Sterically Controlled Late-Stage C-H Alkynylation of Arenes

Article abstract of DOI:10.1021/jacs.9b10868

Phenylacetylenes are key structural motifs in organic chemistry, which find widespread applications in bioactive molecules, synthetic intermediates, functional materials, and reagents. These molecules are typically prepared from prefunctionalized starting materials, e.g. using the Sonogashira coupling, or using directing group-based C-H activation strategies. While highly efficient, these approaches remain limited by their inherent selectivities for specific regioisomers. Herein we present a complementary approach based on an arene-limited nondirected C-H activation. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for late-stage functionalization are demonstrated.

Full text of DOI:10.1021/jacs.9b10868

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Communication
Sterically Controlled Late-Stage C–H Alkynylation of Arenes
Arup Mondal, Hao Chen, Lea Flämig, Philipp Wedi, and Manuel van Gemmeren
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10868 • Publication Date (Web): 12 Nov 2019
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Journal of the American Chemical Society
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Sterically Controlled Late-Stage C–H Alkynylation of Arenes
a
a,‡
b,‡
a,‡
a,b,
Arup Mondal, Hao Chen, Lea Flämig, Philipp Wedi, Manuel van Gemmeren *
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[a] Max-Planck-Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr, Germany. [b]
Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany.
Alkynylation, C–H Activation, Dual-Ligand Catalysis, Palladium Catalysis, Late-Stage Modification
Miyaura and coworkers11 on the Ir-catalyzed borylation of arenes,
ABSTRACT: Phenylacetylenes are key structural motifs in
organic chemistry, which find widespread applications in bioactive
molecules, synthetic intermediates, functional materials and
reagents. These molecules are typically prepared from pre-
functionalized starting materials, e.g. using the Sonogashira
coupling, or using directing group-based C–H activation strategies.
While highly efficient, these approaches remain limited by their
inherent selectivities for specific regioisomers. Herein we present
a complementary approach based on an arene-limited nondirected
C–H activation. The reaction is predominantly controlled by steric
rather than electronic factors and thereby gives access to a
complementary product spectrum with respect to traditional
methods. A broad scope as well as the suitability of this protocol
for late-stage functionalization are demonstrated.
1
2
as well as later studies on related silylations, we hypothesized that
such a method could be enabled through a nondirected catalyst
system predominantly sensitive to steric rather than electronic
1
3
control (path c). At the same time the well-documented suitability
of Pd-catalysts to induce aryl-alkyne bond formation encouraged
6
us to choose this metal for catalyst design. We realized that, in
order to enable the desired process, a Pd-catalyst would be required
that is capable of activating arene C–H bonds in arenes without the
need for a directing group.
Scheme 1. Approaches towards the regioselective C–H
alkynylation of arenes.
DG
R'
R'
path b
path a
R
directed
halogenation;
C–H activation
Sonogashira coupling
R
Complexation control
Electronic control
The alkyne motif constitutes one of the most fundamental
functional groups in organic chemistry. It is therefore not
• R = DG:
ortho-selective
• R = Do: ortho/para = major
• R = EWG: meta = major
1
path c this work
surprising that aryl-substituted alkynes, or phenylacetylenes,
This work:
Steric control
R'
•
complementary selectivity
2
feature in a wide range of contexts, as bioactive molecules,
R
• late-stage functionalization
• one step
• no DG required
3
4
synthetic intermediates, functional materials, reagents (e.g. for
click chemistry), etc. In light of the importance of these
• R = Do/EWG:
meta = major
5
compounds
a
convenient access to all regioisomers of
Traditionally, such processes could only be induced through the
use of a large excess of the arene substrate, a limitation that was
14
phenylacetylenes is highly desirable, especially when considering
the importance of compound libraries in medicinal chemistry,
where the flexible introduction of substituents into advanced
synthetic intermediates is essential.
recently overcome through careful catalyst design by ourselves and
1
5
others. Encouraged by the observation that our method based on
dual ligand catalysis was sensitive to both steric and electronic
control, we argued that it might be possible to further elaborate this
strategy in order to enable a sterically controlled late-stage
alkynylation of arenes.
The arguably most prominent reaction for the synthesis of
phenylacetylene-derivatives is the Sonogashira coupling, which
requires the presence of a (pseudo)halide in the arene substrate. The
regioselectivity of this approach is thus dictated by the
regioselectivity of a preceding (pseudo)halogenation step (Scheme
6
In a continuation of our interest in the development of methods
for the synthesis of challenging phenylacetylene derivatives, we
herein report our realization of this goal.
1
6
1
, path a). Accordingly, ortho and para products are expected to
dominate for substrates bearing donor substituents, while meta
products are expected for substrates bearing acceptors.
Alternatively, when substrates bear a suitable directing group, in
many cases specifically introduced for this purpose, a directed C–
H alkynylation can be performed, which proceeds with ortho-
Starting from the reaction conditions utilized in our previous
7
olefination and cyanation methods and using 1-Bromo-2-
15c,15d
(triisopropylsilyl)acetylene as reagent,
we conducted an
extensive screening of catalysts and reaction conditions. We aimed
not only to maximize the overall yield of the process, which besides
maximizing the C–H activation efficiency involved the additional
8
;9
selectivity (path b).
1
7
While there are ample methods for the synthesis of ortho and
para alkynylated arenes respectively, a method generally favoring
the meta isomer regardless of the donor/acceptor-properties of the
substituents on the substrate is currently not available.
challenge of suppressing undesired reagent dimerization, but also
the sensitivity of the catalyst system to steric influences (see the
Supporting Information for details). These studies allowed us to
identify the reaction conditions shown in Scheme 2.
Inspired by the ground breaking studies by the groups of
1
0
Maleczka, Smith, and coworkers as well as Ishiyama, Hartwig,
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Page 2 of 7
Scheme 2: Reaction scope.a
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TIPS
Pd(OAc)2 (10 mol%), Ac-Phe-OH (30 mol%)
Pyrazine (20 mol%), Ag2O (2 equiv)
R
TIPS
R
+
Br
HFIP (2.3 mL), 60 °C, 18 h
1
2a (1.5 equiv)
3
mono-substituted arene scope

