Synopsis
The thesis entitiled “Synthesis of (–-)-Ovalicin and Development of Synthetic
Methodologies in Ionic Liquids” consists of three chapters.
Chapter-I: This chapter deals with the introduction and biological activity of ovalicin
and the approaches cited in the literature towards the synthesis of ovalicin.
Chapter-II: This chapter deals with the stereoselective synthesis of (–)-ovalicin.
Chapter-III: This chapter provides a brief introduction to ionic liquids and
development of synthetic methodologies in ionic liquids, which is further divided into
four sections.
Section A: This section describes the Bi(OTf)3-[Bmim]PF6 catalyzed formation of
fused pyrano-and furanobenzopyrans.
Section B: This section describes the Bi(OTf)3-catalyzed Synthesis of cis-Aziridine
carboxylates in [Bmim]PF6.
Section C: This section describes Rh2(OAc)4-catalyzed synthesis of cyclopropane
carboxylates in [Bmim]PF6.
Section D: This section describes the α-halogenation of β-dicarbonyl compounds and
cyclic Ketones with N-halosuccinimides in [Bmim]PF6.
Chapter-I: Introduction and biological activity of ovalicin and the approaches cited in
the literature towards the synthesis of ovalicin.
Chapter-II: Stereoselective synthesis of (–)-ovalicin.
(–)-Ovalicin (1) a sesquiterpene alkaloid first isolated from cultures of the
fungus Pseudorotium ovalis Stolk was found to be non-toxic, non-inflammatory and
more potent anti-angiogenesis agent than the structural analog of fumagillin. It
selectively inhibits type 2 methionine amino-peptidase (MetAP 2), which related to
many physiological activities such as angiogenesis. It also exhibits antibiotic, antitumor,
and immunosuppressive properties. TNP-470, a semisynthetic derivative of fumagillin,
has also been shown to inhibit angiogenesis and reduces the proliferation of endothelial
cells.
i
Synopsis
O
Me
OH
Me
Me
O
H
OMe
O
Ovalicin
As an ongoing project on the synthesis of biologically active natural products,
we have initiated a program on the total synthesis of ovalicin. Accordingly, the
disconnection approach provides two major segments 3 and 4 as the key intermediates
for the total synthesis of ovalicin.
O
Me
OH
Me
O
Me
(-)-Ovalicin
OMe
O
2
O
+ Li
OMe
OTBS
3
Me
Me
Me
4
OH
OH
O
D-ribose
O
O
O
O
Scheme 1
Synthesis of key intermediate 3:
The synthesis was started with readily available sugar D-ribose. Treatment of Dribose with 2,2-dimethoxy propane in presence of 2% methanolic HCl in dry acetone
led to O-methyl isopropylidene derivative 5. The alcohol 5 was treated with triphenyl
phosphine and iodine in presence of imidazole in toluene and the reaction mixture was
heated to 120 0C for 3h to obtain iodo glycoside 6. Iodo furanoside 6 which on domino
reaction with allyl bromide and activated zinc dust in THF/H2O (4:1) under sonication
conditions gave diene 7. RCM of 7 with 3 mol% Grubb’s 1st generation catalyst
(benzylidene-bis (tricyclohexylphosphine) dichlororuthenium) under argon atmosphere
in dichloromethane at room temperature proceeded nicely to give the desired
ii
Synopsis
cyclohexene derivative 8. Reduction of the double bond in compound 8 with NaBH4 in
methanol at 0 oC using catalytic amount of NiCl2.7H2O cleanly afforded substituted
cycloheaxanol 9 which was oxidized to ketone 10 using Dess–Martin periodinane.
