Synthesis and spectroscopy of novel-α-pyrazolylglycine derivatives

Article abstract of DOI:10.1002/jccs.200100008

The synthesis of α-pyrazolylglycine derivatives (7a-d) with different substituents, starting from glycine have been prepared. The spectroscopy of intermediate compounds and the final amino acids have been discussed.

Full text of DOI:10.1002/jccs.200100008

JournaloftheChineseChemicalSociety, 2001, 48, 45-48
45
Synthesis and SpectroscopyofNovel- -Pyrazolylglycine Derivatives
MuhammadZia-ul-Haqa,MuhammadArshad*b and Saeed-ur-Rehmanc
aChemistryDepartment,Quaid-i-AzamUniversity,Islamabad,Pakistan
bAppliedPhysicsDivision,PINSTECH,P.O.Nilore,Islamabad,Pakistan
cChemistryDepartment,PeshawarUniversity,Peshawar,N.W.F.P,Pakistan
The syn the sis of -pyrazolylglycinederivatives(7a-d) withdifferentsubstituents,startingfromglycine
have been pre pared. The spec tros copy of in ter me di ate com pounds and the fi nal amino ac ids have been dis-
cussed.
INTRODUCTION
-Aminoacidsserveacentralroleinbiologyandchem-
those derived from electrophilic glycine equivalents are
worthmentioning.3
In the course of our study on cyclization re ac tions4-7 of
different -diketones with hydrazine de riv a tives, we have
been able to pre pare -pyrazolyl- -amino ac ids via Scheme
I. In this pa per we re port the syn the sis and spec tros copy of
theseaminoacidsandtheintermediatecompounds.
istrybeingthefundamentalconstituentsofproteinsandme-
diatorsofnitrogenmetabolismandproviderawmaterialfora
largenumberofbiologicallyimportantprimaryandsecond-
ary metabolites.1 The number of naturally occurring -
amino ac ids has grown sub stan tially from 20-amino ac ids
normallyfoundinproteinstoover700.2 Inadditiontherehas
been a tre men dous surge of in ter est in prep a ra tion of rel a-
tivelyinaccessibleunnaturalaminoacidswhosepotentialbi-
ologicalpropertiesandgeneralsyntheticutilitiesarejustbe-
gin ning to be re al ized. Of the meth ods pres ently avail able,
RESULTS AND DISCUSSION
The acetylation of glycine was car ried out by a re ported
method8 with the same yields and melt ing points of aceturic
Scheme I
O
Br
O
O
Br /h
Et N
2
3
CH
NH
COOCH
3
CH
N
COOCH
3
CH
NH
COOCH
3
3
3
3
AlBN
(2)
(1)
(3)
O
o
O
O
O
3
R
1) R1
R2
N
N
1
2
R
-80 C
RT
R
3
NH -NHR
2
H
b
O
1
+
R
2
2) H O
3
R
O
CH
NH
COOCH
3
3
H
a
CH
NH
COOCH
3
3
(4)
(5)
1
2
4a R =R =CH
3
1
2
3
1
2
5a R =R =CH ,R =H
3
4b R =CH , R =C H
3 6 5
1
2
3
3
5b R =R =CH ,R =C H
6 5
3
R
3
1
2
3
R
5c R =CH ,R =C H ,R =H
3
6 5
N
N
1
2
3
5d R =CH ,R =R =C H
3
6
5
N
N
1
2
+
R
1
- OH/ H O
R
2
R
H O /reflux
3
2
R
O
H N
COOH
2
CH
NH
COOH
3
(7a-d)
(6a-d)

46 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Zia-ul-Haq et al.
