Palladium-catalyzed intermolecular directed C-H amidation of aromatic ketones

Article abstract of DOI:10.1021/ja108450m

Pd-catalyzed directed ortho C-H amidation of aromatic ketones with both sulfonamides and amides has been accomplished. The use of an electron-deficient Pd complex, Pd(OTf)₂, is crucial for the success of this transformation. Some key intermediates of the reaction, that is, the cyclopalladation complexes of ketones, have been characterized by X-ray crystallography. Experimental analysis of these palladacycles and also the experimental results with N-methyl sulfonamides indicate that the new reaction does not seem to proceed through a nitrene intermediate. The utility of the newly developed reaction was demonstrated for the synthesis of useful organic intermediates such as 2- and 3-alkyl indoles and 2-aminophenyl ketones.

Full text of DOI:10.1021/ja108450m

ARTICLE
pubs.acs.org/JACS
Palladium-Catalyzed Intermolecular Directed C-H Amidation of
Aromatic Ketones
Bin Xiao, Tian-Jun Gong, Jun Xu, Zhao-Jing Liu, and Lei Liu*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
S Supporting Information
b
ABSTRACT: Pd-catalyzed directed ortho C-H amidation of
aromatic ketones with both sulfonamides and amides has been
accomplished. The use of an electron-deficient Pd complex,
Pd(OTf)2, is crucial for the success of this transformation.
Some key intermediates of the reaction, that is, the cyclopalla-
dation complexes of ketones, have been characterized by X-ray
crystallography. Experimental analysis of these palladacycles
and also the experimental results with N-methyl sulfonamides
indicate that the new reaction does not seem to proceed through
a nitrene intermediate. The utility of the newly developed
reaction was demonstrated for the synthesis of useful organic
intermediates such as 2- and 3-alkyl indoles and 2-aminophenyl
ketones.
1. INTRODUCTION
2. RESULTS AND DISCUSSION
Recently, Pd-catalyzed chelation-directed C-H activation/
cross-coupling reactions have emerged as powerful methods in
organic synthesis.1 Frequently used directing groups are nitro-
gen-containing moieties (e.g., amides,2 N-heterocycles,3 imines,4
pyridine N-oxides,5 and amines6), while recent studies expanded
the scope to include more challenging substrates such as alcohols7
and carboxylic acids.8 The use of a ketone group as the directing
group is also known, but most previous studies on ketone-
directed C-H activation used Ru catalysts and only afforded
the C-C coupling products.9 In a pioneering study, Miura et al.
discovered Pd-catalyzed multiple arylation of benzyl phenyl ke-
tones with aryl bromides.10 Recently, Cheng et al. described an
important discovery of Pd-catalyzed C-H activation/C-C
coupling of sec-alkyl aryl ketones with aryl iodides.11
Here, we report a practical Pd(II)-catalyzed ortho C-H
amidation of aromatic ketones. This work was inspired by our
recent success in Pd(II)-catalyzed C-H activation/coupling of
phenol esters.12 The significance of the present finding is 2-fold:
(1) ortho-amino aryl ketones are very useful synthetic inter-
mediates in medicinal chemistry; they can also be converted to
other ortho-substituted aryl ketones and indoles (Scheme 1);
and (2) the previous examples of Pd-catalyzed intermolecular
directed C-H amination involve the functionalization of sp2 and
sp3 C-H bonds in pyridine and oxime ether substrates, most
likely via a nitrene insertion mechanism.1b,4b The present study
provides an additional example13-16 for Pd-catalyzed intermo-
lecular directed C-H amination, and our experiments show that
the new reaction may not involve a nitrene intermediate.
2.1. Crystal Structures of the Reaction Intermediates. Our
study began by synthesis of palladacycles of a model aryl ketone
1a (Scheme 2). A yellow crystal of a palladacycle dimer A was
obtained with two OTf- anions bridging two Pd(II) atoms.
