Intramolecular Reductive Cyclization of o-Nitroarenes via Biradical Recombination

Article abstract of DOI:10.1021/acs.orglett.9b00191

A visible-light-induced/thiourea-mediated intramolecular cyclization of o-nitroarenes under mild conditions is realized for the first time, which provides an efficient and environmentally friendly way to access pharmaceutical relevant quinazolinone derivatives. The reaction can be easily extended to gram level by using a continuous-flow setup with high efficiency. Mechanistic investigation including control experiments, transient fluorescence, UV-vis spectra, and DFT calculations suggests that the formation of active biradical intermediates via intramolecular single electron transfer (SET) is key stage in the catalytic cycle.

Full text of DOI:10.1021/acs.orglett.9b00191

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intramolecular Reductive Cyclization of o‑Nitroarenes via Biradical
Recombination
Cong Lu,‡ Zhishan Su,‡ Dong Jing, Songyang Jin, Lijuan Xie, Liangrui Li, and Ke Zheng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
S
* Supporting Information
ABSTRACT: A visible-light-induced/thiourea-mediated intramo-
lecular cyclization of o-nitroarenes under mild conditions is
realized for the first time, which provides an efficient and
environmentally friendly way to access pharmaceutical relevant
quinazolinone derivatives. The reaction can be easily extended to
gram level by using a continuous-flow setup with high efficiency.
Mechanistic investigation including control experiments, transient
fluorescence, UV−vis spectra, and DFT calculations suggests that
the formation of active biradical intermediates via intramolecular
single electron transfer (SET) is key stage in the catalytic cycle.
he development of catalytic methods for direct
conversion of the nitro group into other functional
Scheme 1. Intramolecular Cyclization of o-Nitroarene
Derivatives
T
groups has received a lot of attention from the synthesis
community.1 The nitroarenes are the desired building blocks
for this transformation due to their widespread availability and
appealing synthetic diversities.2,3 Since the initial discovery by
Reissert4 (named as Reissert indole synthesis), a variety of
useful strategies have been developed for the reductive
cyclization of o-functionalized nitroarenes to construct N-
containing heterocycles such as indoles5−8 and carbazoles,9
which are important structural units in both natural products
and synthetic pharmaceuticals.10 Generally, these trans-
formations could be accomplished by using stoichiometric
quantities of a reductant (such as zinc dust,3 Grignard
reagent,5 phosphite,6 [Mo-(CO)6],7 TiCl3,8a CO/Pd,8b,c or
diborane8d), which convert the nitro group into reactive
nitrogen species (Scheme 1a). Very recently, the biphilic
phosphetane and iron phenanthroline complexes were
demonstrated as efficient oxygen-atom transfer catalysts for
the reductive cyclization of o-nitroarenes by the Radosevich
group11 and the Driver group,12 respectively. However, despite
the great progress that has been made in this field, there are
still some limitations (e.g., five-membered N-heterocycles were
generally built, stoichiometric amounts of reductant, speci-
alized reactors, high pressures of CO, high temperatures, or
toxic reagents), which disfavor the use of these trans-
formations, particularly on a large scale. Consequently, the
development of efficient, scalable, facile, and environmentally
friendly methods for this transformation is still highly desirable.
Visible-light-induced photochemistry has undergone a
dramatic development over the past decade.13 As a photo-
sensitive protecting group, the o-nitrobenzyl compounds are
also widely exploited in photoimaging and biochemistry,14 but
there are only limited examples in organic synthesis by using
their photorearrangement.15 Additionally, previous reports
have already shown that alkyl radicals can react readily with
nitroarenes.16 Russell and co-workers have demonstrated that
the photoinduced tert-butyl radicals could react with both
nitroarenes and nitrosoarenes to generate N-alkylated prod-
Received: January 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ucts. Recently, Baran and Hu reported the iron-catalyzed
hydroamination and reductive coupling approach to synthesize
aryl amines from nitroarenes using simple olefins and alkyl
halides as the radical sources, respectively (Scheme 1b).
