P/N Heteroleptic Cu(I)-Photosensitizer-Catalyzed Deoxygenative Radical Alkylation of Aromatic Alkynes with Alkyl Aldehydes Using Dipropylamine as a Traceless Linker Agent

Article abstract of DOI:10.1021/acscatal.0c02454

A deoxygenative radical alkylation of aromatic alkynes with alkyl aldehydes for the preparation of allylarenes has been successfully achieved. This transformation is accomplished through the reaction of alkyl aldehydes with alkynes in the presence of dipr

Full text of DOI:10.1021/acscatal.0c02454

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Letter
P/N Heteroleptic Cu(I)-photosensitizer-Catalyzed Deoxygenative
Radical Alkylation of Aromatic Alkynes with Alkyl Aldehydes
Using Dipropylamine as a Traceless Linker Agent
Hanyang Bao, Bingwei Zhou, Shu-Ping Luo, Zheng Xu, Hongwei Jin, and Yunkui Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02454 • Publication Date (Web): 24 Jun 2020
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ACS Catalysis
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P/N Heteroleptic Cu(I)-photosensitizer-Catalyzed
Deoxygenative Radical Alkylation of Aromatic Alkynes
with Alkyl Aldehydes Using Dipropylamine as a Traceless
Linker Agent
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Hanyang Bao,a Bingwei Zhou,a Shu-Ping Luo,a Zheng Xu,b Hongwei Jin,a and Yunkui Liu*a
aState Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, College of Chemical Engineering,
Zhejiang University of Technology, Hangzhou 310014, P. R. China
bKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
University, Hangzhou 311121, P. R. China
KEYWORDS: Cu(I)-photosensitizer, photoredox catalysis, alkyl radical equivalent, alkyl aldehydes, allylarenes
ABSTRACT: A deoxygenative radical alkyaltion of aromatic alkynes with alkyl aldehydes for the preparation of allylarenes has
been successfully achieved. This transformation is accomplished through the reaction of alkyl aldehydes with alkynes in the presence
of dipropylamine and Hantzsch ester catalyzed by a P/N heteroleptic Cu(I)-based photosensitizer under photoredox catalysis
conditions. Preliminary mechanistic studies reveal that this aldehyde-alkyne coupling process comprises a regioselective radical
addition of in situ generated alkyl-substituted -amino radicals to alkynes with subsequent 1,5-proton transfer, C-N bond cleavage
and concomitant isomerization of the resulting allyl radical species. Thus, in net result, dipropylamine serves as a traceless linker
agent for the deoxygenative radical cross-coupling of alkyl aldehydes with alkynes under photoredox catalysis reaction conditions.
Aldehydes are widely used as carbon sources for the
synthesis of olefins due to their advantages of general
inexpensiveness, ready availability, relative stability and high
reactivity. Among various olefination reactions of aldehydes,
the classic Wittig olefination using phosphonium ylide reagents
is the most famous,1 followed by several other related carbonyl
olefination processes, such as the Horner-wadsworth-
Emmons,1b Julia,2 Peterson3 and Tebbe reactions,4 etc.
Currently, several catalytic processes for the synthesis of
olefins from aldehydes have also been developed.5 On the other
hand, allylarenes are an important class of olefin compounds
and their structural motifs are frequently encountered in natural
products and synthetic bioactive molecules.6 In addition,
allylarenes are utilized as versatile synthetic intermediates in a
broad array of organic transformations.7 Thus, great efforts
have been made to develop efficient methods for the synthesis
of allylarenes,8-11 among which include Friedel-Crafts-type
allylation,8 transition-metal-catalyzed reductive cross-coupling
between organohalides,9 cross-coupling of organometallic
reagents with organohalides,10 and allylation reactions via C-H
bond activation strategy,10a,11 etc. Despite much progress, it is
still highly desirable to develop novel and efficient methods to
access allylarenes from commercially available chemicals (e.g.
from aldehydes and alkynes) under mild reaction conditions.
methods for the carbon-carbon or carbon-heteroatom bond
formation.12-15 In this regard, visible-light-driven photocatalytic
process has proven to be an attractive tool for the mild
generation of radical intermediates to initiate organic radical
reactions.14,15 Currently, the predominant visible-light-driven
photocatalysts are metal complexes based on noble- and heavy-
metals such as ruthenium and iridium. Such photocatalysts have
apparent advantages of strong absorption in the visible-light
region, long-lived excited states, and high redox potentials of
their excited states, but they also have several limitations in
term of rare earth reserves, high costs, and high toxicities.14
Hence, in the last several decades, continuous efforts have been
devoted to explore alternative photocatalysts relied on more
abundant, safe, and lower toxic metals such as copper.15-19
Nevertheless, in the early stage of development, only few
reports were documented on copper-based photoactive
complexes and their applications in visible-light-mediated
organic transformations due to the lack of highly efficient
copper-based photocatalysts (especially lack of those with long
lifetime of excited states).16 Later, with the introduction of N/N
homoleptic and P/N heteroleptic Cu(I)-photocatalysts which are
able to exhibit relatively long lifetimes of excited states, the
field of copper-based visible-light photoredox catalysis indeed
falls across the new phase of fast progress.15,16e,17,18 Despite
some progress being made, the development of novel and
efficient visible-light-driven radical reactions involving copper-
based photosensitizers is still highly expected.
The past two decades has witnessed a rapid renaissance of
organic radical chemistry in the development of efficient
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Among various radical reactions, the radical alkylation-
Page 2 of 11
Hantzsch ester 4 (1.2 equiv) in acetonitrile under the catalysis
of [Cu(bcp)(xantphos)]PF6 (PS3, mol %, bcp
1
2
3
4
5
6
7
8
involved transformations under visible-light photoredox
catalysis conditions continue to blossom due to the ubiquity of
5
=
bathocuproine) and the irradiation of a 15 W blue LED under
nitrogen
alkyl
groups
in
biological
and
pharmaceutical
molecules.14c,14f,14k,20 To realize practical radical alkylations,
much attention has thus been paid to discover cost-effective,
safe, and easily available alkylating precursors. So far, a variety
of alkyl sources have been explored to afford alkyl radical
species under visible-light-driven photoredox catalysis
conditions, including alkyl halides,14k,21 carboxylic acids and
Scheme 1. Visible-light-driven radical alkylation of carbon-
carbon multiple bonds under photoredox catalysis
conditions.
