Ytterbium-catalyzed conjugate allylation of alkylidene malonates

Article abstract of DOI:10.1021/jo200268e

Alkylidene malonates undergo efficient conjugate allylation upon treatment with allylstannanes or allylsilanes under the action of ytterbium catalysis.

Full text of DOI:10.1021/jo200268e

NOTE
pubs.acs.org/joc
Ytterbium-Catalyzed Conjugate Allylation of Alkylidene Malonates
Charlene Fallan,† Paul F. Quigley,‡ and Hon Wai Lam*,†
†EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh,
EH9 3JJ, United Kingdom
‡Shasun Pharma Solutions Ltd., Dudley, Nr. Cramlington, Northumberland, NE23 7QG, United Kingdom
S Supporting Information
b
ABSTRACT: Alkylidene malonates undergo efficient conjugate allylation
upon treatment with allylstannanes or allylsilanes under the action of
ytterbium catalysis.
lthough catalytic conjugate additions of organometallics to
electron-deficient alkenes are fundamentally important
A
transformations,1 such reactions with allylmetal reagents remain
relatively underdeveloped.2ꢀ7 However, encouraging progress in
this area has been reported recently. For example, Jarvo and co-
workers have described palladium-catalyzed conjugate allylation of
R,β-unsaturated N-acylpyrroles8a and alkylidene malononitriles8b
with allylboronic acid pinacol ester, while the Fillion group has
reported scandium-catalyzed conjugate allylation of alkylidene
Meldrum’s acids with allylstannanes.9 Enantioselective catalytic
conjugate allylations have also been documented recently.10,11
Morken and co-workers have described enantioselective allylation
of alkylidene-activated enones using palladium or nickel catalysis,10
while the Snapper group has developed asymmetric copper-
catalyzed allylation of cyclic unsaturated ketoesters.11
Figure 1. Alkylidene malonates employed in this study.
results in the presence of substoichiometric quantities of certain
Lewis acids. Table 1 presents the results obtained in CH2Cl2 at
room temperature for 24 h. None of the intended product 3a
was obtained with use of 10 mol % of Cu(OTf)2, Zn(OTf)2, or
Al(OTf)3 (entries 1, 2, and 5, respectively), while Mg(OTf)2
provided a trace of 3a (entry 3). Markedly improved results were
Despite these advances, the development of catalytic conju-
gate allylations with a greater variety of substrates would be
beneficial in order to increase the range of products that may be
accessed. Herein, we report ytterbium-catalyzed conjugate allyla-
tion of alkylidene malonates using allylstannanes or allylsilanes.12
In consideration of potential substrates for conjugate allylation,
we were drawn to alkylidene malonates for a number of reasons.
First, with two activating groups present, alkylidene malonates
exhibit high reactivity in conjugate addition reactions, including
enantioselective variants.13 Second, the ability of alkylidene malo-
nates to engage in two-point binding with a Lewis acid catalyst14
was anticipated to be favorable for promoting reaction with
allylmetal reagents that are convenient to handle, but which exhibit
low-to-moderate reactivity, such as allylsilanes and allylstannanes.
Third, the malonate functionality in the products may potentially
be exploited in a range of useful transformations.
obtained with catalytic Yb(OTf)3 2H2O16 (entry 7). To ascer-
3
tain whether water was playing an important role in this process,
the reactions with Mg(OTf)2 and Al(OTf)3 were repeated with
the addition of 0.2 equiv of water (entries 4 and 6, respectively).
However, water was not beneficial in the case of Al(OTf)3 (entry
6), and had a negative effect in the case of Mg(OTf)2 (entry 4,
compare with entry 3). With Yb(OTf)3 2H2O as the precata-
3
lyst, the addition of hexafluoroisopropanol (HFIP)17 resulted in
virtually complete conversion of the starting material into 3a
(entry 8).18 Surprisingly, attempts to reduce the loading of
Yb(OTf)3 2H2O to 5 mol % were unsuccessful, with minimal
3
conversion into 3a being observed (entry 9). It should be noted
that while the use of anhydrous Yb(OTf)3 in place of Yb-
(OTf)3 2H2O led to a similarly high conversion (entry 10),
3
Yb(OTf)3 2H2O was preferred on the basis of its lower cost and
3
greater ease of handling.
Figure 1 depicts the alkylidene malonates employed in this
investigation, which were prepared by Knoevenagel conden-
sations under standard conditions,15 except for 1k, which is
commercially available.
The optimized conditions with Yb(OTf)3 2H2O (Table 1,
3
entry 8) were then applied to allylation of alkylidene malonates
Attempted 1,4-addition of a simple allyl group to substrate 1a
revealed that allytributylstannane (2) provided encouraging
Received: February 8, 2011
Published: April 27, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200268e J. Org. Chem. 2011, 76, 4112–4118
|

The Journal of Organic Chemistry
NOTE
Table 1. Evaluation of Conditions for Allylation of 1aa
Table 2. Yb-Catalyzed Allylation of Alkylidene Malonates
with Allyltributylstannanea
entry
M(OTf)x
Cu(OTf)2
additive
conversion (%)b
1
2
<5
<5
Zn(OTf)2
Mg(OTf)2
Mg(OTf)2
Al(OTf)3
Al(OTf)3
3
13
4
H2O (0.2 equiv)
H2O (0.2 equiv)
<5
5
<5
6
<5
7
Yb(OTf)3 2H2O
72
3
8
Yb(OTf)3 2H2O
HFIP (2.0 equiv)
HFIP (2.0 equiv)
HFIP (2.0 equiv)
>95
<10
>95
3
9
Yb(OTf)3 2H2Oc
3
10
Yb(OTf)3
a Reactions were conducted with 0.20 mmol of 1a in 1 mL of CH2Cl2.
b Conversion was measured by 1H NMR spectroscopy after filtration of
the reaction mixtures through a short plug of silica gel. No byproducts
were detected in these reactions. c Using 5 mol % of Yb(OTf)3 2H2O.
3
a Reactions were conducted with 0.50 mmol of 1aꢀi in 2 mL of
CH2Cl2. b Isolated yield. c Conducted with 4.00 mmol of 1c in 10 mL
of CH2Cl2.