Considering the biradical species were proposed as inter-
mediates in the photochemistry of o-nitrobenzyl compounds,17
we speculated that reasonable substrate design combined with
the suitable photochemistry reaction conditions (under visible-
light irradiation) would enable the intramolecular reductive
cyclization of o-nitroarene via biradical recombination. Herein,
we report the first metal-free visible-light-induced/thiourea-
mediated intramolecular reductive cyclization of o-nitroarenes
to synthesize a series of polycyclic quinazolinone derivatives18
without external photocatalysts (Scheme 1c). In addition, the
reaction can be easily scaled up by using a continuous-flow
system under mild conditions.
were obtained in DMF and alcohol, which were commonly
used in reductive coupling reaction by using a nitro group as
the nitrogen source (Table 1, entry 4).3a,16b Among the
thioureas and silanes screened, phenylthiourea and PhSiH3
proved to be the most effective at facilitating transformation
(Table 1, entries 5−9; for more detail, see SI). The yield of 2a
decreased to 71% with reducing the amount of PhSiH3 to 0.5
equiv (Table 1, entry 10). The reaction of 1a under air
atmosphere only leading to 2a in 33% yield indicated that the
reaction was sensitive to oxygen and water (Table 1, entry 11).
Finally, no product was detected for the control experiment in
the dark, indicating that the light was essential for this reaction
(Table 1, entry 12).
With optimal conditions in hand, we investigated the
generality of this protocol. As shown in Scheme 2, a broad
In general, in the primary photorearrangement, the
irradiation of o-nitrobenzyl compounds with intramolecular
1,5-HAT (HAT = hydrogen atom transfer) will generate the
aci-nitro tautomers, which have strong absorption around 400
nm. To start our investigation, the purple LED (395 nm) was
chosen as the light source, as well as o-nitrobenzamide 1a as
the standard substrate, for optimization studies. Initial
screening revealed that the best results were obtained by
using a catalytic amount of phenylthiourea as catalyst with 1.1
equiv of PhSiH3 as a terminal reductant in dry 1,4-dioxane
under purple LED (395 nm) irradiation at room temperature
(for more details, see SI, Tables S1−S4). Under these
optimized conditions, the quinazolinone 2a was obtained in
94% yield (Table 1, entry 1). The use of both phenylthiourea
and PhSiH3 was critical for achieving high yields, and only 24%
and 48% of 2a were obtained in the absence of phenylthiourea
or PhSiH3, respectively (Table 1, entries 2−3). The solvents
have a great influence on the reaction, and only trace products
a
Scheme 2. Scope of o-Nitrobenzamide Compounds
a
Table 1. Optimization of Reaction Conditions
b
entry
variation from the “standard conditions”
yield (%)
1
2
3
none
94
24
48
without phenylthiourea
without PhSiH3
4
5
DMF or EtOH instead of dioxane
3a instead of 3b
trace
31
6
3c instead of 3b
59
7
3d instead of 3b
72
8
9
10
11
12
HSi(Et)3 instead of PhSiH3
HSi(OMe)3 instead of PhSiH3
0.5 equiv PhSiH3
under air
51
64
71
33
a
Reaction condition: phenylthiourea 3b (20 mol %), PhSiH3 (1.1
without light
NR
equiv), and 1a (0.05 mmol) in dry 1,4-dioxane (1.0 mL) under 10 W
b
purple LED (395 nm) at rt for 24 h. Isolated yield. Reaction time
a
c
d
Reactions were performed on a 0.05 mmol scale in dry 1,4-dioxane
was 36 h. Reaction time was 12 h. Isolated combined yields. Isomer
ratios were determined by analysis of the 1H NMR spectra of isolated
products.
b
(1.0 mL) at rt for 24 h under nitrogen. Isolated yield. NR = no
reaction.
