An efficient conversion of nitroaromatics and aromatic amines to tertiary amines in one-pot way

Article abstract of DOI:10.1016/j.tet.2003.09.054

Reductive alkylation and reductive methylation of aromatic primary amines with carbonyls and 37% formaldehyde using decaborane in one-pot way gave the corresponding tertiary amines in high yields. The reaction condition was extended for the reduction of n

Full text of DOI:10.1016/j.tet.2003.09.054

Tetrahedron 59 (2003) 10331–10338
An efficient conversion of nitroaromatics and aromatic amines
to tertiary amines in one-pot way
*
Yeon Joo Jung, Jong Woo Bae, Eun Soo Park, Yu Mi Chang and Cheol Min Yoon
Graduate School of Life Science and Biotechnology, Korea University, Seoul 136-701, South Korea
Received 28 September 2002; revised 17 September 2003; accepted 17 September 2003
Abstract—Reductive alkylation and reductive methylation of aromatic primary amines with carbonyls and 37% formaldehyde using
decaborane in one-pot way gave the corresponding tertiary amines in high yields. The reaction condition was extended for the reduction of
nitroaromatic using decaborane and Pd/C followed by the reductive alkylation and reductive methylation using decaborane to give the
corresponding tertiary amines in high yields.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
reduction followed by reductive alkylation.11 As a continu-
ous study on decaborane, we exteneded decaborane to two
one-pot reactions: the reductive alkylation5 followed by
reductive methylation (so-called double reductive alky-
lation) as well as the reduction of nitroaromatics followed
by reductive alkylation and reductive methylation. Here we
are going to report the synthesis of the corresponding
tertiary amines from primary amines as well as the synthesis
of the corresponding aromatic tertiary amines from
nitroaromatics in methanol using decaborane in a one-pot
way, and their scope and limitation.
Consecutive reactions1 have received much attention
because they efficiently give complex molecules from
simple starting materials. The ideal case for these
consecutive reactions is the one-pot synthesis, in which all
these processes occur in a consecutive way by addition of
reagents successively without isolation of intermediates.2,3
It is necessary that the yield of each step should be
quantitative (at least high) for consecutive reactions in one-
pot way to be successful. One of the synthetic methods of
secondary amines and tertiary amine is the reductive
alkylation of primary amines and secondary amines with
carbonyls using a variety of reducing reagents.4
2. Result and discussion
Decaborane (B10H14)5,6 is a commercially available white
solid that decompose only slowly in air. Decaborane was
reported as a reducing reagent in organic synthesis, but
inefficient in synthetic point of view due to its low reducing
power in a polar solvents.7 By changing solvent to protic
solvents and/or adding additives, decaborane was found to
be quite mild reducing agent in reduction reactions such as
reductive alkylation,8 reductive methylation,9 reductive
etherification,10 reduction of nitro groups and nitro
The consecutive reactions were conducted in methanol
using decaborane as a reducing agent (Scheme 1 and 2). One
is the double reductive alkylation of aromatic primary
amine with various carbonyl and formaldehyde using
decaborane to give aromatic tertiary amine and the other
is the reduction of nitroaromatics using decaborane (Table 1)
and 10% Pd/C system followed by the double reductive
alkylation to give the corresponding aromatic tertiary
amines (Table 2).
Scheme 1.
Keywords: reductive alkylation; reduction; nitroaromatic; decaborane; amines; one-pot reaction.
*
Corresponding author. Tel./fax: þ82-232903433; e-mail: cmyoon@korea.ac.kr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.054

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Y. J. Jung et al. / Tetrahedron 59 (2003) 10331–10338
Scheme 2.
Table 1. Reductive alkylation of anilines followed by methylation
Entry
Substrates
Carbonyls (equiv.)
decaborane (equiv.)/
time (h)
Formaldehydea (equiv.)/
decaborane (equiv.)/
time (h)
Product
Yield (%)b
1
2
Acetone (1.1) 0.3/0.5
2/0.3/10
93
85
Butanone (1.1) 0.3/0.5
2/0.3/12
3
4
Piperonal (1.1) 0.3/8
Propanal (1.1) 0.3/15
2/0.3/3.3
2/0.3/2
96
64
5
6
7
Butanone (1.1) 0.3/1
1.5/0.2/1
2/0.3/1
97
90
98
Acetophenone (1.1) 0.3/12
Benzaldehyde (1.1) 0.3/0.5
1.5/0.2/0.5
8
9
Salicylaldehyde (1) 0.3/1
Piperonal (1) 0.3/0.5
1.5/0.2/4
2/0.3/9
99
98
10
11
Phenylacetaldehyde (1) 0.3/0.5
Ethyl acetoacetate (1.1) 0.3/3
2/0.3/6
58
98
1.5/0.2/0.5

Y. J. Jung et al. / Tetrahedron 59 (2003) 10331–10338
10333
Table 1 (continued)
Entry
Substrates
Carbonyls (equiv.)
