Direct introduction of sp2 carbon to alkynes by the reaction of Cu acetylides with aryl and alkenyl halides to form arylalkynes and alkenylalkynes is known as the Castro reaction [1]. Later it was found that coupling of terminal alkynes (1-alkynes) with halides proceeds more smoothly by using Pd catalysts. There are two methods of Pd-catalyzed coupling. In 1975 direct coupling of 1-alkynes catalyzed by a phosphine-Pd(0) complex in the presence of amines was reported by Heck and Cassar as an extension of the Heck reaction to 1-alkynes [2,3]. In the same year, Sonogashira and Hagihara found that the addition of CuI as a co-catalyst gave better results, and the Pd(0)-CuI-catalyzed reaction is called the
Sonogashira reaction [4,5]. A comprehensive review on Pd-catalyzed alkynylation was published recently by Negishi and Anastasia [6]. Facile Pd(0)-CuI-catalyzed coupling of aryl and alkenyl halides with 1-alkynes is used extensively for the preparation of arylalkynes or enynes.
The reaction is explained by the following mechanism. At first, CuI activates 1-alkynes 1by forming the Cu acetylides6, which undergo transmetallation with arylpalladium halides to form the alkynylarylpalladium species 7, and reductive elimination to give 2 is the final step. However, the coupling proceeds even in the absence of CuI under certain conditions, and it may be possible to form the alkynylarylpalladium species7directly from 1-alkynes. As another less likely pos- sibility, carbopalladation of a triple bond with Ar-Pd-X (or insertion of the triple bond to Ar-Pd-X) generates the alkenylpalladium8 which undergoes dehydropal- ladation to afford disubstituted alkynes 2. In this mechanism, CuI plays no role.
The mechanism of β-H elimination of alkenylpalladium to form alkynes is not clearly known.
R H R Cu
R Pd-Ar
R Ar
+
+ HI
1 +
1 6
7
8
+ Pd(0)
?
R H
R H
X-Pd Ar
R Ar
2 Pd(0)
+ HX +
+ Pd(0)
2
Ar-X Ar-Pd-X
CuI
CuI
+ Pd(0)
Ar-X Ar-Pd-X
Coupling catalyzed by Pd(0) and CuI proceeds via in situ generation of Cu acetylides 6. Later acetylides of main group metals such as Mg, Zn, Sn, and B have been found to be good partners of the coupling. This is the second prepar- ative method of arylalkynes. Coupling of metal acetylides 9 of 1-alkynes with halides proceeds without CuI. In an exact sense, Pd-catalyzed couplings of metal acetylides with halides are different from the Sonogashira reaction. Coupling of Zn acetylides is regarded as a Negishi reaction, and that of Sn acetylides may be called a Kosugi –Migita–Stille reaction. These couplings with metal acetylides are treated in this section for the sake of convenience, rather than in section 3.6, because the same products are obtained by this method and the Sonogashira reac- tion.
M= Mg, Zn, B, Sn, Si
R MX R Ar
2 9
+ Pd(0)
+ MX2
Ar-X
3.4.2.1 Aryl–Alkynyl Coupling (Sonogashira Reaction): Reaction Conditions and Catalysts
Various results are obtained in Sonogashira coupling depending on the substrates used and the reaction conditions. Homocoupling and decomposition of alkynes are serious competitive reactions, and poor results are obtained sometimes due to these side reactions in the Sonogashira reaction particularly when less reactive electron-rich aryl halides are used. It is well known that CuI catalyzes oxidative homocoupling of 1-alkynes in O2 atmosphere (Glaser reaction). Also Pd(II) pro- motes the homocoupling. Therefore the reaction should be carried out with strict exclusion of O2. Homocoupling in the Sonogashira reaction can be decreased by slow addition of alkynes in THF [7] and use of phase-transfer agent (n-Bu4NI) in H2O–toluene [8]. Hoet al. reported that the homocoupling of phenylacetylene with 4-iodoanisole (10) can be reduced drastically by carrying out the reaction in an atmosphere of H2 diluted with N2 or argon [9].
