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

11.2 Ipso Nucleophilic Aromatic Substitutions 373

Tab. 1. Ipso nucleophilic aromatic substitution of arenetricarbonylchromium complexes: CaO, CaS and CaSe bond formation.

Entry	Arene	Nucleophile	Ref., Year
1	PhCl	MeOH, NaOH	6, 1959
2	m- p-MeC6H4Cl	MeOH, NaOH	7a, 1964
3	Tetrahydroquinoline	MeOK	8, 1977
4	PhF	Lactone	20, 1979
5	o-FC6H4(CH2CH2CH2OH)	tBuOK, DMSO	18, 1980
6	R ¼ C6H4F	F /OSi	21, 1985
7	o,m, p-C6H4Cl2	MeOH, iPrOH, KOH	9, 1985
8	o-C6H4Cl2	NaO(CH2)2O(CH2)2ONa	19, 1985
9	o,m, p-MeC6H4F	Me2C bNaOH, KOH	12, 1985
10	RC6H4F, RC6H4Cl	NaOMe	10, 1986
11	p-C6H4Cl2	Me2C bNaOH, KOH	13, 1987
12	PhCl	HONHCO2tBu	14, 1988
13	p-MeOC6H4F	PhONa	17, 1988
14	p-CF3C6H4Cl	CF3CH2ONa	11, 1993
15	o-CH2 b CHaC6H4Cl	MeOH, NaOH	7b, 1994
16	p-MeC6H4F	n-C4H9OLi, THF, HMPA	16, 1996
17	2-F-1,3-diOMeC6H3	primary, secondary alkoxides	15, 1999
18	o,m, p-C6H4Cl2	NaSR	22, 1983
19	o-C6H4Cl2	NaSR	23, 1988
20	RC6H4F, RC6H4Cl	NaSMe	24, 1991
21	m-MeOC6H4Cl	ArSeSeAr	25, 1999

Scheme 7. Ipso SNAr: CaO bond formation.

the authors mentioned the formation of very minor products, that probably corresponded to cine derivatives! Indeed, they observed the presence of para-methoxytoluene-Cr(CO)3 in 0.1 % yield starting from m-chlorotoluene-Cr(CO)3 14b, and the presence of m-methoxytoluene Cr(CO)3 in 0.2 % yield starting from the p-chlorotoluene-Cr(CO)3 complex 14c [7a]. Similarly, treatment of ( )-(o-chlorostyrene)tricarbonylchromium complex 14d with MeONa in refluxing MeOH for 18 h gives the ( )-(o-methoxystyrene) complex 15d in 50 % yield [7b]. The absolute configuration of the chloro complexes was shown to be (1S,2R).

374 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

6-Methoxytetrahydroquinoline and 5-methoxy-3,3-dimethyldihydroindole derivatives 16b and 17b are prepared in the same way by adding KOMe in the presence of 18-crown-6 ether to complexes 16a and 17a, respectively (Scheme 8) [8].

Scheme 8. Ipso SNAr: CaO bond formation.

o- and p-Dichlorobenzenetricarbonylchromium complexes 18a and 18c react with ROH (R ¼ Me, iPr) in the presence of KOH under phase-transfer conditions to give the mono alkoxy products 19a and 19c. The meta isomer 18b also gives the disubstitution product 20b [9]. In DMSO, all three isomers of 18 a ord the dialkoxy derivatives 20 with ROH. These results were discussed in terms of di erent conformations of the tricarbonylchromium tripod (Scheme 9).

Scheme 9. Ipso SNAr: CaO bond formation.

Various substituted fluoroarenetricarbonylchromium complexes 18d react with MeONa in refluxing MeOH to yield the ipso SNAr type products 19d (Scheme 9) [10]. Even a poor nucleophile such as sodium 2,2,2-trifluoroethoxide reacts with m-(trifluoromethyl)chloro- benzenetricarbonylchromium complex 14e at 50 C in THF/TMEDA to a ord the ether 15e in 97 % yield (Scheme 7) [11]. This reaction is greatly facilitated by the presence of the elec- tron-withdrawing CF3 group.

