Improved method of an unusual conversion of aliphatic amines into alcohols

Article abstract of DOI:10.1016/S0040-4039(01)01680-X

An improved method for the synthesis of alcohols from amines was achieved using a degassed diethylene glycol and KOH. Utilizing this method, facile conversion of a cyano group, even a sterically hindered one, to a hydroxy-methyl group was also accomplished.

Full text of DOI:10.1016/S0040-4039(01)01680-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8007–8010
Improved method of an unusual conversion of aliphatic amines
into alcohols
S. M. Abdur Rahman, Hiroaki Ohno and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 9 August 2001; accepted 10 September 2001
Abstract—An improved method for the synthesis of alcohols from amines was achieved using a degassed diethylene glycol and
KOH. Utilizing this method, facile conversion of a cyano group, even a sterically hindered one, to a hydroxy-methyl group was
also accomplished. © 2001 Elsevier Science Ltd. All rights reserved.
5
Although synthesis of alcohols from amines seems to be
a simple conversion, practically efficient synthesis of
aliphatic alcohols from the corresponding amines is
extremely difficult. It is well known that aromatic
amines can be converted into the alcohols via a diazo-
nium salt; however, a successful conversion of aliphatic
amines to the corresponding alcohols via diazonium
ing alcohols 7 and 8 in 76 and 77% yields, respectively,
upon treatment with KOH in degassed diethylene gly-
col at 210°C. The reaction temperature should be
controlled precisely. Similarly, the amine 3 provided
6
7
the alcohol 9 in 69% yield. (±)-a-Phenylethylamine 4
and (±)-a-naphthylethylamine 5 furnished the alcohols
1
0 and 11 in 70 and 47% yields, respectively. Aliphatic
1
a–d
salts is rare.
In some cases, reaction of aliphatic
amine 6 provided the known alcohol 12, albeit in a low
amines with nitrous acid led to a number of rearranged
yield (42%). In contrast, secondary and tertiary amines
1e–k
products with very low yields of the desired alcohols.
8
were inert to this reaction conditions.
Other methods require more than one step and some-
2
times suffer from low yields.
Next, utilization of this reaction to the conversion of
hindered nitriles 13–16 to the alcohols 9 and 17–19 was
investigated. As shown in Table 2, the nitrile 13 was
converted into the corresponding amine by treating
with LiAlH , and the resulting amine, without further
purification, was then subjected to the improved
method of amine-to-alcohol reaction conditions to
provide the corresponding alcohol 9 in 67% yield in two
steps. Similarly, 14 also gave the diol 17 in moderate
3
In the course of our synthetic studies of scopadulin, we
found an efficient one-step reaction for conversion of
primary aliphatic amines into alcohols mediated by
3
a
4
9
KOH. However, our previously reported method pro-
vided moderate yields of alcohols from amines. Herein,
we present an improved method for this conversion and
utilization of this method for convenient and efficient
conversion of a cyano group into a hydroxymethyl
group. Results of experimentation to obtain some
information on the reaction mechanism are also
presented.
10
11
yield. The nitrile 15 and 16, the cyano group of which
is highly hindered due to the presence of both the axial
methyl group and the oxygen functionality, also yielded
12
1
8 and 19 in 79% and 66% yields, respectively.
Although hydrous zirconium oxide-mediated direct
conversion of the cyano group to a hydroxy methyl
As a result of the optimization of the reaction condi-
tions, we found that increased yields were observed
when the reaction was conducted in degassed diethylene
13
group was reported, this method is limited to unhin-
dered nitrile under vapor-phase conditions. Alterna-
tively, the conversion of a cyano group into a
hydroxymethyl group is possible via an aldehyde or a
carboxylic acid; however, conversion of the hindered
4
glycol under a nitrogen atmosphere. Table 1 shows the
results of the conversion of amines 1–6 to the corre-
sponding alcohols 7–12. Phenylbutylamine 1 (entry 1)
and benzylic amine 2 (entry 2) afforded the correspond-
1
4
15
cyano group into the corresponding aldehyde, acid
16
or ester is quite difficult. Moreover, most of these
methods required purification of aldehydes and car-
boxylic acid formed. In contrast, our method is suitably
*
Corresponding author. Tel.: +81-6-6879-8210; fax: +81-6-6879-8214;
e-mail: t-tanaka@phs.osaka-u.ac.jp
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01680-X

