Pd-catalyzed arylation of various phosphorus compounds containing P—H bonds with aryl and alkenyl halides, or triflates offers useful methods of C—P bond for- mation. After pioneering work on Pd-catalyzed arylation and alkenylation of dialkyl phosphonates by Hiraoet al. [1], extensive studies have been carried out on aryla- tion of various phosphorus compounds. The methods are particularly useful for the synthesis of various chiral phosphines used in Pd-catalyzed asymmetric reactions.
3.7.5.1 Arylation of Phosphines and Phosphine Oxides
Arylations of phosphines and phosphine oxides are carried out as shown by the following general equations. The reactions are explained by oxidative addition of aryl halides, followed by ligand exchange with Ph2P-H, which is similar to transmetallation. Finally, reductive elimination affords arylated products.
Arylation of phosphines and phosphine oxides
PhPH2 + ArX Pd(0) PhP(H)Ar Ar′X PhPArAr′ base
Ph2PH + ArX Pd(0) Ph2PAr base
Ph P H O
Ph
+ ArX Pd(0)
base Ph P Ar O
Ph Ar-X + Pd(0) Ar-Pd-X
ligand exchange
Ph2PH
Ar-Pd-PPh2
RE Ph2PAr + Pd(0)
Recently, extensive synthetic studies on multiply functionalized chiral arylphosphines by Pd-catalyzed arylation of primary and secondary phosphines with aryl halides have been carried out by Stelzer [2]. The synthetic methods can be summarized by the following general schemes.
Diphenyarylphosphines3are prepared by coupling Ph2PH (1) with aryl iodides 2. Coupling of Ph2PH (1) with 2-bromoiodobenzene derivatives4affords chemos- electively the bromophenylphosphines 5, and Suzuki coupling with 6 gives the biphenyl-type phosphines7. Consecutive displacements of the hydrogen atoms of the primary phosphine 8 with different aryl iodides 2 and 10 yield the multiply
I
Y
2
Ph2P
Y
3
Ph2P
Y
Br 5
(HO)2B
Z 6
Ph2P
Y
Z
7 I
Y
Br 4
I
Y
2 P
Y
9 Ph
H
I
Y
10
Z 1
8 P
Ph 11 PhPH2 Y
Ph2PH
functionalized phosphines 11. Similarly alkylarylphosphines 13 and 15 are pre- pared by the coupling of primary and secondary alkylphosphines 12 and14 with aryl iodides 2 and 10. Some examples of the syntheses of interesting polyfunc- tionalized phosphines are cited here.
I
Y
R2PH 2 R2P
Y
13 12
I
Y
2 14
RPH2
I
Z
10
Z
P R
15
Y
The chiral phosphine ligand17 was prepared by coupling the congested iodide 16with Ph2PH (1). 5-Diphenylphosphinobenzene-1,2,3-tricarboxylic acid19 as a water-soluble ligand (II-4) was prepared by smooth coupling of bromobenzen- etricarboxylic acid 18. Similarly the water-soluble phosphine 21 was obtained from 1and 20. The bidentate ligand 24was prepared by smooth reaction of 1,3- bis(phenylphosphino)propane (22) with 2-iodoaniline (23) using DPPP as a ligand.
The ligand 24 was a 1 : 1 mixture of two diastereomers, and enrichment of one of the diastereomers in a ratio of 8 : 3 was achieved by recrystallization from MeOH. It is somewhat surprising that the couplings of aryl iodides, 16, 18, and 20, substituted by highly polar substituents, proceed smoothly.
A racemic phosphine28was obtained by consecutive displacement of hydrogen atoms of phenylphosphine (8) with two different aryl iodides 25 and 27. For the coupling of diphenylphosphine with aryl iodides, Pd on carbon is a good catalyst in DMF under microwave dielectric heating in DMF [3].