(a) Various alkyl precursors for generation of alkyl radical species
Ph
R
X (X = Br, I)
9
derivatives,20d,22
alkyl
alcohol
derivatives,23
R
COOH
their
Ph
N
R
Ph
O
alkyltrifluoroborates,20b,24 organosilicon
compounds,20e,24
10
11
12
13
14
15
16
17
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21
22
23
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60
O
h
O
R
Katritzky salts,25 hypervalent iodine(III) reagents,26 or even
unactivated C-H bonds27 (Scheme 1a). Despite their merits,
most of these alkyl reagents still have one or more limitations
that need to be overcome with respect to tedious preparation,
toxicity, explosiveness, and/or production of undesired
byproducts. Alkyl aldehydes, as low toxic, inexpensive and
commercially available feedstocks, are attractive and promising
precursors for the generation alkyl radical intermediates upon
decarbonylation28 or conversion to Hantzsch esters,29 albeit loss
of a carbon fragment (CO) from the parent aldehydes when
producing alkyl radical species (thus, resulting in carbon
skeleton changed in comparison with the parent aldehyde)
(Scheme 1a). This will be particularly disadvantageous when
aldehydes possessing -chiral centers are used because such
strategies for the generation of alkyl radical species from
aldehydes will certainly degrade ee values of the parent
aldehydes. Hence, the direct use of alkyl aldehydes as
deoxygenative-type radical alkylating equivalents without the
occurrence of decarbonylation and loss of a carbon fragment
(namely, with carbon skeleton unchanged) under visible-light
photoredox catalysis conditions remains a challenging but
critically important task. In this context, several examples
involving umpolung of aldehydes to nucleophilic radical
species under photoredox catalysis conditions have been
reported, and in these transformations all carbons of aldehydes
could be incorporated into the final target products.30,31 In 2018,
Gaunt ʹ s group realized an Ir(III)-photosensitizer-catalyzed
three-component reaction of alkenes, alkyl aldehydes, and
dialkylamines to build architecturally complex and functionally
diverse tertiary alkylamines in a single step (Scheme 1b).32 In
the process of this reaction, alkyl aldehydes provided alkyl
motifs and their carbons were all incorporated into the key
intermediate alkyl-substituted -amino radicals. As part of our
N
O
O
I
Ph
R
R
O
O
O
O
R
R1
R2
O
OH (Cs)
alkyl radical
R
H
R3
O
O
O
R
CHO
conversion
R1
R2
O
various radical
transformations
N
O
O
R3
O
R
BF3K
Si
R'OOC
COOR'
R
R
N
H
carbon skeleton changed!
(b) Visible-light-driven multicomponent reaction of alkyl aldehydes, amines, and olefins by Ir-photocatalyst
R
R1
O
C
R1
R2
[Ir], Hantzsch ester
visible light
C
N
N
H
+
+
R3
R2
H
R
R3
Deoxygenation and No occurrence of C-N bond cleavage
(c) Visible-light-driven deoxygenative-type radical alkylation of alkynes by alkyl aldehydes by Cu(I)-photocatalyst
(this work)
H
-
Cu(P^P)(N^N)PF6
O
C
Hantzsch ester
R
R1
N
H
R1
+
+
C
1,4-dioxane/H2O
visible light
Et
H
R
deoxygenative-type:
carbon skeleton unchanged!
H
N
C
1,5-HAT
R1
R
intermediate
copper(I)-based photosensitizer
occurrence of C-N bond cleavage
unexpected migration of C=C bond
dipropylamine as a traceless linker agent
alkyl aldehydes as alkyl radical equivalents with carbon skeleton unchanged
atmosphere at 28 °C for 12 hours, the multicomponent adduct
6aab was indeed obtained in 42% yield, albeit in a poor E/Z
selectivity (E/Z = 1:4) (entry 3, Table S1 in SI). During the
above experiment, an unexpected byproduct allylarene 5aa was
also obtained in 15% yield with an E/Z selectivity of 10:1 (entry
3, Table S1 in SI). These findings sparked our particular interest
in the optimization of reaction conditions for the practical
preparation of 5aa since this will offer the potential for a
uniquely efficient synthesis of allylarenes from easily available
starting material alkyl aldehydes and alkynes. Through
ongoing
transformations,33 herein, we would like to report a P/N
heteroleptic copper(I)-photosensitizer-catalyzed
interest
in
copper-catalyzed
efficient
systematically investigating
a wide range of reaction
multicomponent reaction of alkyl aldehydes, alkynes,
dipropylamine, and Hantzsch ester, wherein, in net result, a
deoxygenative-type radical alkylation of alkynes with alkyl
aldehydes to deliver allylarenes has been successfully achieved,
and in the whole process dipropylamine acts as a traceless linker
agent for the radical coupling of aldehydes and alkynes
(Scheme 1c).
