Mg(OMe)2 promoted allylic isomerization of γ-hydroxy-α,β-alkenoic esters to synthesize γ-ketone esters

Article abstract of DOI:10.1039/c7ob00131b

This work concerns the Mg(OMe)₂ promoted allylic isomerization of γ-hydroxy-α,β-alkenoic esters with TMEDA as an additive. The isomerization proceeded under mild conditions and afforded γ-keto esters in high yield (up to 96%) within 2 h. Both (Z)- and (E)-γ-hydroxy-α,β-alkenoic esters were tolerated under the reaction conditions. This transformation involves the in situ formation of a dienolate intermediate from the easily accessible γ-hydroxy-α,β-alkenoic ester. The in situ generated dienolate can react with benzaldehyde and undergo a practical, useful tandem allylic isomerization-Aldol reaction to afford more functionalized compounds.

Full text of DOI:10.1039/c7ob00131b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Mg(OMe)2 Promoted Allylic Isomerization of γ-Hydroxy-α,β-
Alkenoic Esters to The Synthesis of γ-Ketone Esters
Luhao Lai, a A-Ni Li, b Jiawei Zhou, a Yarong Guo, a Li Lin, a* Wei Chen, a and Rui Wang a*
Received 00th January 20xx,
Accepted 00th January 20xx
This work concerns the Mg (OMe)2 promoted allylic isomerization of γ-hydroxy-α, β-alkenoic esters with TMEDA as an
additive. The isomerization proceeded under mild condition and afforded in high yield of γ-keto esters (up to 96%) within
2h. Both (Z)- and (E)-γ-hydroxy-α,β-alkenoic ester were tolerated under the reaction conditions. This transformation
involves an in-situ formation of dienolate intermediate from easily accessible γ-hydroxy-α,β-alkenoic ester. The in-situ
generated dienolate can reacted with benzaldehyde and provide a practical useful tandem allylic isomerization-Aldol
reaction to more functionalized compounds.
DOI: 10.1039/x0xx00000x
www.rsc.org/
unlike in the field of α/βꢀketo esters synthesis, few facile
methodologies have been reported for γꢀketo esters synthesis. [7]
Introduction
R3
R3
Isomerization of allylic alcohol to the corresponding ketones or
aldehydes represents an attractive oneꢀstep transformation in
Ru, Rh, Ir, Fe, Mo, ...
R2
R4
OH
R2
R4
transition metal complexes
[1]
[2]
organic synthesis.
This atomꢀeconomic process
has
R1
R1
O
received chemists’ great attentions due to the multistep
reductionꢀoxidation procedures as well as production of wastes
could be avoided. During the past decades, people have made
Tr ansition Metal F ree?
Scheme 1. Overview of allylic alcohol isomerization.
Allylic isomerization of γꢀhydroxyꢀα, βꢀalkenoic esters is one
simple strategy for easily obtaining their corresponding γꢀketo
esters (Scheme 2). Unfortunately, electro deficient allylic
alcohols, such as γꢀhydroxyꢀα, βꢀalkenoic esters, were not
suitable substrates for most of the developed transition metal
catalytic systems. So far, only highly toxic Fe(CO)5 was
great efforts to develop various catalysts from over ten
[3]
transition metals (Scheme 1).
These transition metal
complexes are generally costly and/ or highly toxic. In the other
hand, harsh conditions with strong acid, alkali and/or high
temperature have always been conducted. Although less
substituted allylic alcohols can more easily undergo the
isomerization, substrate capability is still a challenging issue
which needs to be overcome. [1c] Due to the strong dependence
upon the substituent of allylic alcohol, electroꢀrich as well as
less hindered allylic alcohols are favored substrates in most
cases. On the contrary, allylic alcohols containing electronꢀ
withdrawing groups on the C=C double bond are not capable.
reported to promote the allylic isomerization of (
α,βꢀalkenoic esters but with very limited examples.
