Full text of DOI:10.1021/acscatal.7b04395

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Article
Broad-Scope Rh-Catalyzed Inverse-Sonogashira
Reaction Directed by Weakly Coordinating Groups
Eric TAN, Ophelie Quinonero, M. Elena de Orbe, and Antonio M. Echavarren
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Broad-Scope Rh-Catalyzed Inverse-Sonogashira Reaction Di-
rected by Weakly Coordinating Groups
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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).
Supporting Information Placeholder
ABSTRACT: We report the alkynylation of C(sp2)-H
The applicability of this strategy in multi-step synthesis is
however limited, as in most cases, the directing groups need
bonds with bromoalkynes (inverse-Sonogashira reaction)
to be installed and/or removed. Therefore, to render this
directed by synthetically useful ester, ketone and ether
approach useful, the development of new protocols using
groups under rhodium catalysis. Other less common direct-
instead widely used functional groups serving as synthetic
ing groups such as amine, thioether, sulfoxide, sulfone, phe-
handles is highly desirable.10
nol ester, and carbamate are also suitable directing groups.
Mechanistic studies indicate that the reaction proceeds by a
alkynylation of naphthols using ruthenium catalysis.11 Ben-
turn-over limiting C-H activation step via an electrophilic-
type substitution
Towards this goal, we recently reported a general peri-
zoic acids can also be alkynylated at the ortho-position,11,12
although the use of other versatile O-functionalities13 14 as
,
KEYWORDS: alkynylation, rhodium catalysis, C-H func-
tionalization, inverse Sonogashira, metallacycle, Hammett
correlation, DFT.
directing groups is still limited, mainly due to the challeng-
ing formation of a weakly coordinated metallacyclic inter-
mediate.15 In particular, despite intense efforts in the field of
catalytic C(sp2)-H functionalization, only two examples of
INTRODUCTION
the use of benzyl ether as directing group has been reported
in the context of C-H borylation.16
Alkynes are among the most versatile functional groups1 and
are widely present in natural products,2 drugs,3 and organic
Here, we report the use of synthetically useful ether, ester,
materials.4 The chemistry of alkynes has gained particular
and ketone as directing groups for the direct alkynylation of
C(sp2)-H bonds with bromoalkynes under rhodium catalysis
momentum in recent years by the discovery of a wide variety
(Scheme 1).17 We also demonstrate for the first time that
of catalytic transformations triggered by gold(I), platinum(II)
and other alkynophilic Lewis acids.5 Therefore, the develop-
amine,18 thioether,19 sulfoxide,20 sulfone,21 carbamate22 and
phenol esters23 are suitable directing groups in this transfor-
ment of methods for the introduction of alkyne groups onto
organic molecules is of high importance. To this end, the
mation. Furthermore, our experimental and theoretical
Sonogashira coupling reaction is the most general method
mechanistic study shows that this Rh-catalyzed alkynylation
for the formation of C(sp)-C(sp2) bonds from aryl or alkenyl
occurs by a turn-over determining C-H activation in which a
(pseudo)halides and terminal alkynes.6
five-membered ring metallacycle is formed by an electro-
philic aromatic substitution-type process.
The main limitation of the Sonogashira coupling reaction
Scheme 1. C(sp2)-H Alkynylation With Bromo-
Alkynes Directed by a Broad Range of Coordinating
resides in the synthetic availability of the required (pseu-
do)halides. An alternative approach that is better suited for
the late-stage functionalization of complex molecules in-
Groups under Rhodium Catalysis
volves the alkynylation of C(sp2)-H bonds with terminal
alkynes or activated acetylenes such as ethynylbenziodoxo-
lone (EBX) reagents or haloalkynes using transition-metal
catalysts.7 Often named inverse-Sonogashira coupling, this
methodology relies on the reactivity of electronically activat-
ed (hetero)arenes8 or on a chelating group to assist a C-H
activation process.9 The former strategy is restricted to aro-
matic C(sp2)-H bonds, which need in addition to be acidic or
electron-rich enough to undergo deprotonation or Friedel-
Crafts type reaction. The latter has been achieved for both
arenes and alkenes,9b with a variety of directing groups, typi-
cally amides or nitrogen coordinating groups such as hetero-
cycles or imine derivatives (oxime, nitrone, azomethine).9c
RESULTS AND DISCUSSION
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ether
ether
ether
ether
with TIPSꢀacetyleneh
0
0
Reaction Scope. Our studies began by evaluating the reac-
i
tions of TIPS-protected bromoacetylene (1) with ethyl ben-
zoate (2a) and benzyl methyl ether (4a). We discovered that
a combination of [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (20 mol
%), Ag2CO3 (1 equiv), LiOAc (20 mol %) in 1,2-dichloroethane
(DCE) at 45 °C provided 3a in 69% yield (Table 1, entry 1).
