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

14.3 Oxidative Coupling Reactions with Hypervalent Iodine Reagents 493

lated most easily as compared to other oxidants (thallium tris(trifluoroacetate) (TTFA) 42–72 %, RuO2 71 %, VOF3 49–69 %, FeCl3 80 %) (Scheme 15 and Table 12).

Scheme 15. Isoxazole-appended phenanthrene synthesis by PIFA-mediated oxidative cyclization.

The authors pointed out the interesting fact that the coupling reaction between simple unsubstituted phenyl groups (60b and 62b) forms the expected biaryl product only in the case of the pyrimidine link (e.g. 63b). This observation suggests that the pyrimidine heterocycle but not the isoxazole analogue can provide su cient stabilization for the putative radical cation intermediate.

These results prompted Faul and co-workers to investigate the intramolecular coupling of bis(indole)maleimides 64 to prepare indolo[2, 3-a]carbazoles 65 [53]. Modest yields were obtained, but the strategy nevertheless proved to be successful (Table 13). It is noteworthy that in the case of 64c, the reaction proceeded in a slurry in solvents such as Et2O or toluene and

Tab. 12. Isoxazole and pyrimidine synthesis by PIFA-mediated oxidative cyclization.

Substrate	R1	R2	R3	R4	Product	Yield (%)
60a	OCH3	H	OCH3	H	61a	85
60b	H	H	H	H	–	–
60c	H	H	OCH3	H	61c	80
60d	OCH3	H	OCH3	OCH3	61d	61
62a	OCH3	H	OCH3	H	63a	74
62b	H	H	H	H	63b	23
62c	H	H	OCH3	H	63c	81
62d	OCH3	H	OCH3	OCH3	63d	51
62e	OCH3	OCH3	OCH3	H	63e	88

49414 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 13. Carbazole synthesis by PIFA-mediated oxidative cyclization of bis(indole)maleimides.

Substrate	R1	R2	R3	Yield 65 (%)
64a	H	CH3	H	56
64b	H	CH3	CH3	30
64c	H	(CH2)3OBn	H	37
64d	H	(CH2)3OBn	CH3	30
64e	CH3	H	H	15
64f	H	H	H	0

that the commonly used solvent CF3CH2OH led to decomposition of the starting materials (Table 14). No reaction was observed in the case of 6-mono-substituted indoles (6-Cl, 6-F). Maleimides 66 and 67 (Figure 1) were not as reactive, and did not lead to the expected cyclization products.

Tab. 14. Solvent e ects in the synthesis of bis(carbazole) 65c from bis(indole) precursor 64c.

Solvent	Yield 65c (%)
CH3CN	20
CF3CH2OH	Decomp.
DMF	Decomp.
Et2O	50
Toluene	40
THF	Decomp.

Fig. 1. Unreactive maleimide derivatives in the PIFA-mediated oxidative cyclization reaction.

14.4 Other Reagents for the Oxidative Coupling Reaction 495

14.4

Other Reagents for the Oxidative Coupling Reaction

14.4.1

Iron(III)

Iron complexes remain in current use even though they were among the first reagents tested in the laboratory oxidative coupling of arenes. Despite the low selectivities described in the early papers, some groups have recently reported results that suggest that higher levels of regiochemical control can be attained.

For example, the synthesis of racemic binaphthyl moieties using iron reagents has been greatly improved from the initial Pummerer report [54]. Bjørnholm and co-workers presented a way of preparing binaphthol on a large scale in a minimal amount of solvent (THF) (Scheme 16) [55].

Scheme 16. Large-scale iron(III)-mediated oxidative dimerization of 2-naphthol (68a).

Reagent solubility is an issue in all of the syntheses involving iron-mediated oxidative coupling. The precedent cited in Scheme 16 uses THF as a good solvent for both FeCl3 6H2O and 2-naphthol. As a means of circumventing these solubility issues, Ding and co-workers devised a two-phase protocol for running the oxidative coupling reaction, whereby the iron reagent is dispersed in water [56]. Very high yields have been obtained with this method (Table 15).

