Enantioselective Mukaiyama-Michael with 2-enoyl pyridine N-oxides catalyzed by PYBOX-DIPH-Zn(ii)-complexes at ambient temperature

Article abstract of DOI:10.1039/c3ob40445e

A chiral PYBOX-DIPH-Zn(ii) catalyzed enantioselective Mukaiyama-Michael reaction of acyclic silyl enol ethers with 2-enoylpyridine N-oxides has been studied in external additive free conditions at ambient temperature. The methodology offers straightforward access to a variety of functionalized chiral 1,5-dicarbonyl compounds, which could easily be elaborated into synthetically viable pyrones via hydrolysis followed by cyclization. A transition state model has been proposed to explain the stereochemical outcome. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40445e

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Enantioselective Mukaiyama–Michael with 2-enoyl
pyridine N-oxides catalyzed by PYBOX-DIPH-Zn(II)-
complexes at ambient temperature†‡
Cite this: DOI: 10.1039/c3ob40445e
Subhrajit Rout,a Sumit K. Rayb and Vinod K. Singh*a,b
A chiral PYBOX-DIPH-Zn(II) catalyzed enantioselective Mukaiyama–Michael reaction of acyclic silyl enol
ethers with 2-enoylpyridine N-oxides has been studied in external additive free conditions at ambient
temperature. The methodology offers straightforward access to a variety of functionalized chiral 1,5-
dicarbonyl compounds, which could easily be elaborated into synthetically viable pyrones via hydrolysis
followed by cyclization. A transition state model has been proposed to explain the stereochemical
outcome.
Received 5th March 2013,
Accepted 13th May 2013
DOI: 10.1039/c3ob40445e
www.rsc.org/obc
Formation of functionalized 1,5-dicarbonyl compounds by unexplored and therefore, there is a need for the development
reaction of silyl enol ether with α,β-unsaturated ketones and of a catalytic system.
esters (also known as the Mukaiyama–Michael reaction),1 is
Recently, Pedro5a–c and Reddy5d,e have reported the poten-
one of the most synthetically useful tools for C–C bond tial utility of 2-enoyl pyridine N-oxide (a versatile prochiral
forming reactions in organic chemistry. The strategy has template for a chiral metal complex) in various asymmetric
gained significant attention due to the milder reaction con- methodologies.5 As a part of our ongoing program to develop
ditions and extraordinary regioselectivity (1,4-addition in com- novel enantioselective strategies using chiral PYBOX-DIPH-
parison to 1,2-addition) obtained over
a metalloenolate metal complexes, we previously reported the utility of 2-enoyl
process.2 Enantioenriched 1,5-dicarbonyls offer an interesting pyridine N-oxides as acceptors in enantioselective Friedel–
synthetic platform to access a variety of biologically and phar- Crafts alkylation of pyrroles,6a indoles6b and dialkyl malonates
maceutically useful compounds and could be accessed both addition6c as well as synthesis of coumarin derivatives6d in
via organocatalysis as well as metal catalysis.3,4 Although con- high yields and excellent levels of enantioselectivities.6
siderable efforts have already been put forth towards asym- Together with its high reactivity, the pyridine N-oxide part of
metric Mukaiyama–Michael reactions, but it is still a difficult 2-enoyl pyridine N-oxide can also be easily cleaved to afford
and challenging task to carry out the reaction without catalyst the corresponding acid, thus making it an attractive platform
activation or in external additive free conditions to afford the to carry out desirable synthetic transformations highlighting
corresponding product in sufficient quantities to make the N-oxide chemistry.7 Very recently, Faita and co-workers have
reaction synthetically useful. Moreover, most of the strategies reported the enantioselective addition of cyclic enol ethers to
require prolonged reaction times. To our knowledge, the 2-enoyl pyridine N-oxide8a catalyzed by enantioenriched bisoxa-
metal-catalyzed asymmetric version of Mukaiyama–Michael zoline-Cu(OTf)2 complex using hexafluoro propanol-2(HFIP) as
reactions known to date, mostly need some alcohol as additive an additive in good yields and >99% enantioselectivity.8
and lower temperatures to achieve good chemical yields and
Continuing our efforts in this direction, herein we wish to
enantioselectivities. However, the asymmetric version of report an additive free, and efficient catalytic asymmetric
Mukaiyama–Michael reaction at ambient temperature is pathway to synthesize enantioenriched functionalized 1,5-
dicarbonyls utilizing 2-enoyl pyridine N-oxide 3 as template for
the Mukaiyama–Michael reaction with acyclic silyl enol ether 2
as nucleophile at ambient temperature, catalyzed by chiral
PYBOX-DIPH-Zn(OTf)2 complexes.9
aDepartment of Chemistry, Indian Institute of Science Education and Research
Bhopal, Bhopal, M.P. 460 023, India
bDepartment of Chemistry, Indian Institute of Technology Kanpur, Kanpur,
UP 208 016, India. E-mail: vinodks@iitk.ac.in; Fax: (+)91-755-4092392
†This work is dedicated to Prof. Goverdhan Mehta on the occasion of his 70th
birthday.
The methodology is operationally simple and affords a
variety of Michael adducts in excellent yields and
enantioselectivities.
Our studies began with silyl enol ether 2a as donor and
2-enoylpyridine N-oxide 3a as the Michael acceptor (Table 1) in
‡Electronic supplementary information (ESI) available. CCDC single number:
934244. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ob40445e
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Effect of different ligands on Mukaiyama–Michael reactionsa
Table 2 Reaction optimization studies for the Mukaiyama–Michael reactionsa
Entrya
Ligand
Time
Yieldb (%)
eec (%) Entry
Solvent
Lewis acid
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
4 h
38 h
13 h
26 h
28 h
23 h
24 h
30 h
9 h
72
89
88
91
84
90
70
72
87
81
21
33
14
52
74
12
12
30
1
2
3
4
5
6
7
8
CH2Cl2
DCE
CHCl3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
CuOTf·PhH
CuOTf·PhMe
Sc(OTf)3
In(OTf)3
4 h
7 h
6 h
72
88
92
87
90
88
88
90
75
87
92
95
99
94
84
Trace
Trace
81
75
89
90
90
93
96
95
91
89
91
92
04
03
02
06
19
THF
11 h
42 h
12 h
13 h
40 h
40 h
4.5 h
4 h
4.5 h
14 h
4 h
5 h
5 d
1,4-Dioxane
Toluene
Benzene
o-Xylene
CCl4
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
9
10
11
12
13
14
15
16
17
a The reactions were carried out by taking 0.2 mmol 3a and 0.6 mmol
2a in 1.0 mL dichloromethane with 5 mol% catalyst 1a-Zn(OTf)2.
b Isolated yield. c Determined by chiral HPLC (chiralcel OJ-H column).
Yb(OTf)3
Mg(OTf)2
Sn(OTf)2
7 d
a The reactions were carried out by taking 0.2 mmol 3a and 0.6 mmol
2a in 1.0 mL solvent with
5
mol% catalyst. b Isolated yield.
c Determined by chiral HPLC using Chiralcel OJ-H column.
