Synthesis, complexation study and reactivity of annelated thiophenic nadh models

oo40-40~/88 53.00 + .@I Q 1988 Pergamon Press pk

Teu&e&on Vol. 44, No. 4. pp. IO79 to 1090. 1988 Pnnted tn Great Bnutm.

SYNTHESIS,

COHPLEZATION

STUDY AND RFXTIVITY

ANNRLATED THIOPHRNIC J.

CAZIN,

T.

TREFODEI.

Laboratoire I.N.S.A.

G. DUPAS,

de Chirie

1.R C.O.F.

J.

SOURGUIQNON*

Organique

B.P.

OF

NAD8 MODELS. G. QWGUINRR.

and

Fine et HdtCrocyclique

08 76130

Rant

Saint

Aiman

France

(Received in Belgium 30 November 1987)

hbstract * The synthesis of two carbaeoyl 4,7- dihydrothi~o potential

nee MM

eodels.

PI WflRstudy

bshaviour of the thisna [2,3-b] leportant of

of the coeplsnation

derivative

role in the coeple~ation.

the thiophenic annelated

is diffrrent

The bioeieetic

nAOH todels

[2,3) pyridines of

eagmiue

of that of the thisno

[S,2-bl

reduction of p.nitroben~aldehyde

is

very

superior to that

of coeeon eodels such as kBanzy1 I,4-dihydronicotinaeide

(MM).

&

and fi

ions

by

is

those

derivative:

in

are The

foreer the sulfur atoe plays an

the

has been studied. The rsactivity

eith & or 2

of quinoline

described. These derivatives coepounds has been perforeed.

analogous. It can be coepared to

goreover k and g can be used in

the reactivity

ewe BIIAII is

conditions

such

eore less effective. Reductions

with

reduced

pyridine

of of

the most widely

great

many

* the chiral

t,4_dihydropyridine nucleotide

derivatives ion

s-rized

of

often

the

as follow

been

extensively

reactions.’ (BNAH)

information6

functional

about

group

studied

Among

as

these

derivatives.

models

models,one There

are

a

:

selectivity

and

use

the

of

synthesis.*

hydrogen

implicated.3

which give

BNAH, its

in asyrnetric

have enzymatic

1.6dihydronicotinamide

in &he literature

and limitations

* the mechanism of metal

N-benzyl

used are

references

scope

derivatives

(NADH) mediated

transfer

The

in such

reduction

of

reductions

and the

a

compound

carbonyl

role

of

for

the divalent

example

can

be

:

;y-O-H hydrolysis

H

CH,Ph

BNAUderivatives of of

the

undergo

reagent.

water. b

These

We have

substrates

could

be

substrates

known to

conditions

involved

side-reactions

reactions

shown that greatly

in these

in

improved

be unreactive

which cause

affect

the

drastic by

towards

reactions

5,Gdouble conditions

the

use

BNAR.

limit

of could

a

dramatic bond the

hyper

yields dry

in

in

favored the

the by

However

efficiency the presence

reduction In

conditions.5

be reduced.

the use of BNAH.

1079

decrease

and are

the

of

come

6ome ca8es. experimental

1080

J. CAZINel al.

Schema 1 I Attemptr to drchlorinxtr

6-formyl 5-chloro thirno [3,2-b]

pyridinr

NHCOCH, + ,C~;NCHO roCT 3 / a

6

Dochlorinxtion of 2 rrrwd problrartioxl, 10 VI trird thr maa nthodr on the arrboxylic rcid 9. Thr product uxx unrxxctivr towrrdr crtxlytic hydroxrnxtion, and to thx rction of xinc md rcatic acid. In the rrcond nthod, 4-hydroxy 5-cyanothimo [2,3-b] pyridinr 9 ir obtrinxd from 2xainothiophmna through x diffioult cyclhtioa rarction which ix performed at hixh tmporrtura. Horrovor the lCCOII to 5-cyxnothirno [2,3-b] pyridinr impliar thx chloriaxtion of thr 0x0 drrivrtiva, followed by thr ramovrl of thr chlorine which could rlro be x probluxticxl rarction. Thr third method which WI did not try rrquirrr tha rynthrrir of thr thiophxnic prwurror (M uino artrr drrivrtiva) followed by rrvrrrl rtrpn to obtrin x chloro thirnopyridinx drrivrtiva.10

wthod which xllowr xccoxa to x cxrbonyl rubrtitutrd thirno [2,3-b] pyridinr in x onx-pot rarctioa with x 32% yix1d.l’ By ~oea improvrmntr of the procrdurx (hixh dilution, crrrful control of thx trmparxturr) WI could obtrin 1 in 45% yirld from birPinxlly

(-2 thirnyl Bchrw

WI urrd m,r

xmonium) hrxxchlorortxnnxtr

2 : Synthxric

0/s\

of 5-rcrtyl

(wham*

2).

[2,3-b]

thirno

pyridinr

1 I

Sn’Hc’* (-J_+

NO 1

FH,COCH,

2

NH2:

A.

D. M. A.+

~:~:CHCH~OCH,

SnCI;‘

acocH’

NBCH 7

(A.

D.