The same authors subsequently reported the cross-coupling reactions between 2-naphthol (68a) and 2-naphthylamine (70a) [57]. The selectivity in favor of formation of the unsymmetrical product 71a was good (Table 16). The authors rationalized this selectivity in favor of the cross-coupling product in terms of the formation of a pre-addition complex 72 between the naphthol and the naphthylamine (Figure 2). This explanation was later challenged by Smrcina and co-workers, who suggested that the energy levels of the molecular orbitals of the reaction components are the important factors for predicting the outcome of the reaction [58, 59].

The oxidative coupling reaction performed under these heterogeneous conditions is much more e cient than in the homogeneous case. The proposed mechanism involves an electron transfer to the surface of the iron reagent from the 2-naphthol. High concentrations of the radicals trapped at the surface may account for the high yields observed. These findings are related to Toda’s work on coupling reactions with FeCl3 in the solid state [60]. In 1997, Ras-

496 14 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 15. Survey of iron(III) sources used in the two-phase oxidative dimerization of 2-naphthol (68a).

Oxidants	Fe3B:68a	Temp. ( C)	Time (h)	Yield 69a (%)
FeCl3 6H2O	2:1	50	1	95
FeCl3 6H2O	1:1	50	1	90
FeCl3 6H2O	1:2	50	1	85
FeCl3 6H2O	1:2	50	1	80a
FeCl3 6H2O	2:1	r.t.	55	90
FeCl3 6H2O	1:4	50	24	40
NH4FeCl4 6H2O	2:1	50	1	95
Fe(NO3)3 9H2O	2:1	50	1	95
Fe(SO4)3 9H2O	4:1	50	3	96
Fe(SO4)3 9H2O	4:1	50	1	75
NH4Fe(SO4)2 12H2O	2:1	50	3	92
NH4Fe(SO4)2 12H2O	2:1	50	1	80

a Conducted under an N2 atmosphere.

Tab. 16. Oxidative coupling of 2-naphthol (68a) and 2-naphthylamine (70a) by various iron(III) sources.

Fe3B:72	T ( C)	time (h)	71a (%)	69a (%)
4:1	55	6	82	14
4:1	55	3	79	13
4:1	r.t.	6	71	14
2.2:1	55	3	71	19
4:1a	55	3	63	19
4:1b	55	3	31	23
4:1b	55	3	42	30
4:1b	55	3	57	18
4:1c	55	5	39	39
4:1d	55	3	78	20

a Ultrasound (25 kHz) was employed;

b Fe2(SO4)3 9H2O, NH4Fe(SO4)2 12H2O and NH4FeCl4 6H2O were the oxidants used;

c The reaction was performed in the solid state;

d 68a and 70a were added separately to the aqueous FeCl3 solution.

14.4 Other Reagents for the Oxidative Coupling Reaction 497

Fig. 2. A 1:1 complex between 2-naphthol (68a) and 2-naphthylamine (70a).

mussen reported an improvement of this procedure by performing the solid-state reaction in a ball mill to a ord the binaphthol 69a in 87 % yield from 2-naphthol [61]. Additional advances have also been achieved by the use of microwave irradiation in order to promote the solid-state reaction [62]. Several substituted 2-naphthols 68a–f have been subjected to these conditions (Table 17).

Bushby has examined the FeCl3-mediated oxidation of hexyl-protected (Hex) phenol ether units in the preparation of triphenylene-based liquid crystals [63]. This strategy allows the formation of unsymmetrically substituted products 75a–l (Table 18) [64]. The use of methanol in the work-up is critical in order to obtain the products in good yield. If the protecting group on the phenol component is isopropyl (74m), the coupling reaction occurs to give the unprotected phenols 76a–c directly (Scheme 17) [65].

In a recent paper, the same authors showed that iron(III) chloride can mediate the oxidative coupling of substituted aryl ethers with an observed regioselectivity that depends on the substitution pattern [66]: meta-substituted phenol ethers 77 led to polymers (Scheme 18a) whereas para-substituted phenol ether 79 gave predominantly biphenyl structures (Scheme 18b). ortho-Substituted phenol ether 81 provided a dimer with the AraAr bond at a position para to one of the methoxy substituents (Scheme 18c).

