α-Dimethylaminomethylenation-induced Houben-Hoesch-type cyclization of cyanoacetanilides: A practical synthesis of 3-formyl-4-hydroxyquinolin-2(1H)- ones

Article abstract of DOI:10.1016/j.tet.2011.03.040

The tandem reaction of cyanoacetanilides with triflic anhydride in DMF proceeded at room temperature to afford 3-formyl-4-hydroxyquinolin-2(1H)-ones in good to high yields. A detailed mechanistic study revealed that the tandem reaction proceeded via α-dim

Full text of DOI:10.1016/j.tet.2011.03.040

Tetrahedron 67 (2011) 3457e3463
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a-Dimethylaminomethylenation-induced HoubeneHoesch-type cyclization
of cyanoacetanilides: a practical synthesis of 3-formyl-4-hydroxyquinolin-
2(1H)-ones
,
a
a
a
a
b
Yusuke Kobayashi a , Terue Nakatani , Rie Tanaka , Mari Okada , Eri Torii , Takashi Harayama ,
*
,
Tetsutaro Kimachi a
*
a School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyubancho, Nikshinomiya, Hyogo 663-8179, Japan
b Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The tandem reaction of cyanoacetanilides with triflic anhydride in DMF proceeded at room temperature
to afford 3-formyl-4-hydroxyquinolin-2(1H)-ones in good to high yields. A detailed mechanistic study
Received 23 February 2011
Received in revised form 12 March 2011
Accepted 14 March 2011
revealed that the tandem reaction proceeded via
subsequent HoubeneHoesch-type cyclization. Both
a
-dimethylaminomethylenation, which promoted the
-functionalization and the cyclization steps were
a
Available online 21 March 2011
optimized, and a multi-gram scale synthesis of 3-formyl-4-hydroxyquinolin-2(1H)-one was achieved.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Electrophilic aromatic substitution
Nitrile
Vilsmeier reagent
Trifluoroacetic anhydride
Triflic anhydride
1. Introduction
The intramolecular HoubeneHoesch reaction (electrophilic ar-
omatic substitution reactions with nitriles1) provides benzene-
fused cyclic ketones, such as 1-tetralone,2 (thio)chromone,3 and
4-quinolone4 derivatives, which are key structural features of nu-
merous pharmaceuticals and biologically active natural products
(Scheme 1). However, aromatic CeH bond functionalization with
nitriles5 has attracted less attention because of the poor reactivity
of nitriles.6 Such reactions generally require strong acidic condi-
tions as well as electron-rich aromatic substrates to achieve high
product yields.1e4 Therefore, the development of mild and efficient
methods for achieving electrophilic aromatic substitution with
intramolecular CN groups is highly desirable. We envisioned that
Scheme 1. Synthetic Strategy for a-functionalized benzene-fused cyclic ketones.
functionalization of the cyclization precursor at the a-position of
the CN group would be useful not only for increasing the reactivity
of the CN groups but also for synthesizing functionalized cyclic
ketones from simple precursors4a,b (Scheme 1).
DMF produced complex mixtures (Eq. 1), the combination of phos-
phoryl chloride with DMF gave the
-functionalized product 2a,9
albeit in low yields (Eq. 2). Interestingly, treatment of 1a with
triflic anhydride (Tf2O) in DMF afforded the 3-formyl-4-hydrox-
yquinolin-2(1H)-ones 3a in 84% yield (Eq. 3), where a-formylation
and cyclization of 1a occurred even at room temperature. These
a
In a preliminary communication4b, we reported the reaction of
cyanoacetanilide7 (1a) under Vilsmeier conditions8 (Eqs. 1e3). Al-
though the reaction of 1a with thionyl chloride or oxalyl chloride in
results prompted us to investigate the details of the tandem reaction
of cyanoacetanilides 1. In this article, we revealed that the
thylaminomethylene substituent of the reaction intermediates 2
a-dime-
* Corresponding authors. Tel./fax: þ81 798 45 9952; e-mail addresses: ykoba@
mukogawa-u.ac.jp (Y. Kobayashi), tkimachi@mukogawa-u.ac.jp (T. Kimachi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.040

3458
Y. Kobayashi et al. / Tetrahedron 67 (2011) 3457e3463
increased the reactivity of the CN groups, facilitating the subsequent
intramolecular HoubeneHoesch-type reactions.
effective in the tandem reactions (entries 7 and 8). Moreover, when
this methodology was followed using cyanoacetanilide 1j, a tricyclic
compound (3j) was obtained in high yield (entry 9). Notably, the
isolationofall products 3aejwaseasilyaccomplishedbyprecipitation
and filtration.
We next focused on the elucidation of the mechanism of the
Tf2O-mediated tandem reaction of 1. The results shown in Eqs. 1e3
indicate that the tandem reaction proceeded via the acrylanilide 2
formed by the reaction of 1 with the Vilsmeier-type reagent A
(Scheme 2). Although the Vilsmeier reagent B derived from POCl3
also reacted with 1 to afford 2, the cyclization product 3 was not
observed at all. These differences intrigued us to explore the re-
activity of 2 and to identify the factors that promote cyclization of 2.
2. Results and discussion
We first examined the scope and limitations of the substrates
availableforthe triflicanhydride-mediated tandem reaction(Table 1).
The tandem reaction of cyanoacetanilides 1b and 1c, substituted at
the para position with an electron-donating methyl or methoxy
groups, occurred smoothly to afford the desired quinolinones 3b and
3c in 79% and 69% yields, respectively (entries 1 and 2). It was note-
worthy that the tandem reactions successfully proceeded with arenes
bearing electron-withdrawing substituents 1def (entries 3e5). The
halogenated products 3d and 3e could in principle be further func-
tionalized by way of transition metal-catalyzed coupling reactions.
Interestingly, the cyanoacetanilide 1g afforded the regioisomers 3g
and 3g0 in a 79% combined yield upon cyclization primarily at the
ortho position to the methyl group (35:65 ratio of para to ortho) (entry
6). The ortho-substituted cyanoacetanilides 1h and 1i were also
Scheme 2. Working hypothesis for the tandem reaction of 1.
Using the cyanoacetanilides 1 with 2.0 equiv of N,N-dime-
thylformamide dimethylacetal (DMFDMA) in toluene, several
acrylanilides 2 were synthesized in 62e93% yields (Table 2).
