters of the reaction mixture was diluted in 1 ml of CCl
4
those reported in entries 3 and 4 in Table 1, even if in this
containing 1-ethylnaphtalene as an internal standard, and the resulting
solution was analyzed without any further manipulation.
case the racemization of the benzylic reactant 1 is not as
S
Chirality DOI 10.1002/chir

9
0
FRASCHETTI ET AL.
Fig. 1. GC chromatogram relative to entry 1 in Table 1.
fast as the previous cases (cf. entry 5 with entries 1 and 3 and rac-2-butanol (entries 7 and 8 in Table 1) under the
in Table 1).
same conditions.
Finally, a product ratio 2RR:2RS:2SR:2SS 5 1:1:1:1 was
These findings unequivocally point to the complete race-
found from the reaction of (1)-(R)-1-phenylethanol (1R) mization of the benzylic carbon atom and the complete
Fig. 2. GC chromatogram relative to entry 2 in Table 1.
Chirality DOI 10.1002/chir

PROTECTION OF CHIRAL ALCOHOL
91
TABLE 2. GC-MS monitoring of the reaction using 1-phenylethanol and 2-octanol
a
a
Alcoholic reagents
Entry Time (min)
1
R
(%)
1
S
(%)
1
total (a.u.)
3
SR (%)
3
RS (%)
3
RR (%)
3
SS (%)
3total (a.u.)
b
b
R-1-phenylethanol (1
R-2-octanol (e.e. 98%)
R
)
)
1
2
<1
25
54.2
54.3
45.8
45.7
560
90
56.5
50.4
n.d.
n.d.
43.5
49.6
n.d.
n.d.
50
910
b
b
b
b
R-1-phenylethanol (1
S-2-octanol (e.e. 98%)
R
3
4
<1
25
50.0
53.0
50.0
47.0
530
50
n.d.
57.6
54.3
n.d.
42.4
45.7
110
940
b
b
n.d.
n.d.
The GC signals of the diastereomeric ethers 3 have been assigned assuming the same elution order for these compounds and for the corresponding 2
analogues on the same chiral column.* Uncertainty ca. 5%.
a
GC peak area (Arbitrary Units).
Not detectable.
b
retention of configuration of the 2-butyl moiety in the for- tants (i.e., substituted benzylic alcohols) deserves more
mation of products 2, which is in marked contrast with attention.
8
Boyer’s conclusions.
ACKNOWLEDGMENTS
To gather further confirmation of our unexpected
results, we decided to repeat Boyer’s synthesis using
Valentina Lilla is acknowledged for helpful technical
8
2
-octanol instead of 2-butanol as the ROH substrate. The contribution.
results, reported in Table 2, show that the formed 1-(2-
octyloxy)ethylbenzene isomers (3)* exhibit a stereochem-
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3
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8
3
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