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Letter
Sequential C#H and C#C Bond Cleavage: Divergent Constructions of Fused N-Heterocycles via Tunable Cascade Xianwei Li, Jianhang Rao, Wensen Ouyang, Qian Chen, Ning Cai, Yu-Jing Lu, and Yanping Huo ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03091 • Publication Date (Web): 22 Aug 2019 Downloaded from pubs.acs.org on August 22, 2019
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ACS Catalysis
Sequential C‒H and C‒C Bond Cleavage: Divergent Constructions of Fused N-Heterocycles via Tunable Cascade Xianwei Li,* Jianhang Rao, Wensen Ouyang, Qian Chen, Ning Cai, Yu-Jing Lu, Yanping Huo School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, China. ABSTRACT: Streamlining generation of diverse highly functionalized molecules from abundant feedstocks, holds great synthetic promises and challenges in pharmaceutical and material discovery. Herein, we report a tunable selectivity in multiple cascade reactions for the divergent assembly of fused N-heterocycles, comprising sequential activation of C-H and C-C bonds. Isolatable indene type intermediates might be responsible for the generation of densely substituted fused pyridines, azepines and azafluorenones products. The tolerance of strongly coordinating N-heterocycles and readily applicable for the late-stage modifications of pharmaceuticals and material molecules precursors, further demonstrated the synthetic robustness of this transformation.
KEYWORDS: multiple oxidative cascade • C-H and C-C cleavage • tunable selectivity • traceless directing group • fused N-heterocycles.
In pursuing green processes for the rapid construction of target molecules via economically and environmentally benign routes, catalytic cascade reaction has emerged as a powerful strategy.1 Fruitful results in the cascade transformations have been achieved, however, the exploration of C-H activation initiated multiple cascade,2 especially for the precise control of the selectivity in cascade reactions that involved the cleavage and reconstruction of multiple chemical bonds, is still elusive. Moreover, sequential activation of inert C-H and C-C bonds triggered multiple cascade for the divergent constructions of complex molecules, remained underexplored. Selective transformations of inert C-C bonds3 have enriched the synthetic arsenal for the constructions of complex skeletons, while typical strategies relied on the use of strained structures or directing groups. In this context, the use of unstrained substrates and traceless directing moiety to facilitate C-C activation cascade, enabling the diversityoriented synthesis (DOS)4, would be extremely attractive. Herein, we reported a sequential C-H and C-C cleavage cascade with switchable selectivity, affording to divergent delivery of fused N-heterocycles (Scheme 1-2). Significantly, selective C-H and C-C bond activation of acyclic system in this transformation could be well tuned, by the choice of oxidant or solvent. Fused N-heterocycles such as pyridines, azepines and azafluorenones,5-6 serve as important structural motifs that occurred widely in natural products, pharmaceuticals and functional materials (Scheme 1-3).7 Notable strategies toward their efficient assembly included condensation of carbonyls with amine precursors and cycloaddition of C-C unsaturated bonds with nitrogen functionalities. However, certain limitations such as multiple steps and troublesome selectivity, were often suffered. Thus, expedient methodologies to efficiently access to these valuable molecular architectures are highly desirable.