decaborane (equiv.)/
time (h)
Formaldehydea (equiv.)/
decaborane (equiv.)/
time (h)
Product
Yield (%)b
12
Benzyl acetoacetate (1.1) 0.3/2
Acetophenone (1.2) 0.4/24
Piperonal (1.1) 0.3/0.5
1.5/0.2/5
2/0.3/1.5
1.5/0.2/1.5
86
90
98
13
14
15
16
Acetone (1.1) 0.3/0.5
1.5/0.2/0.5
1.5/0.2/0.5
91
95
Benzaldehyde (1) 0.3/0.5
17
Piperonal (1.1) 0.3/0.5
1.5/0.2/0.5
92
a
37% Aqueous formaldehyde.
Isolated yields.
b
2.1. Reductive alkylation and reductive methylation
give tertiary amine in 92% yield (entry 17), butylamine with
carbonyls did not give any expected product amine.
The reductive alkylation and reductive methylation of
anilines with various substituents with carbonyls and 37%
aqueous formaldehyde using decaborane in methanol gave
the corresponding aromatic tertiary amine in high yield
(Scheme 1). The amounts of decaborane used are 30 or
40 mol% for the first step and 20 or 30 mol% for the second
step depending on the reactivities of substrates and
secondary amine intermediates. The amount of carbonyl
and formaldehyde used in the reaction was also dependent
on the reactivities of each starting substrate and secondary
amine intermediates. After completion of the first step,
which was identified by TLC using ethyl acetate and hexane
(1:4), 37% aqueous formaldehyde and decaborane was
added to the reaction mixture. The amount of decaborane,
carbonyl and 37% formaldehyde, and reaction time
necessary in each step of the reactions and results are
shown in Table 1. The yields of the reaction are generally
high except for propanal, aliphatic aldehyde (entries 4 and
10), due to the reduction of aldehyde12 or/and irreversible
acetal formation13 under the reaction conditions. Aromatic
nitro and cyano group and aromatic iodide are stable under
the reaction conditions (Table 1, entries 1–4, 8 and 11).
2.2. Reduction of nitroaromatics followed by reductive
alkylation and reductive methylation
As an extension of reduction of nitro group and double
reductive alkylation, the direct conversion of nitroaromatics
into tertiary amine was tried by reduction of nitro group
followed by double reductive alkylation in one-pot way.
The substrates were confined to nitroaromatics with
substituents. 30% Pd/C (w/w) of substrate was used in the
nitro group reduction step of nitroaromatics. Decaborane
was added in each step in all of the examples. 30 mol% of
decaborane (B10H14) was used in the reduction of the nitro
group and 30 or 20 mol% of decaborane for reductive
alkylation and reductive methylation respectively. The
amount of decaborane, reaction time and results are
shown in Table 2. While ketones were added to the reaction
solution from the beginning of the reaction (Eq. 2, Scheme
2), aldehydes were added after the completion of the nitro
group reduction due to possible reductive etherification10
(Eq. 1, Scheme 2). Under the mentioned conditions, the
consecutive reactions were completed in several hours and
gave the corresponding tertiary amines in high yields. The
other reducible functional groups such as halogen (entries 3
and 6) and benzylic group (entry 5) was remained intact
under our consecutive reaction conditions.
The double reductive alkylation of basic aliphatic amine
was not successful due to the basicity of amine. The reason
is that decaborane could not be acted as a catalyst in the
formation of imine from amine and carbonyl probably
because reaction solution become basic in the presence of
basic amine. Decaborane solution in methanol is acidic.
While less basic benzyl amine underwent the double
reductive alkylation with piperonal and formaldehyde to
3. Conclusion
Anilines were converted into the corresponding tertiary

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Y. J. Jung et al. / Tetrahedron 59 (2003) 10331–10338
Table 2. Reduction of nitroaromatics followed by reductive alkylation and reductive methylation
Entry
Substrates
Decaborane (equiv.)/
time (h)
Carbonyl (equiv.)
decaborane (equiv.)/
time (h)
Formaldehydea
(equiv.)/decaborane
(equiv.)/time
Product
Yield (%)b
1
2
0.3/1
Butanone (1.5) 0.2/1
1.5/0.2/1
95
92
0.3/0.5
Butanone (1.5) 0.3/2
1.5/0.2/3
3
4
0.3/2.5
0.3/0.5
Butanone (1.5) 0.2/2
Butanone (1.5) 0.2/2
1.5/0.2/2
2/0.3/1.5
87
95
5
6
0.3/3
Butanone (1.5) 0.2/2.5
Butanone (1.5) 0.2/2
1.5/0.2/3
1.5/0.2/3
86
93
0.3/1.5
7
8
0.3/1.5
0.3/0.5
Ethyl acetoacetate (1.5) 0.2/2
1.5/0.2/3
98
72
4-Bromobenzaldehyde (1.2) 0.2/0.5
1.5/0.2/0.5
9
0.3/1.5
0.3/0.5
4-Hydroxy benzaldehyde (1.5) 0.2/2 1.5/0.2/3
84
99
10
4-Bromobenzaldehyde (1.5) 0.2/0.5
1.5/0.2/0.5
11
12
0.3/2.5
0.3/0.5
Piperonal (1.1) 0.2/1.5
1.5/0.2/0.5
1.5/0.2/0.5
96
87
Acetophenone (1.5) 0.2/0.5
a
37% Aqueous formaldehyde.
