Cationic Pd(II)-catalyzed C-H activation/cross-coupling reactions at room temperature: Synthetic and mechanistic studies

Article abstract of DOI:10.3762/bjoc.12.99

Cationic palladium(II) complexes have been found to be highly reactive towards aromatic C-H activation of arylureas at room temperature. A commercially available catalyst [Pd(MeCN)₄](BF₄)₂ or a nitrile-free cationic palladium(II) complex generated in situ from the reaction of Pd(OAc)₂ and HBF₄, effectively catalyzes C-H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C-H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1) C-H activation to generate a cationic palladacycle; (2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied.

Full text of DOI:10.3762/bjoc.12.99

Cationic Pd(II)-catalyzed C–H activation/cross-coupling
reactions at room temperature: synthetic and
mechanistic studies
Takashi Nishikata, Alexander R. Abela, Shenlin Huang and Bruce H. Lipshutz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1040–1064.
Department of Chemistry & Biochemistry, University of California,
Santa Barbara, CA 93106, USA
doi:10.3762/bjoc.12.99
Received: 18 January 2016
Accepted: 28 April 2016
Published: 20 May 2016
Email:
Bruce H. Lipshutz* - lipshutz@chem.ucsb.edu
* Corresponding author
This article is part of the Thematic Series "C–H
Functionalization/activation in organic synthesis".
Keywords:
arylation; cationic palladium; C–H functionalization; green chemistry;
olefination
Guest Editor: R. Sarpong
© 2016 Nishikata et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Cationic palladium(II) complexes have been found to be highly reactive towards aromatic C–H activation of arylureas at room tem-
perature. A commercially available catalyst [Pd(MeCN)4](BF4)2 or a nitrile-free cationic palladium(II) complex generated in situ
from the reaction of Pd(OAc)2 and HBF4, effectively catalyzes C–H activation/cross-coupling reactions between aryl iodides, aryl-
boronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to
be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reac-
tions at an ortho C–H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent
produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mecha-
nistic investigations led to a proposed catalytic cycle involving three steps: (1) C–H activation to generate a cationic palladacycle;
(2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic
palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the
corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have
also been studied.
Introduction
Transition metal-catalyzed, direct functionalization of aryl C–H While reactions of this type have been known for decades
bonds has made enormous progress over the past decade, and [1-71], serious challenges remain in achieving reactivity and
continues to attract a great deal of attention due to the highly selectivity due to the inertness and ubiquity of C–H bonds. High
efficient routes now available for elaborating aromatic rings. temperatures are frequently required to realize aromatic C–H
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functionalization (>120 °C), increasing the potential for side A fourth approach with considerable potential, and which
reactions and functional group compatibility issues. Indeed, appears to have received considerably less attention, involves
C–H activation transformations until recently have rarely tuning the cationicity of the transition metal catalyst [72-79].
proceeded at ambient temperature due to the typically low reac- Literature studies have suggested that certain anionic ligands on
tivity of these positions [72-79]. In the case of palladium-cata- palladium, such as acetate or carbonate, may assist C–H bond
lyzed C–H activation, the crucial, namesake “C–H activation” cleavage by acting as internal bases as part of a concerted meta-
step typically involves a C–H to C–Pd refunctionalization, lation–deprotonation (CMD) pathway, particularly in the case
generating a reactive aryl-palladium species that is poised for of less electron-rich arenes (Scheme 1, top) [34,108-119]. In
further transformations.
other arrays, particularly those with more electron-rich substitu-
ents, evidence suggests an electrophilic aromatic substitution
Three approaches (Figure 1) have generally been employed to mechanism may be operative. In these instances, electron-poor
enhance the reactivity and promote the key metalation/C–H catalysts, such as those generated from the reaction of Pd(II)
bond cleavage step: (1) tuning of the reaction conditions and TFA, have in some cases been shown to be especially effec-
through inclusion of various additives such as metal salts tive. We reasoned that substitution with a more distant coordi-
[1-22], or strong acids such as TFA or HOAc, in addition to the nating anion would result in a highly Lewis acidic, dicationic
application of heat, although it is not always clear which steps palladium species that might be still more reactive in the elec-
within the overall mechanism are most directly effected under trophilic palladation step, potentially gaining entry to C–H acti-
these conditions; (2) in a major subset of C–H activation chem- vation under even milder reaction conditions for selected
istry, internally chelating ortho-directing groups [71-85] have couplings than have previously been observed (Scheme 1,
been found to effectively promote selective C–H activation, bottom) [120-122].
typically by aiding in the formation of a palladacycle intermedi-
ate. Careful tuning of the structure of the directing group, with Metal cations, in general, are well known to increase the reac-
functionalities including a variety of nitrogen-containing tivity of C–C and C–N double bonds due to their Lewis acidity.
moieties, such as amides [86,87], N-heterocycles [88,89], Cationic palladium complexes [123], in particular, possess a
imines [90,91], pyridine N-oxide [92], amines [93,94], as wide breadth of reactivity, having been used to catalyze
well as a variety of others [1-71], has been found to profoundly Diels–Alder [124,125], aldol and Mannich reactions [126-128],
impact reactivity; (3) tuning of ligands around the transition Wacker oxidations [129], polymerizations of alkenes [130,131],
metal catalyst center has emerged as an especially powerful and asymmetric 1,4-additions with arylboronic [132-134], aryl-
means of enhancing and controlling reactivity in these pro- bismuth [135], and arylsilicon [136] reagents. Although carbo-
cesses [95-107].
cations react with arenes through electrophilic aromatic hydro-
Figure 1: Road map to enhanced C–H activation reactivity.
