Cyanomethylation of Substituted Fluorenes and Oxindoles with Alkyl Nitriles

Article abstract of DOI:10.1021/acs.orglett.0c00160

The first example of metal-free cyanomethylenation from alkyl nitriles of sp³ C-H bonds to afford quaternary carbon centers is described. This oxidative protocol is operationally simple and features good functional group compatibility. This method provides a novel approach to highly functionalized fluorene and oxindole derivatives, which are commonly used in material and pharmaceutical areas. Control experiments provide evidence of a radical reaction process.

Full text of DOI:10.1021/acs.orglett.0c00160

pubs.acs.org/OrgLett
Letter
Cyanomethylation of Substituted Fluorenes and Oxindoles with
Alkyl Nitriles
Gang Hong, Pradip D. Nahide, and Marisa C. Kozlowski*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00160
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The first example of metal-free cyanomethylenation from
alkyl nitriles of sp3 C−H bonds to afford quaternary carbon centers is
described. This oxidative protocol is operationally simple and features
good functional group compatibility. This method provides a novel
approach to highly functionalized fluorene and oxindole derivatives, which
are commonly used in material and pharmaceutical areas. Control
experiments provide evidence of a radical reaction process.
Scheme 1. Dual C−H Activation of Oxindoles and
Fluorenes with Toluenes or Alkylnitriles to Generate
Quaternary Centers
itriles are versatile functional groups in organic synthesis.
NIn addition to being a very useful functional group in
biologically active compounds, they can be readily converted
into amines, carboxylic acids, ketones, and even heterocycles.1
Compounds containing nitrile groups are frequently employed
as building blocks in drug-discovery programs.2 The
introduction of a nitrile group by the activation of the α-
hydrogen of simple aliphatic nitriles is one of the most efficient
and environmentally benign entries to this class of structure.
For example, the generation and reaction of stable α-nitrile
anions is well-explored with a range of electrophiles.3 The
nitrile group also stabilizes radicals arising from α-hydrogen
atom abstraction, and these radicals permit bond disconnec-
tions4 complementary to those available from the α-nitrile
anions. Among these reactions, there are relatively few
involving the C−H activation of a second component, that
is, oxidative fragment coupling. Building off of our prior efforts
in the dual-C−H activation of two components (Scheme 1a),5
the use of acetonitrile was investigated with oxindoles and
fluorenes. To the best of our knowledge, there are no examples
of cross-coupling between sp3 C−H bonds and alkyl nitriles
under metal-free conditions. Herein we communicate our
efforts, culminating in the facile, metal-free oxidative
cyanomethylenation of oxindoles and fluorenes with alkyl
nitriles through C(sp3)−H oxidative radical functionalization
using t-BuOOt-Bu as the oxidant (Scheme 1b,c).
those used in semiconductors,7 optoelectronics,8 and solar
cells.9 In addition, fluorene derivatives have also been playing
an increasing role in pharmaceuticals and biochemistry10 as
seen by the incorporation of fluorene moieties into bioactive
compounds (Figure 1b).11 As a consequence, the development
As an important structural unit, 2-oxindoles with a
quaternary carbon center at the C3 position are a class of
heterocycles existing in many natural products, pharmaceut-
icals, and drug candidates (Figure 1a).6 Their importance has
prompted considerable interest in developing new construction
methods.
Received: January 12, 2020
Similarly, fluorenes have attracted much attention for a
variety of applications involving advanced materials, including
https://dx.doi.org/10.1021/acs.orglett.0c00160
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
substituted oxindoles with acetonitrile (Scheme 3, eq 1).
Notably, the protocols employed by Zhu and Li14a,21 involving
Scheme 3. Reaction of 3-Monosubstituted Oxindoles with
a
Acetonitrile
Figure 1. Structures of bioactive compounds with (a) oxindole or (b)
fluorene moieties.
of practical synthetic methods for the construction of
functionalized fluorenes is in demand.
The asymmetric cyanomethylenation of three-substituted
oxindoles using prefunctionalized cyanomethyl halides has
been reported by different groups (Scheme 2a).12 Recently,
Scheme 2. Approaches to Cyanoalkyl Oxindoles and
Fluorenes
a
Conditions: 1 (0.15 mmol), 2a (1.5 mL, 0.1 M), t-BuOOt-Bu (4
equiv), 130 °C, under Ar, 24 h.
metal catalysts to generate acetonitrile radicals for additions to
alkenes were not effective in these couplings. After an extensive
investigation of the reaction conditions (see the SI), control
reactions revealed that the metal catalyst was unnecessary,
leading to a very straightforward oxidative method for
introducing the cyanomethylene functionality to an oxindole.
The optimum reaction conditions entailed heating a solution
of 1a in acetonitrile (0.1 M) in the presence of t-BuOOt-Bu (4
equiv) to 130 °C for 24 h, which provided 3aa in 48% yield.
