3.6 Cross-Coupling Reactions with Organometallic Compounds
3.6.4 Organozinc Compounds (Negishi Coupling)
3.6.4.1 Introduction and Preparation of Organozinc Compounds
Cross-coupling of organozinc reagents is called Negishi coupling [44]. Reaction of organozinc reagents (aryl, alkenyl, alkyl) with alkenyl and aryl halides pro- ceeds generally with high yields and tolerates a wide range of functionality. Aryl-, alkenyl-, and alkylzinc reagents are prepared most conveniently in situ by the reactions of organolithium, magnesium, and aluminum reagents with ZnCl2, and used without isolation. Gauthier and co-workers suggest that kilogram quantities
97 CO2Me
Me Me Me
I
Me
OAc
CO2Me
Me Me Me
Me
OAc
CO2Me
CO2Me H OTIPS
OTIPS
OAc
H
OAc
Pd(PPh3)4, CuI Et3N, 94%
1. HSnBu3 +
2. I2, 97%
95 96
PdCl2(PPh3)2
steps CO2Me
Me Me Me
Me
OH
CO2Me H OTIPS I
CO2H
Me Me Me
Me
OMOM
CO2Me H OTIPS NC
OMOM
Me Me Me
Me
OH
CO2H H NC
OH
O O
H H
H
Pd(PPh3)4, CuI 97%
98
99 borrelidin
OH Bu3SnCN
of solid ZnCl2can be oven dried at 120◦C in vacuum with N2purge for 3–5 days.
Handling of a THF solution is preferred to the solid, but commercial ZnCl2solution (THF, Aldrich) contains 0.5 % H2O as determined by Karl Fisher titration [45].
Tetramethylpiperidine-zincate 1 is a good reagent for directed ortho zincation of various functionalized aromatic and heteroaromatic compounds. For example, benzoate was converted to biphenyl-2-carboxylate2by zincation with1, followed by coupling with iodobenzene [46].
A facile and convenient preparative method of alkylzinc reagents is direct reaction of alkyl iodides with activated Zn/Cu couple [47] or Zn dust [48]. Huo reported an efficient, general preparative method of alkylzincs from unactivated
alkyl bromides and chlorides, which relied on activation of Zn dust with 1–5 mol%
of iodine [49].
Alkenylzinc reagents are prepared conveniently in situ by hydrozirconation of 1-alkyne, followed by transmetallation from Zr to Zn with ZnX2. Then coupling is carried out without isolation of Zn reagents, and hence a catalytic amount of ZnX2 is enough. For example, hydrozirconation of 1-alkyne 3, followed by coupling with the alkenyl bromide 4 to provide the conjugated (all-E)-oligoene 5 with retention of stereochemistry, was carried out using both Pd complex and ZnCl2as catalysts [50].
1
X = Br, I
1. TMP-zincate THF, rt + 2. Pd(PPh3]4
rt, 58%
1. HZrCp2Cl
+
71%
2. Pd(PPh3)4 , ZnCl2 3
2
4
5
X Li ZnX
N Me Me
Me Me t-Bu Zn t-Bu
CO2Et
CO2Et I
TBSO Br CO2Et
TBSO CO2Et
t-BuLi ZnX2
3.6.4.2 Coupling of Aryl- and Alkenylzinc Reagents
For aryl –aryl coupling, aryl iodides, bromides, and triflates are used. It has been shown that the Negishi coupling of arylzinc reagents with aryl chlorides proceeds smoothly by the use of commercially available, air-stable Pd[P(t-Bu3)]2. Coupling of arylzinc chloride 6 with electron-rich 4-chloroanisole (7) proceeds smoothly in THF–NMP using Pd[P(t-Bu3)]2 as a catalyst to give 8 in high yield [51]. In synthetic studies toward diazonamide, aryl–aryl coupling was employed. Reaction of the arylzinc reagent10, derived from the aryl iodide 9via a Grignard reagent, with 4-iodoindole-3-carboxaldehyde (11) to afford 12 proceeded in high yield using Pd[P(t-Bu3)]2. The yield was poor when DPPF was used as a ligand [52].
