Asymmetric intermolecular Stetter reactions of aromatic heterocyclic aldehydes with arylidenemalonates

Article abstract of DOI:10.1055/s-0028-1083229

The asymmetric Michael addition of aromatic heterocyclic aldehydes to arylidenemalonates catalyzed by N-heterocyclic carbenes is described. The ketomalonates are obtained in 84-98% yields and moderate to good enantioselectivities (30-78% ee). The enantiomeric excesses could be improved to excellent levels of up to 99% ee after a single recrystallization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083229

3864
PAPER
Asymmetric Intermolecular Stetter Reactions of Aromatic Heterocyclic
Aldehydes with Arylidenemalonates
A
symmetric Stette
i
r
React
e
ions ter Enders,* Jianwei Han
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 21 August 2008; revised 2 September 2008
O
O
Abstract: The asymmetric Michael addition of aromatic heterocy-
NHC catalyst
EWG
+
*
R2
R1
EWG
clic aldehydes to arylidenemalonates catalyzed by N-heterocyclic
carbenes is described. The ketomalonates are obtained in 84–98%
yields and moderate to good enantioselectivities (30–78% ee). The
enantiomeric excesses could be improved to excellent levels of up
to 99% ee after a single recrystallization.
R1
H
R2
Scheme 1 The intermolecular Stetter reaction
Key words: Stetter reaction, N-heterocyclic carbene, organocataly-
sis, nucleophilic acylation, umpolung
O
CO2Me
CO2Me
CO2Me
O
NHC
Ph
*
+
base, solvent
CO2Me
O
H
O
Ph
1
2
3
N-Heterocyclic carbene (NHC) organocatalysis is a rapid-
ly growing field allowing a broad range of synthetic trans-
formations.1 Among the various catalytic carbon–carbon
bond-forming processes, the Stetter reaction2 plays an im-
portant role allowing conjugate nucleophilic acylations
and thus the Umpolung of the classical carbonyl reactivi-
ty.3 Although a number of efficient protocols for inter-
and intramolecular Stetter reactions have been developed
recently,4 high asymmetric inductions in the classical in-
termolecular Stetter reaction (Scheme 1) remain a chal-
Bn
Bn
Ph
Bn
N
N
BF4
N
N
N
N
N
N
BF4
BF4
BF4
N
N
N
N
OTBS
Me
O
Ph
OTIPS
OTBDPS
Me
4a
4b
4d
4c
Scheme 2 Asymmetric nucleophilic acylation of benzylidenemalo-
nate catalyzed by different N-heterocyclic carbenes
lenge.
Especially,
enantioselective
nucleophilic
acylations employing heterocyclic aldehydes as substrates
in the intermolecular Stetter reaction5 would open an entry
to pharmaceutically interesting synthetic building blocks.
crucial for the asymmetric Stetter reaction. Increasing the
steric bulk of the catalyst side chain with a geminal di-
methyl group as in 4c did not give 3 and the sterically de-
manding Breslow intermediate8 gave rise to furoin again.
Even the novel and less bulky phenylalaninol-derived pre-
catalyst 4d bearing the crucial N-benzyl group did not re-
sult in the desired Stetter product.
Based on our recent results in nucleophilic acylations of
chalcones6 we now wish to report on the application of the
triazolium salt 4a as a precatalyst in asymmetric intermo-
lecular Stetter reactions of aromatic heterocyclic alde-
hydes with arylidenemalonates.
In order to improve the enantioselectivity, we next
screened various reaction conditions. As shown in
Table 1, organic bases such as Et3N resulted in poor con-
version (8%) and a variety of inorganic bases (t-BuOK,
K2CO3, and Cs2CO3) in THF led to an improvement (en-
tries 6–8). To our delight, the precatalyst 4a with Cs2CO3
in THF gave the desired product in high yield of 90% and
78% ee (entry 8). By switching to other solvents such as
dichloromethane, toluene, or even a protic solvent such as
EtOH, it turned out that THF is the best choice for both the
selectivity and reactivity. It is worthy to note that the sys-
tem of KHMDS combined with toluene afforded compa-
rable results in 77% yield and 70% ee (entry 12).
Increasing the temperature to 40 °C led to a small increase
of the yield from 90 to 94%, but a significant decrease in
enantioselectivity was observed (entry 13).
