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

Depar tment of Chemistry , T singhua Univer sity , Beij ing 100084, P . R. China

Receiv ed Ma rch 17, 2004

　　A convenient method for the chlor ination in ally lic positio n w as developed by using the aqueous solution

o f sodium hypochlor ite ( 2% _ 5% activ e chlo r ine) and an acid as chlor ination r eagent in a diphase system.

T he method has the advantag e of cheap reagents, mild reaction conditions and good yields. The quantity and

t he feeding r ate o f the chlor ination r eagent can be cont ro lled easily . The met hod is par ticula rly suit able fo r

t he chlor ination in labo rato r ies.

Keywords　Chlor ination, A lly lic po sitio n, Sodium hypochlor ite , Diphase system

Article ID　1005-9040( 2005) -02-169-04

* * To w hom cor respondence should be addressed. E-mail: shihc@ mail. t singhua. edu. cn

IntroductionThe chlorinat ion in allylic po sit ion of olefins is

an important t ransfo rmat ion in or ganic synthesis

and many procedures have been established. For

example, the chlo rinat ion of dithioazet idinone

( compound 1, see Scheme 1, an impo rtant synthet-

ic intermediate of cephalospor in ant ibiot ics) can be

completed by elect ro-chlorination or by using

chemical r eagents. No rmally , elect rochlor ina-

t ion[ 1_ 4]has a good select ivity in high y ields( 80% _

90%) , but it is cost ly . The most common

reagents, such as t-butyl hypochlorite[ 5, 6] , dichlo-

rine monoxide[ 7]

and chlo rine gas, run w ith severe

disadvantag es for this purpose. For instance, com-

pound 1 can be converted into compound 2 only in a

30% y ield by using t-butyl hypochlorite. Although

dichlo rine monox ide and chlo rine lead good selec-

tiv ity and yields, they of ten po llute the environ-

ment[ 1_ 4, 8]

. We now repo rt an environmentally

fr iendly method for the chlor inat ion in ally lic posi-

tion o f olef ins. It uses the aqueous solution of sodi-

um hypochlorite( 2% _ 5% act ive chlorine) tog eth-

er w ith an inorganic acid or an o rganic acid as chlo-

rinat ion reagents and is carried out in a diphase sy s-

tem such as CCl4-H2O and CH2Cl2-H2O.

Results and Discussion

As shown in Scheme 1, a dithioazet idinone

derivat ive( compound 1) w as used for the chlo rina-

tion f irst ly and satisfacto ry results w ere obtained

w ith excellent select ivity and high yields ( 80% _

90%) . T he further exper imental r esults indicate

that the method can be used generally for the chlo-

rinat ion in allylic position o f many olef ins w ith

branching on the double bonds ( compounds 1, 3,

5, 8, 10, 12 in Scheme 1) .

R 1NH S _ SO 2 _ Ar

ON

COOR 2

N aClO,AcOH

CCl4-H2O,0℃

R 1NH S _ SO 2 _ Ar

ON

COOR 2

C l

( 80% _ 90% )

1 2

CH3

CH2 N aClO, H3PO4

CH 2Cl2-H 2O, - 15_ 25℃

CH2Cl

C

H1

H2

( 72% )3 4

NaClO, H 3PO4

CCl4-H2O, - 15_ 25 ℃

Cl

H1 H2

+

ClH1

( 30% ) ( 40% )

5 6 7

　　N aClO, H3PO4

CCl4-H 2O, - 15_ 25℃H2

CH 2C l ( 70% )

8 9

C

CH 3

CH 3

C

CH3

CH3

NaClO, H 3PO4

CH2Cl2-H2O, - 15_ 25 ℃H2C C

CH3

C

CH3

CH3Cl

10 11 ( 90% )

C

CH3

CH3

CH

C

O

CH3

NaClO, H3PO4

CCl4-H 2O ,- 15_ 25 ℃

H2C C

CH3

CH

Cl

C

O

CH3

12 13

( 70% )

Scheme 1 　 The chlorination in allylic position of some

olef ins by using sodium hypochlorite and an

acid as chlorination reagents in a diphase sys-

tem.

The real chlorinat ing r eagent is considered to

be mo lecular state Cl 2, w hich is produced by the

CHEM. RES. CHINESE U . 2005, 21( 2) , 169—171

react ion o f sodium hypochlor ite w ith acids in the

aqueous phase show n as follow ing:

NaClO+ Cl-+ 2H

-Cl2+ Na

++ H2O

Then Cl2 goes into the or ganic phase immedi-

ately and the chlorination of olef ins o ccurs in the

org anic phase( see Fig . 1) .

