Preparation and enantiomeric purity determination of new chiral C2 building blocks based on the 4-amino-1,2,4-triazole unit

Tarahedmn: Asymnuoy Vol. 5. No. 7. pp. 1291-1296. 1994 Elscvia science Ltd Printed in Great Britain 0957-4166194 s7.00+0.00

0957-4166(94)00179-O

Preparation and Enantiomeric Purity Determination of New Chiral C2 Building Blocks Based on the 4-Amino-1,2,4=triazole Unit M. Victoria

Martinez-Dfaz.,

Javier de Mendoza,

Fernando

Santos and Tomb

Tarred

Departgnento da Cutmka (C-l), Facuttad da Ciancias, Utivemktad Aut6nana de MadrId, 2EWS-Medrld, Spain

Abstract:

Several new chiral synthons based on the Qamino- 1,2.4-triazole

prepared by the condensation

hydrazine.

reaction of optically active a-hydroxy-

A general method for the determination

disubstituted-1,2,4-triazdes

moiety have been

and a-aminoacids

with

of the optical purity of chiral4-amino-3.5

based on their oxidation with lead tewtate

(LTA) is described.

There has been recent interest in mactocyclic compounds containing ptoton ionizable functional gruups directly incorporated extensively

as building

ourselves.e-11 properties

into a macrocyclic

Recently,

blocks

fmmew0rk.t

for macrocyclic

moiety. In these cases. (S,.+&amino3,5bis-( lactic acid or some of its derivatives by receptors

systems

mainly by Bradshaw

we have reported on the synthesis,

of chiral crown ether macrocycles

ttiazohc macrocycles.

In this regard, 1,2,4_ttiazole subunits have been used complexation

such us 18-m and podands.tt I-hydroxyethyl)-1,2,4triazole

and coworker@

and protonated incorporating

28,prepared

and by

amine transport a 1.2.~triazole

by treatment of (a-

with hydrazine. was used as a chital precursor for the preparation

of the

The modest selectivities found in the enantiomeric recognition of organic ammonium salts

19.10 are probably due to the low chiral barrier provided by the two chiral centen.

In order to

develop new systems having bulkier chiral substituents in a more rigid framework, we decided to prepare other 1.2.dtriazolic

building

blocks

with C2 symmetry t* related to 2 derived

phenyllactic and mandelic acids, or natural a-aminoacids.

1291

from a-hydroxy

acids, such as

1292

M. V. MART~NE~-D~AZ rt al.

The condensation the preparation

of (S)-phenyllactic

of (S,s)-2

afforded

acid with hydmzine

the corresponding

under similar reaction conditions

triazole ($93

[a]~ = - 54.4 (c = 0.5, HCI 2 N), was shown to be a single diastereoisomer data.

Attempts

to check

the

enanttomeric

trifluoromethylphenyl-0-atyl

(MTPA)

reactive functions

in the substrate.

purity of triazole

(X&2.

availability

procedure to establish ago,13 we observed centers

directly

corresponding conditions

This method,

is not always

of both antipodes

purity

derivative

the enantiomeric

bound

to the triazole intermediate,

racemization

by means

due to the presence

of three

of the enantiomeric

and largely

For this reason it was necessary

depends

1,2,4triazole

ring, fragments

on oxidation

fo afford an optically

(Scheme

Not long

1). having stereogenic

with lead tetraacetate

(LTA),

active ninile with the same configuration. this reaction

on the

to develop a general

purity of chiral 4-amino-3,5disubstituted-1.2.4triazoles.

does not take place. Now, we have applied

purity of chiral4-amino-

of its bts-(d)-a-methoxy-a-

probably

in this series of compounds

mixture.

for

to the tH- and t3C-NMR

used by us* in the determination

that a chiral (S,S)4amino3,5disubstituted-

nittene

according

were unsuccessful,

previously

unequivocal

or their racemic

of (S,S)-3

employed

in good yield (63 %). This compound,

to analyse

via the

Under these

the enantiomeric

1,2,4triaroles.

