PRACTICAL SYNTHETIC PROCEDURES
1713
Synthetic Applications of Oxime-Derived Palladacycles as Versatile Catalysts in Cross-Coupling Reactions Ap licationsofPal dacy lesasCat lyst inCros -CouplingReactiA. Diego ons Alonso, Luis Botella, C. Nájera,* Mª Carmen Pacheco Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain Fax +34(965)903549; E-mail:
[email protected] Received 12 January 2004
PSP
22
No
Abstract: Palladacycles 1 and 2, derived from 4,4¢-dichlorobenzophenone and 4-hydroxyacetophenone oximes, respectively, are very efficient and versatile pre-catalysts for a wide range of carbon-carbon bond coupling reactions such as, Mizoroki–Heck, Suzuki–Miyaura, Stille, Ullmann-type, Sonogashira, sila-Sonogashira, Glaser and acylation of alkynes under very low loading conditions in air and either in organic or aqueous solvents, employing reagent-grade chemicals. High yielding, general, and practical procedures for the palladium-catalyzed Mizoroki–Heck, Suzuki–Miyaura, Ullmann-type, Sonogashira and sila-Sonogashira reactions are described. Key words: cross-coupling, palladacycles, Heck reaction, biaryls, alkynes
Cl
OH
Cl HO
HO
N
Cl Pd Pd N Cl OH
Me
OH 2
1
O
I
1 (0.01 mol% Pd)
O
+ MeO
O Et3N, NMP, 110 ºC, 22 h
O
MeO
3
4
5 (85%)
Cl Procedure 2
Me
Pd Pd N Cl OH
Cl
Cl
Procedure 1
N
Cl
2 (1 mol% Pd) Me
+
Me
B(OH)2 K2CO3, TBAB, H2O, 100 ºC, 2 h
CN
CN 6
Procedure 3
8 (55%)
7
1 (0.5 mol% Pd)
S
2 I
S
i-Pr2NEt, DMF, 110 ºC, 20 h
9
S 10 (86%) NHAc
NHAc +
Procedure 4
1 (0.1 mol% Pd) Ph
H Bu4NOAc, NMP, 110 ºC, 2 h
I
Ph 11 I Procedure 5
1 (0.5 mol% Pd) +
2
13 (60%)
12
TMS
TMS Pyrrolidine, CuI, NMP, 110 ºC, 8 h
N 14
Scheme 1
SYNTHESIS 2004, No. 10, pp 1713–1718xx. 204 Advanced online publication: 25.02.2004 DOI: 10.1055/s-2004-815992; Art ID: Z00904SS © Georg Thieme Verlag Stuttgart · New York
15
N
N 16 (85%)
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D. A. Alonso et al.
Introduction Palladium-catalyzed cross-coupling reactions are one of the most important processes in organic chemistry and have been extensively studied since they represent a powerful and popular method for the formation of C–C and C– Het bonds.1 During the past few years, considerable effort has been devoted to the preparation of very active, and at the same time stable, palladium catalysts, in order to improve their versatility and efficiency in C–C bond-forming reactions. In particular, palladacycles have emerged as a very promising family of organometallic catalyst precursors.2 Thus, we have shown very recently that phosphane-free oxime-derived palladacycles 1 and 2 (Scheme 1) are air and water stable pre-catalysts for a wide range of cross-coupling processes such as Heck,3–5 Suzuki,6–8 Stille,3 Ullmann,6 Sonogashira,9,10 silaSonogashira10 and Glaser-type10 reactions in 3,4,6,9,10 organic and aqueous solvents.5,7,8 In addition, the acylation of terminal alkynes with acid chlorides can be performed in the presence of palladacycle 1 in organic solvents.11 We have demonstrated that complexes 1 and 2 combine a good functional group tolerance with a high reactivity in all the processes studied so far.