A P-chirogenic phosphine can be synthesized by Pd-catalyzed asymmetric phos- phination. Coupling of the racemic phosphine 28awith iodobenzene afforded the
Ph2P HN
O
+ Br CO2H
CO2H
CO2H
Ph2P CO2H
CO2H
CO2H n-Bu3N, DMA
130°C, 48 h 79%
19 18
89%
1
I NH Ph
O
1 Me
16
17 Ph Me +
Pd(OAc)2 Pd(OAc)2 Ph2PH DMA
Ph2PH
I
CO2H
SO3H
Ph2P
CO2H
SO3H
HO HO
22
24 +
+
23
n-Bu3N, DMA
20 21
135°C, 16 h 54%
P P
Ph Ph
H H
Pd(OAc)2, I DPPP
H2N
P P
Ph Ph
NH2 H2N 1
AcOK, DMA 65%
Ph2PH
Pd(OAc)2
26
Pd(OAc)2, Et3N 81%
+
27
28 Pd2(dba)3, DPPP
Et3N, MeCN 90 °C, 77%
8
I
CO2H Me
P
CO2H Me
Ph H
I
P
CO2H Me
Ph CO2H
HO2C 25 PhPH2
enantio-enriched phosphine 28b in 88 % yield with 73 % ee. (R,R)-Me-Duphos (XII-10) was used as a chiral ligand [4].
+ PhI
Me3SiONa, toluene, 21 °C, 88%
73% ee
Pd(OAc)2, (R,R )-Me-Duphos (XII-10)
28a 28b
i-Pr
i-Pr i-Pr
P Me
H
i-Pr
i-Pr i-Pr
P Me
Ph
The biphenyl-based phosphine 34 was prepared from 2-bromoiodobenzene (29). Chemoselective coupling of the iodide in 2-bromoiodobenzene (29) with diphenylphosphine (1) gave 2-bromophenyldiphenylphosphine (30), and its Suzuki –Miyaura coupling with 31 afforded the biphenylylphosphine 32. Reaction of 29 with the primary phosphine 8 afforded the di(2- bromophenyl)phenylphosphine (33), and bis-biphenylylphosphine derivative 34 was obtained by Suzuki –Miyaura coupling of 33 with 31, although the yield was not high [2].
Phosphine oxides are conveniently used for the coupling, because diphenyl- phosphine oxide (36) is more easily handled than Ph2PH (1). Reaction of (Z)- alkenyl bromide 34awith diphenylphosphine oxide (36) gave (Z)-diphenylvinyl- phosphine oxide34c with complete retention [5].
29
30
31 31
32 33
Pd(PPh3)4, Et3N toluene, 94%
Pd(OAc)2, K2CO3 toluene, 22%
Pd(PPh3)4, Et3N toluene, 85%
Pd(OAc)2, K2CO3 toluene, 63%
8
34
1 Br
I
Br
PPh2
B(OH)2 Me
Me PPh2 P
Br Ph Br
B(OH)2 Me
P
Me Ph Me
Ph2PH PhPH2
Et3N, 90 °C, 91%
+
34a 36 34c
Ph Br
P O
H Ph
Ph
Ph P
Ph Ph Pd(PPh3)4 O
Triarylphosphine oxides are prepared by coupling aryl halides or triflates with diphenylphosphine oxide (36), and they are reduced to triarylphosphine with HSiCl3. Selective monophosphination of 2,2-bis-triflate of binaphthol (35) with diphenylphosphine oxide occurred to give the optically active phosphine oxide (37) using DPPB or DPPP. No bis-substitution was observed [6,7]. The phosphine oxide 37 can be converted to the phosphine by treatment with HSiCl3 and an amine. Various optically active monodentate phosphines such as MeO-MOP (VI- 12) are prepared from 37 via38. On the other hand, bis-substitution of 35 takes place to afford the bis-phosphine when NiCl2(dppe) is utilized as a catalyst, and the reaction is used for the preparation of BINAP (XV-1) [8].
+
Pd(OAc)2, DPPB, EtN(i-Pr)2
DMSO, 90 °C, 16 h 95%
(S)-35 (S)-37
36
38 OTf
OTf P(O)Ph2
OTf P
O H Ph Ph 1
NiCl2(dppe), DABCO DMF, 100 °C, 75%
(S)-XV-1
2. MeI
PPh2
PPh2
OMe PPh2
OMe P(O)Ph2
(S)-VI-12 1. NaOH
Ph2PH
HSiCl3
Reaction of 2-bromobenzaldehyde (39) with diarylphosphine oxide using Pd(OAc)2 and DPPP afforded the mixed triarylphosphine oxide 40, which was converted to the chiral phosphine ligand40a [9].
