Synergistic combination of visible-light photo-catalytic electron and energy transfer facilitating multicomponent synthesis of β-functionalized α,α-diarylethylamines

Article abstract of DOI:10.1039/c9cc02465d

A synthetic strategy with the visible-light photo-catalytic synergistic combination of electron and energy transfer processes has been developed. The mild reaction conditions allow the radical-radical cross-coupling phenomenon for the multicomponent synthesis of β-arylsulfonyl(diarylphosphinoyl)-α,α-diarylethyl-amines from readily available arylsulfinic acids (diarylphosphine oxides), 1,1-diarylethylenes and arylazides.

Full text of DOI:10.1039/c9cc02465d

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DOI: 10.1039/C9CC02465D
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Synergistic Combination of Visible-Light Photo-Catalytic Electron
and Energy Transfer Facilitating Multicomponent Synthesis of β-
Functionalized α,α-Diarylethylamines
Yanan Wu,a Yipin Zhang,a Mingjie Jiang,a Xunqing Dong,a Hitesh B. Jalani,a,b Guigen Lia,c and
Received 00th January 20xx,
Accepted 00th January 20xx
Hongjian Lu*a
DOI: 10.1039/x0xx00000x
A
synthetic strategy with the visible-light photo-catalytic
synergistic combination of electron and energy transfer processes
has been developed. The mild reaction conditions allow the radical-
radical cross-coupling phenomenone for the multicomponent
synthesis of β-arylsulfonyl(diarylphosphinoyl)-α,α-diarylethyl-
amines from readily available arylsulfinic acids (diarylphosphine
oxides), 1,1-diarylethylenes and arylazides.
Photo-catalysis induced by visible light is an important tool to
access chemistry in which reactive intermediates often cannot
be generated readily in the absence of photo-chemical
strategies.[1] Because such catalysis supports novel chemical
transformations, it has received much attention recently.[2]
Photo-catalysts are known to be excited by absorption of visible
light and the excited forms can be used to activate organic
substrates through different pathways, such as single electron
transfer (SET), energy transfer (EnT) and atom transfer. A
strategy enabling the combination of photo-catalysis with other
types of catalysis has emerged. In such reactions, a photo-
catalyst activates an organic substrate while the second,
nonphoto-chemical catalyst activates another substrate and/or
intermediates, leading to various chemical transformations that
are otherwise either unexpected or difficult.[3] Inspired by such
cooperative strategy and recent relevant examples[4] and
considering the fact that many photo-redox catalysts are also
powerful photosensitizers,[5] a synthetic method dependent on
the synergistic combination of visible-light photo-catalytic SET
and EnT processes is a new reaction paradigm which is
interesting to explore.
Scheme 1 Synergistic combination of electron and energy transfer processes in the
synthesis of tertiary α,α- diarylalkylamines
Diphenylmethylamine derivatives are a class of hydrophobic
and polar molecules present in marketed drugs such as
Cetirizine, Solifenacin and Letrozole (Scheme 1A, top).
However, their counterparts such as α,α-diarylalkylamines
(alkyl ≠ methyl) have been explored less, although this
structural moiety is found in for example, the anti-epileptic drug
Phenytoin Sodium, the N-methyl-D-aspartate antagonist
Dizocilpine,[6] and the calcium sensitizing agent BA41899[7]
(Scheme 1A, bottom). The synthesis of such compounds are
mostly based on the direct 1,2-addition of organometallic
nucleophiles to ketoimines which involves the construction of
C(sp3)−C bonds (Path a, Scheme 1B).[8] The low reactivity of
ketoimines and high reactivity of organometallic nucleophiles
however, make it difficult to construct the appropriate scaffold
and this results in a relative scarcity of the available drugs or
drug candidates with this scaffold. Direct construction of a
C(sp3)−N bond is a simple and feasible strategy for the
a. Institute of Chemistry and BioMedical Sciences, Jiangsu Key Laboratory of
Advanced Organic Materials, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing, 210093, China. E-mail: hongjianlu@nju.edu.cn
b. Smart BioPharm, 310-Pilotplant, Incheon Techno-Park, 12-Gaetbeol-ro, Yeonsu-gu,
Incheon 21999 & Yonsei University, College of Pharmacy, 85-Songdogwahak-ro,
Incheon 21983, South Korea.
c. Department of Chemistry and Biochemistry Texas Tech University, Lubbock, TX
79409-1061, USA
†
Electronic supplementary information (ESI) available. See DOI:
10.1039/x0xx00000x.
