Reductive monoalkylation of nitro aryls in one-pot

Article abstract of DOI:10.1016/j.tet.2008.04.077

The scope of the serendipitous reductive monoalkylation of ethyl (4-methoxy-3-nitrophenyl) acetate taking place during reduction of the nitro functionality to the corresponding primary amine when treated with hydrogen (1 atm) over Pd/C (10%) in ethanol is investigated. Upon prolonged reaction time the reaction conducted in ethanol and methanol yields significant amount of the corresponding secondary amines, while when performed in n-butanol and i-propanol it only resulted in the formation of a small amount of the corresponding secondary amines. Further development of the reductive monoalkylation reaction provided conditions that facilitate conversion of a range of different nitro aryls in one-pot to the corresponding secondary benzyl amino aryls in mostly good to excellent yields. This is accomplished by using hydrogen (1 atm) over Pd/C (10%) as reducing agent and benzaldehyde as the benzyl source combined with a stepwise reaction sequence. This chemistry was further extended to the formation of substituted benzyl amino aryls. The yields of the latter products varied dramatically depending on the substitution patterns associated with the benzaldehyde. However, by altering the reaction conditions it was possible to improve the yields of the benzylated products.

Full text of DOI:10.1016/j.tet.2008.04.077

Tetrahedron 64 (2008) 6406–6414
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reductive monoalkylation of nitro aryls in one-pot
,
b
a,c
Magne O. Sydnes a , Masaki Kuse , Minoru Isobe
*
a Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan
b Chemical Instrument Division, RCMS, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
c Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2008
Received in revised form 21 April 2008
Accepted 21 April 2008
Available online 24 April 2008
The scope of the serendipitous reductive monoalkylation of ethyl (4-methoxy-3-nitrophenyl) acetate
taking place during reduction of the nitro functionality to the corresponding primary amine when
treated with hydrogen (1 atm) over Pd/C (10%) in ethanol is investigated. Upon prolonged reaction time
the reaction conducted in ethanol and methanol yields significant amount of the corresponding
secondary amines, while when performed in n-butanol and i-propanol it only resulted in the formation
of a small amount of the corresponding secondary amines. Further development of the reductive
monoalkylation reaction provided conditions that facilitate conversion of a range of different nitro aryls
in one-pot to the corresponding secondary benzyl amino aryls in mostly good to excellent yields. This is
accomplished by using hydrogen (1 atm) over Pd/C (10%) as reducing agent and benzaldehyde as the
benzyl source combined with a stepwise reaction sequence. This chemistry was further extended to the
formation of substituted benzyl amino aryls. The yields of the latter products varied dramatically
depending on the substitution patterns associated with the benzaldehyde. However, by altering the
reaction conditions it was possible to improve the yields of the benzylated products.
Keywords:
One-pot
Nitro aryls
Reductive monoalkylation
Benzylation
Pd/C
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
munication we reported a simple one-pot procedure for reductive
monoalkylation of nitro aryls using aliphatic aldehydes as alkyl
One-pot reactions, where several steps are performed in the
same reaction vessel, are gaining popularity as we strive towards
conducting our profession in a more sustainable fashion.1 De-
velopment of such reactions is therefore of paramount importance
as chemists aim at minimizing reagent and solvent use, as well as
reducing isolation steps.
source and H2 (1 atm) over Pd/C (10%) as reducing agent (Scheme
1).6,7 This procedure afforded exclusively the secondary amines
even when excess amount of aldehyde was used. Herein we report
on the further development of this chemistry for the synthesis of
benzyl protected aryl amines and substituted benzyl aryl amines.
Compounds containing a nitro group are valuable substrates in
organic synthesis.2 In particular, nitro aryls are important due to
their ready formation from a range of aromatic starting materials3
and their easy conversion to aromatic amines.4 Primary aryl amines
are in its place vital starting materials for numerous products of
great importance, such as pharmaceuticals.5 Often these aryl amines
are taken through severalsteps wherethe use of protection groups is
essential in order to secure the desired outcome. In a recent com-
2. Results and discussion
2.1. Solvent effects
Recently we reported that secondary amine 4a was formed in
a reasonable yield (41%) together with the desired primary amine
2a (47%) when the reduction of nitro aryl 1a was run for a pro-
longed period of time (48 h) in ethanol (Scheme 1).6 However, upon
H2, Pd/C (10%),
R1
R1
R1
R1
R3CHO, EtOH, rt
R3
NHR4
2R
2R
2R
2R
NO2
NH2
N
1
2
3
4
Scheme 1. General outline of the one-pot reductive monoalkylation reaction (intermediates are shown; amine 2 and imine 3).
* Corresponding author. Tel.: þ81 52 789 4186.
E-mail address: sydnes@nuagr1.agr.nagoya-u.ac.jp (M.O. Sydnes).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.077

M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
6407
H2, Pd/C (10%),
EtOH/H2O (9:1),
rt, 3 h
H2, Pd/C(10%),
OMe
OMe
OMe
NH2
OMe
NH2
EtOH, rt, 48h
+
EtO2C
EtO2C
EtO2C
EtO2C
NO2
NHEt
2a 86%
2a 47%
4a 41%
1a
Scheme 2. Formation of secondary amine 4a during reduction of nitro aryl 1a under an atmosphere of H2 over Pd/C (10%) in ethanol.
modification of the reaction conditions, adding small amounts of
water to the solvent (ethanol/water 9:1) and stirring for 3 h
(Scheme 2) or reducing the reaction time to 1 h (reaction condi-
tions not shown in Scheme 2), we were able to obtain compound 2a
cleanly in good yield.8
operating in order to generate acetaldehyde.6 This mechanism is
based on the proposal put forward by Sajiki et al.10 in order to ex-
plain the formation of ketones (in some examples in good yield)
from secondary alcohols when treated under an atmosphere of
hydrogen over Pd/C (10%) in D2O at elevated temperature (reflux)
over a 24 h period. Acetaldehyde thus formed might then react
further with 2 equiv of ethanol forming the corresponding acetal,11
or react with the primary amine giving rise to the corresponding
imine. However, due to the slight acidity of Pd/C12 the equilibrium
between acetaldehyde and the acetal is most likely situated
towards the left, thus favouring the aldehyde. It is also possible that
the reaction outlined in Eq. 2 (Scheme 3) is operating together with
the mechanism depicted in Eq. 1 (Scheme 3). The latter mechanism
would be a palladium variation of the combination of a Meerwein–
Ponndorf–Verlay reduction and Oppenauer oxidation.13
In an attempt to verify the extent of the formation of acetalde-
hyde and/or the corresponding acetal we stirred a mixture of Pd/C
(10%) in ethanol under an atmosphere of hydrogen at room tem-
perature for 5 days. The filtered reaction mixture14 was then sub-
jected to GC–MS analysis, however, this analysis failed to reveal the
formation of acetaldehyde or the corresponding acetal. This finding
verifies our previous speculation that the aldehyde is formed in
extremely small quantities and that the first equilibrium in Scheme
3, Eq. 1 is orientated far to the left. However, in the presence of
a primary amine, which removes acetaldehyde from the reaction
mixture, the two first equilibriums depicted (Scheme 3, Eq. 1) are
slowly driven towards the right.