Scope and limitations Oxime-derived palladacycles are thermally stable complexes, not sensitive to oxygen or moisture. Their synthesis is straightforward from inexpensive and readily available starting materials through aromatic metallation of the corresponding oximes with Li2PdCl4 in MeOH at room temperatue in the presence of NaOAc as base (Scheme 2).4,12 Several palladacycles, derived from a wide variety of aromatic and aliphatic oximes have been prepared and their catalytic activity have been checked. Among all of them, we have previously shown that 4,4¢dichlorobenzophenone-derived catalyst 1 gives the highest activities in the studied C–C bond forming reactions in organic solvents,4 whereas 4-hydroxyacetophenone-derived catalyst 2 was the most active complex when working in aqueous media.8 R2
R2 N
OH
Li2PdCl4, NaOAc N MeOH, r.t., 3d
R1 17, R1 = Cl, R2 = p-ClC6H4 18, R1 = OH, R2 = Me
OH
Pd
R1 Cl
)2
1, R1 = Cl, R2 = p-ClC6H4, 95% 2, R1 = OH, R2 = Me, 92%
Scheme 2
Complex 1 derived from 4,4¢-dichlorobenzophenone, represents a very efficient catalyst precursor for the Mizoroki–Heck olefination of haloarenes in organic solvents (Scheme 1).4 By fine-tuning the reaction conditions, extraordinary turnover numbers (TON = mol product mol Synthesis 2004, No. 10, 1713–1718
© Thieme Stuttgart · New York
Pd–1) and rates (turnover frequencies, TOF = TON h–1), have been obtained under aerobic conditions for aryl iodides (TON up to 1010 and TOF up to 1.4 × 108 h–1), deactivated aryl bromides (TON up to 97000, TOF up to 6063 h–1) and aryl chlorides. With respect to the reaction conditions, aryl bromides and chlorides essentially required high temperatures and the use of inorganic bases such as K2CO3 and tetra-n-butylammonium bromide (TBAB) as additive. The pronounced thermal stability of palladacycle 1, has also been demonstrated by the absence of visible Pd-black precipitation after heating the complex in DMF at 110 ºC during 5 hours. Only trace amounts were detected after very long reaction periods. Additionally, no deactivation of the catalyst was observed in subsequent catalytic runs when coupling phenyl iodide and butyl acrylate under typical reaction conditions (DMF, 110 ºC, Et3N, 0.1 mol% Pd), and GC analysis of 4 cycles yielded a constant rate of conversion (96–99%, 1.2–2 h) of phenyl iodide after adding fresh reagents to the reaction mixture.4 On the other hand, preliminary studies have shown 4-hydroxyacetophenone-derived catalyst 2, as an efficient pre-catalyst as well for the mono- and diarylation reaction of olefins under aqueous conditions.5 The mono and b,b-diarylation of a,b-unsaturated carbonyl compounds with electron-deficient and electron-rich aromatic iodides in water, have been achieved by controlling the stoichiometry of the aryl iodide and the alkene and the catalyst loading. The monoarylation reactions can be performed using (dicyclohexyl)methylamine as base in refluxing water under thermal or microwave conditions and in the absence of inert atmosphere, either with 2 or Pd(OAc)2 as catalysts. However, the diarylation process works only in the presence of complex 2. Complex 1 is also very efficient in a related Heck reaction, the palladium-catalyzed annulation reaction of internal alkynes with o-halobenzaldehydes and o-haloanilines, for the synthesis of indenones and indoles.4 Other aryl-Pd covalently bonded oxime-based palladacycles, derived from diverse carbonyl derivatives such as, acetophenone, benzophenone, benzaldehyde and acetylferrocene, have also been shown by us and others to be efficient catalyst precursors in the Mizoroki–Heck reaction.3,4,13 Oxime derived palladacycles 13,6 and 2,7,8 have also been successfully used as catalyst precursors for the synthesis of biaryls through Suzuki–Miyaura and Ullmann-type processes. Specially relevant has been the contribution of palladacycle derived from acetophenone oxime 2, as very efficient pre-catalyst for the Suzuki–Miyaura coupling of arylboronic acids with aromatic and heteroaromatic chlorides in water.7,8 The presence of TBAB (50 mol%) is crucial for these type of couplings (Scheme 1). The crosscoupling reactions can be carried out under very simple and environmentally friendly conditions in refluxing water and under aerobic conditions. It is also significant to mention that Pd(OAc)2 affords very low yields in this process under the same reaction conditions. In the case of employing aryl bromides in the Suzuki–Miyaura coupling, TONs of up to 105 have been obtained in refluxing water.