The chlorinat ion carried on by Cl2 in non-polar

so lvents has been studied by Poutsma[ 9_ 12]

and ionic

or r adical pathw ays were pr opo sed. T he o lef ins

w ith branches( especially alkyl groups) on the dou-

ble bonds go through mainly an ionic path, w hich

pr oduces a new olefin chlorinated in the allylic po-

sit ion. T herefo re, the chlorinat ion react ions in

Scheme 1 should be in pro gress along an ionic path

and the mechanism of the 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 molecular HCl is produced in the r eac-

tion, the aqueous phase is very important due to

that it can absorb HCl and then the side react ion

caused by HCl can be reduced significant ly. Inor -

ganic acids, such as phosphoric acid, sulfur ic acid

or hydrochloric acid can all be used in this proce-

dure and phosphoric acid is the most effect iv e one,

fo llow ed by sulfuric acid.

It w as found that the chlorination could be

carr ied out w hen w ater -soluble o rganic acids w ere

used. Among them, acet ic acid w as the best .

How ever, the react ion could hardly occur w hen a

w ater insoluble acid such as pentano ic acid or hex-

anoic acid w as used. The situat ion may be caused

by the very st rong af finity existing betw een the

large alkyl groups of the acids and the allylic

gr oups of olefins. T he af finity can inhibit Cl+to re-

act w ith the double bond on the ally lic group.

The acids that react w ith chlor ine or olef ins

canno t be used in this chlorination. For example,

fo rmic acid is f reely soluble in water, how ever , no t

suitable for the chlo rinat ion because it could r educe

chlor ine into chlo rine anion:

HCOOH+ Cl 2 2H+ + 2Cl

- + CO 2↑

The pr oducts, compounds 6, 7, 9, 11 and 13,

are so act iv e that the chemical changes can occur

during the process of flash chromato graphy . How-

ever , their st ructures and the yields can be deter -

m ined from the 1H NMR spectr a of their crude

products. Among those products, compound 13 is

the most active and the chlo ride w ould decompose

more than half o f it w hen it w as kept at ro om tem-

per ature for 2 h, which show s that ev en very act ive

ally lic chlorides could be pr epared by the chlo rina-

t ion method.

Compounds 6, 7 and 9 are substitutes of cy-

clohexene or cyclohexane w ith 3 _ 4 methylenes.

T he NMR peaks of hydrogen atoms on methylenes

are very clo se, even crow ded. Therefore, w hen

the products are not pure, it is hard to determine

the chemical shift of each methylene′hydrogen.

How ever, the chemical shift s of hydrogen atoms

on double bonds and some groups( such as methyl

and chlor o-methy l) can be determ ined.

T he chemical shif t s of hydrogen atoms on

double bonds of chlorides 4, 6, 7, 9 can be est i-

mated w ith empirical fo rmula[ 13] :

H

5. 25+ Z iso+ Zcis+ Z trans

where Z iso, Zc is and Z trans are empir ical parameters.

T he resul ts match w ell w ith the measured results

( see T able 1) , w hich indicates that the o lef ins

( compounds 3, 5, 8, 11) have changed into new

o lef ins chlorinated in al lylic posit ions. T he chemi-

cal shift s o f the chloride( compound 13) could not

be estimated for lack of empirical parameters, but

170　　 CHEM. RES. CHINESE U . Vol. 21

the new chemical shift peaks of hydr ogen atoms on

the double bond appear at 5. 16 and 5. 27, w hich

show s the format ion o f a new double 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 formula

Compound

Chemical sh if t

H1 H 2

1H NMR Es t imat ion 1H NM R Est imat ion

4 5. 44 5. 45 5. 55 5. 57

6 4. 79 4. 84 4. 97 4. 90

7 5. 59 5. 56

9 5. 81 5. 77

11 5. 05 5. 08 4. 85 4. 99

Experimental

The1H NMR spectra were recorded on a

Br uker AC300M NMR spect rometer and r efer -

enced to M e4Si. T he concentrat ion of act ive chlo-

ride in sodium hypochlorite solution w as detected

by iodometry .

