Diastereoselective reaction of sulfoxonium ylides, aldehydes and ketenes: An approach to trans-γ-lactones

Article abstract of DOI:10.1021/jo4003213

In this paper, a novel approach to γ-lactones from the reaction of sulfoxonium ylides, aldehydes, and ketenes is described. The new ylide-based method provides access to γ-lactones from disubstituted ketenes, in good yields, and with good diastereoselectivity favoring the trans-diastereomer (11 examples with dr ≥ 82:18, dr up to 92:8).

Full text of DOI:10.1021/jo4003213

Note
pubs.acs.org/joc
Diastereoselective Reaction of Sulfoxonium Ylides, Aldehydes and
Ketenes: An Approach to trans-γ-Lactones
Mukulesh Mondal,† Han-Jen Ho,† Nicholas J. Peraino,† Melanie A. Gary,† Kraig A. Wheeler,‡
and Nessan J. Kerrigan†,*
†Department of Chemistry, Oakland University, 2200 North Squirrel Road, Rochester, Michigan 48309-4477, United States
‡Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, Illinois 61920-3099, United States
S
* Supporting Information
ABSTRACT: In this paper, a novel approach to γ-lactones
from the reaction of sulfoxonium ylides, aldehydes, and ketenes
is described. The new ylide-based method provides access to γ-
lactones from disubstituted ketenes, in good yields, and with
good diastereoselectivity favoring the trans-diastereomer (11
examples with dr ≥ 82:18, dr up to 92:8).
γ-Lactones are structural elements that are found as part of
many natural products (in about 10% of all natural products),
including the paraconic acids, and numerous bicyclic and
tricyclic ring systems (e.g., xanthatin).1 γ-Lactones have a range
of biological activity including strong antifungal, antibiotic,
antitumor, antiviral, and anti-inflammatory activity, which
underscores their potential for pharmaceutical development.1,2
γ-Lactones have also been used as building blocks for the
synthesis of complex molecules.3 Both intramoleular and
intermolecular approaches to the γ-lactone scaffold have been
investigated.4−6 Methods for the synthesis of γ-lactones are
often characterized by multistep approaches, limited substrate
scope, modest diastereoselectivity or enantioselectivity, and/or
the involvement of expensive reagents for the synthesis of
enantioenriched γ-lactones.1−6 Among the best direct (one-
pot) intermolecular methods are the contributions of Fukuzawa
and Procter involving ephedrinyl chiral auxiliary controlled-
SmI2 reductive coupling of aldehydes and acrylates in solution-
and solid-phase approaches to cis-γ-lactones, albeit with 2−5
equiv of SmI2 required for complete conversion.4a,b N-
Heterocyclic carbenes (NHC) have also been used as
organocatalysts for the construction of cis-γ-lactones, although
this has been one of the less developed NHC-catalyzed
processes with respect to asymmetric induction and substrate
scope.4,7 In recent years, transition-metal catalysis has been
applied to the stereoselective synthesis of γ-lactones, but this
approach, with few exceptions, has been limited to the
intramolecular construction of γ-lactones, is predicated on the
use of expensive catalysts, and often requires many synthetic
steps to assemble the substrates for such cyclization reactions
(e.g., four steps or more).4,8 In this paper, we describe a
versatile and novel strategy for providing access to this
important class of cyclic molecules, which overcomes many
of the deficiencies described with previous systems.
sulfoxonium ylides with aldehydes that provided an important
route to epoxides, and subsequently became known as the
Johnson−Corey−Chaykovsky reaction.9 The synthesis of
epoxides through the reaction of aminosulfoxonium ylides
with aldehydes was later developed by C. R. Johnson.9d,e The
latter reaction was proposed to involve a betaine intermediate,
formed reversibly as part of a stepwise mechanism.10,11
While limited studies have been carried out investigating the
reaction of betaines, derived from aziridines, with cumulenes
such as carbon disulfide under harsh reaction conditions
(refluxing CH3CN or t-BuOH), it is quite striking that no work
has been carried out exploring the reactivity of in situ generated
betaines with ketenes.12 As part of our research program on the
development of new synthetic reaction methodologies
involving ketenes, we began work on the development of a
reaction of onium ylides, aldehydes, and ketenes that we
anticipated would provide access to γ-lactones.13,14 We
proposed that, by carrying out betaine generation from the
reaction of sulfoxonium ylide 2a (derived from sulfoxonium salt
1a) and aldehyde 3 under mild conditions (at −78 °C),
cyclization to give epoxide (Johnson−Corey−Chaykovsky
reaction) would be slowed (Scheme 1). We anticipated that
the betaine intermediate A could be intercepted by a ketene 4
to generate an enolate B at low temperature. The enolate
intermediate B would then be expected to undergo 5-exo-tet
cyclization to generate the 3,5-disubstituted γ-lactone product
C, with concomitant loss of the sulfinamide leaving group X
(Scheme 1).
In preliminary studies, we determined that chiral amino-
sulfoxonium ylide 2a, obtained through treatment of salt 1a
with base, was superior to all other onium ylides for γ-lactone
formation (under Table 1 conditions).15 In all cases,
In the 1960s, A. W. Johnson’s group and Corey’s group
introduced and developed the reaction of sulfonium and
Received: February 17, 2013
Published: April 3, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
6−8). We speculate that the additive MgCl2 has a number of
roles in our reaction system. Primarily, it activates aliphatic
aldehydes, such as isobutyraldehyde, to undergo reaction with
the sulfoxonium ylide 2a. More reactive aromatic aldehydes
(entries 2−10, Table 2) do not need this additive to enable
Scheme 1. Proposal for New Route to γ-Lactones
Table 2. Substrate Scope of the Diastereoselective Synthesis
of γ-Lactones
a
b
c
entry
R1
i-Pr
R2
R3
% yield
dr
lactone
1
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
93
60
70
43
56
40
82
69
73
70
39
62
33
48
88:12
83:17
87:13
83:17
75:25
91:9
5a
5b
5c
5d
5e
5f
2
Ph
3
2-NO2Ph
2-ClPh
2-FPh
4
5
6
2-MePh
3-furyl
3-thienyl
2-NO2Ph
2-MePh
i-Pr
7
84:16
81:19
85:15
82:18
83:17
90:10
92:8
5g
5h
5i
Table 1. Optimization of the Diastereoselective Synthesis of
γ-Lactones
8
9
10
11
12
13
Et
5j
Et
5k
5l
2-NO2Ph
i-Pr
Me
Me
Me
5m
5n
d
14
4-NO2Ph
a
Percent yield is the isolated yield for both diastereomers of 5.