E)ꢀγꢀhydroxyꢀ
[3g, 4b]
Most
importantly, because the toxic Fe(CO)5 is a volatile reagent, the
operation MUST be particularly careful with strict safety
precautions. Thereby, highly stable and safely operated
catalytic systems are urgently in demand. The allylic
[4]
isomerization of more hindered but more easily accessible (Z)ꢀ
The residue of transition metal (especially heavy metal) is
γꢀhydroxyꢀα, βꢀalkenoic esters is a rather challenging issue for
transition metal catalysts. In addition, intramolecular
one of the most serious problems of drug safety, developing
transition metal free strategy in drug synthesis tends to be one
of the greatest challenges for chemists. However, only very
limited transition metal free protocols for the allylic
isomerization has been reported.[5] γꢀketo esters are also
important building blocks and versatile synthetic intermediates
in the synthesis of natural products and drug leads. [6] However,
lactonization of
(Z)ꢀγꢀhydroxyꢀα, βꢀalkenoic esters to γꢀ
butyrolactone could readily take place either in a relative basic
or acidic condition. To the best of our knowledge,
methodologies for the isomerization of (Z)ꢀγꢀhydroxyꢀα, βꢀ
alkenoic esters to γꢀketo esters has rarely been reported. Thus,
new practical protocols need be eagerly developed to deal with
the intense demands of all these challenging issues.
O
CO2Me
OH
Mg(OMe)2
Fe(CO)5
(E/Z)-1
R
R
CO2Me
in reports
this work
(E)-1
2
Scheme 2. Oneꢀpot Synthesis of γꢀketo esters via allylic alcohol
isomerization.
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Although alkaline earth metal catalysis has received more and without using any additive (entry 7). Either increasing or
[8]
more attentions recently,
the applications of these catalysts decreasing the amount of Mg(OMe)2 caused lower yield (entry
are mainly focusing on the 1, 3ꢀdicarbonyl compound addition 1ꢀ6 and 8ꢀ9). The isomerization yield was not improved but
[9]
[10]
and activated estersꢀAldol type reaction.
Catalytic with longer reaction time while using DME or TEA as an
applications of alkaline earth metals especially for magnesium additive (entry 10ꢀ11). When TMEDA was introduced into the
to other novel transformations have been much less disclosed. reaction mixture as the bidentate ligand, it was found that the
[11]
Herein we report a facile Mg(OMe)2 promoted allylic yield of the isomerization was well improved. Isolated yields
isomerization to afford γꢀketo esters involving an inꢀsitu varied from 86% to 91% via changing the loadings of TMEDA
dienolate intermediate.
between 10ꢀ100 mol% (entry 12ꢀ17). A 91% yield of 2o was
obtained while using 67 mol% of Mg(OMe)2 in combination
with 50 mol% of TMEDA (entry 15).
Results and discussion
Table 2. Optimization of reaction conditions.[a]
To expand the enantioselective synthesis of highly
functionalized chiral γꢀhydroxyꢀα, βꢀacetylenic esters to
[12]
synthetic chemistry,
we intended to reduce 1a with
Entry Mg(OMe)2 (mol %)[b] Additive (mol %)[c] Isolated yield (%)
Mg/MeOH, which could be used for the conjugated reduction
[13]
1
10 %
20 %
40 %
60 %
63 %
65 %
67 %
70 %
80 %
67 %
...
None
40.7 %
47.2 %
51.5 %
56.6 %
63.9 %
73.6 %
74.8 %
63.1 %
66.6 %
73.0 %
75.4 %
86.0 %
84.1 %
85.5 %
91 %
of γꢀalkyl/arylꢀα, βꢀ alkenoic esters.
isomerized product (2a) was afforded instead of a reduced
product ( ) (Scheme 3). Subsequent studies indicated that this
process was essentially promoted by Mg(OMe)2.
To our surprise, an
2
...
3
...
3
[14]
4
...
Other
5
...
magnesium alkoxides were also examined in the model reaction
but displayed much poorer catalytic activity. Then a series of
reaction influences involving various alkali alkoxides,
additives, as well as solvents has been well studied.
6
...
7
...
8
...
9
...
10
11
12
13
14
15
16
17
DME (50 %)
TEA (50 %)
TMEDA (10 %)
TMEDA (20 %)
TMEDA (30 %)
TMEDA (50 %)
TMEDA (80 %)
TMEDA (100 %)
...
...
Scheme 3. Discovery of the present allylic isomerization.
...
Although similar transformation was carried out while using
...
