Enantioselective synthesis of coumarin derivatives by PYBOX-DIPH-Zn(II) complex catalyzed Michael reaction

Article abstract of DOI:10.1021/jo301513x

A potential pharmacologically active chiral 3-substituted 4-hydroxy-2-oxo-2H-chromene skeleton has been synthesized by enantioselective Michael addition catalyzed by PYBOX-DIPH-Zn(OTf)₂ complex. The methodology has successfully been employed in

Full text of DOI:10.1021/jo301513x

Note
pubs.acs.org/joc
Enantioselective Synthesis of Coumarin Derivatives by
PYBOX-DIPH-Zn(II) Complex Catalyzed Michael Reaction
Sumit K. Ray,† Pradeep K. Singh,† Nagaraju Molleti,‡ and Vinod K. Singh*,†,‡
†Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208 016, India
‡Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh, 460 023, India
S
* Supporting Information
ABSTRACT: A potential pharmacologically active chiral 3-substituted 4-hydroxy-2-oxo-2H-chromene skeleton has been
synthesized by enantioselective Michael addition catalyzed by PYBOX-DIPH-Zn(OTf)2 complex. The methodology has
successfully been employed in the synthesis of (R)-Warfarin and another related compounds.
oumarin derivatives are an important class of compounds
having a broad range of biological activities such as
C
antibiotic, antifungal, antipsoriasis, cytotoxic, anti-HIV, antico-
agulant and anti-inflammatory activity.1 Currently, most of the
drugs containing coumarin derivatives are administered in the
form of racemate. Since the activity metabolism and pharmaco-
logical effects of the two enantiomers are different, the devel-
opment of efficient enantioselective methods for the synthesis of
enantioenriched coumarin derivatives is of utmost importance.
Several new asymmetric synthetic routes to coumarin derivatives
has been reported in literature.2,3 Among them, the Michael
reaction of 4-hydroxycoumarin to α,β-unsaturated carbonyls is of
great interest because the products obtained are direct precursors
to various other biological active compounds like warfarin,
acenocoumarol, etc.3
Figure 1. Bisoxazoline ligands used in enantioselective Michael reaction.
To our delight, the corresponding Michael product 4a was iso-
lated in 97% yield and 83% ee (Table 1, entry 1). The Michael
addition product 4a was found to exist in rapid equilibrium with
the two diastereomeric forms of the hemiketal 4a′ in solution.3f
The equilibrium is very rapid, and therefore no diastereomers
were observed during HPLC analysis using the mixture of
hexane/2-propanol containing 0.1% TFA as the eluent. However,
it gave highly complicated and concentration-dependent
NMR spectra. Having this encouraging result in hand, various
bisoxazoline ligands (1a−1g) were screened, and results are sum-
marized in Table 1. Among various pybox-diph ligands (1a−1d)
used, ip-pybox-diph (1a) gave the best results. Poor enantio-
selectivities and lower reaction rate with ip-pybox 1e (entry 5)
and cis-1-amino-2-indanol derived pybox 1f (entry 6) clearly
indicate the beneficial effect of gem-diphenyl groups at C5
of oxazoline rings.7 Surprisingly, the bidentatebisoxazoline 1g,
which was used by us in Michael reaction of dialkylmalonate to
Recently, 2-enoylpyridine N-oxide has been proved to be an
excellent prochiral template for various enantioselective
reactions.4 In this direction, we have reported enantioselective
conjugate addition of indoles, pyrroles and dialkylmalonates with
these substrates and achieved excellent yields and enantiose-
lectivities.5 The attractive features associated with 2-enoylpyridin
N-oxide as Michael acceptor are higher reactivity and
enantioselectivity, easy cleavage of pyridine N-oxide ring of
product and characteristic chemistry of pyridine N-oxide ring
to perform several transformations.6 This led us to evaluate
2-enoylpyridine N-oxides in other asymmetric transformation like
enantioselective Michael reaction of cyclic 1,3-dicarbonyl com-
pounds. In this paper, we wish to report the Michael addition of
cyclic 1,3-dicarbonyl compounds to 2-enoylpyridine N-oxide
catalyzed by bisoxazoline-Zn(OTf)2 complexes (Figure 1).
From our earlier studies, ip-pybox-diph (1a)−Zn (OTf)2
complex was found to be an excellent catalyst;7 initial studies
were conducted between 4-hydroxycoumarin (2a) and ben-
zylidene-2-acetylpyridine-N-oxide (3a) in the presence of 5 mol %
of catalyst (1a)−Zn(OTf)2 complex and 10 mol % triethylamine.
Received: July 30, 2012
Published: September 7, 2012
© 2012 American Chemical Society
8802
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808

The Journal of Organic Chemistry
Note
a
Table 1. Enantioselective Michael Reaction of 4-Hydroxycoumarin Catalyzed by Various Bisoxazoline−Zn(OTf)2 Complexes
b
c
entry
ligand
catalyst loading (mol %)
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
5
5
2
2
97
95
87
86
90
92
90
96
96
83
80
15
29
7
5
2
5
5
5
20
6
5
15
0
1g
1a
1a
1a
5
6
10
2
2
80
79
60
3
d
10
5
15
90
a
b
c
All reactions were run on a 0.2 mmol scale in 1.0 mL of dichloromethane, 10 mol % Et3N. Isolated yield. Determined by chiral HPLC using
d
Chiralcel OD-H column. Reaction was carried at −5 °C.
a
Table 2. Effect of Lewis Acids and Solvents
b
c
entry
Lewis acid
Zn(OTf)2
solvent
time (h)
yield (%)
ee (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
2
5
97
92
95
82
86
84
96
94
95
91
90
83
68
65
5
2
Cu(OTf)2
Cu(OTf)2·PhCH3
Sc(OTf)3
3
3
4
9
5
Yb(OTf)3
In(OTf)3
6
3
6
6
11
75
74
81
53
72
7
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
2
8
THF
2
9
(CH2Cl)2
toluene
CH3CN
2
10
11
12
15
a
b
c
All reactions were run on a 0.2 mmol scale in 1.0 mL of solvent, 5 mol % catalyst, 10 mol % Et3N. Isolated yield. Determined by chiral HPLC
using Chiralcel OD-H column.
2-enoylpyridine N-oxide, yielded racemic product with 4-
hydroxycoumarin (Table 1, entry 7).5c
Under optimized condition, we further looked forward for
substrates scope. A series of cyclic 1.3-dicarbonyl compounds
(2a−2f) were used as nucleophile in the Michael reaction with
benzylidene-2-acetylpyridine-N-oxide (Table 4, entries 1−6).
We observed that this catalytic protocol works well with signi-
ficant structural variations, and thus a variety of 4-hydroxycou-
marin derivatives (2a−2c) as well as other analogues such as
4-hydroxy-1-methyl-2(1H)-quinolone (2d), 4-hydroxy-2H-thio-
chromen-2-one (2e) and 4-hydroxy-6-methyl-2H-pyranone (2f)
furnished the corresponding products (4d−4f) in good yields
and high level of enantioselectivities. Next, the effect of sub-
stitutions on electrophile was studied (Table 4, entries 7−16). The
reaction proceeded smoothly with aromatic, heteroaromatic and
aliphatic substrates as well. A substrate having ester group at
β-position (3j) worked well, leading to a highly functionalized
coumarin derivative (4o) (Table 4, entry 15).
