有機金属化学：最新論文からのトピックス④

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有機金属化学：最新論文からのトピックス④

Prof. Yoshiaki Nakao Kyoto U, Grad. Sch. of Eng.

Ph.D. in 2005 w. Tamajiro Hiyama@Kyoto U visiting student in 2001 w. John Hartwig@Yale U

visiting scholar in 2008

w. Manfred Reets@Max-Plank Institute

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

Abstract: Synthesis of biaryls via the Suzuki−Miyaura coupling (SMC) reaction using nitroarenes as an electro- philic coupling partners is described. Mechanistic studies have revealed that the catalytic cycle of this reaction is initiated by the cleavage of the aryl−nitro (Ar−NO₂) bond by palladium, which represents an unprecedented elemental reaction.

The Suzuki–Miyaura Coupling of Nitroarenes

Yadav, M. R.; Nagaoka, M.; Kashihara, M.; Zhong, R.-L.; Miyazaki, T.; Sakaki, S.; Nakao, Y., J. Am. Chem. Soc. 2017, 139, 9423-9426.

・ C-NO

₂

結合の酸化的付加が鍵段階

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-NO

₂

酸化的付加は新しい素反応

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514 MIYAURA, YANAGI, AND ^SUZUKI

of suitable bases as indicated in Scheme 1.

mechanistic pathway is not clear at present, the reaction should involve a transmetallation step from alkenylboranes to alkenyl- pal 1 adi ums

.

Although the detailed

L

Y2 = (Siamyl)2 or

a::

Scheme ¹

In this paper, we wish to report that the palladium-catalyzed cross-coup1 ing reaction ^{o f}phenylboronic acid with haloarenes proceeds smoothly in the presence of bases to give corresponding biaryls in good yields (Scheme 2). At first, we examined the

Scheme 2

effect of reagents, bases, and reaction conditions on the yield of biphenyl in the reaction ^{o f}phenylboronic acid with halo- benzenes using benzene as a solvent and ³mole ^%of Pd(PPh3)4 as

a catalyst. Although we have

not undertaken a detailed study ^{o f}catalysts, Pd(PPh3)4 was found The results are listed in Table ^{I .}

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, N.Cross-Coupling Reactions - A Practical Guide; Springer: Berlin,2002.

最初のビアリール合成の論文

Ref 2:

^{ハロアレーンの}^SMC^の論文

Synth. Commun.1981, 11, 513.

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

Curr. Opin. Drug Discovery Dev.2008,11, 853.

Ref 4

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.2004, 6, 95.

Ref 5

ハロアレーンの代わりにトリフラートを使った論文 Tetrahedron1989, 45, 6679.

Ref 6

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.2003, 125, 11818.

Ref 7

アリールジアゾニウム塩

Tetrahedron Lett.1996, 37, 3857.

Ref 8

チオエーテル

Org. Lett.2002, 4, 979.

Ref 9

アリールトリメチルアンモニウム塩

J. Am. Chem. Soc.2003, 125, 6046.

Ref 10

フッ化アリール

J. Am. Chem. Soc.2006, 128, 15964.

Ref 11

メトキシアレーン

Angew. Chem., Int. Ed.2008, 47, 4866.

Ref 12

アレーンカルボキシラート

J. Am. Chem. Soc.2008, 130, 14468.

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Introduction 2: ニトロ基の利用

Ref 15:

有機合成におけるニトロアレーンの利用の総説 The Nitro Group in Organic Synthesis;

Wiley-VCH: New York,2001.

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.: New York,2001.

Ref 17:

工業化学におけるニトロ化 Nitro Compounds, Aromatic; Ullmann’s Encyclopedia of Industrial Chemistry;

Wiley-VCH: New York,2012.

Green Chem.2012, 14,912.

Ref 17a:ニトロ化合物の工業生産の総説

Ref 17b&18:

銅触媒によるArNO₂のUllman型エーテル合成 (ref 18と同じなので引用場所間違い？)

Ref 19

Org. Lett.2011, 13, 1726.

Rh触媒によるArNO₂のUllman型エーテル合成

Ref 20

Catal. Commun.2013, 41, 123.

Cu触媒によるArNO₂のUllman型チオエーテル合成

Ref 13

フェノキシド

Angew. Chem., Int. Ed.2011, 50, 7097.

needed for the synthesis of halogen analogues of these coupling partners. The present decarbonylative cross-coupling is also applicable to the synthesis of flavone and its derivatives (3ABh

and3ABa), which are of significant scientific and public interest.

