Enantioselective Synthesis of 3,4-Dihydropyran-2-ones via Phase-Transfer-Catalyzed Addition-Cyclization of Acetylacetone to Cinnamic Thioesters

Article abstract of DOI:10.1021/acs.joc.9b03216

Herein, we present the first example of synthesis of 3,4-dihydropyran-2-ones from cinnamic thioesters via a stereoselective phase-transfer-catalyzed domino Michael-cyclization reaction with acetylacetone. The reaction proceeded under the catalysis of Cinchona-derived quaternary ammonium phenoxide that, in combination with inorganic bases, provided 3,4-dihydropyran-2-ones in yields of up to 93% and enantioselectivities of up to 88% enantiomeric excess.

Full text of DOI:10.1021/acs.joc.9b03216

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Article
Enantioselective synthesis of 3,4-dihydropyran-2-ones via PTC
addition-cyclisation of acetylacetone to cinnamic thioesters
Dario Destro, Carlo Bottinelli, Ludovica Ferrari, domenico carlo maria albanese,
Grazia Bencivenni, Malachi Gillick Healy, Brian Kelly, and Mauro F. A. Adamo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03216 • Publication Date (Web): 13 Feb 2020
Downloaded from pubs.acs.org on February 14, 2020
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Enantioselective synthesis of 3,4-dihydropyran-2-ones via
PTC addition-cyclisation of acetylacetone to cinnamic
thioesters
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Dario Destro,a Carlo Bottinelli,b Ludovica Ferrari,b Domenico C. M. Albanese,b Grazia Bencivenni,a Malachi W. Gillick-
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Healy,a Brian G. Kelly,c and Mauro F. A. Adamoa*
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a Centre for Synthesis and Chemical Biology (CSCB), Department of Chemistry, Royal College of Surgeons in Ireland, 123
St. Stephen’s Green, Dublin 2, Ireland. Tel: (+353) 1 4022208; E-mail: madamo@rcsi.ie; b Università degli Studi di Milano,
Department of Chemistry, via Golgi 19, 20133, Milano, Italia; Kelada Pharmachem. Ltd. A1.01, Science Centre South,
c
Belfield, Dublin 4, Ireland.
KEYWORDS: Phase Transfer Catalysis, Desymmetrisation, Michael Initiated Cyclisation Reactions
ABSTRACT: Herein we present the first example of synthesis of 3,4-dihydropyran-2-ones from cinnamic thioesters via a
stereoselective phase-transfer catalysed domino Michael-cyclisation reaction with acetylacetone. The reaction proceeded
under the catalysis of Cinchona-derived quaternary ammonium phenoxide that in combination with inorganic bases provided
3,4-dihydropyran-2-ones in yields of up to 93% and enantioselectivities of up to 88% ee.
nucleophile from ketene silyl acetal precursors (Scheme
INTRODUCTION
2a).9 The ammonium enolates, so obtained, reacted with
3,4-Dihydropyran-2-ones
3
(Scheme 1) are widely
chalcones to provide, after cyclisation, 3,4-dihydropyran-2-
ones with high enantioselectivity.
recognised as useful building blocks for the synthesis of
valuable classes of organic compounds, such as 2-pyrones,1–
Scheme 2: Stereoselective syntheses of chiral substituted
3,4-dihydropyran-2-ones 3.
3
γ-lactones,3 cyclic enamines,4 functionalised enones.5 The
preparation of heterocycles 3 has been a subject of study for
more than two decades.6 The majority of the reported
methods revolved around disconnecting the C4–C5 and C6–
O1 (Scheme 1). This approach identified synthons syn-(i-iv)
as the required building blocks to form 3,4-dihydropyran-2-
ones 3. For example, the reaction of an ester enolate
equivalent syn-(i) with an α,β-unsaturated carbonyl
compound syn-(ii) has been the most frequently reported
method (Scheme 1, path a); the presence of a good leaving
group (LG) on the nucleophilic component was found to be
essential for the cyclisation to take place. A complementary
route is represented by the reaction of a carbonyl enolate
syn-(iii) and a cinnamate equivalent syn-(iv) (Scheme 1,
path b), where LG- represents an imidazole.7,8
Scheme 1: Frequent disconnections adopted for the
assembly of 3,4-dihydropyran-2-ones 3.
Arylacetyl phosphonates reacted with α,β-unsaturated-γ-
keto esters under the catalysis of
a
bifunctional
OR
O
+
aminothiourea providing syn-3,4-dihydropyran-2-ones in
moderate yields, high enantio- and diastereoselectivity.10
Preparation of 3 via NHC catalysis has been reported
(Scheme 2, b-c).11,12 The reaction of α,β-unsaturated
aldehydes and α,β-unsaturated ketones offered an
alternative route to assembling the 3,4-dihydropran-2-one
core 3 based upon disconnecting the C3–C4 and the C6–O1
bonds. This reaction proceeded in the presence of a N-
heterocyclic carbenes (NHC) and an organic base;14 α,β-
unsaturated aldehydes reacted 1,3-dicarbonyls under NHC-
catalysis and in the presence of an additional oxidant
(Scheme 2, b–c).15 NHC catalysts have displayed
R1
R2
syn-(ii)
LG
O
a
b
syn-(i)
O
4
R1
R2
6
OR
O
5
+
50
51
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53
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57
58
59
60
R1
syn-(iii)
LG
R2
syn-(iv)
3
Organocatalytic methodologies have been optimised to
provide 3 via disconnecting C4–C5 and C6–O1.7–13 In this
context, Mukaiyama reported a domino Michael–cyclisation
procedure that was catalysed by Cinchona-derived
quaternary ammonium phenoxides. In this transformation,
the phenoxide nucleophile was used to unleash an enolate
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exceptional activity for a large number of substrates and
demonstrated that compound 3a could be obtained in good
under various reaction conditions; most notably in their
applications in biphasic aqueous/organic systems.11,12,15
However, in spite of the high ees which have been reported,
it should be noted that the preparation of chiral NHCs
involve several steps and therefore are less expeditious
when compared to other types of organocatalytic systems,
for example phase transfer catalysis using Cinchona-based
quaternary ammonium species. Moreover, very reactive
starting materials11,16 and the use of stoichiometric
oxidants15 constitute an important limitation, which has
restricted the scope of NHC-catalysed methodologies. In
this context, the development of a new and mild catalytic
approach for the formation of 3,4-dihydropyran-2-ones fills
a gap in the state of the art, providing an easy-to-execute
procedure to access important compounds. Herein we report
the first stereoselective synthesis of 3,4-dihydropyran-2-
ones 3 from cinnamic thioesters 1 which proceeds via a
phase-transfer catalysed domino Michael–lactonisation
reaction with acetylacetone 2; where the phase-transfer
catalysts (PTC) are Cinchona-derived quaternary
ammonium salts (Scheme 2).
isolated yields, however enantioselectivity was limited to
38% ee. Since this initial set of experiments it was noted
that the reaction time should be prolonged to 48h to achieve
maximal yield in compound 3a. This additional time was
required to aloow lactonisation to occur.
3
4
5
6
7
8
9
Table 1 Screening of Cinchona-derived quaternary
ammonium salts a
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16
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(R)
(R)
Br-
Ph
Br-
R1
OCH3
OCH3
R2
(R)
Br-
H
H
N
N
(S)
(R)
(S)
(R)
OH
N
OH
(S)
OH
(R)
R1
H
N
N
N
4a: R1 = C6H5; R2 = H
4b: R1 = C6H5; R2 = OCH3
5a: R1 = C6H5
5b: R1 = C6F5
6
4c: R1 = 9-anthracenyl; R2 = OCH3
4d: R1 = 3,5-(tBu)2C6H3; R2 = OCH3
4e: R1 = 4-(CF3)C6H4; R2 = OCH3
4f: R1 = 3,5-(CF3)2C6H4; R2 = OCH3
4g: R1 = 2-(OCH3)C6H4; R2 = OCH3
Entry
Catalyst
4a
t (h)
72
48
48
24
48
48
48
48
48
44
Yield (%)b
ee (%)c
27 (S)
18 (R)
38 (S)
20 (R)
-
1
2
50
53
63
65
-
5a
RESULTS AND DISCUSSION
3
4b
5b
4c
We initially attempted the cyclisation of cinnamic thioester
1a and acetylacetone (2) in the presence of an ammonium
phase transfer catalyst—tetrabutylammonium bromide
(TBAB)—with potassium carbonate as the base and
dichloromethane as the solvent. We found those conditions
to furnish the desired 3,4-dihydropyran-2-one 3a in 74%
isolated yield. The dependence of the reaction on PTC was
supported by the control reaction which showed no
conversion to 3a in the absence of TBAB (Scheme 3).