PRACTICAL SYNTHETIC PROCEDURES Applications of Palladacycles as Catalysts in Cross-Coupling Reactions 1715
Similar results, though with lower turnover numbers (up to 104), can be obtained working at room temperature with catalyst 2, but employing a mixture of MeOH–H2O as solvent. A limitation of these catalysts is the low yields usually obtained when electron-rich substrates such as, pchloroanisole are used in the reaction coupling, even in the presence of high catalyst loadings (0.5–1 mol% of Pd) and at high reaction temperatures. It is also significant to underline the importance of the presence of small amounts of water as co-solvent in the reaction when using catalyst 1, which avoids the formation of biphenyl as by-product via an homocoupling process of the phenylboronic acid.14 It should be pointed out that a wide variety of functional groups such as alcohols, amines, aldehydes, carboxylic acids, nitriles and amides are tolerated when oxime-derived palladacycles 1 and 2 are used as catalysts in the Suzuki–Miyaura reaction.3,6–8 Moreover, palladacycles 1 and 2 have also shown a high thermal stability under the employed reaction conditions for the Suzuki coupling, showing little or no deactivation in subsequent catalytic runs.6,8 Complex 1 is a very useful catalyst for the preparation of biphenylmethyl p-tolyl sulfone15 via the Suzuki– Miyaura reaction of the corresponding aryl bromide in organic solvents, which is a very practical synthetic precursor of functionalized 4-biphenylacetic acids.16 A preformed oxime-carbapalladacycle complex, covalently anchored onto mercaptopropyl modified silica gel, has also been shown as a highly active and recyclable catalyst for the Suzuki reaction of aryl bromides and chlorides in water, without appreciable palladium leaching.17 On the other hand, diverse symmetrical biphenyls can be synthesized in high yields via reductive homocoupling Ullmann-type reaction of different iodobenzenes using complex 1 (0.5–2 mol% of Pd) in DMF at 110 ºC in the presence of i-Pr2NEt as base (Scheme 1).6 This protocol has been previously used employing phosphane-derived Herrmann’s palladacycle {trans-di(m-acetato)-bis[o-(dio-tolylphosphino)benzyl]dipalladium(II)}, resulting in longer reaction times and lower yields even with higher catalyst loadings (12 h, 1 mol% of Pd, 70–87% yield).18 Palladacycle 1 (3 mol% of Pd) catalyzes the Stille reaction between activated aryl bromides and phenyltrimethyltin in refluxing toluene.3 When this coupling was performed in NMP and K2CO3 as base lower catalyst loading (0.5 mol% of Pd) was used and the reaction could be performed with unactivated aryl bromides at 110 ºC or at room temperature. Thus, p-bromoanisole reacted with phenyltrimethyltin during 1 hour or 24 hours either at 110 ºC or at room temperature, respectively.19 Unfortunately, the reaction was very sluggish when aryl chlorides were used under the conditions studied.3,19 The importance of biaryl units20 as key components of many compounds such as, pharmaceuticals, herbicides and natural products as well as in the field of engineering materials such as conducting polymers, molecular wires and liquid crystals, points out the promising significant contribution of oxime-derived palladacycles to the synthetic organic chemistry field.
