Catalytic Carbochlorocarbonylation of Unsaturated Hydrocarbons via C?COCl Bond Cleavage**

Article abstract of DOI:10.1002/anie.202108818

Here we report a palladium-catalysed difunctionalisation of unsaturated C?C bonds with acid chlorides. Formally, the C?COCl bond of an acid chloride is cleaved and added, with complete atom economy, across either strained alkenes or a tethered alkyne to generate new acid chlorides. The transformation does not require exogenous carbon monoxide, operates under mild conditions, shows a good functional group tolerance, and gives the isolated products with excellent stereoselectivity. The intermolecular reaction tolerates both aryl- and alkenyl-substituted acid chlorides and is successful when carboxylic acids are transformed to the acid chloride in situ. The reaction also shows an example of temperature-dependent stereodivergence which, together with plausible mechanistic pathways, is investigated by DFT calculations. Moreover, we show that benzofurans can be formed in an intramolecular variant of the reaction. Finally, derivatisation of the products from the intermolecular reaction provides a highly stereoselective approach for the synthesis of tetrasubstituted cyclopentanes.

Full text of DOI:10.1002/anie.202108818

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Catalytic Carbochlorocarbonylation of Unsaturated Hydrocarbons
via C–COCl Bond Cleavage
Authors: Elliott H. Denton, Yong Ho Lee, Sven Roediger, Philip Boehm,
Maximillian Fellert, and Bill Morandi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202108818
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10.1002/anie.202108818
Angewandte Chemie International Edition
RESEARCH ARTICLE
Catalytic Carbochlorocarbonylation of Unsaturated Hydrocarbons
via C–COCl Bond Cleavage
Elliott H. Denton†[a], Yong Ho Lee†[a][b], Sven Roediger[a], Philip Boehm[a], Maximilian Fellert[a] and Bill
Morandi*[a][b]
In memory of Ei-ichi Negishi.
[a]
E. H. Denton, Dr. Y. H. Lee, S. Roediger, P. Boehm, M. Fellert, Prof. Dr. B. Morandi
Laboratorium für Organische Chemie, ETH Zürich
Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland
E-mail: bill.morandi@org.chem.ethz.ch
[b]
[†]
Dr. Y. H. Lee and Prof. Dr. B. Morandi
Max-Planck-Intitut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
In pursuit of realising new atom economical transformations, we
considered if a coupling partner, an electrophile or nucleophile, itself
could be added across an alkene or alkyne (Scheme 1C). Overall, the
synthetic handle would be retained while building molecular
complexity.
Abstract: Here we report a palladium-catalysed difunctionalisation
of unsaturated C–C bonds with acid chlorides. Formally, the C–COCl
bond of an acid chloride is cleaved and added, with complete atom
economy, across either strained alkenes or a tethered alkyne to
generate new acid chlorides. The transformation does not require
exogenous carbon monoxide, operates under mild conditions, shows
a good functional group tolerance, and gives the isolated products
with excellent stereoselectivity. The intermolecular reaction tolerates
both aryl- and alkenyl-substituted acid chlorides and is successful
when carboxylic acids are transformed to the acid chloride in situ. The
reaction also shows an example of temperature-dependent
stereodivergence which, together with plausible mechanistic
pathways, is investigated by DFT calculations. Moreover, we show
that benzofurans can be formed in an intramolecular variant of the
reaction. Finally, derivatisation of the products from the intermolecular
reaction provides a highly stereoselective approach for the synthesis
of tetrasubstituted cyclopentanes.
