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Cp*Co(III)-Catalyzed Branch-Selective Hydroarylation of Alkynes via C-H Activation#Efficient Access to #-gem-Vinylindoles Xukai Zhou, Yixin Luo, Lingheng Kong, Youwei Xu, Guangfan Zheng, Yu Lan, and Xingwei Li ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02248 • Publication Date (Web): 12 Sep 2017 Downloaded from http://pubs.acs.org on September 12, 2017
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Cp*Co(III)-Catalyzed Branch-Selective Hydroarylation of Alkynes via C-H Activation： ： Efficient Access to α-gem-Vinylindoles Xukai Zhou,†,§ Yixin Luo,‡ Lingheng Kong,†,§ Youwei Xu,†,§ Guangfan Zheng,† Yu Lan,*,‡ and Xingwei Li*,† †
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, China § University of Chinese Academy of Sciences, Beijing 100049, China ‡
ABSTRACT: An efficient, atom-economical, and regioselective insertion of indoles into terminal alkynes has been realized via cobalt(III)-catalyzed C-H activation under mild conditions, leading to efficient synthesis of α-gem-vinylindoles. The insertion of the alkynes follows a rare 1,2-selectivity, and silyl alkynes, alkyl alkynes, propargyl alcohols, and protected propargyl amines are all applicable. The mechanism of this hydroarylation system has been studied in details by a combination of experimental and computational approaches. In the reaction of silyl terminal alkynes, the regioselectivity is dictated by the steric effect of the alkyne substituent, especially in the protonolysis stage. However, for protected propargyl amines, the selectivity results from electronic effect during the insertion step, with protonolysis being insignificant in selectivity determining. An internal alkyne also coupled in high efficiency but with low regioselectivity. Comparisons of cobalt, rhodium, and iridium catalysts have also been made in terms of regioselectivity and reactivity, and both are high for cobalt catalysts. KEYWORDS: C-H activation, cobalt, indole, hydroarylation, alkyne insertion
■ INTRODUCTION Transition-metal-catalyzed C-H activation has received increasing attention in the synthesis of value-added organics owing to advantages of stepand atom-economy, environmental friendliness, and unnecessity of prefunctionalized substrates.1 In this context, hydroarylation of alkynes via a C-H activation pathway represents one of the most attractive transformations of arenes for synthesis of alkenes because of its 100% atom-economy, ready
availability of both the arene and alkyne starting materials, and redox-neutrality of the reaction conditions.2 For this transformation, most efforts have been devoted to noble metal catalysis, such as rhodium,3 ruthenium,4 palladium,5 and iridium.6 Thus for sustainability, it is necessary to develop more efficient systems with inexpensive and earth-abundant first-row transition-metal catalysts.7 Recently, Cp*Co(III) catalyst systems have received increasing attention due to its high Lewis acidity and small ionic
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radius in addition to its high activity as a transition metal catalyst for C-H activation.1f,1j,8 Important outcomes in this area have been recently reported by the groups of Kanai and Matsunaga,9 Glorius,10 Ackermann,11 Ellman,12 Chang,13 Li,14 Yu,15 and others.16 Alkynes as an important coupling partner have been widely used in construction of C-C bond via a C-H activation process.2d In most cases, the scope was usually limited to internal alkynes because terminal alkynes bear acidic protons and may undergo oligomerization or other side reactions which makes it difficult to function efficiently in hydroarylation reactions.17 Thus it is necessary to explore applicability of terminal alkynes. Compared to other transition metals, Cp*Co(III)-catalyzed systems seem more compatible with terminal alkynes in C-H activation systems although only limited systems have been achieved by the groups of Matsunaga/Kanai,9a Ackermann,11d Sundararaju,16d and Li.14a Besides reactivity and compatibility, the most important aspect of the coupling of unsymmetrical alkynes is the regioselectivity.2d In the coupling of arenes with commonly used alkyl, aryl-substituted internal alkynes in the presence of Cp*Co(III) catalysts1f,3a,7b,7c,9c or even low-valent cobalt catalysts18 (Scheme 1b), the insertion usually proceeds in such a selectivity that the metal ends up being adjacent to the phenyl group, which corresponds to 2,1-insertion. For a 1-alkyne, while selectivity of 2,1-insertion (C(aryl)-C(1) coupling) and 1,2-insertion (C(aryl)-C(2) coupling) might both be possible (Scheme 1a), the electronic and steric bias of the hydrogen and the substituent is more pronounced to allow higher regioselectivity. Although control of 1,2- versus 2,1-insertion has been well-studied for olefins19 in C-H activation systems, for 1-alkynes the vast majority undergoes 2,1-insertion because this is likely dominated by the electronic effect of the alkyne, with interaction and stabilization between the germinal M and R group in the transition state (Scheme 1a). Thus, the 1,2-insertion is highly rare.4f,20 Scheme 1. Hydroarylation of Alkyne via C-H Activation
