Gold-mediated synthesis and functionalization of chiral halopyridones

Article abstract of DOI:10.1021/jo400827b

A rapid and efficient one-step halopyridone synthesis has been developed based on gold-catalyzed cyclization of β-amino-ynone intermediates and halodeauration process.

Full text of DOI:10.1021/jo400827b

Subscriber access provided by RYERSON UNIV
Article
Gold-Mediated Synthesis and Functionalization of Chiral Halopyridones
Khanh Hung Nguyen, Sophie Tomasi, Myriam Le Roch, Loic
Toupet, Jacques Renault, Philippe Uriac, and Nicolas Gouault
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400827b • Publication Date (Web): 08 Jul 2013
Downloaded from http://pubs.acs.org on July 21, 2013
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 19
The Journal of Organic Chemistry
1
2
3
4
5
Gold-Mediated
Halopyridones
Synthesis
and
Functionalization
of
Chiral
6
7
8
Khanh Hung Nguyen,† Sophie Tomasi,† Myriam Le Roch,† Loïc Toupet,‡ Jacques Renault,† Philippe Uriac† and
Nicolas Gouault†*
9
†
Equipe PNSCM, UMR 6226, Université de Rennes 1, 2 avenue du Pr. Léon Bernard 35043 Rennes Cedex, France.
IPR, UMR 6251, Institut de Physique de Rennes, Université de Rennes 1, 263 avenue du général Leclerc, 35042 Rennes
‡
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
Cedex, France.
Eꢀmail : nicolas.gouault@univꢀrennes1.fr
__________________________________________________________________________________________________
Abstract: A rapid and efficient one step halopyridone synthesis has been developed based on goldꢀcatalyzed cyclization of
βꢀaminoꢀynone intermediates and halodeauration process.
__________________________________________________________________________________________________
■ INTRODUCTION
Among the synthetic approaches reported in the literature to construct heterocyclic molecules, the use
of electrophilic halogen sources have proven very efficient to obtain highly functionalized
heterocyclic compounds.1,2 These methodologies, which typically lead to the incorporation of
halogens into the heterocyclic structure, allow for the creation of molecular diversity and complexity
postꢀcyclization. For example, halopyridones have revealed to be very attractive synthetic building
blocks for the preparation of piperidines. The key step in these methodologies generally involved
Comins’s 2,3ꢀdihydroꢀ4ꢀpyridone intermediates generated from acyl pyridinium then halogenations.3
In this way, methods leading to such intermediates with strict control of regioꢀ and stereochemistry
continue to stand as prominent objective in synthetic organic chemistry.
Besides the classical electrophilic iodocyclization methods,1,2 gold catalysis has emerged in the last
few years as a powerful tool for controlling the formation of carbonꢀhalogen bonds.4 The process, in
such approaches, involved a final halodeauration step (instead of a protodeauration) at the end of the
catalytic cycle.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
5
6
7
8
Recently, we have developed an access to pyridones from the chiral pool of amino acids via a goldꢀ
catalyzed heterocyclization strategy.5 We showed that the use of gold catalysis in this process allowed
an excellent stereocontrol during the cyclization (Scheme 1). It was also demonstrated that this
approach provides a straightforward tool for the total synthesis of natural products such as piperidine
alkaloids (+)ꢀ241ꢀD, isosolenopsin and isoslenopsin A in few steps and good overall yields.5b
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
Scheme 1. GoldꢀCatalyzed Synthesis of Pyridones towards Piperidines Alkaloids.
On the basis of our previous works,5 we describe herein a new approach towards halopyridones.
The strategy is based on a one pot goldꢀcatalyzed tandem reaction consisting of heterocyclization and
halogenation (Scheme 2). The results of our study and some palladium catalyzed coupling reactions
are disclosed in this article.
Scheme 2. Our Proposed Route to Halopyridones.
■ RESULTS AND DISCUSSION
The starting materials, the βꢀaminoꢀynones 1 were prepared from commercially available amino
acids via Weinreb amide formation and subsequent addition of various lithium acetylides.5a,6 We first
performed a catalyst screening to optimize the cyclization conditions. In this way, substrate 1a was
subjected to various catalysts and other activating agents in various conditions (Table 1). As the
stoichiometric use of simple electrophilic halogen sources has been frequently used to construct a
wide range of carbocycles7 and heterocycles,1,2 the reaction of aminoꢀynone 1a was initially examined
2
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
with the use of 2 equiv of I2 or NIS (Table 1, entries 1ꢀ2). Notably, the starting aminoꢀynone did not
react under these conditions or afforded at most small amounts of 5ꢀiodopyridone 2a. Various
catalytic conditions were then investigated to probe the feasibility of the proposed transformation.
8
9
Table 1. Optimization of the Reaction Conditionsa for the Iodocyclization of 1a.
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
O
O
I
Catalyst, Electrophile
Conditions
Ph
1a
NH
N
Ph
Boc
Boc
2a
Entry Catalyst
E+ (equiv)
Time (h) Yield (%)c
1
2
3
4
5
6
7
8
9
ꢀ
NIS (2.0)
I2 (2.0)
24
24
0.5
0.5
72
72
1
nrd
nr
ꢀ
b
b
Ph3PAuSbF6
Ph3PAuSbF6
AuCl
NIS (1.5)
NIS (1.0)
NIS (1.5)
NIS (1.5)
I2 (1.5)
78
60
<10
<10
65
Au2O3
b
Ph3PAuSbF6
Ph3PAuCl
AgSbF6
NIS (1.5)
48
<10
NIS (1.5)
48
<10
a Unless indicated otherwise, a mixture of 1a (0.1 mmol), a gold complex (5 mol%) and electrophile (1.5 equiv) in 1,2ꢀ
DCE (1.0 mL) was stirred at room temp. under argon.
b The Ph3PAuSbF6 was in situ generated from 5 mol% of Ph3PAuCl and 5 mol% of AgSbF6
c Isolated yield.
.
d No reaction.
Several gold sources, in the presence or absence of coꢀcatalyst were tested. Results revealed that the
use of PPh3AuCl in the presence of AgSbF6,8 and NIS as electrophile, in 1,2ꢀdichloroethane (DCE) at
room temperature, afforded in 0.5 h the desired product 2a in good yield (entry 3). Stoichiometric use
of NIS gave the desired product in lower yield (entry 4). The cyclization did not proceed in the
presence of AuCl or Au2O3 as catalysts (entries 5ꢀ6). Complementary study on solvents prompted us
to choose 1,2ꢀDCE that proved to be more efficient than THF or toluene. The use of iodine (entry 7)
instead of NIS as electrophilic iodine source did not improve the reaction. As expected, no reaction
was observed when we used AgSbF6 or PPh3AuCl catalyst independently (entries 8 and 9). These
results emphasize the importance of the anion exchange to obtain catalytic activity. Thus, we selected
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
Ph3PAuSbF6 as catalyst, Nꢀhaloꢀsuccinimide as source of halogen and 1,2ꢀDCE as solvent for further
investigations of this methodology.
