Cycloaddition Reaction of in Situ Formed Azaoxyallyl Cations with Aldehydes: An Approach to Oxazolidin-4-ones

Article abstract of DOI:10.1021/acs.orglett.6b02254

A novel [3 + 2] cycloaddition reaction between in situ formed azaoxyallyl cations and aldehydes has been developed. This concise method allows the rapid formation of a number of oxazolidin-4-ones in high yields with good functional group tolerance at room temperature. Further transformation and late-stage modifications of drug molecules could also be achieved in good yields, highlighting the potential utility of the reaction.

Full text of DOI:10.1021/acs.orglett.6b02254

Letter
pubs.acs.org/OrgLett
[3 + 2] Cycloaddition Reaction of in Situ Formed Azaoxyallyl Cations
with Aldehydes: An Approach to Oxazolidin-4-ones
Kaifan Zhang, Chi Yang, Hequan Yao,* and Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A novel [3 + 2] cycloaddition reaction between
in situ formed azaoxyallyl cations and aldehydes has been
developed. This concise method allows the rapid formation of
a number of oxazolidin-4-ones in high yields with good
functional group tolerance at room temperature. Further
transformation and late-stage modifications of drug molecules
could also be achieved in good yields, highlighting the potential
utility of the reaction.
he N,O-containing oxazolidin-4-ones are key structural
motifs found in natural products and bioactive molecules
Recently, in situ formed azaoxyallyl cations, as newly
designed versatile 1,3-dipoles, have been provided with unique
chemical features for access to various heterocycles. In 2011,
Jeffrey developed the first [4 + 3] cycloaddition reactions
employing azaoxyallyl cations and cyclic dienes to construct
seven-membered azacycles (Scheme 1a).9 Subsequently, Jeffrey,
T
with promising antimicrobial,1 anticancer,2 and antimigraine3
activities, such as lipoxazolidinones A, B, and C and
synoxazolidinones A, B, and C (Figure 1). Because of their
Scheme 1. Reactions of Azaoxyallyl Cations
Figure 1. Selected examples of natural products and bioactive
compounds with oxazolidin-4-one framework.
bioactivities and medicinal value, oxazolidin-4-ones have
received increasing attention from organic and pharmaceutical
chemists in the past few decades.4 Typical methods for the
synthesis of oxazolidin-4-ones include cycloaddition reactions
of oxaziridines with ketenes, azlactones, and ammonium
enolates,5 photoelimination reactions of α-keto amides,6
domino O-alkylation/aza-Michael/retro-Claisen condensation
reaction between enol ethers and α-bromoamido alcohols,7 and
condensation reactions between α-hydroxyamides and carbonyl
compounds in the presence of acids under heating conditions.8
Despite the fact that the aforementioned methods were of
interest in constructing oxazolidin-4-ones, the development of a
more efficient method with facile accessible substrates is still
highly desirable.
Wu, and Liao realized [3 + 2] cycloaddition reactions between
azaoxyallyl cations and 3-substituted indoles to synthesize
pyrroloindolines independently (Scheme 1b).10 Very recently,
Chen reported that [3 + 1] and [3 + 2] cycloaddition reactions
utilizing sulfur ylides as coupling partners reacted with
azaoxyallyl cations for the synthesis of β-lactams and γ-lactams
Received: July 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02254
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Letter
(Scheme 1c).11 In contrast to these works with electron-rich
dienes and indoles as coupling units, the [3 + 2] cycloaddition
reaction of electron-deficient double bonds with azaoxyallyl
cations has not been reported yet. To construct oxazolidin-4-
ones through a concise pathway, we will herein explore the
possibility of [3 + 2] cycloaddition reactions between in situ
formed azaoxyallyl cations and ubiquitous aldehydes at room
temperature (Scheme 1d).
