Copper-Catalyzed (Transfer) Hydrogenation Reactions and Coupling Reactions by Intercepting Reactive Inter- Mediates Thereof

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2020, 52, 2483–2496 short review 2483 en

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

Catch It If You Can: Copper-Catalyzed (Transfer) Hydrogenation Reactions and Coupling Reactions by Intercepting Reactive Inter- mediates Thereof

Lea T. Brechmann Johannes F. Teichert* 0000-0003-1043-8092

Institut für Chemie, Technische Universität Berlin, Straße des 17. Juni 115, 10623 Berlin, Germany [email protected]

Received: 21.05.2020 1 Introduction: H2-Mediated C–C Bond- Accepted after revision: 18.06.2020 Published online: 13.07.2020 Forming Reactions DOI: 10.1055/s-0040-1707185; Art ID: ss-2020-z0281-sr The interception of reactive intermediates of catalytic Abstract The key reactive intermediate of copper(I)-catalyzed alkyne transformations is a typical approach to unravel new reac- semihydrogenations is a vinylcopper(I) complex. This intermediate can tivity in method development for synthetic chemistry. Es- be exploited as a starting point for a variety of trapping reactions. In this manner, an alkyne semihydrogenation can be turned into a pecially for the construction of C–C bonds, the use of or- dihydrogen-mediated coupling reaction. Therefore, the development of ganometallic reagents has proven to be extremely effec- copper-catalyzed (transfer) hydrogenation reactions is closely inter- tive.1,2 However, the use of a stoichiometric organometallic twined with the corresponding reductive trapping reactions. This short review highlights and conceptualizes the results in this area so far, with

H2-mediated carbon–carbon and carbon–heteroatom bond-forming reactions emerging under both a transfer hydrogenation setting as well

as with the direct use of H2. In all cases, highly selective catalysts are required that give rise to atom-economic multicomponent coupling reactions with rapidly rising molecular complexity. The coupling reactions are put into perspective by presenting the corresponding (transfer) hydrogenation processes first.

1 Introduction: H2-Mediated C–C Bond-Forming Reactions 2 Accessing Copper(I) Hydride Complexes as Key Reagents for Cou- pling Reactions; Requirements for Successful Trapping Reactions 3 Homogeneous Copper-Catalyzed Transfer Hydrogenations

4 Trapping of Reactive Intermediates of Alkyne Transfer Semi- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Johannes Teichert (left) is currently a junior professor at Technische hydrogenation Reactions: First Steps Towards Hydrogenative Universität Berlin. He studied at Philipps-Universität Marburg (diploma Alkyne Functionalizations thesis with Prof. Gerhard Hilt) and at Université Paul Sabatier in Tou- 5 Copper(I)-Catalyzed Alkyne Semihydrogenations louse, France. In 2006, he joined the group of Prof. Ben L. Feringa at

6 Copper(I)-Catalyzed H2-Mediated Alkyne Functionalizations; Rijksuniversiteit Groningen, the Netherlands for his Ph.D. in the field of Trapping of Reactive Intermediates from Catalytic Hydrogena- asymmetric catalysis. After a postdoctoral stay with Prof. Jeffrey Bode at tions ETH Zurich, he started his independent research group in Berlin. Johannes’ research interests include method development in organic 6.1 A Detour: Copper(I)-Catalyzed Allylic Reductions, Catalytic Gen- synthesis, transition-metal catalysis and especially reductive transfor- eration of Hydride Nucleophiles from H2 mations employing H2. 6.2 Trapping with Allylic Electrophiles: A Copper(I)-Catalyzed Hydro- allylation Reaction of Alkynes Lea Brechmann (right) is currently working in the group of Johannes Teichert. She studied at Philipps-Universität Marburg and at the Univer- 6.3 Trapping with Aryl Iodides sity of Santiago de Compostela before joining the group of Gerhard Hilt 7 Conclusion for her M.Sc. degree. Since 2017 she has been studying for her Ph.D. focusing on the development of new transition-metal-catalyzed syn- Key words cross-coupling, dihydrogen, copper, catalysis, alkynes thetic methods by activating dihydrogen as the hydride source.

Syn thesis L. T. Brechmann, J. F. Teichert Short Review reagent in, e.g., a cross-coupling reaction, inevitably leads to Exemplary of these is a rhodium-catalyzed enantioselective the formation of a stoichiometric amount of metal-based reductive coupling reaction of enyne 3 with -ketoester 4 waste. The possible avoidance of such waste by means of a (Scheme 1, c).14 Key to this transformation is the activation catalytic process based on dihydrogen (H2) serves as a of dihydrogen by a rhodium complex consisting of bis(1,5- prime inspiration for developing new reactions. This ap- cyclooctadiene)rhodium(I) trifluoromethanesulfonate and proach can be driven from the vantage point of the desire R-Xylyl-WALPHOS (6) followed by the main C–C bond- for atom economy/efficiency,3,4 and can also serve as a forming reaction. This and related methods13 are impressive fruitful inspiration for method development in synthetic in themselves, as the resulting overall transformations are chemistry. elegant and display high chemoselectivity (none of the Dihydrogen can be viewed as an easily accessible and, in alkenes formed in Scheme 1, c suffer any additional over- principle, a sustainably producible and abundant resource, hydrogenation), next to the obvious atom economy. Indeed, and although its use in catalytic hydrogenations is by far H2-mediated processes such as the one highlighted had 5–7 the prime use of H2 in synthesis, the aforementioned fea- been put forward in the literature as being highly sought- tures render it highly desirable as a key reagent for catalytic after.15 The transformations highlighted in Scheme 1 re- C–C (and C–heteroatom) bond-forming reactions. The op- volve around the use of carbonyl and/or carboxyl acceptors. portunity to replace common organometallic reagents with Progressing from these functional groups to other coupling catalytic processes based on H2 was recognized a long time partners would substantially broaden this elegant ap- ago. Probably the most famous H2-mediated C–C bond- proach. forming reactions are the Fischer–Tropsch process (Scheme Departing from noble metal catalysts (mostly based on 1, a)8,9 and alkene hydroformylation (the oxo process, rhodium, iridium and ruthenium) could offer such an op- 10–12 Scheme 1, b). Emanating from this, catalytic H2-mediat- portunity. In particular, base metals, which have only re- ed C–C bond-forming reactions beyond C1 building blocks cently regained popularity in catalytic hydrogenations and bear great potential in synthetic chemistry. In particular, H2 activation processes, might lead the way to such a new rhodium-catalyzed coupling reactions of alkenes/alkynes approach.5,16 and carbonyl derivatives have been intensively studied.13

a) Fischer–Tropsch chemistry

[Co] or [Fe]

n CO + excess H2 CnH2n+2 + CnH2n + n H2O

mixture of products depending on the molar ratio of H2 and CO

b) catalytic hydroformylation/oxo process H O [Rh] or [Co] H H R + CO + 2 R

1 2

c) modern H2-mediated C–C bond formation This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2 mol% Rh(COD)2OTf 2 mol% (R)-Xylyl-WALPHOS (6) O 1 mol% Ph3CCO2H R1 O R1 2 1 bar H2 + R OR3 OR3 1,2-dichloroethane, 60 °C 2 O H R OH 3 4 5 1 2 R = aryl, alkyl R = aryl, alkyl PAr2 R3 = Me, Et PAr2 Fe Me H