+ PdCl2(PPh3)2, CuI, Et3N DMF, 100 °C, N2+ H2
without N2+ H2
+
98% 1.9%
23%
10
70%
Ph I
MeO
MeO Ph Ph
Phenylacetylene is an exceptionally reactive alkyne, and it is true that coupling of some electron-rich aryl halides proceeds smoothly only with phenylacetylene. In many papers, the coupling of phenylacetylene alone is reported. Good results are not always obtained in reactions of other alkynes with electron-rich aryl halides under similar conditions. Aryl iodides, bromides, and triflates are used for the coupling. Curiously, it is generally believed that Sonogashira coupling of aryl chlorides is difficult, and only a few reports on Sonogashira coupling of activated chlorides have been published. Plenio found a versatile catalyst for the Sonogashira coupling of various aryl chlorides. As a ligand, bulky and electron-rich P(t-Bu)3 or (1-Ad)2P(n-Bu) is the most effective. Na2PdCl4/PR3/CuI was found to be a precursor of the efficient catalyst system, and the coupling proceeds in toluene or DMSO at 100◦C [10].
Na2PdCl4, P(t-Bu)3, CuI Na2CO3, toluene 100 °C, 78%
+ Cl
MeO
n-C6H13
n-C6H13 MeO
Alkynes with EWGs such as propiolate are poor substrates for the coupling with halides. Therefore, instead of inactive propiolate, triethyl orthopropiolate (11) is used for the coupling with aryl halides to prepare the arylpropiolate 12. The
coupling product 14 obtained from 3,3-diethoxy-1-propyne (13) and aryl halides is a precursor of the arylalkynal 15[11].
14 11
1. PdCl2(PPh3)2, CuI, Et3N +
13
15 Me
I
OEt OEt
OEt
I
CO2Et
OEt OEt Me
OEt
OEt CHO
12 2. TsOH, 83%
Et3N, DMF, 64%
PdCl2(PPh3)2, CuI +
The Sonogashira reaction is usually carried out at about 80◦C. Pd(OAc)2, PdCl2(PPh3)2 or Pd(PPh3)4 are used in the presence of excess amine in most cases. It should be added that these Pd compounds as precursors do not always show the same behavior and sometimes show different activity. At this tempera- ture, decomposition of some labile alkynes tends to occur. Therefore, the reaction should be carried out under milder conditions as far as possible to prevent the side reaction. Pd on charcoal acts as an efficient catalyst for the coupling of aryl bromides such as 3-bromopyridine in the presence of CuI, PPh3, andi-Pr2NH in DMA–H2O [12].
DMF, reflux, 81%
+ Pd/C, PPh3, CuI, i-Pr2NH N
Br
N n-Bu n-Bu
Thorand and Krause claimed that THF is a very good solvent [7], but Hoet al.
reported that THF is a poor solvent in their reaction [9]. One drawback of the Sonogashira reaction is the use of a large excess of amines almost as a solvent.
Buchwald and Fuet al. reported that coupling of inactivated 4-bromoanisole (16) can be carried out at room temperature by using Pd(PhCN)2Cl2 as a catalyst, P(t-Bu)3 as a ligand, and only 1.2 equivalents of diisopropylamine. Poor results are obtained when PPh3, PCy3, P(o-Tol)3and DPPF are used instead of P(t-Bu)3
under similar conditions [13].
i-Pr2NH (1.2 equiv), dioxane r.t, 2 h, 95%
16
MeO H
Me Me OH
Me OH Me Br
MeO
+
Pd(PhCN)2Cl2, CuI, P(t-Bu)3
Beletskaya et al. reported that the reaction of arylalkynes proceeds smoothly at room temperature in water using only 10 mol% of Bu3N and excess K2CO3. PdCl2(PPh3)2and CuI are catalysts [14]. Mori and co-workers discovered a conve- nient and useful procedure for Sonogashira coupling. They found that the coupling of aryl iodides such as electron-richp-iodoanisole (10) can be carried out smoothly at room temperature using only 2 equivalents of aq. NH3 (0.5 M) in THF [15].