base (metal salt
additive)
metal salt
(equiv)
%
yield
b
Diastereomeric ratio (dr) determined by GC−MS and 1H NMR
a
b
entry
M+
dr
c
analysis of crudes. Entry 1: base = n-BuLi, salt additive = MgCl2 (M+
= MgCl). Entry 2: base = NaHMDS (M+ = Na). Entries 3−14 (except
13): base = n-BuLi (M+ = Li). Entry 13: base = n-BuLi, salt additive =
1
2
3
4
5
6
7
8
NaHMDS
Na
K
15
88:12
KHMDS
trace
32
d
CuI (M+ = Cu). 3 equiv of dimethylketene used.
n-BuLi
Li
88:12
79:21
70:30
86:14
88:12
85:15
c
n-BuLi
Li (50 °C)
ZnCl
61
n-BuLi (ZnCl2)
n-BuLi (MgCl2)
n-BuLi (MgCl2)
n-BuLi (MgCl2)
1
1
2
1
45
betaine formation to proceed efficiently. A second possible
effect is that, under certain conditions, the additive MgCl2 may
enable greater organization (through chelation) in the
transition state for [3,3]-sigmatropic rearrangement of F to G
(Scheme 2). However, no significant effect on diastereose-
lectivity was observed (Table 1, entry 3 vs 6). In most
subsequent substrate investigations, the simple system of n-
BuLi as base proved most general (see Table 2). While in most
cases the reaction was allowed to proceed overnight, a simple
modification involving heating the reaction to 50 °C, following
ketene addition, led to a reduction in total reaction time from
ca. 20 to 4 h (see the Experimental Section), with only slight
loss of diastereoselectivity (Table 1, entry 8). Interestingly,
during this study we found that an unexpected 3,4-disubstituted
regioisomer of the γ-lactone, 5a, was formed as the major
product (with no regioisomer C detected), and so it appeared
that an unanticipated rearrangement of enolate B was occurring
(Scheme 1). Our revised mechanism is discussed later in this
paper (Scheme 2).
We then investigated the substrate scope of the reaction with
respect to variation of aldehyde and ketene structure (Table 2).
Very good diastereoselectivity (dr up to 92:8) in γ-lactone
formation was observed with unsymmetrical ketenes (e.g., entry
3 vs entry 9 vs entry 12, Table 2). Formation of the trans-
isomer as the major diastereomer was confirmed by X-ray
crystallographic analysis of the major diastereomer of 5o,
derived from isobutylphenylketene and 4-NO2PhCHO (see the
MgCl
77
MgCl
93
MgCl (50
°C)
MgBr
MgI
AlCl2
Cu
95
c
9
n-BuLi (MgBr2)
n-BuLi (MgI2)
n-BuLi (AlCl3)
n-BuLi (CuI)
1
1
1
30
56
60
79
86:14
86:14
64:36
74:26
10
11
12
1
a
b
Percent yield is the isolated yield for 5. Diastereomeric ratio (dr)
determined by GCMS and H NMR analysis of crudes. heated at 50
°C for 15 min after ketene addition.
c
1
−
tetrafluoroborate (BF4 ) was used as a non-nucleophilic
counterion for sulfoxonium salt 1a/ylide 2a in order to
minimize side reactions with ketenes (e.g., with iodide as a
counterion). For all entries in Table 1, the aldehyde was added
slowly to the ylide 2a at −78 °C, and then the ketene was
added slowly over 60 min at −78 °C to the reaction solution.
The reaction was allowed to warm to room temperature
overnight in most cases. Carrying out ketene addition at a
higher temperature (e.g., −30 °C) led to poor conversion to γ-
lactone (<20%). The use of bases other than n-BuLi led to
poorer yields of lactone 5a (Table 1, entry 1−3). A variety of
metal salt additives were investigated in an effort to elevate the
yield of 5a without decreasing diastereoselectivity (Table 1,
entry 5−12). Best results were obtained with MgCl2 (entries
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Note
Scheme 2. Possible Reaction Mechanism
Experimental Section). Significantly, the methodology was
found to be versatile enough to tolerate ketenes of quite
different reactivity; including dimethylketene, alkylarylketenes
(entry 1 vs entry 11, entry 13 and entry 14), and even
diphenylketene (35−50% yields, not shown in Table 2).
Furthermore, the level of diastereoselectivity was found to be
good for ortho-substituted aromatic aldehydes (entry 3−6),
heteroaromatic substituted aldehydes (e.g., entry 7), and the α-
branched aliphatic aldehyde, isobutyraldehyde (entry 13).
