3.6 Cross-Coupling Reactions with Organometallic Compounds
3.6.2 Organoboron Compounds (Suzuki –Miyaura Coupling)
Coupling of organoboron compounds with aryl, alkenyl and alkynyl halides is one of the most useful coupling reactions and called Suzuki –Miyaura coupling (abbre- viated to S-MC in this section) [8–10]. Due to low nucleophilicity of organic groups R on the B atom, their transmetallation is difficult. The coupling reac- tion proceeds via transmetallation in the presence of bases [11]. The role of the base is explained by activation of either Pd or boranes. The nucleophilicity of R is enhanced by quaternization of the boron with bases, generating the corre- sponding ‘ate’ complexes1, which undergo facile transmetallation. Alternatively, the formation of (alkoxo)palladium species Ar-Pd-OR2from Ar-Pd-X facilitates the transmetallation with organoboranes. No reaction takes place under neutral
conditions. This is a characteristic feature of organoboron chemistry, which is different from that of other organometallic reagents. Various aryl, alkenyl, and even alkylborane reagents of different reactivity can be used for the coupling with aryl, alkenyl, alkynyl, and some alkyl halides, and the coupling offers very useful synthetic methods.
+ −OR Ar-Pd-R1 Ar-R1
Ar-Pd-R1 + +
Y B Y R1
Y B-OR Y R1
2
1
Y B Y R1
Y B Y RO
Y B Y Ar-Pd-X RO
Ar-Pd-OR Ar-Pd-X
−OR
−
S-MC is the most popular among Pd-catalyzed cross-couplings on account of several advantages:
1. Commercial availability of a large number of organoboranes especially boronic acids and their esters.
2. Stability of boronic acids to heat, air, and moisture.
3. Tolerance to a broad range of functional groups.
4. Mild reaction conditions.
5. Low toxicity, but not non-toxicity.
6. Easy separation of inorganic boron from reaction mixture.
Hydroboration of alkenes and alkynes is an established preparative method of alkyl- and alkenylboranes. Arylboranes, arylboronic acids and their esters (boronates) are prepared from aryllithium or Grignard reagents.
Several new synthetic methods of arylboronates, such as pinacol ester, have been developed. A convenient preparative method of arylboronates 4 is Pd-catalyzed cross-coupling of aryl halides and triflates with bis(pinacolato)diboron (3), which can be handled easily in air. The best ligand for the coupling is DPPF [12]. In addition, one-pot biaryl synthesis can be carried out most conveniently without isolation of the boronate 4 to provide 5 [13]. Ligandless Pd(OAc)2 is active for
I
MeO
O B
O B O
O +
B
MeO AcOK, DMF, 80 °C
O O PdCl2(dppf)
PdCl2(dppf) aq. Na2CO3
81%
3 4
Br
Cl
5
OMe Cl
the coupling of aryl bromides having EWG in DMF [14]. The carbene (XVI-2) was found to be a good ligand for activated aryl chlorides to afford6 [15]. Borylation of alkenyl triflate 7 with 3 affords alkenylboronate 8 when PdCl2(PPh3)2-2PPh3
as a catalyst and PhOK as a base are used, and the method is applied to one-pot synthesis of asymmetrical 1,3-dienes and arylalkenes [16].
3 6
Pd(OAc)2,XVI-2 AcOK, THF 6 h, 85%
+
3
PdCl2(PPh3)4, 2PPh3
PhOK, toluene 50 °C, 88%
Cl
MeO2C
8 7
O B
O B O
O
B MeO2C
O O
OTf B
O O O
B O B O
O +
Borylation of benzyl chloride with 3 in toluene in the presence of AcOK, Pd(dba)2, and tri(4-anisyl)phosphine gives pinacol benzylboronate 9 in high yield [17]. More conveniently benzylboronate 9 can be prepared by borylation of toluene with3by the use of Pd on carbon as a catalyst [18].
