Selective synthesis of polysubstituted dihydroquinolines and α,β-unsaturated amidines by a catalytic reaction of ynamides with ketimines

Article abstract of DOI:10.1055/s-0033-1339191

Ynamides reacted with benzophenone imines in the presence of triflic imide as a catalyst. Ynamides bearing a sulfonamide moiety gave the corresponding 2-amino-3,4-dihydroquinolines selectively in good to high yields. In contrast, yne-carbamates gave the corresponding α,β-unsaturated amidines exclusively. These methods permit simple preparation of sterically crowded polysubstituted quinolines and α,β-unsaturated amidines. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339191

2328▌
PAPER
paper
Selective Synthesis of Polysubstituted Dihydroquinolines and α,β-Unsaturated
Amidines by a Catalytic Reaction of Ynamides with Ketimines
Polysubstituted Dihydroquinolines and α,β-Unsaturated Amidines
Yuusuke Kuroda, Naoya Shindoh, Yoshiji Takemoto, Kiyosei Takasu*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8571, Japan
Fax +81(75)7535604; E-mail: kay-t@pharm.kyoto-u.ac.jp
Received: 01.05.2013; Accepted after revision: 16.05.2013
the formation of an N,N-divinylamine (Scheme 1, b).6
Abstract: Ynamides reacted with benzophenone imines in the pres-
During the course of our continued studies, we found that
ence of triflic imide as a catalyst. Ynamides bearing a sulfonamide
the reaction of ynamides with benzophenone imines,
which have no α-protons, unexpectedly gave 2-amino-
moiety gave the corresponding 2-amino-3,4-dihydroquinolines se-
lectively in good to high yields. In contrast, yne-carbamates gave
the corresponding α,β-unsaturated amidines exclusively. These 3,4-dihydroquinolines as well as α,β-unsaturated ami-
methods permit simple preparation of sterically crowded polysub-
stituted quinolines and α,β-unsaturated amidines.
dines bearing a tetrasubstituted alkene moiety. Here, we
describe a novel synthesis of sterically crowded polysub-
Key words: quinolines, domino reactions, imines, amidines, am-
ides, alkynes, cyclizations
stituted dihydroquinolines and amidines.
Ar
N
EWG
N
EWG
Ar
N
N
R3
R1
Ar
R3
Nitrogen-containing heterocycles are among the most im-
portant and attractive moieties in medicinal and materials
chemistry. Of these, the quinoline skeleton is an important
nucleus that is frequently found as a component in phar-
maceutical agents and biologically active natural prod-
ucts.1 Because of the importance of substituted quinolines
and hydroquinolines, much attention has been paid to the
development of efficient methods for their synthesis.2 Al-
though many syntheses of quinoline derivatives have been
reported, the development of simple methods for synthe-
sizing polysubstituted quinoline derivatives remains an
active area of research.
R1
N
(a)
(b)
Tf2NH
(cat.)
R2
R1
EWG
R2
R3
N
EWG
Ar
R2
Tf2NH
(cat.)
EWG
Ar
N
N
N
R3
R3
R1
N
R1
Ar
N
R2
R2
R3
Scheme 1 Triflic amide catalyzed reactions of ynamides with aldi-
mines (a) or acetophenone imines (b)
Recently, ynamides (alkynylamides) have received much
attention as fascinating building blocks for the synthesis
of nitrogen-containing compounds.3 Ynamides react with
various electrophiles at the β-position to give the corre-
sponding keteniminium ions, which react in turn with nu-
cleophiles at the α-position. Ynamides also participate in
various cycloadditions to give heterocyclic and carbocy-
clic frameworks. We recently reported a domino [2+2] cy-
cloaddition–4π electrocyclization reaction4 of ynamides
with aldimines in the presence of a catalytic amount of tri-
flic imide (Tf2NH).5 The reaction affords good yields of
α,β-unsaturated amidines bearing a di- or trisubstituted al-
kene moiety via the corresponding 1,4-dihydroazet-2-
amines (Scheme 1, a). In marked contrast, when the reac-
tion is conducted with acetophenone imines under similar
conditions, the corresponding N,N-divinylamines are ob-
tained in good to moderate yields. We conjectured that the
reaction occurs by the following mechanism. The sp2 ni-
trogen atom of the ketimine attacks the keteniminium salt
generated from the ynamide and triflic amide, and subse-
quent deprotonation of the iminium intermediate results in
We began by studying the reaction of imine 2a with yn-
amide 1a bearing a benzosultam moiety. A mixture of 1a
and 2a in 1,2-dichloroethane was treated with a catalytic
amount of triflic imide (20 mol%) at 60 °C under the con-
ditions that we used in our previous study on the similar
reactions of aldimines4a (Table 1, entry 1). The α,β-unsat-
urated amidine 4aa was not formed but, unexpectedly, we
1
obtained the quinoline 3aa as a major product. H NMR
spectroscopy indicated that the ortho-position of the N-
aryl moiety of 1a had been substituted and one methyne
proton had been produced. We confirmed that 3aa is a
substituted 3,4-dihydroquinoline by X-ray crystallograph-
ic analysis of the related compound 3ca (see below) (Fig-
ure 1).7 Product 3aa was also obtained in the presence of
other Brønsted or Lewis acids,8 but the chemical yields
and reaction rates were unsatisfactory compared with
those obtained in the presence of triflic imide (entries 2–
4). The reaction in toluene gave the desired dihydroquin-
oline 3aa in moderate yield (entry 5), whereas almost no
reaction occurred in the polar solvents methoxycyclopen-
tane and acetonitrile (entries 6 and 7). Microwave
irradiation9 accelerated the formation of the desired dihy-
droquinoline; the reaction of ynamide 1a with imine 2a in
SYNTHESIS 2013, 45, 2328–2336
Advanced online publication: 25.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339191; Art ID: SS-2013-F0328-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Polysubstituted Dihydroquinolines and α,β-Unsaturated Amidines
2329
1,2-dichloroethane with microwave irradiation gave dihy- reaction of ynamides 1 with ketimines 2 (Table 2). Yne-
droquinoline 3aa in 96% yield (entry 8). The sterically sultams 1b [R1 = n-Hex] and 1c (R1 = H) reacted with 2a
crowded 3,4,4-triaryl-3,4-dihydroquinoline 3aa could to give the corresponding dihydroquinolines 3ba and 3ca,
therefore be efficiently constructed from readily available respectively, in high yield (entries 1 and 2). However, yn-
substrates in a single step.
amide 1d (R1 = TIPS) showed no reaction, possibly be-
cause the triisopropylsilyl group is too bulky to permit the
reaction to occur (entry 3). Interestingly, we found that the
α,β-unsaturated amidine 4ca formed as a side product
(6%) in the reaction of terminal alkyne 1c, whereas no for-
mation of an amidine 4 was observed in the case of 1a or
1b. Reactions with various ketimines 2b–g gave the cor-
responding dihydroquinolines 3 as the major products,
along with a small amount of the amidines 4 (entries 4–9,
12, and 13). It is noteworthy that the unsymmetrical keti-
mine 2g reacted smoothly to give the corresponding poly-
Table 1 Optimization of the Reaction Conditions for the Synthesis
of Dihydroquinoline 3aa
sultam
CF3
O
cat.
