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Research Article
Cite This: ACS Catal. 2018, 8, 2166−2172

pubs.acs.org/acscatalysis

Broad-Scope Rh-Catalyzed Inverse-Sonogashira Reaction Directed by
Weakly Coordinating Groups
Eric Tan,†,§ Ophélie Quinonero,†,§ M. Elena de Orbe,† and Antonio M. Echavarren*,†,‡
†

Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007
Tarragona, Spain
‡
Departament de Química Orgànica i Analítica, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n, 43007 Tarragona, Spain

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S
* Supporting Information

ABSTRACT: We report the alkynylation of C(sp2)−H bonds
with bromoalkynes (inverse-Sonogashira reaction) directed by
synthetically useful ester, ketone, and ether groups under
rhodium catalysis. Other less common directing groups such as
amine, thioether, sulfoxide, sulfone, phenol ester, and
carbamate are also suitable directing groups. Mechanistic
studies indicate that the reaction proceeds by a turnoverlimiting C−H activation step via an electrophilic-type
substitution.
KEYWORDS: alkynylation, rhodium catalysis, C−H functionalization, inverse Sonogashira, metallacycle, Hammett correlation, DFT

■

INTRODUCTION
Alkynes are among the most versatile functional groups1 and
are widely present in natural products,2 drugs,3 and organic
materials.4 The chemistry of alkynes has gained particular
momentum in recent years by the discovery of a wide variety of
catalytic transformations triggered by gold(I), platinum(II), and
other alkynophilic Lewis acids.5 Therefore, the development of
methods for the introduction of alkyne groups onto organic
molecules is of high importance. To this end, the Sonogashira
coupling reaction is the most general method for the formation
of C(sp)−C(sp2) bonds from aryl or alkenyl (pseudo)halides
and terminal alkynes.6
The main limitation of the Sonogashira coupling reaction
resides in the synthetic availability of the required (pseudo)halides. An alternative approach that is better suited for the
late-stage functionalization of complex molecules involves the
alkynylation of C(sp2)−H bonds with terminal alkynes or
activated acetylenes such as ethynylbenziodoxolone (EBX)
reagents or haloalkynes using transition-metal catalysts.7 Often
named inverse-Sonogashira coupling, this methodology relies
on the reactivity of electronically activated (hetero)arenes8 or
on a chelating group to assist a C−H activation process.9 The
former strategy is restricted to aromatic C(sp2)−H bonds,
which need in addition to be acidic or electron-rich enough to
undergo deprotonation or a Friedel−Crafts type reaction. The
latter has been achieved for both arenes and alkenes9b with a
variety of directing groups, typically amides or nitrogen
coordinating groups such as heterocycles or imine derivatives
(oxime, nitrone, azomethine).9c The applicability of this
strategy in multistep synthesis is however limited, as in most
cases the directing groups need to be installed and/or removed.
Therefore, to render this approach useful, the development of
© 2018 American Chemical Society

new protocols using instead widely used functional groups
serving as synthetic handles is highly desirable.10
Toward this goal, we recently reported a general perialkynylation of naphthols using ruthenium catalysis.11 Benzoic
acids can also be alkynylated at the ortho position,11,12 although
the use of other versatile O functionalities13,14 as directing
groups is still limited, mainly due to the challenging formation
of a weakly coordinated metallacyclic intermediate.15 In
particular, despite intense efforts in the field of catalytic
C(sp2)−H functionalization, only two examples of the use of
benzyl ether as a directing group have been reported in the
context of C−H borylation.16
Here, we report the use of synthetically useful ether, ester,
and ketone as directing groups for the direct alkynylation of
C(sp2)−H bonds with bromoalkynes under rhodium catalysis
(Scheme 1).17 We also demonstrate for the first time that
amine,18 thioether,19 sulfoxide,20 sulfone,21 carbamate,22 and
phenol esters23 are suitable directing groups in this transformation. Furthermore, our experimental and theoretical
mechanistic study shows that this Rh-catalyzed alkynylation
occurs by a turnover-determining C−H activation in which a
five-membered ring metallacycle is formed by an electrophilic
aromatic substitution type process.

