Palladium/Norbornene-Catalyzed ortho Aliphatic Acylation with Mixed Anhydride: Selectivity and Reactivity

Article abstract of DOI:10.1021/acs.orglett.7b03514

A palladium/norbornene-catalyzed ortho acylation for the efficient synthesis of functionalized alkyl aryl ketones is reported. Studies on the electronic and steric properties of mixed aryl anhydrides indicated that the cross-coupling favored with the elec

Full text of DOI:10.1021/acs.orglett.7b03514

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium/Norbornene-Catalyzed ortho Aliphatic Acylation with
Mixed Anhydride: Selectivity and Reactivity
Shibo Xu,† Julong Jiang,† Linlin Ding, Yao Fu,* and Zhenhua Gu*
Department of Chemistry and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and
Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: A palladium/norbornene-catalyzed ortho acylation
for the efficient synthesis of functionalized alkyl aryl ketones is
reported. Studies on the electronic and steric properties of mixed
aryl anhydrides indicated that the cross-coupling favored with the
electron-enriched aryl acyl group. DFT calculation on the oxidative
addition of Pd(II) with 2,4,6-(Cl)3C6H2CO2C(O)Ph suggested
that 2,4,6-(Cl)3C6H2C(O)−O bond cleavage was more kinetically
disfavored than that of the PhC(O)−O bond by 11.7 kJ/mol.
etones are one of the most important functional groups in
organic chemistry and material science. They widely exist
Scheme 1. Pd/NBE-Catalyzed ortho Acylation
K
in bioactive natural products and pharmaceutical molecules,
such as methadone, raloxifene, and (−)-steganone1 (Figure 1).
Figure 1. Ketone-containing bioactive molecules.
Ketones are also fundamental building blocks in organic
synthesis, which could be diversely transformed into alkenes,
alcohols, amines, oximes, etc. For the synthesis of ketones, the
classic methods include Friedel−Crafts acylation, Weinreb
amide protocol, and the oxidation of secondary alcohols.
However, the use of excess Lewis/Brønsted acid, along with the
poor regioselectivity observed for the products, significantly
restricts the application of Friedel−Crafts acylation. Recently,
transition-metal-catalyzed ketone synthesis has caught growing
attention, as it provides alternative ways for the construction of
these compounds, and some typical contributors include
Yamamoto,2 Gooßen,3 Liebeskind and Srogl,4 Gong,5 and
Wu and Cui.6
Palladium/norbornene (NBE)-catalyzed ortho functionaliza-
tion of aryl halides, which includes alkylation, arylation,
amination, and chlorination, represents a powerful method
for the construction of polyfunctionalized aromatic compounds,
to which the most significant contributions are from the groups
of Catellani and Lautens.7−13 Recently, Liang, Dong, and our
groups independently developed a protocol for the ortho-
acylation of aryl halides.14 This method provided an efficient
way for regiospecific construction of aryl ketones under mild
conditions (Scheme 1a). However, there are remaining
challenges yet to be solved. First, the reaction worked well
with aromatic acyl chlorides or anhydrides, while poor yields
were obtained for aliphatic acid derivatives with 5 mol % of
palladium, particularly for α-nonbranched aliphatic acid
derivatives. Second, the synthesis of acid anhydride would
consume two molecules of carboxylic acid, in which one of
them was actually discarded as waste in the acylation reaction
(see Scheme 1a). Considering the difficulties encountered in
the multistep synthesis of these complex carboxylic acids, as
well as the atom efficiency, the call for an alternative strategy is
therefore urgent. The formation of ketenes from the facile
elimination of α-nonbranched aliphatic acyl chloride or
anhydride might account for the low yields of the
corresponding desired products. More recently, Dong and co-
workers introduced an alkoxycarbonyl group to various
Received: November 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03514
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Organic Letters
Letter
aromatic rings by selectively cleaving a C(O)O−C(O)OR
bond, where both steric and electronic properties of the mixed
anhydride are believed to play vital roles.15 Given the
importance of aryl alkyl ketones, herein we report our efforts
made for the introduction of aliphatic carbonyl groups to the
ortho position of aryl iodides, where mixed anhydrides from
2,4,6-trichlorobenzoyl chloride showed remarkable reactivity
and selectivity (Scheme 1b).
