Silver-catalysed intramolecular cyclisation of 2-alkynylacetophenones and 3-acetyl-2-alkynylpyridines in the presence of ammonia

Article abstract of DOI:10.1039/c1ob06271a

Silver-catalysed/microwave-assisted domino reactions of 2-alkynyl-acetophenones and 3-acetyl-2-alkynylpyridines in the presence of ammonia are widely described. In most cases the reaction give a mixture of the imino- and carbo-cyclisation products, with a

Full text of DOI:10.1039/c1ob06271a

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 7836
www.rsc.org/obc
PAPER
Silver-catalysed intramolecular cyclisation of 2-alkynylacetophenones and
3-acetyl-2-alkynylpyridines in the presence of ammonia
Monica Dell’Acqua,a Giorgio Abbiati,*a Antonio Arcadib and Elisabetta Rossia
Received 27th July 2011, Accepted 16th August 2011
DOI: 10.1039/c1ob06271a
Silver-catalysed/microwave-assisted domino reactions of 2-alkynyl-acetophenones and 3-acetyl-2-
alkynylpyridines in the presence of ammonia are widely described. In most cases the reaction give a
mixture of the imino- and carbo-cyclisation products, with a general preference for the former. A
plausible mechanism is proposed and the dual activity of silver salts is supported by NMR experiments.
alkynylacetophenones with ammonia under our standard domino
Introduction
conditions, the reactions gave very poor results (see below). These
From many years, we have been interested in the development
outcomes prompted us to investigate the reactions of alkynyl
of domino synthetic strategies1 for the construction of nitrogen-
ketones in more depth.
containing heterocycles2 starting from alkyne derivatives.3 In par-
ticular, many efforts have been devoted to the synthesis of nitrogen-
Whereas the use of 2-alkynylbenzaldehydes (and related com-
pounds characterized by the presence of a g-alkynylaldehyde
framework on an (hetero)aromatic scaffold) as starting materi-
als for the preparation of (hetero)cyclic compounds has been
containing rings by sequential addition/annulation reactions of
g- or d-ketoalkynes in the presence of ammonia.4 For example,
5-exo-dig cyclisation of 4-pentynones5 gave polysubstituted and
widely explored and is in continuous evolution, the reactivity of
keto-homologous, 2-alkynylacetophenones, is less investigated.11
In many articles, 2-alkynylacetophenones are only marginally
treated as a digression in more comprehensive works on 2-
alkynylbenzaldehydes.12 In some cases, 2-alkynylacetophenones
show a different behaviour with respect to the correspond-
ing 2-alkynylbenzaldehydes, in terms of reaction yield13 or
product selectivity.14 It is worth noting that reactions of 2-
alkynylacetophenones or their N-heterocyclic analogues, 3-
acetyl-2-alkynylpyridines, with secondary15 or branched primary
amines15a have only few precedents, whereas, to the best of our
knowledge, no example of their reaction with ammonia has been
reported yet. Thus, in this paper we report our recent findings
on microwave-assisted, domino addition/annulation reactions of
2-alkynyl-acetophenones and 3-acetyl-2-alkynylpyridines in the
presence of ammonia.16
fused pyrrole derivatives (Scheme 1, a), whereas the presence of a g-
ketoalkyne moiety in an aromatic framework is responsible for the
6-endo-dig cyclisation of 5-acetyl-4-alkynylthiazoles6 and 2-acyl-3-
alkynylindoles7 to pyrido[3,4-c]thiazoles and pyrido[3,4-b]indoles,
respectively (Scheme 1, b and c). More recently, we reported an in
depth investigation on the synthesis of the pyrazino[1,2-a]indole
nucleus through the sequential imination/annulation reaction of
2-carbonyl-1-propargylindoles in the presence of ammonia in
methanol.8 The reaction worked well with N-propargylindole-
2-carbaldehydes, but yields and selectivities were unsatisfactory
using 2-acetyl-N-propargylindoles.8a
Moreover, the reaction totally failed when using 2-benzoyl-N-
propargylindoles. These drawbacks were overcome when we found
that 3 equiv. of TiCl4 and microwave heating were able to improve
both yields and selectivities in the reactions of ketone derivatives,
together with a widespread reduction of reaction times8b (Scheme
1, d). This sequential approach to hetero(poly)cyclic rings (with
and without titanium catalysis) has been very recently applied
to the synthesis of pyrrolo[1,2-a]pyrazines and isoquinolines
starting from 2-acetyl-N-propargylpyrroles (Scheme 1, e) and
2-alkynyl-benzaldehydes (Scheme 1, f), respectively,9 and the
approach to isoquinolines was also successfully transformed into
a multicomponent process10 (Scheme 1, g). But, unexpectedly,
when we tried to synthesize 1-methylisoquinolines by reacting 2-
Results and discussion
We started our study looking for the best conditions to trigger the
domino reaction of o-(p-tolylethynyl)acetophenone 1a, chosen as
model compound, with ammonia (Table 1). As mentioned above,
the uncatalysed7,8a reaction of 1a with 2 M ammonia in methanol
at 120 ◦C under microwave heating gave the corresponding iso-
quinoline 2a in very low yield (Table 1, entry 1). A simple tentative
approach to promote the formation of the imine intermediate by
the use of molecular sieves did not result in any improvement
(Table 1, entry 2). On the basis of our previous experiences,8b,9
we planned to catalyse the reaction with 3 equiv. of titanium
tetrachloride, but, under these conditions, only traces of the
aDISMAB – Sezione di Chimica Organica “A. Marchesini”, Universita` degli
Studi di Milano, via G. Venezian, 21, 20133, Milano, Italia
bDipartimento di Chimica, Ingegneria Chimica e Materiali, Universita`
degli Studi dell’Aquila, Via Vetoio, 67010, Coppito, L’Aquila, Italia.
E-mail: giorgio.abbiati@unimi.it
7836 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
amine 3a (Table 1, entry 6). PdCl2 gave poorer results in terms
of yield and regioselectivity (Table 1, entry 7), whereas Cu(OTf)2
gave a similar ratio 2a : 3a but in lower overall yield (Table 1, entry
8). In the presence of CuI, yield and selectivity were comparable to
those observed using Pd(OAc)2 (Table 1, cf. entry 9 and 6). Among
the five silver-based catalysts tested (Table 1, entries 10–14), AgF
and Ag2O gave modest results even after prolonged reaction times
(Table 1, entries 10 and 11), whereas AgSbF6 was more active and
selective, and gave slightly better yield (Table 1, entry 12). AgNO3
was a little more effective than palladium, despite the ratio of
products being slightly shifted toward the naphtalen-1-amine 3a
(Table 1, entry 13). The best result was obtained with AgOTf,
which gave an almost quantitative conversion with a quite good
regioselectivity (with respect to the other catalysts tested) in a
relatively short reaction time (Table 1, entry 14). NaAuCl4 was
ineffective (Table 1, entry 15), whereas PPh3AuCl was as active as
22
AgNO3 (Table 1, entry 16). Surprisingly, in the presence of both
PPh3AuCl and AgOTf a reversed selectivity was observed (Table 1,
entry 17). Finally, indium salts seemed to be completely unsuited
for our purpose (Table 1, entries 18 and 19).
It is worth noting that our results with silver salts “fit-well” with
all other emerging examples in which simple and cheap silver salts
seem to be equally or more effective than more expensive gold
catalysts.12c,23
Afterwards, we investigated the scope and limitations of the ap-
proach. Initially, we prepared a library of 2-alkynylacetophenones
1a–m and 3-acetyl-2-alkynylpyridines 1n–t by a standard Sono-
gashira procedure24 from 2-bromoacetophenones 4a–c and 2-
bromo-3-acetylpyridine 4d in the presence of a variety of ter-
minal alkynes (Table 2). Whereas 2-bromoacetophenone 4a is
a cheap commercially available reagent, the more expensive 2-
bromo-3-acetylpyridine 4d was prepared in two steps in very
good yields by a Grignard reaction of 2-bromonicotinaldehyde
5d with CH3MgBr,15b followed by Jones oxidation25 (Scheme
2). The same procedure was followed to prepare 2-bromo-5-
methoxyacetophenone 4b and 2-bromo-5-fluoroacetophenone 4c
starting from the corresponding aldehydes 5b and 5c, respectively
(Scheme 2).
Scheme 1 Our previous works on cyclization of g- or d-ketoalkynes in
the presence of ammonia.
isoquinoline 2a were identified together with a complex mixture of
tarry unidentified by-products (probably derived from a titanium-
catalysed polymerisation process) (Table 1, entry 3). A similar
behaviour was observed using a catalytic amount of titanium
(Table 1, entry 4), whereas the less acidic complex TiCl4·2THF
also gave poor yield after a prolonged reaction time (Table 1,
entry 5). Due to these disappointing outcomes, we tried some
other metal catalysts potentially able to promote both the imine
formation as a Lewis acid, and the intermolecular hydroamination
step as an alkynophilic catalyst.17 There are many examples in the
literature of this double activity of palladium,18 copper,19 silver,12c
gold20 and indium11b,21 salts and complexes in the intramolecular
cyclizations involving alkynes bearing a neighboring nucleophile.
We were delighted to find that in the presence of Pd(OAc)2 the
reaction gave the desired isoquinoline 2a in a promising 46% yield,
as well as a not negligible amount of the isomeric naphtalen-1-
Scheme 2 Preparation of 2-bromo-5-methoxyacetophenone 4b, 2-bro-
mo-5-fluoroacetophenone 4c and 2-bromo-3-acetylpyridine 4d.
Then, we tested compounds 1b–t in the AgOTf-catalysed
domino reaction with ammonia. The obtained results are depicted
in Table 3.
The reactions of acetophenone derivatives substituted on the
triple bond with an aryl group always lead to a mixture of
isoquinoline and naphtalenamine isomers in variable ratio (Table
3, entries 1–6). Better results were obtained with neutral and
electron-donating groups on the aryl moiety (Table 3, entries 1–
3), whereas electron-withdrawing groups gave lower yields and
worse selectivity or inhibited the reaction (Table 3, entries 4–
6). In the presence of alkyl substituents on the triple bond the
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7836–7848 | 7837
©

View Article Online
Table 1 Screening of reaction conditions for domino addition/annulation of 1a with ammonia
Entry
t/mina
Catalyst
—
2a yield %b
3a yield %b
1a (rec.) yield %b
Overall yield %b
Ratio 2a/3a
1
2
3
4
5
6
7
8
120
120
30
15
80
100
60
120
120
120
120
60
60
45
120
30
60
11c
4
—
—
—
—
—
25
19
13
20
14
10
17
36
40
6
72
45
—
—
18
—
7
11
4
—
—
—
—
-1
˚
4 A molecular sieve (100 mg mmol )
TiCl4 (3 equiv.)
tracesd
tracesd
11
—
—
11
71
42
36
58
29
20
43
82
98
17
75
70
e
TiCl4
TiCl4·2THFe
—
e
Pd(OAc)2
46
23
23
38
15
10
26
46
58
11
41
27
1.8
1.2
1.8
1.9
1.1
1.0
1.5
1.3
1.5
1.8
1.2
0.6
e
PdCl2
e
Cu(OTf)2
8
9
CuIe
—
17
18
4
10
11
12
13
14
15
16
17
AgFe
Ag2Oe
AgSbF6
e
e
AgNO3
9
AgOTfe
—
31
10
—
NaAuCl4·2H2Oe
PPh3AuCle
34
43
PPh3AuCl (7.5 mol%)
AgOTfe
e
18
19
120
120
InCl3
5
—
—
18
—
5
—
—
—
e
In(OTf)3
tracesd
◦
a
Not including 11 min “ramp time” ( 10 C min-1). b Yields refer to pure isolated compounds. c The reaction performed under conventional heating at
~
=
110 ◦C overnight gave only traces of isoquinoline 2a. d The reaction gave a complex mixture of tarry unidentified by-products. e 10 mol%.
reactions run with good yields and a better selectivity toward the
isoquinoline isomers (Table 3, entries 7–12). The approach also
tolerates the presence of bulky substituents on the triple bond such
as cyclohexanol, but in this case the yields were moderate (Table
3, entry 10). An electronic perturbation on the acetophenone
ring does not seem to substantially affect the course of reaction
(Table 3, entries 11–12), although the presence of an electron-
withdrawing substituent leads to a slight reduction of yield (Table
3, entry 12). In the reactions of the aryl- and alkyl-substituted
3-acetyl-2-alkynylpyridines (Table 3, entries 13–19) we observed a
general behavior comparable to that of 3-alkynylacetophenones,
with an improved selectivity to the 1,6-naphthyridine isomer for
the substrates substituted with an aryl moiety on the alkyne (Table
3, entries 13–14, cf . entry 2 with 14). Finally, the reaction of 3-
acetyl-2-(trimethylsilylethynyl)pyridine 1t gave the desilylated 5-
methyl-1,6-naphthyridine in moderate yield (Table 3, entry 19). All
the obtained products have been identified and fully characterized
by NMR spectroscopy, IR and MS.
