Astruc D. - Modern arene chemistry (2002)(en)

11.2 Ipso Nucleophilic Aromatic Substitutions 383

Scheme 25. Ipso SNAr: CaN bond formation.

Optically active Cr-complexed arylphosphines 57 can be prepared in three steps from achiral arene-Cr(CO)3 precursors 56. A successful addition of PPh2Li to the complex 56a with concomitant carbamate displacement has been suggested, giving rise to the desired phosphine complex 57a as an air-stable crystalline solid in 96 % yield (R ¼ H) (Scheme 26). Therefore, e cient CaP bond construction can be achieved by reacting, for example, the biaryl complex 56b with PPh2Li, providing the optically active monophosphine ligand 57b in 87 % yield, which has been used in Pd-catalyzed allylic alkylation reactions (Scheme 26) [42].

Scheme 26. Ipso SNAr: CaP bond formation.

11.2.3

Carbon–Carbon Bond Formation (Table 3)

In this section, we examine ipso substitutions of leaving groups such as halides, phenoxides, and alkoxides by carbanions. They are presented in chronological order in accordance with Table 3.

Highly stabilized carbanions (e.g., a-cyano, a-alkoxycarbonyl carbanions, etc.) react with fluoroor chlorobenzenetricarbonylchromium derivatives by substitution of the halides, even at room temperature [1c]. The authors excluded a pathway involving a transient aryne because the reaction of isobutyronitrile carbanion with p-chlorotoluenetricarbonylchromium complex 14c produces a single p-tolylisobutyronitrile complex 14d (Scheme 27). The same conclusion has been reported for the reactions of the chlorobenzene complex with O and N nucleophiles [43, 44]. Thus, additions of tertiary carbanions of ethylisobutyric ester, isobutyronitrile, and cyanohydrin to chlorobenzenetricarbonylchromium complex 1b a ord the corresponding ipso complexes 3a–c in good yields. These can be oxidized by iodine to produce the free arenes substituted by the nucleophile Nu (Nu ¼ -CMe2CO2Et, -CMe2CN, -COPh) in yields of 85 %, 71 %, and 88 %, respectively. Additions of LiCH(CO2Me)2 and LiC(SR)(CH3)CO2Me to the fluorobenzene complex 1a yield the ipso adducts 3d and 3e, respectively, in yields of 95 % and 94 % [45] (Scheme 27). It is worthy of note that several car-

384 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

Tab. 3. Ipso nucleophilic aromatic substitution of arenetricarbonylchromium complexes: CaC bond formation.

Entry	Arene	Nucleophile	Ref., Year
1	C6H5F, Cl	O, N nucleophiles	43, 1966
2	p-MeC6H4Cl	O, N nucleophiles	44, 1968
3	C6H5F, Cl	LiCMe2CO2Et	45, 1974
		Stabilized carbanions
4	C6H5OPh	LiCMe2CN, LiCMe2CO2tBu	46, 1987
5	1,2-C6H4Cl2	Stabilized carbanions	23, 1988
		Phase-transfer conditions
6	methoxy-estra-1,3,5(10)-triene	LiCH2CN	47, 1988
7	C6H5F	Cyclopentadienylanion	48, 1989
8	C6H5F	Imino esters	49, 1989
9	o,m, p-MeC6H4F	Imino nitriles, esters	51, 1990
10	C6H5F	Imino esters	50, 1991
11	o,m, p-MeC6H4F	Imino nitriles, esters	52, 1991
12	p-Me-C6H4F	LiCMe2CN, double nucleophilic	54, 1991
		substitutions
13	p-C6H4F2	LiC2B10H10Me	54, 1992
14	veratrole derivative	ArMgX	56a, 1996
15	p-MeC6H4X	Cyclopentadienyl anion	57, 1997
16	1,2,3-trimethoxybenzene	LiCMe2CN	58, 1997
17	C6H5Cl	N,N-dimethylhydrazone	59, 1997
18	o-CF3C6H4Cl	PhCH(CN)Li	60, 1999
19	veratrole derivative	ArMgX	56b, 2000

