Synthesis of optically active chloro alkanoic esters

Tetrahedron Letters,Vo1.30,No.34,pp Printed in Great Britain

4555-4558,1989

0040-4039/89 $3.00 Pergamon Press plc

f .Oo

synthesis of @tically R&rive chloro Alkanoic JZstms

Eye Azzena,='* Giovanna Delcq~,~ Giovanni I+~lloni,~and Ore&e

Piccolo.c'*

aDipartitrentodi Chimica, Universita' di Sassari, via Vienna 2, I-07100 Sassari (Italy); bIstituto

C.N.R.

per

1'Applicazione delle

Tecniche

Chimiche

Avanzate

ai

Problemi

Fgrobiologici, via Vienna 2, I-07100 Sassari (Italy); CStudio di Consulenza Scientifica, via Borne' 5, I-22060 Sirtori (Italy).

sunslary: The stereospecific alkyl-2-chloropropionate responding

synthesis (optical yield and (S)-alkyl-3-chlorobutanoate

(S)-2-mesyloxy-

up to 94%) of optically active (RIby the action of AlCl on the cor-

and (R)-J-mesyloxy-derivatives

3

is described.

In the course of our investigation to prepare optically active arylalksnoic esters by AK13 catalyzed stereospecific Friedel-Crafts alkylation of aromatic compounds with optically active esters of (Sl-2-(mesiloxy)propanoicacid (la. b) and CR)-3-(mesiloxylbutanoicacid (lc, d).1-3 we have observed, as a wmpstitive

reaction, the forrmtion of optically active

esters of (R)-2-chloropropionic acid (2a, bl and (S)-3-chlorobutanoic acid (ZC, d). This reaction occurred with inversion of configuration at the chiral carbon atom and, when measured, with a very high stereospecifity (79-93%, based on optical purity of starting materials and maximum spcific

rotations reported in the literature for compounds 2). Under

the experimental conditions used these chloro esters should be able to alkylate aromatic compounds in low extent,4 if ’ any. A1C13 CH3-*CHKS02CH31-KH2),-coOR

CH3-*CHK1)-(CH2)n-CCOR

la: n = 0, R = CH3

2a: n = 0, R = CH3

lb: n = 0, R = C2H5

2b:n=0,R=C2H5

1~: n=l,R=CH3

2c:n=1,R=CH3

Id: n = 1, R = C2H5

2d: n = 1, R = C2H5

Esters of 2-chloropropionic acid are useful intermediates in the synthesis of a variety of products including drugs5 and herbicides6 and there is a strong interest in ths industrial manufacture of them. An example mncerning esters of 3-chlorobutanoic acid as intermediates in the synthesis of herbicides has also been reported.7 It has long been known' that these compounds can be prepared starting fmm

the corresponding

hydroxy-derivatives by reaction with a variety of chlorinating reagents, such as .5X12, x15,

or CoC12 in the presents or absence of a base, e.g. pyridine; furthern-ore,2b has been

also prepared by the reaction of the corresponding chlorosulphonate with aniline or pyridine hydrochloride,8b by the

reaction of tosylate with LiC18c, and by thermal deccmposition of

4555

4556

chlorosulphonateSd and chlorofomte.'g ooour depending on the eqerimental knam

Partial or t 0ta1 racemization of ccmp~unds 2 can

conditions. To tk

best of our knowledge, nothing is

on the reaction of such or similar derivatives with Lewis acids to afford canpounds 2.

We have therefore investigated on the possibility to achieve a new stereospecific synthesis of these interesting substrates in non aromatic solvents.

Table - Preparatim of (RI-2-&l aropmpiamtes CCXlpUnd

Solvent

lY°C)

t(h)

(2a, b) amI (s)-3-&l mmb&am~m

Yield, %

MD

Optical

(Zc, d)wa

[alp=

Ref.

yield, %

2a

cH2C12

40

24

48

31.6b

94.3

33.5b

&I

2b

B2Cl2

10

168

44C

18.4d

92.7

19.8d

5a

2b

CHzCl2 CRC13

40

24

45o

17.8d

90.0

19.8d

5a

61

14

59C

14.2d

71.8

19.8d

CHzCl2

0

2

67

26.ge

91.8

29.3e

5a e

2

76'

25.af

89.0

29.0f

f

2d

cH2C12 cycle-C6H12

0 0

2

42

lO.Of

34.5

29.0f

f

2d

cycle-C6H12

10

2

45

6.6f

22.8

29.0f

f

2b

2c 2d

2c 2d 2d

C6H6

10

4

29

23.4e

79.9

29.3e

e

2

36

26.gf

92.8

29.0f

f

CsHs C6H5C1

10 0

2

35

22.9f

79.0

29.of

f

aAbsolute cmfiguration-optical rotations of compounds 1 [optical purity (o.p.), confidently evaluated on

the

basis of

the 0.~.