According to the literature,12c,23a the proposed mechanism for
the AgOTf-catalysed nucleophilic addition/annulation sequence
involves two key steps (Scheme 3): in the first step, the nucleophilic
attack of ammonia on the carbonyl leads to the formation of
imine intermediate A, in equilibrium with its enamine tautomer
B. Although silver triflate is generally considered a Lewis acid
with a strong p-philic character,12c we believe that it is also able
to increase the electrophilic character of the carbonyl carbon
atom17,18 and therefore promote the nucleophilic attack of am-
monia. In a similar way, it is probably able to also coordinate the
imine,17,26 and affect the tautomeric equilibrium imine/enamine,
thus highlighting the bidentate character of the nucleophilic
intermediate. The second step involves the intramolecular addition
of the N- or C-nucleophile on the Ag-activated triple bond.12c
The cycloisomerisation occurs with selective 6-endo-dig geometry
leading to the corresponding s-silver complex of isoquinoline C
and/or naphtalenamine D. The final products 2 and/or 3 are then
achieved by a solvent-mediated protodemetalation that restores
the catalyst.
To verify the hypothesis that silver can act as a s-philic Lewis
acid and thus is able to enhance the electrophilicity of the carbonyl
and to affect the tautomeric processes, some NMR experiments
were performed. First, we acquired two 13C NMR spectra of
acetophenone in deuterated methanol, in the absence (A) and in
the presence (B) of 1 equiv. of AgOTf (Fig. 1). It is well-known
that one of the most important parameters that determine the
chemical shift in nuclear magnetic resonance is the shielding effect,
determined by the electron density of the atomic nucleus observed.
Therefore, the shift of a signal in response to an interaction with
a catalyst can be related to the change of charge density of the
Fig. 1 Chemical shift of acetophenone carbonyl with and without the
catalyst.
7838 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 2 Preparation of 2-alkynylacetophenones 1a–m and 3-acetyl-2-alkynylpyridines 1n–t
X
R1
H
R2
t/h
Product
Yield%a
98
CH
6
1a
CH
CH
CH
H
H
H
2.5
5
1b
1c
1d
66
62
87
5
CH
CH
H
H
2
1e
1f
38b
45
6.5
CH
H
6.5
1g
39
CH
CH
CH
CH
H
H
H
H
CH3(CH2)4–
CH3(CH2)5–
CH3(CH2)7–
12
12
12
2
1h
1i
57
95
93
98
1j
1k
CH
CH
N
MeO
F
H
CH3(CH2)2–
CH3(CH2)2–
12
1
1
1l
1m
1n
63
94
84
N
N
H
H
1
2
1o
1p
78
84
N
N
N
H
H
H
CH3(CH2)4–
CH3(CH2)5–
1.5
3
1
1q
1r
1s
67
76
98
N
H
1
1t
98
a Yields refer to pure isolated compounds. b Prepared by reaction of 2-ethynylacetophenone with 4-iodoacetophenone under standard Sonogashira
conditions.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7836–7848 | 7839
©

View Article Online
Table 3 AgOTf-catalysed domino addition/cyclization reaction of derivatives 1b–t
Entry
1
1,2,3
X
R1
H
R2
t/mina
2 (yield %)b
3 (yield %)b
b
CH
120
36
44
2
3
c
CH
CH
H
H
90
90
32
35
41
40
d
4
5
e
f
CH
CH
H
H
120
210
23
39
traces
traces
6
g
CH
H
90
traces
—
7
8
9
10
h
i
CH
CH
CH
CH
H
H
H
H
CH3(CH2)4–
CH3(CH2)5–
CH3(CH2)7–
90c
90
63
61
44
25
15
20
14
—
j
90d
120
k
11
12
13
l
m
n
CH
CH
N
MeO
F
H
CH3(CH2)2–
CH3(CH2)2–
150
150
60
71
55
41
17
15
25
14
15
o
p
N
N
H
H
30
48
—
19
—
105
16
17
18
q
r
s
N
N
N
H
H
H
CH3(CH2)4–
CH3(CH2)5–
60
60
60
57
75
20
25
—
7
19
t
N
H
60
(R2 = H) 37e
tracese
◦
Not including 11 min “ramp time” ( 10 C min-1). b Yields refer to pure isolated compounds. c The reaction performed without catalyst under
a
~
=
conventional heating at 110 ◦C overnight gave only the isoquinoline 2h in 35% yield. d Catalysed with AgNO3 (10 mol%). e Desilylated product.
corresponding nucleus. The results showed a slight shift of the C
carbonyl signal at higher frequencies (+0.227 ppm), indicating a
weak interaction between the metal and the carbonyl oxygen with
consequent deshielding of the carbonyl carbon.27
A second dynamic experiment has been performed by recording
the H NMR spectrum of acetophenone in deuterated methanol
at different times with and without the catalyst. The spectra of the
sample containing AgOTf (50 mol%) displayed gradual reduction
1
7840 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 3 Proposed reaction mechanism.
and increasing complexity of the methyl signal of acetophenone
due to progressive deuteration, and the simultaneous rise of the
integral for the signal of the OH of solvent (Table 4 and Fig. 2). This
behavior was not observed in the control experiment, supporting
the hypothesis that the catalyst is able to speed up the tautomeric
equilibria.
and carbo-cyclisation products with a general preference for the
former. A variety of substituted 1-methylisoquinolines and 5-
methyl-1,6-naphthyridines can be synthesized by this approach.
Simple NMR experiments strongly supported the hypothesis that
silver triflate exerts the dual role of s- and p-philic Lewis acid.
Experimental
Conclusions
General
In summary, we found that silver triflate is the catalyst of
choice for the microwave-promoted domino nucleophilic ad-
dition/annulation reaction of a wide variety of 2-alkynyl-
acetophenones and 3-acetyl-2-alkynylpyridines in the presence of
ammonia. In most cases the reactions gave mixtures of imino-
All chemicals and solvents are commercially available. Silica gel
F254 thin-layer plates were employed for thin layer chromatog-
raphy (TLC). Silica gel 40–63 micron/60A was employed for
flash column chromatography. Melting points are uncorrected.
Table 4 Dynamic 1H NMR study
Acetophenone in CD3OD
Integral (ref. to 2 CH arom.)
Acetophenone + AgOTf (50 mol%) in CD3OD
Integral (ref. to 2 CH arom.)
Time/h
CH3-CO-Ph
CD3OH
CH3-CO-Ph
CD3OH
0
3.08
3.11
3.05
3.07
3.09
1.01
1.12
1.09
1.10
1.11
3.30
2.94
2.81
1.92
1.30
2.19
2.40
3.55
4.42
5.05
16
21
44
65
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7836–7848 | 7841
©

View Article Online
Fig. 2 Selected spectra of the dynamic 1H NMR study.
Infrared spectra were recorded on a FT-IR spectrophotometer
using KBr tablets for solids and NaCl disks for oils. Proton
NMR spectra were recorded at room temperature in CDCl3, at
200, 300 or 500 MHz, with residual chloroform as the internal
reference (dH = 7.26 ppm). 13C NMR spectra were recorded at
room temperature in CDCl3 at 50.3, 75.45 or 125.75 MHz, with
the central peak of chloroform as the internal reference (dC = 77.3
ppm). The APT sequence was used to distinguish the methine and
methyl carbon signals from those due to methylene and quaternary
carbons. All 13C NMR spectra were recorded with complete proton
decoupling. Microwave-assisted reactions were performed with a
MILESTONE microSYNT multimode labstation, using 12 mL
sealed glass vessels. The internal temperature was detected with a
fiber optic sensor.
1H, arom. J = 8.8) ppm. These data are in good agreement with
literature values.31
2-Bromo-5-fluoroacetophenone 4c. Colorless oil. 1H NMR
(CDCl3, 200 MHz): d = 2.63 (s, 3H, CH3), 7.03 (ddd, 1H, arom.
J = 8.8, 7.7, 2.9), 7.18 (dd, 1H, arom. J = 8.4, 2.9), 7.58 (dd, 1H,
arom. J = 8.8, 4.7) ppm. These data are in good agreement with
literature values.29
2-Bromo-3-acetylpyridine 4d. Pale yellow oil. 1H NMR
(CDCl3, 200 MHz): d = 2.68 (s, 3H, CH3), 7.36 (dd, 1H, arom.
J = 7.7, 4.7), 7.76 (dd, 1H, arom. J = 7.7, 2.2), 8.45 (dd, 1H, arom.
J = 4.7, 2.2) ppm. These data are in good agreement with literature
values.25,32
General procedure for the synthesis of 2-alkynylacetophenones
1a–m and 3-acetyl-2-alkynylpyridines 1n–t. Under a nitrogen
atmosphere, to a solution 2-bromoacetophenone or 2-bromo-
3-acetylpyridine (5.00 mmol) in TEA (20 mL) the appropriate
alkyne (6.00 mmol) and trans-dichlorobis(triphenylphosphine)-
palladium(II) (0.10 mmol) were added. The reaction was stirred
at rt for 15 min, then CuI (0.05 mmol) was added. The reaction
Compounds 6b–d are known compounds and were prepared
following the method reported in ref. 15b.
1-(2-Bromo-5-methoxyphenyl)ethanol 6b. Yellow wax. 1H
NMR (CDCl3, 200 MHz): d = 1.47 (d, 3H, CH3, J = 6.2 Hz),
1.98 (br, 1H, OH), 3.81 (s, 3H, CH3), 5.19 (q, 1H, CH, J = 6.2
Hz), 6.69 (dd, 1H, arom. J = 8.8, 3.3), 7.16 (d, 1H, arom. J = 2.9),
7.40 (dd, 1H, arom. J = 8.7, 5.1) ppm. These data are in good
agreement with literature values.28
◦
mixture was stirred at 80 C (see Table 2) until no more starting
product was detectable by TLC analysis (eluent: hexane/EtOAc
(95 : 5)). Then, the solvent was evaporated under reduced pressure
and the crude purified by flash chromatography over a silica gel
column (for times and yields see Table 2).
1-(2-Bromo-5-fluorophenyl)ethanol 6c. Yellow oil. 1H NMR
(CDCl3, 200 MHz): d = 1.47 (d, 3H, CH3, J = 6.2 Hz), 2.00 (br,
1H, OH), 5.18 (q, 1H, CH, J = 6.4 Hz), 6.85 (ddd, 1H, arom. J =
8.8, 7.7, 3.3), 7.34 (dd, 1H, arom. J = 9.5, 2.9), 7.46 (dd, 1H, arom.
