One-Pot Synthesis of β,β-Disubstituted α,β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1021/acs.joc.5b01217

TiCl₄-promoted aldol reaction of ketones as aldol acceptors followed by elimination of the titanoxy group from the Ti-aldolates affords β,β-disubstituted α,β-unsaturated carbonyl compounds in a one-pot procedure. The use of additives, such as DMF, N,N,N′,N′-tetramethylethylenediamine, and pyridine, in the elimination step was found to be important.

Full text of DOI:10.1021/acs.joc.5b01217

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Note
One-pot Synthesis of beta,beta-Disubstituted
alpha,beta-Unsaturated Carbonyl Compounds
Masaharu Sugiura, Yasuhiko Ashikari, and Makoto Nakajima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01217 • Publication Date (Web): 18 Aug 2015
Downloaded from http://pubs.acs.org on August 22, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
One-pot Synthesis of β,β-Disubstituted α,β-Unsaturated Car-
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
bonyl Compounds
Masaharu Sugiura,* Yasuhiko Ashikari and Makoto Nakajima
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5ꢀ1 Oeꢀhonmachi, Chuoꢀku, Kumamoto 862ꢀ0973,
Japan
ABSTRACT: TiCl4ꢀpromoted aldol reaction of ketones as aldol acceptors followed by elimination of the titanoxy group from the
Tiꢀaldolates affords β,βꢀdisubstituted α,βꢀunsaturated carbonyl compounds in a oneꢀpot procedure; the use of additives, such as
DMF, N,N,N’,N’ꢀtetramethylethylenediamine, and pyridine, in the elimination step was found to be important.
β,βꢀDisubstituted α,βꢀunsaturated carbonyl compounds are useful compounds themselves and as starting materials for the conꢀ
struction of tetraꢀ or trisubstituted carbon stereogenic centers at the carbonyl βꢀposition. The total syntheses of various natural
products have been accomplished starting from these functional compounds.1 We also reported the Lewis baseꢀcatalyzed enantioseꢀ
lective conjugate reduction of a β,βꢀdisubstituted α,βꢀunsaturated ketone (enone) with trichlorosilane.2
The combination of the Horner–Wadsworth–Emmons reaction of ketones and subsequent transformation to enones via Weinreb
amides is widely used to prepare acyclic β,βꢀdisubstituted enones.3 Sulfenylation/desulfenylation of ketones,4 addition of organoꢀ
metallic reagents to βꢀaminoꢀ, βꢀalkylthioꢀ or βꢀalkoxyenones,5 conjugate addition of organometallic reagents to ynones,6 rearꢀ
rangement of tertiary propargylic alcohols or their acetates,7 and oxidative rearrangement of tertiary allylic alcohols8 have also been
utilized. Recently, Donohoe and coꢀworkers reported an efficient stereoselective method based on the Mizoroki–Heck reaction of
vinyl Weinreb amides.9 However, these precedents all require several reaction steps.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 13
The aldol addition to simple ketones followed by dehydration (the aldol condensation) may offer a straightforward strategy for
the preparation of β,βꢀdisubstituted α,βꢀunsaturated carbonyl compounds from readily available starting materials; however, this
has not yet been systematically studied because of the relatively low reactivity of ketones as electrophiles (aldol acceptors), its proꢀ
pensity for the retroaldol reaction, and generation of undesired selfꢀ and/or crossꢀaldol products. In one of the few examples, Tanaꢀ
be and coꢀworkers reported highly useful diastereoselective TiCl4/Bu3Nꢀpromoted aldol reactions between two ketones or between
phenyl esters/Sꢀphenyl thioesters and ketones.10–13 They also reported the synthesis of a muscone precursor10c and dihydroꢀ
jasmone11b by dehydration of the corresponding isolated aldol products. Inspired by their work, we envisaged that elimination of the
titanoxy group directly from the Tiꢀaldolate intermediate (without isolation of the aldol product) might be feasible by optimizing
the reaction conditions. Here, we report the oneꢀpot synthesis of β,βꢀdisubstituted α,βꢀunsaturated carbonyl compounds by using
additives in the elimination step.
1
2
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
Initially, we investigated the reaction of methyl isopropyl ketone as the aldol donor and acetophenone as the aldol acceptor (Taꢀ
ble 1). According to Tanabe’s procedure with slight modification of the amounts of substrate and reagent,10 methyl isopropyl ketone
(1.0 equiv.) in dichloromethane was treated successively with TiCl4 (1.1 equiv.) and Bu3N (1.2 equiv.) at –78 °C, and acetophenone
(1.0 equiv.) was added to the mixture. After 30 min, formation of the aldol product was confirmed by TLC analysis. If the reaction
was quenched at this stage, the aldol product was obtained in 96% yield. However, when the temperature was increased to rt14
without workup to facilitate the elimination, the desired enone was obtained only in 18% yield (Table 1, entry 1). A large amount of
acetophenone was generated, which indicated progress of the retroaldol reaction. We reasoned that the Tiꢀenolate was regenerated
because Ti strongly coordinated to the carbonyl oxygen atom in the Tiꢀaldolate intermediate. To cleave the coordinate bond, DMF
was added as a ligand of titanium in the elimination step. As expected, the yield of the enone increased (Table 1, entries 2–4); DMF
(5 equiv.) provided the best result. NꢀMethylꢀ2ꢀpyrrolidone (NMP) and N,N’ꢀdimethylpropyleneurea (DMPU) were inferior alternaꢀ
tives to DMF (Table 1, entries 5 and 6).15 In addition to coordination to titanium, deprotonation of a carbonyl αꢀproton would faciliꢀ
tate the elimination step. Thus, tertiary amines were examined as additives. Monoamines were moderately effective (Table 1, enꢀ
tries 7–9),16 whereas N,N,N’,N’ꢀtetramethylethylenediamine (TMEDA), which can bidentately coordinate to titanium, afforded a
good yield (Table 1, entry 10). The use of larger amounts of TMEDA (2.0 equiv.) decreased the yield.17 Next, pyridine and its deꢀ
rivatives were examined (Table 1, entries 11–14).18 Unlike aliphatic amines, larger amounts (5.0 equiv.) of pyridine gave higher
yield than lower amounts (3.0 equiv.) (entiries 11 and 12). Although the E selectivity was lowered, significant rate enhancement
was observed with pyridine and αꢀpicoline. Thus, we identified DMF, TMEDA, and pyridine as effective additives for the eliminaꢀ
tion step. It should also be noted that the titanium residue, which precipitates naturally or on addition of diethyl ether and hexane,
can be removed by simple filtration through a Celite pad without aqueous workup. After evaporation, the filtrate can be directly
purified by column chromatography on silica gel.
Table 1. Screening of Additivesa
2
ACS Paragon Plus Environment

Page 3 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Entry
Additive
(equiv.)
