Diastereoselective α-alkoxylation of lactamide N-alkyl groups via intramolecular formation of oxonium ions as the key intermediate

Article abstract of DOI:10.1039/a805638b

Stereoselective introduction of an alkoxy group to the amine unit of lactamide derivatives, under electrochemical oxidation conditions, was investigated based upon the assumption that a cyclic oxonium ion can be formed between the alkoxy substituent on th

Full text of DOI:10.1039/a805638b

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Diastereoselective á-alkoxylation of lactamide N-alkyl groups via
intramolecular formation of oxonium ions as the key intermediate
Tohru Kamada and Akira Oku*
Department of Chemistry, Faculty of Engineering and Design, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received (in Cambridge) 20th July 1998, Accepted 20th August 1998
Stereoselective introduction of an alkoxy group to the amine unit of lactamide derivatives, under electrochemical
oxidation conditions, was investigated based upon the assumption that a cyclic oxonium ion can be formed between
the alkoxy substituent on the chiral center and a carbocation generated at the α-position of N-alkyl substituents.
With N-monosubstituted lactamides, diastereoselectivity in the N-α-alkoxylated product was not observed. With
N,N-disubstituted lactamides, however, the selectivity appeared though in low ratios (~2.2). Requisite factors that
govern the stereoselectivity, i.e. nucleophilicity of both internal and external nucleophiles and substitution on amine
units, were also examined.
Lactic acid is a naturally occurring inexpensive chiral com-
Introduction
pound.9 However, there are few reports on stereoselective
electro-organic reactions using lactic acid.10 This is because the
highly polar conditions of the reactions disfavor the electro-
static interaction of the hydroxy group of lactic acid, which is
necessary for stereocontrol. In this regard, the authors recently
have found that under highly polar conditions, such as in tri-
fluoroacetic acid solution, the oxygen atom of a cyclic ether
forms a bicyclic oxonium ion with an intramolecularly gener-
ated carbocation, and the oxonium ion underwent either a
ring-expansion or ring-switching reaction [eqn. (2)].11 In this
Recently, for the protection of the environment as well as
energy efficiency, new synthetic methods with high yields,
reduced by-products and reduced energy consumption are
needed. For this purpose, electro-organic reactions seem to be
suitable because they can take place at ambient temperatures, in
heavy metal-free media and with high product selectivity.1 In
the course of extending their domain toward highly-selective
reactions, a number of stereoselective reactions were developed
by the use of, for example, asymmetrically modified electrodes,2
chiral mediators3 and substrates possessing chiral substituents.4
In the study of substrates possessing chiral substituents,
some stereoselective intramolecular reactions were reported5
whereas few satisfactory results were reported for inter-
molecular reactions. This may be attributable to weaker inter-
action between reaction centers and chiral substituents because
electro-organic reactions are ordinarily carried out under highly
polar conditions.6
( )n
( )n
Ag2O
Br
(2)
( )m
( )m
+
O
CF3CO2H
O
( )n
Matsumura and Shono developed many electo-organic reac-
tions of amines utilizable for the synthesis of biologically active
compounds.7 Among them, methoxylation at the position α to
the nitrogen atom of carbamates and amides is a useful method
for introducing a functional group to the α position of amines
[eqn. (1)].8 Since α-methoxyamine derivatives can be activated
( )m
O
+
CF3CO2H
R2
N
R2
OCOF3
+
–2e–
R1
R3
R1
N
R3
( )n
( )m
( )m
MeOH
+
OCOCF3
O
O
( )n
O
O
R
1 = OMe or Alkyl
bicyclooxonium ion formation, one of the key factors that gov-
erns the chemoselectivity is the nucleophilicity of the ethereal
oxygen atom.
R2
R1
N
R3
OMe
Based on this finding, we expected that an alkoxy derivative
of lactic acid may form an oxonium ion with a carbocation
intramolecularly generated by anodic oxidation and result in a
stereoselective reaction. To verify this possibility, the authors
chose the methoxylation reported by Matsumura and Shono8a
as a prototype reaction and applied it to lactamides i [eqn. (3)].
In this anodic methoxylation, the alkoxy-substituted carbon
of lactamides is expected to play a stereogenic role; the
alkoxy group functions as an internal nucleophile to attack the
(1)
O
by Lewis acids, stereoselective introduction of a nucleophile
seems possible by the use of asymmetric Lewis acid catalysts.
Although some stereoselective electro-organic reactions of
chiral amines were reported, the selectivity was attributed to the
non-bonded repulsion between substituents on the asymmetric
center and the species to be introduced.4
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388
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OR1 R2
OR1 R2
R1
R3
ethoxy)carbamates were obtained when trifluoroethanol, poss-
essing a higher oxidation potential than methanol, was used
as a nucleophile in a similar reaction.16 Thus, we carried out
the electrochemical oxidation of trifluoroethoxy-substituted
lactamide 1c and obtained α-trifluoroethoxylation product 4c
in 39% yield [eqn. (6)]. However, an excess amount of electricity
(8 F molϪ1) caused its decomposition.
+
O
–2e–
Nu–
*
N
R3
N
R3
*
N
*
*
*
R2
*
(3)
O
O
Nu
O
i
ii
iii
R1, R2, R3 = alkyl
carbocation on the amine unit, thus forming a cyclic oxonium
ion ii. Then, ii will be attacked by an external nucleophile more
or less in a stereoselective way to give lactamide derivative iii.
In this paper, we report evidence that the alkoxy substituent
of lactamide derivatives can form a cyclic oxonium ion with an
electrochemically generated internal carbocation and, thence, a
stereoselective substitution on the amine unit can be realized.
(6)
–2e– (4.5 F mol–1
CF3CH2OH
)
O
CF3
NH
O
CF3
NH
Et4NBF4 / CH2Cl2
O
O
O
CF3
1c
4c
39% (d.r. = 1 : 1)
29% at 3.0 F mol–1
39% at 4.5 F mol–1
0% at 8.0 F mol–1
Results and discussions
Stabilization of the lactic acid unit as a chiral source
Although oxidation of the acid unit was suppressed by pro-
tecting the hydroxy group with a trifluoroethyl group, the yield
of 4c was still low. We suspected that oxidative decomposition
of the amine unit may be the reason for such a low yield.
In fact, when we carried out the electrochemical oxidation of
N,N-diethyllactamide derivative 1d, N-ethyllactamide deriv-
ative 1e was obtained [eqn. (7)]. This means that the initially
First of all, to make it clear why lactic acid has not been used
widely in electro-organic reactions despite it being an inexpen-
sive chiral source, anodic methoxylation of N-propyllactamide
1a was examined according to Shono’s method12 [eqn. (4)].
OH
–2e– (5 F mol–1
)
NH
MeO
NH
Et4NOTs
MeOH
OMe
OMe
–2e– (6 F mol–1
)
O
O
OMe
24%
N
NH
MeOH
Et4NBF4 / CH2Cl2
1a
anodic oxidation
2a
(4)
O
O
anodic oxidation
(7)
1d
1e (10%)
anodic
oxidation
O
alcoholysis
/ EGA
NH
OMe
N
O
O
OMe
Instead of the expected product N-α-methoxypropyllactamide,
methyl N-α-methoxypropylcarbamate 2a was obtained. It is
known that under electrochemical conditions alcohols are oxid-
ized to carbonyl compounds13 and diketones are cleaved.14 This
means that in the oxidation of lactamides, the hydroxy group
of the lactic acid unit is first oxidized to a carbonyl group and
the diketone, thus formed, is cleaved oxidatively to give methyl
N-α-methoxypropylcarbamate 2a. As a consequence, lactamide
1a is not suitable as a chiral source in electro-organic reactions.
To protect the acid unit from oxidative decomposition,
increasing the oxidation potential of the α oxygenic substituent
might prove effective. In this regard, substrate 1b possessing an
α methoxy group instead of the hydroxy group was examined
[eqn. (5)]. However, electrolysis of 1b gave the expected meth-
formed α-methoxylation product was decomposed by the elec-
trochemically generated acid (EGA).
Now, we have found that having the oxidation potential of
the acid unit higher than that of the amine unit is not appro-
priate because it may not always prevent the oxidation of
N-alkyl groups in the product. Instead, it seems more promising
to reduce the oxidation potential of the amine unit of the start-
ing amide relative to the acid unit. This method can also
suppress the generation of EGA. Based on the report that a
silyl or stannyl group on the α-position of an N-alkyl chain can
reduce the oxidation potential of the amine unit,17 we carried
out electrochemical oxidation of α-silyl-substituted N-alkyl-
lactamide 1f, finding improvement in both the current efficiency
and product yield [eqn. (8)].