J = 8.7, 5.1) ppm. These data are in good agreement with literature
values.29
1-(2-(p-Tolylethynyl)phenyl)ethanone 1a. Eluent for chro-
matography: hexane/EtOAc (97 : 3). Yellow solid. Mp: 45–46 ◦C.
1
IR (KBr): n = 2214, 1687 cm-1. H NMR (CDCl3, 200 MHz):
1-(2-Bromopyridin-3-yl)ethanol 6d. Yellow oil. 1H NMR
(CDCl3, 200 MHz): d = 1.50 (d, 3H, CH3, J = 6.2 Hz), 1.98 (br,
1H, OH), 5.18 (q, 1H, CH, J = 6.2 Hz), 7.30 (dd, 1H, arom. J =
7.7, 4.7), 7.92 (dd, 1H, arom. J = 7.7, 1.8), 8.26 (dd, 1H, arom. J =
4.7, 1.8) ppm. These data are in good agreement with literature
values.25,30
d = 2.38 (s, 3H, CH3), 2.80 (s, 3H, CH3), 7.18 (d, 2H, arom., J =
8.1 Hz), 7.34–7.51 (m, 4H, arom.), 7.62 (d, 1H, arom., J = 7.2
Hz), 7.75 (d, 1H, arom., J = 7.2 Hz) ppm. 13C NMR (CDCl3,
50.3 MHz): d = 21.8, 30.3, 88.2, 95.6, 120.0, 122.2, 128.3, 128.9,
129.5, 131.5, 131.7, 134.0, 139.3, 140.9, 200.7 ppm. ESI-MS m/z:
235 ((M + 1)+, (100)), 102 (13). Calcd for C17H14O (234.29): C,
87.15; H, 6.02. Found: C, 87.11; H, 6.01. These data are in good
agreement with literature values.11a
Compounds 4b–d are known compounds and were prepared
following the methods reported in ref. 25
1
2-Bromo-5-methoxyacetophenone 4b. Colorless oil. H NMR
1-(2-(Phenylethynyl)phenyl)ethanone 1b. Eluent for chro-
matography: hexane/EtOAc (98 : 2). Orange oil. 1H NMR
(CDCl3, 200 MHz): d = 2.79 (s, 3H, CH3), 7.33–7.48 (m, 5H,
(CDCl3, 200 MHz): d = 2.63 (s, 3H, CH3), 3.81 (s, 3H, CH3), 6.85
(dd, 1H, arom. J = 8.8, 2.6), 6.97 (d, 1H, arom. J = 2.9), 7.48 (d,
7842 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
arom.), 7.51–7.57 (m, 2H, arom.), 7.61 (dd, 1H, arom. J = 7.6,
1.1), 7.74 (dd, 1H, arom. J = 7.8, 1.2) ppm. These data are in good
agreement with literature values.11a
50.3 MHz): d = 14.2, 19.9, 22.4, 28.3, 30.3, 31.4, 79.8, 97.1, 122.7,
127.7, 128.5, 131.3, 134.2, 141.2, 201.3 ppm. ESI-MS m/z: 215
((M + 1)+, (100)). Calcd for C15H18O (214.30): C, 84.07; H, 8.47.
Found: C, 83.95; H, 8.41.
1-(2-((4-Methoxyphenyl)ethynyl)phenyl)ethanone 1c. Eluent
for chromatography: hexane/EtOAc (98 : 2). Orange oil. IR
(neat): n = 2213, 1683 cm-1. 1H NMR (CDCl3, 200 MHz): d = 2.79
(s, 3H, CH3), 3.83 (s, 3H, CH3), 6.89 (d, 2H, arom. J = 9.2 Hz),
7.32–7.52 (m, 4H, arom.), 7.60 (d, 1H, arom., J = 7.9 Hz), 7.74 (d,
1H, arom., J = 7.0 Hz) ppm. These data are in good agreement
with literature values.11a,33
1-(2-(Oct-1-ynyl)phenyl)ethanone 1i. Eluent for chromatogra-
1
phy: hexane/EtOAc (98 : 2). Pale yellow oil. H NMR (CDCl3,
200 MHz): d = 0.90 (t, 3H, CH3, J = 6.5), 1.25–1.69 (m, 8H, CH2),
2.45 (t, 2H, CH2, J = 7.0), 2.72 (s, 3H, CH3), 7.27–7.50 (m, 3H,
arom.), 7.66 (dd, 1H, arom. J = 7.7, 1.5) ppm. These data are in
good agreement with literature values.34
1-(2-((4-Methoxy-2-methylphenyl)ethynyl)phenyl)ethanone 1d.
Eluent for chromatography: hexane/EtOAc (97 : 3). Orange oil.
IR (neat): n = 2205, 1688 cm-1. 1H NMR (CDCl3, 200 MHz): d =
2.52 (s, 3H, CH3), 2.78 (s, 3H, CH3), 3.81 (s, 3H, O-CH3), 6.71 (s,
1H, arom.), 6.76 (d, 1H, arom., J = 7.2 Hz), 7.32–7.50 (m, 3H,
arom.), 7.60 (d, 1H, arom., J = 7.2 Hz), 7.75 (d, 1H, arom., J =
8.1 Hz) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 21.3, 30.2, 55.5,
91.1, 94.6, 111.6, 115.2, 115.4, 122.6, 128.0, 128.8, 131.4, 133.6,
134.1, 140.5, 142.5, 160.2, 200.7 ppm. ESI-MS m/z: 265 ((M +
1)+, (100)). Calcd for C18H16O2 (264.32): C, 81.79; H, 6.10. Found:
C, 81.71; H, 6.06.
1-(2-(Dec-1-ynyl)phenyl)ethanone 1j. Eluent for chromatogra-
phy: hexane/EtOAc (99 : 1). Yellow oil. H NMR (CDCl3, 200
1
MHz): d = 0.87 (t, 3H, CH3, J = 7.0), 1.20–1.35 (m, 8H, CH2),
1.44–1.64 (m, 6H, CH2), 2.43 (t, 2H, CH2, J = 7.0), 2.71 (s, 3H,
CH3), 7.31 (t, 1H, arom., J = 7.6), 7.37 (t, 1H, arom., J = 7.6), 7.47
(t, 1H, arom., J = 7.6), 7.65 (t, 1H, arom., J = 7.8) ppm. These
data are in good agreement with literature values.34b
1-(2-((1-Hydroxycyclohexyl)ethynyl)phenyl)ethanone 1k. Elu-
ent for chromatography: hexane/EtOAc (85 : 15). Orange oil. IR
1
(neat): n = 2935, 2219, 1685 cm-1. H NMR (CDCl3, 200 MHz):
d = 1.24–1.28 (m, 2H, CH2), 1.40–2.05 (m, 8H, CH2), 2.43 (br, 1H,
OH), 2.70 (s, 3H, CH3), 7.31–7.54 (m, 3H, arom.), 7.69 (dd, 1H,
arom. J = 6.9, 2.2) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 23.3,
23.4, 25.2, 25.4, 30.1, 39.8, 39.9, 69.3, 83.3, 99.0, 121.6, 128.4,
128.7, 131.4, 134.4, 140.9, 200.6 ppm. ESI-MS m/z: 225 ((M +
1 -OH)+, (100)). Calcd for C16H18O2 (242.33): C, 79.31; H, 7.49.
Found: C, 79.24; H, 7.48.
1-(2-((4-Chlorophenyl)ethynyl)phenyl)ethanone 1e. Eluent for
chromatography: hexane/EtOAc (98 : 2). Orange solid. Mp: 61–
62 ◦C. IR (KBr): n = 2211, 1672 cm-1. 1H NMR (CDCl3, 200 MHz):
d = 2.76 (s, 3H, CH3), 7.31–7.37 (m, 2H, arom.), 7.40–7.52 (m, 4H,
arom.), 7.60 (dd, 1H, arom., J = 7.3, 1.5 Hz), 7.74 (dd, 1H, arom.,
J = 7.3, 1.8 Hz) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 30.0, 89.6,
93.8, 121.6, 121.7, 128.7, 129.0, 129.1, 131.6, 133.0, 134.1, 135.0,
140.8, 200.3 ppm. ESI-MS m/z: 255 ((M + 1)+, (100)). Calcd for
C16H11ClO (254.17): C, 75.45; H, 4.35. Found: C, 75.38; H, 4.39
1-(5-Methoxy-2-(pent-1-ynyl)phenyl)ethanone 1l. Eluent for
chromatography: hexane/EtOAc (98 : 2). Brown oil. IR (neat): n =
1
3306, 2963, 2230, 1682 cm-1. H NMR (CDCl3, 200 MHz): d =
1-(2-((3-Fluorophenyl)ethynyl)phenyl)ethanone 1f. Eluent for
1.05 (t, 3H, CH3, J = 7.0), 1.54–1.69 (m, 2H, CH2), 2.42 (t, 2H,
CH2, J = 7.0), 2.74 (s, 3H, CH3), 3.83 (s, 3H, CH3), 6.95 (dd, 1H,
arom. J = 8.4, 2.9), 7.18 (d, 1H, arom., J = 2.9), 7.34 (dd, 1H,
arom., J = 8.4) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 13.7,
21.8, 22.2, 30.2, 55.6, 79.8, 95.2, 112.8, 115.1, 118.0, 135.5, 142.7,
159.1, 200.9 ppm. ESI-MS m/z: 217 ((M + 1)+, (100)). Calcd for
C14H13O2 (216.15): C, 77.75; H, 7.46. Found: C, 77.82; H, 7.47
chromatography: hexane/EtOAc (97 : 3). Yellow oil. IR (neat):
1
n = 1689 cm-1. H NMR (CDCl3, 200 MHz): d = 2.76 (s, 3H,
CH3), 7.06, (m, 1H, arom.), 7.21–7.53 (m, 5H, arom.), 7.62 (dd,
1H, arom. J = 7.3, 1.5), 7.76 (dd, 1H, arom. J = 7.2, 2.0) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 30.0, 89.5, 93.6 (d, 4JC-F = 3.4),
116.3 (d, 2JC-F = 21), 118.2 (d, 2JC-F = 23), 121.4, 125.0 (d, 3JC-F
=
9.5), 127.7 (d, 4JC-F = 3.1), 128.8, 129.0, 130.3 (d, 3JC-F = 8.4), 131.6,
134.2, 141,0, 162.7 (d, 1JC-F = 247), 200.1 ppm. ESI-MS m/z: 239
((M + 1)+, (100)). Calcd for C16H11FO (238.26): C, 80.66; H, 4.65.
Found: C, 80.56; H, 4.62.
1-(5-Fluoro-2-(pent-1-ynyl)phenyl)ethanone 1m. Eluent for
chromatography: hexane/EtOAc (98 : 2). Brown oil. IR (neat): n =
2965, 2234, 1686 cm-1. 1H NMR (CDCl3, 200 MHz): d = 1.05 (t,
3H, CH3, J = 7.0), 1.55–1.69 (m, 2H, CH2), 2.42 (t, 2H, CH2, J =
7.0), 2.77 (s, 3H, CH3), 7.05–7.14 (m, 1H, arom.), 7.33–7.50 (m,
2H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 13.7, 21.8,
22.1, 30.2, 79.0, 96.7, 115.3 (d, 2JC-F = 23.2), 118.5 (d, 2JC-F = 22.1),
4-((2-Acetylphenyl)ethynyl)benzonitrile 1g. Eluent for chro-
matography: hexane/EtOAc (92 : 8). Orange solid. Mp: 85–86 ◦C.
