1,4-Addition of Bis(iodozincio)methane to α,β-Unsaturated ketones: Chemical and theoretical/computational studies

Article abstract of DOI:10.1002/chem.201000738

1,4-Addition of bis(iodozincio)methane to simple α,β-unsaturated ketones does not proceed well; the reaction is slightly endothermic according to DFT calculations. In the presence of chlorotrimethylsilane, the reaction proceeded efficiently to afford a silyl enol ether of β-zinciomethyl ketone. The CZn bond of the silyl enol ether could be used in a cross-coupling reaction to form another C-C bond in a one-pot reaction. In contrast, 1,4-addition of the dizinc reagent to enones carrying an acyloxy group proceeded very efficiently without any additive. In this case, the product was a 1,3-diketone, which was generated in a novel tandem reaction. A theoretical/computational study indicates that the whole reaction pathway is exothermic, and that two zinc atoms of bis(iodozincio)methane accelerate each step cooperatively as effective Lewis acids.

Full text of DOI:10.1002/chem.201000738

DOI: 10.1002/chem.201000738
1,4-Addition of Bis(iodozincio)methane to a,b-Unsaturated Ketones:
Chemical and Theoretical/Computational Studies
Mutsumi Sada,[a] Taniyuki Furuyama,[b] Shinsuke Komagawa,[b]
Masanobu Uchiyama,*[b, c] and Seijiro Matsubara*[a]
À
Abstract: 1,4-Addition of bis(iodozin-
cio)methane to simple a,b-unsaturated
ketones does not proceed well; the re-
action is slightly endothermic according
to DFT calculations. In the presence of
chlorotrimethylsilane, the reaction pro-
ceeded efficiently to afford a silyl enol
form another C C bond in a one-pot
reaction. In contrast, 1,4-addition of
the dizinc reagent to enones carrying
an acyloxy group proceeded very effi-
ciently without any additive. In this
case, the product was a 1,3-diketone,
which was generated in a novel tandem
reaction. A theoretical/computational
study indicates that the whole reaction
pathway is exothermic, and that two
zinc atoms of bis(iodozincio)methane
accelerate each step cooperatively as
effective Lewis acids.
Keywords: addition reactions
density functional calculations
domino reactions ketones
tandem reactions · zinc
·
À
ether of b-zinciomethyl ketone. The C
Zn bond of the silyl enol ether could
be used in a cross-coupling reaction to
·
·
Introduction
fact, we previously reported sequential coupling of 1 with
organic halides:[5] The first coupling reaction of 1 with an or-
ganic halide affords the organozinc compound, which then
undergoes a further cross-coupling reaction. Similarly, 1,4-
addition of 1 to a,b-unsaturated ketones would be another
possible approach to the introduction of the iodozinciometh-
yl group into organic compounds.[6] The 1,4-addition of an
organometallic reagent has been used as a highly regio- and
stereoselective method for the formation of enolates without
the use of a strong base.[7] It would be more attractive if the
1,4-addition of gem-dizinc 1 could be achieved because the
enolate thus formed would also have a zinciomethyl group
in the same molecule, which would allow further molecular
transformations. Therefore we studied the 1,4-addition of 1
to a,b-unsaturated ketones and found new reactions that ex-
hibit the characteristic features of the dizinc 1.
