A versatile method for the synthesis of γ-pyrones

Article abstract of DOI:10.1139/v2012-067

A versatile three-step procedure to annulate a γ-pyrone onto a methylene ketone was developed involving (i) aldol reaction with a dithiolane-protected β-ketoaldehyde, (ii) oxidation of the aldol adduct to a β-diketone, and (iii) treatment of the resulting dithiolane-protected 1,3,5-trione with 2-iodoxybenzoic acid (IBX) and trifluoromethanesulfonic acid (triflic acid; TfOH) in acetonitrile at ambient temperature to give the corresponding γ-pyrone. Cyclization proceeded with IBX alone, but significantly improved yields were obtained with added acid, particularly triflic acid. A dithiolane was more effective than a dithiane or acyclic dithioacetal protecting group. The method was amenable to the preparation of a variety of substituted γ-pyrones simply by altering the initial aldol reactants. Overall yields of 50%-60% were obtained in six examples. The method was applied to prepare a key fragment for the total synthesis of baconipyrones A and C and siphonarin B.

Full text of DOI:10.1139/v2012-067

954
A versatile method for the synthesis of ␥-pyrones
Garrison E. Beye, Athanasios Karagiannis, Alieh Kazemeini, and Dale E. Ward
Abstract: A versatile three-step procedure to annulate a ␥-pyrone onto a methylene ketone was developed involving (i) aldol
reaction with a dithiolane-protected ␤-ketoaldehyde, (ii) oxidation of the aldol adduct to a ␤-diketone, and (iii) treatment of the
resulting dithiolane-protected 1,3,5-trione with 2-iodoxybenzoic acid (IBX) and trifluoromethanesulfonic acid (triflic acid; TfOH)
in acetonitrile at ambient temperature to give the corresponding ␥-pyrone. Cyclization proceeded with IBX alone, but
significantly improved yields were obtained with added acid, particularly triflic acid. A dithiolane was more effective than a
dithiane or acyclic dithioacetal protecting group. The method was amenable to the preparation of a variety of substituted
␥-pyrones simply by altering the initial aldol reactants. Overall yields of 50%–60% were obtained in six examples. The method
was applied to prepare a key fragment for the total synthesis of baconipyrones A and C and siphonarin B.
Key words: ␥-pyrone synthesis, 2-iodoxybenzoic acid (IBX), 1,3-dione, dithiolane, siphonariid polypropionates.
Résumé : On a développé une méthode versatile, en trois étapes, qui permet de réaliser l’annellation d’une ␥-pyrone sur
une méthylène cétone et qui implique les étapes suivantes : (i) une réaction aldolique impliquant un ␤-cétoaldéhyde
protégé par un dithiolane; (ii) l’oxydation de l’adduit aldolique en ␤-dicétone et (iii) le traitement de la 1,3,5-trione
protégée par un groupe dithiolane qui en résulte par de l’acide 2-iodoxybenzoïque (IBX) et de l’acide trifluorométhanesul-
fonique (acide triflique, TfOH), dans de l’acétonitrile, a la température ambiante, pour conduire a la formation de la
`
`
␥-pyrone correspondante. La cyclisation se produit même si on utilise l’acide IBX seul, mais les rendements sont de
beaucoup améliorés en présence d’un acide additionnel, tel l’acide triflique. Le groupe dithiolane est beaucoup plus efficace
qu’un dithiane ou un dithioacétal acyclique comme groupe protecteur. La méthode peut être utilisée pour la préparation
d’une variété de ␥-pyrones substituées; il suffit de modifier les réactifs aldoliques utilisés. On a obtenu des rendements
allant de 50 % a 60 % dans les six exemples étudiés. La méthode a été appliquée a la préparation de fragments clés dans
`
`
la synthèse totale des baconipyrones A et C et de la siphonarine B.
Mots-clés : synthèse de ␥-pyrone, acide 2-iodoxybenzoïque (IBX), 1,3-dione, dithiolane, polypropionates de siphonariides.
[Traduit par la Rédaction]
product syntheses,3,10 failed applications have also been re-
Introduction
ported.7 Cyclizations of masked derivatives of 1,3,5-triketones
(e.g., ethylene ketals,11 enol ethers,12 silyl enol ethers,13 enam-
ines,14 and 5-hydroxy-1,3-cyclohexanediones15) to produce
␥-pyrones also have been reported. Despite the work thus far,
the scope and limitations of the available methods have not
been systematically investigated especially with respect to the
nature and number of substituents. To the best of our knowl-
edge, there are no methods capable of annulating a ␥-pyrone
onto a ketone that allows flexibility in the substitution
pattern. Herein, we report the synthesis and cyclization of
dithiolane-protected 1,3,5-triketones to afford ␥-pyrones
with a high degree of synthetic versatility.
A ␥-pyrone motif in polypropionate natural products imbues
these privileged structures with a range of biological properties.1
In recent years, there has been a resurgence of interest in the
synthesis of ␥-pyrone-containing natural products and in
the formation of the ␥-pyrone moiety.2,3 The synthesis of
␥-pyrones can be accomplished through a variety of methods,
but many of these methods lack generality.4,5 The most com-
mon approach involves dehydrative cyclization of 1,3,5-
triketones, classically achieved by treatment with strong protic
acids.4 Such harsh conditions are generally not appropriate for
the synthesis of complex natural products, and in recent years
a variety of alternative reagents to achieve this transformation
have been reported, including PPh3/CCl4,6 dimethyl sulfoxide
(DMSO)/(COCl)2 (Swern reagent),6 Amberlyst with P2O5 on
Celite,7 sterically hindered diarylammonium sulfonates,8 and
C6F5SO3H/heptane.9 Although the most popular of these
methods, PPh3/CCl4,6 has been featured in several natural
Results and discussion
In the context of our synthetic studies on the polypropi-
onates from Siphonaria zelandica,16,17 we envisioned the syn-
thesis of the key ␥-pyrone fragment (2) by functional group
Received 22 July 2012. Accepted 31 July 2012. Published at www.nrcresearchpress.com/cjc on 25 November 2012.
G.E. Beye*, A. Karagiannis, A. Kazemeini, and D.E. Ward. Department of Chemistry, University of Saskatchewan, 110 Science
Place, Saskatoon, SK S7N 5C9, Canada.
Corresponding author: Dale E. Ward (e-mail: dale.ward@usask.ca).
*Present address: Bayer Healthcare LLC, 800 Dwight Way, Berkeley, CA.
This article is part of a Special Issue dedicated to Professor Derrick Clive.
Can. J. Chem. 90: 954–964 (2012)
doi:10.1139/v2012-067
Published by NRC Research Press

Beye et al.
955
Scheme 1. Synthetic strategy for ␥-pyrone synthesis.
OPiv
OPiv
O
Pg Pg'
O
1
O
O
O
O
O
O
FGI
O
O
O
O
O
O
O
S
S
2
3
aldol
HO
cyclization
4a
OPiv
O
OPiv
O
OPiv
O
O
5
O
6
O
O
7
O
O
S
S
S
S
oxidation
deprotection
O
O
O
O
O
O
Scheme 2. Synthesis of ␥-pyrones.
O
O
HO
O
O
S
S
S
S
IBX, DMSO, rt
i. LDA, THF -78 °C
R1
R1
R1
R2
R2 R3 R4
R2 R3 R4
ii. 4a or 4b
8a R1 = Et; R2 = Me
8b R1 = Et; R2 = H
8c R1 = Ph; R2 = H
8d R1, R2 = (CH2)4
9a R1 = Et; R2 = R3 = R4 = Me (86%)
9b R1 = Et; R2 = H; R3 = R4 = Me (80%)
9c R1 = Ph; R2 = H; R3 = R4 = Me (78%)
9d R1, R2 = (CH2)4; R3 = R4 = Me (77%)
9e R1 = Et; R2 Me; R3 = R4 = H (95%)
10a R1 = Et; R2 = R3 = R4 = Me (83%)
10b R1 = Et; R2 = H; R3 = R4 = Me (80%)
10c R1 = Ph; R2 = H; R3 = R4 = Me (71%)
10d R1, R2 = (CH2)4; R3 = R4 = Me (81%)
10e R1 = Et; R2 Me; R3 = R4 = H (92%)
R
S
R
S
R
S
R
S
O
O
O HO
S
S
IBX
CH3CN
(see Tables 1 and 2)
8a, LDA
R3 R4
4a R3 = R4 = Me
4c R, R = (CH2)3
4d R = Et
9f R, R = (CH2)3 (86%)
9g R = Et (99%)
4b R3 = R4 = H
O
R2
R1
R3
R4
IBX
DMSO
rt
IBX
DMSO
rt
O
O
O
O
O
O
O
S
S
SEt
11a R1 = Et; R2 = R3 = R4 = Me (92%)
11b R1 = Et; R2 = H; R3 = R4 = Me (90%)
11c R1 = Ph; R2 = H; R3 = R4 = Me (69%)
11d R1, R2 = (CH2)4; R3 = R4 = Me (81%)
11e R1 = Et; R2 Me; R3 = R4 = H (78%)
O
IBX
CH3CN
12
10f (20%)
13 (14%)
+
+
11a (46%) + 12 (15%)
11a (44%) + 12 (20%)
manipulation on 3, obtained via cyclization of the 1,3,5-
triketone intermediate 7 (Scheme 1). The latter would be
accessed from readily available ethyl ketone 116,18 through a
simple three-step procedure: aldol reaction with dithioacetal
aldehyde 4a16 followed by oxidation of the resulting adduct 5
to dione 6 and then hydrolysis of the dithioacetal protecting
group. This strategy would provide significant flexibility in
terms of the timing of installation of the ␥-pyrone as the
sequence might be delayed or interrupted in response to un-
foreseen synthetic challenges.
The planned sequence for introduction of the ␥-pyrone was
tested using 3-pentanone (8a) as a model ketone (Scheme 2).
Addition of aldehyde 4a16 to the lithium diisopropylamide
(LDA)-generated lithium enolate of 8a gave a mixture of aldol
diastereomers 9a in 86% yield. Surprisingly, treatment of 9a
with 2-iodoxybenzoic acid (IBX)19 in hot (80 °C) acetonitrile
according to More and Finney’s20 procedure gave the
known6,21 ␥-pyrone 11a as the only isolable compound in
~30% yield. Despite extensive experimentation, the yield of
this process could not be improved; retro-aldol was suspected
as a significant decomposition pathway. Considering that ox-
idation of the alcohol in 9a must occur prior to cyclization, an
alternative oxidation protocol (i.e., IBX in DMSO at room
temperature) was employed to arrive at diketone 10a. Subject-
ing 10a to IBX oxidation in hot acetonitrile gave a dramati-
cally improved yield of 11a (Table 1, entry 1) compared with
the reaction of 9a under the same conditions.
A series of experiments was performed to further optimize
the formation of 11a from 10a (Table 1). Increasing the
amount of IBX to 1.5 equiv gave a moderate improvement in
the yield that was unchanged using 2 equiv (Table 1, entries 2
and 3). Changing the solvent20 proved deleterious (Table 1,
entries 4 and 5). The addition of water to facilitate hydrolysis
of the dithioacetal attenuated the reaction significantly (Ta-
ble 1, entry 6). The dithiane 9f and diethyl thioacetal 9g were
prepared by aldol reactions of 8a with aldehydes 4c and 4d,
respectively. Oxidation of 9f with IBX in DMSO under the
same conditions that proved successful with 9a, gave pyrone
11a (46%), trione 126,22 (15%), and dione 10f (20%). Despite
extensive experimentation, the yield of 11a from the oxidation
Published by NRC Research Press

956
Can. J. Chem. Vol. 90, 2012
Table 1. Initial optimization of ␥-pyrone formation by
2-iodoxybenzoic acid (IBX) oxidation of diketones.