Our initial study began with the Stetter reaction of 2-fural-
dehyde (1) with dimethyl benzylidenemalonate (2) to
form the keto diester 3 (Scheme 2). Several bicyclic tri-
azolium type precatalysts 4a–d were tested. Based on our
previous studies with chalcone as Michael acceptor,6 we
were pleased to find that the precatalyst 4a (10 mol%),
easily prepared from the cheap enantiopure source pyro-
glutamic acid,6,7 in the presence of DBU as base and THF
as solvent at room temperature gave 3 in good yields
(86%) and with an enantiomeric excess of 59% (Table 1,
entry 1). The closely related precatalyst 4b bearing an N-
benzyl instead of an N-phenyl substituent afforded only
furoin as the product of the corresponding benzoin con-
densation. This indicates that the N-benzyl substituent is
SYNTHESIS 2008, No. 23, pp 3864–3868
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083229; Art ID: Z19408SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
Next, with the optimum catalytic conditions identified,
the scope of the reaction was explored. Employing the de-
veloped protocol, several aromatic heterocyclic aldehydes

PAPER
Asymmetric Stetter Reactions
3865
Table 1 Optimization of the Reaction Conditions for the Keto Di-
ester 3a
Table 2 Substrate Scope of the Asymmetric Intermolecular Stetter
Reaction with Arylidenemalonates
Entry Precat. Base
Solvent
THF
Yield (%)b ee (%)c
7
a
b
c
d
e
f
R1
R2
Yield (%)a
90 (53)
92 (50)
85 (45)
88 (42)
84 (60)
94
ee (%)b,c
78 (99)
62 (95)d
68 (94)
70 (99)
72 (90)d
30e
1
2
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4a
4a
4a
DBU
86
0
59
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-pyridyl
2-furyl
Ph
DBU
THF
–
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
3
DBU
THF
0
–
4
DBU
THF
0
–
5
Et3N
THF
8
n.d.
65
6
K2CO3
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KHMDS
Cs2CO3
THF
66
73
90
5
7
THF
65
g
2-pyridyl
98
40e
a Values in brackets are the yields after recrystallization.
b The enantiomeric excesses were determined by HPLC with a chiral
stationary phase (Daicel Chiralpak AD).
8
THF
78 (>99)d
n.d.
n.d.
48
9
CH2Cl2
toluene
EtOH
toluene
THF
c Values in brackets refer to the enantiomeric excesses after recrystal-
lization.
10
11
12
13
3
d The racemate crystallized, and the enantioenriched products were
obtained from the mother liquor.
42
77
94
e The products were obtained as thick oils.
70 (98)d
60e
Re-attack (favored)
a The reaction was performed at 23 °C for 6 h.
b Determined by GC.
N
N
Ph
Furyl
N
O
c Determined by HPLC with a chiral stationary phase (Daicel Chiral-
pak AD).
OMe
OMe
Ph
d The value in brackets refers to the ee after recrystallization.
e The reaction was performed at 40 °C.
O
H
O
O
Ph
t-Bu
Si
Ph
O
CO2Me
CO2Me
CO2Me
CO2Me
R2
4a (10 mol%)
R1CHO
+
R1
Si-attack (blocked)
Cs2CO3, THF
R2
Figure 1 Proposed transition state
5
6
7
Scheme 3 Asymmetric intermolecular Stetter reactions with aryl-
idenemalonates
The R-configuration given for the keto diesters 7 is based
on the relative topicity shown in the proposed transition
state (Figure 1). The Si-face of the Breslow intermediate
is blocked by the sterically demanding silyl group and the
1,4-addition occurs at the Si-face of the arylidenema-
lonate. This would be in accord with the recently reported
stereochemical outcome of intermolecular Stetter reac-
tions of aromatic aldehydes with chalcones.6
5 and arylidenemalonates 6 could be smoothly trans-
formed to the corresponding Stetter products
7
(Scheme 3). As summarized in Table 2, furfural reacted
with various arylidenemalonates, easily prepared by
Knoevenagel condensation,9 bearing halogen or alkyl
substituents in the para and meta position of the phenyl
ring in excellent yields (84–92%) and enantioselectivities
of 62–78% ee. With a single recrystallization the enantio-
meric excesses of the Stetter products 7a–e could be en-
hanced to practical levels of 90–99% ee. Interestingly, in
two cases, 7b and 7e, the racemate crystallized first and
the highly enantioenriched ketomalonates were isolated
from the mother liquor. Besides furfural, 2-pyridinecar-
baldehyde gave 7f in an excellent yield of 94%; however,
the asymmetric induction was low (ee = 30%). A pyridine
moiety can also be present in the malonate Michael accep-
tor and an excellent yield of 98% could be achieved for
7g, albeit with a modest ee of 40%. In contrast, no reaction
was observed in the case of 2-pyrrolecarbaldehyde.
