The Gold-Catalyzed Hydroarylation of Alkynes with Electron-Rich Heteroarenes – A Kinetic Investigation and New Synthetic Possibilities

Article abstract of DOI:10.1002/adsc.201600940

The gold-catalyzed mono-hydroarylation and two-fold hydroarylation of alkynes with electron-rich heteroarenes was analyzed by a¹H NMR kinetic study. The obtained rate constants for the decreasing alkyne concentration provide information on the reactivity of this addition reaction. The examinations show the orthogonal reactivity of gold and a proton for the two reaction steps. The first hydroarylation is exclusively promoted by gold(I), whereas the second step is premised on a proton which will be reversibly derived from the formation of σ,π-acetylide complexes from the terminal alkynes or by interaction with solvents. Based on kinetic data, it was possible to synthesize a large range of mono-adducts in moderate to good yields, furthermore the synthesis of hetero-di-adducts, bearing two different substituents, was explored. (Figure presented.).

Full text of DOI:10.1002/adsc.201600940

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DOI: 10.1002/adsc.201600940
The Gold-Catalyzed Hydroarylation of Alkynes with Electron-
Rich Heteroarenes – A Kinetic Investigation and New Synthetic
Possibilities
Jasmin Schießl,a Matthias Rudolph,a and A. Stephen K. Hashmia,b,*
a
Heidelberg University, Institute of Organic Chemistry, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
Fax : (+49)-6221-54-4205; e-mail: hashmi@hashmi.de
Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia
b
Received: August 24, 2016; Revised: October 30, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600940.
Abstract: The gold-catalyzed mono-hydroarylation which will be reversibly derived from the formation
and two-fold hydroarylation of alkynes with elec- of s,p-acetylide complexes from the terminal alkynes
1
tron-rich heteroarenes was analyzed by a H NMR or by interaction with solvents. Based on kinetic
kinetic study. The obtained rate constants for the de- data, it was possible to synthesize a large range of
creasing alkyne concentration provide information mono-adducts in moderate to good yields, further-
on the reactivity of this addition reaction. The ex- more the synthesis of hetero-di-adducts, bearing two
aminations show the orthogonal reactivity of gold different substituents, was explored.
and a proton for the two reaction steps. The first hy-
droarylation is exclusively promoted by gold(I), Keywords: gold catalysis; hydroarylation; kinetic
whereas the second step is premised on a proton studies; nucleophilicity scale; proton catalysis
Introduction
ly determined theoretically by DFT calculations,[10]
however, without any experimental proof. This en-
In heterocyclic chemistry, the functionalization of couraged us to shed light on the kinetics of these
electron-rich heteroarenes, especially of simple nitro- transformations with the aim to obtain further mecha-
gen heterocycles receives significant attention due to nistic details as well as the possibility to extend the
their relevance as pharmaceutical agents and natural synthetic scope of this useful reaction. The results of
products.[1] During the last two decades, the interest our study are summarized in this contribution.
in the direct catalytic intermolecular hydroarylation,
a highly atom-economical process that adds an aryl-
or heteroaryl-H bond to an unsaturated C–C bond, Results and Discussion
has arisen. p-Acidic metal catalysts such as rutheni-
um,[2] rhodium,[3] palladium,[4] platinum,[5] nickel,[6] The addition reaction of pyrrole to phenylacetylene
gold[7] as well as gallium[8] and indium[9] promote the was chosen as a test reaction. In order to exclude pos-
transformation. In the majority of cases the metal-cat- sible reactions without the catalyst, pyrrole was react-
alyzed hydroarylation reaction delivers the mono- ed with phenylacetylene. As expected no reaction was
adduct. However, the gold-catalyzed addition reaction observed both without any catalyst and even in the
of electron-rich heteroarenes to terminal alkynes pro- presence of 5 mol% of trifluoromethanesulfonimide.
vides only the product of di-addition.[7] For example, Since an exclusion of water is not necessary in gold
Luo et al. reported on the gold-catalyzed two-fold hy- catalysis, a potential addition of water to phenylacety-
droarylation of terminal alkynes with heterocyclic lene and a subsequent addition or condensation of/
compounds like pyrroles, indoles, furans and thiophe- with the pyrrole was investigated by reactions of ace-
nes.[7b] In 2007, Echavarren et al. observed the gold- tophenone with pyrrole with added IPrAuNTf2 as cat-
catalyzed mono-hydroarylation reaction of alkynes alyst, again no reaction was observed. IPrAuNTf2,
and indoles.[7e] No detailed studies regarding the ki- which is known in the literature to be a highly effi-
netics of the gold-catalyzed transformation have been cient and regio-selective catalyst, was used as bench-
reported to date. The mechanistic details were recent- mark system.[11] For the hydroarylation reaction one
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Scheme 1. Gold-catalyzed alkyne hydroarylation with elec-
tron-rich heteroarenes.
equivalent of phenylacetylene was treated with five
equivalents of freshly distilled pyrrole and 2 mol%
IPrAuNTf2 in acetonitrile-d3 at 258C (Scheme 1).
The heteroarene was added in excess, otherwise
only a partial conversion of the alkyne was observed.
Furthermore, the mechanism[7b] postulated in the liter-
Figure 1. Kinetic profile of the hydroarylation reaction of
ature is based on the use of at least two equivalents phenylacetylene with pyrrole.
of pyrrole, too. The reaction kinetics were observed
by GC first. One equivalent of phenylacetylene was
treated with five equivalents of pyrrole and 2 mol% cedure (see the Supporting Information for further
of IPrAuNTf2 using n-dodecane as internal standard. details). Within a period of maximum ten hours (only
To stop the reaction at a certain point of time, the cat- neglectable further conversion was observed by GC
alyst was quickly removed by filtration over silica gel. detection even after extended reaction times of up to
1
Within nine hours, 22 samples were isolated and ana- 14 days or more), 256 H NMR spectra were record-
lyzed by gas chromatography (Figure 1).
ed. In Figure 2 four selected 1H NMR spectra are
Due to the higher precision of NMR kinetics and shown as an illustration of the starting material con-
higher resolution in time, the further kinetic measure- sumption and the product formation.
ments were conducted by in situ monitoring with
The kinetic analysis was conducted by the integra-
1H NMR spectroscopy at 258C. The spectroscopic tion of characteristic reactant/product peaks at a spe-
principle is based on a continuous measurement pro- cific time (Figure 2). Besides, the phenylacetylene
1
Figure 2. Selected H NMR spectra of the hydroarylation of phenylacetylene with pyrrole.
