Revisiting the Intermolecular Fujiwara Hydroarylation of Alkynes

Article abstract of DOI:10.1002/ejoc.201700033

The Fujiwara hydroarylation of alkynes was reinvestigated using the addition of indole to methyl or ethyl phenylpropiolate catalyzed by Pd(OAc)₂ as a model reaction. Reactions were monitored by both ¹H NMR spectroscopy and electrospray ionization mass spectrometry (ESI/MS), and also through reactions carried out in the gas phase using MS/MS experiments. Contrary to the original suggestion for exclusive heteroarene activation, the data supports the coexistence of both heteroarene activation (C–H activation) and alkyne activation (Friedel–Crafts-type pathway). Under the reaction conditions used in this work, intermediates for both mechanisms were detected by NMR spectroscopy and MS, but alkyne activation seems to be predominant according to ¹H NMR spectroscopic studies and theoretical predictions. Alkyne activation is promoted by the coordination of an electrophilic palladium species to the C–C triple bond, followed by nucleophilic attack of the heteroaryl counterpart. Two previously undetected equilibria in this reaction involving the vinylpalladium intermediates and the final products were also found to be critical to the stereoselectivity of the reaction.

Full text of DOI:10.1002/ejoc.201700033

A Journal of
Accepted Article
Title: Revisiting the Intermolecular Fujiwara's Hydroarylation of Alkynes
Authors: Carlos Duarte Correia, Marla Godoi, Francisco Azambuja,
Pablo Martinez, Nelson Morgon, Vanessa Santos, Thais
Regiani, Denis Lesage, Heloise Dossmann, Richard Cole,
and Marcos Eberlin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700033
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10.1002/ejoc.201700033
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Revisiting the Intermolecular Fujiwara's Hydroarylation of
Alkynes
Marla N. Godoi,†[b] Francisco de Azambuja,†[a] Pablo David G. Martinez,†[a] Nelson H. Morgon,[a]
Vanessa G. Santos,[b] Thaís Regiani,[b] Denis Lesage,[c] Heloise Dossmann,[c] Richard B. Cole,[c]
Marcos N. Eberlin*[b] and Carlos Roque D. Correia*[a]
Dedication ((optional))
Abstract: The Fujiwara's hydroarylation of alkynes was re-
investigated employing the indole addition to methyl or ethyl
phenylpropiolate catalyzed by Pd(OAc)2 as a model. Reactions were
monitored by both 1H-NMR, electrospray ionization mass
spectrometry (ESI/MS) and via reactions performed in the gas phase
using MS/MS experiments. Contrary to the original suggestion for
exclusive heteroarene activation, the data supports the co-existence
of both heteroarene (C-H activation) and alkyne activation (Friedel-
Crafts type pathway). In the present reaction conditions,
intermediates for both mechanisms were detected by NMR and MS
but alkyne activation seems to be predominant according to 1H-NMR
studies and theoretical predictions. Alkyne activation is promoted by
the coordination of an electrophilic palladium species to the C-C
triple bond followed by a nucleophilic attack of the heteroaryl
counterpart. Two previously undetected equilibria in this reaction
involving the vinylpalladium intermediates and the end products
were also found to be critical to the stereoselectivity outcome of the
reaction.
In 2000, Fujiwara and co-workers[4] pioneered an elegant Pd-
catalyzed hydroarylation of unsaturated C-C bonds with direct C-
H functionalization of electron-rich arene counterparts (Scheme
1). Their method efficiently provided aryl-alkenes from simple
arenes and alkynes. Remarkably and in sharp contrast to the
majority of metal mediated C-H functionalization protocols, the
Fujiwara’s reaction was found to proceed in an open flask, room
temperature and an oxidant-free condition.[5] The methodology
was also further extended to some important heteroaromatic
cores, such as pyrroles, indoles and furans (Scheme 1a).[6] In
view of their unique electronic properties, these scaffolds are
ubiquitous in natural and bioactive molecules, being of special
interest not only for medicinal chemists, but also in material
chemistry. [7]
.
Introduction
In organic synthesis, atom economy is an extremely valuable
concept.[1] The transition metal (TM) catalyzed hydroarylation of
alkynes is a remarkable example of a transformation with high
atom efficiency,[2] being used to prepare important building
blocks
such
as
unsaturated
frameworks
bearing
(hetero)aromatic rings, which provide synthetically versatile
multi-functionalized scaffolds. Most traditional hydroarylation
protocols rely on pre-functionalized coupling partners, whereas
the alternative palladium catalyzed C-H activation strategy has
so far found limited applications.[3] To some extent, the often
observed lack of stereocontrol in C-C double bond formation is
still a considerable barrier to the wider use of these Pd-catalyzed
transformations.
[a]
Chemistry Institute, University of Campinas (UNICAMP), Campinas,
SP, 13083-970, Brazil.
E-mail: roque@iqm.unicamp.br
Homepage: www.correia-group.com
[b]
[c]
ThoMSon Mass Spectrometry Laboratory, University of Campinas
(UNICAMP), Campinas, SP, 13083-970, Brazil.
E-mail: eberlin@iqm.unicamp.br
Université Pierre et Marie Curie, Institut Parisien de Chimie
Moléculaire 75252 Paris cedex 05, France.
