Synthesis of C3,C4-Disubstituted Indoles via the Palladium/Norbornene-Catalyzed ortho-Amination/ ipso-Heck Cyclization

Article abstract of DOI:10.1021/acs.orglett.1c01165

Herein, we report the synthesis of C3,C4-disubstituted indoles via the palladium/norbornene cooperative catalysis. Utilizing N-benzoyloxy allylamines as the coupling partner, a cascade process involving ortho-amination and ipso-Heck cyclization takes plac

Full text of DOI:10.1021/acs.orglett.1c01165

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Letter
Synthesis of C3,C4-Disubstituted Indoles via the Palladium/
Norbornene-Catalyzed ortho-Amination/ipso-Heck Cyclization
Alexander J. Rago and Guangbin Dong*
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ABSTRACT: Herein, we report the synthesis of C3,C4-disubsti-
tuted indoles via the palladium/norbornene cooperative catalysis.
Utilizing N-benzoyloxy allylamines as the coupling partner, a cascade
process involving ortho-amination and ipso-Heck cyclization takes
place with ortho-substituted aryl iodides to afford diverse indole
products. The reaction exhibits good functional group tolerance, in
addition to tolerating a removable protecting group on the indole
nitrogen. Divergent reactivity has been observed using the allylamine coupling partner containing more substituted olefins.
Construction of the core framework of mitomycin has also been attempted with this strategy.
ndole and its closely related heterocycles are highly
prevalent in natural products and drug molecules (Figure
reagent.6 The development of coupling with N-benzoyloxy
amines as electrophiles in 2013 allows convenient installation
of various amine moieties at the arene ortho position via the
Pd/NBE catalysis.7 Recently, the Liang group disclosed an
ortho-amination of 2-iodoanilines followed by ipso-cyclization
with norbornadiene and then a retro-Diels−Alder reaction to
access 4-aminoindoles.8 More recently, an ortho-amination
followed by demethylative annulation with internal alkynes was
reported for indole synthesis with moderate efficiency (Scheme
1c).9
I
1).1 Consequently, they have been attractive scaffolds for
In this communication, we describe a convenient method for
preparing C3,C4-disubstituted indoles via an ortho-amination/
Heck cyclization cascade10 between common 2-substituted aryl
iodides and readily available N-benzoyloxy allylamines
(Scheme 1d). It can be envisioned that, upon forming the
key aryl-norbornyl-palladacycle (ANP), the reaction with the
electrophile should install an allylamine moiety at the ortho
position of the arene. Upon NBE extrusion, an ipso-Heck is
expected to take place; the resulting exocyclic alkene then
isomerizes to the more stable internal position to deliver the
indole product.11
The investigation started with 2-iodoanisole (1a) and an N-
methyl-allylamine derived coupling partner (2a) as the model
substrates (Table 1). After careful evaluation of various
reaction parameters, the desired indole product (3aa) was
ultimately formed in 71% yield using Pd(OAc)2 and tri(4-
methoxyphenyl)phosphine as the optimal metal/ligand combi-
Figure 1. Indoles and their derivatives in natural products and
pharmaceuticals
preparation and derivation.1 While numerous effective indole
synthesis methods have been developed to date, it remains
nontrivial to prepare C3,C4-disubstituted indoles in a modular
manner.2 On the other hand, the palladium/norbornene
cooperative catalysis, first reported by Catellani,3 represents
an emerging useful tool for modular synthesis of polysub-
stituted arenes.4 In this transformation, an electrophile and a
nucleophile are coupled at the arene ortho and ipso positions,
respectively (Scheme 1a). Seminal work by Lautens in 2010
described a novel preparation of C2,C7-disubstituted indoles
through an ortho-alkylation/ipso-amination cascade of aryl
iodides with highly strained 2H-azirines (Scheme 1b).5 In
2018, the Liang group devised an elegant approach to
synthesize indolines using widely available aziridines as the
Received: April 4, 2021
Published: April 26, 2021
https://doi.org/10.1021/acs.orglett.1c01165
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3755−3760
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a
Scheme 1. Indole Synthesis via the Pd/NBE Catalysis
Table 1. Selected Optimization of the Reaction Conditions
change from the “standard”
yield of 3aa
yield of 4a
b
b
entry
condition
(%)
(%)
c
1
none
71 (67)
7
2
3
4
5
6
7
8
9
25 mol% ligand
30 mol% ligand
51
65
64
56
38
17
n.d.
