A decarboxylative approach for regioselective hydroarylation of alkynes

Article abstract of DOI:10.1038/nchem.2602

Regioselective activation of aromatic C-H bonds is a long-standing challenge for arene functionalization reactions such as the hydroarylation of alkynes. One possible solution is to employ a removable directing group that activates one of several aromatic C-H bonds. Here we report a new catalytic method for regioselective alkyne hydroarylation with benzoic acid derivatives during which the carboxylate functionality directs the alkyne to the ortho-C-H bond with elimination in situ to form a vinylarene product. The decarboxylation stage of this tandem sequence is envisioned to proceed with the assistance of an ortho-alkenyl moiety, which is formed by the initial alkyne coupling. This ruthenium-catalysed decarboxylative alkyne hydroarylation eliminates the common need for pre-existing ortho-substitution on benzoic acids for substrate activation, proceeds under redox-neutral and relatively mild conditions, and tolerates a broad range of synthetically useful aromatic functionality. Thus, it significantly increases the synthetic utility of benzoic acids as easily accessible aromatic building blocks.

Full text of DOI:10.1038/nchem.2602

ARTICLES
PUBLISHED ONLINE: 5 SEPTEMBER 2016 | DOI: 10.1038/NCHEM.2602
A decarboxylative approach for regioselective
hydroarylation of alkynes
Jing Zhang1, Ruja Shrestha2, John F. Hartwig2 and Pinjing Zhao1
*
Regioselective activation of aromatic C–H bonds is a long-standing challenge for arene functionalization reactions such as
the hydroarylation of alkynes. One possible solution is to employ a removable directing group that activates one of several
aromatic C–H bonds. Here we report a new catalytic method for regioselective alkyne hydroarylation with benzoic acid
derivatives during which the carboxylate functionality directs the alkyne to the ortho-C–H bond with elimination in situ to
form a vinylarene product. The decarboxylation stage of this tandem sequence is envisioned to proceed with the
assistance of an ortho-alkenyl moiety, which is formed by the initial alkyne coupling. This ruthenium-catalysed
decarboxylative alkyne hydroarylation eliminates the common need for pre-existing ortho-substitution on benzoic acids for
substrate activation, proceeds under redox-neutral and relatively mild conditions, and tolerates a broad range of
synthetically useful aromatic functionality. Thus, it significantly increases the synthetic utility of benzoic acids as easily
accessible aromatic building blocks.
ryl-substituted alkenes are prevalent structures in biologically
We hypothesized that the reactions of arenecarboxylic acids
active compounds and important synthetic intermediates for could address the problem of controlling the regioselectivity of
A
fine chemicals and materials. The addition of an arene to an alkyne hydroarylation. The carboxyl functionality could serve as
alkyne is one attractive route to these structures because of the com- an ortho-directing group that would be removed by metal-mediated
mercial and synthetic availability of both reagents1–5. Such alkyne decarboxylation after C–H alkenylation and give products with the
hydroarylations are more atom efficient and produce less salt vinyl group meta or para to the remaining substituents (Fig. 1d)26–30
.
waste than catalytic coupling of alkynes with pre-functionalized This decarboxylative approach to alkyne hydroarylation would use
aromatic compounds (Fig. 1a)2,3,6–8. However, a long-standing ubiquitous benzoic acids as easily accessible aromatic building
challenge that faces practical alkyne hydroarylations is to control blocks, with CO2 as the only by-product and no salt waste.
the regioselectivity for reaction at one of multiple arene C–H bonds. However, catalytic decarboxylation of benzoic acid derivatives is
For example, alkyne hydroarylations by Friedel–Crafts processes typically slow and generally requires ortho-substitution of σ-electron-
require electron-donating arene substituents for satisfactory reactiv- withdrawing or sterically hindered groups for substrate activation31.
ities (Fig. 1b), and the directing effects of these substituents often The vast majority of such decarboxylative transformations also
lead to mixtures of ortho- and para-alkenylarene isomers9,10
.
require high reaction temperatures, often above 140 °C, which
In recent years, various transition-metal catalysts have been devel- thus significantly limits the substrate scope27–31. To achieve satisfac-
oped for alkyne hydroarylation via the formal activation of arene tory reactivity, many decarboxylation processes also utilize stoichio-
C–H bonds to form metal–aryl intermediates4,5. A number of these metric silver(I) or copper(II) salts that further limit the compatibility
reported catalysts are Lewis acidic and cleave the C–H bond by electro- with oxidation-sensitive functional groups, although significant
philic aromatic substitution, which is mechanistically analogous to the progress has been made by Gooβen and co-workers to reduce the
Friedel–Crafts reaction and leads to similar limitations on regioselectiv- amounts of these salt additives27,32–34
ity (Fig. 1b)1,11,12. An alternative approach is the direct cleavage of a
.