We found the aforementioned formation of compound 4a in-
triguing, in particular due to the fact that the corresponding tertiary
amine was not formed under these conditions. This prompted us to
conduct a few experiments in order to verify if it would be possible
to obtain alkyl amine 4a in a synthetic useful yield via this method.
The efforts directed towards this end are summarized in Table 1.
Indeed, by leaving the reaction for 5 days at room temperature
improved the ratio of compounds 2a/4a to 1:3 (Table 1, entry 1),
thus approaching a useful conversion. However, the reaction time
exceeded by far what would be regarded as synthetically useful.
Heating the reaction mixture at 50 ꢀC (entry 2) did not improve
matters; the reaction mixture was now contaminated by small
amounts of unidentified byproducts, which increased in concentra-
tion upon prolonged heating. In addition, the ratio between amines
2a/4a did not seem to improve (2a/4a¼65:35) compared to entry 1
when the reaction was conducted at room temperature. Doubling
the amount of catalyst (entry 3) or utilizing Pd/alumina (10%) as
catalyst (entry 4) gave the same outcome as obtained in entry 1.
As we previously concluded, the alkylation agent under these
conditions is acetaldehyde, which is formed in a small amount from
ethanol during the course of the reaction (Scheme 3).6,9 We pre-
viously proposed that the mechanism outlined in Scheme 3, Eq. 1 is
We then became interested in testing if a similar oxidation/
alkylation reaction would occur when the reaction was conducted
in other alcohols such as methanol, n-butanol, i-propanol and 2,2,2-
trifluoroethanol. When the reaction was performed in methanol it
resulted in the formation of the corresponding secondary amine in
moderate yield after 5 days (Table 1, entry 5). However, in n-butanol
(entry 6) and i-propanol (entry 7) only small amounts of com-
pounds 4c and 4d could be detected by crude 1H NMR analysis,
while 2,2,2-trifluoroethanol (entry 8) resulted in clean conversion
of the nitro aryl to the primary amine 2a. Even after prolonged
reaction time (5 days) no trace of the corresponding secondary
amine could be detected (TLC and 1H NMR analyses). It is also worth
noting that no trans-esterification was observed in these
experiments.
Table 1
Solvent and reaction condition survey conducted with nitro aryl 1a as starting
material
Entry Solvent
Time (days) Temperature (ꢀC) R4a (compound) 2a/4b
1
2
EtOH
EtOH
EtOH
EtOH
MeOH
n-BuOH
i-PrOH
TFE
5
rt
50
rt
rt
rt
rt
rt
rt
Et (4a)6
Et (4a)6
Et (4a)6
Et (4a)6
Me (4b)6
n-Bu (4c)
i-Pr (4d)
CF3CH2
25:75
65:35c
33:67
28:72
58:42
82:18
2
4
5.5
5
5
3d
4e
5
6
7
8
2
92:8
5f
>99:<1g
a
R4 in compound 4 Scheme 1, R1¼o-OMe and R2¼m-CH2CO2Et.
b
c
d
e
f
Based on 1H NMR integration of the crude reaction mixture.
The reaction mixture also contained small amounts of unidentified byproducts.
Double amount of catalyst was used.
Pd/alumina (10%) was used as catalyst.
The reduction of the nitro group was completed in <1 h.
Alkylation product was not detected by 1H NMR of the crude reaction mixture;
The aforementioned results indicate that 2,2,2-trifluoroethanol
potentially could be an ideal solvent for our one-pot reductive
monoalkylation of nitro aryls. Under such conditions the potential
contamination of the product by the adduct resulting from
oxidation of the solvent would be minimized to zero (given that
g
TFE¼2,2,2-trifluoroethanol.
Pd
H
H
OEt
OH
O
O
Pd
2 EtOH
OEt
H
(1)
H
H
oxidative
addition
H Pd H
β-hydride
elimination
slow
H
Pd
Pd
R
H
R
H
fast
R
O
HN
H
Pd
O
H
N
+ Pd
(2)
H
R
H
N
H
H
N
H
H2
Scheme 3. Proposed mechanism for the formation of acetaldehyde from ethanol when treated with hydrogen (1 atm) over Pd/C (10%).

6408
M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
Table 2
Comparative survey of i-propanol (methanol and 2,2,2-trifluoroethanol) versus ethanol as solvent for the reductive monoalkylation reaction
Entry
SM
Solvent
Carbonyl
(equiv)
Time (h)
Product
(secondary amine)
Ratio 2/4a
Isolated yield using
EtOH as solventb,c,6
OMe
OMe
NO2
1
i-PrOH
CH3CHO (1.7)
CH3CHO (1.1)
24
16:84
99% (6 h)
84% (7 h)
EtO2C
EtO2C
NHEt
EtO2C
EtO2C
4e6
1b
F
F
2
3
4
5
i-PrOH
i-PrOH
i-PrOH
i-PrOH
36
23
24
24
42:58
23:77
44:56
35:65
NHEt
NO2
6
4f
1c
OMe
OMe
CH3CHO (1.1)
96% (8 h)
99% (6.5 h)
79% (5 h)
NHEt
NO2
6
4g
OMe
1d
1d
CH3CH2CHO (1.6)
NHn-Pr
6
4h
MeO
MeO
CH3CHO (1.1)
NO2
NHEt
6
4i
1e
6
7
1e
1e
MeOH
TFEd
CH3CHO (1.1)
CH3CHO (1.1)
24
24
4i6
4i6
32:68
62:38
79% (5 h)
79% (5 h)
a
Ratio primary amine 2/secondary amine 4.
Isolated yield of the product when the reaction was conducted in ethanol (see Ref. 6).
Reaction time in ethanol in brackets.
The reduction of the nitro group was completed in <1 h; SM¼starting material; TFE¼2,2,2-trifluoroethanol.
b
c
d
R-alkyl is not the same as ROH). However, due to cost i-propanol
would probably be a preferred candidate in this case, despite the fact
that 2,2,2-trifluoroethanol can be quite easily recycled.15 A few ex-
periments were performed in order to establish if i-propanol could
replace ethanol as solvent in the reductive monoalkylation reaction.
The findings from these experiments are outlined in Table 2.
In all experiments conducted in i-propanol (Table 2, entries 1–5)
the reactions proceed much slower compared with the same re-
action performed in ethanol. None of the reactions had reached
completion within 24 h as judged by TLC analysis and crude 1H
NMR analysis. To be precise, the initial reduction of the nitro
functionality was complete in all cases; however, the concomitant
imine formation proceeded rather slowly in this solvent. The same
was found when methanol and 2,2,2-trifluoroethanol (entries 6
and 7) were used as solvent. Furthermore, of the solvents tested
2,2,2-trifluoroethanol was found to be the least suitable solvent for
this conversion. Judging from the results obtained with 2,2,2-tri-
fluoroethanol we can conclude that this solvent nicely facilitates
the initial reduction of the nitro group to the primary amine (Table
1, entry 8), however, the following imine formation proceeds
sluggishly in this solvent (Table 2, entry 7). Based on these findings
we concluded that the reaction is best conducted in ethanol despite
the fact that small amounts of the secondary ethylamine could be
formed over time in this solvent.
pot. But there is one caveat, hydrogen over Pd/C is also the most
utilized method for cleaving benzyl groups in benzylamines.16
However, the deprotection reaction often proceeds slowly17 so we
envisaged that by fine tuning the reaction conditions it would be
possible to acquire the desired benzyl protected amines in good
yield via this method. After some experimentation using nitro aryl
1a as substrate we arrived at conditions that allowed us to conduct
this transformation in one-pot. The reaction conditions are essen-
tially the same as the optimized conditions used in order to convert
nitro aryl 1a to the corresponding secondary methyl amine in our
previous work.6 These conditions involve conducting the initial
reduction reaction with hydrogen over Pd/C (10%) without benz-
aldehyde present. Benzaldehyde (a slight excess) was then added
once the primary amine was formed and the reaction mixture was
then stirred under an atmosphere of air or argon18 at room tem-
perature until the imine formation had reached completion. Finally,
the resulting imine was reduced by stirring the reaction mixture
under an atmosphere of hydrogen for a short period of time, thus
resulting in the formation of the benzyl protected aryl amine 4j
(Scheme 4, method A).
