From Carbamate to Chalcone: Consecutive Anionic Fries Rearrangement, Anionic Si → C Alkyl Rearrangement, and Claisen-Schmidt Condensation

Article abstract of DOI:10.1021/acs.orglett.8b02269

A highly efficient one-pot procedure was developed for the synthesis of various 2′-hydroxychalcones from phenyl diethylcarbamate, featuring consecutive Snieckus-Fries rearrangement, anionic Si a?' C alkyl rearrangement, and Claisen-Schmidt condensation in a single operation. The applicability of this protocol was demonstrated by the highly efficient synthesis of the anti-inflammatory natural product lonchocarpin. The mechanism insight is also provided.

Full text of DOI:10.1021/acs.orglett.8b02269

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
From Carbamate to Chalcone: Consecutive Anionic Fries
Rearrangement, Anionic Si → C Alkyl Rearrangement, and Claisen−
Schmidt Condensation
Singam Naveen Kumar,† Suhas Ravindra Bavikar,†,‡ Chebolu Naga Sesha Sai Pavan Kumar,†,§
Isaac Furay Yu,∥ and Rong-Jie Chein*,†
†Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan
‡Molecular Science and Technology Program, Taiwan International Graduate Program, Academia Sinica and National Tsing Hua
University, Hsinchu 30013, Taiwan
§Division of Chemistry, Department of Sciences and Humanities, Vignan’s Foundation for Science, Technology, and Research,
Vadlamudi, Guntur, Andhra Pradesh, India
∥Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
S
* Supporting Information
ABSTRACT: A highly efficient one-pot procedure was
developed for the synthesis of various 2′-hydroxychalcones
from phenyl diethylcarbamate, featuring consecutive
Snieckus−Fries rearrangement, anionic Si → C alkyl
rearrangement, and Claisen−Schmidt condensation in a single
operation. The applicability of this protocol was demonstrated
by the highly efficient synthesis of the anti-inflammatory natural product lonchocarpin. The mechanism insight is also provided.
halcones, comprising a common 1,3-diphenyl propenone
human body.13 Thus, chalcones have become a focus of
continued interest among both academic and industrial
researchers. Several synthetic routes have been reported for
the synthesis of chalcones, generally involving a Claisen−
Schmidt condensation under homogeneous conditions in the
presence of acid or base.14 Herein, we report an easy
preparation of 2′-hydroxychalcones from aryl carbamates in a
highly efficient one-pot manner.
C
template, are precursors in the biosynthesis of flavonoids
and isoflavonoids.1 The word Chalcone is derived from the
Greek word Chalcos, meaning bronze, and flavone is derived
from the Latin word flavus, meaning yellow. Chalcones,
flavonoids, and aurones (Figure 1) are composed of pigments,
The expanded use of silicon reagents in organic synthesis,
resulting from their low cost, versatile properties, and
application to a wide range of reactions, has greatly increased
the prominence of organosilicon chemistry.15 In a previous
study, we reported the formation of ortho-Fries hydroxyke-
tones from aryl diethylcarbamate through consecutive
Snieckus−Fries16 and Si → C alkyl rearrangements (Scheme
1).17
Mechanistic studies showed that this transformation
featured a complex-induced proximity effect (CIPE)18 in the
deprotonation of the silyl ether intermediate, followed by an
intramolecular nucleophilic addition for the formation of
oxasilinolate 3 and the fission of 3 to ortho-Fries hydrox-
yketone 5 upon an aqueous workup. Based on these findings,
we raised the following question: if oxasilinolate 3 is the key
intermediate instead of a hypervalent silicon species, can we
use 2 as an enolate source in a variety of reactions to expand
the scope of this ortho-directed acylation methodology? In the
Figure 1. Chalcone as a precursor in the biosynthesis of flavonoids.
of which the color changes from orange to yellow in some
plants. As a primary subgroup of the flavonoid family, naturally
occurring chalcones and their synthetic analogues possess a
wide range of biological activities, including antiviral and
anticancer,1b,2 antibacterial,3 anti-inflammatory,2b,d,3a,4 antimi-
crobial,5 antiulcer and spasmolytic,6 antiproliferative,7 anti-
HIV,8 antioxidant,2d,3a,9 analgesic,1b,3a and immune-modulator
properties.10 Natural chalcones also exist as various types of
dimers, oligomers, Diels−Alder adducts, and conjugates,11
which are primarily attached with hydroxyl and methoxy
functionalities, particularly in the 2′ position.9 More
importantly, the presence of the α,β-unsaturated ketone
moiety was found to be responsible for the observed versatile
biological activities.12 Clinical studies have proven the excellent
bioavailability of chalcones and their maximum tolerance in the
Received: July 20, 2018
© XXXX American Chemical Society
A
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Letter
improve the yield of 4a to 65%. To reduce the unnecessary
consumption of benzaldehyde, MeI was added into the
reaction to trap the lithium diethylamide, further improving
the yield of this optimized reaction condition to 77% (entry 3).
