Photoinduced EDA Complexes Enabled Radical Tandem Cyclization/Arylation of Unactivated Alkene with 2-Amino-1,4-naphthoquinones

Article abstract of DOI:10.1021/acs.orglett.1c00268

A visible-light-induced radical tandem cyclization/arylation between 2-amino-1, 4-naphthoquinone and N-allyl-2-bromo-2,2-difluoroacetamides has been developed without an external photocatalyst. The transformation could be carried out at room temperature a

Full text of DOI:10.1021/acs.orglett.1c00268

pubs.acs.org/OrgLett
Letter
Photoinduced EDA Complexes Enabled Radical Tandem Cyclization/
Arylation of Unactivated Alkene with 2‑Amino-1,4-
naphthoquinones
Bin Sun, Xiayue Shi, Xiaohui Zhuang, Panyi Huang, Rongcheng Shi, Rui Zhu, and Can Jin*
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ABSTRACT: A visible-light-induced radical tandem cyclization/arylation between 2-amino-1, 4-naphthoquinone and N-allyl-2-
bromo-2,2-difluoroacetamides has been developed without an external photocatalyst. The transformation could be carried out at
room temperature and gave a variety of C-3-functionalized 2-amino-1,4-naphthoquinone derivatives in moderate to excellent yields.
Moreover, mechanistic studies revealed that the reaction is driven by the formation of an electron donor−acceptor (EDA) complex.
aphthoquinones, especially those containing an amino
group at the two-position, are widely present among
employing tert-butyl hydroperoxide (TBHP) as an oxidant
and Zn (SO2CF3)2 as a trifluoromethylation reagent7a
(Scheme 1a). Zhang’s group developed a copper-catalyzed
three-component difunctionalization of aromatic alkenes to
access 1,4-naphthoquinone derivatives, in which α-bromocar-
boxylates are used as radical precursors and 2-amino-1,4-
naphthoquinones are used as radical trapping reagents7b
(Scheme 1b). Subsequently, a silver-catalyzed three-compo-
nent difunctionalization of alkenes was also reported by the
same research group, providing an alternative method to access
CF3-functionalized alkyl-substituted quinone derivatives7c
(Scheme 1c). Despite these achievements, developing novel
and environmentally friendly methods for the construction of
more complex 2-amino-1,4-naphthoquinone derivatives via
direct C-3 functionalization is still in high demand.
N
pharmacologically active compounds and synthetic molecules1
(Figure 1) and have gained much attention owing to their
As is well known, nitrogen-containing heterocycles such as γ-
lactam are key motifs in numerous bioactive molecules.8
Meanwhile, because of the widespread application of difluoro-
methylene (CF2)-containing molecules in pharmaceutical and
agricultural chemicals,9 the synthetic methods for the
Figure 1. Examples of Bioactive Amino Naphthoquinone Derivatives
various biological activities such as antimalarial,2 antiinflamm-
tory,3 anticancer,4 antifungal,5 and neuroprotective6 properties.
Therefore, the development of green and efficient methods to
access such compounds is becoming one of the research
interests in synthetic chemistry.7 In the past few years, direct
C−H functionalization at the C-3 position of 2-amino-1,4-
naphthoquinones has served as an ideal and powerful method
to afford the naphthoquinone derivatives. For example, in
2017, Yang and coworkers reported a novel method for the 3-
trifluoromethylation of 2-amino-1,4-naphthoquinones by
Received: January 23, 2021
Published: February 19, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00268
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1862−1867
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(LEDs) at room temperature, giving the desired product 3aa in
28% yield without any external photocatalyst. Other electron
donors including Et3N, N,N-diisopropylethylamine (DIPEA),
4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]-
octane (DABCO), and N,N,N′,N′′,N′′-pentamethyldiethyle-
netriamine (PMDETA) were then screened, and only
PMDETA could give a better result (Table 1, entries 2−6).