a b
,
Scheme 2. Substrate Scope of Aldehydes
We initiated our exploration by investigating the reaction of
benzaldehyde 1a and N-(benzyloxy)-2-bromo-2-methylpropa-
namide 2a (Table 1). Solvent screening indicated that no
a
Table 1. Optimization of Reaction Conditions
b,c
entry
base
solvent
time (h)
yield (%)
1
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
NaOH
DMF
MeCN
DCM
THF
10
10
10
10
10
10
10
2
nr
nr
2
3
nr
4
nr
5
toluene
EtOH
TFE
nr
6
nd
46
7
8
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
74
9
2
nr
10
11
12
13
14
15
2
51
K2CO3
2
67
Cs2CO3
NaOtBu
Et3N
2
trace
trace
45
2
2
DMAP
2
47
d
16
Na2CO3
Na2CO3
2
86
e
17
2
89
nr
e
18
2
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), base (3.0
b
c
equiv) in solvent (1.0 mL) at room temperature. Isolated yields. nr =
no reaction; nd = no desired product was detected by TLC. 2a (1.20
equiv) was used. 2a (1.50 equiv) was used.
d
a
Reaction conditions: 1 (0.25 mmol), 2a (0.375 mmol), Na2CO3 (3.0
e
b
equiv) in solvent (1.0 mL) for 2 h at room temperature. Isolated
yields. 4 mmol scale.
c
product could be formed in general organic solvents, such as
MeCN, DCM, THF, toluene, DMF, and EtOH, in the presence
of Na2CO3 as the base (entries 1−6). To our gratification,
when 2,2,2-trifuoroethanol (TFE) was employed, the desired
product 3aa was obtained in 46% yield (entry 7), which
demonstrated the effect of fluorinated solvent on the process of
this [3 + 2] cycloaddition reaction.12 Changing TFE to
hexafluoroisopropanol (HFIP) gave a superior performance
and afforded 3aa in 74% yield (entry 8). Then various bases
including inorganic and organic bases were examined (entries
9−15), while the yields could not be further improved
compared with Na2CO3. Due to the recovery of some
unreacted 1a, we continued to investigate the substrate
concentration (entries 16 and 17). Excellent yield (89%)
could be achieved when the loading amount of 2a was raised to
1.50 equiv (entry 17). Control experiments showed that no
product was obtained in the absence of base (entry 18).
With the optimized conditions in hand, we next explored the
reaction scope and generality of aldehydes (Scheme 2). Methyl,
methoxyl, or halogen (−F, −Cl, −Br) groups at the para-
position of the arylaldehydes afforded the desired products
3ba−fa in 91−99% yields. The reaction became sluggish with
an electron-withdrawing group at the para-position of the
phenyl ring (3ga). (1,1′-Biphenyl)-4-carboxaldehyde delivered
3ha in 98% yield. Moreover, 3ha could be synthesized on a
gram scale (1.435 g, 96% yield). Aryl aldehydes with
(trimethylsilyl)ethynyl at the para-position afforded 3ia in
86% yield. The cyclization with m-methyl- and o-methyl-
substituted aryl aldehydes proceeded smoothly to offer 3ja and
3ka in 93% and 91% yields. The use of salicyl aldehyde led to
the facile formation of 3la in 81% yield. Benzaldehydes bearing
disubstituted groups resulted 3ma, 3na, and 3oa in 99%, 92%,
and 82% yields. 1-Naphthaldehyde, heterocyclic aldehydes, and
ferrocenecarboxaldehyde were also compatible, giving 3pa−ta
in 87−99% yields. Alkyl aldehydes afforded 3ua and 3va in 58%
and 60% yields. Cycloaddition reactions with crotonaldehyde
and cinnamaldehydes were also effective, delivering 3wa−ya in
95−99% yields. Fortunately, ethyl formate could also offer 3za
in 77% yield.
