Regio- and enantioselective synthesis of functionalized tetrahydroquinolines by palladium-catalyzed cyclization of 2- amidophenylmalonates with allylic bisacetates

Article abstract of DOI:10.1016/j.tet.2012.09.075

A palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic bisacetates is described. Tetrahydroquinolines having a vinyl group at the 3- or 2-position were produced, in which the regioselectivity of the resulting products was altered depending on the substituent on the amino group. The product was transformed to the azabicyclo[3.3.1]nonene via the ring-closing metathesis. Enantioselective reactions also successfully proceeded in the presence of (S)-BINAP to give the optically active tetrahydroquinoline with high enantioselectivity.

Full text of DOI:10.1016/j.tet.2012.09.075

Tetrahedron 68 (2012) 9962e9972
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regio- and enantioselective synthesis of functionalized tetrahydroquinolines
by palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic
bisacetates
*
Masahiro Yoshida , Yohei Maeyama, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 August 2012
Received in revised form 12 September 2012
Accepted 14 September 2012
Available online 25 September 2012
A palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic bisacetates is described.
Tetrahydroquinolines having a vinyl group at the 3- or 2-position were produced, in which the
regioselectivity of the resulting products was altered depending on the substituent on the amino
group. The product was transformed to the azabicyclo[3.3.1]nonene via the ring-closing metathesis.
Enantioselective reactions also successfully proceeded in the presence of (S)-BINAP to give the optically
active tetrahydroquinoline with high enantioselectivity.
Keywords:
Cascade reactions
Cyclizations
Ó 2012 Elsevier Ltd. All rights reserved.
Palladium
Enantioselective reactions
Tetrahydroquinolines
1. Introduction
1,4-diacetoxybut-2-ene 2, in which the substituted tetrahy-
droquinoline 3 or 4 having a vinyl group at the 3- or 2-position has
Palladium-catalyzed allylic substitution with nucleophiles have
received considerable attention and have been extensively studied
due to their versatile and specific reactivities.1 2-Butene-1,4-diol
derivatives, such as the dicarbonate and diacetate are known as
useful substrates for palladium-catalyzed reactions with nucleo-
philes. For example, 1,4-diacyloxy-2-butene reacts with a bis-
nucleophile that contains two nucleophilic parts within the mole-
cule, to afford the cyclized product via successive double allylic
substitutions (Scheme 1). A variety of classes of cyclic molecules,
such as quinoxalines,2 benzoxazines,3 piperidines,4 morpholines,4,5
benzodioxanes,6 oxazolidinones,7 pyrroles,8 and dihydrofurans9
have been synthesized using this methodology. During the course
of our studies on the palladium-catalyzed cascade cyclizations using
bis-nucleophiles,10 we focused on the nucleophilic activity of 2-
amidophenylmalonates toward the 1,4-diacyloxybut-2-ene. It is
expected that substituted tetrahydroquinolines, common struc-
tures in many biologically active compounds,11 could be constructed
in one step by introducing nucleophilic nitrogen and carbon moie-
ties within the molecule. Herein, we describe in full detail the
palladium-catalyzed reaction of 2-amidophenylmalonates 1 with
been constructed regioselectivelyand enantioselectively depending
on the substrate and reaction conditions (Scheme 2).12
Scheme 1.
2. Results and discussion
The 2-amidophenylmalonates 1 for the cyclization reactions
were synthesized as follows (Scheme 3). The nucleophilic aromatic
substitution of 2-fluoronitrobenzene (5a) with dimethyl malonate
in the presence of tBuOK afforded the substituted product 6a in 66%
* Corresponding author. Tel./fax: þ81 88 6337294; e-mail addresses: yoshi@
tokushima-u.ac.jp, yoshida@ph.tokushima-u.ac.jp (M. Yoshida).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.075

M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
9963
Having identified a useful set of reaction conditions, we next
conducted the reactions using the 2-amidophenylmalonates 1bek
having various electron-withdrawing groups on the amino group
(Table 2). Sulfonamide-type substrates 1b and 1c having a benzene-
sulfonyl- and a 2-naphthalenesulfonyl group successfully reacted
with 2 in the presence of the palladium catalyst to produce the 3-
vinyltetrahydroquinolines 3b and 3c in 89% and 55% yield, re-
spectively (entries 1 and 2). Similar results were obtained in the reaction
of 4-nitrobenzenesulfonyl (Ns)- and 3,5-dimethylbenzenesulfonyl-
substituted substrates to afford the corresponding products 3d and 3e in
80% and 82% yield, respectively (entries 3 and 4). On the other hand, it is
interesting to note that the 2-vinyltetrahydroquinoline 4i was produced
predominantly when the benzyloxycarbonyl (Cbz)-substituted sub-
strate 1i was used (entry 5). Although the yield of the resulting product
Scheme 2.
Scheme 3.
yield. After the reduction of the nitro group in 6a, the resulting
amino moiety was protected with various electron-withdrawing
groups to produce the 2-amidophenylmalonates 1aek in moder-
ate to good yields. The substrates 1leo having a methyl and
methoxy group at the aromatic 5-position were also prepared from
the corresponding 2-fluoro- and 2-chloronitrobenzenes 5b and 5c
by following the same procedure.
The initial reactions for the synthesis of tetrahydroquinolines
were attempted using the tosyl-substituted 2-amidophenylmalonate
1a and (Z)-1,4-diacetoxy-2-butene (2) (Table 1). When 1a and 2
were subjected to the reaction with 5 mol % Pd2(dba)3$CHCl3,
20 mol % DPPE, and tBuOK in THF under reflux for 2 h, the 3-
vinyltetrahydroquinoline 3a was obtained in 27% yield (Table 1, en-
try 1). The yield of 3a was improved to 79% with K2CO3 (entry 5) by
changing the base (entries 2e5). After experimenting with various
ligands (entries 6e9), we found that the yield of 3a could beincreased
to 86% yield when DPPP was used as the ligand (entry 8).
4i was low (27%), it was improved to 74% by carrying out the reaction in
the presence of (ꢀ)-BINAP as the ligand (entry 6). Similar reactivity was
observed from the reactions of other carbamate-type substrates. Thus,
compounds 1j and 1k, containing a methoxycarbonyl and a tert-
butoxycarbonyl (Boc) group, were regioselectively transformed to the
corresponding 2-vinyltetrahydroquinolines 4j and 4k in 66% and 82%
yield, respectively (entries 7 and 8). From these results, it has been made
clear that the regioselectivity of the reaction is altered depending on the
electron-withdrawing group on the amine.
The reactions of substituted amidophenylmalonates 1leo are
summarized in Scheme 4. When the tosylamides 1l and 1m, which
have a methyl and a methoxy group on the aromatic ring, were
subjected to the reactions with 2, the 3-vinyltetrahydroquinolines
3l and 3m were obtained in 86% and 92% yield, respectively. Sim-
ilarly, the reactions of the carbamates 1n and 1o also proceeded to
produce the corresponding 2-vinyltetrahydroquinolines 4n and 4o
in 71% and 85% yield, respectively.

9964
M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
Table 1
Effect of base and ligand
A plausible mechanism for the cyclization is shown in Scheme 5.
By reacting with the palladium catalyst, 1,4-diacetoxybut-2-ene 2 is
transformed to the -allylpalladium complex 7, which is further
p
subjected to the reaction with the 2-amidophenylmalonates. In the
case of the sulfonamide-type substrate, the aza-anion 8 was se-
lectively generated because of the strong electron-withdrawing
character of the sulfonyl group.13 As a result, the nucleophilic at-
tack of the sulfonamide initially occurs to afford the intermediate 9,
which is successively subjected to the intramolecular nucleophilic
attack of the malonate moiety in the presence of palladium to
produce the 3-vinyltetrahydroquinoline 3. On the other hand, the
malonate anion 10 would be predominantly produced in the case of
the carbamate-type substrate,13 which would lead to the formation
of the 2-vinyltetrahydroquinoline 4 via the intermediate 11.14
We next attempted the reactions using various allylic bisacetates
(Scheme 6). When (E)-1,4-diacetoxy-2-butene (12) was treated
with the tosylamide 1a and the tert-butoxy carbamate 1k, the cor-
responding products 3a and 4k were obtained in 81% and 57% yield,
respectively. Similarly, 1,2-diacetoxy-3-butene (13) reacted with 1a
and 1k to give the corresponding products 3a and 4k in 81% and 82%
yield, respectively. Although the reason for the difference of the
chemical yield derived from allylic bisacetates 12 and 13 is not clear,
Entry
Base
tBuOK
Et3N
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Ligand
Yield of 3a (%)
1
2
3
4
5
6
7
8
9
DPPE
DPPE
DPPE
DPPE
DPPE
DPPF
DPPB
DPPP
(ꢀ)-BINAP
27
22
58
60
79
61
68
86
36
Table 2
Reactions using various substrates 1bee, 1iek with 2
these results imply that the reactions occurred via the common p-
allylpalladium intermediate 7, regardless of the stereo- and regio-
chemistry of the allylic bisacetates.
The availability of tetrahydroquinolines containing a vinyl group
offers new opportunities to synthesize a variety of structurally
complex molecules that cannot be easily accessed by an alternative
protocol. An example toward the synthesis of azabicyclo[3.3.1]
nonene derivative is shown in Scheme 7. The nosyl group of the 3-
vinyltetrahydroquinoline 3d was removed by thiophenol with
K2CO3 to afford the amine 14, which was subjected to the reaction
with allyl bromide leading to the diene 15. When 15 was subjected to
the reaction with Grubb’s II catalyst, ring-closing metathesis un-
eventfully proceeded to produce the azabicyclo[3.3.1]nonene 16 in
90% yield.
