A Tunable Route to Prepare α,β-Unsaturated Esters and α,β-Unsaturated-γ-Keto Esters through Copper-Catalyzed Coupling of Alkenyl Boronic Acids with Phosphorus Ylides

Article abstract of DOI:10.1002/adsc.201701640

A tunable strategy to prepare α,β-unsaturated esters and α,β-unsaturated-γ-keto esters in good to excellent yields was developed through copper-catalyzed oxidative coupling of phosphorus ylides with alkenyl boronic acids under mild conditions. The reaction without water afforded α,β-unsaturated esters, ketones, and amides while α,β-unsaturated-γ-keto esters, 1,4-α,β-unsaturated diketones and α,β-unsaturated-γ-keto amides were obtained when using 5.0 equiv. of water. H₂O¹⁸ labeling experiments showed that water played an important role in the formation of α,β-unsaturated-γ-keto esters. A plausible formation mechanism for α,β-unsaturated esters and α,β-unsaturated-γ-keto esters was proposed based on mechanistic studies. Phosphonium salts could also be used directly as coupling partners instead of phosphorus ylides. The reaction exhibited a broad substrate scope, good functional group tolerance, good regioselectivity, and diverse coupling products. (Figure presented.).

Full text of DOI:10.1002/adsc.201701640

Title: A Tunable Route to Prepare ɑ,β-Unsaturated Esters and ɑ,β-
Unsaturated-γ-Keto Esters through Copper-Catalyzed Coupling
of Alkenyl Boronic Acids with Phosphorus Ylides
Authors: Hong-Yan Bi, Feng-Ping Liu, Cui Liang, Gui-Fa Su, and
Dong-Liang Mo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701640
Link to VoR: http://dx.doi.org/10.1002/adsc.201701640

10.1002/adsc.201701640
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Tunable Route to Prepare ɑ,β-Unsaturated Esters and ɑ,β-
Unsaturated-γ-Keto Esters through Copper-Catalyzed
Coupling of Alkenyl Boronic Acids with Phosphorus Ylides
Hong-Yan Bi,† Feng-Ping Liu,† Cui Liang, Gui-Fa Su*, and Dong-Liang Mo*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and
Technology of China; School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road
Guilin, 541004, China. E-mail: gfysglgx@163.com; moeastlight@mailbox.gxnu.edu.cn
H.-Y. Bi and F.-P. Liu contributed equally to this work
†
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A tunable strategy to prepare ɑ,β-unsaturated ɑ,β-unsaturated-γ-keto esters.
A
plausible formation
esters and ɑ,β-unsaturated-γ-keto esters in good to excellent mechanism for ɑ,β-unsaturated esters and ɑ,β-unsaturated-
yields was developed through copper-catalyzed oxidative γ-keto esters was proposed based on mechanistic studies.
coupling of phosphorus ylides with alkenyl boronic acids Phosphonium salts could also be used directly as coupling
under mild conditions. The reaction without water afforded partners instead of phosphorus ylides. The reaction
ɑ,β-unsaturated esters, ketones, and amides while ɑ,β- exhibited a broad substrate scope, good functional group
unsaturated-γ-keto esters, 1,4-ɑ,β-unsaturated diketones and tolerance, good regioselectivity, and diverse coupling
ɑ,β-unsaturated-γ-keto amides were obtained when using 5.0 products.
equiv. of water. H2O18 labeling experiments showed that
water played an important role in the formation of
Keywords: alkenyl boronic acids; copper-catalysis; cross-
coupling; phosphorus ylide; ɑ,β-unsaturated ester
Introduction
O
OH OH
OH
O
ɑ,β-Unsaturated esters and ɑ,β-unsaturated-γ-keto
esters have functional importance as versatile
building blocks in organic synthesis, the total
synthesis of natural products, and as constituents of
biologically active compounds, such as (-)-
pyrenophorin, (+)-aspicilin, (-)-A26771B, and (+)-
patulolide A (Figure 1).[1,2] Methods to prepare these
O
O
O
O
Me
Me
O
Me
Me
O
(+)-Aspicilin
(-)-Pyrenophorin
O
compounds
usually
involve
Wittig
or
Horner−Wadsworth−Emmons
(HWE)
reaction
O
O
O
Me
between ɑ-formyl esters and β-keto phosphonates.
However, these methods usually suffer from a lack of
aldehydes availability or produce E/Z-mixtures
(Scheme 1-A).[3] Recently, the preparation of ɑ,β-
unsaturated-γ-keto esters has attracted much
attention,[4] with various synthetic methods having
been developed to overcome the drawbacks of Wittig
or HWE reactions. These include the oxidation of
furan skeletons,[5] conversion of γ-keto esters by
oxidation with selenium dioxide,[6] bromination of γ-
keto esters followed by elimination with a base,[7] and
Zn carbenoid-mediated chain extension of β-
dicarbonyl substrates[8] (Scheme 1-B). However,
these methods suffer from a lack of readily available
starting materials, harsh conditions, laborious
multistep syntheses, and a lack of product diversity.
