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Document DEVICE REPORTLeeetal manuscript
Palladium-catalyzed carboformylation enabled by a molecular shuffling process

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

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

*Correspondence to: [email protected]

Abstract

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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, and the

widespread academic and industrial impact of hydroformylation, the development of

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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 molecular shuffling

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strategy featuring the use of 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 under palladium catalysis. An extension of this protocol to four

chemodivergent carbonylations further highlights the creative opportunity offered by this

molecular shuffling strategy in carbonylation chemistry.

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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

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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 reactions5­13. 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,

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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

alternatives14­21.

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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

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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)2,22­24. Given the importance of creating new C­C bonds25 and the widespread

academic and industrial impact of hydroformylation, the development of carboformylation

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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

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carboformylation has been disclosed thus far by Grigg (Fig. 1b)26­28. 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

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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)29. 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;

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(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 products24,29­34; (3) the use of toxic and

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

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35

2

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

Hydroformylation versus carboformylation. b, Intramolecular carboformylation developed by

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Grigg (1995). c, Challenges for intermolecular carboformylation using a conventional approach.

d, Our strategy - molecular shuffling using acid chlorides as aryl and CO source. cat TM,

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

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

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15

3

We hypothesized that the challenges of developing an intermolecular carboformylation reaction

could potentially be addressed by using acid chlorides as reagents19­21. 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 molecular shuffling process involving a sequence

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of C­C bond cleavage and formation events, mediated by a transition metal catalyst (Fig. 1d)35,36.

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

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bond; (3) the intermediacy of a M­Cl bond should significantly slow down any undesirable C­Cl

reductive elimination prior to the programmed CO reinsertion37­40. 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

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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 molecular shuffling process in which an

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aromatic acid chloride is formally deconstructed to aryl, CO and Cl subcomponents by a Pd

catalyst. The individual subcomponents are then "shuffled" and merged with an alkyne and 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 ,-

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unsaturated aldehydes. The generality of this shuffling concept 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.

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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 synthesis23,41. After observing small amounts of the product using a

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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

40

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. After systematic fine-tuning, two phosphine ligands, BISBI (2,2'-

4

bis(diphenylphosphinomethyl)-1,1'-biphenyl)

and

TDMPP

(tris(2,6-

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)42,43.

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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)20,37,44. Sterically less hindered aroyl

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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. 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

15

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

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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

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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 aldehydes16,45. 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

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complete stereoselectivity. This result clearly demonstrates the potential of this reaction for

preparative synthesis without the need for any specialized equipment46, such as autoclaves or two-

chamber reaction vessels.

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

unless otherwise stated. aTDMPP. bBISBI. cOpen system. dOpen system, 25 mmol scale.

eIsolated as an inseparable mixture of stereoisomers. Mes, Mesityl. 2,6-diClPh, 2,6-

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Dichlorophenyl. 2,6-diFPh, 2,6-Difluorophenyl. For details, see Supplementary Section 3 and

11.

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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. n-Hept, n-Heptyl. n-Pent, n-Pentyl. Mes, Mesityl. For details, see Supplementary

5

Section 3.

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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

5

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)18. Additionally, high regioselectivity was obtained when a highly sterically

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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 materials47­50. With regards to the regioselectivity in this class

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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-

reactions43, 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

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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 our molecular shuffling concept would allow for the inclusion of

alternative nucleophiles, other than a hydride, as well as different skeletal shuffling processes

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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 our molecular

shuffling 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 in the

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shuffling process. 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. 2, top). 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 molecular shuffling concept a modular tool for the

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realization of diverse carbonylation reactions (Fig. 2, bottom). Apart from carboformylation, a

CO-free carboacylation could also be realized by using an aryl stannane as a nucleophile in place

of the silane (66). Furthermore, the use of aliphatic acid chlorides, which can undergo molecular

shuffling to release an alkene, CO and a hydride, unlocked the corresponding hydroformylation

and hydroacylation processes (65, 67), thus significantly expanding the breadth of the strategy.

40

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Fig. 2. Chemodivergent carbonylations by molecular shuffling. All yields are isolated as a

5

single stereoisomer unless otherwise stated. For details, see Supplementary Section 4, 5 and 6.

H­Si, hydrosilane. Ar­Sn, aryl stannane.

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9

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

5

as both a carbon electrophile and CO source through a molecular shuffling 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 are available free of charge from the Cambridge Crystallographic Data

Centre, under reference numbers CCDC 1998285 (10), 2000217 (36, minor), 2000218 (53),

1998290 (62), 1998292 (64), 1998293 (L08) and 1998299 (69). All other data are available in

15

the main text or the Supplementary Information.

Acknowledgements

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

20

(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

25

reaction. B.M. supervised the research. All authors contributed to manuscript writing and editing.

Competing interests The authors declare no competing interests.

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