Generally, best yields of γ-lactone were obtained with aromatic
aldehydes (≥56% for 9 examples, up to 93%), while with one
exception, yields with aliphatic aldehydes were more modest
(ca. 30−40%). The lower yields for the aliphatic aldehyde-
derived lactones may be attributed to side reactions involving
enolates derived from methylphenylketene or ethylphenylke-
tene (e.g., F in Scheme 2).
geometry as depicted in Scheme 2). Enolate F then undergoes a
[3,3]-sigmatropic rearrangement in stereoselective fashion,
presumably via a chair transition state, to afford carboxylate
G. The latter proposed rearrangement is reminiscent of that
observed by Marino and co-workers in the reaction of vinyl
sulfoxides with dichloroketene.19 Protonation of G gives H,
which undergoes intramolecular SN2 (5-exo-tet) cyclization to
provide trans-γ-lactone 5. Further experiments are being
conducted to elaborate details of the reaction mechanism.20
In summary, we have developed a new diastereoselective
reaction that provides access to γ-lactones. Standout features of
the method are that it affords direct access to trans-γ-lactones
via an unprecedented extension to the Johnson−Corey−
Chaykovsky reaction, in good yields (up to 95%), and with
good diastereoselectivity (11 examples with dr ≥82:18, up to
92:8). Current studies are focused on developing an
asymmetric variant of the new reaction, carrying out detailed
mechanistic investigations, and exploring the generality of the
described strategy for the synthesis of other 5-membered ring
systems.
We tentatively propose the mechanism below for the new
reaction (Scheme 2). Ylide 2a adds to aldehyde 3 to give
betaine A, most likely in equilibrium with oxathietane A′.11
A
crossover experiment, with 4-NO2PhCHO added 1.5 h after
PhCHO (followed by isobutylphenylketene), gave a mixture of
lactones 5b (5%) and 5o (95%), suggesting that betaine/
oxathietane formation is reversible under our reaction
conditions (see the Experimental Section for details). Reaction
of betaine A with ketene 4 gives rise to enolate B. Enolate B is
formed stereoselectively as an E-enolate (for M = Li) at this
point. Direct cyclization of B to give γ-lactone regioisomer C
was not observed. Complete regioselectivity for γ-lactone
regioisomer 5 was seen in all cases − no regioisomer C was ever
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out in flame-dried
glassware under a nitrogen atmosphere using standard inert
atmosphere techniques unless otherwise stated. THF was dried
using a sodium/benzophenone ketyl still, and N,N-dimethylethylamine
was distilled from potassium hydroxide under nitrogen.21 2-Phenyl-
acetic acid, 2-phenylpropanoic acid, 2-phenylbutanoic acid, 1-bromo-2-
methylpropane, diphenylacetyl chloride, 2-bromo-2-methylpropionyl
bromide, thionyl chloride, 2-nitrobenzaldehyde, 4-nitrobenzaldehyde,
2-chlorobenzaldehyde, α-D-benzaldehyde, methylphenyl sulfoxide,
sodium azide, formaldehyde, formic acid, trimethyloxonium tetra-
fluoroborate, and n-butyllithium (2.5 M in hexane) were used as
received. Isobutyraldehyde, o-tolualdehyde, 2-fluorobenzaldehyde, and
benzaldehyde were distilled prior to use.
1
detected by GC−MS and H NMR analysis of the crude
products. Presumably, cyclization of enolate B to give six-
membered sulfurane oxide D is faster than formation of lactone
C. Many examples of cyclic sulfurane oxides, even optically
active ones, are known.16,17 Deprotonation of D by a base (e.g.,
ylide 2a) gives sulfurane oxide anion E, which then undergoes
E1cB elimination to give enolate F.18 We propose that enolate
F undergoes equilibration to the thermodynamically more
stable E-enolate geometry under the reaction conditions (final
Iatrobeads (neutral silica, 60 μM particle size) and TLC plates
(UV254, 250 μM) were used as received. (Dimethylamino)-
methylphenyl oxosulfonium fluoroborate was synthesized according
to a literature procedure.22,23 Diphenylketene, methylphenylketene,
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The Journal of Organic Chemistry
Note
ethylphenylketene, and isobutylphenylketene were prepared through
amine-mediated dehydrohalogenation.24a−c Dimethylketene was pre-
pared through zinc-mediated dehalogenation of 2-bromo-2-methyl-
propionyl bromide.24d
3-Isobutyl-3,4-diphenyldihydrofuran-2(3H)-one (5b). The reac-
tion was performed following General Procedure A, with NaHMDS as
base instead of n-BuLi, and using sulfoxonium salt 1a, benzaldehyde,
and isobutylphenylketene. The crude product solution was diluted
with ether (10 mL) and washed with H2O (2 × 10 mL). The crude
product was purified through a plug of neutral silica eluting with 1.5%
EtOAc/hexane, and 5b was isolated as a colorless oil (44 mg, 60%
yield) with a dr = 83:17 as determined by GC−MS analysis of the
crude product: IR (thin film) 1769, 1002 cm−1; 1H (400 MHz, CDCl3,
TMS) for the major diastereomer δ 7.19−7.09 (m, 6H), 6.83−6.81
(m, 2H), 6.71−6.68 (m, 2H), 4.56 (dd, J = 7.4 Hz, 9.1 Hz, 1H), 4.32
(t, J = 9.3 Hz, 1H), 3.86 (dd, J = 7.4 Hz, 9.6 Hz, 1H), 2.06−1.97 (m,
3H), 1.09 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) for the major diastereomer 178.9, 136.7, 135.6,
128.9, 128.1, 128.0, 127.8, 127.6, 127.1, 68.7, 57.0, 51.6, 44.4, 25.2,
24.2, 23.9; MS (EI 70 eV) 294, 238, 193, 131, 103, 77 m/z; (M+ + H)
NMR spectra were recorded on a 200 MHz spectrometer (200
1
MHz for H and 50 MHz for 13C) and on a 400 MHz spectrometer
1
(400 MHz for H and 100 MHz for 13C). NMR chemical shifts were
reported relative to TMS (0 ppm) for 1H and to CDCl3 (77.23 ppm)
for 13C spectra. Low-resolution mass spectra were recorded on a GC−
MS instrument with a mass selective detector, and using a GC column
(30 m, 0.25 mm ID). High resolution mass spectra were recorded on
an Accurate-Mass Q-TOF LC/MS with ESI as ionization method. IR
spectra were recorded on an IR spectrometer.
Diastereoselectivity for γ-lactone formation was determined by
1
GC−MS analysis of the crude product and corroborated by H NMR
analysis in each case.
