Neutral Alcohol Nucleophiles for the Substitution of α-Bromo Aryl Acetates and Applications to Asymmetric Synthesis of Morpholine Derivatives

Article abstract of DOI:10.1002/ejoc.201900207

Highly stereoselective C–O bond formation in AgOTf-catalyzed substitution of configurationally labile α-bromo aryl acetates with neutral alcohol is developed. Also, application of this asymmetric synthetic methodology to the preparation of highly enantioenriched 2-aryl-substituted morpholine derivatives is presented.

Full text of DOI:10.1002/ejoc.201900207

A Journal of
Accepted Article
Title: Neutral Alcohol Nucleophiles for the Substitution of α-Bromo
Arylacetates and Applications to Asymmetric Synthesis of
Morpholine Derivatives
Authors: Wongi Park, Yongtai Kim, and Yong Sun Park
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10.1002/ejoc.201900207
European Journal of Organic Chemistry
COMMUNICATION
Neutral Alcohol Nucleophiles for the Substitution of -Bromo
Arylacetates and Applications to Asymmetric Synthesis of
Morpholine Derivatives
Wongi Park,[a] Yongtae Kim[a] and Yong Sun Park*[a]
Abstract: Highly stereoselective C-O bond formation in AgOTf-
catalyzed substitution of configurationally labile -bromo
arylacetates with neutral alcohol is developed. Also, application of
this asymmetric synthetic methodology to the preparation of highly
enantioenriched 2-aryl substituted morpholine derivatives is
presented.
Figure 1. Asymmetric synthesis of α-alkoxy arylacetates.
Introduction
Structural motifs containing oxygen bearing stereocenters are
ubiquitous in natural products and important bioactive molecules.
Results and Discussion
Synthetic strategies for stereoselective carbon-oxygen bond
Initial studies on the substitution of α-bromo phenylacetate 1a
formation continue to expand the range of functional groups that
were carried out with methanol as a nucleophile as shown in
could be incorporated.1 Despite these advances, the subject of
Table 1. When -bromo phenylacetate 1a of 50:50 dr was
treated with methanol (3.0 equiv) in CHCl3 without Lewis acid
catalyst, no conversion occurred as expected (entry 1). We next
stereoselective reactions of configurationally labile α-halo
acetates with neutral alcohol nucleophiles has never been
explored before.2 Introduction of alkyloxy group by the
attempted the same reaction in the presence of some selected
substitution of alkyl halide with neutral alcohol under base-free
conditions is challenging and offers advantages in mild
conditions and easier handling of reagents.3 As the
nucleophilicity of neutral alcohol is not sufficient for a direct
attack at -halo acetates, the activation of the carbon-halogen
Lewis acids. When AlCl3, FeCl3, or Ag2O was used as a Lewis
acid, the reaction barely proceeded to give α-methoxy
phenylacetate 2 as shown in entries 2-4. With strongly halophilic
silver salts, AgOTf and AgO2CCF3, the reactions with 1a of
50:50 dr were completed within 20 h and produced 2 without a
bond is needed. Lewis acid can complex strongly with a halogen
noticeable stereoselectivity (entries 5 and 6), which indicates
to weaken the carbon-halogen bond.4 We herein report the first
that the dynamic kinetic resolution of α-bromo phenylacetate
(αRS)-1a is not functioning in this Lewis acid catalyzed
Lewis acid catalyzed stereoselective substitution of α-bromo
arylacetates with alcohols to afford α-alkoxy arylacetates. The
substitution. The reaction of α-chloro phenylacetate gave 2 with
practical utility of this methodology is also demonstrated by the
preparation of highly enantioenriched morpholine derivatives.
In our most recent study on the dynamic resolution of α-
dr was treated with methanol under the same conditions, α-
bromo arylacetate 1 using N-benzoyl-L-threonine isopropyl ester,
a much lower conversion (26%) and a little stereoselectivity of
67:33 dr (entry 7). When α-bromo acetate 1a of 86:14 dr or 99:1
methoxy phenylacetate
2
was obtained with somewhat
we observed that a diastereomer of 1 showed interesting
crystallization behavior. Highly diastereoenriched (αR)-1 was
obtained as a solid by crystallization-induced dynamic resolution
(CIDR) with up to >99:1 diastereomeric ratio (dr) and efficiently
used in nucleophilic substitution.5 Given the ready availability of
optically pure -bromo arylacetates by CIDR, we recently
envisaged that (αR)-1 could be activated by Lewis acid for the
reaction with neutral alcohol nucleophiles as shown in Figure 1.
