A tandem reaction initiated by 1,4-addition of bis(iodozincio)methane for 1,3-diketone formation

Article abstract of DOI:10.1021/ja910428y

(Chemical Equation Presented) Treatment of an γ-acyloxy-α, β-unsaturated ketone with bis(iodozincio)methane leads to a novel tandem reaction consisting of three steps: (1) 1,4-addition of the dizinc reagent to the enone, which affords the corresponding zinc enolate of the β-zinciomethylated ketone; (2) intramolecular nucleophilic attack by the enolate on the ester group; and (3) Grob-type fragmentation of the adduct, accompanied by elimination of the zinc alkoxide of allyl alcohol. The overall reaction gives 1,3-diketones efficiently. Copyright

Full text of DOI:10.1021/ja910428y

Published on Web 12/22/2009
A Tandem Reaction Initiated by 1,4-Addition of Bis(iodozincio)methane for
1,3-Diketone Formation
Mutsumi Sada and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoutodaigaku-katsura,
Nishikyo, Kyoto 615-8510, Japan
Received June 12, 2009; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Scheme 2. Plausible Pathway for the Tandem Reaction
The 1,4-addition of organometallic reagents to R,ꢀ-unsaturated
ketones has been used as an alternative method for the formation
of enolates.1 Both organometallics and metal hydrides have been
used in this transformation.2 With this method, it is easier to control
the regio- and chemoselectivity of enolate formation than with
conventional deprotonation using a strong base.3 The ability of this
reaction to tolerate different functional groups is also valuable and
permits the coexistence of an additional electrophilic group, such
as a ketone or an ester group, in the substrate. This means that the
initially formed enolate can be intramolecularly trapped with these
electrophiles. Therefore, 1,4-addition is suitable as the first step in
Various examples of 1,3-diketone synthesis based on our tandem
an intramolecular tandem reaction.4,5 In the course of our studies
reaction are shown in Table 1. Aryl enones (R1 ) Ar) produced
on bis(iodozincio)methane (1),6,7 we considered that the 1,4-addition
the corresponding 1,3-diketones 3 in excellent yields (entries 1-10),
of 1 to an R,ꢀ-unsaturated ketone may simultaneously form two
nucleophilic sites in the same molecule, i.e., the zinc enolate and
a zinciomethyl group, and that these could trigger a novel tandem
reaction.
and alkyl enones (R1 ) alkyl) gave the products in moderate yields
(entries 11-14). Notably, intramolecular nucleophilic attack by the
zinc enolate on the ester group proceeded smoothly even with
sterically hindered substrates such as in entries 3 and 12. Since the
We previously found that the 1,4-addition of 1 to simple enones
substrates 2 can be prepared directly by esterification of the
required a stoichiometric amount of chlorotrimethylsilane and
corresponding alcohols, which are easily available according to our
formed the corresponding (Z)-silyl enol ethers of ꢀ-zinciomethylated
reported procedure,11 this tandem reaction is a general procedure
ketones.8 The formation of the silyl enol ether would be undesirable
for the preparation of 1,3-diketones.
for a tandem reaction, since the sequential reaction by the enolate
Table 1. 1,3-Diketone Preparation by the Tandem Reaction of 2a
would be interrupted. To eliminate the need for a silylation reagent,
we introduced an acyloxy group at the γ-position of the enone,
which is expected to facilitate 1,4-addition by its ability to
coordinate to dizinc 1.9,10 First, we treated (E)-4-acetoxy-1-phenyl-
2-buten-1-one11 (2a, 0.5 mmol) with 1 (0.6 mmol, 0.5 M in THF)
in THF at 25 °C for 2 h and obtained an unexpected product, 1,3-
diketone 3a, in 91% yield after aqueous workup (Scheme 1).12
entry
R1
R2
2
yield (%)b
3
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Me
i-Pr
t-Bu
Ph
p-MeOC6H4
p-CF3C6H4
Me
Me
Me
Me
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
91
91
81
97
>99
95
92
84
91
91
55
61
69
51
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3i
Scheme 1. Formation of 1,3-Diketone 3a from 2a
p-Tol
p-MeOC6H4
p-CF3C6H4
2-naphthyl
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me
9
10
11
12
13
14
To determine the reaction pathway, we tried the reaction in
Scheme 1 with deuterium-labeled bis(iodozincio)methane, CD2-
(ZnI)2 (1-D);13 3a and 3,3-dideuterio-2-propen-1-ol (4-D) were
formed quantitatively.14 On the basis of these observations, the
reaction pathway can be explained as shown in Scheme 2. 1
adds to γ-acyloxy-R,ꢀ-unsaturated ketone 2 in a 1,4-manner to
form zinc enolate 5 with a C-Zn bond. As the second step,
enolate 5 reacts with the ester group intramolecularly to form
6. Finally, Grob-type fragmentation,15 which is induced by C-Zn
bond cleavage, gives the enolate of 1,3-diketone and the zinc
alkoxide of allyl alcohol. Thus, treatment of γ-acyloxy-R,ꢀ-
unsaturated ketones with 1 afforded 1,3-diketones via this unique
tandem reaction, which effectively uses two C-Zn bonds of 1
during three sequential steps.
t-Bu
p-MeOC6H4
p-CF3C6H4
a The substrate (2, 0.5 mmol) and bis(iodozincio)methane (1, 0.6
mmol) were used for the reaction. b Determined by 1H NMR analysis.
All of the products were isolated by silica gel column chromatography
for the identification.
As noted above, enolate formation by a 1,4-addition can be
performed selectively and can tolerate various functional groups.
Therefore, we can obtain enolates with an additional reactive
functional group, such as a ketone or an ester. In the second step
of the tandem reaction, the intramolecular addition of the enolate
9
432 J. AM. CHEM. SOC. 2010, 132, 432–433
10.1021/ja910428y  2010 American Chemical Society

