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Nickel-Catalyzed Straightforward and Regioselective C-H Alkenylation of Indoles with Alkenyl Bromides: Scope and Mechanistic Aspect Rahul A. Jagtap, Chathakudath Prabhakaran Vinod, and Benudhar Punji ACS Catal., Just Accepted Manuscript • Publication Date (Web): 04 Dec 2018 Downloaded from http://pubs.acs.org on December 4, 2018
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ACS Catalysis
Nickel-Catalyzed Straightforward and Regioselective CH Alkenylation of Indoles with Alkenyl Bromides: Scope and Mechanistic Aspect Rahul A. Jagtap,†,‡ C. P. Vinod,§ and Benudhar Punji*,†,‡ †
Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, ‡Academy of Scientific and Innovative Research (AcSIR) and §Catalysis Division, CSIR–National Chemical Laboratory (CSIR–NCL), Dr. Homi Bhabha Road, Pune 411 008, Maharashtra, India
ABSTRACT: Nickel-catalyzed regioselective CH bond alkenylation of indoles and related heteroarenes with alkenyl bromides is accomplished under relatively mild conditions. This method allows the straightforward synthesis of C-2 alkenylated indoles employing an air-stable and well-defined nickel catalyst, (bpy)NiBr2, providing a solution to the limitations associated with hydroindolation and oxidative alkenylation. The reaction conceded the coupling of indole derivatives with various alkenyl bromides, such as aromatic and heteroaromatics, - and -substituted as well as exo- and endo-cyclic alkenyl compounds. An extensive mechanistic investigation, including controlled study, reactivity experiments, kinetics and labeling studies, EPR and XPS analyses, highlights that the alkenylation proceeds through a single-electron transfer (SET) process comprising an odd-electron oxidative addition of alkenyl bromide. Further, the alkenylation operates via a probable Ni(I)/Ni(III) pathway involving the rate-limiting CH nickelation of indole. KEYWORDS: alkenylation, CH activation, indoles, mechanism, nickel, single-electron transfer
INTRODUCTION Indole represents a privileged heterocyclic motif that occurs in many biologically active natural products, medicinal compounds, and functional materials.1 Thus, regioselective direct CH bond functionalization of the indole ring is very crucial considering the development of diverse structural entities bearing this unique heterocyclic frame-work.2 Apart from nitrogen atom, the C-3 position of indole is the most reactive site for various electrophilic substitution reactions,3 however, recent development of the transition-metal-catalyzed CH bond functionalization has unraveled numerous methods for selective C(2)H functionalization.4 Amongst diverse C-2 functionalizations, such as arylation, alkylation, and benzylation of indoles;4 the alkenylation of indoles is of special interest owing to the involvement of alkenyl-functionality in a number of processes including pericyclic reactions and macrocyclizations,5 in addition to the existence of alkenylated indoles in medicinal and natural products.6 Thus far, most of the C-2 alkenylation of indoles has been realized with relatively expensive noble-metal catalysts,7 such as rhodium,8 ruthenium,7b,9 and palladium.10 Yet, in recent years, considerable progress has been made employing naturally abundant firstrow transition-metal catalysts,11 including nickel.12 For example, alkenylation of indoles by Mn,13 Fe14 and Co15 catalysis has been independently reported by the groups of Matsunaga and Kanai, Yoshikai, Ackermann, Li, and others. Similarly, a nickel-catalyzed method for the alkenylation of indoles via hydroindolation is being demonstrated by Nakao and Hiyama,16 however, this method needs an electronwithdrawing substituent at the C-3 position of indole and uses
a highly sensitive Ni(cod)2/PCyp3 system, thus limiting the scope and generality of the methodology. Notably, most of the C-2 alkenylations have been accomplished through redoxneutral hydroindolation of alkynes (Scheme 1a) or oxidative coupling of indoles with alkenes, i.e., Fujiwara-Moritani (FM) type reaction (Scheme 1b). Despite significant advances, these approaches continue to face considerable limitations, including the difficulty in controlling regioselectivity, usage of the stoichiometric amount of secondary metal or peroxide oxidants and are restricted to alkenes bearing an electrondeficient group. A straightforward method to synthesize alkenylated indoles can be envisaged by the direct C(2)H bond alkenylation of indoles with alkenyl (pseudo)halides. In this direction, Ackermann has demonstrated a method for the coupling of indoles with alkenyl-enols via CH/CO activation employing cobalt catalysis (Scheme 1c).17 However, employment of an excess amount of the Grignard base, CyMgCl is essential for this method that limits the process. Unfortunately, there are no precedents on the direct alkenylation of indoles with alkenyl halides,18 not even using the noble metal catalysis. Therefore, the development of a straightforward method for the synthesis of C-2 alkenylated indoles employing a well-defined, inexpensive catalyst system based on naturally abundant first-row transition-metals, such as nickel, is highly desirable for the sustainability in modern organic synthesis. Herein, we report an efficient, straightforward approach for the regioselective alkenylation of indoles with various alkenyl bromides by the nickel catalysis (Scheme 1d). Noteworthy features of our strategy are an excellent predictable regiocontrol, oxidant-free functionalization, challenging CH alkenylation with unacti-
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vated alkenyl bromides using a defined, air-stable nickel catalyst, (bpy)NiBr2, under relatively mild reaction conditions. Additionally, a comprehensive substrates scope with regards to alkenyl bromides has been demonstrated, and an extensive mechanistic study, including control experiment, kinetic analysis, labeling study, and EPR and XPS analysis, has been performed to understand the reaction pathway.
Scheme 1. Strategies for CH Alkenylation of Indoles
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kenylation in solvents such as ortho-xylene, mesitylene, 1,4dioxane was less efficient than the reaction in toluene, which might be due to the disparity in solubility of the LiOtBu and/or Ni-precursor (entry 14, Table 1; and Table S1 in the Supporting Information). Surprisingly, the isolated nickel complex (bpy)NiBr2 (1) as catalyst under the optimized conditions in toluene afforded 50% yield of 6aa (synthesis and characterization of the catalyst are described vide infra). However, the alkenylation reaction using catalyst 1 was highly efficient when 1,4-dioxane was used as a solvent, and the reaction yielded 85% of 6aa at 150 oC (entry 16). Notably, the reaction afforded quantitative yield (84%) even at 120 oC though it needs 24 h for the completion (entry 17). Other bpy derived complexes [(bpy)3Ni]NiBr4 (2) and (bpy)2NiBr2 (3) were found to be as effective and afforded a good yield of the alkenylation product 6aa (entries 18, 19). Lowering the catalyst loading led to a decrease in the yield of product 6aa (entry 20). A nickel catalyst is essential for the reaction, without which no coupling product was observed (entry 21). Under the optimized reaction conditions, only traces (< 5%) of homo-coupled products of indole 4a and alkenyl bromide 5a were observed, even with the increasing loading of catalyst 1. Considering the well-defined nature of 1, the scope and mechanistic studies were performed employing complex 1 in 1,4-dioxane at 120 o C.