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To explore the selectivity of alkyne insertion, we recently briefly reported a catalyst-controlled regiodivergent insertion of alkynes in the context of C-H activation and Diels-Alder reactions (Scheme 1c).14a In case of a Rh(III) catalyst, a common 2,1-migratory insertion of the Rh-aryl bond into the alkyne occurred. However, in case of Co(III) catalyst, an unexpected 1,2-insertion of the alkyne occurred with moderate regioselective. This is probably caused by the smaller ionic radius of Co(III) center which renders it more sensitive to steric perturbation. Despite this progress, the 1,2-regioselectivity is moderate in most cases (~3:1) and the hydroarylated product was not isolable. On the other hand, the site selectivity of arene C-H activation has also been well demonstrated by Matsunaga, Kanai and others in Cp*Co(III)-catalyzed C-H activation of unsymmetrical O-acyl oximes and other arenes.9a,9c,21 Although these systems reported important advances in site-selectivity with respect to arenes, the development of high regioselectivity with respect to 1,2-insertion of alkyne remains largely underexplored. As a continuation of our interest in catalyst-controlled regiodivergent alkyne insertion, we now report Co(III)-catalyzed C-H activation of N-pyrimidylindoles and selective 1,2-insertion into various terminal alkynes under mild reaction conditions (Scheme 1c). ■ RESULTS AND DISCUSSION Optimization Studies. On the basis of our recent work using propargylic alcohol-derived 1,6-enyne as a coupling partner for exploration of insertion selectivity,14a we reasoned that a simple propargylic alcohol might be employed to deliver a hydroarylation product. We initiated our studies with the coupling between N-pyrimidylindole 1a and
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propargyl alcohol 2a (Table 1). The coupling in the presence of Cp*Co(CO)I2 (5 mol %), AgSbF6 (10 mol %), and HOPiv (1 equiv) in DCE afforded the desired branched olefin 3aa as the major product in 76% total yield and with 10:1 regioselectivity (entry 1). Screening of solvent revealed that CF3CH2OH (TFE) was the optimal medium, affording product in 78% yield with excellent regioselectivity (entry 6), but other common solvents such as EtOH, MeOH, 1,4-dioxane and DMF were not viable (entry 2-5). Effects of the reaction temperature were then examined, and room temperature turned out to be optimal (82% yield), while coupling at 60 oC gave inferior results (entry 7-8). Control experiment revealed that no reaction occurred in the absence of the catalyst or HOPiv (entry 9-10). Reducing the amont of the HOPiv or replacement with NaOAc as an additive all gave inferior result (entries 11,12). Table 1. Optimization Studiesa
parenthesis was determined by 1H NMR spectroscopy. d No catalyst was used. eHOPiv was not used. fPivOH (0.5 equiv) was used. gThe HOPiv was replaced by NaOAc (30 mol %). Scheme 2. Substrate Scope of Alkynes.a,b,c
a
entry
T (oC)
solvent
yield (%)b
3aa:3aa’ c
1
40
DCE
76
10:1
2
40
EtOH
20:1
8
RT
TFE
82
> 20:1
9d
RT
TFE
0
-
10e
RT
TFE
0
-
11f
RT
TFE
77
>20:1
12g
RT
TFE
10
-
a
Reactions were carried out using CoCp*(CO)I2 (5 mol %), additive (25 mol %), HOPiv (1 equiv), indole 1a (0.1 mmol), and propargyl alcohol (0.15 mmol) in a solvent (1.0 mL) under N2 for 12 h. bIsolated yield of 3aa and 3aa’ as a mixture after column chromatography. cThe ratio of 3aa to 3aa’ in
Reactions were carried out using [Cp*Co(CO)l2] (5 mol %), AgSbF6 (10 mol %), HOPiv (1 equiv), indole 1a (0.2 mmol), and alkyne 2 (0.3 mmol) in TFE (3 mL) at room temperature for 12 h. bIsolated total yield after column chromatography and the major product could be isolated. cThe ratio of 3:3’ in parenthesis was determined by 1H NMR spectroscopy (3:3’>20:1 unless otherwise mentioned). Scope of Alkyne Substrates. With the optimized conditions in hand, the scope of the alkyne was then investigated (Scheme 2). Propargyl alcohols, propargyl ethers, and propargyl esters all reacted smoothly with 1a to furnish the corresponding α-gem-vinylindoles products as a the major product in 64−80% yields (3ab−3ae). The regioselectivity for propargyl ethers and esters was moderate, but the selectivity was excellent for simple and different 1,1-disubstitued propargyl alcohols (3aa, 3af-3ah). The high regioselectivity might be correlated to the hydrogen-bonding interaction with the TFE solvent. In the case of 1,1-disubstitued propargyl alcohols, the yields were only moderate because of further dimerization of cross-coupled product 4af (CCDC 1560049, see eq 1 and the Supporting Information).22 An internal propargyl alcohol also coupled in high total yield but with lower selectivity (3ai). To our delight, protected propargyl amines also underwent hydroarylation with 1a in good yield and regioselectivity (3aj, 3ak).