Entry
EWG
Yields (%)
We next turned our attention to the application of this process to
an enantioselective reaction. Although various palladium-catalyzed
enantioselective cyclizations of allylic bisacetates or biscarbonates
with nucleophiles are known,2e9 few examples of the production of
the optically active compounds with high enantiomeric excess have
been reported. In the reaction described herein, an asymmetric
3
4
1a
2a
3a
4a
5a
6b
7b
8b
Benzenesulfonyl (1b)
89
55
80
82
7
14
d
d
d
d
2-Naphthalenesulfonyl (1c)
4-Nitrobenzensulfonyl (Ns) (1d)
3,5-Dimethylbenzenesulfonyl (1e)
Benzyloxycarbonyl (Cbz) (1i)
Benzyloxycarbonyl (Cbz) (1i)
Methoxycarbonyl (1j)
27
74
66
82
center is formed via the achiral
p-allylpalladium intermediate 17,
tert-Butoxycarbonyl (Boc) (1k)
and it is anticipated that the enantiocontrolled cyclization could be
achieved by a chiral palladium catalyst (Scheme 8).
a
DPPP was used as the ligand.
b
(ꢀ)-BINAP was used as the ligand.
To achieve this enantioselective process, we first examined the
reactions of 1a with 2 under various conditions (Table 3, Fig. 1).
The reactions were carried out in the presence of 5 mol %
Pd2(dba)3$CHCl3, 20 mol % chiral ligand, and K2CO3 in THF under
reflux. The enantiomeric excess was not observed from the reaction
using (R,R)-DACH-phenyl Trost ligand (23% yield with 0% ee, entry
1), but the optically active 3-vinyltetrahydroquinoline (ꢁ)-3a was
formed in 36% yield with 56% ee when (S)-BINAP was used (entry 2).
Similar results were obtained in the case of (S)-DM-BINAP and (S)-
tol-BINAP, in which (ꢁ)-3a was produced in 49% ee and 43% ee, re-
spectively (entries 3 and 4).15
Attempts for the enantioselective cyclization using various
sulfonamide-substituted substrates 1b,d,feh with 2 in the presence
of (S)-BINAP are summarized in Table 4. When benzenesulfonyl-
substituted substrate 1b was subjected to the reaction, the cyclized
product (ꢁ)-3b was obtained in 60% yield with 57% ee (entry 1). The
substrate 1f having a 4-methoxybenzenesulfonyl group also reacted
with 2 to give the product (ꢁ)-3f in 55% ee (entry 2). When reactions
with 4-trifluoromethyl- and 4-cyanobenzenesulfonyl-substituted
substrates 1g and1h were carriedout, theenantiomeric excessof the
resulting products (ꢁ)-3g and (ꢁ)-3h were improved to 65% and
Scheme 4.

M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
9965
Scheme 5.
Scheme 8.
Table 3
Enantioselective cyclization of 1a with 2
Scheme 6.
76%, respectively (entries 3 and 4). Furthermore, it was found that
the cyclized product (ꢁ)-3d was produced in 50% yield with 99% ee
from the reaction with 4-nitrobenzenesulfonyl-substituted sub-
strate 1d (entry 5).
Entry
Chiral ligand
Yield (%)
ee (%)a
1
2
3
4
(R,R)-DACH-phenyl Trost ligand
(S)-BINAP
(S)-DM-BINAP
23
36
38
31
0
56
49
43
(S)-tol-BINAP
a
Enantiomeric excess were determined by HPLC using
(CHIRALPAK AS-H).
a
chiral column
Further optimization of reaction conditions using 4-
Scheme 7.
nitrobenzenesulfonyl-substituted substrate 1d is shown in Table 5.

9966
M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
After the examinations using various bases, solvents, and reaction
temperatures (entries 1e9), it was made clear that the optically
active 3-vinyltetrahydroquinoline (ꢁ)-3d was formed in 79% yield
with 99% ee when the reaction was carried out in the presence
of K2CO3 in dioxane at 80 ꢂC (entry 8). During the course of this
optimization study, we found the regioisomer of (ꢁ)-3d was
selectively produced by the choice of base. Thus, when K3PO4 and
KOH were employed in the reactions, the optically active
2-vinyltetrahydroquinoline (þ)-4d was obtained predominantly in
46% yield with 92% ee and 52% yield with 83% ee, respectively
(entries 3 and 4). Although the reason is not clear, it is interesting
that the regioselectivity was controlled depending on the base.
3. Conclusion
In summary, the studies described above have resulted in the
regioselective synthesis of vinyltetrahydroquinolines by a palla-
dium-catalyzed cyclization of the 2-amidophenylmalonates and
1,4-diacetoxy-2-butene. The regioselectivity of the reaction can be
altered depending on the substituent on the amino group, in which
substituted tetrahydroquinolines having a vinyl group at the 3- or
2-position were, respectively, produced in a highly regioselective
manner. The resulting product was successfully transformed to the
azabicyclo[3.3.1]nonene via the ring-closing metathesis. Enantio-
selective reactions proceeded to give the optically active tetrahy-
droquinoline with high enantioselectivity. Biologically active
compounds having tetrahydroquinoline structures have been re-
ported,11 and this methodology could provide a new and significant
protocol for the synthesis of these compounds.
Fig. 1. Structure of chiral ligands.
Table 4
Enantioselective cyclization using 1b,d,feh in the presence of (S)-BINAP
4. Experimental section
4.1. General
All nonaqueous reactions were carried out under a positive
atmosphere of argon in dried glassware unless otherwise indicated.
Materials were obtained from commercial suppliers and used
without further purification except when otherwise noted. Sol-
vents were dried and distilled according to the standard protocols.
The phrase ‘residue upon workup’ refers to the residue obtained
when the organic layer was separated and dried over anhydrous
MgSO4 and the solvent was evaporated under reduced pressure.
Entry
EWG
Yield (%)
ee (%)a
1
2
3
4
5
Benzenesulfonyl (1b)
60
31
69
93
50
57
55
65
76
99
4-Methoxybenzensulfonyl (1f)
4-Trifluoromethylbenzenesulfonyl (1g)
4-Cyanobenzenesulfonyl (1h)
4-Nitrobenzensulfonyl (Ns) (1d)
a
Enantiomeric excess were determined by HPLC using a chiral column (CHIR-
ALPAK AS-H).
Table 5
Optimization of the reaction conditions using 1d with 2
Entry
Base
Solvent
Temp (ꢂC)
(ꢁ)-3d
(þ)-4d
Yield (%)
ee (%)a
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
CaCO3
Na2CO3
K3PO4
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
DMSO
DMF
Dioxane
Dioxane
Dioxane
Reflux
Reflux
Reflux
Reflux
100
100
100
80
60
30
29
17
d
86
96
98
d
d
d
46
52
d
d
d
d
d
d
d
92
83
d
d
d
d
d
Trace
62
73
79
75
d
86
99
99
99
a
Enantiomeric excess were determined by HPLC using a chiral column (CHIRALPAK AS-H).
Enantiomeric excess were determined by HPLC using a chiral column (CHIRALPAK AD).
b

M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
9967
4.2. General procedure for the synthesis of 2-
amidophenylmalonates
53.9 (CH), 125.4 (CH), 126.7 (CH), 127.3 (CH), 128.5 (Cq), 129.2 (CH),
129.6 (CH), 131.2 (CH), 135.1 (Cq), 136.9 (Cq), 143.7 (Cq), 168.8 (Cq);
HRMS (ESI) m/z calcd for C18H19NO6NaS [MþþNaþ] 400.0831, found
400.0834.
Synthesis of 6a: To a stirred solution of dimethyl malonate
(1.10 mL, 9.52 mmol) in DMF (20 mL) was added BuOK (1.30 g,
t
11.9 mmol) at rt. After stirring was continued for 10 min at 90 ꢂC,
the resulting mixture was cooled to rt, and 2-fluoronitrobenzene
(5a) (0.50 mL, 4.76 mmol) was added. The mixture was heated at
90 ꢂC for 2 h, and then stored for 16 h at rt. The resulting solution
was diluted with water and extracted with Et2O. The combined
extracts were washed with saturated aqueous NaCl. The residue
upon workup was chromatographed on silica gel with hexane/
AcOEt (80:20, v/v) as eluent to give the 2-nitrophenyl malonate 6a
(1.00 g, 83%) as light yellow prisms.
4.3.2. Dimethyl
2-[2-(phenylsulfonamido)phenyl]malonate
(1b). Yield 68% (two steps); colorless prisms; mp: 98.1e100.1 ꢂC
[AcOEt/hexane (1:1)]; IR (KBr) 3211, 2956, 1736, 1602, 1452, 1276,
1172, 1093, 1006 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.76 (s, 6H),
4.89 (s,1H), 7.02e7.06 (m,1H), 7.18e7.23 (m, 2H), 7.37e7.41 (m,1H),
7.46e7.51 (m, 2H), 7.54 (s, NH), 7.55e7.60 (m, 1H), 7.82 (dd, J¼1.6,
10.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 53.1 (CH3), 54.0 (CH),
125.4 (CH), 126.8 (CH), 127.2 (CH), 128.5 (Cq), 129.1 (CH), 129.2 (CH),
131.3 (CH), 132.9 (CH), 135.0 (Cq), 139.9 (Cq), 168.7 (Cq); HRMS (ESI)
m/z calcd for C17H17NO6NaS [MþþNaþ] 386.0674, found 386.0669.
4.2.1. Dimethyl 2-(2-nitrophenyl)malonate (6a). Yield 83%; light
yellow prisms; mp: 53.0e55.0 ꢂC [benzene/hexane (1:1)]; IR (KBr)
4.3.3. Dimethyl 2-[2-(naphthalene-2-sulfonamido)phenyl]malonate
(1c). Yield 63% yield (two steps); colorless prisms; mp:
114.0e115.5 ꢂC [AcOEt/hexane (1:1)]; IR (KBr) 3284, 2953, 1740,
1738, 1529, 1436, 1349 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.81 (s,
6H), 5.34 (s, 1H), 7.51e7.56 (m, 2H), 7.66 (t, J¼7.6 Hz, 1H), 8.08 (dd,
J¼0.8, 7.6 Hz,1H); 13C NMR (100 MHz, CDCl3)
d
53.1 (CH3), 54.1 (CH),
1627, 1593, 1497, 1456, 1282, 1162, 1095 cmꢁ1 1H NMR (400 MHz,
;
125.2 (CH), 127.9 (Cq), 129.3 (CH), 131.3 (CH), 133.6 (CH), 148.7 (Cq),
167.6 (Cq); HRMS (ESI) m/z calcd for C11H11NO6Na [MþþNaþ]
276.0484, found 276.0486.
