Catalyst-Free One-Pot Reductive Alkylation of Primary and ...

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
One-Pot Mahmood Reductive Alkylation of Primary and Secondary Amines Tajbakhsh,* a Rahman Hosseinzadeh, a Heshmatollah Alinezhad, a Somayeh Ghahari, a Akbar Heydari, b
Samad Khaksarc a Department of Chemistry, University of Mazandaran, P. O. Box 453, Babolsar 47415, Iran
Fax +98(112)5342350; E-mail: Tajbaksh@umz.ac.ir
b Chemistry Department, Tarbiat Modares University, P. O. Box 14115-175, Tehran 18716, Iran
c Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, P.O. Box 678, Amol, Iran
Received 9 November 2010; revised 25 November 2010
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 products
in excellent purity for direct reuse.
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 compounds,
1,2 which are important intermediates in the synthesis
of pharmaceutically active substances, dyes, and
fine chemicals. 3 The direct reductive amination of aldehydes
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 reductive
amination have been developed, including: catalytic
hydrogenation, 4b Et 3SiH–CF 3CO 2H, 5 Zn/AcOH, 6
Bu 2SnClH/HMPA, 7 NaBH 3CN, 8a NaBH(OAc) 3, 8b pyridine·BH
3, 8c ZnCl 2/ZnBH 4, 8d silica gel/Zn(BH 4) 2, 8e
Ti(Oi-Pr) 4/NaBH 4, 8f NiCl 2/NaBH 4, 8g NaBH 4/ZrCl 4, 8h
NaBH 4/H 2SO 4, 8i NaBH 4/H 3PW 12O 40, 8j NaBH 4/guanidine
hydrochloride, 8k NaBH 4/wet clay-microwave, 8l borohydride
exchange resin, 8m N-methylpyrrolidine/zinc borohydride,
9 InCl 3/Et 3SiH, 10 ZnClO 4/InCl 3/Et 3SiH, 11 and zirconium
borohydride/piperazine complex. 12 However,
some of these preparations require relatively expensive
reagents, harsh reaction conditions, and sometimes tedious
workup; produce heavy metals as toxic waste; generate
toxic by-products; have no chemoselectivity; and
suffer from lack of solubility of reagents in most common
organic solvents. Furthermore, sometimes direct reductive
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 reagent
is crucial. If one could perform the direct reductive
SYNTHESIS 2011, No. 3, pp 0490–0496xx.xx.2011
Advanced online publication: 28.12.2010
DOI: 10.1055/s-0030-1258384; Art ID: Z26810SS
© Georg Thieme Verlag Stuttgart · New York
amination of carbonyl compounds in air and in the presence
of moisture, it should be of considerable interest.
Thus, it is challenging to develop such an effective catalyst
or reagent.
Environmental concern associated with chemical synthesis
has posed stringent and compelling demands for greener
processes. 13 Fluorinated solvents have attracted an
increasing interest in the context of green synthesis during
recent years. Fluorinated solvents were initially introduced
as an alternative green reaction media because of
their unique chemical and physical properties of nonvolatility,
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 Reactions
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 interest
in the application of fluorinated solvents for various
organic transformations, 15 we report a simple and convenient
procedure for the high yielding direct reductive
amination of aldehydes and ketones with NaBH4 in 2,2,2trifluoroethanol
(TFE) (Scheme 1).
R 1
O
R 2
+
H
N
R3 R4 NaBH4
TFE
N
R1 R3 R
Scheme 1 Reductive amination of aldehydes and ketones
1 , R2 , R3 , R4 aryl, alkyl
H, =
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 acceleration
on the amination of 4-chlorobenzaldehyde
(Table 1, entry 3), whereas reaction in ethanol and methanol
proceeds quite slowly (entries 1 and 2). Reaction in
R 2
R 4

