An efficient and practical N-methylation of amino acid derivatives.

Article abstract of DOI:10.1021/ol0268440

[reaction: see text] An efficient and practical N-methylation of amino acid derivatives with dimethyl sulfate in the presence of sodium hydride and a catalytic amount of water is described. Reaction of water with sodium hydride generated highly reactive dry sodium hydroxide, which led to much faster reaction rates than powdered sodium hydroxide itself.

Full text of DOI:10.1021/ol0268440

ORGANIC
LETTERS
2003
Vol. 5, No. 2
125-128
An Efficient and Practical N-Methylation
of Amino Acid Derivatives
Mahavir Prashad,* Denis Har, Bin Hu, Hong-Yong Kim, Oljan Repic, and
Thomas J. Blacklock
Process Research and DeVelopment, Chemical and Analytical DeVelopment, NoVartis
Institute for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936
mahaVir.prashad@pharma.noVartis.com
Received September 3, 2002
ABSTRACT
An efficient and practical N-methylation of amino acid derivatives with dimethyl sulfate in the presence of sodium hydride and a catalytic
amount of water is described. Reaction of water with sodium hydride generated highly reactive dry sodium hydroxide, which led to much
faster reaction rates than powdered sodium hydroxide itself.
Several methods are reported in the literature for the synthesis
of N-methylamino acids and derivatives.1 Commonly used
Scheme 1
methods involve N-methylation using methyl iodide as the
methylating agent.2 In a development program, we needed
a practical method for the synthesis of 1a(SS) (Scheme 1).
(1) (a) Effenberger, F.; Burkard, U.; Willfahrt J. Angew. Chem., Int. Ed.
Engl. 1983, 22, 65-66. (b) Freidinger, R. M.; Hinkle, J. S.; Perlow, D. S.;
Arison, B. H. J. Org. Chem. 1983, 48, 77-81. (c) O’Donnell, M. J.; Bruder,
W. A.; Daugherty, B. W.; Liu, D.; Wojciechowski K. Tetrahedron Lett.
1984, 25, 3651-3654. (d) Grieco, P. A.; Bahsas, A. J. Org. Chem. 1987,
52, 5746-5749. (e) Grieco, P. A.; Perez-Medrano, A. Tetrahedron Lett.
1988, 29, 4225-4228. (f) Chu, K. S.; Negrete, G. R.; Konopeski, J. P. J.
Org. Chem. 1991, 56, 5196-5202. (g) Easton, C. J.; Kociuba, K.; Peters,
S. C. J. Chem. Soc., Chem. Commun. 1991, 1475-1476. (h) Dorow, R. L.;
Initially, we prepared 1a(SS) by the N-methylation of 1-
(SS) with methyl iodide (8.0 equiv) in the presence of silver
oxide (4.0 equiv) in DMF.2j Handling an excess of low-
boiling methyl iodide during workup of the reaction mixture
presented air-emission and health-safety problems for large-
scale work. Additionally, silver oxide is an expensive reagent.
We, therefore, studied the N-methylation of 1(SS) with
dimethyl carbonate,3 which, however, under the attempted
conditions led to significant epimerization. Dimethyl sulfate
was selected because it is high boiling, and any excess
reagent can be safely destroyed with ammonium hydroxide.
Gingrich, D. E. J. Org. Chem. 1995, 60, 4986-4987. (i) Vidyasagar Reddy,
G.; Venkat Rao, G.; Iyengar, D. S. Tetrahedron Lett. 1998, 39, 1985-
1986. (j) Vidyasagar Reddy, G.; Iyengar, D. S. Chem. Lett. 1999, 299-
300. (k) Chen, F. M. F.; Benoiton, N. L. Can. J. Chem. 1977, 55, 1433-
1435.
(2) (a) McDermott, J. R.; Benoiton, N. L. Can. J. Chem. 1973, 51, 1915-
1919. (b) Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906-
910. (c) Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 911-915.
(d) Grieco, P. A.; Hon, Y. S.; Perez-Medrano, A. J. Am. Chem. Soc. 1988,
110, 1630-1631. (e) Chiarello, J.; Joullie, M. M. Synth. Commun. 1988,
18, 2211-2223. (f) White, J. D.; Amedio, J. C. J. Org. Chem. 1989, 54,
736-738. (g) Imaeda, T.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1994,
35, 591-594. (h) Xue, C. B.; DeGrado, W. F. Tetrahedron Lett. 1995, 36,
55-58. (i) Boger, D. L.; Chen, J. H.; Saionz, K. W. J. Am. Chem. Soc.
1996, 118, 1629-1644. (j) Olsen, R. K. J. Org. Chem. 1970, 35, 1912-
1915.
(3) Taleb, A. B.; Jenner, G. J. Mol. Catal. 1993, 84, L131-L136.
10.1021/ol0268440 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002