CDCl3) d 3.66 (s, 6H), 4.84 (s, 1H), 7.09e7.11 (m, 1H), 7.15e7.21 (m,
2H), 7.37e7.40 (m, 1H), 7.58e7.67 (m, 3H), 7.79 (dd, J¼2.0, 8.8 Hz,
1H), 7.89 (s, NH), 7.91e7.95 (m, 2H), 8.36 (s,1H); 13C NMR (100 MHz,
CDCl3)
d 53.0 (CH3), 53.7 (CH), 122.4 (CH), 125.9 (CH), 126.9 (CH),
4.2.2. Dimethyl 2-(4-methyl-2-nitrophenyl)malonate (6b). Yield
66%; colorless needles; mp: 97.1e97.8 ꢂC [AcOEt/hexane (1:1)]; IR
(KBr) 2956, 1733, 1533, 1439, 1294, 1248, 1204, 1008 cmꢁ1; 1H NMR
127.5 (CH),127.8 (CH),128.6 (CH),128.7 (CH),128.9 (CH),129.2 (CH),
129.3 (CH), 129.4 (CH), 131.1 (CH), 132.0 (Cq), 134.8 (Cq), 134.9 (Cq),
136.7 (Cq), 168.6 (Cq); HRMS (ESI) m/z calcd for C21H19NO6NaS
[MþþNaþ] 436.0831, found 436.0828.
(400 MHz, CDCl3)
d 2.45 (s, 3H), 3.80 (s, 6H), 5.29 (s, 1H), 7.38 (d,
J¼8.0 Hz,1H), 7.46 (d, J¼8.0 Hz,1H), 7.88 (s,1H); 13C NMR (100 MHz,
CDCl3)
d
21.2 (CH3), 53.4 (CH3), 54.1 (CH), 125.2 (Cq), 125.9 (CH),
4.3.4. Dimethyl
(1d). Yield 80% (two steps); colorless needles; mp: 137.1e138.2 ꢂC
[AcOEt/hexane (1:1)]; IR (KBr) 3249, 1740, 1532, 1350, 1167 cmꢁ1
1H NMR (400 MHz, CDCl3)
2-[2-(4-nitrophenylsulfonamido)phenyl]malonate
131.4 (CH), 134.6 (CH), 140.4 (Cq), 148.8 (Cq), 168.1 (Cq); HRMS (ESI)
m/z calcd for C12H13NO6Na [MþþNaþ] 290.0641, found 290.0643.
;
d
3.77 (s, 6H), 4.77 (s, 1H), 7.11 (dd, J¼1.6,
4.2.3. Dimethyl 2-(4-methoxy-2-nitrophenyl)malonate (6c). Yield
20%; colorless needles; mp: 92.6e93.4 ꢂC [AcOEt/hexane (1:1)]; IR
7.4 Hz, 1H), 7.20e7.28 (m, 2H), 7.36 (dd, J¼1.6, 7.4 Hz, 1H), 8.03 (d,
J¼8.8 Hz, 2H), 8.10 (br s, NH), 8.33 (d, J¼8.8 Hz, 2H); 13C NMR
(KBr) 2957, 1737, 1625, 1536, 1440, 1241, 1165 cmꢁ1
;
1H NMR
(100 MHz, CDCl3) d 53.3 (CH3), 54.8 (CH), 124.3 (CH), 124.7 (CH),
(400 MHz, CDCl3)
d
3.80 (s, 6H), 3.89 (s, 3H), 5.27 (s, 1H), 7.18 (dd,
127.1 (CH), 127.8 (Cq), 128.6 (CH), 129.7 (CH), 131.9 (CH), 134.7 (Cq),
145.9 (Cq), 150.2 (Cq), 168.7 (Cq); HRMS (ESI) m/z calcd for
C17H17N2O8S [MþþHþ] 409.0706, found 409.0708.
J¼2.8, 8.8 Hz, 1H), 7.42 (d, J¼8.8 Hz, 1H), 7.57 (d, J¼2.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 53.0 (CH3), 53.4 (CH), 55.8 (CH3), 110.1
(CH), 119.6 (Cq), 119.7 (CH), 132.2 (CH), 149.3 (Cq), 159.7 (Cq), 167.9
(Cq); HRMS (ESI) m/z calcd for C12H14NO7 [MþþHþ] 284.0770,
found 284.0770.
4.3.5. Dimethyl 2-[2-(3,5-dimethylphenylsulfonamido)phenyl]malo-
nate (1e). Yield 61% (two steps); colorless needles; mp:
127.9e128.5 ꢂC [AcOEt/hexane (1:1)]; IR (KBr) 3254, 2954, 1740,
4.3. General procedure for the synthesis of sulfonamides
1436, 1334, 1157 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.34 (s, 6H),
3.76 (s, 6H), 4.85 (s,1H), 7.04e7.07 (m,1H), 7.17 (br s, NH), 7.20e7.22
(m, 2H), 7.39e7.49 (m, 4H); 13C NMR (100 MHz, CDCl3)
21.1 (CH3),
Synthesis of 1a: To a stirred suspension of PdeC (49.0 mg,
10 wt %) in MeOH was added nitrobenzene 6a (490 mg, 1.94 mmol)
at rt, and stirring was continued for 2 h at the same temperature
under 3.5 atm of hydrogen gas. The reaction mixture was filtered
and concentrated in vacuo. The resulting crude amine was dissolved
in CH2Cl2 (10 mL), and treated with TsCl (553 mg, 2.90 mmol) and
pyridine (0.94 mL, 11.6 mmol) at rt. After stirring was continued for
2 h at the same temperature, the resulting solution was diluted with
water and extracted with CH2Cl2. The combined extracts were
washed with saturated aqueous NaCl. The residue upon work up
was chromatographed on silica gel with hexane/AcOEt (75:25, v/v)
as eluent to give the 2-amidophenylmalonate 1a (498 mg, 68%, two
steps) as colorless needles.
d
53.0 (CH3), 53.8 (CH), 124.7 (CH), 125.7 (CH), 126.7 (CH), 128.6 (Cq),
129.1 (CH), 131.1 (CH), 134.5 (CH), 135.2 (Cq), 139.1 (Cq), 139.7 (Cq),
168.7 (Cq); HRMS (ESI) m/z calcd for C19H22NO6S [MþþHþ]
392.1168, found 392.1165.
4.3.6. Dimethyl
2-[2-(4-methoxyphenylsulfonamido)phenyl]malo-
nate (1f). Yield 34% (two steps); colorless prisms; mp:
112.7e113.2 ꢂC [AcOEt/hexane (1:1)]; IR (KBr) 3251, 1739, 1596,
1498, 1261, 1156 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.76 (s, 6H),
3.85 (s, 3H), 4.89 (s, 1H), 6.92 (d, J¼8.8 Hz, 2H), 7.04e7.07 (m, 1H),
7.18e7.23 (m, 2H), 7.28 (br s, NH), 7.39e7.42 (m, 1H), 7.72 (d,
J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 53.0 (CH3), 53.6 (CH3),
55.5 (CH), 114.2 (CH), 125.8 (CH), 126.8 (CH), 128.7 (Cq), 129.1 (CH),
129.5 (CH), 131.1 (CH), 131.2 (Cq), 135.1 (Cq), 163.1 (Cq), 168.7 (Cq);
HRMS (ESI) m/z calcd for C18H19NO7NaS [MþþNaþ] 416.0780, found
416.0781.
4.3.1. Dimethyl 2-[2-(4-methylphenylsulfonamido)phenyl]malonate
(1a). Yield 68% (two steps); colorless needles; mp: 147.2e149.1 ꢂC
[AcOEt/hexane (1:1)]; IR (KBr) 3263, 1746, 1598, 1495, 1438, 1336,
1282, 1228, 1164, 1093 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.41 (s,
3H), 3.76 (s, 6H), 4.91 (s, 1H), 7.02e7.04 (m, 1H), 7.18e7.22 (m, 2H),
7.26e7.27 (m, 1H), 7.38e7.40 (m, 2H), 7.43 (br s, NH), 7.68 (d,
4.3.7. Dimethyl 2-[2-(4-(trifluoromethyl)phenylsulfonamido)phenyl]
malonate (1g). Yield 56% (two steps); colorless needles; mp:
124.9e125.5 ꢂC (AcOEt/hexane 1:1); IR (KBr) 3248, 1741, 1406, 1324,
J¼8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 21.5 (CH3), 53.1 (CH3),

9968
M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
1170, 1063 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.75 (s, 6H), 4.78 (s,
131.1 (CH), 136.3 (Cq), 136.5 (Cq), 154.2 (Cq), 169.1 (Cq); HRMS (ESI)
1H), 7.12 (dd, J¼2.0, 7.4 Hz, 1H), 7.20e7.28 (m, 2H), 7.38 (dd, J¼2.0,
m/z calcd for C19H19NO6Na [MþþNaþ] 380.1110, found 380.1113.
7.4 Hz, 1H), 7.75 (d, J¼8.0 Hz, 2H), 7.89 (br s, NH), 7.96 (d, J¼8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3)
d
53.2 (CH3), 54.3 (CH), 124.5 (Cq),
4.4.2. Dimethyl
(1j). Yield 72% (two steps); yellow oil; IR (neat) 3347, 2956, 1731,
1590, 1518, 1236, 1114, 1066 cmꢁ1 1H NMR (400 MHz, CDCl3)
2-[2-(methoxycarbonylamino)phenyl]malonate
125.3 (CH), 126.2 (q, J¼3.3 Hz, CF3), 127.0 (CH), 127.8 (CH ꢃ4), 128.2
(Cq), 129.5 (CH), 131.6 (CH), 134.7 (Cq), 143.6 (Cq), 168.7 (Cq); HRMS
(ESI) m/z calcd for C18H16NO6NaSF3 [MþþNaþ] 454.0548, found
454.0550.