[15]
strong alkali KOH,
the corresponding γꢀketo acid was
...
87.9 %
afforded. Other alkali alkoxides showed poorer catalytic
activity for this model transformation. The γꢀketo ester 2a was
obtained in rather lower yields of 41.4% and 43% while using
...
87.9 %
[a] Method B: 0.1mol of 1a was used. [b] Mg(OMe)2 was used as in-situ
prepared in MeOH solution (0.033 M) and without additional MeOH. [c]
The additives were freshly distilled before use.
CH3ONa and tꢀBuOK, respectively (entry 1ꢀ2, Table 1). A
To our delight, Mg(OMe)2 (67mol%) in combination of
TMEDA (50 mol%) can readily promote the isomerization of
γꢀhydroxyꢀα,βꢀalkenoic esters in a wide range (Table 3).
relatively higher yield (66.6%) was obtained when Mg(OMe)2
was introduced into the reaction mixture (entry 3, Table 1).
While using Mg(OtꢀBu)2 in the model reaction, however, no 2a
was found. Complex byproducts was also observed via crude
1H NMR.
Different γꢀsubstituted
alkyl substitutes was tolerated. The corresponding γꢀketo esters
) were afforded favourably with high to excellent yields
under room temperature within 2h. With γꢀaryl substitutes, ( )ꢀ
γꢀketo esters -e (entry 1ꢀ4) and 2g-h (entry 6ꢀ7) were
1 involving with aryl, alkenyl as well as
(
2
Table 1. Preliminary studies of the model reaction.[a]
Z
2
b
obtained with 84%ꢀ96% yields. Lower yields of 79% and 75%
were observed while using 2f and 2i with large steric orthoꢀ
Entry
1a (mmol)
0.1
MOR
equivalent
0.8
Isolated yield (%)
41.4 [b]
43 [b]
1
2
3
4
CH3ONa
tꢀBuOK
subtitutes, respectively (entry
5 and 8). Heteroꢀaromatic
0.1
0.8
substituted 2j and γꢀstyryl 2k were also favourably obtained
with excellent yields (95% and 92%) (entry 9ꢀ10). The
isomerization of alkyl substituted 1l-n proceeded well and gave
moderate to high yields (66ꢀ80%) of the corresponding γꢀketo
0.1
Mg(OMe)2
0.8
66.6
N. D.[b][c]
0.1
Mg(OtꢀBu)2
0.6
[a] Method A. [b] Complex byproducts were observed.[c] No 2a was found.
Loadings of Mg(OMe)2 and different kind of additives were
examined to improve the isomerization of 1a (Table 2). The
isomerization was not completed in very long time (over 24h)
while using low loadings of Mg(OMe)2 (entry 1ꢀ2). It was
interesting to find that 67 mol% of Mg(OMe)2 afforded the
corresponding γꢀketo ester 2a with the highest yield of 74.8%
esters
generated from (
(48h) was required (entry 15).
2
(entry 11ꢀ13). It is noteworthy that 2o could also be
E
)ꢀ1o with 67% yield, but much longer time
2 | J. Name., 2012, 00, 1-3
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Table 3. Allylic isomerization 1 to γꢀKeto Esters. [a]
Exploring the isomerization of 1d to 2d as a model reaction,
solvent influence was subsequently studied (Table 4). It was
found that the solvent played an important role: the reaction
proceeded favourably in MeOH and gave 83% of 2d within 2h
(entry 1). Although similar yield of 81% was obtained while
using toluene as the solvent (entry 2), much longer reaction
time (24h) was necessary for the completion of this process.
Complex byproducts were observed after stirring for long time
in CH2Cl2 (entry 3). Other nonꢀprotic solvents were far more
unsuitable for this reaction due to the poorer solubility of
Mg(OMe)2 (entry 4ꢀ5). The isomerization of 1d was not
completed even after 24h neither in THF nor in Et2O.