Time (h)
Yield (%)b E/Z c
1
none
20
20
20
20
21
23
20
20
20
20
1.5
5
18
58
80
74
19
48
65
48
39
72
63
87
82
71
97:3
96:4
97:3
98:2
97:3
97:3
99:1
97:3
97:3
97:3
87:13
86:14
90:10
88:12
2
DMF (2.0)
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
3
DMF (5.0)
4
DMF (10)
5
NMPd (5.0)
DMPUe (5.0)
Bu3N (1.0)
Et3N (1.0)
6
7
8
9
i-Pr2NEt (1.0)
TMEDAf (1.0)
pyridine (3.0)
pyridine (5.0)
αꢀpicoline (5.0)
10
11
12
13
14
2
2,6ꢀlutidine
(5.0)
21
aThe reaction was carried out by using methyl isopropyl ketone (1.0 mmol), TiCl4 (1.1 mmol), Bu3N (1.2 mmol), acetophenone (1.0
mmol), and additive in dichloromethane (2 mL). bIsolated yield. c Determined by 1H NMR spectroscopic analysis of the crude product. dNꢀ
methylꢀ2ꢀpyrrolidone. eN,N’ꢀDimethylpropyleneurea. N,N,N’,N’ꢀTetramethylethylenediamine.
f
Oneꢀpot reactions of other substrates were investigated with these additives (Table 2). The reaction tolerated a variety of aromatic
and aliphatic ketones. In most cases, pyridine resulted in a shorter reaction time and higher yield but lower E selectivity than DMF
or TMEDA.19,20 In most cases, high E/Z selectivity (>95:5) was observed with DMF and TMEDA additives. When propiophenone
was used as aldol acceptor for the reaction with methyl isopropyl ketone, low E/Z selectivities were observed (Scheme 1).
Based on the above observation for the E/Z selectivity, we speculated that the stereochemical pathway would be different for the
reaction with pyridine versus that with DMF or TMEDA. To verify this hypothesis, several control experiments were performed
(Table 3). First, TMEDA or pyridine, and then (E)ꢀ or (Z)ꢀenone (Ar = pꢀClC6H4, isolated by chromatography after oneꢀpot reacꢀ
tion) were added to a mixture of TiCl4, Bu3N and water in dichloromethane.21 With TMEDA (Table 3, entries 1 and 2), the E/Z ratio
became 97:3 irrespective of the geometry of the starting enone. However, with pyridine (Table 3, entries 3 and 4), the E/Z ratio of
the starting enone was almost retained. Thus, the E/Z selectivity is controlled thermodynamically in the former case and kinetically
in the latter case. Second, hydrogen chloride, a possible side product of the oneꢀpot reaction, also caused isomerization (Table 3,
entry 5), which suggested that the excess of pyridine (5.0 equiv.) trapped HCl and prevented the isomerization (equilibration).
Table 2. Substrate Scopea
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 13
1
2
3
4
5
6
7
8
9
Enꢀ
try
R1
R2
Adꢀ
diꢀ
Time
(h)
Yield
(%)b
E/Zd
tivec
1
Ph
Ph
Ph
Ph
Ph
Ph
D
T
P
20
2
45
64
67
54
68
87
45
86
73
19
38
77
73
72
86
38
78
87
70
62
67
38
71
67
99
98:2
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
2
97:3
3
2
87:13
90:10
92:8
4
pꢀMeOC6H4 Ph
P
2
5
6 e
pꢀClC6H4
pꢀClC6H4
Ph
Ph
P
2
Ph
P
2
92:8
7
iꢀPr
D
T
P
24
1
86:14
87:13
88:12
95:5
8
Ph
iꢀPr
9
Ph
iꢀPr
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
cꢀPr
Ph
D
T
P
7
cꢀPr
Ph
20
1
95:5
cꢀPr
Ph
89:11
97:3
cꢀHex
cꢀHex
cꢀHex
tꢀBu
tꢀBu
tꢀBu
iꢀPr
Ph
D
T
P
20
20
1
Ph
97:3
Ph
85:15
98:2
Ph
D
T
P
20
20
1
Ph
98:2
Ph
86:14
>99:1
98:2
pꢀMeOC6H4
pꢀMeOC6H4
pꢀMeOC6H4
pꢀClC6H4
pꢀClC6H4
pꢀClC6H4
tꢀBu
D
T
P
4
iꢀPr
18
1
iꢀPr
82:18
96:4
iꢀPr
D
T
P
20
20
1
iꢀPr
96:4
iꢀPr
73:27
73:27
iꢀPr
P
2
aThe reaction was carried out by using R1COCH3 (0.5 mmol), TiCl4 (1.1 mmol), Bu3N (1.2 mmol), R2COCH3 (0.5 mmol), and additive
[DMF (2.5 mmol), TMEDA (0.5 mmol), or pyridine (2.5 mmol)] in dichloromethane (1 mL). Isolated yield. D: DMF (5.0 equiv.); T:
TMEDA (1.0 equiv.); P: pyridine (5.0 equiv.). Determined by H NMR spectroscopic analysis of the crude product. The aldol step was
carried out at −45 °C for 1.0 h.
b
c
d
1
e
Scheme 1. Propiophenone as Aldol Acceptor
Table 3. Control Experimentsa
4
ACS Paragon Plus Environment

Page 5 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Entry E/Z (start) Additive
Time
E/Z (end)b
(equiv.)
(h)
12
12
1
1
2
3
4
5
98:2
TMEDA (1.0)
TMEDA (1.0)
pyridine (5.0)
pyridine (5.0)
HCl (1.0)c
97:3
97:3
98:2
3:97
97:3
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
0:100
98:2
0:100
0:100
1
1
aAdditive and enone were successively added to a mixture of TiCl4 (1.1 equiv.), Bu3N (1.2 equiv.) and water (1.0 equiv.) in dichloroꢀ
methane. bDetermined by 1H NMR spectroscopic analysis of the crude product. cHydrogen chloride in Et2O was used instead of a mixture
of TiCl4, Bu3N, and water.
The oneꢀpot reaction was also applicable to the preparation of β,βꢀdisubstituted α,βꢀunsaturated carboxylic acid derivatives
(Scheme 2). The reaction of Sꢀphenyl thioacetate22 with acetophenone using TMEDA or pyridine in the elimination step afforded
the desired unsaturated thioester in good yield with good E selectivity. For the reaction with methyl isopropyl ketone, pyridine proꢀ
vided a much higher yield than TMEDA. In addition, the unsaturated thioester product (100% E, isolated by column chromatogꢀ
raphy) could be transformed to the corresponding Nꢀmethyl amide, aldehyde, or ethyl ketone by treatment with MeNH2,23 diisobuꢀ
tylaluminum hydride (DIBALꢀH),24 and EtZnI/palladium catalyst,25 respectively.26 It should be noted that these products are diffiꢀ
cult to obtain from the oneꢀpot reaction of the corresponding carbonyl compounds (i.e., Nꢀmethyl acetamide, acetaldehyde, and 2ꢀ
butanone).
Scheme 2. Transformation of S-Phenyl Thioacetate
The oneꢀpot method was applied to the oneꢀpot synthesis of simple natural products, arꢀatlantone27 and αꢀatlantone28 (Scheme 3).
The Tiꢀaldol reaction of mesityl oxide with the required ketones followed by elimination with pyridine provided arꢀatlantone and
αꢀatlantone in good yield and E selectivity.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 13
Scheme 3. Synthesis of Atlantones
1
2
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 summary, we have demonstrated a oneꢀpot method to synthesize β,βꢀdisubstituted α,βꢀunsaturated carbonyl compounds by
sequential TiCl4ꢀpromoted aldol reaction to simple ketones and baseꢀpromoted elimination.