;
d
3.757 (s, 3H), 3.763 (s, 6H), 4.70 (s, 1H), 7.16 (t, J¼7.6 Hz, 1H), 7.26
(d, J¼7.6 Hz, 2H), 7.37 (dt, J¼1.6, 7.6 Hz,1H), 7.68 (br s, NH); 13C NMR
(100 MHz, CDCl3)
d 52.3 (CH3), 53.0 (CH3), 55.7 (CH), 125.2 (CH),
4.3.8. Dimethyl 2-[2-(4-cyanophenylsulfonamido)phenyl]malonate
125.5 (Cq), 129.3 (CH ꢃ2), 131.0 (CH), 136.5 (Cq), 154.7 (Cq), 169.0
(Cq); HRMS (ESI) m/z calcd for C13H15NO6Na [MþþNaþ] 304.0797,
found 304.0793.
(1h). Yield 63% (two steps); colorless oil; IR (KBr): 3247, 1739, 1437,
1339, 1164 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.77 (s, 6H), 4.77 (s,
1H), 7.08 (dd, J¼2.0, 7.2 Hz, 1H), 7.20e7.26 (m, 2H), 7.36 (dd, J¼2.0,
7.2 Hz, 1H), 7.79 (d, J¼8.4 Hz, 2H), 7.95 (d, J¼8.4 Hz, 2H), 8.01 (br s,
4.4.3. Dimethyl
2-[2-(tert-butoxycarbonylamino)phenyl]malonate
NH); 13C NMR (100 MHz, CDCl3)
d
53.2 (CH3), 54.4 (CH), 116.5 (Cq),
(1k). Yield 88% (two steps); colorless oil; IR (neat) 3352, 2980,1731,
117.2 (Cq), 125.1 (CH), 127.1 (CH), 127.9 (CH), 128.2 (Cq), 129.5 (CH),
131.7 (CH), 132.9 (CH), 134.5 (Cq), 144.1 (Cq), 168.7 (Cq); HRMS (ESI)
m/z calcd for C18H15N2O6S [MþꢁHþ] 387.0651, found 387.0653.
1589, 1514, 1454, 1241, 1155, 1024 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.50 (s, 9H), 3.77 (s, 6H), 4.70 (s, 1H), 7.13 (t, J¼7.6 Hz, 1H), 7.26 (d,
J¼7.6 Hz, 1H), 7.34 (t, J¼7.6 Hz, 1H), 7.55 (br s, NH), 7.63 (d, J¼7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3)
28.2 (CH3), 53.0 (CH3), 55.7 (CH),
d
4.3.9. Dimethyl 2-[4-methyl-2-(4-methylphenylsulfonamido)phenyl]
malonate (1l). Yield 62% (two steps); colorless prisms; mp:
137.9e139.2 ꢂC [AcOEt/hexane (1:1)]; IR (KBr): 3267, 2955, 1758,
80.2 (Cq), 124.9 (CH), 125.9 (CH), 126.2 (Cq), 129.1 (CH), 130.9 (CH),
136.8 (Cq), 153.5 (Cq), 169.1 (Cq); HRMS (ESI) m/z calcd for
C16H22NO6 [MþþHþ] 324.1447, found 324.1447.
1736, 1586, 1508, 1434, 1261, 1159, 1092 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
2.22 (s, 3H), 2.42 (s, 3H), 3.74 (s, 6H), 4.80 (s, 1H), 6.88 (s,
4.4.4. Dimethyl 2-[2-(tert-butoxycarbonylamino)-4-methylphenyl]
1H), 7.00 (d, J¼8.0 Hz, 1H), 7.24 (d, J¼8.0 Hz, 1H), 7.27 (d, J¼8.4 Hz,
malonate (1n). Yield 81% (two steps); colorless oil; IR (neat) 3356,
2H), 7.38 (s, NH), 7.69 (d, J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
2979, 1731, 1618, 1583, 1241, 1157, 1051 cmꢁ1 1H NMR (400 MHz,
;
d
21.0 (CH3), 21.5 (CH3), 53.0 (CH3), 53.6 (CH), 125.3 (Cq), 126.1 (CH),
CDCl3) d 1.50 (s, 9H), 2.34 (s, 3H), 3.76 (s, 6H), 4.66 (s, 1H), 6.94 (d,
127.3 (CH), 127.5 (CH), 129.6 (CH), 130.8 (CH), 134.8 (Cq), 137.0 (Cq),
139.4 (Cq), 143.6 (Cq), 168.9 (Cq); HRMS (ESI) m/z calcd for
C19H22NO6S [MþþHþ] 392.1168, found 392.1169.
J¼6.8 Hz, 1H), 7.13 (d, J¼6.8 Hz, 1H), 7.47 (s, 1H), 7.53 (br s, NH); 13C
NMR (100 MHz, CDCl3)
d 21.1 (CH3), 28.3 (CH3), 52.9 (CH3), 55.5
(CH), 80.1 (Cq), 123.1 (Cq), 125.8 (CH), 126.3 (CH), 130.7 (CH), 136.6
(Cq), 139.4 (Cq), 153.5 (Cq), 169.3 (Cq); HRMS (ESI) m/z calcd for
C17H23NO6Na [MþþNaþ] 360.1423, found 360.1425.
4.3.10. Dimethyl 2-[4-methoxy-2-(4-methylphenylsulfonamido)phe-
nyl]malonate (1m). Yield 64% (two steps); colorless prisms; mp:
138.1e139.9 ꢂC [AcOEt/hexane (1:1)]; IR (KBr): 3267, 3011, 1754,
1730, 1615, 1506, 1271, 1197, 1159 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.4.5. Dimethyl 2-[2-(tert-butoxycarbonylamino)-4-methoxyphenyl]
malonate (1o). Yield 63% (two steps); colorless prisms; mp:
97.8e99.1 ꢂC [AcOEt/hexane (1:1)]; IR (KBr) 3325, 2977, 1729, 1619,
d
2.41 (s, 3H), 3.67 (s, 3H), 3.75 (s, 6H), 4.73 (s, 1H), 6.67 (d, J¼2.4 Hz,
1H), 6.70 (dd, J¼2.8, 8.4 Hz, 1H), 7.25 (d, J¼8.4 Hz, 1H), 7.28 (d,
1584, 1533, 1242, 1160 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.50 (s,
J¼8.4 Hz, 2H), 7.68 (br s, NH), 7.73 (d, J¼8.4 Hz, 2H); 13C NMR
9H), 3.76 (s, 6H), 3.81 (s, 3H), 4.62 (s, 1H), 6.66 (dd, J¼2.8, 8.4 Hz,
(100 MHz, CDCl3)
d 21.5 (CH3), 53.0 (CH3), 53.6 (CH), 55.2 (CH3),
1H), 7.13 (d, J¼8.4 Hz, 1H), 7.26 (d, J¼2.8 Hz, 1H), 7.64 (br s, NH); 13C
110.2 (CH), 112.2 (CH), 119.6 (Cq), 127.4 (CH), 129.6 (CH), 132.0 (CH),
136.3 (Cq), 137.0 (Cq), 143.7 (Cq), 159.9 (Cq), 169.0 (Cq); HRMS (ESI)
m/z calcd for C19H22NO7S [MþþHþ] 408.1117, found 408.1118.
NMR (100 MHz, CDCl3) d 28.2 (CH3), 52.9 (CH3), 55.1 (CH), 55.3
(CH3), 80.2 (Cq), 110.3 (CH), 110.9 (CH), 117.7 (Cq), 131.7 (CH), 138.0
(Cq), 153.3 (Cq), 160.1 (Cq), 169.3 (Cq); HRMS (ESI) m/z calcd for
C17H24NO7 [MþþHþ] 354.1553, found 354.1552.
4.4. General procedure for the synthesis of carbamate
4.5. General procedure for the synthesis of 3-
vinyltetrahydroquinoline
Synthesis of 1i: To a stirred suspension of PdeC (25.0 mg,10 wt %)
in MeOH was added nitrobenzene 6a (249 mg, 0.985 mmol) at rt,
and stirring was continued for 2 h at the same temperature under
3.5 atm of hydrogen gas. The reaction mixture was filtered and
concentrated in vacuo. The resulting crude amine was dissolved in
CH2Cl2 (5 mL), and treated with CbzCl (0.170 mL, 1.18 mmol) and
pyridine (0.160 mL, 1.97 mmol) at 0 ꢂC. After stirring was continued
for 5 h at the same temperature, the resulting solution was diluted
with water and extracted with CH2Cl2. The combined extracts were
washed with saturated aqueous NaCl. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (80:20, v/v) as
eluent to give the 2-amidophenylmalonate 1i (238 mg, 68%, two
steps) as colorless oil.
Synthesis of 3a (Table 1, entry 8): To a stirred solution of sulfon-
amide1a (30.0 mg, 0.0795mmol)and(Z)-1,4-diacetoxy-2-butene(2)
(16.4 mg, 0.0954 mmol) in THF (2 mL) were added Pd2(dba)3$CHCl3
(4.10 mg, 3.95 mmol), DPPP (6.50 mg,15.8 mmol), and K2CO3 (43.7 mg,
0.318 mmol) at rt, and stirring was continued for 30 min at the same
temperature. The reaction mixture was then allowed to heat to 80 ꢂC,
and stirred for 2 h. After filtration of the reaction mixture using small
amount of silica gel followed by concentration, the residue was
chromatographed on silica gel with hexane/AcOEt (80:20, v/v) as
eluent to give the 3-vinyltetrahydroquinoline 3a (29.3 mg, 86%) as
colorless prisms.
