3.5 Carbonylation and Reactions of Acyl Chlorides
3.5.2 Formation of Carboxylic Acids, Esters, and Amides
Aromatic and α,β-unsaturated carboxylic acids and esters are prepared from aryl and alkenyl halides.
+ CO + NU-H Pd(0) Nu
X
R
X
R
O
Nu O base
+ CO + NU-H Pd(0) base
Carbonylation of reactive iodides proceeds using PdCl2(PPh3)2 as a standard catalyst under mild conditions in the presence of a base. Several modified catalyst systems have been reported. For example, ligandless Pd charcoal is an active catalyst at 140◦C [1]. Uozumi reported that the amphiphilic phosphine-Pd complex (Pd-PEP) bound to PEG-PS resin is a very active and useful catalyst. Carbonylation
of iodobenzene proceeded in H2O without an organic solvent at room temperature and under atmospheric pressure of CO in the presence of Pd-PEP and K2CO3 to give benzoic acid in 97 % yield. No reaction occurred when Pd-PPh3, instead of Pd-PEP, was used under similar conditions. The catalyst can be recycled [2]. Pd- complex immobilized on PAMAM (polyamino amido) dendrimers supported on silica was found to be an active catalyst for efficient carbonylation of iodobenzene in MeOH at 100◦C and 7 atm to produce methyl benzoate and the catalyst was recycled four to five times without loss of activity [2a]. Phenyl benzoate was obtained in high yield from iodobenzene in the presence of phenol in DMF under 1 atm of CO. Addition of CuI accelerated the reaction [3]. Chlorides are difficult to be carbonylated. However, Beller carried out the carbonylation of chlorobenzene using the ferrocenyldicyclohexylphosphine XI-9 in the presence of Na2CO3 at 140◦C inn-BuOH, and obtained butyl benzoate in high yield [4]. Chloropyridines are active chlorides and butyl picolinate (2) was prepared by carbonylation of 2-chloropyridine at 130◦C. DPPF and DPPB were used as effective ligands [5].
Pd-PEP, K2CO3
DMF, 1 atm, 90 °C, 92%
PdCl2(PPh3)2, CuI, n-Bu3N
I CO2H
I
Me
CO2Ph
Me rt, 1 atm, 97%
+ CO + H2O
+ CO + PhOH
PdCl2(PhCN)2, DPPF Et3N, 25 atm, 130 °C, 95 % PdCl2(PhCN)2,XI-9 Na2CO3, MS 4a 1 atm, 145 °C, 97%
2
N Cl N CO2Bu
Cl CO2Bu
+ CO + n-BuOH
+ CO + n-BuOH
Alkenyl halides and triflates are easily carbonylated. Carbonylation of α-iodo enone 3 proceeded at 60◦C using Pd(OAc)2 and DPPP, and the ester 4 was obtained in 62 % yield [6]. The lactam 5 was converted to the vinyl triflate 6, which was carbonylated to afford the α,β-unsaturated ester 7 [7]. Carbonylation of the alkenyl iodide 8, possessing a labile peroxy group proceeded smoothly to give theα,β-unsaturated ester9under 1 atm of CO at 60◦C in DMF. The peroxy group remained intact [8].
Pd(OAc)2, DPPP, 2,6-lutidine THF, 50 atm, 60 °C, 62%
3 O 4
O
Me H
Me H
O MeO2C O
Me H
Me H
I
+ CO + MeOH
PdCl2(PPh3)2, Et3N, MeOH, 75%
5 6
7 R3SiO
NH O H
H
R3SiO
N OTf
H
H
CO2Me
TBDPSO
N CO2Me H
H
CO2Me
9 Pd(OAc)2, PPh3, Et3N,
DMF, 60 °C, 1 atm, 60%
8
I
O O OMe
CO2Me
O O OMe
+ CO + MeOH
Alkenyl iodides can be generated in situ by hydroalumination of alkynes, fol- lowed by iodination, and α,β-unsaturated esters are prepared by carbonylation without isolation of the iodide. As an example, the propargylic alcohol 10 was aluminated regio- and stereoselectively and converted to the alkenyl iodide 11.
The intramolecular carbonylation of11afforded the dibutenolide12in 81 % yield.
The reaction is a key step in the total synthesis of (+)-parviflorin [9].
+ CO
PdCl2(PPh3)2, NH2NH2, K2CO3 81%
10
11
12
3
3 3
1. Red-Al® 2. AcOEt 3. I2
3
O
O
OTBDPS
OTBDPS Me
Me OH
OH
O
O
TBPPSO
TBDPSO
O
O O
O
Me
Me TBDPSO
TBDPSO I
OH OH
I
Carbonylation is widely utilized for preparation of complex molecules of natu- ral products. As one example, Leighton constructed the fully elaborated tetracyclic
core of phomoiderides 16 efficiently by novel domino carbonylation–Cope rear- rangement of the vinyl triflate13as a key step [10]. The acylpalladium species14, generated by the carbonylation of the alkenyl triflate13, was trapped intramolec- ularly by the hemiketal OH group, which was formed from the hydroxy ketone as shown by14to afford the unsaturated lactone 15at 75◦C. The strained molecule of 15 underwent Cope rearrangement as shown by 15 to give 16 in 78 % yield simply by raising the temperature to 110◦C. Interestingly benzonitrile was used as the best solvent.