Scheme 1. Fujiwara’s hydroarylation of alkynes and its previous mechanistic
hypothesis
† These authors contributed equally to this work.
In spite of its discovery more than a decade ago, the actual
mechanism of the Fujiwara reaction has remained controversial.
In his seminal work, Fujiwara proposed a mechanism starting
Supporting information for this article is given via a link at the end of
the document.
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0,50
0,45
0,40
0,35
0,30
0,25
0,20
0,15
0,10
0,05
0,00
with arene activation and a C-H bond metalation as the initial
step (Scheme 1b).[4b] Later, however, Tunge and co-workers[8]
re-evaluated the intramolecular version of the Fujiwara’s
reaction concluding for alkyne activation via a Friedel-Crafts-
type pathway for the hydroarylation (Scheme 1b). Unfortunately,
these initial studies provided very little information regarding the
E/Z selectivity of the resulting olefin, a reasonable challenge in
the synthesis of aryl-alkenes building blocks, in particular with
heteroarenes.[9],[10],[11] As part of our interest in heteroarylated
alkenes, efficient transition metal catalysis,[12] and on the use of
electrospray ionization mass spectrometry (ESI-MS) as a tool in
reaction mechanism studies,[13] we decided to comprehensively
revisit the mechanism of this powerful and somewhat
underexplored reaction using nuclear magnetic resonance
(NMR), ESI-MS and theoretical calculations to search for clues
to the actual steps leading to the hydroarylation of alkynes. As
reported by Fujiwara,[6] we used indoles as the arylating
0
5
10
15
20
25
Time (h)
Alkyne (2a)
3a (E) 3a (Z)
3a (E+Z)
Figure 1 1H-NMR monitoring of the reaction indole (1a) addition to methyl
phenylpropiolate (2a) catalyzed by Pd(OAc)2 over a 24 h period in d3-AcOD.
reagents (Scheme 1a). Based on our findings,
a new
This low stereoselectivity of the hydroarylation of the phenyl
propiolates was intriguing in view of a previous report indicating
the exclusive formation of the E-isomers.[6] Therefore, we
decided to investigate the isomerization process more deeply.
Pure samples of the E and Z-isomers of the adduct 3b were
obtained, dissolved separately in d3-AcOD and their
mechanistic proposal that allows for rationale for the
a
stereoselectivity of alkynes hydroarylation was formulated.
Results and Discussion
1
interconversion followed by H-NMR over a period of ~6 days
Monitoring the Fujiwara’s reaction by 1H-NMR
(Scheme 3). A final E:Z ratio of ~4:1 was then obtained
regardless of the starting stereoisomer, which was basically the
same ratio observed for the hydroarylation reaction carried out
using the conditions described in Scheme 2. Similar results
were also observed with methyl adducts 3a. These results
clearly indicate that the Fujiwara’s hydroarylation adducts are
prone to isomerisation under acid conditions (see SI for details
regarding the NMR studies and bulky reactions).
Based on Fujiwara’s previous work,[6] we selected the Pd-
catalyzed hydroarylation of methyl (2a) and ethyl
phenylpropiolate (2b) with indole (1a) as model reactions
(Scheme 2).
Scheme 2. Model reactions used in this study
We first monitored the reaction described in Scheme 2 (R = Me)
by 1H-NMR (d3-AcOD as solvent) for 24 h (Figure 1). Such
monitoring indicated that methyl phenylpropiolate (2a) was
consumed in ~10 h, and the desired indole propionate 3a
obtained in ~70% yield. Surprisingly, the Z-3a adduct was the
major product in the first 8 h of reaction, but as the reaction
proceeded, interconversion between the E and Z products was
clearly noticed,[14] with the E-isomer predominating after 24 h. As
expected, the exact same behavior was observed with ethyl
phenylpropiolate (2b) as substrate. Replacing acetic acid by
dichloromethane as solvent resulted in a slower reaction, but
quite similar reaction profiles were observed in both solvents
(see SI for details).
Scheme 3 Interconversion of isomeric adducts 3b in d3-AcOD, as followed by
1H-NMR.
Theoretical calculations for the isomerisation of the
products and the putative vinyl palladium intermediates
Theoretical calculations were then performed to evaluate the
energetics about the E/Z isomerisation observed for the final
Fujiwara products (Scheme 4). The calculated ΔG for the ethyl
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adducts E/Z-3b was slightly larger than that for the methyl
products E/Z-3a, by ca. 0.7 kcal mol-1 and 0.4 kcal mol-1,
respectively. Considering the relationship between energy and
equilibrium constant (G = - RTln K), this G is in accordance
with the selectivities observed experimentally (Scheme 3).
Since isomerisation in acetic acid proceeded spontaneously and
because of the push-pull character of the C=C double-bond in
the Fujiwara products 3, a low rotational barrier should be
overcome for such E/Z interconversion.[15] Under thermodynamic
control, it is therefore likely that the initially formed product Z-3
rapidly interconverts to the more stable E-3 isomer.