acid. Esterification of aceturic acid9 with SOCl2/CH3OH
gave (1) in good yield. Photolytic bromination of es ter (1)
with NBS/CCl4 did not give sat is fac tory re sults; how ever,
bromination with Br2/CCl4 in pres ence of AIBN (azobisiso-
butyronitrile),aradicalinitiator,resultedintheformationof
-bromo es ters (2) in good yields.10 On treat ment of (2) with
ter tiary amine, highly re ac tive -acyliminoacetate (3) was
found in situ which on re ac tion with -diketones gave (4a-b)
in rea son ably good yields. These 1,3-diketo de riv a tives, on
cyclocondensation with hydrazine de riv a tives, af fordedN-
protected -pyrazolylglycine es ters (5a-d) which were hy-
dro lysed to N-pro tected amino ac ids (6a-d). N-acetylated
amino ac ids (6a-d) were sub jected to en zy matic deacetyla-
tion with acylase which sur pris ingly failed. This can be at-
trib uted to steric hin drance due to the bulky na ture of the sub-
strateduringthereactionwiththeenzyme.
trile, triethylamine, THF, cit ric acid, so dium hy dro gen car-
bonate,ethylacetate,sodiumsulphate,petroleumether,etha-
nol, hydrazine, phenylhydrazine, poatssium hy drox ide, hy-
drochloricacidandmagnesiumsulphate.Ethanolwasfurther
purifiedbythereportedmethod.8
PREPARATION OF COMPOUNDS
Methyl 2-acetylamino-4-oxo-3-(1 -oxoethyl/phenylmethyl)-
pentanoates (4a-b)
The acylimino es ter (3) was gen er ated by ad di tion of
triethylamine (0.75 mL, 5.5 mmol) to bromo es ter (2) in dry
THF at -78 oC. Af ter 30 min utes the -dicarbonyl com pound
(6 mmol) stirred with triethylamine (6 mmol) in dry THF at
room tem per a ture for 30 min utes, was added slowly to the
acylimino es ter. Af ter warm ing, the mix ture was stirred for
12 hours at room tem per a ture. Then aque ous 20% citiric acid
(5mL)wasaddedandthesolutionwasneutralizedwithaque-
ous so dium hy dro gen car bon ate. The prod uct was ex tracted
with ethyl ac e tate (3 ), dried (Na2SO4) and evap o ratedin
vacuo. Pu ri fi ca tion was pos si ble by recrystallization from
ethylacetate/pet.etherorbycolumnchromatographyusing
ethyl ac e tate/pet.ether as eluent.Methyl 2-acetylamino-4-
oxo-3-(1 -oxoethyl)pentanoates (4a): yield 44%, m.p.
103-5 oC. IR ( max, KBr, cm -1 ): 3304, 2956, 1749, 1725, 1656,
Fol low ing Scheme I, the racemic -amino ac ids (7a-d)
couldbepreparedsuccessfullybydeacetylationof( 6a-d) un-
deracidicconditions.
1
In the H-NMR spectra of compounds (4a-b), two
methine pro tons (Ha and Hb) showed a dou blet of dou blet
and a dou blet at 5.36-5.8 and 4.45-6.3, re spec tively. In
(5a-d)themethineprotonsshowedcouplingwiththeprotons
of N-H and showed a dou blet in the re gion 5.28-6.4. In com-
pound (5b), these methyl groups linked with a pyrazole ring
showedseparatesingletsduetounequalenvironmentalcon-
ditions.
Compounds(6a-d) ob tained by saponification of the
esters(5a-d) were iden ti fied only by IR spec tra where the
C=O vi bra tions were ob served at 1720-1762 cm-1 in place of
car bonyl stretch ing of es ter group at 1704-1785 cm-1. More-
over, C-O-C stretch ing of es ter groups at 1105-1199 cm-1
were also ab sent in these com pounds. The pu rity of ac ids
wereconfirmedbyelementalanalysis.Inthe1H-NMR spec-
tra of (7a-d), the methine pro ton ap peared as sin glet at 5.2.