4.4.1. Dimethyl
2-[2-(benzyloxycarbonylamino)phenyl]malonate
4.5.1. Dimethyl-1-(4-methylphenylsulfonyl)-3-vinyl-2,3-dihydroquino-
line-4,4(1H)-dicarboxylate (3a). Yield 86%; colorless prisms; mp:
111.7e113.8 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 2953, 1746, 1721, 1489,
(1i). Yield 68% (two steps); colorless oil; IR (neat) 3343, 2954, 1731,
1590, 1518, 1455, 1221, 1155, 1041 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.67 (s, 6H), 4.67 (s, 1H), 5.20 (s, 2H), 7.15 (t, J¼7.6 Hz, 1H), 7.24 (d,
1361, 1240, 1178, 1099, 1028 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 2.39
J¼7.6 Hz, 1H), 7.29e7.43 (m, 6H), 7.67 (s, 1H), 7.97 (br s, NH); 13C
(s, 3H), 2.98 (dt, J¼4.0, 9.0 Hz, 1H), 3.56 (s, 3H), 3.64 (s, 3H), 3.99 (dd,
J¼9.0, 13.2 Hz, 1H), 4.09 (dd, J¼4.0, 13.2 Hz, 1H), 5.10 (dd, J¼0.8,
17.2 Hz, 1H), 5.15 (dd, J¼0.8, 10.4 Hz, 1H), 5.86 (ddd, J¼9.0, 10.4,
NMR (100 MHz, CDCl3)
d 53.0 (CH3), 56.0 (CH), 66.9 (CH2), 125.3
(CH), 125.8 (Cq), 128.1 (CH), 128.3 (CH), 128.5 (CH ꢃ4), 129.4 (CH),

M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
9969
17.2 Hz, 1H), 7.09 (dt, J¼0.8, 7.8 Hz, 1H), 7.23 (d, J¼8.8 Hz, 2H), 7.27 (dt,
J¼1.2, 7.8 Hz, 1H), 7.33 (dd, J¼1.2, 7.8 Hz, 1H), 7.57 (d, J¼8.8 Hz, 2H),
139.4 (Cq), 169.3 (Cq), 170.0 (Cq); HRMS (ESI) m/z calcd for
C
23H26NO6S [MþþHþ] 444.1481, found 444.1476.
7.82 (dd, J¼0.8, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.4 (CH3),
43.0 (CH), 47.6 (CH2), 52.5 (CH3), 52.7 (CH3), 60.8 (Cq), 119.0 (CH2),
122.6 (CH), 124.0 (CH), 124.5 (Cq), 127.2 (CH), 128.6 (CH), 129.6 (CH),
131.1 (CH), 134.2 (CH), 136.3 (Cq), 136.5 (Cq), 143.8 (Cq), 169.2 (Cq),
169.9 (Cq); HRMS (ESI) m/z calcd for C22H24NO6S [MþþHþ] 430.1324,
found 430.1320.
4.5.6. Dimethyl-7-methyl-1-(4-methylphenylsulfonyl)-3-vinyl-2,3-
dihydroquinoline-4,4(1H)-dicarboxylate (3l). Yield 86%; yellow oil;
IR (neat) 2953, 1733, 1614, 1572, 1504, 1252, 1165, 1091 cmꢁ1 1H
;
NMR (400 MHz, CDCl3)
d
2.34 (s, 3H), 2.39 (s, 3H), 2.94 (dt, J¼4.0,
9.0 Hz, 1H), 3.56 (s, 3H), 3.62 (s, 3H), 3.96 (dd, J¼9.0, 13.2 Hz, 1H),
4.08 (dd, J¼4.0, 13.2 Hz, 1H), 5.08 (dd, J¼0.8, 17.2 Hz, 1H), 5.14 (dd,
J¼0.8, 10.4 Hz, 1H), 5.83 (ddd, J¼9.0, 10.4, 17.2 Hz, 1H), 6.92 (dd,
J¼2.0, 8.0 Hz, 1H), 7.23 (t, J¼7.6 Hz, 3H), 7.57 (d, J¼8.4 Hz, 2H), 7.65
4.5.2. Dimethyl-1-(phenylsulfonyl)-3-vinyl-2,3-dihydroquinoline-
4,4(1H)-dicarboxylate (3b). Yield 89%; colorless prisms; mp:
93.5e94.7 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 2954, 1738, 1490, 1356,
(s, 1H); 13C NMR (100 MHz, CDCl3)
d 21.4 (CH3), 21.5 (CH3), 42.9
1241, 1172, 1091 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.94 (dt, J¼3.6,
(CH), 47.7 (CH2), 52.5 (CH3), 52.7 (CH3), 60.6 (Cq), 118.9 (CH2), 121.5
(Cq), 123.1 (CH), 125.2 (CH), 127.2 (CH), 129.6 (CH), 130.9 (CH), 134.3
(CH), 136.2 (Cq), 136.7 (Cq), 138.7 (Cq), 140.7 (Cq), 169.4 (Cq), 170.1
(Cq); HRMS (ESI) m/z calcd for C23H26NO6S [MþþHþ] 444.1481,
found 444.1481.
9.0 Hz, 1H), 3.56 (s, 3H), 3.63 (s, 3H), 3.99 (dd, J¼9.0, 13.2 Hz, 1H),
4.11 (dd, J¼3.6, 13.2 Hz, 1H), 5.09 (d, J¼17.2 Hz, 1H), 5.15 (d,
J¼10.4 Hz, 1H), 5.85 (ddd, J¼9.0, 10.4, 17.2 Hz, 1H), 7.11 (dt, J¼1.6,
7.6 Hz, 1H), 7.29 (dt, J¼1.6, 7.6 Hz, 1H), 7.33 (dd, J¼1.6, 7.6 Hz, 1H),
7.45 (t, J¼8.4 Hz, 2H), 7.56 (dt, J¼1.6, 7.6 Hz, 1H), 7.69 (dd, J¼1.2,
8.4 Hz, 2H), 7.83 (dd, J¼1.2, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.5.7. Dimethyl-7-methoxy-1-(4-methylphenylsulfonyl)-3-vinyl-2,3-
d
43.1 (CH), 47.6 (CH2), 52.6 (CH3), 52.8 (CH3), 60.9 (Cq), 119.1 (CH2),
dihydroquinoline-4,4(1H)-dicarboxylate (3m). Yield 92%; colorless
122.8 (CH), 124.2 (CH), 124.6 (Cq), 127.1 (CH), 128.6 (CH), 129.1 (CH),
131.1 (CH), 132.9 (CH), 134.1 (CH), 136.2 (Cq), 139.5 (Cq), 169.2 (Cq),
169.9 (Cq); HRMS (ESI) m/z calcd for C21H21NO6NaS [MþþNaþ]
438.0987, found 438.0990.
oil; IR (neat) 2953, 1733, 1612, 1507, 1254, 1166 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
2.39 (s, 3H), 2.97 (dt, J¼3.6, 8.8 Hz, 1H), 3.58 (s,
3H), 3.62 (s, 3H), 3.79 (s, 3H), 4.02 (dd, J¼8.8, 13.2 Hz, 1H), 4.10 (dd,
J¼3.6, 13.2 Hz, 1H), 5.10 (d, J¼17.2 Hz, 1H), 5.14 (d, J¼10.2 Hz, 1H),
5.81 (ddd, J¼8.8, 10.2, 17.2 Hz, 1H), 6.67 (dd, J¼2.8, 8.4 Hz, 1H),
7.23e7.27 (m, 3H), 7.37 (d, J¼2.8 Hz, 1H), 7.69 (d, J¼8.4 Hz, 2H); 13C
4.5.3. Dimethyl-1-(naphthalen-2-ylsulfonyl)-3-vinyl-2,3-dihydroquino-
line-4,4(1H)-dicarboxylate (3c). Yield 55%; colorless prisms; mp:
127.5e128.4 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 1774, 1351, 1241, 1165,
NMR (100 MHz, CDCl3)
d 21.5 (CH3), 42.7 (CH), 47.7 (CH2), 52.5
(CH3), 52.7 (CH3), 55.3 (CH3), 60.2 (Cq), 106.9 (CH), 111.0 (CH), 115.9
(Cq), 118.9 (CH2), 127.2 (CH), 129.7 (CH), 132.2 (CH), 134.3 (CH),
136.7 (Cq), 137.5 (Cq), 143.9 (Cq), 159.4 (Cq), 169.7 (Cq), 170.2 (Cq);
HRMS (ESI) m/z calcd for C23H26NO7S [MþþHþ] 460.1431, found
460.1433.
1070 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.94 (dt, J¼4.0, 9.0 Hz, 1H),
3.37 (s, 3H), 3.44 (s, 3H), 4.03 (dd, J¼9.0, 13.2 Hz, 1H), 4.18 (dd, J¼4.0,
13.2 Hz, 1H), 5.03 (d, J¼17.2 Hz, 1H), 5.12 (dd, J¼1.2, 10.2 Hz, 1H), 5.83
(ddd, J¼9.0, 10.2, 17.2 Hz, 1H), 7.11 (dt, J¼1.2, 7.6 Hz, 1H), 7.29e7.33 (m,
2H), 7.57e7.65 (m, 3H), 7.86e7.92 (m, 4H), 8.28 (s, 1H); 13C NMR
(100 MHz, CDCl3)
d
43.0 (CH), 47.8 (CH2), 52.5 (CH3), 52.6 (CH3), 60.8
4.6. General procedure for the synthesis of 2-
vinyltetrahydroquinoline
(Cq), 119.2 (CH2), 122.3 (CH), 123.0 (CH), 124.3 (CH), 124.8 (Cq), 127.6
(CH), 127.8 (CH), 128.6 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH ꢃ2),
131.1 (CH), 132.1 (Cq), 134.1 (CH), 134.9 (Cq), 136.2 (Cq), 136.4 (Cq),
169.1 (Cq), 169.8 (Cq); HRMS (ESI) m/z calcd for C25H23NO6NaS
[MþþNaþ] 488.1144, found 488.1146.
Synthesis of 4i (Table 2, entry 6): To a stirred solution of carba-
mate 1i (31.3 mg, 0.0876 mmol) and (Z)-1,4-diacetoxy-2-butene (2)
(18.1 mg, 0.105 mmol) in THF (2 mL) were added Pd2(dba)3$CHCl3
(4.50 mg, 4.38
mmol), (ꢀ)-BINAP (11.0 mg, 17.5
mmol), and K2CO3
4.5.4. Dimethyl 1-(4-nitrophenylsulfonyl)-3-vinyl-2,3-dihydroquino-
line-4,4(1H)-dicarboxylate (3d). Yield 80%; colorless prisms; mp:
164.2e165.4 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 1734, 1532, 1351,
(48.0 mg, 0.350 mmol) at rt, and stirring was continued for 30 min
at the same temperature. The reaction mixture was then allowed to
heat to 80 ꢂC, and stirred for 2 h. After filtration of the reaction
mixture using small amount of silica gel followed by concentration,
the residue was chromatographed on silica gel with hexane/AcOEt
(80:20, v/v) as eluent to give the 2-vinyltetrahydroquinoline 4i
(26.7 mg, 74%) and the 3-vinyltetrahydroquinoline 3i (5.10 mg,14%).
