Palladium-catalyzed oxidative arylalkylation of activated alkenes: Dual C-H bond cleavage of an arene and acetonitrile

Article abstract of DOI:10.1002/anie.201104575

Not one but two: The title reaction proceeds through the dual C-H bond cleavage of both aniline and acetonitrile (see scheme). The reaction affords a variety of cyano-bearing indolinones in excellent yield. Mechanistic studies demonstrate that this reaction involves a fast arylation of the olefin and a rate-determining C-H activation of the acetonitrile. Copyright

Full text of DOI:10.1002/anie.201104575

Communications
DOI: 10.1002/anie.201104575
Synthetic Methods
Palladium-Catalyzed Oxidative Arylalkylation of Activated Alkenes:
À
Dual C H Bond Cleavage of an Arene and Acetonitrile**
Tao Wu, Xin Mu, and Guosheng Liu*
The oxidative difunctionalization of alkenes is a powerful
strategy for the synthesis of various organic compounds.[1]
Recent studies have demonstrated that palladium-catalyzed
oxidative transformations, such as aminooxygenation,[2] dia-
mination,[3] and dioxygenation[4] of alkenes, can be used
efficiently to achieve bond formations at vicinal positions.
However, palladium-catalyzed oxidative dicarbonation of
alkenes is quite challenging.[5,6] Oxidative cross-coupling of
arenes and alkenes using palladium catalysts have been
plished, and would therefore offer a valuable method for
À
constructing two C C bonds simultaneously (Scheme 1).
À
The activation of the C H bond of acetonitrile has been
well-documented by using stoichiometric amounts of a
transition metal,[10] such as Rh,[9a–d] Ni,[9e] Ru,[9f,g,i] and Fe,[9j]
À
etc., to yield LnM CH2CN complexes under various reaction
À
conditions. However, in general the catalytic C H function-
alization of acetonitrile by a transition metal is quite rare,[11]
and a strong base is generally required.[12] Herein, we report a
novel palladium-catalyzed oxidative arylalkylation of alkenes,
extensively explored.[7] These reactions involve C H bond
À
À
À
functionalizations to yield the intermediate A, which usually
undergoes b-hydride elimination to afford Heck-type prod-
ucts (Scheme 1). Recently, Zhu and co-workers have reported
which involves dual C H bond cleavage to form two C C
bonds in the presence of AgF and PhI(OPiv)2. It is worth
À
noting that the rate-determining Csp3 H bond activation of
CH3CN proceeded in the absence of a strong base, and in the
presence of acidic additives.
As part of our efforts to develop catalytic fluorination of
alkenes, our initial investigation focused on the arylfluorina-
tion of 1a. With the previously reported fluorination con-
ditions involving AgF/PhI(OPiv)2,[13] the reaction of 1a only
afforded a small amount of the expected arylfluorination
product 2a (Table 1). Surprisingly, the major product 3a,
having the solvent acetonitrile incorporated, was observed
(Table 1, entry 1). Further optimization of the reaction
conditions exhibited that a bidentate nitrogen-containing
ligand is beneficial to the reaction, and the ligand L4 was
shown to give the best yield (entries 2–6). Notably, no
reaction occurred in the absence of either the palladium
catalyst, AgF, or PhI(OPiv)2 (entries 7, 8, and 10). The
reaction with PhI(OAc)2 also afforded 3a but in low yield
(entry 9). Other oxidants, such as tert-butyl peroxide, oxone,
and benzoquinone, were ineffective (see the Supporting
Information). Additional screening of bases showed that
AgF was unique for this reaction. No desired product 3a was
observed in the presence of other fluoride and nonfluoride
bases, or in the presence of strong bases such as KOtBu and
NaN(SiMe3)2 (entries 11–13). The addition of MgSO4 is
helpful for increasing the yield of 3a (entry 14). It is
remarkable that the reaction is not influenced by acidic
additives such as CH3CO2H or CF3CO2H (entries 15–16).