+ 3 AcOK, toluene, 85%
Pd(dba)2, P(4-MeOC6H4)3
9
9 +
Cl B
O O
Me B
O O 3 toluene
100°C, 74%
+ H2 Pd/C
Masuda and co-workers have found a new and mechanistically interesting syn- thetic method of pinacol arylboronate by the coupling of pinacolborane 10 with aryl triflates and iodides in the presence of DPPF as a ligand and Et3N as the most effective base in dioxane. In this case, the arylboronate 4 is produced as the main product, and hydrogenolysis of halides with boron hydride to give the reduced arene11 is the minor path. The reaction mechanism is shown in the fol- lowing. Transmetallation of 12 to form 13 is a key step. Direct transmetallation of boron hydride to form palladium-hydride is a minor path [19]. Reaction of 5- bromo-2-pyrone (14) with10provided the pinacolboronate in 82 % yield by using PdCl2(PPh3)2 as a catalyst, but a very poor result was obtained when PdCl2(dppf) was used [20]. Triflates are the most reactive.
I
MeO
+
O B
O H
10
PdCl2(dppf) Et3N, dioxane
77%
B
MeO
O O
4
+ H
OMe 11 16%
Ar-X Pd(0)
Ar-Pd-X
H-B(OR)2 + Et3N Et3NHB(OR)2
12
Ar-Pd-B(OR)2 Ar-B(OR)2 Et3NHX
Ar-Pd-X + H-B(OR)2 Ar-Pd-H + X-B(OR)2
Ar-H
13
14
+
O B
O H
10
Et3N, toluene 82%
O
Br O
PdCl2(PPh3)2
O
B O
O O
Although this is not a Pd-catalyzed reaction, direct borylation of arenes 15 with pinacolborane 10 to give arylboronate 16 can be achieved using several transition metal complexes as catalysts. Some Rh and Ir catalysts are known to be active [21,22].
MeO
NMe2
15
+
O B
O H
10
Cp*Rh(η4-C6Me6) cyclohexane, 75%
MeO B
O O
NMe2 16
Phenylboronic acid (17) and its derivatives are widely used. Boronic acids are sometimes difficult to purify because they undergo cyclotrimerization with loss of water to form boroxines. On the other hand, organotrifluoroborate salts18are eas- ily prepared, purified, and handled [23]. Aryltrifluoroborate salts18 are prepared by the reaction of arylboronic acid with HF and base [24]. Alkenyltrifluorobo- rates 19 are prepared by hydroboration of 1-alkynes, followed by treatment with KHF2 [25].
These potassium organotrifluoroborates are good partners of S-MC [26]. Cou- pling of PhBF3K (20) with deactivated p-bromoanisole proceeds with ligandless Pd catalyst in refluxing MeOH in the presence of K2CO3 [27]. Reaction of more
B(OH)2
+ HF + H2O
BF3−H3O+ base
BF3−M+
18
17 M= K, Cs, Bu4N
C8H17 + HBBr2-SMe2
H2O ether
C8H17
B(OH)2
KHF2 H2O, ether
71%
C8H17
BF3K 19
reactive diazonium salt21with20proceeds at room temperature without addition of a base [28].
BF3K +
20
OMe
Br
Pd(OAc)2, K2CO3
MeOH reflux, 2 h, 95% OMe
BF3K +
20
N3BF4
MeO
Pd(OAc)2, dioxane
rt, 69% OMe
OMe
OMe
21
Vinylboronic acid is difficult to purify. On the other hand, coupling of vinyltri- fluoroborate22with diazonium salt23occurs at room temperature in the presence of ligandless Pd without a base [28]. However, use of DPPB or DPPF is neces- sary for the coupling of K or Bu4N salt 24 of alkenyltrifluoroborates with aryl bromides [24,25].
24
23
+
Pd(OAc)2, dioxane rt, 69%
BF3K
N2BF4
EtO2C
CO2Et
BF3M
COMe
Br
COMe M= Bu4N, Pd(OAc)2, DPPB, Cs2CO3, DME, 55%
M= K, PdCl2(dppf),i-PrOH, BuNH2, 80%
+ 22
3.6.2.2 Catalysts and Reaction Conditions
A number of papers claiming ‘A highly active catalyst for Suzuki coupling’, ‘Con- venient and efficient catalyst for S-MC’ or ‘Extremely high-activity catalysts’ have been published. In some cases, these catalysts seem to be active for only limited substrates, and not appropriate for every substrate.
