Tandem chain extension-iodomethylation reactions: formation of α-functionalized γ-keto carbonyls

Article abstract of DOI:10.1016/j.tet.2008.06.063

Sequential exposure of a zinc-organometallic intermediate, generated through a zinc carbenoid-mediated chain extension reaction of a β-keto carbonyl, to trimethylsilylchloride and iodine provided regioselective formation of an α-iodomethyl-γ-keto carbonyl. The iodomethyl functionality can be further manipulated to provide side chains that are potential mimics of α-amino acid side chains.

Full text of DOI:10.1016/j.tet.2008.06.063

Tetrahedron 64 (2008) 8045–8051
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem chain extension–iodomethylation reactions: formation
of a-functionalized g-keto carbonyls
*
Qinglin Pu, Emerald Wilson, Charles K. Zercher
Department of Chemistry, University of New Hampshire, Durham, NH 03824, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2008
Received in revised form 12 June 2008
Accepted 16 June 2008
Available online 20 June 2008
Sequential exposure of a zinc-organometallic intermediate, generated through a zinc carbenoid-medi-
ated chain extension reaction of a
regioselective formation of an -iodomethyl-
ther manipulated to provide side chains that are potential mimics of
b
-keto carbonyl, to trimethylsilylchloride and iodine provided
-keto carbonyl. The iodomethyl functionality can be fur-
-amino acid side chains.
a
g
a
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Zinc
Carbenoid
Chain extension
Homoenolate
1. Introduction
Related to our interest in the further development of this chain
extension methodology as a tool for peptide isostere formation,
we were interested in identifying methods for the further
Selective functionalization of carbon skeletons is essential for
the development of useful synthetic methodology. A zinc carbe-
noid-mediated chain extension reaction1 has been developed in
our research group in which
esters through the intermediacy of a zinc-organometallic in-
termediate that is localized on ester’s -carbon. This organometallic
diversification of the
a-substituents. Alkylation of the chain
extension’s organometallic intermediate would be very useful, al-
though all efforts to induce alkylation have been unsuccessful. This
is consistent with the observation that ethyl iodide, which is
a by-product produced during carbenoid generation,7 is not
b-keto esters are converted to g-keto
a
character is reminiscent of the zinc-containing intermediate
formed in a classic Reformatsky reaction2 and, as such, we have
used this organometallic intermediate in the development of var-
ious tandem reaction processes. Treatment of the organometallic
intermediate with aldehydes completes a tandem chain extension–
aldol process that has been used in peptide isostere formation and
natural product synthesis.3 Treatment of the organometallic in-
termediate with iodine, followed by treatment with a base, pro-
incorporated into the g-keto ester by nucleophilic displacement of
the iodide. Reports from the literature suggest that alkylations of
the zinc Reformatsky intermediate can only occur with activated
alkylating agents, under elevated temperatures and/or with polar
solvents,8 neither of which are compatible with the zinc carbenoid-
mediated chain extension reaction.
As mentioned above, we had developed a limited tandem chain
extension–alkylation variation4 that facilitated incorporation of an
vides facile access to an
been used in a number of natural product syntheses.4 Methylation
at the -position has also been accomplished through the activation
a
,
b
-unsaturated-
g
-keto esters, which has
a-methyl substituent. The proposed mechanism of this reaction
involved formation of a putative, transient trimethylsilylketene
acetal by treatment of the organometallic intermediate with TMSCl,
which then reacts with excess carbenoid to provide a proposed
a
of the organometallic intermediate by treatment with trime-
thylsilylchloride (TMSCl) in the presence of excess carbenoid.5
zinc-homoenolate. The
b-anionic character inherent to a homo-
These
a
-functionalization methods have been complemented
enolate was demonstrated through deuterium quenching of the
reaction mixture. While use of the zinc-homoenolate for additional
carbon–carbon formation may be possible, we were interested in
trapping the homoenolate with an electrophile that would facilitate
a wide variety of addition functionalization strategies. We were
recently by a method that incorporates a
b-substituent when
a substituted carbenoid is used in the chain extension reaction.6
particularly interested in the eventual formation of
that would mimic the
-side chains of amino acids.3b The variability
found within amino acid side chains requires incorporation of
a-side chains
a
* Corresponding author. Tel.: þ1 603 862 2697.
E-mail address: ckz@cisunix.unh.edu (C.K. Zercher).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.063

8046
Q. Pu et al. / Tetrahedron 64 (2008) 8045–8051
O
O
O
O
ZnX
O
Et2Zn, CH2I2
cat TMSCl
OR1
R
R
OR1
OR1
R
R
R
O
TMS
XZnCH2I
O
I
ZnX
OR1
O
I2
OR1
O
O
Scheme 1.
functionality with sufficient flexibility for the formation of a wide
variety of side chains. We report, herein, a tandem chain extension–
chain extension mechanism; however, a report by Saigo12 sug-
gested that the unanticipated regioselectivity could be explained by
cyclopropanation of 7b, followed by ring opening and capture of
the excess carbenoid by the ketone enolate. According to Saigo’s
hypothesis, compound 7b could be generated in the reaction
mixture by zinc-catalyzed isomerization of the TMS group. For-
mation of 7a and 7b would be possible if TMSCl was incorporated
prior to completion of the chain extension reaction. In order to test
this hypothesis, the addition of the TMSCl was delayed while the
chain extension reaction was allowed to proceed for 30 min. This
modification facilitated consumption of the starting material prior
to addition of the TMSCl, with the result being that the by-product,
methylation–iodination reaction (Scheme 1) of
b
-dicarbonyls that
-side chain is
provides a -keto carbonyl product in which the
g
a
appropriately functionalized for additional manipulation.
