Cu-Catalyzed highly regioselective 1,2-hydrocarboxylation of 1,3-dienes with CO2

Article abstract of DOI:10.1039/d0cc05056c

A practical copper-catalyzed highly regioselective 1,2-hydrocarboxylation of terminal 1,3-diene with carbon dioxide has been developed. Under mild reaction conditions, this chemistry afforded 2-benzyl-β,γ-unsaturated acid derivatives as products, which are a kind of important unit for bio-active molecules and versatile precursors for organic synthesis, with good functional group tolerance. The key intermediate in this transformation is illustrated by control experiments.

Full text of DOI:10.1039/d0cc05056c

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Cu-Catalyzed highly regioselective
1,2-hydrocarboxylation of 1,3-dienes with CO2†
Cite this:DOI: 10.1039/d0cc05056c
Penglin Zhang,a Zhanglang Zhou,a Rumeng Zhang,a Qian Zhaoa and
ab
Received 24th July 2020,
Accepted 18th August 2020
Chun Zhang
*
DOI: 10.1039/d0cc05056c
rsc.li/chemcomm
A
practical copper-catalyzed highly regioselective 1,2-hydro- powerful methods for the synthesis of drugs, natural products
carboxylation of terminal 1,3-diene with carbon dioxide has been and functional materials.5 In comparison with the above work,
developed. Under mild reaction conditions, this chemistry afforded the methods for the 1,2-functionalization of terminal 1,3-dienes
2-benzyl-b,c-unsaturated acid derivatives as products, which are are rare, but useful and challenging.6 Recently, considering
a kind of important unit for bio-active molecules and versatile environmental protection and the increasing quest for fossil
precursors for organic synthesis, with good functional group tol- resources, the use of carbon dioxide (CO2) as an abundant,
erance. The key intermediate in this transformation is illustrated by nontoxic and sustainable one-carbon building block attracts
control experiments.
much attention from synthetic communities.7,8 So the highly
selective reaction of 1,3-dienes with CO2 is a fantastic strategy
2-Benzyl-b,g-unsaturated acid derivatives are important motifs to construct a complex compound. In this field, Yu’s group
in biologically active molecules, synthetic drugs or drug candi- developed an elegant research about the highly selective function
dates (for some examples, see Fig. 1).1 Furthermore, they are of 1,3-dienes to obtain valuable hydroxyl compounds (1, B,
used as useful precursors to obtain various meaningful func- Fig. 2).9 The catalytic carboxylation with CO2 could construct
tional groups.2 Therefore, numerous efforts have been made to carboxylic acid, which is a kind of important unit for natural
construct 2-benzyl-b,g-unsaturated acid derivatives.2 To date, products and pharmaceuticals. Martin’s group reported an
the prevalent strategy employs the reaction of active metal amazing highly selective 1,4-dicarboxylation of 1,3-dienes with
reagent intermediates with b,g-unsaturated acid derivatives or CO2 (2, B, Fig. 2).10 Herein, based on our previous studies
a,b-unsaturated acid derivatives (A, Fig. 2).3 Usually, by the about Cu-catalyzed highly selective 1,2-functionalization of
above methods, the branch and linear selectivity is difficult to 1,3-dienes in a one pot reaction,6a and the research on
control. Furthermore, the necessary metal intermediate might copper-catalyzed carboxylation of allylic pinacol boronates with
induce a limited substrate scope. So, despite numerous efforts CO2,11 we developed a mild and practical one pot method for
for the synthesis of 2-benzyl-b,g-unsaturated acid derivatives, highly selective functionalization of 1,3-diene with CO2 to
the development of mild and efficient methods is still desired.
Herein, we present a mild and practical one pot reaction to
synthesize 2-benzyl-b,g-unsaturated acid derivatives from easily
available starting materials with good functional group tolerance.
