Substrates as Electron-Donor Precursors: Synthesis of Naphtho-Fused Oxindoles via Benzannulation of 2-Halobenzaldehydes and Indolin-2-ones

Article abstract of DOI:10.1021/acs.orglett.6b02515

An unusual benzannulation reaction has been realized by integrating intermolecular adol condensation with subsequent intramolercular base-promoted homolytic aromatic substitution. This novel cascade reaction provides a straightforward approach toward various naphtho-fused oxindoles from 2-halobenzaldehydes and indolin-2-ones in the presence of Cs₂CO₃ in DMSO. The enolates of indolin-2-ones as new and internal electron donors have been demonstrated to initiate intramolecular radical dehalogenative coupling.

Full text of DOI:10.1021/acs.orglett.6b02515

Letter
pubs.acs.org/OrgLett
Substrates as Electron-Donor Precursors: Synthesis of Naphtho-
Fused Oxindoles via Benzannulation of 2‑Halobenzaldehydes and
Indolin-2-ones
Feng-Cheng Jia, Cheng Xu, Zhi-Wen Zhou, Qun Cai, Yan-Dong Wu,* and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan, Hubei 430079, P. R. China
S
* Supporting Information
ABSTRACT: An unusual benzannulation reaction has been
realized by integrating intermolecular adol condensation with
subsequent intramolercular base-promoted homolytic aromatic
substitution. This novel cascade reaction provides a straightfor-
ward approach toward various naphtho-fused oxindoles from 2-
halobenzaldehydes and indolin-2-ones in the presence of
Cs2CO3 in DMSO. The enolates of indolin-2-ones as new and
internal electron donors have been demonstrated to initiate intramolecular radical dehalogenative coupling.
Scheme 1. Reaction Design: In Situ Generated Enolate
Anions of Indolin-2-ones Play Dual Roles in the Cascade
Process for the Construction of Naphtho-Fused Oxindoles
rganopromoted dehalogenative coupling between haloar-
enes and arenes is perceived as an extremely attractive
O
means to construct aryl−aryl bonds since the publication of
some pioneering examples demonstrated by Itami, Shi,
Shirakawa/Hayashi, and Kwong/Lei.1 In the following years,
continuous attention has been mainly focused on exploring new
organic molecules for these inter-/intramolecular couplings.2,3
These reactions are mediated by a base (typically KOtBu) and
an organic additive and commonly use the benzene series as
solvent. Although the general reaction profile summarized by
Studer and Curran features base-promoted homolytic aromatic
substitution, the precise role of various organocatalysts in the
radical initiation step remain ambiguous.4 Recently, pivotal
progress was made by Tuttle, Murphy, and co-workers, who
proposed a unifying mechanism where various organic
molecules served as precursors of electron donors that transfer
an electron to halobenzene, leading to the formation of the
initial aryl radicals after release of a halide anion.5 We noticed
that enolates of simple esters, ketones, and cyclic amides could
act as electron donors for the coupling of iodoarenes to
arenes.5b On the basis of the structure−property relationship,
we predicted that indolin-2-ones might initiate this type of C−
C coupling reaction. Herein, a novel and fascinating cascade
reaction related to indolin-2-ones and 2-halobenzaldehydes was
conceived in which indolin-2-ones acted as both the substrate
and electron donor precursors. In our hypothesis, deprotona-
tion of indolin-2-ones would afford electron-rich enolates I in
the presence of base. Most enolates could condense with 2-
halobenzaldehydes to give intermediate II, which would
undergo base-promoted homolytic aromatic substitution with
the assistance of electrons released from the rest of the
enolates, forging aryl−aryl bonds to deliver naphtho-fused
oxindoles (Scheme 1).
aristolactams (1),6 sauristolactam (2),6 anhydrohapaloxindole
A (3),7 prioline (4),8 and cyclopiamides (5)9 (Figure 1). A
Figure 1. Selected polycyclic alkaloids containing the oxindole
framework.
broad array of biological properties, including antitumor,10 anti-
inflammatory,11 and antiplatelet12 activities, have been inves-
tigated for some of these 3,4-fused oxindole alkaloids. Although
naphthoxindoles are structural analogues of the aforementioned
alkaloids, the lack of research about their pharmacological
activities may be attributed to the rare synthetic examples13 for
Polycyclic compounds containing an oxindole framework are
Received: August 22, 2016
widely found in naturally occurring alkaloids such as
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02515
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
preparing diverse candidates for drug screening. Herein, we
present an unusual benzannulation reaction for the direct
construction of diverse naphtho-fused oxindoles; its advantages
include the use of readily available starting materials, simple
reaction conditions, and good functional group compatibility.