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Scheme 1: Concerted metalation–deprotonation and elelectrophilic palladation pathways for C–H activation.
gen substitution in a Friedel–Crafts reaction, the potential for details associated with this C–H activation chemistry, addition-
metal cations to participate in similar chemistry has been far al applications of room temperature Fujiwara–Moritani reac-
less widely examined. A cationic palladium-catalyzed electro- tions including a synthesis of the herbicide boscalid, as well as
philic aromatic C–H substitution without basic anions [137- spectroscopic and mechanistic studies.
142] would hold considerable promise as an alternative and
Results and Discussion
potentially milder approach to achieving valued C–H activation/
C–H arylations of arylureas with aryl iodides
coupling reactions.
and arylboronic acids
While several cationic palladium complexes are commercially
available, they may also be generated in situ via a variety of
routes (Scheme 2), including: (a) reaction of a palladium com-
plex with a non-coordinating anion source, usually an acid or
metal salt; (b) reaction of Pd(II) halide complexes and silver
salts [143-145]; (c) electronic oxidation of Pd(0) [146]; and (d)
chemical oxidation of Pd(0) with HBF4, Cu(BF4)2 or AgBF4
[136,147,148].
Among the most conceptually attractive approaches to aromatic
C–H activation is the efficient synthesis of biaryls through
direct arylation reactions. The widespread availability of aryl
iodides and arylboronic acids make them appealing arylating
agents [149-171]. Previously reported C–H activation reaction
conditions employing these reagents, however, have typically
required high temperatures to obtain the desired coupling prod-
ucts in good yields. In order to successfully carry out these reac-
tions at ambient temperature, several considerations must be
addressed, as illustrated in Figure 1. Optimization studies
initially focused on the choice of an ortho-directing group
together with a cationic palladium(II) catalyst. Although the
combination of acetanilide together with a palladium(II) cata-
lyst lead to the corresponding palladacycle, as reported by
Tremont [172], in the presence of 2a, Pd(OAc)2, HBF4 and
AgOAc at room temperature, acetyl or isopropyl anilides afford
essentially no product. Only after heating to 50 °C did substrate
1a react with iodide 2a. The corresponding pivaloylanilide is
also known to serve as an effective directing group at 130 °C,
but at room temperature a poor yield was obtained. Only the
dimethylurea analog gave satisfactory conversion to the desired
biaryl, thus arriving at optimized conditions, as shown in
Scheme 3 (left). By contrast, the Daugulis group and others
Scheme 2: Routes for generation of cationic palladium(II) species.
We have previously reported that cationic palladium-catalyzed
C–H arylations of arylureas [121,122] and Fujiwara–Moritani
reactions of anilide derivatives [148] can be effected at room
temperature. In this account we disclose, in addition to full
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Scheme 3: Optimized conditions for C–H arylations at room temperature.
[173,174] have demonstrated Pd-catalyzed ortho-arylations of coupling at room temperature. 1,4-Benzoquinone (BQ) was
anilides at temperatures typically greater than 100 °C, and the found to be an effective additive in promoting the reaction,
Sanford group has also studied similar transformations involv- while addition of stoichiometric metal salts (e.g., silver or
ing diaryliodonium salts [175]. Arylureas have recently been copper salts) was unnecessary. Moreover, in this case organic
noticed to be more active coupling partners for C–H functional- solvents were far more effective as the reaction medium than
izations as opposed to anilides, especially at lower tempera- was water, possibly due to BQ solubility issues. EtOAc, rather
tures [176]. A number of strong acids have been previously than EtOH and THF was the most effective (Scheme 3, right),
utilized in C–H activation reactions [1-22], e.g., HBF4 was while other organic solvents (e.g., DMF) gave low-to-moderate
found to be critical for generation of biaryl 3h in good yield. yields of product 3a. Although reduced amounts of both
The structure of the ortho-arylated product was confirmed by phenylboronic acid (2b) and BQ still gave excellent yields,
X-ray analysis. While similar reactions, in addition to requiring lower catalyst loadings caused slower reactions. A neutral palla-
high temperatures, have typically employed strong acids such as dium(II) complex, Pd(OAc)2, showed no catalytic acitivity,
TFA as the organic solvent, here 2 wt % solutions of selected whereas catalytic Pd(OAc)2 in the presence of stoichiometric
surfactants in water were found to be excellent reaction media, HBF4 reacted with an arylurea and arylboronic acid to afford
providing an additional environmentally appealing feature to the biaryl in high yield (Scheme 4).
this protocol. While good yields could be obtained using the
first generation surfactant PTS (polyoxyethanyl α-tocopheryl
sebacate) [121,177,178], several other amphiphiles that are both
less costly and are items of commerce gave comparable results.
Using commercialy available Brij 35 (2 wt %) in water [179-
183] afforded the best levels of conversion and thus, overall
yields, while in its absence (i.e.,”on water”), there was a notice-
able drop in the extent of conversion. In addition, lower load-
ings of HBF4, silver salt, or the palladium catalyst also gave
inferior results.
Scheme 4: Biaryl formation catalyzed by Pd(OAc)2.