Isolated yields.
b
amine by reductive alkylation and reductive methylation
with carbonyls and 37% of formaldehyde in one-pot way
generally in high yields. The yield of reaction with aliphatic
aldehydes was relatively low due to their reduction or/and
their irreversible acetal formation under reaction condition.
The efficient conversion of nitroaromatic into tertiary amine
was developed by reduction of nitroaromatics followed by
double reductive alkylation in one-pot way. The two
reactions were limited to the electron deficient amine such
as aromatic amines as a substrate.
4. Experimental
4.1. General
All solvents and reagents were used as purchased. All of
substrates used are commercially available. Purification by
flash column chromatography were performed using silica
gel 60 0.04–0.063 nm (230–400 mesh) (Merck re: 9385),
and TLC using silica gel 60F254, layer thickness 0.2 nm
on glasses. 1H NMR spectra were recorded on a Bruker AM

Y. J. Jung et al. / Tetrahedron 59 (2003) 10331–10338
10335
200 spectrometer using CDCl3 as a solvent and chemical
shifts are reported as d values (ppm). Mp was measured on
Electrothermal Melting Point Apparatus and uncorrected.
Elemental analysis was measured on EA1110 (CE Instru-
ment Italy) machine.
6.73 (d, 2H, J¼9.6 Hz, aromatic H), 3.94–3.97 (m, 1H,
J¼7.5 Hz, CH2), 2.80 (s, 3H, NCH3), 1.54–1.64 (m, 2H,
J¼7.5 Hz, CH2), 1.17 (d, 3H, J¼6.6 Hz, –CH3), 0.87 (t, 3H,
J¼7.2 Hz, –CH3). Anal. calcd: C, 69.54; H, 8.27; N, 6.76.
Found: C, 69.73; H, 8.11; N, 6.54.
4.2. Double reductive alkylation: reductive alkylation
and reductive methylation (Table 1). A typical
procedure of double reductive alkylation
4.2.6. 4-(N-Methyl-N-1-phenethylamino)benzoic acid
(entry 6). The double reductive alkylation of 4-amino-
benzoic acid with acetophenone and 37% formaldehyde
gave a tertiary amine in 90% yield as a white solid. Mp:
1
4.2.1. N-Isopropyl-N-methyl-4-nitroaniline (entry 1).
To a solution of 4-nitroaniline (100 mg, 0.72 mmol) in
methanol (3.6 ml) was added acetone (58 ml, 0.796 mmol),
decaborane (27 mg, 0.22 mmol). The solution was stirred at
rt for 0.5 h and 37% formaldehyde (109 ml, 1.45 mmol) and
decaborane (27 mg, 0.217 mmol) was added. The resulting
solution was stirred at rt under nitrogen for 10 h. The
mixture was concentrated under reduced pressure, chro-
matographed on silica gel column using a solution of ethyl
acetate and n-hexane (1:10) and concentrated to give a
1548C. H NMR (CDCl3, 300 MHz): d 7.98 (d, 2H, J¼
9.6 Hz, aromatic H), 7.38–7.26 (m, 5H, aromatic H), 6.80
(d, 2H, J¼9.6 Hz, aromatic H), 5.28 (q, 1H, J¼6.6 Hz, CH),
2.77 (s, 3H, NCH3), 1.62 (d, 3H, J¼6.6 Hz, –CH3). Anal.
calcd: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.11; H, 6.84;
N, 5.54.
4.2.7. 2-(N-Benzyl-N-methylamino)benzoic acid (entry
7). The double reductive alkylation of anthranilic acid with
benzaldehyde and 37% formaldehyde gave a tertiary amine
1
1
tertiary amine in 93% yield as a yellow syrup. H NMR
in 98% yield as a light yellow syrup. H NMR (CDCl3,
(CDCl3, 300 MHz): d 8.11 (d, 2H, J¼9.3 Hz, aromatic H),
6.67 (d, 2H, J¼9.3 Hz, aromatic H), 4.21–4.25 (m, 1H,
CH), 2.87 (s, 3H, NCH3), 1.24 (d, 6H, J¼6.6 Hz, (–CH3)2).
Anal. calcd: C, 61.84; H, 7.27; N, 14.42. Found: C, 62.13;
H, 7.01; N, 14.71.
