N-heterocyclic carbene-catalyzed conjugate umpolung for the synthesis of γ-butyrolactones

Article abstract of DOI:10.1055/s-2006-942447

The N-heterocyclic carbene-catalyzed conjugate Umpolung of differently substituted α,β-unsaturated aldehydes, e. g. cinnamaldehydes, α-methylcinnamaldehydes, and crotonaldehydes, is described. Coupling of these compounds with a variety of electrophilic al

Full text of DOI:10.1055/s-2006-942447

2
418
FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung for the Synthesis of
g-Butyrolactones
N
C
-Heterocyclic
C
h
arbene-Cata
r
lyzed Co
i
njugate
s
U
mpolun
t
g
for
t
i
he Syn
a
thesis of
g
-
n
B
utyrolactones Burstein, Serena Tschan, Xiulan Xie, Frank Glorius*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany
Fax +49(6421)2825629; E-mail: glorius@chemie.uni-marburg.de
Received 30 March 2006; revised 4 May 2006
Dedicated to the memory of Professor Nabi Magomedov and his family.
6
homoenolate equivalents ) upon attack of a suitable nu-
cleophilic catalyst on the aldehyde function (Scheme 1).
Here we report an organocatalyzed, chemo- and stereose-
(
Abstract: The N-heterocyclic carbene-catalyzed conjugate Umpol-
ung of differently substituted a,b-unsaturated aldehydes, e. g. cin-
namaldehydes, a-methylcinnamaldehydes, and crotonaldehydes, is
described. Coupling of these compounds with a variety of electro- lective reaction of a,b-unsaturated aldehydes with a vari-
philic aldehydes and ketones results in the selective formation of ety of different aldehydes and ketones to give substituted
7
c
highly substituted b- and g-butyrolactones.
b-lactone and g-butyrolactone products.
Key words: carbenes, Umpolung, lactones, heterocycles, cycliza-
tion
Aromatic Aldehydes as Electrophiles
Our investigation commenced with the reaction of cinna-
maldehyde with 4-chlorobenzaldehyde. The Umpolung of
these two compounds can lead to a variety of different
products: benzoin products, Stetter products and the prod-
ucts arising from conjugate Umpolung (Scheme 2). Many
different catalysts were screened and it became obvious
that the catalyst has a dramatic influence on the outcome
of this transformation. Using a combination of the com-
mercially available thiazolium salt 2 (Figure 1) and an
equimolar amount of base resulted in the formation of the
corresponding benzoin products only, with no g-butyro-
lactone being formed. Interestingly, employing potassium
cyanide (30 mol%) in combination with 18-crown-6 (10
mol%) gave lactone 1a, albeit in low yield (Scheme 3,
Table 1, entry 2).
Introduction
The inversion of the commonly accepted reactivity pat-
1
tern of a functional group, the Umpolung, is a versatile
and fertile concept that allows new chemical transforma-
2
tions. Stoichiometric as well as catalytic methods for
Umpolung have been known for a long time, and have be-
come standard tools in organic synthesis. The catalytic
Umpolung of electrophilic aldehydes upon addition of nu-
cleophilic catalysts like cyanide or thiazolium carbenes is
3
an extraordinarily attractive approach. The resulting nu-
cleophiles can react with aromatic aldehydes (benzoin
4
condensation ) or with electron-poor, polarized olefins
5
1
Stetter reaction ). In contrast to this a -to-d -Umpolung,
1
(
the term ‘conjugate’ Umpolung describes the transforma-
3
tion of a,b-unsaturated aldehydes into d -nucleophiles
N
X
OH
R
O
R
O
2
R CHO
N
R2
R1
R1
H
R1
benzoin
condensation
OH
a1
d1
X
electrophilic
nucleophilic
OH
O
R
N
X
O
R
2
N
R CHO
R1
O
R1
H
lactone
synthesis
this paper)
X
a3
a1
d3
nucleophilic
homoenolate equivalent
R1
R2
(
1
electrophilic
Scheme 1 Umpolung versus conjugate Umpolung
SYNTHESIS 2006, No. 14, pp 2418–2439
x
x.
x
x
.
2
0
0
6
Advanced online publication: 07.07.2006
DOI: 10.1055/s-2006-942447; Art ID: T05706SS
Georg Thieme Verlag Stuttgart · New York
©

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2419
7
c
7d
OH
parallel, we and Bode et al. were the first to find that
,3-dimesityl-2,3-dihydro-1H-imidazol-2-ylidene (IMes)
Me
Me
1
Me
N
N
N
N
(Figure 1) is a competent catalyst for the conjugate Um-
polung of a,b-unsaturated aldehydes resulting in the for-
mation of g-butyrolactones 1. Under optimized
conditions, a 1:1 mixture of cinnamaldehyde and the ben-
zaldehyde derivative in tetrahydrofuran was treated with
IMes (prepared in situ from IMes·HCl and excess KOt-
Bu) and stirred at ambient temperature for 16 hours
Mes
Mes
Me
Cl
Me
N
S
Cl
IMes HCl
Bn
Me
Me
2
IMes
Figure 1
Recently, imidazolium derived N-heterocyclic carbenes
(Scheme 3). A variety of differently substituted g-butyro-
lactones was formed from aromatic aldehydes in yields
(
transition metal catalysis and as organocatalysts.
NHCs) have found numerous applications as ligands in
7
–15
In
Biographical Sketches
Christian Burstein re- der the guidance of Prof. F. 2006. His main research in-
ceived his diploma in 2003 Glorius commenced at the terests are modern organo-
from the Universität Duis- Max-Planck-Institut
für catalytic
methods,
N-
burg, where he worked in Kohlenforschung in 2003 heterocyclic carbenes, and
the laboratory of Prof. D. and was completed at the organometallic chemistry.
Döpp. His Ph. D. work un- Universität Marburg in
Serena Tschan was born in from Philipps-Universität out her graduate work in the
Hamburg, Germany, in Marburg in 2006 under the area of organocatalyzed re-
1981. She obtained her di- direction of Professor Frank actions for the synthesis of
ploma degree in chemistry Glorius, where she carried b- and g-lactones.
Xiulan Xie was born in Chemistry, Philipps-Uni- using modern NMR spec-
Fujian, China, in 1964. She versität Marburg since troscopic techniques in so-
has supervised the NMR 2002. Her main interest is lution.
centre in the Faculty of structure determination by
Frank Glorius was educat- In 2001 he began his inde- cilitate organic synthesis by
ed in chemistry at the Uni- pendent research career at developing new concepts
versität Hannover, Stanford the Max-Planck-Institut für for catalysis. At present his
University (Professor Paul Kohlenforschung in Mül- group focuses on the design
A. Wender), Max-Planck- heim, Germany. In 2004 he of new N-heterocyclic car-
Institut für Kohlenfor- became Professor of Organ- benes, challenging cross-
schung and Universität ic Chemistry at the Philipps- coupling reactions, asym-
Basel (Prof. Andreas Pfaltz), Universität Marburg. The metric hydrogenations, and
and Harvard University purpose of his research pro- organocatalyzed umpolung
(
Professor David A. Evans). gram is to significantly fa- reactions.
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
420
C. Burstein et al.
FEATURE ARTICLE
R1
O
catalyst
2
+
R CHO
H
O
O
R1
O
R1
R2
O
O
O
H
O
H
R1
R2
R1
O
R1
γ-lactones
Stetter products
R1
O
OH
O
O
R1
R1
R2
R1
R2
R2
R2
R1
OH
O
OH
OH
benzoin products
Scheme 2 Possible products of the Umpolung of an a,b-unsaturated aldehyde and another aldehyde
ranging from 30% to 70% with, generally, hardly any ben- Table 1 IMes-Catalyzed Coupling of Cinnamaldehyde with Aro-
a
1
6
zoin or Stetter product being produced. With the excep- matic Aldehydes
tion of 2-chlorobenzaldehyde (Table 1, entry 10), the cis-
1
b
Yield (%) Ratio cis/trans
Entry
R
1
a
a
a
b
c
diastereomer was formed predominantly in all cases
(
diastereomers were separated by column chromatogra-
phy.
1
Table 1). The typical cis/trans ratio was 80:20, and the
7
c
1
2
3
4
5
6
7
8
9
4-ClC H
6
0
33
53
49
70
44
52
61
66
32
–
4
4
4
d,e
4-ClC H
6
80:20
81:19
80:20
79:21
77:23
78:22
79:21
79:21
23:77
4-ClC H
6
O
O
O
O
4-BrC H
6 4
+
O
+
O
1
R
4-MeO CC H
2
Ph
H
H
6
4
1
1
R
Ph
R
Ph
4-F CC H
4
d
e
3
6
cis-1
trans-1
3-FC H
6
4
Scheme 3
3-ClC H
6
f
4
3-BrC H
6
g
h
4
Mechanism
e
1
0
2-ClC H
6
4
A plausible mechanism for the conjugate Umpolung to
give g-butyrolactones is depicted in Scheme 4. Reaction
of the N-heterocyclic carbene with the a,b-unsaturated al-
dehyde gives rise to a zwitterionic structure 3 that isomer-
izes by protonation/deprotonation to give the conjugated
dienamine 4. Nucleophilic attack of 4A or its zwitterionic
a
General reaction conditions: IMes·HCl (0.05 mmol), KOt-Bu (0.1
1
mmol), THF (3 mL), then cinnamaldehyde (1 mmol), R CHO (1.0
mmol), THF, r.t., 16 h. Isolated combined yield of separately isolated
diastereomers.
b
Determined by GC-MS.
Instead of IMes·HCl, thiazolium salt 2 was used as the catalyst.
c
d
1
8
Instead of IMes·HCl, KCN (0.3 mmol) and 18-crown-6 (0.1 mmol)
were employed.
homoenolate tautomer 4B onto the electrophilic alde-
hyde or ketone results in the formation of alkoxide 5, fol-
lowed by isomerization to the corresponding tautomer 6.
Related activated carboxylates are thought to be interme-
diates in N-heterocyclic carbene catalyzed transesterifica-
tion reactions, leading to ester formation when attacked
e
Isolated as mixture of diastereomers.
8
by alcohol nucleophiles. In analogy, intramolecular at-
tack of the alkoxide of 6 or its protonated form onto the
carbonyl group leads to the closing of the lactone ring and
the regeneration of the nucleophilic catalyst.
shielded
OH
shielded
OH
accessible
N
N
It is tempting to speculate that the steric demand of IMes
is key to its success by modulating the reactivity of the nu-
cleophilic species. Namely, the former aldehyde carbons
of benzaldehyde and cinnamaldehyde are significantly
shielded by the catalyst leading to reduced nucleophilicity
of the enamine carbon nearby. In contrast, the conjugate
position does not suffer from this shielding and can still
react with the electrophile (Figure 2).
N
N
Figure 2 Possible sterical influence of the catalyst on the nucleo-
philicity
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2421
OH
Mes
O
O
Mes
OH
Mes
H
N
N
N
R1
R1
R1
R1
H
N
N
N
4
B
Mes
3
Mes
4A
Mes
Mes
O
N
H
R2
N
Mes
O
R2
R1
O
R2
O
O
Mes
OH
Mes
O
N
N
R1
R1
R2
N
N
1
6
Mes
5
Mes
Scheme 4 Suggested mechanism for the formation of g-butyrolactones
1
9
Another Useful Class of Electrophiles: Ketones
salt 10 are unsuitable catalysts for the synthesis of 7a un-
der standard conditions (Table 2, entries 4–6, 0%, 10%,
For a long time, no efficient benzoin condensation with and 0% yields, respectively). In contrast, the N-heterocy-
19
ketones as electrophiles was known. Only recently, re- clic carbene derived from imidazolium salt 11 (Table 2,
ports appeared describing the use of ketones in intramo- entry 7) is a competent catalyst for this transformation.
lecular benzoin condensations. We were pleased to Using 5 mol% of 11 provides 7a in 70% yield
find that for the first time ketones could be employed as improved l/u ratio of 74:26 and an enantiomeric excess of
1
0a,b,d
10a,d,e
with an
intermolecular electrophiles in the conjugate Umpolung 12% and 25%, respectively.
(
7
c,j
Scheme 5). The IMes catalyzed reaction of cinnamal-
dehyde with one equivalent of a,a,a-trifluoroaceto-
phenone smoothly proceeded to give the corresponding
g-butyrolactone 7a, which bears a valuable quaternary
stereocenter, in 70% yield. Using a twofold excess of the
ketone significantly improved the yield to 84% (Table 2,
entry 1). The reaction could be scaled up to 30 mmol with-
O
O
O
O
O
O
+
+
R1
H
R2
Ph
R2
Ph
R1
R1
R2
Ph
l-7
u-7
out a deterioration of the yield (Table 2, entry 2). In addi- Scheme 5
tion, the use of 1,8-diazabicyclo[5.4.0]undec-7-ene
instead of potassium tert-butoxide often resulted in supe-
O
rior results, improving the yield by roughly 10% and in
addition simplifying the reaction set up (Table 2, entry 3)
Methyl benzoylformate and 1-phenylpropane-1,2-dione
were also found to be suitable ketone electrophiles in this
reaction resulting in the formation of the corresponding
g-butyrolactones in good yields (Table 2, entries 10–13).
The a,b-unsaturated aldehyde component can also be var-
ied in these reactions. Namely, electron-rich methoxy- or
dimethylamino-substituted cinnamaldehyde derivatives
can successfully be employed (Table 2, entries 8, 9, 12,
O
N
N
N
N
N
N
Ph
Me
t-Bu
Cl
BF4
8
9
O
O
O
O
N
N
N
N
Me
Me
i-Pr
OTf
OTf
1
0
11
1
3).
In many cases, the like and unlike diastereomer could be Figure 3 Precursors of chiral N-heterocyclic carbene catalysts
separated by column chromatography. The stereochemis-
try of u-7b was unequivocally determined by an X-ray
1
7
structural analysis.
Conjugated Umpolung of Substituted Crotonalde-
hyde Derivatives: Synthesis of g-Butyrolactones
Asymmetric Conjugate Umpolung
Initially, we reasoned that the aromatic group of cinnam-
aldehydes would be crucial for success in the conjugate
Recently, chiral triazolium salt derived N-heterocyclic Umpolung. However, we were pleased to find that alkyl-
2
0
carbenes were successfully used in highly enantioselec- substituted a,b-unsaturated aldehydes can also be suc-
1
0
11
tive benzoin condensation and Stetter reactions. Inter- cessfully used in the conjugate Umpolung (Scheme 6).
1
0c
11a
estingly, triazolium salts 8 and 9 and imidazolium Using activated ketones as electrophiles, high yields of
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
422
C. Burstein et al.
FEATURE ARTICLE
a
Table 2 Reaction of Cinnamaldehydes with Various Ketones
Table 3 Reaction of Alkyl-Substituted a,b-Unsaturated Aldehydes
a
with Ketones
1
2
b
Yield (%) Ratio l/u
Entry
R
R
7
a
a
a
a
a
a
a
b
c
d
e
f
1
2
b
Entry
R
R
12
a
b
c
Yield (%) Ratio I/II
c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
84
84
92
0
66:34
64:36
68:32
–
c
1
2
3
4
Me
Pr
CF3
CF3
CF3
82
90
66
87
71
72
81:19
84:16
c,d
e
c
d
i-Pr
Me
Pr
93:7
c,f
c,g
c
c
d
CO Me
2
d
e
68:32
67:33
65:35
h
10
0
nd
e
5
CO Me
2
c,i
–
f
6
i-Pr
CO Me
2
f
c,j
c
k
70
92
74
55
78
94
98
74:26
66:34
70:30
58:42
50:50
47:53
44:56
a
General reaction conditions: IMes·HCl (0.05 mmol), DBU (0.05
mmol), a,b-unsaturated aldehyde (0.5 mmol), ketone (1.0 mmol),
4-MeOC H4
6
THF (2.5 mL), r.t., 16 h. Yield given for the isolated mixture of dia-
stereomers.
c
4-Me NC H
4
CF3
2
6
b
Determined by GC-MS.
I = like, II = unlike.
l
1
1
1
0
1
2
3
Ph
Ph
C(O)Me
c
d
I = unlike, II = like.
DBU (0.25 mmol), 50 °C.
DBU (0.25 mmol).
CO Me
2
e
f
4-MeOC H4
6
CO Me
2
1
4-(Me N)C H
2
CO Me
2
g
6
4
a
General reaction conditions: IMes·HCl (0.05 mmol), DBU (0.05
mmol), cinnamaldehyde derivative (0.5 mmol), ketone (1.0 mmol),
THF (2.5 mL), r.t., 16 h. Yields given for the isolated mixture of
diastereomers.
Conjugated Umpolung of Substituted Crotonalde-
hyde Derivatives: Synthesis of b-Lactones
b
Determined by GC-MS.
Reaction conditions: IMes·HCl (0.05 mmol), KOt-Bu (0.1 mmol),
c
Under some reaction conditions, an isomeric side product
was obtained. Structural investigation revealed the b-lac-
tone structure of this compound. Interestingly, using the
same substrates and the same catalyst, but changing the
base, the solvent, and the reaction temperature allowed
this reaction to be controlled (Scheme 7). Under opti-
mized reaction conditions, b-lactone 13c formed in 48%
yield (Table 4, entry 3). The use of less polar solvents,
higher temperatures, and triethylamine as a base were op-
timal for this reaction. Methyl benzoylformate could also
be employed as an electrophile after slightly modifying
the reaction conditions.
THF (3 mL), then cinnamaldehyde derivative (1 mmol), ketone (2.0
mmol), r.t., 16 h.
d
3
0 mmol scale.
e
f
10 mmol scale.
Catalyst 8.
g
h
i
Catalyst 9.
Not determined.
Catalyst 10.
Catalyst 11.
like: 12% ee, unlike: 25% ee.
Run at 60 °C.
j
k
l
g-butyrolactones were obtained under our standard condi-
tions. In many cases the diastereomeric ratios were im-
proved compared to the use of cinnamaldehyde (see
Table 3), the best was 93:7 favoring the product 12c-I. In
comparison, reduced selectivities were obtained in the
O
O
O
O
O
O
R1
H
+
R2
2 +
Ph
R
Ph
Ph
R2
u-13
R1
R1
l-13
1
7
cases using methyl benzoylformate.
Scheme 7
O
O
O
O
Mechanistically, we reason that for the formation of b-lac-
tones a protonation/deprotonation sequence transforms
homoenolate 4 into enolate 14 (Scheme 8). Reduced nu-
cleophilicity and a longer lifetime of homoenolate equiv-
alent 15 would favor this process. Finally, attack of the
electrophilic carbonyl component, followed by cycliza-
tion to the b-lactone liberates the N-heterocyclic carbene
catalyst.
R1
H
+
R2
O
+
O
Ph
R2
Ph
R1
R1
R2
Ph
1
2-I
12-II
Scheme 6
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2423
OH
Mes
O
O
Mes
OH
Mes
H
N
N
N
R1
R1
R1
R1
H
N
N
N
4
B
Mes
3
Mes
4A
Mes
Mes
N
N
Mes
R3
O
O
O
O
Mes
Mes
R2
O
N
R3
R2
N
R3
R1
R2
R1
N
N
O
R1 Mes
Mes
13
15
14
Scheme 8 Suggested mechanism for the formation of b-lactones
a
Table 4 b-Lactone Formation by Conjugate Umpolung
assume that the a-methyl substituent would exhibit an un-
favorable steric interaction with the mesityl rings in con-
jugated intermediate 16 (Figure 5). Consequently, the use
of N-heterocyclic carbenes with smaller groups was in-
vestigated. Whereas thiazolium salt 2 failed once again to
provide lactone products, the precatalysts 1-mesityl-3-
methylimidazolium iodide (17) and 1,3-dimethylimidazo-
lium iodide (18) resulted in the formation of small
amounts of product. Gratefully, 1,3-dimethylbenzimida-
zolium iodide (19), electronically slightly different from
1
2
b
Yield (%) Ratio l/u
Entry
R
R
13
a
1
2
3
4
Me
Pr
CF3
CF3
CF3
34
45
48
30
22
60:40
55:45
62:38
70:30
71:29
b
c
i-Pr
Ph
CF3
d
e
c
5
i-Pr
CO Me
2
1
8, resulted in the formation of the highly substituted g-
a
General reaction conditions: IMes·HCl (0.05 mmol), Et N (2.0
3
butyrolactones 20 (Scheme 9, Table 5). Using N,N-di-
methylformamide as the optimal solvent and a-methylcin-
namaldehyde as the substrate, product 20a was formed in
83% yield (Table 5, entry 8). Of the four possible diaste-
reomers, mainly 20-I and 20-II were obtained (Figure 6).