EXPERIMENTAL SECTION
General Methods. Dry dichloromethane (dehydrated) was stored over 4ꢀÅ MS prior to use. Titanium(IV) chloride was distilled under reduced
pressure. Tributylamine, N,N,N’,N’ꢀTetramethylethylenediamine (TMEDA), and pyridine were distilled from CaH2. N,NꢀDimethylformamide
(DMF) was stored over 4Å MS prior to use. All other solvents and chemicals were purified based on standard procedures. Melting points (mp)
1
were uncorrected. H and 13C{1H} NMR spectra were measured in CDCl3 with 400 or 600 MHz spectrometer. Tetramethylsilane (TMS) (δ = 0
1
ppm) and CDCl3 (δ = 77.0 ppm) served as internal standards for H and 13C NMR, respectively. Infrared spectra were recorded on an FTꢀIR
spectrometer. Highꢀresolution mass spectra were recorded on a doubleꢀfocusing magneticꢀsector mass analyzer operating in a FAB mode. Thinꢀ
layer chromatography (TLC) was visualized with UV light, phosphomolybdic acid and/or anisaldehyde. Column chromatography was performed
using sílica gel (spherical, neutral, 63ꢀ210 nm). The reactions under anhydrous conditions were carried out using ovenꢀ and heating gunꢀdried
glassware with a rubber septum and a magnetic stirring bar under argon atmosphere.
Typical Procedure: One-pot Synthesis of β,β-Disubstituted Enone (Table 1, entry 12). TiCl4 (2.82 M in CH2Cl2; 0.39 mL) and Bu3N
(0.29 mL, 1.2 mmol) were successively added to a stirred solution of methyl isopropyl ketone (87.0 mg, 1.0 mmol) in CH2Cl2 (2.0 mL) at –78 °C.
After 30 min, acetophenone (119.7 mg, 1.0 mmol) was added to the mixture at –78 °C. Formation of the aldol product was detected by TLC
analysis after 1 h. Then pyridine (0.40 mL, 5.0 mmol) was added at –78 °C and the reaction mixture was warmed to room temperature. After being
stirred for 5 h, the reaction mixture was diluted with Et2O (5 mL) and hexane (5 mL). The mixture was filtered through a Celite pad and the filtrate
was concentrated. The residue was purified by column chromatography on silica gel (hexane/acetone = 30:1) to give 2ꢀmethylꢀ5ꢀphenylhexꢀ4ꢀenꢀ3ꢀ
one (163.8 mg, 87% yield, E/Z = 86:14).
(E)-2-Methyl-5-phenylhex-4-en-3-one.29 TLC: Rf 0.38 (hexane/acetone = 10:1, stained dark green with anisaldehyde).1H NMR (400 MHz): δ
= 1.17 (d, J = 7.0 H, 6H), 2.55 (s, 3H) 2.73 (sept, J = 7.0 H, 1H), 6.55 (s, 1H), 7.33ꢀ7.43 (m, 3H), 7.44ꢀ7.58 (m, 2H).
1
(Z)-2-Methyl-5-phenylhex-4-en-3-one.29 TLC: Rf 0.35 (hexane/acetone = 10:1, stained dark green with anisaldehyde). H NMR (400 MHz):
δ = 0.99 (d, J = 6.9 Hz, 6H), 2.18 (d, J = 1.4 Hz, 3H), 2.45 (sept, J = 6.9 Hz, 1H), 6.20 (q, J = 1.4 Hz, 1H), 7.13ꢀ7.20 (m, 2H), 7.29ꢀ7.36 (m, 3H).
(E)-1,3-Diphenylbut-2-en-1-one.3f According to the typical procedure, the reaction of acetophenone (57.7 mg) and acetophenone (60.1 mg) at
rt for 2 h gave 1,3ꢀdiphenylbutꢀ2ꢀenꢀ1ꢀone (75.1 mg, 67%, E/Z = 87:13). TLC: Rf 0.30 (hexane/AcOEt = 10:1, stained green with anisaldehyde). 1H
NMR (400 MHz): δ = 2.60 (d, J = 0.9 Hz, 3H), 7.17 (q, J = 0.9 Hz, 1H), 7.37ꢀ7.45 (m, 3H), 7.47 (t, J = 7.8 Hz, 2H), 7.53ꢀ7.59 (m, 3H), 7.98ꢀ8.02
(m, 2H).
6
ACS Paragon Plus Environment

Page 7 of 13
The Journal of Organic Chemistry
1
(Z)-1,3-Diphenylbut-2-en-1-one.3f TLC: Rf 0.24 (hexane/AcOEt = 10:1, stained green with anisaldehyde). H NMR (400 MHz): δ = 2.32 (s,
1
2
3H), 6.69 (brs, 1H), 7.14ꢀ7.27 (m, 5H), 7.34 (t, J = 7.8 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H).
3
4
5
6
7
8
9
(E)-1-(4-Methoxyphenyl)-3-phenylbut-2-en-1-one.3f According to the typical procedure, the reaction of 4ꢀmethoxyacetophenone (150.2 mg)
and acetophenone (123.2 mg) at rt for 2 h gave 1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀphenylbutꢀ2ꢀenꢀ1ꢀone (136.2 mg, 54%, E/Z = 90:10). TLC: Rf 0.36
(hexane/AcOEt = 7:1, stained yellow green with anisaldehyde). 1H NMR (400 MHz): δ = 2.57 (d, J = 1.4 Hz, 3H), 3.88 (s, 3H), 6.95 (d, J = 8.7 Hz,
2H), 7.12 (q, J = 1.4 Hz, 1H), 7.38ꢀ7.45 (m, 3H), 7.55ꢀ7.59 (m, 2H), 8.00 (d, J = 8.7 Hz, 2H).
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
(E)-1-(4-Chlorophenyl)-3-phenylbut-2-en-1-one. TiCl4 (3.0 M CH2Cl2; 0.18 mL) and Bu3N (0.14 mL, 0.6 mmol) were successively added to
a stirred solution of 4ꢀchloroacetophenone (71.2 mg, 0.46 mmol) in CH2Cl2 (1.0 mL) at –78 °C. After 30 min, acetophenone (60.9 mg, 0.51 mmol)
was added to the mixture at –78 °C. After being stirred at −45 °C for 1 h, pyridine (0.20 mL, 2.5 mmol) was added at –45 °C and the reaction
mixture was warmed to room temperature. After being stirred for 2 h, the reaction mixture was diluted with Et2O (5 mL) and hexane (5 mL). The
mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by column chromatography on silica gel
(hexane/AcOEt = 30/1) to give 1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀphenylbutꢀ2ꢀenꢀ1ꢀone (102.7 mg, 87%, E/Z = 92:8). TLC: Rf 0.42 (hexane/AcOEt = 7:1,
stained orange with anisaldehyde). IR (film): 3061, 1657, 1593, 1211, 1090, 762 cmꢀ1. 1H NMR (400 MHz): δ = 2.60 (d, J = 1.4 Hz, 3H), 7.12 (q, J
= 1.4 Hz, 1H), 7.40ꢀ7.47 (m, 5H), 7.55ꢀ7.59 (m, 2H), 7.93 (d, J = 8.2 Hz, 2H). 13C NMR (100 MHz): δ = 19.0, 121.4, 126.5, 128.6, 128.8, 129.3,
129.7, 137.6, 138.9, 142.6, 156.0, 190.4. LRMS (FAB+, CHCl3+NBA): m/z 257 (M+H+, 100), 220 (M+–Cl, 16), 139 (ClC6H4CO+, 48). HRMS
(FAB+, CHCl3+NBA): Calcd for C16H14OCl (M+H+) 257.0733, found 257.0732.
