Palladium-Catalyzed meta-C-H Allylation of Arenes: A Unique Combination of a Pyrimidine-Based Template and Hexafluoroisopropanol

Article abstract of DOI:10.1021/jacs.0c05223

Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important endeavor in contemporary organic synthesis. In this vein, template engineering and mechanistic understanding of new functionalization strategies are essential for enhancing the scope of such methods. Herein, meta-C-H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a critical solvent in this transformation. The role of HFIP throughout the catalytic cycle has been systematically studied. A broad substrate scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid, and 2-phenylbenzoic acid derivatives has been demonstrated. Interestingly, conformationally flexible arenes have also been selectively allylated at the meta-position using allyl phosphate. A combination of 1H NMR, 31P NMR, ESI-MS, kinetic experiments, and density functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta-C-H activation, allyl addition forming a Pd-?-allyl complex which is then followed by a turnover determining the C-C bond formation step leading to the meta-allylated product.

Full text of DOI:10.1021/jacs.0c05223

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Article
Palladium-catalyzed meta-C–H allylation of arenes: A unique
combination of pyrimidine-based template and hexafluoroisopropanol
Sukdev Bag, Surya K, Arup Mondal, Ramasamy Jayarajan, Uttam
Dutta, Sandip Porey, Raghavan B. Sunoj, and Debabrata Maiti
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05223 • Publication Date (Web): 04 Jun 2020
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nation of pyrimidine-based template and hexafluoroisopropanol
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Sukdev Bag, Surya K, Arup Mondal, Ramasamy Jayarajan, Uttam Dutta, Sandip Porey, Raghavan B. Sunoj,* and Debabrata
Maiti*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
ABSTRACT: Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important en-
deavor in contemporary organic synthesis. In this vein, template engineering and mechanistic understanding of new functionalization
strategies are essential for enhancing the scope of such methods. Herein, meta-C–H allylation of arenes has been achieved with the
aid of palladium catalyst, pyrimidine-based auxiliary and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a
critical solvent in this transformation. The role of HFIP throughout catalytic cycle has been systematically studied. A broad substrate
scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid and 2-phe-
nylbenzoic acid derivatives have been demonstrated. Interestingly, conformationally flexible arenes have also been selectively al-
1
31
lylated at meta-position using allyl phosphate. A combination of H NMR, P NMR, ESI-MS, kinetic experiments, and density
functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta-C–H activation, allyl addition
forming a Pd--allyl complex which is then followed by a turn-over determining C–C bond formation step leading to the meta-
allylated product.
INTRODUCTION
Allylation can be considered as one of the most important or-
ganic transformations owing to the prevalence of the allyl group
in drug molecules and their ease of transformation to other func-
1
tional groups. Various methods for allylation have been formu-
lated to address the ever-increasing demands from the synthetic
communities (Figure 1a). A classic example of ortho-allylation
2
is Claisen rearrangement of allylphenol ether. In the case of or-
tho-substituted allyl phenol ethers, one can obtain para-allylic
2
c,3
phenol derivatives through Cope rearrangement.
Alterna-
tively, the more straight forward Friedel−Crafts allylation has
4
been achieved using Lewis acids. However, these methods are
limited to electronically-biased arenes, and often produce a mix-
ture of regioisomers and/or over-allylated products. In this re-
gard, Tsuji-Trost allylation has been considered as the most ver-
satile allylation reaction where nucleophilic coupling partners
5
have been utilized considering soft/hard nature. To address the
selectivity issues, an array of practical directing groups (DGs)
has been developed to achieve proximal ortho-C–H allylation
6
of arenes using transition metal catalysts. However, terminal
meta-C–H allylation of arenes has not been realized, despite an
adequate number of reports on directed and non-directed allyla-
tion.
While an innate functional group and/or an installed DG allows
7
transition metal to access the immediate aryl C–H bond, distal
C–H bonds that are geometrically farther from the DG are chal-
lenging to functionalize in a selective manner making them ra-
8
ther inaccessible. In this endeavor, nitrile-based template has
been modulated to achieve the first meta-selective functionali-
9
zation by Yu and coworkers. Our group has reported the para-
Figure 1. (a) Classical allylation reactions. (b) Prior reports. (c)
The present work; Formation of major allylated product by pro-
posed transition state. (d) Pyrimidine DG.