Bis(iodozincio)methane (1), which can be prepared from
diiodomethane and zinc in the presence of a lead catalyst, is
a useful synthetic tool. Because it has two C Zn bonds in-
À
volving the same carbon atom, it can be regarded as a di-
ACHTUNGTRENNUNG
anion equivalent.[1] Taking advantage of this characteristic
functionality, a number of molecular transformations have
been developed. Methylenation of carbonyl compounds[2]
and cyclopropanation of 1,2-diketones are representative ex-
amples.[3] In these reactions, nucleophilic attack by 1 occurs
À
twice to form two C C bonds in one step. When these two
nucleophilic attacks occur in a stepwise manner, the first re-
action can be regarded as a zinciomethylation reaction.[4] In
[a] M. Sada, Prof. Dr. S. Matsubara
Department of Material Chemistry, Graduate School of Engineering
Kyoudai-katsura, Nishikyo, Kyoto 615-8510 (Japan)
Fax : (+81)75-383-2461
Results and Discussion
1,4-Addition of bis(iodozincio)methane (1) to a,b-unsaturat-
ed ketones: The 1,4-addition of bis(iodozincio)methane (1)
to enones did not proceed efficiently, however, we found
that the reaction went to completion in the presence of a
stoichiometric amount of chlorotrimethylsilane.[6] The corre-
sponding (Z)-silyl enol ethers of b-zinciomethyl ketones
were formed, for example, the reaction of chalcone (2) with
1 in the presence of chlorotrimethylsilane. Quenching the
E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
[b] Dr. T. Furuyama, Dr. S. Komagawa, Prof. Dr. M. Uchiyama
The Institute of Physical and Chemical Research (RIKEN)
Wako, Saitama 351-0198 (Japan)
E-mail: uchi_yama@riken.jp
[c] Prof. Dr. M. Uchiyama
Current address: Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo
Bunkyo-ku, Tokyo 113-0033 (Japan)
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FULL PAPER
intermediary organozinc 3 with a saturated aqueous solution
of NH4Cl gave (Z)-silyl enol ether 4 in a yield of 80%
by using the hybrid density functional method based on
Beckeꢁs three-parameter exchange function and the Lee–
Yang–Parr nonlocal correlation functional (B3LYP).[12] We
used Ahlrich and co-workersꢁ SVP[13] all-electron basis set
for the zinc and iodine atoms
À
[Eq. (1), Scheme 1]. The C Zn bond in 3 was also used in a
À
cross-coupling reaction to form a C C bond. The copper-
and the 6-31G* basis set for the
other atoms (denoted as
631SVPs in the text). Geometry
optimizations and vibrational
analyses were performed at the
same level of theory. All sta-
tionary points were optimized
without any symmetry con-
straints and characterized by
normal coordinate analysis at
the same level of theory
(number of imaginary frequen-
cies (NIMAG): 0 for minima
and 1 for the TSs). We em-
ployed CH2ACTHNUGTRNE(UNG ZnX)2 (X=Cl or I)
Scheme 1. One-pot reactions initiated by the 1,4-addition of bis(iodozincio)methane (1) to chalcone (2).
as chemical models for the
dizinc compounds.
The results of several calcula-
mediated reaction of 3 with allyl bromide gave the coupling
product 5 in a yield of 95% [Eq. (2)].[8] The organozinc 3
was also treated with iodobenzene in the presence of a pal-
ladium catalyst and was converted into 6 in a yield of 70%
[Eq. (3)].[9] The reactions in Scheme 1 can be classified as
typical one-pot reactions. It is
tions indicated that the reaction pathway for the 1,4-addi-
tion of 1 to acrolein shown in Figure 1 is the most probable.
In this pathway the addition of CH2ACHTNUTRGNE(NUG ZnCl)2 to acrolein
occurs first to form an association complex CP1 without
much energy gain (0.7 kcalmolÀ1). In the complex CP1, both
notable that chlorotrimethylsi-
lane was essential for the com-
pletion of the 1,4-addition reac-
tion. Stabilization of the inter-
mediary zinc enolate by trans-
formation into the silyl enol
ether would be the driving
force of the reactions.
Theoretical/computational
study of the 1,4-addition of 1:
Density
functional
theory
(DFT) calculations were per- Figure 1. 1,4-Addition of bis(iodozincio)methane (1) to acrolein.
formed to gain an understand-
ing of the 1,4-addition reactions
of 1. The success of this 1,4-addition in the presence of
chlorotrimethylsilane is considered to be a result of 1) the
different reactivity of the enone moiety at the 1,2- and 1,4-
addition sites, that is, the 1,4-addition site is much more re-
active than the 1,2-site, and 2) the crucial role of chlorotri-
methylsilane in the 1,4-addition reaction.[10] To determine
the reaction mechanism, selectivity, and the effect of chloro-
trimethylsilane on the 1,4-addition reaction, we examined
the reaction of 1 with acrolein as the simplest model reac-
tion by the DFT method.
zinc atoms of 1 are coordinated to the same carbonyl group
À À
of the acrolein causing the Zn C Zn angle (1078) to be
bent by 88 and the C=O bond length (1.24 ꢂ) to be elongat-
À
ed by 2% as compared with those in RT1. C C bond forma-
tion occurs as the methylene group bound to the two zinc
atoms approaches the terminal carbon atom of the acrolein
with an activation energy of 23.6 kcalmolÀ1. The whole reac-
tion is slightly endothermic (4.0 kcalmolÀ1), in good agree-
ment with the failure of the 1,4-addition of 1 to 2 to go to
completion in the absence of chlorotrimethylsilane. The re-
sults of this DFT calculation clearly suggest that the 1,4-ad-
dition of 1 to a,b-unsaturated carbonyl compounds either
does not proceed or it proceeds only slightly because of
All the calculations reported herein were carried out with
the Gaussian 03 program package.[11] The molecular struc-
tures and harmonic vibrational frequencies were obtained
Chem. Eur. J. 2010, 16, 10474 – 10481
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10475

M. Uchiyama, S. Matsubara et al.
thermodynamic preferences rather than for kinetic reasons.
