Vanadium(V)-Induced Oxidative Cross-Coupling of Various Boron and Silyl Enolates

Article abstract of DOI:10.1002/asia.201700470

Intermolecular oxidative cross-coupling of two different enolates is one of the most useful reactions to synthesize unsymmetrical 1,4-dicarbonyl compounds. In this study, the oxovanadium(V)-induced intermolecular oxidative cross-coupling of enolates afforded unsymmetrical 1,4-dicarbonyl compounds. Various boron and silyl enolates underwent the formation of ketone–ester, ester–ketone, ester–ester, amide–ketone and amide–ester coupling products. These results clearly show the versatility of the present oxidative cross-coupling protocol.

Full text of DOI:10.1002/asia.201700470

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CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Vanadium(V)-induced Oxidative Cross-coupling of Various Boron
and Silyl Enolates
Authors: Toru Amaya, Yuma Osafune, Yusuke Maegawa, and
Toshikazu Hirao
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To be cited as: Chem. Asian J. 10.1002/asia.201700470
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Vanadium(V)-induced Oxidative Cross-coupling of Various Boron
and Silyl Enolates
Toru Amaya,*[a] Yuma Osafune,[a] Yusuke Maegawa,[a] and Toshikazu Hirao*[a,b]
Abstract: Intermolecular oxidative cross-coupling of two different
enolates is one of the most useful reactions to synthesize
unsymmetrical 1,4-dicarbonyl compounds. In this study, the
oxovanadium(V)-induced intermolecular oxidative cross-coupling of
enolates was achieved to give the corresponding unsymmetrical 1,4-
dicarbonyl compounds, where combination of various boron and silyl
enolates such as ketone-ester, ester-ketone, ester-ester, amide-
ketone, and amide-ester enolates was adapted. These results clearly
exhibit the versatility of the present oxidative cross-coupling protocol.
Therefore, the more-substituted boron enolate tends to be
favored for high cross-selectivity because it is more easily
oxidized due to electron richness and undesired homo-coupling is
sterically surpassed. For the opposite reason, less-substituted
silyl enolate tends to be favored for high cross-selectivity. So, we
basically select the combination of more-substituted boron
enolate and less-substituted silyl enolate in this study.
Intermolecular oxidative cross-coupling of two different enolates
is one of the most useful reactions to synthesize unsymmetrical
1,4-dicarbonyl compounds, which are found in naturally occurring
products and medicinal compounds (Scheme 1a).[1,2] However,
selective cross-coupling is challenging because undesired homo-
coupling is often seen in the reaction. We have studied the
oxidative coupling of enolates.[3-6] Recently, we reported that
oxovanadium(V)-induced oxidative cross-coupling selectively
takes place by employing a combination of boron and silyl
enolates in a ketone-ketone enolate coupling (Scheme 1b).[6,7] On
the other hand, carbonyl compounds such as not only ketones but
aldehyde, carboxylate, ester, and amide are also candidates as
an enolate precursor, which we had not investigated yet. If any
combinations of them can be allowed in the oxidative cross-
coupling, it is quite beneficial in organic synthesis. In the present
study, we focused on the combination of ketone, ester, and amide
enolates. Although the homo-coupling of enolates derived from
carboxylic acid derivatives has been reported since 1935,[8] their
cross-coupling has not been much studied. So far, as a
combination of ester and ketone, oxidative cross-coupling of
lithium enolates using electrodes by Tokuda et al[9] and CuCl2 by
Saegusa, Ito et al[10] has been reported, however examples are
quite limited. We also reported a few cross-coupling examples of
silyl enolates.[3,4] Narasaka et al reported the selective cross-
coupling using stannyl enolate of ester or amide and silyl enolate
of ketone with ceric ammonium nitrate as an oxidant.[11] Fe(III) and
Cu(II)-induced cross-coupling of lithium enolates for imide-ketone
and imide-ester combinations were investigated by Baran et al,
which was applied to total synthesis of natural products.[1,12] In this
context, we report the investigation for the combination of
enolates such as ketone-ester, ester-ketone, ester-ester, amide-
ketone,
and
amide-ester
in
oxovanadium(V)-induced
intermolecular oxidative cross-coupling of boron and silyl enolates
(Scheme 1c).
Scheme 1. (a) Oxidative cross-coupling of enolates. (b) Our previous work for
V(V)-induced oxidative cross-coupling of boron and silyl enolates derived from
ketones.[6] (c) The present work for V(V)-induced oxidative cross-coupling of
boron and silyl enolates: combination for ketone-ester, ester-ketone, ester-ester,
amide-ketone, and amide-ester.
