Intramolecular Mizoroki-Heck reaction in the regioselective synthesis of 4-alkylidene-tetrahydroquinolines

Article abstract of DOI:10.1002/ejoc.201300048

The Mizoroki-Heck reaction of N-alkenyl-substituted 2-haloanilines is an effective protocol for the synthesis of substituted 4-alkylidene- tetrahydroquinoline derivatives, avoiding isomerization and oxidation. When non-substituted alkenes are used, the regioselectivity of the reaction can be directed towards the formation of an exocyclic or endocyclic double bond by choosing an adequate catalytic system. When the double bond is substituted by an amide moiety, the exocyclic double bond of E geometry is obtained selectively. Thus, this protocol efficiently synthesizes a series of 2-substituted tetrahydroquinolines with an exo α,β-unsaturated amide moiety at the C-4 position. Optimal conditions for Mizoroki-Heck reactions of N-alkenyl-substituted 2-haloanilines have been developed to access 4-alkylidene-tetrahydroquinoline derivatives regioselectively, avoiding isomerization and oxidation. Copyright

Full text of DOI:10.1002/ejoc.201300048

FULL PAPER
DOI: 10.1002/ejoc.201300048
Intramolecular Mizoroki–Heck Reaction in the Regioselective Synthesis of
4-Alkylidene-tetrahydroquinolines
Unai Martínez-Estíbalez,[a] Oihane García-Calvo,[a] Verónica Ortiz-de-Elguea,[a]
Nuria Sotomayor,[a] and Esther Lete*[a]
Keywords: Synthetic methods / C–C coupling / Nitrogen heterocycles / Palladium
The Mizoroki–Heck reaction of N-alkenyl-substituted 2-
haloanilines is an effective protocol for the synthesis of sub-
stituted 4-alkylidene-tetrahydroquinoline derivatives, avoid-
ing isomerization and oxidation. When non-substituted alk-
enes are used, the regioselectivity of the reaction can be di-
rected towards the formation of an exocyclic or endocyclic
double bond by choosing an adequate catalytic system.
When the double bond is substituted by an amide moiety, the
exocyclic double bond of E geometry is obtained selectively.
Thus, this protocol efficiently synthesizes a series of 2-substi-
tuted tetrahydroquinolines with an exo α,β-unsaturated
amide moiety at the C-4 position.
Introduction
Quinoline derivatives are an important class of com-
pounds in the pharmaceutical and agrochemical industries,
as well as building blocks for the total synthesis of natural
products.[1] For example, several 2-aryl-tetrahydroquinol-
ines and their aromatic counterparts have shown antifungal
and anticancer activity,[2] whereas 1,2-dihydro derivatives as
ethoxyquin are known by their antioxidant effects.[3] 4-Alk-
ylidene-tetrahydroquinoline derivatives have attracted much
attention as in vivo potent antagonists of the glycine bind-
ing site associated with the N-methyl-d-aspartic acid recep-
tor, a target for innovative drugs to treat chronic neuro-
pathic pain. The presence of an exo α,β-unsaturated amide
moiety at the C-4 position of these compounds was found
to play a pivotal role in their bioactivities.[4] In addition,
many naturally occurring alkaloids[5] contain the tetra-
hydroquinoline or quinoline unit with the exocyclic double
bond (Figure 1).[6]
Classical methods for quinoline synthesis often do not
allow adequate diversity and substitution on the quinoline
ring system.[7] Therefore, considerable efforts have been
dedicated to developing new methods for the preparation of
these pharmacophores: from acid promoted cycloaddition
reactions to ruthenium or palladium-catalyzed methodolo-
gies.[8] Within that last category, we have reported that
intermolecular palladium-catalyzed arylation followed by
Figure 1. Selected bioactive quinoline derivatives.
Grignard addition to imines, and ring-closing metathesis
provides an efficient approach to 2-phenyl-substituted quin-
oline, benzazocine, and benzazepine derivatives.[9] 2,4-Sub-
stituted tetrahydroquinolines can be obtained through in-
tramolecular carbolithiation of N-alkenyl-substituted 2-
iodoanilines, even enantioselectively.[10]
However, the high reactivity associated with organo-
lithium intermediates narrows the functional group toler-
ance for this procedure. Thus, although a variety of syn-
thetic methods for preparing quinoline derivatives are avail-
able, it is still highly desirable to develop efficient pro-
cedures to obtain useful polyfunctionalized quinolines. In
this context, palladium-catalyzed coupling reactions[11] and,
in particular, the intramolecular Mizoroki–Heck reaction[12]
is of special relevance. These reactions have found wide ap-
plication in synthesis for preparing complex organic struc-
tures,[13] even asymmetrically,[14] and are also applied in the
chemical and pharmaceutical industries.[15]
[a] Departamento de Química Orgánica II, Facultad de Ciencia y
Tecnología, Universidad del País Vasco / Euskal Herriko
Unibertsitatea UPV/EHU,
Apdo. 644, 48080 Bilbao, Spain
Fax: +34-946012748
E-mail: esther.lete@ehu.es
Homepage: http://www.ehu.es
http://www.ehu.es/oms
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300048.
Eur. J. Org. Chem. 2013, 3013–3022
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. Lete et al.
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With these precedents, we envisioned that the Mizoroki–
Heck reaction of N-alkenyl-substituted 2-haloanilines could
lead to an effective protocol for the synthesis of substituted
4-alkylidene-tetrahydroquinoline derivatives II. Thus, we
prepared a series of butenylanilines I, with different substi-
tution patterns in the alkene and α to the nitrogen atom
(Scheme 1), that would lead to tetrahydroquinolines II. This
kind of approach has been studied before, but over-oxi-
dation reactions or formation of regioisomeric mixtures
have been observed. Pd-catalyzed cyclization of I (Y, R1,
R2, R3 = H) was previously reported by Larock[16] and 4-
methylquinoline was obtained through 6-exo cyclization fol-
lowed by double bond migration and oxidation. Starting
from the same substrate, in the presence of Pd/N-heterocy-
clic carbene catalyst, Caddick[17] observed the formation of
a mixture of isomers through 6-exo or 7-endo cyclization
and double bond migration. Thus, the main issue would be
to obtain a regioselective procedure, avoiding over-oxi-
dation and double-bond isomerization reactions that may
occur in this type of reaction. Here we present a full ac-
count of our investigations.
Scheme 2. Synthetic route to compounds 2 and 3.
Table 1. Synthesis of 2-aryl-substituted 4-methylene-quinolines
2a–d.
Substrate
Base, additive
Solvent
2 or 3 [%]
1
2
3
4
5
6
7
8
9
1a[a]
1a[a]
1a[b]
1b[a]
1b[b]
1b[c]
1c[b]
1c[c]
1d[b]
Na2CO3, Bu4NBr
Na2CO3, Bu4NBr
Na2CO3, Bu4NCl
Na2CO3, Bu4NCl
Na2CO3, Bu4NCl
Bu4NOAc
Na2CO3, Bu4NCl
Bu4NOAc
Na2CO3, Bu4NCl
DMF
3a, 50
3a, 33
CH3CN
CH3CN
DMF
CH3CN
DMSO
CH3CN
DMSO
CH3CN
2a, 54
[d]
2b, 71
2b, 49
[e]
2c, 55
2d, 18
3d, 30
2d, 14
10
1d[c]
Bu4NOAc
DMSO
Scheme 1. Mizoroki–Heck approach to 4-alkylidene-substituted
quinolines.
[a] 3 mol-% Pd(OAc)2, no PPh3 was added. [b] 3 mol-% Pd(OAc)2,
20 mol-% PPh3. [c] 10 mol-% Pd(OAc)2, 40 mol-% PPh3. [d] Start-
ing material was recovered. [e] Mixture of products 2c and 3c were
detected by NMR spectroscopy.