Subsequently, a range of 3-substituted oxindoles were
explored for the cyanomethylenation at the C3 position with
acetonitrile (Scheme 3). Electron-neutral (3aa), electron-
donating (3ba, 3ca, 3ea, 3fa), and electron-withdrawing
(3da) substituents on the phenyl ring were all well tolerated
under the optimal reaction conditions. Substituents at the
different positions did not affect the yields significantly. The 6-
chloro-oxindole also gave the corresponding product 3ga in
63% yield. The N-benzyl-substituted oxindole also exhibited
good reactivity, providing 3ha in 52% yield.
many studies focused on the atom-transfer radical addition
reactions of nitriles with olefins.13 Among them, the Zhu group
has made significant contributions to this research field.14 In
2016, the Ge group reported the first example of the
palladium-catalyzed cross-coupling of sp3 C−H bonds with
acetonitrile.15 Thereafter, Wu16 and Shen17 independently
reported the direct oxidative cyanomethylenation reactions by
adding acetonitrile to 1,3-dicarbonyls and tetrahydroisoquino-
lines respectively; however, other alkyl nitrile coupling partners
were unsuccessful.
In 2015, the Liu group developed a simple and efficient
synthesis of 9-arylfluorenes via the metal-free reductive
coupling of arylboronic acids and N-tosylhydrazones.18 Also,
extensive attention has been paid to generating fluorenes via
transition-metal-catalyzed cyclizations or direct dehydrogen-
ative aryl−aryl coupling via C−H bond activation.19 In 2016,
the Ji group developed a copper-mediated radical alkylarylation
of unactivated alkenes with acetonitrile, leading to methylene-
disubstituted fluorenes, which are not easily accessed by
conventional methods (Scheme 2b).20 Nonetheless, this
transformation still suffered from some drawbacks, such as
the use of transition metals and ligands, a narrow substrate
scope (acetonitrile only), and only access to 9-alkyl-substituted
fluorenes, thus limiting its further applications.
The cyanomethylenated products derived from three-
substituted oxindoles are versatile intermediates in organic
synthesis and can be readily converted into other important
building blocks including phenyl-substituted pyrroloindo-
lines.22 To show the utility of this method in producing useful
precursors, a further transformation was carried out on product
3aa (Scheme 4). First, the 2-mmol-scale synthesis of product
Scheme 4. Scale-Up and Synthetic Transformation of the
Cyanomethylenated Product 3aa
With a clear need for alternative strategies to construct
highly functionalized oxindoles, we initiated our investigations
by screening various metal sources (Cu, Fe, Pd, Co, Mn, and
Sc) and reaction conditions (see the Supporting Information
(SI)) for the t-BuOOt-Bu-mediated coupling of three-
B
https://dx.doi.org/10.1021/acs.orglett.0c00160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
3aa proceeded successfully, delivering 3aa in 45% yield. The
reductive cyclization of oxindole 3aa using LiAlH4 provided
pyrroloindoline 4 in 52% yield. Overall, this route provides
comparable or better efficiencies relative to other routes for
generating target 4 with aryl substitution at the angular
carbon.23
The application of the above conditions to the coupling of 9-
phenyl-9H-fluorene 5a24 and acetonitrile 2a provided product
6aa (eq 2) in 49% yield (see the SI). Further experimentation
(see the SI) ultimately revealed that carboxylic acid additives
enhanced the outcome. The optimum conditions were t-
BuOOt-Bu (6 equiv) with PivOH (2 equiv) at 125 °C for 23 h,
which provided 6aa in 65% yield (Scheme 5).
groups at C9 on the fluorene were explored. With either
electron-donating or electron-neutral substituents, the prod-
ucts were formed in good yield (6aa−da). Those bearing an
electron-withdrawing chloro, fluoro, trifluoromethyl, or phenyl
group gave the corresponding products in a slightly lower yield
(6ea−ha). C9-Aryl groups with either methoxy or fluoro
groups at the meta position reacted smoothly with 2a to give
6ia and 6ja in 51 and 61% yield, respectively. A range of
bulkier aryl groups could be tolerated at C9 of the fluorene,
including acetal-derived, naphthyl, and para-carbazolylphenyl
groups, affording the corresponding products in 34−49% yield
(6ka−ma). Of particular note, 9-butylfluorene can also react
with acetonitrile to afford 6na in 51% yield.
With these conditions in hand, the scope of the reaction
with respect to the fluorene component and alkyl nitrile was
evaluated (Scheme 5). First, different para-substituted aryl
Notably, functional groups such as methoxy, halogen, and
nitro can be employed in different positions on the fluorene
component (6oa−qa). 9-Phenyl-9H-xanthene 5r also success-
fully reacted with acetonitrile, albeit with 20% yield (6ra).