Studies investigating the effect of catalyst loading and
temperature showed that 5 mol % catalyst loading and room
temperature is the best combination for this reaction (Table 1,
entries 1 and 8−10). Among various Lewis acids and solvents
screened, Zn(OTf)2 gave the best results when the reaction was
conducted in dichloromethane (Table 2). Next, we investigated
the effect of various basic additives in the reaction (Table 3).
A control experiment (Table 3, entry 1) showed that the basic
additive enhanced the rate as well as enantioselectivity of the
product. The bulky Hunig’s base improved the enantioselectivity
̈
to 86% (Table 3, entry 3). Interestingly, use of DBU further
improved the rate as well as enantioselectivity of the reaction
(88% ee, Table 3, entry 4). Other bases afforded products in the
range of 67−82% ee with high yields (Table 3, entries 5−10).
8803
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808

The Journal of Organic Chemistry
Note
a
Table 3. Effect of Base Additives
b
c
entry
base
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
12
2
90
97
96
99
96
80
95
90
94
95
74
83
86
88
80
79
81
73
82
Et3N
iPr2NEt
2
DBU
1.5
4
NMM
K2CO3
1-Me-Im
pyridine
DMAP
DBN
6
2
2
3
2
67
a
b
All reactions were run on a 0.2 mmol scale in 1.0 mL of dichoromethane, 5 mol % catalyst 1a−Zn(OTf)2, 10 mol % base. Isolated yield.
c
Determined by chiral HPLC using Chiralcel OD-H column.
a
Table 4. Substrates Scope of Enantioselective Michael Addition
b
c
entry
2
R
4
time (h)
yield (%)
ee (%)
f
1
2a
2b
2c
2d
2e
2f
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
4a
4b
4c
4d
4e
4f
2
2
99 (70)
97 (65)
93 (63)
93
88 (97)
f
2
85 (98)
g
g
3
2
80 (96)
97
4
2
5
4
87 (55)
90
70 (81)
96
6
1.5
3
f
7
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2-NO2C6H4 (3b)
3-NO2C6H4 (3c)
4-NO2C6H4 (3d)
3-ClC6H4 (3e)
4-MeOC6H4 (3f)
1-naphthyl (3g)
2-furyl (3h)
4g
4h
4i
95 (63)
96 (70)
98 (62)
98 (45)
87 (55)
95 (60)
99 (45)
85 (74)
80 (66)
91 (96)
89 (96)
g
8
1
f
9
1
89 (>99)
f
10
11
12
13
14
15
16
4j
2
88 (>99.9)
g
4k
4l
3
67 (75)
f
9
53 (84)
g
4m
4n
4o
5
78 (96)
g
(E)-PhCHCH (3i)
2
69 (87)
g
COOEt (3j)
tBu (3k)
7
79 (83)
d
e
72
nr
nd
a
b
All reactions were run on a 0.2 mmol scale in 1.0 mL of dichloromethane, 5 mol % catalyst 1a−Zn(OTf)2, 10 mol % DBU. Isolated yield.
c
d
e
f
Determined by chiral HPLC; yield and ee in parentheses is ee after ethyl acetate treatment. nr = no reaction. nd = not determined. ee of collected
g
solid after washing with ethyl acetate. ee of filtrate after washing with ethyl acetate.
As the products were solid, washing the products with ethyl
acetate improved the enantioselectivities to excellent level (up to
>99.9%). It was observed that in some cases (4a, 4b, 4g, 4i, 4j, 4l),
collected solids show higher enantioselectivities; however, in another
set of products (4c, 4e, 4h, 4k, 4m, 4n, 4o) the filtrate exhibited
higher ee values. This is predominantly due to the self-purification of
enantioenriched compounds through the self-disproportionation of
enantiomers, which is well documented in the literature.8
Single crystal X-ray analysis of compound 4j (see the Supporting
Information; CCDC 888974 also contains the supplementary
8804
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808

The Journal of Organic Chemistry
Note
crystallographic data), which was crystallized from enantiopure
compound, established the absolute configuration of Michael
product to be (R). To rationalize the observed absolute con-
figuration of the Michael reaction, a plausible transition state
model has been proposed.7a The coordination of 2-enoylpyr-
idine-N-oxide (2a) to 1a−Zn(II) complex led to two transition
states TS1 and TS2 as shown in Figure 2. Among two transition
pharmaceutical activities, in 90% yields without losing the
enantiopurity.9
In conclusion, we have developed an enantioselective route to
access optically active hydroxycoumarin derivatives in excellent
enantioselectivities via asymmetric Michael reaction. The present
catalytic methodology can tolerate a significant structural varia-
tion in cyclic 1,3-dicarbonyl compounds. The stereochemistry of
the chiral product has been unambiguously confirmed by single
X-ray crystallography. We have synthesized various biologically
active compounds such as Warfarin 8 and enol lactone 7 from the
Michael product illustrating the importance of the method.
Furthermore, a transition state model has been proposed to
explain the stereochemical outcome of the reaction.
EXPERIMENTAL SECTION
■
General Remarks. Reagents were used as supplied. NMR spectra
1
were determined at 500 MHz for H and 125 MHz for 13C in CDCl3
solvent. IR spectra were recorded with an FT-IR spectrometer. HRMS
were performed on TOF MS ES+ mass instrument.
Procedure for the Synthesis of (E)-2-(4-Ethoxy-4-oxobut-2-
enoyl)pyridine-N-oxide (3j). Ethyl glyoxalate solution (50% in
toluene), (1.6 mL, 8 mmol) was added dropwise to a solution of
2-acetylpyridine-N-oxide (0.915 g, 6.7 mmol) and pyrolidine (110 μL,
1.34 mmol) in dichloromethane (50 mL) at rt and stirred for 4 days. The
mixture was concentrated in vacuo and purified by column chro-
Figure 2. Plausible transition state model for PYBOX-DIPH−Zn(II)
catalyzed enantioselective Michael reaction.
1
matography to give 0.5928 g (40% yield) of product as semisolid: H
states, TS1 will be more reactive because of the trans-influence of
pyridine. In transition state TS2, the reacting center of 2-enoyl-
pyridine-N-oxide 3a is less accessible to nucleophile because
of the steric hindrance of phenyl rings at C5 of oxazoline ring.
Thus, in favored transition state TS1, nucleophile attacks the
2-enoylpyridine-N-oxide from Re face leading to (R)-enantiomer
of the product. Si face attack is hindered by the presence of
isopropyl group at the C4 of the oxazoline ring.
To illustrate the synthetic utility of this method, we have
cleaved the pyridine-N-oxide ring of Michael product 4a in
refluxing 20% aqueous KOH to afford corresponding acid 6 in
40% yield without loss of enantiopurity (Scheme 1). It was found
NMR (500 MHz; CDCl3) δ 1.27−1.31 (m, 3H), 4.21−4.26 (m, 2H),
6.81 (dd, J = 2.0, 15.8 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.41−7.44 (m,
1H), 7.65 (d, J = 7.7 Hz, 1H), 7.86 (dd, J = 2.0, 15.8 Hz, 1H), 8.21 (d, J =
6.6, Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.1, 61.6, 125.4, 125.8,
127.4, 128.7, 130.7, 137.8, 140.4, 165.4, 186.2; HRMS (ES+) calc for
C11H12NO4 [M + H]+ 222.0766, found 222.0764.
