Functionalizations of Mixtures of Regioisomeric Aryllithium Compounds by Selective Trapping with Dichlorozirconocene.

The reaction of mixtures of aryllithium regioisomers obtained either by directed lithiation or by Br/Li exchange with substoichiometric amounts of Cp2ZrCl2 proceeds with high regioselectivity. The least sterically hindered regioisomeric aryllithium is selectively transmetalated to the corresponding arylzirconium species leaving the more hindered aryllithium ready for various reactions with electrophiles. As an application, these regioselective transmetalations from Li to Zr were used to prepare all three lithiated regioisomers of 1,3-bis(trifluoromethyl)benzene.

Organolithium compounds are important organometallic intermediates in organic synthesis.1 The most convenient preparation of aryllithiums involves a halogen–lithium exchange or a directed metalation.2 The presence of a directing group usually ensures lithiation at the ortho‐position; however, in cases where unsymmetrical substrates of type 1 are used, a mixture of regioisomeric aryllithiums 2 and 3 may be produced.3 The formation of such mixtures hampers synthetic applications. This lack of regioselectivity could potentially be solved by a preferential transmetalation of one of two regioisomers 2 and 3. Therefore, we envisioned that a selective transmetalation of the less sterically hindered aryllithium 3 with an appropriate metal salt (M‐X) may selectively produce the new metalated arene 4 leaving the more sterically hindered aryllithium (2) untouched and therefore available for a reaction with an electrophile (E1+) leading to the 1,2,3‐trisubstituted arenes of type 5. On the other hand, in the organometallic species (4), produced after the transmetalation step, the carbon–metal bond should be significantly less reactive than the carbon–lithium bond in 2 and may thus be trapped by a second and different electrophile (E2+) producing the regioisomeric 1,3,6‐trisubstituted arene of type 6 (Scheme 1).

Scheme 1

Nonselective metalation of unsymmetrical arenes followed by selective transmetalation.

Herein, we report a successful method for solving the regioselectivity problem in such arene lithiations. Preliminary experiments for identifying an appropriate metal salt (M‐X) to perform selective transmetalations were performed on 1:1 mixtures of 2,6‐dimethylphenyllithium (7) and 3,5‐dimethylphenyllithium (8) and showed that reactions with various Zn, Mg, Cu, Ti, and Sn salts gave no selective transmetalation. However, Cp2ZrCl2 4 reacted preferentially with 3,5‐dimethylphenyllithium 8 leaving 7 untouched and ready for a selective reaction with an electrophile (Scheme 2). Only the less sterically hindered aryllithium 8 reacts with Cp2ZrCl2 leading to a less reactive diarylzirconium species (A). These encouraging results led us to examine the lithiation of various substrates of type 1. Since oxazolines are important directing groups for ortho‐lithiations, we first examined the lithiation of the 3‐thiomethylaryloxazoline (9).5 Thus, the lithiation of 9 with nBuLi–TMEDA (1.1 equiv, −80 °C, 3 h) produces a 4:1 mixture of the regioisomeric 2‐ and 6‐lithio derivatives as shown by iodolysis. Addition of Cp2ZrCl2 (0.2 equiv, −80 °C, 1 h) achieved a completely selective transmetalation of the sterically less hindered 6‐lithio derivative of 9, providing the zirconium species (11) and leaving the lithiated arene (10 a) untouched. Thus, treatment of a mixture of 10 a and 11 with MeSSMe (0.8 equiv, −80 °C, 1 h) produces only the trisubstituted arene (12 a) in 84 % yield.6, 7 Similarly, the addition of PhCHO (0.8 equiv, −80 °C, 1 h) affords alcohol (12 b) in 88 % yield and quenching with 4‐chlorobenzoyl chloride provides ketone 12 c in 68 % yield (Scheme 3).

Scheme 2

Chemoselective transmetalation using Cp2ZrCl2.

Scheme 3

Regioselective functionalization of oxazoline (9). Conditions: nBuLi (1.1 equiv), TMEDA (1.1 equiv); 2) Cp2ZrCl2 (0.2 equiv); 3) E1 (0.8 equiv); 4) H2O.