8
008
S. M. A. Rahman et al. / Tetrahedron Letters 42 (2001) 8007–8010
Table 1. Improved synthesis of alcohols from amines
Table 2. Conversion of a hindered cyano group to a
hydroxymethyl group
KOH, diethylene glycol
R NH2
R OH
1) LiAlH , THF–Et O
4
2
210 °C
R CH OH
2
R
CN
2) KOH, diethylene glycol
210 °C
Reaction time
Entry
1
Substrate
Product
(Yield)
Substrate
OH
Product
OH
Yield
12 h
NH2
OH
Ph
Ph
(76%)
1
7
6
7%
4%
NH2
OH
1 h
2
3
CN
OH
MeO
(77%)
MeO
13
9
2
8
HO
CN
OH
OH
5
2.5 h
O
O
(
69%)
O
O
O
HO
NH2
OH
3
4
9
1
4
17
NH2
OH
HO
1
.5 h
4
CN
(70%)
79%
H
H
10
OTMS
OH
BnO
BnO
HO
15
18
NH2
OH
4
.5 h
5
6
(
47%)
CN
66%
5
6
11
12
H
H
OH
OH
1
6
19
NH2
OH
8
h
(
42%)
17
reaction of 1 in ethylene glycol-d , 72% of the carbinol
6
protons was deuterated. At the present stage of our
understanding, it is difficult to conclude the mechanism
of this reaction; however, it is apparent that the alco-
holic solvent exerts a significant role in the present
applicable to various hindered nitriles, and requires no
purification of the intermediate amines.
18
transformation.
To reveal the mechanical aspect of this unusual conver-
sion, the stereochemical course of the reaction was
investigated. When (+)-a-phenylethylamine 4 was sub-
jected to the amine-to-alcohol reaction conditions, the
optical rotation of the resulting alcohol 10 was consid-
erably low (<5% ee, Eq. (1)). We next probed into the
solvent effect using some involatile solvents. The reac-
tion of phenylbutylamine 1 in alcoholic solvents such as
ethylene glycol (197°C for 40 h) or glycerin (210°C for
NH2
OH
KOH
diethylene glycol
(
1)
210 °C, 2.5 h
4
10 (<5% ee)
13%-d
Ph
72%-d
KOH
ethylene glycol-d6
8
h) yielded the desired 7, although in low yields (25
Ph
( )2 NH2
( )2 OH
7-d
1
95 °C, 40 h
and 22%, respectively). In contrast, when HMPA,
diphenyl ether, or 1-methyl-2-pyrrolidone was used as
solvent, the reaction did not proceed. Assuming that
the alcoholic solvent would be the key to the progress
of the reaction, we finally conducted a labeling experi-
ment using a deuterated solvent (Eq. (2)). According to
1
(2)
In conclusion, we have developed an improved method
for an efficient one-step synthesis of alcohols from
amines. Use of a degassed solvent increased the reac-
tion yield. This method is superior to all other reported
1
the H NMR spectra of the alcohol 7 obtained by the