1aꢀk to examine the scope of the process, and gratifyingly, all
of these substrates proved to be competent (Table 2). Substrates
containing aromatic substituents of electron-neutral (entries 1
and 6), electron-rich (entries 2ꢀ4), or electron-poor (entry 5)
character were tolerated. With the sterically demanding substrate
1f containing a 1-naphthyl group, the yield was only 30% and
significant starting material remained (entry 6). Furthermore,
substrates containing a heteroaryl (entry 7) or a cycloalkyl group
(entry 8) underwent conjugate allylation successfully. With
alkylidene malonate 1i, the allylation product 3i was isolated in
a modest 47% yield due to the presence of minor, unidentified
side reactions. In addition to substrates prepared from dimethyl
malonate, diethyl malonate-derived acceptors were tolerated
(entries 10 and 11), and in the case of substrate 1j, a larger scale
reaction (4.00 mmol) proceeded successfully to provide 3j in
91% yield (entry 10).
and we were pleased to discover that commercially available
methallyltrimethylsilane (4b) provided good results. Reactions
with this reagent again tolerated a wide range of alkylidene
malonate substrates, providing methallylated products 5aꢀi in
65ꢀ95% yield (Table 3, entries 1ꢀ9). In similar fashion,
trimethyl(2-phenylallyl)silane proved to be a competent nucleophile,
providing conjugate allylation products 6aꢀc with representative
alkylidene malonates 1d, 1f, and 1i (entries 10ꢀ12).
To demonstrate the utility of the products, further manipula-
tion reactions were conducted. For example, Krapcho
decarboxylation20 of 3j proceeded smoothly to provide 7 in
65% yield (eq 2), while oxidative cleavage of the methallyl group
of 5c was accomplished in 68% yield with OsO4/PhI(OAc)2/2,6-
lutidine21 (eq 3).
As expected, the less nucleophilic allyltrimethylsilane (4a)19
proved to be an inferior allylating reagent under these conditions,
with generally only low conversions into the products 3 observed.
However, use of an excess of allyltrimethylsilane (5.0 equiv) at
40 °C under more dilute conditions (0.125 M) in dichloroethane
allowed product 3a to be isolated in 55% yield (eq 1). With more
concentrated conditions, products resulting from competitive
oligomerization were detected.
Current catalytic conjugate allylations are restricted in that
with few exceptions,5a only the additions of simple allyl groups
are described. We were therefore keen to explore whether the
conditions employed in Table 2 could also be applied to the
conjugate addition of more highly substituted allyl nucleophiles,
In conclusion, ytterbium-catalyzed conjugate allylations of
alkylidene malonates with allylsilanes and allyltributylstannane
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NOTE
Table 3. Yb-Catalyzed Allylation of Alkylidene Malonates
with Allylsilanes.a
δ 7.75 (1H, s), 7.29ꢀ7.22 (4H, m), 3.85 (6H, s), 2.36 (3H, s); 13C NMR
(125.8 MHz, CDCl3) δ 167.2, 164.5, 143.1, 138.5, 132.7, 131.5, 130.2,
128.8, 126.4, 125.2, 52.6, 21.3; HRMS (ES) exact mass calcd for C13H15O4
[M þ H]þ 235.0965, found 235.0962.
General Procedure A: Allylation with Allyltributylstannane.
A solution of alkylidene malonate (0.50 mmol), Yb(OTf)3 2H2O (33 mg,
3
0.05 mmol), and hexafluoroisopropanol (105 μL, 1.00 mmol) was stirred
in CH2Cl2 (2 mL) at room temperature for 10 min. Allyltributylstannane
(232 μL, 0.75 mmol) was added dropwise over 1 min and the mixture was
stirred at room temperature for 18 h. The reaction was filtered through a
short plug of silica gel with EtOAc as eluent, and the filtrate was concen-
trated in vacuo. Purification of the residue by column chromatography
(10% EtOAc/hexane) afforded the allylated product.
Dimethyl 2-(1-phenylbut-3-enyl)malonate (3a):12 The title
compound was prepared following General Procedure A from 1a (110 mg,
0.50 mmol) to give a colorless oil (95 mg, 73%). IR (film) 3031, 2954, 2254,
1752 (CdO), 1734 (CdO), 1640, 1435, 1255, 1165 cmꢀ1; 1H NMR (360
MHz, CDCl3) δ 7.31ꢀ7.27 (2H, m), 7.23ꢀ7.17 (3H, m), 5.55 (1H, tdd,
J = 17.1, 10.1, 7.0 Hz), 4.97ꢀ4.89 (2H, m), 3.78 (3H, s), 3.73 (1H, d, J =
10.6 Hz), 3.54ꢀ3.45 (1H, m), 3.45 (3H, s), 2.54ꢀ2.38 (2H, m); 13C NMR
(90.6 MHz, CDCl3) δ 168.7, 168.1, 140.3, 135.1, 128.3, 128.2, 127.0, 117.1,
57.7, 52.6, 52.2, 45.3, 38.2; HRMS (ES) exact mass calcd for C15H22NO4
[M þ NH4]þ 280.1543, found 280.1548.
Allylation of 1a with allyltrimethylsilane: A solution of 1a
(110 mg, 0.50 mmol), Yb(OTf)3 2H2O (33 mg, 0.05 mmol), and
3
hexafluoroisopropanol (262 μL, 2.50 mmol) was stirred in DCE (4 mL)
at room temperature for 10 min. Allyltrimethylsilane (4a) (400 μL, 2.50
mmol) was added dropwise over 1 min and the mixture was then stirred at
40 °C for 18 h. The reaction was filtered through a short plug of silica gel
with EtOAc as eluent, and the filtrate was concentrated in vacuo. Purifica-
tion of the residue by column chromatography (5% EtOAc/hexane) gave
3a (72 mg, 55%) as a colorless oil.
Dimethyl 2-[1-(3-methylphenyl)but-3-enyl]malonate (3b):
The title compound was prepared following General Procedure A from 1b
(117 mg, 0.50 mmol) to give a colorless oil (83 mg, 61%). IR (film) 3079,
2954, 1751 (CdO), 1735 (CdO), 1641, 1436, 1216, 1167 cmꢀ1
;
a Reactions were conducted with 0.50 mmol of 1 in 2 mL of CH2Cl2.
1H NMR (500 MHz, CDCl3) δ 7.17 (1H, t, J = 7.5 Hz), 7.03ꢀ6.97
(3H, m), 5.55 (1H, tdd, J = 17.1, 10.1, 7.0 Hz), 4.97ꢀ4.90 (2H, m), 3.77
(3H, s), 3.71 (1H, d, J = 10.5 Hz), 3.50ꢀ3.44 (1H, m), 3.46 (3H, s),
2.49ꢀ2.39 (2H, m), 2.32 (3H, s); 13C NMR (125.8 MHz, CDCl3)
δ 168.8, 168.1, 140.2, 137.8, 135.2, 128.9, 128.1, 127.7, 125.1, 116.9, 57.7,
52.5, 52.2, 45.2, 38.2, 21.4; HRMS (ES) exact mass calcd for C16H24NO4
[M þ NH4]þ 294.1700, found 294.1696.
b Isolated yield.
have been developed. A range of β-substituents on the alkylidene
malonate are tolerated, and compared with existing catalytic
conjugate allylation reactions,2ꢀ7 this work extends the scope of
the nucleophile to substituted allylating reagents. Future work
will focus on the development of enantioselective variants of
these reactions.