In these two major diastereomers the methyl group at C3
mmol), toluene (2.5 mL), a,b-unsaturated aldehyde (1.0 mmol), ke-
tone (1.0 mmol), 60 °C, 16 h.
b
Determined by GC-MS.
IMes·HCl (0.1 mmol), DBU (0.1 mmol).
c
1
is oriented trans relative to the R substituent at C4. In
agreement with the results obtained for cinnamaldehyde
or crotonaldehyde derivatives, 20-I is formed predomi-
nantly in most cases. However, when 2-methyl-5-phenyl-
penta-2,4-dienal, an a,b-unsaturated aldehyde containing
Umpolung of a-Methylcinnamaldehydes
g-Butyrolactones are ubiquitous motifs in naturally occur-
ring compounds, many of which bear an a-substituent at
1
2
1
an alkene as R substituent, was used as a substrate, dia-
stereomer 20-II was obtained in excess (Table 5, entry
C3 (Figure 4). Therefore, the reactivity of a-methylcin-
namaldehydes was of special interest. Does the conjugate
Umpolung tolerate an a-substituent?
17
1
1).
O
O
O
Me
O
Me
O
R1
OH
O
Me Me
N
R2
Me
HO2C
N
paraconic acids
callitrin
dilatanolide A
1
6
Figure 4 Natural products with a-substituted g-lactone substructure
I
I
I
Under conditions optimized for the previously mentioned
reactions using IMes as the catalyst, the use of a-methyl-
cinnamaldehyde and trifluoroacetophenone did not result
N
+
N
N
+
N
N
+
N
Me
Mes
Me
Me
Me
Me
1
7
18
19
in the formation of the desired product. It is reasonable to Figure 5 Unfavorable steric interactions in hypothetical interme-
diate 16 and precatalysts 17, 18, and 19
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
424
C. Burstein et al.
FEATURE ARTICLE
a
Table 5 Reaction of a-Methylcinnamaldehydes
1
b
Entry
R
Catalyst
2
Solvent
THF
20
a
a
a
a
a
a
a
a
a
b
c
Yield (%)
dr
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0
–
IMes
IMes
17
THF
0
–
DMF
DMF
THF
0
–
traces
traces
–
18
–
b
19
THF
37
66:28:5:1
64:27:7:2
62:30:6:2
63:29:6:2
63:29:6:2
32:66:2:0
b
19
MeCN
DMF
DMF
DMF
DMF
24
19
83
c
19
85
10
4-ClC H
6
19
71
82
4
11
CH=CHPh
19
a
General reaction conditions: a,b-unsaturated aldehyde (0.5 mmol), ketone (1.0 mmol), solvent (2.5 mL), catalyst (0.05 mmol), DBU (0.05
mmol), 75 °C.
b
Determined by GC-MS.
1
c
0 mmol scale.
O
Intramolecular Reaction
O
O
Me
O
R1
H
+
Ph
CF3
The aforementioned intermolecular reactions generate a
g-butyrolactone with up to three contiguous stereocenters.
For a number of reasons an intramolecular variant of this
reaction would be attractive. First of all, less reactive elec-
trophiles, namely unactivated ketones, might become
suitable reaction partners, thereby significantly expanding
the scope of this transformation. Second, in the course of
the intramolecular lactone formation an additional ring
would be formed, leading to bicyclic products. Finally, an
existing stereocenter could influence the reaction leading
to the highly selective formation of the lactone products.
However, frequently the use of an elaborate, multistep
substrate synthesis decreases the attraction of intramolec-
ular approaches.
Me
R1
CF3
Ph
2
0
Scheme 9
O
O
O
O
Me
Me
Me
Me
CF3
O
O
O
O
CF3
Ph
CF3
20-II
Ph
CF3
20-IV
R1
R1
R1
R1
Ph
0-I
Ph
2
20-III
Figure 6 Diastereomers of 20
Another interesting observation was made when using 4- Consequently, our investigation commenced with the de-
chlorocinnamaldehyde as the substrate. In this case, only sign of readily accessible cyclization precursors. But-2-
a small amount (20%) of the expected product 20 was ob- ene-1,4-diol was identified as an ideally suited building
tained. In addition, the isomeric product 21 was formed in block, allowing the synthesis of the cyclization substrates
46% yield (Figure 7). This product could result from a in only two steps. In this sequence, one hydroxy group of
protonation/reprotonation sequence analogous to the one the diol was used for a highly regioselective opening of an
shown in Scheme 8.
epoxide, followed by the parallel oxidation of both hy-
droxy groups of the resulting diol with Dess–Martin peri-
odinane in good yield (Scheme 10).
O
Cl
The IMes-catalyzed cyclization of 22 and 23 resulted in
the formation of g-butyrolactones with an annulated tet-
rahydrofuran ring (Table 6, entries 1 and 2). Interestingly,
only a single diastereomer was formed. Moreover, for the
first time nonactivated, enolizable ketones proved to be
suitable electrophiles in the conjugate Umpolung. Espe-
cially, the synthesis of the tricyclic product 28 is rather
O
CF3
Ph
21
Figure 7
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2425
a
complex and demonstrates the potential of this new syn-
thetic method.
Table 6 Intramolecular Homoenolate Addition
Entry
Substrate
Product
Yield (%)
Another class of substrates for an intramolecular ho-
moenolate addition, leading to the formation of six-mem-
bered rings, was synthesized. Substrates 24, 25, and 26
were easily prepared in two, four, and five steps, respec-
a
1
22
27
O
O
36
41
O
Ph
2
2
tively (Schemes 11 and 12). Once again, IMes allows
the conjugate Umpolung of the unsaturated aldehyde, fol-
lowed by attack onto the nonactivated ketone and the con-
cluding cyclization. In these cases, besides the formation
of the g-butyrolactone, a tetralin or tetrahydroquinoline
ring system formed. Impressively, the cyclization of 24
resulted in the formation of the trans-diastereomer 29,
only (Table 6, entry 3). The stereochemical assignment of
compounds 27–31 was based on elaborate NMR experi-
ments, described in the experimental section.
b
2
23
28
O
O
O
H
c
3
24
25
29
30
O
O
55
23
Me
HO
O
KOt-Bu
DMSO
DMP
CH2Cl2
40 °C
H
O
O
d
4
O
O
6
0 °C
+
7
0%
76%
Ph
Ph
OH
O
Me
2
2
N
H
O
HO
H
e
O
5
26
31
26
BF3
⋅
OEt2
CH2Cl2, r.t.
DMP
CH2Cl2, r.t.
O
O
+
O
8
7%
61%
Me
O
OH
N
Ac
2
3
a
Scheme 10 Synthesis of substrates suitable for an intramolecular
cyclization reaction
IMes·HCl (0.07 mmol), KOt-Bu (0.06 mmol), THF (14 mL), then
substrate (0.34 mmol), 60 °C, 16 h.
b
IMes·HCl (0.11 mmol), KOt-Bu (0.1 mmol), THF (20 mL), then
substrate (0.55 mmol), 60 °C, 5 h.
O
c
IMes·HCl (0.030 mmol), KOt-Bu (0.028 mmol), THF (4 mL), then
substrate (0.2 mmol), 60 °C, 16 h.
Br
a,b
H
Me
d
IMes·HCl (0.036 mmol), DBU (0.03 mmol), THF (15 mL), then sub-
strate (0.30 mmol), 60 °C, 16 h.
Br
e
IMes·HCl (0.036 mmol), DBU (0.03 mmol), THF (6 mL), then sub-
strate (0.285 mmol), 60 °C, 16 h.
O
24
Scheme 11 Reagents and conditions: (a) acetylacetone, K CO ,
2
3
EtOH, 90 °C (75%); (b) H C=CHCH(OEt) , Pd(OAc) , KCl, K CO ,
2
2
2
2
3
Bu NOAc, DMF, 100 °C (49%).
4
O
O
Conclusion
H
a–d
H
The organocatalyzed conjugate Umpolung of a,b-unsat-
urated aldehydes allows the direct, intermolecular, and
cross-linking of an a,b-unsaturated aldehyde with another
aldehyde or ketone, resulting in a flexible one-step syn-
thesis of substituted g-butyrolactones. In intramolecular
Me
NO2
N
R
O
R = H: 25
R = Ac: 26
e
Scheme 12 Reagents and conditions: (a) aq NaBH , EtOH, 0 °C cases, the use of nonactivated ketones as an electrophilic
4
(
AcCH Cl, KHCO , KI, acetone, 50 °C (69%); (d) 2-iodylbenzoic
acid, EtOAc, 50 °C (78%); (e) AcCl, toluene, 80 °C (30%).
98%); (b) FeSO ·7H O, 25% NH OH, MeOH, H O, 80 °C (79%); (c)
4 2 4 2
reaction partner is described, leading to the formation of
multicyclic products. In addition, variation of the reaction
conditions allows the formation of b-lactones in some
cases.
2
3
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
426
C. Burstein et al.
FEATURE ARTICLE
All commercially available compounds were used as received and
all reactions were performed under an atmosphere of argon. The
solvents used were purified by distillation over the drying agents in-
dicated and were transferred under argon: THF (Na), CH Cl
gel, 2.5 cm × 12 cm, pentane–CH Cl , 15:1) to give 13c as a color-
2
less oil; yield: 130 mg (48%).
2
3-Methyl-4,5-diphenyl-5-(trifluoromethyl)tetrahydrofuran-2-
one (20a); Typical Procedure for Table 5
2
2
(CaH ), toluene (CaH ). For flash chromatography, Merck silica gel
2 2
6
0 (230–400 mesh) was used. NMR spectra were recorded on a
Under an atmosphere of argon, 19 (13.7 mg, 0.050 mmol) was dis-
solved in DMF (2.5 mL) in a septum capped vial and (E)-2-methyl-
3-phenylprop-2-enal (73.1 mg, 0.50 mmol) and a,a,a-trifluoroace-
tophenone (174 mg, 1.0 mmol) were added dropwise. Then DBU
(7.60 mg, 0.050 mmol) was added and the soln stirred at 75 °C for
16 h. The solvent was then removed by rotary evaporation and the
residue was purified by column chromatography (silica gel, 2.5
cm × 12 cm, hexane–MTBE, 40:1) to give 20a as a mixture of dias-
tereomers; yield: yielding 132 mg (83%).
ARX 300 or DRX 400 spectrometer (Bruker) in the solvents indi-
cated; chemical shifts are relative to TMS. For the stereochemical
assignment of lactones 27–31, NMR spectra were recorded on
Bruker DRX-500 and AVANCE-600 spectrometers in CDCl at
3
concentration of about 0.3 M. Complete signal assignments were
13
1
carried out on all of the compounds based on H, C, HSQC, DQF-
COSY, and HMBC spectra. Routine pulse sequences with gradients
2
3
were used. The pulse sequence DPFGSE-NOE of Shaka was used
for the selective transient NOE experiments. Gaussian-shaped pulse
was applied for the selective excitation, whose length was opti-
mized for each measurement. Mixing time in the range of 1.0 to 2.0
s was used. 1D-NOE spectra were recorded with 256 scans and a
typical experiment time was about 20 min. IR spectra were recorded
on a Bruker IFS 88. EI-MS were recorded on a Varian CH7 (70 eV)
and HRMS were recorded on a Finnigan LTQ FT or TSQ 700. For
MS data of the diastereomeric mixtures a Agilent Technologies
System (GC: 6890N, column: HP-5MS (0.25 mm × 30 m × 0.25
mm; Agilent G1701DA GC/MSD ChemStation) with a 5973 Net-
work Mass Selective Detector at 70 eV was used. Method 70_20:
Stereochemical Assignment
Table 1, Products 1
1
H NMR signals for the ring protons of the lactones 1 are very sim-
ilar within the cis and trans series. Thus, based on an X-ray struc-
1
tural analysis of cis-1d, comparison of the H NMR data allows the
assignment of the relative stereochemistry. In addition, some aro-
matic protons in the cis-diastereomer show a significant upfield
shift, because they lie in the anisotropic cone of the other aromatic
ring. Furthermore the retention times in the GC-MS are consistent,
i.e. the like-diastereomer has always a shorter retention time than
the unlike-diastereomer.
7
0 °C for 3 min; gradient: 20 °C/min to 280 °C; 280 °C for 3.5 min.
Method 50_20: 50 °C for 3 min; gradient: 20 °C/min to 280 °C;
80 °C for 3.5 min.
2
Table 2, Lactones 7
As for the lactones 1, the NMR signals of the ring protons are very
similar within the I and II series. Based on an X-ray structure of
u-7b, the relative configuration could be assigned. For compounds
Conjugate Umpolung; Typical Procedures
Methyl 4-(5-Oxo-3-phenyltetrahydrofuran-2-yl)benzoate (1c);
Typical Procedure for Table 1
1
9
7a–c the chemical shift in the F NMR of the CF group is also typ-
3
Generation of the catalyst soln (for multiple reactions): Under an at-
mosphere of argon, IMes·HCl (85.2 mg, 0.25 mmol) and KOt-Bu
ical. The signal of the CF group in the like-diastereomer has a up-
3
field shift compared to the unlike-diastereomer. Furthermore the
retention times in the GC-MS are consistent, i.e. the like-diaste-
reomer has always a shorter retention time than the unlike-diaste-
reomer.
(
4
56.1 mg, 0.50 mmol) were suspended in THF (5 mL) and stirred for
5 min at r.t. The preformed catalyst soln (1 mL, 0.05 mmol IMes)
was added over a period of 1 min to a soln of methyl 4-formylben-
zoate (164 mg, 1.0 mmol) and trans-cinnamaldehyde (126 mL, 1.0
mmol) in THF (5 mL). The soln was stirred at r.t. for 16 h, after
which MeOH (2 mL) was added and the soln was stirred for a fur-
ther 15 min. The solvent was evaporated in vacuo, and the residue
Table 3, Products 12
As for the lactones 1, the NMR signals of the ring protons are very
similar within the I and II series. Based on an X-ray structural anal-
ysis of 12c-I, the relative configuration was assigned. For diaste-
reomer I of each compound a significant upfield shift of some
aliphatic protons (am Rest R) can be observed, because they lie in
the anisotropic cone of the aromatic ring. For compounds 12a–c the
–
2
was distilled in a Kugelrohr apparatus (5 × 10 mbar, 150–200 °C).
Purification of the distillate by column chromatography (silica gel,
2.5 cm × 12 cm, MTBE–hexane 1:3) yielded cis-1c (164 mg, 56%)
and, after crystallization (CH Cl –hexane), trans-1c (41 mg, 14%)
as colorless solids.
2
2
1
9
chemical shift in the F NMR of the CF group is also typical. The
3
signal of the CF group in diastereomer I has a upfield shift com-
3
4
(
-Methyl-5-phenyl-5-(trifluoromethyl)tetrahydrofuran-2-one
12a); Typical Procedure for Tables 2 and 3
pared to the diastereomer II. Furthermore the retention times in the
GC-MS for diastereomer I are always shorter than the retention
times for diastereomer II.
Under an atmosphere of argon, IMes·HCl (17.0 mg, 0.050 mmol)
was dissolved in THF (2.5 mL) in a septum capped vial and cro-
tonaldehyde (35.0 mg, 0.50 mmol) and a,a,a-trifluoroacetophenone
Table 4, b-Lactones 13
(
174 mg, 1.0 mmol) were added. DBU (7.60 mg, 0.05 mmol) was
The stereochemical assignment of the b-lactone products is based
on the assignment of the g-lactones as shown above. First of all, in
the series assigned to be like, the CH group of the substituent on C3
of the b-lactone ring experienced a significant upfield shift (aniso-
tropic cone of the phenyl group). This is supported by NOESY ex-
periments, showing an NOE between this CH group and the phenyl
ring. This was not observed for the compounds of the other diaste-
reomeric series. Furthermore, the like-isomers exhibit shorter GC
retention times and are less polar based on column chromatography.
added and the soln stirred at r.t. for 16 h. After this time the solvent
was evaporated and the residue purified by column chromatography
(silica gel, 2.5 cm × 12 cm, hexane–MTBE, 40:1) to give 12a as a
colorless oil; yield: 100 mg (82%).
3-Isobutyl-4-phenyl-4-(trifluoromethyl)oxetan-2-one (13c);
Typical Procedure for Table 4
Under an atmosphere of argon, IMes·HCl (17.0 mg, 0.050 mmol)
was dissolved in toluene (2.5 mL) and 4-methyl-2-pentenal (116
mL, 1.0 mmol) and a,a,a-trifluoroacetophenone (174 mg, 1.0 mmol)
Table 5, g-Lactones 20
were added. Finally, Et N (280 mL, 2.00 mmol) was added and the
3
soln stirred at 60 °C for 16 h. After this time the solvent was evap-
orated and the residue purified by column chromatography (silica
As for the aforementioned lactones, assignment was made based on
an X-ray structural analysis of 20c-II and comparison of the NMR
data. Furthermore the coupling constants of the lactone ring protons
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2427
2
4
are similar to those reported for a comparable structure. Again, the
relative GC retention times of the diastereomers and the chemical
shift of the CF group allow the stereochemical assignment.
a mixture of ice water (100 mL) and toluene (100 mL). The soln was
acidified to pH 1 with concd HCl and the layers were separated. The
aqueous layer was basified to pH 10–11 using K CO , then extract-
3
2
3
ed with CH Cl (3 × 100 mL). The combined extracts were washed
2
2
Table 6, Products 27–31
with H O (3 × 50 mL) and dried (MgSO ) and the solvent was re-
2 4
1
13
Both H and C spectra reveal that the isolated compounds consist
of a single diastereomer only. The one-dimensional NOE experi-
ments with pulsed field gradients for the observation of selective
transient NOEs delivered high quality spectra. These methods en-
able the observation of weak NOE enhancements and even can pro-
moved on a rotary evaporator. The residue was purified by column
chromatography (CH Cl –MeOH, 40:1) to afford a colorless oil;
2
2
yield: 1.45 g (70%).
R = 0.22 (CH Cl –MeOH, 40:1).
f
2
2
2
3
IR (film): 3392, 3062, 3030, 2861, 1651, 1494, 1453, 1362, 1199,
1
vide quantitative distance information. The configuration of the
compounds was thus determined using selective NOE techniques.
–
102, 1065, 1005, 904, 833, 760, 701, 633, 419, 408 cm .
1
1
H NMR (300 MHz, CDCl ): d = 7.40–7.27 (m, 5 H), 5.94–5.77 (m,
3
Methylene protons in molecules containing chiral centers are dia-
stereotopic and often show resolved NMR signals. In this study we
used diastereotopic protons as reference points to deduce the spatial
arrangement of the products. Protons attached to the stereocenters
were selectively excited resulting in distinct NOE contacts with the
diastereotopic methylene protons. The observed NOE contacts al-
low to predict the configurations for 27, 29, and 30 (Table 7).
2
H), 4.90 (dd, J = 3.1, 9.0 Hz, 1 H), 4.15 (d, J = 4.4 Hz, 2 H), 4.07
d, J = 5.0 Hz, 2 H), 3.60 (dd, J = 3.2, 9.8 Hz, 1 H), 3.47 (t, J = 9.4
(
Hz, 1 H), 2.26 (br s, 2 H).
13
C NMR (75 MHz, CDCl ): d = 140.2, 132.6, 128.4, 127.8, 127.3,
3
1
26.1, 75.8, 72.8, 71.2, 62.8.
+
MS (EI): m/z (%) = 208 [M ] (1), 107 (100), 105 (34), 104 (10), 91
(
12), 79 (49), 77 (31).
O
O
O
O
O
O
+
3
3
HRMS (EI): m/z [M ] calcd for C H O : 208.099; found:
12 16 3
3
3
O
4
7
3a
4
7
3a
208.1102.
