Asymmetric synthesis of multifunctional aryl allyl ethers by nucleophilic catalysis

Article abstract of DOI:10.1039/C9RA00155G

Asymmetric allylic substitution of Morita-Baylis-Hillman (MBH) carbonates with less-nucleophilic phenols mediated by nucleophilic amine catalysis was successfully developed. A variety of substituted aryl allyl ethers were afforded with moderate to high yields with excellent enantioselectivities. The chiral MBH alcohol could be easily accessed from the corresponding aryl allyl ether.

Full text of DOI:10.1039/C9RA00155G

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Asymmetric synthesis of multifunctional aryl allyl
ethers by nucleophilic catalysis†
Cite this: RSC Adv., 2019, 9, 11585
Shuai Zhao,
Xiang-Xiang Chen, Zi-Jian Yin and Xin Chen
Lei Jin, Zhi-Li Chen, Xue Rui, Jia-Yi He, Ran Xia, Ke Chen,
*
Received 8th January 2019
Accepted 2nd April 2019
Asymmetric allylic substitution of Morita–Baylis–Hillman (MBH) carbonates with less-nucleophilic phenols
mediated by nucleophilic amine catalysis was successfully developed. A variety of substituted aryl allyl
ethers were afforded with moderate to high yields with excellent enantioselectivities. The chiral MBH
alcohol could be easily accessed from the corresponding aryl allyl ether.
DOI: 10.1039/c9ra00155g
rsc.li/rsc-advances
Morita–Baylis–Hillman (MBH) reactions provide efficient highly intermediates of many naturally occurring molecules and
5,9
functionalized synthons to be used in the total synthesis of pharmaceutical compounds. Moreover, chiral MBH alcohol
1
natural products and biologically relevant compounds. In could be directly accessed from the nal product.
particular, asymmetric transformations of racemic MBH
We initiated the study by investigating the reaction of phenol
carbonates and acetates have provided straightforward access 2a and MBH carbonate 3a in DCM at room temperature. A series
to a wide variety of optically active molecules on the basis of of cinchona alkaloids and their derivatives were screened as
2c
allylic substitution reactions, formal 1,3-dipolar cycloadditions catalysts (Fig. 1). The results are outlined in Table 1. Unmodi-
2
and miscellaneous transformations. Asymmetric allylic ed cinchona alkaloids quinine 1a and quinidine 1b gave the
substitution of racemic MBH carbonates and acetates by desired product 4a with very high yields but with very low ee
nucleophiles (nitrogen, oxygen, carbon, etc.) under the catalysis values (Table 1, entries 1–2). Protecting the hydroxyl group of 1b
3
2
of transition metal complexes or organocatalysts has been gave 1c and 1d, respectively. But both catalysts resulted in
extensively explored in the past few decades. Reactions with decreased yields and very poor ee values (Table 1, entries 3–4).
nucleophilic oxygen result in formation of chiral MBH alcohols
1b,4
or ethers, which are synthetically useful building blocks and
5
bioactive molecules. Despite a few nucleophilic O-substitution
reactions of MBH carbonates and acetates under the catalysis of
6
7
palladium or organocatalysts that have been developed, there
are still many limitations for the enantioselectivity, chemical
yields and generality of the substrates, especially when the less-
7f–7h
nucleophilic phenols were used.
Therefore, the development
of efficient protocols to access enantiomerically pure MBH
alcohols and ethers is still in demand.
As part of our on-going program on developing novel and
8
practical catalytic asymmetric transformations, we herein
present an asymmetric allylic O-substitution reaction of MBH
carbonate with less-nucleophilic phenols mediated by nucleo-
philic amine catalyst. Aer a careful investigation of the reac-
tion conditions, asymmetric allylic substitution of Morita–
Baylis–Hillman (MBH) adducts with less-nucleophilic phenols
was successfully developed. An array of substituted chiral aryl
allyl ethers were obtained with excellent enantioselectivities.
