An Expedient Route to 1H-Benzimidazoles and 1H-Imidazopyridines

Bull. Soc. Chim. Belg. vol.1o2 I n" 5 / 1993

EUROPEAN SECTION

0037-9646 / 92 / $ 2.00 + 0.00

O 1993 Comité van Beheer van het Builetin v.z.w

AN EXPEDIENT ROUTE TO 1II-BENZIMIDAZOLES AND 1H-IMIDAZOPYRIDINES

Jean-Jacques Vanden Eynde,*a Annie Mayence," André Maquestiaua and Ernst Andersbauniversity of Mons-Hainaut, Organic Chemistry Laboratory, Place du Parc 20, 8-7000 Mons, Belgium

blnstitut i.rr Organische Chemie der Universilât Erlangen-Nùrnberg, Henkestrape 42, DAs2o Erlangen, Germany

Beceived : 220511 993 - Accepted : 25106/1993

ÀBSTRÀCT

1H-Benzimidazoles, LH-inidazo [ 4, 5-b]pyridines, and 1II-inidazo [ 4, 5-c] -pyri.dines can be synthesized readily by reaction of unisolated N-(L-chloro-alkyl)pyridinium chlorides with L,2-benzenediamines, 2,3-pyridinediamine, and

3, 4-pyridinediamine respectively.

INTRODUCTION

2-Substituted 1H-benzimidazolesl, ' are welL kwown in the fields ofpharnaceuticals, anthelmintics, and fungicides- They are generally prepared

by heating a 1,2-.benzeaediâmj-ne with a carboxylic acid in hydrochloric acid.However this procedure affords 2-ary1 derivatj-ves i-n poor yields.

Àn alternative route consists in the reaction of the diamine with an

aldehyde and. further oxidation of the so-obtained imine" This variant iswidely applicable but it requires two steps and isolation of tfre desiredproducts is sometimes tedious.

Às N-(1-haloalkyl)azinium halides'-6 are advantageous precursors for thepreparation of nitrogen heterocycles, '-" LL was temptlng to study the.irchemical behavior towards 1, 2-benzenediamines.

RESULTS

In a typical experiment, 1,2-benzenediamine (three equivalents) was

added to a solutioa of N-(cb.loropheaylsethyl)pyridini.un chloride (2a,prepared in situ) in dichlcromethêne at room temperature. After a cl-assicalwork-up-proced.ure, we could rule out ttte formation of an imine or a dihydro-benzj-midazole because. of the absence, in the lH N!4R spectra, of a signalaround 8.5 ppm (IIC=N) or 5"0 pplx (C'-It) respectively. In addition, thenolecular weight (mass spectrometry) of the product was m/z = L94. Thiscorresponds to a 1o6s of two hydrogen atoms from such structures.

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This forced us to conclude that lhe reaction ploduct was z-phenyl-1H-

benzimidazole(4ai95àyi-eldcalculatedonthestartlngaldehyde).Thiswas

confirrned. by comparison with spectral and physical data of a colunercially

avaitable Pure samPle of 4a'

Direct formation of 4a is rlot unique as thirteen other 1lt-benzi'aidazoles

(see Table 1) baYe beet prepared in the s'une way' Overall yields (based on

thealdehydes)aregoodtoexcellerrtastheyexceedT0?withouthavingbeen

optinized.

Ta-ble 1" Selêcted Data for lH-Benziûidazoles 4'

OverallYield (?)"

'H NMR"

6nLit "

iref "

abcdefshilk1

$n

95

75

70

80

8070

75

8013

75

7o

70

8. L-8.3 (n, 2H)'0.9 (t, 3I{), L.B (n, 2H) , 2"8 {t, 2H)

1".3 (d,6H),3.1 (n, 1H)

1.4 (s,9H)5"7 (s, 1H), 7"5 (s, 1OiI)

2.4 (s, 3H), 8.2 (d, 2H)'

8.3 (s,4H)?.9-9.1 (c,4H)8.3 (d, 2H)'6.? (dd, 1H), 7.9 (d, 1H)"

7.3 (c, 1H), ?"9 (dd, 1H), 8"2 (dd, 1ti)

2.3 (s,3H)' 8-1" (d,2H)"8"4 (s,4H)8.2 (d, 2H)"

]-2, L3

14

L5

16

10

13,1920, 2L

)1

24

25

': based on ttre aldehYde'6 f-H" : 7.2-7"8 (c) PPn.