In the case of C–H activation/Suzuki–Miyaura coupling reac-
tions, the commercially available, pre-formed cationic Pd(II)
catalyst [Pd(MeCN)4](BF4)2 [184], was found to efficiently cat-
alyze the reaction between arylureas and arylboronic acids. On
the other hand, C–H arylations with aryl iodides catalyzed by
[Pd(MeCN)4](BF4)2 did not give any of the desired products
(see mechanistic discussion; vide infra). Various neutral palla-
dium catalysts were examined, such as Pd(OAc)2, PdCl2Ln,
Pd2(dba)3, in the absence of added acid, but none led to cross-
Representative results for the reactions between aryl iodides and
arylboronic acids are summarized in Figure 2. These arylations
tolerate various combinations of substrates and reagents having
electron-withdrawing or electron-donating groups, as well as
sterically hindered aromatic rings, all taking place at room tem-
perature. Suzuki–Miyaura-type C–H coupling reactions are typ-
ically more tolerant of electron-withdrawing groups (3d, 3f, 3k)
and ortho-substitution (3g) on the aryl ring. On the other hand,
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Figure 2: C–H arylation results. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water (1 mL) with 10 mol % Pd(OAc)2, AgOAc (2 equiv),
HBF4 (5 equiv), arylurea (1, 0.25 mmol), and ArI (2.0 equiv). Conditions B: Conducted at rt for 20 h in EtOAc (1 mL) with 10 mol %
[Pd(MeCN)4](BF4)2, BQ (2 or 5 equiv), arylurea (1, 0.25 mmol), and ArB(OH)2 (1.5 or 3 equiv). aRun for 48 h. b2 equiv of BQ. cRun for 96 h. dRun for
72 h.
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the reaction with 4-methoxycarbonylphenyl iodide, for exam- trollable double arylation in symmetrical or unsubstituted sub-
ple, gave a low yield of product 3k. Arylureas having only an strates [1-22,173,174]. At ambient temperatures, however, cou-
electron-withdrawing group showed no reactivity towards cou- pling reactions on these more challenging substrate types under-
pling under either set of conditions (3x), consistent with an went selective mono-arylations in water (Figure 3). In fact,
electrophilic aromatic substitution pathway in the initial C–H doubly arylated products were rather difficult to generate under
activation step by a cationic palladium(II) species (vide infra). these room temperature conditions, not unexpected given the
Arylureas with various alkyl substituents in the ortho-position, previously described low reactivity of ureas already possessing
including cyclic arrays, gave good isolated yields (3t, 3v, 3w), an ortho-aryl substituent [121,122].
whereas a 2-phenyl substituted arylurea did not participate in
the C–H activation/coupling reaction under these conditions A 1-naphthylurea also gave excellent selectivity at room tem-
(3y). Overall, C–H Suzuki–Miyaura coupling reactions were perature (Scheme 5). When this substrate was subjected to opti-
applicable to a broader substrate scope than the corresponding mized conditions for the boronic acid C–H coupling, the corre-
reaction with aryl iodides, although the latter protocol remains sponding singly ortho-arylated product was obtained in
appealing for a variety of cross-coupling combinations due to 97% yield solely as the 2-aryl isomer, as confirmed by 1H NMR
both the convenience of aryl iodides as substrates, and the use and X-ray crystallography. Generally, it is difficult to effi-
of water as the gross reaction medium.
ciently control the selectivity between the C2 and C8 positions
in naphthalene rings towards a single isomeric C–H activation
Especially noteworthy are the numerous examples of aniline de- product [163,174,185-189].
rivatives lacking ortho- or meta-substitution, which have previ-
ously been shown to be prone to double arylation (Figure 3). Fujiwara–Moritani reactions
Since literature conditions generally employ elevated tempera- Following these results on biaryl constructions via C–H activa-
tures, directed C–H arylations have often suffered from uncon- tion at room temperature, we next sought to apply our cationic
Figure 3: Monoarylations in water at rt. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water with 10 mol % Pd(OAc)2, AgOAc (2 equiv),
HBF4 (5 equiv), arylurea (1, 0.25 mmol), and ArI (2, 1.5 equiv). Conditions B: Conducted at rt for 20 h in EtOAc with 10 mol % [Pd(MeCN)4](BF4)2,
BQ (5 equiv), arylurea (1, 0.25 mmol), and ArB(OH)2 (2, 1.5 equiv). The ratios of single:double arylation determined by 1H NMR are shown in the
parentheses. aRun for 48 h. b1.2 equiv of ArB(OH)2. c1.2 equiv of ArI. dRun for 72 h.
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generally resorted to elevated temperatures (80–160 °C) and an-
hydrous conditions, and in many cases high pressures of CO or
O2 are also required in order to carry out these Heck-like cou-
pling reactions [1-22,193-203]. Additional progress of note
includes coupling reactions with arenes containing an ortho-
directing group [1-22,45-51,193-203], as well as a meta-selec-
tive Fujiwara–Moritani reaction [204,205]. A recent report em-
ploying arylureas as the C–H coupling partner achieved limited
coupling at ambient temperature, with most examples requiring
heating to 60 °C [74,206].
We have previously reported a methodology enabling Fuji-
wara–Moritani reactions to be run in water at room temperature
using the cationic palladium catalyst [Pd(MeCN)4](BF4)2
(Figure 4, 5a–c, conditions A). While this reaction proceeded
Scheme 5: Selective arylation of a 1-naphthylurea derivative.
palladium(II) conditions to the venerable Fujiwara–Moritani with a number of alkyl anilide derivatives, as well as ureas as
reaction. As reported back in 1967, this direct aryl olefination directing groups (5c), the substrate scope was otherwise some-
reaction is among the first palladium-catalyzed C–H activation what limited; only anilides possessing a strongly donating
reactions to be described [190-192]. Subsequent studies have alkoxy group meta to the directing group (para to the position
Figure 4: Fujiwara–Moritani coupling rreactions in water. Conditions A: 10 mol % [Pd(MeCN)4](BF4)2, 1 equiv BQ, 2 equiv AgNO3, 2 wt % PTS/water,
rt, 20 h. Conditions B: 10 mol % Pd(OAc)2, 1 equiv BQ, 2 equiv AgOAc, 5 equiv HBF4 aq, 2 wt % Brij 35/water, rt, 20 h.