Halide-containing substrates, except for organofluorines, are pro- blematic as aryl–halogen bonds are also activated and arylated by Table 2 | Scope of decarbonylative cross-coupling catalysed by Ni(OAc)2/P(n-Bu)3.

DMAP,N,N0-dimethylaminopyridine.

Reaction conditions:1(0.40 mmol, 1.0 equiv.),2(0.60 mmol, 1.5 equiv.), Ni(OAc)2(0.02 mmol, 5 mol%), P(n-Bu)3(0.08 mmol, 20 mol%), Na2CO3(0.80 mmol, 2.0 equiv.), toluene (1.6 ml, 0.25 M of1), 150!C, 24 h. Isolated yields of3are shown.

*The reaction was carried out at 160!C.

wThe reaction was conducted using 1.2 equiv. of Na2CO3. zThe reaction was conducted using Et3N (1.5 equiv.) instead of Na2CO3.

yThe reaction was conducted on a gram scale:1A(10 mmol), boroxine form of2a(5 mmol), Ni(OAc)2(0.5 mmol, 5 mol%), P(n-Bu)3(2.0 mmol, 20 mol%), Na2CO3(20 mmol, 2.0 equiv.), anisole (40 ml, 0.25 M of1A), reflux, 24 h.

||The reaction was performed using NaCl (1.0 equiv.) as an additive.

zThe reaction was performed using DMAP (0.12 mmol, 30 mol%) as an additive.

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8508 ARTICLE

NATURE COMMUNICATIONS| 6:7508 | DOI: 10.1038/ncomms8508 | www.nature.com/naturecommunications 5

Ref 14

エステル Nat. Commun.2015, 6, 7508.

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This Work 1: Catalyst Optimization

触媒反応条件の最適化

best condition

S3 2. Optimization studies

General procedure for optimization studies. A 15-mL Iwaki screw caped vial was charged with 4- nitroanisole 1a (46 mg, 0.30 mmol), phenylboronic acid 2a (55 mg, 0.45 mmol), catalyst (5.0 mol%), ligand (20 mol%), and base (0.90 mmol). Subsequently, 1,4-dioxane (1.5 mL) was introduced into the vial in a glove box under N2 atmosphere and the vial was taken outside. The reaction mixture was stirred at 130 C. After 24 h, it was allowed to cool to room temperature. The reaction mixture was passed through a shortpad of celite with CH2Cl2 and the solution was concentrated in vacuo. The yield of the product was determined by NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.

Table S1. Optimization of the SMC of 4-nitroanisole.

Entry Variation from the standard conditions Yield of 3 (%)^a

1 none 86 (76)^b

2 w/o 18-crown-6 69

3 SPhos instead of BrettPhos 8

4 RuPhos instead of BrettPhos 15

5 CPhos instead of BrettPhos 9

6 XPhos instead of BrettPhos 56

7 PCy3 instead of BrettPhos <5

8 P^tBu3 instead of BrettPhos <5

9 IPr instead of BrettPhos <5

10 Pd(OAc)2 instead of Pd(acac)2 63

11 Pd(PPh3)4 instead of Pd(acac)2 <5

12 Pd2(dba)3 instead of Pd(acac)2 65

13 PEPPSI™-IPr instead of Pd(acac)2 50

14^c BrettPhos Pd G3 instead of Pd(acac)2 56

15^d K3PO4 instead of K3PO4·nH2O 39

16 K3PO4 + H2O instead of K3PO4·nH2O 67

17 K3PO4 + 2H2O instead of K3PO4·nH2O 69

18^d K2CO3 instead of K3PO4·nH2O <5

19^d Cs2CO3 instead of K3PO4·nH2O 49

20^d CsF instead of K3PO4·nH2O 78

21 Pd(OAc)2 and CsF instead of Pd(acac)2 and K3PO4·nH2O 36 22^c BrettPhos Pd G3 and CsF instead of Pd(acac)2 and K3PO4·nH2O 63

23 toluene instead of 1,4-dioxane 32

24 THF instead of 1,4-dioxane 51

25 addition of carbazole (5.0 mol%) 58

26 addition of LiCl (20 mol%) 67

aDetermined by NMR analysis using 1,3,5-trimethoxybenzene as an internal standard; ^bisolated yield obtained from using 1a (0.60 mmol), 2a (0.90 mmol) and K3PO4·nH2O (1.8 mmol); ^cusing BrettPhos (15 mol%); ^din the absence of 18-crown-6.

