Transition Metal-Free Alkyne-Aldehyde Reductive C?C Coupling trough Cascade Borylation/Olefin Isomerization

Article abstract of DOI:10.1002/hlca.202000028

A direct approach to γ-keto esters through cascade alkyne-aldehyde reductive C?C coupling of propargyl esters and aromatic aldehydes under transition-metal-free (TM-free) fashion was developed. Compared with multistep processes, this procedure provides a

Full text of DOI:10.1002/hlca.202000028

HELVETICA
chimica acta
Accepted Article
Title: Transition metal-free Alkyne-Aldehyde Reductive C-C coupling
via Cascade Borylation/Olefin Isomerization
Authors: Imran Khan, Zhibin Luo, Yin Xu, Jimin Xie, Weihua Zhu, and
Bin Liu
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10.1002/hlca.202000028
Helvetica Chimica Acta
HELVETICA
Transition metal-free Alkyne-Aldehyde Reductive C-C coupling via
Cascade Borylation/Olefin Isomerization
Imran Khan,a,b Zhibin Luo,a* Yin Xu,a Jimin Xie,a Weihua Zhu,a Bin Liua*
a School of chemistry and chemical engineering, Jiangsu University, Zhenjiang, 212013, P.R. China
b School of the environment and safety engineering, Jiangsu University, Zhenjiang, 212013, P.R. China
A direct approach to γ-keto esters via cascade alkyne–aldehyde reductive C–C coupling of propargyl esters and aromatic aldehydes under
transition-metal-free (TM-free) fashion was developed. Compared with multistep processes, this procedure provides a fast path using
commercially available materials and could be handled conveniently to produce various γ-keto esters in moderate yields.
Keywords: transition metal-free • cascade reaction • borylation • γ-keto ester
Introduction
The construction of multiple bonds through cascade strategies,
particularly those in multicomponent environments, provides
a
straightforward and efficient path to the preparation of molecules with
high complexity. [1-4] The unremarkable privileges of cascade protocol
are well known, like the atom economy, as well as saving of time and
improvements in waste controls. The most attractive and powerful
[2]
quality of cascade reaction is the sequential bond-forming
transformations in
intermediates, particularly with those unstable or nonisolable
intermediates, thus enabled a unique route to target structure which
a
single operation without isolation of
[5-8]
is difficult in multistep synthesis. In this way, cascade reactions can be
[9-15]
considered under the banner of green chemistry.
Despite
advantages, cascade reactions are facing some inadequacies. Since
there are several routes leading to the formation of undesired
byproducts in the multi-component environments, it is always a
challenge to drive into the desired path towards target structure with
satisfactory yields. To the best of our knowledge, there is no
comprehensive cascade protocol reported for the straightforward
alkyne-aldehyde reductive C-C coupling [16-20] involving borylation, [21-
Scheme 1. Proposed pathways for alkyne–aldehyde reductive C–C coupling
Results and Discussion
27]
protodeboronation, and olefin isomerization, resulting in γ-keto
ester/amide products.
We started to screen uitable bases for the alkyne–aldehyde
reductive C–C coupling in DMSO at 70 ºC. To our pleasure, the γ-keto
ester product 2a was obtained in 33% yield in the presence of 1
equivalent of NaOH along with several unidentified side products
noticed (Table 1, entry 1). Examination of other alkali metal hydroxides
or stronger bases resulted in no significant improvements in the yields
(entries 2-4). It was worthy to notice that decreased base loading
promoted the reaction slightly affording 2a in 40% yield and when
MeOH (3 equivalent) was used as an additive in dry DMSO, the yield
was further promoted to 46%. In entries 8–10, when the reaction was
conducted in other solvents like 1,4-dioxane, MeCN or DCE (1,2-
dichloroethane), no desired product was observed. Organic bases
were verified to be inferior to the inorganic base in the further
examination as shown in entries 11-12.
Song group reported the borylation and B-O elimination strategy
for various propynols substrates in one pot operation furnishing
various alkenylboronates products in good yields.
recently disclosed basic ionic liquid as a superior medium for the
borylation of unreactive primary propargylic alcohols in transition
metal-free (TM-free) manner. [23] Based on these previous reports, we
envision that γ-hydroxy-α,β-acetylenic esters[28-43] might be generated
via the addition of acetylide ion to aldehyde with further borylation
under the basic condition to build vinylboronates in a cascade fashion
[21]
Our group
without the use of transition metal catalyst. Interestingly, the proposed
[44-48]
products continually undergo olefin isomerization
and
[49-54]
protodeboronation
thereafter affording γ-keto esters in
moderate yields as shown in Scheme 1.
Table 1. Optimization of reaction conditionsa.
1
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10.1002/hlca.202000028