General Procedure for Enantioselective Michael Reaction. A
solution of a ligand 1a (7.3 mg, 0.012 mmol) and Zn(OTf)2 (3.6 mg,
0.01 mmol) in dry dichloromethane (1 mL) was stirred at rt for 1 h
under nitrogen atmosphere. trans-2-Enoylpyridine-N-oxide (0.20
mmol) was added, and mixture was stirred for additional 15 min at rt.
Then cyclic 1,3-dicarbonyl compound (0.24 mmol) was added, and the
reaction mixture was stirred at rt until the completion of the reaction
(monitored by TLC). The mixture was concentrated in vacuo and
purified over silica gel by column chromatography (methanol/ethyl
acetate 1:20) to afford the product. It was further purified by washing
with EtOAc (4 mL). Yield in parentheses is after ethyl acetate treatment.
Enantiomeric excess was determined by HPLC analysis on Daicel
Chiralcel OD-H column (4a, 4g, 4i, 4k, 4m) and Daicel Chiralpack
AD-H column (4b, 4c, 4d, 4e, 4f, 4h, 4j, 4l, 4n, 4o) using n-hexane/
2-propanol (contains 0.1% TFA) as eluent.
Scheme 1. Synthetic Applications of Our Methodology
(R)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpro-
panoyl)pyridine-1-oxide (4a). Light yellow solid, 0.0767 g, 99%
yield (0.0542 g, 70% yield): mp 160−162 °C; [α]D25 +19.7 (c 2.4, CHCl3
for 97% ee); HPLC tR(major) = 36.67 min, tR(minor) = 58.18 min;
1H NMR (500 MHz; CDCl3) δ 2.38 (dd, J = 11.6, 13.2, 0.83 H), 2.75 (dd,
J = 7.3, 13.7 Hz, 0.17H), 2.87 (dd, J = 6.5, 13.5 Hz, 0.83 H), 3.04 (dd, J =
2.7, 13.7 Hz, 0.17 H), 4.33 (dd, J = 2.3, 7.2 Hz, 0.17H), 4.43 (dd, J = 6.3,
11.5 Hz, 0.83 H), 7.19−7.63 (m, 11 H), 7.84 (dd, J = 1.5, 6.6 Hz, 0.83 H),
7.92 (d, J = 6.4 Hz, 0.17 H), 8.30 (dd, J = 1.0, 6.6 Hz, 0.17 H), 8.35 (dd,
J = 1.0, 6.4 Hz 0.83 H), 9.42 (s, 0.11 H), 10.25 (s, 0.62 H); 13C NMR
(125 MHz, CDCl3) δ 34.4, 35.3, 37.1, 40.7, 98.6, 98.8, 105.1, 115.8,
116.6, 116.7, 123.1, 123.2, 123.3, 123.7, 123.9, 124.1, 126.3, 126.4,
126.8, 127.1, 127.7, 128.3, 128.5, 128.7, 128.9, 131.9, 132.2, 140.9,
142.7, 147.0, 153.1, 158.3, 160.9; IR (thin film) ν 3403, 1710, 1628,
1573 cm−1; HRMS (ES+) calc for C23H18NO5 [M + H]+ 388.1185,
found 388.1187.
that the poor yield of 6 was due to the formation of the unwanted
decarboxylated product 5. However, compound 5 could be
converted to the desired hydroxycoumarin derivative 6 when
treated with sodium hydride and diethyl carbonate (DEC). The
acid 6 was then converted into (R)-Warfarin 8 in 97% ee, which
is a potent anticoagulant. The lactonization of 6 with acetic an-
hydride afforded enol lactone 7, an important functionalized
substructure, which shows a variety of interesting biological and
(R)-2-(3-(4-Hydroxy-6-nitro-2-oxo-2H-chromen-3-yl)-3-
phenylpropanoyl)pyridine-1-oxide (4b). Light yellow solid, 0.0839
g, 97% yield (0.0562 g, 65% yield): mp 153−155 °C; [α]D25 +15.2 (c
2.0, CHCl3 for 98% ee); HPLC tR(major) = 15.98 min, tR(minor) =
35.30 min; 1H NMR (500 MHz; CDCl3) δ 2.39−2.44 (m, 0.83H), 2.76
8805
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808

The Journal of Organic Chemistry
Note
(dd, J = 7.5, 13.8 Hz, 0.17H), 2.86 (dd, J = 6.6, 13.2 Hz, 0.83H), 3.02 (dd,
J = 2.3, 13.8 Hz, 0.17H), 4.32 (d, J = 5.2 Hz, 0.17H), 4.42 (dd, J = 6.6,
11.5 Hz, 0.83H), 5.70 (s, 0.17H), 7.15−7.54 (m, 10H), 7.60 (dd, J = 2.0,
8.0 Hz, 0.83H), 7.64 (dd, J = 1.7, 8.0 Hz, 0.17H), 8.34 (d, J = 5.7 Hz,
0.83H), 8.29 (d, J = 6.6 Hz, 0.17H), 9.25 (s, 0.16H), 10.25 (s, 0.4H); 13C
NMR (125 MHz, CDCl3) δ 34.3, 35.5, 37.7, 40.7, 92.2, 98.6, 98.8, 103.0,
105.0, 115.4, 115.7, 116.2, 116.5, 116.7, 123.0, 123.1, 123.3, 123.5, 123.7,
123.8, 123.9, 124.1, 126.3, 126.4, 126.8, 127.1, 127.7, 128.2, 128.8, 128.9,
131.9, 132.1, 132.3, 140.8, 141.9, 146.9, 147.4, 152.9, 153.0, 154.0, 158.4,
158.8, 161.0, 162.0, 164.0, 166.0; IR (thin film) ν 3396, 1710, 1628,
1582 cm−1; HRMS (ES+) calc for C23H17N2O7 [M + H]+ 433.1036,
found 433.1033.
(R)-2-(3-(4-Hydroxy-6-methyl-2-oxo-2H-chromen-3-yl)-3-
phenylpropanoyl)pyridine-1-oxide (4c). White solid, 0.0747 g,
93% yield (0.0506 g, 63% yield): mp 168−169 °C; [α]D25 −4.0 (c 0.8,
CHCl3 for 96% ee); HPLC tR(major) = 11.69 min, tR(minor) = 22.54
min; 1H NMR (500 MHz; CDCl3) δ 2.39 (s, 2.49H), 2.41 (s, 0.51H),
2.43 (m, 0.83 H), 2.75 (dd, J = 7.4, 13.5 Hz, 0.13H), 2.86 (dd, J = 6.4,
13.1 Hz, 0.83H), 3.02(dd, J = 3.4, 14.4 Hz, 0.17H), 4.30 (dd, J = 3.0,
7.5 Hz, 0.17H), 4.42 (dd, J = 6.4, 11.3 Hz, 0.83H), 7.18−7.68 (m, 11H),
8.30 (d, J = 7.3 Hz, 0.17H), 8.34 (d, J = 6.4 Hz, 0.83H), 9.27 (s, 0.15H),
10.24 (s, 0.74H); 13C NMR (125 MHz, CDCl3) δ 32.4, 34.4, 35.4, 37.2,
40.8, 98.5, 104.9, 115.3, 116.4, 122.5, 123.7, 126.4, 126.7, 127.1, 127.6,
128.2, 128.7, 128.8, 132.9, 133.6, 140.8, 142.7, 147.0, 151.2, 158.4,
161.1; IR (thin film) ν 3396, 1710, 1628, 1582 cm−1; HRMS (ES+) calc
for C24H20NO5 [M + H]+ 402.1341, found 402.1346.
