LAH aryl alkyl ether cleavage of BINOL derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.11.091

Herein we report the cleaving of aryl alkyl ethers on BINOL derivatives, using the common reducing agent LAH. The cleavage of the alkyl oxygen bond is observed when the BINOL derivative is treated with LAH, in refluxing dioxane, for 60 h. The resulting BINOL derivative can then be re-alkylated using a standard Williamson ether synthesis. The same procedure was tested on 6-hydroxy-2-naphthoic acid derivatives and cleavage was not observed, thus suggesting a chelating mechanism for the BINOL ether cleavage.

Full text of DOI:10.1016/j.tetlet.2004.11.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 451–453
LAH aryl alkyl ether cleavage of BINOL derivatives
Walter E. Kowtoniuk and Darren K. MacFarland*
Department of Chemistry, Gettysburg College, 300 North Washington Street, Gettysburg, PA 17325, USA
Received 14 October 2004; revised 11 November 2004; accepted 16 November 2004
Available online 30 November 2004
Abstract—Herein we report the cleaving of aryl alkyl ethers on BINOL derivatives, using the common reducing agent LAH. The
cleavage of the alkyl oxygen bond is observed when the BINOL derivative is treated with LAH, in refluxing dioxane, for 60 h. The
resulting BINOL derivative can then be re-alkylated using a standard Williamson ether synthesis. The same procedure was tested on
6-hydroxy-2-naphthoic acid derivatives and cleavage was not observed, thus suggesting a chelating mechanism for the BINOL ether
cleavage.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives, and naphthalene analogues, and subjected
each of them to the LAH reducing conditions.
Lithium aluminum hydride (LAH) is a well-known
reducing agent, used frequently for the reduction of a
variety of functional groups.1 However, ethers are not
considered sensitive to LAH.1 This is not surprising as
ethers are not base sensitive and are usually cleaved by
reaction with strong acid. Ethers are not reduced by
common reducing agents; a literature search yielded
no references to ether cleavage by LAH alone, only in
the presence of AlCl3.2
2. Results and discussion
The ether cleavage was first noticed while trying to re-
duce the diamide 1 shown below in Figure 1. Treatment
of diamide 1 with LAH in refluxing dioxane for 16 h
gave diamine 2; however if the reaction mixture was al-
lowed to reflux 60 h, cleavage of the alkyl oxygen bond
was observed, giving the diol 3. 1H NMR was fairly con-
clusive about the absence of the ether, as signature res-
onances at d 4.0 (OCH2) and d 0.8 (CH3) were
missing. The spectroscopic analysis of ether cleavage
was confirmed upon regeneration of the ether via stan-
dard Williamson ether synthesis.
In performing an amide reduction of a BINOL deriva-
tive 1, we discovered that two ether groups were cleaved,
yielding the binaphthol 3 (Fig. 1). This is the first exam-
ple of this type of reaction. In order to study the gener-
ality of this reaction, we synthesized three other BINOL
Figure 1. Reduction and ether cleavage of BINOL diamide diether followed by reformation of the ether. Reagents and conditions: (i) LAH, dioxane,
reflux 16 h; (ii) LAH, dioxane, reflux 60 h; (iii) 1-bromohexane, acetone, NaOH.
Keyword: Ether cleavage.
*
Corresponding author. Tel.: +1 7173376260; fax: +1 7173376270; e-mail: dmacfarl@gettysburg.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.091