Yield
(%) [b]
Entry Substrate
1
γꢀKeto Esters
O
OMe
88%
O
2b
(Z)ꢀ1b
2
92%
84%
94%
79%
94%
2c
(Z)ꢀ1c
3
O
Cl
CO2Me
Table 4. Solvent effect for the allylic isomerization.[a]
2d
(Z)ꢀ1d
4
O
CO2Me
Cl
2e
(Z)ꢀ1e
Entry
1
Solvent [b]
MeOH
Toluene
CH2Cl2
THF
Time
2h
Isolated yield (%)
5
Cl
O
CO2Me
84
81
47
48
44
2f
2
8h
(Z)ꢀ1f
3
24h
24h
24h
6
O
4 [c]
5 [c]
CO2Me
Et2O
2g
(Z)ꢀ1g
[a] Method C: 1d : Mg(OMe)2 (solid) : TMEDA = 1: 0.67 : 0.5. [b] All of
the reaction was performed in 2 mL of the corresponding solvent. [c] The
reaction was not completed detected by TLC.
7
O
CO2Me
96%
75%
MeO
2h
(Z)ꢀ1h
OH CO2Me
8
O
CO2Me
OMe
OMe
O
2i
2j
(Z)ꢀ1i
(Z)ꢀ1j
9
CO2Me
92%
95%
80%
O
O
OH CO2Me
10
CO2Me
(Z)ꢀ1k
(Z)ꢀ1l
2k
11
O
Scheme 4. Proposed mechanism.
CO2Me
In general, two classes of mechanisms, the metal hydride
additionꢀelimination pathway and the πꢀallyl intermediate
pathway were widely recognized to explain the transition metal
catalyzed allylic isomerization.[16] However, the proposed
dienolate[17] pathway mechanism is more preferred to illustrate
2l
12
13
14
O
78%
66%
C6H13
CO2Me
2m
2n
(Z)ꢀ1m
(Z)ꢀ1n
O
this work (Scheme 4). Firstly, dienolate
B
was generated via
1 with Mg(OMe)2.
C4H9
CO2Me
CO2Me
deprotonating complex in combination of
A
According to the poorer stability of the dienolate compared
with ester enolate, a fast semiꢀprotonation step was followed by.
Meanwhile, one molecular Mg(OMe)2 was generated along
O
O
91%
67%
2o
(Z)ꢀ1o
with the formation of enolate
another molecular Mg(OMe)2 were then afforded during the
second protonation step. For the isomerisation of ( )ꢀ
intermediate was hardly afforded according to the trans
geometry of the C=C bond. Thus, the formation of dienolate
C. Then, γꢀketo ester 2 as well as
15[c]
CO2Me
E
1,
2o
A
ꢀ
(E)ꢀ1o
B
[a] All cases precedded in 0.1 mmol scale for 2h in 2 mL of MeOH,
:TMEDA:Mg(OMe)2 = 1:0.67:0.5. [b] Isolated yields. [c] Reacted for 48h.
1
may undergo an intermolecular deprotonation pathway, and this
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was undoubtedly the critical rateꢀlimiting step as for (
isomerization. From this point of view, it was no hard to a ketoneꢀAldol adduct.
understand why much longer reaction time was required for the with benezaldehyde under standard isomerization condication
isomerization of ( )ꢀ1o compared with ( )ꢀ1o but with much however, compound was not afforded, but only with 2o and
lower yield (entry 14ꢀ15, Table 3). It was suggested that benezaldehyde being remained. Although the relative
additive chelating with magnesium increased the stability of the stereochemistry of compound and the diastereoselectivity of
intermediates and positively affected the reaction yield. this tandem allylic isomerizationꢀAldol reaction were not well
To further understand the mechanism, the deuteration studied, it was noteworthy that only ( )ꢀ10 was isolated via
using TFA. [20] Converting (
)ꢀ10 to
)ꢀ12 was readily carried out in oneꢀpot with an overall yield
Under the of 70%.‡ Thus, the above proposed mechanism was reliably
1o proceeded confirmed via the formation of Reformatskyꢀlike adduct
smoothly and only afforded the γꢀketone ester 2o. However, Additionally, this approach can be applied to the synthesis of αꢀ
E
)ꢀ
1
like adduct 9 was obtained with a high yield of 89% instead of
[19]
While combining γꢀketone ester 2o
E
Z
9
9
E
[5d]
experiment
was carried out as shown in Scheme 5. dehydrating compound
9
E
Following the similar procedure, deuterated 1o
(
Dꢀ
1o) was
(E
readily obtained from a deuterated benzaldehyde
.
standard conditions, the isomerization of
Dꢀ
9.
neither 2o nor Dꢀ2o’ was observed as the deuterated product. alkenylꢀγꢀbutyrolactone which is a significant class of natural
Dꢀ
The result indicated the 1, 2ꢀhydride shift mechanism was product. [21]
excluded in the present isomerization.