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peak at 3.4 ppm and the aromatic signals of the termi- a consequence of influence of the measurement
nal alkyne were included. The concentration decrease object by instrument were excluded. The coefficient
of the excessive amount of pyrrole was calculated by of determination R2 is a criterion to describe a linear
integration of the present doublet peaks at 6.2 and relation. A regression has a goodness-of-fit if the co-
6.8 ppm. The amount of mono-adduct was determined efficient of determination is close to one. Serial kinet-
by integration of the doublet signals at 5.2 and ic measurements were investigated next. For the sim-
5.5 ppm. The signal at 2.1 ppm represents the di- plified approach, the rate constant of the hydroaryla-
adduct. By extrapolation of the determined values tion reaction of one equivalent of phenylacetylene
close to y=0, the integral at the time t=0 was ach- with five equivalents of pyrrole catalyzed by 2 mol%
ieved by graphical analysis. Subsequently, the sub- IPrAuNTf2 was standardized to one. The decreasing
stance concentration was gained by conversion of in- concentration of phenylacetylene was used because of
tegrals considering the for all applied reactions con- the formation of two products. Due to limited time on
stant initial concentration of each compound. An ex- the instruments, it was not possible to observe a com-
ponential decrease of starting material and a satura- plete consumption for each reaction. Initially, the in-
tion curve concerning the increase of products was fluence of the heteroarene concentration on the reac-
observed (Figure 3a). A similar method was used to tion rate was determined for the addition of pyrrole
examine the hydroarylation reaction of phenylacety- to phenylacetylene (Table 1). A linear growth of the
lene and kryptopyrrole. However, in this case the con- rate constant with an increasing pyrrole concentration
centration profile pursued a consecutive reaction was noticed (Figure 4).
progress as expected for the formation of the two-fold
The ratio of mono- to di-adduct was examined after
addition product if one assumes that the first addition a reaction time of ten hours. Interestingly, if com-
is faster than the second addition step (Figure 3b). As pared to higher pyrrole concentrations, the addition
in the upper example, this clearly shows that also in of only one equivalent of pyrrole leads to a higher se-
the presence of a gold catalyst conditions for an en- lectivity towards the di-adduct! With regard to the
richment of a two-fold hydroarylation can be found. catalyst loading (Table 2), a linear dependency of the
The slower second hydroarylation in Figure 3b also rate constant on the IPrAuNTf2 concentration was
indicates a yet unknown synthetic potential for a selec- recognized (Figure 5). However, the point of intersec-
tive mono-hydroarylation.
tion of the regression line and the x-axis at 0.7 mol%
Based on the integration method, the order of reac- indicates catalyst poisoning by halides or basic com-
tion was determined.[12] As a result of graphic correla- pounds introduced by the solvent or by impurities in
tion, the order of reaction and then the rate constant the starting materials.[13] The ratio of mono- to di-
were determined by standard kinetic methods. The adduct concentration operates completely independ-
error is a result of error propagation of random faults ently of the catalyst concentration.
concerning sample preparation. Systematic errors as
Figure 3. Concentration profile; (a) hydroarylation of phenylacetylene with pyrrole; (b) hydroarylation of phenylacetylene
with kryptopyrrole.
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Table 1. Variation of the heteroarene concentration.[a]
Entry
[Pyrrole] [equiv.]
Consumption[b] [%]
Ratio (Mono-/Di-adduct) t=10 h
k [L/(mol h)]
R2
krel
1
2
3
4
1
2
5
10
51
82
100
100
1:1.6
1:1
2.8:1
3.3:1
0.066Æ0.003
0.155Æ0.007
0.316Æ0.021
0.675Æ0.022
0.937
0.985
0.996
0.998
0.21Æ0.01
0.49Æ0.02
1.00Æ0.07
2.13Æ0.07
[a]
Reaction conditions: phenylacetylene (196 mmol, 0.302 mmol/mL), pyrrole (196–1958 mmol), IPrAuNTf2 (2 mol%), CD3CN at
T=258C, observed by H NMR kinetic for 10 h under air in NMR tubes.
Consumption of the phenylacetylene determined by H NMR kinetic after 10 h.
1
[b]
1
Figure 4. (a) Decrease of the concentration of the starting material; (b) linear trend of the plot of krel against [pyrrole].
Table 2. Variation of the catalyst concentration.[a]
Entry [IPrAuNTf2] [mol%] Consumption[b] [%] Ratio (Mono-/Di-adduct) t=10 h k [L/(mol h)] R2
krel
1
2
3
4
1
2
3
5
80
2.5:1
2.8:1
2.4:1
2.4:1
0.105Æ0.007 0.988 0.33Æ0.02
0.316Æ0.021 0.996 1.00Æ0.07
0.617Æ0.011 0.989 1.95Æ0.03
1.185Æ0.010 0.999 3.76Æ0.03
100
100
100
[a]
Reaction conditions: phenylacetylene (196 mmol, 0.302 mmol/mL), pyrrole (979 mmol), IPrAuNTf2 (1–5 mol%), CD3CN at
T=258C, observed by H NMR kinetic for 10 h under air in NMR tubes.
Consumption of the phenylacetylene determined by H NMR kinetic after 10 h.
1
[b]
1
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Figure 5. (a) Decrease of the concentration of the starting material; (b) linear trend of the plot of krel against [IPrAuNTf2].
