Lee Yong Ho

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This document is the Accepted Manuscript version of a Published Work that appeared in final form in Nature Chemistry, copyright © Springer Nature after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1038/s41557-020-00621-x
Palladium-catalysed carboformylation of alkynes using acid chlorides as a dual carbon monoxide and carbon source

Yong Ho Lee, Elliott H. Denton, Bill Morandi*


ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland.

*Correspondence to: [email protected]



Hydroformylation, a reaction which installs both a C­H bond and an aldehyde group across

an unsaturated substrate, is one of the most important catalytic reactions both in industry

and academia. Given the synthetic importance of creating new C­C bonds, the development

of carboformylation reactions, wherein a new C­C bond is formed instead of a C­H bond,


would bear enormous synthetic potential to rapidly increase molecular complexity in the

synthesis of valuable aldehydes. However, the demanding complexity inherent in a four-

component reaction, utilizing an exogenous CO source, has made the development of a direct

carboformylation reaction a formidable challenge. Here, we describe a palladium catalysed

strategy which uses readily available aroyl chlorides as a carbon electrophile and CO source,


in tandem with a sterically congested hydrosilane, to perform a stereoselective

carboformylation of alkynes. An extension of this protocol to four chemodivergent

carbonylations further highlights the creative opportunity offered by this strategy in

carbonylation chemistry.


Carbonylation reactions using carbon monoxide (CO) constitute an industrial core technology.

They provide a direct and atom-economic strategy to convert, on a multimillion ton-scale per year,

bulk chemicals to various carbonyl-containing compounds and their derivatives, which are


essential commodity products in daily life1­4. Due to the importance of these reactions in

preparative chemistry, intense academic and industrial research has been dedicated to the

development of more environmentally benign and robust catalyst systems as well as highly chemo-

, regio- and stereoselective carbonylation reactions5­14. The seminal discovery of transition-metal


catalyzed carbonylations was reported by Reppe, which utilizes feedstock alkenes, CO and a

nucleophile to produce the corresponding carbonylated products4. Later, significant progress in the

field of carbonylation chemistry was made by Heck in 1974, where a palladium catalyst allowed

for the carbonylation of carbon electrophiles with various nucleophiles under a pressurized CO


atmosphere to generate the corresponding carbonyl-containing compounds6,11. Simultaneously,

significant research has focused on vanquishing the hazards associated with the use of toxic and

highly flammable CO, as well as avoiding the use of pressurized reactors to facilitate laboratory

use. Among these strategies, the use of CO surrogates and two-chamber systems operating under

mild conditions, as well as CO transfer by shuttle catalysis and single bond metathesis strategies,


have emerged as valuable alternatives15­22.

Among all carbonylation reactions, catalytic hydroformylation, the addition of CO and H2 across

unsaturated substrates, is an essential reaction to access a wide set of functionalized aldehyde

products. Both the industrial and academic importance of this reaction are clearly highlighted by


the large volumes of aldehydes it generates annually (>12 million tons), as well as the continuous

filing and publication of new patents and manuscripts in this area (>10,000)2. A key feature of

hydroformylation is the possibility to introduce an aldehyde group, arguably one of the most

versatile functional groups in target-oriented synthesis, alongside the formation of a new C­H

bond (Fig. 1A, top)2,23­25. Given the importance of creating new C­C bonds26 and the widespread


academic and industrial impact of hydroformylation, the development of carboformylation

reactions, wherein a new C­C bond is formed instead of a C­H bond, would bear enormous

synthetic potential as a tool to rapidly prepare densely functionalized aldehydes which are

widespread synthetic intermediates (Fig. 1a, bottom).


Despite the promises offered by a carboformylation paradigm, only a single isolated example of

carboformylation has been disclosed thus far by Grigg (Fig. 1b)27­29. This report clearly captures

the challenge of developing such a reaction, as it relies on a carefully designed intramolecular

iodoarylalkene substrate undergoing a "molecular queuing" process, involving a hydrosilane and

CO, to surgically manipulate the selective formation of three sequential bonds and generate the


desired cyclized aldehyde product (Fig. 1b, top). The severity of the method´s limitations can be

illustrated in an example where shortening the tether length by a single atom led to a different

product arising from double insertion of CO (Fig. 1b, bottom)30. This extremely limited reactivity

clearly highlights the universal challenges which have plagued the development of intermolecular

carboformylation reactions (Fig. 1c): (1) the need for a catalyst system that can delicately mediate


a single and selective incorporation of one molecule of CO in the presence of an excess of CO gas;

(2) the nearly impossible task to orchestrate an intermolecular, chemoselective four-component

reaction (an electrophile, CO, a hydride source and an unsaturated substrate), a process which can

potentially lead to the formation of more than 10 different products25,30­35; (3) the use of toxic and

highly flammable CO itself, which has likely limited further research on this topic.