Dimethyl 2-[1-(4-methylphenyl)but-3-enyl]malonate (3c):12
The title compound was prepared following General Procedure A from 1c
(117 mg, 0.50 mmol) to give a colorless oil (129 mg, 95%). IR (film) 3006,
2953, 2253, 1752 (CdO), 1734 (CdO), 1515, 1436, 1256, 1164 cmꢀ1; 1H
NMR (360 MHz, CDCl3) δ 7.08 (4H, br s), 5.55 (1H, tdd, J = 17.1, 10.1,
7.0, Hz), 4.97ꢀ4.89 (2H, m), 3.77 (3H, s), 3.70 (1H, d, J = 10.5 Hz), 3.46
(3H, s), 3.50ꢀ3.40 (1H, m), 2.50ꢀ2.34 (2H, m), 2.30 (3H, s); 13C NMR
(90.6 MHz, CDCl3) δ 168.8, 168.2, 137.2 (C), 136.5, 135.3, 129.0, 128.0,
117.0, 57.8, 52.5, 52.2, 44.9, 38.2, 21.0; HRMS (ES) exact mass calcd for
C16H21O4 [M þ H]þ 277.1434, found 277.1430.
’ EXPERIMENTAL SECTION22
Alkylidene malonates 1aꢀ1e,23 1f,13a 1g,23 1h,23 1i,24 and 1j25 are
known, and were prepared by the reaction of the appropriate dialkyl
malonate with the appropriate aldehyde in the presence of piperidine
and acetic acid in toluene under DeanꢀStark conditions.15 Alkylidene
malonate 1k is commercially available.
Dimethyl 2-(3-methylbenzylidene)malonate (1b): A solu-
tion of dimethyl malonate (3.96 g, 30.0 mmol), 3-methylbenzaldehyde
(3.00 g, 25.0 mmol), AcOH (0.25 mL, 0.40 mmol), and piperidine
(0.38 mL, 0.40 mmol) in toluene (25 mL) was heated to 120 °C for
18 h in a round-bottomed flask fitted with a DeanꢀStark apparatus. The
reaction was cooled to room temperature, diluted with Et2O, and washed
with 1 M HCl and brine. The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by column chromato-
graphy (5% EtOAc/hexane) gave the alkylidene malonate 1b (2.38 g, 41%)
as a white solid. Mp 40ꢀ41 °C; IR (CHCl3) 3020, 2953, 2925, 1735
Dimethyl 2-[1-(4-methoxyphenyl)but-3-enyl]malonate
(3d):12 The title compound was prepared following General Procedure A
from 1d (125 mg, 0.50 mmol) to give a colorless oil (88 mg, 60%). IR (film)
2954, 2253, 1732 (CdO), 1514, 1467, 1179 cmꢀ1; 1H NMR (360 MHz,
CDCl3) δ 7.11 (2H, dm, J = 8.7 Hz), 6.82 (2H, dm, J = 8.7 Hz), 5.55 (1H,
tdd, J = 17.1, 10.1, 7.0 Hz), 4.97ꢀ4.85 (2H, m), 3.78 (3H, s), 3.77 (3H, s),
3.67 (1H, d, J = 10.5 Hz), 3.46 (3H, s), 3.49ꢀ3.42 (1H, m), 2.50ꢀ2.34
(2H, m); 13C NMR (90.6 MHz, CDCl3) δ 168.8, 168.2, 158.4,
135.3, 132.2, 129.2, 117.0, 113.7, 57.9, 55.1, 52.5, 52.3, 44.6, 38.3; HRMS
(ES) exact mass calcd for C16H24NO5 [M þ NH4]þ 310.1649, found
310.1653.
1
(CdO), 1629, 1438, 1375, 1217 cmꢀ1; H NMR (500 MHz, CDCl3)
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NOTE
Dimethyl 2-[1-(4-nitrophenyl)but-3-enyl]malonate (3e):12
The title compound was prepared following General Procedure A from
1e (132 mg, 0.50 mmol) to give a colorless oil (131 mg, 86%). IR (film)
hexane) gave the allylation product 3j (1.10 g, 91%) as a colorless oil. IR
(film) 3078, 2982, 2936, 2253, 1751 (CdO), 1718 (CdO), 1514, 1444,
1252, 1177 cmꢀ1; 1H NMR (360 MHz, CDCl3) δ 7.08 (4H, br, s), 5.56
(1H, tdd, J = 17.1, 10.1, 7.0 Hz), 4.97ꢀ4.88 (2H, m), 4.24 (2H, q, J = 7.1
Hz), 3.91 (2H, q, J = 7.1 Hz), 3.66 (1H, d, J = 10.7 Hz), 3.46 (1H, ddd, J =
10.7, 9.6, 4.6 Hz), 2.52ꢀ2.35 (2H, m), 2.30 (3H, s), 1.29 (3H, t, J = 7.1
Hz), 0.98 (3H, t, J = 7.1 Hz); 13C NMR (90.6 MHz, CDCl3) δ 168.4,
167.8, 137.3, 136.4, 135.3, 128.9, 128.2, 116.9, 61.5, 61.1, 58.0, 44.9, 38.4,
21.0, 14.1, 13.7; HRMS (ES) exact mass calcd for C18H25O4 [M þ H]þ
305.1747, found 305.1750.
1
2954, 2253, 1734 (CdO), 1522, 1436, 1348, 1258 cmꢀ1; H NMR
(360 MHz, CDCl3) δ 8.16 (2H, d, J = 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz),
5.51 (1H, tdd, J = 17.1, 10.4, 7.1 Hz), 4.96ꢀ4.90 (2H, m), 3.80 (3H, s),
3.77 (1H, d, J = 4.6 Hz), 3.65 (1H, ddd, J = 10.2, 9.9, 4.6 Hz), 3.50 (3H, s),
2.58ꢀ2.51 (1H, m), 2.45ꢀ2.36 (1H, m); 13C NMR (62.9 MHz, CDCl3)
δ 168.1, 167.6, 148.2, 146.9, 133.9, 129.2, 123.5, 118.1, 56.8, 52.8, 52.5,
44.9, 37.9; HRMS (ES) exact mass calcd for C15H21N2O6 [M þ NH4]þ
325.1394, found 325.1398.
