& CuIII Intermediates

Aryl-Copper(III)-Acetylides as Key Intermediates in Csp2�Csp ModelCouplings under Mild Conditions

Mireia Rovira,[a] Marc Font,[a] Ferran AcuÇa-Par�s,[a] Teodor Parella,[b] Josep M. Luis,[a]

Julio Lloret-Fillol,[a] and Xavi Ribas*[a]

Abstract: The mechanism of copper-mediated Sonogashiracouplings (so-called Stephens–Castro and Miura couplings)is not well understood and lacks clear comprehension. Inthis work, the reactivity of a well-defined aryl-CuIII species(1ClO4

) with p-R-phenylacetylenes (R = NO2, CF3, H) is reportedand it is found that facile reductive elimination from a puta-tive aryl-CuIII-acetylide species occurs at room temperatureto afford the Caryl�Csp coupling species (IR), which in turn un-dergo an intramolecular reorganisation to afford final heter-ocyclic products containing 2H-isoindole (PNO2

, PCF3, PHa) or

1,2-dihydroisoquinoline (PHb) substructures. Density Func-tional Theory (DFT) studies support the postulated reductiveelimination pathway that leads to the formation of Csp2�Csp

bonds and provide the clue to understand the divergent in-tramolecular reorganisation when p-H-phenylacetylene isused. Mechanistic insights and the very mild experimentalconditions to effect Caryl�Csp coupling in these model sys-tems provide important insights for developing mildercopper-catalysed Caryl�Csp coupling reactions with standardsubstrates in the future.

Introduction

The transition-metal catalysed couplings of aryl halides and ter-minal acetylenes is a fundamental reaction for providingaccess to highly versatile aryl alkyne scaffolds, which are veryimportant precursors in the pharmaceutical industry, as well asin total synthesis and production of organic materials.[1] Thepalladium-copper co-catalysed methodology (Sonogashira–Ha-gihara reaction) is the most widely used, and is thought toproceed through a Pd0/PdII catalytic cycle for effecting the aryl-acetylide coupling. The role of copper as transmetallatingagent from CuI-acetylides is generally proposed.[2] However,this coupling reaction can also proceed under copper catalysis(palladium-free) as reported by Miura’s seminal report in1993.[3] In fact, Castro and Stephens first demonstrated thatCuI-acetylides could directly react with aryl iodides to providethe desired phenyl acetylenes, back in 1963.[4]

More recently, renewed interest in palladium-free methodol-ogies is motivated by economic and toxicity reasons, thuscopper-based Sonogashira couplings appear as an attractive al-ternative.[5] However, copper is known to catalyse the homo-

coupling of terminal alkynes (Glaser–Hay reaction),[6] a cleardrawback that steps down its synthetic utility. Recently, Bolmand co-workers reported that sub-mol % copper loading anda large excess of DMEDA constituted a good methodology toafford the coupling products in quantitative yields,[7] thusavoiding the undesired acetlylene homocoupling.

The mechanism of copper-mediated Sonogashira couplingsis far from being well-understood. The Stephens and Miuragroups supported a mechanism involving the formation ofa mononuclear CuI-acetylide species that reacted with aryliodide in a concerted manner through a 4-centre transitionstate, although no experimental proof was provided (Sche-me 1 A).[3a, 4b] Bolm and co-workers performed kinetic investiga-tions with their methodology using DMEDA in excess and sup-ported also that a monomeric CuI-acetylide complex was theactive species that reacts with aryl iodide, but no further de-tails were provided to explain the key coupling step.[7] More re-cently, Wang and co-workers shed more light on the mecha-nism of this reaction by showing that an aryl iodide moietyembedded in azacalix-[1]arene[3]pyridine can effectivelycouple with phenylacetylene, in a process catalysed by CuI

(30 mol %) at 130 8C, where aryl-CuIII species were clearlyshown as intermediates (Scheme 1 B).[8]

In view of the minor mechanistic information available forCu-based Sonogashira couplings, and in our experience dem-onstrating that aryl-CuIII species are valid intermediates inmodel copper-catalysed Caryl-heteroatom (C�N, C�O, C�S, C�Se, C�P and C�halide)[9] and Caryl�Csp3 coupling reactions,[10] wedecided to investigate in depth the reactivity of well-definedaryl-CuIII species with terminal acetylenes. Here we report onthe ability of aryl-CuIII species to react with phenylacetylenederivatives at room temperature to afford the Csp2�Csp coupling

[a] M. Rovira, M. Font, F. AcuÇa-Par�s, Dr. J. M. Luis, Dr. J. Lloret-Fillol,Dr. X. RibasInstitut de Qu�mica Computacional i Cat�lisi (IQCC) andDepartament de Qu�mica, Universitat de GironaCampus Montilivi, Facultat Ci�ncies, E17071 Girona (Catalonia, Spain)E-mail : xavi.ribas@udg.edu

[b] Dr. T. ParellaServei de RMN, Facultat de Ci�nciesUniversitat Aut�noma de Barcelona (UAB)Campus UAB, E-08193 Bellaterra (Catalonia, Spain)

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201402711.