10
C–H functionalization of arenes. Distance and geometry play
major roles in remote selectivity. Additionally, if there is regio-
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switchable coupling partner, it adds further to the difficulties
ment in the yield was observed when sodium triflate was in-
1
1
with the existing issues. Taking cognizance of the increasing
demands for the design of newer templates and tunable DGs, we
became interested in developing a valuable meta-allyation pro-
cluded as an additive. Increase of the allyl phosphate amount,
reaction time along with lowering the temperature to 90 °C led
to the best optimized yield for 7a (71%; m:others, 15:1). The
desired allylation product was isolated with 68% yield as the
non-separable mixture of meta:others ratio of 15:1 and 21% of
starting material was recovered.
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tocol for various arenes (Figure 1b and 1c). In our previous
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d
report on olefination with activated olefins, we have observed
allylation product formation with cyclic activated olefins. With
cyclic olefins, 1,2-migratory insertion of palladium followed by

-hydride elimination from less hindered secondary carbon cen-
Table 1. Discovering effective allylating reagent, optimiza-
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13
ter delivers the allylation products. Such a reaction is mechanis-
tically distinct compare to the present study and it is only appli-
cable for cyclic olefins. Most importantly, linear acyclic allyla-
tion product formation is not feasible.
tion of reaction conditions and study with different DG
RESULTS AND DISCUSSION
Reaction and template optimization. Although the nitrile-
based template has shown a new direction in distal C–H func-
tionalization, reactions are limited due to weak coordinating
ability of nitrile group. Subsequently, we aimed to explore het-
erocycle-containing DGs which can hold metal strongly and
would deliver the desired functionality selectively at meta- po-
sition. Notably, our recently developed pyrimidine-based DG
was found to be the most effective so far for a variety of func-
9f
tionalizations at meta- position. Therefore, our investigations
for the desired meta-allylation started with pyrimidine-based
scaffold 1 and allyl alcohol in the presence of Lewis acids (Ta-
ble 1). Unfortunately, initial attempts did not deliver any allyla-
tion product. Subsequently, we have varied different allylating
reagents such as allyl chloride/bromide, carbonate, pivalate,
1
3
etc. Detailed studies revealed a trace amount of allylation
product by using allyl acetate and tosylate. Subsequently, allyl
phosphate has yielded promising meta-allylation in the presence
of palladium(II) acetate and mono-protected amino acid
(MPAA) ligand. Upon studying several MPAAs, N-Ac-Gly-OH
and N-Form-Gly-OH were found to be the effective ligands (Ta-
ble 1, entries 1 and 2); out of these two, N-Ac-Gly-OH proved
to be superior (see Supporting Information). As solvent plays a
very important role in distal C–H functionalization, we then fo-
cused on solvent optimization. Polar protic solvents such as
1
,1,1,3,3,3-hexafluoroisopropanol (HFIP) and 2,2,2-trifluoro-
ethanol (TFE) showed effectiveness towards meta-C–H allyla-
tion whereas 1,2-dichloroethane (DCE) slowed down the reac-
tion. The combination of DCE and HFIP enhanced the reactivity
as well as selectivity (entry 5). The high solubility of polar apro-
tic solvent DCE might be influencing the product formation (en-
try 4). No desired product was detected when tetrahydrofuran
(
THF) was used as a solvent (entry 6). The coordinating ability
of acetonitrile with palladium might be the reason for a notice-
able product formation albeit less yield compared to HFIP (en-
try 7). From all of these results we anticipated that HFIP is play-
ing a critical role as hydrogen-bonding (H-bonding) donor. This
polar solvent is likely to have another role as well such as stabi-
lization of the ionic intermediates. In this article, we have sys-
tematically studied the importance of HFIP throughout the cat-
alytic cycle (vide infra). Use of silver(I) acetate (AgOAc) in-
Next, we systematically tested various templates to improve the
yield and meta-selectivity. The nitrile-based scaffold 2 has
failed to deliver the desired allylation product (Table 1). The
prospect of weak coordination and unpredictable binding mode
of nitrile has led us to further explore various substitutions on
2 3
stead of silver(I) carbonate (Ag CO ) improved the yield re-
markably. We assumed that either acetate-bridge between pal-
ladium-and-silver or exchangeable counter anions (i.e., acetate
ion from AgOAc and phosphate ion from allyl phosphate) is re-
sponsible for this observation (vide infra). A slight improve-
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Scheme 1. Scope with phenethyl alcohol derivatives13
the heterocycles.9f,14 The unsubstituted pyridine 3 and isoquino-
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line-based 6 delivered the allylation product in moderate yields.