M. A.)

l

Anaelrttd thiophenic NADH mod&

toa

So, a few yaarr yo, aoleoulrr have bean developad whloh llmit or rupprrrr the ride-rraotionr on the 5,6-double bond. Oar of the iasiert wry to do thir ir to block thir bonA by rnnrlrtlon with 4a rroaatlc ring. Thir method bra barn ArvrlopaA by Japmrrra workrrr who rynthrsirrd WADX nodrlr in tha quinolinr rrrlr,* With there types of model&, mm Wood rrsultr have bren obtained, lrpleirily in proton catrlyrad reduction of rldrhydrr. Wnmvrr in thr clrrrlcrl conditionr urrd with BMW CIolvrnt CW3CW,catalyrt M(ClO4)2] thrrs wdalr are notably lrrr rractlvr. We cm ruppora that the withdrrwinp affect of the annrlrtrd brnrrnr tins, hindrrr the departure of hydrogen involvrd in the traction, For thir reason WI h&v@rynthrrirrd mdrlr b und 1p with an mnrlrtrd thiophrw rink order to protect the 5,6-double bond of the dih~ropyridin~ as wall a# to favor Aaprrturr of hydroprn throurh the rlrctrondoncrtiru rffrct of the thiophrnic ril.

the in the

CONH,

5-crrbamyl 4,7-Aihydro thlrno [2,3-b] pyridlnr h

(I-crrbmoyl 4,7-Aihydro thiano 13,2-b] pyridinr 1p

The firrt results obtained with thir typr of mod.1 ha@ bren described in L prelfainrry comunicrtion: 7 thr model@ are rrrotivr. Thr rrductlon of rctivrtad mbonyl ocapwndr occur@ at ratirfactory rater and the reactivity of aodol~ rminr hish in conditiona were BNAHir very much Aarctivatrd by water, WI wirh to rapott now the rynthrria of tharr modelr, (L rpclctrrl rtudy of thrir complrxrtion with aapnrrium ionr, lnA oou naw rarultr in tha reduction of vrriour rubrtrrtclr. BYWTREeIE There ata only a faw rrportad methoAr, to our knowladsa, which cm br urad to obtain thlmo t2,Jl pyridiner brarim I carbmoyl (or 8 precursor) in tha Y_oorition of the pyridinic ring. Thr firrt nthod rtrttr from J-rocltuido thlophrnr II thr non rubntitutrd thiophonic amino Arrivrtlva.8 Waobtainad in the brrt cala 6-formyl 5-chloro thiano [3,2-b] Pyridina 1 in 50% yield (ochem 1). The rrplrcoarnt of chlorine by hydrogen hrr barn tried by rrvrrrl arthod# tfvinp tha followina rarultr t * tine and acetic rcfdti rive l ltxturr of A-hydroxymethyl thirno C3,2-b3 pyridinr 3 anA Ahydrowymethyl I-chloro thfrno [3,2-b 3 pyrfdina f. * catalytic hyAroWrnolyrir (hydroaan with PA crtrlyrt) alvrr a mlxturr of 6-formyl thlmo [3,2-b lpyridine t and 30 X of unrerctrd 2 from which purr 1 could be irolrtrd in poor yirld, I.

1082

J. CAUN et al.

TO obtain material

6-acetyl

is

acetamido

group

competiting

thieno

[3,2-b]

3-acetylaminothiophene with

hydrochloric

reactions

(scheme

3)

* condensation

on the

free

* condensation

on the

highly

5-methyl

pyridine and

thieno

the

acid.

a

In

similar

step these

procedure

is

the

was

in-situ

conditions

used.

The

starting

deacetylation

ADWA

is

of

involved

the

in

two

:

amine

leading

reactive

C3,2-blpyridine

Scheme 3

NHCOCH, HCI

g

first

to the desired

?-position z.12

r

of the

6-acetyl

thieno

3-acetylamino

C3.2-bl

pyridine

thiophene

leading

8. to

+l

c

2 L

I

ADMA

HCI CH=CH-COCH,

-

CH, Hz0

-

2

- H+ It

is

possible

introduction hours).

of

By using

and the

free

Acetyl

is

derivatives

the

reaction

refluxing the

solvent,

obtained

1

second

in

reaction

to

the

of the

was accomplished

(scheme

through (that

reducing

agents

(sodium

dithionite)

means

than

are

oxydlsed

to

the

salts.

In

methyl

the

a transhydrogenation, that

quinoline

the

group

amino

reaction

requires

may be carried

out

corresponding

carboxylic

our

12

derivatives

12 and 13 with

to obtain

this

at

too

a higher

before long

(8

temperature

41.

dihydropyridine

pyridinium

liberating

in 2 hours.

and s

of compounds

by

ethanol

reaction. The carbamoyl derivatives with amonia in CH2Cl2 as solvent.

The conversion quaternization

ineffective.

as

of NADHmodels

the haloform acid chloride

reduction

suppress

butanol

amine

Preparation

by the

to

ADHA. With HCl

case

of with

dihydrothieno

analogs). dihydropyridines

is iodide

are

performed leading

obtained by the

to

use

‘0

and 11

treatment

following

isosters, 6C In our

C2.3 1 derivatives and 2.

acids after

of

sequence

:

to 14 and 15 and regioselective

quinolinium BNAli itself.

