Palladium-Catalyzed Cascade Saegusa–Heck Reaction: Synthesis of β,β-Diarylacroleins from Arylpropanals and Aryl Iodides

Article abstract of DOI:10.1002/ejoc.201701025

An efficient and convenient Pd-catalyzed Saegusa–Heck cascade protocol was developed, and its potential use in the synthesis of symmetrical and unsymmetrical β,β-diarylacroleins in moderate to high yields was investigated.

Full text of DOI:10.1002/ejoc.201701025

A Journal of
Accepted Article
Title: Pd-Catalyzed Cascade Saegusa-Heck Reaction: Synthesis of
β,β-Diarylacroleins from Aryl Propanals and Aryl Iodides
Authors: Li Xiao, Yilin Zheng, Qiong Xie, and Liming Shao
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10.1002/ejoc.201701025
European Journal of Organic Chemistry
COMMUNICATION
Pd-Catalyzed Cascade Saegusa-Heck Reaction: Synthesis of β,β-
Diarylacroleins from Aryl Propanals and Aryl Iodides
Li Xiao,[a] Yilin Zheng,[a] Qiong Xie*[a] and Liming Shao*[a, b]
Abstract: An efficient and convenient Pd-catalyzed cascade
Saegusa-Heck protocol has been developed, and its potential use in
the synthesis of symmetrical and unsymmetrical β, β-diarylacroleins
with moderate to high yields has been investigated.
variations of aryl groups at the β-position are desired. Heck
reactions have been widely used in the synthesis of unsaturated
carbonyl compounds (e.g. aldehydes, ketones, acids and esters)
[6]. Simple procedures like one-pot diarylation of activated
alkenes[6a] (Scheme 1, a) and cascade oxidative diarylation of
saturated aldehydes[6b] (Scheme 1, b) have also been reported
for the synthesis of symmetrical β,β-diarylacroleins. Zhu and co-
workers[6a] published a triple transition-metal catalyzed domino
reaction (Heck-isomerization /Saegusa /Heck) of allyl alcohol to
give symmetrical β,β-diarylacroleins in one pot (Scheme 1, a). For
the synthesis of unsymmetrical β,β-diarylacroleins, Heck
arylation[7] (Scheme 1, c) of arylacroleins with aryl halides and
Sonogashira-type coupling reaction[8] (Scheme 1, d) of aryl
propiolates with aryl boronic acids are two major approaches.
However, only electron-rich aryl groups were favorable under the
conditions above. Some diaryl compounds could also turn into
β,β-diarylacroleins, such as propargilic aryl carbinols[9] (Scheme
1, e) and diaryl ketones[10] (Scheme 1, f). In 2016, Tiwari and co-
workers[11] developed a novel Weinreb amide to build β,β-
diarylacroleins via sequential Grignard reactions (Scheme 1, g),
which brings in the flexibility for expanding the reaction scope.
Introduction
As versatile synthetic building blocks, β, β-diarylacroleins were
widely used in pharmaceutical industry. β,β-Diarylacroleins could
be utilized to assemble diarylmethine and diarylethene fragments
present in various biologically important molecules (Figure 1),
such as selective serotonin reuptake inhibitor (SSRI) sertraline 1[1],
diphenylbutylpiperidines (DPBPs) D2 receptor antagonist
penfluridol 2[2], competitive muscarinic antagonist (R)-tolterodine
3[3], calcium channel blocker fendiline 4[4] and transient receptor
potential vanilloid 1 (TRPV1) antagonist 5 [5], etc.
Figure 1. Biologically active molecules bearing diarylmethine and diarylethene
fragments
Existing approaches for the synthesis of β,β-diarylacroleins
(unsaturated aldehydes) are limited, particularly when wide
[a]
[b]
Department of Medicinal Chemistry, School of Pharmacy, Fudan
University,
826 Zhangheng Road, Zhangjiang Hi-tech Park, Pudong, Shanghai
201203, P.R. China
E-mail: limingshao@fudan.edu.cn; qxie@fudan.edu.cn
State Key Laboratory of Medical Neurobiology, Fudan University,
138 Yixueyuan Road, Shanghai 200032, P.R.China
Scheme 1. Synthetic strategies of β,β-diarylacroleins.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701025
European Journal of Organic Chemistry
COMMUNICATION
Methods for synthesizing unsymmetrical β,β-diarylacroleins
are still facing problems of low synthetic efficiency, harsh reaction
conditions, multi-step synthesis and extensive polymerization, etc.