We considered that the hydroarylation reaction would bypass
C–H bond at the position ortho to a coordinating functionality via these issues because the alkene unit attached to the initial inter-
cyclometallation (Fig. 1c)13, which was first demonstrated in Lewis mediate formed after C–C bond formation could serve as an activat-
and Smith’s report on cyclometallated ruthenium(II) complexes that ing unit for decarboxylation and would eliminate the need for such
catalysed the ortho-alkylation of phenol with ethylene14. This chelation- a group in the benzoic acid reactant. Although the strategy of utiliz-
assisted C–H functionalization strategy was explored further by ing carboxyl functionality as a removable ortho-directing group has
Murai and co-workers for the ruthenium-catalysed hydroarylations been reported as part of a tandem sequence or in a separate step35–47
,
of alkenes and alkynes with aromatic ketones15,16. Since these pio- the decarboxylative C–H alkenylation with alkynes has not been
neering studies, chelation-assisted alkyne hydroarylation has been reported. The dominant majority of the reported decarboxylative
explored with various transition-metal catalysts and a wide range C–H functionalization processes require high reaction temperatures
of heteroatom-based directing groups4,6,17–20. However, removal of (130–170 °C) and stoichiometric Ag(I) or Cu(II) salts to promote
these ortho-directing groups from the hydroarylation products decarboxylation. Moreover, most of the benzoic acids that
requires additional chemical transformations and is not always undergo these reactions must contain ortho-substituents for acti-
achievable21–23. Thus, access to ortho-substituted alkenylarenes by vation, with just a few exceptions that still needed high reaction
alkyne hydroarylation is limited by the nature of the ortho-directing temperatures of over 120 °C (refs 35,40,46,47). Thus, we sought a
groups, and access to meta- or para-substituted alkenylarenes has new strategy for regioselective alkyne hydroarylations that involves
not been achieved selectively by existing methods for alkyne site selectivity directed by a carboxylate group that is eliminated
hydroarylation24,25
.
in situ under mild conditions.
1Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58102, USA. 2Department of Chemistry, University of
California, Berkeley, California 94720, USA. e-mail: pinjing.zhao@ndsu.edu
*
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ARTICLES
Oxidative
addition
a
FG
X
+
+
LnM
FG
R
R
R´
FG
ML
n
FG
R´
Transmetallation
M´
LnMX
I
–
M´X
R´
b
H
H
R
R
Lewis acid
EDG
EDG
H
H
R
R´
EDG
+
+
R´
EDG
R
R´
LnM
Electrophilic
C–H activation
LnM+
EDG
MLn
EDG
+
+
+
–
H
I
c
DG
DG
DG
Chelation-assisted
C–H activation
R
R
R´
H
MLn
LnMX
+
–
HX
R´
II
d
CO2H
H
CO2H
H
LnMX
LnMX
R
R
FG
FG
FG
+
R
R´
CO2
MLn
+
R´
R´
HO
O
O
O
O
O
MLn
R´
Carboxyl-assisted
C–H activation via
Alkenyl-assisted
decarboxylation via
FG
FG
FG
or
MLn
R´
R
R
III
III´
IIa
Figure 1 | Strategies for catalytic alkyne hydroarylation and the resulting regiochemistry. a, Transition-metal-catalysed alkyne hydroarylation
with aryl halides or main-group metal aryl complexes as sources for transition-metal aryl nucleophiles (I). FG, functional group (aromatic substituent);
X, halogen atoms; M, transition metals; Ln, coordinated ligands; M’, main group metals. b, Friedel–Crafts alkyne hydroarylation with electron-rich arenes by
Lewis acid catalysis or by transition-metal-catalysed electrophilic C–H bond activation. EDG, electron-donating and ortho/para-directing group. c, Transition-
metal-catalysed alkyne hydroarylation via chelation-assisted C–H bond activation to form cyclometallated transition-metal aryl nucleophiles (II). DG, σ-donating
functional group to direct C–H activation at the ortho-position. d, A catalytic decarboxylative alkyne hydroarylation with benzoic acids by a proposed tandem
sequence that involves cyclometallated intermediates of ortho-carboxyl metal aryls (IIa) and ortho-alkenyl metal carboxylates (III or III′).
CO2H
Ru(p-cymene)2(OAc)2 (7) (10 mol%)
Ph
Ph
+
+
CO2
Dioxane/mesitylene/heptane (2:2:1)
Ph
80 °C, 48 h
2.0 equiv.
1.0 equiv.
2a
Ph
1a
3a 90%
Possible by-products from reported catalytic 1a/2a couplings
O
Ph
O
O
Ph
Ru
Ph
Ph
O
O
O
Ph
CH3
O
O
Ph
H3C
7
4a
5a Ph
6a Ph
Figure 2 | Model reaction for the catalyst development of decarboxylative alkyne hydroarylation. Blue and red dots indicate the original ipso and
ortho positions, respectively, of the benzoic acid substrate. Benzoic acid (1a, 2.0 equiv.) reacts with diphenylacetylene (2a, 1.0 equiv.) using 10 mol%
Ru(p-cymene)(OAc)2 (7), 2:2:1 mixed solvent of 1,4-dioxane/mesitylene/heptane and magnetic stirring at 80 °C for 48 hours under N2 atmosphere.