1) Skeleton recognization via C-C activation strategy: X
Y C
or C
C
X
X
Y
C
C
[M]
Y
C
or
X
Y
C
C
2) Sequential C-H and C-C activation cascade:
R N 1
C -C(O) cleavage
R1 R3
OEt
R Ha
NH
R1
Rh(III)
C1
R1
2
C R3
30 min R
3
R
NH2
2
O R
N
R C-Ha/N-H cleavage
2
O R1
OH
R2 R3
isolatable intermediates
OH
R
N C2-C(R3) and C-C(O) cleavage
R1
O2
O
3) Fused nitrogen heterocycles in bioactive and material molecules: Cl
Cl O Cl N
HO
N
O
H N
O NH2
N
N
O
R2
O MeO MeO
AI-III-52 O
Me
N
O
O
N
Pd
Strongly Phosphorescent Pd(II) Complex
thrombin inhibitor
Buttpark 104\40-64
N O
O
O
N R3
O
R1
(+)-ribasine, R1 = R2 = H, R3 = Me (+)-ribasidine, R1 = H, R2 = OH, R3 = Me (+)-norribasine, R1 = R2 = R3 = H
O N
O
NH R
N
Onychine, R = H Dielsine, R = OH
HO O Cephalotaxine
NH
O
indolobenzazepinone (antimitotic activity)
Scheme 1. Sequential activation of C-H and C-C bonds strategy for Fused N-heterocycles Synthesis. We commenced our study by choosing imidate 1a and allylic alcohols 2a as the model substrates under metal catalysis (Table 1).8,9 After extensive screen of catalytic
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parameters, we found that with [Cp*RhCl2]210 and AgNTf2 as the catalyst, NaOAc as the additive, Cu(OAc)2•H2O and molecular oxygen as the terminal oxidant, sequential C-H and C-C bond activation to afford fused pyridine 3a in good yield.11,12 No desired product 3a was obtained in the absence of Rh(III) complex, while Pd(II) and Ir(III) complexes showed no catalytic efficiency, [Ru(p-cymene)Cl2]2 showed relatively lower efficiency. Cu(OAc)2•H2O played a critical role, since low conversion of substrate 1a was observed with AgOAc instead. Moreover, DTBP oxidant totally shut down this reaction. Inferior results were obtained in the absence of either Cu(OAc)2•H2O or NaOAc. Additional base or acid exhibited no significant effect to this oxidative cascade. The use of HFIP or t-Amyl-OH as the solvent led to moderated yields of the desired product 3a. Table 1. Variation of standard conditions.a OEt OH
NH 1a
2a
OH 2a
[Cp*RhCl2]2 (2 mol%) AgNTf2 (4 mol%) NaOAc (10 mol%)
N
H HCO2-
Cu(OAc)2 H2O (30 mol%) O2 (1 atm), DCE, 120 oC, 18 h
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alcohols could also serve as suitable substrates in this cascade reaction. However, pyridine and thiozole-derived allyl alcohols delivered moderate yield of the corresponding fused pyridine products. The structure of the obtained fused pyridine was unambiguously confirmed by X-ray analysis (3x). Notably, regioselective C-H functionalization took place at steric hindered position (3y-3z), probably due to the directing effect of the fluoro and OMe groups.13 Further investigation revealed that the use of meta-Cl benzimidate ester under standard Rh(III) catalysis led to 1:1 regioisomers of fused pyridines; while the reaction took place at less steric hindered C-H position with the use of meta-CF3 benzimidate ester. This sequential C-H and C-C activation cascade could be applied to imidates with two different allylic alcohols (3zf-3zo), indene intermediates might be generated with the addition of 1,2disubstituted allylic alcohols first, and subsequently added mono-substituted allylic alcohols to the reaction systems, various fused pyridines could be obtained. 1) Capture of the released carboxylic byproduct derived from C-C cleavage: OEt
3a
OH
NH
Entry
Variation of standard condition
1a
None
90
2
PdCl2 or [IrCp*Cl2]2 instead of [RhCp*Cl2]2
n.r.
2c
[Ru(p-cymene)2Cl2]2 instead of [RhCp*Cl2]2
72
4
AgOAc or tBuOOtBu instead of Cu(OAc)2 .H2O
< 10 or n.r.
5
Without Cu(OAc)2 .H2O
22
6
Without NaOAc
37
7
Addition of Cs2CO3 or PivOH (30 mol%)
88, 76
8
HFIP or tAmyl-OH as the solvent
81, 77
a Standard conditions: 1a (0.20 mmol), 2a (0.50 mmol), [Cp*RhCl ] (2 mol%), 2 2 AgNTf2 (4 mol%), NaOAc (10 mol%), Cu(OAc)2 .H2O (30 mol%), DCE (1 mL) b under air for 18 h. Isolated yield.
