Rhodium(III)-Catalyzed Cascade Cyclization/Electrophilic Amidation for the Synthesis of 3-Amidoindoles and 3-Amidofurans

Article abstract of DOI:10.1021/acs.orglett.6b00689

A rhodium(III)-catalyzed cascade cyclization/electrophilic amidation using N-pivaloyloxylamides as the electrophilic nitrogen source has been developed. This protocol provides an efficient route for the synthesis of 3-amidoindoles and 3-amidofurans under mild conditions with good functional group tolerance. The synthetic utility of this reaction has been demonstrated through the derivatization of the 3-amidoindoles to several heterocycle-fused indoles.

Full text of DOI:10.1021/acs.orglett.6b00689

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Cascade Cyclization/Electrophilic Amidation
for the Synthesis of 3‑Amidoindoles and 3‑Amidofurans
Zhiyong Hu,†,‡ Xiaofeng Tong,*,† and Guixia Liu*,‡
†Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130
Meilong Road, Shanghai 200237, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A rhodium(III)-catalyzed cascade cyclization/
electrophilic amidation using N-pivaloyloxylamides as the
electrophilic nitrogen source has been developed. This
protocol provides an efficient route for the synthesis of 3-
amidoindoles and 3-amidofurans under mild conditions with
good functional group tolerance. The synthetic utility of this
reaction has been demonstrated through the derivatization of
the 3-amidoindoles to several heterocycle-fused indoles.
he employment of electrophilic nitrogen sources (R2N+)
cascade reactions using electrophilic amination strategy, we
Tcontaining an N−X bond in transition-metal-catalyzed disclose herein a rhodium-catalyzed cascade cyclization/
C−N bond formation has received increasing attention.1
electrophilic amidation of o-alkynylaniline or o-alkynylphenol
with N-pivaloyloxylamide as the amidation reagent. This
protocol provides an efficient method for the synthesis of 3-
amidoindoles and 3-amidofurans under mild conditions with
good functional group tolerance. Moreover, the obtained 3-
amidoindoles could be further transformed to several hetero-
cycle fused indoles, which demonstrates the synthetic value of
this transformation.
Our initial experiments were carried out with o-alkynylaniline
1a and 2-phenyl-N-(pivaloyloxy)acetamide (2a) as the model
substrates in the presence of [Cp*RhCl2]2 (1.25 mol %) (Table
1). Gratifyingly, when the reaction was treated with K2CO3 as a
base in CH3CN at room temperature, the desired 3-
amidoindole (3aa) was produced in 78% yield along with
indole 3aa′ as the main side product (Table 1, entry 1).
Screening of solvents suggested MeOH was the ideal choice,
which afforded the desired product in 91% yield (Table 1,
entries 1−5). Other bases, such as KOAc, NaOAc, DBU, and
Na2CO3, also afforded the desired product in similar yields
(Table 1, entries 6−9). Decreasing the amount of base resulted
in a significant drop in yield (70%, entry 10). In addition, this
cascade cyclization/amidation did not proceed in the absence
of the Rh catalyst or base additive (Table 1, entries 11 and
12).11
Tremendous methodologies have been developed in this area
to construct diverse amines with high efficiency under external
oxidant-free conditions, which provide useful complements to
conventional C−N bond formation reactions. The most
extensively studied electrophilic nitrogen sources include
oximes and O-benzoyl-N,N-dialkylhydroxylamines, which in-
troduce an imino or alkylamino group into the product.1 The
expansion of transition-metal-catalyzed electrophilic amination
to other kinds of nitrogen sources, such as amido-transfer
reagent,2 has not been well studied. Recently, hydroxyamide
derivatives were found to act as the electrophilic nitrogen
source in transition-metal-catalyzed C−H functionalization3
and cross-coupling reactions4 to give the amide products.
Further exploration of hydroxyamide derivatives as the
electrophilic amidation reagent in more diverse cascade
reactions remains untapped.
Indoles are privileged structures in natural and synthetic
biologically active products.5 Among the various indole
derivatives, 3-amino- and 3-amido-substituted indoles are
attractive as useful intermediates for synthetic organic
chemistry6 and as promising candidates for drug design.7
Therefore, the development of efficient synthetic methodology
to access these indole derivatives has received much attention,8
and recently, a few versatile and concise strategies for their
preparation have been developed.9,10 For example, Beller and
co-workers developed a direct synthesis of 2-methyl-3-
amidoindoles by zinc-promoted hydrohydrazination of N-
acylpropargylamines.9 Hirano and Miura reported a copper-
catalyzed annulative electrophilic amination approach to 3-
(dialkylamino)benzoheteroles starting from o-alkynylphenols
and -anilines.10 Based on our interest in the exploration of
Using the optimized conditions, we explored the scope of the
cascade cyclization/electrophilic amidation for the synthesis of
3-amidoindoles (Scheme 1). o-Alkynylanilines with different
functional groups in the phenyl ring reacted smoothly with 2a
with excellent yields (3ba−ha, 88−99%). Both electron-rich