ZnCl Me
Cl
OMe
MeO
Me
+ THF, NMP
7
100°C, 94%
6
8 Pd[P(t-Bu)3]2
9 10 I
OBn CO2TMSE
ZnBr OBn CO2TMSE 1. i-PrMgCl
2. ZnBr2
12 11
N
I CHO
CBz
N
BnO CO2TMSE
BzC CHO 87%
Pd(dba)2/DPPF 27%
Pd[P(t-Bu)3]2
A new ionic phosphine ligand (I-19) is effective for the coupling of arylzinc13 with aryl iodide14at room temperature to give15in a biphasic system containing toluene, THF, and an ionic liquid [bdmim][BF4]. The Pd catalyst always stays in the ionic liquid and can be recycled [53].
+
Pd(dba)2,I-19 rt, 0.3 h, 89%
[bdmim][BF4] toluene, THF ZnBr
OMe
I
OAc
OAc MeO
13 14
15
Coupling of heteroarylzinc halides and heteroaryl halides proceeds smoothly.
The bithiazole18 was obtained in 85 % yield by regioselective coupling of the 2- bromo group in 2,4-dibromothiazole (16) with the 4-thiazolylzinc chloride17 [54].
The tri(furylzinc) reagent 19undergoes smooth coupling with 2-chloropyridine to give the coupling product 20 in the presence of DPPF. All three furyl groups in 19are utilized for the coupling [45].
3
PdCl2(PPh3)2 85%
t-BuLi ZnCl2
1. PdCl2(dppf)
+ 2. 5 N HCl
89%
N S Br
Bu
N S ClZn
Bu
N S Br
Br
N S Br
S
N Bu
16
17
O EtO
EtO ZnLi
18
19 20
N Cl
OHC O
N
Coupling of the sterically congested arylzinc chloride 21 with 1-cyclopentenyl chloride (22) gave23 in high yield when Pd[P(t-Bu3)]2was used as a catalyst in THF–NMP [51].
ZnCl
Me Me
Me
Cl
+ THF, NMP
100°C, 96%
22
Me
Me
Me
21
23 Pd[P(t-Bu)3]2
Arylalkenes, conjugated dienes, and polyenes are produced by the coupling of alkenylzinc reagents. The first total synthesis of cystothiazole E was achieved by applying the Negishi coupling twice and Suzuki–Miyaura coupling once. Coupling of 2-propenylzinc chloride (24) occurred selectively with the 2-bromo group of 2,4-dibromothiazole (16), and25was obtained after hydrogenation of the coupling product. The 4-thiazolylzinc chloride26also reacted selectively with the 2-bromo group of 16 to afford the bromobithiazole27. Finally Suzuki–Miyaura coupling of 27 with the alkenylboronic acid 28 provided the coupling product 29, which was converted to cystothiazole E [55].
+
25°C, THF Pd/C 68%
60°C, THF 97%
ClZn
S N Br
S N Br
Br
24 16
S N ClZn
26 25
27
29 Pd(PPh3)4 , CsOH, 95 °C,
16
S N Br
28 S
N + B(OH)2
TBDMSO OMe
TBDMSO OMe
S N
S N
OMe
S N
S N O
ZnCl2 , 68%
PhH, EtOH, H2O, 94%
cystothiazole E
Pd(PPh3)4 H2
Pd(PPh3)4
t-BuLi
The Negishi coupling was applied as a key reaction to a short synthesis of calyculin. The key building block 33 of the tetraene fragment of calyculin was synthesized fromtrans-bis(tributylstannyl)ethene (30) via four consecutive transfer reactions (Sn-Li-Zn-Pd-C). Exchange of Bu3Sn in 30with ZnCl2 gave 31, which underwent chemoselective coupling with the vinyl bromide32to give 33in 95 % yield [56].
95%
Bu3Sn SnBu3
Br CO2Me
30 31
32
33
Bu3Sn CO2Me
Bu3Sn
ZnCl
Pd(PPh3)4
n-BuLi ZnCl2
3.6.4.3 Coupling of Alkylzinc Reagents
Alkylzinc reagents can be used for the coupling without undergoing β-H elimi- nation. Coupling of n-butylzinc chloride with 2-chlorotoluene proceeds smoothly using Pd[P(t-Bu3)]2 [51]. In the total synthesis of sphingofungin, the alkylzinc 34 was derived from the long-chain alkyl iodide. Coupling of 34 with the alkenyl iodide35 afforded36, and sphingofungin F has been synthesized from 36 [57].