Tab. 17. Microwave-assisted oxidative dimerization of 2-naphthol derivatives by iron(III).

naphthol	Heatinga		Microwaveb		Microwavec
68a	70	C, 1 h, 42 %	280	W, 30 s, 55 %	40	W, 30 s, 96 %
68b			280	W, 20 s, 76 %	40	W, 20 s, 95 %
68c			280	W, 100 s, 34 %	40	W, 100 s, 85 %
68d	70	C, 1 h, >3 %	140	W, 140 s, 3 %	40	W, 140 s, 40 %
68e	70	C, 1 h, 5 %	140	W, 140 s, 10 %	40	W, 140 s, 62 %
68f			140	W, 140 s, 34 %	40	W, 140 s, 84 %

a Oil bath;

b Irradiation with a commercial microwave oven; c Irradiation in a resonance cavity.

49814 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 18. Synthesis of triphenylenes 75 by oxidative coupling of biphenyl and phenyl ether components.

74	R1	R2	R3	R4	Reactant Ratio (73a:74)	Yield (%)
a	H	CH3	CH3	H	xylene solvent	43
b	H	C6H13	C6H13	H	dihexylbenzene solvent	35
c	H	CH3	OCH3	H	1:12	63
d	H	CH3	OC6H13	H	1:12	48
e	H	H	OCH3	H	1:9	5
f	H	Br	OCH3	H	1:12	40
g	H	aO-o-C6H4Oa		H	1:6	25
h	CH3	CH3	OCH3	H	1:12	31
i	CH3	OCH3	CH3	H	1:12	40
j	OC6H13	H	H	OC6H13	1:4	13
k	CH3	OC6H13	OC6H13	H	1:2	73
l	F	OCH3	OCH3	H	1:3.5	67

Scheme 17. Preparation of phenolic triphenylenes from phenyl isopropyl ether substrates and iron(III).

Some natural products have been synthesized by means of oxidative coupling promoted by iron reagents. In 1995, Herbert and co-workers reported the formation of the alkaloid kreysigine (84) by intermolecular oxidative coupling of diaryl substrates 83a/b with iron(III) chloride followed by methanol work-up [67]. The yield for the free phenolic compound 83a was 53 %, whereas the benzyl-protected analogue 83b presumably cyclizes and then debenzylates, in an overall yield of 71 % (Scheme 19).

Galanthamine (51a) has also been targeted by an iron-mediated coupling strategy [68]. The reagent used was potassium ferricyanide and this procedure a orded the expected product 86 in 45–50 % yield on a 12 kg scale (Scheme 20). The bromine atom on 85 prevents the ‘‘wrong’’ regioisomer from forming. Evidently, this reaction is less e cient than the hyper-

14.4 Other Reagents for the Oxidative Coupling Reaction 499

Scheme 18. Iron(III)-mediated oxidative coupling of simple dimethoxyphenols.

Scheme 19. An approach to the synthesis of kreysigine by iron(III)- mediated intramolecular oxidative coupling.

Scheme 20. Large-scale route to galanthamine featuring an iron(III)-mediated oxidative cyclization.

valent iodine version developed by Node (see Section 14.3) [50]. However, the reagents are inexpensive and the reaction is run in a mixture of toluene/aqueous Na2CO3, conditions suitable for the large-scale synthesis of this interesting anti-Alzheimer’s drug.

14.4.2

Vanadium, Thallium, and Lead

The coupling of 2-naphthol to give 2,20-binaphthol has served as a testing ground for many oxidation protocols. For example, binaphthol has been prepared using vanadium reagents

50014 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 19. Vanadium-mediated oxidative dimerization of naphthol derivatives.

Substrate		Temp.	Time	Product	Yield (%)
68a	(5 mM)	0–5 C	3 min	69a	15
87a	(2 mM)	r.t.	20 h	88a	78
87a	(0.05 mM)	r.t.	20 h	88a	55
87b (1 mM)		r.t.	5 min	88b	95
87c	(1 mM)	Reflux	2 h	88c	50
87c	(1 mM)	r.t.	2 h	88c	65
87c	(0.02 mM)	r.t.	2 h	88c	70

as well as the iron-based reagents discussed in the preceding section. Ammonium metavanadate in perchloric acid a ords the coupled compounds 69a and 88a–c in good yields, as reported by Hazra and co-workers (Table 19) [69].