Several types of catalysts are used. From a practical standpoint, ligandless cat- alysts are most useful. Several reactions for the coupling have been reported.
Coupling of phenylboronic acid (17) with iodophenol was carried out in the pres- ence of Pd on carbon as a reusable catalyst and K2CO3 in water [29]. Coupling of mainly electron-deficient aryl chlorides such as 4-chlorotrifluoromethylbenzene (25) catalyzed by Pd on carbon proceeded in DMA/H2O (20 : 1) to give the cou- pling product 26 in high yield [30]. Also Pd on carbon and KF were used in MeOH [31]. Coupling of aryl iodides by a similar catalyst supported on alu- mina proceeds without solvent [32]. Hollow Pd spheres are active catalysts for aryl iodides and bromides in EtOH, and the catalyst was used six times without loss of activity [33]. Reactions catalyzed by Pd nanoparticles are carried out in water [34,35].
HO I
HO Pd/C, K2CO3
17 + B(OH)2
H2O, rt, 97%
+ DMA/H2O (20/1)
80°C, 95%
25
26 Cl
B(OH)2
F3C
CF3
Pd/C, K2CO3
17
Sulfur-containing palladacycle XVIII-13 is a precursor of an effective catalyst in the presence of Bu4NBr [36]. PalladacycleXVIII-1is an efficient catalyst, and high TON(74 000)was obtained in the coupling of electron-deficient aryl bromide 27[37]. Preparation of sterically hindered biaryl 28 was carried out with bulky phenanthrene-based phosphineV-5[38].
Palladacycle (XVIII-13)
17
+ K2CO3, DMF, Bu4NBr 130 °C, 100%
+
Palladacycle (XVIII-1) 0.001 mol%
B(OH)2
28
Me Br
K2CO3, xylene, 130 °C 74%, TON = 74 000
Me
Pd2(dba)3, (V-5), K3PO4
toluene, 110°C, 82%
+
B(OH)2 Br
Me Me
Me Me Me
Me
Me
Me (HO)2B Br
Me
Me
O 27 O
17
Pd(dppe)2with K2CO3in THF–MeOH [39], and combination of diazabutadiene (XVII-4) with Cs2CO3or CsF are effective catalysts. No coupling takes place with bases such as Na2CO3and MeONa [40].
THF-MeOH reflux, 95%
17
Pd(dppe)2, K2CO3 +
+ Pd(OAc)2,XVII-4
Cs2CO3, dioxane, 99%
17 B(OH)2
Br
B(OH)2
Br
Me
Me
In S-MC, ligands, solvents and bases have critical effects and careful selection is necessary. For example, the following comparative survey has been carried out in the coupling of formylated arylboronate 29. In this case, Na2CO3 seems to be superior to K2CO3 [41].
+
XVIII-1
xylene 130°C 0
60°C 0
toluene-EtOH 80 °C 83%
16
solvent base catalyst temp. time yield
2 29
B
CHO O
Br O
O
CHO O
16 K2CO3
THF KOH Pd(PPh3)4
Na2CO3 Pd(PPh3)4
Water is a good solvent for some S-MC. Reaction proceeds in a mixed solvent in the presence of water-soluble ligands which are listed in Table 1.2. Use of water-soluble sulfonate ligandII-1in a mixed solvent of H2O and MeCN at 80◦C is typical [42]. Coupling of electron-rich bromide 30 with 17 proceeds at room temperature in high yield using di-t-butylphosphine, containing the water-soluble trimethylammonium group (II-12). The ligand II-12 gave higher yield thanII-1 in this reaction at room temperature [43].