The desired hydroarylation product 3a was formed in 90% yield by GC analysis. The possible by-products 4a (from alkyne hydrocarboxylation),
5a (from oxidative [4+2] annulation) and 6a (from decarboxylative [2+2+2] annulation) were detected in only trace amounts.
2
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ARTICLES
We report the discovery of a new catalyst for decarboxylative alkyne
hydroarylation with various benzoic acids that overcomes the limitation
on the scope of decarboxylation, generates alkenylarenes with a broad
scope of aromatic substituents in ortho-, meta- and para-positions and
proceeds under sufficiently mild conditions to tolerate a synthetically
useful range of functional groups (Fig. 1d). This catalytic process oper-
ates by a tandem sequence that involves an initial C–H activation stage
during which the carboxyl group causes a specific C–H bond to add to
the metal and an alkyne subsequently inserts into the metal–aryl bond
to form an ortho-alkenylbenzoic acid intermediate (IIa)27,48. This coup-
ling of the arene with the alkyne is followed by a decarboxylation stage
in which the newly installed alkenyl moiety coordinates to the metal
centre of a carboxylate intermediate to facilitate CO2 release either as
an alkenyl σ-donor ligand (III) or as a π-olefin ligand (III′). The
low-energy decarboxylation process from alkenyl coordination effec-
tively eliminates the prior prerequisite of ortho-substitution on
benzoic acids and occurs at a significantly lower temperature than
those of typical decarboxylation processes. The broad substrate scope
of this decarboxylative alkyne hydroarylation is demonstrated by the
regioselective formation of alkenylarenes from benzoic acids with
various ortho-, meta- and para-substituents, as well as the parent
benzoic acid. The mild and redox-neutral reaction conditions allow
remarkable compatibility with unprotected, oxidation-sensitive
functionality, such as anilines and phenols. Thus, our catalyst system
enables decarboxylative alkyne hydroarylation with biomass-derived
phenolic acids, such as vanillic acid, a degradation product from lignin.
Table 1 | Decarboxylative alkyne hydroarylation with ortho-
and para-benzoic acids.
CO2H
X
Ru(p-cymene)(OAc)2
ortho- or para-1
2.0 equiv.
(7) (10 mol%)
Dioxane/mesitylene/
X
+
R
heptane (2:2:1)
80 °C, 24 h
– CO2
meta-3
R
R
R
2
1.0 equiv.
Entry
Starting
material
Product
Yield
(%)
E:Z
ratio
1
2
3
4
para-1
para-1
para-1
para-1
3a: X = H, R = Ph
80*
90
>20:1
60:1
30:1
20:1
3ba: X = OMe, R = Ph
3c: X = Me, R = Ph
3d: X = NMe2, R = Ph
85
88
5
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
3e: X = SMe, R = Ph
3f: X = OH, R = Ph
3g: X = NH2, R = Ph
3h: X = OAc, R = Ph
3i: X = NHAc, R = Ph
3j: X = Ac, R = Ph
69†
85
63
70
85
32
60‡
9
35:1
>20:1
>20:1
40:1
6
7
8
9
42:1
Results and discussion
We began our catalyst development with the model reaction between
benzoic acid (1a in Fig. 2) and diphenylacetylene (2a). We focused
our attention on ruthenium(II)-based catalyst precursors, which
have been explored extensively for chelation-assisted C–H bond
functionalizations, including alkyne hydroarylation49. Ruthenium
catalysts have been explored rarely as promoters of the decarboxyla-
tion of benzoic acids47. A major challenge was to achieve high che-
moselectivity to promote hydroarylation product 3a over multiple
by-products from reported coupling reactions, which include
alkyne hydrocarboxylation (4a)29, oxidative [4+2] heterocyclization
(5a)48 and oxidative [2+2+2] carbocyclization via decarboxylation
(6a)35. To this end, we evaluated a wide range of reaction parameters,
such as ruthenium catalyst precursor, ligand, salt additive, solvent and
reaction temperature. As benzoic acid and its substituted analogues
are generally commercially available and inexpensive, we conducted
the reactions with 2 equiv. benzoic acid to maximize the conversion
of alkyne. In all the reactions we monitored during this study, the
excess benzoic acid remained unreacted after full conversion of the
alkyne; no direct protodecarboxylation of benzoic acids was observed.
Selected results from these experiments are summarized in
Supplementary Table 1. We found that coupling between 1a and
2a was promoted by 10 mol% Ru(p-cymene)(OAc)2 (7) at 80 °C
and in a mixed solvent of 2:2:1 dioxane/mesitylene/heptane. Under
these conditions, 3a formed selectively in 90% yield over 48 hours;
the combined yield of by-products detected was less than 5%.