Room temperature coupling of aryl iodides 10 is possible in the presence of carbamoyl-substituted N-heterocyclic carbene complex (XVI-12) with the coexis- tence of PPh3(1 mol%) and Et3N (1.2 equiv.) in DMF. Reaction of electron-rich aryl bromide 16 proceeds at 80◦C with the same catalyst and Cs2CO3 as the best base [16]. Reaction of the reactive aromatic alkyne 18 with the reactive electron-deficient aryl iodide17 proceeds even at −20◦C in a quantitative yield.
Tri(2,4,6-trimethylphenyl)phosphine (I-8) was used as a ligand [17].
+
XVI-12, CuI, PPh3
PdCl2(PPh3)2, CuI THF, aq. NH3
(2 equiv) r.t, 81%
10
H t-Bu MeO t-Bu
MeO
I
H n-C6H13 MeO n-C6H13
MeO
I + 10
NEt3 (1.2 equiv), DMF r.t, 2 h 93%
i-Pr2NEt,n-Bu4NI, DMF
−20°C, 20 min, 100%
+ XVI-12, CuI, PPh3
Pd2(dba)3, CuI, L ( I-8) +
18
H t-Bu MeO t-Bu
H
OMe
OMe MeO2C
Br MeO
MeO2C
I 16
Cs2CO3 (1.2 equiv), DMF 80 °C, 5 h, 97%
17
Room temperature reaction of p-iodoanisole (10) also takes place in the pres- ence of Bu4NF (TBAF) or hydroxide (TBAOH) without addition of other amines.
PdCl2(PPh3)2and CuI are catalysts [18]. Ag2O, instead of CuI, can be used for the coupling at 60◦C [19]. Furthermore, the coupling proceeds without CuI or Ag2O in the presence of a stoichiometric amount of TBAF [20]. Sonogashira reaction proceeds in aqueous media(MeCN/H2O) at room temperature by the use of the water-soluble sulfonated phosphine ligandII-2without CuI [21]. Also coupling of triple bonds in peptides with aryl iodides was carried out in water in the presence
of II-2 as a ligand [22]. Synthesis of the 65-membered cyclic peptide containing triple bonds was achieved via ‘on resin’ Sonogashira coupling [23].
TBAOH (1.2equiv) THF, r.t, 6 h, 98%
PdCl2(PPh3)2, CuI +
10
MeO I H C6H13 MeO C6H13
H SiMe3 MeO SiMe3
MeO I
THF, 60 °C, 60%
10
+ Pd(PPh)4, Ag2O
10
Pd(OAc)2, L (II-2)
H C6H13 MeO C6H13
MeO I
OHC I
SiMe3
H
OHC
SiMe3 TBAF (1 equiv)
THF, 60 °C, 83%
Pd2(dba)3, PPh3
Et3N, MeCN/H2O 25° C, 80%
+ +
The coupling proceeds in an ionic liquid BMim (1-butyl-3-methylimidazolium hexafluorophosphate) in the absence of CuI. In this medium, the facile separation and recycling of the catalyst are possible [24].
+ PdCl2(PPh3)2, [BMim][PF6] i-Pr2NH, 80°C, 4 h, 87%
[PF6]− I
C6H13
H C6H13
[BMim]
Me Bu
Isomerization of the coupling products of 1-arylpropargyl alcohols with electron- deficient halides generate α,β-unsaturated aryl ketones, which undergo further condensation to afford heterocycles such as pyrroles and pyrimidines [25].