R = COCH=CHPh Scheme Thus,

treatment

Similarly.

the (R&)-2

hydtazine

hydrate

(S)- and (R)-4 corresponding

Comparison

derivatives

excess

cyanhydrin

(Q-4

(c = 1.5. H20) obtained

cyanhydrin

of the tH-NMR

chloride by tH-NMR

acid to 2_phenylacetaldehyde,

LTA Ho (s)-4 R=Me (S)-5 R=CHePh

acid with Reaction

afforded

of the spectra

4 and. by chemical compound

[Lit t4 (R)-5: [a]~ = + 10.5

spectra of the MTPA derivatives

-

of (R)-lactic

(MTPACI)

Analysis

(S,S)- and (R,R)-2. Similarly,

of (S..Y)-3, is also higher than 98 %.

2,3

by reaction

as higher than 98 96 for both cyanhydrins

for their precursors

of cyanhydric

[aID = - 30 (c = 1, chloroform).

(R)-4, [a]D = + 30 (c = 1. chloroform).

clearly distinguishable

(.5)-S, [a]~ = - 10.6 (c = 1. chloroform)

by addition

and therefore

[a]~ = - 31.5

the corresponding

purity to be assessed

LTA affording

with LTA yields

with (S)-a-methoxy-a-trifluoromethylphenylacetyl

same enantiomeric

obtained

enantiomer

affords

MTPA

enanticmeric

of (S,s)-2

1

of (Q-5 and of the racemic

=

reacts

the the with

1, chloroform)].

cyanhydrin

reveals that the enantiomeric

the

allows

correlation,

(S&3 (C

of

(Rs)-5,

purity of (S’)-5.

Chiral building

The reaction optically

inactive

of(s)-

mixture

and (R)-mandelic

acids with hydrazine

of racemic and meso4amino-3.5bis-(

and tacemization

Only a few examples

of condensation *5The reactivity

with those of the a-hydroxyacids Lvaline

described

react slowly with hydmzine

of the axnsponding

triazde.

ratios. Only with L-proline which precipitates prolinhydrazide structurally However, impossibility derivatives,

of isolating chital lanthanide

L&nine thus allowing

+ (9S)S

reactions

above, is significantly

the monohydrazide was it possible

derivatives purity

intermediate

with hydrazine

with hydrazine

to afford

hydrate.

lower. Thus, L-alanine.

1.2.4

in comparison

Lphenylalanine

aad

heating (120 h) at 150 Oc, oily mixtures

and even umeac&d starting aminoacid

in different

to isoiate pure 4-amincF3.5bis-(2-pyrrolidin)-1.2,4-triazole

(8)

in 40 96 yield after 72 h. heating at 150 “C. In this reaction, in 38 % yield. Compound

often lead IO very high asymmetric

of compound

the corresponding

8 could not be determined

nitrile

from the reaction

methyl esters hydrochiorides

of the corresponding

triazoles

the

8 has a great interest because

inductions

in organic

by the LTA method mixture.

synthesis. due the

The use of Masher’s

reagents and HPLC analysis on a chiml phase were also unsuu~&ul

and L-phenylalanine the preparation

of a-aminoacids

of natural a-aminoacids

7 was also isolated as hydrochloride

rigid pyrrolidine

protons in this case should be responsible

hydtate to afford. after prolonged

from the reaction mixture

the enantiomeric

in both cases the same

7.

mvw-6

triazoles have been described.

hydrate affords

I-phenyl-1-hydroxymethyl)-1,2&triazoles

(RS,R.S)-6 and (R..Y)-6. The relative higher acidity of the methyne for the epimetizatkm

1293

blocks based on Csmino-1.2.4triazole

react faster with hydrazine

in this case.

hydrate (48 h),

10 and 12 in 82 96 and 52 % yield, respectively.