Table 3 Effect of catalyst loading and temperature in the Mukaiyama–Michael
a
reactions using Zn(OTf)2
Entry
Catalyst (mol%)
Temp
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
5
10
15
2
1
10
25 °C
25 °C
25 °C
25 °C
25 °C
0 °C
13 h
7 h
3 h
30 h
52 h
12 h
88
92
88
90
93
92
96
95
88
90
93
92
Fig. 1 Pybox and box ligands used for Mukaiyama–Michael reactions.
presence of various pyridine bis-oxazolines-Zn(OTf)2 com-
plexes as catalysts (Fig. 1). It was found that 5 mol% 1a-Zn-
(OTf)2 afford product 4a in 81% ee and 72% yield (Table 1,
entry 1). Under similar condition, 1f-Zn(OTf)2 afforded 4a in
74% ee (entry 6), whereas 1b–e and 1g–i-Zn(OTf)2 complexes
were afforded products only in 12–52% ee (entries 2–5 and
7–9). In order to check the effect of solvent if any on the
a The reactions were carried out by taking 0.2 mmol 3a and 0.6 mmol
2a in 1.0 mL benzene with 5 mol% catalyst 1a-Zn(OTf)2. b Isolated
yield. c Determined by chiral HPLC using Chiralcel OJ-H column.
enantioselectivity of product, the reaction was conducted in (Table 3) showed that 10 mol% of 1a-Zn(OTf)2 complex was
various solvents (Table 2). We observed that, except dichloro- found to be best in terms of yield and reaction rate (Table 3,
ethane (88% yield and 75% ee, entry 2) other solvents were entry 2). The enantioselectivity was found to be almost the
good choices and afforded products in 89–96% ee (entries same in case of 5 mol% catalyst but it needed a longer reaction
3–9). Further screening with various Lewis acids shows that time compared to the use of 10 mol% catalyst loading
Cu(I)OTf (89–92% ee, entries 10–12) proved to be better than (Table 3, entry 1). Further lowering the catalyst loading to
other metal triflates (entries 13–17).
1–2 mol% of 1a-Zn(OTf)2 afforded products in 90–93% ee, but
Thus, extensive optimization studies revealed that benzene with longer reaction times (entries 4–5). No appreciable
proves to be the best solvent and Zn(OTf)2 the best Lewis acid improvement could be observed in the enantioselectivity, by
for this reaction, to afford products comparatively faster in lowering the reaction temperature to 0 °C, even using 10 mol%
good yields and higher enantioselectivities, and hence chosen of catalyst (entry 6, Table 3). Hence, we chose to carry out
for further studies. Optimization towards the catalyst loading further studies using 10 mol% 1a-Zn(OTf)2 in benzene.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 4 Substrates scope under optimized conditionsa
Entry
R1
R2
Product
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (3a)
(4a)
(4b)
(4c)
(4d)
(4e)
(4f)
(4g)
(4h)
(4i)
(4j)
(4k)
(4l)
—
7 h
4 h
4 h
4 h
2.5 h
2.5 h
3 h
3.5 h
18 h
20 h
10 h
28 h
98 h
8 h
92
91
89
88
87
88
88
89
86
81
82
80
nrd
82
88
83
nrd
95
83
90
95
92
95
90
96
92
90
90
83
nde
91
81
87
nde
2-ClC6H4 (3b)
3-ClC6H4 (3c)
4-ClC6H4 (3d)
2-NO2C6H4 (3e)
3-NO2C6H4 (3f)
4-NO2C6H4 (3g)
4-FC6H4 (3h)
4-OMeC6H4 (3i)
2-Furyl (3j)
1-Naphthyl (3k)
(E)-PhCHvCH (3l)
tBu (3m)
Ph (3a)
Ph (3a)
9
10
11
12
13
14
15
16
17
Ph (2a)
4-FC6H4 (2b)
2-Thienyl (2c)
4-BrC6H4 (2d)
tBu (2e)
(4m)
(4n)
(4o)
—
2 h
10 h
96 h
4-ClC6H4 (3d)
4-ClC6H4 (3d)
a The reactions were carried out by taking 0.2 mmol 3 and 0.6 mmol 2 in 1.0 mL benzene with 10 mol% catalyst 1a-Zn(OTf)2. b Isolated yield.
c Determined by chiral HPLC. d nr = no reaction. e nd = not determined.
With optimized conditions in hand, we turned our atten-
Table 5 Use of acyclic trisubstituted silyl enol ether in Mukaiyama–Michael
reactionsa
tion to the substrate scope. As shown in Table 4, a variety of
acyclic silyl enol ethers 2a–e as donors and a variety of 2-enoyl-
pyridine N-oxide 3a–m as the Michael acceptors were studied
for the Mukaiyama–Michael reactions affording the required
adducts in good to excellent enantioselectivities with very high
yields (Table 4). Most of the 2-enoylpyridine N-oxides 3a–i and
3k reacted smoothly with silyl enol ether (2a) to afford pro-
ducts in high yields (86–92%) with excellent enantioselectivi-
ties (90–96% ee, entries 1–9 and 11). It is noteworthy that
2-enoylpyridine N-oxide 3j containing furan as heteroaromatics
also afforded products in 90% ee (entry 10). Silyl enol ethers
2b–d also found to be suitable for this reaction and afforded
products in 87–91% ee (entries 14 and 16). The silyl enol ether a The reactions were carried out by taking 0.2 mmol 3 and 0.8 mmol 2
derived from tertiary-butyl methyl ketone failed to react with
3d to produce the corresponding adduct even after 4 days
(entry 17). However, in the case of 2-enoylpyridine N-oxide 3l, e ee of minor diastereomer. f nd = not determined.
prepared from cinnamaldehyde, we found that the reaction
Yieldb
(%)
dec
(%)
eed,e
(%)
Entry
R2
Product
Time
1
2
3
Ph (3a)
2-ClC6H4 (3b)
4-ClC6H4 (3d)
(6a)
(6b)
(6c)
61 h
50 h
42 h
91
90
92
3 : 2
4 : 1
3 : 1
97/64
65/ndf
98/68
in 1.0 mL benzene with 10 mol% catalyst 1a-Zn(OTf)2. b Isolated yield.
c Determined by 1H NMR analysis of the crude reaction mixture.
d Determined by chiral HPLC (ee reported for major diastereomer).
became sluggish and took 28 h to afford the product in 80%
yield with 83% ee (entry 12). Also, the silyl enol ether 2c, on proposed (see Fig. 2). Among two possible transition states,
reacting with 3a, afforded products in 81% ee (entry 15). The TS-1 if favored over TS-2 because of steric hindrance. In case of
sterically hindered substrate 3m prepared from trimethyl acet- TS-1, the attack of silyl enol ethers takes place from the less
aldehyde did not respond to the protocol.
hindered Re-face of complex (TS-1) formed by the coordination
With these successful results in hand using acyclic disubsti- of ligand and substrate to Zn(II)-complexes. The Si-face is not
tuted silyl enol ethers as Michael donor, we looked forward to accessible due to the steric hindrance between the iPr group of
check the substrate scope with acyclic trisubstituted silyl enol 1a and the approaching silyl enol ethers 2a–d.
ether (5) for Mukaiyama–Michael reactions. Silyl enol ether (5),
The single crystal X-ray analysis of compound 4n and the
prepared from propiophenone on treatment with 3a–b, d, comparison of optical rotation of compound 8 with literature
afforded corresponding Mukaiyama–Michael adducts in good confirm the proposed stereochemistry of the product (Fig. 3).12
diastereoselectivity and up to excellent enantioselectivity (Table 5).