OMe
OMe
–2e– (2 F mol–1
Et4NOTs / MeOH
)
NH
NH
OMe
OMe
(8)
C6H13
(5)
–2e– (2.5 F mol–1
MeOH
)
NH
O
O
OMe
NH
C6H13
SiPhMe2
1b
3b
19% d.r. = 1 : 1
O
Et4NBF4 / CH2Cl2
O
OMe
1f
3f
76% (d.r. = 1 : 1)
oxylation product 3b in only 19% yield. Ethers are known to be
oxidized electrochemically to carbonyl compounds, which are
further decomposed.15 The low product yield of 3b can be
attributed to the electrochemical oxidation of the methoxy
group of the acid unit.
Therefore, an alkoxy group on the acid unit possessing a
higher oxidation potential than that of the amine unit seems
essential for both protecting the acid unit from electrochemical
decomposition and producing the expected α-methoxyamine
derivative in high yields. Matsumura reported that α-(trifluoro-
Internal vs. external nucleophilic attack
So far, appropriate modification of substrate structures had
enabled lactic acid to be used in electro-organic reactions, albeit
that the acid still did not function as a stereogenic unit. In the
ring-expansion reaction,11 when the nucleophilicity of the
internal nucleophile was lower than that of an external one,
the latter attacked the cationic center to disfavor the ring-
3382
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388

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expansion. In the present electrochemical reactions thus far
examined, external alcohols are more nucleophilic than the
internal alkoxy groups because both have the same alkoxy
groups. Therefore, when a carbocation is electrochemically gen-
erated on the amine unit, attack by the external nucleophile can
predominate over the internal one and disfavors intramolecular
oxonium ion formation, which is essential for the stereoselective
reaction we designed.
N-Methyl-N-(á-silylalkyl)-O-alkyllactamide derivatives
The amide cation, in which the cation center is located on the
α-position of the N-alkyl group, tends to release the proton on
the nitrogen to generate a stable imine. The substrates we have
examined thus far were N-monosubstituted amides and, there-
fore, the corresponding amide cations probably underwent
deprotonation to form imines rather than cyclic oxonium ions
(Scheme 1). Therefore, the reaction of N,N-disubstituted
On this assumption, external nucleophiles which are less
nucleophilic than the internal alkoxy substituents were exam-
ined [eqn. (9)]. First, anodic oxidation of N-(α-methoxypropyl)-
OR1
NH
R2
*
OMe
OMe
–2e– (1 F mol–1
CF3CH2OH
)
(9a)
O
NH
NH
–2e–
Et4NBF4 / MeCN
O
O
CF3
O
OMe
3b
4b
10% (d.r = 1 : 1)
OR1
*
NH
R2
+
O
OMe
OMe
–2e– (2.5 F mol–1
)
(9b)
NH
NH
CF3CH2OH
Et4NBF4 / MeCN
–H+
O
SiPhMe2
O
O
CF3
R1O
R2
+
OR1
*
4b
48% (d.r. = 1 : 1)
1g
O
*
N
*
N
R2
*
H
O
O
(9c)
NuH
NuH
–2e– (2.5 F mol–1
)
nonstereoselectively
NH
NH
(stereoselectively)
O
MeOH
Et4NBF4 / CH2Cl2
O
O
SiPhMe2
O
OMe
OR1
*
1h
3h
ca. 100% (d.r. = 1 : 1)
NH
R2
O
Nu
O-methyllactamide 3b was examined in the presence of
CF3CH2OH to discover if the exchange of α-CH3O group on
the N-alkyl substituent for a trifluoroethoxyl group can pro-
duce any diastereoselectivity. However, exchanged product 4b
was obtained in low yield without selectivity [eqn. (9a)].
Second, the similar oxidation of N-(α-silylalkyl)carboxylic
amides 1g and 1h was examined in the presence of CF3CH2OH
for 1g and methanol for 1h. However, again, the expected
diastereoselectivity was not observed in products 4b and 3h
[eqns. (9b) and (9c)].
The starting amides used in the reactions shown in eqn. (9)
were composed of equal amounts of the diastereomers. If the
external nucleophilic attack proceeded directly via an SN2-like
mechanism with these substrates, not via the cyclic oxonium
intermediate, the products would also show diastereomer ratios
of 1:1. To examine this possibility, the exchange reaction of the
α-CH3O group of 3b possessing a diastereomer ratio of 2.38:1
was examined in MeOH under the catalysis of EGA [eqn. (10)].
Scheme 1
amides 5, with which the intermediacy of cyclic oxonium ions
is more likely than with monosubstituted amides, seems more
appropriate for the generation of the expected stereoselectivity.
In advance of the reaction, the relative stability of each
stereoisomer of the oxonium ion was calculated by molecular
mechanics calculation: the oxonium atom was replaced by a
nitrogen atom for these approximate calculations (Table 1). The
calculation predicts that the stereoisomer ii(f) is the most stable.
Based upon this prediction, electrochemical alkoxylation of
N-methyl-N-(α-silylalkyl)-O-alkyllactamides 5a–e was exam-
ined [eqn. (11)] (Table 2). When an external nucleophile possess-
OR1
OR1
(11)
CF3
–2e– / Pt
N
R2
N
R2
CF3CH2OH
Et4NBF3 / CH2Cl2 or MeCN
O
SiPhMe2
O
O
OMe
OMe
(10)
–2e–
5a–e
7a–e
d. r. = 1.2 - 2.2 : 1
NH
NH
Et4NOTs / MeOH
O
OMe
O
OMe
ing the same alkoxy group as that of the internal nucleophile
was used, the diastereomer ratio was 1.2:1 (runs 1 and 5, Table
2). When the external nucleophile was less nucleophilic than the
internal one, the ratio was improved to 1.7:1 (run 3). When no
internal nucleophile existed, the selectivity was not observed
(run 6), probably because intramolecular formation of the
oxonium ion did not take place. This implies that simple
steric hindrance in an acyclic intermediate does not produce
diastereoselectivity. Hence, for the diastereogenesis, internal
oxonium ion formation seems essential, as was indicated by the
3b
3b
0 F mol–1 d.r. = 2.38 : 1
1 F mol–1 d.r. = 1.23 : 1
2 F mol–1 d.r. = 1.18 : 1
The ratio was decreased to 1 after the passage of electricity.
This indicates that the stereoselectivity of the external nucleo-
philic attack on 3b or on the corresponding oxonium ion
intermediate is low, or the reaction proceeds via a different
mechanism.
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388
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Table 1 Relative stability of cyclic oxonium ions estimated by MM2 calculationa
+
O
+
O
+
O
+
O
+
O
+
O
+
N
N
N
N
O
N
N
N
O
O
O
O
O
O
O
a
b
c
d
e
f
g
ii
∆E/kcal mol–1
12.44
7.91
5.72
8.03
7.91
0
8.36
a Substituents are methyl groups. Oxonium ion replaced with a nitrogen atom for the purpose of the calculations.
Table 2 Electrochemical α-alkoxylation of N,N,O-trisubstituted lactamide derivatives
R1
R2
N
R1
R2
N
–2e– (2.5 F mol–1) / Pt
NuH / Et4NBF4
/ CH2Cl2 or MeCN
O
SiPhMe2
O
Nu
Diastereomer
ratio
Run
Substrate
R1
R2
NuH
MeOH
MeOH
CF3CH2OH
MeOH
Product
Yield (%)a
1
2
3
4
5
6
5a
1g
5a
5b
5b
8a
MeO
MeO
MeO
CF3CH2O
CF3CH2O
Et
Me
H
Me
Me
Me
Me
6a
3b
7a
6b
7b
9a
1.2:1
1.0:1
1.7:1
1.0:1
1.2:1
1.0:1
18 (20)
33 (48)
43 (77)
65 (73)
28 (30)
50 (50)
CF3CH2OH
MeOH
a Yields in parentheses are based on the substrate conversion.
Table 3 Electrochemical α-alkoxylation of N,N,O-trisubstituted lactamide derivatives
MeO
Me
N
MeO
Me
N
–2e– (2.5 F mol–1) / Pt
NuH / S.E. / solvent
R
R
O
SiPhMe2
O
Nu
Diastereomer
Run
Substrate
R
NuH
Solvent
S.E.
