Synthesis of Diversely Functionalized Oxindoles Enabled by Migratory Insertion of Isocyanide to a Transient σ-Alkylpalladium(II) Complex

Article abstract of DOI:10.1002/anie.201603950

Palladium-catalyzed intramolecular carbopalladation of N-aryl acrylamides followed by migratory insertion of an isocyanide-coordinated C(sp³)?Pd intermediate afforded an alkylimidoyl?Pd^IIcomplex, which can be intercepted by a nucleophile, including heteroarenes. In addition to amides, the alkylimidoyl?Pd^IIcomplex was successfully converted into esters, ketones, and bis-heterocyclic compounds. An unprecedented palladium-catalyzed enantioselective domino process involving isocyanide was also documented.

Full text of DOI:10.1002/anie.201603950

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603950
German Edition: DOI: 10.1002/ange.201603950
Heterocycles
Synthesis of Diversely Functionalized Oxindoles Enabled by Migratory
Insertion of Isocyanide to a Transient s-Alkylpalladium(II) Complex
Wangqing Kong, Qian Wang, and Jieping Zhu*
Abstract: Palladium-catalyzed intramolecular carbopallada-
tion of N-aryl acrylamides followed by migratory insertion of
3
À
an isocyanide-coordinated C(sp ) Pd intermediate afforded
II
À
an alkylimidoyl Pd complex, which can be intercepted by
a nucleophile, including heteroarenes. In addition to amides,
the alkylimidoyl Pd complex was successfully converted into
esters, ketones, and bis-heterocyclic compounds. An unprece-
dented palladium-catalyzed enantioselective domino process
involving isocyanide was also documented.
II
À
T
he carbene-like reactivity of the isocyano group has been
extensively exploited in the development of multicomponent
reactions,[1] insertion reactions,[2] and polymerization process-
es.[3] Being isoelectronic with carbon monoxide (CO),[4]
isocyanides have recently emerged as a valuable C1 building
block in palladium-catalyzed imidoylative/carbonylative cou-
pling reactions.[5] The added advantages of isocyanide relative
to CO in such transformations reside on its easy handling,
modular reactivity, and ability to bring molecular diversity by
its organic residue. Until now, most of the reported imidoy-
Scheme 1. Palladium-catalyzed isocyanide insertion processes.
2
II
À
lative processes involved a C(sp ) Pd intermediate gener-
ated in situ by oxidative addition of palladium to an aryl/vinyl
halide (Scheme 1a). Reactions involving migratory insertion
unit. We also document an unprecedented asymmetric
carbopalladation/isocyanide insertion/methoxylation process
for the synthesis of enantioenriched imidates (7).
3
II
[6]
À
of isocyanide to C(sp ) Pd complexes remain unexploited.
In contrast, while the coordinating ability of isocyanide to
transition metals has been well appreciated in organometallic
chemistry,[7] this property also renders the development of
isocyanide-based enantioselective transformations difficult.
To the best of our knowledge, only one single example has
been reported from the group of Hayashi.[8]
The reaction between N-(2-iodophenyl)-N-methyl meth-
acrylamide (1a) and tBuNC (2a) was examined in the
presence of a catalytic amount of Pd(OAc)2 and dppp
(Scheme 2; see the Supporting Information for a survey of
reaction conditions). When the reaction was performed in
toluene/H2O in the presence of Cs2CO3, the expected amide
3a was formed in about 15% yield.[12] After having screened
different bases and solvents, we were able to obtain the 3,3-
disubstituted oxindole 3a in 90% yield upon isolation by
performing the reaction in toluene/MeOH at 1008C in the
presence of KOH (2.0 equiv). Interestingly, by simply chang-
ing the solvent and the base [THF, NaOMe (3 equiv)], the
same reaction afforded the ester 4a in 72% yield upon
In connection with our interest in palladium-catalyzed
domino processes[9] and isocyanide chemistry,[10] we envisaged
that an intramolecular carbopalladation of alkenes followed
by migratory insertion of the resulting isocyanide-coordinated
3
II
À
C(sp ) Pd complex A might be an attractive way to form an
alkylimidoyl–PdII species which could be converted into
a diversely functionalized oxindoles (Scheme 1b).[11] We
report herein that palladium-catalyzed reactions of N-aryl-
acrylamides (1) with isocyanides (2) took place smoothly to
afford a diverse set of 3,3-disubstituted oxindoles (3–6)
incorporating an amide, an ester, a ketone, and a benzoxazole
[*] Dr. W. Kong, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products, Institute of Chemical
Sciences and Engineering, Ecole Polytechnique FØdØrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Scheme 2. Palladium-catalyzed reaction of the acetanilide 1a with
tBuNC (2a). Synthesis of the amide 3a and ester 4a by small changes
in reaction conditions: KOH (2.0 equiv) in toluene/MeOH=5:1 (2.0
mL) at 1008C leads to 3a in 90% yield; and NaOMe (3.0 equiv) in
THF (2.0 mL) at 1008C leads to 4a in 72% yield. dppp=
1,3-bis(diphenylphosphanyl)propane.
