Gold-catalyzed ethynylation of arenes

Article abstract of DOI:10.1021/ja909726h

(Figure Presented) A novel gold-catalyzed ethynylation of aromatic rings with electron-deficient alkynes via gold catalyzed C-H activation of both C _sp-H and C_sp2-H bonds has been developed. This transformation provides aromatic propiolates difficult to prepare by other methods, highlighting the synthetic potential of gold chemistry.

Full text of DOI:10.1021/ja909726h

Published on Web 01/20/2010
Gold-Catalyzed Ethynylation of Arenes
Teresa de Haro and Cristina Nevado*
Organic Chemistry Institute, UniVersity of Zu¨rich, Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland
Received November 16, 2009; E-mail: nevado@oci.uzh.ch
Table 1. Optimization for the Au-Catalyzed Ethynylation of 1
entry
reaction conditionsa yield %b
The introduction of acetylenic groups in organic molecules is
an important synthetic transformation. Among all available meth-
ods,1 the Sonogashira cross-coupling reaction is the most widely
1c Ph3PAuNTf2 (5 mol %), 1,2-DCE
2c Ph3PAuOTf (5 mol %), 1,2-DCE
3c Ph3PAuCl (5 mol %), 1,2-DCE
43
70
72
-
-
28/7/6
-
spread.2 Due to its versatility, the palladium-catalyzed Csp -Csp
2
reaction between aryl halides (particularly iodides) and terminal
alkynes, with or without the presence of a copper cocatalyst,
efficiently produces aryl-alkynes, which are precursors for bioactive
natural molecules, pharmaceuticals, and molecular organic materi-
als.3 Nevertheless, several drawbacks still limit the scope of this
ubiquitous transformation: first, alkynes containing electron-
withdrawing groups directly attached to the ethynyl carbon poorly
react with aryl halides.4 Second, if the aromatic halide is “deacti-
vated”, that is, electron-rich, oxidative addition is more difficult
making any cross-coupling reaction extremely challenging.5 Activa-
tion of aromatic C-H bonds followed by C-C bond formation
constitutes a conceptually attractive methodology since it avoids
the otherwise necessary prefunctionalization of the aromatic coun-
terpart.6 Described here is the first ethynylation of “deactivated”
arenes with electron-deficient alkynes via a gold-catalyzed C-H
functionalization of both aromatic and acetylenic counterparts.7
4d Pd(OAc)2 (5 mol %), 1,2-DCE
5d CuI (5 mol %), 1,2-DCE
6c Ph3PAuCl (5 mol %), Toluene/CH3NO2/CH3CN
7c Ph3PAuCl (5 mol %), 1,2-DCE/H2O (100:1)
8c Ph3PAuCl (5 mol %), MgO/ K2CO3 (1.5 equiv), 1,2-DCE 64/77
9c Ph3PAuCl (5 mol %), NaHCO3 (1 equiv), 1,2-DCE
10 Ph3PAuCl (5 mol %), NaHCO3 (1 equiv), PhIO
11 Ph3PAuCl (5 mol %), NaHCO3 (1 equiv), Selectfluor
12 Ph3PAuCl (5 mol %), NaHCO3 (1 equiv), t-BuOOH
85 (81%)e
55
-
-
a Reaction conditions: 1 (2 equiv), 2a (1 equiv), 0.5 M at 90 °C in a
sealed tube for 12 h. b Determined by GC-MS (isolated yield in
brackets). c PhI(OAc)2 (1.5 equiv). d With and without PhI(OAc)2.