Product
ratio (% yield)a
1
2
3
4
5
6
7
8
9
10
11
12
13
5a
5a
5a
5a
5a
5a
5a
5c
5c
5d
5d
5e
5e
Et
Et
Et
Et
Et
Et
Et
Pr
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CO2H
CH3CO2H
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
MeOH
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CF3CH2OH
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
MeCN
Et4NBF4
Bu4NBF4
Et4NClO4
Bu4NClO4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
Et4NBF4
7a
1.7:1 (77)
1.5:1 (47)
1.5:1 (52)
1.5:1 (59)
1.4:1 (70)
decomposed
no reaction
1.5:1 (52)
1.6:1 (52)
2.2:1 (53)
1.6:1 (34)
1.7:1 (50)
1.1:1 (64)
7a
7a
7a
7a
none
none
7c
Pr
7c
heptyl
heptyl
7d
7d
Et (THF)b
Et (THF)b
7e
6e
a Yields in parentheses are based on the substrate conversion. b Compound 5e:
Me
N
O
O
SiPhMe2
observation that the diastereoselectivity appeared only when
the external nucleophile was less nucleophilic than the internal
one.
electrolytes is important for the stabilization of intramolecular
oxonium ion ii, but the diastereoselectivity was not influenced
by the electrolytes examined (runs 2, 3 and 4, Table 3).
Results for the other reactions are shown in Table 3. Again,
the use of external nucleophiles with low nucleophilicity also
leads to the appearance of diastereoselectivity. When aceto-
nitrile was used as the solvent, it gave a better result than
dichloromethane (compare runs 1 with 2, and 10 with 11, Table
3). It was also presumed that the properties of the supporting
The appearance of the diastereoselectivity shown in Tables 2
and 3 can be explained as follows (Scheme 2). Electrochemically
generated carbocation v first forms oxonium ion ii as a result
of internal nucleophilic attack by the alkoxy group. The
stereochemistry of the oxonium ion is controlled by the relative
stability difference (Table 1) to favor isomer f, upon which
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J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388

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OR1
OR1
Materials
N
R2
N
R2
N-Propyllactamide 1a,20 N,N-diethyl-2-methoxypropanamide
1d21 and methyl N-(1-methoxypropyl)carbamate 2a8a are
known compounds.
–2e–
+
–Me2PhSi+
O
SiPhMe2
O
v
iv
N-Propyl-2-methoxypropanamide 1b
N-Propyl-2-bromopropanamide22 (13.3 g, 68.6 mmol) and
sodium methoxide in methanol (28 wt%, 41.2 g, 214 mmol)
were mixed in dry methanol (43 cm3) and the mixture was
refluxed for 1 h. After the solvent was removed, water (50 cm3)
was added to the residue,23 acidified to pH 4 with conc. hydro-
chloric acid, the aqueous solution was extracted with ether
(5 × 50 cm3), organic extracts were combined and dried over
MgSO4. After removing ether, the residue was distilled to
afford 1b (4.4 g, 45%): bp 108 ЊC/18 mmHg; δH 0.90 (3 H, t,
J 7.5), 1.34 (3 H, d, J 6.6), 1.52 (2 H, qd, J 7.5 and 6.9), 3.21
(2 H, td, J 6.9 and 6.9), 3.36 (3 H, s), 3.71 (1 H, q, J 6.6) and
6.57 (1 H, br s); δC 11.17, 18.01, 22.72, 40.34, 57.29, 78.16 and
172.89; νmax/cmϪ1 (liq. film) 3300, 2960, 2940, 2870, 1660, 1540,
1460 and 1120; m/z (EI) (Found: Mϩ, 145.1104. C7H15NO2
requires M, 145.1104).
R2
R1
OR1
+
O
+
Nu–
N
R2
N
O
O
vi
ii(f)
Nu–
Nu–
Nu–
Nu–
OR1
OR1
N
R2
N
R2
O
Nu
O
Nu
iii(anti)
iii(syn)
N-Butyl-2-(2,2,2-trifluoroethoxy)propanamide 1c
To a solution of N-butyl-2-bromopropanamide24 (3.0 g, 14.4
mmol) in 2,2,2-trifluoroethanol (9 cm3) was added 60% sodium
hydride in oil (1.02 g, 25.5 mmol) at ambient temperature under
an Ar atmosphere and the solution was refluxed for 2 h. Water
(20 cm3) was added to the solution. The solution was extracted
with ether (3 × 30 cm3) and the organic extracts were dried over
MgSO4 and evaporated to give a residue, which was subjected
to flash column chromatography (eluent: 10 to 80% ethyl
acetate–hexane) to afford 1c (2.53 g, 77%); δH 0.92 (3 H, t,
J 7.2), 1.34 (2 H, dt, J 7.5 and 7.2), 1.43 (3 H, d, J 6.6), 1.49
(2 H, tt, J 7.5 and 7.2), 3.27 (2 H, m, contains t, J 6.9), 3.87
(2 H, m, contains q, J 8.3), 3.99 (1 H, q, J 6.6) and 6.40 (1 H, br
s); δC 13.58, 18.14, 19.89, 31.50, 38.69, 67.07 (q, J 34.4), 78.41,
123.40 (q, J 278.8) and 171.22; νmax/cmϪ1 (liq. film) 3300, 2960,
2940, 1660, 1540, 1280, 1160, 1130 and 960.
Scheme 2
consecutive attack by an external nucleophile takes place on the
α position of amine unit, namely, an external nucleophile
approaches from the backside of the oxonium atom to give
predominantly diastereomer iii(syn), as shown in Scheme 2. On
the other hand, if carbocation v cannot form ii efficiently, it can
be stabilized in the form of iminium ion vi to which external
nucleophile attack takes place nonstereoselectively. However, in
general, intermediates ii(f) and vi are in equilibrium and, there-
fore, the diastereoselectivity in products iii is attenuated.18
Conclusion
After a large number of discouraging results, we finally
obtained evidence to conclude that the electrochemical alkoxyl-
ation of lactamide derivatives can proceed stereoselectively via
the formation of a cyclic oxonium ion as the key intermediate.
To generate the selectivity, the following factors must be taken
into consideration: (i) the internal nucleophiles, i.e. alkoxy sub-
stituents, must be more nucleophilic than the external ones for
the intramolecular oxonium ion formation, (ii) the secondary
amine unit is essential, not only for oxonium ion formation, but
also for stereocontrol of the consecutive substitution, and (iii)
the combination of an alkoxy group on the lactic acid unit,
which is stable under the oxidation conditions, and a readily
oxidizable substituent on the amine unit must be assembled in
the starting substrate.
N-[1-(Dimethylphenylsilyl)octyl]-2-methoxypropanamide 1f
A general procedure for the preparation of N-(silylalkyl) substi-
tuted lactamides 1g, 1h, 5a–e and 8a.
To a solution of 1-(dimethylphenylsilyl)octanol25 (4.0 g, 15.2
mmol) and dry triethylamine (3.2 cm3, 22.7 mmol) in dichloro-
methane (74 cm3), methanesulfonyl chloride (1.3 cm3, 16.7
mmol) was added at 0 ЊC under an Ar atmosphere.26 After stir-
ring for 15 min, water (80 cm3) was added to the solution, and
the organic layer was separated. The organic layer was dried
over MgSO4 and evaporated to give a residue. The residue was
dissolved in methanol (150 cm3), through which NH3 gas was
bubbled for 3 h at 0 ЊC. After stirring overnight at ambient
temperature, the solution was concentrated to afford a residue.
1  aq. NaOH (100 cm3) was added to the residue and extracted
with ether (4 × 50 cm3). The organic extracts were combined,
dried over MgSO4 and evaporated to give a residue, which was
subjected to flash column chromatography (eluent: 10–100%
ethyl acetate–hexane) to afford 1-(dimethylphenylsilyl)octyl-
amine (1.35 g, 34%).
Experimental
Tetrahydrofuran, dichloromethane, acetonitrile and triethyl-
amine were purified by the usual methods19 and other com-
mercially available chemicals were used without further purifi-
1
cation. H NMR and 13C NMR spectra were measured on a
GE QE-300 spectrometer in CDCl3 solutions using CHCl3 (δH
7.26) and CDCl3 (δC 77.0) as internal standards. Chemical shifts
(δ) are given in ppm and the coupling constants (J) are given in
Hz. IR spectra were recorded on a JASCO IR-810 spec-
trometer. High resolution mass spectra were measured on a
Hitachi M-80 spectrometer or a JEOL MS Station JMD-700.