We hypothesized that the challenges of developing an intermolecular carboformylation reaction could potentially be addressed by using acid chlorides as reagents20­22. We reasoned that they could
simultaneously act as an atom-economic source of a carbon electrophile and CO in a catalytic
carboformylation reaction proceeding through a CO deinsertion/reinsertion process involving a


sequence of C­C bond cleavage and formation events, mediated by a transition metal catalyst,

resulting in a unique combination of well-established elementary steps (Fig. 1d)36,37. The use of

acid chlorides appeared ideal for several reasons: (1) only 1 equivalent of CO would be present in

the entire reaction system, preventing additional insertions often observed using excess CO gas as


a reagent; (2) acid chlorides can rapidly react with a low valent transition metal to generate the

corresponding aryl­M complex (II, e.g. M = Pd), which can then add across a triple bond; (3) the

intermediacy of a M­Cl bond should significantly slow down any undesirable C­Cl reductive

elimination prior to the programmed CO reinsertion38­41. These essential features should lead to

the formation of the final acyl complex (IV) which can then be irreversibly trapped by a hydride,


to develop a general platform for the elusive carboformylation reaction12,13. However, a daunting

challenge to be addressed in this strategy is to prevent any premature trapping of several closely

related organopalladium intermediates (I, II and III) generated under the reaction conditions.

Herein, we report an intermolecular carboformylation reaction of internal alkynes using aroyl


chlorides as a dual aryl and CO source. We describe a programmed CO deinsertion/reinsertion

process in which an aromatic acid chloride is formally deconstructed to aryl, CO and Cl

subcomponents by a Pd catalyst. The individual subcomponents are then shuffled with an alkyne,

and reacted with a silane in a programmed order, providing a conceptual framework for the

realization of a carboformylation reaction (Fig. 1d). Using bulky hydrosilane reductants, we were


able to transform a broad range of alkynes into the corresponding functionalized, tetrasubstituted

,-unsaturated aldehydes. The generality of this unique process is further demonstrated by an

extension of this reactivity, to the chemodivergent formation of three other valuable carbonyl

derivatives, highlighting the potential of this strategy to unlock novel carbonylation reactions.

Results and discussion

To test our initial hypothesis, we chose internal alkynes and aromatic acid chlorides as test

substrates to prepare highly functionalized ,-unsaturated aldehydes which are normally accessed


through tedious multi-step synthesis24,42. After observing small amounts of the product using a

wide variety of different phosphine ligands (see Supplementary Section 2), we reasoned that

selectively intercepting the right Pd intermediate (IV) with a hydride source would be crucial to

improve the yield of the product. We took advantage of the vast palette of commercially available

hydrosilanes exhibiting different steric profiles to probe their influence on the reactivity. A clear


correlation between the yield of the desired product relative to the steric bulk of the silane could

be observed. Using smaller silanes, a larger amount of the undesired aromatic aldehyde was

generated, presumably due to premature reduction of Pd intermediate I (Fig. 1d), whereas

sterically congested silanes, iPr3SiH and (iPr2HSi)2O, resulted in the highest yields of the desired

product. While the desired transformation was observed for a wide variety of phosphine ligands


(Supplementary Section 2), after systematic fine-tuning, two phosphine ligands, BISBI (2,2'-





dimethoxyphenyl)phosphine), were found to be optimal, therefore resulting in two complementary

conditions for the reaction depending on the steric confinement of the aroyl chloride substrate (1,


14, 18)43,44. The highly sterically encumbered nature of TDMPP may suppress the coordination of

a second phosphine to the metal atom. Instead the weakly coordinating methoxy group may

transiently occupy the vacant site and be displaced by the comparatively smaller ligands (i.e. CO

or an alkyne), in which their coordination is a prerequisite for the desired transformation. Similarly,


a weakly chelating bidentate phosphine ligand, BISBI, which possesses a large bite angle and

flexible structure, may act so that one of the P atoms binds in a hemi-labile manner, thus allowing

for the generation of a vacant coordination site. With the optimized catalyst systems, the reaction

of an equimolar ratio of all reaction components (an acid chloride/alkyne/silane = 1:1:1) gave the

desired carboformylation as the major product (1: 44% yield, 18: 40% yield, see Supplementary