parameters (photocatalysts, solvents, amine additives, light
sources, reaction time, etc.) (Table S1-S9, in SI), an optimal
reaction condition was finally established under which 5aa
could be obtained in an acceptable yield (GC yield: 78%;
isolated yield: 72%) when the reaction of 1a (0.2 mmol), 2a (3.0
equiv), dipropylamine 3c (3.0 equiv), and Hantzsch ester 4 (1.2
equiv) was conducted with 7.5 mol
%
PS5
Initially, we envisioned that the multicomponent reaction of
([Cu(N^N)(xantphos)]PF6, N^N 2,9-diisopropyl-4,7-
=
4-phenylphenylacetylene (1a), butyraldehyde (2a), amines (3),
diphenyl-1,10-phenanthroline) in dioxane/H2O mixture (20/1
(V/V), 4.2 mL) under N2 atmosphere using 30 W blue LED light
irradiation at 32 °C for 12 hours (entry 1, Table 1). It was found
that P/N heteroleptic Cu(I)-photosensitizers uniquely exhibited
relatively good catalytic activities for the formation of 5aa,
among which PS5 exhibited the highest efficiency (entries 1-6,
Table 1); whereas other photosensitizers such as Ru(II)-, Ir(III)-,
and
Hantzsch
ester
4
(diethyl
2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate) may deliver allyl amine
derivatives 6 under proper photoredox catalysis conditions
(Table 1; also see Table S1-S9 in the Supporting Information
(SI)).32,34 When 1a was treated with butyraldehyde (2a, 5.0
equiv) in the presence of diethylamine (3b, 5.0 equiv) and
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ACS Catalysis
as well as organic photocatalysts showed inert or lower catalytic increasing the steric hindrance of the groups located at the 4,7-
1
2
3
4
5
6
7
8
activities (entries 7-11, Table 1). We presumed that in the
present tandem transformation (see the proposed mechanism in
Scheme 4, vide infra) the exquisite cooperation of oxidative
species and reductive species derived from photocatalysts is
and 2,9-positions of phenanthroline ligand in the P/N
heteroleptic Cu(I)-photosensitizer is beneficial to the reaction
outcome (entries 1, 2 vs 3; 6 vs 1, Table 1). In 2017, Luo and
co-workers35 reported similar positive steric effects of the N^N
ligands on the H2 production from water using P/N heteroleptic
Cu(I)-photosensitizers. Screening experiments of solvents and
amine additives indicated that a combined 1,4-dioxane/H2O
mixture (20/1 (V/V)) is the most suitable medium and
dipropylamine (3c) is the best choice of linker agent (entries 12-
15 vs 1, Table 1, also see SI). Control experiments revealed that
light, P/N Cu(I)-photocatalyst, and amine additive are
indispensable for the formation of 5aa (entries 16-18, Table 1).
When the reaction was conducted without the protection of N2,
the yield of 5aa was sharply reduced to 16% (entry 19, Table
1). The E/Z selectivities of 5aa were almost around the ratio of
10:1, not significantly influenced by the reaction parameters. It
is interesting that without Hantzsch ester 4, the reaction could
still afford 5aa in 50% yield (entry 20, Table 1), implying that
Hantzsch ester 4 is not the indispensable electronic sacrificial
agent. However, the reaction would give lower or negligible
yield of 5aa when the reaction was carried out under the
standard conditions except in the absence of Hantzsch ester 4
using 1,4-dioxane or acetonitrile as the medium (entries 21, 22,
Table 1), suggesting that water might also play some certain
role in the reaction.
Table 1. Optimization of reaction conditions.a
photocatalyst (7.5 mol %)
Hantzsch ester (4, 1.2 equiv)
dipropylamine (3c, 3.0 equiv)
1,4-dioxane/H2O, 32 C
30 W blue LED, N2, 12 h
H
N
O
C
C
C
+
+
H
Ph
Ph
Ph
1a
2a: 3.0 equiv
5aa (E/Z)
6aac (E/Z)
9
N
C
N
C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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N
H
N
H
N
Ph
H
3g
6aab (E/Z)
6aag (E/Z)
3c
3b
Ph
R2
CF3
CF3
N
R1
F
F
PF6
Ph2P
PF6
PF6
N
N
N
N
Cu
O
N
N
F
F
Ir
Ir
Ph2P
N
R1
R2
N
N
CF3
CF3
PS1: R1 = H, R2 = H
PS2: R1 = Ph, R2 = H
PS3: R1 = Ph, R2 = Me
PS4: R1 = H, R2 = i-Pr
PS5: R1 = Ph, R2 = i-Pr
PS6
PS7
Entry
photocatalyst
Yield [%]b
5aa (E/Z)b 6 (E/Z)b
1
PS5
PS1
PS2
PS3
78 (10/1)
0
15 (6aac, 1/1)
2
0
With the optimized reaction conditions in hand, the substrate
scope of alkynes 1 was first examined as shown in Table 2. Both
electron-withdrawing and electron-donating substituents on the
benzene ring of the aromatic terminal alkynes 1 were
compatible with the reaction conditions and the desired
allylarenes 5 were obtained in moderate to good yields with
modest stereoselectivities (5aa-5pa, Table 2). Generally,
aromatic terminal alkynes 1 bearing electron-withdrawing or
neutral groups (e.g. Cl, Br, CF3, CN, COOMe, SO2Me and
phenyl; 1a-1h, Table 2) furnished the desired products in higher
yields than those bearing
3
0
0
4
55 (10/1)
52 (10/1)
13 (10/1)
trace
10
16 (1/1.5)
18 (1/1.6)
7
-
5
[Cu(dpePhos)(bcp)]PF6
PS4
6
7
Ru(bpy)3Cl2•6H2O
fac-Ir(ppy)3
PS6
trace
27 (1/3)
5
8
9
5
10
11
PS7
trace
trace
trace
trace
Rose bengal
deviation from the conditions in entry 1:
Table 2. Substrate scope of alkynes.a-c
12
1,4-dioxane
dioxane/H2O
instead
of
1,4- 60 (10/1)
11 (1/1.7)
PS5 (7.5 mol %)
4
Hantzsch ester ( , 1.2 equiv)
13
MeCN instead of 1,4-dioxane/H2O
34 (10/1)
22 (1/2)
O
3c
dipropylamine ( , 3.0 equiv)
+
R
R
14c
diethylamine
instead
of 40 (10/1)
25 (6aab, 1/2)
H
1,4-dioxane/H2O = 4 mL/0.2 mL
30 W blue LED, N2
dipropylamine
1
2a
5
15d
16
17
18
19
20
21
22
piperidine instead of dipropylamine
in the dark condition
without photosensitizer
without amine
42 (10/1)
36 (6aag, 1/1.2)
0
0
R
R
Br
0
0
5na
: R = Br, 67%, E/Z = 10/1
5aa
5ma
: R = Ph, 72%, E/Z = 10/1
: 67%, E/Z = 12/1
5oa
: R = Ph, 60%, E/Z = 10/1
5ba
: R = H, 61%, E/Z = 10/1
0
0
CN
electron-withdrawing group:
F
in air
16 (10/1)
50 (10/1)
10 (10/1)
0
9
5ca
: R = Cl, 63%, E/Z= 13/1
5da
: R = Br, 74%, E/Z = 11/1
: R = CF3, 63%, E/Z = 12/1
: R = CN, 68%, E/Z = 10/1
without Hantzsch ester 4
without Hantzsch ester 4 and water
12 (1/1.3)
5ea
5fa
5pa
: 65%, E/Z = 13/1
5qa
: 61%, E/Z = 10/1
4
0
5ga
: R = COOMe, 58%, E/Z = 10/1
: R = SO2Me, 50%, E/Z = 10/1
5ha
without Hantzsch ester 4 and using
MeCN instead of 1,4-dioxane/H2O
electron-donating group:
5ia
5ja
: R = Me, 56%, E/Z = 10/1
N
S
d
: R = OMe, 49% , E/Z = 7/1
aStandard conditions: 1a (0.2 mmol), 2a (0.6 mmol),
dipropylamine 3c (0.6 mmol), PS5 (7.5 mol %), Hantzsch ester 4
(0.24 mmol), 1,4-dioxane/H2O = 4 mL/0.2 mL, irradiation with 30
W blue LED under nitrogen atmosphere at 32 °C for 12 h. bYields
and E/Z ratios were determined by GC analysis using n-dodecane
as the internal standard. cDiethylamine: 3b. dPiperidine: 3g.
d
5ra
: 56%, E/Z = 12/1
5ka
5sa
: 57%, E/Z = 9/1
: R = OBz, 55% , E/Z = 11/1
: R = NHBz, 54%, E/Z = 10/1
5la
Boc
NH
S
MeOOC
S
5ta
: 58%, E/Z = 10/1
5ua
5va
: 43%, E/Z = 11/1
: 48%, E/Z = 9/1
( )7
e
5ya
5za
R
4
: R = 4-CN, 76% , E/Z = 9/1
2
very crucial for the formation of 5aa. PS5 might generate the
most effective oxidative and reductive species which can
guarantee the fulfillment of each tandem step. Note that
e
: R = 2-CN, 78% , E/Z = 7/1
5wa
: 0%
5xa
: 0%
3
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Page 4 of 11
aReaction conditions:
1 (0.2 mmol), 2a (0.6 mmol),
-phenylnitrone) were added into the reaction mixture (Scheme
1
2
3
4
5
6
7
8
dipropylamine 3c (0.6 mmol), PS5 (7.5 mol %), Hantzsch ester 4
(0.24 mmol), 1,4-dioxane/H2O = 4 mL/0.2 mL, irradiated with 30
W blue LED under nitrogen atmosphere at 32 °C for 12 h unless
2a). These results support radical processes under photoredox
catalysis conditions.34,36 Next, when aldehyde 2i was subjected
to the standard reaction conditions, we could detect the desired
allylarene 5ai (40%) along with a small amount of allylarene 7
(< 10%) (Scheme 2b). This result implied that propanal might
be in situ formed in the reaction process followed by the
subsequent conversion of propanal to 7. In addition, when
styrene derivative 8 was subjected to the standard reaction
conditions,
b
c
otherwise noted. Isolated yields. E/Z ratios were determined by
d
GC analysis. 5.0 equivalents of aldehyde and 5.0 equivalents of
e
dipropylamine were used. PS3 (7.5 mol %) was used instead of
PS5.
electron-donating groups (e.g. methyl, methoxy, OBz, and
NHBz; 1i-1l, Table 2). It was found that the steric hindrance of
substituents on the benzene ring of 1 had no significant impact
on the reaction outcome in term of yields (1a vs 1o, 1d vs 1n,
Table 2). In addition, terminal alkynes bearing biphenyl (1a,
1o), naphthalene (1q), heterocycle such as thiophene (1r),
pyridine (1s) or benzothiophene (1t, 1u) motifs were also
compatible with the optimal reaction conditions, and the desired
products could be obtained in moderate to good yields (5aa, 5oa,
5qa, 5ra-5ua, Table 2). An alkyne derived from phenylalanine
was also tolerable under the current reaction conditions,
affording the desired allylarene in synthetically acceptable yield
without erosion ee value of its chiral moiety (5va, 43%, Table
2). Furthermore, aliphatic terminal alkynes (1w and 1x) were
investigated for the reaction. Unfortunately, they failed to give
the desired products (5w, 5x, Table 2). To our delight, aromatic
internal alkynes (1ya, 1za, Table 2) were also suitable
substrates for the present aldehyde-alkyne coupling, and in
these cases, PS3 is the more suitable photosensitizer for getting
satisfactory yields of 5 than PS5. It is worthy noting that in the
cases of internal alkynes as substrates, aldehyde fragments
regioselectively attached to the more electron-deficient sp-
carbons of alkynes, which is consistent with the fact that
electron-deficient carbons are more susceptible to be attacked
by the nucleophilic -amino radicals.32,34 The structure of
regioisomer 5ya was ambiguously determined by comparing
the authentically synthesized sample of (E)-5ya (see SI).
Generally, the E/Z ratios of most allylarenes were around 10:1~
13:1 except in the cases of 5ja and 5za having a lower E/Z
selectivity with a ratio of 7:1.