Elemental analyses were performed on a Yanaco MT-5
analyzer. Molecular mechanics calculation was conducted by the
use of HyperChemTM, Hypercube, Inc. Ether refers to diethyl
ether.
At 0 ЊC under an Ar atmosphere, a solution of 2-methoxy-
propanoic acid27 (0.41 g, 3.89 mmol) in dichloromethane (1.7
cm3) was added into a solution of DCC (0.79 g, 3.82 mmol) in
dichloromethane (2.5 cm3) and stirred for 15 min.28 To this solu-
tion, a solution of 1-(dimethylphenylsilyl)octylamine (1.0 g,
3.83 mmol) in dichloromethane (1.7 cm3) was added, and the
mixture was gradually warmed to ambient temperature under
stirring overnight. The white precipitate was filtered off and
washed with dichloromethane (30 cm3). The filtrate was washed
with water (30 cm3). The organic layer was dried over MgSO4
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388
3385

View Article Online
and evaporated to give a residue, which was subjected to flash
column chromatography (eluent: 5 to 20% ethyl acetate–
hexane) to afford a 1:1 diastereomeric mixture of 1f (1.08 g,
81%): δH 0.32 (1.5 H, s), 0.33 (3 H, s), 0.34 (1.5 H, s), 0.84 (3 H,
t, J 6.6), 1.27 (1.5 H, d, J 6.6), 1.30–1.60 (12 H, m), 1.32 (1.5 H,
d, J 6.6), 3.31 (1.5 H, s), 3.27 (1.5 H, s), 3.68 (0.5 H, q, J 6.6),
3.70 (0.5 H, q, J 6.6), 3.73 (1 H, m), 6.12 (0.5 H, d, J 9.6), 6.15
(0.5 H, d, J 9.6), 7.36 (3 H, m) and 7.50 (2 H, m); δC Ϫ5.18,
Ϫ4.99, Ϫ4.84, Ϫ4.74, 13.98, 18.60, 22.52, 27.05, 27.30, 29.04,
29.29, 30.79, 30.99, 31.70, 38.54, 38.75, 57.46, 57.58, 78.59,
127.83, 129.35, 133.95, 136.06 and 172.38; νmax/cmϪ1 (liq. film)
3300, 2960, 2930, 2850, 1660, 1520, 1250, 1120, 840, 820 and
700; m/z (EI) (Found: Mϩ, 349.2436. C20H35NO2Si requires M,
349.2439).
11.45 (1 H, br s); δC 17.98, 67.34 (q, J 34.4), 75.47, 123.50 (q,
J 276.8), 177.86; νmax/cmϪ1 (liq. film) 3000, 2950, 1730, 1280,
1170, 1140, 970.
According to the general procedure, 2-(2,2,2-trifluoro-
ethoxy)propanoic acid was converted to 5b; δH 0.33 (1.5 H, s),
0.35 (1.5 H, s), 0.38 (3 H, s), 0.84 (1.5 H, t, J 7.2), 0.86 (1.5 H, t,
J 7.2), 1.23 (1.5 H, d, J 6.6), 1.27 (1.5 H, d, J 6.6), 1.60–1.80
(2 H, m), 2.83 (1.5 H, s), 2.84 (1.5 H, s), 3.31 (0.5 H, q, J 8.4),
3.35 (0.5 H, q, J 8.7), 3.67 (0.5 H, q, J 8.7), 3.71 (0.5 H, q, J 9.0),
3.92 (1 H, m), 4.30 (0.5 H, q, J 6.6), 4.31 (0.5 H, q, J 6.6), 7.33
(3 H, m), 7.51 (2 H, m); δC Ϫ4.16, Ϫ4.05, Ϫ3.22, Ϫ3.00, 12.12,
16.83, 17.23, 20.36, 20.49, 33.19, 33.42, 50.26, 50.39, 65.67 (q,
J 34.4), 75.22, 75.42, 123.75 (q, J 274.4), 127.74, 129.23, 133.90,
137.17, 170.04; νmax/cmϪ1 (liq. film) 2960, 2940, 1640, 1280,
1160, 1140, 970, 840; m/z (EI) (Found: Mϩ, 361.1679. C17H26-
NO2F3Si requires M, 361.1686).
N-[1-(Dimethylphenylsilyl)propyl]-2-methoxypropanamide 1g.
Prepared from 1-(dimethylphenylsilyl)propanol;29 δH 0.32
(1.5 H, s), 0.33 (3 H, s), 0.35 (1.5 H, s), 0.86 (1.5 H, t, J 7.2), 0.88
(1.5 H, t, J 7.2), 1.28 (1.5 H, d, J 6.6), 1.31 (1 H, m, containing
J 14.4 and 7.2), 1.33 (1.5 H, d, J 6.6), 1.62 (0.5 H, dq, J 14.4
and 7.2), 1.63 (0.5 H, dq, J 14.4 and 7.2), 3.27 (1.5 H, s), 3.32
(1.5 H, s), 3.63 (1 H, m), 3.69 (0.5 H, q, J 6.6), 3.71 (0.5 H, q,
J 6.6), 6.12 (0.5 H, br s), 6.15 (0.5 H, br s), 7.37 (3 H, m), 7.50
(2 H, m); δC Ϫ5.16, Ϫ4.96, Ϫ4.83, Ϫ4.72, 11.84, 12.17, 18.70,
23.95, 24.18, 40.29, 40.58, 57.55, 57.63, 78.60, 127.87, 129.37,
129.45, 133.96, 136.02, 172.61, 172.75; νmax/cmϪ1 (liq. film)
3400, 3290, 2960, 2930, 1660, 1520, 1250, 1120, 840, 820; m/z
(EI) (Found: Mϩ, 279.1649. C15H25NO2Si requires M,
279.1656).
N-[1-(Dimethylphenylsilyl)butyl]-N-methyl-2-methoxyprop-
anamide 5c. According to the reported method,25 butanal
was converted to 1-(dimethylphenylsilyl)butanol; δH 0.34 (3 H,
s), 0.35 (3 H, s), 0.91 (3 H, t, J 7.2), 1.30 (2 H, m, containing
J 7.2), 1.52 (3 H, m, containing J 9.6 and 4.2), 3.53 (1 H, dd,
J 9.6 and 4.2), 7.39 (3 H, m), 7.57 (2 H, m); δC Ϫ5.71, Ϫ5.42,
13.83, 19.87, 35.48, 65.15, 127.85, 129.25, 134.09, 136.74; νmax
/
cmϪ1 (liq. film) 3400, 2950, 2940, 1430, 1250, 1110, 830, 820,
780, 730, 700; m/z (CI) (Found: Mϩ, 209.1383. C12H20OSi ϩ H
requires M, 209.1362) (Found: C, 69.06; H, 9.71; C12H20OSi
requires C, 69.17; H, 9.67%).
According to the general procedure, 1-(dimethylphenylsilyl)-
butanol was converted to 5c; δH 0.34 (3 H, s), 0.35 (3 H, s), 0.86
(1.5 H, t, J 7.2), 0.87 (1.5 H, t, J 7.2), 1.16 (1.5 H, d, J 6.6), 1.19
(1.5 H, d, J 6.6), 1.46 (2 H, m, containing J 7.2), 1.73 (2 H, m),
2.84 (1.5 H, s), 2.86 (1.5 H, s), 3.17 (1.5 H, s), 3.19 (1.5 H, s),
4.02 (0.5 H, q, J 6.6), 4.03 (0.5 H, q, J 6.6), 4.09 (1 H, m), 7.33
(3 H, m), 7.53 (2 H, m); δC Ϫ4.27, Ϫ3.93, Ϫ3.81, Ϫ3.55, 13.70,
17.23, 20.57, 20.62, 29.47, 29.59, 33.10, 33.35, 47.59, 48.06,
56.28, 56.39, 76.05, 76.44, 127.65, 128.97, 133.85, 133.88,
137.45, 137.54, 171.20; νmax/cmϪ1 (liq. film) 2950, 2930, 1640,
1400, 1250, 1120, 840, 820, 740, 700; m/z (EI) (Found: Mϩ,
307.1964. C17H29NO2Si requires M, 307.1969) (Found: C,
66.75; H, 9.54; N, 4.51; C17H29NO2Si requires C, 66.40; H, 9.51;
N, 4.55%).