Scheme 5. Isomerization of γꢀmethoxyꢀα, βꢀalkenoic esters. i: Lindlar Pd,
H2, Et2O. ii: Mg(OMe)2 (67mol%), TMEDA (50mol%), MeOH.
To trap the enolate intermediate, two isomers of γꢀmethoxyꢀα,
βꢀalkenoic ester
the starting material. Unfortunately, neither (
not afford the desired isomerized product
7
were synthesized using mandelic acid
4
did
as
Scheme 7. Tandem allylic isomerizationꢀAldol reaction for the synthesis of
)ꢀαꢀalkenylꢀγꢀbutyrolactone. i: 1o: Mg(OMe)2: TMEDA: PhCHO= 1: 0.67:
Z)ꢀ7 nor (E)ꢀ7
(
E
8
even after 48h 0.5: 1, 89%. ii: TFA (30 equ.), CH2Cl2, 98%. iii: a) NaBH4 (3 equ.), MeOH,
then b) HCl (1M) in oneꢀpot, 70% for the two steps.
under standard conditions (Scheme 6). In one hand, it was
difficult to deprotonate the γꢀCH of (Z/E)ꢀ7 to form the
dienolate intermediate due to the steric hindrance of the γꢀ
methoxy group. In another point of view, it was supposed that
the ketoneꢀenolate protonation step might be blocked by the
Experimental
Method A (Table 1). Alkaline earth metal alkoxides screening in
the allylic isomerization of 1a: To a roundꢀbottom flask was added
MOR, ROH (2 mL), and γꢀhydroxyꢀα, βꢀalkenoic esters (0.1 mmol).
After stirring at room temperature for 2 h, the resulting solution was
concentrated under vacuum, The residue was purified by
chromatography on silica gel (PE / EA = 9:1 to 7:1) to afford the
compound.
Method B (Table 2 and 3): To a roundꢀbottom flask that was added
γꢀhydroxyꢀα, βꢀalkenoic esters (0.1 mmol), additive and Mg(OMe)2
(0.033M in MeOH and without additional solvent). After stirring the
mixture at room temperature for 2 h, the resulting solution was
concentrated directly under vacuum, The residue was purified by
chromatography on silica gel (PE / EA = 9:1 to 7:1) to afford the
compound.
methylated γꢀhydroxy group (
compound . In other words, it was that the ketoneꢀenolate
protonation of dienolate to afford enolate definitively
8) for the isomerization of
7
B
C
facilitate this isomerization. Thus, the subsequent experiment
was carried out to conform whether the dienolate or ester
enolate intermediate can be captured by an electrophile. If so, it
would be of great significance for the application of this
protocol.
Method C (Table 4). Solvent effect examination for the allylic
isomerization of 1d: To a roundꢀbottom flask that was added γꢀ
hydroxyꢀα, βꢀalkenoic esters (0.1 mmol), TMEDA (7.5 ꢁl, 0.05
mmol, 50 mol %), Mg(OMe)2 (5.75 mg, 0.067 mmol, 67 %) and
solvent. After stirring at room temperature for 2 h (24h while using
Scheme 6. Isomerization of γꢀmethoxyꢀα, βꢀalkenoic esters. i: SOCl2,
MeOH, quantitative. ii: NaH, CH3I, 51%. iii: DIBAL. iv: Ph3PCH2CO2CH3,
58% and 29% yields of (Z)ꢀ7 and (E)ꢀ7 for two steps, respectively. v: CH2Cl2, THF or Et2O as solvent), the resulting solution was
Mg(OMe)2 (67mol%), TMEDA (50mol%), MeOH, 48h.
concentrated directly under vacuum. The residue was then purified
by chromatography on silica gel (PE / EA = 9:1 to 7:1) to afford the
compound.