4
5
6
4d
4e
60
50
20
64
61
28 (S)
35 (S)
35 (S)
33 (S)
37 (S)
7
8
4f
9
4g
10
6
Scheme 3: Michael addition of acetylacetone 2 to cinnamic
thioester 1a promoted by ammonium phase transfer
catalyst.
a
Reaction conditions: 1a (0.10 mmol), acetylacetone 2
(0.12 mmol), K2CO3 (0.10 mmol), catalyst 4a–g, 5 or 6
b
(0.01 mmol), solvent (1 mL), 48h. Isolated yield after
TBAB (10 mol%)
K2CO3 (1.0 eq.)
column chromatography. c Determined by HPLC (Chiralpak
AD).
O
O
O
O
O
Ph
S
Ph
DCM, RT, 24 h
Ph
1a
2
O
3a
This study identified ammonium salt 4b as the catalyst
providing 3a in highest ees. In a following optimisation
step, we reacted 1a and 2 to provide 3a under the catalysis
of 4b in the presence of various bases and solvent systems.
(Table 2). When the reaction was carried out using cesium
fluoride as the base (Table 2, entry 1), the yield of the
model reaction was poor with 3a obtained in just 10% yield
and 21% ee. Potassium phosphate gave a significant
improvement, providing 3a in 61% yield and 41% ee (Table
2, entry 2). Potassium hydroxide produced similar
enantioselectivity (46% ee) but reduced yield (33%). When
lithium hydroxide was tested as the base, there was no
conversion towards 3a (Table 2, entry 4). Tetrahydrofuran,
toluene, diethyl ether, 1,4-dioxane and DCM were tested as
solvents—with potassium carbonate as a base and 48 h of
reaction time—however, none of those solvents produced
results superior to that achieved with dichloromethane,
74% yield with TBAB
(no conversion without TBAB)
We then considered using chiral phase-transfer catalysis to
impart an enantioselective outcome to this reaction. Our
research group has recently described some highly
enantioselective Michael Initiated Cyclisation Reactions
(MICR), which proceed in the presence of chiral Cinchona-
derived quaternary ammonium salts.17–24 Salts of
Quininium/Cinchonidinium 4, Quinidinium
5
and
Dihydroquinidinium 6 can be easily prepared in a single
step by quaternisation of cheap, commercially available
Cinchona alkaloids with a variety of alkylating agents.17–24
Cinchona alkaloids are convenient materials for
organocatalysis, and have been preferred to other classes of
chiral ammonium salts, which require longer syntheses.25
With this in mind, we screened a range of Cinchona-derived
PTCs 4a–g, 5a–b and 6 (Table 1) in the model reaction of
cinnamic thioester 1a and acetylacetone 2. This study
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which provided 3a in 63% yield and 38% ee (Table 2,
entries 5–9).
9
6
44
64
79 (S)
a
Reaction conditions: 1a (0.10 mmol), acetylacetone (0.12
mmol), base (0.10 mmol), catalyst (0.01 mmol), phenol
(0.01 mmol), DCM (1 mL). Isolated yield after column
chromatography. Determined by HPLC (Chiralpak AD).
b
Table 2 Screening of bases and solvents a
c
d
O
4b
(10 mol%)
No phenol added.
O
O
O
O
base (1.0 eq.)
Ph
Hence, the Michael addition of glycine imides to methyl
acrylate were significantly influenced by addition of a softer
base relay such as a phenolate, which suppressed the
undesired uncatalysed background reaction.26 Adapting the
procedure reported by Lygo and co-workers, Cinchona-
derived quaternary ammonium phenoxides (10 mol%) were
generated in situ by stirring a mixture of the ammonium
bromide salts with co-catalytic amounts of phenol and a
stoichiometric amount of K2CO3 at 0 °C for 30 min, before
warming to room temperature and completing the addition
of the cinnamic thioester 1a and acetylacetone 2. This
protocol was applied to the model reaction using a suite of
PTCs (Table 3). Significantly, when compounds 1a and 2
were reacted in the presence of catalyst 4a the addition of
phenolate provoked a significant improvement of the
observed enantioselectivity for 3a, which increased from
23% ee to 45% ee (Table 3, entries 1 and 2). Phenolate
addition to catalysts 4b, 4d and 4e (Table 3, entries 3, 5 and
6) improved their performed equally well, providing desired
3a in significantly higher ees when compared to data
obtained without the phenolate (Table 1). We reasoned that
the anthracenyl-substituted catalyst 4c may have been too
sterically encumbered to allow the reaction to proceed.
Ph
S
Ph
solvent (0.1 M),
RT
9
1a
2
O
10
11
12
13
14
15
16
17
18
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20
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22
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50
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59
60
(S)-3a
Yield
(%)b
Entry
Base
Solvent
t (h)
ee (S, %)c
1
2
3
4
5
6
7
CsF
DCM
DCM
DCM
DCM
toluene
THF
44
45
46
48
48
48
48
10
61
33
-
21
41
46
-
K3PO4
KOH
LiOH
K2CO3
K2CO3
K2CO3
25
53
11
37
28
16
Et2O
1,4-
dioxane
8
9
K2CO3
K2CO3
48
48
58
63
17
38
DCM
a Reaction conditions: 1a (0.10 mmol), acetylacetone (0.12
b
mmol), base (0.10 mmol), 4b (10 mol%), solvent (1 mL).
c
Isolated yield after column chromatography. Determined
by HPLC (Chiralpak AD).
At this point, we considered the addition of a phenolate
additive. Lygo and co-workers have reported the use of
phenolates to impart improved stereoselectivity to certain
types of Cinchona-derived PTC-catalysed Michael
additions that, using strongly activated electrophilic
alkenes, progressed via a base catalysed (hence unselective)
background pathway.
Table 4 Screening of bases and solvents in the
presence of phenol co-catalyst a
O
1) 4b (10 mol%),
phenol (0.1 eq.),
base (1.0 eq.)
solvent (0.1 M), 0 °C, 30 min
O
O
O
O
Ph
Ph
S
R1
Table 3 Screening of catalysts in presence of phenol
2) 1a and 2
solvent (0.1 M), RT, 48 h
1a
2
O
co-catalyst a
(S)-3a
Yield
Entry
Base
Solvent
t (h)
ee (S, %)c
(%)b
1
2
K2CO3
KOH
DCM
DCM
36
48
48
44
44
44
47
50
60
73
71
20
41
16
66
35
80
74
78
70
49
59
81
86
3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DCM
4
toluene
Entry
Catalyst
4a
t (h)
40
40
36
44
44
44
36
44
Yield (%)b
ee (%)c
23 (S)
45 (S)
80 (S)
-
5
THF
1d
2
3
4
5
6
7
8
41
30
62
0
6
CPMEd
DCM
7e
4a
8
CHCl3
4b
a
Reaction conditions: 1a (0.10 mmol), acetylacetone (0.12
mmol), base (0.10 mmol), 4b (0.01 mmol), solvent (1 mL).
b Isolated yield after column chromatography. c Determined
4c
4d
52
30
60
0
80 (S)
82 (S)
78 (R)
-
4e
d
by HPLC (Chiralpak AD). CPME = cyclopentyl methyl
ether. e anhydrous and anaerobic conditions.
5a
5b
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Considering that the presence of phenolate impacted on the
provided compound 3a in
a
significantly reduced
catalyst active concentration and basicity of the reaction
media, a further base/solvent screening was run to ascertain
if higher level of enantioselectivity could be obtained
(Table 4). In this study a small selection of bases, such as
K2CO3, Cs2CO3 and KOH, were selected and were tested in
a suitably wide range of solvent. This study identified
K2CO3 as the best base promoting formation of desired
compound 3a in up to 80% ees (Table 4, entries 1, 7 and 8).
When the reaction was run in chloroform compound 3a was
obtained in highest 86% ees, but in a reduced 35% yield
(Table 4, entry 8). Running the reaction under inert N2
atmosphere did not have an impact on both yield and
enantioselectivity (Table 4, compare entries 1 and 7).
