Unactivated aromatic and alkyl groups can be functionalized by formation of chelate Pd complexes and interesting applications have been published, although most of them are stoichiometric reactions.
Aromatic compounds 413, bearing hetero atom-containing groups at positions suitable for forming mainly five-membered or sometimes six-membered chelating rings, undergo cyclopalladation at an ortho-position to form a σ-arylpalladium bond as in414 by virtue of the stabilization due to the chelation of these hetero atoms. The ortho-palladation products 414 are stable and can be isolated [173].
After the first report on the preparation of the azobenzene andN,N-dimethylbenzy- lamine complexes415and 416[174], numerous complexes have been prepared.
414
N N Pd
Cl
N
Me Me
Pd Cl H2C
+ PdX2
413
A A
Pd-X
416 415
Theσ-arylpalladium bonds in these complexes are reactive and undergo insertion and substitution reactions, and the reactions offer useful methods for the regiospe- cific functionalization of the aromatic rings. Alkenes, alkynes and CO insert under certain conditions. Some classical examples are cited in the following.
The first example is insertion of styrene toN,N-dimethylbenzylamine complex (416) to form the stilbene derivative417, which takes place smoothly at room tem- perature in AcOH [14]. Alkynes insert smoothly. Two moles of diphenylacetylene insert into the benzyl methyl sulfide complex 418 to afford the eight-membered heterocycle419 [175].
+ Pd + HCl +
416 417
N Pd Cl
Me N Me
Ph
Ph
Me Me
AcOH
+
418 419
S +
PdOAc
S Me Me
Ph Ph
Ph
Ph
Ph Ph
AcO-
Facile insertion of CO takes place, and the reaction offers a synthetic method of ortho-substituted benzoic acid derivatives. The 2-aryl-3-indazolone 421 was obtained in high yield by carbonylation of 4-methylazobenzene complex 420 in alcohol or water [176]. Cobalt-catalyzed carbonylation of 421 and subsequent hydrolysis afforded aniline and 5-methylanthranilic acid (422). The results show that theσ-bond formation is an electrophilic substitution of PdCl2 on the benzene ring [176,177].
The alkylation at theortho carbon is possible by the reaction of chelate com- plexes with Grignard reagents, organolithium reagents in the presence of PPh3, or alkyl halides. o-Methylbenzaldehyde was prepared via the formation of a Schiff base complex 423and its reaction with MeLi [178]. The ortho alkylation is pos- sible even with alkyl halides. Treatment of acetanilide (424) with 3 equivalents of
+
422 421
420
84%
CO, EtOH N
N
N HN O
O
Me N
NH
Pd Cl C O
NH2
CO2H
NH2
Me
Me Me
Co2(CO)8
CO
Pd(OAc)2 and an excess of MeI afforded 2,6-dimethylacetanilide (425) by step- wise ortho-palladation and methylation twice [179]. However, treatment of the Schiff base complex 426 with trifluoroacetic acid and alkyl iodide produced the 2,6-dialkylbenzaldehyde 427 after hydrolysis. This reaction can be made semi- catalytic [180].
425 424
(3 equiv.) + Pd(OAc)2
Ph3P 90%
1. PhNH2 2. Pd(OAc)2
3. NaCl
HN
O
Me
Me Pd
OAc O HN
Pd NH
Me O
NHCOMe AcO CHO
HC N
CHO Pd-Cl
HC N Me
Me
423
MeI
MeCN MeI
MeLi H2O
427 426
Pd 84%
N
AcO
C6H13
CHO
C6H13
Ph
C6H13I
CF3CO2H H2O
Due to the chelating effect of nitrogen, facile cyclopalladation of allylamines occurs to form 428 which undergoes insertion reactions [180]. The first classical application is the ingenious synthesis by Holton of a prostaglandin derivative start- ing from 3-(dimethylamino)cyclopentene (429), utilizing facile palladation by the chelating effect of allylic amines [181]. The key steps in the synthesis are the facile and stereoselective introductions of a carbanion and an oxy anion into the cyclopen- tene ring by virtue of the stabilizing chelating effect of the amino group, and the alkene insertion to the Pd–carbon σ-bond. The first step is the stereo-defined carbopalladation with malonate and the subsequentβ-H elimination to form the 3- substituted 4-aminocyclopentene430 in 92 % yield. The attack of the malonate is anti to the amino group. Further treatment of the amino ester430with Li2PdCl4, 2- chloroethanol and diisopropylethylamine in DMSO gave rise to the oxypalladation product 431, which was immediately treated with pentyl vinyl ketone. Insertion of the alkene afforded the desired enone 432 in 50 % yield. The enone 432 was converted to an important intermediate433 for prostaglandin synthesis.
432
430 429
+ 92%
Li2PdCl4
431
428 + MeOH + PdCl2
NMe2
NMe2
Pd MeO
Cl
steps N
N N Pd Cl
Pd Cl N
O Cl
Cl
OH
N
O Cl
O
RO
O O CO2Et
O
CO2Et CO2Et
CO2Et CO2Et CO2Et
CO2Et
CO2Et CO2Et
O CO2Et
50%
+ Li2PdCl4
433
As a recent elegant application of coordination-directed C—H activation and sub- sequent C—C bond formation, Sames synthesized the core of teleocidin B4 [182].