300 MHz): d 8.29 (dd, 2H, J¼9.6 Hz, aromatic H), 7.64–
7.33 (m, 7H, aromatic H), 4.11 (s, 2H, –CH2), 2.72 (s, 3H,
NCH3). Anal. calcd: C, 74.67; H, 6.27; N, 5.81. Found: C,
74.98; H, 6.31; N, 5.67.
4.2.8. N-(2-Hydroxybenzyl)-N-methylanthranilonitrile
(entry 8). The double reductive alkylation of anthranilo-
nitrile with and 37% formaldehyde gave a tertiary amine in
98% yield as a yellow syrup. 1H NMR (CDCl3, 300 MHz): d
7.65–6.80 (m, 8H, aromatic H), 4.36 (s, 2H, –CH2), 2.88
(s, 3H, NCH3), 1.62 (d, 3H, J¼7.2 Hz, –CH3). Anal. calcd:
C, 75.61; H, 5.92; N, 11.76. Found: C, 75.04; H, 5.79; N,
11.69.
4.2.2. N-Isobutyl-N-methyl-4-nitroaniline (entry 2). The
double reductive alkylation of 4-nitroanilne with butanone
and 37% formaldehyde gave a tertiary amine as yellow
1
syrup in 83% yield. H NMR (CDCl3, 300 MHz): d 8.11
(d, 2H, J¼9.9 Hz, aromatic H), 6.68 (d, 2H, J¼9.9 Hz,
aromatic H), 3.95–4.03 (m, 1H, CH), 2.85 (s, 3H, NCH3),
1.57 (m, 2H, CH2), 1.20 (d, 3H, J¼6.6 Hz, –CH3), 0.87
(t, 3H, J¼6.9 Hz, –CH3). Anal. calcd: C, 63.44; H, 7.74; N,
13.45. Found: C, 63.54; H, 7.53; N, 13.79.
4.2.9. N-Methyl-N-piperoylanthranilamide (entry 9).
The double reductive alkylation of 4-anthranilamide with
piperonal and 37% formaldehyde gave a tertiary amine in
98% yield as a white syrup. 1H NMR (CDCl3, 300 MHz): d
8.2 (d, 1H, J¼7.8 Hz, aromatic H), 7.45 (t, 1H, J¼7.2 Hz,
aromatic H), 7.22 (m, 2H, aromatic H), 6.76–6.66 (m, 3H,
aromatic H), 5.95 (s. 2H, –CH2–), 4.02 (s, 2H, –CH2), 2.62
(s, 3H, NCH3). Anal. calcd: C, 67.59; H, 5.67; N, 9.85.
Found: C, 68.77; H, 5.59; N, 9.78.
4.2.3. N-Methyl-N-piperonyl-4-nitroaniline (entry 3).
The double reductive alkylation of 4-nitroaniline with
piperonal and 37% formaldehyde gave a tertiary amine in
96% yield as a yellow solid. Mp: 113.18C. 1H NMR (CDCl3,
300 MHz): d 8.11 (d, 2H, J¼9.6 Hz, aromatic H), 6.77
(d, 1H, J¼8.1 Hz, aromatic H), 6.76 (d, 2H, J¼9.6 Hz,
aromatic H), 6.64–6.68 (m, 4H, aromatic H), 5.95 (s, 2H,
CH2), 4.57 (s, 2H, benzyl H), 3.16 (s, 3H, NCH3). Anal.
calcd: C, 62.93; H, 4.93; N, 9.79. Found: C, 63.34; H, 4.71;
N, 9.63.
4.2.10. N-Methyl-N-propylanthranilamide (entry 10).
The double reductive alkylation of 4-anthranilamide with
phenylacetaldehyde and 37% formaldehyde gave a tertiary
amine in 58% yield. Mp: 127.88C. 1H NMR (CDCl3,
300 MHz): d 8.18–7.12 (m, 9H, aromatic H), 5.39 (s, 2H,
amide NH2), 3.29 (t, 2H, J¼6.9 Hz, –CH2), 2.73 (s, 3H,
NCH3). Anal. calcd: C, 75.56; H, 7.13; N, 11.01. Found: C,
75.29; H, 7.08; N, 10.95.
4.2.4. N-Methyl-N-propyl-4-nitroaniline (entry 4). The
double reductive alkylation of 4-nitroaniline with propanal
and 37% formaldehyde gave a tertiary amine in 64% yield
1
as a yellow syrup. H NMR (CDCl3, 300 MHz): d 8.11
(d, 2H, J¼9.3 Hz, aromatic H), 6.58 (d, 2H, J¼9.3 Hz,
aromatic H), 3.39 (t, 2H, J¼7.5 Hz, CH2), 3.07 (s, 3H,
NCH3), 1.62–1.70 (m, 2H, –CH2), 0.95 (t, 3H, J¼7.5 Hz,
–CH3). Anal. calcd: C, 61.84; H, 7.27; N, 14.24. Found: C,
62.63; H, 7.31; N, 14.43.