67
69
62
14
12
15
13
22
−
−
−
9
15
PPh3 as the ligand
P(p-CF3-Ph)3 as the ligand
P(2-furyl)3 as the ligand
N2 instead of NBE
N3 instead of NBE
N4 instead of NBE
50 mol% NBE
10
11
1:1 1,4-dioxane/toluene as
solvent
12
1,4-dioxane as solvent
52
19
a
Unless otherwise noted, all reactions were carried out with 1a (0.1
b
mmol) and 2a (0.2 mmol), in 1.0 mL of toluene for 18 h. NMR
yields determined using 1,1,2,2-tetrachloroethane as the internal
c
standard; n.d. = not detected; − = not determined. Isolated yield on
a 0.2 mmol scale.
alone resulted in reduced yield and more side-product
formation (entries 11 and 12).
Meanwhile, the kinetic profile of the reaction was measured
(Figure 2). First, the reaction did not show any induction
nation with Cs2CO3 as the base (Table 1, entry 1). A 1:4 ratio
between Pd and the phosphine was found to be necessary to
promote reproducibility of the reaction (Table 1, entries 2 and
3), though the exact reason is unclear (vide infra). Other
monodentate phosphine ligands that are less electron-rich than
tri(4-methoxyphenyl)phosphine or bidentate phosphine li-
gands proved to less efficient and generated more four-
membered side-product 4a (Table 1, entries 4−6 and
Supporting Information, Schemes S1 and S2). It is likely that
tri(4-methoxyphenyl)phosphine can significantly suppress
undesired off-cycle reactivity observed when using the less
electron-rich triarylphosphine ligands. Use of a 5,6-disubsti-
tuted norbornene (N4) was found to deliver similar results as
simple NBE (entry 9).12 Other structurally modified NBEs,13
such as C2-ester-14 and amide-substituted15 NBEs, showed
much lower reactivity, likely due to their steric hindrance when
reacting with bulky electrophile 2a (entries 7 and 8). Reducing
the NBE loading to 50 mol % only gave slightly lower yield and
selectivity (entry 10). Toluene was found to be the best
solvent, which is also consistent with our prior observation
with ortho-amination.7a Increasing the polarity of the solvent
by using a mixture of 1,4-dioxane and toluene or 1,4-dioxane
Figure 2. Kinetic profile of the reaction. NBE (1 equiv) was used.
period, which likely benefited from the excess phosphine ligand
to enable rapid reduction of Pd(II) to Pd(0). The side-product
4a was formed from the beginning of the reaction, alongside
the desired product 3aa, which suggests competing pathways
with the ANP intermediate: oxidative addition with N-
benzoyloxy amine 2a versus direct reductive elimination to
give 4a. The reaction was nearly completed within 1 h,
indicating a rapid reaction rate. Afterward, the coupling partner
2a slowly decomposed, possibly due to the basic reaction
condition and elevated reaction temperature.
With these results in hand, we sought to explore the scope of
the indole-forming reaction (Scheme 2). First, the isolated
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sensitive to the steric environment of the Heck cyclization and
subsequent aromatization. Moreover, a number of heteroarene-
derived iodides were competent substrates, including pyridines
(3ja−c), quinoline (3qa), and benzofuran (3ra). Besides
forming N-methyl indoles, by decreasing the reaction temper-
ature to 80 °C, C3,C4-disubstituted indoles with removable
protecting groups on the nitrogen, i.e., −Bn17 (3jb) and
−PMB18 (3jc), can be constructed with this method.