N-[1-(Dimethylphenylsilyl)propyl]tetrahydro-2-furamide 1h.
δH 0.30 (1.5 H, s), 0.32 (3 H, s), 0.33 (1.5 H, s), 0.83 (1.5 H, t,
J 7.2), 0.87 (1.5 H, t, J 7.2), 1.6–2.2 (6 H, m), 3.62 (0.5 H, td,
J 21.3 and 11.1), 3.64 (0.5 H, td, J 21.6 and 10.5), 3.81 (2 H, dd,
J 13.8 and 6.9), 4.33 (1 H, dd, J 8.4 and 5.4), 6.30 (0.5 H, d,
J 10.2), 6.37 (0.5 H, d, J 11.1), 7.36 (3 H, m), 7.49 (2 H, m);
δC Ϫ5.25, Ϫ5.00, Ϫ4.90, Ϫ4.76, 11.98, 23.93, 24.08, 25.38,
30.34, 40.41, 40.73, 69.28, 78.42, 127.84, 129.39, 133.88, 136.00,
172.68, 172.81; νmax/cmϪ1 (liq. film) 3400, 3300, 2950, 2930,
2870, 1660, 1520, 1250, 1070, 840; m/z (EI) (Found: Mϩ,
291.1647. C16H25NO2Si requires M, 292.1656).
N-[1-(Dimethylphenylsilyl)propyl]-N-methyl-2-methoxy-
propanamide 5a. δH 0.34 (3 H, s), 0.35 (3 H, s), 0.84 (1.5 H, t,
J 7.2), 0.85 (1.5 H, t, J 7.2), 1.17 (1.5 H, d, J 6.6), 1.20 (1.5 H, d,
J 6.6), 1.65 (2 H, m, containing J 7.2), 2.85 (1.5 H, s), 2.87 (1.5
H, s), 3.17 (1.5 H, s), 3.19 (1.5 H, s), 3.90 (1 H, m), 4.03 (0.5 H,
q, J 6.6), 4.04 (0.5 H, q, J 6.6), 7.32 (3 H, m), 7.50 (2 H, m);
δC Ϫ3.77, Ϫ3.28, 12.18, 12.29, 17.37, 17.41, 20.39, 20.56, 33.08,
33.38, 49.97, 50.13, 56.43, 56.57, 76.20, 76.59, 127.71, 129.33,
133.89, 137.66, 171.43; νmax/cmϪ1 (liq. film) 2950, 2930, 1810,
1640, 1460, 1430, 1400, 1250, 1120, 840, 820, 730, 700; m/z (EI)
(Found: Mϩ, 293.1812. C16H27NO2Si requires M, 293.1812)
(Found: C, 65.16; H, 9.26; N, 4.73; C16H27NO2Si requires C,
65.48; H, 9.27; N, 4.77%).
N-[1-(Dimethylphenylsilyl)octyl]-N-methyl-2-methoxyprop-
anamide 5d. δH 0.34 (4.5 H, s), 0.35 (1.5 H, s), 0.84 (3 H, t,
J 7.2), 1.16 (3 H, d, J 6.9), 1.20 (10 H, br), 1.51 (1 H, m), 1.69
(1 H, m), 2.84 (1.5 H, s), 2.86 (1.5 H, s), 3.17 (1.5 H, s), 3.19 (1.5
H, s), 4.00 (1 H, m), 4.02 (0.5 H, q, J 6.9), 4.03 (0.5 H, q, J 6.9),
7.33 (3 H, m), 7.53 (2 H, m); δC Ϫ3.90, Ϫ3.76, Ϫ3.35, Ϫ3.27,
13.99, 17.30, 17.35, 22.53, 27.24, 27.40, 29.13, 29.20, 31.71,
33.38, 35.96, 47.86, 56.34, 56.51, 76.52, 127.68, 129.02, 133.93,
137.61, 171.19; νmax/cmϪ1 (liq. film) 2920, 2850, 1640, 1460,
1400, 1250, 1120, 840, 820, 740, 700; m/z (EI) (Found: Mϩ,
363.2593. C21H37NO2Si requires M, 363.2595) (Found: C,
69.05; H, 10.19; N, 3.73; C21H37NO2Si requires C, 69.37; H,
10.26; N, 3.85%).
N-[1-(Dimethylphenylsilyl)propyl]-N-methyl-2-(2,2,2-tri-
fluoroethoxy)propanamide 5b. 2,2,2-Trifluoroethanol (16.4 g,
0.163 mol) and 2-bromopropanoic acid (12.5 g, 81.7 mmol)
were added dropwise into a suspended solution of sodium
hydride (60% in oil, 6.5 g, 0.164 mol) in tetrahydrofuran (50
cm3) at 0 ЊC under an Ar atmosphere and the solution was
refluxed for 2 h. The solvent was removed, water (30 cm3) was
added to the residue, the mixture was acidified to pH 3 with
conc. hydrochloric acid, the aqueous solution was extracted
with ether (3 × 30 cm3), the organic extracts were combined and
dried over MgSO4. After removing ether, the residue was dis-
tilled to afford 2-(2,2,2-trifluoroethoxy)propanoic acid; bp
103 ЊC/15 mmHg; δH 1.35 (3 H, d, J 6.9), 3.80 (1 H, dd, J 12.3
and 8.4), 4.09 (1 H, dd, J 12.3 and 8.4), 4.21 (1 H, q, J 6.9),
N-[1-(Dimethylphenylsilyl)propyl]-N-methyltetrahydro-2-
furamide 5e. δH 0.32 (1.5 H, s), 0.33 (1.5 H, s), 0.35 (3 H, s), 0.82
(1.5 H, t, J 7.2), 0.84 (1.5 H, t, J 7.2), 1.50–1.73 (3 H, m), 1.76–
2.05 (4 H, m), 2.81 (1.5 H, s), 2.85 (1.5 H, s), 3.83 (2 H, m,
containing J 5.7), 3.93 (0.5 H, dd, J 12.9 and 6.6), 4.06 (0.5 H,
dd, J 11.4 and 4.5), 4.57 (1 H, dd, J 7.8 and 3.9), 7.34 (3 H,
m), 7.51 (2 H, m); δC Ϫ3.96, Ϫ3.80, Ϫ3.62, 12.13, 12.30,
20.45, 20.62, 25.43, 25.59, 28.67, 28.77, 33.05, 33.81, 48.94,
50.18, 50.35, 68.53, 68.89, 75.71, 75.95, 127.62, 127.71, 128.95,
129.09, 133.86, 133.93, 134.00, 171.50; νmax/cmϪ1 (liq. film)
2950, 2930, 2860, 1640, 1430, 1300, 1250, 1110, 1060, 830,
700; m/z (EI) (Found: Mϩ, 305.1814. C17H27NO2Si requires M,
305.1812).
3386
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388

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N-[1-(Dimethylphenylsilyl)propyl]-N,2-dimethylbutanamide
8a. δH 0.31 (1 H, s), 0.32 (1 H, s), 0.33 (1 H, s), 0.34 (1 H, s), 0.35
(1 H, s), 0.36 (1 H, s), 0.82 (3 H, t, J 7.2), 0.99 (1.5 H, t, J 5.4),
1.00 (1.5 H, t, J 4.8), 1.32 (1 H, m, containing J 7.2), 1.49–1.72
(3 H, m, containing J 7.2), 2.52 (1 H, m, containing J 7.2), 2.80
(1.5 H, s), 2.84 (1.5 H, s), 3.91 (0.5 H, dd, J 11.1 and 3.6), 4.16
(0.5 H, dd, J 11.1 and 4.5), 7.34 (3 H, m), 7.52 (2 H, m); δC
Ϫ5.57, Ϫ5.38, Ϫ3.76, Ϫ3.66, Ϫ3.52, Ϫ3.41, 12.09, 12.21, 17.26,
17.42, 20.57, 20.57, 26.46, 27.03, 27.22, 36.63, 36.79, 67.21,
127.69, 129.00, 133.92, 136.87, 176.12; νmax/cmϪ1 (liq. film)
2950, 2930, 2860, 1630, 1460, 1400, 1250, 1110, 830, 770, 730,
700; m/z (CI) (Found: Mϩ, 292.2090. C17H29NOSi ϩ H requires
M, 292.2098).