When A was treated with 4-Cl-C6H4SO2NH2, a green crystal B
was obtained in which the sulfonamide coordinates to Pd(II)
unusually in its neutral form. Addition of an Fþ agent (i.e.,
N-fluoro-2,4,6-trimethyl-pyridinium triflate) or Na2S2O8 con-
verted B to the ortho C-H amidation product 2a at 60 °C in
82% yield. In the absence of these oxidants, B did not afford any
C-H amidation product even when heated to 100 °C. Addition
of weaker oxidants (i.e., Cu(II), Ag(I), O2, and benzoquinone) to
B did not cause the C-H amidation, either. Besides, when TFA
(trifluoroacetic acid) was used with HOTf, a palladacycle C similar
to that reported by Cheng et al.11 was obtained with two TFA anions
bridging two Pd(II). It is interesting to note that Cdid not react with
4-Cl-C6H4SO2NH2 to produce B, but the reverse conversion of
B to C occurred smoothly. In addition, treatment of both A and
C with the nitrene precursor 4-Cl-C6H4SO2NdIPh did not cause
any C-H amidation. This result suggests against the involvement of
nitrene insertion mechanism,3f,4b whereas previous stoichiometric
reactions of related sulfonamide-coordinated palladacycles indicated
that the conversion from B to 2a may involve the intermediacy of a
Pd(IV) imido complex.3b,13b,c
Received: September 27, 2010
Published: January 10, 2011
r
2011 American Chemical Society
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Scheme 1. Possible Use of Pd(II)-Catalyzed Ortho C-H Amidation of Aromatic Ketones
Scheme 2. Transformations under Stoichiometric Conditions
2.2. Reaction Scope. The above results indicate that the use
of HOTf to tune the electrophilicity of Pd(II)17 is a useful
strategy to achieve difficult C-H activation. Subsequently, we
developed a catalytic version of the above C-Hamidationreaction.
As shown in Scheme 3, stirring a solution of 1a with 2 equiv of
sulfonamide, 2 equiv of N-fluoro-2,4,6-trimethyl-pyridinium tri-
flate, 10 mol % Pd(OAc)2, and 0.5 equiv of HOTf at 80 °C in
DCE afforded the desired product 2a in 71% isolated yields.
Other oxidants including Selectfluor and Na2S2O818 could also
be used in the reaction (Supporting Information). When Pd-
(OTf)2 was used as catalyst, the yield improved to 85%. This
observation is consistent with Yu’s finding that the acetate anion
may interfere with some C-H activation processes.19 Moreover,
we tested Cheng’s Pd(II)/TFA conditions11 in our amidation
reaction but failed to obtain any desired product. This result is
consistent with the above studies on the crystals showing that B
can be easily converted to C but the C-to-B transformation is
much more difficult.
Under the optimized conditions, ortho-amidation can occur
smoothly with both alkyl aryl ketones and aryl aryl ketones
carrying a number of substituents (Table 1). The alkyl groups
in the ketones can be primary, secondary, or even tertiary
alkyl groups so that the present reaction is not limited to
nonenolizable ketones. Both electron-rich and electron-poor
aromatic ketones can be converted, while a competition experi-
ment shows that an electron-rich aromatic ketone reacts more
rapidly than an electron-poor substrate (2c0). Importantly,
the bromo and chloro substitutions (2e-2f, 2o, 2y) can
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be well tolerated in this C-N coupling reaction, making
possible additional modifications at the halogenated posi-
tions. Moreover, it is noteworthy that all the transformations
in Table 1 are not sensitive to moisture or air so that these
reactions can be readily conducted without any sophisticated
operation.
Noteworthily, eletron-rich ketones tend to give higher yields
than electron-poor ones in the reaction. Also, aryl alkyl ketones
with tertiary alkyl groups tend to give higher yields than sub-
strates with primary and secondary alkyl groups. To understand
these observations, we carried out experiments to synthesize
palladacycles of 4-trifluoromethylphenyl t-butyl ketone and 1-o-
tolylethanone (Scheme 4) in the presence of TsNH2. Instead of
generating any palladacycle, we obtained a golden crystal corre-
sponding to a TsNH-bridged Pd dimer. This result indicates that
the sulfonamide can compete with the ketone for the coordina-
tion with Pd, which is consistent with the notion that a ketone
group is a weak directing group in palladium catalysis. Compar-
ing Schemes 2 and 4, we concluded that an electron-rich ketone
exhibits a better performance in the C-H amidation reaction
because it coordinates to Pd more strongly. This explanation also
applies to the cases of ketones with tertiary alkyl groups, because
a tertiary alkyl group is a better electron donor than a primary or
secondary alkyl group.