Control experiments showed the essential 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 than DCE led to poor results (Table 1, entries 6-11).
The use of other bromoalkynes, such as (bromo-
ethynyl)benzene or 1-bromooctyne, led to no conversion.24
24
25
26
with [Cp*IrCl2]2
i
with Pd(OAc)2
0
i
with [RuCl2(pꢀcymene)]2
<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
b
1
°
C. Yield of the monoalkynylated product determined by H NMR
c
d
9
using bromomesitylene as internal standard. Instead of 45 °C.
Instead of Ag2CO3 (1 equiv). e Instead of DCE. f Instead of Ag2CO3 and
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LiOAc. g Without LiOAc. h Instead of 1. i Instead of [Cp*RhCl2]2.
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 electron-
withdrawing substituents such as NO2, CF3, and different
halides at the ortho, meta and para positions were well toler-
ated, affording alkynylated products 3e-w in 23-90% yield. In
the case of meta-substituted substrates 2i,k,m, the alkynyla-
tion occurred at the least sterically hindered site. However,
fluoro and methoxy derivatives 2j and 2l favor formation of
the 1,2,3-trisubstituted compounds 3j and 3l, respectively.
Although treatment of benzyl methyl ether (4a) with bromo-
acelytene 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 functionali-
zation 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 oxida-
tion, decomposition, or unproductive reaction.
The alkynylation of ethyl 1-naphthoate (2u) and ethyl py-
rene-1-carboxylate (2w) does not take place at the peri-
position, leading instead to ortho-fuctionalized products 3u
and 3w, 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, afford-
ing 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.
Table 1. Rh-Catalyzed Ortho-C-H Alkynylation of
Ethyl Benzoate and Benzyl Methyl Ether: Optimiza-
tion Conditions24
Scheme 2. Rh-Catalyzed Ortho-C-H Alkynylation of
Alkyl Benzoates
Entry
1
DG
Variation from the “standard conditions”a
none
Yieldb
ester
ester
ester
ester
ester
ester
ester
ester
ester
ester
ester
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
58ꢀ69
2
at 25 ºCc
35
16
41
5
3
at 65 ºCc
4
with Ag2CO3 (0.5 equiv)d
with K2CO3 (1 equiv)d
in dichloromethanee
in toluenee
5
6
8ꢀ14
0
7
8
in tertꢀAmOHe
0
9
in Et2Oe
4
10
11
12
13
14
15
16
17
18
19
20
21
22
in EtOAce
18
0
in MeOHe
none
at 100 ºCc
0
50ꢀ64
0
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
0
0
0
<1.5
12
0
in tertꢀamOHe
in 1,4ꢀdioxanee
0
0
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Yields of isolated monoalkynylated products are shown. In cases in
which diakynylated products were also formed, mono- vs. dialkynyl-
ation selectivity is shown in parentheses.
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 ex-
cellent yield (Scheme 4). Bis(alkynylated)acetophenone 7k
was obtained in quantitative yield from acetophenone at
room temperature, while bulkier alkyl substituents allowed a
mono-selective alkynylation, affording products 7a-c in 50-
95% yield. Diverse substituents at the ortho position of ace-
tophenone were well tolerated to give products 7d-i in 81-
95% yield. 2-acetyl derivatives N-Methyl-pyrrole (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.
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 mono-
alkynylated products are shown. In cases in which diakynylated
products were also formed, mono- vs. dialkynylation selectivity is
shown in parentheses.
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 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, or iodo lead to o-
alkynylated products 5h-u in 32-71% yields. As observed for
the benzoates, the alkynylation of meta-substituted sub-
strates 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 naph-
thyl derivative 4v takes place at C-3 to form 5v in 70% yield.
The reaction of thiophene 4w provided 5w, the product of C-
2 alkynylation, which was isolated in 31% yield.
Scheme 4. Rh-Catalyzed Ortho-C-H Alkynylation of
Aryl Ketones
Scheme 3. Rh-Catalyzed Ortho-C-H Alkynylation of
Benzyl Ethers
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in 44-84% yield, with total control of the stereoselectivity
2
(Scheme 6).