1　 Chlorination Using Sodium Hypochlorite To-

gether with an Organic Acid ( such as AcOH ) as

Chlorinating Agent(Compound 1 as the Substrate)

With w ell st irring, the aqueous so lut ion of

sodium hypochlo rite( 5 mL, 5. 0% act ive chlorine)

w as added dropw ise to a solut ion o f compound 1

( 3. 0 g , about 5 mmol ) in a tet rachloride( 100 mL)

and acetate acid( 10 mL) at - 5 ℃. One hour lat-

er , the solid w as f ilter ed of f and w ashed w ith

methy lene chlo ride( 20 mL) . The org anic lay er w as

separ ated and w ashed w ith the saturated aqueous

so lut ion o f NaCl and dried w ith sodium sulfate an-

hydride. The so lvent w as moved to give about

3. 1 g of the crude product , w hich w as purif ied by

Flash chromato graphy [ silica gel, V ( benzene ) ∶

V ( ethyl acetate) = 2∶1] to give 2. 8 g of com-

pound 2( 88%) as a yellow ish noncrystall ine solid.

2　 Chlorination Using Sodium Hypochlorite To-

gether with an Inorganic Acid( such as Phosphoric

Acid ) as Chlorinating Agent ( Compound 3 as a

Substrate)

With w ell st irring, the aqueous so lut ion of

sodium hypochlorite ( 7. 0 mL, 5. 0% active chlo-

rine ) w as added dr opw ise to a mixture of com-

pound 3 ( 1 mL, about 7. 6 mmol ) in methylene

dichlo ride( 40 mL) , 8 mL of a 25% o f sodium chlo-

ride so lut ion and phosphoric acid ( 2. 0 mL, 85%)

at - 20 ℃. T hen the fo llow ing pro cedures w ere

sim ilar to tho se described above to g ive 0. 84 g

( 72%) of compound 4 as a colorless o il.

3　1H NMR Spectra and IR Spectra

Compound 2:1H NMR ( 300 MHz, 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, 1H) , 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 ) .

IR( KBr ) , ~/ cm- 1

: 3400( NH) , 1780, 1745, 1673

( C O) .

Compound 4:1H NMR ( 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) .

Compound 6: 1H NMR ( 300 MHz, 25 ℃,

CDCl 3) , : 4. 52 ( dd, J = 10. 5, 4. 4 Hz, 1H ) ,

4. 65( s, 1H) , 4. 80( s, 1H) .

Compound 7:1H NMR ( 300 MHz, 25 ℃,

CDCl 3) , : 1. 79( s, 3H) , 4. 42( s, 1H ) , 5. 59( s,

1H) .

Compound 9: 1H NMR ( 300 MHz, 25 ℃,

CDCl 3) , : 3. 98( s, 2H ) , 5. 81( s, 1H) .

Compound 11: 1H NMR ( 300 MHz, 25 ℃,

CDCl 3 ) , : 1. 74( s, 6H ) , 1. 95( s, 3H) , 4. 85( s,

1H) , 5. 05( s, 1H ) .

Compound 13:1H NMR ( 300 MHz, 25 ℃,

CDCl 3 ) , : 1. 78( s, 3H ) , 2. 27( s, 3H) , 4. 85( s,

1H) , 5. 16( s, 1H ) , 5. 27( s, 1H) .

References[ 1 ]　T orii S. , Un eyama K. , Nacai T. , e t al . , T etr ahedr on

L et t. , 1981, 22, 2291

[ 2 ]　T orii S. , Un eyama K. , Nacai T. , e t al . , T etr ahedr on

L et t. , 1981, 22, 3193

[ 3 ]　T orii S. , T an ak a H. , Saitoh N. , et al. , Tet rahed ron L et t. ,

1982, 23, 2187

[ 4 ]　T orii S. , Tanaka H. , Saitoh N. , et al. , Chem. L et t. ,

1982, 11, 1829

[ 5 ]　Cooper R. D. G. , T etrahedron 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 ]　Ken N . , Shinj iro S. , Osamu S. , et al . , EP P atent

0500081, 1992

[ 8 ]　Yosh iok a M. , T su ji T . , Uyeo S . , T etrahedron L et t. , 1980,

21, 351

[ 9 ]　Poutsm a M. L. , S cience, 1967, 157, 997

[10]　Poutsm a M. L. , J . A m. Chem. S oc. , 1963, 85, 3511

[11]　Poutsm a M. L. , J . A m. Chem. S oc. , 1965, 87, 2161

[12]　Poutsm a M. L. , J . A m. Chem. S oc. , 1965, 87, 2172

[13]　Nin g Y. C. , S tr uctur al Id entif i cation of Or ganic Comp ounds

and Or ganic Sp ect roscopy, Science Pub lish ing Company, Bei-

jing , 2000, 28

No 171. 2 WANG Xin-yan et al.