5
6
7
8
9
To demonstrate the scope of this goldꢀmediated haloꢀcyclization reaction, a variety of βꢀaminoꢀ
ynones were examined. As depicted in Table 2, a series of 5ꢀhaloꢀ2,3ꢀdihydropyridone derivatives 2a-
r could be successfully obtained from moderate to excellent yields. Firstly, the nature of halogen
source was checked (entries 1ꢀ2) and both NIS and NBS showed good reactivity, providing the
corresponding products (2a and 2b) in good to excellent yields. However, NCS revealed unreactive
under these conditions since cyclization in 2,3ꢀdihydropyridone occurred without any incorporation of
chlorine atom (entry 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
Table 2. GoldꢀCatalyzed Halocyclization of βꢀAminoꢀynones 1 to 5ꢀHalopyridones 2.a
O
O
X
PPh3AuCl (5 mol%)
AgSbF6 (5 mol%)
R2
+
NXS
R1
NH
R1
N
R2
Boc
Boc
1
2
Entry R1
R2
X
Product Yield
(%)b
Entry R1
R2
X
Product Yield
(%)
1
H
Ph
Ph
Ph
I
78
91
0
12
13
14
15
16
17
18
19
20
21
iꢀBu
nꢀPr
Ph
I
71
79
79
65
87
93
80
48c
47
0
2a
2b
-
2j
2
H
Br
Cl
Bn
Bn
Bn
Bn
Br
I
2k
2l
3
H
Ph
4
H
4ꢀMeOꢀPh Br
85
86
83
88
0
nꢀPr Br
2c
2d
2e
2f
-
2m
2n
2o
2p
2q
2r
-
5
H
4ꢀFꢀPh
4ꢀFꢀPh
nꢀPr
H
Br
I
nꢀPr
Ph
I
6
H
CH2ꢀOBn
CH2ꢀOBn
CH2ꢀOBn
CH2ꢀOBn
H
Br
I
7
H
I
Ph
8
H
I
nꢀPr Br
9
Me
iꢀBu
iꢀBu
nꢀPr
Ph
I
70
97
76
nꢀPr
I
2g
2h
2i
10
11
Br
I
Ph
F
Ph
a Reaction conditions: substrate 1 (1 mmol), NXS (1.5 mmol), PPh3AuCl (5 mol%), AgSbF6 (5 mol%), 1,2ꢀDCE (10.0 mL), r.t., 1 h.
b
Isolated yield.
12 h. were necessary for completion of reaction.
c
We next extended this protocol to various alkynes (entries 3ꢀ8). The results revealed that a
substituent on the phenyl group (entries 4ꢀ6) and a substrate bearing an alkyl group (entry 7) did not
significantly affect the reaction. Unfortunately, none of the desired product was obtained when a
4
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
terminal alkyne (entry 8) was employed. Application to chiral substrates was then investigated.
Actually, a series of substituents on C2 (R1) were tested (entries 9ꢀ20) and it could be noted that all
reactions proceeded smoothly to provide the corresponding products in good to excellent yields.
Attempts to extend this chemistry to the synthesis of fluoro analogues by using selectfluor® as source
of F+ were not successful since only protodeauration product was isolated (entry 21).
Reactivity of a propargylic alcohol in such catalytic conditions was also investigated (Scheme 3).
Propargylic alcohol 3 was obtained quantitatively from 1a via a Luche reduction. We next examined
the reaction of 3 and NIS in the presence of Au catalyst. αꢀIodoketone 4 was obtained in a Meyerꢀ
Schuster rearrangement process and no heterocyclization was observed. Such reactivity of propargylic
alcohols was already reported in the literature.9
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
Scheme 3. Reactivity of propargylic alcohol.
The structures of the halogenation products have been established by NMR analyses. Moreover two
of them were further confirmed by Xꢀray crystallographic analyses.10
Finally, 2g was also prepared starting from Dꢀalanine. With both enantiomers in hand, the
enantiomeric purity of 2g was confirmed by chiral HPLC to be > 98% ee, assessing that no
epimerization occurs during this process.
These halogenated pyridones were further functionalized by applying palladiumꢀcatalyzed
processes such as SuzukiꢀMiyaura,11 Heck12 or Stille13 crossꢀcoupling reactions (Scheme 4).
Scheme 4. PdꢀCatalyzed Modifications of 5ꢀHalopyridones 2.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
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
For instance, compounds 5 and 6 have been successfully obtained in 90% and 78% isolated yield
respectively by the Suzuki crossꢀcoupling reaction of 2j with 4ꢀfluorophenylboronic acid and the
Heck coupling reaction of 2a with ethyl acrylate. It should be mentioned that the temperature had an
incidence on the protecting group in such processes. Actually, when Heck coupling reaction with 2n
and 2r were performed at 110°C (instead of 80°C in the first case), deprotected compounds 7 and 8
could be obtained in good yield (78% and 67% isolated yield respectively). In a similar manner,
reaction of 2g with tributylvinylstannane gave the corresponding Stille coupling adduct 9 in a 88%
isolated yield.
Mechanistically, gold(I) catalyst coordinates to the triple bond to form a complex that undergoes 6ꢀ
endoꢀdig cyclization to give intermediate A (Scheme 5). In a classic manner, next demetalation
proceeds via a proton transfer providing heterocycle B in a protodeauration step. Such heterocycle
could then undergo halogenation to afford 2.3 The other possibility is the attack of a halonium ion
which would result in the direct formation of halopyridone 2 (halodeauration process) excluding
intermediate B.
Scheme 5. Mechanistic Consideration of the Process.
6
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
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
To probe the second mechanistic hypothesis, we conducted control experiments. The kinetic
investigation of this goldꢀcatalyzed cyclization was performed in CD2Cl2 and monitored by 1H NMR.
Goldꢀcatalyzed cyclization in the presence of NIS (eq 1) was shown to be complete within ten
minutes14 whereas goldꢀcatalyzed cyclization in the absence of NIS (eq 2) was complete in more than
thirty minutes. In addition, iodination (NIS) of heterocycle B in the presence of gold catalyst (eq 3)
was faster (reaction complete within 15 minutes) than in absence of gold catalyst (eq 4) (reaction
complete in 1 hour). These results may suggest that this iodocyclization proceeded via a
halodeauration process since the demetalation is faster in the presence of NIS.
Finally, when compared to a two steps protocol, the goldꢀcatalyzed tandem heterocyclizationꢀ
halogenation process revealed more efficient (91 % yield vs 66 %) (Scheme 6).
Scheme 6. One Step vs Two Steps Processes.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
6
O
O
PPh3AuCl (5 mol%)
AgSbF6 (5 mol%)
Br
Ph
1a
N
Ph
NH
NBS
Boc
Boc
(91 %)
2b
DCE, 1 h, r.t.
