Benzylic C-H heteroarylation of: N-(benzyloxy)phthalimides with cyanopyridines enabled by photoredox 1,2-hydrogen atom transfer

Article abstract of DOI:10.1039/d0cc03619f

A visible light initiated α-C(sp3)-H arylation of N-(benzyloxy)phthalimides with cyanopyridines for the construction of highly valuable pyridinyl-containing diarylmethanols, including bioactive motif-based analogues, is reported. This method enables arylation of the C(sp3)-H bonds adjacent to an oxygen atom through alkoxy radical formation by O-N bond cleavage, 1,2-hydrogen atom transfer (HAT), arylation and C-CN bond cleavage cascades, and offers a means to exploit 1,2-HAT modes to incorporate functional groups for constructing functionalized alcohols.

Full text of DOI:10.1039/d0cc03619f

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Benzylic C-H Heteroarylation of N-(Benzyloxy)phthalimides with
Cyanopyridines Enabled by Photoredox 1,2-Hydrogen Atom
Transfer
Received 00th January 20xx,
Accepted 00th January 20xx
Long-Jin Zhong,ab Hong-Yu Wang,b Xuan-Hui Ouyang,*b Jin-Heng Li,*abc and De-Lie An*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
visible light initiated -C(sp3)-H arylation of N-
Recent advances have showed the C(sp3)-H radical
(benzyloxy)phthalimides with cyanopyridines for the construction functionalization reaction enabled by a hydrogen atom transfer
of highly valuable pyridinyl-containing diarylmethanols, including (HAT) process represents a new synthetic alternative to ionic
bioactive motif-based analogues, is reported. This method enables reactions for increasing molecular complexity.5 Typical
arylation of the C(sp3)-H bonds adjacent to an oxygen atom strategies involve radical functionalization of the C(sp3)-H bonds
through alkoxy radical formation by O-N bond cleavage, 1,2- in alcohols and their derivatives,6-7 which is achieved by the
hydrogen atom transfer (HAT), arylation and C-CN bond cleavage formation of alkoxyl radical intermediate followed by HAT,
cascades, and offers a means to exploitation of 1,2-HAT modes to featuring high efficiency and excellent site-selectivity (Scheme
incorporate functional groups for constructing functionalized 1a upper). However, only a few papers that employ the HAT
alcohols.
strategy to site-selectively introduce a functional group to the
C(sp3)-H bonds in alcohols and their derivatives have been
reported, and the most commonly explored transformations
relied on 1,5-HAT.6 At present, approaches via 1,2-HAT have
been significantly less investigated,7 which mainly focus on
direct conversion of the hydroxy group to the carbonyl group
(e.g., aldehydes, ketones).7a-l Very recently, Lan, Chen and co-
workers7n have reported a new 1,2-HAT strategy for -allylation
of N-(alkyloxy)phthalimides for the synthesis of allyl alcohols
beyond the formation of carbonyl compounds wherein visible
light induced transformation of the C(sp3)-H bonds adjacent to
an oxygen atom to the alkoxyl radical followed by 1,2-HAT and
allylation (Scheme 1a lower). Although only a special ethyl 2-
((phenylsulfonyl)methyl)acrylate as the external functional
reagent was used to accomplish this -C(sp3)-H allylation, we
envisioned that employing visible light sensitive functional
reagents, such as heteroaryl-based reagents, would allow the
Diarylmethanols, especially variants possessing heteroaryls,
are important core structural motifs in bioactive natural
products, pharmaceuticals and materials.1 Accordingly,
substantial efforts have been paid to the discovery of efficient
strategies to prepare diarylmethanols.2-4 General methods for
their synthesis include addition of aryl nucleophiles (e.g., aryl
organometallic reagents) to aryl carbonyl compounds2 and
reduction of diaryl ketone derivatives.3 Despite impressive
progress in the field, the known transformations have some
disadvantages, such as limited substrate scope, unsatisfactory
selectivity, and the generation of a stoichiometric amount of
chemical waste. Furthermore, the construction of heteroaryl-
containing diarylmethanol scaffolds, especially nonsymmetric
ones, has been sporadically documented in a few papers and is
an even great challenge, with most concerning addition of
heteroaryl- metallic reagents to the carbonyl compounds. Thus,
the development of general and sustainable routes toward
functionalization
of
-C(sp3)-H
bonds
of
N-
(alkyloxy)phthalimides via 1,2-HAT to access functionalized
methanol derivatives.