+
General Procedure A for Preparation of γ-Lactones.
(Dimethylamino)methylphenyl oxosulfonium fluoroborate 1a was
placed under high vacuum for 0.5 h. After drying, the sulfoxonium
salt 1a (68 mg, 0.25 mmol) was suspended in anhydrous THF (1.5
mL) and stirred at −78 °C. n-Butyllithium (2.5 M in hexane, 0.1 mL,
0.25 mmol) or NaHMDS (1 M in THF, 0.25 mL, 0.25 mmol, for 5b
only) was added dropwise at −78 °C, and the solution was stirred for
45 min. Aldehyde (0.25 mmol) or aldehyde solution (0.25 mmol solid
aldehyde dissolved in 0.5 mL THF) was added dropwise, and the
reaction was stirred for another 1.5 h at −78 °C. Finally, the ketene
solution (0.25 mmol ketene in 0.5 mL THF) was added to the
reaction over 1 h (15 min for dialkylketene). After being stirred for a
further 4 h at −78 °C, the reaction was gradually allowed to warm to
room temperature overnight in the cooling bath. The total reaction
time was typically 20 h. The solvent was then removed to give the
crude product, and the crude product was purified by passing through
a plug of neutral silica (50−100 times × crude weight), eluting with an
EtOAc/hexane solvent system.
General Procedure B for Preparation of γ-Lactones.
(Dimethylamino)methylphenyl oxosulfonium fluoroborate 1a was
placed under high vacuum for 0.5 h. After drying, the sulfoxonium
salt 1a (68 mg, 0.25 mmol) was suspended in anhydrous THF (1.5
mL) and stirred at −78 °C. n-Butyllithium (2.5 M in hexane, 0.1 mL,
0.25 mmol) was added dropwise at −78 °C, and the reaction was
stirred for 45 min. An appropriate metal salt (0.25−0.50 mmol) was
then added to the reaction solution under a positive pressure of
nitrogen. Transmetalation was assumed to be complete after 15 min.
Aldehyde (0.25 mmol) or aldehyde solution (0.25 mmol solid
aldehyde dissolved in 0.5 mL THF) was added dropwise, and the
reaction was stirred for another 1.5 h at −78 °C. Finally, the ketene
solution (0.25 mmol ketene in 0.5 mL THF) was added to the
reaction over 1 h. After being stirred for a further 4 h at −78 °C, the
reaction was gradually allowed to warm to room temperature
overnight in the cooling bath. The total reaction time was typically
20 h. The solvent was then removed to give the crude product and the
crude product was purified by passing through a plug of neutral silica
(50−100 times × crude weight), eluting with an EtOAc/hexane
solvent system.
HRMS m/z calcd for C20H23O2 295.1698, found 295.1693.
3-Isobutyl-4-(2-nitrophenyl)-3-phenyldihydrofuran-2(3H)-one
(5c). The reaction was performed following general procedure A using
sulfoxonium salt 1a, 2-nitrobenzaldehyde, and isobutylphenylketene.
The crude product was purified through a plug of neutral silica eluting
with 3% EtOAc/hexane, and 5c was isolated as a white solid (60 mg,
70% yield) with a dr = 87:13 as determined by GC−MS analysis of the
1
crude product: IR (thin film) 1768, 1524, 1349 cm−1; H (400 MHz,
CDCl3, TMS) for the major diastereomer δ 7.60−7.58 (m, 1H), 7.30−
7.26 (m, 1H), 7.20−7.15 (m, 3H), 7.10−7.00 (m, 4H), 4.87 (dd, J =
7.0 Hz, 9.9 Hz, 1H), 4.63 (dd, J = 2.6 Hz, 7.0 Hz, 1H), 4.44 (dd, J =
2.6 Hz, 9.9 Hz, 1H), 2.25−2.13 (m, 2H), 1.85−1.78 (m, 1H), 0.93 (d,
J = 6.7 Hz, 3H), 0.66 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) for the major diastereomer δ 177.6, 149.8, 137.0, 134.5, 132.8,
129.2, 128.2, 128.1, 128.1, 127.0, 124.5, 70.7, 56.3, 47.7, 47.6, 25.0,
24.6, 24.1; MS (EI 70 eV) 339, 283, 266, 237, 103, 81, 77 m/z; (M+ +
+
H) HRMS m/z calcd for C20H22NO4 340.1549, found 340.1548.
4-(2-Chlorophenyl)-3-isobutyl-3-phenyldihydrofuran-2(3H)-one
(5d). The reaction was performed following general procedure A using
sulfoxonium salt 1a, 2-chlorobenzaldehyde, and isobutylphenylketene.
The crude product was purified through a plug of neutral silica eluting
with 1.5% EtOAc/hexane, and 5d was isolated as a colorless oil (35
mg, 43% yield) with a dr = 83:17 as determined by GC−MS analysis
of the crude product: IR (thin film) 1769 cm−1; 1H (400 MHz, CDCl3,
TMS) for the major diastereomer δ 7.19−7.15 (m, 3H), 7.12−7.06
(m, 3H), 7.01−6.96 (m, 1H), 6.93−6.89 (m, 1H), 6.65−6.63 (m, 1H),
4.72 (dd, J = 7.2 Hz, 9.4 Hz, 1H), 4.46 (dd, J = 4.8 Hz, 7.2 Hz, 1H),
4.31(dd, J = 4.7 Hz, 9.4 Hz, 1H), 2.21−2.17 (m, 2H), 1.99−1.92 (m,
1H), 0.97 (d, J = 6.7 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) for the major diastereomer δ 178.3, 137.1, 136.6,
134.2, 129.6, 129.2, 128.5, 128.4, 127.9, 127.0, 126.9, 70.5, 56.6, 49.1,
47.1, 25.0, 24.9, 24.2; MS (EI 70 eV) 328, 272, 227, 131, 103, 91, 77
+
m/z; (M+ + H) HRMS m/z calcd for C20H22ClO2 329.1308, found
329.1304.