The key step is the selective C—H bond activation of two methyl groups of an ortho-tert-butyl in the Schiff base434. Treatment of 434with Pd(OAc)2afforded the palladacycle435 in 75 % yield by the help of rather strong coordination to N and O functions. The first functionalization was achieved by the reaction with the alkenylboronic acid to yield the alkylated product 436 in 86 % yield, which was converted to437by the Friedel-Crafts reaction. Then the second palladacycle for- mation from437 provided two diastereomers 438, which were, without isolation, subjected to carbonylation (40 atm) at room temperature. Treatment of crude reac- tion mixture with silica gel cleaved the Schiff base and spontaneous lactonization occurred to give a mixture of the lactones439and440(6 : 1). The main product was N-alkylated to yield441. Finally, the fourth ring was constructed by a Heck-type reaction on the aromatic ring to give the desired compound.
Friedel-Crafts PdCl2, AcONa
AcOH, 75%
Ag2O, DMF, 86%
PdCl2, AcONa
434 435
436
437 OMe
N
OMe
MeO
OMe
N Pd O Cl Me
B(OH)2 MeO
OMe
N
OMe
MeO
N MeO OMe MeSO3H
1. CO, MeOH 2. SiO2, CHCl3
65%
+
438 439
440 OMe
N Pd O Cl Me
MeO
NH OMe
O Me
Me NH OMe
O Me
Me
441 2. BBr3
teleocidin B4 core
Br Br
1. Pd(OAc)2, P(t-Bu)3
N OH
O Me
Me Br
N OH
O Me
Me Cs2CO3, DMA, 57%
t-BuOK
Synthetic reactions utilizing the stable chelate complexes cited above are mostly stoichiometric. However, studies on catalytic reactions involving chelate com- plexes are attracting attention as more useful synthetic methods. The amide car- bonyl of acetanilide (442) is capable of forming a six-membered chelate ring 443, and undergoes alkene insertion [183]. Importantly, the reaction of the acetanilide 442 with butyl acrylate via the complex 443 can be carried out in AcOH with a catalytic amount of Pd(OAc)2(2 mol%) and BQ as an oxidant to give the coupling product in 85 % yield [184].
Pd(OAc)2 (2 mol %) BQ, AcOH, 85%
442 443
+ HN
O
HN
O
CO2Bu CO2Bu
HN
Pd O OAc
Similarly, the catalytic functionalizationt-butyl group has been investigated. Using 2-thiobenzylidene Schiff base 444, phenylation of the methyl group with Ph2Si(OH)Me was carried out in the presence of Pd(OAc)2(2.5 mol%) and Cu(OAc)2 (2 equiv.) in DMF, and the phenylated product was obtained in 51 % yield with TON 20. Although the reaction is not efficient, further improvement is expected [185].
Recently, regioselective oxidative coupling of alkenes with aromatics as useful synthetic methods has been developed based on participation of some functional groups such as OH and amino present in suitable positions of aromatic rings, even though no stable chelate complex is isolated. Oxidative coupling of 2- phenylphenol (445) with acrylate using Pd(OAc)2 and Cu(OAc)2 in the presence of MS 4A under air occurred regioselectively at the 2 carbon due to coordination
Pd(OAc)2, Cu(OAc)2
444
+ Ph2Si(OH)Me
DMF, 100 °C, 51%
TON 20 N
S
N Me
S Me
of phenolic oxygen to Pd(II) species as shown by 446 to give 447 as a pri- mary product. Subsequent Michael-type addition afforded 6H-dibenzo[b,d]pyran- 6-acetate448in 69 % yield [186]. Sulfonamide in biphenyl449 is a good coordi- nating group, and regioselective coupling of acrylate at 2 carbon occurred to give 450, and subsequent Michael-type addition afforded ethyl 5,6-dihydro-5- (benzenesulfonyl)phenanthridine-6-acetate (451).
445
Pd(OAc)2, Cu(OAc)2
448
MS 4A, air, DMF, 79%
446
447 OH
CO2Bu
O
CO2Bu
O PdOAc
OH
CO2Bu +
PhO2SHN
CO2Et
N
PhO2S CO2Et
PhO2SHN EtO2C
449
450
451
+ Pd(OAc)2 , Cu(OAc)2 AcONa, MS 4A, air
DMF, 84%
Furthermore, regioselective reaction of styrene at theorthoposition ofp-metho- xybenzoic acid (452) gave 453 as a primary product. Subsequent oxypalladation of 453to give454 and455, andβ-H elimination produced two lactones 456and 457[187].
Clean regiocontrol by weak coordination of Pd to OH, NHR and COOH groups is remarkable.
+ +
26% 14%
CO2H
Ph
452
CO2H
453 Ph
455
456 457
O O
Ph 454
O O
Ph PdX
O
Ph O OMe
MeO
MeO MeO
O
Ph O
MeO
XPd +
Pd(OAc)2 , Cu(OAc)2 AcONa, MS 4A, air
OMe DMF
Pd(OAc)2
Cu(OAc)2