Divergent Syntheses of Indoles and Quinolines Involving N1-C2-C3 Bond Formation through Two Distinct Pd Catalyses

Article abstract of DOI:10.1021/acs.orglett.0c02898

Pd-catalyzed annulative couplings of 2-alkenylanilines with aldehydes using alcohols as both the solvent and hydrogen source have been developed. These domino processes allow divergent syntheses of two significant N-heterocycles, indoles and quinolines, from the same substrate by tuning reaction parameters, which seems to invoke two distinct mechanisms. The nature of the ligand and alcoholic solvent had a profound influence on the selectivity and efficiency of these protocols. Particularly noteworthy is that indole formation was achieved by overcoming two significant challenges, regioselective hydropalladation of alkenes and subsequent reactions between the resulting Csp3-Pd species and less reactive imines.

Full text of DOI:10.1021/acs.orglett.0c02898

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Letter
Divergent Syntheses of Indoles and Quinolines Involving N1−C2−C3
Bond Formation through Two Distinct Pd Catalyses
Su San Jang, Young Ho Kim, and So Won Youn*
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ABSTRACT: Pd-catalyzed annulative couplings of 2-alkenylanilines with
aldehydes using alcohols as both the solvent and hydrogen source have been
developed. These domino processes allow divergent syntheses of two
significant N-heterocycles, indoles and quinolines, from the same substrate
by tuning reaction parameters, which seems to invoke two distinct mechanisms.
The nature of the ligand and alcoholic solvent had a profound influence on the
selectivity and efficiency of these protocols. Particularly noteworthy is that
indole formation was achieved by overcoming two significant challenges,
regioselective hydropalladation of alkenes and subsequent reactions between
the resulting Csp3−Pd species and less reactive imines.
Scheme 1. Divergent Domino Reactions for Selective
Formation of N-Heterocycles
ransition-metal-catalyzed domino annulations enable
Tseveral transformations in one operation with high
selectivity and efficiency, leading to synthesis of a diverse
range of carbo- and heterocycles from relatively simple starting
materials.1 In these reactions, the subsequent reactions occur
as a consequence of the functionality achieved in the prior step.
Thus, switching the reacting sequence may allow access to
diverse scaffolds. In recent years, catalytic reactions to
transform common substrates or intermediates into distinct
molecular scaffolds have increasingly been explored. In this
regard, use of different ligands often allows modulation of
chemo- and/or regioselectivity, resulting in selective formation
of divergent products.2
Pd-catalyzed cyclization of nitrogen-containing unsaturated
compounds is a straightforward method for constructing N-
heterocycles such as indoles and quinolines.1a−i When
aldehydes are added as another reactant in this process, two
reaction pathways could occur: (1) aminopalladation followed
by nucleophilic addition of the resulting Pd species to
aldehydes (Scheme 1a, path a) or (2) initial imine formation
followed by annulative coupling (path b).
For path a, Han and Lu reported a cationic Pd-catalyzed
domino aminopalladation, nucleophilic addition with alde-
hydes, and protonation to afford 2-aryl-3-hydroxymethylin-
doles involving the alkenylpalladium (Csp2−Pd) species (left
upper quadrant in the box of Scheme 1a).3a Recently, Huang
successfully demonstrated such reactions with alkenylamines
by controlling β-hydride elimination of the resulting
alkylpalladium (Csp3−Pd) species,4 which is highly challenging
(left lower quadrant).3b In this protocol, only electron-
donating alkyl groups on the N atom could promote the
reaction, while free NH2 gave only the corresponding imines
resulting from the reaction with aldehydes.
In contrast, a different reaction order in Pd catalysis (path b)
was observed by Yamamoto’s group. The initial imine
formation triggers hydropalladation of an alkyne moiety
followed by annulative addition of the resulting Csp2−Pd
species to imine, leading to 3-alkenylindoles by forming the
N1−C2−C3 bonds of the pyrrole nucleus of indoles (right
Received: September 1, 2020
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© XXXX American Chemical Society
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upper quadrant).5 Related cationic Pd-catalyzed tandem
processes involving initial hydropalladation and sequential
intramolecular addition of alkyne-tethered carbonyl com-
pounds using ethanol as a hydrogen source were also reported
by Han and Lu.6 Inspired by these prior studies,3b,5,6 we
envisioned that initially formed imines from 2-alkenylanilines
and aldehydes might undergo regioselective hydropalladation
of alkenes followed by annulative coupling of the resulting
Csp3−Pd species with an imine to give indoles (right lower
quadrant).
Table 1. Optimization Studies
Here, we disclose the realization of this proposal. Pd-
catalyzed annulative couplings of 2-alkenylanilines with
aldehydes led to divergent syntheses of indoles and quinolines,
which are both significant heterocycles due to their ubiquity
and broad applications (Scheme 1b).7,8 In sharp contrast to
prior work using 2-alkynylanilines,9,10 alcohols were used as
both the hydrogen source11 and solvent rather than a
nucleophile, in the reactions presented herein.