Table 2
Synthesis of 2-cyano-3-dimethylaminoacrylanilides 2a
Table 1
Tf2O-mediated tandem formylation/cyclization of cyanoacetanilides 1beja,b
Entry
1 (R1, R2)
Products
Yieldb (%)
1
2c
3
4
5
6
7
8
1a (H, Me)
1a
2a
2a
2b
2g
2h
2i
91
99
85
61
76
93
62
83
Entry
1 (R1, R2)
Products
Yieldc (%)
1b (p-Me, Me)
1g (m-Me, Me)
1h (o-Me, Me)
1i (o-OMe, Me)
1k (H, PMB)
1l (H, H)
1
2
3
4
5
6
7
8
1b (p-Me, Me)
1c (p-OMe, Me)
1d (p-Cl, Me)
1e (p-Br, Me)
1f (p-CF3, Me)
1g (m-Me, Me)
1h (o-Me, Me)
1i (o-OMe, Me)
3b
3c
3d
3e
79
69
80
68
61
78d
80
69
2k
2l
3f
3g (5-Me)þ3g0 (7-Me)
a
All reactions were carried out with 3.0 mmol of substrates in toluene.
Isolated yields.
3h
3i
b
c
Compound 1a (80 mmol) was used.
We then investigated the reactivity of 2 toward various reagents
(Table 3). Importantly, treatment of 2a with Tf2O in DMF cleanly
afforded 3a in 88% yield (entry 1). This result strongly suggests that
the tandem reaction of 1 proceeded via the acrylamide 2a (Scheme
2). We found DMF was essential for the cyclization of 2a10 (entry 1
vs entry 2). As expected, the treatment of 2a with POCl3 did not
9
82
a
Unless otherwise stated, the reactions were carried out with 3.0 mmol of sub-
strates in N,N-dimethylformamide (3.0 mL, 13 equiv).
afford 3a at all11 (entry 3). In addition, the Bronsted-acid-mediated
€
b
Tf¼trifluoromethanesulfonyl.
c
HoubeneHoesch reaction was not included in the tandem reaction
because 2a did not react with TfOH, which was expected to be
Isolated yields.
d
The ratio between 3g and 3g0 determined by 1H NMR experiment was 35:65.

Y. Kobayashi et al. / Tetrahedron 67 (2011) 3457e3463
3459
Table 4
formed in situ (entry 4). It is worth noting that trifluoroacetic an-
hydride (TFAA) facilitated the cyclization of 2a to furnish the qui-
nolone 3a in 89% yield (entry 5), indicating that Tf2O was not
necessarily required for the cyclization of 2a. The TFAA-mediated
HoubeneHoesch cyclization of 2 may provide a practical method
for synthesizing 3 because TFAA is a much cheaper and safer regent
than Tf2O.12 Thus, a large-scale reaction can be conducted easily and
inexpensively (entry 6). We then applied TFAA-mediated reactions
to several acrylanilides 2 (entries 7e12). To our delight, the TFAA-
mediated HoubeneHoesch reactions of para- (entry 7), meta- (en-
try 8), and ortho-substituted acrylanilides (entries 9 and 10), as well
as N-(4-methoxybenzyl)-acrylanilide (entry 11), proceeded
smoothly to afford the corresponding quinolinones 3 in 70e95%
yields. The annulation of the secondary acrylanilide 2l did not occur
(entry 12), most likely due to conformational constraints.13
The influence of a-substituents on HoubeneHoesch-type cyclization of 2
Entry
1
Substrates (X)
Yielda (%)
55
84
2 c
Table 3
Investigation of the reactivity of 2a
3
62
64
4
5
6
42
Entry
2 (R1, R2)
Reagent
Products
Yieldb (%)
1
2a (H, Me)
2a
2a
2a
2a
Tf2O
Tf2O
3a
3a
3a
3a
3a
3a
3b
3gþ3g0
3h
3i
3k
3l
88
0d
2 c
3
0b
0c
POCl3
TfOH
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
0d
4
0d
5
89
88
91
86f
83
70
95
0d
7
2s (eOEt)
6e
7
2a
a
2b (p-Me, Me)
2g (m-Me, Me)
2h (o-Me, Me)
2i (o-OMe, Me)
2k (H, PMB)
2l (H, H)
Isolated yields.
b
c
8
9
10
11
12
The reaction led to a complex mixture.
Compound 2s (56%) was recovered.
accelerated the reaction of the CN group with the electrophile A
(or C15,16), activating the CN group by triflation (or tri-
fluoroacetylation16). The Vilsmeier reagent B, however, could not
activate the CN group in such a manner.9,11 The activated CN
groups of the intermediates A0 (or C017) would be subject to the
subsequent electrophilic aromatic substitution to furnish the
quinolinones 3 after aqueous work-up.
a
Unless otherwise noted, all reactions were carried out with 1.0 mmol of sub-
strates in DMF.
b
c
d
e
f
Isolated yields.
Dichloromethane was used as solvent instead of DMF.
No reaction occurred.
Compound 2a (80 mmol) was used.
The ratio between 3g and 3g0 determined by 1H NMR experiment was 35:65.
We finally investigated the factors that promoted the TFAA-
mediated cyclization of 2. We hypothesized that the a-dimethyla-
minomethylene substituents should play an important role in the
cyclization of 2, and we compared the reactivity of the 2-cyanoa-
crylanilides 2mes bearing different substituents (X) at the C3 po-
sition (Table 4). When the substituents (X) were N,N-dialkylamino
groups, the TFAA-mediated reaction of 2mep proceeded smoothly
to furnish 3a in 55e84% yields (entries 1e4). In the case of 2q, the
nitrogen lone pair on the substituent (X) was delocalized into the
aromatic ring, and 3a was obtained in a relatively low yield (entry
5). Furthermore, the reactions of 2r and 2s, with weaker electron-
donating groups,14 did not produce the desired quinolone 3a (en-
tries 6 and 7). These results suggest that the electron-donating
effects of the
a-substituents facilitated the HoubeneHoesch-type
cyclization of 2.
Taking these results into consideration, a plausible mechanism
for the reactions of 1 (and 2) under the Vilsmeier conditions is
shown in Scheme 3. Initially, the active methylene of 1 reacted
with the Vilsmeier-type reagent A (or B) at the iminium carbon to
generate the acrylanilides 2. The mesomeric electron-donating
effect14 (þM) of the
a-dimethylaminomethylene substituent of 2
Scheme 3. A plausible mechanism.