Since it can afford multiple complex isomeric products from
simple precursors, functionalization of conjugated dienes with
high selectivity is an important strategy in organic synthesis.4,5
In recent years, a lot of breakthroughs focused on the 1,4-
or 3,4-functionalization of terminal 1,3-dienes have provided
a Institute of Molecular Plus, Tianjin Key Laboratory of Molecular Optoelectronic
Science, Department of Chemistry, School of Sciences, Tianjin University,
Weijin Rd. 92, Tianjin 300072, China. E-mail: chunzhang@tju.edu.cn
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Examples of bio-active molecules.
d0cc05056c
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one (entry 3, Table 1). The efficiency of this transformation
decreased when using other kinds of solvents, such as tetra-
hydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide
(entries 4–6, Table 1 and the ESI†). Then the effect of different
copper catalysts was studied. Compared with CuCl2, Cu(OTf)2 and
CuCl resulted in low yields (entries 1, 7 and 8, Table 1). Further
studies indicated that different kinds of ligands could affect the
results of this reaction (entries 9–12, Table 1). Under the same
conditions, ICyCl, IPrCl and PCy3 resulted in low yields. Interest-
ingly, PPh3, which is a kind of easily available ligand, afforded the
best result. Moreover, the 2-benzyl-b,g-unsaturated acid product
could not be detected from the reaction without the copper
catalyst (entry 13, Table 1).
Once the optimized reaction conditions were established,
the substrate scope for this Cu-catalyzed highly regioselective
carboxylation of 1,3-diene with CO2 was investigated (Table 2).
To demonstrate that this chemistry could employ the readily
available 1,3-diene to produce 2-benzyl-b,g-unsaturated acid
derivatives, trans-version and cis-version mixed starting materials
were selected, because, compared with absolute trans-1,3-dienes,
they are much more easily prepared, and could afford nearly the
same yield (see the ESI†). In general, modest to good yields using
either electron-rich or electron-deficient aryl substituted 1,3-
diene were obtained (3a to 3v, Table 2). Notably, the ortho-
substituents did not affect the efficiency of this transformation
(3d and 3e, Table 2). Interestingly, when chloric-substituted
aromatic 1,3-diene was employed as a starting material, the
corresponding product could be afforded, which could be used
for further transformation (3o, Table 2). To our delight, the
methylthio group, which widely exists in bio-active molecules,
could survive under these reaction conditions (3p, Table 2).
Importantly, this method could be used to obtain boron ester
groups containing the product, which is a kind of versatile
intermediate for a lot of well-established C–C and C–heteroatom
bond forming reactions (3q, Table 2). As expected, heterocyclic
substrates worked well under this reaction condition, such as
oxygen-containing heterocyclic-, thienyl- and indole-groups (3r to
3v, Table 2). The potentiality for pharmaceutical molecule
modification of this reaction was well demonstrated by these
results. We then tried to extend the application range to alkyl
1,3-dienes. The data suggested that the corresponding product
could be obtained from an alkyl starting material, but the
efficiency needed further improvement (3w, Table 2).
Fig. 2 New strategy to prepare 2-benzyl-b,g-unsaturated acid derivatives.
synthesise 2-benzyl-b,g-unsaturated acid derivatives, which exist
extensively in bio-active molecules (C, Fig. 2).
Our study commenced with a one pot copper-catalyzed
reaction of trans-buta-1,3-dien-1-ylbenzene, B2Pin2 and CO2
(1 atm). At the beginning, this practical protocol afforded
2-benzyl-b,g-unsaturated acid (2a) with 4% yield (entry 1,
Table 1). We then surveyed the effect of different bases (entries
2 and 3, Table 1). Among them, KOtBu was selected as the best
Table 1 Effect of different reaction conditionsa
Entry
[Cu]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuCI2
CuCI2
CuCI2
CuCI2
CuCI2
CuCI2
Cu(OTf)2
CuCI
CuCI2
CuCI2
CuCI2
CuCI2
None
IMesHCI
IMesHCI
IMesHCI
IMesHCI
IMesHCI
IMesHCI
IMesHCI
IMesHCI
ICyHCI
IPrHCI
LiOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NMP
NMP
NMP
THF
DMF
DMA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
4
8
50
7
41
43
24
46
39
9
10
11
12
13
26
2-Benzyl-b,g-unsaturated acid, which could be obtained by
this method at a 1 mmol-scale (eqn (1), Scheme 1), is a kind of
versatile intermediate for chemical synthesis. As shown in
Scheme 1, the product 2a could undergo a reductive reaction
to yield a homo-allylic alcohol compound with 88% yield
(a, Scheme 1). Furthermore, an iodo-lactone compound could
be synthesized from 2a with good efficiency (b, Scheme 1).