By utilizing these conditions we were able to convert nitro aryls
1a (Scheme 3),1d and 1f to the corresponding benzyl protected aryl
one-pot
Method A
1) H2,1 h
2.2. Reductive monobenzylation of nitro aryls
2) benzaldehyde, 25 h
3) H2, 15 min
OMe
1a
A useful extension of the reductive monoalkylation chemistry,
which we recently reported,6 would be if benzaldehyde could be
used as the alkyl source in order to generate the corresponding
benzyl protected amine from the corresponding nitro aryl in one-
EtO2C
Pd/C (10%), EtOH, rt
NHBn
4j 81%
Scheme 4. Synthesis of benzylamine 4j using method A.

M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
6409
Table 3
One-pot synthesis of benzyl protected aryl amines
Entry
SM
Equivalents of benzaldehyde
Method
A
Solvent
EtOH
Reaction timea
Product
Isolated yield (%)
81
OMe
NO2
OMe
EtO2C
1
1.4
1 hþ25 hþ15 min
EtO2C
NHBn
4j
1a
OMe
OMe
2
3
4
1.2
2.6
1.3
A
A
A
EtOH
EtOH
EtOH
2 hþ18 hþ15 min
2 hþ48 hþ45 min
2 hþ4.5 hþ15 min
86
99
58
NO2
NO2
NHBn
4k
1d
NHBn
4l
1f
OMe
OMe
HO2C
NO2
HO2C
NHBn
1g
4m
F
F
5
6
3.9
1.2
A
A
EtOH
EtOH
2 hþ18 hþ5 min
2 hþ5 hþ15 min
0
0
EtO2C
MeO
NO2
EtO2C
MeO
NHBn
1c
4n
NO2
NHBn
4o
1e
1e
1e
1e
1c
7
8
9
10
1.2
1.2
1.2
3.8
A
B
B
B
EtOH
EtOH
i-PrOH
EtOH
2 hþ5 hþ2 min
4o
4o
4o
4n
21
94
71
43
1.5 hþ4 hþ10 min
1.5 hþ4 hþ10 min
2.5 hþ45.5 hbþ10 min
OMe
OMe
NO2
11
3.9
B
EtOH
1.5 hþ96 hbþ10 min
41
EtO2C
NHBn
EtO2C
4p
1b
a
The times given correspond to the following reactions: reductionþimine formationþreduction.
The reaction was not completed; SM¼starting material.
b
amines in 81, 86 and 99% yield, respectively (Table 3, entries 1–3).
the presence of O-benzyl ether.19 It occurred to us that a similar
strategy might be possible to utilize for the final reduction of the
imine. Gratifyingly, when 0.5 equiv (compared to nitro aryl) of
triethylamine was added before the final imine reduction it resul-
ted in the isolation of benzylamine 4o in 94% yield (Scheme 5,
method B; Table 3, entry 8).
The conversion of compound 1g, possessing a free carboxylic acid,
proceeded rather sluggishly and gave the desired product in only
58% yield (entry 4). However, this method failed to yield the cor-
responding benzylamine when substrates 1c and 1e were treated
under the exact same conditions (entries 5 and 6). Only the cor-
responding primary amine could be isolated in these two examples
resulting from over-reduction. A small amount of benzylamine 4o
could be isolated when the exposure time to hydrogen was reduced
from 15 to 2 min for the final reduction step, viz. reduction of the
imine. However, this also failed to give the desired product in
a synthetically useful yield (21%) (entry 7).
Subjecting nitro aryl 1e to the same conditions as used in
entry 8, but changing the solvent to i-propanol resulted in the
formation of the desired product 4o in a reduced yield (71%)
(Table 3, entry 9), thus providing further evidence that ethanol
is the solvent of choice for this reaction. The reduced yield when
i-propanol was used as solvent is due to the fact that there still
was unreacted primary amine left in the reaction mixture at the
stage of the final hydrogenation reaction. Treating ethyl 4-fluoro-
3-nitrobenzoate (1c) under these revised conditions (method B)
resulted in a moderate yield of the desired product 4n (entry
10). A similar outcome was also the case when compound 1b
was used as substrate (entry 11). The low yield is mostly due to
the lack of conversion in the imine formation step and the re-
action was subjected to the final hydrogenation while there still
was a significant amount of unreacted primary amine left in the
reaction mixture as evident from TLC analysis. The slow for-
mation of the imine in these two examples is probably due to
steric hindrance caused by the adjacent fluorine and methoxy
groups, respectively.
Sajiki and Hirota reported some time ago that using nitrogen
containing bases (e.g., ammonia, triethylamine, pyridine and
ammonium acetate) as catalyst poison in Pd/C catalyzed hydroge-
nation reactions resulted in selective reduction of a double bond in
one-pot
Method B
1) H2,1.5 h
2) benzaldehyde, 4 h
3) H2, Et3N, 10 min
MeO
MeO
Pd/C (10%), EtOH, rt
NO2
NHBn
4o 94%
Scheme 5. Synthesis of benzylamine 4o using method B.
1e

6410
M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
Table 4
One-pot synthesis of substituted benzyl amino aryls
OMe
OMe
NO2
Method
B
NHCH2Ar
4
1d
Entry
1
Aldehyde
Equivalents of aldehyde
Solvent
EtOH
Reaction timea
Product
Isolated yield (%)
67
p-Anisaldehyde
1.2
1.2
1.2
1.5 hþ21.5 hþ10 min
1.5 hþ22.5 hþ10 min
1.5 hþ48 hþ10 min
OMe
4q
2
3
p-Fluorobenzaldehyde
B
B
EtOH
EtOH
71
F
4r
p-Dimethylaminobenzaldehyde
19b
NMe2
4s
4
5
p-Dimethylaminobenzaldehyde
1.2
1.2
B
B
EtOH
EtOH
1.5 hþ144 hþ10 min
1.5 hþ89 hþ20 min
4s
28b
54b
2,4-Dimethylbenzaldehyde
4t
OMe
6
2,5-Dimethoxybenzaldehyde
1.3
B
EtOH
1.5 hþ66 hbþ10 min
5c
MeO
4u
7
8
9
10
2,4-Dimethylbenzaldehyde
p-Dimethylaminobenzaldehyde
2,5-Dimethoxybenzaldehyde
2,4-Dimethylbenzaldehyde
1.2
1.3
1.05
1.2
C
Benzene
Benzene
Benzene
7 hþ23 hdþ30 min
7 hþ21 hdþ15 min
7 hþ24 hdþ15 min
3 hþ26 hdþ30 min
4t
4s
4u
4t
68
C
41b
54c
58
Ce
D
EtOH/benzene (1:1)
a
The times given correspond to the following reactions: reductionþimine formationþreduction.
b
c
Imine formation was not finalized before the reaction mixture was subjected to the final hydrogenation.