diarylmethanols,
containing diarylmethanols, is highly desirable and urgent.
especially
nonsymmetric
heteroaryl-
Herein, we report a new strategy for producing pyridinyl-
containing diarylmethanols via -C(sp3)-H arylation of N-
(benzyloxy)phthalimides with cyanopyridines8 enabled by the
visible light photoredox catalysis (Scheme 1b). Visible light-
induced cleavage of the O-N bond results in the formation of
benzyloxy radical is crucial, allowing 1,2-HAT and arylation
a State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University,
Changsha 410082, China
b Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources
Recycle, Nanchang Hangkong University, Nanchang 330063, China
c State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, China
cascades
to
access
highly
valuable
nonsymmetric
E-mail: xuanhuiouyang@163.com, jhli@hnu.edu.cn, deliean@hnu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
diarylmethanols, including bioactive motif-based analogues.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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a) Previous work:
DMF instead of DMSO
MeCN instead of DMSODOI: 10.1039/D0CC0630619F
MeOH instead of DMSO
at 40 oC
53
10
11
12
13
14
15
16b
OH
View Article Online
1,5-HAT
1,2-HAT
H
H
R
R
OR1
O
H
R
R
52
87
0
32
85
H
H
H
OH
alkyloxy radical
Lan/Chen: a-C(sp3)-H allylation via 1,2-HAT
in dark
extra dry DMSO
none
O
R
O
fac-Ir(ppy)2 (1 mol%)
Hantzsch ester (1.5 equiv)
OH
SO2Ph
CO2Et
N
R'
R
+
H
CO2Et
4 W blue LED, MeOH, rt
a
O
R'
Reaction conditions: 1a (0.2 mmol), 2a (2 equiv),
R = alkyl, aryl
Board a-C(sp3)-H bonds but only one allylation regent
Special Hantzsch ester as the single-electron transfer reagent
i
Ir(ppy)2(dtbbpy)(PF6) (1 mol%), Pr2NEt (2.2 equiv), DMSO (2 mL),
b
argon, 30 W blue LED light, room temperature and 12 h. 1a (1
b) This work: Benzylic C-H heteroarylation via 1,2-hydride shift
O
CN
OH
mmol).
R2
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
R1
H
O
N
+
R1
R2
iPr2NEt, 30 W blue LED
DMSO, rt, 12 h
N
We next evaluated the substrate scope of this benzylic C-H
heteroarylation protocol (Table 2). The optimized conditions were
compatible with a wide range of N-(benzyloxy)phthalimides 1 (3ba-
oa). Treatment of substrate 1b was converted efficiently to 3ba in
85% yield. Several substituents, including Ph, Cl, CF3, Me, Br and
various ethynyl groups, on the aryl ring of the benzyloxy moiety
were well tolerated (3ba-la), and the electronic property affected
the reactivity. While substrates 1a and 1f bearing an ortho-electron-
donating group (e.g., Me, Et) furnished 3aa and 3fa in excellent
yields, substrate 1e having a para-electron-withdrawing CF3 group
delivered 3ea in moderate yield. Halogen groups (e.g., Cl, Br) were
tolerated,
H
N
O
3
2
1
Broad a-C(sp3)-H bonds and heteroarylation regents
Common amines as the single-electron transfer reagent
Scheme 1. Hydrogen Atom Transfer of Alkoxy Radicals.