In our reaction system, the reactivity of enolates is mainly
controlled by counter cationic metal species such as boron and
silicon, where boron enolate is more reactive than silyl one. More
specifically, boron enolate is considered to be first oxidized to
form -carbonyl radical species and it attacks to the silyl enolate.[6]
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Investigation began with the ketone-ester enolate cross-
coupling, where boron enolate from ketone and silyl enolate from
ester were employed as a substrate combination. To the
CH2Cl2/THF solution of boron enolate 1a and silyl enolate 2a (1:
1.1 molar ratio) was added VO(OEt)Cl2 (2.9 equivalents to 1a as
a one-electron oxidant) at room temperature. The reaction mixture
was stirred for 2 h. -Substituted -ketoester 3aa was obtained as
a cross-coupling product in 66% yield with homo-coupling
products 4a and 5a, the molar ratio of 3aa: 4a: 5a is 76: 19: 5
(Table 1, entry 1). The reaction was also conducted at -35 °C for
19 h, but the yield and selectivity were low (Table 1, entry 2). Use
of VO(OPr-i)Cl2 were also not effective (Table 1, entry 3). So,
VO(OPr-i)2Cl was employed as a milder oxidant. As a result, the
homo-coupling of ester enolate 5a was suppressed (Table 1,
entry 4). Finally, the selective cross-coupling took place with 2.2
equivalents of VO(OPr-i)2Cl at -35 °C for 24 h, where yield and
selectivity as a molar ratio of 3aa: 4a: 5a were 91% and 97: 3: 0,
respectively (Table 1, entry 5). In the 2.0 mmol scale reaction, the
selectivity was almost retained although the yield was lowered
(Table 1, entry 5). Further mild oxidant VO(OPr-i)3 did not induce
the oxidative coupling (Table 1, entry 6).
Ester-ketone enolate coupling was then investigated to
synthesize -substituted -ketoester, where boron enolate from
ester and silyl enolate from ketone are employed as a substrate
combination. Bulky dicyclohexylboryl ethyl ketene acetal 1b
instead of the 9-BBN derivative was employed as a boron
enolate.[13] Boron enolate 1b and silyl enolate 2b (1: 1 molar ratio)
were treated with VO(OEt)Cl2 (2.5 equivalents to 1b as a one
electron oxidant) at room temperature. -Substituted -ketoester
3bb was obtained as a cross-coupling product in 71% yield with
high selectivity (Table 1, entry 1), where the small amount of
homo-coupling product 4b was observed and homo-coupling
product 5b was not observed. The reaction conditions at low
temperature and use of VO(OPr-i)2Cl were not effective for this
reaction (Table 2, entries 2-4).
Table 2. Oxidative cross-coupling of boron enolate 1b and silyl enolate 2b
(ester-ketone)[a]
Table 1. Oxidative cross-coupling of boron enolate 1a and silyl enolate 2a
(ketone-ester)[a]
Entry
1
V(V) oxidant
VO(OEt)Cl2
Temp.
[°C]
Yield of 3bb
Molar ratio
3bb : 4b : 5b
[%][c]
rt
71
67(64)[d,e]
96 : ~4 : 0
(96: ~4: 0)
2
3
4
VO(OEt)Cl2
VO(OPr-i)2Cl
VO(OPr-i)2C
-35
rt
58
44
44
>99 : n.d : 0
>99 : n.d : 0
>99 : n.d : 0
Entry
V(V) oxidant[c]
Temp.
[°C]
Time
[h]
Yield of
3aa [%][d]
Molar ratio
3aa : 4a : 5a
-35
[a] 0.1 mmol of each of 1b and 2b was used, respectively. [b] Defined on the
assignment of the highest priority designation to the OBCy2 group. [c] Yield
of 3bb = 100% × moles of 3bb/moles of 1b (or 2b). Yield was calculated by
the integral ratio of the peaks for 3a and internal standard (1,3,5-
trimethoxybenzene) in 1H NMR spectrum of the crude mixture. [d] 0.5 mmol
of each of 1b and 2b and 1.25 mmol of VO(OEt)Cl2 were used. Reaction
time was 1 h. [e] Number in parenthesis is isolated yield.
1
2
3
4
5
VO(OEt)Cl2
VO(OEt)Cl2
VO(OPr-i)Cl2
VO(OPr-i)2Cl
VO(OPr-i)2Cl
rt
-35
rt
2
19
2
66
43
44
44
76 : 19 : 5
61 : 39 : 8
54 : 18 : 28
64 : 36 : 0
rt
2
Table 3 shows the scope of the oxidative cross-coupling.