We then extended our study to unsymmetrical arenes 13–16 (Table 1). Thus, the methoxy‐substituted oxazoline 13 produces after lithiation with nBuLi–TMEDA (1.1 equiv, −80 °C, 3 h) a 93:7 mixture. 1,3‐Dicyanobenzene (14) affords, after metalation with TMPLi (TMP=2,2,6,6‐tetramethylpiperidyl; 1.05 equiv, −80 °C, 0.5 h), an 85:15 mixture; the reaction of benzonitrile 15 with TMPLi (1.0 equiv, −80 °C, 20 min) gives a 60:40 mixture. Alkynylbenzene 16 also furnishes an 80:20 mixture after lithiation with TMPLi (1.0–1.1 equiv, −80 °C, 0.5 h). Treatment of these aryllithium mixtures with the appropriate amount of Cp2ZrCl2 allows selective transmetalation of the less sterically hindered aryllithium providing a less reactive arylzirconium species and leaving the major aryllithium reagent ready to react with various electrophiles producing >97% regioisomerically pure products of type 17–20. In a typical experiment, the lithiated aryloxazolines derived from 13 were treated with Cp2ZrCl2 (0.1 equiv, −80 °C, 1 h) followed by the addition of ethyl chloroformate (0.9 equiv, −80 °C, 1 h) providing the 2‐carbomethoxy arene (17 a) in 85 % yield free of any regioisomeric by‐product. Similarly addition of BuSSBu led to the production of thioether 17 b in 83 % yield. The 85:15 mixture of lithiated 14 was similarly treated with Cp2ZrCl2 (0.15 equiv, −80 °C, 0.5 h) followed by various electrophiles ((pTolS)2, (BrCCl2)2, TMSCl), furnishing regioisomerically pure 1,2,3‐trisubstituted dinitriles 18 a–c in 66–75 % yield (entries 3–5). The same strategy was applied to arene 15. After the addition of Cp2ZrCl2 (0.35–0.4 equiv, −80 °C, 0.5 h), the more sterically hindered 3‐lithio isomer reacted with various electrophiles (furfural, (ICH2)2, or cyclopropanecarbonyl chloride in the presence of 10 % Sc(OTf)3 8) producing the regioisomerically pure products (crude ratio 97:3) 19 a–c in 61–78 % yield (entries 6–8). Also, the unselective lithiation of 16 leads, after the addition of Cp2ZrCl2 (0.25 equiv, −80 °C, 0.5 h) and various electrophiles (cyclohexyl isocyanate, iPrOBpin, 4‐chlorobenzaldehyde, furfural, (ICH2)2, (BrCCl2)2, MeSSMe, 2,4‐dichlorobenzoyl chloride), to isomerically pure products (20 a–h) in 72–95 % yield (entries 9–16).

Table 1

Regioselective functionalization of unsymmetric arenes.

Entry	Substrate	Electrophile	Product[a]
1	13	ClCO2Et	17 a: E1=CO2Et, 85 %
2	13	BuSSBu	17 b: E1=SBu, 83 %
3	14	(pTolS)2	18 a: E1=SpTol, 73 %
4	14	(BrCCl2)2	18 b: E1=Br, 75 %
5	14	TMSCl	18 c: E1=TMS, 66 %
6	15		19 a: E1=CH(OH)2‐furyl, 75 %
7	15	(ICH2)2	19 b: E1=I, 78 %
8	15		19 c: E1=COcPr, 61 %[b]
9	16	cHexNCO	20 a: E1=CONHcHex, 85 %
10	16	iPrOBpin	20 b: E1=Bpin, 90 %
11	16	4‐ClC6H4CHO	20 c: E1=CH(OH)4‐ClC6H4, 79 %
12	16		20 d: E1=CH(OH)2‐furyl, 95 %
13	16	(ICH2)2	20 e: E1=I, 74 %
14	16	(BrCCl2)2	20 f: E1=Br, 72 %
15	16	MeSSMe	20 g: E1=SMe, 87 %
16	16		20 h: 77 %

[a] Yield of analytically pure product (>99 %). [b] Sc(OTf)3 was added.

This methodology was also successfully applied to regioisomeric mixtures of aryllithiums obtained by Br/Li exchange (Scheme 4). Indeed, dibromobiphenyl 21 undergoes a nonregioselective Br/Li exchange with nBuLi (THF, 1.05 equiv, −80 °C, 0.5 h) producing a 70:30 mixture of isomers 22 a and 22 b. The addition of Cp2ZrCl2 (0.15 equiv, −80 °C, 1.5–2 h) led to a selective transmetalation (>97:3) of the less sterically hindered aryllithium (22 b), providing the bis‐aryl zirconocene (23) and unreacted 22 a. Functionalization of 22 a with a range of electrophiles (4‐methoxybenzaldehyde, 4‐chlorobenzoyl chloride, phenyl isocyanate, ethyl cyanoformate) produces the corresponding products (24 a–d) in 68–83 % yield. The remaining diarylzirconocene (23) was converted back to the starting dibromide 21 in 60–75 % yield by adding bromine.9

Scheme 4

Regioselective functionalization of dibromobiphenyl (21). Conditions: i) nBuLi (1.05 equiv), ii) Cp2ZrCl2 (0.15 equiv), iii) E1 (0.70–0.75 equiv), iv) Br2 (excess). All products obtained in >97:3 regioisomeric ratio.