Table 2. Optimization of ␥-pyrone formation by 2-iodoxybenzoic
acid (IBX) oxidation of diketones 10 in the presence of acid
additives.
IBX
Yield
(%)a
Entry
Diketone
Solvent
(equiv)
Pyrone
Acid
Temp. Time
Yield
Pyrone (%)a
Entry Diketone (equiv)
(°C)
(h)
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10a
10f
10b
10c
10d
MeCN
MeCN
MeCN
EtOAc
DMSO
aq MeCNc
MeCN
MeCN
MeCN
MeCN
1
1.5
2
2
2
2
2
2
2
11a
11a
11a
63
77
77
NRb
Decomp.
Ͻ40d
38
29
27
31
1
2
3c
4
5
6
7
8
9
10a
10a
10a
10f
p-TsOH (0.1)
p-TsOH (1)
p-TsOH (2)
p-TsOH (1)
p-TsOH (1)
p-TsOH (1)
CH3COOH (1) 80
CF3COOH (1) 80
CF3SO3H (1)
80
80
80
80
80
80
24
24
24
24
24
24
24
24
24
24
24
24
24
1
11a
11a
83
Ͼ95b
NRd
90
11a
11a
11a
11b
11c
11d
11a
11b
11b
11d
11d
11d
11d
11d
11d
11d
11d
11d
11d
11d
11a
11b
11c
11d
11e
10b
10d
10d
10d
10d
10d
10d
10d
10d
10d
10d
10d
10d
10a
10b
10c
10d
10e
50
64
41
51
10
2
80
83
10
CF3SO3H (0.1) 80
CF3SO3H (0.5) 80
50b
70b
80b
Ͻ15b
65b
75b
80b
80b
92
Note: Reaction of diketone (~0.2 mmol, 0.04 mol/L) for 24 h at 80 °C.
11
12
13c
14
15
16
17
18
19
20
21
22
aIsolated yield of pyrone.
bNo reaction.
CF3SO3H (2)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
CF3SO3H (1)
80
80
rte
rte
rte
rte
rte
rte
rte
rte
rte
cH2O (5% v/v).
dYield estimated by 1H NMR spectroscopy using an internal standard.
3
13
24
18
16
2
of 9f could not be significantly improved. It is noteworthy that
subjecting triketone 12 to IBX gave little, if any, pyrone 11a.
However, subjecting 10f to IBX in hot acetonitrile gave 11a,
albeit in poor yield (Table 1, entry 7). Treatment of 9g with
IBX in DMSO at room temperature also produced 11a (44%)
and 12 (20%), along with the dihydropyran 13 (14%) but
without evidence of the desired diketone. Having established
conditions for the transformation of 10a into pyrone 11a in
reasonable yield (Table 1, entries 2 and 3), oxidations of
diones 10b–10d, prepared analogously to 10a, were attempted
(Table 1, entries 7–10). Unfortunately, only modest yields of
the corresponding pyrones 11b–11d were obtained; thus, ad-
ditional optimization studies were conducted.
88
69
81
78
16
16
Note: Reaction of diketone (~0.2 mmol, 0.04 mol/L) and IBX (2 equiv)
in acetonitrile.
aIsolated yield of pyrone.
bYield estimated by 1H NMR spectroscopy using an internal standard.
cReaction without IBX.
dNo reaction.
eRoom temperature (rt, ~21 °C).
The hydrolysis of dithioacetals by treatment with IBX in
DMSO is well-known, with dithianes and acyclic dithioacetals
being much more susceptible than dithiolanes.23,24 The fate of
the dithiane moiety under these oxidative conditions is likely
1,2-dithiolan-1,1-dioxide25 and we could identify this com-
pound in the 1H NMR spectra of the crude products from IBX
oxidations of 9f in DMSO and of 10f in hot acetonitrile.
However, the byproduct(s) of oxidative hydrolysis of
dithiolanes and in IBX-mediated formation of 11a from 10a
(or 9a) is (are) uncertain. Speculating that acidic byproducts
were plausible (vide infra), the effect of an added acid on the
reaction of 10a with IBX was investigated (Table 2). A small
improvement in yield of 11a was observed on addition of a
catalytic amount of p-TsOH·H2O (Table 2, entry 1), but near
quantitative conversion was observed with stoichiometric
amounts (Table 2, entry 2). Reaction of 10a with p-TsOH in
the absence of IBX returned starting material (Table 2, entry
3), confirming the crucial role of IBX in the transformation.
Reaction of 10f with IBX gave a markedly higher yield of 11a
in the presence of p-TsOH (1 equiv) (Table 2, entry 4; cf.
Table 1, entry 7); however, these conditions gave more modest
improvements with 10b and 10d (Table 2, entries 5 and 6; cf.
Table 1, entries 8 and 10).
entries 6–9) and the highest conversion was obtained with
trifluoromethanesulfonic acid (triflic acid; TfOH) (1 equiv;
Table 2, entry 9). Conversions improved with increasing
amounts of triflic acid up to 1 equiv (Table 2, entries 10–12),
but there was little reaction in the absence of IBX (Table 2,
entry 13). Although pyrone formation does not occur at room
temperature with IBX alone (heterogeneous mixture), the con-
version of 10d to 11d was complete within ~13 h with added
triflic acid (homogeneous mixture) (Table 2, entries 14–17).
Subjecting diketones 10a–10e to these optimized conditions
and monitoring the reaction progress by thin layer chromatog-
raphy (TLC) gave the corresponding pyrones 11a–11e in good
to excellent yields (Table 2, entries 18–22).
A plausible mechanism for the formation of pyrone 11a from
diketone 10a is illustrated in Scheme 3. In analogy with previous
proposals,23,24 we suggest that one of the dithiolane sulfur
atoms becomes associated with IBX (i.e., I), a process that
would be facilitated by acid, and assistance from the neigh-
boring sulfur atom leads to the fragmented sulfonium ion II. In
the case of dithianes, it was proposed that the analogous
sulfonium ion is attacked by the iodoxy oxygen ultimately
leading to deprotected ketone.23 With the much less reactive
dithiolanes and in the presence of acid (i.e., giving a less
nucleophilic OH versus O(–) on IBX), we suggest that II might
rearrange to III (and iodosobenzoic acid (IBA)) that could be
The effect of acid additives was further explored with the
recalcitrant 10d (Table 2, entries 6–17). The yield of pyrone
11d increased with increasing acidity of the additive (Table 2,
Published by NRC Research Press

Beye et al.
957
Scheme 3. Plausible mechanism for ␥-pyrone formation.
(-)OTf
H-OTf
O
(-)OTf
O
(-)OTf
HO
O
O
IBX
O
I
O
O
HO
O
(+)S
I
I
(+)S
SOH
HO
S
S
O
I
S
(+) S
S
O
H
O
O
H
H
O
O
O
IBA
O
O
O
O
O
II
I
III
10a
IBX
(-)OTf
(+)S
HOTf
S(O)nH
S
S-X
+
O
S(O)n
(O)mS
O
V
IV
O
O
O
O
14
11a
Scheme 4.
Table 3. Optimization of 2-iodoxybenzoic acid (IBX)-mediated
transformation of 6 to ␥-pyrone 15.
OPiv
O
OPiv
O
Entry
Acid (equiv)
Temp. (°C)
Time (h)
Yield (%)a
O
6
O
O
S
S
O
O
1
None
None
p-TsOH (1)
p-TsOH (1)
CF3SO3H (1)
80
80
80
rtd
rtd
24
24
24
72
16
41
48
60c
63
81
O
O
2b
3
1
IBX
(CH2SH)2
4
5
IBX Table 3
56%
O
Note: Reaction of 6 (~0.1–0.2 mmol, 0.04 mol/L) with IBX (2 equiv) in
O
acetonitrile.
O
O
aIsolated yield of 15.
O
bIBX added portionwise.
O
O
cIncluding 20% of an unidentified diastereomer of 15.
dRoom temperature (rt, ~21 °C).
16
FGI
5 steps (45%)
15
2
(i.e., with variations in reaction time, temperature, stoichiom-
etry, IBX addition rate, concentration, etc.). Although these
conditions resulted in the formation of the desired pyrone,
elimination of the pivaloate and hydrolysis of the ketal in 6
occurred concomitantly. The latter transformations were pre-
sumed to be acid-mediated and the acidity of IBX was sus-
pected.26 However, ketone 1 was inert to IBX (and its reduced
congeners IBA and o-iodobenzoic acid) under these reaction
conditions. Interestingly, the addition of ethanedithiol (0.1
equiv) to a reaction of 1 and IBX (1 equiv) in acetonitrile at
80 °C gave the dihydropyrone 16 in 56% yield. This result
suggested that IBX-mediated cyclization of diketones 10
might produce acidic compounds by oxidation of the
dithiolane byproducts and prompted a study of the effect of
acid additives on the reaction (Table 2). Indeed, the addition of
p-TsOH·H2O (1 equiv) to the reaction of 6 with IBX at 80 °C
improved the yield of 15 but also produced ~20% of an
unwanted diastereomer (Table 3, entry 3); however, prolonged
reaction at room temperature suppressed the isomerization
(Table 3, entry 4). Finally, the reaction of 6 with IBX and
triflic acid at room temperature gave 15 in excellent yield
(Table 3, entry 5). Straightforward functional group transfor-
mations on 15 produced 2, a key fragment in the total synthe-
ses of baconipyrones A and C and siphonarin B.16
further oxidized by IBX (e.g., to IV). In any event, the sul-
fonium ions II–IV are poised to cyclize by attack of the
␦-carbonyl group, ultimately leading to the pyrone 11a after
elimination of the sulfide group. Presumably, the cyclization
occurs via the keto tautomers of the diketones 10 as the
intramolecular hydrogen bond in the enol tautomers would
prevent ring closure. Thus, another possible beneficial effect
of added acid is accelerated keto–enol tautomerism. Interest-
ingly, 10a, the diketone easiest to cyclize, is predominantly in
the keto form, whereas 10b–10e are almost exclusively in the
enol form (by 1H NMR in CDCl3). Because we were unable to
detect signals in the 1H NMR spectra of the crude product (or
by monitoring reactions conducted in CD3CN) that would corre-
spond to the methylene groups originating from the dithiolane, the
formation of a polymeric material is suggested (e.g., 14).
Towards the total synthesis of siphonariid polypropi-
onates, this methodology was applied to the synthesis of the
key ␥-pyrone fragment (2; Scheme 1).16 Aldol reaction of the
readily available ketone 1 with aldehyde 4a followed by
oxidation of the resulting adducts 5 gave diketone 6 in excel-
lent yield.16 Reactions of 6 with IBX under a variety of
conditions were investigated (Scheme 4 and Table 3). Using
the method initially successful with 10a (cf. Table 1, entry 3)
resulted in the formation of 1516 as the only isolable pyrone-
containing product in moderate yield (Table 3, entry 1). The
yield of 15 could not be improved by modifying the procedure
Conclusion
A simple three-step procedure to annulate a ␥-pyrone onto a
methylene ketone was developed involving (i) aldol reaction with
Published by NRC Research Press

958
Can. J. Chem. Vol. 90, 2012
a dithiolane-protected ␤-ketoaldehyde, (ii) oxidation of the aldol
adduct to a ␤-diketone, and (iii) treatment of the resulting
dithiolane-protected 1,3,5-trione with 2-iodoxybenzoic acid
(IBX) and triflic acid in acetonitrile at ambient temperature.