We commenced our studies by exploring the cascade
reaction between 2-bromobenzaldehyde (1a) with indolin-2-
one (2a) to optimize the reaction conditions. After extensive
screening of various reaction parameters, treatment of 1a (1
equiv) with 2a (1.6 equiv) and Cs2CO3 (3 equiv) under Ar
atmosphere at 120 °C for 2 h gave the highest yield of the
desired naphtho[3,2,1-cd]indol-5(4H)-one (3aa), which was
identified by X-ray crystallographic analysis (Table 1). Among
Scheme 2. Substrate Scope of 2-Halobenzaldehydes and Free
N−H Indolin-2-ones
a,b
a
Table 1. Screening of Optimal Reaction Conditions
a
Reaction conditions: 1a−f (0.5 mmol, 1 equiv), 2a−h (0.8 mmol, 1.6
equiv), Cs2CO3 (1.5 mmol, 3 equiv), 4 mL DMSO, 120 °C, under Ar.
b
Isolated yields. For the crystal structure of compound 3aa, see the
b
Supporting Information.
entry
variation from the standard conditions
yield (%)
1
2
none
84
K2CO3 instead of Cs2CO3
K3PO4 instead of Cs2CO3
KOH instead of Cs2CO3
DBU instead of Cs2CO3
piperidine instead of Cs2CO3
KOtBu instead of Cs2CO3
under air or O2
72
benzannulation transformation (3fa, 86%). The reaction
conditions were well compatible with various substitutions at
the C5 position of indolin-2-ones regardless of the electronic
properties, and the target products were obtained in satisfactory
yields (72−82%, 3ab−ae). A prolonged time and elevated
temperature were required to accomplish the conversion of 5-
nitroindolin-2-one and 2-bromobenzaldehyde, albeit in lower
yield (54%, 3af). Indolin-2-ones bearing halogen groups (Cl
and Br) at the C6 position also showed moderate reactivities
and afforded the corresponding products, which could undergo
further synthetic modification (70% and 56%, 3ag and 3ah).
The dehalogenated product (3aa) was obtained in 47% isolated
yield when 5-bromoindolin-2-one and 2-bromobenzaldehyde
were used as substrates.14 2-Iodobenzaldehyde also exhibited
good reactivity under the optimized conditions; however, 2-
chlorobenzaldehyde reacted sluggishly with 1a to afford the
condensation products.
Various 2-bromobenzaldehydes and N-substituted indolin-2-
ones were then examined to broaden the substrate scope. As
shown in Scheme 3, when 1-methylindolin-2-one (2i) was
treated with 2-bromobenzaldehydes bearing various substitu-
ents (H, −Me, −OMe, −F, and −Cl) at the 4-position of the
aromatic ring, products 3ai−ei were obtained in 64−74% yield.
Heteroaryl aldehydes were suitable substrates and afforded the
two novel scaffords 3fi and 3gi in 77% and 75% yield,
respectively. Interestingly, when 2-bromobenzaldehydes with
substituents at the 5-position of phenyl were reacted with 1-
methylindolin-2-one (2i), the cascade provided the separable
regioisomers in moderate combined yield (3hi−ji and 3hi′−
ji′).15 2-Bromobenzaldehyde (1a) with 1-methylindolin-2-ones
with electron-rich substituents (5-Me and 5-OMe) were
smoothly converted into the desired products in good yields
(74% and 65%, 3aj and 3ak). Halogen atoms at the 5-, 6-, and
7- positions of 1-methylindolin-2-ones were all tolerated and
gave the corresponding products in moderate to good yields
(46−72%, 3al−ao). Indolin-2-ones with two substituents on
the nitrogen atom were tested and delivered the desired
products in good yields (78% and 76%, 3op and 3oq).
3
75
4
76
5
12
6
trace
81
7
8
trace
80
9
1 equiv of H2O was used
5 mmol of 1a was used, 12 h
10
76
a
Reaction conditions: 1a (0.30 mmol), 2a (0.48 mmol), Cs2CO3 (0.9
mmol), and DMSO (4 mL) under Ar atmosphere at 120 °C for 2 h.