RESULTS AND DISCUSSION Optimization of Reaction Conditions. We initially examined the alkenylation of 1-(pyridin-2-yl)-1H-indole (4a) with (2-bromovinyl)benzene (5a, E:Z = 98:2) employing nickel catalyst precursors with or without added phosphine ligands in the presence of LiOtBu in toluene (Table 1, entries 1-4; for detailed optimization, see Table S1 in the Supporting Information). The use of sole nickel precursors (diglyme)NiBr2 or (thf)2NiBr2 as catalyst did not produce alkenylated product (E)-1-(pyridin-2-yl)-2-styryl-1H-indole (6aa), however, employment of the phosphine ligands, such as dppm, dppf along with (thf)2NiBr2 afforded trace amount of 6aa. Notably, the alkenylation reaction using nitrogen-donor ligand 1,10phenanthroline (phen) with (thf)2NiBr2 afforded 6aa in 47% yield (entry 5). The nitrogen-containing ligand might essential in stabilizing the organometallic intermediates during the catalytic process. Surprisingly, the alkenylation reaction produced a good yield of 6aa (71%) upon employing 2,2’-bipyridine (bpy) with (thf)2NiBr2 (entry 8). As the bpy/(thf)2NiBr2 catalyst system delivered satisfactory yield for the alkenylation, we screened several other nickel precursors, such as (diglyme)NiBr2, (CH3CN)2NiBr2 and Ni(cod)2 along with added bpy ligand, wherein a similar or slightly lower activity was observed (entries 9-11). Interestingly, better efficiency of the Ni(II) precursors than a Ni(0) system seems more advantageous due to the stability issues associated with the later. Al-
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ACS Catalysis
Table 1. Optimization of the Reaction Conditions a
entry
[Ni]
ligand
base
solvent
1
(diglyme)NiBr2
--
LiOtBu
toluene
6aa (%)b --
2
(thf)2NiBr2
--
LiOtBu
toluene
--
t
3
(thf)2NiBr2
dppm
LiO Bu
toluene
trace
4
(thf)2NiBr2
dppf
LiOtBu
toluene
trace
t
5
(thf)2NiBr2
phen
LiO Bu
toluene
47
6
(thf)2NiBr2
LiOtBu
toluene
26
7
(thf)2NiBr2
LiOtBu
toluene
trace
LiO Bu
toluene
71c
8
(thf)2NiBr2
batho cuproine neo cuproine bpy
9
(diglyme)NiBr2
bpy
LiOtBu
toluene
69
10
(CH3CN)2NiBr2
bpy
LiOtBu
toluene
65
t
60
t
11
Ni(cod)2
bpy
LiO Bu
toluene
12
(thf)2NiBr2
bpy
Na2CO3
toluene
--
13
(thf)2NiBr2
bpy
K3PO4
toluene
--
14
(thf)2NiBr2
bpy
LiOtBu
1,4-dioxane
69
15
cat. 1
--
LiOtBu
toluene
50
16
cat. 1
--
LiOtBu
1,4-dioxane
85c
17
cat. 1
--
LiO Bu
1,4-dioxane
84 c,d
18
cat. 2
--
LiOtBu
1,4-dioxane
82 c,d
19
cat. 3
--
LiOtBu
1,4-dioxane
79 c,d
20
cat. 1
--
LiOtBu
1,4-dioxane
64d,e
1,4-dioxane
--
21
--
--
t
t
LiO Bu
a Reaction Conditions: 4a (0.058 g, 0.3 mmol), 5a (0.110 g, 0.6 mmol), [Ni] precursor (0.015 mmol, 5 mol %), ligand (0.015 mmol, 5 mol %), LiOtBu (0.048 g, 0.6 mmol), solvent (1.0 mL). Catalyst 1 (0.0056 g, 0.015 mmol), catalyst 2 (0.0068 g, 0.015 mmol), catalyst 3 (0.0079 g, 0.015 mmol). bGC yield using ndecane as an internal standard. cIsolated yield. dReaction performed at 120 oC for 24 h. eEmploying 3.0 mol % of catalyst. dppm = 1,1-bis(diphenylphosphino)methane, dppf = 1,1'bis(diphenylphosphino)ferrocene, phen = 1,10-phenanthroline, bpy = 2,2’-bipyridine.
Effect of the N-Substituents of Indoles on Alkenylation. We have investigated the effect of the nitrogen substituents of indole on the C-2 alkenylation reaction employing various Nprotected indoles with alkenyl bromide 5a (Scheme 2). All the reactions were performed using catalyst 1 (5 mol %) in the presence of LiOtBu in 1,4-dioxane at 120 oC. As optimized before, the reaction of N-(2-pyridyl)-indole (4a) with 5a exclusively afforded the C-2 olefinated product 6aa in 84% yield. Similarly, the 2-pyrimidinyl as a nitrogen substituent in the substrate N-(2-pyrimidinyl)-indole reacted efficiently to produce desired product 6ga in 81% yield. To understand the directing (coordinating) ability versus the electronic impact of the N-substitution of indole, the N-(4-pyridyl)-indole was subjected to the alkenylation reaction, wherein coupling was not observed suggesting the role of N-substitution as a directing (coordinating) group rather than the electronic influence of the same. Additionally, the indole bearing thiophenyl or sulphonyl as N-substituent directing group did not afford the alkenylation product highlighting that strong -donor nitrogen coordination is essential for the nickel catalyzed alkenylation of indole. Notably, the indole containing a –COtBu group as N-substituent undergone base-assisted N-deprotection and subsequent nickel-catalyzed N-alkenylation to deliver (E)-1styryl-1H-indole in 92% yield (Scheme 2). As expected, the N-methyl indole did not produce the alkenylation, and a C-2 substituted N-pyridinyl indole unable to deliver the C-3 or C-7 alkenylated product. All these observations indicate that a nitrogen donor substituent at the N-atom of indole is essential, and under the optimized conditions a C-2 selective alkenylation is highly feasible. Scheme 2. Effect of Directing Group on Alkenylation
Synthesis and Characterization of Nickel Catalysts. As the nickel precursor (thf)2NiBr2 with added bpy ligand efficiently catalyzes the alkenylation of 1-(pyridin-2-yl)-1Hindole (4a) with (2-bromovinyl) benzene (5a), we were curious to identify the type of nickel complex formed during this process. Besides, we also wanted to know the activity of isolated nickel complex during the catalytic process. In that vein, we have performed the reaction of (thf)2NiBr2 with 1.0 equiv of bpy in THF at room temperature, which afforded complex (bpy)NiBr2 (1)19 as a light green solid (see Figure S1 in the Supporting Information). However, the treatment of
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(thf)2NiBr2 with 2.0 equiv of bpy produced [(bpy)3Ni].NiBr4 (2) in quantitative yield.20 Both the complexes 1 and 2 are NMR silent, and hence, were characterized by elemental analysis. Compound 2 could exist as a mixture of (bpy)2NiBr2 and (bpy)NiBr2. We have recently demonstrated the synthesis and characterization of similar complexes of 1,10-phenanthroline ligand.21 The composition of all the nickel complexes was analyzed by elemental analysis. The complex 3 was synthesized following the literature procedure.22 Substrate Scope for the Alkenylation of Indoles. After an extensive screening of all the reaction parameters including various nickel precursors and nickel complexes 1-3 for the alkenylation of indole, we started substrate scope for the alkenylation reaction with diversely substituted indoles and other azoles (Scheme 3). Indoles bearing alkyl (Me) and alkoxy (OMe) moieties at C-5 position reacted smoothly with (E)(2-bromovinyl) benzene (5a) to yield the desired C-2 alkenylated products 6ba and 6ca in 82% and 86%, respectively. Indole containing C-5 fluoro group is less reactive and requires 10 mol % loading of catalyst to achieve a good yield of 6da. The 5-Cl and 5-Br indoles reacted with low pace to deliver the products 6ea and 6fa in 57% and 32% yields, respectively; which is crucial for potential post-functionalization. As discussed before, the indoles bearing easily removable 2pyrimidinyl group reacted smoothly to deliver the desired products (6ga-ia) in good yields. Sterically hindered C-3 substituted indole 4j and 4k were alkenylated in moderate activity to give 6ja and 6ka, respectively. Unfortunately, the indoles bearing electron-withdrawing groups, such as −CN, −CHO, −NO2 at the C-3 or C-5 positions did not undergo alkenylation reaction under the optimized reaction conditions. The benzyloxy substituted indole 4l and azaindole 4m reacted in moderate activity to produce the alkenylation products 6la and 6ma in 57% and 59% yields, respectively. Additionally, a pyrazole derivative 4n could be easily alkenylated to afford the C5 alkenylation product 6na in 65% yield. In general, the present alkenylation protocol is highly selective to the C(2)−H functionalization, and the C(3)−H and C(7)−H bonds remained untouched, and provided access to the diversely substituted indole derivatives.
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Scheme 3. Substrate Scope for Alkenylation of Indole Derivativesa
a Conditions: Substrate 4 (0.30 mmol), 5a (0.110 g, 0.60 mmol), LiOtBu (0.048 g, 0.60 mmol), cat. 1 (0.0056 g, 0.015 mmol, 5.0 mol %), 1,4-dioxane (1.0 mL). Yield of isolated compound. b10 mol % of catalyst 1 was employed.
Further, the feasibility of the alkenylation reaction of 2-py or 2-pym substituted indoles with diversely substituted β-bromo alkenes was investigated (Scheme 4). Thus, the β-bromo olefins bearing a variety of substituents on the aromatic rings were subjected for alkenylation, which afforded C-2 olefinated indoles 6ab-6ag in good to excellent yields with exclusive Estereochemistry. The 2-pym substituted indole 4g reacted with good activity; whereas the C-3 substituted indoles, 4j and 4k afforded moderate yields of 6jc and 6kc. It is important to note that a heteroarene such as thiophenyl moiety tolerated under the optimal reaction condition to provide 43% of product 6ah. We next turned our attention to the sterically hindered αsubstituted bromo olefins. It was found that α-bromo styrene reacts smoothly with indole 4a and delivers the product 6ai in 69% yield. In addition to the aromatically substituted bromo olefins, electronically-rich α-substituted bromo alkene such as 2-bromopropene reacted to produce 50% of desired product 6aj. Interestingly, a SiMe3 group at the α-position is tolerated under the optimized reaction condition, which could be high synthetic importance. Further, the scope of the alkenylation is extended to endocyclic and exocyclic alkenes, which deliver the products 6al and 6am in low to moderate yields. Notably, the alkenylation proceeded in a regio specific manner affording E-stereomers exclusively in good yields. Generally, the similar regioselectively substituted products 6 are less common through hydroindolation of alkynes or oxidative alkenylations.