Yield based on HPLC analysis (see Section 4.6.2 for details).
d
e
Reflux with removal of water with a Dean–Stark trap.
Triethylamine was not used as catalyst poison in this reaction.
The remarkable difference in reactivity in the final imine re-
during the imine forming step (method C). Pd/alumina (10%)20
was chosen as catalyst for these experiments due to its increased
stability over Pd/C at elevated temperatures.21 Although the ini-
tial reduction of the nitro group proceeded much slower in
benzene compared to in ethanol, presumably due to poor solu-
bility of hydrogen gas in benzene, the overall reaction time could
be cut in half (Table 4, entry 7) compared with the same reaction
using method B (entry 5). By such means compound 4t could be
isolated in 68% yield after column chromatography. Subjecting p-
dimethylaminobenzaldehyde and 2,5-dimethoxybenzaldehyde to
these revised conditions, viz. method C, resulted in improved
yields in both cases (entries 8 and 9). Keeping the reaction
conditions the same but switching solvent to a mixture of etha-
nol and benzene (1:1) (method D) resulted in a quicker reduction
of the nitro group compared to the same reaction run in pure
benzene, however, the overall yield of the reaction dropped
slightly (entry 10).
An attempt to conduct the benzylation reaction on aliphatic
nitro compounds has thus far not been successful. Although the
desired compound was formed, as evident from crude 1H NMR
analysis, it was never formed in a synthetically useful yield and was
always accompanied by several other products. This is possibly due
to the fact that aliphatic amines are more basic compared to aro-
matic amines and therefore forms the corresponding ammonia
duction between the corresponding imine of 3-nitroanisole and
4-nitroanisole entries 2 and 6, respectively, is most likely due to the
electron-donating effect of the methoxy group. When the methoxy
group is in para position it results in a more electron rich imine and
benzylamine (after reduction) compared with the corresponding
meta intermediate, which results in a quicker reduction and
deprotection.
2.3. Synthesis of substituted benzyl amino aryls
Next we tested if these conditions were suitable when
substituted benzaldehydes were used as the alkyl source together
with 3-nitroanisole (1d) as substrate. The reaction worked rea-
sonably well when the substituent on benzaldehyde was methoxy
or fluorine positioned in the para position (Table 4, entries 1 and 2).
However, for para-dimethylaminobenzaldehyde the yield was very
low (entries 3 and 4). Not surprisingly the yield was also dramati-
cally reduced when the substituents were placed closer to the
aldehyde functionality (entries 5 and 6). This represents a big
drawback and a revised strategy was sought.
In an attempt to address this issue the reaction was conducted
in benzene with reflux of the reaction mixture and simultaneous
removing of water azeotropically by means of a Dean–Stark trap

M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
6411
compound,22 which is not reactive enough to form the corre-
sponding imine upon exposure to aldehyde.
4.2.2. Ethyl 3-(isopropylamino)-4-methoxyphenyl acetate (4d)
(Table 1, entry 7)
Compound 4d was obtained in 7% yield as a light yellow oil by
flash chromatography (silica, hexane/Et2O 3:2 elution) Rf 0.5. IR nmax
3415, 2965, 2933, 1735, 1601, 1523, 1465, 1444, 1428, 1256, 1225,
3. Conclusion
1175, 1033 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d
6.68 (d, J¼8.0 Hz, 1H),
We found that the best solvent for performing the one-pot
monoalkylation reaction is ethanol, however, when the imine
forming step proceeds slowly, benzene and heating the reaction
mixture at reflux were found to be the conditions of choice. The
current work demonstrates that the reductive monoalkylation re-
action is useful for the formation of benzyl protected amines in
one-pot starting from nitro aryls. Further improvement of this
methodology also resulted in development of a useful approach for
the preparation of substituted benzyl amino aryls.
6.53–6.51 (m, 2H), 4.14 (q, J¼7.2 Hz, 2H), 4.05 (br s, 1H), 3.81 (s, 3H),
3.62 (app. quintet, J¼6.4 Hz, 1H), 3.50 (s, 2H), 1.28–1.22 (m, 9H); 13
C
NMR (CDCl3, 101 MHz) d 172.2, 145.9, 137.4, 126.9, 116.3, 111.1, 109.4,
ꢃ
60.6, 55.4, 43.7, 41.3, 22.9, 14.2; MS (EIþ) m/z 251 (Mþ , 52%), 236
(100), 222 (7), 208 (10), 178 (12),162 (9), 148 (9); HRMS (EIþ) Found:
ꢃ
ꢃ
Mþ , 251.1529 C14H21NO3 requires Mþ , 251.1521; Anal. Found: C
66.90, H 8.45, N 5.59%. C14H21NO3 requires: C 66.91, H 8.42, N 5.57%.
4.3. General procedure for reductive monoalkylation of nitro
aryls in i-propanol with addition of aldehyde, as exemplified
for ethyl 3-(ethylamino)-4-methoxybenzoate (4e)
4. Experimental
4.1. General experimental
Pd/C (10%) (3.6 mg, 3.38 mmol) was added to a stirred solution of
nitro aryl 1b (17.4 mg, 0.0773 mmol) and acetaldehyde (0.30 mL of
ca. 2% solution in DMF, ca. 0.129 mmol) in i-propanol (1.3 mL). The
resulting reaction mixture was then subjected to three cycles of
vacuum followed by flush with H2 before being stirred vigorously
under an atmosphere of H2 (balloon) for 24 h. The reaction mixture
was then diluted with ethanol (10 mL), filtered through a plug of
CeliteÒ and washed after with ethanol (3ꢁ5 mL). After concentra-
tion under reduced pressure the resulting product mixture was
analyzed by 1H NMR.
NMR chemical shifts were recorded as
d values in parts per
million (ppm) using tetramethylsilane (
d
¼0.00 ppm) as internal
standard for proton (1H) NMR and residual chloroform
(
(
d
¼77.0 ppm) as internal standard for carbon (13C) NMR. Fluorine
19F) NMR spectra were referenced externally to 1,1,1-tri-
fluorotoluene at
d¼0.00 ppm. Reactions were monitored by thin-
layer chromatography (TLC) carried out on 0.25 mm silica gel
coated glass plates 60F254 using UV light as visualizing agent and
basic KMnO4 solution followed by heating as developing agent.
Silica gel 60 (particle size 0.063–0.2 mm ASTM) was used for flash
chromatography. Elemental analyses were performed at the
Analytical Laboratory, Bioagricultural Sciences, Nagoya University.
Non-commercial starting materials were prepared according to
literature methods (compounds 1a,8 1b,23 1c8).
