Synthesis of Benzofused N-Heterocycles via Rh(III)-Catalyzed Direct

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Synthesis of Benzofused N-Heterocycles via Rh(III)Catalyzed Direct Benzannulation with 1,3-Dienes Chujun Zhou, Hui Gao, Shi-Liang Huang, Shang-Shi Zhang, Jia-Qiang Wu, Bai Li, Xianxing Jiang, and Honggen Wang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03595 • Publication Date (Web): 07 Dec 2018 Downloaded from http://pubs.acs.org on December 7, 2018

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Synthesis of Benzofused N-Heterocycles via Rh(III)-Catalyzed Direct Benzannulation with 1,3Dienes Chu-Jun Zhou,†a Hui Gao,†b Shi-Liang Huang,a Shang-Shi Zhang,a Jia-Qiang Wu,a Bai Lia Xianxing Jiang*a and Honggen Wang*a a

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

b

Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical

Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.

ABSTRACT: Benzofused nitrogen heterocycles are prevalent as key core structural motifs in functional molecules. Major syntheses of benzofused nitrogen heterocycles focus on the construction of the heterocyclic ring starting from (poly-)substituted benzene derivatives. Given that poly-substituted benzene derivatives are not always easily available, the flexibility of these methods may be problematic. The direct benzannulation reactions of simple N-heterocycles thus provide a complementary and valuable strategy. However, this approach has been far less explored, especially when non-prefunctionalized N-heterocycles are used as starting materials. In recent years, the metal-catalyzed direct functionalization of inert C-H bond has become a powerful tool to construct (hetero)aromatics. In the C-H benzannulation reactions, alkynes, activated

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alkenes, enaldiazo compounds and biaryl compounds were previously utilized as efficient coupling partners. Reported herein is a de novo synthesis of a benzene ring through the rhodium-catalyzed benzannulation of N-heterocycles with 1,3-dienes. The π-allyl metal complex derived from C-H activation/1,3-diene insertion is intercepted by the position of N-heterocycles via an intramolecular nucleophilic allylic substitution reaction. The protocol allows for the construction of a variety of diversely functionalized benzofused heterocycles including carbazoles, quinolin2(1H)-ones, phenanthridin-6(5H)-ones, acridin-9(10H)-ones and indoles from the corresponding N-heterocycles.

Keywords: benzannulation • C-H activation • 1,3-diene • nitrogen heterocycle • rhodium

INTRODUCTION Benzofused nitrogen heterocycles are ubiquitous core structural motifs in natural products and pharmaceutically relevant compounds.1 Major syntheses of benzofused nitrogen heterocycles rely on the construction of the heterocyclic ring via the reactions of (poly-)substituted benzene derivatives.1 Such synthetic strategy is useful, however, given that poly-substituted benzene derivatives are not always easily available, the flexibility of these methods may be problematic. On the other hand, the direct benzannulation reactions of simple N-heterocycles may provide a complementary and valuable strategy.2-9 In this context, substitution diversity on the benzene ring could be expanded significantly, provided the reactant for benzannulation is easily available and modifiable. However, this approach has been far less explored, especially when nonprefunctionalized N-heterocycles are used as starting materials. In recent years, the metalcatalyzed direct functionalization of inert C-H bond has become a powerful tool to construct


