3.5 Carbonylation and Reactions of Acyl Chlorides
3.5.3 Formation of Aldehydes and Ketones
Aldehydes are prepared by carbonylation in the presence of hydride sources. For- mation of aldehydes can be understood by transmetallation of acylpalladium 56 with a hydride to give acylpalladium hydride 57, followed by reductive elimina- tion. Metal hydrides and hydrogen are used for aldehyde synthesis. Hydrosilane is one of the hydrides. Reaction ofβ-naphthyl triflate (58) with Et3SiH using DPPF as a ligand under mild conditions afforded the aldehyde59 [28]. Carbonylation of the alkenyl triflate60in the presence of tin hydride and LiCl afforded the aldehyde 61in 95 % yield [29].
+
reductive elimination
OTf CHO
Ar O
Pd-X Ar
O
Pd-H Ar
O M′H H
transmetallation
56 57
58
+ CO + Et3SiH
Pd(OAc)2, DPPF, Et3N DME, 1 atm, 70 °C, 84%
59 M′X
TfO
OTBS H OTBS
OHC
OTBS OTBS H
Pd(PPh3)4, LiCl THF, 50 °C, 95%
+ CO + Bu3SnH
60
61
Ketones are prepared by transmetallation of acylpalladium 62 with organo- metallic reagents. Phenyl triflate was converted to acetophenone (64) by carbony- lation in the presence of Me4Sn [30].
In the total synthesis of strychnine, Overman prepared the alkenyl aryl ketone67 in 80 % yield by the carbonylation of the aryl iodide65with the alkenylstannane 66using AsPh3 as a ligand [31].
Chloroanisole, activated by coordination of electron-attracting Cr carbonyl68, reacted with CO and dimethylindium69to afford the methyl ketone70under mild conditions [32]. Also Bu3In was used for the preparation of butyl phenyl ketone (71) [33].
+ CO + Me4Sn
Pd(OAc)2, DPPP, Et3N DMF, 60 °C, 84%
63
64 OTf
Me O reductive elimination transmetallation
M′R Ar
O
Pd-X Ar
O
Pd-R Ar
O R 62
+
+ CO + Pd2(dba)3, AsPh3
65 66
67 N MeN
MeN O
Me3Sn I
NMP, 70 °C, 80%
N MeN
MeN O
ButO
ButO OTIPS
OTIPS
O
50°C, 5 atm, 84%
Pd(PPh3)4, THF
+ CO + PdCl2(PPh3)2,THF
68 69 70
71 1 atm, 66 °C, 87%
Cr(CO)3
Cl
Cr(CO)3
Me O N
In Me Me
Me Me
OMe OMe
I
O + CO +n-Bu3In
Ketones are also prepared by carbonylation in the presence of alkenes. Carbony- lation of 4-iodoanisole in the presence of dihydrofuran (72) provided the ketone 73 via insertion of the double bond in dihyrofuran to acylpalladium, followed by β-H elimination [34].
PdCl2, PPh3, Et3N benzene, 5 atm 120 °C, 66%
72 73
I
O O
O MeO
MeO
+ CO +
Carbonylation of 2-iodostyrene (74) afforded indanone (75) and indenone (76) via intramolecular acylpalladation of the double bond. In the presence of Bu4NCl and pyridine, protonation occurred to give indanone (75). When Et3N was used, indenone (76) was obtained. Under high pressure CO (40 atm), the keto ester 77 was the main product [35].
77 74
75
76 PdCl2(PPh3)2, Et3N
MeOH, DMF, 100 °C, 40 atm, 74%
I
O
O
O
CO2Me + CO
Pd(OAc)2, pyridine Bu4NCl, DMF, 100 °C 1 atm, 100%
PdCl2(PPh3)2, Et3N MeCN, 80 °C, 1 atm, 50%
O
Pd-X
There are several possible reaction paths in the carbonylation of 1-iodo-1,4-, 1,5- , and 1,6-dienes, and chemoselectivity depends on reaction conditions and ligands.
For example, the 1-iodo-1,4-diene78 reacted with two CO molecules to give the keto ester79 in high yield by domino insertion of CO, alkene, and CO [36]. The diketo ester81was obtained from iodotriene80. In this reaction, domino insertion of CO, alkene, and CO occurred to give rise to the diketo ester 81in 54 % yield.