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where the C–H activation would occur) were reactive. Howev- tially reactive ortho-aromatic C–H bonds in 1g, the mono-acry-
er, we have since found that use of acetonitrile-free, in situ lated product was obtained exclusively.
generated cationic palladium with arylureas as the directing
group expanded the substrate scope to include reactions with Under optimized conditions, various acrylates and amides can
3-alkyl-substituted ureas, as well as a wider variety of acrylates be synthesized via C–H activation reactions (Figure 6). Methyl
and even some acrylamides (Figure 4, 5d–h, conditions B). acrylate, which did not show good general reactivity with
Many combinations of acrylates and more challenging arylureas under previous conditions, could be coupled in excel-
arylureas, however, did not produce the desired product in satis- lent yields (5i, 5j, 5k). As previously mentioned, a drawback
factory yields, and the reaction still required the use of stoichio- characteristic of several ortho-directed C–H activation cross-
metric silver salts in addition to benzoquinone.
coupling approaches has been the undesired coupling at both
sites ortho- to the directing group. These new conditions com-
To overcome these limitations, further optimization of the cata- pletely inhibited second-stage alkenylation, thereby generating
lyst system was conducted (Figure 5). A combination of singly derivatized arylureas in good yields (5l, 5m, 5n).
AgNO3 or AgOAc and BQ was critical to obtain good yields of Arylureas containing halogens, which are slightly electron-defi-
the same products formed earlier in water (vide supra), but as cient but provide useful synthetic handles for subsequent func-
seen previously in the corresponding Suzuki–Miyaura reactions, tionalization, reacted cleanly to form the desired products (5p,
a switch to EtOAc obviated the need for a silver salt. In the 5q). Arylureas bearing ortho-alkyl substituents also gave excel-
presence of BQ and HBF4, the reaction of 1g and acrylate 4 was lent yields (5o, 5r), while acrylamides having simple amine or
efficiently catalyzed by Pd(OAc)2 (Figure 5, runs 3 and 4). amino acid moieties also participated in cross-coupling reac-
Lower loadings of BQ and HBF4 also gave good results tions with the arylurea to produce the corresponding amide de-
(Figure 5, runs 5 and 7). Much lower loading of HBF4, howev- rivatives in moderate to good yields (5s, 5t).
er, afforded a low yield of product 5 (Figure 5, run 8). In the
Total synthesis of boscalid® via C–H
absence of acid or BQ, the product was not obtained (Figure 5,
runs 6 and 9). The pre-formed cationic palladium(II) complex, activation
[Pd(MeCN)4](BF4)2, was also found to effectively catalyze the The rationale behind the attention recently accorded C–H acti-
reaction between 1g and ester 4 at room temperature, without vation chemistry has been based, in part, on its potential to
additional acid, although somewhat longer reaction times were streamline routes towards valuable synthetic targets. As a
necessary (Figure 5, run 10). Despite the presence of two poten- demonstration of the utility of our C–H activation approach, we
Figure 5: Optimization. Conducted at rt for 8 h or as otherwise noted in EtOAc with 10 mol % Pd catalyst, AgOAc, HBF4, arylurea (1g, 0.25 mmol),
BQ and acrylate (2c, 2.0 equiv). a2 wt % Brij 35 in water instead of EtOAc.
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Figure 6: Representative results in EtOAc. Conducted at rt in EtOAc with 10 mol % Pd(OAc)2, HBF4 (1 equiv), arylurea (1, 0.25 mmol), BQ (3 equiv)
and acrylate (2, 2.0 equiv).
chose to synthesize boscalid®, a pesticide currently prepared on tion strategy, however, might provide a highly efficient, alterna-
a yearly kiloton scale by means of a traditional Suzuki–Miyaura tive route originating from just aniline. The corresponding
coupling. It is used to control a range of plant pathogens in phenylurea can be prepared in high yield (96%), which is then
broadacre and horticultural crops (Scheme 6) [207]. Felpin and subjected to C–H Suzuki–Miyaura coupling at room tempera-
co-workers have reported its synthesis starting from aryldiazo- ture (91%). Sequential deprotection and acylation with
nium salts [208], while the Heinrich group has employed a free- 2-chloronicotinoyl chloride result in boscalid in four steps in an
radical biaryl cross-coupling of diaminobenzene promoted by overall yield of 86%, which compares favorably with all known
TiCl3 [209]. A number of additional syntheses can also be routes to this pesticide shown in Scheme 6 [86,208-213].
found in the literature [86,210]. Moreover, the BASF has
patented routes using a traditional Suzuki–Miyaura cross-cou- Mechanistic insight
pling in the presence of 0.5 mol % Pd catalyst to reach the same Although there have been a number of mechanistic studies on
nitro-intermediate found in the Felpin route [211-213].
C–H activation reactions involving neutral palladium species
[34,108-119], those catalyzed by cationic palladium have been
Many of these syntheses require large excesses of iron or other much less thoroughly examined. We hypothesized that our cata-
stoichiometric metals to obtain high yields (Scheme 6). As lytic cycles for the Fujiwara–Moritani, arylboronic acid, and
shown in Scheme 7, a synthesis that proceeds via a C–H activa- aryl iodide coupling reactions catalyzed by cationic palladium
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Scheme 6: Previous syntheses of boscalid®.
