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Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne Annulation Fan Xu, Yan-Jie Li, Chong Huang, and Hai-Chao Xu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00373 • Publication Date (Web): 09 Mar 2018 Downloaded from http://pubs.acs.org on March 9, 2018
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ACS Catalysis
Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne Annulation Fan Xu,† Yan-Jie Li,† Chong Huang, and Hai-Chao Xu* State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, Collaborative Innovation Center of Chemistry for Energy Materials, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005 (P. R. China) ABSTRACT: A ruthenium-catalyzed electrochemical dehydrogenative annulation reaction of aniline derivatives and alkynes has been developed for the synthesis of indoles. Electric current is used to recycle the active ruthenium-based catalyst and promote H₂ evolution. The electrolysis reaction is operationally convenient as it employs a simple undivided cell, proceeds efficiently in an aqueous solution, and is insensitive to air. KEYWORDS: electrochemistry, C–H activation, ruthenium, annulation, indole
Introduction Transition metal-catalyzed C–H activation reactions have significantly streamlined organic synthesis often by eliminating the need of substrate pre-functionalization. Particularly, dehydrogenative alkyne annulation has emerged as an enabling tool for the preparation of heterocycles.1 However, the method generally requires a stoichiometric amount of organic or metal-based oxidant, which is a common characteristic of oxidative C–H functionalization reactions. Like many other oxidative C–H functionalization reactions, these reactions usually employ stoichiometric amount of metal, such as CuII or AgI, or organic oxidants. The potential safety and environmental impacts of these oxidative reagents, consequently, have substantially limited the application scope and industrial utility of the C–H functionalization reactions.2 Electrosynthesis, which achieves redox reactions with traceless electric current, is an attractive synthetic tool3-9 and has led to the development of various oxidant-free dehydrogenative coupling reactions.10-21 Particularly, few elegant studies have achieved Pd-catalyzed electrochemical C–H activation to form C–C and C–heteroatom bonds (Scheme 1a).22-26 A common theme in these methodologies involves the use of divided cells to avoid the cathodic deactivation or decomposition of the metal catalysts. Very recently, Ackermann and coworkers reported Co-catalyzed electrochemical C–H functionalization reactions.27,28 Ruthenium is an attractive metal for C–H bond activation due to its excellent catalytic reactivity and relatively low cost when compared with Pd and Rh.29-32 Ru-catalyzed annulation reactions via C–H activation33,34 have been developed for the synthesis of various heterocyclic compounds including indoles (Scheme 1b).34 We have been interested in electrochemical dehydrogenative annulation reactions35,36 and have previously described the facile preparation of (aza)indoles via intramolecular C–H/N–H functionalization.35 Here we report a Rucatalyzed electrochemical C–H activation reaction using a simple undivided cell. Our method allows efficient access to
important indole products through (3+2) annulation of aniline derivatives with internal alkynes without the use of chemical oxidants (Scheme 1c). Previous work a) Electrochemical C–H activation/functionalization M
C H
C
X
M = Pd, Co b) CuII -mediated annulation by Ackermann (Ref. 34) R2
1
R
NH N
R2 cat. RuII
+ R3
N
R3
R1 N
Cu(OAc)2 (2 equiv)
N
N
This work c) Ru-catalyzed annulation via H2 evolution R2
R2
1
R
NH N
N
Ru
+
R3
R1 N
3
R
Undivided cell Annulation
N
+ H2
N
Scheme 1. Transition Metal-Catalyzed Electrochemical C– H Activation We began our study by optimizing the reaction conditions for the coupling of N-2-pyrimidyl substituted aniline 1 and diphenylacetylene 2 (Table 1). The 2-pyrimidyl group had been shown by Ackermann to be an effective and removable directing group for ruthenium catalyzed C–H functionalization reactions.34,37 The setup for the constant current electrolysis consisted of an undivided cell (a three-necked round-bottomed flask) equipped with a reticulated vitreous carbon (RVC) anode and a Pt plate cathode. The reaction was conducted using 2 equiv of 2 under reflux in the presence of 20 mol % of KPF638 and 20 mol % of NaOAc.33, 40-42 The salt additives also served as supporting electrolytes. Under these conditions, the annulation product 3 was formed in 37% yield after the con-