Hence, DCM and K2CO3 were finally selected as the
optimal solvent / base system for the preparation of 3a.
enantioselectivity. In contrast, when additives with similar
acidity to phenol were employed, i.e. 4-Br-phenol and 2-
naphthol (Table 5; entries 5 and 7), 3a was obtained in
similarly high ees. Ultimately, unsubstituted phenol was
identified as the optimal additive for this reaction. A control
experiment in which only 0.1 equiv of inorganic base was
used, which provided the desired compound 3a in only
17%, but in increased 88% ee; meanwhile, reacting 3a and
1 in the presence of 4b and one equivalent of potassium
phenoxide provided no conversion. These experiment
proved that there is, albeit minimal, a contribution from an
uncatalysed background reaction under the optimised
conditions.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In order to demonstrate scope of the reaction, an array of
cinnamic thioesters 1a–l were reacted with 2 under the
optimised reaction conditions (Table 6). Cinnamic
thioesters with electron withdrawing groups reacted equally
well, providing their target compounds in nominally high
isolated yields and good enantioselectivities (Table 6;
entries 2–4, 6–7, 10–12). Conversely, cinnamic thioester 1e
bearing electron-donating methoxy reacted sluggishly,
providing the resulting product with moderate yield and as
essentially a racemic mixture (Table 6, entry 5). A naphthyl
substituent proved to be too sterically encumbering for the
reaction to proceed (Table 6, entry 9). Reaction of aliphatic
-unsaturated thioesters 1m and 1n and 2 under optimised
conditions provided correspondent 3m and 3n in good
Table 5 Co-catalyst screening under optimised
conditions a
O
4b
1)
(10 mol%),
co-catalyst (0.1 eq.),
K2CO3 (1.0 eq.)
DCM (0.1 M), 0 °C, 30 min
O
O
O
O
Ph
Ph
S
R1
1a
2
and
2)
DCM (0.1 M), RT, 48 h
O
1a
2
(S)-3a
pKa
Entry
co-catalyst
t (h) Yield (%)b ee (S, %)c
9.95
7.00
1
2
3
phenol
36
48
48
60
40
50
80
40
73
thiophenol
yields
and
enantioselectivity,
demonstrating
the
10.20
11.10
4-OCH3-phenol
2,4,6-
trimethylphenol
4-bromophenol
4-nitrophenol
2-naphthol
applicability of the methodology reported herein to the
preparation of aromatic and aliphatic title compounds.
Table 6 Substrate scope under optimised conditions a
4
40
75
67
9.32
7.14
9.50
5
6
7
44
46
44
45
30
54
77
56
77
O
1) 4b (10 mol%),
phenol (0.1 eq.),
K2CO3 (1.0 eq.)
O
O
O
O
Ph
R1
DCM (0.1 M), 0 °C, 30 min
S
R1
a Reaction conditions: 1a (0.10 mmol), acetylacetone (0.12
mmol), base (0.10 mmol), 4b (0.01 mmol), additive (0.01
mmol), DCM (1 mL); Nitrogen atmosphere and dry DCM
2) 1a-l and 2
DCM (0.1 M), RT, 48 h
1a–l
2
O
(S)-3a–l
Entry Product
R1
Ph
Yield (%)b
ee (S, %)c
b
were used. Isolated yield after column chromatography;
apart from the desired product, only unreacted starting
1
2
3a
3b
3c
3d
3e
3f
82
78
72
72
44
93
93
75
-
77
88
57
82
5
c
material was isolated. Determined by HPLC (Chiralpak
2-ClC6H4
3-ClC6H4
4-ClC6H4
AD).
3
A screening of phenolic co-catalysts was also performed
using the optimised reaction conditions identified in Table 4
for the benchmark reaction of cinnamic thioester 1a and
acetylacetone 2 (Table 5). When thiophenol was used as the
additive compound (S)-3a was obtained in 40% yield and in
a reduced 40% ee (Table 5, entry 2). Anisole, 4-
bromophenol, 4-nitrophenol, and β-naphthol, each provided
compound (S)-3a in 30–50% yield and 56–77% ee; i.e. also
inferior to phenol (Table 5; entries 3, 5–7). In the case of
2,4,6-trimethylphenol, however, (S)-3a was obtained in
slightly higher yield of 75%, but reduced enantioselectivity
of 67% ee. We have reported (Table 5) the pKa values of
the additives.27 A comparison of the pKa of the additive
used and the observed ees for 3a indicated a link between
these figures. Hence additives more acidic than phenol, i.e.
thiophenol and 4-NO2-phenol (Table 5; entries 2 and 6),
4
5
4-(OMe)C6H4
4-FC6H4
6
80
83
76
-
7
3g
3h
3i
4-CF3C6H4
4-MeC6H4
1-naphthyl
2-furyl
8
9
10
11
12
13
14
3j
75
55
80
72
74
76
77
88
78
77
3k
3l
5-methylfur-2-yl
Thiophenyl
CH3(CH2)2
CH3
3m
3n
a
Reaction conditions: 1a–l (0.10 mmol), 2 (0.12 mmol),
base (0.10 mmol), 4b (10 mol%), phenol (0.01 mmol),
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b
DCM (1 mL), 48 h under nitrogen atmosphere. Isolated
Cinnamic thioesters have been scarcely investigated, with
only one report in the literature describing their use in the
preparation of amino acid derivatives.29 Therefore the
chemistry described herein proposes thioesters as an
efficient synthetic handle to impart improved reactivity with
cinnamates in Michael reactions. Furthermore, introduction
of a phenolate anion to the reaction manifold dramatically
improved reaction performance, which indicated that the
basic anion facilitates formation of the enolate complex 5.
The use of Cinchona-derived ammonium phenolate PTCs
permitted access to a range of chiral 3,4-dihydropyran-2-
ones 3 in up to 93% yield and 88% ee. The substrate scope
of this new transformation was found to tolerate a range of
electron rich and electron poor functional groups, providing
3 in generally good yield and enantioselectivity for the
range of cinnamic thioesters tested.
c
yield after column chromatography. Determined by chiral
HPLC (Chiralpak AD).
Use of ethyl acetoacetate 11 as the Michael donor, with
potassium phosphate as the base, provided the
corresponding 3,4-dihydropyran-2-one (S)-3m (Scheme 4)
in 21% yield and 75% ee, where the absolute
stereochemistry was confirmed by previously reported
literature.28
9
10
11
12
13
Scheme 4: Preparation of (S)-3m
O
O
Ph
(0.1 eq.)
4b
O
S
Ph
1a
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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53
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59
60
Phenol (0.1 eq.)
K3PO4 (1.0 eq.)
DCM (0.1 M), rt, 48h
Ph
3o
21% yield
75% ee
O
O
EtO
O
OEt
11 (3 eq.)
The proposed catalytic cycle for the domino Michael–
lactonisation process (Scheme 5) is proposed to start via
deprotonation of acetylacetone 2 by a basic phenoxide
anion of chiral quaternary ammonium phenoxide salt 10.
The resulting chiral ammonium–enolate complex 5 then
EXPERIMENTAL SECTION
Materials and Methods: NMR experiments were
performed on a Bruker Avance 400 instrument and samples
were obtained in CDCl3 (referenced to 7.26 ppm for 1H and
77.0 for 13C) and in DMSO-d6 (referenced to 2.52 and 3.35
performs
a stereoselective Michael addition to the
1
ppm for H and 40.0 for 13C). Coupling constants (J) are in
electrophilic olefin moeity of cinnamic thioester 1a, where
the enantiofacial selectivity is directed by the interaction of
the enolate 5 with the chiral Cinchona-derived cation. The
resulting intermediate 7 proceeds via an intramolecular
proton transfer to form intermediate 8, which finally
undergoes enantioselective lactonisation to give 3,4-
dihydropyran-2-one (3a). The resulting chiral ammonium
thiophenolate 9 may then undergo an ion exchange to
reform 10, thus completing the catalytic cycle.
Hz. Multiplicities are reported as follows: s, singlet; d,
doublet; dd, doublets of doublets; t, triplet, q; quartet, m,
multiplet; c, complex; and br, broad. The enantiomeric
excess (ee) of the products was determined by chiral
stationary phase HPLC (Daicel Chiralpak AD, Chiralcel
OD), using a UV detector operating at 254 nm.
Tetrahydrofuran was freshly distilled over sodium
benzophenone prior to use according to standard procedure.
All other reagents and solvents were used as purchased
from Aldrich. Reactions were monitored for completion by
TLC (EM Science, silica gel 60 F254). Flash
chromatography was performed using silica gel 60 (0.040–
0.063 mm, 230–400 mesh). Retention factors (Rf) are
reported to ± 0.05. Mass spectra and HRMS were recorded
using a MALDI ToF mass spectrometer. Catalysts 4a–e,
5a–b, and 6 were prepared according to the procedures
reported by Lygo30 and Corey.31
Scheme 5: Proposed catalytic cycle for the stereoselective
formation of 3
R4N+
O
O
O
PhOH
O
O
Ph
PhS
Michael
1a
2
5
proton
transfer
addition
PhO R4N+
10
PhS
O
O
R4N+
PhS
anion
exchange
O
H
PhO
Ph
General procedure A: for the stereoselective synthesis of
3,4-dihydropyran-2-ones (3a–n).