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Full PaperDOI: 10.1002/chem.201402711

products, which in turn evolve to 2H-isoindole final productsthrough an intramolecular cyclisation due to nucleophilicattack of secondary amines over the inserted alkyne. Experi-mental and theoretical evidence showing that monomeric aryl-CuIII-acetylides undergo reductive elimination as the key stepof this reaction are presented, and therefore, we providea mechanistic basis to suggest that these species are plausibleintermediates in Pd-free copper-mediated Sonogashiracouplings.

Results and Discussion

Reactivity of aryl-CuIII (1ClO4) with p-R-phenylacetylene (SR)

This study is inspired by our previous experience with C-heter-oatom and Caryl�Csp3 cross-coupling catalysis involving the well-defined aryl-CuIII species.[10] Here we report on the reactivity ofaryl-CuIII complex 1ClO4

with p-R-phenylacetylene (R = NO2, CF3,H) derivatives (SR, Scheme 2). Since we have reported that theoxidative addition step within these model aryl halide sub-strates is extremely favoured,[9g] we concentrated our effortson finding the experimental conditions to achieve a putativeCaryl�Csp reductive elimination step. We were pleased to ob-serve that the reaction of 1ClO4

with the three p-R-phenylacety-lene derivatives tested afforded the desired arylated phenyla-

cetylene compounds at room temperature in less than 2 h, al-though these were unstable and underwent intramolecularcyclisation through the attack of one of the secondary aminesof the substrate scaffold over the alkyne moiety (Scheme 2) inan overall 8 h reaction time.

Final cyclised products contained 2H-isoindole (PNO2, PCF3

,PHa) or 1,2-dihydroisoquinoline (PHb) substructures. Yields wereexcellent for p-NO2 and p-CF3 derivatives whereas a global aryl-CuIII conversion of 78 % was found for the reaction with SH (PHa

42 %, PHb 36 %, in almost a 1:1 ratio). No Csp�Csp Glaser–Hay ho-mocoupling side products were detected in any of these reac-tions. The chemical structure of PNO2

and PCF3has been un-

equivocally established by means of NMR spectroscopy andESI-MS studies. In the case of PHa and PHb, their separation hasnot been possible but a complete structure characterisationand unambiguous chemical-shift assignment of both mole-cules has been successfully performed from the careful analysisof multidimensional NMR spectra of the mixture. As an exam-ple, the 1H NMR spectrum of PCF3

is depicted in Figure 1. Intra-molecular cyclisation imposes rigidity in the molecule and con-verts all methylene protons into diastereotopic pair signals,which are assigned from COSY and 1H-13C HSQC spectra. Themain features that identify the 2H-isoindole moiety in PCF3

were deduced from the analysis of NOESY and 1H-13C HMBCspectra. The NOESY experiment allowed us to assign Hc and Hd

due to its through-space connectivity with He, Hf and the aro-matic Hb protons. NOE data were also observed between thebenzylic Hs and Ht protons with the aromatic Hu protons fromthe p-CF3-phenyl moiety, which evidenced the loss of the triplebond. A key point to elucidate the compound structure wasthe singlet resonance (Hl proton) resonating at 7.47 ppm anddirectly attached to the carbon resonating at 115.6 ppm (viaHSQC), a characteristic value for a Csp2. This Hl proton showedNOE with the aromatic Hb‘ and the methylene Hm and Hn pro-tons. On the other hand, the connectivities observed in the

Scheme 1. Mechanistic proposals for the Cu-catalysed Sonogashira couplingreaction. a) Stephens–Castro and Miura’s 4-centre transition state proposal,and b) Wang’s model system involving an aryl-CuIII species.

Scheme 2. Reaction between the well-defined aryl-CuIII complex (1ClO4) and

phenylacetylene derivatives (SR) that undergo Csp2�Csp coupling and furtherintramolecular cyclisation to form products containing 2H-isoindole (PNO2

,PCF3

, PHa) or 1,2-dihydroisoquinoline (PHb) scaffolds (general conditions:[1ClO4

] = 12 mm, [nucleophile] = 24 mm, 25 8C, CD3CN; product yields werecalculated by 1H NMR spectroscopy integration related to the internal stan-dard).