1247, 1173 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.00 (dt, J¼4.4, 9.4 Hz,
1H), 3.55 (s, 3H), 3.63 (s, 3H), 3.99 (dd, J¼9.4, 13.2 Hz, 1H), 4.15 (dd,
J¼4.4, 13.2 Hz, 1H), 5.12 (d, J¼17.2 Hz, 1H), 5.18 (d, J¼10.4 Hz, 1H),
5.81 (ddd, J¼9.4, 10.4, 17.2 Hz, 1H), 7.16 (dt, J¼1.2, 7.6 Hz, 1H), 7.32
(dt, J¼1.2, 7.6 Hz, 1H), 7.36 (dd, J¼1.2, 7.6 Hz, 1H), 7.80 (dd, J¼1.2,
7.6 Hz, 1H), 7.84 (d, J¼9.2 Hz, 2H), 8.27 (d, J¼9.2 Hz, 2H); 13C NMR
4.6.1. 1-Benzyl 4,4-dimethyl 2-vinyl-2,3-dihydroquinoline-1,4,4-
(100 MHz, CDCl3)
d
43.2 (CH), 47.9 (CH2), 52.6 (CH3), 52.9 (CH3), 60.8
tricarboxylate (4i). Yield 74%; colorless oil; IR (neat) 2953, 1732,
(Cq), 119.5 (CH2), 122.7 (CH), 124.3 (CH), 125.0 (CH), 125.2 (Cq),128.4
(CH), 128.9 (CH), 131.3 (CH), 133.7 (CH), 135.5 (Cq), 144.9 (Cq), 150.3
1712, 1644, 1604, 1585, 1321, 1130, 1036 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
2.16 (dd, J¼9.2, 13.6 Hz, 1H), 3.01 (dd, J¼8.0, 13.6 Hz, 1H),
(Cq), 168.9 (Cq), 169.6 (Cq); HRMS (ESI) m/z calcd for C21H20N2O8
3.51 (s, 3H), 3.86 (s, 3H), 4.96 (ddd, J¼6.4, 10.4, 16.9 Hz, 1H), 5.08 (d,
J¼10.4 Hz, 1H), 5.16 (d, J¼12.4 Hz, 1H), 5.18 (d, J¼10.4 Hz, 1H), 5.23
(d, J¼12.4 Hz, 1H), 5.70 (ddd, J¼8.0, 9.2, 10.4), 7.07 (dd, J¼1.2, 7.8 Hz,
1H), 7.14 (dt, J¼1.2, 7.6 Hz, 1H), 7.26e7.33 (m, 6H), 7.51 (d, J¼8.0 Hz,
-
NaS [MþþNaþ] 483.0838, found 483.0835.
4.5.5. Dimethyl 1-(3,5-dimethylphenylsulfonyl)-3-vinyl-2,3-dihy-
droquinoline-4,4(1H)-dicarboxylate (3e). Yield 82%; colorless oil; IR
(KBr) 2953, 1735, 1490, 1355, 1246, 1163 cmꢁ1; 1H NMR (400 MHz,
1H); 13C NMR (100 MHz, CDCl3)
d 38.4 (CH2), 52.9 (CH3), 53.0 (CH3),
53.4 (CH), 57.6 (Cq), 67.5 (CH2), 115.5 (CH2), 124.8 (CH), 125.6 (CH),
126.5 (CH), 127.87 (CH), 127.94 (CH), 128.1 (CH), 128.3 (CH), 131.2
(Cq), 135.7 (Cq), 136.2 (Cq), 136.8 (CH), 154.2 (Cq), 169.8 (Cq), 170.0
(Cq); HRMS (ESI) m/z calcd for C23H23NO6Na [MþþNaþ] 432.1423,
found 432.1421.
CDCl3)
d
2.31 (s, 6H), 2.95 (dt, J¼4.0, 9.0 Hz, 1H), 3.58 (s, 3H), 3.65 (s,
3H), 4.00 (dd, J¼9.0, 13.2 Hz, 1H), 4.08 (dd, J¼4.0, 13.2 Hz, 1H), 5.07
(d, J¼17.0 Hz, 1H), 5.15 (d, J¼10.4 Hz, 1H), 5.85 (ddd, J¼9.0, 10.4,
17.0 Hz, 1H), 7.10 (t, J¼7.6 Hz, 1H), 7.16 (s, 1H), 7.28e7.29 (m, 3H),
7.36 (d, J¼7.6 Hz, 1H), 7.77 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
21.1 (CH3), 43.0 (CH), 47.7 (CH2), 52.5 (CH3), 52.7 (CH3),
4.6.2. 1-Benzyl 4,4-dimethyl 3-vinyl-2,3-dihydroquinoline-1,4,4-
60.9 (Cq), 118.9 (CH2), 122.8 (CH), 124.0 (CH), 124.4 (Cq), 124.7 (CH),
128.6 (CH), 131.2 (CH), 134.4 (CH), 134.6 (CH), 136.5 (Cq), 139.2 (Cq),
tricarboxylate (3i). Yield 14%; colorless oil; IR (neat) 2953, 1734,
1494, 1435, 1391, 1329, 1260, 1151, 1028 cmꢁ1 1H NMR (400 MHz,
;

9970
M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
CDCl3)
d
3.25 (ddd, J¼4.0, 7.2, 9.6 Hz, 1H), 3.63 (s, 3H), 3.75 (s, 3H),
(Cq), 153.1 (Cq), 159.1 (Cq), 170.4 (Cq), 170.5 (Cq); HRMS (ESI) m/
z calcd for C21H28NO7 [MþþHþ] 406.1866, found 406.1870.
3.86 (dd, J¼4.0, 13.0 Hz, 1H), 4.18 (dd, J¼7.2, 13.0 Hz, 1H), 5.10 (dd,
J¼1.2, 9.6 Hz, 1H), 5.18 (d, J¼12.4 Hz, 1H), 5.19 (d, J¼12.4 Hz, 1H),
5.25 (d, J¼12.4 Hz, 1H), 5.86 (dt, J¼9.6, 17.0 Hz, 1H), 7.10 (dt, J¼1.2,
7.2 Hz, 1H), 7.28e7.42 (m, 7H), 7.74 (d, J¼7.6 Hz, 1H); 13C NMR
4.7. Dimethyl 3-vinyl-2,3-dihydroquinoline-4,4(1H)-di-
carboxylate (14)
(100 MHz, CDCl3) d 45.1 (CH), 46.5 (CH2), 52.6 (CH3), 52.9 (CH3), 61.1
(Cq), 67.7 (CH2), 119.2 (CH2), 123.7 (CH), 124.0 (CH), 124.8 (Cq),
128.04 (CH), 128.07 (CH), 128.11 (CH), 128.5 (CH), 130.2 (CH), 134.2
(CH), 136.1 (Cq), 137.5 (Cq), 154.4 (Cq), 169.4 (Cq), 170.1 (Cq); HRMS
(ESI) m/z calcd for C23H24NO6 [MþþHþ] 410.1604, found 410.1605.
To a stirred solution of 3-vinyltetrahydroquinoline 3d (48.7 mg,
0.106 mmol) in DMF (2 mL) was added K2CO3 (43.8 mg,
0.317 mmol) and thiophenol (10.0 m
L, 0.127 mmol) at 0 ꢂC, and
stirring was continued for 13 h at rt. The resulting solution was
filtered using small amount of silica gel and concentrated in vacuo.
The residue was chromatographed on silica gel with hexane/AcOEt
(80:20, v/v) as eluent to give the amine 14 (29.1 mg, quant.) as
4.6.3. Trimethyl 2-vinyl-2,3-dihydroquinoline-1,4,4-tricarboxylate
(4j). Yield 66%; yellow oil; IR (neat) 2954, 1732, 1644, 1604, 1493,
1440, 1257, 1197, 1079 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.19 (dd,
yellow oil; IR (neat) 3410, 2952, 1730, 1608, 1503, 1226 cmꢁ1
;
1H
J¼9.2, 13.6 Hz, 1H), 3.01 (dd, J¼8.0, 13.6 Hz, 1H), 3.65 (s, 3H), 3.69 (s,
3H), 3.86 (s, 3H), 4.94 (tddd, J¼1.2, 6.0, 8.0, 9.2 Hz, 1H), 5.09 (td,
J¼1.2, 10.4 Hz, 1H), 5.20 (td, J¼1.2, 17.2 Hz, 1H), 5.69 (ddd, J¼6.0,
10.4, 17.2 Hz, 1H), 7.08 (dd, J¼1.6, 7.8 Hz, 1H), 7.14 (dt, J¼1.2, 7.8 Hz,
1H), 7.32 (dt, J¼1.6, 7.8 Hz, 1H), 7.49 (dd, J¼1.2, 7.8 Hz, 1H); 13C NMR
NMR (400 MHz, CDCl3) d
3.21e3.25 (m, 1H), 3.29 (dd, J¼5.8, 11.4 Hz,
1H), 3.65 (dd, J¼3.2, 11.4 Hz, 1H), 3.69 (s, 3H), 3.73 (s, 3H), 3.98 (br s,
NH), 5.07 (dd, J¼1.6, 10.0 Hz, 1H), 5.16 (dd, J¼1.6, 17.2 Hz, 1H), 5.95
(dt, J¼10.0, 17.2 Hz, 1H), 6.52 (dd, J¼1.2, 8.0 Hz, 1H), 6.69 (dt, J¼1.2,
8.0 Hz, 1H), 7.08 (dt, J¼1.2, 8.0 Hz, 1H), 7.33 (dd, J¼1.2, 8.0 Hz, 1H);
(100 MHz, CDCl3)
d
38.4 (CH2), 53.0 (CH3 ꢃ2), 53.1 (CH3), 53.4 (CH),
13C NMR (100 MHz, CDCl3)
d 43.1 (CH), 43.7 (CH2), 52.3 (CH3), 52.6
57.6 (Cq), 115.5 (CH2), 124.8 (CH), 125.9 (CH), 126.4 (CH), 128.2 (CH),
130.9 (Cq), 135.9 (Cq), 136.9 (CH), 154.9 (Cq), 169.9 (Cq), 170.1 (Cq);
HRMS (ESI) m/z calcd for C17H19NO6Na [MþþNaþ] 356.1110, found
356.1107.
