Revisiting the Addition of in-situ Nucleophiles to Allenic Ketones: An Entry Towards Synthesis of Benzodioxins

Article abstract of DOI:10.1002/ejoc.202000076

The manuscript delineates a revisit towards regioselective addition of in situ generated negative nucleophiles to allenic ketones in the presence of a base. A wide variety of allenic ketones as well as nucleophiles are viable in this transformation. A dir

Full text of DOI:10.1002/ejoc.202000076

A Journal of
Accepted Article
Title: Revisiting the addition of Insitu Nucleophiles to Allenic Ketones:
An Entry Towards Synthesis of Benzodioxins
Authors: Sushree Ranjan Sahoo and Debayan Sarkar
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10.1002/ejoc.202000076
European Journal of Organic Chemistry
COMMUNICATION
Revisiting the addition of Insitu Nucleophiles to Allenic Ketones:
An Entry Towards Synthesis of Benzodioxins
Sushree Ranjan Sahooa and Debayan Sarkara*
Abstract: The manuscript delineates a revisit towards regioselective
Scheme 2. Regioselective β-vinyl α,β-unsaturated ketone syntheses
Concurrently, the generation of benzodioxin motifs are
addition of insitu generated negative nucleophiles to allenic ketones
in the presence of a base. A wide variety of allenic ketones as well as
considered note-worthy. The benzodioxins exhibit a wide
range of natural products5 and drug research (Figure-1),6 as
nucleophiles are viable in this transformation. A direct ring annulation
well as building blocks in some organic processes7.
towards the challenging benzodioxin skeleton synthesis has been
Furthermore, their unique chemical and structural properties
create further curiosity.8
developed. Environmentally benign protocol and wide substrate
scope are the notable features of this methodology.
Functionalized vinyl sulphides,1 vinyl ethers2 and vinyl
azides3 are potential ingredients in organic synthesis. Among
these functionalized β-vinyl sulphides, ethers and azides,
those containing a Michael acceptors such as a keto group
at the adjacent sp2 carbon, have great synthetic potential.
Furthermore, they have combined the chemical reactivity to
the molecules associated with these types of reactions. At
present, there are very few reports for the preparation of
these above vinyl compounds. Sugita4 reported the formation
of sulphides employing allenic ketone and thiol, but the main
drawbacks were (1) formation of four different isomers
depending upon starting materials and nucleophiles added,
(2) reaction was carried out in deuterated solvents, (3)
reaction was done in NMR tube, (4) limited substrate scope,
(5) applicable to small scale synthesis. (Scheme-1
)
Figure 1. Biologically important natural products based on the
benzodioxin skeleton
However, methodologies available for the construction of
benzodioxin skeletons are documented below (Scheme-3):
Scheme 1. Sugita report
The addition of insitu generated nucleophiles to allenic
ketones to form only one regioselective β-vinyl α,β-
unsaturated ketones has been described as under (Scheme-
2
):
[a]
Sushree Ranjan Sahoo; Prof. Debayan Sarkar
National Institute of Technology, Department of Chemistry,
Rourkela, Odisha, India, Pin-769008
Scheme 3. Strategies for the synthesis of benzodioxin moiety
The study was initiated by evaluating the parameters of the
reaction, including the variation of bases, solvents, and
temperature in the reaction of allenic ketone 1f with p-
E-mail: sarkard@nitrkl.ac.in
http://www.nitrkl.ac.in/CY/~sarkard/
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thiocresol
2 (Table-1). Firstly, bases were screened with
THF as the solvent at r.t. - 35 oC. Li2CO3 was found to be the
most effective base, with the reaction providing the desired
sole product 2f in 96 % yield (Table-1, entry 7) at 35 oC. On
screening of solvents
(
Table-1
,
entries 9-13), our
observation suggested that THF was optimum for the
present reaction. Similar experiments were conducted in
deuterated chloroform (CDCl3) as a solvent and varying the
base. The results are enlisted below (Table-1, entries 16-
17).