1
IR (KBr): n = 2226, 1672 cm-1. H NMR (CDCl3, 200 MHz):
d = 2.72 (s, 3H, CH3), 7.41–7.61 (m, 2H, arom.), 7.63–7.77 (m,
5H, arom.), 7.80 (dd, 1H, arom., J = 6.7, 1.8 Hz) ppm. 13C NMR
(CDCl3, 50.3 MHz): d = 29.7, 92.7, 92.9, 112.1, 118.6, 120.8, 128.1,
129.2, 129.3, 131.7, 132.3, 132.4, 134.4, 140.8, 199.5 ppm. ESI-MS
m/z: 246 ((M + 1)+, (100)). Calcd for C17H11NO (245.28): C, 83.25;
H, 4.52; N, 5.71. Found: C, 83.42; H, 4.50; N, 5.67.
118.9, 136.1 (d, 3JC-F = 7.6), 143.2 (d, 3JC-F = 6.5), 161.9 (d, 1JC-F
=
247), 199.6 ppm. ESI-MS m/z: 205 ((M + 1)+, (50)), 176 (100).
Calcd for C13H13FO (204.24): C, 76.45; H, 6.42. Found: C, 76.38;
H, 6.39
1-(2-(p-Tolylethynyl)pyridin-3-yl)ethanone 1n. Eluent for chro-
◦
matography: hexane/EtOAc (9 : 1). Brown solid. Mp: 50–51 C.
1-(2-(Hept-1-ynyl)phenyl)ethanone 1h. Eluent for chromatog-
raphy: hexane/EtOAc (98 : 2). Yellow oil. IR (neat): n = 2232, 1685
cm-1. 1H NMR (CDCl3, 200 MHz): d = 0.92 (t, 3H, CH3, J = 6.9
Hz), 1.25–1.47 (m, 4H, 2 CH2), 1.58–1.67 (m, 2H, CH2), 2.45 (t,
2H, CH2, J = 7.7), 2.72 (s, 3H, CH3), 7.31–7.50 (m, 3H, arom.),
7.64 (dd, 1H, arom., J = 6.9, 1.8 Hz) ppm. 13C NMR (CDCl3,
IR (KBr): n = 2924, 2215, 1675, 1552 cm-1. 1H NMR (CDCl3, 200
MHz): d = 2.38 (s, 3H, CH3), 2.85 (s, 3H, CH3), 7.19 (d, 2H, arom.,
J = 8.1 Hz), 7.34 (dd, 1H, arom. J = 7.7, 4.7), 7.51 (d, 2H, arom.,
J = 8.1 Hz), 8.06 (dd, 1H, arom. J = 8.0, 1.8), 8.73 (dd, 1H, arom.
J = 4.7, 1.5) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 21.8, 30.3,
87.8, 95.7, 118.9, 122.75, 129.6, 132.7, 136.7, 136.8, 140.2, 141.4,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7836–7848 | 7843
©

View Article Online
152.5, 199.4 ppm. ESI-MS m/z: 236 ((M + 1)+, (50)), 221 (100).
Calcd for C16H13NO (235.28): C, 81.68; H, 5.57; N, 5.95. Found:
C, 81.60; H, 5.59; N, 5.92. These data are in good agreement with
literature values.11a
NMR (CDCl3, 50.3 MHz): d = 23.2, 25.3, 30.1, 39.7, 69.0, 82.8,
99.6, 122.9, 136.4, 137.1, 140.7, 152.1, 199.2 ppm. ESI-MS m/z:
244 ((M + 1)+, (100)). Calcd for C15H17NO2 (243.30): C, 74.05; H,
7.04; N, 5.76. Found: C, 73.98; H, 7.02; N, 5.71.
1-(2-((4-Methoxyphenyl)ethynyl)pyridin-3-yl)ethanone
1o.
1-(2-((Trimethylsilyl)ethynyl)pyridin-3-yl)ethanone 1t. Eluent
for chromatography: hexane/EtOAc (8.5 : 1.5). Yellow oil. IR
(neat): n = 3369, 2961, 2168, 1689, 1417 cm-1. 1H NMR (CDCl3,
200 MHz): d = 0.29 (s, 9H, 3 CH3), 2.81 (s, 3H, CH3), 7.34 (dd,
1H, arom. J = 8.0, 4.7), 8.01 (dd, 1H, arom. J = 8.0, 1.8), 8.69 (dd,
1H, arom. J = 4.7, 1.8) ppm. 13C NMR (CDCl3, 50.3 MHz): d =
-0.4, 30.2, 102.1, 103.0, 123.2, 136.5, 137.7, 140.7, 152.2, 199.4
ppm. ESI-MS m/z: 218 ((M + 1)+, (100)). Calcd for C12H15SiNO
(217.09): C, 66.31; H, 6.96; N, 6.44. Found: C, 66.24; H, 6.97; N,
6.41. These data are in good agreement with literature values.15b
Eluent for chromatography: hexane/EtOAc (98 : 2). Brown oil.
IR (neat): n = 3369, 2964, 2936, 2217, 1682, 1553 cm-1. 1H NMR
(CDCl3, 200 MHz): d = 2.85 (s, 3H, CH3), 3.84 (s, 3H, CH3), 6.91
(d, 2H, arom., J = 8.7 Hz), 7.32 (dd, 1H, arom. J = 8.0, 4.7), 7.56
(d, 2H, arom., J = 8.7 Hz), 8.05 (dd, 1H, arom. J = 8.0, 1.5),
8.71 (dd, 1H, arom. J = 4.7, 1.8) ppm. 13C NMR (CDCl3, 50.3
MHz): d = 30.2, 55.5, 87.5, 95.7, 114.1, 114.5, 122.4, 133.8, 136.5,
136.8, 141.6, 152.3, 160.9, 199.2 ppm. ESI-MS m/z: 252 ((M +
1)+, (100)). Calcd for C16H13NO2 (251.14): C, 76.48; H, 5.21; N,
5.57. Found: C, 76.53; H, 5.19; N, 5.54.
General procedure for microwave-assisted/AgOTf-catalyzed cy-
clization reaction of 2-alkynylacetophenones 1a–m and 3-acetyl-2-
alkynylpyridines 1n–t. In a sealed tube, a well stirred solution of
the appropriate 2-alkynylacetophenone (1 a–m) (0.359 mmol) or
3-acetyl-2-alkynylpyridines (1 n–t) and AgOTf (0.009 mg, 0.036
mmol) in dry ammonia in methanol (NH3/MeOH 2 M solution,
3.59 mL, 7.18 mmol), was heated at 120 ◦C in a multimode
microwave oven, until no more starting product was detectable
by TLC. The reaction mixture was evaporated to dryness and the
crude purified by flash chromatography over a silica gel column
yielding progressively the 3-substituted-1-methylisoquinoline (2a–
m) and the 3-substituted-1-naphthalenamine (3a–m), or the 1,6-
naphthyridine (2n–t) and the quinolin-5-amine (3n–s), respectively
(for times and yields see Table 3).
1-(2-((3-(Trifluoromethyl)phenyl)ethynyl)pyridin-3-yl)ethanone
1p. Eluent for chromatography: hexane/EtOAc (8 : 2). Brown
1
oil. IR (neat): n = 3369, 2929, 2220, 1683, 1556 cm-1. H NMR
(CDCl3, 200 MHz): d = 2.82 (s, 3H, CH3), 7.39 (dd, 1H, arom.
J = 8.0, 4.7), 7.47–7.55 (m, 1H, arom.), 7.65 (d, 1H, arom., J = 8.1
Hz), 7.79 (d, 1H, arom., J = 7.7 Hz), 7.87 (s, 1H, arom.), 8.07 (dd,
1H, arom. J = 8.0, 1.8), 8.74 (dd, 1H, arom. J = 4.7, 1.8) ppm.13C
NMR (CDCl3, 50.3 MHz): d = 29.9, 89.5, 92.8, 123.1, 123.2, 123.8
(q, 1JC-F = 272 Hz), 126.2 (q, 3JC-F = 3.81 Hz), 128.9 (q, 3JC-F = 3.81
2
Hz), 129.3, 131.5 (q, JC-F = 32.8 Hz), 135.2, 136.6, 137.1, 140.6,
152.5, 198.5 ppm. ESI-MS m/z: 290 ((M + 1)+, (100)). Calcd for
C16H10F3NO (289.25): C, 66.44; H, 3.48; N, 4.84. Found: C, 66.38;
H, 3.48; N, 4.84.
1-(2-(Hept-1-ynyl)pyridin-3-yl)ethanone 1q. Eluent for chro-
matography: hexane/EtOAc (8 : 2). Yellow oil. IR (neat): n = 3369,
2932, 2227, 1684, 1423 cm-1. 1H NMR (CDCl3, 200 MHz): d = 0.90
(t, 3H, CH3, J = 7.0), 1.25–1.59 (m, 4H, 2 CH2), 1.63–1.73 (m, 2H,
CH2), 2.50 (t, 2H, CH2, J = 7.0), 2.77 (s, 3H, CH3), 7.28 (dd, 1H,
arom. J = 8.0, 4.7), 7.97 (dd, 1H, arom. J = 8.0, 1.8), 8.64 (dd, 1H,
arom. J = 4.7, 1.8) ppm.13C NMR (CDCl3, 50.3 MHz): d = 13.9,
19.8, 22.3, 27.9, 30.1, 31.4, 80.1, 97.9, 122.3, 136.3, 137.1, 141.6,
152.1, 199.7 ppm. ESI-MS m/z: 216 ((M + 1)+, (100)). Calcd for
C14H17NO (215.29): C, 78.10; H, 7.96; N, 6.51. Found: C, 78.18;
H, 7.99; N, 6.48.
1-Methyl-3-p-tolylisoquinoline4 2a. Eluent for chromatogra-
phy: hexane/EtOAc (95 : 5). Brown wax. IR (KBr): n = 3056, 2920,
1
1621 cm-1. H NMR (CDCl3, 200 MHz): d = 2.43 (s, 3H, CH3),
3.04 (s, 3H, CH3), 7.30 (d, 2H, arom. J = 8.1 Hz), 7.05–7.69 (m, 2H,
arom.), 7.86 (t, 2H, arom. J = 7.0 Hz), 8.07 (t, 2H, arom. J = 8.4
Hz), 8.14 (s, 1H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): d =
21.5, 22.9, 114.9, 125,9, 126.7, 126.8, 127.0, 127.8, 129.7, 130.2,
137.0, 137.3, 138.4, 150.3, 158.7 ppm. ESI-MS m/z: 234 ((M +
1)+, (100)). Calcd for C17H15N (233.31): C, 87.52; H, 6.48; N, 6.00.
Found: C, 87.45; H, 6.42; N, 6.03.
1-Methyl-3-phenylisoquinoline 2b. Eluent for chromatogra-
phy: hexane/EtOAc (97 : 3). Brown oil. IR (neat): n = 3058, 2920,
1-(2-(Oct-1-ynyl)pyridin-3-yl)ethanone 1r. Eluent for chro-
matography: hexane/EtOAc (8 : 2). Brown oil. IR (neat): n = 3369,
1
1622, 1569, 1441, 1029 cm-1. H NMR (CDCl3, 200 MHz): d =
1
2931, 2229, 1686, 1423 cm-1. H NMR (CDCl3, 200 MHz): d =
3.05 (s, 3H, CH3), 7.39–7.64 (m, 5H, arom.), 7.86 (d, 1H, arom. J =
7.7), 7.92 (s, 1H, arom.), 8.14 (dd, 3H, arom. J = 8.1, 1.1 Hz) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 22.9, 115.5, 125.9, 126.8, 127.0,
127.2, 127.8, 128.5, 128.9, 130.3, 137.0, 140.0, 150.2, 158.8 ppm.
ESI-MS m/z: 220 ((M + 1)+, (100)). Calcd for C16H13N (219.28):
C, 87.64; H, 5.98; N, 6.39. Found: C, 87.76; H, 5.94; N, 6.34.