For the hydroarylation of phenylacetylene with dif- sideration of heterocycles with increasing amount of
ferent electron-rich heteroarenes significant devia- N-atoms, like in imidazole, the nucleophilicity is re-
tions of the rate constants were observed (Table 3, duced in such a way that nearly no reactivity was ob-
Figure 6).
served (entry 7). The hydroarylation of phenylacety-
In a first set of experiments differently substituted lene with 2-methylfuran, 2-methylthiophene and thio-
pyrroles bearing one or more alkyl substituents were phene shows almost no conversion (entries 11–13).
converted. In comparison to unsubstituted pyrroles With regard to the kinetic examination of the nucleo-
and as expected, an up to eleven times faster reaction philic attack of the electron-rich heteroarenes, the ob-
was observed for the more electron-rich systems (en- served sequence of reactivity to a large extent corre-
tries 1–6). Indole derivatives reacted considerable lates with the predictions of Mayr et al.[14] Minimal
slower than the pyrrole systems (entries 8–10). In con- discrepancies are merely within the sequence of alkyl-
Table 3. Variation of electron-rich heteroarenes.[a]
Entry Heteroarene Consumption[b] [%] t=10 h Time[c] [h] Product and Yield[d]
k [L/(molh)] R2
krel
1
2
100 (2.8:1)
100 (3.8:1)
10
2
1a (65%) 0.316Æ0.021 0.996 1.00Æ0.07
1b (57%) 1.309Æ0.001 0.997 4.15Æ0.01
3
100 (1:4.4)
1
1c (6%)
0.685Æ0.022 0.993 2.17Æ0.07
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Table 3. (Continued)
Entry Heteroarene Consumption[b] [%] t=10 h Time[c] [h] Product and Yield[d]
k [L/(molh)] R2
krel
4
5
6
100 (1:2.0)
100 (1:1.5)
100 (1:3.3)
0.2
0.3
2
1d (39%) 3.556Æ0.043 0.994 11.27Æ0.14
1e (38%) 1.300Æ0.092 0.992 4.12Æ0.29
1f (41%) 0.546Æ0.025 0.990 1.73Æ0.08
7
2
–
–
–
–
–
–
–
–
–
–
–
[e]
[e]
[f]
8
70 (1:11.8)
57 (1:2.2)
85 (Only di-adduct)
0.074Æ0.006 0.998 0.24Æ0.02
0.042Æ0.005 0.991 0.13Æ0.02
0.119Æ0.002 0.983 0.38Æ0.01
9
10
11
12
20[g]
72
1g (6%)
0.003Æ0.004 0.988 0.01Æ0.01
<1
–
–
–
–
–
–
–
–
–
–
13
< <1
[a]
Reaction conditions: phenylacetylene (196 mmol, 0.302 mmol/mL), heteroarene (979 mmol), IPrAuNTf2 (2 mol%), CD3CN
1
at T=258C, observed by H NMR kinetic for 10 h under air in NMR tubes.
[b]
1
Consumption of the phenylacetylene determined by H NMR-kinetic; in parentheses is the ratio of mono- to di-adduct
determined by 1H NMR-kinetic.
[c]
[d]
[e]
[f]
Reaction time to yield the mono-adduct.
Yield of product isolated by flash column chromatography.
Product is not isolated due to same polarity within reaction mixture.
Exclusive formation of the di-adduct.
[g]
Product signals were too small to determine a significant ratio.
substituted pyrroles. This might originate from the ap- sion of the alkyne. As visible from the kinetic analy-
plication of different electrophiles as well as varying sis, maximum concentrations of mono-adduct are ob-
solvents in the literature. The ratio of mono- to di- tained at early stages of the reaction which encour-
adduct concentration after a measurement period of aged us to isolate these species by stopping the reac-
ten hours is dependent on different electron-rich het- tions early. In dependency of the applied nucleophile
eroarenes. The addition reaction of 1-methylindole to a strong adaption of reaction times needed to be
phenylacetylene turned out to be the only reaction done leading to reaction times ranging from few mi-
that selectively delivered the di-adduct while all the nutes to more than a week. By following this strategy,
other reactions delivered mixtures after full conver- mono-adducts 1a–f could be obtained in good to mod-
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Figure 6. Reaction progress; decrease of the concentration of phenylacetylene.
erate yields (38–65%), demonstrating that under care- lene exhibits a twice as fast reaction progress (en-
fully adjusted conditions mono-adducts can also be tries 1 and 5). The rate constant for 1-octyne is an
synthesized in the presence of a gold catalyst. The order of magnitude smaller than that in the case of
yield of the mono-adduct 1g is with 6% relatively low phenylacetylene (entry 6). This effect should be based
due to low conversion. The mono-adducts of phenyla- on the stabilization of the aromatic p-system. The re-
cetylene with various indole derivatives could not be action of 3-phenyl-1-propyne shows a rate constant
isolated due to the same polarity as the two-fold addi- reduced by 25% in comparison to phenylacetylene.
tion product within the reaction mixture. The central The trend that compounds with electron-withdrawing
problem of the purification was the rapidly occurring groups on the aromatic ring indicate an accelerated
polymerization of the mono-adducts.[15] The hydroary- attack of a nucleophile compared to electron-donat-
lation of different alkynes with pyrrole as benchmark ing substituents is not dominating. Apart from 4-bi-
system shows substantial variation in their rate con- phenylacetylene, the rate constants of alkyl-substitut-
stants (Table 4, Figure 7). Thereby, reactions of al- ed phenylacetylene derivatives achieved the highest
kynes with aryl groups which include either electron- values (entries 2 and 7–9). By using halide-substituted
withdrawing or electron-donating groups were accen- phenylalkynes, an expedited reaction was observed
tuated. Moreover, also internal alkynes and various (entries 10–13). The influence of the position of this
aliphatic alkynes were used.
substituent was determined as well. The conversion of
In direct comparison to cyclohexylacetylene, it is o-, m- and p-chlorophenylacetylenes demonstrated
noteworthy that the aromatic compound phenylacety- only little discrepancies concerning the rate constant.