Despite the lower reactivity of dithiolanes towards IBX, cycliza-
tion of the dithiolane-protected 1,3,5-trione was much more ef-
fective than the corresponding dithiane or S,S-diethyl acetal
protecting groups. In contrast to other approaches, the method
provides easy access to a variety of substituted ␥-pyrones
simply by changing the ketone and (or) aldehyde components.
Dithiolane-protected ␤-ketoaldehydes are readily prepared on
gram scale from commerically available ␤-ketoesters. The
synthetic utility of the method was demonstrated through the
synthesis of a key intermediate used in the total synthesis of
several natural products.
m (multiplet), br (broad), and ap (apparent); lists of coupling
constants (J) correspond to the order of the multiplicity as-
signment. Coupling constants (J) are reported to the nearest
0.5 Hz (i.e., Ϯ0.25 Hz as consistent with the digital resolution
1
~0.2 Hz/point). The H NMR assignments were made based
on chemical shift and multiplicity and were confirmed by
homonuclear decoupling and (or) two-dimensional correlation
experiments (gradient correlation spectroscopy (gCOSY), gra-
dient heteronuclear single quantum coherence (gHSQC), and
gradient heteronuclear multiple bond coherence (gHMBC)).28
The 13C NMR assignments were made on the basis of chem-
ical shift and multiplicity29 (as determined by 13C-DEPT (dis-
tortionless enhancement by polarization transfer) or gHSQC)
1
and were confirmed by two-dimensional H/13C correlation
experiments (gHSQC and (or) gHMBC).28 1H and 13C NMR
spectra for all reported compounds can be found in the Sup-
plementary data.
Experimental
General methods
Materials
Anhydrous solvents were distilled under argon atmosphere
as follows: tetrahydrofuran (THF) from benzophenone sodium
ketyl and DMSO from CaH2 at reduced pressure (stored over
4 Å molecular sieves). All experiments involving air- and (or)
moisture-sensitive compounds were conducted in an oven-
dried round-bottom flask capped with a rubber septum, and
attached via a needle and connecting tubing to an argon
manifold equipped with a mercury bubbler (~5 mm positive
pressure of argon). Low-temperature baths were ice/water
(0 °C) and CO2(s)/acetone (–78 °C). Unless otherwise noted,
reaction temperatures refer to that of the bath. Concentration
refers to the removal of volatiles at water aspirator pressure on
a rotary evaporator. Preparative TLC (PTLC) was carried out
on glass plates (20 ϫ 20 cm2) precoated (0.25 mm) with silica
gel 60 F254. Materials were detected by visualization under an
UV lamp (254 nm) and (or) by treating a 1 cm vertical strip
removed from the plate with a solution of phosphomolybdic
acid (5%) containing a trace of ceric sulfate in aqueous sul-
furic acid (5% v/v) followed by charring on a hot plate. Flash
column chromatography (FCC) was performed according to
Still et al.27 with silica gel 60 (40–63 ␮m). All mixed solvent
eluents are reported as v/v solutions. Unless otherwise noted,
all reported compounds were homogeneous by TLC and by 1H
NMR.
The following compounds and reagents were prepared as
described previously: 1, 4a, 6, and 15;16 IBX30; and ethyl
2-methyl-3-oxopentanoate.31 Aldehyde 4b was prepared from
ethyl acetoacetate according to Rama Rao et al.32 except IBX
(88% yield) was used in the final step instead of pyridinium
dichromate (PDC; 65% yield). i-Pr2NH was freshly distilled
under argon atmosphere from CaH2. All other reagents were
commercially available and, unless otherwise noted, were used
as received.
General procedure for LiAlH4 reduction of esters
A solution of ester (typically 40–60 mmol) in THF
(~0.5 mol/L) was added dropwise via syringe to a stirred
suspension of lithium aluminum hydride (1.2 equiv) in THF
(~0.5 mol/L) at 0 °C under Ar. The mixture was allowed to
warm to ambient temperature and the reaction progress was
monitored by TLC until the ester was consumed (~1–2 h). The
mixture was cooled to 0 °C and water (n mL for n g of lithium
aluminum hydride) was added slowly. (Caution: H2 evolu-
tion.) To the vigorously stirred suspension, 15% aq NaOH (n
mL) and water (3n mL) were added dropwise sequentially.
The initially gray suspension turned white over 1 h. The
mixture was filtered through Celite washing with ethyl acetate.
The combined filtrate and washings were dried over Na2SO4
and concentrated to give the product.
Spectral data
General procedure for IBX oxidation of primary
alcohols
High-resolution mass spectra (HR-MS) and low-resolution
mass spectra (LR-MS) were obtained on a double-focusing
high-resolution spectrometer; only partial data are reported.
Electron impact (EI) ionization was accomplished at 70 eV. IR
spectra were recorded on a Fourier transform interferometer
using a diffuse reflectance cell (i.e., diffuse reflectance infrared
Fourier transform (DRIFT) spectroscopy); only diagnostic and
(or) intense peaks are reported. Unless otherwise noted, NMR
IBX (1.5 equiv) was added to a stirred solution of alcohol
(typically 20–30 mmol) in anhydrous DMSO (~0.5 mol/L) at
room temperature. When TLC analysis indicated complete
consumption of alcohol (~2 h), the mixture was diluted with
ethyl acetate and washed sequentially with saturated aq
NaHCO3, water, and brine, dried over Na2SO4, and concen-
trated to give the crude aldehyde.
1
spectra were measured in CDCl3 solution at 500 MHz for H
and 125 MHz for 13C. Signals due to the solvent (13C NMR)
or residual protonated solvent (1H NMR) served as the internal
standard: CDCl3 (7.26 ␦H, 77.23 ␦C); C6D6 (7.16 ␦H, 128.39
2-(2-Methyl-1,3-dithiolan-2-yl)acetaldehyde (4b)
IBX oxidation of 2-(2-methyl-1,3-dithiolan-2-yl)ethanol32
(3.69 g, 22.5 mmol) according to the general procedure fol-
lowed by fractionation of the crude product by FCC (10%
1
␦C); and (CD3)2SO (2.50 ␦H, 39.52 ␦C). The H NMR chem-
ical shifts and coupling constants were determined assuming
first-order behavior. Multiplicity is indicated by one or more of
the following: s (singlet), d (doublet), t (triplet), q (quartet),
ethyl acetate in hexane) gave the title compound (3.21 g,
1
88%). IR ␯
(cm–1): 1721. H NMR (500 MHz, CDCl3) ␦:
max
9.78 (1H, br s, HC-1), 3.46–3.32 (4H, m, H2C-4, H2C-5=),
Published by NRC Research Press

Beye et al.
959
2.97 (2H, br s, HC-3), 1.85 (3H, s, H3C-1Љ). 13C NMR
(125 MHz, CDCl3) ␦: 200.7 (d, C-1), 61.3 (s, C-2), 56.7
(t, C-2), 40.6 (t ϫ 2, C-4, C-5=), 33.7 (q, C-1Љ). LR-MS (EI)
m/z (relative intensity): 162 ([M]ϩ, 77), 146 (6), 134 (12), 119
(100), 87 (11), 74 (45), 58 (95). HR-MS m/z calcd for
C6H10OS2: 162.0173; found: 162.0169 (EI). Spectral data
were in accord with those previously reported.32
2.01–1.89 (2H, m, HC-1Љ, H2C-5=), 1.18 (3H, d, J ϭ 7 Hz,
H3C-3), 1.03 (3H, t, J ϭ 7.5 Hz, H3C-2Љ). 13C NMR
(125 MHz, CDCl3) ␦: 202.5 (s, C-1), 54.5 (s, C-2), 50.8 (d,
C-2), 29.4 (t, C-1Љ), 26.1 (t, C-4), 25.5 (t, C-6), 24.9 (t, C-5=),
9.7 (q, C-3), 9.4 (q, C-2Љ). LR-MS (EI) m/z (relative intensity):
204 ([M]ϩ, 23), 175 (9), 147 (100), 107 (16), 102 (20), 87 (7),
73 (28). HR-MS m/z calcd for C9H16OS2: 204.0643; found:
204.0650 (EI).
Preparation of aldehyde 4c from ethyl
2-methyl-3-oxopentanoate
Preparation of aldehyde 4d from ethyl acetoacetate
Ethyl 2-(2-ethyl-1,3-dithian-2-yl)propanoate
Ethyl 3,3-bis(ethylthio)-2-methylpentanoate
F3B·OEt2 (6.2 mL, 6.9 g, 49 mmol) was added to a stirred
solution of ethyl 2-methyl-3-oxopentanoate (7.0 g, 45 mmol)
and 1,2-dithioethane (4.8 mL, 5.4 g, 47 mmol) in CH2Cl2
(64 mL) at room temperature under Ar. After 30 min (reaction
complete by TLC analysis), the mixture was diluted with
diethyl ether (300 mL) and saturated aq NaHCO3 (200 mL)
was added with vigorous stirring. (Caution: effervescence.)
After 30 min, the organic layer was washed sequentially with
water and brine, dried over Na2SO4, concentrated, and frac-
tionated by FCC (15% ethyl acetate in hexane) to give the title
Freshly distilled TiCl4 (0.90 mL, 8.2 mmol) was added via
syringe to a stirred solution of ethyl acetoacetate (1.30 g,
8.2 mmol) and ethanethiol (1.6 mL, 21 mmol) at 0 °C under
Ar. After 1 h, the ice bath was removed and, after 24 h, the
reaction was quenched by the addition of ice cold saturated aq
NaHCO3. The mixture was diluted with diethyl ether, washed
sequentially with ice cold sat aq NaHCO3 and brine, dried over
Na2SO4, concentrated, and fractionated by FCC (5% ethyl
acetate in hexane) to give the title compound (440 mg, 20%).
1
IR ␯
(cm–1): 1735. H NMR (500 MHz, CDCl3) ␦: 4.14–
compound as a pale yellow oil (9.5 g, 86%). IR ␯
(cm–1):
4.03m(2axH, m, H2CO), 2.90 (1H, q, J ϭ 7 Hz, HC-2), 2.72–2.48
(4H, m, H2CS ϫ 2), 2.00–1.83 (2H, m, H2C-4), 1.26 (3H, d,
J ϭ 7 Hz, H3CC-2), 1.22 (3H, t, J ϭ 7 Hz, H3CCO), 1.15 (3H,
t, J ϭ 7.5 Hz, H3CCS), 1.14 (3H, t, J ϭ 7.5 Hz, H3CCS), 1.01
(3H, t, J ϭ 7.5 Hz, H3C-5). 13C NMR (125 MHz, CDCl3) ␦:
173.4 (s, C-1), 65.9 (s, C-3), 60.5 (t, CH2O), 48.3 (d, C-2),
30.5 (t, C-4), 23.83 (t, CH2S), 23.77 (q, CH2S), 14.3 (q,
CH3CO), 14.2 (q, CH3C-2), 13.9 (q, CH3CS), 13.7 (q,
CH3CS), 9.8. LR-MS (EI) m/z (relative intensity): 264 ([M]ϩ,
1), 203 (53), 157 (33), 129 (100), 101 (8), 67 (17). HR-MS m/z
calcd for C12H24O2S2: 264.1218; found: 264.1216 (EI).
max
1
1734. H NMR (500 MHz, CDCl3) ␦: 4.22–4.09 (2H, m,
H2CO), 3.40 (1H, q, J ϭ 7 Hz, HC-2), 3.12 (1H, ddd, J ϭ 3,
11.5, 14.5 Hz, HC-4), 2.93 (1H, ddd, J ϭ 3, 11.5, 14.5 Hz,
HC-6), 2.71–2.66 (2H, m, HC-4, HC-6), 2.19 (1H, dq, J ϭ 7.5,
15 Hz, HC-1Љ), 2.05–1.99 (1H, m, HC-5=), 1.89–1.78 (2H, m,
HC-1Љ, HC-5=), 1.31 (3H, d, J ϭ 7 Hz, H3C-3), 1.27 (3H, t,
J ϭ 7 Hz, H3CCH2), 1.10 (3H, t, J ϭ 7.5 Hz, H3C-2Љ). 13C
NMR (125 MHz, CDCl3) ␦: 173.5 (s, C-1), 60.6 (t, CH2O),
55.6 (s, C-2), 46.3 (d, C-2), 27.9 (t, C-1Љ), 26.2 (t, C-4 ), 26.1
(t, C-6), 24.8 (t, C-5=), 14.4 (q, H3CCH2), 13.7 (q, C-3), 9.4 (q,
C-2Љ). LR-MS (EI) m/z (relative intensity): 248 ([M]ϩ, 20),
219 (13), 147 (100), 128 (20), 100 (7), 68 (10). HR-MS m/z
calcd for C11H20O2S2: 248.0905; found: 248.0904 (EI).