O
O
O
CO2H
O
(+)-Patulolide A
(-)-A26771B
Figure 1. Biologically active compounds containing ɑ,β-
unsaturated systems.
The development of efficient, practical, and benign
synthetic methods to construct the diverse organic
intermediates from a simple material has attracted
much attention in modern synthetic chemistry. The
use of aryl, alkenyl, and alkyl boronic acids to
construct new C−O, C−N, and C−C bonds in cross-
1
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10.1002/adsc.201701640
Advanced Synthesis & Catalysis
Results and Discussion
coupling reactions indicates the importance of these
simple compounds.[9] Oxidative cross-coupling
Initially, phosphorus ylide 1a and (E)-hex-1-
enylboronic acid 2a were chosen as model substrates.
When 1a and 2a were treated with Cu(OAc)2 (1.0
equiv.), pyridine (pyr, 10.0 equiv.) as base, and
Na2SO4 as additive in dichloroethane (DCE) under air,
ɑ,β-unsaturated ester 3aa was obtained in 79% yield,
accompanied by minor product ɑ,β-unsaturated-γ-
keto ester 4aa (Table 1, entry 1). Product 3aa was
assigned as the E-isomer according to the double
reactions
between
arylboron
reagents
and
nucleophilic partners are among the most valuable
strategies for constructing diverse organic
compounds,[10] but are more appealing when alkenyl
boron reagents are used owing to the rich potential
transformations of double bonds in the coupling
products.[11] In contrast, Chan-Evans-Lam reactions,
used to form C−C bonds by coupling organoboron
reagents with carbon-based nucleophiles, have been
rarely reported.[12] In 2016, Lundgren and coworkers
developed a general and powerful coupling reaction
of tertiary malonates or amido esters with
functionalized aryl or alkenyl boron reagents to
prepare ɑ-arylated or alkenylated carbonyl
compounds under copper-mediated conditions
1
bond H-NMR coupling constant. Solvent screening
showed that toluene, THF, DMF, and DMSO gave
good yields of 3aa, while MeOH and MeCN gave
lower yields of 3aa (Table 1, entries 2-7). In
particular, product 4aa was isolated in 15% yield in
MeCN (Table 1, entry 7). Different copper salts were
also evaluated (Table 1, entries 8-10). Both Cu(II)
and Cu(I) species promoted the reaction, but
Cu(OAc)2 was the best catalyst (Table 1, entries 8-10
vs entry 1). Reducing the amount of Cu(OAc)2 to 0.5
equiv increased the yield of 3aa to 83% while a
decreased yield was observed using 0.2 equiv. of
Cu(OAc)2 (Table 1, entries 11 and 12). Product 3aa
was obtained in 85% yield using 5.0 equiv. of
pyridine and in 73% yield using 3.0 equiv of pyridine
(Table 1, entries 13 and 14). Other bases were also
tested, but pyridine gave the best result (Table 1,
entries 15-17 vs entry 13). To our surprise, removing
Na2SO4 clearly decreased the yield of 3aa but
increased the yield of 4aa to 21% (Table 1, entry 18).
Pleasingly, the yield of 4aa was improved to 30%
when 3.0 equiv. of H2O was added (Table 1, entry
19). This indicated that water served as a nucleophile
in the reaction. Product 4aa was isolated in 64% yield
using MeCN as a solvent with 5.0 equiv. of H2O
(Table 1, entries 20 and 21). Reducing the amount of
Cu(OAc)2 to 0.2 equiv. improved the yield of 4aa to
72%, accompanied by 3aa in 8% yield (Table 1, entry
22). When air was replaced with H2O2 under argon,
product 4aa was afforded in 56% yield companied by
a 14% yield of 3aa (Table 1, entry 23). Therefore, the
optimal conditions for preparing 3aa were Cu(OAc)2
(0.5 equiv.), pyridine (5.0 equiv.) in DCE with
Na2SO4 as additive (Condition A) while the optimal
conditions for preparing 4aa were Cu(OAc)2 (0.2
equiv.), pyridine (5.0 equiv.) in MeCN with H2O (5.0
equiv.) as additive (Condition B).
(Scheme 1-C).[13] Despite being
a
powerful
methodology, the substrates were limited to
malonates derivatives with only four examples
reported, which resulted in a lack of diversity in the
coupling products. Therefore, exploring new and
general strategies for constructing C−C bonds by
coupling
carbon-based
nucleophiles
with
alkenylboron reagents remains desirable. During our
studies into the selective coupling of N−O bonds with
alkenyl boronic acids using the Chan-Evans-Lam
reaction,[14] we hypothesized that phosphorus ylides
might serve as carbon-based nucleophiles to couple
with alkenyl boronic acids directly and construct new
C−C bonds (Scheme 1-D). Herein, we report a
tunable strategy to prepare ɑ,β-unsaturated esters and
ɑ,β-unsaturated-γ-ketoesters through the copper-
catalyzed coupling of phosphorus ylides with alkenyl
boronic acids under mild reaction conditions.
