A photoredox catalyzed radical-radical coupling reaction: Facile access to multi-substituted nitrogen heterocycles

Article abstract of DOI:10.1039/c6cc02027e

Visible light induced photoredox catalysis is an efficient method for radical activation. Herein, we report the photoredox catalysis involving an intramolecular radical-radical coupling reaction that proceeds through a biradical intermediate. This protocol represents a new synthetic route to construct multi-substituted N-heterocycles. Four, five and six-membered N-heterocyclic structures with a quaternary carbon center are accessible under mild conditions.

Full text of DOI:10.1039/c6cc02027e

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Photoredox Catalyzed Radical-Radical Coupling Reaction: Facile
Access to Multi-Substitued Nitrogen Heterocycles
Weipeng Li,a Yingqian Duan,a Muliang Zhang,a Jian Cheng a and Chengjian Zhu*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) Previous procedure: ketyl formation
Visible light induced photoredox catalysis is an efficient method
for radical activation. Herein, we report a photoredox catalyzed
intramolecular radical-radical coupling reaction that proceeds
through biradical intermediate. This protocol represents a new
synthetic route to construct multi-substituted N-heterocycles.
E-D
E-D
hv
PC
PC*
ketyl-olefin
cyclizations
X
Knowles' work
Rueping's work
O
O
OH
PC
O
Ar
Ar
R
Ar
b)
R
R
HO
H
OH
Ar
pinacol coupling
Ar
Four, five and six-mumber N-heterocyclic structures with
a
R
R
quaternary carbon center are accessible under mild conditions.
Meggers' work: cross-coupling of ketyl and amine radicals
Ar1
N
OH
CF3
Ar1
N
O
Ar1
N
R
The nitrogen heterocycles, as basic alkaloid scaffolds, appear
in numerous bioactive products, pharmaceuticals, and
agrochemicals.1 As a result, the synthesis and functionalization
of N-heterocycles have attracted a long-lasting interest in
synthetic field.2 In the past years, a couple of strategies have
been developed for the synthesis of N-heterocycles including
piperidines, pyrrolidines, azetidines, and indoles.3 Despite the
great achievements in this area, an efficient method for the
construction of multi-substituted N-heterocycles with
quaternary carbon centre from simple substrates is still
desirable. Herein, we present a new way to synthesize four,
five and six-membered aminated heterocyclic structures via
visible-light-induced photoredox catalysis.
hv
F3C
HO
R1
+
R1
+
Ar2
CF3
Ar2
R
Ar2
PC
R1
c) Our work: intramolecular radical-radical coupling
Ar1
N
Ar2
HO
R1
OH
cyclization
O
H
PC, thiol
Ar2
blue LED
n
n
N
n
R1
N
Ar2
n= 0,1,2
R1
Ar1
Ar1
biradical
intermediate
up to 95% yield
n= 0,1,2
Scheme 1.Photoredox catalysed ketyl formation reaction.
sacrificial electron-donor reagent was needed to initiate catalytic
cycle (Scheme 1-a). Meggers and co-workers also introduced a
visible-light-driven asymmetric intermolecular ketyl/α-amine radical
coupling reaction between one electron-acceptor (E-A) and one
electron-donor (E-D) which avoids the use of an extra sacrificial
electron-donor (Scheme 1-b). However, only electron-deficient
trifluoromethyl ketones are suitable substrates. Inspired by our
recent success in visible light photoredox catalysis,10 we assumed
that a substrate bearing both ketone as electron-acceptor and
tertiary amine as electron-donor11 would generate an active
biradical intermediate which undergo radical- radical cyclization
under visible light photoredox catalysis (Scheme 1-c).
Visible-light-induced photocatalysis has proven to be one of the
most effective methods for radical activation,4 a large number of
radical reactions have been realized via visible light irradiation.5
Ketyl is valuable synthetic radical in organic synthesis.6 However,
the unfavorable activation barrier during ketyl formation severely
prevented their wider application. Recently, the groups of Knowles
7
8
and Rueping reported efficient protocols to access ketyls under
mild conditions by visible light photoredox catalysis. In their work, a
In order to demonstrate our hypothesis mentioned above, we
synthesized compound 1a as a model substrate. However, visible
light irradiation of substrate 1a in MeCN solution containing 1 mol%
Ir(ppy)2(dtbbpy)PF6 led to no conversion (Table 1, entry 1). Addition
of protonic acid (PhO)2PO2H was also ineffective (Table 1, entry 2).