Previous work that has focused on retaining the synthetic
handle while forming two new C–C bonds across alkenes or alkynes
is limited, highlighting the demanding nature of such
transformations.7–11 So far, research has focused on cleaving C–
C(acyl) bonds. For example, a directing group can be used with a
metal catalyst to cleave the C–C(acyl) bond of diaryl ketones. An
alkene can then undergo migratory insertion into the product of
oxidative addition to give the difunctionalised product (Scheme 1D).11
Related work by Hiyama, Nakao, and co-workers demonstrated the
nickel-catalysed arylcyanation of unsaturated C–C bonds. They
showed that an organonitrile such as benzonitrile could be used, via
activation of the C−CN bond, for the difunctionalisation of alkenes
(Scheme 1E).7c
We considered whether acid chlorides could be utilised in a
similar manner to achieve a carbochlorocarbonylation reaction.
Previously, Tsuji,12a,b Nomura,12c and Tanaka12d,e demonstrated that
acid chlorides can react with terminal alkynes in the presence of an
iridium or rhodium catalyst for acyl chlorination or decarbonylative
Introduction
The concept of atom economy is a cornerstone of sustainable
organic synthesis.1 Yet, achieving this goal in synthetic
transformations which generate multiple C–C or C–X bonds, and
therefore drastically increase molecular complexity, is challenging.
Given their unique reactivity, transition metals can mediate
remarkable transformations that can form new bonds in a highly
selective manner.2 One area of research which has attracted
significant attention in catalysis over recent decades is
hydrofunctionalisation (Scheme 1A).3 These reactions have been
developed into transformations which are often completely atom
economic and can be performed with excellent control of selectivity.
However, these reactions are limited by the addition of one functional
group across the unsaturated C–C bond.
carbochlorination (Scheme 1F). While this results in
a
difunctionalisation reaction, the acid chloride synthetic handle is lost,
and, in addition, only one new C–C bond is formed.
Recently, our group reported a carboformylation reaction where
an acid chloride served as both the carbon unit and carbon monoxide
source (Scheme 1G).13a Formally, this allowed for addition of the C–
CO bond of an acid chloride across an alkyne. Given this precedent,
we questioned whether it would be possible to add both the carbon
unit and an acyl chloride unit of an acid chloride across an unsaturated
C–C bond. The acid chloride would enable the transformation to occur
and be conserved in the product, generating new acid chlorides which
are highly reactive electrophiles.14 Moreover, this precludes the
requirement to handle carbon monoxide, a toxic gas requiring
specialised equipment on a laboratory scale.15–16
A key challenge to realise this transformation is finding a
catalyst system capable of both the selective and sequential
elementary steps over undesired pathways.12,17–18 Here, we present
the realisation of this concept, in which the C–COCl bond of an acid
chloride is formally cleaved and added across either a strained alkene
or a tethered alkyne to generate the difunctionalised products
(Scheme 1H). Notably, the retention of the highly electrophilic acid
chloride moiety allows a wide variety of synthetic modifications of the
product.14,16,19
By
contrast,
difunctionalisation
reactions,
including
dicarbofunctionalisations, rapidly increase molecular complexity
(Scheme 1B).4–5 This has emerged as a creative platform for the
installation of two new C–C or C–X bonds across an unsaturated bond
in a single step to generate a diverse array of compounds.6 While this
line of research has resulted in several novel transformations, they
commonly rely on reactions which take a “single-use” approach to
synthetic handles. For example, a reaction can add an electrophile,
e.g. an aryl halide, across an alkene or alkyne with a nucleophilic
partner, such as an aryl boronic ester, in the presence of a metal
catalyst. This delivers the difunctionalised product, but the synthetic
handle, e.g. the halide or boronic ester, is not retained in the final
product. As such, the overall atom economy is reduced and the
synthetic handle is lost after a single transformation.
1
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RESEARCH ARTICLE
Scheme 1. Context of the research.
Results and Discussion
Table 1. Optimisation
Intermolecular reaction
We initiated our studies using Pd2dba3 in combination with
4-methylbenzoyl chloride (1) and norbornadiene (NBD, 2) (Table 1).