PAPER One-Pot Reductive Alkylation of Primary and Secondary Amines 491
Table 1 Reductive Amination of 4-Chlorobenzaldehyde with
Aniline in Different Solvents
Entry Solvent Time (h) Yield (%) a
1 EtOH 10 80
2 MeOH 10 84
3 TFE 10 min 93
4 H 2O 12 33
5 MeCN 12 48
6 THF 12 45
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 aliphatic,
aromatic and heterocyclic carbonyl compounds (1
mmol) with primary and secondary amines (1 mmol) using
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 filtration
of the reaction mixture and distilling off the solvent
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 proceeded
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-cinnamaldehyde
with aniline similarly afforded the expected
Table 2 Reductive Amination of Carbonyl Compounds Using NaBH 4 in TFE a
amine in high isolated yield (Table 2, entry 14). Comparably,
ketones were efficiently aminated with the aromatic
and aliphatic amines (Table 2, entries 20 and 27–32).
In addition, N,N-dimethylamines are important intermediates
in the production of pharmaceuticals, agrochemicals,
and fragrance compounds. 1,2 Several reagents for N-methylation
of the amino function to give tertiary amines have
been developed, including: sodium or potassium hydridotetracarbonyl
ferrate in ethanol or tetrahydrofuran, 33 sodium
borohydride in methanol, 34 sodium
cyanotrihydridoborate in acetonitrile, 35 ZnCl2/NaBH4, 36
NaBH4 in THF, 37 MeS·BH3, 38 zinc-modified cyanoborohydride,
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 cyanoborohydride,
47 formaldehyde/zinc, 48 and formaldehyde/Pd(OH)
2/C49 have been reported for their synthesis
in the literature. Good yields and selectivities for the preparation
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 transition-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).
Entry Aldehyde/ketone Amine Product b Time (min) Yield (%) c
1 PhCHO PhNH 2 PhCH 2NHPh 6 95 16
2 4-NCC 6H 4CHO PhNH 2 4-NCC 6H 4CH 2NHPh 7 94 17
3 4-ClC 6H 4CHO PhNH 2 4-ClC 6H 4CH 2NHPh 10 93 12
4 2-ClC 6H 4CHO PhNH 2 2-ClC 6H 4CH 2NHPh 10 94 18
5 3-ClC 6H 4CHO PhNH 2 3-ClC 6H 4CH 2NHPh 10 93 18
6 2-O 2NC 6H 4CHO PhNH 2 2-O 2NC 6H 4CH 2NHPh 10 90 8k
7 4-MeC 6H 4CHO PhNH 2 4-MeC 6H 4CH 2NHPh 15 92 19
8 4-MeOC 6H 4CHO PhNH 2 4-MeOC 6H 4CH 2NHPh 35 94 16
9 PhCHO 4-ClC 6H 4NH 2 4-ClC 6H 4NHCH 2Ph 5 93 20
10 PhCHO 4-O 2NC 6H 4NH 2 4-O 2NC 6H 4NHCH 2Ph 10 92 8b
11 PhCHO 4-MeOC 6H 4NH 2 4-MeOC 6H 4NHCH 2Ph 5 94 20
12 PhCHO 4-EtOC 6H 4NH 2 4-EtOC 6H 4NHCH 2Ph 10 96 21
13 PhCHO 4-MeC 6H 4NH 2 4-MeC 6H 4NHCH 2Ph 4 94 22
14 PhCH=CHCHO PhNH 2 PhCH=CHCH 2NHPh 20 90 23
15 PhCHO PhCH 2NH 2 PhCH 2NHCH 2Ph 16 93 20
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York

492 M. Tajbakhsh et al. PAPER
Table 2 Reductive Amination of Carbonyl Compounds Using NaBH 4 in TFE a (continued)
Entry Aldehyde/ketone Amine Product b Time (min) Yield (%) c
16 PhCHO PhNHMe PhCH 2N(Me)Ph 30 94 24
17 PhNH2 6 8816 H
O
18 PhNH2 8 9016 O
H
19 PhCHO 5 91 25
20 PhCOMe PhNH2 PhCH(Me)NHPh 27 9023 NH2
N N N
H
21 PhCHO morpholine 4-benzylmorpholine 2 92 9
22 PhCHO piperidine 1-benzylpiperidine 4 95 26
23 PhCHO pyrrolidine 1-benzylpyrrolidine 8 94 27
24 PhCHO CH 2=CHCH 2NH 2 PhCH 2NHCH 2CH=CH 2 1 92 27
25 PhCHO i-PrNH 2 PhCH 2NHi-Pr 2 90 28
26 PhCHO t-BuNH 2 PhCH 2NHt-Bu 2 93 8b
27 cyclohexanone PhNH 2 cyclohexylphenylamine 22 92 16
28 cyclohexanone morpholine 4-cyclohexylmorpholine 5 91 16
29 cyclohexanone piperidine 1-cyclohexylpiperidine 1 93 29
30 cyclohexanone pyrrolidine 1-cyclohexylpyrrolidine 4 94 30
31 cyclohexanone CH 2=CHCH 2NH 2 allylcyclohexylamine 1 92 28
32 Me(CH 2) 4COMe PhNH 2 Me(CH 2) 4CH(Me)NHPh 2 92 31
33 MeCH 2CH 2CHO PhNH 2 MeCH 2CH 2CH 2NHPh 5 93 19
34 MeCH 2CH 2CHO pyrrolidine 1-butylpyrrolidine 1 90 32
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
R 1 N R 2
+
S
(HCHO)n
R
Scheme 2 Reductive methylation of amines
1 , R2 alkyl, aryl
H, =
O
NaBH 4
TFE, reflux
Similar to reductive amination, the effect of solvent was
examined and the results in Table 3 for the reaction of ptoluidine
with paraformaldehyde and NaBH 4 in 1:5:2 molar
ratio showed beneficial rate acceleration in the formation
of N,N-dimethyl-p-toluidine in TFE (Table 3, entry
3). When phenylglycine, as representative of an amino
acid, reacted with paraformaldehyde and NaBH 4 in a 1:9:4
molar ratio in TFE for 40 hours, a high yield (89%) of
N,N-dimethylphenylglycine was obtained, whereas this
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York
Me
R 1 N R 2
O
S
H
Ph N
H
Ph N
Ph
reaction in other solvents listed in Table 3 did not afford
any reasonable yield of the product (