0.90 (t, 3H, CH3, J = 7.0), 1.25–1.49 (m, 6H, 3 CH2), 1.61–1.70
(m, 2H, CH2), 2.50 (t, 2H, CH2, J = 7.0), 2.77 (s, 3H, CH3), 7.29
(dd, 1H, arom. J = 8.0, 4.7), 7.97 (dd, 1H, arom. J = 8.0, 1.8),
8.65 (dd, 1H, arom. J = 4.7, 1.8) ppm.13C NMR (CDCl3, 50.3
MHz): d = 14.2, 19.9, 22.7, 28.2, 28.9, 30.3, 31.5, 80.1, 97.9, 122.4,
136.4, 136.9, 141.5, 152.2, 199.8 ppm. ESI-MS m/z: 230 ((M + 1)+,
(100)). Calcd for C15H19NO (229.32): C, 78.56; H, 8.35; N, 6.11.
Found: C, 78.44; H, 8.39; N, 6.15.
3-(4-Methoxyphenyl)-1-methylisoquinoline 2c. Eluent for
chromatography: hexane/EtOAc (96 : 4). Brown solid. Mp:
125–129 ◦C (dec.). IR (KBr): n = 3022, 2924, 1605, 1567, 1513,
1
1-(2-((1-Hydroxycyclohexyl)ethynyl)pyridin-3-yl)ethanone 1s.
Eluent for chromatography: hexane/EtOAc (1 : 1). Brown oil. IR
(neat): n = 3368, 2935, 2222, 1694, 1424 cm-1. 1H NMR (CDCl3,
200 MHz): d = 1.24–2.12 (m, 10H, 5 CH2), 2.76 (s, 3H, CH3),
2.81 (s, 1H, OH), 7.32 (dd, 1H, arom. J = 8.0, 4.7), 7.99 (dd, 1H,
arom. J = 8.0, 1.8), 8.68 (dd, 1H, arom. J = 4.7, 1.8) ppm.13C
1439, 1248, 1175, 1030, 835 cm-1. H NMR (CDCl3, 200 MHz):
d = 3.03 (s, 3H, CH3), 3.88 (s, 3H, CH3), 7.03 (d, 2H, arom. J =
8.9 Hz), 7.53 (ddd, 1H, arom. J = 8.1, 6.9, 1.3 Hz), 7.65 (ddd, 1H,
arom. J = 8.2, 6.9, 1.3 Hz), 7.82 (d, 1H, arom. J = 7.6), 7.84 (s,
1H, arom.), 8.07–8.13 (m, 3H, arom.) ppm. 13C NMR (CDCl3,
50.3 MHz): d = 22.9, 55.6, 114.3, 114.4, 125.9, 126.4, 126.6, 127.7,
7844 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
128.4, 130.2, 132.8, 137.1, 150.0, 158.6, 160.2 ppm. ESI-MS m/z:
250 ((M + 1)+, (100)), 235 (8). Calcd for C17H15NO (249.31): C,
81.90; H, 6.06; N, 5.62. Found: C, 81.84; H, 6.03; N, 5.62.
30.4, 32.3, 38.5, 116.9, 125.9, 126.2, 126.4, 127.2, 130.2, 137.1,
154.9, 158.4 ppm. ESI-MS m/z: 256 ((M + 1)+, (100)). Calcd for
C18H25N (255.40): C, 84.65; H, 9.87; N, 5.48. Found: C, 84.72; H,
9.84; N, 5.50.
3-(4-Methoxy-2-methylphenyl)-1-methylisoquinoline 2d. Elu-
ent for chromatography: hexane/EtOAc (96 : 4). Light brown
solid. Mp: 107–110 ◦C. IR (KBr): n = 2953, 2921, 1707, 1608,
1-(1-Methylisoquinolin-3-yl)cyclohexanol 2k. Eluent for chro-
matography: hexane/EtOAc (9 : 1). Violet solid. Mp: 89–92 ◦C. IR
(KBr): n = 3398, 2920, 2853, 1627, 1591, 1569, 1446, 1415, 1386,
1
1567, 1505, 1442, 1241, 1162, 1045, 751 cm-1. H NMR (CDCl3,
1
200 MHz): d = 3.41 (s, 3H, CH3), 3.01 (s, 3H, CH3), 3.85 (s, 3H,
CH3), 6.82–6.86 (m, 2H, arom.), 7.45 (d, 1H, arom. J = 9.2 Hz),
7.55–7.71 (m, 3H, arom.), 7.82 (d, 1H, arom. J = 7.8 Hz), 8.15 (d,
1H, arom. J = 7.7) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 21.1,
22.7, 55.5, 111.5, 116.4, 118.8, 125.8, 126.1, 126.9, 127.6, 130.2,
131.5, 133.9, 136.7, 138.0, 152.5, 158.1, 159.6 ppm. ESI-MS m/z:
264 ((M + 1)+, (100)), 249 (5). Calcd for C18H17NO (263.33): C,
82.10; H, 6.51; N, 5.32. Found: C, 81.97; H, 6.48; N, 5.35.
742 cm-1. H NMR (CDCl3, 200 MHz): d = 1.22–1.41 (m, 2H,
CH2), 1.56–1.99 (m, 8H, 4 CH2), 2.96 (s, 3H, CH3), 5.12 (bs, 1H,
OH), 7.50–7.65 (m, 3H, arom.), 7.78 (d, 1H, arom. J = 7.7 Hz),
8.01 (dd, 1H, arom. J = 7.7, 1.1 Hz) ppm. 13C NMR (CDCl3, 50.3
MHz): d = 22.6, 22.7, 26.2, 39.2, 72.7, 113.6, 126.0, 126.7, 126.9,
127.8, 130.4, 137.2, 157.4, 158.8 ppm. ESI-MS m/z: 242 ((M + 1)+,
(100)). Calcd for C16H19NO (241.33): C, 79.63; H, 7.94; N, 5.80.
Found: C, 79.54; H, 7.97; N, 5.76.
3-(4-Chlorophenyl)-1-methylisoquinoline 2e. Eluent for chro-
matography: hexane/EtOAc (98 : 2). Brown oil. IR (neat): n =
3369, 2924, 1622 cm-1. 1H NMR (CDCl3, 200 MHz): d = 3.03 (s,
3H, CH3), 7.47 (d, 2H, arom. J = 8.8 Hz), 7.51–7.71 (m, 2H, arom.),
7.85 (d, 1H, arom. J = 7.3 Hz), 7.89 (s, 1H, arom.), 8.05–8.15 (m,
3H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 22.8, 115.3,
125.9, 126.9, 127.2, 127.8, 128.4, 129.1, 130.4, 134.6, 136.9, 138.5,
148.9, 158.9 ppm. ESI-MS m/z: 254 ((M + 1)+, (100)). Calcd for
C16H12NCl (253.73): C, 75.74; H, 4.77; N, 5.52. Found: C, 75.65;
H, 4.75; N, 5.54.
7-Methoxy-1-methyl-3-propylisoquinoline 2l. Eluent for chro-
matography: hexane/EtOAc (9 : 1). Brown solid. Mp: 99–100 ◦C.
IR (KBr): n = 3369, 2958, 2929, 2871, 1597, 1572, 1411, 1227
cm-1. 1H NMR (CDCl3, 200 MHz): d = 1.00 (t, 3H, CH3, J = 6.9),
1.75–1.86 (m, 2H, CH2), 2.84 (t, 2H, CH2, J = 7.7), 2.91 (s, 3H,
CH3), 3.95 (s, 3H, CH3), 7.26–7.32 (m, 3H, arom.), 7.62 (dd, 1H,
arom. J = 9.1, 1.1 Hz) ppm. 13C NMR (CDCl3, 50.3 MHz): d =
14.0, 22.6, 23.4, 40.2, 55.6, 103.9, 116.5, 122.6, 126.9, 128.5, 132.4,
152.7,156.5, 157.8 ppm. ESI-MS m/z: 216 ((M + 1)+, (100)). Calcd
for C14H17N (215.29): C, 78.10; H, 7.96; N, 6.51. Found: C, 78.00;
H, 7.98; N, 6.48.
1-Methyl-3-pentylisoquinoline 2h. Eluent for chromatography:
hexane/EtOAc (98 : 2). Yellow oil. IR (neat): n = 3067, 2954, 2927,
7-Fluoro-1-methyl-3-propylisoquinoline 2m. Eluent for chro-
matography: hexane/EtOAc (95 : 5). Violet wax. IR (KBr): n =
3027, 2954, 2927, 2868, 1593, 1505, 1393, 1184, 878 cm-1. 1H NMR
(CDCl3, 200 MHz): d = 1.00 (t, 3H, CH3, J = 7.3), 1.76–1.87 (m,
2H, CH2), 2.85 (t, 2H, CH2, J = 7.7), 2.89 (s, 3H, CH3), 7.31 (s, 1H,
arom.), 7.35–7.45 (m, 1H, arom.), 7.62–7.76 (m, 2H, arom.) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 14.0, 22.5, 23.3, 40.3, 109.2 (d,
1
2857, 1625, 1591, 1569, 1445, 1390, 747 cm-1. H NMR (CDCl3,
200 MHz): d = 0.90 (t, 3H, CH3, J = 6.9), 1.28–1.46 (m, 4H, 2
CH2), 1.79 (qt, 2H, CH2, J = 7.7), 2.92 (t, 2H, CH2, J = 7.7), 2.94
(s, 3H, CH3), 7.31 (s, 1H, arom.), 7.40–7.63 (m, 2H, arom.), 7.72
(d, 1H, arom. J = 8.0 Hz), 8.00 (d, 1H, arom. J = 8.4 Hz) ppm. 13
C
NMR (CDCl3, 50.3 MHz): d = 14.3, 22.6, 22.8, 29.9, 31.9, 38.4,
116.7, 125.7, 126.0, 126.2, 127.0, 129.9, 136.9, 154.8, 158.2 ppm.
ESI-MS m/z: 214 ((M + 1)+, (100)). Calcd for C15H19N (213.54):
C, 84.46; H, 8.98; N, 6.57. Found:C, 84.42; H, 8.97; N, 6.59.
5
2
2JC-F = 20.9 Hz), 116.4 (d, JC-F = 1.5 Hz), 120.3 (d, JC-F = 25.1
Hz), 126.6 (d, 3JC-F = 7.6 Hz), 129.4 (d, 3JC-F = 8.4 Hz), 133.9, 154.2
(d, 4JC-F = 2.7 Hz), 157.5 (d, 4JC-F = 5.7 Hz), 160.4 (d, 1JC-F = 247
Hz) ppm. ESI-MS m/z: 204 ((M + 1)+, (100)). Calcd for C13H14FN
(203.26): C, 76.82; H, 6.94; N, 6.89. Found: C, 76.89; H, 6.97; N,
6.83.
3-Hexyl-1-methylisoquinoline4 2i. Eluent for chromatography:
hexane/EtOAc (96 : 4). Yellow–green oil. IR (neat): n = 2953, 2925,
1
2855, 1692, 1625, 1590, 1568, 1444, 1390, 747 cm-1. H NMR
(CDCl3, 200 MHz): d = 0.88 (t, 3H, CH3, J = 7.0), 1.31–1.37 (m,
6H, 3 CH2), 1.79 (qt, 2H, CH2, J = 7.6), 2.88 (t, 2H, CH2, J = 7.6),
2.95 (s, 3H, CH3), 7.32 (s, 1H, arom.), 7.50 (ddd, 1H, arom. J =
8.2, 6.8, 1.5 Hz), 7.61 (ddd, 1H, arom. J = 8.2, 6.8, 1.3 Hz), 7.72 (d,
1H, arom. J = 7.5), 8.07 (d, 1H, arom. J = 7.8 Hz) ppm. 13C NMR
(CDCl3, 50.3 MHz): d = 14.3, 22.6, 22.9, 29.4, 30.2, 32.0, 38.5,
116.7, 125.8, 126.1, 126.2, 127.0, 129.9, 136.9, 154.9, 158.2 ppm.