A) Preparation of
R2O2C
PPh3
-unsaturated ester by Wittig or HWE reaction
O
R2O2C
R
+
H
R
R1
R1
mixture of E/Z
B) Preparation of
R2O2C
-unsaturated -keto esterytrditionlstrteies


R1
R2O2C
oxidation
R
R
SeO2
R
R1
O
R1
O
R2O
O
R2O2C
R
O
O
ZnEt2, CH2I2
unavailable materials, or multistep synthesis
Br2, Base
R2O
R
R1
O
C) Lundgren's work in 2016, coupling of malonates with alkenyl boron reagents
R1
Cu(OTf)2 (2.2 equiv)
CsOAc (1.1 equiv)
R1
EWG
R
Table 1. Optimization of the reaction conditions.a
(R4O)2B
R2O2C
+
R
EWG
NEt3 (3 equiv)
DCE, 30 °C
CO2R2
O
4 examples
50% ~ 70% yields
EWG = electron-withdrawing group
n-Bu 3aa
O
BnO
BnO
(HO)2B
Cu salt, base
solvent, Na2SO4
rt, in air
PPh3
D) This work, coupling of phosphorus ylides and alkenyl boronic acids
R1
+
n-Bu
+
O
BnO
n-Bu
1a
2a
4aa
R1
Na2SO4
R
R'O2C
R
R
O
(HO)2B
major
R1
Entry Cu salt
Solvent Base
Cu(OAc)2 DCE pyr
Cu(OAc)2 toluene pyr
3aa %b 4aa %b
R'O2C
PPh3
Cu(OAc)2 (20 mol%)
air, rt
O
H2O
1
2
3
4
5
6
79
68
65
72
76
23
<5
<5
<5
<5
<5
<5
R'O2C
major
Cu(OAc)2 THF
Cu(OAc)2 DMF
pyr
pyr
Scheme 1. Strategies to prepare ɑ,β-unsaturated-γ-keto
esters.
Cu(OAc)2 DMSO pyr
Cu(OAc)2 MeOH pyr
2
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10.1002/adsc.201701640
Advanced Synthesis & Catalysis
7
8
9
10
Cu(OAc)2 MeCN pyr
32
64
44
65
83
65
85
73
67
37
15
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
21
30
54
64
72
56
3aj). Alkenyl boronic acids bearing sterically bulky
R2 groups, such as i-Pr, t-Bu, and Cy groups, were
also compatible (3ae-ag). Interestingly, alkenyl
boronic acid 2h, containing a chloro-group, also gave
product 3ah in 85% yield under the coupling
conditions. Styrenyl boronic acids 2i and 2j reacted
smoothly to afford the products 3ai and 3aj in
moderate yields. To our surprise, styrenyl boronic
acid 2k with a methoxy group did not afford ɑ,β-
unsaturated ester 3ak, but it gave ɑ,β-unsaturated-γ-
keto ester 4ak in 25% yield, accompanied by a 1,3-
diene product generated from self-coupling of
styrenyl boronic acid 2k. In all cases, the ɑ,β-
unsaturated esters, ketones, and amides were obtained
as only E-isomers, demonstrating the high
stereoselectivity of this coupling reaction, while the
ɑ,β-unsaturated-γ-keto esters 4 were afforded in
yields below 18% in most cases under Condition A.
CuSO4
Cu(OTf)2 DCE
CuI DCE
DCE
pyr
pyr
pyr
11c
12d
13c,e
14c,f
15c
16c
17c
18c,g
Cu(OAc)2 DCE
Cu(OAc)2 DCE
Cu(OAc)2 DCE
Cu(OAc)2 DCE
Cu(OAc)2 DCE
Cu(OAc)2 DCE
Cu(OAc)2 DCE
Cu(OAc)2 DCE
pyr
pyr
pyr
pyr
NEt3
Bipyr
Cs2CO3 44
pyr
pyr
60
20
10
10
8
19c,g,h Cu(OAc)2 DCE
20c,g,h Cu(OAc)2 MeCN pyr
21c,g,i Cu(OAc)2 MeCN pyr
22d,g,i Cu(OAc)2 MeCN pyr
23d,g,j Cu(OAc)2 MeCN pyr
14
a)
Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol, 3.0
equiv.), base (3 mmol, 10 equiv.), Na2SO4 (10 equiv.),
b)
c)
Table 2. Substrate scope for the formation of ɑ,β-
unsaturated esters 3.a,b
solvent (3 mL), 25 °C, 2−18 h;
Isolated yield;
d)
e)
Cu(OAc)2 (0.5 equiv.); Cu(OAc)2 (0.2 equiv.); pyr (5.0
f)
g)
h)
EWG
R2
equiv.); pyr (3.0 equiv.); without Na2SO4; H2O (3.0
i)
j)
R1
+
equiv.); H2O (5.0 equiv.); H2O2 instead of air under
argon.