3460
Y. Kobayashi et al. / Tetrahedron 67 (2011) 3457e3463
3. Conclusions
114.6,106.1, 28.8; IR (KBr) 3428 (OeH),1657 (C]O) cmꢁ1; HRMS (ESI-
TOF) calcd for C11H9NNaO3 ([MþNa]þ): 226.0475; found: 226.0474.
We have identified the detailed mechanism of the Tf2O-medi-
ated tandem formylation/cyclization of the cyanoacetanilides 1. The
Tf2O-derived reagent A played two different roles in the tandem
reaction: (1) introduction of dimethylaminomethylene sub-
stituents into the active methylene of 1 and (2) electrophilic acti-
vation of the CN groups of 2. The ability to activate the CN groups is
a significantly different between the reagents A and B. We also
revealed that the introduction of dimethylaminomethylene sub-
4.3.2. 4-Hydroxy-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-car-
baldehyde (3b). Pale yellow solid; mp 167e169 ꢀC (EtOH); 1H NMR:
d
14.58 (br, 1H), 10.20 (s, 1H), 7.89 (s, 1H), 7.51 (d, 1H, J¼8.4 Hz), 7.18
(d, 1H, J¼8.4 Hz), 3.59 (s, 3H), 2.42 (s, 3H); 13C NMR:
d 196.2, 171.4,
161.8, 140.7, 136.5, 132.2, 125.2, 114.52, 114.45, 106.1, 28.7, 20.5; IR
(KBr) 3436 (OeH), 1641 (C]O) cmꢁ1; HRMS (ESI-TOF) calcd for
C12H11NNaO3 ([MþNa]þ): 240.0631; found: 240.0632.
stituents into the a-position with respect to the CN groups greatly
increased the reactivity of the CN groups. Moreover, we found that
the relatively inexpensive and safe reagent C was effective for
achieving the HoubeneHoesch-type cyclization of 2. These findings
have great potential to widen the scope of the chemistry of elec-
trophilic aromatic substitution reactions with nitriles.
4.3.3. 4-Hydroxy-6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-
3-carbaldehyde (3c). Yellow needles; mp 183e185 ꢀC (EtOH); 1H
NMR:
d
14.62 (br,1H),10.21 (s,1H), 7.48 (d,1H, J¼2.8 Hz), 7.31 (dd,1H,
J¼9.2, 2.8 Hz), 7.23 (d, 1H, J¼9.2 Hz), 3.89 (s, 3H), 3.60 (s, 3H); 13C
NMR: d 196.4,170.9,161.5,154.9,137.4,124.8,116.1,115.1,106.2,106.0,
55.7, 28.8; IR (KBr) 3437 (OeH), 1645 (C]O) cmꢁ1; HRMS (ESI-TOF)
calcd for C12H11NNaO4 ([MþNa]þ): 256.0580; found: 256.0588.
4. Experimental section
4.1. General information
4.3.4. 6-Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-
carbaldehyde (3d). Pale yellow solid; mp 177e179 ꢀC (EtOH); 1H
NMR:
d
14.59 (br, 1H), 10.23 (s, 1H), 8.09 (d, 1H, J¼2.8 Hz), 7.65 (dd,
1H, J¼8.8, 2.4 Hz), 7.27 (d, 1H, J¼8.8 Hz), 3.63 (s, 3H); 13C NMR:
TLC analysis of the reaction mixtures was performed using Merck
silica gel 60 F254 TLC plates. Forcolumn chromatography, Kanto silica
gel 60 N (spherical, neutral, 100e210 mm) was used. The melting
points were reported without correction. Unless otherwise noted,
NMR spectra were recorded in CDCl3 at the ambient temperature
(27e35 ꢀC). 1H NMR (400 or 500 MHz) spectra were recorded using
Bruker AV-400, JEOL JNM-ECP400, or JEOL JNM-ECP500 spectrom-
d
196.3, 170.4, 161.6, 141.0, 135.1, 128.3, 125.1, 116.2, 115.8, 106.4,
29.0; IR (KBr) 3435 (OeH),1637 (C]O) cmꢁ1; HRMS (ESI-TOF) calcd
for C11H8ClNNaO3 ([MþNa]þ): 260.0085; found: 260.0087.
4.3.5. 6-Bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-
carbaldehyde (3e). Pale yellow solid; mp 194e197 ꢀC (EtOH); 1H
eters, and chemical shifts were expressed in d (ppm) relative toTMS
NMR:
d
14.58 (br, 1H), 10.22 (s, 1H), 8.22 (d, 1H, J¼2.0 Hz), 7.76 (dd,
(in CDCl3) as the internal standard. 13C NMR (100 or 125 MHz)
spectra were referenced with respect to the residual CHCl3 signals.
1H NMR multiplicities were reported as follows: br¼broad;
m¼multiplet; s¼singlet; d¼doublet; t¼triplet; and q¼quartet. IR
spectra were recorded by using a PerkineElmer FT-IR system 2000
spectrophotometer and expressed by wavenumber (cmꢁ1). Mass
spectra (MS) were obtained using JEOL JMS-700 instruments or
a Bruker MicroTOF spectrometer fitted with an ESI.
1H, J¼8.8, 2.4 Hz), 7.20 (d, 1H, J¼9.2 Hz), 3.61 (s, 3H); 13C NMR:
d
196.3, 170.3, 161.5, 141.4, 137.8, 128.1, 116.4, 116.1, 115.5, 106.4, 28.9;
IR (KBr) 3447 (OeH), 1655 (C]O) cmꢁ1; HRMS (ESI-TOF) calcd for
C11H8BrNNaO3 ([MþNa]þ): 303.9580; found: 303.9586.
4.3.6. 4-Hydroxy-1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihy-
droquinoline-3-carbaldehyde (3f). Pale yellow solid; mp 125e128 ꢀC
(EtOH); 1H NMR:
d 14.65 (br, 1H), 10.24 (s, 1H), 8.42 (s, 1H), 7.92 (dd,
1H, J¼8.8, 2.0 Hz), 7.44 (d, 1H, J¼8.8 Hz), 3.68 (s, 3H); 13C NMR:
d
196.2, 170.9, 161.7, 144.4, 131.2 (q, J¼3.0 Hz), 124.8 (q, J¼33 Hz),
4.2. Materials
123.5 (q, J¼4.0 Hz), 123.4 (q, J¼270 Hz); 115.3, 114.5, 106.5, 29.1; IR
(KBr) 3437 (OeH), 1660 (C]O) cmꢁ1; HRMS (ESI-TOF) calcd for
C12H7F3NNa2O3 ([MꢁHþ2Na]þ): 316.0168; found: 316.0172.