tBu
SiMe3
OMe
NHAc
NPhth
Hal

3
a, 78%
3b, 69%
: > 95:5
3c, 76%
m:p = 56:44
3d, 72%
m:p = 53:47
3e, 66%
m:p = 69:31
3f, 66%
o:m:p = 22:35:43
3g, 50%
o:m:p = 40:52:8
3h, 60%
m:p = 66:34
Hal = F 3i, 67%, o:m:p = 43:31:26
Hal = Cl 3j, 74%, o:m:p = 51:30:19
Hal = Br 3k, 72%, o:m:p = 71:19:10

di-substituted arene scope
0
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



OMe
OMe
OTIPS
CO2Me
CO2Et
CONiPr2






O
'
3
l,b 51%
3m,b 52%
o:m:p = 39:44:17
3n,b 53%
o:m:p = 34:32:34
3o, 80%
-only
3p, 79%
-only
3q, 51%
 = 65:35
3r, 55%
-only
3s,e 51%
o:m:p = 34:49:17
' = 51:49


CO2Me
CONiPr2
OMe
OMe




OAc
'
'








MeO
Cl
3
t,b 51%
3u,b 54%
' = 50:50
3v, 71% (60%)c
-only
3w, 72%
 = 72:28
3x, 40%
 = 66:34
3y, 62%
 = 70:30
3z, 60%
 = 83:17
3aa, 52%
-only
' = 56:44
tri-substituted arene and heteroarene scope
OMe
F
Cl
MeO









Cl
CO2Me
S
S




Cl

3ab,69%
3ac,75%
-only
3ad, 60%
-only
3ae, 67%
-only
3af, 55%
-only
3ag,d 78%
 = 91:9
3ah,d 61%
-only

