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

14.2 Mechanistic Overview 483

Scheme 6. Phenoxonium cation generation.

The question as to whether the reactive intermediate is the phenol–metal/leaving group complex 21/22 or the free phenoxonium ion 17 has been studied in the particular case of hypervalent iodine. Pelter and co-workers presented permissive evidence in support of a mechanism involving the free oxonium species 17 (Scheme 7): PhI(OAc) is an extremely good nucleofuge, no transfer of chirality is observed when homochiral hypervalent iodine compounds are used, and calculations made on the cation species correctly predict the regioselectivity of the substitution reaction [32, 33].

Scheme 7. Phenoxonium ion generation using hypervalent iodine precursors.

Biaryl formation through oxidative coupling of phenol ethers has also been explored. Although vanadium and lead complexes are known to e ect these transformations [34], thallium reagents give the best results [35–37]. More recently, Kita and co-workers have developed the e cient oxidative coupling of phenol ethers using hypervalent iodine reagents activated by BF3 Et2O [38, 39]. The formation of a single electron transfer (SET) complex 25 is proposed to occupy a central role in the mechanism of these reactions (Scheme 8) [40]. Coupling then occurs between two cation radicals 26 or between the cation radical 26 and a neutral phenol ether molecule 24 [41].

Scheme 8. Hypervalent iodine-mediated phenyl methyl ether oxidative coupling.

It is di cult to make generalizations about the oxidative coupling of arenes, given the number of possible mechanisms. Factors that influence the reaction course include the oxidation potential of each aryl unit, the substitution pattern, the solvent system, and the oxidation reagents themselves. Optimization then becomes a case-by-case e ort in order to obtain the best selectivities and the best yields. Nevertheless, results over the last decade have

48414 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 1. PIFA-mediated intramolecular biaryl formation.

Solvent	Temp. ( C)	Yield of 28 (%)
		No BF3QEt2O	Containing BF3QEt2O
(CF3)2CHOH	25	63	63
CF3CH2OH	40	65	84
CH3CN	40	46	73
CH2Cl2	40	25	91

demonstrated that thallium, vanadium, lead, copper, and hypervalent iodine are the most general and reliable reagents for this kind of biaryl-forming reaction.

14.3

Oxidative Coupling Reactions with Hypervalent Iodine Reagents

In recent years, hypervalent iodine reagents have found increasingly broad application in a wide variety of reactions [31, 42, 43]. The oxidative coupling of phenols and phenol ethers is one important field in which these reagents have clearly been used to good advantage. Phenol ethers display only modest reactivity towards hypervalent iodine reagents, but Kita and co-workers have developed conditions under which they participate readily in such reactions [41, 44]. The key appears to be enhancing the electrophilicity of the iodine reagent by activation with BF3 Et2O (Table 1). These conditions can be applied to a large range of phenol ether substrates (Table 2).

Table 3 shows the application of these intramolecular biaryl-forming conditions to the indirect synthesis of acyclic biaryls using a temporary tether strategy (Scheme 9). Silaketal tethers (Y ¼ SiR2 and X ¼ O, 31a–f ) react e ciently to give the biaryl unit. A sulfide derivative (Y ¼ S, X ¼ CH2, 31g) led to many oxidized products, but sulfoxides (Y ¼ SO,

Scheme 9. Removable tether strategy for biaryl formation.

14.3 Oxidative Coupling Reactions with Hypervalent Iodine Reagents 485

Tab. 2. Substituent e ects on the PIFA-mediated intramolecular oxidative cyclization of a,o-biaryls.

R1	R2	R3	R4	R5	n	X	Yield 30 (%)
OCH3	H	OCH3	OCH3	H	1	CH2	91
aOCH2Oa		aOCH2Oa		H	1	CH2	91
OCH3	OCH3	OCH3	OCH3	H	1	CH2	99
OCH3	OCH3	OCH3	OCH3	OCH3	1	CH2	92
OCH3	OCH3	OCH3	OTBS	H	1	CH2	75
OCH3	H	OCH3	OCH3	H	2	NCOCF3	89
OCH3	OCH3	OCH3	OCH3	H	2	NCOCF3	68
OCH3	OCH3	OCH3	OCH3	OCH3	2	NCOCF3	52
aOCH2Oa		aOCH2Oa		H	1	NCOCF3	94
OCH3	OCH3	OCH3	OCH3	H	1	NCOCF3	85
OCH3	OCH3	OCH3	OCH3	OCH3	1	NCOCF3	85
OCH3	OCH3	OCH3	OTBS	H	1	NCOCF3	64
OCH3	OCH3	OCH3	OAc	H	1	NCOCF3	60