We initiated our study with optimization of conditions for the -
C(sp3)-H arylation of N-((2-methylbenzyloxy)phthalimide 1a with
isonicotinonitrile 2a (Table 1). We found that substrate 1a reacted
with nitrile 2a, 1 mol% of Ir(ppy)2(dtbbpy)(PF6) and 2.2 equiv of
iPr2NEt in DMSO under argon atmosphere and 30 W blue LED light
at room temperature was optimal, affording the desired product
3aa in 90% yield (entry 1). These parameters, Ir photocatalyst,
organic base and additional visible light, were proved to be crucial
because omission of each resulted in no reaction (entries 2, 6 and
14). However, the common Ir(ppy)3 exhibited lower reactivity (entry
3), and both Ru(bpy)3Cl2 and Eosin Y had no catalytic activity
Table 2. Variation of the N-(Alkyloxy)phthalimides (1) and
Isonicotinonitrile Derivatives (2)a
O
CN
OH
R2
N
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
R1
O
N
R1
+
R2
iPr2NEt, 30 W blue LED
DMSO, rt, 12 h
i
(entries 4-5). While organic bases (e.g., Pr2NEt, Et3N) were the key
N
O
1
3
2
to initiate the reaction (entries 1, 6 and 7), inorganic bases (e.g.,
K3PO4, K2CO3) were inert (entries 8-9). The results suggest that
organic bases may act as single-electron transfer reagents. Three
other solvents, DMF, MeCN and MeOH, both were inferior to DMSO
(entries 10-12). A higher temperature (40 oC) had no obvious
improvement on yield (entry 13). No reaction was observed in dark
(entry 14). The desired product 3aa was obtained in 32% yield when
using extra dry DMSO, indicating that the water assisted this
process (entry 15). Strikingly, the reaction with 1 mmol scale of 1a
proceeded efficiently, giving 3aa in 85% yield (entry 16).
OH
OH
R
OH
R = Ph, 3ca, 68%
R = Cl, 3da, 88%
R = CF3, 3ea, 65%
N
N
N
R
3ba, 85%
N
R = Et, 3fa, 86%
R = Br, 3ga, 60%
Ph
OH
OH
OH
HO
H
H
O
N
H
O
N
3ha, 80%
3ia, 82%
3ja, 58%
N
N
NBoc
O
OH
OH
O
O
Table 1 Optimization of the Reaction Conditionsa
3ka, 65%
3la, 85%
Ph
OH
OH
O
CN
OH
MeO
OH
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
HO
+
O
N
iPr2NEt, 30 W blue LED
DMSO, rt, 12 h
N
N
N
O
N
N
S
O
OMe
N
3aa
1a
3na, 70%
3oa, 66%
2a
3ma, 72%
3pa, 62%
OH
OH
Entry
Variation from the standard conditions
Yield (%)
R'
Cl
OH
R' = H, 3bb, 77%
Ph
1
2
3
4
5
6
7
none
90
0
9
trace
trace
trace
70
trace
trace
Ph
R' = MeO, 3bc, 60%
R' = vinyl, 3bd, 40%
R' = CF3, 3be, 63%
N
Ph
Ph
N
Ph
without Ir(ppy)2(dtbbpy)(PF6)
Ir(ppy)3 instead of Ir(ppy)2(dtbbpy)(PF6)
N
3bg, 65%
3bf, 58%
OH
OH
OH
F
OH
OH
TMS
Ru(bpy)3Cl2 instead of Ir(ppy)2(dtbbpy)(PF6)
Eosin Y instead of Ir(ppy)2(dtbbpy)(PF6)
without iPr2NEt
N
Ph
Ph
Ph
Ph
N
N
N
N
3bk, traceb
3bi, 67%b
3bj, 70%b
3bl, traceb
3bh, 53%
Et3N instead of iPr2NEt
a
Reaction conditions:
1
(0.2 mmol),
2
(2 equiv),
K3PO4 instead of iPr2NEt
K2CO3 instead of iPr2NEt
8
9
i
Ir(ppy)2(dtbbpy)(PF6) (1 mol%), Pr2NEt (2.2 equiv), DMSO (2
mL), argon, 30 W blue LED light, room temperature and 12 h.
b
2 | J. Name., 2012, 00, 1-3
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(Path I),8 which sequentially undergoes cleavage of C-CN bonds to
For 24 h.
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DOI: 10.1039/D0CC03619F
afford the desired product 3aa.
thus offering potential in the late stage modification (3da, 3ga).