Scheme 3. Catalytic Version of the C-H Amidation
Reaction
Table 1. Catalytic Ortho C-H Amidation of Aromatic Ketones (Ar = 4-Cl-C6H4-)a
a Isolated yields for the reactions conducted with 10 mol % Pd(OTf)2. Yields in the parentheses were obtained with 10 mol % Pd(OAc)2 and 0.5 equiv of
HOTf. b At 60 °C. c 4 equiv of Na2S2O8 was used as oxidant. d 2 equiv of Selectfluor was used as oxidant. e 10 mol % Pd(OTf)2 and 0.3 equiv of HOTf
were used. f The ratio was determined by NMR.
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Further studies on the electronic effect in the transformation
reveal an interesting Hammett relationship between the product
distribution and the substituent electronic constants. As shown
in Figure 1, the log value of the product distribution (i.e.,
log([P1]/[P2])) is found to have a linear dependence on the
Hammett susbtituent constants in the diphenyl ketone system.
This observation again indicates that an electron-rich ketone
exhibits a better performance in the C-H amidation reaction. In
addition, by using an isotope labeled diphenyl ketone, we obtained a
KIE (kinetic isotope effect) value of 4.9 (Scheme 5). This result
indicates that C-H activation is the rate-limiting step of the
present transformation.
para-CF3 (2gi) substitution. An alkylsulfonamide, that is, metha-
nesulfonamide, can also be used in the reaction to give a modest
yield (2gp, 51%). Moreover, several amides of electron-deficient
carboxylic acids, pentafluorobenzamide (2gq, 37%), 2,3,5,6-
tetrafluorobenzamide (2gr, 20%), and 2,6-bis(trifluoromethyl)
benzamide (2gs, 17%), can be coupled with the aromatic C-H
bonds, suggesting that sulfonamide is not necessary in this chem-
istry but the electronic nature of the amide is vital. Finally, it is
important to note that several N-methyl arylsulfonamides (2gv,
2gw, 2gx) can be converted to the desired products. This obser-
vation provides a second evidence against the involvement of
nitrene insertion mechanism,3f,4b,15 because an N-methyl arylsulfo-
namide cannot generate any nitrene intermediate. On the other
hand, the reaction with an N-methyl arylsulfonamide can be readily
explained by a mechanism involving the intermediacy of a Pd(IV)
imido complex (Figure 2).3b,13b,c
As to the amide partner (Table 2), we found that both
electron-rich and electron-poor arylsulfonamides can be used
for the transformation (from 2g to 2go). The optimal yield
(82%) is obtained for arylsulfonamides carrying a para-Cl (2g) or
Finally, the reaction can be readily scaled up to gram-scale
transformation (Scheme 6). Moreover, it is interesting to report
that the reaction of a 3-indole ketone using the newly devel-
oped catalytic system causes C-H amidation at the 4-position
(Scheme 7). The steric hindrance of the N-Ts group may be the
reason for the occurrence of the C-H activation at the 4-position.
2.3. Applications. The utility of the new ortho C-H amida-
tion reaction was examined for the synthesis of some useful
organic intermediates. Shown in Scheme 8 is a new, alternative
synthetic route to 2- or 3-substituted indoles from simple aryl
alkyl ketones. The first step of the synthesis, that is, catalytic
ortho C-H amidation, has already been shown in Table 1. As to
the second step, we found that the aryl alkyl ketones with nPr
substitution (Table 3, entries 1,2) can be directly converted to
3-alkyl indoles (3a, 3b) in good yields (80-83%) through a
previously reported method20 of TMSC(Li)N2-mediated cycli-
zation (Table 3). When the ketones carry longer side chains
(Table 3, entries 3,4), the cyclization step produces the desired
3-alkyl indoles (3c, 3d) in modest yields (49-58%). Besides, we
also observed the formation of some N-sulfonyl-o-alkynylani-
lines (4c, 4d) presumably through the rearrangement of the
alkylidene carbene intermediates generated from TMSC-
(Li)N2 and the ketones. CuI-catalyzed cyclization21 is then
conducted to convert the N-sulfonyl-o-alkynylanilines to the
2-alkyl indoles (5c and 5d).
Figure 1. Hammett relationship in the C-H amidation reaction.