Section 2.6) alongside the side-products (the corresponding arene and aryl aldehyde) formed by

premature reduction. To ensure the reaction was driven to high yield versus the alkyne as the

limiting reagent, a 2-fold excess of acid chloride and silane was used, resulting in an increased

yield (1: 71% yield, 18: 72% yield, see Supplementary Section 2.6), albeit, with an increase in

side-product formation. For the reaction scope, the equivalents of both acid chloride and silane


(1.5 to 3.0 equiv.) versus the alkyne were employed according to the steric congestion of the acid

chloride (see Supplementary Section 3).

With the optimized conditions in hand, we set out to investigate the scope of this carboformylation.

Various (hetero)aroyl chlorides bearing ortho-substituents successfully participate in this Pd-


catalyzed carboformylation with 4-octyne, producing the desired ,-unsaturated aldehydes with

excellent (Z)-selectivities and in good yields (Table 1)21,38,45. Sterically less hindered aroyl

chlorides provided moderate yields accompanied by 5­20% of the corresponding (E)-isomer,

suggesting that the ortho-substituents of aroyl chlorides impede E/Z isomerization11,12. While

sterically encumbered aroyl chlorides can be used in near stoichiometric amounts (1.5 equivalent


versus an alkyne) for high yields, a 2- to 3-fold excess of the other acid chlorides were employed

to obtain synthetically relevant yields. Methyl-, ethyl-, benzyl- and trifluoromethyl ethers (3, 5,

21, 22), esters (4, 24), nitriles (6, 26), trifluoromethyl groups (7, 28), ketones (10) and

sulfonamides (29) are tolerated. Aryl halogenides (Cl (8, 15), Br (25)) and aryl boronate esters

(23), which are, respectively, ubiquitous carbon electrophiles and nucleophiles in conventional


cross-coupling reactions, are compatible. Furthermore, a benzyl protecting group (22) remained

intact under the reducing reaction conditions, namely a Pd catalyst and a hydride source,

illustrating the orthogonality and chemoselectivity of this new reaction. Heteroaromatic acid

chlorides, including thiophene (11), benzofuran (12), pyridine (13), isoxazole (16) and thiazole

(30) derivatives, are also effective reaction partners. In addition, two derivatives of carboxylic


acid-containing pharmaceutical compounds (probenecid (29) and febuxostat (30)) participated in

this carboformylation. Notably, aroyl chlorides bearing electron-withdrawing substituents showed

moderate yields and diminished stereoselectivity. GC analysis of the crude reaction mixtures

showed an increased yield of a side product arising from competing hydroarylation, indicating that

CO reinsertion (III to IV) is less favored with electron-poor substrates. Finally, using isotopically


labelled reagents, the D and 13C labels were efficiently incorporated into the desired products (2,

20), highlighting the synthetic potential of this method as an addition to medicinal chemistry's

toolbox for the preparation of isotopically labelled ,-unsaturated aldehydes17,46. Gratifyingly,

the reaction could be performed on a multi-gram scale (25 mmol), delivering the product (1) in

excellent yield (83%, 4.8 g) with complete stereoselectivity. This result clearly demonstrates the


potential of this reaction for preparative synthesis without the need for any specialized

equipment47, such as autoclaves or two-chamber reaction vessels.


Next, the generality of this method with respect to symmetrical and unsymmetrical internal alkynes

was explored using o-, p-toluoyl and mesitoyl chlorides as representative acid chloride substrates

(Table 2). Alkyl chlorides (34), phthalimides (40), esters (41­44, 47­49), carbamates (45), alkenes


(52), amides (53), silyl ethers (57) and aldehydes (62) were all tolerated. Several internal alkynes

tethered with a polar functional group such as phthalimides, esters, carbamates and ethers were

also probed to explore whether directing effects could influence the reaction´s regioselectivity.

While most of them resulted in only slightly improved or negligible regioselectivity, an ester at

the -position relative to the alkyne led to a synthetically useful ratio of separable isomers (up to


3:1, 42­44)19. Additionally, high regioselectivity was obtained when a highly sterically

encumbered alkyne is reacted with a bulky aroyl chloride (35), displaying preferential aryl

insertion at the distal position relative to the bulky group, presumably to minimize steric repulsion.