Pd(PPh3)4,i-Pr2NEt, PhCN, 54 atm 70~115°C, 78%
+ CO
13
14 O
R
Me
TESO
OTf
OTBDMS
OH OH
O R
TESO
OTBDMS
OH OH
Pd-X O
Cope rearrangement
15
16 R
Me
TESO
OTBDMS
OH O
O O
R
Me
TESO
OTBDMS
OH O
O O
R = (E)-MeCH=CH(CH2)5- O
O OTBDMS O
R Me
OH
OTES
In the total synthesis of ciguatoxins, the enol phosphate 18, derived from the nine-membered lactone 17, was carbonylated smoothly to give the unsaturated ester 19[11].
O
O O
(PhO)2(O)PO H O
OBn H
Ph
H H
Pd(PPh3)4, Et3N,
+ CO + MeOH O
O O
MeO2C H O
OBn H
Ph
H H 17
19
18
DMF, 50 °C, 70%
O
O O
H O
OBn H
Ph
H H O
Benzylic alcohols are reactive in the presence of an acid as an activator. Asym- metric carbonylation of 1-(6-methoxy-2-naphthyl)ethanol (20) by using DDPPI as a chiral ligand in the presence of CuCl2 and p-TsOH as activators afforded the methyl ester of (S)-naproxen (21) with 81 % ee [12]. Benzyl alcohol was carbony- lated to phenylacetic acid under somewhat harsh conditions in the presence of HI.
Presumably the carbonylation of benzyl iodide, generated by the reaction of benzyl alcohol with HI, occurred. 1,2-Di(hydroxymethyl)benzene (22) was carbonylated to give 3-isochromanone 25 in 88 % yield. In this reaction, one of the benzylic alcohols is converted to benzylic iodide23 and the lactone25 was obtained via acylpalladium24 [13].
20
21
Pd(PPh3)4, HI acetone-H2O + CO
90 atm, 90 °C 88%
+ Pd(0) + HI
22 23
24 25
O O OH
OH
OH I
OH O
PdI
+ CO + MeOH
PdCl2, CuCl2 DDPPI,p-TsOH
8 MPa, 100 °C 54%, 81% ee MeO
Me OH
MeO
Me H CO2Me
O O H
H PPh2
Ph2P DDPPI
CO
Pd-catalyzed reaction ofα-naphthol, isobutyraldehyde, and CO in the presence of CF3CO2H afforded naphthofuran-2(3H)-one 28 in 79 % yield. The reaction is explained by acid-catalyzed formation of 1-(2-naphthyl)butanol 27, followed by carbonylation of the benzylic alcohol. Although its reactivity is lower, the phenol derivative29reacted with acetaldehyde to generate the benzylic alcohol30, which was carbonylated to provide the benzofuranone31 in 54 % yield [14].
Pd(PPh3)4, CF3CO2H + CO + i -PrCHO
120°C, 5 atm, 79%
27 28 OH
O O
i -Pr OH
i -Pr 26
OH
CO
+ CH3CHO + CO
Pd(PPh3)4, CF3CO2H 125°C, 5 atm, 54%
29 OH
O O
OH
O O
OH Me
O O
O O
Me
30 31
CO
Although it is not a benzylic type, the mesylate 32 was carbonylated under normal conditions to give the methyl ester 33 as a precursor of camptothecin in high yield [15].
33
PdCl2(PPh3)2, Et3N N
N O
OMs
N
N O
O O HO Et 10 atm, 60 °C 84% from alcohol + CO + MeOH
camptothecin N
N O
CO2Me steps 32
Carbonylation in the presence of secondary amines provides either amides orα- keto amides by single and double carbonylations. Also, the corresponding α-keto esters are prepared. It was reported that ratios of single and double carbonylations depend mainly on the nature of the phosphine ligands. It was claimed that PMePh2
or DPPB is a suitable ligand for double carbonylation [16].
R2NH
Ar NR2 O
Ar NR2
O
O
Ar OR
O
Ar OR
O
O Ar-I + 2CO + NuH
+
ROH +
Later several ligands, including PPh3, were found to be effective depending on the substrate. Carbonylation of 2,5-dibromo-3-methylpyridine (34) in the presence of aniline produced the 2-picolinamide35regio- and chemoselectively when 2,2- bipyridine was used as a ligand. Poor yield and selectivity were obtained by the use of ubiquitous phosphine ligands. The monoamide 35 was isolated in 82 % yield in a chemical plant in 600 kg scale production [17].