The mass spec tra of (7a-d) showed base peaks due to the loss
of –COOH group. The pri mary frag men ta tion con sis tent in
all of the com pounds was char ac ter ized by the pres ence of
m/z M+ -44 and M + -45 due to the loss of CO2 and –COOH
fromthemolecularion,respectively.
1
1548. H-NMR (CDCl3, -values): 2.0 (s, 3H, NCOCH3),
2.23 (s, 3H, COCH3), 2.32 (s, 3H, COCH3), 3.71 (s, 3H,
COOCH3), 4.46 (d, 1H Hb, J = 2 Hz), 5.26 (dd, 1H, Ha,J = 5
Hz). Methyl 2-acetylamino-4-oxo-3-(1 -oxophenylmethyl)-
pentanoates (4b): yield 48%, m.p. 96-9 oC. IR ( max, KBr,
cm-1):3280, 3076, 2956, 1758, 1722, 1650, 1602, 1584, 1527,
1446, 1329, 1284, 1H-NMR (CDCl3, -val ues): 2.03 (s, 3H,
COCH3), 2.36 (s, 3H, N-COCH3), 3.68 (s, 3H, COOCH3),
4.72 (s, 1H, Hb), 5.3 (dd, 1H, Ha, J = 7 Hz), 7.62 (m, 5H,
Ar-H).
Methyl 2-acetylamino-2-(substitutedpyrazol-4-yl)acetates
(5a-d)
Compound (4) (5 mmole) dis solved in eth a nol (50 mL)
and af ter ad di tion of hydrazine hy drate (100%) or phenyl-
hydrazine (5 mmol), the mix ture was refluxed for 2-3 hours.
After evap o ra tion to dry ness the prod uct was pu ri fied by
recrystallization from ethyl ac e tate/pet.ether or by col umn
EXPERIMENTAL
chromatography. Methyl 2-acetylamino-2-(3,5- dimethyl-
o
Chemicals
pyrazol-4-yl)ac e tate (5a):yield 61%, m.p. 95 C. IR (
,
max
The fol low ing chem i cals ob tained from Sigma and
Aldrichwereusedthroughoutthisworkwithoutfurtherpuri-
ficationnamely,glycine,methylsulphate,ammoniasolution,
acetone,alcohol,carbontetrachloride,azobisisobutyroni-
KBr, cm -1 ): 3292, 1740, 1647, 1536, 1122. 1H-NMR (CDCl3,
-val ues): 1.92 (s, 3H, CH3CO), 2.16 (s, 6H, 2 CH3-), 3.61
(s, 1H), 4.01 (s, 3H, COOCH3), 5.28 (s, 1H), 7.22 (s, 1H).
Methyl2-acetylamino-2-(3,5-dimethyl-1-phenylpyrazol-

Novel- -PyrazolylglycineDerivatives
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 47
4-yl)acetate(5b): yield 70%, m.p. 140-1 oC. IR ( max , KBr,
cm-1): 3078, 2956, 2848, 1752, 1635, 1137. 1H-NMR (CDCl3,
-val ues): 2.05 (s, 3H, -COCH3), 2.28 (s, 3H, CH3-), 3.33 (s,
3H, -CH3), 3.75 (s, 3H, COOCH3), 5.54 (d, 1H, Ha, J = 1.6
Hz), 7.34 (m, 5H, Ar-H). Methyl 2-acetylamino-2-(3-
methyl-5-phenylpyrazol-4-yl)acetate(5c):yield 54%. m.p.