Next, other alkyl nitriles, such as propionitrile, n-butyronitrile,
n-valeronitrile, and 2-methoxyacetonitrile, were discovered to
be effective in this reaction, affording the corresponding
fluorenes in 42−75% yield (6ab−ae). The steric hindrance of
these compounds is manifest as judged by the proton and
carbon NMR spectra, where the phenylfluorene is desymme-
trized from hindered rotation. Tertiary nitriles, such as
isobutyronitrile 2f and cyclohexanecarbonitrile 2g, smoothly
underwent oxidative C−H activation at the α-position to give
6af and 6ag in 42 and 61% yield, respectively. Notably, these
adducts arise from the approach of two hindered tertiary
centers and give rise to compounds with two adjacent
quaternary centers. However, some other nitriles were
unreactive, including cyanocyclopropane, 2-methoxypropioni-
trile, bromoacetonitrile, and ethyl cyanoacetate.
Scheme 5. Reaction of Various 9-Substituted Fluorenes with
a
Alkyl Nitriles
Some control experiments were carried out to gain a better
understanding of the mechanism (Scheme 6). The cyanome-
Scheme 6. Control Experiments
a
Conditions: 5 (0.15 mmol), 2 (1.5 mL, 0.1 M), t-BuOOt-Bu (6
equiv) PivOH (2 equiv), 125 °C, under Ar, 23 h.
C
https://dx.doi.org/10.1021/acs.orglett.0c00160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
thylenation reaction was completely inhibited when 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-
hydroxytoluene (BHT) was added into the reaction system
(Scheme 6a). Moreover, the corresponding adducts 7 and 8
were detected in the reaction mixture by ESI-MS (see the SI).
In addition, we found that compound 10 was isolated in 33%
yield from (1-cyclopropylvinyl)benzene 9 (Scheme 6b). This
adduct arises from sequential ring opening of a cyclo-
propylmethyl radical intermediate and cyclization,13cb and
this intermediate presumably arises from the addition of a
cyanomethylenyl radical to the alkene. Together, the above
experiments suggest that the current reaction is triggered by a
free-radical process. Moreover, all of the experiments point to
formation and reaction of a cyanomethylenyl radical. Next, an
intermolecular kinetic isotopic effect (KIE) experiment was
performed in a mixture of acetonitrile (0.75 mL) and
acetonitrile-d3 (0.75 mL). As a result, a kH/kD = 6.7 was
obtained (Scheme 6c), indicating that the acetonitrile C−H
bond cleavage is involved in a product-determining step.
The lack of adducts from either the fluorene or the oxindole
with any of the radical traps described above (Scheme 6a,b),
implies that these stabilized radicals are less reactive than the
cyanomethyl radical. It is likely that the resting states of the
fluorenyl or oxindole radicals are the dimers, as we5,25 and
others26 have observed previously under oxidative conditions.
Integrating the formation of the dimer with reports of related
systems,13f,16,27 we propose the mechanism outlined in Scheme
7. First, t-BuOOt-Bu decomposes to give the tert-butoxyl
expected to be able to react, which is supported by the lack of
reactivity with 9(2′-methylphenyl)fluorene.
In summary, we have developed a novel and efficient metal-
free method to activate the C(sp3)−H bond of alkyl nitriles for
the synthesis of highly functionalized fluorene and oxindole
derivatives. On the basis of the control experiments, the
transformation is proposed to proceed via a radical process.
None of the compounds described herein have been previously
reported, illustrating the absence of methods to generate such
hindered nitrile-derived structures. In particular, there are few
examples in the literature of any nitrile-derived fluorenes.18−20
Thus this method contributes to new chemical space as well as
provides a means to generate highly hindered quaternary
centers, including compounds with adjacent quaternary/
tertiary or quaternary/quaternary centers.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00160.
Experimental procedures, reaction condition screening,
analytical data, and copies of spectra for all compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Scheme 7. Proposed Mechanism
Marisa C. Kozlowski − Department of Chemistry, Roy and
Diana Vagelos Laboratories, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States; orcid.org/
0000-0002-4225-7125; Email: marisa@sas.upenn.edu
Authors
Gang Hong − Department of Chemistry, Roy and Diana Vagelos
Laboratories, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States; orcid.org/0000-0003-
1562-0942
Pradip D. Nahide − Department of Chemistry, Roy and Diana
Vagelos Laboratories, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States; orcid.org/0000-0002-
0250-569X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00160
radical (A) at high temperature. The oxindole27 or fluorene
undergoes facile hydrogen atom abstraction due to the weak
C−H bonds (71 and 72 kcal/mol, respectively)5b forming tert-
butanol and the corresponding radical B, which is in
equilibrium with its dimer C. Substrates lacking the 9-phenyl
groups (e.g., fluorene) were not reactive, presumably due to
the greater barrier to formation of the corresponding radical C,
consistent with this hypothesis. In addition, the dimers of 1a
(C′)5b and 5a (C)28 both gave rise to the product under the
reaction conditions (see the SI). At this stage, the excess t-
BuOOt-Bu may cause the alkyl nitrile (CH bond dissociation
energy = 96 kcal/mol)29 to undergo a hydrogen atom
abstraction to generate the radical. Subsequent recombination
with the oxindole or fluorene radical or dimer would generate
the product (e.g., 6aa in Scheme 7). Alternately, the dimer (C)
may react directly with the nitrile to generate one equivalent of
product (6aa) and one equivalent of the starting material (5a).