X ¼ CH2, 31h–k) and sulfones (Y ¼ SO2, X ¼ CH2, 31l,m) participated e ectively in the oxidative coupling reaction. Dibenzyl ethers (Y ¼ O, X ¼ CH2, 31n–r) were also coupled in fair to good yields. Cleavage of the temporary tether subsequently delivers the acyclic biaryls

33a–r.

Recently, Kita and co-workers also applied the optimized PIFA/BF3 Et2O conditions to intermolecular coupling reactions [39]. Thus, several phenol ethers undergo dimerization through oxidative coupling in very good yields (Table 4). Apparently, the reaction leads to a single biaryl regioisomer. No reaction is observed when the ring is substituted by the electron-withdrawing group NO2 (substrate 34d).

For the coupling of binaphthyl compounds, the authors note that 0.55 equivalents of PIFA and a temperature below 0 C are necessary conditions to obtain the best yields (Table 5). Carbon–carbon bond formation occurs between the most highly oxygenated aryl rings of the naphthyl units.

The hypervalent iodine reagents PIFA and PIDA have also been used in the synthesis of naturally occurring structures, primarily the amaryllidaceae alkaloids and related species. Work by White’s group showed the feasibility of this method for the synthesis of 6aepipretazettine and (–)-codeine [45, 46]. In the early 1990s, Rama Krishna and co-workers demonstrated that PIDA can promote the oxidative phenolic coupling of diaryl substrates 38a–e to deliver cyclohexadienones 39a–e, respectively, in consistent 30 % yields for all of the substrates examined (Scheme 10) [47].

Kita and co-workers elaborated upon these earlier studies by examining substrates bearing a strategically placed nitrogen atom as a route to members of the amaryllidaceae alkaloid

48614 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 3. Substituent e ects in the PIFA-mediated coupling of various linked biaryls.

31	R1	R2	R3	R4	R5	R6	X	Y	Yield 32 (%)
a	OCH3	OCH3	H	H	OCH3	OCH3	O	SiiBu2	56
b	aOCH2Oa		H	H	aOCH2Oa		O	SiiBu2	69
c	OCH3	OCH3	H	H	aOCH2Oa		O	SiiBu2	46
d	OCH3	OCH3	H	H	OCH3	OCH3	O	SitBu2	81
e	aOCH2Oa		H	H	aOCH2Oa		O	SitBu2	89
f	OCH3	OCH3	H	H	aOCH2Oa		O	SitBu2	83
g	OCH3	OCH3	H	H	OCH3	OCH3	CH2	S	–
h	OCH3	OCH3	H	H	OCH3	OCH3	CH2	SO	73
i	aOCH2Oa		H	H	aOCH2Oa		CH2	SO	71
j	OCH3	OCH3	H	H	aOCH2Oa		CH2	SO	59
k	OCH3	OCH3	OCH3	H	OCH3	OCH3	CH2	SO	42
l	OCH3	OCH3	H	H	OCH3	OCH3	CH2	SO2	78
m	aOCH2Oa		H	H	aOCH2Oa		CH2	SO2	72
n	OCH3	OCH3	H	H	OCH3	OCH3	CH2	O	85
o	aOCH2Oa		H	H	aOCH2Oa		CH2	O	80
p	OCH3	OCH3	H	H	aOCH2Oa		CH2	O	51
q	OCH3	OCH3	OCH3	H	OCH3	OCH3	CH2	O	50
r	OCH3	OCH3	OCH3	OCH3	OCH3	OCH3	CH2	O	38

Tab. 4. Intermolecular PIFA-mediated oxidative arylic coupling.

34	R1	R2	R3	Time (h)	Yield 35 (%)
a	OCH3	OCH3	OCH3	1.5	92
b	OCH3	OCH3	CH3	1.5	93
c	OCH3	OCH3	Br	1.5	97
d	OCH3	OCH3	NO2	24	–
e	OCH3	CH3	OCH3	1.5	92
f	OCH3	Br	OCH3	1.5	91
g	Br	OCH3	H	3	72

14.3 Oxidative Coupling Reactions with Hypervalent Iodine Reagents 487

Tab. 5. PIFA-mediated binaphthyl formation from substituted naphthyl ethers.