e 2-Iodo-1,3,5-trimethoxybenzene 4 could be isolated in 20% yield in
entries 1-10.12
Table 2. Scope of Au-Catalyzed Ethynylation of 1a
entry
substrate
product (yield %)b
1
2
3
4
5
6
7
8
9
2b, Z ) CO2Et
3b (75)
3c (60)
3d (72)
3e (68)
3f (70)
3g (31)c
3h (66)
3i (48)
3j (25)
2c, Z ) CO2tBu
The reaction of 1,3,5-trimethoxybenzene (1) with methyl pro-
piolate (2a) in the presence of AuCl3 (5 mol %) and PhI(OAc)2
(1.5 equiv) in 1,2-dichloroethane at 90 °C afforded 3-(2,4,6-
trimethoxyphenyl)propiolate (3a) in 45% yield (eq 1). Neither
previously described hydroarylation of the alkyne8 nor homocou-
pling of the aromatic counterpart was detected in the reaction
mixture.9 This result prompted us to optimize the reaction conditions
and study its scope.10
2d, Z ) COPh
2e, Z ) CO(3,5-dimethoxy-phenyl)
2f, Z ) CO(p-CF3C6H4)
2g, Z ) COtBu
2h, Z ) CO(C7H12)
2i, Z ) (CH3)CdCH2
2j, Z ) Ph
a Reactions carried out with 1 (2 equiv), 2b-j (1 equiv), 0.5 M in a
sealed tube. b Isolated yield after column chromatography. c Microwave
reactor: 62% yield based on recovered starting material (1).
We first examined the influence of the gold source on the reaction:
cationic gold complexes such as Ph3PAuNTf2 or Ph3PAuOTf afforded
3a in 43 and 70% yield respectively (Table 1, entries 1-2). Surpris-
ingly, when neutral PPh3AuCl was used, 72% yield of 3a was obtained
becoming the catalyst of choice for the reaction (entry 3). Other metals
such as Pd(II) or Cu(I) did not effect the above-mentioned transforma-
tion (Table 1, entries 4 and 5). Next, we studied the sensitivity of the
reaction to both solvent polarity and coordinating ability: toluene
afforded 3a in 28% yield, whereas polar nitromethane or acetonitrile
delivered the product in trace amounts (entry 6). The presence of water
totally inhibited the desired reactivity (Table 1, entry 7). Addition of
different bases was also examined:10 MgO and K2CO3 showed
moderate improvement (entry 8), whereas NaHCO3 afforded 3a in an
optimized 85% yield (entry 9). Finally, the key role of the oxidant
was unravelled. PhIO gave 3a in 55% yield (entry 10), whereas neither
selectfluor nor tert-butylhydroperoxide, well-known oxidants for gold
catalysts,11 effects any conversion of 1 (Table 1, entries 11-12). Thus,
we decided to use conditions from entry 9 to study the reaction scope.
The ethynylation reactions of 1 with various terminal alkynes
have been summarized in Table 2. Ethyl and tert-butyl propiolates
2b-c showed a comparable reactivity to 2a (Table 2, entries 1-2).
Aromatic as well as aliphatic acetylenic ketones (2d-h) could also
be efficiently coupled with this method to give arylated products
3d-h in moderate to good yields (entries 3-7). The reaction of 1
with methyl enyne 2i afforded aryl-substituted enyne 3i in 48%
yield (entry 8). Finally, phenyl acetylene 2j produced the expected
ethynylated product (3j) in low yield due to homocoupling of the
alkyne (entry 9).
We have extended this reaction to other electron-rich aromatic rings.
The presence of groups such as benzyl, iso-propyl, and methoxymethyl
(MOM) ethers (5a-d) was well tolerated affording the corresponding
ethynylation products 6a-d as regiomeric mixtures in good yields
(Table 3). Substrates such as 5e-h were transformed into single
regioisomers 6e-h in moderate yields, revealing that para/ortho- is
9
1512 J. AM. CHEM. SOC. 2010, 132, 1512–1513
10.1021/ja909726h  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Scope of Au-Catalyzed Ethynylation of Arenesa
With these results in hand, two possible reaction pathways can be
envisioned starting with the formation of the gold(I)-acetylide complex
(I). In the presence of PhI(OAc)2, I can be oxidized to a gold(III)-
alkynyl intermediate (II).15 The reaction of the arene with complex II
might occur via electrophilic aromatic substitution to give complex
III.16 Finally, upon reductive elimination, the new Csp -Csp bond is
2
formed and the alkynylated products (IV) are obtained (Scheme 1,
red path). Alternatively, the reaction of I with PhI(OAc)2 could afford
an electrophilic alkynyl-iodonium complex (V). A gold-mediated
addition of the aromatic ring to the triple bond in V affords a vinyl
gold intermediate VI, which upon ꢀ-elimination would deliver the
arylated alkynes IV (Scheme 1, blue path).