So we needed &

and 13

the

this case

are classical

this

reduction reagent

probably reducing

is

stronger agent

Annelated thiophenic NADH models However some problems crystalline quateroieation pyridine

h

carefully

With 15 I&,

was found

in

we had still

the yield

order

perchlorate.13

E’ollouing

: Synthesis

Scheme 4

mineral

this

Finally

difficult

impurities

to

obtain

18

of

some

G

5,7-dihydro

thieno

procedure

yield

described

unsuccessful

by substitution

the reduction

in a

out the thieno

thoroughly.

the above

after

counter-ion

modification

of carbamoyl

is

by using

:

than 20%. the

it

purity. It is necessary to carry other cases) and to wash the dihydro

difficulties

change

of 14

case

to eliminate

greater

to

the

an analytical of CH3CN in

uas never better

necessary

: in

remained

and with DMF (instead

form in

1083

reaches

for

attempts of

iodide

it with

60%.

C2.31 pyridines

&

and j&

COCH,

5-acetyl

thieno(2,3-blpyridine

: 1

6-acetyl

thieno(3,2_b)pyridine

: 0

14 Ea

x I Ix : Ix : c104-

15b -

z

Reagents

: a) Br2/NaOH b) SOCl2

--->

j5J

e) Na2S204.

The

regioselectivity

spectra a

to

the

or J&

1,4-dihydropyridine

corresponds II.

of

of compounds &

c)

: -la

6-carbamoyl pyridine

: -lb

reduction

is

and

a 1,2-dihydropyridine

the

by

signals

the

in the case

examination

in the 3.8

absence

derivative

thieno(3,2-b)

d)ICH3 than nS(ClO4)2

confirmed of

thieno(2,3-b)

4,7-dihydro

NH3 in CH2Cl2

: the presence

derivative

4,7-dihydro

5-carbamoyl pyridine

of

of

ppm region

signals

in

the

the

of

NMR

corresponds 4.2

ppm

to

region

14.

SPECTRALSTUDYOF THE COWLEXATIONOF MAGNESIUM IONS. Most of

the reductions

as cofactor. -it

This

enhances

complexation,

in the -it

the

reduction seems,

substrate, mediated particularly

the

complexation

molecular

with

is

a triple the

of the

substrate lowest

the model (HOt40) is

require

role.13c

it

(a

lovers

use

carbonyl

unoccupied its

increased

the

of

a divalent

metal

ion

example)

by

and l5 compound

molecular

reactivity

and

the

for

(LURO).

orbital

: the energy

departure

of

the

of the

hydrogen

highest involved

more difficult.

metal

by a metal

with NADRmodels

of

energy

orbital

nowever,

the

plays

reactivity

lowering

-through occupied

performed

ion probably

that ion

ion

important

this

and

the

departure model

in an intermediate in asymmetric

is can

possible

only

be built.16 ternary

reductions

with

if

a ternary

The process

sandwich-type chiral

charge

mode1s.17

complex of

between

hydrogen transfer

the

transfer complex

is

1084

J.

CAWN

rt a/.

60 it rppertr,thrt the mode of complexrtlon of M# 2t with our model, lr important in view to rpprrclrtr thr rerotlvlty of modelr b end 1p. A rprctrorcopic rtudy of the complexrtion of BNAii with Zn2* her been bevrloped by RUOHER end PRINCE.(R In our cme, we recorded 13C NUR rpectrer of JJ end 1p, flrrt without end then with increerlrU mountr of m(ClO4)2 in CD$N ea aolvent. The chemical ehlftr of crrbon rtomr era compared with thore of homoloa dome in RNAHin the mue conditlonr. The vrrirtlon of chemical rhiftm (AA) e@ l function of mount of wneeh on tha followitu curve) (fl#. 1). Fig.1 A8 of crrbon atom8 In RNAR,b and fi e.) 1 function of urnerlum

Lo

reprerented

CONH,

CONHI ,

BNAH From

lb

theBe rerultr It cm be obrerved : Ab for howlot crrbonr in BNW end in u lre rimllrr. 2) for coapounb b the rituation ie different : - the Ad of the crrbon &tom of the crrbuoyl #roup ir notably lower then thrt of homoloa orrbonr in BNAR or In uB - on the other hen& the 2-thiophenlo carbon her l Ab hlrher thrt the Ad of the NW rtom in 1p. In fact the thiophenic rifu eeeme more effected by muneriw crrbon complexetlon Ln the thleno [2,3-b] berivetlve then In the thieno [3,2-b] derlvrtive. eulfur end nitrouen rtomr lerdr to a We think thet in the former the vlolnlty of the by there atom. Am l coneequence portibllity of complexrtion of H# 2' by the cleft ford the cerbemoyl group lr lerr Involved then in h or in BNARto inrure the complexrtion t 10 itr effect on the chemicrl shift of the crrbon atom ir lowered. III. REDUCTION OF BURRTRATER~ 1) Reduction of p. nltrobenrrldehyde. In e previour publicrtion, we hrve rhown thrt modelr b or 1p remeln rerctlve in the prerence of wrter, in condltionr, where BNAR becomer lerr effective (5), 1) the

Annelated

The major reinvestigated are surarized Table

in table

1. Reduction

results

thiophmic

concerning

models

NADH

the reduction

1085

of

p.nitrobenzaldchyde

(p.NRA)

1.

of p. nitrobenzaldehyde

with NADHmodels. +

raaction

tine

utrr

yitld in

add8d

at 60

rsductiwl

._ _____________.._ 100 \

of each reagent (substrate,

B h.