More conveniently, reaction can be carried out in water without a cosolvent under certain conditions. Coupling of substrates insoluble in water such as 30 proceeds with TON up to 20 000 in water when an insoluble and assembled Pd catalyst and a non-cross-linked amphiphilic (amphiphilic) polymer, containing diphenylphosphine group, are used. The catalyst system was used 10 times with- out any decrease in activity [44]. Also an amphiphilic resin-supported Pd catalyst can be used in water many times giving nearly quantitative yields of coupling products [45].
+ B(OH)2
17
Br
MeO
OMe Pd(OAc)2, II-12
rt, 98%
Pd(OAc)2, II-1 i-Pr2NH, H2O, MeCN
80°C, 98%
30
Na2CO3, H2O, MeCN
Furthermore, coupling of aryl bromides proceeds in water in the presence of lig- andless Pd(OAc)2as a precursor and 1 equivalent of Bu4NBr. Use of 1 equivalent is important. Aryl iodides and triflates are not good substrates under the condi- tions [46]. 5-Phenylthiophene-2-carboxaldehyde (31) was prepared under similar conditions at room temperature [47]. Reaction of17with30proceeded rapidly in 5–10 min under microwave irradiation at 150◦C [48].
Na2CO3, H2O 17
+
100°C, 87%
Pd(OAc)2, Bu4NBr +
B(OH)2
K2CO3, H2O Br
MeO
OMe
70°C, 98%
Pd
B(OH)2 Br
AcHN
NHAc Me
Me 30
microwave irradiation 17
+
150°C, 5 min. 86%
Pd(OAc)2, Bu4NBr 17
+
Na2CO3, H2O Pd(OAc)2, Bu4NBr
rt, 2 h, 67%
B(OH)2 Br
MeO
OMe B(OH)2
Br S CHO
S CHO
K2CO3, H2O
30
31
S-MC of diazonium salt32proceeds with ligandless Pd at room temperature in dioxane in the absence of a base [49]. Pd(OAc)2 and carbene ligand XVI-2 are effective for the coupling of aryldiazonium tetrafluoroborates with aryl, alkenyl, and alkyl boronates at room temperature [50].
+ Pd(OAc)2, dioxane
rt, 4 h, 87%
17
B(OH)2 N2BF4
Me
Me 32
3.6.2.3 Coupling of Arylboranes
Arylboranes with aryl bromides and iodides Coupling of arylboranes with aryl bromides and iodides offers an extremely useful synthetic method for biaryl com- pounds, and numerous examples are known. Asymmetric S-M aryl –aryl coupling of 33 with 34 in the presence of chiral 2-aminobinaphthyl-based phosphine (S)- VI-8afforded the highly enantiomerically enriched biaryl35(92 % ee), which was converted to the axially chiral 1-aryl-2-naphthylphosphine 36. BINAP is not an effective ligand for this asymmetric reaction [51].
+
Pd2(dba)3, (S)-(+)-VI-8 K2CO3, toluene, 70 °C 96%, 92% ee
1. PhMgBr
2. PMHS, Ti(O-i-Pr)4 B(OH)2
Et
Br
P(O)(OEt)2
35 36
Et P(O)(OEt)2
Et PPh2 34
33
Total synthesis of proteasome inhibitor TMC-95A was achieved by smooth cou- pling of the functionalized boronate37with the iodide38without touching labile functional groups to give39in 75 % yield in the presence of PdCl2(dppf)as a key reaction [52].
PdCl2(dppf), K2CO3
+ DME, 80 °C, 2 h, 75%
37 38
39 BnO
B
CO2Me HN
Cbz
NH I
O O N
O O Boc
BnO
CO2Me HN Cbz NH O
O N Boc
Arylboranes with aryl chlorides and triflates Aryl chlorides are now regarded as good partners of the coupling by the discovery of a number of effective ligands.
In this section, mainly coupling of aryl chlorides are surveyed. P(t-Bu)3and PCy3 have been found to be very effective ligands [53]. In the case of S-MC, aryl triflates are known to be less reactive than the corresponding iodides and bromides.