In order to obtain insight into this multiple cascade, some control experiments were conducted (Scheme 2), and the results revealed that: 1) With addition of MeI to this reaction under standard condition, methyl benzoate product was obtained, which might derive from C-C bond cleavage of allylic alcohol moiety; 2) Oxidative Heck product A and A’ were isolated within 30 minutes with 1a and 1,2-disubstituted olefins 2d, and further addition of 2a into this catalytic system led to densely substituted fused pyridines in high yields in one-pot manner. This observation indicated that indene might serve as the key intermediate in this multiple cascade. With the optimal condition, we next explored the synthetic generality of this C-H/C-C activation cascade, broad substrate scope with great functional group tolerance was observed (Scheme 3). (Pseudo)halides including F (3b), Cl (3c), Br (3d), I (3e), CF3 (3g), OTs (3i) and OTf (3k) could be well tolerated, providing new opportunities for the further diversification. Readily transformable functionality including nitro (3h), benzylic chloride (3l), ester (3m), phenolic hydroxyl (3j), amine (3n) and ethers (3o-3p) were compatible. Methyl (3q-3t), ethyl (3zc), phenyl (3u-3x) and heterocycles including furan (3zd) and thiophene (3ze) derived allylic
2c
N
1) 'standard condition'
Ph O O
Ph
2) MeI, K2CO3 3u, 75%
Me
isolated
2) Isolation of oxidative Heck products as the intermediates in this multiple cascade: R2
OEt NH
3
OH
Ph
Yieldb (%)
1
Ph
Rh(III) cat. standard condition
1a Me
30 min OH
R1 2d, R1 = H (1.25 equiv.); 2e, R1 = Me (1.25 equiv.)
NH2 O
OH 2 (1.25 equiv.)
R2 N
H 120 oC, 16 h Me Me intermediate A, 95%; 2a, R2 = H; 2b, R2 = Me; intermediate A', 93% 2 3zf, R = H, 86% from A; 83% from A' ; 3zg, R2 = Me, 82% from A; 80% from A'
Scheme 2. Preliminary mechanism studies. Regioselective C-H functionalization of multiple substituted arenes holds significant utility in the late-stage modification of bioactive molecules and materials. Nevertheless, the search for proper catalytic system for the effective discrimination of specific C-H bond in the complex molecules remained challenging. In this context, Yu, Dai, and Ackermann have developed efficient C-H transformations that could overcome the commonly encountered limitations of C-H activation with strongly coordinating N-heterocycles. 14 We were also intrigued of the directing priority towards multiple functionalized arenes in this C-H functionalization initiated multiple cascade reaction. To our delight, imine functionality outcompete ketone (4a, 4b), carboxlic acid ester (4c), phenol ester OPiv (4d) and NHPiv (4e), leading to the desired products in a selective manner. Significantly, heterocycles that are widely used in materials and pharmaceuticals included pyridine (4f), pyrimidine (4g) and pyrazine (4h), could also be compatible in this transformation. To further exploration of the synthetic utility of this reaction, we selected fused heterocycles that were frequently used in materials for the diversification. Naphthalene (5a), indoles (5b), benzothiophene (5c), tertiary aromatic amine (5d), fluorenone (5e), dibenzo[b,d]thiophene (5f), carbazole (5g), thiophene (3zi) derived highly fused heterocycle could be readily accessed, which might provide inspiration into organic optoelectronic materials discovery.15,16 This transformation also enabled late-stage modification of bioactive molecules, including pioglitazone (5h), probenecid
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ACS Catalysis (5i), ibuprofen (5j) and estrone (5k), demonstrating their synthetic potential in pharmaceutical discovery. OEt R
R2
R3
NH
1
OH
R2
N
R1
NaOAc (10 mol%), Cu(OAc)2 • H2O (30 mol%) O2 (1 atm), DCE, 120 oC, 18 h
OH
2 (1.25 equiv.)
1
[Cp*RhCl2]2 (2 mol%) AgNTf2 (4 mol%)
R2
R3 3, 4, 5
2 (1.25 equiv.)
