Mechanochemical Ruthenium-Catalyzed Hydroarylations of Alkynes under Ball-Milling Conditions

Article abstract of DOI:10.1021/acs.orglett.7b02973

Under solventless grinding conditions, mechanochemical ruthenium-catalyzed hydroarylations of alkynes with acetanilides lead to trisubstituted alkenes. Only catalytic amounts of pivalic acid or copper acetate are required, and without the need for externa

Full text of DOI:10.1021/acs.orglett.7b02973

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Mechanochemical Ruthenium-Catalyzed Hydroarylations of Alkynes
under Ball-Milling Conditions
Hanchao Cheng, Jose G. Hernandez, and Carsten Bolm*
́
́
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: Under solventless grinding conditions, mechanochemical ruthenium-catalyzed hydroarylations of alkynes with
acetanilides lead to trisubstituted alkenes. Only catalytic amounts of pivalic acid or copper acetate are required, and without the
need for external heating, the reaction times are shorter than those of their solution-based counterpart. Mechanochemical
oxidative annulations through palladium-catalyzed intramolecular amination convert the products into N-acetylindoles.
ransition-metal-catalyzed hydroarylations of alkynes by
C−H bond functionalization have attracted much
and AgSbF6 (20 mol %) as catalytic system.12 To our delight,
the solventless mechanochemical conditions proved suitable,
and the hydroarylation reaction (at 30 Hz) provided exclusively
the E-isomer of 3aa in 70% yield. Interestingly, the milling
period was only 198 min (3.3 h), which was significantly
shorter than the required time in solution (for details, see the
SI).13 Further screening revealed that the amount of pivalic acid
could be reduced to catalytic quantities (20 mol %), while the
yield of 3aa increased to 82% after the same milling time
(Table 1, entry 1). In the absence of either the silver salt or
PivOH, the product was not formed (Table 1, entries 2 and 3).
Substituting AgSbF6 for tetrafluoroborate (AgBF4) led to a
drop in the yield of 3aa from 82% to 25% (Table 1, entries 1
and 4). Replacing PivOH with an acetate-containing additive
[Cu(OAc)2·H2O, AgOAc, Fe(OAc)2, and NaOAc] led to
variable results (Table 1, entries 5−8). In all cases, 3aa was
formed, albeit in different amounts. The most effective additive
was Cu(OAc)2·H2O, giving 3aa in 80% yield (Table 1, entry 5).
This result was unexpected because in solution the use of this
copper salt predominantly led to indoles by C−H functional-
ization followed by oxidative annulation.12d Thus, the use of the
mechanochemical conditions allowed alteration of the product
portfolio by interrupting the reaction path commonly observed
in solution. Further tuning of the reaction conditions showed
that the milling time could be reduced from 198 to 99 min
without significantly affecting the yield of 3aa (83%, entry 9).
In addition, carrying out a 2-fold scale-up of the C−H
hydroarylation proved possible, and in the mixer mill the
reaction afforded product 3aa in 71% yield (Table 1, entry 10).
At this stage, a few observations of the mechanochemical
hydroarylation reaction leading to 3aa in the mixer mill shall be
highlighted because they differ from their solution-based
T
attention in recent years.1 Aromatics with directing groups
undergo regio- and stereoselective ortho-alkenylations in a
highly atom-economical manner. As catalysts for such cross-
coupling reactions, rhodium,2 ruthenium,3 and cobalt com-
plexes4 have proven particularly effective. Typically, these
catalytic systems, and in particular those of ruthenium, require a
stoichiometric amount or even an excess of an organic acid for
activation.5 In addition, long reaction times and high
temperatures are often indispensable for the hydroarylation to
proceed.
In the past decade, mechanochemical activation by milling,
grinding, shearing, cavitation, or pulling has led to remarkable
advances in organic synthesis.6 Specifically, ball-milling
techniques allowed the improvement of traditional trans-
formations and the discovery of new chemical reactivity using
little or no organic solvent.7 In this context,8 we recently
reported the first mechanochemical rhodium(III)-catalyzed C−
H bond functionalization of acetanilides in ball mills.9 Iridium
catalysis was utilized in analogous benzamide amidations with
sulfonyl azides.10 Encouraged by these results, we wondered if
mechanochemical conditions would also allow the use of less
expensive ruthenium complexes for solventless C−H bond
functionalizations. To verify this idea, we decided to investigate
ruthenium-catalyzed hydroarylations of alkynes with acetani-