This process could be extremely useful for the asymmetric
synthesis of α-alkoxy arylacetates using a wide variety of easily
available alcohol nucleophiles.
decreased stereoselectivities of 74:26 dr and 91:9 dr,
respectively, as shown in entries 8 and 9. The observed
conversions and drs of 2 indicate that the -bromo stereogenic
center is configurationally labile under the reaction conditions
and the rate of substitution is not sufficiently fast with respect to
the epimerization promoted by AgOTf.6
In order for -bromo phenylacetate (αR)-1a to be
advantageously utilized in the reaction with alcohol, the
substitution should be much faster than the epimerization of
(R)-1a on exposure to Lewis acid. As a simple way of
increasing the rate of substitution with respect to the
epimerization, we used more excess amounts of methanol as
shown in entries 10-15. The nucleophilic substitution (SN2) of
(R)-1a of 99:1 dr with 10 equiv. of methanol produced (αS)-2
with 96:4 dr (entry 10).7 Our attempt to improve the dr of 2 using
other solvents such as n-hexane, DMF, THF and CH3CN didn’t
succeed to give higher yield and dr as shown in entries 11-14.
We next explored the utility of neat conditions with 10 equiv. of
methanol nucleophile. Pleasingly, as shown in entry 15, the neat
[a]
W. Park, Y. Kim, Prof. Y. S. Park
Department of Chemistry
Konkuk University
120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
E-mail: parkyong@konkuk.ac.kr
Homepage: http://home.konkuk.ac.kr/~parkyong/lab.htm
Supporting information for this article is given via a link at the end
of the document.
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10.1002/ejoc.201900207
European Journal of Organic Chemistry
COMMUNICATION
reaction of (αR)-1a with methanol in the presence of AgOTf are
completed faster than the solution reactions to afford (αS)-2 with
99:1 dr.8
provided α-aryloxy substituted acetate exclusively and following
reduction with LiAlH4 afforded phenoxyethanol 12 with 97:3
enantiomeric ratio (er) in 58% overall yield. In contrast, in the
reaction with ortho-methoxyphenol, C-alkylation is favored over
O-alkylation. The substitution of (αR)-1a with ortho-
methoxyphenol and following reduction provided diarylethanol
13 and phenoxyethanol 14 in a ratio of 3:1. The AgOTf-
catalyzed Friedel-Crafts alkylation product 13 was isolated in
51% overall yield with 98:2 er and the O-alkylation product 14
was isolated in 20% overall yield with 97:3 er.9
Table 1. Optimization of the substitution conditions
Entry[a]
Dr of 1a
Lewis Acid
Equiv of Nuc
(Solvent)
Conv.[b]
Dr[b]
Table 2. Nucleophilic substitutions with alcohols
1
50:50
50:50
50:50
50:50
50:50
50:50
50:50 (Cl)
86:14
99:1
none
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
3.0 (CHCl3)
10 (CHCl3)
10 (n-hexane)
10 (DMF)
0
-
2
AlCl3
0
-
3
FeCl3
7
51:49
-
4
Ag2O
0
5
AgOTf,
AgO2CCF3
AgOTf,
AgOTf,
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
99
99
26
99
99
99
74
13
47
5
53:47
51:49
67:33
74:26
91:9
96:4
96;4
93:7
96:4
95:5
99:1
Entry [a]
ROH
Product
Yield (%)
Dr[b]
99:1
98:2
6
7
1
2
92
98
3
4
8
9
10
11
12
13
14
15
99:1
3
4
5
84
91
88
99:1
99:1
99:1
5
6
7
99:1
99;1
99:1
10 (THF)
99:1
10 (CH3CN)
10 (neat)
99:1
99
[a] The reactions were carried out with Lewis acid (1.2 equiv) in solvent (0.5
M) at rt for 20 h. [b] The conversions and drs were determined by 1H NMR of
the reaction mixture.
6
83
99:1
8
7
8
38
87
99:1
99:1
9
A range of alcohols was then investigated as nucleophiles
in the substitution reaction with α-bromo phenylacetate (αR)-1a
under neat conditions. All the tested aliphatic alcohols
underwent the substitution reaction smoothly to afford the
corresponding α-alkoxy acetates 3-11 with excellent yields (85–
95%) and high drs. The steric demand of the alkyl group of
alcohol nucleophile did not play an important role, with most of
selected primary and secondary alcohols furnishing the best
results described in entries 1-6. However, no substitution
product was obtained in the reaction with highly sterically
hindered tert-butyl alcohol. In the reaction with ethylene glycol,
the mono substituted hydroxyethyl ether 9 was isolated in a
much lower yield of 38% with the same high dr (entry 7). In
addition, coupling of (αR)-1a with protected amino alcohols such
10
9
90
99:1
11
[a] All the reactions were carried out with 1.2 equiv of AgOTf at rt for 10 h
under neat conditions (if needed for solubility reason, we used least possible
amount of solvent, CHCl3). [b] The dr values were determined by 1H NMR of
the reaction mixture.
as
N-tosyl-2-aminoethanol
and
N-Boc-2-aminoethanol
successfully yielded α-(2-aminoethoxy) phenylacetates 10 and
11 with 99:1 dr in 87% and 91% yields, respectively, as shown in
entries 8 and 9.