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(hetero)aromatics.10-28 In the benzannulation reaction,29-32 [2+2+2] annulation with two alkyne equivalents via the dual cleavage of C-H bonds is well established, allowing the efficient synthesis of densely substituted condensed arenes (Figure 1a).33-48 On the other hand, the C–H alkenylation/Diels–Alder reaction cascade with two equivalents of activated alkenes is also effective for cycloaromatization (Figure 1b).49-53 We54 and Katukojvala55,56 reported independently the synthesis of carbazoles from indoles with enaldiazo compounds as intriguing coupling partners (Figure 1c). The biaryl compounds were also applicable in the dual C-H arylation reaction, and lead to the synthesis of extended polycyclic aromatic hydrocarbons (Figure 1d).57-62 1,3-Dienes are intriguing synthons in organic synthesis.63-65 Nevertheless, the use of 1,3-diene in the metal-catalyzed C-H activation reaction is only recent.66-80 In most cases, the reaction provided the 1,2-difunctionalization product wherein the directing group was involved as an intramolecular nucleophile or electrophile.66-77 The direct hydrocarbonation reaction via an interesting allyl-to-allyl 1,4-Rh(III) migration, which leads to the allylation product is also known.78 Recently, Booker–Milburn realized an intramolecular palladium-catalyzed 1,2diheteroarylation of 1,3-diene via a cascade C-H activation reaction.79 These reactions are undoubtedly useful; however, very limited substrate scope on the 1,3-diene part was generally observed. Furthermore, the 1,4-difunctionalization of 1,3-diene via C-H activation mechanism is underdeveloped thus far. Herein, we describe our realization of a Rh(III)-catalyzed formal [4+2] cycloaddition of nitrogen heterocycles with 1,3-dienes by fully exploiting the multi-fold reactivities of nitrogen heterocycles (Figure 1e). The easy availability and structural diversity of the 1,3-dienes allow the facile synthesis of five types of benzofused nitrogen heterocycles with diverse substitution patterns from simple starting materials. Mechanistically, the π-allylmetal


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species, which is generated via C-H activation/diene insertion, is trapped by the nucleophilic position of the N-heterocycles, which leads to a formal [4+2] cyclization reaction.

Figure 1. Benzannulation via C-H activation reaction. RESULTS AND DISCUSSION Evaluation of reaction conditions. Our investigation started with the reaction of 1-(pyrimidin2-yl)-1H-indole 1a with 1,3-diene 2a in the presence of a catalytic amount of [Cp*Rh(CH3CN)3](SbF6)2 (5 mol %) (Figure 2). After extensive screening, the desired benzannulation product carbazole 3aa could be obtained in good yield with either Cu(OAc)2•H2O (2.0 equiv, 89% yield, conditions A) or AgF (4.0 equiv, 81% yield, conditions B) as oxidant in DCE and acetone respectively. The use of dioxygen as a terminal oxidant was also feasible with 20 mol % of Cu(OAc)2•H2O as co-oxidant in MeOH at 40 oC (85% yield, conditions C), which highlighted the mildness and environmental friendliness of the reaction. Free indole, N-methyl or N-tosyl indole showed no reactivity, suggesting the need for a directing group for the transformation.80


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Figure 2. Reaction screening. Substrate scope. The scope of the reaction was investigated (Figure 3). With the catalytic Cu(OAc)2 system (conditions C, Figure 2), a broad range of substituted indoles could be converted to the corresponding carbazoles with moderate to good efficiency. Several commonly encountered functional groups, such as fluoro (3ba, 3fa), chloro (3ca, 3ga), ether (3da, 3ha, 3na), ester (3ia, 3ma), cyano (3ja), nitro (3ea, 3ka) and even formyl (3la), were well tolerated. In addition to pyrimidine, other N-containing heterocycles, such as pyridine (3pa, 3qa) and thiazole (3ra) could serve as efficient directing groups. The above success led us to investigate the feasibility of using the same strategy for other benzofused nitrogen heterocycles syntheses. Pyridine-2(1H)-ones, with the assistance of a pyridinyl directing group, were transformed easily to quinolin-2(1H)-ones (4aa4la). The functional group compatibility is, again, very broad, with moderate to good yields being obtained. Of note, the 4-substituted pyridine-2(1H)-ones (4fa-4ja), whose reactivities towards cyclization may have been inhibited for steric reasons, also underwent a benzannulation reaction without difficulty. Full substitution on the heterocyclic ring was possible (4ja). Isoquinolin-1(2H)ones were viable substrates too, and they delivered the corresponding cyclization products, phenanthridin-6(5H)-ones 5, in good yields. The reaction of quinolin-4(1H)-one gave the unsymmetrical acridin-9(10H)-one 6aa in 68% yield. The coupling reaction of pyridin-4(1H)-one,


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however, was well suited for symmetrical acridin-9(10H)-one (6ba) synthesis via two-fold cyclizations. Not unexpectedly, pyrroles were also amenable to cyclization to form indoles 7. Double cyclizations were observed when pyrrole was used as substrate (7ca). The reaction of 1(pyrimidin-2-yl)-1H-benzo[g]indole were also attempted but no desired product was found probably for steric reason.


