Palladium-catalyzed tandem intramolecular oxy/amino-palladation/isocyanide insertion: Synthesis of α-benzofuranyl/indolylacetamides

Article abstract of DOI:10.1021/ol501048x

A novel palladium-catalyzed approach to 2-benzofuranyl/indolylacetamides from 1-(o-hydroxy/aminophenyl)propargylic alcohols and isocyanides is described. The reaction proceeds through a cascade that includes oxy/aminopalladation, isocyanide insertion, and 1,4-hydroxyl migration. No oxidant or ligand is needed to promote the cascade, and the reactions are carried out under mild conditions to afford the products through high functional tolerance.

Full text of DOI:10.1021/ol501048x

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Tandem Intramolecular Oxy/Amino-
Palladation/Isocyanide Insertion: Synthesis of α‑Benzofuranyl/
Indolylacetamides
Nuligonda Thirupathi,† Madala Hari Babu,† Vikas Dwivedi,† Ruchir Kant,§ and Maddi Sridhar Reddy*,†,‡
§
†Medicinal & Process Chemistry Division and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute,
BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
‡Academy of Scientific and Innovative Research, New Delhi 110001, India
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed approach to 2-
benzofuranyl/indolylacetamides from 1-(o-hydroxy/amino-
phenyl)propargylic alcohols and isocyanides is described. The
reaction proceeds through a cascade that includes oxy/
aminopalladation, isocyanide insertion, and 1,4-hydroxyl migra-
tion. No oxidant or ligand is needed to promote the cascade,
and the reactions are carried out under mild conditions to afford
the products through high functional tolerance.
socyanide insertion has taken a new turn, for its
reemergence, in recent chemistry with the assistance of
Scheme 1. Synthesis of α-Benzofuranyl/Indolylacetamides
via Electrophilic Cyclization
I
palladium catalysis. Recent works by the groups of Wu,1 Jiang,2
Orru,3 and others3 for the synthesis of a variety of cyclic and
acyclic motifs ensure a promising future for the profound usage
of isocyanide as one carbon unit for a facile and simultaneous
Pd-catalyzed stitching of two new and valuable C−C or C−
heteroatom bonds. In continuation of our interest in the
electrophilic cyclization of functionalized alkynes,4 we herein
report the synthesis of α-benzofuranyl/indolylacetamides via
tandem intramolecular oxy/aminopalladation and isocyanide
insertion. Benzofuran and indole derivatives have been
considered among the highly privileged scaffolds for various
medicinal chemistry aspects.5 Synthesis of these moieties with
diverse substitution patterns has always been one of the top
priorities of chemists.
Earlier, Gabriele et al. reported a novel conversion of 1 to the
α-benzofuranylacetamides 2 through CO insertion (Scheme
1).6 The reaction required high pressure (30 atm) and
temperature (100 °C), rendering it a specific benchtop
reaction. Moreover, allylation was necessary for the initial
palladium coordination, and the reaction was applicable for
internal alkynes only (to produce branched substitution),
whereas terminal alkynes adopted a different mode of
cyclization.7 Herein, we report a facile conversion of various
nonallylated hydroxyphenyl propargyl alcohols 3 with a
terminal alkyne to the corresponding α-benzofurnaylacetamides
4 at room temperature using PdCl2 as the catalyst where no
assistance of any ligand or additive was required (Scheme 1).
Additionally, various aminophenyl propargyl alcohols 5 were
converted to the α-indolylacetamides 6 under slightly modified
conditions.
Initially, we used the conditions, for the conversion of 3a to
4a (Table 1) via palladium-catalyzed tandem cyclization and
isocyanide insertion, developed by Zhu et al.3h for the synthesis
of indole-3-carboxamide via isocyanide insertion. Pleasingly, the
expected product 4a was obtained in 55% yield through a
cascade of reactions (entry 1). Inspired by this result, some
reaction parameters such as catalyst, solvent, and base effects
were investigated for the purpose of improving the yield. Other
Received: April 10, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of α-Benzofuranylacetamides 4 via
a
Oxypalladation and Isocyanide Insertion
b
entry
catalyst
base
solvent
yield (%)
1
2
PdCl2
Pd(OAc)2
Pd(TFA)2
PdCl2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMSO
DMSO
55
30
22
48
35
85
70
40
20
65
45
3
DMSO
4
DCE
5
PdCl2
toluene
CH3CN
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
6
PdCl2
7
PdCl2
8
PdCl2
9
PdCl2
CS2CO3
morpholine
TEA
10
11
12
PdCl2
PdCl2
PdCl2
a
t
Reaction conditions: BuNC (2.0 mmol), 3a (1.0 mmol), base (2.0
b
mmol) Pd(II)-cat. (0.05 mmol), solvent (4 mL), rt, open air. Isolated
yield.