クラウンエーテル無し＝収率低下

配位子の選択が重要他の配位子だとほとんど低収率

XPhosだけ少しいい ^OMe

PCy₂ MeO

SPhos

OⁱPr PCy₂

iPrO

RuPhos

NMe₂ PCy₂ Me₂N

CPhos

iPr

PCy₂

iPr

XPhos

iPr

N CN

IPr

Ref 21

BrettPhosの報告

J. Am. Chem. Soc.2008, 130, 13552.

Pd前駆体も影響大

N N

iPr

iPr ⁱPr

iPr

Pd Cl Cl

N Cl PEPPSI™-IPr

H₂N Pd L MeSO₂O

L = BrettPhos BrettPhos Pd G3 他のSMCに高活性

でも少し収率低い無水K₃PO₄は活性低下

無水K₃PO₄に水添加で活性回復塩基はK₃PO₄がベスト Cs塩もまあまあ

Ref 22

クラウンエーテル添加でSMC加速 Tetrahedron2005, 61, 7438.

Ref 23

Buchwaldビアリール配位子の総合論文 Acc. Chem. Res.2008, 41, 1461.

Ref 24

SMCに高活性を示すPEPPSI-IPrの論文 Angew. Chem., Int. Ed.2012, 51,3314.

Ref 25

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,2014.

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This Work 2: Substrate Scope

基質適用範囲の探索

pyridine, which is the initial product for the industrial derivatization of pyridine. The scope of arylboronic acids was also examined, and the results revealed that a range of substituted phenylboronic acids can participate in the SMC with diﬀerent nitroarenes, irrespective of the electronic and/or steric environ- ment of the reaction site, to give the corresponding biaryls. Biaryl 35can be a useful precursor to prepare an intermediate of AMG 837, which is a pharmaceutically important GPR40 receptor agonist.²⁶ Naphthyl- and thienylboronic acids were also susceptible to this biaryl synthesis.

To gain insight into the underlying reaction mechanism, the reactions of1aand2awere examined in the presence of radical scavengers such as TEMPO or Galvinoxyl, which aﬀorded 3in modest yields, suggesting that radical pathways are unlikely. We also found that nitrosobenzene and aniline, which can be formed in situ from the reduction of nitrobenzene, did not furnish any biaryls. An aqueous solution obtained from the workup of a reaction under the optimized cross-coupling reactions was analyzed by ion chromatography to reveal the formation of nitrite ions in a yield estimated to be comparable with that of3.

We then examined a stoichiometric reaction of (cod)Pd- (CH₂SiMe₃)₂, a Pd(0) precursor, with nitroarenes in the presence of BrettPhos. The reaction with nitrobenzene at 60°C aﬀorded BrettPhosPd(Ph)(NO₂) (41) via the oxidative addition of the Ph−NO₂ bond (Scheme 1). (BrettPhos)Pd(η²-nitrobenzene) (vide infra), (BrettPhos)Pd(cod), and free BrettPhos were also observed in this reaction. This result represents the ﬁrst observation of an oxidative addition of an Ar−NO2bond onto a

Pd(0) center. Similar reactions have been proposed for allylic²⁷ and benzylic²⁸ C−NO2 bonds, and the formation of nitro complexes upon radical-based cleavage of an aryl− and alkyl−

NO₂bond has also been reported.²⁹The unprecedented oxidative addition product 41 was characterized by multinuclear NMR spectroscopy, IR spectroscopy, and elemental analysis. The molecular structure of41was determined by a single-crystal X-ray diﬀraction study and found to be similar to that derived from the oxidative addition of aryl halides²¹with the Pd center coordinated not only by the phosphorus atom but also by the triisopropyl- phenyl ring of BrettPhos (Figure S4). The oxidative addition could be reversible, as 41 reacted with bromoarenes to give arylpalladium bromides. The reductive elimination of nitroarenes Table 1. Substrate Scope for the SMC of Nitroarenes

aIsolated yield after hydrolysis of the corresponding acetals.^bReaction with arylboronic acid (1.2 mmol).^cReaction with CsF (1.8 mmol) in toluene (3.0 mL). ^dReaction with CsF (3.0 mmol) in toluene (3.0 mL).^eReaction with RuPhos (20 mol %) instead of BrettPhos and CsF (1.8 mmol).

fReaction with CsF (1.8 mmol). ^gReaction with22 (0.58 mmol).^hReaction without 18-crown-6. ⁱReaction with Pd(acac)₂ (10 mol %).