4-(2-Fluorophenyl)-3-isobutyl-3-phenyldihydrofuran-2(3H)-one
(5e). The reaction was performed following general procedure A using
sulfoxonium salt 1a, 2-fluorobenzaldehyde, and isobutylphenylketene.
The crude product was purified through a plug of neutral silica eluting
with 2% EtOAc/hexane, and 5e was isolated as a colorless oil (44 mg,
56% yield) with a dr =75:25 as determined by GC−MS analysis of the
crude product: IR (thin film) 1769 cm−1; 1H (400 MHz, CDCl3,
TMS) for the major diastereomer: δ 7.14−7.02 (m, 6H), 6.90−6.85
(m, 1H), 6.82−6.78 (m, 1H), 6.54−6.50 (m, 1H), 4.63 (dd, J = 7.4
Hz, 9.2 Hz, 1H), 4.35 (dd, J = 7.0 Hz, 9.2 Hz, 1H), 4.21 (t, J = 7.2 Hz,
1H), 2.17−2.08 (m, 2H), 2.03−1.94 (m, 1H), 1.02 (d, J = 6.6 Hz,
3H), 0.76 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) for the
major diastereomer: δ 178.4, 160.8 (d, J = 244.0 Hz), 137.2, 129.6 (d, J
= 8.5 Hz), 129.2 (d, J = 8.6 Hz), 128.1, 128.0, 127.2, 124.7 (d, J = 13.7
Hz), 124.0 (d, J = 3.4 Hz), 115.4 (d, J = 23.1 Hz), 69.1, 56.6, 45.9,
45.2, 25.1, 25.0, 24.0; MS (EI 70 eV) 312, 269, 256, 211, 131, 103, 91,
77 m/z; (M+ + H) HRMS m/z calcd for C20H22FO2+ 313.1604, found
313.1605.
3-Isobutyl-4-isopropyl-3-phenyldihydrofuran-2(3H)-one (5a).
The reaction was performed following general procedure B with
MgCl2 (0.5 mmol, 2 equiv) using sulfoxonium salt 1a, isobutyr-
aldehyde, and isobutylphenylketene. The crude product solution was
diluted with ether (10 mL) and washed with H2O (2 × 10 mL). 5a
was isolated as a colorless oil (60 mg, 93% yield) in 95% purity and
with a dr = 88:12 as determined by GC−MS analysis of the crude
1
product: IR (thin film) 1764 cm−1; H (400 MHz, CDCl3, TMS) for
the major diastereomer δ 7.38−7.32 (m, 4H), 7.29−7.24 (m, 1H),
4.21 (dd, J = 6.6 Hz, 9.3 Hz, 1H), 4.11 (dd, J = 5.8 Hz, 9.3 Hz, 1H),
2.64 (app q, J = 6.2 Hz, 1H), 2.07−1.99 (m, 1H), 1.97−1.86 (m, 2H),
1.72−1.63 (m, 1H), 0.89−0.87 (m, 6H), 0.81−0.79 (m, 6H); 13C
NMR (100 MHz, CDCl3) for the major diastereomer δ 180.1, 140.2,
128.5, 127.4, 127.3, 67.3, 53.7, 53.3, 38.5, 26.4, 24.4, 24.2, 24.2, 21.8,
18.9; MS (EI 70 eV) 260, 204, 161, 117, 91 m/z; (M+ + H) HRMS m/
3-Isobutyl-3-phenyl-4-o-tolyldihydrofuran-2(3H)-one (5f). The
reaction was performed following general procedure A using
+
z calcd for C17H25O2 261.1855, found 261.1861.
4590
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The Journal of Organic Chemistry
Note
sulfoxonium salt 1a, 2-methylbenzaldehyde, and isobutylphenylketene.
The crude product was purified through a plug of neutral silica eluting
with 2% EtOAc/hexane, and 5f was isolated as a colorless oil (31 mg,
40% yield) with a dr = 91:9 as determined by GC−MS analysis of the
crude product: IR (thin film) 1766 cm−1; 1H (400 MHz, CDCl3,
TMS) for the major diastereomer δ 7.10−7.03 (m, 5H), 7.00−6.95
(m, 2H), 6.89−6.84 (m, 1H), 6.50 (d, J = 7.8 Hz, 1H), 4.67 (dd, J =
7.1 Hz, 9.3 Hz, 1H), 4.32 (dd, J = 5.6 Hz, 9.3 Hz, 1H), 4.02 (dd, J =
5.6 Hz, 7.0 Hz, 1H), 2.28 (s, 3H), 2.22−2.07 (m, 2H), 2.00−1.90 (m,
1H), 0.97 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) for the major diastereomer: δ 178.8, 136.9, 136.5,
136.1, 130.5, 128.6, 128.1, 127.7, 127.2, 127.0, 126.0, 70.9, 56.9, 49.2,
46.9, 25.0, 24.9, 24.4, 20.6; MS (EI 70 eV): 308, 252, 118, 103 m/z;
(M+ + H) HRMS m/z calcd for C21H25O2+ 309.1855, found 309.1850.
4-(Furan-3-yl)-3-isobutyl-3-phenyldihydrofuran-2(3H)-one (5g).
The reaction was performed following general procedure A using
sulfoxonium salt 1a, 3-furalcarboxaldehyde, and isobutylphenylketene.