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Table 4. Variation of alkynes.[a]
Entry Alkyne
Consumption[b]
[%] t=10 h
Time[c]
[h]
Product and Yield[d]
k
R2
krel
[L/(mol h)]
1
100 (2.8:1)
10
2
1a (65%)
0.316Æ0.021 0.996 1.00Æ0.07
2
3
100 (1.4:1)
1h (78%) 0.920Æ0.048 0.996 2.92Æ0.15
9
504
1i (35%)
1j (33%)
–
–
–
4
5
89[e]
24
1
0.237Æ0.009 0.994 0.75Æ0.03
0.140Æ0.010 0.995 0.44Æ0.03
91 (1:41.0)
trace
6
7
72 (1:2.6)
14
trace
0.028Æ0.006 0.896 0.09Æ0.02
94 (only mono-
adduct)
3.5
1k (60%) 0.586Æ0.042 0.995 1.86Æ0.13
87 (only mono-
adduct)
8
9
14
5
1l (45%)
0.525Æ0.024 0.931 1.66Æ0.08
0.665Æ0.016 0.998 2.11Æ0.05
1m (72%)
+
1n (7%)
100 (only mono-
adduct)
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Table 4. (Continued)
Entry Alkyne
Consumption[b]
[%] t=10 h
Time[c]
[h]
Product and Yield[d]
k
R2
krel
[L/(mol h)]
1o (40%)
10
11
100 (2.8:1)
100 (4.7:1)
10
10
+
0.488Æ0.003 0.999 1.55Æ0.01
1p (8%)[f]
1q (40%) 0.396Æ0.002 0.999 1.25Æ0.01
12
13
100 (1.9:1)
100 (1.6:1)
10
4
1r (40%)
1s (78%)
0.408Æ0.001 0.999 1.29Æ0.00
0.525Æ0.008 0.999 1.66Æ0.03
35 (only mono-
adduct)
14
15
72
1t (7%)[f]
0.024Æ0.006 0.968 0.08Æ0.02
92 (1.2:1)
2.5
1u (66%) 0.155Æ0.004 0.997 0.49Æ0.01
98 (only mono-
adduct)
16
17
18
4
1v (46%)
0.201Æ0.009 0.995 0.64Æ0.03
90 (3.3:1)
81 (1.8:1)
6
1w (70%)[f] 0.148Æ0.002 0.996 0.47Æ0.01
1x (41%)[f] 0.186Æ0.019 0.947 0.59Æ0.06
1.5
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Table 4. (Continued)
Entry Alkyne
Consumption[b]
[%] t=10 h
Time[c]
[h]
Product and Yield[d]
k
R2
krel
[L/(mol h)]
92 (only mono-
adduct)
19
10
1y (57%)
0.166Æ0.003 0.998 0.53Æ0.01
[a]
Reaction conditions: alkyne (196 mmol, 0.302 mmol/mL), pyrrole (979 mmol), IPrAuNTf2 (2 mol%), CD3CN at T=258C,
observed by 1H NMR kinetic for 10 h under air in NMR tubes.
[b]
1
Consumption of the phenylacetylene determined by H NMR kinetic; in parentheses is the ratio of mono- to di-adduct
determined by 1H NMR kinetic.
[c]
[d]
[e]
[f]
Reaction time to yield the mono-adduct.
Yield of product isolated by flash column chromatography.
No ratio of mono- to di-adduct was determined because of overlapping signals.
1
The H NMR spectra contain signals of impurities caused by occurring polymerization.
Further reactions with electron-withdrawing trifluoro- pyrrole after a reaction time of six hours showed no
methyl, carboxylic acid ester and nitro groups on the further change of the mono- to di-adduct ratio even
aromatic ring showed a half as fast reaction progress after prolonged reaction times. Only the reaction of
in contrast to phenylacetylene (entries 15–17 and 19). 3-ethyl-2,4-dimethylpyrrole proceeded until almost
The rate constant of 4-methoxyphenylacetylene is exclusively the di-adduct was formed. From the reac-
comparable to the results of 4-trifluoromethylpheny- tion progress it becomes obvious that the presence of
lacetylene; this result cannot be explained yet, but phenylacetylene is essential for a further conversion
has been verified by repetitions of these experiments. to the di-adduct. The mono- to di-adduct ratio exam-
The reaction of diphenylacetylene consumed only 9% ined after a reaction time of ten hours for the hydro-
of the starting material within the measurement arylation of phenylacetylene with various pyrrole con-
period of ten hours. Consequently, diphenylacetylene centrations is an excellent evidence for this discovery
and 4-(dimethylamino)phenylacetylene exhibit the (Table 2). Thereby, if compared to higher pyrrole con-
lowest rate constants of the used alkynes (entries 3 centrations, the addition of only one equivalent of
and 14). In addition to the kinetic data, the ratio of pyrrole leads to a higher selectivity towards the di-
mono- to di-adduct concentration after a measurement adduct which seems to be contraintuitive. But, higher
period of ten hours was analyzed. The reaction mix- pyrrole concentrations induce a fast formation of the
tures with electron-donating groups contain after the mono-adduct and therefore after short reaction times
obtained reaction time almost exclusively mono-ad- all of the phenylacetylene is consumed and the fur-
ducts. Whereas, the hydroarylation of electron-with- ther conversion to the di-adduct stops. The observed
drawing alkynes show a 2:1 ratio of mono-adduct to phenomena might be explained by a competing
di-adduct on average. Only the reactions of cyclohex- proton-catalyzed step that is operating for the second
ylacetylene and 1-octyne have a substantial incidence addition step. The presence of protons in the media
of di-adduct. In addition to the kinetic research, the might be derived by the reversible formation of s,p-
isolation of the maximum yield of mono-adduct was acetylide complexes, a process that is known to pro-
addressed. As in the upper case, the reaction time duce one equivalent of the corresponding acid.[16]
was modified for each alkyne. Following this princi- After the consumption of phenylacetylene, this equi-
ple, the mono-adducts 1h–y were synthesized in good librium of s,p-acetylide complexes/free protons with
to moderate yields (33–78%). The hydroarylation of phenylacetylene is shifted back, which then stops the
cyclohexylacetylene and 1-octyne yielded nevertheless acid-catalyzed second hydroarylation. To prove this
no mono-product. As mentioned before the central assumption, 5 mol% of trifluoromethanesulfonimide
problem for purification was the rapidly occurring were added to the reaction of phenylacetylene with
polymerization of the mono-adducts.[15]
pyrrole and indeed the transformation of mono- to di-
Although the electron-rich heteroarenes were used adduct was completed after only a few minutes
in excess, the kinetic research shows that the reaction [Scheme 2, Eq. (1)]. In order to exclude a possible
just stops after reaching a ratio of mono- to di-adduct gold-catalyzed reaction, the isolated mono-adduct 1a
which is specific for each reaction (Figure 3). For ex- was reacted with pyrrole and 5 mol% of trifluorome-
ample, the hydroarylation of phenylacetylene with thanesulfonimide [Scheme 2, Eq. (2)]. A gold-cata-
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Figure 7. Reaction progress; decrease of the concentration of the starting material.