Hence, we can conclude that the addition of chlorotrime-
thylsilane improves the conversion of the 1,4-addition by
transforming the initially formed zinc enolate into the corre-
sponding stable silyl enol ether.
Scheme 2. Formation of 1,3-diketone 8a from 7a.
We also identified a four-centered TS, TS2, for the 1,2-ad-
dition reaction (Figure 2). However, TS1 is energetically
much more favorable than TS2 by DDG° =12.4 kcalmolÀ1.
The 1,2-addition reaction is therefore kinetically much less
likely to take place than the 1,4-addition.
of the mixture obtained showed the quantitative formation
of 1,3-diketone 8a and 3,3-dideuterioprop-2-en-1-ol (10;
Scheme 3).
To obtain additional information about the reaction path-
ways and mechanisms, we then
examined the reaction of 1 and
(E)-4-oxobut-2-enyl
formate
with two molecules of Me2O by
means of DFT (B3LYP/
631SVPs) calculations (Figure 3
and Scheme 4). The reactants
first form an association com-
plex T-CP1 with little energy
gain. The cyclic intermediate T-
CP1 bears two Zn…O bridges
between 1 and the substrate.
The 1,4-addition reaction of the
methylene group of the dizinc
reagent proceeds via the TS T-
TS1, which retains both the
Figure 2. 1,2 -Addition of bis(iodozincio)methane (1) to acrolein.
Replacement of CH2ACHTNUTRGENN(UG ZnCl)2 with CH2ACHTUGNTREN(NUGN ZnI)2 does not
much affect the geometry of the intermediates/TSs or their
energy profiles and so does not change the conclusions of
the above analysis (see the Supporting Information).
Scheme 3. Reaction of 7a with CD2ACTHNUTRGNEU(GN ZnI)2 (9).
Tandem reactions of 1 with g-acyloxy-a,b-unsaturated ke-
tones: Based on the above computational analysis, we intro-
duced an acyloxy group at the g-position of the enone as an
intramolecular electrophile in the reaction with the dizinc 1
instead of stabilizing the initially formed zinc enolate by si-
lylation. The acyloxy group would trap the zinc enolate in-
tramolecularly and was expected to facilitate the 1,4-addi-
tion of 1. We treated (E)-4-acetoxy-1-phenylbut-2-en-1-one
(7a; 0.5 mmol) with bis(iodo-
Zn…O coordinations, with a reasonable activation energy
(24.2 kcalmolÀ1) to give the Zn–enolate intermediate T-CP2
with an exothermicity of approximately 10 kcalmolÀ1, prob-
ably due to the stabilization of the two Zn…O bonds. After
the 1,4-addition, the geometry/orientation of the formate
group changes drastically so that the enolate anion can ap-
zincio)methane (1; 0.6 mmol,
0.5m in THF) in THF at 258C
for 2 h and obtained an unex-
pected product, 1,3-diketone
8a, in a yield of 91% after
aqueous workup (Scheme 2).[14]
Mechanistic investigation of the
reaction pathway of the tandem
reaction: The reaction of 7a
was also performed with deute-
rium-labeled bis(iodozincio)me-
thane (CD
[D8]THF and quenched with
2ACHTUNGTRENNUNG
(ZnI)2, 9)[15] in
[D4]acetic acid. NMR analysis Figure 3. Tandem reaction of bis(iodozincio)methane (1) and (E)-4-oxobut-2-enyl formate.
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Chem. Eur. J. 2010, 16, 10474 – 10481

Bis(iodozincio)methane Addition to Unsaturated Ketones
FULL PAPER
Preparation of various 1,3-dike-
tones by the tandem reaction:
Various examples of the synthe-
sis of 1,3-diketones by using our
strategy are shown in Table 1.