O 9
3
a
3
a
Ph
4
9a Me
9
9a Me
9
(
E)-4-(2-Oxo-2-phenylethoxy)but-2-enal (22)
A soln of (E)-4-(2-hydroxy-2-phenylethoxy)but-2-en-1-ol (0.791 g,
.80 mmol, 1 equiv) in CH Cl (5 mL) was added to a soln of Dess–
5
a
4
6
O
N
H
O
6
H
28
3
2
2
27
29
30
Martin periodinane (8.20 g, 19.2 mmol, 5 equiv) in CH Cl (60 mL)
2
2
Scheme 13 Relative configurations given as determined by NMR;
numbering used in Table 7
and the mixture was stirred at 40 °C for 3 h. MTBE (70 mL) and sat.
NaHCO soln (60 mL) containing Na (12 g) were added and
S O
2 2 3
3
the mixture was stirred until the white solid had completely dis-
solved. Further MTBE (50 mL) was added and the organic layer
was washed with sat. NaHCO soln (50 mL) and then with H O (50
The determination of the conformation of 28 is more complicated.
For 28, which contains three stereocenters, four pairs of enanti-
omers are possible and two of them might exist in two different fa-
vorable conformations. Protons on axial positions of the
cyclohexane ring served as reference points. Furthermore, NOE
3
2
mL) and dried (MgSO ). The solvent was removed and the residue
4
purified by column chromatography (hexane–EtOAc, 1.5:1) to af-
ford a white solid; yield: 0.61 g (76%).
contacts were used in combination with coupling constants. The
3
coupling constant J
Rf = 0.14 (hexane–EtOAc, 1.5:1).
is equal to 9.1 Hz, which reveals the axial
orientation of H . The NOE contacts detected are given in Table 7.
5a–6ax
IR (film): 2834, 2740, 1679, 1596, 1579, 1451, 1399, 1301, 1227,
–1
1163, 1133, 1076, 1030, 970, 751, 687, 646, 575, 550 cm .
5
a
Of the possible configurations, only the one shown for 28 corre-
sponds to the NMR observation and it is thus determined to be the
correct configuration of compound 28.
1
H NMR (300 MHz, CDCl ): d = 9.60 (d, J = 7.9 Hz, 1 H), 7.93–
3
.90 (m, 2 H), 7.63–7.58 (m, 1 H), 7.51–7.46 (m, 2 H), 6.87 (dt,
7
J = 15.8, 4.2 Hz, 1 H), 6.40 (ddt, J = 15.8, 7.9, 1.9 Hz, 1 H), 4.85 (s,
2
H, 4.45 (dd, J = 4.2, 1.9 Hz, 2 H).
a,b-Unsaturated Aldehyde Substrates for the Conjugate Um-
polung
1
3
C NMR (75 MHz, CDCl ): d = 195.6, 193.0, 151.8, 134.6, 133.8,
3
(
E)-4-(2-Hydroxy-2-phenylethoxy)but-2-en-1-ol
132.1, 128.8, 127.8, 73.4, 70.0.
Styrene oxide (1.14 mL, 10.0 mmol, 1 equiv) was added to a stirred
and heated (60 °C) mixture of KOt-Bu (3.40 g, 30.3 mmol, 3 equiv)
and but-2-ene-1,4-diol (5.30 g, 60.2 mmol, 6 equiv) in DMSO
+
MS (ESI, MeOH): m/z = 227 [M + Na ].
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 227.0679;
found: 227.0677.
12 12
3
(
30 mL). The mixture was stirred for 2 h and then it was poured into
Table 7
a
Diastereotopic Protons NOE
a,b
Lactone
Config
2
7
8
H4A, H ; H6A, H6B
4B
H –H (s), H –H (s), H –H ; H –H , H –H (s)
6A
unlike
3a
ar
3a
4A
3a
ar
4A
ar
6A
2
H3A, H ; H4A, H4B
3B
H –H (s), H –H , H –H , H –H ; H –H , H –H , H –H (s),
6eq
as shown in
Scheme 13
3a
4A
3a
6ax
3a
8ax
3a
9eq
5a
4B
5a
3B
5a
H –H , H –H , H –H (s)
5a
5
a
6ax
5a
7ax
9ax
2
9
0
H8A, H8B
H9A, H9B
H –CH (w), H –H ; CH –H
3
like
3a
3
3a
8A
8B
9B
3
H –CH (w), H –H ; CH –H
3
unlike
3a
3
3a
9A
a
The subscripts are positional descriptors.
s’ = strong, ‘w’ = weak, ‘ax’ = axial, ‘eq’ = equatorial.
b
‘
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
428
C. Burstein et al.
FEATURE ARTICLE
2
-[(E)-4-Hydroxybut-2-enyloxy]cyclohexanol
Rf = 0.34 (hexane–EtOAc, 2:1).
IR (film): 3411, 3333, 3063, 3027, 2821, 2743, 1715, 1677, 1622,
A soln of cyclohexene oxide (1.12 mL, 10.75 mmol, 1 equiv) in
CH Cl (2 mL) was added dropwise over 5 h to a stirred and cooled
(15–20 °C) soln of but-2-ene-1,4-diol (4.74 g, 53.8 mmol, 5 equiv)
in CH Cl (30 mL) containing BF ·OEt (150 mL, 1.19 mmol, 0.11
2
2
–1
600, 1483, 1364, 1294, 1162, 1128, 1094, 974, 757 cm .
1
1
H NMR (300 MHz, CDCl ): d = 9.75 (d, J = 7.9 Hz, 1 H), 7.83 (d,
3
2
2
3
2
J = 15.8 Hz, 1 H), 7.62–7.59 (m, 1 H), 7.38–7.24 (m, 3 H), 6.68 (dd,
J = 15.8, 7.9 Hz, 1 H), 3.08 (t, J = 7.5 Hz, 2 H), 2.76 (t, J = 7.5 Hz,
equiv). The mixture was stirred at r.t. for 30 min and then Et N (0.5
3
mL, 3.6 mmol, 0.34 equiv) was added. The mixture was evaporated
to dryness and the residue was purified by column chromatography
2
H), 2.16 (s, 3 H).
(
CH Cl –MeOH, 18:1) to afford the product as a colorless oil; yield:
2
13
2
C NMR (75 MHz, CDCl ): d = 206.9, 193.7, 149.5, 140.9, 132.4,
3
1
3
.74 g (87%) together with but-2-ene-1,4-diol (3.58 g, 40.7 mmol,
.8 equiv).
1
31.1, 130.2, 130.0, 127.1, 127.0, 44.7, 30.0, 26.6.
+
MS (EI): m/z (%) = 202 [M ] (1), 184 (3), 169 (1), 159 (13), 144
R = 0.35 (CH Cl –MeOH, 17:1).
f
2
2
(100), 141 (23), 131 (70), 129 (32), 128 (17), 117 (20), 116 (34),
1
15 (46), 103 (8), 91 (34), 89 (5), 77 (12), 65 (6), 43 (71).
IR (film): 3381, 3007, 2934, 2861, 1854, 1653, 1451, 1370, 1303,
1
–
1
234, 1160, 1093, 1008, 928, 849, 592 cm .
+
HRMS (EI): m/z [M + H ] calcd for C H O : 203.1072; found:
203.1071.
1
3
15
2
1
H NMR (300 MHz, CDCl ): d = 5.86–5.70 (m, 2 H), 4.13–4.00 (m,
3
3
2
H), 3.93–3.82 (m, 1 H), 3.40–3.20 (m, 3 H), 3.07–2.99 (m, 1 H),
.02–1.89 (m, 2 H), 1.70–1.54 (m, 2 H), 1.28–0.99 (m, 4 H).
1
-{2-[(E)-3-Hydroxyprop-1-enyl]phenylamino}propan-2-one
-Chloropropan-2-one (463 mg, 5.0 mmol, 1.5 equiv) was added to
1
a mixture of (E)-3-(2-aminophenyl)prop-2-en-1-ol (500 mg, 3.35
1
3
C NMR (75 MHz, CDCl ): d = 132.4, 127.6, 82.8, 73.5, 68.6,
3
6
2.3, 32.1, 29.1, 24.0 (CH ), 23.8.
2
mmol, 1 equiv), KHCO (335 mg, 3.35 mmol, 1 equiv), and KI (110
3
+
MS (ESI, MeOH): m/z = 209 [M + Na ].
mg, 0.67 mmol, 0.2 equiv) in acetone (10 mL). The mixture was
stirred at 50 °C for 24 h, then silica gel was added and the solvent
removed on the rotary evaporator. The powder was purified by col-
umn chromatography (pentane–EtOAc, 1:1) to afford the product as
a yellow solid; yield: 472 mg (69%).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 209.1148;
found: 209.1146.
1
0
18
3
(E)-4-(2-Oxocyclohexyloxy)but-2-enal (23)
A soln of 2-[(E)-4-hydroxybut-2-enyloxy]cyclohexanol (0.80 g, 4.3
Rf = 0.11 (pentane–EtOAc, 1:1).
mmol, 1 equiv) in CH Cl (3 mL) was added to a soln of DMP (4.58
2
2
IR (KBr): 3413, 1722, 1601, 1574, 1504, 1453, 1359, 1295, 1185,
1
g, 10.8 mmol, 2.5 equiv) in CH Cl (35 mL) and the mixture was
2
–1
147, 1098, 1013, 958, 751, 608, 531, 498, 466 cm .
2
stirred at r.t. for 1 h. MTBE (50 mL) and sat. NaHCO soln (40 mL)
3
1
H NMR (300 MHz, CDCl ): d = 7.27–7.25 (m, 1 H), 7.20–7.14 (m,
3
containing Na S O (14.0 g) were added and the mixture was stirred
2
2
3
1
1
2
H), 6.76–6.70 (m, 2 H), 6.48 (d, J = 8.1 Hz, 1 H), 6.25 (dt, J = 5.7,
5.7 Hz, 1 H), 4.78 (s, 1 H), 4.35 (d, J = 5.7 Hz, 2 H), 4.01 (s, 2 H),
.26 (s, 3 H).
until the white solid had completely dissolved. Further MTBE (50
mL) was added and the organic layer was washed with sat. NaHCO3
soln (50 mL) and also with H O (50 mL) and then dried (MgSO ).
2
4
The solvent was removed and the residue purified by column chro-
matography (hexane–EtOAc, 2:1) to afford a colorless oil; yield:
13
C NMR (75 MHz, CDCl ): d = 204.1, 143.9, 131.3, 128.8, 127.8,
3
1
26.4, 123.4, 117.9, 110.9, 63.9, 54.3, 27.4.
0
.48 g (61%).
+
MS (EI): m/z (%) = 205 [M ] (21), 162 (55), 146 (14), 145 (11), 144
Rf = 0.16 (hexane–EtOAc, 2:1).
(100), 143 (29), 133 (10), 132 (92), 131 (20), 130 (90), 118 (22),
1
17 (40), 116 (16), 115 (31), 91 (20), 77 (16).
IR (film): 3434, 2942, 2868, 1721, 1690, 1450, 1355, 1216, 1123,
9
–
69, 883, 838, 575 cm .
1
+
HRMS (EI): m/z [M ] calcd for C H NO : 205.1103; found:
205.1095.
1
2
15
2
1
H NMR (300 MHz, CDCl ): d = 9.58 (d, J = 7.9 Hz, 1 H), 6.84 (dt,
3
J = 15.8, 4.1 Hz, 1 H), 6.36 (ddt, J = 7.2, 15.8, 2.0 Hz, 1 H), 4.55
(ddd, J = 2.0, 3.9, 16.8 Hz, 1 H), 4.20 (ddd, J = 1.9, 4.2, 16.8 Hz, 1
H), 3.91–3.85 (m, 1 H), 2.54–2.47 (m, 1 H), 2.34–2.21 (m, 2 H),
(
1
E)-3-[2-(2-Oxopropylamino)phenyl]prop-2-enal (25)
-{2-[(E)-3-Hydroxyprop-1-enyl]phenylamino}propan-2-one (821
mg, 4.0 mmol, 1 equiv) was dissolved in EtOAc, (50 mL) and 2-io-
dylbenzoic acid (IBX; 3.36 g, 12.0 mmol, 3 equiv) was added. The
resulting suspension was stirred at 50 °C for 5 h and was then fil-
tered through Celite. The solvent was removed on a rotary evapora-
tor and the residue purified by column chromatography (pentane–
EtOAc, 1:1) to afford an orange solid; yield: 630 mg (78%). The
product was stored under an argon atmosphere in the fridge.
2
.04–1.89 (m, 2 H), 1.82–1.61 (m, 3 H).
1
3
C NMR (75 MHz, CDCl ): d = 209.4, 193.2, 152.7, 131.7, 82.8,
3
6
8.5, 40.6, 34.4, 27.4, 23.2.
+
MS (EI): m/z (%) = 182 [M ] (2), 164 (10), 136 (15), 135 (18), 114
(
6
12), 107 (15), 98 (100), 97 (22), 86 (17), 83 (21), 79 (16), 70 (60),
9 (93), 68 (58), 67 (27), 57 (52), 55 (49).
+
HRMS (EI): m/z [M ] calcd for C H O : 182.0943; found:
Rf = 0.45 (pentane–EtOAc, 1:1).
1
0
14
3
1
82.0942.
IR (KBr): 3422, 1718, 1668, 1602, 1567, 1503, 1454, 1413, 1366,
1
334, 1291, 1262, 1231, 1190, 1161, 1146, 1130, 1075, 962, 757
–1
cm .
(
E)-3-[2-(3-Oxobutyl)phenyl]prop-2-enal (24)
A suspension of 4-(2-bromophenyl)butan-2-one (3.76 g, 16.6
1
H NMR (300 MHz, CDCl ): d = 9.70 (d, J = 7.7 Hz, 1 H), 7.66 (d,
3
mmol), 3,3-diethoxypropene (6.51 g, 50.0 mmol), Pd(OAc) (224
2
J = 15.7 Hz, 1 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.30 (m, 1 H), 6.78 (t,
J = 7.5 Hz, 1 H), 6.66 (dd, J = 7.7, 15.7 Hz, 1 H), 6.55 (d, J = 8.2
Hz, 1 H), 5.07 (br s, 1 H), 4.06 (d, J = 4.1 Hz, 2 H), 2.30 (s, 3 H).
13
mg, 1.0 mmol), KCl (1.24 g, 16.6 mmol), K CO (3.44 g, 24.9
3
2
mmol), and tetrabutylammonium acetate (10.0 g, 33.2 mmol) in
DMF (50 mL) was stirred at 100 °C for 15 h. The mixture was
cooled to r.t., 2 M HCl (50 mL) and then MTBE (150 mL) were add-
C NMR (75 MHz, CDCl ): d = 203.0, 193.8, 147.7, 145.3, 132.6,
3
ed and the resulting soln washed with H O (2 × 75 mL). The organ-
2
128.8, 128.8, 119.7, 118.1, 112.1, 53.8, 27.4.
ic phase was dried (Na SO ). After evaporation of the solvent the
2
4
+
MS (EI): m/z = 203 [M ] (21), 160 (73), 132 (57), 131 (20), 130
residue was purified by column chromatography (silica gel, hex-
ane–EtOAc, 2:1); yield: 1.65 g (49%).
(100), 118 (29), 117 (51), 115 (12), 103 (12), 77 (20).
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2429
+
HRMS (EI): m/z [M ] calcd for C H NO : 203.0947; found:
+
HRMS (EI): m/z [M + Na ] calcd for C H ClNaO : 295.0502;
found: 295.0501.
1
2
13
2
16 13
2
2
03.0938.
N-{2-[(E)-3-Oxoprop-1-enyl]phenyl}-N-(2-oxopropyl)acet-
amide (26)
cis-5-(4-Bromophenyl)-4-phenyltetrahydrofuran-2-one (cis-1b)
Colorless oil; yield: 118 mg (37%).
A few drops of pyridine and AcCl (220 mL, 3.08 mmol, 1.25 equiv)
were added to a soln of (E)-3-[2-(2-oxopropylamino)phenyl]prop-
Rf = 0.10 (hexane–EtOAc, 7:1).
tR (50_20): 13.03 min.
2
-enal (500 mg, 2.46 mmol, 1 equiv) in toluene (10 mL). The mix-
ture was stirred at 80 °C for 30 min, then H O (10 mL) was added.
2
IR (film): 3088, 3064, 3032, 2929, 1783, 1594, 1491, 1455, 1409,
1318, 1302, 1173, 1144, 1030, 1010, 980, 879, 795, 731, 701, 514
–1
cm .
The organic layer was washed with H O (5 mL) and dried (MgSO )
2
4
and the solvent was removed on the rotary evaporator. The residue
was purified by column chromatography (hexane–EtOAc, 1:1) to
afford a colorless resin; yield: 178 mg (30%).
1
H NMR (400 MHz, CDCl ): d = 7.30–7.23 (m, 2 H), 7.19–7.13 (m,
3
3 H), 6.89–6.75 (m, 4 H), 5.79 (d, J = 6.8 Hz, 1 H), 4.10–4.02 (m, 1
H), 3.08 (dd, J = 17.4, 8.3 Hz, 1 H), 2.93 (dd, J = 17.4, 5.8 Hz, 1 H).
Rf = 0.06 (hexane–EtOAc, 1:1).
IR (film): 3449, 2922, 1730, 1671, 1597, 1483, 1459, 1380, 1357,
13
C NMR (100 MHz, CDCl ): d = 176.3, 136.4, 134.6, 131.0, 128.4,
3
1
cm .
311, 1287, 1257, 1228, 1174, 1128, 1062, 1040, 980, 752, 600
1
1
27.8, 127.6, 127.3, 121.8, 83.9, 46.6, 35.0.
–
+
MS (EI): m/z (%) = 318 [M ] (6), 316 (6), 185 (2), 165 (1), 132 (2),
104 (100), 78 (8), 77 (6), 51 (3).
1
H NMR (300 MHz, CDCl ): d = 9.73 (d, J = 7.7 Hz, 1 H), 7.85 (d,
3
J = 16.1 Hz, 1 H), 7.73 (d, J = 7.4 Hz, 1 H), 7.40–7.51 (m, 3 H),
6.71 (dd, J = 7.7, 16.1 Hz, 1 H), 4.72 (d, J = 22.6 Hz, 1 H), 4.08 (d,
J = 17.6 Hz, 1 H), 2.17 (s, 3 H), 1.82 (s, 3 H).
+
HRMS (EI): m/z [M + Na ] calcd for C H BrNaO : 338.9997;
found: 338.9997.
1
6
13
2
1
3
C NMR (75 MHz, CDCl ): d = 201.5, 193.4, 170.7, 146.4, 142.5,
3
trans-5-(4-Bromophenyl)-4-phenyltetrahydrofuran-2-one
trans-1b)
Light yellow oil; yield: 37 mg (12%).
1
32.4, 132.0, 131.0, 129.1 (Ph-C), 128.4, 127.7, 59.1, 27.2, 21.9.
(
+
MS (EI): m/z (%) = 245 [M ] (6), 203 (17), 202 (40), 186 (15), 160
(78), 132 (71), 131 (19), 130 (100), 103 (10), 77 (20).
Rf = 0.22 (hexane–EtOAc, 7:1).
+
HRMS (EI): m/z [M ] calcd for C H NO : 245.1052; found:
1
4
15
3
tR (50_20): 13.35 min.
2
45.1054.
IR (film): 3063, 3031, 2924, 1786, 1594, 1491, 1455, 1416, 1268,
1
–
194, 1142, 1071, 1035, 1004, 880, 808, 760, 699, 637, 504 cm .
1
Lactone Products
cis-5-(4-Chlorophenyl)-4-phenyltetrahydrofuran-2-one (cis-1a)
Colorless oil; yield: 121 mg (44%).
1
H NMR (400 MHz, CDCl ): d = 7.49–7.43 (m, 2 H), 7.40–7.30 (m,
3
3 H), 7.20–7.14 (m, 2 H), 7.09–7.02 (m, 2 H), 5.37 (d, J = 8.6 Hz, 1
H), 3.57–3.46 (m, 1 H), 3.05 (dd, J = 17.7, 8.3 Hz, 1 H), 2.93 (dd,
J = 17.6, 11.0 Hz, 1 H).