Homepage: http://lspn.epfl.ch
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603950.
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isolation. To the best of our knowledge, direct conversion of
isocyanides into esters under imidoylative conditions is
unprecedented.
A three-component reaction of 1a, 2a, and 2-phenyl-
1,3,4-oxadiazole (8a) was next investigated. The underlying
principle is shown in Scheme 3. Oxidative addition of
Scheme 4. Synthesis of the oxindole-benzoxazole framework 6a.
intermediate E, which, upon methanolysis, would afford the
phenoxide F. Ligand exchange followed by reductive elimi-
nation would then provide the compound 6a with concurrent
regeneration of the palladium(0) catalyst. Alternatively, rapid
hydrolysis of acetate followed by cyclization would convert
2b into 11, which can then be alkylated by A (R = H, R1 =
R2 = Me) to give 6a.[18]
The scope and limitations of these new transformations
were next examined and the results are shown in Table 1.
Reaction of the N-benzyl acetanilide 1b with tBuNC under
four sets of reaction conditions afforded four different
compounds, 3b, 4b, 5b, and 6a in good to excellent yields
(entry 2). Since the N-benzyl group is readily removed, it
constitutes a route to NH oxindoles. The introduction of an n-
hexyl (1c), a methoxymethyl (1d), and a phenyl (1e)
substituent at the Ca-position (R1) of the acrylamide exerted
only a minor effect on the reaction outcome (entries 3–5).
Substrates bearing an electron-donating group (1 f–h;
entries 6–8) and an electron-withdrawing group (1i, 1j;
entries 9 and 10) on the aniline residue all underwent the
domino process efficiently. Even the sterically encumbered
C3-substituted aryl iodide 1h participated in the reaction to
provide the desired oxindoles in good yields (entry 8). N-
(Naphthalen-2-yl)amide 1k was converted to 3k 4k, 5k and
6k, respectively, without event (entry 11). Finally, reaction of
1,1,3,3-tetramethylbutyl isocyanide with 1a afforded 3l and
4a in yields of 85 and 62%, respectively (for structure of 3l,
see the Supporting Information).
The development of a metal-catalyzed enantioselective
isocyanide-based domino process remained exceptionally
challenging. Indeed, coordination of isocyanide to the
metal/chiral ligand complex could destroy or modify its
chiral coordination sphere, hence the asymmetric induction.
Our initial efforts on the enantioselective version of the
aforementioned transformations using isocyanides 2a and 2b
met with failure.[19] Reasoning that bulky aryl isocyanides
might diminish the adverse coordinative interaction of
isocyanide with palladium, 2,6-dimethylphenyl isocyanide
(2c) was chosen as a reaction partner (Scheme 5). Interest-
ingly, the carboximidate 7ac was isolated in 90% yield under
reaction conditions optimized for the formation of compound
6a [1a (0.1 mmol), Pd(OAc)2 (0.1 equiv), dppp (0.2 equiv), 2c
(2 equiv), Cs2CO3 (2 equiv), toluene/MeOH = 5:1 (2.0 mL),
1008C].[20] Furthermore, 7ac was isolated in 58% yield with
an enantiomeric ratio (e.r.) of 62.5:37.5 when (R)-BINAP was
used as a ligand (see Table S4–1).[21] Addition of Ag3PO4 as
Scheme 3. Three-component synthesis of ketone 5. Optimized reaction
conditions: 1a (0.1 mmol), Pd(OAc)2 (0.1 equiv), tBuDavePhos
(0.2 equiv), 2-phenyl-1,3,4-oxadiazole (8a, 1.5 equiv), 2a (2.0 equiv),
Cs2CO3 (2.0 equiv), MeCN (2.0 mL), 1108C; then HCl (1N), RT, 2 h.
tBuDavePhos=2-Di-tert-butylphosphino-2’-(N,N-dimethylamino)-
biphenyl.
isocyanide-ligated palladium(0) to aryliodide would afford
B, which upon intramolecular carbopalladation, would fur-
3
II
nish the C(sp ) Pd intermediate A (R = H, R1 = R2 = Me).