To illustrate the preparative utility of the enantioselective
Stetter reaction, the addition of 2-furaldehyde to ben-
zylidenemalonate was performed on a 10 mmol scale to
give 2.58 g (82% yield) of 7a in 80% ee, which opens a
practical entry to gram-scale nucleophilic acylation prod-
ucts.
In summary, we have developed an asymmetric intermo-
lecular Stetter reaction of aromatic heterocyclic aldehydes
with arylidenemalonates, which afforded ketomalonates
in good yields and excellent enantiomeric excesses after a
single recrystallization. Efforts to extend the reaction
scope and to optimize the catalyst structures are currently
under way in our laboratories.
Synthesis 2008, No. 23, 3864–3868 © Thieme Stuttgart · New York

3866
D. Enders, J. Han
PAPER
J = 16.1 Hz, 1 H, C(N)CHHO], 4.96 [d, J = 16.1 Hz, 1 H,
C(N)CHHO], 5.40 (s, 2 H, NCH2Ph), 7.13–7.22 (m, 5 H, Ph-H),
7.33–7.40 (m, 5 H, Ph-H), 9.37 (s, 1 H, NCHN).
13C NMR (75 MHz, CDCl3): d = 38.4, 56.2, 56.8, 61.9, 65.5, 127.6,
127.7, 129.1, 129.2, 129.3, 129.4, 129.5, 131.6, 134.5, 141.3, 149.4.
All solvents were dried by conventional methods. Toluene and THF
were freshly distilled from Na/Pb alloy under argon. The aldehydes
were freshly distilled or recrystallized, the arylidenemalonates were
prepared according to standard literature procedures.8 Other starting
materials and reagents were purchased from commercial suppliers
and used without further purification. Preparative column chroma-
tography: Merck silica gel 60, particle size 0.040–0.063 mm (230–
240 mesh, flash). Analytical TLC: silica gel 60, F254 plates from
Merck, Darmstadt. Optical rotations were measured on a Perkin-
Elmer P241 polarimeter. IR spectra were taken on a Perkin-Elmer
–
MS (ESI): m/z = 306 (100, M+), 240 (1), 87 (100, BF4 ).
–
Anal. Calcd for C19H20N3O+BF4 : C, 58.04; H, 5.13; N, 10.69.
Found: C, 58.05; H, 5.66; N, 10.42.
1
FT/IR 1760 spectrophotometer. H and 13C NMR spectra were re-
Asymmetric Intermolecular Stetter Reaction; (R)-Dimethyl 2-
[1-Phenyl-2-(furan-2-yl)-2-oxoethyl]malonate (7a); Typical
Procedure
corded on Varian Gemini 300, Mercury 300 or Inova 400 spectrom-
eters and all measurements were performed with TMS as internal
standard. Mass spectra were acquired on a Finnigan SSQ 7000 spec-
trometer (CI 100 eV; EI 70 eV). Microanalyses were obtained with
a Vario EL element analyzer. Melting points were determined with
a Tottoli melting point apparatus and are uncorrected. Analytical
HPLC was performed on Hewlett-Packard 1100 Series chromato-
graphs using chiral stationary phases (Daicel OD, Daicel AD,
Whelk).
A dry, argon-flushed Schlenk tube was charged with precatalyst 4a
(27 mg, 0.05 mmol, 10 mol%), anhyd Cs2CO3 (16 mg, 0.05 mmol)
and the dimethyl benzylidenemalonate (6a; 110 mg, 0.5 mmol). Af-
ter the addition of absolute THF (1 mL) at r.t., 2-furaldehyde (58
mg, 0.6 mmol) was added and the mixture was stirred for 6 h. The
solvent was evaporated and the residue was directly purified by
flash chromatography on silica gel (eluent: pentane–Et2O, 2:1) to
give the Stetter product (127 mg, 90%) as a colorless solid. Crystal-
lization from Et2O afforded 7a (75 mg, 53%) as a flocky colorless
solid; mp 103 °C; [a]D23 –194.5 (c 1.01, CHCl3).
