Photogenerated Neutral Nitrogen Radical Catalyzed Bifunctionalization of Alkenes

Article abstract of DOI:10.1002/chem.201901665

Alkene bifunctionalizations are powerful tools for the rapid construction of structurally complex and valuable scaffolds, and such reactions typically involve the use of transition-metal catalysts or organocatalysts. Here, we report for the first time a p

Full text of DOI:10.1002/chem.201901665

A Journal of
Accepted Article
Title: Photogenerated Neutral Nitrogen Radical-Catalyzed
Bifunctionalization of Alkenes
Authors: Quan-Qing Zhao, Jun Chen, Xue-Song Zhou, Xiao-Ye Yu,
Jia-Rong Chen, and Wen-Jing Xiao
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Photogenerated
Neutral
Nitrogen
Radical-Catalyzed
Bifunctionalization of Alkenes
Quan-Qing Zhao, Jun Chen, Xue-Song Zhou, Xiao-Ye Yu, Jia-Rong Chen,* and Wen-Jing Xiao*
Abstract: Alkene bifunctionalizations are powerful tools for the rapid
construction of structurally complex and valuable scaffolds, and such
reactions typically involve the use of transition-metal catalysts or
organocatalysts. Here, we report for the first time a photogenerated
of nitrogen radicals to unsaturated systems are the most popular
and powerful reaction class.[10] Moreover, increasing attention
has been devoted to the application of such neutral radical
species to inert C-H bond activation (because of their unique
HAT properties[11]) as well as to C-C bond cleavage,[12] thus
neutral
nitrogen
radical-catalyzed
intermolecular
alkene
bifunctionalization using allyl sulfones as the source of both the
carbon and the sulfone functionalities under mild conditions. The key
to the success of this protocol involves the visible light-mediated
photocatalytic in situ generation of a nitrogen-centred radical from the
N-(2-acetylphenyl) benzenesulfonamide catalyst, and its activation of
the allyl sulfones to generate reactive species. The preliminary
control experiments supported the postulated mechanism.
allowing
a
diverse range of remote site-selective
functionalizations. These transformations often require
N-prefunctionalization on the substrates or incorporation of the
N-radical precursor into the final products. Remarkably,
MacMillan and co-workers documented that amine radical cation,
generated from quinuclidines by photoredox catalysis, could
serve as an efficient HAT catalyst to activate the SP3 C-H and
aldehyde C-H bonds (Scheme 1B).[13] Quite recently, the
Melchiorre group disclosed that the redox-active carbazole
moiety of a rationally designed amine catalyst could serve as an
electron pool to drive the conversion of a transient α-iminyl
radical cation to an imine intermediate through an electron-relay
process.[14] Despite these impressive efforts, to the best of our
knowledge, the use of in situ-formed neutral NCRs as catalysts
to promote radical reactions remain unknown.
Organic chemists generally capitalize on polar reactivity to
address the challenges in molecular activation and new chemical
bond
construction
through
transition
metal-[1]
or
organocatalyst[2]-mediated closed-shell mechanisms. Radicals
are historically considered chaotic, uncontrollable and fleeting
species. Consequently, although a plethora of elegant and useful
reactions using radical intermediates have been developed over
the years, there has been limited success in developing
radical-catalyzed transformations.[3] The pioneering works on
thiyl radical-catalyzed radical-chain hydrosilylations of alkenes
from the group of Roberts,[4] and radical [3+2] cycloadditions of
vinylcyclopropanes from the groups of Feldman, Oshima, and
Maruoka have revolutionized this field,[5] demonstrating that thiyl
radicals can mediate radical bond-forming reactions.[6] Recently,
the MacMillan group revealed that thiyls, generated in situ from
thiols by visible light photoredox catalysis, could serve as an
general type of HAT catalysts to selectively activate benzylic
ether C-H bonds.[7a] Despite these ground breaking contributions,
other types of heteroatom-centred radical catalysts remain
largely unexplored.[7b,c]
With the recent advances in photoredox catalysis,[8] a myriad
of approaches for the efficient and controllable generation of
neutral nitrogen-centred radicals (NCRs) using such enabling
tool have been developed, setting the stage for the various
synthetic applications of NCRs.[9] Established reactivity modes of
photogenerated neutral NCRs in organic synthesis fall into three
categories (Scheme 1A). Of these, C-N bond-forming additions
[*]
Q.-Q. Zhao, J. Chen, X.-S. Zhou, X.-Y. Yu, Prof. Dr. J.-R. Chen, Prof.