-only
a
b
c
All reactions were conducted on a 0.2 mmol scale. This reaction was conducted at 70 °C. The yield given in parenthesis was obtained
on a 5 mmol scale. This reaction was performed in HFIP/DMSO (1:1, 2.3 mL). Isolated after OTIPS deprotection.
d
e
Under these conditions simple benzene (3a) and naphthalene
3b) underwent smooth alkynylation. A wide range of mono-
substituted arenes could be functionalized to give 3c-n, with
electronic properties ranging from electron-rich anisole (3f) to
single products in all cases studied (3ab-ae) and a 1,2,4-tri-
substituted substrate could be functionalized with perfect
regiocontrol (3af). Finally, our protocol was also found to be
amenable to thiophene derivatives (3ag-ah).
(
1
9
1
8
electron-poor benzoates and benzamides (3l-n). Our studies on
these simple arenes revealed that the reaction is highly sensitive to
steric effects, with even a methyl-group being sufficient to
completely suppress the formation of ortho product. Electronic
effects were found to be less dominant, evidenced for example by
the formation of substantial amounts of meta product from anisole
(3f). Finally, the reaction was found to be sensitive to directing
effects by suitable functional groups in the substrate. This can for
example be seen by comparing the regioselectivities in 3g, in which
the acetamide group directs the C–H activation, and 3h, where the
directing ability is suppressed by the phthaloyl protecting group.
These observations imply, that in multiply substituted substrates,
high regioselectivities can be expected in many cases. Accordingly,
when we studied symmetric 1,2-di-substituted arenes, single
isomers were obtained in most cases (3o-r). Interestingly, the
products 3s-u, formed from non-symmetric 1,2-di-substituted
arenes were obtained as nearly equal mixtures in the sterically
accessible yet electronically very different β and β’ positions, once
again highlighting the low sensitivity of this method to electronic
effects. We thus proceeded to study 1,3-di-substituted substrates.
In these substrates, the electronically and sterically preferred
positions are in competition with one another and we observed the
formation of the sterically favored position as the major or only
product in all cases (3v-y). It is particularly remarkable that even
the strong directing effect exerted by a methoxy-group can be
overcome in favor of the sterically more accessible position (3w).
Good regioselectivities were also observed for 1,4-di-substituted
substrates (3z-aa). Similarly, 1,2,3-tri-substituted arenes delivered
We furthermore investigated the use of varied bromoalkynes in
our protocol (Scheme 3).
Scheme 3. Variation of the bromoalkyne reagent.a
Pd(OAc)2 (10 mol%)
Ac-Phe-OH (30 mol%)
Pyrazine (20 mol%)
R
R
(
Het)ArH
+
Br
2 (1.5 equiv)
(Het)Ar
Ag2O (2 equiv)
HFIP (2.3 mL), 60 °C, 18 h
1
TBSO
TBS
Ada
Cl
S
4, 63%
5, 41%
6, 40%
7,b 45%
aAll reactions were conducted on a 0.2 mmol scale. bThis
reaction was performed in DMSO (2.3 mL).
As expected based on literature reports, switching to a TBS-
protecting group gave product 4 in a synthetically useful yield.
Alkyl-substituted reagents gave products 5 and 6 in modest yields.
Similarly, product 7, derived of an aryl-substituted reagent was
obtained in 45% yield. The lower yields observed for products 4-7
can be explained by the lower stability of the respective reagents
8c,8s
under the reaction conditions.
The unusually strong sensitivity of our catalyst to steric rather
than electronic control of the site-selectivity, together with the
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ability to employ the arene as the limiting reagent implies that this
required for the reaction to take place, which is in good agreement
with the known ability of such ligands to facilitate C–H activation
1
2
3
4
5
6
7
8
9
method may be highly useful to access otherwise challenging
products in late-stage modifications. In order to probe this
potential, we tested our protocol with a series of structurally
complex small molecules as substrates (Scheme 4).
2
2
by acting as an intramolecular base. In contrast to this, the
reaction was found to occur in the absence of the pyrazine ligand,
albeit with a lower overall yield. This could be explained by two
possible roles of the pyrazine. It could either stabilize palladium
species at other stages of the catalytic cycle against decomposition
and affect the yield by increasing the catalyst lifetime, or a
catalytically more active species could be formed in the presence
of pyrazine. To distinguish between these scenarios, we compared
the initial rates with and without this ligand and found that it not
only increases the overall yield, but also the rate of the reaction,
which supports the formation of a catalytically more active
Scheme 4. Suitability for late-stage modification.a
TIPS
Pd(OAc)2 (10 mol%), Ac-Phe-OH (30 mol%)
R
Pyrazine (20 mol%), 2a (1.5 equiv)
R
Ag2O (2 equiv)
HFIP (2.3 mL), 60 °C, 18 h
1
1
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O
OMe