Rf = 0.07 (hexane–MTBE, 4:1).
tR (50_20): 12.53 min.
13
C NMR (75 MHz, CDCl ): d = 174.8, 137.3, 136.8, 131.8, 129.2,
3
IR (film): 3064, 3033, 2927, 1782, 1600, 1494, 1455, 1413, 1318,
1
28.1, 127.3, 127.2, 122.6, 86.6, 50.7, 37.1.
1
5
1
301, 1173, 1144, 1091, 1030, 1013, 980, 878, 818, 798, 734, 701,
15 cm .
–1
Methyl cis-4-(5-Oxo-3-phenyltetrahydrofuran-2-yl)benzoate
(cis-1c)
Colorless solid; yield: 164 mg (56%).
H NMR (400 MHz, CDCl ): d = 7.17–7.07 (m, 5 H), 6.86–6.79 (m,
3
4 H), 5.79 (d, J = 6.8 Hz, 1 H), 4.08–4.00 (m, 1 H), 3.06 (dd,
J = 17.6, 8.2 Hz, 1 H), 2.92 (dd, J = 17.4, 5.8 Hz, 1 H).
Rf = 0.13 (hexane–MTBE, 3:1).
1
3
C NMR (100 MHz, CDCl ): d = 176.0, 136.1, 133.8, 133.4, 128.1,
3
tR (50_20): 13.34 min.
1
27.8, 127.5, 127.3, 126.7, 83.6, 46.4, 34.7.
IR (KBr): 3033, 2954, 1779, 1708, 1437, 1280, 1176, 984, 698
–1
cm .
+
MS (EI): m/z (%) = 274 [M ] (3), 272 (8), 178 (1), 165 (1), 139 (2),
1
32 (2), 115 (1), 104 (100), 78 (6), 51 (2).
1
H NMR (400 MHz, CDCl ): d = 7.77 (dt, J = 8.3, 1.8 Hz, 2 H),
3
+
HRMS (EI): m/z [M ] calcd for C H ClO : 272.0604; found:
2
1
6
13
2
7.09–7.05 (m, 3 H), 6.97 (m, 2 H), 6.82–6.77 (m, 2 H), 5.84 (d,
J = 6.8 Hz, 1 H), 4.06 (m, 1 H), 3.84 (s, 3 H), 3.07 (dd, J = 17.4, 8.3
Hz, 1 H), 2.91 (dd, J = 17.4, 5.6 Hz, 1 H).
72.0605.
trans-5-(4-Chlorophenyl)-4-phenyltetrahydrofuran-2-one
trans-1a)
Colorless oil; yield: 24 mg (9%).
1
3
C NMR (100 MHz, CDCl ): d = 175.9, 166.2, 140.4, 136.1, 129.3,
3
(
1
28.9, 128.1, 127.5, 127.3, 125.3, 83.7, 51.7, 46.4, 34.8.
+
MS (EI): m/z (%) = 296 [M ] (8), 265 (5), 191 (1), 178 (2), 165 (2),
Rf = 0.15 (hexane–MTBE, 4:1).
1
33 (3), 115 (2), 104 (100), 78 (6).
tR (50_20): 12.79 min.
+
HRMS (EI): m/z [M ] calcd for C H O : 296.1049; found:
1
8
16
4
IR (film): 3064, 3032, 2925, 1787, 1601, 1493, 1455, 1413, 1268,
1
2
96.1048.
–
195, 1144, 1091, 1002, 810, 760, 699, 511 cm .
1
1
Methyl trans-4-(5-Oxo-3-phenyltetrahydrofuran-2-yl)benzoate
trans-1c)
Colorless solid; yield: 41 mg (14%).
H NMR (400 MHz, CDCl ): d = 7.41–7.28 (m, 5 H), 7.21–7.08 (m,
3
(
4 H), 5.38 (d, J = 8.8 Hz, 1 H), 3.58–3.48 (m, 1 H), 3.06 (dd,
J = 17.6, 8.5 Hz, 1 H), 2.94 (dd, J = 17.4, 11.1 Hz, 1 H).
1
3
Rf = 0.31 (hexane–MTBE, 3:1).
C NMR (75 MHz, CDCl ): d = 174.6, 137.2, 136.2, 134.4, 129.0,
3
1
28.7, 127.9, 127.2, 126.8, 86.5, 50.6, 36.9.
tR (50_20): 13.67 min.
+
MS (EI): m/z (%) = 274 [M ] (2), 272 (7), 139 (2), 132 (2), 131 (2),
IR (KBr): 3030, 2961, 1786, 1717, 1435, 1277, 1106, 991, 775, 700
–1
cm .
1
15 (2), 111 (2), 104 (100), 78 (6), 77 (6), 51 (2).
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
430
C. Burstein et al.
FEATURE ARTICLE
1
H NMR (400 MHz, CDCl ): d = 7.9 (dt, J = 8.3, 1.8, 2 H), 7.32–
3
.22 (m, 3 H), 7.16 (m, 2 H), 7.09 (m, 2 H), 5.38 (d, J = 8.6 Hz, 1
IR (KBr): 3079, 3031, 2962, 2927, 1775, 1765, 1756, 1591, 1489,
1455, 1382, 1304, 1273, 1179, 1148, 1139, 1082, 1027, 986, 969,
7
H), 3.83 (s, 3 H), 3.46 (m, 1 H), 2.99 (dd, J = 17.7, 8.6 Hz, 1 H),
–
866, 791, 777, 729, 705, 693, 522 cm .
1
2
.86 (dd, J = 17.7, 10.9 Hz, 1 H).
1
H NMR (400 MHz, CDCl ): d = 7.16–7.06 (m, 4 H), 6.87–6.79 (m,
3
1
3
C NMR (100 MHz, CDCl ): d = 174.8, 166.5, 142.7, 137.4, 130.4,
3
29.9, 129.2, 128.1, 127.4, 125.4, 86.7, 52.1, 50.8, 37.0.
3 H), 6.73–6.67 (m, 1 H), 6.65–6.59 (m, 1 H), 5.80 (d, J = 6.8 Hz, 1
H), 4.09–4.02 (m, 1 H), 3.07 (dd, J = 17.4, 8.3 Hz, 1 H), 2.93 (dd,
J = 17.6, 5.9 Hz, 1 H).
1
+
MS (EI): m/z (%) = 296 [M ] (9), 265 (2), 191 (1), 178 (1), 165 (2),
1
1
3
33 (3), 115 (2), 104 (100), 78 (7).
C NMR (100 MHz, CDCl ): d = 176.3, 162.5 (d, J = 247 Hz),
3
+
HRMS (EI): m/z [M ] calcd for C H O : 296.1049; found:
138.2 (d, J = 8 Hz), 136.4, 129.5 (d, J = 8 Hz), 128.4, 127.8, 127.6,
21.3 (d, J = 3 Hz), 114.7 (d, J = 21 Hz), 112.9 (d, J = 23 Hz), 83.8
1
8
16
4
1
2
96.1048.
(
d, J = 2 Hz), 46.8, 35.0.
1
9
cis-4-Phenyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-
one (cis-1d)
Colorless solid; yield: 108 mg (35%).
F NMR (282 MHz, CDCl ): d = –63.00.
3
+
MS (EI): m/z (%) = 256 [M ] (8), 228 (3), 183 (1), 132 (1), 123 (1),
1
04 (1), 95 (2), 78 (7), 77 (5), 51 (2).
Rf = 0.21 (hexane–MTBE, 3:1).
+
HRMS (EI): m/z [M ] calcd for C H FO : 256.0900; found:
256.0901.
1
6
13
2
tR (50_20): 11.34 min.
IR (KBr): 3091, 3065, 3034, 2931, 1775, 1759, 1623, 1429, 1422,
trans-5-(3-Fluorophenyl)-4-phenyltetrahydrofuran-2-one
(trans-1e)
Colorless oil; yield: 16 mg (6%).
1
7
1
330, 1187, 1163, 1121, 1069, 1029, 1018, 981, 859, 828, 739, 720,
–
00, 604, 516 cm .
1
H NMR (400 MHz, CDCl ): d = 7.38 (d, J = 8.3 Hz, 2 H), 7.16–
3
Rf = 0.28 (hexane–EtOAc, 6:1).
tR (50_20): 11.73 min.
7
.07 (m, 3 H), 7.06–7.00 (m, 2 H), 6.85–6.77 (m, 2 H), 5.86 (d,
J = 6.8 Hz, 1 H), 4.13–4.05 (m, 1 H), 3.10 (dd, J = 17.7, 8.3 Hz, 1
H), 2.94 (dd, J = 17.4, 5.6 Hz, 1 H).
IR (film): 3065, 3033, 2926, 1787, 1616, 1593, 1490, 1454, 1419,
1270, 1195, 1146, 1035, 1003, 967, 907, 875, 789, 759, 699, 522
1
3
C NMR (100 MHz, CDCl ): d = 176.2, 139.7, 136.3, 130.1 (q,
3
–
cm .
1
J = 33 Hz), 128.5, 127.8, 127.7, 126.0, 124.9 (q, J = 4 Hz), 123.8 (q,
J = 269 Hz), 83.8, 46.7, 35.1.
1
H NMR (400 MHz, CDCl ): d = 7.44–7.27 (m, 4 H), 7.24–7.18 (m,
3
1
9
F NMR (282 MHz, CDCl ): d = –113.17.
3
2 H), 7.08–7.00 (m, 1 H), 6.98–6.92 (m, 2 H), 5.44 (d, J = 8.6 Hz, 1
H), 3.63–3.53 (m, 1 H), 3.09 (dd, J = 17.7, 8.6 Hz, 1 H), 2.94 (dd,
J = 17.7, 10.6 Hz, 1 H).
+
MS (EI): m/z (%) = 306 [M ] (4), 287 (3), 178 (1), 173 (1), 165 (1),
1
45 (2), 104 (100), 78 (7), 77 (5), 51 (2).
1
3
+
HRMS (EI): m/z [M + Na ] calcd for C H F NaO : 329.0765;
found: 329.0765.
C NMR (100 MHz, CDCl ): d = 174.8, 162.8 (d, J = 248 Hz),
3
1
7
13
3
2
1
1
40.4 (d, J = 7 Hz), 137.6, 130.3 (d, J = 8 Hz), 129.2, 128.1, 127.3,
21.1 (d, J = 3 Hz), 115.6 (d, J = 21 Hz), 112.6 (d, J = 22 Hz), 86.5
(
d, J = 2 Hz), 50.6, 37.1.
trans-4-Phenyl-5-[4-(trifluoromethyl)phenyl]tetrahydrofuran-
-one (trans-1d)
Colorless oil; yield: 27 mg (9%).
1
9
2
F NMR (282 MHz, CDCl ): d = –112.08.
3
+
MS (EI): m/z (%) = 256 [M ] (10), 228 (3), 196 (1), 183 (2), 165 (1),
133 (2), 123 (2), 104 (100), 95 (3), 78 (7), 77 (6), 51 (2).
Rf = 0.38 (hexane–MTBE, 3:1).
+
HRMS (EI): m/z [M + Na ] calcd for C H FNaO : 279.0797;
found: 279.0800.
tR (50_20): 11.57 min.
16
13
2
IR (film): 3063, 3034, 2929, 1788, 1622, 1498, 1420, 1326, 1271,
1
cm .
193, 1166, 1127, 1069, 1037, 1009, 851, 817, 761, 699, 611, 510
1
–
cis-5-(3-Chlorophenyl)-4-phenyltetrahydrofuran-2-one (cis-1f)
Colorless solid; yield: 135 mg (50%).
1
H NMR (400 MHz, CDCl ): d = 7.59 (d, J = 8.3 Hz, 2 H), 7.43–
3
Rf = 0.09 (hexane–MTBE, 4:1).
7
.31 (m, 3 H), 7.31–7.27 (m, 2 H), 7.22–7.18 (m, 2 H), 5.48 (d,
J = 8.6 Hz, 1 H), 3.58–3.48 (m, 1 H), 3.08 (dd, J = 17.7, 8.6 Hz, 1
H), 2.95 (dd, J = 17.7, 11.1 Hz, 1 H).
tR (50_20): 12.42 min.
IR (KBr): 3030, 1775, 1758, 1575, 1495, 1454, 1377, 1303, 1260,
–1
1177, 1145, 1028, 982, 945, 882, 783, 741, 705, 685 cm .
1
3
C NMR (100 MHz, CDCl ): d = 174.7, 141.8, 137.3, 130.9 (q,
3
J = 33 Hz), 129.3, 128.2, 127.4, 125.7, 125.7 (q, J = 4 Hz), 123.9 (q,
J = 272 Hz), 86.4, 50.8, 37.2.
1
H NMR (400 MHz, CDCl ): d = 7.17–7.08 (m, 4 H), 7.04 (t,
3
J = 7.7 Hz, 1 H), 6.92–6.89 (m, 1 H), 6.86–6.80 (m, 2 H), 6.79–6.75
(m, 1 H), 5.78 (d, J = 7.1 Hz, 1 H), 4.09–4.02 (m, 1 H), 3.07 (dd,
J = 17.4, 8.3 Hz, 1 H), 2.93 (dd, J = 17.6, 6.0 Hz, 1 H).
1
9
F NMR (282 MHz, CDCl ): d = –62.93.
3
+
MS (EI): m/z (%) = 306 [M ] (5), 287 (4), 173 (2), 145 (3), 127 (2),
1
3
1
15 (2), 104 (100), 78 (7), 77 (5), 51 (2).
C NMR (100 MHz, CDCl ): d = 176.2, 137.7, 136.4, 134.1, 129.2,
3
+
HRMS (EI): m/z [M + Na ] calcd for C H F NaO : 329.0765;
found: 329.0769.
128.5, 128.0, 127.9, 127.7, 125.9, 123.8, 83.8, 46.8, 35.0.
1
7
13
3
2
+
MS (EI): m/z (%) = 272 [M ] (3), 244 (1), 178 (2), 165 (2), 139 (2),
1
32 (1), 131 (1), 115 (3), 104 (100), 91 (1), 89 (2), 77 (6), 63 (1).
cis-5-(3-Fluorophenyl)-4-phenyltetrahydrofuran-2-one (cis-1e)
Colorless solid; yield: 119 mg (46%).
+
HRMS (EI): m/z [M ] calcd for C H ClO : 272.0604; found:
1
6
13
2
2
72.0605.
Rf = 0.22 (hexane–EtOAc, 6:1).
tR (50_20): 11.53 min.
trans-5-(3-Chlorophenyl)-4-phenyltetrahydrofuran-2-one
trans-1f)
Colorless solid; yield: 31 mg (11%).
(
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2431
Rf = 0.17 (hexane–MTBE, 4:1).
IR (film): 3064, 3032, 1786, 1597, 1575, 1497, 1478, 1455, 1445,
1
–
266, 1194, 1174, 1145, 1034, 1001, 882, 759, 701, 621 cm .
1
tR (50_20): 12.67 min.
1
H NMR (400 MHz, CDCl ): d = 7.52–6.87 (m, 9 H, D1 + D2),
3
IR (KBr): 3064, 3032, 2925, 1787, 1600, 1575, 1497, 1456, 1354,
1
–
318, 1270, 1194, 1145, 1035, 1000, 891, 786, 760, 699, 643 cm .
1
6.14 (d, J = 6.1 Hz, 1 H, D2), 5.88 (d, J = 5.3 Hz, 1 H, D1), 4.33–
4
.26 (m, 1 H, D2), 3.73–3.74 (m, 1 H, D1), 3.27 (dd, J = 17.7, 8.6
Hz, 1 H, D2), 3.06 (dd, J = 17.7, 8.8 Hz, 1 H, D1), 2.96 (dd,
J = 17.7, 2.3 Hz, 1 H, D2), 2.81 (dd, J = 17.9, 6.6 Hz, 1 H, D1).
1
H NMR (400 MHz, CDCl ): d = 7.40–7.15 (m, 8 H), 7.04–6.99 (m,
3
1 H), 5.38 (d, J = 8.6 Hz, 1 H), 3.60–3.50 (m, 1 H), 3.05 (dd,
J = 17.4, 8.6 Hz, 1 H), 2.91 (dd, J = 17.6, 10.7 Hz, 1 H).
1
3
C NMR (100 MHz, CDCl ): d = 176.4 (D2), 176.1 (D1), 139.8,
3
1
3
C NMR (100 MHz, CDCl ): d = 174.8, 139.9, 137.5, 134.7, 129.9,
3
137.7, 136.2, 133.7, 132.2, 130.8, 130.0, 129.7, 129.0, 128.8, 128.8,
28.2, 127.8, 127.4, 127.3, 127.2, 127.0, 126.9, 126.5, 126.4, 84.2
(D1), 82.3 (D2), 48.7 (D1), 44.3 (D2), 36.5 (D2), 35.8 (D1).
1
29.2, 128.8, 128.1, 127.3, 125.7, 123.7, 86.4, 50.6, 37.0.
1
+
MS (EI): m/z (%) = 274 [M ] (3), 272 (7), 144 (1), 165 (2), 139 (1),
1
32 (1), 115 (2), 104 (100), 78 (7), 51 (3).
+
MS (EI): m/z (%) = 274 [M ] (3), 272 (8), 165 (1), 139 (2), 132 (2),
131 (2), 104 (100), 78 (6), 77 (6), 51 (2).
+
HRMS (EI): m/z [M ] calcd for C H ClO : 272.0604; found:
1
6
13
2
2
72.0608.
+
HRMS (EI): m/z [M + Na ] calcd for C H ClNaO : 295.0512;
found: 295.0501.
1
6
13
2
cis-5-(3-Bromophenyl)-4-phenyltetrahydrofuran-2-one (cis-1g)
–
4
Purification by Kugelrohr distillation (5 × 10 mbar, 130–150 °C),
followed by column chromatography (hexane–MTBE, 5:1); color-
less solid; yield: 155 mg (49%).
l-4,5-Diphenyl-5-(trifluoromethyl)tetrahydrofuran-2-one (l-7a)
–2
Purification by Kugelrohr distillation (3 × 10 mbar, 90–120 °C),
followed by column chromatography (hexane–MTBE, 25:1), yel-
lowish oil; yield: 164 mg (53%).
Rf = 0.10 (hexane–MTBE, 5:1).
tR (50_20): 12.89 min.
Rf = 0.42 (hexane–EtOAc, 14:1).
IR (KBr): 3064, 3030, 3007, 2927, 1773, 1756, 1598, 1570, 1495,
tR (50_20): 10.42 min.
1
9
1
476, 1454, 1434, 1416, 1320, 1303, 1261, 1177, 1145, 1073, 1028,
–1
IR (film): 3065, 3036, 1806, 1500, 1174, 1055, 726, 703 cm .
–
80, 937, 882, 781, 738, 702, 676, 508 cm .
1
1
H NMR (400 MHz, CDCl ): d = 7.21–7.06 (m, 8 H), 6.85–6.80 (m,
3
H NMR (400 MHz, CDCl ): d = 7.29–7.23 (m, 1 H), 7.17–7.12 (m,
3
2 H), 4.27 (dd, J = 9.6, 5.3 Hz, 1 H), 3.31 (ddq, J = 18.4, 9.6, 1.3 Hz,
1
3
H), 5.77 (d, J = 6.8 Hz, 1 H), 4.08–4.01 (m, 1 H), 3.07 (dd, J = 17.6,
8
H), 7.07–7.04 (m, 1 H), 6.98 (t, J = 7.8 Hz, 1 H), 6.87–6.79 (m, 3
H), 2.76 (ddq, J = 18.2, 5.5, 1.4 Hz, 1 H).
1
3
C NMR (100 MHz, CDCl ): d = 173.8, 137.6, 131.3, 128.8, 128.5,
3
.2 Hz, 1 H), 2.93 (dd, J = 17.6, 5.9 Hz, 1 H).
128.4, 127.8, 126.8, 126.8, 124.5 (q, J = 286 Hz), 88.5 (q, J = 29
Hz), 45.8, 36.8.
1
3
C NMR (100 MHz, CDCl ): d = 176.2, 137.9, 136.3, 130.9, 129.4,
3
1
28.9, 128.5, 127.9, 127.7, 124.3, 122.2, 83.7, 46.8, 34.9.
