Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands

Article abstract of DOI:10.1039/b504498g

The Src homology 3 (SH3) domains are small protein-protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines

Full text of DOI:10.1039/b504498g

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A R T I C L E
Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3
domain ligands
Steven Inglis,a,b Rhiannon Jones,a Daniel Fritz,a Cvetan Stojkoski,b Grant Bookerb and
Simon Pyke*a
a Discipline of Chemistry, School of Chemistry and Physics, The University of Adelaide,
Adelaide, SA, 5005, Australia. E-mail: simon.pyke@adelaide.edu.au; Fax: +61 8 8303 4358;
Tel: +61 8 8303 5358
b Discipline of Biochemistry, School of Molecular and Biomedical Science, The University of
Adelaide, Adelaide, SA, 5005, Australia
Received 1st April 2005, Accepted 24th May 2005
First published as an Advance Article on the web 13th June 2005
The Src homology 3 (SH3) domains are small protein–protein interaction domains that mediate a range of important
biological processes and are considered valuable targets for the development of therapeutic agents. We have been
developing 2-aminoquinolines as ligands for SH3 domains—so far the only reported examples of entirely
small-molecule ligands for the SH3 domains. The highest affinity 2-aminoquinolines so far identified are
6-substituted compounds. In this article, the synthesis of several new 2-aminoquinolines, including 5-, 6- and
7-substituted compounds, for Tec SH3 domain ligand binding studies is presented. As a part of the synthetic
investigation, the utility of different methods for the synthesis of 2-aminoquinolines was explored and potentially
powerful methods were identified for the synthesis of 2-aminoquinolines with diverse functionality. Of the
compounds prepared, the 5-substituted-2-aminoquinolines generally bound with similar affinities to unsubstituted
2-aminoquinoline, whilst the 7-substituted compounds generally bound with similar or lower affinity than
unsubstituted 2-aminoquinoline. However, the 6-substituted-2-aminoquinolines generally bound with significantly
higher affinity than unsubstituted 2-aminoquinoline. In addition, one 6-substituted-N-benzylated-2-aminoquinoline
was also tested for SH3 binding and some evidence for the formation of additional contacts at other regions of the
SH3 domain was found. These results provide new and useful SAR information that should greatly assist with the
challenge of developing high affinity small-molecule ligands for the SH3 domains.
Introduction
The Src homology 3 (SH3) domains are small, non-catalytic
protein modules that bind to proline-rich peptide sequences
and mediate a range of important biological processes. These
domains are involved in protein–protein interactions that lead
to the development of large protein complexes, which mediate
signalling pathways within a cell, controlling important pro-
cesses such as gene expression and cell proliferation.1,2 Because
the deregulation of events involving SH3 domains is known
to be associated with human diseases including cancer and
osteoporosis, the SH3 domains have been appealing targets for
the development of potential therapeutics. A number of ap-
proaches for research into high affinity SH3 domain ligands have
been reported, including the development of peptide ligands
with non-peptide binding elements,3,4 or ‘peptoid’ ligands that
contain non-natural N-substituted amino acids.5,6 These studies
led to the development of ligands with enhanced affinity and
selectivity over native ligands. However, because they are peptide
ligands, they are poor candidates for drug development. Until
recently, no examples of small-molecule ligands for SH3 do-
mains had been reported. In our laboratory, we have been using
the SH3 domain from the mouse Tec kinase enzyme as a model
system for structure based drug design. Recently we reported the
discovery that 2-aminoquinolines (for example 1–5 as illustrated
in Fig. 1A) bind to the Tec SH3 domain, with weak to moderate
affinity.7 SAR information, in conjunction with NMR chemical
shift perturbation experiments and site directed mutagenesis
with the Tec SH3 protein were used to characterise the binding
of 2-aminoquinolines to the Tec SH3 domain and a model for
the mechanism of the binding was developed, involving two
highly conserved residues in the proline-rich peptide binding
site. In this model, p–p stacking occurs between the ring systems
of the ligand and the side-chain of tryptophan 215 (W215)
Fig. 1 (A) The structures and equilibrium binding dissociation con-
stants (Kds) of some 2-aminoquinolines previously tested7 for Tec SH3
binding. (B) Model for the mechanism of 2-aminoquinoline–Tec SH3
domain binding and regions adjacent to the 2-aminoquinoline binding
site, predicted to make contacts with 5-, 6- or 7-position substituents.
and a salt bridge is formed between the protonated ligand
and a proximal aspartate residue (D196) on the SH3 domain
(Fig. 1B). Of the 2-aminoquinolines so far tested for binding to
the Tec SH3 domain, the highest affinity ligands (3–5 in Fig. 1A),
with equilibrium binding dissociation constants (Kd) in the 20–
50 lM range, were 6-substituted-2-aminoquinolines that con-
tained bulky lipophilic functionality attached to the quinoline
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 4 3
©

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platform. It was thus concluded that a new lipophilic contact
was formed between the substituent and residues adjacent to the
2-aminoquinoline binding site on the SH3 domain (Fig. 1B).
In this article, we report the synthesis and binding studies with
the Tec SH3 domain of a range of new 2-aminoquinolines with
substitution at either the 5-, 6- or 7-position of the quinoline
ring. These include the equivalent 5- and 7-positional isomers of
ligands 3 and 4, which have already been reported (Fig. 1A),
in addition to several new derivatives in the 5-, 6- and 7-
position with more hydrophilic functionality. Similar to the
synthesis of the 6-substituted-2-aminoquinolines,7 the general
approach used here was the synthesis of 2-chloroquinolines
with the desired ring-functionality in place and conversion of
these into 2-aminoquinolines, using the method of Ko´ro´di,8
involving acetamide as the amination reagent, at near reflux
temperature. However, as part of the current investigations, some
limitations of the Ko´ro´di method were uncovered and these
will also be discussed. In order to overcome these limitations,
alternative approaches for the conversion of 2-chloroquinolines
into 2-aminoquinolines were explored and the results from these
studies are also presented. The binding of all the new ligands
with the Tec SH3 domain is then reported and the new SAR
information obtained is discussed. Of key importance in this
investigation is a comparison of ligand affinities between the 5-,
6- and 7-position isomers synthesised here and previously.
purified by chromatography on silica gel and the major isolate
was a mixture of 2-chloro-5-dibromomethylquinoline 10 and
2-chloro-7-dibromomethylquinoline 11 in 73% yield. A small
amount of the corresponding 5- and 7-bromomethyl products 12
and 13 as an impure mixture was also isolated. The mixture of 10
and 11 was subsequently treated with hexamethylenetetraamine
in aq. ethanol with heating at reflux, again according to the
method of Newman and Lee,10 to afford a mixture of aldehydes
8 and 9. Following chromatography on silica gel, both aldehydes
8 and 9 were isolated in pure forms in 29% and 37% yields,
respectively. Each of 8 and 9 were subsequently converted into
both dioxolane and dioxane acetals 14–17 in moderate to good
yields (51–79%) by treatment with the appropriate diols in the
presence of a catalytic amount of p-toluenesulfonic acid and
heating at reflux in benzene (Scheme 1). 2-Chloroquinolines
14–17 were then converted into 2-aminoquinolines 18–21 in
moderate to good yields (43–73%) according to the method
of Ko´ro´di,8 involving treatment with acetamide at near reflux
temperature in the presence of potassium carbonate (Scheme 1).