Electron-poor fluorine-substitution over pyridine moiety 5 af-
forded better yield as compared to the electron-rich methyl-sub-
stituted pyridine 4. However, pyrimidine-based 1 was found to
9
f,15
be the most suitable choice.
Scope of meta-C–H allylation. Having learned the optimized
reaction conditions using pyrimidine-based template, we ex-
plored the scope of allylation with differently substituted allyl
coupling partners (Scheme 1). Simple allyl and -methyl allyl
phosphate have produced exclusive meta-allylation in 68% (7a)
and 71% (7b) isolated yields, respectively. The - methyl (7c),
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
-ethyl (7d), -propyl (7e) and -pentyl (7f) substituted allyl
phosphates provided good yield and excellent meta-selective al-
lylation with promising linear/branched ratios. In case of entries
7e and 7e’, we used terminal (primary) allyl phosphate and in-
ternal (secondary) allyl phosphate, respectively. But we ob-
served the linear allylation as the major product (L:B, 10:1 for
both cases). These observations suggest: (1) The product was
formed through a common reversible  - isomerized allyl-
Pd()-complex and (2) the linear:branched ratio was most likely
governed by steric hindrance between appended n-propyl chain
1
3
1
3
in allyl moiety and palladium coordination sphere.
Subsequently, various aryl coupling partners have been evalu-
ated under the optimized reaction conditions (Scheme 1). Or-
tho-substituted electron-rich arenes (7h and 7i) preferentially
delivered allylation at sterically less hindered meta-position
with good yield and excellent selectivity. Interestingly, exclu-
sive meta-allylation product has been obtained for 7j and 7k.
Moreover, sterically encumbered para-substituted arenes also
provided selective meta-allylation product (7m) with syntheti-
cally useful yield. We decided to fine-tune the linker length be-
tween the DG and the target arene. To validate the efficacy of
pyrimidine-based DG, the chain-length has been gradually elon-
gated from two to three, four and five-methylene-bridge with
appended arene substrate. Intriguingly, good yield and high
meta-selectivity have been observed even with five-carbon
ether-linked substrates (7o-7t). Phenols are electronically-bi-
ased for ortho- and para-directed functionalization. To over-
come this limitation, the template-backbone has been tuned with
two ether linkages appended to the pyrimidine DG. Ortho-tert-
butyl-substituted phenol (7u) provided 57% yield with major
meta-selective allylation products. The current protocol can be
expanded to include versatile starting precursors for the synthe-
sis of natural products such as eugenol derivative (7v) with pre-
parative yield and promising meta-selectivity. Although we
have observed a satisfactory result with chloro-substituted aryl
scaffold (7l), meta-bromo-substituted phenethyl ether provided
a much lower yield (<10%) whereas iodo-substituted arene did
not provide the desired product. Such reactivity can be ex-
plained as palladium might react with aryl halides such as ArBr,
ArI, etc. The ether linkage of product 7a was cleaved using ceric
ammonium nitrate (CAN) to obtain meta-allylated phenethyl al-
1
6
cohol (7a ).
1
Sulfonyl-ester-linked benzyl (9a-9c), phenethyl (9d-9h) and
phenpropyl substrate (9i) have been examined with allyl and
substituted allyl coupling partners, which also provided meta-
selective allylation products with promising yield (Scheme 2).
Various natural products and drug molecules contain phenyla-
cetic acid core structure. Substituted phenylacetic acids have
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Scheme 2. Scope with sulfonyl and carbonyl ester-based scaffolds and removal of DG13
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been evaluated under the optimized conditions and provided se-
lective meta-allylation products (11a-11c). For ester scaffolds,
we excluded the additive because of slight deviation of the ex-
pected yield which is due to DG cleavage. Furthermore, hydro-
cinnamic acid derivatives (11d-11f) also provided meta-allyla-
tion product in good yield and excellent selectivity (Scheme 2).
Distal selective C–H bond functionalization of complex molec-
ular structure is one of the important goals in this approach. 2-
Phenyl benzoic acid substrate has been taken to fulfill the prac-
ticability of pyrimidine-based template and the standard reac-
tion provided moderate to good yield and excellent selectivity
with differently substituted allyl coupling partners (11g-11i).