7
8
9
O
O
O
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
PPh3AuCl (5 mol%)
AgSbF6 (5 mol%)
H
Br
NBS
Ph
1a
N
Ph
N
Ph
NH
DCE, 1 h, r.t.
DCE, 1 h, r.t.
Boc
Boc
Boc
2b
(85 %)
(78 %)
■ CONCLUSION
In conclusion, we have developed a convenient goldꢀcatalyzed approach for the synthesis of 5ꢀ
halopyridone derivatives from βꢀaminoꢀynone intermediates via a halodeauration process. The
reactions proceeded under mild conditions and generally provided the pyridone products in good to
excellent yields. This methodology could provide a straightforward tool for the synthesis of naturally
occurring 2,5,6ꢀtrisubstituted piperidines and other decahydroquinolines.
■ EXPERIMENTAL SECTION
General Procedure for the Tandem Heterocyclization/halogenation Reaction. To the aminoꢀ
ynone 1 (1 mmol, 1 eq) in 1,2ꢀdichoroethane (10 mL) at room temperature under argon atmosphere
was added NXS (1.5 eq). After 5 minutes, a dry mixture of PPh3AuCl (5 mol%) and AgSbF6 (5
mol%) was added to the solution. After the resulting mixture was stirred at room temperature for 1 h,
Et2O was added and the resulting mixture was filtered over a Celite® plug. After removal of solvents
in vaccuo, the crude product was purified by silica gel column chromatography using dichloromethane
as an eluant to yield pure products.
(2a) : yellow solid, mp: 124ꢀ126oC, 311mg (78 %); 1H NMR (500 MHz, CDCl3): δ = 1.05 (s, 9H),
2.87ꢀ2.91 (m, 2H), 4.22ꢀ4.27 (m, 2H), 7.38ꢀ7.44 (m, 5H); 13C NMR (125 MHz, CDCl3): δ = 189.5,
158.7, 151.9, 140.0, 129.7, 128.8, 127.9, 89.7, 83.3, 46.4, 37.7, 27.4; HRMS (ESI, m/z): Calcd. for
8
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
C16H18INO3Na: 422.0229, found [M+Na]+: 422.0228; IRꢀFT ( DRA) 2967, 1711, 1669, 1590, 1346
cmꢀ1.
1
(2b): yellow oil, 320 mg (91 %); H NMR (300 MHz, CDCl3): δ = 1.05 (s, 9H), 2.85 (t, J = 6.5
8
9
Hz, 2H), 4.25 (t, J = 6.6 Hz, 2H), 7.40ꢀ7.44 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 188.1, 155.4,
152.0, 137.3, 129.7, 128.7, 128.0, 109.2, 83.3, 46.1, 38.5, 27.4; HRMS (ESI, m/z): Calcd. for
C16H18BrNO3Na: 374.0368, found [M+Na]+: 374.0371; IRꢀFT ( ATR) 2978, 1711, 1677, 1538, 1337
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
cmꢀ1.
(2c) : yellow oil, 325 mg (85 %); 1H NMR (500 MHz, CDCl3): δ = 1.10 (s, 9H), 2.82ꢀ2.84 (m, 2H), 3.86 (s,
3H), 4.21ꢀ4.24 (m, 2H), 6.93 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ =
188.3, 160.9, 155.3, 152.3, 130.5, 129.5, 113.3, 108.9, 83.1, 55.4, 46.0, 38.7, 27.5; HRMS (ESI, m/z): Calcd.
for C17H20BrNO4Na: 404.0473, found [M+Na]+: 404.0471; IRꢀFT ( ATR) 2976, 1707, 1673, 1503, 1337
cmꢀ1.
(2d): yellow solid, mp: 120ꢀ122oC, 318 mg (86 %); 1H NMR (300 MHz, CDCl3): δ = 1.08 (s, 9H),
2.80ꢀ2.84 (m, 2H), 4.20ꢀ4.24 (m, 2H), 7.06ꢀ7.12 (m, 2H), 7.38ꢀ7.41 (m,2H); 13C NMR (75 MHz,
CDCl3): δ = 187.9, 163.2 (d, JCF = 250.9 Hz), 154.2, 151.8, 133.2 (d, JCF = 3.5 Hz), 130.7 (d, JCF = 8.6
Hz), 115.0 (d, JCF = 21.9 Hz), 109.5, 83.4, 46.0, 38.4, 27.4; HRMS (ESI, m/z): Calcd. for
C16H17FBrNO3Na: 392.0274, found [M+Na]+: 392.0274; IRꢀFT (DRA) 2341, 1741, 1727, 1364, 1216
cmꢀ1.
(2e): orange solid, mp: 98ꢀ100oC, 346 mg (83 %); 1H NMR (300 MHz, CDCl3): δ = 1.12 (s, 9H,),
2.87ꢀ2.91 (m, 2H), 4.24ꢀ4.28 (m, 2H), 7.16ꢀ7.20 (m, 2H), 7.40ꢀ7.44 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ = 189.5, 163.3 (d, JCF = 250.9 Hz), 157.7, 151.8, 136.0 (d, JCF = 3.5 Hz), 131.0 (d, JCF = 8.6
Hz), 115.1 (d, JCF = 21.9 Hz), 90.2, 83.6, 46.4, 37.8, 27.5; HRMS (ESI, m/z): Calcd. for
C16H17IFNO3Na: 440.0135, found [M+Na]+: 440.0132; IRꢀFT ( DRA) 2357, 1741, 1726, 1381, 1216
cmꢀ1.
1
(2f): yellow oil, 322.4 mg (88%); H NMR (500 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 2.90H), 1.54 (s,
9H), 1.64ꢀ1.67 (m, 2H), 2.72ꢀ2.74 (m, 2H), 3.07ꢀ3.10 (m, 1.90H), 3.99ꢀ4.02 (m, 1.90H); 13C NMR (125 MHz,
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
CDCl3): δ = 188.8, 163.1, 151.5, 92.4, 83.5, 46.7, 41.8, 36.9, 28.1, 21.1, 13.8; HRMS (ESI, m/z): Calcd. for
3
4
C13H20INO3Na: 388.0386, found [M+Na]+: 388.0383; IRꢀFT ( ATR) 2968, 1712, 1673, 1551, 1142 cmꢀ1.
