Synthesis of N-alkyl-N-methyl amino acids. Scope and limitations of base-induced N-alkylation of Cbz-amino acids

Article abstract of DOI:10.1016/j.tetasy.2008.03.025

The reaction of N-benzyloxycarbonyl derivatives of aliphatic amino acids with NaH/alkyl iodides gave the corresponding N-Cbz-N-alkyl derivatives in good to high yields. The scope and limitations of this simple N-alkylation reaction were investigated as a convenient and flexible attempt to prepare unsymmetrically N,N-diprotected α-amino acids. The procedure is based on the N-alkylation of N-carbamoyl amino acids, a one-pot deprotection/protection sequence without extensive purification of the products. Protection of the carboxyl function is not required while the starting materials are inexpensive and commercially available.

Full text of DOI:10.1016/j.tetasy.2008.03.025

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 970–975
Synthesis of N-alkyl-N-methyl amino acids. Scope and limitations
of base-induced N-alkylation of Cbz-amino acids
Maciej Stodulski and Jacek Mlynarski*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 25 February 2008; accepted 27 March 2008
Abstract—The reaction of N-benzyloxycarbonyl derivatives of aliphatic amino acids with NaH/alkyl iodides gave the corresponding
N-Cbz-N-alkyl derivatives in good to high yields. The scope and limitations of this simple N-alkylation reaction were investigated as
a convenient and flexible attempt to prepare unsymmetrically N,N-diprotected a-amino acids. The procedure is based on the N-alkyl-
ation of N-carbamoyl amino acids, a one-pot deprotection/protection sequence without extensive purification of the products. Protection
of the carboxyl function is not required while the starting materials are inexpensive and commercially available.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the general N-alkylation of amino acids with non-methyl
alkylating agents (Et, Pr, Bu, etc.) seems convoluted mostly
due to the steric hindrance of longer carbon chains. In light
of this, the synthesis of amino acids with two different alkyl
groups attached to the N-terminus of the molecule seems to
be even more challenging.
Amino acids, which are essentially incorporated in pro-
teins, peptides, enzymes, and large numbers of bio-active
phenomena have recently gained much interest in synthetic
organic chemistry as extremely desirable building blocks,
chiral auxiliaries, catalysts, and ligands. While Nature’s
creativity and precision in the construction of various
structures is impressive, the development of practical and
efficient synthetic methodologies for the construction of
amino acids is still in its infancy.
On the other hand, such complex yet simple molecules are
desirable for the sensitive and iterative tuning of the ligand
structure en route to various kind of asymmetric metal
complexes.6 Despite the hidden potential of these building
blocks for asymmetric synthesis, knowledge about their
synthetic and therapeutic properties remains narrow, and
the number of structures tested is still restricted mostly
due to the tedious and inefficient known synthetic
procedures.7
N-Methyl amino acids are a group of important modified
amino acids, which have been widely used in medicinal
chemistry and biochemistry to change the conformation,
restrict the flexibility, and enhance the potency of the mole-
cule.1 Various protocols have been developed for the syn-
thesis of optically active N-methyl amino acids,2 but the
methods for installing the N-methyl moiety in the full range
of amino acids still remain difficult.3
Herein, we report our studies on the simple synthesis of
N-alkyl-N-methyl amino acids without need for the protec-
tion of the carboxylic function. The efficient synthetic
procedure is performed via consecutive alkylation of
benzyloxycarbamoyl (Cbz) amino acids and smart one-
pot Cbz-deprotection and methylation of amino function.
An adequately selected simple reaction sequence resulted
in clean and efficient formation of two different alkyl
groups on the nitrogen-end of the molecule. The most
important feature of this protocol is all-step chromato-
graphy-free process resulting from efficient reaction steps.
In contrast to the previously described protocols, the
separation of the reaction products after each step of the
Incorporation of N-alkyl amino acids into peptides often
improves the biological profile by increasing the proteolytic
stability, conformational rigidity, and lipophilicity. At the
present time, however, flexible synthetic routes to higher
N-alkyl amino acids are unknown4,5 and the problem with
*
Corresponding author. Tel.: +48 22 343 2115; fax: +48 22 632 6681;
e-mail: mlynar@icho.edu.pl
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.025

M. Stodulski, J. Mlynarski / Tetrahedron: Asymmetry 19 (2008) 970–975
971
reaction is easy, and routine aqueous workup replaces the
tedious and expensive chromatography. The important
problem of the racemization of chiral amino acids under
basic reaction conditions is investigated while scope and
limitation of the elaborated base-induced N-alkylation of
amino acids are recognized.
