Exchange reactions with phenyllithium. V. Behavior of the halogenated anisoles toward phenyllithium.

Abstract

It has been found (C. A. 32, 9074.6) that anisole with PhLi in ether at 100° exchanges its o-H for Li, and that p-BrC6H4OMe reacts in the same way even in the cold, whereas with halogen in the o-position the reaction is entirely different. Thus, in m-C6H4(OH)2 Li replaces the H between the MeO groups, but in 2,4-(MeO)2C6H3Br the expected H-Li exchange does not occur and it is the Br which is immediately and completely replaced. It seemed worthwhile to investigate this smooth replacement of a strongly electroneg. by a pronouncedly electropos. substituent on the 4 o-haloanisoles and the corresponding m- and p-isomers. o-Haloanisoles. When equiv. solns. of o-IC6H4OMe and PhLi in ether are mixed and decompd. after 2 min. with water there is formed about 90% of PhOMe and of PhI; treatment of the reaction mixt. with Ph2CO instead of H2O also gives about 90% of o-MeOC6H4C(OH)Ph2. The reaction therefore proceeds according to the equation o-MeOC6H4I + PhLi → o-MeOC6H4Li + PhI. o-BrC6H4OMe reacts in the same way but more slowly (90% reaction in 1 h. at room temp.). o-ClC6H4OMe, on the other hand, is recovered for the most part (90%) unchanged after 20 h. The remaining 10% reacts according to the equation o-MeOC6H4Cl + PhLi → o-MeOC6H4Ph + LiCl. Replacement of H in the o-position to the MeO (or to the Cl) by Li, if it occurs at all, must be very slight, for on treatment of the reaction mixt. with Ph2CO, Ph3COH was the only carbinol which could be isolated. o-FC6H4OMe behaves like the Cl compd.; after 20 h. reaction hydrolysis gives 25% o-MeOC6H4Ph, together with an ill-defined resin, and 45% unchanged FC6H4OMe. In the o-haloanisoles, therefore, I is rapidly, Br more slowly, replaced by Li, while Cl and F (F more rapidly than Cl) combine with the Li to give LiX, with concomitant formation of o-MeOC6H4Ph. m-Haloanisoles. The reaction, which is more rapid than with the o-compds., was allowed to proceed only 5 h. Unless otherwise stated, all expts. were run in 0.5 N solns. at 15-20°. With m-IC6H4OMe the course of the reaction was complicated. Hydrolysis gave 40% PhI and about 25% m-MeOC6H4Ph (I) and a considerable amt. of resin. Treatment with Ph2CO gave carbinols from which, by treatment with AcOH and fractional crystn. from cyclohexane, were isolated 1-methoxy- (II), m. 180.5-1.0°, and 1,5-(or 1,8)-dimethoxy-9,9-diphenylfluorene (III), m. 201-2°. 2(or 4)-Br deriv. of II, from II and Br in boiling AcOH, m. 222.5-3°. II, but not III, was also obtained from the other 3 m-haloanisoles; when the reaction mixt. was worked up in MeOH instead of AcOH there was obtained, instead of II, the tritanol, 6,2-Ph(MeO)C6H3C(OH)Ph2 (IV), which in boiling AcOH imparted a transient dark brown color to the solvent (halochromism) and was converted into II. II is therefore formed according to the reactions 6,2-Ph(MeO)C6H3Li (V) + Ph2CO → IV (+ AcOH) → II. To det. whether V is formed from 6,2-X(MeO)C6H3Li (VI) + PhLi or whether the non-metalized m-XC6H4OMe gives I with PhLi and I then yields V with PhLi, I was treated under the same conditions with PhLi and then with Ph2CO. There was obtained, in addn. to unchanged I, 10% of a carbinol, sol. unchanged in boiling AcOH or concd. H2SO4 with cherry-red color, and which, from its compn. and properties, may be assumed to be 4,2-Ph(MeO)C6H3C(OH)Ph2, formed from I and 4,2-Ph(MeO)C6H3Li. Since the metalation of I gives not the o- but exclusively the p-biphenyllithium deriv., the possibility that V is formed in this way is excluded. Hence, in the formation of V, the Li must have entered the anisyl residue before the formation of I; PhLi first metalates the m-XC6H4OMe between the MeO and X and then combines with the resulting VI to form V. The formation