Signals associated with compounds 4e, 4f, 4g, 4h, and 4i in the
respective 1H NMR spectra were in full agreement with the data
previously reported.6
4.4. Method A: general procedure for reductive
monobenzylation of nitro aryls, as exemplified for
ethyl 3-(benzylamino)-4-methoxyphenyl acetate (4j)
4.2. General procedure for reductive monoalkylation without
addition of carbonyl, as exemplified for ethyl 3-(ethylamino)-
4-methoxyphenyl acetate (4a) (Table 1, entry 1)
Pd/C (10%) (5.6 mg, 5.26 mmol) was added to a stirred solution of
nitro aryl 1a (16.9 mg, 0.0707 mmol) in ethanol (1.5 mL). The
resulting reaction mixture was then subjected to three cycles of
vacuum followed by flush with H2 before being stirred vigorously
under an atmosphere of H2 (balloon) for 2 h. The H2 atmosphere
was then replaced with air and the reaction mixture was stirred
Pd/C (10%) (7.5 mg, 7.05 mmol) was added to a stirred solution of
nitro aryl 1a (16.1 mg, 0.0673 mmol) in ethanol (1.5 mL). The
resulting reaction mixture was then subjected to three cycles of
vacuum followed by flush with H2 before being stirred vigorously
under an atmosphere of H2 (balloon) for 5 days. The reaction
mixture was then diluted with ethanol (10 mL), filtered through
a plug of CeliteÒ and washed after with ethanol (3ꢁ5 mL). After
concentration under reduced pressure the resulting product mix-
ture was analyzed by 1H NMR.
vigorously for 5 min before benzaldehyde (10.0 mL, 0.098 mmol)
was added. The resulting reaction mixture was stirred for 25 h
before being subjected to three cycles of vacuum followed by flush
with H2 before being stirred vigorously under an atmosphere of
H2 for 15 min. The crude reaction mixture was subjected to
flash chromatography (silica, hexane/Et2O/Et3N 90:9.95:0.05/
80:19.95:0.05/60:39.95:0.05 gradient elution) and concentration
of the relevant fractions (Rf 0.3 in hexane/Et2O) gave the desired
compound 4j (17.1 mg, 81%) as a light yellow oil. IR nmax 3423, 2925,
2851, 1734, 1600, 1523, 1452, 1252, 1225, 1142, 1030 cmꢂ1; 1H NMR
Signals associated with compound 4a and 4b in the respective
1H NMR spectra were in full agreement with the data previously
reported.6
4.2.1. Ethyl 3-(butylamino)-4-methoxyphenyl acetate (4c) (Table 1,
entry 6)
(CDCl3, 400 MHz) d 7.39–7.32 (m, 4H), 7.29–7.27 (m, 1H), 6.71 (d,
J¼8.0 Hz, 1H), 6.58 (dd, J¼2.0 and 8.0 Hz, 1H), 6.53 (d, J¼2.0 Hz, 1H),
Compound 4c was obtained in 11% yield as a light yellow oil by
flash chromatography (silica, hexane/hexane/Et2O 3:2 elution) Rf
0.5 (in hexane/Et2O 3:2). IR nmax 3426, 2957, 2928, 2858, 1735,1602,
4.58 (br s, 1H), 4.34 (s, 2H), 4.10 (q, J¼7.2 Hz, 2H), 3.82 (s, 3H), 3.48
(s, 2H), 1.21 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 101 MHz)
d 172.1,
145.9, 139.4, 138.1, 128.6, 127.6, 127.1, 126.9, 117.1, 110.8, 109.3, 60.6,
ꢃ
1524, 1461, 1445, 1366, 1248, 1225, 1163, 1033, 783 cmꢂ1
;
1H NMR
55.5, 48.0, 41.2, 14.2; MS (EIþ) m/z 299 (Mþ , 6%), 226 (11), 211 (11),
(CDCl3, 400 MHz)
d
6.68 (d, J¼8.0 Hz, 1H), 6.55–6.52 (m, 2H), 4.14
134 (16), 104 (33), 91 (100), 77 (16), 65 (32); HRMS (EIþ) Found:
ꢃ
ꢃ
(q, J¼7.2 Hz, 2H), 3.82 (s, 3H), 3.51 (s, 2H), 3.11 (t, J¼7.2 Hz, 2H), 1.64
(quintet, J¼7.2 Hz, 2H), 1.56 (s, 1H), 1.45 (quintet, J¼7.2 Hz, 2H), 1.25
(t, J¼7.2 Hz, 3H), 0.96 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 101 MHz)
Mþ , 299.1541 C18H21NO3 requires Mþ , 299.1521; Anal. Found: C
72.23, H 7.13, N 4.68%. C18H21NO3 requires: C 72.22, H 7.07, N 4.68%.
d
172.2, 145.8, 138.5, 127.0, 116.5, 110.5, 109.2, 60.7, 55.5 (CH3), 43.3,
4.4.1. N-Benzyl-3-methoxyaniline (4k) (Table 3, entry 2)
ꢃ
41.3, 31.6, 20.4,14.2,14.0; MS (EIþ) m/z 265 (Mþ , 92%), 250 (16), 222
Compound 4k24 was obtained in 86% yield as a light yellow oil
by flash chromatography (silica, hexane/Et2O/Et3N 90:9.95:0.05/
60:39.95:0.05 gradient elution) Rf 0.7 (in hexane/Et2O 60:40). 1H
ꢃ
(100), 207 (7), 192 (14), 134 (18); HRMS (EIþ) Found: Mþ , 265.1683
C
ꢃ
15H23NO3 requires Mþ , 265.1678.

6412
M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
ꢃ
NMR (CDCl3, 400 MHz)
d
7.38–7.31 (m, 4H), 7.29–7.26 (m, 1H), 7.07
273.1195. C16H16FNO2 requires Mþ , 273.1165; Anal. Found: C 70.37,
H 5.63, N 5.29%. C16H16FNO2 requires: C 70.31, H 5.90, N 5.12%.
(t, J¼8.0 Hz, 1H), 6.29–6.24 (m, 2H), 6.19 (t, J¼2.2 Hz, 1H), 4.31 (s,
2H), 4.03 (br s, 1H), 3.76 (s, 3H); 13C NMR (CDCl3, 101 MHz)
d
160.8,
149.6, 139.3, 130.0, 128.6, 127.5, 127.2, 106.0, 102.7, 98.9, 55.1, 48.3.
4.5.2. Ethyl 3-(benzylamino)-4-methoxybenzoate (4p) (Table 3,
entry 11)
4.4.2. N-Benzylaniline (4l) (Table 3, entry 3)
Compound 4p was obtained in 41% yield as a yellow oil by flash
chromatography (silica, hexane/Et3N 99.95:0.05/hexane/Et2O/
Et3N 80:19.95:0.05 gradient elution) Rf 0.2 (in hexane/Et2O 80:20).