Scheme 1. C-3 Functionalization of 2-Amino-1,4-
naphthoquinones
a
Table 1. Optimization of the Reaction Conditions
b
entry
amines
solvent
yield (%)
1
2
3
4
5
6
7
8
TMEDA
Et3N
DIPEA
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DCM
DMSO
DCE
28
trace
trace
NR
NR
50
43
30
75
15
trace
25
24
45
70
trace
48
NR
NR
54
DMAP
DABCO
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
9
10
11
12
13
14
15
16
17
18
19
introduction of a CF2 group into the γ-lactam have been
extensively studied. In particular, the radical-mediated
intermolecular 1,2-difunctionalization of alkenes and the
intramolecular cyclization of N-allylhalodifluoroacetamide
have become the most attractive approaches to α,α-difluoro-
γ-lactams.10 Considering the positive biological activities of 2-
amino-1,4-naphthoquinones and α,α-difluoro-γ-lactams, we
assume that combining the above two partners could lead to
the discovery of a series of pharmacologically active
compounds.
EA
dioxane
acetone
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
d
e
f
g
PMDETA
PMDETA
h
20
In the past decade, photoredox catalysis has become a hot
area in organic chemistry due to its mild conditions,
environmental friendliness, and low-energy irradiation.11
However, traditionally, precious metal complexes or elaborate
organic dyes are usually required in such approaches.
Nowadays, with the growing demand for the discovery of
greener synthetic methods, visible-light-induced organic trans-
formations in the absence of photocatalysts have received great
attention due to their excellent atomic economy and synthetic
value, especially those photoinduced transformations mediated
by the electron donor−acceptor (EDA) complex.12 With our
ongoing studies on photoinduced C−H functionalization,13
herein, we developed an EDA-mediated, external catalyst-free,
radical tandem cyclization/arylation of an unactivated alkene
with 2-amino-1,4-naphthoquinones, providing a convenient
and practical avenue to the naphthoquinone derivatives.
Initially, 2-(4-methylphenylamino)-1,4-naphthoquinone 1a
and N-allyl-2-bromo-N-(4-bromophenyl)-2,2-difluoroaceta-
mide 2a were chosen as the model substrates for the
optimization of reaction conditions. In the process of the
investigation of this model reaction, we observed a high-degree
background reaction upon mixing two colorless reagents, 2a
and tetramethylethylenediamine (TMEDA), according to the
color changes of the mixture, which implied that the EDA
complex might be formed. To our delight, this transformation
could be successfully initiated in the presence of TMEDA in
MeCN with the irradiation of blue light-emitting diodes
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), amine (0.4
mmol), solvent (2 mL), rt, under N2, 3 W blue LEDs, 24−48 h.
b
c
d
Isolated yield. PMDETA (0.2 mmol). PMDETA (0.6 mmol).
e
f
g
h
Green LEDs. White LEDs. Without light. Under air.
To further enhance the yield of 3aa, several commonly used
solvents such as dimethylformamide (DMF), dichloromethane
(DCM), dimethyl sulfoxide (DMSO), diethylcarbamazine
(DCE), ethyl acetate (EtOAc), dioxane, and acetone were
also examined, and the experimental results indicated that
DMSO displayed a higher efficiency compared with other
solvents (Table 1, entries 7−13). Decreasing or increasing the
amount of PMDETA did not lead to a significant improvement
(Table 1, entries 14 and 15). Different light sources were then
examined, and the results demonstrated that the blue light was
still the best choice under the standard conditions compared
with green or white lights (Table 1, entries 16 and 17). Finally,
the control experiments indicated that the organoamine and
irradiation were both essential for this reaction, and a
decreased yield of 3aa was obtained when this transform was
carried out under air (Table 1, entries 18−20).
With the optimized conditions established, the substrate
scope of 1,4-naphthoquinones incorporating amino groups at
the two-position was originally evaluated (Scheme 2). The
experimental results revealed that a variety of 2-amino-
naphthoquinone derivatives were all suitable for this method,
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naphthalene group could undergo this tandem reaction
smoothly, giving the corresponding products (3oa−3qa) in
moderate yields. We also found that a substrate with an R1
group as a quinoline moiety also could work satisfactorily,
furnishing products 3ra and 3sa in 78 and 52% yields,
respectively. Finally, the 3,4-methylenedioxyphenyl-containing
derivative 2t was tested for this reaction, and the desired
products 3ta was obtained in 53% yield.