PAPER One-Pot Reductive Alkylation of Primary and Secondary Amines 493
Table 4 Reductive Methylation of Amines and Amino Acids with (HCHO) n/NaBH 4 in TFE a
Entry Amine or amino acid Product b Time (h) Yield (%) c
1 PhNHMe PhNMe 2 1.10 93 21
2 4-MeOC 6H 4NH 2 4-MeOC 6H 4NMe 2 1.30 93 36
3 4-MeC 6H 4NH 2 4-MeC 6H 4NMe 2 2 94 28
4 4-EtOC 6H 4NH 2 4-EtOC 6H 4NMe 2 1.15 95 21
5 4-BrC 6H 4NH 2 4-BrC 6H 4NMe 2 4.30 94 40
6 4-ClC 6H 4NH 2 4-ClC 6H 4NMe 2 6.30 90 51
7 4-O 2NC 6H 4NH 2 4-O 2NC 6H 4NMe 2 7 92 51
8 morpholine 4-methylmorpholine 3.20 87 28
9 piperidine 1-methylpiperidine 4.15 85 29
10 pyrrolidine 1-methylpyrrolidine 3.50 88 52
11 PhCH 2NH 2 PhCH 2NMe 2 3.10 90 8h
12 cyclohexylamine N,N-dimethylcyclohexylamine 2.40 91 53
13 4-H 2NC 6H 4NH 2 4-Me 2NC 6H 4NMe 2 16 93 42
14 a-phenylglycine N,N-dimethyl-a-phenylglycine 40 89
15 alanine N,N-dimethylalanine 48 90
16 glycine N,N-dimethylglycine 24 91
17 L-phenylalanine
{[a] D 20 –34}
To test the generality of this procedure, various amines
were subjected to reductive methylation and the results
are presented in Table 4. As shown in Table 4, reductive
methylation of aromatic amines with different substituents
gives excellent yields of the corresponding tertiary
amines (Table 4, entries 1–4). We did not encounter any
problem in the methylation of low basicity amines such as
4-nitro- and 4-chloroanilines, but just for completion of
the reaction, higher amounts of reagents were required
(Table 4, entries 5–7). Reductive methylation of aliphatic
amines such as piperidine, cyclohexylamine, pyrrolidine,
morpholine, and benzylamine under reaction conditions
gave good to excellent yields of the expected tertiary
amines (Table 4, entries 8–12). Similarly, 1,4-phenylenediamine
was reacted to give N,N,N¢,N¢-tetramethyl-1,4phenylenediamine
in excellent yield (Table 4, entry 13).
This procedure was then applied to some amino acids. As
shown in Table 4, the amino acids were N,N-dimethylated
under reaction conditions (Table 4, entries 14–19). It is interesting
to mention that during the course of this reaction
the stereogenic center of starting amino acid is not
N,N-dimethyl-L-phenylalanine
{[a] D 20 +76}
24 89
18 leucine N,N-dimethylleucine 48 88
19 proline N-methylproline 72 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.
changed as determined by measurement of optical rotation
of the corresponding product (Table 4, entry 17). An
interesting feature of this method is that TFE can be easily
recovered by distillation and reused for several times.
In summary, we have introduced a simple procedure for
the reductive amination of aldehydes and ketones with
NaBH4 in TFE without using any catalyst or additives. In
addition, N-methylation of amines and amino acids to
their corresponding tertiary products were also achieved
using paraformaldehyde and NaBH4 in TFE. Simple
workup procedure, excellent yields, neutral reaction conditions,
recovery of solvent, and no special handling techniques
are some advantages of this protocol, which makes
it a good alternative to the existing methods.
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
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York

494 M. Tajbakhsh et al. PAPER
stirred. After stirring for 5 min, NaBH 4 (1.2 mmol) was added and
the progress of the reaction conversion was followed by TLC (hexane–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 chromatography
with EtOAc–hexane as eluent. All products were characterized
on the basis of their spectroscopic data (IR, NMR) and by comparison
with those reported in the literature.
N,N-Dimethylation of Amines and Amino Acids; General Procedure
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 reaction
was complete (Table 4, entries 5–7 and 14–19). 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 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 recrystallized
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.
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).
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-(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,
127.78, 119.06, 118.04, 112.95, 110.77, 47.74.
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.
N-(2-Nitrophenyl)benzylamine (Table 2, entry 6)
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-Benzyl-N-(4-ethoxyphenyl)amine (Table 2, entry 12)
1 H 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).
Synthesis 2011, No. 3, 490–496 © Thieme Stuttgart · New York
13 C 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)
1 H 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).
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)
1 H 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).
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.
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,N-Dimethylalanine (Table 4, entry 15)
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).
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,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.
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).
13C NMR (100 MHz, DMSO-d6): d = 171.14, 67.48, 41.18, 37.34,
23.45, 22.38.

PAPER One-Pot Reductive Alkylation of Primary and Secondary Amines 495
N-Methylproline (Table 4, entry 19)
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).
13C NMR (100 MHz, DMSO-d6): d = 154.65, 71.78, 56.46, 41.50,
29.76, 22.87.
Acknowledgment
Financial support of this work from the Research Council of University
of Mazandaran is gratefully acknowledged.
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