Catalyst-free one-pot reductive alkylation of primary and secondary amines and N,N-dimethylation of amino acids using sodium borohydride in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1055/s-0030-1258384

A simple and convenient procedure for the reductive alkylation of primary and secondary amines and N,N-dimethylation of amino acids is described using sodium borohydride as a reducing agent in 2,2,2- trifluoroethanol without use of a catalyst or any other additive. The solvent can be readily recovered from reaction products in excellent purity for direct reuse. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258384

490
PAPER
Catalyst-Free One-Pot Reductive Alkylation of Primary and Secondary
Amines and N,N-Dimethylation of Amino Acids Using Sodium Borohydride in
2,2,2-Trifluoroethanol
O
ne-Pot Reductive Alk
a
ylation of
h
y
and
mS
econdary Amines ood Tajbakhsh,*a Rahman Hosseinzadeh,a Heshmatollah Alinezhad,a Somayeh Ghahari,a Akbar Heydari,b
Samad Khaksarc
a
Fax +98(112)5342350; E-mail: Tajbaksh@umz.ac.ir
Chemistry Department, Tarbiat Modares University, P. O. Box 14115-175, Tehran 18716, Iran
Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, P.O. Box 678, Amol, Iran
b
c
Received 9 November 2010; revised 25 November 2010
amination of carbonyl compounds in air and in the pres-
Abstract: A simple and convenient procedure for the reductive
alkylation of primary and secondary amines and N,N-dimethylation
of amino acids is described using sodium borohydride as a reducing
agent in 2,2,2- trifluoroethanol without use of a catalyst or any other
additive. The solvent can be readily recovered from reaction prod-
ucts in excellent purity for direct reuse.
ence of moisture, it should be of considerable interest.
Thus, it is challenging to develop such an effective cata-
lyst or reagent.
Environmental concern associated with chemical synthe-
sis has posed stringent and compelling demands for green-
er processes.13 Fluorinated solvents have attracted an
increasing interest in the context of green synthesis during
recent years. Fluorinated solvents were initially intro-
duced as an alternative green reaction media because of
their unique chemical and physical properties of nonvola-
tility, nonflammability, polarity, high ionizing power, and
low nucleophilicity. Therefore, today they have marched
far beyond this border, showing their significant role in
controlling the reaction as powerful reaction media.14 Re-
actions in fluorinated solvents are generally selective and
without effluents, allowing thus a facile isolation of the
product and a recovery of the solvent by distillation. Due
to the current challenges for developing environmentally
benign synthetic processes and in continuation of our in-
terest in the application of fluorinated solvents for various
organic transformations,15 we report a simple and conve-
nient procedure for the high yielding direct reductive
amination of aldehydes and ketones with NaBH4 in 2,2,2-
trifluoroethanol (TFE) (Scheme 1).
Key words: reductive amination, 2,2,2-trifluoroethanol, sodium
borohydride, reductive methylation
Secondary or tertiary amino group is often embedded as a
structural motif in various biologically active com-
pounds,1,2 which are important intermediates in the syn-
thesis of pharmaceutically active substances, dyes, and
fine chemicals.3 The direct reductive amination of alde-
hydes and ketones with metal hydride reagents is one of
the most useful methods for the synthesis of secondary
and tertiary amines.4 Several reagents which effect reduc-
tive amination have been developed, including: catalytic
hydrogenation,4b
Et3SiH–CF3CO2H,5
Zn/AcOH,6
Bu2SnClH/HMPA,7 NaBH3CN,8a NaBH(OAc)3,8b pyri-
dine·BH3,8c ZnCl2/ZnBH4,8d silica gel/Zn(BH4)2,8e
Ti(Oi-Pr)4/NaBH4,8f NiCl2/NaBH4,8g NaBH4/ZrCl4,8h
NaBH4/H2SO4,8i NaBH4/H3PW12O40,8j NaBH4/guanidine
hydrochloride,8k NaBH4/wet clay-microwave,8l borohy-
dride exchange resin,8m N-methylpyrrolidine/zinc borohy-
dride,9 InCl3/Et3SiH,10ZnClO4/InCl3/Et3SiH,11 and zir-
conium borohydride/piperazine complex.12 However,
some of these preparations require relatively expensive
reagents, harsh reaction conditions, and sometimes te-
dious workup; produce heavy metals as toxic waste; gen-
erate toxic by-products; have no chemoselectivity; and
suffer from lack of solubility of reagents in most common
organic solvents. Furthermore, sometimes direct reduc-
tive amination is performed under anhydrous conditions
in order to avoid decomposition of the reducing agents or
catalysts, and to enhance generation of the intermediate
imines or iminium ions. As a result, the selection of the re-
agent is crucial. If one could perform the direct reductive
O
H
N
R2
R1
R4
R3
NaBH4
TFE
+
N
R1
R2
R3
R4
R1, R2 , R3 , R4 = H, aryl, alkyl
Scheme 1 Reductive amination of aldehydes and ketones
To show the effectiveness of TFE in this reaction, aniline
was treated with 4-chlorobenzaldehyde in the presence of
NaBH4 at 35–40 °C in different organic solvents and the
results are presented in Table 1.