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ACS Catalysis
Scheme 4. Scope with Various Alkenyl Bromidesa H
H H + Br
R2
N R1
4
cat. 1 (5 mol %) LiOtBu (2 equiv) 1,4-dioxane 120 oC, 24 h
N
5
R1
6
R2
R2
OMe
N
Me
N
2-py
OMe
2-pym
2
R = Me, (6ab): 71% R2 = OMe, (6ac): 76% R2 = F, (6ad): 67% R2 = Cl, (6ae): 62% 2 R = Ph, (6af): 70%
N
6gc: 64%
R1 R1 = 2-py, (6jc): 44% R1 = 2-pym, (6kc): 45% S N
O
N
Ph N
2-py
2-py
N
R3
2-py 3
b
50% R = Me (6aj): R3 = SiMe 3 (6ak): 50% b
6ai: 69%
6ah: 43%
6ag: 58%
Ph
2-py
N
N
2-py
2-py
6al: 53%
6am: 17%
a
Conditions: Substrate 4 (0.30 mmol), alkenyl bromide 5 (0.60 mmol), LiOtBu (0.048 g, 0.60 mmol), cat. 1 (0.0056 g, 0.015 mmol), 1,4-dioxane (1.0 mL). Yield of isolated compound. bYield determined by 1H NMR.
MECHANISTIC CONSIDERATIONS Kinetics Analysis of Alkenylation. Considering the excellent activity of nickel catalyst (bpy)NiBr2 (1) for the alkenylation of indoles with alkenyl bromides, we have performed detailed mechanistic studies to know the working mode of the catalyst and to gain information about the catalytic process. Initially, we performed kinetic analysis of the nickel-catalyzed alkenylation reaction. In the standard rate measurement, a Teflon screw cap vessel was introduced with catalyst 1 (0.0056 g, 0.015 mmol, 0.015 M), LiOtBu (0.048 g, 0.60 mmol), alkenyl bromide 5a (0.110 g, 0.60 mmol, 0.60 M), indole 4a (0.058 g, 0.30 mmol, 0.30 M) and n-decane (0.030 mL, 0.154 mmol; internal standard). 1,4-Dioxane (0.9 mL) was added to the reaction vessel to make the total solution to 1.0 mL. The tube containing the reaction mixture was heated at 120 oC in a preheated oil bath, and the reaction progress was monitored by gas chromatography at regular intervals (see, Table S2 and Figure S2(A) in the Supporting Information). Notably, the kinetic profile of the alkenylation shows a significant induction period, 1% of product 6aa detected only after 75 min and 0.015 M (TON = 1) of product formed at 150 min (Table S2), which highlights that the complex (bpy)NiBr2 is most likely a precatalyst and the active catalyst generation occurs during the initial period. Upon performing the reaction employing 15 mol % (0.045 M) of catalyst, the product formation was found to be consistent (1% and 2% product formed at 20 and 30 min, respectively; Figure S2B). Assuming the Ni(0) species might be the active catalyst, a standard alkenylation reaction was performed using Ni(COD)2/bpy under the optimized conditions at 120 oC, wherein 19% of 6aa was obtained
after 24 h. As the product formation was less using Ni(COD)2/bpy system, the kinetic experiment for the same was not conducted. All these observations highlight that a nickel(0)-species as an active catalyst is unlikely. The rate order of alkenylation reaction was determined to understand the effect of various reaction components on the alkenylation by the initial rate method. First, the rate order of the alkenylation reaction on indole 4a was determined by measuring the initial rate of reaction at different initial concentrations of 4a (0.15, 0.30, 0.60 and 1.20 M) employing 0.045 M of catalyst 1 (see Table S3 in the Supporting Information for details). As depicted in Figure S3, the rate of the alkenylation increases upon increased initial concentrations of 4a, and a slope of 1.09 was acquired from the plot of log(rate) versus log(conc. 4a) (Figure 1A). This observation highlights a crucial and divergent role of indole 4a in the alkenylation reaction. The reaction rates were almost comparable when different initial concentrations of alkenyl bromide 5a were used; demonstrating zeroeth order behavior with regards to the concentration of 5a (see Table S4 and Figure S4 in the Supporting Information). However, the rate of alkenylation was found to be inconsistent with different equivalents of LiOtBu. Notably, the rate of alkenylation reaction increases upon increased loadings of catalyst 1; (see Table S5 and Figure S5 in the Supporting Information) and a slope of 0.77 was obtained from the plot of log(rate) versus log(conc. 1) (Figure 1B). This finding highlights that the reaction is fractional order concerning the nickel catalyst 1. In light of the participation of catalyst in multiple steps during the alkenylation reaction, the observed rate order seems to be reasonable. Considering the positive fractional rate order with indole 4a and catalyst 1, the catalytic step involving the activation of indole 4a with cat 1 appears to be crucial. Further, the rate of the alkenylation reaction was measured using electronically distinct indoles and alkenyl bromides to illustrate the electronics effect of substrates on the reaction. As shown in Scheme 5a, the rate of alkenylation reaction is almost similar for both the electron-rich indole 4c (7.34 x 10-4 M min-1) and electron-deficient indole 4d (8.54 x 10-4 M min-1) (see Figure S6 in the Supporting Information for details). This finding rules out the probability of an electrophilic-type CH activation of indole.23 Notably, the rate of alkenylation using alkenyl bromide 5d (16.31 x 10-4 M min-1) is almost three-time faster than that employing an electron-rich alkenyl bromide 5c (5.19 x 10-4 M min-1) highlighting a reasonable reaction of alkenyl bromide towards a low-valent nickel-species (Scheme 5b, and Figure S7 in the Supporting Information). Considering the unlikeliness of Ni(0)-species being an active catalyst (discussed via supra), the probable reaction of alkenyl bromide towards a Ni(I)-species can be presumed.
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(A)
-2.6
log(rate)
-2.8 -3.0 -3.2 y = 1.0927 x -2.6549 2 R = 0.96668
-3.4 -3.6 -0.8
-0.6
-0.4
-0.2
0.0
0.2
log (conc. 4a)
-3.20
(B)
-3.25 -3.30 -3.35
log(rate)
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
-3.40 -3.45
y = 0.77355x -2.1567 2 R = 0.9380
-3.50 -3.55 -3.60 -1.9
-1.8
-1.7
-1.6
-1.5
-1.4
-1.3
log (conc. 1)
Figure 1. (A) Plot of log(rate) vs log(conc. 4a) and (B) plot of log(rate) vs log(conc. 1).
Scheme 5. Kinetic Analysis of Alkenylation with Electronically Distinct Substrates
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ture of new Ni-species that might have formed.19a,22 A stoichiometric reaction of indole 4a with (bpy)NiBr2 in the presence of LiOtBu at 120 oC resulted in the exclusive formation of 1,1'di(pyridin-2-yl)-1H,1'H-2,2'-biindole (self-coupling of 4a), which disrupt the isolation of a possible intermediate (bpy)Ni(2-indolyl-2-pyridine). However, this Ni-species was detected by the MALDI-TOF analysis of the reaction mixture. The oxidative self-coupling of indole could occur via the Ni(II)-mediated process in the presence of LiOtBu. Notably, self-coupling of indole was negligible in the presence of electrophile 5a during the standard alkenylation conditions. The treatment of 5a with (bpy)NiBr2 in the presence of LiOtBu at 120 oC did not lead to any product, and alkenyl bromide 5a was recovered. This indicates that the nickel-species react with the indole 4a prior to the electrophile 5a. Next, we probed the reactivity pattern of alkenyl bromide with the nickel-species under catalytic conditions. The alkenyl bromide would react with nickel species in three different ways: coordinative insertion, one-electron oxidation (halideatom transfer) or two-electron oxidative addition pathway. Notably, the independent catalytic alkenylation reaction of indole 4a with (E)-(2-chlorovinyl)benzene or with styrene did not afford the alkenylation product 6aa. This finding suggests that the alkenylation reaction via a coordinative insertion/halide elimination approach of (E)-(2-halovinyl)benzene is unlikely because the (E)-(2-chlorovinyl)benzene could have delivered the desired product if the reaction proceeds through a coordinative pathway.21 Additionally, the electrophile (Z)-(2bromovinyl)benzene affords only a trace of the alkenylated product upon treatment with 4a, supporting the observations that the coordinative insertion reaction of alkenyl bromide with Ni-species is extremely remote. Surprisingly, the reaction of indole 4a with (E)-(2-iodovinyl)benzene under the catalytic conditions unable to afford the product 6aa, ruling out a twoelectron oxidative addition approach of (E)-(2halovinyl)benzene towards nickel enter. Considering our inability to detect a diamagnetic nickel species during NMR analysis, we presumed the occurrence of a single-electron reaction pathway of alkenyl bromide with the nickel catalyst. Probing Radical Pathway. The standard alkenylation reaction of 4a in the presence of radical inhibitor TEMPO was suppressed entirely, whereas in the presence of galvinoxyl the reaction afforded 17% of coupled product 6aa (Scheme 6). These observations highlight a single-electron pathway for the reaction. Notably, we could not detect any coupled product arising from the reaction of TEMPO or galvinoxyl with alkenyl bromide 5a. Although the TEMPO or galvinoxyl are known to react with organic radicals, it has also been demonstrated that the TEMPO can interact with Ni(I) species leading to a TEMPO-bound Ni(II) species,24 thus suppressing a reaction catalyzed by an odd-electron active nickel catalyst.