100 t 100 \ 76 \ 100\ 100t

in acctonitrile

a

h.

until

no

1 8quiv.

I aquiv. 1 equiv.

further rsation

These

results

are

perhaps

they

are

than

still

the validity

less

effective

quinoline

conditions). Fig.2

comfirm

a little

in the

of

BNAA,

la,

our strategy

thah

presence with

:

the maximum yield

Reactivity

of

reactive

analogs

of

BNAH

of

water.

reduction

results

Moreover

p.NBA.

annelated reported

they

NADH models

on

but

fig.2)

reactive

are much tire

1,4-dihydrcquinoline,

of p.NBA is

llg(ClO,)? and ~8~1)

as solvsnt.

: thiophenic the

(see

3-carbamoyl

towards

j&

1 aquivalml

Note : reductions are perforbad rlth

1 hours

in

(even

drastic

low.

Sche‘oe 5: activation

of a substrate

by B

Ar \ 10

,, ’

I

2

,‘/ 10

,

I’

I

,’

30

CONHz

,’

,(

‘0

,

I

.,

,‘I

40

’ ’

10

IJ ,I

’

10 I 10

,

’

I -4

,I

d

: ,

7

,

. .

0’

>

On the grade

a

1

other

.

acetonitrile

thiophenic

9

hand,

,

in

*

r

I

the

instead

models

become

.

dim.

(h0U.l)

presence of

of

superior

to

of

1 equivalent

hyper-dry

acetonitrile

BNAR

water(i..e.

which

: quantitative

yields

whereas with BNAR the yield decreases quickly as a function of Moreover in a CH3CN/R2Omixture (6/l) we obshrved that p.NBA model 2

(yield

in

isolated

alcohol

15%).

is

if

we

use to

difficult can

always

be

technical prepare) obtained,

the amount of water. could still be reduced

In the same conditions,

BNAH

is

destroyed

30

times

with and ~2

is unreactive. This

important

- with concentration complexed

a

difference large

between models &

amount of

water

used in the experiments

by water

: activation

(in

and 2 this

reported

of the reduction

can be explained

case

in table through

it 2)

:

represents

the PBgnesium ions

the ternary

the

water

are cdmpletely

complex cannot

occur.

1086

CAZINet d.

J. - in the case

carried the

out

substrate

former

in

enhanced

of J&

by the slight is

the situation polarization

slightly

the

insured

neighbourhood

by the solvents

different the

by the

of

used

is of

the

activation

:

sulfur

model

atom

and

of

(scheme

moreover

transferred

the substrate 5).

this

hydrogen.

can be

Activation

of

phenomenon sets

This

activation

the

can

be

in the experiment.

2) Other substrates. By using such

standard

conditions

3-formyl

pyridine.

as

reported

to

after

be very

20

models

in table

1, we have reduced

The yield

for

BNAX.lg

With &

grade

acetonitrile.

with

poor in

hours ,

defined

technical

reduction

of

this

other

this

substrate

This

aromatic

compound was is

confirms

reduced the

aldehydes previously

quantatively.

efficiency

of

our

in mild conditions.

So as to extend reduction

of

the scope

the carbon

Activated

For

Nitrostyrenes

the

activation

pyridines,

dihydro-pyridine

with

we

performed

the

in

chloro

derivatives

poor

tris

yield

various

N.propyl

(triphenylphosphine)

or BNAH in different and 2-pheny21

in

with

1,4-

rhodium.20

ways of activation.21

1-nitroethene

technical

in

:

gave cyclohexanone model

behaviour

[2,3]

reduced

with WANTZSCH ester

are as follows

This

with is

reduction of 2-cyclohexenone in presence of M(ClO4)2.

- 2-cyclohexenone because

thieno

with la.

reduced

2-cyclohexenone

are reduced

The results

recovered.

are

(PNAH) after

We studied the grade acetonitrile

stopped

double-bond

bonds

example

dihydronicotinamide

the 5,7-dihydro

carbon

ethylenic

conditions.

of

of

in 76X yield

eventually

was

the

model

after The

consumed.

in

slow

reductions

4 days

; the reaction

remaining will

be

was

2-cyclohexenone discussed

in

was another

pub1 ication. -

2-phenyl

polymeric starting

l-nitroethene

compounds [which material

From these

it

of

of the molecule -

2-phenyl

conditions

; this

implicated

energy

explains

is of

in

interest

such

double-bond

that

means that

it

in

reductions

in

is

confirmed

the

77X 22 1

yield

and dimeric

after

17

hours.

or No

2-cyclohexenone

the difference

is

1-nitroethene a large

in reactivities.

under orbital

more

By the

molecular

P-phenyl

be

orbital6 : 0.593

:

regioselective reactive

by the values

reaction.

unoccupied

there

to

that is

is placed

appears

LUWOof seen

to observe

conjugated

LIMO of be

formed

1-nitroethane

the

feature

of the lowest

As can

are often

1-nitroethene

which

are

2-phenyl

was recovered.

results

- reduction site

gave

of

: it occurs

than

the energy

CNDO method

on the

soft

control.

the

are as follow

2-cyclohexenone of

in

the molecular

calculated

these

orbital

values

of

the

:

eV.