2. Results and discussion
The treatment of methyl pivaloylacetate 1 for 10 min with the
Furukawa reagent, generated from diiodomethane and diethyl zinc,
provided an intermediate that was treated sequentially with cata-
lytic TMSCl (20 mol %) and iodine (2 equiv). The reaction can also be
presumably
With optimized conditions now available, the formation of
iodomethyl- -keto products from -keto ester and amide starting
b-iodomethyl-g-keto ester 6, was not formed.
performed by treatment of the b-dicarbonyl with diethyl zinc to
induce enolate formation, followed by addition of the diiodo-
methane, which reacts with the excess diethyl zinc to generate the
a
-
g
b
materials was studied. The ester starting materials were consistent
performers in this reaction, producing isolated yields ranging from
Furukawa reagent. The corresponding a-iodomethyl-g-keto ester 2
was isolated after chromatographic purification (Scheme 2). Iodine
was chosen as the electrophile due to iodide’s anticipated lability in
further manipulations, as well as the recognition that excess iodide
is already present in the carbenoid mixture. Efforts to utilize bro-
mine as an electrophile in tandem chain extension reactions have
been complicated by iodide’s ability to substitute for the bromide.9
58% to 62% (Table 1). Since secondary
b-keto amides were in-
efficient substrates for the chain extension–methylation reaction5
and the modestly acidic NH of a secondary amide would be pre-
dicted to quench both the Reformatsky-like organometallic in-
termediate and the zinc-homoenolate, the decision was made to
I
O
O
O
OMe
OMe
OMe
OMe
Me3C
Me3C
Me3C
Me3C
O
O
O
3
O
O
2
a) Et2Zn, CH2I2
b) cat TMSCl
c) I2
Me3C
OMe
O
I
1
O
4
5
Scheme 2.
While isolation of the desired
a
-iodomethyl-g-keto ester was
focus on the reactivity of tertiary b-keto amides. Unfortunately, the
possible, chromatography was necessary to separate compound 2
from a number of side products. Analysis of the crude reaction
mixture by 1H NMR revealed the presence of the known compounds
tertiary amide starting materials were poor substrates for this
tandem reaction. N,N-Diisopropyl 3-oxo-butyramide provided
none of the desired
a-iodomethylated material. The pyrrolidine
g
-keto ester 3,10
presence of 3 and 5 suggested that the
a-methylated 4, and
a
-iodo-
g
-keto ester 5.11 The
amide 14 provided the desired
a
-iodomethyl- -keto amide 15 in
g
a
-methylation step of this
only 12% yield. The activation of the Reformatsky-like organome-
tallic intermediate by TMSCl appears to be very inefficient with
these substrates, even though Hilgenkamp had reported5 that chain
three-step process was not proceeding efficiently, while the for-
mation of 4 suggested that insufficient iodine was present to capture
the homoenolate. An increase in the reaction time after addition of
the TMSCl from 30 min to 60 min inhibited the formation of 3 and 5,
while the use of 5 equiv of iodine ensured that no 4 was formed.
One other by-product was observed in the crude reaction mix-
tures and proved difficult to separate from the desired product. This
compound was believed to be the isomeric iodomethyl-substituted
TMS
O
O
I
TMS
OMe
O
O
O
OMe
Me3C
OMe
Me3C
Me3C
O
6
7a
7b
g-keto ester 6 (Fig. 1). The development of nucleophilic character at
the -carbon of the -keto ester is inconsistent with our proposed
b
g
Figure 1.

Q. Pu et al. / Tetrahedron 64 (2008) 8045–8051
8047
Table 1
Table 2
Entry
Starting material
R1
R2
Product
Yield (%)
Entry
TMSCl
Time
23
24
1
2
3
4
5
1
8
10
12
14
C(CH3)3
CH3
CH3
CH3
CH3
OCH3
OC(CH3)3
OBn
N(i-Pr)2
N(–CH2–)4
2
9
11
13
15
58
62
60
d
1
2
3
20%
20%
100%
1
2
1
26
23
20
28
35
41
12
We also explored the chain extension–iodomethylation of chiral
oxazolidinone 22 (Scheme 5). A mixture of diastereomeric iodo-
methylated products 23 and cyclopropanols 24 was generated.
Consistent with the reactivity of compound 16, amounts of cyclo-
propane and iodomethylated products were influenced by reaction
time and the amount of TMSCl. Independentof the reaction time and
TMSCl equivalencies, the crude reaction mixture revealed that the
iodomethylated compounds 23 were formed in an approximate 5:1
diastereomeric ratio, although it was not possible to identify the
stereochemistry. Since the facial selectivity in tandem chain exten-
extension–methylation of an N,N-dimethyl
b-keto amide pro-
ceeded in 53%. The additional steric bulk of tertiary amides 12 and
14 may be responsible for inhibiting formation of the TMS-enol
ether (Scheme 3).
I
O
O
O
a) Et2Zn, CH2I2
R2
b) cat TMSCl
c) I2
R1
R1
R2
sion–aldol reaction of b
-keto imides is known3a and the preferred
O
facial selectivities in tandem chain extension–aldol and the tandem
chain extension–homoenolate generation reactions on amino acid-
Scheme 3.