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sumption of 3.2 F mol−1 of electricity. A variety of organic cosolvents were tested (entries 2–6). Gratifyingly, the yield of 3 was boosted to 71% by using H2O/EtOH (1:1) as the solvent (entry 2). Other alcohols such as iPrOH (entry 3), tBuOH (entry 4), or tAmOH (entry 5) were more effective than EtOH leading to the formation of 3 in around 90% yield. The use of MeCN afforded only trace amount of 3 (entry 6). iPrOH was selected as the co-solvent for further optimization due to its low cost. The yield was reduced to 70% when the amount of the alkyne was reduced to 1.2 equiv (entry 7). While NaOAc (entry 8) and KPF6 (entry 9) were important for optimal reaction efficiency, the Ru-catalyst was indispensable for product formation (entry 10). Screening of electrode materials revealed that replacing the RVC anode with glassy carbon plate (entry 11) or graphite plate (entry 12) resulted in a sharp drop in yield. On the other hand, nickel plate could effectively substitute for Pt as the cathode (entry 13), but not RVC (entry 14). The method showed no apparent sensitivity to oxygen and therefore could be performed under atmospheric conditions (entry 15). Table 1. Optimization of Reaction Conditionsa
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of the less reactive substrates. When the N-(2pyrimidyl)aniline was substituted at one of the meta positions, the electrolytic annulation resulted in regioselective formation of 6-substituted indoles (7, 8). Sterically hindered substrates, such as that derived from 3,5-dimethylaniline, exhibited poor reactivity and did not afford any target products (15). These results suggested the importance of steric effects for regioselectivity and reactivity. On the other hand, diphenylacetylene 2 could be replaced with an internal alkyne functionalized with an alkyl group on one terminus and an aryl on the other, which led to the preferential formation of 2-aryl indoles (16–23). However, a higher catalyst loading was found necessary when R2
R1 +
NH DG
3
R
DG = 2-pyrimidyl
(2 equiv)
Ph
10, 70%
N DG
N DG 21, 72%b (10:1)
Ph N DG 15, 0% nBu S
OH Me
N DG
N DG 20, 63%b (6.9:1)
19, 69% (4.5:1) Me Me
OH
We next explored the reaction scope by varying both coupling substrates (Scheme 2). As shown, the aniline could be unsubstituted (4) or carry functional groups of different electronic properties at various positions (5–14), although substituents such as CO2Me (8) and CF3 (13) showed a detrimental effect on reactivity and thus required a higher catalyst loading to ensure complete substrate conversion. Note that for less efficient substrates, tAmOH was used as the co-solvent instead of iPrOH to provide a higher reaction temperature. Attempts to increase the conversion by passing more charge was unsuccessful suggesting catalyst deactivation during the electrolysis
14, 77%b
R
Ph
Ph Me
nBu
16, 89% (11:1) 17, R = F, 73% (7:1) 18, R = OMe, 83% (6:1)
Reaction conditions: RVC anode (100 PPI), Pt plate cathode, 1 (0.3 mmol), solvent (6 mL), argon, 10 mA, 3.2 F mol−1. bYield determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as the internal standard, unreacted 1 in parenthesis. cIsolated yield. d 1 cm x 1 cm.
N DG
MeO
nBu Ph
Ph
Cl N DG 13, 78%b
Me
11, 86%
Ph
12, 69%
N DG
Me
Ph
F3C N DG
Ph
N DG
Ph Ph
a
F Ph
9, 84%b
Ph
Ph
MeO
N DG
8, 87%b
7, 94% Ph
Ph
Ph
N DG
Me
6, 91%
Ph
N DG
Ph
N DG
F
5, 95% Ph
Me
Ph
N OMe DG
4, 99%
N DG
Ph
Ph
Ph N DG
Et
N DG product, yielda
Ph
Br
R3
R1
KPF6 (20 mol %), NaOAc (20 mol %) H2O/iPrOH (1:1), reflux, 1.8–3.9 h
Ph
MeO2C
R2
RVC Pt [RuCl2(p-cymene)]2 (5 mol %)
Ph N DG 22, 98%b (14:1)
OH
nBu nBu
N DG 23, 39%b
F
N DG 24, 75%b
Scheme 2. Substrate Scope. Reaction conditions: Aniline derivative (0.3 mmol), 10 mA (janode ≅ 0.13 mA cm−2), 2.3–4.9 F mol−1. aIsolated yield. Regioisomeric ratio in parenthesis was determined by 1H NMR analysis of crude reaction mixture. bReaction with 10 mol % [RuCl2(p-cymene)]2 in H2O/tAmOH (1:1).