: 2.494 ev. difference

between

the

respective

energies

which

maY

Annelated thiophenic NADH models

1087

ExPERImAL The infra The

red

opectra

‘H Nl4R spectra

were were

recorded

recorded

on a BECKMAN IR 4250 spectrcmeter. on a VARIAN 006OL

spectrowter

and

the

13C spectra

on a

RRUCKRRUIi 90 spectrometer. Microanalyse

were

flyper-dry

recorded

acctonitrile

storage under molecular Anbydrous tfg(ClOb)2 1) Synthesis acetamido This

of

on a CARM RRllA 1106 apparatus.

was

obtained

sieves. was purchased

thieno

[3,2-b]

by

refluxing

distillation

on

calcium

hydride

and

from Merck. pyridine

derivatives

after

condensation

of

DMF t

POC13 on 3-

thiophene. condensation

was performed

by the method

Yield in 5-cbloro 6-formyl thieno [3.2-b a) Reduction of 2 with Zn + CH3CCCH. A suspension

of 0.5

evaporated

and the

pyridine

g.

of 2 (0.0025

residue

wle)

was analyzed

and 6-hydroxymethyl

After

chromatography

5-chloro

H=

in the

literature.*

2:51X.

and 1.0

g.

on silica

gel

by ‘H RNR

of

zinc

powder

3.0;

N=

7.3:

: it contains

thieno

[3,2-b]

(ether

as eluent)

mg. of impure alcohol 2 were obtained. Yield in 4:24X; F=l33-134-C; Analysis: 47.7;

described

lpyridine

in

15

ml.

of

acetic

After cooling then filtration of water was warred at 75-C during 4 hours. was neutralized with HC03Na and extracted with CH2C12. The solvent

acid and 1.0 ml. resulting solution

c=

and

6-hydroxymethyl

[3,2-b]

pyridine. 120 mg. of the chloro

CgH6ClNOS; Cal X C= 48.12;

NMR:(CMSO d6):

thieno

tbe was

8.49(s.lH:H7);

H= 3.01;

alcohol

4

and 120

N= 7.02.

8.06(d.lH:H2);

Found X

7.42(d,lH:H3);

4.42(d,2H:CH2). b) Reduction suspension

A

ethanol

was

evaporation

of 2 with of

3.0

stirred of the

pyridine

2

g.

hydrogen of 2 (0.015

under

an

solvent

and

the

unreacted

mole),

hydrogen solid 2.

was analysed

After

8.7;

N=

8.60(d,lH:H7);

IR v(C=O):

8.0(d,lR:H2);

g.

of

MgO, 4.0

for

18 hours.

by ‘11 NHR : it

chromatography

ether/hexane l/l), 0.4 g. of 6-formyl thieno Yield 162; P=l26-127-C ; hlySiS:CgH5NOS; H= 3.4;

0.6

atmosphere

1680cd

on

a

g.

of

10X

After contains silica

PI/C

in

filtration 6-foray1

column

thieno

H=

1.8;

N=

6.6;

[3,2-h] with

(elut ion

[3.2-b] pyridine 2 was obtained. Cal X C= 58.89; H= 5.07; N= 8.59. Found X C= 58.5;

: l0.l5(s,lH:CHO);

Nm (CDC13)

;

9.lO(d,lR:H5)

6-carboxylic acid : 5 g. of AgNO3 (0.01 mole)

and 0.8

8.

of NaOH (0.02

in 15 ml. of water is slowly added, at O’C.l.0 g.(O.OOS mole) of 2. After two hours the filtrate is acidified with HNO3 and the precipitate is isolated, and dried. 90X; P>25O’C

of by

;

7.65(d,lH:H3).

c) 5-chloro thieno [3,2-b] pyridine To a suspension obtained from 1.8

Yield

10011

followed

; Analysis:

IR:v(C=O):

CgH4ClNO2S; Cal X C= 44.96; 174oc.-1

;

RHR (PM0

H= 1.87;

N= 6.55.

8.9(s,lH:H7);

d6):

mole) at

O’C,

Found % C= 44.9; 8.35(d.lH:H2);

7.60(d,lH:H3). 2) Synthesis a)

5-acetyl

of acetyl thieno

To a SusPension of ethanol

and

thieno

[2,3-b

of 30 g.of

50 ml of

C2.3 lpyridine

lpyridine bis

(2-thienyl

concentrated

derivatives.