banions fail to react with halogeno complexes. Indeed, LiCH2CMe2CO2Me, LiCH2COCMe3, LiCH2CN, LiCCH, and 2-lithio-1,3-dithiane e ectively give complexes 2b–d, but isomerization to 2a is di cult due to a high associated energy barrier (Scheme 2). Indirect evidence of this has been obtained by adding I2 to a mixture of isobutyronitrile carbanion and chlorobenzene complex at 0 C; no chlorobenzene was detected, in good agreement with a complete conversion of complex 1b. Free arenes corresponding to o- and m- chlorophenylisobutyronitriles 14e were isolated in yields of 2 % and 56 %, respectively [45b]. The ipso complex 3b was recovered in 19 % yield (Scheme 27). Thus, the initial attack of the nucleophile at low temperature occurs preferentially at the meta position, and then the course of the reaction depends on the reversibility of the initial addition, which, in turn, depends on the reactivity of the carbanion. For example, NaCH(CO2Et)2 adds reversibly, whereas the more reactive carbanions 2-methyl-1,3-dithianyl and CH2CN add irreversibly at the ortho and meta positions; ipso substitution no longer occurs. It is shown below that there is a possibility of losing the halide by protonation of the h5-cyclohexadienyl anionic intermediate, which promotes the elimination of HX.

11.2 Ipso Nucleophilic Aromatic Substitutions 385

Scheme 27. Ipso SNAr: CaC bond formation.

Treatment of the o-methyl diphenyl ether complex 58a with isobutyronitrile carbanion at78 C and then allowing the reaction mixture to warm up to room temperature a ords the ipso complex 59a almost quantitatively. Ipso SNAr of the phenoxy group also occurs with acetonitrile, propionitrile, and alkoxycarbonyl carbanions (Scheme 28) [46]. Similarly, addition of isobutyronitrile carbanion to 2,3-dimethyl diphenyl ether complex 58b gives exclusively complex 59b under the same experimental conditions.

Scheme 28. Ipso SNAr: CaC bond formation.

The o-, m-, and p-dichlorobenzenetricarbonylchromium complexes 18a–c react with stabilized carbanions LiCHRR1 (R ¼ Ph, CO2Et; R1 ¼ CN, CO2Et) both under phase-transfer conditions and in DMSO solution. Only one chloro substituent is replaced by the carbanion. In all cases, the intermediates are not isolated but are directly oxidized with iodine. Shorter reaction times and/or lower reaction temperatures are required in DMSO. It is possible to replace the second chloro substituent of the o- and p-dichloro regioisomers with a di erent nucleophile such as nBuS or CH(CN)CO2Et [23].

Nucleophilic attack by the lithium anion of acetonitrile has been extended to Cr complexes of ring A aromatic steroids, thereby allowing access to more elaborate derivatives. For example, the diastereomeric tricarbonylchromium complexes of 17b-(tert-butyldimethylsily- loxy)-3-methoxyestra-1,3,5-triene 60a give the corresponding ipso 3-cyanomethyl complexes 60b after displacement of the methoxide group. The free arene was obtained in 46 % yield after I2 oxidation (Scheme 29) [47].

Cyclic anions, such as the cyclopentadienyl anion, in ethereal solvents at 0 C, can substitute the fluoride of fluorobenzenetricarbonylchromium complex 1a, thereby generating

386 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

Scheme 29. Ipso SNAr: CaC bond formation.

phenylcyclopentadiene complexes 3g and 3h in good yields [48] (Scheme 29). Phenylation of indenyl, fluorenyl, 2,4-dimethyl-1,3-pentadienyl, and 1,10,5,50-tetramethyl-1,3-pentadienyl carbanions can be similarly achieved in an ipso SNAr fashion.

A synthesis of a-arylamino acids has been reported using Schi -base anions 61 derived from amino esters, which are arylated with fluorobenzene complex 1a to give a-aryl imino esters 62 in 48–76 % yield (R ¼ H, Me, CH2Ph) [49]. Using the same procedure, these authors reported a convenient synthesis of optically pure a-aryl amino acid precursors 64 by enantioselective substitution of fluorobenzene complex 1a using the Schi base of l-alanine methyl ester with (1R,2R,5R)-2-hydroxy-3-pinanone 63 in the presence of LDA (Scheme 30) [50].

Scheme 30. Ipso SNAr: CaC bond formation.

