CHEM . RES . CHIN ESE U .

2005, 21( 2) , 169 171

A Convenient Method for Chlorination in Allylic Position

WANG Xin-yan, SH I Hong-chang * , CHEN Gang, HONG Xiao y in and XU Shou-yi Dep ar tment of Chemistry , T si nghua Univer sity , Beij ing 100084, P . R . China
Receiv ed M a rch 17, 2004 A conv enient method for the chlor ination in ally lic positio n w as dev elo ped by using the aqueo us solutio n o f so dium hypochlor ite ( 2% _ 5% activ e chlo r ine) and an acid as chlor ination r eag ent in a diphase system . T he method has the advantag e of cheap r eagents, mild reaction conditio ns and g oo d yields. T he quantity and t he feeding r ate o f the chlor inatio n r ea gent can be co nt ro lled easily . T he met ho d is par ticula rly suit able fo r t he chlor inatio n in labo rato r ies. Keywords Chlor ination , A lly lic po sitio n , Sodium hypo chlor ite , Diphase system Articl e ID 10059040( 2005) 0216904

Introduction
T he chl orinat ion in allylic po sit ion of olefins is an import ant t ransfo rmat io n in or ganic synt hesis and many procedures have been est ablished. F or example, t he chlo rinat ion of dithioazet idino ne ( compound 1 , see Scheme 1, an im po rtant synt het ic int ermediat e of cephalospor in ant ibiot ics) can be co mpl et ed by elect ro -chlorination or by using chemical r eag ent s. No rmally , elect rochlor inat ion[ 1_ 4] has a g ood select ivit y in hig h y ields( 80% _ 90% ) , but it is cost ly . T he most com mon reagent s, such as t -but yl hypochl orit e[ 5, 6] , dichlo[ 7] rine m onoxide and chlo rine gas , run w it h severe disadvantag es f or this purpose . For inst ance , co mpound 1 can be convert ed int o com pound 2 o nly in a 30% y ield by using t-but yl hypo chlorit e . Alt hough dichlo rine monox ide and chlo rine lead g ood selectiv it y and yields , t hey of ten po llute t he environ[ 1_ 4, 8] ment . We now repo rt an environment all y fr iendly m et hod f or t he chlor inat ion in ally lic positio n o f ol ef ins. It uses t he aqueous solution of sodium hy pochlorit e( 2% _ 5% act ive chlorine) t og ether w ith an inorganic acid or an o rganic acid as chlorinat ion reag ent s and is carried out in a diphase sy stem such as CCl4 -H 2O and CH 2Cl2-H 2 O.

branching on the doubl e bonds ( compounds 1 , 3, 5, 8, 10 , 12 in Scheme 1) .

R 1N H N O CO O R 2 1 CH 3 CH 2
N aClO, H3 PO 4 CH 2C l2 H 2 O , - 15_ 25

S _ SO 2 _ A r

N aClO , AcOH C Cl4 -H2 O, 0

R 1N H N O

S _ SO 2 _ A r Cl

C OO R 2 ( 80% _ 90% ) 2 CH 2 Cl C H2 ( 72% ) 4 + Cl H

1

H1

3
NaC lO , H 3 PO 4 CC l4 H2 O, - 15_ 25
2

H1

Cl ( 40% ) 7

H ( 30% ) 6

5
N aClO , H3 PO 4 CC l4 H 2 O , - 15_ 25

8 CH 3 C CH 3 10 CH 3 C CH 3 C H 12 O C CH 3 C CH 3 CH 3

H2 CH 2C l 9

( 70% ) CH 3 CH 3

NaC lO, H 3P O 4 C H2 C l2-H2 O , - 15_ 25

H2C

C Cl CH 3

11
NaClO, H3 PO 4 CC l4 H 2O , - 15_ 25

( 90% )

Results and Discussion

As show n in Scheme 1, a dithioazet idino ne derivat ive( compound 1) w as used f or t he chlo rinatio n f irst ly and satisfacto ry result s w ere obt ained w ith excell ent select ivit y and hig h yields ( 80% _ 90% ) . T he furt her exper im ent al r esult s indicat e t hat t he met hod can be used g enerally for t he chlorinat ion in all ylic position o f m any olef ins w it h

H2C

CH 3 H C C

O C CH 3 ( 70% )

Cl 13

Scheme 1 The chlorination in allylic position of some olef ins by using sodium hypochlorite and an acid as chlorination reagents in a diphase system.