Consistent with previous observations,7,8 small amounts (∼10%)
of the corresponding quinolin-2(1H)-ones 22–25 were also
isolated from the amination reactions. The purified sample of
2-chloro-7-methylquinoline 7 was also converted into 2-amino-
7-methylquinoline 26 using the method of Ko´ro´di, however the
quinoline-2(1H)-one by-product was not isolated in this case
(Scheme 1).
Results and discussion
Synthesis of 5-, 6- and 7-subsituted-2-aminoquinolines with more
hydrophilic functionality—acyclic alcohols
Synthesis of 5- and 7-subsituted-2-aminoquinolines with
lipophilic functionality
In order to continue the exploration of the SH3 domain binding
surface at regions adjacent to the 2-aminoquinoline binding
site, 5-, 6- and 7-substituted-2-aminoquinolines with more
hydrophilic functionality were also sought. As a step towards ob-
taining such compounds, it was decided to pursue the conversion
of cyclic acetals 14–17 prepared above, in addition to 27 and 28
reported previously,7 into acyclic alcohols as potential amination
precursors. Thus, the ring opening conditions for cyclic acetals
reported by Daignault and Eliel11 were adapted with 14–17,
27 and 28 (Scheme 2), involving reduction of the cyclic acetals
with lithium aluminium hydride, in the presence of aluminium
chloride, in THF at reflux temperature. This led to the synthesis
of alcohols 29–34 in good to excellent yields (67–97%). In the
case of alcohol 30, a small amount (9%) of the corresponding
3,4-dihydroquinolin-2(1H)-one product 35 was also isolated. It
was thought that 35 arose due to reduction of the C(3)–C(4)
bond, the likeliness of which is considerably increased by the
The synthesis of 2-chloro-5-methylquinoline 6 and 2-chloro-7-
methylquinoline 7 as an unseparated mixture has been reported,
starting from 3-methylcinnamanilide.9 In a similar fashion to the
previous syntheses of 6-substituted-2-aminoquinolines,7 it was
anticipated that the 5- and 7-methylquinoline derivatives could
be functionalised by the same approach, provided that the 5- and
7-isomers could be separated. Using fractional crystallisation,
a pure sample of 7 but not 6 was obtained. However, it was
envisaged that aldehydes 8 and 9 (Scheme 1) might have signif-
icantly greater differences in their physical properties and hence
be amenable to separation using silica gel chromatography. Thus,
the mixture of 6 and 7 obtained via the method of Johnston et al.9
(ca. 1 : 2 of 6/7) was treated with two eq. of NBS and a catalytic
amount of benzoyl peroxide and heated at reflux in benzene, as
illustrated in Scheme 1, in an adaption of the method of Newman
and Lee.10 The crude material isolated from this reaction was
Scheme 1 Reagents and conditions: (i) NBS, (PhCO2)2, benzene, D; (ii) hexamethylenetetraamine, ethanol–water, D; (iii) HOCH2(CH2)nOH,
p-TosOH–H2O, benzene, D; (iv) AcNH2, K2CO3, ∼200 ◦C.
2 5 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

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Scheme 2 Reagents and conditions: (i) AlCl3, LiALH4, THF, D; (ii) (29, 30, 33 and 34) 1). AcNH2, K2CO3, ∼200 ◦C, 2). NaOH, H2O, D; (31 and 32)
AcNH2, K2CO3, ∼200 ◦C.
formation of a complex between the acetal oxygen atoms and
aluminium hydride, a possible intermediate in the ring opening
process. The proximity of this complex to C(4) of the quinoline
ring may then result in reduction in the case of the 5-substituted
quinoline only. The 2-chloro substituent was then hydrolysed
during workup, to form the 3,4-dihydroquinolin-2(1H)-one.
2-Chloroquinolines 29–34 were all converted into 2-
aminoquinolines 36–41 using the method of Ko´ro´di (Scheme 2),
however the yields in these cases were less than satisfactory (3–
15%) and a number of by-products, including the correspond-
ing quinolin-2(1H)-ones and others that were not identified,
were formed during the reaction. In these cases, only the 2-
aminoquinolines were isolated from the crude product mixtures.
The use of polar solvents in the reaction workups led to
products contaminated with acetamide. In some cases, the
excess acetamide was decomposed by treatment with aq. sodium
hydroxide at reflux prior to workup and the yields were slightly
improved. These results clearly highlight the incompatibility
of the Ko´ro´di amination method with 2-chloroquinolines that
contain a polar functionality.
Scheme
3
Reagents and conditions: (i) 4-methoxybenzylamine
(PMBNH2), ca. 130 ◦C, 30 h; (ii) TfOH, rt, 48 h; (iii) TFA, ca. 50 ◦C,
1 h.
conversion of 45 to the primary 2-aminoquinoline 39 proceeded
after 1 h and, following chromatography, pure 39 was isolated in
59% yield. This improved method was also used for the synthesis
of 38 in two steps from 31 with similar success (98% yield for
amination and 69% yield for de-protection).
Synthesis of 5-, 6- and 7-subsituted-2-aminoquinolines with
simple hydrophilic functionality—towards covergent synthesis
At this point, an alternative method for the synthesis of
2-aminoquinolines from 2-chloroquinolines was sought. As
there are well known methods for the mild de-protection
of 4-methoxybenzyl ethers with either DDQ12 or cerium(IV)-
ammonium nitrate,13 the use of 4-methoxybenzylamine as
an alternative nucleophile was investigated as a means of
introducing a protected amino group at C(2). Using 2-chloro-
6-methylquinoline 42 as a model (prepared according to
literature14,15 methods), treatment with 4-methoxybenzylamine
at ca. 130 ◦C for 30 h resulted in isolation of pure 43 in 94%
yield following workup and chromatography (Scheme 3). De-
protection with either DDQ12 or cerium(IV)ammonium nitrate13
was unsuitable when applied to the 4-methoxybenzylamine 43,
however when 43 was treated with trifluoromethanesulfonic acid
at rt by adapting the method of Anderson and Morris,16 the
primary amine 2 was afforded in 95% yield. The conversion
of 2-chloroquinolines 31 and 32 to 2-(4-methoxybenzylamino)-
quinolines 44 and 45 also proceeded in high yield (98% and
93% respectively) and protection of the hydroxyl groups of the
starting materials was not necessary. The de-protection of 45
was tested using trifluoromethanesulfonic acid under similar
conditions used for the successful de-protection of 43 to 2,
however only low recovery of an insoluble material was observed
when tested with 45. But when 45 was stirred in trifluoroacetic
As a step towards the development of a more convergent syn-
thetic approach for the preparation of 5-, 6- and 7-substituted-
2-aminoquinolines, it was anticipated that bromomethyl-2-
acetamidoquinolines such as 46–48 (Scheme 4) might be useful
‘key intermediates’. To test this approach, a one step conversion
of 2-chloro-6-methylquinoline 42 to the 2-acetamidoquinoline
derivative 49 was employed, involving treatment of 42 with a
large excess of acetamide in the presence of potassium carbonate
and heating at reflux overnight (Scheme 4) according to the
method of Watanabe et al.18 This transformation proceeds under
similar conditions to the method of Ko´ro´di8 for the synthesis of
2-aminoquinolines from 2-chloroquinolines (as in Scheme 1and
Scheme 2), however the method of Watanabe and coworkers
involves a larger excess of acetamide and a much longer reaction
time. The precise mechanism of both of these conversions is
unclear, however thin layer chromatography indicated that the
2-aminoquinoline forms first in both cases, consistent with the
reaction times (1–2 h) for the method of Ko´ro´di. By continuing
the reaction overnight (as in the method of Watanabe et al.),
the 2-acetamidoquinoline then forms. When this reaction was
tested on a small scale (0.25 g of 42), acetamide 49 was isolated
in 68% yield after workup and purification, consistent with the
literature. However, the 1H NMR spectrum of the crude isolate
indicated that a small amount of both the 2-aminoquinoline
2 and quinolin-2(1H)-one 50 was also present in the mixture.