In an effort to broaden the scope of the chain extension–iodo-
methylation reaction, we investigated the reactivity of -keto imide
starting materials (Scheme 4). The achiral starting material 1613
was converted to a mixture of the -iodomethylated compound 19
derived b
-keto amides are identical,3b the stereochemistry of 23 is
b
tentatively assigned as S,S. Interestingly, the diastereoselectivity in
the formation of cyclopropane 24 was much higher, in the order of
19:1, although stereochemical assignment has not been made. If
cyclopropane formation takes place by intramolecular cyclization of
the homoenolate, one of the homoenolates appears to cyclize to the
cyclopropane more quickly. Isolated yields for the iodomethylated
material and the cyclopropanes are listed in Table 2.
a
and cyclopropane 20, which was believed to result from either zinc
carbenoid cyclopropanation of the TMS-enol ether 17 or cyclization
of the homoenolate 18. No cyclopropane-containing products had
been observed in
a-methylation studies performed with b-keto
ester or amide starting materials, which suggests that direct
cyclopropanation of the TMS-enol ether is unlikely. In an effort to
understand the formation of this unusual product, the reaction was
investigated by addition of TMSCl alone to the chain extended
The attractiveness of an iodomethylated product is that a num-
ber of functionalized products are available from the primary iodide.
One method involves palladium-catalyzed Negishi cross-coupling
between an organozinc intermediate available from the primary
SiR3
O
SiR3
O
+
O
O
O
O
O
a) Et2Zn, CH2I2
b) cat TMSCl
N
O
N
O
N
O
O
O
ZnX
18
16
17
I2
O
O
O
O
O
OH
N
O
+
N
O
N
O
O
O
O
I
21
20
19
Scheme 4.
Reformatsky-like intermediate (removal of the iodination step).
Both an increase in the amount of TMSCl and longer reaction times
iodide and an aryl iodide. The cross-coupling reaction was suc-
cessfullyand reproducibly performed with different aryl iodides and
increased the cyclopropane/
a
-methylation (20/21) product ratio,
alkenyl bromides and starting g-dicarbonyl compounds, albeit in
which suggests that the homoenolate intermediate 18 participates
as a precursor to the cyclopropanation event. Based upon the
guidance from equivalency and time studies, the formation of the
iodomethylated 19 was effected in 31%, a modest yield consistent
with the reactions involving tertiary amides described above.
rather disappointing yields (Scheme 6, Table 3). Nevertheless, the
30% yield achieved in the reaction between 2 and iodobenzene is
comparable to the 35–39% yield reported14 on a similar system. A
major by-product in this reaction is the
a-methylated material 4,
which indicates that the homoenolate was formed, but that cross-
O
O
OH
O
O
O
O
a) Et2Zn, CH2I2
b) cat TMSCl
N
O
N
O
N
O
O
O
I
Bn
Bn
Bn
22
23
24
Scheme 5.

8048
Q. Pu et al. / Tetrahedron 64 (2008) 8045–8051
O
O
O
O
R1
a) Zn°
R
(CH3)3C
KSAc
THF, rt
65%
(CH3)3C
1
R
2
R
2
OMe
OMe
SAc
b) R3-X, Pd2dba3, P(o-Tol)3
O
O
O
O
I
R
3
I
2
29
Scheme 6.
Scheme 7.
pump. Melting points are uncorrected. Optical rotations were
conducted in the specified solution and concentrations are given in
gram per milliliter. Methylene chloride was dried by passing the
solvent through a column of alumina or molecular sieves using an
Innovative Technology Inc. solvent delivery system. Ethyl acetate
(EtOAc) and hexanes used for chromatography were distilled prior
to use. Iodine was sublimed prior to use. Column chromatography
coupling was not efficient. The proposed intermediacy of a zinc-
homoenolate (i.e., 18) in the iodomethylation reaction suggested
that the palladium-catalyzed cross-coupling might be able to be
performed on the zinc-homoenolate generated in the chain exten-
sion reaction. Unfortunately, all efforts, which included variations in
concentrations, temperatures, and solvents, to effect the one-pot
chain extension–homoenolate generation–cross-coupling reaction
was unsuccessful. The major by-product isolated under these con-
was performed with flash silica gel (32–63 mm). The mobile phase
was prepared as noted in the individual experimental section. Thin
Layer Chromatography (TLC) was carried out on glass-backed silica
plates with the indicated mobile phase and visualized by UV and
anisaldehyde or KMnO4 stains. Nuclear Magnetic Resonance (NMR)
spectroscopy was performed on a Varian Mercury operating at
399.768 MHz for 1H nuclei and 100.522 MHz for 13C nuclei, or
a Varian Inova operating at 499.766 MHz for 1H nuclei and
ditions was the a-methylated material, indicating that the cross-
coupling step does not take place under these reaction conditions.
One of the motivations for this study was the desire to expand
the library of
chains in a ketomethylene isostere. For example, the Negishi cross-
coupling chemistry provided access to -substituents that could
a-substituents that would mimic a-amino acid side
a
serve as phenylalanine side-chain mimics and, upon hydrogenation
of 28, isoleucine mimics. We also felt that the iodomethyl
substituents provided a resource for addressing other side chains.
For example, cysteine mimics could be accessed through sulfur
displacement of the iodide. A number of nucleophilic sulfur re-
agents have been used for this displacement,15 although we found
that use of potassium thioacetate provide the most efficient for-
mation of a protected cysteine mimic 29 (Scheme 7). Deprotection
of the thioacetate functionality is well-precedented.16
1
125.679 MHz for 13C nuclei. All 13C are H-decoupled. All chemical
shifts are reported in parts per million (ppm) downfield of tetra-
methylsilane (TMS) internal standard.