Results and Discussion
It has been shown that the presence of a heterocyclic ring
substituent (R2) is one of the main structural requirements
for the biological activity of homoallylamines with general
These conditions were applied to α-heteroaryl-substi-
structure I and their quinoline or tetrahydroquinoline deriv- tuted amines 1b–d. Although 1b gave expected product 2b
atives (II).[18] For this reason we started our study preparing in good yield (Table 1, Entry 5), oxidation could not be avo-
a series of secondary butenylanilines 1a–d, which carry a ided with 1c and 1d, leading to low isolated yields of tetra-
phenyl or heteroaryl group α to the nitrogen atom, in high hydroquinoline 2d, or a mixture of products in the case of
overall yields, by condensation of o-iodo or o-bromoaniline 1c (Table 1, Entries 7 and 9). However, the use of Bu4NOAc
and the corresponding aldehyde, followed by addition of and dimethyl sulfoxide (DMSO) with a larger amount of
allylmagnesium chloride (Scheme 2).[19] When 1a was phosphane, improved the results with 1c (Table 1, Entry 8).
treated under phosphane-free Jeffery conditions,[20] These conditions would favor a cationic pathway for the
(Table 1, Entry 1), 4-methyl-2-phenylquinoline 3a was ob- alkene insertion, and have been shown to favor the direct
tained in moderate yield after 6-exo cyclization, isomeriza- arylation reaction of the pyrrole nucleus.[21] However, no
tion and oxidation, as has been described for o-iodobuten- arylation products of the pyrrole or the thiophene ring were
ylaniline under analogous conditions.[16] Various reaction observed with 1b–d.
conditions were tested to avoid this isomerization and oxi-
We next focused our attention on the reaction of tertiary
dation. A change in the solvent to acetonitrile (Table 1, En- anilines. For this purpose, we chose butenyl anilines 4a–d,
try 2) gave a sluggish reaction, obtaining also 3a as the that incorporate different functionality on the α position to
main product, in moderate yield. However, in the presence nitrogen (Scheme 3). By using a similar approach, amines
of PPh3, 4-methylene-trahydroquinoline 2a was obtained 4a, 4c, and 4d were prepared by condensation with the cor-
(Table 1, Entry 3).
responding aldehyde, followed by allylation of the imine,
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Regioselective Synthesis of 4-Alkylidene-tetrahydroquinolines
and subsequent methylation. Amine 4b was obtained by se- ence of tetrabutylammonium acetate and allyltrimethylsil-
quential alkylation reactions.[19]
ane, with lower catalyst loading (3 mol-%; Table 2, Entries 4
and 8). The presence of allylsilane is relevant because the
reaction does not proceed without this additive. In fact, the
presence of dibenzylideneacetone has been shown to de-
crease the rate of oxidative addition of aryl iodides when
Pd(dba)2/PPh3 systems are employed.[23] Although the for-
mation of palladium complexes with allysilanes is
known,[24] the use of allyltrimethylsilane as an additive in
Mizoroki–Heck reactions has not been described to the best
of our knowledge, and its role has not been studied in de-
tail. Dihydroquinolines 6a–d were selectively obtained in
good yields by using Pd(PPh3)4/Et3N as catalytic system
(Table 2, Entries 5, 9, 13 and 17), though the reaction re-
quires high catalyst loadings to reach reasonable yields.
Thus, the Mizoroki–Heck reaction allowed the selective
synthesis of quinolines with exocyclic or endocyclic double
bonds, and it is compatible functional groups on C-2, like
an ester (5c and 6c) or a protected alcohol (5d and 6d).
To access tetrahydroquinolines with an exo α,β-unsatu-
Scheme 3. Synthesis of tetrahydroquinolines 5 and 1,2-dihydro-
quinolines 6.
Under Pd0 conditions, the substitution on the nitrogen
atom on amines 4a–d would avoid the formation of aro-
matic quinolines, but the regioselectivity of the formation
of the double bond would still be an issue (Scheme 3). Thus,
1,2-dihydroquinolines 6, with a more stable endocyclic
double bond, could be formed by isomerization of the exo-
cyclic double bond of tetrahydroquinolines 5 by reinsertion rated amide moiety at the C-4 position, a series of tertiary
of the hydropalladium species formed after β-elimination, butenylanilines with trans-substituted double bonds were
followed by a second elimination. Optimization of the reac- prepared. Thus, 7a–g were obtained in good yields dia-
tion conditions led to the selective formation of each re- stereoselectivity from 4a–d through oxidative cleavage of
gioisomer, as shown in Table 2.
the double bond followed by a Wittig reaction in a one-pot
When butenylanilines 4a–d were treated with Pd(OAc)2 procedure,[4b,19] as shown in Scheme 4.
in the presence of a base and tetrabutylammonium halide,
When optimized reaction conditions [Method A:
under various conditions, the reaction was non selective, Pd(OAc)2/PPh3, AgCO3, DMF, 90 °C] were applied to 7a
obtaining mixtures of 4-methylenetetrahydroquinolines 5 and 7b the corresponding 2-phenyl-substituted quinolines
together with isomerized 6 (Table 2, Entries 1, 6, 10 and 14). 8a,b were obtained regioselectivity in good yield (Table 3,
Phosphane-free conditions led to sluggish reactions, and a Entries 1 and 2). No formation of the endo double bond
mixture of isomers (Table 2, Entries 2, 11 and 15). However, was detected, and the tetrahydroquinolines were obtained
isomerization could be avoided by the addition of silver as single E isomers. The geometry of the double bond,
salts.[22] In the presence of silver carbonate, tetrahydroquin- which was confirmed by NOESY experiments, is consistent
olines 5a–d were formed regioselectively in good yields with a syn β-hydride elimination. These conditions were ex-
(Table 2, Entries 3, 7, 12 and 16). We also found that quin- tended to the synthesis of 8c–g, with consistently good
olines 5a and 5b could be selectively obtained without the yields (Table 3, Entries 3–7). The same regioisomers were
use of silver additives, by using Pd(dba)2/Ph3P in the pres- obtained when Pd(PPh3)4/Et3N was used as catalytic system
Table 2. Mizoroki–Heck reactions of 4a–d.
Substrate
Pd
PPh3 [mol-%] Base, additive
Solvent
Temperature
5 [%]
6 [%]
[a]
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4d
4d
4d
4d
Pd(OAc)2[a]
Pd(OAc)2[b]
Pd(OAc)2
20
–
30
14
–
30
30
14
–
30
–
30
–
30
–
30
–
Na2CO3, Bu4NBr
Na2CO3, Bu4NBr
Ag2CO3
Bu4NOAc, allylTMS
Et3N
NaHCO3, Bu4NCl
Ag2CO3
Bu4NOAc, allylTMS
Et3N
DMF
DMF
DMF
DMF
toluene
DMF
DMF
90 °C
90 °C
90 °C
50 °C
reflux
90 °C
90 °C
50 °C
reflux
reflux
reflux
90 °C
reflux
reflux
reflux
90 °C
reflux
46
35
78
75
4
4
–
–
76
[a]
Pd(dba)2
[c]
Pd(PPh3)4
–
[b]
[d]
Pd(OAc)2[b]
Pd(OAc)2
Pd(dba)2
69
71
–
22
17
78
–
45
52
53
–
–
[a]
DMF
9
Pd(PPh3)4
toluene
CH3CN
CH3CN
DMF
toluene
CH3CN
CH3CN
DMF
55[e]
51
52
–
69
15
10
–
[c]
[b]
10
11
12
13
14
15
16
17
Pd(OAc)2[b]
NaHCO3, Bu4NCl
NaHCO3, Bu4NCl
Ag2CO3
Pd(OAc)2[b]
Pd(OAc)2 [c]
Pd(PPh3)4
Et3N
[b]
Pd(OAc)2[b]
NaHCO3, Bu4NCl
NaHCO3, Bu4NCl
Ag2CO3
Pd(OAc)2[b]
Pd(OAc)2 [c]
Pd(PPh3)4
Et3N
toluene
60
[a] 3 mol-% of precatalyst was used. [b] 10 mol-% Pd(OAc)2. [c] 30 mol-% Pd(PPh3)4. [d] Mixture of products. [e] Reduced tetrahydroquin-
oline was obtained.
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E. Lete et al.
FULL PAPER
conditions previously tested (Scheme 5). Tetrahydroquinol-
ine 8h was obtained in excellent yields, as a single E isomer,
with no isomerization of the double bond. Finally, this pro-
cedure could be successfully applied to the synthesis of en-
antiomerically pure tetrahydroquinoline 8i. Enantiomer-
ically pure butenylaniline 7i was prepared following the
same synthetic strategy, staring from o-iodoaniline and (R)-
2,2-dimethyl-1,3-dioxolane-4-carbaldehyde.[19] Treatment of
7i with both catalytic systems afforded tetrahydroquinoline
8i as a single isomer, with no loss of optical purity. The
synthesis of enantiopure tetrahydroquinolines with an exo
α,β-unsaturated amide moiety at the C-4 position had been
reported by Di Fabio, in an approach that used an (R)-(+)-
tert-butyl lactate as chiral auxiliary.[4b] The regioselectivity
could also be controlled by the catalytic system, and the
best results for the formation of the exocyclic double bond
were obtained when the Heck reaction was carried out with
Pd(PPh3)4/Et3N in toluene. Thus, the results obtained in
this work are in agreement with these previous results, and
expand the scope of this reaction for the synthesis of hetero-
cycles.