Dimethyl 2-(1-methylbut-3-enyl)malonate (3k):26 The title
compound was prepared following General Procedure A from 1k (86 mg,
0.50 mmol) to give a colorless oil (86 mg, 75%). IR (film) 2982, 2937,
2358, 2254, 1724 (CdO), 1640, 1370, 1265, 1178 cmꢀ1; 1H NMR (360
MHz, CDCl3) δ 5.82ꢀ5.71 (1H, m), 5.07ꢀ5.02 (2H, m), 4.20 (4H, q, J =
7.1 Hz), 3.27 (1H, d, J = 8.0 Hz), 2.41ꢀ2.30 (1H, m), 2.26ꢀ2.19 (1H, m),
2.04ꢀ1.97 (1H, m), 1.27 (6H, t, J = 7.1 Hz), 1.00 (3H, d, J = 6.8 Hz); 13C
NMR (62.9 MHz, CDCl3) δ 168.9, 168.7, 135.8, 117.1, 61.2, 61.1, 56.8,
38.7, 33.1, 16.8, 14.1; HRMS (ES) exact mass calcd for C12H21O4
[M þ H]þ 229.1434, found 229.1434.
Dimethyl 2-[1-(3-naphthyl)but-3-enyl]malonate (3f): The
title compound was prepared following General Procedure A from 1f (135
mg, 0.50 mmol) to give a colorless oil (47 mg, 30%). IR (film) 2952, 2920,
1
1754 (CdO), 1736 (CdO), 1434, 1220 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 8.24 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J = 8.1 Hz), 7.74 (1H, d, J =
8.1 Hz), 7.55 (1H, ddd, J = 8.5, 6.8, 1.5 Hz), 7.49 (1H, ddd, J = 8.0, 6.8, 1.1
Hz), 7.44 (1H, t, J = 7.7 Hz), 7.36 (1H, dd, J = 7.2, 1.1 Hz), 5.53 (1H, tdd,
J = 17.1, 10.1, 7.1 Hz), 4.94 (1H, br d, J = 17.1 Hz), 4.86 (1H, br d, J = 10.1
Hz), 4.55ꢀ4.53 (1H, br s), 3.99ꢀ3.96 (1H, m), 3.79 (3H, s), 3.33 (3H, s),
2.67ꢀ2.63 (2H, m); 13C NMR (125.8 MHz, CDCl3) δ 168.8, 168.2, 136.8,
134.8, 133.9, 131.9, 128.8, 127.5, 126.1, 125.5, 125.1, 124.0, 123.2, 117.3,
57.2, 52.6, 52.2, 38.3, 38.2; HRMS (ES) exact mass calcd for C19H24NO4
[M þ NH4]þ 330.1700, found 330.1703.
General Procedure B: Allylation with 2-Methallyltri-
methylsilane. A solution of alkylidene malonate (0.50 mmol),
Yb(OTf)3 2H2O (33 mg, 0.05 mmol), and hexafluoroisopropanol
3
(105 μL, 1.00 mmol) was stirred in CH2Cl2 (2 mL) at room temperature
for 10 min. 2-Methallyltrimethylsilane (175 μL, 1.00 mmol) was added
dropwise over 1 min and the mixture was stirred at room temperature for
1 h. The reaction was filtered through a short plug of silica gel with
EtOAc as eluent, and the filtrate was concentrated in vacuo. Purification
of the residue by column chromatography (10% EtOAc/hexane, unless
otherwise specified) afforded the allylated product.
Dimethyl 2-(1-thiophen-2-ylbut-3-enyl)malonate (3g):
The title compound was prepared following General Procedure A from
1g (113 mg, 0.50 mmol) to give a colorless oil (118 mg, 88%). IR (film)
3077, 2953, 2253, 1734 (CdO), 1640, 1436, 1262, 1161 cmꢀ1; 1H NMR
(360 MHz, CDCl3) δ 7.17 (1H, d, J = 5.1 Hz), 6.92ꢀ6.89 (1H, m), 6.85
(1H, d, J = 3.4 Hz), 5.65 (1H, tdd, J = 17.1, 10.1, 7.0 Hz), 5.04ꢀ4.97
(2H, m), 3.84 (1H, dt, J = 9.4, 4.9 Hz), 3.76 (3H, s), 3.70 (1H, d, J = 9.8
Hz), 3.55 (3H, s), 2.58ꢀ2.41 (2H, m); 13C NMR (90.6 MHz, CDCl3)
δ 168.3, 167.9, 143.5, 134.7, 126.4, 125.6, 124.1, 117.6, 58.3, 52.6, 52.4, 40.6,
39.1; HRMS (ES) exact mass calcd for C13H20NO4S [M þ NH4]þ
286.1108, found 286.1112.
Dimethyl 2-(3-methyl-1-phenylbut-3-enyl)malonate (5a):
The title compound was prepared following General Procedure B from
1a (110 mg, 0.50 mmol) to give a colorless oil (117 mg, 85%). IR (film)
2954, 2253, 1754 (CdO), 1734 (CdO), 1454, 1456, 1256, 1160 cmꢀ1
;
1H NMR (360 MHz, CDCl3) δ 7.28ꢀ7.24 (2H, m), 7.20ꢀ7.17
(3H, m), 4.61 (1H, br s, 1H), 4.50 (1H, br s), 3.75 (3H, s), 3.69 (1H,
d, J = 10.2 Hz), 3.61 (1H, td, J = 10.2, 4.7 Hz), 3.42 (3H, s), 2.45 (1H, dd,
J = 13.6, 4.7 Hz), 2.37 (1H, dd, J = 13.6, 9.5 Hz), 1.62 (3H, s); 13C NMR
(62.9 MHz, CDCl3) δ 168.7, 168.1, 142.3, 140.3, 128.2, 126.9, 113.2,
58.3, 52.5, 52.2, 43.9, 42.3, 22.0; HRMS (ES) exact mass calcd for
C16H24NO4 [M þ NH4]þ 294.1700, found 294.1703.