4.2. Experimental procedures
4.2.1. General procedure for the preparation of
-keto esters
An oven-dried, one-necked, 50-mL round-bottomed flask
a-iodomethyl
g
3. Conclusion
equipped with a rubber septum and magnetic stir-bar was cooled
to room temperature under a nitrogen atmosphere, and charged
with 15 mL of methylene chloride. The solvent was cooled to 0 ꢀC in
an ice bath and methylene iodide (0.32 mL, 4.0 mmol) was added
dropwise into the flask. Diethyl zinc (4.0 mL, 1.0 M in hexane,
4.0 mmol) was added slowly to the reaction mixture at 0 ꢀC over
2 min. The resulting white suspension was stirred for 10 min, and
In summary, a tandem chain extension–iodomethylation re-
action has been developed for b-keto esters and b-keto imides. The
yields for this reaction are modest, in large part, due to the per-
formance of three sequential transformations in one reaction ves-
sel. This variation on the zinc carbenoid-mediated chain extension
reaction provides the ability to convert readily available
b-keto
then the starting
the solution was stirred for 30 min, trimethylsilylchloride (25
b
-keto ester (1.0 mmol) was added rapidly. After
L,
ester starting materials into products that are nicely functionalized
m
at ester’s
site of the
a
g
-carbon, which is the least thermodynamically-acidic
-keto ester. The long-term utility of the iodomethylated
0.2 mmol) was added in one portion by micro-syringe. The mixture
was allowed to stir for 45 min at room temperature followed by the
addition of iodine (1.269 g, 5.0 mmol) to the reaction mixture. The
reaction mixture quickly became a pink suspension and was stirred
for 10 min, quenched with 10 mL of saturated aqueous ammonium
chloride, and extracted with diethyl ether (3ꢁ10 mL). The com-
bined organic layers were washed with saturated sodium thiosul-
fate solution (2ꢁ15 mL) and brine (3ꢁ20 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure
(25 ꢀC, 30 Torr). The residue was purified by column chromatog-
materials available from this reaction remains to be seen, although
palladium-mediated coupling and nucleophilic displacement re-
actions are possible. A by-product observed in this reaction when
performed on b-keto imides is a substituted-cyclopropyl alcohol,
most likely resulting from cyclization of homoenolate. The uses of
this cyclopropyl alcohol as a chiral homoenolate equivalent and
a chiral cyclopropanone equivalent are under investigation.
4. Experimental
raphy on silica to provide the a-iodomethyl-g-keto ester.
4.1. General information
4.2.2. 2-Iodomethyl-5,5-dimethyl-4-oxo-hexanoic acid methyl
ester 2
All reactions were run in oven-dried glassware and stirred with
Teflon-coated magnetic stir-bars. The term concentrated under re-
duced pressure refers to the use of a rotary-evaporator or vacuum
Column chromatography on silica (30:1, hexane/ethyl acetate,
Rf¼0.16)provided 0.181 g(58%)of2-iodomethyl-5,5-dimethyl-4-oxo-
hexanoic acid methyl ester (2) as a clear yellow liquid. 1H NMR
Table 3
Entry
SM
R1
R2
R3
Product
Yield (%)
1
2
3
4
2
2
19
2
–C(CH3)3
–C(CH3)3
–CH3
–OCH3
–OCH3
–Oxazolidinone
–OCH3
C6H5–
p-Cl–C6H4–
C6H5–
25
26
27
28
30
25
23
25
–C(CH3)3
CH2]C(CH3)–

Q. Pu et al. / Tetrahedron 64 (2008) 8045–8051
8049
(400 MHz, CDCl3)
d
3.73 (s, 3H), 3.45 (dd, J¼6.0,10.0 Hz,1H), 3.38 (dd,
1 mmol) dissolved in 15 mL of methylene chloride. The solvent was
cooled to 0 ꢀC in an ice bath and diethyl zinc (5.0 mL, 1.0 M in
hexane, 5.0 mmol) was added slowly to the flask at 0 ꢀC over 2 min
to form an enolate. The reaction mixture was stirred for 15 min, and
then methylene iodide (0.24 mL, 3.0 mmol) was added into the
flask. An additional portion of methylene iodide (0.16 mL,
2.0 mmol) was added to the reaction mixture at 0 ꢀC after 15–
20 min. The resulting solution was stirred for 30 min, and trime-
J¼5.4,10.0 Hz,1H), 3.20 (m,1H), 3.11 (dd, J¼7.0,17.9 Hz,1H), 2.80 (dd,
J¼5.4, 18.0 Hz, 1H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 213.3,
172.5, 52.6, 44.3, 42.0, 39.2, 26.8, 6.3; IR (neat, cmꢂ1): 2967,1738,1705,
1477, 1366, 1232. HRMS (EI) m/z calcd 312.0222, found 312.0225.
