Solid-phase synthesis of methyl N-(pyrimidin-2-yl)glycinate

Article abstract of DOI:10.3390/80600467

A versatile method for the preparation of N-heteroaryl substituted aminoacid derivatives is suggested. The method avoids facile diketopiperazine formation.

Full text of DOI:10.3390/80600467

Molecules 2003, 8, 467-471
molecules
ISSN 1420-3049
http://www.mdpi.org
Second Eurasian Meeting on Heterocyclic Chemistry
“Heterocycles in Organic and Combinatorial Chemistry“
Solid-Phase Synthesis of Methyl N-(pyrimidin-2-yl)glycinate
Denis S. Ermolat'ev and Eugene V. Babaev*
Chemistry Department, Moscow State University, Moscow 119899, Russia. Tel.: (+7) 095-939-3020,
Fax: (+7) 095-932-8846.
* Author to whom correspondence should be addressed; e-mail: babaev@org.chem.msu.su,
chemistry@hotbox.ru,
Received: 13 May 2003; in revised form: 17 June 2003 / Accepted: 17 June 2003 / Published: 30 June
2003
Abstract: A versatile method for the preparation of N-heteroaryl substituted aminoacid
derivatives is suggested. The method avoids facile diketopiperazine formation.
Keywords: Solid-phase organic synthesis, N-substituted aminoacids.
Introduction
Aminoacid derivatives, in particular N-substituted α-aminoacids, are important synthetical
precursors and building blocks in combinatorial chemistry. It is sometimes very difficult to obtain such
N-substituted acids, especially for the cases when a heterocyclic substituent is attached to the amino
group. Attempting to prepare ethyl N-(pyrimidin-2-yl)glycinate via reaction of 2-chloropyrimidine and
ethyl glycinate we observed predominant formation of diketopiperazine. An alternative strategy –
alkylation of the endocyclic nitrogen of 2-aminopyrimidine with chloroacetic acid (or its esters)
followed by Dimroth rearrangement (which usually is a safe route to 2-alkylaminopyrimidines) – also
failed due to intramolecular self-condensation between the 2-amino group and the acetic acid fragment.
An alternative strategy is therefore required to prepare such a target.

Molecules 2003, 8
468
Results and Discussion
Our aim was to synthesize N-(pyrimidin-2-yl)glycinate (I). This compound can be formally
considered as a 2-alkylaminopyrimidine, and there are two main synthetic routes for this class of
compounds (Scheme 1).
Scheme 1
OH
O
B
A
Hal
H2N
N
N
+
N+
NH2
+
N
N
N
N
N
R
N
N
N
R
R
H
X
HN
I
NH2
R
The first route (A) is the Dimroth rearrangement of 1-alkylpyrimidinium salts, which in turn can be
easily prepared by alkylation of the endocyclic nitrogen atom of 2-aminopyrimidine (one would expect
that for the target molecule I such an alkylating agent might correspond to an α-halogenated acetic
acid derivative). The second strategy (B) is a nucleophilic substitution in a pyrimidine ring with a good
leaving group in the alpha position by amines.
We have attempted to apply strategy A by alkylating 2-aminopyrimidine with ethyl bromoacetate
and sodium chloroacetate. Both salts were obtained, and their structures were proven by NMR.
However, our attempts to perform the Dimroth rearrangement gave undesirable compounds with deep
coloration. It was assumed that the expected intramolecular self-condensation between the 2-amino
group and the acetic acid fragment occurred, probably followed by further oxidative dimerization
under basic conditions (Scheme 2):
Scheme 2
N
-
N
N
N
base
NH2
OH
O2
-
OH
O
N
N
N+
N
N
N
O
-
Hal
O
HN
O
N
O
OR
N
N
O
The second route to prepare the target compound I is the nucleophilic substitution in the
pyrimidine ring bearing a good leaving group in the alpha position by amines. Such nucleophilic
substitutions in pyrimidine rings are well-studied reactions [1]. We tried to apply this reaction to
2-chloropyrimidine using ethyl glycinate chlorohydrate in the presence of strong base (Scheme 3).
Unfortunately, the expected substitution proceeds quite slowly, in contrast to the quick self-reaction of
ethyl glycinate, and consequently we observed predominant formation of diketopiperazine.