■

RESULTS AND DISCUSSION
Reaction Scope. Our studies began by evaluating the
reactions of TIPS-protected bromoacetylene (1) with ethyl
benzoate (2a) and benzyl methyl ether (4a). We discovered
that a combination of [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (20
Received: December 20, 2017
Revised: January 23, 2018
Published: January 29, 2018
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Scheme 1. C(sp2)−H Alkynylation with Bromoalkynes
Directed by a Broad Range of Coordinating Groups under
Rhodium Catalysis

role of all reaction components (Table 1, entries 2−11). Thus,
lower yields of 3a were obtained at temperatures lower or
higher than 45 °C (Table 1, entries 2 and 3). Similar results
were obtained by decreasing the amount of Ag2CO3 to 0.5
equiv or replacing this silver salt by K2CO3 (Table 1, entries 4
and 5). Solvents different from DCE led to poor results (Table
1, entries 6−11). The use of other bromoalkynes, such as
(bromoethynyl)benzene and 1-bromooctyne, led to no
conversion.24
Although treatment of benzyl methyl ether (4a) with
bromoacetylene 1 under essentially the same conditions did
not lead to the product of alkynylation (Table 1, entry 12),
simply increasing the temperature to 100 °C led to 5a in 64%
yield (Table 1, entry 13). Using ethynyltriisopropylsilane
instead of 1 did not afford 5a (Table 1, entry 23). Replacing
[Cp*RhCl2]2 with other metal catalysts typically used in C−H
functionalization did not lead to alkynylated product (Table 1,
entries 24−26). The alternative hydroxy-directed alkynylation
of primary, secondary, or tertiary benzyl alcohol led to
oxidation, decomposition, or unproductive reaction.
Different alkyl benzoates 2a−d could be ortho-alkynylated,
with ethyl benzoate 2a giving the highest yield (Scheme 2).
Electron-donating alkyl or methoxy groups and electronwithdrawing substituents such as NO2, CF3, and different

mol %), Ag2CO3 (1 equiv), and LiOAc (20 mol %) in 1,2dichloroethane (DCE) at 45 °C provided 3a in 69% yield
(Table 1, entry 1). Control experiments showed the essential
Table 1. Rh-Catalyzed o-C−H Alkynylation of Ethyl
Benzoate and Benzyl Methyl Ether: Optimization
Conditions24

Scheme 2. Rh-Catalyzed o-C−H Alkynylation of Alkyl
Benzoatesa
entry

DG

variation from the “standard conditions”a

yield (%)b

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26

ester
ester
ester
ester
ester
ester
ester
ester
ester
ester
ester
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether

none
at 25 °Cc
at 65 °Cc
with Ag2CO3 (0.5 equiv)d
with K2CO3 (1 equiv)d
in dichloromethanee
in toluenee
in t-AmOHe
in Et2Oe
in EtOAce
in MeOHe
none
at 100 °Cc
without [Cp*RhCl2]2
without Ag2CO3
without LiOAc
without AgSbF6
with AgOAc (1.2 equiv)f
AgOAc (1 equiv) + Ag2CO3 (0.2 equiv)g
in toluenee
in tert-amOHe
in 1,4-dioxanee
with TIPS-acetyleneh
with [Cp*IrCl2]2i
with Pd(OAc)2i
with [RuCl2(p-cymene)]2i

58−69
35
16
41
5
8−14
0
0
4
18
0
0
50−64
0
0
0
0
<1.5
12
0
0
0
0
0
0
<3

a
Standard reaction conditions: 2a or 4a (0.2 mmol), 1 (2 equiv),
[Cp*RhCl2]2 (2.5 mol % for DG = ester, 3 mol % for DG = ether),
Ag2CO3 (1 equiv), AgSbF6 (0.2 equiv), LiOAc (0.2 equiv), DCE, 16 h,
45 °C. bYield of the monoalkynylated product determined by 1H
NMR using bromomesitylene as internal standard. cInstead of 45 °C.
d
Instead of Ag2CO3 (1 equiv). eInstead of DCE. fInstead of Ag2CO3
and LiOAc. gWithout LiOAc. hInstead of 1. iInstead of [Cp*RhCl2]2.

Legend to conditions: (a) 45 °C, 16−24 h; (b) 45 °C, 48 h; (c) 45
°C, 72 h; (d) 60 °C, 48 h; (e) 70 °C, 24−72 h; (f) 90 °C, 72 h (0.2
mmol scale). Yields of isolated monoalkynylated products are shown.
In cases in which diakynylated products were also formed, mono- vs
dialkynylation selectivity is shown in parentheses.

