J. Org. C h e m . 1983,48,635-640
635
Effect of Nucleophilicity and Leaving Group Ability on the SN2Reactions of Amines with (Acy1oxy)alkyl a-Halides: A Product Distribution Study Kenneth B. Sloan* and Suzanne A. M. Koch Department of Medicinal Chemistry, College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610 Received J u l y 20, 1982
The course of the reaction of amines with (acy1oxy)alkyla-halideshas been found to depend on the nucleophilicity of the amines and the leaving group ability of the halides. More nucleophilic amines tended to give acylated products 2 from the reaction while less nucleophilic amines gave alkylated produds 3. The use of a better leaving group also tended to favor the formation of a greater amount of alkylated product. These results have been compared to the observations of Westaway on the effect of leaving group ability and nucleophilicity on the bond lengths in the transition state of SN2reactions. In addition, secondary amines have been shown to cause the rearrangement of 2-formylbenzamides to 3-amino-l(3~-isobenzofuranones. The reactions of amines with (acy1oxy)alkyl a-halides
(la or 9) lead to unusual results because the halides are ambident electrophiles. A nucleophile such as an amine can react with them a t two different electrophilic centers-the carbonyl carbon atom (acylation of the amine) or the halo carbon atom (alkylation of the amine)-to give two different products. Adams' has shown that generally the reaction of tertiary amines with (acy1oxy)alkyl ahalides gives quaternary salts while the same halide upon reaction with a secondary or primary amine gives the corresponding amides derived from the acyl group. However, Bohme2 and V01z3 have shown that (acy1oxy)alkyl derivatives of secondary amines can be prepared from the reaction of the (halomethy1)amineswith salts of the desired acid, and Wheeler4 has shown that the reaction of 3hydroxy-l(3H)-isobenzofuranone (le) with secondary amines gives 3-(substituted amino)-1(3H)-isobenzofuranones (such as 3c), so it is clear that the (acy1oxy)alkyl derivatives of secondary amines that derive from the reaction of (acy1oxy)alkyl a-halides with amines are not too unstable to be isolated but that the reaction conditions that have been used previously were not suitable for their isolation. Since (acy1oxy)alkyl derivatives of secondary amines were of interest as a means of latentiating (prodrug) the delivery of drugs containing a carboxylic acid5 or an amino group, a systematic investigation of the factors influencing the formation of (acy1oxy)alkyl derivatives of amines was undertaken to determine which factors favored alkylation of the amine rather than acylation. The 3-halo-3-substituted and unsubstituted 1(3H)-isobenzofuranones were chosen for study as being representative of (acy1oxy)alkyl a-halides because the products (3) of their reactions with amines were perceived to be more stable6 and hence easier to isolate and quantitate than their acyclic counterparts. In addition, 3 could be prepared independently by the route mentioned above so their identities could be assured. Finally, although the reactions of aniline,"" methylaniline,12 and primary UGh, L. H.; Adams, R. J. Am. Chem. SOC. 1921,43,660. Bohme, H.; Bockhaus, P. Liebigs Ann. Chem. 1975,1790. Volz, H.;Ruchti, L. Liebigs Ann. Chem. 1977,33. Wheeler, D. D.; Young, D. C.; Erley, D. S. J. Org. Chem. 1957,22, (5)Sloan, K. B. European Patent 81 106277.7,Dec 1981. (6)Normal BAc2cleavage of the ester portion of an (acy1oxy)alkyl a-amine such as 3c would generate a nucleophile capable of causing an intramolecular-based recyclization of the ringopened species similar to that implicated in the ring closure of o-(hydroxymethy1)benzoatesto phthalide? and the hydrolysis of methyl o-formylbenzoate to le. Such intramolecular assistance to reversing the hydrolysis reaction is not possible with acyclic systems. (7)Cain, B. J. Org. Chem. 1976,41, 2029. (8)Bender, M.L.; Reinstein, J. A,; Silver, M. S.; Mikulak, R. J. Am. Chem. SOC. 1965,87,4545.