30.42, 55.60, 55.73, 69.37, 78.13, 78.27, 81.72, 173.81; νmax/cmϪ1
(liq. film) 3400, 3300, 2960, 2930, 2870, 1670, 1510, 1080.
N-[1-(2,2,2-Trifluoroethoxy)propyl]-2-methoxypropanamide
4b. δH 0.95 (1.5 H, t, J 7.5), 0.97 (1.5 H, t, J 7.5), 1.36 (1.5 H, d,
J 6.3), 1.37 (1.5 H, J 6.6), 1.62 (1 H, qd, J 7.5 and 6.6), 1.78
(1 H, qd, J 7.5 and 6.6), 3.38 (1.5 H, s), 3.40 (1.5 H, s), 3.79
(1 H, q, J 6.6), 3.95 (2 H, m), 5.18 (0.5 H, t, J 6.6), 5.22 (0.5 H, t,
J 6.6), 6.90 (1 H, br s); δC 8.93, 17.67, 17.84, 28.19, 57.27, 57.38,
65.89 (q, J 35.5), 66.09 (q, J 33.9), 77.87, 81.40, 81.67, 123.73 (q,
J 275.7), 174.03; νmax/cmϪ1 (liq. film) 3400, 3300, 2980, 2940,
2830, 1680, 1510, 1460, 1280, 1160, 1120, 1100, 980.
N-[1-(2,2,2-Trifluoroethoxy)butyl]-2-(2,2,2-trifluoroethoxy)-
propanamide 4c. δH 0.93 (3 H, t, J 7.4), 1.44 (1.5 H, d, J 6.9),
1.47 (1.5 H, d, J 6.9), 1.3–1.8 (4 H, m), 3.8–4.3 (5 H, m), 5.28
(0.5 H, td, J 9.9 and 3.0), 5.29 (0.5 H, td, J 9.9 and 3.0), 6.81
(0.5 H, br d, J 9.9), 6.84 (0.5 H, br d, J 9.9); δC 13.41, 17.43,
18.09, 36.96, 66.10 (q, J 34.6), 67.17 (q, J 34.4), 78.13, 80.32,
80.56, 123.32 (q, J 279.9), 123.70 (q, J 276.7), 172.18, 172.34;
νmax/cmϪ1 (liq. film) 3300, 2960, 2940, 2880, 1680, 1520, 1280,
1170, 970; m/z (EI) (Found: Mϩ, 324.0956. C11H17NO3F6 Ϫ H
requires M, 324.1035).
Electrolysis of lactamide derivatives: typical procedures
Method (a).12 In methanol. A solution of lactamide derivative
(0.7 mmol) and the supporting electrolyte (0.2 mmol) in
methanol (4 cm3) was placed in an undivided cell equipped with
a carbon rod anode (i.d. 0.5 cm) and a platinum plate cathode
(2 × 1 cm2). Constant current (20 mA) was passed at room tem-
perature. After the electricity shown in the equations or Tables
was consumed, the reaction mixture was partitioned between
brine and ether. The ether layer was separated and dried over
MgSO4. After evaporation of the solvent, the crude product
was purified via flash column chromatography (eluent: ethyl
acetate–hexane) to obtain the product.
N-(1-Methoxypropyl)-N-methyl-2-methoxypropanamide 6a.
δH 0.85 (1.4 H, t, J 7.5), 0.85 (1.6 H, t, J 7.5), 1.38 (1.6 H, d,
J 6.6), 1.40 (1.4 H, d, J 6.6), 1.45–1.60 (1 H, m), 1.60–1.80 (1 H,
m), 2.86 (3 H, s), 3.21 (1.4 H, s), 3.22 (1.6 H, s), 4.15 (q, J 6.6)
and 4.17 (q, J 6.6)(1 H), 4.90 (0.2 H, t, J 5.4), 4.92 (0.2 H, t,
J 5.7), 5.57 (0.3 H, t, J 6.6), 5.59 (0.3 H, t, J 6.6); δC 8.98, 9.58,
17.03, 17.21, 25.07, 55.36, 56.47, 75.14, 75.45, 77.01, 77.44,
85.35, 85.56, 88.21, 88.56, 173.08; νmax/cmϪ1 (liq. film) 2880,
2840, 1660, 1460, 1120, 1090, 1060; m/z (EI) (Found: Mϩ,
189.1373. C9H19NO3 requires M, 189.1365).
Method (b).17a In dichloromethane or acetonitrile. A solution
of lactamide derivative (0.7 mmol), alcohol (7.0 mmol) and the
supporting electrolyte (0.2 mmol) in dichloromethane or
acetonitrile (4 cm3) was placed in an undivided cell equipped
with a platinum plate anode (2 × 1 cm2) and a platinum plate
cathode (2 × 1 cm2). Electrolysis and work-up were carried out
in a similar way to that for Method (a). Yields and diastereomer
ratios of the products are shown in the equations or Tables.
N-(1-Methoxypropyl)-N-methyl-2-(2,2,2-trifluoroethoxy)-
propanamide 6b. δH 0.84 (1.5 H, t, J 7.2), 0.86 (1.5 H, t, J 7.5),
1.45 (1.5 H, d, J 6.6), 1.47 (1.5 H, J 6.6), 1.51 (1 H, m), 1.68
(1 H, m), 2.84 (3 H, s), 3.20 (1.5 H, s), 3.22 (1.5 H, s), 3.71 (2 H,
m), 3.94 (2 H, m), 4.48 (1 H, q, J 6.6), 5.54 (0.5 H, t, J 6.9), 5.56
(0.5 H, t, J 6.6); δC 8.82, 16.78, 17.01, 25.02, 26.19, 26.59, 54.83,
55.34, 65.66 (q, J 32.7), 74.08, 74.81, 85.53, 85.72, 88.52, 123.70
(q, J 274.2), 171.61; νmax/cmϪ1 (liq. film) 2970, 2940, 2880, 2830,
1660, 1460, 1410, 1280, 1160, 1140, 1060, 960; m/z (EI) (Found:
Mϩ, 257.1244. C10H18NO3F3 requires M, 257.1239).
N-Ethyl-2-methoxypropanamide 1e. δH 1.13 (1.5 H, t, J 7.4),
1.13 (1.5 H, t, J 7.4), 1.33 (1.5 H, d, J 6.6), 1.34 (1.5 H, d, J 6.6),
3.28 (1 H, q, J 7.4), 3.28 (1 H, q, J 7.4), 3.35 (1.5 H, s), 3.36
(1.5 H, s), 3.69 (0.5 H, q, J 6.6), 3.70 (0.5 H, q, J 6.6), 6.52 (1 H,
br s); δC 14.74, 17.93, 33.62, 57.32, 78.15, 172.85; νmax/cmϪ1
(liq. film) 3300, 2980, 2940, 1660, 1530, 1450, 1120.
N-(1-Methoxypropyl)-2-methoxypropanamide 3b. δH 0.90
(1.5 H, t, J 6.9), 0.92 (1.5 H, t, J 6.9), 1.35 (1.5 H, d, J 6.6), 1.40
(1.5 H, d, J 6.6), 1.54 (1 H, m, containing J 6.9 and 6.0), 1.69 (1
H, m, containing J 6.9 and 6.0), 3.29 (1.5 H, s), 3.32 (1.5 H, s),
3.37 (1.5 H, s), 3.39 (1.5 H, s), 3.74 (0.5 H, q, J 6.6), 3.76 (0.5 H,
q, J 6.6), 5.01 (1 H, td, J 10.5 and 6.0), 6.64 (1 H, br d, J 6.0);
δC 8.91, 18.15, 18.24, 28.45, 55.56, 55.83, 57.35, 57.53, 77.93,
78.07, 81.62, 81.88, 173.76; νmax/cmϪ1 (liq. film) 3300, 2970,
2940, 2830, 1670, 1520, 1460, 1370, 1200, 1120, 1030; m/z (CI)
(Found: Mϩ, 176.1270. C8H17NO3 ϩ H requires M, 176.1287).