D-ribose
O
HO
2,2-dimetoxy propane
OMe
Acetone, 2%MeOH-HCl
O
I2, toluene
O
O
I
TPP, Imidazole
O
5
OMe
O
6
OH
OH
Allyl bromide, Zn
Grubbs catalyst
O
THF:H2O (4:1)
O
NaBH4, MeOH
CH2Cl2
NiCl2.7H2O
O
O
7
OH
O
8
O
OTMS
DMP, NaHCO3
LDA, THF
CH2Cl2
TMSCl
O
O
9
O
10
11
OH
OTBDPS
O
1) MCPBA, DCM
O
O
2) TBAF
O
TBDPSCl
imidazole, DMAP
O
O
O
O
12
13
Scheme 2
Introduction of the 2-α-OH was achieved by the Rubottom oxidation,12 via a
sequence of silyl enol ether formation, epoxidation, and desilylation depicted in
(Scheme 3). Accordingly, Ketone 10 was deprotonated with LDA in dry THF -78 °C for
30 min and resulting lithium enolate was trapped with TMSCl as its trimethylsilyl enol
ether 11. The crude silyl enol ether was subjected to epoxidation with MCPBA at low
temperature (-20 0C) in dry DCM proceeded nicely and α-hydroxy cyclohexanone 12
iii
Synopsis
was obtained after treatment with TBAF. Silylation of alcohol 12 with tertbutyldiphenylsilyl chloride gave silyl ether 13.
As shown in scheme 3 the ketone 13 was converted into corresponding dithiane
14 with 1,3-propane dithiol in the presence of Yb(OTf)3 in CH3CN at reflux
temperature. Simultaneously deprotection of the acetonide group occurred in the same
operation. Our efforts to protect the carbonyl group without affecting acetonide were
failed. The diol moiety in 14 was protected as diacetate 15. The cleavage of tertbutyldimethylsilyl
(TBDPS)
group
was
achieved
by
treating
15
with
tetrabutylammonium fluoride (TBAF) in THF provided 16. Oxidation of 16 with the
Dess–Martin periodinane (DMP), afforded cyclohexenone 17. Wittig olefination of
ketone 17 using either Corey’s reagent (Ph3P=CHLi) or the Tebbe reaction resulted only
recovery of the starting material. The steric environment of this ketone impeded
attempts to effect this transformation directly.
OTBDPS
O
O
TBDPSO
TBDPSO
1,3-propane dithiol
13
DMAP, CH2Cl2
OAc
14
15
OAc
OAc
16
17
THF
S
OAc
S
OAc
CH2Cl2
TBAF
S
S
DMP, NaHCO3
S
OAc
S
OAc
OH
O
OH
S
Ac2O, TEA
S
OH
Yb(OTf)3, CH3CN
O
S
S
OAc
Scheme 3
We therefore modified our strategy and the following reaction sequence was
successfully investigated. Since the hydroxyl group on C5 needs to be methylated in the
final product, compound 17 was then desilylated back to diol by treated with potassium
carbonate in methanol. At this point, having as the goal the interception of the advanced
intermediate we tried the selective protection of vicinal diol moiety of 18. Since the
iv
Synopsis
hydroxy function at C5 is sterically encumbered by the vicinal dithiane group, we were
able to protect selectively the axial hydroxy group at C6 with TBSCl. This was
accomplished performing the reaction in DCM at 0 0C for 30 min then at room
temperature giving rise to the formation of mono protected derivative 19.
O
O
S
K2CO3
S
OAc
OH
17
18
O
S
MeI, Ag2O
S
OH
OTBS
Et2O
20
TBSCl
S
OH
MeOH
OAc
O
O
S
imidazole
CH2Cl2
S
Me3S+OI-, NaH
S
OH
OTBS
LiI, DMSO/THF
00C to rt
19
O
S
O
MCPBA
S
OMe Ac2O, Et3N, H2O
OTBS
21
OMe
OTBS
3
Scheme 4
The next task was diastereoselective introduction of epoxide moiety from ketone. To
introduce the oxirane moiety stereoselectively, we used the Corey-Chaykovsky
protocol. The ylide derived from trimethylsulfoxonium iodide had been shown to afford
the desired epoxide 20 as the major product resulting from attack on the si face of the
ketone17. It is readily separated from the minor isomer by silica gel column
chromatography. The absolute stereochemistry was confirmed by the subsequent
conversion of 20 into the known Barton’s intermediate 3. Methylation of 20 with MeI
and Ag2O in diethyl ether at 50 0C led to methylated product 21. The dithiane was
oxidized to the monosulfoxide (mCPBA, 0 °C), and the crude monosulfoxide was
exposed to the action of Ac2O, Et3N, and H2O to give the desired ketone 3 in 59% yield.
