Convenient one pot conversion of acetals into alcohols

Article abstract of DOI:10.1055/s-1999-2549

Various acetals are conveniently converted into alcohols using a one pot procedure that combines hydrolysis of an acetal by triflouromethanesulfonic acid in tetrahydrofuran and tert-butylamine borane reduction of the resulting aldehyde.

Full text of DOI:10.1055/s-1999-2549

LETTER
59
Convenient One Pot Conversion of Acetals into Alcohols
a
a
a
a
b
Kirill A. Lukin, * ChengXi Yang , John R. Bellettini, B. A. Narayanan, M. Robert Leanna,
b
Michael Rasmussen
a
Process Research, Chemical and Agricultural Products Division, Abbott Laboratories, R-13, North Chicago, IL 60064-4000, USA
Process Research, Pharmaceutical Products Division, Abbott Laboratories, R-8, North Chicago, IL 60064-4000, USA
b
Received 6 November 1998
acetals possessing basic groups (e.g. amino or nitrogen
containing heterocycles) form salts at the acidic sites of
resins and hence are absorbed on its surface resulting in
poor recovery of aldehydes. After analysis of other hydro-
lytic conditions we decided to use aqueous trifluo-
romethanesulfonic acid as a cleaving agent and
tetrahydrofuran as a solvent. We have found that most
common acetals and aldehydes are soluble in this system
and hydrolysis proceeds smoothly at room temperature in
a reasonable amount of time (vide infra).
Abstract: Various acetals are conveniently converted into alcohols
using a one pot procedure that combines hydrolysis of an acetal by
triflouromethanesulfonic acid in tetrahydrofuran and tert-buty-
lamine borane reduction of the resulting aldehyde.
Key words: acetals, alcohols, one pot, triflouromethanesulfonic ac-
id, tert-butylaminoborane
Selective functionalization of one hydroxyl group in the
presence of others can be a challenging problem often re-
quiring additional protection – deprotection steps. In- Reduction conditions. It has been well established that al-
stead, stepwise conversion of various functional groups dehydes can be readily reduced to alcohols under variety
2
into a hydroxyl, followed by their subsequent functional- of conditions. Boron hydrides seemed to be more suitable
ization could be a useful synthetic alternative. In this re- for the one-pot procedure, viz., aqueous tetrahydrofuran
gard we were particularly interested in the possibility of media. However the most common reductant - sodium
an efficient conversion of acetals into hydroxyls.
borohydride could not be used for the following reasons:
a) selectivity of the reduction diminished in the presence
of water and alcohols (hydrolysis byproducts); b) highly
basic reaction media (pH > 10) caused transesterification
and ester hydrolysis if these groups were present in the
molecule; c) partial decomposition of sodium borohy-
dride required its use in excess.
Although both synthetic steps required in this transforma-
1
tion namely, hydrolysis of an acetal and reduction of the
2
resulting aldehyde are well investigated, the isolation of
reactive and sometimes unstable aldehydes often presents
a problem. We thought that if we would be able to find
conditions allowing to combine these steps into a ‘one-
pot’ procedure the conversion of acetals into alcohols We found that the readily available but still only occasion-
would be a useful synthetic tool. Unfortunately, most ally used reagent – tert-butylamine borane offered signif-
common conditions used for hydrolyses and reductions icant advantages.5 Indeed, this compound is stable in
are hardly compatible; the former usually requires fairly water and alcohols and highly selective toward aldehyde
acidic aqueous media, while the latter transformation is reduction. Moreover the pH of the reaction mixture re-
usually conducted in a neutral/basic and anhydrous envi- mains between 7 and 8 preventing undesirable side reac-
,6
ronment.
tions. Under our conditions two hydrogens of the borane
were transferred in reductions requiring only 0.67 molar
equivalents of the reagent.
After examining various possibilities (vide infra) we were
able to find an appropriate procedure for the one-pot prep-
aration of alcohols from acetals which is presented in this Application of the selected conditions to the conversion of
Letter. We also provide a brief study of the compatibility dimethoxybenzaldehyde (1) into benzyl alcohol (2) gave
of this method to other functional groups, and finally dem- very satisfying results. Hydrolysis using 0.5 molar equiv-
onstrate the utility of this procedure for the synthesis of a alent of 50% triflic acid was complete in less then 0.5 hour
prospective anti-viral drug candidate.
at room temperature. Sodium bicarbonate pH adjustment
followed by tert-butylamine borane addition at 10 – 20 ºC
resulted in immediate and quantitative reduction of the al-
dehyde (HPLC monitoring). Extractive work up and dis-
tillation gave benzyl alcohol in 83% yield.
Selection of hydrolytic conditions. Protic or Lewis acids
in various solvents have been used to convert acetals into
2
aldehydes. More recently acidic resins (e.g. Amberlist-
3
4
1
5) and Montmorillonite K-10 were introduced as mild
deprotecting agents for acetals. These latter reagents Scheme 1 provides further examples of one-pot conver-
seemed particularly suitable for a one-pot procedure as sions of acetals into alcohols. We have found that the pro-
they can be simply filtered-off and the resulting aldehyde cedure is applicable to aliphatic, aromatic, and
solution would be directly used in the reduction. Unfortu- heteroaromatic compounds (including basic, nitrogen
nately the rate of hydrolysis of many acetals with these re- containing heterocycles e.g. 11 and 15). It tolerates such
agents is so low that very high loads of clay or resin are functional groups as halogen, tosyl, nitro, ester (examples
3
,4
required to achieve satisfactory conversions. In addition
Synlett 1999, No. 1, 59–60 ISSN 0936-5214 © Thieme Stuttgart · New Yorkrk