IR nmax 3423, 2931, 1707, 1599, 1523, 1454, 1294, 1252, 1223, 1106,
Compound 4l25 was obtained in 99% yield as a white solid, mp 33–
34 ꢀC, lit.25 mp 35–38 ꢀC, by flash chromatography (silica, hexane/
Et2O/Et3N 90:9.95:0.05/80:19.95:0.05 gradient elution) Rf 0.8 (in
hexane/Et2O 60:40). 1H NMR (CDCl3, 400 MHz)
d
7.70–7.33 (m, 7H),
6.91–6.77 (m, 3H), 4.46 (s, 2H), 4.07 (br s, 1H); 13C NMR (CDCl3,
101 MHz) 148.1, 139.4, 129.2, 128.5, 127.4, 127.1, 117.4, 112.8, 48.2.
1026, 764 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d 7.45 (m, 7H), 6.77 (d,
J¼8.4 Hz, 1H), 4.59 (br s, 1H), 4.38 (s, 2H), 4.31 (q, J¼7.2 Hz, 2H), 1.36
d
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 101 MHz)
d 167.0, 150.4, 139.1,
137.7, 128.6, 127.8, 127.3, 123.4, 119.5, 110.5, 108.4, 60.5, 55.6, 48.0,
ꢃ
4.4.3. 3-(Benzylamino)-4-methoxybenzoic acid (4m) (Table 3,
entry 4)
14.4; MS (EIþ) m/z 285 (Mþ , 14%), 223 (55), 208 (100), 180 (82), 164
(44),150 (32),135 (36),104 (36), 91 (56), 77 (67); HRMS (EIþ) Found:
ꢃ
ꢃ
Compound 4m was obtained in 58% yield as light yellow oil by
flash chromatography (silica, Et2O/hexane/Et3N 59.9:40:0.1 elu-
tion) Rf 0.3 (in Et2O/hexane 60:40). IR nmax 3382 (broad), 2926,
Mþ , 285.1373. C17H19NO3 requires Mþ , 285.1365; Anal. Found: C
71.57, H 6.87, N 4.77%. C17H19NO3 requires: C 71.56, H 6.71, N 4.91%.
2853, 1625, 1519, 1451, 1227 cmꢂ1
;
1H NMR (CDCl3, 400 MHz)
4.5.3. N-(4-Methoxybenzyl)-3-methoxyaniline (4q) (Table 4,
entry 1)
d
6.37–7.16 (m, 5H), 6.65 (d, J¼8.4 Hz, 1H), 6.10 (d, J¼2.8 Hz, 1H),
6.03 (dd, J¼2.8 and 8.4 Hz, 1H), 4.25 (s, 2H), 3.77 (s, 3H), 3.73–3.59
(br s, 2H); 13C NMR (CDCl3, 101 MHz)
143.3, 140.4, 139.9, 137.2,
Compound 4q27 was obtained in 67% yield as a clear oil by flash
chromatography (silica, hexane/Et3N 99.95:0.05/hexane/Et2O/
Et3N 80:19.95:0.05 gradient elution) Rf 0.2 (in hexane/Et2O 80:20).
IR nmax 3412, 2954, 2933, 2834, 1614, 1512, 1463, 1302, 1248, 1210,
d
128.5, 127.5, 127.1, 112.5, 102.5, 101.2, 56.4, 49.1; MS (EIþ) m/z 257
ꢃ
ꢃ
(Mþ , 8%), 228 (99), 213 (52), 91 (100); HRMS (EIþ) Found: Mþ
,
ꢃ
257.1049. C15H15NO3 requires Mþ , 257.1052.
1162,1036, 825, 758, 688 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d 7.29 (d,
J¼8.8 Hz, 2H), 7.08 (t, J¼8.0 Hz, 1H), 6.89 (d, J¼8.8 Hz, 2H), 6.30–
6.25 (m, 2H), 6.20 (t, J¼2.2 Hz, 1H), 4.25 (s, 2H), 3.96 (br s, 1H), 3.81
4.5. Method B: general procedure for reductive
monobenzylation of nitro aryls, as exemplified for
N-benzyl-4-methoxyaniline (4o) (Table 3, entry 8)
(s, 3H), 3.76 (s, 3H); 13C NMR (CDCl3, 101 MHz)
d 160.8, 158.9, 149.6,
131.3, 130.0, 128.8, 114.0, 106.0, 102.7, 98.9, 55.3, 55.1, 47.8; MS (EIþ)
ꢃ
ꢃ
m/z 243 (Mþ , 43%), 121 (100), 91 (22); HRMS (EIþ) Found: Mþ
,
ꢃ
243.1250. C15H17NO2 requires Mþ , 243.1259; Anal. Found: C 74.06,
H 6.91, N 5.89%. C15H17NO2 requires: C 74.05, H 7.04, N 5.76%.
Pd/C (10%) (6.2 mg, 5.83 mmol) was added to a stirred solution of
4-nitroanisole (1e) (48.1 mg, 0.314 mmol) in ethanol (2.0 mL). The
resulting reaction mixture was then subjected to three cycles of
vacuum followed by flush with H2 before being stirred vigorously
under an atmosphere of H2 (balloon) for 1.5 h. The H2 atmosphere
was then replaced with air and the reaction mixture was stirred
4.5.4. N-(4-Fluorobenzyl)-3-methoxyaniline (4r) (Table 4, entry 2)
Compound 4r was obtained in 71% yield as a clear oil by flash
chromatography (silica, hexane/Et3N 99.95:0.05/hexane/Et2O/
Et3N 80:19.95:0.05 gradient elution) Rf 0.2 (in hexane/Et2O 80:20).
vigorously for 5 min before benzaldehyde (38.9
was added. The resulting reaction mixture was stirred for 4 h before
triethylamine (22.0 L, 0.157 mmol) was added to the reaction
mL, 0.382 mmol)
IR nmax 3413, 2931, 1612, 1508, 1219, 1159, 823 cmꢂ1
;
1H NMR
(CDCl3, 400 MHz)
d 7.33–7.30 (m, 2H), 7.09–6.99 (m, 3H), 6.29 (ddd,
m
J¼0.6, 2.4, 8.0 Hz, 1H), 6.24 (ddd, J¼0.8, 2.4, 8.0 Hz, 1H), 6.17 (t,
mixture. The resulting reaction mixture was subjected to three
cycles of vacuum followed by flush with H2 before being stirred
vigorously under an atmosphere of H2 (balloon) for 10 min. The
crude reaction mixture was subjected to flash chromatography
(silica, hexane/Et2O/Et3N 80:19.95:0.05 elution) and concentration
of the relevant fractions (Rf 0.4 in hexane/Et2O 80:20) gave the
desired compound 4o26 (63.0 mg, 94%) as a light yellow solid, mp
J¼2.48 Hz, 1H), 4.27 (s, 2H), 4.01 (br s, 1H), 3.74 (s, 3H); 13C NMR
(CDCl3, 101 MHz)
d
162.1 (d, JC–F¼251 Hz), 160.8, 149.3, 135.0 (d,
JC–F¼3 Hz), 130.0, 129.0 (d, JC–F¼8 Hz), 115.4 (d, JC–F¼21 Hz), 106.0,
102.8, 99.0, 55.0, 47.6; 19F NMR (CDCl3, 376 MHz)
d
ꢂ52.9; MS (EIþ)
ꢃ
m/z 231 (Mþ , 60%), 205 (100),136 (40), 109 (94), 93 (24), 80 (32), 77
ꢃ
ꢃ
(25); HRMS (EIþ) Found: Mþ , 231.1018. C14H14FNO requires Mþ
,
231.1059; Anal. Found: C 72.73, H 6.16, N 6.10%. C14H14FNO requires:
C 72.71, H 6.10, N 6.06%.