Chiral aryl allyl ethers are valuable substructures and synthetic
School of Pharmaceutical Engineering
Changzhou, 213164, P. R. China. E-mail: Xinchen@cczu.edu.cn
Electronic supplementary information (ESI) available: Experimental procedures,
& Life Science, Changzhou University,
†
Fig. 1 Chiral nucleophilic catalysts screened.
analytical data and NMR spectra. See DOI: 10.1039/c9ra00155g
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a
Table 1 Optimization of reaction parameters
moderate yield and ee value (Table 1, entry 15). 1j and 1k are two
analogs of catalyst 1h, but both failed to give better results than
1h (Table 1, entries 16–17). As a summary, the optimal condi-
tions for the asymmetric allylic substitution reaction included
using catalyst 1h (20 mol%) in 1,4-dioxane (0.05 M) at room
temperature.
With the optimized conditions in hand, the substrate scope
of the asymmetric allylic substitution reaction was investigated.
As shown in Table 2, a variety of substituted phenols and MBH
carbonates were well tolerated in this catalytic system,
providing the desired products in moderate to high yields (up to
96%) with excellent enantioselectivities (up to 95%). The
substituents' position in the phenyl ring of phenol 2 had no
signicant impact on the enantioselectivity (4b–4d, 4e–4g, 4h–
C
ꢀ1
b
c
Entry
1
Solvent
(mol L
)
t (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1h
1h
1h
1h
1h
1h
1i
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
0.05
0.05
0.05
0.05
0.05
0.05
24
22
72
72
72
48
48
72
66
72
120
84
84
96
75
52
52
94
98
58
37
67
95
77
84
30
79
91
51
92
95
68
94
93
ꢀ4
7
10
8
7
4j, 4k–4m). Both electron-donating and electron-withdrawing
ꢀ3
ꢀ45
41
79
73
74
76
77
95
ꢀ73
86
89
substituents were compatible with this catalytic system (4b–
4n), although lower yields were observed when the substrates
9
d
10
11
12
13
14
15
16
17
e
Table 2 Substrate scope of the asymmetric allylic substitution
e
a,b,c
reaction
e,f
e,f
e,f
e,f
e,f
DCM
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1j
1k
a
Unless otherwise noted, the reaction was carried out with 2a (0.1
mmol), 3a (0.1 mmol) and 1 (10 mol%) in specied solvent at room
b
c
d
temperature. The isolated yield. Determined by HPLC. The
e
reaction was carried out with 0.2 mmol 3a. The reaction was carried
out with 0.3 mmol 3a. The reaction was carried out with 20 mol% 1.
f
Aer the double bonds in 1a and 1b were hydrogenated, the
resulting catalysts 1e and 1f failed to improve the enantiose-
lectivity of the asymmetric allylic substitution reaction (Table 1,
entries 5–6). In addition, b-isocupreidine (b-ICD, 1g) gave the
desired product in 77% yield and 45% ee (Table 1, entry 7). When
the cinchona alkaloid dimer (DHQD) PHAL (1h) was tested as the
2
catalyst, the product was obtained in 84% yield and 41% ee
(Table 1, entry 8). At a lower concentration of 2a (from 0.2 M to 0.1
M) and under the catalysis of 1h (10 mol%), the ee value of 4a was
greatly improved (from 41% to 79%), although the yield was
decreased (Table 1, entry 9). In order to increase the yield, more
amounts of 3a (2 and 3 equivalents to 2a) and extended reaction
time were used, and resulted in signicantly improved yields
(
(
from 30% to 79% and 91%) and with slightly decreased ee values
73% and 74%) (Table 1, entries 10–11). Aer the concentration
of 2a was further diluted to 0.05 M, 4a was obtained in 51% yield
and 76% ee (Table 1, entry 12). When 20 mol% 1h was used at
this concentration of 2a, the desired product 4a was afforded in
92% yield and 77% ee (Table 1, entry 13).