Cu(OAc)2 (0.5 equiv)
3
Ph3P
EWG
(HO)2B
+
R2
pyr, DCE, Na2SO4
rt, air
R1
1
EWG
R2
2
R1
O
4
O
O
O
n-Bu
n-Bu
n-Bu
n-Bu
4aa
With the optimized conditions in hand, we first
explored the general applicability of phosphorus
ylides 1 and alkenyl boronic acids 2 for the
O
O
RO
R = Bn,
3aa
, 85% ( , <5%)
X
N
R = n-Bu, 3ba, 92% (4ba, <5%)
R = t-Bu, 3ca, 96% (4ca, <5%)
R = Ph, 3da, 50% (4da, 8%)
X = O, 3ea, 89% (4ea, 8%)
X = S, 3fa, 90% (4fa, 6%)
3ga
4ga
, 11%)
, 32% (
i-Pr
O
O
preparation of ɑ,β-unsaturated esters
3
using
O
O
n-Bu
n-Bu
Condition A. As shown in Table 2, a variety of
phosphorus ylides containing esters, ketone, and
amides reacted smoothly with (E)-hex-1-enylboronic
acid 2a to afford the corresponding ɑ,β-unsaturated
esters, ketones, and amides in moderate to excellent
yields (3aa-3pa). Phosphorus ylides 1 with ester
groups containing sterically bulky alkyl groups,
heterocycles, alkenyl, and alkynyl groups were
tolerated (3aa-ia). In particular, (-)-menthol
substituted ylide 1j afforded desired product 3ja in 92%
yield, which could be used as a chiral auxiliary to
control the diastereoselectivity in subsequent
reactions of ɑ,β-unsaturated esters. Phosphorus ylides
1l and 1m with phenyl and methyl N-substituents,
respectively, afforded the desired products 3la and
3ma in lower yields because the phosphorus ylides
were not completely consumed, even after longer
reaction times. Pleasingly, when the R1 group at the
ester ɑ-position was a methyl group, the desired ɑ,β-
unsaturated ester 3na was obtained in 60% yield as
only the E-isomer, as determined from its nuclear
Overhauser effect (NOE) spectrum. This established
a good alternative method for preparing trisubstituted
ɑ,β-unsaturated esters with a defined configuration.
Estrone-derived phosphorus ylides 1o and 1p also
afforded the desired products 3oa and 3pa in 46%
and 35% yields, respectively, providing an alternative
route toward late-stage modification of complex
molecules. The substrate scope of alkenyl boronic
acids 2 was also examined. Various alkenyl boronic
acids containing alkyl and aryl groups afforded ɑ,β-
unsaturated esters in moderate to high yields (3ab-
O
Ph
O
Ph
3ia, 81% (4ia, 12%)
n-Bu
3ja, 92% (4ja, <5%)
3ha, 79% (4ha, 10%)
Me
O
O
O
Ph
n-Bu
n-Bu
N
R
MeO
Ph
Me
NOE
3la
4la
, 31% ( , 11%)
R = Me, 3ma, 24% (4ma, 15%)
R = Ph,
3ka
4ka
, 50% ( , 12%)
3na, 60% (4na, <5%)
O
O
O
Me
R2
n-Bu
O
Me
BnO
H
R2 = n-Pr,
, 6%)
3ab
4ab
, 92% (
H
n-Bu
R2 = n-hexyl, 3ac, 98% (4ac, <5%)
H
H
H
H
R2 = Bn,
R2 = i-Pr,
3ad, 93% (4ad, <5%)
O
O
MeO
3ae
4ae
, 72% ( , <5%)
3oa, 46% (4oa, 9%)
3pa, 35% (4pa, <5%)
R2 = t-Bu, 3af, 95% (4af, <5%)
X
O
O
O
Cl
5
BnO
BnO
X = H,
BnO
3ag
3ah, 85% (4ah, 7%)
3ai
4ai
4ag
, 89% ( , <5%)
, 57% ( , 12%)
X = F, 3aj, 50% (4aj, 8%)
X = OMe, 3ak, <5% (4ak, 25%)
a)
Condition A: 1 (0.3 mmol), 2 (0.9 mmol, 3.0 equiv.),
Cu(OAc)2 (0.15 mmol, 0.5 equiv.), pyr (1.5 mmol, 5.0
equiv.), Na2SO4 (10.0 equiv.), DCE (3 mL), 25 °C, 2−18 h;
b) Isolated yield.