B
DOI: 10.1021/acs.orglett.9b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
range of o-nitrobenzamides participated in the reaction,
affording a series of polycyclic quinazolinone derivatives in
good to high yields (up to 94% yield, 2b−2aj). The results
indicated this method is insensitive to electronics of the
substituents on the o-nitroarene moiety, and both electron-
donating and electron-withdrawing groups, as well as electro-
neutral groups, at different positions of benzene ring A were
well tolerated in the reaction (2b−2q), although substrates
with substituents at the 4-position generally gave lower yields
in some cases (2l and 2m). The substrates 2o, 2p, and 2q with
disubstituted phenyl groups (ring A) underwent the reductive
cyclization smoothly to afford the corresponding quinazoli-
nones in high yields. Similarly, benzene ring B of the
tetrahydroisoquinoline moiety bearing various electronic
properties in different position was also compatible in the
reaction (49−90% yields 2r−2aa). To our delight, it was found
that the isoindoline (ring C) derivatives with a range of
electronically diverse aryl groups were also tolerable and
showed high efficiency in the transformation (75−94% yields
of 2ab−2ah). Moreover, the substrates with methyl or ester
group substituted on ring C performed well, delivering the
corresponding products 2ai and 2aj with good outcomes,
respectively. To further demonstrate the synthetic utility of this
method, a simple continuous-flow setup was assembled for the
scale up to the gram scale, which has potential application in
industry (2a, 80% yield, 1.0 g/24 h). After investigating the
scope of o-nitrobenzamides, the reaction was next explored to
varieties of o-nitroaniline compounds (Scheme 3). Under the
Scheme 4. Control Experiments
a
Reaction condition: phenylthiourea 3b (20 mol %), PhSiH3 (1.1
equiv), and 1a (0.05 mmol) in dry 1,4-dioxane (1.0 mL) under 10 W
purple LED (395 nm) at rt for 12 h. Isolated yield. SM = starting
material
aniline 9a treated with the standard conditions, and only 26%
yield of 2a was given in 2 h for o-nitrosoarene 9b. Thus, direct
cyclization of in situ formed active aniline or o-nitrosoarene can
be ruled out as the main reaction pathway. Notably, compared
to no reaction of 10a (X = H), 100% conversion of starting
material was observed but without cyclization product, when
the o-nitroarenes 10b (X = NO2) bearing a cyclopropyl moiety
(radical clock) were utilized under the optimal conditions. The
ring-opened product 11 (X = NO2) was detected by LC-MS
analysis, supporting the involvement of biradical intermediate
in the reaction. Furthermore, the reaction of 1a with N-methyl-
substituted phenylthiourea such as 3c and 3d gave the
cyclization product only in lower yield, indicating that both
NH group and NH2 group of the phenylthiourea were essential
for this transformation, which might help stabilize the
photoactive biradical intermediate via hydrogen-bonding
interaction (for more details, see SI, Table S5).
a
Scheme 3. Scope of o-Nitroaniline Compounds
To further understand the mechanism of the reaction,
transient fluorescence and UV−vis spectra,19 as well as DFT
calculation, were performed (for more details, see SI). A triplet
biradical intermediate IV was located at the UB3LYP-
D3(BJ)(PCM, 1,4-dioxane)/def2-SVP theoretical level, and
the corresponding SOMOs with unpaired electrons were
visualized in Figure 2. According to the Salem rules, these two
SOMOs with different orientation could interact rapidly to
form a C−N bond. On the basis of the experimental results,
DFT calculations, and previous reports,17e we envisioned that
the cyclization might undergo the biradical recombination
pathway (Figure 1): first, the irradiation of o-nitrobenzamide
1a with internal 1,7-HAT generates the aci-nitro tautomer
intermediate I, in which the ground state reactant 1a was first
excited to triple state I with high reactivity. The energy barrier
in this step was predicted to be 3.7 kcal/mol, indicating that
this process was facile to occur. Sequentially, the thiourea
interacted with intermediate II by hydrogen bonding, forming
a molecular complex intermediate III. This step was
exothermic by 62.7 kcal/mol, suggesting that the thiourea
a
Reaction conditions: Phenylthiourea 3b (20 mol %), PhSiH3 (1.1
equiv), and 1a (0.05 mmol) in dry 1,4-dioxane (1.0 mL) under 10 W
purple LED (395 nm) at rt for 12 h. Isolated yield. Reaction time
was 48 h.
b
optimal conditions, the corresponding tetracyclic imidazole
products 5a−5e were observed with moderate to good yields.
All of these results showed that this transformation exhibited
excellent functional group tolerance, and the reactive groups
such as halides, ketone, ester, hydroxy, and cyano groups do
not affect the outcomes.
To identify the mechanism of the reaction, several control
experiments were performed (Scheme 4). First, the o-
nitrobenzamide 6 was subjected to the standard conditions,
and no reduction products 7 or 8 were detected with almost all
starting material 6 recovered, suggesting that silane cannot
directly reduce the nitro group under the optimal conditions.
Moreover, no cyclization product 2a was obtained for the
C
DOI: 10.1021/acs.orglett.9b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kzheng@scu.edu.cn.
ORCID
Zhishan Su: 0000-0001-5168-3823
Ke Zheng: 0000-0002-3345-7715
Author Contributions
‡C.L. and Z.S. contributed equally.
Notes
The authors declare no competing financial interest.