5
6
7
8
(2g): yellow oil, 265.4 mg (70%); [α]D25= +129.0 (c 0.4, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ
= 1.03 (t, J = 7.3 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.56 (s, 9H), 1.55ꢀ1.77 (m, 2H), 2.56 (sys ABX,
JAB = 16.9 Hz, JAX = 1.6 Hz, 1H), 2.92ꢀ2.98 (m, 1H), 3.00 (sys ABX, JAB = 16.9 Hz, JBX = 5.9 Hz, 1H),
3.23ꢀ3.29 (m, 1H), 4.77 (m, 1H); 13C NMR (125 MHz, CDCl3): δ = 187.7, 159.8, 151.8, 90.4, 83.4,
52.0, 42.1, 42.0, 28.0, 20.9, 16.6, 13.9; HRMS (ESI, m/z): Calcd. for C14H22INO3Na: 402.0537, found
[M+Na]+: 402.0537; IRꢀFT ( ATR) 2967, 1711, 1669, 1590, 1346 cmꢀ1; IRꢀFT (ATR) 2958, 1710,
1670, 1539, 1312 cmꢀ1.
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
(2h) : orange oil, 396 mg (97 %); [α]D25 = + 22.8 (c 1.2, MeOH); 1H NMR (500 MHz, CDCl3): δ
= 1.01 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 1.05 (s, 9H), 1.48ꢀ1.54 (m,1H), 1.69ꢀ1.87 (m,2H),
2.69 (dd, J = 17.0 Hz, J = 1.1 Hz, 1H,), 3.14 (dd, J = 17.0 Hz, J = 5.9 Hz, 1H), 4.85ꢀ4.92 (m, 1H),
7.36ꢀ7.83 (m, 5H); 13C NMR (125 MHz, CDCl3): δ = 187.4, 152.9, 152.6, 138.1, 129.6, 128.6, 128.0,
108.6, 83.2, 53.9, 42.4, 39.3, 27.4, 25.3, 22.7, 22.6; HRMS (ESI, m/z): Calcd. For C20H26NO3BrNa:
430.0994, found [M+Na]+: 430.0995; IRꢀFT (ATR) 2956, 1707, 1677, 1541, 1312 cmꢀ1.
(2i): yellow oil, 346 mg (76 %); [α]D25 = + 15.8 (c 1.2, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ
= 1.02 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 1.06 (s, 9H), 1.48ꢀ1.52 (m, 1H), 1.73ꢀ1.78 (m,
2H), 2.74 (dd, J = 17.2 Hz, J = 1.0 Hz, 1H), 3.15 (dd, , J = 17.1 Hz, J = 5.8 Hz, 1H), 4.83ꢀ4.86 (m,
1H), 7.33ꢀ7.42 (m, 5H); 13C NMR (125 MHz, CDCl3): δ = 188.7, 156.3, 152.4, 140.8, 129.5, 128.7,
127.9, 89.2, 83.2, 54.1, 41.6, 39.3, 27.4, 25.2, 22.8, 22.6; HRMS (ESI, m/z): ): Calcd. for
C20H26INO3Na: 478.0855, found [M+Na]+: 478.0858; IRꢀFT ( ATR) 2956, 1706, 1670, 1530, 1286
cmꢀ1.
(2j): yellow oil, 299.3 mg (71 %); [α]D25 = + 295.8 (c 1.1, MeOH); 1H NMR: (500 MHz, CDCl3)
δ = 0.90 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H), 1.29ꢀ1.31 (m, 1H),
1.54 (s, 9H), 1.54ꢀ1.63 (m, 4H), 2.60 (d, J = 17.1 Hz, 1H), 2.88ꢀ2.91 (m, 1H), 2.95 (dd, J = 17.1 Hz, J
= 5.8 Hz, 1H), 3.19ꢀ3.25 (m, 1H), 4.68ꢀ4.72 (m, 1H); 13C NMR (125 MHz, CDCl3): δ = 187.8, 160.4,
10
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
152.0, 91.7, 83.3, 54.4, 42.2, 40.9, 39.2, 28.0, 24.8, 22.7, 22.4, 21.0, 14.0; HRMS (ESI, m/z): Calcd.
3
4
5
6
for C17H28INO3Na : 444.1011, found [M+Na]+ 444.0999; IRꢀFT (ATR) 2958, 1711, 1670, 1537, 1312
:
cmꢀ1.
7
8
9
25
1
(2k) : yellow oil, 349.5 mg (79%); [α]D = + 315.6 (c 1.2, CH2Cl2); H NMR (500 MHz,
CDCl3): δ = 1.04 (s, 9H), 2.67 (d, J = 17.3 Hz, 1H), 3.00 (dd, 1H, J = 17.3 Hz, J = 6.0 Hz), 3.07ꢀ3.12
(m, 1H), 3.17ꢀ3.21 (dd, J = 13.6 Hz, J = 6.0 Hz, 1H) 5.07ꢀ5.11 (m, 1H), 7.26ꢀ7.39 (m, 10H); 13C
NMR (125 MHz, CDCl3): δ = 187.0, 152.9, 152.2, 137.7, 136.4, 129.6, 129.5. 128.7, 128.6, 127.9,
127.0, 108.5, 83.4, 56.1, 40.5, 36.4, 27.3; HRMS (ESI, m/z): Calcd. for: C23H24NO3Br : 464.0837,
found [M+Na]+: 464.0835; IRꢀFT ( ATR) 2979, 1707, 1674, 1538, 1316 cmꢀ1.
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
(2l): yellow oil, 386 mg (79%); [α]D25 = + 315.6 (c 1.3, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ
= 1.04 (s, 9H), 2.72 (d, J = 17.1 Hz, 1H), 2.99ꢀ3.08 (m, 2H), 3.17 (dd, J = 13.4 Hz, J = 6.2 Hz, 1H),
13
5.02ꢀ5.06 (m, 1H), 7.22ꢀ7.37 (m, 10H); C NMR (125 MHz, CDCl3): δ = 188.4, 156.3, 152.1, 140.4,
136.4, 129.5, 128.7. 127.9, 127.0, 88.9, 83.4, 56.4, 39.6, 36.3, 27.3; HRMS (ESI, m/z): Calcd. for:
C23H24INO3Na : 512.0699, found [M+Na]+: 512.0699; IRꢀFT ( ATR) 2981, 1698, 1670, 1533, 1317
cmꢀ1.
(2m): yellow oil, 265.4 mg (65%); [α]D25 = + 18.5 (c 0.8, CH2Cl2); 1H NMR (300 MHz, CDCl3):
two rotamers in a ratio 85/15 δ = 0.97 (t, J = 7.4 Hz, 0.45H), 1.03 (t, J = 7.4 Hz, 2.55H),1.39 (s, 1.5H),
1.48 (s, 7.5H), 1.64ꢀ1.70 (m, 2H), , 2.57 (dd, J = 7.2 Hz, J = 1.7 Hz, 1H), 2.80ꢀ3.10 (m, 5H), 4.80ꢀ4.84
(m, 1H), 7.11ꢀ7.33 (m, 5H); 13C NMR (75 MHz, CDCl3):185.9, 157.6, 151.6, 136.7, 129.4, 128.6,
126.9, 109.9, 83.5, 57.3, 39.8, 37.6, 36.3, 27.9, 20.8, 14.1; HRMS (ESI, m/z): Calcd. for
C20H26NO3BrNa : 430.0994, found [M+Na]+: 430.0993; IRꢀFT ( ATR) 2970, 1715, 1673, 1547, 1136
cmꢀ1.