Reactions conducted with a single solvent of the mixed-solvent
system occurred with a similarly high level of high chemoselectivity
for 3a as those with the mixed solvent, but in a much lower yield
(Supplementary Table 1 gives details).
10
11
12
13
14
20:1
3k: X = CONMe2, R = Ph
3l: X = F, R = Ph
18:1
>20:1
>20:1
>20:1
3m: X = Cl, R = Ph
3n: X = Br, R = Ph
30
35
15
16
17
18
19
20
21
22
23
24
25
26
27
28
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
para-1
3o: X = I, R = Ph
42†
42†
<10§
<10§
<10§
65
75:1
10:1
ND
3p: X = CF3, R = Ph
3pa: X = NO2, R = Ph
3pb: X = CHO, R = Ph
3pc: X = CO2Me, R = Ph
3bg: X = OMe, R = nPr
3bh: X = OMe, R = nBu
3bi: X = OMe, R = CH2OMe
ND
ND
40:1
40:1
1:30
<1:20
ND
55
80
3bj: X = OMe, R = 2-(MeO)Ph 93
3bk: X = OMe, R = 3-(MeO)Ph 81
3bl: X = OMe, R = 4-(MeO)Ph 63
50:1
<1:20
50:1
50:1
3bm: X = OMe, R = 2-(F)Ph
3bn: X = OMe, R = 4-(F)Ph
84
71
3bo: X = OMe, R = 4-(CF3)Ph 66
29
30
31
ortho-1
ortho-1
ortho-1
3c: X = Me, R = Ph
3ba: X = OMe, R = Ph
3f: X = OH, R = Ph
63
88
90
20:1
60:1
22:1
With conditions for the catalytic process identified, we investi-
gated the decarboxylative hydroarylation of 2a with various substi-
tuted benzoic acids (Table 1, entries 1–19 and 29–33). All the
reactions occurred with a high stereoselectivity for syn-hydroarylation.
The observed regioselectivity was consistent with the envisioned
tandem sequence of ortho-C–H alkenylation and subsequent
decarboxylation40. Thus, reactions with para-substituted benzoic acids
proceeded with exclusive regioselectivity to give meta-substituted
alkenylarenes 3ba and 3c–3p. High yields were achieved with
32
33
ortho-1
ortho-1
3q: X = Ph, R = Ph
3l: X = F, R = Ph
70
30:1
60:1
84||
Conditions: 1 (0.4 mmol), 2 (0.2 mmol), 7 (0.02 mmol), 2:2:1 dioxane/mesitylene/n-heptane (10 ml
in total), 80 °C, 24 hours; average isolated yields of two runs; stereoselectivity and regioselectivity
determined by 1H NMR spectroscopy. *Reaction time 48 hours. †Reaction temperature 100 °C.
‡Reaction temperature 100 °C and 1,4-dioxane solvent. §Estimated yield by GC analysis.
||Dichloromethane solvent. ND, not determined.
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ARTICLES
Table 2 | Product selectivity when using meta-benzoic acids and differentially substituted alkynes.
CO2H
X
para- or meta-1
2.0 equiv.
Ru(p-cymene)(OAc)2
(7) (10 mol%)
X
+
R2
Dioxane/mesitylene/heptane
(2:2:1)
80 °C, 24 h
– CO2
3
R1
R1
R2
2
1.0 equiv.
Entry
Starting
material
Product(s)
Product Yield
E:Z
ratio
Entry Starting
material
Product(s)
Product
ratio
Yield
(%)
E:Z
ratio
ratio
(%)
1
para-1
para-1
para-1
3bb + 3bb´
>20:1
(3bb)
4
5
6
para-1
para-1
meta-1
meta-3be:
X = OMe,
3be
Exclusively
77
1:25
1:25
NA
60*
16:1
R1 = CH2OMe, R2 = Ph
MeO
Ph
Me
meta-3bf:
X = OMe,
R1 = CH2OMe, R2 = 4-BrPh
3bf
Exclusively
66
3bb
+
3r:
3r + 3r´
Mixture of four
isomers,
50†
X = OMe,
MeO
Me
R
1 = R2 = Ph
Ph
10:7:2:1
3bb´
7
8
meta-1
meta-1
meta-1
meta-1
3s:
para-3s
Exclusively
50†
70†
74†
75
2:1
60:1
2
3bc + 3bc´
10:1
>20:1
(3bc)
73*
X = NMe2,
R1 = R2 = Ph
MeO
Ph
3t:
X = iPr,
R1 = R2 = Ph
para-3t
Exclusively
Et
3bc
+
9
3u:
X = tBu,
para-3u
Exclusively
100:1
40:1
1 = R2 = Ph
MeO
Et
R
Ph
3bc´
10
3v
Exclusively
3
3bd + 3bd´
>20:1
(3bd)
77*
Ph
9:1
O
O
Ph
MeO
Ph
3v
nBu
3bd
MeO
HO
11
meta-1
3w
Exclusively
66
12:1
+
Ph
Ph
nBu
MeO
3w
Ph
3bd´
Conditions: 1 (0.4 mmol), 2 (0.2 mmol), 7 (0.02 mmol), 2:2:1 dioxane/mesitylene/heptanes (10 ml in total), 80 °C, 24 hours; average isolated yields of two runs; stereo- and regioselectivity determined by
1H NMR spectroscopy. *Dichloromethane solvent. †Reaction time 48 hours.