H
23
O
species. These observations and the analogy to previous

15c,15d,15h
H
studies,
as well as a recently concluded detailed


1
5i
MeO
mechanistic study on our olefination catalyst are consistent with
the C–H activation by a palladium catalyst bearing both of the
ligands present. Notably, control experiments indicate that the
increased degree of steric control in comparison to our previous


'
(–)-menthol ether 8
propofol methyl ether 9
estrone methyl ether 10
5
1%, -only
52%, -only
41%, -only
O
O
O
O
1
5c,15d,15h
studies,
is induced by the catalyst system, rather than being
OEt
OMe
OMe
15e,20
inherent to the transformation at hand.
We were furthermore


NPhth
Cl
NPhth
MeO


interested in the role of silver in this reaction. Our control
experiments showed that it is indispensable for product formation
both under catalytic and stoichiometric conditions. Since previous
studies on related systems have established that the C–H activation
clofibriate 11
2%,  = 46:54
phenylalanine derivative 12
tyrosine derivative 13
4
57%, m:p = 50:50
40%, -only
O
N
O
OMe
OMe
1
5d,15h
O
OMe
can take place without the participation of silver,
this suggests
O
O
that the silver salt is required in the subsequent steps of the catalytic
cycle. The most commonly described mechanisms for the reaction
of organometallic species with bromo alkynes are an oxidative
HN
'
O

O
Evans-type reagent 14
5%, m:p = 50:50
nateglinide methyl ester 15 guaifenesin derivative 16
addition/reductive
insertion/β-bromide elimination pathway.
elimination
sequence
and
an
5
50%, o:m:p = 21:42:37
56%, :' = 58:42
5
c,8c,24
Since these events
H
take place after the rate-limiting step of our reaction, an
experimental differentiation between these pathways is not
possible. However, it seems reasonable based on our data that the
silver could be required as a π-Lewis acid to aid oxidative addition
or for bromide abstraction during this part of the catalytic cycle.
Scheme 5. Preliminary mechanistic investigations.a
H
H
H
O
cholesterol ether 17