Unless otherwise noted, all commercial materials were used
withoutfurtherpurification. Solvents werepurchased fromWakoand
Kanto Chemical Co., Inc. Trifluoromethanesulfonic anhydride (Tf2O, in
an ampoule) was purchased from Wako Chemical Co., Inc. The use of
Tf2O from other suppliers (in glass bottles) gave poor results.
4.3.7. 4-Hydroxy-1,5-dimethyl-2-oxo-1,2-dihydroquinoline-3-car-
baldehyde (3g0). From 3.00 mmol (565 mg) of 1g, an inseparable
mixture of 3g and 3g0 (510 mg, 78%, 3g/3g0¼35/65) was obtained.
1H NMR:
d
15.62 (br, 1H), 10.17 (s, 1H), 7.53 (dd, 1H, J¼8.4, 7.6 Hz),
4.3. General procedure for the triflic anhydride-mediated
reaction of cyanoacetanilides 1
7.16 (d, 1H, J¼8.8 Hz), 7.02 (d, 1H, J¼7.6 Hz), 3.60 (s, 3H), 2.78 (s, 3H).
4.3.8. 4-Hydroxy-1,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-car-
To a solution of cyanoacetanilide 1 (3.0 mmol) in DMF (3.0 mL)
was carefully added Tf2O (1.5 mL, 9.0 mmol) at 0 ꢀC. The mixture
was stirred at room temperature for 12 h, at which point TLC
analysis indicated that the reaction was completed. The reaction
mixture was then poured into ice-cold water (100 mL). The pre-
cipitate was collected by filtration and washed with water, EtOH,
and ether. Recrystallization from EtOH gave pure 3.
baldehyde (3g). 1H NMR:
d 14.59 (br, 1H), 10.17 (s, 1H), 7.99 (d, 1H,
J¼8.4 Hz), 7.09e7.07 (m, 2H), 3.60 (s, 3H), 2.51 (s, 3H).
4.3.9. 4-Hydroxy-1,8-dimethyl-2-oxo-1,2-dihydroquinoline-3-car-
baldehyde (3h). Yellow needles; mp 137e140 ꢀC (EtOH); 1H NMR:
d
14.55 (br, 1H), 10.22 (s, 1H), 8.02 (dd, 1H, J¼8.0, 1.2 Hz), 7.49 (dd,
1H, J¼7.6, 0.8 Hz), 7.17 (dd, 1H, J¼7.6, 7.6 Hz), 3.74 (s, 3H), 2.68 (s,
3H); 13C NMR:
196.0, 171.9, 163.9, 144.1, 139.6, 125.7, 123.9, 122.8,
The mother and washing liquors were acidic. They were treated
with solid NaHCO3 prior to disposal.
d
116.7, 105.7, 36.2, 23.7; IR (KBr) 3436 (OeH), 1645 (C]O) cmꢁ1
;
HRMS (ESI-TOF) calcd for C12H11NNaO3 ([MþNa]þ): 240.0631;
4.3.1. 4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbalde-
found: 240.0640.
hyde (3a). Pale yellow needles; mp 176e178 ꢀC (EtOH); 1H NMR:
d
14.62 (br,1H),10.24 (s,1H), 8.16 (dd,1H, J¼8.0,1.6 Hz), 7.72 (ddd,1H,
J¼8.8,7.6,1.6Hz),7.32(d,1H,J¼8.8Hz), 7.29(dd,1H,J¼7.6, 8.0 Hz), 3.64
(s, 3H); 13C NMR:
196.3, 171.7, 162.0, 142.7, 135.2, 125.9, 122.4, 114.7,
4.3.10. 4-Hydroxy-8-methoxy-1-methyl-2-oxo-1,2-dihydroquino-
line-3-carbaldehyde (3i). Yellow solid; mp 155e157 ꢀC (EtOH); 1H
d
NMR:
d14.50 (br, 1H), 10.24 (s, 1H), 7.76 (dd, 1H, J¼4.8, 4.4 Hz), 7.19

Y. Kobayashi et al. / Tetrahedron 67 (2011) 3457e3463
3461
(d, 2H, J¼4.8 Hz), 3.91 (s, 3H), 3.86 (s, 3H); 13C NMR:
d
196.5, 171.2,
(EIþ) m/z (relative intensity) 243 (Mþ, 28), 123 (100); HRMS (EIþ)
163.1, 148.6, 134.3, 123.0, 117.79, 117.78, 116.9, 106.1, 56.6, 34.7; IR
(KBr) 3447 (OeH), 1650 (C]O) cmꢁ1; HRMS (ESI-TOF) calcd for
C12H11NNaO4 ([MþNa]þ): 256.0580; found: 256.0589.
calcd for C14H17N3O ([M]þ): 243.1372; found: 243.1369.
4.4.6. N-(4-Methoxybenzyl)-2-cyano-3-(dimethylamino)-N-phenyl-
acrylamide (2k). White powder; mp 104e105 ꢀC; 1H NMR:
d 7.79
4.3.11. 1-Ethyl-4-hydroxy-2-oxo-1,2-dihydrobenzo[h]quinoline-3-
(br, 1H), 7.31 (dd, 2H, J¼7.3, 7.3 Hz), 7.25 (dd, 1H, J¼7.3, 6.9 Hz), 7.14
carbaldehyde (3j). Yellow needles; mp 137e139 ꢀC (EtOH); 1H
(d, 2H, J¼8.3 Hz), 7.09 (d, 2H, J¼7.3 Hz), 6.77 (d, 2H, J¼7.8 Hz), 4.90
NMR:
d
14.42 (br, 1H), 10.24 (s, 1H), 8.36 (d, 1H, J¼8.8 Hz), 7.97 (d,
(s, 2H), 3.75 (s, 3H), 3.15 (br, 6H); 13C NMR:
d 167.8, 158.8, 158.7,
1H, J¼8.4 Hz), 7.87 (dd, 1H, J¼8.4, 0.8 Hz), 7.65 (ddd, 1H, J¼7.6, 7.2,
0.8 Hz), 7.58e7.54 (m, 2H), 4.45 (q, 2H, J¼6.8 Hz), 1.72 (t, 3H,
143.1, 130.1, 129.8, 129.2, 128.1, 127.1, 117.8, 113.7, 73.9, 55.2, 54.4,
47.7, 38.3; IR (thin film) 2191 (C^N),1645 (C]O) cmꢁ1; MS (EIþ) m/
z (relative intensity) 335 (Mþ, 43), 121 (100); HRMS (EIþ) calcd for
C20H21N3O2 ([M]þ): 335.1634; found: 335.1634.