(R)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-(2-nitrophenyl)-
propanoyl)pyridine-1-oxide (4g). Light yellow solid, 0.0821 g, 95%
yield (0.0544 g, 63% yield): mp 178−180 °C; [α]D = −62.1 (c 0.3,
25
CHCl3 for 96% ee); HPLC tR(major) = 28.28 min, tR(minor) = 70.64
min; 1H NMR (500 MHz; CDCl3) δ = 2.35 (bs, 0.48 H), 2.90 (dd, J =
8.1, 14.4 Hz, 0.52 H), 3.03 (d, J = 14.4 Hz, 0.53 H), 3.32 (bs, 0.47 H),
5.00 (d, J = 8.1 Hz, 0.18 H), 5.06 (bs, 0.52 H), 7.21−7.69 (m, 9 H), 7.84
(d, J = 7.8 Hz, 0.52 H), 7.90−7.94 (m, 1 H), 8.07 (d, J = 8.3 Hz, 0.4 8 H),
8.32 (d, J = 6.6 Hz, 0.48 H), 8.39 (d, J = 6.4 Hz, 0.52 H), 10.08 (s, 0.41
H), 10.40 (s, 0.48 H); 13C NMR (125 MHz, CDCl3) δ 31.2, 35.9, 99.2,
102.4, 116.6, 116.8, 123.1, 123.3, 123.4, 123.6, 124.0, 124.2, 124.9, 125.3,
126.4, 126.5, 127.7, 128.8, 131.7, 132.1, 132.4, 132.9, 133.2, 137.5, 140.9,
141.0, 146.8, 153.0, 159.4, 161.7; IR (thin film) ν 3390,1708, 1628,
1576, cm−1; HRMS (ES+) calc for C23H17N2O7 [M + H]+ 433.1036,
found 433.1030.
(R)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-(3-nitrophenyl)-
propanoyl)pyridine-1-oxide (4h). White solid 0.0830 g, 96% yield
(0.0605 g, 70% yield): mp 167−170 °C; [α]D25 −36.4 (c 0.3, CHCl3 for
1
96% ee); HPLC tR(major) = 24.19 min, tR(minor) = 35.75; H NMR
(500 MHz; CDCl3) δ 2.37 (t, J = 12.5 Hz, 0.70 H), 2.78 (dd, J = 8.9,
13.8 Hz, 0.30 H), 2.90 (dd, J = 6.4, 13.1 Hz, 0.70 H), 3.01 (d, J = 13.5 Hz,
0.30 H), 4.42 (d, J = 7.0 Hz, 0.30 H), 4.54 (dd, J = 6.2, 11.7 Hz, 0.70 H),
7.25−7.68 (m, 8 H), 7.85 (d, J = 7.7 Hz, 0.70 H), 7.89 (d, J = 8.0 Hz, 0.30
H), 8.03−8.08 (m, 1.7 H), 8.20 (bs, 0.30 H), 8.30 (d, J = 6.1 Hz 0.30 H),
8.36 (d, J = 6.1 Hz 0.70 H), 9.75 (s, 0.23 H), 10.37 (s, 0.56 H); 13C NMR
(125 MHz, CDCl3) δ 34.1, 35.4, 36.5, 40.2, 98.5, 98.9, 101.5, 103.6,
115.3, 115.5, 116.7, 116.8, 121.6, 121.8, 122.0, 123.2, 123.3, 123.3, 123.4,
123.7, 124.2, 124.3, 126.5, 126.6, 128.9, 129.0, 129.7, 132.3, 132.6,
134.2, 134.4, 140.9, 144.4, 145.0, 146.5, 146.7, 148.2, 148.6, 153.0,
159.1, 159.4, 160.9, 162.1; IR (thin film) ν 3405, 1708, 1626,
1573 cm−1; HRMS (ES+) calc for C23H17N2O7 [M + H]+ 433.1036,
found 433.1035.
(R)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-(4-nitrophenyl)-
propanoyl)pyridine-1-oxide (4i). White solid 0.0847 g, 98% yield
(0.0536 g, 62%): mp 193−195 °C; [α]D25 −69.2 (c 0.7, CHCl31for >99%
ee); HPLC tR(major) = 27.46 min, tR(minor) = 51.75 min; H NMR
(500 MHz; CDCl3) δ 2.30−2.35 (m, 0.7 H), 2.76 (dd, J = 7.6, 13.7 Hz,
0.70 H), 2.89 (dd, J = 6.4, 13.2 Hz, 0.70 H), 3.05 (d, J = 13.7 Hz, 0.30 H),
4.42 (d, J = 7.1 Hz, 0.30 H), 4.56 (dd, J = 6.4, 12.0 Hz, 0.70 H), 7.26−
7.66 (m, 8 H), 7.85 (d, J = 7.8 Hz, 0.70 H), 7.91 (d, J = 7.8 Hz, 0.30 H),
8.14 (d, J = 8.8 Hz, 0.6 H), 8.18 (d, J = 8.8 Hz, 1.4 H), 8.31 (d, J = 6.4 Hz
0.30 H), 8.37 (d, J = 6.6 Hz, 0.70 H), 9.64 (s, 0.24 H), 10.36 (s, 0.53 H);
13C NMR (125 MHz, CDCl3) δ 34.2, 35.6, 36.6, 40.2, 98.4, 98.7, 103.7,
(R)-2-(3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-
yl)-3-phenylpropanoyl)pyridine-1-oxide (4d). White solid,
25
0.0745 g, 93% yield: mp 184−185 °C; [α]D −3.7 (c 0.4, CHCl3 for
1
97% ee); HPLC tR(major) = 17.90 min, tR(minor) = 45.66 min; H
NMR (500 MHz; CDCl3) δ 2.46 (dd, J = 10.9, 13.2 Hz, 0.79H), 2.71
(dd, J = 7.5, 13.8 Hz, 0.21H), 2.89 (dd, J = 6.9, 13.5 Hz, 0.79H), 3.04 (dd,
J = 3.2, 13.7 Hz, 0.21H), 3.61 (s, 2.4H), 3.70 (s, 0.60H), 4.38 (dd, J = 2.9,
7.2 Hz, 0.21H), 4.48 (dd, J = 6.7, 10.9 Hz, 0.79H), 7.15−7.65 (m, 11H),
8.04 (dd, J = 1.4, 8.0 Hz, 0.79H), 8.12 (d, J = 8.0 Hz, 0.21H), 8.27−8.30
(m, 1H), 8.98 (s, 0.23H), 9.73 (s, 0.73H); 13C NMR (125 MHz;
CDCl3) δ 29.4, 29.5, 35.0, 36.1, 37.6, 40.9, 97.6, 97.9, 110.4, 113.9, 114.0,
116.1, 121.7, 121.9, 123.2, 123.7, 125.8, 126.0, 126.3, 127.0, 127.7, 128.1,
128.3, 128.6, 130.7, 130.9, 139.4, 140.6, 144.2, 148.0, 154.7, 161.8; IR
(thin film) ν 3397, 1636, 1595 cm−1; HRMS (ES+) calc for C24H21N2O4
[M + H]+ 401.1501, found 401.1507.