Interestingly, the related 2,5‐dibromotoluene (25) also undergoes an unselective Br/Li exchange with nBuLi (THF, 1 equiv, −80 °C, 0.5 h) producing a 30:70 mixture of the two regioisomeric lithium species 26 a and 26 b (Scheme 5). The major regioisomer (26 b) is converted into the corresponding diarylzirconocene (27) upon addition of Cp2ZrCl2 (0.3 equiv, −80 °C, 1.5 h). Quenching of the aryllithium 26 a with (BrCH2)2 or 4‐MeOC6H4CHO (0.4–0.45 equiv, −80 °C, 0.5–1 h) generates the starting material (25) or the corresponding alcohol 28, leaving the zirconocene species 27 untouched. Further allylation, acylation, 1,4‐addition, and cross‐coupling allows functionalization of the zirconocene 27 providing the expected products (29 a–d) in 73–79 % yield.

Scheme 5

Regioselective functionalization of 2,5‐dibromotoluene (25). Conditions: i) nBuLi (1.0 equiv), ii) Cp2ZrCl2 (0.3 equiv), iii) (BrCH2)2 or ArCHO (0.40–0.45 equiv), iv) E2 (0.45–0.55 equiv). All products obtained in >97:3 regioisomeric ratio.

CF3‐substituted aromatics are very important pharmaceutical targets and much recent work on the selective preparation of CF3‐substituted molecules has been reported.10 The lithiation of 1,3‐bis(trifluoromethyl)benzene (30) proceeds without any appreciable regiocontrol.11 Thus, metalation with nBuLi in THF produces a 40:60 mixture of the 2‐ and 4‐lithio derivatives 31 a and 31 b. Alternatively, the use of tBuLi in ether leads to a 40:60 mixture of the 4‐ and 5‐lithio derivatives 31 b and 31 c (Scheme 6). The production of regioisomeric mixtures makes these lithiations preparatively useless. However, using the zirconium transmetalation, it was possible to regioselectively functionalize the three positions of 30. Selective lithiation at position 2 is reached by treating 30 with nBuLi (THF, 1 equiv, −40 °C, 1 h), followed by subsequent addition of Cp2ZrCl2 (0.7 equiv, −80 °C, 1.5 h); 31 b is converted into the corresponding zirconium species leaving 31 a as the sole remaining lithiated reagent. Its reaction with different electrophiles (4‐MeOC6H4CHO, and (ICH2)2) furnishes the corresponding products 32 a and 32  b in 81 and 50 % yield, respectively (Scheme 7). The selective functionalization at position 4 is possible using tBuLi (Et2O, 1 equiv, −40 °C, 18 h) followed by the addition of Cp2ZrCl2 (0.3 equiv, −80 °C, 1–1.5 h) to the 40:60 mixture of 31 b and 31 c. In this case, 31 c is transmetalated into the corresponding zirconium species and the lithium reagent (31 b) is quenched with various electrophiles: (2‐PyrS)2, 3‐bromobenzoyl chloride leading to 33 a and 33 b with 68 and 69 % yield, respectively. On the other hand, lithiation with tBuLi in ether has been also used to functionalize the position 5, but in this case the mixture of 31 b and 31 c was treated with Cp2ZrCl2 (0.3 equiv, −80 °C, 1.5 h) followed by the addition of 4‐MeOC6H4CHO (0.5 equiv, −80 °C, 1 h), which reacted exclusively with the lithio species (31 b). The zirconium species reacted with subsequently introduced electrophiles (4‐chlorobenzoyl chloride, ethyl 4‐iodobenzoate) to produce the products 34 a and 34 b in 92 and 79 % yield, respectively.

Scheme 6

Unselective 2‐, 4‐, or 5‐lithiation of 1,3‐bis(trifluoromethyl)benzene (30).

Scheme 7

Selective 2‐, 4‐, or 5‐functionalization of 1,3‐bis(trifluoromethyl)benzene (30).

In conclusion, we have demonstrated that the regioselective transmetalation of isomeric mixtures of various aryllithiums can be readily achieved using a substoichiometric amount of Cp2ZrCl2 as the transmetalating agent. This selectivity is best explained by steric considerations. This method allows the selective differentiation of a mixture of regioisomeric aryllithiums.

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