1
9
F NMR (282 MHz, CDCl ): d = –77.5.
3
+
MS (EI): m/z (%) = 318 (7), 316 [M ] (7), 185 (2), 183 (2), 165 (2),
1
+
MS (EI): m/z (%) = 306 [M ] (9), 278 (1), 191 (0.6), 178 (1), 165
(
15 (2), 104 (100), 78 (8), 76 (2), 51 (3).
2), 115 (1), 104 (100), 77 (7).
+
HRMS (EI): m/z [M ] calcd for C H BrO : 316.0099; found:
3
1
6
13
2
+
HRMS (EI): m/z [M ] calcd for C H F O : 306.0868; found:
3
1
7
13
3
2
16.0099.
06.0866.
trans-5-(3-Bromophenyl)-4-phenyltetrahydrofuran-2-one
trans-1g)
Colorless oil; yield: 53 mg (17%).
u-4,5-Diphenyl-5-(trifluoromethyl)tetrahydrofuran-2-one
u-7a)
Colorless solid; yield: 95 mg (31%).
(
(
Rf = 0.18 (hexane–MTBE, 5:1).
Rf = 0.35 (hexane–EtOAc, 14:1).
tR (50_20): 13.20 min.
tR (50_20): 11.11 min.
IR (film): 3063, 3031, 2925, 1786, 1599, 1571, 1456, 1432, 1318,
IR (KBr): 3069, 3038, 1792, 1500, 1307, 1176, 1136, 1029, 928,
1
6
1
268, 1194, 1144, 1095, 1074, 1035, 998, 886, 784, 759, 733, 698,
78, 643 cm .
–
761, 726, 699 cm .
1
–1
1
H NMR (400 MHz, CDCl
): d = 7.56–7.49 (m, 2 H), 7.45–7.36, m,
H), 7.34–7.30 (m, 2 H), 3.99 (t, J = 9.3, 1 H), 3.14 (ddq, J = 27.5,
3
H NMR (400 MHz, CDCl ): d = 7.41–7.36 (m, 1 H), 7.34–7.20 (m,
3
6
9
4
H), 7.14–7.06 (m, 3 H), 7.01–6.95 (m, 1 H), 5.30 (d, J = 8.3 Hz, 1
H), 3.52–3.42 (m, 1 H), 2.99 (dd, J = 17.7, 8.6 Hz, 1 H), 2.84 (dd,
J = 17.6, 10.7 Hz, 1 H).
.6, 1.2 Hz, 1 H), 2.91 (ddq, J = 27.0, 9.1, 1.2 Hz, 1 H).
1
3
C NMR (100 MHz, CDCl ): d = 173.2, 135.6, 133.9, 129.5, 129.3,
3
1
3
129.3, 128.8, 128.7, 125.5, 123.8 (q, J = 285 Hz), 87.5 (q, J = 29
Hz), 51.5, 35.2.
C NMR (100 MHz, CDCl ): d = 174.8, 140.1, 137.5, 131.8, 130.2,
3
1
29.2, 128.5, 128.1, 127.3, 124.2, 122.8, 86.3, 50.6, 37.0.
1
9
+
MS (EI): m/z (%) = 318 (6), 316 [M ] (6), 185 (2), 183 (2), 165 (2),
F NMR (282 MHz, CDCl ): d = –71.6.
3
+
MS (EI): m/z (%) = 306 [M ] (6), 278 (2), 209 (1), 178 (1), 165 (1),
131 (1), 115 (1), 104 (100), 77 (7).
1
31 (2), 115 (3), 104 (100), 91 (2), 78 (8), 76 (2), 51 (3).
+
HRMS (EI): m/z [M ] calcd for C H BrO : 316.0099; found:
1
6
13
2
+
HRMS (EI): m/z [M ] calcd for C H F O : 306.0868; found:
3
16.0100.
1
7
13
3
2
3
06.0867.
5-(2-Chlorophenyl)-4-phenyltetrahydrofuran-2-one (1h)
Diastereomeric mixture; yield: 87 mg (32%).
4-(4-Methoxyphenyl)-5-phenyl-5-(trifluoromethyl)tetrahydro-
furan-2-one (7b)
Diastereomeric mixture, colorless solid; yield: 310 mg (92%).
Rf = 0.11 (hexane–EtOAc, 6:1).
tR (50_20): 12.13 (D1, cis); 12.51 min (D2, trans).
l-7b
Rf = 0.19 (hexane–EtOAc, 14:1).
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
432
C. Burstein et al.
FEATURE ARTICLE
tR (50_20): 11.61 min.
tR (50_20): 13.32 min.
IR (film): 3065, 3037, 3005, 2959, 2842, 1806, 1613, 1586, 1516,
1
IR (KBr): 2925, 2896, 2814, 1798, 1621, 1533, 1450, 1363, 1309,
1210, 1185, 1167, 1159, 1130, 1057, 1027, 921, 888, 788, 765, 725,
–
451, 1417, 1297, 1257, 1174, 911, 833, 726, 703, 553, 523 cm .
1
–
1
699, 653, 511 cm .
1
H NMR (400 MHz, CDCl ): d = 7.25–7.01 (m, 5 H), 6.78–6.71 (m,
3
1
2
(
H), 6.67–6.60 (m, 2 H), 4.25 (dd, J = 9.5 Hz, 6.2 Hz, 1 H), 3.71
s, 3 H), 3.32–3.22 (m, 1 H), 2.77–2.68 (m, 1 H).
H NMR (400 MHz, CD Cl ): d = 7.59–7.51 (m, 2 H), 7.49–7.42
2
2
(m, 3 H), 7.22–7.15 (m, 2 H), 6.78–6.70 (m, 2 H), 3.93 (t, J = 9.6
Hz, 1 H), 3.17–3.07 (m, 1 H), 2.98 (s, 6 H), 2.93–2.83 (m, 1 H).
1
3
C NMR (100 MHz, CDCl ): d = 173.8, 159.1, 131.3, 129.6, 129.2,
3
1
3
128.8, 127.8, 126.9, 124.6 (q, J = 286 Hz), 113.8, 88.5 (q, J = 29
Hz), 55.2, 45.2, 36.6.
C NMR (100 MHz, CD Cl ): d = 173.6, 150.8, 136.0, 130.1,
2 2
129.5, 128.8, 125.7, 124.3 (q, J = 286 Hz), 120.5, 112.2, 87.4 (q,
J = 27 Hz), 51.0, 40.3, 35.4.
1
9
F NMR (282 MHz, CDCl ): d = –76.9.
3
1
9
+
MS (EI): m/z (%) = 336 [M ] (24), 165 (1), 161 (1), 134 (100), 119
F NMR (282 MHz, CD Cl ): d = –71.9.
2 2
+
MS (EI): m/z (%) = 349 [M ] (45), 174 (1), 147 (100), 131 (5), 118
(1), 105 (3), 91 (1), 77 (6), 51 (1).
(
11), 105 (2), 91 (8), 77 (4), 65 (3), 51 (1).
+
HRMS (ESI): m/z [M ] calcd for C H F O : 336.0969; found:
3
1
8
15
3
3
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NNaO : 372.1187;
found: 372.1186.
36.0970.
1
9
18
3
2
u-7b
Rf = 0.10 (hexane–EtOAc, 14:1).
5-Acetyl-4,5-diphenyltetrahydrofuran-2-one (7d)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless solid;
yield: 77 mg (55%).
tR (50_20): 12.32 min.
IR (KBr): 3062, 3038, 3005, 2963, 2935, 2843, 1801, 1614, 1582,
Rf = 0.05 (hexane–MTBE, 20:1).
1
7
1
518, 1452, 1411, 1314, 1292, 1183, 1156, 1131, 1030, 922, 888,
–
98, 767, 725, 699, 530 cm .
1
tR (70_20): 12.64 (D1), 13.19 min (D2).
H NMR (400 MHz, CDCl ): d = 7.49–7.42 (m, 2 H), 7.39–7.33 (m,
IR (KBr): 3032, 2924, 2853, 1790, 1716, 1496, 1455, 1410, 1353,
–
1176, 1140, 1088, 1061, 1030, 992, 969, 754, 698 cm .
3
1
3 H), 7.21–7.24 (m, 2 H), 6.89–6.83 (m, 2 H), 3.88 (t, J = 9.6 Hz, 1
H), 3.77 (s, 3 H), 3.10–2.99 (m, 1 H), 2.87–2.77 (m, 1 H).
1
H NMR (500 MHz, CDCl ): d = 7.75–6.90 (m, 10 H, D1 and 10 H,
3
1
3
C NMR (100 MHz, CDCl ): d = 173.3, 159.8, 135.6, 130.4, 129.4,
3
D2), 4.61 (dd, J = 8.6, 4.5 Hz, 1 H, D1), 4.12 (d, J = 7.9 Hz, 1 H,
D2), 3.02 (dd, J = 18.0, 8.9 Hz, 1 H, D1), 2.88–2.65 (m, 1 H, D1 and
2 H, D2), 2.21 (s, 3 H), 1.96 (s, 3 H).
129.2, 128.7, 125.5, 123.9 (q, J = 286 Hz), 114.2, 87.4 (q, J = 29
Hz), 55.3, 50.9, 35.4.
1
9
13
F NMR (282 MHz, CDCl ): d = –71.7.
3
C NMR (125 MHz, CDCl ): d = 204.8, 204.6, 175.5, 174.9, 138.8,
3
+
MS (EI): m/z (%) = 336 [M ] (14), 134 (100), 119 (9), 117 (7), 105
137.8, 137.7, 133.7, 129.0, 128.9, 128.8, 128.4, 128.2, 128.2, 128.0,
1
3
27.7, 127.2, 125.5, 125.2, 95.5, 95.4, 51.8 (D2), 46.3 (D1), 36.4,
6.3, 27.6, 25.4.
(
2), 103 (1), 91 (7), 89 (1), 77 (4), 65 (3), 51 (2).
+
HRMS (ESI): m/z [M ] calcd for C H F O : 336.0969; found:
1
8
15
3
3
MS (EI) D1: m/z (%) = 237 (100), 219 (37), 178 (4), 168 (2), 167
12), 165 (11), 152 (6), 131 (3), 115 (5), 106 (3), 105 (40), 91 (2),
9 (1), 77 (16), 63 (1), 51 (4).
3
36.0973.
(
8
4-[4-(Dimethylamino)phenyl]-5-phenyl-5-(trifluoromethyl)tet-
rahydrofuran-2-one (7c)
MS (EI) D2: m/z (%) = 237 (100), 220 (6), 219 (37), 209 (2), 193
(5), 191 (10), 181 (1), 178 (4), 167 (12), 165 (11), 159 (1), 152 (6),
131 (3), 115 (5), 105 (40), 91 (2), 77 (16), 63 (1), 51 (4).
Diastereomeric mixture, off-white solid which decomposes upon
standing in air; yield: 259 mg (74%).
+
HRMS (ESI): : m/z [M + Na ] calcd for C H NaO : 303.0992;
found: 303.0990.
1
8
16
3
l-7c
Rf = 0.45 (hexane–EtOAc, 6:1).
tR (50_20): 12.47 min.
Methyl 5-Oxo-2,3-diphenyltetrahydrofuran-2-carboxylate (7e)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless solid;
yield: 115 mg (78%).
IR (KBr): 3090, 3030, 2986, 2894, 2811, 1796, 1616, 1526, 1450,
1
8
1
353, 1269, 1199, 1182, 1166, 1058, 1021, 998, 937, 910, 889, 821,
–
12, 732, 700, 659, 522 cm .
1
Rf = 0.25 (hexane–MTBE, 4:1).
H NMR (400 MHz, CD Cl ): d = 7.19–7.08 (m, 3 H), 7.08–7.03
tR (70_20): 13.28 (D1), 13.77 min (D2).
2
2
(
m, 2 H), 6.62–6.56 (m, 2 H), 6.39–6.33 (m, 2 H), 4.13 (dd, J = 9.3
IR (KBr): 3031, 1790, 1736, 1449, 1434, 1286, 1266, 1231, 1179,
1
Hz, 6.6 Hz, 1 H), 3.12 (ddq, J = 18.2, 9.3, 1.3 Hz, 1 H), 2.75 (s, 6
H), 2.62 (ddq, J = 18.2, 6.7, 1.2 Hz, 1 H).
–1
143, 1090, 1052, 1024, 1005, 954, 888, 751, 725, 697 cm .
1
H NMR (500 MHz, CDCl ): d = 7.72–7.65 (m, 2 H), 7.46–7.27 (m,
3
1
3
C NMR (100 MHz, CD Cl ): d = 174.7, 150.8, 132.4, 130.0,
2
2
8 H), 7.19–7.06 (m, 8 H), 6.94–6.89 (m, 2 H), 4.52 (dd, J = 8.5, 4.3
Hz, 1 H, D1), 4.08 (dd, J = 8.3, 5.0 Hz, 1 H, D2), 3.81 (s, 3 H), 3.39
(s, 3 H), 3.11 (dd, J = 17.7, 8.5 Hz, 1 H, D1), 2.93–2.76 [m, 1 H
(D1), 2 H (D2)].
129.5, 128.5, 127.7, 125.5 (q, J = 285 Hz), 124.8, 112.6, 89.2 (q,
J = 29 Hz), 46.0, 40.8, 37.2.
1
9
F NMR (282 MHz, CD Cl ): d = –77.3.
2
2
+
MS (EI): m/z (%) = 349 [M ] (45), 174 (1), 147 (100), 131 (5), 117
13
C NMR (75 MHz, CDCl ): d = 174.7, 174.5, 171.1, 168.5, 137.8,
3
(
1), 105 (2), 91 (1), 77 (5), 51 (1).
137.7, 137.3, 134.2, 128.9, 128.8, 128.5, 128.3, 128.3, 128.3, 128.2,
127.9, 127.8, 127.5, 125.8, 125.6, 90.7, 90.6, 53.5, 52.5, 52.1, 49.0,
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NNaO : 372.1187;
found: 372.1186.
1
9
18
3
2
3
6.2, 35.9.
+
MS (EI) D1: m/z (%) = 296 [M ] (1), 239 (2), 238 (18), 237 (100),
220 (3), 219 (18), 194 (1), 193 (3), 191 (6), 189 (2), 179 (2), 178 (4),
167 (6), 165 (8), 152 (5), 132 (1), 131 (3), 115 (4), 106 (3), 105 (30),
u-7c
Rf = 0.36 (hexane–EtOAc, 6:1).
1
04 (79), 103 (10), 77 (18), 51 (4).
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2433
+
MS (EI) D2: m/z (%) = 296 [M ] (1), 237 (51), 219 (8), 191 (3), 178
4-Methyl-5-phenyl-5-(trifluoromethyl)tetrahydrofuran-2-one
(12a)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless oil;
yield: 100 mg (82%).
(
(
3), 167 (3), 165 (5), 152 (3), 105 (24), 104 (100), 91 (2), 89 (1), 77
15), 63 (1), 51 (3).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 319.0941;
found: 319.0934.
1
8
16
4
Rf = 0.18 (hexane–MTBE, 9:1).
tR (70_20): 8.98 (D1), 9.13 min (D2).
Methyl 3-(4-Methoxyphenyl)-5-oxo-2-phenyltetrahydrofuran-
-carboxylate (7f)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless solid;
IR (film): 2983, 1806, 1495, 1452, 1426, 1389, 1361, 1281, 1171,
1
2
–
1
104, 1014, 934, 916, 765, 718, 700 cm .
yield: 153 mg (94%).
1
H NMR (500 MHz, CDCl ): d = 7.6–7.4 (m, 5 H, D1, 5 H, D2),
3
3
D2), 2.78–2.70 (m, 1 H, D2), 2.56–2.48 (m, 1 H, D2), 2.30–2.23 (m,
.21–3.13 (m, 1 H, D1), 3.09–3.02 (m, 1 H, D1), 3.04–2.99 (m, 1 H,
Rf = 0.26 (hexane–EtOAc, 4:1).
tR (70_20): 14.42 (D1), 15.10 min (D2).
1
H, D1), 1.58–1.54 (m, 3 H, D2), 0.84 (d, J = 7.2 Hz, 3 H, D1).
IR (KBr): 2953, 2840, 1781, 1742, 1612, 1516, 1459, 1449, 1407,
13
C NMR (125 MHz, CDCl ): d = 174.0 (D1), 173.3 (D2), 135.8,
3
1
7
1
293, 1252, 1252, 1202, 1175, 1138, 1055, 1032, 962, 890, 828,
01 cm .
1
1
29.5, 129.3, 128.7, 128.5, 126.1 (d, J = 1.4 Hz), 125.6, 125.3,
24.8 (q, J = 285 Hz), 88.1 (q, J = 29 Hz), 86.4 (q, J = 28 Hz), 39.8
–1
H NMR (300 MHz, CDCl ): d = 7.70–7.60 (m, 2 H), 7.46–7.34 (m,
(D2), 36.4 (D1), 36.1 (D2), 34.0 (D1), 18.0 (D1), 15.7 (D2).
3
3
H), 7.23–7.10 (m, 7 H), 6.92–6.78 (m, 4 H), 6.64–6.75 (m, 2 H),
.46 (dd, J = 8.4, 4.8 Hz, 1 H, D1), 4.07–4.00 (m, 1 H, D2), 3.81 (s,
H), 3.79 (s, 3 H), 3.68 (s, 3 H), 3.42 (s, 3 H), 3.06 (dd, J = 17.8,
.5 Hz, 1 H, D1), 2.93–2.68 (m, 3 H D1, D2).
19
F NMR (282 MHz, CDCl ): d = –73.5 (D2), –76.7 (D1).
3
4
3
8
+
MS (EI) D1: m/z (%) = 244 [M ] (9), 175 (100), 164 (2), 128 (2),
1
15 (4), 105 (61), 91 (4), 77 (15), 69 (3), 51 (4).
+
MS (EI) D2: m/z (%) = 244 [M ] (11), 175 (100), 164 (2), 145 (1),
1
3
C NMR (75 MHz, CDCl ): d = 174.7, 174.6, 171.1, 168.6, 159.4,
3
1
28 (2), 115 (6), 105 (60), 91 (4), 77 (16), 69 (3), 51 (5).
1
1
5
58.7, 137.7, 134.2, 129.4, 129.4, 129.1, 129.0, 128.8, 128.4, 128.1,
27.8, 125.8, 125.6, 114.1, 113.6, 90.6, 90.6, 55.2, 55.0, 53.4, 52.5,
1.4 (D2), 48.3 (D1), 36.2, 35.9.
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NaO : 267.0603;
found: 267.0603.
1
2
11
3
2
+
MS (EI) D1: m/z (%) = 326 [M ] (8), 294 (2), 267 (10), 249 (3), 225
5
-Phenyl-4-propyl-5-(trifluoromethyl)tetrahydrofuran-2-one
12b)
(
1
3), 197 (5), 178 (1), 165 (3), 153 (2), 152 (2), 135 (10), 134 (100),
19 (8), 115 (1), 105 (6), 91 (6), 89 (1), 78 (1), 77 (7), 65 (2).
(
Diastereomeric mixture (D1 = like, D2 = unlike), colorless oil;
yield: 123 mg (90%).
+
MS (EI) D2: m/z (%) = 326 [M ] (5), 267 (4), 225 (1), 197 (2), 165
(
(
2), 153 (1), 135 (11), 134 (100), 119 (9), 105 (4), 91 (6), 89 (1), 77
5), 65 (2), 51 (2).
Rf = 0.3 (hexane–MTBE, 9:1).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 349.1046;
found: 349.1040.
tR (70_20): 9.98 (D1), 10.33 min (D2).
1
9
18
5
IR (film): 2963, 2876, 1808, 1497, 1451, 1300, 1277, 1245, 1169,
1
–
050, 1028, 947, 906, 765, 720, 701 cm .
1
Methyl 3-[4-(Dimethylamino)phenyl]-5-oxo-2-phenyltetrahy-
drofuran-2-carboxylate (7g)
Diastereomeric mixture (D1 = like, D2 = unlike), off-white solid
which decomposes upon standing; yield: 166 mg (98%).
