Novel synthesis of optically active 2-ethylhexanoic acid, 2-ethylhexanol, and 2-ethylhexylamine via the asymmetric favorskii rearrangement

Article abstract of DOI:10.1080/00397910500374740

The asymmetric Favorskii rearrangement of optically active α-haloketones, which are easily prepared from chiral menthyl-4- toluenesulfoxide in several steps using primary or secondary amines, yields their corresponding secondary or tertiary chiral amides.

Full text of DOI:10.1080/00397910500374740

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Novel Synthesis of Optically Active
2‐Ethylhexanoic Acid, 2‐Ethylhexanol, and
2‐Ethylhexylamine via the Asymmetric
Favorskii Rearrangement
Motofumi Miura a , Masaharu Toriyama a & Shigeyasu Motohashi a
a College of Pharmacy, Nihon University, Chiba, Japan
Version of record first published: 19 Aug 2006
To cite this article: Motofumi Miura, Masaharu Toriyama & Shigeyasu Motohashi (2006): Novel Synthesis of
Optically Active 2‐Ethylhexanoic Acid, 2‐Ethylhexanol, and 2‐Ethylhexylamine via the Asymmetric Favorskii
Rearrangement, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:3, 259-264
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Synthetic Communicationsw, 36: 259–264, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500374740
Novel Synthesis of Optically Active
2-Ethylhexanoic Acid, 2-Ethylhexanol,
and 2-Ethylhexylamine via the Asymmetric
Favorskii Rearrangement
Motofumi Miura, Masaharu Toriyama, and
Shigeyasu Motohashi
College of Pharmacy, Nihon University, Chiba, Japan
Abstract: The asymmetric Favorskii rearrangement of optically active a-haloketones,
which are easily prepared from chiral menthyl-4-toluenesulfoxide in several steps
using primary or secondary amines, yields their corresponding secondary or tertiary
chiral amides. The secondary chiral amides were converted to acids or amines using
acylation followed by hydrolysis or reduction. In addition, the tertiary amides were
directly reduced to alcohol with Super-Hydridew.
Keywords: Asymmetric Favorskii rearrangement, enantioselective reactions, optically
active amide
The Favorskii rearrangement is a well-known organic reaction that uses
a-haloketones. These a-haloketones, when treated with a base such as
hydroxide, alkoxide, or amine, can undergo a rearrangement reaction to
give carboxylic acids or carboxylic acid derivatives.[1,2]
We have previously reported that this rearrangement is applicable to the
asymmetric reaction, and that this reaction may be followed by the formation
of cyclopropanone intermediated via the six-membered cyclic transition state.[3]
Received in Japan May 30, 2005
Address correspondence to Shigeyasu Motohashi, College of Pharmacy, Nihon
University, 7-7-1, Narashinodai Funabashi-shi, Chiba 274-8555, Japan. Tel.: þ81-
47-465-6406; E-mail: motohasi@pha.nihon-u.ac.jp
259

260
M. Miura, M. Toriyama, and S. Motohashi
Figure 1. Synthesis of (R)-2-chloro-2-tosyl ketone 5.
2-Ethylhexanoic acid and 2-ethylhexanol, each of which has a chiral
center in its alkyl branch, are biologically active substances,[4] and these
compounds are useful building blocks for novel functionalized optically
active surfactants.[5]
Therefore, we attempted a synthesis of enantiomers and 2-ethylhexyla-
mine as a corresponding amine using the asymmetric Favorskii rearrangement.
First, optically active a-haloketones 5 (75–99% ee) were easily prepared
from (2)-(1R, 2S, 5R)-menthyl-4-toluenesulfoxide 1 in six steps (Figure 1 and
Table 1).[6]
Next, in the asymmetric Favorskii rearrangement, optically active a-halo-
ketones 5 were treated with NaH in dry THF with benzylamine or piperidine at
08C for 2.5 h[3] (Scheme 1).
A clean reaction took place, and chiral amides 6 were obtained in good
yield. The sulfonyl group of 6 was reduced with a Na-Hg amalgam in
absolute methanol[7] at 08C for 2 h to give optically active amides 7 (Table 2).
Table 1. Synthesis of (R)-2-chloro-2-tosyl ketone 5 from
(l)-menthyl sulfoxide 1
a
R1
R2
Product
Yield
[a]D
ee (%)b
Me
n-Bu
Et
2a
2b
3a
3b
4a
4b
5a
5b
99
94
93
85c
97
98
92
96
—
—
—
—
—
—
—
—
75
99
n-Pr
Me
n-Bu
Et
—
—
n-Pr
Me
n-Bu
Et
—
—
n-Pr
Me
n-Bu
Et
233.9
230.6
n-Pr
aMeasured in acetone at room temperature.
bCalculated from HPLC using Daicel OD-H column.
cRecrystallization from petroleum ether.