J¼6.8 Hz); 13C NMR:
d 195.9, 171.2, 164.6, 144.2, 137.7, 129.2, 129.0,
125.79, 125.76, 124.0, 123.3, 119.8, 112.6, 106.0, 46.1, 15.3; IR (KBr)
3436 (OeH), 1649 (C]O) cmꢁ1
; HRMS (ESI-TOF) calcd for
C16H13NNaO3 ([MþNa]þ): 290.0788; found: 290.0790.
4.4.7. Cyano-3-(dimethylamino)-N-phenylacrylamide (2l). All spec-
tral data agreed with the corresponding data in the literature; see
Ref. 9a.
4.4. General procedure for the synthesis of 2ael
4.4.8. 2-Cyano-N-methyl-N-phenyl-3-(pyrrolidin-1-yl)acrylamide
(2m). A mixture of acrylamide 2a (687 mg, 3.0 mmol) and pyrro-
lidine (0.81 mL, 15 mmol) was stirred at room temperature for 2 h.
The reaction mixture was then poured into ice-cold water (20 mL).
The precipitate was collected by filtration, washed with water
(three times), and n-hexane (three times), and dried under vacuum
to give the title compound (470 mg, 61%), which was used in the
subsequent reaction without further purification. White solid; mp
To a solution of cyanoacetanilide 1 (5.0 mmol) in toluene (15 mL)
was added N,N-dimethylformamide dimethylacetal (1.32 mL,
10 mmol) at room temperature. The mixture was stirred at 90 ꢀC for
1e4 h, when TLC indicated the reaction was completed. The reaction
mixture was then concentrated invacuo. The residue was collected by
filtration and washed with ether (three times) to give pure 2, which
was used in the subsequent reaction without further purification.
109e111 ꢀC; 1H NMR:
d
7.94 (s,1H), 7.39 (ddd, 2H, J¼1.9, 8.3, 6.0 Hz),
4.4.1. 2-Cyano-3-(dimethylamino)-N-methyl-N-phenylacrylamide
7.29 (ddd, 1H, J¼1.4, 7.3, 7.4 Hz), 7.23 (dd, 2H, J¼8.7, 2.3 Hz), 3.69 (t,
(2a). Colorless solid; mp 142e143 ꢀC; 1H NMR:
d 7.74 (s, 1H), 7.39
2H, J¼6.4 Hz), 3.57 (t, 2H, J¼6.4 Hz), 3.34 (s, 3H), 1.96 (m, 2H), 1.86
(dd, 2H, J¼7.6, 6.0 Hz), 7.29 (dd, 1H, J¼7.6, 6.0 Hz), 7.22 (d, 2H,
(m, 2H); 13C NMR:
d 167.2, 154.9, 144.8, 129.3, 127.0, 126.8, 118.3,
J¼7.2 Hz), 3.35 (s, 3H), 3.17 (br, 6H); 13C NMR:
d
167.3, 158.2, 144.6,
73.7, 55.0, 47.7, 39.3, 25.8, 24.3; IR (thin film) 2190 (C^N), 1652 (C]
O) cmꢁ1; MS (EIþ) m/z (relative intensity) 255 (Mþ, 22), 149 (100);
HRMS (EIþ) calcd for C15H17N3O ([M]þ): 255.1372; found: 255.1370.
129.3, 126.9, 126.8, 117.8, 73.1, 47.5, 39.3, 38.2; IR (thin film) 2189
(C^N), 1652 (C]O) cmꢁ1; HRMS (ESI-TOF) calcd for C13H15N3NaO
([MþNa]þ): 252.1107; found: 252.1095.
4.4.9. 2-Cyano-N-methyl-N-phenyl-3-(piperidin-1-yl)acrylamide
(2n). A mixture of acrylamide 2a (229 mg, 1.0 mmol) and piperi-
dine (1.0 mL, 10 mmol) in DMF (2.0 mL) was stirred at 80 ꢀC for 2 h.
The reaction mixture was then poured into ice-cold water (50 mL).
The precipitate was collected by filtration, washed with water
(three times), and dried under vacuum to give the title compound
(181 mg, 67%), which was used in the subsequent reaction without
4.4.2. 2-Cyano-3-(dimethylamino)-N-methyl-N-p-tolylacrylamide
(2b). White solid; mp 158e160 ꢀC; 1H NMR:
d
7.71 (s, 1H), 7.17 (d,
2H, J¼6.6 Hz), 7.09 (d, 2H, J¼6.6 Hz), 3.29 (s, 3H), 3.14 (br, 6H), 2.35
(s, 3H); 13C NMR:
167.3, 158.2, 142.1, 136.5, 130.0, 126.7, 117.9, 73.3,
d
47.5, 39.4, 38.2, 21.1; IR (thin film) 2187 (C^N), 1652 (C]O) cmꢁ1
;
MS (EIþ) m/z (relative intensity) 243 (Mþ, 25), 123 (100); HRMS
(EIþ) calcd for C14H17N3O ([M]þ): 243.1372; found: 243.1373.
further purification. White solid; mp 106e108 ꢀC; 1H NMR:
d 7.74 (s,
1H), 7.38 (dd, 2H, J¼7.4, 8.3 Hz), 7.27 (dd, 1H, J¼7.3, 7.4 Hz), 7.21 (d,
4.4.3. 2-Cyano-3-(dimethylamino)-N-methyl-N-m-tolylacrylamide
2H, J¼8.3 Hz), 3.71 (br, 2H), 3.45 (br, 2H), 3.34 (s, 3H), 1.64 (br, 6H);
(2g). Pale yellow solid; mp 99e101 ꢀC; 1H NMR:
d
7.72 (s, 1H), 7.25
(dd, 1H, J¼7.7, 7.7 Hz), 7.08 (d, 1H, J¼7.3 Hz), 7.03e7.00 (m, 2H), 3.32
(s, 3H), 3.15 (br, 6H), 2.36 (s, 3H); 13C NMR:
167.3, 158.2, 144.6,
13C NMR:
d 167.7, 156.5, 144.8, 129.4, 127.1, 126.8, 118.0, 72.0, 57.6,
47.1, 39.4, 26.1, 23.7; IR (thin film) 2189 (C^N), 1640 (C]O) cmꢁ1
;
d
MS (EIþ) m/z (relative intensity) 269 (Mþ, 19), 163 (100); HRMS
139.2, 129.1, 127.64, 127.61, 124.1, 117.9, 73.4, 47.5, 39.4, 38.2, 21.3; IR
(thin film) 2194 (C^N), 1652 (C]O) cmꢁ1; MS (EIþ) m/z (relative
intensity) 243 (Mþ, 31), 123 (100); HRMS (EIþ) calcd for C14H17N3O
([M]þ): 243.1372; found: 243.1371.