Table 1. Optimization of reaction conditionsa for the formation of 2f and
2f’
Entry
No.
Solvent
Base
Temp. oC
Yield (%)b
(2f:2f’)
1
2
CH3CN
THF
K2CO3
K2CO3
Na2CO3
Na2CO3
Cs2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Et3N
r.t.
r.t.
r.t.
40
40
40
35
r.t.
35
35
35
35
35
35
35
35
35
60 (60:40)
70 (65:35)
75 (65:35)
80 (85:15)
70 (85:15)
85 (90:10)
96 (100:0)
96 (55:45)
85 (100:0)
70 (65:35)
78 (100:0)
75 (100:0)
80 (100:0)
75 (83:17)
70 (65:35)
72 (80:20)
80 (100:0)
3
THF
4
THF
5
THF
6
THF
7
THF
8
THF
9
Dioxane
Benzene
CHCl3
DCM
DCE
10
11
12
13
14
15
16
17
THF
THF
Pyridine
Et3N
CDCl3
CDCl3
With the wider substrate scope of β-vinyl thioether in hand,
the next target was to expand the synthetic utility of our
methodology with the replacement of substituted thiophenols
to substituted phenols, which delivered the regioselective β-
vinyl ethers in good to excellent yields in the standard
conditions and the results are summarized in Table-3. In this
case also, the reaction was quite general and delivered for a
wide substrate scope of substituted aromatic allenic ketones
and aliphatic allenic ketones. Both electron-donating as well
as electron-withdrawing groups in different substituents of
the aromatic ring smoothly afforded the desired products in
high to excellent yields. At the same point, both electron-
donating as well as electron-withdrawing groups containing
aromatic phenol and aliphatic alcohol delivered the scopes
of the β-vinyl ethers in excellent yields.
Li2CO3
[a] Reaction conditions:
1 (1 equiv.), 2 (1.1 equiv.), base (1.1 equiv.), dry
solvent (5 mL), for 5 h under air atmosphere. [b] E/Z is determined by 1H-
NMR.
With the optimized reaction conditions in hand, the scopes of
the β- vinyl thioethers were investigated and the results are
summarized in Table-2. The reaction is quite general and
delivered a wide substrate scope of substituted aromatic
allenic ketones and aliphatic allenic ketones. Both electron-
donating as well as electron-withdrawing groups in different
substituents of the aromatic ring smoothly afforded the
desired products in high to excellent yields. Likewise, both
electron-donating as well as electron-withdrawing groups
containing aromatic thiol and aliphatic thiol, delivered the
scopes of the β- vinyl thioethers in excellent yields.
Table 3. Substrate scope for (E) β-vinyl ether
Table 2. Substrate scope for synthesis of (E) β-vinyl thioether
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The relative stereo-chemistry has been confirmed with
multiple nOe for β-vinyl derivatives. (Figure-2
)
Figure 2. nOe experiments
With the wider substrate scope of β-vinyl ketones in hand,
the next target was to expedite the synthetic utility of our
methodology with different allenic ketones and substituted
ortho-hydroxyl benzaldehydes to deliver the challenging
benzodioxin molecular skeletons in good to excellent yields
(
Table-5) in the presence of Li2CO3 and oxone with DMF
solvent at room temperature under open-air conditions. The
utility of this reaction concludes in transforming three
reaction steps into a single step, which is an effective
development towards the molecule.
After this regioselective β-vinyl thioether and β-vinyl ether
synthesis, our next target was to extend this methodology for
the regioselective synthesis of β-vinyl azide. Fortunately, we
were able to get our desired regioselective β-vinyl azides
were achieved employing TMS-N3 as a nucleophile in good
to excellent yields without any external base and the results
are summarized in Table-4. Both electron-donating as well
as electron-withdrawing groups placed as substituents in the
aromatic ring and aliphatic allenic ketones smoothly afforded
the desired products in high to excellent yields.
