Palladium-Catalyzed Domino Synthesis of 2,3-Difunctionalized Indoles via Migratory Insertion of Isocyanides in Batch and Continuous Flow

Article abstract of DOI:10.1002/adsc.202100339

We report, herein, a palladium-catalyzed cascade comprising carbopalladation, migratory insertion of isocyanide and triple bond activation followed by a nucleophilic attack (OR^?) to construct difunctionalized acyl indoles. The process involves

Full text of DOI:10.1002/adsc.202100339

Title: Palladium-Catalyzed Domino Synthesis of 2,3-Difunctionalized
Indoles via Migratory Insertion of Isocyanides in Batch and
Continuous Flow
Authors: Su Chen, Monica Oliva, Luc Van Meervelt, Erik Van der
Eycken, and Upendra K. Sharma
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100339
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Domino Synthesis of 2,3-Difunctionalized
Indoles via Migratory Insertion of Isocyanides in Batch and
Continuous Flow
Su Chen,a Monica Oliva,a Luc Van Meervelt,b Erik V. Van der Eycken,a,c Upendra K.
Sharmaa,*
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven
(KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Email: upendrakumar.sharma@kuleuven.be, usharma81@gmail.com.
Biomolecular Architecture, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, RU-117198 Moscow, Russia.
b
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. We report, herein, a palladium-catalyzed
cascade comprising carbopalladation, migratory insertion
of isocyanide and triple bond activation followed by a
nucleophilic attack (OR-) to construct difunctionalized acyl
indoles. The process involves multiple bond formations via
key palladium-chemistry steps, to construct these bis-
heterocycles containing two privileged scaffolds (indole
and oxindole) in a single operational step, along with
attempts to generate enantioselectivity at a quaternary
carbon center. The methodology also demonstrates a
continuous-flow process to synthesize aryl isocyanides
within minutes and using them in a telescopic manner.
Keywords: Palladium-catalyzed cascade reaction; domino
cyclizations; isocyanide insertion; triple bond activation;
acyl indoles.
Isocyanides have been at the center stage of various
multicomponent reactions such as the Passerini and
Ugi reaction as irreplaceable building blocks.[1]
Because of their unique reactivity they play an
important role in the synthesis of various heterocycles,
besides being important C-1 precursor analogues to
Scheme 1. Background on 2,3-difunctionalized indoles.
CO.[2] In addition, their ability to coordinate transition-
metal centers, especially palladium, has resulted in a
variety of innovative chemical reactions.[3] Palladium-
toward the rapid generation of molecular diversity and
catalyzed iminoacylation generated by isocyanide
complexity in a minimum number of steps.
insertion is an efficient pathway for the construction of
2,3-Difunctionalized indoles have generated a lot of
C-C, C-O and C-N bonds as well as involving cascade
interest among synthetic chemists due to their
C-H activation processes. Likewise, the Heck-
biological value (Scheme 1a).[7] Among these, some
Mizoroki reaction[4] has been particularly well studied
representative examples (both of natural as well as of
for forming carbo- and heterocyclic scaffolds such as
synthetic origin) find relevance in medicinal chemistry
indoles, benzofurans, and oxindoles, via σ–alkyl
and hence are useful targets. For example,
tryprostatins A and B, natural products isolated from
palladium intermediates in a domino process with a
variety of nucleophiles[5] as well as via intramolecular
Aspergillus fumigatus BM939, can selectively arrest
cascades.[6] In this work, we envisioned creating an
the cell cycle at the mitotic phase in tsFT210 cells.[8]
amalgamation of these transient palladium species
Similarly, Pravadoline is an analgesic drug with
1
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
multiple bioactive derivatives.[9] Henceforth, there
have been continuous efforts to synthesize these
privileged scaffolds and derivatives in a more efficient
manner with an intriguing diversity.[10] In recent years,
cyclizations of o-alkynylisocyanobenzene have been
well studied towards the synthesis of 5- or 6-
membered N-containing heterocycles (Scheme 1b).[11]
However, their synthetic utility has been compromised
owing to their foul odor and unstable nature and hence
are used without purification. Flow chemistry is an
interesting alternative to develop odorless isocyanides,
with easy scale-up options and telescoped synthesis
towards the final product.[12]
We initial explored the feasibility of the proposed
strategy in the reaction by applying N-(2-Iodophenyl)-
N-methylacrylamide
(1a)
and
2-(2-
phenylethynyl)phenyl isocyanide (2a) as test
substrates (Table 1) in the presence of Pd(OAc)2 (5
mol%), Ad2PnBu (10 mol%), and Cs2CO3 (3.0 equiv)
in DMF (3 mL) at 100 °C for 12 h (Table 1, entry 1).