PhS R4N+
7
9
proton
transfer
R4N+
O
In
a
10 mL test tube N-benzylquininium bromide
lactonisation
O
(0.02 mmol), K2CO3 (0.20 mmol) and phenol (0.02 mmol)
were dissolved in dry DCM (1.8 mL) and the resulting
purple reaction mixture was stirred for 30 min at 0 °C.
Cinnamic thioester 1a (0.20 mmol) and acetylacetone
(41 μL, 0.40 mmol) were added and the reaction was
allowed to warm to room temperature and stirred for 48 h
under nitrogen. The solvent was evaporated in vacuo and
the crude was purified by silica flash chromatography
(AcOEt : petroleum ether, 1 : 5). Pure 3,4-dihydropyran-2-
ones 3a–l were obtained as solid materials.
O
O
O
PhS
Ph
R4N+
derived cation
=
Cinchona-
Ph
O
H
3a
(
)-
S
8
In conclusion, a new synthesis of 3,4-dihydropyran-2-ones
starting from cinnamic thioesters 3 and acetylacetone was
uncovered and optimised, where the reaction proceeds
exclusively in the presence of quaternary ammonium PTCs
and a stoichiometric base. Cinnamic esters are known to be
poor Michael acceptors, for which reason a number of
cinnamic ester synthetic equivalents, including 4-nitro-5-
styrylisoxazoles,17 have been developed.
General procedure B: for the racemic synthesis of 3,4-
dihydropyran-2-ones (3a–n).
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In a 10 mL test tube cinnamic thioester 3a–l (0.20 mmol),
(S)-5-Acetyl-4-(4-chlorophenyl)-6-methyl-3,4-
dihydropyran-2-one (3d).
TBAB (0.02 mmol), K2CO3 (0.20 mmol) and phenol
(0.02 mmol) were dissolved in dry DCM (1.8 mL).
Acetylacetone (0.40 mmol) was added and the reaction
mixture was stirred for 24 h under nitrogen. After
evaporation of the solvent, crude mixture was purified by
silica flash chromatography (AcOEt : petroleum ether,
1 : 5).
Yellow wax, 38 mg, 72% yield (general procedure A), 35
1
mg, 67% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.34 – 7.29 (m, 2H), 7.12 – 7.06 (m, 2H), 4.17 –
4.12 (m, 1H), 2.96 (dd, J = 15.7, 7.2 Hz, 1H), 2.81 (dd, J =
15.7, 2.5 Hz, 1H), 2.43 (s, 3H), 2.14 (s, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 197.5, 165.3, 160.7, 138.3,
133.9, 129.6, 128.1, 117.2, 38.2, 37.0, 31.6, 29.9, 29.7,
22.7, 19.2, 14.1 ppm. HRMS m/z: [M+H]+ calcd for
C14H14ClO3 265.0631; found 265.0636. Chiral HPLC
(Chiralpak OD, n-hexane/ethanol 95 : 5, 1 mL/min 82% ee);
retention time = 17.74 min, 22.51 min. Physical and spectral
data agreed with the literature values.33
9
10
11
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14
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(S)-5-Acetyl-6-methyl-4-phenyl-3,4-dihydropyran-2-one
(3a).
White solid, m.p. 69-71 °C, 38 mg, 82% yield (general
1
procedure A), 20 mg, 44% yield (general procedure B). H
NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 3H), 7.18 – 7.12
(m, 2H), 4.18 – 4.13 (m, 1H), 2.98 (dd, J = 15.7, 7.2 Hz,
1H), 2.84 (dd, J = 15.7, 2.6 Hz, 1H), 2.43 (s, 3H), 2.13 (s,
3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 198.1, 165.7,
160.4, 129.5, 127.6, 126.7, 117.3, 38.9, 38.8, 37.2, 29.6,
19.1 ppm. FTIR (cm-1): 3024, 2924, 1774, 1689, 1627,
1489, 1442, 1357, 1026, 948, 864. HRMS m/z: [M+H]+
calcd for C14H15O3 231.1021; found 231.1018. Chiral
HPLC (Chiralpak AD, n-hexane/ethanol 95 : 5, 1 mL/min,
76% ee); retention time = 15.96 min, 17.22 min. Physical
and spectral data agreed with the literature values.32
(S)-5-Acetyl-4-(4-methoxyphenyl)-6-methyl-3,4-
dihydropyran-2-one (3e)
Yellow wax, 23 mg, 44% yield (general procedure A), 9
1
mg, 17% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.02 – 6.96 (m, 2H), 6.82 – 6.76 (m, 2H), 4.05 –
4.01 (m, 1H), 3.71 (s, 3H), 2.87 (dd, J = 15.6, 7.1 Hz, 1H),
2.74 (dd, J = 15.6, 2.6 Hz, 1H), 2.35 (s, 3H), 2.05 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 202.8, 175.6, 158.8,
131.3, 129.1, 127.8, 114.8, 114.2, 55.2, 40.5, 38.9, 29.9,
19.1. HRMS m/z: [M+H]+ calcd for C15H17O4 261.1127;
found 261.1130. Chiral HPLC (Chiralpak AD, n-
hexane/ethanol 95 : 5, 1 mL/min, 5% ee); retention time =
20.75 min, 32.00 min. Physical and spectral data agreed
with the literature values.34
(R)-5-Acetyl-4-(2-chlorophenyl)-6-methyl-3,4-
dihydropyran-2-one (3b).
Yellow wax, 41 mg, 78% yield (general procedure A), 39
1
mg, 72% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.45 – 7.43 (m, 1H), 7.26 – 7.21 (m, J = 6.4, 2.5
Hz, 2H), 7.06 – 7.02 (m, 1H), 4.64 (dd, J = 6.7, 2.0 Hz, 1H),
2.96 (dd, J = 15.8, 6.7 Hz, 1H), 2.90 (dd, J = 15.8, 2.0 Hz,
1H), 2.47 (s, 3H), 2.07 (s, 3H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 197.6, 165.3, 161.6, 136.3, 133.1, 130.6,
129.5, 127.9, 127.4, 116.0, 35.6, 34.9, 29.3, 19.1 ppm.
HRMS m/z: [M+H]+ calcd for C14H14ClO3 265.0631; found
265.0635. Chiral HPLC (Chiralpak AD, n-hexane/ethanol
95 : 5, 1 mL/min 88% ee); retention time = 21.31 min,
22.96 min. Physical and spectral data agreed with the
literature values.33
(S)-5-Acetyl-4-(4-fluorophenyl)-6-methyl-3,4-
dihydropyran-2-one (3f).
Yellow solid, 46 mg, 93% yield (general procedure A), 33
1
mg, 66% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.15 – 7.08 (m, 2H), 7.07 – 6.97 (m, 2H), 4.19 –
4. 14 (m, 1H), 2.96 (dd, J = 15.7, 7.2 Hz, 1H), 2.81 (dd, J =
15.7, 2.5 Hz, 1H), 2.43 (s, 3H), 2.14 (s, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 197.6, 165.5, 163.5, 162.3 (d, J
= 247.0 Hz), 135.5, 135.4, 128.4 (d, J = 8.2 Hz), 117.4,
116.4 (d, J = 21.6 Hz), 38.1, 37.2, 37.2, 29.9, 19.2 ppm. 19
F
NMR (376 MHz, CDCl3) δ –114.37 ppm. HRMS m/z:
[M+H]+ calcd for C14H14FO3 249.0927; found 249.0929.
Chiral HPLC (Chiralpak AD, n-hexane/ethanol 95 : 5,
1 mL/min, 80% ee); retention time = 14.92 min, 19.55 min.
Physical and spectral data agreed with the literature
values.33
(S)-5-Acetyl-4-(3-chlorophenyl)-6-methyl-3,4-
dihydropyran-2-one (3c).
Orange wax, 38 mg, 72% yield (general procedure A), 26
1
mg, 50% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.29 – 7.26 (m, 2H), 7.14 (s, 1H), 7.06 – 7.01 (m,
1H), 4.18 – 4.13 (m, 1H), 2.97 (dd, J = 15.7, 7.3 Hz, 1H),
2.83 (dd, J = 15.7, 2.5 Hz, 1H), 2.45 (s, 3H), 2.16 (s, 3H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 197.3, 165.2,
160.9, 141.8, 135.3, 130.8, 128.3, 127.0, 124.8, 116.9, 38.4,
36.9, 30.0, 19.3 ppm. HRMS m/z: [M+H]+ calcd for
C14H14ClO3 265.0631; found 265.0633. Chiral HPLC
(Chiralpak AD, n-hexane/ethanol 95 : 5, 1 mL/min, 57%
ee); retention time = 13.21 min, 14.43 min. Physical and
spectral data agreed with the literature values.16
(S)-5-Acetyl-6-methyl-4-(4-(trifluoromethyl)phenyl)-3,4-
dihydropyran-2-one (3g).