(E)-3,4-Dimethyl-1-phenylpent-2-en-1-one.6 According to the typical procedure, the reaction of acetophenone (115.4 mg) and methyl
isopropyl ketone (88.9 mg) at −78 °C for 2 h gave 3,4ꢀdimethylꢀ1ꢀphenylꢀ2ꢀpentenꢀ1ꢀone (131.9 mg, 73%, E/Z = 88:12). TLC: Rf 0.18
1
(hexane/CH2Cl2 = 2:1, stained orange with anisaldehyde). H NMR (400 MHz): δ = 1.15 (d, J = 7.2 Hz, 6H), 2.17 (s, 3H), 2.49 (sept, J = 7.2 Hz,
1H), 6.74 (s, 1H) , 7.43ꢀ7.47 (m, 2H), 7.47ꢀ7,56 (m, 1H), 7.92 (d, J = 7.2 Hz, 2H).
(Z)-3,4-Dimethyl-1-phenyl-2-penten-1-one.6 TLC: Rf 0.24 (hexane/CH2Cl2 = 2:1, stained orange with anisaldehyde).1H NMR (400 MHz): δ
= 1.08 (d, J = 7.0 Hz, 6H), 1.92 (s, 3H), 3.78 (sept, 1H), 6.61 (s, 1H), 7.40ꢀ7.50 (m, 2H), 7.50ꢀ7.56 (m, 1H), 7.93 (d, J = 7.3 Hz, 2H).
(E)-1-Cyclopropyl-3-phenylbut-2-en-1-one. According to the typical procedure, the reaction of cyclopropyl methyl ketone (46.2 mg) and
acetophenone (60.7 mg) at rt for 1 h gave 1ꢀcyclopropylꢀ3ꢀphenylbutꢀ2ꢀenꢀ1ꢀone (71.7 mg, 77%, E/Z = 89:11). TLC: Rf 0.49 (hexane/AcOEt = 10:1,
1
stained dark green with anisaldehyde). IR (ATR): 3008, 1668, 1597, 1574, 1381, 1102, 1094, 974, 895, 760, 693 cmꢀ1. H NMR (600 MHz): δ =
0.89ꢀ0.94 (m, 2H), 1.09ꢀ1.13 (m, 2H), 2.03ꢀ2.08 (m, 1H), 2.54 (d, J = 1.3 Hz, 3H), 6.66 (q, J = 1.3 Hz, 3H), 7.34ꢀ7.41 (m, 3H), 7.49ꢀ7.52 (m, 2H).
13C NMR (150 MHz): δ = 11.2, 18.5, 22.8, 124.9, 126.5, 128.5, 128.9, 142.7, 152.9, 201.0. LRMS (FAB+, CHCl3+NBA): m/z 187 (M+H+, 100),
145 (PhMeC=CHCO+, 33). HRMS (FAB+, CHCl3+NBA): Calcd for C13H15O (M+H+) 187.1123, found 187.1119.
(E)-1-Cyclohexyl-3-phenylbut-2-en-1-one. According to the typical procedure, the reaction of cyclohexyl methyl ketone (60.5 mg) and
methyl acetophenone (61.0 mg) at rt for 1 h gave 1ꢀcyclohexylꢀ3ꢀphenylbutꢀ2ꢀenꢀ1ꢀone (94.1 mg, 86%, E/Z = 85:15). TLC: Rf 0.59
(hexane/acetone = 10:1, stained dark green with anisaldehyde). IR (ATR): 2926, 2852, 1678, 1598, 1573, 1446, 1145, 966, 757, 694 cmꢀ1. 1H NMR
(400 MHz): δ = 1.15ꢀ1.46 (m, 5H), 1.60ꢀ1.72 (m, 1H), 1.77ꢀ1.85 (m, 2H), 1.86ꢀ1.94 (m, 2H), 2.40ꢀ2.49 (m, 1H), 2.53 (d, J = 1.4 Hz, 3H), 6.54 (q, J
= 1.4 Hz, 1H), 7.34ꢀ7.42 (m, 3H), 7.46ꢀ7.51 (m, 2H). 13C NMR (100 MHz): δ = 18.4, 25.8, 25.9, 28.6, 52.1, 123.6, 126.4 128.5, 128.9, 142.8,
154.0, 204.6. LRMS (FAB+, CHCl3+NBA): m/z 229 (M+H+, 96), 145 (PhMeC=CHCO+, 100). HRMS (FAB+, CHCl3+NBA): Calcd for C16H21O
(M+H+) 229.1592, found 229.1591.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 13
(E)-2,2-Dimethyl-5-phenylhex-4-en-3-one. According to the typical procedure, the reaction of tertꢀbutyl methyl ketone (49.4 mg) and
acetophenone (60.0 mg) at rt for 1 h gave 2,2ꢀdimethylꢀ5ꢀphenylhexꢀ4ꢀenꢀ3ꢀone (86.3 mg, 87%, E/Z = 86:14). TLC: Rf 0.47 (hexane/acetone = 10:1,
stained black with anisaldehyde). IR (ATR): 2966, 1674, 1597, 1573, 1446, 1088, 958, 764, 694 cmꢀ1. 1H NMR (400 MHz): δ = 1.21 (s, 9H), 2.50
(d, J = 1.4 Hz, 3H), 6.74 (q, J = 1.4 Hz, 1H), 7.34ꢀ7.42 (m, 3H), 7.46ꢀ7.51 (m, 2H). 13C NMR (100 MHz): δ = 18.6, 26.6, 44.2, 120.8, 126,4 128.5,
128.8, 143.2, 154.1, 206.7. LRMS (FAB+, CHCl3+NBA): m/z 203 (M+H+, 61), 145 (PhMeC=CHCO+, 100). HRMS (FAB+, CHCl3+NBA): Calcd
for C14H19O (M+H+) 203.1436, found 203.1433.
1
2
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
(E)-5-(4-Methoxyphenyl)-2-methylhex-4-en-3-one. According to the typical procedure, the reaction of methyl isopropyl ketone (40.7 mg)
and pꢀmethoxyacetophenone (74.1 mg) at rt for 1 h gave 5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylhexꢀ4ꢀenꢀ3ꢀone (68.7 mg, 67%, E/Z = 82:18). TLC: Rf 0.47
1
(hexane/AcOEt = 7:1, stained dark green with anisaldehyde). IR (film): 2966, 1680, 1593, 1512, 1252, 1180, 829 cmꢀ1. H NMR (400 MHz): δ =
1.16 (d, J = 6.9 Hz, 6H), 2.54 (d, J = 1.4 Hz, 3H), 2.71 (sept, J = 6.9 Hz, 1H), 3.83 (s, 3H), 6.53 (q, J = 1.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 7.47
(d, J = 8.7 Hz, 2H). 13C NMR (100 MHz): δ = 18.2, 18.5, 42.0, 55.3, 113.8, 121,6 127.8, 134.8, 153.8, 160.4, 205.0. LRMS (FAB+, CHCl3+NBA):
m/z 219 (M+H+, 75), 175 (ArMeC=CHCO+, 100). HRMS (FAB+, CHCl3+NBA): Calcd for C14H19O2 (M+H+) 219.1385, found 219.1384.