◦
acid at ca. 50 C by adapting the method of Ford et al.,17 the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 4 5

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Scheme 4 Reagents and conditions (i) AcNH2, K2CO3, D, 16 h; (ii) NBS, (PhCO2)2, benzene, D; (iii) AcOK, DMF, ca. 80 ◦C; (iv) (51) K2CO3,
MeOH, rt; (58 and 59) K2CO3, MeOH, ca. 50 ◦C; (v) potassium phthalimide, DMF, ca. 80 ◦C; (vi) NaOH–H2O, D.
When the reaction was repeated on a large scale (7.54 g of 42),
acetamide 49 was isolated in 39% yield and quinolin-2(1H)-one
50 was produced in 31% yield, but none of the 2-aminoquinoline
was observed. It was thus concluded that this reaction is difficult
to control on such a large scale.
additional 10% recovery of a ca. 4 : 1 mixture of 59 : 58 was also
obtained. Acetates 58 and 59 were subsequently converted into
the corresponding hydroxymethyl-2-aminoquinolines 60 and
61, respectively, again using potassium carbonate in methanol,
however in these cases the temperature was raised to ca. 50 ◦C
and one eq. of potassium carbonate was used. Using this
approach, 58 was converted into the 2-aminoquinoline 60 in 93%
yield, and the ca. 19 : 1 mixture of 59 : 58 was converted into the
corresponding mixture of 61 : 60 in 88% yield, from which isola-
tion of pure 61 was possible in 44% yield, after chromatography.
A common feature of the acetamide derivatives prepared (46–
49, 51, 52, 54 and 56–59) was the observation of significant line
Acetamide 49 was then treated with a slight excess of NBS
and a catalytic amount of benzoyl peroxide in benzene at reflux
(Scheme 4) to produce the bromomethyl derivative 46 in 56%
yield following workup and purification. To test the utility of
46 in substitution chemistry, 46 was treated with◦two eq. of
potassium acetate in DMF with heating at ca. 80 C, to form
the acetate derivative 51 in 87% yield. It was anticipated that
6-hydroxymethyl-2-acetamidoquinoline 52 may also be a useful
intermediate within a convergent synthetic approach. Thus, a
selective de-acetylation method for 51 was sought. Treatment of
51 with 0.5 eq. of potassium carbonate in methanol at rt led to
the formation of the hydroxymethyl derivative 52 in 72% yield,
however the entirely deacetylated 2-aminoquinoline 53 was also
obtained in 20% yield (Scheme 4). As a means of producing
the corresponding aminomethyl derivative, the bromomethyl
derivative 46 was treated with potassium phthalimide in DMF at
ca. 80 ◦C overnight to produce the phthalimide derivative 54 in
81% yield (Scheme 4). In this case, the aminomethyl derivative 55
was obtained by treating 54 with aq. sodium hydroxide at reflux
(Scheme 4). Amine 55 was formed in ca. 50% yield, however
the product contained approximately 5% of the hydroxymethyl
derivative 53 as an unexpected by-product in the reaction, as
judged by 1H NMR. The formation of this by-product was
thought to occur because the resonance donating effect of the
2-amino group (after hydrolysis of the acetamide) led to the dis-
placement of the phthalimide to form an activated intermediate.
Attack by hydroxide then resulted in the formation of 53. This
material was sufficiently pure (>95% by NMR) to be used in the
ligand binding experiments without any further purification.
Using the same approach as described above, the mixture of
2-chloro-5-methylquinoline 6 and 2-chloro-7-methylquinoline 7
was also converted to the corresponding 2-acetamidoquinoline
mixture of 56 and 57, respectively, in 52% yield (Scheme 4).
The mixture of 56 and 57 was subsequently converted into the
corresponding bromomethyl mixture of 47 and 48, respectively,
in 46% yield, prior to conversion into the mixture of acetates 58
and 59 (Scheme 4). At this point, partial separation of the 5- and
7-positional isomers was possible by chromatography: pure 58
was isolated in 32% yield, together with a ca. 19 : 1 mixture of
59 : 58 (as judged by 1H NMR spectroscopy) in 26% yield. An
1
broadening of the signal for C(3)H in the H NMR spectra.
This is attributed to a relatively slow rotational exchange on
the NMR timescale of the N–C bond of the acetamide group.
Additionally, in the 13C NMR spectrum of the amines 60 and 61
the signals for both C(3) and C(8) are significantly broadened.
This is most likely due to tautomerism between the amino and
imino forms of these quinolines as illustrated below.
Binding studies of 5-, 6- and 7-substituted-2-aminoquinolines
with the Tec SH3 domain
All the 2-aminoquinolines, for which the synthesis was described
above, were tested for binding to the Tec SH3 domain using
either fluorescence polarisation (FP)19 peptide displacement
assays and/or NMR chemical shift perturbation experiments,
using uniformly 15N-labelled Tec SH3 protein. In the FP
assay, the ability of the small-molecule ligand to compete
with a fluorescently labelled proline-rich peptide (fluorescein–
bA-RRPPPPIPPE–CO2H, hereafter referred to as PRP-1) for
binding to the Tec GST–SH3 fusion protein was measured.
The use of this approach in the current ligand binding studies
has been previously reported7 and leads to the calculation
of the concentration of small-molecule ligand at which 50%
displacement of PRP-1 (EC50) from the SH3 domain occurs.