Figure 1. Proposed mechanism.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21602142) and the Fundamental Research Funds for the
Central Universities. We thank the Xiaoming Feng Laboratory
(SCU) for access to equipment. We also thank the
comprehensive training platform of the Specialized Laboratory
in the College of Chemistry at Sichuan University for
compound testing.
Figure 2. Visualization of the frontier orbitals (SOMOs) in triplet
biradical intermediate IV (isovalue = 0.04).
REFERENCES
■
(1) For selected reviews, see: (a) Blaser, H. U.; Steiner, H.; Studer,
M. Selective catalytic hydrogenation of functionalized nitroarenes: an
update. ChemCatChem 2009, 1, 210−221. (b) Mondal, M.;
Bharadwaj, S. K.; Bora, U. O-Arylation with nitroarenes: metal-
catalyzed and metal-free methodologies. New J. Chem. 2015, 39, 31−
37. (c) Ricci, A.; Fochi, M. Reactions between organomagnesium
reagents and nitroarenes: past, present, and future. Angew. Chem., Int.
Ed. 2003, 42, 1444−1446.
would stabilize intermediate II. The photoactive intermediate
III undergoes intramolecular single electron transfer (SET) to
form triplet-phased biradical intermediate IV (Figure 1). Then,
formation of H2O and recombination of the radical pair ensure
the C−N formation, accompanied with the construction of a
six-membered ring intermediate V. The basic N atom in
thiourea abstracted the H atom from V, affording intermediate
VI.20 Finally, the quinazolinone product 2a was obtained via
reduction of the resulting intermediate VI in the presence of
PhSiH3.
In conclusion, we established intramolecular reductive
cyclization of o-nitroarenes for the synthesis of useful
quinazolinone derivatives with visible light, thiourea, and
terminal reductant silane. Mild reaction conditions, broad
substrate scope, and facile procedure show the potential for the
practical synthesis. Moreover, the reaction can be easily scaled
up when combined with flow chemistry. Mechanistic studies
suggested that the reaction undergoes a biradical recombina-
tion pathway. Further application of this novel strategy in
intermolecular reactions is underway.
(2) Yang, Y. Palladium-Catalyzed Cross-Coupling of Nitroarenes.
Angew. Chem., Int. Ed. 2017, 56, 15802−15804.
(3) (a) Cheung, C. W.; Ploeger, M. L.; Hu, X. Amide synthesis via
nickel-catalysed reductive aminocarbonylation of aryl halides with
nitroarenes. Chem. Sci. 2018, 9, 655−659. (b) Cheung, C. W.; Ma, J.
A.; Hu, X. Manganese-Mediated Reductive Transamidation of
Tertiary Amides with Nitroarenes. J. Am. Chem. Soc. 2018, 140,
6789−6792. (c) Cheung, C. W.; Ploeger, M. L.; Hu, X. Direct
amidation of esters with nitroarenes. Nat. Commun. 2017, 8, 14878.
(d) Cheung, C. W.; Ploeger, M. L.; Hu, X. Nickel-Catalyzed
Reductive Transamidation of Secondary Amides with Nitroarenes.
ACS Catal. 2017, 7, 7092−7096.
̈
(4) Reissert, A. Einwirkung von oxalester und natriumathylat auf
nitrotoluole. Synthese nitrirter phenylbrenztraubensauren. Ber. Dtsch.
Chem. Ges. 1897, 30, 1030−1053.
(5) (a) Gao, H.; Xu, Q. L.; Yousufuddin, M.; Ess, D. H.; Kurti, L.
̈
̈
Rapid synthesis of fused N-heterocycles by transition-metal-free
electrophilic amination of arene C-H bonds. Angew. Chem., Int. Ed.
2014, 53, 2701−2705. (b) Bartoli, G.; Palmieri, G.; Bosco, M.;
Dalpozzo, R. The reaction of vinyl Grignard reagents with 2-
substituted nitroarenes: a new approach to the synthesis of 7-
substituted indoles. Tetrahedron Lett. 1989, 30, 2129−2132.
(c) Dalpozzo, R.; Bartoli, G. Bartoli indole synthesis. Curr. Org.
Chem. 2005, 9, 163−178. (d) Bartoli, G.; Bosco, M.; Dalpozzo, R.;
Palmieri, G.; Marcantoni, E. Reactivity of nitro-and nitroso-arenes
with vinyl grignard reagents: synthesis of 2-(trimethylsilyl) indoles. J.