(R)-2-(3-(4-Hydroxy-2-oxo-2H-thiochromen-3-yl)-3-phenyl-
propanoyl)pyridine-1-oxide (4e). White solid, 0.0702 g, 87% yield
(0.0444 g, 55% yield): mp 176−178 °C; [α]D25 + 4.9 (c 1.6, CHCl3 for
115.4, 116.7, 123.1, 123.2, 123.5, 123.6, 124.2, 124.3, 124.4, 126.5, 126.6,
128.1, 128.8, 132.4, 132.6, 140.9, 146.5, 146.8, 150.7, 153.1, 159.0,
160.9; IR (thin film) ν 3423, 1709, 1627 cm−1; HRMS (ES+) calc for
C23H17N2O7 [M + H]+ 433.1036, found 433.1035.
1
81% ee); HPLC tR(major) = 16.16 min, tR(minor) = 24.01 min; H
NMR (500 MHz; CDCl3) δ 2.42−2.49 (m, 0.80H), 2.72−2.75 (m, 0.20
H), 2.86 (dd, J = 7.1, 13.2 Hz, 0.79H), 3.02 (dd, J = 2.8, 13.5 Hz, 0.21H),
4.53 (dd, J = 6.7, 11.3 Hz, 1H), 7.16−7.63 (m, 11H), 8.18 (d, J = 8.2 Hz,
0.79H), 8.27 (d, J = 8.2 Hz, 0.21H), 8.30 (d, J = 6.4 Hz, 0.21H), 8.35 (d,
J = 6.4 Hz, 0.79H), 9.23 (s, 0.12H), 9.98 (s, 0.51H); 13C NMR (125
MHz; CDCl3) δ 34.7, 36.4, 40.6, 97.9, 116.3, 123.6, 123.8, 125.3,
126.1, 126.2, 126.5, 126.9, 127.6, 128.1, 128.5, 128.7, 129.9, 136.0,
140.8, 143.8, 147.3, 158.6, 182.8; IR (thin film) ν 3397, 1710, 1594,
1549 cm−1; HRMS (ES+) calc for C23H18NO4S [M + H]+ 404.0957,
found 404.0952.
(R)-2-(3-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-3-phenyl-
propanoyl)pyridine-1-oxide (4f). Semisolid, 0.0632 g, 90% yield:
[α]D25 + 29.3 (c 2.8, CHCl3 for 96% ee); HPLC tR(major) = 9.37 min,
tR(minor) = 13.12 min; 1H NMR (500 MHz; CDCl3) δ 2.18 (s, 0.27H),
2.20 (s, 2.40H), 2.25 (s, 0.33H), 2.29 (d, J = 11.8 Hz, 0.83H), 2.64 (dd,
J = 7.4, 13.7 Hz, 0.17H), 2.75 (dd, J = 6.3, 13.1 Hz, 0.83H), 2.93 (dd,
J = 2.9, 13.8 Hz, 0.17H), 4.15 (m, 0.17H), 4.26 (dd, J = 6.3, 11.5 Hz,
0.83H), 5.75 (s, 0.12H), 5.89 (s, 0.77H), 5.97(s, 0.16H), 7.18−7.55
(m, 8H), 8.24 (d, J = 6.6 Hz, 0.17H), 8.28 (d, J = 6.3 Hz, 0.83H), 9.09 (s,
0.14H), 10.09 (s, 0.74H); 13C NMR (125 MHz; CDCl3) δ 19.9,
33.6, 34.7, 37.1, 40.6, 98.2, 100.3, 100.4, 101.8, 123.2, 123.6, 126.1,
126.2, 126.3, 126.7, 127.1, 127.6, 128.2, 128.5, 128.7, 140.7, 142.6,
146.9, 161.6, 162.8, 163.2; IR (thin film) ν 3419, 1691, 1579 cm−1;
HRMS (ES+) calc for C20H18NO5 [M + H]+ 352.1185, found
352.1185.
(R)-2-(3-(3-Chlorophenyl)-3-(4-hydroxy-2-oxo-2H-chromen-
3-yl)propanoyl)pyridine-1-oxide (4j). White solid, 0.0827 g, 98%
25
yield (0.0380 g, 45% yield): mp 165−167 °C; [α]D −13.9 (c 0.3,
CHCl3 for >99.9% ee); HPLC tR(major) = 11.56 min, tR(minor) =18.24
min; 1H NMR (500 MHz; CDCl3) δ 2.31−2.39 (m, 0.78 H), 2.72 (dd,
J = 7.4, 13.5 Hz, 0.22 H), 2.86 (dd, J = 6.4, 13.5 Hz, 0.78 H), 3.00 (d, J =
15.8 Hz, 0.22 H), 4.31 (d, J = 5.5 Hz, 0.22 H), 4.41 (dd, J = 6.4, 11.6 Hz,
0.78 H), 7.17−7.63 (m, 10 H), 7.84 (dd, J = 1.6, 8.0 Hz, 0.78 H), 7.90 (d,
J = 8.0 Hz, 0.22 H), 8.07 (d, J = 7.1 Hz, 0.22 H), 8.32 (d, J = 5.5 Hz,
0.22 H), 8.36 (d, J = 5.8 Hz, 0.58 H), 9.44 (s, 0.22 H), 10.23 (s, 0.52 H);
13C NMR (125 MHz, CDCl3) δ 34.1, 35.3, 36.8, 40.5, 42.1, 98.6, 104.3,
115.6, 116.7, 116.8, 123.1, 123.2, 123.6, 124.0, 124.2, 125.7, 126.1, 126.3,
126.5, 126.7, 127.1, 128.1, 128.5, 128.6, 128.8, 129.4, 130.1, 132.1, 132.3,
134.5, 140.9, 144.8, 146.7, 153.1, 158.6, 160.8; IR (thin film) ν 3397,
1708, 1626, 1573 cm−1; HRMS (ES+) calc for C23H17ClNO5 [M + H]+
422.0795, found 422.0797.