With the NMR chemical shift perturbation experiments, the
ability of the small-molecule ligand to bind the SH3 domain
2 5 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

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Table 1 Binding constants of 5-, 6- and 7-substituted-2-aminoquinolines with the Tec SH3 domain, as studied by either fluorescence polarisation
peptide displacement or NMR chemical shift perturbation experiments
5-Position
6-Position
7-Position
R
Compound
EC50/lMa
Compound
EC50/lMa
Kd/lMb
Compound
Kd/lMb
18
19
249 39
3
4
34 5c
40 8c
20
21
207 48
269 83
26 6c
52 16c
439 101
HO(CH2)2OCH2
HO(CH2)3OCH2
HOCH2
Me
H
36
37
60
—
238 82
254 40
76 11d
—
38
39
53
2
40
51
71
8
4
9
38
—
9
40
41
61
26
176 44
182 21
195 34
369 93
—
75 15c
61 6c
1
160 36c
125 24c
a Quoted values are mean standard deviation over three replicate experiments. b Quoted values are mean standard deviation over residues where
1H (H–N) chemical shift changes of the SH3 domain were at least 0.1 ppm at or near saturation binding of ligand. c As reported in Inglis et al.7
d Determined by NMR chemical shift perturbation experiments; quoted value is mean standard deviation over residues where 1H (H–N) chemical
shift changes of the SH3 domain were at least 0.1 ppm at or near saturation binding of ligand.
was measured by recording Heteronuclear Single Quantum
Coherence (HSQC)20 experiments with uniformly 15N-labelled
SH3 protein, in the presence of the small-molecule ligand. As
reported previously,7 equilibrium binding dissociation constants
(Kds) were obtained using this approach.
The 5-substituted-2-aminoquinolines 18 and 19 with bulky
lipophilic functionality competed for binding with PRP-1 for
the SH3 domain with approximately eight-fold reduced affinity
relative to the equivalent 6-position ligands 3 and 4 (EC50’s ca.
250 lM for 18 and 19 and ca. 30 lM for 3 and 4,7 Table 1). In the
case of the corresponding 7-position ligands, the 5-membered
acetal 20 bound the SH3 domain with approximately five-fold
reduced affinity relative to the 6-position ligand 37 (Kds 207 lM
and 40 lM for 20 and 3, respectively, Table 1), whilst the 6-
membered acetal 21 bound with even lower affinity (Kd = 439
lM), approximately eight-fold lower than the corresponding 6-
position ligand 4 (Kd = 52 lM).7 Of the 2-aminoquinolines 36–
41 with more hydrophilic and flexible substituents, the 6-position
ligands 38 and 39 displayed the highest affinity (EC50’s ca. 45 lM;
Fig. 2, Table 1), whilst the corresponding 5-substituted (36 and
37) and 7-substituted compounds (40 and 41) all bound with
similar affinities (EC50’s ca. 200 lM for 36 and 37, Fig. 2a; Kds ca.
180 lM for 40 and 41, Table 1). Of the hydroxymethyl derivatives
53, 60 and 61, the 5- and 6-positional isomers bound the SH3
domain with similar affinities (EC50 = 71 lM for 53, Kd = 76 lM
for 60, Fig. 1B, Table 1), whilst the 7-position compound bound
Fig. 2 Tec SH3 domain–5-, 6- and 7-substituted-2-aminoquinolines
binding studies. (A) Isotherms obtained from independent experiments
for competition of fluorescently labelled proline-rich peptide PRP-1
by 36 and 38 synthesised here and 1 and 3 previously reported7 for
comparison, from Tec GST–SH3 fusion protein using fluorescence po-
larisation assay. (B) Isotherms obtained from independent experiments,
represented as the mean of the normalised change in chemical shift of
residues involved in binding of ligands 20 and 60, and 1 previously
reported7 for comparison, as determined with NMR chemical shift
perturbation experiments.
with approximately two and a half-fold lower affinity (Kd
=
195 lM, Table 1). 2-Amino-7-methylquinoline 26 bound the
SH3 domain with approximately six-fold reduced affinity (Kd =
369 lM) relative to the corresponding 6-position ligand (Kd =
61 lM).7 The 6-aminomethyl-2-aminoquinoline derivative 55
competed for binding with PRP-1 with an EC50 of 102 lM,
whilst the 6-substituted-2-(4-methoxybenzyl)aminoquinoline 45
bound the SH3 domain with Kd = 81 lM (Table 2).
the case of 60, the mechanism that mediates the ca. two-fold im-
provement in affinity of this ligand relative to 2-aminoquinoline
is unclear. It is possible that a weak, entropically unfavourable
hydrogen bond is made with a hydrophilic residue on the protein
surface. However, inspection of regions adjacent to where 60 sits
on the SH3 domain structure according to the ligand binding
model, does not provide obvious insight into how this hydrogen
bond is mediated. In addition, it seems unlikely that the same
interaction(s) that mediates the improvement in affinity of the
similar 6-substituted ligands 2 and 53 is responsible for the
improvement observed for 60, because a significantly different
and potentially less than optimal orientation of the quinoline
Discussion
With the exception of 60, a general trend is evident, indicating
that substituents at the 5-position of the 2-aminoquinoline
platform (ligands 18, 19, 36 and 37), regardless of their chemical
properties, do not appear to make any additional contacts with
the SH3 domain surface and thus the affinities of these ligands
are not significantly different to that of 2-aminoquinoline 1.
This is consistent with the prediction that substituents at the
5-position would be directed away from the protein surface. In
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 4 7

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Table 2 Binding studies of additional 2-aminoquinolines
of a hydrogen bond, but in the case of the larger 6-membered
acetal of 21 the steric violations are too great and hence the level
of compensation gained through hydrogen bond formation is
reduced. In a similar fashion, the 7-position ligands 40 and 41
may also make a non-ideal hydrogen bond, however less steric
penalties are observed in these cases due to the high flexibility
of the alkyl functionality attached to the benzylic oxygen atoms.
Given that the affinity of hydroxymethyl derivative 61 is similar
to the ligands 40 and 41, this suggests that the alkyl chains
of 40 and 41 do not make any additional interactions with
the protein. Despite these observations, a general conclusion
that can be made about the 7-substituted-2-aminoquinolines is
that substitution at this position is not well tolerated. This is
consistent with the prediction that substituents at this position
would be directed into the protein surface and would therefore
potentially lead to steric clashes.
R1, R2
EC50/lMa Kd/lMb
H, H
1
160 36c
55 102 17
125 24c
—
H2NCH2, H
HO(CH2)3OCH2, CH2C6H4-p-OMe 45
H, Me
—
—
81 10
62
380 40c
a Quoted values are mean
standard deviation over three replicate
experiments. b Quoted values are mean
standard deviation over
residues where 1H (H–N) chemical shift changes of the SH3 domain were
at least 0.1 ppm at or near saturation binding of ligand. c As reported in
Inglis et al.7
The affinity of the 6-substituted 2-(4-methoxybenzyl)amino-
quinoline derivative 45 (Kd = 81 lM, Table 2) indicates that
an approximately two-fold reduction in affinity has occurred
compared with the related primary amines 38 and 39 (EC50s 38
and 39 ca. 45 lM, Kd 38 = 38 lM, Table 1). This is consistent
with the observation that the N-methylated-2-aminoquinoline
derivative 62 bound the SH3 domain with approximately three-
fold reduced affinity7 relative to 2-aminoquinoline 1. However,
the reduction in affinity in the case of 45 is less severe than
in the case of the N-methylated compound 62, suggesting that
additional contacts between the substituent at the 6-position
of the ligand and the protein surface residues have been made.