a

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thiophene 4w provided 5w, the product of C-2 alkynylation,
which was isolated in 31% yield.
Under conditions similar to those used for the reaction of the
ester derivatives, a wide variety of aryl ketones 6a−p could be
alkynylated in a general manner to give 7a−p in good to
excellent yield (Scheme 4). Bis(alkynylated)acetophenone 7k

halides at the ortho, meta, and para positions were well
tolerated, affording alkynylated products 3e−w in 23−90%
yield. In the case of meta-substituted substrates 2i,k,m, the
alkynylation occurred at the least sterically hindered site.
However, fluoro and methoxy derivatives 2j,l favor formation of
the 1,2,3-trisubstituted compounds 3j,l, respectively.
The alkynylation of ethyl 1-naphthoate (2u) and ethyl
pyrene-1-carboxylate (2w) does not take place at the peri
position, leading instead to ortho-fuctionalized products 3u,w,
respectively. Reaction of ethyl 2-naphthoate (2v) afforded
exclusively the product of alkynylation at C-3 (3v). Furan and
thiophene esters were also alkynylated to give 3x (62%) and 3y
(85%), respectively. The carbonyl group of isochroman-1-one
is also an effective directing group, affording 3z in 59% yield.
On the other hand, the alkynylation of ethyl phenylacetate
required heating at 90 °C and was less efficient, leading to 3aa
in 18% yield along with an equivalent amount of the
dialkynylated product.
Whereas the alkynylation of 4a leads to 5a in 64% yield,
substrates 4b−d with bulkier alkyl or silyl groups failed to give
the expected products (Scheme 3). Similarly, MOM-protected

Scheme 4. Rh-Catalyzed o-C−H Alkynylation of Aryl
Ketonesa

Scheme 3. Rh-Catalyzed o-C−H Alkynylation of Benzyl
Ethersa

a
Legend to conditions: (a) 45 °C, (1 equiv 1); (b) 90 °C, (1 equiv 1);
(c) 25 °C, (2 equiv 1); (d) 45 °C, (2 equiv 1); (e) 100 °C, (2 equiv
1).

was obtained in quantitative yield from acetophenone at room
temperature, while bulkier alkyl substituents allowed a
monoselective alkynylation, affording products 7a−c in 50−
95% yield. Diverse substituents at the ortho position of
acetophenone were well tolerated to give products 7d−i in 81−
95% yield. 2-Acetyl derivatives N-methylpyrrole (6n), furan
(6o), and thiophene (6p) were alkynylated at C-3 in 75−95%
yield. The double alkynylation of 1,5-dichloroanthraquinone
(6q) proceeded at 100 °C to give dialkynylated product 7q in
82% yield.
As an example of late-stage functionalization of a
pharmaceutical compound, fenofibrate (6r) was alkynylated
in 35% yield for the major product (Scheme 5).

a

Yields of isolated monoalkynylated products are shown. In cases in
which diakynylated products were also formed, mono- vs dialkynylation selectivity is shown in parentheses.

benzyl alcohol 4e and esters 4f,g were unreactive substrates. On
the other hand, methyl benzyl ethers bearing diverse
substituents at the ortho, meta, or para positions such as i-Pr,
CF3, fluoro, chloro, bromo, and iodo led to o-alkynylated
products 5h−u in 32−71% yields. As observed for the
benzoates, the alkynylation of meta-substituted substrates
4n,o occurred at the least sterically hindered site, whereas
fluoro derivative 4m led to a mixture of ortho-alkynylated
derivatives 5m, favoring the formation of the 1,2,3-trisubstituted product. Again, the alkynylation of naphthyl derivative
4v takes place at C-3 to form 5v in 70% yield. The reaction of

Scheme 5. Late-Stage Alkynylation of Fenofibratea

a

Standard conditions for the Rh-catalyzed reaction using 2 equiv of
bromoalkyne, at 50 °C, 14 h.

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Stereocontrolled synthesis of conjugated enynes or acyclic
tri- and tetrasubstituted alkenes is a longstanding challenge in
organic chemistry.25 We were pleased to find that the
alkynylation of vinyl C−H bonds of α,β-unsaturated esters
8a−e and ketones 8f,g proceeded under the standard
conditions at 45−85 °C to afford a series of Z-configured
1,3-enynes 9a−g in 44−84% yield, with total control of the
stereoselectivity (Scheme 6).

tertiary amine functional groups, giving products 11c−h in 53−
75% yield. Boc-protected pyrrole 10i could also be dialkynylated to give product 11i in 66% yield.
Mechanistic Studies. Several experiments were carried out
in order to shed light on the reaction mechanism. First, the C−
H functionalization step was found to be irreversible according
to the reaction of 2a-d5 in the presence of water and in the
absence of bromoalkyne 1 (Scheme 8i). The intermolecular