To our surprise, when thioacetic acid (CH3COSH) was employed,
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Table 2. Substrate scope [a]
36% yield of pyrrolidine product was obtained with 2.5:1 mixture of
diastereomers (Table 1, entry 3). While MacMillan and co-workers
Table 1. Optimization studies [a]
five-mumbered ring:
2b:Ar2 =4-Me-Ph, 85% yield, dr=9:1
Ph
OH
Ph
OH
Ar2
2c: Ar2 =4-OMe-Ph, 51% yield, dr=7:1
2d: Ar2 =4-CF3-Ph, 93% yield, dr=8:1
2e: Ar2 =4-F-Ph, 75% yield, dr=9:1
2f: Ar2 =4-Cl-Ph, 84% yield, dr=13:1
2g: Ar2 =4-Br-Ph, 87% yield, dr=15:1
Ph
N
N
Ph
Entry
Solvent
Additive[b]
Yield/%
cis:trans [c]
-
Ph
2a [b]: 83%, dr=10:1,
1
CH3CN
CH3CN
CH3CN
CH3CN
DCM
THF
0
trace
36
66
64
36
82
73
7
2
(PhO)2PO2H
CH3COSH
-
Ph
OH
Ph
OH
Ar2
2h:Ar2 =3-Me-Ph, 70% yield, dr=3:1
2i: Ar2 =3-F-Ph, 77% yield, dr=4:1
2j: Ar2 =3-Cl-Ph, 74% yield, dr=4:1
2k:Ar2 =2-Me-Ph, 74% yield, dr=3:1
S
3
2.5:1
2:1
1.5:1
2.3:1
12:1
14:1
ND
12:1
ND
12:1
-
N
N
Ph
4
Thiol 3a, K2HPO4
Thiol 3a, K2HPO4
Thiol 3a, K2HPO4
Thiol 3a, K2HPO4
Thiol 3a, K2HPO4
Thiol 3a, K3PO4
Thiol 3a, KH2PO4
Thiol 3a, K2CO3
Thiol 3a, KHCO3
K2HPO4
Ph
2l: 76%, dr=5:1
5
Ph
OH
Ph
OH
6
2n: Ar1 =4-Me-Ph,73% yield, dr=7:1
2o[c]: Ar1 =4-CF3-Ph,52% yield, dr=6:1
Ph
7
DMF
N
N
Ar1
Ph
Ph
8
DMSO
DMF
2m: 87% yield, dr=6:1
9
Ph
R1
OH
10
11
12
13
14
15[d]
16 [e]
DMF
70
13
64
0
OH
Ph
2q: R1=4-Me-Ph, 78% yield, dr=10:1
1
Ph
2r : R =4-CF3-Ph, 86% yield, dr=10:1
DMF
N
Ph
Me
N
Ph
2p[c]: 52% yield, dr=11:1
DMF
DMF
Ph
NPh
HO
Et
Me
OH
OH
Ph
DMF
Thiol 3a
trace
0
-
Ph
H
N
N
DMF
Thiol 3a, K2HPO4
Thiol 3a, K2HPO4
-
Ph
Ph
2u[c]: 61% yield, dr=1.5:1
DMF
0
-
2t: 93% yield, dr>20:1
2s: 95% yield, dr>20:1
[a] Optimization reactions performed on 0.2 mmol scale with anhydrous solvent
under Argon atmosphere. Isolated yield. [b] All additives were used in 0.2 eq. [c]
Determined by 1HNMR. [d] No catalyst. [e] No light. ND = not determined.
Ph
Ph
HO
H
Ph
NPh
HO
NPh
PhN
OH
H
O
H
have pioneered the strategy for thiol activation of C-H bonds
via photoredox catalysis.12 We guessed that the electrophilic R-
S. radical generated from MeCOSH may have an acceleration
2v[c]:59% yield, dr=1.4:1
2x[d]: 90% yield, dr=13:1
2w[d]: 71% yield, dr=3:1
effect on the reaction by abstraction of H. from substrate 1a
.