Migratory insertion of isocyanide would provide the alkyl-
imidoyl–PdII species C which was expected to activate,
À
À
intermolecularly, the C H bond of 8a leading to D. Reductive
elimination would afford 9a,[13] whose hydrolysis under acidic
À
conditions would then furnish the ketone 5a. Three C C
bonds would be created in this multicomponent reaction.
After extensive screening of reaction conditions, the desired
ketone 5a was isolated in 72% yield together with 10a (12%)
by performing the reaction in MeCN in the presence of
Pd(OAc)2 (0.1 equiv), tBu-Davephos (0.2 equiv), and Cs2CO3
(2.0 equiv) at 1008C. The formation of 10a could be
accounted for by migratory insertion of isocyanide from B
followed by direct imidoylation of oxadiazole.[14] It is inter-
esting to note that the ligand plays a key role in the product
distribution. Using dppp as ligand under otherwise identical
reaction conditions, 5a and 10a were formed in a one to one
ratio (for details, see Table S2 in the Supporting Information).
The fact that direct arylation of the palladium(II) intermedi-
ates A (R = H, R1 = R2 = Me) and B by oxadiazole[15,16] was
not observed indicates that migratory insertion of isocyanide
from these two complexes was a kinetically faster process. The
high chemoselectivity observed is truly remarkable since
neither the amide 3a nor ester 4a were isolated although
methanol was used as a cosolvent.
Reaction of the functionalized isocyanide 2b with 1a
afforded the bis(heterocyclic) compound 6a in 79% yield
under optimized reaction conditions (Scheme 4; see
Table S3).[17] The domino process went presumably via the
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Table 1: Synthesis of diversely functionalized oxindoles.
providing 7ac with a promising e.r. value of 80:20.
Aiming at further increasing the enantioselectivity
of the process, the structure of the aryl isocyanides
was next examined (Scheme 6). Gratefully, using
the sterically more demanding 2,6-diisopropyl-
phenyl isocyanide (2d), the desired product 7ad
was isolated in 69% yield with an e.r. value of
87.5:12.5. A similar result was obtained with 2,6-
di(3,5-dimethylphenyl)-6-methylphenyl isocyanide
(2 f). However, enantioselectivity was reduced
with the bulkier isocyanide 2e. By using electron-
deficient isocyanides 2g (R’ = F) and 2h (R’ = CF3),
only the reduced product 12 was isolated in yields of
50 and 52%, respectively.
Applying this enantioselective domino imidoy-
lative Heck reaction to 1g and 1k led to the
formation of the corresponding oxindoles (S)-7gd
and (S)-7kd with e.r. values of 85.5:14.5 and 86:14,
respectively (Scheme 7). Hydrolysis of (S)-7gd
under acidic conditions (2.0 N HCl, THF, RT)
afforded the ester 4g whose absolute configuration
was determined to be S by comparison of its optical
rotation value with that reported in the literature.[23]
(S)-4g is a known precursor of (À)-physovenine
(14), (À)-esermethole (15, and (À)-physostigmine
(16).[23] We note that previous efforts on the
palladium-catalyzed carbonylative Heck reaction
of 1a with CO afforded 4 with an e.r. value of
64:36.[24]
Entry
1
Yield [%][a]
3
4
5
6
1
2
3
4
5
6
7
8
9
10
R=H, R1 =R2 =Me (1a)
3a (90) 4a (71) 5a (72) 6a (79)
3b (80) 4b (70) 5b (70) 6b (74)
3c (71) 4c (78) 5c (64)[b] 6c (65)
R=H, R1 =Me, R2 =Bn (1b)
R=H, R1 =nC6H13, R2 =Me (1c)
R=H, R1 =CH2OMe, R2 =Me (1d) 3d (51) 4d (60) 5d (68) 6d (64)
R=H, R1 =Ph, R2 =Me (1e)
R=4-tBu, R1 =R2 =Me (1 f)
R=4-OMe, R1 =R2 =Me (1g)
R=3-Me, R1 =R2 =Me (1h)
R=4-F, R1 =R2 =Me (1i)
R=5-Cl, R1 =R2 =Me (1j)
3e (72) 4e (70) 5e (<5) 6e (70)
3 f (83) 4 f (66) 5 f (62) 6 f (78)
3g (72) 4g (70) 5g (74) 6g (78)
3h (75) 4h (66) 5h (66) 6h (76)
3i (74) 4i (61) 5i (60)
3j (68) 4j (55) 5j (68)
6i (73)
6j (70)
11
3k (74) 4k (68) 5k (67) 6k (76)
Reaction conditions: a) 1 (0.1 mmol), Pd(OAc)2 (0.1 equiv), dppp (0.2 equiv), 2a