Dimethyl 2-(1-cyclohexylbut-3-enyl)malonate (3h): The
title compound was prepared following General Procedure A (0.50 mmol)
from 1h (113 mg) to give a colorless oil (101 mg, 75%). IR (film) 2929,
2853, 2253, 1729 (CdO), 1639, 1435, 1242, 1162 cmꢀ1; 1H NMR (360
MHz, CDCl3) δ 5.78ꢀ5.68 (1H, m), 5.03ꢀ4.95 (2H, m), 3.72 (3H, s),
3.69 (3H, s), 3.50 (1H, d, J = 7.5 Hz2), 2.31ꢀ2.05 (3H, m), 1.75ꢀ1.72
(2H, m), 1.66ꢀ1.61 (3H, m), 1.45ꢀ1.35 (1H, m), 1.28ꢀ0.94 (5H, m);
13C NMR (62.9 MHz, CDCl3) δ169.8, 168.5, 137.7, 116.0, 53.7, 52.3, 52.1,
43.6, 40.3, 33.5, 30.8, 29.1, 26.8, 26.7, 26.5; HRMS (ES) exact mass calcd for
C15H25O4 [M þ H]þ 269.1747, found 269.1749.
Dimethyl 2-[3-methyl-1-(3-methylphenyl)but-3-enyl]-
malonate (5b): The title compound was prepared following General
Procedure B from 1b (117 mg, 0.50 mmol) and purified by column
chromatography (5% EtOAc/hexane) to give a colorless oil (115 mg, 79%).
IR (film) 3020, 2925, 1757 (CdO), 1735 (CdO), 1436, 1310, 1216,
Dimethyl 2-(1-phenethylbut-3-enyl)malonate (3i): The title
compound was prepared following General Procedure A from 1i (124 mg,
0.50 mmol) to give a colorless oil (68 mg, 47%). IR (film) 3028, 2952, 2256,
1161 cmꢀ1
;
1H NMR (500 MHz, CDCl3) δ 7.17ꢀ7.14 (1H, m),
7.01ꢀ6.98 (3H, m), 4.63 (1H, s), 4.53 (1H, s), 3.76 (3H, s), 3.67 (1H,
d, J = 10.2 Hz), 3.59 (1H, app td, J = 10.2, 5.0 Hz), 3.45 (3H, s), 2.45 (1H,
dd, J = 13.7, 5.0 Hz), 2.38 (1H, ddd, J = 13.7, 9.8, 0.5 Hz), 2.32 (3H, s), 1.64
(3H, s); 13C NMR (125.8 MHz, CDCl3) δ 168.8, 168.2, 142.4, 140.3,
137.6, 129.0, 128.0, 127.7, 125.2, 113.1, 58.4, 52.5, 52.2, 43.7, 42.3, 22.1,
21.4; HRMS (ES) exact mass calcd for C17H26NO4 [M þ NH4]þ
308.1856, found 308.1858.
1
1734 (CdO), 1436, 1254, 1195 cmꢀ1; H NMR (500 MHz, CDCl3)
zδ 7.30ꢀ7.26 (2H, m), 7.21ꢀ7.16 (3H, m), 5.80ꢀ5.72 (1H, m),
4.97ꢀ4.90 (2H, m), 3.73 (3H, s), 3.73 (3H, s), 3.52 (1H, d, J = 7.2 Hz),
2.72ꢀ2.66 (1H, m), 2.64ꢀ2.58 (1H, m), 2.36ꢀ2.29 (1H, m), 2.27ꢀ2.19
(2H, m), 1.77ꢀ1.64 (2H, m); 13C NMR (125.8 MHz, CDCl3) δ 169.3,
169.2, 141.9, 135.4, 128.4, 128.3, 125.9, 117.5, 54.5, 52.3, 37.7, 35.4, 33.1,
32.8; HRMS (ES) exact mass calcd for C17H26NO4 [M þ NH4]þ
308.1856, found 308.1859.
Dimethyl 2-[3-methyl-1-(4-methylphenyl)but-3-enyl]-
malonate (5c): The title compound was prepared following Gen-
eral Procedure B from 1c (117 mg, 0.50 mmol) to give a colorless oil
(94 mg, 65%). IR (film) 2953, 2254, 1752 (CdO), 1734 (CdO),
1514, 1436, 1256, 1160 cmꢀ1; 1H NMR (360 MHz, CDCl3) δ 7.07
(4H, br s), 4.62 (1H, br s), 4.52 (1H, br s), 3.76 (3H, s), 3.66 (1H, d,
J = 10.2 Hz), 3.59 (1H, ddd, J = 10.2, 9.8, 4.7 Hz), 3.45 (3H, s), 2.45
(1H, dd, J = 13.6, 4.7 Hz), 2.37 (1H, dd, J = 13.6, 9.8 Hz), 2.29 (3H, s),
1.63 (3H, s); 13C NMR (90.6 MHz, CDCl3) δ 168.8, 168.2, 142.4,
137.2, 136.4, 128.9, 128.0, 113.1, 58.4, 52.5, 52.2, 43.4, 42.2, 22.0,
Diethyl 2-[1-(4-methylphenyl)but-3-enyl]malonate (3j):12
A solution of 1j (1.05 g 4.00 mmol), Yb(OTf)3 2H2O (248 mg,
3
0.40 mmol), and hexafluoroisopropanol (0.84 mL, 8.00 mmol) in CH2Cl2
(10 mL) was stirred at room temperature for 10 min. Allyltributylstannane
(1.8 mL, 6.0 mmol) was added over 1 min and the mixture was stirred at
room temperature for 18 h. The reaction was filtered through a short plug
of silica gel with EtOAc aseluent, and the filtrate was concentratedin vacuo.
Purification of the residue by column chromatography (10% EtOAc/
4115
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The Journal of Organic Chemistry
NOTE
21.0; HRMS (ES) exact mass calcd for C17H26 NO4 [M þ NH4]þ
308.1856, found 308.1854.
br s), 4.61ꢀ4.50 (1H, m), 4.51ꢀ4.50 (1H, m), 4.22 (2H, q, J = 7.1 Hz),
3.89 (2H, q, J = 7.1 Hz), 3.64ꢀ3.52 (m, 2H), 2.49ꢀ2.33 (2H, m), 2.28
(3H, s), 1.62 (3H, s), 1.28 (3H, t, J = 7.1 Hz), 0.96 (3H, t, J = 7.1 Hz);
13C NMR (90.6 MHz, CDCl3) δ 168.4, 167.8, 142.5, 137.2, 136.2, 128.7,
128.1, 113.0, 61.4, 61.0, 58.7, 43.4, 42.4, 22.1, 21.0, 14.0, 13.6; HRMS
(ES) exact mass calcd for C19H30NO4 [M þ NH4]þ 336.2169, found
336.2170.