Based on this hypothesis and after screening several similar
conditions (see more details in Table 1 in ESI), the combination
of methyl thioglycolate (thiol 3a) and K2HPO4 was adopted. In
survey of various solvents, it was found that polar solvents
provided better results. With DMF as reaction medium, the
desired N-heterocycle 2a was obtained in 82% yield with high
level of diastereoselectivity (Table 1, entries 4-8). Bases have a
great influence on reaction yield (Table 1, entries 9-12). Among
the bases screened, K2HPO4 proved to be the best choice (see
more details in Table 1 in SI). Control experiments indicated
the necessary of photocatalyst, thiol, light, and base, no
desired product was detected in absence of any elements
mentioned above (Table 1, entries 13-16).
[a] isolated Yields, d.r. was determined by 1H NMR. [b] Average yield of two runs
(81% and 85%). [c] thiol (0.25 mmol), K2HPO4 (0.25 mmol). [d] relative
configuration was determined by NOE.
With the optimized conditions in hand, we next engaged to
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define the substrate generality of this protocol. When the reaction Table 3. Substrates scope of indole formation [a]
was performed on 0.5 mmol scale, model substrate 1a provided
O
Me
cyclized product in an undiminished yield (83%) as a 10:1 mixture of
diastereomers (Table 2, 2a). We then investigated a variety of Ar2
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CH3CN (5 mL), 5 W blue LED
Me
Ar
N
groups. Both electron-rich and electron-poor substrates functioned
well in this process (Table 2, 2b-2k). Substrates with strong
electron-withdrawing group (CF3) on the benzene ring (Table 2, 2d)
resulted in high yield (93%) but in slow conversion. It was found
that the position of substituents have great impact on the
diastereomeric ratio. Meta-substituted and orth-substitued
analogues led to poor diastereoselectivity (Table 2, 2h-2k).
Heteroarene structures are prevalence in bioactive molecules,
so heteroaromatic substrate (Table 2, 2l) was tested too, and 76%
yield of product was obtained. Conjugated substrate was also
suitable for this system which could offer 2-vinyl substituted N-
heterocycle in 76% yield (Table 2, 2m). The effect of Ar1 groups
were examined too, all underwent reaction to provide desired
products in moderate to good yields (Table 2, 2n-2o). The two
aromatic groups (Ar1 and Ar2) are necessary to the successful of
this transformation, while replacing of either Ar1 or Ar2 by aliphatic
groups lead to no conversion (see details in ESI Table 2).
Notably, α-alkyl branched substrate was successfully cyclized to
provide product containing two continuous quaternary
carbons in 52% yield with good diastereoselectivity (Table 2,
2p). Aliphatic ketones 1s and 1t were also tolerable substrates
(Table 2, 2s and 2t), furnishing cyclization in good results with
high level diastereoselectivity (dr>20:1). Multi-substituted
pyrrolidine fused to 6-, 7- membered rings were readily
accessible via this protocol (Table 2, 2u-2w). The bridged
bicyclic structure was also prepared in 90% yield which further
demonstrated the generality of this method in constructing N-
heterocycle compounds (Table 2, 2x). Next, we explored the
possibility of expanding this protocol to synthesize N-heterocycles
of different sizes. At first, we employed our protocol to synthesize
piperidine scaffold. The corresponding piperdines could be isolated
in good yields (Table 2, 4a-4f). Then, we questioned if it is possible
to obtain azetine with high ring strain. To our delight, the cyclization
procedure proceeded well to provide multi-substituted azetidines in
moderate yields (Table 2, 5a-5b). It was needed to mention that
substrates with N-Me or N-Et substitution also could smoothly
furnish the cyclization reactions (Table 2, 5a-5f). Gram-scale
experiments were also performed to test the potential application
of this method in organic synthesis (see results in ESI, page of 6).
With N-substituted amino acetophenone as substrate, we
get dehydration products which led to 1, 2, 3,-trisubstituted
indoles. In consideration of the widely existence of indole
scaffolds in natural products, the generality of this method
was then examined (see optimization studies in Table 3 in ESI),
the results are shown in Table 3. A range of functional groups
on the aryl moiety were tolerated very well (Table 3, 7a-7i).