Aryl enones produced the cor-
responding 1,3-diketones 8 in
excellent yields (R1 =Ar, en-
tries 1–13)
whereas
alkyl
enones gave the products in
moderate yields (R1 =alkyl, en-
tries 14–17). Notably, intramo-
lecular nucleophilic attack of
the zinc enolate on the ester
group proceeded smoothly,
even with sterically hindered
substrates, for example, en-
tries 3 and 15. As shown in en-
tries 4–6, the yields of 8 were
not affected by the electrophi-
licity of the aryloyl group in the
ester moiety. On the other
hand, an electron-donating
group on the benzene ring in
the Michael acceptor slightly
decreased the yield, although it
was still good (entry 9).
Scheme 4. Detailed structures of the intermediates and transition states presented in Figure 3.
proach it. Intramolecular acyl rearrangement occurs with a
slightly lower activation energy (19.0 kcalmolÀ1) than that of
the 1,4-addition. The intramolecular acylation reaction pro-
À
ceeds with the rupture of one of the two Zn C bonds in 1
and the resultant hemiacetal moiety becomes attached to
À
the detached Zn Cl moiety to produce intermediate T-CP3
with a stabilization of 23.5 kcalmolÀ1. The hemiacetal com-
plex T-CP3 is further stabilized by the recombination of sev-
À
eral bonds, including the C Zn cleaved bond, with an over-
all loss of energy of only 17.8 kcalmolÀ1. A Grob-type frag-
mentation product T-PD, which possesses the enolate of the
1,3-diketone and zinc chloride prop-2-en-1-olate, is finally
formed with a reasonably large stabilization energy.
This mechanistic investigation by theoretical methods has
revealed that 1) this unique reaction using the gem-dizinc re-
agent takes place as a three-step sequential reaction, that is,
1,4-addition (RDS), acyl rearrangement, and Grob-type
fragmentation[16] (Scheme 5), 2) each reaction step is facili-
tated by the synergy of the two zinc atoms of the gem-dizinc
reagent, and 3) the activation energies from the first to third
step decrease gradually and the products become more sta-
bilized as reaction proceeds. This is in good agreement with
the fact that no intermediate was observed in this reaction
and with the occurrence of the so-called “tandem reac-
tion”.[17]
Scheme 5. Plausible pathway for the tandem reaction.
Application of the tandem reaction to triketone synthesis:
The formation of enolates by 1,4-addition can be achieved
selectively and various functional groups can be tolerated.
Therefore we can obtain enolates with extra reactive func-
tional groups such as a ketone group as well as an ester
group. In the second step of the tandem reaction, the intra-
molecular addition of the enolate to the ester group should
also proceed selectively, even in the presence of another
ketone group, because it proceeds preferentially in a 5-exo-
trigonal manner.[18] Thus, the preparation of 1,3-diketones
based on the acylation of enolates can be realized even in
the presence of an extra ketone group. As shown in
Scheme 6, substrates containing another ketone group were
examined in our tandem reaction. Compounds 11 and 13
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10477

M. Uchiyama, S. Matsubara et al.
Table 1. Preparation of the 1,3-diketones 8 by the tandem reaction of
7.[a]
a-proton of the carbonyl group, but reacted selectively by
1,4-addition to form the enolate regioselectively.
Tandem reactions of d-acyloxy-a,b-unsaturated ketones with
1: If we consider the mechanism of this tandem reaction
Entry
R1
R2
7
8
Yield [%][b]
starting from g-acyloxy-a,b-unsaturated ketone
7
in
Scheme 5, d-acyloxy-a,b-unsaturated ketone 17 may also be
a suitable substrate to give 1,3-diketone 8. In the latter case,
the initially formed enolate from 17 will react intramolecu-
larly with the ester group in a 6-exo-trigonal manner and
will release homoallyl alcohol in a Grob-type fragmentation.