For example, domino coupling–isomerization–condensation reactions of 1- phenylpropargyl alcohol (17), 2-bromothiazole, and methylhydrazine generated the enone 18, and the pyrazoline 19 was obtained by the reaction of methylhydrazine [25].
Pd on carbon and CuI, combined with phosphine ligands, are used as good catalysts in some cases. The coupling of N-propargylamino acid 20 with 3- bromopyridine proceeded in an aqueous phase to give 21. Pd on carbon and water-soluble diphenylphosphinobenzoic acid (II-3) were used [26].
+ S
N Br
H
OH Ph
S N
OH Ph
S N
Ph O
S N
N Me N
Ph
+ PdCl2(PPh3)2, CuI
Et3N, 69%
19 17
MeNHNH2
MeNHNH2
18
Pd/C, CuI, L (II-3) DME/H2O
75%
+
21 N CO2H
Boc
Me Boc N CO2H
Me
N Br
N 20
Aryl and alkenyl triflates are reactive partners. Coupling of ditriflate of catechol (22) with the alkyne 23 gave the 1,2-dialkynylbenzene 24 in good yield in the presence of n-Bu4NI (300 mol %) [27]. Functionalization of some heterocycles is possible by the reaction of their triflates. Coupling of the 5-acetyl-4-thiazolyl triflate25 proceeded at room temperature in the presence of Pd(PPh3)4 and CuI, and the product26was converted to the pyrido[3.4-c]thiazole27by treatment with ammonia [28]. The triflate 29 was prepared from the corresponding oxazolone, and its Sonogashira reaction with methylN-propargylcarbamate (28) afforded the 2-alkynyloxazole 30in 84 % yield [29].
Bu4NI, Et3N, DMF 70°C, 91%
PdCl2(PPh3)2, CuI
22
Pd(PPh)4, CuI Et3N, DME, r.t
67%
24
25 +
+
H SiMe3
OTf
OTf
SiMe3 SiMe3
H N
S F
F
OTf
O
HO 23
75%
26 27
N S F
F O
HO
N S F
F
N HO NH3
+
Pd(PPh3)4, CuI
SiR3= TBDMS
2,6-lutidine dioxane,
rt, 84%
28 29 30
O N
OSiR3 HN
CO2Me H
HN CO2Me
O N
OSiR3 TfO
3.4.2.2 Alkenyl–Alkynyl Coupling (Sonogashira Reaction)
Aryl iodides, bromides, and triflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pd- catalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cis-1,2-dichloroethylene (31) can be coupled with 1- alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two dif- ferent 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric (E)-enediyne37 was obtained in a one-pot reaction of 1-alkynes 33 and23 withtrans-1,2-dichloroethylene35.
PdCl2(PhCN)2 piperidine, rt
Cl Cl
1) Pd(PPh3)4, CuI BuNH2, rt
2)
33 H (CH2)4OH
31 32
34 73%
H C5H11
C5H11 (CH2)4OH +
Cl
Cl 33
+ 1) Pd(PPh3)4, CuI H C5H11
H SiMe3
C5H11
SiMe3
piperidine, rt
75%
PdCl2(PhCN)2 piperidine, rt 2)
23
37 35
The novel [6.6]metacyclophane40was prepared by coupling31with 1-alkynes as a key reaction. The shortest way to40is the coupling ofm-diethynylbenzene (41)
with31. The yield of the attempted reaction was only 2 %. Then39was prepared in 67 % yield by coupling38with31, from which40was obtained by Ti-mediated intramolecular coupling of aldehydes [33].
+
31
39
40 41
+
Pd(PPh3)4, CuI BuNH2, rt, 67%
31 O
O
Cl
Cl
O O
O O
Cl
Cl 38
Pd(PPh3)4, CuI BuNH2, rt 2%
Both chlorines of 1,1-dichloroethylene (42) react stepwise with different 1- alkynes 43 and 44 to form the asymmetric enediyne 45[34]. The enediyne sys- tem 48 was prepared by Pd-catalyzed stereoselective hydrogenolysis of the 1,1- dibromo-1-alkene 46 with tin hydride to give 47, followed by coupling with 1-alkyne23 in a one-pot reaction [35].