Dimethyl 2-[1-(4-methoxyphenyl)-3-methylbut-3-enyl]-
malonate (5d): The title compound was prepared following General
Procedure B from 1d (125 mg, 0.50 mmol) to give a colorless oil (94 mg,
65%). IR (film) 2954, 2253, 1754 (CdO), 1733 (CdO), 1513, 1435,
1249, 1179 cmꢀ1; 1H NMR (250 MHz, CDCl3) δ 7.11 (2H, dm, J = 8.8
Hz), 6.81 (2H, dm, J = 8.8 Hz), 4.64ꢀ4.62 (1H, m), 4.52 (1H, br s), 3.78
(3H, s), 3.76 (3H, s), 3.64 (1H, d, J = 10.3 Hz2), 3.62ꢀ3.53 (1H, m),
3.46 (3H, s), 2.44 (1H, dd, J = 13.7, 4.4 Hz), 2.34 (1H, dd, J = 13.7, 8.9
Hz), 1.63 (3H, s); 13C NMR (90.6 MHz, CDCl3) δ 168.8, 168.2, 158.3,
142.4, 132.2, 129.2, 113.5, 113.1, 58.5, 55.0, 52.5, 52.2, 43.1, 42.3, 22.0;
HRMS (ES) exact mass calcd for C17H26NO5 [M þ NH4]þ 324.1805,
found 324.1808.
Dimethyl 2-[3-methyl-1-(4-nitrophenyl)but-3-enyl]malo-
nate (5e): The title compound was prepared following General Procedure
B from 1e (132 mg, 0.50 mmol) to give a colorless oil (131 mg, 82%). IR
(film) 2954, 2253, 1754 (CdO), 1735 (CdO), 1523, 1436, 1348,
1258 cmꢀ1; 1H NMR (250 MHz, CDCl3) δ 8.15 (2H, dm, J = 8.8 Hz),
7.38 (2H, dm, J = 8.8 Hz), 4.63 (1H, br s), 4.47 (1H, br s), 3.79 (3H, s),
3.77ꢀ3.69 (2H, m), 3.48 (3H, s), 2.51 (1H, dd, J = 13.9, 3.6 Hz),
2.41ꢀ2.32 (1H, m), 1.64 (3H, s); 13C NMR (62.9 MHz, CDCl3)
δ 168.1, 167.6, 148.2, 146.9, 141.2, 129.2, 123.5, 114.0, 57.5, 52.8, 52.5,
43.4, 42.1, 21.9; HRMS (ES) exact mass calcd for C16H23N2O6 [M þ
NH4]þ 339.1551, found 339.1550.
General Procedure C: Allylation with Trimethyl-(2-phenyl-
allyl)silane. A solution of alkylidene malonate (0.50 mmol), Yb-
(OTf)3 2H2O (33 mg, 0.05 mmol), and hexafluoroisopropanol (105 μL,
3
1.00 mmol) was stirred in CH2Cl2 (2 mL) at room temperature for 10 min.
Trimethyl-(2-phenylallyl)silane27 (160 μL, 0.75 mmol) was added dropwise
over 1 min and the mixture was stirred at room temperature for 1 h. The
reaction was filtered through a short silica plug eluted with EtOAc as eluent,
and the filtrate was concentrated in vacuo. Purification of the residue by
column chromatography (10% EtOAc/hexane, unless otherwise specified)
afforded the allylated product.
Dimethyl 2-[1-(4-methoxyphenyl)-3-phenylbut-3-enyl]-
malonate (6a): The title compound was prepared following General
Procedure C from 1d (125 mg, 0.50 mmol) to give a yellow oil (176 mg,
95%). IR (film) 2954, 2253, 1753 (CdO), 1734 (CdO), 1514, 1250,
1179 cmꢀ1; 1H NMR (360 MHz, CDCl3) δ 7.34ꢀ7.24 (5H, m), 6.93
(2H, d, J = 8.7 Hz), 6.75 (2H, d, J = 8.7 Hz), 5.07 (1H, s), 4.76 (1H, s),
3.78 (3H, s), 3.76 (3H, s), 3.70 (1H, d, J = 10.4 Hz), 3.50 (1H, dt, J =
10.7, 4.3 Hz), 3.42 (3H, s), 3.12 (1H, dd, J = 13.9, 4.1 Hz), 2.66 (1H, dd,
J = 13.9, 10.9 Hz); 13C NMR (90.6 MHz, CDCl3) δ 168.8, 168.1, 158.3,
145.4, 140.3, 131.8, 129.3, 128.2, 127.4, 126.4, 115.4, 113.4, 58.1, 55.1,
52.5, 52.2, 43.1, 40.0; HRMS (ES) exact mass calcd for C22H28NO5
[M þ NH4]þ 386.1962, found 386.1968.
Dimethyl 2-(3-methyl-1-thiophen-2-ylbut-3-enyl)malo-
nate (5f): The title compound was prepared following General Procedure
B from 1g (113 mg, 0.50 mmol) to give a colorless oil (135 mg, 95%). IR
(film) 3076, 2953, 2253, 1752, 1734 (CdO), 1649, 1436, 1262,
1
1161 cmꢀ1; H NMR (360 MHz, CDCl3) δ 7.15 (1H, dd, J = 5.0,
Dimethyl 2-(3-phenyl-1-thiophen-2-yl-but-3-enyl)malo-
nate (6b): The title compound was prepared following General
Procedure C from 1g (113 mg, 0.50 mmol) to give a yellow oil (112 mg,
65%). IR (film) 3154, 3003, 2954, 2253, 1733 (CdO), 1448, 1377,
1261, 1197 cmꢀ1; 1H NMR (360 MHz, CDCl3) δ 7.26ꢀ7.18 (5H, m),
7.05 (1H, d, J = 5.1 Hz), 6.77 (1H, dd, J = 5.1, 3.3 Hz), 6.60 (1H, d, J =
3.3 Hz), 5.09 (1H, s), 4.84 (1H, s), 3.78 (1H, dt, J = 10.0, 4.5 Hz), 3.69
(3H, s), 3.65 (1H, d, J = 9.4 Hz), 3.44 (3H, s), 3.10 (1H, dd, J = 14.0, 4.2
Hz), 2.68 (1H, dd, J = 14.0, 10.4 Hz); 13C NMR (90.6 MHz, CDCl3)
δ 168.4, 167.9, 145.0, 143.1, 139.9, 128.3, 127.6, 126.4, 126.3, 125.9,
124.0, 115.7, 58.4, 52.6, 52.4, 40.8, 39.3; HRMS (ES) exact mass calcd
for C19H24NO4S [M þ NH4]þ 362.1421, found 362.1429.