11.2 Ipso Nucleophilic Aromatic Substitutions 387

Similarly, the addition of a-imino esters or nitriles to o-, m-, and p-fluorotoluene complexes 22a–c gives a-substituted arylimino esters or nitriles by fluoride displacement. For example, addition of the Schi -base anions LiCH(NbCPh2)Y (Y ¼ CO2Me, CN) in THF containing HMPA (5 equiv.) to a solution of the o-fluorotoluene complex 22a at 78 C, followed by allowing the mixture to warm to room temperature for 24 h, gives complexes 65a,b and 65c,d in 45 % yield (Scheme 29). 1H NMR data indicate that the two diastereomers 65a (1S,7S) and 65b ð1S,7RÞ are obtained in a 1:1 ratio [51]. It is worthy of note that these diastereomers can be separated by column chromatography on silica gel. The X-ray structure of complex 65a L couple [(1S)(7S),(1R)(7R)] shows that the H6 proton is almost eclipsed by a CraCO bond [52]. In solution, 1H NMR data of this (1S)(7S) diastereomer indicate that the H6 proton resonates at low field (d ¼ 6:4), indicating a similar conformation in solution and in the solid state [53]. The H6 proton of the U couple resonates at higher field, at d ¼ 5:93. The addition of 2-methyl iminoester (Z ¼ Me) also gives a mixture of two diastereomers, in the ratio L:U ¼ 80:20. In this case, the chemical shift di erence between the two H6 protons amounts to 0.91 ppm!

The addition of two nucleophiles to a coordinated h6-arene is a synthetically important goal. A ‘‘one-pot’’ synthesis of 1,3-disubstituted cyclohexadienes involving an initial ipso addition to fluoroarene complexes is possible. Indeed, p-fluorotoluenetricarbonylchromium complex 22c reacts with isobutyronitrile carbanion (2 equiv.) in THF to give, after 5 days at30 C and acidic treatment under CO atmosphere, the cyclohexadiene 66 in 47 % yield (Scheme 31) [53]; the yield can reach 75 % after several weeks! Carbon monoxide was used in order to decoordinate the h4-cyclohexadiene intermediate and to recover Cr(CO)6 needed for the preparation of the starting material [54].

Scheme 31. Double functionalization of an arene.

Carbon–boron clusters (‘‘carboranes’’) have been shown to react with Cr-coordinated haloarenes. For example, reaction of 2 equiv. of LiC2B10H10(CH3) with para-difluorobenzene- tricarbonylchromium complex in refluxing THF results in the displacement of both fluoride substituents from the arene ring to yield the para-phenylene compound, albeit in just 9 % yield owing to the e ect of the steric bulk of the carborane [55].

Axially chiral biaryls have been diastereoselectively synthesized by means of ipso substitution of the methoxide group of 2,4,6-trimethylphenyl-2-methoxybenzoatetricarbonylchro- mium complex with aryl Grignard reagents [56]. Thus, the reaction of veratrole derivative 67 with o-tolylmagnesium bromide leads to a diastereomeric mixture of anisole complexes 68a and 68b in 68 % yield and in a 98:2 ratio (Scheme 32). The most plausible reaction mechanism accounting for the high diastereoselectivity would require predominant Grignard approach from the exo side with respect to the Cr(CO)3 tripod [56].

388 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

Scheme 32. Ipso SNAr: CaC bond formation.

The complex 3-[(h6-4-toluene)tricarbonylchromium]indene (69) is obtained in 69 % yield from the ipso nucleophilic substitution of (h6-p-fluorotoluene)tricarbonylchromium complex 22c with indenyllithium (70) [57]. A 1,3-shift of the benzylic proton probably takes place after the ipso addition of indenyllithium (Scheme 33).

Scheme 33. Ipso SNAr: CaC bond formation.

The following examples show interesting reactions in which CaC bonds are simultaneously created by both ipso and tele-meta substitutions (the latter is discussed in Section 11.3). Treatment of (h6-1,2,3-trimethoxybenzene) (71) with the acetonitrile carbanion in THF and then with trifluoroacetic acid leads to a mixture of complexes 72 and 73 in yields of 42 % and 22 %, respectively. The expected formation of complex 72 involves a tele-meta substitution of the MeO group, whereas complex 73 is formed irreversibly, even at 78 C, through an ipso SNAr at the eclipsed C3 carbon, which is somewhat unexpected under these experimental conditions. Treatment of complex 71 with nBuLi in THF at 78 C for 30 min, and then with CF3CO2D, a ords not only the monoand di-deuterated complexes 74 and 75, but also the 3-butyl-4,6-dideuterioveratroletricarbonylchromium 76 as a minor by-product. Its formation can easily be explained in terms of a surprising ipso addition of nBuLi to one of the carbons bearing a methoxy group (Scheme 34) [58]. This is indicative of the electrophilic character of the eclipsed carbon C1 of complex 71.