9
Table 3. Substrate scope of aldehydes.a-c
10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PS5 (7.5 mol %)
4
Hantzsch ester ( , 1.2 equiv)
O
R
3c
dipropylamine ( , 3.0 equiv)
+
H
R
1,4-dioxane/H2O = 4 mL/0.2 mL
30 W blue LED, N2
Ph
Ph
5
1a
2
Cl
Ph
Ph
Ph
Ph
5ab
5ad
: 46%, E/Z = 10/1
5ac
: 57%, E/Z = 11/1
: 62%, E/Z = 10/1
CN
Ph
Ph
Ph
5ae
d
: 55% , 53%[f], E/Z = 13/1
e
: 40%d,e, E/Z = 10/1
: 45% , E/Z = 10/1
5ag
5af
Boc
N
Ph
Ph
5ai
e
d
d
5aj
: 60% , E/Z = 20/1
: 40% , E/Z = 20/1
5ah
: 57% , E/Z = 16/1
Ph
Ph
5ak
: 0%
5al
: 0%
aReaction condition: 1a (0.2 mmol),
2
(0.6 mmol),
dipropylamine 3c (0.6 mmol), PS5 (7.5 mol % based on 1a),
Hantzsch ester 4 (0.24 mmol), 1,4-dioxane/H2O = 4 mL/0.2 mL,
irradiated at 30 W blue LED under nitrogen atmosphere at 32 °C
b
c
for 12 h unless otherwise noted. Isolated yields. E/Z ratios were
determined by GC analysis. d5.0 equivalents of aldehydes and 5.0
equivalents of dipropylamine were used. eReaction time was
prolonged to 16 h. f2.0 mmol scale was carried out.
Next, we set out to investigate the scope of aldehydes 2 and
the results were shown in Table 3. A range of linear aldehydes
or functional group-tethered linear aldehydes (e.g. Cl-, CN- and
phenyl-tethered linear aldehydes) were well compatible with
the optimal reaction conditions and the desired allylarenes were
synthesized in moderate yields (40-62%, 5ab-5af, Table 3).
Citronellal is also a viable substrate under the current reaction
conditions, and the desired allylarene 5ag was obtained in 55%
yield with an E/Z ratio of 13/1 (5ag, Table 3). In addition, a 2
mmol-scale (2.0 mmol 1a and 10.0 mmol 2g were used) for the
synthesis of 5ag was also tried, and 5ag was obtained in 53%
yield (also see SI). Furthermore, -branched aldehydes also
worked well to deliver the corresponding allylarenes in
moderate yields under the standard reaction conditions (5ah-
5aj, Table 3). Note that enhanced E-selectivities of the target
allylarenes were observed when -branched aldehydes were
used (5ah-5aj, E/Z = 16/1 ~ 20/1, Table 3). Unfortunately,
benzaldehyde and acetone failed to afford the desired
allylarenes, and the starting materials were almost recovered
(5ak, 5al, Table 3).
the multicomponent adduct 9 was obtained in 82% yield
without the occurrence of C-N bond cleavage (Scheme 2c).
Furthermore, we also synthesized (E)-6aac and subjected this
compound to the optimal reaction conditions. It was found that
15% yield of 5aa was obtained along with some recovered 6aac
(81% yield) whose configuration was turned into an E/Z
mixture under the photoredox catalysis conditions (Scheme
2d).37 These results do not sufficiently support that 6aac might
be the likely key intermediate for the formation of 5aa due to
the low conversion of 6aac to 5aa under the standard reaction
conditions.
Scheme 2. Preliminary mechanistic experiments.
To gain insight into the mechanism of the reaction, a series
of mechanistic experiments were conducted (Scheme 2). First,
radical-scavenging experiments indicated that the reaction of 1a,
2a, 3c, and Hantzsch ester 4 was almost suppressed when 4.0
equivalents of TEMPO or 2.0 equivalents of PBN (N-tert-butyl-
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ACS Catalysis
incorporated 5aa-d4 which comprises 86% D-enrichment of
(a) Radical scavenging experiments
O
std condition
radical scavenger
1
2
3
4
one benzyl-hydrogen at the 1-position, 92% D-enrichment of
the vinyl-hydrogen at the 2-position, and total 88% D-
enrichment of the methylene-hydrogens at the 4-position was
obtained in 64% yield (eq.(1) in Scheme 3). Next, If the
multicomponent reaction was conducted under the standard
conditions except using Hantzsch ester-d3, no D/H exchange
occurred in 5aa (54% yield, eq.(2) in Scheme 3). In addition,
when using Hantzsch ester-d3 and dehydrated 1,4-dioxane
under otherwise the identical as the optimal conditions, the
resulting 5aa-d4 (26% yield) comprises 12% D-enrichment of
one benzyl-hydrogen at the 1-position, 13% D-enrichment of
the vinyl-hydrogen at the 2-position, and total 6.5% D-
enrichment of the methylene-hydrogens at the 4-position (eq.(3),
Scheme 3). Furthermore, when both Hantzsch ester-d3 and D2O
were used under otherwise the same as the optimal conditions,
high degrees of D-incorporated rate for one of the benzyl-
hydrogens at the 1-position, the vinyl-hydrogen at the 2-
position, and the methylene-hydrogens at the 4-position of 5aa-
d4 were achieved (≥92.5%, eq.(4), Scheme 3). In contrast, the
reaction gave none of D-incorporated isotopic isomers of 5aa at
any position of carbon 1-4 when the multicomponent reaction
of 1a, 2a, 3c, and Hantzsch ester 4 was carried out under the
standard reaction conditions except in a 1,4-dioxane-d8
(99.9%-D enrichment)/H2O medium (eq.(5), Scheme 3). On the
basis of the results demonstrated in eq.(1), eq.(3), eq.(4), and
eq.(5), we speculated that one of the benzyl protons in 5aa was
originated from water and/or dipropylamine rather than 1,4-
dioxane. When diethylamine-d10 (99%-D enrichment) was
used as the linker agent, an 81% D-incorporated rate for one of
the benzyl-hydrogens at the 1-position in the resulting 5aa-d1
was achieved (eq.(6), Scheme 3), suggesting 1,5-HAT
(hydrogen atom transfer) process should occur.32 Finally, an 89%
D-incorporated rate for the terminal alkynyl-hydrogen in 1a
was detected when 1a was treated with dipropylamine (3 equiv)
in dioxane/D2O at room temperature for 12 h (eq.(7) in Scheme
3, also see SI), this result could rationally explain the deuterium
source at the C2-position in 5aa.