O
S
(20 mol%)
+
N
N
60 °C
Ph
Ar
Ar
1a
2a (Ar = 4-Tol)
substituted dihydroquinolines (entries
9 and 13).
sultam
N
However, amidines 4 were the main products from the re-
action of 2h, which has an electron-rich N-aryl moiety
(entries 10 and 14). The ratio of the dihydroquinoline 3 to
the amidine 4 appeared to be affected by electronic effects
in both the ynamine 1 and the ketimine 2. We have previ-
ously reported that the reaction of ynamides with aldi-
mines in the presence of triflic imide gives α,β-
unsaturated amidines exclusively. In the present work, we
confirmed that, even with microwave irradiation at 60 °C,
no dihydroquinoline 3ci was produced from aldimines 2i,
although a large amount of amidine 4ci was formed (entry
11). Toluenesulfonamide 1e gave both the dihydroquino-
line 3ea and the amidine 4ea (entry 15). The structure of
the amidines 4 was established by X-ray crystallography
of 4ch (Figure 2).7
sultam
Ph
N
Ar
CF3
Ph
CF3
Ar
4aa
Ar Ar
3aa
Entrya Catalyst
Solvent
Time
(h)
Yieldb of
3aa (%)
1
2
3
4
5
6
7
8c
Tf2NH
TfOH
DCE
DCE
DCE
DCE
toluene
3
3
3
3
3
3
3
1
70
38
45
<5
50
<5
0
BF3·OEt2
TMSOTf
Tf2NH
Tf2NH
Tf2NH
Tf2NH
methoxycyclopentane
MeCN
DCE
96
a Reaction conditions: 1a (0.10 mmol), 2a (0.11 mmol), catalyst (20
mol%), solvent (0.50 mL).
b Isolated yield.
c Microwave irradiation (120 W) was applied and the temperature was
maintained at 60 °C.
Figure 2 X-ray crystallographic structure of the α,β-unsaturated am-
idine 4ch; hydrogen atoms are omitted for clarity
The yne-carbamates (alkynyl oxazolidinones) 1f and 1g
reacted with benzophenone imines in the presence of tri-
flic imide. However, to our surprise, amidine 4 was ob-
tained exclusively in good to excellent yield (entries 16–
18). No formation of quinolines 3 was detected, even on
reaction at higher temperatures for longer periods under
Figure 1 X-ray crystallographic structure of dihydroquinoline 3ca;
hydrogen atoms are omitted for clarity
Having identified the optimal reaction conditions, we ex-
amined the substrate scope of the triflic amide catalyzed
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2328–2336

2330
Y. Kuroda et al.
PAPER
microwave irradiation. The results therefore show that the dicated that it was indeed obtained as a mixture of two
presence of an electron-withdrawing group on the nitro- diastereomers in a ratio of 77:23, but attempts to separate
gen atom of the ynamide controls whether the product will these were unsuccessful. Variable-temperature NMR
be a dihydroquinoline 3 or an amidine 4.
studies proved that the rotational barrier of the chiral axis
is not sufficiently high to permit separation of the diaste-
reomers at ambient temperatures. Therefore, the axial chi-
rality of 4ja is induced by a thermodynamic and not a
kinetic factor.10
Next, we studied the reaction of ynamide 1j, which con-
tained a chiral oxazolidinone auxiliary, to see if it would
give an axially chiral, α,β-unsaturated amidine (Scheme
2). 1H NMR spectroscopy of the resulting amidines 4ja in-
Table 2 Triflic Imide Catalyzed Reaction of Yne-Sulfonamides or Yne-Carbamates with Ketimines
Entrya Ynamide 1
Ketimine 2
Temp (°C) Product 3
Yield (%) Product 4 Yield (%)
O
EWG
EWG
R2
8
O
S
N
N
N
N
R
R
N
R2
R2
N
Ar1
Ar2
6
R1
R2
Ar1
Ar2
R1
Ar1 Ar2
1
2
3
4
5
6
7
8
9
1b (R1 = n-Hex)
2a (Ar1 = Ar2 = 4-Tol; R2 = 4-CF3)
2a
60
60
60
60
60
60
60
60
60
3ba (R2 = 6-CF3)
3ca (R2 = 6-CF3)
3da
87
4ba
4ca
4da
4cb
4cc
4cd
4ce
4cf
0
6
1c (R1 = H)
76
0
1d (R1 = TIPS)
2a
0
1c
1c
1c
1c
1c
1c
2b (Ar1 = Ar2 = 4-Tol; R2 = H)
2c (Ar1 = Ar2 = 4-Tol; R2 = 4-Br)
2d (Ar1 = Ar2 = 4-Tol; R2 = 2-Br)
2e (Ar1 = Ar2 = 4-Tol; R2 = 3,5-Br2)
2f (Ar1 = Ar2 = Ph; R2 = 4-CF3)
3cb (R2 = H)
3cc (R2 = 6-Br)
3cd (R2 = 8-Br)
60
65
75
10
5
trace
trace
4
3ce (R2 = 4,7-Br2) 70
3cf (R2 = 6-CF3)
3cg (R2 = 6-CF3)
64
57
2g (Ar1 = 4-MeOC6H4;
4cgc
6
Ar2 = 4-F3CC6H4; R2 = 4-CF3)b
10
11
12
13
14
1c
2h (Ar1 = Ar2 = 4-Tol; R2 = 4-MeO)
60
3ch (R2 = 6-MeO) 22
4ch
4ci
47
74
0
1c
2i (Ar1 = 4-Tol; Ar2 = H; R2 = 4-CF3) 60
3ci
0
76
93
13
1a (R1 = Ph)
2b
2gb
2h
100d
60
3ab (R2 = H)
3age
4ab
4ag
4ah
1a
0
1a
60
3ah
35
Ts
N
Bn
15
2a
60f
3ea
26
4ea
34
H
1e
O
O
N
R1
16
17
18
1f (R1 = Ph)
1g (R1 = H)
1g
2a
2a
2d
80d
80d
80d
3fa
3ga
3gd
0
0
0
4fa
4ga
4gd
69
86
98
a Reaction conditions: 1 (0.10 mmol), 2 (0.11 mmol), Tf2NH (20 mol%), DCE (0.50 mL), MW (120 W), 1 h.
b The substrate was a 3:2 mixture of geometrical isomers.
c The geometrical ratio was not determined.
d When the reaction was carried out at 60 °C, substrate 1 was not consumed within 1 h.
e Obtained as a mixture of diastereomers (dr = 84:16); the stereochemistry was not assigned.
f The reaction was carried out for 5 h.
Synthesis 2013, 45, 2328–2336
© Georg Thieme Verlag Stuttgart · New York

PAPER
Polysubstituted Dihydroquinolines and α,β-Unsaturated Amidines
2331
O
In summary, we have developed an unprecedented cata-
lytic reaction that provides polysubstituted quinolines
from yne-sulfonamides and benzophenone imines in good
yields. The reaction is accelerated by microwave irradia-
tion. In contrast, we found that α,β-unsaturated amidines
are obtained by the reaction of yne-carbamates under the
same conditions. It is noteworthy that these reactions per-
mit ready preparations of sterically crowded polysubsti-
tuted quinolines as well as α,β-unsaturated amidines.
axial
chirality
O
O
O
2a (1.1 equiv)
Tf2NH (20 mol%)
N
N
N
Ph
Ar
DCE
MW, 80 °C
CF3
Ph
Ph
Ph
Ar
1j
Ar = 4-Tol
4ja
69% (dr = 77:23)
Scheme 2 Chiral-auxiliary-induced stereoselective synthesis of axi-
ally chiral amidines 4ja
All reactions were carried out under a positive pressure of argon in
dried glassware unless otherwise noted. Solvents and materials
were obtained from commercial suppliers and used without further
purification. The reactions under microwave irradiation conditions
were conducted on a focused microwave instrument (CEM Corp.).