(2n) : yellow oil, 396.1 mg (87 %); [α]D25 = + 223.6 (c 0.8, CH2Cl2); 1H NMR (500MHz, CDCl3)
δ = 1.02 (t, J = 7.4 Hz, 3H), 1.49 (s, 9H), 1.63ꢀ1.70 (m, 1H), 2.62 (d, J = 17.1 Hz, 1H), 2.78ꢀ2.96 (m,
4H), 3.17ꢀ3.23 (m, 1H), 4.76ꢀ4.80 (m, 1H), 7.11ꢀ7.31 (m, 5H); 13C NMR (125 MHz, CDCl3): δ =
187.4, 160.2, 151.5, 136.8, 129.4, 128.6, 126.8, 90.6, 83.5, 57.4, 42.2, 38.9, 36.3, 27.9, 21.2, 14.0;
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
6
HRMS (ESI, m/z): Calcd. for C20H26INO3Na : 478.0855, found [M+Na]+ : 478.0857; IRꢀFT (ATR)
2968, 1715, 1666, 1533, 1248 cmꢀ1.
25
1
(2o) : orange oil, 439.3 mg (93%); [α]D = + 195.5 (c 1.05, CH2Cl2); H NMR (500 MHz,
CDCl3): δ = 1.04 (s, 9H), 2.81 (d, J = 17.7 Hz, 1H), 3.16 (dd, J = 17.7 Hz, J = 6.4 Hz, 1H), 3.66 (dd, J
= 17.0 Hz, J = 6.0 Hz, 1H), 3.85ꢀ3.89 (m, 1H), 4.58 (d, syst.AB, J = 11.9 Hz, 1H), 4.65 (d, syst. AB, J
= 11.9 Hz, 1H), 5.09ꢀ5.13 (m, 1H), 7.26ꢀ7.39 (m, 10H); 13C NMR (125 MHz, CDCl3): δ = 186.8,
153.0, 152.4, 138.0, 137.6, 129.5, 128.8, 128.4, 127.8, 127.8, 127.7, 109.1, 83.3, 73.2, 68.1, 53.8, 39.6,
27.4; HRMS (ESI, m/z): Calcd. for C24H26BrNO4Na: 494.0943, found [M+Na]+: 494.0941; IRꢀFT
( ATR) 2978, 1707, 1677, 1543, 1311 cmꢀ1.
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
25
1
(2p) : orange oil, 415.5 mg (80 %); [α]D = + 250.9 (c 1.2, CH2Cl2); H NMR (500 MHz,
CDCl3): δ = 1.04 (s, 9H), 2.86 (d, J = 17.5 Hz, 1H), 3.18 (dd, J = 17.7 Hz, J = 6.4 Hz, 1H), 3.64 (dd, J
= 10.1 Hz, J = 6.4 Hz, 1H), 3.85 (dd, 1H, J = 10.1 Hz, J = 8.1 Hz), 4.58 (d, syst. AB, J = 11.9 Hz, 1H),
4.64 (d, syst. AB, J = 11.9 Hz, 1H), 5.07ꢀ5.10 (m, 1H), 7.18ꢀ7.41 (m, 10H); 13C NMR (125 MHz,
CDCl3): δ = 188.3, 156.4, 152.3, 140.6, 137.6, 129.5, 128.4, 127.8, 127.8, 127.7, 89.6, 83.3, 73.2, 68.0,
54.0, 38.8, 27.4 HRMS (ESI, m/z): calcd for C24H26INO4Na: 542.0804, found [M+Na]+: 542.0803;
IRꢀFT ( ATR) 2968, 1707, 1670, 1533, 1143 cmꢀ1.
(2q): orange oil, 210.4 mg (48 %); [α]D25 = + 219.2 (c 1.2, CH2Cl2); 1H NMR (500 MHz, CDCl3):
δ = 0.97 (t, J = 7.4 Hz, 3H), 1.54 (m, 11H), 2.80 (dd, J1 = 17.5 Hz, J2 = 0.9 Hz, 1H), 2.85 (m, 1H),
2.93 (dd, J1 = 17.5 Hz, J2 = 6.4 Hz, 1H), 3.05 (m, 1H), 3.50 (dd, J1 = 9.6 Hz, J2 = 7.2 Hz, 1H), 3.65
(dd, J1 = 9.6 Hz, J2 = 6.9 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.91 (m, 1H),
7.33 (m, 5H); 13C NMR (125 MHz, CDCl3): δ = 185.7, 157.8, 152.0, 137.6, 128.4, 127.7, 127.5, 110.6,
83.6, 73.2, 68.1, 54.6, 38.6, 37.6, 28.0, 20.7, 14.1; HRMS (ESI, m/z): Calcd. for C21H28BrNO4Na:
460.1099, found [M+Na]+: 460.1099; IRꢀFT ( ATR) 2968, 1712, 1674, 1551, 1312 cmꢀ1.
(2r): orange oil, 228 mg (47 %); [α]D25 = + 201.9 (c 1.2, CH2Cl2); 1H NMR (300 MHz, CDCl3): δ
= 0.98 (td, J = 7,2 Hz, J = 1.6 Hz, 3H), 1.52 (1, 9H), 1.52ꢀ1.60 (m, 2H), 2.81ꢀ2.97 (m, 3H), 3.16ꢀ3.22
(m, 1H), 3.43ꢀ3.49 (m, 1H), 3.58ꢀ3.61 (m, 1H), 4.47 (d, syst. AB, J = 10.6 Hz, 1H), 4.49 (d, syst. AB,
12
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
J = 10.6 Hz, 1H), 4.84ꢀ4.89 (m, 1H), 7.26ꢀ7.37 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 187.2, 160.6,
151.8, 137.6, 128.4, 127.7, 127.5, 91.6, 83.6, 73.2, 68.0, 54.8, 42.3, 37.7, 28.0, 21.1, 14.0; HRMS
(ESI, m/z): Calcd. for C21H28INO4Na: 508.0961, found [M+Na]+: 508.0963; IRꢀFT ( ATR) 2924,
1789, 1712, 1453, 1112 cmꢀ1.
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
Preparation of propargylic alcohol 3. To a solution of 26 mg (0.09 mmol) of amino ynone 1a in
1 mL of EtOH at 0°C was added CeCl3.7H2O (11 mg, 0.03 mmol) and NaBH4 (4 mg, 0.095 mmol).
The resulting solution was stirred at 0 °C for 1 h. The reaction was then quenched by addition of
saturated NH4Cl solution (5 mL). After extraction with EtOAc (3 x 5 mL), the organic phase was
dried over sodium sulphate, concentrated under reduced pressure to give the pure product 3 as clear
oil (26 mg, quantitative); 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H), 1.94ꢀ2.00 (m, 2H), 3.24ꢀ3.50
(m, 3H), 4.68ꢀ4.72 (m, 1H), 4.94 (bs, 1H), 7.29ꢀ7.32 (m, 3H), 7.41ꢀ7.44 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ =156.8, 131.7, 128.4, 128.2, 122.5, 89.5, 84.8, 79.7, 60.4, 38.1, 36.8, 28.4.