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Other Directing Groups. With slight modification of the
reaction conditions, we discovered that other functional
groups are viable chelating groups (Scheme 7). As rare exam-
ples of the use of simple phenol ester as directing group,23
the ortho-alkynylation of phenol pivalate (10a) and 1-naphtol
acetate (10b) led to 11a-b in moderate yields. Although con-
sidered to bind too tightly to metals to be involved in catalyt-
ic processes, strongly coordinating groups could also be used
under similar conditions. Thus, the reaction proceeds on
substrates bearing sulfoxide, thioether, thioacetal, sulfone, or
tertiary amine functional groups, giving products 11c-h in 53-
75% yield. Boc-protected pyrrole 10i could also be dialkynyl-
ated to give product 11i in 66% yield.
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Scheme 7. Rhodium-Catalyzed C(sp2)-H Alkynylation
with Other Directing Groups
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).
As an example of late-stage functionalization of a pharma-
ceutical compound, fenofibrate 6r was alkynylated in 35%
yield for the major product (Scheme 5).
Scheme 5. Late-stage Alkynylation of Fenofibrate
a
c
Conditions: a 90 °C, 72 h. b 70 °C, 24 h. 100 °C, 16 h. d 50 °C, (1, 1.1
Standard conditions for the Rh-catalyzed reaction using 2 equiv of
equiv), 16 h e 90 °C, 16 h. f 45 °C, 16 h.
bromoalkyne, at 50 °C, 14 h.
Scheme 6. Alkynylation of Vinyl C-H Bonds
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 ac-
cording to the reaction of 2a-d5 in the presence of water and
in the absence of bromoalkyne 1 (Scheme 8, i). The intermo-
lecular and parallel competition experiments between deu-
terated and hydrogenated labelled substrates (Scheme 8, ii)
showed the same kinetic isotope effect (KIE = 3.1) in both
cases, indicating that the C-H bond cleavage probably occurs
in the rate-determining 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
8, iii) suggests that substrates bearing electron donating
groups (Me or MeO) at the meta position of the C-H func-
tionalization site are more reactive. This result indicates that
the C-H-functionalization step might occur through an elec-
trophilic aromatic substitution-type mechanism.12b,28
Conditions: a 85 °C 48 h, (2 equiv 1). b 45 °C, 16 h (1 equiv 1).
Stereocontrolled synthesis of conjugated enynes or acyclic
tri- and tetra-substituted 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
Scheme 8. D/H Exchange, Kinetic, and Competition
Experiments24
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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 (∆G‡ = 11.2 kcal/mol) to give Int5a, followed by
AgOAc-assisted bromide elimination (∆G‡ = 2.3 kcal/mol)
leads to Int7a and then, Int8a. The catalytic cycle restarts
upon ligand exchange, delivering the final alkynylated prod-
uct 3ab and regenerating Int1a.
9
Scheme 9. Proposed Mechanism of the Rh-Catalyzed
C(sp2)-H Alkynylation based on DFT Calculationsa
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a Yield of the monoalkynylated product determined by 1H NMR using
bromomesitylene as internal standard.
+
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 electro-
philic aromatic substitution-type mechanism.
a Free energies in kcal/mol.
Analysis of the Mulliken atomic charges in Int1a, Ts1-2
a
andInt2a24 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 TS1-2a, the carbon involved in the C-H activa-
tion 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 to
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 TS1-2a,
which suggests that the formation of the Rh-C bond preceeds
the cleavage of the C-H bond in a concerted, but asynchro-
nous process.