Therefore, developing more convenient method for the synthesis
of β,β-diarylacroleins continues to be challenging. Saegusa
oxidation is a convenient method for producing α,β-unsaturated
aldehydes from saturated ones[12], which could serve as the
alkene source for Heck reaction to afford the corresponding β-
7a,
arylation products[6d,
7b]. Herein, we developed a novel Pd-
catalyzed cascade Saegusa-Heck reaction to synthesize β,β-
diarylacroleins efficiently utilizing stable and readily available aryl
propanals and aryl iodides. Furthermore, this method is suitable
for building various symmetrical and unsymmetrical β,β-
diarylacroleins, including some electron-withdrawing aryl
products.
Entry Catalyst[b]
Additive
(equiv.)
Ligand
Solvent
Yield[c]
[%]
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
AgOAc (1.5)
AgNO3 (1.5)
AgTFA (1.5)
Ag2CO3 (1.5)
－
－
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
toluene
DMF
26
8
－
3
－
28
55
trace
50
48
55
78
62
21
45
32
0
4
－
－
Results and Discussion
5
Initially, phenylpropyl aldehyde 6a (1.0 mmol, 1 equiv.) and
iodobenzene 7a (1.5 mmol, 1.5 equiv.) were employed as the
starting materials. The reaction was performed in the presence of
10 mol% Pd(OAc)2 and 1.5 equiv. of AgOAc in AcOH at 100 ℃
for 6 h (Table 1, entry 1), and the product 8a was obtained in 26%
yield. In order to increase the yield, we tried to optimize the
reaction conditions. Firstly, various Ag salts (Table 1, entries 1-4)
were tested where Ag2CO3 (Table 1, entry 4, 55%) seemed to be
the most efficient. The yield increased from 26% to 50% by
doubling the amount of AgOAc (entry 1, entry 6), indicating the
importance of the silver ion amount. After further investigation, 1.2
equiv. was found to be the optimal amount of Ag2CO3 to achieve
the best yield (Table 1, entry 8). Homo-coupling of 7a was
observed as a major side reaction. Therefore, the amount of 7a
was increased to 2.5 equiv., which led to a significant increase in
yield to 78% (Table 1, entry 9). Subsequently, a series of Pd
catalysts (Table 1, entries 9-13) were screened, and Pd(OAc)2
gave the highest yield (Table 1, entry 9, 78%). In the absence of
palladium catalyst (Table 1, entry 14), no reaction occurred.
Various solvents (Table 1, entries 15-17) and bases (Table 1,
entries 18-20) were also examined in this reaction. Acetic acid
was proved the optimal solvent regarding the yield of 8a as
compared to water (Table 1, entry 17), toluene (Table 1, entry 15)
and DMF (Table 1, entry 16). In basic conditions (Table 1, entries
18-20), yields of 8a decreased significantly. To further optimize
the reaction conditions, we screened a variety of ligands[12b, 13]
(Table 1, entries 21-26), but did not get better results. Screening
of the reaction temperatures in the range of 80 to 120 ℃ revealed
that the best results were obtained at 100 ℃ (Table 1, entries 9,
27-28). Reducing the concentration of O2 led to lower yield (44%)
of the desired 8a (Table 1, entry 29). Therefore, it could be
concluded that the optimized reaction should be performed under
the catalysis of 10 mol% Pd(OAc)2 using 1.2 equiv. of Ag2CO3 in
AcOH at 100 ℃ for 6 h (Table 1, entry 9, 78%).
6
AgOAc (3.0)
Ag2CO3 (1.0)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
K2CO3 (1.5)
NaHCO3 (3.0)
NEt3 (3.0)
－
7
－
8
－
9
－
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27[d]
28[e]
29[f]
－
Pd(PPh3)4
Pd(TFA)2
Pd(dba)2
－
－
－
－
－
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
－
0
－
0
－
H2O
34
31
18
0
－
DMF
－
DMF
－
DMF
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
Ag2CO3 (1.2)
L1 (0.2)
L2 (0.2)
L3 (0.2)
L4 (0.2)
L5 (0.2)
L6 (0.2)
－
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
29
67
38
53
57
19
30
71
44
－
－
[a] Reaction condition: 6a (1 mmol, 1 equiv.), 7a (1.5 equiv. in entries 1-8, 2.5
equiv. in entries 9-29), the mixture was stirred at 100 ℃ (in entries 1-26)
under air in sealed tube for 6 h. [b] 10 mol%. [c] Isolated yield based on 6a.
