有機金属化学 : 最新論文からのトピックス 4

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1 有機金属化学 : 最新論文からのトピックス 4 The Suzuki Miyaura Coupling itroarenes Yadav, M. R.; agaoka, M.; Kashihara, M.; Zhong, R.-L.; Miyazaki, T.; Sakaki, S.; akao, Y., J. Am. Chem. Soc. 017, 139, Abstract: Synsis biaryls via Suzuki Miyaura coupling (SMC) reaction using nitroarenes as an electro- philic coupling partners is described. Mechanistic studies have revealed that catalytic cycle this reaction is initiated by cleavage aryl nitro (Ar O ) bond by palladium, which represents an unprecedented elemental reaction. タイトルと TOC グラフィックから読み取れること ニトロベンゼンとボロン酸で鈴木 宮浦カップリング ビアリールホスフィンと塩基の組み合わせで 40 例以上 C-O 結合の酸化的付加が鍵段階 Pr. Yoshiaki akao Kyoto U, Grad. Sch. Eng. Ph.D. in 005 w. Tamajiro Hiyama@Kyoto U visiting student in 001 w. John Hartwig@Yale U visiting scholar in 008 w. Manfred Reets@Max-Plank Institute Abstract から追加で読み取れること 反応機構解析で見いだされた C-O 酸化的付加は新しい素反応

2 Introduction: クロスカップリングにおけるハロアレーン代替 Ref 1: 鈴木 宮浦カップリング (SMC) の総説 Miyaura,. Cross-Coupling Reactions - A Practical Guide; Springer: Berlin, 00. Ref : ハロアレーンのSMCの論文 Ref 3: クロスカップリングにおけるハロアレーンを代替できる反応の総説 最初のビアリール合成の論文 Synth. Commun. 1981, 11, 513. Curr. Opin. Drug Discovery Dev. 008,11, 853. Ref 7 アリールジアゾニウム塩 Ref 8 チオエーテル Ref 9 Tetrahedron Lett. 1996, 37, Org. Lett. 00, 4, 979. Ref 4 アリールトリメチルアンモニウム塩 J. Am. Chem. Soc. 003, 15, Ref 10 フッ化アリール ハロアレーンの代わりに塩化スルホニルを使った論文 Org. Lett. 004, 6, 95. Ref 5 Ref 11 J. Am. Chem. Soc. 006, 18, ハロアレーンの代わりにトリフラートを使った論文 Tetrahedron 1989, 45, Ref 6 メトキシアレーン Angew. Chem., Int. Ed. 008, 47, Ref 1 アレーンカルボキシラート J. Am. Chem. Soc. 008, 130, ハロアレーンの代わりにアリールスルホナートを使った論文 J. Am. Chem. Soc. 003, 15,

3 Introduction : ニトロ基の利用 Ref 13 フェノキシド RE COMMUICATIOS DOI: /ncomms8508 Angew. Chem., Int. Ed. 011, 50, Ref 14 エステル at. Commun. 015, 6, ARTICLE Ref 15: 有機合成におけるニトロアレーンの利用の総説 The itro Group in Organic Synsis; Wiley-VCH: ew York, 001. Ref 16: 有機化学の教科書 : ニトロ化の説明 March s Advanced Organic Chemistry, 5th ed.; John Wiley & Sons, Inc.: ew York,001. Ref 17: 工業化学におけるニトロ化 Ref 17a: ニトロ化合物の工業生産の総説 itro Compounds, Aromatic; Ullmann s Encyclopedia Industrial Chemistry; Wiley-VCH: ew York, 01. Ref 17b&18: 銅触媒によるArO のUllman 型エーテル合成 (ref 18と同じなので引用場所間違い?) Green Chem. 01, 14,91. Ref 19 Rh 触媒によるArO のUllman 型エーテル合成 Org. Lett. 011, 13, 176. Ref 0 Cu 触媒による ArO の Ullman 型チオエーテル合成 Catal. Commun. 013, 41, 13.