Precatalysts 4c and 4d; General Procedure
A 100 mL round-bottomed flask was charged with the correspond-
ing lactam7,10 (5 mmol) and CH2Cl2 (50 mL). Trimethyloxonium
tetrafluoroborate (0.8 g, 5.5 mmol) was added and the mixture
stirred for 12 h at r.t. Benzylhydrazine (0.6 mL, 5.5 mmol) was add-
ed to the solution and stirred for another 12 h. The solvent was re-
moved in vacuo and the product was used without further
purification. Trimethyl orthoformate (30 mL) was added and the
mixture was refluxed for 12 h. The excess of orthoformate was re-
moved in vacuo to give the desired product. Compound 4c was pu-
rified by chromatography on silica gel (eluent: EtOAc) to yield the
product as a thick oil. Compound 4d was purified by recrystalliza-
tion from hot EtOAc to afford colorless crystals.
HPLC: tR = 5.75 and 8.02 min (Daicel OD, 250 × 4.6 mm, n-hep-
tane–i-PrOH, 8:2, 1.0 mL/min); tR = 8.02 min; ee = 78%; ee after
recrystallization, >99%.
IR (KBr): 3854, 3744, 3432, 2361, 2340, 1742, 1668, 1560, 1464,
1313, 1194, 1150, 1088, 1015, 939, 784, 560 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.46 (s, 3 H, OCH3), 3.73 (s, 3 H,
OCH3), 4.45 [d, J = 11.6 Hz, 1 H, CH(CO2Me)], 5.12 (d, J = 11.6
Hz, 1 H, PhCH), 6.46 (m, 1 H, furyl-H), 7.21 (m, 1 H, furyl-H),
7.23–7.33 (m, 5 H, Ph-H), 7.53 (m, 1 H, furyl-H).
13C NMR (100 MHz, CDCl3): d = 52.4, 52.6, 53.0, 54.7, 112.4,
118.5, 128.0, 128.8, 128.9, 146.7, 168.2, 168.3, 185.5.
MS (EI, 70 eV): m/z (%) = 316 (20, M+), 300 (20), 284 (24), 253
(11), 252 (35), 225 (10), 184 (15), 162 (6), 156 (3), 131 (18), 121
(37), 95 (100), 77 (6).
(S)-2-Benzyl-5-[2-(tert-butyldimethylsilyloxy)propan-2-yl]-6,7-
dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluorobo-
rate (4c)
Yield: 1.35 g (60%); thick oil; [a]D23 –12.6 (c 1.01, CHCl3).
IR (KBr): 3139, 3036, 2951, 2856, 2812, 2361, 1833, 1648, 1586,
1532, 1459, 1379, 1258, 1047, 882, 835, 757, 522 cm–1.
Anal. Calcd for C17H16O6: C, 64.55; H, 5.10. Found: C, 64.39; H,
5.03.
1H NMR (300 MHz, CDCl3): d = 0.00 and 1.10 (2 s, 6 H, SiCH3),
0.67 [s, 9 H, SiC(CH3)3], 1.38 and 1.52 [2 s, 6 H,C(CH3)2], 2.77 (m,
1 H, NCHCHH), 2.97 (m, 1 H, NCHCHH), 3.07–3.16 [m, 2 H,
C(N)CH2], 4.76 (dd, J = 8.5, 3.6 Hz, 1 H, NCH), 5.53 (d, J = 5.8
Hz, 1 H, NCHHPh), 5.67 (d, J = 5.8 Hz, 1 H, NCHHPh), 7.23–7.60
(m, 5 H, Ph-H), 9.73 (s, 1 H, NCHN).
13C NMR (75 MHz, CDCl3): d = –2.7, –2.5, 17.5, 21.6, 25.3, 26.2,
27.3, 28.6, 56.4, 70.0, 73.9, 108.5, 128.8, 129.0, 129.1, 129.2,
132.1, 138.9, 162.8.
(R)-Dimethyl 2-[1-(4-Chlorophenyl)-2-(furan-2-yl)-2-oxoeth-
yl]malonate (7b)
Yield: 161 mg (92%); colorless solid; mp 95 °C; [a]D23 –222.2 (c
1.01, CHCl3).