It is clear from Table 1 that TFE exert beneficial rate ac-
celeration on the amination of 4-chlorobenzaldehyde
(Table 1, entry 3), whereas reaction in ethanol and meth-
anol proceeds quite slowly (entries 1 and 2). Reaction in
SYNTHESIS 2011, No. 3, pp 0490–0496
x
x
.
x
x
.2
0
1
1
Advanced online publication: 28.12.2010
DOI: 10.1055/s-0030-1258384; Art ID: Z26810SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Reductive Alkylation of Primary and Secondary Amines
491
amine in high isolated yield (Table 2, entry 14). Compa-
rably, ketones were efficiently aminated with the aromatic
and aliphatic amines (Table 2, entries 20 and 27–32).
Table 1 Reductive Amination of 4-Chlorobenzaldehyde with
Aniline in Different Solvents
Entry
Solvent
EtOH
MeOH
TFE
Time (h)
10
Yield (%)a
In addition, N,N-dimethylamines are important intermedi-
ates in the production of pharmaceuticals, agrochemicals,
and fragrance compounds.1,2 Several reagents for N-meth-
ylation of the amino function to give tertiary amines have
been developed, including: sodium or potassium hydri-
dotetracarbonyl ferrate in ethanol or tetrahydrofuran,33 so-
1
2
3
4
5
6
80
84
93
33
48
45
10
10 min
12
H2O
dium
borohydride
in
methanol,34
sodium
cyanotrihydridoborate in acetonitrile,35 ZnCl2/NaBH4,36
NaBH4 in THF,37 MeS·BH3,38 zinc-modified cyanoboro-
hydride,4e Zr(BH4)2Cl2(dabco)2, ZrBDC,21 ZBNMPP,39
Ti(Oi-Pr)4/NaBH4,40 carboxylic acids/NaBH4,41 and
NaBH3CN/MeCN.8a Besides, N,N-dimethylated a-amino
acids are very important compounds in biological
chemistry42 and several reagents such as formaldehyde/
palladized charcoal/H2,43–46 formaldehyde/sodium cy-
anoborohydride,47 formaldehyde/zinc,48 and formalde-
hyde/Pd(OH)2/C49 have been reported for their synthesis
in the literature. Good yields and selectivities for the prep-
aration of N,N-dimethylamino acids have been achieved
only by indirect multistep procedures.50 Although most of
these procedures are effective, some of them have certain
drawbacks, for example: tedious workup,33 formation of
aminodiethers34 or cyanide ion,35 partial methylation,35
long reaction times,36 acidic condition,37 and use of tran-
sition-metal catalyst or hydrogen atmosphere.43–46 Here,
we report an efficient method for N-methylation of
amines and amino acids to tertiary products using
paraformaldehyde and NaBH4 in TFE (Scheme 2).
MeCN
THF
12
12
a Yields refer to the isolated product, N-(4-chlorophenyl)benzylamine.
other solvents even at longer time did not give acceptable
yield of the product (entries 4–6).
Then, the reductive amination of a wide variety of aliphat-
ic, aromatic and heterocyclic carbonyl compounds (1
mmol) with primary and secondary amines (1 mmol) us-
ing NaBH4 (1.2 mmol) in TFE (2 mL) was examined at
35–40 °C for 1–35 minutes. The pure desired products
were obtained in excellent yields (88–96%), simply by fil-
tration of the reaction mixture and distilling off the sol-
vent as summarized in Table 2. It is worth to mention that
under our standard conditions, direct reductive amination
of 4-cyano- or 2-nitrobenzaldehydes with aniline pro-
ceeded smoothly to give the desired alkylated anilines
(Table 2, entries 2 and 6). With these results in hand, the
regioselective one-pot reductive amination of trans-cin-
namaldehyde with aniline similarly afforded the expected
Table 2 Reductive Amination of Carbonyl Compounds Using NaBH4 in TFEa
Entry
1
Aldehyde/ketone
PhCHO
Amine
Productb
Time (min)
Yield (%)c
9516
PhNH2
PhCH2NHPh
6
7
2
4-NCC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
3-ClC6H4CHO
2-O2NC6H4CHO
4-MeC6H4CHO
4-MeOC6H4CHO
PhCHO
PhNH2
4-NCC6H4CH2NHPh
4-ClC6H4CH2NHPh
2-ClC6H4CH2NHPh
3-ClC6H4CH2NHPh
2-O2NC6H4CH2NHPh
4-MeC6H4CH2NHPh
4-MeOC6H4CH2NHPh
4-ClC6H4NHCH2Ph
4-O2NC6H4NHCH2Ph
4-MeOC6H4NHCH2Ph
4-EtOC6H4NHCH2Ph
4-MeC6H4NHCH2Ph
PhCH=CHCH2NHPh
PhCH2NHCH2Ph
9417
3
PhNH2
10
10
10
10
15
35
5
9312
4
PhNH2
9418
5
PhNH2
9318
6
PhNH2
908k
7
PhNH2
9219
8
PhNH2
9416
9
4-ClC6H4NH2
4-O2NC6H4NH2
4-MeOC6H4NH2
4-EtOC6H4NH2
4-MeC6H4NH2
PhNH2
9320
10
11
12
13
14
15
PhCHO
10
5
928b
PhCHO
9420
PhCHO
10
4
9621
PhCHO
9422
PhCH=CHCHO
PhCHO
20
16
9023
PhCH2NH2
9320
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York