452
W. E. Kowtoniuk, D. K. MacFarland / Tetrahedron Letters 46 (2005) 451–453
Our initial hypothesis was that a byproduct of the
carbonyl reduction (AlH3 perhaps?) that was coordin-
atively unsaturated could chelate to the BINOL oxy-
gens, then transfer a hydride to give an aluminum
complex. This is not consistent with the observation of
ether cleavage in the case with no carbonyl, however,
as the byproduct is not generated without a reducible
substrate. We also considered the possibility that an
impurity in the LAH was catalyzing cleavage, but the
absence of cleavage in the naphthalene examples is not
consistent with this possibility, as the impurity would
be present in all cases.
It is possible that aluminum could become six coordi-
nate (four hydrides and the chelating oxygens), which
would circumvent the need for prereaction of the
LAH. Six-coordinate aluminum hydride complexes are
known,4 though for hydride alkoxy complexes, it is the
five-coordinate AlH3(OR)2 complexes that are re-
ported.5 It is also possible that at the elevated reaction
temperature, the AlH4ꢀ degrades into AlH3. Thus, the
geometries required for BINOL–LAH chelation are
known and reasonable for either five or six-coordinate
chelation. In either case, the aluminum could act as a
Lewis acid and lead to nucleophilic hydride attack on
the alkyl.
Figure 2. General reduction/cleavage scheme for BINOL and naphthol
ethers derivatives. Reagents and conditions: (i) LAH, dioxane, reflux
60 h.
Such an unusual reaction required further study. Two
questions were of particular interest: (1) is the reaction
general to reduction of other carbonyls? and (2) is the
reaction general to other, non-BINOL ethers? We de-
signed and synthesized two sets of ether-reduction po-
tential substrates. For both the BINOL and
naphthalene cases, we tested three carbonyls (an amide,
acid, and ester), and a ÔcontrolÕ with no carbonyl (Fig.
2). To test if the BINOL was acting as a chelate, we syn-
thesized ether derivatives of 2-hydroxy-6-naphthoic
acid. These naphthalene analogues have the same elec-
tronic state in the aromatic ring, and the same ether to
be cleaved, but cannot chelate a metal.
In each of the BINOL cases, cleavage of some or all of
the ethers was observed. Thus, the cleavage did not de-
pend on the group being reduced (X = acid, ester, or
amide), or even on the presence of a reducible group
(X = H). This last case was most interesting to us be-
cause no alcohol– or amine–aluminum complex could
be present to facilitate the ether cleavage.
3. Experimental
Each of the BINOL carbonyls was cleanly reduced, and
in each case some ether cleavage was observed (Table 1).
Even in the ÔcontrolÕ no carbonyl case, ether cleavage
was observed. Only the amide gave complete cleavage
of both BINOL ethers. All the other cases (acid, ester,
control) gave monoether–mononaphthol as the major
product, with some binaphthol observed as well. Why
the different functional groups give cleavage to different
extents is unclear.
3.1. Reduction procedure
LAH (6 equiv) per carbonyl to be reduced were placed
in a round bottom flask with a minimal amount of
freshly distilled dioxane (15–20 mL). The dioxane was
allowed to reflux while stirring for approximately an
hour until a homogenous slurry was obtained. The reac-
For each of the naphthoic acid derivative ethers 11–13,
reduction of the carbonyl was clean, but no ether cleav-
age was observed (Table 2). No cleavage was observed
for the naphthalene ÔcontrolÕ 14 as well, with only start-
ing material recovered. Thus, we propose that cleavage
involves a chelate of the BINOL ether oxygens. Chelat-
ing BINOL complexes of aluminum are known, though
they are considered four coordinate.3
Table 2. Results of LAH reduction/cleavage of naphthol derivatives
(determined by GC/MS)
Reaction
X
Y
R1 = H % R1 = decyl %
11!15
12!16
13!17
14!18
CONBn2
COOH
CH2NBn2
CH2OH
0
0
0
0
100
100
100
100
COOndecyl CH2OH
H
H
Table 1. Results of LAH reduction/cleavage of BINOL derivatives (determined by GC/MS)
Reaction
X
Y
R1 = R2 = H %
R1 = H, R2 = hex %
R1 = R2 = hex %
1!7
4!8
5!9
6!10
CON(CH3CHPh)2
CH2N(CH3CHPh)2
100
58
0
0
42
90
53
0
0
COOH
COOiPr
H
CH2OH
CH2OH
H
10
21
26

W. E. Kowtoniuk, D. K. MacFarland / Tetrahedron Letters 46 (2005) 451–453
453
tion mixture was allowed to cool below boiling. The
compound to be reduced was dissolved in warm freshly
distilled dioxane and added to the LAH slurry. The
reaction mixture was then brought back to reflux and al-
lowed to reflux for 60 h at which point the reaction mix-
ture was allowed to cool. The reaction slurry was placed
on ice, and the LAH was quenched with 50 mL of stock
THF followed by x mL H2O, x mL 3 M NaOH, and
3x mL H2O, in that order, where x equals the grams
of LAH. Once the reaction mixture reached a milky
white color 1 M HCl was added to acidify the slurry,
with the exception of the amide reductions. The slurry
was filtered and the filtrate was dried with MgSO4,
and concentrated under vacuum. Thus, for reduction
of diamide 1 to diamine 7, LAH pellets (1.00 g,
26.4 mmol) were ground, placed in 10 mL freshly dis-
tilled dioxane, and allowed to reflux while stirring until
a homogenous suspension was obtained. Diamide 1
(2.12 g, 2.21 mmol) was dissolved in 5 mL of the freshly
distilled dioxane and added to the LAH suspension. The
reaction mixture was allowed to reflux 60 h with stirring.
The reaction mixture was quenched with 50 mL of stock
THF, followed by 1 mL water, 1 mL 3 M NaOH, and
3 mL water, in that order. Once the reaction mixture be-
came milky white it was filtered through a pad of Celite.
The solvent was removed from the filtrate under vacuum
resulting in a highly viscous oil (1.090 g, 52.9% yield
from diacid 4). Analysis of the crude mixture was per-
formed by GC/MS, and product ratios were determined
by integration of the GC peaks.
the 6-hydroxy-2-naphthoic acid derivatives leads us to
conclude that the cleavage takes place through an alumi-
num oxygen chelate complex. The aluminum must che-
late to the two oxygens in order to allow a hydride to
cleave the alkyl chain.
Acknowledgements
Acknowledgment is made to the Donors of the Ameri-
can Chemical Society Petroleum Research Fund for sup-
port of this research (grant #37788-B1).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.11.091. The supplementary data is available online
with the paper in ScienceDirect. Included within the
supplemental data are detailed procedures and spectro-
scopic data.
References and notes
1. Smith, M. B.; March, J. MarchÕs Advanced Organic
Chemistry, 5th ed.; John Wiley & Sons: New York, 2001.
2. Bailey, W. J.; Markscheffel, F. J. Org. Chem. 1960, 25,
1797–1800.
3. Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J.
Am. Chem. Soc. 1984, 106, 6709–6716.
4. Ashby, E. C.; James, B. D. Inorg. Chem. 1969, 8, 2468–
2472.
4. Conclusion
Ether cleavage by LAH is reported in the absence of a
Lewis acid catalyst for the first time. Observation of
ether cleavage on the BINOL derivatives but not on
5. Sokolova, T. Y. S. A. I.; Bulychev, B. M.; Rozova, E. A.;
BelÕskii, V. K.; Soloveichik, G. L. J. Organomet. Chem.
1990, 388, 11–19.