: 1 HCl,

mnium) was

added

hexachlorostannate 40

8.

of

(0.056mle)

b,b-diwthoxy

2-butanone

in 350 111 (APRA)

J. CAZIN t-f al.

1088

(0.303 mole). The mixture was warmed to 75-C for 8 hours, 590 ml of 2N NaOH. After extraction with CH2Cl2, the residue

was extracted

Yield:

several

41%; P= 117’C

b) 6-acetyl

thieno

IO

3-acetylamino

8.

of

concentrated g.

of

AOMA (0.417

Yield:

[2,3]

mixture

which

53.6:

H= 2.55;

53.35;

H= 2.65;

the

temperature solution residue

pyridines

acids

The acetyl for

E

then

H= 3.3;

thieno

[2,3]

mle)

of

v(C=O):

1715

Cal

of 55

raised

80-C

in

4

5-C.

g (0.034

room temperature.

After

was

slowly

mole)

added

was poured

acidification

to

in ethanol.

X C= 53.63;

H= 2.79:

N= 7.82.

9.O(d,1H:H6);

Found

X C=

8.75(d,lH:A4);

X C= 53.63; NMR (MS0

pyridines

12 and 12.

H= 2.79;

d6):

N= 7.82.

9,15(d,lH:H5);

Found

X C=

9,0(d,lH:R7);

the

After with

acid

or

(2

ll)

IR:

N= 16.0.

were

refluxed

with

elimination of volatile products, the aumonia at 0-C for 2 hours. The solvent

30

of

ml

thionyle

residue was dissolved is evaporated and the

or in ethanol-water.

v(C=O):

NRR (MIS0

1680 cm-‘;

7.60(m,lH:N-H);

IR: v(C=O):

% C= 53.93;

H= 3.37; d6)

N= 15.73.

9.05(d,iH:H6);

Found % C=

8.75(d,lR:H4);

7.50(d,lH:H3).

1680 cm-‘;

% C = 53.93; RMR (OK50 d6):

H= 3.37;

N= 15.73.

9.15(d,lH:H7);

Found % C=

8.95(d,lR:H5);

7.65(d,lH:H2).

c) Quaternization

14 and 15 are

at

6.0

RMR (IMSO d6):

cm-‘;

cm-‘;

7.90(d,lA:H2);

H= 3.3;

iodide

4Oml.

cooling,

s

6-carbamoyl thieno [3,2-b] pyridine 2. Yield: 90%; P=225’C; Analysis: C8H6N2OS; Cal

methyl

gradually

, maintained

(4 or 9).

at

IR:v(C=0):1705

in ethanol

N= 15.5.

8.30(m,lH:N-A);

They were

and

After

and 2

recrystallised

5-carbamoyl thieno [2,3-b] pyridine 12. CSH6N2OS; Cal Yield: 90%; Fx25O.C; Analysis:

53.75;

was

n.butanol hours.

was made basic with NaOH 2N and was extracted with hot hexane.

&

derivative

5-carboxylic acid Analysis:CSH5N02S;

N= 7.65:

recrytallised

8.30(d,lH:R3);

of 2.5

and 11.

12 hours

was filtered,

chloride for 12 hours. in CH2C12, then treated

53.5;

for

7.65(d,lH:H2).

g.(O.Oll

is

12Oml.

atmosphere

cold the

12.31

carboxylic

IR:

The

7.55(d,lH:H3)

b) Carbamoyl

solid

and

in

mole)

[3,2-b] pyridine 6-carboxylic acid 11. Cal 80%; D25O’C; Analysis:C8H5N02S;

8.35(d,lH:H3);

2

added

was stirred

N= 7.7;

7.95(d,lH:H2); Thieno Yield:

(0.071

g. of NaOH in 360 ml of water

Thieno[2,3_b]pyridine Yield: 71%; P>25O’C;

with

hexane.

an argon

thieno

(0.11 mole).

, the precipitate

basic

evaporated.

P=l34’C).

5,7-dihydro

of 20.5

was

: g

under

were

pyridine

ml of bromine the

refluxed mle)

of

To a solution into

pyridine thiophene

55%; F= 134-C (litt.”

a) Thieno

pH 2-3

hot

maintained for 8 hours. The with CH2C12. After evaporation,

3) Synthesis

6.1

with

and made

P=l16-17-C).

[3,2-b]

HCl were

hours and extracted

times

(litt.”

then cooled organic layer

of 12 and 12.

performed in 70 ml. obtained

by warming

7.0

of OMPduring in nearly

g.

of

the

8 hours.

quantitative

above

products

(0.039

After

filtration

the

yields.

role)

with

pyridinium

25 ml. derivatives

of

Annelated thiophenic NADH models N-*thy1 FB25O.C; N= 8.7.

S-carbamoyl thieno [2,3-b lpyridinium Analysie: CgH9N2OSI; Cal X C= 33.75;

IR:v(C=0):1690

7.90(d,lR:H3);

C.-I;

NMR (DMSO d6):

iodide 2. H= 2.81; N= 8.75. 9.60(s,lH:H6);

N= 8.5;

IR: VC=O:l680

cm-‘;

NHR (not

acetonitrile iodide

by

the

were is

refluxed

not

H=

3.3;

middle.

the

yellow

Analysis:

N=

9.7;

e) Reduction

salt

water.