Scheme 4. Synthesis of 4-alkylidene-substituted quinolines 8a–g.
Table 3. Synthesis of 4-alkylidene-substituted quinolines 8a–g.
Substrate
Method[a]
Product
Yield [%]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7a
7b
7c
7d
7e
7f
A
A
A
A
A
A
A
B
B
B
B
B
B
B
C
C
C
C
C
C
C
8a
8b
8c
8d
8e
8f
8g
8a
8b
8c
8d
8e
8f
79
72
67
67
57
73
61
85
77
76
67
61
81
67
74
60
61
60
40
68
82
9
10
11
12
13
14
15
16
17
18
19
20
21
7g
7a
7b
7c
7d
7e
7f
8g
8a
8b
8c
8d
8e
8f
7g
8g
[a] Method A: Pd(OAc)2 (10 mol-%), PPh3 (30 mol-%), AgCO3
(1.5 equiv.), dimethylformamide (DMF), 100 °C, 6 h; Method B:
Pd(PPh3)4 (30 mol-%), Et3N (2.2 equiv.), toluene, reflux, 6 h;
Method C: Pd(OAc)2 (15 mol-%), NaHCO3 (2.2 equiv.), Bu4NCl
(1.3 equiv.) CH3CN, reflux, 6 h.
Scheme 5. Synthesis of (E)-alkylidene-quinolines 8.
Conclusions
(Table 3, Entries 8–14, Method B), probably owing to the
stabilization of the exo double bond by the amide group
An intramolecular Heck reaction provides mild and re-
that precludes isomerization. These conditions gave higher gioselective access to 2-substituted 4-alkylidene-tetra-
yields of the quinolines but, once again, required high cata- hydroquinoline derivatives, similar to other methods de-
lyst loadings to reach completion in reasonable reaction scribed in the literature.[25] In all cases a 6-exo-trig process
times. Finally, the Mizoroki–Heck reaction could also be occurs obtaining quinoline derivatives in good yields. When
performed under phosphane-free conditions (Table 3, En- non-substituted alkenes are used, the regioselectivity of the
tries 15–21, Method C) obtaining E-quinolines, though in reaction can be directed towards the formation of an exocy-
generally lower yields, with the exception of 8g (Table 3, clic or endocyclic double bond by choosing a suitable cata-
Entry 21). As can be seen in Table 3, the use of diethyl lytic system. When the double bond is substituted by an
amides or Weinreb amides led to comparable yields of cor- amide moiety, intramolecular cyclization is favored, ob-
responding tetrahydroquinolines 8. Some biologically active taining selectively the exocyclic double bond of E geometry.
quinolines bear chlorine atoms, mainly in the C-5 and/or The formation of this isomer does not depend on the pre-
C-7 position.[2,4] To access this type of 4-alkylidene-quinol- catalyst used.[26] Optimal conditions have been found for
ines, butenylaniline 7h was prepared starting from 5-chloro- the efficient preparation of a variety of 2-substituted tetra-
2-iodoaniline,[19] and was submitted to Mizoroki–Heck hydroquinolines with an exo α,β-unsaturated amide moiety
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Regioselective Synthesis of 4-Alkylidene-tetrahydroquinolines
1H NMR (300 MHz, CDCl3): δ = 2.68–2.96 (m, 2 H, H3), 3.69 (s,
3 H, CH3), 4.07 (s, 1 H, NH), 4.54 (dd, J = 11.2, 3.3 Hz, 1 H, H2),
4.86 (s, 1 H, =CHa), 5.50 (s, 1 H, =CHb), 6.08–6.16 (m, 1 H, H4Ј),
6.16–6.24 (m, 1 H, H3Ј), 6.52–6.65 (m, 2 H, H8, H5Ј), 6.73 (t, J =
7.5 Hz, 1 H, H6), 7.09 (t, J = 7.5 Hz, 1 H, H7), 7.56 (d, J = 7.5 Hz,
1 H, H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 34.1 (CH3), 38.8
(C3), 49.8 (C2), 106.4 (C3Ј), 106.8 (C=CH2), 107.1 (C4Ј), 115.3 (C8),
118.0 (C6), 120.0 (C4a), 122.7 (C5Ј), 124.7 (C5), 129.1 (C7), 133.5
(C2Ј), 139.7 (C8a), 144.3 (C4) ppm. MS (70 eV, EI): m/z (%) = 224
(100) [M+], 223 (87), 222 (39), 221 (85), 209 (32), 208 (11), 207 (15),
194 (11), 180 (10), 143 (99). 142 (25), 115 (39), 81 (45), 77 (10), 65
(6). HRMS (ESI+): calcd. for C15H17N2 [MH+] 225.1392; found
225.1392.
at the C-4 position, showing high functional group toler-
ance. This procedure can also be applied to chiral sub-
strates, thus achieving a synthesis of enantiopure quinolines
with the configuration of known glycine antagonists.
Experimental Section
General Methods: Melting points were determined in unsealed cap-
illary tubes. IR spectra were recorded as films over NaCl pellets,
on KBr pellets or with an ATR. NMR spectra were recorded at
20–25 °C, at 300 MHz for 1H and 75.5 MHz for 13C or at 500 MHz
1
for H and 125.7 MHz for 13C in CDCl3 solutions. Assignments of
1
individual 13C and H resonances are supported by DEPT experi-
4-Methylene-2-(thiophen-3-yl)-1,2,3,4-tetrahydroquinoline (2d):
(Table 1, Entry 9) According to the general procedure, amine 1d
(385 mg, 1.25 mmol) was treated with Pd(OAc)2 (9 mg,
0.037 mmol) and PPh3 (66 mg, 0.25 mmol), Na2CO3 (332 mg,
3.13 mmol) and nBu4NCl (417 mg, 1.8 mmol) in CH3CN (20 mL).
The reaction mixture was heated to reflux for 12 h. After work-
ments and 2D correlation experiments (COSY, HSQCed or
HMBC). Selective NOE or NOESY experiments were performed
when necessary. Mass spectra were recorded with electron impact
(EI) at 70 eV, under chemical ionization (CI) at 230 eV or with
electrospray ionization (ESI). HRMS data was recorded with a
TOF detector. TLC was carried out with 0.2 mm thick silica gel
plates. Visualization was accomplished by UV light. Flash column
chromatography[27] was performed on silica gel (230–400 mesh) or
on alumina (70–230 mesh). All solvents used in reactions were an-
hydrous and purified according to standard procedures.[28] All air-
or moisture-sensitive reactions were performed under argon; the
glassware was dried (130 °C) and purged with argon.
up, flash column chromatography (silica gel, 1% hexane/AcOEt)
1
afforded 2d (50 mg, 18%) as an oil. IR (ATR): ν = 3385 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 2.76–2.83 (m, 2 H, H3), 4.22 (s, 1
H, NH), 4.51–4.67 (m, 1 H, H2), 4.84 (s, 1 H, =CHa), 5.48 (s, 1 H,
=CHb), 6.58 (d, J = 7.5 Hz, 1 H, H8), 6.73 (t, J = 7.5 Hz, 1 H, H6),
7.09 (t, J = 7.5 Hz, 1 H, H7), 7.14 (dd, J = 5.0, 1.0 Hz, 1 H, H4Ј),
7.24–7.26 (m, 1 H, H2Ј), 7.33 (dd, J = 5.0, 3.0 Hz, 1 H, H5Ј), 7.57
(d, J = 7.5 Hz, 1 H, H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
40.1 (C3), 52.8 (C2), 106.9 (C=CH2), 115.1 (C8), 118.0 (C6), 120.1
(C4a), 121.1 (C2Ј), 124.7 (C5), 126.1, 126.5 (C4Ј, C5Ј), 129.1 (C7),
139.3 (C3Ј), 144.2 (C8a), 144.7 (C4) ppm. MS (230 eV, CI): m/z (%)
= 228 (100) [MH+], 227 (72), 226 (30), 225 (7), 212 (6), 144 (12).
HRMS (CI): calcd. for C14H14NS [MH+] 228.0847; found
228.0839.
Synthesis of 2-Aryl-4-methylenequinolines 2. General Procedure:
Pd(OAc)2 (3 mol-%) and PPh3 (20 mol-%) were added to a mixture
of butenylamine 1 (1 mmol), Na2CO3 (2.5 mmol) and nBu4NCl
(1.5 mmol) in dry CH3CN. The mixture was heat to reflux until
TLC showed complete reaction. The reaction mixture was then di-
luted with AcOEt (50 mL) and filtered through a Celite pad. The
resulting filtrate was washed with saturated NH4Cl (3ϫ 30 mL)
and brine (3ϫ 30 mL), dried with Na2SO4, filtered and concen-
trated. The crude oil was purified by flash column chromatography
(silica gel, hexane/AcOEt) to give corresponding tetrahydroquinol-
ines 2.