Ar = 3,5-xylyl

R-Xylyl-WALPHOS 6

Scheme 1 Overview of catalytic, H2-mediated C–C bond-forming processes. Only the most common metals are displayed for the processes in (a) and (b)

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

In recent years, many studies employing copper as a cat- σ-bond metathesis alytic metal for reductive coupling reactions have been put forward (see Section 3), and first endeavors into copper- – HOR1 H2 L Cu OR1 catalyzed H2-mediated bond-forming reactions have ap- n 8 peared.17–19 One of the key advantages of copper catalysis is HH the fact that it opens up the possibility for widening the re- BDE H–H: 104 kcal mol–1 action space beyond carbonyl/carboxyl derivatives as cou- 1 LnCu–OR LnCu–H pling partners, which have been prevalent thus far (see 7 11 above). This review summarizes the developments based 1 on copper catalysts for reductive coupling reactions of LnCu OR alkynes under hydrogenative or transfer hydrogenative H–E H E – EOR1 9 10 20 conditions and aims at discussing the various approaches. hydride donor BDE Si–H: 92 kcal mol–1 E = SiR3, BR2, SnR3 2 Accessing Copper(I) Hydride Complexes as Scheme 2 Similar yet different: Formation of copper(I) hydrides from Key Reagents for Coupling Reactions; Re- H2 vs hydroelement reagents via -bond metathesis quirements for Successful Trapping Reactions structural motif for the formation of copper(I) hydrides: In

Fundamental for the development of H2-mediated the presence of a hydrosilane as the hydride source, cop- bond-forming processes is the efficient in situ generation of per(I) hydride 11 is known to be formed via -bond me- copper(I) hydrides, which has to be compatible with all tathesis of the hydrosilane and copper(I) complexes 7 bear- other envisaged downstream reactions. Copper(I) hydrides ing a Cu–O bond, liberating silyl ether 10 as a by-product (E 25,26 are widely used and well-studied reagents in organic syn- = Si) (Scheme 2, bottom). The activation of H2 leading to thesis, probably best known for their prototypical reactivi- copper(I) hydrides 11 resembles that of the hydrosilane ty in the conjugate reduction (i.e., 1,4-reductions) of ,- pathway (Scheme 2, top). Based on only circumstantial evi- 27 unsaturated carbonyl or carboxyl compounds, or 1,2-reduc- dence, activation of H2 had been suggested in the 1950s. tions.21 In addition, catalytic reductive alkene or alkyne These two comparable pathways leading to the same prod- functionalization reactions have been intensively studied in uct differ markedly by the corresponding bond strengths of the last decade.17,18 Generally, for all the aforementioned the formal hydride donors (Si–H: 92 kcal mol–1 vs H–H: 104 transformations, hydrosilanes serve as salient stoichiomet- kcal mol–1),28 in addition to the significant driving force that ric hydride sources.21–24 The mechanism of formation of the arises from the formation of the strong Si–O bond in 10 in actual copper(I) hydride complex is outlined in Scheme 2. the case of hydrosilanes. Accessing copper(I) hydride

The presence of a copper–oxygen bond is the necessary complex 11 from H2 requires a key heterolytic H–H bond

Copper hydrides and alkynes: Catalytic semihydrogenations vs. hydrofunctionalizations

no E+ reaction a) no trapping reaction remains at in the absence of 13 [Cu] [Cu] an electrophile H–SiR 3 H 1 hydrosilane as R hydride source R2 E This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. + E+ 13 H b) trapping with electrophile no intrinsic R1 no competitive electrophile R2 protodecupration R1 14 R2 [Cu] E 12 + HO H + E H c) trapping with electrophile 1 R trapping with E+ 2 [Cu] R ⇒ H2-mediated coupling or H–H 15 H competing pathways R1 H2 or H2 equivalent as hydride source R2 H 13 H d) protodecupration 1 proton as an intrinsic R trapping with H+ electrophile R2 ⇒ hydrogenation 16 Scheme 3 Catalytic reductive functionalizations of alkynes with copper(I) hydride compounds. Diverging/competing pathways and challenges associ-

ated with H2-mediated coupling reactions

Syn thesis L. T. Brechmann, J. F. Teichert Short Review cleavage along the Cu–O bond. In fact, the Cu–O bond is high degree on the ‘quality’ of the electrophile (i.e., the represent in the vast majority of all homogeneous catalytic action rate of the trapping reaction of 13). As the copper(I) 26,29,30 hydrogenations with copper complexes. hydride formation from H2 necessarily produces a proton The copper(I) hydrides 11 thus generated display a high equivalent (mostly in the form of an alcohol), a proton (or reactivity towards alkynes, which can be exploited for both an alcohol as a protic molecule in the mixture) can always catalytic hydrogenations as well as catalytic hydrofunction- serve as an intrinsic electrophile for vinylcopper(I) complex alizations.19,31 Both types of reactions share a common first 13. This would lead to an overall catalytic hydrogenation step: a syn-hydrocupration of the copper(I) hydride with and therefore to the ‘simple’ alkene 16 (Scheme 3, d). Any the alkyne generates a vinylcopper(I) complex 13 as a pri- catalytic hydrofunctionalization of alkynes with H2 and mary reactive intermediate (12 → 13 in Scheme 3).32 The copper complexes must therefore overcome the challenge vinylcopper(I) complex 13 is the main bifurcation point for of this unwanted protodecupration process. In other words, the following reactions. Scheme 3 attempts to highlight the the key trapping reaction with an electrophile or a coupling various pathways and the additional challenges that go partner needs to exhibit a significantly higher rate than the along with a seemingly simple switch from hydroelement protodecupration. Therefore, catalytic hydrofunctionaliza- compounds as the hydride source to H2. Vinylcopper(I) tions of alkynes based on H2 are significantly more chal- compound 13 can react with a suitable electrophile forming lenging to develop compared to their counterparts based on substituted alkenes 14, resulting in an overall catalytic hy- hydrosilanes (Scheme 3, c). drofunctionalization of the alkyne starting material One general advantage of these overall reductive func- (Scheme 3, b). On the other hand, in the absence of an elec- tionalizations is the fact that they deliver the corresponding trophile, the reaction remains at vinylcopper(I) complex 13, substituted alkenes in a highly stereoselective manner. The resulting in no catalytic turnover (Scheme 3, a).32 Therefore, selectivity ultimately stems from the high stereoselectivity when hydrosilanes are employed, the reaction rate of the of the syn-hydrocupration.32 In addition, regioselective pro- trapping reaction with the externally added electrophile cesses with non-symmetric alkyne starting materials 12 does not play a crucial role for the overall process 12 → 14 might be realized with a suitable catalyst or a (sterically or as the reaction is simply halted at vinylcopper(I) complex electronically) biased substrate. As one main advantage, the 13. In stark contrast to this, the realm of hydrogenative cop- reactivity of the vinylcopper(I) complex 13 with electro- per(I) hydride based reactions with alkynes depends to a philes potentially leads away from the necessity of a

a) ammonia borane as H2 equivalent b) iso-propanol as H2 equivalent c) hypophosphorous acid as H2 equivalent