N
H
+
+
H
Ph
Ph
1a
2a
3c
5aa
5aa
PBN
TEMPO
Yield of 5aa
26%
Yield of
0%
2.0 equivalents
4.0 equivalents
2.0 equivalents
trace
5
6
7
2i
(b) Formation of byproduct when was used as the alkylation reagent
from propanal
7
O
std conditions
8
+
1a
+
+ 3c
H
conversion: 81%
Ph
Ph
9
5ai
: 40%
2i
7
: < 10%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
(c) Use of to trap alkyl-substituted -amino radicals
N
std condition
5aa
: 0%
+
3c
+
2a
+
conversion: 100%
Ph
Ph
8
9
: 82%
6aac 5aa
to
(d) Conversion of preparative
N
under the standard conditions
N
std conditions
5aa
: 15%
+
2a
3c
+
+
Ph
Ph
6aac:
mixture of E/Z isomers: 81%
6aac:
(E)-isomer
Scheme 3. Deuterium-labeling experiments.
86%
D
3
H
std conditions
2
4
(1)
1a
+
2a
+
3c
1
except in
1,4-dioxane/D2O
(99.9% D-enrichment)
H(D)
D
H(D)
Ph
total deuteration
rate: 88%
92%
a
5aa-d4
(yield: 64%)
O
O
D
D
EtO
OEt
N
D
H
H
Hantzsch ester-d3
(95.0% D-enrichment)
1a
1a
+
+
2a
2a
+
+
3c
3c
(2)
H
H
H
PS5 (7.5 mol %)
1,4-dioxane/H2O
30 W blue LED
Ph
a
5aa
(no D-incoporated; yield: 54%)
12%
D
3
H
PS5 (7.5 mol %)
Hantzsch ester-d3
2
4
1
H(D)
(3)
total deuteration
D
H(D)
1,4-dioxane
30 W blue LED
Ph
13%
a
rate: 6.5%
5aa-d4
(yield: 26%)
On the basis of the above mentioned results and the previous
literature,18,32,34,38-41 a possible mechanism for the production of
5aa under the Cu(I)-photoredox catalysis conditions is
proposed in Scheme 4. Upon irradiation with blue light, the
Cu(I)-based PS5 was excited to its excited state Cu(I)*
(E1/2[CuI*/Cu0] = 1.04 V versus SCE (saturated calomel
electrode) in MeCN, see SI), which was quenched by
dipropylamine 3c (Ep/2[(n-Pr)2NH•+/(n-Pr)2NH] = 0.89 V vs
SCE in MeCN, see SI; literature value38: Ep[(n-Pr)2NH• +/(n-
Pr)2NH] = 0.90 V vs SCE) and/or Hantzsch ester 4 (E[(HE•
+/HE] = 0.79 V vs SCE; E[(HE•+)/HE*] = -2.28 V vs SCE39)
through an SET process,18,32 leading to the generation of
dipropylamine radical cation species 3cʹ and/or Hantzsch ester
radical cation species 4ʹ, and the reactive Cu(0) complex. The
above quenching processes were further confirmed by Stern-
Volmer studies (see Figure S13 & S14 in SI). Then the reactive
Cu(0) complex (E1/2(CuI/Cu0) = -1.66 V vs SCE, see SI)
underwent SET reduction of in-situ generated alkyliminium salt
10 (from butyraldehyde 2a and dipropylamine 3c in the
presence of H+) to give alkyl-substituted-amino radical
species 12.32 Addition of 12 to alkyne 1a leading to the
formation of radical species 13, which easily underwent 1,5-
HAT to deliver radical intermediate 14.32,40 14 underwent a -
fission involving the homolytic cleavage of its N-C bond
leading to allyl radical species 15 and imine 16 (Path a).41
92%
H
D
3
PS5 (7.5 mol %)
Hantzsch ester-d3
2
4
1a
1a
+
+
2a
2a
+
+
3c
3c
1
D
97%
H(D)
(4)
1,4-dioxane/D2O
30 W blue LED
H(D)
Ph
total deuteration
rate: 92.5%
a
5aa-d4
(yield: 39%)
H
3
H
2
4
std conditions
except in
1,4-dioxane-d8 (99.9%
(5)
1
H
H
H
Ph
5aa
D-enrichment)/H2O
a
(no D-incoporated, yield: 70%)
81%
D
H
std condition
1a
+
2a
(6)
(7)
H
except using diethylamine-d10
(99% D-enrichment)
instead of dipropylamine
H
H
Ph
a
5aa-d1
(yield: 25%)
D
dipropylamine (3 equiv)
1a
Ph
89%
1,4-dioxane/D2O
r. t., 12 h
a
1a-d1
(yield: 95%)
aIsolated yield; rate of deuterium-incorporation was measured by
1H NMR.
To further elucidate the process of the C-N bond cleavage
and the migration of the C=C bond in 6aac, a series of
deuterium-labeling experiments were carried out (Scheme 3).