MeI, THF) to the synthesis of N-methyl Cbz-L-alanine 2,
the reaction was clean and efficient (Scheme 1). In general,
N-alkylation was highly privileged (>90% isolated yield).
At this stage, the temperature of the reaction was higher
(60 °C) to check if some level of racemization affected the
enantiomeric purity of the products. The measured specific
rotation value of 2 ([a]D = ꢀ24.9) match perfectly the liter-
ature data for the same compound ([a]D = +24.5 for D-
enantiomer).12b Having this evidence in hand, we started
to test the alkylation of some other amino acids.
2. Results and discussion
2.1. Synthesis of N-alkyl-N-methyl amino acids
To our delight, the same reaction of alanine with ethyl
iodide in THF at 60 °C resulted in clean and efficient
formation of desired product 3. Our careful investigation
of the reaction revealed that only 3 equiv of NaH allows
for a good conversion after 20 h. We were pleased to find
that not only ethyl iodide, but also other tested alkyl
iodides delivered the desired N-alkyl-N-benzyloxycarb-
amoyl-a-alanines in good yields (Scheme 1).
Commercially available N-methyl amino acids are still very
expensive; therefore this method employs commercially
available and relatively inexpensive Cbz-amino acids.8
Our method started with the N-alkylation of the Cbz-pro-
tected amino acids. The most broadly applied method for
the N-methyl amino acid synthesis is N-methylating an
N-carbamoyl derivative with sodium hydride and methyl
iodide in THF/DMF at 80 °C, as developed by Benoiton.9
Subsequently, the same methylation in neat THF at room
temperature was described.10 The latter method is prefera-
ble since the former also esterifies the carboxyl group, while
the removal of the ester group by saponification is accom-
panied by some level of racemization (Fig. 1). The carb-
oxylic methyl ester, formed as an undesired co-product,
was removed using harsh, basic conditions. This base-
mediated method, of course, does not proceed without
racemization at the a-carbon of the amino acids.
(i)
HO
HO
R
NHCbz
1 (L-alanine)
N
Cbz
O
O
2 R = Me (12 h, 90 %)
3 R = Et (20 h, 90 %)
4 R = Pr (36 h, 91 %)
5 R = Bu (120 h, 45%)
Scheme 1. Reagents and conditions: (i) NaH, alkyl iodide (RI), THF,
60 °C.
Thus, a direct route to N-methyl amino acids was necessary
so as to avoid hydrolysis of the ester and therefore prevent
racemization. It was also found that (ambient) reaction
temperature was an important factor in avoiding O-alkyl-
ation leading to undesired methyl ester formation.11 Many
others have since utilized this method and variations there-
of in producing optically active N-methyl amino acids in
THF at rt.12
Thus, the treatment of a THF solution of chiral L-alanine 1
with NaH in the presence of ethyl, propyl or butyl iodide at
an elevated temperature afforded alkyl derivatives 2–5 in
good to excellent yields ranging from 45% to 91%. In the
case of propyl and butyl iodide, longer reaction time was
necessary to complete the reaction. For the butyl iodide,
the isolated yield of the product was, however, lower due
to steric hindrance between alkyl group and the a-located
methyl group of the amino acid.
We checked, however, that this methodology failed for
alkyl chains longer than methyl. All attempts to obtain
N-alkyl amino derivative from Cbz-alanine with NaH
and ethyl iodide at ambient temperature were unpromising.
Application of other bases was also not efficient: LiHMDS
was too weak and Cs2CO3 led to the clean formation of
carboxylic esters as sole products.
In the case of methyl and ethyl derivatives, satisfactory
levels of purity of the products were achieved after the
usual wet-workup. The last two compounds needed filtra-
tion through a short pad of silica gel.