3,3-Bis(ethylthio)-2-methylpentan-1-ol
LiAlH4 reduction of the ethyl 3,3-bis(ethylthio)-
2-methylpentanoate (454 mg, 1.70 mmol) according to the
general procedure followed by fractionation of the crude prod-
2-(2-Ethyl-1,3-dithian-2-yl)propan-1-ol
LiAlH4 reduction of the above ethyl 2-(2-ethyl-1,3-dithian-
2-yl)propanoate (5.5 g, 22 mmol) according to the general
procedure followed by fractionation of the crude product by
uct by FCC (20% ethyl acetate in hexane) gave the title
1
compound (367 mg, 97%). IR ␯
(cm–1): 3356. H NMR
(500 MHz, CDCl3) ␦: 3.88 (1H, bmradx, J ϭ 11 Hz, HC-1), 3.68
(1H, br d, J ϭ 11 Hz, HC-1), 2.67–2.60 (4H, m, H2CS ϫ 2),
2.40 (1H, br s, HO), 2.10–2.03 (1H, m, HC-2), 1.89–1.77 (2H,
m, H2C-4), 1.22 (3H, t, J ϭ 7.5 Hz, H3CCS), 1.21 (3H, t, J ϭ
7.5 Hz, H3CCS), 1.14 (3H, d, J ϭ 7 Hz, H3CC-2), 1.02 (3H,
t, J ϭ 7.5 Hz, H3C-5). 13C NMR (125 MHz, CDCl3) ␦: 67.8
(s, C-3), 65.7 (t, C-1), 43.8 (d, C-2), 30.6 (t, C-4), 24.1 (t,
CH2S), 24.0 (t, CH2S), 14.7 (q, CH3CS), 14.4 (q, CH3CS),
13.7 (q, CH3C-2), 9.6 (q, C-5). LR-MS (EI) m/z (relative
intensity): 222 ([M]ϩ, 1), 163 (5), 161 (100), 131 (38), 103
(31). HR-MS m/z calcd for C10H22OS2: 222.1112; found:
222.1120 (EI).
FCC (20% ethyl acetate in hexane) to give the title compound
1
(4.0 g, 89%). IR ␯
(cm–1): 3419. H NMR (500 MHz,
CDCl3) ␦: 3.96 (1H,mdadxd, J ϭ 5.5, 6,11.5 Hz, HC-1), 3.73 (1H,
ddd, J ϭ 5.5, 6.5, 11.5 Hz, HC-1), 2.89–2.72 (4H, m, H2C-4,
H2C-6), 2.40 (1H, dd, J ϭ 6, 6.5 Hz, HO), 2.25–2/17 (1H, m,
HC-2), 2.11 (1H, dq, J ϭ 7.5, 15 Hz, HC-1Љ), 1.97–1.87 (3H,
m, HC-1Љ, H2C-5=), 1.11 (3H, d, J ϭ 7 Hz, H3C-3), 1.03 (3H,
t, J ϭ 7.5 Hz, H3C-2Љ). 13C NMR (125 MHz, CDCl3) ␦: 65.5
(t, C-1), 57.8 (s, C-2), 41.1 (d, C-2), 28.8 (t, C-1Љ), 25.9 (t, C-4 ),
25.8 (t, C-6), 25.3 (t, C-5=), 12.8 (q, C-3), 9.4 (q, C-2Љ).
LR-MS (EI) m/z (relative intensity): 206 ([M]ϩ, 13), 177 (10),
147 (100), 99 (10), 73 (17). HR-MS m/z calcd for C9H18OS2:
206.0790; found: 206.0792 (EI).
3,3-Bis(ethylthio)-2-methylpentanal (4d)
IBX oxidation of the 3,3-bis(ethylthio)-2-methylpentan-1-ol
(1.52 g, 7.4 mmol) according to the general procedure fol-
lowed by fractionation of the crude product by FCC (10%
2-(2-Ethyl-1,3-dithian-2-yl)propanal (4c)
IBX oxidation of the above 2-(2-ethyl-1,3-dithian-2-yl)
propan-1-ol (1.52 g, 7.4 mmol) according to the general pro-
cedure followed by fractionation of the crude product by FCC
(10% ethyl acetate in hexane) gave the title compound (1.24 g,
83%). IR ␯max (cm–1): 1716, 2830, 2733. 1H NMR (500 MHz,
CDCl3) ␦: 9.96 (1H, d, J ϭ 2.5 Hz, HC-1), 2.86–2.79 (5H, m,
HC-2, H2C-4, H2C-6), 2.12 (1H, dq, J ϭ 7.5, 15 Hz, HC-1Љ),
ethyl acetate in hexane) gave the title compound (1.24 g,
1
83%). IR ␯
(cm–1): 1720. H NMR (500 MHz, CDCl3) ␦:
max
9.97 (1H, d, J ϭ 2 Hz, HC-1), 2.70–2.60 (5H, m, HC-2,
H2CS ϫ 2), 1.90–1.80 (2H, m, H2C-4), 1.23 (3H, t, J ϭ
7.5 Hz, H3CCS), 1.22 (3H, d, J ϭ 7 Hz, H3CC-2,), 1.21 (3H,
t, J ϭ 7.5 Hz, H3CCS), 1.03 (3H, t, J ϭ 7.5 Hz, H3C-5).
Published by NRC Research Press

960
Can. J. Chem. Vol. 90, 2012
13C NMR (125 MHz, CDCl3) ␦: 203.3 (d, C-1), 65.4 (s, C-3),
54.0 (d, C-2), 30.8 (t, C-4), 23.7 (t, CH2S), 23.5 (t, CH2S),
14.05 (q, CH3CS), 14.03 (q, CH3CS), 10.6 (q, CH3C-2), 9.6
(q, C-5). LR-MS (EI) m/z (relative intensity): 220 ([M]ϩ, 3),
159 (100), 131 (83), 101 (30), 84 (24), 69 (60). HR-MS m/z
calcd for C10H20OS2: 220.0956; found: 220.0953 (EI).
4-(2-Ethyl-1,3-dithiolan-2-yl)-3-hydroxy-1-phenylpentan-
1-one (9c)
Following the general procedure, aldol reaction of ace-
tophenone (0.24 g, 2.0 mmol) with 4a (317 mg, 1.67 mmol)
and fractionation of the crude product by FCC (50% ethyl
acetate in hexane) gave the title compound as a Ͼ10:1 mixture
of diastereomers (401 mg, 78%). IR ␯max (cm–1): 3497, 3059,
1
1677. H NMR (500 MHz, CDCl3) ␦: 7.98 (2H, ap d, J ϭ
General procedure for aldol reaction
7 Hz, Ph), 7.57 (1H, t, J ϭ 7 Hz, Ph), 7.47 (2H, ap t, J ϭ 8 Hz,
Ph), 4.99 (1H, dd, HC-3), 3.38 (1H, d, J ϭ 2 Hz, HO), 3.29
(1H, dd, J ϭ 8, 16 Hz, HC2), 3.30–3.23 (4H, m, H2C-4,
H2C-5=), 2.98 (1H, dd, J ϭ 4.5, 16.5 Hz, HC-2), 2.07 (3H,
ap q, J ϭ 7 Hz, H2C-1Љ, HC-4), 1.19 (3H, d, J ϭ 7 Hz), 1.08
(3H, t, J ϭ 7 Hz). 13C NMR (125 MHz, CDCl3) ␦: 199.6 (s,
C-1), 137.3 (s, Ph), 133.5 (d, Ph), 128.8 (d ϫ 2, Ph), 128.4
(d ϫ 2, Ph), 77.8 (q, C-2), 68.8 (t, C-3), 46.1 (d, C-5), 44.9 (t,
C-2), 40.3 (t, C-4), 39.8 (t, C-5=), 36.3 (t, C-1Љ), 11.3 (q, C-5),
10.9 (q, C-2Љ). LR-MS (EI) m/z (relative intensity): 310 ([M]ϩ,
1), 263 (1), 217 (2), 190 (2), 161 (3), 133 (100), 105 (30), 77
(18). HR-MS m/z calcd for C16H22O2S2: 310.1061; found:
310.1067 (EI).
A solution of n-BuLi in hexane (1.2 equiv) was added
dropwise via syringe to a stirred solution of freshly distilled
diisopropylamine (1.25 equiv) in THF (~0.2 mol/L) at 0 °C
under argon. After 15 min, the mixture was cooled to –78 °C
and the ketone (1.2 equiv) was added dropwise via syringe.
After 30 min, a solution of aldehyde (typically 2–10 mmol) in
THF (~0.3 mol/L, 1.0 equiv) was added via syringe. After
15 min, the reaction was quenched by the addition of saturated
aq NaHCO3. The reaction mixture was diluted with ethyl
acetate, washed sequentially with saturated aq NaHCO3 and
brine, dried over Na2SO4, and concentrated to give the crude
aldol product.
2-(1-Hydroxy-2-(2-ethyl-1,3-dithiolan-2-yl)-propyl)
cyclohexanone (9d)
6-(2-Ethyl-1,3-dithiolan-2-yl)-5-hydroxy-4-methylheptan-
3-one (9a)
Following the general procedure, aldol reaction of 3-
pentanone (0.17 g, 2.0 mmol) with 4a (316 mg, 1.66 mmol) and
fractionation of the crude product by FCC (30% ethyl acetate in
Following the general procedure, aldol reaction of cy-
clohexanone (0.62 g, 6.5 mmol) with 4a (1.01 g, 5.32 mmol)
and fractionation of the crude product by FCC (30% ethyl
acetate in hexane) gave the title compound as a 12:1 mixture
hexane) gave the title compound as a 48:42:10 mixture of diaste-
of diastereomers (1.18 g, 77%). IR ␯
(cm–1): 3469, 1707.
