Copper-Catalyzed Radical Difluoroalkylation and Redox Annulation of Nitroalkynes for the Construction of C2-Tetrasubstituted Indolin-3-ones

Article abstract of DOI:10.1021/acs.orglett.7b03678

An efficient and convenient method with wide applicability for the synthesis of C2-tetrasubstituted indolin-3-ones via copper-catalyzed redox cycloisomerization of nonprefunctionalized nitroalkynes has been developed. This protocol features simple operati

Full text of DOI:10.1021/acs.orglett.7b03678

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Radical Difluoroalkylation and Redox Annulation
of Nitroalkynes for the Construction of C2-Tetrasubstituted
Indolin‑3-ones
Wenqiang Fu and Qiuling Song*
Institute of Next Generation Matter Transformation, Fujian Provincial Key Laboratory of Biochemical Technology, College of
Chemical Engineering, College of Materials Science and Engineering at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian
361021, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and convenient method with wide
applicability for the synthesis of C2-tetrasubstituted indolin-3-ones
via copper-catalyzed redox cycloisomerization of nonprefunctional-
ized nitroalkynes has been developed. This protocol features simple
operation, readily available starting materials, good functional group
tolerance, broad scope, and diboron as the reductant.
Scheme 1. Recent Advances in the Synthesis of Indolin-3-
ones Bearing a C2-Tetrasubstituted Center
ndolin-3-ones are one of the privileged core skeletons that
continually appear in natural products and pharmacologically
I
active compounds.1 Among them, pseudoindoxyls bearing C2
stereocenters have emerged as crucial intermediates that are
generally included in diverse biologically compounds and
pharmaceutical agents such as halichrome A,2 duocarmycins C1
and B1,3 cephalinone,4 LipidGreen and austamide,5 etc. (Figure
1). The intramolecular cyclization of an o-nitroalkyne is one of
of internal cycloisomerization, noble metals such as palladium
and gold catalysts were widely used species in the
representative strategies.2,6−8 The incorporation of difluoroalkyl
groups into organic compounds has emerged as a substantially
attractive tactic, since it can improve the biological and
physicochemical properties of the parent molecules.9,10 Because
of the significance and effectiveness of indolin-3-one com-
pounds, finding a straightforward and efficient way of
incorporation of difluoroalkyl groups into the indolin-3-one
skeleton from readily accessible substrates is highly desirable.
We recently reported that bromodifluoroacetate could serve
as a source of difluoroalkyl radical under Cu/B2pin2 catalysis,
and most remarkably, this difluoroalkyl radical exhibits unique
Figure 1. Several bioactive molecules containing C2-tetrasubstituted
indolin-3-ones.
the most simple and convenient routes for the synthesis of C2-
tetrasubstituted 3-oxindole derivatives. In 2015, Harrity’s group
reported a Cu-promoted cyclization of 2-nitrophenyl iodoace-
tylenes for the synthesis of 2-iodoisatogens,6 although it is of
note that C2 is not a stereocenter in this case. Formation of
non-carbon quarternary center pseudoindoxyls through tran-
sition-metal-catalyzed inter- or intramolecular nucleophilic
group attack on C2 was reported (Scheme 1a).2,7 Among the
metal-catalyzed activations of nitroalkynes for the construction
Received: November 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03678
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactivity.9 Although significant advances have been achieved in
fluoroalkylation using functionalized fluoroalkyl reagents, direct
and efficient strategies for the synthesis of tetrasubstituted
carbons containing difluorinated functional groups has not been
reported to date to our knowledge. As part of our ongoing
interest in the reactivity of difluoroalkylated carbon radicals
catalyzed by the copper/B2pin2 system, herein we report a facile
Cu-catalyzed radical difluoroalkylation/redox annulation of 2-
alkynylnitroarenes to produce fluorine-containing C2-tetrasub-
stituted indolin-3-one derivatives in moderate to excellent
yields (Scheme 1b). There are several obvious advantages of
our strategy over the precedent reports: (1) one-pot protocol
instead of stepwise operation; (2) cheaper and low-toxicity
copper catalyst in place of noble-metal catalysts; (3) unique
catalytic system with diboron as the reductant; (4) novel radical
mechanism instead of the precedent nucleophilic mechanism;
(5) formation of a fluorine-containing non-carbon quaternary
center. However, the major challenges of this strategy are
twofold: (1) the nitro group could be reduced to an amino
group in the presence of diboron as the reductant before
cyclization,11 and (2) the difluoroalkyl radical could directly
attack the CC bond under the Cu(II)/B2pin2 catalytic
system.9b
We commenced our study by using 1-(cyclopropylethynyl)-
2-nitrobenzene (1a) and BrCF2CO2Et (2a) as model
substrates. To our delight, the desired product 3a was obtained
in 74% yield when CuCl2 (10 mol %)/dtbbpy (L1) (10 mol %)
was employed in the presence of B2pin2 (2.5 equiv) and
Na2CO3 (2.5 equiv) in 1,4-dioxane (0.1 M) at 100 °C for 12 h,
which turned out to be the optimal conditions (Table 1, entry
1). Various alterations were performed to test the influences on
the optimal conditions (Table 1). First, lower reactivity was
observed when the reaction was conducted under air (entry 2).