lyzed addition reaction of pyrrole onto the mono-
As a result of these control experiments, the forma-
adduct 1a was inter alia investigated by the addition tion of the di-adduct is an exclusively proton-cata-
of IPrAuNTf2 [Scheme 2, Eq. (3)]. As expected, in lyzed step. As a consequence, we were curious if
the absence of a proton source no reaction was ob- these two pathways can be coupled in order to obtain
served.
the hetero-di-hydroarylation of phenylacetylene with
various electron-rich heteroarenes a two-step, one-pot
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Conclusions
In conclusion, the mono- and two-fold hydroarylation
reaction of alkynes with electron-rich heteroarenes
was examined and optimized by 1H NMR kinetics.
Thereby, the rate constants for diverse reaction condi-
tions as well as the detailed reaction progress were
determined. It was demonstrated that the electronic
effect of the substituents on phenylacetylene signifi-
cantly affects the rate constant. However, the addition
of electron-rich heteroarenes onto functionalized phe-
nylacetylenes is not following a defined pattern. Inter
alia, the measurements showed that a specific mono-
to di-adduct ratio was formed in the reactions (de-
pending on the applied starting materials) and even
though nucleophile was still present no further reac-
tion was monitored in the presence of the gold cata-
lyst. Based on the kinetic data, by stopping the reac-
tion at an early stage, the mono-adducts could be iso-
lated in moderate to good yields (33–78%). More-
over, from the obtained kinetic data it became obvi-
ous that protons reversibly derived from the
formation of s,p-acetylide complexes from the termi-
nal alkynes are crucial for the second step of the addi-
tion cascade. This observation is in accordance with
recently published density functional theory (DFT)
Scheme 2. Mechanistic investigation.
synthesis. Therefore, first one equivalent of phenyla- calculations.[10] By employing the orthogonal reactivity
cetylene was treated with an appropriate amount of of gold and a proton for the two reaction steps, the
heteroarene and the after a specific reaction time five synthesis of hetero-di-adducts could be achieved in
equivalents of a different heteroarene and 5 mol% of moderate to good yields (10–84%). Based on the col-
trifluoromethanesulfoneimide were added. The results lected kinetic data and the possibility of converting
of this study are shown in Table 5.
the obtained intermediates, this opens up new syn-
The appropriation of this method allows the synthe- thetic possibilities for further applications in the syn-
sis of homo-di-adducts (entry 1) as well as hetero-di- thesis of hetero-addition products.
adducts (entries 2–12). As expected, the addition re-
action of pyrrole with phenylacetylene proceeded
smoothly to afford di-adduct 2a with 89% yield. The Experimental Section
hetero-di-adducts 2b–j were gained in moderate to
good yields (10–84%). Here, the H NMR kinetic re- General Procedure 1 for the H NMR Kinetic
1
1
search is playing a key role. On the basis of the meas-
urements, it was possible to predict the ratio of mono-
(1 equiv.) and freshly distilled heteroarene (5 equiv.) in ace-
To an NMR tube charged with a solution of alkyne
to di-adduct as well as the reaction speed for specific
electron-rich heteroarenes. In combination of both as-
pects, the chronological order of adding the heteroar-
enes was calculated. On two representative reactions
the relevance of the chronological order was demon-
strated. The change of chronological order of addition
of pyrrole and 2,4-dimethylpyrrole decreased the
yield of 50% (entry 3) to 2% (entry 4). Moreover, en-
tries 5 and 6 point out that the yield is decreasing
enormously as soon as the reaction is not conducted
in a two-step, one-pot principle. Thereby, a loss of
63% yield was determined. The moderate yields of
the hetero-di-adducts 2b, f–j depend on the close po-
larity of the reaction mixture. Another reason for re-
duced yields is the loss of selectivity for nucleophiles
with nearly similar rate constants.
tonitrile-d3, IPrAuNTf2 (0.02 equiv.) was added. The reaction
was observed at T=258C by 1H NMR kinetic for 10 h.
Here, the equipment Avance DRX-300, after an instrument
defect Avance DRX-400, of Bruker Devices was selected.
Due to the often varying relaxation times, the measurement
period differs from substance to substance.
General Procedure 2 for the Mono-Hydroarylation of
Alkynes with Electron-Rich Heteroarenes
To a reaction mixture of alkyne (1 equiv.) and freshly dis-
tilled heteroarene (5 equiv.) in acetonitrile-d3, IPrAuNTf2
(0.02 equiv.) was added. The reaction was conducted without
stirring at room temperature for a certain time (see Table 3
and Table 4). The solvent was removed under reduced pres-
sure. The crude residue was purified by column chromatog-
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Table 5. Synthesis of di-adducts.[a]
[a]
Reaction conditions: phenylacetylene (1 equiv., 0.302 mmol/mLÀ1), heteroarene X (1–5 equiv.), heteroarene Y (5 equiv.),
HNTf2 (5 mol%), IPrAuNTf2 (2 mol%), CD3CN at T=258C.
Reaction time to start the proton-catalyzed step.
Yield of product isolated by flash column chromatography.
One-step, one-pot reaction.
[b]
[c]
[d]
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raphy on silica gel (petroleum ether/ ethyl acetate) to afford
the corresponding product.