Removal of the DG was demonstrated using basic hydrolysis
conditions with selected examples of products. Meta-allylation
critical role in the C–H bond activation step as compared to the
17, 18
other steps in the case of pyrimidine-DG.
To validate this,
1
systematic H NMR experiments were carried out as summa-
rized in Figure 2. Successive introduction of the catalyst, HFIP,
and mono-protected amino acid ligand N-Ac-Gly-OH was per-
3
formed to the substrate dissolved in CDCl and the spectrum
was recorded after each such addition. We have observed a
change in the overall splitting pattern of the substrate 3-methyl
phenethyl ether after the addition of palladium(II) acetate (Fig-
13
ure 2b). This observation suggests the formation of a sub-
strate-palladium coordination complex. However, we could not
observe any pronounced splitting pattern for C–H activation in
the target aromatic region (highlighted in blue-dotted box). In
the above-mentioned mixture, we added silver(I) acetate (Fig-
ure 2c) to detect possible palladium-silver bimetallic cluster me-
diated C–H activation intermediate. Although clear assign-
ment of meta-carbopalladated intermediate was not feasible, the
overall changes in NMR spectra and the rise of three singlet pat-
terns along with other multiplets indicate the involvement of sil-
ver salt in the CH activation to some extent. These observa-
tions suggest that silver acetate is likely to be involved in the
carbopalladation step of the reaction. Interestingly, in the
products of phenylmethanesulfonic acid (9a
acid (11a ) were obtained in synthetically useful yield (82% and
1%, respectively) under different basic conditions (Scheme 2).
Versatility of the sulfonyl ester moiety has been further pre-
1
) and phenylacetic
9
b
1
9
sented by converting to styrenyl product (9a ) via Julia-type ole-
2
fination.
Mechanistic studies. Based on our experimental observations,
we hypothesize that solvent HFIP might exert a relatively more
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Figure 2. Meta-C–H bond activation followed by carbopalladation. (a) H NMR of substrate, (b) mixture of substrate and palladium
acetate, (c) mixture of substrate, palladium acetate and silver acetate, (d) after addition of N-Ac-Gly-OH and HFIP in the mixture of
substrate and palladium acetate, (e) after addition of N-Ac-Gly-OH and HFIP in c.
1
Figure 3. H-bonding with substrate-palladium intermediate. (a) H NMR of substrate, (b) HFIP, (c) mixture of substrate and palladium
acetate, (d) after addition of HFIP in the mixture of substrate and palladium acetate, (e) after addition of N-Ac-Gly-OH and HFIP in
the mixture of substrate and palladium acetate.
presence of N-Ac-Gly-OH and HFIP, three clear singlets are
visible in the target aromatic region (Figure 2d) that suggests
the formation of carbopalladation intermediate which might
have followed a concerted-metallation deprotonation (CMD)
is an indication of three singlets, AgOAc is likely playing less
crucial role in the C–H activation step as Pd(OAc) and N-Ac-
2
Gly-OH can do the same job.
The role of HFIP all through the catalytic cycle appears to be
substantial. Detail analysis suggests the presence of H-bonding
interactions at the DG site as well as with the metal center and
19
mechanism to abstract proton. Furthermore, we have per-
1
formed H NMR study in the presence of palladium(II) acetate,
silver(I) acetate and N-Ac-Gly-OH (Figure 2e). Although there
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Figure 4. H-bonding between substrate and HFIP. (a) H NMR of substrate, (b) HFIP, (c) after addition of HFIP into the solution of
substrate in CDCl , (d) 1D NOE of c.
3
ligand (Figure 3).13,17 and 18 Change in H NMR pattern in the py-
rimidine region (blue shaded box) and shifting of the OH peak
of HFIP are strong indications of this aspect. Due to the extra
electron-withdrawing nitrogen atom, pyrimidine can act as a σ-
donor as well as a better π-acceptor ligand that might assist the
coordination between palladium and oxygen atom of HFIP. Our
DFT studies suggested that binding of the substrate to Pd
through one of the pyrimidine nitrogen atoms is energetically
more preferred for the formation of catalyst-substrate complex
1
1
A (shown in Figure 11). Certain interesting features of the
ether-linked pyrimidine-based DG are worth noting at this junc-
ture. The pyridyl nitrogen as well as the ether oxygen can en-
gage in hydrogen bonding with the solvent HFIP. Consequently,
bulky HFIP might play a key role to allow the target meta-posi-
tion conformationally more populated towards directing moi-
ety. In this context, H-bonding of HFIP with phenethyl ether
scaffold has been demonstrated by H NMR and 1D NOE cor-
relation spectra (Figure 4). Upon irradiation, -OH peak of HFIP
showed a clear interaction with neighboring protons (Figure
1
Figure 5. ESI-MS of meta-carbopalladated macrocyclic inter-
mediate with N-Ac-Gly-OH ligand binding.