492
M. Tajbakhsh et al.
PAPER
Table 2 Reductive Amination of Carbonyl Compounds Using NaBH4 in TFEa (continued)
Entry
16
Aldehyde/ketone
PhCHO
Amine
Productb
Time (min)
30
Yield (%)c
9424
PhNHMe
PhCH2N(Me)Ph
8816
9016
9125
H
H
17
18
19
PhNH2
PhNH2
6
8
5
N
Ph
Ph
O
O
O
S
H
H
N
S
O
PhCHO
Ph
N
N
N
NH2
H
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
PhCOMe
PhNH2
PhCH(Me)NHPh
27
2
9023
929
PhCHO
morpholine
piperidine
pyrrolidine
CH2=CHCH2NH2
i-PrNH2
4-benzylmorpholine
1-benzylpiperidine
PhCHO
4
9526
9427
9227
9028
938b
9216
9116
9329
9430
9228
9231
9319
9032
PhCHO
1-benzylpyrrolidine
PhCH2NHCH2CH=CH2
PhCH2NHi-Pr
8
PhCHO
1
PhCHO
2
PhCHO
t-BuNH2
PhCH2NHt-Bu
2
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
Me(CH2)4COMe
MeCH2CH2CHO
MeCH2CH2CHO
PhNH2
cyclohexylphenylamine
4-cyclohexylmorpholine
1-cyclohexylpiperidine
1-cyclohexylpyrrolidine
allylcyclohexylamine
Me(CH2)4CH(Me)NHPh
MeCH2CH2CH2NHPh
1-butylpyrrolidine
22
5
morpholine
piperidine
pyrrolidine
CH2=CHCH2NH2
PhNH2
1
4
1
2
PhNH2
5
pyrrolidine
1
a All reactions were carried out at 35–40 °C and the molar ratio of NaBH4/carbonyl compound/amine was 1.2:1:1.
b All products were characterized by spectroscopic data (NMR, IR), physical properties, and by comparison with authentic samples.
c Yields refer to pure isolated products.
H
N
reaction in other solvents listed in Table 3 did not afford
any reasonable yield of the product (<10%).
Me
N
NaBH4
+
(HCHO)n
R1
R2
TFE, reflux
R1
R2
Table 3 Screening of Solvents for N,N-Dimethylation of p-Tolu-
idine with Paraformaldehyde
R1, R2 = H, alkyl, aryl
Scheme 2 Reductive methylation of amines
Entry
Solventa
EtOH
MeOH
TFE
Time (h)
Yield (%)b
1
2
3
4
5
2
20
24
93
15
15
Similar to reductive amination, the effect of solvent was
examined and the results in Table 3 for the reaction of p-
toluidine with paraformaldehyde and NaBH4 in 1:5:2 mo-
lar ratio showed beneficial rate acceleration in the forma-
tion of N,N-dimethyl-p-toluidine in TFE (Table 3, entry
3). When phenylglycine, as representative of an amino
acid, reacted with paraformaldehyde and NaBH4 in a1:9:4
molar ratio in TFE for 40 hours, a high yield (89%) of
N,N-dimethylphenylglycine was obtained, whereas this
2
1.30
2
H2O
THF
2
a All reactions were carried out at the solvent’s boiling point.
b Yields refer to the isolated product, N,N-dimethyl-p-toluidine.
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York

PAPER
One-Pot Reductive Alkylation of Primary and Secondary Amines
493
Table 4 Reductive Methylation of Amines and Amino Acids with (HCHO)n/NaBH4 in TFEa
Entry
1
Amine or amino acid
PhNHMe
Productb
Time (h)
1.10
1.30
2
Yield (%)c
9321
9336
9428
9521
9440
9051
9251
8728
8529
8852
908h
9153
9342
89
PhNMe2
2
4-MeOC6H4NH2
4-MeC6H4NH2
4-EtOC6H4NH2
4-BrC6H4NH2
4-ClC6H4NH2
4-O2NC6H4NH2
morpholine
4-MeOC6H4NMe2
4-MeC6H4NMe2
3
4
4-EtOC6H4NMe2
4-BrC6H4NMe2
1.15
4.30
6.30
7
5
6
4-ClC6H4NMe2
7
4-O2NC6H4NMe2
4-methylmorpholine
1-methylpiperidine
1-methylpyrrolidine
PhCH2NMe2
8
3.20
4.15
3.50
3.10
2.40
16
9
piperidine
10
11
12
13
14
15
16
17
pyrrolidine
PhCH2NH2
cyclohexylamine
4-H2NC6H4NH2
a-phenylglycine
alanine
N,N-dimethylcyclohexylamine
4-Me2NC6H4NMe2
N,N-dimethyl-a-phenylglycine
N,N-dimethylalanine
N,N-dimethylglycine
40
48
90
glycine
24
91
L-phenylalanine
N,N-dimethyl-L-phenylalanine
{[a]D20 +76}
24
89
{[a]D20 –34}
18
19
leucine
proline
N,N-dimethylleucine
N-methylproline
48
72
88
87
a All reactions were carried out at reflux temperature with a molar ratio of amine/paraformaldehyde/NaBH4 = 1:5:2 for entries 1–4 and 8–13;
1:8:4 for entries 5–7; and 1:9:4 for entries 14–19.
b All products were characterized by spectroscopic data (NMR, IR), physical properties, and by comparison with authentic samples.
c Yields refer to pure isolated products.