This journal is © The Royal Society of Chemistry 2019
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construction of α,α-diarylalkylamines, but it is hindered by the
challenging synthesis of the necessary starting materials (Path
b, Scheme 1B). Radical-radical cross-coupling reactions have an
activation energy close to zero and have emerged as a powerful
tool in the construction of new chemical bonds.[9] Herein, we
report a new strategy enabling such multicomponent synthesis
of α,α-diarylalkylamines, wherein a visible-light photocatalytic
SET and EnT process are combined to facilitate the desired
outcome. This enables the construction of sterically hindered
C(sp3)−N bonds through a radical-radical cross-coupling process
(Scheme 1C). The major challenge in such a reaction is the
difficulty in controlling the regio- and chemo-selectivity in the
presence of multiple active species.
Table 2. β-Arylsulfonyl-α,α-diarylethylamines[a]
View Article Online
DOI: 10.1039/C9CC02465D
Organic azide is an efficient and convenient amino source due
to the advantages of easy preparation, non-oxidative
conditions, and clean reactions with N2 as the only by-
product.[10] Activation of organic azides by visible-light photo-
catalysis has recently received some attention.[11,12] A visible-
light photocatalyst can oxidize arylsulfinic acids to arylsulfonyl
radicals,[13] and this results in the formation of arylsulfones,
structural moieties common in bioactive compounds.[14] The
sulfone unit is useful in various chemical transformations.[15]
Inspired by our own research work on C−H amination using
different azides,[16] we tested a suitable photo-catalyst to
activate both azides and arylsulfinic acids in presence of olefins,
eventually producing compounds which are otherwise difficult
to construct. We began by reacting phenyl azide 1a and
phenylsulfinic acid 2a with 1,1-diphenylethylene 3a under
photo-redox catalysis conditions (Table 1). The reaction
provided the expected product 4a in 41% yield (entry 1).
Different solvents and photo-catalysts were investigated, and
DMF or DMSO as the solvent and Ir(mppy)3 as the catalyst were
found optimal (entries 2-9). Fine-tuning the amount of
Ir(mppy)3 to 1.5 mol% reduces the efficiency (entry 10). Use of
an additional inorganic base such as NaHCO3 does not
significantly influence the reaction (entry 11). In the absence of
visible light, Ir(mppy)3 or an N2 atmosphere, the reaction fails to
proceed (entries 12-14).
[a] Conditions: 1 (0.12 mmol), 2 (0.10 mmol), 3 (0.20 mmol), Ir(mppy)3 (2.5 mol%),
DMF (1.0 mL), blue light (λmax = 470nm), N2, rt, 24 h. Isolated yield.
With the optimal reaction conditions available, the scope and
generality of this reaction were explored (Table 2). Electron-rich
or electron-deficient substituents in the p-position of the
arylazide do not influence the reaction (4a-h) and reactions with
m-substituted arylazides proceed well (4i-j). Sterically hindered
o-substituted arylazides deliver the desired products in good
yield (4k-m). Unsubstituted phenyl azide works well (4n) and a
heterocyclic 3-pyridyl counterpart can serve as a reaction
partner giving the target product (4o). When o-tert-
butylphenylazide (1p) was used, compound 4p with two tertiary
carbons was obtained in moderate yield. This unexpected result
could be due to the presence of the bulky t-butyl and sulfonyl
groups obstructing nearby positions and therefore allowing
flexible radical walking into a different 1,1-diphenylethylene.
Phenylsulfinic acids bearing electron-rich (4-Me, 4a), electron-
neutral (H, 4q), electron-deficient (4-Cl, 4r; 4-Br, 4s) or sterically
hindered (2-Me, 4t) groups at different positions on the phenyl
ring are tolerated well (69-78% yield). Finally, the feasibility of
different substituted 1,1-diarylethylenes (3) was explored.