Our primary goal was to find a proper activation reagent that
could activate the aliphatic acid while the activation reagent
itself would not act as an acylation reagent (Scheme 2). The
Scheme 2. Electronic Effect
Figure 2. (a) Correlation between the reaction rate and the loading of
palladium catalyst. (b) Optimized charge distributions on TS1a and
TS1b.
Scheme 3. Energy Profile of the Pathway Leading to the
Major Product Prod1a
reaction with mixed anhydride from benzoic acid and 2,6-
dimethoxybenzoyl chloride gave a mixture of biaryl ketones 2
and 3a with a ratio of 1:6.6. It indicated that the reaction
favored coupling with the electron-enriched aryl acyl group. In
other words, the selectivity depended more on the electronic
property rather than steric effects. The reaction of p-
fluorobenzoyl chloride gave a 1:1 mixture of 2:3b, while the
one with 2-chlorobenzoyl chloride offered a 2:1 mixture
favoring the formation of the desired product 2. The use of
2,6-dichlorobenzoyl chloride or Yamaguchi reagent (2,4,6-
trichlorobenzoyl chloride) could further improve the selectivity
on the product 2. A complicated mixture was detected when 4-
nitrobenzoyl chloride was used.
To gain more insight into the selectivity, DFT calculations
were performed with the B3LYP hybrid functional,16 which was
corrected with empirical dispersion term (Grimme-D3).17
Kinetic experimental studies by using benzoic anhydride and
N-methyl-N-tosyl-4-iodo-3-methylaniline as the model com-
pounds found that the reaction rate had a first-order
dependence on the concentration of PdCl2 (Figure 2a) (see
Supporting Information for details). These results suggested
that the reaction preferred to proceed via a palladium monomer
species rather than a bimetallic pathway.18 Thus, our theoretical
study focused on the Pd(0)−Pd(II)−Pd(IV) process. It was
found that the Pd(IV) is more satisfied with the six-coordinate
pattern and adopts an octahedral geometry. Carboxylate acts as
a bidentate ligand to bind with the Pd(IV) atom in Int1a and
Int1b (Schemes 3 and 4), and the maps the ESP charge
distributions on the transition states were shown in Figure 2b.
This bidentate model might also account for our previous
observation that acid anhydrides showed a high reactivity while
acyl chlorides were inert under the identical conditions. The
intermediate Int4 is more stable than Int5 by 10.3 kJ/mol,
indicating Int4 is the thermodynamically controlled product.
Scheme 4. Energy Profile of the Pathway Leading to the Side
Product Prod1b
B
DOI: 10.1021/acs.orglett.7b03514
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Organic Letters
Letter
a
Shown in Schemes 3 and 4 are the detailed mechanism of the
oxidative addition and the subsequent reductive elimination.
Since all of the transition states along the pathways have been
successfully located, it is straightforward to figure out that the
oxidative addition is both the rate-determining step and the
selectivity-determining step. Compared to the oxidative
addition, the reductive elimination of Pd(IV) complexes are
more feasible. Moreover, inspection of the mapped free profile
suggests the C(acyl_EDG)−O bond cleavage is kinetically
preferred over that of the C(acyl_EWG)−O bond by 11.7 kJ/
mol, indicating a ratio of rate constant as 1:0.009.
Scheme 5. Substrate Scope
Efforts were also taken to offer a reasonable explanation for
why the Pd atom prefers to interact with the electron-rich C-X
bond in this case. Calculations using Merz−Kollmann scheme
were first conducted to map the ESP charge distributions for
these two Pd transition states TS1a and TS1b (Figure 2).
Interestingly, we found the Pd atom in TS1b is more positively
charged (i.e., + 0.528) than the one involved in TS1a (+0.008).