Scheme 7: Synthesis of boscalid®. aConducted at rt for 20 h in EtOAc with 10 mol % [Pd(MeCN)4](BF4)2, BQ (5 equiv), arylurea (1, 0.25 mmol), and
ArB(OH)2 (2, 1.5 equiv). bNaOH, dioxane/water, reflux, then 2-chloronicotinoyl chloride, Et3N, THF, rt.
complexes are composed of three key steps; (1) aromatic C–H The C–H activation step
activation by cationic palladium; (2) reaction of the resulting Although aromatic C–H bond activation through palladacycle
intermediate (a cationic palladacycle) with a corresponding [214] generation is a critical step in the ortho-directed, activa-
reagent; and (3) re-generation of the active catalyst (Scheme 8). tion/cross-coupling sequence, many of its specific mechanistic
In order to test this hypothesis we explored the viability of each features are still controversial. Previous studies with arylureas
of these individual steps.
[73,206,215] have formulated a palladacycle as the likely initial
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Scheme 8: Hypothetical reaction sequence for cationic Pd(II)-catalyzed aromatic C–H activation reactions.
intermediate associated with palladation and subsequent C–H
bond cleavage.
In order to confirm palladacycle formation in our reactions
with arylureas, the dicationic palladium complex
[Pd(MeCN)4](BF4)2 was exposed to one equivalent of
3-methoxyphenylurea 1f at room temperature for 20 minutes
(Scheme 9). This stoichiometric reaction led to the correspond-
ing palladacycle 6 in 95% yield, without the aid of additives
(i.e., no Ag salt or protic acid). In harmony, in situ-generated
cationic palladium from the reaction of Pd(OAc)2 and HBF4
gave the same palladacycle upon addition of acetonitrile, as
confirmed by NMR. The facile formation of this species
supports the intermediacy of a palladacycle in the catalytic
cycle. The structure of the isolated palladacycle was confirmed
by X-ray analysis [216].
Figure 7: X-ray structure of palladacycle 6 with thermal ellipsoids at
the 50% probability level. BF4 and hydrogen atoms were omitted for
clarity. Selected bond length (Å): Pd–C(5) = 1.980, Pd–N(3) = 1.995,
Pd–N(4) = 2.126, Pd–O(2) = 1.988. Selected angles (°):
C(5)–Pd–N(3) = 94.15, N(3)–Pd–N(4) = 87.81, N(4)–Pd–O(2) = 86.07,
O(2)–Pd–C(5) = 91.98.
An ORTEP plot for palladacycle 6 is shown in Figure 7. The those of Pd–N(3), Pd–C(5), Pd–O(2) bonds, likely due to a trans
molecular structure consists of a Pd atom with an arylurea and effect of the strong σ-donor aryl group as has been observed in
two molecules of acetonitrile assembled in a square-planar ge- a related urea palladacycle [73,215]. The bond length of Pd–N
ometry around the metal. The sum of the angles around Pd is is 1.96 Å in [Pd(MeCN)4](BF4)2.
360.01°. The C(5)–Pd–O(2) angle (91.98°) is slightly larger
than that of N(3)–Pd–N(4) (87.81°), but it is similar to the NMR spectroscopic studies on the reaction between a cationic
angles of neutral PdCl2(Ph2PCH2CH2CH2PPh2)(dppp)) (angle Pd(II) complex and an arylurea to generate a palladacycle are
of P–Pd–P: 90.58°) having a six-membered ring conformation illustrated in Figure 8. The pure palladacycle from pre-formed
[217], and palladacycles reported previously [73,206,215]. The cationic palladium [Pd(MeCN)4](BF4)2 is shown as spectrum in
length of the Pd–N4 bond, (2.126 Å), is slightly longer than Figure 8A. Generally, monocationic arylpalladium(II) com-
Scheme 9: Palladacycle formation.
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Figure 8: NMR studies. A: The reaction of [Pd(MeCN)4](BF4)2 and 3-MeOC6H4NHCONMe2 in acetone-d6. B: The reaction of Pd(OAc)2 and
3-MeOC6H4NHCONMe2 in the presence of HBF4 and MeCN in acetone-d6. C: The reaction of Pd(OAc)2 and 3-MeOC6H4NHCONMe2 in the pres-
ence of MeCN in acetone-d6. D: 3-MeOC6H4NHCONMe2 in acetone-d6.
plexes without strongly coordinating ligands are unstable even
at low temperatures [218-220]; nonetheless, this cationic
palladacycle, aided by the presence of strongly coordinating
MeCN, was found to be quite stable at room temperature. While
Scheme 10: The generation of cationic Pd(II) from Pd(OAc)2.
the in situ generated cationic palladium species from the reac-
tion of Pd(OAc)2 and HBF4 gave the same palladacycle upon
treatment with the arylurea (spectrum Figure 8B), the reaction the concerted metalation-deprotection (CMD) or electrophilic
in the absence of HBF4 did not result in palladacycle formation palladation pathways (Scheme 1) [221-224]. Although control
(spectrum Figure 8C). Here, essentially no conversion of the experiments had previously indicated the importance of condi-
starting material was detected by 1H NMR in acetone-d6 (spec- tions involving cationic palladium for achieving overall reac-
trum Figure 8D). Indeed, for reactions starting from Pd(OAc)2, tion conversion, our studies of palladacycle formation suggest
no cross-coupling product was observed without adding a BF4− that a cationic palladium catalyst is specifically required for the
source for the Fujiwara–Moritani reaction (Figure 5, run 9), initial C–H activation step itself. Since the crystal structure of 6
Suzuki–Miyaura coupling (Scheme 4), and arylation with aryl (Figure 7) is indicative of a monocationic palladacycle, the
iodide [121,122,150]. HBF4 apparently acts as an acetate scav- cationicity of the metal may still play a role as well in subse-
enger to generate the active cationic palladium(II) species quent steps. However, the much higher reactivity of a cationic
(Scheme 10).