Table 1. N-Methylation of Amino Acid Derivatives with Dimethyl Sulfate
NaH, catalytic water, THF
powdered NaOH, THF
conversiona (%) yieldb (%)
entry
1
substrate
product
timea
conversion (%)
yieldb (%)
time
1(SS)
1a (SS)
1 min
30 min
84
99
1 min
30 min
2 h
4 h
24 h
36
63
76
80
88
94
NI
2
3
4
5
1(RR)
1(RS)
1(SR)
2
1a (RR)
1a (RS)
1a (SR)
2a
30 min
30 min
30 min
1 min
>99
>99
>99
95
92
94
92
1 min
30 min
2 h
42
75
89
30 min
>99
93
4 h
94
24 h
1 min
30 min
2 h
>99
46
64
84
90
99
38
53
95
93
NI
NI
NI
NI
NI
NI
6
7
3
3a
4c
4c
5c
5c
6c
6c
1 min
30 min
98
>99
94
95
4 h
24 h
1 min
30 min
2 h
4
1 min
>99
72
79
84
4 h
24 h
1 min
30 min
2 h
8
4a
5
1 min
30 min
99 (96)c
>99 (98)c
97 (15)c
97 (33)c
97 (56)c
97 (64%)c
97 (79)c
26
35
54
65
94
65 (12)c
80 (23)c
96 (49)c
99 (66)c
>99 (90)c
20
35
60
75
94
92
98
97
97
90
4 h
24 h
1 min
30 min
2 h
9
1 min
30 min
99
>99
4 h
24 h
1 min
30 min
2 h
10
11
12
5a
6
1 min
30 min
99 (99)c
>99 (99)c
4 h
24 h
1 min
30 min
2 h
1 min
30 min
99
>99
4 h
24 h
1 min
30 min
2 h
4 h
24 h
6a
1 min
30 min
99 (90)c
>99 (95)c
70 (10)c
81 (20)c
92 (35)c
96 (54)c
96 (70)c
a Time after the addition of dimethyl sulfate is finished. b Isolated yield. c Conversion to dimethylated product.
Herein, we report the development of an efficient and
practical method for the N-methylation of amino acid
derivatives in the presence of sodium hydride and a catalytic
amount of water. Water-assisted reactions have been re-
viewed recently, but such a reaction is not reported therein.4
Initially, reaction of 1(SS) with dimethyl sulfate in the
presence of sodium hydride (2.0 equiv) in tetrahydrofuran
did not lead to any N-methylation. However, when the
reaction was allowed to proceed for an extended period of
time, the desired N-methylated product 1a(SS) was obtained
as the only product. We postulated that, with time, absorbed
moisture from nitrogen reacted with sodium hydride to
generate in situ highly reactive, dry sodium hydroxide, which
was the actual base.5 The amount of water was subsequently
optimized to be 0.2 equiv of the substrate. Use of methanol
(4) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299-307.
126
Org. Lett., Vol. 5, No. 2, 2003