First, when the multicomponent reaction of 1a, 2a, 3c, and
Hantzsch ester 4 was conducted under the standard reaction
conditions except in a 1,4-dioxane/D2O medium, deuterium-
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19 from water and/or 3cʹ to delivered 5aa might be unlikely
Alternatively, the -amino radical species 14 could be oxidized
by the excited Cu(I)* (E1/2[CuI*/Cu0] = 1.04 V vs SCE in MeCN)
complex to yield iminium salt 17,32 which was further reduced
by the active Cu(0) complex to access allyl species 15 (Eo
(17/15 = -1.06 V vs SCE in MeCN calculated by DFT and
E1/2(CuI/Cu0) = -1.66 V vs SCE in MeCN as measured, see SI)
and imine 16.25a 15 could be isomerized to 18 which abstracted
a hydrogen from dipropylamine radical cation species 3cʹ
and/or water to deliver the final product 5aa. An alternative
pathway involving the reduction of 18 (Eo (18/19 = -1.80 V vs
SCE in MeCN calculated by DFT, see SI) by Cu(0) via SET
process followed by a protonation of the resulting anion species
Scheme 4. Proposed mechanism for the formation of 5aa.
1
2
3
4
5
6
7
8
according to DFT calculations, but can not be completely
excluded.32 By the way, the hydrolysis of imine 16 may produce
propanal, which could also serve as an alkylating source to
deliver byproduct 7 under the standard reaction conditions (also
see Scheme 2b, vide supra).
On the basis of the above proposed mechanism, a rational
explanation for the deuterium-incorporation at the positions of
carbon 1-4 in 5aa (also see Scheme 3, vide supra) is illustrated
in Scheme 5.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pr
N
11
Et
O
Et
Pr
+ H+
- H+
H
H
N
H2O
1a
Pr
Pr
Et
2a
N
N
Pr
Pr
+
Radical addition
Et
PyH+
Pr
H+
10
Cu(0)
13
12
Ph
Et
N
SET
H
3c
3c'
and/or
Cu(I)
1,5-HAT
Et
Cu(I)*
Pr
HE
4'
(n-Pr)2NH and/or
N
SET
3c'
SET
Pr
Path b
Cu(0)
14
Et
N
Ph
HE
(n-Pr)2NH and/or
Pr
Pr
Cu(I)*
3c
4
Path a
1a 3c HE
,
,
Pr
hydrolysis
homolytic
C-N bond
cleavage
Et
N
Et
O
7
byproduct
16
Ph
17
Cu(0)
SET
3c'
H2O and/or
HAT
Pr
Cu(0)
Pr
5aa
Ph
Ph
18
15
16
SET
Cu(I) +
E1/2(CuI/Cu0) = -1.66 V vs SCE in MeCN
-
3c'
H2O and/or
Pr
o
17 15
Theoretical E (
/
) = -1.06 V vs SCE in MeCN
o
Ph
18 19
Theoretical E (
/
) = -1.79 V vs SCE in MeCN
19
H
H
H
H
EtOOC
PyH+:
4''
COOEt
EtOOC
COOEt
SET
EtOOC
COOEt
- H
HE
4
HE
:
4'
:
+
Cu(I)*
N
N
N
H
H
H
SET
N
H
N
Cu(I)*
H
3c'
3c
Scheme 5. Rational explanation for deuterium-labeling
experiments
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ACS Catalysis
R
(1) (a) Takeda, T. Mordern Carbonyl Olefination: Methods and
HAT
1
R'
R'
D
1,5-HAT
Applications. John wiley & Sons: 2006; pp 1-365. (b) Maryanoff, B.
E.; Reitz, A. B. The Wittig olefination reaction and modifications
involving phosphoryl-stabilized carbanions. Stereochemistry,
mechanism, and selected synthetic aspects. Chem. Rev. 1989, 89, 863-
927.
D
N
1
2
3
1
Pr
18
13
Ph
Ph
using D2O
using deuterated amines
4
5
6
7
8
9
(2) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. A direct synthesis
of olefins by reaction of carbonyl compounds with lithio derivatives of
2-[alkyl- or (2ʹ-alkenyl)- or benzyl-sulfonyl]-benzothiazoles.
Tetrahedron Lett. 1991, 32, 1175-1178.
(3) Peterson, D. J. Carbonyl olefination reaction using silyl-
substituted organometallic compounds. J. Org. Chem. 1968, 33, 780-
784.
(4) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. Olefin Homologation
with Titanium Methylene Compounds. J. Am. Chem. Soc. 1978, 100,
3611-3613.
1-position possible approaches
D
Pr
Et
N
D+
3
11
H
2
4
1
using D2O
H(D)
H(D)
+ H+(D+)
4
4-position
possible
D
- H+ (D+)
or HE-d3
Ph
approaches
Pr
N
5aa
-dn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
possible
approaches
2-position
H(D)
Et
10
2
base
using D2O
Ph
H
Ph
D
(5) For selected examples, see: (a) Becker, M. R.; Watson, R. B.;
Schindler, C. S. Beyond olefins: new metathesis directions for
synthesis. Chem. Soc. Rev. 2018, 47, 7867-7881. (b) Ainembabazi, D.;
Reid, C.; Chen, A.; An, N.; Kostal, J.; Voutchkova-Kostal, A.
Decarbonylative Olefination of Aldehydes to Alkenes. J. Am. Chem.
Soc. 2020, 142, 696-699. (c) Wang, S.; Lokesh, N.; Hioe, J.; Gschwind,
R. M.; König, B. Photoinitated carbonyl-metathesis: deoxygenative
reductive olefination of aromatic aldehydes via photoredox catalysis.
Chem. Sci. 2019, 10, 4580-4587. (d) Rivero-crespo, M. A.; Tejeda-
Serrano, M.; Pérez-Sánchez, H.; Cerón-Carrasco, J. P.; Leyva-Pérez, A.
Intermolecular Carbonyl-olefin Metathesis with Vinyl Ethers
Catalyzed by Homogeneous and Solid Acids in Flow. Angew. Chem.,
Int. Ed. 2020, 59, 3846-3849; Angew. Chem. 2020, 132, 3874-3877. (e)
Qian, B.; Zhang, G.; Ding, Y.; Huang, H. Catalytic cross deoxygenative
and dehydrogenative coupling of aldehydes and alkenes: a redox
neutral process to produce skipped dienes. Chem. Commun. 2013, 49,
9839-9841. (f) Rhee, J. U.; Krische, M. J. Alkynes as Synthetic
Equivalents to Stabilized Wittig Reagents: Intra- and Intermolecular
Carbonyl Olefinations Catalyzed by Ag(I), BF3 and HBF4. Org. Lett.