Orange solid, 55 mg, 93% yield (general procedure A), 45
1
mg, 75% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H),
4.28 – 4.24 (m, 1H), 3.00 (dd, J = 15.8, 7.3 Hz, 1H), 2.84
(dd, J = 15.8, 2.3 Hz, 1H), 2.46 (s, 3H), 2.17 (s, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 197.1, 165.1, 161.0,
143.9, 130.3 (q, J = 32.6 Hz), 127.9, 127.2, 126.5 (q, J = 3.7
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Hz), 124.5 (q, J = 273.7 Hz), 117.1, 125.2, 122.5, 119.8,
(R)-5-Acetyl-6-methyl-4-(thiophen-2-yl)-3,4-
dihydropyran-2-one (3l)
38.5, 36.7, 30.0, 19.3 ppm. 19F NMR (376 MHz, CDCl3) δ –
62.66 ppm. FTIR (cm-1): 2922, 2853, 1323, 1108, 1067,
838. HRMS m/z: [M+H]+ calcd for C15H14F3O3 299.0895;
found 299.0891. Chiral HPLC (Chiralpak AD, n-
hexane/ethanol 95 : 5, 1 mL/min, 83% ee); retention time =
12.48 min, 19.02 min. Physical and spectral data agreed
with the literature values.35
Yellow solid, 38 mg, 80% yield (general procedure A), 17
1
mg, 35% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.21 (dd, J = 5.1, 1.1 Hz, 1H), 6.93 (dd, J = 5.1,
3.6 Hz, 1H), 6.84 (d, J = 3.6 Hz, 1H), 4.45 (dd, J = 6.1, 2.9
Hz, 1H), 3.00 (dd, J = 15.8, 2.9 Hz, 1H), 2.95 (dd, J = 15.8,
6.1 Hz, 1H), 2.41 (s, 3H), 2.27 (s, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 197.2, 165.4, 160.8, 143.1, 127.5,
125.2, 124.8, 118.1, 37.4, 33.8, 29.8, 19.4 ppm. HRMS m/z:
[M+H]+ calcd for C12H13O3S 237.0585; found 237.0588.
9
(S)-5-Acetyl-6-methyl-4-(4-tolyl)-3,4-dihydropyran-2-one
(3h).
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11
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15
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19
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Orange wax, 37 mg, 75% yield (general procedure A), 24
1
mg, 50% yield (general procedure B). H NMR (400 MHz,
Chiral HPLC (Chiralpak AD, n-hexane/ethanol 95 : 5,
1 mL/min, 88% ee); retention time = 17.72 min, 28.45 min.
Physical and spectral data agreed with literature values.37
CDCl3) δ 7.16 – 7.11 (m, 2H), 7.06 – 6.99 (m, 2H), 4.12 –
4.08 (m, 1H), 2.95 (dd, J = 15.6, 7.1 Hz, 1H), 2.81 (dd, J =
15.6, 2.7 Hz, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 198.1, 165.8,
160.2, 137.7, 136.6, 130.1, 126.6, 117.4, 38.5, 37.3, 29.7,
21.0, 19.1 ppm. FTIR (cm-1): 2923, 1772, 1694, 1662, 1597,
1417, 1109, 1018, 819. HRMS m/z: [M+H]+ calcd for
(R)-5-acetyl-6-methyl-4-propyl-3,4-dihydro-2H-pyran-2-
one (3m)
Pale yellow oil, 30 mg, 72% yield (general procedure A), 24
mg, 19% yield (general procedure B).1H NMR (400 MHz,
CDCl3) δ 2.94 (dd, J = 11.4, 5.8 Hz, 1H), 2.74 (dd, J = 15.9,
1.7 Hz, 1H), 2.59 (dd, J = 15.9, 6.4 Hz, 1H), 2.36 (s, 3H),
2.28 (s, 3H), 1.50 – 1.31 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 197.81, 167.13,
158.87, 120.37, 35.58, 33.05, 32.03, 30.27, 19.81, 19.35,
13.87. HRMS m/z: [M+H]+ calcd for C11H17O3 197.1178;
found 197.1179. Chiral HPLC (Chiralpak AD, n-
hexane/ethanol 95 : 5, 1 mL/min, 78% ee); retention time =
9.14 min, 14.71 min. Physical and spectral data agreed with
the literature values.38
C15H17O3 245.1178;
found 245.1181. Chiral HPLC
(Chiralpak AD, n-hexane/ethanol 95 : 5, 1 mL/min, 78%
ee); retention time = 10.86 min, 14.05 min. Physical and
spectral data agreed with the literature values.35
(R)-5-Acetyl-4-(furan-2-yl)-6-methyl-3,4-dihydropyran-2-
one (3j)
Orange solid, 33 mg, 75% yield (general procedure A), 26
1
mg, 60% yield (general procedure B). H NMR (400 MHz,
CDCl3) δ 7.35 – 7.31 (m, 1H), 6.29 – 6.25 (m, 1H), 6.08 (d,
J = 3.3 Hz, 1H), 4.27 – 4.25 (m, 1H), 3.04 (dd, J = 15.9, 2.1
Hz, 1H), 2.84 (dd, J = 15.9, 6.8 Hz, 1H), 2.36 (s, 3H), 2.30
(s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 197.1,
165.5, 161.0, 152.5, 142.8, 115.7, 110.4, 106.6, 33.8, 32.3,
29.8, 19.4 ppm. FTIR (cm-1): 2922, 1782, 1689, 1606, 1145,
1114, 1012, 942, 740. HRMS m/z: [M+H]+ calcd for
C12H13O4 221.0814; found 221.0809. Chiral HPLC
(Chiralpak OD, n-hexane/ethanol 95 : 5, 1 mL/min, 76%
ee); retention time = 15.76 min, 19.45 min. Physical and
spectral data agreed with literature values.36
(R)-5-acetyl-4,6-dimethyl-3,4-dihydro-2H-pyran-2-one (3n)
Pale yellow oil, 24 mg, 72% yield (general procedure A), 24
1
mg, 6 mg, 19% yield (general procedure B). H NMR (400
MHz, CDCl3) δ 3.09 – 2.99 (m, 1H), 2.67 (dd, J = 15.7, 6.1
Hz, 1H), 2.58 (dd, J = 15.7, 2.1 Hz, 1H), 2.35 (s, 3H), 2.28
(s, 3H), 1.14 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 197.55, 166.93, 159.10, 120.64, 35.81, 30.06,
27.48, 19.38, 19.34. HRMS m/z: [M+H]+ calcd for C9H13O3
169.0865; found 169.0861. Chiral HPLC (Chiralpak AD, n-
hexane/ethanol 95 : 5, 1 mL/min, 77% ee); retention time =
13.39 min, 20.99 min. Physical and spectral data agreed
with the literature values.34
(R)-5-Acetyl-6-methyl-4-(5-methylfuran-2-yl)-3,4-
dihydropyran-2-one (3k)
Orange wax, 26 mg, 55% yield (general procedure A), 7
1
mg, 15% yield (general procedure B). H NMR (400 MHz,
Ethyl
6-methyl-4-phenyl-3,4-dihydropyran-2-one-5-
CDCl3) δ 5.94 (d, J = 3.0 Hz, 1H), 5.84 (d, J = 3.0 Hz, 1H),
4.18 (d, J = 6.4 Hz, 1H), 3.04 (dd, J = 15.8, 2.1 Hz, 1H),
2.82 (dd, J = 15.8, 6.4 Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H),
2.23 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
197.1, 165.5, 161.0, 152.5, 142.8, 115.7, 110.4, 106.6, 33.8,
32.3, 29.8, 19.4 ppm. FTIR (cm-1): 2922, 1782, 1689, 1606,
1145, 1114, 1012, 942, 740. HRMS m/z: [M+H]+ calcd for
carboxylate (3o).