instead of water also facilitated this reaction. However, water
was preferred over methanol because methanol could lead
to the formation of dimethyl ether as the byproduct.
Thus, treatment of a solution of 1(SS) in tetrahydrofuran
with dimethyl sulfate (1.8 equiv) in the presence of sodium
hydride (2.0 equiv) and water (0.2 equiv) at 17-20 °C
afforded 1a(SS) in 94% yield (entry 1, Table 1).6 To ensure
that there was no epimerization under these newly developed
conditions, the three other diastereomers 1a(RR), 1a(RS),
and 1a(SR) (Scheme 1) were also synthesized using this
method. A chiral HPLC method7 revealed that there was no
epimerization. Temperature was critical for this reaction as
∼10% epimerization was observed at 30 °C.
N-methylated products in >90% yield. Di-N-methylation of
4a-6a (Scheme 2) was also achieved in >90% yield (entries
8,10, and 12) using 4.0 equiv of sodium hydride, 0.4 equiv
of water, and 3.6 equiv of dimethyl sulfate.
N-Methylation of BOC-L-valine (7), BOC-L-phenylalanine
(8), BOC-L-3-(2-naphthyl)alanine (9), BOC-L-leucine(10),
and 1-(BOC-amino)cyclopentanecarboxylic acid (11) with
dimethyl sulfate (3.1 equiv) in the presence of sodium
hydride (4.6 equiv) and water (0.2 equiv) at 17-20 °C also
afforded N-methylated amino acids (7a-11a, Scheme 3) in
Scheme 3
The N-methylation of 1(SS) in the presence of powdered
commercially available sodium hydroxide was also studied
and was found to be much slower (24 h, entry 1, Table 1)
compared to sodium hydride and water conditions (30 min).
To test the general synthetic utility of this method, we
studied the N-methylation of several substrates (2-6; Scheme
2), and the results are listed in Table 1.8 In all cases, the
Scheme 2
excellent yield (Table 2). A chiral HPLC method9 indicated
that there was ∼1% racemization in the case of 8 and 9 under
these conditions. Again, at higher temperature (26 °C), ∼5%
Table 2. N-Methylation of Amino Acids
entry
substrate
product
time (h)
yield (%)
1
2
3
4
5
7
8
9
10
11
7a
8a
9a
10a
11a
2
2
2
1
1
91
90
80
92
85
reaction was faster in the presence of sodium hydride and
water compared to powdered sodium hydroxide, yielding the
racemization was observed; however, a recrystallization of
crude products from a mixture ethyl acetate and heptane
afforded 8a and 9a with undetectable amounts of the
undesired enantiomer.10 As before, powdered sodium hy-
droxide led to much slower reaction in all three cases (after
(5) Pure sodium hydride is not as reactive as sodium hydroxide, perhaps
due to lower solubility in tetrahydrofuran.
(6) Typical Procedure. To a suspension of sodium hydride (60%
dispersion in mineral oil; 10.0 mmol) in tetrahydrofuran (12 mL) was added
a solution of the substrate (5.0 mmol) and water (1.0 mmol) in tetrahy-
drofuran (10 mL) dropwise over a period of 20 min while maintaining an
internal temperature of 17-20 °C. The mixture was stirred at the same
temperature for 10 min, and dimethyl sulfate (9.0 mmol) was added over
a period of 20 min while maintaining an internal temperature of 17-20
°C. The stirring was continued at the same temperature for the specified
time in Table 1, and the reaction was monitored by HPLC. The reaction
mixture was quenched with 30% ammonium hydroxide (6 mL) over a period
of 10 min while maintaining an internal temperature of 17-20 °C, and the
stirring was continued for an additional 1 h (to ensure complete destruction
of dimethyl sulfate as monitored by GC). The mixture was diluted with
toluene (20 mL) and water (10 mL). The organic layer was separated,
washed with water (10 mL), and concentrated under reduced pressure, and
the crude product was purified by silica gel chromatography. (The procedure
with powdered sodium hydroxide was similar except no water was used.)
(7) Chiral purity was determined on a Waters HPLC system using a
Chiralcel OD column (4.6 × 250 mm) and a mixture of hexane/ethanol/
TFA (100:2:0.2 v/v/v) as the mobile phase (isocratic at a flow rate of 1
mL/min and UV detector at 210 nm) at 40 °C. The retention times for
1a(RS), 1a(RR), 1a(SS), and 1a(SR) were 19.3, 23.0, 25.4, and 36.4 min,
respectively.
(8) All the compounds gave satisfactory spectral data.
(9) Determined by derivatizing the amino acid (obtained from depro-
tecting the BOC group) with 2,3,4,6-tetra-o-acetyl-â-D-glucopyranosyl
isothiocyanate (GITC), using a Waters Symmetry C-18 column (4.6 × 150
mm) and a mixture of acetonitrile (40%) and water (60%, contaning 0.1%
TFA) as the mobile phase (isocratic at a flow rate of 1.5 mL/min and UV
detector at 254 nm).
Org. Lett., Vol. 5, No. 2, 2003
127

20 h: 47% conversion for 7, 8% conversion for 8, and 10%
conversion for 9).
faster reaction rates than powdered commercially available
sodium hydroxide itself. This new water-catalyzed N-
methylation of amino acid derivatives promises to be an
important addition to the area of water-assisted reactions.4
In summary, an efficient and practical N-methylation of
amino acid derivatives with dimethyl sulfate in the presence
of sodium hydride and catalytic amounts of water is
described. Reaction of water with sodium hydride generated
a highly reactive dry sodium hydroxide, which led to much
Acknowledgment. We thank Prof. R. K. Boeckman, Jr.,
of the University of Rochester for helpful discussions, Dr.
D. Munch and Ms. Jiayu Li for the chiral HPLC method,
and Dr. Wen Shieh for an N-methylation experiment with
dimethyl carbonate.
(10) Enantiomeric enrichment by recrystallizations is known. For
example: (a) Jacques, J. Collet, A.; Wilen, S. H. In Enantiomers, Racemates,
and Resolution; Wiley-Interscience Publication: New York, 1981; pp 369-
377. (b) Shieh, W.; Carlson, J. A. J. Org. Chem. 1994, 59, 5463-5465. (c)
Prashad, M.; Har, D.; Chen, L.; Kim, H. Y.; Repic, O.; Blacklock, T. J. J.
Org. Chem. 2002, 67, 6612-6617.
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