Terminal and internal alkynes 1h-l were well tolerated (3ha-la),
making the protocol more attractive in synthesis. Notably, this
protocol was applicable to the incorporation of the important
pharmacophore cores,9 including ethisterone, adamantane and
proline motifs, into the diarylmethanol frameworks (3ja-la), thereby
providing a vistas for the translational potential of this protocol in
pharmaceutically relevant field. Heteroaryl (e.g., furan-2-yl, 3-
methylthiophen- 2-yl) possessing substrates 1n-o were viable for
we cannot rule out Path II wherein the direct addition of the
radical E to 2a to form the intermediate G, followed by single
electron reduction by the radical cation A and C-CN bond cleavage
to afford product 3aa.
O
Ar
OH
CN
Ar
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
+
(1)
iPr2NEt, 30 W blue LED
DMSO, rt, 12 h
MeO
4q (Observed by
GC-MS analysis)
O
O
N
+
N
N
2a
3qa, 0%
O
Ar = 4-MeOC6H4
1q
OH
O
O
CN
O
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
O
N
furnishing
nonsymmetrical
diheteroarylmethanols
3na-oa.
(2)
(3)
tBu
+
iPr2NEt, 30 W blue LED
DMSO, rt, 12 h
N
tBu
OR
N
2a
Delightedly, tertiary alcohols 3pa could be constructed in moderate
yield.
O
1r
3ra, 15%
CN
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
+
OR
iPr2NEt, 30 W blue LED
DMSO, rt, 12 h
The optimized conditions were general for benzylic C-H
heteroarylation with various cyanopyridines (3bb-bj). A number of
substituents, such as Ph, 4-MeOC6H4, 4-vinylC6H4, 4-MeOC6H4, 4-
CF3C6H4, 4-PhC6H4, Cl and (trimethylsilyl)ethynyl, at 2 position of the
pyridine ring were accommodated, affording 3bb-bh in moderate to
good yields. Using 3-F-4-cyanopyridine 2i delivered 3bi smoothly in
67% yield. Gratifyingly, 2-cyanopyridine 2j also underwent the
benzylic C-H heteroarylation successfully (3bj). However, both
quinoline-4-carbonitrile 2k and isoquinoline-1-carbonitrile 2l were
unsuitable substrates (3bk-bl).
N
R = H, 1s
R = Me, 1t
N
R = H, 3ba, 0%
R = Me, 3ta, 0%
2a
O
OH
CN
Additive (3 equiv)
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
(4)
+
iPr2NEt, 30 W blue LED
DMSO, 30 oC, 12 h
O
N
N
N
2a
O
3aa
1a
Additive
Yield of 3aa
TEMPO
hydroquinone
BHT
trace
trace
35%
Ph
O
Ar
(3 equiv)
CN
N
Ph
NiPr2
Ph
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
O
N
3aa
40%
(5)
+
+
+
HNiPr2
iPr2NEt, 30 W blue LED
DMSO, 30 oC, 12 h
Ph
(Observed by
5 (Observed by
O
GC-MS analysis)
GC-MS analysis)
2a
1a
Ar = 2-MeC6H4
As shown in Scheme 2, using 2-(3-(4-methoxyphenyl)-
propoxy)isoindoline-1,3-dione 1q gave the intramolecular
cyclization product 4q, not the desired product 3qa (Eq 1). For 2-(2-
((4-(tert-butyl)benzyl)-oxy)ethoxy)isoindoline-1,3-dione 1r the 1,5-
HAT reaction occurred to afford 3ra (Eq 2). The results suggest that
this current protocol includes a HAT process, and the alkyl chain of
the N-(alkyloxy) moiety affects the chemoselectivity. However, both
benzyl alcohol 1s and benzyl methyl ether 1t were not suitable
substrates (Eq 3), implying that generation of the alkoxy radical
requires the phthalimide group to assist it. The reaction of substrate
Ir(ppy)2(dtbbpy)(PF6) (1 mol%)
O
Ar
O
CO2Et
iPr2NEt, 30 W blue LED
DMSO, 30 oC, 12 h
O
N
Ar
O
SO2Ph
(3 equiv)
N
+
+
(6)
3aa
trace
O
EtO2
C
HO
6, 65%
7 (Observed by GC-MS analysis)
+
+
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
A
A
SET
SET
O
IrII
IrII
IrIII
*
IrIII
*
CN
O
O
N
visible
light
Ir = Ir(ppy)2(dtbbpy)(PF6
)
Ir = Ir(ppy)2(dtbbpy)(PF6)