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Figure 3. Benzannulation toward the synthesis of different types of benzofused heterocycles. a

2a (1.2 equiv), [RhIII] (2.5 mol %), Cu(OAc)2H2O (20 mol %), MeOH, O2, 40 oC. b2a (3.0 equiv),

[RhIII] (5 mol %), Cu(OAc)2H2O (2.0 equiv), PivOH (1.0 equiv), DCE, 80 oC. c2a (3.0 equiv), [RhIII] (5 mol %), AgF (4.2 equiv), PivOH (1.0 equiv), acetone, 60 oC. The results obtained for the benzannulation with variously substituted 1,3-diene are summarized in Figure 4. Buta-1,3-diene underwent reaction effectively, and rendered the synthesis of benzannulated products (3ab, 4fb, 5bb, 7ab) with no substituent on the newly formed benzene ring. Other 2,3-disubstituted dienes, that bear either an aromatic (3ac, 3ah), aliphatic (3ad-3af) or ester (3ag) substituent, were also applicable for cyclization, although the ester substituent resulted in a lower yield (3ag). The coupling of unsymmetrical (3-methylbuta-1,3-dien-2-yl)benzene gave a mixture of regioisomers (3ah). The 2-substituted 1,3-dienes, such as isoprene, 2-phenyl-1,3butadiene, and myrcene, were also reactive toward annulation, with the substituent being installed proximal to the directing group (3ai-3ak).81 The benzannulations of 1-substituted 1,3-dienes were also possible, with exclusive regioselectivity being observed (3al-3ao). Again, the electrondeficient dienoate showed less reactivity (3ao). The coupling reactions of 1,2-disubstituted 1,3dienes were also feasible, and gave the 3,4-disubstituted carbazoles in moderate yields (3ap, 3aq). Therefore, our protocol allowed a straightforward synthesis of benzofused nitrogen heterocycles with diverse substitution patterns. Some of these products would be difficult to synthesize via other methods.


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Figure 4. Substrate scope on 1,3-dienes. a2a (3.0 equiv), [RhIII] (2.5 mol %), Cu(OAc)2H2O (20 mol %), MeOH, O2, 40 oC. b2a (3.0 equiv), [RhIII] (5 mol %), Cu(OAc)2H2O (2.0 equiv), PivOH (1.0 equiv), DCE, 80 oC. c2a (1.2 equiv), [RhIII] (2.5 mol %), Cu(OAc)2H2O (20 mol %), MeOH, O2, 40 oC. dRegioisomeric ratio, the major isomer was shown. e2a (3.0 equiv), [RhIII] (5 mol %), AgF (4.2 equiv), PivOH (1.0 equiv), acetone, 60 oC. The reaction could be scaled up easily to gram-scale synthesis. With a slight excess of 2a (1.2 equiv) under the catalytic Cu(OAc)2 reaction conditions, the benzannulation of indole 1a (5.0 mmol) delivered 1.20 g carbazole 3aa in 88% yield (Scheme 1). Upon treatment with NaOMe, the directing pyrimidinyl group could be efficiently removed (Scheme 1).


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[RhIII ] (2.5 mol %) Cu(OAc) 2•H 2O (20 mol %) N pym 1a (5.0 mmol )

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Me

Me NaOMe

+ 2a

Me MeOH, O2, 40 °C

N pym

Me (1) DMSO, 135 °C

N H

gram-scale (1.2 eq)