Controlled Reactivity Studies. The alkenylation reaction was monitored by 1H NMR employing 25% of catalyst 1 in toluene-d8 to detect any observable nickel-intermediates. Unfortunately, neither the nickel-species nor the free-ligand was encountered in the NMR-tube reaction. Inability to observe any diamagnetic nickel containing species is likely due to the tetrahedral geometry of (bpy)NiBr2 and/or paramagnetic na-
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Scheme 6. External Additive Experiments
that the CH nickelation is very crucial and most likely the turnover-limiting step during the alkenylation.29 This observation is complemented by the observed rate order with indole 4a and catalyst 1, wherein a significant influence of substrate 4a was observed during the reaction. Further, the H/D scrambling was not observed upon performing a reaction of [2-D]4a and 4c (in the absence or presence of alkenyl bromide) in the same reaction vessel for early reaction time (Scheme 7b). This discloses that the CH activation is an irreversible process and does not occur via a simple deprotonationmetalation pathway.
Electron Paramagnetic Resonance Studies. The EPR experiments have been carried out on a frozen aliquot of the incomplete reaction between indole 4a, alkenyl bromide 5a, (bpy)NiBr2 (1) and LiOtBu, which confirmed the presence of a nickel-bound organic radical. The g-factor of the cross-over point of the peak was found to be 2.057 (Figure 2). The spectrum was simulated with the Easyspin25 software. Unfortunately, the hyperfine splitting was not observed. The g-value found (2.057) is close to a nickel-bound organic free-radical,26 as the g-values for free-radical nature of an unpaired electron and Ni(III) are typically found in the range of 2.002-2.00427 and 2.15-2.2028 respectively. Thus, the intermediacy of a carboncentered radical of the alkenyl-nickel bound species can be presumed. EPR experiments on other controlled experiments, such as i) indole 4a + cat 1 + LiOtBu, ii) alkenyl bromide 5a + cat 1 + LiOtBu and iii) cat 1 + LiOtBu in 1,4-dioxane led to the signals that are too broad to make any meaningful judgment on the nature of radical species. The EPR analysis indicates that the presence of all the reaction components is essential for the intermediacy of a radical species.
exp sim
3000
3100
3200
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3400
3500
3600
3700
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Magnetic Field (G)
Figure 2. EPR spectrum of an incomplete alkenylation reaction mixture.
Deuterium Labeling Studies. The initial rates of alkenylation reactions employing indole 4a and indole [2-D]-4a were calculated independently, wherein the kinetic isotope effect (KIE) value was found to be 4.7 (Scheme 7a, and Figure S8 in the Supporting Information). The high KIE value indicates
Scheme 7. Deuterium Labeling Experiments
X-ray Photoelectron Spectroscopy Studies. The XPS analysis of the incomplete reaction mixture (between indole 4a, alkenyl bromide 5a, (bpy)NiBr2 (1) and LiOtBu) as well as other controlled reaction mixture has been carried out to determine the oxidation state of involved Ni-species. As shown in Figure 3(A), the Ni 2p3/2 XPS spectrum of starting complex (bpy)NiBr2 (1) displays a sharp peak centered around 855.7 eV, which can be assigned to Ni(II) complex. The corresponding 2p1/2 is also indexed at 873.6 eV (matching with a 17 eV separation between spin-orbit split) along with the satellite feature at 861 eV. The XPS spectrum of the incomplete reaction mixture between 4a, 5a, (bpy)NiBr2 (1) and LiOtBu also shows a peak centered around 855.7 eV thus suggesting a Ni(II)-species (see Figure S9(B) in the Supporting Information). Notably, in the case of the controlled reaction mixture between (bpy)NiBr2 (1), 4a and LiOtBu (in the absence of 5a), the XPS spectrum is much broader with a larger FWHM indicating multiple oxidation states (Figure 3(B)). Accordingly, two peaks could be fitted in the main 2p3/2 photoelectron peak at 853.4 eV and 855.7 eV. The later peak can be easily assigned to starting Ni(II)-species whereas the former (853.4 eV) has binding energy value higher than the Ni(0) (852.6 eV).30 Since the binding energy 853.4 eV is lower than the same observed for Ni(II), we can convincingly assign this as a Ni(I) intermediate formed during the process. XPS analyses of other controlled experiments, such as i) cat 1 + 5a + LiOtBu
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ACS Catalysis and ii) cat 1 + LiOtBu exhibit sharp peak around 855.7 eV indicating a Ni(II) complex (Figure S9(A) and S9(C) in the Supporting Information). All these experiments highlight that the reaction components (bpy)NiBr2 (1), 4a and LiOtBu are essential to generate an odd-electron Ni-species. Considering the trace formation of self-coupling of indole during the catalytic reaction, the initial formation of a Ni(0) species from the reaction of (bpy)NiBr2 (1) with 4a in the presence of LiOtBu can be assumed, which in turn can comproportionate with (bpy)Ni(II)Br2 (1) to produce a Ni(I) complex. This assumption is consistent with the observed induction period employing Ni(II) catalyst, and low reaction with a Ni(0) complex. (A): Cat 1 (experimental) (A): Cat 1 (peak fitting) (B): Cat 1 +4a +LiOtBu (experimental) (B): Cat 1 +4a +LiOtBu [(peak fitting, assigned to Ni(I)] (B): Cat 1 +4a +LiOtBu [(peak fitting, assigned to Ni(II)]
tron-rich Ni(I) center in B rather than with the species A in the first step, which is also consistent with the high reaction rate of electron-deficient alkenyl bromide. Intermediate C would undergo homolytic CBr cleavage and a one-electron oxidative addition to afford Ni(III) complex D. Reductive elimination of product 6aa from D will regenerate the active catalyst A. Intermediates B and D were identified by the MALDI-TOF analysis of an incomplete stoichiometric reaction. Our experimental studies strongly support all the elementary steps discussed here. Though, many reports suggest the mechanistic proposal on the Ni-catalyzed CH functionalization,34 the demonstration of a comprehensive mechanistic study is rare. Herein, we have explicitly established a unified mechanism for the Ni-catalyzed CH alkenylation that proceeds via the Ni(I)/Ni(III) pathway involving a single-electron transfer (SET) process. (bpy)NiBr2 + 4a
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N
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LiBr + tBuOH
(A) Ph
(B)
N
N N
Br
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N
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Figure 3. X-ray photoelectron spectra: (A) (bpy)NiBr2 (1) and (B) reaction mixture containing 1, 4a and LiOtBu.
Probable Catalytic Cycle. Considering our mechanistic findings and related literature reports,31 we have proposed a plausible mechanism for the Ni-catalyzed alkenylation of indole with alkenyl bromide (Figure 4). A portion of catalyst (bpy)NiBr2 (1) in the presence of LiOtBu and 4a undergo reduction to Ni(0), followed by comproportionation with (bpy)NiBr2 (1) to form an active catalyst (bpy)Ni(I)Br (A).32 Observation of trace self-coupling of indole 4a supports the probable formation of (bpy)Ni(0) that would comproportionate with (bpy)NiBr2 to form A, later of which is confirmed by XPS analysis. The indole 4a reacts with the active catalyst A in the rate-limiting CH nickelation step to deliver intermediate B. The species B would trigger the radical formation on alkenyl bromide 5a and undergo a one-electron oxidation to produce intermediate C. Experiments and EPR analysis strongly support the single-electron transfer (SET) pathway and involvement of a metal-bound carbon-centered radical. Notably, the use of -bromoalkene would lead to a relatively less stable primary radical corresponding to intermediate C. Nevertheless, the intermediacy of similar primary radicals has extensively been demonstrated in the alkylation mechanism; hence, intermediate C is evident enough to propose.31c,d,33 We assume that alkenyl bromide 5a would react with a more elec-
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Br
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Binding Energy (eV)
N N (B)
(D)
850
(I)
Ni
N
Ni
Ph
Br (5a)
Ni N
N (C)
Figure 4. Plausible mechanistic pathway for alkenylation catalyzed by (bpy)NiBr2 (1).
Gram Scale Synthesis and Synthetic Utility. Given the significant importance of the C-2 alkenylated indole, we have scaled up the synthesis of compound 6ga (Scheme 8). Thus, the compound 4g (1.0 g) was treated with alkenyl bromide 5a (1.86 g) under the optimized conditions to afford product 6ga in 76% isolated yield. The scaling up of the compound 6ga was performed as this compound bears a trace and easily removable directing group. Further, we have demonstrated the removal of 2-py and 2-pym directing groups from the alkenylated indoles,35 as the free NH alkenylated indole could bring more synthetic values (Scheme 9). Hence, the treatment of 6aa with MeOTf and NaOH in dichloromethane and MeOH in succession afforded the free NH alkenylated indole 7aa. In a similar vein, the 2-pym group on 6ga was smoothly deprotected using NaOEt in DMSO to produce 7aa in good yield. This free N-H C-2 alkenylated indole can be readily functionalized at C(3)H and N-H to synthesize biologically active intermediates.
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Scheme 8. Gram Scale Synthesis of Alkenylated Indole
AUTHOR INFORMATION Corresponding Author *E-mail for B.P.:
[email protected].