In summary, we report here the first gold-catalyzed ethynylation
of arenes with electron-deficient alkynes via gold catalyzed C-H
2
activation of both Csp and Csp -H bonds. This transformation
a Reaction conditions: arene (2 equiv), 2a (1 equiv), Ph3PAuCl (5
mol %), PhI(OAc)2 (1.5 equiv) in 1,2-DCE (0.5 M) at 90 °C in a sealed
provides aromatic propiolates difficult to prepare by other methods.
Further studies to expand the reaction scope and gain a deeper
insight into the reaction mechanism are currently underway and
will be reported in due course.
b
tube. Undefined substituents: RxdH; Z ) sCtC(CO2Me). c Isolated
yield after column chromatography. d Ratio 2:1. e PhI(OAc)2 (1 equiv),
preheated oil bath.
Acknowledgment. The Organic Chemistry Institute of the
University of Zu¨rich is kindly acknowledged for financial support.
preferred over ortho/ortho-activation in the arene. The presence of
inductive donating groups as in the case of 5i-k was also well
accommodated although mesomeric activation seemed to be preferred.
Heteroaromatic rings are also suitable substrates for this reaction:13
N-benzyl pyrrol (7) delivered ethynylated regioisomers 8a and 8b in
43 and 26% yield respectively. N-Benzyl indole 9 afforded 10a in
60% yield together with acetoxy derivative 10b. Finally, conjugated
system 11 produced the cross-coupling products in both the chromene
(12a) and aromatic ring (12b) in 48 and 22% yield respectively. In all
cases, no hydroarylation products could be detected in the reaction
mixtures.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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Scheme 1. Mechanistic Proposal for the Au-Catalyzed Ethynylation
of Arenes
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NMR experiments were conducted to elucidate the reaction mech-
anism. 31P NMR analysis of the reaction of 2a with a stoichiometric
amount of Ph3PAuCl in CD2Cl2 showed a sharp peak at 34.2 ppm,
which corresponds to the pure complex. Upon heating to 90 °C, a
new signal at 42.3 ppm was observed. This peak is attributed to the
formation of gold(I)-acetylide I (see Scheme 1, Z ) CO2Me) by
comparison with a pure sample of this complex synthesized indepen-
dently.14 Interestingly, in the catalytic reaction of compound 5i with
2a, the formation of complex I could also be detected by 1H and 31
P
(12) Reaction of 4 with 2a under the optimized conditions from Table 1 did
not afford compound 3a, ruling out a gold-catalyzed Sonogashira reaction
mechanism; see: Gonza´lez-Arellano, C.; Abad, A.; Corma, A.; Garc´ıa, H.;
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NMR.10
Reaction kinetics were also studied, showing this transformation to
be first-order in both alkyne and arene reactants.10 The rates of the
reactions of 1 vs 1-d3 and 2d vs 2d-d1 were compared to determine if
C-H/C-D bond breaking was involved in the rate-determining step.
The rate constants were found to be 1.2 × 10-4 and 1.3 × 10-4 s-1
for 2d and 2d-d1 and 2.3 × 10-5 s-1 and 2.0 × 10-5 s-1 for 1 and
1-d3 respectively. The lack of primary effect in these intermolecular
isotope effect experiments clearly indicated that neither the Csp nor
(14) Bruce, M. I.; Horn, E.; Matisons, J. G.; Snow, M. R. Aust. J. Chem. 1984,
37, 1163.
(15) (a) Iglesias, A.; Mun˜iz, K. Chem.sEur. J. 2009, 48, 9346. (b) MuSchuster,
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1429.
2
(16) If Csp -H activation would be involved, primary KIE should have been
observed: Gretz, E.; Oliver, T. F.; Sen, A. J. Am. Chem. Soc. 1987, 109,
8109.
2
the Csp -H bond breaking is involved in the rate-determining step of
this ethynylation reaction.
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