45%,  = 52:48

aAll reactions were conducted on a 0.2 mmol scale.
A. Kinetic Isotope Effect (KIE)
Pd(OAc)2 (10 mol%)
Ac-Phe-OH (30 mol%)
Pyrazine (20 mol%)
D
TIPS
The (–)-menthol ether of m-cresol could be alkynylated with
perfect regiocontrol in favor of the sterically-favored but
electronically disfavored β-position (8). Similarly, the products
derived from propofol methyl ether and estrone methyl ether (9 and
and D C
/
D
D
Me
3
or
D
2a (1.5 equiv), Ag2O (2 equiv)
HFIP (1.2 mL), 60 °C, 45 min
D
8
1c
1c-d
3c
1
0) were obtained as single regioisomers. The lipid-lowering agent
KIE competition = 3.3
KIE parallel exp. = 2.3
clofibrate (11), protected phenylalanine (12) and tyrosine (13), an
Evans-type reagent (14), as well as derivatives of nateglinide (15),
guaifenesin (16), and cholesterol (17) could all be alkynylated,
giving access to regioisomers, which would otherwise be
challenging to obtain. These studies also revealed that a wide range
of functional groups is tolerated in this protocol, such as ethers (8-
B. Control Experiments
TIPS
Pd(OAc)2 (10 mol%), Ac-Phe-OH (30 mol%)
Me
Pyrazine (20 mol%), 2a (1.5 equiv)
Ag2O (2 equiv)
HFIP (1.2 mL), 60 °C, 18 h
1c
3c
1
1, 16, 17), ketones (10), halides (11), esters (11-13, 15), imides
As above:
77%
-
o:m:p = 2:55:42
(12, 13), and amides (14, 15).
No Pd(OAc)2
No Ac-Phe-OH:
No Pyrazine:
-
rel. initial rate: 1.57:1
Having studied the applicability of our protocol, we became
-
traces
interested in obtaining information about the mechanism of the
o:m:p = 2:51:47
52%
2
0
transformation. First, parallel and competition experiments were
conducted to determine the kinetic isotope effect (Scheme 5A). The
results indicate that the C–H activation step is (at least in part) rate-
determining. Attempts to probe the reversibility of this step through
H/D-exchange experiments remained inconclusive. H/D-exchange
was observed to occur under the reaction conditions. However,
control experiments suggest that the H/D-exchange proceeds
aAll reactions were conducted on a 0.1 mmol scale.
Finally, we engaged in a case study on the complementarity
between our protocol and traditional approaches (Scheme 4). To
this end, the silyl-protected meta-cresol 18 was first subjected to a
sequence of bromination, Sonogashira coupling, and deprotection
path a). The regioselectivity of this sequence is determined in the
bromination step, which proceeds under electronic control, thereby
2
1
through a pathway different from a reversal of the C–H activation.
In order to get insights into the nature of the catalytically active
species, the control experiments shown in Scheme 5B are highly
informative. These experiments confirm that Ac-Phe-OH is
(
resulting in the formation of product 19, in which alkynylation has
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Journal of the American Chemical Society
Page 4 of 7
been achieved selectively in the γ-position. The synthesis of the
corresponding α-isomer 20 starting from meta-cresol has been
described using several directing groups (path b).
(1)
(a) Modern Acetylene Chemistry; Wiley-VCH Verlag GmbH:
Weinheim, 1995; (b) Acetylene Chemistry: Chemistry, Biology, and
Material Science; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
1
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2
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2
005.
(
2)
(a) Duvic, M. Tazarotene: a review of its pharmacological
profile and potential for clinical use in psoriasis, Expert Opinion on
Investigational Drugs 1997, 6, 1537; (b) Tang, P. A.; Tsao, M.-S.; Moore,
M. J. A review of erlotinib and its clinical use, Expert Opinion on
Pharmacotherapy 2006, 7, 177; (c) Talpur, R.; Cox, K.; Duvic, M. Efficacy
and safety of topical tazarotene: a review, Expert Opinion on Drug
Metabolism & Toxicology 2009, 5, 195; (d) Yang, Z.-Y.; Yuan, J.-Q.; Di,
M.-Y.; Zheng, D.-Y.; Chen, J.-Z.; Ding, H.; Wu, X.-Y.; Huang, Y.-F.; Mao,
C.; Tang, J.-L. Gemcitabine Plus Erlotinib for Advanced Pancreatic Cancer:
A Systematic Review with Meta-Analysis, PLOS ONE 2013, 8, e57528; (e)
Hoy, S. M. Ponatinib: A Review of Its Use in Adults with Chronic Myeloid
Leukaemia or Philadelphia Chromosome-Positive Acute Lymphoblastic
Leukaemia, Drugs 2014, 74, 793.
Scheme 6. Complementarity with traditional approaches.
OTIPS
path a
path c