4-Methyl-2-(thiophen-3-yl)quinoline (3d):[29] (Table 1, Entry 9;
85 mg, 30 %). IR (ATR): ν = 1600 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 2.74 (s, 3 H, CH3), 7.44 (dd, J = 5.1, 3.0 Hz, 1 H,
H4Ј), 7.52 (t, J = 7.5 Hz, 1 H, H7), 7.62 (s, 1 H, H3), 7.70 (t, J =
7.5 Hz, 1 H, H6), 7.87 (dd, J = 5.1, 1.1 Hz, 1 H, H5Ј), 7.97 (d, J =
7.5 Hz, 1 H, H8), 8.03 (dd, J = 3.0, 1.1 Hz, 1 H, H2Ј), 8.12 (d, J =
7.5 Hz, 1 H, H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 18.9
(CH3), 119.7 (C3), 123.6 (C8), 124.4 (C2Ј), 125.8 (C7), 126.2 (C4Ј),
126.8 (C5Ј), 127.2 (C4a), 129.3 (C6), 130.0 (C5), 142.7 (C3Ј), 144.7
(C4), 148.1 (C8a), 153.0 (C2) ppm. MS (70 eV, EI): m/z (%) = 226.1
(19) [M+ + 1], 225.1 (100) [M+], 224.1 (40), 210 (11), 199 (5), 181.1
(6), 180.1 (6), 168.1 (3), 115 (5), 77 (1), 65 (1).
4-Methylene-2-phenyl-1,2,3,4-tetrahydroquinoline (2a): (Table 1, En-
try 3) According to the general procedure, amine 1a (111 mg,
0.318 mmol) was treated with Pd(OAc)2 (2 mg, 0.009 mmol) and
PPh3 (17 mg, 0.064 mmol), Na2CO3 (90 mg, 0.80 mmol) and
nBu4NCl (124 mg, 0.47 mmol) in CH3CN (10 mL). The reaction
mixture was heated to reflux for 12 h. After work-up, flash column
chromatography (silica gel, 2% hexane/AcOEt) afforded 2a (38 mg,
1
54%) as an oil. H NMR (300 MHz, CDCl3): δ = 2.74–2.78 (m, 2
H, H3), 4.16 (s, 1 H, NH), 4.43–4.49 (m, 1 H, H2), 4.81 (s, 1 H,
=CHa), 5.46 (s, 1 H, =CHb), 6.58 (d, J = 8.0 Hz, 1 H, H8), 6.72 (t,
J = 8.0 Hz, 1 H, H6), 7.10 (t, J = 8.0 Hz, 1 H, H7), 7.31–7.53 (m,
5 H, Ph), 7.56 (d, J = 8.0 Hz, 1 H, H5) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 40.8 (C3), 57.2 (C2), 106.7 (C=CH2), 115.0 (C8), 117.8
(C6), 119.8 (C4a), 124.7, 126.6, 127.6, 128.7, 129.2 (C5, C7, C–
Harom), 139.6 (C8a), 143.4 (C–Carom), 144.6 (C4) ppm. MS (70 eV,
EI): m/z (%) = 221 (2) [M+], 219 (100), 218 (37), 204 (57), 109 (6),
77 (5).
4-Methylene-2-(1-methyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-
quinoline (2c): (Table 1, Entry 8) Pd(OAc)2 (11 mg, 0.049 mmol)
and PPh3 (52 mg, 0.20 mmol) were added to a mixture of amine 1c
(151 mg, 0.49 mmol) and nBu4NOAc (231 mg, 0.74 mmol) in dry
DMSO (10 mL), and the mixture was heated at 60 °C for 24 h. The
reaction mixture was washed with saturated NH4Cl (2ϫ 30 mL)
and brine (2ϫ 30 mL), dried with Na2SO4, filtered and concen-
trated. The crude oil was purified by flash column chromatography
(silica gel, 10% hexane/AcOEt) to afford 2c (60 mg, 55%) as an
2-(1-Methyl-1H-pyrrol-2-yl)-4-methylene-1,2,3,4-tetrahydro- oil. IR (ATR): ν = 3385 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
quinoline (2b): (Table 1, Entry 5) According to the general pro-
cedure, amine 1b (158 mg, 0.52 mmol) was treated with Pd(OAc)2
2.69–2.92 (m, 2 H, H3), 3.66 (s, 3 H, CH3), 4.13 (s, 1 H, NH), 4.43
(dd, J = 8.9, 5.3 Hz, 1 H, H2), 4.85 (s, 1 H, =CHa), 5.49 (s, 1 H,
(4 mg, 0.016 mmol) and PPh3 (26 mg, 0.11 mmol), Na2CO3 =CHb), 6.20 (s, 1 H, H4Ј), 6.52–6.67 (m, 3 H, H8, H2Ј, H5Ј), 6.68–
(137 mg, 1.30 mmol) and nBu4NCl (173 mg, 0.62 mmol) in CH3CN 6.78 (m, 1 H, H6), 7.04–7.15 (m, 1 H, H7), 7.57 (d, J = 7.8 Hz, 1
(20 mL). The reaction mixture was heated to reflux for 18 h. After
work-up, flash column chromatography (silica gel, 10% hexane/Ac-
H, H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 36.1 (CH3), 40.6
(C3), 50.6 (C2), 106.1 (C4Ј), 106.5 (C=CH2), 115.0 (C8), 117.5 (C6),
OEt) afforded 2b (83 mg, 71%) as an oil. IR (ATR): ν = 3375 cm–1. 118.9, 121.9 (C2Ј, C5Ј), 120.0 (C3Ј), 124.6 (C5), 126.7 (C4a), 129.0
˜
Eur. J. Org. Chem. 2013, 3013–3022
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3017

E. Lete et al.
FULL PAPER
(C7), 140.3 (C8a), 144.8 (C4) ppm. MS (70 eV, EI): m/z (%) = 224 5.38 (s, 1 H, =CHb), 6.64–6.69 (m, 2 H, H6, H8), 7.16 (td, J = 7.7,
(100) [M+], 223 (77), 209 (51), 208 (8), 207 (10), 194 (11), 180 (10), 1.3 Hz, 1 H, H7), 7.51 (dd, J = 7.7, 1.3 Hz, 1 H, H5) ppm. 13C
143 (25), 115 (17), 81 (28), 77 (7), 65 (4). HRMS (ESI+): calcd. for
C15H17N2 [MH+] 225.1392; found 225.1392.
NMR (75.5 MHz, CDCl3): δ = 32.1 (C3), 39.6 (NCH3), 51.8 (C2),
105.7 (C=CH2), 112.1 (C8), 116.7 (C6), 121.4 (C4a), 124.6 (C5),
129.3 (C7), 140.6 (C8a), 146.3 (C4) ppm. C11H13N (159.23): calcd.
C 82.97, H 8.23, N 8.80; found C 82.71, H 7.93, N 8.77.