To show the versatility of our methodology, one of the pro-
Further, in order to explain the stereochemical outcome of ducts (4a with 95% ee) was converted to carboxylic acid 7
the Michael adduct, a transition state model has been under saponification conditions (Scheme 1), which was then
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
important natural products (9a–d) on further synthetic
elaboration.10
In conclusion, an additive-free enantioselective methodo-
logy for the Mukaiyama–Michael reaction of a variety of
2-enoylpyridine N-oxides 3 with acyclic silyl enol ethers 2 and
5 has been developed at room temperature using 1a-Zn(OTf)2
complex. The strategy offers an interesting platform to syn-
thesize functionalized 1,5-dicarbonyl compounds in very good
yields and excellent enantioselectivities (up to 96%). A tran-
sition state has been proposed to explain the stereochemical
outcome of the Mukaiyama–Michael adduct. Further efforts
towards its application in the natural product synthesis are
currently under way.
Fig. 2 Proposed transition states of Mukaiyama–Michael reactions.
Experimental section
1H and 13C NMR spectra were recorded on Jeol (500 MHz)
spectrometers in CDCl3. Chemical shifts are reported in delta
(δ) units, in parts per million (ppm). Coupling constants were
reported in Hz. Splitting patterns are designated as s for
singlet; d for doublet; t for triplet; q for quartet; m for multi-
plet and bs for broad singlet. IR spectra were measured with
Bruker FT/IR Vector 22 spectrometer. Mass spectrometric ana-
lysis was done on waters Q Tof Premier Micromass (ESI). All
the chromatographic separations were carried out by using
silica gel (Acme’s, 100–200 mesh). Zinc(II) triflate, Silyl enol
ether 2a and 2e were commercially available from Sigma-
Aldrich and used without further purification. Silyl enol ether
2b–2d were prepared according to literature known pro-
cedure.11 Silyl enol ether 5 was prepared according to literature
reported procedure.13 Ligands 1a–1g were prepared according
to our procedure.9e–g 1h–1i were commercially available.
2-Enoylpyridine-N-oxides were prepared by earlier reported
method.6a,b
Fig. 3 X-ray structure of 4n.
General procedure of silyl enol ether preparation
A solution of ketone (1 eq) in anhydrous dichloromethane was
stirred at room temperature under N2 atmosphere. Triethyl-
amine (1.8 eq) and then trimethylsilyltrifluoromethanesulfo-
nate (1.2 eq) were added to the reaction mixture. After three
hours, the reaction was diluted with dichloromethane and
washed with a solution of sat. NH4Cl. The aqueous layer was
extracted thrice with ethyl acetate. The organic layers were
further washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. Silyl
enol ethers were used without further purification.
Scheme 1 Synthetic elaboration of compound 4a and further opportunity to
General procedure for enantioselective Mukaiyama–Michael
access various natural products.
reaction
A solution of a ligand 1a (14.54 mg, 0.024 mmol) and Zn(OTf)2
treated with excess oxalyl chloride and catalytic amount of di- (7.26 mg, 0.02 mmol) in dry dichloromethane (1 mL) was
methylformamide to afford the synthetically useful 3,4- stirred at room temperature for 1 h under nitrogen atmos-
dihydro-α-pyrone 8 with slight loss in enantioselectivity (90% phere. trans-2-Enoylpyridine-N-oxide (0.20 mmol) was added
ee). Besides this, the enantioenriched δ-keto acid (7) could and the whole mixture was stirred for an additional 15 min at
also serve as a template for the synthesis of various biologically rt. Silyl enol ether (0.6 mmol) was added and the reaction
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
mixture and stirred at room temperature until the completion eluent, flow rate = 1.0 mL min−1. tR (major) = 31.77 min, tR
of the reaction (monitored by TLC). The mixture was concen- (minor) = 43.16 min. 1H NMR (500 MHz; CDCl3): δ 3.33 (dd, J =
trated in vacuo and purified over silica gel by column chrom- 7.4, 17.1 Hz, 1H), 3.40 (dd, J = 6.45, 17.4 Hz, 1H), 3.64 (dd, J =
atography (methanol–ethyl acetate 1 : 20) to afford the product. 5.5, 17.8 Hz, 1H), 3.72 (dd, J = 7.9, 17.4 HZ, 1H), 4.02–4.06 (m,
(R)-2-(5-Oxo-3,5-diphenylpentanoyl)pyridine 1-oxide (4a). The 1H), 7.18–7.48 (m, 9H), 7.53 (td, J = 1.5, 7.4 Hz, 1H), 7.88 (d, J
compound 4a was isolated as solid in 92% yield and 95% = 8.2 Hz, 2H), 8.17–8.19 (m, 1H). 13C NMR (125 MHz, CDCl3): δ
ee; [α]2D5 = +49.5 (c 0.3, CHCl3). The enantiomeric ratio was 36.2, 44.9, 48.8, 126.2, 127.0, 128.0, 128.1, 128.7, 129.1, 132.3,
determined by chiral HPLC using Daicel Chiralcel OJ-H 133.2, 136.8, 140.5, 146.6, 195.7, 198.0. IR (thin film): ν = 3061,
column, n-hexane–2-propanol (70 : 30) as eluent, flow rate = 2923, 2852, 1684, 1597, 1580, 1492, 1448, 1429, 1360 cm−1
.
1.0 mL min−1. tR (major) = 28.86 min, tR (minor) = 42.95 min. HRMS (ES+): Exact mass calc for C22H19ClNO3 [M + H]+:
1H NMR (500 MHz; CDCl3): δ 3.34–3.44 (m, 2H), 3.65 (dd, J = 380.1053. Found: 380.1053.
6.5, 17.1 Hz, 1H), 3.73 (dd, J = 8.0, 17.1 Hz, 1H), 4.05–4.08 (m,
(R)-2-(3-(2-Nitrophenyl)-5-oxo-5-phenylpentanoyl)pyridine 1-
1H), 7.12–7.45 (m, 10H), 7.52 (t, J = 7.4 Hz, 1H), 7.89 (dd, J = oxide (4e). The compound 4e was isolated as semisolid in
7.0, 8.6 Hz, 2H), 8.23 (d, J = 6.4 Hz, 1H). 13C NMR (125 MHz, 87% yield and 92% ee; [α]D25 = +24.1 (c 0.7, CHCl3). The enan-
CDCl3): δ 37.0, 45.1, 48.9, 126.7, 126.9, 127.4, 127.7, 127.9, tiomeric ratio was determined by chiral HPLC using Daicel
128.1, 128.6, 135.1, 140.3, 143.6, 146.8, 195.9, 198.3. IR (thin Chiralcel OD-H column, n-hexane–2-propanol (70 : 30) as
film): ν = 3457.3, 2924.3, 2052.9, 1682.9, 1601.7, 1494.9, eluent, flow rate = 1.0 mL min−1. tR (major) = 28.01 min, tR
1
1448.5, 1430.4 cm−1
.
HRMS (ES+): Exact mass calc for (minor) = 36.80 min. H NMR (500 MHz; CDCl3): δ 3.41–3.52
C22H20NO3 [M + H]+: 346.1443. Found: 346.1445.
