Effect of substituents and benzyne generating bases on the orientation to and reactivity of haloarynes

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Introduction
In Roberts' seminal paper 1 on substituent effects in benzyne chemistry, o-haloarenes possessing electron-attracting groups (-I) were shown to react with NaNH 2 in liquid ammonia to generate 3substituted arynes that undergo nucleophilic amination regioselectively at the 1-position to give meta substituted anilines.This conversion of an ortho substituted reactant to a meta substituted product, which is unique to benzyne chemistry, is known as cine substitution.Such substitutions have been used extensively in synthesis and as confirmation of the intermediacy of an aryne intermediate.The genesis of the regioselective addition to C-1 is probably due to the greater stabilization of the developing negative charge at the adjacent carbon (C-2) by the electron-attracting 3-substituent in the amination transition state as compared to that of the developing negative charge at the remote site (C-1) from the -I group.
With 4-substituted benzynes the situation is complicated because the inductive effect of substituents is less strong and other electronic effects may be operable.For example, Roberts observed that 3-and 4-substituted anilines were obtained in a ratio of about 1:1 from the amination of 4-methoxy-and 4-trifluoromethylbenzyne, whereas the amination of 4fluorobenzyne gave a 4:1 ratio of para to meta anilines. 1Shortly thereafter, Wotiz reported that ammonia added exclusively to the 1-position of 4-chlorobenzyne yielding an isomer-free 4chloroaniline. 2This surprising result, which is listed as one of the most widely cited reviews on benzyne chemistry, 3 if correct, would be the first example of a regioselective addition to a 4aryne.
Recently, 4-chlorofluorobenzene was reported to react with tert-BuLi to give 4chlorobenzyne to which benzonitrile added regioselectively to C-1 to give 2,8-dichloro-6phenylphenanthridine. 9We were intrigued not only with the reported regioselective addition to 4-chlorobenzyne, but also that fluoride ion was eliminated preferentially over chloride ion.This is opposite to what is observed when strong amide bases such as sodium amide or LDA are used to generate benzynes.Although tert-BuLi has been used to generate benzynes from fluoroarenes, to our knowledge, no study has been carried out on the orientation and reactivity of 4-haloarynes generated from p-fluorohaloarenes with tert-BuLi.

Results and Discussion
Before starting a detailed investigation on substituent effects in 4-arynes, we first repeated the reaction of 1,4-dichlorobenzene with NaNH 2 in liquid ammonia.Using a more accurate analytical method, i.e.GC/MS on the crude reaction mixture, we determined the product distribution of 4-chloroaniline and 3-chloroaniline to be 83:17, respectively which is very similar to that obtained by Sanguini who used a less accurate UV analytical method.
Interestingly, the reaction of 1-chloro-4-fluorobenzene (1a) with LDA also gave 4-chloro-N,N-diisopropylaniline (3b) in 22% yield, but none of the 3-chloroaniline product was found.This strongly argues that 3b was not formed from the benzyne intermediate 2b), but was formed by a S N AR reaction involving direct displacement of fluoride by LDA.Such a substitution pathway is consistent with the higher leaving group reactivity of F -as compared to Cl -and would explain the observed product distributions.
We attempted to trap the LDA-generated 4-haloarynes with furan in the anticipation of obtaining 6-halooxonorbornadienes.However, the yields of norbornadienes were severely compromised by the unavoidable amination side reaction.Encouraged by several reports on the use of t-BuLi to generate benzyne, [10][11][12][13][14] we treated the 4-chloro (1a)-, 4-bromo (1b)-, 4-fluoro (1c)-and 4-iodo (1f) derivatives of fluorobenzene with tert-BuLi in the presence of furan in THF.The reaction of 1b was first carried using the same reaction conditions as the LDA mediated ones.However as shown in eq. 1,