This reaction condition resulted in poor conversion
providing the desired product 3a in 4% yield (for X-
ray crystal structure analysis, see Table 2 and the
Supporting Information). Based on previous reports,
we found that using the syringe pump to slowly drip
the 2-(2-Phenylethynyl)phenyl isocyanide (2a) to the
reaction solution significantly improved the product
3a in 50% yield (entry 2). Considering the oxygen
source (nucleophile) for the last step of this reaction,
different additives were screened (entries 3-5), and
preliminary results showed that the addition of acetic
acid (2 equiv) slightly increased the yield to 52%.
Thereafter, the screening of the bases revealed that
Cs2CO3 performed better than other bases such as
Na2CO3, Et3N, and NaOAc (entries 6-8). Further, we
tested the effect of phosphine ligands (MePhos, Sphos,
Xphos, PPh3, BINAP, Xantphos) (entries 9-14) and
palladium catalysts (Pd(PPh3)4, Pd2(dba)3) (entries 15-
16), but without any positive effects. Considering the
acid-sensitive nature of the isocyanide in the reaction,
we tried CsOAc (3 equiv) to replace the combination
of Cs2CO3 and AcOH (entry 17), which effectively
increased the yield of 3a to 66%. Replacing CsOAc
with NaOAc (3 equiv) alone as the base, trace amount
of product was formed (entry 18). We concluded that
in this reaction CsOAc is not only acting as a base but
also as source of nucleophile under these reaction
conditions as higher yields were obtained by
increasing the amount of CsOAc (entries 19-20). We
finally established the optimized conditions as 1a (0.1
mmol), 2a (0.2 mmol), Pd(OAc)2 (5 mol%), Ad2PnBu
(10 mol%), and CsOAc (5 equiv) in DMF at 100 °C
for 12 h (entry 20).
In continuation of our work on trapping of
intermediate palladium species (alkyl and vinyl) to
trigger various domino reactions,[13] we, herein, report
a
palladium-catalyzed
cascade
comprising
carbopalladation, migratory insertion of isocyanide
and triple bond activation, followed by a nucleophilic
attack (OR-) to construct difunctionalized acyl indoles
in a single operational step under enabling conditions
(Scheme 1c).
Table 1. Optimization of the reaction conditions.[a]
entry catalyst
ligand
base
additive
yield[b] (%)
1[c] Pd(OAc)2 Ad2PnBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
Et3N
NaOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
-
-
4
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 MePhos
Pd(OAc)2 SPhos
Pd(OAc)2 XPhos
Pd(OAc)2 PPh3
Pd(OAc)2 BINAP
Pd(OAc)2 Xantphos Cs2CO3
Pd(PPh3)4 Ad2PnBu
Pd2(dba)3 Ad2PnBu
Pd(OAc)2 Ad2PnBu
Pd(OAc)2 Ad2PnBu
50
trace
4
52
35
51
30
50
15
9
40
13
10
43
20
66
trace
71
77
25
PivOH
H2O
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
-
Encouraged by these results, we investigated the
substrate scope of this reaction under the optimal
conditions.
Initially,
substituted
2-(2-
phenylethynyl)phenyl isocyanides 2 were examined
and most of the functional groups were found to be
well tolerated (Table 2). The effect of the R1
substituent was first investigated. It was found that a
methyl group at the para and ortho position reacted
efficiently to give the desired products 3b and 3d in
good yield (71%, 70%), while methyl substitution at
the meta position decreased the yield to 43% (3c).
Thereafter, few electron-donating groups in para
position (methoxy, ethyl, pentyl and phenyl) were
investigated which afforded the corresponding
products 3e-3h in a range of 85% to 60%. The weakly
electron-withdrawing Cl-substitution was tolerated at
the para (3i, 35%), meta (3j, 54%) and ortho position
(3k, 47%) with moderate yields. Strong electron-
withdrawing R1 substituents (CF3 and CO2Me) were
also investigated and gave the desired products 3l−3m
in 60% and 20% yields, respectively. This indicates
Cs2CO3
Cs2CO3
CsOAc
NaOAc
CsOAc
CsOAc
CsOAc
-
-
-
-
19[d] Pd(OAc)2 Ad2PnBu
20[e] Pd(OAc)2 Ad2PnBu
21[e, f] Pd(OAc)2 Ad2PnBu
[a]
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), 5
mol% of catalyst, 10 mol% of ligand, 3.0 equiv of base,
2.0 equiv of additive in DMF (1 mL) with stirring under
nitrogen for 12 h. Oil bath temperature 100 °C;
isocyanide 2a in DMF (2 mL) was added dropwise to the
solution by using a syringe pump within 1 h.