Synthesis of Active Amide via Asymmetric Favorskii Rearrangement
261
Scheme 1.
Optically active 2-ethylhexanoic acid was easily converted from 7a-1 and
7b-1.[8] 7a-1 was treated with an excess of 3-acetoxy-2,2-dimethylpropionyl
chloride in the presence of triethylamine and a catalytic amount of N,N-
dimethylaminopyridine (DMAP) in CH2Cl2 at room temperature. The
product, 8a, was hydrolyzed by LiOH aqueous solution under mild conditions
(Scheme 2).
As a result of the acylation/hydrolysis, (S)-2-ethylhexanoic acid 9a was
obtained in 72% yield (two steps) and 96% ee. Through the same procedure,
(R)-2-ethylhexanoic acid 9b was synthesized from 7b-1 (Table 3).
Table 2. Synthesis of optically active amides 7 via the asymmetric Favorskii
rearrangements of 5
HNR3R4
Compound
R3
R4
H
Product
Yield (%)
ee (%)a
5a
PhCH2
6a-1
6a-2
93
88
—
—
–(CH2)52
PhCH2
–(CH2)52
PhCH2
–(CH2)52
PhCH2
–(CH2)52
5b
5a
5b
H
H
H
6b-1
6b-2
97
82
85b
90
90b
85
—
—
7a-1
7a-2
99
—
7b-1
7b-2
99
—
aCalculated from HPLC using Daicel OJ-H column.
bRecrystallization from petroleum ether.
Scheme 2.

262
M. Miura, M. Toriyama, and S. Motohashi
Table 3. Synthesis of 2-ethylhexanoic acid enantiomer 9 from
optically active amide 7
ee (%)b
a
Compound
Product
Yield (%)
[a]D
7a-1
7b-1
7a-1
7b-1
8a
8b
92
92
83
81
—
—
—
—
96
92
9a (S)
9b (R)
þ11.2
210.6
aMeasured in acetone at room temperature.
bThe ee of 9 was derived for its 2-nitro benzyl amide derivative,
which calculated from HPLC using Waters Opti Pak-TA column.
(S)-2-Ethylhexylamine 11a was prepared as shown in Scheme 3.
Chiral amide 7a-1 was reduced with BH3-THF solution at room tempera-
ture for 2 h, which gave the (S)-benzylamine derivative, 10a, in good yield. The
10a was treated with a 10% Pd/C catalytic reduction for (S)-2-ethylhexyl amine
11a, which was produced in good enantiomeric excess[9] and yield (Table 4).
(S)-2-Ethylhexanol 12a was synthesized from a tertiary amide of 7a-2.
The tertiary amide, 7a-2, was treated with a 2.5 eq. Super-Hydridew in THF
at 08C for 40 min.[10] The reduction occurred immediately, and (S)-2-ethyl-
hexanol 12a was obtained (Scheme 4).
The enantiomeric excess of 12a was determined and calculated by HPLC
analysis of its 4-nitro benzoyl ester derivative (Table 5).
Scheme 3.
Table 4. Synthesis of 2-ethylhexylamine enantiomer 11 from
optically active amide 7
a
Compound
Product
Yield (%)
[a]D
ee (%)
7a-1
7b-1
7a-1
7b-1
10a
10b
92
90
94
92
—
—
—
—
99
99
11a (S)
11b (R)
þ1.16
21.17
aMeasured in acetone at room temperature.

Synthesis of Active Amide via Asymmetric Favorskii Rearrangement
263
Scheme 4.
Table 5. Synthesis of 2-ethylhexanol enantiomer 12 from optically
active amide 7
a
Compound
Product
Yield (%)
[a]D
ee (%)b
7a-2
7b-2
12a (S)
12b (R)
85
94
þ2.6
23.3
75
91
aMeasured in acetone at room temperature.
bThe ee of 12 was derived for its 4-nitro benzoyl ester derivative,
which was calculated from HPLC using Daicel AS-H column.
In conclusion, we succeeded in synthesizing the optically active enantio-
mers of 2-ethylhexanoic acid, 2-ethylhexanol, and 2-ethylhexylamine. We
were able to synthesize only a small amount of the (R)-enantiomer of (S)-2-
ethylhexanol.
As far as we know, this is the first report of the synthesis of these compounds
using asymmetric Favorskii rearrangement. The reaction can be used widely for
the synthesis of various optically active compounds that have functional groups.
ACKNOWLEDGMENT
We are grateful to Yumiko Kimura and Kouichi Metori for the spectral
measurements. We also express great thanks to Hiroshi Hinou, Kumiko
Yoshihara, and Ayako Ohigashi for technical research.
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