Scheme 6. Alkynylation of Vinyl C−H Bondsa

Scheme 8. D/H Exchange, Kinetic, and Competition
Experimentsa,24

Legend to conditions: (a) 85 °C 48 h, (2 equiv 1); (b) 45 °C, 16 h (1
equiv 1).

a

Other Directing Groups. With slight modification of the
reaction conditions, we discovered that other functional groups
are viable chelating groups (Scheme 7). As rare examples of the
Scheme 7. Rhodium-Catalyzed C(sp2)−H Alkynylation with
Other Directing Groupsa

a

Yield of the monoalkynylated product determined by 1H NMR using
bromomesitylene as internal standard.

and parallel competition experiments between deuterated and
hydrogenated labeled substrates (Scheme 8ii) showed the same
kinetic isotope effect (KIE = 3.1) in both cases, indicating that
the C−H bond cleavage probably occurs in the ratedetermining step of the catalytic cycle,26 which is consistent
with related rhodium-catalyzed C−H functionalizations.27
Finally, the intermolecular competition between electron-rich
and electron-poor substrates (Scheme 8iii) suggests that
substrates bearing electron-donating groups (Me or MeO) at
the meta position of the C−H functionalization site are more
reactive. This result indicates that the C−H functionalization
step might occur through an electrophilic aromatic substitution
type mechanism.12b,28
A Hammett correlation was found (R2 = 0.99 using σp+) for
meta-substituted substrates (Figure 1).29 A negative ρ value
also suggests that electron density decreases at the aryl ring in
the product-determining step, which is in accordance with a C−
H functionalization step occurring through an electrophilic
aromatic substitution type mechanism.
To get a deeper insight into the reaction mechanism, we
performed DFT calculations (Scheme 9).30,31 According to our
studies, the C−H functionalization of methyl benzoate (2b)
proceeds from Int1a by the intramolecular assistance of the

Legend to conditions: (a) 90 °C, 72 h; (b) 70 °C, 24 h; (c) 100 °C,
16 h; (d) 50 °C, (1 equiv 1), 16 h; (e) 90 °C, 16 h; (f) 45 °C, 16 h.

a

use of a simple phenol ester as a directing group,23 the ortho
alkynylation of phenol pivalate (10a) and 1-naphthol acetate
(10b) led to 11a,b in moderate yields. Although they are
considered to bind too tightly to metals to be involved in
catalytic processes, strongly coordinating groups could also be
used under similar conditions. Thus, the reaction proceeds on
substrates bearing sulfoxide, thioether, thioacetal, sulfone, and
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Figure 2. Calculated structures for the C−H activation via TS1‑2a.24
Figure 1. Hammett plot for the reaction of meta-substituted
benzoates.24

TS1−2a, the carbon involved in the C−H activation shows a
certain sp3 character (the Rh−C−H angle is 73.8°).24 The C−
Rh distance (2.23 Å) in TS1‑2a is slightly longer than that of the
metallacycle Int2a (2.02 Å), whereas the C−H distance is
lengthened from 1.09 Å in Int1a to 1.30 Å in TS12a, which
suggests that the formation of the Rh−C bond preceeds the
cleavage of the C−H bond in a concerted, but asynchronous,
process.

Scheme 9. Proposed Mechanism of the Rh-Catalyzed
C(sp2)−H Alkynylation on the Basis of DFT Calculationsa

Table 2. Substituent Effect in the Activation Energy of the
C−H Activation of Benzoatesa

entry

R1

R2

TS1‑2d−i

ΔG⧧(d−i)

Int2d−i

ΔG°(d−i)

1
2
3
4
5
6

H
H
H
H
H
F

OMe
Me
Br
CF3
F
H

TS1‑2d
TS1‑2e
TS1‑2f
TS1‑2g
TS1‑2h
TS1‑2i

17.2
18.9
20.8
21.5
19.5
17.8

Int2d
Int2e
Int2f
Int2g
Int2h
Int2i

2.9
3.3
3.1
3.4
2.5
2.7

a
a

Free energies in kcal/mol.

Free energies in kcal/mol.