Scheme 2. Substrate Scope of 2-Aminonaphthoquinones
Derivatives
a b
,
After examining the substrate scope of 2-amino-1,4-
naphthoquinone, we next turned our attention to explore the
scope of N-allyl-2-bromo-2,2-difluoroacetamides with different
substituents on the benzene ring (Scheme 3). When acetamide
Scheme 3. Scope of N-Allyl-2-bromo-2,2-difluoro-
a b
,
acetamines
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), amine (0.4
mmol), solvent (2 mL), rt, under N2, 3 W blue LEDs, 24−48 h.
b
Isolated yield.
and the corresponding products 3aa−3ta were obtained in
41−80% yields. First, the 2-aminonaphthoquinones without a
substituent on the benzene ring could give the desired product
3ba in 65% yield. Substituents with different electronic effects
on this reaction were then investigated. The experimental
results indicated that the 1,4-naphthoquinone derivatives
containing electron-donating groups (4-methyl 1a, isopropyl
1c, methoxy 1d) showed good reactivity for this trans-
formation, providing the desired products in moderate to good
yields. The substrates bearing those electron-withdrawing
groups (4-bromo 1e, 4-fluoro 1f) showed a slightly lower
reactivity, giving the products 3ea and 3fa in 53 and 68%
yields. In addition, the effect of the position of substituents on
the phenyl was then studied. Three-substituted derivatives
exhibited good tolerance for this reaction, providing the
products 3ga−3ia in 62−72% yields. However, two-substituted
compounds, such as 1j or 1k, afforded the corresponding
products in lower yields compared with the three- or four-
substituted compounds, which was attributed to steric effects.
Substrates with a multisubstituted phenylamino were also
suitable for the reaction, and the corresponding products 3la,
3ma, and 3na were obtained in yields of 71, 43, and 67%,
respectively. Moreover, this transformation also showed good
tolerance when the aniline group was replaced by other
aromatic amine, affording the products 3oa−3ta in satisfying
yields (52−78%). For example, compounds 1o−1q bearing a
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), amine (0.4
mmol), solvent (2 mL), rt, under N2, 3 W blue LEDs, 24−48 h.
b
Isolated yield.
2b without a substituent on the benzene ring was used as the
substrate under identical conditions, the target product 3ab
was obtained in 65% yield. Bromodifluoroacetamide bearing
either electron-withdrawing groups (4-chloro 2c, 4-fluoro 2d)
or electron-donating groups (4-methyl 2e, 4-isopropyl 2f)
furnished the corresponding products in moderate to good
yields (50−81%). In addition, meta-substituted compounds
such as 3ag (−Br), 3ah (−CF3), 3ai (−CH3), and 3aj
(−OCH3) also performed well for this reaction, giving the
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desired products 3ag−3aj in 79, 64, 60, and 58% yields,
respectively. Additionally, the ortho-substituted compound 2k
underwent this tandem process well and afforded the desired
product 3ak in 55% yield. Finally, the disubstituted
bromodifluoroacetamide 2l containing methyl groups in the
three- and five-positions was also a suitable substrate for this
reaction and gave the corresponding product 3al in 52% yield.
To further study the reaction mechanism, a series of control
experiments were conducted, as shown in Scheme 4. When the
Scheme 4. Radical Inhibitor Experiment
Figure 2. UV−vis absorption spectra. Insert: Photos of 2, PMDETA,
and 2 + PMDETA in DMSO (0.02 M).
Figure 3. Light on−off experiment.
Scheme 5. Proposed Mechanism
reaction was performed in the presence of 2,6-di-tert-butyl-4-
methylphenol (BHT) or 1,1-diphenylethylene, the trans-
formation was found to be completely inhibited, and no
product was detected (Scheme 4a,b). These results suggested
that the reaction might proceed via a radical mechanism. To
confirm the formation of a difluoroacetamide radical, another
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) was then applied to the same reaction system. As
expected, the target product 3ac was not detected, whereas the
radical-captured product 4 was isolated in a yield of 40%. To
explore whether this photochemical reaction was mediated by
the EDA complex of the N-allyl-2-bromo-2,2-difluoro-
acetamines and PMDETA, the UV−visible (UV−vis) analysis
of the different reaction components was carried out. After
mixing the N-allyl-2-bromo-2,2-difluoro-acetamines and
PMDETA, the optical absorption spectrum obviously shifted
to the visible region (Figure 2). Finally, the results of the light
on−off experiment demonstrated that visible light is a
necessary component of the reaction (Figure 3).