36	R1	R2	R3	R4	Time (h)	Yield 37 (%)
a	H	H	H	OCH3	3	91
b	H	H	OCH3	OCH3	1.5	61
c	Br	H	H	OCH3	1.5	98
d	H	OCH3	H	H	3	94
e	OCH3	H	H	OCH3	3	82

Scheme 10. Cyclohexadienone formation from PIDA-mediated oxidative coupling of phenolic substrates.

family. In 1996, they described an exploration of the coupling of norbelladine derivative 40a to a ord tricyclic compound 41a, an intermediate in the synthesis of amaryllidaceae alkaloids [22]. Apparently, the reactions only proceeded e ciently in (CF3)2CHOH at –40 C using PIFA (see Table 6) [48]. Other solvents (CH3CN, benzene, CH2Cl2, etc.) gave unsatisfactory results.

Subtle e ects on the coupling e ciency exerted by the nitrogen substituent were uncovered. No AraAr coupling products were observed with NCH3 or unprotected nitrogen (Table 7).

Further substrate variants were explored in order to ascertain the e ect of the phenoxy substituents on coupling e ciency (Table 8). The subtle influence of remote substituents is again illustrated by these results, with both more electron-rich (R1 ¼ R2 ¼ TBDMS, 40j) and more electron-deficient (R1 ¼ CH3, R2 ¼ Ac, 40n) analogues performing less satisfactorily than the parent dimethoxy ether 40a.

48814 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 6. Solvent e ects in the PIFA-mediated oxidative coupling of phenolic substrates.

Solvent	Yield (%)	Solvent	Yield (%)
(CF3)2CHOH	70	Et2O	30
CF3CH2OH	61	DMF	18
CH3CN	50	THF	15
C6H6	44	C6H5CH3	14
CH2Cl2	30	–	–

Finally, reactions with O-protected phenol 40 were studied, but only silyl ethers (40s–u, R ¼ TMS, TBDMS) a orded the cyclohexadienone product 41 in good yield. Other protecting groups primarily yielded the biaryl coupling product 42 (Table 9).

The authors proposed a mechanistic explanation for these di erent behaviors. For the case of the free phenol cyclization precursor 40a, an ionic mechanism via intermediate 44 leads to the nucleophilic intramolecular para substitution product 41a (Scheme 11). For the O- protected derivatives 40s–w, an alternative mechanism leads to the formation of the cation radical 45, which then participates in an intramolecular cyclization to deliver an activated

Tab. 7. E ect of remote nitrogen substituents on the PIFA-mediated coupling of phenolic substrates.

40	R	Yield 41 (%)
a	COCF3	61
b	CO2 tBu	49
c	CO2(CH2)2TMS	54
d	CO2Et	48
e	COC6F5	50
f	CH3	–
g	H	–

14.3 Oxidative Coupling Reactions with Hypervalent Iodine Reagents 489

Tab. 8. E ect of various ether substituents on the PIFA-mediated coupling of phenolic substrates.

40	R1	R2	Yield 41 (%)
a	CH3	CH3	61
h		aCH2 a	56
i	TBDMS	CH3	42
j	TBDMS	TBDMS	42
k	CH3	TBDMS	35
l	PhCH2	CH3	49
m	CH3	tBuCO	32
n	CH3	CH3CO	37
o	CH3CO	CH3	Trace
p	H	CH3	19
q	CH3	H	Trace
r	H	H	Trace

Tab. 9. E ect of phenol ether substitution and solvent variation on the PIFA-mediated oxidative coupling of polyether substrates.

40	R	Solvent	Time	41a (%)	42 (%)
a	H	CF3CH2OH	5 min	61	–
s	TMS	CF3CH2OH	30 min	57	–
t	TBDMS	CF3CH2OH	4.5 h	66	–
u	TBDPS	CF3CH2OH	4 h	23	12
v	PhCH2	CF3CH2OH	24 h	–	48
w	CH3	CF3CH2OH	30 min	–	47
w	CH3	(CF3)2CHOH	1 h	–	42
w	CH3	CH3CN	3.5 h	33	23
w	CH3	CH2Cl2	24 h	22	–

49014 Oxidative Aryl-Coupling Reactions in Synthesis

dienone intermediate 46. This species proceeds towards the cyclohexadienone product 41a in the case of R ¼ TMS or TBDMS (route a). In the case of R ¼ CH3 or PhCH2 in poorly nucleophilic solvents, the reaction follows route b (1,2-aryl shift) to a ord the biaryl compounds 42u–w (Scheme 11).