Furthermore, it may be concluded that the reduction in affinity
in the case of the N-benzyl substituent of ligand 45, is less
severe than may have been expected from substitution of the
amino group with a methyl group alone. Thus, it may also be
concluded that additional contacts are made between surface
residues on the other side of the 2-aminoquinoline binding site
and the 4-methoxybenzyl motif attached to the amino group
of 45. Additional support for this is found by consideration
of the [1H,15N] HSQC spectra of the SH3 domain, where an
unusual exchange process is observed in the presence of ligand
45. For the majority of the ligands studied in this work, fast
exchange processes on the NMR timescale have been observed
in the [1H,15N] HSQC spectra of the SH3 domain. In some
cases however, intermediate exchange processes were observed,7
as evidenced by the complete loss of, or substantial drops in,
ring would be expected for the 5-position substituent to make
the same contact(s).
On the other hand, substituents at the 6-position are clearly
well placed for the formation of new contacts with the SH3
domain, as evidenced by all the 6-substituted ligands presented
here binding with a higher affinity than 2-aminoquinoline 1.
In the case of ligands 38 and 39, the improvement in affinity
was approximately three to four-fold relative to the binding of
2-aminoquinoline 1. Furthermore, the affinities of 38 and 39
are not substantially different to those of their ‘parent’ cyclic
acetal ligands 3 and 4 (Table 1). This suggests that 38 and 39
make similar and/or additional contacts with the SH3 domain
to 3 and 4. The formation of hydrogen bonds between the
hydroxyl groups of 38 or 39 with hydrophilic residues on the
SH3 domain possibly mediates the improvement in the affinities
of these ligands relative to 1, however entropic costs associated
with hydrogen bond formation, due to the high flexibility of the
substituents on 38 and 39, do not result in optimal affinity. In the
case of the 6-hydroxymethyl and 6-aminomethyl derivatives 53
and 55, their affinities are similar to 2-amino-6-methylquinoline
2 (EC50s = 71, 102 and 75 lM for 53, 55 and 2,7 respectively,
Table 1 and Table 2) suggesting that a small lipophilic contact
mediates the improvement in affinity in these cases.
Additional consideration is required to rationalise the obser-
vations made with the 7-position ligands. Given that 2-amino-
7-methylquinoline 26 binds the SH3 domain with an approxi-
mately three-fold reduced affinity relative to 2-aminoquinoline
1, this suggests that the simple substituent of 26 is poorly
accommodated in the region adjacent to the 2-aminoquinoline
binding site and a steric penalty leads to the reduction in affinity.
However, the similar affinity of the 7-substituted-5-membered
cyclic acetal derivative 20 with 2-aminoquinoline 1 (Table 1)
suggests that the bulky lipophilic substituent of 20 is better
accommodated than the smaller substituent of 26 and thus
a new lipophilic and/or hydrophilic contact is made at this
region, but an overall improvement in affinity relative to 1 is
not observed as there are entropic penalties for the SH3 domain
associated with accommodating the substituent of 20. In the case
of the equivalent 6-membered cyclic acetal 21, an approximately
three-fold reduction in affinity relative to 2-aminoquinoline 1
is observed, suggesting that the larger size of this substituent is
poorly accommodated at the binding site relative to 20. In the
case of ligands 40, 41 and 61 with more hydrophilic and flexible
substituents, the affinities again are not substantially different to
2-aminoquinoline and are similar to the 5-membered cyclic ac-
etal 20. Hence the apparent steric clashes that lead to the reduced
affinity of the 7-methyl ligand 26 and the 6-membered acetal
21 are off-set for all the other 7-position ligands. These results
suggest that the oxygen atom(s) attached to the benzylic carbon
atom of the 7-position ligands may mediate the improvement in
affinities observed by way of a non-ideal hydrogen bond. For the
5-membered cyclic acetal 20, the steric clash observed with the
smaller 5-membered acetal is compensated for by the formation
1
intensity of the H (H–N) cross-peaks for some residues at or
near the 2-aminoquinoline binding site, at concentrations of
ligand less than one molar eq. (see for 38 in Fig. 3A). Prior to
the testing of compound 45, all examples of the intermediate
exchange observation were dependent on the concentration of
the ligand; at equimolar to excess levels of the ligand, fast
exchange characteristics were again observed (Fig. 3A). But
in the case of 45, the intermediate exchange observation for
many protein residues was observed at all ligand concentrations,
even when a large excess of ligand was present. Specifically,
in the case of the indole 1H (H–N) of the side-chain of
tryptophan 215 (W215e1), a residue central to the ligand-
binding site (Fig. 1B), the signal was not observed at any ligand
concentration (Fig. 3B). This suggests that the exchange process
for ligand 45 is closer to slow exchange than fast exchange on
the NMR timescale, possibly a result of a reduction in the off-
rate constant koff. This apparent reduction in koff may in turn
be a consequence the formation of multiple contacts between
the ligand and the protein, providing some evidence for the
formation of new contacts between the 4-methoxybenzyl motif
of the ligand and regions adjacent to where this motif sits in the
ligand-binding site. However, an overall higher affinity ligand
is not obtained in this case, possibly due to an accompanying
reduction in the on-rate constant kon. This may in turn be a
consequence of the benzyl substituent on the amino group of 45
leading to entropic costs associated with salt bridge formation
with D196.
2 5 4 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

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Fig. 3 Comparison of HSQC spectra of the Tec SH3 domain in the presence of ligands 38 and 45, which exhibit intermediate exchange properties on
the NMR timescale. (A) Overlaid HSQC spectra in the presence of intermediate exchange ligand 38, recorded with a 240 lM sample of the uniformly
15N-labelled SH3 protein. (B) As for (A), using intermediate exchange ligand 45, with a 125 lM sample of the uniformly 15N-labelled SH3 protein.
The red box indicates the region of the spectrum where the signal for W215e1 is normally observed at saturation binding of ligand [compare with 38
in (A)].
However, ligand 45 and others presented in this report remain
unsuitable for the determination of the 3D structure of the
ligand when bound to the SH3 domain, as ligands that bind
in slow exchange on the NMR timescale are necessary for this.
Slow exchange allows sufficient time for inter-molecular nuclear
Overhauser effect build-up and transfer between the ligand and
the protein, from which structure calculations are possible. Thus,
confirmation of the binding modes of the ligands discussed here
with a structure is not yet possible.
protein surface. Thus, the 6-position of the 2-aminoquinoline
platform remains the best prospect for development of optimal
interactions with regions on the SH3 domain surface adjacent to
the 5-, 6- or 7-position of the quinoline ring. The highest affinity
ligands discovered in this work (eg. ligand 38, Kd = 38 lM),
bound with comparable affinity to the highest affinity ligands
previously reported.7 However, no further improvements in
affinities were obtained. Thus further work into the development
of 6-substituted-2-aminoquinolines as Tec SH3 domain ligands,
potentially leading to optimal ligands, and with more drug-
like properties, is required. In addition, further investigation
into formation of contacts on the other side of the quinoline
ring, similar to those suggested by the binding of the 2-(4-
methoxybenzyl)aminoquinoline 45, would also be beneficial.