Column chromatography was performed on Merck silica gel 60
(230–400 mesh), and flash column chromatography was performed
on Cica silica gel 60 (spherical, 40–100 μm). Preparative TLC was
performed on Merck Silica Gel 60 F254 (0.5 mm or 2.0 mm). Reac-
tion mixtures and chromatography fractions were analyzed by TLC
on precoated silica gel plates (Merck Silica Gel 60 F254). All melt-
ing points were measured on YANACO MP-500P micro melting
point apparatus, and are uncorrected. IR spectra were recorded on a
Shimadzu FTIR-8300 spectrometer or a JASCO FT/IR-410 spec-
trometer. The 1H and 13C NMR spectra were recorded on JEOL AL-
400, JEOL ECA-600, and JEOL ECP-500 spectrometers with TMS
as internal standard. Low- and high-resolution mass spectra were
recorded on JEOL JMS-01SG-2 and JMS-HX/HX 110A mass spec-
trometers. Elemental analyses were performed on YANACO CHN
CORDER MT-6 equipment. X-ray crystal analyses were performed
on a Rigaku RAPID-S diffractometer.
In the reaction sequence for the formation of dihydroquin-
olines 3 from ynamides 1 and ketimines 2, one double-
bond cleavage, two single-bond formations, and one dou-
ble-bond formation occur overall. Amidine 4 is produced
by a domino [2+2] cycloaddition and 4π-electrocyclic
ring opening via the 1,2-dihydroazete intermediate 5 with
the assistance of the triflic imide catalyst. Initially, we as-
sumed that dihydroquinoline 3 would probably be formed
by a cyclization (cycloisomerization) of 4 through an in-
tramolecular Friedel–Crafts-type reaction or a thermal 6π-
electrocyclic pathway (Scheme 3, path a). To test our hy-
pothesis, we investigated the transformation of the isolat-
ed amidine 4ch into 3ch, but no reaction occurred in either
the presence or the absence of triflic imide. Even under
harsher conditions (higher temperatures, longer reaction
times, stoichiometric amount of triflic imide), no forma-
tion of 3ch was detected. Appropriate experiments also
ruled out the possibility that substrate 1 or 2 with triflic
imide promotes the cycloisomerization of 4. As a possible
alternative mechanism, if ortho-azoquinone methide 7
could be generated in situ from ketimine 2, an intermolec-
ular Diels–Alder reaction11 with ynamide 1 would provide
3 (path b). However, despite considerable efforts, we were
unable to obtain any evidence for the production of me-
thide 7. We now think that dihydroquinoline 3 might be
formed directly from azetine 5, before the formation of 4,
by a 4π-electrocyclic ring-opening reaction (path c). Fur-
ther studies to elucidate the reaction mechanism are under
way.
Ynamides 1; General Procedure
Ynamides 1a, 1b, 1d, and 1f were prepared according to Hsung’s
procedure.12 A flame-dried flask was charged with HC≡CBr (12
mmol), the appropriate amide (10 mmol), K3PO4 (20 mmol),
CuSO4·5H2O (2.0 mmol), 1,10-phenanthroline (4.0 mmol), and an-
hyd toluene (20 mL). The flask was fitted with a reflux condenser
then heated in an oil bath at 90 °C. When the HC≡CBr was con-
sumed (TLC), the mixture was cooled to r.t. and filtered through
Celite. The filtrate was concentrated under reduced pressure, and
the residue was purified by flash chromatography (silica gel).
Ynamides 1c and 1g were prepared by desilylation of the corre-
sponding TIPS-substituted ynamides by treatment with TBAF.
3,3,5-Trimethyl-2-(phenylethynyl)-2,3-dihydro-1,2-benzisothi-
azole 1,1-Dioxide (1a)
Pale-yellow crystals; yield: 1.62 g (52%); mp 135–136 °C.
IR (KBr): 2234, 1648, 1345, 1313, 1182 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 1 H), 7.52–
7.50 (m, 2 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.35–7.29 (m, 3 H), 7.23 (s,
1 H), 2.50 (s, 3 H), 1.73 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 145.0, 142.2, 131.8, 130.4, 129.2,
128.2, 128.0, 123.3, 122.7, 121.5, 75.4, 75.1, 65.6, 27.0, 21.9.
R2
sultam
R1
N
Tf2NH sultam
R1
R2
N
1 + 2
Ar
Ar
4π electro-
cyclization
[2+2]
Ar
Ar
cycloaddition
5
4
6π electro-
path b
path c
path a
R2
cyclization
LRMS (FAB): m/z 311 [M+], 312 [M + 1]+.
R2
sultam
N
R2
sultam
N
HN
Anal. Calcd for C18H17NO2S; C, 69.43; H, 5.50; N, 4.50. Found: C,
69.14; H, 5.32; N, 4.52.
H+
R1
Ar
R1
H
3,3,5-Trimethyl-2-oct-1-yn-1-yl-2,3-dihydro-1,2-benzisothia-
zole 1,1-Dioxide (1b)
Colorless crystals; yield: 2.07 g (65%); mp 84–85 °C.
Diels–
Alder
Ar Ar
Ar Ar
Ar
7
3
6
IR (ATR): 2254, 1604, 1460, 1319, 1179 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 1 H), 7.34 (d,
J = 8.0 Hz, 1 H), 7.20 (s, 1 H), 2.48 (s, 3 H), 2.41 (t, J = 6.9 Hz, 2
Scheme 3 Three possible reaction pathways for formation of dihy-
droquinolines 3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2328–2336

2332
Y. Kuroda et al.
PAPER
H), 1.63 (s, 6 H), 1.59 (m, 2 H), 1.44 (m, 2 H), 1.32 (m, 4 H), 0.90
(t, J = 6.9 Hz, 3 H).
reduced pressure, and the residue was purified by column flash
chromatography (silica gel).
13C NMR (125 MHz, CDCl3): δ = 144.7, 142.4, 130.2, 129.3, 123.2,
121.4, 75.1, 65.6, 64.8, 31.3, 28.9, 28.5, 26.7, 22.5, 21.9, 18.8, 14.0.
LRMS (FAB): m/z 319 [M+], 320 [M + 1]+.
N-[Bis(4-tolyl)methylene]-4-(trifluoromethyl)aniline (2a)
Pale-yellow crystals; yield: 848 mg (80%); mp 108–109 °C.
IR (ATR): 1601, 1323, 1220, 1161 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.38 (d,
J = 8.3 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 7.7 Hz, 2 H),
6.97 (d, J = 7.7 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 2 H), 2.41 (s, 3 H),
2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.2, 154.7, 141.5, 138.9, 136.7,
132.7, 129.5, 129.4, 129.0, 128.7, 125.7 (q, 3J(C,F) = 3.6 Hz), 124.7
(q, 2J(C,F) = 32.4 Hz), 124.5 (q, 1J(C,F) = 271 Hz), 120.9, 21.5, 21.3.
Anal. Calcd for C18H25NO2S: C, 67.67; H, 7.89; N, 4.38. Found: C,
67.77; H, 7.98; N, 4.32.
2-Ethynyl-3,3,5-trimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-
Dioxide (1c)
Colorless crystals; yield: 1.78 g (75%); mp 133–134 °C.
IR (ATR): 2132, 1601, 1311, 1174 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 1 H), 7.37 (d,
J = 8.0 Hz, 1 H), 7.21 (d, J = 0.5 Hz, 1 H), 3.05 (s, 1 H), 2.49 (s, 3
H), 1.68 (s, 6 H).
LRMS (FAB): m/z 353 [M+], 354 [M + 1]+.
Anal. Calcd for C22H18F3N; C, 74.77; H, 5.13; N, 3.96. Found: C,
75.06; H, 4.89; N, 4.02.
13C NMR (125 MHz, CDCl3): δ = 145.2, 141.9, 130.4, 128.8, 123.3,
121.3, 69.2, 65.1, 64.1, 26.7, 21.9.
LRMS (FAB): m/z 236 [M + 1]+.
N-[Bis(4-tolyl)methylene]-4-bromoaniline (2c)
Pale-yellow crystals; yield: 252 mg (69%); mp 124–125 °C.