According to the above experiments and literature reports, a
possible mechanism for this visible-light-mediated cyclization/
arylation between 2-amino-1,4-naphthoquinone and N-allyl-2-
bromo-2,2-difluoroacetamides is proposed (Scheme 5). This
reaction was initiated by the formation of an EDA complex
between the organoamine and N-allyl-2-bromo-2,2-difluoro-
acetamines. Irradiation of the EDA complex with visible light
triggers a single-electron transfer (SET) process to form amino
radical cation A, accompanied by the generation of
difluoroalkyl radical (B) after releasing a bromide anion from
the N-allyl-2-bromo-2,2-difluoroacetamide radical anion. The
acquired radical B then immediately underwent an intra-
molecular cyclization process to form the cyclic radical
intermediate C, which was subsequently trapped by the 2-
amino-1,4-naphthoquinone to form another radical D. The
target product 3 could be obtained via a hydrogen atom
abstract process from radical D to amino radical cation A.
In conclusion, we have developed an EDA-complex-
mediated radical tandem cyclization/arylation of unactivated
alkenes with 2-amino-1,4-naphthoquinone analogues by the
irradiation of blue LEDs. The mechanistic studies have
demonstrated that N-allylbromodifluoroacetamide was capable
of generating an EDA complex with organoamine, which was
the key step for triggering this transformation. Furthermore,
this protocol features external photocatalyst-free, mild
conditions, good functional group tolerance, and excellent
regioselectivity, providing a novel environmentally friendly
method to naphthoquinone derivatives.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00268.
Experimental details and spectroscopic data for new
compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Can Jin − Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals and College of
Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, P. R. China; orcid.org/0000-0003-
1997-6209; Email: jincan@zjut.edu.cn
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(CF3SO2)2Zn: synthesis and antiproliferative evaluation. J. Org.
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H.; Liu, H.; Liu, Z.; Zhuang, W.; Qiao, C.; Wang, A.; Xiao, Y.; Zhang,
C. Copper-catalyzed three-component difunctionalization of aromatic
alkenes with 2-amino-1,4-naphthoquinones and α-bromocarboxylates.
J. Org. Chem. 2019, 84, 10649−10657. (c) Wang, Q.; Wang, B.; Deng,
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Authors
Bin Sun − Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
Xiayue Shi − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Xiaohui Zhuang − Collaborative Innovation Center of Yangtze
River Delta Region Green Pharmaceuticals, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Panyi Huang − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Rongcheng Shi − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Rui Zhu − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
(8) (a) Mailyan, A. K.; Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu,
P.; Zakarian, A. Cutting-edge and time-honored strategies for
stereoselective construction of C-N bonds in total synthesis. Chem.
Rev. 2016, 116, 4441−4557. (b) Berlinck, R. G. S.; Romminger, S.
The chemistry and biology of guanidine natural products. Nat. Prod.
Rep. 2016, 33, 456−490. (c) Ye, L.-W.; Shu, C.; Gagosz, F. Recent
progress towards transition metal-catalyzed synthesis of γ-lactams.
Org. Biomol. Chem. 2014, 12, 1833−1845. (d) Caruano, J.; Muccioli,
G. G.; Robiette, R. Biologically active γ-lactams: synthesis and natural
sources. Org. Biomol. Chem. 2016, 14, 10134−10156. (e) Pandey, G.;
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00268
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (22078299) and Zhejiang Provincial
Natural Science Foundation of China (LY21B060005,
LQ20B060007). We are also grateful to the College of
Pharmaceutical Sciences, Zhejiang University of Technology
and Collaborative Innovation Center of Yangtze River Delta
Region Green Pharmaceuticals for the financial help.
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pharmaceutical industry: fluorine-containing drugs introduced to the
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