Encouraged by these promising results, we tested the reac-
tion of ethyl iodide with another amino acids. Reaction of
D-alanine with ethyl iodide led to desired product 6 with
78% isolated yield. The alkylation of glycine 7, L-valine
8, and L-phenylalanine 9 is depicted in Scheme 2.
Thus, we decided to test similar reaction conditions at ele-
vated temperatures. When we applied this protocol (NaH,
R1
*
O
R1
*
O
THF/NaH/MeI
0 °C - rt
only methyl iodie
R
N
H
COOH
R
N
COOH
R1
R1
(i)
HO
HO
THF/DMF
NaH/MeI
NHCbz
N
R1
*
NaOH
MeOH
80 °C
O
Cbz
35 °C
partial
O
O
7 R1 = H (glycine)
10 R1 = H (12 h, 100%)
11 R1 = i-Pr (36 h, 61%)
12 R1 = CH2Ph (48 h, 64%)
R
COOMe
8 R1 = i-Pr (L-valine)
razemization
9 R1 = CH2Ph (L-phenylalanine)
Figure 1. Reaction of derivatives of aliphatic amino acids with sodium
hydride/methyl iodide to form the corresponding N-methyl amino acids.
Scheme 2. Reagents and conditions: (i) NaH, EtI, THF, 60 °C.

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M. Stodulski, J. Mlynarski / Tetrahedron: Asymmetry 19 (2008) 970–975
The ethylation of both ‘higher’ amino acids (valine and
phenylalanine) has been easily achieved using elaborated
conditions by using ethyl iodide in the presence of alkali.
The reaction was virtually complete in 36–48 h for the ste-
rically hindered amino acids. Unfortunately, as a result of
the prolonged reaction time, the formation of some
amount of the methyl esters of both valine and phenylala-
nine was observed (<10%).
to dryness desired N-alkyl-N-methyl amino acids in excel-
lent yields and high level of purity.
2.2. Determination of the enantiomeric purity of prepared
amino acids
The elaborated base-mediated method, even at elevated
temperature, proceeded mostly without racemization, as
proven by the comparison of the specific rotation values
with the published data (Table 1).
Following the isolation of the N-alkyl derivatives, the Cbz
group was removed via catalytic hydrogenolysis. For this
purpose, we used two methods of deprotection leading to
N-methyl- (Scheme 3, route (i)) and N-alkyl-N-methyl ami-
no acids (Scheme 3, route (ii)), respectively. The simple
deprotection of Cbz group revealed known N-alkyl amino
acids 2a–6a and 10a–12a with high yield (Scheme 3).
Table 1. Specific rotation values of N-alkyl amino acids
Entry Product
Cond.
[a]D
Lit. [a]D
HO
1
12 h, 60 °C
ꢀ5.6
+5.613
N
H
O
2a
R1
(i)
HO
HO
HO
R
+10.2 +10.05
N
2
20 h, 60 °C
36 h, 60 °C
N
H
H
O
O
3a
R1
2a-6a, 10a-12a
R1
HO
R
(ii)
HO
N
3
+6.8
+6.914
N
R
N
Cbz
H
O
O
O
4a
2 R = Me, R1 = Me (L-alanine)
3 R = Et, R1 = Me (L-alanine)
4 R = Pr, R1 = Me (L-alanine)
5 R = Bu, R1 = Me (L-alanine)
6 R = Et, R1 = Me (ent) (D-alanine)
10 R = Et, R1 = H (glycine)
2b (97%)
3b (95%)
4b (90%)
5b (88%)
6b (95%)
10b (100%)
11b (80%)
HO
19.1a,15
+6.6b
N
4
120 h, 60 °C +3.2
H
O
5a
11 R = Et, R1 = i-Pr (L-valine)
12 R = Et, R1 = CH2Ph (L-phenylalanine) 12b (85%)
HO
ꢀ10.5 +10.0 (ent)5
N
Scheme 3. Reagents and conditions: (i) H2, Pd–C (10%), EtOH, H2O,
20 h, rt; (ii) HCHO, H2, Pd–C (10%), EtOH, H2O, 20 h, rt.