When the substituent groups are in the p-position of the phenyl
ring, the reaction achieves good yields with symmetrical (4u) or
asymmetric olefins (4v-4x). Substrates with substituents at
different positions in the phenyl ring are also well tolerated (4y-
Table 1 Optimization of the Reaction Conditions[a]
entry
1
2
3
4
5
6
7
8
PC (mol%)
Ir(mppy)3 (2.5 mol%)
Ir(mppy)3 (2.5 mol%)
Ir(mppy)3 (2.5 mol%)
Ir(mppy)3 (2.5 mol%)
Ir(mppy)3 (2.5 mol%)
Ir(ppy)3 (2.5 mol%)
Ir(dtbby)(ppy)2PF6 (2.5 mol%)
Ru(bpy)3(PF6)2 (2.5 mol%)
EosinY (2.5 mol%)
Ir(mppy)3 (1.5 mol%)
Ir(mppy)3 (2.5 mol%)
—
solvent
THF
DCE
yield (%)[b]
41
4a').
A
moderate yield was obtained for 1,1-(1-
15
47
88
88
49
2
17
trace
72
naphthyl)phenylethylene (4b').
CH3CN
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Organophosphorus compounds have broad applications in
agro-chemicals, drugs and drug candidates[17] and their
derivative α,β-amino-phosphinoyl compounds attributes
special biological activities.[18] Therefore, we began to explore
9
10
11[c]
12
13[d]
14[e]
Table 3. β
-Diarylphosphonyl-α,α-diarylethylamines[a]
70
N.D.
N.D.
N.D.
Ir(mppy)3 (2.5 mol%)
Ir(mppy)3 (2.5 mol%)
[a] Conditions: 1a (0.12 mmol), 2a (0.10 mmol), 3a (0.20 mmol), photocatalyst (Pc)
(1.5/2.5 mol%), solvent (1.0 mL), blue light (λmax = 470nm), nitrogen, rt, 24 h. [b]
All yields were assessed by crude 1H NMR spectroscopy using dibromomethane as
an internal standard. [c] Additional NaHCO3 (2.0 equiv). [d] No light. [e] In the air.
2 | Chem. Commun., 2019, 00, 1-5
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[a] Conditions: 1 (0.25 mmol), 3 (0.20 mmol), 5 (0.10 mmol), Ir(dF-ppy)3 (1.0 mol%),
View Article Online
DMF (1.0 mL), 4 Å MS (50 mg/0.1 mmol), white light, N2, rt, 24 h. Isolated yield.
DOI: 10.1039/C9CC02465D
diarylphosphine oxide (5) in place of arylsulfinic acids (2) in this
reaction. After screening different reaction conditions (see
details in Table S1 in SI), the optimized reaction conditions were
identified using Ir(dF-ppy)3 as a photocatalyst with white light
irradiation. The scope with respect to the olefin (3) was
evaluated (Table 3). Symmetrical, asymmetric, electronic rich
and electronic deficient substrates all worked well, providing
Scheme 3. Plausible Reaction Pathway
the desired
β-diarylphosphonyl-α,α-diarylethylamines (6a-6k)
governed by the photo-catalyst through an EnT process and the
triplet nitrene is formed.[19] When methylenecyclopropane (3j)
was used, a ring opening product (11a) was formed (Eq 6),
implying PhSO2• radical is generated. When the reaction of 2a
and 3a was performed (Eqs 7 and 8), the addition products 12a
and 13a were observed. Compound 13a is thought to be
in good yields.
To investigate the mechanism of this reaction, we conducted
several control experiments (Scheme 2). The photocatalyst can
significantly promote decomposition of 1a, in which the diazo
product (7a) was obtained (Eq 1) and product 8a containing two
TEMPO units was achieved in the present of TEMPO (Eq 2).
Direct photosis of o-phenyl phenylazide (1k) is known to
promote the formation of a singlet nitrene species via an energy
transfer process, providing carbazole (9k) with 50% yield (Eq
3).[19] While the same reaction was carried in presence of
photocatalyst, the diazo compound (10k) was obtained and the
yield of 9k was reduced to 13% (Eq 4). When TEMPO was added
to the standard reaction, 8a was observed predominantly over
4a (Eq 5). These results suggest that activation of azide is
generated from the β-H elimination of the α,α-diarylalkyl cation,
and this implies that the α,α-diarylalkyl radical intermediate can
be oxidized easily. Since the PhSO2• radical can be generated by
a radical initiator,[20] TBHP was used to test this feasibility
(condition A). In the reaction with TBHP, a small amount of 12a
was formed and 13a was obtained in 64% yield (Eq 9). While the
reaction of 1a and 2a produces the coupled product
sulfonamide (14a) in moderate yield, no 14a is formed during
TBHP-induced radical reaction (Eqs 10 and 11). The multi-
component reaction of 1a, 2a and 3a is able to selectively
produce 4a, but no obvious products (12a-14a) from the
coupling of two components are observed (Eq 12). In contrast,
the TBHP-induced radical reaction fails to produce 4a (Eq 13).