CuI, 81%
48 + 75%
+
63%
47
Br Br
Ph
Pd(PPh3)4/CuI i-Pr2NEt, 70%
Br H
Ph
46
Ph TMS
TMS 42
45
44 C5H11
Cl Cl
C5H11 C3H7
Cl
C5H11
C3H7 43
23 Pd(PPh3)4
HSnBu3 Pd(PPh3)4
Alkenyl triflates are reactive partners. In the total synthesis of (−)-tricholo- menyn (52b), coupling of the vinyl triflate 49 with 23 gave the enyne 50a, and reaction of the vinyl iodide 51 with the deprotected 1-alkyne 50b afforded 52a.
Combined use of PdCl2(PPh3)2, CuI, and i-Pr2NH gave the best results in this case. The reaction in THF and di-isopropylamine at 0◦C is important. Under usual conditions of the Sonogashira reaction, no product was obtained [36]. Coupling of ethynyloxirane 53 with alkenyl triflate afforded the epoxyenediyne 54 in high yield without attacking the labile epoxyalkyne system. AgI is a better cocatalyst than CuI in this reaction [37].
OTf
I O
O
OTBS 49
O
O
OR +
51
TMS
52a, R = TBS
52b, R = H, tricholomenyn PdCl2(PPh3)2, CuI
R
OTf
t-Bu
O
SiPh2t-Bu
O
SiPh2t-Bu t-Bu
50a 50b
53 23
+
Pd(PPh3)4, AgI i-Pr2NH, DMF 90%
54 i-Pr2NH, 85%
R = TMS R = H
PdCl2(PPh3)2, CuI i-Pr2NH, 0 °C 54%
Vinyl tosylates are also used. Coupling of the vinyl tosylate55with an 1-alkyne afforded the enyne 56. Only the use of PdCl2(PPh3)2, CuI, and i-Pr2NH gave satisfactory results [38].
+
56 PdCl2(PPh3)2, CuI
55
i-Pr2NH, THF rt, 90%
H CH2OMe
Ph H
SPh OTs
Ph H
SPh
CH2OMe
3.4.2.3 Coupling and cyclization
Coupling of 1-alkynes with aryl halides having a nucleophilic group at anorthoposi- tion and subsequent cyclization offer useful synthetic methods of heterocycles [39].
Two types are known. In type 1, the halides57react with 1-alkynes to generate58, which undergo cyclization to afford 2-substituted heterocycles 59. β-Substituted alkenyl halides60behave similarly to give 2-substituted heterocycles61.
Sonogashira Pd(0), CuI
57 58 59
YH = OH, NH2
+
Sonogashira Type 1
X
YH YH
R
Y R
X
YH
R R
YH R
Y R
61 Pd(0), CuI
+
60
In type2, the ethynyl derivatives62 and63 react with aryl halides to generate disubstituted alkynes, which cyclize to afford59 and61.
These reactions are used extensively for the preparation of heterocycles59and 61 such as benzo[b]furans, butenolides, and indoles. In some cases, cyclization proceeds spontaneously to give59 in a one-pot reaction.
+ Ar-X
59
63
+ Ar-X
61 62
YH YH
Ar
Y Ar Type 2
YH YH
Ar
Y Ar R
R
R
R
R
R
Furan derivatives are prepared by reaction of o-iodophenols. 2-Phenylbenzo- [b]furan was prepared by the reaction of o-iodophenol (64) with 1-alkyne in one step [40]. It should be noted that similar 2-arylbenzo[b]furan formation occurred by the use of Pd-free, copper-phosphine complex [41]. Similarly 2-substituted furo[3.2-b]pyridine 66 was prepared from 2-iodo-3-pyridinol (65) in a one-pot reaction [42]. Naturally occurring ailanthoidol was synthesized by the reaction of 67and 68to give the cyclized product69 [43].