Isolated yield.
b
various inorganic or organic bases, Cs2CO3 proved to be
excellent, although KOtBu worked almost equally as well (entry
1 versus entries 2−7). Several solvents, including DMF,
toluene, and 1,4-dioxane, were subsequently examined, and
DMSO proved to be the most effective solvent (entry 1 versus
Table S1, entries 1−3). Increasing or decreasing the temper-
ature of the reaction did not lead to any further improvements
in the yield (Table S1, entries 4 and 5). For the amounts of
indolin-2-one (2a) used, we found that 1.6 equiv of 2a was
preferred for the benzannulation reaction (entry 1 versus Table
S1, entries 6−9). Increasing the amount of Cs2CO3 had no
effect on the reaction (Table S1, entry 10), but decreasing the
amount of Cs2CO3 had a negative effect (Table S1, entry 11).
The poor reactivity observed in the presence of air or O2 is
consonant with a radical mechanism (entry 8). Notably, the
standard conditions were well compatible with water and show
capacity for the gram-scale synthesis of 3aa in 76% yield
(entries 9 and 10).
With the optimal reactions in hand, we investigated the
generality of the benzannulation reaction with respect to 2-
halobenzaldehydes and free N−H indolin-2-ones (Scheme 2).
The electronic effects exerted by the substituents at the C4
position of 2-bromobenzaldehydes are weak and the corre-
sponding free N−H naphthoxindoles 3aa−ea were obtained in
moderate to good yields. Reactions involving electron-deficient
2-bromobenzaldehydes are faster than those using electron-
donating or electron-neutral ones (compared 3da−ea to 3aa−
ca). 3-Bromothiophene-2-carbaldehyde was suitable for this
Having established the scope of our new cascade reaction, we
turned our attention to evaluating the reaction mechanism as
postulated in the design plan. Initially, the reactions of 2-
B
DOI: 10.1021/acs.orglett.6b02515
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3ac) in the presence of 0.6 equiv of 2i or 2c, while sole 3aa was
formed in 62% yield with 2f as the organic additive.16 These
results suggest that various indolin-2-ones could promote the
coupling reaction of intermediate 4.
Scheme 3. Substrate Scope of 2-Bromobenzaldehydes and N-
Substituted Indolin-2-ones
a,b
To investigate the effect of blocking the benzylic position of
indolin-2-ones, 3-methylindolin-2-one (2r) and 3,3-dimethy-
lindolin-2-one (2s) were tested under the reaction conditions,
and 3-methylindolin-2-one (2r) turned out to be an efficient
additive to facilitate the C−H arylation, whereas 3,3-
dimethylindolin-2-one (2s) did not promote the formation of
the intramolecular aryl−aryl bond. These results indicated that
benzylic C−H deprotonation of indolin-2-ones is the major
pathway for the electron-donor formation. Other organic
molecules with active methylene such as N,N-dimethyl-3-
oxobutanamide and cyclohexanone were found to be effecitive
initiators for the intramolecular BHAS reaction, which further
demonstrated that the enolate anions play crucial roles in the
radical initiation step. Taken together, these control experi-
ments indicated that the enolates of indolin-2-ones serve as
organic donors to initiate the intramolecular radical dehaloge-
native coupling (Scheme 4b).
On the basis of the above observations and literature
reports,4,5,17 a radical chain propagation pathway is proposed
using 2-bromobenzaldehyde (1a) and indolin-2-one (2a) as
examples (Scheme 5). Initially, deprotonation of the CH2
Scheme 5. Possible Mechanism
a
Reaction conditions: 1a−j (0.5 mmol, 1equiv), 2i−q (0.8 mmol, 1.6
equiv), Cs2CO3 (1.5 mmol, 3 equiv), 4 mL of DMSO, 120 °C, under
b
Ar. Isolated yields. For the crystal structures of compound 3bi, 3ci,
and 3ii′ see the Supporting Information.
bromobenzaldehyde (1a) and indolin-2-one (2a) were
conducted under the standard conditions for 1 min, and only
(E)-3-(2-bromobenzylidene)indolin-2-one (4) was isolated in
83% yield (Scheme 4a). Various organic additives were then
Scheme 4. Control Experiments
protons within indolin-2-one (2a) generates the eletron-rich
enolate anion (A) in the presence of Cs2CO3. Most of enolate
anion A condenses with 2-bromobenzaldehyde, leading to the
formation of 4, and the rest acts as an eletron donor to transfer
an electron to the eletron acceptor 4. The resulting radical-
anion intermediate B is prone to collapse to release C and
bromide anion. A phenyl radical induced aromatic 1,6-hydrogen
transfer may occur at this stage, and two regioisomers would be
obtained when 5-substituted 2-bromoaldehyde is involved (see
the SI). The aryl radical C could then form a cyclohexadienyl
radical D via a 6-endo cyclization, followed by the second
deprotonation to yield the radical anion E. Finally, single-
electron transfer (SET) from this radical anionic species to the
intermediate aryl bromide 4 gives the target product 3aa and
completes the radical-chain process. Moreover, the mechanism
involving Michael addition of enolates A to 4 followed by
intermolecular electron transfer is also possible (see the SI).