4
d). The bottom stacked spectra are zoom-in region of the
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
3
Figure 6. H NMR of reaction mixture recorded at various time intervals to detect the  -Pd--allyl intermediate and phosphate
1
3
release. Hydrogen-bonding and ionic charge are omitted due to clarity.
mentioned protons where N and O atoms are interacting with
lar solvent is likely to have another role as well such as stabili-
zation of cationic intermediates, or solubilizing the base, salt
and the intermediates. ESI-MS studies of the reaction mixture,
HFIP. The chemical shifts of protons H
a b c d e
, H , H , H and H of
the substrate are indeed shifted upon addition of HFIP. This po-
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in the absence of the allylating reagent, indeed indicated the for-
Role of different components on meta-allylation and kinetic
1
3
mation of a macrocyclic palladacycle as shown in Figure 5.
Identification of such an intermediate can be considered as an
evidence for a ligand assisted C–H activation in this example.
studies. To gain more insights into catalytic cycle, we have car-
ried out several spectroscopic and kinetic experiments. The ini-
tial rate of the reactions was determined by excluding different
reagents such as catalyst, ligand, silver salt or additive from the
standard condition. Desired allylation product was not detected
in the absence of palladium-catalyst. Expectedly, sluggish reac-
tivity was observed in the absence of N-Ac-Gly-OH (blue-col-
ored curve) as well as silver(I) acetate (greenish blue-colored
curve) whereas additive sodium triflate (red-colored curve) did
not show much impact on initial reaction rate and the overall
yield (Figure 8). Subsequently, kinetic studies were performed
to determine the order with respect to substrate, allyl phosphate
and palladium(II) acetate (Figures 9 and 10).
Subsequently, we focused on the allylation step more closely.
The conventional allylation mechanism is mainly based on ei-
ther metal insertion into olefin and subsequent elimination of
1
3
the leaving group or through  - isomerized intermediate, fol-
2
0,21
lowed by reductive elimination.
To determine the interme-
0
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9
0
diate in the meta-allylation reaction with allyl phosphate, we
1
have performed H NMR studies of the crude reaction mixture
(
Figure 6). NMR results indicate an initial coordination of allyl
phosphate with ligand-palladium complex and followed by ox-
1
idative addition of palladium into allyl phosphate to form an  -
3
From the initial slope calculations, a first order rate dependency
with respect to allyl phosphate and palladium acetate, and frac-
intermediate then rapid formation of  -intermediate (Figure 6,
bottom spectra). Broadening of the spectra is likely an indica-
1
3
1
3
tional order with respect to substrate were obtained. Observed
fractional order with respect to the substrate is likely due to the
formation of a palladium-substrate complex, which is in pre-
equilibrium with catalytically active palladium-substrate that
tion of a rapid  -to- isomerization via a - interaction in Pd-
2
1
-allyl complex (in Figure 6; A, B and B’). To confirm the
source of such broadening, we have compared the reaction mix-
ture spectra in the presence of allyl phosphate with; 1) palla-
dium acetate and N-Ac-Gly-OH and 2) palladium acetate, N-
Ac-Gly-OH and silver acetate (Figure 6, top spectra). During
delivers the product and another undesired palladium-substrate
20b,23
complex.
The computational studies are consistent with
1
1
3
carbon-carbon bond formation (i.e., P1) from (η -allyl)palla-
dium intermediate 6A as the overall rate determining step
rapid  -to- isomerization, the mixture contains chemically
different protons in allyl moieties of A, B and B’ (Figure 6).
1
3
Due to rapid  -to- isomerization, the switching in chemical
shift of all protons led to the broadening of spectra in the as-
21
signed region. Investigation to detect -allyl intermediate
commenced by assigning of the peaks which revealed that no
protons of the substrate and ligand N-Ac-Gly-OH are present in
the mentioned region (Figure 6f and 6g).