F Br
Eq. 1 when the mixture was initially stirred for 15 min at -70 °C before warming to room temperature, both 6-fluoro (5c) and 6-bromo (5b) derivatives of oxonorbornadiene as well as fluorobenzene (8) were obtained.A possible mechanism to account for these products is shown in Scheme 1.We subsequently found that excellent yields could be obtained by adding tert-BuLi to the 4halofluorobenzene at -78 °C and maintaining that temperature for 1h before allowing the reaction mixture to warm to room temperature.This allows the complete lithiation (deprotonation) of the 2-carbon which then is able to generate 4-halobenzynes with the absence of lithium-halogen exchange.These arynes were trapped by furan to give 6-chloro-(5a), 6bromo-(5b), and 6-fluoroxabenzonorbornadienes (5c) respectively in 85-98% yields as shown in Table 2. GC/MS analysis of the successful tert-BuLi crude reaction mixtures consisted of essentially one peak, which was easily identified as the product.No tert-butylated products were observed.The vastly increased yields of oxabenzonorbornadienes in the tert-BuLi mediated reactions as compared to the LDA-mediated reactions most likely reflects the larger steric bulk of tert-BuLi as compared to LDA.

Substrate
Benzyne Products A summary of the important features of the LDA and tert-BuLi results reported to here are: 1) without exception LDA adds to both positions of the isomeric 4-haloarynes, 2) deprotonation by tert-BuLi occurs at the carbon adjacent to the fluorine atom, and 3) LDA displaces the fluorine atom in 4-chloro-1-fluorobenzene most likely by a S N Ar mechanism.Now in the reported reaction of tert-BuLi with 4-chloro-1-fluoroaniline with benzonitrile, it was assumed that the product (10) was formed by regioselective addition to 4-chlorobenzyne, although no formal mechanism was shown.Actually, our results indicate it is quite possible that 4chlorobenzyne was not formed in that reaction but rather was the result of a non-arynic pathway shown in Scheme 2. As shown 2-lithiated 4-chloro-1-fluorobenzene derivative 11 adds to benzonitrile to give adduct 12 in which the resulting nitrogen anion adds in ipso fashion to the fluoro atom in 4fluoro-1-chlorobenzene affording carbanion 13.This is followed by intramolecular cyclization to the tricyclic carbanion 14 which loses HF and LiF to give 10.In support of a non-benzyne reaction, we repeated the phenanthrene synthesis in the presence of furan and failed to detect 5chlorooxonorbornadiene.
The reactions of a series of m-fluorohalobenzenes (1j-l) with tert-BuLi were carried out in the presence of furan in order to determine which 3-haloaryne would be formed.The results are shown in Table 3.As can be seen, the reaction of 1-bromo-3-fluorobenzene (1k) and 3-iodo-1fluorobenzene (1l) with tert-BuLi in THF (entries 2 and 3, respectively) yielded the same aryne, namely, 3-fluorobenzyne (2e) which subsequently reacted with furan to yield 5fluoroxobenzonorbornadiene (5e) in 67% and 92% yields, respectively.The reaction of 3-chloro-1-fluorobenzene (1j) in THF (entry 1) also proceeded predominantly via 3-fluorobenzyne (2e) predominantly to yield 5e (73% yield).In addition, a small amount of 5chloroxobenzonorbornadiene (5f) was obtained via 3-chlorobenzyne (2f).On the other hand, when the reaction of 1j was run in ether the 5-chloro derivative 5f was obtained in 72% yield and the 5-fluoro derivative 5e was obtained in only 11% yield.However, in the presence of 12crown-4 the ether reaction of 1f gave results similar to those found in THF, with the 5-fluoro derivative 5e being formed in 62% yield and the 5-chloro compound 5f in only 12% yield.fluorobenzene (16a) and 2-deutero-1-fluoro-3-iodobenzene (16b), respectively.Furthermore, addition of 12-crown-4 to the reaction slurry containing the salts afforded a clear solution which after stirring for 2 h gave 5e in 70% and 62% yields, respectively.A possible explanation for the regiochemistry observed in the reactions of 1j-l is shown in Scheme 3. The regiochemistry is dictated first and foremost by the acidities of the benzene hydrogen atoms.The most acidic hydrogen, which is the between the fluorine and the other halogen atom, is lost first in all cases; its loss would lead to the intermediates 15a-c.Intermediate 15a could decompose to give either 3-chlorobenzyne 2f, or 3-fluorobenzyne (2e), leading to 5chloro 5f or 5-fluoro 5e products.In the case of 15a the dissociative pathway predominates yielding 5e via 3-fluorobenzyne (2e).This pathway is favored due to the good leaving group abilities of the halide ions.In the case of 15a (X = Cl) reactions in THF, a small amount of 5f is also formed via 3-chlorobenzyne (2f) by the S N Ar solvent assisted pathway.This pathway is actually favored when the reaction is run in ether.However, with the use of 12-crown-4, the negative charge on the 2-lithio site is increased which perhaps decreases the ability of ether to assist in the S N Ar pathway.Intermediates 15b and 15c proceed by the dissociative pathway most likely due to the better leaving abilities of Br and I vs Cl.Finally, the reaction with 2-halo-1-fluorobenzenes (1m-o) and furan with tert-BuLi was carried out, with the results shown in Table 4.As might be expected, the fluorine atom was eliminated in each case yielding the appropriate 3-haloaryne (2e,j).However, benzyne (2i) was formed in each reaction (by the loss of FX) which subsequently reacted with furan giving 9oxonorbornadiene (5i).The formation of 2i most likely is the result of initial lithium exchange of Cl, Br, or I, respectively by tert-BuLi followed by loss of LiF.Consequently these reactions give mixtures of oxonorbornadiene which diminishes the use of 1,2-dihaloarenes in the synthesis of 5halo derivatives of oxonorbornadiene.In conclusion we have shown that 4-haloarynes generated from the reaction of 1,4dihaloarenes and LDA in THF give mixtures of m-and p-diisopropylamino products.In cases where the halogen atoms are different, the 4-aryne is formed by the loss of an HX containing the halogen with the better leaving group ability.On the other hand, 4-halo-1-fluorobenzenes lithiate exclusively at the carbon adjacent to the fluorine atom with tert-BuLi.These intermediates then eliminate fluoride ion to give 4-halobenzynes which are trapped by furan to give 5halooxonorbornadienes in excellent yields.1-Fluoro-2-halobenzenes behave similarly with tert-BuLi, with the exception that some oxynorbornadiene is formed by the reaction of furan with benzyne formed by an alternate lose of XF. 1-Fluoro-3-halobenzenes undergo lithiation at the carbon between the two halogen atoms.3-bromo-and 3-iodofluorobenzene, the 2-lithio intermediates proceed to give 5-fluorooxonorbornadiene when the reactions are run in THF.However when these reactions are carried out in ether the lithiated intermediates precipitate from solution and do not undergo benzyne formation.However, with the addition of 12-crown-4, the precipitates dissolve and proceed to give 5-fluorooxonorbornadiene.On other hand, the reaction of 3-chlorofluorobenzene gives predominantly 5-fluorooxonorbornadiene and a minor amount of 5-chlorooxonorbornadiene when the reactions are run in THF or ether/12-crown-4, while the reaction conducted in ether gives mainly 5-chlorooxonorbornadienes and minor amounts of 5fluorooxonorbornadiene.