For the ketone-ester enolate coupling, boron enolate 1c and 1d
with aryl chloride and bromide moieties were cross-coupled with
2a under the optimized conditions in Table 1 to give the
corresponding -ketoester 3ca and 3da in 71% and 89% yield,
respectively (Table 3, entries 1 and 2). Aryl halide moiety is
tolerated under the conditions. When boron enolate 1f as an
aliphatic substituted substrate was used, the product 3fa was
obtained in moderate yield (Table 3, entry 4). For the ester-ketone
enolate coupling, boron enolate 1b was cross-coupled with silyl
enolates 2c, 2d, and 2e under the optimized conditions in Table
2. The reaction with 2c took place to give the corresponding
product 3bc in moderate yield (Table 3, entry 5). When the
-35
24
91[e]
76(53)[f,g]
97 : 3 : 0 [e]
(93 : 7 : 0)
6
VO(OPr-i)3
rt
2
0
-
[a] 0.05 mmol of 1a and 0.055 mmol of 2a were used. [b] Ca. 33 equivalents
of THF to 1a was used. [c] 2.9 equivalents of oxidant to 1a was used. [d] Yield
of 3aa = 100% × moles of 3aa/moles of 1a. Yield was calculated by the
integral ratio of the peaks for 3a and internal standard (1,3,5-
trimethoxybenzene) in 1H NMR spectrum of the crude mixture. It is also
described in our previous paper.[6] [f] 2.0 mmol of 1a and 2.4 mmol of 2a, 4.8
[e]
[g]
mmol of VO(OPr-i)2Cl, and 54.2 mmol of THF were used.
parenthesis is isolated yield.
Number in
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Table 3. Oxidative cross-coupling of boron enolate 1 and silyl enolate 2 (ketone-ester, ester-ketone, and ester-ester)
Entry
Boron enolate 1
Silyl enolate 2
Cross-coupling product 3
Yield of 3 [%][a]
Conditions[b]
1
2
71
89
A
A[c]
3
60
A
4[d]
63
67
A[e]
5
B
6
7
54
33
B[f]
B
8
67
C
[a]
Yield of 3 = 100% × moles of 3/moles of 1. Yield was calculated by the integral ratio of the peaks for 3 and internal standard (phenanthrene or 1,3,5-
trimethoxybenzene) in 1H NMR spectrum of the crude mixture. Isolation of the products 3 was carried out by silica-gel chromatography. [b] Conditions A: similar
to entry 5 in Table 1. Amounts of substrates and reagents: 1 (0.5 mmol), 2a (0.6 mmol), VO(OPr-i)2Cl (1.3 mmol), THF (16.5 mmol ). Conditions B: similar to
entry 1 in Table 2. Amounts of substrates and reagents: 1b (0.5 mmol), 2 (0.5 mmol), VO(OEt)Cl2 (1.25 mmol). Conditions C: same as conditions B except the
temperature (-70 °C). Amounts of substrates and reagents: 1b (0.1 mmol), 2a (0.11 mmol), VO(OEt)Cl2 (0.25 mmol). [c] VO(OPr-i)2Cl (1.4 mmol) was used. [d] It
is also described in our previous paper.[6] [e] Reaction scale is small (0.05 mmol of 1f). [f] 1.5 equivalents of 2d were used.
aliphatic silyl enolates 2d and 2e were employed, the yields were
relatively low (Table 3, entries 6 and 7). Ester-ester enolate
results.). O-dicyclohexylboryl ketene N,O-acetal 1g and silyl
ketene acetal 2a were employed as boron and silyl enolates. The
coupling was also demonstrated using 1b and 2a (1: 1 molar ratio). same conditions as shown in entry 8 of Table 3 gave the
The reaction was carried out using VO(OEt)Cl2 (2.5 equivalents
to 1b as a one-electron oxidant) at -70 °C for 20 h to give the
cross-coupling product 3ba in 67% yield (Table 3, entry 8).
corresponding cross-coupling product 3ga in 19% yield (Table S1,
entry 3), where homo-coupling product of 1g was observed to a
small extent. The major by-product was ,-unsaturated amide
6g, which was obtained in 43% yield. Yield of 3ga increased up
to 39% by using excess amount of 2a (Scheme 1a), where 6g
was formed in 14%. The cross-coupling for amide-ketone enolate
Amide-ketone and amide-ester enolate coupling were
carried out, which were difficult to be achieved. Amide-ester
enolate coupling was first studied (Table S1 summarizes the
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