strongly electron-donating para-substituents, which included (GC) analysis) and the competitive formation of by-product 6a by
methyl, methoxy and dimethylamino groups (products 3ba, 3c [2+2+2] decarboxylative carbocyclization35.
and 3d). With the weakly electron-donating para-methylthio
With ortho-substituted benzoic acids, the same meta-substituted
group, the reaction required a higher temperature of 100 °C to alkenylarenes should form as are formed from the para-substituted
give product 3e in 69% yield. The redox-neutral property of the analogues. This envisioned regioselectivity was observed from the
current process tolerated not only acyl-protected but also reactions of several benzoic acids that contained ortho-substituents,
unprotected phenol and aniline functionality to form meta-O- or including methyl, methoxy, hydroxy, phenyl and fluoro groups
N-functionalized products 3f–3i in good yields. In contrast, sig- (Table 1, entries 29–33). These ortho-substituted benzoic acids led
nificantly lower reactivity was observed with arenes containing to the exclusive formation of meta-substituted alkenylarenes
para-substituents that are deactivating groups for electrophilic without the detectable formation of ortho-substituted alkenylarenes
aromatic substitution. For example, benzoic acids with para or the corresponding arenes from protodecarboxylation. This lack
halogen, acetyl, carboxamido and CF3 groups led to products of ipso-selective decarboxylative transformations with ortho-substituted
3j–3p in low-to-modest yields, even at a higher reaction temperature benzoic acids supported our proposed decarboxylation pathways
of 100 °C. Similarly, benzoic acids with para-nitro, -formyl and that involve coordination with the in situ attached ortho-alkenyl
-methoxycarbonyl groups led to low yields of the desired hydroar- moiety, rather than decarboxylation facilitated by the steric properties
ylation products (3pa–3pc, less than 10% by gas chromatography of pre-existing ortho-substituents.
4
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H
O
O
Ln
R
O
Ru
Path A´
O
R
R2
R2
2HX
Path B
R
R
+
LnRu(0)
RuLn
– CO2
R1
R2
3
R1
V
III
R1
+
R2
R1
LnRuX2
5
Path A
R1
R2
Path C
HX
HX
2
O
O
R2
RuLn
O
O
R1
R2
X
RuLn
R
– CO2
RuLn
R
R
R2
R
+
LnRu(0)
R2
– CO2
H
IV R1
VI
R1
R1
R1
R1
III´
R2
R2
6
Figure 3 | Proposed divergent reactivity of a cyclometallated alkenylruthenium(II) carboxylate intermediate. The catalytic process occurs by a tandem
decarboxylation process from ortho-alkenyl benzoate intermediates. A cyclometallated alkenylruthenium(II) carboxylate complex forms by carboxylate-
directed C–H activation and the insertion of the alkyne into the Ru–C bond. Protonation of the Ru–alkenyl bond in III generates the alkenyl-chelated Ru(II)
carboxylate intermediate III′ (Path A), which forms the hydroarylation product 3 and, after protonation, the Ru(II) aryl intermediate IV. An alternative
decarboxylation process can occur from intermediate III (Path A′). The ruthenacycle V is doubly protonated at the Ru–aryl and Ru–alkenyl bonds to form 3.
The competing process, C−O bond-forming reductive elimination, would generate 5 via oxidative [4+2] annulation (Path B). A third possible reaction
involves the insertion of a second alkyne 2 into the Ru–alkenyl bond (Path C), which leads to by-product 6 via sequential decarboxylation and C−C reductive
elimination. HX, acidic proton sources such as HOAc, benzoic acid substrate or PivOH additive.