The bicyclic monoketo ester82 was formed in 14 % yield by premature trapping of acylpalladium intermediate with MeOH [37].
80
78 79
MeCN, benzene 40 atm, 100 °C, 82%
+ CO + + CO +
54%
+
I O
I
O
O
CO2Me
14% 82
CO2Me O
PdCl2(PPh3)2, Et3N
PdCl2(PPh3)2, Et3N MeCN, benzene 40 atm, 95 °C, 54%
81
CO2Me MeOH
MeOH
Carbonylation of 2-(3-pentenyl)iodobenzene (83) afforded a mixture of the ketone 84, γ-lactone 85, and δ-lactone 86. When DPPE instead of PPh3 was used, the γ-lactone 85was obtained as the main product [38].
I
O
O O
Me
O Me
O Et3N, 100 °C
O O
Me
THF, MeCN, 100 °C
+
43% 15% 26%
52%
Pd(OAc)2, DPPE, 83
85 84 86
+ CO
PdCl2(PPh3)2,Et3N
85 +
Efficient enantioselective carbonylative cyclization of the o-allylphenyl triflate 87 occurred using (S)-BINAP, Pd(OCOCF3)2, and PMP (pentamethylpiperidine) to provide the ketone88 with 95 % ee [39].
87 88
MS-4A, PMP, dioxane,1 atm 80 °C, 89%, 95% ee + CO Pd(OCOCF3)2, (S)-BINAP OTf
O
In the carbonylation of the iodo amide 89, insertion of the sterically hindered double bond in89occurred at first, generating a quaternary carbon, and subsequent CO insertion gave the lactam ester 90in 77 % yield [40].
Pd(OAc)2, P(o-Tol)3
Et3N, Bu4NBr, DMA, 85 °C, 77%
+ CO + MeOH
89
90
N OTBS
Cl
Cl I
Me O
Br
N O Me
Br CO2Me
TBSO
Cl Cl
The three-component reaction of 2-iodophenol (91), norbornene (92), and CO provided the ketone94 and theδ-lactone93depending on the order of insertions of CO and alkene, which was controlled by ligands [41]. The ketone 94 was produced via insertions of CO and then alkene when DPPP was used. Formation of the lactone93occurred via alkene and CO insertions when PPh3was used [42].
I
OH
O O
O
O
+ CO
+ Pd(OAc)2, TlOAc
DMF, 1 atm
+
100 : 0 3 : 97
82%
70%
93
91 92
94 93 : 94
PPh3
DPPP
Carbonylation of 2-iodophenol (91) in the presence of 1,2-nonadiene (95) afforded 2-(n-hexyl)-3-methylene-2,3-dihydro-4H-1-benzopyran-4-one (97) in 74 % yield, showing that selective attack of phenoxy group at the substituted terminus ofπ-allylpalladium intermediate96occurred. Uses of DPPB and K2CO3
were important [43].
Pd(OAc)2, DPPB +
I
OH
C6H13
OH O
C6H13
Pd-X
O O
C6H13
K2CO3, benzene 20 atm, 100 °C, 74%
91
95
96
97
+ CO
•
Acylpalladium was generated by the oxidative addition of acyl chloride 98 to Pd(0), and reacted with 1,1-dimethylallene (99) to give π- allylpalladium intermediate 100. Then transmetallation of100 with diborane and reductive elimination provided 2-acylallylboronate 101. Thus highly regio- and stereoselective acylboration of allenes occurred using ligandless Pd catalyst [44].
Cacchi found a new and simple CO-free methyl ketone synthesis using acetic anhydride. Acetophenone was obtained in 74 % yield by the reaction of iodobenzene with acetic anhydride using ligand-free Pd catalyst in the presence of
+ PdCl2(MeCN)2
toluene, 80 °C, 80%
99
100 101
t-Bu
COCl B B
O
O O
O
O t-Bu
Pd-X
O t-Bu
B O O 98
• +
LiCl [45]. As one explanation, insertion of C=O bond to Ph-PdX generates 102, from which acetophenone is formed.