5 mol% 5 mol% 10 mol% copper citrate [IPrCuOH] (19) [SIMesCuCl] (22) 5 mol% HMAT 2 H 2 H H R 3 equiv. H3N BH3 R 1.1 equiv. NaOtBu H 2 equiv. H3PO2 H H H 2 2 1 R 1 R 1 H R THF, 50 °C, 5–48 h R iPrOH, 140 °C, 24 h R DMF, 130 °C, 6 h R1 R1 R1

17 18 20 21 23 24 R1 = aryl, alkyl 19 examples R1 = aryl, alkyl 11 examples R1 = aryl, alkyl 23 examples 50–80% 48–96% R2 = aryl, alkyl R2 = aryl, alkyl 66–99%a Z/E = 95:5 to >99:1 Z/E = 82:18 to 99:1 <20% alkane iPr iPr NN N N

iPr Cu iPr Cu This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. OH Cl 19 22 [IPrCuOH] [SIMesCuCl]

H H H H H H H H H OBn H OBn H H H H H H ( ) ( ) C H H H H 3 3 5 11 C5H11 TIPSO Cl

MeO OMe Br O 18a 18b 21a 21b 21c 24a 24b 24c 80% 74% 91% 84% 61% 90% 84% 80% Z/E >99:1 Z/E >99:1 Z/E = 94:6 Z/E = 97:3 Z/E = 99:1

a Scheme 4 Copper(I)-catalyzed transfer alkyne semihydrogenation reactions with selected substrates and various H2 equivalents. The isolated yield was only reported for a few substrates. (HMAT = hexamethylenetetramine)

Syn thesis L. T. Brechmann, J. F. Teichert Short Review carbonyl or carboxyl electrophile as compared to the trans- terminal alkenes 24 by employing hypophosphorous acid as formations based on noble metals as discussed above the H2 equivalent, while internal alkynes remained intact (Scheme 1). (Scheme 4, c).41

Reductive functionalization reactions could alternative- As a much more practical and ready available H2 equiva- ly be realized in a transfer hydrogenation setting.33 In these lent, it was recently shown that iso-propanol can also be cases, similar challenges arise, as by default, transfer hydro- employed in copper(I)-catalyzed transfer hydrogenations.42 genation reagents as H2 replacements bear a proton equiva- With a simple NHC/copper(I) complex 22 in catalytic lent (again, a competitive intrinsic electrophile), which amounts and NaOtBu as a basic additive, internal alkynes could also deter the overall reductive functionalization by 20 could be converted into Z-alkenes 21 in moderate to very directly diverging into a transfer hydrogenation of alkynes. good yield (48–96%), while maintaining a high to excellent In the following sections, the parent copper(I)-catalyzed Z/E ratio (82:18 to 99:1) (Scheme 4, b). Remarkably, even semihydrogenations or transfer semihydrogenations are under these drastic conditions, no overreduction to the cor- highlighted first, followed by the corresponding trapping responding alkane was observed, again underscoring the reactions, which often rely on the established protocols for key influence of the NHC ligand on the chemoselectivity. catalytic semihydrogenations. Transfer hydrogenation pro- The reaction requires elevated temperatures, and either cesses are discussed first (Sections 3 and 4) followed by conventional heating (140 °C) or heating in a microwave

‘real’ hydrogenative processes using H2 (Sections 5 and 6). (120 °C) could sustain the catalytic reaction. While up until now the substrate scope remains rather limited, this exam-

ple marks the first use of the standard H2 equivalent iso- 3 Homogeneous Copper-Catalyzed Transfer propanol in the realm of homogeneous copper(I)-catalyzed Hydrogenations transfer hydrogenation.43

Copper(I)-catalyzed hydrogenation reactions often re- quire high pressure and therefore need specialized equip- 4 Trapping of Reactive Intermediates of ment.29 To circumvent this requirement, transfer hydroge- Alkyne Transfer Semihydrogenation Reac- nation reactions with homogeneous copper catalysts have tions: First Steps Towards Hydrogenative 34 been developed. Ammonia borane (H3N·BH3) has been Alkyne Functionalizations shown to be a formidable H2 equivalent in copper(I)-catalyzed transfer hydrogenations.35 Remarkably, N-heterocyclic carbene/copper(I) hydroxide complex 19,36,37 which Based on the transfer hydrogenations discussed in Sec- had been successfully used in catalytic alkyne semihydro- tion 3, suitable external electrophiles tolerant of the proto- genations earlier,38,39 can be employed under almost identi- decupration and the concomitant generation of copper(I) cal conditions in a transfer hydrogenation setting by hydrides (Scheme 3, path d vs path c) have been identified. switching to ammonia borane. In this manner, a variety of In this manner, the transfer hydrogenations can be ren- alkynes 17 could be converted into the corresponding Z- dered reductive functionalizations of alkynes. While in cop- alkenes 18 in good yields (reaching up to 80%) and with ex- per(I)-catalyzed transfer hydrogenations with ammonia bo- cellent stereoselectivity (Z/E > 95:5, Scheme 4, a). The ex- rane the intermediate vinylcopper(I) complex 13 leads to ceptionally high Z-selectivity stems from the proposed ste- the corresponding alkenes 16, it could also be trapped with reospecific syn-hydrocupration as the key step forming vi- a halogen electrophile forming value-added substituted nylcopper(I) complex 13,32 as highlighted in Scheme 3. alkenes 15 in a stereoselective fashion, resulting in a net