Scheme 4. Reactions with Less Electron-Rich Ketones
For aryl alkyl ketones carrying side chains with larger steric
hindrance (Table 3, entries 5-10), it is interesting to find that
the LDA/TMSCHN2 treatment only produces N-sulfonyl-o-
alkynylanilines (4e-4j) in high yields (78-88%). Subsequent
CuI-catalyzed cyclization of the N-sulfonyl-o-alkynylanilines is
also a highly efficient transformation providing the 2-alkyl indoles
(5e-5j) in excellent yields (95-98%). Thus, the results in Table 3
show a new method for the preparation of either 2- or 3-alkyl
indoles depending on the steric hindrance of the side chain. The
advantage of this method is the easy synthesis of ortho amidated
aromatic ketones directly from readily available aryl alkyl ketones.
Scheme 5. Kinetic Isotope Effect
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Table 2. Catalytic C-H Amidation with Different Amidesa
a Isolated yields. b 100 °C. c 2 h at 120 °C; Selectfluor was used as oxidant.
Moreover, shown in Scheme 9 is a new, simple synthesis of a
key intermediate22 for the blood glucose-lowering drug Prandin
in 52% yield through three steps from readily available isovaler-
ophenone. In this example, a simple synthesis of 2-aminophenyl
ketone from a phenyl ketone compares favorably with the pre-
vious methods that involve either reaction of 2-aminobenzoni-
trile with an alkyl Grignard reagent or ortho-metalation of N-acyl
aniline followed by C-acylation.20,22
3. CONCLUSIONS
In summary, Pd-catalyzed directed ortho C-H amidation of
aromatic ketones with sulfonamides and amides was accomplished.
The use of an electron-deficient Pd complex, Pd(OTf)2, was
found to be crucial for the success of this transformation. Key
intermediates of the reaction, that is, the cyclopalladation com-
plexes of ketones, were characterized by X-ray crystallography.
Experimental analysis of these palladacycles and also the experimental
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results with N-methyl sulfonamides indicated that the new
reaction does not seem to involve a nitrene intermediate. The
utility of the newly developed reaction was demonstrated for
the synthesis of useful organic building blocks such as 2- and
3-alkyl indoles and 2-aminophenyl ketones.
a dry place. Pd(OTf)2 2H2O was synthesized according to the reported
3
method.23 Aryl ketones were commercially available or easily synthe-
sized from acyl chlorides and Grignard reagents. 1H NMR spectra were
recorded on 400 MHz spectrometers. Chemical shifts of 1H NMR
spectra were reported in parts per million relative to tetramethylsilane
(δ = 0). 13C NMR spectra were recorded on 100 MHz spectrometers.
Chemical shifts were reported in parts per million relative to the solvent
resonance as the internal standard (CDCl3, δ 77.16 ppm). High-
resolution mass spectra (HRMS) were recorded on a BRUKER VPEXII
spectrometer with EI mode.
4. EXPERIMENTAL SECTION
4.1. General Information. Dichloroethane (DCE) was pur-
chased from a commercial source and used without further treatment.
Pd(OAc)2 (>99.9%) and HOTf was purchased from Aldrich and kept in
4.2. General Procedure for Synthesis of A. To a 10 mL vial
were sequentially added Pd(OAc)2 (56.5 mg, 0.25 mmol), adamantan-1-
yl-(3,4-dimethyl-phenyl)-methanone (1a) (107.3 g, 0.4 mmol), and
DCE (1 mL). The vial was stirred at 40 °C for 5 min. Next, HOTf (45
mg, 0.3 mmol) was added. The vial was stirred at the 40 °C for 2.5 min
and then cooled to room temperature. The reaction mixture was filtered
and washed with 2 mL of a mixture of petroleum ether/DCE (1:1)
to give the desired OTf’s bridged palladacycle product as yellow needles
(128 mg, 98%) that can be characterized by X-ray crystallography.
This palladacycle compound was stable at room temperature in the dry
solid state for about 1 week but sensitive to moisture.