Monitoring the Fujiwara’s reaction by ESI(+)-MS
To circumvent the fact that no palladium intermediates could be
isolated, we envisioned that ESI-MS could work as an efficient
tool to fish out possibly elusive species from the reaction
solution for their MS characterization. The model reaction using
methyl phenylpropiolate 2a (Scheme 2) was then monitored in
full by ESI(+)-MS with eventual intermediate characterization via
ESI(+)-MS/MS.[6] First, we evaluated the reaction in acetic acid,
diluting 5 µL aliquots of the crude reaction solution in 1 mL of
MeOH, and analyzing it immediately by ESI(+)-MS. After only 1
min of reaction, a key and very abundant ion of m/z 702 (9a,
Scheme 5) was predominant in the ESI(+)-MS. Hence, such ion
should constitute a major reaction solution species (Figure 2).[18]
Notably, when its ESI(+)-MS/MS was collected, no dissociation
of 9a either by alkyne or indole loss was detected (see Figure
S13). This behavior is compatible with 9a being a stable,
covalently bonded intermediate (See insert in Figure 2).
Theoretical calculations agreed well with the acyclic form
proposed for 9a (see SI for details).[17]
Figure 2 ESI(+)-MS of the solution for the model hydroheteroarylation reaction
using the same conditions described by Fujiwara et al. after 1 min.
But after 1 h of reaction, three new intermediates of m/z 1022
(10a), m/z 1182 (11a), and m/z 542 (8a) could also be detected
as major ions. When their collision induced dissociation (CID)
were investigated, 10a and 11a were found to dissociate to 9a
by two or three consecutive releases of alkyne 2a, which
indicates loose coordination to Pd (L in Scheme 5). As further
ESI(+)-MS monitoring revealed, the overall picture observed at 1
h remained nearly constant throughout the entire reaction but
after 24 h, as originally reported,[6] Pd intermediates were no
longer detected. Therefore, via ESI(+)-MS monitoring, 9a of m/z
702 (and its complexes 10a and 11a), which could be originated
from both alkyne or aryne activation, was the only significant
intermediate, as far as the actual mechanism is concerned,
unequivocally detected initially at high abundance and then at
slowly decreasing abundance during the whole reaction period
until its disappearance at the end (24h).
Scheme 4 Calculated energy differences between the E/Z isomers of the final
Fujiwara products 3 and the vinylpalladium intermediates 7.
We also calculated the energy difference between the isomeric
vinylpalladium intermediates 7a (R = Me), that is, the putative
precursors of the hydroarylated products E-3a and Z-3a. A G
difference of ca. 1.9 kcal mol-1 in favor of the Z-7a (R = Me)
isomer was found. The rotational barrier for the C=C double-
bond of 7a was also calculated and found to be on the order of
ca. 32 kcal mol-1. Recently, Werz and co-workers[16] reported a
value of 21.5 kcal mol-1 for the rotation of a vinylpalladium
intermediate in a formal anti-carbopalladation reaction using
non-activated alkynes, but proceeding at 100 °C. Therefore, we
concluded that the equilibrium between Z-7a and E-7a
intermediates is a rather slow process.[17]
Fast protodemetallation of vinylpalladium E-7 gives adduct Z-3a,
the kinetic product in the first stage of the hydroarylation, which
was observed in the 1H-NMR studies. Interconversion of Z-3 and
E-3 would then favor Fujiwara’s thermodynamic product E-3, as
observed after 24h (Figure 1). These findings point to the
preferential formation of vinylpalladium intermediate E-7 in the
present reaction conditions, which is evidence for preferential
alkyne activation, as discussed below.
In an attempt to intercept new species by ESI(+)-MS, the
reaction was then performed in dichloromethane (DCM). DCM
was selected as the solvent since hydroarylation is known to be
much slower in this solvent as compared to AcOH. In sharp
contrast to the straightforward detection of intermediate 9a in
AcOH, no palladium complexes for the reaction in DCM were
detected when MeOH was used to dilute the reaction aliquots.
Hence, dilution was done in a mixture of MeOH/MeCN (8/2).
Interestingly, intermediate 9a of m/z 702 was again promptly
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10.1002/ejoc.201700033
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intercepted among a complex mixture of other species, probably
corresponding to acetonitrile adducts of 9a. ESI(+)-MS
snapshots of the reaction solution after 3 h and ca. 6 h also
revealed the presence of a minor ion of m/z 382, which seems to
correspond to the key vinylic palladium intermediate 7a (Scheme
1b) prior to the protodemetalation step, but with no clue to
whether arene or alkyne activation. Similar ESI(+)-MS
monitoring was also performed for hydroarylations employing
substituted indoles, i.e., N-methylindole 1b and 3-methylindole
1f. In both cases, the key intercepted intermediates were
analogous to those described for indole 1a (see SI for details).
In an attempt to stabilize the crucial intermediate 5 via solvent
coordination, a MeCN/AcOH (1:1) mixture was then used as the
solvent. Indeed, under MeCN stabilization, 5 was quickly
intercepted and identified as an σ-indole-palladium complex
stabilized by two (5b of m/z 304) or three (5a of m/z 345) MeCN
ligands (Figure 3).[19] The [Pd(MeCN)2OAc]+ complex (4a) of m/z
247 was also fished out by ESI(+) from the reaction solution
(Figure 3).
Figure 3 ESI/MS of the reaction of 1a and Pd(OAc)2 after 1 min.