Generally, the use of NHC (NHC = N-heterocyclic carbene) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ligands in copper(I)-catalyzed (transfer) hydrogenation H H+ suppresses any reactivity towards unactivated alkenes, sup- H protodecupration R1 40 undesired porting the high chemoselectivity of the overall processes. 2 1 [Cu] R R [Cu–H] Using this method, internal diaryl-, aryl/alkyl- and dialkyl- H 16 R1 alkynes 17 with a variety of functional groups were tolerat- R2 R2 E ed. Though the addition of ammonia borane had to occur + reductive alkyne 12 13 + E H R1 hydro- slowly in order to avoid catalytic dehydrocoupling (release functionalization generated under R2 of H2 from ammonia borane), it has been shown that the transfer hydrogenation 15 overall protocol manifests a ‘true’ transfer hydrogenation conditions and not, as one might suspect, a hydrodecoupling releasing H2 (i.e., intrinsic electrophile + and subsequent catalytic hydrogenation. H present) In a related process, terminal alkynes 23 (which are not Scheme 5 Comparison of two possible reaction pathways based on a tolerated by the abovementioned protocol based on ammo- vinylcopper(I) intermediate. Transfer hydrogenation vs reductive alkyne nia borane) could be converted into the corresponding hydrofunctionalization

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

hydrohalogenation of alkynes. Therefore, the trapping of a) 5.0 mol% [IPrCuCl] (31) the key vinylcopper(I) intermediate 13 offers an entry into 5.0 equiv. NaOH 2.0 equiv. H N BH 3 3 Br H substituted alkenes with controlled stereochemistry Ph 2.3 equiv. (CCl2Br)2 (32) H + Br (Scheme 5). Ph Ph THF, 0 °C, 3 h In this vein, it has been found that electrophilic halogenation reagents react suitably fast in the trapping of the 25 26 27 67% conversion vinylcopper(I) complex 13 and lead to substituted vinyl ha- 26/27 lides in a stereoselective fashion.44 Highly substituted vinyl 64:36 no regiocontrol bromides such as 29 are sought-after substrates for cross- coupling reactions,1 which are hard to access in any other b) H way.45 In this manner, highly stereoselective hydrochlorina- Br tions, -brominations and -iodinations leading to vinyl ha- 5.0 mol% [IPrCuCl] (31) R 5.0 equiv. NaOH lides were achieved using commercially available [IPrCuCl] 2.0 equiv. H N BH Het 3 3 29 (31) and NaOH as a basic additive. Again, just as in the earli- R 2.3 equiv. (CCl2Br)2 (32) + er transfer hydrogenation35 (compare Scheme 4), slow addi- Het THF, 0 °C, 3 h Br tion of both ammonia borane and the electrophile was cru- 28 H cial. This suppresses the competitive dehydrocoupling and Het = OTBDPS R OTBS undesired protodecupration (essentially leading to the NMeTs Het 30 transfer hydrogenation product 16, Scheme 5). An addition- R = alkyl 18 examples al bifurcation of the reaction needs to be controlled, namely 51–86% 29/30 = 13:1 to 50:1 the regioselectivity of the initial hydrocupration, which sets regioselective through the positioning of the halide. The employment of electroni- electronically biased substrates cally unbiased internal alkynes such as 25 led to no signifi- iPr iPr Cl NN Cl cant control of the regioselectivity (26/27 = 64:36) (Scheme Cl iPr Br 6, a). This regioselectivity, however, could be controlled iPr Cu Cl Br electronically by modifying the alkyne via the inductive ef- Cl fect46 exerted by propargylic silyl ethers or protected prop- 31 32 [IPrCuCl] argylic amines 28. With these starting materials, a highly (CCl2Br)2 regioselective syn-hydrocupration using dibromotetrachlo- roethane (32) as the source of electrophilic bromine gave H H H O Br Br Br rise to the selective formation of one of the hydrobromina- ( ) ( ) 4 Br 2 Ph tion regioisomers favoring halogenation at the -position of NC OTBS OTBS NMeTs the heteroatom (29/30 = 13:1 to 50:1, Scheme 6, b). Inter- estingly, other leaving groups that have been shown to re- 29a 29b 29c act with copper(I) hydrides, such as alkyl tosylates,47 were 86% 74% 51% 29/30 = 96:4 29/30 = 96:4 29/30 = 94:6 not attacked by the catalytically generated nucleophilic copper(I) hydride. Switching to the related propargylic sul- Scheme 6 Intercepting the vinylcopper(I) complex in a transfer hydrogenation setting: Copper(I)-catalyzed regio- and stereoselective alkyne fonyl amide 28 resulted in moderate yield but still good se- hydrobrominations lectivity. In addition, it is notable that terminal alkynes such as 33 could be transformed into the terminal alkene

34, a substrate class that was barred so far due to the highly 5 mol% [IPrCuCl] (31) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. basic additives. In this case, however, NaOH allowed for the 5 equiv. NaOH 2 equiv. H3N BH3 H rare conversion of 33 into 34 (Scheme 7). 2.3 equiv. (CCl Br) (32) Ph 2 2 Ph Br Using N-chlorosuccinimide (NCS) or N-iodosuccinimide THF, 0 °C, 3 h (NIS), the corresponding vinyl chlorides or iodides 36/37 33 34 were obtained with similarly high selectivity (13:1 to 22:1) 67% 5% protodecupration (Scheme 8), albeit with slightly reduced yields due to competitive transfer hydrogenation. Nevertheless, the overall Scheme 7 NaOH as the key additive enlarges the substrate scope in catalytic stereo- and regioselective hydrohalogenation rep- the copper(I)-catalyzed transfer hydrobromination of terminal alkynes resents a both general and versatile catalytic entry to highly functionalized building blocks, namely highly substituted vinyl chlorides, bromides and iodides.48