HRMS (FAB): m/z [M + 1]+ calcd for C12H14NO2S: 236.0745;
IR (ATR): 1600, 1479, 1314, 1296, 1140 cm–1.
found: 236.0748.
1H NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz, 2 H), 7.23 (d,
J = 8.6 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.06 (d, J = 8.0 Hz, 2 H),
6.96 (d, J = 8.0 Hz, 2 H), 6.58 (d, J = 8.6 Hz, 2 H), 2.40 (s, 3 H),
2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.9, 150.5, 141.2, 138.7, 137.0,
132.9, 131.4, 129.5, 129.4, 128.9, 128.7, 122.8, 115.9, 21.4, 21.3.
3,3,5-Trimethyl-2-[(triisopropylsilyl)ethynyl]-2,3-dihydro-1,2-
benzisothiazole 1,1-Dioxide (1d)
Colorless crystals; yield: 3.37 g (86%); mp 148–149 °C.
IR (ATR): 2164, 1603, 1463, 1313, 1174 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 8.1 Hz, 1 H), 7.35 (dd,
J = 8.1, 0.7 Hz, 1 H), 7.20 (d, J = 0.7 Hz, 1 H), 2.48 (s, 3 H), 1.67
(s, 6 H), 1.12 (s, 21 H).
LRMS (FAB): m/z 363 [M+], 364 [M + 1]+.
Anal. Calcd for C21H18BrN: C, 69.52; H, 4.92; N, 3.68. Found: C,
69.24; H, 4.98; N, 3.85.
13C NMR (125 MHz, CDCl3): δ = 144.8, 142.0, 130.3, 129.3, 123.3,
121.4, 89.2, 74.8, 65.1, 26.8, 21.9, 18.7, 11.3.
LRMS (FAB): m/z 392 [M + 1]+.
N-[Bis(4-tolyl)methylene]-2-bromoaniline (2d)
Pale-yellow crystals; yield: 170 mg (47%); mp 82–83 °C.
HRMS (FAB): m/z [M + 1]+ calcd for C21H34NO2SSi: 392.2080;
found: 392.2091.
IR (ATR): 1622, 1604, 1580, 1462, 1314, 1296, 1180 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.45 (dd,
J = 8.0, 1.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.01–7.07 (m, 5 H),
6.77 (dt, J = 8.0, 1.4 Hz, 1 H), 6.54 (dd, J = 7.7, 1.4 Hz, 1 H), 2.41
(s, 3 H), 2.29 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.3, 150.4, 141.4, 138.7, 136.4,
133.2, 132.3, 129.6, 128.9, 128.8, 128.5, 127.4, 123.9, 121.3, 115.4,
21.5, 21.3.
4,4-Dimethyl-3-(phenylethynyl)-1,3-oxazolidin-2-one (1f)
Colorless crystals; yield: 1.61 g (75%); mp 62–63 °C.
IR (KBr): 2249, 1758, 1412, 1206, 1077 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.48–7.43 (m, 2 H), 7.32–7.29 (m,
3 H), 4.19 (s, 2 H), 1.50 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 155.0, 131.6, 128.3, 128.1, 122.4,
76.3, 75.7, 73.5, 60.3, 24.9.
LRMS (FAB): m/z 215 [M+], 216 [M + 1]+.
LRMS (FAB): m/z 363 [M+], 364 [M + 1]+.
Anal. Calcd for C21H18BrN: C, 69.52; H, 4.92; N, 3.68. Found: C,
69.46; H, 5.11; N, 3.81.
HRMS (FAB): m/z [M+] calcd for C13H13NO2: 215.0946; found:
215.0937.
N-[Bis(4-Tolyl)methylene]-3,5-dibromoaniline (2e)
Pale-yellow solid; yield: 152 mg (34%); mp 107–108 °C.
IR (ATR): 1622, 1603, 1571, 1524, 1409, 1296, 1180 cm–1.
3-Ethynyl-4,4-dimethyl-1,3-oxazolidin-2-one (1g)
Colorless crystals; yield: 101 mg (73%); mp 75–76 °C.
1H NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 8.3 Hz, 2 H), 7.12 (d,
J = 8.3 Hz, 2 H), 7.18 (t, J = 1.7 Hz, 1 H), 7.09 (d, J = 7.7 Hz, 2 H),
6.98 (d, J = 7.7 Hz, 2 H), 6.79 (d, J = 1.7 Hz, 2 H), 2.39 (s, 3 H),
2.32 (s, 3 H).
IR (ATR): 2148, 1748, 1400, 1341 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.16 (s, 2 H), 2.91 (s, 1 H), 1.45
(s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 155.4, 75.7, 62.1, 61.9, 59.8, 24.5.
LRMS (FAB): m/z 140 [M + 1]+.
13C NMR (125 MHz, CDCl3): δ = 170.0, 153.9, 141.7, 139.2, 136.3,
132.3, 129.5, 129.3, 129.0, 128.8, 128.0, 122.8, 122.4, 21.5, 21.4.
LRMS (FAB): m/z 441 [M+], 443 [M + 2]+.
Anal. Calcd for C7H9NO2; C, 60.42; H, 6.52; N, 10.07. Found: C,
60.24; H, 6.53; N, 9.81.
Anal. Calcd for C21H17Br2N: C, 56.91; H, 3.87; N, 3.16. Found: C,
57.01; H, 3.79; N, 3.09.
Ketimines 2; General Procedure
Ketimines 2 were prepared according to Jørgensen’s procedure.13
A
N-{(4-Methoxyphenyl)[4-(trifluoromethyl)phenyl]methylene}-
4-(trifluoromethyl)aniline (2g)
Pale-yellow solids; yield: 368 mg [77%; mixture of anti- and syn-
isomers (60:40)]; mp 118–119 °C.
flame-dried flask was charged with Pd2(dba)3 (0.5 mmol), BINAP
(0.75 mmol), t-BuONa (12 mmol), the appropriate aryl bromide (10
mmol), the appropriate imine (10 mmol), and anhyd toluene (50
mL). The resulting mixture was heated at 80 °C for 12 h, cooled to
r.t., and filtered through Celite. The filtrate was concentrated under
IR (ATR): 1645, 1597, 1551, 1524, 1402, 1180 cm–1.
Synthesis 2013, 45, 2328–2336
© Georg Thieme Verlag Stuttgart · New York

PAPER
Polysubstituted Dihydroquinolines and α,β-Unsaturated Amidines
2333
1H NMR (500 MHz, CDCl3): δ (major isomer) = 7.67 (d, J = 8.5 Hz,
2 H), 7.55 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.24 (d,
J = 8.0 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.0 Hz, 2 H),
3.86 (s, 3 H); δ (minor isomer) = 7.85 (d, J = 8.0 Hz, 2 H), 7.67 (d,
J = 9.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 9.0 Hz, 2 H),
6.80 (t, J = 8.5 Hz, 4 H), 3.79 (s, 3 H).
3-Hexyl-4,4-bis(4-tolyl)-6-(trifluoromethyl)-2-[3,3,5-trimethyl-
1,1-dioxido-1,2-benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline
(3ba)
White solid; yield: 58.6 mg (87%); mp 109–110 °C.