The solution

(0.023 After

Iwle) and 15 minutes,

temperature.

14

salts (2.0

was poured

The residue

H= 5.0;

N= 14.35;

3.70(8,2H:H4

2: at

in a flask

30-C

under

introduced sevral

with

of

a light

The

because

H= 5.1;

J& cristallizes

6.70(d,lH:H3); 4) Typical

N= 14.3;

IR:

S.SO(m.28: procedure

following

but

the

salt

was

Found % C=

9.20(s,lH:H5);9.l0(s,lH:H7);

pyridines of

procedure

recristallised

4.0

in 8.

&

and lb

40

ml.

of sodium

amount

The flask and

H= 5.15;

at

1655cm-';

of

room

(l/l) Found % C=

6.65(6,2H:H2

in 30 ml.

of

deoxysenated

of

(1

to

water

40-C

hot

water. at

N= 14.43.

7.15(s,lH:H6);

was storred

dried

of

dithionite

:

in ethanol/water

Nl4R (CDC13):

one molecule

reduction

of

be monitored

N= 9.57.

dissolved

in

under

1 ml.) torr.

ethanol was

a refrigerator 0.5

and

then

during (Drying

is

of water)

[3,2-b] pyridine: 2 CgH1ON20S; Cal X C= 55.67;

v(C=O):

the

evaporation,

ml.

soluble,

could

H= 3.08;

was

was dissolved

filterd with

is

50

decahydrate (0.017 mole) in 40 ml. with CH2Cl2, dried and concentrated

NH2); 3.87(s.2H:H4 for

or -15b

A small

appears.

was

6-carbamoyl -4.7 dihydro thieno Yield: 58%; p: 84-C; Analysis: 55.7:

(DHSO d6):

in

salt

exchame

After

in a solution

product argon.

turbidity

precipitate

the

R?lR

1660 cm-‘;

0.132

of

perchlorate of

[2,3-b] pyridine: 3 C9H1ON2OS; Cal X C= 55.67;

crude

Found X C= 33.7;

Mg(ClO4)2

of dihydro-thieno

then

3.20(6,3H:CH3).

atmosphere

progress

% C= 36.92;

mole)

by the

water

N= 8.75.

of

Cal

, with stirring,

IR:v(C=O):

g.

pyridinium

: obtention

and H’4);

an

until

days.

necessary

8.33(d,lH:H2);

4.l(s,3H:CH3).

8 : 0.01

5-carbawyl -4.7 dihydro thieno Yield: 91%; F= 94-C; Analysis: 55.3;

cm-‘;

was purified

washed

mole)

precipitate.

5.0 g. of sodium carbonate the solution was extacted

&a: was carefully

H3);

the So the

7.5(m,2H:NH2);

of pyridinium

The pyridinlum

c. H= 2.81;

(0.002

CgHgClN205S;

IR: 1680

7.7(d,lH:H2);

8.

2 hours;

in the of

recritallised in water. Yield 95X; P>25O’C

8.5(d,lH:H3);

during

soluble

disappearance

36.55;

9.40(s,lH:H4);

Ii= 2.6;

in common solvents).

soluble

d) Exchange iodide/perchlorate in 15a. mole) aZ0.5 0.32 8. of _15a (0.001

the

Found X C= 33.8;

4.6O(s,3R:CH3)

N-methyl 6-carbawyl thieno [3.2-b] pyridinium iodide F: 240’C(dec.); Analysis: CglIgN2OSI; Cal X C= 33.75; H= 2.75;

1089

NHR

H= 5.15;

(CDC13):

and H’4);

N= 14.43.

7.25(d,lH:H5);

Poun d % C= 7.15(d.lH:H2);

3.25(s,3H:CH3).

of a substrate.

In a flask stopped with a septum were introduced 0.194 g.(O.OOl mole) of model & or lJ, 0.223 8. of & (ClO4)2 (0.001 mole) and 0.001 mole of the substrate dissolved in 5 ml. of acetonitrile spectroscopy the

(technical

The reactionnal residue was

elimination

or

or by HPLC until

of the

mixture suspended solvent,

super-dry).

The

course

no dihydro-pyridine

of

the

derivative

crude

product

is

purified

was

monitored

by

RMR

can be detected.

was treated with 1 ml. of water. in IO ml. of water and extracted the

reduction

The solvent was evaporated with 3x50 ml. of CH2C12. After

by conventionnal

procedures.

J. CAZINet al.

1090

REFERBNCBS

1) a)

Zehani,

S.,

2) a)

Inouye,

Oda, J.,

Aaymetric

Uahida,

Rio-Organic

c)

Bruice,

Inagaki,

s.,

b) Kim, C.S.Y.,

P.,

P.,

Verlag

8eriin,

D.L.,

G.,

Press,

New-York.

Reduction.

Lecture

Notes in

(1986).

1982,

104, 5834.

105,

7139.

Japan, 1977, 50, 3360.

C.H.,

Netzler,

D.E.

3i~be~fstr~,

1963.

689.

1968, 2339.