Indolo[2,1-a]isoquinoline structures were also accessible in
N
Ar
K2HPO4 (0.5eq.), thiol 3a(0.5 eq.),
Ar, 48 h, rt
Ar
Ar
0.5 mmol
6
7
Me
Me
7b:Ar=4-Me-Ph, 70%; 7c: Ar=4-F-Ph, 65%
7d:Ar=4-Cl-Ph, 67%; 7e: Ar=4-CF3-Ph, 52%
7f: Ar=3-Me-Ph, 63%; 6g: Ar=3-Cl-Ph, 60%
7h: Ar=2-Cl-Ph, 56%
Ph
Ar
N
N
Ph
Ar
7a: 68% yield
MeO
Me
N
N
Ph
N
MeO
Me
Me
Me
7j: 91% yield
7k: 87% yield
7i: 62% yield
[a] Reaction conditions: substrate (0.5 mmol), thiol (0.25 mmol), K2HPO4 (0.25
mmol), Ir(ppy)2(dtbbpy)PF6 (0.005 mmol), CH3CN (5mL) irradiate by 5 W blue LED
under argon atmosphere for 48 hours. Yields of isolated products.
Based on our experiment results (see details in ESI) and the
previous research done in visible light photoredox catalysis,12
a
plausible mechanism is proposed in Scheme 2. Visible light
irradiation of IrIII photocatalyst lead to
long-lived
a
photoexcited state *IrIII. *IrIII undergoes a single electron
transfer (SET) oxidation process with thiol to generate thiyl
radical and reduced photocatalyst IrII. The thiol radical
abstracts H. from 1a, providing α-amino radical 1a-1. At this
juncture, electron transfer to the ketone part of 1a-1 by the IrII
forms biradical intermediate 1a-2 while concomitantly
regenerating the IrIII. The active biradical 1a-2 prefers to go
through intramolecular coupling in the less hindered
conformation, which leads to cis
-
2a as the main diastereomer.
O
Ph
H
N
Ph
Ph
1a
MeO2C SH
abstrcation
H
*Ir(III)
O
hv
SET
Ph
N
Ph
Ph
MeO2C
S
Ir(III)
Ir(II)
1a-1
PCET
H
Ph
OH
Ph
Bn
1a-2
Ph
OH
Ph
1a-1
H
biradical
cyclization
OH
N
Bn
N
N
Ph
cis-2a
1a-2
OH
H
H
N
OH
less sterically
hindered
N
Bn
Bn
sterically
hindered
good yields (Table 3, 7j-7k).
unfavored
conormation
favored
conformation
Scheme 2. Proposed catalytic cycles for radical-radical coupling.
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Wang, Y. Wang, J. Chen and W.-J. Xiao, Angew. Chem. Int. Ed.,
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Miller, G. J. Choi, H. S. Orbe and R. R. Knowles, J. Am. Chem.
Conclusions
In conclusion, we have developed
a visible light
photoredox catalyzed radical-radical coupling reaction to
construct 4-, 5-, and 6-membered N-heterocycles. Ketyl and α-
amino radical were formed in one catalytic cycle via proton-
coupled electron transfer without extra sacrificial electron
donor. We anticipate this reaction will prove to be a versatile
method for N-heterocycles formation and find synthetic utility
among orgnic synthesis.
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We gratefully acknowledge the National Natural Science
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21372114) for financial support.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6CC02027E
ketone
activation
C-H activation
H
R2
R1
HO
R3
OH
N
O
n
N
R2
Ir photocatalyst
cyclization
R1
n
n
R3
R3
N
visible light, thiol
R1
n= 0,1,2
R2
up to 95% yield
biradical
intermediate
n= 0,1,2
multi-substituted N-heterocycles
mild reaction condition
wide substrate scope
A visible light mediated radical-radical coupling reaction towards valuable nitrogen heterocyle
has been developed. Piperidines, pyrrolidine, indoles, and azetidines scafolds were synthesized in
good to excellent yields from simple substrates.