The 1H and
13
C NMR spectra and optical rotation of the ketone 3 is in complete
agreement with those previously reported. The ketone 3 is vital intermediate in the
synthesis of ovalicin. Thus the formal synthesis of ovalicin was accomplished.
v
Synopsis
Synthesis of Alkenyllithium 4:
The preparation of alkenyllithium was achieved by applying the method
developed by E. J. Corey.
ClSO3H
SO2Cl
CH2Cl2
NH2NH2
SO2NHNH2
THF, 00C
23
22
24
O
S N
N
O
n-BuLi/DME, -78oC
Acetone
SO2NHN=C
Br
-780C to -660C
25
n-BuLi/TMEDA
-780C to -30C
Li
Scheme 5
4
Treatment of 2,4,6-Triisopropyl benzene 22 with chlorosulfonic acid at 0 0C for
one hour gave 2,4,6-triisopropyl benzenesulfonyl chloride 23. A solution of 2,4,6Triisopropyl benzenesulfonyl chloride 23 in THF was treated with distilled hydrazine at
0 0C for 4 hours to afford 2,4,6-Triisopropyl benzenesulfonyl hydrazine 24. Treatment
of 2,4,6-triisopropyl benzenesulfonyl hydrazine 24 with freshly distilled acetone for half
an hour exclusively afforded benzenesulfonyl hydrazone 25 after simply evaporating
excessive acetone and vacuum-dried overnight. The alkenyllithium olefin was prepared
from acetone 2,4,6- triisopropylbenzene-sulfonylhydrazone and 3,3- dimethylallyl
bromide using Shapiro reaction. Addition of alkenyllithium 4 to ketone 3 was
performed immediately after the reagent was prepared.
vi
Synopsis
Addition of alkenyl lithium reagent to ketone 3:
Introduction of the side chain into ketone 3 was performed according to Barton’s
procedure. Freshly prepared alkenyl lithium 4 was added to a solution of 3 in dry
toluene at -78 0C, stirred at this temperature for 3 hours and then warmed gradually to 0
0
C to give compound 26. Desilylation of 26 was carried out with TBAF at 0 0C to give
the alcohol 27. Oxidation of 27 using Dess–Martin periodinane gave ketone 2.
Selectively epoxidation of compound 2 using vanadyl acetylacetonate and t-BuOOH
with the assistance of allylic alcohol on C4 position gave (–)-ovalicin with 48% yield
whose data was identical in all respects with that already reported.
O
O
OMe
OTBS
O
Li
O
OH
4
OH
TBAF
toluene, -780C, 3h
3
OMe
THF
OMe
OTBS
OH
27
26
O
OH
O
DMP, NaHCO3
OH
VO(acac)2
DCM
OMe
O
OMe
TBHP, toluene, 00C
O
O
2
1
Scheme 6
In summary (–)-ovalicin was prepared stereoselectively. The strategy described
herein should be applicable to the preparation of pharmacologically important
analogues of ovalicin.
vii
Synopsis
CHAPTER III: This chapter describes the development of synthetic methodologies in
ionic liquids, which is further divided into four sections.
