Radical based strategy toward the synthesis of 2,3-dihydrofurans from aryl ketones and aromatic olefins

Article abstract of DOI:10.1021/ol502688r

A copper-mediated annulation of aryl ketones with a wide range of aromatic olefins has been developed. This strategy allowed convenient access to 2,3-dihydrofuran derivatives. The versatility of the protocol is shown by synthesizing α-methyl dihydrofurans, which serve as an intermediate for the synthesis of vitamin B1. In addition, the applicability of the protocol in conjugated systems is demonstrated. A radical pathway was presumed and supported for annulation of aryl ketones with olefins. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502688r

Letter
pubs.acs.org/OrgLett
Radical Based Strategy toward the Synthesis of 2,3-Dihydrofurans
from Aryl Ketones and Aromatic Olefins
Togati Naveen, Rajesh Kancherla, and Debabrata Maiti*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
S
* Supporting Information
ABSTRACT: A copper-mediated annulation of aryl ketones with a
wide range of aromatic olefins has been developed. This strategy allowed
convenient access to 2,3-dihydrofuran derivatives. The versatility of the
protocol is shown by synthesizing α-methyl dihydrofurans, which serve
as an intermediate for the synthesis of vitamin B1. In addition, the
applicability of the protocol in conjugated systems is demonstrated. A
radical pathway was presumed and supported for annulation of aryl ketones with olefins.
mong the five-membered heterocycle derivatives, 2,3-
dihydrofuran is one of the most important motifs present
optimization (Table 1),9 the expected dihydrofuran product 3a
was obtained in 85% (GC) yield (isolated, 83%) after stirring at
A
in a number of pharmaceuticals (e.g., aflatoxin B1, clerodin,
etc.)1 and natural products (e.g., azadirachtin, austocystin A,
etc.).1 The 2,3-dihydrofurans are also extremely useful synthetic
intermediates in the preparation of highly functionalized
tetrahydrofurans with good stereoselectivity.2 These scaffolds
are used in 1,3-dipolar cycloaddition reactions to synthesize
heterocyclic compounds with different ring size and atoms.3
Given the importance of 2,3-dihydrofurans in natural and
synthetic substances, the development of a selective and
straightforward intermolecular approach to construct polysub-
stituted dihydrofurans from simple and economical chemical
reagents is still in great demand.4−6
Alkenes have been recognized as important starting materials
in synthetic chemistry because of their low cost and ready
availability. Following our recent efforts to utilize alkene for
generating value-added compounds,7 we envisioned that these
moieties can be employed for the synthesis of 2,3-dihydrofurans
through carbon−carbon and carbon−oxygen bond formation.
In this context, Fukuzawa reported the synthesis of 2,3-
dihydrofurans starting from 2,2-dibromo-1,2-diphenylethanone
and a styrene as the annulation partners (Scheme 1).8 Although
Table 1. Reaction Optimization
a
entry change of the standard conditions
A:B
GC yield of A (%)
1
standard conditions
CuCl
10:1
7:1
9:1
8:1
7:1
3:1
5:1
6:1
6:1
7:1
8:1
8:1
2:1
3:1
2:1
1:1
−
85
48
70
19
34
40
70
75
40
52
61
63
6
2
3
CuOAc
4
CuBr
5
CuF2·H2O
6
0.1 mmol of Cu(OAc)2·H2O
0.2 mmol of Cu(OAc)2·H2O
0.3 mmol of Cu(OAc)2·H2O
0.25 mmol of ketone
0.5 mmol of ketone
1.0 mmol of ketone
0.5 mmol of styrene
DMSO
7
8
9
10
11
12
13
14
15
16
17
CH3CN
35
25
8
benzene
Scheme 1. Synthesis of 2,3-Dihydrofuran from Olefin
1,4-dioxane
no copper salts
0
a
The ratio of 2,3-dihydrofuran (A) and its respective furan (B) is
measured based on GC analysis of the crude reaction mixture.
110 °C for 24 h using dichloroethane (DCE) as the solvent. No
desired product was obtained in the absence of Cu(OAc)2
(Table 1, entry 17). Attempts to reduce the reaction time
resulted in lower yields.9
Under the optimized reaction conditions, various styrenes
were tested to access the expected dihydrofuran products
use of dibromo starting material limited the utility of this
method,8 it provided us the inspiration to synthesize 2,3-
dihydrofuran from a simple ketone and an olefin. We
envisioned that a radical intermediate generated at the α-
position of the ketone will attack the styrene and subsequent
cyclization will lead to substituted 2,3-dihydrofuran (vide infra).
Our initial efforts were focused on the reaction of
deoxybenzoin with styrene by using Cu(OAc)2. Upon extensive
Received: September 11, 2014
Published: October 2, 2014
© 2014 American Chemical Society
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Letter