(R)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-(4-methoxy-
phenyl)propanoyl)pyridine-1-oxide (4k). Light yellow solid,
25
0.0726 g, 87% yield (0.0459 g, 55% yield): mp 160−161 °C; [α]D
+
12.4 (c 0.6, CHCl3 for 75% ee); HPLC tR(major) = 23.49 min,
1
tR(minor) = 42.30 min; H NMR (500 MHz; CDCl3) δ 2.37−2.42
(m, 0.82 H), 2.73 (dd, J = 7.7, 14.0 Hz, 0.18 H), 2.84 (dd, J = 6.8,
13.5 Hz, 0.82 H), 2.97(dd, J = 2.5, 13.8 Hz, 0.18 H), 3.75 (s, 0.54 H),
8806
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808

The Journal of Organic Chemistry
Note
3.76 (s, 2.46 H), 4.28 (d, J = 7.7 Hz, 0.18 H), 4.38 (dd, J = 6.4, 11.6 Hz,
0.82 H), 6.80−6.84 (m, 2H), 7.12−7.64 (m, 8H), 7.83(d, J = 7.9 Hz,
0.82H), 7.90(d, J = 7.9 Hz, 0.18H), 8.30 (d, J = 5.8 Hz, 0.18H), 8.34(d,
J = 5.8 Hz, 0.82H), 9.31(s, 0.17H), 10.23(s, 0.68H); 13C NMR (125
MHz, CDCl3) δ 33.6, 34.6, 37.1, 40.8, 55.2, 55.3, 98.6, 98.8, 105.2, 113.7,
114.2, 115.7, 116.5, 116.7, 123.0, 123.1, 123.2, 123.7, 123.9, 124.1, 126.3,
126.4, 128.1, 128.7, 128.8, 131.8, 132.1, 134.6, 140.8, 146.9, 153.0, 158.2,
158.3, 160.9; IR (thin film) ν 3416, 1711, 1625, 1573 cm−1; HRMS
(ES+) calc for C24H20NO6 [M + H]+ 418.1291, found 418.1297.
(R)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-(naphthalen-
1-yl)propanoyl)pyridine-1-oxide (4l). Light yellow solid, 0.0831 g,
95% yield (0.525 g, 60% yield): mp 160−162 °C; [α]D25 + 117.1 (c 1.5,
CHCl3 for 84% ee); HPLC tR(major) = 36.18 min. tR(minor) = 28.01
1633, 1611, 1576 cm−1; HRMS (ES+) calc for C20H18NO7 [M + H]+
384.1083, found 384.1087.
Cleavage of Pyridine N-Oxide Ring (Scheme 1). 4a (387.4 mg, 1
mmol) was suspended in 5 mL of 20% aqueous KOH, and mixture was
refluxed for 1 h. The reaction mixture was acidified with concentrated
HCl at 0 °C and extracted with EtOAc. The organic layer was con-
centrated in vacuo and purified column chromatography to afford the
product 5 and 6.
25
Data for 5. Semisolid, 0.0852 g, 30% yield: [α]D = +15.5 (c 3.5,
1
acetone); H NMR (500 MHz; CDCl3) δ 2.71−2.75 (m, 1H), 2.82−
2.87 (m, 1H), 3.37−3.42 (m, 1H), 3.82−3.88 (m, 1H), 6.85−6.88
(m, 1H), 7.94 (dd, J = 1.0, 8.5 Hz, 1H), 7.19−7.31(m, 5H), 7.43−7.46
(m, 1H), 7.73 (dd, J = 1.5, 8.0 Hz, 1H), 12.12 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 37.1, 40.4, 44.2, 118.7, 119.1, 119.4, 127.2, 127.4, 128.8,
129.9, 136.6, 142.6, 162.5, 177.9, 204.2; IR (thin film) ν = 3030, 1706,
1639, 1614, 1580 cm−1; HRMS (ES+) calc for C17H17O4 [M + H]+
285.1127, found 285.1125.
1
min; H NMR (500 MHz; CDCl3) δ 2.43 (bs, 0.67 H), 2.83−2.86
(m, 0.33 H), 3.03 (bs, 0.68 H), 3.12 (d, J = 13.5 Hz, 0.32 H), 5.04 (d, J =
6.9 Hz, 0.32 H), 5.32 (bs, 0.68 H), 5.58 (s, 0.28 H), 7.19−8.07 (m,
13 H), 8.20 (d, J = 6.3 Hz, 0.64 H), 8.30 (d, J = 5.5 Hz, 1.46 H), 9.29
(s, 0.19 H), 10.48 (s, 0.66 H); 13C NMR (125 MHz, CDCl3) δ 30.7,
34.9, 92.1, 98.8, 98.9, 103.1, 105.4, 115.5, 115.9, 116.1, 116.6, 116.7,
122.6, 122.7, 123.1, 123.2, 123.3, 123.5, 123.7, 124.0, 124.2, 125.1, 125.3,
125.8, 125.9, 126.1, 126.3, 126.4, 126.5, 127.5, 128.9, 129.1, 129.2, 129.5,
130.7, 131.2, 131.9, 132.2, 132.3, 134.2, 134.3, 136.4, 140.8, 146.6, 147.2,
152.9, 153.0, 153.9, 159.2, 161.0, 162.1, 164.1, 166.0; IR (thin film)
ν 3405, 1712, 1627, 1574 cm−1; HRMS (ES+) calc for C27H20NO5
[M + H]+ 438.1341, found 438.1349.
Data for 6. Semisolid, 0.0124 g, 40% yield (overall 0.0171 g, 55%
25
1
yield): [α]D +72.5 (c 1.3, acetone); H NMR (500 MHz; CDCl3) δ
3.20−3.23 (m, 1H), 3.53−3.59 (m, 1H), 4.12 (dd, J = 7.0, 14.0 Hz, 1H),
4.78 (dd, J = 3.5, 9.5 Hz, 1H), 7.17−7.32 (m, 7H), 7.43−7.49 (m, 1H),
7.87(d, J = 8.0 Hz, 1H); 13C NMR (500 MHz, CDCl3) δ 35.2, 36.1, 37.1,
40.3, 44.1, 107.5, 116.4, 118.6, 119.4, 123.8, 124.0, 127.1, 127.2, 127.4,
127.8, 128.6, 128.9, 129.8, 132.0, 136.6, 139.4, 142.6, 161.1, 162.5, 177.4,
177.6, 204.2; IR (thin film) ν = 3225, 1704, 1609, 1565 cm−1; HRMS
(ES+) calc for C18H15O5 [M + H]+ 311.0919, found 311.0919.
Transformation of Compound 5 to Compound 6. A solution of
5 (57 mg, 0.2 mmol) in diethylcarbonate (1 mL) was added to a
suspension of NaH (60% dispersion in mineral oil) in diethylcarbonate
(1 mL) at 0 °C. The mixture was heated at 100 °C for 4 h and then
cooled to 0 °C and quenched by water. The mixture was extracted by
diethyl ether, and aqueous phase was acidified with 2 N HCl to pH 3.
The resulting mixture was extracted with dichloromethane, concen-
trated in vacuo and purified by column chromatography to give 31.1 mg
(50%) of 6.