The deoxynucleoside 72 was prepared in two steps by coupling the 5-iodo nucleoside70with 1-dodecyne, and CuI-catalyzed cyclization of71[44].
65
piperidine,CuI, 80% O I
OH
Ph Ph +
64
N N
O I
OH
OEt OEt
OEt OEt 66
piperidine, DMF, 82 % Pd(OAc)2(PPh3)2, CuI +
Pd(OAc)2(PPh3)2
Et3N, MeCN, 68%
ailanthoidol +
69
PdCl2(PPh3)2, CuI
67
I OH MeO2C
OMe
OBn OMe
MeO2C
OMe O
OBn OMe
OMe O
OH OMe HO
68
71 72
MeOH, 58%
Pd(PPh3)4, CuI i-Pr2EtN, DMF, 57%
CuI, Et3N N
HN
O HO
HO O
O I
C10H21
N HN
O HO
HO O
O C10H21
N N
O HO
HO O
O
C10H21
70
+
Sonogashira coupling of o-iodothioanisole (73) with phenylacetylene affords o-(1-alkynyl)thioanisole74, which cyclizes to give 2-substituted 3-iodobenzothio- phene75by the treatment with iodine. Furthermore, Suzuki coupling of75affords the 2,3-disubstituted benzothiophene76 [45]. The iminoalkyne 78is prepared by Sonogashira coupling of the alkenyl iodide77, and the substituted pyridine 79 is obtained by the CuI-catalyzed cyclization [46].
74
75 76
+ Et3N, 25 °C, 100%
I2, CH2Cl2 25°C,100%
Pd(OAc)2, Na2CO3, DMF, 92%
NaBPh4 PdCl2(PPh3)2, CuI
73 I
SMe
Ph
SMe Ph
S S
Ph
Ph I
Ph
79
78 77
+
CuI (10 mol%)
PdCl2(PPh3)2, CuI (1 mol%) Et3N, 55 °C, 57%
DMF, 100 °C H
Ph I
N t-Bu
N Ph Ph
Ph
H
Ph
N t-Bu
Ph
As an alternative procedure (type 2 reaction), coupling of the o-ethynylphenol 80with the alkenyl triflate81 proceeds smoothly to yield the benzofuran82 [40].
Coupling of 2-bromothiazole with an enolate of 1,3-dicarbonyl compound was used for preparation of 2,5-disubstituted furan83[47]. Coupling of 2-iodoanisole
OH Me
O
O
Ph OTf
O Me
Ph
O O Me
N Br S
Me O S
O N
+ Pd(OAc)2(PPh3)2, CuI Et3N, DMF, 50%
+
Pd(Ph3P)4 K2CO3, DMF, 73%
80 81
82
83
withN-propargylbenzamide (84) generated the coupling product in the presence of t-BuONa, which underwent base-catalyzed in situ cyclization to yield 2,5- disubstituted oxazole 85[48].
84
Pd2(dba)3, TFP (I-3)
+ t-BuONa, MeCN
83%
OMe
I
HN Ph
O
N O
Ph MeO
HN Ph
O MeO
85
The coupling of theo-iodoaniline derivative86with 1-alkynes in aqueous media at room temperature by the use of the water soluble ligand II-2, followed by intramolecular amination gave the indoles87aand87b[49]. As a type 2 reaction, the indole91 was obtained by coupling 2-ethynylaniline (88) with the triflate 89 and cyclization [50].