Eliason,

J. Amer. Chew Sot.,

J.

Bourguignon,

cited.

reagents.

Fd. Academic

1983,

Chem. Sot.

Suelter,

Biochemistry,

S.

Grier,

mlpas,

91 (1983),

J. Amer. Chem. Sot.,

J.L.,

dfhydropyrfdines

Uodels of Asymetric

Y.Bull.

Gardner,

Chaykin,

c) Van Ekeren, 5) Tintillier,

A, p.

cited.

1982, 21 and references

with cbiral

J. Amer. Chew. Sot.,

T.C.

Hirabayasbi,

C.C.,

part

Ed. Springer T.C.

H.F.Bruice,

4) a) Johnston,

II,

10, 511 and references

1986,

Rng. Prod. Res. Dev.,

Mechanistic

Chemfstry.

H.F.,

b) Powell,

Vol. 5.

de Cbiric,

N. Reductions

Saba,

synthesis.

b) Ohno, A.,

Journ.

A. Ind.

Kurfilrst,

Y.,

3) a) Powell,

G. NOW.

Gelbard,

b) Kuthan J.,

J.,

Q&miner,

101, 7406.

1977,

Tetrahedron

0.

Lett.,

1986, 27,

Japan,

1979,

2537. 6) a) Shinkai,

S.,

Ramada,

b) Shinkaf.

S.,

Hamada, H.,

Manabe,

0.

c) Sbinkai,

S.,

Hamada, H.,

Kusano,

Y.,

S.,

Hamada, H.,

H.,

Ide,

T.,

Manabe,

Cbem. Lett.,

0.

Tetrahedron Nanabe,

Lett.,

1978,

685.

1979, 1397.

0.

Bull.

Cbem. , Sot.

0.

J. Chew Sot.

52,

2600. d) Shinkai,

e) Ohno, A.. Xshihara, 7) Cazin,

J.,

Dupas,

8) Meth-Cohn,

O.,

9) Ain-Khan, 10)

G.,

B.,

Guarponi,

J.M.,

Kusano,

Y.,

Uehida.

Bourguignon,

Narine,

M.,

Barker,

Y.,

Uanabe,

Tetrahedron

S.,

Oka,

J.,

@&gufner,

Tarnowski,

S.

B. J.

6.

Cbea.

Huddleston,

P.,

Holees,

D.

Zell,

R.,

Keenan,

G.J.

J.

1982, 23, 3185.

Lett.,

Tetrahedron

1986,

27,

2375.

Perkin I, 1981, 1531.

Sot.

J. Het. Chem., 1977,

A.,

Perkin 11, 1979, 699.

Lett.,

14, 807.

Chea. Research

(S),

1985,

214;

&I

1985,

2501. 11) Klem, 34,

Klopfenstein,

L.H.,

C.E.,

Hc Coy,

D.R.,

Klerr,

J. Org. Chew. 1969,

R.A.

347.

12) Barker,

J.N.,

Huddelston,

P.,

J. Cbem. Research (S),

1982,

158;

(xf

lt26. 13) Kellogg,

R.N.

14) Roberts,

R.N.G.,

J. Amer. Cbea. Sm.

and al.

Ostovic,

Kreevoy,

D.,

15) a) Creighton,

D.H.,

Sigman,

b) Creighton.

D.J.,

Had-in, J.,

16) Newkow, 17) Kimura,

Oka,

18) af Hu&es, b) Hughes,

i9)

Shirai,

Sigman,

J. Amer. Cber. Sot., Wyeth,

P.

R.H.,

Wyeth,

P. J. Inorg.

Fujii,

S.,

T.,

Tanaka,

M. Bull.

M., Ohno, A.,

Kusano,

Y.,

Ide,

Oka, T.,

S.

Sone,

Cher.,

1976.

1980.

Nucl. Chee.,

Cher. Sot.

98, 4619.

60,

7t3.

1980, 40, 719.

Japan, 1975. 48, 1079.

Chem. Letters, T.,

2053.

6314.

SO, 4238. Nuci.

J. Ioorg.

R.H.,

Prince,

Chishfna,

48,

93,

101, 7036.

1979.

Prince,

K.,

1983,

1971,

J. Amer. Chem. Sot.,

D.S.

J. Org. Chem.. 1985,

C.R.

3981.

J. Amer. Cbem Sot.,

D.S.

M,,

21) a) Shinkai,

Manabe,

1984, 925. 0.

B&f.

Chen.

SAC. Japen,

51, 3544.

b) Nakamura, K.,

c) Nakamura, 22)

S.

107,

J. Org. Men.

N.,

M.,

20) Nakaaura, 1978,

Marston,

G.R., T.,

1985,

H.N.

a) Kruse, b) Neyers,

K.,

L.I., A.I.,

Pujii,

M., Ohno, A.,

Fujii,

M., Oka, S.,

Oka, S,

Ohno, A. Cher.

Hilbert,

E.L.,

Heterocyctes,

Sricar,

J.C.,

J.

Org.

Cher.,

Letters,

Tetrahedron

1983, 1967,

Letters, 20, 32.

1373. 4134.

1984, 3985.

1985, 523.

1982,