A series of o-arylhydroxylamines, which are interesting intermediates for the preparation of benzofurans, hydroxybiphenyls, and catechols, have been synthesized starting from Cr(CO)3-activated fluoroarenes. Oxime 21 reacts with m-fluorotoluenetricarbonylchromium

11.2 Ipso Nucleophilic Aromatic Substitutions 375

complex 22b to yield the m-aryloxime 23 (Scheme 10) [12]. This oxime can be converted to benzofuran derivatives 24 by oxidation with I2 and treatment of the free arene with H2SO4 [13]. Reactions of complexes 1b, 14, and 18 with hydroxylamine 25 a ord the ipso complex 26 in 90–95 % yield (Scheme 11) [14].

Scheme 10. Ipso SNAr: CaO bond formation.

Scheme 11. Ipso SNAr: CaO bond formation.

As part of a program aimed at discovering new sodium channel blockers, authentic samples of both enantiomers of the class I-B antiarhythmic agent mexiletine are required. Thus, for this purpose, a variety of primary and secondary alkoxides bearing unprotected primary, secondary, and tertiary amino functionalities have been used to displace the fluoride from the sterically demanding 1,3-dimethyl-2-fluorobenzenetricarbonylchromium complex 27. The corresponding ether 29 (Scheme 12) obtained with (S)-(þ)-2-amino-1-propanol 28 represents the mexiletinetricarbonylchromium complex with an enantiomeric purity of b99 % ee [15]. A similar sequence, using (R)-( )-2 amino-1-propanol, provides the (R)-mexiletine hydrochloride complex.

Scheme 12. Ipso SNAr: CaO bond formation.

An unexpected reaction occurs when p-fluorotoluenetricarbonylchromium complex 18e is treated with lithium phenylacetylide (generated from nBuLi and phenylacetylene) in THF

37611 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

and HMPA, furnishing (h6-4-butyloxytoluene)tricarbonylchromium complex 19e in 44 % yield. The authors rationalized this reaction by suggesting that nBuOLi might be formed, arising from either aerial oxidation of nBuLi or ring-opening of THF by nBuLi [16].

It is worthy of note that treatment of p-fluoroanisoletricarbonylchromium complex with 5

equivalents of PhONa in DMSO at 100 C does not lead to an ipso SNAr reaction [17]! It had been envisaged that the lack of reactivity in this case could be overcome by the use of the 1,4- dichlorobenzene complex. However, p-dichlorobenzenetricarbonylchromium complex 18c reacts smoothly with PhONa in DMSO at room temperature to give the mono ipso adduct 19c, R0 ¼ Ph [17]. Treatment of this complex with MeONa in DMSO gives 20c (R ¼ Ph, R0 ¼ Me) in 52 % yield (Scheme 9). This process represents an interesting sequential replacement of chloride from the p-dichlorobenzene complex.

The intramolecular version of the substitution of chloride or fluoride has also been studied. For example, reaction of 3-(2-fluorophenyl)-1-propanol tricarbonylchromium 30 with excess tBuOK for 3 h at 25 C gives the chromane complex 31 (Scheme 13) in 75 % yield, from which the free chromane 32 can be obtained by oxidation with I2 [18].

Scheme 13. Intramolecular ipso SNAr: CaO bond formation.

Both activation by Cr(CO)3 complexation and the use of phase-transfer conditions are necessary for success in the following synthesis. A cyclic bis-ether can easily be obtained from the o-dichlorobenzene complex 18a (Scheme 14). Indeed, reaction of 18a with Na[O(CH2)2]2OH in (MeOCH2)2O and with Bu4NBr as a phase-transfer catalyst at 50 C for 8 h, followed by decomplexation with I2 directly a ords dibenzo-18-crown-6 35 in 27 % yield. Compound 34, which can also be converted into 35, can be obtained in 84 % yield by heating 18a, NaH, and diethylene glycol for 24 h in DME at 50 C [19]. The authors demonstrated the potential of this synthesis by preparing di erent crown ethers with various heteroatoms.

Scheme 14. Intramolecular ipso SNAr: CaO bond formation.

11.2 Ipso Nucleophilic Aromatic Substitutions 377

Cyclization can also occur through halide displacement after initial metalation. For example, acylation of o-lithiofluorobenzenetricarbonylchromium with g-butyrolactone at 25 C for 24 h is followed by spontaneous fluoride displacement to give complex 36. Oxidation with excess iodine liberates the lactone in 48 % overall yield (Scheme 15) [20].

Scheme 15. Intramolecular ipso SNAr: CaO bond formation.