(CH3), 59.9 (Cq), 114.6 (CH), 116.8 (CH), 117.1 (CH2), 128.7 (CH),
132.36 (CH), 136.3 (CH), 144.0 (Cq), 170.4 (Cq), 171.1 (Cq); HRMS
(ESI) m/z calcd for C15H17NO4Na [MþþNaþ] 298.1055, found
298.1060.
4.6.4. 1-tert-Butyl 4,4-dimethyl 2-vinyl-2,3-dihydroquinoline-1,4,4-
4.8. Dimethyl 1-allyl-3-vinyl-2,3-dihydroquinoline-4,4(1H)-
tricarboxylate
103.9e105.6 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 2980, 1740, 1694,
1491, 1250, 1160, 1132, 1071 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1.46
(4k). Yield
82%;
colorless
needles;
mp:
dicarboxylate (15)
d
To a stirred solution of amine 14 (82.6 mg, 0.300 mmol) in DMF
(2 mL) was added K2CO3 (124 mg, 0.900 mmol) and allyl bromide
(0.0770 mL, 0.900 mmol) at rt. The reaction mixture was then
allowed to heat to 80 ꢂC, and stirred for 2 h. The resulting solution
was filtered using small amount of silica gel and concentrated in
vacuo. The residue was chromatographed on silica gel with hexane/
AcOEt (80:20, v/v) as eluent to give the allylamine 15 (80.9 mg, 86%)
(s, 9H), 2.13 (dd, J¼8.0, 13.6 Hz, 1H), 2.99 (dd, J¼8.0, 13.6 Hz, 1H),
3.68 (s, 3H), 3.87 (s, 3H), 4.86 (tddd, J¼1.2, 6.4, 8.0, 9.6 Hz, 1H), 5.07
(td, J¼1.2, 10.4 Hz, 1H), 5.17 (td, J¼1.2, 17.2 Hz, 1H), 5.68 (ddd, J¼6.4,
10.4, 17.2 Hz, 1H), 7.04 (dd, J¼1.6, 7.6 Hz, 1H), 7.10 (dt, J¼1.6, 7.6 Hz,
1H), 7.29 (dt, J¼0.8, 7.6 Hz, 1H), 7.49 (dd, J¼0.8, 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 28.2 (CH3), 38.8 (CH2), 53.00 (CH3), 53.03 (CH3),
53.2 (CH), 57.8 (Cq), 81.0 (Cq), 115.1 (CH2), 124.4 (CH), 125.4 (CH),
126.8 (CH), 127.9 (CH), 131.3 (Cq), 136.4 (Cq), 137.4 (CH), 153.3 (Cq),
170.1 (Cq), 170.3 (Cq); HRMS (ESI) m/z calcd for C20H25NO6Na
[MþþNaþ] 398.1580, found 398.1582.
as colorless oil; IR (neat) 1734, 1604, 1504, 1231 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
3.19e3.30 (m, 2H), 3.58 (dd, J¼3.2, 11.2 Hz, 1H),
3.69 (s, 3H), 3.74 (s, 3H), 3.83 (dd, J¼4.8,17.4 Hz,1H), 3.93 (dd, J¼4.8,
17.4 Hz, 1H), 5.07e5.20 (m, 4H), 5.76e5.85 (m, 1H), 5.97 (dt, J¼10.0,
16.8 Hz, 1H), 6.63 (d, J¼8.0 Hz, 1H), 6.67 (t, J¼8.0 Hz, 1H), 7.15 (dt,
J¼1.6, 8.0 Hz, 1H), 7.28 (dd, J¼1.6, 8.0 Hz, 1H); 13C NMR (100 MHz,
4.6.5. 1-tert-Butyl 4,4-dimethyl 7-methyl-2-vinyl-2,3-dihydroquino-
line-1,4,4-tricarboxylate (4n). Yield 71%; colorless prisms; mp:
104.5e105.9 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 2986, 1746, 1732,
1703, 1504, 1436, 1256, 1147, 1067 cmꢁ1; 1H NMR (400 MHz, CDCl3)
CDCl3)
d 43.6 (CH), 50.7 (CH2), 52.4 (CH3), 52.6 (CH3), 53.8 (CH2),
60.7 (Cq), 111.6 (CH), 115.8 (CH), 116.2 (Cq), 116.3 (CH2), 117.5 (CH2),
129.0 (CH), 131.8 (CH), 132.9 (CH), 136.2 (CH), 144.4 (Cq), 170.4 (Cq),
171.1 (Cq); HRMS (ESI) m/z calcd for C18H21NO4Na [MþþNaþ]
338.1368, found 338.1368.
d
1.47 (s, 9H), 2.12 (dd, J¼9.6, 13.4 Hz, 1H), 2.34 (s, 3H), 2.96 (dd,
J¼8.0, 13.4 Hz, 1H), 3.68 (s, 3H), 3.85 (s, 3H), 4.85 (ddd, J¼6.4, 8.0,
9.6 Hz,1H), 5.06 (d, J¼10.0 Hz,1H), 5.16 (d, J¼17.2 Hz,1H), 5.67 (ddd,
J¼6.4, 10.0, 17.2 Hz, 1H), 6.92 (s, 2H), 7.35 (s, 1H); 13C NMR
4.9. Dimethyl 2-benzo-1-azabicyclo[3.3.1]-6-nonene-4,4-
dicarboxylate (16)
(100 MHz, CDCl3)
d 21.3 (CH3), 28.2 (CH3), 38.6 (CH2), 52.9 (CH3),
53.0 (CH3), 53.2 (CH), 57.4 (Cq), 80.9 (Cq), 115.0 (CH2), 125.1 (CH),
125.3 (CH), 127.2 (CH), 128.1 (Cq), 136.1 (Cq), 137.4 (CH), 137.8 (Cq),
153.3 (Cq), 170.3 (Cq), 170.4 (Cq); HRMS (ESI) m/z calcd for
C21H27NO6Na[MþþNaþ] 412.1736, found 412.1739.
To a stirred solution of allylamine 15 (11.0 mg, 0.0349 mmol) in
CH2Cl2 (2 mL) was added Grubbs’ second catalyst (1.50 mg,
1.74 mmol) at rt. After being refluxed for 1 h, the reaction mixture
was evaporated. The residue was chromatographed on silica gel
with hexane/AcOEt (70:30, v/v) as eluent to give the 16 (9.00 mg,
90%) as colorless prisms; mp: 157.5e158.8 ꢂC [AcOEt/hexane (4:1)];
4.6.6. 1-tert-Butyl 4,4-dimethyl 7-methoxy-2-vinyl-2,3-dihydroquino-
line-1,4,4-tricarboxylate (4o). Yield 85%; colorless prisms; mp:
92.7e93.6 ꢂC [AcOEt/hexane (2:1)]; IR (KBr) 2978, 2953, 1739,
IR (neat) 1730, 1481, 1262, 1223 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
1614, 1505, 1168, 1047 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.48
d
3.15 (s, 1H), 3.32 (dd, J¼2.8, 13.6 Hz, 1H), 3.54 (s, 1H), 3.57e3.59
(s, 9H), 2.18 (dd, J¼9.2, 13.6 Hz, 1H), 2.95 (dd, J¼7.6, 13.4 Hz, 1H),
3.69 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 4.89 (ddd, J¼5.6, 7.6,
9.2 Hz, 1H), 5.06 (dd, J¼1.2, 10.4 Hz, 1H), 5.15 (dd, J¼1.2, 17.0 Hz,
1H), 5.67 (ddd, J¼5.6, 10.4, 17.0 Hz, 1H), 6.66 (dd, J¼2.8, 8.6 Hz,
1H), 6.98 (d, J¼8.6 Hz, 1H), 7.13 (d, J¼2.8 Hz, 1H); 13C NMR
(m, 1H), 3.77 (s, 3H), 3.79 (s, 3H), 4.00 (dd, J¼1.2, 18.2 Hz, 1H),
5.58e5.62 (m, 1H), 5.75 (dd, J¼2.8, 9.8 Hz,1H), 7.08 (t, J¼8.0 Hz,1H),
7.09 (d, J¼8.0 Hz, 1H), 7.27 (t, J¼8.0 Hz, 1H), 7.60 (d, J¼8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3)
d 31.5 (CH), 48.1 (CH2), 52.7 (CH3), 53.0
(CH3), 57.0 (CH2), 60.4 (Cq), 123.0 (CH), 123.8 (Cq), 125.6 (CH), 126.0
(CH), 128.8 (CH), 129.2 (CH), 132.9 (CH), 150.4 (Cq), 170.3 (Cq), 170.6
(Cq); HRMS (ESI) m/z calcd for C16H18NO4 [MþþHþ] 288.1236,
found 288.1239.