General Procedure 3 for the Two-Fold Hydroary-
lation of Alkynes with Various Electron-Rich
Heteroarenes
2-(1-Phenylvinyl)-1H-pyrrole (1a):[17] Phenylacetylene
(21.5 mL, 196 mmol, 1 equiv.), pyrrole (67.9 mL, 979 mmol,
5 equiv.) and IPrAuNTf2 (3.4 mg, 4 mmol, 0.02 equiv.) were
dissolved in 0.56 mL acetonitrile-d3 following the general
procedure 2. The reaction was stopped after 10 hours. Purifi-
cation by column chromatography (SiO2, PE/EA=200:1) af-
forded 1a as orange oil; yield: 21 mg (127 mmol, 65%); Rf
(PE/EA=200:1)=0.13. 1H NMR (300 MHz, CD3CN): d=
5.08 (d, J=0.5 Hz, 1H), 5.40 (d, J=0.5 Hz, 1H), 6.03–6.06
(m, 1H), 6.13–6.16 (m, 1H), 6.81–6.83 (m, 1H), 7.37–7.41
(m, 3H), 7.42–7.47 (m, 2H), 9.33 (bs, 1H); 13C NMR
(75 MHz, CD3CN): d=109.00 (t, 1C), 109.74 (d, 1C), 110.10
(d, 1C), 120.17 (d, 1C), 128.92 (d, 1C), 129.20 (d, 2C),
129.24 (d, 2C), 132.66 (s, 1C), 141.95 (s, 1C), 142.70 (s, 1C);
To an NMR tube charged with a solution of alkyne
(1 equiv.) and freshly distilled heteroarene (1.1–5 equiv.) in
acetonitrile-d3, IPrAuNTf2 (0.02 equiv.) was added. Con-
sumption of the starting material was controlled by TLC
and 1H NMR. A different heteroarene (5 equiv.) and tri-
fluoromethanesulfonimide (0.05 equiv.) were added after
a specific time. The reaction was completed after 5 minutes.
The solvent was removed under reduced pressure. The
crude residue was purified by flash chromatography over
silica gel (petroleum ether/ ethyl acetate) to afford the cor-
responding product.
2,5-Dimethyl-3-[1-phenyl-1-(1H-pyrrol-2-yl)ethyl]-1H-pyr-
role (2d): Phenylacetylene (43.0 mL, 0.392 mmol, 1 equiv.),
pyrrole (136.0 mL, 1.958 mmol, 5 equiv.) and IPrAuNTf2
(6.8 mg, 0.008 mmol, 0.02 equiv.) were dissolved in 0.5 mL
acetonitrile-d3 following the general procedure 3. After 10
hours, 2,5-dimethylpyrrole (199.0 mL, 1.958 mmol, 5 equiv.)
and trifluoromethanesulfonimide (5.5 mg, 0.020 mmol,
0.05 equiv.) were added. Purification by column chromatog-
raphy (SiO2, PE/EA=20:1) afforded 2d as orange-red solid;
yield: 85 mg (0.322 mmol, 82%); mp 568C; Rf (PE/EA=
8:1)=0.38. 1H NMR (300 MHz, CD3CN): d=1.57 (s, 3H),
1.91 (s, 3H), 2.11 (s, 3H), 5.38–5.39 (m, 1H), 5.74–5.76 (m,
1H), 5.98–6.01 (m, 1H), 6.59–6.62 (m, 1H), 7.14–7.18 (m,
3H), 7.22–7.25 (m, 2H), 8.44 (bs, 1H), 8.54 (bs, 1H);
13C NMR (100 MHz, CD3CN): d=12.53 (q, 1C), 12.75 (q,
1C), 30.27 (q, 1C), 44.64 (s, 1C), 106.32 (d, 1C), 107.47 (d,
1C), 108.03 (d, 1C), 117.18 (d, 1C), 122.93 (s,1C), 124.64 (s,
1C), 126.53 (d, 1C), 126.62 (s, 1C), 128.39 (d, 2C), 128.60
˜
IR (film): n=3424, 3266, 3089, 3055, 3024, 2974, 1610, 1572,
1547, 1492, 1444, 1251, 1081, 1027, 883, 776, 701, 645 cmÀ1
;
MS (EI+): m/z (%)=169.1 (100) [M]+, 154.1 (50)
[MÀCH3]+; HR-MS (EI+): m/z=169.0894, calcd. for
C12H11N: 169.0891.
1,2,5-Trimethyl-3-(1-phenylvinyl)-1H-pyrrole (1e): Phenyl-
acetylene (43.0 mL, 392 mmol, 1 equiv.), 1,2,5-trimethylpyr-
role (264.9 mL, 1958 mmol, 5 equiv.) and IPrAuNTf2 (6.8 mg,
8 mmol, 0.02 equiv.) were dissolved in 1.0 mL acetonitrile-d3
following the general procedure 2. The reaction was aborted
after 20 minutes. Purification by column chromatography
(SiO2, PE/EA=200:1) afforded 1e as orange oil; yield:
1
31 mg (147 mmol, 38%); Rf (PE/EA=200:1)=0.09. H NMR
(300 MHz, CD3CN): d=1.96 (s, 3H), 2.16 (s, 3H), 3.37 (s,
3H), 5.05 (d, J=2.0 Hz, 1H), 5.26 (d, J=2.0 Hz, 1H), 5.63
(m, 1H), 7.29–7.34 (m, 5H); 13C NMR (75 MHz, CD3CN):
d=11.64 (q, 1C), 12.36 (q, 1C), 30.67 (q, 1C), 107.41 (d,
1C), 111.79 (t, 1C), 124.74 (s, 1C), 127.91 (s, 1C), 128.27 (d,
1C), 128.48 (d, 2C), 128.69 (s, 1C), 129.00 (d, 2C), 144.00 (s,
˜
(d, 2C), 140.32 (s, 1C), 150.99 (s, 1C); IR (film): n=3418,
3382, 3098, 3083, 3056, 3021, 2976, 2932, 1596, 1555, 1493,
1444, 1397, 1370, 1243, 1202, 1183, 1099, 1081, 1027, 943,
790, 763, 704, 643 cmÀ1; MS (EI+): m/z (%)=264.1 (35)
[M]+, 249.1 (100) [MÀCH3]+; HR-MS (EI+): m/z=264.1605,
calcd. for C18H20N2: 264.1621; m/z=249.1369, calcd. for
C17H17N2: 249.1386.
˜
1C), 146.42 (s, 1C); IR (Film): n=3346, 3080, 3054, 3023,
2927, 2857, 1699, 1657, 1603, 1572, 1491, 1444, 1398, 1377,
1254, 1156, 1027, 882, 780, 701, 620 cmÀ1; GS-MS (EI): m/z
(%)=211.1 (100) [M]+; HR-MS (EI+): m/z=211.1341,
calcd. for C15H17N: 211.1631.