5
48 h, 60 °C
H
O
6a
On the route to N-alkyl-N-methyl amino acids, we decided
to modify slightly a routine protocol to combine two differ-
ent reactions: deprotection and methyl protection using a
one-pot, one-catalyst procedure. A promising and common
method for installing the N-methyl function is reductive
amination, which offers the possibility of placing alkyl
groups other than methyl, by simply varying the carbonyl
source. In our protocol, we devised a method for reducing
the intermediate Schiff base involving palladium-catalyzed
hydrogenation.
HO
6
36 h, 60 °C
+27.5 +28.84
N
H
O
11a
Ph
7
48 h, 60 °C
+16.6 +33.34
HO
N
H
O
12a
a Incorrect literature data which was corrected by additional experiment.
To complete the synthesis, previously prepared N-alkyl-N-
benzyloxycarbamoyl-a-amino acids were submitted to
hydrogenolysis in the presence of formaldehyde (2 equiv).
Reactions were performed overnight in an aqueous etha-
nol. This protocol proved that if hydrogenolysis is carried
out in the presence of a carbonyl source, the in situ released
amine is directly and quantitatively converted to methyl
derivatives 2b–6b and 10b–12b (Scheme 3). Despite its sim-
plicity, this protection–deprotection protocol has never, to
the best of our knowledge, been recorded in the literature.
The crude reaction mixtures were filtered and evaporated
b Product was obtained using EtCHO, NaBH3CN, MeOH, 0 °C (16 h).
All collected data for both D- and L-alanine derivatives
showed high enantiomeric purity of the products (entries
1–3 and 5). However, the observed situation in the case
of butyl derivative was more puzzling. After a one-day
reaction, only small amounts of desired product were
detected (10%). Thus, a prolonged reaction time (120 h)
was necessary for a satisfactory yield. Such harsh
conditions resulted in a high level of racemization (48%

M. Stodulski, J. Mlynarski / Tetrahedron: Asymmetry 19 (2008) 970–975
973
enantiomeric purity). This value was calculated from the
specific rotation measured for the sample of N-butyl ala-
nine prepared via an alternative route in our laboratory
(+6.6) as the literature data for this compound was not
correctly determined (+19.1).15
the benzyl group was removed via catalytic hydrogenation
to afford N-methyl amino acids in poor yields. We proved
that this procedure was not flexible enough to be adopted
for free amino acids (yields less then 15%). Nevertheless,
it delivered analytical samples of the desired amino acids.
All the isolated compounds were subjected to a second
reductive amination using acetic aldehyde and NaBH3CN
in ethanol (Scheme 4).
Thus, the a-carboxyl group when ionized provides some
protection against racemization by preventing ionization
at the a-carbon atom. This protection failed, however,
when long exposure to basic conditions is necessary. It
might be expected that amino acids with alkyl side-chains
would be less prone to racemize during alkylation than
amino acids with electron-withdrawing a-substituents.
The specific rotations of the products obtained from valine
(entry 6) showed only small levels of racemization, if any
(>95% ee), while the calculated enantiomeric purity of
phenylalanine (entry 7) was only 50%.
The properties of the derivatives prepared are recorded in
Scheme 4. The results are in agreement with the previously
presented data (Table 1). Only slight racemization was
observed during base-induced alkylation of valine (95%
enantiomeric purity), while alanine derivatives showed no
racemization as verified by the specific rotation method.
However, the prepared sample of N-ethyl-N-methyl-
phenylalanine was found to be partially racemized. It is
known that phenylalanine derivatives are more susceptible
to the base-catalyzed racemization than most other amino
acids.9
The enantiomeric integrity of products obtained under
elaborated conditions of the both latter type amino acids
still remains to be established by unambiguous synthetic
methods. For the discussion above, we used the literature
specific rotation values, in order to verify the results via
an alternative path.
3. Conclusions
Herein, we have presented an insight into the simple
preparation of some unsymmetrically protected di-N-alkyl
amino acids with free carboxylic functions by way of the
alkylation of benzyloxycarbamoyl derivatives and a one-
pot, one-catalyst deprotection–protection sequence. The
procedures are simple, practical, and scalable. The racemi-
zation of Cbz-amino acids during base-induced N-alkyl-
ation has also been investigated. The obtained methyl,
ethyl, and butyl derivatives of alanine do not show any
detectable racemization. The purification of the products
requires only routine manipulations and chromatographi-
cal purification can be omitted in most cases.