[3g, 18]
As we expected, a tandem allylic isomerizationꢀAldol
reaction was carried out while benzaldehyde was introduced as
the electrophile under standard conditions (Scheme 7). When
the reaction was performed on a 2 mmol scale, unlike the
transition metal catalyzed allylic isomerization, a Reformatskyꢀ
Conclusions
4 | J. Name., 2012, 00, 1-3
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9
Selected examples: (a) M. Agostinho and S. Kobayashi, J. Am. Chem.
In conclusion, we have developed a Mg(OMe)2 promoted
allylic isomerization of γꢀhydroxyꢀα,βꢀalkenoic esters using
TMEDA as an additive. A series of γꢀketo esters were readily
Soc. 2008, 130, 2430; (b) T. Tsubogo, Y. Yamashita and S. Kobayashi,
Angew. Chem., Int. Ed. 2009, 48, 9117; (c) T. Poisson, Y. Yamashita and S.
Kobayashi, J. Am. Chem. Soc. 2010, 132, 7890.
afforded in high yield (up to 96%) under very mild conditions. 10 Selected examples: (a) D. A. Evans and S. G. Nelson, J. Am. Chem. Soc.
1997, 119, 6452; (b) T. Tsubogo, S. Saito, K. Seki, Y. Yamashita and S.
Kobayashi, J. Am. Chem. Soc. 2008, 130, 13321; (c) H. V. Nguyen, R.
Matsubara and S. Kobayashi, Angew. Chem. Int. Ed. 2009, 48, 5927.
In addition, an inꢀsitu dienolate pathway mechanism was
proposed and verified by a tandem allylic isomerizationꢀAldol
reaction, which can be applied to the synthesis of αꢀalkenylꢀγꢀ
butyrolactones. Applications and extensions of this protocol are
under investigating in our group.
11 Our recent examples: (a) L. Lin, J. Zhang, X. Ma, X. Fu and R. Wang,
Org. Lett., 2011, 13, 6410; (b) D. Yang, L. Wang, F. Han, D. Zhao, B. Zhang
and R. Wang, Angew. Chem. Int. Ed., 2013, 52, 6739; (c) D. Yang, L. Wang,
F. Han, D. Zhao and R. Wang, Chem. –Eur. J., 2014, 20, 8584; (d) D. Yang,
L. Wang, F. Han, D. Li, D. Zhao, Y. Cao, Y. Ma, W. Kong, Q. Sun and R.
Wang, Chem. –Eur. J., 2014, 20, 16478; (e) L. Wang, D. Yang, F. Han, D. Li,
D. Zhao and R. Wang, Org. Lett., 2015, 17, 176; (f) D. Yang, L. Wang, F.
Han, D. Li, D. Zhao and R. Wang, Angew. Chem. Int. Ed., 2015, 54, 2185; (g)
L. Wang, D. Yang, D. Li R. Wang, Org. Lett., 2015, 17, 3004; (h) D. Li, L.
Wang, D. Yang, B. Zhang and R. Wang, ACS Catal., 2015, 5, 7432; (i) L.
Wang, D. Li, D. Yang, K. Wang, J. Wang, P. Wang, S. Wu and R. Wang,
Chem. –Asian J., 2016, 11, 691; (j) Li, D. Wang, Y. J. Wang, L. Q. Wang, J.
Wang, P. X. Wang, K. Z. Lin, L. Liu, D. S. Jiang, X. X. Yang, D. X. Chem.
Commun., 2016, 52, 9640.
Acknowledgements
We gratefully acknowledge financial support from NSFC (nos.
21002043 and 21272107), the National S&T Major Project of
China (2012ZX09504ꢀ001ꢀ003), and the Fundamental
Research Funds for the Central Universities (2022016zr0064).
12 (a) L. Lin, X. X. Jiang, W. X. Liu, L. Qiu, Z. Q. Xu, J. K. Xu, A. S. C.
Chan and R. Wang, Org. Lett. 2007, 9, 2329; (b) L. Lin, Q. Y. Zhao, A.ꢀN.
Li, F. B. Ren, F. Z. Yang and R. Wang, Org. Biomol. Chem. 2009, 7, 3663.