lides in a mixer mill. To render this catalytic process even more
synthetically attractive, a subsequent a subsequent mechano-
chemical conversion of the resulting trisubstituted alkenes into
indoles by palladium-catalyzed intramolecular aminations was
envisaged. The results of this study are presented here.
To begin, we adopted the reaction conditions reported by
Manikandan and Jeganmohan11 with N-phenylacetamide (1a)
and diphenylacetylene (2a) as starting materials and a mixture
of [RuCl2(p-cymene)]2 (5.0 mol %), pivalic acid (5.0 equiv),
Received: September 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of Acetanilides 1 with Alkynes 2
b
entry
silver salt
additive
PivOH
t (min)
yield (%)
82
1
2
3
4
5
6
7
8
9
AgSbF6
AgSbF6
198
198
198
198
198
198
198
198
99
PivOH
AgBF4
PivOH
25
80
34
60
40
83
71
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
Cu(OAc)2·H2O
AgOAc
Fe(OAc)2
NaOAc
PivOH
c
10
PivOH
99
a
Reaction conditions: A mixture of 1a (81.1 mg, 0.60 mmol), 2a
(128.3 mg, 0.72 mmol), [RuCl2(p-cymene)]2 (18.4 mg, 0.03 mmol,
5.0 mol %), silver salt (20 mol %), and the additive (20 mol %) was
milled under argon at 30 Hz in a stainless steel milling jar (10 mL)
b
with one ball (10 mm in diameter) of the same material. After
c
column chromatography. Use of 1.2 mmol of 1a (2-fold scale-up).
counterparts: (1) The reaction leads to E-3aa in good yields
and with high positional- and diasteroselectivity. In contrast to
other protocols, oxidative cyclizations toward indoles are
irrelevant. (2) Presumably due to the efficient mixing during
the neat grinding, the process proceeds with only catalytic
amounts of the organic acid PivOH or Cu(OAc)2·H2O. In
solution, an excess of such additives is often applied. (3)
Because of the high reactant concentrations during the neat
grinding, the mechanochemical hydroarylation occurs faster
than in an organic solvent, and importantly, external heating is
not required (99 min at 30 Hz vs i-PrOH at 100 °C for 12 h).
Regarding the latter, it is worth mentioning that the dynamic
nature of a high-speed ball milling process can inherently
increase the temperature inside the milling container.14 Milling
of organic and inorganic mixtures under similar operational
conditions (milling media, time, and frequency of milling) has
been reported to raise the temperature to 87 °C.14c,d Therefore,
in our case, such thermal effects could have complemented the
mechanical milling, facilitating the mechanochemical C−H
activation.
Using commercially available [RuCl2(p-cymene)]2 (5.0 mol
%), AgSbF6 (20 mol %), and PivOH (20 mol %), the scope of
the mechanochemical hydroarylation reaction was investigated
(Scheme 1). A variety of anilides 1 reacted smoothly with
alkyne 2a to give the corresponding E-configured trisubstituted
alkenes 3aa−la in good yields. Both electron-rich and electron-
deficient para-substituted anilides exhibited high efficiency
affording the products in yields ranging from 68% to 83%. This
included anilides 1d−f, where the p-halo substituents were well
tolerated. Notably, acetanilide 1g bearing a carboxyl group in
the para-position of the aromatic ring could also be used,
providing the corresponding product 3ga in 76% yield (Scheme
1). Similarly, para-substituted acetanilides 1h and 1i bearing
CF3 and SF5 groups, respectively, reacted smoothly in the mixer
mill to afford the alkenes 3ha and 3ia in yields of 72% and 70%.
In addition, meta-substituted anilides were examined. In these
cases, the hydroarylation exclusively occurred at the sterically
less hindered C−H position leading to the expected products
3ja−la in 72−85% yield (Scheme 1).
a
Yields in parentheses refer to results obtained with Cu(OAc)2·H2O
(20 mol %) instead of PivOH.
Next, various alkynes were applied using acetanilide 1a as a
representative reaction partner (Scheme 1). Symmetric diary-
lalkynes with electron-donating and electron-withdrawing
substituents on the arenes (2b−g) coupled with almost the
same efficiency as 2a providing the corresponding products
3ab−ag in yields ranging from 65 to 74%. In addition,
unsymmetrically substituted 1-phenyl alkynes 2h−j reacted
well, affording alkenes 3ah−aj in yields up to 80%.
Noteworthy was the high regioselectivity with the hydro-
arylation occurring exclusively at the alkyl-substituted carbon.
In solution, the pyrazolyl substituent is an efficient directing
group in ruthenium-catalyzed hydroarylation reactions.3a,15
Using the standard mechanochemical reaction conditions,
solventless milling of 1-phenyl-1H-pyrazole (1m) with 2h
gave dialkenylated 3mh in 80% yield (Scheme 2 (a)).
Encouraged by this positive result, a competition experiment