1
H NMR (500 MHz, CDCl ): d = 7.6–7.4 (m, 5 H, D1, 5 H, D2),
3
3
D2), 2.59–2.51 (m, 1 H, D2), 2.39–2.31 (m, 1 H, D1), 2.18–2.09 (m,
1
.03–2.89 (m, 2 H, D1), 2.90–2.82 (m, 1 H, D2), 2.82–2.74 (m, 1 H,
H, D2), 1.81–1.70 (m, 1 H, D2), 1.55–1.44 (m, 1 H, D2), 1.38–
Rf = 0.25 (hexane–EtOAc, 4:1).
1.37 (m, 1 H, D2), 1.37–1.13 (m, 4 H, D1), 1.02 (t, J = 7.4 Hz, 3 H,
D2), 0.81 (t, J = 7.3 Hz, 3 H, D1).
tR (70_20): 15.56 (D1), 16.67 min (D2).
1
3
C NMR (125 MHz, CDCl ): d = 174.1, 173.4, 135.9, 131.7, 129.5,
3
IR (KBr): 2993, 2807, 1785, 1742, 1618, 1528, 1449, 1434, 1359,
1
29.2, 128.7, 128.5, 126.1 (d, J = 1.8 Hz), 125.6, 124.7 (q, J = 285
1
7
1
267, 1238, 1202, 1173, 1136, 1071, 1056, 1023, 950, 802, 755,
29, 697 cm .
–1
Hz), 124.3 (q, J = 276 Hz), 88.0, (q, J = 29 Hz), 86.4 (d, J = 28.4
Hz), 45.4 (D2), 39.2 (D1), 34.3, 33.5, 33.3, 32.5 (d, J = 1.8 Hz),
2
H NMR (300 MHz, CDCl ): d = 7.70–7.61 (m, 2 H), 7.45–7.34 (m,
3
2.0, 20.2, 13.8 (D2), 13.6 (D1).
3
H), 7.20–7.08 (m, 7 H), 6.80–6.65 (m, 4 H), 6.48–6.40 (m, 2 H),
.41 (dd, J = 8.3, 5.3 Hz, 1 H, D1), 3.98 (t, J = 7.3 Hz, D2, 1 H),
.79 (s, 3 H), 3.46 (s, 3 H), 3.08–2.97 (m, 1 H, D1), 2.96 (s, 6 H),
.88–2.67 (m, 3 H), 2.83 (s, 6 H).
1
9
F NMR (282 MHz, CDCl ): d = –73.3 (D2), –76.5 (D1).
3
4
3
2
+
MS (EI) D1: m/z (%) = 272 [M ] (2), 203 (100), 175 (7), 133 (2),
1
15 (5), 105 (44), 91 (4), 77 (11), 70 (10), 55 (7).
1
3
C NMR (75 MHz, CDCl ): d = 175.1, 175.0, 171.2, 168.8, 150.3,
3
+
MS (EI) D2: m/z (%) = 272 [M ] (9), 203 (100), 175 (20), 133 (2),
1
1
4
49.7, 138.0, 134.4, 129.1, 128.7, 128.6, 128.3, 128.0, 127.8, 125.9,
25.8, 124.4, 124.2, 112.3, 112.1, 90.8, 90.7, 53.4, 52.5, 51.6, 48.4,
0.3, 40.3, 36.2, 35.9.
1
15 (5), 105 (47), 91 (3), 77 (14), 70 (29), 55 (12).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaF O : 295.0916;
found: 295.0914.
1
4
15
3
2
+
MS (EI) D1: m/z (%) = 340 [M ] (7), 339 (35), 280 (2), 238 (5), 210
(
1
3), 194 (1), 174 (2), 165 (2), 148 (11), 147 (100), 146 (26), 131 (4),
17 (1); 105 (3), 77 (5).
4-Isopropyl-5-phenyl-5-(trifluoromethyl)tetrahydrofuran-2-
one (12c)
+
Diastereomeric mixture (D1 = unlike, D2 = like), colorless solid;
yield: 90 mg (66%).
MS (EI) D2: m/z (%) = 340 [M ] (7), 339 (32), 280 (2), 238 (4), 210
2), 174 (2), 148 (11), 147 (100), 146 (29), 131 (5), 117 (1), 105 (3),
03 (2), 77 (5).
(
1
Rf = 0.32 (hexane–MTBE, 9:1).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NNaO : 362.1363;
found: 362.1356.
2
0
21
4
tR (70_20): 9.84 (D1), 10.18 min (D2).
IR (KBr): 2962, 1805, 1495, 1472, 1451, 1426, 1395, 1376, 1269,
1
–
168, 1124, 1092, 1015, 943, 917, 888, 767, 730, 709 cm .
1
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
434
C. Burstein et al.
FEATURE ARTICLE
1
H NMR (500 MHz, CDCl ): d = 7.59–7.39 (m, 5 H, D1, 5 H, D2),
3
.01–2.89 (m, 2 H, D1), 2.80–2.73 (m, 1 H, D2), 2.66–2.52 (m, 2 H,
Methyl 5-Oxo-2-phenyl-3-propyltetrahydrofuran-2-carboxy-
late (12e)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless oil;
yield: 93 mg (71%).
3
D2), 2.56–2.49 (m, 1 H, D1), 2.40–2.33 (m, 1 H, D2), 2.00–1.90 (m,
1 H, D1), 1.01 (d, J = 6.6 Hz, 3 H, D2), 0.93 (d, J = 6.6 Hz, 3 H,
D2), 0.89 (d, J = 6.9 Hz, 3 H, D1), 0.39 (d, J = 6.7 Hz, 3 H, D1).
Rf = 0.25 (hexane–MTBE, 4:1).
1
3
C NMR (125 MHz, CDCl ): d = 174.6, 173.9, 136.4, 131.3, 129.4,
3
tR (70_20): 11.84 (D1), 12.18 min (D2).
1
Hz), 88.2 (d, J = 29.3 Hz), 53.2, 43.4, 31.3, 29.3 (D1), 27.5, 27.2
(
29.2, 128.7, 128.3, 126.6, 126.0, 125.9, 123.6, 93.4 (d, J = 27.5
IR (film): 3566, 2959, 2873, 2065, 1794, 1740, 1493, 1450, 1436,
1
–
1
227, 1164, 1116, 1052, 1029, 906, 738, 701 cm .
D1), 23.1 (D2), 21.4 (D1), 19.6 (D2), 14.6 (D1).
1
1
9
H NMR (500 MHz, CDCl ): d = 7.60–7.23 (m, 5 H, D1 and 5 H,
3
F NMR (282 MHz, CDCl ): d = –70.8 (D2), –77.7 (D1).
3
D2), 3.77 (s, 3 H, D1 and 3 H, D2), 3.20–3.13 (m, 1 H, D1), 2.94–
+
MS (EI) D1: m/z (%) = 272 [M ] (1), 203 (100), 175 (2.6), 161 (2),
2
.85 (m, 1 H, D2), 2.72 (dd, J = 17.5, 7.7 Hz, 1 H, D1), 2.67 (dd,
J = 17.1, 8.1 Hz, 1 H, D2), 2.46 (dd, J = 17.4, 8.5 Hz, 1 H, D2), 2.40
dd, J = 17.4, 4.4 Hz, 1 H, D1), 1.92–1.82 (m, 1 H, D2), 1.52–1.10
1
5
60 (2), 133 (12), 115 (5), 105 (30), 91 (2), 77 (10), 70 (12), 69 (9),
5 (12).
(
+
MS (EI) D2: m/z (%) = 272 [M ] (19), 203 (61), 175 (8), 160 (3),
(m, 4 H, D1 and 3 H, D2), 0.98 (t, J = 7.1 Hz, 3 H, D2), 0.79 (t,
J = 7.0 Hz, 3 H, D1).
1
33 (10), 115 (9), 105 (33), 77 (21), 70 (100), 69 (14), 55 (40).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaF O : 295.0916;
found: 295.0917.
13
C NMR (125 MHz, CDCl ): d = 174.8, 174.6, 171.3, 169.7, 137.9,
3
1
4
15
3
2
134.4, 128.8, 128.6, 128.5, 128.5, 125.7, 125.3, 90.1, 89.2, 53.3
(
D1), 52.8 (D2), 45.5 (D2), 42.9 (D1), 34.0, 33.9, 32.9, 31.8, 21.2,
0.1, 13.9 (D2), 13.7 (D1).
u-12c (single diastereomer obtained from crystallization (CH Cl –
2
2
2
hexane).
+
MS (EI) D1: m/z (%) = 262 [M ] (1), 205 (1), 204 (14), 203 (100),
75 (1), 160 (1), 157 (1), 133 (2), 131 (2), 129 (3), 128 (2), 117 (3),
115 (5), 106 (5), 105 (66), 103 (1), 91 (3), 77 (14), 51 (2).
Rf = 0.32 (hexane–MTBE, 9:1).
1
tR (70_20): = 9.84 min.
IR (KBr): 2962, 2880, 1798, 1495, 1471, 1451, 1294, 1270, 1244,
1
MS (EI) D2: m/z (%) = 207 (2), 204 (16), 203 (100), 143 (2), 133
(3), 131 (3), 129 (3), 117 (5), 115 (6), 106 (5), 105 (70), 103 (3), 91
(3), 77 (16), 55 (3), 51 (3).
–
196, 1168, 1124, 1092, 1063, 1016, 943, 768, 730, 709 cm .
1
1
H NMR (300 MHz, CDCl ): d = 7.58–7.38 (m, 5 H), 3.03–2.86 (m,
3
2
3
H), 2.60–2.46 (m, 1 H), 2.05–1.87 (m, 1 H), 0.89 (d, J = 6.80 Hz,
H), 0.39 (d, J = 6.61 Hz, 3 H).
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 285.1097;
found: 285.1093.
1
5
18
4
1
3
C NMR (125 MHz, CDCl ): d = 174.6, 131.3, 129.2, 128.3,
3
Methyl 3-Isopropyl-5-oxo-2-phenyltetrahydrofuran-2-carbox-
ylate (12f)
126.7–126.6 (m), 122.9, 88.2 (q, J = 28.7 Hz), 43.4, 29.3 (q, J = 2.5
Hz), 27.2, 21.4, 14.6.
Diastereomeric mixture (D1 = unlike, D2 = like), colorless oil;
yield: 94 mg (72%).
1
9
F NMR (282 MHz, CDCl ): d = –77.7.
3
+
MS (EI): m/z (%) = 272 [M ] (1), 203 (100), 175 (2), 165 (1), 164
Rf = 0.24 (hexane–MTBE, 4:1).
(
(
1), 160 (2), 157 (2), 145 (1), 133 (11), 115 (4), 105 (29), 91 (2), 70
12), 55 (11).
tR (70_20): 11.75 (D1), 12.07 min (D2).
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NaO : 295.0916;
found: 295.0915.
IR (film): 2970, 2881, 1788, 1737, 1491, 1470, 1449, 1433, 1273,
1
1
4
15
3
2
–
1
242, 1188, 1156, 1128, 1090, 1060, 1024, 980, 940, 743, 708 cm .
1
H NMR (500 MHz, CDCl ): d = 7.62–7.33 (m, 5 H, D1 and 5 H,
3
Methyl 3-Methyl-5-oxo-2-phenyltetrahydrofuran-2-carboxy-
late (12d)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless solid
and oil; yield: 101 mg (87%).
D2), 3.79 (s, 3 H, D2), 3.74 (s, 3 H, D1), 3.23–3.19 (m, 1 H, D1),
2
(
(
.96–2.91 (m, 1 H, D2), 2.65 (dd, J = 17.9, 8.4 Hz, 1 H, D1), 2.51
dd, J = 17.8, 1.9 Hz, 1 H, D1), 2.47–2.40 (m, 2 H, D2), 2.29–2.21
m, 1 H, D2), 1.85–1.75 (m, 1 H, D1), 0.97 (d, J = 6.7 Hz, 3 H, D2),
0.91 (d, J = 6.7 Hz, 3 H, D2), 0.87 (d, J = 6.9 Hz, 3 H, D1), 0.49 (d,
J = 6.9 Hz, 3 H, D1).
tR (70_20): 10.99 (D1), 11.34 min (D2).
Rf = 0.1 (hexane–MTBE, 9:1).
1
3
C NMR (125 MHz, CDCl ): d = 175.2, 174.9, 171.8, 169.5, 138.4,
3
IR (KBr): 2959, 1794, 1737, 1489, 1448, 1383, 1266, 1212, 1162,
1
1
5
34.0, 128.9, 128.5, 128.5, 128.3, 126.0, 125.7, 90.5, 89.6, 53.5,
2.8, 51.2, 47.5, 28.1, 26.5, 22.0, 21.5, 17.4, 15.4.
–
1
109, 1027, 996, 932, 804, 733, 700, 632 cm .
1
H NMR (300 MHz, CDCl ): d = 7.61–7.30 (m, 5 H, D1, 5 H, D2),
3
+
MS (EI) D1: m/z (%) = 262 [M ] (1), 205 (2), 204 (14), 203 (100),
3
.764 (s, 3 H, D2), 3.757 (s, 3 H, D1), 3.34 (dq, J = 7.3, 3.1 Hz, 1
H, D1), 3.12–2.99 (m, 1 H, D2), 2.82 (dd, J = 17.4, 7.6 Hz, 1 H,
D1), 2.64 (dd, J = 17.2, 7.9 Hz, 1 H, D2), 2.36 (dd, J = 17.3, 6.9 Hz,
1
1
75 (2), 161 (3), 160 (2), 157 (3), 134 (2), 133 (19), 131 (3), 129 (1),
17 (1), 115 (5), 106 (4), 105 (46), 103 (1), 91 (2), 77 (13), 55 (4).
MS (EI) D2: m/z (%) = 205 (1), 204 (14), 203 (100), 175 (2), 161
1
3
H, D2), 2.29 (dd, J = 17.4, 3.0 Hz, 1 H, D1), 1.30 (d, J = 7.0 Hz,
H, D2), 0.76 (d, J = 7.2 Hz, 3 H, D1).
(
(
2), 160 (2), 157 (3), 134 (2), 133 (17), 131 (3), 129 (2), 115 (7), 106
4), 105 (49), 91 (2), 77 (13), 69 (4), 55 (5), 51 (2).
1
3
C NMR (75 MHz, CDCl ): d = 174.6, 174.4, 171.3, 169.4, 137.7,
3
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 285.1097;
found: 285.1092.
1
(
34.4, 128.8, 128.6, 128.5, 125.6, 125.3, 90.0, 89.6, 53.3 (D1), 52.8
D2), 40.3, 37.9, 36.7, 36.1, 16.3 (D1), 16.3 (D2).
15 18
4
+
MS (EI) D1: m/z (%) = 234 [M ] (1), 175 (100), 147 (1), 131 (1),
3-Ethyl-4-phenyl-4-(trifluoromethyl)oxetan-2-one (13a)
Diastereomeric mixture, colorless oil; yield: 84 mg (34%).
1
29 (5), 115 (4), 105 (74), 91 (4), 89 (1), 77 (18), 63 (1), 51 (4).
+
MS (EI) D2: m/z (%) = 234 [M ] (1), 175 (100), 147 (1), 131 (2),
1
29 (6), 115 (4), 106 (6), 91 (5), 89 (1), 77 (18), 63 (1), 51 (4).
l-13a
R = 0.08 (pentane–CH Cl , 15:1).
f 2 2
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 257.0784;
found: 257.0780.
1
3
14
4
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2435
+
MS (EI): m/z (%) = 272 [M ] (1), 173 (10), 172 (100), 165 (15), 164
IR (film, mixture of diastereomers): 3069, 2978, 2942, 2884, 1851,
1
9
1
502, 1452, 1327, 1306, 1268, 1176, 1129, 1079, 1041, 1027, 969,
(11), 115 (15), 105 (20), 103 (17), 98 (32), 80 (10), 77 (17), 69 (14),
55 (20).
–
41, 761, 726, 702 cm .
1
+
HRMS (EI): m/z [M ] calcd for C H F O : 272.1024; found:
272.1020.
H NMR (300 MHz, CDCl ): d = 7.45–7.49 (m, 5 H), 4.00 (dd,
3
14 15
3
2
J = 6.4, 10.2 Hz, 1 H), 1.49–1.63 (m, 1 H), 1.26–1.41 (m, 1 H), 0.99
(
t, J = 7.4 Hz, 3 H).
1
3
3-Isobutyl-4-phenyl-4-(trifluoromethyl)oxetan-2-one (13c)
Diastereomeric mixture, colorless oil; yield: 130 mg (48%).
C NMR (75 MHz, CDCl ): d = 167.5, 129.8, 129.3, 128.8, 126.4,
3
1
23.8 (q, J = 282.1 Hz), 78.9 (q, J = 32.81 Hz), 58.2, 19.8, 11.0.
1
9
F NMR (282 MHz, CDCl ): d = –78.1.
3
l-13c
R = 0.22 (pentane–CH Cl , 10:1).
+
MS (EI): m/z (%) = 244 [M ] (12), 185 (30), 165 (14), 131 (24), 115
f
2
2
(
14), 105 (42), 91 (14), 77 (30), 70 (100), 55 (53), 51 (11).
IR (film, mixture of diastereomers): 2963, 2936, 2875, 1853, 1470,
1452, 1310, 1267, 1227, 1177, 1130, 1077, 1045, 1025, 980, 948,
7
+
HRMS (EI): m/z [M ] calcd for C H F O : 244.0711; found:
2
1
2
11
3
2
–
62, 728, 715, 700 cm .
1
44.0706.
1
H NMR (300 MHz, CDCl ): d = 7.44–7.50 (m, 5 H), 4.13 (dd,
3
u-13a
R = 0.08 (pentane–CH Cl , 15:1).
J = 7.2, 9.6 Hz, 1 H), 1.72–1.86 (m, 1 H), 1.15–1.31 (m, 2 H), 0.89
(d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H).
f
2
2
1
H NMR (300 MHz, CDCl ): d = 7.42–7.49 (m, 5 H), 3.85 (dd,
3
13
C NMR (75 MHz, CDCl ): d = 167.7, 129.8, 129.3, 128.8, 126.4,
3
123.9 (q, J = 282.1 Hz), 79.0 (q, J = 32.6 Hz), 55.2, 34.7, 25.4, 22.6,
21.7.
J = 7.3, 9.3 Hz, 1 H), 2.04–2.26 (m, 2 H), 1.24 (t, J = 7.5 Hz, 3 H).
1
3
C NMR (75 MHz, CDCl ): d = 167.5, 133.3, 129.8, 128.7, 126.2,
3
1
23.5 (q, J = 282.7 Hz), 79.2 (q, J = 32.2 Hz), 63.4, 18.6, 12.3.
19
F NMR (282 MHz, CDCl ): d = –77.9.
3
1
9
F NMR (282 MHz, CDCl ): d = –73.9.
3
+
MS (EI): m/z (%) = 272 [M ] (9), 197 (12), 185 (11), 173 (12), 172
+
MS (EI): m/z (%) = 244 [M ] (5), 200 (11), 185 (45), 165 (19), 164
(84), 165 (31), 164 (16), 145 (11), 117 (12), 115 (34), 105 (67), 98
(100), 77 (41), 70 (25), 69 (59), 56 (14), 55 (92), 51 (14).
(
(
11), 131 (37), 116 (10), 115 (18), 105 (31), 103 (11), 91 (16), 77
29), 70 (100), 55 (47), 51 (14).
+
HRMS (EI): m/z [M ] calcd for C H F O : 272.1024; found:
272.1026.
1
4
15
3
2
+
HRMS (EI): m/z [M ] calcd for C H F O : 244.0711; found:
1
2
11
3
2
2
44.0709.
u-13c
R = 0.22 (pentane–CH Cl , 10:1).
3-Butyl-4-phenyl-4-(trifluoromethyl)oxetan-2-one (13b)
Diastereomeric mixture, colorless oil; yield: 122 mg (45%).
f
2
2
1
H NMR (300 MHz, CDCl ): d = 7.4–7.5 (m, 5 H), 3.99 (dd,
3
J = 5.4, 9.7 Hz, 1 H), 1.99–2.11 (m, 1 H), 1.83–1.97 (m, 2 H), 1.04
d, J = 6.4 Hz, 3 H), 1.01 (d, J = 6.28 Hz, 3 H).
l-13b
R = 0.15 (pentane–CH Cl , 10:1).