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HMBC spectrum allowed the assignment of all quaternary car-bons and indicated the formation of 5-membered cyclised ringcorresponding to a 2H-isoindole type. Thus, the benzylic Ht

proton presented HMBC cross-peaks with C18, C19, C16 and C15

carbons, whereas Hl were correlated with C3, C12, C14, C15 andC16.

Analogous structural characterisation of PNO2and PHa, bear-

ing the same 2H-isoindole substructure, is fully detailed in theSupporting Information. On the other hand, PHb has been char-acterised by NMR spectroscopy and found to contain a 6-membered 1,2-dihydroisoquinoline moiety; full characterisa-tion details are also given in the Supporting Information.

It is worth mentioning that copper-catalysed alkynylation–cyclisation cascade reactions had been described for the syn-thesis of 1H-indole substructures,[11] but the synthesis of 2H-isoindole using this strategy is, to our knowledge, unprece-dented. On the other hand, Cu-catalysed cascade reactions in-volving aryl–acetylide coupling followed by intramolecular re-organisation for the synthesis of isoquinoline derivatives hasbeen recently reported using phenyl-pyrazoles as substrates.[12]

Characterisation of Caryl�Csp coupling intermediate species(IR)

The structural characterisation of final products immediatelysuggests the initial formation of a Caryl�Csp coupling intermedi-ate species (IR) as depicted in Figure 2, which suffersan intramolecular reorganisation to form PR (videinfra). In order to prove this hypothesis, we attempt-ed the isolation or accumulation of ICF3

by monitoringthe reaction of 1ClO4

with SCF3by NMR spectroscopy at

low temperature. Upon optimisation of the condi-tions we found that the reaction of 1ClO4

with SCF3at

0 8C allowed the accumulation of ICF3during 30 min

without any sign of evolution to the intramolecularlycyclised final product PCF3

(Figure 2). This species wasfully characterised by 1D and 2D NMR spectroscopystudies and by high resolution mass spectrometry(HRMS) using a cryospray device to inject the sampleat �40 8C, thus warranting the integrity of ICF3

duringthe measurement (see the Supporting Information).Subsequently, compound ICF3

underwent reorganisa-tion to finally form PCF3

quantitatively in 18 h at 0 8C(see the Supporting Information).

To further substantiate the plausible implication ofaryl-CuIII-acetylide species as key intermediates forthe formation of Caryl�Csp coupling species (IR) we un-dertook a theoretical DFT study on the reaction of1ClO4

with SH as depicted in Figure 3 (see the Support-ing Information for computational details). A first in-termediate species B was identified, consisting of the axial p-coordination of the alkyne to the CuIII centre. As a first attemptto explain the reactivity, an intramolecular deprotonation ofphenylacetylene by one of the secondary amines of the com-plex was found to be too high in energy (DG = 47.1 kcal mol�1),suggesting that the CuIII oxidation state cannot be stabilisedupon decoordination of one of the amine sites (Figure S40 in

the Supporting Information). On the contrary, by using an ex-ternal model base (i.e. , Et2NH was selected as modelled baseowing to the possibility that minor amounts of free ligand areavailable in the reaction mixture), a much smaller barrier wasfound leading to aryl-CuIII-acetylide (intermediate C ; DG� =

13.0 kcal mol�1). This species rapidly undergoes reductive elimi-nation to form IH·CuI, which corresponds to IH with the CuI

Figure 1. 1H NMR spectrum (CD3CN, 25 8C, 400 MHz) of compound PCF3with

proton assignment. ~: 1,3,5-trimethoxybenzene (internal standard); &:excess of p-CF3-phenylacetylene.

Figure 2. 1H NMR monitoring study showing full formation of Caryl�Csp coupling inter-mediate species ICF3

upon treatment of 1ClO4with 2 equiv of SCF3

(general conditions:[1ClO4

] = 78.6 mm, [nucleophile] = 157.2 mm, CD3CN, 0 8C, 400 MHz; *: 1ClO4, N : ICF3

).

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cation still coordinated in the macrocyclic pocket. DFT calcula-tions nicely agree with the experimental isolation of analogousICF3

starting from the well-defined aryl-CuIII species (1ClO4).