Dr. W.-J. Xiao
CCNU-uOttawa Joint Research Centre, Hubei International Scientific
and Technological Cooperation Base of Pesticide and Green
Synthesis, Key Laboratory of Pesticides & Chemical Biology Ministry
of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China
E-mail: chenjiarong@mail.ccnu.edu.cn; wxiao@mail.ccnu.edu.cn
Prof. Dr. W.-J. Xiao
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032,
China
Scheme 1. Diverse reactivity of photogenerated nitrogen-centred radicals
(NCRs) and the development of NCR-catalyzed alkene carbosulfonylation
reactions. NCRs = nitrogen-centred radicals, HAT = hydrogen atom transfer,
PC = photoredox catalysis.
In our efforts to develop NCR-mediated functionalization of
alkenes, we noted that the substituents on nitrogen atoms had
obvious effects on their reactivity.[10a,12b] Our mechanistic studies
have also shown that NCRs could reversibly add to a tethered
alkene moiety to form 5-exo or 6-endo radical cyclization
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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products.[15] Inspired by these results, we speculated that
rationally designed NCR catalysts could catalytically activate
olefin derivatives towards new radical reactions. Alkene
bifunctionalizations are powerful tools for the rapid construction
of structurally complex and valuable scaffolds, and such
reactions are typically catalyzed by transition-metal catalysts or
organocatalysts.[16] In this context, despite the fact that
allylsulfone derivatives have recently been widely used as allyl
radical precursors under photoredox conditions,[17] use of
photogenerated nitrogen-radical to trigger carbosulfonylations of
alkenes using this reagent as both the carbon and sulfonyl donor
have yet to be reported. The Whitham group disclosed that
benzoyl peroxide (BPO)-derived benzoyl radical could initiate this
process in refluxing CHCl3.[18] It should also be noted that the
Reiser group reported an unprecedented visible light-driven
copper-catalyzed trifluoromethylchlorosulfonylation of alkenes
using triflyl chloride, without SO2 extrusion;[19a,b] this reaction
provides a novel method for carbosulfonylations of alkenes but
with only single triflyl chloride used. Quite recently, Zhu et al.
that use allyl sulfones as the ally radical precursors,[17] the
current protocol allows convergent incorporation of both the allyl
and sulfonyl moieties into the final products.
Table 1: Exploring reaction conditions.[a]
Entry
Photocatalyst
NCR precursor
Solvent
DMF
Yield [%][b]
4
25
20
23
31
7
1
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2bpyPF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
5
DMF
2
6a
6b
6c
6d
6e
6f
DMF
3
disclosed
an
interesting
visible
light-induced
DMF
4
sulfonylation/intramolecular heteroaryl migration of alkenes with
sulfonyl chlorides as radical sources.[19c] As a proof-of-concept,
we thus focused on the development of a photogenerated neutral
DMF
5
DMF
34
19
30
50
50
56
70
6
DMF
7
nitrogen
radical-catalyzed
intermolecular
alkene
DMF
8
bifunctionalization using allyl sulfones (Scheme 1C).[20] This
reaction would provide an alternative method for accessing
potentially useful sulfonyl-containing compounds.[21] For this
strategy to be effective, the usual polar reactivity of NCR
precursors must be bypassed. The incorporation of an
electron-withdrawing group on the nitrogen atom to increase the
acidity of the N-H bond and facilitate its conversion to a nitrogen
radical, would also increase the nucleophilicity, making these
species excellent reagents in SN2’ substitutions of allyl sulfones.
Thus, the success of our proposed reaction relies on the
identification of suitable NCR catalysts, and conditions to
suppress its normal ionic reactivity, forcing the reaction towards a
radical-catalyzed process.