HPLC: tR = 7.79 and 9.69 min (Daicel OD, 250 × 4 mm, n-heptane–
i-PrOH, 9:1, 1.0 mL/min); tR = 9.69 min; ee = 62%; ee after
recrystallization, 97%.
IR (KBr): 3130, 2959, 1743, 1668, 1226, 1194, 1149, 1090, 1013,
940, 906, 784, 752, 716, 622, 562 cm–1.
–
MS (ESI): m/z = 372 (100, M+), 240 (1), 87 (100, BF4 ).
1H NMR (300 MHz, CDCl3): d = 3.42 (s, 3 H, OCH3), 3.64 (s, 3 H,
OCH3), 4.35 [d, J = 11.6 Hz, 1 H, CH(CO2Me)2], 5.05 (d, J = 11.6
Hz, 1 H, PhCH), 6.52 (dd, J = 3.5, 2.5 Hz, 1 H, furyl-H), 7.15 (m,
1 H, furyl-H), 7.18–7.21 (m, 4 H, Ph-H), 7.64 (dd, J = 0.7, 1.8 Hz,
1 H, furyl-H).
13C NMR (100 MHz, CDCl3): d = 52.2, 52.6, 52.9, 54.5, 112.5,
118.7, 129.2, 130.2, 132.8, 134.2, 146.9, 151.4, 167.8, 168.2, 185.5.
HRMS: m/z calcd for [C21H34N3OSi+ – 2 H]: 370.2315; found:
370.2309.
(S)-2,5-Dibenzyl-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]ox-
azin-2-ium Tetrafluoroborate (4d)
Yield: 1.7 g (85%); colorless crystals; mp 132 °C; [a]D23 –46.5 (c
1.01, CHCl3).
MS (EI, 70 eV): m/z (%) = 350 (8, M+), 317 (5), 285 (10), 258 (3),
195 (4), 164 (16), 154 (17), 136 (8), 114 (4), 102 (12), 101 (11), 95
(100), 75 (4), 59 (11).
IR (KBr): 3437, 3176, 3063, 3030, 2959, 2854, 2361, 2340, 1357,
1545, 1496, 1453, 1402, 1370, 1305, 1190, 1160, 1062, 941, 903,
868, 830, 761, 709 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.13 (dd, J = 13.6, 9.4 Hz, 1 H,
PhCHHCH), 3.37 (dd, J = 13.6, 6.4 Hz, 1 H, PhCHHCH), 3.95 (d,
J = 1.4 Hz, 2 H, CHCH2O), 4.79 (m, 1 H, NCHBn), 4.80 [d,
Anal. Calcd for C17H15ClO6: C, 58.21; H, 4.31. Found: C, 58.33; H,
4.66.
Synthesis 2008, No. 23, 3864–3868 © Thieme Stuttgart · New York

PAPER
Asymmetric Stetter Reactions
3867
(R)-Dimethyl 2-[1-(3-Chlorophenyl)-2-(furan-2-yl)-2-oxoeth-
yl]malonate (7c)
MS (EI, 70 eV): m/z (%) = 330 (34, M+), 298 (19), 266 (49), 239 (7),
235 (10), 198 (4), 191 (10), 176 (5), 149 (3), 145 (21), 135 (100),
115 (14), 95 (39), 59 (6).
Yield: 148 mg (85%); colorless solid; mp 78 °C; [a]D23 –240.0 (c
1.01, CHCl3).
Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.27; H,
5.37.
HPLC: tR = 11.62 and 13.76 min (Whelk M, 250 × 4.6 mm, n-hep-
tane–EtOH, 95:5, 1.0 mL/min); tR = 11.62 min; ee = 68%; ee after
recrystallization, 94%.
(R)-Dimethyl2-[1-Phenyl-2-(pyridin-2-yl)-2-oxoethyl]malonate
(7f)
IR (KBr): 3418, 3127, 2956, 2363, 1739, 1656, 1564, 1463, 1394,
1310, 1255, 1225, 1194, 1086, 1023, 977, 615, 590, 540, 511cm–1.