Regardless, very hindered forms of the radical B are not
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (CHE1827457) and the NIH
(GM131902) for financial support of this research. Partial
instrumentation support was provided by the NIH and NSF
(1S10RR023444, 1S10RR022442, 3R01GM118510-03S,
3R01GM087605-06S1, CHE-0840438, CHE-0848460,
1S10OD011980, CHE-1827457) as well as the Vagelos
Institute for Energy Science and Technology. G.H. and
P.D.N. thank the Chinese Scholarship Council and the
University of Guanajuato, respectively, for financial support.
Dr. Charles W. Ross, III (UPenn) is acknowledged for
obtaining accurate mass data.
D
https://dx.doi.org/10.1021/acs.orglett.0c00160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Based Small Molecule Acceptors for Organic Photovoltaic Cells.
Chem. Commun. 2014, 50, 8235.
REFERENCES
■
(1) (a) Levay, K.; Hegedus, L. Recent Achievements in the
Hydrogenation of Nitriles Catalyzed by Transitional Metals. Curr.
Org. Chem. 2019, 23, 1881−1900. (b) Kouznetsov, V. V.; Galvis, C. E.
P. Strecker reaction and a-amino nitriles: Recent advances in their
chemistry, synthesis, and biological properties. Tetrahedron 2018, 74,
773−810. (c) Lindsay-Scott, P. J.; Gallagher, P. T. Synthesis of
heterocycles from arylacetonitriles: Powerful tools for medicinal
chemists. Tetrahedron Lett. 2017, 58, 2629−2635. (d) Opatz, T. The
chemistryof deprotonated α-aminonitriles. Synthesis 2009, 2009 (12),
1941−1959. (e) Friedrich, K.; Wallenfels, K. The Chemistry of the
Cyano Group; Wiley-Interscience: New York, 1970; pp 341−421.
(2) (a) Fleming, F. F.; Yao, L. H.; Ravikumar, P. C.; Funk, L.;
Shook, B. C. Nitrile-Containing Pharmaceuticals: Efficacious Roles of
the Nitrile Pharmacophore. J. Med. Chem. 2010, 53, 7902.
(b) Caggiano, T. J.; Brazzale, A.; Ho, D. M.; Kraml, C. M.;
Trybulski, E.; Chadwick, C. C.; Chippari, S.; Borges-Marcucci, L.;
Eckert, A.; Keith, J. C.; Kenney, T.; Harnish, D. C. Estrogen Receptor
Dependent Inhibitors of NF-κB Transcriptional Activation-1 Syn-
thesis and Biological Evaluation of Substituted 2-Cyanopropanoic
Acid Derivatives: Pathway Selective Inhibitors of NF-κB, a Potential
Treatment for Rheumatoid Arthritis. J. Med. Chem. 2007, 50, 5245.
(10) (a) Kakadiya, R.; Dong, H.; Lee, P.-C.; Kapuriya, N.; Zhang, X.;
Chou, T.-C.; Lee, T.-C.; Kapuriya, K.; Shah, A.; Su, T.-L. Potent
Antitumor Bifunctional DNA Alkylating Agents, Synthesis and
Biological Activities of 3a-Aza-Cyclopenta[A]Indenes. Bioorg. Med.
Chem. 2009, 17, 5614. (b) Bradner, W. T. Mitomycin C: A Clinical
Update. Cancer Treat. Rev. 2001, 27, 35. (c) Tomasz, M.; Palom, Y.
The Mitomycin Bioreductive Antitumor Agents: Cross-Linking and
Alkylation of DNA as the Molecular Basis of Their Activity.
Pharmacol. Ther. 1997, 76, 73.
(11) (a) Ni, S.; Yuan, Y.; Huang, J.; Mao, X.; Lv, M.; Zhu, J.; Shen,
X.; Pei, J.; Lai, L.; Jiang, H.; Li, J. Discovering Potent Small Molecule
Inhibitors of Cyclophilin A Using de Novo Drug Design Approach. J.
Med. Chem. 2009, 52, 5295. (b) Burch, R. M.; Weitzberg, M.; Blok,
N.; Muhlhauser, R.; Martin, D.; Farmer, S. G.; Bator, J. M.; Connor, J.
R.; Green, M.; Ko, C. N-(fluorenyl-9-methoxycarbonyl) amino acids,
a class of antiinflammatory agents with a different mechanism of
action. Proc. Natl. Acad. Sci. U. S. A. 1991, 88, 355. (c) Banala, A. K.;
Levy, B. A.; Khatri, S. S.; Furman, C. A.; Roof, R. A.; Mishra, Y.;
Griffin, S. A.; Sibley, D. R.; Luedtke, R. R.; Newman, A. H. N-(3-
Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine1-yl)butyl)-
arylcarboxamides as Selective Dopamine D3 Receptor Ligands:
Critical Role of the Carboxamide Linker for D3 Receptor Selectivity.