Curiously no coupling of aryl triflates took place with the catalyst [Pd/(P(t-Bu)3] even at 60◦C. On the other hand, PCy3, which is less bulky and less basic than P(t-Bu)3, was found to be an effective ligand for triflates, and coupling of43with 4-methoxyphenyl triflate proceeded at room temperature using Pd(OAc)2-PCy3. The sterically hindered biaryl42was prepared at 90◦C from40and41by the use of PCy3. Since reaction of aryl triflates proceeds at room temperature when PCy3is used, the different behavior of P(t-Bu)3and PCy3offers interesting chemoselective reactions. The most remarkable is the unprecedented chemoselectivity observed in the reaction of 4-chlorophenyl triflate (44) with 2-tolylboronic acid (43) at room temperature; chemoselective coupling of aryl chloride took place to give45when P(t-Bu)3 was used. On the other hand, chemoselective reaction of the triflate group occurred to afford46in 87 % yield at room temperature in the presence of PCy3[54].
+ KF, THF, 90 °C, 93%
Pd2(dba)3, PCy3
40 41 42
Cl Me (HO)2B
Me
Me
Me
Me Me
Me
Me
43 +
44 45
Pd2(dba)3, P(t-Bu)3 KF, THF, rt, 95%
TfO Cl
(HO)2B TfO
Me Me
43 +
44 46
Pd(OAc)2, PCy3
KF, THF, rt, 87%
TfO Cl
(HO)2B Cl
Me Me
Furthermore higher reactivity of chloride over triflate was demonstrated by inter- molecular competitive reaction of the aryl chloride47and the triflate 48with17.
Reaction at room temperature in the presence of P(t-Bu)3 provided the biphenyl 49 with high selectivity. Recovery of the chloride 47was only 8 %. The catalyst [Pd/(P(t-Bu)3] activates the C—Cl bond in preference to the C—OTf bond to afford49at room temperature in excellent selectivity and high yield. The chemos- electivity observed shows that the belief that the C—OTf bond is more reactive than the C—Cl bond is no longer valid when Pd/P(t-Bu)3is used.
Cl OTf B(OH)2
99%
1 equiv.
47 48
KF, THF, rt
8% 48
O O
1 equiv.
1 equiv.
O
49
Cl OTf
Pd2(dba)3, P(t-Bu)3
47
O O
93%
+
17
+ + +
Generally speaking, alkenyl halides are more reactive than aryl halides. An oppo- site chemoselectivity was observed in the competitive reaction of chlorobenzene (50) and 1-cyclopentenyl chloride (51) with 43. A higher yield of 52 (62 %) than that of 53 (34 %) was obtained. The result shows that aryl chloride 50 is more reactive than the alkenyl chloride 51in the presence of P(t-Bu)3 [54].
1 equiv.
Pd2(dba)3, P(t-Bu)3
KF, THF, 60 °C +
52 53
62% 34%
43
Cl B(OH)2
Cl Me
Me Me
1 equiv. 1 equiv.
51 50
+ +
P(t-Bu)3 is a remarkable ligand, but it is gradually oxidized. Fu reported that its phosphonium salt [P(t-Bu)3H]BF4, is air-stable and can be used more conve- niently. The salt shows the same reactivity as that of free P(t-Bu)3in the coupling of43 with54to afford 55[55]. Triarylphosphines are rather poor ligands for the reactions of aryl chlorides. However, ferrocenylphosphine VIII-6, which is a tri- arylphosphine, was found to be an unexpectedly effective ligand, and coupling of electron-rich and hindered aryl chloride 56 with 43 proceeded at room tem- perature to afford 57. The ferrocenyl ligand VIII-5, missing the TMS group, is ineffective [56].