The crude product solution was diluted with ether (10 mL) and
washed with H2O (2 × 10 mL). The crude product was purified
through a plug of neutral silica eluting with 5% EtOAc/hexane, and 5g
was isolated as a yellow oil which was crystallized from MeOH to give
a pale yellow solid (58 mg, 82% yield) with a dr = 84:16 as determined
by GC−MS analysis of the crude product: IR (thin film) 1775 cm−1;
1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.22−7.18
(m, 5H), 6.99−6.96 (m, 3H), 4.48 (dd, J = 7.4 Hz, 8.8 Hz, 1H), 4.06
(dd, J = 8.9 Hz, 10.2 Hz, 1H), 3.81 (dd, J = 7.4 Hz, 10.2 Hz, 1H), 2.04
(d, J = 1.0 Hz, 2H), 1.96−1.87 (m, 1H), 1.09 (d, J = 6.6 Hz, 3H), 0.91
(d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) for the major
diastereomer δ 179.0, 142.9, 140.5, 136.8, 128.1, 127.8, 120.3, 119.5,
110.2, 68.6, 56.4, 43.7, 42.3, 25.3, 25.3, 24.1; MS (EI 70 eV) 284, 241,
dr = 82:18 as determined by GC−MS analysis of the crude product:
IR (thin film) 1769 cm−1; 1H (400 MHz, CDCl3, TMS) for the major
diastereomer δ 7.17−6.17 (m, 9H), 4.53 (dd, J = 7.4 Hz, 9.0 Hz, 1H),
4.31 (t, J = 8.8 Hz, 1H), 4.14 (t, J = 7.7 Hz, 1H), 2.36 (s, 3H), 2.23−
2.12 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
for the major diastereomer δ 179.0, 136.7, 136.5, 134.4, 130.7, 128.7,
128.4, 128.1, 127.4, 127.4, 125.7, 70.1, 57.9, 47.0, 29.7, 20.6, 9.2; MS
(EI 70 eV): 280, 146, 118 m/z; (M+ + H) HRMS m/z calcd for
+
C19H21O2 281.1543, found 281.1542.
3-Ethyl-4-isopropyl-3-phenyldihydrofuran-2-one (5k). The reac-
tion was performed following general procedure A using sulfoxonium
salt 1a, isobutyraldehyde, and ethylphenylketene. The crude product
was purified through a plug of neutral silica eluting with 5% EtOAc/
hexane, and 5k was isolated as a colorless oil (23 mg, 39% yield) with a
dr = 83:17 as determined by GC−MS analysis of the crude product:
IR (thin film) 1766 cm−1; 1H (400 MHz, CDCl3, TMS) for the major
diastereomer δ 7.38−7.24 (m, 5H), 4.23 (dd, J = 7.0 Hz, 9.3 Hz, 1H),
4.07 (dd, J = 6.7 Hz, 9.3 Hz, 1H), 2.55 (app q, J = 6.8 Hz, 1H), 2.17−
2.09 (m, 1H), 2.06−1.95 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.89 (d, J =
6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
for the major diastereomer δ 180.2, 140.7, 128.7, 127.8, 127.3, 68.1,
54.3, 49.8, 29.6, 26.7, 23.2, 22.0, 19.6; MS (EI 70 eV) 232, 145, 117, 91
+
m/z; (M+ + H) HRMS m/z calcd for C15H21O2 233.1542, found
233.1543.
3-Methyl-4-(2-nitrophenyl)-3-phenyldihydrofuran-2(3H)-one (5l).
The reaction was performed following general procedure A using
sulfoxonium salt 1a, 2-nitrobenzaldehyde, and methylphenylketene.
The crude product was purified through a plug of neutral silica eluting
with 5% EtOAc/hexane, and 5l was isolated as a white solid (46 mg,
62% yield) with a dr = 90:10 as determined by GC−MS analysis of the
1
crude product: IR (thin film) 1771, 1524, 1351 cm−1; H (400 MHz,
+
228, 174, 131, 103, 91; (M+ + H) HRMS m/z calcd for C18H21O3
CDCl3, TMS) for the major diastereomer δ 7.69−7.66 (m, 1H), 7.30−
7.21 (m, 2H), 7.16−7.12 (m, 3H), 6.96−6.93 (m, 2H), 6.65−6.63 (m,
1H), 4.69 (dd, J = 7.2 Hz, 9.3 Hz, 1H), 4.58 (t, J = 7.0 Hz, 1H), 4.45
(dd, J = 6.7 Hz, 9.2 Hz, 1H), 1.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) for the major diastereomer δ 179.3, 150.7, 137.2, 132.3, 131.3,
129.5, 128.52, 128.50, 127.7, 127.6, 124.7, 69.5, 53.6, 47.5, 24.5; MS
(EI 70 eV): 297, 132, 104, 77 m/z; (M+ + H) HRMS m/z calcd for
285.1491, found 285.1487.
3-Isobutyl-3-phenyl-4-(thiophene-3-yl)dihydrofuran-2(3H)-one
(5h). The reaction was performed following general procedure A using
sulfoxonium salt 1a, 3-thiophenecarboxaldehyde, and isobutylphenyl-
ketene. The crude product solution was diluted with ether (10 mL)
and washed with H2O (2 × 10 mL). The crude product was purified
through a plug of neutral silica eluting with 5% EtOAc/hexane, and 5h
was isolated as a yellow oil (52 mg, 69% yield) with a dr = 81:19 as
determined by GC−MS analysis of the crude product: IR (thin film)
1772 cm−1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer δ
7.40−7.38 (m, 1H), 7.18−7.11 (m, 3H), 6.85−6.82 (m, 2H), 6.61−
6.60 (m, 1H), 6.42 (dd, J = 1.2 Hz, 5.0 Hz, 1H), 4.52 (dd, J = 7.3 Hz,
8.9 Hz, 1H), 4.21 (dd, J = 7.3 Hz, 10.1 Hz, 1H), 4.01 (dd, J = 7.3 Hz,
10.1 Hz, 1H), 2.05 (d, J = 5.4 Hz, 2H), 2.03−1.94 (m, 1H), 1.10 (d, J
= 6.4 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
for the major diastereomer δ 178.9, 136.8, 135.9, 127.9, 127.7, 127.4,
127.3, 125.5, 123.0, 68.7, 56.9, 46.8, 43.9, 25.3, 25.2, 23.9; MS (EI 70
eV): 284, 241, 228, 174, 131, 103, 91; (M+ + H) HRMS m/z calcd for
+
C17H16NO4 298.1079, found 298.1078.