J. Med. Chem. 2011, 54, 3581.
́
(3) Lopez, R.; Palomo, C. Cyanoalkylation: Alkylnitriles in Catalytic
C-C Bond-Forming Reactions. Angew. Chem., Int. Ed. 2015, 54,
13170.
(12) (a) Lee, T. B. K.; Wong, G. S. K. Asymmetric Alkylation of
Oxindoles: An Approach to the Total Synthesis of (−)-Physostig-
mine. J. Org. Chem. 1991, 56, 872. (b) Deng, F.; Moteki, S. A.;
Maruoka, K. Catalytic Asymmetric Alkylation of 3-Aryl-Substituted
Oxindoles to Give 3,3-Disubstituted Oxindoles under Phase-Transfer
Conditions. Asian J. Org. Chem. 2014, 3, 395. (c) Bleith, T.; Deng, Q.
H.; Wadepohl, H.; Gade, L. H. Radical Changes in Lewis Acid
Catalysis: Matching Metal and Substrate. Angew. Chem. 2016, 128,
7983.
(13) (a) Xiao, Y.; Liu, Z.-Q. Free Radical Addition of Nitrile,
Ketone, and Ester to Alkyne and the Selectivity Discussion. Org. Lett.
2019, 21, 8810. (b) Wang, K.; Chen, X.; Yuan, M.; Yao, M.; Zhu, H.;
Xue, Y.; Luo, Z.; Zhang, Y. Silver-Mediated Cyanomethylation of
Cinnamamides by Direct C(sp3)−H Functionalization of Acetonitrile.
J. Org. Chem. 2018, 83, 1525. (cb) Qiao, K.; Zhang, D.; Zhang, K.;
Yuan, X.; Zheng, M. W.; Guo, T. F.; Fang, Z.; Wan, L.; Guo, K.
Iron(II)-Catalyzed C-2 Cyanomethylation of Indoles and Pyrroles via
Direct Oxidative Cross-Dehydrogenative Coupling with Acetonitrile
Derivatives. Org. Chem. Front. 2018, 5, 1129. (cd) Wu, X. S.; Riedel,
J.; Dong, V. M. Transforming Olefins into γ,δ-Unsaturated Nitriles
through Copper Catalysis. Angew. Chem., Int. Ed. 2017, 56, 11589.
(e) Zhu, N. B.; Wang, T.; Ge, L.; Li, Y. J.; Zhang, X. H.; Bao, L. H. γ-
Amino Butyric Acid (GABA) Synthesis Enabled by Copper-Catalyzed
Carboamination of Alkenes. Org. Lett. 2017, 19, 4718. (f) Hu, M.;
Zou, H. X.; Song, R. J.; Xiang, J. N.; Li, J. H. Copper-Catalyzed C−H
Oxidative Radical Functionalization and Annulation of Aniline-Linked
1,7-Enynes: Evidence for a 1,5-Hydride Shift Mechanism. Org. Lett.
2016, 18, 6460. (g) Lan, X. W.; Wang, N. X.; Bai, C. B.; Lan, C. L.;
Zhang, T.; Chen, S. L.; Xing, Y. L. Unactivated C(sp3)−H Bond
Functionalization of Alkyl Nitriles with Vinylarenes and Mechanistic
Studies. Org. Lett. 2016, 18, 5986.
(14) (a) Bunescu, A.; Wang, Q.; Zhu, J. P. Copper-Mediated/
Catalyzed Oxyalkylation of Alkenes with Alkylnitriles. Chem. - Eur. J.
2014, 20, 14633. (b) Bunescu, A.; Wang, Q.; Zhu, J. P. Copper-
Catalyzed Cyanomethylation of Allylic Alcohols with Concomitant
1,2-Aryl Migration: Efficient Synthesis of Functionalized Ketones
Containing an α-Quaternary Center. Angew. Chem., Int. Ed. 2015, 54,
3132. (c) Chatalova-Sazepin, C.; Wang, Q.; Sammis, G. M.; Zhu, J. P.
Copper-Catalyzed Intermolecular Carboetherification of Unactivated
Alkenes by Alkyl Nitriles and Alcohols. Angew. Chem., Int. Ed. 2015,
54, 5443. (d) Ha, T. M.; Chatalova-Sazepin, C.; Wang, Q.; Zhu, J. P.
Copper-Catalyzed Formal [2 + 2+1] Heteroannulation of Alkenes,
Alkylnitriles, and Water: Method Development and Application to a
Total Synthesis of ( )-Sacidumlignan D. Angew. Chem., Int. Ed. 2016,
(4) For recent review, see: (a) Chu, X.-Q.; Ge, D.; Shen, Z.-L.; Loh,
T.-P. Recent Advances in Radical-Initiated C(sp3)−H Bond
Oxidative Functionalization of Alkyl Nitriles. ACS Catal. 2018, 8, 258.