3aa, 1.20 g, 88%

8, 86%

Scheme 1. Gram-scale synthesis and removal of directing group. Mechanistic proposals. Regarding the reaction mechanism, four different mechanistic scenarios could be evoked (Figure 5). Initially, Rh(III)-catalyzed C-H activation delivers a rhodacyle A. Thereafter, the coordination and insertion of 1,3-diene generates a σ-allyl metal species B. At this stage, one possibility is that the -H elimination from B yields a heteroarylated 1,3-diene C (in either E or Z form, path a, Figure 5). A 6 π electrocyclic cyclization and the followup oxidative aromatization converts C to the final benzannulated product.82 Recent studies by Lam revealed that 1,4-Rh(III) migration is a feasible process.78 Accordingly, it is likely that the allylto-aryl 1,4-Rh(III) migration occurs to deliver a heteroaryl metal species E (path b, Figure 5). This species then undergoes intramolecular alkene insertion and -H elimination to furnish G, which is aromatized to the final product via oxidation. Alternatively, the proximity of rhodium to the position of indole in B might trigger a second C-H activation reaction to form a new rhodacyle H (path c, Figure 5). The subsequent isomerization and C-C reductive elimination furnishes a cyclized compound J. Finally, σ-allyl metal species B is expected to be in equilibrium with the πallylmetal species K. The intrinsic nucleophilicity of the C3 position will lead to an intramolecular nucleophilic allylic substitution to form intermediate L (path d, Figure 5), which is deprotonated to give J. J is then converted to the final product via oxidation.


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Figure 5. Mechanistic proposals. Experimental mechanistic studies. Experimental mechanistic studies were conducted to distinguish these four pathways. First, the rhodacycle A was synthesized via the stoichiometric reaction of 1a with [Cp*Rh(III)].83 Its reaction with 1,3-diene 2a in the presence of Cu(OAc)2 and O2 as oxidant furnished the benzannulation product 3aa in 47% yield (Figure 6a). In addition, complex A was demonstrated to be an effective catalyst for the title reaction (Figure 6b). These results indicate that C-H activation occurs in this reaction and A may be involved as a reaction intermediate. Second, both E- and Z-type heteroarylated 1,3-dienes 9 were synthesized and subjected to the standard reaction conditions C. However, no cyclization reaction took place (Figure 6c). In addition, for all the reported cases (Figures 3 and 4), we did not detect the heteroarylated 1,3-diene intermediate. These observations, along with the fact that 6 π electrocyclic reaction generally requires harsher reaction conditions,82 ruled out the intermediacy of a heteroarylated 1,3-diene intermediate in this reaction (path a, Figure 5). If the allyl-to-aryl 1,4Rh(III) migration (path b, Figure 5) is operative, the use of -deuterium substituted indole substrate


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(10) would deliver the cyclization product with partial deuterium incorporation. However, our experiments showed that no deuterium incorporated product was found (Figure 6d), which suggests that path b is less likely.84 Interestingly, the use of naphthalene-derived substrate led only to the formation of dienylation products in low yield (Figure 6e). The absence of cyclization product may be attributed to the low nucleophilicity of the third position of naphthalene ring, making the nucleophilic allylic substitution less favored than -H elimination. This result imples that path d (Figure 5) is more likely than path c (Figure 5).

Figure 6. Experimental mechanistic studies. Theoretical mechanistic studies. To better distinguish path c and path d (see Figure 5), theoretical mechanistic studies were performed by using density functional theory (DFT) calculations.85 The energetic profiles for both pathways were summarized in Figure 7. Complex Cp*Rh(OAc)2 (cat.) was selected as the starting point. The formation of rhodacycle A (or INT-3) is a thermodynamically favored process, which is accomplished by a free energy barrier of 14.6 kcal/mol via a concerted metalation-deprotonation mechanism. The migratory insertion of olefin 2a (via TS-2) requires an activation barrier of 20.2 kcal/mol, leading to a seven-membered rhodacycle intermediate INT-6. Thereafter, the isomerization of INT-6 to its π-allylmetal species INT-7 is exergonic by 6.6 kcal/mol. An outersphere intramolecular nucleophilic allylic