4.2.11. Ethyl 3-(N-4-iodophenyl-N-methylamino)-
butanoate (entry 11). The double reductive alkylation of
4-iodoaniline with ethyl acetoacetate and 37% formalde-
hyde gave a tertiary amine in 98% yield as a light yellow
syrup. 1H NMR (CDCl3, 300 MHz): d 7.45 (dd, 2H,
J¼7.2 Hz, aromatic H), 6.61 (dd, 2H, J¼7.2 Hz, aromatic
H), 4.36–4.43 (m, 1H, C–H), 4.05 (q, 2H, J¼7.2 Hz,
O–CH2–**), 2.69 (s, 3H, NCH3), 2.61 (q, 1H, J¼6.9 Hz;
CH2), 2.42 (q, 1H, J¼6.9 Hz, NCH2–), 1.15–1.20 (m, 6H,
4.2.5. 4-(N-Isobutyl-N-methylamino)benzoic acid (entry
5). The double reductive alkylation of 4-aminobenzoic acid
with 2-butanone and 37% formaldehyde gave a tertiary
1
amine in 97% yield as a white solid. Mp: 1198C. H NMR
(CDCl3, 300 MHz): d 7.95 (d, 2H, J¼9.6 Hz, aromatic H),

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Y. J. Jung et al. / Tetrahedron 59 (2003) 10331–10338
–(CH3)2). Anal. calcd: C, 44.97; H, 5.23; N, 4.03. Found: C,
45.16; H, 5.34; N, 4.11.
4.3. Reduction of nitro group followed by double
reductive alkylation using ketones and 37% formalde-
hyde (Table 2, entries 1–7). A typical procedure
4.2.12. Benzyl 3-(N-4-acetylaminophenyl-N-methyl-
amino)-butanoate (entry 12). The double reductive
alkylation of 4-aminoacetanilide with benzyl acetoacetate
and 37% formaldehyde gave a tertiary amine in 86% yield
as a pale lemon syrup. 1H NMR (CDCl3, 300 MHz): d
7.33–7.04 (m, 7H, aromatic H), 6.80 (d, 2H, J¼9.6 Hz,
aromatic H), 5.04 (d, 2H, J¼5.4 Hz, –CH2–), 4.39–4.44
(m, 1H, CH), 2.67 (s, 3H, NCH3), 2.15 (s, 3H, COCH3), 1.15
(d, 3H, J¼6.6 Hz, –CH3). Anal. calcd: C, 70.56; H, 7.11; N,
8.23. Found: C, 70.72; H, 7.02; N, 8.49.
4.3.1. 4-(N-Isobutyl-N-methylamino)benzoic acid (entry
1). To
a solution of 4-nitrobenzoic acid (50 mg,
0.299 mmol) in methanol (5 ml) was added 2-butanone
(40 ml, 0.448 mmol), decaborane (11 mg, 0.089 mmol) and
10% Pd/C (15 mg). The resulting solution was stirred at ca.
408C for 1 h. The mixture was then cooled to rt and
decaborane (11 mg, 0.089 mmol) was added. The resulting
solution was stirred at rt under nitrogen for 1 h. And then
37% formaldehyde (33 ml, 0.448 mmol) and decaborane
(7.3 mg, 0.059 mmol) were added to the mixture. The
resulting solution was stirred at rt under nitrogen for 2 h.
The mixture was concentrated under reduced pressure,
chromatographed on a short pad of silica gel using a solution
of ethyl acetate and n-hexane (1:6) and concentrated to give
tertiary amine (59 mg, 95%) as a crystalline white solid.
4.2.13. N-Methyl-N-(1-phenethyl)-4-acetamidoaniline
(entry 13). The double reductive alkylation of 4-amino-
acetanilide with acetophenone and 37% formaldehyde gave
a tertiary amine in 91% yield as a pale gray syrup. 1H NMR
(CDCl3, 300 MHz): d 7.25–7.18 (m, 7H, aromatic H), 6.71
(d, 2H, J¼9 Hz, aromatic H), 4.97 (q, 1H, J¼9 Hz, –CH),
2.57 (s, 3H; NCH3), 2.06 (s, 3H, COCH3), 1.44 (s, 3H,
J¼6.9 Hz, –CH3). Anal. calcd: C, 76.09; H, 7.51; N, 10.44.
Found: C, 76.18; H, 7.54; N, 10.42.
1
Mp: 119.78C. H NMR (CDCl3, 300 MHz): d 7.95 (d, 2H,
J¼9.6 Hz, aromatic H), 6.73 (d, 2H, J¼9.6 Hz, aromatic H),
3.94–3.97 (m, 1H, CH), 2.80 (s, 3H, NCH3), 1.54–1.67 (m,
2H, CH2), 1.17 (d, 3H, J¼6.6 Hz, CH3), 0.87 (t, 3H,
J¼7.5 Hz, CH3). Anal. calcd: C, 69.54; H, 8.27; N, 6.76.