1
reomers (393 mg, 86%). IR ␯
(cm–1): 3480, 1707. H NMR
max
max
1H NMR (500 MHz, CDCl3) ␦: 4.38 (1H, br d, J ϭ 9 Hz,
HC-1), 3.49 (1H, d, J ϭ 2.5 Hz, HO), 3.27–3.15 (4H, m,
H2C-4Љ, H2C-5=), 2.47–2.41 (2H, m, HC-2, HC-6), 2.33 (1H,
ddd, J ϭ 5, 11, 13 Hz, HC-6), 2.18–1.93 (5H, m, H2, C-1Љ,
HC-3, HC-5, HC-2), 1.94–1.87 (1H, m, HC-4), 1.79–1.56
(2H, m, HC-4, HC-5), 1.49–1.42 (1H, m, HC-3), 1.12 (3H, d,
J ϭ 7 Hz, H3C-3=), 1.07 (3H, t, J ϭ 7 Hz, H3C-2Љ). 13C NMR
(125 MHz, CDCl3) ␦: 215.3 (s, C-1), 78.3 (s, C-2Љ), 71.1 (d,
C-1), 55.0 (d, C-2), 43.3 (d, C-2), 42.6 (t, C-6), 40.4 (t, C-4Љ),
39.7 (t, C-5=), 35.2 (t, C-1Љ), 30.4 (t, C-3), 28.1 (t, C-5), 24.4
(t, C-4), 10.84 (q, C-2Љ or C-3=), 10.80 (q, C-2Љ or C-3=).
LR-MS (EI) m/z (relative intensity): 288 ([M]ϩ, 1), 241 (1),
195 (1), 161 (1), 133 (100), 81 (6), 73 (6). HR-MS m/z calcd
for C14H24O2S2: 288.1218; found: 288.1216 (EI).
(500 MHz, CDCl3) ␦: 4.50–4.42 (0.9H, m, HC-5), 4.26 (0.1H, br
d, J ϭ 8.5 Hz, HC-5), 3.86 (0.1H, br s, HO), 3.27 (4H, br s,
H2C-4, H2C-5=), 3.19 (0.48H, br s, HO), 3.16 (0.42H, br s, HO),
2.77–2.65 (1H, m, HC-4), 2.60–2.40 (2H, m, H2C-2), 2.22–1.80
(3H, m, H2C-1Љ, HC-6), 1.20 (1.5H, d, J ϭ 7 Hz, H3CC-4), 1.14
(0.3H, d, J ϭ 7 Hz, H3CC-4), 1.13–0.99 (6H, m, H3C-2Љ, H3C-7),
0.97 (1.3H, d, J ϭ 7 Hz, H3CC-4). 13C NMR (125 MHz, CDCl3;
two major isomers only) ␦: 215.4 (s), 214.6 (s), 77.9 (s), 77.6 (s),
74.5 (d), 72.8 (d), 51.6 (d), 49.7 (d), 43.4 (d), 41.9 (d), 40.24 (t),
40.19 (t), 39.75 (t), 39.67 (t), 37.0 (t), 36.8 (t), 36.6 (t), 35.2 (t),
14.1 (q), 13.9 (q), 11.6 (q), 11.1 (q), 10.9 (q), 10.8 (q), 7.9 (q), 7.7
(q). LR-MS (EI) m/z (relative intensity): 276 ([M]ϩ, 1), 229 (1),
190 (1), 161 (2), 133 (100). HR-MS m/z calcd for C13H24O2S2:
276.1208; found: 276.1218 (EI).
6-(2-Ethyl-1,3-dithiolan-2-yl)-5-hydroxyheptan-3-one (9e)
Following the general procedure, aldol reaction of
3-pentanone (0.18 mL, 0.15 g, 1.7 mmol) with 4b (317 mg,
1.55 mmol) and fractionation of the crude product by FCC
(20% ethyl acetate in hexane) gave the title compound as 1.5:1
6-(2-Ethyl-1,3-dithiolan-2-yl)-5-hydroxyheptan-3-one (9b)
Following the general procedure, aldol reaction of butanone
(1.2 mL, 0.99 g, 14 mmol) with 4a (2.00 g, 10.5 mmol) and
fractionation of the crude product by FCC (25% ethyl acetate in
hexane) gave the title compound as a 7:1 mixture of diastereom-
mixture of diastereomers (386 mg, 86%). IR ␯
(cm–1):
max
ers (2.05 g, 80%). IR ␯
(cm–1): 3477, 1710. 1H NMR
1
3503, 1710. H NMR (500 MHz, CDCl3) ␦: 4.60 (0.4H, ddd,
J ϭ 1, 3.5, 8 Hz, HC-5), 4.56 (0.6H, ddd, J ϭ 1, 3.5, 9.5 Hz,
HC-5), 3.00–2.84 (2H, m, HC-4, HC-6), 2.76-.240 (6H, m,
H2C-2, HC-4, HC-4, HC-6, HO), 2.31–2.17 (1H, m, HC-1Љ),
2.11–1.95 (2H, m, HC-1Љ, HC-5=), 1.92–1.72 (2H, m, HC-5=,
HC-6), 1.20 (1.2H, d, J ϭ 7 Hz, H3CC-4), 1.07 (2.4H, d, J ϭ
7 Hz), 1.05 (1.2H, d, J ϭ 7 Hz), 1.04 (2.4H, t, J ϭ 7 Hz), 1.03
(1.2H, t, J ϭ 7 Hz), 0.98 (2.4H, d, J ϭ 7 Hz, H3CC-4), 0.97
(2.4H, t, J ϭ 7 Hz), 0.95 (1.2H, t, J ϭ 7.5 Hz). 13C NMR
(125 MHz, CDCl3; *major isomer) ␦: 215.3* (s, C-3), 214.6
(s, C-3), 73.6* (d, C-5), 71.7 (d, C-5), 59.6 (s, C-2), 59.2* (s,
C-2), 51.4 (d, C-4), 49.7* (d, C-4), 41.6 (d, C-6), 40.2* (d,
max
(500 MHz, CDCl3; major isomer only) ␦: 4.78 (1H, m, HC-5),
3.25 (1H, d, J ϭ 2 Hz, HO), 3.24–3.19 (4H, m, H2C-4, H2C-5=),
2.67 (1H, dd, J ϭ 9, 16 Hz, HC-4), 2.51–2.42 (2H, m, H2C-1),
2.32 (1H, dd, J ϭ 4, 16 Hz, HC-4), 2.05–1.95 (2H, m, H2C-1Љ),
1.98 (1H, br q, J ϭ 7 Hz, HC-6), 1.05 (3H, d, J ϭ 7 Hz, H3C-7),
1.01 (6H, ap t, J ϭ 7 Hz, H3C-1, H3C-2Љ). 13C NMR (125 MHz,
CDCl3; ) ␦: 210.9 (s, C-3), 77.6 (d, C-2), 68.4 (s, C-5), 48.6 (t,
C-4), 45.7 (d, C-6), 40.1 (t, C-4), 39.6 (t, C-5=), 36.8 (t, C-1Љ or
C-2), 36.1 (t, C-1Љ or C-2), 11.0 (q, C-2Љ or C-7), 10.7 (q, C-2Љ or
C-7), 7.7 (q, C-1). HR-MS m/z calcd for C12H22O2S2: 262.1053;
found: 262.1056 (EI).
Published by NRC Research Press

Beye et al.
961
C-6), 36.6* (t, C-2), 35.3 (t, C-2), 29.4 (t, C-1Љ), 29.3 (t, C-1Љ),
26.03 (t, C-4), 25.99* (t, C-4), 25.97* (t, C-6), 25.88 (t, C-6),
25.36 (t, C-5=), 25.35* (t, C-5=), 14.1* (q ϫ 2, CH3C-4), 9.6*
(q, C-2Љ), 9.5 (q, C-2Љ), 7.9* (q ϫ 2), 7.7 (q), 7.3* (q). LR-MS
(EI) m/z (relative intensity): 290 ([M]ϩ, 4), 204 (4), 183 (1),
175 (6), 147 (100). HR-MS m/z calcd for C14H26O2S2:
290.1374; found: 290.1384 (EI).
General procedure for IBX oxidation of aldol adducts
IBX (2 equiv) was added to a stirred solution of the aldol
(typically 0.2–0.5 mmol) in DMSO (~0.04 mol/L at ambient
temperature. When TLC analysis indicated the consumption of
aldol (~24 h), the mixture diluted with ethyl acetate, washed
sequentially with saturated NaHCO3, water and brine, dried
over Na2SO4, and concentrated to give the crude product.
5-Hydroxy-4-methyl-6-(2-methyl-1,3-dithiolan-2-yl)hexan-
3-one (9f)
2-(2-Ethyl-1,3-dithiolan-2-yl)-4-methylheptane-3,5-dione
(10a)
Following the general procedure, aldol reaction of 3-
pentanone (0.42 g, 4.9 mmol) with 4c (650 mg, 4.01 mmol)
and fractionation of the crude product by FCC (30% ethyl
acetate in hexane) gave the title compound as a 2.5:1 mixture
of diastereomers (955 mg, 95%). IR ␯max (cm–1): 3476, 1706.
1H NMR (500 MHz, CDCl3) ␦: 4.24 (0.7H, dddd, J ϭ 2,
2.5, 4, 8.5 Hz, HC-5), 4.09 (0.3H, dddd, J ϭ 2, 4, 7, 9 Hz,
HC-5), 3.51 (0.3H, d, J ϭ 4, Hz, HO), 3.46 (0.7H, d,
J ϭ 2.5, Hz, HO), 3.41–3.32 (4H, m, H2C-4, H2C-5=), 2.72–2.62
(1H, m, HC-4), 2.58–2.50 (2H, m, H2C-2), 2.13–1.94 (2H, m,
H2C-6), 1.83 (2.1H, s, H3C-1), 1.82 (0.9H, s, H3C-1), 1.14 (2.1H,
d, J ϭ 7 Hz, H3CC-4), 1.10 (0.9H, d, J ϭ 7 Hz, H3CC-4), 1.05
(3H, ap t, H3C-1). 13C NMR (125 MHz, CDCl3; *major isomer)
␦: 215.34 (s, C-3), 215.29* (s, C-3), 72.3 (d, C-5), 70.7* (d, C-5),
65.7* (s, C-2), 65.5 (s, C-2), 51.7 (d, C-4), 51.4* (d, C-4), 48.61*
(t, C-6), 48.59 (t, C-6), 40.3 (t, C-4), 40.22* (t, C-4), 40.18* (t ϫ
2, C-5=), 36.3 (t, C-2), 35.6* (t, C-2), 34.0 (t, C-1Љ), 33.8* (t,
C-1Љ), 13.5 (q, CH3C-4), 11.4* (q, CH3C-4), 7.8* (q, C-1), 7.7 (q,
C-1). LR-MS (EI) m/z (relative intensity): 248 ([M]ϩ, 39), 187
(7), 171 (14), 155 (21), 133 (56), 121 (36), 101 (23), 74 (37), 57
(100). HR-MS m/z calcd for C11H20O2S2: 248.0905; found:
248.0912 (EI).