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substitution can then occur via TS-3 (G ≠ = 24.4 kcal/mol), leading to a six-membered intermediate INT-8 with a free energy of 2.7 kcal/mol. Finally, the acetate-assisted deprotonation is a highly exergonic process, resulting in the formation of cyclized rhodium-chelated INT-9. Alternatively, the replacement of the directing pyridinyl group in INT-6 with acetate sets the stage for a second C-H activation. However, our calculation demonstrates that the transition state (TS4) for a concerted metalation-deprotonation type C-H activation is associated with a high free energy barrier of 31.4 kcal/mol. In addition, due to the high stability of the thus formed rhodacycle INT-12, the follow-up reductive elimination also requires a high activation barrier of 24.7 kcal/mol, which is close to the overall activation barrier of path d (Figure 5, 24.4 kcal/mol). In all, the theoretical calculation suggests the allylic substitution pathway (path d, Figure 5) is more favorable and might be the operating mechanism, which is in good agreement with the results obtained from the experimental mechanistic studies. The reactions of other heteroarenes may follow a similar mechanistic scenario considering their appreciable nucleophilicity at C3 positions.86-88 Regarding the regioselectivity, the predominant formation of 3-substituted carbazole derivatives (3ai-3ak) when 2-substituted 1,3-dienes were used could be attributed to the preferential coordination of the electron-rich double bond to rhodium (analog to INT-3), giving that the metal center is highly cationic. However, with increasing steric (for 1-substituted (3al3ao) and 1,2-disubstituted (3ap and 3aq) 1,3-dienes), the reaction at the less sterically hindered double bond is favored.


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DGPCM(MeOH)-M06/6-311++G(d,p)&SDD//B3LYP/6-31G(d)&LanL2DZ kcal/mol

H Rh

N pym

1a

O

N pym

2a

H

O Rh

Cp*

N pym

O H

Rh

Cp*

N

N

N

H Rh Cp*

N pym

13.9 TS-2 N

0.0 cat. Cp* Rh AcO OAc

N

4.9 INT-1 AcO

Cp*

2.5 INT-2

Rh N

2a

AcO

HO

O

Cp*

Rh N

N

Cp*

INT-11

N

N

15.0 TS-5

HOAc 2.7 INT-8

INT-6

INT-5

H

-6.8

Cp* Rh N

N pym

TS-3

AcO

N

OAc Rh N

N pym

17.6

-0.2

-6.3 INT-4

Cp*

Rh

INT-10

-0.7

HOAc

INT-3 (A)

N

Cp*

AcO

-5.4

N

25.8

11.9

Rh N

Rh

*Cp Cp*

Rh

N

N 14.6 TS-1 AcO

O

AcO

N

1a

HO

31.2 TS-4

O

Cp* TS-3

INT-7

N

N

N pym

N

N pym

Rh N Cp* Rh Cp*

Rh Cp*

-9.7 INT-12 *Cp

*Cp Rh

Rh

AcO N pym

N N pym

INT-2

HOAc -30.1 INT-9

Figure 7. Theoretical mechanistic studies. CONCLUSION In conclusion, a Rh(III)-catalyzed benzannulation of N-heterocycles with 1,3-dienes allowed for the synthesis of a variety of benzofused nitrogen heterocycles under mild reaction conditions, starting from non-prefunctionalized N-heterocycles. This protocol complements the classic synthetic strategy that focuses on the construction of a N-heterocyclic ring, and provides advantages in that diverse substitution patterns can be introduced easily in the newly formed benzene ring. The high nucleophilicity of the position of the corresponding N-heterocycle was believed to be important for the observed reactivity. Theoretical calculation points out an intramolecular nucleophilic allylic substitution is involved in the reaction mechanism, which is in good agreement with the experimental mechanistic observations.

ASSOCIATED CONTENT


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AUTHOR INFORMATION Corresponding Author *Email: [email protected]; [email protected] Author Contributions †

These authors contributed equally.

Notes The authors declare no competing financial interest. Supporting

Information.

Experimental

procedures,

characterization

of

products,

computational details and copies of 1H and 13C spectra are provided. This material is available free of charge via the Internet at http://pubs.acs.org ACKNOWLEDGMENT Generous financial support from the Key Project of Chinese National Programs for Fundamental Research and Development (2016YFA0602900), the National Natural Science Foundation of China (21472250), the National Science and Technology Major Project of the Ministry of Science and Technology of China (2018ZX09735010), the "1000-Youth Talents Plan", and the Natural Science Foundation of Guangdong Province (2017A030313058) are gratefully acknowledged.