1) functional group tolerance: N
N
F
N
Cl 3b, 88%
3d, 89%
N
TsO
HO 3i, 92%
3k, 79%
N
MeO
N
O
Ph
N
N
3v, 77%
TsO 3t, 87%
3u, 75%
H
Ph
TsO
H
MeO
3y, 82%
X-ray structure of 3x
3z, 89%
OEt NH
from
N
Et
N
N O
N
3za, 87%
N
F
3x, 73%
N
Cl
Ph
N
N
3w, 72%
N
Me
N
3s 85%
Cl
F3C
3o, 83%
3n, 72%
F3C
N
F3C
Br
O
Me
N
3r, 81% Ph
N
Br
TsHN
Me
Br 3p,88%
3h, 81% N
3m, 78%
3l, 73%
Me
N
3q, 84%
3g, 90% N
O
3j, 59%
MsO
Cl
TfO
O 2N
3f, 91% N
N
F3C
3e, 82%
N
N
MeO
I
3c, 87% N
N
N
Br
Cl
3zb:3zb' = 1:1, 80%
3zc, 81%
S
3zd, 91%
3ze, 83%
2) Oxidative C-H and C-C actviation cascade of imidates with two different allylic alcohols: R2
Me
N
N
N
Me
N
S
R1
Me Me 3zh, R1 = H, R2 = Ph, 81%; 3zk, 70% 3zi, R1 = H, R2 = 2-thiophene, 72% 3zj, R1 = Cl, R2 = Me, 79%
O O
Me
Me
N
N
3zl, 73%
Cl
Me
N
O
3zm, 67%
O i S N Pr2 O
O 3
Me
O
3zn, 67%
3zo, 78%
3) Directing groups priority: R N
H
O
N
H
N
N N
O
4d, X = O, 59% 4e, X = NH, 61%
4c, 85%
N
H
X
O
4a, R = H, 82% 4b, R = Ph, 62%
N
H
O
EtO
N
H O
4f, 63%
N
H
N
O
4g, 66%
N
4h, 78%
4) Synthetic utility in materials precurors and pharmaceuticals: N
N
O
N
N
N
N
S
N Ts 5a, 87%
N Ts
S 5c, 52%
5b, 65%
5d, 54%
5e, 71%
5g, 67%
OMe N
O
Et N
N
N O
5f, 81%
OMe
pioglitazone analog, 5h, 78%
i
O N
3O
O i S N Pr2 O
Bu
O
O
N O 3O
probenecid analog, 5i, 64%
H
ibuprofen analog, 5j, 76%
H
H
N estrone analog, 5k, 51%
Scheme 3. Sequential C-H and C-C activation for assembly of fused pyridines: 1) functional group tolerance; 2) imidates with two different allylic alcohols; 3) directing groups priority; 4) synthetic utility in material and pharmaceuticals. Intriguingly, oxidative double C-H Heck cascade reaction of arylimidates with allylic alcohols took place in the absence of Cu(II) salt under lower temperature. Further optimization revealed that with isolatable indenes, which were obtained from imidates with 1,2-disubstituted allylic alcohols under Rh(III) catalysis in 30 minutes; subsequent addition of another mono-substituted allylic alcohol, affording to the densely fused azepines under 70 oC within 3 hours (Scheme 4). Halogens such as F (6d), Cl (6e), OTs (6h) and alkyl chloride (6g) could be well compatible, leading to densely substituted azepines. Moreover, fused azepines (6i, 6j) were also readily accessible from indole and naphthalene substrates, providing a valuable platform for the rapid construction of molecular libraries of azepines. The moderated efficiency that observed
might be contributed to the insufficient directing abilities for the oxidative Heck reaction and partial decomposition of the primary amine moieties.
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R
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
R
R3
NH
R1
2
R
OH 1
2
2
R 6
Me
R
Me
N
N
N
N
O
Me 6a, R = Me, 68% 6b, R = Ph, 56%
Me
Cl
Me 6d, R = Me, 55% 6e, R = Ph, 51%
Me
N
N
H
TsO
Rh(III), [O]
N Ts
H Me 6h, 48%
O
H
2
R
[O]
R2
2
O
Scheme 5. Azafluorenones synthesis via multiple oxidative CH/C-C activation cascade.