As ɑ,β-unsaturated-γ-keto ester 4aa was afforded
in good yield under Condition B, we also explored
the scope for preparing ɑ,β-unsaturated-γ-keto esters
4. As shown in Table 3, a variety of ɑ,β-unsaturated-
γ-keto esters, 1,4-ɑ,β-unsaturated diketones, and ɑ,β-
unsaturated-γ-keto amides were obtained in moderate
to good yields by coupling phosphorus ylides 1 and
alkenyl boronic acids
2
using Condition B.
Phosphorus ylides 1 with sterically bulky alkyl
groups, heterocycles, alkenyl and alkynyl groups, and
ketone and amide groups were tolerated (4aa-4oa).
Pleasingly, when R1 at the ester ɑ-position was a
methyl group, the desired ɑ,β-unsaturated γ-keto ester
3
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10.1002/adsc.201701640
Advanced Synthesis & Catalysis
4na was obtained in 62% yield. Estrone-derived ɑ,β-
unsaturated γ-keto ester 4oa was obtained in 41%
yield. The scope of alkenyl boronic acids 2 was also
evaluated. Alkenyl boronic acids containing alkyl and
aryl groups afforded ɑ,β-unsaturated γ-keto esters in
moderate to good yields (4ab-4ak, 4kc, 4ce and 4ke).
In all cases, ɑ,β-unsaturated γ-keto esters 4 were only
obtained as E-isomers, while ɑ,β-unsaturated esters 3
unsaturated-γ-keto ester 4aa was water-derived.
When boronic acid 2a was subjected to condition A
without phosphorus ylide 1a, (E)-hex-1-enyl acetate
(5a) was afforded in 12% yield, while hexanal was
not observed (Scheme 2-4). When boronic acid 2a
was subjected to condition B without phosphorus
ylide 1a, compound 5a was not produced and hexanal
and boronic acid 2a were recovered in 90% yield
were afforded in yields below 20% using Condition B. (Scheme 2-5). When 5a reacted with ylide 1a using
condition B, products 3aa and 4aa were not produced,
Table 3. Substrate scope for the formation of ɑ,β-
and 5a was recovered in 92% yield (Scheme 2-6). 86%
yield of 3aa was obtained even if phenyl hydrazine
was used as additive under condition A (Scheme 2-7).
These experiments suggested that ɑ,β-unsaturated
ester 3 and ɑ,β-unsaturated-γ-keto ester 4 might not
be formed from the direct Wittig reaction of
phosphorus ylides and aldehydes which were
generated by oxidation and tautomerization of the
alkenyl boronic acids in the presence of copper salts.
Water prevented the formation of 5a from alkenyl
boronic acid 2a and served as a nucleophile in the
coupling reaction.
unsaturated-γ-keto esters 4.a,b
EWG
EWG
R2
R1
Cu(OAc)2 (0.2 equiv)
3
EWG
PPh3
(HO)2B
+
R2
+
pyr, MeCN, H2O
rt, air
R2
R1
1
2
R1
O
4
O
O
O
n-Bu
n-Bu
n-Bu
RO
O
O
O
X
O
N
O
4aa
, 72% (
R = n-Bu, 4ba, 66% (3ba, 13%)
R = t-Bu, 4ca, 82% (3ca, 10%)
3aa
, 8%)
R = Bn,
X = O, 4ea, 55% (3ea, 9%)
X = S,
4ga, 51% (3ga, 12%)
4fa
3fa
, 55% ( , 11%)
4da
3da
, 11%)
R = Ph,
, 57% (
O
O
O
n-Bu
n-Bu
Ph
n-Bu
Ph
O
Ph
O
O
O
O
O
Cu(OAc)2 (0.2 equiv)
O
n-Bu
4ka, 56% (3ka, 5%)
n-Bu
4ia, 54% (3ia, 8%)
4ha
3ha
BnO
, 42% (
, 6%)
BnO
1)
2)
pyr, MeCN, H2O
rt, in air
O
A
O
4aa
3aa
, 0%
O
O
n-Bu
O
O
Ph
N
n-Bu
H
n-Bu
O
MeO
