Photo-Driven Synthesis of C6-Polyfunctionalized Phenanthridines from Three-Component Reactions of Isocyanides, Alkynes, and Sulfinic Acids by Electron Donor-Acceptor Complex

Article abstract of DOI:10.1021/acs.orglett.8b00171

A novel and efficient photoinduced synthesis of C6-polyfunctionalized phenanthridines from three-component reactions of isocyanides, alkynes and sulfinic acids was developed. The reactions generated the corresponding products with high selectivity through

Full text of DOI:10.1021/acs.orglett.8b00171

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photo-Driven Synthesis of C6-Polyfunctionalized Phenanthridines
from Three-Component Reactions of Isocyanides, Alkynes, and
Sulfinic Acids by Electron Donor−Acceptor Complex
Yang Li,† Tao Miao,*,† Pinhua Li,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: A novel and efficient photoinduced synthesis of C6-polyfunctionalized phenanthridines from three-component
reactions of isocyanides, alkynes and sulfinic acids was developed. The reactions generated the corresponding products with high
selectivity through the photochemical activity of the formed electron donor−acceptor (EDA) complex during the reaction via a
radical tandem process under mild conditions.
ince the pivotal work of Melchiorre and co-workers in
through a radical cascade procedure is highly valuable and more
challenging.
1
S2013,
the photochemical transformations by electron
donor−acceptor (EDA) complexes, which are the transient
combination of electron-rich with electron-accepting sub-
strates,2 as the alternative photocatalysts for the photoinduction
of electron transfer without the need for external photo-
sensitizer have received great attention.3 To date, the reported
EDA complexes are mainly focused on using alkyl halide as
electron acceptor and enamine, indole or enolate as electron
donor. It is desirable to explore the novel EDA complexes for
the new photoreactions.
In this paper, we disclose a novel EDA complex generated
from arylsulfinic acid and biaryl isocyanide. To our delight, a
unique three-component reaction of arylsulfinic acid, alkyne,
and biaryl isocyanide can be driven by the photochemical
activity of the formed EDA complex to provide C6-(vinyl
sulfone) phenanthridines in high selectivity via a radical tandem
process. The reactivity and selectivity of the reaction are
dependent on the reaction conditions (Scheme 1).
Phenanthridines are widespread in natural products and
pharmaceuticals with remarkable biological activities4 and draw
considerable interest from synthetic chemists. Recently, a
cascade radical pathway through a radical addition to 2-
isocyanobiphenyls from an imidolyl radical, followed by an
intramolecular homolytic aromatic substitution, has been
established, providing the rapid assembly of C6-functionalized
phenanthridines.5 Most recently, valuable approaches to
phenanthridines from isocyanides via photoredox catalysis
with external photocatalysts have been developed by Yu et al.6
Vinyl sulfones, as important biologically active molecules and
synthetic intermediates,7 and their preparation directly from the
reactions of alkenes or alkynes with sodium sulfinates or sulfinic
acids have received substantial attention.8 Compared with
stepwise chemical process, radical cascade reaction, in which a
series of consecutive radical steps occur and several chemical
bonds are formed, has proven to be a powerful strategy for
efficient building molecular architectures in high selectivity and
atom economy.9 However, the direct introduction of two
different functional groups to a carbon−carbon triple bond via a
radical cascade reaction is limited. To develop novel method-
ology for the difunctionalization of alkyne in good selectivity
Scheme 1. EDA-Complex Photo-Driven Three-Component
Reaction
Initially, a model reaction of p-toluenesulfinic acid (1a), 1-
heptyne (2a), and 2-isocyanobiphenyl (3a) was chosen to
optimize the reaction conditions (Table S1). When the model
reaction was performed in a mixed solvent (DMSO/H2O) in
the presence of pyridine under air with blue LED irradiation for
16 h, a product of the three-component reaction of 1a, 2a, and
Received: January 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00171
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Letter
3a, (E)-6-(1-tosylhept-1-en-2-yl)phenanthridine (4a), was
generated in 48% yield (Table S1, entry 1). When the reaction
was carried out under O2 atmosphere, 4a was isolated in 71%
yield with 10:1 of E/Z ratio (Table S1, entry 2). It is important
to note that no product was detected in the absence of light
even when the reaction was heated at 60 °C for 16 h (Table S1,
entries 3 and 4). Following this, the yield of 4a was decreased
to 38% under the irradiation with green LED (Table S1, entry
5). Notably, (Z)-6-(1-tosylhept-1-en-2-yl)phenanthridine
(4a′), a Z-isomer of 4a, was obtained in 73% yield under UV
irradiation for 24 h (Table S1, entry 6).10 While the model
reaction was irradiated with UV light for 24 h under N2
atmosphere, no desired product 4a or 4a′ was observed
(Table S1, entry 7). Further optimization of solvent and base
indicated that a mixed-solvent DMSO/H2O in 8:1 (V/V) and
pyridine was the best choice among the tested parameters
(Table S1, entries 8−19). Furthermore, reducing the amount of
1a or 2a led to decreased yields of 4a (Table S1, entries 20 and
21).