When diphenylmethylsilyl chloride was used as the alkyl
source, the two larger phenyl groups hindered the
condensation step, decreasing the yield of 4a to 65% (entry
4). Interestingly, 1,3-diphenyl-2-methyl propenone (4a-1) in a
predominant E form was prepared in good yield using
triethylsilyl chloride in the same method (entry 5). Other
chlorosilanes such as tripropylsilyl chloride (entry 6) and
tribuylsilyl chloride (enrty 7) were also subjected to the same
conditions to construct the trisubstituted olefins 4a-2 and 4a-3
in 36% and 55% yield.
Scheme 1. Concise Synthesis of ortho-Fries Hydroxyketone
and Chalcones from Phenyl Carbamate
We next explored the substrate scope of the aldehyde and
hydroxyamide in this transformation. As shown in Table 2,
Table 2. Scope of Aldehyde and Hydroxyamide
present study, we first examined the use of lithium enolate ion
3 as an effective nucleophile in aldol and Claisen−Schmidt
condensations to develop a new and capable method to
synthesize chalcone derivatives 4 from aryl carbamate 1.
To simplify this investigation, lithium enolate ion 3 was first
generated from ortho-Fries hydroxyamide 2 by treatment with
4 equiv of lithium diisopropylamide (LDA) and 1.2 equiv of
trimethylsilyl chloride (TMSCl) in tetrahydrofuran (THF) at 0
°C. After 30 min at room temperature, the reaction mixture
containing lithium enolate ion 3 was trapped by the addition of
benzaldehyde. To our delight, chalcone 4a was isolated in 38%
yield (Table 1, entry 1), along with 2-hydroxyacetophenone,
Table 1. Optimization of the Reaction Conditions
a
entry silyl chloride PhCHO (equiv) additive (equiv)
yield (%)
38
65
77
65
1
2
3
4
5
6
7
TMSCl
TMSCl
TMSCl
Ph2MeSiCl
Et3SiCl
1.3
2.0
1.3
1.3
1.6
2.6
2.6
-
-
MeI (1.2)
MeI (1.2)
MeI (1.2)
MeI (1.2)
MeI (1.2)
bc
,
73 (97:3)
36 (90:10)
bc
,
Pr3SiCl
Bu3SiCl
bc
,
55 (93:7)
a
b
a
b
c
Isolated yield. Aldehyde was added at 0 °C, and the reaction was
Isolated yield. Ratio of E/Z isomers. 40 h reaction time.
c
kept at rt. 2.6 equiv of aldehyde was used, and the reaction was kept
at 50 °C. Reaction was kept at 45 °C.
d
N,N-diethylbenzamide, and benzyl alcohol. Apparently, lithium
diethylamide was produced from an intramolecular nucleo-
philic addition of the α-silyl carbanion, followed by reaction
with benzaldehyde through a Cannizzaro-type reaction to give
the disproportionation products, phenyl diethylamide and
benzyl alcohol.19 Unreacted 3 was degraded to 2-hydrox-
yacetophenone (5) after an aqueous workup, which deterio-
rated the yield of the chalcone product. Based on the above
reactivity, 2 equiv of benzaldehyde was used in entry 2 to
benzaldehydes bearing electron-donating (entries 1, 2, 4, 5)
and electron-withdrawing (entries 6−10) functional groups in
the para or meta position were all tolerated in the reaction at
35 °C, with the corresponding chalcones (4b, 4c, 4e−4k)
isolated in 66−78% yields. The reaction with bulkier ortho-
toluylaldehyde (entry 3), which could interfere with the
nucleophilic addition, afforded 4d in slightly lower yield
B
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(58%). In addition to substituted benzaldehydes, 2-naph-
thaldehyde (entry 11), cinnamaldehyde (entry 12), and
heteroaryl aldehydes (entries 13 and 14) also underwent this
one-pot transformation in 67−76% yields. The reaction with
cyclohexyl aldehyde (entry 15) at a higher reaction temper-
ature (50 °C) with an increased amount of each employed
aldehyde (2.6 equiv) smoothly gave product 4p in 52% yield
after 48 h. Finally, hydroxyamides bearing electron-donating
groups (Me, OMe), an electron-withdrawing group (CF3), and
naphthalene were tested, and the corresponding chalcone
products (4q−4t) were isolated in 51−64% yields (entries
16−19).