182-3 oC. IR ( max, KBr, cm-1): 3238, 3064, 2956, 1749, 1662,
1539, 1128. Methyl 2-acetylamino-2-(3-methyl-1,5-di-
plied to an ion ex change col umn (Amberlite CG 120, 20 mL
of resin bed). The col umn was eluted with fol lowed by 2%
aqueousNH3 solution.Theaq.ammoniafractionwasevapo-
rated in vacuo. The crude prod ucts were recrystallized from
ethanol/acetone. (3,5-Dimethylpyrazol-4-yl)glycine) (7a):
yield 69%, m.p. 233oC (decom.). IR ( max, KBr, cm-1): 2908,
1641, 1518, 1446, 1377, 1344, 1287, 1212, 1149, 1044, 999,
894, 825, 738, 696. 1H-NMR(D2O, -val ues): 2.25 (s, 6H, 2
CH3-), 5.20 (s, 1H, Ha). MS: m/z (%): 169 (M+ , 1.15), 125
(17), 124 (100), 122 (34), 109 (26), 108 (37), 97 (38), 95 (7),
o
phenylpyrazol-4-yl)acetate(5d):yield 58%, m.p. 172 C.
IR ( max, KBr, cm-1): 3298, 3064, 3004, 2962, 1752, 1692,
1599, 1506, 1128.
56 (17), 52 (10). (3,5-Dimethyl-1-phenylpyrazol-4-yl)-
o
glycine) (7b): yield 72%, m.p. 220 C (decom.). IR (
,
max
2-Acetylamino-2-(substituted pyrazol-4-yl)acetic acids
(6a-d)
KBr, cm-1): 3064, 1635, 1503, 1431, 1380, 1206, 1116, 1017,
693, 759. 1H-NMR (D2O, -val ues): 2.12 (s, 3H, -CH3), 2.18
(s, 3H, -CH3), 5.2 (s, 1H, CH), 7.4 (s, 5H, Ar-H). MS: m/z
(%): 245 (M+ , 2%), 201 (21), 200 (100), 185 (35), 184 (40),
173 (16), 77 (59). (3-Methyl-5-phenylpyrazol-4-yl)glycine
(7c): yield 58%, m.p. 230 oC (decom.). IR ( max, KBr, cm -1 ):
3148, 2866, 1605, 1527, 1488, 1452, 1368, 1344, 1296, 1263,
The N-pro tected amino methyl es ters (5a-d) (1 mmol)
were refluxed for one hour with a mix ture of eth a nol (20 mL)
and 1N KOH (1.5 mL). Then the sol vent was evap o rated un-
derreducedpressure,theresiduedissolvedinwater(20mL),
acidifiedwith1NHCl(2mL)andextractedwithethylacetate
(3 20 mL). The or ganic layer was dried with an hy drous
MgSO4 and evap o rated to dry ness. The crude acid was pu ri-
fied by recrystallization from ethyl acetate/pet.ether. 2-
Acetylamino-2-(3,5-dimethylpyrazol-4-yl)acetic acids
1
1215, 1155, 1098, 999, 969, 792, 771, 729, 693. H-NMR
(D2O, -value): 2.52 (s, 3H, -CH3), 5.2 (s, 1H, CH), 7.2 (s,
5H, Ar-H). MS: m/z (%): 231 (M+ ,1.5), 187 (26), 186 (100),
184 (13), 171 (23), 170 (14), 159 (15), 77 (32). (3-Methyl-
1,5-diphenylpyrazol-4-yl)glycine(7d): yield 63%, m.p. 216
oC (decom.). IR ( max, KBr, cm-1): 3364, 3160, 3046, 2716,
2548, 1617, 1506, 1449, 1431, 1371, 1323, 1296, 1262, 1107,
1074, 1011, 969, 912, 825, 792, 762, 696. 1H-NMR (D2O,
-value): 2.24 (s, 3H, -CH3), 4.07 (s, 1H, -CH), 7.25 (s, 10H,
Ar-H). MS: m/z (%): 307 (M+ , 1.5), 263 (30), 262 (100), 246
o
(6a): yield 51%, m.p. 203 C. IR ( max, KBr, cm-1): 3351,
3192, 2940, 1742, 1652, 1575, 1529, 1511, 1477, 1321, 1262,
1101,1047,721,715.Elemental Analysis:(C9H13N3O3; 211)