1H NMR (500 MHz, CDCl3): δ = 8.00 (d, J = 1.4 Hz, 1 H), 7.71 (d,
J = 8.0 Hz, 1 H), 7.52 (dd, J = 8.1, 1.4 Hz, 1 H), 7.40 (d, J = 8.0 Hz,
2 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.25 (d, J = 8.1 Hz, 1 H), 7.23 (s, 1
H), 7.13 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 6.98 (d,
J = 8.0 Hz, 2 H), 3.97 (d, J = 6.9 Hz, 1 H), 2.51 (s, 3 H), 2.34 (s, 3
H), 2.20 (s, 3 H), 2.09 (s, 3 H), 1.80–1.74 (m, 1 H), 1.73 (s, 3 H),
1.60–1.53 (m, 1 H), 1.22–0.79 (m, 7 H), 0.75 (t, J = 7.2 Hz, 3 H),
–0.11 to –0.20 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ (mixture of isomers) = 167.7,
166.9, 162.4, 160.4, 154.2, 154.0, 143.0, 139.5, 132.5 (q,
2
2J(C,F) = 32.3 Hz), 131.4, 131.1, 131.0, 130.8 (q, J(C,F) = 32.3 Hz),
129.9, 129.6, 126.8, 126.0 (q, 3J(C,F) = 4.8 Hz), 125.9 (q, 3J(C,F) = 3.5
3
Hz), 125.5, 125.3, 125.2 × 2 (q, J(C,F) = 3.6 Hz), 125.1 (q,
1
1J(C,F) = 271 Hz), 124.8, 124.0 (q, J(C,F) = 271 Hz), 123.3, 122.6,
13C NMR (125 MHz, CDCl3): δ = 161.3, 146.4, 145.2, 143.9, 141.4,
120.8 × 2, 113.8, 113.7, 55.5, 55.3.
LRMS (FAB): m/z 423 [M+].
HRMS (FAB): m/z [M+] calcd for C22H15F6NO: 423.1058; found:
139.1, 136.7, 136.0, 132.0, 130.3, 130.1, 128.9, 128.6, 128.5, 126.3,
3
2
126.1 (q, J(C,F) = 3.6 Hz), 125.9 (q, J(C,F) = 32.2 Hz), 124.5 (q,
3J(C,F) = 3.5 Hz), 124.5 (q, 1J(C,F) = 270 Hz), 123.1, 120.7, 67.8, 55.6,
43.3, 31.3, 29.5, 28.9, 27.9, 27.2, 27.0, 22.3, 22.0, 20.8, 20.7, 14.0.
423.1051.
LRMS (FAB): m/z 673 [M + 1]+.
HRMS (FAB): m/z [M+] calcd for C40H43F3N2O2S: 672.2997;
N-[Bis(4-Tolyl)methylene]-4-methoxyaniline (2h)
Pale-yellow crystals; yield: 347 mg (87%); mp 96–97 °C.
IR (ATR): 1605, 1501, 1290, 1241, 1179 cm–1.
found: 627.2991.
1H NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz, 2 H), 7.38 (d,
J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 2 H),
6.97 (d, J = 8.0 Hz, 2 H), 6.78 (d, J = 8.0 Hz, 2 H), 3.73 (s, 3 H),
2.41 (s, 3 H), 2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 167.9, 155.6, 144.9, 140.7, 138.2,
137.6, 133.7, 129.6, 129.2, 128.8, 128.6, 122.5, 113.7, 55.3, 21.4,
21.3.
4,4-Bis(4-tolyl)-6-(trifluoromethyl)-2-[3,3,5-trimethyl-1,1-diox-
ido-1,2-benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3ca)
Colorless crystals; yield: 47.7 mg (76%); mp 244–245 °C.
IR (ATR): 1590, 1574, 1325, 1256, 1161 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 1 H), 7.52 (dd,
J = 8.1, 1.7 Hz, 1 H), 7.36 (dd, J = 8.1, 0.62 Hz, 1 H), 7.31 (d,
J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 7.14 (d, J = 1.7 Hz, 1 H), 7.05 (m, 8
H), 3.91 (s, 2 H), 2.49 (s, 3 H), 2.30 (s, 6 H), 1.83 (s, 6 H).
LRMS (FAB): m/z 315 [M+], 316 [M + 1]+.
13C NMR (125 MHz, CDCl3): δ = 156.6, 146.5, 145.3, 143.9, 140.0,
Anal. Calcd for C22H21NO; C, 83.78; H, 6.71; N, 4.44. Found: C,
83.71; H, 6.55; N, 4.41.
136.5, 135.0, 130.3, 128.8, 128.7, 128.5, 126.4 (q, 2J(C,F) = 32.2 Hz),
3
3
125.6, 125.0 (q, J(C,F) = 3.2 Hz), 124.8 (q, J(C,F) = 3.2 Hz), 124.5
(q, 1J(C,F) = 271 Hz), 123.0, 120.9, 67.3, 50.3, 37.0, 27.4, 22.0, 20.9.
Triflic Imide-Catalyzed Reaction of Ynamides 1 with Ketimines
2; General Procedure
A 0.4 M soln of Tf2NH in DCE (50 μL, 20 μmol, 20 mol%) was add-
ed to a stirred soln of ynamide 1 (0.1 mmol) and ketimine 2 (0.1
mmol) in DCE (0.5 mL) in a microwave reaction vessel at r.t. under
N2 in a glove-box. The vessel was sealed and subjected to micro-
wave irradiation at 120 W for 1 h. The mixture was then diluted with
CHCl3, and the reaction was quenched with sat. aq NaHCO3 (1.0
mL). The aqueous phase was extracted with CHCl3 (2 × 2.0 mL) and
the organic layers were combined, washed with brine (3.0 mL),
dried (MgSO4), filtered, and concentrated in vacuo. The crude prod-
uct was purified by flash column chromatography [silica gel,
EtOAc–hexane (1:20)] to give quinoline 3 and/or amidines 4.
LRMS (FAB): m/z 588 [M+].
HRMS (FAB): m/z [M+] calcd for C34H31F3N2O2S: 588.2058;
found: 588.2051.
Crystal data:7 C34H31F3N2O2S, colorless needles (MeOH), triclinic,
space group P1, a = 8.849(7) Å, b = 12.44(1) Å, c = 13.68(1) Å,
β = 85.90(2)°, V = 1422(1) Å3, Z = 2, Dcalc = 1.374 g/cm3,
R = 0.059, Rw = 0.069, GOF = 1.262.
4,4-Bis(4-tolyl)-2-[3,3,5-trimethyl-1,1-dioxido-1,2-benzisothia-
zol-2(3H)-yl]-3,4-dihydroquinoline (3cb)
Colorless crystals; yield: 31.3 mg (60%); mp 237–238 °C.
3-Phenyl-4,4-bis(4-tolyl)-6-(trifluoromethyl)-2-[3,3,5-trimeth-
yl-1,1-dioxido-1,2-benzisothiazol-2(3H)-yl]-3,4-dihydroquino-
line (3aa)
IR (ATR): 1592, 1512, 1363, 1317, 1261, 1175 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.0 Hz, 1 H), 7.34 (d,
J = 8.0 Hz, 1 H), 7.25 (m, 2 H), 7.17 (s, 1 H), 7.05 (m, 9 H), 6.85
(dd, J = 8.0, 1.3 Hz, 1 H), 3.88 (s, 2 H), 2.47 (s, 3 H), 2.28 (s, 6 H),
1.82 (s, 6 H).
White solid; yield: 63.8 mg (96%); mp 277–278 °C.
IR (ATR): 1589, 1576, 1330, 1244, 1164, 1121 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.62 (s, 1 H), 7.55 (d, J = 8.1 Hz,
2 H), 7.46 (br s, 1 H), 7.42 (d, J = 8.1 Hz, 2 H), 7.30 (d, J = 8.0 Hz,
1 H), 7.19 (s, 1 H), 7.10–7.05 (m, 3 H), 6.95 (d, J = 7.9 Hz, 2 H),
6.78 (d, J = 7.5 Hz, 2 H), 6.55 (d, J = 7.5 Hz, 2 H), 6.34 (s, 2 H),
5.32 (s, 1 H), 2.47 (s, 3 H), 2.26 (s, 6 H), 2.06 (s, 3 H), 1.83 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.0, 145.1, 144.3, 143.6, 141.1,
136.2, 134.4, 130.2, 129.0, 128.6, 128.1, 127.7, 125.6, 124.9, 123.1,
122.5, 121.0, 67.2, 50.5, 37.3, 27.5, 22.1, 21.0.