4 触媒反応条件の最適化 Table S1. Optimization SMC 4-nitroanisole. This Work 1: Catalyst Optimization Entry Variation from standard conditions Yield 3 (%) a 1 none best condition 86 (76) b w/o 18-crown-6 クラウンエーテル無し= 収率低下 69 3 SPhos instead BrettPhos 8 4 RuPhos instead BrettPhos 15 5 CPhos instead BrettPhos 配位子の選択が重要 9 6 XPhos instead BrettPhos 他の配位子だと 56 7 PCy3 instead BrettPhos ほとんど低収率 <5 8 P t Bu3 instead BrettPhos XPhosだけ少しいい <5 9 IPr instead BrettPhos <5 10 Pd(OAc) instead Pd(acac) Pd(PPh3)4 instead Pd(acac) Pd 前駆体も影響大 <5 1 Pd(dba)3 instead Pd(acac) PEPPSI -IPr instead Pd(acac) 他のSMCに高活性 c BrettPhos Pd G3 instead Pd(acac) でも少し収率低い d K3PO4 instead K3PO4 nho 無水 K 3 PO 4 は活性低下 K3PO4 + HO instead K3PO4 nho 無水 K 3 PO 4 に K3PO4 + HO instead K3PO4 nho 水添加で活性回復 d KCO3 instead K3PO4 nho <5 19 d 塩基はK CsCO3 instead K3PO4 nho 3 PO 4 がベスト 49 0 d Cs 塩もまあまあ CsF instead K3PO4 nho 78 1 Pd(OAc) and CsF instead Pd(acac) and K3PO4 nho 36 c BrettPhos Pd G3 and CsF instead Pd(acac) and K3PO4 nho 63 3 toluene instead 1,4-dioxane 3 4 THF instead 1,4-dioxane 51 5 addition carbazole (5.0 mol%) 58 6 addition LiCl (0 mol%) 67 a Determined by MR analysis using 1,3,5-trimethoxybenzene as an internal standard; b isolated yield obtained from using 1a (0.60 mmol), a (0.90 mmol) and K3PO4 nho (1.8 mmol); c using BrettPhos (15 mol%); d in absence 18-crown-6. Ref 1 BrettPhosの報告 J. Am. Chem. Soc. 008, 130, Ref クラウンエーテル添加でSMC 加速 Tetrahedron 005, 61, Ref 3 Buchwaldビアリール配位子の総合論文 Acc. Chem. Res. 008, 41, Ref 4 SMCに高活性を示すPEPPSI-IPrの論文 Angew. Chem., Int. Ed. 01, 51,3314. Ref 5 Buchwaldの開発した環状触媒前駆体シリーズの総合論文 : 残存カルバゾールの効果についても言及 The Strem Chemiker XXVII; Strem Chemicals, Inc.: MA, 014. MeO SPhos PCy OMe XPhos O PCy Cl Pd Cl RuPhos Cl PEPPSI -IPr PCy O C IPr Me H L Pd MeSO O CPhos L = BrettPhos BrettPhos Pd G3 PCy Me

5 基質適用範囲の探索 Table 1. Substrate Scope for SMC itroarenes This Work : Substrate Scope acetal 保護 脱保護必要 e-rich e-rich e-rich e-rich e-poor e-poor ニトロアレーンの適用範囲を調べるため Ph と 4-MeOC 6 H 4 を使用 e-poor ortho e-rich O は一つ残せる ortho ortho O は一つ残せる peri peri peri peri peri O は一つ残せる ヘテロ環 ヘテロ環 ヘテロ環 ボロン酸の適用範囲 e-rich e-rich e-rich e-poor e-poor e-poor e-poor e-poor ortho ortho a Isolated yield after hydrolysis corresponding acetals. b ortho + peri Reaction with arylboronic acid (1. mmol). c ヘテロ環ヘテロ環 Reaction with CsF (1.8 mmol) in toluene (3.0 ml). d Reaction with CsF (3.0 mmol) in toluene (3.0 ml). e Reaction with RuPhos (0 mol %) instead BrettPhos and CsF (1.8 mmol). f Reaction with CsF (1.8 mmol). g Reaction with (0.58 mmol). h Reaction without 18-crown-6. i Reaction with Pd(acac) (10 mol %). Ref 6 GPR40 受容体作動薬の合成 Org. Process Res. Dev. 011, 15, 570.