(EIþ) calcd for C16H19N3O ([M]þ): 269.1528; found: 269.1528.
4.4.10. 2-Cyano-N-methyl-3-morpholino-N-phenylacrylamide
(2o). A mixture of acrylamide 2a (459 mg, 2.0 mmol) and mor-
pholine (1.75 mL, 20 mmol) in DMF (4.0 mL) was stirred at 80 ꢀC for
2.5 h. The reaction mixture was then poured into ice-cold water
(50 mL). The precipitate was collected by filtration, washed with
water (three times), and dried under vacuum to give the title com-
pound (228 mg, 42%), which was used in the subsequent reaction
without further purification. White solid; mp 140e144 ꢀC; 1H NMR:
4.4.4. 2-Cyano-3-(dimethylamino)-N-methyl-N-o-tolylacrylamide
(2h). Pale yellow solid; mp 135e138 ꢀC; 1H NMR:
d
7.77 (s, 1H),
7.24e7.18 (m, 3H), 7.07 (d, 1H, J¼6.2 Hz), 3.20 (s, 3H), 3.13 (br, 6H),
2.28 (s, 3H); 13C NMR:
167.3, 158.5, 143.0, 136.1, 131.1, 128.5, 128.1,
d
126.9, 117.3, 72.7, 47.6 (2C), 38.3, 17.8; IR (thin film) 2190 (C^N),
1645 (C]O) cmꢁ1; MS (EIþ) m/z (relative intensity) 259 (Mþ, 32),
123 (100); HRMS (EIþ) calcd for C14H17N3O2 ([M]þ): 259.1321;
found: 259.1323.
d
7.74 (s, 1H), 7.39 (dd, 2H, J¼7.8, 7.8 Hz), 7.29 (ddd, 1H, J¼1.4, 7.3,
7.4 Hz), 7.21 (dd, 2H, J¼8.7,1.1 Hz), 3.69 (br, 7H), 3.34 (s, 3H), 3.16 (br,
1H); 13C NMR:
166.9, 156.7, 144.5, 129.5, 127.08, 127.05, 117.5, 73.6,
d
66.4, 47.5, 39.5, 38.3; IR (thin film) 2191 (C^N), 1645 (C]O) cmꢁ1
;
4.4.5. 2-Cyano-3-(dimethylamino)-N-(2-methoxyphenyl)-N-methyl-
MS (EIþ) m/z (relative intensity) 271 (Mþ, 31),165 (100); HRMS (EIþ)
acrylamide (2i). Pale yellow solid; mp 143e144 ꢀC; 1H NMR:
d
7.72
calcd for C15H17N3O2 ([M]þ): 271.1321; found: 271.1324.
(s, 1H), 7.32 (ddd, 1H, J¼1.2, 7.3, 6.2 Hz), 7.11 (dd, 1H, J¼1.5, 6.2 Hz),
6.96e6.94 (m, 2H), 3.87 (s, 3H), 3.22 (s, 3H), 3.14 (br, 6H); 13C NMR:
4.4.11. 3-(N-Benzyl-N-methylamino)-2-cyano-N-methyl-N-phenyl-
acrylamide (2p). A mixture of acrylamide 2a (687 mg, 3.0 mmol) and
benzylamine (1.64 mL,15 mmol) was stirred at room temperature for
d
167.6, 158.3, 155.6, 132.9, 129.5, 129.2, 120.9, 117.7, 112.4, 73.1, 55.7,
47.4, 38.1, 37.8; IR (thin film) 2186 (C^N), 1652 (C]O) cmꢁ1; MS

3462
Y. Kobayashi et al. / Tetrahedron 67 (2011) 3457e3463
3h. Thereactionmixturewasthenpouredintoice-coldwater(20mL).
The precipitate was collected by filtration, washed with water (three
times) and EtOH (three times), and dried under vacuum to give 3-
(benzylamino)-2-cyano-N-methyl-N-phenylacrylamide S-1 (699 mg,
80%), which was used in the subsequent reaction without further
purification. To a stirred solution of the above-prepared S-1 (291 mg,
1.0 mmol) inTHF (5.0 mL) was added NaH (48.0 mg,1.2 mmol, ca. 60%
in mineral oil) at 0 ꢀC and the reaction mixture was stirred at room
temperature for 1 h. To this clear pale yellow solution was added MeI
(0.13 mL, 2.0 mmol), and the reaction mixture was stirred for 2 h
before being quenched with satd NH4Cl. The product was extracted
with EtOAc three times and the combined extracts were washed with
water and brine, dried over Na2SO4, and evaporated to afford a crude
oil, which was purified by silica gel column chromatography (EtOAc/
n-hexane¼1/1)togivethetitlecompound2pasawhitesolid(266mg,
silica gel column chromatography (EtOAc/n-hexane¼1/1) to obtain
2s as a colorless solid (1.13 g, 33%). Mp 118e121 ꢀC; 1H NMR:
7.98
d
(s, 1H), 7.42 (dd, 2H, J¼6.9, 7.8 Hz), 7.36 (dd, 1H, J¼7.4, 7.4 Hz), 7.21
(d, 2H, J¼7.8 Hz), 4.23 (q, 2H, J¼7.3 Hz), 3.36 (s, 3H), 1.36 (t, 3H,
J¼7.4 Hz); 13C NMR:
d 172.2, 162.5, 143.0, 129.8, 128.2, 127.4, 112.0,
89.1, 73.0, 38.9, 15.2; IR (thin film) 2210 (C^N), 1645 (C]O) cmꢁ1
;
MS (EIþ) m/z (relative intensity) 230 (Mþ, 100); HRMS (EIþ) calcd
for C13H14N2O2 ([M]þ): 230.1055; found: 230.1058.