Figure 1. Hammett Plot for the Reaction of m-
Substituted Benzoates24
To get a deeper insight into the reaction mechanism, we
,
performed DFT calculations (Scheme 9).30 31 According to
C1
C1
H1
our studies, the C-H functionalization of methyl benzoate
(2b) proceeds from Int1a by the intramolecular assistance of
the acetate ligand through the 6-membered cyclic transition
state TS1-2a (∆G‡ = 19.8 kcal/mol). The alternative 4-
membered cyclic transition state (∆G‡ = 34.6 kcal/mol) or
H1
C1
O1
C2
Int1a
TS1-2
a
Int2a
d(C1ꢀRh) = 2.02 Å
d(C1ꢀH1) = 1.09 Å
d(C1ꢀRh) = 2.23 Å
d(C1ꢀH1) = 1.30 Å
d(H1ꢀO1) = 1.34 Å
the intermolecular acetate-assisted C-H activation (∆G‡
51.2 kcal/mol) would require much higher energy barriers.24,32
=
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using rhodium catalysis in a general manner. This is the first
Figure 2. Calculated Structures for the C-H Activation
via TS1-2a.24
report of a broad-range ortho-C-H functionalization of weak-
ly-coordinating benzyl ethers. The Rh-catalyzed alkynylation
of aryl esters and aryl ketones takes place under milder con-
ditions (45-70 °C for esters and 25-90 °C for ketones) than
those recently reported using Ir catalysis (120 °C). The al-
kynylation of vinyl C-H bonds of α,β-unsaturated esters and
ketones is also possible using rhodium catalysis. Further-
more, other uncommon functional groups such as amine,
thioether, thioacetal, sulfoxide, sulfone, phenol ester, and
carbamate can also be used as directing group for the al-
kynylation. Our mechanistic study shows that the alkynyla-
tion reaction proceeds by a turn-over limiting C-H activation
step via an electrophilic-type substitution, followed by inser-
tion of the bromoalkyne and bromide elimination.
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. Based on the
computed energies, the C-H metalation is the rate-
determining step, which is in agreement with the experi-
mental results. Similar energy profiles were found in the case
of methyl benzyl ether 4a (Scheme 9, pathway b) and aceto-
phenone 6k (Scheme 9, pathway c) which means that the
same reaction mechanism presumably operates for them.24
Consistently with the experimental results, among the differ-
ent substrates, the C-H functionalization of the ketones is
the most energetically favored (∆G‡ = 18.4 kcal/mol), where-
as the corresponding to the benzyl ethers is the most ener-
getically costly (∆G‡ = 20.6 kcal/mol).
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
In addition, the C-H activation step was computed for differ-
ently m-substituted methyl benzoates to study the influence
of the electronic effects on the energy barrier. Calculations
showed that the more electron-rich the substituent is, the
lower the activation energy results (Table 2, entries 1-4). This
is in total agreement with the experimental results observed
for m-substituted ethyl benzoates (Figure 1) and supports an
electrophilic substitution-type mechanism for the formation
of the five-membered ring rhodacycle.
Additional details, experimental procedures, characterization
data for compounds and computational results (PDF).
AUTHOR INFORMATION
Corresponding Author
* E mail for A.M.E. aechavarren@iciq.es
Author Contributions
§
E.T. and O. Q. contributed equally.
ORCID
Table 2. Substituent effect in the Activation Energy of
the C-H Activation of Benzoatesa
Antonio M. Echavarren: 0000-0001-6808-3007
Ophélie Quinonero: 0000-0003-4561-8763
M. Elena de Orbe: 0000-0001-9603-3699
Notes
No competing financial interests have been declared.
ACKNOWLEDGMENTS
We thank Agencia Estatal de Investigación (CTQ2016-75960-
P MINECO/AEI/FEDER, UE), Severo Ochoa Excellence Acredi-
tation 2014-2018 (SEV-2013-0319 and Severo Ochoa pre-
doctoral 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 CERCA
Program / Generalitat de Catalunya for financial support. We
also thank CELLEX-ICIQ HTE laboratory.
Entry R1
R2
OMe
Me
TS1-2d-i
TS1-2
TS1-2
TS1-2
∆G‡ (d-i)
17.2
Int2d-i
Int2d
Int2e
∆Gº (d-i)
2.9
1
2
H
H
d
e
18.9
3.3
REFERENCES
3
4
5
6
H
H
H
F
Br
CF3
F
f
20.8
21.5
19.5
17.8
Int2f
Int2g
Int2h
Int2i
3.1
3.4
2.5
2.7
TS1-2
TS1-2
g
h
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H
TS1-2i
a Free energies in kcal/mol.
In the case of m-fluoro benzoate, the C-H activation prefer-
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entry 6) rather than the para-position (∆G‡ = 19.5 kcal/mol,
Table 2, entry 5) respect to the fluoro substituent. This ortho
fluorine-effect has been experimentally observed with fluoro-
meta-substituted benzoate 3j (Scheme 2) or benzyl ether
compounds 5m (Scheme 3), as the metal-carbon bond
strength would be increased at this position.34
CONCLUSIONS
In summary, we have found that alkynylation of benzyl me-
thyl ethers, aryl esters and aryl ketones can be carried out
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-
unsaturated ketone were also reported in this study.
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Keywords : C
calculations.
−
H Activation, Alkynylation, Rhodium catalysis, Weakly coordinating groups, Synthetic method, DFT
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