6 instability,3 it was tentatively assigned to be an η-arene complex, whose arene ligand coordinates to Pd through π-bonds. Conversely, reaction (cod)pd(chsime3), BrettPhos, yield after hydrolysis corresponding acetals. breaction with arylboronic acid (1. mmol). creaction with CsF (1.8 mmol) in tolueneand 1-nitronaphthalene instead nitrobenzene furnished. dreaction with CsF (3.0 mmol) in toluene (3.0 ml). ereaction with RuPhos (0 mol %) instead BrettPhos and CsF (1.8 mmol).isolable η-arene complex 4 (Scheme 1). A single-crystal X-ray with CsF (1.8 mmol). greaction with (0.58 mmol). h Reaction without 18-crown-6. ireaction with Pd(acac) (10 mol %). diffraction study on 4 showed that π-bond between C3 本文の記載 中間体の単離 C-O酸化的付加錯体 and C4 positions naphthalene ring coordinated to Pd, which is initial product for industrial Scheme 1. Stoichiometric Reactions BrettPhos Pd(0) with TEMPOやGalvinoxyl添加条件でも center (Figure S4). In 31P MR spectrum 4, a signal 41はPhBrと反応して ation pyridine. The scope arylboronic acids was itrobenzene and 1-itronaphthalene 反応は中程度の収率で進行 emerged at δ 40.9 ppm, which is identical to that observed during PhBr酸化的付加錯体に X線結晶解析あり mined, and results revealed that a range substituted ラジカル機構ではないだろう Ref 30 酸化的付加は可逆 catalytic coupling reaction 1-nitronaphthalene with a. oronic acids can participate in SMC with different t tbu C-O 還元的脱離の提案 0価Pdの Bu These results strongly indicate that η -arene complex is a nes, irrespective electronic and/or steric environη6-pho Tetrahedron Lett. 005, 46, 良い前駆体 resting state in catalytic cycle. Finally, 41 reacted with b at 5 reaction site, to give corresponding biaryls. Biaryl O 錯体も観測 O J. Am. Chem. Soc. 009, 131, O C in presence K3PO4 nho or CsF to afford 3, possibly via e a useful precursor to TEMPO prepare an intermediate tbu AMG tbu (MR) transmetalation and a subsequent reductive elimination (eq 1). ich is a pharmaceutically important1-oxyl GPR40galvinoxyl receptor,,6,6-tetramethylpiperidine This Work 3: Mechanistic Study 酸化的付加錯体からのビアリール生成 6 aphthyl- (ニトロベンゼンが還元されたら生成するはずの) and thienylboronic acids were also ble to this biarylアニリンは反応に関与しない synsis. Figure 1. DFT-calculated geometries and Gibbs energy changes proposed catalytic cycle. in insight into系内にo underlying reaction mechanism, は生成しない 3 s 1a and a O were examined in presence radicalref 7,8 which41は中間体だと言える oxidative addition Ar O bond should occur has been proposed.30 During formation 41, 31P MR が酸化剤にはなっていない ers such as TEMPO or Galvinoxyl, which afforded 3 inベンジル アリル位でのC-O spectrum revealed a結合切断の報告 signal at δ 39.6 ppm, which should be (Scheme ). Transmetalation between resulting Pd(II) X線結晶 attributed tosoc. a reaction addition. In 触媒サイクルまとめ yields, suggesting that radical pathways are unlikely. We J. Am. Chem. 198,intermediate 104, 377. oxidative 31 解析あり 1 The formation biaryl Catalytic was observed H MR spectrum intermediate, signals derived Scheme. Plausible Cycleeven in absence a nd that nitrosobenzene and aniline, which can be formed J. Chem. Soc., Chem. Commun. 1986, base, albeit reaction rate was slower and thus heating at 60 C from metaand para-positions nitrobenzene moiety om reduction nitrobenzene, did not furnish any 7 実験ではPhO Hδ4O Pd(0)were center. Similar have been proposed These for allylic Journal American Chemical Society Communication より4-CF 3C 6reactions の方が収率高い observed at 5.61 and 4.90, respectively. signals was necessary. This result supports that 41 is an intermediate 8 An aqueous 反応機構の解明 DFT計算 solution obtained from workup 酸化的付加が律速段階であることと矛盾せず a and benzylic C O upfield bonds,inand formation nitro present SMC nitroarenes to form biaryls. observed significantly comparison with thoseobserved under optimized cross-coupling reactions was complexes upon radical-based