Complex 2 readily catalyzes the formation of C(sp2)– C(sp3) bonds, through the cross-coupling reaction of trimethylboroxine and n-butylboronic acid with activated aromatic bromides and chlorides under water reflux in the presence of K2CO3 as base and TBAB as additive.8 This type of C(sp2)–C(sp3) coupling between activated aryl halides and alkylboronic acids, has been previously reported employing Pd(dppf)2Cl2 (10 mol%) either under inert atmosphere (for the coupling between activated aryl chlorides and trimethylboroxine),21 or in the presence of an excess of Ag2O (for the coupling between aryl bromides and n-butylboronic acid)22 as an additive. The simple reaction conditions employed with catalyst 2 emphasizes the importance of the obtained results. A major drawback of this protocol is the generation in variable amounts of the corresponding symmetrical biaryls as by-products, due to the Ullmann-type coupling processes of the aryl halides. This type of reaction resulted unfruitful when using palladacycle 1 in organic solvents. Employing oxime-derived palladacycles 16 and 2,7,8 the Suzuki palladium-catalyzed methodology has also been extended to the coupling of allylic and benzylic chlorides as well as allylic acetates with arylboronic acids under smooth reaction conditions. Palladacycle 2 works as pre-catalyst (0.01–0.1 mol% of Pd) in acetone–water (3:2) at room temperature with KOH as base and in the presence of TBAB.7,8 Very recently, we have also shown oxime-derived palladacycles as efficient pre-catalysts for the copper- and amine-free Heck coupling (Sonogashira-type) between terminal acetylenes and aryl iodides and aryl and vinyl bromides, (Scheme 1) achieving turnover numbers (TON) of up to 72000 for aryl iodides and 960 for aryl bromides.9,10 The reaction, which usually needs very short times, is performed in NMP as solvent and employing tetra-n-butylammonium acetate (TBAA) as base. Complex 1 has been confirmed as an effective promoter of the silaSonogashira coupling between alkynylsilanes and aryl iodides and bromides in the presence of CuI or TBAB as cocatalysts (Scheme 1).10 Tuning the reaction conditions, it is possible to control the reaction outcome to obtain either diarylated alkynes or silylated monoarylated alkynes using mono- or bis(trimethylsilyl)acetylene, respectively. Thus, symmetrically diarylated alkynes were obtained when aryl halides reacted with bis(trimethylsilyl)acetylene in the presence of CuI as co-catalyst and pyrrolidine as solvent at 90 ºC. However, when the reaction was carried out in NMP as solvent and in the presence of TBAB and pyrrolidine at 110 ºC, silylated alkynes were obtained.10 This methodology has been used for the synthesis of asymmetrically substituted alkynes via silaSonogashira coupling of 1-chloro-4-iodobenzene with phenyl(trimethylsilyl)acetylene. Complex 1 efficiently promotes the homocoupling reaction (Glaser-type coupling) between 1-alkynes in NMP with pyrrolidine as base and in the presence of CuI (5 mol%) under low catalyst loadings (TONs of up to 1000) either at 110 ºC or at room temperature.10 It is noteworthy note that the homocoupling process proceeded sluggishly Synthesis 2004, No. 10, 1713–1718
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D. A. Alonso et al.
in the absence of oxygen, which was shown as an essential component in the catalytic cycle to regenerate the palladium active species. Internal acetylenes, enynes and diynes are very important compounds present in numerous natural and biologically active compounds and in new materials with unusual electrical and optical properties. We have also demonstrated that phosphane-free oximederived palladacycle 1 is an efficient pre-catalyst for the copper-free acylation of terminal alkynes with carboxylic acid chlorides in toluene in the presence of TEA as base.11 The reaction coupling can be normally performed under air or inert atmosphere when using very low catalyst loadings (10–3 mol% of Pd, TON up to 23000, TOF up to 958 h–1), or sensitive carboxylic acid chlorides, giving the corresponding ynones in good yields. The protocol allows performing the synthesis of ynones at 110 ºC, room temperature or under microwave irradiation conditions, with good yields for aromatic and aliphatic carboxylic acid chlorides and different acetylenes. Pd(OAc)2 catalyzes the ligandless cross-coupling process as well but this usually works under higher loading conditions.11 Other authors have also shown that oxime-derived palladacycles are good pre-catalysts for other different processes, such as the palladium-catalyzed carbonylation of aryl iodides23 and the degradation of thiophosphate pesticides, where the palladacycle catalysts work as efficient organophosphate hydrolases mimetics.24 Finally, with respect to the mechanistic considerations, it seems that palladacycles 1 and 2 (and the palladacycle complexes in general) are not the true active catalysts in the C–C bond forming reactions. Instead, they could be pre-catalysts that undergo an activation process. Bedford has pointed out the possibility that these systems and related ones, could suffer a reductive process allowing the formation of colloidal palladium nanoparticles, which
could act as the true active catalysts in the reactions.2b,25 We have also observed by transmission electronic microscopy (TEM), the presence of Pd nanoparticles of 0.9–1.2 nm in size and aggregates of Pd nanoparticles (10 nm) in reaction samples of the Heck coupling between iodobenzene and methyl acrylate in DMF at 110 ºC catalyzed by oxime-derived palladacycle 1.19 In summary, phosphane-free oxime-derived palladacycles 1 and 2 are very efficient and versatile pre-catalysts for a wide range of C–C bond coupling reactions (Scheme 3). These complexes usually work under very low loading conditions in air and employing reagent-grade chemicals, which enhances their utility and potential applications in organic chemistry.