N-(1-Methoxypropyl)-N-methyltetrahydro-2-furamide 6e. δH
0.83 (1.4 H, t, J 7.2), 0.84 (1.6 H, t, J 7.5), 1.40–1.80 (2 H,
m), 1.80–2.20 (4 H, m) 2.84 (1.6 H, s), 2.85 (1.4 H, s), 3.19
(1.6 H, s), 3.20 (1.4 H, s), 3.89 (2 H, m), 4.65 (1 H, m), 5.03
(0.2 H, t, J 6.6), 5.04 (0.2 H, t, J 6.6), 5.53 (0.3 H, t, J 6.9), 5.54
(0.3 H, J 6.9); δC 8.96, 9.03, 9.35, 9.49, 25.14, 25.19, 25.56,
25.79, 26.51, 26.64, 28.12, 28.67, 28.90, 54.88, 55.40, 68.72,
68.92, 69.07, 75.61, 75.95, 76.04, 85.29, 85.49, 88.26, 88.90,
171.76, 173.31; νmax/cmϪ1 (liq. film) 2970, 2940, 2880, 1650,
1450, 1410, 1300, 1140, 1080, 1060, 920; m/z (EI) (Found: Mϩ,
201.1369. C10H19NO3 requires M, 201.1366).
N-(1-Methoxyoctyl)-2-methoxypropanamide 3f. δH 0.86 (3 H,
t, J 6.3), 1.36 (3 H, d, J 6.9), 1.20–1.44 (10 H, br), 1.52 (1 H, m),
1.68 (1 H, m), 3.29 (1.5 H, s), 3.33 (1.5 H, s), 3.37 (1.5 H, s), 3.40
(1.5 H, s), 3.74 (0.5 H, q, J 6.9), 3.78 (0.5 H, q, J 6.9), 5.07 (1 H,
dt, J 9.3 and 6.3), 6.67 (1 H, br t, J 9.3); δC 13.70, 18.13, 22.52,
24.70, 29.06, 29.14, 31.63, 35.44, 55.83, 57.58, 78.09, 80.75,
173.55; νmax/cmϪ1 (liq. film) 3300, 2930, 2850, 1680, 1520, 1460,
1120, 1060; m/z (EI) (Found: Mϩ, 230.1753. C13H27NO3 Ϫ CH3
requires M, 230.1757).
N-Methyl-N-[1-(2,2,2-trifluoroethoxy)propyl]-2-methoxy-
propanamide 7a. δH 0.87 (t, J 7.2) and 0.88 (t, J 7.5)(3 H), 1.37
(1.1 H, d, J 6.6), 1.39 (1.9 H, d, J 6.6), 1.56 (1 H, m, containing
J 7.5 and 7.2), 1.77 (1 H, m, containing J 7.5 and 7.2), 2.89
(1.1 H, s), 2.90 (1.9 H, s), 3.31 (1.9 H, s), 3.33 (1.1 H, s), 3.77
(2 H, m), 4.14 (0.4 H, d, J 6.6), 4.15 (0.6 H, d, J 6.6), 5.78 (0.6
H, t, J 6.9), 5.79 (0.4 H, t, J 6.9); δC 8.92, 16.79, 16.89, 24.94,
26.47, 26.72, 56.36, 56.56, 65.58 (q, J 33.8), 75.99, 76.12, 85.23,
85.36, 129.52 (q, J 273.7), 173.51; νmax/cmϪ1 (liq. film) 2980,
2950, 2830, 1660, 1460, 1410, 1380, 1280, 1210, 1160, 1110, 980;
m/z (CI) (Found: Mϩ, 258.1306. C10H18NO3F3 ϩ H requires M,
258.1312).
N-(1-Methoxypropyl)tetrahydro-2-furamide 3h. δH 0.87 (1.5 H,
t, J 7.2), 0.90 (1.5 H, t, J 7.2), 1.5–2.2 (6 H, m), 3.27 (1.5 H, s),
3.29 (1.5 H, s), 3.89 (2 H, m), 4.32 (0.5 H, dd, J 8.3 and 5.7),
4.37 (0.5 H, dd, J 8.4 and 5.7), 4.96 (0.5 H, t, J 6.0), 4.99 (0.5 H,
t, J 6.0), 6.79 (1 H, br s); δC 8.94, 25.40, 28.37, 28.53, 30.19,
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388
3387

View Article Online
Y. Yanagisawa, F. Kurashima, J. Anzai, T. Osa and J. M. Bobbitt,
Chem. Commun., 1996, 2745.
3 S. Torii, H. Tanaka, M. Sasaoka, Y. Kameyama and R. Kikuchi, Jap
P 09249984 [97249984], Appl. 85834/1996 (Chem. Abstr., 1997, 127,
312464).
4 K. Danielmeier, K. Schierle and E. Steckhan, Tetrahedron, 1996, 52,
9743.
5 T. Fuchigami, Proceedings of the 21th Electroorganic Chemistry
Symposium, Nagasaki, 1997, p. 33.
6 (a) H. Lund and P. Iversen, in Organic Electrochemistry, ed. M. M.
Baizer, Dekker, New York, 1973, p. 200; (b) N. L. Weinberg, in
Technique of Electroorganic Synthesis Part I, ed. N. L. Weinberg,
Wiley-Interscience, New York, 1974, p. 12.
N-Methyl-N-[1-(2,2,2-trifluoroethoxy)propyl]-2-(2,2,2-tri-
fluoroethoxy)propanamide 7b. δH 0.87 (1.6 H, t, J 7.2), 0.89
(1.4 H, t, J 7.5), 1.45 (1.6 H, d, J 6.9), 1.46 (1.4 H, d, J 6.9),
1.50–1.70 (1 H, m), 1.75–1.90 (1 H, m), 2.90 (3 H, s), 3.60–4.00
(4 H, m), 4.48 (1 H, q, J 6.9), 5.76 (0.6 H, t, J 6.9), 5.77 (0.4 H, t,
J 6.9); δC 8.86, 16.70, 16.85, 24.96, 26.76, 65.68 (q, J 35.6), 65.92
(q, J 36.8), 74.81, 75.10, 85.49, 123.62 (q, J 275.9), 127.35 (q,
J 285.1), 172.22; νmax/cmϪ1 (liq. film) 2970, 2940, 1660, 1460,
1410, 1280, 1160, 970; m/z (EI) (Found: Mϩ, 325.1092. C11H17-
NO3F6 requires M, 325.1113).
N-Methyl-N-[1-(2,2,2-trifluoroethoxy)butyl]-2-methoxyprop-
anamide 7c. δH 0.91 (t, J 6.9) and 0.92 (t, J 6.9)(3 H), 1.37 (d,
J 6.6) and 1.38 (d, J 6.6)(3 H), 1.52 (2 H, m), 1.74 (2 H, m), 2.90
(s) and 2.91 (s)(3 H), 3.31 (1.8 H, s), 3.33 (1.2 H, s), 3.77 (2 H,
m), 4.14 (q, J 6.6) and 4.15 (q, J 6.6)(1 H), 5.87 (1 H, J 6.9);
δC 13.55, 16.83, 17.96, 18.06, 26.79, 33.81, 56.34, 56.57, 65.47
(q, J 33.9), 75.93, 76.06, 83.92, 127.25 (q, J 265.2), 173.33,
173.53; νmax/cmϪ1 (liq. film) 2960, 2940, 2880, 2820, 1660, 1460,
1410, 1380, 1280, 1210, 1160, 1110, 1080, 980; m/z (CI) (Found:
Mϩ, 272.1468. C11H20NO3F3 ϩ H requires M, 272.1474).
7 (a) T. Shono, in Comprehensive Organic Synthesis, Vol. 7, ed. B. M.
Trost and I. Fleming, Pergamon Press, Oxford, 1991, p. 789; (b)
T. Shono, Tetrahedron, 1984, 40, 811; (c) T. Shono, Electroorganic
Synthesis, Academic Press, London, 1990; (d) T. Shono, Top. Curr.
Chem., 1988, 148, 131.
8 (a) T. Shono, H. Hamaguchi and Y. Matsumura, J. Am. Chem. Soc.,
1975, 97, 4264; (b) T. Shono, Y. Matsumura and K. Tsubata, J. Am.
Chem. Soc., 1981, 103, 1172; (c) T. Shono, Y. Matsumura and
K. Tsubata, Tetrahedron Lett., 1981, 22, 2411; (d) T. Shono,
Y. Matsumura and K. Tsubata, Tetrahedron Lett., 1981, 22, 3249; (e)
T. Shono, Y. Matsumura, K. Tsubata and J. Takata, Chem. Lett.,
1981, 1121; ( f ) T. Shono, Y. Matsumura, K. Tsubata, Y. Sugihara,
S. Yamane, T. Kanazawa and T. Aoki, J. Am. Chem. Soc., 1982, 104,
6697.