The synthesis of the samples of amino acids required a reli-
able and racemization-free methodology. Thus, we decided
to apply a safe step-by-step technique for the preparation
of the final products. For this test, we chose representative
ethyl derivatives of enantiomeric alanines—3b, 6b, valine—
11b, and phenylalanine—12b (Scheme 4). At first, we
obtained N-methyl amino acids. The applied procedure
was performed, without the protection of carboxylic
function, via consecutive reductive amination reactions,
first with benzaldehyde, then with paraformaldehyde. A
similar protocol was adopted to the facile synthesis of
N-methyl amino acid esters.2b Following the isolation,
4. Experimental
HO
HO
HO
HO
All reactions involving organometallic or other moisture-
sensitive reagents were carried out under an argon atmo-
sphere using standard vacuum line techniques and glass-
ware that was flame dried and cooled under Ar before
use. Solvents were dried according to the standard proce-
dures. All organic solutions were dried over Na2SO4. Thin
layer chromatography was performed on aluminum plates
coated with 60 F254 silica (Merck). Plates were visualized
using UV light (254 nm) and 10% ethanolic ninhydrine
solution. Reaction products were purified by flash chromato-
graphy using Silica Gel 60 (240–400 mesh). (Merck).
Optical rotations were measured with a JASCO Dip-360
Digital Polarimeter at room temperature. Specific rotations
are reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in
gram per 100 mL. 1H NMR spectra were recorded on Var-
ian-200 or Varian-400 spectrometers in CD3OD or CDCl3
with Me4Si as the internal standard. High resolution mass
spectra were taken on a Mariner PerSeptive Biosystems
mass spectrometer with a time-of-flight (TOF) detector.
IR spectra were taken with a Perkin Elmer FT-IR-1600
spectrophotometer as either a thin film on NaCl plates
NH2
NH2
N
O
O
O
[α]D +5.0 {3b [α]D +5.0 (100% ee)}
N
O
[α]D -5.0 {6b [α]D -5.0 (100% ee)}
(i), (ii)
HO
HO
HO
HO
NH2
N
O
O
[α]D +17.9 {11b [α]D +16.7 (93% ee)}
Ph
Ph
NH2
N
O
O
[α]D +24.7 {12b [α]D +12.6 (51% ee)}
Scheme 4. Reagents and conditions: (i) PhCHO (1 h), NaBH3CN (12 h),
(CH2O)n (5 h), NaBH3CN (12 h), MeOH, rt than H2, Pd–C (10%), EtOH,
20 h, rt; (ii) CH3CHO, NaBH3CN, EtOH.

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M. Stodulski, J. Mlynarski / Tetrahedron: Asymmetry 19 (2008) 970–975
(film), as a KBr disc (KBr), or chloroform solutions in
0.1 mm cells (CHCl3), as stated.
4.4. N-Butyl-N-methyl-L-alanine 5b
By using the general procedure described above, 5b was
4.1. General procedure for the synthesis of N-ethyl-N-methyl
amino acids
obtained from L-alanine in 88% yield and 55% ee.
19:8
½aꢂD ¼ þ3:2 (c 0.50, EtOH). Mp 115–117 °C. IR (KBr):
3427, 3043, 2963, 2940, 2875, 2723, 1624, 1466, 1398,
N-Carbobenzoxy amino acid (223 mg, 1 mmol, Fluka) was
dissolved in THF (5 mL). Ethyl iodide (0.65 mL, 8 mmol)
was added and the mixture was cooled to 0 °C. Sodium
hydride (144 mg, 50% suspension in mineral oil, 3 mmol)
was slowly added. The cooling bath was removed, and
the reaction mixture was heated to 60 °C. The temperature
was maintained for 12–48 h (see Schemes 1 and 2). Excess
of sodium hydride was destroyed with water and the result-
ing suspension was extracted with EtOAc (3 ꢁ 10 mL). The
aqueous fraction was then acidified with citric acid solution
to pH 4 and extracted with EtOAc (3 ꢁ 10 mL). The
organic fraction was washed with brine, dried over
anhydrous sodium sulfate, and evaporated to give
N-carbobenzoxy-N-ethyl amino acid which was subjected
to further step without purification.