DMSQ-d6/TMS; 6 u-t: between 5.0 and 9'5;other signals are overlaPPed'

The determining role played by sulfur dioxide (evolved duriaq the

formatlon of tbe salts) was again" ascertained as follows: N-tchloro(3-

nitrophenyl)nethyllpyridinium chloride (2h) was isolated (by filtration) and

reacted ulder our conditioas (dichloromethane at room temperature) with 1'2-

benzenediamine to afford N- [ ( 3-nitrophenyl )nethylene ] - 1 , 2-benzenediamine ( 3h)

(80 & yiefd) - On the other band, when this i@ine 3h was suspended in the

solution in whictr salt 2b trad been prepared' it cyclized to 2-(3-

nitrophenyl)-1l{-benzimidazole (4h) within a few hours (?5 ? vield)' The

latter result suggests that our oae-pot synthesis of the benzimidazoles 4

could proceed through the transiett forûation of imines' Further steps of the

reactlons woul4 involve a ring-chain tautoûerisn with dihydrobenzimidazores

followed bY the dehYdrogenation'

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cq2ct2/0-20ôc60 min

I.n I| \-u/ct- |I l* +SO"l| ôH 'lLn" 'ct I2o-k

,o.,,.f)*R1cHo\-H/

1o - k

, o'LY*n'

VNHz20 oC; 18 hours

[,KX:.'-'l .Ç +2-'Kx:::

'"3a-n

N

)-*,N

H

40-n

1,2 3, 4 R1

abcdeT

gbijk

Ph

n-PriPrt-Bu( Ph),cH

4-(NO,)C6Hé

3-{NO,)C6H4

4-C 1CéH,

2-Furanyl2-Thienyl

abcd

fshijkIm

n

Ph

n-PriPrt-Bu( Ph) ?cH4 -MeC€Il,4-(NO,)C6H4

3-(NO,)C6lt"4-CrC"H"2-Furanyl2-ThienyI4-MeC6H4

4-(NO,)C6rî.4-ClC,H"

H

E

H

H

H

H

H

H

ltc1NO,

NO.

Sctrse 1

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We also observed that yields decrease dramatically when the whole

procedure is performed under a flow of dry nitrogen' Since oxidation by

atmospheric oxygeû seems unlikely (most imines derived from 1'2-benzene-

dia.rainesarerrotair-sensitive),weratiorralizeourresultsasfollows:sulfur dioxide is known'o to form higtrly hygroscopic addition complexes with

anines; therefore, appreciable arnouûts of hydrogen sulfi-te are present in

the solvent and this oxid.i-zing speci-es" can be responsible for the fornation

of 1l{-benzinidazoles (or 1H-perimidinese) but, obviously, only when the

intermediate N-(1-hatoalkyl)azi.nium halidês are not isolated and when the

slmtheses are carried out under almospheric conditions'

we extended our work by studying the chemical behavior of (unisolated)

N-(1-chloroalkyl)pyridinir:.nchloridestowardspyridinediamines'Indeedpreparation of 1H-inidazopyridines' which are known to be potent cardiotonic

agents,?6 often requires drastic conditions Iike prolonged heating in

polyphosphori-c acid."''"Thus,wefoundthattreatmentof4-nethylbenzaldetrydewithamixtureof

thionyt chloride and pyridine in d.ichloromethane, followed by reaction with

2,3-pyridinediamine {three equivalents) produced 3-[(4-methyrpbenyl)-

methylene]amino-2-pyridlneamine(5).wereasonedtlratexperimentalconditionswere too urild to effect the coaversion of the imine into the imidazopyridine

system- ?bis l-ed us to mix the reactants in chlorobenzene' to ctleck the

formationofthelmine5,andthentoheatthereactionmj-xtureunderrefluxfor 4 hours. In this way, the final product we isolated was 2-(4-nethyl-

phenyl)-1{-imidazo[4,S-b]pyridine6(85gyield)'compounds?-12(Table2)were prepared sinilarlY-

From a mechanistic point of view, these results confirm that imines are

obligatoryintermed.iatesinttrereactiÔflsdescribedinthiswork.Therefore,N-(1-haloalkyl)azinium halides effectively behave like the precursol

aldehydes towards N-nucleophites- The aroloatization step is only due to the

evolution of sulfur dloxide during ttreir preparation- The solubility of the

intermedj,ate imines and their proPensy to cyclise are anong the factors that

govern the rate of that aroo.atization step' Tlre ûecessity of heating the

reaction mixtures to obtain imid.azopyridines ulrder our conditlons is ptobably

due to a conbination of both factots: imine 5, for example' is poorly soluble

in coamca crgaaic solve:rts a;1C the ê.:nino g::oup in position 2 of the Pyridine

ring is weaklY nucleoPhilic.'?e'30

- JOU

TABTE 2- Selected Data for Coûpounds 5 - 12.

N=CllRr

NHary

X Y Overall

\7h-'E-12

1H NMRb (ppm) Lit.Ref.Yield (?)'