Meta-substituted benzoic acids were expected to undergo 6a. The active catalyst is regenerated by oxidizing Ru(0) to Ru(II)
competitive C–H functionalization at two different ortho-sites of carboxylate complexes, which are needed to initiate the C–H acti-
the carboxyl group. Indeed, 3-methoxybenzoic acid reacted with vation that leads to the formation of the desired hydroarylation
2a to give an inseparable mixture of four regio- and stereoisomers product 3. Compared with alkynes that contain simple alkyl
of hydroarylation products in 50% overall yields and low selectivities groups, methoxymethyl-substituted arylacetylenes reacted faster
(products 3r/r′ (Table 2)). We hypothesized that both electronic and and no Cu(OAc)2 additive was required to achieve good yields
steric properties of meta-substituents could affect the regioselectiv- (products 3be and 3bf). This enhancement in reactivity by a meth-
ity. The more sterically demanding meta-substituents should inhibit oxymethyl substituent was also observed for symmetrical dialkyl-
ortho-alkenylation and promote para-alkenylation. Consistent with acetylenes (products 3bg–3bi). Results from reactions with several
this assertion, sterically demanding meta-dimethylamino, isopropyl symmetrical diarylacetylenes provided additional information on
and tert-butyl substituents led to the exclusive formation of para- steric effects on alkyne reactivity (products 3bj–3bo). In particular,
alkenylation products 3s–3u in 50–74% yields. This control over higher yields were observed with alkynes that contained ortho-
regioselectivity by aromatic substituents was also observed with substituted aryl groups (products 3bj and 3bm) than with those
two protocatechuic acid derivatives that contained both meta- and that contained meta- or para-substituted aryl groups.
para-substituents. The exclusive formation of ortho-alkenylation
We propose that the overall catalytic process occurs by a tandem
product 3v suggested a dominant electronic effect and negligible sequence that involves decarboxylation from ortho-alkenyl benzoate
steric effect from the acetal-protected 3,4-dihydroxy moiety. In con- intermediates (Fig. 1d). A cyclometallated alkenylruthenium(II)
trast, the reaction with vanillic acid led to the exclusive formation of carboxylate complex (III in Fig. 3) probably forms by carboxy-
product 3w via regioselective C–H activation and alkenylation at late-directed C–H activation and subsequent insertion of the
the aromatic site that is para to the methoxy group and meta to alkyne into the Ru–aryl linkage (Supplementary Fig. 1 gives
the hydroxy group.
details of the proposed catalytic cycle). Protonation of the Ru–
The scope of the alkyne that undergoes this hydroarylation was alkenyl bond in III would generate the alkenyl-chelated Ru(II) car-
investigated with 4-methoxybenzoic acid as the reaction partner boxylate intermediate III′ (Path A in Fig. 3), which would form the
(Table 1, entries 20–28, and Table 2, entries 1–5). No coupled pro- hydroarylation product 3 via decarboxylation and subsequent pro-
ducts were detected from reactions with terminal alkynes, such as tonation of the resulting alkenyl-chelated Ru(II) aryl intermediate
phenylacetylene; the absence of such products possibly resulted IV. An alternative decarboxylation process is the direct decarboxy-
from the formation of unproductive Ru(II) alkynyl or vinylidenyl lation from intermediate III, which is the microscopic reverse of
complexes. Unsymmetrical aryl–alkyl alkynes reacted with exclusive Ru–aryl addition across a C=O double bond in CO2 (Path A′).
regioselectivity to form 1-alkyl-1-meta-anisyl alkene products The resulting ruthenacycle V undergoes double protonation of the
(3bb–3bf). Methyl-, ethyl- and n-butyl-substituted phenylacety- Ru–aryl and Ru–alkenyl bonds to release hydroarylation product
lenes were less reactive than diphenylacetylene (2a) and required 3. Both Path A and Path A′ feature decarboxylation assisted by
20 mol% Cu(OAc)2 additive to give products 3bb–3bd in 60–77% coordination of the ortho-alkenyl moiety, which occurs through
yields as well as small amounts of the isocoumarin by-product 5 π-alkene complexation in Path A and σ-alkenyl ligation in Path A′.
and the naphthalene by-product 6a from oxidative annulation As a competing process, C−O bond-forming reductive elimination
reactions35,48. The observed higher overall yields and lower chemo- from III would generate an isocoumarin 5 as the by-product of
selectivity with added Cu(OAc)2 probably results from its well- oxidative [4+2] annulation (Path B)48. As a third possible reaction
known role as an oxidizing reagent for ruthenium-catalysed of III, the insertion of a second equivalent of alkyne 2 into the
oxidative C–H functionalization processes26,49. We propose that Ru–alkenyl bond (Path C) would lead to the formation of an
Cu(OAc)2 helps to regenerate the active catalyst from a deactivated oxidative [2+2+2] by-product 6 via sequential decarboxylation
catalyst created from the side reactions that form by-products 5 and and C−C reductive elimination to close the ring35. If alkenyl-assisted
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2602
ARTICLES
a
b
CO2H
X
Ph
Ph
Ru(p-cymene)(OAc)2 (7)
O
1
(10 mol%)
Ru
(2a, 2 equiv.)
Ru
2.0 equiv.
Ph
Ph
Ph
Ph
O
O
Ph
Dioxane/mesitylene/
heptane (2:2:1)
50 mol% PivOH,
80 °C, 24 h,
Benzene, 48 h
Room
temperature
O
+
X
Ph
Ph
8
9, >95%
3
Ph
Ph
Ph
– CO2
2a
1.0 equiv.