In a 10 mL test tube N-benzylquininium bromide (10 mg,
0.02 mmol), K3PO4 (47 mg, 0.22 mmol) and phenol (2 mg
0.02 mmol) were dissolved in dry DCM (2.0 mL). The
resulting purple reaction mixture was stirred for 30 min at 0
°C. Cinnamic thioester 1a (48 mg, 0.20 mmol) and ethyl
acetoacetate (53 μL, 0.60 mmol) were added and the
reaction was allowed to warm up to room temperature and
stirred for 48 h under nitrogen. The solvent was evaporated
in vacuo and the crude was purified by silica flash
chromatography (Et2O : petroleum ether, 1 : 15) to afford
11 mg of 3o as a white solid material (21% yield). 1H NMR
C13H15O4 235.0970;
found 235.0972. Chiral HPLC
(Chiralpak OD, n-hexane/ethanol 95 : 5, 1 mL/min, 77%
ee); retention time = 11.82 min, 15.12 min.
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(400 MHz, CDCl3) δ 7.35 – 7.20 (m, 3H), 7.19 – 7.10 (m,
(AcOEt : petroleum ether, 1 : 100) and crystallized with
2H), 4.29 – 4.22 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.95 (dd,
J = 15.9, 7.6 Hz, 1H), 2.83 (dd, J = 15.9, 2.3 Hz, 1H), 2.48
(d, J = 0.9 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 166.1, 166.0, 161.3, 140.7,
129.0, 127.5, 126.6, 110.0, 60.9, 37.9, 36.4, 18.9, 14.1 ppm.
HRMS m/z: [M+H]+ calcd for C15H16O4 260.1049; found
260.1047. Chiral HPLC (Chiralcel OD, n-hexane/i-propanol
90 : 10, 1 mL/min, 75% ee (S)-enantiomer); retention time
= 7.83 min, 14.69 min. [α]D = +91° (c = 0.6, CHCl3).
Physical and spectral data agreed with literature values.39
Et2O from n-hexane yielding 1c as white needles (407 mg,
94% yield, m.p.128-131 °C). 1H NMR (400 MHz, CDCl3) δ
7.60 (d, J = 16 Hz, 1H), 7.55 (s, 1H), 7.53 – 7.41 (m, 6H),
7.41 – 7.31 (m, 2H), 6.78 (d, J = 16 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 187.8, 139.8, 135.9, 135.07, 134.6,
130.6, 130.3, 129.6, 129.3, 128.1, 127.3, 126.7, 125.4. FTIR
(cm-1): 1608, 1673, 1019, 806, 785, 749, 689. HRMS m/z:
[M+H]+ calcd for C15H12OClS 275.0297; found 275.0301.
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(2E)‐3‐(4‐chlorophenyl)‐1‐(phenylsulfanyl)prop‐2‐en‐1‐one
(1d).
(2E)-3-phenyl-1-(phenylsulfanyl)prop-2-en-1-one (1a).
4-Chlorocinnamic acid (554 mg, 3.0 mmol) was refluxed
with thionyl chloride (3.0 mL, 42.5 mmol) in 17 mL of
DCM overnight. The reaction mixture was cooled down to
room temperature and concentrated to give a yellow oily
solution. The concentrated oil was dissolved in 15 mL of
dry DCM, and thiophenol (0.4 mL, 4.0 mmol) and
triethylamine (5.7 mL, 41.0 mmol) were slowly added. The
resulting solution was stirred at room temperature
overnight, washed with 2% HCl until acidic pH was
reached and extracted with DCM. The combined organic
layer was washed with saturated NaHCO3, saturated NaCl,
dried over anhydrous Na2SO4 and concentrated under
vacuum. Crude was purified via silica flash chromatography
(petroleum ether) yielding 1d as a brown powder (205 mg,
To a solution of cinnamoyl chloride (4.00 g, 24.0 mmol) in
30 mL of dry DCM, was added triethylamine (2.02 mL,
14.4 mmol) under nitrogen. A solution of thiophenol (1.32
g, 12.0 mmol) in 10 mL of dry DCM was added dropwise to
the reaction mixture over twenty minutes. The reaction was
stirred for 22 h than was diluted with 30 mL of DCM and
extracted with 1M HCl (2 x 25 mL). The organic phase was
than extracted with 25 mL of 5% NaHCO3 with 20 mL of
water. The organic layer was dried over sodium sulfate and
was evaporated under vacuum. The crude was purified by
silica flash chromatography (AcOEt : petroleum ether, 1:25)
than crystallized in 40 mL of refluxing hexane. Product 1a
was obtained as a white solid (2.34 g, 82%).1H NMR (400
MHz, CDCl3) δ 7.68 (d, J = 16 Hz, 2H), 7.61 – 7.53 (m,
2H), 7.53 – 7.47 (m, 2H), 7.47 – 7.36 (m, 5H), 6.80 (d, J =
16 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 188.0,
141.5, 134.6, 134.0, 130.7, 129.4, 129.2, 129.0, 128.5,
127.6, 124.1. Spectral data agreed with literature values.40
1
25% yield). H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 16
Hz, 1H), 7.52 – 7.47 (m, 4H), 7.47 – 7.42 (m, 3H), 7.41 –
7.35 (m, 2H), 6.76 (d, J = 16 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 187.8, 140.0, 136.7, 134.6, 132.5, 129.6,
129.6, 129.3, 129.3, 127.4, 124.6. Spectral data agreed with
literature values.41
(2E)-3-(2-chlorophenyl)-1-(phenylsulfanyl)prop-2-en-1-one
(1b).
(2E)‐3‐(4‐methoxyphenyl)‐1‐(phenylsulfanyl)prop‐2‐en‐1‐o
ne (1e).
S-phenyl 2-(triphenylphosphoranylidene)ethanethioate was
added to a solution of 2-chlorobenzaldehyde (1.0 g, 2.4
mmol) in 15 mL of dry toluene, at room temperature. The
resulting mixture was stirred under N2 atmosphere for 48 h
at 60 °C. Crude was concentrated, purified via silica flash
chromatography (AcOEt : petroleum ether 1 : 200) and
crystallized with Et2O/n-Hexane to obtain 1b (131 mg, 30%
(E)-4-Methoxycinnamic acid (1.0 g, 5.6 mmol) was
refluxed with thionyl chloride (4.5 mL, 62.0 mmol) in 28
mL of DCM overnight. The reaction solution was cooled
down to room temperature and concentrated to give a
yellow oily solution. The concentrated oil was dissolved in
15 mL of DCM, and thiophenol (0.6 mL, 5.6 mmol) and
triethylamine (8.3 mL, 60.0 mmol) were slowly added. The
resulting solution was stirred at room temperature
overnight, washed with 2% HCl until acidic pH was
reached and extracted with DCM. The combined organic
layer was washed with saturated NaHCO3, saturated NaCl,
dried over anhydrous Na2SO4 and concentrated. Crude was
purified via silica flash chromatography (AcOEt : petroleum
ether, 1 : 20) yielding 1e as a white powder (353 mg, 23%
1
yield). H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 16 Hz,
1H), 7.66 (dd, J = 7, 2 Hz, 1H), 7.53 – 7.41 (m, 6H), 7.38 –
7.27 (m, 2H), 6.78 (d, J = 16 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 187.9, 137.4, 135.6, 134.6, 132.4, 131.5,
130.3, 129.6, 129.3, 127.7, 127.4, 127.2, 126.6. Spectral
data agreed with literature values.40
1
(2E)‐3‐(3‐chlorophenyl)‐1‐(phenylsulfanyl)prop‐2‐en‐1‐one
(1c).
yield). H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 16 Hz,
1H), 7.55 – 7.46 (m, 4H), 7.46 – 7.42 (m, 3H), 6.95 – 6.89
(m, 2H), 6.68 (d, J = 16 Hz, 1H), 3.85 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 187.9, 161.9, 141.3, 134.7,
130.3, 129.3, 129.2, 127.9, 126.7, 121.8, 114.5, 55.4.
Spectral data agreed with literature values.41
S-phenyl 2-(triphenylphosphoranylidene)ethanethioate was
added to a solution of 3-chlorobenzaldehyde (1.0 g, 2.4
mmol) in 15 mL of dry toluene, at room temperature. The
resulting pink reaction mixture was stirred under N2
atmosphere for 48 h at room temperature. Crude was
concentrated, purified via silica flash chromatography
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7H), 7.21 (d, J = 8 Hz, 2H), 6.75 (d, J = 16 Hz, 1H), 2.39 (s,
(2E)‐3‐(4‐fluorophenyl)‐1‐(phenylsulfanyl)prop‐2‐en‐1‐one
(1f).