Arylation of N,N-dimethylhydrazone 77 with (h6-chlorobenzene)tricarbonylchromium complex 1b can be achieved in 64 % yield. The copper lithium azaenolate 78 is trapped with the chromium complex at 70 C to give a-phenyl ketone 80 as a result of an ipso substitution (Scheme 35) [59]. This represents an easy access to a-aryl carbonyl compounds, some of which may exhibit anti-inflammatory properties.

A final example of a carbon–carbon bond formation relates to the reaction of o-chlorotri- fluoromethylbenzenetricarbonylchromium complex 81 with ‘‘in situ’’ generated phenylacetonitrile carbanion, which, under phase-transfer catalysis (TBAB, toluene, 50 % aqueous NaOH), quantitatively a ords two diastereomeric products 82, decomplexation of which yields a-phenyl-a-[2-(trifluoromethyl)phenyl]acetonitrile (Scheme 36) [60]. Activation of this

11.2 Ipso Nucleophilic Aromatic Substitutions 389

Scheme 34. Ipso and tele SNAr: CaC bond formation.

Scheme 35. Ipso SNAr: CaC bond formation.

Scheme 36. Ipso SNAr: CaC bond formation.

process by both tricarbonyl complexation and nitro group substitution has been evaluated, and the activating power of the Cr(CO)3 entity was estimated to be ten times smaller than that exerted by a para nitro group. This reaction o ers an interesting approach to the synthesis of biologically active substituted diphenylmethanes.

11.2.4

Carbon–Hydrogen and Carbon–Metal Bond Formation (Table 4)

It has been reported that hydrides can be used as nucleophiles towards chromium complexes, and that treatment of 3-ethyl-anisoletricarbonylchromium 83a with LiEt3BD in refluxing THF for 2 h quantitatively a ords 3-deuterio-ethylbenzenetricarbonylchromium 84a,

390 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

Tab. 4. Ipso nucleophilic aromatic substitution of arenetricarbonylchromium complexes: CaH and C– metal bond formation.

Entry	Arene	Nucleophile	Remarks	Ref., Year

1	C6H5Cl	KCpFe(CO)2
2	C6H5Cl	Na2Fe(CO)4
3	1,4-C6H4XF	NaC5H5Fe(CO)2, Na2M(CO)5
4	anisole derivatives	LiEt3BH(D)
5	tetralin	LiAlH4
6	dibenzofuran	LiEt3BH
7	C6H5F	Na(C5H4Me)Fe(CO)2
8	1,3,5-	LiAlH4
	trimethoxybenzene

CaFe bond formation	65, 1988
CaFe bond formation	64, 1988
CaCr, CaW, CaFe	67, 1989
CaH bond formation	60, 1990
CaH bond formation	61, 1991
CaH bond formation	62, 1992
CaFe bond formation	68, 1992
CaH bond formation	63, 1995

with no other isomer being detected. The three methoxide groups of 1,3,5-trimethoxybenz- enetricarbonylchromium 83b can be displaced by deuteride in a one-pot reaction to quantitatively a ord 1,3,5-trideuteriobenzene tricarbonylchromium 84b. These reactions represent the first hydro-(deuterio)-dealkoxylations reported for alkoxyarenechromium complexes (Scheme 37) [61].

Scheme 37. Ipso SNAr: CaD bond formation.

Treatment of 2-(2-methoxyphenyl)-N,N-diisopropylethylaminetricarbonylchromium 85 with LiAlH4 gives an almost quantitative yield of demethoxylated product 86 after decomplexation. If LiAlD4 is used, the deuteride replaces the methoxy group in a regiospecific manner through an ipso substitution (Scheme 38) [62]. Similarly, LiAlD4 reacts with complexes 87a,b to give complexes 88a,b. This reaction occurs more rapidly with the endo than with the exo isomer, suggesting that a substituent located syn to the Cr(CO)3 unit promotes the demethoxylation (Scheme 38). This could be the result of an eclipsed conformation of the tripod with respect to the OMe group.