With lower reaction times, the reactions afforded also the corresponding

hydmzides

9 and 11 as major products

that can be isolated as hydrochlorides. Treatment

13b in a 6535 ratio analyzed 30 % for the triazol compound

13a and

by *H-NMR of their MTPA derivatives,

thus indicating an enantiomeric

purity of

10. The same result was obtained in the analysis

12 In this case.. (s)- and (R)-2-amino-3-phenylpropanenitriles

63:37 ratio. Similar enantiomeric and D-phenylalanine

and (R)-2-aminopropanenitriles

of 10 with LTA in methanol gave a mixture of(s)-

of the cnantiomeric

purity (26 %) of

140 and lob were obtained

in a

excesses were observed for the triazoles obtained in the reaction of D-alanine

methyl esters with hydmziue.

M. V. MART&Z-D~AZ

I294

The condensation

of the L-proline

yield (tH-NMR)

yield obtained. The reaction

reaction

conditions

10

ester with hydrazine

methyl

cstcr hydrochloride

is also faster than with the free aminoacid,

From the data obtained

hydrate

it can be concluded

difficult

the heterocyclization

mixture

character of the aminotriazoles

as described

derived from aminoacids

triazole

before,

with hydra&e

the intermediate

in the reactions between a-hydroxyis. The low solubility

gives

from the reaction

7 in almost mixture.

despite

hydrate

hydmzide

in common

organic

the lower triazole

15 being the major

and a-aminoacids

are in the a-position

For

under the same

but, even after % h, the corresponding

( lH-NMR),

that, the bulkier the substituents reaction

hydrate

does not precipitate

to prepare 7 from the free aminoacid

of L-valinc

16 is present only in a 40 8 in the reaction component.

methyl

after 48 h, but the compound

this reason it is more convenient

R=CH3 12 R=CHfi 16 R = CH(CH&

9 R=CH3 11 R=CH#h 15 R = CH(CH&

R = CH3, CHzPh, CH(CHJ 2

quantitative

et al.

with hydrazine

of the substrates.

the more

solvents and the hygroscopic

hinder to a great extent the isolation

and purification

of

the compounds.

10,12

,-)

R

LTA

a4

(S)-MTPACI *

13 R=CH3 14 R=CH#‘h

The contrast

in the stereochemical

give 2 and 3) and related a-ammoacids considering

excesses

of a-hydroxyacids

(such as lactic and phenyllactic

and phenylalanine

to afford 9 and 11) could be explained

that the low reactivities nf these .whs~rate.n require rhe use of more draak

particular longer reaction protons

behaviour (like alanine

0

in compounds

times and higher excess of hydrazine.

2 and 3 should

also play an important

acids to

reActinn conditions,

in

On the other hand, the lower acidity of the arole in explaining

the excellent

enantiomeric

found in these cases. In conclusion,

can be prepared

we hnvc confirmed

the other hand, a-alkyla-aminoacids cnantiomeric

excesses

3,ldisubstituted Acknowledgements:

that chiral building

from a-alkyl-a-hydroxyacids afford

blocks based on the 4-amino-1,2,4triazolc

in good yields and excellent modemte

to good yields of the corresponding

(around 30 8). A general method to determine

1,2,4-triazoles Thanks

(> 98 96) enantiomeric

of practical value as well as operational are due to BASF Ludwigshafen

the. enantiomeric simplicity

(Germany)

unit

purities.

triazoles

On

in low

purity of chin4 4-amino

has been also developed.

for a gift of (m-lactic

acid.

Chiral building

Experimental General 1.2.4-~iazoles.

Procedure for the Preparation

A well-stirred

ester hydrochloride distilled

of 4-amino-3.5~bis-(l-hydroayalkyl)a-hydroxyacid.

and (l-aminoaikyl)-

a-aminoacid

or a-amincacid

hydrate was heated at 120 “c for 8 h. The excess of hydtazine

off while the temperature

temperature

Section

mixture of the corresponding

and hydrarine

1295

blocks based on 4-amino-1,2,4_triazole

was raised up slowly

for 5 h. The reaction was monitored

was repeated until the intermediate

to 160 “c and then the mixture

methyl

and Hz0 were

was kept at this

by tH-NMR and the cycle -addition of hydrazine and heating-

hydraaide disappeared.