Another intramolecular substitution has been used for the synthesis of an intermediate in a proposed route to 3-substituted benzofurans. A b-methylene-dihydrobenzofuran complex was obtained upon fluoride-induced removal of the SiR3 protecting group from complex 37 (Scheme 16) in an ipso SNAr process. Desilylation resulted in spontaneous cyclization to the stable methylene complex 38 in 89 % yield. No isomerization occurred and the 3-methyl benzofuran complex was not detected [21].

Scheme 16. Intramolecular ipso SNAr: CaO bond formation.

The reactivity of complexed haloarenes toward thiolates has been studied, and it has been reported that o-, m-, and p-dichlorobenzenetricarbonylchromium complexes 18a–c react with thiolates (RS ; R ¼ Me, nBu, tBu Scheme 17, path i) under phase-transfer conditions or in DMSO to give 39 and 40a–c. The orthoand para-complexes 18a and 18c undergo stepwise substitution of the two Cl atoms in a reaction sequence that can be easily controlled by the amount of added thiolate. The meta complex 18b shows a lower selectivity and gives a mixture of monoand disubstituted products even in the presence of substoichiometric amounts of thiolate (Scheme 17) [22]. Similarly, LiCH(CO2Et)CN and BuSH react with the o- dichlorobenzene complex 18a to give complex 39d and then disubstituted arene 40d, showing that this substitution can be performed with two di erent nucleophiles (Scheme 17) [23]. Phase-transfer catalysis has also been applied to fluoroarene-Cr(CO)3 complexes, which are more reactive toward thiolates than are the corresponding chloro derivatives [22].

Other approaches to Cr-mediated aromatic thiation have been studied [24], and quenching of lithiated arenetricarbonylchromium complexes by electrophilic sulfur has been compared to halogen displacement by nucleophilic sulfur.

378 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

Scheme 17. Ipso SNAr: CaS bond formation.

Unsymmetrical diaryl selenides can be prepared by nucleophilic displacement of chloride from chloroarene-Cr(CO)3 complexes with areneselenolate complexes in DMSO at 70 C. Selenolates can be generated in situ by reduction of the corresponding diselenides with hydrazine in DMSO in the presence of potassium carbonate (Scheme 17, path ii). Thus, chloroarene complexes 18a and 18f yield diaryl selenides in moderate to good yields [25]. Product yields are increased with increasing reactivity of the complex and with increasing nucleophilicity of the selenolate reagent. 4-tert-Butyloxycarbonylchlorobenzene-Cr(CO)3 18g is particularly reactive, a ording the substitution product 39g at room temperature. 4-Dimethyla- minoselenolate reacts more e ciently than 4-chloroselenolate (Scheme 17) [25].

11.2.2

Carbon–Nitrogen and Carbon–Phosphorus Bond Formation (Table 2)

Reaction of (h6-fluorobenzene)tricarbonylchromium 1a with primary and secondary amines proceeds rapidly at 25 C. The formation of (h5-cyclohexadienyl)complex 2a (X ¼ F, NuH ¼ NHR2) has been postulated on the basis of kinetic data. A rate-determining loss of fluoride from the endo side of the ring a ords the aniline derivative 3j (Scheme 18) [26].

Nucleophilic substitution of the fluoride of fluorobenzenetricarbonylchromium by morpholine leads to phenylation of the nitrogen (Scheme 18) [27]. However, in the case of imidazole, substitution is e ected only with the anion of the nitrogen base.

Other aminations of more substituted arene complexes allow the regiospecific synthesis of polysubstituted aromatics. For example, p-fluoroanisoletricarbonylchromium complex can first be lithiated and quenched with chloroformate to give 33b (R ¼ OMe, R0 ¼ CO2Me). After substitution of the fluoride by pyrrolidine, complex 3l is obtained in 89 % yield (Scheme 18) [29].

o-Lithiated fluorobenzenetricarbonylchromium complex can be trapped by bifunctional electrophiles such as dimethyl-N-carboxy anhydride 41 to give the five-membered ring 42 after spontaneous decarboxylation and displacement of fluoride (Scheme 19) [28]. With two equivalents of phenyl isocyanate, PhNCO, the six-membered heterocycle 43 is recovered. This process has also been extended to seven-membered benzo-fused heterocycles.