F
Cl
Ph
Ph
Ph
Ph
3l, 42%
E:Z = 55:1
3m, 57%
E:Z = 40:1
Br
MeO
Ph
Ph
CH2OMe
Ph
3n, 45%
E:Z = 70:1
3be, 91%
E:Z > 50:1
c
d
CO2H
CO2H
X
X
Ru(p-cymene)(OAc)2 (7)
Ru(p-cymene)(OAc)2 (7)
1
(10 mol%)
(10 mol%)
8.0 mmol
1
X
2.0 equiv.
X
Dioxane/mesitylene/
heptane (2:2:1)
20 ml total volume,
80 °C, 48 h
Dioxane/mesitylene/
heptane (2:2:1)
80 °C, 24 h
Ph
Ar
+
+
Ph
3
Ar
3
– CO2
– CO2
Ph
Ph
syn:anti adduct > 20:1
Ar
Ar
Ar, 2-MeOC6H4
Portionwise addition
of 2a over 24 h
2a
4.0 mmol
2b
1.0 equiv.
3ba, 96% (1.1 g)
E:Z = 60:1
X = OMe:
X
Ph
X = F:
3l, 55% (0.61 g)
E:Z = 55:1
F
F3C
F3C
Ar
Ar
Ph
Ar
Ar
3ya, 92%
3yb, 66%
X = CF3:
3p, 50% (0.65 g)
E:Z = 20:1
MeO
Ph
HO
Ph
Ph
O
NC
Ar
Ar
O
Ph
Ar
Ar
3yc, 73%
3yd, 83%
3v, 95% (1.15 g)
E:Z = 40:1
3w, 87% (1.05 g)
E:Z = 12:1
Figure 4 | Mechanism-guided efforts towards catalyst improvement. a, Improved yields of hydroarylation products with the additive of 50 mol% PivOH.
b, Stoichiometric formation of a Ru(η6-p-cymene)(η4-tetraphenylnaphthalene) complex 9 and the ORTEP diagram of its X-ray structure. Thermal ellipsoids
are set at 30% probability level, and all hydrogen atoms are omitted for clarity. c, Improved yields of hydroarylation products with a sterically bulky alkyne
substrate 2b. d, Results of scale-up reactions under the modified catalytic conditions of slow addition for alkyne substrate 2a.
decarboxylation proceeds via Path A′, then intermediate V could improvement of the catalyst. First, acid additives favoured formation
undergo further alkyne insertion and subsequent ring closure by of the hydroarylation product 3 over by-products, presumably by
C–C reductive elimination to generate by-product 6.
facilitating the protonation steps in Path A. The coupling between
The proposed diverse reactivity of intermediate III was sup- 2a and various para-substituted benzoic acids conducted with
ported by several experimental results and guided further 50 mol% pivalic acid (PivOH)28 led to hydroarylation products 3l,
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2602
ARTICLES
3m and 3be in higher yields than produced in the absence of the This new decarboxylation strategy eliminates the prerequisite of
acid (Fig. 4a). Second, a 2:1 reaction between 2a and a Ru(II) benzoate ortho-substituents in the arene that induce decarboxylation and
complex, Ru(p-cymene)(OBz)2 (8), at room temperature over 48 thereby allows a broad scope of substituted benzoic acids to serve
hours led to the quantitative formation of the Ru(0) complex 9 as aromatic components of the alkyne hydroarylation. A series of
(Fig. 4b). The solid-state structure of complex 9 was established meta- and para-substituted alkenylarenes, as well as alkenylarenes
by single-crystal X-ray diffraction (Supplementary Fig. 2 and that possess unprotected phenol and aniline functionality, can be
Supplementary Tables 2 and 3 give more details). This complex con- prepared conveniently by this method. We expect that the alkenyl
tains an η4-1,2,3,4-tetraphenylnaphthalene ligand, in addition to the assistance demonstrated in this study can be exploited further to
η6-p-cymene ligand, and displayed no catalytic reactivity for decar- facilitate decarboxylative transformations.
boxylative alkyne hydroarylation. The naphthalene ligand was
presumably generated by [2+2+2] annulation in Path C35,38. The
mild temperature for the stoichiometric formation of complex 9
and its complete lack of catalytic activity suggest that Path C is detri-
mental to the hydroarylation process and leads to catalyst deactiva-
Methods
The general procedure for decarboxylative alkyne hydroarylation is as follows. In a
nitrogen-atmosphere glovebox, [Ru(p-cymene)(OAc)2] (7, 71 mg, 0.2 mmol) and
10.0 ml of mixed solvent (4.0 ml dioxane, 4.0 ml mesitylene and 2.0 ml heptanes)
were added into a 20 ml scintillation vial equipped with a magnetic stir bar. The
mixture was stirred for ten minutes to be used as a homogeneous stock solution of
tion. Consistent with this assertion, 1,2,3,4-tetrasubstituted
naphthalenes (6) were the major by-products of the reactions of catalyst precursor. A 4 ml scintillation vial equipped with a magnetic stir bar was
charged with the alkyne substrate (0.2 mmol, 1.0 equiv.), arenecarboxylic acid
substrate (0.4 mmol) and 1.0 ml of the stock solution of catalyst precursor
(containing 0.02 mmol of complex 7). The vial was then sealed with a Teflon-lined
cap, transferred out of the glovebox and stirred in an 80 °C oil bath for 24 hours.