LRMS (FAB): m/z 521 [M + 1]+.
13C NMR (125 MHz, CDCl3): δ = 158.5, 146.8, 145.2, 143.9, 140.9,
Anal. Calcd for C33H32N2O2S; C, 76.12; H, 6.19; N, 5.38. Found: C,
76.15; H, 6.40; N, 5.35.
137.9, 136.5, 136.4, 134.2, 132.7, 130.8, 130.5, 130.3, 128.9, 128.8,
2
127.7, 127.6, 127.2, 126.7 (q, J(C,F) = 32.2 Hz), 126.5, 126.3 (q,
6-Bromo-4,4-bis(4-tolyl)-2-[3,3,5-trimethyl-1,1-dioxido-1,2-
benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3cc)
Colorless crystals; yield: 38.9 mg (65%); mp 271–272 °C.
IR (ATR): 1608, 1363, 1311, 1250, 1175, 1142 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 8.0 Hz, 1 H), 7.38 (dd,
J = 8.3, 2.2 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.18 (s, 1 H), 7.10
(d, J = 8.3 Hz, 1 H), 7.05 (m, 8 H), 7.00 (d, J = 2.2 Hz, 1 H), 3.86
(s, 2 H), 2.48 (s, 3 H), 2.23 (s, 6 H), 1.80 (s, 6 H).
3
1
3J(C,F) = 3.7 Hz), 124.9 (q, J(C,F) = 3.5 Hz), 124.5 (q, J(C,F) = 271
Hz), 123.1, 120.7, 67.8, 57.6, 50.0, 29.8, 27.6, 27.4, 22.1, 21.0,
20.9.
LRMS (FAB): m/z 665 [M + 1]+.
Anal. Calcd for C40H35F3N2O2S; C, 72.27; H, 5.31; N, 4.21. Found:
C, 72.27; H, 5.03; N, 4.14.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2328–2336

2334
Y. Kuroda et al.
PAPER
13C NMR (125 MHz, CDCl3): δ = 155.0, 145.1, 144.0, 142.6, 140.2,
136.5, 136.4, 130.7, 130.6, 130.2, 128.8, 128.7, 128.6, 127.1, 123.0,
120.8, 117.8, 67.2, 50.4, 36.9, 27.3, 22.0, 20.9.
LRMS (FAB): m/z 599 [M+].
HRMS (FAB): m/z [M+] calcd for C33H31BrN2O2S: 598.1289;
3.87 (d, J = 16.0 Hz, 1 H), 3.79 (s, 3 H), 2.49 (s, 3 H), 1.87 (s, 3 H),
1.76 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 158.7, 156.1, 147.4, 146.4, 145.5,
143.7, 134.1, 133.9, 130.4, 129.9, 129.5, 129.3 (q, 2J(C,F) = 32.2 Hz),
128.2, 126.7 (q, 2J(C,F) = 32.2 Hz), 125.8, 125.3 (q, 3J(C,F) = 3.2 Hz),
3
3
125.0 (q, J(C,F) = 3.2 Hz), 124.5 (q, J(C,F) = 3.2 Hz), 124.2 (q,
found: 598.1287.
1J(C,F) = 271 Hz), 124.0 (q, J(C,F) = 271 Hz), 123.1, 120.9, 113.7,
1
67.4, 55.2, 50.4, 36.9, 27.4, 27.1, 22.0.
MS (FAB): m/z 658 [M+].
HRMS (FAB): m/z [M+] calcd for C34H28F6N2O3S: 658.6531;
found: 658.6533.
8-Bromo-4,4-bis(4-tolyl)-2-[3,3,5-trimethyl-1,1-dioxido-1,2-
benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3cd)
Colorless solid; yield: 44.9 mg (75%); mp 239–140 °C.
IR (ATR): 1608, 1360, 1309, 1254, 1175, 1141 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 8.0 Hz, 1 H), 7.54 (dd,
J = 8.0, 1.3 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 7.05
(m, 8 H), 6.89 (t, J = 7.8 Hz, 1 H), 6.79 (dd, J = 7.6, 1.3 Hz, 1 H),
3.91 (s, 2 H), 2.48 (s, 3 H), 2.29 (s, 6 H), 1.90 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 155.3, 145.2, 144.2, 141.7, 140.4,
136.4, 136.3, 131.7, 130.2, 128.9, 128.6, 128.5, 127.4, 125.3, 123.1,
121.6, 120.8, 67.5, 51.1, 36.9, 27.0, 22.0, 20.9.
3-Phenyl-4,4-bis(4-tolyl)-2-[3,3,5-trimethyl-1,1-dioxido-1,2-
benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3ab)
Colorless solid; yield: 45.2 mg (76%); mp 144–145 °C.
IR (ATR): 1616, 1590, 1315, 1240, 1173, 1141 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.1 Hz, 2 H), 7.49 (br
s, 2 H), 7.35–7.27 (m, 3 H), 7.18 (s, 1 H), 7.11 (dt, J = 7.3, 1.7 Hz,
1 H), 7.07–7.04 (m, 3 H), 6.94 (t, J = 7.7 Hz, 2 H), 6.75 (d, J = 7.7
Hz, 2 H), 6.60 (d, J = 7.7 Hz, 2 H), 6.37 (d, J = 6.3 Hz, 2 H), 5.28
(s, 1 H), 2.45 (s, 3 H), 2.25 (s, 3 H), 2.23 (s, 3 H), 2.05 (s, 3 H), 1.82
(s, 3 H).
LRMS (FAB): m/z 599 [M+].
Anal. Calcd for C33H31BrN2O2S; C, 66.11; H, 5.21; N, 4.67. Found:
C, 65.87; H, 5.50; N, 4.37.
13C NMR (125 MHz, CDCl3): δ = 156.5, 144.8, 144.1, 143.7, 141.6,
138.7, 135.88, 135.86, 134.7, 131.9, 131.0, 130.6, 130.0, 129.24,
129.17, 128.8, 128.8, 128.5, 127.7, 127.3, 127.2, 126.9, 126.3,
125.1, 122.9, 120.6, 67.5, 57.5, 50.3, 29.7, 27.5, 27.3, 22.0, 20.9,
20.8.
LRMS (FAB): m/z 596 [M+].
HRMS (FAB): m/z [M+] calcd for C39H36N2O2S: 596.2497; found:
5,7-Dibromo-4,4-bis(4-tolyl)-2-[3,3,5-trimethyl-1,1-dioxido-1,2-
benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3ce)
Pale-yellow crystals; yield: 47.3 mg (70%); mp 261–262 °C.
IR (ATR): 1594, 1326, 1310, 1239, 1120 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.0 Hz, 1 H), 7.50 (d,
J = 2.0 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H), 7.34 (dd, J = 8.0, 0.5 Hz,
1 H), 7.16–7.14 (m, 5 H), 7.06 (d, J = 8.0 Hz, 4 H), 3.82 (s, 2 H),
2.48 (s, 3 H), 2.30 (s, 6 H), 1.74 (s, 6 H).
596.2498.
13C NMR (125 MHz, CDCl3): δ = 155.4, 147.3, 145.3, 143.8, 138.5,
136.6, 133.6, 132.2, 130.1, 128.9, 128.8, 128.5, 128.2, 124.3, 123.0,
121.1, 120.9, 67.2, 52.3, 40.0, 27.2, 22.0, 21.0.