Finally, the reaction mixture was cooled down and

worked up as indicated in each case. (R.R)-4-amino-3,5-bis-(l-hydroxyethyl)-1,2,4-triazo& 53 g. 0.23 mol) and hydrazine Yield 56 % (acetonitrile); (c = 1.5, H20)];

2. From (K)-lactic acid (40 % in water solution,

hydrate (25 ml. 0.51 md) a syrup was obtained

which solidified

on standing.

white solid, mp 128-30 “C; [a]D = - 31.5 (c = 1.5. H20); [Lit* (S.s)-2: [a]D = + 32 (&-dmso):

tH-NMR

TV= 5.76 (s broad, 2H, NH2). 5.39 (d, J=6.7 Hz, 2H. OH), 4.90 (q.

J=6.7 Hz,, 2H, CH), 1.47 ppm (d, J=6.7 Hz, 6H. CH3). (S,S)-4-~ino-3.5-bis-(l-hydroxy-2-phenylelyl)-1,2,4-triazole mmol) and hydmzine

Y icld 63 % (acetonitrilc); 7.3-7.1

white needles; mp 220-2°C; [a& = - 54.4 (c = 0.5, HCl2N);

(m. lOH, Ph), 5.7 (s, 2H, NH&

2H, CHsPh); EHCHz),

3. From L-phenyllactic

hydrate (10 ml. 0.2 mol). after two reaction cycles, triazole 3 precipitated

t3C-NMR

(de-dmso):

40.5 ppm (cH2Ph);

acid (2 g. 12 as a white solid.

tH-NMR (dg-dmso): 6 =

5.55 (d, ZH, J=6.5 Hz, OH), 4.93 (m. 2H. CI$ZHz).

6 = 155.7 (C-triazole),

138.6,

129.5,

128.0,

3.2 ppm (m.

126.0 (arom),

MS (FAB) m/z = 325 (M + H+); Anal. Calcd for Ct&&J4O2:

64.5

C. 66.65; H.

6.21; N, 17.27. Found: C. 66.46; H. 6.19; N, 17.40. (RS,RS)-

and (R.~-4-amino-3.5-bis-(l-hydroxy-l-pheny~methyl)-l,2,4-tri~ole

mandelic acid (0.5 g. 3.3 mmol) and hydrazine racemic

and meso-triazolcs

6 was obtained

(c = 0.5, HCl 2N); tH-NMR

(dc-dmso):

5.83 ppm (s. 2H, NH2); t3C-NMR

6. From L- or D-

hydrate (5 ml, 0.1 mol), after two reaction cycles, a mixture of Yield 60 % (acetonitrile);

white needles; mp 218-20 Oc; [& = 0

6 = 7.5-7.2 (m, lOH, arom). 6.2 (m. 2H. OH). 5.95 (d. 2H. CH).

(Q-dmso):

8 = 155.7. 155.6 (C-triazole).

141.3.

141.2, 127.9. 127.3.

126.8 (arom). 65.4 ppm (CH). MS (EI) m/z = 2% (M+, 3). 279 (9), 262 (30). 260 (56). 259 (91); Anal Calcd C, 64.85; H, %4

for C&t&$02:

; N, 18.91. Found

4-amino-3,5-bi.-(2-pyrrolidin)-l,2,4-triazole (100 ml, 2.1 mol). after five reaction cycles, compound white hygroscopic

(5 g, 43 mmol) and hydrazine

hydrate

8 precipitated as a white sobd. Yield 40% (acctonitrile);

solid; mp 129-31 “c; [ah, = + 5.6 (c = 1, H20); tH-RMN

NHz), 4.24 (dd, 2H,CH), (C-triazole),

C, 64.82; H, 5.36; N. 19.02.