Scheme 2. Substrate Scope of the ortho-Amination/Heck
Cyclization Cascade
a
Apart from simple allylamine electrophiles, we questioned
whether N-benzoyloxy amines with a more substituted internal
olefin would react in the same manner. Consequently, the
coupling reagents containing a 1,2-disubstituted alkene (2d)
and a trisubstituted alkene (2e) were prepared. Interestingly,
2d provided a separable mixture of the desired indole product
(3ad) and an indoline isomer (3ad′), resulting in a combined
yield of 65% (Scheme 3). In contrast, sole indoline product
(3ae′) was isolated in good yield when using the amine
coupling partner with a trisubstituted olefin (2e).
a
Scheme 3. Aminating Reagents with Internal Olefins
a
All reactions were carried out with 1a (0.2 mmol) and 2 (0.4 mmol)
in 2.0 mL of toluene for 18 h; all yields are isolated yields.
The divergent reactivity with substituted allylamines
provides useful insights into the reaction mechanism and
selectivity, particularly regarding the ipso-Heck cyclization
(Scheme 4). During the Heck coupling, the terminal
monosubstituted alkene moiety undergoes kinetically favorable
5-exo-trig cyclization, followed by β-hydrogen elimination, to
give an exocyclic alkene intermediate, which leads to the
desired indole products. When a 1,2-disubstiuted alkene is
used, the moderate steric hindrance allows the β-hydrogen
elimination to occur at either direction (inward and outward),
resulting in a mixture of indole and indoline products. In
contrast, in the case of the trisubstituted alkene, the inward
elimination would be largely inhibited due to the strong steric
repulsion between the ortho-substituent (i.e., −OMe) and the
nearly coplanar alkene substituent (i.e., −Me). Therefore, high
selectivity toward the indoline formation through a less bulky
outward elimination is observed with the trisubstituted alkene.
Finally, to explore the potential synthetic application of this
method, construction of the core carbon skeleton of the
mitomycin family of natural products has been explored
(Scheme 5).19 Utilizing a more complex 2-vinylpyrrolidine
derived coupling partner (2f), the desired ortho-amination/
ipso-Heck cyclization can indeed take place under the standard
condition. On the basis of the crude NMR analysis, the
indoline product with an exocyclic olefin was formed in 31%
a
Unless otherwise noted, all reactions were carried out with 1 (0.2
mmol) and 2 (0.4 mmol) in 2.0 mL of toluene for 18 h; all yields are
isolated yields. Carried out with Pd(TFA)2 instead of Pd(OAc)2, 1a
(1.0 mmol), and 2a (2.0 mmol) in toluene (10.0 mL). Carried out
with 40 mol % of P(p-OMe-Ph)3 as the ligand. Carried out with 2a-2
(see the Supporting Information) instead of 2a and with PPh3 as the
ligand at 120 °C. Run at 80 °C.
b
c
d
e
yield of the model product 3aa can reach 72% on the larger 1.0
mmol scale.16 In addition, a diverse range of functional groups,
such as methyl (3ba) and benzyl ethers (3ia), an unprotected
tertiary alcohol (3ca), ester (3ea), bromide (3da), chloride
(3ma), nitro (3fa and 3oa), acetal (3ha), and tertiary amine
(3la), were tolerated under the reaction conditions, affording
various C3,C4-disubstituted indoles. Both electron-rich and
-deficient substituents are compatible for this transformation.
Notably, the yields for the highly electron-poor nitro-
substituted aryl iodides (3fa and 3oa) can be increased by
changing the phosphine ligand to the electron-deficient tris-(4-
trifluoromethylphenyl)phosphine (see Supporting Information
for more details). Up to 83% yield can be obtained for the 4-
chloroindole product (3ma). A clear trend can be observed:
the yield of the indole product typically decreases if the ortho-
substituent is larger in size, indicating that the reaction is
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Scheme 4. Divergent Reaction Pathways for Substituted
Alkene Coupling Partners
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01165.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Guangbin Dong − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0003-1331-6015; Email: gbdong@
uchicago.edu
Author
Alexander J. Rago − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01165
Notes
a
Scheme 5. Attempt to Access the Skeleton of Mitomycin
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the University of Chicago and NIGMS
(1R01GM124414-01A1) are acknowledged. Dr. Xin Liu (the
University of Chicago) is acknowledged for checking the
experimental procedures. Mr. Marcelo de la Mora (the
University of Chicago) is acknowledged for the preparation
of some starting materials.
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a
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