2005, 7, 2493-2495.
(6) For selected examples, see: (a) Sun, S.-G.; Chen, R.-Y.; Yu, D.-
Q. Structure of two new benzofuran derivatives from the bark of
mulberry tree (Morus macroura Miq.). J. Asian Nat. Prod. Res. 2001,
3, 253-259. (b) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. DYKAT of
Baylis-Hillman Adducts: Concise Total Synthesis of Furaquinocin E.
J. Am. Chem. Soc. 2002, 124, 11616-11617. (c) Du, J.; He, Z.-D.; Jiang,
R.-W.; Ye, W.-C.; Xu, H.-X.; But, P. P.-H. Antiviral flavonoids from
the root bark of Morus alba L. Phytochemistry 2003, 62, 1235-1238.
(d) Sohn, H.-Y.; Son, K. H.; Kwon, C.-S.; Kwon, G.-S.; Kang, S. S.
Antomicrobial and cytotoxic activity of 18 prenylated flavonoids
isolated from medicinal plants: Morus alba L., Morus mongolica
Schneider, Broussnetia papyrifera (L.) Vent, Sophora flavescens Ait
and Echinosophora koreensis Nakai. Phytomedicine 2004, 11, 666-672.
(e) Ni, G.; Zhang, Q.-J.; Zheng, Z.-F.; Chen, R.-Y.; Yu, D.-Q. 2-
Arylbenzofuran Derivatives from Morus cathayana. J. Nat. Prod. 2009,
72, 966-968.
(7) (a) Tahara, S.; Ibrahim, R. K. Prenylated isoflavonoids-an update.
Phytochemistry 1995, 38, 1073-1094. (b) Knölker, H.-J.; Reddy, K. R.
Isolation and Synthesis of Biologically Active Carbozole Alkaloids.
Chem. Rev. 2002, 102, 4303-4428.
(8) For Selected examples, see: (a) Niggemann, M.; Meel, M. J.
Calcium-catalyzed Friedel-Crafts alkylation at room temperature.
Angew. Chem. Int. Ed. 2010, 49, 3684-3687; Angew. Chem. 2010, 122,
3767-3771. (b) Rueping, M.; Nachtsheim, B. J. A review of new
developments in Friedel-Crafts alkylation. From green chemistry to
asymmetric catlaysis. Beilstein J. Org. Chem. 2010, 6, 6.
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R.; Weix, D. J. Selective Cross-Coupling of Organic Halides with
Allylic Acetates. J. Org. Chem. 2012, 77, 9989-10000. (b) Wang, S.;
Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl
Halides with Secondary Alkyl Bromides and Allylic Acetate. Org. Lett.
2012, 14, 3352-3355. (c) Cui, X.; Wang, S.; Zhang, Y.; Deng, W.;
Qian, Q.; Gong, H. Nickel-catalyzed reductive allylation of aryl
bromides with allylic acetates. Org. Biomol. Chem. 2013, 11, 3094-
3097.
5aa
C2-position of
In summary, we have successfully realized the
deoxygenative-type radical alkylation of alkynes with alkyl
aldehydes through using dipropylamine as a traceless linker
agent under photoredox catalysis conditions. A variety of
allylarenes were synthesized in moderate to good yields with
broad functional group tolerance. The present protocol for the
synthesis of allylarenes features 1) the use of easily available
alkyl aldehydes and aromatic alkynes as the starting materials,
2) the use of Cu(I)-based photocatalyst, and 3) under mild
reaction conditions. It is more important that the present studies
open a unique way to utilize commercially available alkyl
aldehydes as deoxygenative-type alkyl radical equivalents
without the occurrence of decarbonylation.31 Further
elucidation of the mechanism and application of our strategy in
the exploration of new deoxygenative-type radical alkylating
reactions using alkyl aldehydes as the alkyl radical equivalents
under photoredox catalysis conditions are currently undertaken
in our laboratory.
AUTHOR INFORMATION
Corresponding Author
* E-mail: ykuiliu@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS
Publications website at http://pubs.acs.org.
The detailed data for the optimization of reaction parameters,
experimental procedure and characterization of new compounds
(1H NMR and 13C NMR spectra), and experimental procedure and
related charts for mechanistic studies (PDF).
ACKNOWLEDGMENT
Financial support by the Natural Science Foundation of China (No.
21772176 and 21372201) and Zhejiang Province (No.
LY20B020013) are greatly appreciated.
REFERENCES
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(10) For selected examples, see: (a) Mishra, N. K.; Sharma, S.; Park,
Chemistry Enabled by Visible Light-Induced Electron Transfer. Acc.
J.; Han, S.; Kim, I. S. Recent Advances in Catalytic C(sp2)-H Allylation
Reactions. ACS Catal. 2017, 7, 2821-2847, and references cited therein.
(b) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo, W.-H.; Zhang, X. Highly
Chem. Res. 2016, 49, 2295-2306. (m) Schultz, D. M.; Yoon, T. P. Solar
Synthesis: prospect in visible light photocatalysis. Science 2014, 343,
1239176.
1
2
3
4
5
6
7
8
9
Selective
gem-Difluoroborons
of
Organoborons
with
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ACS Catalysis
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H
C
-
[Cu(P^P)(N^N)]PF6
O
C
Hantzsch ester
R
R1
N
H
R1
+
+
1,4-dioxane/H2O
visible light
H
R
E/Z
deoxygenative-type
alkyl radical equivalent
Et
H
N
C
1,5-HAT
R1
R
intermediate
alkyl aldehydes as alkyl radical equivalents without the occurrence of decarbonylation
copper(I)-based photosensitizer
occurrence of C-N bond cleavage
dipropylamine as a traceless linker agent
unexpected migration of C=C bond
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