9 (a) B. Seuring and D. Seebach, Helv. Chim. Acta, 1977, 60, 1175;
(b) D. Seebach and R. Naef, Helv. Chim. Acta, 1981, 64, 2704; (c)
D. Seebach, R. Naef and G. Calderari, Tetrahedron, 1984, 40,
1313; (d) J. Mattay, J. Mertes and G. Mass, Ber., 1989, 122, 327;
(e) M. Hirama, I. Nishizaki, T. Shigemoto and S. Ito, J. Chem.
Soc., Chem. Commun., 1986, 393; ( f ) G. Cainelli, M. Panunzio,
D. Giacomini, G. Martelli and G. Spunta, J. Am. Chem. Soc., 1988,
110, 6879.
N-Methyl-N-[1-(2,2,2-trifluoroethoxy)octyl]-2-methoxyprop-
anamide 7d. δH 0.85 (3 H, t, J 6.3), 1.15–1.30 (10 H, br), 1.37
(0.9 H, d, J 6.6), 1.38 (2.1 H, d, J 6.6), 1.54 (1 H, m), 1.77 (1 H,
m), 2.90 (2.1 H, s) and 2.91 (0.9 H, s), 3.31 (2.1 H, s), 3.33 (0.9
H, s), 3.76 (2 H, m), 4.14 (0.3 H, q, J 6.6), 4.15 (0.7 H, q, J 6.6),
5.85 (1 H, t, J 6.9); δC 13.94, 16.79, 16.91, 22.50, 24.61, 24.69,
26.80, 29.01, 29.13, 31.60, 31.79, 56.36, 56.57, 65.52 (q, J 33.5),
76.02, 76.13, 84.09, 84.21, 123.63 (q, J 276.5), 173.35, 173.52;
νmax/cmϪ1 (liq. film) 2930, 2900, 1660, 1460, 1410, 1370, 1280,
1160, 1110, 1080, 980; m/z (EI) (Found: Mϩ, 327.1988. C15H28-
NO3F3 requires M, 327.2022).
10 O. Onomura, Ph.D. Thesis, Kyoto University, 1988.
11 T. Kamada, Ge-Qing, M. Abe and A. Oku, J. Chem. Soc., Perkin
Trans. 1, 1996, 413.
12 T. Shono, Y. Matsumura and K. Tsubata, Org. Synth., 1990, Coll.
Vol. 7, 307.
N-Methyl-N-[1-(2,2,2-trifluoroethoxy)propyl]tetrahydro-2-
furamide 7e. δH 0.87 (1.9 H, t, J 7.5), 0.88 (1.1 H, t, J 7.5), 1.50–
2.20 (6 H, m), 2.76 (0.6 H, s), 2.77 (0.4 H, s), 2.89 (0.7 H, s), 2.90
(1.3 H, s), 3.65–3.84 (2 H, m), 3.84–4.05 (2 H, m), 4.48 (0.4 H,
dd, J 6.3 and 6.0), 4.53 (0.6 H, dd, J 6.6 and 6.0), 4.64 (0.7 H,
dd, J 8.1 and 6.0), 4.66 (1.3 H, dd, J 8.8 and 5.7), 5.36 (0.4 H, t,
J 6.9), 5.38 (0.6 H, t, J 6.9), 5.74 (0.7 H, t, J 6.9), 5.75 (1.3 H,
t, J 6.9); δC 8.97, 8.91, 9.23, 24.97, 25.56, 26.27, 26.91, 28.63,
65.28 (q, J 33.75), 68.73, 68.85, 69.08, 69.16, 75.86, 76.09,
84.95, 85.30, 123.73 (q, J 277.05), 173.63; νmax/cmϪ1 2960, 2880,
1660, 1440, 1410, 1280, 1150, 1090, 1060, 970; m/z (EI) (Found:
Mϩ. 269.1248. C11H18NO3F3 requires M, 269.1239).
13 E. A. Mayeda, J. Am. Chem. Soc., 1975, 97, 4012.
14 (a) L. L. Miller, V. K. Koch, M. E. Larsheid and J. F. Wolf,
Tetrahedron Lett., 1971, 1389; (b) S. Torii, R. Oi and T. Inokuchi,
presented at the 41th Annual Meeting of the Chemical Society of
Japan, 3K33, 1980.
15 (a) T. Shono and Y. Matsumura, J. Am. Chem. Soc., 1969, 91, 2803;
(b) S. D. Ross, J. E. Barry, M. Finkelstein and E. J. Rudd, J. Am.
Chem. Soc., 1973, 95, 2193; (c) A. I. Kirsanova and M. G. Smirnova,
Electrokhimiya, 1978, 14, 627.
16 Y. Matsumura, T. Tomita, M. Sudoh and N. Kise, Tetrahedron Lett.,
1994, 35, 1271.
17 (a) J. Yoshida and S. Isoe, Tetrahedron Lett., 1987, 28, 6621; (b)
J. Yoshida, Y. Ishichi and S. Isoe, J. Am. Chem. Soc., 1992, 114,
7594; (c) J. Yoshida, M. Itoh and S. Isoe, J. Chem. Soc., Chem.
Commun., 1993, 547; (d) J. Yoshida, M. Itoh, Y. Morita and S. Isoe,
J. Chem. Soc., Chem. Commun., 1994, 549.
18 Independently, we tried to separate the diastereomers of 7a to
determine their configuration but the isomer separation was
unsuccessful.
19 D. D. Perrin, L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, 2nd edn., Pergamon Press, Oxford, 1990.
20 R. Kluger, J. F. Chow and J. J. Croke, J. Am. Chem. Soc., 1984, 106,
4017.
21 R. Munz and G. Simchen, Liebigs Ann. Chem., 1979, 628.
22 B. Koppenhoefer, E. M. Eckhard, G. J. Nicholson and E. Bayer,
J. Chromatogr., 1987, 406, 157.
23 R. C. Fuson and B. H. Wojcik, Org. Synth., 1943, Coll. Vol. 2, 260.
24 E. Koch, G. J. Nicholson and E. Bayer, J. High Resolut.
Chromatogr., Chromatogr. Commun., 1984, 7, 398.
N-[(1-Methoxy)propyl]-N,2-dimethylbutanamide 9a. δH 0.83
(1.5 H, t J 7.5), 0.87 (1.5 H, t, J 7.2), 0.88 (1.5 H, t, J 7.5), 0.90
(1.5 H, t, J 7.2), 1.09 (0.5 H, d, J 6.9), 1.10 (1 H, d, J 12.0), 1.13
(1 H, d, J 12.3), 1.15 (0.5 H, d, J 6.6), 1.30–1.60 (2 H, m), 1.60–
1.80 (2 H, m), 2.63 (1 H, m), 2.74 (1 H, s), 2.81 (1 H, s), 2.81
(1 H, s), 3.19 (1 H, s), 3.19 (1 H, s), 3.21 (0.5 H, s), 3.22 (0.5 H,
s), 4.83 (0.3 H, dd, J 12.0 and 6.6), 5.61 (0.7 H, dd, J 13.2 and
6.2); δC 9.06, 11.93, 12.06, 17.27, 17.40, 25.33, 25.40, 26.82,
26.94, 38.30, 38.41, 55.24, 55.30, 84.91, 85.11, 88.84, 89.11,
178.04; νmax/cmϪ1 (liq. film) 2960, 2930, 2870, 2820, 1640, 1460,
1400, 1300, 1140, 1110, 1080, 1060, 940; m/z (EI) (Found: Mϩ.
187.1567. C10H21NO2 requires M, 187.1573).
25 J. Yoshida, T. Maekawa, T. Murata, S. Matsunaga and S. Isoe,
J. Am. Chem. Soc., 1990, 112, 1962.
26 R. K. Crossland and K. Servis, J. Org. Chem., 1970, 35, 3195.
27 T. Purdie and J. C. Irvine, J. Chem. Soc., 1899, 75, 483.
28 J. R. Beck, R. Kwok, R. N. Booher, A. C. Brown, L. E. Patterson,
P. Pranc, B. Rockey and A. Pohland, J. Am. Chem. Soc., 1968, 90,
4706.
29 C. H. Wong, Y. Fong, W. J. Hennen and K. A. Babiak, Eur. Pat.
Appl. EP357009 (Cl. C12P41/00) 07 Mar 1990 (Chem. Abstr., 1991,
114, 5485).
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3388
J. Chem. Soc., Perkin Trans. 1, 1998, 3381–3388