After knowing the need for MeCN stabilization, solutions from
the reaction performed in CH2Cl2 were then diluted with MeCN
and indeed intermediates 5a,b were again detected by ESI(+)-
MS. Nonetheless, 5 formed via arene activation was observed
only at the onset of the reaction (snapshot collected at 1 min)
and in the absence of the alkyne, but when the alkyne was
present (Figure 2), 5 was no longer detected and the late
intermediate 9a predominated.
Gas phase MS experiments were then performed to try to
access the intrinsic Fujiwara reactivity and the operation of
either arene or alkyne activation in the absence of solvents and
counterions.[13c] Indole (1a) and Pd(OAc)2 were then dissolved in
AcOH/MeCN, and ESI(+) was used to try to fish out 5a,b from
the reaction solution. The naked Pd-indole adduct 5 of m/z 222
(formed upon in-source CID) was selected and then directed to
the reaction chamber of a triple quadrupole mass spectrometer
in which the reaction of gaseous 5 with a model alkyne (i.e., 1-
phenyl-1-propyne (2c)) was performed (Figure 4). Fortunately,
the key product of carbopalladation, that is 7c of m/z 338, was
formed and clearly detect together with its coordination
complexes with one (7c’ of m/z 454) or two (7c’’ of m/z 570)
alkyne molecules. In addition, the ion of m/z 232 (3’c), which
corresponds to the loss of Pd from 7c of m/z 338, was also
detected. These gas phase results demonstrate the intrinsic
feasibility of arene activation followed by alkyne insertion into the
Ar-Pd bond leading to the final Fujiwara’s product. In principle,
therefore, the ESI(+)-MS interception of 5 (as 5a,b) indicates
that arene activation can indeed occur. The structures of the
product ions 3’c of m/z 232 and 7c of m/z 338 were also
investigated by CID, and their ESI(+)-MS/MS data supported the
proposed structures. Besides, in fully accordance to its proposed
structure, 7c of m/z 338 (Figure S47) was found to dissociate by
the loss of a naked Pd atom to form the Fujiwara-like product 3’c
of m/z 232.
Scheme 5 Main reaction intermediates detected and characterized by ESI(+)-
MS.
Control experiments with indole 1a were also performed to
investigate the putative C-H activation step in the absence of the
alkyne (Scheme 6).
Scheme 6: Reaction of indole 1a with Pd in the absence of alkyne
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formation of the σ-indolyl palladium intermediate followed by a
syn-migratory insertion, resulting in the Z-7 (path A). In contrast,
the trans-arylpalladation would result from a nucleophilic attack
of the indole 1a to
a Pd-alkyne complex, leading to
vinylpalladium E-7 intermediate (path B). Based on literature
precedents, the trans-addition pathway resembles a Friedel-
Crafts reaction, a widely studied mechanism[21] employing
several different metals.[22] The migratory insertion in an anti
fashion, as originally proposed by Fujiwara, was based on a
single example of tungsten hydride (W-H) addition to alkynes.[4b,
23]
A Pt-H overall trans-addition was also reported to proceed
through a radical mechanism, [24] which is unlikely for the “open-
flask” protocol used in our studies. Moreover, the calculated
rotational barrier for interconversion of the vinylpalladium
intermediates 7a was of a considerable magnitude (~32 kcal
mol-1), consequently only
a
slow equilibration involving
intermediates Z-7 and E-7 is possible. Since there are very few
precedents for the anti-migratory insertion, we were led to
reconsider the Fujiwara’s proposition involving C-H activation in
the case of indoles as indeed feasible, but a less likely
secondary pathway.
Key evidences for our proposal (Scheme 7) were the rather poor
stereoselectivity outcome of our experiments, which were fully
supported by the kinetic profile obtained by NMR monitoring
(Figure 1), as well as the theoretical calculations involving
vinylpalladium intermediates 7a. The kinetic profile indicates the
quick formation of the Z-3 isomer, and its conversion to the more
stable E-3 isomer under acidic conditions. Therefore, any
mechanistic rationale should consider the rapid formation of Z-3.
Considering the general picture illustrated in Scheme 7, the
hydroarylated products can be generated through path A or path
B, which differ from each other by the role of the electrophilic
palladium, whether leading to arene palladation or Lewis acid
activation of the alkyne. With the reasonable assumption that
under the reaction conditions protodemetallation is a fast
process occurring with retention of configuration,[25] the
vinylpalladium E-7 affords the Z-3 product, whereas the
vinylpalladium Z-7 leads to the E-3 product. The preferential
generation of Z-3 at the beginning of the reaction directly
correlates with the faster formation of vinylpalladium E-7, the
less stable stereoisomer (Scheme 4). Therefore, formation of E-
7 through path B and its quick protodepalladation is proposed as
the most likely route to the product formation (kinetic control).
Subsequent equilibration between Z-3 and E-3 provides the final
stereochemical outcome observed at the end of the reaction
favoring the Fujiwara’s product E-3 (thermodynamic product).
The intrinsic feasibility of arene activation was demonstrated via
ESI(+)-MS monitoring and the gas phase data, but a major role
for the C-H palladation pathway (path A) under the present
reaction conditions seems unlikely in view of the minor amounts
of E-3 product observed by NMR monitoring at the beginning of
the reaction.[26] However, a partial interconversion of the
vinylpalladium intermediates favoring the more stable Z-7
followed by fast protodemetalation could also concomitantly
occur and it represents a competitive (minor in our case)
pathway for the formation of the E-3 product.