Here, the release of strain energy would provide a thermodynamic
driving force to favour migratory insertion under mild conditions.20 As
sterically bulky ligands favour reductive elimination by relieving steric
crowding of the metal centre,16,17,21 we tested a selection of ligands
which have been used for similarly challenging reductive
eliminations.16,22 We found that Xantphos provided the acid chloride
product 3 in 88% yield (Table 1, Entry 1). Other ligands, including
electron-poor phosphines, gave little, if any, of the desired product
(Entries 2–5). Whilst an alternative palladium source, [Pd(allyl)Cl]2,
only gave 3% yield of the product even at elevated temperature (Entry
6), a reduced loading of Pd2dba3 could be used, albeit with a slightly
reduced yield of 72% (Entry 7). Notably, a 1:1 ratio of the two starting
materials reacted to give the product in 83% yield (Entry 8). The
palladium catalyst is essential for the reaction to proceed as reactions
in the absence of palladium (Entry 9) or in the presence of other metal
sources (Entry 10) failed to form the desired product. The
stereochemistry of the product was determined by NOESY NMR
analysis and by X-ray crystallography of derivatives of the acid
chloride product. It was found that the that the substituents undergo
syn addition to the alkene, and both are exo relative to the bicycle (see
SI).7c
Entry
Deviations from standard conditions
Yield of 3 [%][a][b]
1
2
none
tBuXantPhos
P(tBu)3
88
0
3
0
4
DPEPhos
dArFpe
1
5
6[c]
7[d]
0
[Pd(allyl)Cl]2
3
Pd2dba3 (2.5 mol%)
NBD (2) (1.0 equiv.)
Without [Pd]
72
83
0
8
9
10[e]
[Ni], [Rh], [Ir]
0
[a]Reactions on a 0.25 mmol scale in 1 mL of toluene. [b]The GC yields
are based on moles of 1 versus n-dodecane. The products are
derivatives to the corresponding methyl esters. [c]100 °C. [d]5.0 mol%
Xantphos. [e]See SI for details.
2
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10.1002/anie.202108818
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RESEARCH ARTICLE
Scheme 2. Scope of the reaction with different acid chlorides. All products were isolated as the corresponding methyl esters unless noted
otherwise. See SI for details. [a]All isolated products gave a >95:5 cis exo:trans endo selectivity unless noted otherwise. [b]80 °C for 21 h. [c]21
h. [d]93:7 cis exo:trans endo ratio of isomers. [e]The acid chloride was generated in situ from the corresponding acid with Ghosez’s reagent (1
equiv.). [f]Reactions performed on a 10 mmol scale.
With the optimised conditions in hand, we explored the scope of the
reaction (Scheme 2). 4-Methylbenzoyl chloride and benzoyl chloride
were successful in the reaction giving the products 3 and 4 in 80%
and 85% yields, respectively. The reaction of a 13C-labelled benzoyl
chloride also gave the product 5 in 85% yield with excellent 13C
incorporation (>95%), highlighting the potential of the present
chemistry to be used as a platform for isotopic labelling. 2-Naphthoyl
chloride reacted to give the product 6 in 83% yield while the more
sterically encumbered 2-methylbenzoyl chloride formed the product
3
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RESEARCH ARTICLE
Figure 1. Gibbs free energy profile for the palladium-catalysed formation of acyl chloride 4 from benzoyl chloride and NBD (2) at the
PBE0-D3(BJ)/SMD(toluene)-def2tzvp//PBE0-D3(BJ)/def2svp-def2tzvp(Pd) level of theory. The optimised geometries of the transition states
TS3 and TS4-exo are depicted. Hydrogen atoms are omitted for clarity.
7 in 50% yield at an elevated temperature of 80 °C. We observed that
4-fluoro-, 4-chloro-, and 4-bromobenzoyl chloride successfully
reacted to give the products 8, 9, 10 in 63%, 66% and 65% yields,
respectively. While 3-Bromobenzoyl chloride gave the product 11 in
24% yield. Notably, these functional groups offer parallel reactivity to
the acid chloride, demonstrating the chemoselectivity of this reaction.