Next, aryl-alkyl and diaryl alkynes (50­53, 64) were shown to be suitable substrates for this

transformation, offering new opportunities to access novel conjugated aldehydes with potential


applications in imaging and organic materials48­51. With regards to the regioselectivity in this class

of substrates, electronic effects seem to prevail slightly over steric effects since arylation occurred

at the more hindered position of an alkyne, resulting in geminal diaryl functionalities (51). While

terminal alkynes failed to deliver the anticipated product, likely because of polyinsertion side-

reactions44, we found that a number of alkyl-silyl (54­57), aryl-silyl alkynes (58­62), and even an


aryl-boryl alkyne (63) reacted with complete regio- and stereoselectivity. While being valuable

products in their own right, they also grant access, after deprotection, to synthetically desirable

products not directly accessible through the direct carboformylation of terminal alkynes.

We next investigated whether this programmed CO de/reinsertion process would allow for the


inclusion of alternative nucleophiles, other than a hydride, as well as different pathways (i.e. -H

elimination) depending on the structure of the acid chloride reagent. Such extensions would allow

for a chemodivergent and modular process, which is enabled by the discovery of this new strategy.

As a proof-of-concept, we were interested in replacing both the hydride with an aryl nucleophile,

to generate either an aldehyde or a ketone, as well as the aroyl chloride electrophile with an


aliphatic acid chloride, to allow for potential reactivity divergences. Such a set of experiments

involving all the permutations would enable us to transform the same alkyne substrate into four

kinds of diversified products under a nearly identical set of reaction conditions (Fig. 2a).

Remarkably, with only subtle modification of the reaction conditions, four different carbonylated

products could indeed be obtained in good yields and excellent stereoselectivities, making this


programmed CO de/reinsertion process a modular tool for the realization of a diverse range of

carbonylation reactions (Fig. 2b). Apart from carboformylation, a CO-free carboacylation could

also be realized by using stannane reagents as carbon nucleophiles in place of the silane (67­71).

In an alternative pathway, aliphatic acid chlorides can undergo -H elimination to release an

alkene. The H­Pd(II)­Cl intermediate and CO generated from this step can then be combined with


a hydride or aryl nucleophile, to unlock the corresponding hydroformylation and hydroacylation

reactions (65­66, 72­75), thus significantly expanding the breadth of the strategy. It is noteworthy

that unlike the carbofomylation reaction presented above, a terminal alkyne can undergo both

carbo- and hydroacylation (71, 75). The inverse regioselectivity between a silyl substituted alkyne

(70) and a terminal alkyne (71) shown in this carboacylation results in yet another handle for


synthetic control.




In summary, we have developed a reaction for the carboformylation of alkynes. Not only does this

reaction add a versatile aldehyde moiety across an alkyne, but it does so concomitantly while

forming a new C­C bond, offering a facile route to densely functionalized aldehydes which are

otherwise challenging to access. The enabling feature of this reaction is the use of an aroyl chloride

as both a carbon and CO source through a programmed CO de/reinsertion strategy. In a broader


context, this reactivity clearly highlights the potential of this approach for the development of a

vast array of new, CO-free carbonylation reactions as demonstrated in a striking example of

chemodivergent catalysis.



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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the

Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1998285 (10),


2018417 (33), 2000217 (36, minor), 2000218 (53), 2018418 (59), 2018419 (59-Z), 1998290 (62),

1998292 (64), 1998293 (L08) and 1998299 (76). Copies of the data can be obtained free of charge

via https://www.ccdc.cam.ac.uk/structures/. All other data is available in the main text or the

Supplementary Information.



We acknowledge the ETH Zürich, the European Research Council under the European Union's Horizon 2020 research and innovation program (Shuttle Cat, Project ID: 757608), and LG Chem (fellowship to Y.H.L.) for financial support. We thank the NMR, MS (MoBiAS) and X-ray (SMoCC) service departments at ETH Zürich for technical assistance.


Author contributions

Y.H.L. designed and discovered the reaction. Y.H.L. and E.H.D. performed the scope of the reaction. B.M. supervised the research. All authors contributed to manuscript writing and editing.


Competing interests

The authors declare no competing interests.