catalysts like Pd(OAc)2 and Pd(TFA)2 under the same
conditions were found to be less productive (entries 2 and
3). When various solvents were screened against PdCl2 catalyst
(entries 4−7), CH3CN was found to produce the best yield
(85%) of the product. Change of bases (entries 8−11) only led
to decrease the yield. No product was obtained in the absence
of the base (entry 12). Notably, all the reactions were carried
out in open-air conditions. Interestingly, the reaction proceeded
equally well in anhydrous/inert conditions, suggesting that
there is no role of O2 in the regeneration of the catalyst (vide
infra, see mechanism).
a
Reaction conditions: R1NC (2.0 mmol), 3 (1.0 mmol), base (2.0
mmol), PdCl2 (0.05 mmol), MeCN (0.2 M), open air, rt.
With the optimized conditions in hand, we evaluated the
generality of the method with respect to propargyl alcohols as
well as isocyanides. A variety of hydroxyphenyl propargyl
alcohols 3 were synthesized following the literature prece-
dents.7,9 As is evident from Scheme 2, a variety of substituents
like alkyl, aryl, halogen, methoxy, and nitro groups were
tolerated in the reaction to afford the products in moderate to
high yields. Initially, various 3°-alcohols, the substrates prepared
from o-hydroxyacetophenones and o-hydroxybenzophenones,
were subjected to the reaction to obtain the corresponding
products with a substitution at C3. Thus, 3,6-dimethylbenzo-
furanylacetamide 4b was obtained in high yield (82%), similar
to product 4a. The presence of a bromo group as in the case of
substrate 3c did not affect the outcome, producing 4c in 74%
yield. Electron-poor substrate 3d was found to react equally
well (to yield 4d in 82%), whereas its electron-rich counterpart
3e produced the corresponding product 4e in a moderate yield
of 52%. Similarly, 3-phenyl-substituted benzofuran adducts 4f−
h were obtained from 3°-alcohols 3f−h in comparative yields
(75−81%). Then, various electron rich, neutral and poor 2°-
alcohols, prepared from salicylaldehydes, were subjected to the
cascade reaction. Delightedly, they all produced the corre-
sponding products (4i−m) although in relatively slightly lower
yields (50−72% compared to 52−82%). Next, we aimed to
evaluate the reactivity of a variety of commercially available
isocyanides. Thus, isopropyl, tetramethylbutyl, and cyclohexyl
isocyanides were subjected to the transformation. All of them
smoothly produced the corresponding products in 63−75%
yields, although the relative productivity was less compared
with tert-butyl isocyanide. Unfortunately, phenyl isocyanide was
found to be unreactive under the given conditions. This
diminished reactivity and inertness of less hindered and aryl
isocyanides, respectively, is in accordance with the recent
observations by Ji et al.3f Setting a limitation, the reaction did
not work for the internal alkyne, which produced a non-
isocyanide-inserted product.8
Our curiosity next turned toward the extension of this
reaction to 2-aminophenyl propargyl alcohols 5,10 which might
give valuable indole counterparts 6. Under the standardized
conditions described above, the corresponding product (6) was
obtained only in traces. After some optimization studies,11 we
found that 5 mol % of Pd(TFA)2 in the presence of 2 equiv of
Cs2CO3 in acetonitrile with a slightly elevated temperature (60
°C) allowed the transformation with reasonable to high yields
(Scheme 3). Thus, 3-phenyl-2-indolylacetamide (6a) and its 5-
methyl adduct (6b) were obtained in 72% and 70% yields,
respectively. Then a variety of the substrates were synthesized
from various commercially or readily available 2-amino-
acetophenones and 2-aminobenzophenones10 to evaluate the
generality of the method.
Halogen groups on the core reaction part (5c) as well as on
the pendant phenyl ring (5d−j) were well tolerated in the
reaction to produce the corresponding products 6c−j in yields
ranging from 65% to 85%.