(5) (a) Curto, J. M.; Kozlowski, M. C. Chemoselective Activation of
sp3 vs sp2 C−H Bonds with Pd(II). J. Am. Chem. Soc. 2015, 137, 18−
21. (b) Hong, G.; Nahide, P. D.; Neelam, U. K.; Amadeo, P.; Vijeta,
A.; Curto, J. M.; Hendrick, C. E.; VanGelder, K. F.; Kozlowski, M. C.
Palladium-Catalyzed Chemoselective Activation of sp3 vs sp2 C−H
Bonds: Oxidative Coupling To Form Quaternary Centers. ACS Catal.
2019, 9, 3716.
(6) (a) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Recent Advances in
Organocatalytic Methods for the Synthesis of Disubstituted 2- and 3-
Indolinones. Chem. Soc. Rev. 2012, 41, 7247. (b) Badillo, J. J.;
Hanhan, N. V.; Franz, A. K. Enantioselective Synthesis of Substituted
Oxindoles and Spirooxindoles with Applications in Drug Discovery.
Curr. Opin. Drug Discovery Dev. 2010, 13, 758. (c) Jensen, B. S. BMS-
204352: A Potassium Channel Opener Developed for the Treatment
of Stroke. CNS Drug Rev. 2002, 8, 353. (d) Chen, J.-Y.; Yu, X.-Y.;
Xiao, W.-J. Difunctionalization of Acrylamides through C−H
Oxidative Radical Coupling: New Approaches to Oxindoles. Synthesis
2015, 47, 604.
(7) (a) Ie, Y.; Umemoto, Y.; Nitani, M.; Aso, Y. Perfluoroalkyl-
Annelated Conjugated Systems toward n-type Organic Semi-
conductors. Pure Appl. Chem. 2008, 80, 589. (b) Anthony, J. E.
Functionalized Acenes and Heteroacenes for Organic Electronics.
Chem. Rev. 2006, 106, 5028.
(8) (a) Bernius, M. T.; Inbasekaran, M.; O’Brien, J.; Wu, W.
Progress with Light-Emitting Polymers. Adv. Mater. 2000, 12, 1737.
(b) Scherf, U.; List, E. J. W. Semiconducting PolyfluorenesTowards
Reliable Structure−Property Relationships. Adv. Mater. 2002, 14, 477.
(c) Belfield, K. D.; Yao, S.; Bondar, M. V. Two-photon Absorbing
Photonic Materials: From Fundamentals to Applications. Adv. Polym.
Sci. 2008, 213, 97. (d) Bendikov, M.; Wudl, F.; Perepichka, D. F.
Tetrathiafulvalenes, Oligoacenenes, and Their Buckminsterfullerene
Derivatives: The Brick and Mortar of Organic Electronics. Chem. Rev.
2004, 104, 4891.
(9) (a) Li, M.; Liu, Y.; Ni, W.; Liu, F.; Feng, H.; Zhang, Y.; Liu, T.;
Zhang, H.; Wan, X.; Kan, B.; Zhang, Q.; Russell, T. P.; Chen, Y. A
Simple Small Molecule as an Acceptor for Fullerene-Free Organic
Solar Cells with Efficiency Near 8%. J. Mater. Chem. A 2016, 4, 10409.
(b) Kim, Y.; Song, C. E.; Moon, S.-J.; Lim, E. Effect of Dye End
Groups in Non-Fullerene Fluorene- and Carbazole-Based Small
Molecule Acceptors on Photovoltaic Performance. RSC Adv. 2015, 5,
62739. (c) Kim, Y.; Song, C. E.; Moon, S.-J.; Lim, E. Rhodanine Dye-
E
https://dx.doi.org/10.1021/acs.orglett.0c00160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
55, 9249. (e) Bunescu, A.; Ha, T. M.; Wang, Q.; Zhu, J. P. Copper-
Catalyzed Three-Component Carboazidation of Alkenes with
Acetonitrile and Sodium Azide. Angew. Chem. 2017, 129, 10691.
(f) Ha, T. M.; Wang, Q.; Zhu, J. P. Copper-Catalysed Cyanoalkylative
Cycloetherification of Alkenes to 1,3-Dihydroisobenzofurans: Devel-
opment and Application to the Synthesis of Citalopram. Chem.
Commun. 2016, 52, 11100.
(15) Liu, Y. B.; Yang, K.; Ge, H. B. Palladium-Catalyzed Ligand-
Promoted Siteselective Cyanomethylation of Unactivated C(sp3)−H
Bonds with Acetonitrile. Chem. Sci. 2016, 7, 2804.
(16) Wang, C. Y.; Li, Y. B.; Gong, M.; Wu, Q.; Zhang, J. Y.; Kim, J.