4.5. General procedure for the reaction of 2 with TFAA
To a solution of 2-cyano-3-(N,N-dimethylamino)acetanilide 2
(1.0 mmol) in DMF (3.0 mL) was added TFAA (0.28 mL, 2.0 mmol) at
room temperature. The mixture was stirred at room temperature
for 24 h, when TLC indicated the reaction was completed. The re-
action mixture was then poured into ice-cold water (30 mL). The
precipitate was collected by filtration and washed with water
(three times). Recrystallization from CHCl3/n-hexane gave pure 3.
The mother and washing liquors were acidic. They were treated
with solid NaHCO3 prior to disposal.
87%). Mp 118e121 ꢀC; 1H NMR:
(br, 2H), 3.37 (s, 3H), 3.09 (s, 3H); 13C NMR:
d
7.96 (br,1H), 7.41e7.17 (m,10H), 4.43
167.2, 158.0, 144.7, 134.7,
d
129.3, 129.0, 128.4, 127.6, 126.9, 126.8, 117.6, 73.8, 64.0, 39.3, 36.3; IR
(thin film) 2190 (C^N), 1645 (C]O) cmꢁ1; MS (EIþ) m/z (relative
intensity) 305 (Mþ, 32), 91 (100); HRMS (EIþ) calcd for C19H19N3O
([M]þ): 305.1528; found: 305.1526.
4.5.1. 1-(4-Methoxybenzyl)-1,2-dihydro-4-hydroxy-2-oxoquinoline-
3-carbaldehyde (3k). Pale orange solid; mp 203e209 ꢀC (CHCl3/n-
4.4.12. 3-[N-(4-Methoxyphenyl)-N-methylamino]-2-cyano-N-
methyl-N-phenylacrylamide (2q). A solution containing acrylamide
2a (687 mg, 3.0 mmol) and p-anisidine (123 mg, 1.0 mmol) in tol-
uene (3.0 mL) was stirred under reflux (oil bath temp 120 ꢀC) for 6
days. The reaction mixture was directly purified by silica gel col-
umn chromatography (EtOAc/n-hexane¼1/1) to give 3-(4-me-
thoxyphenylamino)-2-cyano-N-methyl-N-phenylacrylamide S-2
(210 mg, 68% based on p-anisidine). To a stirred solution of the
above-prepared S-2 (200 mg, 0.65 mmol) in THF (2.0 mL) was
added NaH (39.0 mg, 1.2 mmol, ca. 60% in mineral oil) at 0 ꢀC and
the reaction mixture was stirred at room temperature for 1 h. To
this clear pale yellow solution was added MeI (0.08 mL, 1.3 mmol),
and the reaction mixture was stirred overnight before being
quenched with satd NH4Cl. The product was extracted with EtOAc
three times and the combined extracts were washed with water
and brine, dried over Na2SO4, and evaporated to afford a crude oil,
which was purified by silica gel column chromatography (EtOAc/n-
hexane¼1/1) to give the title compound 2q as a white solid
hexane); 1H NMR:
d 14.73 (br, 1H), 10.31 (s, 1H), 8.17 (d, 1H,
J¼6.6 Hz), 7.57 (dd, 1H, J¼8.2, 7.7 Hz), 7.27 (d, 1H, J¼8.7 Hz), 7.22
(dd, 1H, J¼7.7, 7.7 Hz), 7.18 (d, 2H, J¼8.7 Hz), 6.84(d, 2H, J¼8.7 Hz),
5.41 (s, 2H), 3.75 (s, 3H); 13C NMR:
d 196.4, 172.0, 162.3, 159.0, 142.3,
135.2, 128.1, 127.9, 126.0, 122.5, 115.6, 115.2, 114.4, 106.2, 55.3, 44.9;
IR (KBr) 3437 (OeH), 1650 (C]O) cmꢁ1; MS (EIþ) m/z (relative in-
tensity) 309 (Mþ, 26), 121 (100); HRMS (EIþ) calcd for C18H15NO4
([M]þ): 309.1001; found: 309.1003.
Acknowledgements
This work was financially supported in part by an award from
Mukogawa Women’s University. We thank the Instrument Analysis
Centre of Mukogawa Women’s University for assistance with the
NMR and MS measurements.
Supplementary data
(141 mg, 68%). Mp 102e104 ꢀC; 1H NMR:
d 7.97 (s, 1H), 7.40 (dd, 2H,
J¼7.3, 7.8 Hz), 7.29 (dd, 1H, J¼7.3, 7.4 Hz), 7.24 (d, 2H, J¼7.3 Hz), 7.06
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.03.040. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
(d, 2H, J¼8.7 Hz), 6.86 (d, 2H, J¼9.2 Hz), 3.78 (s, 3H), 3.56 (s, 3H),
3.36 (s, 3H); 13C NMR:
d 166.8,158.4, 156.4, 144.6,140.2, 129.4, 127.0,
123.5, 116.9, 114.7, 77.0, 55.5, 39.4 (two carbon peaks were missing
due to overlapping); IR (thin film) 2197 (C^N), 1645 (C]O) cmꢁ1
;
MS (EIþ) m/z (relative intensity) 321 (Mþ, 40), 215 (100); HRMS
References and notes
(EIþ) calcd for C19H19N3O2 ([M]þ): 321.1477; found: 321.1477.
1. (a) Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.; Wiley-Inter-
science: New York, NY, 2001; p 723; (b) Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.;
Shudo, K. J. Am. Chem. Soc. 1995, 117, 3037; (c) Spoerri, P. E.; DuBois, A. S. In The
Hoesch Synthesis; Bachman, W. E., Fieser, L. F., Blatt, A. H., Johnson, J. R., Eds.;
John Wiley: New York, NY, 1949; pp 388e412; (d) Houben, J. Ber. 1926, 59, 2878;
(e) Hoesch, K. Ber. 1915, 48, 1122.
2. (a) Kim, B.-T.; Kim, H.-S.; Moon, W. S.; Hwang, K.-J. Tetrahedron 2009, 65, 4625;
(b) Nakamura, S.; Sugimoto, H.; Ohwada, T. J. Org. Chem. 2008, 73, 4219; (c)
Colquhoun, H. M.; Lewis, D. F.; Williams, D. J. Org. Lett. 2001, 3, 2337.
3. (a) van Delden, R. A.; ter Wiel, M. K. J.; de Jong, H.; Meetsma, A.; Feringa, B. L.