visible
light
1a
O
N
2a
O
IrIII
IrIII
CN
OH
N
CN
Path I
+
H2O
OH
1a with 2a was inhibited by
a
radical scavenger, TEMPO,
C
O
O
N
1,2-H
shift
N
B
F
E
hyroquinone, 2,6-di-tert-butyl-4-methyl-phenol (BHT) (Eq 4), 1,1-
diphenylalkene (Eq 5) or ethyl 2-((phenylsulfonyl)methyl)acrylate7n
(Eq 6). Notably, the reaction was inhibited by 1,1-diphenylalkene
D
+
iPr2NEt
2a
A
Path II
O
CN-
OH
OH
+
NiPr2
+
CN
NH
iPr2NEt
A
i
i
attributing to reaction with Pr2NEt to form 5 and Pr2NH, and was
O
N
N
iPr2NEt + CN-
G
3aa
suppressed by 2-((phenylsulfonyl)methyl)acrylate due to its direct
i
reaction with both Pr2NEt and 1a leading to 6 and 7, suggesting a
Scheme 2. Other N-(Alkyloxy)phthalimides 1, Control
Experiments and Possible Mechanisms.
different mechanism from the results of Lan/Chen group7n and
i
verifying Pr2NEt as the single-electron transfer reagent. The light
turn/off experiments support this current protocol via visible light
photoredox catalysis (Figure S2; Supplementary Information).
The possible mechanisms for this -C(sp3)-H arylation protocol
were proposed (Scheme 2).5-8 The IrIII* excited state is formed from
the IrIII species under blue LED light, followed by reduction with
iPr2NEt to afford the active IrII species and the iPr2NEt radical cation
A. The single electron reduction (SER) of 4-cyanopyridine 2a by the
active IrII species delivers the 4-cyanopyridine radical anion B8m and
regenerates the IrIII species.8 Meanwhile, the SER of N-((2-
methylbenzyloxy)phthalimide 1a by the active IrII species yields the
radical intermediate C and then reaction with the radical cation A
forms the benzyloxy radical D.7n The radical D undergoes 1,2-HAT
assisted by H2O to form the benzyl carbon-centered radical E (also
supported the results of entry 12; Table 1).7d,7k The cross coupling
between the radical B and the radical E offers the intermediate F
In summary, we have developed a novel, general and robust
method for the -C(sp3)-H arylation of N-(alkyloxy)- phthalimides
with readily accessible cyanopyridines as the pyridinyl group
resources through a visible light photoredox-enabled 1,2-HAT of the
alkoxy radical process. The use of both a blue-light-sensitized
Ir(ppy)2(dtbbpy)(PF6) photocatalyst and an organic base was crucial
for accomplishment of the -C(sp3)-H arylation reaction with high
efficiency and excellent selectivity. This method allows
transformation
cyanopyridines
of
to
various
highly
N-(alkyloxy)phthalimides
valuable pyridinyl-containing
and
diarylmethanols, including bioactive motif-based analogues, by a
sequence of the O-N bond cleavage, 1,2-HAT, arylation and C-CN
bond cleavage, and can be expected as a versatile strategic design
to other type of two radical cross coupling via 1,2-HAT.
This journal is © The Royal Society of Chemistry 20xx
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We thank the National Natural Science Foundation of China
(Nos. 21625203, 21871126 and 21901100) for financial support.
Conflict of interest
There are no conflicts to declare.
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DOI: 10.1039/D0CC03619F
Benzylic C‐H Heteroarylation of N‐(Benzyloxy)phthalimides with Cyanopyridines Enabled by
Photoredox 1,2‐Hydrogen Atom Transfer
Long‐Jin Zhong, Hong‐Yu Wang, Xuan‐Hui Ouyang,* Jin‐Heng Li,* and De‐Lie An*
Visible light initiated ‐C(sp3)‐H hetroarylation of N‐(benzyloxy)phthalimides with cyanopyridines via
1,2‐hydrogen atom transfer is depicted.