Figure S7 for details). Furthermore, sulfonylated oxindole 8 was
obtained in 55% yield when N-methyl-N-phenylmethacryla-
mide 7 was added to the reaction of 1a and 3a with 3 W blue
LED irradiation for 16 h, indicating that sulfonyl radical
intermediate A′ was involved in the reaction (Figure 1d). These
observations demonstrate that the formation of EDA complex I
and the dissociation of radical ion pair II to produce sulfonyl
radical A′ and radical intermediate C are the key drivers in this
photochemical process (Figure 1e).
With the optimal reaction conditions established, we then
examined the substrate scope of this radical tandem reaction. In
general, this tandem reaction exhibited high regio- and
stereoselectivity, and E- or Z-products were isolated in good
yields under blue LED or UV irradiation. As described in
Scheme 2, a variety of arylsulfinic acids with electron-donating
a−c
Scheme 2. Scope of Sulfinic Acids
To gain a better understanding of this photoinduced radical
process, a series of optical absorption spectra of the solution
were recorded. As shown in Figure 1a, the solution developed a
Figure 1. (a) Optical absorption spectra of the reaction components.
(b) Job’s plot for ratio between 1a and 3a. (c) Reaction of 1a and 3a.
(d) Reaction of N-methyl-N-phenylmethacrylamide (7) with 1a and
3a. (e) Visible-light-triggered generation of S-centered radical A′ and
the imidoyl radical C by EDA complex.
yellowish color change from colorless when 1a was mixed with
3a and pyridine in DMSO/H2O (8:1), and its optical
absorption spectra showed a bathochromic displacement in
the visible region, which is diagnostic of an EDA complex.1,3
Then a Job’s plot using UV/vis absorption experiments was
drawn to evaluate the stoichiometry of the EDA complex I
between 1a and 3a. The maximal absorption at 50% molar
fraction of 3a suggested a 1:1 ratio of 1a and 3a (Figure 1b).
The dissociation constant KEDA between 1a and 3a was found
to be 5.29 M−1 in DMSO/H2O (8:1) via the Benesi−
Hildebrand method.11 To further understand the structure of
the EDA complex, a reaction of 1a and 3a was stirred in a
mixture of DMSO/H2O (8:1) without 2a under blue LED
irradiation for 8 h, providing 5 and 6. The deuterium
experiments indicated H2O and acid are the sources of proton,
and methylation is not coming from methyl radicals produced
by DMSO (Figure 1c). Therefore, 5 and 6 probably originated
from H2O, H+, and radical intermediate C′, which was
generated from intermediate B′ via an abstraction of H+ (see
a
Reaction conditions: 1 (0.75 mmol), 2a (0.50 mmol), 3a (0.25
mmol), pyridine (6.0 equiv), DMSO/H2O (8:1, 4.5 mL) in O2 at
room temperature under 3 W blue LED (450 5 nm) irradiation for
16 h (method A) or 3 W UV (365
(method B). Isolated yield based on 3a. E/Z ratio determined by
isolated yield of 4 or H NMR analysis of the crude products 4a and
4a′. In 5.0 mmol scale.
5 nm) irradiation for 24 h
b
c
1
d
groups or electron-withdrawing groups on the aryl rings reacted
efficiently with 2a and 3a to give the corresponding products
4a−k and 4a′−k′ in good yields. The structures of products
(Z)-4a′ and (E)-4d were further characterized by X-ray
crystallographic analysis. o-Chlorophenylsulfinic acid gave the
products 4i and 4i′ in 51% and 56% yield, respectively.
Furthermore, 2-naphthyl and 2-thienylsulfinic acid were also
B
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Letter
successful in this transformation with 53−61% yields of the
corresponding products. Importantly, n-butylsulfinic acid, an
aliphatic sulfinic acid, was also a suitable substrate for the
reaction, providing the corresponding products 4n and 4n′ in
70 and 66% yields. When the reaction of 1a, 2a, and 3a was
performed on a 5.0 mmol scale with irradiation of 3 W UV for
24 h, the product 4a′ was obtained in 69% yield.
(4w−z and 4w′−z′) in 52−71% yields. 2,4-Dichloro-2′-
isocyano-1,1′-biphenyl also gave good results (4aa and 4aa′).
For isocyanide with a m-methyl on the phenyl ring, the reaction
preferentially took place at the more crowded position, and 4ab
was isolated in 52% yield with 2.6:1 selectivity. Meanwhile, a
more hindered isomer 4ab-1′ was the exclusive product in 47%
yield with irradiation of 3 W UV for 24 h.