Methoxy-substituted substrate 5k also smoothly transformed
to the indolylacetamide 6k in 80% yield. The 3-methyl-2-
B
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Letter
a
Scheme 3. Synthesis of α-Indolylacetamides 6 via Aminopalladation and Isocyanide Insertion
a
Reaction conditions: R1NC(2.0 mmol), 5 (1.0 mmol), base (2.0 mmol), Pd(TFA)2 (0.05 mmol), MeCN (0.3 M), open air, 60 °C.
indolylacetamide 6l was obtained in moderate yield of 55%,
which can be attributed to the instability of the substrate 5l that
could not be purified but was used as the crude product after
the Grignard reaction. Surprisingly, electron-poor substrate 5m
was found to be unreactive in the transformation, which is in
sharp contrast to its benzofuran counterpart (4d, 4h, 4n, and
4s) synthesis. Next, tetramethylbutyl isocyanide was used as the
reaction partner with various halo-substituted and methoxy-
substituted substrates to obtain the corresponding products
6n−r in 62−72% yields. Unfortunately, less hindered isopropyl
isocyanide and phenyl isocyanide were found to be unreactive
in the reaction. In addition, the internal alkyne found to be
inert in the reaction even after the prolonged reaction time and
at the elevated temperatures.8
1
The structures of all the products were characterized by H
NMR, 13C NMR and HRMS. For unambiguous structure
confirmation, we have taken single-crystal X-ray structures of
4b and 6j12 (one from each group of products) which are
depicted in Figure 1.
A plausible mechanism for the cascade of reactions in the
above transformations is described in Figure 2. We speculate
that the palladium catalyst shuttles between two oxidation
states (2 and 0) in each cycle, which helps effective
regeneration of the catalyst without the use of any oxidant.
Accordingly, activation of alkyne moiety by PdX2 may lead to
oxy/amino palladation in anti and 5-exo-dig fashion to give
intermediate A. Isocyanide insertion (B) followed by
coordination palladium with spatially closer hydroxyl group
would form 6-membered oxapalladacycle C. Reductive
elimination of Pd(0) followed by its immediate insertion in
to allylic ether of D, a well-established phenomenon, in the
newly formed strained 5-membered oxacycle may give 6-
membered oxapalladacycle E which on protodepalladation by
two molecules of HX (generated in the cycle) would lead to the
formation of intermediate F. The concomitant 1,3-H shift and
tautomerization of the iminol group would furnish 4 and
protected 6 (G). The sensitive trifluoroacetyl group in 6 would
Figure 1. X-ray crystal structures of 4b (CCDC No. 978848) and 6j
(CCDC No. 996275).12
subsequently undergo hydrolysis in the presence of Pd(II) with
the help of moisture (air) to liberate 6.
In conclusion, a novel and efficient palladium-catalyzed
intramolecular oxy/aminopalladative isocyanide insertion ap-
proach for the synthesis of 2-benzofuranyl/indolylacetamides is
C
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Figure 2. Proposed catalytic cycle.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and copies of H and 13C spectra for
1
compounds 4a−v, 5, and 6a−r. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(7) Gabriele, B.; Mancuso, R.; Salerno, G.; Plastina, P. J. Org. Chem.
2008, 73, 756−759.
*E-mail: msreddy@cdri.res.in, sridharreddymaddi@yahoo.com.
Notes
(8) See the Supporting Information.
The authors declare no competing financial interest.
(9) (a) Li, X.; Xue, J.; Chen, R.; Li, Y. Synlett 2012, 23, 1043−1046.
(b) Schevenels, F.; Tinant, B.; Declercq, J.-P.; Marko, I. E. Chem.
Eur. J. 2013, 19, 4335−4343.
ACKNOWLEDGMENTS
■
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12, 2841−2843. (b) Jeffrey, A. S.; Gregory, J. P.; Richard, F. C.; Jill, R.
C.; George, F. D.; Stephen, S. G.; David, K. J.; George, W. K.; Maggie,
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(c) Gao, W. C.; Jiang, S.; Wang, R. L.; Zhang, C. Chem. Commun.
2013, 49, 4890−4892. (d) Aurelio, L.; Flynn, B. L.; Scammells, P. J.
Org. Biomol. Chem. 2011, 9, 4886−4902. (e) Amegadzie; Kudzovi, A.
PCT Int. Appl. 091226, Nov 6, 2003. (f) Zhang, P.; Terefenko, E. A.;
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We thank Dr. Tejender S. Thakur of the MSB Division, CSIR-
CDRI, for supervising the X-ray data collection and structure
determination. N.T., M.H.B., and V.D. thank CSIR for the
fellowships. We thank SAIF division CSIR-CDRI for the
analytical support. We gratefully acknowledge financial support
by CSIR-Network project “BSC0102” (CSIR-CDRI-THUN-
DER) and by DST under “Fast Track Proposal Scheme for
Young Scientists” (CS-399/2012). CDRI Communication No:
8688.
(11) For optimization studies, see the Supporting Information.
(12) The ORTEP diagram of 6j in Figure 1 shows an average
structure of two atropisomers, and hence, the F atom is shown 50%
each on both ortho positions of the pendant phenyl ring.
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