Following the general procedure, IBX oxidation of 9a
(393 mg, 1.42 mmol) and fractionation of the crude product by
FCC (20% ethyl acetate in hexane) gave the title compound
(326 mg, 83%). IR ␯
(cm–1): 3400, 1722, 1699, 1574.
max
1H NMR (500 MHz, CDCl3; a 30:35:35 mixture of enol and
two keto (a and b) tautomers, respectively) ␦: 16.84 (0.3H, s,
HO enol), 3.96 (0.35H, q, J ϭ 7 Hz, HC-4 keto a), 3.88
(0.35H, q, J ϭ 7 Hz, HC-4 keto b), 3.39 (0.35H, q, HC-2 keto
a or b), 3.35 (0.35H, q, HC-2 keto a or b), 3.30 (0.3H, q, HC-2
enol), 3.25–3.10 (4H, m, H2C-4, H2C-5=), 2.58–2.40 (2H, m,
H2C-6), 2.11–1.83 (2H, m, H2C-1Љ), 1.86 (0.9H, s, H3CC-4
enol), 1.38 (0.9H, d, J ϭ 7 Hz, H3C-1 enol), 1.33–1.27 (4.2H,
m, H3C-1, H3CC-4 keto), 1.15–0.97 (6H, m, H3C-2Љ, H3C-7
enol and keto). 13C NMR (125 MHz, CDCl3) ␦: 208.9 (s),
208.7 (s), 208.1 (s), 207.5 (s), 196.4 (s), 192.8 (s), 103.9 (s),
75.4 (s), 74.0 (s), 62.4 (d), 61.5 (d), 56.7 (d), 56.5 (d), 47.5 (d),
41.0 (t), 40.40 (t), 40.38 (t), 40.23 (t), 40.21 (t), 40.13 (t),
39.69 (t), 35.6 (t), 34.7 (t), 34.2 (t), 32.5 (t), 32.4 (t), 30.0 (t),
15.8, 15.6 (q), 15.4 (q), 13.2 (q ϫ 2), 12.4 (q), 10.7 (q), 10.31
(q), 10.29 (q), 9.3 (q), 7.8 (q), 7.7 (q). LR-MS (EI) m/z
(relative intensity): 274 ([M]ϩ, 3), 245 (2), 189 (1), 159 (10),
133 (100), 113 (6), 57 (26). HR-MS m/z calcd for C13H22O2S2:
274.1061; found: 274.1060 (EI).
7,7-Bis(ethylthio)-5-hydroxy-4,6-dimethylnonan-3-one (9g)
Following the general procedure, aldol reaction of 3-
pentanone (0.12 mL, 0.10 g, 1.1 mmol) with 4d (192 mg,
0.871 mmol) and fractionation of the crude product by FCC
(20% ethyl acetate in hexane) gave the title compound as a 3:1
6-(2-Ethyl-1,3-dithiolan-2-yl)heptane-3,5-dione (10b)
Distilled DMSO (0.069 mL, 76 mg, 0.97 mmol) was added
to a stirred solution of oxalyl chloride (0.050 mL, 74 mg,
0.58 mmol) in CH2Cl2 (5.8 mL) at –78 °C under Ar. After
15 min, a solution of 9b (101 mg, 0.386 mmol) in CH2Cl2
(1 mL) was added dropwise via syringe over 10 min. After 1 h,
i-Pr2EtN (0.54 mL, 3.1 mmol) was added to the reaction
mixture and the reaction was allowed to warm to 0 °C. The
mixture was diluted with ethyl acetate and washed sequen-
tially with saturated aq NH4Cl, saturated aq NaHCO3 and
brine, dried over Na2SO4, concentrated, and fractionated by
mixture of diastereomers (265 mg, 99%). IR ␯
(cm–1):
max
1
3436, 1715. H NMR (500 MHz, C6D6) ␦: 4.50 (0.75H, br d,
J ϭ 9 Hz, HC-5), 4.45 (0.25H, dd, J ϭ 1.5, 9.5 Hz,
HC-5), 3.70 (0.25H, d, J ϭ 2 Hz, HO), 3.66 (0.75H, d,
J ϭ 2 Hz, HO), 2.72–2.50 (4H, m, HC-2, HC-4, HCS ϫ 2),
2.41–2.12 (3H, m, HC-2, HCS ϫ 2), 2.10–1.95 (1H, m,
HC-6), 1.85–1.64 (2H, m, H2C-8), 1.23 (0.75H, d, J ϭ 7 Hz),
1.18 (0.75H, d, J ϭ 7 Hz), 1.10* (2.25H, d, J ϭ 7 Hz), 1.09
(2.25H, t, J ϭ 7 Hz), 1.04 (0.75H, t, J ϭ 7 Hz), 1.02–0.88
(6H, m), 0.82 (2.25H, d, J ϭ 7 Hz). 13C NMR (125 MHz,
C6D6; *major isomer) ␦: 213.4* (s, C-3), 213.2 (s, C-3), 74.1*
(d, C-5), 72.2 (d, C-5), 69.5 (d, C-7), 69.1* (s, C-7), 51.5 (d,
C-4), 49.6* (d, C-4), 43.7 (d, C-6), 42.0* (d, C-6), 37.4* (t,
C-2), 35.9 (t, C-2), 30.6* (t ϫ 2, C-8), 25.1* (t, CH2S), 23.7*
(t, CH2S), 15.1 (q, CH3C-4), 14.5 (q, CH3CS), 14.4* (q,
CH3CS), 14.23* (q, CH3CS), 14.20 (q, CH3CS), 13.9* (q,
CH3C-4), 10.09 (q), 9.51* (q), 9.48 (q), 9.37* (q), 8.16* (q),
8.13 (q). LR-MS (EI) m/z (relative intensity): 306 (1), 245
(10), 227 (13), 159 (10), 131 (100), 115 (20), 73 (10). HR-MS
m/z calcd for C15H30O2S2: 306.1687; found: 306.1692 (EI).
FCC (25% ethyl acetate in hexane) to give the title compound
1
(80 mg, 80%). IR ␯
(cm–1): 3408, 1718, 1699, 1599. H
max
NMR (500 MHz, CDCl3; Ͼ10:1 enol form) ␦: 15.49 (1H, s,
OH), 5.62 (1H, s, HC-4), 3.20–2.90 (4H, m, H2C-4, H2C-5=),
2.87 (1H, q, J ϭ 7 Hz, HC-2), 2.32 (2H, ap q, J ϭ 7.5 Hz,
H2C-6), 2.10 (1H, dq, J ϭ 7, 15 Hz, HC-1Љ), 1.94 (1H, dq, J
ϭ 7, 15 Hz, HC-1Љ), 1.42 (3H, d, J ϭ 7 Hz, H3C-1), 1.13 (3H,
t, J ϭ 7.5 Hz, H3C-7), 1.10 (3H, t, J ϭ 7 Hz, H3C-2Љ). 13C
NMR (125 MHz, CDCl3; Ͼ10:1 enol form) ␦: 196.7 (s, C-3),
194.4 (s, C-5), 99.3 (d, C-4), 74.8 (s, C-2), 53.3 (d, C-2), 41.0
(d, C-4), 40.1 (d, C-5=), 35.9 (d, C-1Љ), 31.3 (s, C-6), 16.4 (d,
C-1), 10.8 (d, C-2Љ), 9.9 (d, C-7). HR-MS m/z calcd for
C12H20O2S2; 260.0905; found: 260.0905 (EI).
Published by NRC Research Press

962
Can. J. Chem. Vol. 90, 2012
enol), 7.8 (q, C-1 keto). LR-MS (EI) m/z (relative intensity):
246 ([M]ϩ, 13), 145 (6), 133 (11), 119 (100), 101 (7), 57 (37).
HR-MS m/z calcd for C11H18O2S2: 246.0748; found: 246.0710
(EI).
4-(2-Ethyl-1,3-dithiolan-2-yl)-1-phenylpentane-1,3-dione
(10c)
Following the general procedure, IBX oxidation of 9c
(347 mg, 1.12 mmol) and fractionation of the crude product by
FCC (50% ethyl acetate in hexane) gave the title compound
6-(2-Ethyl-1,3-dithian-2-yl)-4-methylheptane-3,5-dione
(10f)
1
(246 mg, 71%). IR ␯
(cm–1): 3058, 1601, 1570. H NMR
max
(500 MHz, CDCl3; Ͼ10:1 enol form) ␦: 16.12 (1H, s, HO
enol), 7.88 (2H, ap d, J ϭ 7 Hz, Ph), 7.52 (1H, t, J ϭ 7.5 Hz,
Ph), 7.45 (2H, ap t, J ϭ 7.5 Hz, Ph), 6.35 (1H, s, HC-2),
3.30–3.20 (4H, m, H2C-4, H2C-5=), 3.04 (1H, q, J ϭ 7 Hz,
HC-4), 2.13–1.97 (2H, m, H2C-1Љ), 1.50 (3H, d, J ϭ 7 Hz,
H3C-4), 1.14 (3H, t, J ϭ 7 Hz, H3C-2Љ). 13C NMR (125 MHz,
CDCl3; Ͼ10:1 enol form) ␦: 199.5 (s, C-1), 182.4 (s, C-3),
134.9 (s, Ph), 132.5 (d, Ph), 128.8 (d ϫ 2, Ph), 127.2 (d ϫ 2,
Ph), 97.1 (d, C-2), 74.9 (s, C-2), 54.1 (d, C-4), 41.0 (t, C-4),
40.2 (t, C-5=), 36.1 (t, C-1Љ), 16.4 (q, C-5), 10.9 (q, C-2Љ).
LR-MS (EI) m/z (relative intensity): 308 ([M]ϩ, 2), 279 (2),
215 (2), 189 (3), 159 (6), 147 (34), 133 (100), 105 (46), 77
(37). HR-MS m/z calcd for C16H20O2S2: 308.0905; found:
308.0898 (EI).
Following the general procedure, IBX oxidation of 9f
(96 mg, 0.33 mmol) and fractionation of the crude product by
FCC (50% ethyl acetate in hexane) gave 11a (27 mg, 46%),
126,22 (10 mg, 15%), and the title diketone (19 mg, 20%). IR
1
␯
(cm–1): 3394, 1724, 1696, 1625. H NMR (500 MHz,
max
(CD3)2SO; a 1.3:1 mixture of diastereomers along with ϳ5%
of the enol form) ␦: 17.03 (0.05H, s, HO enol), 4.17–4.09
(1H, m, HC-4), 3.87 (0.41H, q, J ϭ 7 Hz, HC-6), 3.72 (0.54H,
q, J ϭ 7 Hz, HC-6), 3.16–2.40 (6H, m, H2C-4, H2C-5=,
H2C-6), 2.06–1.62 (4H, m, H2C-2, H2C-1Љ), 1.23 (1.25H, d,
J ϭ 7 Hz), 1.17 (1.65H, d, J ϭ 7 Hz), 1.12 (1.25H, d, J ϭ 7 Hz),
1.10 (1.65H, d, J ϭ 7 Hz), 1.01 (1.25H, t, J ϭ 7 Hz), 0.99
(1.65H, t, J ϭ 7 Hz), 0.94 (1.65H, t, J ϭ 7 Hz), 0.90 (1.25H,
t, J ϭ 7 Hz). 13C NMR (125 MHz, CDCl3) ␦: 210.6, 210.2,
209.2, 209.0, 64.9, 62.7, 56.1, 56.0, 50.45, 50.39, 34.5, 33.9,
28.5, 28.3, 27.0, 26.9, 26.3, 24.90, 24.86, 14.4, 14.2, 13.7,
12.9, 9.5, 9.4, 7.93, 7.86. LR-MS (EI) m/z (relative intensity):
288 ([M]ϩ, 21), 213 (1), 181 (9), 175 (41), 149 (10), 147
(100). HR-MS m/z calcd for C14H24O2S2: 288.1218; found:
288.1224 (EI).
2-[2-(2-Ethyl-1,3-dithiolan-2-yl)-1-oxopropyl]cyclohexanone
(10d)
Following the general procedure, IBX oxidation of 9d
(297 mg, 1.03 mmol) and fractionation of the crude product by
FCC (20% ethyl acetate in hexane) gave the title compound
(239 mg, 81%). IR ␯
(cm–1): 3454, 1714, 1587, 1579.
1H NMR (500 MHz, CmDaCx l3; Ͼ10:1 enol form) ␦: 16.15 (1H,
s, HO enol), 3.33 (1H, q, J ϭ 7 Hz, HC-2), 3.24–3.12 (4H, m,
H2C-4, H2C-5=), 2.45–2.20 (4H, m, H2C-3, H2C-6), 2.15–1.87
(2H, m, H2C-1Љ), 1.75–1.62 (4H, m, H2C-4, H2C-5), 1.36 (3H,
d, J ϭ 7 Hz, H3C-3=), 1.06 (3H, t, J ϭ 7 Hz, H3C-2Љ).