of

the

corresponding hydroxyl esters]:

(S)-la:

1~1~25~ - 56.4 (c = 1, CHCl3), o.p. 100%; (S)-lb: [+,25= -53.9 (c = 1, CHC13), 0-p. 100%; (R)-lc: aD20 = -46.5 (neat), 0-p. 99.4%; (R)-ld: CQ~~= -39.5 (neat), 0.p. 100%. bffeasuredin cc141 c = 1, at 30°C; the same sample showed [&],25= 25.6 (neat, d425= 1.1431, o.y. 92.1%, according to ref. 9. %ss rizovered 1. dMeasxd

of optical activity not exceeding 3-5% has been observed for

on neat cmpound

in excellent agreement with

at 20°C, d420= 1.0720;*' the [a]px

[c~],~~rnax = 19.7 (neat), calculated in this work by acidic

hydrolysis to CR)-2-chloropropionicacid.lo %asured the [ol]px attmpts

value was found

value has been calmlated

on neat can~und at-2S°C, d425= 1.077;

by us from data reported in ref. 11 and 12; our

to confirm this datum, aa well as the corresponding datum for 2d, by acidic

hydrolysis to 3-chlorobutanoic acid gave unreliable results; also HPLC and GIL methods with ccmmercially available chiral columns were, in our hands, useless. fMeasured in CEC13, c = 5 at 25OC; the [cc]px = 29.0 has been calculated by us frm

data reported in ref. 4 and 12,

and used to calculate the stereoselectivity of the reactions; [alD20max = 31.2 d4 20= 1.0517) has ken

(neat,

reported in ref. 4; the latter value is unreliable, in OUT opinion,

due to a wrong calculation of the optical purity of the corresponding hydroxy-derivative, used as a starting material; see also the preceding note.

4557

In a typical experiment,15 ~1

of compound 1 were added to a suspensionof 30 nnol of

AK13 in 15 ml of dry solvent chilled to O°C, and the reactionmixture was stirred at the reportedtqature.

After the indicatedreactiontime, the mixture was quenchedwith 10%

aqueousXl; usual work-up and careful fractionaldistillationaffordedthe products. The resultsare reportedin the Table, where it is shown that compounds2 can be obtainedin fair to good chemical yields with optical yields up to 94%. As a compariscn,it can be observed

that

nucleophilic displacement of

the

tosylate

group

of

ethyl

2-(tosyloxy)propanoate with LiCl occurred with 21.5% optical yield,8c whereas reaction of the correspondingchlorosulphonate with pyridinehydrochlorideoccurredwith 79.3% optical yield;Sb in the latter case, optical yields up to 95% were obtained using aniline hydrochloride but, as pointedout by the authors,the secondaryreactionof anilinewith the sulphonateseriouslyaffectedthe chemicalyield.8b To explainthe high stereospecificity of this reaction,as well as the differentreactivity of compounds 1 (n = 0 vs n = 1, cfr., for example, entries 2 and 6 of the Table), we conplex between suggest, as a necessary requirement,the formation of an inter;mediate munds

1 and the Lewis acid (Schema,fig. A, brackets,[J, meaniq that we are not able

to spcify the environmentof Al and Cl).

PI -

L

U42ln /

\/OR

CH~--‘CH II’ ‘L,

X ‘.

c

S&am:

8’0

#’

‘\ ‘* [A’] **

Fig. A, X = 0SO$H3 Fig. B, X = Cl

A

similar hypothesis has been advanced to

justify the stereospecificityin

the

Friadel-Crafts alkylationof aranaticsubstrates(ArH) with can~unds 1,1m3 as well as with compound 2d,4 where ArH attacks the chiral carbon atan from the backside (the different relative concentrationand nucleophilicability of Aridand [Cl]- account for the results obtainedwhen both are present in the reactionmixture). The observed partial Ices of optical activity of compunds 2 might be explainedadmitting that a similar intermediatecanplex is formed and subsequentlyattackedby [Cl]- (Schema, fig. 81, this scramblingof chlorineatoms causing racemizationwithout apparentreaction. According to this hypothesis,the optical activity of compounds 1 recovered from the reactiormixtures (entries2, 3, 4 and 6 of the Table) results almost unchanged.Also the considerable loss of optical activity of cornFunds 2c and 2d under typical reaction conditions,13in agreementwith a literaturereprt,4 supports such a mechanisticpicture: however, it should be pinted out that, in related experiments,ccm~unds 2a and 2b do not racemize to a similar extent.l4 Of course, all the reactionparametersthat influencethe stabilityof such canplexes,i.e., the solvent,the reacticn temprature, tha value of n

4558

(and perhaps also the nature of the R group, although no clear-cut evidenoa has been obtained so far), affect chemic&l and optical yields. Work is in progress to define the importance of such parameters and to thraw light on soma contradictory data on max. optical rotatory powers of compounds 2 reported in the literature.