was carried out. Grinding a mixture of 1a, 1m, and 2h in the
presence of the catalyst and additives for 30 min gave a mixture
of 3ha/3mh in a ratio of 1:8.25 (Scheme 2 (b)). This result
revealed a significantly higher reactivity of the pyrazole
compared to the acetanilide. With various alkynes (used in 3-
fold excess), 4-pyrazolyl-substituted acetanilide 1n served as an
analogous intramolecular probe (Scheme 2 (c)). The selective
formation of 3nh−nk showed a dominant directing power of
the pyrazolyl substituent over the amido moiety. When the
same type of milling experiment was conducted with a
combination of N-(4-acetylphenyl)acetamide (1o) and 1-
phenyl-1-propyne (2h), the amido group prevailed over the
ketonic carbonyl to give exclusively product 3oh in 31% yield
(Scheme 2 (d)).
The mechanochemical hydroarylation was further inves-
tigated by mechanistic studies. (1) The reaction of acetanilide
1a-d5 with alkyne 2a gave the expected product 3aa-dn in 28%
B
DOI: 10.1021/acs.orglett.7b02973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
experiment in 2-propanol (at 100 °C for 1 h). We conclude
that the C−H bond cleavage step is mechanistically similar. (3)
An intermolecular competition experiment with substituted
acetanilides 1c/1h and the alkyne 2a conducted in the mixer
mill showed higher reactivity for electron-deficient acetanilide
1h than for 1c. Then a competition reaction between
acetanilide (1a) and alkynes 2b/2f revealed a slightly higher
preference for the more electron-deficient alkyne 2f over 2b in
the hydroarylation by ball milling (see the SI for details).17
Based on the above observations, we suggest that in most
parts the mechanism of the mechanochemical hydroarylation
reaction is similar to the one proposed for the solution-based
counterpart.5 It begins with a C−H bond activation of the
metal-coordinated acetanilide forming the characteristic six-
membered metallacycle. Subsequent migratory insertion of the
alkyne followed by protodemetalation with the organic acid
liberates the product and regenerates the active catalyst, which
enters the next catalytic cycle.
Scheme 2. Competition Experiments for the Ru-Catalyzed
Mechanochemical Hydroarylation
The aforementioned mechanochemical C−H bond function-
alization strategy was complemented by the development of a
palladium-catalyzed conversion of products 3 to indoles 4 by
oxidative C(sp2)−H/N−H coupling in a mixer mill.18,19 Using
Pd(OAc)2 (10 mol %) and PhI(OAc)2 (2.2 equiv), various
indoles (4a−f) were obtained in yields ranging from 40% to
76% (Scheme 4).
In summary, we performed ruthenium-catalyzed hydro-
arylations of alkynes with acetanilides under mechanochemical
conditions. The solventless reactions in the mixer mill proved
faster than their reported solution-based counterparts, and they
proceeded without external heating. The mechanochemically
prepared hydroarylation products were further converted into
indoles by palladium catalyzed C(sp2)−H/N−H coupling in a
mixer mill.
yield after 30 min of milling (Scheme 3 (a)). The significant
deuterium/proton exchange at the 6 position of the arene
Scheme 3. Deuterium-Labeling Experiments under
Mechanochemical Conditions
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02973.
Experimental procedures, characterization data, NMR
spectra (PDF)
AUTHOR INFORMATION
■
(20%) suggested that the C−H bond cleavage step was
reversible. In addition, 10% of the olefinic proton of 3aa-dn was
exchanged by deuterium.16 (2) From an experiment with an
equimolar mixture of acetanilides 1a and 1a-d5 under
mechanochemical conditions, a kinetic isotopic effect (KIE)
of 2.13 was determined (Scheme 4 (b)). This value was similar
to the one (KIE = 3.35) found by performing an analogous
Corresponding Author
*E-mail: carsten.bolm@oc.rwth-aachen.de.
ORCID
Carsten Bolm: 0000-0001-9415-9917
Notes
The authors declare no competing financial interest.
Scheme 4. Mechanosynthesis of Indoles
ACKNOWLEDGMENTS
■
H.C. thanks the China Scholarship Council (CSC) for a
predoctoral stipend. We also thank RWTH Aachen University
for support from the Distinguished Professorship Program
funded by the Excellence Initiative of the German Federal and
State Governments. Dr. Christoph Rauber and Plamena Staleva
̈
(both RWTH Aachen University) are acknowledged for the 2D
NMR analysis.
C
DOI: 10.1021/acs.orglett.7b02973
Org. Lett. XXXX, XXX, XXX−XXX

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Org. Biomol. Chem. 2015, 13, 2901. For an example of a pyrazole
directed hydroarylation by ruthenium, see ref 3a.
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