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O
t-BuOLi (30 or 50 mol%)
DMSO, 70oC, 12h
MeOH (3 eq)
CO2R'
+ B2pin2
R
O
R
CO2R'
2 or 3
1
with propargyl ester
O
O
O
Entry
1
Base
NaOH
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
Dioxane
DCE
Yield (%)b
33
CO2Me
CO2Me
CO2Me
2b
2d
48%
NC
2c
2
LiOH
35
43%
45%
3
t-BuONa
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
Et3N
34
O
O
O
4
37
CO2Me
CO2Me
CO2Me
5c
39
2g
F
2e
Br
2f
O
6d
40
37%
41%
47%
7d,e
8d
46
O
O
O
n.r.
n.r.
n.r.
22
CO2Me
EtO
CO2Me
CO2Me
Ph
9d
N
2i
2j
Br
2h
Ph
OEt
10d
11d
12d
36%
36%
35%
DMSO
DMSO
O
O
CO2Me
O
DBU
n.r.
CO2Me
CO2Me
CO2Me
N
[a] Reaction scale: 1a (0.2 mmol), base (0.2 mmol), propargyl ester (0.6 mmol),
B2pin2 (0.4 mmol) in DMSO (1 mL) at 70 oC. (B2pin2 = bis(pinacolato)diboron). [b]
Isolated yield. [c] 50 mol% of base used. [d] 30 mol% of base used. [e] MeOH (3
equivalent) in dry DMSO.
2l
2k
Cl
Cl
2m
51%
34%
53%
O
O
O
O
O
Br
CO2Me
CO2Me
2p
2o
2n
Although the low yield could be ascribed to miscellaneous
intermediates, this method, however, provided a straightforward path
to the construction of γ-keto esters from commercially available
starting materials.[9] We then explored the generality of this cascade
reaction. Substrates bearing both electron-withdrawing and -donating
groups were well tolerated under the reaction condition affording γ-
keto esters (2b-2h) in moderate yields ranging from 36% to 48%.
Acetal-substituted substrate 1i could be successfully converted into
the desired product although in low yield. Meanwhile, substituents on
ortho-position could participate in the reaction while no significant
steric interference was observed (Figure 1, 2j-2k). Reactions performed
with naphthaldehydes showed slightly higher yields. When employing
heterocyclic aldehydes, γ-keto esters 2n-2o were obtained
respectively. However, aliphatic aldehydes showed no reactivity under
our conditions (2p not detected). Further examination utilizing
pyrrolidine propiolate was also successful and with improvement in
yields as compared to that of methyl propiolate in Scheme 2.
n.d.
41%
31%
with propargyl amide
O
O
O
N
N
O
3a
O
O
3c
O
3b
Cl
46%
63%
58%
O
O
O
N
O
N
3e
O
3d
62%
50%
Scheme 2. Substrate scope.
In-situ NMR was applied to gain insight into the mechanism. After
stirring the reaction mixture in d-DMSO at room temperature for 6h, a
set of new signals indicating the formation of compound 4 was
observed which is the key intermediate of this cascade protocol. The
parallel experiment at 70 oC after 12h showed desired product 2a
along with some unidentified impurities. Further control experiment
starting from the key intermediate 4 under standard condition led to
the formation of γ-keto esters, and traces of starting material were
recovered as shown in Scheme 3. But unfortunately, no improvement
in yield was observed even in this manner.
Scheme 3. In-situ NMR and control reactions
2
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Conclusions
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In summary, we have developed a straightforward cascade strategy
to access γ-keto esters from commercially available materials. 4 steps
including alkyne-aldehyde coupling, borylation, protodeboronation,
and olefin isomerization were suggested to be involved during this
transformation. Further studies to broaden the application scope and
improve the selectivity is currently underway in our group.
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a) Methyl propiolate (0.6 mmol), aldehyde (0.2 mmol), B2pin2 (0.4
mmol), and t-BuOLi (30 mol%) were dissolved in dry DMSO (1.0 mL)
along with MeOH (3 eq) and stirred at 70 ℃ for 12 hours. The
completion of the reaction was confirmed by TLC. The mixture was
purified by column chromatography using eluent (10:1) petroleum
ether and ethyl acetate.
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(0.4 mmol), and t-BuOLi (50 mol%) were added in dry DMSO (1.0 mL)
along with MeOH (3 eq) and stirred at 70 ℃ for 12 hours. The reaction
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ethyl acetate (3:1) and finally increased the polarity of eluent to (1:1)
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The authors acknowledge the financial support from the Natural
Science Foundation of China (21801099) and the Senior Talent
Foundation of Jiangsu University (18JDG016 and 13JDG062).
I. Khan acknowledges Jiang Wenruo Foundation and its chairman Prof.
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Author Contribution Statement
B. L., Z. L. planned the research and wrote the manuscript. J. X., W. Z.
supervised the research in all aspects. The experimental work was
performed by I. K., Y. X.
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Entry for the Table of Contents
A cascade alkyne-aldehyde reductive C-C coupling approach involving borylation and olefin isomerization was developed to
straightforwardly access the constructions of γ-keto esters.
5
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