After the successful synthesis of chalcones from N,N-diethyl-
2-hydroxybenzamide through the Claisen−Schmidt condensa-
tion between oxasilinolate 3 and aldehydes, we next examined
the feasibility of implanting an anionic Fries rearrangement
into the one-pot protocol. Gratifyingly, the ortho-lithiated
phenyl diethylcarbamate [1-H] underwent a facile intra-
molecular [1,3]-acyl migration to afford o-carbamoyl phenolate
[2-H] at room temperature, which was subsequently quenched
with TMSCl at 0 °C and benzaldehyde at room temperature in
the presence of MeI to furnish chalcone 4a in a one-pot
procedure with 57% yield (Table 3, entry 1). Likewise, the
employment of various benzaldehydes readily provided B-ring
substituted chalcones 4b, 4f, 4h, and 4j in similar yields
(entries 2−5). The use of 2-naphthaldehyde (entry 6) and
cinnamaldehyde (entry 7) gave adducts 4l and 4m in 51%
yields. Reactions with 2-furaldehyde and 2-thenaldehyde
afforded 4n and 4o in 52% and 51% yields, respectively
(entries 8 and 9). Finally, a series of substituted phenyl
diethylcarbamates were tested in this method. para-Tolyl,
para-(tert-butyl)phenyl, and ortho-phenyl phenyl diethylcarba-
mates were transferred to chalcones 4q, 4u, and 4v smoothly in
41−61% yields. Lithium tetramethylpiperidide and TBDMSCl
were used instead of LDA and TMSCl to promote the
efficiency of the Fries rearrangement of para-methoxy and
para-trifluoromethyl phenyl diethylcarbamates, and 4w and 4s
were obtained in 60% and 54% yields, respectively (entries 13
and 14). Interestingly, when naphthyl diethylcarbamate was
submitted to the standard reaction conditions, methylation on
oxasilinolate 3 happened as a side reaction. The resulting ethyl
ketone and the desired chalcone 4x were formed in a 1:3 ratio
in 50% yield. The yield of 4x was further improved to 61% by
using a greater amount of benzaldehyde instead of adding MeI
(entry 15).
With the success of the one-pot protocol lending credibility
to intermediate 3 and our proposed mechanism, we were also
interested in further mechanism studies based on our previous
report. The failures in isolating oxasilinone led us to replace
the hydroxyl with an amine and use bulkier groups to protect
the silicon atom. To our delight, in the case of the analogous
ortho-(methylamino)amide the corresponding azasilinanone
was isolated in 84% yield after treatment with 4 equiv of LDA
and 2.5 equiv of tert-butyldimethylsilyl chloride (TBDMSCl)
in THF at 0 °C.20 The 5-bromo derivative similarly gave the
azasilinanone 6 in 67% yield. Recrystallization from chloroform
yielded crystals suitable for X-ray diffraction (shown in Figure
2), providing further evidence supporting the mechanism we
proposed in our previous report17 as well as the existence of
intermediate 3.
Table 3. Syntheses of Various 2′-Hydroxychalcones from
Aryl N,N-Diethylcarbamates
Figure 2. Molecular structure of 6. Thermal ellipsoids are set at 50%
probability level. Selected bond distances (Å) and angles (deg): N1−
Si1 1.746, C1−Si1 1.859, N1−Si1−C1 101.29, O−C2−C3−C4
21.94.
The applicability of this one-pot transformation was
demonstrated by a concise and protecting-group-free synthesis
of lonchocarpin, a natural product that possesses numerous
pharmacological properties such as anti-inflammatory,21
antioedematogenic,22 antibacterial,23 and gastroprotective
effect by inhibiting H+, K+ ATPase activity24 and inhibition
of nitric oxide production in lipopolysaccharide-stimulated
BV2 microglial cells.25 As shown in Scheme 2, 2,2-dimethyl-
2H-chromen-5-ol 7 prepared from senecio aldehyde and 1,3-
cyclohexanedione through a reported two-step procedure26
was transferred to carbamate 8 in 89% yield. Carbamate 8 was
then subjected to the one-pot protocol under standard reaction
conditions to furnish natural product lonchocarpin 9 in 62%
yield.27
a
b
Isolated yield. Aldehyde was added at 0 °C, and the reaction was
c
kept at rt. Lithium tetramethylpiperidide and TBDMSCl were used
instead of LDA and TMSCl. RCHO (2 equiv) without MeI.
d
C
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Scheme 2. Concise Synthesis of Lonchocarpin
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bearing different substituents in the A- and B-rings. The
concise synthesis of the anti-inflammatory agent lonchocarpin
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02269.
Experimental details and characterization data (PDF)
Accession Codes
CCDC 1564702 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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Corresponding Author
*E-mail: rjchein@chem.sinica.edu.tw.
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ACKNOWLEDGMENTS
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We thank Academia Sinica and the Ministry of Science and
Technology (Taiwan) (104-2113-M-001-011, 105-2113-M-
001-003, 106-2113-M-001-002) for financial support and the
MS laboratory of the Institute of Chemistry, Academia Sinica,
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This paper is dedicated to Professor E. J. Corey in celebration
of his 90th birthday.
D
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