		11.2	Ipso Nucleophilic Aromatic Substitutions			379
Tab. 2. Ipso nucleophilic aromatic substitution of arenetricarbonylchromium complexes: CaN and CaP
bond formation.
Entry	Arene	Nucleophile	Remarks	Ref., Year
1	C6H5F	R2NH	aniline	26a, 1967–68
2	C6H5F	R2NH	aniline	26b, 1971
3	C6H5F	R2NH	morpholine	27, 1979
4	C6H5F	R2NH	benzo-fused	28, 1979
5	C6H5F	R2NH	heterocycles	28, 1986
6	RC6H4F	R2NH	pyrrolidine	29, 1986
7	p-CO2MeC6H4F	[WaNcN]	arylation of nitrogen	30, 1992
8	RC6H4Cl	NaH, NH2COCF3	aniline	31, 1992
9	CF3C6H4Cl	NaNH2/NH3	aniline	32, 1993
10	C6H5OCH2CH2NH2	RNH2	Smiles reaction	33, 1995
11	RC6H4F	piperazine	aryl piperazine	35, 1996
12	RC6H4F	amines	rate of SNAr	36, 1998
13	RC6H4F	LiNR2	N-aryl indoles	38, 1998
14	RC6H4OCON(iPr)2	PPh2Li	arylphosphines	39, 1999
15	RC6H4F	pyrrolidine, piperidine	polymer-haloarene	40, 2000
16	RC6H4F	NH2NH2, H2O	indazole	42, 2000

Scheme 18. Ipso SNAr: CaN bond formation.

Scheme 19. Intramolecular ipso SNAr: CaN bond formation.

380 11 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

A reaction corresponding to a novel arylation of molecular nitrogen through bimetallic activation has been reported. Thus, reaction of [nBu4N][W-(NCS)(N2)(dpe)2] (44) with p- fluorobenzoic ester complex 45 in THF at room temperature gave complex 46 as a result of an ipso SNAr process [30] (Scheme 20), showing the e ectiveness of this method for the direct arylation of coordinated nitrogen.

Scheme 20. Ipso SNAr: CaN bond formation.

Trifluoroacetamide may be successfully employed as a nucleophile in the synthesis of aniline complexes. The formation of aniline derivatives 14g can be realized by adding the ‘‘in situ’’ generated trifluoroacetamide anion CF3CONH to the o-chlorotoluenetricarbonyl- chromium complex 14a followed by KOH treatment (Scheme 21) [31].

Scheme 21. Ipso SNAr: CaN bond formation.

The synthesis of aniline derivatives can also be realized by direct addition of the NH2 unit, if the arene ring is made more electrophilic through activation by a trifluoromethyl group. For example, in the case of p-trifluoromethylchlorobenzenetricarbonylchromium complex 47, the aniline derivative 48 can be obtained in 32 % yield using NaNH2/NH3 in HMPT (Scheme 22) [11].

Scheme 22. Ipso SNAr: CaN bond formation.

The tricarbonylchromium entity promotes ipso-Smiles rearrangement of the O-phenyl derivatives of ephedrine and pseudoephedrine to the N-phenyl derivatives [32]. Indeed, treatment of the sodium alkoxide derived from ð1R,2SÞ-ephedrine with fluorobenzene complex

11.2 Ipso Nucleophilic Aromatic Substitutions 381

1a generates the required phenyl ether 49a in good yield. Upon treatment with nBuLi in THF at 78 C, complex 49a smoothly undergoes the Smiles rearrangement to liberate the phenylamine 50a in 96 % yield. Treatment of 4-fluoroanisole complex 1c with the alkoxide derived from ð1S,2SÞ-ephedrine yields complex 49c in 91 % yield, and complex 50c in 97 % yield upon treatment with nBuLi at 78 C. The ipso regioselectivity of these reactions is evident from the aromatic AB system in the 1H NMR spectrum of 50, which is diagnostic of 1,4-substitution. Thus, the spiro intermediate 51 can be postulated, and it would be interesting to trap it, e.g. with ClSnPh3 [33] (Scheme 23).

Scheme 23. Ipso SNAr: CaN bond formation.

Arylpiperazines can be prepared in a one-pot procedure by ipso SNAr of piperazine derivatives with h6-fluoroarene complexes 1a, 33a,b,d. Indeed, piperazine derivatives react with fluorobenzene derivatives in DMSO in the presence of K2CO3 at 80 C to give, after 2.5 h, complexes 3m and 3k (Nu ¼ piperazine) in good yields (Scheme 18) [34]. Piperazine itself may be used as a nucleophile and gives the monoarylpiperazine derivative uncontaminated by any symmetrical N,N 0-bis(aryl)piperazine, allowing the direct preparation of unprotected compounds.