(Scheme 2). Both electron-withdrawing and -donating styrenes
were successfully employed, and it is noteworthy that steric
To further explore the substrate scope, different aryl ketones
were investigated (Scheme 4). Deoxybenzoin bearing sub-
stituents such as methoxy (6a), chloro (6b−d), and bromo
(6e) delivered the corresponding dihydrofurans (7a−e) in
preparatively useful yields.
a
Scheme 2. Scope with Different Styrenes
a
Scheme 4. Scope with Different α-Arylketones
a
Isolated yields of 7. The ratio of 2,3-dihydrofuran (7) and respective
furan is measured based on GC analysis of the crude reaction mixture
(see Table 1).
a
Isolated yields of 3. The ratio of 2,3-dihydrofuran (3) and respective
Since α-methyl dihydrofuran serves as an intermediate for
the synthesis of vitamin B1,10 we thought to synthesize such
scaffolds following this method. Interestingly, the present
method can be extended to synthesize α-methyl dihydrofurans
(9b−d) from α-methylstyrene (Scheme 5). In the case of (Z)-
β-methylstyrene (8a), only the trans-isomer of the dihydrofuran
(9a) was obtained.
furan is measured based on GC analysis of the crude reaction mixture
(see Table 1).
effects had little influence on this reaction. Regardless of the
substitution pattern of styrenes (ortho, meta, or para) used in
the reaction, expected dihydrofuran products were obtained.
Several important functional groups such as −NO2 (3g),
−CHO (3h), −OCOCH3 (3i), −COOCH3 (3j), and halogens
(−F, −Cl, and −Br, 3k−m) were tolerated under the current
reaction conditions, which allow high diversity in the synthesis
of functionalized dihydrofurans. It was also found that
substituted styrenes with electron-donating groups such as
methyl (3b) and tert-butyl (3d) delivered better yields than
those obtained with electron-withdrawing groups (3g−j).
Next, we tested propiophenone with styrenes (Scheme 3)
bearing halogens (−Cl, −Br, 5b and 5c) and electron-
withdrawing substituents (−OCOCH3, −CHO, 5d and 5e).
All of them gave the corresponding dihydrofurans in moderate
to good yields. Unfortunately, dialkyl ketones did not give the
desired product under the standard reaction conditions.
a
Scheme 5. Scope with α- and β-Methyl Styrenes
a
Isolated yields of 9. The ratio of 2,3-dihydrofuran (9a) and respective
furan is measured based on GC analysis of the crude reaction mixture
(see Table 1).
a
Scheme 3. Scope with Propiophenone
Replacing the styrene with a cyclic olefin such as indene (10)
also afforded the dihydrofurans (11a−c) in moderate to good
yields (Scheme 6). These dihydrofuran-fused cycloalkanes are
important for the synthesis of biologically active natural
products, such as aflatoxin, asteltoxin, etc.11 Different aryl
ketones with methoxy (6b) and chloro (6c) substituents were
also well tolerated under the current reaction conditions.
Furthermore, we thought to replace the styrene with
(1E,3E)-1,4-diphenylbuta-1,3-diene (12) under the optimized
reaction conditions (Scheme 7). Formation of 2-styryl-2,3-
dihydrofurans (13a−d) demonstrated the applicability of the
protocol in conjugated systems.
a
Isolated yields of 5. The ratio of 2,3-dihydrofuran (5) and respective
The addition of 2 equiv of DTBP (di-tert-butylperoxide)
under the standard conditions resulted in a negligible amount
furan is measured based on GC analysis of the crude reaction mixture
(see Table 1).
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Letter
a
styrene will lead to B. The subsequent single electron transfer
and intramolecular cyclization will produce D, which will form
2,3-dihydrofuran upon deprotonation.
Scheme 6. Scope with Indene
In summary, we have demonstrated a copper-mediated
annulation of aryl ketones and aromatic olefins. This reaction
provides a novel synthetic route to 2,3,5-tri-, 2,3,5,5′-tetra-, and
2,3,4,5-tetrasubstituted dihydrofurans from readily available
starting materials.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Isolated yields of 11. The ratio of 2,3-dihydrofuran (11) and
respective furan is measured based on GC analysis of the crude
reaction mixture (see Table 1).
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
a
Scheme 7. Scope with Conjugated Olefin
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dmaiti@chem.iitb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This activity is supported by SERB, India (SB/S5/GC- 05/
2013). Financial support received from CSIR-India (fellowships
to T.N.) and DST Fast Track Scheme (R.K.) is gratefully
acknowledged
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