1366 cmꢀ1 1H NMR (CD3OD, 400 MHz): 0.98 (t, 3H,
.
J = 7.3 Hz), 1.41 (q, 2H, J = 7.7 Hz), 1.47 (d, 3H, J =
7.2 Hz), 1.67–1.75 (m, 2H), 2.79 (s, 3H), 2.97–3.12 (m,
2H), 3.66 (q, 1H, J = 7.2 Hz). 13C NMR (CD3OD,
100 MHz): 12.6, 13.94, 20.9, 27.8, 38.3, 66.4, 97.2, 173.4.
HRMS (EI): calcd for C8H17NO2, M+: 159.1259. Experi-
mental: 159.1264.
4.5. N-Ethyl-N-methyl-D-alanine 6b
By using the general procedure described above, 6b was
obtained from D-alanine in 95% yield and 100% ee.
17:5
½aꢂD ¼ ꢀ5:0 (c 0.28, EtOH). Mp 128–131 °C. IR (KBr):
3413, 3058, 2992, 2886, 2740, 1622, 1458, 1399,
1370 cmꢀ1 1H NMR (CD3OD, 200 MHz): 1.44 (t, 3H,
.
J = 7.4 Hz), 1.56 (d, 3H, J = 7.0 Hz), 2.89 (s, 3H), 3.26
(qd, 2H, J = 8.0, 2.4 Hz), 3.77 (q, 1H, J = 7.0 Hz). 13C
NMR (CD3OD, 50 MHz): 11.8, 14.4, 39.3, 52.2, 67.4,
175.3. HRMS (EI): calcd for C6H13NO2, M+: 131.0946.
Experimental: 131.0951.
The N-carbobenzoxy-N-ethyl amino acid was dissolved in
ethanol–water (1:1, 2 mL). Formaline (2 equiv) and Pd
(1 weight equiv, 10% on activated charcoal, Fluka) were
added and the solution was vigorously stirred under H2
atmosphere (balloon) for 20 h. Filtration through Celite
and concentration in vacuo afforded the N-ethyl-N-methyl
amino acid in an analytically pure form.
4.6. N-Ethyl-N-methyl-glycine 10b
By using the general procedure described above, 10b was
obtained from glycine in 100% yield. Mp 115–117 °C. IR
(KBr): 3414, 3056, 2986, 2879, 2842, 1629, 1472, 1402,
The known N-alkyl amino acids 2a (97%),13 3a (94%),5 4a
(91%),14 5a (89%),15 6a (95%),13 10a (92%),16 11a (83%
after chromatography),4 and 12a (80% after chromato-
graphy)4 were prepared according to the general procedure
(deprotection of Cbz was performed without formaldehyde
additive).
1325 cmꢀ1 1H NMR (CD3OD, 400 MHz): 1.28 (t, 3H,
.
J = 7.3 Hz), 2.77 (s, 3H), 3.09 (q, 2H, J = 7.3 Hz), 3.49
(s, 2H). 13C NMR (CD3OD, 100 MHz): 10.2, 41.4, 52.8,
59.7, 171.4. HRMS (EI): calcd for C5H11NO2, M+:
117.0790. Experimental: 117.0792.
4.2. N-Ethyl-N-methyl-L-alanine 3b
4.7. N-Ethyl-N-methyl-L-valine 11b
By using the general procedure described above, 3b was
obtained from L-alanine in 95% yield and 100% ee.
19:8
By using the general procedure described above, 11b was
½aꢂD ¼ þ5:0 (c 0.5, EtOH). Mp 128–131 °C. IR (KBr):
19:5
obtained from L-valine in 80% yield and 95% ee. ½aꢂD
¼
3413, 3058, 2992, 2886, 2740, 1622, 1458, 1399,
1370 cmꢀ1 1H NMR (CD3OD, 200 MHz): 1.44 (t, 3H,
.
þ16:7 (c 0.10, EtOH). Mp 127–128 °C. IR (CHCl3):
3401, 2970, 1617, 1467, 1384, 1332 cmꢀ1 1H NMR
.