When we reduced the reaction temperature from 100 to 80 °C,
the yield of 3a was slightly decreased to 73% (entry 3). Only
marginal improvements were achieved when other copper salts
were employed instead of CuCl2 (entries 4 and 5). Employing a
series of other bipyridine ligands (L2, L3, L4) resulted in lower
yields of the desired product 3a (entries 6−8). Regrettably,
shortening the reaction time led to a decreased yield of 3a
(entry 9). KF also demonstrated itself as an effective base,
giving 3a in 70% isolated yield (entry 10). Of note, the
reactivity was entirely restrained when an organic base such as
pyridine was used (entry 11). When the reactions were carried
out in the absence of CuCl2 and ligand (entries 12 and 13), no
product 3a was obtained. Solvent screening indicated that 1,4-
dioxane was superior to THF and acetonitrile (entries 14 and
15). Reducing the amount of B2pin2 decreased the yield of 3a
(entry 16). Among the boron reagents investigated, B2pin2
showed the optimal efficiency compared with B2cat2 and
B2(OH)2 (entries 17 and 18).
a
Table 1. Optimization of the Reaction Conditions
b
entry
variation from the standard conditions
yield (%)
c
1
2
none
78 (74)
13
under air
3
at 80 °C
73
4
CuBr2 instead of CuCl2
CuF2·H2O instead of CuCl2
L2 instead of L1
75
5
73
6
34
7
L3 instead of L1
46
8
L4 instead of L1
35
9
6 h instead of 12 h
KF instead of Na2CO3
pyridine instead of Na2CO3
without CuCl2 and L1
without ligand
69
c
10
11
12
13
14
15
16
17
18
76 (70)
N.R
N.R
N.R
24
THF instead of 1,4-dioxane
MeCN instead of 1,4-dioxane
2 equiv of B2pin2
54
70
B2cat2 instead of B2pin2
B2(OH)2 instead of B2pin2
trace
45
a
Reaction conditions: 1 (0.2 mmol), BrCF2CO2Et (2 equiv), Na2CO3
(2.5 equiv), B2pin2 (2.5 equiv), CuCl2 (10 mol %), and L1 (10 mol %)
in 1,4-dioxane (0.1 M) at 100 °C for 12 h. Yields were determined by
b
c
GC analysis. Isolated yield.
a
Scheme 2. Scope of 2-Alkynylnitroarenes 1
The optimized conditions were used to investigate the
substrate scope and reaction parameters. First, we examined the
reactions of 2-alkynylnitroarene derivatives 1 with 2a (Scheme
2). Compared with the 2-cyclopropyl-substituted substrates, 2-
phenyl-substituted 1b exhibited relatively low reactivity,
probably as a result of the electron-inductive effect of the
phenyl group. Although the R2 group made a difference in the
reactivity, the substituent R1 on the aromatic ring of the 2-
alkynylnitroarene had no distinct influence, and the corre-
sponding 3-oxindoles were obtained in moderate yields (3c−e).
The structure of 3c was confirmed by X-ray analysis, which
analogously signified the texture of product 3. Noteworthily,
a
Reaction conditions: 1 (0.2 mmol), BrCF2CO2Et (2 equiv), Na2CO3
(2.5 equiv), B2pin2 (2.5 equiv), CuCl2 (10 mol %), and L1 (10 mol %)
in 1,4-dioxane (0.1 M) at 100 °C for 12 h. 1f (0.5 mmol), CuCl2 (5
mol %), and L1 (5 mol %) in 1,4-dioxane (4 mL) at 80 °C.
b
product 3f was obtained in an inferior yield; this result was
consistent with our previous report,12 in which the property of
the substituent para to the NO2 group significantly affected the
reductive cyclization, with electron-withdrawing groups favor-
B
DOI: 10.1021/acs.orglett.7b03678
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ing the reaction, since the Hammett plot suggested that an
anionic or partially anionic moiety was formed during the
process. In addition to 2-cyclopropyl substituents, the alkyl-
substituted substrates 1g−k were also amenable to these
reaction conditions, rendering the products 3g−k in moderate
yields. It is not surprising that the yields gradually declined in
the order of 3g to 3i, probably because of increasing steric
congestion. To our delight, alcohol and ether were also good
substrates in our reactions, rendering the corresponding
products 3j and 3k in moderate yields. Amides were compatible
with our standard conditions as well, and interestingly, the X
group in the amide had a significant influence on the efficiency
of the reaction: the yield observably increased in the sequence
of ethyl < isopropyl < tert-butyl substitution on the substrate
(1l, 1m, and 1n), respectively, delivering the products 3l−n in
53%, 72%, and 94% yield.
and the product 3n was readily isolated in 87% yield (1.28 g)
(Scheme 4b).