Procedures Herein, we described five typical synthetic procedures demonstrating the synthetic scope of oxime-based palladacycles as very efficient pre-catalysts in cross-coupling reactions. In Procedure 1, we report the preparation of 2ethylhexyl methoxycinnamate (5), an active organic ingredient in sunscreens,26 via a high yield palladium-catalyzed Heck olefination reaction between commercially available p-iodoanisole (3) and acrylate 4 in NMP as solvent and Et3N as base. In the second procedure (Procedure 2), a Suzuki–Miyaura reaction between ochlorobenzonitrile (6) and p-tolylboronic acid (7) in water is used to prepare, in a 55% yield, 4′-methylbiphenyl-2carbonitrile (8), a key intermediate in the synthesis of modern angiotensin II receptor antagonists such as the antihypertensive drugs losartan, valsartan, irbesartan, and tasosartan.27 The third reaction (Procedure 3) describes how palladacycle 1 effectively promotes the reductive homocoupling of 2-iodothiophene (9) to produce the corresponding 2,2′-bithiophene28 (10) in a high 86% isolated
Alkynes acylation
Mizoroki-Heck
Glaser R2 N
sila-Sonogashira
Cl
Sonogashira
Scheme 3
© Thieme Stuttgart · New York
Suzuki-Miyaura
)2
1, R1 = Cl, R2 = p-ClC6H4 2, R1 = OH, R2 = Me
Ullmann
Synthesis 2004, No. 10, 1713–1718
OH
Pd
R1
Stille
PRACTICAL SYNTHETIC PROCEDURES Applications of Palladacycles as Catalysts in Cross-Coupling Reactions 1717
yield. Procedures 4 and 5 deal with C(sp2)–C(sp) bond forming processes. In Procedure 4, the copper-free Sonogashira-type coupling between 2-iodoacetanilide (11)29 and phenylacetylene (12) catalyzed by oxime derived palladacycle 1 is described. The prepared acetylene 13 is a versatile precursor of indoles.30 Finally, in Procedure 5, the versatility of oxime-based palladacycles is demonstrated with the preparation of symmetrically substituted alkyne 16 via sila-Sonogashira coupling between commercially available 3-iodopyridine (14) and bis(trimethylsilyl)acetylene (15). Compound 16 is commonly used in crystal engineering science due to its rigidity and hydrogen-bonding acceptor character.31 All reagents and solvents were obtained from commercial sources and were generally used without further purification. Palladacycles 1 and 2 were purchased from MEDALCHEMY S. L. Florisil (60– 100 mesh) was purchased from SDS. Silica gel (40–60 mesh), was purchased from Merck. The catalysts were weighed out in an electronic microscale (Sartorius, XM1000P) with a precision of 1 mg, or dissolved in toluene, taking aliquots when performing very low loading experiments. When mentioned, the reactions were set up with the aid of an RR98030 12 place Carousel Reaction StationTM from Radleys Discovery Technologies, equipped with gas-tight threaded caps with a valve, cooling reflux head system, and digital temperature controller. TLC was performed on Polygram® Silica Gel 60 UV254 plates, purchased from Merk. Melting points were measured in a Reichert Thermovar apparatus. High vacuum distillations were carried out in an Edwards High vacuum equipment series 500 (10–2–10–7 mbar pressure measuring range). Purification by distillation described in Procedure 2 was carried out in a Büchi GKR-51 Kugel-Röhr distillation apparatus. Gas chromatographic analyses were performed on an HP-5890 instrument equipped with a WCOT HP-1 fused silica capillary column using decane as internal standard. IR data were collected on a Nicolet Impact 400D-FT spectrometer. 