13 I. K. Youn, G. H. Yon and C. S. Pak, Tetrahedron Lett. 1986, 27, 2409.
14 Aforehand prepared methanol solution of Mg(OMe)2 was used when the
reaction solvent was MeOH, otherwise solid state of Mg(OMe)2 was used.
Mg(OMe)2 was prepared following the literature : L. I. Smith and P. F.
Wiley, J. Am. Chem. Soc. 1946, 68, 887.
15 No detailed datas or subsequent report were disclosed: M. D. Giacomo, P.
Leggeri, O. Azzolina, D. Pirillo and G. Traverso, J. Chem. Res; (S) 1990, 16.
16 An excellent mechanism study by R. H. Grubbs: D. V. McGrath and R.
H. Grubbs, Organometallics 1994, 13, 224.
Notes and references
‡ Unꢀoptimized conditions.
1
Selected reviews: (a) L. A. Yanovskaya and Kh. Shakhidayatov, Russ.
Chem. Rev. 1970, 39, 859; (b) R. C. Van der Drift, E. Bowman and E. Drent,
J. Organomet. Chem. 2002, 650, 1; (c) R. Uma, C. Crévisy and R. Grée,
Chem. Rev. 2003, 103, 27; (d) V. Cadierno, P. Crochet and J. Gimeno, Synlett
2008, 8, 1105; (e) P. LorenzoꢀLuis, A. Romerosa and M. SerranoꢀRuiz, ACS
Catal. 2012, 2, 1079; (f) N. Ahlsten, A. Bartoszewicz and B. MartínꢀMatute,
Dalton Trans. 2012, 41, 1660; (g) D. Cahard, S. Gaillard and J. L. Renaud,
Tetrahedron Lett. 2015, 56, 6159; (h) H. Li and C. Mazet, Acc. Chem. Res.
2016, 49, 1232.
17 (a) Z. Lu, G. B. Chai and S. M. Ma, J. Am. Chem. Soc. 2007, 129, 14546;
(b) A. Yamaguchi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
10842.
2
3
B. M. Trost, Science 1991, 254, 1471.
Selected examples: (a) B. M. Trost and R. J. Kulawiec, J. Am. Chem. Soc.
1993, 115, 2027; (b) K. Tanaka, S. Qiao, M. Tobisu, M. M.ꢀC. Lo and G. C.
Fu, J. Am. Chem. Soc. 2000, 122, 9870; (c) D. Finnegan, B. A. Seigal and M.
L. Snapper, Org. Lett. 2006, 8, 2603; (d) V. Cadierno, S. E. GarcíaꢀGarrido, J.
Gimeno, A. VarelaꢀÁlvarez and J. A. Sordo, J. Am. Chem. Soc. 2006, 128,
1360; (e) T. Doi, T. Fukuyama, S. Minamino, G. Husson and I. Ryu, Chem.
Commun. 2006, 17, 1875; (f) D. H. Leung, R. G. Bergman and K. N.
Raymond, J. Am. Chem. Soc. 2007, 129, 2746; (g) J. Petrignet, I. Prathap, S.
Chandrasekhar, J. S. Yadav and R. Grée, Angew. Chem. Int. Ed. 2007, 46,
6297; (h) B. LastraꢀBarreira, J. Díez and P. Crochet, Green Chem. 2009, 11,
1681; (i) L. Mantilli and C. Mazet, Tetrahedron Lett. 2009, 50, 4141; (j) M.
Batuecas, M. A. Esteruelas, C. GarcíaꢀYebra and E. Oňate, Organometallics
2010, 29, 2166.
18 Selected examples: (a) B. M. Trost, L. Dong and G. M. Schroeder, J. Am.
Chem. Soc. 2005, 127, 2844; (b) D. Cuperly, J. Petrignet, C. Crévisy and R.
Grée,Chem. Eur. J. 2006, 12, 3261; (c) N. Ahlstena and B. MartínꢀMatute,
Adv. Synth. Catal. 2009, 351, 2657. And references cited in.
19 It is different from the intramolecular tandem allylic isomerizationꢀAldol
reaction reported by René Grée in ref. 3g. The Reformatskyꢀlike adduct 4
was not observed while stirring 2o and benzaldehyde under standard
conditions over 24 hours.
20 B. Madrigal, P. Puebla, R. Peláez, E. Caballero and M. Medarde, J. Org.
Chem. 2003, 68, 854.