Scheme 11. Mechanistic speculation on the di erent pathways taken by phenolic and phenyl ether substrates in the PIFA-mediated oxidative coupling reaction.

The first application of this methodology in natural products synthesis involved the preparation of an essential intermediate 48 for the synthesis of (þ)-maritidine (49) (Scheme 12) [38, 48, 49]. Other complex systems of the same family have been synthesized according to analogous strategies (Scheme 13). These oxidative phenolic coupling reactions encounter the problem of regioselectivity upon CaC bond formation. Incorporation of R3Siand CPh2

Scheme 12. An approach to maritidine using PIFA-mediated aryl coupling.

14.3 Oxidative Coupling Reactions with Hypervalent Iodine Reagents 491

Scheme 13. Galanthamine-type alkaloids targeted by oxidative coupling methodology.

protecting groups (e.g. 50f ) was found to give the desired regioselectivity in the highest yield (Table 10). Exclusive p-p0 coupling to deliver the undesired isomer 54 was obtained when the p0 position was not blocked.

Very recently, Node and co-workers improved the e ciency of this particular oxidative phenolic coupling in the context of a synthesis of (G)-galanthamine (51a) [50]. By using a trialkoxyarene as one of the aryl units, they were able to obtain yields of 56b of up to 90 % when the nitrogen was protected with a formyl group and the donor aryl’s oxygen atoms were capped by benzyl moieties (Table 11). These authors were even able to isolate an inter-

esting narwedine-type product 57a in low yield.
A	similar kind of strategy, as developed by Kita,	has also been successfully applied
in a	diversity-oriented synthesis of galanthamine-like	molecules (Scheme 14) [51]. The

Tab. 10. Regiochemical control in the PIFA-mediated oxidative coupling of unsymmetrically substituted biaryl substrates.

Substrate				Isolated Yield (%)
50	R1	R2	X	53 (p-oO)	54 (p-pO)
a	CH3	CH3	SPh	0	0
b	CH3	CH3	TMS	0	26
c		aCH2 a	Br	6	2
d		aCH2 a	SPh	0	0
e		aCH2 a	TMS	32	0
f		aCPh2 a	TMS	36	9
g		aC(CH3)2 a	TMS	46	12
h		aCPh2 a	H	0	60
i		aC(CH3)2 a	H	0	55
j		aCPh2 a	TES	37	0
k		aCPh2 a	TBS	28	0

49214 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 11. A higher-yielding PIFA-mediated oxidative cyclization approach to galanthamine-type alkaloids.

55	R1	R2	R3	Temp ( C)	Time (min)	Product	Yield (%)
a	H	CH3	COCF3	20	20	57a	12
b	Bn	Bn	CHO	40	120	56b	90
c	CH3	CH3	CHO	40	15	56c	95
d	Bn	CH3	CHO	40	60	56d	82
d	Bn	CH3	CHO	r.t.	15	56d	85
e	Allyl	CH3	CHO	40	30	56e	48
f	MOM	CH3	CHO	40	10	56f	43
g	CH3	CH3	COCF3	40	120	56g	75
h	Bn	CH3	COCF3	40	60	56h	53

Scheme 14. PIFA-mediated, solid-phase synthesis of galanthamine analogue precursors.

tris(allyl)-protected precursor 58 was cyclized under standard conditions. Pelish and coworkers took good advantage of the selectivity and the mildness of the hypervalent iodine reagent to perform the coupling without a ecting the resin connection or other parts of the molecule.

In 1999, Dominguez and co-workers showed that phenanthro[9, 10-d] fused isoxazoles 61 and related pyrimidines 63 could be obtained from the biarylisoxazoles 60 and biarylpyrimidines 62, respectively, with PIFA as the oxidant [52]. This reagent proved to be the most e cient and a orded product mixtures from which the desired biaryl product could be iso-