1H NMR spectra were recorded on a Bruker AC-300 MHz spectrometer. Chemical shifts are reported in ppm using TMS (d = 0.00 ppm) as internal standard. 13C NMR spectra were recorded at 75 MHz with CDCl3 as the internal reference unless otherwise stated. Mass spectra (MS) were obtained at 70 eV on a Hewlett Packard HP 6890 series GC system with a 5973 network mass selective detector, fragment ions in m/z with relative intensities (%) in parenthesis. 2-Ethylhexyl methoxycinnamate (5)32 A reaction tube of the carousel reaction equipment was charged with 4-iodoanisole (3, 1.195 g, 5 mmol), decane (0.97 mL, 5 mmol), 2-ethylhexyl acrylate (1.12 mL, 1 mmol), TEA (0.98 mL, 7 mmol), 1 (0.204 mg, 0.00025 mmol, 10–2 mol% Pd) and NMP (8 mL). The mixture was stirred at 110 ºC in air and the reaction progress was analyzed by GLC. The crude reaction mixture was extracted with water and EtOAc (3 × 25 mL). The organic phases were washed with water (5 × 15 mL), dried with MgSO4, evaporated (15 mm Hg). The resulting crude material was purified by distillation in high vacuum distillation equipment (170–180 ºC, 75 × 10–6 mm Hg), affording pure 5 as a pale yellow oil (1.21 g, 85%); Rf 0.35 (hexane– EtOAc, 9:1). IR (film): 1711, 1635 cm–1. 1
H NMR: d = 0.89–0.95 (m, 6 H), 1.23–1.47 (m, 8 H), 1.61–1.67 (m, 1 H), 3.84 (s, 3 H), 4.10–4.12 (m, 2 H), 6.32 (d, J = 15.9 Hz, 1 H), 6.90, 7.48 (2 × d, J = 8.73 Hz, 4 H), 7.63 (d, J = 16.1 Hz, 1 H).
MS: m/z (%) = 290 (8), 179 (13), 178 (100), 161 (59), 134 (15), 133 (16). 4¢-Methylbiphenyl-2-carbonitrile (8)32,33 A reaction tube of the carousel reaction equipment was charged with 2-chlorobenzonitrile (6, 0.28 g, 2 mmol), 4-tolylboronic acid (7, 0.41 g, 3 mmol), K2CO3 (0.55 g, 4 mmol), TBAB (0.64 g, 2 mmol), 2 (5.837 mg, 0.01 mmol) and water (7 mL). The reaction mixture was stirred under reflux and the reaction progress was analyzed by GLC. After 2 h the reaction was cooled, poured into EtOAc (40 mL) an extracted with water (2 × 30 mL). The organic phase was dried with MgSO4 and filtered through silica gel, washed with EtOAc (40 mL). The solvents and the unreacted 2-chlorobenzonitrile were distilled off in a Kugel-Röhr at 150 ºC (0.1 mm Hg) to obtain 8 as a brown solid (98% pure by GLC) (218 mg, 55%). Crystallization in hexane produced a white solid; mp 47–48 ºC (hexane) (Lit.33 mp 48–49.5 ºC); Rf 0.50 (hexane–EtOAc, 5:1). IR (KBr): 2223 cm–1. 1
H RMN: d = 2.41 (s, 3 H), 7.29 (d, J = 7.77 Hz, 2 H), 7.38–7.50 (m, 4 H), 7.62 (dt, J = 7.65, 1.26 Hz, 1 H), 7.74 (dd, J = 7.65, 0.87 Hz, 1 H). 13
C RMN: d = 21.2, 111.1, 118.8, 127.2, 128.5, 129.4, 129.9, 132.7, 133.6, 135.2, 138.6, 145.6. MS: m/z (%) = 193 (100), 165 (35), 82 (17). 2,2¢-Bithiophene (10)32,34 A reaction tube of the carousel reaction equipment, was charged with 2-iodotiophene (9, 0.56 mL, 5 mmol), decane (0.97 mL, 5 mmol), diisopropylethylamine (2.06 mL, 12 mmol), 1 (10.2 mg, 0.0125 mmol, 0.5 mol% Pd) and DMF (8 mL). The mixture was stirred at 110 ºC in air and the reaction progress was analyzed by GLC. The crude reaction mixture was extracted with water and EtOAc (3 × 25 mL) and washed with H2O (3 × 15 mL). The organic phases were dried with MgSO4, evaporated (15 mm Hg) and the resulting crude material was purified by florisil chromatography (hexane) affording pure 10 as a white solid (0.36 g, 86%); mp 28–30 ºC (hexane) (Lit.34 mp 33 ºC); Rf 0.47 (hexane). IR (film): 3105, 3070 cm–1. H NMR: d = 6.92, 6.90 (2 × d, J = 3.6 Hz, 2 H), 7.08–7.11 (m, 4 H).