REFERENCES (1) Li, J. J. Heterocyclic Chemistry in Drug Discovery (Wiley, Hoboken, 2013).


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(42) Annamalai, P.; Chen, W.-Y.; Raju, S.; Hsu, K.-C.; Upadhyay, N. S.; Cheng, C.-H.; Chuang, S.-C. Palladium-Catalyzed Selective Aryl Ring C–H Activation of N-acyl-2-aminobiaryls: Efficient Access to Multiaryl-Substituted Naphthalenes. Adv. Synth. Catal. 2016, 358, 36423648. (43) Guo, T.; Jiang, Q.; Yu, Z. Palladium-Catalyzed Oxidative Annulation of in situ Generated Enones to Pyrroles: a Concise Route to Functionalized Indoles. Org. Chem. Front. 2015, 2, 1361-1365. (44) Wu, J.; Cui, X.; Mi, X.; Li, Y.; Wu, Y. Palladium Catalyzed Synthesis of Highly Substituted Naphthalenes via Direct Ring Construction from Amides with Alkynes. Chem. Commun. 2010, 46, 6771-6773. (45) Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M. Fused Ring Construction around Pyrrole, Indole, and Related Compounds via Palladium-Catalyzed Oxidative Coupling with Alkynes. J. Org. Chem. 2009, 74, 7481-7488. (46) Wu, Y.-T.; Huang, K.-H.; Shin, C.-C.; Wu, T.-C. Palladium-Catalyzed Formation of Highly Substituted Naphthalenes from Arene and Alkyne Hydrocarbons. Chem. Eur. J. 2008, 14, 6697-6703. (47) He,

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(56) Rathore, K. S.; Harode, M.; Katukojvala, S. Regioselective π-Extension of Indoles with Rhodium Enalcarbenoids-Synthesis of Substituted Carbazoles. Org. Biomol. Chem. 2014, 12, 8641-8645. (57) Matsuoka, W.; Ito, H.; Itami, K. Rapid Access to Nanographenes and Fused Heteroaromatics

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(69) Nguyen, K. D.; Herkommer, D.; Krische, M. J. Enantioselective Formation of All-Carbon Quaternary Centers via C-H Functionalization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation. J. Am. Chem. Soc. 2016, 138, 14210-14213. (70) Khan, I.; Chidipudi, S. R.; Lam, H. W. Synthesis of Spiroindanes by Palladium-Catalyzed Oxidative Annulation of Non- or Weakly Activated 1,3-Dienes Involving C–H Functionalization. Chem. Commun. 2015, 51, 2613-2616. (71) Zhao, D.; Lied, F.; Glorius, F. Rh(III)-catalyzed C–H Functionalization/Aromatization Cascade with 1,3-Dienes: a Redox-Neutral and Regioselective Access to Isoquinolines. Chem. Sci. 2014, 5, 2869-2873. (72) Lu, B.; Wang, Y.; Ge, Y.; Liu, J.; Luan, X. Diastereoselective Synthesis of Dibenzo[b,d]azepines by Pd(II)-Catalyzed [5 + 2] Annulation of o-Arylanilines with Dienes. Org. Lett. 2017, 19, 1734−1737. (73) Nishimura, T.; Nagamoto, M.; Ebe, Y.; Hayashi, T. Enantioselective [3 + 2] Annulation via C–H Activation between Cyclic N-acyl Ketimines and 1,3-Dienes Catalyzed by Iridium/Chiral Diene Complexes. Chem. Sci. 2013, 4, 4499-4504. (74) Nishimura, T.; Ebe, Y.; Hayashi, T. Iridium-Catalyzed [3 + 2] Annulation of Cyclic Nsulfonyl Ketimines with 1,3-Dienes via C–H Activation. J. Am. Chem. Soc. 2013, 135, 20922095. (75) Li, Q.; Yu, Z.-X. Enantioselective Rhodium-Catalyzed Allylic C-H Activation for the Addition to Conjugated Dienes. Angew. Chem. Int. Ed. 2010, 50, 2144-2147.