21 O. Reiser and M. Seitz, Curr. Opin. Chem. Biol. 2005, 9, 285. And
references cited in.
4
Limited catalytic systems see: (a) X. Lu, J. Ji, D. Ma and W. Shen, J.
Org. Chem. 1991, 56, 5774; (b) H. Cherkaoui, M. Soufiaoui and R. Grée,
Tetrahedron 2001, 57, 2379.
5
(a) D. R. Dimmel, W. Y. Fu and S. B. Gharpure, J. Org. Chem.1976, 41,
3092; (b) G. A. Schmid, H.ꢀJ. Borschberg, Helv.Chim. Acta. 2001, 84, 401;
(c) A. J. S. Johnston, M. G. McLaughlin, J. P. Reid and M. J. Cook, Org.
Biomol. Chem. 2013, 11, 7662; (d) H.ꢀX. Zheng, Z.ꢀF. Xiao, C.ꢀZ. Yao, Q.ꢀQ.
Li, X.ꢀS. Ning, Y.ꢀB. Kang and Y. Tang, Org. Lett. 2015, 17, 6102; (e) K.
Mondal, B. Mondal and S. C. Pan, J. Org. Chem. 2016, 81, 4835; (f) S.
MartinezꢀErro, A. SanzꢀMarco, A. B. Gómez, A. VázquezꢀRomero, M. S. G.
Ahlquist and B. MartínꢀMatute, J. Amer. Chem. Soc., 2016, 138, 13408.
6
(a) A. G. Csaky and J. Plumet, Chem. Soc. Rev. 2001, 30, 313; (b) G.
Piancatelli, M. D’Auria, F. D’Onofrio, Synthesis 1994, 867; (c) Y. S. Rao,
Chem. Rev. 1976, 76, 625; (d) L. Chen, T.ꢀD. Shi and J. Zhou, Chem. Asian
J., 2013, 8, 556–559.
7
(a) C. Nájera and M. Yust, J. Chem. Soc. Perkin. Trans. I, 1989, 8, 1387;
(b) G. M. Coppola and R. E. Damon, J. Heterocyclic Chem., 1995, 32, 1133;
(c) J. L. Shamshina and T. S. Snowden, Org. Lett. 2006, 8, 5881.
8
Recent reviews for alkalineꢀearth metal catalyzed CꢀC bond formation:
(a) U. Kazmaier, Angew. Chem., Int. Ed. 2009, 48, 5790; (b) S. Harder, Chem.
Rev. 2010, 110, 3852. And references cited in; (c) S. Kobayashi and Y.
Yamashita, Acc. Chem. Res. 2011, 44, 58.
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Organic & Biomolecular Chemistry
Page 6 of 6
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DOI: 10.1039/C7OB00131B
Mg(OMe)2 Promoted Allylic Isomerization of γꢀHydroxyꢀα,βꢀAlkenoic
Esters to The Synthesis of γꢀKetone Esters
Luhao Lai, a AꢀNi Li, b Jiawei Zhou, a Yarong Guo, a Li Lin, a* Wei Chen, a and Rui Wang a*
a School of Life Sciences, School of Basic Medical Sciences, Institute of Biochemistry and Molecular
Biology, and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University,
Lanzhou 730000, China, bThe first laboratory of Lanzhou Institute of Biological Products Co., Ltd.,
Lanzhou 730046, China.
E-mail: linli@lzu.edu.cn, wangrui@lzu.edu.cn
This work concerns the Mg (OMe)2 promoted allylic isomerization of γꢀhydroxyꢀα, βꢀalkenoic esters
with TMEDA as an additive. The isomerization proceeded under mild condition and afforded in high
yield of γꢀketo esters (up to 96%) within 2h. Both (Z)ꢀ and (E)ꢀγꢀhydroxyꢀα,βꢀalkenoic ester were
tolerated under the reaction conditions. This transformation involves an inꢀsitu formation of dienolate
intermediate from easily accessible γꢀhydroxyꢀα, βꢀalkenoic ester. The inꢀsitu generated dienolate can
reacted with benzaldehyde and provide a practical useful tandem allylic isomerizationꢀAldol reaction
to more functionalized compounds.