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

Cl/I H H+ H OTBS H protodecupration R1 5 mol% [IPrCuCl] (31) overall semi- 2 5 equiv. NaOH R 1 [Cu] R hydrogenation R [Cu–H] 2 equiv. H3N BH3 36 H 16 4 equiv. NCS/NIS R1 OTBS R2 + 2 R R E THF, 0 °C, 3 h + H2-mediated alkyne H 12 13 + E H R1 hydro- 35 Cl/I OTBS 2 functionalization R = alkyl generated using H2 R iPr iPr R (i.e., intrinsic electrophile 15 NN 37 H+ present) iPr iPr 6 examples Cu 32–52% Scheme 9 Comparison of two possible reaction pathways of alkynes Cl 36/37 = 13:1 to 22:1 under hydrogenative conditions 31 [IPrCuCl] Scheme 8 Expanding the scope: Copper(I)-catalyzed regio- and propanol), as indicated by deuteration experiments. This stereoselective alkyne hydrochlorinations and -iodinations protocol allowed the transformation of alkynes into alkenes with good to high yields (52–99%) and excellent stereose- It should be noted that the related hydrobromination of lectivity (Z/E = 97:3 to >99:1). Despite an elevated tempera- terminal alkynes to give vinyl bromides using hydrosilanes ture (100 °C), almost no overreduction was observed at re- as terminal reducing agents (thus no competitive transfer markably low H2 pressure (5 bar). hydrogenation to be feared, general pathway b in Scheme 3) Copper(I)-catalyzed semihydrogenations often rely on 49 had been developed earlier. This protocol allows the alkoxide bases as additives for the activation of H2, meaning transformation of alkyl- and aryl-alkynes in moderate to the requirement of a Cu–O bond for heterolytic cleavage of high yields. Using this approach, only hydrobrominations dihydrogen [compare Scheme 2 (-bond metathesis)].27 To were feasible. circumvent the need for high amounts of this additive, which can be detrimental for the tolerance of functional groups, a Z-selective copper(I)-catalyzed semihydrogena- 5 Copper(I)-Catalyzed Alkyne Semihydroge- tion using a tethered copper(I) alkoxide complex derived nations from NHC precursor 40 has been developed.55 The catalyst features an intramolecular Cu–O bond by virtue of biden- Stereoselective semihydrogenations of alkynes are im- tate ‘tethered’ NHC/alkoxide ligand 40 (Scheme 10, a).56 Us- 50 portant catalytic alternatives for olefination reactions. ing 100 bar H2 pressure at 40 °C, internal alkynes 38 could Most prominent is the Lindlar51 catalyst delivering Z- be transformed into the corresponding Z-alkenes 39 by em- alkenes, however, this catalyst requires careful monitoring ploying catalytic amounts of mesitylcopper(I) (41), imidaz- of the reactions due to isomerization processes and fre- olinium salt 40 and n-BuLi for in situ activation. This proto- quently occurring overreduction. Therefore, selective semi- col ensures the formation of the required Cu–O bond. Imid- hydrogenation reactions not requiring close reaction con- azolinium salt 40 also served as an intramolecular proton trol are highly desirable and represent an active field of re- shuttle for which reason both hydrogen atoms from dihy- search.5,6,52 As depicted in Scheme 9, copper(I)-based drogen are transferred to the alkyne 38 in a ‘real’ semihy- processes again rely on stereoselective syn-hydrocupra- drogenation reaction. This was underpinned by deuteration tions, which offer high Z-selectivity for the overall alkyne experiments forming Z-alkene 39 with high deuterium in- 32 semihydrogenation. In this case, the catalytically generat- corporation (see also Scheme 14). This protocol is applica- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ed proton (equivalent) plays the role of electrophile for 13, ble for diaryl-, dialkyl- and aryl/alkyl-alkynes 38, proceed- meaning that already at this stage, hydride and electrophile ing in moderate to high yields (60–95%) and excellent are decoupled in reactivity. Early alkyne semihydrogena- stereoselectivity (Z/E up to 99:1), while remarkably, no tions indeed drew upon the stoichiometric use of hydrosila- overreduction to the alkane was observed, even over pro- nes under acidic conditions to effect a formal semihydroge- longed reaction times. This catalyst tolerates other reduc- nation of alkynes, in which the hydride and proton were ible functional groups such as esters, ketones and nitriles as delivered from different sources.53 More recently, much well as heterocycles such as pyridines. more atom economic3,4 variants of these catalytic conver- Circumventing high-pressure equipment, a copper(I)- sions based on H2 have been disclosed. catalyzed semihydrogenation at atmospheric H2 pressure The first copper(I)-catalyzed formal semihydrogenation could be achieved by employing [SIMesCuCl] (22) as the 57 required [(PPh3)CuCl]4 as the catalyst, LiOtBu as the basic catalyst and NaOtBu as the activator (Scheme 10, b). At el- additive for activation and iso-propanol as the proton evated temperature, catalytic semihydrogenation of source.54 This combination led to the transfer of a hydride alkynes 42 resulted in the formation of Z-alkenes 43 in and a proton from the different sources (namely H2 and iso- moderate to good yield (36–88%) and good to excellent

Syn thesis L. T. Brechmann, J. F. Teichert Short Review selectivity (Z/E ratios of 87:13 to >99:1), with a maximum tive since catalyst 19 is already preactivated towards the re- of 10% overreduction to the corresponding alkane being ob- action with H2, bearing a Cu–O bond itself. Along with the served. Despite the achievement of running the reaction at excellent chemoselectivity, almost completely suppressing

1 bar of H2 pressure, the yield and selectivity were generally the formation of alkanes, Z-alkenes 45 were obtained in inferior compared to the catalytic semihydrogenations high to excellent yield (80–99%) and excellent stereoselec- mentioned above. tivity of Z/E >99:1 under 80 bar of H2 pressure at 40 °C. This A related NHC/copper(I) complex, namely [IPrCuOH] protocol tolerated functional groups such as halides, esters (19)36,37 displayed enhanced air and moisture stability re- and ethers, while a ketone was partially reduced to the cor- sulting in a much more practical protocol for Z-selective responding alcohol. Overall, the high stability of 19 makes it semihydrogenations of internal alkynes 44.38 (This catalyst the catalyst of choice for Z-selective alkyne semihydrogena- is also applicable to the related transfer hydrogenation, see tions based on copper. Section 3.) Moreover, there is no need for an alkoxide addi- This protocol could also be extended to the catalytic hydrogenation of 1,3-diynes.39 Surprisingly, in these reac-

a) 5/10 mol% [MesCu] (41) tions, the stereoselectivity is controlled by the diyne sub- 6/12 mol% 40 stituents: Whereas diaryl-substituted 1,3-diynes 46 were 6/12 mol% nBuLi H R2 100 bar H converted into the corresponding E,E-1,3-dienes 47 (which 2 H R2 R1 THF, 40 °C, 18 h is counterintuitive to the observed semihydrogenations of 1 R alkynes, Scheme 10, c), complementary to this, dialkyl- 38 39 substituted 1,3-diynes 48 were transformed into Z,Z-1,3- R1 = aryl, alkyl 15 examples 60–95% R2 = aryl, alkyl dienes 49 (Scheme 11). As a plausible explanation for this Z/E >95:5 orthogonal selectivity, a facilitated rearrangement of the in- • + high pressure termediate vinylcopper(I) complex was put forward. N N Cu • moderate temperature Mes • variety of functional groups – Ar 5 mol% [IPrCuOH] (19) PF6 HO H H 100 bar H2 E Ar 40 41 Ar E [MesCu] THF, 40 °C, 17 h Ar H H