To test the generality of this procedure, various amines changed as determined by measurement of optical rota-
were subjected to reductive methylation and the results tion of the corresponding product (Table 4, entry 17). An
are presented in Table 4. As shown in Table 4, reductive interesting feature of this method is that TFE can be easily
methylation of aromatic amines with different substitu- recovered by distillation and reused for several times.
ents gives excellent yields of the corresponding tertiary
In summary, we have introduced a simple procedure for
amines (Table 4, entries 1–4). We did not encounter any
the reductive amination of aldehydes and ketones with
problem in the methylation of low basicity amines such as
NaBH4 in TFE without using any catalyst or additives. In
4-nitro- and 4-chloroanilines, but just for completion of
addition, N-methylation of amines and amino acids to
the reaction, higher amounts of reagents were required
their corresponding tertiary products were also achieved
(Table 4, entries 5–7). Reductive methylation of aliphatic
using paraformaldehyde and NaBH4 in TFE. Simple
amines such as piperidine, cyclohexylamine, pyrrolidine,
workup procedure, excellent yields, neutral reaction con-
morpholine, and benzylamine under reaction conditions
ditions, recovery of solvent, and no special handling tech-
gave good to excellent yields of the expected tertiary
niques are some advantages of this protocol, which makes
amines (Table 4, entries 8–12). Similarly, 1,4-phenylene-
it a good alternative to the existing methods.
diamine was reacted to give N,N,N¢,N¢-tetramethyl-1,4-
phenylenediamine in excellent yield (Table 4, entry 13).
This procedure was then applied to some amino acids. As
N-Monoalkylation of Amines and Amine Derivatives; General
Procedure
A solution of the appropriate carbonyl compound (1 mmol) and
TFE (2 mL) was magnetically stirred at 35–40 °C. After 5 min, the
respective amine (1 mmol) was added, and the mixture vigorously
shown in Table 4, the amino acids were N,N-dimethylated
under reaction conditions (Table 4, entries 14–19). It is in-
teresting to mention that during the course of this reaction
the stereogenic center of starting amino acid is not
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York

494
M. Tajbakhsh et al.
PAPER
stirred. After stirring for 5 min, NaBH4 (1.2 mmol) was added and
the progress of the reaction conversion was followed by TLC (hex-
ane–EtOAc, 4:1). After completion of the reaction, the mixture was
filtered and the residue was washed with TFE (2 mL). The solvent
was distilled off (to recover for the next run) and the pure product
was obtained (Table 2). If necessary, the crude product was further
purified either by crystallization or silica gel column chromatogra-
phy with EtOAc–hexane as eluent. All products were characterized
on the basis of their spectroscopic data (IR, NMR) and by compar-
ison with those reported in the literature.
13C NMR (100 MHz, CDCl3): d = 151.55, 142.57, 139.88, 128.69,
127.66, 127.25, 115.87, 114.19, 64.17, 49.29, 15.16.
N-Benzyl-N-(4-methylphenyl)amine (Table 2, entry 13)
1H NMR (400 MHz, CDCl3): d = 7.47–7.34 (m, 5 H), 7.08 (d,
J = 8.1 Hz, 2 H), 6.65 (d, J = 8.1 Hz, 2 H), 4.38 (s, 2 H), 3.90 (br s,
1 H), 2.34 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 146.01, 139.77, 129.85, 128.69,
127.59, 127.24, 126.81, 113.11, 48.71, 20.51.
N,N-Dimethyl-p-anisidine (Table 4, entry 2)
N,N-Dimethylation of Amines and Amino Acids; General Pro-
cedure
1H NMR (300 MHz, CDCl3): d = 6.86 (d, J = 9.2 Hz, 2 H), 6.79 (d,
J = 9.2 Hz, 2 H), 3.78 (s, 3 H), 2.88 (s, 6 H).
In a round-bottomed flask (25 mL) equipped with a magnetic stirrer
and a condenser, a mixture of the required amine or amino acid (1
mmol) and paraformaldehyde (5–9 mmol) in 2,2,2-trifluoroethanol
(5 mL) was prepared. Then, NaBH4 (2–4 mmol) was added and the
mixture was stirred under reflux conditions. In some cases
paraformaldehyde and NaBH4 were added gradually until the reac-
tion was complete (Table 4, entries 5–7 and 14–19). After comple-
tion of the reaction, the mixture was filtered and the residue was
washed with TFE (2 mL). The solvent was distilled off (to recover
for next run) and the pure product was obtained. If necessary, the
crude product was further purified by column chromatography on
silica gel. In the case of amino acids, the crude products were re-
crystallized from MeOH–acetone (Table 4). All products are known
compounds and characterized by comparison with those reported in
the literature. 1H and 13C NMR spectra of known compounds were
found to be identical with those reported in the literature.