(E)-5-(4-Chlorophenyl)-2-methylhex-4-en-3-one. According to the typical procedure, the reaction of methyl isopropyl ketone (41.3 mg) and
pꢀchloroacetophenone (72.8 mg) at rt for 1 h gave 5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀmethylhexꢀ4ꢀenꢀ3ꢀone (70.1 mg, 67%, E/Z = 73:27). TLC: Rf 0.57
(hexane/AcOEt = 10:1, stained dark green with anisaldehyde). IR (ATR): 2968, 1682, 1600, 1562, 1489, 1071, 1063, 1011, 967, 821, 770 cmꢀ1. 1H
NMR (400 MHz): δ = 1.15 (d, J = 6.9 Hz, 6H), 2.51 (d, J = 1.4 Hz, 3H), 2.71 (sept, J = 6.9 Hz, 1H), 6.52 (q, J = 1.4 Hz, 1H), 7.35 (d, J = 8.7 Hz,
2H), 7.42 (d, J = 8.7 Hz, 2H). 13C NMR (100 MHz): δ = 18.1, 18.2, 41.9, 123.3, 127.6, 128,5 134.8, 141.0, 152.5, 204.7. LRMS (FAB+,
CHCl3+NBA): m/z 223 (M+H+, 97), 179 (ArMeC=CHCO+, 100). HRMS (FAB+, CHCl3+NBA): Calcd for C13H16OCl (M+H+) 223.0890, found
223.0895.
(Z)-5-(4-Chlorophenyl)-2-methylhex-4-en-3-one. TLC: Rf 0.49 (hexane/AcOEt = 10:1, stained dark green with anisaldehyde). IR (ATR):
1
2970, 1689, 1616, 1594, 1490, 1092, 1013, 843, 823, 765 cmꢀ1. H NMR (600 MHz): δ = 1.02 (d, J = 6.9 Hz, 6H), 2.15 (d, J = 1.4 Hz, 3H), 2.51
(sept, J = 6.9 Hz, 1H), 6.24 (q, J = 1.4 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H). 13C NMR (150 MHz): δ = 18.2, 27.0, 40.8, 125.4,
128.3, 128.4, 133.8, 139.4, 151.2, 204.6. LRMS (FAB+, CHCl3+NBA): m/z 223 (M+H+, 100), 179 (ArMeC=CHCO+, 95). HRMS (FAB+,
CHCl3+NBA): Calcd for C13H16OCl (M+H+) 223.0890, found 223.0892.
(E)-2,5,6,6-Tetramethylhept-4-en-3-one.5b According to the typical procedure, the reaction of methyl isopropyl ketone (40.5 mg) and tertꢀ
butyl methyl ketone (48.3 mg) at rt for 2 h gave 2,5,6,6ꢀtetramethylheptꢀ4ꢀenꢀ3ꢀone (79.1mg, 99%, E/Z = 73:27). TLC: Rf 0.50 (hexane/AcOEt =
1
10:1, stained black with anisaldehyde). H NMR (400 MHz): δ = 1.09 (s, 9H), 1.12 (d, J = 6.9 Hz, 6H), 2.12 (s, 3H), 2.63 (sept, J = 6.9 Hz, 1H),
6.17 (s, 1H).
(E)-2-Methyl-5-phenylhept-4-en-3-one. According to the typical procedure, the reaction of methyl isopropyl ketone (44.1 mg) and
propiophenone (69.0 mg) with TMEDA (150 ꢀL) at rt for 24 h gave 2ꢀmethylꢀ5ꢀphenylheptꢀ4ꢀenꢀ3ꢀone (88.8 mg, 86%, E/Z = 56:44). TLC: Rf 0.52
(hexane/AcOEt = 10:1, stained dark green with anisaldehyde). IR (ATR) 2968, 1682, 1595, 1574, 1463, 1445, 1068, 1056, 764, 695. 1H NMR (600
MHz): δ = 1.06 (t, J = 7.2 Hz, 3H), 1.15 (d, J = 7.2 Hz, 6H), 2.70 (sept, J = 7.2 Hz, 1H), 3.04 (q, J = 7.2 Hz, 2H), 6.42 (s, 1H), 7.37ꢀ7.39 (m, 3H)
7.44ꢀ7.46 (m, 2H). 13C NMR (100 MHz): δ = 13.6, 18.4, 24.7, 42.0, 123.0, 126.8, 128.5, 128.8, 141.7, 160.7, 204.8. LRMS (FAB+, CHCl3+NBA):
m/z 203 (M+H+, 69), 159 (PhEtC=CHCO+, 100), 77 (Ph+, 87). HRMS (FAB+, CHCl3+NBA): Calcd for C14H19O (M+H+) 203.1436, found
203.1427.
8
ACS Paragon Plus Environment

Page 9 of 13
The Journal of Organic Chemistry
(Z)-2-Methyl-5-phenylhept-4-en-3-one. Rf 0.45 (hexane/AcOEt = 10:1, stained dark green with anisaldehyde). IR (ATR): 2968, 1693, 1672,
1
2
3
4
5
6
7
1618, 1598, 1464, 1442, 1381, 1092, 1013, 832, 765, 697. 1H NMR (400 MHz): δ = 0.97 (d, J = 7.2 Hz, 6H), 1.05 (d, J = 7.8 Hz, 3H), 2.38ꢀ2.52
(m, 3H), 6.15 (s, 1H), 7.10ꢀ7.16 (m, 2H) 7.26ꢀ7.38 (m, 3H). 13C NMR (100 MHz): δ = 12.3, 18.3, 33.2, 40.4, 124.0, 127.2, 127.7, 128.1, 140.5,
157.6, 206.2. LRMS (FAB+, CHCl3+NBA): m/z 203 (M+H+, 100), 159 (PhEtC=CHCO+, 100), 77 (Ph+, 90), 71 (iPrCO+, 85). HRMS (FAB+,
CHCl3+NBA): Calcd for C14H19O (M+H+) 203.1436, found 203.1442.
8
9
S-Phenyl (E)-3-phenylbut-2-enethioate. According to the typical procedure, the reaction of Sꢀphenyl thioacetate (76.3 mg) and acetophenone
(67.2 mg) at rt for 5 h gave Sꢀphenyl 3ꢀphenylbutꢀ2ꢀenethioate (108.3 mg, 85%, E/Z = 91:9). TLC: Rf 0.57 (hexane/AcOEt = 10:1, stained pale red
with anisaldehyde). mp 63–64 °C. IR (ATR): 3056, 1682, 1597, 1572, 1438, 1047, 936, 833, 735, 690, 566 cmꢀ1. 1H NMR (400 MHz): δ = 2.55 (d,
J = 1.4 Hz, 3H), 6.49 (q, J = 1.4 Hz, 1H), 7.37ꢀ7.54 (m, 10H). 13C NMR (100 MHz): δ = 18.9, 122.6, 126.6, 128,3 128.6, 129.1, 129.3, 129.5,
134.6, 141.5, 154.1, 187.7. LRMS (FAB+, CHCl3+NBA): m/z 255 (M+H+, 19), 145 (PhMeC=CHCO+, 100). HRMS (FAB+, CHCl3+NBA): Calcd
for C16H15OS (M+H+) 255.0844, found 255.0847.