LRMS (FAB): m/z 676 [M+].
HRMS (FAB): m/z [M+] calcd for C33H30Br2N2O2S: 676.0395;
(4S)-4-(4-Methoxyphenyl)-3-phenyl-6-(trifluoromethyl)-4-[4-
(trifluoromethyl)phenyl]-2-[3,3,5-trimethyl-1,1-dioxido-1,2-
benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3ag)
Pale-yellow oil; yield: 68.3 mg [93%; mixture of rotational isomers
(84:16)].
IR (ATR): 1671, 1566, 1450, 1223, 1160, 1110 cm–1.
found: 676.0396.
1H NMR (500 MHz, CDCl3): δ (major rotamer) = 7.60 (d, J = 9.0
Hz, 2 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.49–7.47 (m, 3 H), 7.31 (d,
J = 8.0 Hz, 1 H), 7.24 (br s, 2 H), 7.21 (s, 1 H), 7.11 (t, J = 7.5 Hz,
1 H), 6.99–6.95 (m, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.59 (br s, 1 H),
6.57 (d, J = 7.5 Hz, 1 H), 6.53 (d, J = 7.5 Hz, 2 H), 5.33 (s, 1 H),
3.74 (s, 3 H), 2.47 (s, 3 H), 2.06 (s, 3 H), 1.85 (s, 3 H).
4,4-Diphenyl-6-(trifluoromethyl)-2-[3,3,5-trimethyl-1,1-dioxi-
do-1,2-benzisothiazol-2(3H)-yl]-3,4-dihydroquinoline (3cf)
Colorless crystals; yield: 35.4 mg (64%); mp 242–243 °C.
IR (ATR): 1574, 1366, 1330, 1258, 1165, 1120 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 8.5 Hz, 1 H), 7.53 (dd,
J = 8.5, 1.5 Hz, 1 H), 7.35 (dd, J = 8.0, 0.5 Hz, 1 H), 7.32 (d, J = 8.0
Hz, 1 H), 7.28–7.21 (m, 6 H), 7.18 (s, 1 H), 7.15–7.14 (m, 4 H), 7.10
(d, J = 2.0 Hz, 1 H), 3.96 (s, 2 H), 2.49 (s, 3 H), 1.77 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 158.5, 157.8, 146.5, 145.3 × 2,
143.7, 133.5, 131.6, 131.1, 130.3, 129.1 (q, 2J(C,F) = 32.2 Hz), 128.6,
127.8, 127.7, 127.6, 127.5, 126.9 (q, 2J(C,F) = 32.2 Hz), 126.8, 125.7
(q, 3J(C,F) = 3.2 Hz), 125.3 (q, 3J(C,F) = 3.2 Hz), 124.9 (q, 3J(C,F) = 3.6
13C NMR (125 MHz, CDCl3): δ = 156.5, 146.5, 145.4, 143.9, 142.8,
1
1
134.7, 130.3, 128.9, 128.4, 128.2, 127.1, 126.6 (q, 2J(C,F) = 31.8 Hz),
Hz), 124.2 (q, J(C,F) = 271 Hz), 124.1 (q, J(C,F) = 271 Hz), 123.1,
1
3
120.7, 67.8, 57.6, 55.2, 49.8, 27.4 × 2, 22.0.
LRMS (FAB): m/z 734 [M+].
126.4 (q, J(C,F) = 271 Hz), 124.9 (× 2) (q, J(C,F) = 3.2 Hz), 123.0,
120.9, 67.4, 51.0, 36.8, 29.7, 27.3, 22.0.
LRMS (FAB): m/z 561 [M + 1]+.
HRMS (FAB): m/z [M+] calcd for C40H32F6N2O3S: 734.2038;
HRMS (FAB): m/z [M + 1]+ calcd for C32H28F3N2O2S: 561.1824;
found: 734.2041.
found: 561.1815.
N-[(1E)-3,3-Bis(4-tolyl)-1-[3,3,5-trimethyl-1,1-dioxido-1,2-
benzisothiazol-2(3H)-yl]prop-2-en-1-ylidene]-4-methoxyani-
line (4ch)
4-(4-Methoxyphenyl)-6-(trifluoromethyl)-4-[4-(trifluorometh-
yl)phenyl]-2-[3,3,5-trimethyl-1,1-dioxido-1,2-benzisothiazol-
2(3H)-yl]-3,4-dihydroquinoline (3cg)
Pale-yellow needles; yield: 25.9 mg (47%); mp 124–125 °C.
IR (ATR): 1604, 1504, 1319, 1234, 1175, 1142 cm–1.
Pale-yellow oil; yield: 37.5 mg (57%).
IR (ATR): 1710, 1647, 1440, 1255 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.1 Hz, 1 H), 7.35 (d,
J = 8.1 Hz, 1 H), 7.24 (s, 1 H), 7.09 (d, J = 8.6 Hz, 2 H), 7.05 (d,
J = 8.6 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 2 H), 6.85 (d, J = 8.0 Hz, 2 H),
6.66 (s, 1 H), 6.59 (d, J = 8.6 Hz, 2 H), 6.28 (d, J = 8.6 Hz, 2 H),
3.71 (s, 3 H), 2.51 (s, 3 H), 2.32 (s, 6 H), 1.96 (s, 6 H).
1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 1 H), 7.56 (dd,
J = 8.0, 2.0 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.37 (dd, J = 8.0, 0.5
Hz, 1 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.20
(d, J = 0.5 Hz, 1 H), 7.09 (d, J = 2.0 Hz, 1 H), 7.04 (dd, J = 8.5, 2.0
Hz, 2 H), 6.84 (dd, J = 9.5, 2.5 Hz, 2 H), 3.98 (d, J = 16.0 Hz, 1 H),
Synthesis 2013, 45, 2328–2336
© Georg Thieme Verlag Stuttgart · New York

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Polysubstituted Dihydroquinolines and α,β-Unsaturated Amidines
2335
13C NMR (125 MHz, CDCl3): δ = 155.2, 150.3, 150.1, 144.7, 144.2,
141.2, 138.7, 138.2, 137.6, 136.4, 130.1, 129.7, 129.5, 128.7, 128.4,
128.1, 123.0, 122.7, 120.9, 115.5, 113.4, 66.7, 55.5, 27.0, 22.0,
21.3, 21.2.
(4S)-3-{(1E)-2-Phenyl-3,3-bis(4-tolyl)-N-[4-(trifluorometh-
yl)phenyl]prop-2-enimidoyl}-4-phenyl-1,3-oxazolidin-2-one
(4ja)
Colorless oil; yield: 42.5 mg (69%; dr 77:23).
LRMS (FAB): m/z 550 [M+].
IR (ATR): 3055, 2920, 1775, 1604, 1323, 1165, 1107, 1064, 910
cm–1.
Anal. Calcd for C34H34N2O3S; C, 74.15; H, 6.22; N, 5.09. Found: C,
73.99; H, 6.22; N, 5.23.
Crystal data:7 C34H34N2O3S, colorless prisms (MeOH), monoclinic,
space group P21/n, a = 8.500(3) Å, b = 17.691(3) Å, c = 20.323(7)
Å, β = 103.337(8)°, V = 2973(1) Å3, Z = 4, Dcalc = 1.230 g/cm3,
R = 0.094, Rw = 0.132, GOF = 1.720.