Considering fused N-heterocycles that are widely existed in natural products and pharmaceuticals, we further demonstrate the synthetic application of this transformation for the concise delivery of onychine using our methodology. As depicted in Scheme 6, by using benzimidate ester 1a and terminal allylic alcohol 2c under Rh(III) catalysis for 30 minutes, and subsequent addition of the second 1,2-disubstituted allylic alcohol 2d in HOAc under molecular oxygen atmosphere for 48 hours, onychine could be obtained. The observed moderate efficiency of the overall transformation is probably due to the steric hinderance of the second added 1,2-disubstituted allylic alcohol. Inspired by Chang’s work on catalytic C-H amidation using
indene intermediates
O
NH
HN Rh(III) O 70 oC R
1
b
R2
Rh(III) O 120 oC
2 R1 R
NH
2 oxidative Heck reaction
c
oxidative Heck reaction
R Rh(III) NH
N
R N
R2
i
HOAc f (7a', isolated when R1 = R = Me)
g
-H elimination
NH2 R R1 j
2
O
O 2 R R d
condensation
1
R1 2 R
e
O
H2O, Cu(II), base
re-aromatization induced C-C(O) cleavage R N HOAc, O2
or retro-Claisen reaction O R2
O
R1 fused pyridines 3, 4, 5 MeI, K2CO3
R
O
R N R
HO R1
O
R1
O 7h, 74%
O
R1 h
HO
O 7g, 62%
Rh(III), base
R2
2
N
O 7f, 83%
O S N O
O 3
N
R1
(III)Rh NH
R
O
O
base
NH R1 a
O
7e, 81%
O O
O O
7d, 79%
N Ts
MeO
O O
N
N
N
NH2
OEt Rh(III)
O 7c, 85%
Ph
Me 6j, 61%
Scheme 4. Fused azepines synthesis via multiple oxidative CH Heck reaction using allyl alcohols. Notably, with isolatable intermediate A and further addition of 2b in HOAc under Rh(III) catalysis, azafluorenone products were obtained (Scheme 5). Readily transformable functional groups including iodo (7c), ketone (7d), ester (7e), OTs (7f) and strong coordination nitrogen heterocycles (7g) could be compatible. Moreover, late-stage modification of pharmaceuticals such as Probenecid was also operational, demonstrating the synthetic potential of this transformation. Control experiments with fused pyridine 3zg under standard conditions in HOAc solvent revealed that the azafluorenone product 7a could be isolated, together with detectable amount of benzylic C-H oxygenated fused pyridine 7a’. We speculated that a benzylic C-H oxidation followed by dehydration to give the olefin intermediate 8, and subsequent oxidative cleavage of C-C double bonds might be involved.17
1
I
7b, 83%
8 N
N
O
O 7a, 81%
H
Me 6i, 55%
HOAc, O2 HO Me 7a', 12%
N
N
N O
N
HOAc, O2
Me
Me
Me N
Me 3zg
Me 6f, 54%
N
O 7a, 81% Oxidative C-H & C-C activation cascade
Me
Me
O
HOAc, O2, 120 oC, 48 h
N
H
Me
O
Me 6g, 50%
Cl
N
2b
OH
2b
Rh(III) cat.
O
H
F
6c, 65%
Me
2d
O
H
92%
OH
Me
Me O
H Me intermediate A
30 min
1a
2
R3
NH2
Rh(III) cat. standard conditions
NH
O R1
R
O
O
N
NaOPiv (30 mol%) 1,4-dioxane/DCE (4:1) O2 (1 atm), 70 oC, 3 h
OH
Me OEt
[Cp*RhCl2]2 (2 mol%) AgNTf2 (5 mol%)
OEt
condensation & oxidative aromatization
C=C oxidative cleavage
Rh(III), HOAc, O2
R N
R2
O
Me N
O
Me
O R2 = Ph
R1 fused azepines 6
O 7a
isolated
azides as the amidation reagents,18 we investigated the reactivity of TsN3 in this multiple cascade reaction. Intriguingly, with indene intermediate that could be readily
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ACS Catalysis accessed from imidate ester 1a with allylic alcohol 2e under Rh(III) catalysis, further addition of TsN3 under standard condition revealed that a C-H and C-C bond action for the amidation reaction took place, and further efforts toward the optimization and synthetic application of this transformation is in progress. OEt
Ph
NH
OH
1a
2c
OEt NH
1a
OH
Me
Me
2d
Me OH
2e (1.25 equiv.)
TsN3
(2.5 equiv.)
O
[Cp*RhCl2]2 (2 mol%) AgNTf2 (4 mol%) NaOAc (30 mol%) Cu(OAc)2• H2O (30 mol%) DCE/HOAc = 1:4 O2 (1 atm), 120 oC, 48 h
Me
N 9, onychine, 43%
NHTs NH 2
[Cp*RhCl2]2 (2 mol%) AgNTf2 (4 mol%) NaOAc (30 mol%) Cu(OAc)2• H2O (30 mol%) DCE, 60 oC, 12 h
NHTs Me 10, 51%
Scheme 6. Synthetic applications: 1) concise synthesis of Onychine; 2) amidation reaction via C-H and C-C activation cascade.