electronic control
steric control

18
path b – directed
from m-cresol)
) DG Introduction
0
1
2
3
4
5
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7
8
9
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1) Bromination
) Sonogashira Coupling
3) Deprotection
1) C–H Alkynylation
2) Deprotection
(
2
1
2
) C–H Alkynylation
3) DG Removal
OH
(3)
(a) Hintermann, L.; Labonne, A. Catalytic Hydration of Alkynes
OH
OH
and Its Application in Synthesis, Synthesis 2007, 2007, 1121; (b) Severin,
R.; Doye, S. The catalytic hydroamination of alkynes, Chem. Soc. Rev.
2
Palladium Catalysts, Chem. Rev. 2014, 114, 1783; (d) Fürstner, A. In
Handbook of Metathesis; Wiley-VCH Verlag GmbH & Co. KGaA: 2015, p
007, 36, 1407; (c) Chinchilla, R.; Nájera, C. Chemicals from Alkynes with
TIPS
TIPS
9, 57% (3 steps)
-only
TIPS
1
20, 3 steps in literature
-only
21, 52% (2 steps)
-only

4
45; (e) Li, J.; Lee, D. In Handbook of Metathesis; Wiley-VCH Verlag
GmbH & Co. KGaA: 2015, p 381.
4) (a) Diederich, F.; Rubin, Y. Synthetic Approaches toward
Molecular and Polymeric Carbon Allotropes, Angew. Chem. Int. Ed. Engl.
992, 31, 1101; (b) H. F. Bunz, U.; Rubin, Y.; Tobe, Y. Polyethynylated
Our protocol perfectly complements these two synthetic
sequences. Starting from substrate 18; the sterically controlled
alkynylation, followed by deprotection, delivered the β-isomer 21
selectively (path c).
(
1
cyclic π-systems: scaffoldings for novel two and three-dimensional carbon
networks, Chem. Soc. Rev. 1999, 28, 107.
(5)
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In summary, we have developed the first Pd-catalyzed
nondirected C–H alkynylation of arenes. The reaction was found to
possess a wide substrate scope, tolerating a broad range of
functional groups. A key feature of this protocol is the strong
influence of steric control on the site-selectivity, which renders the
reaction complementary to established synthetic strategies. We
have demonstrated the suitability of this protocol, which employs
the arene as the limiting reagent, for late-stage functionalization
and expect that its ability to give access to otherwise challenging
regioisomers will prove highly valuable in this context.
(a) Lutz, J.-F. 1,3-Dipolar Cycloadditions of Azides and
(6)
(a) Sonogashira, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis; John Wiley & Sons, Inc.: 2003, p 493; (b)
Chinchilla, R.; Nájera, C. The Sonogashira Reaction:ꢀ A Booming
Methodology in Synthetic Organic Chemistry, Chem. Rev. 2007, 107, 874;
(
c) Chinchilla, R.; Nájera, C. Recent advances in Sonogashira reactions,
Chem. Soc. Rev. 2011, 40, 5084.
7) It should be noted that for some very electron-poor or electron-
ASSOCIATED CONTENT
Supporting Information
(
rich arenes, a para-selective C–H alkynylation has also been reported: (a)
de Haro, T.; Nevado, C. Gold-Catalyzed Ethynylation of Arenes, J. Am.
Chem. Soc. 2010, 132, 1512; (b) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong,
M. Copper-Catalyzed Direct Alkynylation of Electron-Deficient
Polyfluoroarenes with Terminal Alkynes Using O as an Oxidant, J. Am.
Chem. Soc. 2010, 132, 2522; (c) Brand, J. P.; Waser, J. Para-Selective Gold-
Catalyzed Direct Alkynylation of Anilines, Org. Lett. 2012, 14, 744; (d)
Brand, J. P.; Li, Y.; Waser, J. Gold-Catalyzed Alkynylation: Acetylene-
Transfer instead of Functionalization, Isr. J. Chem. 2013, 53, 901.
The Supporting Information is available free of charge on the ACS
Publications website.
Preparative procedures and analytical data.
2
AUTHOR INFORMATION
Corresponding Author
(8)
Catalyzed Ortho-Ethynylation of Phenols, J. Am. Chem. Soc. 2002, 124,