n-Bu
(HO)2B
BnO
H
n-Bu
R
O
H
H
n-Bu
O
Me
O
BnO
H
2a
H
4la
3la
R = Ph,
, 31% ( , 6%)
PPh3
O
O
4oa
4na, 62% (3na, 10%)
+
H
O
BnO
BnO
R = Me, 4ma, 53% (3ma, 7%)
3oa
, 41% ( , 11%)
Cu(OAc)2 (0.5 equiv)
pyr, DCE, D2O
rt, in air
60% D
15% D
63% D
1a
X
O
D-4aa
, 30%
D-3aa
O
, 63%
O
Cl
BnO
R
O
BnO
5
(HO)2B
n-Bu
2a
O
BnO
O
O
n-Bu
O18
O
4ai, 72% (3ai, <5%)
X = OMe, 4ak, 53% (3ak, <5%)
n-Bu
O
PPh3
BnO
+
4ah, 66% (3ha, 8%)
BnO
3)
X = H,
Cu(OAc)2 (0.2 equiv)
R = n-Pr, 4ab, 50% (3ab, 7%)
R = i-Pr, 4ae, 61% (3ae, 15%)
R = t-Bu, 4af, 46% (3af, 20%)
pyr, MeCN, H2O18
1a
4aa
3aa, 14%
, 70%
O
O
Me
Me
rt, in air
4ag
3ag
, 54% ( , 12%)
R = Cy,
n-hexyl
Ph
R
Cu(OAc)2 (0.5 equiv)
AcO
4) (HO)2B
+
+
2a
n-Bu +
n-Bu
n-Bu
OHC
< 5%
O
O
n-Bu
pyr, DCE, Na2SO4
rt, in air, 10 h
R = t-BuO, 4ce, 69% (3ce, 11%)
2a
4kc
3kc
, 78% ( , 6%)
5a, 12%
AcO
60%
4ke 3ke
R = Ph,
, 88% ( , 8%)
Cu(OAc)2 (0.2 equiv)
a)
Condition B: 1 (0.3 mmol), 2 (0.9 mmol, 3.0 equiv.),
(HO)2B
5)
+
2a
OHC
< 5%
n-Bu
n-Bu
pyr, MeCN, rt, in air, 10 h
Cu(OAc)2 (0.06 mmol, 0.2 equiv.), pyr (1.5 mmol, 5.0
equiv.), H2O (1.5 mmol, 5.0 equiv.), DCE (3 mL), 25 °C,
2−18 h; b) Isolated yield.
2a
90%
5a, < 5%
H2O
O
O
PPh3
O
BnO
n-Bu
AcO
BnO
6)
7)
n-Bu
1a
BnO
+
n-Bu
BnO
O
Cu(OAc)2 (0.2 equiv)
pyr, MeCN, rt, in air, 10 h
H2O
5a
3aa, <5%
4aa, 0%
To gain insight into the formation mechanism of
ɑ,β-unsaturated esters 3 and ɑ,β-unsaturated-γ-keto
esters 4, several control experiments were performed.
When treating 3aa using Condition B, ɑ,β-
unsaturated-γ-keto ester 4aa was not observed, which
suggested that 3aa was not a direct intermediate in
the formation of 4aa (Scheme 2-1). Adding 5.0 equiv.
of D2O to Condition A afforded 3aa in 63% yield,
with 60% of deuterium found in the double bond and
15% found in the allyl position, as well as
accompanied by a 25% yield of 4aa with 63% of
deuterium in the double bond (Scheme 2-2). These
results showed that double bond formation might
involve an isomerization. When H2O was replaced
O
O
PhNHNH2
PPh3
(HO)2B
n-Bu
+
BnO
3aa, 86%
n-Bu
Cu(OAc)2 (0.5 equiv)
pyr, DCE, Na2SO4
rt, in air, 10 h
1a
2a
Scheme 2. Mechanistic studies.
During optimizing the reaction conditions of 1a
with 2a, alcohol 6 was isolated in 9% yield by using
CuI as catalyst (Scheme 3-1). When alcohol 6 was
treated with copper acetate and pyridine in MeCN
under air for 10 h without additives, compound 4aa
was not observed (Scheme 3-2). However, 4aa was
obtained in 8% yield when 2.0 equiv. of 2a was
added. Furthermore, 4aa was afforded in 30% yield
when 2.0 equiv. of B(OH)3 was added, which might
be generated from the alkenyl boronic acid. These
18
with H2 O, ɑ,β-unsaturated-γ-keto ester 4aa
containing 18O was observed in 70% yield,
accompanied by a 14% yield of 3aa (Scheme 2-3).
This showed that the carbonyl group in ɑ,β-
4
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10.1002/adsc.201701640
Advanced Synthesis & Catalysis
results suggested that alcohol 6 might be the
precursor to product 4aa.