+
43
54
Pd2(dba)3, [P(t-Bu)3H]BF4
43
57 55 KF (3.3 equiv.), THF
rt, 98%
B(OH)2
Me
I
MeO
Me
OMe
(HO)2B Cl
Me Me
Me
Me
Me Me + Pd2(dba)3,VIII-6
56
K3PO4, toluene 70°C, 88%
Buchwald group reported biphenylyl(dicyclohexyl)phosphine derivatives such as IV-2 andIV-12 are effective for coupling of deactivated aryl chlorides. Reaction of the sterically hindered substrate 58 proceeds at 80◦C, but coupling of 4- chloroanisole (60) occurs at room temperature when IV-12 is used [57]. The polymer-supported ligand is equally active and can be recycled [58]. CarbeneXVI- 1is an excellent ligand, and the most effective base is Cs2CO3(96 % yield). Other bases such as CsF (65 %), K2CO3(53 %), and Na2CO3(6 %) are less effective [59].
59 +
B(OH)2
Me Cl Me
Me
Pd(OAc)2,IV-2 K3PO4, toluene 80 °C, 96%
+ Pd(OAc)2,IV-12
CsF, dioxane rt, 92%
Me
Me Me
+ Pd2(dba)3,XVI-1 Cs2CO3, dioxane
80°C, 96%
43 58
B(OH)2
60 Cl
MeO 17
17
OMe
B(OH)2
Cl
Me
Me
High TON(11 600)was obtained in the reaction of m-chloroanisole with17in the presence of bulky diadamantyl-n-butylphosphine (I-20) [60]. Adamantyl(di-t- butyl)phosphine (I-21) is more effective and coupling of 4-chloroanisole (60) with 17 proceeded at room temperature in 5 min, giving 4-methoxybiphenyl in 96 % yield [61]. Aryldicyclohexylphosphine (I-17) is also an effective ligand for cou- pling of 3-chloroanisole [62].ortho-Palladated triaryl phosphite complex (XVIII- 18) and additional PCy3, is highly effective and TON as high as 33 000 was obtained. It should be pointed out that the triaryl phosphite alone is not an effective ligand [63]. High yield (97 %) was obtained by using di(t-butyl)phosphine oxide (XVIII-4) as a precursor of the phosphinous acid ligand [64]. It was claimed that very high TON(6 800 000)was obtained in the coupling of activated aryl chlorides, such as 2-chloro-5-(trifluoromethyl)nitrobenzene, with17using the tetraphosphine (X-1) [65].
Some heteroaryl halides are good coupling partners, and their reactions offer a versatile method of functionalization of heterocycles. Tosyl as a leaving group can be used for the coupling. 4-Tosyl-2-(5H)-furanone (61) has been found to undergo facile coupling in the presence of KF [66]. 2-Substituted oxazoles such as62were prepared by S-MC of ethyl 2-chloroxazole-4-carboxylate [67].
A practical kilogram scale synthesis of carbapenem L-742,728 was carried out by applying the coupling of the doubly quaternarized boronic acid 65 with the triflate64 under carefully optimized conditions to afford the coupling product 66 after deprotection in a yield of 60 % over the four steps from63. Li2CO3 was the best base [68].
Pd(dba)2,I-17, CsF toluene, 100 °C, 93%
+ Cs2CO3, dioxane, 100 °C, 99%
TON 33 000
Pd2(dba)3, [(t-Bu)2P(O)H] (XVIII-4) CsF, 100 °C, 97%
XVIII-18 (0.0015) + PCy3 (0.003)
60 MeO B(OH)2 Cl
17
OMe
B(OH)2
Cl OMe OMe
Pd(OAc)2,I-21, KOH THF, 5 min, 96%
+
Pd(OAc)2,I-20, K3PO4 toluene, 100 °C, 58%
TON 11 600
17
PdCl2(PPh3)2, KF (H2O) THF, 60 °C, 63%
+
Pd(PPh3)4, K2CO3 toluene, 90 °C, 87%
62 61
17
+ B(OH)2 MeO
O OTs
O O
O
OMe B(OH)2
O N EtO2C
Cl O
N EtO2C
65
66 1. Pd2(dba)3, Li2CO3
DMF, CH2Cl2, H2O
60% from 63
2 TfO− TfO−
−
63
+
64
2. deprotection N O
OTf TESO Me
CO2p-NB (HO)2B
O
N
N CONH2
O
N
N CONH2 N
Me H
O NH
CO2p-NB O
HO
CO2p-NB
TESO Me
O N2 H
H H
H
H
Br [Rh]
Heteroaromatic methyl thioethers (pyridyl, pyrimidyl, oxazolyl, thiazolyl, thio- phenyl, 1,2,4-triazinyl) can be used for the coupling in the presence of 1.2 equiv- alents of copper thiophene-2-carboxylate (CuTC) and Zn(OAc)2. Congested 2- pyridyl methyl thioether68reacts with the boronic acid67using TFP [69,70]. 2- DeoxyguanosineO6-arylsulfonate69 underwent facile coupling with17. Amino- biphenylylphosphine IV-12 was the effective ligand [71]. Also 6-chloropurine can be used for the coupling [72]. Three chlorides in 2,4,6-trichloropyrimidine 70 have different reactivity, and couplings proceed step-wise in the order of positions 4>6>2 to give triphenylpyrimidine 71 in 93 % yield as the final product [73].