6d
6d
6d
6d
DMSO
DMSO
DMSO
DMSO
9
10[c]
11[c]
12[c,d,e]
[a] Reaction Conditions: 1a (0.1 mmol), 2a (0.3 mmol), photocatalyst (0.002
mmol, 2 mol%), NCR catalyst (20 mol%), K2CO3 (0.1 mmol), solvent (2.0 mL),
7 W blue LEDs, rt, 3 h. [b] Yields were determined by 1H NMR spectroscopy
with 1,3,5-trimethoxybenzene as an internal standard. [c] K2CO3 (0.5 equiv). [d]
DMSO (1.0 mL). [e] Ir(ppy)2(dtbbpy)PF6 (0.5 mol%).
With the optimal conditions in hand, we examined the
substrate scope of alkenes by reacting a range of commercially
available styrene derivatives 1 with allylsulfones 2a on a 0.2
mmol scale (Table 2A). As demonstrated by the reactions of
1a-1g, this protocol is highly tolerant of a wide range of functional
As a starting point for this study, we examined hydrazone 4
as an NCR catalyst in the reaction of styrene (1a) and allyl
sulfone 2a. The corresponding neutral NCR can be generated by
a visible-light photocatalytic SET oxidation of the in situ-formed
nitrogen anion in the presence of base.[10a,15] Using
Ir(ppy)2bpyPF6 as a photocatalyst and K2CO3 as a base in DMF
under the irradiation of 7 W blue LEDs, we found that the
reaction indeed gave desired product 3aa in 25% NMR yield
(entry 1). The substitution pattern on nitrogen atom can influence
the stability and reactivity of NCRs; thus, we extensively explored
nitrogen radical catalysts, and N-aryl sulfonamides were
identified as promising candidates, and they can be easily
groups,
although
photosensitive
pinacol
borane
(Bpin)-substituted styrene 1h leads to fair yield. Variations in the
electronic properties of the substituent at the para-position of the
benzene ring influence the efficiency; substrates 1a-1d with
electron-neutral and electron-donating groups (e.g., Me, OMe,
and Ph) afford slightly higher yields (3aa-3da, 57-75%) than
substrates (1e-1g) with electron-withdrawing groups (e.g., Cl, Br,
and CO2Me) (3ea-3ga, 40-54%). Moreover, as demonstrated by
the reactions of 1i and 1j, the substitution pattern and steric
hindrance on the aryl ring have no obvious impact on the
reaction outcome, as products 3ia and 3ja were obtained in 79%
and 68% yields, respectively. 2-Vinylnaphthalenes such as 1k
and 1l were also suitable for the reaction, producing 3ka and 3la
in acceptable yields. The reactions of substrates bearing
heteroaromatic 2-pyridyl or 2-indolyl moieties also proceeded
well and gave 3ma and 3na in good yields. Notably, challenging
internal alkene 1o and simple aliphatic alkene 1p are also
compatible with the reaction, while 3oa and 3pa were obtained in
moderate yields.
synthesized via
a high-yielding one-step procedure from
commercial compounds. The redox properties of the sulfonamide
scaffold can be easily tuned by introducing substituents on both
arenes. To our delight, N-(2-acetylphenyl) benzenesulfonamide
(6d) proved to be superior to other analogues (entry 6). With 6d
in hand, we tested several typical solvents, photocatalysts, and
other parameters.[22] The results showed that the optimal
conditions are as follows: 0.5 mol% of Ir(ppy)2(dtbbpy)PF6 as the
photocatalyst, 20 mol% of 6d as the NCR catalyst, 0.5 equiv of
K2CO3 as the base in DMSO at room temperature (entry 12). As
expected, a series of control experiments confirmed that the
photocatalyst, NCR catalyst, base, and visible light are all
necessary.[20] Unlike many of the previously reported reactions
Remarkably, our catalytic system could be extended to
electron-deficient alkenes (Table 2B). α,β-Unsaturated ketone
1q, amide 1r, and acrylonitrile 1s are suitable substrates, and
products 3qa-3sa were obtained in moderate to good yields. The
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reactions of benzyl and 2-naphthyl acrylates also gave good
yields of products 3ta and 3ua; notably, the reactive benzylic
C-H bonds in these substrates remain intact. Moreover, sterically
demanding α-methyl acrylate 1v reacts smoothly with 2a to
furnish 3va in 39% yield. Building on these results, we continued
to apply this protocol to alkenes containing biologically relevant
moieties (Table 2C). Both complex bioactive estrones and
simple amino acid-derived styrenes participated well in the
reaction and gave products 7 and 8 in good yields. This method
could also be applied to synthesis of febuxostat derivative 9,
highlighting its potential in medical chemistry.