3,5-Dimethyl-2-[1-(1-methyl-1H-pyrrol-2-yl)-1-phenyleth-
yl]-1H-pyrrole (2h): Phenylacetylene (21.5 mL, 0.196 mmol,
1 equiv.), 1-methylpyrrole (86.9 mL, 0.979 mmol, 5 equiv.)
and IPrAuNTf2 (3.4 mg, 0.004 mmol, 0.02 equiv.) were dis-
solved in 0.5 mL acetonitrile-d3 following the general proce-
2-{1-([1,1’-biphenyl]-4-yl)vinyl}-1H-pyrrole (1h): 4-Biphe-
nylacetylene (69.8 mg, 392 mmol, 1 equiv.), pyrrole
(135.8 mL, 1958 mmol, 5 equiv.) of pyrrole and IPrAuNTf2
(6.8 mg, 8 mmol, 0.02 equiv.) were dissolved in 1.16 mL ace-
tonitrile-d3 following the general procedure 2. The reaction
was stopped after 2 hours. Purification by column chroma-
tography (SiO2, PE/EA=200:1) afforded 1h as yellowish
solid; yield: 75 mg (306 mmol, 78%); Rf (PE/EA=200:1)=
dure 3. After
3 hours, 2,4-dimethylpyrrole (100.8 mL,
0.979 mmol 5 equiv.) and trifluoromethanesulfonimide
(2.8 mg, 0.010 mmol, 0.05 equiv.) were added. Purification
by column chromatography (SiO2, PE/EA=50:1) afforded
2h as orange oil; yield: 17 mg (0.061 mmol; 31%); Rf (PE/
1
0.08; mp 1158C. H NMR (300 MHz, CD3CN): d=5.13 (s,
1H), 5.40 (s, 1H), 6.05–6.07 (m, 1H), 6.12–6.15 (m, 1H),
6.81–6.83 (m, 1H), 7.35–7.41 (m, 1H), 7.45–7.54 (m, 4H),
7.64–7.71 (m, 4H), 9.37 (bs, 1H); 13C NMR (75 MHz,
CD3CN): d=109.12 (t, 1C), 109.75 (d, 1C), 110.12 (d, 1C),
120.22 (d, 1C), 127.69 (d, 2C), 127.83 (d, 2C), 128.53 (d,
1C), 129.79 (d, 2C), 129.95 (d, 2C), 132.56 (s, 1C), 141.07 (s,
1C), 141.36 (s, 1C), 141.41 (s, 1C), 142.26 (s, 1C); IR
1
EA=40:1)=0.39. H NMR (400 MHz, CD3CN): d=1.52 (s,
3H), 2.02 (s, 3H), 2.10 (d, J=0.4 Hz, 3H), 3.11 (s, 3H),
5.57–5.58 (m, 2H), 5.90–5.92 (m, 1H), 6.56–6.57 (m, 1H),
7.14- 7.17 (m, 2H), 7.29–7.33 (m, 3H), 7.98 (bs, 1H);
13C NMR (100 MHz, CD3CN): d=12.14 (q, 1C), 12.80 (q,
1C), 29.56 (q, 1C), 35.96 (q, 1C), 45.69 (s, 1C), 106.53 (d,
1C), 109.35 (d, 1C), 110.52 (d, 1C), 116.02 (s, 1C), 124.51
(d, 1C), 127.28 (d, 1C), 128.72 (d, 2C), 129.02 (d, 2C),
129.44 (s, 1C), 129.77 (s, 1C), 139.19 (s, 1C), 148.21 (s, 1C);
˜
(ATR): n=3431, 3055, 3029, 2926, 1603, 1580, 1547, 1487,
1448, 1332, 1117, 1096, 1033, 1007, 883, 847, 804, 770, 729,
697 cmÀ1; GS-MS (EI): m/z (%)=245.1 (100) [M]+, 230.0
(80) [M-CH3]+; HR-MS (EI+): m/z=245.1201, calcd. for
C18H15N: 245.1204; m/z=230.1014, calcd. for C17H12N:
230.0970.
˜
IR (ATR): n=3452, 3057, 2981, 2934, 2871, 1700, 1595,
1492, 1444, 1396, 1297, 1227, 1094, 1066, 1028, 786, 759, 706,
638 cmÀ1; MS (EI+): m/z (%)=278.1 (36) [M]+, 263.1 (100)
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[MÀCH3]+; HR-MS (EI+): m/z=278.1772, calcd. for
C19H22N2: 278.1777; m/z=263.1538, calcd. for C18H19N2:
263.1542.
Chem. 2010, 82, 801–820; e) C. Ferrer, C. H. M. Amijs,
A. M. Echavarren, Chem. Eur. J. 2007, 13, 1358–1373;
f) A. S. K. Hashmi, M. C. Blanco, Eur. J. Org. Chem.
2006, 4340–4342; g) M. Alfonsi, A. Arcadi, G. Bianchi,
F. Marinelli, A. Nardini, Eur. J. Org. Chem. 2006, 2393–
2402; h) M. Alfonsi, A. Arcadi, M. Aschi, G. Bianchi,
F. Marinelli, J. Org. Chem. 2005, 70, 2265–2273; i) M. T.
Reetz, K. Sommer, Eur. J. Org. Chem. 2003, 68, 3465–
3496; j) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M.
Frost, Angew. Chem. 2000, 112, 2382–2385; Angew.
Chem. Int. Ed. Engl. 2000, 39, 2285–2288.
Acknowledgements
The authors thank Umicore AG & Co. KG for the generous
donation of gold salts.
[8] J. S. Yadav, B. V. S. Reddy, B. Padmavani, M. K. Gupta,
References
Tetrahedron Lett. 2004, 45, 7577–7579.
[9] a) T. Tsuchimoto, T. Wagatsuma, K. Aoki, J. Shimotori,
Org. Lett. 2009, 11, 2129–2132; b) T. Tsuchimoto, T.
Ainoya, K. Aoki, T. Wagatsuma, E. Shirakawa, Eur. J.
Org. Chem. 2009, 2437–2440.
[10] T. Mehrabi, A. Ariafard, Chem. Commun. 2016, 52,
9422–9425.