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENTS
Scheme 9. Removal of Directing Groups
This work was financially supported by SERB, New Delhi, India (EMR/2016/000989). R.A.J. thanks UGC-New Delhi for a research fellowship. We are thankful to Prof. Debabrata Maiti (IIT, Bombay) for his help on EPR analysis. We are grateful to Dr (Mrs) Shanthakumari for HRMS and Dr. S.P. Borikar for GC-MS analysis.
REFERENCES CONCLUSION In summary, we have reported an efficient, straightforward method for the regioselective C-2 alkenylation of indoles catalyzed by an air-stable, inexpensive and well-defined nickel complex (bpy)NiBr2. In this approach broad indole substrates, azaindole and pyrazole were regioselectively alkenylated with diverse alkenyl bromides under relatively mild reaction conditions. Many alkenyl bromides, such as aromatic and heteroaromatics, and -substituted as well as exo- and endo-cyclic alkenyl functionality were tolerated. Detailed mechanistic investigation of the alkenylation reaction by kinetics analysis, controlled reactivity and deuterium labeling studies, EPR and XPS analyses highlights that the reaction follows a singleelectron transfer (SET) pathway involving an odd-electron oxidative addition of alkenyl bromide. Mechanistic findings strongly support a Ni(I)/Ni(III) process for the reaction comprising the rate-limiting CH nickelation of indole. Synthetic utility of this nickel-catalyzed method is established by the demonstration of a gram-scale synthesis and by the facile removal of directing groups. We believe the Ni-catalyzed straightforward alkenylation, and the comprehensive mechanistic investigation demonstrated herein will provide a new avenue for the design and development of novel catalyst system for many other crucial CH functionalization.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publication website at DOI: 10.1021.acscatal.xxxxxx 13
Full experimental and characterization data, including 1H and C NMR of all compounds
(1) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry, 2nd ed.; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1996, 2, 119-206. (b) Gribble, G. W. Recent Developments in Indole Ring Synthesis-Methodology and Applications. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075. (c) Garg, N. K.; Sarpong, R.; Stoltz, B. M. The First Total Synthesis of Dragmacidin D. J. Am. Chem. Soc. 2002, 124, 13179-13184. (d) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893-930. (e) Chen, F.-E.; Huang, J. Reserpine: A Challenge for Total Synthesis of Natural Products. Chem. Rev. 2005, 105, 4671-4706. (f) Bandini, M.; Eichholzer, A. Catalytic Functionalization of Indoles in a New Dimension. Angew. Chem. Int. Ed. 2009, 48, 9608-9644. (g) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Variolins and Related Alkaloids. Chem. Rev. 2009, 109, 3080-3098. (h) KochanowskaKaramyan, A. J.; Hamann, M. T. Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010, 110, 4489-4497. (i) Zhou, G.; Wu, D.; Snyder, B.; Ptak, R. G.; Kaur, H.; Gochin, M. Development of Indole Compounds as Small Molecule Fusion Inhibitors Targeting HIV-1 Glycoprotein-41. J. Med. Chem. 2011, 54, 7220-7231. (j) Shiri, M. Indoles in Multicomponent Processes (MCPS). Chem. Rev. 2012, 112, 35083549. (k) Melander, R. J.; Minvielle, M. J.; Melander, C. Controlling Bacterial Behavior with Indole-Containing Natural Products and Derivatives. Tetrahedron 2014, 70, 6363-6372. (l) Lancianesi, S.; Palmieri, A.; Petrini, M. Synthetic Approaches to 3-(2-Nitroalkyl) Indoles and Their Use to Access Tryptamines and Related Bioactive Compounds. Chem. Rev. 2014, 114, 7108-7149. (2) For selected reviews on CH functionalization, see: (a) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed C-H Functionalization Reactions. Chem. Rev. 2010, 110, 1147-1169. (b) Ackermann, L. Carboxylate-Assisted Transition-Metal-Catalyzed C– H Bond Functionalizations: Mechanism and Scope. Chem. Rev. 2011, 111, 1315-1345. (c) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Towards Mild Metal-Catalyzed C-H Bond Activation. Chem. Soc. Rev. 2011, 40, 4740-4761. (d) Hirano, K.; Miura, M. Direct Carbon– Hydrogen Bond Functionalization of Heterocyclic Compounds. Synlett 2011, 294-307. (e) Han, W.; Ofial, A. R. No Detours: Palladium-Catalyzed Oxidative C–H/C–H Cross-Couplings of Heteroarenes. Synlett 2011, 1951-1955. (f) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Recent Advances in the Transition MetalCatalyzed Twofold Oxidative C–H Bond Activation Strategy for C–C and C–N Bond Formation. Chem. Soc. Rev. 2011, 40, 5068-5083. (g) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C–H Bond Functionalization: Emerging Synthetic Tools for Natural Products and
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Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960-9009. (h) Mercier, L. G.; Leclerc, M. Direct (Hetero)Arylation: A New Tool for Polymer Chemists. Acc. Chem. Res. 2013, 46, 1597-1605. (i) Zhang, F.; Spring, D. R. Arene C–H Functionalisation Using a Removable/Modifiable or a Traceless Directing Group Strategy. Chem. Soc. Rev. 2014, 43, 6906-6919. (j) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Recent Advances in Directed C–H Functionalizations Using Monodentate Nitrogen-Based Directing Groups. Org. Chem. Front. 2014, 1, 843-895. (k) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal Chemist's Toolbox for Late-Stage Functionalization of Drug-Like Molecules. Chem. Soc. Rev. 2016, 45, 546-576. (l) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Mild MetalCatalyzed C–H Activation: Examples and Concepts. Chem. Soc. Rev. 2016, 45, 2900-2936. (m) Wedi, P.; van Gemmeren, M. AreneLimited Nondirected CH Activation of Arenes. Angew.Chem. Int. Ed. 2018, 57, 13016-13027. (n) Tang, K.-X.; Wang, C.-M.; Gao, T.H.; Chen, L.; Fan, L.; Sun, L.-P. Transition Metal-Catalyzed CH Bond Functionalizations by Use of Sulfur-Containing Directing Groups. Adv. Synth. Catal. 2018, DOI:10.1002/adsc.201800484. (o) Yoshino, T.; Matsunaga, S. Cobalt-Catalyzed C(sp3)H Functionalization Reactions. Asian J. Org. Chem. 2018, 7, 1193-1205. (3) (a) Olah, G. A.; Khrishnamurti, R.; Prakash, G. K. S. in Comprehensive Organic Synthesis, 1st Ed. (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford 1991, 3, 293-335. (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Organocatalytic Strategies for the Asymmetric Functionalization of Indoles. Chem. Soc. Rev. 2010, 39, 4449-4465. (c) Dalpozzo, R. Strategies for the Asymmetric Functionalization of Indoles: An Update. Chem. Soc. Rev. 2015, 44, 742-778. (d) Joule, J. A. In Adv. Heterocyclic Chem.; Scriven, E. F. V., Ramsden, C. A., Eds.; Academic Press: 2016, 119, 81-106. (4) For selected reviews, see: (a) Joucla, L.; Djakovitch, L. Transition Metal-Catalysed, Direct and Site-Selective N1-, C2- or C3Arylation of the Indole Nucleus: 20 Years of Improvements. Adv. Synth. Catal. 2009, 351, 673-714. (b) Sandtorv, A. H. Transition Metal-Catalyzed C–H Activation of Indoles. Adv. Synth. Catal. 2015, 357, 2403-2435. (c) Leitch, J.; Bhonoah, Y.; Frost, C. G. Beyond C2 and C3: Transition-Metal-Catalyzed C–H Functionalization of Indole. ACS Catal. 