(1.5 equiv), KOH (2.0 equiv), toluene/MeOH=5:1 (1.8 mL), 1008C. b) 1
(0.1 mmol), Pd(OAc)2 (0.1 equiv), dppp (0.2 equiv), 2a (1.5 equiv), NaOMe (5.4m
in MeOH, 0.05 mL), THF (2.0 mL), 1008C. c) 1 (0.1 mmol), Pd(OAc)2 (0.1 equiv),
tBuDavePhos (0.2 equiv), 2-phenyl-1,3,4-oxadiazole (8a, 1.5 equiv), 2a (2.0 equiv),
Cs2CO3 (2.0 equiv), MeCN (2.0 mL), 1108C; then HCl (1 N), RT, 2 h. d) 1
(0.1 mmol), Pd(OAc)2 (0.1 equiv), dppp (0.2 equiv), 2b (2.0 equiv), Cs2CO3
(2.0 equiv), toluene/MeOH=5:1 (1.8 mL), 1008C. [a] Yield is that of the isolated
product. [b] 2-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole was used instead of 8a.
In conclusion, we have developed a series of
palladium-catalyzed domino processes involving
3
À
migratory insertion of isocyanide to the C(sp )
Scheme 6. Effect of isocyanide structure on the enantioselectivity of
the domino process.
PdII complex generated by an intramolecular carbopallada-
tion reaction. Depending on the reaction conditions, the
reaction can be tuned to generate either the amides 3 or esters
4.[25] In addition, a three-component reaction involving a key
intermolecular direct arylation of an alkylimidoyl–PdII com-
plex was documented for the first time[26] and a cyclizative
heterocoupling reaction[27] leading to the indolinone-benzox-
azole framework was achieved using a functionalized isocy-
anide (2b). An enantioselective domino carbopalladation/
isocyanide insertion/methoxylation has been developed.
Efforts are ongoing to decipher factors controlling the
enantioselectivity of transition metal catalyzed processes
involving isocyanide as a substrate, a still unsolved problem
in asymmetric catalysis.
Scheme 5. Enantioselective domino process between 1a and 2c.
BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, Tf =trifluoro-
methanesulfonyl.
a halide scavenger provided 1,3,3-trimethylindolin-2-one (12)
as a major product in 50% yield. In line with this result, the
aryl triflate 13 failed to afford the desired product.
Encouraged by this preliminary result, a wide range of
chiral ligands was screened (Scheme 5; see Table S4–2). An
electron-rich and conformationally rigid P-stereogenic
bis(phospholane) ligand (1R,1’R,2S,2’S-Duanphos)[22] proved
to be the most effective in terms of enantioselectivity, thus
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Scheme 7. Application of enantioselective imidoylative Heck process.
THF=tetrahydrofuran.
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edged.
Keywords: asymmetric synthesis · heterocycles ·
multicomponent reactions · palladium · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 9714–9718
Angew. Chem. 2016, 128, 9866–9870
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[18] We thank referee for this suggestion. The following control
experiments have been performed: a) treatment of 2b under our
reaction conditions for 2 h afforded the corresponding benzox-
azole 11 in 88% yield; b) reaction of 1a with 11 under standard
conditions provided 6a, albeit in only 30% yield; c) reaction of
1a with 11 using tBuOLi as a base under otherwise identical
conditions furnished 6a in 86% yield. Therefore, we assumed
that both pathways might be operational. For details, see the
Supporting Information.
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[26] The same reaction using CO as a C1 synthon is, to the best of our
knowledge, unknown. The compound 5 was not formed when
the reaction was performed using CO (1 atm) instead of tBuNC
under otherwise identical reaction conditions. The direct C-
arylation product was isolated instead. For details, see the
Supporting Information. We thank referee for suggesting this
experiment.
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Received: April 23, 2016
Revised: May 27, 2016
Published online: June 29, 2016
9718
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Angew. Chem. Int. Ed. 2016, 55, 9714 –9718