amines1'J3 with various 3-halo-1(3H)-isobenzofuranones have been reported, the reactions of secondary or tertiary amines15 with these 3-halophthalides have not been thoroughly investigated. The amines that were studied in these reactions were chosen to represent as wide a range of nucleophilicities as possible but with as similar steric requirements as could be obtained conveniently. Thus, on the basis of Pearson's ncH81 values in methanol,16we have assumed that the order of nucleophilicity is piperidine (ncHBI = 7.30) > pyrrolidine (nCHSI = 7.23) > imidazole (nCHII = 4.97). Methylaniline is between pyrrolidine and imidazole based on nCHd = 5.70 for aniline and nCH31 = 5.64 for dimethylaniline while morpholine is only somewhat less nucleophilic than either pyrrolidine or piperidine based on their reactions with 2,4-dinitrochlorobenzenein ethanol ( n = 5.29 vs. 5.59 and 5.67, respectively)." The leaving groups in the reactions that have been studied were chloride and iodide. It was felt that they represented sufficiently extreme ends of the leaving group spectrum to give a good idea of how the leaving group effected the product distribution. Acetone, an aprotic solvent, was chosen as the solvent in which to run the reactions to ensure SN2-typecharacter in reactions with a substrate that could also undergo SN1 reactions. The reason for this concern was that it was assumed that if the reaction became more SN1-like,the resultant intermediate would behave more like a carbenium ion, and MIND0/3 SCF MO calculations18on the carbenium ion generated from la indicated that significantly more positive charge resided on the 1-position than on the 3-position in such a carbenium Therefore, if the reaction was more SN1-like,there would be more acylated and less alkylated products formed because there would be more opportunity for the positive charge being (9)Halford, J. 0.; Weissmann, B. J. Org. Chem. 1952,17, 1646. (10)Pojer, P. M.;Ritchie, E.; Taylor, W. C. Aust. J . Chem. 1968,21, 1378. (11)Kubota, Y.; Tatauno, T. Chem. Pharm. Bull. 1971,19,1226. (12)Wawzonek, S.; Laitinen, H. A.; Kwiatkowslti,S. J. J. Am. Chem. SOC. 1944,66, 830. (13)The reaction of adenine with 5-bromo-4-ethyl-3-methyl-2(5H)furanone" should also be considered as a member of this type of reaction in spite of the unusual cyclic product obtained. (14)Doerr, I. L.; Willetts R. E. J. Org. Chem. 1973,22,3878. (15)Bodor, N.;Wood, R.; Raper, C.; Kearney, P.; Kaminski, J. J. J . Med. Chem. 1980,23,474. (16)Pearson, R. G.;Sobel, H.; Songstad, J. J. Am. Chem. SOC.1968, 90,319. (17)Hall, H.K. J. Org. Chem. 1964,29,3539. (18)Bingham, R. C.;Dewar, M. J. S.; Lo, D.H.J . Am. Chem. SOC. 1975,97,1285. (19)Bodor, N.,private communication, The University of Florida, Gainesville. FL.
0022-3263/83/ 1948-0635$01.50/0 0 1983 American Chemical Society
Sloan and Koch
636 J. Org. Chem., Vol. 48, No. 5, 1983 Scheme I1
Scheme I n
0
la
C-NRi 2 HNR;
la, R = H; X = C1
b, R = C,H,; X = C1 c, R = CH,; X = C1 d, R = H; X = I e, R = H ; X = OH f, R =CH,;X = OH
CH3N3
8a,
and/or
ocefane
R
-
R” =
C H a t N 3 : X=CI-
R”X
H
II
8
0 2a, R = H; NR’, = 4 b, R = H; NR’, = 5 c, R = H; NR’, = 6 d, R = H; NR’, = 7 e, R = H; NR‘, = NCH,C,H, f, R = C,H,; NR‘, = 6 g, R = CH,; NR’, = 6
same and no unusual reversal of reactivities or preferences for electrophilic sites should obscure the results.
Results and Discussion The reactions between hydroxyphthalide le and the secondary amines (Scheme I) all gave the corresponding 3 except for imidazole. The reaction with imidazole gave a salt that tentatively has been assigned as the imidazole salt of 2-formylbenzoic acid. Careful heating of the salt at 50 “C gave a mixture that appeared to contain some 3d by NMR spectroscopy and TLC, but it could not be iso3a, R = H; NR’, = 4 lated. Similarly, the reaction of I f with morpholine a t b, R = H; NR’, = 5 room temperature gave a mixture containing an unstable c, R = H; NR’, = 6 d, R = H; NR’, = 7 intermediate as a major product (80%) that was neither e, R H; NR’, = NCH,C,H, acylated product (by comparison of its NMR spectrum f, R = C,H, ; NR’, = 7 with that of 2g) nor alkylated product 3g on the basis of g, R = CH,;NR’, = 6 the chemical shift of its CH3C absorption (6 2.47). The 4 = - ~ ~ 5 = - ~ ~ 6 \;=Li - ~ ~ ~ =minor - ~product ~ ~ (20%) did contain a CH3C absorption (6 1.77) that a product such as 3g might be expected to exhibit. With time (3 days) a t room temperature the abgenerated a t the 3-position to redistribute to the 1-position sorption at 6 1.77 increased to represent 40% of the mixand hence more opportunity for the amine to react a t the ture while the absorption a t 6 2.47 decreased accordingly, 1-position to give acylated products. Thus, it was imand a small absorption (