Found: C, 69.83; H, 8.12; N, 6.51.
4.2.14. N-Methyl-N-piperoyl-4-acetamidoaniline (entry
14). The double reductive alkylation of 4-aminoacetanilide
with piperonal and 37% formaldehyde gave a tertiary amine
in 98% yield as a white solid. Mp: 141.68C. 1H NMR
(CDCl3, 300 MHz): d 7.32 (s, 1H, NH), 7.22 (d, 2H, J¼
8.7 Hz, aromatic H), 6.68–6.59 (m, 5H, aromatic H), 5.84
(s, 2H, –CH2–), 4.31 (s, 2H, CH2), 2.87 (s, 3H, NCH3), 2.04
(s, 3H, –COCH3). Anal. calcd: C, 68.44; H, 6.08; N, 9.39.
Found: C, 68.20; H, 6.15; N, 9.05.
4.3.2. Methyl 4-(N-isobutyl-N-methylamino)benzoate
(entry 2). The reduction of methyl 4-nitrobenzoate followed
by double reductive alkylation with 2-butanone and 37%
formaldehyde gave a tertiary amine in 92% yield as a pale
yellow syrup. 1H NMR (CDCl3, 300 MHz): d 7.87 (dd, 2H,
J¼7.2, 2.1 Hz, aromatic H), 6.70 (dd, 2H, J¼7.2, 2.1 Hz,
aromatic H), 3.89–3.96 (m, 1H, CH), 3.84 (s, 3H,
COOCH3), 2.78 (s, 3H, NCH3), 1.53–1.61 (m, 2H, CH2),
1.15 (d, 3H, J¼6.6 Hz, –CH3), 0.86 (t, 3H, J¼7.2 Hz,
–CH3). Anal. calcd: C, 70.56; H, 8.65; N, 6.33. Found: C,
10.23; H, 8.73; N, 6.14.
4.2.15. N-Isopropyl-N-methyl-p-toluidine (entry 15). The
double reductive alkylation of p-toluidine with acetone and
37% formaldehyde gave a tertiary amine in 91% yield as a
1
pale yellow syrup. H NMR (CDCl3, 300 MHz): d 7.05
(d, 2H, aromatic H), 6.83 (d, 2H, J¼9 Hz), 6.74 (d, 2H,
J¼9 Hz) 4.03 (m, 1H, C–H), 2.70 (d, 3H, J¼0.9 Hz,
NCH3), 2.26 (s, 3H, CH3), 1.14 (m, 6H, (–CH3)2). Anal.
calcd: C, 80.93; H, 10.50; N, 8.58. Found: C, 81.14; H,
10.69; N, 8.84.
4.3.3. 4-(N-Isobutyl-N-methylamino)phenylacetonitrile
(entry 3). The reduction of 4-nitrophenylacetonitrile
followed by double reductive alkylation with 2-butanone
and 37% formaldehyde gave a tertiary amine in 87% yield
1
as a yellow syrup. H NMR (CDCl3, 300 MHz): d 7.07
(d, 2H, J¼8.7 Hz, aromatic H), 6.67 (d, 2H, J¼8.7 Hz,
aromatic H), 3.75 (m, 1H, CH), 3.56 (s, 2H, benzyl-CH2),
2.63 (s, 3H, NCH3), 1.52 (m, 2H, –CH2), 1.04 (d, 3H,
J¼6.6 Hz, –CH3), 0.80 (t, 3H, J¼7.5 Hz, –CH3). Anal.
calcd: C, 77.18; H, 8.97; N, 13.85. Found: C, 76.95; H, 9.11;
N, 13.69.
4.2.16. N-Benzyl-N-methyl-4-anisidine (entry 16). The
double reductive alkylation of p-anisidine with benz-
aldehyde and 37% formaldehyde gave a tertiary amine in
95% yield as a pale yellow syrup. 1H NMR (CDCl3,
300 MHz): d 7.31–7.23 (m, 5H, aromatic H), 6.83 (d,
4H, J¼9 Hz, aromatic H), 4.43 (s, 2H, benzyl –CH2),
3.75 (s, 3H, O–CH3), 2.92 (s, 3H, N–CH3). Anal. calcd:
C, 79.26; H, 7.54; N, 6.16. Found: C, 78.95; H, 7.79; N,
6.31.
4.3.4. (N-Isobutyl-N-methyl)-4-acetamidoaniline (entry
4). The reduction of 4-nitroacetanilide followed by double
reductive alkylation with 2-butanone and 37% formal-
dehyde gave a tertiary amine in 95% yield as a white solid.