4.3. General Procedure for Synthesis of B. A (52.3 mg,
0.05 mmol) and 4-chloro-benzenesulfonamide (19.2 mg, 0.1 mmol)
were stirred in 1 mL of DCE at room temperature for 1 h, during
which period the palladacycle and sulfonamide dissolved. The
resulting solution was kept in 15 °C for 8 h. The crystal was formed,
filtered, and washed with 2 mL of a mixture of petroleum ether and
DCE (1:1) to give B DCE (71 mg, 87%) as light green needles,
3
Figure 2. Proposed mechanism for the C-H amidation reaction.
which were characterized by X-ray crystallography.
Scheme 6. Gram-Scale Reaction
Scheme 7. C-H Amidation of an Indole Substrate
Scheme 8. An Alternative Synthetic Route to 2- or 3-Substituted Indoles from Simple Aryl Alkyl Ketones
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Table 3. Synthesis of 2- and 3-Alkyl Indolesa
a Isolated yields.
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Scheme 9. Synthesis of a Key Intermediate for Prandin
4.4. General Procedure for Synthesis of C. To a 10 mL vial
were sequentially added Pd(OAc)2 (56.5 mg, 0.25 mmol), adamantan-
1-yl-(3,4-dimethyl-phenyl)-methanone (1a) (107.3 mg, 0.4 mmol), and
DCE (1 mL). TFA (114 mg, 1 mmol) was added. The vial was stirred at
40 °C for 5 min, and then HOTf (45 mg, 0.3 mmol) was added. The vial
was stirred at the 40 °C for 10 min and then cooled to room temperature.
The reaction mixture was filtered and washed with 2 mL of a mixture of
petroleum ether and DCE (1:1) to give the desired OTFA’s bridged
palladacycle C as orange needles (109 mg, 90%). C was much more
stable than A, and no decomposition was observed even after staying in
atmosphere for at least 4 weeks, which was characterized by X-ray crys-
tallography without further recrystallization. When C and 4-chloro-
benzenesulfonamide were stirred in DCE for 12 h (room temperature or
60 °C), the solid did not dissolve, and no product was observed after
even 3 days. Conversely, when B was stirred in TFA, an orange solid was
formed immediately to produce C according to NMR analysis.
’ ACKNOWLEDGMENT
This study was supported by the National Natural Science
Foundation of China (grant nos. 20832004, 20802040) and the
Specialized Research Fund for the Doctoral Program of Higher
Education (grant no. 200800030074). This work was also
supported by the national “973” grants from the Ministry of
Science and Technology (no. 2011CB965300).
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4.5. General Procedure for C-H Amidation. To a 10 mL vial
were added ketone (0.25 mmol), sulfonamide (0.5 mmol), N-fluoro-
2,4,6-trimethyl-pyridinium triflate (145 mg, 0.5 mmol), Pd(OTf)2 2H2O
3
(11 mg, 0.025 mmol, 10 mol %), and DCE (1 mL). The vial was sealed
and heated at 80 °C for 8 h. After the completion of the reaction, the
mixture was purified by flash chromatography (EtOAc/petroleum
ether) to give the desired product as a white or pale yellow solid.
4.6. General Procedure for Synthesis of 3-Alkyl or 2-Alkyl
Indoles (Table 3, Entry 4). To a solution of 4-chloro-N-[2-(3-
methyl-butyryl)-phenyl]-benzene-sulfonamide (35.2 mg, 0.1 mmol)
and TMSCHN2 (2 M in n-hexane, 60 μL, 0.12 mmol) in 1 mL of
THF at -78 °C under Ar was added LDA (1.8 M in THF, 140 μL, 0.25
mmol). The mixture was stirred at -78 °C for 30 min and warmed to
room temperature. The reaction was quenched with aqueous NH4Cl,
extracted with Et2O, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash chromatography with EtOAc/petroleum ether
(1:50) to give the 3-iBu indole as a white solid (17.0 mg, 49%) and then
EtOAc/petroleum ether (1:10) to give the o-ynylaniline (13.9 mg, 40%).
The o-ynylaniline (13.9 mg, 0.04 mmol) and CuI (1.5 mg, 0.2 equiv)
were dissolved in 0.6 mL of DMF and 1 mL of Et3N, and then heated to
80 °C for 1 h. The reaction was quenched with aqueous NH4Cl, extracted
with Et2O, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash chromatography with EtOAc/petroleum ether
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Supporting Information. Experimental details and com-
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’ AUTHOR INFORMATION
Corresponding Author
lliu@mail.tsinghua.edu.cn
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