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Studies on the Steric Effects of Silyl Alkynes. Since the cobalt(III) catalyst are known to be more sensitive to steric perturbation, we then examined the insertion selectivity of a series of steric hindered silyl alkynes (Table 2). As expected, the coupling of alkynes bearing a very bulky triisopropylsilyl (TIPS) (2l) or tert-butyldimethylsilyl (TBDMS) (2m) group afforded exclusively the 1,2-insertion product. Decreasing the size of the silyl group to a TES or TMS consequently attenuated the selectivity of 1,2-insertion although the total yield of the product remianed excellent in all cases. The same trend was also observed for several alkyl substituted alkynes (3ap−3ar). Furthermore, acid additives of different sizes have been carefully examined in this system (for detailed information see Supporting Information). The acid with large steric effect such as 2,4,6-trimethylbenzoic acid could improve the regioslectivity in some cases (such as for the reaction of trimethylsilylacetylene) at the expense of the overall yield (Scheme 2 and the SI). However, the general applicability of this acid is not satisfactory. In contrast, exclusive trans-olefin products were obtained for phenylacetylene and ethyl propiolate (3as, 3at). Scope of Arenes. Subsequently, the scope of arene was explored with (triisopropylsilyl)acetylene (2l) as the coupling partner (Scheme 3). Different directing groups such as pyrimidyl, pyridyl, 1-pyrrolidinylformyl were compared and the pyrimidyl is the optimal choice (3al, 3bl), with no reactivity being observed for a urea directing group. With various electron-donating and –withdrawing groups at the C4-, C5-, and C6-positions of indoles,
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the coupling afforded the corresponding branched olefins in high to excellent yields (3cl-3pl). Of note, introduction of a substituent to the C7- and C3-position exerted maximal influence possibly due to steric effects. Thus, subjection of 3-methylindole to the standard conditions gave no alkenylation product, and the reaction of 7-ethylindole afforded 3ql in 57% yield, while the coupling of 7-fluoroindole afforded 3rl in good yield, indicating sensitivity of the Co catalyst toward steric perturbation at these positions. The arene substrate is not limited to indoles, a pyrrole and phenylpyridine were also viable substrates albeit with lower reactivity (3sl, 3tl). Scheme 3. Substrate Scope of Arene.a
a
See Scheme 2 for the detailed reaction conditions. bwith 1 mol % catalyst loading for 24 h. c45 oC, 24 h.
Table 2. Studies on the Steric and Electronic Effects of 1-Alkynesa,b
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See scheme 2 for detailed reaction conditions. bProducts were isolated as a mixture for 3an-3ar in the case of PivOH (only the branched product was indicated). cHOPiv was replaced by MesCO2H (0.5 equiv). a
Comparisons of Cobalt, Rhodium, and Iridium Catalysts. In order to further investigate and compare the catalytic activity of different group 9 Cp*M(III) catalysts, we selected the coupling of 1a and silyl alkyne 2l as the model reaction (Table 3). Under the standard conditions except using [RhCp*Cl2]2/AgSbF6 as the catalyst, although good selectivity for 3al was observed, the yields were inferior (entries 2 and 5). In contrast, the trans olefin 3al’ was exclusively obtained in 47% yield when a [IrCp*Cl2]2/AgSbF6 catalyst was used (entry 3). Moreover, when we moved to propargyl alcohol 2a, almost no reaction took place between 1a and 2a under iridium catalysis (entry 6). These differences in the reactivity among Cp*CoIII, Cp*RhIII, and Cp*IrIII catalysts probably reflect the difference in Lewis acidity and polarizing effect toward π-bonds.9a,9c,10a,14a Indeed, our recent studies showed that a Rh(III) catalyst was only effective for terminal alkynes of a 1,6-enyne entity, while its Co(III) congener was effective for both such terminal and internal alkynes.14a As for the differences in regioselectivity among these catalysts, the ionic radius may play a vital role in the selectivity of alkyne insertion. Table 3. Comparison of Cobalt, Rhodium, and Iridium Catalysis
+ N Pym 1a
R
[Cp*Co(CO)I2] (5 mol %) AgSbF6 (10 mol %)
N R Pym
HOPiv (1 equiv) TFE, RT, N2, 12 h
R
+
3a
2
N Pym 3a'
entry
conditionsa
R
yield (%)
1a/3/3’c
1
TIPS (2l) TIPS
84b
0/100/0
2
Standard Conditions Rh instead of Co
19c
81/19/0
3
Ir instead of Co
TIPS
47c
53/0/47
4
CH2OH (2a) CH2OH
82b
0/100/0
5
Standard Conditions Rh instead of Co
13c
87/13/0
6
Ir instead of Co
CH2OH