T he real chlorinat ing r eag ent is considered t o be mo lecul ar st at e Cl 2, w hich is pro duced by t he

* * T o w ho m cor respondence should be addr essed. E-mail: shihc@ mail. t sing hua. edu. cn

 170

CHEM . R ES . CHIN ESE U .

V ol . 21

react ion o f sodium hypochlor it e w ith acids in t he aqueo us phase show n as f ollow ing : + NaClO+ Cl + 2H Cl2+ Na + H 2O T hen Cl2 go es int o t he or ganic phase im mediately and the chlorination of olef ins o ccurs in t he org anic phase( see Fig . 1) . T he chl orinat ion carried o n by Cl2 in no npolar [ 9_ 12] so lvent s has been st udied by P outsma and ionic

or r adical pat hw ays were pr opo sed. T he o lef ins w ith branches( especially alkyl groups) on t he doubl e bonds go t hrough m ainly an ionic pat h , w hich pr oduces a new olefin chlorinat ed in the allylic posit ion . T herefo re , t he chlorinat ion react ions in Scheme 1 should be in pro gress along an ionic pat h and t he m echanism of t he react ion is described in Fig . 1.

Fig. 1 The mechanism of the chlorination in allylic position by using sodium hypochlorite and an acid as chlorination reagents in a diphase system.

Since m olecular HCl is produced in t he r eactio n, t he aqueo us phase is very import ant due t o t hat it can absorb HCl and t hen t he side react ion caused by HCl can be reduced significant ly. Inor ganic acids, such as phosphoric acid, sulf ur ic acid or hy drochloric acid can all be used in t his procedure and phosphoric acid is t he most eff ect iv e one, fo llow ed by sulf uric acid. It w as fo und t hat t he chlorination could be carr ied o ut w hen w at er solubl e o rganic acids w ere used. Amo ng t hem , acet ic acid w as t he best . How ever, t he react ion co uld hardly occur w hen a w ater insoluble acid such as pent ano ic acid or hex anoic acid w as used. T he sit uat ion may be caused by t he very st ro ng af finit y existing bet w een t he large alkyl groups of t he acids and t he allylic + gr oups of olefins. T he af finity can inhibit Cl t o react w it h t he double bo nd on the ally lic group . T he acids t hat react w it h chlor ine or olef ins canno t be used in this chlorination. F or ex ampl e, fo rmic acid is f reely soluble in wat er , how ever , no t suit able f or t he chlo rinat ion because it could r educe chlor ine into chlo rine anion: 2H + + 2Cl- + CO 2 HCOOH + Cl 2 T he pr oduct s , co mpo unds 6, 7, 9, 11 and 13, are so act iv e t hat t he chemical changes can o ccur during the process of flash chro mato graphy . Ho w ev er , t heir st ruct ures and t he yields can be det er -