Ionic liquids as green high tech reaction media of the future are considered as
environmentally benign alternatives for volatile organic solvent. They posses many
interesting properties such as tunable polarity, wide liquid range, negligible vapor
pressure, high thermal stability, good solvating ability for a wide range of substrates and
catalysts, and also ease of recyclability. They are particularly promising as solvents for
the immobilization of transition metal catalysts, Lewis acids and enzymes. The
hallmark of such ionic liquids is the ability to alter their properties as desired by
manipulating their structure with respect to the choice of organic cation, anion, or sidechain attached to organic cation. Their nonvolatile nature can reduce the emission of
toxic organic compounds and facilitate the separation of products and/or catalysts from
the reaction solvents. Owing to the high polarity and ability to solubilize both organic
and inorganic compounds, ionic liquids can enhance reaction rates and selectivities
compared to conventional solvents, thus finding increasing applications in organic
synthesis. In view of the promising importance of ionic liquids as green solvents, we
have developed some useful synthetic methodologies in ionic liquids.
Section A: Bi(OTf)3-[Bmim]PF6 catalyzed formation of fused pyrano-and
furanobenzopyrans.
2H-1-Benzopyrans
(chromenes)
and
3,4-dihydro-2H-1-benzopyrans
(chromanes) are important classes of oxygenated heterocycles that have attracted much
synthetic interest because of the biological activity of naturally occurring
representatives. Numerous 4-amino benzopyrans and their derivatives have drawn
considerable attention as modulators of potassium channels influencing the activity of
the heart and blood pressure and found to exhibit a wide range of biological activities,
including antihypertensive and antiischemic behavior.
Lanthanide triflates are unique Lewis acids that are currently of great research
interest. Bismuth(III) triflate has attracted the interest of synthetic organic chemists
because it is inexpensive, highly stable and it can be easily prepared.
viii
Synopsis
We herein report the use of bismuth (III) triflate in ionic liquids as a novel and
recyclable catalytic system for the synthesis of cis-fused furano and pyranobenzopyrans
through one-pot coupling of o-hydroxybenzaldehydes, aromatic amines, and enol ethers
under mild reaction conditions.
HN
CHO
+
[Bmim]PF6, rt
O
O
R
R
1
2
H
Bi(OTf)3
R1 NH2 +
OH
R1
DHF
H
O
3
Scheme 1
Treatment of o-hydroxybenzaldehyde 1 and aniline 2 with 2,3-dihydrofuran in the
presence of 10 mol% Bi(OTf)3 in 3 mL of ionic liquid, [bmim]PF6 at ambient
temperature affords the cis-fused furanochroman 3 in 92% yield (Scheme 5). In a
similar fashion, substituted o-hydroxybenzaldehydes, and ortho, para-substituted
aromatic amines reacted smoothly with 2,3-dihydrofuran to give corresponding cisfused acetals in good yields (Table 1). In further reactions, treatment of ohydroxybenzaldehydes and aromatic amines with 3,4-dihydropyran in the presence of
10 mol% Bi(OTf)3 in ionic liquid, [bmim]PF6 affords the cis-fused pyranochromans as
an inseparable mixture of diasteromers predominantly 4 with a minor amount of 5
(Scheme 2).
CHO
R1
+
+
NH2
OH
1
2
R1
HN
H
H
R1
HN
H
H
Bi(OTf)3
O
[Bmim]PF6, rt
+
O
4
DHP
H
O
O
H
O
5
Scheme-2
In summary, we developed a simple and efficient one-pot method for the
diasteroselective synthesis of cis-fused pyrano and furanobenzopyrans catalyzed by
Bi(OTf)3 in air and moisture-stable [bmim]PF6. The simple experimental and product
isolation procedures combined with ease of recovery and reuse of this novel reaction
media is expected to contribute to the development of green strategy for the synthesis of
pyrano and furanobenzopyrans.