DMSO, 100 °C, 20 h 40%
39
+ Pd(OAc)2, DPPP, EtN(i-Pr)2 Ar= 3,5-Me2-C6H4
40a
40 CHO
Br
P O
H Ar Ar
CHO P O
Ar Ar
O S
PAr2 OH
SH
Imamoto reported that Pd-catalyzed coupling of phosphine-borane with aryl halides is useful for preparation of asymmetric phosphines. Phosphines can be easily isolated from phosphine-boranes by exchange reaction with amines such as pyrrolidine and DABCO [10]. Lipshutz found that aryl nonaflates (∗Nf=nonafluorobutanesulfonate) and triflates are good substrates for coupling with BH3-stabilized diarylphosphines. Selective coupling with nonaflate without
attacking bromide in 41 gave the asymmetric phosphine-borane 42 in MeCN using Pd(PPh3)4 and K2CO3[11]. In the synthetic studies directed toward P-chiral phosphines, Imamoto disclosed that the reaction of optically active (S)-(menthyloxy)phenylphosphine-borane (43) with 2-iodoanisole (44) gave the phosphine-borane 45 with complete retention of configuration in MeCN using K2CO3as a base. Solvents are crucial and nearly complete inversion was observed to give 46in THF [12–14].
+ Pd(0)
base Ph2PAr
+ Pd(PPh3)4, K2CO3
Br
ONf
Br
PPh2
41 42
MeCN, 93%
NR3
Ph2PH BH3 Ar-X BH3
Ph2PH BH3
BH3 BH3
NR3
100 : 0 Pd(PPh3)4, K2CO3
43 MenO P
Ph H
MeCN, 93%
45 MenO P
Ph
46 OMe
I
OMe
+
MenO P Ph + OMe
44
BH3
BH3
BH3
Phosphorylation of Ar2PH-BH3with aryl halides proceeds under mild conditions using Pd-Cu catalyst and P-chiral phosphine-boranes of high enantiopurity are pre- pared by this method. As an effective ligand, MePPh2is used with Pd(OAc)2. The phosphine-borane 50was prepared in 68 % yield by phosphorylation of optically active (Sp)-methylphenylphosphine-borane (47) via 48 with the iodide 49 in the presence of the Pd(OAc)2-MePPh2 catalyst and CuI as a cocatalyst at 0◦C for 3 days. The reaction proceeded with retention of stereochemistry and the asym- metrically substituted phosphine 51with 99 % ee was obtained [15].
49
50 48
47 Ph P
Me
H P
Ph Me
Cu P
Ph Me I
O N
O N
Ph P Me
O N Pd(OAc)2, PMePh2
THF, 0 °C, 3 days 68%, >99% ee
51 amine
BH3 BH3 H3B
CuI EtN(i-Pr)2
An interesting direct synthetic method of phosphines 53 is an exchange reac- tions between Ar-Pd-X and PPh3 via the phosphonium salt 52. The exchange is frequently observed as a side-reaction in coupling reactions catalyzed by Pd(0)- PPh3[16]. The functionalized phosphine 56 was prepared by the Pd-catalyzed exchange reaction between the triflate 54 and the phosphine 55. Pd(OAc)2 or Pd/C is used as a catalyst. Treatment of either the triflate54 or bromide 57 wih 2.5 equivalents of PPh3for 20–30 h afforded the phosphine58in 40–50 % yield.
Triflates are more reactive than bromides in the exchange reaction [17].
Ph-X 53
Ar-X Pd(0)
52
X= Br, I, Cl, OTf
Ar-PPh3,X +
Ar-Pd-X Pd
Ar X Ph3P
PPh3
Pd Ph X Ph3P
PArPh2
Ar-PPh2
PPh3
PPh3 (2.5 equiv.) Pd/C, 160 °C DMF, 160 °C 8 h, 28%
3 55
32 h, 46%
56 +
+
Pd(OAc)2
OTf O
Br O
PPh2
O
P
Me Me
Me
Me Me
Me P
O
54
57 58
3.7.5.2 Arylation of Phosphonates and Phosphinates
Phosphonates and phosphinates are arylated as shown by the following gen- eral schemes.
Hiraoet al. synthesized diethyl p-anisylphosphonate61 by arylation of diethyl phosphonate (60) with p-bromoanisole (59) [1]. The reaction was applied to the synthesis of the phosphonate63aby coupling of the alkenyl bromide 62with the phosphonate63 [18].
The optically active isopropyl methylvinylphosphinate 65 (97 % ee) was pre- pared from isopropyl methylphosphinate64 (97 % ee) with complete retention of stereochemistry [19].