of III from m-IC6H4OMe can be explained by combination of m-MeOC6H4Li (formed by Li-I exchange) with VI to give 2,6-MeO(3-MeOC6H4)C6H3Li, which with Ph2CO gives III. The reactions of m-IC6H4OMe lead to the conclusion, therefore, that it exchanges both I and H for Li in concurrent primary reactions. The reaction with m-BrC6H4OMe is simpler. After hydrolysis there were obtained 55% I and 20% unchanged m-BrC6H4OMe. With Ph2CO instead of H2O, the reaction mixt. yielded, besides 20% unchanged BrC6H4OMe, only 35% IV. In m-BrC6H4OMe, therefore, the H between the Br and MeO groups is replaced by Li and the Br in the resulting VI is so activated by the adjacent Li that it reacts further with PhLi to form V and LiBr. That, along with the 15% V (isolated as II), 35% non-metalated I was still isolated can be explained by assuming that V, concurrently with PhLi, metalates the m-BrC6H4OMe: V + m-BrC6H4OMe → I + VI. The relationships are therefore the same as in the formation of Ph2 from PhF and PhLi (part IV above); a prerequisite of biphenyl and LiX formation is replacement by Li of the H in the o-position to the halogen. m-ClC6H4OMe behaves entirely like the Br compd. Along with 35% I there is obtained about 15% II. m-FC6H4OMe, which reacts more rapidly than the other m-haloanisoles, gives after 5 h. under the usual conditions in greater part (about 80%) an ill-defined light yellow resin. Under milder conditions (1 h. at 0°) there were obtained, along with resinous products, about 30% II and a carbinol, m. 156.2-6.8°, believed to be 2-methoxy-6-fluorotritanol. In the m-haloanisoles, then, the H between the halogen and the MeO groups is readily replaced by Li and the formation of I and LiX predominates, whereas the halogen-Li exchange is subordinate and was obsd. only with the I compd. p-Haloanisoles. With the generally more slowly reacting p-compds. the reaction was allowed to proceed 20 h. p-IC6H4OMe gave 35% of PhI and of PhOMe, and 40% was metalated, giving with Ph2CO 5-iodo-2-methoxytritanol, m. 136-7°. With p-BrC6H4OMe the halogen-metal exchange (10%) was repressed in favor of the replacement of the H in the o-position to the MeO (60%). p-ClC6H4OMe gave 75% 5,2-Cl(MeO)C6H3Li. p-FC6H4OMe (VII) yielded 30% 5,2-F(MeO)C6H3Li (isolated as 5-fluoro-2-methoxytritanol, m. 129.5-31°, sol. in concd. H2SO4 with green color), and 50% p-MeOC6H4Ph. Here the combination of Li and F to form LiF competes on equal terms with the replacement of the o-H to the MeO group by Li. As the formation of Ph2 from PhF and PhLi can be shown to proceed through o-FC6H4Li, the reaction of VII can be represented by the equations VII + PhLi → 5,2-F(MeO)C6H3Li and VII + PhLi → 2,5-F(MeO)C6H3Li + PhLi → 2,5-Ph(MeO)C6H3Li. Common to the p-haloanisoles, then, is the metalation of "labile" H, which is favored by increasing electronegativity of the halogen. The results are discussed from the standpoint of the theory of induced alternating polarities (cf. C. A. 32, 9074.6, and part IV above). Addendum. Reaction of some non-halogenated anisole derivs. with PhLi. I (from m-HOC6H4Ph and Me2SO4), treated 20 h. with 1 equiv. PhLi in ether and then with Ph2CO, gave 13% 2-methoxy-4-phenyltritanol, m. 138.5-9.5°, sol. in concd. H2SO4 with permanent cherry-red color. Veratrole after 60 h. yielded 67% 2,3-dimethoxytritanol (VIII), m. 110-11.5°, imparting brown-red halochromism to concd. H2SO4; in a 2nd expt., there were obtained from 6.9 g. veratrole after only 5 h. 3.1 g. unchanged veratrole, 3.0 g. Ph3COH and 7.8 g. VIII (49%). 1,2,3-C6H3(OMe)3 in 16 h. gave 5,6-(MeO)2C6H3OH (isolated as the benzoate (1.5 g.), m. 114-15°), 1.4 g. unchanged C6H3(OMe)3, 1.5 g. Ph3COH and 0.5 g. 2,3,4-(MeO)3C6H2C(OH)Ph2, m. 140-0.8°. 2,3,5-C6H3(OMe)3 after 60 h. gave 86%, after 5 h. 67%, of 2,4,6-(MeO)3C6H2C(OH)Ph2, m. 114-15°. [on SciFinder(R)]