Figure 4 Schematic representation of the triple quadrupole mass spectrometer
used to perform gas-phase Fujiwara reactions and the ESI(+)-MS/MS product
ion spectrum for the reaction of gaseous 5 of m/z 222 with PhCCMe (2c, 116
Da).
To determine which mechanism indeed predominates when both
the alkyne and arene are present from the start, another NMR
monitoring was performed. We now mixed indole 1a and
catalytic Pd(OAc)2 in d3-AcOD for 11 h before adding alkyne 2a,
and then monitored the reaction by 1H-NMR. Somewhat
surprisingly, the reaction profile followed the same trends
depicted in the former NMR experiments (Figure 1), i.e., initially
the Z-3 product appears as the major one, with the E-3 product
predominating after 10h, up to the final ratio of E:Z of 3:1, as
observed before in the previous experiments in solution (Figure
1).
Overall, the ESI-MS and NMR experiments seem to indicate the
feasibility and coexistence of the two competing mechanisms for
hydroarylation. The σ-indole-palladium intermediate supporting
arene activation was detected by ESI(+)-MS in the experiments
using CH2Cl2 but only at the first 2 h, disappearing thereafter.
Hence, it is reasonable to assume that the minor amount of the
E-product observed at the early stages of the reaction originates
partially from arene activation and proceeded via the σ-indole-
palladium intermediate 5. Once 5 is consumed, the alkyne
activation mechanism becomes prevalent, and the observed
stereochemical outcome is compatible with such a mechanism
for the hydroarylation under the present conditions.
A
mechanistic
proposal
for
hydroarylation
of
phenylpropiolates
Scheme 7 summarizes our interpretation of the combined MS
and NMR results and theoretical predictions. We considered two
possible pathways involving namely cis and trans-
arylpalladation.[20] The cis-arylpalladation would require the
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Scheme 7 The equilibria involving the E- and Z-3 and the E- and Z-7 and its correlation with the reaction pathway
Therefore, we propose in Scheme 8 a new catalytic cycle for the
classical intermolecular Fujiwara’s reaction between indole (1a)
and phenyl propiolates 2a,b which would predominate for
reactions performed under common Fujiwara conditions, as the
one used herein. The first, cation 4 is formed in the acetic acid
medium by the loss of an acetate ligand from Pd(OAc)2. Then,
the highly electrophilic 4 quickly coordinates to alkyne 2 to form
the Pd-alkyne complex 6, which is attacked by indole 1a to
afford the vinylpalladium E-7. The fast protodemetalation of E-7
gives the final Fujiwara product Z-3, which equilibrates to the
more stable E-3.
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Table 1 Hydroarylation of ethyl phenylpropiolate (2b) with other heteroarenes.
Entry
Ar-H
Yield (%)a
E:Z a
4.7:1
1:2.5
2:1
1
2
3
4
N-methylindole (1c)
Pyrrole (1d)
57
83
70
36b
2-methylindole (1e)
2-methylfuran (1f)
1:12.5
a Determined by 1H-NMR. b Isolated yield.
Conclusions
Using NMR and solution and gas phase MS monitoring as well
as theoretical calculations, we have comprehensively scrutinized
the mechanism of the Fujiwara’s hydroheteroarylation of alkynes
using the addition of indole to methyl/ethyl phenylpropiolate as a
model reaction. Major intermediates have been detected and
characterized via both NMR and MS monitoring, whereas
theoretical calculations were used to compare the stabilities of
concurrent species. Evidence for two previously undetected
equilibria involving the Fujiwara’s products 3 and the putative
intermediates vinylpalladium species 7 were collected. The low
stereoselectivity outcome was attributed to the equilibration of
the hydroarylated products 3 in the acidic medium rather than to
the vinylpalladium species 7, which have a rather large energy
barrier for interconversion. Although arene activation is believed
to be exclusive, evidence for the operation and feasibility of both
the alkyne and aryne activation mechanisms have been
collected but the equilibria observed allowed us to assign the
alkyne activation pathway as the main operating mechanism in
the case of the intermolecular addition of electron-rich
heteroarenes under the conditions used herein. These findings
are expected to foster new and broader hydroarylation protocols
in a mild, practical and efficient way. Based on this expanded
knowledge of the Fujiwara mechanism, further developments to
circumvent the current synthetic limitations of this synthetic
strategy are ongoing in our laboratories.
Scheme 8 Full overview of the catalytic cycle (L = alkyne 2a)
The detection of 9a of m/z 702 is likely a Pd reservoir as
evidenced by its detection as the most abundant solution
species by ESI(+)-MS monitoring (Figure 2). The off-cycle
species 9a would result from the reversible insertion of alkynes
into 7a.[17] Moreover, a linear structure for 9a was predicted as
the most stable by theoretical calculations (see SI for details).
After the migratory insertion step, protodemetalation occurs
regenerating the cationic palladium 4. Due to the much faster
reaction in acetic acid, this solvent is also suggested as the most
likely proton source in these reactions.