(S)-2-(3-(Furan-2-yl)-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-
propanoyl)pyridine-1-oxide (4m). Yellow solid, 0.0747 g, 99% yield
(0.0340 g, 45% yield): mp 142−143 °C; [α]D25 −6.7 (c 1.0, CHCl3 for
1
96% ee); HPLC tR(major) = 19.76 min, tR(minor) = 29.16; H NMR
(500 MHz; CDCl3) δ 2.54 (dd, J = 6.8, 13.7 Hz, 0.27 H), 2.75 (m, 1.45
H), 3.29 (dd, J = 1.7, 13.5 Hz, 0.28 H), 4.42 (d, J = 6.6 Hz, 0.28 H), 4.54
(dd, J = 7.8, 9.0 Hz, 0.72 H), 6.09 (d, J = 3.2 Hz, 0.28 H), 6.22 (d, J =
3.2 Hz, 0.76 H), 6.28 (dd, J = 2.0, 3.5 Hz, 0.72 H), 6.30 (dd, J = 2.0,
3.5 Hz, 0.28 H), 7.22−7.57(m, 6.75 H), 7.65 (dd, J = 1.7, 8.0 Hz,
0.25 H), 7.82 (dd, J = 1.5, 8.0 Hz, 0.75 H), 7.85 (dd, J = 1.5, 7.8 Hz, 0.25
H), 8.32−8.33 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 28.2, 29.1,
33.0, 36.5, 98.4, 98.5, 101.1, 102.7, 110.6, 110.7, 115.4, 115.5, 116.6,
116.7, 123.1, 123.2, 123.3, 123.7, 123.9, 124.1, 126.4, 128.6, 128.8, 132.1,
132.3, 140.7, 140.8, 140.9, 141.2, 146.8, 147.1, 152.9, 153.7, 154.2, 158.0,
158.4, 160.8, 162.1; IR (thin film) ν 3413, 1713, 1629, 1611, 1575 cm−1;
HRMS (ES+) calc for C21H16NO6 [M + H]+ 378.0978, found 378.0975.
(R)-(E)-2-(3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-5-phenyl-
pent-4-enoyl)pyridine-1-oxide (4n). Yellow solid, 0.0703 g, 85%
yield (0.0612 g, 74% yiled): mp 127−129 °C; [α]D25 −64.7 (c 1.5, CHCl3
for 88% ee); HPLC tR(major) = 15.14 min, tR(minor) = 31.36 min; 1H
NMR (500 MHz; CDCl3) δ = 2.44−2.53 (m, 1H), 2.74(dd, J = 6.5,
13.5 Hz, 0.49H), 2.87 (dd, J = 1.6, 13.5 Hz, 0.51H), 3.86−3.88 (m, 0.51H),
4.02−4.06 (m, 0.49H), 6.32(dd, J = 7.7, 15.9 Hz, 0.51H), 6.59 (d, J =
15.9 Hz, 0.49H), 6.69−6.78 (m, 1H), 7.12−7.54 (m, 10H), 7.62(dd, J =
1.9, 8.0 Hz, 0.49H), 7.67(dd, J = 1.9, 8.0 Hz, 0.51H),7.83 (dd, J = 1.5,
8.0 Hz, 0.49H), 8.35 (dd, J = 6.4, 9.1 Hz, 1H), 9.91 (s, 0.38H), 10.12(s,
0.42 H); 13C NMR (125 MHz, CDCl3) δ 31.8, 32.9, 35.3, 37.2, 98.3,
98.6, 103.5, 104.5, 115.5, 116.5, 116.6, 123.0, 123.3, 123.7, 123.9, 126.3,
126.4, 126.5, 127.2, 127.3, 128.4, 128.5, 128.7, 129.6, 130.4, 131.1, 131.6,
131.9, 137.1, 137.4, 140.8, 140.9, 147.2, 147.5, 152.7, 152.9, 157.0, 157.6,
161.4, 162.0; IR (thin film) ν 3420, 1705, 1625, 1573 cm−1; HRMS
(ES+) calc for C25H20NO5 [M + H]+ 414.1341, found 414.1345.
(S)-2-(4-Ethoxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-4-
oxobutanoyl)pyridine-1-oxide (4o). Yellow semisolid, 0.0613 g,
80% yield (0.0506 g, 66% yield): [α]D25 −8.7 (c 0.6, CHCl3 for 83% ee);
HPLC tR(major) = 16.21 min, tR(minor) = 20.82 min; 1H NMR (500
MHz; CDCl3) δ 1.23−1.32 (m, 3H), 2.44−2.50 (m, 1.0 H), 2.90 (dd, J =
5.8, 11.7 Hz, 0.42H), 3.31 (d, J = 12.9 Hz, 0.58 H), 3.92 (d, J = 5.8 Hz,
0.58H), 4.08 (dd, J = 6.0, 11.9 Hz, 0.42H), 4.17−4.27 (m, 2.0 H), 7.21−
7.57(m, 5H), 7.66 (dd, J = 7.7, 15.6 Hz, 1.0H), 7.78 (d, J = 7.7 Hz, 1.0H),
8.35−8.37 (m, 1.0H), 10.26 (s, 0.42 H), 10.29 (s, 0.58H); 13C NMR
(125 MHz, CDCl3) δ 14.1, 14.2, 32.0, 33.6, 34.0, 35.6, 61.6, 61.7, 98.1,
115.3, 116.7, 122.9, 123.1, 123.5, 123.6, 124.0, 126.6, 128.7, 128.9, 132.2,
140.9, 146.5, 152.9, 156.9, 161.6, 186.3; IR (thin film) ν 3396, 1713,
Synthesis of Enol Lactone and Warfarin (Scheme 1). Enol
Lactone 7.9a A solution of 6 (62.2 mg, 0.2 mmol) in 0.2 mL of acetic
anhydride was refluxed for 5 min and poured into ice water. Then the
resulting mixture was extracted with dichloromethane, concentrated in
vacuo and purified by column chromatography to give 52.8 mg (90%)
25
of 7: mp 138−141 °C; [α]D −151.3 (c 1.0, CHCl3 for 97% ee);
[lit9a][α]D −164.9 (c 0.33, CHCl3 for 91% ee R isomer)]; HPLC
25
Daicel Chiralpack AD-H column, n-hexane/2-propanol (90:10), flow
1
rate 1.0 mL/min. tR(major) = 19.85 min, tR(minor) = 29.14 min; H
NMR (500 MHz; CDCl3) δ 3.13 (dd, J = 1.8, 16.2 Hz, 1H), 3.21(dd, J =
7.5, 16.2 Hz, 1H), 4.52 (dd, J = 7.7, 1.9 Hz, 1H), 7.24−7.39 (m, 7H),
7.60−7.63 (m, 1H), 7.91(dd, J = 1.5, 8.0 Hz, 1H); 13C NMR (500 MHz,
CDCl3) HRMS (ES+) calc for C18H13O4 [M + H]+ 293.0814, found
293.0816.
(R)-Warfarin 8.3a,c,d 1.6 mmol of methyllithium was added to a
stirred solution of 6 (62.2 mg, 0.2 mmol) in 1 mL of dry THF at 0 °C.
After 3 h at 0 °C, 6 mmol of Me3SiCl was added while stirring continued.