Altogether this constitutes a solid argument to the proposalthat the aryl-CuIII-acetylide species is involved in Cu-based So-nogashira couplings. However, in our model system IR under-goes further reorganisation to PR. We propose that an initialnucleophilic attack of a NH group occurs over the triple bondof the inserted acetylide, as depicted in Scheme 3. This attackcan in principle take place at both carbons of the triple bondof IR, although we have clearly observed that for R = NO2 orCF3, the attack exclusively occurs at the proximal carbon toafford 5-membered ring 2H-isoindole products (PNO2

, PCF3, PHa),

whereas for R = H the attack occurs equally at both Csp atoms,thus affording almost 1:1 ratios of PHa and six-membered ring1,2-dihydroisoquinoline PHb. In either case, proton shifts and/orrearomatisation arrangements are envisioned to finally affordthe structure of the end products (Scheme 3).

At this stage, we were intrigued by three important mecha-nistic aspects concerning the evolution of IR to PR. On onehand, we wondered if the initial nucleophilic attack of NH overthe triple bond requires its electrophilic activation by the coor-dination of the CuI cation formed in solution. To check this hy-

pothesis, we fully formed ICF3ex-

clusively at 0 8C and we com-pared the time consumed toform PCF3

with and without theaddition of 1,10-phenanthroline(phen) in excess (2.5 equiv),owing to the high affinity ofphen to complexate CuI as thehighly stable [CuI(phen)2]+ .[13] Weobserved that upon sequester-ing CuI by the addition of phen,the formation of PCF3

from ICF3

was slowed down by twofold(see the Supporting Informa-tion). This result clearly points toa substantial activation of thetriple bond by CuI coordination,which is reminiscent of thechemistry of silver(I) andgold(I),[14] although it also arguesin favour of a slower intramolec-ular rearrangement in the ab-sence of an electrophilic activa-tion of the alkyne moiety.

Another consideration to takeinto account is the occurrence ofa secondary amine moiety to ini-tiate the nucleophilic attack overthe triple bond. To verify that anNH group is essential for the in-tramolecular reorganisation toproceed, we performed the reac-tion of a triazamacrocyclic modelaryl halide bearing three perme-

thylated tertiary amines (L5-Cl) with 1 equiv of the [CuI-(CC-Ph-p-CF3)] complex prepared independently (Scheme 4).[15] The re-action afforded 76 % yield of the I’CF3

product, which remainedstable in solution for days with no signs of intramolecular rear-rangement. Therefore, we can conclude that the nucleophilicattack of the amine over the alkyne is effective only if protonshifts are allowed.

Finally, the third important question was related to the com-prehension of the regioselective attack to one Csp atom for R =

NO2, CF3, whereas for R = H both Csp atoms suffer the nucleo-philic attack indistinctly. We calculated theoretical charge den-sities (natural population analysis (NPA) and Mulliken charges)on the alkyne moiety for the IR·CuI species, but no significantdifferences were found (Figure S41 in the Supporting Informa-tion). However, the representation of the frontier molecular or-bitals for IH·CuI and INO2

·CuI species nicely showed that whenan electron-withdrawing group, such as�NO2, is present in themolecule, the LUMO orbital that receives the nucleophilicattack of the amine completely excludes any orbital participa-tion of the Csp atom closer to the electron-withdrawing centre,thus exclusively allowing for a 5-membered ring formation(Figure 4). On the contrary, if R = H, both Csp atoms of thealkyne do participate in the corresponding LUMO equally,

Figure 3. DFT Gibbs energy profile of the reaction of 1ClO4with SH in the presence of Et2NH as external model

base (DG in kcal mol�1). Et2NH and Et2NH2+ molecules are necessary to ensure the correct energetic balance in all

the steps of the reaction, and are included in the calculation. The interaction between the copper complex andthe external base was only explicitly modelled in the TS1 structure. Irrelevant hydrogen atoms in the figures areomitted for clarity.

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which is translated to the almost equimolar formation of 5-membered ring PHa and 6-membered ring PHb products.

All information extracted from the above-reported experi-ments using 1ClO4

as our starting reactant provided the funda-mental basis to attempt a catalytic version for producinga Caryl�Csp coupling product within our model system. Exhaus-tive experimental optimisation of the catalysis of L1-Br with

2 equiv of SNO2employing 10 mol % [CuI(CH3CN)4]OTf did not

afford any trace of PNO2(Table S1 in the Supporting Informa-

tion), although L1-Br was completely consumed. We reasonedthat the heterocyclic nature of the PNO2

product is unstableunder catalytic conditions and decomposes completely. There-fore, we screened the copper-catalysed reaction using L5-Br orL5-Cl with 2 equiv of SCF3

and 4 equiv of base (to assist theacetylene deprotonation) to form the nonheterocyclic couplingproduct I’CF3

(Table S2 in the Supporting Information). Wefound yields of product close to the copper(I) loading used,thus indicating that only stoichiometric amounts of productwere obtained. Similar results were found when CuI-acetylidewas used as copper catalyst. These observations suggest theinhibition or entrapment of CuI released upon reductive elimi-nation. At present we have not been able to overcome the in-activation of the CuI released in solution to achieve catalyticturnover, despite the fact that different strategies have beenexplored (see the Supporting Information).