Isolated yield.
No slow addition of the isocyanide.
4 equiv of base.
5 equiv of base.
open air conditions. Ad = 1-adamantyl.
[b]
[c]
[d]
[e]
[f]
2
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
that the electronic nature of R1 substitution of the aryl
employment of a trimethylsilyl group (TMS) resulted
isocyanides has a strong influence on the reaction yield. in desilyation 3r in 46% yield. Introduction of
substituents of R2 (4-F and 4-Cl) was well tolerated,
Table 2: Substrate scope for various isocyanides.a
giving the corresponding products 3s and 3t in 35%
and 56%, respectively. However, the substrate bearing
a 4-Br substituent did not afford the desired product 3u,
as some unidentified side products were formed.
We next turned our attention to examine N-(2-
Iodophenyl)-N-methylacrylamide derivatives (1)
under standard conditions (Table 3). Introducing an
electron-donating methyl group or an electron-
withdrawing group (CF3) to the 2-iodoaniline core
resulted in 64% yield. Notably, employing other
electron-withdrawing groups, such as fluoro, chloro
and bromo the indoles 4c, 4d and 4e could be isolated
in 59%, 71% and 25% yield, respectively, offering the
possibility for further functionalization. Then, the
substitution on the acrylamide core was evaluated. The
desired domino reaction of 2-phenylacrylamide
proceeded smoothly giving the corresponding acyl
indole 4f in 62% yield. Furthermore, the analogous
reaction with carbocyclic aryl halides provided the
corresponding carbohalogenated product 4g in 46%
yield. We also examined the effect of the haloaniline
subunit on the reaction outcome, whereby N-(2-
bromo-3-methylphenyl)-N-methylmethacrylamide
afforded the target product 4h in 71% yield.
During the optimization studies, the intramolecular
asymmetric carbopalladation[14] of N-aryl acrylamides
was also attempted under conditions as described in
Table 1, entry 5, which resulted in a moderate yield
and enantioselectivity of 3a (Scheme 3). Employing
ligand L1, product 3a was obtained in 36% yield with
a low enantioselectivity. Reaction with ligand L2
improved the yield to 77% but with low ee. However,
with L3 43% yield with an ee of 73% was obtained.
Using the optimized conditions (Table 1, entry 20), the
yield and ee were not improved further (for details, see
the SI).
[a]
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol),
Pd(OAc)2 (5 mol%), Ad2PnBu (10 mol%), CsOAc (5
equiv) in DMF (1 mL) at 100 °C under N2 for 12 h. A
solution of isocyanide 2 in DMF (2 mL) was added by
using a syringe pump within 1 h.
Table 3: Substrate scope of acrylamide.a
[a]
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol),
Pd(OAc)2 (5 mol%), Ad2PnBu (10 mol%), CsOAc (5
equiv) in DMF (1 mL) at 100 °C, in N2 for 12 h. A
solution of isocyanide 2a in DMF (2 mL) was added by
using a syringe pump within 1 h.
Scheme 2: Enantioselective version of the reaction.
Aryl isocyanides are commonly synthesized from
the corresponding anilines via formylation, followed
by dehydration. The precursors (N-formylaniline and
anilines) are bench stable, easy to handle, with high
commercially availability in contrast to aryl
isocyanides which have a pungent odor and are
Furthermore, the replacement of the phenyl group
with a naphthyl, thiophenyl and even an aliphatic
substituent (tert-butyl, and cyclohexyl) affords the
desired products 3n-3q in low to moderate yields. The
3
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
unstable. Thus, encouraged by the work of Kim[12a] and
Jamison,[15] we developed an odorless isocyanide
chemistry in which the aryl isocyanides can be
synthesized in situ from the formanilides (for details
and optimization experiments see the SI). This
telescopic procedure led to the formation of the desired
compound 3a in 58% yield in two steps (Scheme 3).
To further validate our optimized flow conditions for
the synthesis of difunctionalized acyl indoles 3, we
performed the preparation and in-line aqueous
extraction of isocyanides to construct 3a (82%), 3e
(88%), 3i (35%), 3m (29%), and 4e (43%) under batch
conditions. Pleasingly, this resulted in a slight increase
in yields, compared to normal batch synthesis of
isocyanides (for details see SI, Scheme S1).
Scheme 4: Control experiment.