The reaction mixture was allowed to warm to rt. Then 1 mL of 1 N HCl
was added and stirred at rt for 1 h. The mixture was then extracted with
dichloromethane; organic layer was concentrated in vacuo and purified
by column chromatography to give 8. White solid, 0.0250 g, 40% yield:
25
mp 156−159 °C; [α]D +12.1 (c 0.5, acetonitrile for 97% ee);
[lit3d][α]D = −12.0 (c 0.3, acetonitrile for 96% ee S isomer]; HPLC
22
Daicel Chiralpack AD-H column, n-hexane/2-propanol (80:20), flow
1
rate 1.0 mL/min. tR(major) = 5.67 min, tR(minor) = 15.21 min; H
NMR (500 MHz; CDCl3) δ 1.65 (s, 1.40H), 1.67 (s, 1.60H), 1.94−1.99
(m, 0.47H), 2.27(s, 0.3H), 2.36−2.52 (m, 1.3H), 3.30 (d, J = 18.0 Hz,
0.1H), 3.44 (bs, 0.33H), 3.83 (dd, J = 10.1, 19.6 Hz, 0.1H), 3.91 (s,
0.52H), 4.15 (dd, J = 6.7, 11.3 Hz, 0.53H), 4.25 (dd, J = 3.4, 6.7 Hz,
0.37H), 4.70 (d, J = 8.0 Hz, 0.1H), 7.19−7.35 (m, 7H), 7.46 (t, J =
7.9 Hz, 0.55H), 7.53−7.56 (m, 0.34H), 7.79 (d, J = 8.3 Hz, 0.46H), 7.88
(d, J = 7.7 Hz, 0.33H), 7.92 (d, J = 7.7 Hz, 0.1H); HRMS (ES+) calc for
C19H17O4 [M + H]+ 309.1127, found 309.1124.
8807
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808

The Journal of Organic Chemistry
Note
(7) (a) Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 3480. (b) Singh, P.
K.; Singh, V. K. Pure Appl. Chem. 2012, 84, 1651. (c) Singh, P. K.; Singh,
V. K. Pure Appl. Chem. 2010, 82, 1845. (d) Bisai, A.; Singh, V. K. Org.
Lett. 2006, 8, 2405. (e) Ginotra, S. K.; Singh, V. K. Org. Biomol. Chem.
2006, 4, 4370. (f) Sekar, G.; DattaGupta, A.; Singh, V. K. J. Org. Chem.
1998, 63, 2961. (g) DattaGupta, A.; Singh, V. K. Tetrahedron Lett. 1996,
37, 2633. (h) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron
1994, 50, 13725.
(8) (a) Liu, L.; Zhang, S.; Xue, F.; Lou, G.; Zhang, H.; Ma, S.; Duan,
W.; Wang, W. Chem.Eur. J. 2011, 17, 7791. (b) Soloshonok, V. A.
Angew. Chem., Int. Ed. 2006, 45, 766. (c) Soloshonok, V. A.; Ueki, H.;
Yasumoto, M.; Mekala, S.; Hirschi, J. S.; Singleton, D. A. J. Am. Chem.
Soc. 2007, 129, 12112.
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra and HPLC chromatograms for all new
compounds and crystal data (CIF) for 4j. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: vinodks@iitk.ac.in.
Notes
■
The authors declare no competing financial interest.
(9) (a) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett.
2005, 7, 979. (b) Itoh, K.; Kanemasa, S. Tetrahedron Lett. 2003, 44,
1799.
ACKNOWLEDGMENTS
■
V.K.S. thanks the Department of Science and Technology
(DST), India, for a research grant through a J. C. Bose fellowship.
S.K.R. and N.M. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for research fellowships. We thank
Dr. Alakesh Bisai and Dr. Vishnumaya Bisai from IISER Bhopal
for their help.
REFERENCES
■
(1) (a) Murray, R. D. H.; Mendez, J.; Brown, S. A. In The Natural
Coumarins: Occurrence, Chemistry and Biochemistry; Wiley: New York,
1982. (b) O’Kennedy, R.; Thornes, R. D. In Coumarins: Biology,
Applications and Mode of Action; Wiley: New York, 1997. (c) Bhatnagar,
A.; Sharma, P. K.; Kumar, N.; Dudhe, R. Pharm. Lett. 2010, No. 2, 297.
(d) Musa, M. A.; Cooperwood, J. S.; Khan, M. O. F. Curr. Med. Chem.
́
2008, 15, 2664. (e) Hoult, J. R. S.; Paya, M. Gen. Pharmacol. 1996, 27,
713. (f) Chohan, Z. H.; Shaikh, A. U.; Rouf, A.; Supuran, C. T. J. Enzyme
Inhib. Med. Chem. 2006, 27, 741. (g) Jung, J.-C.; Park, O.-S. Molecules
2009, 14, 4790.
(2) (a) Kuang, Y.; Liu, X.; Chang, L.; Wang, M.; Lin, L.; Feng, X. Org.
Lett. 2011, 13, 3814. (b) Teichert, J. F.; Feringa, B. L. Chem. Commun.
2011, 47, 2679. (c) Guo, H.; Herdtweck, E.; Bach, T. Angew. Chem., Int.
Ed. 2010, 49, 7782. (d) Kim, H.; Yuna, J. Adv. Synth. Catal. 2010, 352,
1881. (e) Corbu, A.; Castro, J. M.; Aquino, M.; Gandara, Z.; Retailleau,
P.; Arseniyadis, S. Eur. J. Org. Chem. 2010, 1483. (f) Ulgheri, F.;
Marchetti, M.; Piccolo, O. J. Org. Chem. 2007, 72, 6056. (g) Tanaka, K.;
Fujiwara, T. Org. Lett. 2005, 7, 1501.
(3) (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 4955. (b) Halland, N.; Velgaard, T.; Jørgensen, K. A. J. Org.
Chem. 2003, 68, 5067. (c) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org.
Lett. 2006, 8, 5239. (d) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.;
Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413. (e) Kristensen, T. E.;
Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem. 2009, 5185.
(f) Chen, X.-K.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao,
G.; Cao, W.-G. Adv. Synth. Catal. 2010, 352, 1648. (g) Xu, D.-Q.; Wang,
Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem.
Eur. J. 2010, 16, 4177. (h) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Chem.
Eur. J. 2010, 16, 13068. (i) Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.;
Cheng, Y. Org. Lett. 2011, 13, 4382. (j) Dong, Z.; Feng, J.; Cao, W.; Liu,
X.; Lin, L.; Feng, X. Tetrahedron Lett. 2011, 52, 3433. (k) Mei, R.-Q.; Xu,
X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X. Tetrahedron Lett.
2011, 52, 1566. (l) Rogozin
Green Chem. 2011, 13, 1155.
́
ska, M.; Adamkiewicz, A.; Mlynarski, J.
(4) (a) Barroso, S.; Blay, G.; Pedro, J. R. Org. Lett. 2007, 9, 1983.
(b) Barroso, S.; Blay, G.; Munoz, M. C.; Pedro, J. R. Adv. Synth. Catal.
̃
2009, 351, 107. (c) Barroso, S.; Blay, G.; Munoz, M. C.; Pedro, J. R. Org.
̃
Lett. 2011, 13, 402. (d) Livieri, A.; Boiocchi, M.; Desimoni, G.; Faita, G.
Chem.Eur. J. 2011, 17, 516. (e) George, J.; Reddy, B. V. S. Org. Biomol.
Chem. 2012, 10, 4731.
(5) (a) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121. (b) Singh, P.
K.; Singh, V. K. Org. Lett. 2010, 12, 80. (c) Ray, S. K.; Singh, P. K.; Singh,
V. K. Org. Lett. 2011, 13, 5812.
(6) Katritzky, A. R.; Lagowski, J. M. In Chemistry of the Heterocyclic N-
Oxides; Academic Press: Waltham, MA, 1971.
8808
dx.doi.org/10.1021/jo301513x | J. Org. Chem. 2012, 77, 8802−8808