Chem. Soc., Perkin Trans. 1 1991, 2757−2761.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00191.
■
S
General procedures, analytical data, NMR spectra, and
DFT calculation data (PDF)
Accession Codes
CCDC 1888418 and 1888420 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
(6) (a) Sundberg, R. J.; Kotchmar, G. S., Jr. An Investigation of
Stereochemistry and Migratory Aptitude in the Reductive Cyclization
of β,β-Disubstituted o-Nitrostyrenes to 2,3-Disubstituted Indoles. J.
Org. Chem. 1969, 34, 2285−2288. (b) Sundberg, R. J.; Yamazaki, T.
D
DOI: 10.1021/acs.orglett.9b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Rearrangements and ring expansions during the deoxygenation of β,β-
disubstituted o-nitrostyrenes. J. Org. Chem. 1967, 32, 290−294.
(7) (a) Jana, N.; Zhou, F.; Driver, T. G. Promoting Reductive
Tandem Reactions of Nitrostyrenes with Mo(CO)6 and a Palladium
Catalyst To Produce 3H-Indoles. J. Am. Chem. Soc. 2015, 137, 6738−
6741. (b) Zhou, F.; Wang, D. S.; Guan, X.; Driver, T. G. Nitroarenes
as the Nitrogen Source in Intermolecular Palladium-Catalyzed Aryl C-
H Bond Aminocarbonylation Reactions. Angew. Chem., Int. Ed. 2017,
56, 4530−4534.
(8) (a) Tong, S.; Xu, Z.; Mamboury, M.; Wang, Q.; Zhu, J. Aqueous
Titanium Trichloride Promoted Reductive Cyclization of o-Nitro-
styrenes to Indoles: Development and Application to the Synthesis of
Rizatriptan and Aspidospermidine. Angew. Chem., Int. Ed. 2015, 54,
11809−11812. (b) Zhou, F.; Wang, D. S.; Driver, T. G. Palladium-
Catalyzed Formation of N-Heteroarenes from Nitroarenes using
Molybdenum Hexacarbonyl as the Source of Carbon Monoxide. Adv.
Synth. Catal. 2015, 357, 3463−3468. (c) Okuro, K.; Gurnham, J.;
Alper, H. Ionic diamine rhodium complex catalyzed reductive N-
heterocyclization of 2-nitrovinylarenes. J. Org. Chem. 2011, 76, 4715−
4720. (d) Yang, K.; Zhou, F.; Kuang, Z.; Gao, G.; Driver, T. G.; Song,
Q. Diborane-Mediated Deoxygenation of o-Nitrostyrenes To Form
Indoles. Org. Lett. 2016, 18, 4088−4091.
(9) For examples of carbazole synthesis, see: (a) Creencia, E. C.;
Kosaka, M.; Muramatsu, T.; Kobayashi, M.; Iizuka, T.; Horaguchi, T.
Microwave-assisted Cadogan reaction for the synthesis of 2-aryl-2H-
indazoles, 2-aryl-1H-benzimidazoles, 2-carbonylindoles, carbazole,
and phenazine. J. Heterocycl. Chem. 2009, 46, 1309−1317. (b) Free-
man, A. W.; Urvoy, M.; Criswell, M. E. Triphenylphosphine-mediated
reductive cyclization of 2-nitrobiphenyls: a practical and convenient
synthesis of carbazoles. J. Org. Chem. 2005, 70, 5014−5019. (c) Peng,
H.; Chen, X.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. Solvent-free
synthesis of δ-carbolines/carbazoles from 3-nitro-2-phenylpyridines/
2-nitrobiphenyl derivatives using DPPE as a reducing agent.
Tetrahedron 2011, 67, 5725−5731. (d) Smitrovich, J. H.; Davies, I.
W. Catalytic C-H functionalization driven by CO as a stoichiometric
reductant: application to carbazole synthesis. Org. Lett. 2004, 6, 533−
535.
Containing Heterocyclic Compounds Using Visible-light Photoredox
Catalysis. Chem. Rec. 2016, 16, 319−334. (f) Romero, N. A.;
Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116,
10075−10166.