1
4.2.17. N-Benzyl-N-methyl-N-piperoylamine (entry 17).
The reaction of benzylamine with piperonal and 37%
formaldehyde gave a tertiary amine in 92% yield as a
Mp: 109.48C. H NMR (CDCl3, 300 MHz): d 7.28 (d, 2H,
J¼8.7 Hz, aromatic H), 6.72 (d, 2H, J¼8.7 Hz, aromatic H),
3.73–3.75 (m, 1H, CH), 2.67 (s, 3H, NCH3), 2.13 (s, 3H,
–COCH3), 1.64–1.44 (m, 2H, –CH2), 1.08 (d, 3H, J¼
6.6 Hz, –CH3), 0.85–0.91 (m, 3H, –CH3). Anal. calcd: C,
70.87; H, 9.15; N, 12.72. Found: C, 71.11; H, 9.23; N, 12.79.
1
colorless syrup. H NMR (CDCl3, 300 MHz): d 7.34–7.29
(m, 5H, aromatic H), 6.91 (s, 1H), 6.75 (d, 2H, J¼1.2 Hz,
aromatic H), 5.94 (s, 2H, benzyl –CH2), 3.50 (s, 2H,
–CH2), 3.42 (s, 2H, –CH2), 2.16 (s, 3H, NCH3). Anal.
calcd: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.51; H, 6.98;
N, 5.69.
4.3.5. 4-(N-Isobutyl-N-methylamino)benzyl alcohol
(entry 5). The reduction of 4-nitrobenzyl alcohol followed

Y. J. Jung et al. / Tetrahedron 59 (2003) 10331–10338
10337
by double reductive alkylation with 2-butanone and 37%
formaldehyde gave a tertiary amine in 86% yield as a light
yellow syrup. H NMR (CDCl3, 300 MHz): d 7.07 (d, 2H,
J¼8.7 Hz, aromatic H), 6.67 (d, 2H, J¼8.7 Hz, aromatic H),
3.75 (m, 1H, CH), 3.56 (s, 2H, benzyl-CH2), 2.63 (s, 3H,
NCH3), 1.45–1.57 (m, 2H, –CH2), 1.04 (d, 3H, J¼6.6 Hz,
–CH3), 0.80 (t, 3H, J¼7.5 Hz, –CH3). Anal. calcd: C,
74.57; H, 9.91; N, 7.25. Found: C, 74.35; H, 9.80; N, 7.02.
using a solution of ethyl acetate and n-hexane (1:7) gave a
tertiary amine in 84% yield as a pale yellow syrup. 1H NMR
(CDCl3, 300 MHz): d 7.10 (d, 2H, J¼8.4 Hz, aromatic H),
7.03 (d, 2H, J¼6.6 Hz, aromatic H), 6.76 (d, 2H, J¼6.6 Hz,
aromatic H), 6.68 (d, 2H, J¼8.4 Hz, aromatic H), 2.92 (s,
2H, benzyl-CH2), 2.27 (s, 3H, NCH3). Anal. calcd: C, 79.26;
H, 7.54; N, 6.16. Found: C, 79.51; H, 7.41; N, 6.31.
1
4.4.3. N-(4-[Methyl-(1-(4-bromobenzyl)-4-acetamido-
aniline (entry 10). The reduction of 4-nitroacetanilide
followed by double reductive alkylation with 4-bromoben-
zaldehyde and 37% formaldehyde (31 ml, 0.416 mmol) and
chromatography on silica gel column using a solution of
ethyl acetate and n-hexane (1:1) gave a tertiary amine
4.3.6. N-Isobutyl-N-methyl-p-toluidine (entry 6). The
reduction of 4-nitrotoluene followed by double reductive
alkylation of 2-butanone and 37% formaldehyde gave a
tertiary amine in 93% yield as a light yellow syrup. 1H NMR
(CDCl3, 300 MHz): d 7.03 (d, 2H, J¼8.7 Hz, aromatic H),
6.71 (d, 2H, J¼8.7 Hz, aromatic H), 3.71–3.78 (m, 1H,
CH), 2.67 (s, 3H, NCH3), 2.24 (s, 3H, –CH3), 1.56–1.63
(m, 2H, –CH2), 1.08 (d, 3H, J¼6.6 Hz, –CH3), 0.88 (t, 3H,
J¼7.2 Hz, –CH3). Anal. calcd: C, 81.30; H, 10.80; N, 7.90.
Found: C, 81.02; H, 10.48; N, 8.12.
1
(92 mg, 99%) as a pale white solid. Mp: 1178C. H NMR
(CDCl3, 300 MHz): d 7.41 (d, 2H, J¼8.7 Hz, aromatic H),
7.28 (d, 2H, J¼9 Hz, aromatic H), 7.08 (d, 2H, J¼8.7 Hz,
aromatic H), 6.66 (d, 2H, J¼9 Hz, aromatic H), 4.43 (s, 2H,
benzyl-CH2), 2.97 (s, 3H, NCH3), 2.13 (s, 3H, –COCH3).