Scheme 7. Possible mechanism for the sequential C-H and C-C bond activation cascade. According to precedent literatures and the experimental observations, a tentative mechanism was proposed (Scheme 7): with the assistance of acetate ion, Rh(III) catalyzed C-H activation of imines 1 with alkenes 2 took place, which followed by β-H elimination8,19 and condensation to give key indene intermediates (eg. al., A or A’). Subsequent coordination of Rh(III) or Cu(II) to indene intermediates led to two pathways, which might be controlled by the temperature, solvent and Cu(II) salt as a Lewis acid and oxidant20 (See Supporting Information for details): 1) When the reaction was conducted at 120 oC in the presence of Cu(OAc)2·H2O, Rh(III) intermediate b might be generated, which followed by oxidative Heck reaction. Further condensation and C-C bond cleavage took place to afford the desired fused pyridines products, together with the release of carboxylic acid derivatives, which could be captured by the addition of MeI, to generate PhCO2Me (detected by GC-MS). We assumed that re-aromatization or retro-Claisen reaction,21,22 which might serve as the driving force for the CC bond cleavage in this process,20,23 was assisted by water and Cu(II) salt. 2) When the reactions were conducted in the absence of Cu(II) salt under lower temperature, with the assistance of primary amines, regioselective aryl Csp2-H oxidative Heck reaction took place, which followed by condensation and oxidative aromatization to give the desired fused azepines products 6.24 On the other hand, while under acidic conditions, oxidative hydroxylation of benzylic C-H bond with molecular oxygen led to hydroxylated fused pyridine intermediate (which was isolated as 7a’ when R1 = R = Me). Upon further dehydration, C-C double bonds were formed, which underwent oxidative cleavage under Rh(III)-catalyzed aerobic oxidation,17 affording to azafluorenone products 7.
In summary, we have successfully accomplished an attractive strategy for the modular delivery of densely functionalized fused N-heterocycles via sequential C-H and CC bond cleavage. Significantly, tunable selectivity for the diverse products generation was obtained, which might be contributed to the retro-Claisen type reaction or rearomatization as the driving force. This methodology features broad substrate scope and great functional group tolerance, and enabled divergent access of building blocks that might be used in organic optoelectronic materials and bioactive molecules. This strategy might provide new insight into C-C bond activation, showcasing the viability of late-stage modification of complex molecules toward a diversity-oriented synthesis.
AUTHOR INFORMATION Corresponding Author *Email:
[email protected] Notes The authors declare no competing financial interest.
ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental procedures and spectra data for all new compounds (PDF)
ACKNOWLEDGMENT We are grateful for the financial supported by the National Natural Science Foundation of China (21602032), the One Hundred Young Talent program of Guangdong University of Technology and GDUT Analysis and Test Center for the HRMS analysis. We also appreciated Dr. Zihang Qiu, Dr. Dianhu Zhu and Dr. Yu-Feng Liang and Prof. Chao-Jun Li at McGill University for helpful comments and discussions.