Furthermore, there was no effect on this transformation when
Scheme 1. Palladium-catalyzed functionalization of alkenes initiated by
À
C H bond cleavage.
an oxidative intramolecular arylacetoxylation of alkenes in
II
À
which the C Pd bond of intermediate A can be oxidized by
PhI(OAc)2 to form a C O bond.[8a] This discovery presents an
intriguing strategy for the carbonation of alkenes. We
À
À
postulated that if an additional C H bond activation can
take place at the palladium center of intermediate A,[9] the
highly desired dicarbonation of alkenes could be accom-
[*] T. Wu, X. Mu, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn
2,2,6,6-tetramethyl-1-piperidinyloxyl
employed as a radical scavenger (entry 17).
(TEMPO)
was
The scope of substrates was investigated as shown in
Schemes 2 and 3. The effect of the protecting group on the
nitrogen atom was firstly probed. For the substrates bearing
an alkyl or aryl group on N, the reactions proceeded smoothly
to provide products 3a and 3b in excellent yields. In contrast,
the substrates with an electron-withdrawing group on N did
not yield the desired products 3c and 3d. The position of the
substituents on the aryl ring has no significant influence on
[**] We are grateful for the financial support from the National Natural
Science Foundation of China (20821002, 20872155, 20972175, and
20923005), the National Basic Research Program of China (973-
2009CB825300), and the “Hundred Talent Project” of Chinese
Academy of Science.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104575.
12578
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Angew. Chem. Int. Ed. 2011, 50, 12578 –12581

Table 1: Screening of reaction conditions.[a]
Entry
[O]
Additive
L
Yield (3a [%])
1[c]
2
3
4
5
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
–
PhI(OAc)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
–
56
61
65
76
79
92
0
0
38
0
0
0
0
71
89
84
88
bpy
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
6
7[d]
8
9
AgF
–
KF or CsF
10
11
12
13
14[e]
15
16
17
KOtBu or NaN(SiMe3)2
CsCO3 or Ag2CO3
AgF
AgF/AcOH[f]
AgF/TFAOH[f]
AgF/TEMPO[g]
[a] Reaction conditions: 1a (0.1 mmol), [Pd] (5 mol%), Ligand
(7.5 mol%), AgF (0.4 mmol), PhI(OPiv)2 (0.11 mmol), MgSO4 (20 mg,
0.17 mmol) in 1.0 mL of CH3CN at 808C for 12 h. [b] Yield as determined
by GC using tetradecane as an internal standard. [c] Product 2a (8%
yield). [d] Without palladium catalyst. [e] Without MgSO4. [f] 2 equiv
HOAc or TFAOH were used as additive. [g] TEMPO (1 equiv) was used
as additive. bpy=bipyridine, L=ligand, Piv=pivaoyl, TFA=trifluoro-
acetic acid.
Scheme 2. Palladium-catalyzed oxidative arylalkylation of alkenes. Reac-
tions were conducted at 0.2 mmol scale. Yields are those of the
isolated product. [a] The ratio of 3r and 3r’ was determined by
1H NMR spectroscopy. Bn=benzyl, Ts=4-toluenesulfonyl.
the efficiency. The substrates bearing electron-withdrawing or
electron-donating group always afforded the desired products
3e–3t in good to excellent yields. Notably, both halides and
ester groups, which are sensitive to strong base, were tolerated
and furnished the corresponding products 3l–3o, 3p, and 3q
with excellent yields. The substrates bearing meta substitents
exhibited very good reactivity but poor regioselectivity (3r).
The substrates having two substituents on the aryl ring are still
good for this transformation (3s–3u). Finally, when the
benzene ring of the substrates was changed to naphthalene,
the reactions successfully provided the arylalkylation prod-
ucts 3v–3w. Importantly, the pyridine group was also
compatible with these oxidative reaction conditions (3x).