Other heteroarenes
Finally, we also decided to evaluate other substrates originally
reported by Fujiwara (Table 1).[6] For that, ethyl phenylpropiolate
(2b) was submitted to the same hydroarylation conditions
reported above using either N-methylindole (1c), pyrrole (1d), 2-
methylindole (1e) or 2-methylfuran (1f) as heteroarenes. As for
indole, the hydroarylation adducts were observed as a mixture of
isomers in moderate to good yields. These results, together with
Experimental Section
General Information
NMR analyses were performed on 250, 400 or 500 MHz
spectrometers in the deuterated solvents indicated. Chemical
1
shifts (δ) for H and 13C NMR spectra are given in ppm relative
those for indole (1a),
support our proposed mechanism
to TMS (CDCl3: δH = 7.26 ppm). Data are reported as follows:
chemical shift (δ), multiplicity, integrated intensity and coupling
(Scheme 7) involving equilibration of the hydroarylated products
in acidic media.[27]
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constant (J) in Hertz. Exact ESI mass spectra were recorded on
using EI ion source and time-of-flight (TOF) analyzer.
Procedure for the separation of the isomers. Using the crude
reaction mixture, an initial column chromatography was
performed. The separated products were divided into three
fractions: initial, middle and final portions. The initial and final
portions were successively re-crystallized from CHCl3-petroleum
ether to furnish pure products or enriched mixtures of the
products. For the ethyl series 3b products, pure samples (i.e.,
isomeric ratio >95:5) of both isomers were successfully obtained.
For the methyl series 3a products, the E isomer was purified up
to a ratio >95:5, whereas the Z isomer was obtained as a
mixture of Z:E = 3:1. The products were fully characterized by
NMR and MS and the data obtained were coherent with those
reported in the literature.[6, 11b, 28] For adduct E-3b, the X-ray
crystallographic structure was achieved. These purified
stereoisomers aliquots were used to follow the isomerisation in
acetic acid.
Methyl phenylpropiolate (2a), ethyl phenylpropiolate (2b), indole
(1a), N-methylindole (1c) and 3-methylindole (1g) were
purchased and used without further purifications. Pyrrole (1d)
and 2-methylfuran (1f) were distilled prior to use. The purity
1
grade of such reagents was confirmed by H-NMR spectra in
CDCl3 and/or d3-AcOD. Palladium acetate used was purchased
from Sigma-Aldrich (Lot# STBC1689V). Both acetic acid and
CH2Cl2 employed were P.A. grade. Internal standards for 1H-
NMR were purchased and not purified. All the reactions were
performed in a 0.5 mmol scale, except for ESI/MS and some
NMR studies. The procedures always involved non-dried
glassware, reagents or catalysts. Reactions were carried out
under open-flask conditions when using acetic acid as solvent or
capped with a septum when using CH2Cl2 as solvent.
The procedures for the Fujiwara hydroheteroarylations followed
the original depicted by Fujiwara et. al. and are described below.
The experiments described along with the manuscript followed
the same protocol, except for changes in stoichiometry or the
isolation procedure. The same protocols were followed
independently of the alkyne used.
Isomerisation in acid medium. Few milligrams of the pure
isomers E- or Z-3b were placed in a 5 mm NMR tube and
dissolved in d3-AcOD. The same procedure was carried out
using the enriched mixture of adduct 3a (initially E:Z = 1:3). The
three samples were analyzed by 1H-NMR in the following times:
0 h, 0.5 h, 24 h, 96 h and 128 h.
Procedure
for
hydroheteroarylation
of
methyl
phenylpropiolate (2a). In a 5 mL round bottom-flask with
magnetic stir bar were added indole (1.5 mmol, 175 mg) and
Pd(OAc)2 (0.025 mmol, 5.6 mg). The appropriate solvent (AcOH
or CH2Cl2) was added (0.5 mL) followed by the immediately
addition of alkyne 2a (0.5 mmol, 80 mg). The mixture was then
(E)-methyl 3-(1H-indol-3-yl)-3-phenylacrylate (3a)[28] White
solid. HRMS (ESI-TOF) m/z: [M] Calcd for C18H15NO2
+
·
277.1103; Found 277.1109. 1H-NMR (400 MHz, CDCl3, TMS), :
3.61 (s, 3H), 6.57 (s, 1H), 6.76 (d, 1H, J= 1.2 Hz), 7.17-7.24 (m,
2H), 7.28-7.34 (m, 6H), 7.77 (d, 1H, J= 4.0 Hz), 8.60 (s, 1H).
13C-NMR (125 MHz, CDCl3, TMS), : 51.0 (OCH3), 111.3 (CH),
111.9 (CH), 118.4 (C0), 120.7 (CH), 121.3 (CH), 123.0 (CH),
124.9 (C0), 127.7, (CH), 127.8 (CH), 128.7 (CH), 129.6 (CH),
137.1 (C0), 140.0 (C0), 153.1 (C0), 167.4 (C0).
stirred for 24-48
h (see Table S1 for details) at room
temperature. After completion, the crude mixture was isolated by
two independent procedures, i.e., aqueous work-up (following
exactly the procedure adopted in the original Fujiwara’s paper)[6]
or filtration through a plug of silica gel (see Table S1 for details).
For aqueous work-up: Brine (5 mL) was added to the reaction
and the mixture was transferred to a separatory funnel. The
aqueous phase was extracted with diethyl ether (3 x 10 mL).