Scheme 1. Stoichiometric Reactions of BrettPhos−Pd(0) with Nitrobenzene and 1-Nitronaphthalene

Journal of the American Chemical Society Communication

DOI:10.1021/jacs.7b03159 J. Am. Chem. Soc.2017, 139, 9423−9426

9424

ニトロアレーンの適用範囲を調べるためPhと4-MeOC₆H₄を使用

e-rich e-rich e-rich e-rich e-poor e-poor

acetal保護・脱保護必要

e-poor

NO₂は一つ残せる ortho

e-rich ortho ortho

NO₂は一つ残せる

peri peri

peri×2

peri peri

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×2

ortho×2 + peri

ortho

ヘテロ環ヘテロ環

Ref 26

GPR40受容体作動薬の合成 Org. Process Res. Dev.2011, 15, 570.

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This Work 3: Mechanistic Study

中間体の単離： C-NO

₂

酸化的付加錯体

pyridine, which is the initial product for the industrial derivatization of pyridine. The scope of arylboronic acids was also examined, and the results revealed that a range of substituted phenylboronic acids can participate in the SMC with diﬀerent nitroarenes, irrespective of the electronic and/or steric environ- ment of the reaction site, to give the corresponding biaryls. Biaryl 35can be a useful precursor to prepare an intermediate of AMG 837, which is a pharmaceutically important GPR40 receptor agonist.²⁶ Naphthyl- and thienylboronic acids were also susceptible to this biaryl synthesis.

To gain insight into the underlying reaction mechanism, the reactions of1aand2awere examined in the presence of radical scavengers such as TEMPO or Galvinoxyl, which aﬀorded3in modest yields, suggesting that radical pathways are unlikely. We also found that nitrosobenzene and aniline, which can be formed in situ from the reduction of nitrobenzene, did not furnish any biaryls. An aqueous solution obtained from the workup of a reaction under the optimized cross-coupling reactions was analyzed by ion chromatography to reveal the formation of nitrite ions in a yield estimated to be comparable with that of3.

We then examined a stoichiometric reaction of (cod)Pd- (CH₂SiMe₃)₂, a Pd(0) precursor, with nitroarenes in the presence of BrettPhos. The reaction with nitrobenzene at 60°C aﬀorded BrettPhosPd(Ph)(NO2) (41) via the oxidative addition of the Ph−NO2 bond (Scheme 1). (BrettPhos)Pd(η²-nitrobenzene) (vide infra), (BrettPhos)Pd(cod), and free BrettPhos were also observed in this reaction. This result represents the ﬁrst observation of an oxidative addition of an Ar−NO2bond onto a

Pd(0) center. Similar reactions have been proposed for allylic²⁷ and benzylic²⁸ C−NO2 bonds, and the formation of nitro complexes upon radical-based cleavage of an aryl− and alkyl−

NO₂bond has also been reported.²⁹The unprecedented oxidative addition product 41 was characterized by multinuclear NMR spectroscopy, IR spectroscopy, and elemental analysis. The molecular structure of41was determined by a single-crystal X-ray diﬀraction study and found to be similar to that derived from the oxidative addition of aryl halides²¹with the Pd center coordinated not only by the phosphorus atom but also by the triisopropyl- phenyl ring of BrettPhos (Figure S4). The oxidative addition could be reversible, as 41 reacted with bromoarenes to give arylpalladium bromides. The reductive elimination of nitroarenes Table 1. Substrate Scope for the SMC of Nitroarenes

aIsolated yield after hydrolysis of the corresponding acetals.^bReaction with arylboronic acid (1.2 mmol).^cReaction with CsF (1.8 mmol) in toluene (3.0 mL).^dReaction with CsF (3.0 mmol) in toluene (3.0 mL).^eReaction with RuPhos (20 mol %) instead of BrettPhos and CsF (1.8 mmol).

fReaction with CsF (1.8 mmol).^gReaction with22(0.58 mmol).^hReaction without 18-crown-6. ⁱReaction with Pd(acac)2(10 mol %).