4.2.3. 2-Iodomethyl-4-oxo-pentanoic acid tert-butyl ester 9
Column chromatography on silica (15:1, hexane/ethyl acetate,
Rf¼0.15) provided 0.201 g (63%) of 2-iodomethyl-4-oxo-pentanoic
acid tert-butyl ester (9) as a clear yellow liquid. 1H NMR (400 MHz,
thylsilylchloride (50 mL, 0.4 mmol) was added by micro-syringe in
one portion. The mixture was allowed to stir for 45 min, quenched
with 10 mL of saturated aqueous ammonium chloride, and
extracted with ethyl acetate (3ꢁ20 mL). The combined organic
layers were washed with brine (3ꢁ15 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure
(25 ꢀC, 20 Torr). The residue was purified by column chromatog-
raphy on silica (2:1, hexane/ethyl acetate, Rf¼0.08) to yield 0.06 g
CDCl3)
3.07 (m, 1H), 3.00 (dd, J¼5.5, 17.6 Hz, 1H), 2.62 (dd, J¼5.0, 17.6 Hz,
1H), 2.20 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3)
206.0,
d
3.46 (dd, J¼5.6, 9.9 Hz, 1H), 3.35 (dd, J¼4.4, 9.9 Hz, 1H),
d
170.8, 82.0, 45.3, 42.5, 30.4, 28.1, 7.3. HRMS (EI) m/z calcd for
t
C6H8IO3 (Mꢂ Bu) 254.9518, found 254.9507.
4.2.4. 2-Iodomethyl-4-oxo-pentanoic acid benzyl ester 11
(30%) of 20 as a colorless liquid. 1H NMR (400 MHz, CDCl3)
d 4.28–
Column chromatography on silica (25:1, hexane/ethyl acetate,
Rf¼0.21) provided 0.208 g (58%) of 2-iodomethyl-4-oxo-pentanoic
acid benzyl ester (11) as a clear yellow liquid. 1H NMR (400 MHz,
4.16 (m, 2H), 3.76–3.66 (m, 2H), 2.56 (dd, J¼4.1, 17.4 Hz, 1H), 2.35
(dd, J¼8.8, 18.2 Hz, 1H), 2.09 (s, 3H), 1.64–1.59 (m, 2H), 1.18 (m, 1H),
0.78 (t, J¼6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 209.1, 158.2,
CDCl3)
d
7.36 (s, 5H), 5.15–5.14 (m, 2H), 3.48 (dd, J¼7.5, 11.4 Hz, 1H),
65.2, 62.8, 43.4, 42.3, 30.3, 20.9, 20.5; IR (neat, cmꢂ1): 3442 (br),
2927, 1775, 1699, 1390, 1227, 1039. HRMS (CI, NH3) [MþH]þ m/z
calcd 200.0923, found 200.0917.
3.39 (dd, J¼4.6, 10.1 Hz, 1H), 3.23 (m, 1H), 3.06 (dd, J¼7.4, 18.1 Hz,
1H), 2.71 (dd, J¼5.4, 18.2 Hz, 1H), 2.18 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d
205.8, 171.7, 135.6, 128.8, 128.7, 67.5, 45.3, 41.9, 30.4, 6.1.
Compound 21 was also isolated from the crude reaction mixture
by column chromatography on silica (Rf¼0.16) in a 22% yield
HRMS (EI) m/z calcd 346.0066, found 346.0070.
(0.043 g) as a colorless liquid. 1H NMR (400 MHz, CDCl3)
d 4.43–
4.2.5. 2-Iodomethyl-1-(2-oxo-oxazolidin-3-yl)-pentane-1,4-
dione 19
4.30 (m, 2H), 4.41–3.95 (m, 3H), 3.10 (dd, J¼10.3, 18.1 Hz, 1H), 2.53
(dd, J¼4.1, 18.2 Hz, 1H), 2.14 (s, 3H), 1.18 (d, J¼7.0 Hz, 3H); 13C NMR
An oven-dried, one-necked, 100-mL round-bottomed flask
equipped with a rubber septum and magnetic stir-bar was cooled to
room temperature under a nitrogen atmosphere, and charged with
1-(2-oxo-oxazolidin-3-yl)-butane-1,3-dione 16 (0.346 g, 2.0 mmol)
dissolved in 30 mL of methylene chloride. The solvent was cooled to
0 ꢀC in an ice bath and diethyl zinc (10.0 mL, 1.0 M in hexane,
10.0 mmol) was added slowly to the flask at 0 ꢀC over 2 min to form
an enolate. The reaction mixture was stirred for 15 min, and then
methylene iodide (0.48 mL, 6.0 mmol) was added into the flask. An
additional portion of methylene iodide (0.32 mL, 4.0 mmol) was
added to the reaction mixture at 0 ꢀC after 15–20 min. The resulting
(100 MHz, CDCl3) d 207.1, 176.8, 153.4, 62.2, 47.4, 42.9, 33.3, 29.8,
17.3. IR (neat, cmꢂ1): 1775, 1698, 1392, 1264, 1202. HRMS (EI) m/z
calcd 199.0845, found 199.0841.
4.2.7. 1-((S) 4-Benzyl-2-oxo-oxazolidin-3-yl)-butane-1,3-dione 22
An oven-dried, one-necked, 100-mL round-bottomed flask
equipped with a rubber septum and magnetic stir-bar was cooled
to room temperature under a nitrogen atmosphere, and charged
with a solution of (S)-4-benzyl-oxazolidin-2-one (1.4 g, 8.0 mmol)
in 50 mL of anhydrous tetrahydrofuran. The THF solution was
cooled to ꢂ78 ꢀC and n-butyl lithium (4.0 mL, 10.0 mmol of a 2.5 M
solution in hexane) was added dropwise to the flask. After the
completion of the addition, the reaction mixture was warmed to
0 ꢀC for 10 min. The mixture was cooled to ꢂ78 ꢀC again, and
diketene (1.23 mL, 16.0 mmol) was added slowly to the mixture.