Acid chlorides containing benzothiophene, benzofuran, ether, or azo
functional groups gave the products 12, 13, 14, and 15 in good yields
of 71%, 75%, 68%, and 54%, respectively. When a benzoyl chloride
bearing an electron-withdrawing cyanide group was used, we found
that an increase of the temperature to 80 °C was required to obtain
the product 16 in a synthetically useful yield of 69%. In this instance,
the product was isolated with a 93:7 ratio of cis exo: trans endo
isomers. Other very electron poor acid chlorides such as 4-
nitrobenzoyl chloride and pentafluorobenzoyl chloride did not afford
the desired product. Excitingly, we could show that benzoic acids
could be used directly with Ghosez’s reagent13b to generate the acid
chloride in situ, as demonstrated by the reaction of 4-(trimethylsilyl
ethynyl) benzoic acid which provided the product 17 in a very good
yield of 82%. An acid chloride containing a boronic ester gave the
product 18 in 54% yield, highlighting the tolerance of an orthogonal
functional handle to the acid chloride. We were also able to expand
the acid chloride scope beyond that of aromatic systems to α,β-
unsaturated acid chlorides as demonstrated with 3,3-dimethyl acryloyl
chloride and trans-4-phenylcinnamic acid, with Ghosez’s reagent,
which gave the products 19 and 20 in 57% and 27% yield, respectively.
Further, two reactions were performed on a 10 mmol scale, showing
that the reaction is insensitive to scale. Trapping with methanol gave
the product 3a in 83% yield (2.0 g). A second run trapping with 2,6-
diisopropyl aniline also gave the product 3b in 83% yield (3.2 g).17f
While only 2 different nucleophiles are shown here, our previous work
has highlighted the synthetic versatility of acid chlorides.16
endo)-22 in 67% yield, providing an example of temperature-
dependent stereodivergence.23
Computational studies
In order to study the feasibility of different mechanistic pathways
and gain an understanding of the temperature-dependent
stereodivergence, we performed a computational analysis of the
transformations.
Conformer searches were conducted with CREST using default
settings.24 The obtained conformers were subjected to additional
density functional theory (DFT) calculations, using the Gaussian09
suite of programs.25 The keyword integral(grid=ultrafine) was used in
all calculations to limit grid-based errors.26 Optimisations were
conducted at the PBE0 level of theory27-30 including Grimme’s
dispersion correction (D3) with Becke-Johnson damping31,32 and
thermal correction to 333 K.Palladium was modelled with the def2tzvp
basis set and ECP.33,34 All other atoms were modelled with the def2svp
basis set. Thermochemical corrections were calculated at the same
level of theory as the optimisations, and quasi-harmonic vibrational
corrections35 were applied using GoodVibes.36 Single point energies
were calculated at the PBE0D3-(BJ) level of theory includingthe SMD
solvent model37 for toluene. All atoms were modelled with the def2tzvp
basis set. The corresponding ECP was used for palladium. Structures
were visualised with CYLview.38,39
The reaction of NBD (2) and benzoyl chloride was selected as
a model system (Figure 1) to evaluate different plausible mechanistic
pathways. Based on previous results by our group,13,16 it is likely that
the reaction is initiated by the molecular deconstruction of benzoyl
chloride to form a palladium phenyl species. This process proceeds
through a low barrier oxidative addition of palladium species A into
the C–Cl bond of benzoyl chloride (TS1) and
a subsequent
Beyond NBD, we could successfully react norbornene (NBE,
21) at 80 °C to obtain the product with the same selectivity observed
for NBD (2), (cis, exo)-22 in 53% yield. Notably, by increasing the
reaction temperature to 100 °C we could obtain the product (trans,
decarbonylation step (TS2), delivering the palladium phenyl
complex D.