+ CO + PhNH2
DBU, 65 °C, 5.5 atm, 90%
34 35 N
Br Me
Br N
Br Me
NHPh O PdCl2(PPh3)2, bipyridine
4-Pyridylglyoxamide37was prepared by double carbonylation of 4-iodopyridine (36). High selectivity and yield of37were obtained when PCy3 andi-PrOH were used as a ligand and nucleophile, respectively. When a primary amine,n-BuNH2, was used, the Schiff base of keto amide38was obtained in high yield [18]. Domino double carbonylation and hydrogenation of the Schiff base occurred in the reaction ofp-iodotoluene with cyclohexylamine under CO and H2pressure using ligandless Pd on charcoal to afford the α-amino amide 39in high yield [19].
55 atm 7 atm
36 37
Pd(OAc)2, PCy3 50°C, 60 atm, 90%
36 38
39 N
I
N
O
N-i-Pr2 O
N
I
N
N
NHBu O
Bu
I
Me
HN
NHBu O Cy
Me + CO + i-Pr2NH
+ CO + n-BUNH2
Pd(OAc)2, PCy3 50°C, 60 atm, 91%
+ CO + H2 + CyNH2
Pd/C, Et3N MS 4A 120 °C, 88%
Carbonylation of iodoferrocene 40 in the presence of morpholine gave rise to the amide 41 and the keto amide 42 by using PPh3 as a ligand [20]. A slight difference in temperature and pressure had a marked influence on the product ratios. The keto amide42was obtained as the main product with 80 % selectivity at 60◦C and 50 atm. The amide41 was obtained as a single product at 100◦C.
40 100 >99 : 1 Fe
I
Fe O
N O
Fe O
O N
O O
H N
100
41 : 42 40
+ CO + Pd(OAc)2, PPh3
+
temp. press. (atm) conv. % ratio
50 92 20 : 80
41
60
42
Carbonylation of a mixture of more reactive p-iodoacetophenone (44) and o- iodoaniline (43) occurred stepwise chemoselectively to give the amide 45, and further carbonylation of45 afforded 2-aryl-4H-3,1-benzoxazolin-4-one 46[21].
I
NH2
I + CO
+ Pd(PPh3)4, MeCN
K2CO3, 1 atm, 60 °C, 85%
I
NH
COMe O
N O
COMe O
43 44
45 46
O
CO
Carbonylation of iodobenzene in the presence ofN-benzylideneamine47 using DPPF as a ligand proceeded via formation of amide 48 by insertion of 47 to the acylpalladium bond, and 3-phenyl-2,3-dihydro-1H-isoindol-1-one (49) was obtained [22].
Direct preparation of primary amides by carbonylation in the presence of NH3
is not easy. As one solution, Indolese carried out carbonylation ofp-bromotoluene
+ CO + PdCl2(dppf), Et3N benene, 120 °C 20 atm, 46%
I PhN=CH
N Pd
O Ph
Ph X
N Ph Ph O
47
48
49
using formamide as an ammonia equivalent in the presence of Lewis bases such as DMAP or imidazole, and obtained toluamide (50) in good yield [23].
+ HCONH2+ CO
dioxane, 120 °C, 82%
PdCl2(PPh3)2, DMAP
50
Br CONH2
Me Me
Several attempts to find CO-free preparative methods of esters and amides have been carried out using alkyl formate or formamide as CO sources. Methyl ben- zoate (51) was obtained in 98 % yield by the reaction of iodobenzene with methyl formate in the presence of MeONa [24]. DMF can be used as an amide source.
Reaction of aryl iodides with DMF in the presence of 2 equivalents of POCl3
using ligandless Pd catalyst afforded the N,N-dimethylbenzamide 52. Formation of a Vilsmeier reagent from DMF and POCl3 is expected and the amide may be formed by Pd-catalyzed reaction of aryl iodide with the Vilsmeier reagent [25].
Aminocarbonylation of aryl bromides with DMF was carried out using Pd-DPPF as a catalyst in the presence of stoichiometric amounts of imidazole andt-BuOK to afford N,N-dimethylbenzamide 53[26]. Also, N,N-dimethylbenzamide (55) was prepared by the reaction of aryl bromide with carbamoylsilane 54, which is prepared from DMF [27].
+ HCO2Me + MeONa PdCl2(PPh3)2, CH2Cl2
40°C, 98%
+ HCONMe2 Pd2(dba)3, POCl3
120 °C, 87%
52 51
I CO2Me
I CONMe2
MeO MeO
+ HCONMe2 Pd(OAc)2, DPPF, imidazole t-BuOK, 180 °C, 15 min, 59%
+ Pd(PPh3)4, toluene
100°C, 88% +
54
53
55
Br CONMe2
Me Me
TMS NMe2
O Br CONMe2
DMF Me3SiBr