(
f
2
2
13
C NMR (75 MHz, CDCl ): d = 167.4, 133.4, 129.8, 128.7, 126.1,
3
IR (film, mixture of diastereomers): 2962, 2935, 2875, 1854, 1451,
1
2
23.5 (q, J = 282.9 Hz), 78.9 (q, J = 32.1 Hz), 60.0, 33.6, 26.4, 22.5,
2.1.
1
7
1
384, 1333, 1271, 1178, 1153, 1125, 1077, 1049, 970, 948, 806,
–
63, 719, 700 cm .
1
1
9
F NMR (282 MHz, CDCl ): d = –73.9.
3
H NMR (300 MHz, CDCl ): d = 7.45–7.49 (m, 5 H), 4.08–4.03 (m,
H), 1.18–1.50 (m, 6 H), 0.81 (t, J = 7.2 Hz, 3 H).
3
+
MS (EI): m/z (%) = 272 [M ] (3), 173 (13), 172 (100), 165 (28), 164
1
(12), 117 (14), 115 (28), 105 (37), 103 (11), 98 (67), 77 (30), 70
(16), 69 (37), 56 (12), 55 (55).
1
3
C NMR (75 MHz, CDCl ): d = 167.6, 129.8, 129.3, 128.8, 126.4,
3
1
1
23.8 (q, J = 282.1 Hz), 79.0 (q, J = 32.6 Hz), 56.8, 28.5, 25.8, 22.2,
3.5.
+
HRMS (EI): m/z [M ] calcd for C H F O : 272.1024; found:
1
4
15
3
2
2
72.1027.
1
9
F NMR (282 MHz, CDCl ): d = –78.0.
3
+
MS (EI): m/z (%) = 272 [M ] (6), 185 (10), 173 (10), 172 (100), 165
3-Benzyl-4-phenyl-4-(trifluoromethyl)oxetan-2-one (13d)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless oil;
yield: 93 mg (30%).
(
(
19), 164 (14), 145 (11), 115 (20), 105 (47), 103 (19) 98 (62), 83
11), 80 (22), 77 (30), 70 (21), 69 (29), 55 (42).
+
HRMS (EI): m/z [M ] calcd for C H F O : 272.1024; found:
R = 0.08 (pentane–CH Cl , 10:1).
f
2
2
1
4
15
3
2
2
72.1019.
IR (film): 3066, 3034, 2930, 1854, 1499, 1452, 1329, 1268, 1177,
1
–
146, 1109, 1080, 1047, 1024, 991, 954, 938, 750, 726, 699 cm .
1
u-13b
Characterized from a mixture with the like isomer.
R = 0.15 (pentane–CH Cl , 10:1).
1
H NMR (300 MHz, CDCl ): d = 7.51–7.21 (m, 10 H, D2 and 8 H,
3
D1), 7.07–7.03 (m, 2 H, D1), 4.45 (t, J = 8.2 Hz, 1 H, D1), 4.23 (t,
J = 7.7 Hz, 1 H, D2), 3.5 (dd, J = 8.2, 14.8 Hz, 1 H, D2), 3.31 (dd,
J = 7.4, 14.7 Hz, 1 H, D2), 2.72 (d, J = 8.2 Hz, 2 H, D1).
13
f
2
2
1
H NMR (300 MHz, CDCl ): d = 7.43–7.47 (m, 5 H), 3.91 (dd,
3
J = 6.9, 9.4 Hz, 1 H), 1.97–2.21 (m, 2 H), 1.17–1.73 (m, 4 H), 0.97
(
C NMR (75 MHz, CDCl ): d = 166.9, 136.5, 135.4, 132.8, 130.0,
3
t, J = 7.2 Hz, 3 H).
1
29.8, 129.0, 129.0, 128.8, 128.8, 128.7, 128.6, 128.5, 127.4, 127.2,
1
3
126.6, 126.2, 123.8 (q, J = 282.36 Hz, D1), 123.5 (q, J = 282.8 Hz,
D2), 79.5 (q, J = 32.3 Hz, D2), 79.3 (q, J = 32. 7 Hz, D1), 63.0 (D2),
C NMR (75 MHz, CDCl ): d = 167.6, 133.3, 129.8, 128.7, 126.2,
3
1
1
19.0 (q, J = 282.6 Hz), 79.1 (q, J = 32.1 Hz), 61.9, 29.8, 24.7, 22.3,
3.6.
5
7.4 (D1), 31.7 (D1), 31.0 (D2).
1
9
1
9
F NMR (282 MHz, CDCl ): d = –77.7 (D1), –73.7 (D2).
3
F NMR (282 MHz, CDCl ): d = –74.0.
3
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
436
C. Burstein et al.
FEATURE ARTICLE
+
MS (EI) D1: m/z (%) = 306 [M ] (52), 307 (10), 193 (14), 178 (10),
tR (70_20): 12.46 (D1), 12.93 min (D2).
IR (film): 3033, 2981, 2937, 1804, 1496, 1451, 1271, 1173, 1138,
1
7
32 (34), 131 (100), 115 (25), 105 (27), 104 (33), 103 (14), 91 (15),
8 (10), 77 (24).
–1
094, 1031, 958, 832, 761, 711, 700 cm .
1
+
MS (EI) D2: m/z (%) = 306 [M ] (79), 307 (14), 262 (32), 261 (14),
1
H NMR (300 MHz, CDCl ): d = 7.47–7.38 (m, 4 H, D1), 7.37–
3
1
1
7
93 (49), 191 (11), 184 (34), 178 (30), 165 (15), 133 (13), 132 (83),
31 (100), 115 (74), 105 (41), 104 (57), 103 (21), 91 (33), 78 (19),
7 (37), 51 (15).
7
.32 (m, 1 H, D1), 7.29–7.21 (m, 6 H, D2), 7.21–7.16 (m, 3 H, D2),
.95 (d, J = 7.8 Hz, 2 H, D1), 6.69 (d, 7.8 Hz, 2 H, D1), 3.81 (d,
6
J = 12.5 Hz, 1 H, D1), 3.45–3.32 (m, 2 H, D2), 2.86–2.77 (m, 1 H,
D1), 1.23 (d, J = 7.0 Hz, 3 H, D1), 1.18 (d, J = 6.6 Hz, 3 H, D2).
+
HRMS (EI): m/z [M ] calcd for C H F O : 306.0868; found:
1
7
13
3
2
3
06.0869.
13
C NMR (75 MHz, CDCl ): d = 175.2, 175.1, 135.5, 135.0, 134.6,
3
1
1
31.8, 130.0, 130.9, 130.3, 129.5, 129.4, 129.2, 128.7, 128.6, 128.2,
26.7, 125.3, 123.0, 123.0, 85.6 (q, J = 30.2 Hz), 84.9 (q, J = 28
Methyl 3-Isobutyl-4-oxo-2-phenyloxetane-2-carboxylate (13e)
Diastereomeric mixture (D1 = like, D2 = unlike), colorless oil;
yield: 57 mg (22%).
Hz), 59.6, 53.7, 40.4, 39.4, 14.1, 12.9.
1
9
F NMR (282 MHz, CDCl ): d = –71.0, –75.6.
3
R = 0.26 (pentane–CH Cl , 2:1).
2
f
2
+
MS (EI) D1: m/z (%) = 354 [M ] (3), 165 (2), 154 (32), 152 (100),
1
8
IR (film): 2958, 1872, 2043, 1840, 1743, 1450, 1389, 1370, 1255,
1
27 (2), 125 (3), 118 (3), 117 (32), 115 (15), 105 (6), 101 (2), 91 (3),
9 (2), 77 (6), 75 (2).
–
192, 1158, 1131, 1058, 934, 815, 757, 736, 699, 506, 420 cm .
1
1
H NMR (300 MHz, CDCl ): d = 7.50–7.39 (m, 5 H, D1 and 5 H,
3
+
MS (EI) D2: m/z (%) = 354 [M ] (3), 282 (1), 179 (2), 154 (33), 152
D2), 4.26 (t, J = 8.2 Hz, 1 H, D2), 3.94 (t, J = 8.2 Hz, 1 H, D1), 3.84
(
7
100), 127 (2), 125 (2), 117 (31), 115 (15), 105 (6), 91 (4), 77 (6),
5 (2).
(
(
(
1
s, 3 H, D2), 3.82 (s, 3 H, D1), 2.04–1.90 (m, 1 H, D1), 1.77–1.65
m, 2 H, D1 and 1 H, D2), 1.17 (t, J = 8.2 Hz, 2 H, D2), 1.02–0.97
m, 6 H, D1), 0.87–0.81 (m, 6 H, D2).
+
HRMS (ESI): m/z [M + Na ] calcd for C H ClF NaO : 377.0527;
found: 377.0528.
18 14
3
2
3
C NMR (75 MHz, CDCl ): d = 169.9, 169.5, 168.8, 168.4, 136.5,
3
1
(
2
32.6, 129.2, 129.0, 128.7, 128.6, 125.7, 125.6, 81.1, 80.9, 60.9
D1), 57.8 (D2), 53.4, 53.1, 35.3, 34.5 (D2), 25.7 (D1), 25.5, 22.5,
2.5, 22.2, 22.0.
3-Methyl-5-phenyl-4-styryl-5-(trifluoromethyl)tetrahydrofu-
ran-2-one (20c)
Diastereomeric mixture [D1 = diastereomer I, D2 = diastereomer II
(see Figure 6)], colorless solid and oil; yield: 142 mg (82%).
+
MS (ESI, MeOH): m/z = 285 [M + Na ].
+
HRMS (ESI): m/z [M + Na ] calcd for C H NaO : 285.1097;
found: 285.1099.
Rf = 0.3 (hexane–MTBE, 9:1).
1
5
18
4
tR (70_20): 13.02 (D1), 13.32 min (D2).
IR (KBr): 3063, 3030, 2980, 2938, 1803, 1496, 1450, 1315, 1284,
1
3-Methyl-4,5-diphenyl-5-(trifluoromethyl)tetrahydrofuran-2-
one (20a)
–
1
258, 1227, 1171, 1134, 1069, 1024, 969, 948, 754, 732, 701 cm .
Diastereomeric mixture [D1 = diastereomer I, D2 = diastereomer II
(
1
H NMR (500 MHz, CDCl ): d = 7.71–7.65 (m, 4 H), 7.55–7.27 (m,
3
6 H), 6.70 (d, J = 15.6 Hz, 1 H, D2), 6.66 (d, J = 15.9 Hz, 1 H, D1),
.47–6.38 (m, 1 H, D2), 5.54 (dd, J = 15.7, 9.5 Hz, D1), 3.34 (dd,
see Figure 6)], colorless solid and oil; yield: 132 mg (83%).
1
6
Rf = 0.38–0.34 (hexane–MTBE, 9:1).
J = 11.9, 9.6 Hz, D1), 3.17 (t, J = 11.0 Hz, 1 H, D2), 2.99–2.89 (m,
H, D2), 2.51–2.42 (m, 1 H, D1), 1.30 (m, 3 H, D1), 1.28 (d, J = 7.2
Hz, 3 H, D2).
tR (70_20): 11.62 (D1), 12.05 min (D2).
1
IR (KBr): 3036, 2937, 1803, 1707, 1501, 1455, 1272, 1172, 1137,
1
–
070, 1031, 948, 784, 764, 725, 704 cm .
1
13
C NMR (125 MHz, CDCl ): d = 175.6 (D2), 175.4 (D1), 136.2
3
1
H NMR (300 MHz, CDCl ): d = 7.45–7.06 (m, 10 H, D2 and 6 H,
3
(D2), 136.0 (D2), 135.9 (D1), 135.8 (D2), 135.4 (D1), 130.8 (D1),
129.6 (D1), 129.4 (D2), 128.8 (D2), 128.8 (D1), 128.6 (D2), 128.4
(D1), 126.7 (D2), 126.5 (D1), 125.8 (D2), 124.1 (q, J = 286 Hz,
D2), 124.1 (D1), 123.0 (D1), 87.7, 83.9 (q, J = 28 Hz, D2), 57.9
(D2), 52.2 (D1), 40.3 (D2), 39.1 (D1), 13.7 (D2), 12.6 (D1).
D1), 6.85 (d, J = 7.7 Hz, 2 H, D1), 6.70 (d, J = 7.4 Hz, 2 H, D1),
3
.78 (d, J = 12.7 Hz, 1 H, D1), 3.44–3.28 (m, 2 H, D2), 2.89–2.74
m, 1 H, D1), 1.16 (d, J = 7.0 Hz, 3 H, D1), 1.13–1.08 (m, 3 H, D2).
(
1
3
C NMR (75 MHz, CDCl ): d = 175.7, 175.5, 135.7, 133.2, 132.3,
3
1
9
1
1
8
30.6, 129.7, 129.7, 129.3, 129.3, 128.9, 128.9, 128.6, 128.5, 128.3,
27.9, 126.7 (q, J = 2 Hz), 125.4 (q, J = 2 Hz), 124.2 (q, 280 Hz),
5.8 (q, J = 30 Hz), 85.1 (q J = 30 Hz), 60.2 (D2), 54.3 (D1), 40.4
F NMR (282 MHz, CDCl ): d = –73.8 (D2), –76.5 (D1).
3
+
MS (EI) D1: m/z (%) = 346 [M ] (9), 202 (2), 144 (100), 129 (77),
1
15 (10), 105 (6), 103 (2), 91 (6), 89 (2), 77 (8), 65 (2).
(
D2), 39.3 (D1), 14.1 (D2), 13.0 (D1).
+
MS (EI) D2: m/z (%) = 346 [M ] (11), 202 (2), 144 (100), 129 (75),
1
9
F NMR (282 MHz, CDCl ): d = –71.1, –75.6.
3
1
15 (9), 105 (7), 102 (2), 89 (2), 77 (8), 65 (2).
+
MS (EI) D1: m/z (%) = 320 [M ] (2), 189 (1), 178 (2), 165 (2), 118
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NaO : 369.1073;
found: 369.1075.
2
0
17
3
2
(
100), 115 (8), 105 (6), 91 (7), 77 (7), 65 (1), 51 (2).
+
MS (EI) D2: m/z (%) = 320 [M ] (1), 189 (1), 178 (2), 118 (100),
1
15 (7), 105 (5), 91 (7), 89 (2), 77 (7), 65 (1), 51 (2).
20c-II
Single diastereomer isolated by crystallization (CH
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NaO : 343.0915;
found: 343.0950.
Cl –hexane).
2 2
1
8
15
3
2
Rf = 0.3 (hexane–MTBE, 9:1).
tR (70_20): 13.32 min.
4-(4-Chlorophenyl)-3-methyl-5-phenyl-5-(trifluoromethyl)tet-
rahydrofuran-2-one (20b)
IR (KBr): 3063, 3042, 2979, 2938, 1803, 1495, 1450, 1315, 1259,
1
–
1
228, 1171, 1133, 1069, 1021, 967, 754, 732, 701 cm .
Diastereomeric mixture [D1 = diastereomer I, D2 = diastereomer II
(
see Figure 6)]; yellowish oil; yield: 126 mg (71%).
1
H NMR (300 MHz, CDCl ): d = 7.72–7.62 (m, 2 H), 7.55–7.31 (m,
3
8
1
H), 6.69 (d, J = 15.7 Hz, 1 H), 6.48–6.34 (m, 1 H), 3.22–3.10 (m,
H), 3.00–2.85 (m, 1 H), 1.27 (d, J = 6.99 Hz, 3 H).
Rf = 0.24 (hexane–EtOAc, 9:1).
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2437
1
3
C NMR (75 MHz, CDCl ): d = 175.6, 136.2, 136.0, 135.8, 129.4,
3
mL) was stirred for 30 min at r.t. (E)-4-(2-Oxocyclohexyloxy)but-
2-enal (23, 100 mg, 0.55 mmol, 1 equiv) was added and the mixture
was stirred at 60 °C for 5 h. Silica gel was added and the solvent re-
moved on the rotary evaporator. The residue was purified by col-
umn chromatography (hexane–EtOAc, 1:3.5) to afford 28 as a light
yellow oil; yield: 41 mg (41%).
128.8, 128.6, 126.7, 125.8, 124.1 (q, J = 288 Hz), 123.2, 83.9 (q,
J = 28 Hz), 57.9, 40.3, 13.7.
1
9
F NMR (282 MHz, CDCl ): d = –73.8.
3
+
MS (EI), m/z (%) = 346 [M ] (6), 215 (1), 202 (2), 144 (100), 129
(
75), 115 (9), 105 (7), 102 (2), 89 (2), 77 (8), 65 (2).
Rf = 0.34 (hexane–EtOAc, 1:3.5).
+
HRMS (ESI): m/z [M + Na ] calcd for C H F NaO : 369.1073;
found: 369.1070.
2
0
17
3
2
IR (film): 3509, 2939, 2864, 1774, 1452, 1423, 1320, 1290, 1261,
1
–
227, 1209, 1154, 1080, 1051, 1023, 983, 960, 949, 933, 885 cm .
1
1
3-(2-Chlorobenzyl)-5-phenyl-5-(trifluoromethyl)tetrahydrofu-
ran-2-one (21)
Diastereomeric mixture, yellowish oil; yield: 81 mg (46%).
H NMR (300 MHz, CDCl ): d = 4.25 (t, J = 9.4 Hz, 1 H), 3.98 (dd,
3
J = 6.3, 9.0 Hz, 1 H), 3.65 (dd, J = 4.5, 9.7 Hz, 1 H), 2.88–2.73 (m,
2 H), 2.47 (d, J = 16.1 Hz, 1 H), 1.98–1.62 (m, 5 H), 1.52–1.23 (m,
3
H).
Rf = 0.13 (hexane–MTBE, 40:1).
1
3
C NMR (75 MHz, CDCl ): d = 175.4, 93.7, 80.7, 72.6, 41.2, 35.2,
3
tR (70_20): 13.07 (D1), 13.17 min (D2).
3
1.4, 26.8, 21.9, 21.1.
IR (film): 3065, 2931, 1799, 1573, 1475, 1449, 1304, 1268, 1095,
1
+
MS (EI): m/z (%) = 182 [M ] (37), 141 (88), 125 (11), 124 (35), 123
–
032, 976, 910, 679, 651, 599, 548 cm .
1
(100), 114 (12), 113 (59), 111 (69), 110 (41), 109 (18), 105 (13),
104 (10), 98 (31), 97 (52), 96 (24), 95 (40), 94 (20), 85 (33), 84 (15),
1
H NMR (300 MHz, CDCl ): d = 7.49–7.21 (m, 12 H), 7.22–7.02
3
(m, 6 H), 3.48–3.24 (m, 3 H), 3.05–2.79 (m, 3 H), 2.73–2.45 (m, 3
H), 2.36–2.22 (m, 1 H).
8
6
3 (27), 82 (19), 81 (22), 80 (16), 79 (28), 77 (11), 70 (20), 69 (78),
8 (69), 67 (74), 57 (25), 55 (92), 54 (12), 53 (14).
1
3
C NMR (75 MHz, CDCl ): d = 175.6, 175.0, 135.4, 135.4, 135.3,
3
+
HRMS (EI): m/z [M ] calcd for C H O : 182.0943; found:
1
0
14
3
1
1
34.0, 134.0, 131.1, 130.9, 129.9, 129.8, 129.7, 129.5, 128.7, 128.6,
27.2, 127.2, 126.3, 126.1, 125.5, 122.3, 121.7, 83.1 (q, J = 30.6
1
82.0941.
Hz), 83.1 (q, J = 32.0 Hz), 39.4, 38.8, 35.7, 34.8, 34.7, 33.5.
(3aR*,9aR*)-3a-Methyl-3a,4,5,9b-tetrahydronaphtho[2,1-b]fu-
ran-2(1H)-one (29)
1
9
F NMR (282 MHz, CDCl ): d = – 79.5 (D1), –79.6 (D2).