Preparation of a-iodoenone 4. To a solution of 26 mg (0.09 mmol) of propargylic alcohol 3 in 1
mL of 1,2ꢀDCE was added NIS (24mg mg, 0.1 mmol), PPh3AuCl (2 mg, 5 mol%) and AgSbF6 (1.5
mg, 5 mol%). The resulting mixture was stirred at rt for 18 h. Et2O was added and the resulting
mixture was filtered over a Celite® plug. After removal of solvents in vaccuo, the crude product was
purified by silica gel column chromatography using dichloromethane as an eluant to yield 4 as a
1
yellow oil (20 mg, 72%) (Z/E: 85/15); H NMR (500 MHz, CDCl3): δ = 1.44 (s, 9H), 2.18ꢀ2.22 (m,
2H), 3.18ꢀ3.20 (m, 2H), 4.68 (bs, 1H), 6.59 (t, J = 8.0 Hz,1H), 7.48ꢀ7.61 (m, 3H), 7.98 (d, J = 7.9 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ = 192.3, 155.8, 142.7, 134.1, 133.4, 129.9, 128.9, 92.1, 79.4,
39.1, 33.5, 28.4.
Preparation of tert-butyl 2-i-butyl-5-(4-fluorophenyl)-4-oxo-6-propyl-3,4-dihydropyridine-
1(2H)-carboxylate (5) by Suzuki coupling reaction. To a solution of 60 mg (0.14 mmol) of the tertꢀ
butyl 2ꢀiꢀbutylꢀ5ꢀiodoꢀ4ꢀoxoꢀ6ꢀpropylꢀ3,4ꢀdihydropyridineꢀ1(2H)ꢀcarboxylate in 1 mL of toluene was
added 4ꢀfluorophenylboronic acid (30 mg, 0.21 mmol), SꢀPhos (6 mg, 0.014 mmol), K3PO4 (60 mg,
0.28 mmol). The resulting solution was degassed with argon. Pd(OAc)2 (1.6 mg, 5 mol%) was added,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
6
7
and the mixture was heated to 80 °C for 24 h and then cooled to room temperature. Et2O was added
and the resulting mixture was filtered through Celite®. The organic phase was concentrated under
reduced pressure. The residue was purified by silica gel column chromatography using a mixture of
8
9
25
cyclohexane/EtOAc to give the pure product 5 as clear oil (50 mg, 90 %); [α]D = + 310.0 (c 1.0,
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
CH2Cl2); 1H NMR (500 MHz, CDCl3): δ = 0.78 (t, J = 7.3 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.00 (d,
J = 6.5 Hz, 3H), 1.20ꢀ1.30 (m, 1H), 1.35ꢀ1.47 (m, 2H), 1.55 (s, 9H), 1.58ꢀ1.65 (m, 1H), 1.72ꢀ1.78 (m,
1H), 2.16ꢀ2.22 (m, 1H), 2.45 (dd, J = 17.2 Hz, J = 1.2 Hz, 1H), 2.96 (dd, J = 17.2 Hz, J = 6.0 Hz, 1H),
3.00ꢀ3.06 (m, 1H), 4.76ꢀ4.83 (m, 1H), 7.02ꢀ7.08 (m, 4H); 13C NMR (125 MHz, CDCl3): δ =192.8,
162.1 (d, JCF = 246.1 Hz), 155.7, 153.0, 132.2 (d, JCF = 8.1 Hz), 131.0 (d, JCF = 8.6 Hz), 124.8, 115.2
(d, JCF = 21.5 Hz), 82.6, 53.9, 42.1, 39.7, 34.3, 28.2, 24.9, 22.8, 22.7, 21.1, 14.1; HRMS (ESI, m/z):
Calcd. for C23H32NO3FNa : 412.2258, found [M+Na]+ : 412.2262.
Preparation
of
(E)-tert-butyl
5-(3-ethoxy-3-oxoprop-1-enyl)-4-oxo-6-phenyl-3,4-
dihydropyridine-1(2H)-carboxylate (6) by Heck coupling reaction. To a solution of 100 mg (0.25
mmol) of the tertꢀbutyl 5ꢀiodoꢀ4ꢀoxoꢀ6ꢀphenylꢀ3,4ꢀdihydropyridineꢀ1(2H)ꢀcarboxylate in 2 mL of dry
DMF was added ethyl acrylate (53 ꢁl, 0.5 mmol), triethylamine (70 ꢁL, 0.5 mmol). The resulting
solution was degassed with argon. Pd(PPh3)4 (28.9 mg, 0.025 mmol) was added, and the mixture was
heated to 110 °C for 24 h and then cooled to room temperature. Et2O was added and the resulting
mixture was rinsed with the mixture of Et2O/CH2Cl2 (50/50) and filtered through Celite®. The
organic phase was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography using a mixture of dichloromethane/ diethyl ether to give the pure product 6 as
yellow oil (72 mg, 78 %). Rf = 0.50 (petroleum ether/ diethyl ether = 50/50).
1H NMR (300 MHz, CDCl3): δ = 1.05 (s, 9H), 1.23 (t, J = 6.1 Hz, 3H), 2.71ꢀ2.76 (m, 2 H), 4.13 (q, J
= 6.1 Hz, 2H), 4.21ꢀ4.25 (m, 2H), 7.00 (s, 2H), 7.28ꢀ7.45 (m, 5H); 13C NMR (75 MHz, CDCl3): δ
=193.6, 168.1, 159.2, 152.5, 137.5, 136.2, 130.3, 129.2, 128.4, 120.7, 116.5, 83.3, 60.0, 46.1, 39.0,
27.3, 14.2; HRMS (ESI, m/z): Calcd. for C21H25NO5Na : 394.1630, found [M+Na]+ : 394.1630; IRꢀFT
(ATR) 2978, 2926, 1708, 1673, 1613, 1521 cmꢀ1.
14
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Preparation of (S,E)-ethyl 3-(6-benzyl-4-oxo-2-propyl-1,4,5,6-tetrahydropyridin-3-yl)-
acrylate (7) by Heck coupling reaction. To a solution of 250 mg (0.55 mmol) of the (S)ꢀtertꢀbutyl 2ꢀ
benzylꢀ5ꢀiodoꢀ4ꢀoxoꢀ6ꢀpropylꢀ3,4ꢀdihydropyridineꢀ1(2H)ꢀcarboxylate in 5 mL of dry DMF was added
ethyl acrylate (117 ꢁl, 1.1 mmol), triethylamine (153 ꢁL, 1.1 mmol). The resulting solution was
degassed with argon. Pd(PPh3)4 (64 mg, 0.05 mmol) was added, and the mixture was heated to 130 °C
for 48 h and then cooled to room temperature. Et2O was added and the resulting mixture was rinsed
with the mixture of Et2O/CH2Cl2 (50/50) and filtered through Celite®. The organic phase was
concentrated under reduced pressure. The residue was purified by silica gel column chromatography
using a mixture of dichloromethane/ diethyl ether to give the pure product 7 as yellow oil (140 mg,
78 %). Rf = 0.30 (dichloromethane/ diethyl ether = 80/20).