Pd species (even under acetate-free conditions), the lack of
effectiveness of Pd(OAc)2 alone in palladacycle formation,
and the observed reactivity trends that strongly favor more elec-
tron-rich arylureas, all appear to be most consistent with an
As discussed previously herein, there are several routes avail-
able for cyclopalladation and C–H bond cleavage, most notably
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electrophilic palladation pathway over a CMD mechanism acids, and aryl iodides appeared to be significantly suppressed
(Scheme 11). However, it is appreciated that further study by the presence of stoichiometric MeCN. The inhibitory effect
might provide additional insight on this point.
of this ligand had been previously observed in the coupling
reactions of aryl iodides (in which even 40 mol % of MeCN
was enough to almost completely shut down the reaction) [121].
In a cationic palladium(II) complex-catalyzed 1,4-addition of
Reactions of palladacycle 6 with Ph–I,
PhB(OH)2, and an acrylate
Having demonstrated the potential for facile palladacycle for- arylsilane, the nitrile-free cationic Pd(II) catalyst was much
mation at room temperature, we next examined the reactivity of more effective than a PhCN-containing cationic palladium(II)
this intermediate with coupling partners for each of the three complex towards transmetallations with arylsilicon-containing
reaction types studied. Stoichiometric reactions between the iso- partners and insertion of mono-cationic arylpalladium(II)
lated palladacycle 6 and an acrylate or arylboronic acid were species into olefins [136]. The detrimental effect of MeCN
first attempted at room temperature (Scheme 12). Initial experi- under our C–H activation conditions was further established
ments, however, resulted in no formation of the desired prod- through a series of reactions as illustrated in Scheme 13. Under
ucts. Although the palladacycles were subjected to various optimized conditions previously determined, where C–H func-
conditions in the presence of BQ and HBF4, the anticipated tionalized products were obtained in good yields, in the pres-
reaction did not proceed from isolated catalyst complexes con- ence of added MeCN (1 equiv relative to 1f) all three reactions
taining the stabilizing ligand MeCN.
were completely inhibited, in all likelihood due to its strong
coordinating ability as a ligand on cationic palladium.
Although the initial C–H activation step proceeded readily in
the presence of MeCN in these stoichiometric reactions, subse- On the other hand, when nitrile-free conditions were applied to
quent reactions of the palladacycle with acrylates, arylboronic urea 1f, with in situ-generated palladacycle (from Pd(OAc)2 and
Scheme 11: Electrophilic substitution of aromatic hydrogen by cationic palladium(II) species.
Scheme 12: Attempted reactions of palladacycle 6.
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
Scheme 13: The impact of MeCN on C-H activation/coupling reactions.
HBF4; Figure 8), followed by addition of the usual reagents, the presence of base in THF under reflux conditions to produce
each reaction proceeded to give the anticipated acrylated/ the corresponding coupling product, our cationic palladacycle
arylated product (Scheme 14; unoptimized yields). Notably, all underwent coupling without added base (Scheme 15) [178]. In
three stoichiometric reactions now proceeded in the absence of fact, it has been previously shown that cationic palladium
other additives, such as BQ or Ag(I) salts, which are required species can undergo transmetalation with an arylboronic acid in
for the catalytic versions to proceed efficiently.
the absence of base even at 0 °C [219,220]. Wu and co-workers
have also reported the interesting reactivities of neutral pallada-
cycles with arylboronic acids (Scheme 15). Under their condi-
tions, BQ and high temperature were critical to obtain the prod-
Although Lloyd-Jones and Booker-Milburn also reported the
reaction of a urea-derived palladacycle and arylboronic acid in
Scheme 14: Stoichiometric MeCN-free reactions. a2% Brij 35 was used instead of EtOAc.
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
proceed under stoichiometric palladium conditions in the
absence of additives, such as BQ and AgOAc, which had been
necessary in the corresponding optimized catalytic reactions. To
establish the roles of these additives, the reaction of the
palladacycle in the presence of excesses of both coupling part-
ners was carried out (Scheme 16). In Fujiwara–Moritani and
Suzuki–Miyaura coupling reactions, 41 and 39% of the prod-
ucts (isolated yields based on the palladacycle) were obtained,
respectively, in the absence of BQ, indicating that no catalyst
turnover was occurring without this additive. When 20 equiva-
lents of BQ were added, along with the coupling partners, how-
ever, 847% (TON = 8.5) and 467% (TON = 4.7) yields of
the products were obtained, respectively, supporting a key role
for BQ in regeneration of the active dicationic species
(PdL4(BF4)2).