2017, 7, 5618-5627. (d) Chen, J.; Jia, Y. Recent Progress in Transition-Metal-Catalyzed Enantioselective Indole Functionalizations. Org. Biomol. Chem. 2017, 15, 3550-3567. (5) (a) Luo, S.; Zificsak, C. A.; Hsung, R. P. Intramolecular Formal Aza-[3+3] Cycloaddition Approach to Indoloquinolizidine Alkaloids. A Stereoselective Total Synthesis of (±)-Tangutorine. Org. Lett. 2003, 5, 4709-4712. (b) Padwa, A.; Lynch, S. M.; Mejía-Oneto, J. M.; Zhang, H. Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles and Related Heteroaromatic Systems. J. Org. Chem. 2005, 70, 22062218. (c) Bergonzini, G.; Gramigna, L.; Mazzanti, A.; Fochi, M.; Bernardi, L.; Ricci, A. Organocatalytic Asymmetric Povarov Reactions with 2- and 3-Vinylindoles. Chem. Comm. 2010, 46, 327329. (d) Mei, G.-J.; Shi, F. Design and Application of 3-Alkyl-2Vinylindoles in Brønsted Acid Catalyzed Reactions. Synlett 2016, 27, 2515-2524. (6) (a) Rawat, M.; Wulff, W. D. Total Synthesis of Carbazoquinocin C: Application of the O-Benzannulation of Fischer Carbene Complexes to Carbazole-3,4-Quinone Alkaloids. Org. Lett. 2004, 6, 329-332. (b) Guella, G.; N'Diaye, I.; Fofana, M.; Mancini, I. Isolation, Synthesis and Photochemical Properties of Almazolone, a New Indole Alkaloid from a Red Alga of Senegal. Tetrahedron 2006, 62, 1165-1170. (c) Blanchard, S.; William, A. D.; Lee, A. C. H.; Poulsen, A.; Teo, E. L.; Deng, W.; Tu, N.; Tan, E.; Goh, K. L.; Ong, W. C.; Ng, C. P.; Goh, K. C.; Bonday, Z.; Sun, E. T. Synthesis and Evaluation of Alkenyl Indazoles as Selective Aurora Kinase Inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 2443-2447. (d) Dethe, D. H.; Erande, R. D.; Ranjan, A. Biomimetic Total Syntheses of Flinderoles B and C. J. Am. Chem. Soc. 2011, 133, 2864-2867. (7) For reviews, see: (a) Rossi, R.; Bellina, F.; Lessi, M. Alkenylation Reactions of Heteroarenes by Transition-Metal
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Catalysts. Synthesis 2010, 4131-4153. (b) Kozhushkov, S. I.; Ackermann, L. Ruthenium-Catalyzed Direct Oxidative Alkenylation of Arenes through Twofold C–H Bond Functionalization. Chem. Sci. 2013, 4, 886-896. (c) Petrini, M. Regioselective Direct CAlkenylation of Indoles. Chem. Eur. J. 2017, 23, 16115-16151. (8) (a) Patureau, F. W.; Glorius, F. Rh Catalyzed Olefination and Vinylation of Unactivated Acetanilides. J. Am. Chem. Soc. 2010, 132, 9982-9983. (b) Schipper, D. J.; Hutchinson, M.; Fagnou, K. Rhodium(III)-Catalyzed Intermolecular Hydroarylation of Alkynes. J. Am. Chem. Soc. 2010, 132, 6910-6911. (c) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.; Wang, B. Regioselective C2 Oxidative Olefination of Indoles and Pyrroles through Cationic Rhodium(III)-Catalyzed C– H Bond Activation. Chem. Eur. J. 2013, 19, 11863-11868. (d) Tang, C.-Y.; Tao, Y.; Wu, X.-Y.; Sha, F. Rhodium(III)-Catalyzed Direct C2 Olefination of Unactivated Indoles Utilizing OH/NH2 as Directing Group. Adv. Synth. Catal. 2014, 356, 609-615. (e) Zhang, L.; Qiu, R.; Xue, X.; Pan, Y.; Xu, C.; Wang, D.; Wang, X.; Xu, L.; Li, H. Rh(I)Catalyzed Decarbonylative Direct C2-Olefination of Indoles with Vinyl Carboxylic Acids. Chem. Comm. 2014, 50, 12385-12388. (f) Sharma, S.; Han, S.; Kim, M.; Mishra, N. K.; Park, J.; Shin, Y.; Ha, J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Rh-Catalyzed Oxidative C–C Bond Formation and C–N Bond Cleavage: Direct Access to C2Olefinated Free (NH)-Indoles and Pyrroles. Org. Biomol. Chem. 2014, 12, 1703-1706. (g) Gong, B.; Shi, J.; Wang, X.; Yan, Y.; Li, Q.; Meng, Y.; Xu, H. E.; Yi, W. Rhodium(III)-Catalyzed Regioselective Direct C-2 Alkenylation of Indoles Assisted by the Removable N-(2Pyrimidyl) Group. Adv. Synth. Catal. 2014, 356, 137-143. (h) Sharma, S.; Han, S.; Shin, Y.; Mishra, N. K.; Oh, H.; Park, J.; Kwak, J. H.; Shin, B. S.; Jung, Y. H.; Kim, I. S. Rh-Catalyzed Oxidative C2Alkenylation of Indoles with Alkynes: Unexpected Cleavage of Directing Group. Tetrahedron Lett. 2014, 55, 3104-3107. (i) Xue, X.; Xu, J.; Zhang, L.; Xu, C.; Pan, Y.; Xu, L.; Li, H.; Zhang, W. Rhodium(III)-Catalyzed Direct C–H Olefination of Arenes with Aliphatic Olefins. Adv. Synt. Catal. 2016, 358, 573-583. (j) Zhou, C.N.; Xie, H.-H.; Zheng, Z.-A.; Xiao, Y.-C.; Li, G.; Shen, Y.-H.; Peng, W.-M.; Wang, L. Synthesis of Terminal Vinylindoles via Rh(III)Catalyzed Direct C–H Alkenylation with Potassium Vinyltrifluoroborate. Chem. Eur. J. 2018, 24, 5469-5473. (9) (a) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Ruthenium-Catalyzed Oxidative C–H Alkenylations of Anilides and Benzamides in Water. Org. Lett. 2012, 14, 728-731. (b) Padala, K.; Jeganmohan, M. Highly Regio- and Stereoselective Ruthenium(II)Catalyzed Direct Ortho-Alkenylation of Aromatic and Heteroaromatic Aldehydes with Activated Alkenes under Open Atmosphere. Org. Lett. 2012, 14, 1134-1137. (c) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.; Wang, B. Ruthenium-Catalyzed Regioselective C2 Alkenylation of Indoles and Pyrroles via C–H Bond Functionalization. J. Org. Chem. 2013, 78, 9345-9353. (d) Lanke, V.; Prabhu, K. R. Highly Regioselective C2-Alkenylation of Indoles Using the N-Benzoyl Directing Group: An Efficient Ru-Catalyzed Coupling Reaction. Org. Lett. 2013, 15, 2818-2821. (e) Zhang, L.-Q.; Yang, S.; Huang, X.; You, J.; Song, F. Aerobic Ru-Catalyzed Direct C2-Olefination of NHeteroarenes with Alkenes Directed by a Removable NDimethylcarbamoyl Group. Chem. Commun. 2013, 49, 8830-8832. (f) Liang, L.; Fu, S.; Lin, D.; Zhang, X.-Q.; Deng, Y.; Jiang, H.; Zeng, W. Ruthenium(II)-Catalyzed Direct Addition of Indole/Pyrrole C2–H Bonds to Alkynes. J. Org. Chem. 2014, 79, 9472-9480. (g) Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Electronic Nature of Ketone Directing Group as a Key to Control C-2 vs C-4 Alkenylation of Indoles. Org. Lett. 2016, 18, 5496-5499. (10) (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Palladium-Catalyzed Intermolecular Alkenylation of Indoles by Solvent-Controlled Regioselective C–H Functionalization. Angew. Chem. Int. Ed. 2005, 44, 3125-3129. (b) Capito, E.; Brown, J. M.; Ricci, A. Directed Palladation: Fine Tuning Permits the Catalytic 2Alkenylation of Indoles. Chem. Commun. 2005, 1854-1856. (c) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Regioselective C–H Functionalization Directed by a Removable Carboxyl Group:
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Palladium-Catalyzed Vinylation at the Unusual Position of Indole and Related Heteroaromatic Rings. Org. Lett. 2008, 10, 1159-1162. (d) García-Rubia, A.; Arrayás, R. G.; Carretero, J. C. Palladium(II)Catalyzed Regioselective Direct C2 Alkenylation of Indoles and Pyrroles Assisted by the N-(2-Pyridyl)Sulfonyl Protecting Group. Angew. Chem. Int. Ed. 2009, 48, 6511-6515. (e) García Rubia, A.; Urones, B.; Arrayás, R. G.; Carretero, J. C. PdII-Catalysed C–H Functionalisation of Indoles and Pyrroles Assisted by the Removable N-(2-Pyridyl)Sulfonyl Group: C2-Alkenylation and Dehydrogenative Homocoupling. Chem. Eur. J. 2010, 16, 9676-9685. (f) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Palladium-Catalyzed Oxidative C–H/C– H Cross-Coupling of Indoles and Pyrroles with Heteroarenes. Angew. Chem. Int. Ed. 2011, 50, 5365-5369. (g) Suarez, L. L.; Greaney, M. F. Tandem Indole C–H Alkenylation/Arylation for Tetra-Substituted Alkene Synthesis. Chem. Commun. 2011, 47, 7992-7994. (h) Yan, Z.L.; Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Wang, Y.-Q. Palladium-Catalyzed Intermolecular C-2 Alkenylation of Indoles Using Oxygen as the Oxidant. Adv. Synth. Catal. 2014, 356, 10851092. (i) Gemoets, H. P. L.; Hessel, V.; Noël, T. Aerobic C–H Olefination of Indoles via a Cross-Dehydrogenative Coupling in Continuous Flow. Org. Lett. 2014, 16, 5800-5803. (11) For reviews, see: (a) Kulkarni, A. A.; Daugulis, O. Direct Conversion of Carbon–Hydrogen into Carbon–Carbon Bonds by First-Row Transition-Metal Catalysis. Synthesis 2009, 4087-4109. (b) Su, B.; Cao, Z.-C.; Shi, Z.-J. Exploration of Earth-Abundant Transition Metals (Fe, Co, and Ni) as Catalysts in Unreactive Chemical Bond Activations. Acc. Chem. Res. 2015, 48, 886-896. (c) Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for C–H Activation. Chem. Rev. 2018, DOI: 10.1021/acs.chemrev.8b00507. (12) For selected reviews, see: (a) Yamaguchi, J.; Muto, K.; Itami, K. Recent Progress in Nickel-Catalyzed Biaryl Coupling. Eur. J. Org. Chem. 2013, 19-30. (b) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances in Homogeneous Nickel Catalysis. Nature 2014, 509, 299-309. (c) Castro, L. C. M.; Chatani, N. Nickel Catalysts/N,NBidentate Directing Groups: An Excellent Partnership in Directed CH Activation Reactions. Chem. Lett. 2015, 44, 410-421. (d) Yamaguchi, J.; Muto, K.; Itami, K. Nickel-Catalyzed Aromatic C–H Functionalization. Top. Curr. Chem. 2016, 374, 55. (e) Richmond, E.; Moran, J. Recent Advances in Nickel Catalysis Enabled by Stoichiometric Metallic Reducing Agents. Synthesis 2018, 50, 499-513. (13) (a) Shi, L.; Zhong, X.; She, H.; Lei, Z.; Li, F. Manganese Catalyzed C–H Functionalization of Indoles with Alkynes to Synthesize Bis/Tri Substituted Indolylalkenes and Carbazoles: The Acid Is the Key to Control Selectivity. Chem. Commun. 2015, 51, 7136-7139. (b) Zell, D.; Dhawa, U.; Müller, V.; Bursch, M.; Grimme, S.; Ackermann, L. C–F/C–H Functionalization by Manganese(I) Catalysis: Expedient (Per)Fluoro-Allylations and Alkenylations. ACS Catal. 2017, 7, 4209-4213. (c) Wang, C.; Rueping, M. Rhenium- and Manganese-Catalyzed Selective Alkenylation of Indoles. ChemCatChem 2018, 10, 2681-2685. (14) Wong, M. Y.; Yamakawa, T.; Yoshikai, N. Iron-Catalyzed Directed C2-Alkylation and Alkenylation of Indole with Vinylarenes and Alkynes. Org. Lett. 2015, 17, 442-445. (15) (a) Ding, Z.; Yoshikai, N. Mild and Efficient C2-Alkenylation of Indoles with Alkynes Catalyzed by a Cobalt Complex. Angew. Chem. Int. Ed. 2012, 51, 4698-4701. (b) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. Pyrroloindolone Synthesis via a Cp*CoIII-Catalyzed Redox-Neutral Directed C–H Alkenylation/Annulation Sequence. J. Am. Chem. Soc. 2014, 136, 5424-5431. (c) Wang, S.; Hou, J.-T.; Feng, M.-L.; Zhang, X.-Z.; Chen, S.-Y.; Yu, X.-Q. Cobalt(III)-Catalyzed Alkenylation of Arenes and 6-Arylpurines with Terminal Alkynes: Efficient Access to Functional Dyes. Chem. Comm. 2016, 52, 2709-2712. (d) Fallon, B. J.; Derat, E.; Amatore, M.; Aubert, C.; Chemla, F.; Ferreira, F.; PerezLuna, A.; Petit, M. C2-Alkylation and Alkenylation of Indoles Catalyzed by a Low-Valent Cobalt Complex in the Absence of Reductant. Org. Lett. 2016, 18, 2292-2295. (e) Zhou, X.; Luo, Y.;
Kong, L.; Xu, Y.; Zheng, G.; Lan, Y.; Li, X. Cp*CoIII-Catalyzed Branch-Selective Hydroarylation of Alkynes via C–H Activation: Efficient Access to Α-Gem-Vinylindoles. ACS Catal. 2017, 7, 72967304. (16) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. Hydroheteroarylation of Alkynes Under Mild Nickel Catalysis. J. Am. Chem. Soc. 2006, 128, 8146-8147. (17) Moselage, M.; Sauermann, N.; Richter, S. C.; Ackermann, L. C–H Alkenylations with Alkenyl Acetates, Phosphates, Carbonates, and Carbamates by Cobalt Catalysis at 23 °C. Angew. Chem. Int. Ed. 2015, 54, 6352-6355. (18) For selected examples on CH bond alkenylation of other (hetero)arenes using alkenyl halides, see: (a) Besselièvre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Stereoselective Direct CopperCatalyzed Alkenylation of Oxazoles with Bromoalkenes. Org. Lett. 2008, 10, 4029-4032. (b) Gottumukkala, A. L.; Derridj, F.; Djebbar, S.; Doucet, H. Alkenyl Bromides: Useful Coupling Partners for the Palladium-Catalysed Coupling with Heteroaromatics via a C–H Bond Activation. Tetrahedron Lett. 2008, 49, 2926-2930. (c) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. New and Efficient Palladium(0)-Mediated Microwave-Assisted Direct C3 Alkenylation of Imidazo[1,2-a]Pyridines. Synthesis 2008, 25372542. (d) Verrier, C.; Hoarau, C.; Marsais, F. Direct PalladiumCatalyzed Alkenylation, Benzylation and Alkylation of Ethyl Oxazole-4-Carboxylate with Alkenyl-, Benzyl- and Alkyl Halides. Org. Biomol. Chem. 2009, 7, 647-650. (e) Mousseau, J. J.; Bull, J. A.; Charette, A. B. Copper-Catalyzed Direct Alkenylation of NIminopyridinium Ylides. Angew. Chem. Int. Ed. 2010, 49, 1115-1118. (f) Sahnoun, S.; Messaoudi, S.; Brion, J.-D.; Alami, M. Pd/CuCatalyzed Direct Alkenylation of Azole Heterocycles with Alkenyl Halides. Eur. J. Org. Chem. 2010, 6097-6102. (g) Vabre, R.; Chevot, F.; Legraverend, M.; Piguel, S. Microwave-Assisted Pd/Cu-Catalyzed C-8 Direct Alkenylation of Purines and Related Azoles: An Alternative Access to 6,8,9-Trisubstituted Purines. J. Org. Chem. 2011, 76, 9542-9547. (h) Mahuteau-Betzer, F.; Piguel, S. Synthesis and Evaluation of Photophysical Properties of Series of Π-Conjugated Oxazole Dyes. Tetrahedron Lett. 2013, 54, 3188-3193. For Nicatalyzed alkenylation of heteroarenes other than indoles, see: (i) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. A Strategy for C−H Activation of Pyridines: Direct C-2 Selective Alkenylation of Pyridines by Nickel/Lewis Acid Catalysis. J. Am. Chem. Soc. 2008, 130, 2448-2449. (j) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. Nickel-Catalyzed Alkenylation and Alkylation of Fluoroarenes via Activation of C−H Bond over C−F Bond. J. Am. Chem. Soc. 2008, 130, 16170-16171. (k) Meng, L.; Kamada, Y.; Muto, K.; Yamaguchi, J.; Itami, K. C–H Alkenylation of Azoles with Enols and Esters by Nickel Catalysis. Angew. Chem. Int. Ed. 2013, 52, 10048-10051. (l) Lee, W.-C.; Shih, W.-C.; Wang, T.-H.; Liu, Y.; Yap, G. P. A.; Ong, T.-G. Nickel Promoted Switchable Hydroheteroarylation of Cyclodienes via C–H Bond Activation of Heteroarenes. Tetrahedron 2015, 71, 4460-4464. (19) (a) Broomhead, J. A.; Dwyer, F. P. Mono Complexes of 2,2'Bipyridine and 1,10-Phenanthroline with Metal Halides. Aust. J. Chem. 1961, 14, 250-252. (b) Khrizanforov, M.; Khrizanforova, V.; Mamedov, V.; Zhukova, N.; Strekalova, S.; Grinenko, V.; Gryaznova, T.; Sinyashin, O.; Budnikova, Y. Single-Stage Synthetic Route to Perfluoroalkylated Arenes via Electrocatalytic Cross-Coupling of Organic Halides Using Co and Ni Complexes. J. Organomet. Chem. 2016, 820, 82-88. (20) For similar Ni complexes, see: (a) Allan, J. R.; McCloy, B.; Paton, A. D. Thermal, Structural and Electrical Studies of the Chloro Complexes of Cobalt, Nickel and Copper with 1,10-Phenanthroline. Thermochimica Acta 1993, 214, 211-217. (b) Liu, L.; Zhang, X.; Liu, H.; Zhang, X.; Sun, G.; Zhang, H. Synthesis of Cationic Nickel(II) Compounds for Butadiene Polymerization. J. Appl. Polym. Sci. 2014, 131, 40511-40518. (21) (a) Khake, S. M.; Soni, V.; Gonnade, R. G.; Punji, B. A General Nickel-Catalyzed Method for C−H Bond Alkynylation of Hete-