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 188.0, 141.6,
141.4, 134.7, 131.3, 129.9, 129.4, 129.2, 128.5, 127.8,
123.1, 21.6. Spectral data agreed with literature values.42
N,N’-Dicyclohexylcarbodiimide (3.0 g, 14.0 mmol) was
added to a stirring solution of (E)-4-fluorocinnamic acid
(2.0 g, 12.0 mmol), thiophenol (1.1 mL, 11.0 mmol) and
DMAP (29.0 mg, 0.24 mmol) in 5 mL of dry DCM at 0 °C.
After stirring for 1 h at 0 °C, the solution was stirred at
room temperature overnight. The precipitated solid was
filtered on celite and the filtrate was concentrated under
vacuum. Crude was purified by silica flash chromatography
(Et2O : petroleum ether, 1 : 30) and then crystallized with
Et2O, obtaining compound 1f as white needles (275 mg, 9%
(2E)-3-(naphthalen-2-yl)-1-(phenylsulfanyl)prop-2-en-1-on
e (1i).
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(E)-3-(1-Naphthyl)prop-2-enoic acid (916 mg, 4.7 mmol)
was refluxed with thionyl chloride (4.0 mL, 52.0 mmol) in
23 mL of DCM overnight. The reaction solution was cooled
down to room temperature and concentrated to give a
yellow oily solution. The concentrated oil was dissolved in
17 mL of dry DCM, then thiophenol (0.5 mL, 5.0 mmol)
and triethylamine (7.0 mL, 49.0 mmol) were slowly added.
The resulting solution was stirred at room temperature
overnight, washed with 2% HCl until acidic pH was
reached and extracted with DCM. The combined organic
layer was washed with saturated NaHCO3, saturated NaCl,
dried over anhydrous Na2SO4 and concentrated under
vacuum. Crude was purified via silica flash chromatography
(AcOEt : petroleum ether, 1 : 50) obtaining 1i as an orange
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yield, m.p: 98-118 °C). H NMR (400 MHz, CDCl3) δ 7.64
(d, J = 16 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.52 – 7.41 (m,
5H), 7.15 – 7.06 (m, 2H), 6.72 (d, J = 16 Hz, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 187.8, 164.2 (d, J = 252.4 Hz),
140.2, 134.6, 130.4 (d, J = 8.6 Hz), 130.3 (d, J = 3.4 Hz),
129.5, 129.3, 127.5, 123.9, 116.2 (d, J = 22.0 Hz). 19F NMR
(376 MHz, CDCl3) δ -108.56. FTIR (cm-1): 1679, 1595,
1507, 1031, 1022, 816. HRMS m/z: [M+H]+ calcd for
C15H12FOS 259.0593; found 259.0581.
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powder (253 mg, 19% yield, m.p. 100-102 °C). H NMR
(2E)‐1‐(phenylsulfanyl)‐3‐[4‐(trifluoromethyl)phenyl]prop‐
2‐en‐1‐one (1g).
(400 MHz, CDCl3) δ 8.54 (d, J = 15 Hz, 1H), 8.19 (d, J = 8
Hz, 1H), 7.92 (dd, J = 15, 8 Hz, 2H), 7.82 (d, J = 7 Hz, 1H),
7.65 – 7.43 (m, 8H), 6.89 (d, J = 15 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 188.0, 138.5, 134.7, 133.7, 131.7,
131.3, 131.1, 129.5, 129.3, 129.1, 128.9, 127.1, 126.6,
126.4, 125.5, 125.3, 123.3. FTIR (cm-1): 2924, 1476, 1438,
796, 685.83. HRMS m/z: [M+H]+ calcd for C19H15OS
291.0844; found 291.0845.
N,N’ Dicyclohexylcarbodiimide (1.0 g, 5.0 mmol) was
added
to
a
stirring
solution
of
(E)-4-
trifluoromethylcinnamic acid (850 mg, 4.0 mmol),
thiophenol (0.4 mL, 3.6 mmol) and DMAP (8.0 mg, 0.08
mmol) in 2 mL of dry DCM at 0 °C. After stirring for 1 h at
0 °C, the solution was stirred at room temperature
overnight. The precipitated solid was filtered on celite and
the filtrate was concentrated under vacuum. Crude was
purified via silica flash chromatography (Et2O : petroleum
ether, 1 : 30) and then crystallized with Et2O obtaining 1g
as colourless needles (170 mg, 14% yield, m.p.: 101-106
(2E)-3-(furan-2-yl)-1-(phenylsulfanyl)prop-2-en-1-one (1j).
(E)-3-(2-Furyl)prop-2-enoic acid (940 mg, 7.0 mmol) was
refluxed with thionyl chloride (5.5 mL, 76.0 mmol) in 34
mL of DCM overnight. The reaction solution was cooled
down to room temperature and concentrated to give a
yellow oily solution. The concentrated oil was dissolved in
17 mL of dry DCM, then thiophenol (0.5 mL, 5.0 mmol)
and triethylamine (7.0 mL, 49.0 mmol) were slowly added.
The resulting solution was stirred at room temperature
overnight, washed with 2% HCl until acidic pH was
reached and extracted with DCM. The combined organic
layer was washed with saturated NaHCO3, saturated NaCl,
dried over anhydrous Na2SO4 and concentrated under
vacuum. Crude was purified via silica flash chromatography
(petroleum ether) yielding 1j as an orange powder (143 mg,
1
°C). H NMR (400 MHz, CDCl3) δ 7.71 – 7.64 (m, 5H),
7.53 – 7.43 (m, 5H), 6.85 (d, J = 16 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 187.7, 139.4, 137.4, 134.6, 131.1 (q, J
= 32.7 Hz), 129.7, 129.3, 128.6, 127.2, 126.4, 126.0 (q, J =
3.8 Hz), 123.8 (q, J = 272.3 Hz). 19F NMR (376 MHz,
CDCl3) δ -62.89. FTIR (cm-1): 1677, 1617, 1318, 1109,
1021, 990, 821, 755, 741, 691. HRMS m/z: [M+H]+ calcd
for C16H12OF3S 309.0561; found 309.0560.
(2E)‐3‐(4‐methylphenyl)‐1‐(phenylsulfanyl)prop‐2‐en‐1‐on
e (1h).
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N,N’-Dicyclohexylcarbodiimide (3.0 g, 14.0 mmol) was
added to a stirring solution of (E)-4-methylcinnamic acid
(2.0 g, 12.0 mmol), thiophenol (1.1 mL, 11.0 mmol) and
DMAP (27.0 mg, 0.22 mmol) in 5 mL of dry DCM at 0 °C.
After stirring for 1 h at 0 °C, the solution was stirred at
room temperature overnight. The precipitated solid was
filtered on celite and the filtrate was concentrated under
vacuum. Crude was purified by silica flash chromatography
9% yield). H NMR (400 MHz, CDCl3) δ 7.54 – 7.45 (m,
3H), 7.45 – 7.35 (m, 4H), 6.73 – 6.63 (m, 2H), 6.52 – 6.46
(m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 187.6, 150.6,
145.3, 134.6, 129.4, 129.2, 127.7, 127.5, 121.5, 116.6,
112.7. Spectral data agreed with literature values.40
(2E)‐3‐(5‐methylfuran‐2‐yl)‐1‐(phenylsulfanyl)prop‐2‐en‐1‐
one (1k).
(Et2O : petroleum ether, 1 : 30) yielding 1h as
white/yellow powder (303 mg, 10% yield). H NMR (400
a
1
N,N’ Dicyclohexylcarbodiimide (2.0 g, 10.0 mmol) was
added to a stirring solution of (E)-3-(5-methylfuran-2-
MHz, CDCl3) δ 7.66 (d, J = 16 Hz, 1H), 7.53 – 7.40 (m,
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yl)prop-2-enoic acid (1.3 g, 8.5 mmol), thiophenol (0.7 mL,
ASSOCIATED CONTENT
7.6 mmol) and DMAP (21.0 mg, 0.17 mmol) in 3.5 mL of
dry DCM at 0 °C. After stirring for 1 h at 0 °C, the solution
stirred at room temperature overnight. The precipitated
solid was filtered on celite and the filtrate was concentrated.
Crude was purified via silica gel chromatography (Et2O :
petroleum ether, 1 : 30) and then crystallized with Et2O
obtaining 1k as orange needles (1.25 g, 60% yield, m.p.: 76
80 °C). 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.45 (m, 2H),
7.45 – 7.38 (m, 3H), 7.34 (d, J = 15 Hz, 1H), 6.61 (d, J = 3
Hz, 1H), 6.60 (d, J = 15 Hz, 1H), 6.11 (d, J = 3 Hz, 1H),
2.37 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 187.5,
156.3, 149.3, 134.6, 129.3, 129.1, 128.0, 127.5, 119.8,
118.5, 109.4, 14.0. FTIR (cm-1): 2954, 2922, 2853, 1460,
1017, 964, 824, 786, 742, 709, 688, 623. HRMS m/z:
[M+H]+ calcd for C14H13O2S 245.0636; found 245.0641.