Figure legends


Fig. 1. Comparison between conventional hydroformylation and carboformylation, and the

conceptual blueprint for a general intermolecular carboformylation. a, Hydroformylation is

a reaction which is performed on a 10-million-ton scale per year; is the subject of >10,000

publications and patents to date; and is widely used in industry and academia. By contrast, the

analogous carboformylation reaction, which has considerable synthetic potential, has a single


reported example which is intramolecular and is the topic of only 2 publications (Grigg, ref. 26-


27). b, The intramolecular carboformylation developed by Grigg (1995), which utilizes a carefully

engineered substrate, and changes in tether length results in a different product. c, Challenges for

the intermolecular carboformylation using a conventional approach include the possible formation

of products (>10); non-selective insertion of CO, where excess CO favors polycarbonylation. The


use of pressurized CO gas also limits R&D efforts in academia. d, Our conceptual blueprint ­ the

deconstruction of acid chlorides, as an aryl and CO source, and its merging across an alkyne

substrate in programmed order. e, Our strategy ­ the oxidative addition of a metal catalyst into the

acyl­Cl bond of an acid chloride (I); reversible CO deinsertion (II); a migratory insertion reaction

with an unsaturated C­C bond to generate the alkenyl­M complex (III); reversible CO reinsertion


(IV); The carboformylated product resulted from irreversible trapping by a hydrosilane. Cat. TM,

transition metal catalyst. R­X, carbon electrophile. Y­H, hydride source. Cat. Pd, palladium

catalyst. Si­H, hydrosilane. Cl­Si, chlorosilane. L, ligand.


Fig. 2. Chemodivergent carbonylation reaction. a, The modular process is capable of producing

a diverse range of carbonyl-containing compounds. b, Chemodivergent carbonylation reactions


using different acid chlorides or nucleohpiles can generate (1) carboformylation products; (2)

hydroformylation products; (3) carboacylation products; (4) hydroacylation products. c, scope of

the carboacylation reaction. d, scope of the hydroformylation reaction. e, scope of the

hydroacylation reaction. All yields are isolated as a single stereo- and regioisomers unless stated


otherwise. For details, see Supplementary Section 4, 5 and 6. H­Si, hydrosilane. R­Sn, aryl, vinyl or allyl stannane. n-Hex, n-Hexyl.
5 10 15

Table 1. Scope with respect to aroyl chlorides. All isolated yields as a single stereoisomer unless

otherwise stated. aTDMPP. bBISBI. cOpen system. d25 mmol scale. eIsolated as an inseparable

mixture of stereoisomers. iPr, isopropyl. Mes, Mesityl. 2,6-diClPh, 2,6-Dichlorophenyl. 2,6-


diFPh, 2,6-Difluorophenyl. Bn, Benzyl. For details, see Supplementary Section 3 and 11.


Table 2. Scope with respect to internal alkynes. All yields are isolated as a single stereo- and

regioisomer unless otherwise stated. aTDMPP. bBISBI. cIsolated as an inseparable mixture of

regioisomers. dNMR yield. n-Hept, n-Heptyl. n-Pent, n-Pentyl. Mes, Mesityl. For details, see


Supplementary Section 3.



As general procedure for mono-ortho-substituted aroyl chloride, in a glovebox, a 4 mL screw-cap

vial equipped with a stirring bar was charged with [Pd(allyl)Cl]2 (2.5 mol%, 6.25 mol, 2.29 mg


or 1.0 mL as 6.25 mM stock solution in anhydrous chlorobenzene) and TDMPP (10.0 mol%, 0.025

mmol, 11.06 mg, or 221.0 mg as 5.0 wt% stock solution in anhydrous chlorobenzene) then

anhydrous chlorobenzene (2 mL, or 1mL when stock solutions were used). The solution was stirred

at room temperature for 10 min. To a pre-mixed solution were added aroyl chloride (3 equiv, 0.75

mmol), alkyne (1.0 equiv, 0.25 mmol) and iPr3SiH (3 equiv, 0.75 mmol, 118.77 mg). The reaction


mixture was stirred at 130 °C for 3 h. The reaction was cooled to room temperature then quenched

with sodium methoxide (3 equiv, 0.75 mmol, 140 L of 5.4 M solution in methanol, note: the

quenching step could be omitted for substrates bearing a base-labile functional group) and diluted

with dichloromethane (2 mL). The resulting solution was filtered through a celite/silica plug and

concentrated under reduced pressure. The crude product was purified by column chromatography


on silica gel (pentane/dichloromethane, pentane/ethyl acetate or pentane/methyl tert-butyl ether).

Correspondence and requests for materials should be addressed to B.M.


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