1H NMR (500 MHz, DMSO-d6, 130 °C): δ = 7.34–7.30 (m, 3 H),
7.27 (d, J = 8.5 Hz, 2 H), 7.20 (dd, J = 8.0, 2.0 Hz, 2 H), 7.01–6.99
(m, 5 H), 6.87 (d, J = 8.5 Hz, 4 H), 6.79 (d, J = 8.0 Hz, 2 H), 6.66
(d, J = 8.5 Hz, 2 H), 6.35 (d, J = 8.0 Hz, 2 H), 5.47 (dd, J = 8.5, 4.0
Hz, 1 H), 4.41 (t, J = 8.5 Hz, 1 H), 4.10 (dd, J = 8.5, 4.0 Hz, 1 H),
2.35 (s, 3 H), 2.18 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 153.7, 153.4, 153.1, 150.1, 149.8,
146.0, 145.3, 139.9, 139.6, 139.5, 138.4 (× 2), 138.3, 138.2, 138.1,
137.8, 137.3, 137.2, 130.9, 130.7, 130.6, 130.3, 129.7, 129.5, 128.6,
128.5, 128.4, 128.3, 128.2, 127.9 (× 2), 127.8, 127.4, 127.1, 126.9,
126.6, 125.1 (q, 3J(C,F) = 3.6 Hz), 125.0 (q, 2J(C,F) = 32.2 Hz), 125.0,
124.4 (q, 1J(C,F) = 269 Hz), 120.5, 120.2, 70.0, 69.7, 60.0, 58.9, 21.3
(× 2), 21.2.
3-{(1E)-2-Phenyl-3,3-bis(4-tolyl)-N-[4-(trifluoromethyl)phe-
nyl]prop-2-enimidoyl}-4,4-dimethyl-1,3-oxazolidin-2-one (4fa)
White amorphous solid; yield: 39.2 mg (69%); mp 158–159 °C.
IR (ATR): 1771, 1605, 1320, 1168, 1065 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H), 7.00 (d,
J = 8.1 Hz, 2 H), 6.87 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 8.0 Hz, 2 H),
6.73 (d, J = 8.0 Hz, 2 H), 6.55 (d, J = 8.1 Hz, 2 H), 3.74 (d, J = 8.0
Hz, 1 H), 3.66 (d, J = 8.0 Hz, 1 H), 2.36 (s, 3 H), 2.20 (s, 3 H), 1.60
(s, 3 H), 1.50 (s, 3 H).
LRMS (FAB): m/z 617 [M+].
HRMS (FAB): m/z [M+] calcd for C39H31F3N2O2: 617.2416; found:
13C NMR (125 MHz, CDCl3): δ = 155.0, 153.9, 150.5, 145.4, 139.9,
138.8, 138.5, 137.9, 137.1, 130.7 × 2, 129.6, 129.3, 128.5, 128.3,
127.5, 126.8, 126.5 (q, 1J(C,F) = 269 Hz), 125.1 (q, 3J(C,F) = 3.2 Hz),
124.8 (q, 2J(C,F) = 32.2 Hz), 120.2, 75.3, 61.4, 31.9, 23.5, 23.4, 21.3,
21.2.
LRMS (FAB): m/z 568 [M+].
HRMS (FAB): m/z [M+] calcd for C35H31F3N2O2: 568.2337; found:
617.2418.
Acknowledgment
This work was supported by Grants-in Aid for Young Scientists and
the Platform for Drug Design, Discovery, and Development from
MEXT, Japan, the Uehara Memorial Foundation, and the Naito
Foundation.
568.2339.
3-{(1E)-3,3-Bis(4-tolyl)-N-[4-(trifluoromethyl)phenyl]prop-2-
enimidoyl}-4,4-dimethyl-1,3-oxazolidin-2-one (4ga)
Colorless solid; yield: 42.3 mg (86%); mp 171–172 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
IR (ATR): 1767, 1604, 1319, 1167, 1063 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 8.3 Hz, 2 H), 7.12 (d,
J = 8.3 Hz, 2 H), 7.05 (s, 4 H), 6.92 (d, J = 8.0 Hz, 2 H), 6.75 (d,
J = 8.0 Hz, 2 H), 6.23 (s, 1 H), 3.62 (s, 2 H), 2.39 (s, 3 H), 2.30 (s,
3 H), 1.47 (s, 6 H).
References
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13C NMR (125 MHz, CDCl3): δ = 154.7, 152.4, 151.5, 149.2, 138.9,
138.3, 138.2, 136.4, 129.4, 129.0, 128.8, 128.3, 125.9 (q,
1
2
3J(C,F) = 3.5 Hz), 125.6 (q, J(C,F) = 271 Hz), 125.5 (q, J(C,F) = 33.3
Hz), 121.0, 116.9, 75.7, 61.6, 23.5, 21.4, 21.3.
LRMS (FAB): m/z 493 [M + 1]+.
HRMS (FAB): m/z calcd for C29H28F3N2O2: 493.2103 [M + 1]+;
found: 493.2105.
3-[(1E)-N-(2-Bromophenyl)-3,3-bis(4-tolyl)prop-2-enimidoyl]-
4,4-dimethyl-1,3-oxazolidin-2-one (4gd)
Pale-yellow crystals; yield: 49.3 mg (98%); mp 158–159 °C.
IR (ATR): 1677, 1540, 1328, 1179 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.48 (d, J = 8.0 Hz, 1 H), 7.13–
7.03 (m, 7 H), 6.97 (d, J = 7.5 Hz, 2 H), 6.82 (dd, J = 8.0, 1.5 Hz, 1
H), 6.63 (dt, J = 7.5, 1.0 Hz, 1 H), 6.29 (s, 1 H), 3.66 (s, 2 H), 2.40
(s, 3 H), 2.30 (s, 3 H), 1.56 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 154.8, 152.8, 148.4, 146.7, 138.9,
138.5, 138.2, 132.9, 129.7, 128.9, 128.7, 128.4, 127.6, 124.5, 122.2,
117.3, 116.1, 75.7, 61.6, 23.8, 21.4, 21.3.
LRMS (FAB): m/z 502 [M+].
HRMS (FAB): m/z [M+] calcd for C28H27BrN2O2: 502.1256; found:
(5) Takasu, K. Synlett 2009, 1905.
(6) Shindoh, N.; Takemoto, Y.; Takasu, K. Heterocycles 2011,
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502.1251.
(7) Crystallographic data for compounds 3ca and 4ch have been
deposited with the accession numbers CCDC 945444 and
945445, respectively, and can be obtained free of charge
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2328–2336

2336
Y. Kuroda et al.
PAPER
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK, Fax: +44(1223)336033,
E-mail: deposit@ccdc.cam.ac.uk, Web site:
(10) A DFT study (B3LYP/6-31G*) indicated that the ground-
state energy difference (ΔGo) between the two diastereomers
of 4ja was 4.32 kJ/mol (Boltzmann distribution 86:15). The
calculated value is reasonably consistent with the
experimental one (77:23).
www.ccdc.cam.ac.uk/conts/retrieving.html.
(8) No reaction occurred in the presence of the following Lewis
acids: Ce(OTf)3, Yb(OTf)3, In(OTf)3, Y(OTf)3, AgOTf,
Sc(OTf)3, Zn(OTf)2, Fe(OTf)3, and PtCl4 .
(9) For selected recent reviews, see: (a) Caddick, S.;
Fitzmaurice, R. Tetrahedron 2009, 65, 3325. (b) Kappe, C.
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Curr. Org. Chem. 2008, 12, 836. (e) Solinas, A.; Taddei, M.
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(a) Hodgett, I.; Noyce, S. J.; Storr, R. C. Tetrahedron Lett.
1984, 25, 5435. (b) Wu, H.; Xiao, X.; Qin, Y. Synlett 2011,
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Synth., Coll. Vol. XI; John Wiley & Sons: London, 2009,
677.
(13) Larsen, S. B.; Andersen, B. B.; Johansen, T. N.; Jørgensen,
M. Tetrahedron 2008, 64, 2938.
Synthesis 2013, 45, 2328–2336
© Georg Thieme Verlag Stuttgart · New York