5 4-MeC6Hu 85 2-4 {s, 31i, CHe), 6.1- (br, zif, NH,), 31

6-7 (dd, 11{, If), 7-3 (c, 3H, H3 andII5 Ar, Ila), 8.1 (c, 3i{, lf, and If Àr,If),8-7 (s, 1iI, N=CH)

6 N CH 4-MeC6H4 85 2-4 (s, 3I{, CII3), 6"0 (br, 1H, NIt) , 27

?.3 (dd, 1-H, F), 7-4 (d, 2H, E3 andE Ar), 8.1 {dd, 1H, If ), 8-2 (d, 2n,H' and If Àr), 8.4 (dd, 1H, If")

? N C!{ Ph 80 6.8 (br, LH, NII), 7-3 (dd, lH, Hs), 27

7-8 {c, 3Ë, ll3, Ito, and If Ar), 8.1(dd, 1H, If ) 8.3 (c, 2Il, It' and Hô Ar),8 - 4 (dd, 1H, lI')

I N cH 3- (NO, )Cén4 80 " 28

9 N CH 2-CIC6H, 90 5.8 (br, 1H, NII), 7.3 (dd, l-l{, If ) , 28

7 -6-7 -A (c, 3H, If , It", and Hs Ar),8.0 (c, 1H, E6 Ar), 8-1 (dd, l-H, Ir"),8-4 (dd,1H, n-)

10 N cH 2-Thienyl 85 6.9 (br, rH, NH), 7.3 (dd, lH, If), 27

7=4 (dd, l-H, I1" Th), 7-8-8.0 (c,2H,lI3 and H'?h), 8-1 (aa, LH, If),8.4 (dd, l"H, rr')

l-1" CH N 4-MeC"H, 75 2-4 (Ê, 3lI, CIl3) , 6-4 (br, 1H, NH) , 26

7 .4 (d, 2H, H3 and II5 Ar), 7.6(d, lH, t1'), 8-Z (d, 211, H'and If Ar),8-4 {d, 1H, If), 9-0 (s, 1H, H")

fZ CH N 4-FC6H' 70 5-6 (br, l-H, Nn), 7-4 {t' 2}t, E3 and Z6

ï' Ar), 7.7 {d, t-H, rr7), 8.3 (d, l-H,tf ), 8.4 (d, ?tt, If and lf Ar),9.1 (s, 1H, It4)

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In conclusion, we have found a new one-pot roethod for preparing i-H-

benz imidazoles, l-H- inidazo [ 4, 5-b ] pyridines, and 1H- iBidazo [ 4, 5- c ] pyr j.dines -

It could not be foreseen anâ it is characterized by its simplicj.ty. By

comparison with classical routes, it reguires milder conditions, it appears

to be more general and it can give higher yields" For example, 5-chloro-z-(4-

chlorophenyl)-1ll-benzimidazole (4i) was prepared i-n 36 â yield from 4-chloro-

1,2-benzenediamine and the bisulfite adduct of 4-chlorobenzaldehyde." Througtrour procedure, we could obtain 4i in 75 ? yieId. Another noteworthyimprovement is illustrated by the synttresis of LH-inidazopyridines since,through our method, the use of hot polyphosporic acid 27.23 is unnecessary-

In addition, excess of diamines and pyridine can be recovered and recycled,if necessary.

ÀCKNOIdIEDGEUENT

We are grateful to UCB s.a- (Brussels, Belgium) for its financialsupport. irle also would like to thank M. Call1iau-Renard and F. Delmarquettefor their t'ech4ical assistance-

EXPERIUEI{TAI

ÀlI compounds were characterized by their spectral data ('Ii NMR: Varian

EM 360-L; IR: Perkin-Elmer 5?7; l"1S: Varj-an Mat 3114). Melting points(uncorrected) were delermined on a hot-stage microscope- Compounds l-a-k3-6 and

3tr'?a have been described i-n the literature" For the other d.erivatives, the

corresponding references are qBoted in the Tables-

General procedure for the preparation of 1H-benzimidazoles

A solutlon of thionyl chloride (O-9 nl; 12 nmol) in dichloromethane (10

ml) was cooled down to 0 "C- Then a solution of pyridine (1"0 !r1; 12 mol)

in dichloromethane (6 mf) was added dropwise followed by the aldehyde (10

mmol). The mixture was allowed to warm to room temperature for one hour and

formai.ion of the N-{1-chloroalkyl)pyridirLium chloride was confirmed by NMR."

?he diamiÊe (30 rt,rol) was then slcwly added and stirring was mainlaineC

overnight, The. solvent was evaporated under reduced pressure and the residuewas lriturated with water to yleld the crude firal product-

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!

I

I

(

(:

{l

t1

{1

General procedure for the preparalion of 1H-imidazopyridines

A solutior of thionyl chroride (0,9 m1,' lz rmol) in chlorobenzene (10 m1)

was coofed down to 0'c- Then pyridine (1.0 nlt 12 mmol) was added dropwiserfoll,owed by the aldehyde (10 mor). The aixture was alrowed. lo warm to roonl

teRperature for one hour during which time the pyri.dinium salt separated froûrthe solvent. TLle diamine (30 mfto]) was then slowly added and stirring und.elreflux was maintained for 4 tlours. The solvent was evaporated. und.er reduced.pressure and the residue was triturated with a solution of sod.ium hydroxide(0.1 M; 3 x 10 ml)- The crude imidazopyrid.ine was firtered. and thoroughrywashed wilh water-

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