(m, 2H), 3.77 (dd, J = 7.2, 12.5 Hz, 1H), 3.82 (dd, J = 4.5, 7.0 Hz,
(R)-2-(3-(2-Chlorophenyl)-5-oxo-phenylpentanoyl)pyridine 1- 1H), 4.51–4.57 (m, 1H), 7.27–7.64 (m, 8H), 7.71–7.77 (m, 1H),
oxide (4b). The compound 4b was isolated as solid in 91% 7.89–7.92 (m, 3H), 8.22 (d, J = 6.4 Hz, 1H). 13C NMR (125 MHz,
yield and 83% ee; [α]D25 = +35.9 (c 0.5, CHCl3). The enantio- CDCl3): δ 36.2, 44.1, 48.1, 114.1, 124.4, 127.1, 127.3, 128.1,
meric ratio was determined by chiral HPLC using Daicel Chir- 128.6, 128.8, 129.4, 132.8, 133.3, 134.6, 136.5, 139.3, 140.6,
alcel OJ-H column, n-hexane–2-propanol (70 : 30) as eluent, 146.2, 152.2, 197.5. IR (thin film): ν = 3432, 2922, 2852, 1683,
flow rate = 1.0 mL min−1. tR (major) = 19.25 min, tR (minor) = 1599, 1579, 1523, 1423, 1353, 1297 cm−1. HRMS (ES+): Exact
27.24 min. 1H NMR (500 MHz; CDCl3): δ 3.40–3.46 (m, 2H), mass calc for
3.74 (dd, J = 6.7, 18.0 Hz, 1H), 3.80 (dd, J = 7.5, 17.6 Hz, 1H), 391.1293.
C22H19N2O5 [M +
H]+: 391.1294. Found:
4.49–4.55 (m, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz,
(R)-2-(3-(3-Nitrophenyl)-5-oxo-5-phenylpentanoyl)pyridine 1-
1H), 7.32–7.36 (m, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.52–7.69 (m, oxide (4f). The compound 4f was isolated as semisolid in 88%
4H), 7.92 (d, J = 7.1 Hz, 2H), 8.45–8.50 (m, 1H). 13C NMR yield and 95% ee; [α]D25 = +24.5 (c 0.5, CHCl3). The enantio-
(125 MHz, CDCl3): δ 33.4, 43.6, 47.1, 126.9, 127.1, 127.8, 128.2, meric ratio was determined by chiral HPLC using Daicel Chir-
128.4, 128.6, 130.0, 133.2, 133.8, 136.8, 140.8, 195.6, 198.2. IR alcel OJ-H column, n-hexane–2-propanol (80 : 20) as eluent,
(thin film): ν = 3447, 3048, 2923, 2852, 1683, 1650, 1579, 1475, flow rate = 1.0 mL min−1. tR (major) = 74.62 min, tR (minor) =
1447, 1354 cm−1
.
HRMS (ES+): Exact mass calc for 99.75 min. 1H NMR (500 MHz; CDCl3): δ 3.43 (dd, J = 7.4,
17.4 Hz, 1H), 3.51 (dd, J = 6.5, 17.5 Hz, 1H), 3.62–3.71 (m, 2H),
C22H19ClNO3 [M + H]+: 380.1053. Found: 380.1052.
(R)-2-(3-(3-Chlorophenyl)-5-oxo-phenylpentanoyl)pyridine 1- 3.99–4.05 (m, 1H), 7.18–7.22 (m, 4H), 7.239–7.44 (m, 2H), 7.51
oxide (4c). The compound 4c was isolated as semisolid in (dd, J = 2.2, 7.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.72 (d, J =
89% yield and 90% ee; [α]2D5 = +3.1 (c 0.9, CHCl3). The enantio- 8.6 Hz, 3H), 8.31 (d, J = 5.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ
meric ratio was determined by chiral HPLC using Daicel Chir- 36.2, 44.5, 48.8, 121.9, 122.5, 127.2, 128.1, 128.2, 128.4, 128.7,
alcel OD-H column, n-hexane–2-propanol (90 : 10) as eluent, 129.5, 133.5, 134.6, 136.5, 140.8, 146.0, 148.4, 194.6, 197.5. IR
flow rate = 1.0 mL min−1. tR (major) = 74.27 min, tR (minor) = (thin film): ν = 3435, 3061, 2923, 2853, 1685, 1674, 1596, 1579,
85.42 min. 1H NMR (500 MHz; CDCl3): δ 3.42–3.70 (m, 2H), 1530, 1480, 1437, 1348 cm−1. HRMS (ES+): Exact mass calc for
3.65 (dd, J = 6.4, 18.0 Hz, 1H), 3.71 (dd, J = 8.0, 16.8 Hz, 1H), C22H19N2O5 [M + H]+: 391.1294. Found: 391.1299.
4.02–4.07 (m, 1H), 7.12–7.25 (m, 4H), 7.43 (t, J = 7.6 Hz, 2H),
(R)-2-(3-(4-Nitrophenyl)-5-oxo-5-phenylpentanoyl)pyridine 1-
7.53–7.57 (m, 4H), 7.89 (d, J = 7.3 Hz, 2H), 8.45 (bs, 1H). 13C oxide (4g). The compound 4g was isolated as semisolid in
NMR (125 MHz, CDCl3): δ 36.5, 44.8, 48.8, 114.1, 126.0, 127.0, 88% yield and 90% ee; [α]2D5 = +45.5 (c 1.1, CHCl3). The enan-
127.1, 127.8, 128.1, 128.7, 129.9, 133.3, 134.3, 136.7, 139.3, tiomeric ratio was determined by chiral HPLC using Daicel
145.8, 194.8, 198.0. IR (thin film): ν = 3385, 3061, 2924, 2853, Chiralpak IA-3 column, n-hexane–2-propanol (80 : 20) as
1684, 1597, 1572, 1475, 1470, 1430, 1360 cm−1. HRMS (ES+): eluent, flow rate = 1.0 mL min−1. tR (major) = 58.84 min, tR
Exact mass calc for C22H19ClNO3 [M + H]+: 380.1053. Found: (minor) = 70.50 min. 1H NMR (500 MHz; CDCl3): δ 3.41 (dd, J =
380.1059.
7.6, 17.4 Hz, 1H), 3.48 (dd, J = 6.5, 17.4 Hz, 1H), 3.72 (dd, J =
(R)-2-(3-(4-Chlorophenyl)-5-oxo-phenylpentanoyl)pyridine 1- 6.1, 18.0 Hz, 1H), 3.79 (dd, J = 8.0, 18.0 Hz, 1H), 4.18–4.23 (m,
oxide (4d). The compound 4d was isolated as semisolid in 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.40–7.58 (m, 7H), 7.88 (d, J = 8.3
88% yield and 95% ee; [α]2D5 = +31.2 (c 0.8, CHCl3). The enan- Hz, 2H), 8.10 (d, J = 8.3 Hz, 2H), 8.25 (d, J = 6.4 Hz, 1H). 13C
tiomeric ratio was determined by chiral HPLC using Daicel NMR (125 MHz, CDCl3): δ 36.3, 44.4, 48.6, 123.8, 127.1, 127.5,
Chiralcel OJ-H column, n-hexane–2-propanol (80 : 20) as 128.0, 128.4, 128.7, 133.5, 136.5, 140.7, 146.1, 146.7, 151.7,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
194.8, 197.5. IR (thin film): ν = 2922, 2851, 1683, 1597, 1516, Chiralpak IA-3 column, n-hexane–2-propanol (80 : 20) as
1429, 1345 cm−1. HRMS (ES+): Exact mass calc for C22H19N2O5 eluent, flow rate = 1.0 mL min−1. tR (major) = 30.02 min, tR
1
[M + H]+: 391.1294. Found: 391.1290.