As shown in Scheme 7, 5-benzoyloxy-1-phenylpent-2-en-1-
one (17a) was treated with 1. Whereas the corresponding g-
acyloxy-a,b-unsaturated ketone, 4-benzoyloxy-1-phenylbut-
2-en-1-one (7d), was transformed into 8d exclusively
(entry 4, Table 1), 17a gave a mixture of 8d, 18, and 19. The
product 18 was obtained by protonation of the enolate,
which was formed by the 1,4-addition of 1 to 17a. The prod-
uct 19 was obtained by intermolecular 1,4-addition of the
enolate to 17a followed by a Grob-type fragmentation. By
prolonging the reaction time, the yield of 8d increased to
50%, but the formation of 18 and 19 could not be avoided
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
o-Tol
p-Tol
Me
iPr
tBu
7a
7b
7c
7d
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
8a
8b
8c
8d
8e
8 f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8j
91
91
81
97
>99
95
88
92
84
91
>99
73
91
55
61
Ph
p-MeOC6H4
p-CF3C6H4
Me
Me
Me
Me
Me
Me
Me
Me
tBu
9
p-MeOC6H4
p-CF3C6H4
p-BrC6H4
1-naphthyl
2-naphthyl
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me
10
11
12
13
14
15
16
17
p-MeOC6H4
p-CF3C6H4
69
51
[a] The substrate 7 (0.5 mmol) and bis(iodozincio)methane (1; 0.6 mmol)
were used for the reaction. [b] Determined by H NMR spectroscopy. All
1
products were isolated by silica gel column chromatography for identifi-
cation.
(Scheme 7).
A theoretical/computational study of the
tandem reaction in Figure 3 revealed that the reaction of T-
CP2 to T-CP3 proceeds smoothly via T-TS2. In particular, in
T-TS2, the two zinc atoms on the methylene group operate
cooperatively in the fused six- and five-membered-ring
structure. In the case of 17a, the transition state of the intra-
molecular acylation step would be unfavorable for the for-
mation of a fused ring structure like T-TS2. Therefore the
second step of this tandem reaction did not proceed effi-
ciently with 17a. Thus, in this novel tandem reaction, g-acyl-
AHCTUNGTREGoNNUN xy-a,b-unsaturated ketone 7 is more suitable as a substrate
than 17.
Preparation of cyclic 1,3-diketones by a ring-contraction re-
action: Another characteristic feature of the tandem reac-
tions of g-acyloxy-a,b-unsaturated ketones with 1 is the
elimination of three atoms. When the reaction was applied
to lactones, they were transformed into the corresponding
cyclic 1,3-diketones by a ring contraction with the elimina-
tion of three atoms. Thus, as shown in Scheme 8, 14-mem-
bered lactone 20a (X=CH2, n=1) was treated with 1 at
258C for 2 h and at 408C for 5 h, and was converted into the
cyclic 1,3-diketone 21a in a yield of 78%. Without heating,
b-methylated product 22, which results from the 1,4-addition
of 1, was formed as the sole product after aqueous workup.
Scheme 6. Preparation of triketones by the tandem reaction.
were easily prepared by esterification of (E)-4-hydroxy-1-
phenylbut-2-en-1-one[19] with the corresponding keto carbox-
ylic acids. Compound 15 was also prepared by acylation of a
g-hydroxy-a,b-unsaturated ketone carrying an extra ketone
group, which was easily obtained from 4-propionylbenzalde-
hyde according to our reported
procedure.[19] The substrates 11,
13, and 15 were efficiently con-
verted into the corresponding
triketones 12, 14, and 16 in high
yields. In these transformations
it is notable that bis(iodozin-
cio)methane (1) did not func-
tion as a base at all, which
would have deprotonated the Scheme 7. Reaction of d-benzoyloxy-a,b-unsaturated ketone 17a with bis(iodozincio)methane (1).
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Chem. Eur. J. 2010, 16, 10474 – 10481

Bis(iodozincio)methane Addition to Unsaturated Ketones
FULL PAPER
When pyrometallurgy zinc dust was
used instead of pure zinc, it was not
necessary to add PbCl2. Both pure zinc
and pyrometallurgy zinc are commer-
cially
available.
Diiodomethane
(50 mmol) in THF (45 mL) was added
dropwise to the mixture over 30 min
at 08C with vigorous stirring. The mix-
ture was stirred for 4 h at 258C. Then
the reaction vessel was allowed to
stand undisturbed for several hours.
Excess zinc was separated by sedimen-
Scheme 8. Preparation of cyclic 1,3-diketones 21 from lactones 20 by the tandem reaction proceeding with ring
contraction.
tation. The 1H NMR spectrum of the supernatant obtained showed a
broad singlet at À1.2 ppm at 08C, which corresponded to the methylene
proton of 1. The supernatant was used in subsequent reactions as a solu-
tion of 1 in THF (0.4–0.5m). Bis(iodozincio)methane in THF can be kept
without decomposing for at least a month in a sealed reaction vessel.