1.2 Hz), 6.90ꢀ6.85 (2H, m), 4.71 (1H, s), 4.63 (1H, s), 3.96 (1H, dt, J =
9.6, 5.0 Hz), 3.75 (3H, s), 3.67 (1H, d, J = 9.4 Hz), 3.54 (3H, s), 2.52 (1H,
dd, J = 13.8, 5.0 Hz), 2.40 (1H, ddd, J = 13.8, 9.9, 0.6 Hz), 1.68 (3H, s); 13C
NMR (62.9 MHz, CDCl3) δ 168.4, 167.9, 143.6, 141.9, 126.3, 125.6, 124.0,
113.5, 58.7, 52.5, 52.4, 43.3, 39.1, 21.8; HRMS (ES) exact mass calcd for
C14H22NO4S [M þ NH4]þ 300.1264, found 300.1266.
Dimethyl 2-(1-cyclohexyl-3-methylbut-3-enyl)malonate
(5g): The title compound was prepared following General Procedure B
from 1h (125 mg, 0.50 mmol) to give a colorless oil (125 mg, 89%). IR
(film) 2929, 2253, 1730 (CdO), 1449, 1435, 1261, 1160 cmꢀ1; 1H NMR
(250 MHz, CDCl3) δ 4.74 (1H, br s), 4.70 (1H, br s), 3.71 (3H, s), 3.66
(3H, s), 3.48 (1H, d, J = 7.4 Hz2), 2.39ꢀ2.30 (1H, m), 2.21 (1H, dd, J =
14.3, 5.7 Hz), 2.03 (1H, dd, J= 14.3, 7.8 Hz), 1.80ꢀ1.54 (5H, m), 1.70 (3H,
s), 1.47ꢀ1.35 (1H, m), 1.25ꢀ0.95 (5H, m); 13C NMR (62.9 MHz,
CDCl3) δ 169.8, 169.6, 144.0, 112.3, 53.8, 52.2, 52.0, 41.0, 40.0, 37.6, 30.5,
29.0, 26.8, 26.7, 26.5, 21.7; HRMS (ES) exact mass calcd for C16H30NO4
[M þ NH4]þ 300.2169, found 300.2166.
Dimethyl 2-(3-phenyl-1-phenethylbut-3-enyl)malonate
(6c): The title compound was prepared following General Procedure C
from 1i (124 mg, 0.50 mmol) and purified by column chromatography
(50% CH2Cl2/hexane) to give a colorless oil (89 mg, 49%). IR (film) 3029,
2927, 2253, 1738 (CdO), 1732 (CdO), 1455, 1378, 1254, 1198 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 7.41ꢀ7.39 (2H, m), 7.35 (2H, t, J = 7.4 Hz),
7.31ꢀ7.23 (3H, m), 7.17 (1H, t, J = 7.3 Hz), 7.08 (2H, d, J = 7.4 Hz), 5.35
(1H, s), 5.13 (1H, s), 3.73 (3H, s), 3.71 (3H, s), 3.52 (1H, d, J = 6.0 Hz),
2.79 (1H, dd, J = 14.3, 6.5 Hz), 2.66 (1H, dd, J = 14.3, 8.3 Hz), 2.59 (2H, t,
J = 8.2 Hz), 2.34ꢀ2.27 (1H, m), 1.76ꢀ1.68 (2H, m); 13C NMR (125.8
MHz, CDCl3) δ 169.3, 169.2, 146.3, 141.9, 140.3, 128.4, 128.3, 127.6,
126.4, 125.8, 115.3, 53.9, 52.3, 52.2, 37.3, 36.1, 32.7, 32.6; HRMS (ES) exact
mass calcd for C23H30NO4 [M þ NH4]þ 384.2169, found 384.2170.
Ethyl 3-(4-methylphenyl)hex-5-enoate (7): A solution of 3j
(80 mg, 0.26 mmol), NaCl (20 mg, 0.34 mmol), and H2O (25 μL,
1.39 mmol) in DMSO (0.5 mL) was heated at 170 °C for 30 min in a
microwave synthesizer. After the solution was cooled to room tempera-
ture, H2O was added and the mixture was extracted with Et2O.
The combined organic layers were dried (MgSO4) and concentra-
ted in vacuo. Purification of the residue by column chromatography
(5% EtOAc/hexane) gave the monoester 7 (39 mg, 65%) as a colorless
oil. IR (film) 3019, 2925, 1730 (CdO), 1640, 1515, 1373, 1260,
Dimethyl 2-(1-phenethyl-but-3-enyl)malonate (5h): The
title compound was prepared following General Procedure B from 1i
(124 mg, 0.50 mmol) and purified by column chromatography (50%
CH2Cl2/hexane) to give a colorless oil (128 mg, 84%). IR (film) 3028,
2952, 2254, 1734 (CdO), 1436, 1377, 1234, 1158 cmꢀ1; 1H NMR (500
MHz, CDCl3) δ 7.30ꢀ7.27 (2H, m), 7.20ꢀ7.16 (3H, m), 4.83 (1H, s),
4.75 (1H, s), 3.75 (3H, s), 3.72 (3H, s), 3.57 (1H, d, J = 5.9 Hz), 2.65
(2H, t, J = 8.2 Hz), 2.41ꢀ2.37 (1H, m), 2.22ꢀ2.14 (2H, m), 1.82ꢀ1.66
(2H, m), 1.62 (3H, s); 13C NMR (125.8 MHz, CDCl3) δ 169.5, 169.2,
143.1, 141.9, 128.4, 128.3, 125.8, 113.1, 54.0, 52.3, 52.2, 40.2, 35.7, 32.9,
21.9; HRMS (ES) exact mass calcd for C18H28NO4 [M þ NH4]þ
322.2013, found 322.2015.