Experimental Section
General Procedures.All reagents and solvents, unless otherwise specified were treated according to standard methods. 1 H NMR spectra were recorded in CDCl 3 at rt.Chemical shifts are given in parts per million relative to that of TMS as an internal standard.
General procedure for the LDA-mediated aryne reactions.A 50 mL flask was dried overnight at 150 °C in an oven and then cooled to rt under Ar atmosphere.Diisopropylamine (1.92 mL, 1.39 g, 13.7 mmol) and 20 mL of dry THF was added via syringe into the flask.The contents in the flask was cooled in a dry-ice bath with stirring to -70 °C.At -70 °C, n-BuLi (1.6M) in hexanes (8.2 mL, 13.7 mmol) was added and the resulting solution was stirred for 10 min.Then the appropriate dihalobenzene 1 (4.5 mmol) was added via syringe and stirred for 30 min at -70 °C.The dry-ice acetone bath was removed and the reaction mixture was allowed to warm to rt, where it was stirred an additional 3 h.The reaction mixture was quenched with 5 mL of water, diluted with 75 mL of ethyl acetate, and washed with water (3 X 200 mL) then with brine (50 mL).After the solution was dried (Na 2 SO 4 ), it was filtered and the mother liquor was concentrated (rotatory evaporator).The resulting crude product was then subjected to GC/MS and 1 H NMR analysis in order to access product distributions of 4-halo-(3) and 3haloanilines (4).

Table 1 .a
Scheme 1 mixture in which no halooxonorbornadienes were detected.

Scheme 2 .
Scheme 2. Possible mechanism for the formation of compound 10.