46 47 b) 10 mol% [SIMesCuCl] (22) 8 examples 10 mol% NaOtBu 75–92% H 2 E,E/Z,Z >95:5 R 1 bar H2 H R2 R1 octane/1,4-dioxane (4:1) R1 100 °C, 12 h Alkyl 5–10 mol% [IPrCuOH] (19) 43 Alkyl H 42 100 bar H2 Z R1 = aryl, alkyl 9 examples H 36–88% H R2 = aryl, alkyl THF, 40 °C, 17 h Z Z/E = 87:13 to >99:1 Alkyl H Alkyl <10% alkane 48 49 NN • mild conditions 2 examples • lower yield 85–95% Cu • reduced selectivity Z,Z/E,E >95:5 Cl Scheme 11 Copper(I)-catalyzed diyne semihydrogenation 22 [SIMesCuCl] 6 Copper(I)-Catalyzed H -Mediated Alkyne c) 5 mol% [IPrCuOH] (19) 2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2 H R 80 bar H2 H Functionalizations; Trapping of Reactive In- 2 1 R R THF, 40 °C, 24 h R1 termediates from Catalytic Hydrogenations

44 45 R1 = aryl, alkyl 13 examples 80–99% Taking inspiration from H -mediated C–C bond forma- R2 = aryl, alkyl 2 Z/E >99:1 tion reactions with precious metals such as rhodium, as iPr iPr • high pressure mentioned in the introduction (Section 1), one can wonder NN • moderate temperature whether similar processes based on catalytically generated • preactivated iPr Cu iPr copper(I) hydride complexes would also be feasible. As pre- OH viously discussed (see Scheme 3), reductive coupling reac- 19 tions with copper(I) catalysts mostly relying on hydrosila- [IPrCuOH] nes are a mainstay in synthetic chemistry.17–19 However, to Scheme 10 Copper(I)-catalyzed alkyne semihydrogenations: An over- date, the mechanistically challenging trapping reactions of view of available catalysts and protocols catalytic hydrogenations remain rare. Reactions relying

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

solely on dihydrogen (H2) would synthetically be elegant, sures the suppression of any reactivity with unactivated however, they inherently bear the problem that a rapid pro- alkenes, which is in stark contrast to the well-known reduc- todecupration 13 → 16 must be overcome (Scheme 12, tive alkene functionalizations relying on phosphine li- compare also Scheme 3). gands.17–19 Therefore, the terminal alkenes generated in the As already shown in the previous section (Section 5), allylic substitution remain untouched. On the other hand, copper(I)-catalyzed semihydrogenation reactions rely on a regioselectivity could ideally be controlled to access selec- syn-hydrocupration of alkynes 12, forming vinylcopper(I) tively either the SN2′ or SN2 product. The use of deuterium intermediate 13. At this stage, a new reaction pathway gas not only underpins the proposed mechanism, but also could be accessed: If 13 is not trapped by a proton to form leads to selective monodeuteration, forming value-added the corresponding alkene 16, but instead reacts with anoth- products potentially useable in drug discovery,59 elucida- er electrophile, this opens up the possibility of new C–C tion of biosynthetic pathways60 or mechanistic studies.61 bond (or C–heteroatom bond) formation reactions (13 → Employing NHC/copper(I) catalyst 53 and NaOtBu as an ac-

15). tivator with 90 bar of D2 pressure, allylic chlorides 50 were successfully converted into the corresponding terminal H alkenes 51 in yields of up to 82%, excellent /-ratios (up to H+ H protodecupration R1 undesired >95:5), and with excellent deuterium incorporation 2 58 1 [Cu] R throughout (>96%) (Scheme 13). Following this protocol, R [Cu–H] H 16 R1 halides, esters and tosylates as potential leaving groups, as R2 R2 E well as silyl- or benzyl-protected alcohols (the latter are + reductive alkyne 12 13 + E H 62 R1 hydro- generally cleaved under hydrogenative conditions) were functionalization generated under R2 tolerated. Crucial for high regioselectivity of the allylic sub- transfer hydrogenation 15 stitution was the Z-configuration of the allylic chloride: conditions Whereas E-cinnamyl chloride resulted in a poor /-ratio of (i.e., intrinsic electrophile H+ present) 61:39, Z-cinnamyl chloride on the other hand gave high selectivity (/ = 89:11).63 It should be noted that a similar Scheme 12 Comparison of two possible reaction pathways for alkynes under hydrogenative conditions process has been published earlier employing hydrosilanes as terminal reducing agents.64

6.1 Detour: Copper(I)-Catalyzed Allylic Reductions, 5 mol% 53 2 1.5 equiv. NaOtBu 2 R R2 D R Catalytic Generation of Hydride Nucleophiles from H2 90 bar D2 + R1 Cl R1 γαR1 D 1,4-dioxane/benzene (1:1) One approach to trapping reactions is the use of allylic 50 10 or 40 °C, 48 h 51 52 electrophiles in combination with alkynes and copper(I) R1 = aryl, alkyl 20 examples hydride complexes. However, as outlined in Section 6.2 and R2 = aryl, alkyl 30–82% γ/α = 68:32 to >95:5 Scheme 15, a possible unwanted side reaction is the direct NN >96% D hydride transfer from the copper(I) hydride complex to the MeO OMe Cu allylic electrophile. This reaction has also been developed Cl and is therefore presented at this stage before the actual 53 trapping reactions are discussed. These reactions highlight a key feature of the heterolytic D

H2 activation with copper(I) complexes, namely the catalyt- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. D D ic generation of nucleophilic hydrides from H . Such a reac- H 2 BnO tivity is rare in the realm of the catalytic activation of H 2 H H with transition-metal complexes and sets apart copper(I)- TBDPSO catalyzed reactions from transformations with noble tran- 51a 51b 51c sition metals as highlighted above (Scheme 1).6 The catalyt- 100% conversion 82% 76% γ/α = 90:10 γ/α = 95:5 γ/α >95:5 ic hydride transfer from H2 to allylic chlorides 50, the so- 96% D 99% D >99% D called allylic reduction, generates terminal alkenes 51 Scheme 13 Copper(I)-catalyzed allylic reduction; regioselective trans- 58 (Scheme 13). In this transformation, two main challenges fer of catalytically generated deuteride nucleophiles from D2 have to be overcome. On the one hand, the chemoselectivity needs to be controlled, as many transition-metal catalysts for dihydrogen activation are also formidable catalysts As part of this study, the two fundamentally different 6 for alkene hydrogenation. This is even more pressing, as processes involving copper(I) hydride compounds from H2 many copper(I) hydride mediated processes with alkenes with different functional groups (alkyne semihydrogena- are known.17–19 In this approach, the use of NHC ligands en- tion and allylic reduction), as outlined above, were high-

Syn thesis L. T. Brechmann, J. F. Teichert Short Review lighted in a reaction sequence leading to the selective terminal reductants, in which no protodecupration can oc- preparation of isotope labeling patterns. Through the com- cur. In this vein, the formation of skipped dienes from inter- bination of an alkyne semihydrogenation reaction (see nal alkynes and allylic phosphates has been reported.46,66