The resultant orange solution was maintained at ꢂ78 ꢀC for an
additional 30 min after the addition was complete, and then
allowed to stir at 0 ꢀC for 2 h. The mixture was quenched with
15 mL of saturated NH4Cl solution and concentrated under reduced
pressure (25 ꢀC,18 Torr) to remove the solvent THF. The residue was
extracted by methylene chloride (3ꢁ20 mL), and the combined
organic layers were washed with satd NaHCO3 solution (2ꢁ20 mL)
and brine (3ꢁ20 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica (4:1, hexane/ethyl acetate,
Rf¼0.14) to yield 0.80 g (38%) of 22 as a light yellow solid. Mp 97–
solution was stirred for 30 min, and trimethylsilylchloride (50 mL,
0.4 mmol) was added by micro-syringe in one portion. The mixture
was allowed to stir for 30 min at room temperature followed by the
addition of iodine (2.58 g, 10.0 mmol) to the reaction mixture. The
reaction mixture quickly became a pink suspension and was stirred
for 10 min, quenched with 10 mL of saturated aqueous ammonium
chloride, and extracted with ethyl acetate (5ꢁ20 mL). The combined
organic layers were washed with saturated sodium thiosulfate so-
lution (2ꢁ25 mL) and brine (3ꢁ25 mL), dried over anhydrous so-
dium sulfate, filtered, and concentrated under reduced pressure
(25 ꢀC, 20 Torr). The residue was purified by column chromatogra-
phy on silica (2:1, hexane/ethyl acetate, Rf¼0.16) to yield 0.101 g
(31%) of 2-iodomethyl-1-(2-oxo-oxazolidin-3-yl)-pentane-1,4-
dione (19) as a yellowsolid. Mp 71–75 ꢀC; 1H NMR (400 MHz, CDCl3)
d
4.50–4.42 (m, 2H), 4.31 (m, 1H), 4.12–3.97 (m, 2H), 3.39 (dd, J¼5.4,
10.2 Hz,1H), 3.32 (dd, J¼6.5,10.1 Hz,1H), 3.16 (dd, J¼9.9,18.1 Hz,1H),
98.5 ꢀC; lit. mp 97–98 ꢀC;17 1H NMR (400 MHz, CDCl3)
d 7.36–7.22
2.75 (dd, J¼4.1, 18.0 Hz, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3)
(m, 5H), 4.72 (m,1H), 4.25–4.16 (m, 2H), 4.11–4.06 (m, 2H), 3.37 (dd,
d
206.1, 172.3, 153.4, 62.4, 46.6, 42.9, 39.0, 29.9, 4.4. HRMS (EI) m/z
J¼3.4, 13.5 Hz, 1H), 2.80 (dd, J¼9.6, 13.5 Hz, 1H), 2.29 (s, 3H); 13C
calcd 324.9811, found 324.9813.
NMR (100 MHz, CDCl3) d 201.1, 166.6, 153.9, 135.3, 129.7, 129.2,
127.6, 66.6, 55.2, 51.6, 38.4, 30.4; enol form:
129.7, 129.2, 127.6, 90.1, 66.3, 54.9, 38.4, 22.4.
d 180.5, 153.9, 135.3,
4.2.6. 3-[1-Hydroxy-2-(2-oxo-propyl)-cyclopropyl]-oxazolidin-2-
one 20 and 2-methyl-1-(2-oxo-oxazolidin-3-yl)-pentane-1,4-
dione 21
An oven-dried, one-necked, 100-mL round-bottomed flask
equipped with a rubber septum and magnetic stir-bar was cooled
to room temperature under a nitrogen atmosphere, and charged
with 1-(2-oxo-oxazolidin-3-yl)-butane-1,3-dione 16 (0.171 g,
4.2.8. 1-((S)-4-Benzyl-2-oxo-oxazolidin-3-yl)-2-iodomethyl-
pentane-1,4-dione 23 and (S)-4-benzyl-3-[1-hydroxy-2-(2-oxo-
propyl)-cyclopropyl]-oxazolidin-2-one 24
An oven-dried, one-necked, 50-mL round-bottomed flask
equipped with a rubber septum and magnetic stir-bar was cooled

8050
Q. Pu et al. / Tetrahedron 64 (2008) 8045–8051
to room temperature under a nitrogen atmosphere, and charged
with a solution of 1-((S) 4-benzyl-2-oxo-oxazolidin-3-yl)-butane-
1,3-dione 22 (0.261 g, 1.0 mmol) in 15 mL of methylene chloride.
The solvent is cooled to 0 ꢀC in an ice bath and diethyl zinc (5.0 mL,
1.0 M in hexane, 5.0 mmol) was added slowly to the flask at 0 ꢀC
over 2 min to form an enolate. The reaction mixture was stirred for
15 min, and then methylene iodide (0.24 mL, 3.0 mmol) was added
into the flask. An additional portion of methylene iodide (0.16 mL,
2.0 mmol) was added to the mixture at 0 ꢀC after 15–20 min. The
resultant solution was stirred for 30 min, and trimethylsilylchloride
saturated citric acid solution was added in order to break the
emulsion. The mixture was extracted with diethyl ether (3ꢁ10 mL),
and the combined organic layers were washed with deionized
water (2ꢁ10 mL) and brine (2ꢁ10 mL), dried over anhydrous so-
dium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography.