4-Isopropyl-3-methyl-3-phenyldihydrofuran-2(3H)-one (5m). The
reaction was performed following general procedure B with CuI (0.5
mmol, 2 equiv) using sulfoxonium salt 1a, isobutyraldehyde, and
methylphenylketene. The crude product solution was diluted with
ether (10 mL) and washed with saturated sodium thiosulfate solution
(2 × 10 mL) and H2O (2 × 10 mL). The crude product was purified
through a plug of neutral silica eluting with 2% EtOAc/hexane, and
5m was isolated as a colorless oil (18 mg, 33% yield) with a dr = 92:8
as determined by GC−MS analysis of the crude product: IR (thin
film) 1771 cm−1; 1H (400 MHz, CDCl3, TMS) for the major
diastereomer δ 7.38−7.24 (m, 5H), 4.41 (dd, J = 7.5 Hz, 9.2 Hz, 1H),
4.03 (t, J = 9.1 Hz, 1H), 2.59−2.53 (m, 1H), 1.95−1.83 (m, 1H), 1.58
(s, 3H), 0.88 (d, J = 6.6 Hz, 3H), 0.66 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) for the major diastereomer δ 181.3, 142.7, 128.6,
127.2, 126.8, 69.0, 54.7, 50.3, 27.5, 21.3, 20.0, 15.9; MS (EI 70 eV)
+
C18H21SO2 301.1262, found 301.1261.
3-Ethyl-4-(2-nitrophenyl)-3-phenyldihydrofuran-2-one (5i). The
reaction was performed following general procedure A using
sulfoxonium salt 1a, 2-nitrobenzaldehyde, and ethylphenylketene.
The crude product was purified through a plug of neutral silica eluting
with 2% EtOAc/hexane, and 5i was isolated as a white solid (57 mg,
73% yield) with a dr = 85:15 as determined by GC−MS analysis of the
+
218, 131, 118, 91 m/z; (M+ + H) HRMS m/z calcd for C14H19O2
219.1385; found: 219.1388.
crude product: IR (thin film) 1770, 1526, 1352 cm−1; H (400 MHz,
1
3,3-Dimethyl-4-(4-nitrophenyl)dihydrofuran-2-one (5n). The re-
action was performed following general procedure A using
(dimethylamino)methylphenyl oxosulfonium fluoroborate 1a, 4-nitro-
benzaldehyde, and dimethylketene (0.75 mmol, 3 equiv), with the
ketene solution being added over 15 min. The crude product was
purified through a plug of neutral silica eluting with 10% EtOAc/
hexane, and 5n was isolated as a white solid (23 mg, 48% yield): IR
CDCl3, TMS) for the major diastereomer δ 7.64−7.61 (m, 1H), 7.27−
7.21 (m, 2H), 7.11−7.08 (m, 3H), 7.05−7.03 (m, 2H), 6.83−6.80 (m,
1H), 4.77 (dd, J = 7.2 Hz, 9.6 Hz, 1H), 4.65 (dd, J = 4.7 Hz, 7.2 Hz,
1H), 4.44−4.41 (m, 1H), 2.30−2.21 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) for the major diastereomer δ 177.7,
150.3, 136.3, 133.2, 132.5, 129.6, 128.4, 128.2, 128.1, 127.3, 124.5,
70.3, 57.5, 46.1, 31.2, 9.1; MS (EI 70 eV): 311, 117, 91 m/z; (M+ + H)
1
(thin film) 1769, 1519, 1349 cm−1; H (400 MHz, CDCl3, TMS) δ
+
HRMS m/z calcd for C18H18NO4 312.1236, found 312.1234.
8.26−8.22 (m, 2H), 7.39−7.36 (m, 2H), 4.64 (dd, J = 7.2 Hz, 9.5 Hz,
1H), 4.53 (dd, J = 7.6 Hz, 9.5 Hz, 1H), 3.55 (t, J = 7.4 Hz, 1H), 1.40
(s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 180.6, 147.8,
144.4, 129.1, 124.2, 68.6, 52.4, 43.6, 24.7, 20.1; MS (EI 70 eV) 235,
3-Ethyl-3-phenyl-4-o-tolyldihydrofuran-2-one (5j). The reaction
was performed following general procedure A using sulfoxonium salt
1a, 2-methylbenzaldehyde, and ethylphenylketene. The crude product
was purified through a plug of neutral silica eluting with 2% EtOAc/
hexane, and 5j was isolated as a white solid (54 mg, 70% yield) with a
+
174, 130, 115, 91 m/z; (M+ + H) HRMS m/z calcd for C12H14NO4
236.0923, found 236.0919.
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The Journal of Organic Chemistry
Note
3-Isobutyl-4-(4-nitrophenyl)-3-phenyldihydrofuran-2-one (5o).
The reaction was performed following general procedure A using
sulfoxonium salt 1a, n-BuLi as base, 4-nitrobenzaldehyde, and
isobutylphenylketene. The crude product was purified through a
plug of neutral silica eluting with 20% EtOAc/hexane, and 5o was
isolated as a white solid (37 mg, 44% yield) with a dr = 60:40 as
determined by GC−MS analysis of the crude product: IR (thin film)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Science
Foundation: Grant Nos. CHE-0911483 and CHE-1213638 to
N.J.K, CHE-0722547 to K.A.W., CHE-0821487 for NMR
facilities at Oakland University, and CHE-1048719 for LC-MS
facilities at Oakland University.
