Desulfonylative Methenylation of β-Keto Sulfones

Article abstract of DOI:10.1021/acs.orglett.5b02455

A one-step strategy for the synthesis of α-methenyl ketones from β-keto sufones is reported. Success of the methodology is elaborated for the synthesis of chromanones and isoflavanones in one-step.

Full text of DOI:10.1021/acs.orglett.5b02455

Letter
pubs.acs.org/OrgLett
Desulfonylative Methenylation of β‑Keto Sulfones
Ganesh Pandey* and Janakiram Vaitla
Molecular Synthesis and Drug Discovery Laboratory, Centre of Biomedical Research, SGPGIMS Campus Lucknow 226014, India
S
* Supporting Information
ABSTRACT: A one-step strategy for the synthesis of α-methenyl ketones
from β-keto sufones is reported. Success of the methodology is elaborated for
the synthesis of chromanones and isoflavanones in one-step.
onor−Acceptor (D−A) cyclopropanes serve as versatile
cyclopropantion reaction of rhodium carbenoid with cyclo-
pentadiene.3b
D
building blocks in diverse chemical transformations,
including cycloaddition, ring opening, and rearrangement
reactions in organic synthesis.1,2 It is established that D−A
cyclopropanes 1 undergoes selective “a” bond cleavage
(Scheme 1) due to polarization by the push−pull effect of
With this information in hand, we sought to prepare
biologically active tropane alkaloids 7 by the cyclopropanation
of the enolate of the optically pure 54a (0.1 M, CH2Cl2, 0 °C)
using Furukawa-modified Simmons−Smith reagent [(Et2Zn, (2
equiv), CH2I2 (2 equiv)], which gave a mixture of 6 and 7 (3:1)
in 54% yield (Table 1, entry 2).5
Scheme 1. Traditional and Developed Activation of D−A
Cyclopropanes
Table 1. Optimization of Regioselective Bond
Fragmentation of D−A Cyclopropane Intermediate
a
b
no.
equiv
temp (°C)
time (min)
6:7
c
c
1
2
3
4
5
6
7
2
2
4
4
4
4
6
−78
0
120
60
120
45
30
5
no reaction
30:12
−78
0
no reaction
50:22
0−25
30
72:0
20:0
0−25
10
48:0
a
b
Equivalents of Et2Zn and CH2I2 to 1 equiv of 5. Isolated yields.
c
Starting material recovered.
The formation of α-methenyl ketone 6, however, was
unexpected in this reaction. To obtain 7 as the major product,
several experiments (Table 1) were performed; however, this
remained elusive. It was surprising to note that reaction at 0−
25 °C produced exclusively 6 in 72% isolated yield (Table 1,
entry 5). Although this result was disappointing, we visualized
its application in the preparation of the α-methenyl ketones
from β-keto sulfones in one step. α-Methenyl ketones are
important starting materials in cycloaddition,6 Michael
donor and acceptor groups. In fact, this property has been very
well exploited to synthesize enol ether 2a by the selective “a”
bond dissociation of 1a.3a
Similarly, Davies et al. have also used this reaction to prepare
γ-keto sulfone 2b from the dissociation of 1b, generated by
Received: August 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02455
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
addition,7 Morita−Baylis−Hillman reaction,8 Nazarov cycliza-
4o, containing an acid-labile protecting group, without
compromising the enantiomeric purity. Notably, α-sulfonyl
aldehydes did not afford the desired acrolein derivatives under
the optimized reaction conditions.
It may be worth emphasizing that, generally, α-methenyl
ketones are prepared in three steps by a Mannich reaction−
alkylation−elimination sequence with Eschenmoser’s salt
(dimethylmethylideneammonium iodide)17 or a transiently
formed methyleneammonium salt.18 Although these ap-
proaches are elegant, regioselective α-methenylation of aliphatic
ketones is a major limitation (Scheme 2).19 For example, α-
tion,9 and several catalytic transformation reactions.10
We report herein the successful transformation of a series of
β-keto sulfones to α-methenyl ketones in one step by the
reaction of diethylzinc in the presence of CH2I2.