Cl
Me
n-Bu
Me +
THF, NMP 100°C, 83%
5 Pd(PPh3)4, THF, rt, 68%
34
sphingofungin F 35
36
5 5
O O
C6H13 I
O O
C6H13 ZnI
O N
O Ph
O I
TBSO H
Me
O N
O Ph
O
TBSO H
Me C6H13
O O
C6H13 O
CO2H OH
OH OH
Me NH2 n-BuZnCl
Pd[P(t-Bu)3]2
t-BuLi ZnCl2
Total synthesis of (+)-pumiliotoxin A (39) has been achieved based on the Negishi coupling of the alkylzinc chloride37, derived from the alkyl iodide, with the alkenyl iodide38at room temperature, and subsequent deprotection [58]. The alkylzinc reagent41was prepared conveniently by the reaction of the alkyl iodide 40 with Zn/Cu couple, and treated with 2-iodoimidazole 42 to afford the adduct 43[47].
1. Pd(PPh3)4 benzene
rt, 60%
37
38
2. Et3N,-3HF
MeCN, 88% 39
N
I Me
OTBDMS Me
N
ZnCl Me
OTBDMS Me
N Me
OH Me
Me
OH I
Me
OBn
t-BuLi ZnCl2
42
PdCl2(PPh3)2, DMA, 40 °C, 79%
41 Zn/Cu couple
43 40
BnO I
O
NHTrt
BnO ZnI
O
NHTrt
N
I N CO2-t-Bu
Boc NHBoc
N
N CO2-t-Bu Boc
NHBoc BnO
NHTrt O
Coupling of the alkenyl triflate 44 with the Zn homoenolate 45 proceeded smoothly to give 46. The coupling of triflate is the key reaction to construct a cyclic polyether fragment in the total synthesis of gambierol [59]. The methyl group was introduced in high yield by the reaction of the alkenyl triflate47 with Me2Zn to afford 48[60].
O O
O OTf
IZn
CO2Me Ph
H H
+
benzene, rt 74%
44
45
46 O
O
O Ph
H H
CO2Me Pd(PPh3)4
O
CO2t-Bu
TfO
DPSO
O
CO2t-Bu
Me
DPSO
+ 91%
48 47
Me2Zn Pd(PPh3)4
A versatile and regio- and stereoselective synthetic method of terpenoids con- taining 1,5-diene units has been developed by Negishi. Chemoselective coupling of the alkylzinc bromide49with the alkenyl iodide in 50provided 51. The alkyl iodide in51 was converted to alkylzinc bromide, which was coupled again with the alkenyl iodide 50to provide52. Coenzyme Q10 (53) was synthesized in 26 % overall yield by repeating a similar sequence of the coupling reactions [61].
50
9
+ PdCl2(dppf)
THF, 23 °C 96%
THF, 23 °C, 90%
PdCl2(dppf)
2
TMS I
TMS ZnBr I
I 49
TMS I
O O MeO
MeO 50
51
52
53 ZnBr2
t-BuLi
Aryl cyanides can be synthesized by Pd-catalyzed cyanation of halides or pseu- dohalides with Zn(CN)2. As an example, the triflate group in the pyrimidone 54 was displaced with CN group to afford 55in high yield [62].
54 55
N
N Et
O OTf
Ph
TMS
N
N Et
O CN
Ph
TMS
+ DMF, 94%
Pd(PPh3)4 Zn(CN)2
A formal total synthesis of nostoclide has been carried out based on regiose- lective coupling of 3,4-dibromo-2(5H)-furanone (56). Coupling of the dibromide
56with 2-propenyltributylstannane (57) afforded58regioselectively using AsPh3
as a ligand. Coupling of the corresponding boron and magnesium reagents were unsatisfactory. After hydrogenation of 58, the key intermediate 61 was obtained by coupling59with benzylzinc bromide (60). Curiously, attempted coupling of58 with 60 produced only 1,2-diphenylethane and no desired coupling product was obtained [63].
60
61
56 57 58
59
O O
Br Br
SnBu3
PdCl2(PhCN)2
O O
Br
PdCl2[P(o-Tol)3]2
AsPh3, NMP rt, 78%
O O
Br
nostoclide DMF, 35%
ZnBr
O O
+ H2
RhCl(PPh3)3
The benzylzinc bromide 63 reacted preferentially with the polymer-bound aryl iodide62, without attacking the triflate. Then the benzylzinc bromide64was added to the reaction mixture, and coupling with the triflate occurred to afford65 after cleaving from the polymer [64].
1.
62
63
64 65
Pd(dba)2, TFP, rt 2.
Pd(dba)2, DPPF, 70 °C
I OTf
BrZn
OMe BrZn
O O
OMe 3. TFA
CO2H P