Table 5. Substrate scope for benzodioxin skeleton synthesis
Table 4. Substrate scope for (E) β-vinyl azides
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General procedure (A) for vinyl α,β-unsaturated ketone: Allenic Ketones (1
equiv.) was taken in an oven dried single neck round bottom flask (10 mL
capacity) equipped with a magnetic stir within THF (5 mL) in open
atmosphere followed by addition of Li2CO3 (1.1 equiv.) (except azide) and
corrsponding nucleophile (1.1 equiv.) and left it at 35 oC for 4-7 h. The
progress of the reaction was monitored by TLC. After the complication of
the reaction, the reaction mixture was quenched with water and extracted
with ethyl acetate (3 X 20 mL). The organic part was washed with brine
solution and dried over anhydrous sodium sulphate. Then, the solvent was
evaporated under reduced pressure and the obtained crude mass was
purified by column chromatography using silica gel in a specified solvent
combination to deliver the desired compounds with expected purity.
General procedure (B) for benzodioxin synnthesis: Allenic Ketones (1
equiv.) was taken in an oven dried single neck round bottom flask (10 mL
capacity) equipped with a magnetic stir within DMF (5 mL) in open
atmosphere followed by addition of Li2CO3 (1.2 equiv.), substituted ortho-
hydroxy benzaldehyde (1.1 equiv.) and oxone (1.2 equiv.), left it at room
The β- vinyl thioether
with oxone in DMF solvent to access β-vinyl sulfone
2
was further functionalized by treating
and
6
7
o
temperture (25 C) for 12 h. The progress of the reaction was monitored
with an excellent yield at room temperature under open-air
conditions due to sulfones containing molecules are
by TLC. After the complication of the reaction, the reaction mixture was
quenched with water and extracted with ethyl acetate (3 X 20 mL). The
organic part was washed with brine solution and dried over anhydrous
sodium sulphate. Then, the solvent was evaporated under reduced
pressure and the obtained crude mass was purified by column
chromatography using silica gel in a specified solvent combination to
deliver the desired compounds with expected purity.
bioactive in nature.17
(Scheme-4) Similarly, when β-vinyl
ether 3m was treated with oxone in DMF solvent, it delivered
the benzodioxins 5b with 94 % at room temperature under
open-air conditions. This further proved the reaction
sequence of above one pot synthesis of benzodioxin
skeletons. Further synthesis of exciting 2,5-disubstituted
oxazoles
8 was executed with thermolysis of β-vinyl azides
4
by just heating at 120 oC in toluene under a nitrogen
Acknowledgements
atmosphere with excellent yields via 2H-azirines.3
We sincerely acknowledge Department of Science and
Technology (DST), Govt. of India (Grant no. EEQ/2016/000518)
and INSPIRE-DST, Govt. of India (Grant No. 04/2013/000751).
SRS thanks to DST-Inspire for fellowship.
Keywords: •regioselective •insitu nucleophiles •β-vinyl
•benzodioxins
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benzaldehyde addition cascade towards the synthesis of the
benzodioxin skeleton. Thus, the approach represents an
economic and eco-friendly reaction pathway towards the adducts.
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Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
Sushree Ranjan
Sahooa
and
Debayan Sarkara*
Page No. – Page
No.
Revisiting
the
addition of Insitu
Nucleophiles to
Allenic Ketones:
An
Entry
Towards
Synthesis
of
Benzodioxins
Keywords:
Nucleophilic
addition; allenyl
ketones
A revisit towards regioselective addition of insitu generated negative nucleophiles to allenic ketones in
the presence of a base. A direct ring annulation towards the benzodioxin skeleton synthesis has been
developed. In the process, the obtained E-vinyl kenones were readily transformed into sulfones and 2,5-
disubstituted oxazole.
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