In this transformation, the 1,4-addition of 1 to 20a proceed-
ed at 258C but the subsequent intramolecular nucleophilic
attack required heating at 408C to enable intramolecular ad-
dition of the enolate in a 5-exo-trigonal manner across the
ring structure along with the formation of a more strained
ring. In the reactions of other lactones 20b–e, the corre-
sponding 1,3-diketones 21b–e were obtained by ring con-
traction even at 258C, with heating to 408C improving the
yield slightly. The ethereal oxygen atom in the ring (X in
20b–e) may facilitate the reaction by reducing the ring
strain of the intermediate corresponding to T-TS2 in
Figure 3.
Preparation of 5 by 1,4-addition and Cu-mediated coupling: Bis(iodozin-
cio)methane in THF (1, 0.4m, 1.0 mmol) was added dropwise to a solu-
tion of chalcone (2; 1.0 mmol) and chlorotrimethylsilane (1.1 mmol) in
THF (3 mL) at 208C. The mixture was stirred for 1 h and cooled to
À108C. A solution of CuCN (1.0 mmol) and LiCl (2.0 mmol) in THF
(2 mL) was added to the mixture at À108C and the whole was stirred for
5 min at the same temperature. Allyl bromide (1.2 mmol) in THF (1 mL)
was added to the mixture and the resulting mixture was stirred for 1 h at
À108C. Et3N (5 mL) was then added to the mixture. The resulting mix-
ture was stirred for 5 min and poured into an ice-cooled saturated aque-
ous solution of NH4Cl, and extracted with diethyl ether. The organic
layers were washed with a saturated aqueous solution of Na2S2O3 and
brine. The ethereal solution was dried over MgSO4. Concentration in
vacuo gave a yellow oil. Short column chromatography on neutral silica
gel gave 5 in a yield of 95%. Aqueous workup before the addition of
allyl bromide gave 4[20] in a yield of 80%.
Conclusion
The 1,4-addition of bis(iodozincio)methane (1) to an enone
gave the zinc enolate of b-zinciomethyl ketone, but the reac-
tion did not go to completion. The reaction was shown to be
endothermic by a theoretical/computational study. Addition
of chlorotrimethylsilane allowed the 1,4-addition reaction to
proceed efficiently and gave the silyl enol ether of b-zincio-
methyl ketone in high yield. Thus, the products formed were
Preparation of (E)-4-oxo-4-phenylbut-2-enyl acetate (7a): The substrate
7a was easily obtained by acetylation of the corresponding g-hydroxy-
a,b-unsaturated ketone, (E)-4-hydroxy-1-phenylbut-2-en-1-one, which
was obtained in four steps from benzaldehyde in an overall yield of 49%
following our reported procedure.[19]
Pyridine (24 mmol), acetic anhydride (12 mmol), and N,N-dimethyl-4-
aminopyridine (0.5 mmol) were added to a solution of (E)-4-hydroxy-1-
phenylbut-2-en-1-one (10 mmol) in dichloromethane (10 mL) and the
mixture was stirred for 12 h at 258C. A saturated aqueous solution of am-
monium chloride was added and then the mixture was extracted with
ethyl acetate. The combined organic layers were washed with brine, dried
over sodium sulfate, and concentrated in vacuo. After a purification by a
flash silica gel column chromatography (hexane/ethyl acetate, 5:1), the
pure acetate 7a was isolated in a yield of 96%.
À
still reactive towards C C bond forming reactions because
À
the C Zn bond in the silyl enol ether could be converted
À
into a C C bond in a cross-coupling reaction.
The introduction of an acyloxy group at the g position of
the a,b-unsaturated ketone also facilitated the 1,4-addition
of 1 to form the zinc enolate, which underwent intramolecu-
lar nucleophilic addition and then Grob-type fragmentation
to afford the 1,3-diketone effectively. By achieving the 1,4-
addtion of 1 to g-acyloxy-a,b-unsaturated ketone 7, we in-
troduced two nucleophilic sites, zinc enolate and a zincio-
methyl group, which induced the intramolecular addition
and Grob-type fragmentation, respectively. A theoretical/
computational study showed that the two addition reaction
steps in our tandem reaction were promoted in a coopera-
tive manner by the two zinc atoms acting as Lewis acids.