m ined fro m the 1H NMR spectr a of t heir crude product s. Am ong those product s, compound 13 is t he m ost active and t he chlo ride w oul d deco mpose m ore t han half o f it w hen it w as kept at ro om t emper at ure for 2 h, which show s that ev en very act ive ally lic chlorides could be pr epared by t he chlo rinat ion m et hod. Com po unds 6, 7 and 9 are substit utes of cyclohex ene or cyclo hex ane w it h 3 _ 4 m et hylenes. T he NM R peaks of hydrog en at oms o n methyl enes are very clo se , even crow ded . T heref ore , w hen t he pro duct s are not pure , it is hard to det er mine t he chemical shift of each m et hylenehydrogen. Ho w ever, the chemical shift s of hy drog en at om s o n double bonds and so me gro ups( such as met hyl and chlor o-met hy l) can be det erm ined. T he chemical shif t s of hydrog en at o ms on double bonds of chlorides 4, 6, 7, 9 can be est i[ 13] m at ed w it h empirical fo rmula : 5. 25+ Z iso + Z cis + Z trans H w here Z iso , Zc is and Z trans are empir ical parameters . T he resul ts mat ch w ell w it h t he m easured result s ( see T able 1) , w hich indicat es that t he o lef ins ( compounds 3, 5 , 8 , 11 ) have changed int o new o lef ins chlorinated in al lylic posit ions. T he chemical shift s o f t he chloride( compound 13) could not be estim at ed f or lack of em pirical paramet ers, but

N o. 2

WA N G X in y an et al .
1

171

t he new chemical shift peaks of hydr ogen ato ms on t he doubl e bo nd appear at 5. 16 and 5. 27, w hich show s t he f ormat ion o f a new do uble bond ( see Scheme 1) .
Table 1 The chemical shifts of the hydrogen atoms on the double bonds f rom NMR detection and estimation by empirical f ormula
Chemical sh if t Compound
1H

H1 NMR Es t imat ion 5. 45 4. 84 5. 56 5. 77 5. 08 4. 85

1H

H2 NM R Est imat ion 5. 57 4. 90 5. 55 4. 97

4 6 7 9 11

5. 44 4. 79 5. 59 5. 81 5. 05

4. 99

Experimental
T he H NM R spect ra were recorded on a Br uker AC 300M NM R spect ro meter and r ef er enced t o M e 4Si. T he concent rat ion of act ive chlo ride in sodium hypo chlorit e solution w as detected by iodomet ry . 1 Chlorination Usi ng Sodium Hypochl orite To gether with an Organic Acid ( such as AcOH ) as Chl orinating Agent ( Compound 1 as the Substrate) Wit h w ell st irring , t he aqueous so lut ion of so dium hypochlo rite ( 5 m L , 5. 0% act ive chl orine ) w as added dropw ise t o a sol ut ion o f co mpound 1 ( 3. 0 g , about 5 m mol ) in a t et rachl oride ( 100 mL ) and acet ate acid( 10 m L ) at - 5 . One hour lat er , t he solid w as f ilt er ed of f and w ashed w it h met hy lene chlo ride( 20 m L ) . T he org anic lay er w as separ at ed and w ashed w ith the sat urat ed aqueous so lut ion o f NaCl and dried w it h so dium sulfat e anhy dride. T he so lvent w as moved t o give about 3. 1 g of t he crude pro duct , w hich w as purif ied by Fl ash chrom at o graphy [ silica gel, V ( benzene ) V ( et hyl acetat e) = 21] t o give 2. 8 g of com pound 2( 88% ) as a yellow ish no ncryst all ine solid. 2 Chlorination Usi ng Sodium Hypochl orite To gether with an Inorganic Acid( such as Phosphoric Acid ) as Chlorinating Agent ( Compound 3 as a Substrate ) Wit h w ell st irring, t he aqueous so lut ion of so dium hypo chlorit e ( 7. 0 mL , 5. 0% active chlo rine ) w as added dr opw ise to a mixt ure of com pound 3 ( 1 m L , about 7. 6 mm ol ) in methyl ene dichlo ride( 40 mL ) , 8 m L of a 25% o f sodium chlo ride so lut ion and phosphoric acid ( 2. 0 m L , 85% ) at - 20 . T hen the fo llow ing pro cedures w ere sim ilar t o t ho se described abo ve t o g ive 0. 84 g ( 72% ) of compound 4 as a colorless o il.
1