Diethyl 2-[3-methyl-1-(4-methylphenyl)but-3-enyl]malo-
nate (5i): The title compound was prepared following General
Procedure B (131 mg, 0.50 mmol) from 1j to give a colorless oil (113
mg, 71%). IR (film) 2982, 2937, 2254, 1751 (CdO), 1719 (CdO),
1513, 1444, 1254, 1156 cmꢀ1; 1H NMR (250 MHz, CDCl3) δ 7.07 (4H,
1
1216 cmꢀ1; H NMR (500 MHz, CDCl3) δ 7.11 (2H, J = 8.4 Hz),
4116
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The Journal of Organic Chemistry
NOTE
7.09 (2H, J = 8.4 Hz), 5.68 (1H, tdd, J = 17.1, 10.1, 7.0 Hz), 5.03ꢀ4.97
(2H, m), 4.09ꢀ4.00 (2H, m), 3.19 (1H, app quin, J = 7.5 Hz), 2.67 (1H,
dd, J = 15.3, 6.8 Hz), 2.55 (1H, dd, J = 15.3, 8.4 Hz), 2.41ꢀ2.37 (2H, m),
2.32 (3H, s), 1.16 (3H, t, J = 7.1 Hz); 13C NMR (125.8 MHz, CDCl3)
δ 172.4, 140.5, 136.1, 135.9, 129.0, 127.3, 116.7, 60.2, 41.4, 40.73, 40.65,
21.0, 14.1; HRMS (ES) exact mass calcd for C15H21O2 [M þ H]þ
233.1536, found 233.1539.
(4) Catalysis of conjugate allylation by HNTf2: Kuhnert, N.; Peverley,
J.; Robertson, J. Tetrahedron Lett. 1998, 39, 3215–3216.
(5) Catalysis of conjugate allylation by indium-based reagents in the
presence of superstoichiometric TMSCl: (a) Lee, P. H.; Lee, K.; Sung,
S.-y.; Chang, S. J. Org. Chem. 2001, 66, 8646–8649. (b) Lee, P. H.;
Seomoon, D.; Kim, S.; Nagaiah, K.; Damle, S. V.; Lee, K. Synthesis
2003, 2189–2193.
(6) Catalysis of conjugate allylation by FeCl3/TMSCl: Xu, L. W.;
Yang, M.-S.; Qiu, H.-Y.; Lai, G.-Q.; Jiang, J.-X. Synth. Commun. 2008,
38, 1011–1019.
(7) Catalysis of conjugate allylation by I2: Yadav, J. S.; Reddy,
B. V. S.; Sadasiv, K.; Satheesh, G. Tetrahedron Lett. 2002, 43, 9695–9697.
(8) (a) Shaghafi, M. B.; Kohn, B. L.; Jarvo, E. R. Org. Lett. 2008,
10, 4743–4746. (b) Waetzig, J. D.; Swift, E. C.; Jarvo, E. R. Tetrahedron
2009, 65, 3197–3201.
(9) Dumas, A. M.; Fillion, E. Org. Lett. 2009, 11, 1919–1922.
(10) (a) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 2214–2215. (b) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008,
130, 4978–4983. (c) Brozek, L. A.; Sieber, J. D.; Morken, J. P. Org. Lett.
2011, 13, 995–997.
(11) Shizuka, M.; Snapper, M. L. Angew. Chem., Int. Ed. 2008, 47,
5049–5051.
(12) For the conjugate allylation of alkylidene malonates with
allylsamarium bromide, see: Zheng, Y. F.; Bao, W. L.; Zhang, Y. M.
Chin. Chem. Lett. 2000, 11, 5–8.
(13) For selected examples of catalytic enantioselective conjugate
additions to alkylidene malonates, see: (a) Evans, D. A.; Rovis, T.;
Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000,
122, 9134–9142. (b) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry
2001, 12, 1151–1157. (c) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002,
124, 9030–9031. (d) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.;
Tanaka, F.; Barbas., C. F., III Synthesis 2004, 1509–1521. (e) Zhou, J.;
Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309–1320.
(f) Schuppan, J.; Minnaard, A. J.; Feringa, B. L. Chem. Commun.
2004, 792–793. (g) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc.
2008, 130, 14066–14067. (h) Zhao, G.-L.; Dziedzic, P.; Ullah, F.;
Eriksson, L.; Cꢀordova, A. Tetrahedron Lett. 2009, 50, 3458–3462.
(i) Liu, J.; Yang, Z.; Liu, X.; Wang, Z.; Liu, Y.; Bai, S.; Lin, L.; Feng, X.
Org. Biomol. Chem. 2009, 7, 4120–4127.
Dimethyl 2-[3-oxo-1-(4-methylphenyl)butyl]malonate (8):
To a solution of 5c (100 mg, 0.35 mmol) and PhI(OAc)2 (259 mg,
0.80 mmol) in THF (1 mL) at room temperature were added H2O
(0.1 mL), 2,6-lutidine (0.1 mL, 0.86 mmol), and OsO4 (4% soln in H2O,
50 μL, 0.008 mmol), then the mixture was stirred at room temperature for
18 h. The reaction wasquenchedwith saturatedaqueous Na2S2O3 solution
and extracted with EtOAc. The combined organic layers were washed with
saturated aqueous CuSO4 solution, dried (NaSO4), filtered, and concen-
trated in vacuo. Purification of the residue by column chromatography
(5% EtOAc/hexanef20% EtOAc/hexane) gave the ketone 8 (70 mg,
68%) as a colorless oil. IR (film) 3053, 3020, 2985, 1751 (CdO), 1735
(CdO), 1437, 1378, 1265, 1216 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ
7.11 (2H, d, J = 8.2 Hz), 7.07 (2H, d, J = 8.0 Hz), 3.94 (1H, dt, J = 9.1, 5.3
Hz), 3.72 (3H, s), 3.71 (1H, d, J = 10.8 Hz), 3.51 (3H, s), 2.92 (2H, dq, J =
16.7, 7.0 Hz), 2.29 (3H, s), 2.03 (3H, s); 13C NMR (100.6 MHz, CDCl3)
δ 206.1, 168.6, 168.1, 137.2, 136.8, 129.2, 127.8, 57.2, 52.6, 52.3, 47.2, 40.1,
30.2, 21.0; HRMS (ES) exact mass calcd for C16H21O5 [M þ H]þ
293.1384, found 293.1385.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra for all
b
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: h.lam@ed.ac.uk.
(14) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325–335.
(15) See for example: Ahmad, S.; Doweyko, L. M.; Dugar, S.;
Grazier, N.; Ngu, K.; Wu, S. C.; Yost, K. J.; Chen, B.-C.; Gougoutas,
J. Z.; DiMarco, J. D.; Lan, S.-L.; Gavin, B. J.; Chen, A. Y.; Dorso,
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’ ACKNOWLEDGMENT
This work was supported by the Scottish Funding Council, the
University of Edinburgh, and Shasun Pharma Solutions Ltd.
Preliminary experiments were conducted at Harvard University
and Professor David A. Evans is gratefully acknowledged for
support. We also thank the EPSRC National Mass Spectrometry
Service Centre at the University of Wales, Swansea, for providing
high-resolution mass spectra.
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NOTE
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