1
1771, 1521, 1348 cm−1; H (400 MHz, CDCl3, TMS) for the major
diastereomer δ 8.24−8.21 (m, 2H), 7.44−7.31 (m, 7H), 4.52−4.45
(m, 2H), 4.05 (t, J = 5.4 Hz, 1H), 1.65−1.57 (m, 2H), 1.39−1.33 (m,
1H), 0.63 (d, J = 6.3 Hz, 3H), 0.47 (d, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) for the major diastereomer δ 178.1, 147.8, 144.9,
138.2, 129.6, 129.2, 128.3, 127.3, 124.2, 69.5, 56.0, 53.8, 41.3, 24.5,
24.4, 24.4; MS (EI 70 eV) 339, 296, 283, 192, 131, 103, 77 m/z; (M+ +
REFERENCES
■
+
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sample of the major diastereomer of 5o was crystallized from hexane
and acetone to provide crystals suitable for X-ray crystallographic
analysis. See the Supporting Information (CIF) for full details of the
crystal structure analysis. The crystal structure shows the trans-relative
stereochemistry of the major diastereomer of γ-lactone 5o. The
relative stereochemistry of γ-lactones 5a−n was assigned to be trans by
analogy.
Thermal Procedure: 3-Isobutyl-4-isopropyl-3-phenyldihy-
drofuran-2(3H)-one (5a). The reaction was performed following
general procedure B with MgCl2 (0.25 mmol) using sulfoxonium salt
1a, isobutyraldehyde, and isobutylphenylketene. Fifteen minutes after
ketene addition had finished, the reaction was placed in a 50 °C oil
bath for 15 min (total reaction time = 4 h). The crude product
solution was diluted with ether (10 mL) and washed with H2O (2 ×
10 mL). The crude product was purified through a plug of neutral
silica eluting with 2.5% EtOAc/hexane. Compound 5a was isolated as
a colorless oil (61.8 mg, 95%) with a dr = 85:15 as determined by
(4) (a) Fukuzawa, S.-i.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am.
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(5) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett.
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Y. H. Tetrahedron Lett. 2008, 49, 1616−1618. (e) Whitehead, D. C.;
Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132,
3298−3300. (f) Steward, K. M.; Gentry, E. C.; Johnson, J. S. J. Am.
Chem. Soc. 2012, 134, 7329−7332.
1
GC−MS analysis of the crude product: IR (thin film) 1764 cm−1; H
(400 MHz, CDCl3, TMS) for the major diastereomer δ 7.38−7.32 (m,
4H), 7.29−7.24 (m, 1H), 4.21 (dd, J = 6.6 Hz, 9.3 Hz, 1H), 4.11 (dd, J
= 5.8 Hz, 9.3 Hz, 1H), 2.64 (app q, J = 6.2 Hz, 1H), 2.07−1.99 (m,
1H), 1.97−1.86 (m, 2H), 1.72−1.63 (m, 1H), 0.89−0.87 (m, 6H),
0.81−0.79 (m, 6H); 13C NMR (100 MHz, CDCl3) for the major
diastereomer δ 180.1, 140.2, 128.5, 127.4, 127.3, 67.3, 53.7, 53.3, 38.5,
26.4, 24.4, 24.2, 24.2, 21.8, 18.9; MS (EI 70 eV) 260, 204, 161, 117, 91
(6) Murahashi, S.; Ono, S.; Imada, Y. Angew. Chem., Int. Ed. 2002, 41,
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(7) Chiang, P.-C.; Bode, J. W. N-Heterocyclic Carbene Catalyzed
Reactions of α-Functionalized Aldehydes. In Science of Synthesis
Reference Library, Asymmetric Organocatalysis, Vol. 1, Lewis Base and
Acid Catalysts; List, B., Ed.; Thieme: Stuttgart, 2012; Chapter 1.1.15,
pp 639−672.
+
m/z; (M+ + H) HRMS m/z calcd for C17H25O2 261.1855, found
261.1861.
Crossover Experiment of PhCHO and 4-NO2PhCHO. The
reaction was performed following general procedure A with some
modifications using sulfoxonium salt 1a, n-BuLi as base, benzaldehyde,
4-nitrobenzaldehyde, and isobutylphenylketene. After addition of n-
butyllithium to sulfoxonium salt 1a and 45 min of stirring at −78 °C,
benzaldehyde dissolved in THF was added dropwise, and the reaction
was stirred for 1.5 h at −78 °C. Then 4-nitrobenzaldehyde, dissolved
in THF, was added dropwise, and the reaction was stirred for another
1.5 h at −78 °C. Finally, a THF solution of isobutylphenylketene was
added as per General Procedure A. The reaction was worked up by
diluting the crude product solution with ether (10 mL), and washing
the organics with H2O (2 × 10 mL). The crude product was analyzed
by GC−MS, and it was determined that the reaction proceeded with a
conversion of >95%, being composed of ca. 5% 5b (dr = 86:14) and
ca. 95% 5o (dr = 62:38): MS (EI 70 eV) for 5b: 294, 238, 193, 131,
103, 77 m/z; MS (EI 70 eV) for 5o 339, 296, 283, 192, 131, 103, 77
m/z.
(8) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
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ASSOCIATED CONTENT
(12) Wu, J.-Y.; Luo, Z.-B.; Dai, L.-X.; Hou, X.-L. J. Org. Chem. 2008,
73, 9137−9139.
■
S
* Supporting Information
1H NMR spectra, 13C NMR spectra, and GC traces for all
products and X-ray data for 5o (CIF). This information is
available free of charge via the Internet at http://pubs.acs.org.
(13) (a) Ibrahim, A. A.; Nalla, D.; Van Raaphorst, M.; Kerrigan, N. J.
J. Am. Chem. Soc. 2012, 134, 2942−2945. (b) Chen, S.; Salo, E. C.;
Wheeler, K. A.; Kerrigan, N. J. Org. Lett. 2012, 14, 1784−1787.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: kerrigan@oakland.edu.
■
(15) Phosphonium, sulfonium, and trimethylsulfoxonium ylides were
found to be inferior to 2a in facilitating formation of 5a.
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The Journal of Organic Chemistry
Note
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(20) (a) When PhCDO was used as a substrate in reaction with 2a
and isobutylphenylketene, D-5b was obtained with >95% conversion
and with deuterium incorporated at C4. (b) When 18O-labeled
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