Molecules 2003, 8
469
Scheme 3
+
OEt
N
N
DABCO
slow
H3N
+
OEt
-
Cl
Cl
O
N
N
H
N
O
O
O
fast
NH
HN
OEt
H2N
O
Attempting to resolve the problem, we have applied a solid-phase synthetic approach (Scheme 4).
At first Boc-protected glycine (in the form of its cesium salt) was attached onto Merrifield resin under
standard conditions [2] in order to prevent possible self-condensation. Solid phase supported glycine
was deprotected and successfully involved in the reaction with 2-chloropyrimidine. The degree of
conversion was monitored by the ninhydrin test. Finally, the product was cleaved from the Merrifield
resin in the presence of sodium methoxide in the methanol/tetrahydrofuran solution [3].
Scheme 4
O
O
Cs2CO3, KI
NHBoc
NHBoc
Cl
+
O
P
P
DMF, 80oC, 10 hrs
HO
N
N
N
O
O
O
H
1. TFA/DCM
2. TEA/CHCl3
, DIEA
Cl
N
N
NH2
O
P
P
DMF, 85o C, 15 hrs
N
H
O
MeONa
Overall yield - 76 %
Purity - 95 %
N
N
HO
MeOH/THF
Conclusions
We have found a solid-phase synthetic strategy to be advantageous for synthesis of the target
compound I, compared to usual liquid phase processes.

Molecules 2003, 8
470
Acknowledgments
This work was supported by INTAS (Grant No. INTAS 00-0711).
Experimental
General
1H-NMR spectra were obtained using a Bruker AC 400 NMR spectrometer and were recorded at
360 MHz. Merrifield resin (2% crosslinked with divinylbenzene) was obtained from Reanal. All
reagents were obtained from ACROS.
Synthetic procedure
Merrifield resin (1 g, 1.0 mmol) was swelled in DMF solution (6 mL) containing of Boc-protected
glycine (0.525 g, 3 mmol), cesium carbonate (0.49 g, 1.5 mmol) and potassium iodide (0.17 g, 1
mmol). The mixture was constantly stirred and heated at 80oC for about 10 hours. The resin was
washed successively with DMF, MeOH, DCM and dried in vacuo. Immobilized glycine was
deprotected by suspending the resin (1.15 g) in a 1:1 mixture of TFA and DCM at room temperature
for 0.5 hours [4]. The resin was washed sequentially with 1:1 DCM-DMF, DCM, MeOH, 1:10 TEA-
CHCl3, and MeOH. In the next step dried resin (1.06 g) was heated in DMF solution containing
2-chloropyrimidine (1.137 g, 10 mmol) and DIEA (0.55 mL, 4 mmol) at 90oC for at least 15 hours.
The resin turned to brown color and gave a negative ninhydrin test. After washing by DMF, DCM and
drying we obtained 1.13 g of dark colored resin. Then this amount of resin was refluxed for 6 hours in
a 4:1 mixture of THF-MeOH (5 mL) in the presence of sodium methoxide (0.5 mL of 0.2 M MeONa
solution in MeOH). The resin was filtered and washed with THF (15 mL) and MeOH (10 mL, twice).
After evaporation of solvents a solid residue was obtained (0.126 g) and analyzed without further
purification. The overall yield was 76% and the purity of the product was evaluated as 95%. The
structure was proven by its 1H-NMR spectra (CDCl3, 360 MHz), δ: 8.21-8.25 (2CH, d, J=7.6 Hz, 2H);
6.49-6.62 (CH, t, J=7.5 Hz, 1H); 5.45-5.60 (NH, bs, 1H); 4.13-4.16 (CH2CO2, d, J=5.2 Hz, 2H); 3.70
(CH3, s, 3H).
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Reagents for the Synthesis of alpha-Amino Acid Libraries J. Comb. Chem. 2000, 2, 438-440

Molecules 2003, 8
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