(minor) = 27.52 min. H NMR (500 MHz; CDCl3): δ 3.47–3.56
(R)-2-(3-(4-Fluorophenyl)-5-oxo-phenylpentanoyl)pyridine 1- (m, 2H), 3.80 (dd, J = 6.2, 17.1 Hz, 1H), 3.93 (dd, J = 7.6, 16.8
oxide (4h). The compound 4h was isolated as semisolid in Hz, 1H), 4.91–5.02 (m, 1H), 7.31–7.51 (m, 10H), 7.67 (d, J =
89% yield and 96% ee; [α]D25 = +28.3 (c 1.1, CHCl3). The enan- 8.00 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.89 (m, 2H), 8.19 (d, J =
tiomeric ratio was determined by chiral HPLC using Daicel 6.4 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H). 13C NMR (125 MHz,
Chiralcel OJ-H column, n-hexane–2-propanol (90 : 10) as CDCl3): δ 37.3, 44.9, 48.3, 123.2, 125.4, 125.7, 126.4, 126.8,
eluent, flow rate = 1.0 mL min−1. tR (major) = 87.65 min, tR 127.3, 127.9, 128.1, 128.6, 128.9, 133.2, 134.0, 136.9, 140.0,
1
(minor) = 110.12 min. H NMR (500 MHz; CDCl3): δ 3.32 (dd, 140.3, 146.7, 196.1, 198.5. IR (thin film): ν = 3250, 2920, 2850,
J = 7.6, 16.8 Hz, 1H), 3.29 (dd, J = 6.4, 16.8 Hz, 1H), 3.62 (dd, 1682, 1597, 1429, 1293 cm−1. HRMS (ES+): Exact mass calc for
J = 6.4, 17.1 Hz, 1H), 3.70 (dd, J = 8.0, 17.4 Hz, 1H), 4.03–4.08 C26H22NO3 [M + H]+: 396.1600. Found: 396.1600.
(m, 1H), 6.92 (t, J = 8.3 Hz, 2H), 7.21–7.27 (m, 2H), 7.42 (t, J =
(R,E)-2-(3-(2-Oxo-2-phenylethyl)-5-phenylpent-4-enoyl)pyridine
7.7 Hz, 2H), 7.50–7.55 (m, 4H), 7.88 (d, J = 7.7 Hz, 2H), 8.45 1-oxide (4l). The compound 4l was isolated as semisolid
(bs, 1H). 13C NMR (125 MHz, CDCl3): δ 36.1, 45.1, 49.0, 115.2, in 80% yield and 83% ee; [α]D25 = +20.3 (c 0.5, CHCl3). The
115.4, 126.8, 127.0, 128.1, 128.3, 128.6, 129.1, 129.3, 133.2, enantiomeric ratio was determined by chiral HPLC using
136.8, 139.4, 140.5, 146.6, 160.5, 162.5, 196.0, 198.2. IR (thin Daicel Chiralcel OD-H column, n-hexane–2-propanol (90 : 10)
film): ν = 2923, 2833, 1684, 1593, 1509, 1462, 1376 cm−1
.
as eluent, flow rate = 1.0 mL min−1. tR (major) = 69.62 min, tR
1
HRMS (ES+): Exact mass calc for C22H19FNO3 [M + H]+: (minor) = 86.40 min. H NMR (500 MHz; CDCl3): δ 3.19–3.28
364.1349. Found: 364.1349.
(m, 2H), 3.49 (dd, J = 6.1, 17.1 Hz, 1H), 3.55 (dd, J = 7.0, 16.8
(R)-2-(3-(4-Methoxyphenyl)-5-oxo-phenylpentanoyl)pyridine Hz, 1H), 3.59, 3.64 (m, 1H), 6.21 (dd, J = 8.3, 15.9 Hz, 1H), 6.43
1-oxide (4i). The compound 4i was isolated as semisolid in (d, J = 16.2 Hz, 1H), 7.16–7.19 (m, 1H), 7.23–7.29 (m, 4H),
86% yield and 92% ee; [α]D25 = +40.7 (c 0.8, CHCl3). The enan- 7.343–7.56 (m, 5H), 7.70 (dd, J = 1.9, 7.7 Hz, 1H), 7.94 (m, 2H),
tiomeric ratio was determined by chiral HPLC using Daicel 8.48 (d, J = 6.1 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 36.7,
Chiralcel OJ-H column, n-hexane–2-propanol (70 : 30) as 43.5, 47.5, 126.3, 127.0, 127.2, 127.3, 128.0, 128.5, 128.7, 130.8,
eluent, flow rate = 1.0 mL min−1. tR (major) = 24.44 min, tR 131.7, 133.2, 137.0, 139.3, 140.5, 146.5, 146.8, 196.1, 198.6. IR
1
(minor) = 36.68 min. H NMR (500 MHz; CDCl3): δ 3.31–3.40 (thin film): ν = 2921, 2851, 1683, 1597, 1492, 1448, 1429, 1361,
(m, 2H), 3.58–3.70 (m, 2H), 3.73 (s, 3H), 3.96–4.01 (m, 1H), 1293 cm−1. HRMS (ES+): Exact mass calc for C24H22NO3
6.76 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.40–7.54 (m, [M + H]+: 372.1600. Found: 372.1593
6H), 7.89 (d, J = 7.7 Hz, 2H), 8.44 (bs, 1H). 13C NMR (125 MHz,
(R)-2-(5-(4-Fluorophenyl)-5-oxo-phenylpentanoyl)pyridine 1-
CDCl3): δ 36.3, 45.3, 49.2, 55.3, 114.0, 127.1, 128.1, 128.6, oxide (4m). The compound 4m was isolated as semisolid in
130.3, 133.2, 135.4, 136.9, 140.4, 158.3, 195.4, 198.5. IR (thin 82% yield and 91% ee; [α]2D5 = +40.0 (c 0.6, CHCl3). The enan-
film): ν = 3361, 3060, 2923, 2851, 1683, 1580, 1513, 1448, 1362, tiomeric ratio was determined by chiral HPLC using Daicel
1296 cm−1. HRMS (ES+): Exact mass calc for C23H22NO4 Chiralcel OJ-H column, n-hexane–2-propanol (80 : 20) as
[M + H]+: 376.1549. Found: 376.1543.
(R)-2-(3-(Furan-2-yl)-5-oxo-5-phenylpentanoyl)pyridine
eluent, flow rate = 1.0 mL min−1. tR (major) = 57.67 min, tR
1- (minor) = 78.60 min. H NMR (500 MHz; CDCl3): 3.33 (dd, J =
1
oxide (4j). The compound 4j was isolated as semisolid in 81% 7.4, 17.1 Hz, 1H), 3.39 (dd, J = 6.7, 16.8 Hz, 1H), 3.63–3.73 (m,
yield and 90% ee; [α]2D5 = +12.0 (c 0.5, CHCl3). The enantio- 2H), 4.00–4.06 (m, 1H), 7.08 (t, J = 8.6 Hz, 2H), 7.14 (t, J =
meric ratio was determined by chiral HPLC using Daicel Chir- 6.7 Hz, 1H), 7.21–7.26 (m, 4H), 7.32–7.42 (m, 3H), 7.90–7.93
alcel OD-H column, n-hexane–2-propanol (85 : 15) as eluent, (m, 2H), 8.26 (d, J = 6.1 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ
flow rate = 1.0 mL min−1. tR (major) = 43.94 min, tR (minor) = 37.0, 45.1, 48.9, 115.6, 115.8, 126.8, 126.9, 127.6, 128.0, 128.7,
1
51.55 min. H NMR (500 MHz; CDCl3): δ 3.35 (dd, J = 7.0, 17.4 130.7, 130.8, 133.3, 140.4, 143.5, 146.7, 164.7, 166.8, 195.9,
Hz, 1H), 3.47 (dd, J = 6.7, 17.1 Hz, 1H), 3.60 (dd, J = 6.1, 17.4 196.8. IR (thin film): ν = 3419, 3063, 2919, 2851, 1884, 1597,
Hz, 1H), 3.73 (dd, J = 7.7, 17.4 Hz, 1H), 4.15–4.21 (m, 1H), 6.07 1506, 1453, 1430, 1410, 1365 cm−1. HRMS (ES+): Exact mass
(d, J = 2.8 Hz, 1H), 6.20–6.21 (m, 1H), 7.22–7.28 (m, 1H), 7.44 calc for C22H19FNO3 [M + H]+: 364.1349. Found: 364.1345.