4-Methyl-2-phenylquinoline (3a):[30] (Table 1, Entry 1). Pd(OAc)2
(8 mg, 0.036 mmol) was added to a mixture of butenylamine 1a
(432 mg, 1.2 mmol), Na2CO3 (341 mg, 3.2 mmol) and nBu4NBr
(498 mg, 1.5 mmol) in dry DMF (20 mL). The mixture was heated
at 60 °C for 18 h. The reaction mixture was then diluted with of
AcOEt (20 mL) and filtered through a Celite pad. The resulting
filtrate was washed with saturated NH4Cl (3ϫ 20 mL) and brine
(3ϫ 20 mL), dried with Na2SO4 filtered and concentrated. The
crude oil was purified by flash column chromatography (silica gel,
5% hexane/AcOEt) to give quinoline 3a (130 mg, 50%) whose data
2-Benzyloxymethyl-1-methyl-4-methylene-1,2,3,4-tetrahydro-
quinoline (5c): (Table 2, Entry 12) According to general procedure
A, amine 4c (180 mg, 0.45 mmol) was treated with Pd(OAc)2
(10 mg, 0.04 mmol), PPh3 (36 mg, 0.13 mmol) and Ag2CO3
(176 mg, 0.67 mmol) in DMF (20 mL). The reaction mixture was
stirred at 90 °C for 5 h. After work-up, flash column chromatog-
raphy (silica gel, 5% hexane/AcOEt) afforded 5c (96 mg, 78%) as
1
an oil. IR (NaCl): ν = 875 cm–1. H NMR (300 MHz, CDCl ): δ
˜
3
= 2.71 (dd, J = 13.8, 2.3 Hz, 1 H, H3), 2.78–2.82 (m, 1 H, H3), 3.07
(s, 3 H, NCH3), 3.39–3.46 (m, 1 H, CH2O), 3.54–3.60 (m, 1 H,
CH2O), 3.63–3.72 (m, 1 H, H2), 4.52–4.54 (m, 2 H, PhCH2), 4.85
(s, 1 H, =CHa), 5.49 (s, 1 H, =CHb), 6.60 (d, J = 7.5 Hz, 1 H, H8),
6.70 (t, J = 7.5 Hz, 1 H, H6), 7.20 (t, J = 7.5 Hz, 1 H, H7), 7.33–
7.43 (m, 5 H, Ph), 7.53 (d, J = 7.5 Hz, 1 H, H5) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 32.6 (C3), 38.7 (NCH3), 58.8 (C2), 69.7
(CH2O), 73.4 (PhCH2), 107.8 (C=CH2), 111.0 (C8), 115.6 (C6),
120.3 (C4a), 124.5 (C5), 127.4, 127.5, 128.3 (C–Harom), 128.4 (C–
are coincidental with those reported.[30] IR (NaCl): ν = 1600 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 2.75 (s, 3 H, CH3), 7.47–7.58 (m,
4 H, H3, H3Ј, H4Ј, H5Ј), 7.70–7.76 (m, 2 H, H2Ј, H6Ј), 7.99 (d, J =
8.3 Hz, 1 H, H8), 8.15–8.22 (m, 3 H, H6, H7, H5) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 18.9 (CH3), 119.7 (C3), 123.5 (C8), 125.9
(C7), 127.1 (C4a), 127.4, 128.7, 129.1, 129.2 (C6, C–Harom), 130.1
(C5), 139.7 (Carom–C), 144.7 (C4), 148.0 (C8a), 156.9 (C2) ppm. MS
(70 eV, EI): m/z (%) = 220 (18) [M+ + 1], 219 (100) [M+], 218 (35),
204 (63), 109 (13), 102 (14), 95 (11), 77 (8).
C
arom), 129.5 (C7), 138.2 (C8a), 143.8 (C4) ppm. MS (70 eV, EI):
m/z (%) = 279 (3) [M+], 158 (100), 143 (11), 115 (10), 91 (12), 83
(18). HRMS (EI): calcd. for C19H21NO 279.1623; found 279.1631.
C19H21NO (279.38): calcd. C 81.68, H 7.58, N 5.01; found C 81.45,
H 7.32, N 5.22.
Synthesis of 4-Methylenequinolines 5. General Procedure A:
Ag2CO3 (1.5 mmol), PPh3 (30 mol-%) and Pd(OAc)2 (10 mol-%),
were added to a solution of amine 4 (1 mmol) in dry DMF
(30 mL). The mixture was stirred at 90 °C until TLC showed com-
plete reaction. The reaction mixture was then diluted with Et2O
(20 mL), and filtered through a Celite pad. The resulting filtrate
was washed with brine (3ϫ 30 mL), dried with Na2SO4, filtered
and concentrated. The crude oil was purified by flash column
chromatography (silica gel, hexane/AcOEt) to give corresponding
tetrahydroquinolines 5.
Ethyl 1-Methyl-4-methylene-1,2,3,4-tetrahydroquinoline-2-carboxyl-
ate (5d): (Table 2, Entry 16) According to general procedure A,
amine 4d (156 mg, 0.50 mmol) was treated with Pd(OAc)2 (11 mg,
0.05 mmol), PPh3 (40 mg, 0.15 mmol) and Ag2CO3 (210 mg,
0.75 mmol) in DMF (15 mL). The reaction mixture was stirred at
90 °C for 5 h. After work-up, flash column chromatography (silica
gel, 10% hexane/AcOEt) afforded 5d (59 mg, 53%) as an oil. IR
(NaCl): ν = 1735, 875 cm–1. 1H NMR (300 MHz, CDCl ): δ = 1.18
1-Methyl-4-methylene-2-phenyl-1,2,3,4-tetrahydroquinoline (5a):
(Table 2, Entry 3) According to general procedure A, amine 4a
(135 mg, 0.37 mmol) was treated with Pd(OAc)2 (8.3 mg,
0.037 mmol) PPh3 (28.8 mg, 0.11 mmol) and Ag2CO3 (153 mg,
0.55 mmol) in DMF (10 mL). The reaction mixture was stirred at
90 °C for 12 h. After work-up, flash column chromatography (silica
gel, hexane) afforded 5a (68 mg, 78%) as a white solid. M.p. (hex-
˜
3
(t, J = 7.1 Hz, 3 H, CH2CH3), 2.91 (d, J = 4.0 Hz, 2 H, H3), 2.99
(s, 3 H, NCH3), 4.02–4.18 (m, 3 H, H2, CH2CH3), 4.78 (d, J =
1.1 Hz, 1 H, =CHa), 5.38 (s, 1 H, =CHb), 6.63–6.70 (m, 2 H, H6,
H8), 7.18 (t, J = 7.6 Hz, 1 H, H7), 7.44 (dd, J = 7.7, 1.5 Hz, 1 H,
H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.2 (CH2CH3), 34.1
(C3), 39.1 (NCH3), 60.8 (CH2CH3), 63.1 (C2), 107.9 (C=CH2),
111.5 (C8), 116.8 (C6), 120.8 (C4a), 124.4 (C5), 129.5 (C7), 137.4
(C8a), 144.4 (C4), 172.0 (CO) ppm. MS (70 eV, EI): m/z (%) =
231(Ͻ1) [M+] 158 (56), 97 (15), 85 (40), 71 (39), 57 (100). HRMS
(EI): calcd. for C14H17NO2 231.1259; found 231.1258. C14H17NO2
(231.29): calcd. C 72.70, H 7.41, N 6.06; found C 72.32, H 7.18, N
5.80.
ane) 64–66 °C. IR (KBr): ν = 890 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 2.62–2.73 (m, 1 H, H3), 2.88 (s, 3 H, NCH3), 2.97–
3.04 (m, 1 H, H3), 4.50 (t, J = 5.2 Hz, 1 H, H2), 4.61 (s, 1 H,
=CHa), 5.32 (s, 1 H, =CHb), 6.67–6.73 (m, 2 H, H6, H8), 7.12–7.49
(m, 7 H, H5, H7, Ph) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 38.0
(NCH3), 39.4 (C3), 64.1 (C2), 107.7 (C=CH2), 111.1 (C8), 116.0
(C6), 121.4 (C4a), 124.6, 126.4, 127.0, 128.3, 129.6 (C5, C7, C–
Harom), 138.2 (C–Carom), 142.9 (C8a), 145.4 (C4) ppm. MS (70 eV,
EI): m/z (%) = 235 (41) [M+], 234 (16), 159 (15), 158 (100), 143
(10), 115 (13), 91 (11), 77 (11). C17H17N (235.33): calcd. C 86.77,
H 7.28, N 5.95; found C 86.56, H 7.02, N 5.72.
Synthesis of 1,2-Dihydroquinolines 6. General Procedure B:
Pd(PPh3)4 (30 mol-%) and Et3N (2 mmol) were added to a solution
of amine 4 (1 mmol) in dry toluene (30 mL). The mixture was
heated to reflux for 5–12 h. The reaction mixture was then diluted
with AcOEt (20 mL), and filtered through a Celite pad. The re-
sulting filtrate was washed with brine (3 ϫ 30 mL), dried with
Na2SO4, filtered and concentrated. The crude oil was purified by
flash column chromatography (silica gel, hexane/AcOEt) to give
corresponding 1,2-dihydroquinolines 6.
1-Methyl-4-methylene-1,2,3,4-tetrahydroquinoline (5b): (Table 2,
Entry 7) According to general procedure A, amine 4b (120 mg,
0.43 mmol) was treated with Pd(OAc)2 (10 mg, 0.043 mmol) and
PPh3 (33.8 mg, 0.129 mmol) and Ag2CO3 (178 mg, 0.64 mmol) in
DMF (10 mL). The reaction mixture was stirred at 90 °C for 12 h.