It seems from our calculation that the electron-withdrawing
group, when attached to the acyl rather than the carboxylic
group, can significantly further lower the electron density on
the Pd atom, making it even more positively charged.
a
The reactions were performed with 0.20 mmol of 1, carboxylic acid
(0.40 mmol, 2.0 equiv), 2,4,6-trichlorobenzoyl chloride (0.40 mmol,
2.0 equiv), Pd(TFP)2Cl2 (5 mol %), and Cs2CO3 (0.80 mmol, 4.0
Along with the ESP charge analysis, the distortion/
interaction analysis gave us some more details about the
selectivity (Figure 3). The distortion is much more severe for
b
equiv) in 1,4-dioxane (2.0 mL). Bicyclo[2.2.1]hept-5-ene-2-carbalde-
hyde instead of norbornene was used. (4-Methoxyphenyl)boronic
acid (2.0 equiv) was used instead of ethyl acrylate. In the absence of
ethyl acrylate. 2-(Cyclohex-1-en-1-yl)acetic acid (4.0 equiv) was used.
c
d
e
The products were characterized after hydrogenation.
acid as termination reagent resulted in a low yield (4k). The
reaction of 2-iodotoluene and 2-iodoanisole derivatives
performed equally efficiently for this ortho acylation reaction
(4l−o). With carboxylic acids bearing a proper C−C double
bond, ring-fused compounds 3,4-dihydronaphthalen-1(2H)-
one analogues could be synthesized efficiently in one step
from aryl iodides (4p−t). The utility of this transformation was
further demonstrated by the 1.0 mmol scale reactions of 4i and
4p, which gave comparative or better yields.
The reaction of 4-fluoro-1-iodo-2-methylbenzene 1f gave a
mixture of 4u and 3f with a ratio of 1.5:1, indicating that the
selectivity was also influenced by the substituents on aryl
halides though the origin of this observation is tentatively
unclear to date (Scheme 6a). The use of highly bulky carboxylic
acids (e.g., 2,2-dimethylbutanoic acid or 1-adamantanecarbox-
ylic acid) resulted in the formation of 2,4,6-trichlorobenzoyl
compound 3g exclusively (Scheme 6b). These results indicated
Figure 3. Distortion/interaction analysis (activation strain model) for
both types of oxidative additions
the anhydride involved in TS1b than the one in TS1a.
Meanwhile, the distortion energies for the Pd complexes are
almost same in these two different types of addition (TS1a of
+16.2 kJ/mol vs TS1b of +13.2 kJ/mol). It implies that
breaking the O−C1 bond is more difficult than cleaving the O−
C2 bond.
Scheme 6. Substrate Scope
In light of the above rationale, our effort then focused on the
ortho acylation by the use of aliphatic carboxylic acids,
particularly for those α-nonbranched carboxylic acids, which
were usually poor substrates in previous studies. After the
optimization of reaction conditions, it was found that the
reaction in 1,4-dioxane with Cs2CO3 as the base proceeded
most efficiently (Scheme 5). The reaction of 1-iodonaphthalene
with primary or secondary aliphatic acids, such as acetic acid
and pentanoic acid, proceeded smoothly to deliver the
corresponding ketone in good yields (4a−c, 4j), where the
phenyl group, ester, ether, and amide functional groups were
also compatible (4d−h). The use of p-methoxyphenyl boronic
C
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(7) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
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transferred by the use of bulky reagents.
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In summary, we have developed a practical palladium/
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group to the ortho position of aryl iodides. An electronic effect
played a vital role in chemical selectivity, rather than the steric
effect. DFT calculation indicated that the electron-donating
group on the phenyl acyl moiety can stabilize the positive
charged Pd(IV) intermediate by increasing the electron density
on the Pd(IV) atom.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03514.
1
Experimental procedure, spectroscopic data, and H and
13C NMR spectra of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: fuyao@ustc.edu.cn.
*E-mail: zhgu@ustc.edu.cn.
ORCID
Julong Jiang: 0000-0002-2357-1127
Yao Fu: 0000-0003-2282-4839
Zhenhua Gu: 0000-0001-8168-2012
Author Contributions
†S.X. and J.J. contributed equally.
Notes
The authors declare no competing financial interest.
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Chem., Int. Ed. 2013, 52, 5305. (b) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu,
Z. J. Am. Chem. Soc. 2013, 135, 9318.
ACKNOWLEDGMENTS
■
This work was partly supported by NSFC (21472179,
21622206, 21325208, 21572212), the ’973’ project from the
MOST of China (2015CB856600). The supercomputer center
in the USTC is also acknowledged for providing the
computational resources.
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DOI: 10.1021/acs.orglett.7b03514
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