Formation of monoaryl, and symmetric or asymmetric diarylphosphinates is expected by stepwise arylation of methyl phosphinate (66). However, methyl phosphinate is a very unstable compound. Lei et al. found that its reaction can
Arylation of dimethyl phosphonate (dimethoxyoxophosphorane)
+
base
Arylation of methyl phosphinate (methoxyoxophosphorane)
Ar′X
+ Pd(0)
O P H MeO
OMe
O P H H
OMe
O P Ar MeO
OMe
O P Ar H
OMe
Arylation of methyl arylphosphinate (arylmethoxyoxophosphorane) Pd(0)
Pd(0) base
base
O P Ar H
OMe
O P Ar Ar′
OMe + ArX
ArX
59
+ Pd(PPh3)4
Br
MeO
P O
H OEt
OEt
Et3N, 90 °C, 90%
60 61
P
MeO
EtO OEt
O
O Br NH
TBDPSO
O
Me O
+ Pd(OAc)2, PPh3
Et3N, DMF, 42%
62
O P NH
TBDPSO
O
Me O
63
O O
NH Me
O O O
NH
O
O
Me O
63a TBSO
TBSO
MeO O MeO P
O H
Pd(PPh3)4 Et3N, 98%
+
97%ee 97%ee
65 64
P Me O
i-PrO H Br P
Me O i-PrO
be carried out smoothly in the presence of trimethyl orthoformate [20]. Methyl phenylphosphinate67was obtained from66in 63 % yield by this method. Asym- metric methyl diarylphosphinate68was prepared by stepwise reaction of 66with two different aryl iodides. Schwabacher and Stefanescu reported thatt-butyl phos- phinate (69) is much more stable than the corresponding methyl ester 66 and preparative method of phosphinates can be improved by usingt-butyl phosphinate (69). Actually the functionalized arylphosphinate 70 was prepared in good yield as the t-butyl ester [21]. Reaction of anilinium hypophosphite 71a with alkenyl bromide or triflate 71 afforded the monosubstituted alkenylphosphinic acid 72 without forming the symmetric phosphinic acid by disubstitution. The best ligand is DPPP [22].
H P OMe O
H
P H
OMe Ph
P O
OMe
Ph I I Ph
O + Ph-I
HC(OMe)3, Et3N H P OMe
O
H
67
68 66
Pd(OAc)2, Ph3P
N-methylmorpholine, 51%
66
1. 2.
Pd(OAc)2, PPh3, HC(OMe)3
N-methylmorpholine, 63%
Pd(PPh3)4
71a
+ Et3N, benzene
reflux, 64%
71 72
Pd(OAc)2, DPPP NHBoc
BocHN
I
+ Et3N, MeCN
90°C, 75%
P O
H H O-t-Bu
69
70 NHBoc BocHN
P O
O-t-Bu H
N OTf
P O
H PhNH3O H
N H P OH
O
CO2-t-Bu CO2-t-Bu
PdCl2(PPh3)2
Reaction of dimethyl phosphonate (74) with the steroidal dienyl triflate73gave the dimethyl alkenylphosphonate75 [23]. Dimethyl alkynylphosphonate (77) was produced in one step by the reaction of 1,1-dibromo-1-alkenes 76 with dimethyl phosphonate (74) in DMF using Pd(OAc)2-DPPF as a catalyst and propylene oxide as a scavenger of HBr. The expected monocoupling product, bromovinylphos- phonate, was not obtained [24]. Phosphonates 78 can be converted to arylphos- phines 79 by reaction with aryl Grignard reagents, followed by reduction with HSiCl3 [25].
C8H17
TfO
H P(OMe)2 O
(MeO)2P
C8H17
O
Pd(OAc)2, DPPF
DMF, 76%
76
77 Br
Br
H P(OMe)2
O P
O OMe O OMe
78
+ 2 ArMgX HSiCl3
PPhAr2 74
+
Ph P(OMe)2
O
Ph PAr2 O
79 73
74
75 Pd(PPh3)4
+ 90%
As a related reaction, functionalized arylarsines81 can be prepared by the Pd- catalyzed exchange reaction of activated aryl triflates80with AsPh3under solvent- free conditions at 115◦C [26].
+ AsPh3
110°C, 51%
80 81
OTf O
AsPh2 O
Pd(OAc)2
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