ix
Synopsis
Table 1: Bi(OTf)3-catalyzed synthesis of pyrano and furano Benzopyrans in [Bmim]PF6
Entry
R
R1
1
2
H
a
Enol ether
C6H5
Time(h)
Yieldb
2.0
92
1.5
86
2.0
90
2.5
80
3.0
78
1.5
85
2.5
88
3.0
79
3.0
72
2.0
90
2.5
78
3.0
76
Ratioc
100:0
O
b
H
4-MeC6H4
100:0
O
H
c
C6H5
86:14
O
OMe
d
C6H5
100:0
O
H
e
4-OMeC6H4
100:0
O
H
f
4-MeC6H4
75:15
O
H
g
4-BrC6H4
100:0
O
h
OEt
4-ClC6H4
100:0
O
i
H
4-NO2C6H4
70:30
O
j
OMe
4-MeC6H4
100:0
O
k
H
4-BrC6H4
80:20
O
l
H
2-MeC6H4
O
a
All products charactarized by 1H NMR, IR and MS
Isolated and unoptimized yields after column chromatography
c
Product ratio was determined by the 1H NMR spectrum of the crude product
b
x
100:0
Synopsis
Section B: Bi(OTf)3-Catalyzed Synthesis of cis-Aziridine carboxylates in
[Bmim]PF6.
Aziridines are carbon electrophiles capable of reacting with various nucloephiles
and their ability to undergo regioselective ring opening leads to many biologically
active compounds such as ,-unsaturated amino esters, -lactam antibiotics and
alkaloids. Aziridine-2-carboxylates are interesting compounds in view of their structural
relationship with - as well as -amino acids and the intrinsic high reactivity of the
three membered rings. Aziridine-2-carboxylates and their derivatives are useful
intermediates for the synthesis of various amine-containing molecules.
In this part of work we explored the facile synthesis of highly diastereoselective
cis-aziridine carboxylates by one pot coupling of aldehydes, amines and ethyl
diazoacetate using bismuth (III) triflate in ionic liquids (Scheme 3).
O
R
H
1
+
Ar NH2 + N2CHCOOEt
2
Bi(OTf)3
[Bmim]PF6
EDA
Ar
N
Ar
N
+
R
COOEt
3 (cis)
R
COOEt
4 (trans)
Scheme 3
Treatment of benzaldehyde and aniline with ethyl diazoacetate in the presence of 2
mol% of bismuth(III) triflate in hydrophobic [bmim]PF6 ionic liquid gave the
corresponding ethyl 1,3-diphenylaziridine-2-carboxylate (3a) in 87% yield with high
cis-selectivity. In a similar fashion, various aldimines (generated in situ from aldehydes
1 and amines 2) reacted efficiently with ethyl diazoacetate to produce the corresponding
aziridine carboxylates 3 in high yields (Table 2).
In summary, we demonstrates the successful use of ionic liquids as novel
reaction media for the synthesis of cis-aziridine carboxylates through the three
component coupling reactions of aldehydes, amines and ethyl diazoacetate using 2
mol% of bismuth(III) triflate or 5 mol% of scandium(III) triflate as catalyst. The notable
features of this procedure are mild reaction conditions, improved yields, enhanced
reaction rates, greater cis-selectivity, operational simplicity.
xi
Synopsis
Table 2: Bi(OTf)3-Catalyzed Synthesis of cis-Aziridine Caboxylates in [Bmim]PF6
Entry
Aldehyde
RCHO (1)
Producta
Amine
Time (h)
Yield (%)b
Ar
N
ArNH2 (2)
R
COOEt
a
PhCHO
PhNH2
3a
2.5
87
b
4-ClC6H4CHO
4-ClC6H4NH2
3b
2.0
90
c
PhCHO
4-ClC6H4NH2
3c
3.5
85
d
4-MeC6H4CHO
4-ClC6H4NH2
3d
2.5
91
e
PhCHO
4-MeOC6H4NH2
3e
2.0
86
f
4-MeOC6H4CHO
PhNH2
3f
2.5
82
g
PhCHO
2-OHC6H4NH2
3g
3.0
85
h
PhCHO
4-O2NC6H4NH2
3h
3.5
78c
i
PhCHO
PhCH2NH2
3i
3.0
85
j
PhCHO
3j
2.5
87
k
t-C4H9CHO
PhNH2
3k
3.0
82
l
C5H11CHO
4-ClC6H4NH2
3l
3.5
75
O
NH2
a
All products were characterized by 1H and 13C NMR, IR and mass spectroscopy.