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roarenes through Chelation Assistance. Chem. Eur. J. 2017, 23, 29072914. (b) Khake, S. M.; Jain, S.; Patel, U. N.; Gonnade, R. G.; Vanka, K.; Punji, B. Mechanism of Nickel(II)-Catalyzed C(2)–H Alkynylation of Indoles with Alkynyl Bromide. Organometallics 2018, 37, 2037-2045. (22) Harris, C. M.; McKenzie, E. D. Nitrogenous Chelate Complexes of Transition Metals-III: Bis-Chelate Complexes of Nickel (II) with 1,10-Phenanthroline, 2,2′-Bipyridyl and Analogous Ligands. J. Inorg. Nucl. Chem. 1967, 29, 1047-1068. (23) (a) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Room-Temperature Cyclometallation of Amines, Imines and Oxazolines with [MCl2Cp*]2 (M = Rh, Ir) and [RuCl2(P-Cymene)]2. Dalton Trans. 2003, 4132-4138. (b) Li, L.; Brennessel, W. W.; Jones, W. D. An Efficient Low-Temperature Route to Polycyclic Isoquinoline Salt Synthesis via C−H Activation with [Cp*MCl2]2 (M = Rh, Ir). J. Am. Chem. Soc. 2008, 130, 1241412419. (24) Chakraborty, U.; Urban, F.; Mühldorf, B.; Rebreyend, C.; de Bruin, B.; van Velzen, N.; Harder, S.; Wolf, R. Accessing the CpArNi(I) Synthon: Reactions with N-Heterocyclic Carbenes, Tempo, Sulfur, and Selenium. Organometallics 2016, 35, 1624-1631. (25) Stoll, S.; Schweiger, A. Easyspin, a Comprehensive Software Package for Spectral Simulation and Analysis in EPR. J. Mag. Reson. 2006, 178, 42-55. (26) (a) Adhikari, D.; Mossin, S.; Basuli, F.; Huffman, J. C.; Szilagyi, R. K.; Meyer, K.; Mindiola, D. J. Structural, Spectroscopic, and Theoretical Elucidation of a Redox-Active Pincer-Type Ancillary Applied in Catalysis. J. Am. Chem. Soc. 2008, 130, 3676-3682. (b) Zhou, Y.-Y.; Uyeda, C. Reductive Cyclopropanations Catalyzed by Dinuclear Nickel Complexes. Angew. Chem. Int. Ed. 2016, 55, 31713175. (27) (a) Chen, W.-C.; Hsu, Y.-C.; Shih, W.-C.; Lee, C.-Y.; Chuang, W.-H.; Tsai, Y.-F.; Chen, P. P.-Y.; Ong, T.-G. Metal-Free Arylation of Benzene and Pyridine Promoted by Amino-Linked Nitrogen Heterocyclic Carbenes. Chem. Commun. 2012, 48, 67026704. (b) Chen, J.; Wu, J. Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides. Angew. Chem. Int. Ed. 2017, 56, 39513955. (28) (a) Shimazaki, Y.; Tani, F.; Fukui, K.; Naruta, Y.; Yamauchi, O. One-Electron Oxidized Nickel(II)−(Disalicylidene)Diamine Complex: Temperature-Dependent Tautomerism between Ni(III)−Phenolate and Ni(II)−Phenoxyl Radical States. J. Am. Chem. Soc. 2003, 125, 10512-10513. (b) Zheng, B.; Tang, F.; Luo, J.; Schultz, J. W.; Rath, N. P.; Mirica, L. M. Organometallic Nickel(III) Complexes Relevant to Cross-Coupling and Carbon–Heteroatom Bond Formation Reactions. J. Am. Chem. Soc. 2014, 136, 6499-6504. (c) Xu, H.; Diccianni, J. B.; Katigbak, J.; Hu, C.; Zhang, Y.; Diao, T. Bimetallic C–C Bond-Forming Reductive Elimination from Nickel. J. Am. Chem. Soc. 2016, 138, 4779-4786. (29) Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope Effects in C–H Bond Functionalizations by Transition-Metal Complexes. Angew. Chem. Int. Ed. 2012, 51, 3066-3072. (30) Grosvenor, A. P.; Biesinger, M. C.; Smart, R. S. C.; McIntyre, N. S. New Interpretations of XPS Spectra of Nickel Metal and Oxides. Surf. Sci. 2006, 600, 1771-1779. (31) (a) Anderson, T. J.; Jones, G. D.; Vicic, D. A. Evidence for a NiI Active Species in the Catalytic Cross-Coupling of Alkyl Electrophiles. J. Am. Chem. Soc. 2004, 126, 8100-8101. (b) Lin, X.; Phillips, D. L. Density Functional Theory Studies of Negishi Alkyl– Alkyl Cross-Coupling Reactions Catalyzed by a MethylterpyridylNi(I) Complex. J. Org. Chem. 2008, 73, 3680-3688. (c) Lu, Z.; Wilsily, A.; Fu, G. C. Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl Chlorides. J. Am. Chem. Soc. 2011, 133, 8154-8157. (d) Dudnik, A. S.; Fu, G. C. Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles, Including Unactivated Tertiary Halides, to Generate Carbon–Boron Bonds. J. Am. Chem. Soc. 2012, 134, 10693-10697. (e) Zultanski, S.
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L.; Fu, G. C. Nickel-Catalyzed Carbon–Carbon Bond-Forming Reactions of Unactivated Tertiary Alkyl Halides: Suzuki Arylations. J. Am. Chem. Soc. 2013, 135, 624-627. For a review, see: (f) Hu, X. Nickel-Catalyzed Cross Coupling of Non-Activated Alkyl Halides: A Mechanistic Perspective. Chem. Sci. 2011, 2, 1867-1886. (32) (a) Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc. 2014, 136, 16588-16593. (b) Cao, Z.-C.; Xie, S.-J.; Fang, H.; Shi, Z.-J. Ni-Catalyzed Cross-Coupling of Dimethyl Aryl Amines with Arylboronic Esters under Reductive Conditions. J. Am. Chem. Soc. 2018, 140, 13575-13579 (33) (a) Soni, V.; Jagtap, R. A.; Gonnade, R. G.; Punji, B. Unified Strategy for Nickel-Catalyzed C-2 Alkylation of Indoles through Chelation Assistance. ACS Catal. 2016, 6, 5666-5672. (b) Soni, V.; Khake, S. M.; Punji, B. Nickel-Catalyzed C(sp2)-H/C(sp3)-H Oxidative Coupling of Indoles with Toluene Derivatives. ACS Catal. 2017, 7, 4202-4208. (c) Mai, W.-P.; Wang, F.; Zhang, X.-F.; Wang, S.-M.; Duan, Q.-P.; Lu, K. Nickel-Catalysed Radical Tandem Cyclisation/Arylation: Practical Synthesis of 4-Benzyl-3,3-Difluoro-Lactams. Org. Biomol. Chem. 2018, 16, 6491-6498. (34) (a) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Palladium- and Nickel-Catalyzed Direct Alkylation of Azoles with Unactivated Alkyl Bromides and Chlorides. Chem. Eur. J. 2010, 16, 12307-12311. (b) Ackermann, L.; Punji, B.; Song, W. User-Friendly [(Diglyme)NiBr2]Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through C–H Bond Cleavages. Adv. Synth. Catal. 2011, 353, 3325-3329. (c) Aihara, Y.; Chatani, N. Nickel-Catalyzed Direct Alkylation of C–H Bonds in Benzamides and Acrylamides with Functionalized Alkyl Halides via Bidentate-Chelation Assistance. J. Am. Chem. Soc. 2013, 135, 5308-5311. (d) Wu, X.-L.; Zhao, Y.; Ge, H. Nickel-Catalyzed Site-Selective Alkylation of Unactivated C(sp3)– H Bonds. J. Am. Chem. Soc. 2014, 136, 1789-1792. (e) Obata, A.; Ano, Y.; Chatani, N. Nickel-Catalyzed C-H/N-H Annulation of Aromatic Amides with Alkynes in the Absence of a Specific Chelation System. Chem. Sci. 2017, 8, 6650-6655. (35) (a) Tiwari, V. K.; Kamal, N.; Kapur, M. Ruthenium-Catalyzed Heteroatom-Directed Regioselective C–H Arylation of Indoles Using a Removable Tether. Org. Lett. 2015, 17, 1766-1769. (b) Ackermann, L.; Lygin, A. V. Ruthenium-Catalyzed Direct C–H Bond Arylations of Heteroarenes. Org. Lett. 2011, 13, 3332-3335.
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Table of Contents Graphic
Nickel-Catalyzed Straightforward and Regioselective CH Alkenylation of Indoles with Alkenyl Bromides: Scope and Mechanistic Aspect Rahul A. Jagtap, C. P. Vinod, and Benudhar Punji * R2 Br N
Br
N
Br
N
Ni N
[Ni]
R3 Ni N
N
base
H
H
R2 1
R
N
H + Br
[Ni] R3
base
2-py straightforward alkenylation
R1
R2
R3
N 2-py
phosphine-free, inxepensive, defined catalyst Ni(I)/Ni(III) pathway with SET process
high regioselectivity and excellent scope
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