These results show that the activation of the azide by
photocatalyst is necessary for the success of the reaction. With
addition of p-Tol-NH2, the reaction still proceeds smoothly
without the formation of 4a, suggesting that α,α-diphenylalkyl
cation intermediate is not involved (Eq 14). Several fluorescence
quenching experiments were performed (Scheme 2D and Figure
S2 in SI). It was observed that the fluorescence intensity of
Ir(mppy)3 decreases with increasing concentration of 1a or 2a.
A linear relationship between I0/I and the concentrations of 1a
or 2a was observed showing that the Ir(mppy)3* is quenched by
1a or 2a. The fluorescence intensity of Ir(mppy)3 remains
unchanged with increasing concentrations of 3a.
On the basis of these observations and information in the
literatures,10,11,21 a plausible reaction mechanism is proposed in
Scheme 3. Visible-light induces [Ir(mppy)3]3+ to produce
[Ir(mppy)3]3+* through energy transfer. Subsequently, 2 and
[Ir(mppy)3]3+* participate in a SET process to obtain the valence-
lower [Ir(mppy)3]2+ and arylsulfonyl radical (A) accompanied by
proton dissociation. A is then captured by 3 to form the α,α-
diarylalkyl radical (B) as a persistent radical. At the same time,
[Ir(mppy)3]3+* transfers energy to 1 resulting in loss of N2 and
the formation of triplet nitrene (C). After undergoing a SET
process and protonation, C is converted to a nitrogen radical (D)
as a transient radical which is then coupled with the persistent
radical B to give the product (4).
Scheme 2. Mechanistic Studies
Conclusions
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Acc. Chem. Res., 2016, 49, 2261; (c) D. C. Fabry and M.
In summary, we have achieved a synthetic strategy involving a
synergistic combination of SET and EnT processes using a single
photocatalyst. This enables the multicomponent synthesis of α,α-
diarylalkylamine scaffolds. Using Ir(mppy)3 as photo-redox catalyst
and photosensitizer, the readily available arylsulfinic acid or
diphenylphosphine oxide, 1,1-diarylethylenes and arylazides were
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4
5
easily
converted
to
β-arylsulfonyl(diarylphosphinoyl)-α,α-
diarylethylamines. The sulfonyl and phosphinoyl groups present in
the β-position of desired amines can be potentially useful and
transferable, and this may enhance the utility of this reaction.
Mechanistic studies showed that arylsulfinic acid undergoes a SET
process and deprotonation to form ArSO2• which adds to 1,1-
diarylethylene to form an α,α-diarylalkyl radical as a persistent
radical. Simultaneously, the azide goes through an EnT process, a SET
process and protonation with visible-light photocatalysis to produce
a transient nitrogen radical. The cross-coupling of the α,α-diarylalkyl
radical and this nitrogen radical is crucial to the construction of
sterically hindered C(sp3)-N bonds which are difficult to prepare with
ionic chemistry. Further investigation of the reaction mechanism and
applications of this newly discovered reaction are currently in
progress.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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We are grateful for financial support by National Natural
Science Foundation of China (21871131) and the Fundamental
Research Funds for the Central Universities (No.
020514380131).
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DOI: 10.1039/C9CC02465D
H
b
Ar
Ar'
R
Ar N3
EnT
SET
Ar NH
Ar
R
+
a
Ar
Ar'
Ar'
R H
N2
Ir(III)
Ar NH
sterically hindered
C(sp3)-N bond formation
R = ArSO2; Ar2PO
Stepwise
Radical Transfers
Dual activation
One photocatalyst
Readily available
Mild and no-oxidative
Multicomponent synthsis
Functional group tolerance
Biologically active skeleton
High chemo- and regio-selectivity
A synthetic strategy which takes advantage of the synergistic combination of electron and
energy transfer processes using only one photocatalyst has been developed for the
multicomponent synthesis of the α,α-diarylalkylamine skeleton, providing a simplified and
feasible synthetic method for the direct construction of sterically hindered C(sp3)-N bonds.