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(76) Li, Q.; Yu, Z.-X. Conjugated Diene-Assisted Allylic C−H Bond Activation: Cationic Rh(I)-Catalyzed Syntheses of Polysubstituted Tetrahydropyrroles, Tetrahydrofurans, and Cyclopentanes from Ene-2-dienes. J. Am. Chem. Soc. 2010, 132, 4542-4543. (77) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; BookerMilburn, K. I. Distinct Reactivity of Pd(OTs)2: the Intermolecular Pd(II)-Catalyzed 1,2Carboamination of Dienes. J. Am. Chem. Soc. 2008, 130, 10066-10067. (78) Korkis, S. E.; Burns, D. J.; Lam, H. W. Rhodium-Catalyzed Oxidative C–H Allylation of Benzamides with 1,3-Dienes by Allyl-to-Allyl 1,4-Rh(III) Migration. J. Am. Chem. Soc. 2016, 138, 12252-12257. (79) Cooper, S. P.; Booker-Milburn, K. I. A Palladium(II)-Catalyzed C-H Activation Cascade Sequence for Polyheterocycle Formation. Angew. Chem. Int. Ed. 2015, 54, 6496-6500. (80) See Supporting Information for details. (81) CCDC 1582020 (3ai), 1582021 (3an) contain the supplementary crystallographic data. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. (82) Kim, H. T.; Ha, H.; Kang, G.; Kim, O. S.; Ryu, H.; Biswas, A. K.; Lim, S. M.; Baik, M.H.; J. M. Joo, Ligand-Controlled Regiodivergent C−H Alkenylation of Pyrazoles and Its Application to the Synthesis of Indazoles. Angew. Chem. Int. Ed. 2017, 56, 16262-16266. (83) Yang, L.; Zhang, G. Y.; Huang, H. M. An Efficient Rhodium/Oxygen Catalytic System for Oxidative Heck Reaction of Indoles and Alkenes via C-H Functionalization. Adv. Synth. Catal. 2014, 356, 1509-1515.


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(84) There might be several possible mechanisms for 1,4-rhodium(III) migration: 1) concerted metalation-deprotonation, followed by protonolysis; 2) C-H oxidative addition followed by C-H reductive elimination; and 3) sigma-complex-assisted metathesis. In either case, the deuterium transfer is expected to be observed, see ref 78 and references cited therein. (85) For computational details, see Supporting Information. Considering that different density theory and the polarization functions might affect the description of transition metal, all the key geometries have been re-optimized at the level of D3-B3LYP and the basis set LanL2TZ(f) for Rh. However, the trend and results are consistent with that of the PCM(MeOH)-M06/6-311++G(d,p)&SDD//B3LYP/6-31G(d)&LanL2DZ level. (86) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Suzuki–Miyaura Cross-Coupling and Ring-Closing Metathesis: a Strategic Combination to the Synthesis of Indeno[1,2c]isoquinolin-5,11-diones. Tetrahedron Lett. 2011, 52, 1481–1484. (87) Austin, K. A.; Herdtweck, E.; Bach, T. Intramolecular [2+2] Photocycloaddition of Substituted Isoquinolones: Enantioselectivity and Kinetic Resolution Induced by a Chiral Template. Angew. Chem. Int. Ed. 2011, 50, 8416-8419 (88) Gan, Z.; Hu, B.; Song, Q.; Xu, Y. Convenient Chlorination of Some Special Aromatic Compounds Using N-chlorosuccinimide. Synthesis 2012, 7, 1074-1078.


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RhIII

H Het N

+ [O]

H

Page 28 of 28

via Het

RhIII

N GD

N

int-1

five types of benzofused heterocycles accessible O

N H

N H

NH O

N H

O

N H


28

Synthesis of Benzofused N-Heterocycles via Rh(III)-Catalyzed Direct

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