Scheme 3. Synthetic Application
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ACS Catalysis
the internal alkyne carried a thiophene (20), a secondary (22) or hydroxyl-substituted (21, 23) alkyl group.43 5-Decyne was also compatible with our electrolytic annulation reaction (24). The synthetic utility of our method was further demonstrated by the electrochemical annulation of 25 and 26 (Scheme 3), which was performed on a gram scale and furnished the expected indole derivative 27 in 88% yield (10.6 g). The 2pyrimidyl group could then be removed by following a reported procedure34 to generate the free indole 28, a critical synthetic precursor to the anti-osteoporotic drug bazedoxifene.44
Besides indole synthesis, preliminary results showed that the Ru-catalyzed electrochemical C–H activation method could also be employed to accomplish (4+2) annulation of benzylamine with alkynes for the preparation of isoquinolines as demonstrated by the synthesis of compounds 31 and 33 [Eq. (1)].45
Mechanistic investigation of the Ru-catalyzed electrochemical reaction indicated that the activation of the aryl C–H bond in the aniline derivative was reversible and did not involve the alkyne substrate, as evidenced by the finding that the H/D exchange at the ortho position of 1 in deuterated solvent was independent of 2 (Scheme 4a). The H/D exchange also occurred at rt albeit at a slower rate than reflux. Competition experiments using anilines or alkynes with different electronic properties revealed that the annulation could be facilitated by increased electron density in the coupling partners (Scheme 4b, c), in consistence with what Ackermann et al. observed in the CuII-mediated oxidative C–H activation reactions.34 The reduced yield of compounds 17 and 18 in the competition experiment was due to decreased conversion, which suggested an inhibitory effect of the alkyne coupling partner.43 Indeed, the conversion of 1 was reduced when the alkyne 37 was increased from 2 equiv to 6 equiv (Scheme 4d). Performing the reaction of 1 and 2 in the presence of 1 equiv of RuII but without electricity afforded the product 3 in 71% yield (Scheme 4e). These results suggested that the electric current served to regenerate the active ruthenium catalyst and did not affect other steps of the catalytic cycle.
Scheme 5. Proposed Mechanism
Scheme 4. Mechanistic Studies
A plausible mechanism for the RuII-catalyzed electrolytic annulation reaction was proposed based on the findings in this and previous studies,33,34 though further investigation would be needed to elucidate its details (Scheme 5). In the presence of the NaOAc, the dimeric pre-catalyst [RuCl2(p-cymene)]2 is converted to the ruthenium diacetate complex A. Reaction of A with the alkyne may lead to unproductive complexes and result in the observed inhibitory effect at high concentration of the alkyne.43 Complexation of A with 1, followed by reversible C–H activation, forms the six-membered ruthenacycle C, whose acetate ligand is subsequently displaced by the alkyne substrate 2 as a result of π-coordination to give D. The coordination of 2 prompted its migratory insertion into the Ru–C bond, triggering the metal center to dissociate from the pyrimidyl nitrogen and instead complex with the amino group of the aniline moiety to obtain the six-membered ruthenacycle in the resultant intermediate E. The sensitivity of the annulation reaction to the electronic and steric properties of the aniline ring and the alkyne substituents suggests that the insertion step might be rate-limiting. Eventually, reductive elimination of E
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furnishes the indole product 3 and a Ru0 species (F), the latter of which is oxidized on the anode to regenerate the catalytically active RuII complex. Correspondingly, protons are reduced on the cathode to generate H2, which obviates the need for external oxidants or H-acceptors. In the preparative scale electrolysis, the catalyst resting state was most likely more resistant to cathodic reduction than the protons, allowing the use of an undivided cell. In summary, we have demonstrated that electric current can be used to promote Ru-catalyzed C–H activation/annulation processes. Our method can be used to prepare a diverse range of indole derivatives from easily accessible alkynes and aniline derivatives, and is fully compatible with a simple undivided cell.
AUTHOR INFORMATION Corresponding Author *
[email protected] Author Contributions †
F.X. and Y.-J.L. contributed equally to this work.
Notes The authors declare no competing financial interest.
ASSOCIATED CONTENT Supporting Information. The experimental procedure, characterization data, and copies of 1H and 13C NMR spectra. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT We are grateful for financial support of this research from MOST (2016YFA0204100), NSFC (21672178), the “Thousand Youth Talents Plan”, and Fundamental Research Funds for the Central Universities.
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