In summary, we have developed a novel cascade reaction
underlining the dual roles of indolin-2-ones, in which the
enolate anions of indolin-2-ones generated in situ form
added to convert (E)-3-(2-bromobenzylidene)indolin-2-one 4
into the target product (3aa). The desired product 3aa was not
formed in the absence of 2a, but the use of 0.6 equiv of 2a gave
3aa in 76% yield. To further elucidate the role of indolin-2-ones
in the benannulation process, 4 was treated with other indolin-
2-ones (0.6 equiv) bearing varying substituents under the
optimized conditions. The desired products 3aa were obtained
in 38% and 42% yield along with two new products (3ai and
C
DOI: 10.1021/acs.orglett.6b02515
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett. 2012, 14, 4466.
(d) Wu, Y.; Wong, S. M.; Mao, F.; Chan, T. L.; Kwong, F. Y. Org. Lett.
2012, 14, 5306. (e) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh,
J. A.; Konar, S.; Kumar, S. Org. Lett. 2012, 14, 2838.
(4) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018.
(5) (a) Zhou, S.; Anderson, G. M.; Mondal, B.; Doni, E.;
Ironmonger, V.; Kranz, M.; Tuttle, T.; Murphy, J. A. Chem. Sci.
2014, 5, 476. (b) Zhou, S.; Doni, E.; Anderson, G. M.; Kane, R. G.;
MacDougall, S. W.; Ironmonger, V. M.; Tuttle, T.; Murphy, J. A. J. Am.
Chem. Soc. 2014, 136, 17818. (c) Barham, J. P.; Coulthard, G.; Kane,
R. G.; Delgado, N.; John, M. P.; Murphy, J. A. Angew. Chem., Int. Ed.
2016, 55, 4492.
intermediates by condensation with 2-halobenzaldehydes and
also act as radical initiators to complete the downstream
intramolecular base-promoted homolytic aromatic substitution.
This simple reaction system provides a valuable access to
diverse naphtho-fused oxindoles from available starting
materials with good functional group compatibility. This
methodology may open an avenue to new chemistry for
oxindoles. Further studies of this property of indolin-2-ones for
design of new radical cascade reactions and construction of
other fascinating structures containing the oxindole unit are in
progress in our laboratory.
(6) (a) Kumar, V.; Poonam; Prasad, A. K.; Parmar, V. S. Nat. Prod.
Rep. 2003, 20, 565. (b) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444.
(7) Moore, R. E.; Yang, X. Q. G.; Patterson, G. M. L. J. Org. Chem.
1987, 52, 3773. (b) Millemaggi, A.; Taylor, R. J. K. Eur. J. Org. Chem.
2010, 2010, 4527.
(8) (a) Li, M.; Zhang, J. S.; Ye, Y. M.; Fang, J. N. J. Nat. Prod. 2000,
63, 139. (b) Wu, Y. B.; Ni, Z. Y.; Shi, Q. W.; Dong, M.; Kiyota, H.; Gu,
Y. C.; Cong, B. Chem. Rev. 2012, 112, 5967.
(9) Xu, X.; Zhang, X.; Nong, X.; Wei, X.; Qi, S. Tetrahedron 2015, 71,
610.
(10) (a) Choi, Y. L.; Kim, J. K.; Choi, S. U.; Min, Y. K.; Bae, M. A.;
Kim, B. T.; Heo, J. N. Bioorg. Med. Chem. Lett. 2009, 19, 3036.
(b) Couture, A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02515.
■
S
X-ray crystallographic data for compount 3aa (CIF)
X-ray crystallographic data for compount 3bi (CIF)
X-ray crystallographic data for compount 3ci (CIF)
X-ray crystallographic data for compount 3ii′ (CIF)
Experimental procedures, product characterization, crys-
1
tallographic data, and H and 13C NMR spectra (PDF)
́
Leonce, S.; Pfeiffer, B.; Renard, P. Bioorg. Med. Chem. Lett. 2002, 12,
3557.
(11) (a) Lan, Y. H.; Chia, Y. C.; Chang, F. R.; Hwang, T. L.; Liaw, C.
C.; Wu, Y. C. Helv. Chim. Acta 2005, 88, 905. (b) Zhang, Y. N.;
Zhong, X. G.; Zheng, Z. P.; Hu, X. D.; Zuo, J. P.; Hu, L. H. Bioorg.