Importantly, 2-benzyl-b,g-unsaturated acid was reported as the
starting material to synthesise a novel type of irreversible
PCy3
PPh3
PPh3
24
68 (63)c
0
a
trans-1a (0.2 mmol), B2Pin2 (0.4 mmol), KOtBu (0.4 mmol), [Cat]
(10 mol%), PPh3 (11 mol%), MeOH (0.25 mmol), NMP (1.5 ml),
after 1.5 h; then CO2 (1 atm), KOtBu (0.4 mmol) 70 1C, 24 h then HCl inhibitor for carboxypeptidase A (c, Scheme 1).12
b
(aq.) was added, r.t. Yields were determined by GC using 2-
Control experiments were designed to understand the
mechanism of this transformation. First, this transformation
did not work without B2Pin2 (eqn (1), Scheme 2). Furthermore,
methoxynaphthalene as an internal standard. Based on the data of
raw 1H-NMR and GC-Ms, there is no 5-phenylpent-3-enoic acid (1,4-
c
selective product) in the reaction system. Isolated yields.
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Table 2 Cu-catalyzed highly regioselective 1,2-hydrocarboxylation of
a
1,3-dienes with CO2
Scheme 1 Further transformation of the product: (a) 2a (0.40 mmol), LiAlH4
(1.2 mmol), THF (2.0 mL), isolated yield. (b) 2a (0.32 mmol), oxone (0.64 mmol)
and KI (0.64 mmol), CH3CN:H2O = 1 : 1 (4.0 mL), the isolated yield.
Scheme 2 Control experiments.
Based on the above results, the proposed mechanism for
this carboxylate reaction is illustrated in Scheme 3. The active
copper catalyst was generated in the first step of this transfor-
mation. It reacted with B2Pin2 to form Cu–B complex 8, which
could react with 1,3-diene to afford the key intermediate boron
ester 6.13 After the above steps, the transmetalation reaction of
copper salt and boron ester 6 could afford intermediate 9,13
a
1 (0.2 mmol), B2Pin2 (0.4 mmol), KOtBu (0.4 mmol), CuCl2 (10 mol%),
PPh3 (11 mol%), MeOH (0.25 mmol), NMP (1.5 ml), after 1.5 h; CO2
(1 atm), KOtBu (0.4 mmol) 70 1C, 24 h, then MeI (0.6 mmol) was added,
b
r.t., 3 h. Isolated yields.
boron ester 6 could be detected in the reaction system without which reacted with carbon dioxide to produce the desired
carbon dioxide with 90% GC-yield (eqn (2), Scheme 2 and the product 2a.11,14 Furthermore, in this reaction system, com-
ESI†). Without the copper catalyst, the intermediate 6 could not pound 11 could be detected by GC-MS and HRMS. It was
be detected, which suggested that the step to generate 6 is a generated from the reaction of B2Pin2 with CO2, and it could
copper-catalyzed process (eqn (3), Scheme 2).13 Further study consume and deactivate the copper catalyst to induce a nega-
revealed that the boron ester 6 could be used as a starting tive effect on the result of the desired reaction path.15
material to obtain the product 3a under standard conditions
In conclusion, we have demonstrated a novel Cu-catalyzed
with good efficiency (eqn (4), Scheme 2). These results sug- highly regioselective carboxylation of 1,3-diene with CO2. This
gested that the boron ester 6 should be one of the key inter- chemistry could realize the synthesis of 2-benzyl-b,g-unsaturated
mediates in this chemistry. However, the above reaction, which acid derivatives, which are versatile precursors for a lot of
converted 6 into the product, did not work without CuCl2, and transformations and are important motifs for bioactive molecules,
this result suggested that copper-salt plays a key role as a from easily available starting materials with good functional
catalyst in this step (eqn (5), Scheme 2).
group tolerance. The key boron ester intermediate of this
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