+ Pd2(dba)3, LiCl i-Pr2NEt, DMF I
Me O Me
Ph O
I-Pd O
Ph Me
O
100°C, 74%
102 (MeCO)2O
Miura found that the aldehyde group in salicylaldehyde (103) can be converted to aryl ketone106in high yield by the reaction with aryl iodide using ligandless PdCl2
and LiCl in the presence of Na2CO3in DMF. The reaction is explained by the fol- lowing mechanism. The first step is formation of phenylpalladium phenoxide104.
Oxidative addition of the C-H bond of aldehyde to the phenyl(aryloxy)palladium 104 generates Pd(IV) species 105, which was converted to the ketone 106 by reductive elimination [46].
CHO
OH + Ph-l
PdCl2, LiCl Na2CO3
DMF, 91%
CHO
O Pd 104
O Pd O
Ph Ph H
105
OH Ph O
106 103
A good synthetic method for substituted fluoren-9-ones is the carbonylation ofo- halobiaryls [47]. Carbonylation of 2-bromobiphenyl (107) in DMF in the presence of cesium pivalate gave rise to fluoren-9-one (109) in quantitative yield via the palladacycle 108. Use of PCy3 as a ligand is important.
Br
107
+CO PdCl2(PCy)3
Cs pivalate, 1 atm 120°C, 100%
Pd O
108
O
109
A well-established preparative method of alkynyl ketones110is the Sonogashira- type carbonylation of aryl halides in the presence of terminal alkynes. (Trimethylsi- lyl)pyridylethyne (111), deprotectedin situ, reacted with 3-iodotoluene and CO to give the alkynylm-tolyl ketone112using DPPF as a ligand. Pd-catalyzed reductive cyclization of112using HCO2H afforded the 1,8-naphthyridine113[48].
Ar-l + CO + R Pd(0)
R O
Ar
Me l
+
N Me
NH2 TMS
111
+ CO
PdCl2(dppf), Et3N Bu4NF, rt, 65%
N Me
NH2
112
Me O
Pd(OAc)2(PPh3)2, HCO2H, Bu3N
DMF, 70 °C, 65% N N Me
113 Me
110
The 12-membered cyclic alkynyl alkenyl ketone115was obtained by carbonyla- tive cyclization of the alkenyl triflate with alkynylstannane in114 [49].
SnMe3
OTf
114
+ CO
PdCl2(dppf), LiCl DMF, 36%
O
115
Formation of flavone116and aurone117by carbonylation of 2-iodophenol (91) in the presence of terminal alkyne is known [50]. Also 1,4-dihydro-4-oxoquinoline 119is obtained by the reaction of 2-iodoaniline with CO and terminal alkynes [51].
These reactions proceed via the formation of the aryl alkynyl ketones 118 as intermediates.
l
OH 91
+ CO + Ph Pd(0)
O O
Ph
116 117
O Ph
O +
l
NH2
+ CO + Ph Pd(0)
NH2
O
118 119
NH O
Ph Ph
Yang carried out extensive studies on selective formation of the flavones 116, and found that the acetate of iodophenol 120, as a latent hydroxy group, was superior to free iodophenol 91 and formation of the aurone117 was suppressed.
As a catalyst, PdCl2(PPh3)2, combined with DPPP and thiourea, was found to be the best one. Under these conditions and 1 atm, the flavone116 was obtained selectively in 92 % yield without isolating the alkynyl ketone 121[52].
thiourea, Et2NH DBU, 40 °C,
1 atm 92%
116 120
121
+ +
PdCl2(PPh3)2, I DPPP
OAc
Ph
OAc O
Ph CO
Formation of indole derivative by the reaction of 2-ethynylaniline, aryl halide and CO is known [53]. Cacchi extended the reaction to the synthesis of indolo[3.2- c]quinoline. Reaction of 2-(2-aminophenylethynyl)trifluoroacetanilide 122, 4- iodoanisole and CO occurred as shown by 123 to provide 124 and then the 3-aroylindole 125. Treatment of 125 with a base gave the indoloquinoline 126 in 70 % overall yield [54].
+ CO
ArCO-PdX
123
124
125
126 NH2
NHCOCF3
I
MeO
NH2 NHCOCF3
N ArCOPd
COCF3 NH2
NH NH2
Ar O
NH N 122
MeO K2CO3, 70%
Pd(PPh3)4, MeCN
K2CO3 +