Yield: 154 mg (94%); colorless solid; mp 102 °C; [a]D23 –123.1 (c
1.01, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.52 (s, 3 H, OCH3), 3.74 (s, 3 H,
OCH3), 4.43 [d, J = 11.7 Hz, 1 H, CH(CO2Me)2], 5.12 (d, J = 11.7
Hz, 1 H, PhCH), 6.51 (dd, J = 1.7, 3.6 Hz, 1 H, furyl-H), 7.23–7.24
(m, 4 H, Ph-H), 7.26 (m, 1 H, furyl-H), 7.58 (dd, J = 1.0, 1.8 Hz, 1
H, furyl-H).
13C NMR (100 MHz, CDCl3): d = 52.4, 52.6, 53.1, 54.6, 112.6,
118.8, 127.1, 128.5, 128.9, 130.1, 147.1, 167.0, 168.0, 185.0.
HPLC: tR = 9.45 and 11.71 min (Daicel OD, 250 × 4.6 mm, n-hep-
tane–i-PrOH, 8:2, 0.7 mL/min); tR = 11.71 min; ee = 30%.
IR (KBr): 3049, 3007, 2954, 1750, 1728, 1696, 1581, 1493, 1439,
1295, 1258, 1191, 1158, 1093, 1027, 995, 965, 943, 918, 782, 761,
701, 603, 548 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.50 (s, 3 H, OCH3), 3.71 (s, 3 H,
OCH3), 4.34 [d, J = 12.0 Hz, 1 H, CH(CO2Me)2], 5.04 (d, J = 12.0
Hz, 1 H, Ph-H), 7.15–7.28 (m, 3 H, Ph-H), 7.37–7.43 (m, 3 H, Ph-
H and pyridyl-H), 7.66 (m, 1 H, pyridyl-H), 8.00 (m, 1 H, pyridyl-
H), 8.70 (m, 1 H, pyridyl-H).
13C NMR (75 MHz, CDCl3): d = 50.3, 52.4, 52.8, 55.2, 122.8,
127.1, 127.7 128.6, 129.4, 134.3, 136.7, 149.0, 152.0, 168.2, 168.7,
168.3, 168.7, 198.2.
MS (EI, 70 eV): m/z (%) = 327 (85, M+), 295 (85), 268 (100), 263
(70), 235 (75), 208 (70), 195 (75), 180 (50), 167 (60), 131 (85), 121
(80), 106 (75), 77 (80), 59 (45), 51 (46).
MS (EI, 70 eV): m/z (%) = 350 (10, M+), 332 (8), 319 (10), 286 (10),
218 (10), 165 (10), 155 (8), 95 (100).
Anal. Calcd for C17H15ClO6: C, 58.21; H, 4.31. Found: C, 58.64; H,
4.13.
(R)-Dimethyl 2-[1-(4-Bromophenyl)-2-(furan-2-yl)-2-oxoeth-
yl]malonate (7d)
Yield: 173 mg (88%); colorless solid; mp 138 °C; [a]D23 –168.6 (c
1.01, CHCl3).
HPLC: tR = 8.35 and 9.65 min (Daicel OD, 250 × 4.6 mm, n-hep-
tane–i-PrOH, 8:2, 0.7 mL/min); tR = 9.65; ee = 70%; ee after re-
crystallization, 99%.
Anal. Calcd for C18H17NO5: C, 66.05; H, 5.32; N, 4.28. Found: C,
66.06; H, 5.24; N, 4.26.
IR (KBr): 3127, 2953, 2361, 2339, 1745, 1656, 1561, 1468, 1435,
1399, 1325, 1266, 1231, 1202, 1158, 1013, 939, 783, 748, 556 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.44 (s, 3 H, OCH3), 3.65 (s, 3 H,
OCH3), 4.34 [d, J = 12.2 Hz, 1 H, CH(CO2Me)2], 5.04 (d, J = 12.2
Hz, 1 H, PhCH), 6.41 (dd, J = 1.7, 3.6 Hz, 1 H, furyl-H), 7.15 (m,
4 H, Ph-H), 7.33 (m, 2 H, furyl-H).
(R)-Dimethyl 2-[2-(Furan-2-yl)-1-(pyridin-2-yl)-2-oxoethyl]ma-
lonate (7g)
Yield: 155 mg (98%); colorless oil; [a]D23 –175.0 (c 1.01, CHCl3).
HPLC: tR = 9.07 and 11.35 min (Daicel OD, 250 × 4.6 mm, n-hep-
tane–i-PrOH, 6:4, 0.7 mL/min); tR = 11.35 min; ee = 40%.