Alternative alkynylation pathways were also considered,
although they proved to be less favored.24 For instance, the
oxidative addition of the C(sp)−Br bond to the metal center in
Int4a to form a Rh(V) intermediate33 demands a highly
unlikely activation energy of 41.6 kcal/mol. On the basis of the
computed energies, the C−H metalation is the ratedetermining step, which is in agreement with the experimental
results. Similar energy profiles were found in the case of methyl
benzyl ether 4a (Scheme 9, pathway b) and acetophenone 6k
(Scheme 9, pathway c), which means that the same reaction
mechanism presumably operates for them.24 Consistent with
the experimental results, among the different substrates, the C−
H functionalization of the ketones is the most energetically
favored (ΔG⧧ = 18.4 kcal/mol), whereas the corresponding to
the benzyl ethers is the most energetically costly (ΔG⧧ = 20.6
kcal/mol).
In addition, the C−H activation step was computed for
differently meta-substituted methyl benzoates to study the
influence of the electronic effects on the energy barrier.
Calculations showed that the more electron-rich the sub-

acetate ligand through the six-membered cyclic transition state
TS1−2a (ΔG⧧ = 19.8 kcal/mol). The alternative four-membered
cyclic transition state (ΔG⧧ = 34.6 kcal/mol) or the
intermolecular acetate-assisted C−H activation (ΔG⧧ = 51.2
kcal/mol) would require much higher energy barriers.24,32 The
resulting Int2a undergoes dissociative ligand exchange with
bromoacetylene 1b through Int3a (not shown)24 to form the
(η2-alkyne)rhodium complex Int4a. Subsequent alkyne insertion (ΔG⧧ = 11.2 kcal/mol) to give Int5a, followed by
AgOAc-assisted bromide elimination (ΔG⧧ = 2.3 kcal/mol)
leads to Int7a and then Int8a. The catalytic cycle restarts upon
ligand exchange, delivering the final alkynylated product 3ab
and regenerating Int1a.
Analysis of the Mulliken atomic charges in Int1a, TS1‑2a, and
Int2a24 shows that the process involves an ambiphilic metal
ligand activation.32e Both an electrophilic metal center and an
intramolecular basic ligand are key for the heterolytic scission of
the C−H bond and formation of the C−Rh bond (Figure 2). In
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for financial support. We also thank CELLEX-ICIQ HTE
laboratory.

stituent, the lower the activation energy results (Table 2, entries
1−4). This is in total agreement with the experimental results
observed for meta-substituted ethyl benzoates (Figure 1) and
supports an electrophilic substitution type mechanism for the
formation of the five-membered-ring rhodacycle.
In the case of m-fluorobenzoate, the C−H activation
preferentially occurs at the ortho (ΔG⧧ = 17.8 kcal/mol,
Table 2, entry 6) rather than the para position (ΔG⧧ = 19.5
kcal/mol, Table 2, entry 5) respect to the fluoro substituent.
This o-fluorine effect has been experimentally observed with mfluoro-substituted benzoate 3j (Scheme 2) or benzyl ether
compound 5m (Scheme 3), as the metal−carbon bond strength
would be increased at this position.34

■

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■

CONCLUSIONS
In summary, we have found that the alkynylation of benzyl
methyl ethers, aryl esters, and aryl ketones can be carried out
using rhodium catalysis in a general manner. This is the first
report of a broad-range o-C−H functionalization of weakly
coordinating benzyl ethers. The Rh-catalyzed alkynylation of
aryl esters and aryl ketones takes place under milder conditions
(45−70 °C for esters and 25−90 °C for ketones) in
comparison to those recently reported using Ir catalysis (120
°C). The alkynylation of vinyl C−H bonds of α,β-unsaturated
esters and ketones is also possible using rhodium catalysis.
Furthermore, other uncommon functional groups such as
amine, thioether, thioacetal, sulfoxide, sulfone, phenol ester,
and carbamate can also be used as directing groups for the
alkynylation. Our mechanistic study shows that the alkynylation
reaction proceeds by a turnover-limiting C−H activation step
via an electrophilic-type substitution, followed by insertion of
the bromoalkyne and bromide elimination.

■

ASSOCIATED CONTENT

S
* Supporting Information

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.7b04395.
Additional details, experimental procedures, characterization data for compounds, and computational results
(PDF)

■

REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail for A.M.E.: aechavarren@iciq.es.
ORCID

Ophélie Quinonero: 0000-0003-4561-8763
M. Elena de Orbe: 0000-0001-9603-3699
Antonio M. Echavarren: 0000-0001-6808-3007
Author Contributions
§

E.T. and O.Q. contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS
We thank the Agencia Estatal de Investigación (CTQ201675960-P MINECO/AEI/FEDER, UE), Severo Ochoa Excellence Acreditation 2014-2018 (SEV-2013-0319 and Severo
Ochoa predoctoral fellowship to M.E.d.O.), Juan de la Cierva
postdoctoral fellowship (O.Q.), the European Research
Council (Advanced Grant No. 321066), the AGAUR (2014
SGR 818), and the CERCA Program/Generalitat de Catalunya
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Research Article

ACS Catalysis

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