Substrates with various olefins were additionally exam-
ined. For substrates without a substituent at the a position
(R3 = H) of the olefin, the reaction did not afford the desired
product 4a (Scheme 3). Analogous to substrate 1a, substrates
with ethyl, methoxymethyl, acetoxymethyl, and imide groups
at the a position generated the corresponding products 4b–4e
in excellent yields. Substrates with an aryl group at the
a position also afforded products 4 f and 4g in moderate to
good yields. In contrast, substrates with a phenyl group at the
b position undergoes arylation with opposite regioselectivity
to afford the six-membered product 5h in 77% yield, but with
low diastereoselectivity. Finally, a series of nitriles were also
tested. As shown in Scheme 3, a significant steric effect was
observed, and the reactivity of the nitrile decreased as
follows: CH3CN > EtCN > nPrCN > iPrCN. The reactions of
propionitrile and n-butyronitrile furnished the products 4i
and 4j in 83% and 54% respectively; the lower yield of 4k
was delivered with methoxyacetonitrile, and no reaction
occurred in the solvent of isobutyronitrile (4l). Except for
acetonitrile, these reactions were carried out at 1108C.
À
The formation of 3 and 4 indicates that a dual C H bond
functionalization of both aniline and acetonitrile was involved
À
in this reaction. To probe the mechanism of the C H bond
cleavage, a mixture of the substrates 1a and [D5]-1a (1:1) was
subjected to the standard reaction conditions to determine
the intermolecular isotope effect, and substrate [D1]-1a was
used to probe the intramolecular isotope effect. Neither intra-
nor intermolecular kinetic isotopic effects were observed [kH/
kD = 1.0, Eqs. (1) and (2)].[14] The absence of an intramolec-
ular isotope effect suggests that the reaction involves an
electrophilic aromatic substitution process.[15] Interestingly,
when the reaction of 1a was conducted in a 1:1 mixture of
CH3CN/CD3CN as the solvent, a large primary isotope effect
(kH/kD = 3.5) was obtained [Eq. (3)]. A similar KIE value
(2.8) was also observed in the individual reaction in CH3CN
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Communications
À
indicate that the C C bond formation might be derived from
a PdIV intermediate: 1) the reaction occurred in the presence
of PhI(OPiv)2, but no reaction occurs with other oxidants,
such as BQ or O2. 2) The desired product 3a was not obtained
and starting material 1a was recovered from the stoichio-
metric reaction in the absence of an oxidant. 3) The good
compatibility of halide (Br for 3n, I for 3o) also suggests that
the Pd0/II cycle is less likely.
Compared to acetonitrile, no reaction takes place in
noncoodinating protonic solvents, such as EtOAc and
MeNO2.[16] This observation indicates that the coordination
of acetonitrile with AgF or the palladium complex may be
[10]
À
crucial for the C H bond activation of acetonitrile. Addi-
tionally, the reaction occurs in the presence of AgF, and is
quite sensitive to the amount of AgF.[17] Such observations
À
suggest that AgF plays a key role in activating Csp3 H bond of
Scheme 3. Palladium-catalyzed oxidative arylalkylation of alkenes. Reac-
tions were conducted at 0.2 mmol scale. Yields are those of the
acetonitrile.[18]
isolated products. [a] The ratio in parentheses is the diasteroselectivity
On the basis of the above analysis, a possible catalytic
cycle is shown in Scheme 4. The reaction is initiated by
coordination of the olefin to PdII, with subsequent nucleo-
philic attack of the tethered arene to give the palladium
1
of the reaction as determined by H NMR spectroscopy. [b] The
reaction was conducted at 1108C. PhthNH=Phthalimide.
complex C.[19] Then the Csp3 H bond activation of CH3CN
À
takes place in the presence of PhI(OPiv)2 and AgF, thus
generating the PdIV complex D that undergoes reductive
elimination to afford the product 3a.[20,21]
In conclusion, we have discovered a novel palladium-
catalyzed oxidative arylalkylation of alkenes, in which dual
À
C H bond activation of both aniline and acetonitrile are
involved. The addition of PhI(OPiv)2 and AgF are the key for
this transformation, and AgF plays a roles to promote the
À
Csp3 H bond cleavage in acetonitrile. The reactions afford a
variety of nitrile-bearing indolinones in excellent yields.