Considering several reports on the effect of N-protecting
groups in aminopalladation,3,12 we first examined various N-
protecting groups under Huang’s conditions3b to identify one
with a delicately balanced nucleophilicity for aminopalladation
and imine/iminium ion formation.13 Among them, N-Boc, N-
alkyl, and NH2 free derivatives afforded the desired products,
and NH2 free anilines were the optimal substrate for this
reaction, promoting rapid imine formation rather than
aminopalladation.
Subsequently, we conducted an extensive investigation of
this process using 1a and PhCHO. Ideally, suitable ligands
could stabilize the speculated Csp3−Pd species and allow
switching of the regioselectivity of the proposed reaction. After
careful examination of the reaction parameters, we found that a
reagent blend consisting of [Pd(allyl)Cl]2 and Xantphos in
EtOH afforded 3a along with a smaller amount of 4a.13 When
the solvent was changed to F-containing alcohol, the ratio of
4a to 3a increased (entries 5 and 6). Selectivity for 4a was
markedly improved by switching the ligand from Xantphos to
DPEphos in F-containing alcohol solvents (entries 13−16).
From the evaluation of bidentate phosphine ligands (Table 1,
bottom), we observed preliminary relationships among ligand
bite angle, reactivity, and selectivity.14 With the exception of
dppf, bisphosphine ligands with bite angles of ∼110° showed
good efficiency for indole formation, and the use of Xantphos
(108°) provided the best result, while DPEphos had an
optimal bite angle (104°) for quinoline formation.
a
1
Determined by H NMR. Values in parentheses indicate isolated
b
c
d
e
yields. Using (Z)-1a instead of (E)-1a. For 4 h. At 100 °C. Yields
of 3a/4a. Using 2.5 mol % Pd catalyst and 5.5 mol % ligand at 120
°C.
f
Although Conditions A and B selectively provided 3a and
4a, respectively, the selectivity for 3a over 4a and the yields of
both were only moderate. In addition, although the ratio of 4a
to 3a was generally good under Conditions B, a non-negligible
amount of an indoline side product (e.g., 5a)13 was always
observed. Therefore, a variety of additives were examined to
determine more effective conditions, but no beneficial effect
was obtained in any case.
Under Conditions A and B, the reaction of (Z)-1a also
afforded 3a and 4a, respectively, in comparable selectivity but
lower yields compared to (E)-1a (entry 7 vs 8, entry 19 vs 20).
During the course of these studies, we observed that
substituents residing on the aromatic moiety of anilines had
a very intriguing effect on the reactivity and selectivity of
indole formation. When 1b (R = Me) was used as a substrate,
both yield and ratio of products were significantly improved to
afford 3b as the sole product in 90% yield (entry 9), while this
was unsuitable for quinoline formation (entry 21). While the
reason for this substituent effect in indole synthesis remains
unclear at this stage, we surmised that the steric effect of ortho-
Me substituent might render the imine’s C atom being in close
proximity to a speculated Csp3−Pd species (arising from
hydropalladation of alkene) to cause a more favorable
subsequent reaction (for a detailed explanation, see the
Supporting Information).13
It should be noted that both cationic Pd(II) species3a,15 and
typical Lewis acids were unable to promote this reaction for
formation of 3a, whereas all tested Lewis acids afforded 4a in
low to moderate yield.13 These findings suggest that indole
formation under Conditions A is unlikely to involve Lewis acid
catalyzed electrophilic cyclization via imine activation, which
might be involved in the synthesis of quinolines under
Conditions B.16 Control experiments indicated that all the
B
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reaction components (Pd, ligand, alcohol) were necessary for
both reactions to occur (entries 10−12 and 22−24).
With viable catalytic systems for each indole and quinoline
synthesis, we explored the substrate scope of these processes.
First, we examined the reaction of various aldehydes with 1b
under Conditions A (Scheme 2a). In general, a variety of
Next, we explored the substituent effect (R1) at the alkene
moiety of 1 (Scheme 2b-1). Various (hetero)aryl-substituted
alkenes smoothly underwent this reaction to afford 3aa−an in
good to high yields. Unfortunately, alkyl-substituted alkenes
resulted in low conversion. The effects of substituents (R2)
residing on the aromatic moiety of 1 were also investigated
(Scheme 2b-2). As mentioned earlier, a methyl substituent at
the ortho position had a significant influence on chemical
reactivity, forming 3at−au with excellent yields and
selectivities. In contrast, other substituents (e.g., OMe, OH,
F) located at the same position had deleterious effects,
producing low yields (7−24%) of the desired products.