N,N-Dimethyl-p-phenetidine (Table 4, entry 4)
1H NMR (400 MHz, CDCl3): d = 6.87 (d, J = 9.0 Hz, 2 H), 6.79 (d,
J = 9.0 Hz, 2 H), 4.01 (q, J = 7.0 Hz, 2 H), 2.90 (s, 6 H), 1.42 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 151.32, 145.72, 115.49, 114.94,
64.05, 41.86, 15.05.
4-Bromo-N,N-dimethylaniline (Table 4, entry 5)
1H NMR (300 MHz, CDCl3): d = 7.30 (d, J = 9.0 Hz, 2 H), 6.59 (d,
J = 9.0 Hz, 2 H), 2.93 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 149.51, 131.68, 114.11, 108.51,
40.57.
4-Chloro-N,N-dimethylaniline (Table 4, entry 7)
1H NMR (400 MHz, CDCl3): d = 7.19 (d, J = 9.0 Hz, 2 H), 6.66 (d,
J = 9.0 Hz, 2 H), 2.95 (s, 6 H).
Spectroscopic data for selected examples follow:
N-Phenylbenzylamine (Table 2, entry 1)
1H NMR (300 MHz, CDCl3): d = 7.48–7.35 (m, 5 H), 7.28 (t,
J = 8.4 Hz, 2 H), 6.82 (t, J = 7.3 Hz, 1 H), 6.72 (d, J = 8.5 Hz, 2 H),
4.40 (s, 2 H), 4.10 (br s, 1 H, NH).
N,N,N¢,N¢-Tetramethyl-1,4-phenylenediamine (Table 4, entry
13)
1H NMR (400 MHz, CDCl3): d = 6.84 (s, 4 H), 2.90 (s, 12 H).
13C NMR (100 MHz, CDCl3): d = 144.05, 115.43, 42.08.
13C NMR (75 MHz, CDCl3): d = 148.25, 139.56, 129.37, 128.73,
127.61, 127.32, 117.66, 112.97, 48.39.
N,N-Dimethyl-a-phenylglycine (Table 4, entry 14)
1H NMR (400 MHz, DMSO-d6): d = 7.44–7.36 (m, 5 H), 4.15 (s, 1
H), 2.47 (s, 6 H).
13C NMR (100 MHz, D2O): d = 171.80, 131.12, 130.28, 129.52,
129.15, 74.50.
N-(4-Cyanobenzyl)-N-phenylamine (Table 2, entry 2)
1H NMR (300 MHz, CDCl3): d = 7.61 (d, J = 8.3 Hz, 2 H), 7.49 (d,
J = 8.3 Hz, 2 H), 7.21 (t, J = 8.0 Hz, 2 H), 6.77 (t, J = 7.3 Hz, 1 H),
6.62 (br d, J = 8.1 Hz, 2 H), 4.44 (s, 2 H), 4.33 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 147.56, 145.62, 132.47, 129.42,
N,N-Dimethylalanine (Table 4, entry 15)
127.78, 119.06, 118.04, 112.95, 110.77, 47.74.
1H NMR (400 MHz, DMSO-d6): d = 3.31 (q, J = 7.2 Hz, 1 H), 2.59
(s, 6 H), 1.25 (d, J = 7.2 Hz, 3 H).
N-(3-Chlorophenyl)benzylamine (Table 2, entry 5)
1H NMR (400 MHz, CDCl3): d = 7.46 (s, 1 H), 7.36–7.32 (m, 3 H),
7.31 (t, J = 8.0 Hz, 2 H), 6.85 (t, J = 7.3 Hz, 1 H), 6.70 (d, J = 8.1
Hz, 2 H), 4.38 (s, 2 H), 4.01 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 147.90, 141.90, 134.59, 130.01,
129.43, 127.50, 127.45, 125.52, 117.94, 113.01, 47.81.
13C NMR (100 MHz, DMSO-d6): d = 170.46, 65.45, 40.87, 13.00.
N,N-Dimethylglycine (Table 4, entry 16)
1H NMR (400 MHz, DMSO-d6): d = 3.26 (s, 2 H), 2.62 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 167.31, 60.90, 43.73.
N-(2-Nitrophenyl)benzylamine (Table 2, entry 6)
N,N-Dimethylphenylalanine (Table 4, entry 17)
1H NMR (400 MHz, DMSO-d6): d = 7.29–7.24 (m, 5 H), 3.42 (dd,
J = 8, 6.8 Hz, 1 H), 2.99 (dd, J = 14.0, 8.0 Hz, 1 H), 2.86 (dd,
J = 14.0, 6.8 Hz, 1 H), 2.37 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 171.27, 139.15, 129.50,
128.62, 126.56, 69.47, 41.68, 34.74.