Pd(OAc)2, L (II-2) Et3N, MeCN/H2O
rt, 70%
86
87a
88
64%
+ +
89 87b I
Bu H
NHCOCF3
N Bu COCF3
NH Bu
NH2
NH2
OTf
NH
91 CuI
Pd(II)
Pd(PPh3)4 +
The γ-alkylidenebutenolide 93 was prepared by domino coupling of (Z)-3- bromoacrylic acid (92) with 1-alkynes to generate an enyne acid, followed by lactonization [51]. Negishi synthesized γ-alkylidenebutenolide 98 by the cou- pling–lactonization reaction [52]. The 3-aryl-3-iodocinnamic acid96, a coupling partner, was prepared by the coupling of Zn acetylide of ethyl propiolate with95, followed by hydroiodination. As described earlier, Sonogashira coupling of pro- piolate itself is very difficult. The coupling–lactonization of96 with the 1-alkyne 97afforded the acetate of rubrolide (98) in 70 % yield via lactonization.
Ph
H Br CO2H
O Ph
O Ph
O + HO
Pd(PPh3)4, CuI Et3N, 80%
92
93
98 +
Pd(Ph3P)4, CuI Et3N, MeCN 25 °C, 70%
AcO
Br
Br
O
AcO Br
Br
O AcO
Br
Br
I
CO2Et BrZn
CO2Et Br
Br AcO
AcO
Br
Br
I CO2H Br
Br AcO
AcO
Br
Br
CO2H
AcO Br
Br 94
95 96
97 Pd(PPh3)4
Stereoselective preparation of (E)-5-stannyl-γ-alkylidenebutenolide 100 was achieved by the reaction of tin acetylide with tributylstannyl 3-iodopropenoate derivative 99, and the arylbutenolide 101 was obtained by the Migita–Kosugi – Stille reaction of100[53].
+
DMF, 70%
PdCl2(MeCN)2 70%
99 O I OSnBu3
100 101
SnBu3 MeO H
O OSnBu3 MeO
SnBu3
O O
MeO
Bu3Sn O O
MeO S I S
Pd(PPh3)4
3.4.2.4 Acetylene Surrogates
Selective monosubstitution of acetylene to prepare 1-alkynes is not easy. It can be done by the use of protected acetylenes. As one method, trimethylsilylacetylene (TMS-acetylene) (23) is used. After its coupling with halides, the TMS group is removed by treatment with a base or fluoride anion to give 1-alkynes. Among numerous examples, an application to synthesize a rigid macrocycle with two exo- topic phenanthroline binding sites is cited. In this synthesis, TMS-acetylene (23) and triisopropylsilylacetylene (102) are used as protected acetylenes [54]. At first the dialkynes103, protected with TMS and triisopropylsilyl groups, were prepared fromp-bromoiodobenzene in high yield, and the TMS group in103was selectively removed to give104, which undergoes coupling with the dibromophenanthroline
CuI, Et3N rt, 98%
CuI, Et3N rt, 98%
I Br
103
104
SiMe3
H Br SiMe3
Si(i-Pr)3 H
SiMe3 23
102 +
+
Pd(0), CuI 23
(i-Pr)3Si
H (i-Pr)3Si
SiMe3
Ar Ar H
SiMe3 H
PdCl2(PPh3)2
KOH
PdCl2(PPh3)2 MeOH
F− Ar-X
105 to give 106a in 91 % yield. Deprotection of 106a afforded the diyne 106b.
Coupling of 106bwith two molecules of the 1,3-diiodobenzene107afforded 108 in 84 % yield. Finally the macrocycle 109 was obtained by the coupling of 108 with106bin 16 % yield.
+ 104
CuI, Et3N rt, 91%
105 106a R = -Si(i-Pr)3
106b R = H N
N C6H13
C6H13
Br
Br
N
N C6H13
C6H13
R
R I I
OMe
t-Bu 107 84%
PdCl2(PPh3)2
Pd(PPh3)4
Et3N, benzene reflux 40 h, 16%
106b N
N C6H13
C6H13
N
N C6H13
C6H13
108
t-Bu
I OMe
OMe I
t-Bu
t-Bu
OMe
OMe
t-Bu
N
N
109
C6H13
C6H13
Pd(PPh3)4