[d] Reaction temperature was 80 ℃. [e] Reaction temperature was 120 ℃. [f]
The mixture was purge with argon.
Table 1. Optimization of reaction conditions for the synthesis of β,β-
diarylacroleins.[a]
With the reaction conditions optimized, we further explored
the scope and generality of the methodology. As shown in Table
2, a variety of aryl iodides (7a−s) were able to react smoothly with
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10.1002/ejoc.201701025
European Journal of Organic Chemistry
COMMUNICATION
benzenepropanal 6a to give the desired β,β-diarylacroleins
(8a−s) in yields of 30−83% (Table 2, entries 1-19) under
standardized conditions. The results showed that electron-
donating groups on the aryl iodides (Table 2, entries 2-4, entry 10,
and entries 12-16) were more beneficial to this reaction than
electron-withdrawing groups (Table 2, entries 5-9, entry 11, and
entries 17-19). The position of substituents also influenced the
reaction outcome. When ortho-substituted iodobenzenes (Table
2, entry 2 and entry 5) were employed, the yields decreased
significantly due to steric effects. In comparison, meta- (Table 2,
entry 3 and entry 6) or para-substituted iodobenzenes (Table 2,
entry 4 and entry 7) still retained moderate to good yields.
Furthermore, some other aryl propanals 6b-d were successfully
transformed to their corresponding products 8’a-m (Table 2, entry
20-32). However, no desired product had been detected (Table 2,
entry 33) when 3-(2-fluorophenyl)propanal (6e) was employed as
the starting material. Thirty unsymmetrical β,β-diarylacrolein
compounds were obtained as a mixture of geometrical isomers in
this study, since they are difficult to be well separated. As shown
in Table 2, the ratios of the stereoisomers had been calculated
based on the NMR data. The trans or cis configurations of 8d, 8h,
8j, 8k and 8p (Table 2) were identified by comparison with the
spectroscopic data reported in literatures[5, 7b, 8b, 14]. The results
showed that the major products were trans type. Additionally,
when 7b was employed as the substrate (Table 2, entry 2 and
entry 20), more isomers were detected in NMR due to the steric
effect of ortho-methyl group (see supporting information).
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
6a
6a
6b
6b
6b
6b
6b
6b
6c
6c
6c
6c
6d
6d
6d
6e
7r: 4-NO2C6H4
7s: 4-CF3C6H4
7b: 2-MeC6H4
7c: 3-MeC6H4
7d: 4-MeC6H4
7e: 2-ClC6H4
7f: 3-ClC6H4
7g: 4-ClC6H4
7d: 4-MeC6H4
7g: 4-ClC6H4
7f: 3-ClC6H4
7a: C6H5
12
20
12
12
28
12
16
20
12
12
12
10
10
10
10
10
8r, 39
8s, 67
8’a, 32
8’b, 65
8’c, 71
8’d, 37
8’e, 54
8’f, 66
8’g, 46
8’h, 50
8’i, 48
8’j, 64
8’k, 66
8’l, 58
8’m, 55
8’n, 0
1: 1.3
1: 5
－
1: 2.4
1: 4.2
1: 1.9
1: 4.8
－
1: 2.5
1: 2.5
1: 2
1: 2.5
1: 2
7d: 4-MeC6H4
7g: 4-ClC6H4
7f: 3-ClC6H4
7a: C6H5
1: 1.8
1: 2.5
－
[a] Reaction condition: 6 (1 mmol), 7 (2.5 mmol), Ag2CO3 (1.2 mmol), and
Pd(OAc)2 (0.1 mmol) were stirred in AcOH at 100 ℃ under air in sealed tube for
6-30 h. [b] Isolated yield based on 6. [c] Mixture of geometrical isomers. [d]
Calculated based on NMR data.
Table 2. Synthesis of β,β-diarylacroleins from aryl iodides and aryl propanals.[a]
Considering all the mechanisms suggested in earlier
reports[6a, 15], a plausible reaction mechanism of the Pd-cascade
Saegusa-Heck process for the formation of β, β-diarylacroleins is
proposed (Figure 2).