We acknowledge financial support from the Consiglio Nazionale delle Ricer&e,

Italy.

1. 0. Piccolo, F. Spreafico, G. Visentin, and E. Valoti, J. Orq. Chem., 50, 3945 (1985). 2. U. Azzena and 0. Piccolo, Abstracts of XVII National Meeting on Organic Chemistry, It. Chem. Sot., Fiuggi (I), P-5, pag. 49 (1987). 3. 0. Piccolo, U. Azzena, G. Delqu, 4. T. Nakajim,

G. Melloni, and

E.

Valoti, unpublished results.

S. Masuda, S. Nakashima, T. Kondo, Y. Nakamoto, and S. Suga, Bull. Chem.

Sot. Japan, 52, 2377 (1971). 5. a1 J. Biedermann, A. Leon-Lomali, H. 0. Borbe, and G. Prop, J. Med. Chem., 29, 1183 (1986), and references therein: b) D. R. Feller, V. S. Kamanna, H. A. I. Newman, K. J. Romstedt, D. T. Witiak, G. Bettoni, S. H. Bryant, D. Conte-&merino, F. Loicdice, and V. Tortorella, J. Med.Chem., 30,1265 (19871, and references therein. 6. R. M. Scott, G. D. Antritage, and E. Haddock, Ger. Offen. 2,946,652 (1978), C.A. 93, 185974g (1980); G. Gras, Ger. Offen. 3,024,265 (19811, C.A. 94, 191956q (1981); S. Fujinawa, I. Hashiba, K. Suzuki, S. Tsuchiya, and Y. Takakuwa, Jpn. Kokai Tokkyo Koho .JP 61,158,947 [86,158,947] (1984), 3 Tsuchiya, and Y. Takahwa,

106, 18108h (1987); K. Suzuki, I. Hashiba, S.

Jpn. Kokai Tokkvo Koho JP 62 16,446 187 16.4461 (1984), C.A.

107, 39415s (19871. 7. K. Matter-stock,P. Langelueddeke, and E. F. Schulze, Ger. Offen. 2,417,487 (19751, C.A. 84, 30693e (1976). 8. a) E. Fisher and H. Scheibler, Ber. Dtsch. Chem. Ges., 42, 1219 (1909);

b) P. F.

Frankland and W. E. Garner, J. Chem. Sot., 105, 1101 (1914); c) J. Kenyon, H. Phillips, and H. G. Burley, J. Chem. Sot., 127, 399 (1925); d) W. Gerrard, J. Kenyon, and H. Phillips, J. Chem. Sot., 153 (1937); e) J. Crosby, UK Pat.Appl. 2,055.802, C. A. 95, 149970k (198111; f) H. Kaminakai, Jpn. Kokai Tokkyo Koho JP 61 68,445 [86 68,445] (19841, C.A. 105, 97017h (1986); g) J. Crosby, Eur. Pat. A@.

EP 163,435 (1985), &&

105, 114607~ (1986); h) H. Kaminakai and M. Nekawa, Jpn. Kokai Tokkyo Koho JP 61,271,249 [86,271,249] (1986), C.A. 107, 9326w (1987). 9. K. Freudenberg, W. Kuhn, and I. Bunenn, Ber. Dtsch. Chem. Ges., 63, 2380 (1930). 10. S.-C. J. Fu, S. M. Birnbaum, and J. P. Greenstein, J. Am. Chem. See., 76, 6054 (19541. 11. E. Fischer and H. Scheibler, Justus Liebigs Ann. Chem., 383, 337 (1911). 12. D. Seebach and H. Zueger, Helv. Chim. Acta, 65, 495 (1982). 13. Loss of optical activity up to 60% has been observed when canpounds 2c and Xl were allowed to react with 2 equivalents of AlC13 in CH2C12 at O°C. 14. Loss of optical activity not exceeding 5-7% has been observed when canpounds 2a ard 2b were allowed to react with 2 equivalents Of AlCl3 in boiling CHC13. (Received

in UK 8 March

1989)