afforded in 75% yield (Scheme 5-3), which is also a
powerful intermediate in organic synthesis.[19]
O
O
(HO)2B
O
O
n-Bu
Cu(OAc)2 (0.5 equiv)
(HO)2B
PPh3
PPh3
n-Bu
OH
+
+
2a
PPh3
Me
BnO
Me
3al, 33%
BnO
6, 9% yield
1) BnO
4aa
43% yield
pyr, DCE, Na2SO4
rt, in air
3aa
+
1)
2)
+
BnO
Me
CuI (0.2 equiv)
pyr, MeCN, H2O
rt, in air
1a
2l
8% yield
1a
O
O
O
Cu(OAc)2 (0.5 equiv)
O
O
(HO)2B
2)
BnO
BnO
O
pyr, DCE, Na2SO4
rt, in air
1a
Cu(OAc)2 (0.2 equiv)
n-Bu
OH
n-Bu
2m
BnO
BnO
7, 43%
Me
pyr, MeCN, rt, in air, 10 h
additive
O
6
O
4aa
0%
8%
additive
none
2a (2.0 equiv)
O
Cu(OAc)2 (0.2 equiv)
Me
(HO)2B
PPh3
+
BnO
Me
3)
BnO
pyr, MeCN, H2O
rt, in air
O
Me
1a
2l
8, 75%
B(OH)3 (2.0 equiv)
30%
Scheme 5. Testing disubstituted alkenyl boronic acids.
Scheme 3. Isolation of alcohol 6.
To facilitate operation of this coupling reaction,
phosphonium salts were used directly under the
optimized conditions. When phosphonium salt 9a
was treated using Condition A, desired ɑ,β-
unsaturated ester 3aa was obtained in 56% yield
(Scheme 6-1). Treatment of salt 9a with alkenyl
boronic acid 2a using Condition B afforded ɑ,β-
unsaturated γ-keto ester 4aa in 41% yield (Scheme 6-
2). Interestingly, when benzyl phosphonium salt 9b
was used under Condition B, ɑ,β-unsaturated ketone
10 was afforded in 28% yield (Scheme 6-3). Using
these easily accessible and stable phosphonium salts
makes this coupling procedure a more convenient
operation.
Based on our experimental results and previously
reported mechanistic studies of the Chan-Evans-Lam
reaction,[15] we proposed a plausible mechanism for
the formation of products 3 and 4. As shown in
Scheme 4, phosphorus ylide 1 coupled with alkenyl
boronic acid
2
to give allyl phosphonium
intermediate A.[16] Next, attack of an OAc anion or
base at the phosphorus cation was favored condition
A, affording intermediate B.[17] Intermediate B
isomerized to intermediate C, which then underwent
protonation of γ-position to give compound 3. This
was supported by the deuteration experiment. The
C3-position of intermediate A can also be attacked by
water to give intermediate D through a retro Morita-
Baylis-Hillman reaction, as supported by the O18-
labeling results. Intermediate D was then oxidized
under Condition B to afford product 4.[18]
O
O
Cu(OAc)2 (0.5 equiv)
n-Bu
n-Bu
(HO)2B
(HO)2B
PPh3Br
PPh3Br
+
BnO
n-Bu
n-Bu
n-Bu
1)
2)
3)
BnO
pyr, DCE, Na2SO4
rt, in air
9a
3aa, 56%
2a
2a
O
PPh3
EWG
O
EWG
R2
Cu(OAc)2 (0.2 equiv)
1
BnO
Ph
+
BnO
Ph
3
pyr, MeCN, H2O
rt, in air
(HO)2B
O
R2
9a
4aa, 41%
2
protonation
EWG
Cu(OAc)2
air
Cu(OAc)2 (0.2 equiv)
n-Bu
attack P-atom
(HO)2B
2a
PPh3Br
9b
+
EWG
R2
R2
pyr, MeCN, H2O
rt, in air
B
O
C
base
H2O
10, 28%
PPh3
3
EWG
1
R2
2
A
Scheme 6. Testing phosphonium salts.
O
OH
R2
Cu(OAc)2
B(OH)3 / air
EWG
R2
EWG
attack C3-atom
4
D
Conclusion
Scheme 4. Proposed mechanism.
We have reported a copper-catalyzed coupling of
phosphorus ylides with alkenyl boronic acids to
construct C−C bonds under mild conditions. This
reaction provides a diversity-oriented approach to the
preparation of ɑ,β-unsaturated esters, ketones, and
amides, and ɑ,β-unsaturated-γ-keto esters, 1,4-ɑ,β-
unsaturated diketones, and ɑ,β-unsaturated-γ-keto
amides, in good to excellent yields. Various
phosphorus ylides and alkenyl boronic acids are
tolerated in this transformation. Mechanistic studies
showed that water played an important role in the
formation of ɑ,β-unsaturated-γ-keto esters. This
tunable strategy provides a good preparation method
for ɑ,β-unsaturated compounds.
Disubstituted alkenyl boronic acids were also
tested in this coupling strategy. To our surprise, when
phosphorus ylide 1a was coupled with (Z)-but-2-en-
2-ylboronic acid 2l using Condition A, compound 3al
was isolated in 33% yield (Scheme 5-1). This
suggested that (Z)-but-2-en-2-yl boronic acid 2l went
through a C−C bond cleavage during the formation of
3al. To elucidate the transformation of the C−C bond
cleavage, (Z)-but-2-en-2-ylboronic acid 2l was
replaced with cyclopentenylboronic acid 2m.