K.; Huang, M. M.; Wu, Y. J. Method for Direct Synthesis of α-
Cyanomethyl-β-dicarbonyl Compounds with Acetonitrile and 1,3-
Dicarbonyls. Org. Lett. 2016, 18, 4151.
tion for the Synthesis of 3,3-Disubstituted Oxindoles. Org. Lett. 2018,
20, 4323. (e) Zhu, S.; MacMillan, D. W. C. Enantioselective
CopperCatalyzed Construction of Aryl Pyrroloindolines via an
ArylationCyclization Cascade. J. Am. Chem. Soc. 2012, 134, 10815.
(f) He, R.; Ding, C.; Maruoka, K. Phosphonium Salts as Chiral Phase-
Transfer Catalysts: Asymmetric Michael and Mannich Reactions of 3-
Aryloxindoles. Angew. Chem., Int. Ed. 2009, 48, 4559−4561. (g) Ma,
S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Catalytic
Enantioselective Stereoablative Alkylation of 3-Halooxindoles: Facile
Access to Oxindoles with C3 All-Carbon Quaternary Stereocenters.
Angew. Chem., Int. Ed. 2009, 48, 8037−8041.
(24) Vougioukalakis, G. C.; Roubelakis, M. M.; Orfanopoulos, M.
Radical Reactivity of Aza[60]fullerene: Preparation of Monoadducts
and Limitations. J. Org. Chem. 2010, 75, 4124.
(25) (a) Kang, H.; Jemison, A. L.; Nigro, E.; Kozlowski, M. C.
Oxidative Coupling of 3-Oxindoles with Indoles and Arenes.
ChemSusChem 2019, 12, 3144−3151. (b) Ohnishi, R.; Sugawara,
M.; Akakabe, M.; Ezawa, T.; Koshino, H.; Sohtome, Y.; Sodeoka, M.
Cross-Coupling Reaction of Dimer-Derived Persistent Tertiary-
Carbon-Centered Radicals with Azo Compounds. Asian J. Org.
Chem. 2019, 8, 1017−1023. (c) Tanaka, T.; Hashiguchi, K.; Tanaka,
T.; Yazaki, R.; Ohshima, T. Chemoselective Catalytic Dehydrogen-
ative Cross-Coupling of 2- Acylimidazoles: Mechanistic Investigations
and Synthetic Scope. ACS Catal. 2018, 8, 8430−8440.
(26) (a) Kang, H.; Jemison, A. L.; Nigro, E.; Kozlowski, M. C.
ChemSusChem 2019, 12, 3144−3151. (b) Kozlowski, M. C.;
DiVirgilio, E. S.; Malolanarasimhan, K.; Mulrooney, C. A. Oxidation
of Chiral α-Phenylacetate Derivatives: Formation of Dimers with
Contiguous Quaternary Stereocenters versus Tertiary Alcohols.
Tetrahedron: Asymmetry 2005, 16, 3599−3605.
(27) (a) Chu, X. Q.; Meng, H.; Zi, Y.; Xu, X. P.; Ji, S. J. Oxidative
C(sp3)-H Functionalization of Acetonitrile and Alkanes with Allylic
Alcohols Under Metal-Free Conditions. Org. Chem. Front. 2015, 2,
216. (b) Huang, H. Y.; Cheng, L.; Liu, J. J.; Wang, D.; Liu, L.; Li, C. J.
Transition-Metal-Free Alkynylation of 2-Oxindoles through Radical−
Radical Coupling. J. Org. Chem. 2017, 82, 2656. (c) Kong, D. L.;
Cheng, L.; Yue, T.; Wu, H. R.; Feng, W. C.; Wang, D.; Liu, L. Cobalt-
Catalyzed Peroxidation of 2-Oxindoles with Hydroperoxides. J. Org.
Chem. 2016, 81, 5337. (d) Wei, W. T.; Zhu, W. M.; Ying, W. W.;
Wang, Y. N.; Bao, W. H.; Gao, L. H.; Luo, Y. J.; Liang, H. Metal-Free
Nitration of the C(sp3)−H Bonds of 2-Oxindoles through Radical
Coupling Reaction at Room Temperature. Adv. Synth. Catal. 2017,
359, 3551.
(28) Frenette, M.; Aliaga, C.; Font-Sanchis, E.; Scaiano, J. C. Bond
Dissociation Energies for Radical- Dimers Derived from Highly
Stabilized Carbon-Centered Radicals. Org. Lett. 2004, 6, 2579−2582.
(29) (a) Luo, Y.-R. Handbook of Bond Dissociation Energy in Organic
Compound; CRC Press: Boca Raton, FL, 2002. (b) Li, Z.-J.; Xiao, Y.-
X.; Liu, Z.-Q. A radical anti-Markovnikov addition of alkyl nitriles to
simple alkenes via selective sp3 C−H bond functionalization. Chem.
Commun. 2015, 51, 9969.