Next, the organic phase was separated, dried with MgSO4,
(E)-ethyl 3-(1H-indol-3-yl)-3-phenylacrylate (E-3b)[6] White
+
·
solid. HRMS (EI-TOF) m/z: [M]
Calcd for C19H17NO2
291.1259; Found 291.1267. 1H-NMR (400 MHz, CDCl3, TMS), :
1.12, (t, 3H, J= 7.0 Hz), 4.05 (q, 2H, J= 7.0 Hz), 6.56 (s, 1H),
filtered, and the solvent was evaporated under reduced pressure. 6.80 (d, 1H, J= 3.0 Hz), 7.17-7.36 (m, 8H), 7.78 (d, 1H, J= 8.5
Solvent residues were eliminated in high-vacuum pump for at
least 30 minutes.
This isolation protocol was used for N-methylindole (1b), 2-
methylindole (1f) and pyrrole (1e).
Filtration through a plug of silica gel: The reaction mixture was
placed directly at the top of the plug of silica gel and washed
with ethyl acetate (~ 100 mL). The solvents were then removed
under reduced pressure. Solvent residues were eliminated in
high-vacuum pump for at least 30 minutes.
Hz), 8.52 (s, 1H). 13C-NMR (62.5 MHz, CDCl3, TMS), : 14.1
(CH3), 59.7 (OCH2), 111.8 (CH), 112.2 (CH), 118.6 (C0), 120.8
(CH), 121.3 (CH), 122.9 (CH), 125.0 (C0), 127.6, (CH), 127.7
(CH), 128.8 (CH), 129.2 (CH), 137.1 (C0), 140.2 (C0), 152.4 (C0),
167.1 (C0). The structure of this compound has also been
confirmed by X-ray crystallographic analysis.
(Z)-ethyl 3-(1H-indol-3-yl)-3-phenylacrylate (Z-3b)[11b] Yellow
1
solid. H-NMR (400 MHz, CDCl3, TMS), : 1.16, (t, 3H, J= 7.0
Once the crude reaction mixture was dried, regardless of the
isolation protocol employed, the yields and E:Z ratios were
evaluated by 1H-NMR in CDCl3 using an internal standard.
When necessary, the product purification was performed by
chromatographic column in silica gel (Hexanes: EtOAc = 8:2).
Some analytical samples were crystallized from a mixture of
CHCl3-petroleum ether.
Hz), 4.11 (q, 2H, J= 7.2 Hz), 6.26 (s, 1H), 6.96 (d, 1H, J= 4.0 Hz),
7.05-7.20 (m, 1H), 7.27-7.45 (m, 7H), 8.59 (s, 1H). 13C-NMR
(125 MHz, CDCl3, TMS), : 14.2 (CH3), 60.0 (OCH2), 111.3 (CH),
113.6 (C0), 116.0 (CH), 120.0 (CH), 120.5 (CH), 122.0 (CH),
127.0 (C0), 127.8 (CH), 128.1 (CH), 128.8 (CH), 129.2 (CH),
135.9 (C0), 142.2 (C0), 150.5 (C0), 166.7 (C0).
(Z)-ethyl 3-(5-methylfuran-2-yl)-3-phenylacrylate (3f)[6] Light
yellow oil. 1H-NMR (500 MHz, CDCl3, TMS), : 1.30 (t, 3H,
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10.1002/ejoc.201700033
European Journal of Organic Chemistry
FULL PAPER
J=7.1Hz), 2.31 (s, 3H), 4.23 (q, 2H, J=7.1Hz), 5.88 (s, 1H), 6.08
(d, 1H, J=3.2Hz), 6.53 (d, 1H, J=3.2Hz ), 7.33-7.42 (m, 5H). 13C-
NMR (125 MHz, CDCl3, TMS), : 13.8, 14.2, 60.3, 107.9, 116.0,
116.2, 128.1, 128.8, 129.0, 139.7, 142.0, 149.3, 153.9, 166.6.
desolvation and nebulization gas. The source and desolvation
temperatures were kept at 100°C. The sample solutions were
introduced into the electrospray ionization source (ESI) of the
mass spectrometer using an infusion pump at a flow rate of 400
µL.h-1. Fully experimental details and an illustration of the
modified apparatus (Figure S45) are given in the Supporting
Information.
Reaction monitoring in condensed phase using 1H-NMR. To
a mixture of Pd(OAc)2 (25 µmol, 5.6 mg) and d3-AcOD (0.20 mL)
in a 5 mm NMR tube, it was added sulfolane (23.8 L, 0.25
mmol) as an internal standard. Then, a solution of indole (1a)
(174 mg, 1.5 mmol) in d3-AcOD (0.25 mL) was added
immediately followed by addition of methyl phenylpropiolate (74
L, 0.5 mmol) or ethyl phenylpropiolate (82 L, 0.5 mmol). The
mixture was stirred manually when its color changed
immediately from orange to dark brown. The first 1H-NMR
spectrum was recorded 10 min after alkyne addition, then every
15 min in the first 6 hours, and every 1 hour for the next 18
hours. The same procedure was employed when using CD2Cl2,
except for the different reaction times for the snapshots (15 min
interval for the first 3 h and then every hour for the subsequent
14 h).