1
Supporting Information: copies of the H- and 13C- NMR
of compounds 1a-o and 3a-o. Copies of chiral HPLC traces
for experiments listed in Table 6. HPLC obtained for
compound 3a by using 0.1 equiv of base only. The
Supporting Information is available free of charge on the
ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
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* Centre for Synthesis and Chemical Biology (CSCB),
Department of Chemistry, Royal College of Surgeons in
Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland. Fax:
(+353) 1 4022168; E-mail: madamo@rcsi.ie.
Funding Sources
(2E)‐1‐(phenylsulfanyl)‐3‐(thiophen‐2‐yl)prop‐2‐en‐1‐one
(1l).
We acknowledge the Irish Research Council (IRC) for
grants to DD and MWGH.
N,N’-Dicyclohexylcarbodiimide (2.7 g, 13.0 mmol) was
added to a stirring solution of (E)-3-(thiophen-2-yl)prop-2-
enoic acid (1.7 g, 11.0 mmol), thiophenol (1.0 mL,
10.0 mmol) and DMAP (27.0 mg, 0.22 mmol) in 5 mL of
dry DCM at 0 °C. After stirring for 1 h at 0 °C, the solution
was stirred overnight at room temperature. The precipitated
solid was filtered on celite and the filtrate was concentrated
under vacuum. The crude was purified via silica gel
chromatography (AcOEt : petroleum ether, 1 : 30) and then
crystallized with Et2O yielding 1l as yellow crystals
REFERENCES
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Transformations of Eburicoic Acid. IV. Side-Chain Degradation to
14-Methylpregnane Derivatives. J. Am. Chem. Soc. 1963, 85, 3971.
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3-aryl- or 3-alkenyl-4,6-dimethyl-2-pyrones by silver ion promoted
rearrangement of 4-aryl- or 4-alkenyl-3-bromo-4,6-dimethyl-3,4-
dihydro-2-pyrones. Tetrahedron Lett. 1988, 29, 3825.
(3) Mandal, A. K.; Jawalkar, D. G. Studies toward the Syntheses of
Functionally Substituted γ-Butyrolactones and Spiro-γ-
butyrolactones and Their Reaction with Strong Acids: A Novel
Route to β-Pyrones. J. Org. Chem. 1989, 54, 2364.
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Michael reactions of cyclic 1,3-dicarbonyl compounds and
enamines catalyzed by chiral bisoxazoline-copper(II) complexes. J.
Org. Chem. 2003, 68, 5067.
(5) Zhang, F.-Y.; Corey, E. J. Highly Enantioselective Michael
Reactions Catalyzed by a Chiral Quaternary Ammonium Salt.
Illustration by Asymmetric Syntheses of (S)-Ornithine and Chiral
2-Cyclohexenones. Org. Lett. 2002, 2, 1097.
1
(801 mg, 30% yield, m.p: 86-91 °C). H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 15 Hz, 1H), 7.53 – 7.40 (m, 6H), 7.33
(d, J = 4 Hz, 1H), 7.09 (d, J = 4 Hz, 1H), 6.59 (d, J = 15 Hz,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 187.5, 139.3,
134.6, 133.9, 132.3, 129.5, 129.3, 129.2, 128.4, 127.6,
122.8. FTIR (cm-1): 1661, 1597, 1277, 1203, 1018, 865,
834, 823, 746, 714. HRMS m/z: [M+H]+ calcd for
C13H11OS2 247.0251; found 247.0254.
(6) Albanese, D. C. M.; Gaggero, N. N-heterocyclic carbene catalysis
as a tool for gaining access to the 3,4-dihydropyran-2-one skeleton.
Eur. J. Org. Chem. 2014, 2014, 5631.
(7) Kobayashi, S.; Moriwaki, M. Facile synthesis of 3,4-dihydro-α-
pyrones via Michael reaction-O-acylation sequences. Synlett 1997,
551.
S-phenyl (E)-hex-2-enethioate (1m)
Compound 1m was obtained according to the procedure
reported by Tingoli and coworkers as an oil, (713 mg, 71%
1
(8) (a) Katritzky, A. R.; Denisko, O. V. 1,2- vs 1,4-Addition of
acylbenzotriazoles to α,β-unsaturated aldehydes and ketones. A
novel route to 3-alkyl-4,6-diaryl-3,4-dihydropyran-2-ones. J. Org.
Chem. 2002, 67, 3104; (b) Robinson, E. R. T.; Fallan, C.; Simal,
C.; Slawin, A. M. Z.; Smith, A. D., Anhydrides as -unsaturated
acyl ammonium precursors:isothiourea-promoted catalytic
asymmetric annulation precesses, Chem. Sci. 2013, 4, 2193.
(9) Tozawa, T.; Nagao, H.; Yamane, Y.; Mukaiyama, T.
Enantioselective synthesis of 3,4-dihydropyran-2-ones by domino
Michael addition and lactonization with new asymmetric
organocatalysts: Cinchona-alkaloid-derived chiral quaternary
ammonium phenoxides. Chem. Asian J. 2007, 2, 123.
(10) Zhang, M. L.; Wu, Z. J.; Zhao, J. Q.; Luo, Y.; Xu, X. Y.; Zhang,
X. M.; Yuan, W. C. Michael Addition-Lactonization of Arylacetyl
Phosphonate to β,γ-Unsaturated α-Keto Esters for the Synthesis of
Chiral syn-3,4-Dihydropyranones and 5,6-Dihydropyranones. Org.
Lett. 2016, 18, 5110.
yield). H NMR (400 MHz, CDCl3) δ 7.40 – 7.30 (m, 5H),
6.97 – 6.86 (m, 1H), 6.12 (d, J = 15.5 Hz, 1H), 2.15 (q, J =
7.2 Hz, 2H), 1.51 – 1.39 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 187.1, 145.7, 133.7,
128.3, 128.1, 126.9, 126.6, 33.3, 20.2, 12.7. Spectral data
agreed with literature values.43
S-phenyl (E)-but-2-enethioate (1n)
Compound 1n was obtained according to the procedure
reported by Tabarelli and coworkers as an oil, (498 mg,
1
56% yield). H NMR (400 MHz, CDCl3) δ 7.47 – 7.36 (m,
5H), 6.99 (dq, J = 13.8, 6.9 Hz, 1H), 6.21 (dd, J = 15.4, 1.5
Hz, 1H), 1.91 (dd, J = 6.9, 1.5 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 188.0, 142.2, 134.8, 129.4, 129.2, 129.1,
127.7, 18.2. Spectral data agreed with literature values.44
(11) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chiral N -Heterocyclic
Carbene-Catalyzed Formal [4+2] Cycloaddition of Ketenes with
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Enones: Highly Enantioselective Synthesis of trans - and cis -δ-
Lactones. Chem. Eur. J. 2008, 14, 8473.
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N-heterocyclic carbene catalyzed annulation of α,β- unsaturated
aldehydes with 1,3-dicarbonyls. Chem. Commun. 2011, 47, 8670.
(29) Lins, F. F. T.; da Cunha, L. P.; Pouliquen, Y. B. M.; Lemos, T. L.
G.; de Mattos, M. C. Diastereoselectivity in the Synthesis of
Unnatural α-Amino Acid Esters by Phase Transfer Catalysis. Z.
Naturforsch. B 2018, 59, 305.
(30) Lygo, B.; Andrews, B. I. Asymmetric phase-transfer catalysis
utilizing chiral quaternary ammonium salts: Asymmetric alkylation
of glycine imines. Acc. Chem. Res. 2004, 37, 518.
(31) Corey, E. J.; Xu, F.; Noe, M. C. A Rational Approach to Catalytic
Enantioselective Enolate Alkylation Using a Structurally Rigidified
and Defined Chiral Quaternary Ammonium Salt under Phase
Transfer Conditions. J. Am. Chem. Soc. 1997, 119, 12414.
(32) Wu, X.; Zhang, Y.; Wang, Y.; Ke, J.; Jeret, M.; Reddi, R. N.;
Yang, S.; Song, B. A.; Chi, Y. R. Polyhalides as Efficient and Mild
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SYNOPSIS TOC
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Br-
Ph
OCH3
O
O
H
N
O
OH
Ph
S
9
R1
N
4b
(0.1 eq.)
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R1
O
O
Phenol (0.1 eq.)
K2CO3 (1.0 eq.)
DCM (0.1 M), rt, 48h
O
yields 44-93%
up to 88% ees
12
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