J = 7.4 Hz), 1.56 (d, 3H, J = 7.0 Hz), 2.89 (s, 3H), 3.26
(qd, 2H, J = 8.0, 2.4 Hz), 3.77 (q, 1H, J = 7.0 Hz). 13C
NMR (CD3OD, 50 MHz): 11.8, 14.4, 39.3, 52.2, 67.4,
175.3. HRMS (EI): calcd for C6H13NO2, M+: 131.0946.
Experimental: 131.0951.
(CD3OD, 400 MHz): 1.00 (d, 3H, J = 6.8 Hz), 1.13 (d,
3H, J = 6.8 Hz), 1.30 (t, 3H, J = 7.3 Hz), 2.21–2.31 (m,
1H), 2.76 (s, 3H), 3.05–3.40 (m, 3H). 13C NMR (CD3OD,
100 MHz): 9.7, 17.5, 20.9, 27.4, 76.1, 174.3. HRMS (EI):
calcd for C8H17NO2, M+: 159.1259. Experimental:
159.1253.
4.3. N-Methyl-N-propyl-L-alanine 4b
By using the general procedure described above, 4b was
4.8. N-Ethyl-N-methyl-L-phenylalanine 12b
obtained from L-alanine in 90% yield and 99% ee.
20:3
½aꢂD ¼ þ3:2 (c 1, EtOH). Mp 136–139 °C. IR (KBr):
By using the general procedure described above, 12b was
3418, 3048, 2973, 2882, 2721, 1623, 1461, 1399,
obtained from L-phenylalanine in 85% yield and 50% ee.
19:8
1365 cmꢀ1
.
1H NMR (CD3OD, 400 MHz): 1.00 (t, 3H,
½aꢂD ¼ þ12:6 (c 1.00, EtOH). Mp 165–168 °C. IR (KBr):
J = 7.5 Hz), 1.47 (d, 3H, J = 7.3 Hz), 1.70–1.80 (m, 2H),
2.79 (s, 3H), 2.96–3.08 (m, 2H), 3.67 (q, 1H, J = 7.3 Hz).
13C NMR (CD3.OD, 100 MHz): 11.2, 12.5, 19.2, 38.3,
66.4. 97.3, 173.4. HRMS (EI): calcd for C7H15NO2, M+:
145.1102. Experimental: 145.1098.
3448, 3062, 3029, 2982, 2960, 2299, 1628, 1354,
1271 cmꢀ1 1H NMR (CD3OD, 200 MHz): 1.35 (t, 3H,
.
J = 7.3 Hz), 2.86 (s, 3H), 3.15–3.40 (m, 4H), 3.96 (t, 1H,
J = 6.8 Hz), 7.30–7.50 (m, 5H). 13C NMR (CD3OD):
11.0, 35.8, 39.4, 52.2, 72.3, 128.9, 130.1, 131.1, 139.0,

M. Stodulski, J. Mlynarski / Tetrahedron: Asymmetry 19 (2008) 970–975
975
173.0. HRMS (EI): calcd for C12H17NO2, M+: 207.1259.
Experimental: 207.1268.
7. For examples, of synthesis and application of N-methyl-N-
alkyl amino acids see: (a) Leonard, F.; Horn, H. J. Am.
Chem. Soc. 1956, 78, 1199; (b) Ryder, T. R.; Hu, L.-Y.;
Rafferty, M. F.; Millerman, E.; Szoke, B. G.; Tarczy-
Hornoch, K. Bioorg. Med. Chem. Lett. 1999, 9, 1813; (c)
Park, J. D.; Lee, K. J.; Kim, D. H. Bioorg. Med. Chem. 2001,
9, 237.
8. The price in euro is: 15.60 (25 g) Ala, 35.60 (25 g) Z-Ala-OH,
158.50 (5 g) N-Me-Ala.
9. Coggins, J. R.; Benoiton, N. L. Can. J. Chem. 1971, 49, 1968.
10. Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906.
11. McDermott, J. R.; Benoiton, N. L. Can. J. Chem. 1973, 51,
1915.
Acknowledgment
Financial support by the Polish State Committee for the
Scientific Research (KBN Grant N N204 4094 33) is grate-
fully acknowledged.
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