Next, the solvent of the asymmetric allylic substitution
reaction was further optimized (see ESI†) and 1,4-dioxane was
determined as the optimal one (Table 1, entry 14). To our
delight, this optimized condition resulted 4a in high yield (95%)
and with excellent ee (95%) (Table 1, entry 14). In addition,
catalyst (DHQ) PHAL (1i), the pseudo enantiomer of 1h, was
2
also tested for the reaction, and gave the enantiomer of 4a in temperature. The isolated yield. Determined by HPLC.
a
Unless otherwise noted, the reaction was carried out with 2 (0.1
mmol), 3 (0.3 mmol) and 1h (20 mol%) in 2 mL 1,4-dioxane at room
b
c
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with electron-withdrawing substituents (4h–4n) were used
except for 4l and 4n. The reaction with 1-naphthol gave
a slightly decreased ee under the optimal conditions (4o). With
respect to MBH carbonate 3, we were pleased to observe very
satisfactory results for the desired products (4p–4x), although
three compounds (4p, 4u and 4v) had moderate yields. Both the
substituents' position and electronic nature of the aromatic
rings in 3 had little impact on the yields and enantioselectivity.
The substrates with disubstituted phenyl ring (4w) and with
a heterocyclic ring (4x) were also well tolerated in the optimized
conditions. However, when the MBH carbonate from propio-
naldehyde was used, the corresponding allylic substitution
product could not be detected.
In the process of optimizing the reaction conditions, we
synthesized the MBH carbonate 5a and found that it could
generate 4a with high yield and ee under the catalysis of 1h
Scheme 2 Proposed mechanism of the asymmetric allylic substitution
reaction.
10
(
Scheme 1, eqn (a)). To the best of our knowledge, such a ster-
ꢀ
by (DHQD)
with releasing one molecule of CO
2
PHAL 1h results in the intermediate I and tBuO
eoselective transformation has not been reported before in
ꢀ
11
2
. Then the tBuO deproto-
nates the pronucleophile PhOH and affords PhO . As for the
MBH carbonate 5a, nucleophilic attack by 1h gives intermediate
literature. And it represents an alternative way to the synthesis
of chiral multifunctional aryl allyl ethers. To determine the
absolute conguration of 4, we conducted a reaction of 4g with
CAN (ceric ammonium nitrate) and the valuable chiral MBH
alcohol 6 was isolated with the ee value retained (Scheme 1, eqn
ꢀ
ꢀ
I and nucleophile PhO directly with releasing the CO
2
. The
intermediate I would be preferentially formed as the E-isomer in
accordance with the literature reports. The p–p stacking
between the quinoline moiety and phenyl ring not only stabi-
lizes the cation intermediate I, but also shields the Re-face of the
alkene for enantioselective control. Finally, the nucleophile
12
(
b)). By comparing the optical rotation value of 6 with those in
7a,7c,7f
literature reports,
determined as S conguration.
To demonstrate the potential application of this method-
ology, the 1, 3-dipolar cycloaddition reaction of the aryl allyl
ether 4a with chlorobenzaldoxime was performed, and two
the stereochemistry of 6 and 4 was
ꢀ
PhO would presumably approach the Si-face in the preferable
0
S
N
2 /anti elimination manner to give the nal product 4a.
0
In conclusion, we have successfully developed an asym-
diastereomers 7a and 7a were isolated with high yield and ee
(
13
metric allylic O-substitution reaction of MBH carbonates with
less-nucleophilic phenols mediated by nucleophilic amine
catalyst. A series of chiral multifunctional aryl allyl ethers were
obtained in moderate to high yield (up to 96%) with excellent
enantioselectivity (up to 95%). In addition, the MBH phenyl
carbonate was synthesized and found to be able to generate the
same chiral aryl allyl ether with excellent enantioselectivity by
nucleophilic catalysis. The synthetic potential of the disclosed
methodology was demonstrated by the synthesis of chiral MBH
alcohol and the 1, 3-dipolar cycloaddition reaction of the aryl
allyl ether with chlorobenzaldoxime.
Scheme 1, eqn (c)).
Based on the experimental observation and literature
7f,13,14
reports,
a plausible transition state is proposed for the
asymmetric allylic substitution reaction (Scheme 2). First,
nucleophilic addition to the vinylic moiety of MBH carbonate 3a
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We gratefully acknowledge the nancial support from the
National Science Foundation of China (21602018, 21272029).
Notes and references
Scheme 1 (a) Synthesis of aryl allyl ether 4a from MBH carbonate 5a
by nucleophilic catalysis. (b) Synthesis of chiral MBH alcohol 6. (c) 1,3-
dipolar cycloaddition reaction of aryl allyl ether 4a and
chlorobenzaldoxime.
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