4.2.10. 2-Benzyl-5,5-dimethyl-4-oxo-hexanoic acid methyl ester 25
The residue was purified by column chromatography (30:1,
hexane/ethyl acetate, Rf¼0.14) to yield 0.79 g (30%) of 2-benzyl-5,5-
dimethyl-4-oxo-hexanoic acid methyl ester (25) as a clear orange
(25 mL, 0.2 mmol) was added by micro-syringe in one portion. The
mixture was allowed to stir for 30 min at room temperature fol-
lowed by adding iodine (1.265 g, 5.0 mmol) to the reaction. The
reaction mixture quickly became a pink suspension and was stirred
for 10 min, quenched with 10 mL of saturated aqueous ammonium
chloride, and extracted with ethyl acetate (3ꢁ20 mL). The com-
bined organic layers were washed with saturated sodium thiosul-
fate solution (2ꢁ15 mL) and brine (3ꢁ15 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica (3:1,
hexane/ethyl acetate, Rf¼0.28) to yield 0.11 g (26%) of 23 as a light
yellow liquid of two diastereoisomers with a ratio of 2.5:1, as de-
termined by integration of the reaction material’s 1H NMR spec-
liquid. 1H NMR (400 MHz, CDCl3)
d
7.26 (t, J¼7.4 Hz, 2H), 7.19 (t,
J¼7.3 Hz, 1H), 7.13 (d, J¼6.8 Hz, 2H), 3.61 (s, 3H), 3.14 (m, 1H), 2.99
(dd, J¼6.6, 13.5 Hz, 1H), 2.92 (dd, J¼9.0, 18.2 Hz, 1H), 2.72 (dd, J¼8.3,
13.6 Hz, 1H), 2.56 (dd, J¼4.6, 18.1 Hz, 1H), 1.08 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 214.3, 175.6, 138.8, 129.4, 129.1, 126.8, 51.9, 44.1,
42.2, 37.9, 26.6; IR (neat, cmꢂ1): 2966, 1736, 1704, 1476, 1366, 1230;
MS (ESI): calcd for C16H22O3 (MþþNaþ) 285.1919, found 285.1.
HRMS (EI) m/z calcd 262.1569, found 262.1568.
4.2.11. 2-(4-Chloro-benzyl)-5,5-dimethyl-4-oxo-hexanoic acid
methyl ester 26
The residue was purified by column chromatography (20:1,
hexane/ethyl acetate, Rf¼0.18) to yield 0.075 g (25%) of 2-(4-chloro-
benzyl)-5,5-dimethyl-4-oxo-hexanoic acid methyl ester (26) as
trum. 1H NMR (400 MHz, CDCl3)
d 7.33–7.20 (m, 5H), 4.80–4.67 (m,
1H), 4.31–4.16 (m, 3H), 3.42 (d, J¼5.5 Hz, 2H), 3.36–3.33 (m, 1H),
3.20 (dd, J¼10.1, 18.1 Hz, 1H), 2.87–2.69 (m, 2H), 2.19 (s, 3H); 13C
a clear orange liquid. 1H NMR (400 MHz, CDCl3)
d
7.25 (d, J¼8.6 Hz,
NMR (100 MHz, CDCl3)
d
206.0, 172.0, 153.3, 140.9, 129.6, 129.2,
2H), 7.09 (d, J¼8.3 Hz, 2H), 3.62 (s, 3H), 3.15 (m, 1H), 2.96 (dd, J¼7.0,
11.9 Hz, 1H), 2.92 (dd, J¼8.5, 18.0 Hz, 1H), 2.71 (dd, J¼7.8, 13.8 Hz,
1H), 2.54 (dd, J¼4.9, 18.1 Hz, 1H), 1.09 (s, 9H); 13C NMR (100 MHz,
127.7, 66.8, 55.5, 46.4, 40.0, 38.5, 37.8, 29.9, 4.9; LRMS (MALDI):
calcd for C16H18O4NI (MþꢂI) 288.2, found 287.7. HRMS (EI) m/z
calcd 415.0281, found 415.0285. Small quantities of the
a
,b
-
CDCl3) d 214.0, 175.6, 137.3, 132.6, 130.5, 128.8, 52.1, 44.3, 42.2, 38.5,
unsaturated compound 1-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-
pent-2-ene-1,4-dione was also present in the reaction mixture.
Resonances observed for this compound: 1H NMR (400 MHz,
36.6, 26.6; IR (neat, cmꢂ1): 2967, 1736, 1704, 1492, 1169. HRMS (EI)
m/z calcd 296.1179, found 296.1173.
CDCl3)
(100 MHz, CDCl3)
d
8.0 (d, J¼15.9 Hz, 1H), 7.1 (d, J¼15.9 Hz, 1H); 13C NMR
4.2.12. 2-Benzyl-1-(2-oxo-oxazolidin-3-yl)-pentane-1,4-dione 27
The residue was purified by column chromatography (1:1, hex-
ane/ethyl acetate, Rf¼0.47) to yield 0.066 g (24%) of 2-benzyl-1-(2-
oxo-oxazolidin-3-yl)-pentane-1,4-dione (27) as a white solid. Mp
d 198.1, 164.4, 135.1, 27.8.
One predominant stereoisomer of 24 was also isolated in the
amount of 0.08 g (28%) as a colorless crystal during column chro-
matography on silica (TLC data: 1:1, hexane/ethyl acetate, Rf¼0.12).