8. From L-Proline

(de-dmso):

2.8 (m. 4H, NCH2), 2.2-1.6 ppm (m. 8H, CH2); W-RMN

B = 5.9 (s broad, 2H, (dg-dmso):

a = 155.9

52.2 (CH), 46.1 (NCHz), 29.3, 25.4 ppm (CH2); MS (FAB) m/z = 223 (M + H+); Anal Calcd

for Ct,,H]r&j:

C. 54.03; H, 8.16 ; N, 37.81. Found: C, 53.97; H, 8.12; N, 38.00. 10. From L- or D- alaninatc methyl ester hydrochloride

4-amino-3,5-bis-(l-amirwe~hyl)-l,2,4-rriczole (1 g. 7 mmol) and hydrazine

hydrate (17 ml, 0.35 mol), after four reaction cycles, a syrup was obtained,

It was

dried in vacua and then treated with methanol (20 ml). The solution was filtered over Celile and the solvent was evaporated.

Yield 82 8; oil; tH-RMN

ppm (d, 6H, J=6.8 Hz, CHs); t3C-NMR (high resolution.

(dedmso): (d&m@:

EI) m/z = Calcd for CeHt&le

4-amino-3.5bis-(1 ester hydrochlorides

6 = 6.2-5.8 (2 x s, NH2), 4.08 (q, 2H. J=6.8 Hz, CI-I). 1.36 6 = 157.5 (C-triazde),

41.7 (CH), 21.1 ppm (CH3); EM

: 170.1280. Found: 170.1279.

-amino-2-phenylethyl)-1.2.4~triazol

(2 g, 9.3 mmol) and hydrazine

12. From D-. L- or DL-phenylalanine

methyl

hydrate (23 ml, 0.47 mol). after four reaction cycles, the

1296

M. V. MART--DfAZ

resulting

precipitate

was treated

with sodium

et al.

bicarbonate

(0.2 g. 2.4 mmol)

was filtered over Celite and the residue was evaporated.

suspension

132-5 “c; [aID = + 5.2 (c = 1, MeOH) (from L-aminoacid); tH-NMR

(a-dmso):

CH2); t3C-NMR (CH2);

6 = 7.2 (m. 1OH. arom),

(ds-dmso):

MS m/z (relative

Ct&2N6:

C. 67.06; General

fragmentation

5.9-5.8

6 = 156.8 (C-ttiazole).

[aID = - 7.3 (c = 1, MeOH)

H, 6.88; N. 26.06. Found: for the Optical

tetraacetate

139.0, 129.4. 128.0. 126.0 (arom).

Purity

Determination

(LTA,

1 mmol) in methanol

of Chiral

4-amino- 1,2&triazole

( 1 mmd)

Caid for

nitrile

by

in methanol

(10

was stirred at room

(30 ml) and the suspension

was treated with CHgh

was dried in vucuo. To a solution

(2 ml) under argon (9) -a-methoxy*-trifluoromethylphenylacetyl

mdar excess) and.triethylamine

Anal.

I-amino-1,2,4-triazoks

(5 ml) was added. The mixture

filtered on Celite. The solvent was removed and the remaining residue in chloroform

48.2 (CH). 41.4 ppm

C, 67.36; H, 7.15; N. 25.81.

for 2 h and then evaporated. The residue

temperature

(from D-aminoacid);

(2 x s. NHz), 4.2 (dd, 2H. CI-I), 3.1 ppm (m. 4H.

with LTA. To a solution of the corresponding

ml) at 0 “c 14

(30 ml). The white solid; mp

322 (M+ , 2). 307 (IO), 289 (9). 231 (75). 216 (100);

intensity)

Procedure

in acetonitrile

Yield 52 % (ethyl acetate);

of the

(MTPACI.

1.5

(2.5 mdar excess) were added. The mixture was stirred at room temperature

for

was lilte~~~Ioff and the solvent was evaporated

1 h and then diethyl ether was added. The precipitate corresponding Mosherk derivative(s). Finally.

chloride

the diastereorneric

excess was determined

to give the

by *H-NMR_

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