Scheme 10) and an allylic reduction, with the judicious If H2 was to be employed for a related hydrogenative choice of H2 or D2 for the different processes, unique deu- coupling reaction, the overall process would be more atom teration patterns were accessible. In this manner, propar- economic, since common hydride sources (such as hydro- gylic silyl ether 54 was semihydrogenated with high deute- silanes, aluminum hydrides or borohydrides) and the con- rium incorporation (>91% D) and subsequently converted comitant formation of stoichiometric amounts of waste into the corresponding allylic chloride 55-d2. Dependent on would be circumvented, whilst the molecular complexity the use of dihydrogen or deuterium gas, either terminal could increase drastically in such a three-component cou- alkene 56-d3 or 56-d2 was formed with excellent regioselec- pling, as highlighted in the previous paragraph. tivity (>95:5) and high deuterium incorporation (Scheme Indeed, the first hydrogen-mediated copper(I)-cata- 14). lyzed reductive coupling reaction by trapping of the generated vinylcopper(I) complex 13 intermediate with an allylic alkyne semihydrogenation chloride to form skipped dienes 60 was published recent- 1) 10 mol% CuCl ly.58 As can be seen from Scheme 15, this process would re- 16 mol% 40 31 mol% nBuLi 91% quire finely balanced rates of the single reaction steps. In 90 bar D2 D principle, the copper(I) hydride complex is able to open up THF, 60 °C, 48 h 92% OTIPS D Cl BnO three different pathways: (a) Reaction with alkyne 57 leads ( ) 4 2) 2 equiv. TBAF THF, rt, 4 h ( )4 to a semihydrogenation via protodecupration (13 → 16), BnO 3) 2 equiv. LiCl leading to the alkene 59, (b) allylic reduction, i.e., direct hy- 542 equiv. MsCl 55-d2 2 equiv. 2,6-lutidine 51% (over 3 steps) dride transfer to the allylic chloride 58 (itself a feasible reac- DMF, 0 °C to rt, 14 h tion,58 see Section 6.1, Scheme 13), or (c) the desired trap- 86% ping of the vinylcopper(I) intermediate 13 with allylic chlo- D 56-d2 91% H allylic reduction ride 58 installing a new C–C bond. 81% D γ/α >95:5 5 mol% 53 ( )4 1.2 equiv. NaOtBu a) alkyne BnO H 90 bar H2/D2 semihydrogenation H R2 1,4-dioxane/benzene (1:1) only 57 reacts 82% R2 R1 40 °C, 48 h D 59 56-d3 89% D R1 minor 75% D γ/α >95:5 57 H R3 R4 ( )4 [Cu–H] c) H2-mediated coupling BnO + R1 both, 57 and 58 react R4 R2 N N + 60 N N 3 major Mes R Cl MeO OMe 58 Cu R4 H PF6 HO b) allylic reduction Cl R3 only 58 reacts 53 40 61 Scheme 14 Formation of isotope labeling patterns by combination of minor

alkyne semihydrogenation and allylic reduction with H2 or D2 Scheme 15 Possible reaction pathways of alkynes and allylic chlorides in the presence of copper(I) hydride complexes This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 6.2 Trapping with Allylic Electrophiles: A Copper(I)- Catalyzed Hydroallylation Reaction of Alkynes Hinging on the catalytic generation of nucleophilic hy-

drides from H2 by employing copper(I)/NHC catalysts, a C–C Another possibility to intercept the catalytically formed bond-forming process can be realized as outlined in vinylcopper(I) intermediate 13 would be a subsequent al- Scheme 15. If a prior hydrocupration of an alkyne is suit- lylic substitution. In this manner, the copper(I) complex ably fast, then the vinylcopper(I) intermediate 13 can itself serves a dual role, as it would not only mediate the hydro- be used as the nucleophile for an allylic substitution. This cupration, but also serve as a catalyst for the trapping reac- would open up a new avenue to C–C bond formation, lead- tion (the allylic substitution).65 In this manner, one could ing to skipped dienes 64 (Scheme 16).58,67 Therefore, condi- depart from the imperative of C(sp2)–C(sp2) bond formation tions which suppress the two side reactions, namely the in a cross-coupling reaction, but instead one would forge a semihydrogenation of the alkyne and the allylic reduction new C(sp2)–C(sp3) bond. Such processes, which offer the (i.e., direct transfer of the copper(I) hydride to the allylic additional advantage of possibly generating a stereogenic chloride, compare Scheme 13), but instead promoting the center, are indeed known for reactions with hydrosilanes as C–C bond formation are necessary. In this reaction, the

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

simultaneous control of stereo- and regioselectivity under 5 mol% 53 4 1.5 equiv. NaOtBu 3 4 hydrogenative conditions poses many challenges for cata- 1 R H R R R 100 bar H2 lyst development. Moreover, the catalyst has to be chemo- + R3 Cl R1 γ R2 1,4-dioxane, 40 °C, 24 h selective to avoid over reduction of the newly formed R2 alkene to the corresponding alkane, even with an elevated 62 63 R1 = aryl R3 = alkyl, H 64 H2 pressure. Furthermore, the attack of the vinylcopper(I) R2 = aryl, alkyl R4 = alkyl intermediate 13 has to proceed in a regioselective fashion NN to distinguish between an S 2 or S 2′ product. Remarkably, MeO OMe N N Cu even though a metal hydride is the key reactive intermedi- Cl ate in the overall reaction, no isomerization of the skipped 53 1,4-diene 64 to the thermodynamically favored 1,3-diene is observed. Employing NHC/copper(I) species 53, NaOtBu as selected examples the activator and allylic chloride 63 as the electrophile, H H Ph alkynes 62 could be successfully coupled to give skipped γγ dienes 64 with yields of up to 94% at 40 °C with 100 bar of S S H2 pressure (Scheme 16). This protocol tolerates electron- poor as well as electron-rich alkynes and is applicable for Cl diaryl-alkynes as well as aryl/alkyl-alkynes. Noteworthy is γ-64a γ-64b/α-64b r.r. 97:3 98:2 the formation of -64a from a non-symmetric alkyne. With 94% 91% such substrates, the regioselectivity of the initial alkyne hy- OH drocupration brings up an additional complication. The cat- >95% D alysts employed, however, led to a highly regioselective hy- H Ph γ drocupration (favoring the placement of copper in a quasi- Ph γ Ph benzylic position) as can be seen in the highly regio- Ph γ-64d selective formation (97:3 r.r.) of -64a. A heteroarene-sub- γ-64c/α-64c using D 86:14 2 stituted alkyne was also tolerated, resulting in thiophene- 56% 48% substituted skipped diene -64b in high yield and selectivity (-64b/-64b = 98:2). Moreover, the use of 3,3-disubsti- Scheme 16 Dihydrogen-mediated copper(I)-catalyzed coupling reaction of alkynes with allylic chlorides. (Newly formed bonds are high- tuted allylic chlorides led to a significant broadening of the lighted in bold)69 substrate scope, as quaternary centers are also accessible under identical conditions. In this way, terpene-like product 64c was obtained from commercially available farnesyl As a noteworthy extension of this methodology, 1,3- chloride. Employing D2 indicated syn-hydrocupration as the diynes can also be employed as starting materials, leading first step followed by the attack on vinylcopper(I) interme- to multiply unsaturated products with high catalytic con- diate of the allylic chloride leading to diene 64d with excel- trol of the selectivities as outlined above. In this manner, lent deuterium incorporation of >95%. This result supports diyne 65 is converted in high yield (92%) and excellent the current mechanistic rationale as outlined in Scheme 12. In all cases, the competitive alkyne semihydrogenation could be suppressed reaching high chemoselectivity (up to 94:6). Furthermore, no overreduction of the formed 1,4-di-