[11] a) L. Ricard, F. Gagosz, Organometallics 2007, 26,
4704–4707; b) M. Trinchillo, P. Belanzoni, L. Belpassi,
L. Biasiolo, V. Busico, A. DꢅAmora, L. DꢅAmore, A.
Del Zotto, F. Tarantelli, A. Tuzi, D. Zuccaccia, Organo-
metallics 2016, 35, 641–654; c) J. Zhao, X. Yuan, Z.
Wang, S. Chen, Z. Zhang, W. Xue, Org. Chem. Front.
2015, 2, 34–37; d) M. Chen, N. Sun, H. Chen, Y. Liu,
Chem. Commun. 2016, 52, 6324–6327.
[1] a) R. Khajuria, S. Dham, K. K. Kapoor, RSC Adv.
2016, 6, 37039–37066; b) S. S. Gholap, Eur. J. Med.
Chem. 2016, 110, 13–31; c) V. Bhardwaj, D. Gumber, V.
Abbot, S. Dhiman, P. Sharma, RSC Adv. 2015, 5,
15233–15266; d) H. Fan, J. Peng, M. T. Hamann, J. Hu,
Chem. Rev. 2008, 108, 264–287; e) F. Bellina, R. Rossi,
Tetrahedron 2006, 62, 7213–7256; f) A. Fꢁrstner,
Angew. Chem. 2003, 115, 3706–3728; Angew. Chem.
Int. Ed. 2003, 42, 3582–3603; g) A. Alberola, A. G.
Ortega, M. L. Sꢂdaba, C. SaÇudo, Tetrahedron 1999, 55,
6555–6566; h) C. Y. de Leon, B. Ganem, Tetrahedron
1997, 53, 7731–7752; i) J. A. H. Lainton, J. W. Huffman,
B. R. Martin, D. R. Compton, Tetrahedron Lett. 1995,
36, 1401–1404.
[12] a) P. W. Atkins, J. Paula, Physikalische Chemie, Wiley-
VCH, 4th edn., 2006; b) P. L. Houston, Chemical Kinet-
ics and Reaction Dynamics, Dover Publications, Inc.,
Minola, New York, 2012; c) W. Bechmann, J. Schmidt,
Einstieg in die Physikalische Chemie fꢀr Nebenfꢁchler,
B. G. Teubner, 1st edn., 2001; d) H. G. Elias, Makromo-
lekꢀle: Chemische Struktur und Synthesen, Wiley-VCH,
6th edn., 1999.
[2] a) L. Liang, S. Fu, D. Lin, X. Zhang, Y. Deng, H. Jiang,
W. Zeng, J. Org. Chem. 2014, 79, 9472–9480; b) R.
Manikandan, M. Jeganmohan, Org. Biomol. Chem.
2015, 13, 10420–10436; c) S. T. Tan, Y. C. Teo, W. Y.
Fan, J. Organomet. Chem. 2012, 708–709, 58–64.
[3] a) L. Rubio-Pꢃrez, M. Iglesias, R. Castarlenas, V. Polo,
J. J. Pꢃrez-Torrente, L. A. Oro, ChemCatChem 2014, 6,
3192–3199; b) C. C. Roberts, D. M. Matꢄas, M. J. Gold-
fogel, S. J. Meek, J. Am. Chem. Soc. 2015, 137, 6488–
6491; c) D. A. Colby, R. G. Bergman, J. A. Ellman,
Chem. Rev. 2010, 110, 624–655.
[4] a) N. Tsukada, K. Murata, Y. Inoue, Tetrahedron Lett.
2005, 46, 7515–7517; b) W. Lu, C. Jia, T. Kitamura, Y.
Fujiwara, Org. Lett. 2000, 2, 2927–2930.
[5] a) J. Oyamada, T. Kitamura, Tetrahedron 2009, 65,
3842–3847; b) M. L. Keita, T. Mizuhara, J. Oyamada, T.
Kitamura, Chem. Lett. 2007, 36, 1150–1151.
[13] M. Kumar, G. B. Hammond, B. Xu, Org. Lett. 2014, 16,
3452–3455.
[14] a) H. Mayr, A. Ofial, C. Singer. Mayrꢂs Database of Re-
activity Parameters, Web, 12th August 2015,
http://www.cup.lmu.de/oc/mayr/reaktionsdatenbank2/
(accessed 9th October 2015); b) H. Mayr, S. Lakhdar, B.
Maji, A. Ofial, Beilstein J. Org. Chem. 2012, 8, 1458–
1478; c) S. Minegishi, S. Kobayashi, H. Mayr, J. Am.
Chem. Soc. 2004, 126, 5174–5181.
[6] a) Y. Nakao, Chem. Rec. 2011, 11, 242–251; b) K. S. Ka-
nyiva, Y. Nakao, T. Hiyama, Angew. Chem. 2007, 119,
9028–9030; Angew. Chem. Int. Ed. 2007, 46, 8872–8874.
[7] a) R. Dorel, A. M. Echavarren, Chem. Rev. 2015, 115,
9028–9072; b) C. Luo, H. Yang, R. Mao, C. Lu, G.
Cheng, New J. Chem. 2015, 39, 3417–3423; c) M. E.
Muratore, A. M. Echavarren, in: The Chemistry of Or-
ganogold Compounds, Wiley, Vol.2, 2014, pp 805–900;
d) P. de Mendoza, A. M. Echavarren, Pure Appl.
[15] A. S. K. Hashmi, S. Schꢆfer, V. Gçker, C. D. Eisenbach,
K. Dirnberger, Z. Zhao-Karger, P. Crewdson, Aust. J.
Chem. 2014, 67, 500–506.
[16] a) T. J. Brown, R. A. Widenhoefer, Organometallics
2011, 30, 6003–6009; b) A. Grirrane, H. Garcia, A.
Corma, E. ꢇlvarez, ACS Catal. 2011, 1, 1647–1653.
[17] M. Austin, C. Covell, A. Gilbert, R. Hendrickx, Liebigs
Ann./Recueil 1997, 5, 943–946.
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16 The Gold-Catalyzed Hydroarylation of Alkynes with
Electron-Rich Heteroarenes – A Kinetic Investigation and
New Synthetic Possibilities
Adv. Synth. Catal. 2017, 359, 1 – 16
Jasmin Schießl, Matthias Rudolph, A. Stephen K. Hashmi*
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