Computational details. Electronic and molecular structures of
compounds
originated
from
the
model
Fujiwara
hydroheteroarylation reaction were theoretically investigated
through calculation. These calculations were performed using
DFT employing the new hybrid meta exchange-correlation
functional (M06-2X). This functional is parameterized including
both transition metals and nonmetals.[29] Geometry optimizations
and evaluation of harmonic frequencies were performed at the
M06-2X/[BS1] level. The optimized structures were confirmed to
be minimal by vibrational frequency analysis. The Basis set 1
(BS1) presents a combination of the Pople basis set, 6-31G(d,p),
for the main group elements (H,C, N, and O) and the relativistic
energy-consistent pseudopotential (RECP) basis set SDD[30] for
transition metal (Pd). The single point energy calculations were
carried out at M06-2X/[BS2] level on corresponding optimized
geometries. In this new basis set [BS2], the main group
elements were represented by 6-31G(3df,2p) basis set and to
the basis set employed to describe the transition metal was
added one f basis function. All computations were performed
using the Gaussian 09 package.[31]
General procedure for the ESI(+)-MS and ESI(+)-MS/MS
experiments. All experiments were performed on a tandem high
definition mass spectrometer equipped with an ESI source in
positive ion mode and a TOF mass analyzer. For typical
electrospray ionization (ESI) conditions, the samples were
directly infused into ESI source using syringe pump at a flow of
the 10 µL.min-1. The main conditions were the following: capillary
voltage, 3000 eV; cone voltage, 30 eV; source temperature,
100°C; desolvation temperature, 100°C. The cationic species
were subjected to collision-induced dissociation (CID) with argon
by using collision energies ranging from 5 to 45 eV.
Supporting Information Initial bulky reaction’s results, selected
NMR and MS data gathered during the reaction monitoring,
crystallographic analysis of 3b and full set of computational
results are provided. This material is available free of charge via
the Internet at http://
Hydroheteroarylation of methyl phenylpropiolate (2a)
monitored by ESI(+)-MS. The reaction was performed as
described above in a scale of 0.3 mmol of alkyne 2a. The
ESI/MS monitoring was made by periodically taken 1 µL aliquots,
diluting those in MeOH (1 mL) containing 0.1% of HCOOH for
the reactions carried out in AcOH and MeOH:MeCN 8:2 (1 mL)
for the reactions carried out in CH2Cl2, followed by injection into
the MS spectrometer. MS spectra were recorded as indicated in
the general procedure for ESI(+)-MS(/MS) experiments.
Acknowledgements
Financial support from São Paulo Research Foundation
(FAPESP grants: C. R. D. C. 2011/23832-6; F. A. 2010/11068-7;
P. D. G. M. 2008/00122-0; M. N. G. 2010/00257-3) and the
Brazilian National Research Council (CNPq; 457027/2014-2) are
gratefully acknowledged. MNE thanks Université Pierre et Marie
Curie, Institut Parisien de Chimie Moléculaire, for a visiting
scholarship during which the ESI-MS studies in the gas phase
were carried out. We also thank Dr. D. A. Simoni (UNICAMP) for
the X-ray crystallographic analysis of compound 3b.
Control experiments for indole (1a) monitored by ESI(+)-MS.
To a suspension of Pd(OAc)2 (10 µmol, 2.2 mg) in HOAc:MeCN
(1:1; 0.2 mL) was added indole 1a (0.2 mmol, 23.4 mg). The
mixture was stirred at room temperature for 10 minutes. Next, a
1 µL aliquot was diluted in MeOH (1 mL) containing 0.1% of
HCOOH. The resulting solution was injected into the MS
spectrometer.
Keywords: Fujiwara’s reaction • hydroheteroarylation • alkynes
• indoles • cross-couplings
Hydroheteroarylation of 1-phenyl-1-propyne (1c) in gas-
phase monitored by ESI(+)-MS. Triple-quadrupole experiments
were recorded using a homemade modified mass spectrometer
equipped with a Z-spray source. The ESI capillary voltage was
maintained at 3.5 kV, and the cone voltage was varying from 25
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10.1002/ejoc.201700033
European Journal of Organic Chemistry
FULL PAPER
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accordance with those reported by Fujiwara (ethyl propiolate,
phenylpropiolic acid and diphenylacetylene were used as alkyne
substrates), especially regarding their stereoselectivity. Therefore, we
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
H
Ph
Palladium catalysis*
Pd(II)
CO2R1
+
Ph
CO2R1
H+
Marla N. Godoi,† Francisco de
N
New mechanistic insights
for an iconic reaction!
HN
H
Azambuja,† Pablo David G. Martinez,†
Nelson H. Morgon, Vanessa G. Santos,
Thaís Regiani, Denis Lesage, Heloise
Dossmann, Richard B. Cole, Marcos N.
Eberlin* and Carlos Roque D. Correia*
[PdII]+
[PdII]+
or



unprecedented equilibria
stereochemical course investigation
new intermediates by ESI/MS
Ph
CO2R1
N
H
Arene
Alkyne
activation
activation
Page No. – Page No.
Arene or Alkyne activation? The Fujiwara's hydroarylation of alkynes was re-
investigated. Reactions were monitored by both 1H-NMR, electrospray ionization
mass spectrometry (ESI/MS) and via reactions performed in the gas phase using
MS/MS experiments.
Revisiting the Intermolecular
Fujiwara's Hydroarylation of Alkynes
*one or two words that highlight the emphasis of the paper or the field of the study
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