13C NMR (125 MHz, CDCl3; Ͼ10:1 enol form) ␦: 203.2 (s,
C-1), 183.5 (s, C-1), 106.7 (s, C-2), 75.1 (s, C-2Љ), 48.1 (d,
C-2), 40.9 (t, C-4Љ), 39.6 (t, C-5=), 35.7 (t, C-1Љ), 31.6 (t, C-6),
24.3 (t, C-3), 23.1 (t, C-4 or C-5), 21.7 (t, C-4 or C-5), 15.7 (q,
C-3=), 10.8 (q, C-2Љ). LR-MS (EI) m/z (relative intensity): 286
([M]ϩ, 2), 257 (1), 225 (1), 193 (5), 159 (7), 133 (100).
HR-MS m/z calcd for C14H24O2S2: 286.1061; found:
286.1058 (EI).
General procedure for pyrone formation
IBX (2 equiv) was added to a stirred solution of diketone
(~0.2 mmol) in acetonitrile (5 mL, ~0.04 mol/L) at ambient
temperature. CF3SO3H (1 equiv) or p-TsOH·H2O (1 equiv) (or
no acid) was added. The mixture was heated at the temperature
indicated in Tables 1–3. After the indicated time, the mixture
was diluted with ethyl acetate, washed with saturated aq
NaHCO3 and brine, dried over Na2SO4, concentrated, and
fractionated by FCC (60%–80% ethyl acetate in hexane) to
give the product.
2,6-Diethyl-3,5-dimethyl-4H-pyran-4-one (11a)
1H NMR (500 MHz, CDCl3) ␦: 2.57 (4H, q, J ϭ 7.5 Hz,
H2C ϫ 2), 1.92 (6H, s, H3CC ϫ 2), 1.19 (6H, t, J ϭ 7.5 Hz,
H3CCH2 ϫ 2). 13C NMR (125 MHz, CDCl3) ␦: 180.1 (s, C-4),
164.5 (s ϫ 2, C-2, C-6), 118.0 (s ϫ 2, C-3, C-5), 25.0 (t ϫ 2,
CH2), 11.5 (q ϫ 2, CH3CH2), 9.6 (q ϫ 2, CH3C). LR-MS (EI)
m/z (relative intensity): 180 ([M]ϩ, 72), 179 (100), 171 (12),
151 (11), 149 (46). HR-MS m/z calcd for C11H16O2: 180.1150;
found: 180.1144 (EI). Spectral data were in accord with those
previously reported.6,21
3-Methyl-1-(2-methyl-1,3-dithiolan-2-yl)hexane-2,4-dione
(10e)
Following the general procedure, IBX oxidation of 9e
(955 mg, 3.85 mmol) and fractionation of the crude product by
FCC (25% ethyl acetate in hexane) gave the title compound
1
(880 mg, 92%). IR ␯
(cm–1): 3404, 1726, 1699. H NMR
(500 MHz, CDCl3; 2.m7a:x1 mixture of keto and enol tautomers)
␦: 16.38 (1H, s, HO enol), 3.71 (1H, q, J ϭ 7 Hz, HC-4 keto),
3.39–3.24 (4H, m, H2C-4, H2C-5= keto/enol), 3.25 (1H, d, J ϭ
17 Hz, HC-6 keto), 3.19 (1H, d, J ϭ 17 Hz, HC-6 keto), 3.16
(1H, s, HC-6 enol), 2.61–2.42 (2H, m, H2C-2 keto/enol), 1.91
(3H, s, H3C-1Љ enol), 1.860 (3H, s, H3CC-4 enol), 1.856 (3H, s,
H3C-1Љ keto), 1.32 (3H, d, J ϭ 7 Hz, H3CC-4 keto), 1.14 (3H,
t, J ϭ 7.5 Hz, H3C-1 enol), 1.05 (3H, t, J ϭ 7.5 Hz, H3C-1
keto). 13C NMR (500 MHz, CDCl3) ␦: 207.7 (s, C-3 keto),
204.3 (s, C-5 keto), 195.0 (s, C-3 enol), 188.4 (s, C-5 enol),
105.1 (s, C-4 enol), 64.0 (s, C-2 enol), 62.0 (s, C-2 keto), 61.4
(t, C-4 keto), 56.4 (d, C-6 keto), 50.6 (d, C-6 enol), 39.88 (t,
C-4 enol), 39.86 (t, C-4 keto), 39.7 (t ϫ 2, C-5= keto/enol),
35.0 (t, C-2 keto), 32.7 (q, C-1Љ enol), 32.0 (q, C-1Љ keto), 29.7
(t, C-2 enol), 12.8 (q, C-4 keto), 12.7 (q, C-4 enol), 9.4 (q, C-1
2,6-Diethyl-3-methyl-4H-pyran-4-one (11b)
1
IR ␯
(cm–1): 1664, 1625, 1601. H NMR (500 MHz,
CDCl3)ma␦x: 6.1 (1H, s, HC-5), 2.61 (2H, q, J ϭ 7.5 Hz,
H2CC-2), 2.51 (2H, q, J ϭ 7.5 Hz, H2CC-6), 1.90 (3H, s,
H3CC-3), 1.23 (3H, t, J ϭ 7.5 Hz, H3CCC-2 or H3CCC-6),
1.22 (3H, t, J ϭ 7.5 Hz, H3CCC-2 or H3CCC-6). 13C NMR
(125 MHz, CDCl3) ␦: 180.6 (s, C-4), 169.3 (s, C-6), 166.0 (s,
C-2), 119.7 (s, C-3), 110.9 (d, C-5), 26.9 (t, H2CC-6), 25.0 (t,
H2CC-2), 11.6 (q, H3CCC-2 or H3CCC-6), 11.1 (q, H3CCC-2
or H3CCC-6), 9.4 (q, CH3C-3). LR-MS (EI) m/z (relative
intensity): 166 ([M]ϩ, 79), 165 (100), 151 (9), 123 (9), 99 (25),
83 (9). HR-MS m/z calcd for C10H14O2: 166.0994; found:
166.0993 (EI).
Published by NRC Research Press

Beye et al.
963
6-Ethyl-3-methyl-6-phenyl-4H-pyran-4-one (11c)
2,6-Diethyl-2-(ethylthio)-3,5-dimethyl-2H-pyran-4(3H)-one
(13)
Following the general procedure, IBX oxidation of aldol 9g
IR ␯max (cm–1): 1651, 1618. 1H NMR (500 MHz, CDCl3) ␦:
7.77–7.74 (2H, m, Ph), 7.49–7.46 (3H, m, Ph), 6.73 (1H, s,
HC-5), 2.75 (2H, q, J ϭ 7.5 Hz, H2CC-2), 2.01 (3H, s,
H3CC-3), 1.34 (3H, t, J ϭ 7.5 Hz, H3CC-1). 13C NMR
(125 MHz, CDCl3) ␦: 180.4 (s, C-4), 165.5 (s, C-2), 162.6 (s,
C-6), 132.0 (s, Ph), 131.2 (d, Ph), 129.2 (d ϫ 2, Ph), 125.8
(d ϫ 2, Ph), 120.6 (s, C-3), 109.6 (d, C-5), 25.2 (t, C-1Љ), 11.7
(q, CH3CC-2), 9.6 (q, CH3C-3). LR-MS (EI) m/z (relative
intensity): 214 ([M]ϩ, 100), 199 (7), 171 (15), 147 (10), 105
(18), 77 (17). HR-MS m/z calcd for C14H14O2: 214.0994;
found: 214.0993 (EI). Spectral data were in accord with those
previously reported.33
(93 mg, 0.30 mmol) and fractionation of the crude product by
FCC (5% ethyl acetate in hexane) gave 11a (24 mg, 44%),
126,22 (12 mg, 20%), and the title compound (10 mg, 14%). IR
1
␯
(cm–1): 1721, 1665, 1622. H NMR (500 MHz, CDCl3)
max
␦: 2.58 (1H, dq, J ϭ 12, 7.5 Hz, HCS), 2.49–2.45 (1H, m,
J ϭ 12, 7.5 Hz, HCS), 2.4 (1H, q, J ϭ 7 Hz, HC-3), 2.32 (2H,
ap q, J ϭ 7.5 Hz, H2CC-6), 2.05–1.85 (2H, m, H2CC-2), 1.76
(3H, s, H3CC-5), 1.19 (3H, t, J ϭ 7.5 Hz, H3CCS), 1.13
(3H, t, J ϭ 7.6 Hz, H3CCC-6), 1.06 (3H, d, J ϭ 7.2 Hz,
H3CC-3), 0.99 (3H, t, J ϭ 7.46 Hz, H3CCC-2). 13C NMR
(125 MHz, CDCl3) ␦: 195.8 (s, C-4), 167.5 (s, C-6), 108.4 (s,
C-5), 95.4 (s, C-2), 46.0 (s, C-3), 27.5 (s, CH2C-2), 25.6 (s,
CH2C-6), 22.4 (s, CH2S), 14.5 (q, CH3CS), 12.7 (q, CH3C-3),
11.2 (q, CH3CC-6), 9.4 (q, CH3C-5), 8.4 (q, CH3CC-2).
LR-MS (EI) m/z (relative intensity): 242 ([M]ϩ, 5), 181 (100),
149 (9), 130 (50), 113 (40), 101 (38), 83 (30), 69 (15). HR-MS
m/z calcd for C13H22O2S: 242.1341; found: 242.1339 (EI).
2-Ethyl-3-methyl-5,6,7,8-tetrahydro-4H-chromen-4-one
(11d)
IR ␯
1
(cm–1): 1705, 1660, 1612. H NMR (500 MHz,
max
CDCl3) ␦: 2.56 (2H, q, J ϭ 7.5 Hz, H2CC-2), 2.50–2.47 (2H,
m, H2C-8), 2.44–2.41 (2H, m, H2C-5), 1.93 (3H, s, H3CC-3),
1.81–1.75 (2H, m, H2C-7), 1.71–1.65 (2H, m, H2C-6), 1.20
(3H, t, J ϭ 7.5 Hz, H3CCC-2). 13C NMR (125 MHz, CDCl3)
␦: 179.6 (s, C-4), 164.6 (s, C-2), 162.4 (s, C-8a), 120.2 (s,
C-4a), 118.4 (s, C-3), 27.5 (t, C-8), 25.0 (t, CH2C-2), 22.1 (t,
C-7), 21.8 (t, C-6), 21.1 (t, C-5), 11.7 (q, CH3CC-2), 9.5 (q,
CH3C-3). LR-MS (EI) m/z (relative intensity): 192 ([M]ϩ, 79),
191 (100), 177 (18), 125 (6). HR-MS m/z calcd for C12H16O2:
192.1150; found: 192.1147 (EI).
(2R,3S)-3,5-dimethyl-2-((S)-3-oxopentan-2-yl)-2H-pyran-
4(3H)-one (16)
IBX (24 mg, 0.086 mmol) and ethanedithiol (6 ␮L, 6 mg,
0.07 mmol) were added to a stirred solution of 6 (an approx-
imately 1:1 mixture of anomers; 24 mg, 0.7 mmol) in acetoni-
trile (4 mL) at 80 °C. After 1 day, the solution was diluted with
ethyl acetate and washed with saturated aq NaHCO3 and brine,
dried over Na2SO4, concentrated, and fractionated by PTLC
(50% ethyl acetate in hexanes) to give the title compound
(8 mg, 56%, unoptimized). IR ␯max (cm–1): 1718, 1672, 1623.