We examined different pathways for the carbopalladation of
NBD (2) (see Figure S13 for full overview). One possibility is that
NBD (2) could directly insert into the Pd–Ph bond of the carbonyl-
containing complex D. The lowest energy transition state we found for
this process (TS3) features an elongated Pd–Cl bond distance of 3.0
Å and is therefore best described as a contact-ion pair rather than a
neutral structure with a bound chlorido ligand.40-42 The dissociation of
the chlorido ligand is presumably due
4
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10.1002/anie.202108818
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RESEARCH ARTICLE
Figure 2. DFT rationalisation for the observed temperature-dependent stereodivergence.
to the coordinative saturation of the palladium centre. This ion pair
formation is associated with a large energy penalty in the non-polar
toluene solvent, resulting in a very high energy barrier of 38.9 kcal/mol
for TS3. This pathway is therefore unlikely to operate under the
experimental conditions. The most favourable pathway involves
carbon monoxide dissociation from the carbonyl-containing
complex D to form the tetracoordinated complex E from which the
migratory insertion of NBD (2) can take place via transition state TS4-
exo. Notably, the computational model correctly predicts the
experimentally observed high exo selectivity (TS4-exo: 25.9 kcal/mol;
TS4-endo: 29.6 kcal/mol).
Further investigation of the reaction led to the discovery that it
can be successful in an intramolecular setting (Scheme 3).8a,b,e
The migratory insertion process of NBD (2) to generate the
substituted NBE fragment in complex G is exergonic by 29.2 kcal/mol
and the main driving force of the reaction. Interestingly, the
thermodynamics of this step is only partially accounted for by the
release of ring strain as the difference in ring strain energy between
NBD (2) and NBE (21) is only 10.7 kcal/mol.43 Re-coordination of the
second phosphine moiety of the Xantphos ligand from F, the structure
preceding the insertion event, to G and favourable interactions of the
palladium centre with the hydrocarbyl fragment of complex G are likely
to also play a significant role.
Complex G can recapture CO in a nearly thermoneutral fashion
(complex H). Carbonylation of the norbornyl fragment (TS5) and
subsequent reductive elimination (TS6) complete the formation of the
acyl chloride product 4.
During the experimental part of this work, it was found that
NBE (21) did not react at 60 °C, but required a reaction temperature
of 80 °C to form the corresponding product. To probe the origin of this
observation, we also calculated the proposed reaction mechanism
with NBE (21) as the substrate (see Figure S14). Overall, the energy
profiles are very similar, with the exception of the migratory insertion
of the bicyclic alkene into the Pd–Ph bond of complex E. A comparison
between the reactions of NBE (21) and NBD (2) shows that this step
has a higher energy barrier (NBE: 27.3 kcal/mol; NBD: 25.9 kcal/mol)
for the reaction of NBE (21). This higher reaction barrier for NBE (21)
compared to NBD (2) is likely the reason why the reaction of NBE (21)
requires a higher temperature.
Scheme 3. The intramolecular addition of acid chlorides across
alkynes. The products are isolated as the corresponding methyl
ester.
Tethered alkynes could successfully react with the acid chlorides to
generate benzofuran products with retention of the acid chloride
moiety. Again, a palladium catalyst was used in combination with
Xantphos at 125 °C to deliver the product. In this instance, the double
bond migrated into the ring which can be rationalised through the
thermodynamic preference to form an extended aromatic system. The
tethered alkynes reacted to generate benzofuran products 25, 26, 27,
and 28 in 43%, 75%, 56% and 41% yield, respectively. The reaction
showed no significant difference in reactivity between electron-
donating and electron-withdrawing groups at the 4-position relative to
the acid chloride.