cleavage an 7.74 aryl alkyl with free nitrobenzene (δ 7.60 for metaand forand para) shouldthe catalytic cycle present reaction should thus be LPd(Ar)(F)からのトランスメタル化も 9 by ion chromatography to reveal formation O bond has also been reported. The unprecedented oxidative be ascribed to π-coordination nitrobenzene to electron吸熱反応だが可能性はある initiated by formation a nitroarene Pd complex, from ns in a yield estimated to be comparable with that 3. rich product Pd(0) center with characterized strong back-donation an electron from addition 41 was by multinuclear MR n examined a stoichiometric reaction (cod)pdpd to IR benzene ring. It is noteworthy that arene Pd(0) spectroscopy, spectroscopy, and elemental analysis. The 945 Me3), a Pd(0) precursor, with nitroarenes in presence species was alsoobserved under catalytic conditions. Although molecular structure 41 was determined by a single-crystal X-ray observed intermediate nottobethat isolated because its Phos. The reaction with nitrobenzene at 60 C afforded diffraction study3and found to becould similar derived from 1 instability, it was tentatively assigned to be an η -arene complex, ospd(ph)(o) (41) via oxidative addition oxidative addition aryl halides with Pd center coordinated 塩基にCsF whose ligand coordinates Pd by through π-bonds. not only by arene phosphorus atom buttoalso triisopropyl bond (Scheme 1). (BrettPhos)Pd(η -nitrobenzene) Conversely, reaction (cod)pd(ch SiMe ) BrettPhos, 3 ra), (BrettPhos)Pd(cod), and free BrettPhos were also phenyl ring BrettPhos (Figure S4). The oxidative, addition 6. Sequential Functionalization itroarenes and 1-nitronaphthalene instead nitrobenzene furnished 8.0 MRで d in this reaction. This result represents first could be reversible, 6.6 as 41 reacted with bromoarenes to give 多段階反応への応用(SI) Scheme S1. Sequential Functionalizations itroarenes isolable η -arene complex 4 (Scheme 1). A single-crystal X-ray (9.6) 生成確認 intermediate and arylboronic acid, followed by reductive arylpalladium bromides. The reductive nitroarenes ion an oxidative addition an Ar O bond onto a 11.5thatelimination diffraction(5.) study on 4 showed π-bond between C3 elimination, should n generate biaryl. The ratedetermining step could be oxidative addition Ar O bond η-arene complex. Competition between 1a with 4-trifluoromethylnitrobenzene giving a biaryl from latter in a higher yield could also support this assumption (see Supporting Information (SI)). DFT calculations also supported catalytic resting state cycle Scheme, as shown in Figure 1, where CsF was employed SAr反応に続くニトロ基のSMCで as a Lewis base instead K3PO4 because CsF was also effective for (律速の一つ手前) いろいろな構造を合成できる this cross-coupling reaction. First, 1a should form a stable πcomplex with Pd(BrettPhos), and n cleavage Ar O bond should occur via oxidative addition to Pd(BrettPhos) with Figure 1. DFT-calculated geometries and Gibbs energy changes proposed catalytic cycle. Gibbs activation energy (ΔG ) 9.6 kcal mol 1 to afford Pd(II)(C6H4OMe-p)(O)(BrettPhos) 46. Because MR which oxidative addition Ar O bond should occur has been proposed.30 During formation 41, 31P MR 944 and C4 positions naphthalene ring coordinated to Pd DOI: /jacs.7b03159 J. Am. Chem. Soc. 017, center (Figure S4). In 31P MR spectrum 139, 4, a signal emerged at δ 40.9 ppm, which is identical to that observed during catalytic coupling reaction 1-nitronaphthalene with a. These results strongly indicate that η-arene complex is a resting state in catalytic cycle. Finally, 41 reacted 5.6 with b at 5 C in presence K3PO4 nho or CsF to afford 3, possibly via transmetalation and a subsequent reductive elimination (eq 1). in el d 4 h In cy as th co b th P m fo w re b 4 (O

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