(t, J = 8.0 Hz, 2H), 7.48–7.56 (m, 3H), 7.65–7.69 (m, 1H),
(S)-2-(5-Oxo-3-phenyl-5-(thiophen-2-yl)pentanoyl)pyridine 1-
7.91–7.93 (m, 2H), 8.47–8.49 (m, 1H). 13C NMR (125 MHz, oxide (4n). The compound 4n was isolated as solid in 88%
CDCl3): δ 30.5, 42.5, 46.6, 105.6, 110.3, 114.1, 127.1, 128.1, yield and 81% ee; [α]2D5 = −41.3 (c 0.4, CHCl3). The enantio-
128.5, 133.2, 136.8, 140.4, 141.2, 146.5, 155.9, 195.2, 198.0. IR meric ratio was determined by chiral HPLC using Daicel Chir-
(thin film): ν = 2922, 2851, 1684, 1597, 1505, 1448, 1480, alcel OJ-H column, n-hexane–2-propanol (70 : 30) as eluent,
1360 cm−1. HRMS (ES+): Exact mass calc for C20H18NO4 flow rate = 1.0 mL min−1. tR (major) = 39.37 min, tR (minor) =
[M + H]+: 336.1236. Found: 336.1236.
59.52 min. 1H NMR (500 MHz; CDCl3): δ 3.31 (d, J = 7.1 Hz,
(R)-2-(3-(Naphthalen-1-yl)-5-oxo-5-phenylpentanoyl)pyridine 2H), 3.64 (dd, J = 6.1, 17.1 Hz, 1H), 3.74 (dd, J = 8.3, 17.4 Hz,
1-oxide (4k). The compound 4k was isolated as semisolid in 1H), 3.99–4.05 (m, 1H), 7.09 (t, J = 4.6 Hz, 1H), 7.15 (t, J = 7.4
82% yield and 90% ee; [α]D25 = +43.4 (c 0.4, CHCl3). The enan- Hz, 1H), 7.22–7.28 (m, 3H), 7.47–7.58 (m, 4H), 7.60 (d, J = 5.2
tiomeric ratio was determined by chiral HPLC using Daicel Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H).
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
13C NMR (125 MHz, CDCl3): δ 37.4, 45.8, 48.7, 114.1, 127.0,
2-((3S)-3-(4-Chlorophenyl)-4-methyl-5-oxo-5-phenylpenta-
127.2, 127.6, 128.2, 128.7, 132.2, 134.0, 140.3, 143.1, 191.3, noyl)pyridine 1-oxide (6c). The compound 6c was isolated as
194.8. IR (thin film): ν = 2921, 2856, 1656, 1415, 1254 cm−1
semisolid in 92% overall yield, 98% ee (for major diastereo-
HRMS (ES+): Exact mass calc for C20H18NO3S [M + H]+: mer) and 68% ee (for minor diastereomer). The enantiomeric
352.1007. Found: 352.1004. ratio was determined by chiral HPLC using Daicel Chiralpak
.
(R)-2-(5-(4-Bromophenyl)-3-(4-chlorophenyl)-5-oxopentanoyl)- IC-3 column, n-hexane–2-propanol (70 : 30) as eluent, flow rate
pyridine 1-oxide (4o). The compound 4o was isolated as semi- = 1.0 mL min−1. tR (major) = 48.69 min, tR (minor) =
solid in 83% yield and 87% ee; [α]2D5 = +38.2 (c 0.3, CHCl3). The 86.89 min. and for minor isomer tR (major) = 58.80 min, tR
1
enantiomeric ratio was determined by chiral HPLC using (minor) = 53.95 min. H NMR (500 MHz; CDCl3): δ 0.95 (d, J =
Daicel Chiralcel OD-H column, n-hexane–2-propanol (70 : 30) 5.8 Hz, 2.25H), 1.29 (d, J = 6.4 Hz, 0.75 Hz), 3.00–3.42 (m, 1H),
as eluent, flow rate = 1.0 mL min−1. tR (major) = 35.86 min, tR 3.66–3.83 (m, 3H), 7.05–7.62 (m, 10H), 7.76 (d, J = 7.3 Hz,
(minor) = 23.92 min. 1H NMR (500 MHz; CDCl3): δ 3.29 (dd, J = 0.5H), 7.98 (d, J = 7.3 Hz, 1H), 7.23–7.29 (m, 4H), 7.343–7.56
7.7, 17.1 Hz, 1H), 3.37 (dd, J = 6.4, 17.1 Hz, 1H), 3.62–3.71 (m, (m, 5H), 7.70 (dd, J = 1.9, 7.7 Hz, 1H), 7.94 (m, 2H), 8.48 (d, J =
2H), 4.00–4.05 (m, 1H), 7.18–7.22 (m, 4H), 7.39–7.52 (m, 3H), 6.1 Hz, 1.5H), 8.16 (d, J = 6.1 Hz, 0.75H), 8.21 (d, J = 6.1 Hz,
7.56 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 8.31 (d, J = 5.8 0.25H). 13C NMR (125 MHz, CDCl3): δ 15.6, 16.2, 42.8, 43.3,
Hz, 1H). 13C NMR (125 MHz, CDCl3): δ IR (thin film): ν = 3083, 45.2, 45.6, 46.1, 47.4, 126.8, 127.1, 127.3, 128.0, 128.1, 128.1,
2923, 2852, 1684, 1584, 1491, 1429, 1397, 1360 cm−1. HRMS 128.4, 128.6, 128.7, 128.9, 129.6, 130.0, 132.3, 132.5, 133.1,
(ES+): Exact mass calc for C22H18BrClNO3 [M + H]+: 458.0159. 133.4, 136.5, 140.2, 140.3, 141.3, 146.5, 146.7, 195.6, 196.3,
Found: 458.0159.
202.9, 203.2. IR (thin film): ν = 3062, 2925, 2853, 1680, 1597,
1- 1491, 1447, 1429, 1374, 1293 cm−1. HRMS (ES+): Exact mass
2-((3S)-4-Methyl-5-oxo-3,5-diphenylpentanoyl)pyridine
oxide (6a). The compound 6a was isolated as semisolid in calc for C23H21ClNO3 [M + H]+: 394.1210. Found: 394.1214.