A
possible explanation for the observed temperature-
dependent stereodivergence could be that β-hydride elimination
occurs from acyl complex I-NBE through transition state TS7 (Figure
2).44 The resulting palladium hydride species K can reinsert into the
formed ketene 24 from the other face of the molecule, leading to
epimerization at this position. The energy barrier of 33.1 kcal/mol for
the β-hydride elimination process is too high for this to operate to a
significant extent at 80 °C. However, this step becomes kinetically
accessible at elevated temperature. Through this pathway, the
kinetically formed (cis, exo)-product 23 could equilibrate to the
thermodynamically favoured (trans endo)-product 23 (–2.9 kcal/mol
relative to (cis, exo)-23).
Norbornene product derivatisation
To highlight the utility of the products from the intermolecular
reaction, we transformed them by two different ring-opening reactions
to stereoselectively obtain the corresponding 1,2,3,4-tetrasubstituted
cyclopentanes. Notably, the tolerance of alkenes as well as the
orthogonal selectivity compared to related approaches such as the
Diels-Alder reaction,45 makes this a useful entry for their synthesis.
First, we performed an oxidative cleavage of the alkene 3a, followed
Intramolecular reaction
5
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10.1002/anie.202108818
Angewandte Chemie International Edition
RESEARCH ARTICLE
by an esterification to form 29a in 74% yield (Scheme 4).7c Next, we
subjected 3a to ring-opening cross-metathesis with allyl alcohol to
afford 30a as a separable mixture of regioisomers (55:45 rr) with a
combined yield of 40%, without optimisation.46
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Scheme 4. Derivatisation of the products from the intermolecular
reaction. Abbreviated reaction conditions are given, see SI for full
details. a) RuCl3.nH2O (5 mol%), NaIO4 (4.5 equiv.), then
trimethylsilyl diazomethane (2.5 equiv). b) Hoveyda-Grubbs 2nd
generation catalyst (5 mol%), allyl alcohol (10 equiv.). rr =
regiomeric ratio.
Conclusion
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In conclusion, we have developed a reaction which uses a
palladium catalyst to add an acid chloride across a strained
unsaturated C–C bond. This reaction uses the acid chloride as the
limiting reagent to generate substituted norbornenes decorated with
aryl or alkenyl carbon units, and an acid chloride. The reaction
showed a good functional group tolerance, and with NBE we observed
a temperature-dependent stereodivergence. A DFT study provides
support for a plausible reaction pathway as well as a rationale,
consistent with the observed experimental results, for the reactivity
and selectivity of the intermolecular reaction with NBD and NBE. We
also show that an intramolecular version of this reaction is possible,
generating substituted benzofurans. Further, the opportunity, after
derivatisation, to stereoselectively access 1,2,3,4-tetrasubtituted
cyclopentanes from the products of the intermolecular reaction will
streamline synthesis of these important synthetic cores.
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Acknowledgements
The financial support by the European Research Council under the
European Union’s Horizon 2020 research and innovation program
(Shuttle Cat, Project ID: 757608), the ETH Zꢀrich, the Max-Planck-
Society, the MPI fꢀr Kohlenforschung, LG Chem (fellowship to Y.H.L.),
the FCI (scholarships to P.B. and S.R.) and both the Cusanuswerk
and Swiss-European Mobility Programme (scholarships to M.F.) are
gratefully acknowledged. We thank the NMR, MS (MoBiAS), and X-
ray (SMoCC) service departments at ETH Zꢀrich for technical
assistance. We acknowledge Laura Gürtler for reproducing results.
We are also grateful to our group for critical proofreading of the
manuscript.
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Keywords: Acid chlorides • Carbonylation • CO-free •
Difunctionalisation • Palladium
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RESEARCH ARTICLE
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
Using a catalytic system comprised of Pd and Xantphos, acid chlorides can be added across strained alkenes or tethered alkynes to
form two new C–C bonds via formal C–COCl cleavage. This reaction allows for a dicarbofunctionalisation in which an acid chloride
group is retained in the product. DFT studies are used to rationalise a plausible pathway, while product derivatisation highlights the
synthetic utility of the method.
Institute and/or researcher Twitter usernames: @morandilab
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