(100 MHz, CDCl3)
d 28.2 (CH3), 38.3 (CH2), 52.9 (CH3), 53.0
(CH3), 53.2 (CH), 55.3 (CH3), 56.9 (Cq), 81.1 (Cq), 110.3 (CH),
112.0 (CH), 115.2 (CH2), 122.7 (Cq), 126.6 (CH), 137.2 (CH), 137.4

M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
9971
4.10. General procedure for the enantioselective cyclization of
2-amidophenylmalonates
(dd, J¼0.8, 10.2 Hz, 1H), 5.84 (ddd, J¼8.8, 10.2, 17.6 Hz, 1H), 7.15 (dt,
J¼1.2, 7.8 Hz, 1H), 7.29e7.35 (m, 2H), 7.70 (d, J¼8.0 Hz, 2H), 7.79 (d,
J¼8.0 Hz, 2H), 7.84 (dd, J¼1.2, 7.8 Hz, 1H); 13C NMR (100 MHz,
Synthesis of (ꢁ)-3d (Table 5, entry 8): To a stirred solution of
sulfonamide 1d (35.0 mg, 0.0857 mmol) and (Z)-1,4-diacetoxy-2-
butene (2) (17.7 mg, 0.103 mmol) in dioxane (2 mL) were added
CDCl3) d 43.2 (CH), 47.8 (CH2), 52.5 (CH3), 52.8 (CH3), 60.9 (Cq),
119.3 (CH2), 123.0 (CH), 124.8 (CH), 125.3 (Cq), 126.2 (q, J¼33 Hz,
CF3), 127.7 (CH ꢃ4),128.8 (CH), 131.2 (CH),133.9 (CH), 135.8 (Cq ꢃ2),
142.9 (Cq), 169.0 (Cq), 169.7 (Cq); HRMS (ESI) m/z calcd for
C22H20NO6NaSF6 [MþþNaþ] 506.0861, found 506.0861. Enantio-
meric excess was determined by HPLC analysis [CHIRALCEL AS-H
Pd2(dba)3$CHCl3 (4.40 mg, 4.29
m
mol), (S)-(ꢁ)-BINAP (10.7 mg,
17.1 mol), and K2CO3 (47.0 mg, 0.343 mmol) at rt, and stirring was
m
continued for 30 min at the same temperature. The reaction mix-
ture was then allowed to heat to 80 ꢂC, and stirred for 2 h. After
filtration of the reaction mixture using small amount of silica gel
followed by concentration, the residue was chromatographed on
silica gel with hexane/AcOEt (80:20, v/v) as eluent to give the op-
tically active 3-vinyltetrahydroquinoline (ꢁ)-3d (31.3 mg, 79%, 99%
ee) as colorless prisms.
column, hexane/iPrOH (9:1 v/v), 0.5 mL/min,
time 19.4 min and 22.8 min].
l¼254 nm, retention
4.10.5. (ꢁ)-Dimethyl
1-(4-cyanophenylsulfonyl)-3-vinyl-2,3-dihy-
droquinoline-4,4(1H)-dicarboxylate [(ꢁ)-3h]. Yield 93%, 76% ee;
ꢂ
colorless prisms; mp: 138.9e139.9 C [AcOEt/hexane (2:1)]; IR
(KBr): 1734,1489, 1363,1249,1168 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.10.1. (ꢁ)-Dimethyl 1-(4-nitrophenylsulfonyl)-3-vinyl-2,3-dihy-
d
2.97 (dt, J¼4.0, 9.2 Hz,1H), 3.56 (s, 3H), 3.66 (s, 3H), 3.98 (dd, J¼9.2,
droquinoline-4,4(1H)-dicarboxylate [(ꢁ)-3d]. Yield 79%, 99% ee;
13.2 Hz,1H), 4.12 (dd, J¼4.0,13.2 Hz,1H), 5.11 (d, J¼17.2 Hz,1H), 5.17
(d, J¼10.4 Hz, 1H), 5.82 (ddd, J¼9.2, 10.4, 17.2 Hz, 1H), 7.15 (dt, J¼1.2,
7.8 Hz, 1H), 7.31 (dt, J¼1.6, 7.8 Hz, 1H), 7.36 (dd, J¼1.6, 7.8 Hz, 1H),
26
yellow oil; [
a]
ꢁ17.3 (c 1.50 in CHCl3). Enantiomeric excess was
D
determined by HPLC analysis [CHIRALCEL AS-H column, hex-
ane/iPrOH (8:2 v/v), 0.5 mL/min,
l¼254 nm, retention time
7.72e7.79 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 43.2 (CH), 47.9
30.9 min and 37.6 min]. Other spectral data coincides with those of
(CH2), 52.6 (CH3), 53.0 (CH3), 60.8 (Cq), 116.7 (Cq), 117.1 (Cq), 119.4
(CH2),122.7 (CH),124.9 (CH),125.1 (Cq),127.8 (CH),128.9 (CH),131.3
(CH), 132.8 (CH), 133.7 (CH), 135.6 (Cq), 143.4 (Cq), 168.9 (Cq), 169.7
(Cq); HRMS (ESI) m/z calcd for C22H20N2O6NaS [MþþNaþ] 463.0940,
found 463.0939. Enantiomeric excess was determined by HPLC
analysis [CHIRALCEL AS-H column, hexane/iPrOH (8:2 v/v), 0.5 mL/
the racemic 3d.
4.10.2. (þ)-Dimethyl
1-(4-nitrophenylsulfonyl)-2-vinyl-2,3-dihy-
droquinoline-4,4(1H)-dicarboxylate [(þ)-4d]. Yield 52%, 83% ee
26
(Table 5, entry 4); colorless oil; [
a
]
þ62.4 (c 0.87 in CHCl3); IR
D
(neat) 1736, 1531, 1351, 1250, 1172 cmꢁ1; 1H NMR (400 MHz, CDCl3)
min,
l¼254 nm, retention time 45.2 min and 56.6 min].
d
2.48 (d, J¼5.6 Hz, 2H), 3.55 (s, 3H), 3.74 (s, 3H), 5.09e5.13 (m, 1H),
5.10 (d, J¼10.8 Hz, 1H), 5.23 (d, J¼17.2 Hz, 1H), 5.64 (ddd, J¼5.6, 10.8,
17.2 Hz, 1H), 7.21 (dt, J¼1.2, 7.8 Hz, 1H), 7.25e7.28 (m, 2H), 7.36 (dt,
J¼1.2, 7.8 Hz, 1H), 7.82 (d, J¼9.2 Hz, 2H), 8.26 (d, J¼9.2 Hz, 2H); 13C
Acknowledgements
This study was supported in part by a Grant-in-Aid for the En-
couragement of Young Scientists (B) from the Japan Society for the
Promotion of Science (JSPS), Uehara Memorial Foundation, Takeda
Science Foundation and the Program for Promotion of Basic and
Applied Research for Innovations in the Bio-oriented Industry
(BRAIN). We are grateful to Dr. Tatsusada Yoshida for helpful sug-
gestions about pKa calculations.
NMR (100 MHz, CDCl3)
d 34.4 (CH2), 53.2 (CH3), 53.3 (CH3), 55.4
(CH), 55.7 (Cq), 117.5 (CH2), 124.2 (CH), 125.0 (CH), 125.7 (CH), 126.8
(Cq), 128.7 (CH), 129.1 (CH), 129.9 (CH), 134.2 (Cq), 135.1 (CH), 145.0
(Cq), 150.3 (Cq), 169.8 (Cq), 170.0 (Cq); HRMS (ESI) m/z calcd for
C21H21N2O8S [MþþHþ] 461.1019, found 461.1017. Enantiomeric ex-
cess was determined by HPLC analysis [CHIRALCEL AD column,
hexane/iPrOH (9:1 v/v), 0.5 mL/min,
46.4 min and 56.4 min].
l¼254 nm, retention time
Supplementary data
4.10.3. (ꢁ)-Dimethyl 1-(4-methoxyphenylsulfonyl)-3-vinyl-2,3-
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.tet.2012.09.075.
dihydroquinoline-4,4(1H)-dicarboxylate [(ꢁ)-3f]. Yield 31%, 55%
26
ee; colorless prisms; mp: 97.0e97.8 ꢂC [AcOEt/hexane (2:1)]; [
a]
D
ꢁ13.5 (c 0.72 in CHCl3); IR (KBr) 2953, 1733, 1596, 1497, 1354, 1261,
1161 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.98 (dt, J¼4.0, 9.0 Hz, 1H),
References and notes
3.57 (s, 3H), 3.64 (s, 3H), 3.83 (s, 3H), 3.96 (dd, J¼9.0, 13.2 Hz, 1H),
4.09 (dd, J¼4.0, 13.2 Hz, 1H), 5.10 (d, J¼17.6 Hz, 1H), 5.15 (d,
J¼10.2 Hz, 1H), 5.86 (ddd, J¼9.0, 10.2, 17.6 Hz, 1H), 6.89 (d, J¼8.8 Hz,
2H), 7.09 (dt, J¼1.2, 7.6 Hz, 1H), 7.28 (dt, J¼1.2, 7.6 Hz, 1H), 7.32 (dd,
J¼1.2, 7.6 Hz, 1H), 7.61 (d, J¼8.8 Hz, 2H), 7.84 (dd, J¼1.2, 7.6 Hz, 1H);
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13C NMR (100 MHz, CDCl3)
d 43.0 (CH), 47.6 (CH2), 52.5 (CH3), 52.7
(CH3), 55.6 (CH3), 60.9 (Cq), 114.2 (CH), 119.0 (CH2), 122.8 (CH),
124.0 (CH), 124.6 (Cq), 128.6 (CH), 129.3 (CH), 131.0 (CH), 131.1 (Cq),
134.3 (CH), 136.4 (Cq), 163.2 (Cq), 169.2 (Cq), 169.9 (Cq); HRMS (ESI)
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Enantiomeric excess was determined by HPLC analysis [CHIRALCEL
AS-H column, hexane/iPrOH (8:2 v/v), 0.5 mL/min,
tention time 67.9 min and 89.3 min].
l¼254 nm, re-
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2,3-dihydroquinoline-4,4(1H)-dicarboxylate [(ꢁ)-3g]. Yield 69%,
27
65% ee; colorless oil; [
a
]
ꢁ13.6 (c 0.42 in CHCl3); IR (KBr) 1736,
D
1324, 1248, 1173, 1063 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 2.93 (dt,
~
J¼4.0, 8.8 Hz, 1H), 3.53 (s, 3H), 3.62 (s, 3H), 3.98 (dd, J¼8.8, 13.2 Hz,
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9972
M. Yoshida et al. / Tetrahedron 68 (2012) 9962e9972
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15. When Boc-substituted substrate 1k was subjected to the reaction in the
presence of chiral ligand, the enantiomeric excess was not observed in the
resulting product 4k.