S. M. A. Rahman et al. / Tetrahedron Letters 42 (2001) 8007–8010
8009
methods for the related conversion in terms of yield,
convenience, cost, and synthetic usefulness. A facile
conversion of the hindered cyano group into a hydroxy-
methyl group was achieved utilizing this method.
Detailed study of the mechanistic pathway is now
under investigation.
8. Reactions of the secondary and tertiary amines 20 and 21
with KOH in diethylene glycol at 210°C gave a trace
amount of the desired alcohol 7 (2% and less than 0.5%,
respectively). In both cases, most of the starting materials
were recovered unchanged.
KOH
diethylene glycol
NHMe
7 (2%)
Ph
recovery of 20
20
210 °C, 20 h
(
ca. 62%)
References
KOH
7
(< 0.5%)
NMe2 diethylene glycol
Ph
1
. (a) Larock, R. C. Comprehensive Organic Transformation,
nd ed.; John Wiley & Sons, 1999; p. 973; (b) Barton, D.
H. R.; Narang, S. C. J. Chem. Soc., Perkin Trans. 1 1977,
114; (c) Mori, K.; Sasaki, M.; Tamada, S.; Suguro, T.;
recovery of 21
(ca. 96%)
21
210 °C, 20 h
2
9
. The reaction product of LiAlH4 was simply filtered
through a filter paper and subjected to the reaction
conditions.
1
Masuda, S. Tetrahedron 1979, 35, 1601; (d) McGarver,
G. J.; Kimura, M. J. Org. Chem. 1986, 51, 3913; (e)
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Schaeffer, W. D. J. Am. Chem. Soc. 1957, 79, 2888; (i)
Harris, C. M.; Schneider, M. J.; Ungemach, F. S.; Hill, J.
E.; Harris, T. M. J. Am. Chem. Soc. 1988, 110, 940; (j)
Brosch, D.; Kirmse, W. J. Org. Chem. 1991, 56, 907; (k)
Della, E. W.; Head, N. J. J. Org. Chem. 1995, 60, 5303.
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Tashiro, M.; Ohara, K.; Kumai, M. Chem. Pharm. Bull.
1
1
0. Although Fraud and Lenze investigated the conversion of
neopentyl amines into alcohols, neopentylamines gave
1e
only the rearranged product.
1. Rahman, S. M. A.; Ohno, H.; Yoshino, H.; Satoh, N.;
Tsukaguchi, M.; Murakami, K.; Iwata, C.; Maezaki, N.;
Tanaka, T. Tetrahedron 2001, 57, 127.
2. Our previously-reported overall yield for the conversion
of 15 to 18 was 49% (three steps).
3. Takahashi, K.; Shibagaki, M.; Matsushita, H. Chem.
1
1
1
3a
Lett. 1990, 311.
2
4. For the conversion of nitriles to aldehydes, see: (a)
Rabinovitz, M. In The Chemistry of the Cyano Group;
Rapport, Z., Ed.; Interscience: New York, 1970; pp.
1
960, 8, 266; (d) Brasen, W. R.; Hauser, C. R. In Org.
3
07–340; (b) Nagata, W. Tetrahedron 1961, 13, 287; (c)
Synth.; Rabjohn, N., Ed.; John Wiley & Sons: New
York, 1963; Collect. Vol. 4, pp. 582–584; (e) Katritzky,
A. R.; Saba, A.; Patel, R. C. J. Chem. Soc., Perkin Trans.
1981, 1492; (f) Guziec, Jr., F. S.; Wei, D. Tetrahedron
Lett. 1992, 33, 7465.
. (a) Rahman, S. M. A.; Ohno, H.; Maezaki, N.; Iwata, C.;
Tanaka, T. Org. Lett. 2000, 2, 2893; (b) Rahman, S. M.
A.; Ohno, H.; Murata, T.; Yoshino, H.; Satoh, N.;
Murakami, K.; Patra, D.; Iwata, C.; Maezaki, N.;
Tanaka, T. J. Org. Chem. 2001, 66, 4831.
. Diethylene glycol was degassed by evacuating the reac-
tion vessel and nitrogen flushing (several times).
. Our previous method for this reaction provided 7 and 8
Nagata, W.; Hirai, S.; Itazaki, H.; Takeda, K. Liebigs
Ann. Chem. 1961, 641, 196; (d) Brown, H. C.; Garg, C. P.
J. Am. Chem. Soc. 1964, 86, 1085; (e) Fry, J. L.; Ott, R.
A. J. Org. Chem. 1981, 46, 602; (f) Corriu, R. J. P;
Moreau, J. J. E.; Pataud-Sat, M. J. Org. Chem. 1981, 46,
1
3
3
1
2
372; (g) Goering, H. L.; Tseng, C. C. J. Org. Chem.
981, 46, 5250; (h) M a´ lek, J.; Cerny, M. Synthesis 1972,
17.
1
5. For the hydrolysis of nitriles to carboxylic acids, see: (a)
DiBiase, S. A.; Wolak, Jr., R. P.; Dishong, D. M.; Gokel,
G. W. J. Org. Chem. 1980, 45, 3630; (b) Rounds, W. D.;
Eaton, J. T.; Urbanowicz, J. H.; Gribble, G. W. Tetra-
hedron Lett. 1988, 29, 6557; (c) Cohen, M. A.; Sawden,
J.; Turner, N. J. Tetrahedron Lett. 1990, 31, 7223; (d)
Kakeya, H.; Sakai, N.; Sano, A.; Yokoyama, M.; Sugai,
T.; Ohta, H. Chem. Lett. 1991, 1823; (e) de Raadt, A.;
Klempier, N.; Faber, K.; Griengl, H. J. Chem. Soc.,
Perkin Trans. 1 1992, 137.
4
5
6
3a
in 59 and 54% yields, respectively.
. Typical experimental procedure: Amine, KOH pellets
about 20 equiv.), and diethylene glycol (0.05–0.1 M
(
solution) were placed in a round-bottomed flask equipped
with a refluxing condenser, and the flask was evacuated
and flushed by nitrogen several times. The mixture was
7
then heated at 210°C for the indicated time (Table 1).
16. In our synthetic studies of scopadulin, we experienced
variable yields of acid/ester from a hindered nitrile.
17. Diethylene glycol-d10 is not commercially available.
11
After the dark solution obtained was cooled to rt, Et O
and H O were added and stirred for few minutes. The
2
2
organic phase was separated and the aqueous layer was
18. The deuterium incorporation can be rationalized by the
solvent-mediated redox mechanism: for example, (1)
imine formation, hydrolysis by KOH and solvent-medi-
ated Meerwein–Ponndorf–Verley type reduction (MPV
reduction) of the resulting aldehyde, or (2) aldehyde
formation from the solvent, transamination and MPV
reduction by the solvent. Although less than 50% of
d-incorporation would be theoretically expected only by
the MPV reduction, we observed 72%-d at the carbinol
position (Eq. (2)). So, we speculate that there would be a
reversible process that enables an additional deuteration
19
extracted several times with Et O.
The combined
organic layers were then washed with water, dried
MgSO ), filtered and concentrated. Purification of the
2
(
4
residue by column chromatography provided the desired
alcohol. The alcohol was further purified by passing it
through a short column of Al O where necessary.
2
3
7
. We found that the reaction proceeds quite slowly at a
temperature below 200°C. When the temperature was
raised to 220°C, an undesired intensely UV positive spot
was detected on TLC.

8
010
S. M. A. Rahman et al. / Tetrahedron Letters 42 (2001) 8007–8010
(for example, reversible oxidation of an amine to the
19. Usually Et O extraction instead of EtOAc extraction is
2
imine mediated by ethylene glycol-d ). However, more
preferred. However, in some cases (for example, entry 2
8
detailed investigations will be necessary to establish the
mechanism of the reaction.
in Table 2), the alcohol could not be completely extracted
by several Et O extractions.
2