The substrates 7b–q and 15 were also synthesized by esterification of hy-
droxyenones with the corresponding carboxylic anhydrides or acyl chlor-
ides in the presence of amines. The substrates 11 and 13 were prepared
by esterification with the corresponding carboxylic acids and N,N-dicyclo-
hexylcarbodiimide (DCC).
The precursor of lactone 20a was prepared following the reported proce-
dure,[19, 21] and its macrolactonization was achieved by using lipase.[22] The
lactones 20b–e were prepared by the following procedure.
Preparation of macrolactones 20b–e: The substrate 20b was obtained
from commercially available 2-hydroxybenzyl alcohol (23) in five steps.
Selective etherification of 23 with allyl 6-bromohexanoate (24) was per-
formed following the reported procedure.[23] Hexanoate 24 (20 mmol)
and potassium carbonate (60 mmol) were added to a solution of 23
(25 mmol) in acetone (120 mL) and the resulting mixture was vigorously
stirred at reflux for 24 h and then cooled. The acetone was then removed
under reduced pressure, the resulting residue was partitioned between
ethyl acetate and 1.0m aq. HCl, and the aqueous layer was washed twice
with ethyl acetate. The combined organic layers were dried over sodium
sulfate and concentrated in vacuo. After purification by flash silica gel
column chromatography (hexane/ethyl acetate, 3:1), the corresponding
pure ether 25 was obtained in 34% yield. Ether 25 was oxidized with pyr-
Experimental Section
Full experimental procedures and characterization data are given in the
Supporting Information.
Preparation of bis(iodozincio)methane (1): A mixture of pure zinc dust
(150 mmol), diiodomethane (1.0 mmol), and PbCl2 (0.005 mmol) in THF
(5.0 mL) was sonicated for 1 h in an ultrasonic cleaner bath under argon.
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M. Uchiyama, S. Matsubara et al.
idinium chlorochromate (PCC) and SiO2 in dichloromethane at room
temperature for 1 h to give the corresponding aldehyde. The aldehyde
was then converted into allylic alcohol 26 by using vinyl magnesium bro-
mide in THF at À788C for 2 h. Purification by flash silica gel column
chromatography (hexane/ethyl acetate, 10:1) gave pure 26 in a yield of
44% in two steps.
[2] a) S. Matsubara, K. Oshima in Modern Carbonyl Olefination (Ed.:
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After bubbling argon through a solution of 26 in dry dichloromethane
(0.01m) for 20 min, 5 mol% of Grubbs second generation catalyst was
added and the mixture was stirred at room temperature for 24 h.[24] The
catalyst was removed by filtration and a 14-membered-ring lactone was
obtained. Oxidation with MnO2 in dichloromethane at room temperature
for 12 h and purification by flash silica gel column chromatography
(hexane/ethyl acetate, 3:1) gave the substrate 20b in a yield of 67% in
two steps.
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The substrates 20c–e were also obtained in the same way using the corre-
sponding allyl esters instead of 24.
General procedure for the preparation of 1,3-diketones: The reactions
were performed in a 20 mL round-bottomed flask filled with argon. Bis-
ACHTUNGTRENNUNG(iodozincio)methane (1; 0.6 mmol, 0.5m in THF) was added to a solution
of a g-acyloxy-a,b-unsaturated ketone (7, 11, 13, 15; 0.5 mmol) in THF
(2.0 mL). Then the mixture was stirred at 258C for 2–5 h (aryl enones:
7a–m, 11, 13, 15) or 6–12 h (alkyl enones: 7n–q). Then a saturated aque-
ous ammonium chloride solution was added and the mixture was extract-
ed with ethyl acetate. The combined organic layers were washed with
brine, dried over sodium sulfate, and concentrated in vacuo. Purification
by flash silica gel column chromatography gave the corresponding pure
1,3-diketones 8, 12, 14, and 16.
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When the lactones 20 were used as substrates, the reaction mixtures were
stirred at 258C and then at 408C. The reaction times were as follows:
20a: 2 h at 258C and 5 h at 408C; 20b–e: 1.5 h at 258C and 10 h at 408C.
By employing higher temperatures, the desired reaction proceeded effi-
ciently; after purification as described above, the pure cyclic 1,3-dike-
tones 21 were obtained.
Acknowledgements
The calculations were performed by using the RIKEN Integrated Cluster
of Clusters (RICC) facility. This work was supported by the Japanese
Ministry of Education, Culture, Sports, Science and Technology.
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Received: March 24, 2010
Published online: July 19, 2010
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www.chemeurj.org
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