6
0
K. A. Lukin et al.
LETTER
such as methanol. Nevertheless, using the one-pot proce-
dure alcohol 16 was prepared in 80 % yield further dem-
onstrating utility of the method in the synthesis of
complex polyfunctional compounds. This procedure was
successfully repeated on a 10 – 20 kg scale at the chemical
pilot plant.
We hope that the one-pot conversion of acetals into alco-
hols will find its place in the growing arsenal of modern
synthetic methods.
Typical Procedure for Conversion of Acetals into Al-
cohols. Preparation of 4-Nitrobenzylalcohol (4)
Trifluoromethanesulfonic acid (4.6 g, 50 % in water, 15
mmol) was added dropwise to a solution of an 4-nitroben-
zaldehyde diethylacetal (2.25 g, 10 mmol) in tetrahydro-
furan (20 mL) at 17 – 22 ºC under nitrogen. The mixture
was stirred at this temperature for 4 - 5 hours until the ac-
etal was consumed. Water (6.6 mL) was added to the re-
action mixture followed by sodium bicarbonate (1.7 g).
The mixture was cooled to 10 –15 ºC and t-butylamine bo-
rane (0.52 g, 6 mmol) was added in three portions over 0.5
h. After additional 0.5 h water (20 mL) was added and the
mixture was extracted with dichloromethane (2 x 20 mL).
Combined organic layer was concentrated under vacuum
and water (10 ml) was added to the residue. pH of the mix-
ture was adjusted to 2 – 3 with 2 N HCl and the product
was extracted with dichloromethane (2 x 10 mL). Com-
Scheme 1
1
1, 3, 7, 13, 15 respectively) and can be applied to a-b bined organic layer was dried over magnesium sulfate and
unsaturated aldehyde derivatives as well (compound 5).
concentrated under vacuum to give the desired alcohol
1
(
1.2 g, 80%). H NMR spectrum was identical to the one
Several additional observations regarding these reactions
would be appropriate. Most acetals that we examined
were hydrolyzed slower then dimethoxybenzaldehyde
and it was found beneficial to use up to 1.5 molar equiva-
lents of 50 % triflic acid to achieve good conversions
within 5 hours at room temperature. Competitive ester
group hydrolysis was observed in less reactive acetals
such as 7. However it was usually possible to achieve
higher then 95 % conversion of the acetal retaining more
then 95 % of the ester. Hydrolysis of acetal 15 containing
a guanine base in the molecule was so slow that conden-
sation of the resulting aldehyde and competitive hydroly-
sis of the stearate ester became prevailing reactions. These
problems were circumvented when 2.6 equivalents of tri-
flic acid were used – higher then 95% conversion was
achieved within 1.5 h at room temperature. It turned out
that cleavage of the intermediate borate esters occurred in
aqueous media at pH 6-7. However isolation of pure alco-
hols usually required pH adjustment to 2 - 3 with 2 N hy-
drochloric acid (see Experimental procedure below).
from the reference sample obtained from Aldrich.
References and Notes
(
1) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley; New York, 1991.
(2) Greeves, N. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Ed.; Pergamon: Oxford, 1991; Vol. 8; p1.
(3) Coppola, G. M. Synthesis 1984, 1021.
(4) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 1881.
(
(
(
5) Hutchins, R. O.; Learn, K.; Nazer, B.; Pytlewski, D.; Pelter, A.
Org. Prep. Proc. Int. 1984, 16, 337.
6) Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1980, 21,
693.
7) Ohta, H; Tetsukawa, H.; Noto, N. J. Org. Chem. 1982, 47,
2400.
(8) All new compounds were fully characterized. For alcohol 16:
1
H NMR (DMSO-d ): 0.9 (t, 3H); 1.25 (m, 24 H); 1.5 (m, 4 H);
6
2
.28 (t, 2 H), 2.41 (m, 1 H); 3.5 (m, 2 H) 3.85 – 4.05 (m, 4H),
1
3
4.63 (t, 1 H), 6.68 (s, 2 H); 7.69 (s, 1 H). C NMR (DMSO-
d ): 13.9 (CH ), 22.1 (CH ), 24.3 (CH ), 28.5 (CH ), 28.7
6
3
2
2
2
Preparation of alcohols 14 and 16 - important intermedi-
ates in the synthesis of antiviral ABT-606 – was particu-
larly challenging as these compounds were very sensitive
and underwent intramolecular transesterification under
both acidic and basic conditions, or even in polar solvents
(CH
2
), 29.0 (CH
2
), 29.1 (9C, CH
2
), 31.3 (CH
2
), 31.6 (CH ),
2
9
33.3 (CH ), 34.8 (CH), 44.5 (CH ), 58.1 (CH ), 63.8 (CH ),
2 2 2 2
116.2 (C), 137.7 (CH), 151.4 (C), 153.7 (C), 156.8 (C), 172.8
(C).
(
9) ABT-606 is an antiviral found to be active against Herpes
Zoster.
Synlett 1999, No. 1, 59–60 ISSN 0936-5214 © Thieme Stuttgart · New York