1H NMR (500 MHz, CDCl3): ␦ 7.12 (1H, s, HC-6), 4.49 (1H,
dd, J ϭ 3, 10.5 Hz, HC-2), 3.03 (1H, dq, J ϭ 10.5, 7 Hz,
HC-2), 2.64–2.49 (2H, m, H2C-4), 2.40 (1H, dq, J ϭ 3,
7.5 Hz, HC-3), 1.64 (3H, s, H3CC-5), 1.08 (3H, t, J ϭ 7 Hz,
H3C-5=), 1.07 (3H, d, J ϭ 7.5 Hz, H3CC-3), 0.99 (3H, d, J ϭ
7 Hz, H3C-1). 13C NMR (125 MHz, CDCl3) ␦: 212.4 (s, C-3=),
197.2 (s, C-4), 159.0 (d, C-6), 112.8 (s, C-5), 83.2 (d, C-2),
56.0 (d, C-2), 41.0 (d, C-3=), 36.8 (t, C-4), 12.6 (q, C-1), 10.7
(q, CH3C-5), 9.7 (q, CH3C-3), 7.6 (q, C-5=). LR-MS m/z
(relative intensity): 210 ([M]ϩ, 15), 195 (12), 153 (12), 141
(9), 125 (19), 85 (52), 69 (13), 57 (100) (EI). HR-MS m/z calcd
for C12H18O3: 210.1256; found: 210.1248 (EI).
2-Ethyl-3,6-dimethyl-4H-pyran-4-one (11e)
1
IR ␯
(cm–1): 1661, 1603, 1585. H NMR (500 MHz,
max
CDCl3) ␦: 6.05 (1H, s, HC-5), 2.58 (2H, q, J ϭ 7.5 Hz,
H2CC-2), 2.21 (3H, s, H3CC-6), 1.92 (3H, s, H3CC-3), 1.21
(3H, t, J ϭ 7.5 Hz, H3CCC-2). 13C NMR (125 MHz, CDCl3)
␦: 180.3 (s, C-4), 165.7 (s, C-2), 164.6 (s, C-5), 119.6 (s, C-3),
112.6 (d, C-5), 25.0 (t, CH2C-2), 19.8 (q, CH3C-6), 11.6 (q,
CH3C-3), 9.4 (q, CH3CC-2). LR-MS (chemical ionization
(CI)) m/z (relative intensity): 152 ([M]ϩ, 85), 151 (100), 137
(9), 108 (17), 85 (37), 67 (7). HR-MS m/z calcd for C9H12O2:
152.0837; found: 152.0834 (EI).
4,6-Dimethylnonane-3,5,7-trione (12)6,22
IR ␯
(cm–1): 3364, 1711, 1668, 1616. 1H NMR
max
(500 MHz, CDCl3; an approximately 4:1:1 mixture of enol and
two keto (a and b) diastereomers, respectively) ␦: 16.55
(1H, s, HO; enol), 3.85 (0.5H, q, J ϭ 7 Hz, HC-4, HC-6; keto
a), 3.84 (0.5H, q, J ϭ 7 Hz, HC-4, HC-6; keto b), 3.71 (1H, q,
J ϭ 7 Hz, HC-4; enol), 2.60–2.30 (6H, m, H2C-2, H2C-8; keto
and enol), 1.89 (3H, s, H3CC-6; enol), 1.74 (1H, s, H3C-1,
H3C-9; dienol?), 1.34 (3H, d, J ϭ 7 Hz, H3CC-4; keto), 1.32
(1.5H, d, J ϭ 7 Hz, H3CC-4, H3CC-6; keto a or b), 1.31
(1.5H, d, J ϭ 7 Hz, H3CC-4, H3CC-6; keto a or b), 1.16 (3H,
t, J ϭ 7 Hz, H3C-9; enol), 1.12 (1H, t, J ϭ 7 Hz, H3C-1,
H3C-9; dienol?), 1.08–1.02 (6H, m, H3C-1 (enol) and H3C-1,
H3C-9 (keto a and b)). 13C NMR (125 MHz, CDCl3; approx-
imately a 4:1:1 mixture of enol and two keto (a and b)
diastereomers, respectively)) ␦: 206.6, 206.0, 205.8, 204.4,
201.8, 196.5, 184.6, 106.0, 102.7, 57.5, 57.3, 50.2, 33.7, 32.7,
32.0, 28.4, 11.28, 11.27, 11.2, 10.2, 7.0, 6.0, 5.81, 5.76.
LR-MS (EI) m/z (relative intensity): 198 ([M]ϩ, 1), 169 (20),
142 (18), 113 (62), 84 (40), 66 (43), 57 (100). HR-MS m/z
calcd for C11H18O3: 198.1256; found: 198.1267 (EI).
Supplementary data
Supplementary data are available with the article through
the journal Web site http://nrcresearchpress.com/doi/suppl/
10.1139/v2012-067.
Acknowledgements
Financial support from the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) and the University
of Saskatchewan is gratefully acknowledged.
References
(1) Wilk, W.; Waldmann, H.; Kaiser, M. Bioorg. Med. Chem. 2009,
17 (6), 2304. doi:10.1016/j.bmc.2008.11.001.
(2) Sharma, P.; Powell, K. J.; Burnley, J.; Awaad, A. S.; Moses,
J. E. Synthesis 2011, 2865. doi:10.1055/s-0030-1260168.
(3) Yamamura, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1997, 70
(9), 2025. doi:10.1246/bcsj.70.2025.
Published by NRC Research Press

964
(4) Afarinkia, K.; Vinader, V. In Science of Synthesis; Thomas,
E. J., Ed.; Georg Thieme Verlag: Stuttgart, New York, 2003;
Vol. 14, pp 275–346.
(5) Brimble, M. A.; Gibson, J. S.; Sperry, J. In Comprehensive
Heterocyclic Chemistry III; Black, D., Ed. Elsevier: Oxford,
2008; Vol. 7, pp 419–699.
Can. J. Chem. Vol. 90, 2012
(19) Duschek, A.; Kirsch, S. F. Angew. Chem. Int. Ed. 2011, 50 (7),
1524. doi:10.1002/anie.201000873.
(20) More, J. D.; Finney, N. S. Org. Lett. 2002, 4 (17), 3001.
doi:10.1021/ol026427n.
(21) Mullock, E. B.; Suschitzky, H. J. Chem. Soc. C 1967, 828.
doi:10.1039/j39670000828.
(22) (a) Sakakibara, M.; Mori, K. Tetrahedron Lett. 1979, 20 (26),
2401. doi:10.1016/S0040-4039(01)86303-6; (b) Ansell, J. M.;
Hassner, A.; Burkholder, W. E. Tetrahedron Lett. 1979, 20 (27),
2497. doi:10.1016/S0040-4039(01)86330-9; (c) Mori, K.;
Ebata, T.; Sakakibara, M. Tetrahedron 1981, 37 (4), 709. doi:
10.1016/S0040-4020(01)97687-2.
(23) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am.
Chem. Soc. 2004, 126 (16), 5192. doi:10.1021/ja0400382.
(24) (a) Wu, Y. K.; Shen, X.; Huang, J. H.; Tang, C. J.; Liu, H. H.;
Hu, Q. Tetrahedron Lett. 2002, 43 (36), 6443. doi:10.1016/
S0040-4039(02)01346-1; (b) Shukla, V. G.; Salgaonkar, P. D.;
Akamanchi, K. G. Synlett 2005, 1483. doi:10.1055/s-2005-
868496.
(25) (a) Luiken, S.; Kirschning, A. J. Org. Chem. 2008, 73 (5), 2018.
doi:10.1021/jo7025146; (b) Field, L.; Barbee, R. B. J. Org.
Chem. 1969, 34 (1), 36. doi:10.1021/jo00838a010.
(26) Gallen, M. J.; Goumont, R.; Clark, T.; Terrier, F.; Williams,
C. M. Angew. Chem. Int. Ed. 2006, 45 (18), 2929. doi:10.1002/
anie.200504156.
(27) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43 (14),
2923. doi:10.1021/jo00408a041.
(28) Reynolds, W. F.; Enríquez, R. G. J. Nat. Prod. 2002, 65 (2),
221. doi:10.1021/np010444o.
(29) The multiplicity of 13C NMR signals refers to the number of
attached Hs (i.e., s ϭ C, d ϭ CH, t ϭ CH2, q ϭ CH3).
(30) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999,
64 (12), 4537. doi:10.1021/jo9824596.
(31) Brown, C. A. Synthesis 1975, 1975 (05), 326. doi:10.1055/s-
1975-23746.
(6) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1990, 31 (39), 5619. doi:10.1016/S0040-4039(00)97913-9.
(7) Lister, T.; Perkins, M. V. Angew. Chem. Int. Ed. 2006, 45 (16),
2560. doi:10.1002/anie.200504573.
(8) Sakakura, A.; Watanabe, H.; Nakagawa, S.; Ishihara, K. Chem.
Asian J. 2007, 2 (4), 477. doi:10.1002/asia.200600380.
(9) Sakakura, A.; Watanabe, H.; Ishihara, K. Org. Lett. 2008, 10
(12), 2569. doi:10.1021/ol800860p.
(10) (a) Paterson, I.; Chen, D. Y.-K.; Acena, J. L.; Franklin, A. S.
Org. Lett. 2000, 2 (11), 1513. doi:10.1021/ol000027n;
(b) Paterson, I.; Chen, D. Y.-K.; Franklin, A. S. Org. Lett. 2002,
4 (3), 391. doi:10.1021/ol017082w; (c) Yadav, J. S.; Sathaiah,
K.; Srinivas, R. Tetrahedron 2009, 65 (17), 3545. doi:10.1016/
j.tet.2008.12.049.
(11) Dorman, L. C. J. Org. Chem. 1967, 32 (12), 4105. doi:10.1021/
jo01287a101.
(12) Koreeda, M.; Akagi, H. Tetrahedron Lett. 1980, 21 (13), 1197.
doi:10.1016/S0040-4039(00)71369-4.
(13) (a) Gillingham, D. G.; Hoveyda, A. H. Angew. Chem. Int. Ed.
2007, 46 (21), 3860. doi:10.1002/anie.200700501; (b) Jung,
M. E.; Salehi-Rad, R. Angew. Chem. Int. Ed. 2009, 48 (46),
8766. doi:10.1002/anie.200904607.
(14) McCombie, S. W.; Metz, W. A.; Nazareno, D.; Shankar, B. B.;
Tagat, J. J. Org. Chem. 1991, 56 (16), 4963. doi:10.1021/
jo00016a028.
(15) Mizuno, A.; Kusama, H.; Iwasawa, N. Chem. Eur. J. 2010, 16
(28), 8248. doi:10.1002/chem.201001068.
(16) Beye, G. E.; Ward, D. E. J. Am. Chem. Soc. 2010, 132 (20),
7210. doi:10.1021/ja102356j.
(17) Becerril-Jiménez, F.; Ward, D. E. Org. Lett. 2012, 14 (6), 1648.
doi:10.1021/ol300432y.
(32) Rama Rao, A. V.; Venkatswamy, G.; Javeed M., S. M.;
Deshpande, V. H.; Ramamohan Rao, B. J. Org. Chem. 1983, 48
(9), 1552. doi:10.1021/jo00157a039.
(18) Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett. 2005, 7
(6), 1181. doi:10.1021/ol050195l.
(33) Wittek, P. J.; Hindley, K. B.; Harris, T. M. J. Org. Chem. 1973,
38 (5), 896. doi:10.1021/jo00945a010.
Published by NRC Research Press