a
Scheme 2. Substrate Scope: Indoles
As shown in Scheme 3, diversely substituted 1 and 2 could
also be successfully employed to give the corresponding 2,3-
a
Scheme 3. Substrate Scope: Quinolines
a
Isolated yields. In most cases, indole (e.g., 3a) and indoline (e.g., 5a)
1
byproducts were obtained in 0−≤5% and 10−25% H NMR yields,
respectively, unless otherwise noted. Indoline byproducts were not
observed. 7b was obtained in 14% yield.
b
a
Isolated yields. Quinoline byproducts (e.g., 4a) were obtained in
c
b
≤5% yields unless otherwise noted. Quinolines were obtained in 5−
c
15% 1H NMR yields. Quinolines were obtained in 15−25% 1H NMR
d
yields. Inseparable mixture of 3f and dechlorinated product (i.e., 3b)
e
diaryl-substituted quinolines 4, albeit in moderate yields. We
note that various functional groups were commonly well
tolerated in both indole- and quinoline-forming reactions
except for a nitro group. No matter where the NO2 group
resided in 1 and 2, no reaction occurred or only imine
intermediates were observed.
A series of control experiments were performed to gain
mechanistic insight into these reactions.13 Imine intermediates
such as 6a were observed during the reaction progress.
Therefore, probable intermediates (6a−b) were synthesized
and subjected to Conditions A and B. Each reaction resulted in
formation of 3b and 4a in 88% and 40% yield, respectively
was obtained with a 10:1 ratio in 74% combined yield. 2.1 equiv of
1b and 1 equiv of terephthalaldehyde were used.
arylaldehydes were well tolerated with little electronic and
steric dependence, leading to diversely substituted indoles
(3a−s) in high yields with good to excellent selectivities.
Heteroaryl- (3t-v), ester- (3w), alkenyl- (3x), and secondary
alkyl-substituted (3y) aldehydes proved to be suitable, while
the reaction failed with primary alkylaldehydes. The reaction
with terephthalaldehyde proceeded uneventfully to afford
bisindole 3z in 71% yield.
C
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(Scheme 4a); the latter result is distinct from a related Pd
catalysis reported by Jiang.17
while the latter produced 3-methylindole 3aw along with 4w,
albeit in low yields (Scheme 4e). This constitutes evidence
against an electrophilic pathway involving a carbocationic
intermediate and ethanol as a proton source in the indole-
forming reaction under Conditions A.
Scheme 4. Mechanistic Studies
Although more detailed investigations are needed to clarify
the mechanism, our experimental findings suggest that these
two reactions proceed through different mechanistic path-
ways.13 For quinoline (4) synthesis, the reaction seems to take
place through 6π-electrocyclization of imine intermediates (6)
promoted by Lewis acidic Pd salt.16 In sharp contrast, indole
(3) formation presumably commences with regioselective
insertion of the alkene moiety of 6 into the Pd−H bond.19
Then, subsequent reactions between the resulting Csp3−Pd
species and imine moiety may occur through either oxidative
addition/reductive elimination17 or carbopalladation/β-hy-
dride elimination,5,6 followed by isomerization to afford 3.
To highlight the synthetic utility of this transformation,
dearomatization of indoles, a powerful tool for construction of
spiroindolenine and polycyclic indoline skeletons,20 was
undertaken (Scheme 5). I2-mediated cyclization21 and
Scheme 5. Synthetic Applications
Next, deuterium-labeling experiments were carried out. The
reaction of 1b or 1a with PhCDO afforded 3b or 4a with no
deuterium incorporation (Scheme 4b), excluding the involve-
ment of initial oxidative addition of an imine C−D bond to
Pd17 followed by carbopalladation or hydropalladation to an
alkene moiety. When the reaction of 1b with 2a was carried
out in CH3CH2OD under Conditions A, indole 3b with
deuterium at the benzylic position of the C3 substituent (88%
D) was formed, whereas no deuterium incorporation was
observed in CH3CD2OH (Scheme 4c, upper).11e−g Similarly,
quinoline 4a deuterated at the C4 position (42% D) was
obtained using CF3CH2OD under Conditions B, while
deuterium was not incorporated into 4a in CF3CD2OH
(Scheme 4c, lower). These findings indicate that the incoming
hydrogen atoms for the benzylic position of the C3 substituent
of 3b and for the C4 position of 4a are derived from O−H
groups11c−i instead of the αC−H bond of alcohols.6,11j−p
Moreover, as mentioned, quinoline synthesis was accompanied
by some byproducts, such as N-benzylanilines (7) generated
by reduction of 618 and their cyclized products, indolines (e.g.,
5a).13 Interestingly, 7 deuterated at the benzylic position was
also obtained in the reactions using ROD-type solvents.