3 H NMR Spectra and IR Spectra 1 Com po und 2: H NM R ( 300 M Hz, 25 , CDCl 3) , : 7. 79( d, J = 7. 8 Hz, 2H ) , 7. 58 ( d, J = 7. 2 Hz , 3H ) , 7. 48( d , J = 7. 8, 2H ) , 7. 28( m , 7H ) , 6. 89( d , J = 8. 5 Hz , 2H ) , 6. 18( d , J = 8. 9 Hz , 1 H ) , 5. 85( d , J = 4. 9 Hz , 1H ) , 5. 16_ 5. 01 ( m, 5H ) , 4. 65 ( s, 1H ) , 4. 08( dd, J 1 = 47 Hz, J 2= 12. 5 Hz, 2H) , 3. 81( s, 3H) , 3. 57( s, 2H ) . - 1 IR( KBr ) , ~/ cm : 3400( NH) , 1780, 1745, 1673 ( C O) . 1 Com po und 4: H NM R ( 300 MHz, 25 , CDCl 3) , : 4. 47( s, 2H) , 5. 45( s, 1H ) , 5. 56( s, 1H ) , 7. 26_ 7. 20( m , 3H ) , 7. 47( d , J = 7. 2 Hz , 2H ) . 1 Com po und 6: H NM R ( 300 M Hz , 25 , CDCl 3) , : 4. 52 ( dd, J = 10. 5, 4. 4 Hz, 1H ) , 4. 65( s, 1H) , 4. 80( s, 1H) . 1 Com po und 7: H NM R ( 300 M Hz, 25 , CDCl 3) , : 1. 79( s, 3H) , 4. 42( s, 1H ) , 5. 59( s, 1H) . Com po und 9: 1H NM R ( 300 M Hz, 25 , CDCl 3) , : 3. 98( s, 2H ) , 5. 81( s, 1H) . 1 Com po und 11 : H NMR ( 300 M Hz, 25 , CDCl 3 ) , : 1. 74( s , 6H ) , 1. 95( s, 3H ) , 4. 85( s , 1H) , 5. 05( s, 1H ) . 1 Com po und 13 : H NMR ( 300 M Hz, 25 , CDCl 3 ) , : 1. 78( s, 3H ) , 2. 27( s, 3H) , 4. 85( s, 1H ) , 5. 16( s , 1H ) , 5. 27( s, 1H ) . Ref erences
[ 1 ] T orii S. , U n eyama K . , N acai T. , e t al . , T etr ahedr on L et t. , 1981, 22, 2291 [ 2 ] T orii S. , U n eyama K . , N acai T. , e t al . , T etr ahedr on L et t. , 1981, 22, 3193 [ 3 ] T orii S. , T an ak a H. , Sait oh N . , et al. , Tet rahed ron L et t. , 1982, 23, 2187 [ 4 ] T orii S. , Tanaka H. , Sait oh N . , et al. , Chem . L et t. , 1982, 11, 1829 [ 5 ] Cooper R . D. G. , T etrahe dron L ett . , 1980, 21, 781 [ 6 ] T an iguch i M . , M isaw a T. , T orii S . , et al . , Bul l . Chem . S oc . Jp n, 1995, 8, 577 [ 7 ] K en N . , Shinj iro S. , O s amu S. , 0500081, 1992 et al . , EP P ate nt

[ 8 ] Y osh iok a M . , T su ji T . , U yeo S . , T etrahe dron L et t. , 1980, 21, 351 [ 9 ] Pout sm a M . [ 10] Pout sm a M . [ 11] Pout sm a M . [ 12] Pout sm a M . L. , S ci ence, L . , J . A m. L. , J . A m . L. , J . A m . 1967, 157, 997 Chem . S oc. , 1963, 85, 3511 Chem . S oc. , 1965, 87, 2161 Chem . S oc. , 1965, 87, 2172

[ 13] N in g Y . C. , S tr uctur al Id entif i cation of Or ganic Comp ounds and Or gani c Sp ect roscopy , Science Pub lish ing Comp any, Beijing , 2000, 28