Benzoquinone (BQ) has been well studied as an oxidant for
Pd(0) to Pd(II) processes, generating hydroquinone as a byprod-
uct. For the Fujiwara–Moritani coupling, addition of the
Scheme 15: The reactions of divalent palladacycles.
uct from their 5-membered isoxazoline-containing palladacycle palladacycle 6 to an acrylate followed by β-hydride elimination
[160,168,225]. Although BQ is sometimes used as a ligand for and reductive elimination of HPd+BF4− would result in a Pd(0)
palladium to accelerate reductive elimination [103,226-230], its species unable to participate in palladacycle formation until it is
presence was not necessary in our stoichiometric reaction of a oxidized by BQ to Pd2+(BF4)2, whereupon it reacts with
cationic 6-membered ring palladacycle.
another equivalent of arylurea (Scheme 17) [231]. Similarly,
BQ’s role in C–H coupling of boronic acids would likely be to
oxidize Pd(0) to Pd(II) after the product forming step
(Scheme 18). Transmetallation between the palladacycle and
Regeneration of active catalyst; the roles of
additives BQ, AgOAc, and HBF4
As shown in previous sections herein, both the formation of arylboronic acid followed by reductive elimination would give
palladacycles from arylureas and their subsequent coupling the expected product and Pd(0), where the metal can be subse-
reactions with acrylates, arylboronic acids, and aryl iodides quently oxidized with BQ.
Scheme 16: Role of BQ in stoichiometric Fujiwara–Moritani and Suzuki–Miyaura coupling reactions. aYields based on Pd.
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
Scheme 17: Proposed role of BQ in Fujiwara–Moritani reactions.
Scheme 18: Proposed role of BQ in Suzuki–Miyaura coupling reactions.
In the reaction with aryl iodides, when an excess of coupling the corresponding product in 342% yield relative to palladium
partner was employed, a yield of ca. 90% (TON = 0.9) of the (TON = 3.4) (Scheme 19).
product was obtained with or without additional HBF4
(Scheme 19), in this case indicating that no catalyst turnover
was occurring in the absence of a Ag(I) salt. Surprisingly, when
15 equivalents of AgOAc were added along with an excess of
both coupling partners, but without the addition of HBF4
beyond the three equivalents required for initial palladacycle
formation, no coupling product was observed. Under these
conditions, a large excess of acetate anion relative to BF4−
would exist, which may decrease the cationicity of the cationic
palladium(II) species formed in the initial cyclopalladation
(Scheme 20), or otherwise disrupt the reaction sequence subse-
quent to palladacycle formation. On the other hand, the reac-
tion in the presence of both silver salt and excess of HBF4 gave
Based on these results, the proposed roles of silver and acid are
shown in Scheme 21. After the coupling of the palladacycle and
aryl iodide, I–Pd+BF4− is generated, which is catalytically inac-
tive. Then, I–Pd+BF4− reacts with AgOAc and HBF4 to regen-
erate active cationic Pd2+(BF4−)2. Under this proposed se-
quence, AgOAc would primarily act, therefore, as an iodide
scavenger.
In our previous studies it was found that when AgBF4 was used
in place of AgOAc under optimized conditions for C–H aryl-
ation with aryl iodides, HBF4 (or any other added acid) was
unnecessary for the catalytic reaction to occur. Here, since
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
Scheme 19: Stoichiometric C–H arylation of iodobenzene. aYields based on Pd.
Scheme 20: Impact of acetate on the cationicity of Pd.
Scheme 21: Roles of additives in C–H arylation.
AgBF4 apparently reacts with I–Pd+BF4− to produce catalytical- Fujiwara–Moritani reactions. At the first stage of the catalyt-
ly active Pd2+(BF4)2− (Scheme 22), and there are no stoichio- ic cycle, an active divalent cationic palladium species is gener-
metric quantities of competing acetate anions, additional acid is ated from the reaction of a neutral complex, Pd(OAc)2, and
not needed to produce and maintain active catalyst.
HBF4 [232]. This reaction results in the formation of a monoca-
tionic arylpalladium(II) palladacycle, likely via a Wheland-like
intermediate (Scheme 23) [233-237]. The product-forming
Proposed mechanisms
Our results have demonstrated that a dicationic palladium com- portion of the cycle may proceed in a manner resembling a
plex effectively catalyzes C–H activation of arylureas at room traditional Heck cross-coupling. In this case, addition of the
temperature. Based on these studies of the major steps for each palladacycle to an acrylate followed by β-hydride elimination
reaction, proposed catalytic cycles are illustrated below.
yields the corresponding product 5. As previously demon-
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
Scheme 22: Cross-coupling in the presence of AgBF4.
Scheme 23: A proposed catalytic cycle for Fujiwara–Moritani reactions.
strated in palladium-catalyzed Mizoroki–Heck reactions [238- process. The reaction also presumably starts from the genera-
240], insertion of a alkenyl double bond into C–Pd+ present tion of a cationic palladacycle, which may undergo a facile
within the cationic palladacyle is facile, owing to the high transmetalation with an arylboronic acid without prior activa-
Lewis acidity of the metal center. This is a noteworthy advan- tion by base (Scheme 24) [241-248]. This step is followed by
tage associated with the use of cationic palladium(II) catalysts. reductive elimination of a diarylpalladium(II) species, affording
Finally, BQ oxidizes the Pd(0) that is reductively eliminated the coupling product and Pd(0). The resulting Pd(0) is then
from the HPd(II)+BF4− formed to regenerate the active cationic oxidized with BQ to regenerate the dicationic palladium
palladium species Pd2+(BF4)2−.
species, which can re-enter the catalytic cycle.
C–H boronic acid coupling reactions. Unlike traditional Arylation with an aryl iodide. Coupling reactions of aryl
Suzuki–Miyaura coupling reactions [241-243], C–H coupling iodides have fewer similarities in terms of traditional cross-cou-
reactions catalyzed by a cationic palladium(II) complex require pling reactions compared with features characteristic of other
an oxidant instead of a strong base, but otherwise likely share a room temperature C–H activations we have studied, and are
number of features with this widely used C–C bond-forming more difficult to rationalize with a Pd(II)/Pd(0) catalytic cycle.