3
A soln of IMes·HCl (10.2 mg, 0.030 mmol, 0.15 equiv) and KOt-Bu
(
MS (EI) D1: m/z (%) = 321 (2), 319 (100), 299 (15), 285 (8), 202
3.14 mg, 0.028 mmol, 0.14 equiv) in freshly distilled THF (4 mL)
(
(
2), 182 (5), 172 (18), 159 (3), 147 (69), 127 (17), 125 (43), 115
16), 105 (65), 91 (8), 89 (10), 77 (23), 63 (3), 51 (5).
was stirred for 30 min at r.t. (E)-3-[2-(3-Oxobutyl)phenyl]prop-2-
enal (24, 40.5 mg, 0.20 mmol, 1 equiv) was added and the mixture
was stirred at 60 °C for 16 h. Silica gel was added and the solvent
removed on the rotary evaporator. The residue was purified by col-
umn chromatography (hexane–EtOAc, 4.5:1) to afford 29 as a white
solid; yield: 22 mg (55%).
MS (EI) D2: m/z (%) = 319 (100), 299 (15), 285 (4), 202 (2), 182
6), 172 (21), 159 (3), 147 (79), 125 (47), 105 (50), 77 (21), 63 (4),
1 (5).
(
5
+
HRMS (ESI): m/z [M + Na ] calcd for C H ClF NaO : 377.0527;
found: 377.0533.
1
8
14
3
2
Rf = 0.52 (hexane–EtOAc, 2:1).
IR (film): 3013, 2949, 1767, 1489, 1452, 1425, 1384, 1348, 1319,
1
(
(
3aR*,6aS*)-6a-Phenyltetrahydrofuro[3,4-b]furan-2(3H)-one
27)
–1
287, 1222, 1189, 1115, 1074, 1045, 972, 931, 889, 770, 741 cm .
1
H NMR (300 MHz, CDCl ): d = 7.24–7.13 (m, 3 H), 6.98–6.95
3
A soln of IMes·HCl (23.3 mg, 0.0684 mmol, 0.2 equiv) and KOt-Bu
6.73 mg, 0.060 mmol, 0.175 equiv) in freshly distilled THF (14
(
2
m, 1 H), 3.49 (dd, J = 7.7, 13.3 Hz, 1 H), 3.25–3.15 (m, 1 H), 3.04–
.92 (m, 1 H), 2.88–2.70 (m, 2 H), 2.28–2.15 (m, 2 H), 1.01 (s, 3 H).
(
mL) was stirred at r.t. for 30 min. (E)-4-(2-Oxo-2-phenyl-
ethoxy)but-2-enal (22, 69.8 mg, 0.342 mmol, 1 equiv) was added
and the mixture was stirred at 60 °C for 16 h. Silica gel was added
and the solvent removed on the rotary evaporator. The residue was
purified by column chromatography (hexane–EtOAc, 2:1) to afford
13
C NMR (75 MHz, CDCl ): d = 175.9, 135.5, 135.2, 128.5, 127.1,
3
1
26.1, 124.6, 85.3, 47.4, 33.6, 30.8, 26.4, 18.9.
+
MS (EI): m/z (%) = 202 [M ] (26), 174 (38), 159 (25), 156 (46), 143
(
1
16), 142 (19), 141 (14), 132 (14), 131 (100), 130 (22), 129 (32),
28 (30), 117 (25), 116 (23), 115 (46), 91 (21).
2
7 as colorless oil; yield: 25 mg (36%).
Rf = 0.18 (hexane–EtOAc, 2:1).
+
HRMS (EI): m/z [M ] calcd for C H O : 202.0994; found:
1
3
14
2
IR (film): 3523, 3061, 2978, 2928, 2863, 1776, 1498, 1449, 1417,
1
2
02.0991.
–
274, 1233, 1203, 1176, 1104, 1060, 1033, 951, 925, 760, 701 cm .
1
1
(3aR*,9aS*)-3a-Methyl-3a,4,5,9b-tetrahydrofuro[2,3-c]quino-
lin-2(1H)-one (30)
DBU (4.5 mL, 0.030 mmol, 0.1 equiv) was added to a soln of (E)-3-
H NMR (300 MHz, CDCl ): d = 7.45–7.32 (m, 5 H), 4.30 (d,
3
J = 10.7 Hz, 1 H), 4.22 (dd, J = 7.0, 9.5 Hz, 1 H), 3.95 (dd,
J = 3.3, 9.6 Hz, 1 H), 3.87 (d, J = 10.7 Hz, 1 H), 3.17–3.10 (m, 1 H),
[
2-(2-oxopropylamino)phenyl]prop-2-enal (25, 61.0 mg, 0.30
2
.95–2.86 (m, 1 H), 2.56 (dd, J = 2.4, 18.4 Hz, 1 H).
mmol, 1 equiv) and IMes·HCl (12.6 mg, 0.0370 mmol, 0.125 equiv)
in THF (6 mL). The mixture was stirred at 60 °C for 16 h and the
solvent was removed on the rotary evaporator. The residue was pu-
rified by column chromatography (pentane–MTBE, 1:1) to afford
30 as an orange oil; yield: 14 mg (23%).
1
3
C NMR (75 MHz, CDCl ): d = 175.3, 138.9, 128.8, 128.3, 124.6,
3
9
5.5, 80.4, 76.1, 47.6, 34.7.
+
MS (EI): m/z (%) = 204 [M ] (36), 146 (31), 105 (100), 77 (29).
+
HRMS (EI): m/z [M ] calcd for C H O : 204.0787; found:
1
2
12
3
2
04.0787.
Rf = 0.53 (pentane–MTBE, 1:1).
IR (KBr): 3410, 2978, 2929, 2871, 1786, 1612, 1497, 1383, 1312,
(
2
3aR*,5aS*,9aR*)-Hexahydro-7H-furo[3,2-c]benzofuran-
(3H)-one (28)
A soln of IMes·HCl (37.5 mg, 0.11 mmol, 0.2 equiv) and KOt-Bu
10.8 mg, 0.096 mmol, 0.175 equiv) in freshly distilled THF (20
1287, 1250, 1209, 1186, 1134, 1122, 1078, 1049, 974, 890, 751
–1
cm .
1
H NMR (400 MHz, CDCl ): d = 7.07 (t, J = 7.7 Hz, 1 H), 6.85 (d,
3
(
J = 7.4 Hz, 1 H), 6.66 (t, J = 7.4 Hz, 1 H), 6.51 (d, J = 8.0 Hz, 1 H),
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

2
438
C. Burstein et al.
FEATURE ARTICLE
3
2
.99 (br s, 1 H), 3.67 (d, J = 9.9 Hz, 1 H), 3.44–3.52 (m, 2 H), 2.70–
.85 (m, 2 H), 1.15 (s, 3 H).
(6) For excellent reviews, see: (a) Ahlbrecht, H.; Beyer, U.
Synthesis 1999, 365. (b) Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1984, 23, 932. (c) Westiuk, N. Tetrahedron 1983, 39,
1
3
C NMR (100 MHz, CDCl ): d = 175.8, 143.1, 128.3, 125.0, 119.1,
3
17.0, 112.6, 80.3, 53.1, 45.6, 30.1, 18.2.
205. See also: (d) Hoppe, D.; Zschage, O. Angew. Chem.,
1
Int. Ed. Engl. 1989, 28, 69. (e) Zschage, O.; Hoppe, D.
Tetrahedron 1992, 48, 5657.
+
MS (EI): m/z (%) = 203 [M ] (100), 204 (15), 161 (11), 160 (83),
1
1
58 (23), 144 (17), 143 (11), 133 (11), 132 (94), 118 (21), 117 (35),
15 (12), 77 (16).
(
7) For N-heterocyclic carbene catalyzed conjugate Umpolung
and related reactions, see: (a) Chow, K. Y.-K.; Bode, J. W.
J. Am. Chem. Soc. 2004, 126, 8126. (b) Reynolds, N. T.;
Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
+
HRMS (EI): m/z [M ] calcd for C H NO : 203.0946; found:
1
2
13
2
2
03.0943.
9518. (c) Burstein, C.; Glorius, F. Angew. Chem. Int. Ed.
2
004, 43, 6205. (d) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J.
(3aR*,9bR*)-5-Acetyl-3a-methyl-3a,4,5,9b-tetrahydrofuro[2,3-
c]quinolin-2(1H)-one (31)
Am. Chem. Soc. 2004, 126, 14370. (e) He, M.; Bode, J. W.
Org. Lett. 2005, 7, 3131. (f) Sohn, S. S.; Bode, J. W. Org.
Lett. 2005, 7, 3873. (g) Chan, A.; Scheidt, K. A. Org. Lett.
DBU (4.3 mL, 0.030 mmol, 0.1 equiv) was added to a soln of N-{2-
(E)-3-oxoprop-1-enyl]phenyl}-N-(2-oxopropyl)acetamide
[
6
(26,
9.9 mg, 0.285 mmol, 1 equiv) and IMes·HCl (12.3 mg, 0.0360
2
005, 7, 905. (h) Reynolds, N. T.; Rovis, T. J. Am. Chem.
Soc. 2005, 127, 16406. (i) Zeitler, K. Org. Lett. 2006, 8,
37. Very recently, the formation of spiro g-butyrolactones
mmol, 0.125 equiv) in freshly distilled THF (15 mL). The mixture
was stirred at 60 °C for 16 h, silica gel was added and the solvent
removed on the rotary evaporator. The residue was purified by col-
umn chromatography (hexane–EtOAc, 1:1) to afford 31 as a white
solid; yield: 18 mg (26%).
6
by conjugate Umpolung using cyclic 1,2-diketones as the
electrophiles was reported: (j) Nair, V.; Vellalath, S.;
Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507.
8) For N-heterocyclic carbene catalyzed transesterification
reactions, see: (a) Grasa, G. A.; Kissling, R. M.; Nolan, S. P.
Org. Lett. 2002, 4, 3583. (b) Grasa, G. A.; Guveli, T.; Singh,
R.; Nolan, S. P. J. Org. Chem. 2003, 68, 2812. (c) Singh,
R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P. J. Org.
Chem. 2004, 69, 209. (d) Singh, R.; Nolan, S. P. Chem.
Commun. 2005, 5456. (e) Nyce, G. W.; Lamboy, J. A.;
Connor, E. F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett.
2002, 4, 3587. (f) Connor, E. F.; Nyce, G. W.; Myers, M.;
Mock, A.; Hedrick, J. L. J. Am. Chem. Soc. 2002, 124, 914.
(g) Nyce, G. W.; Glauser, T.; Connor, E. F.; Mock, A.;
Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2003,
125, 3046. For a related amidation, see: (h) Schmidt, M.
A.; Movassaghi, M. Org. Lett. 2005, 7, 2453.
(
Rf = 0.22 (hexane–EtOAc, 1:2).
IR (film): 1781, 1649, 1606, 1489, 1462, 1377, 1341, 1322, 1296,
1
–
272, 1211, 1185, 1166, 1130, 1087, 1052, 980, 938, 889, 770 cm .
1
1
H NMR (300 MHz, CDCl ): d = 7.37–7.10 (m, 4 H), 4.26 (br s, 1
3
H), 3.63 (br d, 1 H), 3.38 (t, J = 10.4 Hz, 1 H), 2.83 (d, J = 10.6 Hz,
2
H), 2.27 (s, 3 H), 0.78 (s, 3 H).
1
3
C NMR (75 MHz, CDCl ): d = 174.5, 170.6, 137.9, 129.9, 127.8,
3
1
26.0, 125.1, 124.0, 84.7, 55.3, 44.7, 29.0, 23.1, 20.4.
+
MS (EI): m/z (%) = 245 [M ] (56), 204 (13), 203 (100), 161 (10),
1
1
60 (80), 158 (21), 144 (24), 132 (77), 130 (31), 118 (15), 117 (22),
15 (10), 77 (16).
+
HRMS (EI): m/z [M ] calcd for C H NO : 245.1052; found:
1
4
15
3
(
9) For the N-heterocyclic carbene catalyzed kinetic resolution
of alcohols, see: (a) Suzuki, Y.; Yamauchi, K.; Muramatsu,
K.; Sato, M. Chem. Commun. 2004, 2770. (b) Kano, T.;
Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347.
10) For N-heterocyclic carbene catalyzed benzoin
condensations, see: (a) Enders, D.; Niemeier, O.;
2
45.1050.
Acknowledgment
(
Generous financial support by the Deutsche Forschungsgemein-
schaft (Priority program organocatalysis), the Fonds der Chemi-
schen Industrie (Dozentenstipendium), Lilly Germany (Lilly
Lecture Award) and the BASF AG (BASF Catalysis Award) is gra-
tefully acknowledged. We thank Dr. K. Harms and Dr. C. W. Leh-
mann for the X-ray analyses.
Balensiefer, T. Angew. Chem. Int. Ed. 2006, 45, 1463.
(b) Enders, D.; Niemeier, O. Synlett 2004, 2111. (c)Enders,
D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743.
(d) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc.
2003, 125, 8432. (e) Hachisu, Y.; Bode, J. W.; Suzuki, K.
Adv. Synth. Catal. 2004, 346, 1097. See also: (f) Dudding,
T.; Houk, K. N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
References
5770. (g) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org. Chem.
2
004, 2025.
(
(
1) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
2) For example the use of deprotonated dithianes as masked
carbonyl anion synthons has become a very popular
stoichiometric approach, see: Seebach, D.; Corey, E. J. J.
Org. Chem. 1975, 40, 231.
(
11) For N-heterocyclic carbene catalyzed Stetter reactions, see:
a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
(
Soc. 2002, 124, 10298. (b) Kerr, M. S.; Rovis, T. J. Am.
Chem. Soc. 2004, 126, 8876. (c) Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2005, 127, 6284. (d) Mattson, A. E.;
Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
(
(
(
3) (a) Eisch, J. J. J. Organomet. Chem. 1995, 500, 101.
(
5
b) Pohl, M.; Lingen, B.; Müller, M. Chem. Eur. J. 2002, 8,
288.
4) (a) Wöhler, F.; Liebig, J. Ann. Pharm. 1832, 3, 249.
b) Lapworth, A. J. Chem. Soc. 1903, 83, 995. (c) Breslow,
R. J. Am. Chem. Soc. 1958, 80, 3719.
5) (a) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407.
1
1
26, 2314. (e) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006,
28, 2552. (f) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org.
Lett. 2001, 3, 3297. (g) Bharadwaj, A. R.; Scheidt, K. A.
Org. Lett. 2004, 6, 2465. (h) Myers, M. C.; Bharadwaj, A.
R.; Milgram, B. C.; Scheidt, K. A. J. Am. Chem. Soc. 2005,
(
127, 14675.
(
b) Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890.
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York

FEATURE ARTICLE
N-Heterocyclic Carbene-Catalyzed Conjugate Umpolung to Synthesize g-Butyrolactones
2439
(
12) For some other N-heterocyclic carbene catalyzed reactions,
see: (a) Suzuki, Y.; Toyota, T.; Imada, F.; Sato, M.;
the lactone ring hydrogens of 1a–h is very similar within the
cis and trans series. The stereochemistry of the products 1
was therefore assigned by comparison of the NMR data for
these compounds with that of cis-1d, whose structure was
unequivocally established by X-ray structural analysis. The
stereochemistry of lactones 7, 12, and 20 was assigned in an
analogous manner. CCDC-246600 (cis-1d), CCDC-250238
(u-7b), CCDC-603356 (12c-I) and CCDC-603357 (20c-II)
contain the crystallographic data (excluding structure
Miyashita, A. Chem. Commun. 2003, 1314. (b) Song, J. J.;
Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.; Senanayake,
C. H. Org. Lett. 2005, 7, 2193. (c) Song, J. J.; Gallou, F.;
Reeves, J. T.; Tan, Z.; Yee, N. K.; Senanayake, C. H. J. Org.
Chem. 2006, 71, 1273. (d) Duong, H. A.; Cross, M. J.;
Louie, J. Org. Lett. 2004, 6, 4679. (e) Mattson, A. E.;
Scheidt, K. A. Org. Lett. 2004, 6, 4363. (f) Fischer, C.;
Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc.
2
5
factors) for this paper. This data can be obtained free of
charge from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44
(1223)336033; e-mail: deposit@ccdc.cam.ac.uk.
(18) Bode et al. found that when using cis-cinnamaldehyde the
same stereochemical outcome as with trans-
2006, 128, 1472.
(
13) For the stoichiometric use of N-heterocyclic carbenes as
reagents, see: (a) Nair, V.; Bindu, S.; Sreekumar, V.; Rath,
N. P. Org. Lett. 2003, 5, 665. (b) Rigby, J. H.; Wang, Z.
Org. Lett. 2002, 4, 4289. (c) Enders, D.; Breuer, K.; Raabe,
G.; Runsink, J.; Teles, J. H. Liebigs Ann. Chem. 1996, 2019.
cinnamaldehyde was observed. Moreover, stopping the
reaction of cis-cinnamaldehyde prior to completion a
significant amount of trans-cinnamaldehyde was observed,
showcasing the importance of homoenolate resonance
structure IIb: ref. 7d.
(
d) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem. Int. Ed.
2004, 43, 5130. (e) Ma, C.; Yang, Y. Org. Lett. 2005, 7,
1343.
(
14) For excellent reviews on N-heterocyclic carbenes in
organocatalysis, see: (a) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534. (b) Johnson, J. S. Angew. Chem.
Int. Ed. 2004, 43, 1326. (c) Christmann, M. Angew. Chem.
Int. Ed. 2005, 44, 2632. (d) Zeitler, K. Angew. Chem. Int.
Ed. 2005, 44, 7506. For general reviews on N-heterocyclic
carbenes, see: (e) Herrmann, W. A. Angew. Chem. Int. Ed.
(19) (a) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C.
Chem. Commun. 2002, 2704. For the successful application
of these ligands in the Suzuki cross-coupling of sterically
hindered aryl chlorides, see: (b) Altenhoff, G.; Goddard, R.;
Lehmann, C. W.; Glorius, F. Angew. Chem. Int. Ed. 2003,
42, 3690. (c) Altenhoff, G.; Goddard, R.; Lehmann, C. W.;
Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195.
(20) Crotonaldehyde and a-methylcinnamaldehyde were
reported to be unreactive under the conditions employed by
Bode et al.: ref. 7 of ref. 7d.
2002, 41, 1291. (f) Herrmann, W. A.; Köcher, C. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2162. (g) Arduengo, A. J.
III; Krafczyk, R. Chem. Unserer Zeit 1998, 32, 6.
(h) Bourissou, D.; Guerret, O.; Gabbaï, F. P.; Bertrand, G.
Chem. Rev. 2000, 100, 39. (i) Perry, M. C.; Burgess, K.
Tetrahedron: Asymmetry 2003, 14, 951. (j) Cesar, V.;
Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc. Rev. 2004,
(21) For lactones in natural products, see: Seitz, M.; Reiser, O.
Curr. Opin. Chem. Biol. 2005, 9, 285.
(22) For the first step of the synthesis of aldehyde 23, see:
(a) Boatman, S.; Harris, T. M.; Hauser, C. R. J. Org. Chem.
1965, 30, 3321. For the Heck reaction methodology used in
the second step, see: (b) Battistuzzi, G.; Cacchi, S.; Fabrizi,
G. Org. Lett. 2003, 5, 777.
33, 619.
(
15) For excellent reviews on modern organocatalysis, see:
(
(
a) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5
138. (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
(23) Stott, K.; Keeler, J.; Van Q, N.; Shaka, A. J. J. Magn. Reson.
1997, 125, 302.
2001, 40, 3726. (d) Berkessel, A.; Gröger, H. Asymmetric
Organocatalysis; VCH: Weinheim, 2004.
(24) Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001.
(25) (a) Lehmann, C. W. private communication to the
Cambridge Structural Database (2004), deposition numbers
CCDC-246600 and 250238. (b) Harms, K. private
communication to the Cambridge Structural Database
(2006), deposition numbers CCDC-603356 and 603357.
(
16) Under a different set of reaction conditions (t-BuOH, DBU,
THF) and using two equivalents of electrophilic aldehyde,
Bode et al. reported improved yields: ref. 7d.
(
17) The stereochemistry of the lactones 1, 7, 12, and 20 was
1
assigned by X-ray and NMR analysis. The H NMR data for
Synthesis 2006, No. 14, 2418–2439 © Thieme Stuttgart · New York