reaction of alkyl-substituted allyl sulfone 2i also proceeded well
and gave 3ai in 46% yield.
To elucidate the mechanism, we carried out several control
experiments with substrates 1a and 2a (Scheme 2). Upon the
addition of the radical scavenger TEMPO, complete inhibition of
the desired reaction was observed. TEMPO-adduct 10 was
detected in the reaction mixture by ESI-HRMS, which should
result from the trapping of benzylic radical intermediate 1a-A by
TEMPO (Scheme 2a). Allyl sulfones are a well-established class
of radical acceptors;[17] thus, we hypothesized that the in
situ-formed neutral NCR might initially activate the allyl sulfones
by addition to the alkene moiety. Then, we carried out the
crossover experiment by subjecting 1a, 2a and 1.5 equivalents of
NCR catalyst 6d-derived sulfonamide 11 to the standard
conditions (Scheme 2b). Though we did not isolate product 3aa
resulting from the two-component coupling between 1a and 2a,
we indeed obtained product 3ab in 19% yield, which should be
formed through the reaction between 11 and radical intermediate
1a-A. Moreover, treatment of a mixture of NCR catalyst 6d and
2b in DMSO with base K2CO3 did not give any sulfonamide 11,
and both starting materials remain intact (SI, page 18).[22] These
results suggest that compound of type 11 should be involved as
possible intermediate in the process. Notably, the model reaction
of 1a and 2a also proceeded smoothly, when using dimer 12 as
NCR catalyst (Scheme 2c). [22] Moreover, when using 6f as a
NCR catalyst in the model reaction of 1a and 2a, the dimer 12
could also be detected in the reaction mixture by HRMS analysis.
It is well known that transient sulfonamidyl radicals typically exist
as the corresponding dimmers;[23] thus dimer 12 should result
from sulfonamidyl radical 6f-A. Taken together, these results
suggested that the current alkene bifunctionalization should be
enabled by photo-generated sulfonamidyl radicals such as 6f-A.
Table 2: Scope with respect to alkenes and ally sulfones.[a,b]
[a] 1 (0.2 mmol), 2 (0.6 mmol), Ir(ppy)2bpyPF6 (0.001 mmol, 0.5 mol%), NCR
catalyst 6d (20 mol%), K2CO3 (0.1 mmol), DMSO (2.0 mL), 7 W blue LEDs, rt,
4 h. [b] Yield of isolated product after flash chromatograph.
Then, we proceeded to investigate the substrate scope of allyl
sulfones in reactions with 1a (Table 2D). Again, a series of allyl
sulfones 2b-2e with ethyl, iso-propyl, benzyl or cyclohexyl ester
moieties smoothly afforded products 3ab-3ae in 59-67% yields.
As shown in the synthesis of 3af-3ah, electron-donating (Me)
and electron-withdrawing groups (e.g., F and Cl) could be
incorporated into the phenyl moiety of the resulting sulfones. The
Scheme 2. Control experiments.
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Moreover, 1H NMR analysis of 6d revealed that the addition of
K2CO3 to its DMSO-d6 solution led to complete deprotonation of
6d, and its full conversion to nitrogen anion intermediate 6d-A.