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
Scheme 24: Proposed catalytic cycle of C–H activation/Suzuki–Miyaura coupling reactions.
Hence, a possible Pd(II)/Pd(IV) catalytic cycle, similar to that inate in the C–C bond forming step. The resulting I–Pd(II)–X
previously proposed by Daugulis [8], is proposed below species could then be converted back to the active cationic
(Scheme 25). A mono-cationic palladium intermediate reacts palladium species through reactions with the silver salt and
with the aryl iodide, albeit in a poorly understood step of the se- HBF4 (or in situ generated AgBF4).
quence. Stoichiometric studies reveal that this step occurs in the
absence of AgOAc, and in fact its presence in excess relative to The specific nature of the reaction between the palladacycle and
HBF4 inhibits the reaction (Scheme 19). In one possible path- aryl iodide and resulting intermediate is lacking in details. It is
way, an oxidative addition to the aryl iodide would provide a known that divalent palladacycles react with alkyl iodides or
Pd(IV) intermediate, which could then rapidly reductively elim- diaryliodonium salts, and this process likely involves a Pd(IV)
Scheme 25: A proposed catalytic cycle for C–H arylation involving a Pd(IV) intermediate.
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
intermediate. Tremont and co-workers previously proposed a
Pd(IV) intermediate in C–H alkylation of acetoanilides and
alkyl iodides [172]. In this case the reaction of a divalent
palladacycle and MeI readily occurred at room temperature and
was shown not to proceed through a radical pathway. Notably,
in 2011 Vicente and co-workers obtained the crystal structure of
a Pd(IV) complex obtained by the room temperature oxidative
addition of an internally-chelated Pd(II) species into an aryl
iodide, and demonstrated this species’ competence as a pre-
catalyst for C–H olefinations. Liu [73] and Sanford reported the
stoichiometric reaction of palladacycles and aryliodonium salts
at high temperature to give the corresponding products through
Pd(II)/Pd(IV) or Pd(III)/Pd(III) dimeric species bridged by
acetates (Scheme 26) [68,175,249,250]. Sequences involving
Pd(III) intermediates have been suggested as alternatives to
Pd(II)/Pd(IV) cycles in some cases, but most well-studied ex-
amples involve Pd(III)/Pd(III) dimers formed with the aid of
bridging anionic ligands such as acetate or nitrate [251,252] that
do not match as well with the cationic palladium conditions em-
ployed here. Silver-mediated one electron oxidations to form
monomeric Pd(III) complexes have also been studied [251], but
the successful implementation of silver-free conditions with
stoichiometric palladium herein would appear to eliminate this
as a key step. To the best of our knowledge, the existence of
Pd(IV) complexes has yet to be conclusively demonstrated from
Scheme 26: Selected reactions of divalent palladacycles.
the oxidative addition of anilide-derived, divalent palladacycles insight into the roles of additives HBF4, BQ, and AgOAc, as
into aryl halides, although formation of octahedral Pd(IV) com- well as the crucial steps of each reaction’s catalytic cycle.
plexes from N-substituted biphenyl palladacycles that possess Lastly, this study highlights the advantages of dicationic palla-
similar highly planar structures as found in the urea-derived dium complexes in synthesis, and their tolerance to aqueous
palladacycle (Figure 7) have been well studied [253-255].
media. Such cationic reagent/medium combinations, potentially
applicable to other group 10 metals, and Ni in particular, may
well offer related synthetic opportunities.
Conclusion
In conclusion, we have demonstrated that a dicationic palla-
dium complex enables facile C–H activation reactions of
arylureas with aryl iodides, arylboronic acids, and acrylates at
room temperature. In many cases nanomicelles in water can be
used in place of organic solvents, allowing for some of the
mildest and environmentally responsible conditions yet
achieved in C–H activation chemistry. The practical value of
this approach has been further demonstrated with an efficient,
streamlined application to the synthesis of the herbicide
boscalid. Mechanistic investigations revealed that a dicationic
Pd(II) complex reacts readily with an arylurea to rapidly
produce a mono-cationic palladacycle at room temperature, and
this likely, catalytically competent species has been character-
ized by X-ray crystallography. Experiments revealed that a
highly cationic palladium complex is required for the formation
of this palladacycle at room temperature. While some key steps,
including the precise nature of the reaction between this
cationic palladacycle and aryl iodides, require further clarifica-
tion, studies using stoichiometric palladium have provided
Supporting Information
Supporting Information File 1
Experimental procedures and characterization of all new
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-99-S1.pdf]
Supporting Information File 2
Crystal structure of 6.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-99-S2.cif]
Supporting Information File 3
Crystal structure of 6 No 2.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-99-S3.pdf]
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Beilstein J. Org. Chem. 2016, 12, 1040–1064.
26. Thuy-Boun, P. S.; Villa, G.; Dang, D.; Richardson, P.; Su, S.; Yu, J.-Q.
J. Am. Chem. Soc. 2013, 135, 17508–17513. doi:10.1021/ja409014v
27. Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 5332–5333. doi:10.1021/ja070388z
Acknowledgements
We warmly thank the NIH for support of this work (GM
86485), and Johnson Matthey (Dr. Thomas Colacot) for
supplying the Pd(OAc)2 used in this work.
28. Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 3202–3203. doi:10.1021/ja017351d
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232.Some previous C–H activation reactions catalyzed by Pd(OAc)2
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