Although the outgoing phosphate is visible in the spectra, it is
rather difficult to ascertain whether the phosphate is bound to
45
40
3
1
the palladium or remains as a counter anion. P NMR of the
crude reaction mixtures reveals the interaction of phosphate
3
3
2
2
1
1
5
0
5
0
5
0
5
0
1
3,22
s tan d ard co n d itio n s
w ith o u t N aO T f
with palladium and silver (Figure 7).
w ith o u t N -A c-G ly-O H
w ith o u t A g O A c
0
50
1 00 1 50 20 0 25 0 30 0 350 40 0
tim e (m in )
Figure 8. Control experiments by varying different reagents.
6
5
4
0
0
0
Figure 7. 31P NMR of reaction mixture with and without of sil-
ver(I) acetate.
30
2
0
The formation of silver phosphate precipitate under the experi-
mental condition most likely arises through these mechanistic
steps. The next step is an allyl C–C bond formation between the
Pd-bound allyl and aryl groups that results in the final product
P1.
10
0
s u b stra te : allyl p h o s p h ate
s u b stra te : allyl p h o s p h ate
s u b stra te : allyl p h o s p h ate
=
=
=
1:3
2:3
1:2
0
1 00
20 0
30 0
40 0
5 00
6 00
tim e (m in )
Figure 9. Order determination with respect to substrate and al-
lyl phosphate.
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close to one and C–H activation step is no longer RDS. Even,
the C–H activation step is no longer RDS in case of nitrile-based
2
4c
template mediated meta-C–H olefination by Yu group. Our
recent report on meta-deuteration with pyrimidine-based scaf-
folds suggested that the C–H activation step can be reversible
1
5a
(see the Supporting Information).
5
4
3
2
1
0
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Computational Studies. To probe the effectiveness of the py-
rimidine-based directing group and the role of additives, we
have carried out detailed density functional theory computations
1
1
1
1
1
1
1
1
1
1
2
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2
2
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2
2
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3
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2
5
by using the B3LYP-D3 functional. For easier comprehen-
sion, the following sections are organized into generation of po-
tential active catalyst, discussion on the primary catalytic cycle
without the silver salt, role of solvent HFIP as well as the silver
salt.
1
1
0 mol% Pd(OAc) wrt substrate
2
5 mol% Pd(OAc) wrt substrate
2
First, we considered different ligand combinations around the
0
100
200
300
400
500
600
Pd center and have identified an important species A that could
2
6
time (min)
serve as the potential active catalyst (Figure 12). The active
species A consists of Pd(II) center with a chelated N-acetyl
glycinyl ligand, an acetic acid, and a HFIP as the other ligands.
Similarly, we have considered hydrogen bonding interaction of
solvent HFIP with the carbonyl oxygen of the N-acetyl glycinyl
2
Figure 10. Order determination with respect to Pd(OAc) .
27
ligand in all the intermediates and transition states.
The first step in the catalytic cycle A is the binding of substrate
1
to the Pd center through the pyrimidine-N by displacement of
a molecule of acetic acid to form catalyst-substrate complex 1A
28
of energy -4.1 kcal/mol. Expulsion of labile HFIP from the Pd
center in 1A can help in improving the proximity between the
aryl group of the substrate the Pd as shown in intermediate 2A.
Herein we harness the experimental evidences, such as NMR
detection of HFIP-bound intermediates such as 1A and 2A to
narrow down the mechanistic possibilities that are considered
for an in-depth computational study. The next step is a ligand-
assisted meta-CH bond activation via TS1A to form a pal-
4
0
29
ladacycle intermediate 3A. The ESI-MS studies of the reaction
mixture, in the absence of the allylating reagent, indeed indi-
cated the formation of a macrocyclic species as shown in Figure
30
20
5
(experimental part). Identification of 3A could be considered
9a
9a-d4
as an evidence for a ligand assisted CH activation in this ex-
ample. An alternative possibility with explicit inclusion of sil-
1
0
0
30
ver salt was found to be of higher energy. The next step in the
catalytic cycle involves the binding of substrate allyl phospho-
nate (R2) to 3A to form another intermediate 4A. The mode of
binding of R2 is found to involve a key hydrogen-bonding be-
tween the enol proton of the N-acetyl glycinyl ligand and the
phosphate oxygen. This mode of binding is energetically more
preferred over an alternative direct coordination of the phos-
0
50 100 150 200 250 300 350 400
time (min)
Figure 11. Kinetic isotope effect studies13
RDS). The found order rate dependency on substrate and
allyl phosphate indicates the CH activation step is unlikely
the rate-limiting step in overall reaction which was further
confirmed by the intermolecular kinetic studies with pro-
31
phate to the Pd center. The transfer of allyl moiety to the Pd
via TS2A can then provide an allyl-Pd(IV) intermediate (5A).