ene 64 was observed even under high H2 pressure. While This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. this copper(I)-catalyzed H2-mediated coupling is still being H investigated, it clearly shows the great potential of atom 5 mol% 53 γ economic C–C bond formations employing dihydrogen gas 65 1.5 equiv. NaOtBu 68 100 bar H2 and abundant and inexpensive base metals. Also, while +

H2-mediated C–C bond-forming reactions have served as 1,4-dioxane, 40 °C, 64 h Cl inspiration for these developments, the highlighted trans- 66 formations relying on copper catalysts offer the advantage of using different coupling partners in comparison to the 67 reactions with noble metal catalysts. Therefore, these new γ/α = 95:5 transformations offer an orthogonal approach to atom-eco- 92% nomic H2-mediated C–C bond-forming reactions. Scheme 17 H2-mediated copper(I)-catalyzed coupling reaction of a 1,3-diyne with an allylic chloride. (Newly formed bond is highlighted in bold)70

Syn thesis L. T. Brechmann, J. F. Teichert Short Review regioselectivity into dienyne 67, while the formation of 7 Conclusion only one new C–C bond was observed (dienyne/triene = 95:5) (Scheme 17). In this review, an emerging field of method development for synthetic chemistry has been highlighted. Ema-

6.3 Trapping with Aryl Iodides nating from H2-mediated C–C bond formations revolving around the carbonyl functional group, recently, copper(I) In this vein, a hydrogenative cross-coupling reaction of catalysis in combination with dihydrogen as a stoichiomet- internal symmetric alkynes 68 with aryl iodides 69 has ric reducing agent has proven to be a powerful orthogonal 71 been disclosed. Employing NHC/copper(I) complex 22, approach. Ultimately, H2 as the key source for copper(I) hy- LiOtBu as the activator, and a phosphine/palladium com- drides builds a fertile ground for novel C–C bond and C–he- plex, the key vinylcopper(I) intermediate is trapped by a teroatom bond formations. These processes could employ 72 palladium-catalyzed cross-coupling process (Scheme 18). conditions of transfer hydrogenations with a suitable H2

In this co-catalytic H2-mediated process, internal diaryl equivalent or H2 directly. In all cases, the trapping reactions alkynes 68 are transformed into the corresponding trisub- have to be fine-tuned to overcome the intrinsic challenge of stituted alkenes 70 in moderate to good yield (38–73%) protodecupration, and in this vein, well-defined NHC/cop- with high stereoselectivity, as can be expected (E/Z = 86:14 per(I) complexes have excelled so far. Employing these cata- to 98:2 and Z/E = 95:5 to 98:2).73 It is worth noting that an lysts, several recent results have underlined that indeed aryl, alkyl-alkyne results in a mixture of regioisomers for such remarkable H2-mediated coupling reactions based on 70c (59:41), which shows that the hydrocupration displays copper(I) catalysts are feasible. This opens up a broad stage little regioselectivity. For high efficiency, palladium/copper for further developments to come, of which enantioselec- cooperative catalysis is required, but in the absence of the tive processes are just one open goal at this stage. It will be copper(I) catalyst 22, alkene 70 is still formed with 20% exciting to see whether H2-driven processes will emerge as yield and high stereoselectivity. Overall, this procedure powerful synthetic transformations and how this method- marks a remarkable cross-coupling process in which the or- ology can be broadened. In comparison to the related cata- ganometallic component [namely vinylcopper(I) complex lytic reactions based on hydrosilanes, these H2-mediated 13] is catalytically generated, circumventing the need for a reactions are still in their infancy, but it will be great to see stoichiometric organometallic coupling partner. how new reactions based on H2 –which are not hydrogenations –will be developed in the future. 1 mol% [IMesCuCl] (22) 1 mol% Pd(OAc)2 4 mol% PCy3 2 equiv. LiOtBu Funding Information H R 5 atm H2 + Ar Ar I R This work was supported by the Deutsche Forschungsgemeinschaft R toluene, 100 °C, 15 h (DFG) (German Research Council) (Emmy Noether Fellowship for J.F.T., R TE1101/2-1) and by the Fonds der Chemischen Industrie (Liebig- 68 69 70 R = aryl 11 examples Stipendium for J.F.T.).Deutsche Forschungsgemeinschaft (TE1101/2-1)Verband der Chemischen Industrie () 38–73% E/Z = 86:14 to 98:2 NN Acknowledgment Cu Cl Prof. Dr. Martin Oestreich (TU Berlin) is kindly thanked for generous 22 support. [SIMesCuCl] This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

H H H References TBSO Ph Ph C4H9 (1) Metal-Catalyzed Cross-Coupling Reactions and More; de Meijere, Ph Ph A.; Bräse, S.; Oestreich, M., Ed.; Wiley-VCH: Weinheim, 2014. Cl (2) Organometallics in Synthesis, Third Manual; Schlosser, M., Ed.; John Wiley & Sins: Hoboken, 2013. Cl (3) Anastas, P. T.; Warner, J. C. Green Chemistry. Theory and Prac- 70a 70b 70c 70% 44% 42% (NMR) tice; Oxford University Press: Oxford, 2000. E/Z = 98:2 E/Z = 5:95 r.r. = 59:41 (4) (a) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437. (b) Sheldon, R. A. Chem. Commun. 2008, 3352. (c) Trost, B. M. Angew. Chem. Int. Scheme 18 Palladium/copper co-catalyzed hydrogenative cross- Ed. 1995, 34, 259. coupling of internal alkynes with aryl iodides. Newly formed bonds are highlighted in bold. (5) Homogeneous Hydrogenation with Non-Precious Catalysts; Teichert, J. F., Ed.; Wiley-VCH: Weinheim, 2020. (6) The Handbook of Homogeneous Hydrogenation; de Vries, J. G.; Elsevier, C. J., Ed.; Wiley-VCH: Weinheim, 2006.

Syn thesis L. T. Brechmann, J. F. Teichert Short Review

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