Additional studies on the mechanism and synthetic applica-
tion are in progress.
and CD3CN. Furthermore, no significant substituent effect on
the reaction rate was observed in the competition experi-
À
ments [Eq. (4)]. These results suggest that a Csp3 H bond
activation of acetonitrile contributed to the rate-determining
step.
The detailed mechanism of the oxidative arylalkylation of
alkenes is not clear to us at the moment. Preliminary studies
Scheme 4. The proposed mechanism for this oxidative arylalkylation of
alkenes.
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Angew. Chem. Int. Ed. 2011, 50, 12578 –12581

[9] For recent reports on palladium-catalyzed carboamination of
Experimental Section
À
À
alkenes, C H bond activation of arenes was promoted by a Csp3
Pd complex. See: a) C. F. Rosewall, P. A. Sibbald, D. V. Liskin,
F. E. Michael, J. Am. Chem. Soc. 2009, 131, 9488 – 9489; b) K.-T.
Yip, D. Yang, Org. Lett. 2011, 13, 2134 – 2137; The Au-catalyzed
carboamination of alkenes, see: c) G. Zhang, Y. Luo, Y. Wang, L.
Zhang, Angew. Chem. 2011, 123, 4542 – 4546; Angew. Chem. Int.
Ed. 2011, 50, 4450 – 4454; For the Cu-catalyzed carboamination,
see: d) W. Zeng, S. R. Chemler, J. Am. Chem. Soc. 2007, 129,
12948 – 12949.
General procedure: In a TFE sealed dry glass tube, Pd(OAc)2
(2.2 mg, 0.01 mmol), AgF (102 mg, 0.8 mmol), PhI(O2CtBu)2
(90 mg, 0.22 mmol), 2,2’-bipyrimidine (2.4 mg, 0.015 mmol), MgSO4
(40 mg, 0.34 mmol), and alkene 1a (0.2 mmol) were dissolved in dry
CH3CN (2.0 mL). The mixture was stirred at 808C for 24 h. Then
ethyl acetate was added and the mixture was filtered through a plug of
celite. After removal of the solvent under vacuum, the residue was
purified by column chromatography on silica gel with a gradient
eluant of petroleum ether and ethyl acetate to afford the product 3a
(39 mg, 90% yield).
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Received: July 2, 2011
Revised: September 9, 2011
Published online: November 11, 2011
À
Keywords: acetonitrile · alkenes · arylalkylation · C
.
H activation · palladium
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[14] For the reaction in Equation (1), no H/D scrambling was
observed in the recovered starting material 1a and [D5]-1a.
For details, see the Supporting Information.
[15] For the corresponding KIE value of electrophilic aromatic
substitution process, see: a) J. A. Tunge, L. N. Foresee, Organo-
metallics 2005, 24, 6440 – 6444; b) R. Taylor in Electrophilic
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À
[18] A reasonable explanation is that the C H bond of actonitrile
might be activated by coordination to Ag, and then the weaker
À
C H was cleaved by a second AgF, which serves as a base at this
point. For details, see the Supporting Information.
[19] The intermediate C does exist in the catalytic cycle as a signal for
m/z 438.05 was detected by ESI/MS. For details, see the
Supporting Information.
[20] For the catalytic C C bond formation from a PdIV complex, see:
À
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À
[21] For the final C C bond formation, the alternative pathway
involving a nucleophilic attack by the carbanion of acetonitrile
on the carbon center of the PdIV complex cannot be excluded.
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