Recently, Uang and co-workers have published a catalytic version of this oxidative coupling [70]. Their goal was to minimize the amount of toxic vanadium used. Dioxygen has been found to be the reagent of choice to oxidize V(IV) to V(V) without interfering with the coupling reaction itself. Except for 68f, with which the reaction is fairly ine cient, yields of coupled products are high (Table 20).

Tab. 20. Vanadium-mediated dimerization of various 2-naphthol derivatives.

naphthol	R1	R2	R3	Time (h)	Product	Yield (%)
68a	H	H	H	24	69a	92
68f	H	H	CO2CH3	120	69f	35
68g	H	OCH3	H	9	69g	76
68h	Br	H	H	24	69h	90

14.4 Other Reagents for the Oxidative Coupling Reaction 501

Oxidative coupling of simple monocyclic phenolic units is not as e cient by this method. Phenol itself does not undergo the reaction. Compounds 89 and 91, however, lead to the desired ortho-ortho coupling products, 90 and 92, respectively, in moderate yields (the starting phenol or decomposition products are also present at the end of the reaction) (Scheme 21).

Scheme 21. Vanadium(IV)-mediated dimerization of simple phenol derivatives.

In 1999, Kumar and co-workers published a new application of the reagent VOCl3 to the synthesis of triphenylene structures by oxidative coupling. In the presence or absence of concentrated H2SO4, the reaction of phenol ethers 93 a orded moderate yields of the desired compounds 94 (Table 21) [71, 72]. The authors showed that 2.5 equiv. of VOCl3 in CH2Cl2 at room temperature are the optimal conditions for this remarkable trimerization. Changes in the amount of reagent (higher or lower), other solvents, and/or lower temperatures led to

Tab. 21. VOCl3-mediated trimerization of catechol ethers.

93	R	Yield (%)
a	C3H7	53
b	C4H9	86
b	C4H9	79a
c	C5H11	85
c	C5H11	83a
d	C9H19	56
e	C10H21	70
f	C11H23	70
g	(CH2)2CH(CH3)(CH2)3CH(CH3)2	65

a In the presence of 0.4 % of H2SO4.

50214 Oxidative Aryl-Coupling Reactions in Synthesis

lower yields of the trimeric product 94. Unsymmetrical triphenylene derivatives 95a–c can be obtained in 50 % yield by applying this procedure to the biaryl substrates 93a–c (Scheme 22). Related structures, such as heptaalkoxytriphenylenes 98, could also be formed in similar yields (20–51 %) (Scheme 23).

Scheme 22. Triphenylene synthesis by VOCl3-mediated oxidative coupling of catechol ethers with biphenyls.

Scheme 23. Triphenylene synthesis by VOCl3-mediated oxidative coupling of trialkoxybenzenes with biphenyls.

Oxidative coupling was used to form alkyland alkoxy-substituted phenanthrenedione products 100a–d (Table 22) [73]. These compounds can be obtained by other methods, albeit in much lower yields. In this instance, oxidative coupling proceeds even with carbonylsubstituted arenes, and VOF3 gives much better results than thalliumor palladiummediated coupling procedures.

The use of VOF3 in a mixture of CH2Cl2 and TFA allowed Comins and co-workers to complete the total synthesis of tylophorine (102), first in racemic form and then as a chiral compound [74, 75]. The oxidative cyclization of septicine (101) leads directly to tylophorine in 68 % yield (Scheme 24).

Syntheses of members of the biphenomycine family of antibiotics rely on the oxidative coupling of tyrosine derivatives. Edwards and co-workers have shown that VOCl3 or VOF3 can create the biaryl bond of 104 in yields of 40 % and 20 %, respectively, from the simple tyrosine derivative 103 (Scheme 25) [76].

Lead tetraacetate has shown its usefulness in the total synthesis of natural compounds. In a paper describing the preparation of several bioactive biphenyls such as magistophorenes