Fluoroarene-Cr(CO)2L complexes 33p [L ¼ CO, PPh3, P(OPh)3, P(pyrrolyl)3, P(pyrolyl)2 (NMeBn)], where L is a potential linker ligand for solid-phase synthesis, have been evaluated with regard to the rates of nucleophilic substitution by amines [35]. The preparative and kinetic results indicate that SNAr reactions on tris(pyrrolyl)phosphine-modified fluoroarenechromium complexes proceed rapidly and with high e ciency, and are thus appropriate for the development of solid-phase versions for use in combinatorial synthesis (Scheme 18).

The authors set out to ascertain whether the addition of pyrrolidine (k1; Scheme 18) to give complex 2p or the loss of fluoride (k2) to give complex 3p was the rate-determining step. The reverse of nucleophile addition, k 1, was assumed to be faster than the addition. All the results of a series of kinetic determinations in DMF at 25 C by 19F NMR spectroscopy were consistent with k1 relating to the rate-determining step (half-lives: 67–180 s). Unlike simple aminophosphines, tris(pyrrolyl)phosphine is relatively stable toward cleavage of the NaP bond and shows a relatively strong electron-withdrawing e ect, nearly comparable to that of

38211 Arenetricarbonylchromium Complexes: Ipso, Cine, Tele Nucleophilic Aromatic Substitutions

CO [36]. This is consistent with a half-life of 91 s, only 1.4 times longer than that of the parent fluorobenzene-Cr(CO)3 complex.

Mild N-arylations of indoles can be achieved in good yields by nucleophilic substitution reactions of the sodium salt of indole on various haloarenetricarbonylchromium complexes. Thus, o-fluoroanisole-Cr(CO)3 33a reacts with the indole N anion within 0.75 h at 0 C to give complex 3m (Nu ¼ indolyl) in 83 % yield. The chloro derivatives require longer reaction times and higher temperatures (Scheme 18) [37]. The authors were able to extend this procedure to the introduction of two indole rings on the same aromatic nucleus.

New polymer-bound haloarene chromiumdicarbonyl isocyanide complexes have been prepared and used in solid-phase chemistry to react with nitrogen nucleophiles according to an ipso SNAr mechanism [38]. Polymer-bound isocyanides have proved to be valuable ligands for anchoring haloarene-Cr(CO)3 complexes by means of their substitution of a CO group. It is known from solution chemistry that the coordination of a phosphine group to the chromium atom greatly reduces the reactivity of the aromatic ring to nucleophilic attack, except in particular cases [36]. Thus, the isocyanide ligand is used, the electronic properties of which are similar to those of the CO group. Irradiation of the fluoroarene complex 1a at room temperature in the presence of cyclooctene gives complex 52a, treatment of which with the appropriate isocyanide (L ¼ RNC) for 20 min at 55 C, a ords the stable complex 52b. Di erent nucleophiles can react in DMF at room temperature (Nu ¼ pyrrolidine, piperidine, benzyl thiolate, methoxide anion) to give the corresponding complexes 52c, showing that the aromatic ring is only slightly a ected by modification of the ligands. The problem of preparing arene complexes bound to appropriate isocyanide resins has been solved. Indeed, fluorobenzene-Cr(CO)3 can be supported on the resin by direct photochemical irradiation for 1 h to form 52b (L ¼ isocyanide resin). The resin reacts at room temperature in DMF, for example with pyrrolidine, to give in 80 % yield a resin showing no 19F NMR signal, as befits an ipso SNAr displacement of the fluoride by the nitrogen nucleophile (Scheme 24).

Scheme 24. Ligand exchange.

The formation of these CaN bonds is interesting, because it is not easy to create them in the case of non-coordinated arenes [40]. Very often, another form of activation is necessary [41]. The last example of a CaN bond formation is represented by the recent preparation of the indazole s-chromium complex 55, which was obtained by cyclization of h6-2-(20- phenylhydrazine)-1,3-dioxolane-Cr(CO)3 (54) under acidic conditions. The ipso SNAr was achieved by refluxing with 2.5 equivalents of hydrazine and one equivalent of 2-(20- fluorophenyl)-1,3-dioxolane-Cr(CO)3 (53) for 2 days [39].