528; (b) Amemiya, R.; Fujii, A.; Yamaguchi, M. GaCl -Catalyzed ortho-
3
(a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. GaCl -
*
mvangemmeren@uni-muenster.de.
Author Contributions
H.C., L.F., and P.W. contributed equally to this work.
8
3
ethynylation reaction of N-benzylanilines, Tetrahedron Lett. 2004, 45,
4333; (c) Tobisu, M.; Ano, Y.; Chatani, N. Palladium-Catalyzed Direct
Alkynylation of C−H Bonds in Benzenes, Org. Lett. 2009, 11, 3250; (d)
Ano, Y.; Tobisu, M.; Chatani, N. Palladium-Catalyzed Direct ortho-
Alkynylation of Aromatic Carboxylic Acid Derivatives, Org. Lett. 2012,
14, 354; (e) Kim, S. H.; Park, S. H.; Chang, S. Palladium-catalyzed
oxidative alkynylation of arene C–H bond using the chelation-assisted
strategy, Tetrahedron 2012, 68, 5162; (f) Zhao, Y.; He, G.; Nack, W. A.;
Chen, G. Palladium-Catalyzed Alkenylation and Alkynylation of ortho-
‡
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Max Planck
Society (Otto Hahn Award to M.v.G.), FCI (Liebig Fellowship to
M.v.G.), and WWU Münster. We thank the members of our NMR
and MS departments for their excellent service, as well as S.
Bognar, M. Farizyan, and Dr. T. Patra for valuable discussions.
Furthermore, we are indebted to Prof. F. Glorius for his generous
support.
2
C(sp )–H Bonds of Benzylamine Picolinamides, Org. Lett. 2012, 14, 2948;
(g) Feng, C.; Loh, T.-P. Rhodium-Catalyzed C H Alkynylation of Arenes
at Room Temperature, Angew. Chem. Int. Ed. 2014, 53, 2722; (h) Shang,
M.; Wang, H.-L.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Cu(II)-Mediated Ortho
C–H Alkynylation of (Hetero)Arenes with Terminal Alkynes, J. Am. Chem.
Soc. 2014, 136, 11590; (i) Theunissen, C.; Evano, G. Room-Temperature
Direct Alkynylation of Arenes with Copper Acetylides, Org. Lett. 2014, 16,
4
488; (j) Xie, F.; Qi, Z.; Yu, S.; Li, X. Rh(III)- and Ir(III)-Catalyzed C–H
Alkynylation of Arenes under Chelation Assistance, J. Am. Chem. Soc.
2014, 136, 4780; (k) Liu, Y.-H.; Liu, Y.-J.; Yan, S.-Y.; Shi, B.-F. Ni(II)-
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nitrobenzene were found to be unreactive under our reaction conditions.
(19) Electron-poor heterocycles such as pyridines were found to be
Even more electron-poor substrates such as trifluorotoluene or
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For details on the mechanistic experiments discussed in this
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Combined IM-MS/DFT Study on [Pd(MPAA)]-Catalyzed Enantioselective
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An alternative interpretation of our results could be that
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analogous to work by Sanford and coworkers (Ref 14i), the addition of
pyrazine influences the speciation in the system, leading to an increased
concentration of the active species, without necessarily being part of it. To
probe this hypothesis, we conducted a control experiment analogous to the
one shown in Scheme 5B in the absence of pyrazine with further substrates
(1f, 1m). For these substrates the pyrazine influences not only the yield, but
also the regioselectivity of the reaction substantially. This indicates that a
different rather than more of the same catalytically active species is formed
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Pd(OAc)2
Ac-Phe-OH
Pyrazine
TIPS
H
R
R
Ag-salt
Br
TIPS
•
•
•
Steric control of regioselectivity
Complementary to previous approaches
Suitable for late-stage modification
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
ACS Paragon Plus Environment