Based on the previous reports and control
experiments, a plausible catalytic cycle of this reaction
is outlined in scheme 5. The reaction begins with the
oxidative addition of Pd(0) to the C-I bond of N-(2-
Iodophenyl)-N-methylacrylamide 1a, forming the
arylpalladium species A, which undergoes
intramolecular
carbopalladation
to
generate
intermediate B. Subsequent migratory insertion of the
2-(2-phenylethynyl)phenyl isocyanide 2a into the
intermediate B furnishes the imidoyl palladium
species C. Intramolecular addition to the triple bond
and further attack of an oxy-nucleophile generate
intermediate D. Thereafter, reductive elimination of
intermediate
D resulted in the formation of
intermediate E, followed by an isomerization step to
deliver the desired product 3a.
Scheme 3: Continuous-flow synthesis of isocyanide and its
direct use for the synthesis of difunctionalized acyl indoles.
Scheme 5: Proposed mechanism.
To identify the oxygen source in product 3a isotope
labelling studies were performed. The 18O
incorporated product 3a-18O was formed in the
In summary, we have developed an efficient
methodology comprising a cascade carbopalladation,
18
presence of H2 O as an additive under standard
reaction conditions, delivering a mixture of 3a and 3a-
18O in 20% isolated yield. Molecule 3a-18O was
detected by LC−MS (EI) analysis (see Supporting
Information). The experiment suggested that H2O is
one of the oxygen sources, and other species such as
acetate and carbonate could also supply an oxygen-
atom (Scheme 4).
an
isocyanide
insertion
and
an
alkyne
functionalization to construct difunctionalized aryl
indoles. Over 29 examples of structurally and
functionally diverse products were successfully
synthesized. Moreover, initial exploration of the
asymmetric
reaction
provided
moderate
enantioselectivity. Furthermore, we have also
extended the methodology to a continuous-flow
platform comprising synthesis, in-line aqueous work-
up and consumption of isocyanide in a single step
providing odorless isocyanide chemistry.
4
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
Experimental Section
[2] Representative examples see: a) C. G. Saluste, R. J.
Whitby, M. Furber, Angew. Chem. 2000, 112, 4326-
4328; Angew. Chem. Int. Ed. 2000, 39, 4156-4158; b) H.
Jiang, B. Liu, Y. Li, A. Wang, H. Huang, Org. Lett. 2011,
13, 1028–1031; c) T. Soeta, K. Tamura, Y. Ukaji, Org.
Lett. 2012, 14, 1226-1229; d) V. N. Bochatay, P. J.
Boissarie, J. A. Murphy, C. J. Suckling, S. Lang, J. Org.
Chem. 2013, 78, 1471-1477; e) C. H. Lei, D. X. Wang,
L. Zhao, J. Zhu, M. X. Wang, J. Am. Chem. Soc. 2013,
135, 4708-4711; f) Y. J. Liu, H. Xu, W. J. Kong, M.
Shang, H. X. Dai, J. Q. Yu, Nature 2014, 515, 389-393;
g) Y. Y. Pan, Y. N. Wu, Z. Z. Chen, W. J. Hao, G. G. Li,
S. J. Tu, B. Jiang, J. Org. Chem. 2015, 80, 5764-5770;
h) Q. Gao, P. Zhou, F. Liu, W. J. Hao, C. S. Yao, B.
Jiang, S. J. Tu, Chem. Commun. 2015, 51, 9519-9522.
General procedure for the synthesis of isocyanides 2: To
a solution of formanilide (0.200 mmol, 1equiv.) and
(iPr)2NEt (1.6 mmol, 8 eqiuv.) in DCM (0.1M), was slowly
added POCl3 (0.3 mmol, 1.5 equiv.) at 0 °C and stirred at
the same temperature for 4 h. After the total conversion of
the starting material, the reaction was quenched with a
saturated aqueous solution of NaHCO3 and extracted with
DCM. The combined extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure to
dry. The obtained solution was filtered through alumina
column chromatography with EtOAc. The obtained solution
was concentrated under reduced pressure without further
purification and used for the next step.
General procedure for the synthesis of product 3: A 4 mL
screw cap vial equipped with a stirring bar containing 1
(0.100 mmol, 1.0 equiv.), Pd(OAc)2 (5 mol%), Ad2PnBu (10
mol%) and CsOAc (0.5 mmol, 5.0 equiv), was evacuated
and purged with nitrogen three times. N,N-
Dimethylformamide (1 mL) was sequentially added to the
system at rt. The reaction mixture was heated with stirring
at 100 °C. Then the freshly prepared 1-isocyano-2-
(phenylethynyl)benzene 2 in DMF (2 mL) was added
dropwise to the solution using a syringe pump in 1 h. After
the addition of isocyanide, the reaction mixture was stirred
at 100 °C for another 11 h. After cooling to rt, the reaction
mixture was diluted with EtOAc and washed with H2O. The
aqueous phase was extracted with EtOAc, and the combined
organic phases were dried over Na2SO4. After filtration and
evaporation under reduced pressure, the residue was
purified via silica gel column chromatography directly by
using n-heptane/ethyl acetate (3:1, v/v) as eluent to give the
corresponding products. The structures were confirmed via
1H NMR, 13C NMR and HRMS-ESI.