1
13
C NMR: d = 123.6, 124.2, 127.6, 137.2.
MS: m/z (%) = 167 (11), 166 (100), 134 (16), 121 (35), 69 (11). N-Acetyl-2-phenylethynylaniline (13)35 A reaction tube of the carousel reaction equipment, was charged with 2-iodoacetylaniline29 (11, 1.044 g, 4 mmol), decane (0.78 mL, 4 mmol), phenylacetylene (12, 0.54 mL, 4.8 mmol), 1 (1.627 mg, 0.002 mmol, 0.1 mol% Pd) and NMP (8 mL). The mixture was stirred at 110 ºC in air and the reaction progress was analyzed by GLC. After the reaction was completed, water (10 mL) was added to the reaction mixture and crude 13 precipitated as a brown solid, which was filtered and recrystallized in MeOH affording pure 13 as a pale grey solid (0.56 g, 60%); mp 118–120 ºC (MeOH) (Lit.35 mp 119–120 ºC); Rf 0.30 (hexane–EtOAc, 3:1). IR (KBr): 3305, 1661, 1532 cm–1. 1
H NMR: d = 2.24 (s, 3 H), 7.07 (t, J = 7.55 Hz, 1 H), 7.32–7.40 (m, 4 H), 7.48–7.55 (m, 3 H), 7.97 (s, 1 H), 8.41 (d, J = 8.22 Hz, 1 H).
13
C NMR: d = 24.9, 84.3, 96.4, 111.8, 119.3, 122.3, 123.4, 128.6, 128.9, 129.7, 131.5, 131.6, 138.9, 168.1. MS: m/z (%) = 235 (40), 194 (16), 193 (100), 192 (16), 165 (34), 90 (13), 89 (11).
13
C NMR: d = 11.0, 14.0, 23.0, 23.8, 28.9, 30.5, 38.8, 55.3, 66.8, 114.3, 115.8, 127.2, 129.7, 144.1, 161.3, 167.5.
Synthesis 2004, No. 10, 1713–1718
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D. A. Alonso et al.
Di(3-pyridyl)acetylene (16)36 A reaction tube of the carousel reaction equipment, was charged with 3-iodopyridine (14, 0.42 g, 2 mmol), decane (0.39 mL, 2 mmol), bis(trimethylsilyl)acetylene (15, 0.27 mL, 1.2 mmol), pyrrolidine (0.51 mL, 6 mmol), CuI (19.4 mg, 0.1 mmol), 1 (4.069 mg, 0.005 mmol, 0.5 mol% Pd) and NMP (4 mL). The mixture was stirred at 110 ºC in air and the reaction progress was analyzed by GLC. To the crude reaction mixture water was added and was extracted with EtOAc (3 × 25 mL) and washed with H2O (3 × 15 mL). The organic phase was dried with MgSO4 and evaporated (15 mm Hg) to afford the crude product 16 (>95% pure by 1H NMR) (0.15 g, 85%); mp 57–59 ºC (EtOAc); Rf 0.50 (EtOAc). IR (film): 3049, 3038 cm–1. 1 H NMR: d = 7.30 (dd, J = 7.95, 4.83 Hz, 2 H), 7.83 (dt, J = 7.95, 1.71 Hz, 2 H), 8.58 (dd, J = 4.83, 1.23 Hz, 2 H), 8.79 (br s, 2 H). 13
C NMR: d = 89.0, 119.5, 122.9, 138.3, 148.8, 152.0.
MS: m/z (%) = 181 (14), 180 (100), 179 (26), 152 (11), 127 (18), 100 (10), 98 (10), 74 (20).
Acknowledgment This work has been supported by the Dirección General de Investigación of the Ministerio de Ciencia y Tecnología (MCyT) (BQU2001-0724-CO2-01). M. C. P. and L. B. thank Generalitat Valenciana for pre-doctoral fellowships.
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