Initially, to demonstrate this transformation, reaction of 2-
phenylsulfonylacetophenone (3a) [4 equiv of Et2Zn, 4 equiv of
CH2I2, and 1 equiv of 3a in 0.1 M CH2Cl2 at 0 °C] was
performed, and acrylophenone (4a) (Figure 1) was obtained in
Scheme 2. Traditional and Developed Method for α-
Methenyl Ketones
methenylation of 8 is known to afford a 1:1 mixture of 4t and
4t′ in 63% yield.19 However, in our case, easily accessible β-keto
sufone20 3t under the present reaction conditions afforded 4t
exclusively. Furthermore, traditional α-methenylation of 9
proceeds selectively at a benzylic position to afford 4u′;19a
however, in the present case 4u was formed in 73% yield.
Further application of this reaction was carried out by one-
step transformation of 10a to chromanone (11a) and 10b to
isoflavanones (11b) (Scheme 3) in moderate yields (54−58%).
These compounds are shown to display a range of biological
activity and have been shown to act as immunosuppressive
agents,21 possess antibacterial22 and anticancer activity,23 and
act as α-glucosidase inhibitors.24 Furthermore, 10c is trans-
formed to 11c in two steps,25 which is a precursor of bioactive
sophorapterocarpan A.26 Our attempt to synthesize dihydro-
quinolne 12 by identical reaction of 10d, however, did not
succeed.
Figure 1. Example of the desulfonylative methenylation of β-keto
sufones. (a) All of the reactions were carried out in the presence of 2
mmol of Et2Zn and CH2I2 to 0.5 mmol of 3. (b) Isolated yields.
77% yield. This reaction can be used for gram-scale synthesis of
α-methenyl ketones11 with consistent yields. Usually, in
Simmons−Smith reactions alkenes are starting materials for
cyclopropanation;12 however, in this reaction, formation of
activated alkenes is observed. It may be noted that this is the
first report of this kind where β-keto sulfones are easily
transformed into α-methylene ketones. Previous reports show
the transformation of β-keto sulfones to alkynyl,13 alkenyl,14
carbonyl,15 and dicarbonyl16 functionalities.
The generality of the reaction was established by carrying it
out with a variety of β-keto sufones, and the results are shown
in Figure 1. It is observed that all aromatic, heteroaromatic, and
aliphatic β-keto sufones provided the corresponding α-
methylene ketones in good yields (59−92%).
From Figure 1, it is clear that aromatic β-keto sufones
provided higher yields compared to aliphatic β-keto sufones.
Furthermore, it was noticed that aromatic β-keto sufones
bearing electron-withdrawing substituents 4l gave slightly
higher yields than the electron-donating groups. This protocol
is safely used for the transformation of enantiomerically pure
On the basis of the above observations, a plausible reaction
mechanism has been shown in Scheme 4.
It seems that reaction of 3 by zinc carbenoid or diethylzinc
leads to 13, which undergoes Simmons−Smith reaction to
provide D−A cyclopropane 1c. Subsequently, the leaving group
ability28 of the phenylsulfone group4b of activated D−A
cyclopropane undergoes fragmentation to generate α,β-
unsaturated ketone 4. In order to support the mechanism, we
have also analyzed the crude reaction mixture of 5 by mass
B
DOI: 10.1021/acs.orglett.5b02455
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthetic Applications of Desulfonylative
Methenylation of β-Keto Sufones
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02455.
Experimental procedures, compound characterization
data, copies of NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gp.pandey@cbmr.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST, New Delhi for financial support, and J.V.
thanks CSIR, New Delhi, for the award of a research fellowship.
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DOI: 10.1021/acs.orglett.5b02455
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