(17) Zhang, W.; Yang, S.; Shen, Z. Copper-Catalyzed Cyanome-
thylation of Substituted Tetrahydroisoquinolines with Acetonitrile.
Adv. Synth. Catal. 2016, 358, 2392.
(18) Shen, X.; Gu, N. N.; Liu, P.; Ma, X. W.; Xie, J. W.; Liu, Y.; He,
L.; Dai, B. A Simple and Efficient Synthesis of 9-Arylfluorenes via
Metal-Free Reductive Coupling of Arylboronic Acids and N-
Tosylhydrazones in situ. RSC Adv. 2015, 5, 63726.
(19) (a) Hwang, S. J.; Kim, H. J.; Chang, S. Highly Efficient and
Versatile Synthesis of Polyarylfluorenes via Pd-Catalyzed C−H Bond
Activation. Org. Lett. 2009, 11, 4588. (b) Fuchibe, K.; Akiyama, T.
Low-Valent Niobium-Mediated Double Activation of C−F/C−H
Bonds: Fluorene Synthesis from o-Arylated α,α,α-Trifluorotoluene
Derivatives. J. Am. Chem. Soc. 2006, 128, 1434. (c) Yeung, C. S.;
Dong, V. M. Catalytic Dehydrogenative Cross-Coupling: Forming
Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds.
Chem. Rev. 2011, 111, 1215. (d) Itoh, M.; Hirano, K.; Satoh, T.;
Shibata, Y.; Tanaka, K.; Miura, M. Rhodium- and Iridium-Catalyzed
Dehydrogenative Cyclization through Double C−H Bond Cleavages
to Produce Fluorene Derivatives. J. Org. Chem. 2013, 78, 1365.
(20) Chu, X. Q.; Xing, Z. H.; Meng, H.; Xu, X. P.; Ji, S. J. Copper-
Mediated Radical Alkylarylation of Unactivated Alkenes with
Acetonitrile Leading to Fluorenes and Pyrroloindoles. Org. Chem.
Front. 2016, 3, 165.
(21) (a) Hu, M.; Li, M.; Tan, F. L.; Song, R. J.; Xie, Y. X.; Li, J. H.
Oxidative Divergent Bicyclizations of 1,n-Enynes through α-C(sp3)−
H Functionalization of Alkyl Nitriles. Adv. Synth. Catal. 2017, 359,
120. (b) Liu, Y. Y.; Yang, X. H.; Song, R. J.; Luo, S. L.; Li, J. H.
Oxidative 1,2-Carboamination of Alkenes with Alkyl Nitriles and
Amines Toward G-Amino Alkyl Nitriles. Nat. Commun. 2017, 8,
14720.
(22) (a) Zhou, Y. J.; Duan, K. Y.; Zhu, L.; Liu, Z. F.; Zhang, C. B.;
Yang, L. J.; Li, M. Y.; Zhang, H. B.; Yang, X. D. Synthesis and
Cytotoxic Activity of Novel Hexahydropyrrolo[2,3-B] Indole
Imidazolium Salts. Bioorg. Med. Chem. Lett. 2016, 26, 460.
(b) Pinto, A.; Jia, Y. X.; Neuville, L.; Zhu, J. P. Palladium-Catalyzed
Enantioselective Domino Heck−Cyanation Sequence: Development
and Application to the Total Synthesis of Esermethole and
Physostigmine. Chem. - Eur. J. 2007, 13, 961. (c) Rivera-Becerril,
E.; Joseph-Nathan, P.; Perez-Alvarez, V. M.; Morales-Rios, M. S.
Synthesis and Biological Evaluation of (−)- and (+)-Debromoflustr-
amine B and Its Analogues as Selective Butyrylcholinesterase
Inhibitors. J. Med. Chem. 2008, 51, 5271.
(23) (a) Wang, X.; Ma, G.; Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T.
D.; Wang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of
Electron-Rich Aryl Iodides with Tertiary Alkyl Halides. J. Am.
Chem. Soc. 2018, 140, 14490. (b) Tong, S.; Limouni, A.; Wang, Q.;
Wang, M. X.; Zhu, J. P. Catalytic Enantioselective Double
Carbopalladation/C-H Functionalization with Statistical Amplifica-
tion of Product Enantiopurity: A Convertible Linker Approach.
Angew. Chem., Int. Ed. 2017, 56, 14192. (c) Naresh Babu, K.;
Kariyandi, N. R.; Saheeda, M. K. S.; Kinthada, L. K.; Bisai, A. Lewis
Acid-Catalyzed Malonate Addition onto 3-Hydroxy-2- oxindoles:
Mechanistic Consideration and Synthetic Approaches to the
Pyrroloindoline Alkaloids. J. Org. Chem. 2018, 83, 12664−12682.
(d) Yen, A.; Lautens, M. Nickel-Catalyzed Intramolecular Arylcyana-
F
https://dx.doi.org/10.1021/acs.orglett.0c00160
Org. Lett. XXXX, XXX, XXX−XXX