C O M M U N I C A T I O N S
to the ester group should also proceed selectively even in the
presence of another ketone group, since it proceeds preferentially
in a 5-exo-trigonal manner16 (Scheme 2). As shown in Scheme 3,
substrates that contained another ketone group were examined with
our tandem reaction. During the reaction, the extra ketone group
remained intact. Treatment of the substrates 7, 9, and 11 with 1
gave the corresponding triketones 8, 10, and 12 selectively in good
to excellent yields.
more strained ring. Other lactones 16b-e were also converted to
the corresponding 1,3-diketones 17b-e via ring contraction under
the same conditions.
Scheme 5. Preparation of Cyclic 1,3-Diketones 17 from Lactones
16 via Ring Contraction by the Tandem Reaction
Scheme 3. Preparation of Triketones by the Tandem Reaction
Thus, we have demonstrated a novel tandem reaction initiated
by bis(iodozincio)methane (1) that affords various types of 1,3-
diketones efficiently and selectively, accompanied by the elimination
of three atoms. The reaction consists of three sequential steps: 1,4-
addition of 1 to the enone, intramolecular addition to the ester group,
and Grob-type fragmentation. The two nucleophilic sites, i.e., the
zinc enolate and a zinciomethyl group, that were introduced by
the 1,4-addition of gem-dizinc 1 induced the intramolecular addition
and Grob-type fragmentation, respectively. Further mechanistic
investigations are now underway, and we suppose that the two
addition reaction steps in our tandem reaction would be promoted
in a cooperative manner by the two zinc atoms, which can act as
Lewis acids.
In view of the mechanism of this tandem reaction starting from
γ-acyloxy-R,ꢀ-unsaturated ketone 2 as shown in Scheme 2,
δ-acyloxy-R,ꢀ-unsaturated ketone 13 may also be a suitable
substrate to give 1,3-diketone 3. In the latter case, the enolate
initially formed from 13 should react intramolecularly with the ester
group in a 6-exo-trigonal manner and release homoallyl alcohol
by Grob-type fragmentation. As shown in Scheme 4, 5-benzoyloxy-
1-phenylpent-2-en-1-one (13a) was treated with 1. While the
corresponding γ-acyloxy-R,ꢀ-unsaturated ketone 4-benzoyloxy-1-
phenylbut-2-en-1-one (2d) was transformed into 3d exclusively
(Table 1, entry 4), 13a gave a mixture of 3d, 14, and 15. The
product 14 was obtained by protonolysis of the enolate, which was
formed by the 1,4-addition of 1 to 13a; product 15 was obtained
by intermolecular 1,4-addition of the enolate to 13a, which was
followed by Grob-type fragmentation. After a prolonged reaction
period, the yield of 3d was improved to 50%, but the production
of 14 and 15 could not be avoided. Therefore, in this novel tandem
reaction, γ-acyloxy-R,ꢀ-unsaturated ketone 2 is more suitable as a
substrate than 13.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for the substrates and products. This
material is available free of charge via the Internet at http://pubs.acs.org.
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In addition to the selectivity shown in Scheme 3, a characteristic
feature of this method is the elimination of three atoms in the last
step of the tandem reaction. When this reaction is applied to a
lactone, it is transformed into a cyclic 1,3-diketone via ring
contraction with the elimination of three atoms. As shown in
Scheme 5, 14-membered lactone 16a (X ) CH2, n ) 1) was treated
with 1 at 25 °C for 2 h and at 40 °C for 5 h. At 25 °C, ꢀ-methylated
product 18, which resulted from the 1,4-addition of 1, was formed
as the sole product after aqueous workup. In this transformation,
the 1,4-addition of 1 to 16a proceeded at 25 °C, and the subsequent
intramolecular nucleophilic attack required heating to 40 °C, since
intramolecular addition of the enolate in a 5-exo-trigonal manner
across the ring structure proceeded along with formation of the
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(14) The 1H NMR spectra of the reaction mixture (in THF-d8) are shown in the
Supporting Information.
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