Yields refer to pure products after column chromatography.
c
The product was obtained as a mixture of cis- and trans-isomers in a ration of 2:1.
b
xii
Synopsis
Section C: Rh2(OAc)4-catalyzed synthesis of cyclopropane carboxylates in
[Bmim]PF6.
Metal-catalyzed cyclopropanation remains of great interest because of its
versatile applications in synthetic organic chemistry. The cyclopropane ring is a core
structure in a number of biologically active compounds. Indeed, the strain associated
with the three-membered ring allows cyclopropanes to undergo a variety of
synthetically useful ring-opening reactions and also serve as versatile synthetic
intermediates for the preparation of functionalized cycloalkanes and acyclic
compounds. Cyclopropanation of styrene with ethyl diazoacetate (EDA) often serves as
the bench-mark reaction for the evaluation of almost any new catalyst.
We herein report the use of ionic liquids as recyclable reaction medium for the
cyclopropanation of alkenes with ethyl diazoacetate using a catalytic amount of
Rh2(OAc)4 under mild conditions (Scheme 4).
COOEt
+ N2CHCOOEt
R
Rh2(OAc)4
R
COOEt
R
+
[Bmim]PF6, r.t
1
trans
3
2
cis
4
Scheme 4
Treatment of styrene with ethyl diazoacetate in the presence of 1 mol % of
Rh2(OAc)4 in 3 mL of [bmim]PF6 ionic liquid resulted in the formation of ethyl 2phenyl-1-cyclopropanecarboxylate in 88% yield. The product was obtained as a mixture
of 3 trans- and 4 cis-isomers, favoring trans-diastereomer 3. Both electron-rich and
electron-deficient styrene derivatives afforded cyclopropanecarboxylates in high yields.
In all cases, the reaction proceeds smoothly at room temperature with high transselectivity (Table 3).
In summary, we describe a simple and efficient protocol for the
cyclopropanation of olefins with ethyl diazoacetate using Rh2(OAc)4 immobilized in
air- and moisture-stable [bmim]PF6. The simple experimental and product isolation
procedures combined with ease of recovery and reuse of this novel reaction media are
expected to contribute to the development of green strategy for the synthesis of
cyclopropanes.
xiii
Synopsis
Table 3: Rh2(OAc)4-catalyzed synthesis of cyclopropane carboxylates in [Bmim]PF6
Entry
Cyclopropanea
Alkene
Time
Yield (%)b trans/cisc
R
R
COOEt
R
COOEt
a
R=Ph
R=Ph
6.0
88
90:10
b
R=3-Cl-Ph
R=3-Cl-Ph
7.0
82
85:15
c
R=4-Cl-Ph
R=4-Cl-Ph
6.5
86
87:13
d
R=4-Br-Ph
R=4-Br-Ph
7.5
85
83:17
e
R=3-Me-Ph
R=3-Me-Ph
6.0
89
89:11
f
R=4-AcO-Ph
R=4-AcO-Ph
8.0
78
84:16
R=4-MeO-Ph
R=4-MeO-Ph
6.5
87
87:13
R=2-napthyl
R=2-napthyl
7.5
84
90:10
R=n-hexyl
R=n-hexyl
8.5
79(60)c
60:40
9.0
85(54)e
79:21d
8.0
86(62)e
75:25
6.5
91(71)
82:18
g
h
i
EtOOC
H
H
COOEt
j
endo
k
exo
Ph
COOEt Ph
Ph
l
Ph
COOEt
cis
trans
Ph
Me
Me
COOEt Ph
COOEt
cis
trans
a
All products were chacterized by 1H NMR, IR and mass spectroscopy
Yield refers to pure products after column chromatography
c
The rations were determined by 1H NMR
d
Ratio of endo:exo
e
Yield reported in parethesis refers to isolated products in the absence of ionic liquid
b
xiv
Synopsis
Section D: α-halogenation of β-dicarbonyl compounds and cyclic Ketones with Nhalosuccinimides in [Bmim]PF6.