In order to acquire further insight into the reaction
mechanism, some control experiments were performed. When
3-oxo-2-(phenoxymethyl)-3H-indole-1-oxide (5) was submit-
ted to the standard conditions, the desired product 3k was
obtained in 38% yield (vs 41% in Scheme 2) (Scheme 5a).
Scheme 5. Control Experiments for Mechanistic Studies
Next, we investigated the reactivity of other difluoroalkyl
radicals (Scheme 3). Although relatively low conversion was
a
Scheme 3. Scope of Bromodifluoroalkanes 2
a
BrCF2CO2Et (2 equiv), Na2CO3 (2.5 equiv), B2pin2 (2.5 equiv),
CuCl2 (10 mol %), and L1 (10 mol %) in 1,4-dioxane (0.1 M) at 100
b
°C for 12 h. Anhydrous 1,4-dioxane (0.1 M).
Also, isatogen 5 as an ambiguous precursor was not generated
when the reaction was performed in the absence of
bromodifluoroalkane (Scheme 5b), which implies that the 3-
oxo-3H-indole-1-oxide compound is not the key intermediate
for this transformation. Radical trapping experiments were
performed to help in understanding the mechanism. Not
surprisingly, this reaction was absolutely suppressed in the
presence of TEMPO, and the TEMPO−CF2CO2Et complex 6
was detected by GC−MS, indicating that a difluoroalkyl radical
is indeed generated in this process (Scheme 5c). To elucidate
the origin of the carbonyl oxygen atom of the products, an
oxygen-18 labeling experiment was performed. No 18O-labeled
3a was detected by HRMS when the reaction was conducted in
the presence of 10 equiv of H218O, indicating that the carbonyl
oxygen atom in the product should be derived from the nitro
group rather than H2O in the solvent (Scheme 5d).
a
Reaction conditions: 1a (0.2 mmol), 2 (2 equiv), Na2CO3 (2.5
equiv), B2pin2 (2.5 equiv), CuCl2 (10 mol %), and L1 (10 mol %) in
1,4-dioxane (0.1 M) at 100 °C for 12 h. 2 (1.2 equiv).
b
observed when N-monosubstituted difluorobromoacetamides
were used as difluoroalkyl reagents (3o−t), the N,N′-
disubstituted difluorobromoacetamides were good candidates
and delivered the corresponding products in good yields (3u−
x).
The product 3j is a valuable compound. When it was
subjected to Ley oxidation conditions, the tricycylic compound
ethyl 2-(6,10-dioxo-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indol-
9a-yl)-2,2-difluoroacetate (4) was obtained in 34% yield
(Scheme 4a).13 To verify the practicality of this protocol, the
scaled-up reaction of N-(3-(2-nitrophenyl)prop-2-yn-1-yl)-
pivalamide (1n) (4 mmol, 1.06 g) with 2a was carried out,
According to our previous work,9,12 a plausible mechanism
for the copper-catalyzed redox cyclizations is described in
Scheme 6. Initially, the LCuIX complex translates into LCuI−
Bpin species A with the help of B2pin2 and Na2CO3. Then 2 is
activated by single electron transfer (SET) and reacts with A to
afford a radical complex, leading to species C via B. C attacks
and activates the substrate 1 to give species D. Then nitroxide
addition to the triple bond of D produces E, after which redox
of E affords species F.14 Subsequently, the isatogen structure
complex G is generated by intramolecular trapping of the
nitroso group in 5-exo annulation of F,2,6,7 whereupon, with the
help of diboron/base, G is transformed to N−O−Bpin species
H, which undergoes diborane-mediated deoxygenation and
reductive elimination of the copper catalyst to deliver the
product 3 and regenerates species A.
Scheme 4. Further Transformation and Large-Scale
Synthesis
In conclusion, we have disclosed an efficient synthesis of 3-
oxindoles via inexpensive copper-catalyzed internal redox
C
DOI: 10.1021/acs.orglett.7b03678
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Organic Letters
Letter
of Fujian Province (2016J01064), the Fujian Hundred Talents
Plan, the Program of Innovative Research Team of Huaqiao
University (Z14X0047), and the Subsidized Project for
Cultivating Postgraduates’ Innovative Ability in Scientific
Research of Huaqiao University (for W.F.) is gratefully
acknowledged. We also thank the Instrumental Analysis Center
of Huaqiao University for analysis support.
Scheme 6. Plausible Mechanism
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Experimental procedures, characterization data, and
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Accession Codes
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: qsong@hqu.edu.cn. Fax: 86-592-6162990.
ORCID
Qiuling Song: 0000-0002-9836-8860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Recruitment Program of Global
Experts (1000 Talents Plan), the Natural Science Foundation
■
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DOI: 10.1021/acs.orglett.7b03678
Org. Lett. XXXX, XXX, XXX−XXX