Conclusions
In this report, a significant extension of the initial work on
the synthesis of 6-substituted-2-aminoquinolines for Tec SH3
domain binding studies7 has been presented. Key synthetic
advancements include the preparation of several 5- and
7-substituted-2-aminoquinolines. The mixture of 2-chloro-5-
methylquinoline 6 and 2-chloro-7-methylquinoline 7 prepared
according to the method of Johnston et al.9 was con-
verted into the 2-chloro-5-formylquinoline 8 and 2-chloro-
7-formylquinoline 9, which could be separated using silica
gel chromatography, and these precursors were subsequently
used for the preparation of several 5- and 7-substituted-2-
aminoquinolines for ligand binding studies. In addition, new
methodology for the synthesis of 2-aminoquinolines from 2-
chloroquinolines was explored. This led to the development
of methods for the synthesis of 5-, 6- and 7-substituted-2-
aminoquinolines with a range of functionality. Of particular
interest is the conversion of 2-chloroquinolines into 2-(4-
methoxybenzyl)amines and their subsequent de-benzylation
with trifluoroacetic acid. With additional exploratory research
to establish milder reaction conditions for the amination re-
action, this approach may lead to the development of powerful
new methods for the synthesis of 2-aminoquinolines with diverse
functionality. In addition, the utility of ‘key intermediates’, such
as the bromomethyl-2-acetamidoquinolines 46–48, in a conver-
gent synthetic strategy also requires additional exploration.
The SAR information provided by testing all the ligands
presented here provides new and useful information about
the 2-aminoquinoline–Tec SH3 domain binding event. With
the exception of the 5-substituted ligand 60, of all the 5-,
6- and 7-substituted-2-aminoquinolines reported here, only the
6-substituted compounds bound the SH3 domain with an
improvement in affinity. It may be concluded that functionality
at the 5-position does not make any interactions with the
SH3 domain as these ligands bind with similar affinity to 2-
aminoquinoline 1. It may also be concluded that addition of new
functionality at the 7-position of the quinoline ring generally
leads to unfavourable interactions between the ligand and the
Experimental
Ligand binding studies
The testing of binding of compounds for Tec SH3 domain
binding, using either the fluorescence polarisation (FP) peptide
displacement assays or the NMR chemical shift perturbation
experiments, were performed according to protocols previously
described.7
Chemistry: general
All solvents were distilled, dried and stored according to
standard procedures.21 Melting points were determined using a
Kofler hot-stage apparatus equipped with a Reichart microscope
and values are uncorrected. Infrared spectra were recorded
on an ATI Mattson Genesis FTIR spectrometer either as
nujol mulls or as liquid films between sodium chloride plates.
1H and 13C NMR spectra were recorded on either a Varian
Gemini-2000 spectrometer (1H: 200.13 MHz, 13C: 50.32 MHz
or 1H: 300.13 MHz, 13C: 74.47 MHz), or a Varian INOVA 600
spectrometer (1H: 599.842 MHz, 13C: 150.842 MHz). The Varian
13
INOVA 600 spectrometer was fitted with a 1H{ C/15N} inverse
triple resonance PFG probe with z-axis gradients. Spectra were
recorded as solutions in CDCl3 [tetramethylsilane (dH = 0.0) or
CDCl3 (dC = 77.7) as internal references], d6-acetone [dH = 2.05,
dC = 29.9 as internal references], d6-DMSO [dH = 2.50, dC
=
39.5 as internal references] or d4-methanol [dH = 3.31, dC = 49.2
as internal references]. Chemical shift values are given on the d
scale quoted in parts per million, followed by the integration,
multiplicity, coupling constant J (given in Hz) and assignment.
The following abbreviations have been used: s, singlet; d,
doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br,
broad. Multiplicity marked with a dagger (†), is indicative of a
broadened signal due to unresolved J coupling(s). 13C signals
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 4 9

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for new compounds were assigned from heteronuclear multiple
quantum correlation (HMQC) and heteronuclear multiple bond
correlation (HMBC) experiments. Flash chromatography was
performed using Scharlau Silica Gel 60, 230–400 mesh. Thin
layer chromatography (TLC) was performed on aluminium
backed silica gel 60 plates (Merck) and were visualised under UV
light (254 nm) or by staining with a KMnO4–K2CO3 solution.
Electron impact (EI) mass spectra were recorded using a Vacuum
Generators ZAB 2HF mass spectrometer. High resolution mass
spectrometry was performed at Monash University (Victoria,
Australia) or the University of Tasmania (Tasmania, Australia).
Elemental analyses were performed at the University of Otago
(Dunedin, New Zealand).
and 1565; dH(600 MHz, CDCl3) 7.57 [1 H, d, J3,4 9.0, C(3)H],
7.91 [1 H, dd, J6,7 7.2 J7,8 8.4, C(7)H], 8.06 [1 H, dd, J6,8 1.2
J6,7 7.2, C(6)H], 8.26 [1 H, ddd, J4,8 0.6 J6,8 1.2 J7,8 8.4, C(8)H],
9.56 [1 H, dd, J4,8 0.6 J3,4 9.0, C(4)H], 10.32 [1H, s, C(5)CHO];
dC(150 MHz, CDCl3) 124.41 [C(4a)], 124.94 [C(3)], 129.55 [C(7)],
131.57 [C(5)], 135.23 [C(8)], 136.47 [C(4)], 136.92 [C(6)], 148.14
[C(8a)], 151.89 [C(2)], 192.73 [CO]; m/z (EI) 193 (M+. [37Cl], 33),
192 (M+. [37Cl]–H, 48), 191 (M+. [35Cl], 100), 190 (M+. [35Cl]–H,
91), 164 (15), 162 (43), 127 (27).
9: (found: C, 62.4; H, 3.05; N, 7.25%. C10H6ClNO requires
C, 62.7; H, 3.15; N, 7.3%); mmax(nujol)/cm−1 1684 (CO), 1587
and 1555; dH(600 MHz, CDCl3) 7.53 [1 H, d, J3,4 8.4, C(3)H],
7.94 [1 H, d, J5,6 8.4, C(5)H], 8.06 [1 H, dd, J6,8 1.6 J5,6 8.4,
C(6)H], 8.18 [1 H, dd, J4,8 0.6 J4,5 8.4, C(4)H], 8.46 [1 H, dt,
JCHO,8 = J4,8 0.6 J6,8 1.6 C(8)H], 10.22 [1 H, d, J 0.6, C(7)CHO];
dC(150 MHz, CDCl3) 123.80 [C(6)], 124.83 [C(3)], 128.77 [C(5)],
130.25 [C(4a)], 133.92 [C(8)], 137.68 [C(7)], 138.72 [C(4)], 147.56
[C(8a)], 152.06 [C(2)], 191.53 [CO]; m/z (EI) 193 (M+. [37Cl], 35),
192 (M+. [37Cl]–H, 48), 191 (M+. [35Cl], 100), 190 (M+. [35Cl]–H,
89), 164 (16), 162 (43), 127 (27).