Incoming of silver acetate and the decoordination of the pyrim-
idine DG in 5A lead to the formation of 6A. In 6A, the acetate
from the silver acetate was found to remain hydrogen bonded
with the Pd-bound glycinyl ligand. The silver phosphate precip-
itate noted under the experimental condition most likely arises
through these mechanistic steps. The next step is the CC bond
formation between the Pd-bound allyl moiety and the Pd-aryl
group of the substrate via TS3A that leads to the final product
(
H D H D
tiated and deuterated-substrates (i.e., k /k = 1.22 and P /P
1.33) (Figure 11).
1
3,24
=
Often in case of distal C–H functionalization, C–H activation is
the rate determining step (RDS) as high energy is required to
form the large macrocyclic transition state. However, the cur-
rent kinetic isotope effect studies of allylation along with other
functionalization with pyrimidine-based directing group such as
32
P1. As a result of this reductive elimination, Pd(IV) in 6A goes
the native Pd(II) oxidation state. The decoordination of the
product P1 from the catalyst can then regenerate the active spe-
cies A.
2
4b
H D H D
meta-C–H cyanation revealed that k /k and P /P values are
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Figure 12. The mechanistic cycle for the Pd-catalyzed meta-allylation reaction without the explicit participation of silver salt.
The overall energetic features of this catalytic cycle can be un-
derstood by using the Gibbs free energy profile provided in Fig-
ure 13. It can be noticed that TS3A for the CC bond formation
with a relative Gibbs free energy of 27.0 kcal/mol is the highest
energy point on the profile. The application of the energetic
span model suggests that intermediate 1A and TS3A are respec-
tively the turn-over determining intermediate (TDI) and turn-
light on the role of HFIP (Figure 14). Among several possibili-
ties, we note that TS1A with four HFIP molecules, two on the
substrate and two on the Pd-N-acetyl glycinyl ligand, was ener-
3
4
getically the most favorable one. Interestingly, the NMR sig-
natures as shown in Figure 4 (experimental part), are in line with
the involvement of the HFIP-bound substrate. Hence, the ensu-
ing intermediates and transition states with HFIP binding were
considered in this study.
33
over determining transition state (TDTS). The energy differ-
ence of 31.1 kcal/mol between them is the energetic span (E)
In addition, a greater number of noncovalent interactions be-
tween the HFIP molecule with both the substrate and the cata-
lyst in the lower energy meta-CH activation transition state
for this catalytic cycle.
Next, we have examined the role of HFIP, first, by hypothesiz-
ing that the solvent HFIP might exert a critical role in the reac-
tion mechanism since maximum yield was observed when HFIP
is used as the solvent. Various possible meta-CH activation
transitions states, with and without explicit HFIP molecules
bound to the substrate and/or catalyst, were considered to shed
0
TS1A compared to similar transition states TS1A and TS1A
35
with no or lesser number of explicit HFIP molecules. These
interactions help in lowering the energies of all such HFIP-
bound stationary points. The lower yield for the reaction
1
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F
N
Pd
H
H
C
O
2.45
N
2.07
Pd
C
O
2.28
F
F
1
.25
.38
H
1
2.16
Pd
N
1
1
1
1
1
1
1
1
1
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2
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2
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3
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7
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9
0
1
2
3
4
5
6
7
8
9
0
O
C
Figure 13. Gibbs free energy profile for meta-allylation reaction catalyzed by active species A as obtained at the SMD(iso-
butanol)/B3LYP-D3/SDD(Pd),6-31G** level of theory. The relative Gibbs free energies (in kcal/mol) of intermediates and transition
states are with respect to active species A.
observed with other solvents could be due to less effective in-
teractions with such solvents other than HFIP. A comparison of
the energies of all stationary points with and without explicit
HFIP molecules indicates that the unique combination of tem-
plate, solvent and allylating reagent are important to the present
protocol. Thus, it can be concluded that the role of HFIP all
through the catalytic cycle appears to be substantial.