Received: March 10, 2016
© XXXX American Chemical Society
A
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Letter
and electron-deficient aryl substituents at the alkyne terminus
were tolerated, producing the desired 3-amidoindoles in
moderate to good yields (3ia−ma, 32−85%).12 In addition to
alkyl- or aryl-substituted alkynes, terminal alkyne 1o was
suitable substrate as well (3oa, 45%). Furthermore, various N-
pivaloyloxylamides were also explored, wherein both alkyl- and
alkenyl-derived substrates could participate in the reaction with
1a. The use of 2-chloroacetamide derivative led to an excellent
yield of the corresponding product 3af, leaving the sp3 C−Cl
bond intact. When α,β-unsaturated hydroxamic acid derivatives
2g−i were employed, the reactions proceeded readily to afford
the desired products in good yields (3ag−ai, 64−85%) without
any 1,4-addition byproducts. The good functional group
tolerance makes this transformation be useful for further
structural manipulations. Of note, N-pivaloyloxyl benzamide is
not an effective coupling partner.
Table 1. Reaction Optimizations for the Synthesis of 3-
Amidoindoles
a
b
yield (%)
entry
base
solvent
3aa
3aa′
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaOAc
KOAc
CH3CN
DCE
78
15
14
41
THF
ND
5
ND
75
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
91
35
Inspired by the above success, we turned our attention to o-
alkynylphenols for the synthesis of 3-amidobenzofurans. Under
the standard conditions, a series of 3-amidobenzofurans were
synthesized in good yields (Scheme 2). A variety of functional
85
41
91
41
85
33
DBU
85
14
c
10
K2CO3
70
19
Scheme 2. Substrates Scope for the Coupling of o-
11
ND
ND
ND
90
a
Alkynylphenols 4 with N-pivaloyloxylamide 2
d
12
K2CO3
a
Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), [Cp*RhCl2]2
(1.25 mol %), and base (0.1 mmol) in solvent (0.5 mL) at room
b
c
temperature for 12 h. Isolated yield. 0.5 equiv of K2CO3 was used.
d
Without catalyst.
Scheme 1. Substrates Scope for the Coupling of o-
a
Alkynylanilines 1 with N-Pivaloyloxylamide 2
a
Reaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), [Cp*RhCl2]2
(1.25 mol %) and K2CO3 (0.1 mmol) in MeOH (0.5 mL) at room
temperature for 12 h; isolated yield was reported. [Cp*RhCl2]2 (2.5
mol %) was used.
b
groups on o-alkynylphenol were compatible with the reaction
conditions, and N-pivaloyloxylamides possessing alkyl or vinyl
substituents exhibited good reactivity.
To highlight the synthetic value of the new reaction, several
transformations were conducted (Scheme 3). Deprotection of
TBS ether in 3na could easily give the alcohol 6 in excellent
yield (Scheme 3a). The one-step cyclization of 6 with
Lawesson’s reagent in toluene proceeded smoothly to produce
the 4,5-dihydro-1,3-thiazino[5,4-b]indoles 7,13a which is known
as a latent inhibitor of human leukocyte elastase and α-
chymotrysin. In another example, removal of the tosyl group in
3ia was carried out with excess Mg in methanol to produce
compound 8 (Scheme 3b). The cyclization of 8 with the aid of
P2O5 furnished 11H-indolo[3,2-c]isoquinoline 9 in 39%
a
Reaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), [Cp*RhCl2]2
(1.25 mol %), and K2CO3 (0.1 mmol) in MeOH (0.5 mL) at room
temperature for 12 h; isolated yield was reported. [Cp*RhCl2]2 (2.5
mol %) was used. 1o (0.1 mmol) and 2a (0.14 mmol) were used.
b
c
B
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Letter
+3 oxidation state.4,16c Pathway b features a reductive
eliminatioin/oxidative addition sequence involving RhIII/RhI/
RhIII cycle.16 Both pathways could afford intermediate E, which
upon protonolysis provides the expected 3-amidobenzohetero-
cycle and regenerates RhIII to complete the catalytic cycle.17
In conclusion, we have developed a novel and efficient
method to construct 3-amidoindoles and 3-amidobenzofurans
via rhodium(III)-catalyzed nucleophilic attack/umpolung ami-
dation cascade process. This process employed N-pivaloylox-
ylamide as the umpolung amidating reagent, which might find
further application in more diverse cascade reactions. The
synthetic value of this reaction was highlighted by its utility in
the synthesis of heterocycle fused indoles.
Scheme 3. Derivatizations of 3-Amidoindoles
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00689.
yield.13b Surprisingly, upon reaction with aqueous NaOH in the
solution of MeOH and THF, indole 3ia was transformed to
tricyclic indole 10, which was possibly caused by a radical
process with the oxygen in air as the oxidant (Scheme 3c).14
On the basis of the experimental results and the precedent
literature, the mechanism hypotheses are proposed (Scheme 4).
Experimental procedures, compound characterization
data, and copies of NMR spectra (PDF)
Crystallographic data for compound 3ma (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 4. Proposed Reaction Mechanism
*E-mail: tongxf@ecust.edu.cn.
*E-mail: guixia@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (No.
2015CB856600), the National Natural Science Foundation of
China (Nos. 21202184, 21232006, and 21572255), and the
Chinese Academy of Sciences for financial support.
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