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
S-Phenyl (E)-3,4-dimethylpent-2-enethioate. According to the typical procedure, the reaction of Sꢀphenyl thioacetate (79.0 mg) and methyl
isopropyl ketone (41.0 mg) at rt for 20 h gave Sꢀphenyl 3,4ꢀdimethylpentꢀ2ꢀenethioate (102.5 mg, 97%, E/Z = 87:13). TLC: Rf 0.62
(hexane/CH2Cl2 = 1:1, stained pale red with anisaldehyde). IR (ATR): 2964, 1683, 1616, 1440, 1031, 1023, 883, 830, 729, 688 cmꢀ1. 1H NMR (400
MHz): δ = 1.09 (d, J = 6.9 Hz, 6H), 2.11 (s, 3H), 2.38 (sept, J = 6.9 Hz, 1H), 6.07 (s, 1H), 7.38ꢀ7.46 (m, 5H). 13C NMR (100 MHz): δ = 17.6, 20.8,
38.2, 119.7, 128.5, 129.0, 129.1, 134.7, 164.8, 187.7. LRMS (FAB+, CHCl3+NBA): m/z 221 (M+H+, 23), 111 (iPrMeC=CHCO+, 100). HRMS
(FAB+, CHCl3+NBA): Calcd for C13H17OS (M+H+) 221.1000, found 221.1003.
Control Experiments for E/Z Isomerization. Table 3, entry 1 (from E isomer): TiCl4 (3.00 M in CH2Cl2; 0.12 mL) was added to a stirred
solution of H2O (6.1 ꢀL, 0.34 mmol) and Bu3N (0.1 mL, 0.41 mmol) in CH2Cl2 (0.68 mL) at –78 °C. After 0.5 h, TMEDA (0.05 mL, 0.34 mmol)
was added at –78 °C and the reaction mixture was warmed to room temperature. After 0.5 h, (E)ꢀ5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀmethylhexꢀ4ꢀenꢀ3ꢀone (76.7
mg, 0.34 mmol, E/Z = 97:3) was added to the mixture. After being stirred for 12 h, the reaction mixture was diluted with Et2O (5 mL) and hexane
1
(5 mL). The mixture was filtered through a Celite pad. The filtrate was concentrated to give the sufficiently pure crude product, which HꢀNMR
spectroscopic analysis indicated the E/Z ratio to be 97:3.
Table 3, entry 2 (from Z isomer): Similarly to the above procedure, (Z)ꢀ5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀmethylhexꢀ4ꢀenꢀ3ꢀone (6.8 mg, E/Z = 0:100) was
treated with the mixture of TiCl4 (3.00 M CH2Cl2; 0.01 mL), H2O (0.5 ꢀL), Bu3N (8.5 ꢀL) and TMEDA (4.5 ꢀL) in CH2Cl2 (0.06 mL) at room
temperature for 12 h. The 1HꢀNMR spectroscopic analysis of the crude product indicated the E/Z ratio to be 97:3.
Transformation of α,βꢀUnsaturated S-Phenyl Thioester to (E)-N-Methyl-3-phenylbut-2-enamide. According to the reported procedure,23
40% MeNH2 in H2O (12 ꢀL, 0.24 mmol) was added over 30 min to a stirred solution of Sꢀphenyl (E)ꢀ3,4ꢀdimethylpentꢀ2ꢀenethioate (50.9 mg, E/Z
= 100:0) in MeOH (2.6 mL) at 0 °C. After 2 h, the reaction mixture was concentrated. The residue was gave purified by column chromatography
on silica gel (hexane/AcOEt = 10:1) to give (E)ꢀNꢀmethylꢀ3ꢀphenylbutꢀ2ꢀenamide (30.5 mg, 87%, E/Z = 100:0). TLC: Rf 0.14 (hexane/AcOEt =
10:1, stained white with anisaldehyde). mp 119ꢀ120 °C. IR (ATR): 3251, 3077, 2919, 1651, 1619, 1563, 1447, 1365, 1287, 1234, 875, 764, 689
cmꢀ1. 1H NMR (600 MHz): δ = 2.55 (d, J = 1.1 Hz, 3H), 2.89 (d, J = 8.7 Hz, 3H), 5.70 (brs, 1H), 6.00 (q, J = 1.1 Hz, 1H), 7.30ꢀ7.37 (m, 3H), 7.40ꢀ
7.43 (m, 2H). 13C NMR (150 MHz): δ = 17.6, 26.1, 119.8, 126.1, 128.4, 142.7, 150.5, 167.6. LRMS (FAB+, CHCl3+NBA): m/z 176 (M+H+, 100),
145 (PhMeC=CHCO+, 24). HRMS (FAB+, CHCl3+NBA): Calcd for C11H14NO (M+H+) 176.1075, found 176.1077.
Transformation of α,βꢀUnsaturated S-Phenyl Thioester to (E)-3-Phenylbut-2-enal. DIBALꢀH (1.0 M in hexane, 0.30 mL) was added to a
stirred solution of Sꢀphenyl (E)ꢀ3,4ꢀdimethylpentꢀ2ꢀenethioate (50.4 mg, E/Z = 100:0) in methylcyclohexane (2.0 mL) at –78 °C. The reaction
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 13
mixture was stirred at –78 °C for 0.5 h and quenched with NaOH/H2O/EtOH (0.3 g/1.25 mL/1.75 mL). The mixture was extracted with AcOEt
(3×15mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/AcOEt = 20:1) to give (E)ꢀ3ꢀphenylbutꢀ2ꢀenal30 (23.9 mg, 82%, E/Z = 93:7). TLC: Rf 0.47 (hexane/AcOEt =
10:1, stained black with anisaldehyde). 1H NMR (400 MHz): δ = 2.58 (d, J = 1.4 Hz, 3H), 6.40 (dd, J = 7.8, 1.4 Hz, 1H), 7.36ꢀ7.48 (m, 3H), 7.50ꢀ
7.60 (m, 2H), 10.19 (d, J = 7.8 Hz, 1H).