Another important question pertaining to the regio- and chemo-
selectivities are addressed at this stage. Different modes of or-
tho-, meta-, and para- CH activation transition states were
Figure 14. Qualitative representation of the meta-CH activation transition states with and without bound HFIP molecules. The
relative Gibbs free energies (in kcal/mol) of intermediates are respect to active species A and the separated reactants. The energies
are obtained at the SMD(iso-butanol)/B3LYP-D3/SDD(Pd),6-31G** level of theory.
1
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1
.31
2.15
Pd
1.38
1.38
1.25 H
O
1
.31 H
O
2.16
Pd
N
2
.16
N
1.25
H
O
Pd
F
C
C
C
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Figure 15. Optimized geometries and corresponding relative Gibbs free energies (in kcal/mol) for the ligand assisted ortho-, meta-,
and para- CH activation transition states, calculated with respect to the active species A and the separated reactants. The energies
are obtained at the SMD(iso-butanol)/B3LYP-D3/SDD(Pd),6-31G** level of theory.
located in order to develop more understanding about why the
catalyst. The silver salt additive has been found to play a key
role in the allylation step by facilitating the removal of phos-
phate from the allyl phosphate. The turn-over determining tran-
sition state was found to be the CC bond formation step that
leads to the product.
3
6
present reaction offers meta. The Gibbs free energies of ligand
assisted transition states for the ortho- and para- CH activation
were found to be respectively 18.4 and 2.4 kcal/mol higher than
that at the meta-position (Figure 15). The corresponding ele-
mentary step barriers with respect to the respective preceding
intermediates for ortho-, meta-, and para- CH activation tran-
sition states were found to be 23.4, 6.8 and 10.0 kcal/mol, re-
spectively. These energetic details are line with the experimen-
tally observed meta selective CH activation. The reaction also
yielded a branched minor product P2. This minor product is
formed by the CC bond formation between the more substi-
tuted allyl position and the aryl group via TS4A of energy 31.8
kcal/mol (Figure 16). The higher energy of TS4A compared to
TS3A explains the formation of branched product as the minor
product P2.
CONCLUSION
We have explored the meta-C–H allylation with the aid of py-
rimidine-based DG using various allyl phosphate as effective
allylating reagent. The broad substrate scope has been presented
with ether, sulfonyl and carbonyl ester linkages. Present proto-
col has been validated with long-chain ether-tethered substrates.
Synthesis of eugenol derivative by applying the current protocol
made this strategy attractive. The mechanistic studies showed
that the solvent HFIP, pyrimidine directing group on the sub-
strate and the amino acid ligand play important role. The pyrim-
idine directing group helps in better coordination of substrate to
palladium center. While HFIP lower the energy of transition
states and intermediates through its interactions with catalysts
and substrates, MPAA ligand N-Ac-Gly-OH helps in C–H acti-
vation. The turn-over determining transition state were found to
be the allyl C–C bond formation step that leads to the product.
H
F
C
ASSOCIATED CONTENT
N
Supporting Information. The supporting information includes ex-
perimental procedures, characterization data, and copies of NMR
spectra for all products; computed energy components, Cartesian
coordinates of all of the DFT-optimized structures is available free
of charge on the ACS publications website at http://pubs.acs.org.
2
.06
O
Pd
.70
2
2.42
AUTHOR INFORMATION
Corresponding Author
Figure 16. The optimized geometry of alternative transition
state that lead to the branched product P2 obtained at the
SMD(iso-butanol)/B3LYP-D3/SDD(Pd),6-31G** level of theory.
*
E-mail: dmaiti@chem.iitb.ac.in
*E-mail: sunoj@chem.iitb.ac.in
The mechanistic studies showed that the solvent HFIP, pyrimi-
dine directing group on the substrate and the N-acetyl glycinyl
ligand play important roles. The pyrimidine directing helps in
better coordination of the substrate to palladium center. Solvent
HFIP lowers the energy of transition states and intermediates in
the CH activation step through hydrogen bonding interactions
with the substrates as well as the N-acetyl glycinyl ligand of the
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This activity was supported by SERB, India (CRG/2018/003915).
Financial support from UGC (S.B. and S. K.) is gratefully acknowl-
edged.
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