ESI-MS m/z: 228 ((M + 1)+, (100)). Calcd for C16H21N (227.343):
C, 84.53; H, 9.31; N, 6.16. Found: C, 84.41; H, 9.22; N, 6.19.
5-Methyl-7-p-tolyl-1,6-naphthyridine 2n. Eluent for chro-
matography: hexane/EtOAc (8 : 2). Brown wax. IR (KBr): n =
1
3369, 2920, 1605, 1423 cm-1. H NMR (CDCl3, 200 MHz): d =
2.43 (s, 3H, CH3), 3.03 (s, 3H, CH3), 7.30 (d, 2H, arom. J = 8.1),
7.41 (dd, 1H, arom. J = 8.4, 4.4), 8.08 (d, 2H, arom. J = 8.1), 8.14
(s, 1H, arom.), 8.37 (dd, 1H, arom. J = 8.4, 1.5 Hz), 9.08 (dd, 1H,
arom. J = 4.4, 1.5 Hz) ppm.13C NMR (CDCl3, 50.3 MHz): d =
21.4, 22.2, 115.9, 121.6, 121.7, 127.3, 129.7, 133.9, 136.6, 139.1,
152.0, 154.1, 154.5, 159.4 ppm. ESI-MS m/z: 235 ((M + 1)+, (100)).
Calcd for C16H14N2 (234.30): C, 82.02; H, 6.02; N, 11.96. Found:
C, 81.90; H, 5.96; N, 11.99.
1-Methyl-3-octylisoquinoline 2j. Eluent for chromatography:
hexane/EtOAc (98 : 2). Yellow oil. IR (neat): n = 3067, 2953, 2925,
1
2855, 1626, 1591, 1569, 1446, 1391, 747 cm-1. H NMR (CDCl3,
7-(4-Methoxyphenyl)-5-methyl-1,6-naphthyridine 2o. Eluent
300 MHz): d = 0.90 (t, 3H, CH3, J = 6.9), 1.28–1.46 (m, 10H, 5
CH2), 1.79 (qt, 2H, CH2, J = 7.7), 2.88 (t, 2H, CH2, J = 7.7), 2.94
(s, 3H, CH3), 7.31 (s, 1H, arom.), 7.45–7.65 (m, 2H, arom.), 7.72
for chromatography: hexane/EtOAc (8 : 2). Yellow oil. IR (neat):
1
n = 3391, 2957, 2935, 1601, 1575, 1515, 1441 cm-1. H NMR
(CDCl3, 200 MHz): d = 3.02 (s, 3H, CH3), 3.89 (s, 3H, CH3), 7.04
(d, 2H, arom. J = 8.1 Hz), 7.45 (dd, 1H, arom. J = 8.4, 4.4 Hz),
8.11 (s, 1H, arom.), 8.15 (d, 2H, arom. J = 8.1 Hz), 8.42 (dd, 1H,
(d, 1H, arom. J = 8.0 Hz), 8.06 (d, 1H, arom. J = 8.1 Hz) ppm. 13
C
NMR (CDCl3, 75.45 MHz): d = 14.5, 22.6, 23.1, 29.7, 29.8, 29.9,
This journal is The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7836–7848 | 7845
©

View Article Online
arom. J = 8.4, 1.5 Hz), 9.04 (dd, 1H, arom. J = 4.4, 1.8 Hz) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 22.2, 55.5, 114.5, 115.2, 121.4,
127.0, 131.9, 133.8, 133.9, 152.1, 153.7, 154.5, 159.3, 160.8 ppm.
ESI-MS m/z: 251 ((M + 1)+, (100)). Calcd for C16H14N2O (250.29):
C, 76.78; H, 5.64; N, 11.19. Found: C, 76.63; H, 5.69; N, 11.22.
C17H15N (233.31): C, 87.52; H, 6.48; N, 6.00. Found: C, 87.44; H,
6.43; N, 6.08.
3-Phenylnaphthalen-1-amine 3b. Eluent for chromatography:
hexane/EtOAc (97.5 : 2.5). Brown solid. Mp: 79–81 ◦C. IR (KBr):
n = 3435, 2925, 2854, 1626, 1454, 1403, 1075, 763 cm-1. 1H NMR
(CDCl3, 300 MHz): d = 4.26 (bs, 2H, NH2), 7.07 (d, 1H, arom, J =
1.6 Hz), 7.36–7.42 (m, 1H, arom), 7.47–7.54 (m, 4H, arom), 7.56
(s, 1H, arom), 7.71–7.76 (m, 2H, arom.), 7.84–7.89 (m, 2H, arom)
ppm. 13C NMR (CDCl3, 75.45 MHz): d = 109.7, 117.6, 121.1,
123.4, 125.3, 126.7, 127.6, 127.7, 129.1, 129.3, 135.1, 139.6, 141.8,
142.9. ESI-MS m/z: 220 ((M + 1)+, (100)). Calcd for C16H13N
(219.28): C, 87.64; H, 5.98; N, 6.39. Found: C, 87.65; H, 5.99; N,
6.40.
5-Methyl-7-pentyl-1,6-naphthyridine 2q. Eluent for chro-
matography: hexane/EtOAc (8 : 2). Yellow oil. IR (neat): n = 3401,
1
2954, 2927, 1609, 1568 cm-1. H NMR (CDCl3, 200 MHz): d =
0.87 (t, 3H, CH3, J = 6.9), 1.32–1.42 (m, 4H, 2 CH2), 1.75–1.83
(m, 2H, CH2), 2.91 (t, 2H, CH2, J = 7.0), 2.91 (s, 3H, CH3), 7.40
(dd, 1H, arom. J = 8.4, 4.0 Hz), 7.56 (s, 1H, arom.), 8.35 (dd, 1H,
arom. J = 8.4, 1.5 Hz), 8.98 (dd, 1H, arom. J = 4.0, 1.5 Hz) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 14.1, 21.9, 22.7, 29.5, 31.8,
38.5, 118.1, 120.9, 121.2, 133.9, 151.7, 154.3, 158.9, 159.3 ppm.
ESI-MS m/z: 215 ((M + 1)+, (100)). Calcd for C14H18N2 (214.30):
C, 78.46; H, 8.47; N, 13.07. Found: C, 78.38; H, 8.44; N, 13.11.
3-(4-Methoxyphenyl)naphthalen-1-amine 3c. Eluent for chro-
matography: hexane/EtOAc (96 : 4). Dark purple solid. Mp: 125–
129 ◦C (dec.). IR (KBr): n = 3435, 2918, 1625, 1510, 1457, 1402,
1
7-Hexyl-5-methyl-1,6-naphthyridine 2r. Eluent for chromatog-
raphy: hexane/EtOAc (8 : 2). Red oil. IR (neat): n = 3206, 2956,
2926,2856, 1610, 1569, 1379 cm-1. 1H NMR (CDCl3, 200 MHz):
d = 0.87 (t, 3H, CH3, J = 6.9), 1.21–1.87 (m, 8H, 4 CH2), 2.93 (t,
2H, CH2, J = 8.0), 2.93 (s, 3H, CH3), 7.42 (dd, 1H, arom. J = 8.4,
4.2 Hz), 7.58 (s, 1H, arom.), 8.38 (dd, 1H, arom. J = 8.4, 1.5 Hz),
9.00 (dd, 1H, arom. J = 4.2, 1.5 Hz) ppm. 13C NMR (CDCl3, 50.3
MHz): d = 14.3, 21.9, 22.8, 29.3, 29.9, 31.9, 38.5, 118.1, 120.9,
121.3, 134.1, 151.6, 154.1, 159.1, 159.3 ppm. ESI-MS m/z: 229
((M + 1)+, (100)). Calcd for C15H20N2 (228.33): C, 78.90; H, 8.83;
N, 12.27. Found: C, 78.99; H, 8.80; N, 12.23.
1239, 1172, 1110, 1022, 822 cm-1. H NMR (CDCl3, 200 MHz):
d = 3.87 (s, 3H, CH3), 4.37 (bs, 2H, NH2, exchange with D2O), 7.00
(m, 3H, arom.), 7.45 (m, 3H, arom.), 7.63 (d, 2H, arom. J = 8.8
Hz), 7.83 (m, 2H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): d =
55.6, 109.4, 114.4, 116.7, 120.9, 122.9, 124.9, 126.5, 128.6, 129.0,
134.2, 135.0, 139.0, 142.6, 159.4 ppm. ESI-MS m/z: 250 ((M +
1)+, (100)), 235 (6). Calcd for C17H15N (249.31): C, 91.90; H, 6.06;
N, 5.62. Found: C, 91.84; H, 6.01; N, 5.68.
3-(4-Methoxy-2-methylphenyl)naphthalen-1-amine 3d. Eluent
for chromatography: hexane/EtOAc (96 : 4). Brown oil. IR (neat):
n = 3436, 2916, 1626, 1499, 1454, 1288, 1229, 1160, 1115, 1041,
1
1-(5-Methyl-1,6-naphthyridin-7-yl)cyclohexanol 2s. Eluent for
chromatography: hexane/EtOAc (6 : 4). Brown wax. IR (KBr): n =
3399, 3253, 2952, 2927, 2913, 2854, 1609, 1584, 1568, 1448, 1418,
1382 cm-1. 1H NMR (CDCl3, 200 MHz): d = 1.67–1.91 (m, 10H,
5 CH2), 2.96 (s, 3H, CH3), 4.87 (bs, 1H, OH), 7.46 (dd, 1H, arom.
J = 8.4, 4.0), 7.81 (s, 1H, arom.), 8.40 (dd, 1H, arom. J = 8.4, 1.5
Hz), 9.03 (dd, 1H, arom. J = 4.0, 1.5 Hz) ppm. 13C NMR (CDCl3,
50.3 MHz): d = 21.9, 22.4, 25.9, 38.8, 72.8, 115.1, 121.5, 121.9,
134.1, 151.8, 154.7, 158.3, 162.9 ppm. ESI-MS m/z: 243 ((M +
1)+, (100)). Calcd for C15H18N2O (242.32): Found: C, 74.24; H,
7.54; N, 11.59.
822 cm-1. H NMR (CDCl3, 200 MHz): d = 3.31 (s, 3H, CH3),
3.85 (s, 3H, CH3), 4.18 (bs, 2H, NH2, exchange with D2O), 6.79
(m, 3H, arom.), 7.22 (s, 1H, arom.), 7.47 (m, 3H, arom.), 7.82 (m,
2H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 21.1, 55.5,
111.2, 112.2, 115.9, 119.6, 120.9, 122.7, 124.9, 126.4, 128.8, 131.1,
134.6, 135.1, 137.2, 140.1, 141.8, 159.0 ppm. ESI-MS m/z: 264
((M + 1)+, (100)), 249 (7). Calcd for C18H17NO (263.33): C, 82.10;
H, 6.51; N, 5.32. Found: C, 82.01; H, 6.49; N, 5.34.
3-(4-Chlorophenyl)naphthalen-1-amine 3e. Eluent for chro-
matography: hexane/EtOAc (98 : 2 – 9 : 1). Brown oil. IR (neat):
1
n = 3435, 2923, 1625, 1492, 1090, 820 cm-1. H NMR (CDCl3,
5-Methyl-1,6-naphthyridine 2t. Eluent for chromatography:
hexane/EtOAc (8 : 2). Red oil. IR (neat): n = 3212, 2959, 1605
200 MHz): d = 4.29 (bs, 2H, NH2), 6.99 (s, 1H, arom.), 7.40–7.48
(m, 4H, arom.), 7.62 (d, 2H, arom, J = 8.4 Hz), 7.80–7.87 (m,
3H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 109.0, 117.3,
120.9, 123.2, 125.4, 126.7, 128.8, 129.0, 129.1, 133.5, 134.9, 138.1,
140.1, 142.9 ppm. ESI-MS m/z: 254 ((M + 1)+, (100)). Calcd for
C16H12NCl (253.73): C, 75.74; H, 4.77; N, 5.52. Found: C, 75.61;
H, 4.72; N, 5.56.