(14) For selected examples, see: (a) Pramanick, S.; Kim, J.; Kim, J.;
Saravanakumar, G.; Park, D.; Kim, W. J. Synthesis and Character-
ization of Nitric Oxide-Releasing Platinum(IV) Prodrug and
Polymeric Micelle Triggered by Light. Bioconjugate Chem. 2018, 29,
885−897. (b) Wong, P. T.; Tang, S.; Mukherjee, J.; Tang, K.; Gam,
K.; Isham, D.; Murat, C.; Sun, R.; Baker, J. R.; Choi, S. K. Light-
controlled active release of photocaged ciprofloxacin for lip-
opolysaccharide-targeted drug delivery using dendrimer conjugates.
Chem. Commun. 2016, 52, 10357−10360. (c) Wong, P. T.; Choi, S.
K. Mechanisms of drug release in nanotherapeutic delivery systems.
Chem. Rev. 2015, 115, 3388−3432. (d) Wong, P. T.; Tang, S.;
Cannon, J.; Chen, D.; Sun, R.; Lee, J.; Phan, J.; Tao, K.; Sun, K.;
Chen, B.; Baker, J. R., Jr.; Choi, S. K. Photocontrolled Release of
Doxorubicin Conjugated through a Thioacetal Photocage in Folate-
Targeted Nanodelivery Systems. Bioconjugate Chem. 2017, 28, 3016−
3028.
(15) (a) Fielden, R.; Meth-Cohn, O.; Suschitzky, H. Thermal and
photolytic cyclisation, rearrangement, and denitration reactions of o-
nitro-t-anilines. Tetrahedron Lett. 1970, 11, 1229−1234. (b) Preston,
P. N.; Tennant, G. Synthetic methods involving neighboring group
interaction in o-substituted nitrobenzene derivatives. Chem. Rev.
1972, 72, 627−677. (c) Lin, W. C.; Yang, D. Y. Visible light
photoredox catalysis: synthesis of indazolo[2,3-a]quinolines from 2-
(2-nitrophenyl)-1,2,3,4-tetrahydroquinolines. Org. Lett. 2013, 15,
4862−4865.
(16) (a) Russell, G. A.; Yao, C.-F. Deoxygenation of nitro and
nitrosoaromatics by photolysis with t-BuHgl/Kl. Regiochemistry of
tert-Butyl radical addition to nitrosoaromatics. Heteroat. Chem. 1993,
4, 433−444. (b) Gui, J.; Pan, C. M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B.
J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.;
Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Practical
olefin hydroamination with nitroarenes. Science 2015, 348, 886−891.
(c) Cheung, C. W.; Hu, X. Amine synthesis via iron-catalysed
reductive coupling of nitroarenes with alkyl halides. Nat. Commun.
2016, 7, 12494.
(10) For selected reviews, see: (a) Kaushik, N. K.; Kaushik, N.; Attri,
P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Biomedical
importance of indoles. Molecules 2013, 18, 6620−6662. (b) Schmidt,
(17) (a) Wettermark, G. Photochromism of o-nitrotoluenes. Nature
1962, 194, 677. (b) Wettermark, G. Light-induced isomerization of o-
nitrotoluene in water solution. J. Phys. Chem. 1962, 66, 2560−2562.
(c) Yip, R. W.; Sharma, D. K.; Giasson, R.; Gravel, D. Photochemistry
of the o-nitrobenzyl system in solution: evidence for singlet-state
intramolecular hydrogen abstraction. J. Phys. Chem. 1985, 89, 5328−
̈
A. W.; Reddy, K. R.; Knolker, H. J. Occurrence, biogenesis, and
synthesis of biologically active carbazole alkaloids. Chem. Rev. 2012,
112, 3193−3328.
(11) (a) Nykaza, T. V.; Harrison, T. S.; Ghosh, A.; Putnik, R. A.;
Radosevich, A. T. A Biphilic Phosphetane Catalyzes N-N Bond-
Forming Cadogan Heterocyclization via PIII/PV=O Redox Cycling. J.
Am. Chem. Soc. 2017, 139, 6839−6842. (b) Nykaza, T. V.; Cooper, J.
C.; Li, G.; Mahieu, N.; Ramirez, A.; Luzung, M. R.; Radosevich, A. T.
Intermolecular Reductive C-N Cross Coupling of Nitroarenes and
Boronic Acids by PIII/PV=O Catalysis. J. Am. Chem. Soc. 2018, 140,
15200−15205. (c) Nykaza, T. V.; Ramirez, A.; Harrison, T. S.;
Luzung, M. R.; Radosevich, A. T. Biphilic Organophosphorus-
Catalyzed Intramolecular Csp2-H Amination: Evidence for a Nitrenoid
in Catalytic Cadogan Cyclizations. J. Am. Chem. Soc. 2018, 140,
3103−3113.