Calc. (Found): C = 51.18 (51.02); H = 6.16 (5.95); N = 19.9
(19.7). 2-Acetylamino-2-(3,5-dimethyl-1-phenylpyrazol-
o
4-yl)ace tic ac ids (6b):yield 57%, m.p. 186.3 C. IR (
,
max
KBr, cm-1): 3941, 3313, 3237, 1729, 1629, 1535, 1432,
1401, 1387, 1271, 1120, 1034, 739. Elemental Analysis:
(C15H17N3O3; 287) Calc. (Found): C = 62.7 (62.2); H = 5.9
(5.1); N = 14.6 (14.2). 2-Acetylamino-2-(3-methyl-5-
phenylpyrazol-4-yl)aceticacids(6c): yield 65%, m.p. 207
oC. IR ( max, KBr, cm-1): 3208, 3051, 2955, 1762, 1631, 1540,
1448, 1382, 1290, 1260, 1209, 1123, 1070, 985, 700, 651. El-
ementalAnalysis: (C14H15N3O3; 273) Calc. (Found): C = 61.5
(60.98); H = 5.49 (5.11); N = 15.38 (14.89). 2-Acetylamino-
2-(3-methyl-1,5-diphenylpyrazol-4-yl)aceticacids(6d):
(19), 247 (12) 131 (10), 77 (59).
,
INSTRUMENTATION
The melt ing points are un cor rected and re corded on a
Gallenkampdigitalmeltingpointapparatus.Forrecording
IR, 1H-NMR and mass spec tra, a Hitachi 270-50, Jeol Model
JNM FX 900 and Varian Mat CH-5 were used, re spec tively.
TheelementalanalysiswascarriedoutonCarloErbaModel
DP 200. The NMR spec tra of all the com pounds were re-
corded in CDCl3 ex cept the fi nal amino ac ids (7a-d), where
D2O was used as sol vent.
o
yield 61%, m.p. 192 C. IR ( max, KBr, cm-1): 3256, 3060,
3010, 2857, 1728, 1647, 1600, 1522, 1480, 1371, 1335, 1320,
1256, 1214, 1156, 1101, 1039, 760. Elemental Analysis:
(C20H19N3O3; 349) Calc. (Found): C = 68.76 (68.14); H = 5.4
(5.05); N = 16.86 (16.33).
ACKNOWLEDGEMENT
(Substituted pyrazol-4-yl)glycines (7a-d)
The sus pen sion of N-acetylamino acid (1 mmol) in 20
mL of 10% HCl was refluxed for 50 hours. A cold mix ture
was ex tracted with ethyl ac e tate and aque ous phase was ap-
One of us (Muhammad Zia-ul Haq) is thankful to
Quaid-I-Azam University for the award of a fellowship.
Thanks are also due to Nadeem Ahmad and Irfan Waheed for

48 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Zia-ul-Haq et al.
extendingtheirtechnicalassistance.
H. Angew Chem., Int. Ed. 1983, 22, 816. (c) Greenstein,
J. P.; Winitz, M. ChemistryoftheAminoAcids; Rob ert E.
Krieger, FL, 1984, Vol. 1-3.
Received July 5, 2000.
3. Bin-Ishai, D.; Altmann, J.; Bernstein, Z.; Peled, N. Tet ra-
hedron 1978, 34, 467.
Key Words
4. Ahmed, R.; Zia-ul-Haq, M. J. Chem. Soc. Pak. 1993, 15,
48.
-Amino acids; -Diketones; Pyrazolylglycine de-
rivatives.
5. Ahmed, R.; Zia-ul-Haq, M.; Khan, N.; Kausar, N. The
Ara bian J. for Sci. and Engin. 1996, 21, 393.
6. Ahmed, R.; Zia-ul-Haq, M. Turk. J. Chem. 1995, 19, 101.
7. Ahmed, R.; Zia-ul-Haq, M.; Jabeen, R.; Duddeck, H.
Turk. J. Chem. 1996, 20, 186.
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