α-Halogenation of 1,3-dicarbonyl compounds is an important transformation as
the α-halogenated products are versatile intermediates in organic synthesis since their
high reactivity makes them prone to react with a large number of nucleophiles to
provide a variety of useful compounds.
We report here the use of an ionic liquid for the halogenation of a wide range of
functionalized ketones using N-halosuccinimides without the requirement for catalyst,
and under mild conditions. The reaction was initially carried out by treating ethyl
benzoylacetate 1a (R1=Ph, R2=Et) with 1.05 eq NBS in 2 mL of ionic liquid, [bmim]PF6
at ambient temperature affording the -brominated product in 94% yield (Scheme 5).
O
O
O
R1
R2
+
N X
r.t.
O
R2
R1
X
O
X=Br, Cl, I
1
O
[Bmim]PF6
2
3
Scheme 5
Next we tested the possibility of chlorination and iodination of compound 1 with NCS
or NIS under the same conditions and the 2-chloro- and 2-iodo-1,3-keto-esters were
obtained in 96% and 89% yields, respectively. A variety of 2-unsubstituted and 2substituted 1,3-keto-esters and 1,3-diketones reacted well under these conditions to give
the corresponding -halogenated products in high yields. The results are summarized in
Table 4. The method was applied to cyclic ketones, under the same reaction conditions
giving exclusively -mono halo products with high yields in short reaction times.
In summary, room temperature ionic liquids (ILs) are used as a green recyclable
reaction media for the α-monohalogenation of 1,3-diketones, β-keto-esters and cyclic
ketones with N-halosuccinimides in excellent yields in the absence of a catalyst. The
recovered ionic liquid was reused five to six times with consistent activity.
xv
O
93
pd(OAc)2
Ph3P, Ag3PO4
O
O
H3C
CF3
+
EDTA, NaHCO3
Oxone
H2O
OTBS
OsO4, NMO
t-BuOH, acetone
H2O
OTBS
OTBS
95
96
94
Synopsis
Table 4: 2-Halogenation of various 1,3-keto-esters with N-halosuccinimides
O
O
OH
OH
OTBS
a
97
O
Producta
OCOPh
OH
X=3 Br, 3'=Cl,
3"=1
+
OH
OH
O
O
OTBS
OTBS
PhCOCl
Entry 1.1eq
1,3-Keto-esters
+
OH
OTBS
O
OH
Et3N, THF
O
O
Ph
98
OEt
X
Time (min)
Yield (%)b
Br
Cl
I
20
20
25
95
93
89
Br
Cl
I
30
35
30
92
88
86
Br
Cl
I
50
45
50
89
85
86
Br
Cl
I
15
20
35
90
87
78
Ph
Br
Cl
I
10
10
20
90
92
87
OEt
Br
Cl
I
20
30
30
94
89
82
Br
Cl
I
55
60
60
92
92
90
Br
Cl
I
20
20
40
90
88
85
Br
Cl
I
45
60
75
82
80
76
Br
Cl
I
60
75
75
88
85
87
Ph
99
OEt
98
X
Scheme 15
O
O
O
O
OCH2Ph
b
O
O
OCH2Ph
X
O
O
O
c
O
OEt
OEt
X
O
O
O
O
OEt
OEt
d
N
N
O
e
O
Ph
X
O
Ph
O
Ph
X
O
O
O
O
OEt
f
X
O
O
g
O
O
OEt
OEt
X
O
O
O
O
OMe
h
O
i
X
O
O
OEt
CH2Ph
O
j
O
OEt
CH2Ph
X
O
O
O
OCH2Ph
OCH2Ph
X
a
OMe
1
All products were characterized by H NMR, IR and mass spectroscopy
Isolated and unoptimized yield.
b
xvi