1
cm-1. H NMR (CDCl3, 200 MHz): d = 2.96 (s, 3H, CH3), 7.51
(dd, 1H, arom. J = 8.4, 4.0 Hz), 7.77 (d, 1H, arom. J = 5.9 Hz), 8.43
(dd, 1H, arom. J = 8.4, 1.5 Hz), 8.61 (d, 1H, arom. J = 6.2 Hz), 9.06
(dd, 1H, arom. J = 4.4, 1.8 Hz) ppm. 13C NMR (CDCl3, 50.3 MHz):
d = 21.9, 120.9, 122.2, 122.8, 133.9, 145.8, 151.0, 154.4, 159.7 ppm.
ESI-MS m/z: 145 ((M + 1)+, (100)). Calcd for C9H8N2 (144.17):
C, 74.98; H, 5.59; N, 19.43. Found: C, 75.12; H, 5.59; N, 19.43.
3-Pentylnaphthalen-1-amine 3h. Eluent for chromatography:
hexane/EtOAc (98 : 2 – 97 : 3). Brown oil. IR (neat): n = 3369,
2955, 2924, 2851, 1627, 1598, 1576, 1514, 1463, 1409, 742 cm-1. 1H
NMR (CDCl3, 500 MHz): d = 0.93 (t, 3H, CH3, J = 6.9), 1.29–1.39
(m, 4H, 2 CH2), 1.69–1.74 (m, 2H, CH2), 2.70 (t, 2H, CH2, J =
7.6), 4.12 (bs, 2H, NH2), 6.69 (s, 1H, arom), 7.14 (s, 1H, arom),
7.39–7.46 (m, 2H, arom), 7.75–7.80 (m, 2H, arom.) ppm. 13C NMR
(CDCl3, 125.75 MHz): d = 13.3, 21.9, 29.0, 30.2, 35.5, 110.5, 117.1,
119.9, 121.6, 123.3, 125.1, 127.3, 133.9, 140.5, 141.1 ppm. ESI-MS
m/z: 214 ((M + 1)+, (100)). Calcd for C15H19N (213.54): C, 84.46;
H, 8.98; N, 6.57. Found: C, 84.56; H, 9.02; N, 6.53.
3-p-Tolylnaphthalen-1-amine4 3a. Eluent for chromatography:
hexane/EtOAc (95 : 5). Brown wax. IR (KBr): n = 3425, 3024,
1
2915, 2855 cm-1. H NMR (CDCl3, 200 MHz): d = 2.43 (s, 3H,
CH3), 4.22 (bs, 2H, NH2), 7.05 (d, 1H, arom, J = 1.1 Hz), 7.28
(d, 2H, arom, J = 8.4 Hz), 7.44–7.50 (m, 2H, arom), 7.52 (s,
1H, arom), 7.61 (d, 2H, arom, J = 8.1 Hz), 7.79–7.89 (m, 2H,
arom) ppm. 13C NMR (CDCl3, 50.3 MHz): d = 21.4, 109.5, 117.1,
120.9, 123.1, 125.0, 126.5, 127.4, 129.1, 129.7, 134.9, 137.3, 138.7,
139.3, 142.6 ppm. ESI-MS m/z: 234 ((M + 1)+, (100)). Calcd for
7846 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
3-Hexylnaphthalen-1-amine4 3i. Eluent for chromatography:
hexane/EtOAc (98 : 2). Yellow-orange oil. IR (neat): n = 3369,
2954, 2926, 2854, 1626, 1597, 1576, 1512, 1460, 1408, 741 cm-1. 1H
NMR (CDCl3, 200 MHz): d = 0.90 (t, 3H, CH3, J = 6.8), 1.27–1.41
(m, 6H, 3 CH2), 1.61–1.76 (m, 2H, CH2), 2.68 (t, 2H, CH2, J =
7.6), 3.82 (bs, 2H, NH2), 6.66 (s, 1H, arom), 7.12 (s, 1H, arom),
7.35–7.46 (m, 2H, arom), 7.70–7.79 (m, 2H, arom) ppm. 13C NMR
(CDCl3, 50.3 MHz): d = 14.4, 22.9, 29.3, 31.5, 32.0, 36.5, 111.5,
118.0, 120.9, 122.6, 124.2, 126.1, 128.3, 134.9, 141.4, 142.0 ppm.
ESI-MS m/z: 228 ((M + 1)+, (100)), 144 (40). Calcd for C16H21N
(227.343): C, 84.53; H, 9.31; N, 6.16. Found: C, 84.36; H, 9.28; N,
6.12.
7-(4-Methoxyphenyl)quinolin-5-amine 3o. Eluent for chro-
matography: hexane/EtOAc (8 : 2). Yellow oil. IR (neat): n = 3349,
3214, 2960, 2836, 1608, 1589, 1564, 1505, 1248, 830 cm-1. 1H NMR
(CDCl3, 200 MHz): d = 3.87 (s, 3H, CH3), 4.22 (bs, 2H, NH2), 7.01
(d, 2H, arom. J = 8.1), 7.06 (s, 1H, arom.), 7.32 (dd, 1H, arom. J =
8.4, 4.4), 7.67 (d, 2H, arom. J = 8.1), 7.75 (s, 1H, arom.), 8.16 (dd,
1H, arom. J = 8.4, 1.5 Hz), 8.89 (dd, 1H, arom. J = 4.4, 1.5 Hz)
ppm. 13C NMR (CDCl3, 50.3 MHz): d = 55.6, 109.6, 114.6, 117.8,
117.9, 119.4, 128.6, 129.5, 133.4, 142.6, 142.7, 149.8, 150.8, 159.9
ppm. ESI-MS m/z: 251 ((M + 1)+, (100)). Calcd for C16H14N2O
(250.29): C, 76.78; H, 5.64; N, 11.19. Found: C, 76.65; H, 5.69; N,
11.14.
3-Octylnaphthalen-1-amine 3j. Eluent for chromatography:
hexane/EtOAc (98 : 2). Brown oil. IR (neat): n = 3369, 2953, 2925,
2855, 1626, 1591, 1569, 1446, 747 cm-1.1H NMR (CDCl3, 200
MHz): d = 0.88 (t, 3H, CH3, J = 6.8), 1.27–1.40 (m, 10H, 5 CH2),
1.63–1.71 (m, 2H, CH2), 2.67 (t, 2H, CH2, J = 7.6), 3.40 (bs, 2H,
NH2), 6.68 (s, 1H, arom), 7.12 (s, 1H, arom), 7.37–7.43 (m, 2H,
arom), 7.71–7.80 (m, 2H, arom) ppm. ESI-MS m/z: 256 ((M +
1)+, (100)). Calcd for C18H25N (255.40): C, 84.65; H, 9.87; N, 5.48.
Found: C, 84.74; H, 9.89; N, 5.45.
7-Pentylquinolin-5-amine 3q. Eluent for chromatography: hex-
ane/EtOAc (8 : 2). Green oil. IR (neat): n = 3342, 3215, 2929, 1621,
1570 cm-1. 1H NMR (CDCl3, 200 MHz): d = 0.88 (t, 3H, CH3, J =
6.9), 1.33–1.39 (m, 4H, 2 CH2), 1.65–1.76 (m, 2H, CH2), 2.70 (t,
2H, CH2, J = 7.7), 4.14 (bs, 2H, NH2), 6.68 (s, 1H, arom.), 7.26
(dd, 1H, arom. J = 8.4, 4.4), 7.37 (s, 1H, arom.), 8.11 (dd, 1H,
arom. J = 8.4, 1.5 Hz), 8.83 (dd, 1H, arom. J = 4.0, 1.5 Hz) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 14.1, 22.7, 30.7, 31.7, 36.5,
111.7, 117.5, 118.9, 119 3, 129.4, 142.0, 145.6, 149.6, 150.3 ppm.
ESI-MS m/z: 215 ((M + 1)+, (100)). Calcd for C14H18N2 (214.30):
C, 78.46; H, 8.47; N, 13.07. Found: C, 78.32; H, 8.51; N, 13.11.
7-Methoxy-3-propylisoquinolin-1-amine 3l. Eluent for chro-
◦
matography: hexane/EtOAc (9 : 1). Brown solid. Mp: 51–54 C.
IR (KBr): n = 3359, 2960, 2928, 2868, 1626, 1604, 1511, 1260,
1-(5-Aminoquinolin-7-yl)cyclohexanol 3s. Eluent for chro-
matography: hexane/EtOAc (6 : 4). Brown oil. IR (neat): n = 3369,
1
1024 cm-1. H NMR (CDCl3, 200 MHz): d = 0.96 (t, 3H, CH3,
J = 7.3), 1.64–1.75 (m, 2H, CH2), 2.64 (t, 2H, CH2, J = 7.3), 3.92
(s, 3H, CH3), 6.71 (s, 1H, arom.), 7.06–7.15 (m, 3H, arom.), 7.63
(d, 1H, arom. J = 8.8 Hz) ppm. 13C NMR (CDCl3, 50.3 MHz):
d = 14.0, 24.5, 38.3, 55.6, 100.3, 112.9, 118.4, 118.6, 123.6, 129.8,
130.3, 138.5, 140.3, 157.1 ppm. ESI-MS m/z: 216 ((M + 1)+, (100)).
Calcd for C14H17N (215.29): C, 72.19; H, 7.46; N, 12.95. Found:
C, 72.11; H, 7.49; N, 12.99.
1
3235, 2927, 2853, 1617, 1590, 1571, 1446, 1407 cm-1. H NMR
(CDCl3, 200 MHz): d = 1.71–1.88 (m, 10H, 5 CH2), 4.18 (bs, 2H,
NH2), 4.70 (bs, 1H, OH), 7.07 (s, 1H, arom.), 7.31 (dd, 1H, arom.
J = 8.4, 4.4), 7.64 (s, 1H, arom.), 8.13 (dd, 1H, arom. J = 8.4, 1.5
Hz), 8.85 (dd, 1H, arom. J = 4.0, 1.5 Hz) ppm. 13C NMR (CDCl3,
50.3 MHz): d = 22.4, 25.8, 38.8, 73.5, 108.2, 115.8, 117.9, 119.6,
129.5, 142.3, 149.3, 150.5, 151.9 ppm. ESI-MS m/z: 243 ((M +
1)+, (100)). Calcd for C15H18N2O (242.32): C, 74.35; H, 7.49; N,
11.56. Found: C, 74.24; H, 7.52; N, 11.51.
7-Fluoro-3-propylisoquinolin-1-amine 3m. Eluent for chro-
matography: hexane/EtOAc (95 : 5). Brown oil. IR (neat): n =
3369, 3232, 2958, 2929, 2870, 1624, 1517, 1473, 1193, 852 cm-1.
1H NMR (CDCl3, 200 MHz): d = 0.96 (t, 3H, CH3, J = 7.3), 1.64–
1.79 (m, 2H, CH2), 2.65 (t, 2H, CH2, J = 7.3), 3.99 (bs, 2H, NH2),
6.68 (s, 1H, arom.), 7.11 (s, 1H, arom.), 7.15–7.25 (m, 1H, arom.),
7.37 (dd, 1H, arom. J = 11, 2.2), 7.71 (dd, 1H, arom. J = 8.8, 5.8)
ppm. 13C NMR (CDCl3, 50.3 MHz): d = 14.0, 24.4, 38.4, 104.8 (d,
2JC-F = 21.7 Hz), 112.4, 116.1 (d, 2JC-F = 24.8 Hz), 118.1, 123.08 (d,
Notes and references
1 For reviews on domino reactions, see: (a) D. Enders, C. Grondal and
M. R. M. Hu¨ttl, Angew. Chem., Int. Ed., 2007, 46, 1570; (b) L. F. Tietze,
G. Brasche, K. Gericke, Domino Reactions in Organic Synthesis, Wiley-
VCH, Weinheim, 2006; (c) H.-C Guo and J.-A. Ma, Angew. Chem., Int.