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Activation/Annulation Reaction Sequence of Naphthalene Aldehydes with Alkynes. Angew. Chem., Int. Ed. 2017, 56, 13094. d) Wang, Z.; Yin, J.; Zhou, F.; Liu, Y.; You, J. Multicomponent Reactions of Pyridines To Give Ring-Fused Pyridiniums: In Situ Activation Strategy Using 1,2-Dichloroethane as a Vinyl Equivalent. Angew. Chem., Int. Ed. 2019, 58, 254. e) Yin, J.; You, J. Concise Synthesis of Polysubstituted Carbohelicenes by a C−H Activation/Radical Reaction/C−H Activation Sequence. Angew. Chem., Int. Ed. 2019, 58, 302. (17) a) Stowers, K. J.; Kubota, A.; Sanford, S. Nitrate as a Redox Co-Catalyst for the Aerobic Pd-Catalyzed Oxidation of Unactivated sp3-C–H bonds. Chem. Sci. 2012, 3, 3192. b) Wang, A.; Jiang, H. Palladium-Catalyzed Direct Oxidation of Alkenes with Molecular Oxygen: General and Practical Methods for the Preparation of 1,2Diols, Aldehydes, and Ketones. J. Org. Chem. 2010, 75, 2321. c) Morandi, B.; Wickens, Z. K.; Grubbs, R. H. Practical and General Palladium-Catalyzed Synthesis of Ketones from Internal Olefins. Angew. Chem. Int. Ed. 2013, 52, 2944. (18) Shin, K.; Kim, H.; Chang, S. Transition-Metal-Catalyzed C−N Bond Forming Reactions Using Organic Azides as the Nitrogen Source: A Journey for the Mild and Versatile C−H Amination. Acc. Chem. Res. 2015, 48, 1040. (19) Allyl alcohols could also undergo C-H allylation via β-OH elimination: a) Suzuki, Y.; Sun, B.; Sakata, K.; Yoshino, T.; Matsunaga, S.; Kanai, M. Dehydrative Direct C-H Allylation with Allylic Alcohols under [Cp*Co(III)] Catalysis. Angew. Chem. Int. Ed. 2015, 54, 9944. b) Kalsi, D.; Laskar, R. A.; Barsu, N.; Premkumar, J. R.; Sundararaju, B. C-8-Selective Allylation of Quinoline: A Case Study of β-Hydride vs β-Hydroxy Elimination. Org. Lett. 2016, 18, 4198. c) Bunno, Y.; Murakami, N.; Suzuki, Y.; Kanai, M.; Yoshino, T.; Matsunaga, S. Cp*CoIII-Catalyzed Dehydrative C–H Allylation of 6-Arylpurines and Aromatic Amides Using Allyl Alcohols in Fluorinated Alcohols. Org. Lett. 2016, 18, 2216. d) Kumar, G. S.; Kapur, M. Ruthenium-Catalyzed, Site-Selective C–H Allylation of Indoles with Allyl Alcohols as Coupling Partners. Org. Lett. 2016, 18, 1112. e) Hu, X.-Q.; Hu, Z.; Trita, A. S.; Zhang, G.; Gooßen, L. J. Carboxylate-Directed C-H Allylation with Allyl Alcohols or Ethers. Chem. Sci. 2018, 9, 5289. (20) a) He, C.; Guo, S.; Huang, L.; Lei, A. Copper Catalyzed Arylation/C−C Bond Activation: An Approach toward α-Aryl Ketones. J. Am. Chem. Soc. 2010, 132, 8273. b) Ke, J.; He, C.; Liu, H.; Xu, H.; Lei, A. Alcohol Assisted C–C Bond Breaking: CopperCatalyzed Deacetylative α-Arylation of β-Keto Esters and Amides. Chem. Commun. 2013, 49, 6767. (21) Zhang, G.; Hu, Z.; Belitz, F.; Ou, Y.; Pirkl, N.; Gooßen, L. J. Rhodium-Catalyzed Annulation of Benzoic Acids with α,βUnsaturated Ketones with Cleavage of C−H, CO−OH, and C−C Bonds. Angew. Chem. Int. Ed. 2019, 58, 6435. (22) a) Guo, X.; Wang, J.; Li, C.-J. An Olefination via RutheniumCatalyzed Decarbonylative Addition of Aldehydes to Terminal Alkynes. J. Am. Chem. Soc. 2009, 131, 15092. b) Shuai, Q.; Yang, L.; Guo, X.; Baslé, O.; Li, C.-J. Rhodium-Catalyzed Oxidative C−H Arylation of 2-Arylpyridine Derivatives via Decarbonylation of Aromatic Aldehydes. J. Am. Chem. Soc. 2010, 132, 12212. (23) a) Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. IndiumCatalyzed Retro-Claisen Condensation. Angew. Chem., Int. Ed. 2007, 46, 7793. b) Hussein, M. A.; Huynh, V. T.; Hommelsheim, R.; Koenigs, R. M.; Nguyen, T. V. An Efficient Method for RetroClaisen-type C–C Bond Cleavage of Diketones with Tropylium catalyst. Chem. Commun. 2018, 54, 12970. (24) He, C.; Whitehurst, W. G.; Gaunt, M. J. Palladium-Catalyzed C(sp3)–H Bond Functionalization of Aliphatic Amines. Chem. 2019, 5, 1031.
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ACS Catalysis R
Sequential C-H and C-C activation cascade:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
N 1
C -C(O) cleavage
R1 R3
OEt
R
NH
R1
H Rh(III) 30 min
R
3
R OH
2
R1
a
NH2 C1
2
C R3
O R
2
R
N
C-Ha/N-H cleavage
O R1
OH
R2 R
isolatable intermediates
3
R N
2
3
C -C(R ) and C-C(O) cleavage O2
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R1 O
9