Sources of compounds
Compounds 6 and 7 were prepared as a ca. 1 : 2 mixture
according to a literature procedure.9 Compounds 27,7 287 and
4214,15 were also prepared according to literature methods.
A pure sample of 7 was obtained by fractional crystallisation
of the 6–7 mixture with aq. methanol to afford 7 as white crystals,
mp 83–84 ◦C (lit.,22 83–84 ◦C); mmax(nujol)/cm−1 1621, 1595 and
1541; dH(200 MHz; CDCl3) 2.55 [3 H, s, C(7)Me], 7.30 [1 H, d,
J 8.6, C(3)H], 7.38 [1 H, dd, J6,8 1.6 J5,6 8.2, C(6)H], 7.69 [1 H,
d, J5,6 8.2, C(5)H], 7.79 [1 H, dd, J6,8 1.6 J4,8 0.8, C(8)H], 8.03 [1
H, dd, J4,8 0.8 J3,4 8.4, C(4)H].
General procedure for acetal formation
The formyl compound (8 or 9), the diol (1.1–2 eq.) and p-
toluenesulfonic acid monohydrate (0.05–0.1 eq.) were heated at
reflux in benzene (∼4 mL mmol−1 aldehyde) using a Dean Stark
apparatus until thin layer chromatography indicated that all the
starting material had been consumed. After cooling, the benzene
was removed under a reduced pressure and the residue was taken
up into dichloromethane, washed twice with water and once with
brine, dried (Na2SO4) and the solvent was removed. The residue
was then chromatographed on silica gel using dichloromethane
as eluant to afford the analytically pure product.
2-Chloro-5-formylquinoline 8/2-chloro-7-formylquinoline 9.
The 6–7 mixture‡ (2.50 g, 14.1 mmol), N-bromosuccinimide
(5.00 g, 28.2 mmol) and benzoyl peroxide (0.34 g, 1.41 mmol)
were heated at reflux in benzene (10 mL) for 15 h. After cooling,
the benzene was removed and the residue was filtered through sil-
ica gel using dichloromethane as eluant. Following purification
by column chromatography on silica gel (4 : 1 dichloromethane–
hexane), a mixture of the dibrominated products 10 and 11
(2.89 g, 73%) (Rf 0.54) was isolated, in addition to a small
amount of a ca. 5 : 1 mixture of monobrominated/dibrominated
products (12 and 13)/(10 and 11) (Rf 0.43).
‡ Prior to the reaction, the 6–7 mixture was partially purified
by filtration through silica gel using dichloromethane as eluant.
10/11: dH(200 MHz; CDCl3) 6.81 [1 H, s, C(7*)CHBr2], 7.16
[1 H, s, C(5)CHBr2], 7.43 [1 H, d, J3,4 8.4, C(3*)H], 7.56 [1 H,
d, J3,4 8.9, C(3)H], 7.67 [1 H, t, J6,7 and J7,8 8.0, C(7)H], 7.82
[1 H, d, J6,7 8.0, C(6)H], 7.88 [2 H, m, C(5*, 6*)H], 8.05 [1 H,
d, J4,8 0.8, C(8*)H], 8.08–8.13 [2 H, m, C(4*, 8)H], 8.87 [1 H,
d, J3,4 8.9, C(4)H]; m/z (EI) 332.8541 (C10H679Br235ClN requires
332.8555), 256 (100%).
2-Chloro-5-(1,3-dioxolan-2-yl)quinoline 14. 2-Chloro-5-
formylquinoline 8 (0.70 mg, 3.65 mmol) was treated with
ethylene glycol (0.45 g, 7.30 mmol) and p-toluenesulfonic acid
monohydrate (0.021 g, 0.11 mmol) in 10 mL of benzene as
described above. Following workup and chromatography, the
title compound 14 (0.68 g, 79%) (Rf 0.31) was isolated, mp
100–103 ◦C. (Found: C, 61.4; H, 4.15; N, 5.85%. C12H10ClNO2
requires C, 61.15; H, 4.3; N, 5.95%); mmax(nujol)/cm−1 1613, 1594
and 1568; dH(200 MHz, CDCl3) 4.15–4.21 [4 H, m, C(4ꢀ, 5ꢀ)H],
6.34 [1 H, s†, C(2ꢀ)H], 7.43 [1 H, d, J3,4 9.0, C(3)H], 7.72 [1 H,
ꢀ
dd, J6,7 7.2 J7,8 7.8, C(7)H], 7.80 [1 H, ddd, J2 ,6 0.6 J6,8 1.8 J6,7
7.2, C(6)H], 8.04 [1 H, ddd, J4,8 0.8 J6,8 1.8 J7,8 7.8, C(8)H], 8.55
[1 H, dd, J4,8 0.8 J3,4 9.0, C(4)H]; dC(150 MHz, CDCl3) 65.51
[C(4ꢀ, 5ꢀ)], 101.92 [C(2ꢀ)], 122.22 [C(3)], 124.73 [C(4a)], 124.77
[C(6)], 129.77 [C(7)], 129.91 [C(8)], 133.84 [C(5)], 135.89 [C(4)],
148.27 [C(8a)], 150.55 [C(2)]; m/z (EI) 237 (M+. [37Cl], 8), 235
(M+. [35Cl], 22), 163 (9), 165 (3).
* Refers to 11.
12/13: dH(200 MHz; CDCl3) 4.65 [1 H, s, C(5)CH2Br], 4.87
[1 H, s, C(7*)CH2Br], 7.34–7.70 [m, C(Ar)H], 7.76–7.86 [m,
C(Ar)H], 7.97–8.10 [m, C(Ar)H], 8.42 [1 H, dd, J 0.8 J 8.8, C(4*
or 8)H]; m/z (EI) 257 (M+. [79Br37Cl], 8), 256 (M+. [79Br37Cl]–H,
14), 255 (M+. [79Br35Cl], 5), 254 (M+. [79Br35Cl]–H, 4) 192 (20),
178 (M+. [79Br37Cl]–Br, 30), 176 (M+. [79Br35Cl]–Br, 100), 163 (36),
128 (39).
2-Chloro-5-(1,3-dioxan-2-yl)quinoline 15. 2-Chloro-5-
formylquinoline 8 (0.60 g, 3.13 mmol) was treated with 1,3-
propanediol (0.48 g, 6.26 mmol) and p-toluenesulfonic acid
monohydrate (0.018 g, 0.939 mmol) in 9 mL of benzene as
described above. Following workup and chromatography the
title compound 15 (0.59 g, 73%) (Rf 0.16) was isolated, mp
101–103 ◦C. (Found: C, 62.55; H, 4.75; N, 5.55%. C13H12ClNO2
requires C, 62.55; H, 4.85; N, 5.6%); mmax(nujol)/cm−1 1590 and
* Refers to 13.