Competition experiments with deuterium-labeled 2a demon-
strated a kinetic isotope effect of 3.5 (Scheme 4d), suggesting
that C−H bond cleavage of imine17 may be involved in the
rate-determining step.
fluoroetherification22 of 3ag proceeded smoothly to afford
spiroindolenine 8a and fused indoline 8b, respectively.
Subsequent acetylation or benzylation gave indolenines 8c−d
containing a fluorinated quaternary carbon center through ring
opening. On the other hand, 3-(indolylmethyl)carbazole
derivatives are known as highly efficient hosts for phosphor-
escent OLEDs23a and as colorimetric/fluorometric detectors of
DNA.23b Reaction of carbazole-tethered 1ao with PhCHO was
readily accomplished to afford 3ax in 88% yield.
In summary, we developed Pd-catalyzed domino annulative
processes, one of which involves the significant challenges
associated with controlling both regioselective hydropallada-
tion and reaction of alkylpalladium species with less reactive
imines. We demonstrated that exquisite tuning of reaction
parameters such as ligand and solvent could modulate the
reaction propensity and pathway for formation of different
molecular frameworks from the same substrate. In these
protocols, alcohols were used as the hydrogen source as well as
solvent, delivering hydrogen atoms from O−H groups rather
than the αC−H of alcohols. To the best of our knowledge, this
represents the first example of Pd-catalyzed domino couplings
between alkenes and imines generated in situ from amines and
Reactions employing β,β-disubstituted (1al−am) and
terminal alkenes (1an) as a substrate were undertaken to
demonstrate that Lewis acid catalyzed Prins-type reac-
tions10,11q,r are a possible mechanistic pathway in the indole-
forming process. The former failed to give the desired indoles,
D
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ASSOCIATED CONTENT
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Accession Codes
CCDC 2012360 and 2012365−2012366 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
So Won Youn − Center for New Directions in Organic Synthesis,
Department of Chemistry and Research Institute for Natural
Sciences, Hanyang University, Seoul 04763, Korea;
orcid.org/0000-0002-2134-6487; Email: sowony73@
hanyang.ac.kr
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T. E.; Katou, K.; Konig, B. Controllable Isomerization of Alkenes by
Dual Visible-Light-Cobalt Catalysis. Angew. Chem., Int. Ed. 2019, 58,
5723. (e) Youn, S. W.; Ko, T. Y.; Jang, Y. H. Palladium-Catalyzed
Regioselective Synthesis of 3-Arylindoles from N-Ts-Anilines and
Styrenes. Angew. Chem., Int. Ed. 2017, 56, 6636. (f) Hyster, T. K.;
Dalton, D. M.; Rovis, T. Ligand design for Rh(III)-catalyzed C−H
activation: an unsymmetrical cyclopentadienyl group enables a
regioselective synthesis of dihydroisoquinolones. Chem. Sci. 2015, 6,
254. (g) Fujino, D.; Yorimitsu, H.; Osuka, A. Regiocontrolled
Palladium-Catalyzed Arylative Cyclizations of Alkynols. J. Am. Chem.
Soc. 2014, 136, 6255. (h) Tang, S.-Y.; Guo, Q.-X.; Fu, Y. Mechanistic
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Activation/Arylation of Thiophenes. Chem. - Eur. J. 2011, 17, 13866.
(3) (a) Han, X.; Lu, X. Pd(II)-Catalyzed Tandem Reaction of 2-
Arylethynylanilines and Aldehydes: An Efficient Synthesis of
Substituted 3-Hydroxymethyl Indoles. Org. Lett. 2010, 12, 3336.
(b) Hu, Y.; Xie, Y.; Shen, Z.; Huang, H. Palladium-Catalyzed Ring-
Forming Aminoalkenylation of Alkenes with Aldehydes Initiated by
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Authors
Su San Jang − Center for New Directions in Organic Synthesis,
Department of Chemistry and Research Institute for Natural
Sciences, Hanyang University, Seoul 04763, Korea
Young Ho Kim − Center for New Directions in Organic
Synthesis, Department of Chemistry and Research Institute for
Natural Sciences, Hanyang University, Seoul 04763, Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02898
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(4) For reviews on the preference of β-hydride elimination of
alkylpalladium species, see: (a) Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: New
York, 2004. (b) Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol. I; Negishi, E.-i., Ed.; Wiley-Interscience: New York,
This work was supported by both the Basic Science Research
Program and Nano·Material Technology Department Program
through the National Research Foundation of Korea (NRF)
funded by the Korea government (MSIT) (Nos.
2012M3A7B4049644, 2018R1A2A2A05018392, and 2014-
011165). We thank Dr. Ji-Eun Lee (Central Instrument
Facility, Gyeongsang National University) for X-ray crystallo-
graphic analysis.
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Catalyzed Alkyl−Alkyl Cross-Coupling Reactions. Angew. Chem., Int.
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