Phenoxide group displacement by a hydride or a deuteride takes place in the case of the dibenzofuran complex. Indeed, on treating the dibenzofuran complex 89 with LiEt3BD, ring-

11.2 Ipso Nucleophilic Aromatic Substitutions 391

Scheme 38. Ipso SNAr: CaH bond formation.

opening to the diphenyl complex 90 occurs in 75 % yield (Scheme 39). The CaO bond is cleaved in an ipso SNAr of phenoxide group by deuteride, the mechanism of which has been clearly established by isolating one of the reaction intermediates [33].

Scheme 39. Ipso SNAr: CaD bond formation.

Deuterio-dealkoxylation also occurs on treating 4-tert-butyl-anisoletricarbonylchromium complex 83c with LiEt3BD, giving p-tert-butyl-deuteriobenzene complex 84c. Carbon– nitrogen bonds can be similarly cleaved by hydride: p-dimethylamino anisole complex 83d a ords, under the same experimental conditions, complex 84d in 24 % yield (Scheme 37) [63].

Metal-based nucleophiles may react with activated haloarenechromium complexes leading to substitution of the halides. The reaction of Collman’s reagent Na2[Fe(CO)4] with chloroarenetricarbonylchromium complexes in THF/N-methylpyrrolidinone produces the yellow anionic dinuclear complexes 91a in 45 % yield (Scheme 40) as a result of an ipso SNAr [64]. Spectroscopic data suggest that complex 91a adopts the h6 structure as opposed to the alternative h5-cyclohexadienyl carbene structure 92. Similarly, it has been reported by the same group that the potassium salt of [CpFe(CO)2] participates in ipso nucleophilic attack on chloroarenechromium substrates, producing dinuclear complexes 91b in 92 % yield (Scheme 40) [65].

Organometallic dianions [M(CO)5]2 (M ¼ Cr, W) also react with chlorobenzenetricarbonylchromium in THF at 0 C to form anionic complexes 91c in yields of 33 % and 11 %, respectively [66].

392 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

Scheme 40. Ipso SNAr: CaM bond formation.

The reaction of Na(C5H5)Fe(CO)2 with (h6-1,4-C6H4XR)Cr(CO)3 chloro derivatives produces the bimetallic products 91b in 32 % yield (Scheme 40) [67]. Similarly, reaction of NaCpFe(CO)2 (Cp ¼ C5H4Me, indenyl, C5H5) with fluorobenzenetricarbonylchromium affords the respective complexes [C6H5Cr(CO)3]Fe(CO)2Cp 91b, for which X-ray structures have been obtained. They each display nonplanar benzene rings, with the iron atoms and the ipso carbon atoms to which they are bound being substantially bent away from the Cr(CO)3 tripod. This is due primarily to the p-electron donation from the iron centers to the aromatic rings, rather than to the steric bulk of the iron-containing substituents [68].

11.3

Cine and Tele Nucleophilic Aromatic Substitutions (Table 5)

11.3.1

Cleavage of CxF and CxCl Bonds

Ipso nucleophilic aromatic substitutions represent the main substitution processes known in the case of arenetricarbonylchromium complexes bearing a fluoro or a chloro group. Another procedure involves the initial addition of a nucleophile to the ortho, meta, or para positions of the C6H5X ring (X ¼ F, Cl), followed by the addition of a strong acid (usually CF3CO2H). 1,5-Hydrogen migration in the (h4-cyclohexadiene) intermediate allows rearomatization by loss of HX (Scheme 5). The result is a substitution in which the nucleophile occupies a site ortho, meta, or para to the leaving group. These reactions are called cine, telemeta, and tele-para SNAr (Scheme 6).

The regiochemical course of these cine and para-tele reactions can be conveniently followed by using deuterated trifluoroacetic acid [69]. Thus, addition of Li(CMe2)CN and CF3CO2D to p-chlorotoluenetricarbonylchromium complex 14c gives the cine deuterated complex 93a and cyclohexadienes 94a in yields of 42 % and 20 %, respectively (Scheme 41) [69a, 69c]. The chloro substituent is o-directing and the methyl substituent is m-directing. LiC(Ph)[S(CH2)3S] reacts with the same complex to give, after CF3CO2H treatment,