108–111 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.30–7.27 (m, 5H), 4.45–
25
Mp 102–103 ꢀC; [
(400 MHz, CDCl3)
a
]
þ4.8 (c 0.0053 g/mL, CHCl3). 1H NMR
4.30 (m, 3H), 4.05 (dd, J¼6.7, 9.4 Hz,1H), 3.93 (dd, J¼6.9, 9.3 Hz,1H),
3.09 (dd, J¼5.1, 13.1 Hz, 1H), 3.03 (dd, J¼10.7, 18.0 Hz, 1H), 2.51 (dd,
J¼10.0, 13.1 Hz, 1H), 2.45 (dd, J¼3.5, 18.3 Hz, 1H), 2.07 (s, 3H); 13C
D
d 7.39–7.25 (m, 5H), 4.75 (s, 1H), 4.22 (m, 1H),
4.07–3.98 (m, 2H), 3.54 (dd, J¼3.8, 13.4 Hz, 1H), 2.83 (dd, J¼4.5,
18.4 Hz, 1H), 2.71–2.62 (m, 2H), 2.22 (s, 3H), 1.54 (m, 1H), 1.38 (dd,
J¼5.9,10.1 Hz,1H), 0.96 (t, J¼6.2 Hz,1H); 13C NMR (100 MHz, CDCl3)
NMR (100 MHz, CDCl3) d 207.2,175.7,153.4,138.2,129.4,128.7,126.9,
62.2, 44.4, 42.9, 40.2, 37.9, 29.9; IR (KBr, cmꢂ1): 2921, 1773, 1715,
d
208.5, 157.8, 136.7, 129.7, 129.2, 127.1, 66.9, 64.8, 57.6, 42.1, 38.4,
1480, 1395, 1263. HRMS (EI) m/z calcd 275.1158, found 275.1152.
30.2, 21.8, 19.6; IR (KBr, cmꢂ1): 3317 (br), 3029, 2921, 1745, 1603,
1413, 1246. LRMS (MALDI): calcd for C16H19O4N (MþþNaþ) 312.2,
found 312.1; calcd for C16H19O4N (MþþKþ) 328.3, found 328.1.
HRMS (CI, NH3) [MþH]þ m/z calcd 290.1392, found 290.1391.
4.2.13. 5,5-Dimethyl-2-(2-methyl-allyl)-4-oxo-hexanoic acid
methyl ester 28
The residue was purified by column chromatography (20:1,
hexane/ethyl acetate, Rf¼0.15) to yield 0.075 g (12%) of 5,5-di-
methyl-2-(2-methyl-allyl)-4-oxo-hexanoic acid methyl ester (28)
4.2.9. General procedure for the palladium-catalyzed Negishi
coupling
as a clear orange liquid. 1H NMR (400 MHz, CDCl3)
d 4.79 (s, 1H),
A mixture of zinc dust (0.09 g, 1.4 mmol) and iodine (2.0 mg,
0.005 mmol) was placed into an oven-dried, 25-mL round-bot-
tomed flask equipped with a rubber septum and magnetic stir-bar.
The flask was allowed to cool to room temperature under nitrogen
gas. Dimethylformamide (1 mL) was added via syringe into the
4.69 (s, 1H), 3.66 (s, 3H), 3.07 (m, 1H), 2.92 (dd, J¼9.3, 18.1 Hz, 1H),
2.58 (dd, J¼4.2, 18.1 Hz, 1H), 2.38 (dd, J¼6.8, 14.2 Hz, 1H), 2.14 (dd,
J¼8.5, 14.6 Hz, 1H), 1.79 (s, 3H), 1.14 (s, 9H); 13C NMR (100 MHz,
CDCl3)
d 214.4, 175.9, 142.8, 113.2, 51.9, 44.2, 40.5, 38.4, 38.1, 26.5,
21.9. HRMS (EI) m/z calcd 226.1569, found 226.1575.
flask, followed by the addition of a solution of the a-iodomethyl-g-
keto carbonyl starting material (2 or 19) (1.0 mmol) in 4 mL of DMF
dropwise by syringe. The reaction mixture was stirred at 0 ꢀC (ice
bath) for 30 min. The ice bath was removed and the septum was
replaced with a reflux condenser after the sp2-hybridized halide
(1.1–1.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (45 mg,
0.05 mmol) and tri-o-tolylphosphine (60 mg, 0.2 mmol) were
added. The reaction mixture was heated to 60 ꢀC and stirred for 5 h.
The resulting black mixture was decanted to an Erlenmeyer flask
containing 10 mL of deionized water. An additional 5 mL of
4.2.14. 2-Acetylsulfanylmethyl-5,5-dimethyl-4-oxo-hexanoid acid
methyl ester 29
Into an oven-dried, one-necked, 10-mL round-bottomed flask
equipped with a rubber septum and magnetic stir-bar with a flow of
nitrogen were placed potassium thioacetate (0.23 g, 2.0 mmol),
compound 2 (0.312 g, in 1 mL of tetrahydrofuran, 1.0 mmol) and
4.0 mL of tetrahydrofuran. The light yellow suspension was allowed
to stir overnight at room temperature. The resultant brown suspen-
sionwasextractedwithdiethylether(3ꢁ15 mL)andtheorganiclayer

Q. Pu et al. / Tetrahedron 64 (2008) 8045–8051
8051
was removed using a pipette. The combined ether extracts were
References and notes
washed with brine (3ꢁ15 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica (15:1, hexane/ethyl
acetate, Rf¼0.10) to yield 0.17 g (65%) of 2-acetylsulfanylmethyl-5,5-
dimethyl-4-oxo-hexanoid acid methyl ester (29) as a orange liquid.
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d
3.63 (s, 3H), 3.16 (dd, J¼8.0,15.6 Hz,1H),
3.08–3.02 (m, 2H), 2.96 (dd, J¼7.2, 18.0 Hz, 1H), 2.64 (dd, J¼4.2,
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Acknowledgements
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.063.