Entry
6
7: Ar2
Time (h) 8, 8’, Yield[b][c] Isomer ratio[d]
[%]
1
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
7a: C6H5
7b: 2-MeC6H4
7c: 3-MeC6H4
7d: 4-MeC6H4
7e: 2-ClC6H4
7f: 3-ClC6H4
6
8a, 78
8b, 30
8c, 67
8d, 83
8e, 34
8f, 52
8g, 61
8h, 42
8i, 55
－
－
2
8
3
12
24
10
14
30
16
12
8
1: 3
4
1: 4.2 (Z /E)
1: 4.8
5
6
1: 3
7
7g: 4-ClC6H4
7h: 4-FC6H4
1: 4.2
8
1: 3 (Z /E)
1: 2.8
9
7i: 4-BrC6H4
10
11
12
13
14
15
16
17
7j: 4-MeOC6H4
7k: 4-CF3OC6H4
7l: 4-EtC6H4
8j, 66
1: 2.8 (Z /E)
1: 3.3 (Z /E)
1: 3.2
14
12
14
12
24
24
18
8k, 58
8l, 72
7m: 4-iPrC6H4
7n: 4-tBuC6H4
7o: 3,4-Me2C6H3
7p: 3,5-Me2C6H3
7q: 3,4-Cl2C6H3
8m, 38
8n, 47
8o, 74
8p, 65
8q, 60
1: 4.2
Figure 2. Proposed mechanism for Pd-catalyzed cascade Saegusa-Heck
reaction.
1: 2.1
1: 3.1
1: 2.8 (Z /E)
1: 3.4
Initially, 6 turns to 9 through tautomerism catalyzed by acid.
A classic Saegusa oxidative process transforms 9 to 11 via the
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reaction as an oxidant. Pd(0) is generated from Pd(OAc)2 via
reduction, and then reacts in the catalytic cycle. 11 undergoes a
typical Heck reaction with aryl iodides 7 catalyzed by palladium to
give the desired β,β-diarylacroleins 8. During the reaction, silver(I)
ion was precipitated to give silver iodides and the Heck reaction
was promoted by this process.
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To summarize, we developed a novel and efficient strategy for
one-pot synthesis of β,β-diarylacroleins through Pd-catalyzed
cascade Saegusa-Heck reaction. It is convenient and has
potential extensive application. Thirty-two β,β-diarylacroleins
were synthesized by using various aryl propanals and aryl iodides
with moderate to good yields (30%~83%). The method tolerates
a wide range of functional groups, including some electron-
withdrawing groups. The polymerization of 6 and homo-coupling
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General Procedure for the Preparation of 8 and 8’: In a sealed tube
equipped with a magnetic stirring bar, starting materials 6 (1.0 mmol), 7
(2.5 mmol), Ag2CO3 (1.2 mmol) and catalyst Pd(OAc)2 (22.4 mg, 0.1 mmol,
10 mol%) were added, then the tube was sealed and the mixture was
stirred at 100 ℃ until the 1H NMR spectrum showed complete conversion.
The mixture was then filtered through a short plug of silica gel. Solvents
were removed under reduced pressure. Purification by column
chromatography on silica gel (n-hexane/ EtOAc, 20:1) afforded the
corresponding product 8a–s, 8’a-m.
Acknowledgements
We acknowledge financial support from National Natural Science
Foundation of China (No. 81473076 and 81673292)，National
Basic Research Program of China (973 Program,
2015CB931804) and the Science and Technology Commission of
Shanghai Municipality (No. 15431900100).
Keywords: Synthetic methods • β, β-diarylacroleins • Saegusa-
Heck reaction
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COMMUNICATION
COMMUNICATION
Organocatalysis*
Li Xiao, Yilin Zheng, Qiong Xie* and
Liming Shao*
Page No. – Page No.
Title: Pd-Catalyzed Cascade Saegusa-
Heck Reaction: Synthesis of β,β-
Diarylacroleins from Aryl Propanals
and Aryl Iodides
An efficient Pd-catalyzed cascade Saegusa-Heck protocol for the synthesis of
synthetically useful β,β-diarylacroleins from aryl propanals and aryl iodides in
moderate to high yields (30%-83%) has been developed.
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