IR (KBr): 2954, 2359, 2340, 1742, 1677, 1569, 1464, 1303, 1198,
1158, 1027, 758, 599 cm–1.
13C NMR (75 MHz, CDCl3): d = 52.3, 52.7, 52.8, 54.5, 112.5,
120.2, 122.3, 130.5, 132.2, 133.2. 146.5, 149.3, 167.7, 168.1, 185.3.
1H NMR (300 MHz, CDCl3): d = 3.54 (s, 3 H, OCH3), 3.75 (s, 3 H,
OCH3), 4.69 [d, J = 11.4 Hz, 1 H, CH(CO2Me)2], 5.38 (d, J = 11.4
Hz, 1 H, pyridyl-H), 6.50 (dd, J = 3.7, 1.7 Hz, 1 H, furyl-H), 7.15
(m, 1 H, pyridyl-H), 7.30 (dd, 1 H, J = 3.5, 1.0 Hz, pyridyl-H), 7.44
(m, 1 H, pyridyl-H), 7.56 (dd, J = 1.7, 0.7 Hz, 1 H, furyl-H), 7.63
(m, 1 H, pyridyl-H), 8.55 (m, 1 H, furyl-H).
13C NMR (75 MHz, CDCl3): d = 52.6, 52.9, 53.4, 55.3, 112.5,
119.0, 122.7, 124.1, 136.8, 146.8, 149.9, 151.7, 154.7, 168.2, 168.5,
184.5.
MS (EI, 70 eV): m/z (%) = 318 (44, M + 1+), 317 (23, M+), 289
(100), 263 (17), 258 (29), 254 (50), 231 (11), 230 (75), 226 (22),
204 (38), 198 (27), 190 (16), 186 (77), 170 (12), 158 (14), 132 (28),
104 (16), 95 (96), 78 (14), 78 (14), 51 (8).
MS (EI, 70 eV): m/z (%) = 396 (13, M+), 364 (10), 362 (10), 332
(21), 330 (22), 211 (7), 209 (11), 201 (12), 199 (15), 184 (3), 155
(2), 128 (4), 102 (11), 95 (100), 75 (2), 59 (7), 51 (2).
HRMS: m/z calcd for [C17H15O6Br]: 394.0052; found: 394.0054.
(R)-Dimethyl 2-[1-p-Tolyl-2-(furan-2-yl)-2-oxoethyl]malonate
(7e)
Yield: 138 mg (84%); colorless solid; mp 82 °C, [a]D23 –180.8 (c
1.01, CHCl3).
HPLC: tR = 7.13 and 9.29 min (Daicel OD, 250 × 4.6 mm, n-hep-
tane–i-PrOH, 9:1, 1.0 mL/min); tR = 9.29; ee = 72%; ee after re-
crystallization, 90%.
IR (KBr): 3137, 2958, 2863, 2359, 2341, 1745, 1667, 1565, 1513,
1465, 1309, 1228, 1188, 149, 1039, 951, 776, 585 cm–1.
HRMS: m/z calcd for [C16H15NO6]: 318.0978; found: 318.0978.
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H, 4-CH3Ph), 3.41 (s, 3
H, OCH3), 3.49 (s, 3 H, OCH3), 4.36 [d, J = 11.8 Hz, 1 H,
CH(CO2Me)2], 5.01 (d, J = 11.8 Hz, 1 H, 4-CH3PhCH), 6.38 (dd,
J = 3.7, 1.8 Hz, 1 H, furyl-H), 7.01 (m, 2 H, Ph-H), 7.12 (m, 2 H,
Ph-H), 7.13 (m, 1 H, furyl-H), 7.45 (dd, J = 0.7, 1.8 Hz, 1 H, furyl-
H).
13C NMR (75 MHz, CDCl3): d = 17.9, 52.49, 52.60, 52.90, 54.70,
113.1, 118.5, 128.7, 129.6, 131.1, 137.9, 149.4, 151.6, 168.1, 168.5,
186.0.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Priority Programme 1179 Organocatalysis) and the Fonds der Che-
mischen Industrie. We thank the former Degussa AG, BASF AG,
Bayer AG, and Wacker Chemie for the donation of chemicals.
Synthesis 2008, No. 23, 3864–3868 © Thieme Stuttgart · New York

3868
D. Enders, J. Han
PAPER
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