68 +
B(OH)2
OMe
MeO N SMe
CN Me
Me N
CN Me
Me
MeO
OMe Pd2(dba)3,
TFP, CuTC Zn(OAc)2, THF, 76%
67
B(OH)2
Pd(OAc)2,IV-12, dioxane K3PO4, 80 °C,
76%
OR= OTBDMS +
69 N
N N
OSO2Ar
O RO
OR
N N N
Ph
O RO
OR 17
2 4
70
71
6
Pd(OAc)2, PPh3, DME
Na2CO3, 80°C, 93%
N N
Cl
Cl
Cl N
N Ph
Cl Cl
17
N N
Ph
Ph Cl
N N
Ph
Ph Ph
B(OH)2 +
The bipyridyl74was prepared by the coupling of 3-pyridylboronic acid72with 2-bromo-5-methoxypyridine 73 in good yield. Similarly heteroarylpyridines were prepared [74]. Coupling of theβ-chloro-α,β-unsaturated aldehyde75 occurred in water without a co-solvent in the presence of Bu4NBr [75].
+ N MeO
B(OH)2
DMF, 80 °C, 83%
N Br
OMe +
N Pd(PPh3)4, Na2CO3
OMe N
MeO
72 73
74
75
Bu4NBr, H2O, 75%
Pd(OAc)2, K2CO3
B(OH)2
OMe
Cl
CHO
CHO MeO
Arylboranes with alkyl halides Interestingly, Fu and co-workers discovered that alkyl halides can be used for the coupling. No β-H elimination occurs. Clearly, reductive elimination takes place beforeβ-H elimination. Reaction of17with octyl bromide proceeded smoothly to give octylbenzene (76) in 85 % yield in the pres- ence of P(t-Bu)2Me as a ligand andt-BuOK as a base at room temperature [76].
Phenylacetate (77) was prepared by coupling 17 with bromoacetate. P(o-Tol)3 is the most effective ligand [77].N,N-Dimethyltolylacetamide (78) was obtained by the coupling of tolyldioxaborolane with 2-bromo-N,N-dimethylacetamide using PCy3 as a ligand and hydroquinone as a free-radical scavenger [78]. Heteroaryl- boronic acids are used for coupling. Thiophene-3-boronic acid reacts with iodocy- clopropane 79to give80 in the presence of CsF as a base. This reaction showed for the first time that cyclopropyl iodide can be used as a coupling partner [79].
+
Pd(OAc)2, P(t-Bu)2Me
76 t-BuOK, tert-amyl alcohol
rt, 85%
Pd(OAc)2, P(o -Tol)3
77 +
K3PO4, THF, H2O 89%
17 17
B(OH)2 n-Hex Br
n -Hex
B(OH)2 Br CO2Et CO2Et
+ Pd(OAc)2, PPh3
CsF, DMF, 78%
79 80
+ BrCH2CONMe2
K3PO4, hydroquinone THF, 72%
Pd(dba)2,PCy3
78
S
B(OH)2 H
I H
O Ph
S H
H
O Ph
B O O
Me
CH2CONMe2
Me