[3] Selected reviews see: a) T. Vlaar, E. Ruijter, B. U. W.
Maes, R. V. A. Orru, Angew. Chem. 2013, 125, 7222-
7236; Angew. Chem. Int. Ed. 2013, 52, 7084–7097; b)
G. Qiu, Q. Ding, J. Wu, Chem. Soc. Rev. 2013, 42, 5257-
5269; c) S. Lang, Chem. Soc. Rev. 2013, 42, 4867-4880;
d) V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin, V. Y.
Kukushikin, Chem. Rev. 2015, 115, 2698-2779; e) J. W.
Collet, T. R. Roose, E. Ruijter, B. U. Maes, R. V. Orru,
Angew. Chem. 2020, 132, 548-566; Angew. Chem. Int.
Ed. 2020, 59, 540 -558; f) J. W. Collet, T. R. Roose, B.
Weijers, B. U. W. Maes, E. Ruijter, R. V. A.
Orru, Molecules 2020, 25, 4906.
[4] a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn.
1971, 44, 581-581; b) R. F. Heck, J. P. Nolley, J. Org.
Chem. 1972, 37, 2320-2322.
X-Ray Diffraction Study of 3a
CCDC-2062995 (3a) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data request/cif.
[5] Selected reviews see: a) S. Ma, Z. Gu, Angew. Chem.
2005, 117, 7680-7685; Angew. Chem. Int. Ed. 2005, 44,
7512-7517; b) Y. Liu, S.-J. Han, W.-B. Liu, B. M. Stoltz,
Acc. Chem. Res. 2015, 48, 740–751; c) Z. Garlets, D. R.
White, J. P. Wolfe, Asian J. Org. Chem. 2017, 6, 636-
653; d) J. Li, S. Yang, W. Wu, H. Jiang, Chem. Asian J.
2019, 14, 4114-4128; e) H. A. Dondas, M. D. G.
Retamosa, J. M. Sansano, Organometallics 2019, 38,
1828-1867; f) Y. Ping, Y. Li, J. Zhu, W. Kong, Angew.
Chem. 2019, 131, 1576-1587; Angew. Chem. Int. Ed.
2019, 58, 1562-1573.
Acknowledgements
The authors wish to thank the FWO Fund for Scientific Research-
Flanders (Belgium) and the Research Fund of the University of
Leuven (KU Leuven) for financial support. SC is grateful to the
University of Leuven for the doctoral funding. MO is thankful to
the FWO for her PhD fellowship. LVM thanks the Hercules
Foundation for supporting the purchase of the diffractometer
through project AKUL/09/ 0035. This paper has been supported
by the RUDN University Strategic Academic Leadership Program.
[6] Selected examples: a) R. Grigg, P. Fretwell, C.
Meerholtz, V. Sridharan, Tetrahedron 1994, 50, 359-
370; b) D. Brown, R. Grigg, V. Sridharan, V.
Tambyrajah, Tetrahedron Lett. 1995, 36, 8137-8140; c)
T. Piou, L. Neuville, J. Zhu, Org. Lett. 2012, 14, 3760-
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2012, 124, 11729-11733; Angew. Chem. Int. Ed. 2012,
51, 11561-11565; e) V. P. Mehta, J.-A. Garcia-Ljpez,
Chem. Cat. Chem 2017, 9, 1149-1156; f) I. Franzoni, H.
Yoon, J.-A. GarcíaLopez, A. I. Poblador-Bahamonde, M.
Lautens, Chem. Sci. 2018, 9, 1496-1509; g) Z. Zuo, J.
Wang, J. Liu, Y. Wang, X. Luan, Angew.
Chem. 2020, 132, 663 -667; Angew. Chem. Int. Ed. 2020,
59, 653-657.
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
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10.1002/adsc.202100339
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-Catalyzed Domino Synthesis of 2,3-
Difunctionalized Indoles via Migratory Insertion of
Isocyanides in Batch and Continuous Flow
Adv. Synth. Catal. Year, Volume, Page – Page
Su Chen, Monica Oliva, Luc Van Meervelt, Erik V.
Van der Eycken, Upendra K. Sharma*
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