Anal. calcd: C, 57.67; H, 5.14; N, 8.41. Found: C, 57.39; H,
4.01; N, 8.68.
4.3.7. Ethyl 3-(N-methyl-N-4-tolylamino)butanoate
(entry 7). The reduction of 4-nitrotoluene followed by
double reductive alkylation with ethyl acetoacetate and 37%
formaldehyde (30 ml, 1.09 mmol) gave a tertiary amine in
98% yield as a light yellow syrup. 1H NMR (CDCl3,
300 MHz): d 7.04 (d, 2H, J¼8.4 Hz, aromatic H), 6.78 (d,
2H, J¼8.4 Hz, aromatic H), 4.37–4.39 (m, 1H, CH), 4.07
(q, 2H, J¼7.2 Hz, COOCH2), 2.68 (s, 3H, NCH3), 2.60 (dd,
1H, J¼7.5 Hz, CH2), 2.40 (dd, 1H, J¼7.5 Hz, CH2), 2.24 (s,
3H, –CH3), 1.16–1.22 (m, 6H, –(CH3)2). Anal. calcd: C,
71.46; H, 8.99; N, 5.95. Found: C, 71.14; H, 9.13; N, 5.71.
4.4.4. N-Piperoyl-N-methyl-4-aminophenylacetonitrile
(entry 11). The reduction of 4-nitrophenylacetonitrile
followed double reductive alkylation with piperonal and
37% formaldehyde and chromatography on silica gel
column using a solution of ethyl acetate and n-hexane
(1:4) gave a tertiary amine in 96% yield as a pale yellow
1
syrup. H NMR (CDCl3, 300 MHz): d 7.13 (d, 2H, J¼
8.7 Hz, aromatic H), 6.77–6.65 (m, 5H, aromatic H), 5.93
(s, 2H, –CH2), 4.43 (s, 2H, benzyl-CH2), 3.63 (s, 2H,
benzyl-CH2), 3.00 (s, 3H, NCH3). Anal. calcd: C, 72.84; H,
5.75; N, 9.99. Found: C, 72.66; H, 5.97; N, 9.67.
4.4. Reduction of nitro group followed by double
reductive alkylation using aldehydes and 37%
formaldehyde (Table 2, entries 8–11)
4.4.5. N-4-[Methyl-(1-phenylethyl)-amino]-phenylaceta-
mide (entry 12). The reduction of 4-nitroacetanilide
followed double reductive alkylation with acetophenone
and 37% formaldehyde and chromatography on silica gel
column using a solution of ethyl acetate and n-hexane (1:4)
gave a tertiary amine in 87% yield as a white solid. Mp:
128–1298C. 1H NMR (CDCl3, 300 MHz): d 7.35–7.25 (m,
7H, aromatic H), 7.01 (s, 1H), 6.80–6.77 (d, 2H, J¼9.0 Hz),
5.09–5.02 (q, 1H, J¼6.6 Hz), 2.65 (s, 3H), 2.14 (s, 3H),
1.53 (d, 3H, J¼6.6 Hz). Anal. calcd: C, 76.09; H, 7.51; N,
10.44. Found: C, 75.82; H, 7.39; N, 10.69.
4.4.1. N-4-Bromobenzyl-N-methyl-4-chloroaniline
(entry 8). To a solution of 1-chloro-4-nitrobenzene
(50 mg, 0.317 mmol) in methanol (5 ml) was added two
drops of acetic acid, decaborane (11 mg, 0.095 mmol) and
10% Pd/C (15 mg). The resulting solution was heated to
reflux under nitrogen for 0.5 h and the mixture was cooled
to room temperature. 4-Bromobenzaldehyde (70.5 mg,
0.380 mmol) and decaborane (7.7 mg, 0.063 mmol) were
then added to the reaction mixture. The solution was stirred
at rt under nitrogen for 0.5 h. And then 37% formaldehyde
(35 ml, 0.475 mmol), decaborane (7.7 mg, 0.063 mmol) was
added to the mixture. The resulting solution was stirred at rt
under nitrogen for 0.5 h. The mixture was concentrated
under reduced pressure, chromatographed on a short pad of
silica gel using a solution of methylene chloride and
n-hexane (1:20) and concentrated to give a tertiary amine
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1
(71 mg, 72%) as a pale yellow syrup. H NMR (CDCl3,
300 MHz): d 7.43 (d, 2H, J¼8.4 Hz, aromatic H), 7.14
(d, 2H, J¼9 Hz, aromatic H), 7.06 (d, 2H, J¼8.4 Hz,
aromatic H), 6.61 (d, 2H, J¼9 Hz, aromatic H), 4.44 (s, 2H,
benzyl-CH2), 2.99 (s, 3H, NCH3). Anal. calcd: C, 54.13; H,
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