The substitutions with phenol derivatives showed
interesting results as depicted in Scheme 1. Our first
examination with phenol and p-chlorophenol showed that they
do not have appropriate reactivity with 1a to give substitution
products under the same conditions and most of 1a was
recovered. When phenol was activated with an electron donating
methoxy group, the reactions provided the substitution products
and showed interesting regioselectivity, which is markedly
dependent on the structure of methoxyphenol nucleophiles. With
para-methoxyphenol nucleophile, the substitution of (αR)-1a
Scheme 1. Substitutions of (αR)-1a with methoxyphenols.
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10.1002/ejoc.201900207
European Journal of Organic Chemistry
COMMUNICATION
Morpholines are common structural cores of a broad range
of biological and pharmacological natural or synthetically
important organic molecules.10 Given the prevalence and
importance of this class of compounds, we applied the synthetic
methodology to the asymmetric preparation of morpholine
analogues starting from (αR)-1a-c and N-tosyl 2-aminoethanols
as building blocks. The four-step synthetic sequences afforded
morpholine derivatives 15-23 in 28-40% overall yields with high
stereoselectivities up to 99:1 er or dr. The substitution of (αR)-
1a-c with N-tosyl 2-aminoethanol, reduction by NaBH4, tosylation
of the alcohol and ring closure with K2CO3 afforded N-tosyl 2-aryl
substituted morpholines 15, 16 and 17 with 99:1 er, 96:4 er, and
97:3 er, respectively as shown in Scheme 2. Also, 2,5-
disubstituted morpholine derivatives 18-23 were successfully
prepared using 2-alkyl substituted 2-aminoethanols. In the
reactions of (αR)-1a with N-tosyl L- and D-alaninol nucleophiles,
no stereo-differentiation with the chiral alcohols was observed in
the substitution step and the substitution products were obtained
with 99:1 dr in both reactions. After the four-step transformation
sequence, however, cis-morpholine 18 was obtained with a
lower dr of 95:5 than that of trans-morpholine 19. Similar results
were found with N-tosyl L- and D-phenylalaninol nucleophiles to
produce cis-morpholine 20 with 95:5 dr and trans-morpholine 21
with 99:1 dr.11 In addition, the same reactions of (αR)-1c with D-
alaninol and D-phenylalaninol produced trans-morpholines 22
with 98:2 dr and 23 with 97:3 dr, respectively.
catalyzed substitution of -bromo arylacetates with alcohol
nucleophiles. At the best of our knowledge, no previous studies
have investigated the stereoselective substitution of -halo
acetates with neutral alcohols under mild acidic conditions. The
capacity to install oxygen bearing stereocenters in direct proximity
to ester groups allows for a diverse range of synthetic elaboration.
The evidence for the synthetic efficiency of this method was
demonstrated by a concise asymmetric synthesis of N-tosyl 2-
aryl-morpholine derivatives.
Experimental Section
Supporting Information (see footnote on the first page of this article):
Experimental details and copies of NMR spectra and HPLC
chromatograms are provided in supporting information
Acknowledgments
This paper was supported by Konkuk University in 2017.
Keywords: Asymmetric synthesis • Nucleophilic Substitution •
Crystallization • Lewis acid • Alcohol
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Scheme 2. Asymmetric synthesis of N-tosyl-2-aryl-morpholines.
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[9]
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Conclusions
methyl
2-(4-benzyloxy-3-methoxyphenyl)-2-phenylacetate
by
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We have developed an efficient synthetic method for the highly
stereoselective carbon–oxygen bond formation by AgOTf-
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stable trans-morpholines 19 and 21 under the basic conditions. When a
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Stereoselective C–O bond formation*
W. Park, Y. Kim, Y. S. Park*
Page No. – Page No.
Neutral Alcohol Nucleophiles for the
Substitution of -Bromo Arylacetates
and Applications to Asymmetric
Highly stereoselective C-O bond formation in AgOTf-catalyzed substitution of -
bromo arylacetates with neutral alcohol nucleophiles is developed and applied to
the preparation of highly enantioenriched 2-aryl-morpholine derivatives.
Synthesis of Morpholine Derivatives
*nucleophilic substitution
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