Finally, luminescence quenching experiments with 6d also
revealed that only in the presence of base (K2CO3) can NCR
catalyst 6d efficiently quench the excited state photocatalyst.[22]
On the basis of these experimental results, a reaction
mechanism was then proposed (Scheme 3). The reaction starts
with a visible light-induced SET oxidation of the in situ-formed
N-(2-acetylphenyl) benzenesulfonamide anion (6d-A) to
generate sulfonamidyl radical 6d-B by the photoexcited *IrIII
catalyst with concomitant release of reduced IrII. Then, a radical
addition of 6d-B to allyl sulfone 2a, resulting in the formation of
sulfonyl radical 2a-A and 3° N-sulfonamide intermediate 6d-C.
Subsequently, the open-shell sulfonyl radical 2a-A could add to
the terminal position of alkene 1a to furnish secondary carbon
radical 1a-A, which is trapped by 3° N-sulfonamide intermediate
6d-C to deliver product 3aa and regenerate NCR 6d-B.
Alternatively, desired product 3aa could be formed through the
trapping of 1a-A by another molecule of 2a, regenerating sulfonyl
radical 2a-A; such a short radical-chain process could not be
ruled out. Then, we determined the quantum yield of the reaction
of 1a and 2a to be 3.0-3.9, which suggested that radical
chain-propagation might render certain contribution.[24] However,
conducting the reaction in the absence and presence of light
confirmed that continuous light irradiation is critical to full
conversion.[22] Thus, the reaction should proceed through the
photo-generated N-radical catalyzed process as the major
pathway. Finally, SET from the reduced IrII form of the
photocatalyst to NCR 6d-B or sulfonyl radical 2a-A would
regenerate the ground state IrIII photocatalyst, delivering
benzenesulfonamide anion 6d-A and benzenesulfinate anion
2a-B. Notably, the whole reaction is a redox-neutral process and
does not require the addition of any external oxidant or
reductant.[25]
Scheme 4. Photogenerated neural NCR-catalyzed alkynylsulfonylation of
styrene.
In conclusion, a photogenerated neutral NCR-catalyzed
intermolecular bifunctionalization of alkenes is presented for the
first time. The preliminary control experiments support the
proposed mechanism, which features generation of an NCR by a
photoredox-catalyzed SET oxidation of in situ-formed
sulfonamidyl anion and subsequent radical addition to an ally
sulfone with release of a reactive sulfonyl radical. This type of
nitrogen radical catalysis is likely to be quite general, and we
anticipate diverse applications of this method to many
transformations that rely on stoichiometric radical initiators.
Acknowledgements
We are grateful to the NNSFC (91856119, 21622201,
21820102003, and 21772053), the Science and Technology
Department of Hubei Province (2016CFA050 and 2017AHB047),
and the Program of Introducing Talents of Discipline to
Universities of China (111 Program, B17019) for their support of
this research.
Conflict of interest
The authors declare no conflict of interest.
Base
N
H
N
O
O
O
O
S
S
+HBase
*IrIII
MeO2C
Ph
Ph
2a-A
Keywords: visible light • photocatalysis • nitrogen radicals •
6d
6d-A
2a
alkene bifunctionalization • sulfones
SET
N
N
Photoredox
Catalysis
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IrIII
IrII 6d-B
MeO2C
detected by HRMS
path a
SET
6d-B
MeO2C
SO2Ph
O
O
1a
2a
SO2Ph
PhSO2
Ph
3aa
S
6d-A
Ph
Ph
2a-B
1a-A
2a-A
path b 2a-A
Scheme 3. Proposed mechanism.
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10.1002/chem.201901665
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Photochemistry
Q.-Q. Zhao, J. Chen, X.-S. Zhou, X.-Y.
Yu, J.-R. Chen,* W.-J. Xiao*
Page No. – Page No.
Photogenerated Neutral Nitrogen
Radical‐Catalyzed Bifunctionalization of
Alkenes
A photogenerated neutral nitrogen radical-catalyzed intermolecular alkene
bifunctionalization using allyl sulfones as the source of both the carbon and
sulfone functionalities under mild conditions is described. The key to the
success of this protocol is the in situ photogeneration of a neutral
nitrogen-centred radical from the N-(2-acetylphenyl) benzenesulfonamide
catalyst, and its activation of the radical acceptors to reactive species.
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