45–46 ꢀC, lit.26 mp 48 ꢀC. 1H NMR (CDCl3, 400 MHz)
d 7.36–7.20 (m,
5H), 6.76 (d, J¼9.0 Hz, 2H), 6.58 (d, J¼9.0 Hz, 2H), 4.26 (s, 2H), 3.75
(br s, 1H), 3.71 (s, 3H); 13C NMR (CDCl3, 101 MHz)
139.7, 128.5, 127.5, 127.1, 114.9, 114.1, 55.7, 49.2.
d
152.2, 142.4,
4.6. Method C: general procedure for reductive
monobenzylation of nitro aryls, as exemplified for N-(2,4-
dimethylbenzyl)-3-methoxyaniline (4t) (Table 4, entry 7)
4.5.1. Ethyl 3-(benzylamino)-4-fluorobenzoate (4n) (Table 3,
entry 10)
Pd/alumina (10%) (6.6 mg, 6.20 mmol) was added to a stirred
Compound 4n was obtained in 43% yield as a light yellow oil by
flash chromatography (silica, hexane/Et3N 99.95:0.05/hexane/
Et2O/Et3N 80:19.95:0.05 gradient elution) Rf 0.4 (in hexane/Et2O
80:20). IR nmax 3417, 2925, 1741, 1618, 1523, 1437, 1296, 1254, 1188,
solution of 3-nitroanisole (1d) (32.6 mg, 0.213 mmol) in benzene
(2.0 mL). The resulting reaction mixture was then subjected to
three cycles of vacuum followed by flush with H2 before being
stirred vigorously under an atmosphere of H2 (balloon) for 7 h. The
H2 atmosphere was then replaced with air and the reaction mixture
was stirred vigorously for 5 min before 2,4-dimethylbenzaldehyde
1103 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d 7.40–7.26 (m, 7H), 7.00 (dd,
J¼8.4 and 11.2 Hz, 1H), 4.40 (s, 2H), 4.32 (q, J¼7.2 Hz, 2H), 1.56 (br s,
1H), 1.36 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 101 MHz)
d
166.3, 154.2
(35.6
was stirred at reflux with azeotropic removal of water with a Dean–
Stark trap for 23 h. Triethylamine (14.9 L, 0.107 mmol) was added
mL, 0.255 mmol) was added. The resulting reaction mixture
(d, JC–F¼248 Hz), 138.4, 136.5 (d, JC–F¼12 Hz), 128.8, 127.6 (3), 127.5
(7), 127.1 (d, JC–F¼3 Hz), 119.0 (d, JC–F¼8 Hz), 114.2 (d, JC–F¼20 Hz),
m
113.3 (d, JC–F¼5 Hz), 60.9, 47.8, 14.3; 19F NMR (CDCl3, 376 MHz)
to the reaction mixture and the resulting reaction mixture was
subjected to three cycles of vacuum followed by flush with H2 be-
fore being stirred vigorously under an atmosphere of H2 (balloon)
ꢃ
d
ꢂ66.9; MS (EIþ) m/z 273 (Mþ , 48%) 205 (100), 196 (79), 168 (63),
ꢃ
138 (35), 136 (31), 91 (76), 77 (21); HRMS (EIþ) Found: Mþ
,

M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
6413
for 30 min. The crude reaction mixture was subjected to flash
chromatography (silica, hexane/Et3N 99.95:0.05/hexane/EtOAc/
Et3N 95:4.95:0.05/90:9.95:0.05 gradient elution) and concentra-
tion of the relevant fractions (Rf 0.2 in hexane/EtOAc 90:10) gave
the desired compound 4t (34.8 mg, 68%) as a clear oil. IR nmax 3410,
2920, 1614, 1502, 1460, 1209, 1161 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
Postdoctoral Fellowship for foreign researchers and a JSPS Grant-
in-Aid for Encouragement of Young Scientists (15780085), re-
spectively. The authors would like to thank Dr. Oyama, Chemical
Instrument Division RCMS, Nagoya University, for technical assis-
tance during GC–MS analysis. The authors would also like to thank
Kawaken Fine Chemical for the gift of Pd/C (10%) used during this
work.
d
7.19 (d, J¼7.6 Hz, 1H), 7.07 (t, J¼8.2 Hz, 1H), 7.01 (s, 1H), 6.97 (d,
J¼7.6 Hz, 1H), 6.27 (dd, J¼2.2 and 8.2 Hz, 1H), 6.24 (dd, J¼2.2 and
8.2 Hz, 1H), 6.18 (t, J¼2.2 Hz, 1H), 4.20 (s, 2H), 3.76 (br s, 1H), 3.75 (s,
3H), 2.32 (s, 3H), 2.30 (s, 3H); 13C NMR (CDCl3, 101 MHz)
d 160.9,
Supplementary data
149.7, 137.1, 136.2, 133.9, 131.2, 130.0, 128.5, 126.7, 105.8, 102.4, 98.7,
ꢃ
55.0, 46.1, 21.0, 18.8; MS (EIþ) m/z 241 (Mþ , 63%), 119 (100), 91 (22);
Copies of 1H and 13C NMR spectra of all new compounds are
included as supplementary materials. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.04.077.
ꢃ
ꢃ
HRMS (EIþ) Found: Mþ , 241.1452. C16H19NO requires Mþ , 241.1467;
Anal. Found: C 79.59, H 8.16, N 5.87%. C16H19NO requires: C 79.63, H
7.94, N 5.80%.
4.6.1. N-(4-(N,N-Dimethylamino)-benzyl)-3-methoxyaniline (4s)
(Table 4, entry 8)
Compound 4s was obtained in 41% yield as a light yellow oil by
flash chromatography (silica, hexane/Et3N 99.95:0.05/hexane/
Et2O/Et3N 80:19.95:0.05/60:39.95:0.05 gradient elution) Rf 0.3 (in
hexane/Et2O 60:40). IR nmax 3411, 2921,1612,1520,1460,1342,1205,
References and notes
1. (a) Broadwater, S. J.; Roth, S. L.; Price, K. E.; Kobaslija, M.; McQuade, D. T.
Org. Biomol. Chem. 2005, 3, 2899–2906; (b) Tietze, L. F. Chem. Rev. 1996, 96,
115–136; (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131–163.
2. Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York, NY, 2001.
3. Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York, NY, 2001;
pp 3–9.
1161 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d
7.23 (d, J¼8.6 Hz, 2H), 7.07
(t, J¼8.2 Hz, 1H), 6.72 (d, J¼8.6 Hz, 2H), 6.28–6.25 (m, 2H), 6.21 (t,
J¼2.2 Hz, 1H), 4.18 (s, 2H), 3.88 (br s, 1H), 3.76 (s, 3H), 2.94 (s, 6H);
4. Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York, NY, 2001;
pp 170–172.
13C NMR (CDCl3, 101 MHz)
d
160.8, 150.1, 149.8, 129.9, 128.8, 127.0,
ꢃ
112.8, 106.0, 102.5, 98.7, 55.1, 48.0, 40.7; MS (EIþ) m/z 256 (Mþ
,
5. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785–7811.