1,4-Dimethyl-2-phenyl-1,2-dihydroquinoline (6a): (Table 2, Entry 5)
According to general procedure B, amine 4a (201 mg, 0.55 mmol)
was treated with Pd(PPh3)4 (192 mg, 0.17 mmol) and Et3N
(0.15 mL, 1.10 mmol) in dry toluene (15 mL), and the mixture was
heated to reflux for 12 h. After work-up, flash column chromatog-
After work-up, flash column chromatography (silica gel, hexanes)
1
afforded 5b (47 mg, 69%) as an oil. IR (NaCl): ν = 1595 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 2.69 (t, J = 6.0 Hz, 2 H, H3), 2.91
(s, 3 H, NCH3), 3.26 (t, J = 6.0 Hz, 2 H, H2), 4.77 (s, 1 H, =CHa),
3018
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3013–3022

Regioselective Synthesis of 4-Alkylidene-tetrahydroquinolines
raphy (silica gel, hexanes) afforded 6a (98 mg, 76%) as an oil. IR
(C=CH), 115.7 (C6), 121.0 (C4a), 125.0 (C5), 126.1, 126.9, 128.3,
1
(NaCl): ν = 815 cm–1. H NMR (300 MHz, CDCl ): δ = 2.01 (s, 3
130.6 (C7, C–Harom), 141.1 (C–Carom), 142.1 (C8a), 145.8 (C4), 167.0
˜
3
H, CH3), 2.70 (s, 3 H, NCH3), 5.07 (d, J = 4.7 Hz, 1 H, H2), 5.53 (CO) ppm. MS (70 eV, EI): m/z (%) = 334 (56) [M+], 260 (60), 234
(d, J = 4.7 Hz, 1 H, H3), 6.44 (d, J = 8.3 Hz, 1 H, H8), 6.65 (t, J
= 7.3 Hz, 1 H H6), 7.09–7.28 (m, 7 H, H5, H7, Ph) ppm. 13C NMR HRMS (EI): calcd. for C22H26N2O 334.2045; found 334.2041.
(45), 220 (47), 219 (35), 184 (100), 158 (20), 130 (13), 69 (49).
(75.5 MHz, CDCl3): δ = 18.7 (CH3), 36.2 (NCH3), 65.5 (C2), 109.4
(C8), 116.0 (C3), 122.2 (C4), 123.1, 123.6 (C5, C6), 126.3, 127.5,
128.6, 129.6 (C7, C–Harom), 142.8, 144.8 (C4a, C8a, C–Carom) ppm.
MS (70 eV, EI): m/z (%) = 235 (13) [M+], 221 (13), 220 (29), 158
(100), 115 (11), 77 (13).
C22H26N2O (334.46): calcd. C 79.00, H 7.84, N 8.38; found C
78.81, H 7.83, N 8.13.
(E)-N-Methoxy-N-methyl-2-[1-methyl-2-phenyl-2,3-dihydroquinolin-
4(1H)-ylidene]acetamide (8b): (Table 3, Entry 9) According to gene-
ral procedure B, amine 7b (134 mg, 0.30 mmol) was treated with
Pd(PPh3)4 (112 mg, 0.09 mmol) and Et3N (0.08 mL, 0.60 mmol) in
dry toluene (10 mL), and the mixture was heated to reflux for 6 h.
2-Benzyloxymethyl-1,4-dimethyl-1,2-dihydroquinoline (6c): (Table 2,
Entry 13) According to general procedure B, amine 4c (230 mg,
0.56 mmol) was treated with Pd(PPh3)4 (192 mg, 0.17 mmol) and After work-up, flash column chromatography (silica gel, 30% hex-
Et3N (0.16 mL, 1.13 mmol) in dry toluene (15 mL), and the mix-
ture was heated to reflux for 5 h. After work-up, flash column
chromatography (silica gel, hexanes) afforded 6c (107 mg, 69%) as
ane/AcOEt) afforded 8b (72 mg, 77%) as an oil. IR (NaCl): ν =
˜
1640 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.93 (s, 3 H, NCH3),
3.10 (s, 3 H, NCH3), 3.24–3.32 (m, 1 H, H3), 3.30 (s, 3 H, OCH3),
3.75 (dd, J = 14.7, 4.5 Hz, 1 H, H3), 4.56 (t, J = 4.5 Hz, 1 H, H2),
6.58 (s, 1 H, =CH), 6.65–6.72 (m, 2 H, H6, H8), 7.09–7.32 (m, 6
H, H7, Ph), 7.43 (dd, J = 7.8, 1.4 Hz, 1 H, H5) ppm. 13C NMR
an oil. IR (NaCl): ν = 1655, 740 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 2.05 (s, 3 H, CH3), 3.03 (s, 3 H, NCH3), 3.37 (dd, J
= 9.7, 4.3 Hz, 1 H, CHHO), 3.56 (dd, J = 9.7, 7.0 Hz, 1 H, CHHO),
4.12–4.22 (m, 1 H, H2), 4.45 (s, 2 H, PhCH2), 5.54 (d, J = 5.8 Hz, (75.5 MHz, CDCl3): δ = 32.2 (NCH3), 33.1 (C3), 38.0 (NCH3), 61.2
1 H, H3), 6.54 (d, J = 8.0 Hz, 1 H, H8), 6.68 (t, J = 7.4 Hz, 1 H,
H6), 7.10–7.19 (m, 2 H, H5, H7), 7.27–7.37 (m, 5 H, Ph) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 18.8 (CH3), 38.2 (NCH3), 60.1 (C2),
72.7 (CH2O), 73.1 (PhCH2), 110.7 (C8), 116.0 (C6), 119.5 (C3),
(OCH3), 63.3 (C2), 110.3 (C=CH), 111.2 (C8), 115.9 (C6), 121.0
(C4a), 125.3 (C5), 126.4, 126.9, 128.3 (C–Harom), 131.3 (C7), 142.0
(C–Carom), 146.3, 146.5 (C4, C8a), 167.5 (CO) ppm. MS (70 eV, EI):
m/z (%) = 322 (6) [M+], 292 (26), 281 (15), 262 (68), 234 (28), 215
122.9 (C4), 123.6 (C5), 127.3, 127.4, 128.3, 128.8 (C7, C–Harom), (11), 184 (81), 126 (10), 84 (62), 72 (93), 69 (31), 59 (100), 55 (60).
131.8 (C4a), 138.3 (C–Carom), 144.4 (C8a) ppm. MS (70 eV, EI): m/z HRMS (EI): calcd. for C20H22N2O2 322.1681; found 322.1693.
(%) = 279 (1) [M+], 173 (17), 82 (100), 77 (29). C19H21NO (279.38):
calcd. C 81.68, H 7.58, N 5.01; found C 81.39, H 7.45, N 5.34.
C
20H22N2O2 (322.41): calcd. C 74.51, H 6.88, N 8.69; found C
74.26, H 6.77, N 8.38.
Ethyl 1,4-Dimethyl-1,2-dihydroquinoline-2-carboxylate (6d): (E)-N,N-Diethyl-2-[1-methyl-2,3-dihydroquinolin-4(1H)-ylidene]-
(Table 2, Entry 17) According to general procedure B, amine 4d acetamide (8c): (Table 3, Entry 3) According to general procedure
(131 mg, 0.42 mmol) was treated with Pd(PPh3)4 (150 mg, A, amine 7c (90 mg, 0.23 mmol) was treated with Pd(OAc)2 (8 mg,
0.13 mmol) and Et3N (0.12 mL, 0.84 mmol) in dry toluene 0.023 mmol) PPh3 (20 mg, 0.07 mmol) and Ag2CO3 (100 mg,
(15 mL), and the mixture was heated to reflux for 5 h. After work-
up, flash column chromatography (silica gel, 5% hexane/AcOEt)
0.35 mmol) in DMF (10 mL). The reaction mixture was stirred at
90 °C for 5 h. After work-up, flash column chromatography (silica
gel, 20% hexane/AcOEt) afforded 8c (40 mg, 67%) as an oil. IR
1
afforded 6d (58 mg, 60%) as an oil. IR (NaCl): ν = 1740 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 3 H, CH2CH3), (NaCl): ν = 1625 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.16–
˜
2.03 (s, 3 H, CH3), 2.92 (s, 3 H, NCH3), 4.12 (q, J = 7.1 Hz, 2 H,
1.21 (m, 6 H, 2ϫCH2CH3), 2.91 (s, 3 H, NCH3), 3.05–3.12 (m, 2
CH2CH3), 4.61 (d, J = 5.9 Hz, 1 H, H2), 5.60 (d, J = 5.9 Hz, 1 H, H, H3), 3.21–3.27 (m, 2 H, H2), 3.38–3.50 (m, 4 H, 2ϫCH2CH3),
H3), 6.57 (d, J = 8.0 Hz, 1 H, H8), 6.68 (t, J = 7.5 Hz, 1 H, H6),
7.10 (dd, J = 7.5, 1.4 Hz, 1 H, H7), 7.16 (td, J = 7.5, 1.4 Hz, 1 H,
H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.1 (CH2CH3), 18.7
6.39 (s, 1 H, =CH), 6.64–6.68 (m, 2 H, H6, H8), 7.20 (td, J = 7.4,
1.4 Hz, 1 H, H7), 7.45 (dd, J = 7.4, 1.4 Hz, 1 H, H5) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 13.3, 14.5 (2ϫNCH2CH3), 27.2
(CH3), 37.3 (NCH3), 60.7 (CH2CH3), 63.4 (C2), 110.2 (C8), 116.3, (C3), 39.4 (NCH3), 39.9, 42.6 (2ϫNCH2CH3), 51.0 (C2), 111.7
116.8 (C3, C6), 122.1 (C4), 123.8 (C5), 129.3 (C7), 132.8 (C4a), 144.5 (C=CH), 112.3 (C8), 116.7 (C6), 121.0 (C4a), 124.7 (C5), 130.4 (C7),
(C8a), 170.9 (CO) ppm. MS (70 eV, EI): m/z (%) = 231 (3) [M+],
158 (67), 97 (11), 85 (42), 83 (100), 71 (23), 57 (62). HRMS (EI):
calcd. for C14H17NO2 231.1259; found 231.1253.