̈
5330. (d) Il’ichev, Y. V.; Schworer, M. A.; Wirz, J. Photochemical
reaction mechanisms of 2-nitrobenzyl compounds: methyl ethers and
caged ATP. J. Am. Chem. Soc. 2004, 126, 4581−4595. (e) Schmierer,
T.; Laimgruber, S.; Haiser, K.; Kiewisch, K.; Neugebauer, J.; Gilch, P.
Femtosecond spectroscopy on the photochemistry of ortho-nitro-
toluene. Phys. Chem. Chem. Phys. 2010, 12, 15653−15664. (f) Gerbig,
D.; Schreiner, P. R. Formation of a Tunneling Product in the
Photorearrangement of o-Nitrobenzaldehyde. Angew. Chem., Int. Ed.
2017, 56, 9445−9448.
(18) For selected examples, see: (a) Huang, Y.; Lei, Y. Y.; Zhao, L.;
Gu, J.; Yao, Q.; Wang, Z.; Li, X. F.; Zhang, X.; He, C. Y. Catalyst-free
and visible light promoted trifluoromethylation and perfluoroalkyla-
tion of uracils and cytosines. Chem. Commun. 2018, 54, 13662−
13665. (b) Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal,
J.; Saeed, A. Quinazolines and quinazolinones as ubiquitous structural
fragments in medicinal chemistry: An update on the development of
synthetic methods and pharmacological diversification. Bioorg. Med.
Chem. 2016, 24, 2361−2381. (c) Khan, I.; Ibrar, A.; Abbas, N.; Saeed,
A. Recent advances in the structural library of functionalized
quinazoline and quinazolinone scaffolds: synthetic approaches and
multifarious applications. Eur. J. Med. Chem. 2014, 76, 193−244.
(d) Kshirsagar, U. A. Recent developments in the chemistry of
quinazolinone alkaloids. Org. Biomol. Chem. 2015, 13, 9336−9352.
(e) Maiden, T. M. M.; Harrity, J. P. A. Recent developments in
(12) Shevlin, M.; Guan, X.; Driver, T. G. Iron-Catalyzed Reductive
Cyclization of o-Nitrostyrenes Using Phenylsilane as the Terminal
Reductant. ACS Catal. 2017, 7, 5518−5522.
(13) For selected reviews, see: (a) Marzo, L.; Pagire, S. K.; Reiser,
̈
O.; Konig, B. Visible-Light Photocatalysis: Does It Make a Difference
in Organic Synthesis? Angew. Chem., Int. Ed. 2018, 57, 10034−10072.
(b) Narayanam, J. M. R.; Stephenson, C. R. J. Visible light photoredox
catalysis: applications in organic synthesis. Chem. Soc. Rev. 2011, 40,
102−113. (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible
light photoredox catalysis with transition metal complexes:
applications in organic synthesis. Chem. Rev. 2013, 113, 5322−
5363. (d) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox
Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898−6926.
(e) Zhou, L.; Lokman Hossain, M.; Xiao, T. Synthesis of N-
E
DOI: 10.1021/acs.orglett.9b00191
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
transition metal catalysis for quinazolinone synthesis. Org. Biomol.
Chem. 2016, 14, 8014−8025.
(19) The data of the UV−vis spectra and transient fluorescence
indicated that the substrate 1a has weak absorption around 400 nm
and could be excited at 395 nm.
(20) (a) Burke, P. J.; Wong, L. C.; Jenkins, T. C.; Knox, R. J.;
Stanforth, S. P. The synthesis of 2-nitroaryl-1,2,3,4-tetrahydroisoqui-
nolines, nitro-substituted 5,6-dihydrobenzimidazo[2,1-a]isoquinoline
N-oxides and related heterocycles as potential bioreducible substrates
for the enzymes NAD(P)H: quinone oxidoreductase 1 and E. coli
nitroreductase. Bioorg. Med. Chem. Lett. 2011, 21, 7447−7450.
(b) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Redox
condensation of o-halonitrobenzene with 1,2,3,4-tetrahydroisoquino-
line: involvement of an unexpected auto-catalyzed redox cascade.
Chem. Commun. 2016, 52, 4914−4917.
F
DOI: 10.1021/acs.orglett.9b00191
Org. Lett. XXXX, XXX, XXX−XXX