Ed., 2006, 45, 354; (d) L. F. Tietze, Chem. Rev., 1996, 96, 115; (e) L. F.
Tietze and U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993, 32, 131.
2 For reviews on domino approaches to heterocycles, see: (a) A. Padwa
and S. K. Bur, Tetrahedron, 2007, 63, 5341; (b) L. F. Tietze and N.
Rackelmann, Pure Appl. Chem., 2004, 76, 1967; (c) A. Padwa, Pure
Appl. Chem., 2003, 75, 47.
3
4
3JC-F = 7.6 Hz), 130.5 (d, JC-F = 8.8 Hz), 131.8, 140.2 (d, JC-F
=
2.7 Hz), 141.6 (d, 4JC-F = 5.3 Hz), 160.1 (d, 1JC-F = 247 Hz) ppm.
ESI-MS m/z: 204 ((M + 1)+, (100)). Calcd for C13H14FN (203.26):
C, 70.57; H, 6.42; N, 13.72. Found: C, 70.64; H, 6.44; N, 13.71.
3 For some representative examples see: (a) M. Dell’Acqua, D. Fa-
coetti, G. Abbiati and E. Rossi, Tetrahedron, 2011, 67, 1552; (b) M.
Dell’Acqua, D. Facoetti, G. Abbiati and E. Rossi, Synthesis, 2010,
2367; (c) D. Facoetti, G. Abbiati, L. d’Avolio, L. Ackermann and E.
Rossi, Synlett, 2009, 2273; (d) G. Abbiati, A. Arcadi, V. Canevari and
E. Rossi, Tetrahedron Lett., 2007, 48, 8491; (e) G. Abbiati, A. Arcadi,
F. Marinelli, E. Rossi and M. Verdecchia, Synlett, 2006, 3218; (f) G.
Abbiati, A. Arcadi, E. Beccalli, G. Bianchi, F. Marinelli and E. Rossi,
Tetrahedron, 2006, 62, 3033; (g) G. Abbiati, A. Arcadi, V. Canevari, L.
Capezzuto and E. Rossi, J. Org. Chem., 2005, 70, 6454; (h) G. Abbiati,
V. Canevari, S. Caimi and E. Rossi, Tetrahedron Lett., 2005, 46, 7117.
4 For a recent review see: A. Arcadi, G. Abbiati and E. Rossi, J.
Organomet. Chem., 2011, 696, 87.
7-p-Tolylquinolin-5-amine 3n. Eluent for chromatography:
hexane/EtOAc (8 : 2). Brown oil. IR (neat): n = 3351, 3214, 2917,
1
2850, 1612, 1588, 1560, 1503, 1397, 807 cm-1. H NMR (CDCl3,
200 MHz): d = 2.42 (s, 3H, CH3), 4.25 (bs, 2H, NH2), 7.09 (s, 1H,
arom.), 7.29 (d, 2H, arom. J = 8.1), 7.32 (dd, 1H, arom. J = 8.4,
4.4), 7.63 (d, 2H, arom. J = 8.1), 7.79 (s, 1H, arom.), 8.17 (dd, 1H,
arom. J = 8.4, 1.5 Hz), 8.90 (dd, 1H, arom. J = 4.4, 1.5 Hz) ppm.
13C NMR (CDCl3, 50.3 MHz): d = 21.3, 109.8, 118.0, 118.1, 119.5,
127.4, 129.6, 129.8, 137.9, 138.0, 142.7, 143.0, 149.7, 150.7 ppm.
ESI-MS m/z: 235 ((M + 1)+, (100)). Calcd for C16H14N2 (234.30):
C, 82.02; H, 6.02; N, 11.96. Found: C, 81.95; H, 6.00; N, 11.97.
5 (a) A. Arcadi and E. Rossi, Synlett, 1997, 667; (b) A. Arcadi and E.
Rossi, Tetrahedron, 1998, 54, 15253.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7836–7848 | 7847
©

View Article Online
6 (a) A. Arcadi, O. A. Attanasi, B. Guidi, E. Rossi and S. Santeusanio,
Chem. Lett., 1999, 59; (b) A. Arcadi, O. A. Attanasi, B. Guidi, E. Rossi
and S. Santeusanio, Eur. J. Org. Chem., 1999, 3117.
7 G. Abbiati, E. Beccalli, A. Marchesini and E. Rossi, Synthesis, 2001,
2477.
18 N. Asao, T. Nogami, K. Takahashi and Y. Yamamoto, J. Am. Chem.
Soc., 2002, 124, 764.
19 N. T. Patil and Y. Yamamoto, J. Org. Chem., 2004, 69, 5139.
20 T. Yao, X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2004, 126,
11164.
8 (a) G. Abbiati, A. Arcadi, E. Beccalli and E. Rossi, Tetrahedron
Lett., 2003, 44, 5331; (b) G. Abbiati, A. Arcadi, A. Bellinazzi,
E. Beccalli, E. Rossi and S. Zanzola, J. Org. Chem., 2005, 70,
4088.
9 M. Alfonsi, M. Dell’Acqua, D. Facoetti, A. Arcadi, G. Abbiati and E.
Rossi, Eur. J. Org. Chem., 2009, 2852.
10 M. Dell’Acqua, D. Facoetti, A. Arcadi, G. Abbiati and E. Rossi,
Synlett, 2010, 2672.
11 For a selection of recent examples see: (a) N. Chernyak, V. Gevorgyan
and S. I. Gorelsky, Angew. Chem., Int. Ed., 2011, 50, 2342; (b) A.
Mukherjee and R.-S. Liu, Org. Lett., 2011, 13, 660; (c) A. Das, H.-H.
Liao and R.-S. Liu, J. Org. Chem., 2007, 72, 9214.
12 For some representative examples see: (a) S. Bhunia, K.-C. Wang and
R.-S. Liu, Angew. Chem., Int. Ed., 2008, 47, 5063; (b) S. Obika, H.
Kono, Y. Yasui, R. Yanada and Y. Takemoto, J. Org. Chem., 2007, 72,
4462; (c) T. Godet, C. Vaxelaire, C. Michel, A. Milet and P. Belmont,
Chem.–Eur. J., 2007, 13, 5632; (d) B. K. Ghorai, S. Duan, D. Jiang and
J. W. Herndon, Synthesis, 2006, 3661; (e) D. Yue, N Della Ca` and R.
C. Larock, Org. Lett., 2004, 6, 1581; (f) N. Asao, T. Kasahara and Y.
Yamamoto, Angew. Chem., Int. Ed., 2003, 42, 3504; (g) T. Godet, J.
Bosson and P. Belmont, Synlett, 2005, 2786; (h) L.-P. Liu and G. B.
Hammond, Org. Lett., 2010, 12, 4640.
21 R. Yanada, S. Obika, H. Kono and Y. Takemoto, Angew. Chem., Int.
Ed., 2006, 45, 3822.
22 For a critical comparison among copper, silver and gold catalysts see:
A. S. K. Hashmi, in Silver in Organic Chemistry (Ed. M. Harmata),
John Wiley and Sons Inc., Hoboken, 2010, 357-379; Chapter 12.
23 For some representative examples see: (a) T. Godet and P. Belmont,
Synlett, 2008, 2513; (b) T. J. Harrison, J. A. Kozak, M. Corbella-Pane´
and G. R. Dake, J. Org. Chem., 2006, 71, 4525; (c) C. H. Oh, H. J. Yi
and J. H. Lee, New J. Chem., 2007, 31, 835.
24 K. Sonogashira, in Handbook of Organopalladium Chemistry for
Organic Synthesis, E. Negishi, Ed.; John Wiley and Sons, New York,
2002, Cap. III.2.8.1 pagg. 493-530.
25 F. Marsais, B. Laferdrix, T. Gungor, M. Mallet and G. Queguiner, J.
Chem. Res., (M), 1982, 2863.
26 For a recent example of silver-imine coordination see: C. H. Oh, S.
Karmakar, H. S. Park, Y. C. Ahn and J. W. Kim, J. Am. Chem. Soc.,
2010, 132, 1792.
27 (a) D. R. Crist, Z.-H. H. Hsieh, C. O. Quicksall and M. K. Sun, J. Org.
Chem., 1984, 49, 2478; (b) for an analogous experiment with Pd salts
see ref. 13.
28 L. Uehlin and T. Wirth, Org. Lett., 2001, 3, 2931.
29 Elan Pharmaceuticals, Inc., M. S. Dappen, J. J. Jagodzinski, L. H.
Latimer, J. Wu, J. D. Godfrey Jr., R. M. Matunas, T. W. Drabb, Patent
WO2010/111418 A2, 2010.
13 N. Asao, K. Takahashi, S. Lee, T. Kasahara and Y. Yamamoto, J. Am.
Chem. Soc., 2002, 124, 12650.
14 (a) J. Barluenga, H. Va´zquez-Villa, I. Merino, A. Ballesteros and J. M.
Gonza´lez, Chem.–Eur. J., 2006, 12, 5790; (b) J. Barluenga, H. Va´zquez-
Villa, A. Ballesteros and J. M. Gonza´lez, J. Am. Chem. Soc., 2003, 125,
9028; (c) H. Kusama, H. Funami, M. Shido, Y. Hara, J. Takaya and N.
Iwasawa, J. Am. Chem. Soc., 2005, 127, 2709; (d) D. Yue, N. Della Ca
and R. C. Larock, J. Org. Chem., 2006, 71, 3381; (e) D. Yue, N. Della
Ca and R. C. Larock, Org. Lett., 2004, 6, 1581.
15 (a) F.-R. Gou, P.-F. Huo, H.-P. Bi, Z.-H. Guan and Y.-M. Liang, Org.
Lett., 2009, 11, 3418; (b) M. Tiano and P. Belmont, J. Org. Chem.,
2008, 73, 4101; (c) P. Belmont and T. Belhadj, Org. Lett., 2005, 7, 1793;
(d) J. W. Herndon, Y. Zhang and K. Wang, J. Organomet. Chem., 2001,
634, 1.
30 M. Mallet, G. Branger, F. Marsais and G. Queguiner, J. Organomet.
Chem., 1990, 382, 319.
31 Genelabs Technologies, Inc., F. U. Schmitz, S. M. Pham, C. D. Roberts,
R. C. Griffith, J. Botyanszki, Patent WO2008/8912 A1, 2008.
32 (a) A. Couture, P. Grandclaudon and E. Huguerre, Synthesis, 1989,
456; (b) D. L. Romero, R. A. Morge, C. Biles, N. Berrios-Pena, P. D.
May, J. R. Palmer, P. D. Johnson, H. W. Smith, M. Busso, C.-K. Tan,
R. L. Voorman, F. Reusser, I. W. Althaus, K. M. Downey, A. G. So,
L. Resnick, W. G. Tarpley and P. A. Aristoff, J. Med. Chem., 1994, 37,
999.
33 C. P. Casey, N. A. Strotman and I. A. Guzei, Organometallics, 2004,
23, 4121.
16 Preliminary results of this work have been published, see ref. 4.
17 For a recent review on s- and p-electrophilic Lewis acids see: Y.
Yamamoto, J. Org. Chem., 2007, 72, 7817.
34 (a) F. Makra, J. C. Rohloff, A. V. Muehldorf and J. O. Link, Tetrahedron
Lett., 1995, 36, 6815; (b) M. Feuerstein, F. Berthiol, H. Doucet and M.
Santelli, Synthesis, 2004, 8, 1281.
7848 | Org. Biomol. Chem., 2011, 9, 7836–7848
This journal is
The Royal Society of Chemistry 2011
©