1H NMR (400 MHz, CDCl3): d = 8.11 (br d, J = 8.0 Hz, 1 H), 7.72
(d, J = 8.0 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1
H), 7.22 (t, J = 8.0 Hz, 2 H), 6.79 (t, J = 7.3 Hz, 1 H), 6.63 (d,
J = 8.4 Hz, 2 H), 4.76 (s, 2 H), 4.41 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 148.26, 147.53, 135.78, 133.77,
129.80, 129.42, 128.03, 125.21, 118.02, 112.95, 45.74.
N,N-Dimethylleucine (Table 4, entry 18)
1H NMR (400 MHz, DMSO-d6): d = 3.15 (dd, J = 8.8, 5.6 Hz, 1 H),
2.48 (s, 6 H), 1.74–1.67 (m, 1 H), 1.55–1.48 (m, 1 H), 1.43–1.38 (m,
1 H), 0.88 (t, J = 5.8 Hz, 6 H).
N-Benzyl-N-(4-ethoxyphenyl)amine (Table 2, entry 12)
1H NMR (400 MHz, CDCl3): d = 7.49–7.35 (m, 5 H), 6.89 (d,
J = 8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 4.36 (s, 2 H), 4.04 (q,
J = 7.0 Hz, 2 H), 3.79 (br s, 1 H), 1.48 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 171.14, 67.48, 41.18, 37.34,
23.45, 22.38.
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One-Pot Reductive Alkylation of Primary and Secondary Amines
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N-Methylproline (Table 4, entry 19)
M. J. Mol. Catal. A: Chem. 2007, 274, 169. (l) Varma, R.
S.; Dahiya, R. Tetrahedron 1998, 54, 6293. (m) Yoon, N.
M.; Kim, E. G.; Son, H. S.; Choi, J. Synth. Commun. 1993,
23, 1595.
1H NMR (400 MHz, DMSO-d6): d = 2.92 (t, J = 8.2 Hz, 1 H), 2.42–
2.38 (m, 1 H), 2.21 (s, 3 H), 2.06–1.99 (m, 1 H), 1.85–1.82 (m, 1 H),
1.69–1.57 (m, 3 H).
(9) Alinezhad, H.; Tajbakhsh, M.; Salehian, F.; Fazli, K.
Tetrahedron Lett. 2009, 50, 659.
(10) Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem.
2008, 73, 8829.
13C NMR (100 MHz, DMSO-d6): d = 154.65, 71.78, 56.46, 41.50,
29.76, 22.87.
(11) Lee, O. Y.; Law, K. L.; Yang, D. Org. Lett. 2009, 6, 3302.
(12) Heydari, A.; Khaksar, S.; Esfandyari, M.; Tajbakhsh, M.
Tetrahedron 2007, 63, 3363; and references cited therein.
(13) Gua, Y.; Lia, G. Adv. Synth. Catal. 2009, 351, 817.
(14) (a) Ben-Daniel, R.; De Visser, S. P.; Shaik, S.; Neumann, R.
J. Am. Chem. Soc. 2003, 125, 12116. (b) Abe, H.; Amii, H.;
Uneyama, K. Org. Lett. 2001, 3, 313. (c) Bégué, J. P.;
Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18. (d) Iskra,
J.; Bonnet-Delpon, D.; Bégué, J. P. Tetrahedron Lett. 2002,
43, 1001. (e) Legros, J.; Crousse, B.; Bonnet-Delpon, D.;
Bégué, J.-P. Eur. J. Org. Chem. 2002, 3290. (f)Ravikumar,
K. S.; Zhang, Y. M.; Bégué, J. P.; Bonnet-Delpon, D. Eur. J.
Org. Chem. 1998, 2937. (g) Kobayashi, S.; Tanaka, H.;
Amii, H.; Uneyama, K. Tetrahedron 2003, 59, 1547.
(15) (a) Heydari, A.; Khaksar, S.; Tajbakhsh, M. Synthesis 2008,
3126. (b) Heydari, A.; Khaksar, S.; Tajbakhsh, M.
Tetrahedron Lett. 2009, 50, 77. (c) Heydari, A.; Khaksar,
S.; Tajbakhsh, M.; Bijanzadeh, H. R. J. Fluorine Chem.
2009, 130, 609. (d) Khaksar, S.; Heydari, A.; Tajbakhsh,
M.; Bijanzadeh, H. R. J. Fluorine Chem. 2010, 131, 106.
(16) (a) Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725.
(b) Mohanazadeh, F.; Forozani, M.; Taheri, A. Monatsh.
Chem. 2007, 138, 1187. (c) Varma, R. S.; Dahiya, R.
Tetrahedron 1998, 54, 6293. (d) Imao, D.; Fujihara, S.;
Yamamoto, T.; Ohta, T.; Ito, Y. Tetrahedron 2005, 61, 6988.
(17) Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.; Bhanage,
B. M. Tetrahedron Lett. 2007, 48, 1273.
(18) Alinezhad, H.; Ardestani, E. Lett. Org. Chem. 2007, 4, 473.
(19) (a) Sreedhar, B.; Surendra Reddy, P.; Keerthi Devi, D.
J. Org. Chem. 2009, 74, 8806. (b) Bhor, M. D.; Bhanushali,
M. J.; Nandurkar, N. S.; Bhanage, B. M. Tetrahedron Lett.
2008, 49, 965.