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
[α]D25 = + 96.4 (c 0.96, CH2Cl2).
1H NMR (500 MHz, CDCl3) : δ = 0.95 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.55ꢀ1.62 (m, 2H),
2.39ꢀ2.50 (m, 3H), 2.59 (dd, J = 15.9 Hz, J = 4.9 Hz, 1H), 2.84ꢀ2.95 (m, 2H), 3.85ꢀ3.88 (m, 1H), 4.19
(q, J = 7.1 Hz,2H ), 5.69 (bs, 1H), 6.98 (d, J = 15.4 Hz, 1H), 7.17 (d, J = 7.0 Hz, 2H), 7.27ꢀ7.36 (m,
3H), 7.40 (d, J = 15.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) : δ = 190.1, 169.8, 167.2, 137.2, 136.1,
129.0, 127.3, 113.4, 104.6, 59.6, 52.9, 42.1, 40.0, 35.2, 21.6, 14.4, 13.7; HRMS (ESI, m/z): Calcd. For
C20H25NO3Na: 350.1732, found [M+Na]+ : 350.1736; IRꢀFT (ATR) 3266, 2963, 1693, 1631, 1529 cmꢀ
1
.
Preparation
of
(R,E)-ethyl
3-(6-(benzyloxymethyl)-4-oxo-2-propyl-1,4,5,6-
tetrahydropyridin-3-yl)-acrylate (8) by Heck coupling reaction. To a solution of 122 mg (0.25
mmol) of the (R)ꢀtertꢀbutyl 2ꢀ(benzyloxymethyl)ꢀ5ꢀiodoꢀ4ꢀoxoꢀ6ꢀpropylꢀ3,4ꢀdihydropyridineꢀ1(2H)ꢀ
carboxylate in 2 mL of dry DMF was added ethyl acrylate (53 ꢁl, 0.5 mmol), triethylamine (70 ꢁL,
0.5 mmol). The resulting solution was degassed with argon. Pd(PPh3)4 (29 mg, 0.025 mmol) was
added, and the mixture was heated to 110 °C for 24 h and then cooled to room temperature. Et2O was
added and the resulting mixture was rinsed with the mixture of Et2O/CH2Cl2 (50/50) and filtered
through Celite®. The organic phase was concentrated under reduced pressure. The residue was
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
6
7
purified by silica gel column chromatography using a mixture of dichloromethane/ diethyl ether to
give the pure product 8 as yellow oil (60 mg, 67 %). Rf = 0.50 (dichloromethane/ diethyl ether =
70/30). [α]D25 = + 17.6 (c 0.98, CH2Cl2).
8
9
δ = 1.01 (t, J = 7.3 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.59ꢀ1.69 (m, 4H), 2.30ꢀ2.57 (m, 4H), 3.47ꢀ3.62
(m, 2H), 3.85ꢀ3.94 (m, 1H), 4.18 (q, J = 7.1 Hz,2H ), 5.82 (bs, 1H), 6.97 (d, J = 15.3 Hz, 1H), 7.27ꢀ
7.35 (m, 5H), 7.37 (d, J = 15.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) : δ = 189.3, 169.8, 167.3, 137.1,
128.7, 128.3, 127.9, 113.7, 104.6, 73.5, 71.2, 59.7, 51.4, 38.6, 35.4, 21.7, 14.4, 13.8; HRMS (ESI,
m/z): Calcd. For C21H27NO4Na : 380.1838, found [M+Na]+ : 380.1839; IRꢀFT (ATR) 3270, 2962,
1693, 1632, 1536 cmꢀ1.
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
Preparation of tert-butyl 4-oxo-6-propyl-5-vinyl-3,4-dihydropyridine-1(2H)-carboxylate (9)
by Stille coupling reaction. To a solution of 182 mg (0.5 mmol) of the iodide compound in 4 mL of
dry toluene was added 58 mg (0.05 mmol) of Pd(PPh3)4. The resulting solution was degassed with
argon. Tributylvinyltin (190 ꢁL, 0.65 mmol) was added, and the mixture was heated to 90 °C for 24 h
and then cooled to room temperature. A solution of EtOAc/H2O (1/1, 10 mL) was added, and the
aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography using a mixture of petroleum ether/ diethyl ether to give the pure product 9 as
orange oil (118 mg, 88 %). Rf = 0.28 (petroleum ether/ diethyl ether = 70/30).
1H NMR (500 MHz, CDCl3): δ = 0.94 (t, J = 7.3 Hz, 3H), 1.53 (s, 9H), 2.54ꢀ2.59 (m, 2H), 2.81ꢀ2.86
(m, 2H), 3.94ꢀ3.98 (m, 2H), 5.40 (dd, J1 = 11.6 Hz, J2 = 2.1Hz, 1H), 5.60 (dd, J = 17.6 Hz, J = 2.1Hz,
1H) 6.3 (dd, J = 17.6 Hz, J = 11.6 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 194.0, 158.1, 152.5,
128.9, 121.8, 120.4, 82.6, 46.2, 38.8, 33.4, 28.1, 21.4, 14.0; HRMS (ESI, m/z): Calcd. for
C15H23NO3Na: 288.1576, found [M+Na]+: 288.1575; IRꢀFT (ATR) 3399, 2961, 1708, 1669, 1557,
1127 cmꢀ1.
■ ASSOCIATED CONTENT
16
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
Supporting Information
3
4
5
6
7
Copies of NMR spectra o all compounds and crystal data (CIF). This material is available free of
charge via the internet at http://pubs.acs.org.
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
■ AUTHOR INFORMATION
Corresponding Author
Eꢀmail : nicolas.gouault@univꢀrennes1.fr
■ ACKNOWLEDGEMENTS
This project was financially supported by the Région Bretagne and by la Ligue contre le Cancer,
Comité d’Ille et Vilaine. 500 MHz NMR experiments were performed on the plateforme PRISM (Dr.
Arnaud Bondon, Université de Rennes 1).
■ REFERENCES
(1) For reviews, see: (a) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Chem. Eur. J. 2012, 18,
5460. (b) Mphahlele, M. J. Molecules 2009, 14, 4814. (c) Godoi, B.; Schumacher, R. F.; Zeni, G.
Chem. Rev. 2011, 111, 2937. (d) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem. Int. Ed.