1
2
3
4
5
6
7
8
9
Transformation of α,βꢀUnsaturated S-Phenyl Thioester to (E)-5-Phenylhex-4-en-3-one. According to the reported procedure with a
modification,25 EtZnI (0.50 M in THF/Et2O/hexane; 1.2 mL, prepared from diethylzinc and iodine according to the reported procedure31) was
added to a stirred solution of Sꢀphenyl (E)ꢀ3,4ꢀdimethylpentꢀ2ꢀenethioate (50.9 mg, E/Z = 100:0) and PdCl2(PPh3)2 (14.0 mg, 10 mol %) in toluene
(0.67 mL) at room temperature. After being stirred for 2 h, the reaction mixture was diluted with AcOEt and concentrated. The residue was gave
purified by column chromatography on silica gel (hexane/AcOEt = 30:1) to give (E)ꢀ5ꢀphenylhexꢀ4ꢀenꢀ3ꢀone3f (31.3 mg, 90%, E/Z = 100:0). TLC:
Rf 0.52 (hexane/AcOEt = 10:1, stained black with anisaldehyde). 1H NMR (400 MHz): δ = 1.13 (t, J = 7.3 Hz, 3H), 2.55 (d, J = 0.9 Hz, 3H), 2.57
(q, J = 7.3 Hz, 2H), 6.50 (q, J = 0.9 Hz, 1H), 7.33ꢀ7.42 (m, 3H), 7.45ꢀ7.52 (m, 2H).
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
Synthesis of ar-Atlantone. According to the typical procedure, the reaction of mesityl oxide (98.4 mg) and pꢀmethylacetophenone (134.2 mg)
1
at rt for 1 h gave arꢀatlantone27b (167.2 mg, 78%, E/Z = 91:9). TLC: Rf 0.57 (hexane/AcOEt = 7:1, stained black with anisaldehyde). H NMR
(CDCl3): δ = 1.92 (s, 3H), 2.22 (s, 3H), 2.37 (s, 3H), 2.56 (s, 3H), 6.19 (brs, 1H), 6.49 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H).
Synthesis of
α-Atlantone. According to the typical procedure, the reaction of mesityl oxide (51.2 mg) and 1ꢀ(4ꢀmethylꢀ3ꢀcyclohexenꢀ1ꢀ
yl)ethanone32 (66.0 mg) at rt for 2 h gave αꢀatlantone28c (74.4 mg, 71%, E/Z = 90:10). TLC: Rf 0.56 (hexane/AcOEt = 10:1, stained black with
anisaldehyde). 1H NMR (CDCl3): δ = 1.62 (s, 3H), 1.65ꢀ2.20 (m, 7H), 1.85 (s, 3H), 2.13 (s, 6H), 5.41 (brs, 1H), 6.06 (brs, 1H), 6.08 (brs, 1H).
ASSOCIATED CONTENT
Supporting Information
1H NMR spectra of the known compounds (the products in Table 1, the products in entries 1–4, 7–9, and 25 of Table 2, the products in
1
Scheme 1, (E)ꢀ3ꢀphenylbutꢀ2ꢀenal and (E)ꢀ5ꢀphenylhexꢀ4ꢀenꢀ3ꢀone in Scheme 2, arꢀatlantone and αꢀatlantone in Scheme 3). H and 13C
NMR spectra of the new compounds (the products in entries 5, 6 and 10–24 of Table 2, and the thioester products in Scheme 2). This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
msugiura@kumamotoꢀu.ac.jp
Author Contributions
All authors have given approval to the final version of the manuscript.
ACKNOWLEDGMENT
This work was partially supported by JSPS KAKENHI Grant Number 23590009 and 26460010.
10
ACS Paragon Plus Environment

Page 11 of 13
The Journal of Organic Chemistry
REFERENCES
1
2
3
4
5
6
7
8
9
(1) For selected examples, see: (a) Salomon, R. G.; Lal, K.; Mazza, S. M.; Zarate, E. A.; Youngs, W. J. J. Am. Chem. Soc. 1988, 110, 5213. (b)
Salomon, R. G.; Mazza, S. M.; Lal, K. J. Org. Chem. 1989, 54, 1562. (c) Li, S.; Chiu, P. Tetrahedron Lett. 2008, 49, 1741. (d) Esumi, T.; Mori, T.;
Zhao, M.; Toyota, M.; Fukuyama, Y. Org. Lett. 2010, 12, 888. (e) Esumi, T.; Yamamoto, C.; Fukuyama, Y. Synlett 2013, 1845. (f) Ciesielski, J.;
Gadon, V.; Frontier, A. J. J. Org. Chem. 2013, 78, 9541. (g) McGrath, K. P.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2014, 53, 1910. (h) Radomkit,
S.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2014, 53, 3387.
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
(2) Sugiura, M.; Sato, N.; Kotani, S. Nakajima, M. Chem. Commun. 2008, 4309.
(3) (a) Wadsworth Jr., W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. (b) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473. (c) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851. (d) Kanazawa, Y.;
Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J.; Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Chem. Eur. J. 2006, 12, 63. (e) Lu, S.ꢀM.; Bolm, C.
Chem. Eur. J. 2008, 14, 7513. (f) Nishikawa, Y.; Yamamoto, H. J. Am. Chem. Soc. 2011, 133, 8432.
(4) (a) Menger, F. M.; Saito, G. J. Am. Chem. Soc. 1973, 95, 6840. (b) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98,
4887.
(5) (a) Kashima, C.; Yamamoto, T. Heterocycles 1982, 19, 1211. (b) Dieter, R. K.; Silks, L. A. J. Org. Chem. 1986, 51, 4687. (c) Bartoli, G.;
Marcantoni, E.; Petrini, M.; Sambri, L. Chem. Eur. J. 1996, 2, 913. (d) Lipshutz, B. H.; Amorelli, B.; Unger, J. B. J. Am. Chem. Soc. 2008, 130,
14378.
(6) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 8862.
(7) (a) Sugawara, Y.; Yamada, W.; Yoshida, S.; Ikeno, T.; Yamada, T. J. Am. Chem. Soc. 2007, 129, 12902. (b) Yu, M.; Li, G.; Wang, S.;
Zhang, L. Adv. Synth. Catal. 2007, 349, 871. (c) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027. (d) Egi, M.; Yamaguchi, Y.; Fujiwara, N.;
Akai, S. Org. Lett. 2008, 10, 1867. (e) Pennell, M. N.; Turner, P. G.; Sheppard, T. D. Chem. Eur. J. 2012, 18, 4748.
(8) (a) Shibuya, M.; Ito, S.; Takahashi, M.; Iwabuchi, Y. Org. Lett. 2004, 6, 4303. (b) Li, J.; Tan, C.; Gong, J.; Yang, Z. Org. Lett. 2014, 16,
5370.
(9) Baker, B.; Gallagher, P. T. Donohoe, T. J. Tetrahedron 2013, 69, 3690.
(10) For titaniumꢀpromoted aldol reactions between simple ketones, see: (a) Yoshida, Y.; Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron
Lett. 1997, 38, 8727. (b) Yoshida, Y.; Matsumoto, N.; Hamasaki, R.; Tanabe, Y. Tetrahedron Lett. 1999, 40, 4227. (c) Tanabe, Y.; Matsumoto, N.;
Higashi, T. Misaki, T.; Itoh, T.; Yamamoto, M.; Mitarai, K.; Nishii, Y. Tetrahedron 2002, 58, 8269.
(11) For titaniumꢀpromoted aldol reactions of phenyl esters or Sꢀphenyl thioesters and simple ketones, see: (a) Tanabe, Y.; Matsumoto, N.;
Funakoshi, S.; Manta, N. Synlett 2001, 1959. (b) Nagase, R.; Matsumoto, N.; Hosomi, K.; Higashi, T.; Funakoshi, S.; Misaki, T.; Tanabe, Y. Org.