Org. Biomol. Chem. 2004, 153; (b) Koumura, N.; Geertsema, E. M.; van Gelder, M.
B.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 5037.
4. (a) Kobayashi, Y.; Katagiri, K.; Azumaya, I.; Harayama, T. J. Org. Chem. 2010, 75,
2741; (b) Kobayashi, Y.; Harayama, T. Tetrahedron Lett. 2009, 50, 6665; (c)
Hutchinson, I.; Stevens, M. F. G. Org. Biomol. Chem. 2007, 114.
5. For the Pd-catalyzed addition of aromatic CeH bonds to nitriles, see: (a) Zhou,
C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551; (b) Zhou, C.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 2302.
4.4.13. 2-Cyano-3-(1H-imidazol-1-yl)-N-methyl-N-phenyl-
acrylamide (2r). A mixture of acrylanilide 2s (112 mg, 0.48 mmol)
and imidazole (98.9 mg, 1.45 mmol) in toluene (3.0 mL) was stirred
under reflux (oil bath temp 120 ꢀC) for 6 h, and the mixture was
directly purified by silica gel column chromatography (EtOAc/n-
hexane¼2/1) to obtain 2r as a white solid (12.6 mg, 10%). Mp
170e175 ꢀC (decomp.); 1H NMR:
d
8.31 (s, 1H), 7.93 (s, 1H), 7.79 (m,
1H), 7.48e7.40 (m, 3H), 7.26e7.23 (m, 2H), 7.16 (d, 1H, J¼0.9 Hz),
3.45 (s, 3H); 13C NMR:
161.4, 143.9, 142.4, 139.6, 132.6, 130.1, 128.7,
d
127.3, 117.1, 113.2, 95.1, 39.5; IR (thin film) 2217 (C^N), 1662 (C]O)
cmꢁ1; MS (EIþ) m/z (relative intensity) 252 (Mþ, 100); HRMS (EIþ)
calcd for C14H12N4O ([M]þ): 252.1011; found: 252.1014.
6. For reviews of FriedeleCrafts and related reactions, see: (a) Heaney, H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, 1991; Vol. 2; Chapter 3.2, pp 733e752; (b) Ruske, W. In
FriedeleCrafts and Related Reactions; Olah, G. A., Ed.; Wiley: New York, NY, 1964;
Vol. 3, pp 383e497.
4.4.14. 2-Cyano-3-ethoxy-N-methyl-N-phenylacrylamide
(2s). A
mixture of cyanoacetanilide 1a (2.61 g, 15 mmol) and zinc chloride
(204 mg, 1.5 mmol) in triethyl orthoformate (7.5 mL, 45 mmol) was
heated at 130 ꢀC for 10 h, and the mixture was directly purified by

Y. Kobayashi et al. / Tetrahedron 67 (2011) 3457e3463
3463
7. Cyanoacetanilides 1aej were easily prepared, purified, and obtained as solid,
see: Kobayashi, Y.; Harayama, T. Org. Lett. 2009, 11, 1603.
Vilsmeier-type reagent C not only trifluoroacetylated the active methylene of
1a (C-trifluoroacetylation) but also activated the CN group by N-tri-
fluoroacetylation4a (Eq. 4).
8. For reviews, see: (a) Jones, G.; Stanforth, S. P. The Vilsmeier Reaction of Fully
Conjugated Carbocycles and Heterocycles In. Organic Reactions; Paquette, L. A.,
Ed.; John Wiley: New York, NY, 1997; Vol. 49, p 1; (b) Marson, C. M.; Giles, P. R.
Synthesis Using Vilsmeier Reagents; CRC: Boca Raton, 1994; p 1; (c) Marson, C. M.
Tetrahedron 1992, 48, 3659; (d) Jutz, C. Iminium Salts in Organic Chemistry In.
Advances in Organic Chemistry; Taylor, E. C., Ed.; John Wiley: New York, NY,
1976; Vol. 9; Part I, p 225.
9. (a) Selvi, S.; Perumal, P. T. Org. Prep. Proced. Int. 2001, 33, 194; (b) Meth-Cohn, O.;
Rhouati, S.; Tarnowski, B.; Robinson, A. J. Chem. Soc., Perkin Trans. 1 1981, 1537.
10. This result suggests that the Vilsmeier-type reagent A would be a stronger
electrophile than Tf2O, see Scheme 3. However, in the presence of DMAP
(13 equiv), Tf2O-mediated reaction of 2 surprisingly did not proceed at all in
CH2Cl2 (or even in pyridine).
11. It was reported that treatment of 2 (R1¼EDG, R2¼H) with POCl3 caused
18
MetheCohn cyclization
to give 2-chloro-3-cyanoquinolines, see: Adams, D.
R.; Adams, C. Synth. Commun. 1990, 20, 469 However, HoubeneHoesch-type
cyclization of 2 has not been reported.
12. TFAA is ca. 9600 JPY/mol whereas Tf2O is ca. 57000 JPY/mol (Aldrich, 2010).
13. (a) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K.
Tetrahedron Lett. 1989, 30, 6177; (b) Nanjan, M. J.; Kannappan, V.; Ganesan, R.
Indian J. Chem. 1979, 18B, 461; (c) Pederson, B. F.; Pederson, B. Tetrahedron Lett.
1965, 6, 2995.
14. The electron-donating effects of the substituents (X) can be estimated by the
comparison among the chemical shifts of the C2 (and CN carbon) atoms in the
13C NMR spectra; the C2 atoms of 2aeq, having stronger electron-donating
substituents (X), were shielded (71.3e77.0 ppm) relative to those of 2r and 2s
(95.0 and 89.1 ppm, respectively). The CN carbon atoms of 2aeq were de-
shielded (116.9e119.7 ppm) than those of 2r and 2s (113.2 and 112.0 ppm,
respectively)
15. Mekhalfia, A.; Mutter, R.; Heal, W.; Chen, B. Tetrahedron 2006, 62, 5617.
16. In contrast to the reaction of 1a with Tf2O in DMF, the reaction of 1a with TFAA
in DMF afforded 4-hydroxy-3-trifluoroacetylquinolin-2(1H)-one 4 where the
17. To detect the intermediate, such as, C0, we carried out the NMR experiments
using piperidine-derived acrylamide with TFAA and DMF. However, we could
not observe the cation species, such as C0 on the NMR time scale, see the
Supplementary data.
18. (a) Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 20, 3111; (b)
Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 19, 2045.