Interestingly, compound 7 was obtained in 43% yield,
as determined using 2D NMR spectra (Scheme 5-2).
However, when phosphorus ylide 1a reacted with 2l
under Condition B, β,γ-unsaturated ɑ-keto ester 8 was
5
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10.1002/adsc.201701640
Advanced Synthesis & Catalysis
Experimental Section
4390; f) H. Zhang, E. C. Yu, S. Torker, R. R. Schrock,
A. H. Hoveyda, J. Am. Chem. Soc. 2014, 136, 16493.
General procedure for the preparation of ɑ,β-
unsaturated ester 3: In a 25-mL flask was charged with
phosphorus ylide 1 (0.3 mmol), alkenyl boronic acid 2 (0.9
mmol, 3.0 equiv.), Cu(OAc)2 (0.15 mmol, 0.5 equiv.) and
Na2SO4 (10 equiv.) in an air atmosphere. Then, DCE (3.0
mL) and pyridine (1.5 mmol, 5.0 equiv.) were added via
syringe. The reaction flask was then capped with a septum
pierced with a ventilation needle and the reaction mixture
was stirred vigorously at 30 °C for 8−24 h until the
phosphorus ylide 1 disappeared (monitored by TLC). At
this time, the reaction was quenched by H2O (10 mL) and
extracted with DCM (3 × 10 mL). Then, dried over with
Na2SO4 and filtered. The solvent was removed under
reduced pressure and the crude product was purified by
flash chromatography (the crude residue was dry loaded on
silica gel, 1/100 to 1/20, ethyl acetate/petroleum ether) to
give ɑ,β-unsaturated ester 3.
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General procedure for the preparation of ɑ,β-
unsaturated-γ-keto ester 4: In a 25-mL flask was charged
with phosphorus ylide 1 (0.3 mmol), alkenyl boronic acid 2
(0.9 mmol, 3.0 equiv.), Cu(OAc)2 (0.06 mmol, 0.2 equiv.)
in an air atmosphere. Then, CH3CN (3.0 mL), pyridine (1.5
mmol, 5.0 equiv.) and H2O (0.027 mL, 1.5 mmol, 5.0
equiv.) was added via syringe. The reaction flask was then
capped with a septum pierced with a ventilation needle and
the reaction mixture was stirred vigorously at 30 °C for
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8−24
h until the phosphorus ylide 1 disappeared
(monitored by TLC). At this time, the reaction was
quenched by H2O (10 mL) and extracted with DCM (3 ×
10 mL). Then, dried over with Na2SO4 and filtered. The
solvent was removed under reduced pressure and the crude
product was purified by flash chromatography (the crude
residue was dry loaded on silica gel, 1/100 to 1/20, ethyl
acetate/petroleum ether) to give compound 4.
[10] Recent reviews for oxidative coupling reactions, see: a)
S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003,
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Acknowledgements
This work was supported by National Natural Science
Foundation of China (21562005, 21602037, 21462008), Natural
Science Foundation of Guangxi (2015GXNSFCA139001,
2016GXNSFFA380005), State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, Ministry of
Science and Technology of China (CMEMR2015-A05), and
“Oversea 100 Talents Program” of Guangxi Education. We also
thank Dr. Simon Partridge, from Liwen Bianji, Edanz Editing
China (www.liwenbianji.cn/ac), for the manuscript proofreading.
[11] Selected examples for coupling of O- or N-atoms with
alkenyl boronic acids, see: a) R. E. Shade, A. M. Hyde,
J. C. Olsen, C. A. Merlic, J. Am. Chem. Soc. 2010, 132,
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A. Wink, L. L. Anderson, Org. Lett. 2012, 14, 5180; e)
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Anderson, Angew. Chem. Int. Ed. 2012, 51, 7799;
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Advanced Synthesis & Catalysis
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more details in Supporting Information. Some
7
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10.1002/adsc.201701640
Advanced Synthesis & Catalysis
FULL PAPER
A Tunable Route to Prepare ɑ,β-Unsaturated Esters
and ɑ,β-Unsaturated-γ-Keto Esters through
Copper-Catalyzed Coupling of Alkenyl Boronic
Acids with Phosphorus Ylides
EWG
R2
DCE
(HO)2B
R1
Na2SO4
25 examples
24-94% yields
EWG
PPh3
R2
R1
Cu(OAc)2, pyr, rt
open to air
Adv. Synth. Catal. Year, Volume, Page – Page
EWG
R2
MeCN
H2O
EWG = ester, ketone, amide
R1
25 examples
31-88% yields
O
Hong-Yan Bi,† Feng-Ping Liu,† Cui Liang, Gui-Fa
Su*, and Dong-Liang Mo*
8
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