Biomol. Chem. 2007, 5, 151. Tanabe and his coꢀworkers also reported synthesis of triꢀ and tertrasubstitued α,βꢀunsaturated esters by crossꢀcoupling
reactions of enol tosylates, see: (c) Nakatsuji, H.; Ueno, K.; Misaki, T.; Tanabe, Y. Org. Lett. 2008, 10, 2131. (d) Nakatsuji, H.; Nishikado, H.;
Ueno, K.; Tanabe, Y. Org. Lett. 2009, 11, 4258. (e) Nishikado, H.; Nakatsuji, H.; Ueno, K.; Tanabe, Y. Synlett 2010, 2087. (f) Ashida, Y.; Sato,
Y.; Suzuki, T.; Ueno, K.; Kai, K.; Nakatsuji, H.; Tanabe, Y. Chem. Eur. J. 2015, 21, 5934.
(12) For other aldol additions to simple ketones, see: (a) Nozaki, N.; Oshima, K.; Takai, K.; Ozawa, S. Chem. Lett. 1979, 379. (b) Tsuji, J.;
Yamamda, T.; Kaito, M.; Mandai, T. Bull. Chem. Soc. Jpn. 1980, 53, 1417. (c) Allan, J. F.; Henderson, K. W.; Kennedy, A. R. Chem. Commun.
1999, 1325. (d) Cergol, K. M.; Turner, P.; Coster, M. J. Tetrahedron Lett. 2005, 46, 1505. (e) Cergol, K. M.; Jensen, P.; Turner, P.; Coster, M. J.
Chem. Commun. 2007, 1363. (f) Alcoberro, S.; GómezꢀPalomino, A.; Solà, R.; Romea, P.; Urpí, F.; FontꢀBardia, M. Org. Lett. 2014, 16, 584. For
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 13
Mukaiyama aldol reactions to ketones, see: (g) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 12, 1851. (h) Yanai, H.; Yoshino, Y.;
Takahashi, A.; Taguchi, T. J. Org. Chem. 2010, 75, 5375.
1
2
3
4
5
6
7
8
9
(13) We have reported the first enantioselective crossꢀaldol reaction between simple ketones, see: (a) Aoki, S.; Kotani, S.; Sugiura, M.;
Nakajima, M.; Chem. Commun. 2012, 48, 5524. For the first enantioselective aldol addition of silyl ketene acetals to simple ketones, see: (b)
Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233. (c) Denmark, S. E.; Fan, Y.; Eastgate, M. D. J. Org. Chem. 2005, 70, 5235. For a
review of catalytic enantioselective aldol additions to ketones, see: (d) Adachi, S.; Harada, T. Eur. J. Org. Chem. 2009, 22, 3661.
(14) Lower temperatures than rt (even 0 °C) for the elimination step significantly decreased the reaction rate and did not improve the E/Z
selectivity.
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
(15) NMP has been used as additive for TiCl4ꢀpromoted asymmetric aldol reactions, see: (a) Crimmins, M. T.; She, J. Synlett 2004, 1371. (b)
Sreenithya, A.; Sunoj, R. B. Org. Lett. 2012, 14, 5752.
(16) When the reaction was initiated with Bu3N (2.2 equiv.) at beginning, the yield of the desired enone was decreased to 52% yield.
(17) In this case, the desired enone, the aldol product (5ꢀhydroxyꢀ2ꢀmethylꢀ5ꢀphenylhexanꢀ3ꢀone), and a selfꢀaldol product (3ꢀhydroxyꢀ1,3ꢀ
1
diphenylbutanꢀ1ꢀone) were obtained in 59%, 15%, and 21% yields, respectively, according to the H NMR analysis of the crude product.
When TMEDA (1.0 equiv.) was used (Table 1, entry 10), no selfꢀaldol product but the aldol product was obtained in 3% yield along with the
desired enone. These results indicate that the excess amount of TMEDA suppressed the elimination and promoted the retroꢀaldol reaction.
(18) Pyridine and DMAP have been used as effective additives for acetylation of aluminium hemiacetals (intermediates of DIBALꢀH reduction
of esters), see: (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191.
(19) In Table 2, entry 7, β,γꢀunsaturated ketone 3,4ꢀdimethylꢀ1ꢀphenylpentꢀ3ꢀenꢀ1ꢀone was obtained in 38% yield, which indicated that DMF did
not deprotonate the carbonyl αꢀproton. In Table 2, entry 10, ringꢀopened product (E)ꢀ7ꢀchloroꢀ2ꢀphenylheptꢀ2ꢀenꢀ4ꢀone was obtained in 57% yield.
(20) The configurations of the known enone products were assigned on comparison with the literature data and those of the unknown enones
were determined by analogy.
(21) Water was added to reproduce the reaction conditions after the aldol reaction followed by the elimination of water.
(22) The reaction of phenyl acetate resulted in selfꢀClaisen condensation. Tanabe et al. did not employ phenyl acetate and Sꢀphenyl thioacetate
for their TiCl4ꢀpromoted aldol reaction, see ref. 11.
(23) Bae, H. Y.; Sim, J. H.; Lee, J.ꢀW.; List, B.; Song, C. E. Angew. Chem. Int. Ed. 2013, 52, 12143.
(24) Corey, E. J.; Huang, H.ꢀC. Tetrahedron Lett. 1989, 30, 5235.
(25) (a) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2004, 37, 87. (b) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (c) Zhou, G.; Lim, D.; Coltart, D. M. Org. Lett. 2008, 10, 3809.
(26) To the best of our knowledge, these functional group transformations have not been applied to β,βꢀdisubstituted α,βꢀunsaturated Sꢀphenyl
thioesters before. Especially, our modification for the DIBALꢀH reduction (use of methylcyclohexane as the solvent and workup under basic condiꢀ
tions) was found to be important for retaining the geometry of the starting material.
(27) Synthesis of arꢀatlantone: Sakai, (a) T.; Miyata, K.; Ishikawa, M.; Takeda, A. Tetrahedron Lett. 1985, 26, 4727. (b) Strunz, G. M.; Ya, L.
Can. J. Chem. 1992, 70, 1317.
(28) Synthesis of αꢀatlantone: (a) Crawford, R. J.; Erman, W. F.; Broaddus, C. D. J. Am. Chem. Soc. 1972, 94, 4298. (b) Babler, J. H.; Olsen, D.
O.; Arnold, W. H. J. Org. Chem. 1974, 39, 1656. (c) Andrianome, M.; Delmond, B. J. Org. Chem. 1988, 53, 542.
12
ACS Paragon Plus Environment

Page 13 of 13
The Journal of Organic Chemistry
(29) Barbee, T. R.; Albizati, K. F. J. Org. Chem. 1991, 56, 6764.
(30) Takaya, J.; Sasano, K.; Iwasawa, N. Org. Lett. 2011, 13, 1698.
1
2
3
4
5
(31) Charette, A. B.; Gagnon, A., Fournier, J.ꢀF. J. Am. Chem. Soc. 2002, 124, 386.
(32) Babler, J. H.; Olsen, D. O.; Arnold, W. H. J. Org. Chem. 1974, 39, 1656.
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
13
ACS Paragon Plus Environment