(20) (a) Lai, R. Y.; Lee, C. I.; Liu, S. T. Tetrahedron 2008, 64,
1213. (b) Itoh, T.; Nagata, K.; Miyazaki, M.; Ishikawa, H.;
Kurihara, A.; Ohsawa, A. Tetrahedron 2004, 60, 6649.
(c) Itoh, T.; Nagata, K.; Miyazaki, M.; Kurihara, A.;
Ohsawa, A. Tetrahedron Lett. 2002, 43, 3105.
(21) (a) Firouzabadi, H.; Iranpoor, N.; Alinezhad, H. Bull. Chem.
Soc. Jpn. 2003, 76, 143. (b) Firouzabadi, H.; Iranpoor, N.;
Alinezhad, H. J. Iran. Chem. Soc. 2009, 6, 177; Chem. Abstr.
2009, 151, 225651m.
(22) Alinezhad, H.; Tajbakhsh, M.; Salehian, F. Monatsh. Chem.
2005, 136, 2029.
Acknowledgment
Financial support of this work from the Research Council of Uni-
versity of Mazandaran is gratefully acknowledged.
References
(1) Selected examples: (a) Lee, Y.; Ling, K. Q.; Lu, X.;
Silverman, R. B.; Shepard, E. M.; Dooley, D. M.; Sayre, L.
M. J. Am. Chem. Soc. 2002, 124, 12135. (b) Pettersson, B.;
Curvall, M.; Enzell, C. R. Toxicology 1982, 23, 41.
(c) Pettersson, B.; Curvall, M.; Enzell, C. R. Toxicology
1980, 18, 1; and references cited therein.
(2) Selected examples: (a) Occhiato, E. G.; Prandi, C.; Ferrali,
A.; Guarna, A.; Venturello, P. J. Org. Chem. 2003, 68,
9728. (b) Boger, D. L.; Yun, W.; Cai, H.; Han, N. Bioorg.
Med. Chem. 1995, 3, 761.
(3) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J.
J. Comb. Chem. 1999, 1, 55. (b) Henkel, T.; Brunne, R. M.;
Mueller, H.; Reichel, F. Angew. Chem. Int. Ed. 1999, 38,
643. (c) Berger, M.; Albrecht, B.; Berces, A.; Ettmayer, P.;
Neruda, W.; Woisetschläger, M. J. Med. Chem. 2001, 44,
3031. (d) Sharp, D. B. In Herbicides: Chemistry,
Degradation, and Mode of Action; Kearney, P. C.; Kaufman,
D. D., Eds.; Marcel Dekker: New York, 1988, 301.
(e) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M.
Tetrahedron 1992, 48, 4475.
(4) (a) Rylabder, P. N. Hydrogenation Methods; Academic
Press: New York, 1985. (b) Tarasevich, V. A.; Kozlov, N.
G. Russ. Chem. Rev. 1999, 68, 55. (c) Borch, R. F.;
Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93,
2897. (d) Hutchins, R. O.; Markowitz, M. J. Org. Chem.
1981, 46, 3571. (e) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.;
Kim, Y. J. J. Org. Chem. 1985, 50, 1927. (f) Mattson, R. J.;
Pham, K. M.; Leuck, D. J.; Cowen, K. A. J. Org. Chem.
1990, 55, 2552. (g) Brussee, J.; Van Benthem, R. A. T. M.;
Kruse, C. G.; van der Gen, A. Tetrahedron: Asymmetry
1990, 1, 163.
(5) Chen, B.-C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Znao,
R. Tetrahedron Lett. 2001, 42, 1245.
(6) Micovic, I. V.; Ivanovic, M. D.; Piatak, D. M.; Bojic, V. D.
Synthesis 1991, 1043.
(7) Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synthesis
2000, 789.
(23) Kangasmetsa, J. J.; Johnson, T. Org. Lett. 2005, 7, 5653.
(24) Alinezhad, H.; Tajbakhsh, M.; Hamidi, N. Chinese Chem.
Lett. 2010, 21, 47.
(25) Reddy, P. S.; Kanjilal, S.; Sunitha, S.; Prasad, R. B. N.
Tetrahedron Lett. 2007, 48, 8807.
(26) (a) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 55, 2552. (b) Saidi, M. R.;Stan Brown,
R.; Ziyaei-Halimjani, A. J. Iran. Chem. Soc. 2007, 4, 194;
Chem. Abstr. 2007, 147, 5416995v.
(27) (a) Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y.
Tetrahedron 2004, 60, 7899. (b) Robichaud, A.; Nait Ajjou,
A. Tetrahedron Lett. 2006, 47, 3633.
(8) (a) Lane, C. F. Synthesis 1975, 135. (b) Abdel-Magid, A.
F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R.
D. J. Org. Chem. 1996, 61, 3849. (c) Bomann, M. D.; Guch,
I. C.; Dimare, M. J. Org. Chem. 1995, 60, 5995.
(d) Bhattacharyya, S.; Chatterjee, A.; Duttachowdhury, S. K.
J. Chem. Soc., Perkin Trans. 1 1994, 1. (e) Ranu, B. C.;
Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63, 370.