On the other hand, this transformation was applicable to
various aromatic alkynes, giving (Z)-C6-(vinyl sulfone)
phenanthridines only in good yields under N2 atmosphere
with UV irradiation for 24 h, and the results are listed in
Scheme 4. A variety of arylacetylenes with different functional
We then turned our attention to exploring the scope of the
alkynes (2) and isocyanides (3), as shown in Scheme 3. First,
a−c
Scheme 3. Scope of Alkyl Alkynes and Isocyanobiphenyls
a,b
Scheme 4. Scope of Arylacetylenes
a
Reaction conditions: 1 (0.75 mmol), 2 (0.25 mmol), 3a (0.50 mmol),
pyridine (6.0 equiv), DMSO (4.0 mL), and H2O (15 equiv) in N2 with
b
c
3 W UV (365 5 nm) for 24 h. Isolated yield based on 2. 3 W blue
LED (450 5 nm) for 24 h.
groups (alkyl, methoxyl, and halogen) on the phenyl rings
underwent the reactions smoothly to give the corresponding
products (4ac′−al′) in 51−73% yields. As expected, arylsulfinic
acids containing alkyl and halogen substituents on the benzene
rings are amenable to the current protocol, generating the
products (4am′−ar′) in good yields. When phenylacetylene
reacted with 1a and 3a with irradiation of 3W blue LED, the
reaction also proceeded smoothly to give the desired product
4am′ in 53% yield. It is important to note that the high
stereoselectivity for a sole isomer 4am′ was obtained with
irradiation of 3 W UV (365 5 nm) or 3 W blue LED (450
5 nm). The structure of 4am′ was unambiguously confirmed by
X-ray crystallography. Furthermore, β-keto sulfone was
obtained as a byproduct when 2a was reacted with 1a and 3a
under O2 atmosphere with UV irradiation.9d
a
Reaction conditions: 1a (0.75 mmol), 2 (0.50 mmol), 3 (0.25 mmol),
pyridine (6.0 equiv), DMSO/H2O (8:1, 4.5 mL) in O2 at room
temperature under 3 W blue LED (450 5 nm) irradiation for 16 h
(Method A) or 3 W UV (365 5 nm) irradiation for 24 h (Method
b
c
B). Isolated yield based on 3. E/Z ratio determined by isolated yield
of 4 or H NMR analysis of the isolated crude products 4.
1
To gain mechanistic insights, a radical-trapping experiment
was conducted. The reaction was completely inhibited by the
radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO). More importantly, the vinyl radical formed in situ
was trapped by TEMPO to form radical adduct 10 (determined
by HPLC−HRMS analysis), supporting the proposed radical
pathway of the reaction (Scheme 5a). In addition, optical
absorption of the product 4a was also examined in DMSO/
H2O (8:1) (Figure S9). The UV−vis spectrum exhibits a strong
absorption band in the ultraviolet range below 365 nm. Under
UV light irradiation at 365 nm for 24 h, 4a was converted into
its (Z)-isomer (4a′) in 93% yield (Scheme 5b).
other aliphatic alkynes including n-propyl, n-butyl, n-hexyl, and
n-heptylacetylene worked well with 1a and 3a, providing the
desired products 4o−r and 4o′−r′ in 65−72% yields. In
particular, cyclopropropylacetylene was also effective in the
reactions, leading to the products 4s and 4s′ in 51% and 53%
yields. Subsequently, the substitution effect on the aromatic
rings of isocyanides 3 was examined. The results indicated that
the reactions were not sensitive to the nature of the substituent
groups, as evidenced by the yields of 4t−ab and 4t′−ab′. 2-
Isocyanobiphenyls containing Me, Cl, CF3, and CO2Me at the
para-position of the nonisocyanide phenyl rings reacted with 1a
and 2a, affording the corresponding phenanthridine derivatives
On the basis of the results of our studies and previous related
reports,1−3 a plausible mechanism is proposed (Scheme 6).
C
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isocyanides as electron acceptors will open new avenues for
their applications in photochemical transformations. Further
effort on the reaction mechanism is underway.
Scheme 5. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00171.
Full experimental details and characterization data for all
products (PDF)
Accession Codes
Scheme 6. Proposed Mechanism for the Formation of 4
CCDC 1564340−1564342 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: taomiaochem@163.com.
*E-mail: leiwang88@hotmail.com.
ORCID
Lei Wang: 0000-0001-6580-7671
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21772062, 21602072, 21572078) and
the Anhui Provincial Natural Science Foundation
(1508085QB42) for financial support.
With the assistance of pyridine and H2O, an arylsulfinate anion
can form an EDA complex (I) with isocyanide 3a. The formed
EDA complex I undergoes a SET process upon light excitation
to generate dipolar species II. Subsequent fragmentation of II
produces an oxygen-centered radical A and a radical anion B.
The generated A can resonate with sulfonyl radical A′, which
reacts with the carbon−carbon triple bond of terminal alkyne 2
to afford a vinyl radical D, which is trapped by TEMPO.
Thereafter, an addition of D to the terminal carbon of 3a
generates the imidoyl radical E, which undergoes an intra-
molecular homolytic aromatic substitution to give a radical F.
Then F is oxidized by O2 to form cationic intermediate G and
O2•−. Ultimately, a base-assisted deprotonation yields final
product phenanthridine 4. On the other hand, the generated B′
from B through a resonance can abstract a hydrogen cation to
form an imidoyl radical C, which can store a hydrogen radical.
Under an O2 atmosphere, radical C can be captured by O2•− to
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