144.2 (C8a), 147.5 (C4), 167.4 (CO) ppm. MS (70 eV, EI): m/z (%)
= 258 (52) [M+], 184 (56), 158 (100), 143 (21). HRMS (EI): calcd.
for C16H22N2O 258.1732; found 258.1738. C16H22N2O (258.36):
calcd. C 74.38, H 8.58, N 10.84; found C 74.86, H 8.77, N 10.96.
(E)-N,N-Diethyl-2-[1-methyl-2-phenyl-2,3-dihydroquinolin-4(1H)-
ylidene]acetamide (8a): (Table 3, Entry 8) According to general pro-
cedure B, amine 7a (148 mg, 0.32 mmol) was treated with Pd-
(PPh3)4 (112 mg, 0.09 mmol) and Et3N (0.09 mL, 0.64 mmol) in
dry toluene (15 mL), and the mixture was heated to reflux for 6 h.
After work-up, flash column chromatography (silica gel, 40% hex-
(E)-N-Methoxy-N-methyl-2-[1-methyl-2,3-dihydroquinolin-4(1H)-
ylidene]acetamide (8d): (Table 3, Entry 11) According to general
procedure B, amine 7d (95 mg, 0.25 mmol) was treated with
Pd(PPh3)4 (89 mg, 0.08 mmol) and Et3N (0.08 mL, 0.50 mmol) in
dry toluene (10 mL), and the mixture was heated to reflux for 6 h.
After work-up, flash column chromatography (silica gel, 40% hex-
ane/AcOEt) afforded 8a (86 mg, 85%) as an oil. IR (NaCl): ν =
˜
1
1600 cm–1. H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 7.1 Hz,
ane/AcOEt) afforded 8d (40 mg, 67%) as an oil. IR (NaCl): ν =
˜
3 H, CH2CH3), 1.01 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.69–2.85 (m,
1650 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.91 (s, 3 H, NCH3),
2 H, CH2CH3), 2.93 (s, 3 H, NCH3), 3.03–3.14 (m, 2 H, H3,
3.21–3.23 (m, 2 H, H3), 3.23 (s, 3 H, NCH3), 3.37–3.39 (m, 2 H,
CHHCH3), 3.31 (dd, J = 14.0, 4.2 Hz, 1 H, H3), 3.41–3.53 (m, 1 H2), 3.72 (s, 3 H, OCH3), 6.64–6.72 (m, 3 H, C=CH, H6, H8), 7.22
H, CHHCH3), 4.58 (t, J = 4.2 Hz, 1 H, H2), 6.22 (s, 1 H, =CH), (t, J = 7.1 Hz, 1 H, H7), 7.55 (d, J = 7.9 Hz, 1 H, H5) ppm. 13C
6.64–6.70 (m, 2 H, H6, H8), 7.00–7.07 (m, 2 H, PhЈ, H7), 7.16–7.29 NMR (75.5 MHz, CDCl3): δ = 26.7 (C3), 32.3 (NCH3), 39.3
(m, 4 H, Ph), 7.35 (dd, J = 7.6, 1.3 Hz, 1 H, H5) ppm. 13C NMR (NCH3), 50.8 (C2), 61.5 (OCH3), 106.9 (C=CH), 112.4 (C8), 116.6
(75.5 MHz, CDCl3): δ = 12.8, 13.8 (CH2CH3), 33.8 (C3), 37.9
(C6), 121.0 (C4a), 124.9 (C5), 131.0 (C7), 148.1 (C8a), 149.4 (C4),
(NCH3), 39.2, 41.6 (CH2CH3), 63.2 (C2), 110.7 (C8), 115.2 168.1 (CO) ppm. MS (230 eV, CI): m/z (%) = 247 (34) [MH+], 246
Eur. J. Org. Chem. 2013, 3013–3022
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3019

E. Lete et al.
(21) [M+], 217 (82), 216 (81), 186 (100), 158 (30), 144 (17). HRMS 3 H, H2, CH2CH3), 6.41 (s, 1 H, =CH), 6.64–6.70 (m, 2 H, H6,
FULL PAPER
(CI): calcd. for C14H19N2O2 247.1447; found 247.1436.
H8), 7.22 (td, J = 7.7, 1.5 Hz, 1 H, H7), 7.38 (dd, J = 7.8, 1.5 Hz,
1 H, H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 13.2, 14.1, 14.3
(3ϫCH3), 28.8 (C3), 38.8 (NCH3), 39.8, 42.5 (2ϫ CH2CH3), 60.8
(OCH2CH3), 62.3 (C2), 111.8 (C6), 113.6 (C=CH), 116.8 (C8), 120.3
(C4a), 124.5 (C5), 130.7 (C7), 141.8 (C8a), 145.4 (C4), 166.6 (CO),
171.6 (CO) ppm. MS (70 eV, EI): m/z (%) = 330 (7) [M+], 257
(42), 184 (92), 84 (100), 72 (12), 59 (15). HRMS (EI): calcd. for
C19H26N2O3 330.1943; found 330.1940.
(E)-2-[2-Benzyloxymethyl-1-methyl-2,3-dihydroquinolin-4(1H)-
ylidene]-N,N-diethylacetamide (8e): (Table 3, Entry 12) According
to general procedure B, amine 7e (132 mg, 0.26 mmol) was treated
with Pd(PPh3 )4 (91 mg, 0.08 mmol) and Et3N (0.08 mL,
0.52 mmol) in dry toluene (10 mL), and the mixture was heated to
reflux for 6 h. After work-up, flash column chromatography (silica
gel, 40% hexane/AcOEt) afforded 8e (60 mg, 61%) as an oil. IR
(E)-2-[7-Chloro-1-methyl-2-phenyl-2,3-dihydroquinolin-4(1H)-
ylidene]-N,N-diethylacetamide (8h): According to general procedure
A, amine 7h (120 mg, 0.24 mmol) was treated with Pd(OAc)2 (8 mg,
0.024 mmol) PPh3 (20 mg, 0.07 mmol) and Ag2CO3 (100 mg,
0.36 mmol) in DMF (10 mL). The reaction mixture was stirred at
90 °C for 5 h. After work-up, flash column chromatography (silica
gel, hexane) afforded 8h (85 mg, 96 %) as an oil. 1H NMR
(300 MHz, CDCl3): δ = 0.81 (t, J = 7.1 Hz, 3 H, CH2CH3), 0.99
(t, J = 7.1 Hz, 3 H, CH2CH3), 2.65–2.82 (m, 2 H, CH2CH3), 2.92
(s, 3 H, NCH3), 2.99–3.11 (m, 2 H, H3, CHHCH3), 3.32 (dd, J =
14.1, 3.7 Hz, 1 H, H3), 3.38–3.54 (m, 1 H, CHHCH3), 4.53–4.63
(m, 1 H, H2), 6.19 (d, J = 1.3 Hz, 1 H, C=CH), 6.56–6.69 (m, 2 H,
H6, H8), 6.95–7.05 (m, 2 H, Ph, H5), 7.12–7.29 (m, 4 H, Ph) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 12.8, 13.7 (2ϫ CH2CH3), 33.6
(C3), 38.0 (NCH3), 39.2, 41.6 (2ϫ CH2CH3), 63.0 (C2), 110.3 (C8),
115.6 (C=CH), 115.7 (C6), 119.4 (C4a), 127.0 (C5), 125.9, 128.5 (C–
(NaCl): ν = 1630 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.16–
˜
1.21 (m, 6 H, 2ϫ CH2CH3), 2.71 (dd, J = 14.6, 5.5 Hz, 1 H, H3),
3.07 (s, 3 H, NCH3), 3.35–3.50 (m, 5 H, CHHO, 2ϫ CH2CH3),
3.55–3.60 (m, 2 H, H3, CHHO), 3.67–3.72 (m, 1 H, H2), 4.48 (d, J
= 11.9 Hz, 2 H, CH2Ph), 6.48 (s, 1 H, =CH), 6.59 (d, J = 8.0 Hz,
1 H, H8), 6.60–6.70 (m, 1 H, H6), 7.21–7.36 (m, 6 H, H7, Ph), 7.44
(dd, J = 8.0, 1.3 Hz, 1 H, H5) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 13.2, 14.4 (2ϫ CH2CH3), 27.8 (C3), 38.9 (NCH3), 39.8, 42.6
(2ϫ CH2CH3), 58.7 (C2), 71.0 (CH2O), 73.4 (CH2Ph), 111.5 (C8),
113.7 (C=CH), 115.4 (C6), 119.7 (C4a), 124.6 (C5), 127.4, 127.5,
128.4, 130.7 (C7, C–Harom), 138.4 (C–Carom), 142.1 (C8a), 144.9
(C4), 167.2 (CO) ppm. MS (70 eV, EI): m/z (%) = 257 (15) [M+
CH2OBn], 184 (100), 91 (8). HRMS (EI): calcd. for C24H30N2O2
378.2307; found 378.2328. C24H30N2O2 (378.51): calcd. C 76.16, H
7.99, N 7.40; found C 75.98, H 8.01, N 6.99.