91% overall yield, 97% ee (for major diastereomer) and 64% ee
(for minor diastereomer). The enantiomeric ratio was deter-
mined by chiral HPLC using Daicel Chiralcel OD-H column,
n-hexane–2-propanol (90 : 10) as eluent, flow rate = 1.0 mL
min−1. For major diastereomer, tR (major) = 42.41 min, tR
(minor) = 40.41 min. and for minor diastereomer, tR (major) =
77.61 min, tR (minor) = 52.37 min. 1H NMR (500 MHz; CDCl3):
δ 0.96 (d, J = 9.0 Hz, 1.8H), 1.26 (d, J = 3.1 Hz, 1.2 H), 3.37–3.42
(m, 0.6H), 3.67–3.87 (m, 3.4H), 7.00–7.55 (m, 11H), 7.75 (dd,
J = 1.0, 7.9 Hz, 1H), 7.97–7.99 (m, 1H), 8.12 (d, J = 6.4 Hz,
0.6H), 8.18 (d, J = 6.4 Hz, 0.4H). 13C NMR (125 MHz, CDCl3): δ
15.3, 16.7, 43.6, 44.2, 45.0, 45.9, 46.3, 47.4, 126.6, 126.7, 126.8,
126.9, 127.0, 127.7, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5,
128.8, 132.9, 133.2, 136.8, 140.1, 141.6, 142.6, 146.8, 147.0,
196.2, 196.9, 203.3, 203.5. IR (thin film): ν = 3060, 2927, 1679,
1597, 1495, 1448, 1429, 1373, 1294 cm−1. HRMS (ES+): Exact
mass calc for C23H22NO3 [M + H]+: 360.1600. Found: 360.1602.
2-((3S)-3-(2-Chlorophenyl)-4-methyl-5-oxo-5-phenylpenta-
noyl)pyridine 1-oxide (6b). The compound 6b was isolated
as semisolid in 90% overall yield and 65% ee (for major dia-
stereomer); The enantiomeric ratio was determined by chiral
HPLC using Daicel Chiralpak IC-3 column, n-hexane–2-propa-
Cleavage of pyridine N-oxide ring (Scheme 1)
The compound 4a (172.69 mg, 0.5 mmol) was suspended in
3 mL 20% aqueous KOH and the reaction mixture was heated
to reflux for 5 h. The reaction mixture was cooled to room
temperature and washed with ethyl acetate. The aqueous layer
was cooled to 0 °C and acidified with conc. HCl and extracted
with ethyl acetate thrice. The combine organic layer was
washed with saturated brine solution and the mixture was con-
centrated in vacuo and purified over silica gel by column
chromatography to afford the product 7.
The compound 7 was obtained in 70% yield. [α]2D5 = −16.8 (c
1
1.1, CHCl3). H NMR (500 MHz; CDCl3): 2.71 (dd, J = 7.7, 16.0
Hz, 1H), 2.86 (dd, J = 6.9, 16.0 Hz, 1H), 3.30–3.40 (m, 2H),
3.83–3.88 (m, 1H), 7.18–7.29 (m, 5H), 7.42 (t, J = 7.8 Hz, 2H),
7.53 (t, J = 7.2 Hz, 1H), 7.89 (d, J = 7.5 HZ, 2H). IR (thin film):
ν = 3441, 2924, 2853, 1706, 1675, 1596, 1496, 1450, 1418,
1357 cm−1. HRMS (ES+): Exact mass calc for C17H16NaO3
[M + Na]+: 291.0997. Found: 291.0998.
The synthesis of compound 8
nol (70 : 30) as eluent, flow rate = 1.0 mL min−1. tR (major) = The compound 7 (0.2 mmol) was suspended in 2 mL dichloro-
97.28 min, tR (minor) = 116.20 min. 1H NMR (500 MHz; methane and allowed to stirred at room temperate. 0.3 mmol
CDCl3): δ 1.01 (d, J = 7.1 Hz, 2.4H), 1.22 (d, J = 3.0 Hz, 0.6 Hz), of oxalyl chloride was added to the reaction mixture slowly.
3.46–4.00 (m, 3.2H), 4.36 (m, 0.8 H), 7.07–7.55 (m, 10H), 7.90 Then 1–2 drops of DMF was added to the reaction mixture.
(d, J = 7.4 Hz, 0.4H), 7.94 (d, J = 7.4 Hz, 1.6H), 8.20 (d, J = 6.4 After two hours, the reaction was diluted with dichloro-
Hz, 0.8H), 8.25 (d, J = 6.4 Hz, 0.2H). 13C NMR (125 MHz, methane. The organic layer was further washed with brine and
CDCl3): δ 16.6, 16.7, 43.3, 43.4, 43.6, 43.7, 46.3, 126.8, 127.1, dried over anhydrous sodium sulfate. The mixture was concen-
127.2, 127.8, 127.9, 128.0, 128.1, 128.3, 128.4, 128.6, 128.8, trated in vacuo and purified over silica gel by column chrom-
129.8, 129.9, 133.1, 133.3, 136.6, 136.7, 139.4, 140.3, 146.5, atography to afford the product 8.
195.6, 203.1, 203.2. IR (thin film): ν = 3061, 2925, 2853, 1676,
The compound 8 was obtained in 85% yield. The enantio-
1596, 1475, 1429, 1374, 1293, 1259 cm−1. HRMS (ES+): Exact meric ratio was determined by chiral HPLC using Daicel Chir-
mass calc for C23H21ClNO3 [M + H]+: 394.1210. Found: alcel OJ-H column, n-hexane–2-propanol (95 : 5) as eluent, flow
394.1219.
rate = 1.0 mL min−1. tR (major) = 32.62 min, tR (minor) =
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
25.80 min. [α]2D5 = −36.7 (c 0.5, CHCl3) for 90% ee (S) isomer
[lit12 [α]D20 = +6.0 (c 0.28, CHCl3) for 70% ee (R) isomer].
Tetrahedron, 1997, 53, 13009; (d) H. Kitajima and
T. Katsuki, Synlett, 1997, 568; (e) D. A. Evans, T. Rovis,
M. C. Kozlowski and J. S. Tedrow, J. Am. Chem. Soc., 1999,
121, 1994; (f) H. Nishikiori, K. Ito and T. Katsuki, Tetra-
hedron: Asymmetry, 1998, 9, 1165; (g) D. A. Evans,
J. S. Johnson and E. J. Olhava, J. Am. Chem. Soc., 2000, 122,
1635; (h) D. A. Evans, M. C. Willis and J. N. Johnston, Org.
Lett., 1999, 1, 865; (i) D. A. Evans, T. Rovis, M. C. Kozlowski,
C. W. Downey and J. S. Tedrow, J. Am. Chem. Soc., 2000,
122, 9134; ( j) D. A. Evans, K. A. Scheidt, J. N. Johnston and
M. C. Willis, J. Am. Chem. Soc., 2001, 123, 4480;
(k) G. Desimoni, G. Faita, S. Filippone, M. Mella,
M. G. Zampori and M. Zema, Tetrahedron, 2001, 57, 10203;
(l) T. Harada, H. Iwai, H. Takatsuki, K. Fujita, M. Kubo and
A. Oku, Org. Lett., 2001, 3, 2101; (m) X. Wang, S. Adachi,
H. Iwai, H. Takatsuki, K. Fujita, M. Kubo, A. Oku and
T. Harada, J. Org. Chem., 2003, 68, 10046; (n) H. Suga,
T. Kitamura, A. Kakehi and T. Baba, Chem. Commun., 2004,
1414; (o) X. Wang, T. Harada, H. Iwai and A. Oku, Chirality,
2003, 15, 28; (p) G. Desimoni, G. Faita, M. Guala,
A. Laurenti and M. Mella, Chem.–Eur. J., 2005, 11, 3816;
(q) T. Harada, S. Adachi and X. Wang, Org. Lett., 2004, 6,
4877; (r) K. Ishihara and M. Fushimi, Org. Lett., 2006, 8,
1921; (s) X. Xu, W. H. Hu and M. P. Doyle, Angew. Chem.,
Int. Ed., 2011, 50, 6392.