With regard to α-halohydroxamates (Scheme 3), replacing
the benzyl group with tert-butyl, ethyl, and methyl groups
B
DOI: 10.1021/acs.orglett.6b02254
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a
Scheme 3. Substrate Scope of α-Halohydroxamates
Scheme 4. Late-Stage Modifications and Transformation
under dark reaction conditions (Scheme 5a). Cyclopropane-
carboxaldehyde 1A could react with 2a smoothly to offer 3Aa
Scheme 5. Control Experiments
a
Reaction conditions: 1h (0.25 mmol), 2 (0.375 mmol), Na2CO3 (3.0
b
equiv) in solvent (1.0 mL) for 2 h at room temperature. Isolated
c
yields. Diastereoisomeric ratio (dr) was determined by crude 1H
d
NMR analysis. 50 °C, 48 h.
delivered 3hb−hd in excellent yields. The reaction of α-chloro
hydroxamate with an α-phenyl group provided 3he in 71%
yield with 3.5:1 dr. By increasing the temperature to 50 °C and
extending the reaction time to 48 h, α-halo hydroxamates with
a monoalkyl group could afford 3hf−hh in 56−68% yields with
moderate diastereoselectivity (2.9:1−4.1:1).
In order to expand the utilities of our reaction, this
innovative method was developed to modify complex drug
molecules. As a dual EGFR/HER-2 inhibitor used to treat
advanced or metastatic breast cancer, lapatinib has aroused
wide interest from the chemical and medicinal community.13
Herein, the oxazolidin-4-one motif could be incorporated into
lapatinib intermediate 4a, offering 5aa in 78% yield (Scheme
4a). Antipyrine 4b is an analgesic and antipyretic, and its
derivatives have been investigated considerably.14 The
introduction of formyl group into 4b offered substrate 4c,
which could be further transformed to antipyrine derivative 5ca
in 90% yield (Scheme 4b). The successful modification of drug
molecules could be beneficial to improve the druggability and
minimize adverse side effect. Then, the generated oxazolidin-4-
one 3ha was transformed as shown in Scheme 4c. N-
Unprotected oxazolidin-4-one 6ha could be easily synthesized
by removing the phenylmethoxyl group via reflux with
Mo(CO)6 in the mixed solvents of MeCN and H2O, which
could be regarded as a precursor for conveniently synthesizing
oxazolidin-4-one derivatives.
As observed in previous work, α-halohydroxamate 2a
underwent dehydrohalogenation to generate azaoxyallyl cati-
onic intermediate, which was stabilized in HFIP by hydrogen
bonding and/or dipole−dipole interaction.9a,10b To further
demonstrate the mechanistic details of this formal [3 + 2]
cycloaddition reaction, common radical scavengers TEMPO
and BHT were introduced into the system, and these reactions
were not restrained. This reaction could also perform well
in 96% yield rather than ring-opening product 7 (Scheme 5b),
indicating that the radical process could be ruled out.15
Moreover, N-(allyloxy)-2-bromo-2-methylpropanamide 2i was
prepared to further explore the reaction (Scheme 5c), and 3hi
was obtained in 97% yield without the formation of 8 through
the intramolecular carbene insertion pathway.16 Additionally,
replacing the electron-donating group (−OBn) with a benzyl
group (−Bn) failed to give the cycloadduct under standard
conditions (Scheme 5d).
On the basis of the above results and previous work,9a
a
plausible mechanism was proposed as illustrated in Scheme 6.
Under mild, weakly basic conditions, azaoxyallyl cation A is
generated in situ, and the electron-donating group (−OBn) is
C
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nucleophilic attack of 1 would deliver a zwitterion intermediate
B. Eventually, the nitrogen anion undergoes intramolecular
nucleophilic attack to form the final product 3. On the other
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In summary, we have developed a formal [3 + 2]
cycloaddition reaction between in situ formed azaoxyallyl
cations and aldehydes to synthesize oxazolidin-4-ones. This
concise procedure exhibited good functional group tolerance
and gram-scale ability under mild conditions. Late-stage
modifications of drug molecules could also be achieved in
good yields, highlighting the potential utility of our reaction.
Preliminary mechanism studies were conducted, and further
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ASSOCIATED CONTENT
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02254.
1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hyao@cpu.edu.cn; cpuhyao@126.com.
*E-mail: ajlin@cpu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC 21572272 and NSFC21502232),
the Natural Science Foundation of Jiangsu Province
(BK20140655), the Foundation of State Key Laboratory of
Natural Medicines (ZZYQ201605), and the Innovative
Research Team in University (IRT_15R63) is gratefully
acknowledged.
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DOI: 10.1021/acs.orglett.6b02254
Org. Lett. XXXX, XXX, XXX−XXX