(f) Bhattacharyya, S.; Neidigh, K. A.; Avery, M. A.;
Williamson, J. C. Synlett 1999, 1781. (g) Saxena, I.; Borah,
R.; Sarma, J. C. J. Chem. Soc., Perkin Trans. 1 2000, 503.
(h) Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928.
(i) Verardo, G.; Giumanin, A. G.; Strazzolini, P.; Poiana, M.
Synthesis 1993, 121. (j) Heydari, A.; Khaksar, S.; Akbari, J.;
Esfandyari, M.; Pourayoubi, M.; Tajbakhsh, M. Tetrahedron
Lett. 2007, 48, 1135. (k) Heydari, A.; Arefi, A.; Esfandyari,
(28) The Aldrich Library NMR Spectra, Edition II, Vol. 1;
Pourchet, C. J., Ed.; Aldrich Chemical Co.: Milwaukee,
1983.
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York

496
M. Tajbakhsh et al.
PAPER
(29) (a) Alinezhad, H.; Tajbakhsh, M.; Enayati Ahangar, R.
Monatsh. Chem. 2008, 139, 21. (b) Grenga, P. N.; Sumbler,
B. L.; Beland, F.; Priefer, R. Tetrahedron Lett. 2009, 50,
6658.
(30) Patmore, E. L.; Chafetz, H. J. Org. Chem. 1967, 32, 1254.
(31) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G.
Tetrahedron Lett. 1990, 31, 5595.
(32) Alinezhad, H.; Tajbakhsh, M.; Zare, M. Synth. Commun.
2009, 39, 2907.
(33) Boldrini, G. P.; Panunzio, M.; Umani-Ronchi, A. Synthesis
1974, 733.
and Hall: London, 1985. (e) Boulvin, G.; Ottinger, R.; Pais,
M.; Chiurdoglu, G. Bull. Soc. Chim. Belg. 1970, 78, 583;
Chem. Abstr. 1970, 72, 90691q. (f) Raverty, W. D.;
Thomson, R. H.; King, T. J. J. Chem. Soc., Perkin Trans. 1
1977, 1204.
(43) Bowman, R. E.; Stroud, H. H. J. Chem. Soc. 1950, 1342.
(44) Bowman, R. E. J. Chem. Soc. 1950, 1346.
(45) Bowman, R. E. J. Chem. Soc. 1950, 1349.
(46) Ikutani, Y. Bull. Chem. Soc. Jpn. 1968, 41, 1679.
(47) Jentoft, N.; Dearborn, D. G. Methods Enzymol. 1983, 91,
570.
(34) Sondengam, B. L.; Hemo, J. H.; Charles, G. Tetrahedron
Lett. 1973, 14, 261.
(35) Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673.
(36) Bhattacharyya, S. Synth. Commun. 1995, 25, 2061.
(37) Giumanini, A. G.; Chiavari, G.; Musiani, M. M.; Rossi, P.
Synthesis 1980, 743.
(48) da Silva, R. A.; Estevam, I. H. S.; Biebera, L. W.
Tetrahedron Lett. 2007, 48, 7680.
(49) Song, Y.; Sercel, A. D.; Johnson, D. R.; Colbry, N. L.; Sun,
K. L.; Roth, B. D. Tetrahedron Lett. 2000, 41, 8225.
(50) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B. Chem. Rev.
2004, 104, 5823.
(38) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315.
(39) Alinezhad, H.; Tajbakhsh, M.; Zamani, R. Synth. Commun.
2006, 36, 3609.
(40) Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401.
(41) Gribble, G. W.; Jasinski, J. M.; Pellicone, J. T.; Panetta, J. A.
Synthesis 1978, 766.
(51) (a) Goetz, V. H.; Nerdel, F.; Rehse, K. Justus Liebigs Ann.
Chem. 1965, 681, 1. (b) Srinivasan, C.; Perumal, S.;
Arumugam, N. J. Chem. Soc., Perkin Trans. 2 1985, 1855.
(c) Selva, M.; Perosa, A.; Tundo, P.; Brunelli, D. J. Org.
Chem. 2006, 71, 5770. (d) Penner, G. H.; McCullough, A. J.
Org. Chem. 2006, 71, 8794.
(42) (a) White, A.; Handler, P.; Smith, E. L. Principles of
Biochemistry; McGraw Hill: New York, 1968. (b) Bell, E.
A. FEBS Lett. 1976, 64, 29. (c) Mandava, N.; Anderson, J.
D.; Dutky, S. R. Photochemistry 1974, 13, 2853. (d) Hunt,
S. The Non-Protein Amino Acids, In Chemistry and
Biochemisrry of Amino Acids; Barrett, G. C., Ed.; Chapman
(52) (a) Fluka Catalogue of Organic and Biochemicals; Fluka:
Buchs / Switzerland, 2001–2002. (b) Barton, D. H. R.;
Ozbalik, N.; Ramesh, M. Tetrahedron Lett. 1988, 29, 857.
(53) Merck FT-IR Atlas; Pachler, G. R. K.; Matlok, F.; Gremlich,
H.-U., Eds.; Wiley-VCH: Weinheim, 1989.
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York