Conclusion

In summary, here we report the feasibility of aryl-CuIII speciesas key intermediates in copper-mediated Csp2�Csp coupling re-actions by studying the reactivity of well-defined aryl-CuIII

(1ClO4) with phenylacetylene derivatives to afford PNO2

, PCF3, PHa

and PHb coupling products at room temperature. The latterheterocyclic products are formed by intramolecular reorganisa-tion of biaryl acetylene species IR, in which the nucleophilicattack of the secondary amine is facilitated via Lewis activationof the alkyne moiety by CuI. This reorganisation is blocked iftertiary amines are present in the model aryl halide substrates(L5-X). Catalytic turnover was not possible in these model sys-tems due to inhibition or entrapment of CuI released upon re-ductive elimination. Most importantly, the copper-mediatedCsp2�Csp reductive elimination step was proven to easily occurat room temperature, thus adding mechanistic understandingto copper-mediated Stephens–Castro (stoichiometric)[4] andMiura’s (catalytic)[3] reactions. Along with Wang’s reportedprecedent,[8] this work is relevant in the mechanistic compre-hension of Pd-free Cu-mediated Sonogashira couplings and

Scheme 3. Global mechanistic proposal for the formation of PR productsthrough aryl-CuIII-acetylide species, and subsequent intramolecular cyclisa-tions following divergent pathways depending on R.

Scheme 4. Reaction of L5-Cl with p-CF3-phenylacetilide copper(I) complex toafford the stable I’CF3

product.

Figure 4. LUMO frontier orbitals for IH·CuI and INO2·CuI species and simplified

scheme of the possible nucleophilic attacks in each molecule (CuI cationomitted for clarity).

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covers strategies and limitations to be translated in copper-cat-alysed Csp2�Csp couplings. Ongoing studies are focused on ap-plying the insights learned from these studies to Miura’s cataly-sis with standard substrates. Furthermore, this study may beused as a fundamental basis to extend the Cu-catalysed alky-nylation–cyclisation cascade reactions to produce 2H-isoindoleproducts using (2-halophenyl)methanamine-type of substrates.

Experimental Section

Synthesis of products PNO2, PCF3

, PHa and PHb

In an inert-atmosphere glove box, a sample of the aryl-CuIII com-plex 1ClO4

(14.2 mg, 28 mmol) was dissolved in CD3CN (1.6 mL) anda solution of 1,3,5-trimethoxybenzene (0.4 mL) was added as an in-ternal standard. A portion of this solution (0.6 mL) was loaded intoan NMR tube, and 2 equivalents of the corresponding acetylenenucleophile were added to the tube (0.1 mL, 168 mm). Final con-centrations: [1ClO4

] = 12 mm, [p-R-phenylacetylene] = 24 mm. Thetube was sealed with a screw-cap and the reaction was allowed toproceed at room temperature and was monitored by 1H NMR spec-troscopy until reaction completion. Final yields were: PNO2

(98 %),PCF3

(98 %), PHa (42 %) and PHb (36 %). 1H, COSY, NOESY, TOCSY, 1H-13C HSQC, 1H-13C HMBC and 13C NMR spectra and mass spectromet-ric analysis were obtained directly from crude reactions. Reactionyields were obtained by relative integration of the 1H NMR signalsto the internal standard. Full characterisation details can be foundin the Supporting Information.

Acknowledgements

We acknowledge financial support from European ResearchCouncil for Starting Grant Project ERC-2011-StG-277801 to X.R. ,MICINN of Spain (INNPLANTA project INP-2011-0059-PCT-420000-ACT1 to X.R. , CTQ2012-32436 to T.P. , CTQ2012-37420-C02-01/BQU to Dr. M. Costas, RyC contract to J.Ll.-F. and PhDFPI grant to M.F.), Consolider-Ingenio CSD2010-00065, and theCatalan DIUE of the Generalitat de Catalunya (2009SGR637).X.R. thanks an ICREA-Acad�mia award.

Keywords: Caryl�Csp cross coupling · copper(III) · densityfunctional calculations · reaction mechanisms · Pd-freeSonogashira

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Received: March 21, 2014

Published online on July 10, 2014

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