2012, 51, 10938. (e) Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.; Werness, J. B.;
Tang, W. Chem. Eur. J. 2012, 18, 7296. (f) Castellanos, A.; Fletcher, S. P. Chem. Eur. J. 2011, 17,
5766. (g) Veisi, H.; GhorbaniꢀVaghei, R. Tetrahedron 2010, 66, 7445. (h) Yamamoto, Y.; Gridnev, I.
D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075ꢀ5087.
(2) (a) Chen, G.; Ma, S. Angew. Chem. Int. Ed. 2010, 49, 8306. (b) Yang, F.; Jin, T.; Bao, M.;
Yamamoto, Y. Tetrahedron 2011, 67, 10147. (c) Robin, S.; Rousseau, G. Tetrahedron 1998, 54,
13681.
(3) (a) Sugiyama, N.; Yamamoto, M.; Kashima, C. Bull. Chem. Soc. Jpn. 1969, 42, 2690. (b) Comins,
D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett. 1995, 36, 9141. (c) Donohoe, T. J.; Johnson, D. J.;
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
5
6
7
8
Mace, L. H.; Bamford, M. J.; Ichihara, O. Org. Lett. 2005, 7, 435. (d) Focken, T.; Charette, A. B. Org.
Lett. 2006, 8, 2985. (e) Comins, D. L.; Hiebel, A.ꢀC.; Huang, S. Org. Lett. 2001, 3, 769. (f) Krafft, M.
E.; Cran, J. W. Synlett 2005, 1263. (g) Wang, X.; Turunen, B. J.; Leighty, M. W.; Georg, G. I.
Tetrahedron Lett. 2007, 48, 8811. (h) Tanaka, T.; Inui, H.; Kida, H.; Kodama, T.; Okamoto, T.;
Takeshima, A.; Tachi, Y.; Morimoto, Y. Chem. Commun. 2011, 47, 2949. (i) Kranke, B.; Kunz, H.
Org. Biomol. Chem. 2007, 5, 349. (j) Donohoe, T. J.; Johnson, D. J.; Mace, L. H.; Thomas, R. E.;
Chiu, J. Y. K.; Rodrigues, J. S.; Compton, R. G.; Banks, C. E.; Tomcik, P.; Bamford, M. J.; Ichihara,
O. Org. Biomol. Chem. 2006, 4, 1071. (k) Comins, D. L.; Kuethe, J. T.; Miller, T. M.; Février, F. C.;
Brooks, C. A. J. Org. Chem. 2005, 70, 5221.
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
(4) a) Corma, A.; LeyvaꢀPérez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (b) Gockel, B.;
Krause, N. Eur. J. Org. Chem. 2010, 311. (c) Buzas, A.; Gagosz, F. Org. Lett. 2006, 8, 515. (d) Buzas,
A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957. (e) Kirsch, S. F.; Binder, J. T.; Crone, B.; Duschek,
A.; Haug, T. T.; Liébert, C.; Menz, H. Angew. Chem. Int. Ed. 2007, 46, 2310. (f) Poonoth, M.; Krause,
N. Adv. Synth. Catal. 2009, 351, 117. (g) Crone, B.; Kirsch, S. F. J. Org. Chem. 2007, 72, 5435. (h)
Hashmi, A. S. K.; Ramamurthi, T. D.; Todd, M. H.; Tsang, A. S.ꢀK.; Graf, K. Aus. J. Chem. 2010, 63,
1619. (i) Ye, L.; Zhang, L. Org. Lett. 2009, 11, 3646. (j) Qiu, D.; Mo, F.; Zheng, Z.; Zhang, Y.; Wang,
J. Org. Lett. 2010, 12, 5474. (k) Liao, H.ꢀH.; Liu, R.ꢀS. Chem. Commun. 2011, 47, 1339. (l) Mo, F.;
Yan, J. M.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2010, 49, 2028. (m) Li, Y.;
Wheeler, K. A.; Dembinski, R. Eur. J. Org. Chem. 2011, 2767.
(5) (a) Gouault, N.; Le Roch, M.; Cheignon, A.; Uriac, P.; David, M. Org. Lett. 2011, 13, 4371. (b)
Gouault, N.; Le Roch, M.; de Campos Pinto, G.; David, M. Org. Biomol. Chem. 2012, 10, 5541.
(6) (a) Niphakis, M. J.; Turunen, B. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6793. (b) Passarella, D.;
Angoli, M.; Giardini, A.; Lesma, G.; Silvani, A.; Danieli, B. Org. Lett. 2002, 4, 2925. (c) Acharya, H.
P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 5223. (d) Chen, D.; Banphavichit, V.; Reibenspies, J.;
Burgess, K. Organometallics 2007, 26, 855.
(7) Palisse, A.; Kirsch, S. F. Org. Biomol. Chem. 2012, 10, 8041.
18
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(8) The Ph3PAuSbF6 was in situ generated from 5 mol% of Ph3PAuCl and 5 mol% of AgSbF6. To
ensure that Ph3PAuSbF6 is the true catalyst, an ex situ preparation was also performed by stirring
Ph3PAuCl and AgSbF6 in DCE for 10 minutes then elimination of the AgCl precipitate and addition
of the filtrate to the reaction medium. This experiment gave the same results.
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
(9) (a) Ye, L.; Zhang, L. Org. Lett. 2009, 11, 3646. (b) Yu, M.; Zhang, G.; Zhang, L. Tetrahedron
2009, 65, 1846. (c) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147. (d) Pennell, M. N.;
Unthank, M. G.; Turner, P.; Sheppard, T. D. J. Org. Chem. 2011, 76, 1479. (e) Pennell, M. N.;
Unthank, M. G.; Turner, P.; Sheppard, T. D. Chem.Eur. J. 2012, 18, 4748. (f) Cadierno, V.; Crochet,
P.; GarciaꢀGarrido, S. E.; Gimeno, J. Dalton Trans. 2010, 39, 4015. (g) Ramon, R. S.; Marion, N.;
Nolan, S. P. Tetrahedron 2009, 65, 1767.
(10) CCDC 906744 (2l) and CCDC 906820 (2k) contain the supplementary crystallographic data for
the structures in this paper. These data can be obtained, free of charge, from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
(11) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem.
1999, 576, 147.
(12) (a) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379. (b) Shibasaki, M.; Boden,
C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371. (c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28,
2. (d) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423.
(13) (a) Negishi, E.; Dumond, Y. Handb. Organopalladium Chem. Org. Synth. 2002, 1, 767. (b)
Kosugi, M.; Fugami, K. Handb. Organopalladium Chem. Org. Synth. 2002, 1, 263. (c) Kosugi, M.;
Fugami, K. J. Organomet. Chem. 2002, 653, 50.
1
(14) There was only 10% of starting material after 5 minutes (determined by H NMR on the crude
material) and no more starting material after 10 minutes.
19
ACS Paragon Plus Environment