Med. Chem. 2007, 15, 988.
(12) (a) Chia, Y. C.; Chang, F. R.; Teng, C. M.; Wu, Y. C. J. Nat.
Prod. 2000, 63, 1160. (b) Chen, Y. C.; Chen, J. J.; Chang, Y. L.; Teng,
C. M.; Lin, W. Y.; Wu, C. C.; Chen, I. S. Planta Med. 2004, 70, 174.
(13) (a) Nassar-Hardy, L.; Deraedt, C.; Fouquet, E.; Felpin, F. X.
Eur. J. Org. Chem. 2011, 2011, 4616. (b) Li, J.; Wang, N.; Li, C.; Jia, X.
Org. Lett. 2012, 14, 4994. (c) Park, K. Y.; Kim, B. T.; Heo, J. N. Eur. J.
Org. Chem. 2014, 2014, 164.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chwuyd@mail.ccnu.edu.cn.
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21272085 and 21472056) for financial
support. This work is also supported by “The Fundamental
Research Funds for the Central Universities” (CCNU15ZX002
and CCNU16A05002). We acknowledge an excellent doctoral
dissertation cultivation grant from Central China Normal
University (2016YBZZ039). We also thank Professor Lei Jiao
(Department of Chemistry, Tsinghua University) for discussion
of the reaction mechanism.
(14) (a) Dewanji, A.; Muck-Lichtenfeld, C.; Studer, A. Angew. Chem.,
̈
Int. Ed. 2016, 55, 6749. (b) Sword, R.; O’Sullivan, S.; Murphy, J. A.
Aust. J. Chem. 2013, 66, 314.
(15) (a) Karady, S.; Abramson, N. L.; Dolling, U. H.; Douglas, A. W.;
McManemin, G. J.; Marcune, B. J. Am. Chem. Soc. 1995, 117, 5425.
(b) Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656.
(c) Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del Rio, E.; Dormer,
P. G.; Marcune, B. F.; Reamer, R. A.; Sordo, T. L. Org. Lett. 2003, 5,
1175.
(16) A possible dynamic equilibrium between 4 and 4′ had been
proposed to explain why the mixtures of products were formed, and
additional control experiments suggest that the intermediate generated
from Michael addition of enolates to 4 was also a possible cyclization
precursor (see the SI).
REFERENCES
■
(1) (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673. (b) Sun, C. L.; Li, H.; Yu, D. G.; Yu, M.; Zhou, X.; Lu,
X. Y.; Huang, K.; Zheng, S. F.; Li, B. J.; Shi, Z. J. Nat. Chem. 2010, 2,
1044. (c) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He,
C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132,
16737. (d) Shirakawa, E.; Itoh, K. I.; Higashino, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 15537. (e) Sun, C. L.; Shi, Z. J. Chem. Rev. 2014,
114, 9219.
(17) (a) Yang, C.; Liu, Y.; Yang, J. D.; Li, Y. H.; Li, X.; Cheng, J. P.
Org. Lett. 2016, 18, 1036. (b) Studer, A.; Curran, D. P. Nat. Chem.
2014, 6, 765. (c) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016,
55, 58.
(2) For selected examples on organopromoted intermolecular
dehalogenative couplings see: (a) Qiu, Y.; Liu, Y.; Yang, K.; Hong,
W.; Li, Z.; Wang, Z.; Yao, Z.; Jiang, S. Org. Lett. 2011, 13, 3556.
(b) Tanimoro, K.; Ueno, M.; Takeda, K.; Kirihata, M.; Tanimori, S. J.
Org. Chem. 2012, 77, 7844. (c) Liu, W.; Tian, F.; Wang, X.; Yu, H.; Bi,
Y. Chem. Commun. 2013, 49, 2983. (d) Dewanji, A.; Murarka, S.;
Curran, D. P.; Studer, A. Org. Lett. 2013, 15, 6102. (e) Song, Q.;
Zhang, D.; Zhu, Q.; Xu, Y. Org. Lett. 2014, 16, 5272.
(3) For selected examples on organopromoted intramolecular
dehalogenative couplings, see: (a) Roman, D. S.; Takahashi, Y.;
Charette, A. B. Org. Lett. 2011, 13, 3242. (b) Sun, C. L.; Gu, Y. F.;
Huang, W. P.; Shi, Z. J. Chem. Commun. 2011, 47, 9813. (c) De, S.;
D
DOI: 10.1021/acs.orglett.6b02515
Org. Lett. XXXX, XXX, XXX−XXX