5 (a) S. Barroso, G. Blay and J. R. Pedro, Org. Lett., 2007, 9,
1983; (b) S. Barroso, G. Blay, M. C. Muñoz and J. R. Pedro,
Org. Lett., 2011, 13, 402; (c) S. Barroso, G. Blay,
M. C. Muñoz and J. R. Pedro, Adv. Synth. Catal., 2009, 351,
107; (d) J. George and B. V. S. Reddy, Org. Biomol. Chem.,
2012, 10, 4731; (e) J. George and B. V. S. Reddy, Adv. Synth.
Catal., 2013, 355, 383.
6 (a) P. K. Singh and V. K. Singh, Org. Lett., 2010, 12, 80;
(b) P. K. Singh and V. K. Singh, Org. Lett., 2008, 10, 4121;
(c) S. K. Ray, P. K. Singh and V. K. Singh, Org. Lett., 2011,
13, 5812; (d) S. K. Ray, P. K. Singh, N. Molleti and
V. K. Singh, J. Org. Chem., 2012, 77, 8802.
1H NMR (500 MHz; CDCl3): 2.77 (dd, J = 8.6, 15.8 Hz, 1H),
3.01 (dd, J = 6.6, 15.8 Hz, 1H), 3.93–3.97 (m, 1H), 5.94 (d, J =
5.1 Hz, 1H), 7.23–7.38 (m, 8H), 7.64–7.65 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ 36.9, 37.1, 104.3, 124.7, 127.0, 127.6, 128.6,
129.1, 129.3, 132.2, 141.5, 150.9, 171.2. HRMS (ES+): Exact mass
calc for C17H14NaO2 [M + Na]+: 273.0891 Found: 273.0891.
X-ray crystallographic study
The crystal data for the compound 4n was collected on a
Bruker SMART APEX CCD Diffractometer. We used SMART
software package (version 5.628) for collecting data frames,
SAINT software package (version 6.45) for integration of the
intensity and scaling and SADABS for absorption correction.
The structure was determined and refined by full-matrix least-
squares on F2 using SHELXTL software package.14 Non-hydro-
gen atoms were refined with anisotropic displacement para-
meters. Fig. 3 and their bonding parameters were obtained
from the DIAMOND 3.1f software package.15 The program
package ORTEP was utilized for molecular graphics generation
in Fig. 3. The absolute configuration of compound 4n is (S).
Acknowledgements
V. K. S. thanks the Department of Science and Technology
(DST), Government of India for a J. C. Bose fellowship. S. R.
and S. K. R. thank the Council of Scientific and Industrial
Research (CSIR) for SRF. We are thankful to Dr Vishnumaya
Bisai (IISER Bhopal) for useful discussions during manuscript
preparation and Mr Chandrajeet Mohapatra (IIT Kanpur) for
help with the X-ray crystallographic study.
Notes and references
1 K. Narasaki, K. Soai and T. Mukaiyama, Chem. Lett., 1974,
1223.
7 A. R. Katritzky and J. M. Lagowski, in Chemistry of the
Heterocyclic N-oxides, Academic Press, 1971.
2 (a) D. A. Oare and C. A. Heathcock, in Topics in Stereo-
chemistry, ed. E. L. Eliel and S. H. Wilen, Wiley, New York,
1989, vol. 19, pp. 227–407; (b) D. A. Oare and
C. A. Heathcock, in Topics in Stereochemistry, ed. E. L. Eliel
and S. H. Wilen, Wiley, New York, 1991, vol. 20, pp.
124–170.
3 (a) S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J.
Am. Chem. Soc., 2003, 125, 1192; (b) F.-Y. Zhang and
E. J. Corey, Org. Lett., 2001, 3, 639; (c) J. Robichaud and
F. Tremblay, Org. Lett., 2006, 8, 597; (d) W. Wang, H. Li and
J. Wang, Org. Lett., 2005, 7, 1637; (e) E. K. Kempainen,
G. Sahoo, A. Valkonen and P. M. Pihko, Org. Lett., 2012, 14,
1086.
8 (a) A. Livieri, M. Boiocchi, G. Desimoni and G. Faita,
Chem.–Eur. J., 2012, 18, 11662; (b) A. Livieri, M. Boiocchi,
G. Desimoni and G. Faita, Chem.–Eur. J., 2011, 17, 516.
9 (a) P. K. Singh and V. K. Singh, Pure Appl. Chem., 2012, 84,
1651; (b) P. K. Singh and V. K. Singh, Pure Appl. Chem.,
2010, 82, 1845; (c) A. Bisai and V. K. Singh, Tetrahedron,
2012, 68, 3480; (d) A. Bisai and V. K. Singh, Org. Lett., 2006,
8, 2405; (e) S. K. Ginotra and V. K. Singh, Org. Biomol.
Chem., 2006, 4, 4370; (f) S. K. Ginotra and V. K. Singh,
Tetrahedron, 2006, 62, 3573; (g) G. Sekar, A. DattaGupta and
V. K. Singh, J. Org. Chem., 1998, 63, 2961; (h) A. DattaGupta
and V. K. Singh, Tetrahedron Lett., 1996, 37, 2633;
(i) A. DattaGupta, D. Bhuniya and V. K. Singh, Tetrahedron,
1994, 50, 13725.
4 (a) A. Bernardi, G. Colombo and C. Scolastico, Tetrahedron
Lett., 1996, 37, 8921; (b) H. Kitajima, K. Ito and T. Katsuki, 10 (a) H. Lim, J. W. Nam, E.-K. Seo, Y. S. Kim and H. P. Kim,
Tetrahedron, 1997, 53, 17015; (c) A. Bernardi,
Arch. Pharmacal Res., 2009, 32, 1509; (b) H. A. Oketch-
K. Karamfilova, S. Sanguinetti and C. Scolastico,
Rabah, S. F. Dossaji, S. B. Christensen, K. Frydenvang,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
E. Lemmich, C. Cornett, C. E. Olsen, M. Chen, A. Kharazmi 11 F. Nanteuil and J. Waser, Angew. Chem., Int. Ed., 2011, 50,
and T. Theander, J. Nat. Prod., 1997, 60, 1017; (c) Y. Hirose, 12075.
N. Oishi, H. Nagaki and T. Nakatsuka, Tetrahedron Lett., 12 L. G-Qiang, D. L-Xin and Y. S-Li, Org. Lett., 2009, 11, 1623.
1965, 6, 3665; (d) K. Graikou, N. Aligiannis, I. Chinou, 13 C. H. Heathcock, S. K. Davidsen, K. T. Hug and
A. Skaltsounis, F. Tillequinand and M. Litaudon, Helv.
Chim. Acta, 2005, 88, 2654; (e) O. Muraoka, B-Z. Zheng, 14 G. M. Sheldrick, SHELXTL version 6.14, Bruker AXS Inc.,
N. Fujiwara and G. Tanabe, J. Chem. Soc., Perkin Trans. 1, Madison, WI, 2003.
1995, 405; (f) E.-A. Bae, E.-K. Park, H.-J. Yang, N.-I. Baek 15 DIAMOND version 3.1f, Crystal Impact GbR, Bonn,
L. A. Flippin, J. Org. Chem., 1986, 51, 3027.
and D.-H. Kim, Planta Med., 2006, 72, 1328.
Germany, 2004.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.