Scheme 1. Stoichiometric Reactions of BrettPhos−Pd(0) with Nitrobenzene and 1-Nitronaphthalene

DOI:10.1021/jacs.7b03159 J. Am. Chem. Soc.2017, 139, 9423−9426 9424

has been proposed.³⁰During the formation of41, the³¹P NMR spectrum revealed a signal at δ 39.6 ppm, which should be attributed to a reaction intermediate of the oxidative addition. In the¹H NMR spectrum of the intermediate,³¹the signals derived from themeta- andpara-positions of the nitrobenzene moiety were observed at δ 5.61 and 4.90, respectively. These signals observed signiﬁcantly upﬁeld in comparison with those observed with free nitrobenzene (δ7.60 formetaand 7.74 forpara) should be ascribed to theπ-coordination of nitrobenzene to the electron- rich Pd(0) center with strong back-donation of an electron from Pd to the benzene ring. It is noteworthy that the arene−Pd(0) species was also observed under catalytic conditions. Although the observed intermediate could not be isolated because of its instability,³²it was tentatively assigned to be anη²-arene complex, whose arene ligand coordinates to Pd through the π-bonds.

Conversely, the reaction of (cod)Pd(CH₂SiMe₃)₂, BrettPhos, and 1-nitronaphthalene instead of nitrobenzene furnished isolableη²-arene complex42(Scheme 1). A single-crystal X-ray diﬀraction study on42showed that theπ-bond between the C3 and C4 positions of the naphthalene ring coordinated to the Pd center (Figure S4). In the ³¹P NMR spectrum of 42, a signal emerged atδ40.9 ppm, which is identical to that observed during the catalytic coupling reaction of 1-nitronaphthalene with 2a.

These results strongly indicate that the η²-arene complex is a resting state in the catalytic cycle. Finally,41reacted with2bat 25

°C in the presence of K₃PO₄·nH₂O or CsF to aﬀord3, possibly via transmetalation and a subsequent reductive elimination (eq 1).

The formation of the biaryl was observed even in the absence of a base, albeit the reaction rate was slower and thus heating at 60°C was necessary. This result supports that41is an intermediate of the present SMC of nitroarenes to form biaryls.

The catalytic cycle of the present reaction should thus be initiated by the formation of a nitroarene−Pd complex, from

which the oxidative addition of the Ar−NO₂bond should occur (Scheme 2). Transmetalation between the resulting Pd(II)

intermediate and the arylboronic acid, followed by reductive elimination, should then generate the biaryl. The rate- determining step could be the oxidative addition of the Ar−

NO₂bond of theη²-arene complex. Competition between1awith 4-trifluoromethylnitrobenzene giving a biaryl from the latter in a higher yield could also support this assumption (seeSupporting Information(SI)). DFT calculations also supported the catalytic cycle ofScheme 2, as shown inFigure 1, where CsF was employed as a Lewis base instead of K₃PO₄because CsF was also effective for this cross-coupling reaction. First, 1a should form a stable π- complex with Pd(BrettPhos), and then cleavage of the Ar−NO₂ bond should occur via oxidative addition to Pd(BrettPhos) with the Gibbs activation energy (ΔG°^‡) of 29.6 kcal·mol⁻¹to afford Pd(II)(C₆H₄OMe-p)(NO₂)(BrettPhos) 46. Because NMR measurements indicated that boronic acid interacts with CsF to form boronate species Cs[Ph−B(OH)₂F] 47, the formation of which was estimated to be highly exerganoic, and that46did not react with CsF, it is likely that the next step is transmetalation between this Pd(II) complex and a boronate anion.47reacts with 46 to afford an intermediate Pd(II)(C₆H₄OMe-p){FB- (OH)₂Ph}Cs(NO₂) 48 in which the nitro group dissociates Figure 1.DFT-calculated geometries and Gibbs energy changes of the proposed catalytic cycle.