electron-poor benzoic acids that were less reactive towards decar-
boxylative hydroarylation (products 3l–3p in Table 1). However,
more-hindered alkynes, which would be less prone to undergo
two consecutive insertion reactions, formed the hydroarylation
products in high yields (products 3bj and 3bm in Table 1).
The higher chemoselectivity towards hydroarylation with
1,2-di(ortho-anisyl)acetylene (2b) was evident from reactions with
electron-deficient benzoic acids (Fig. 4c). 4-Fluorobenzoic acid
and 4-trifluoromethylbenzoic acid both reacted with 2b to give
significantly higher yields (products 3ya and 3yb) than those
with diphenylacetylene (2a) (3l and 3p in Table 1) and without
the need for added PivOH or a higher reaction temperature.
4-Cyanobenzoic acid, which did not react with 2a at 80–100 °C,
also reacted with 2b to form 3yc in 73% yield. The chemoselectivity
for hydroarylation was also higher for reactions with higher ratios of
benzoic acid to alkyne or for reactions in which the alkyne was
added slowly to the reaction system. With this modified procedure
that involved the slow addition of the alkyne (Fig. 4d), couplings
between 2a and several substituted benzoic acids occurred in
higher yield on scales up to 4.0 mmol than they did on a small
scale (0.1 mmol), which allowed isolation of gram quantities of
hydroarylation products.
Most of the benzoic acids employed in the current procedure are
commercially available and less expensive than other aromatic
building blocks used in regioselective catalytic coupling with
alkynes7–9. In particular, the reactions of the benzoic acids provide
new opportunities for phenolic acids derived from biomass to
serve as renewable aromatic building blocks in chemical synthesis
(products 3ba–3bo, 3f, 3s/s′, 3w and 3x). As a leading example,
4-hydroxybenzoic acid can be separated from biomass sources,
including lignin, and is now (2016) commercially available at
∼60US$ per kilogram (8.3US$ mol–1) from Sigma-Aldrich.
Decarboxylative hydroarylation with 4-hydroxybenzoic acid gave
meta-alkenylphenol 3f in high yield and dominant (E)-stereoselectivity
(Table 1, entry 6). In comparison, other reported alkyne hydroary-
lation procedures with various arenes or aryl nucleophiles were
either incompatible with unprotected phenol functionality, gave
inseparable mixtures of ortho/para-alkenylation products with
phenol ether substrates10 or used more-expensive halophenols (for
example, 3-iodophenol at ∼780US$ mol–1 from Sigma-Aldrich)
and generated stoichiometric halide salt waste50.
The reaction mixture was cooled to room temperature and then all volatile materials
were removed under reduced pressure. Further purification was achieved by flash
column chromatography using dichloromethane, ethyl acetate and hexanes as the
eluent. The E/Z alkene stereo- and regioselectivity for aromatic substitution was
determined by 1H NMR spectroscopy of the unpurified reaction mixture. Yields of
the isolated products are based on the average of two runs under identical
conditions. Supplementary Figs 3–92 and Supplementary Methods give full
experimental details and analytical data for the characterization of new compounds.
Data availability. The X-ray crystallographic coordinates for the structure reported
in this study are deposited at the Cambridge Crystallographic Data Centre (CCDC)
under deposition numbers CCDC 1483081 (9 at 100 K, high-temperature phase).
These data can be obtained free of charge.
Received 27 February 2015; accepted 26 July 2016;
published online 5 September 2016
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Acknowledgements
We thank the National Science Foundation (CHE-1301409 and RII-1330840 in association
with the North Dakota Experimental Program to Stimulate Competitive Research (ND
EPSCoR) to P.Z. and J.Z.) and ND EPSCoR (EPS-0447679, fellowship to J.Z.) for their
financial support. The work of J.F.H. and R.S. was supported by the Director, Office of
Science, US Department of Energy, under Contract no. DE-AC02-05CH11231. We also
thank A. Ugrinov for assistance with the X-ray diffraction data collection and analysis.
Author contributions
J.Z. performed the experiments and data analysis. R.S. participated in the high-throughput
screening experiments for catalyst development. J.Z., J.F.H. and P.Z. designed the catalytic
sequence and developed the reaction conditions. P.Z. and J.F.H. prepared this manuscript
with feedback from J.Z. and R.S.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests formaterials shouldbe addressed to P.Z.
Competing financial interests
The authors declare no competing financial interests.
8
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