6. Sydnes, M. O.; Isobe, M. Tetrahedron Lett. 2008, 49, 1199–1202.
7. For similar transformations from other groups using different alkyl sources and
different reducing agents, see the following references: H2 and Raney nickel as
reducing agent and alcohol as alkyl source (the alcohol is oxidized to the
corresponding aldehyde under the reaction conditions), see: (a) Jiang, Y.-L.;
Hu, Y.-Q.; Feng, S.-Q.; Wu, J.-S.; Wu, Z.-W.; Yuan, Y.-C.; Liu, J.-M.; Hao, Q.-S.; Li,
D.-P. Synth. Commun. 1996, 26, 161–164; (b) Xiaojian, Z.; Zuwang, W.; Li, L.;
Guijuan, W.; Jiaping, L. Dyes Pigments 1998, 36, 365–371; decaboran as reducing
agent and carbonyls as alkyl source, see: (c) Bae, J. W.; Cho, Y. J.; Lee, S. H.;
Yoon, C.-O. M.; Yoon, C. M. Chem. Commun. 2000, 1857–1858; (d) Jung, Y. J.; Bae,
J. W.; Park, E. S.; Chang, Y. M.; Yoon, C. M. Tetrahedron 2003, 59, 10331–10338;
H2 and Pd/C (10%) as reducing agent and nitriles as alkyl source, see: (e) Sajiki,
H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977–4980; (f) Sajiki, H.; Ikawa, T.;
Hirota, K. Org. Process Res. Dev. 2005, 9, 219–220; ammonium formate and Pd/C
(5%) as reducing agent and nitriles as alkyl source, see: (g) Nacario, R.; Kota-
konda, S.; Fouchard, D. M. D.; Tillekeratne, L. M. V.; Hudson, R. A. Org. Lett.
2005, 7, 471–474; (h) Fouchard, D. M. D.; Tillekeratne, L. M. V.; Hudson, R. A.
Synthesis 2005, 17–18; polymethylhydrosiloxane and Pd(OH)2/C (20%) as re-
ducing agent and nitriles as alkyl source, see: (i) Reddy, C. R.; Vijeender, K.;
Bhusan, P. B.; Madhavi, P. P.; Chandrasekhar, S. Tetrahedron Lett. 2007, 48, 2765–
2768; for a related methodology where nitro aryls were converted to the
corresponding carbamates (Boc and CO2Et) using Sn/NH4Cl and Boc2O or
ClCO2Et, see: (j) Chandrasekhar, S.; Narsihmulu, Ch.; Jagadeshwar, V. Synlett
2002, 771–772.
33%), 147 (26), 134 (99), 118 (100), 95 (49), 91 (39), 77 (27), 65 (19);
ꢃ
ꢃ
HRMS (EIþ) Found: Mþ
, ,
256.1532. C16H20N2O requires Mþ
256.1576; Anal. Found: C 74.98, H 7.61, N 10.85%. C16H20N2O re-
quires: C 74.97, H 7.86, N 10.93%.
4.6.2. N-(2,5-Dimethoxybenzyl)-3-methoxyaniline (4u) (Table 4,
entry 9)
Compound 4u28 was obtained in 54% yield as evident from HPLC
analysis. A pure sample of the product for spectroscopic analysis
was obtained by preparative HPLC [Cosmosil 5C18-AR
(10ꢁ250 mm i.d.), CH3CN, 2 mL/min]. Concentration of the relevant
fraction (tR 7.9 min) gave the desired product 4u as a yellow oil. IR
nmax 3412, 2938, 2834, 1613, 1497, 1464, 1277, 1215, 1162,
1046 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d
7.06 (t, J¼8.0 Hz, 1H), 6.91
(d, J¼2.8 Hz, 1H), 6.81 (d, J¼8.8 Hz, 1H), 6.75 (dd, J¼2.8 and 8.8 Hz,
1H), 6.29–6.26 (m, 2H), 6.22 (t, J¼2.4 Hz, 1H), 4.29 (s, 2H), 3.82 (s,
3H), 3.76 (s, 3H), 3.73 (s, 3H); 13C NMR (CDCl3, 151 MHz)
d 160.8,
153.7, 151.6, 149.8, 129.9, 128.6, 115.4, 112.3, 111.3, 106.3, 102.6, 99.1,
ꢃ
55.9, 55.7, 55.1, 43.5; MS (EIþ) m/z 273 (Mþ , 94%), 151 (100), 121
8. Sydnes, M. O.; Doi, I.; Ohishi, A.; Kuse, M.; Isobe, M. Chem. Asian J. 2008, 3,
102–112.
ꢃ
(46), 91 (19), 77 (23); HRMS (EIþ) Found: Mþ , 273.1353. C16H19NO
ꢃ
requires Mþ , 73.1365.
9. Ethanol (99.5%) from Wako Pure Chemical Industries, Ltd. was used as solvent
for these experiments. According to the analytical data sheet provided by the
company the ethanol contains <0.001% mass/mass of aldehydes and ketones.
This rules out the possibility that acetaldehyde is present in the solvent as
a contaminant in high quantity from the start of the reaction.
10. Esaki, H.; Ohtaki, R.; Maegawa, T.; Monguchi, Y.; Sajiki, H. J. Org. Chem. 2007, 72,
2143–2150.
11. Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851–4854.
12. Ikawa, T.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60, 6189–6195.
13. Laue, T.; Plagens, A. Named Organic Reactions, 2nd ed.; Wiley: New York, NY,
2005; p 200.
4.7. Method D: general procedure for reductive
monobenzylation of nitro aryls, as exemplified for N-(2,4-
dimethylbenzyl)-3-methoxyaniline (4t) (Table 4, entry 10)
The reaction was conducted as in method C take for the use of
ethanol/benzene 1:1 as solvent. The crude product was purified as
given above in method C. Concentration of the relevant fractions
gave 58% yield of the desired compound 4t, which was identical in
all respects with the product obtained via method C.
14. The reaction mixture was filtered through a PTFE filter in order to remove Pd/C
(10%) prior to GC–MS analysis.
´
´
15. Ravikumar, K. S.; Kesavan, V.; Crousse, B.; Bonnet-Delpon, D.; Begue, J.-P. Org.
Synth. 2003, 80, 184–186.
16. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley: New York, NY, 1999; pp 579–580.
17. Hartung, W. H.; Simonoff, R. Org. React. 1953, 7, 263–326.
18. No significant difference in the yields was found when the imine forming step
was conducted under an atmosphere of air or argon. This step was therefore
generally conducted under an atmosphere of air.
19. Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981–13996.
20. Palladium, 10 wt % on alumina (powder), reduced form was used for these
experiments.
Acknowledgements
Financial support from Grant-in-Aid for Specially Promoted
Research (16002007) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) is gratefully acknowl-
edged. M.O.S. and M.K. are grateful for the provision of a JSPS
21. Kudo, D.; Masui, Y.; Onaka, M. Chem. Lett. 2007, 36, 918–919.

6414
M.O. Sydnes et al. / Tetrahedron 64 (2008) 6406–6414
22. March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, NY, 1992;
pp 248–253.
26. TCI Organic Chemicals Catalogue, TCI Chemicals: Tokyo, Japan, 2006–2007,
p 211.
23. Jones, B.; Robinson, J. J. Chem. Soc. 1955, 3845–3850.
24. Zhang, X.-X.; Harris, M. C.; Sadighi, J. P.; Buchwald, S. L. Can. J. Chem. 2001, 79,
1799–1805.
25. Aldrich Handbook of Fine Chemicals, Aldrich Chemical Company: St. Louis, MO,
USA, 2007; p 295.
27. Sokolowska-Gajda, J. Dyes Pigments 1992, 18, 103–113; no data was reported for
this compound in the paper.
28. Compound 4u has the same Rf value as 2,5-dimethoxybenzaldehyde in all
solvent systems tested. A pure sample of the product was therefore prepared
by preparative HPLC.