Scheme 2. Plausible Catalytic Cycle

反応機構の解明： DFT 計算

has been proposed.³⁰During the formation of41, the³¹P NMR spectrum revealed a signal at δ 39.6 ppm, which should be attributed to a reaction intermediate of the oxidative addition. In the¹H NMR spectrum of the intermediate,³¹the signals derived from the meta- and para-positions of the nitrobenzene moiety were observed at δ 5.61 and 4.90, respectively. These signals observed signiﬁcantly upﬁeld in comparison with those observed with free nitrobenzene (δ7.60 formetaand 7.74 forpara) should be ascribed to theπ-coordination of nitrobenzene to the electron- rich Pd(0) center with strong back-donation of an electron from Pd to the benzene ring. It is noteworthy that the arene−Pd(0) species was also observed under catalytic conditions. Although the observed intermediate could not be isolated because of its instability,³²it was tentatively assigned to be anη²-arene complex, whose arene ligand coordinates to Pd through the π-bonds.

Conversely, the reaction of (cod)Pd(CH2SiMe3)2, BrettPhos, and 1-nitronaphthalene instead of nitrobenzene furnished isolableη²-arene complex42(Scheme 1). A single-crystal X-ray diﬀraction study on42showed that theπ-bond between the C3 and C4 positions of the naphthalene ring coordinated to the Pd center (Figure S4). In the ³¹P NMR spectrum of 42, a signal emerged atδ40.9 ppm, which is identical to that observed during the catalytic coupling reaction of 1-nitronaphthalene with 2a.

These results strongly indicate that the η²-arene complex is a resting state in the catalytic cycle. Finally,41reacted with2bat 25

°C in the presence of K3PO4·nH2O or CsF to aﬀord3, possibly via transmetalation and a subsequent reductive elimination (eq 1).

NO2bond of theη²-arene complex. Competition between1awith 4-triﬂuoromethylnitrobenzene giving a biaryl from the latter in a higher yield could also support this assumption (seeSupporting Information(SI)). DFT calculations also supported the catalytic cycle ofScheme 2, as shown inFigure 1, where CsF was employed as a Lewis base instead of K₃PO₄because CsF was also eﬀective for this cross-coupling reaction. First, 1a should form a stable π- complex with Pd(BrettPhos), and then cleavage of the Ar−NO2

bond should occur via oxidative addition to Pd(BrettPhos) with the Gibbs activation energy (ΔG°^‡) of 29.6 kcal·mol⁻¹to aﬀord Pd(II)(C6H4OMe-p)(NO2)(BrettPhos) 46. Because NMR measurements indicated that boronic acid interacts with CsF to form boronate species Cs[Ph−B(OH)₂F] 47, the formation of which was estimated to be highly exerganoic, and that46did not react with CsF, it is likely that the next step is transmetalation between this Pd(II) complex and a boronate anion.47reacts with 46 to aﬀord an intermediate Pd(II)(C6H4OMe-p){FB- (OH)2Ph}Cs(NO2) 48 in which the nitro group dissociates Figure 1.DFT-calculated geometries and Gibbs energy changes of the proposed catalytic cycle.

DOI:10.1021/jacs.7b03159 J. Am. Chem. Soc.2017, 139, 9423−9426

9425

酸化的付加錯体からのビアリール生成

has been proposed.³⁰During the formation of41, the³¹P NMR spectrum revealed a signal at δ 39.6 ppm, which should be attributed to a reaction intermediate of the oxidative addition. In the¹H NMR spectrum of the intermediate,³¹the signals derived from themeta- andpara-positions of the nitrobenzene moiety were observed at δ 5.61 and 4.90, respectively. These signals observed signiﬁcantly upﬁeld in comparison with those observed with free nitrobenzene (δ7.60 formetaand 7.74 forpara) should be ascribed to theπ-coordination of nitrobenzene to the electron- rich Pd(0) center with strong back-donation of an electron from Pd to the benzene ring. It is noteworthy that the arene−Pd(0) species was also observed under catalytic conditions. Although the observed intermediate could not be isolated because of its instability,³²it was tentatively assigned to be anη²-arene complex, whose arene ligand coordinates to Pd through the π-bonds.

Conversely, the reaction of (cod)Pd(CH₂SiMe₃)₂, BrettPhos, and 1-nitronaphthalene instead of nitrobenzene furnished isolableη²-arene complex42(Scheme 1). A single-crystal X-ray diﬀraction study on42showed that theπ-bond between the C3 and C4 positions of the naphthalene ring coordinated to the Pd center (Figure S4). In the³¹P NMR spectrum of 42, a signal emerged atδ40.9 ppm, which is identical to that observed during the catalytic coupling reaction of 1-nitronaphthalene with 2a.