–
H
arom), 136.21 (C7), 139.9 (C–Carom), 141.5 (C8a), 146.5 (C4), 166.6
(E)-2-[2-Benzyloxymethyl-1-methyl-2,3-dihydroquinolin-4(1H)-
ylidene]-N-methoxy-N-methylacetamide (8f): (Table 3, Entry 13)
According to general procedure B, amine 7f (176 mg, 0.35 mmol)
was treated with Pd(PPh3)4 (120 mg, 0.11 mmol) and Et3N
(0.10 mL, 0.71 mmol) in dry toluene (10 mL), and the mixture was
heated to reflux for 6 h. After work-up, flash column chromatog-
raphy (silica gel, 40% hexane/AcOEt) afforded 8f (101 mg, 81%)
(CO) ppm. MS (230 eV, CI): m/z (%) = 371 (31) [MH+ + 2], 369
(100) [MH+], 333 (37), 296 (17). HRMS (CI): calcd. for
C22H26ClN2O [MH+] 369.1734; found 369.1736.
(–)-(E)-2-{(R)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-methyl-2,3-di-
hydroquinolin-4(1H)-ylidene}-N,N-diethylacetamide (8i): According
to general procedure A, amine 7i (160 mg, 0.32 mmol) was treated
with Pd(OAc)2 (7 mg, 0.032 mmol) PPh3 (23 mg, 0.09 mmol) and
Ag2CO3 (132 mg, 0.48 mmol) in DMF (10 mL). The reaction mix-
ture was stirred at 90 °C for 5 h. After work-up, flash column
chromatography (silica gel, 20 % hexane/AcOEt) afforded 8i
(80 mg, 68%) as an oil. [α]2D0 = –65.5 (c = 5, CH2Cl2). IR (NaCl):
as an oil. IR (NaCl): ν = 1640 cm–1. 1H NMR (300 MHz, CDCl ):
˜
3
δ = 2.70–2.77 (m, 1 H, H3), 3.06 (s, 3 H, NCH3), 3.24 (s, 3 H,
NCH3), 3.41–3.46 (m, 1 H, CHHO), 3.54–3.59 (m, 1 H, CHHO),
3.69 (broad s, 4 H, OCH3, H2), 4.11 (dd, J = 15.1, 2.3 Hz, 1 H,
H3), 4.44 (s, 2 H, CH2Ph), 6.57–6.66 (m, 2 H, H6, H8), 6.76 (s, 1
H, =CH), 7.22–7.34 (m, 6 H, H7, Harom), 7.50 (dd, J = 7.8, 1.4 Hz,
1 H, H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 27.2 (C3), 32.4
(NCH3), 38.9 (NCH3), 58.6 (C2), 61.5 (OCH3), 70.8 (CH2O), 73.3
(CH2Ph), 109.1 (C=CH), 111.7 (C8), 115.5 (C6), 119.7 (C4a), 124.9
(C5), 127.2, 127.4, 128.3, 131.4 (C7, C–Harom), 138.3 (C–Harom),
145.4 (C8a), 147.2 (C4), 168.1 (CO) ppm. MS (70 eV, EI): m/z (%)
= 366 (9) [M+], 306 (39), 245 (45), 215 (82), 184 (100), 157 (19),
144 (12), 136 (11), 122 (12), 91 (52), 72 (24), 59 (32), 55 (28).
HRMS (EI): calcd. for C22H26N2O3 366.1943; found 366.1936.
C22H26N2O3 (366.46): calcd. C 72.11, H 7.15, N 7.64; found C
72.03, H 7.16, N 7.53.
ν = 1630 cm–1 1H NMR (300 MHz, CDCl3): δ = 1.00 (t, J =
.
˜
7.1 Hz, 3 H, CH2CH3), 1.17 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.30 (s,
3 H, CH3), 1.41 (s, 3 H, CH3), 2.62 (dd, J = 13.3, 2.2 Hz, 1 H, H3),
2.73 (ddd, J = 13.3, 5.1, 2.2 Hz, 1 H, H3), 3.03 (s, 3 H, NCH3),
3.20–3.40 (m, 2 H, CH2CH3), 3.43–3.48 (m, 1 H, H2), 3.54–3.66
(m, 2 H, CH2CH3), 3.77 (t, J = 7.5 Hz, 1 H, OCHH), 3.92 (dd, J
= 13.1, 7.5 Hz, 1 H, OCH), 4.02 (dd, J = 7.5, 5.6 Hz, 1 H, OCHH),
5.69 (s, 1 H, =CH), 6.50–6.58 (m, 2 H, H8, H6), 7.12–7.18 (m, 1 H,
H7), 7.43 (dd, J = 7.8, 1.4 Hz, 1 H, H5) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 12.4, 14.1 (CH2CH3), 25.7, 26.8 (CH3), 33.0 (C3), 39.0
(CH2CH3), 40.0 (NCH3), 42.6 (CH2CH3), 62.0 (C2), 67.6 (OCH),
76.7 (OCH2), 108.5 (OOC), 111.2 (C8), 115.9 (C6), 118.6 (C4a),
118.9 (C=CH), 127.8 (C5), 130.3 (C7), 134.0 (C8a), 144.3 (C4), 168.9
(CO) ppm. C21H30N2O3 (358.48): calcd. C 70.36, H 8.44, N 7.81;
found C 70.27, H 8.37, N 7.61.
Ethyl (E)-4-[2-(Diethylamino)-2-oxoethylidene]-1-methyl-1,2,3,4-
tetrahydroquinoline-2-carboxylate (8g): (Table 3, Entry 21) Pd-
(OAc)2 (16 mg, 0.07 mmol), NaHCO3 (88 mg, 1.05 mmol) and
nBu4NCl (176 mg, 0.632 mmol) were added to a solution of buten-
ylamine 7g (197 mg, 0.48 mmol) and in dry CH3CN (10 mL), and
the mixture was heated to reflux for 6 h. The reaction mixture was
then diluted with Et2O (10 mL), and filtered through a Celite pad.
The resulting filtrate was washed with saturated NH4Cl (2 ϫ
10 mL) and brine (2ϫ 10 mL), dried with Na2SO4, filtered and
concentrated. The crude oil was purified by flash column
chromatography (silica gel, 50 % hexane/AcOEt) to afford 8g
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of precursors 1a–d, 4a–d, and
7a–i. Copies of 1H and 13C NMR spectra of compounds described
(130 mg, 82%) as an oil. IR (NaCl): ν = 1735, 1680 cm–1. 1H NMR
˜
Acknowledgments
(300 MHz, CDCl3): δ = 1.17 (t, J = 7.1, Hz, 9 H, CH2CH3), 2.92
(dd, J = 15.1, 3.0 Hz, 1 H, H3), 2.98 (s, 3 H, NCH3), 3.26–3.54 (m,
The authors wish to thank the Ministerio de Ciencia e Innovación
4 H, CH2CH3), 3.85 (dd, J = 15.1, 3.0 Hz, 1 H, H3), 4.03–4.11 (m, (MICINN) (CTQ2009-07733) and the Universidad del País Vasco/
3020
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3013–3022

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Received: January 11, 2013
Published Online: March 27, 2013
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Eur. J. Org. Chem. 2013, 3013–3022