These results strongly indicate that theη²-arene complex is a resting state in the catalytic cycle. Finally,41reacted with2bat 25

°C in the presence of K₃PO₄·nH₂O or CsF to aﬀord3, possibly via transmetalation and a subsequent reductive elimination (eq 1).

NO₂bond of theη²-arene complex. Competition between1awith 4-trifluoromethylnitrobenzene giving a biaryl from the latter in a higher yield could also support this assumption (seeSupporting Information(SI)). DFT calculations also supported the catalytic cycle ofScheme 2, as shown inFigure 1, where CsF was employed as a Lewis base instead of K₃PO₄because CsF was also effective for this cross-coupling reaction. First, 1a should form a stable π- complex with Pd(BrettPhos), and then cleavage of the Ar−NO₂ bond should occur via oxidative addition to Pd(BrettPhos) with the Gibbs activation energy (ΔG°^‡) of 29.6 kcal·mol⁻¹to afford Pd(II)(C₆H₄OMe-p)(NO₂)(BrettPhos) 46. Because NMR measurements indicated that boronic acid interacts with CsF to form boronate species Cs[Ph−B(OH)₂F] 47, the formation of which was estimated to be highly exerganoic, and that46did not react with CsF, it is likely that the next step is transmetalation between this Pd(II) complex and a boronate anion.47reacts with 46 to afford an intermediate Pd(II)(C₆H₄OMe-p){FB- (OH)₂Ph}Cs(NO₂) 48 in which the nitro group dissociates Figure 1.DFT-calculated geometries and Gibbs energy changes of the proposed catalytic cycle.

触媒サイクルまとめ本文の記載

TEMPOやGalvinoxyl添加条件でも反応は中程度の収率で進行

→ラジカル機構ではないだろう

N O TEMPO

2,2,6,6-tetramethylpiperidine 1-oxyl

O

tBu

O

galvinoxyl

(ニトロベンゼンが還元されたら生成するはずの) アニリンは反応に関与しない

系内にNO₃^–は生成しない

＝NO₂^–が酸化剤にはなっていない

Ref 27,28

ベンジル・アリル位でのC-NO₂結合切断の報告 J. Am. Chem. Soc.1982, 104, 3727.

J. Chem. Soc., Chem. Commun.1986, 1040.

X線結晶解析あり

η⁶-PhNO₂ 錯体も観測 (NMR)

41はPhBrと反応して PhBr酸化的付加錯体に

→酸化的付加は可逆

Ref 30

C-NO₂還元的脱離の提案 Tetrahedron Lett.2005, 46, 4715.

J. Am. Chem. Soc.2009, 131, 12898.

X線結晶解析あり

41は中間体だと言える 0価Pdの

良い前駆体

実験ではPhNO₂より4-CF₃C₆H₄NO₂の方が収率高い

→酸化的付加が律速段階であることと矛盾せず

塩基にCsF NMRで生成確認 28.0

(29.6) 26.6

(25.2)

LPd(Ar)(F)からのトランスメタル化も吸熱反応だが可能性はある

resting state (律速の一つ手前)

25.6 11.5

S_NAr反応に続くニトロ基のSMCでいろいろな構造を合成できる

多段階反応への応用 (SI)

S19 6. Sequential Functionalization of Nitroarenes Scheme S1. Sequential Functionalizations of Nitroarenes

9-([1,1'-Biphenyl]-4-yl)-9H-carbazole (55). The reaction of 9-(4- nitrophenyl)-9H-carbazole 54 (173 mg, 0.60 mmol) and phenylboronic acid2a (110 mg, 0.90 mmol) with optimized condition stirred for 16 h.

The crude reaction mixture subjected to oxidation condition (CH2Cl2

solvent) followed by purification by MPLC-Purif-espoir 2 (25 g Biotage® SNAP Ultra column (25 m size), n-hexane/ethyl acetate = 100:0 to 92:8) gave the title compound (112 mg, 0.35 mmol, 59%) as a white solid. ¹H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 7.3 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.56–7.38 (m, 7H), 7.31 (t, J = 7.8 Hz, 2H); ¹³C NMR (101 MHz, CDCl3): δ 140.8, 140.3, 136.8, 128.9, 128.5, 127.6, 127.3, 127.1, 126.0, 123.4, 120.3, 120.0, 109.8 (one ¹³C value merged with other peaks). Spectral data obtained for the compound are in agreement with the reported data.³³

(7)

Other Experiments and Next Approach

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(8)

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