The mixture of 10 and 11 prepared above (2.80 g, 8.35 mmol)
was treated with hexamethylenetetraamine (3.51 g, 25.1 mmol)
in 50% aq. ethanol (10 mL) with heating at reflux for 2.5 h. After
cooling, concentrated hydrochloric acid (1.5 mL) was added and
the mixture was heated at reflux for a further 30 min. After
cooling, brine (10 mL) was added and the mixture was extracted
with dichloromethane (3 × 15 mL). The combined extracts were
dried (Na2SO4) and the solvent was removed. The residue was
chromatographed on silica gel using 4 : 1 dichloromethane–
hexane as eluant to provide the pure title compound 8 (0.460 g,
29%) (Rf 0.34) as white crystals, mp 144–146 ◦C (from aq.
ethanol). In addition, the pure title compound 9 (0.590 g, 37%)
(Rf 0.19) was also isolated as a white solid, mp 130–133 ◦C.
8: (found: C, 62.4; H, 2.95; N, 7.3%. C10H6ClNO requires C,
62.7; H, 3.15; N, 7.3%); mmax(nujol)/cm−1 1693 (CO), 1606, 1583
ꢀ
ꢀ
ꢀ
ꢀ
1570; dH(600 MHz, CDCl3) 1.53 [1 H, dtt, J4 eq,5 eq 1.3 J4 ax,5 eq
2.6 J5 ax,5 eq 13.7, C(5ꢀ)Heq], 2.34 [1 H, dtt, J4 eq,5 ax 5.0 J4 ax,5 ax 12.5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J5 ax,5 eq 13.7, C(5ꢀ)Hax], 4.05–4.10 [2 H, m, C(4ꢀ, 6ꢀ)H], 4.32–4.35
ꢀ
ꢀ
[2 H, m, C(4ꢀ, 6ꢀ)H], 5.91 [1 H, s†, C(2ꢀ)H], 7.39 [1 H, d, J3,4 9.0,
ꢀ
C(3)H], 7.69 [1 H, dd, J6,7 7.2 J7,8 8.2, C(7)H], 7.72 [1 H, ddd, J2 ,6
0.8 J6,8 1.6 J6,7 7.2, C(6)H], 8.01 [1 H, ddd, J4,8 0.8 J6,8 1.6 J7,8 8.2,
C(8)H], 8.69 [1 H, dd, J4,8 0.8 J3,4 9.0, H(4)]; dC(150 MHz, CDCl3)
25.73 [C(5ꢀ)], 67.66 [C(4ꢀ, 6ꢀ)], 101.33 [C(2ꢀ)], 122.01[C(3)], 124.32
[C(4a)], 125.46 [C(6)], 129.68 [C(7)], 129.81 [C(8)], 134.50 [C(5)],
136.67 [C(4)], 148.31 [C(8a)], 150.40 [C(2)]; m/z (EI) 251 (M+.
2 5 5 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

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[37Cl], 21), 249 (M+. [35Cl], 63), 192 (19), 190 (52), 165 (19), 163
(63).
(C12H12N2O2 requires 216.0899), 172 (11), 171 (16), 144 (100),
143 (18).
22: dH(200 MHz, CDCl3) 4.08–4.24 [4 H, m, C(4ꢀ, 5ꢀ)H], 6.21
2-Chloro-7-(1,3-dioxolan-2-yl)quinoline 16. 2-Chloro-7-
formylquinoline 9 (0.60 g, 3.13 mmol) was treated with ethy-
lene glycol (0.39 g, 6.26 mmol) and p-toluenesulfonic acid
monohydrate (0.018 g, 0.939 mmol) in 9 mL of benzene as
described above. Following workup and chromatography, the
title compound 16 (0.38 g, 51%) (Rf 0.14) was isolated, mp
88–90 ◦C. (Found: C, 60.85; H, 4.1; N, 5.75%. C12H10ClNO2
requires C, 61.15; H, 4.3; N, 5.95%); mmax(nujol)/cm−1 1590 and
1566; dH(200 MHz, CDCl3) 4.06–4.22 [4 H, m, C(4ꢀ, 5ꢀ)H], 6.02
[1 H, s†, C(2ꢀ)H], 7.41 [1 H, d, J3,4 8.8, C(3)H], 7.68 [1 H,
dd†, J6,8 1.6 J5,6 8.4, C(6)H], 7.85 [1 H, d, J5,6 8.4 Hz, C(5)H],
8.10–8.14 [2 H, m, C(4, 8)H]; dC(50 MHz, CDCl3) 65.6 [C(4ꢀ,
5ꢀ)], 103.3 [C(2ꢀ)], 122.9 [C(3)], 125.2 [C(6)], 126.8 [C(8)], 127.2
[C(4a)], 128.0 [C(5)], 138.7 [C(4)], 140.0 [C(7)], 147.7 [C(8a)],
151.2 [C(2)]; m/z (EI) 237 (M+. [37Cl], 23) 235 (M+. [35Cl], 70),
192 (11), 190 (28), 165 (27), 163 (100).
[1 H, s†, C(2ꢀ)H], 6.76 [1 H, d, J3,4 10.0, C(3)H], 7.41–7.50 [3 H,
m, C(6, 7, 8)H], 8.27 [1 H, d, J3,4 10.0, C(4)H], 12.19 [1 H, br s,
NH].
2-Amino-5-(1,3-dioxan-2-yl)quinoline 19. 2-Chloro-5-(1,3-
dioxan-2-yl)quinoline 15 (0.200 g, 0.801 mmol) was treated
with acetamide (0.950 g, 16.0 mmol) and potassium carbonate
(0.550 g, 4.01 mmol) as described above. After workup and
chromatography, the title compound 19 (0.135 g, 73%) (Rf 0.16)
was isolated, mp 186–210 ◦C. In addition, the by-product 5-(1,3-
dioxan-2-yl)quinolin-2(1H)-one 23 (0.028 g, 15%) (Rf 0.41) was
isolated, mp >230 ◦C.
19: (found: C, 67.9; H, 6.0; N, 12.0%. C13H14N2O2 requires
C, 67.8; H, 6.15; N, 12.15%); mmax(nujol)/cm−1 3458 and 3316
(NH), 1654, 1618, 1572 and 1522; dH(200 MHz, CDCl3) 1.52 [1
H, dtt, J4 eq,5 eq 1.4 J4 ax,5 eq 2.6 J5 ax,5 eq 13.4, C(5ꢀ)Heq], 2.20 [1 H,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
dtt, J4 eq,5 ax 5.2 J4 ax,5 ax 12.0 J5 ax,5 eq 13.4, C(5ꢀ)Hax], 4.02–4.27 [4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2-Chloro-7-(1,3-dioxan-2-yl)quinoline 17. 2-Chloro-7-
formylquinoline 9 (0.60 g, 3.13 mmol) was treated with 1,3-
propanediol (0.48 g, 6.26 mmol) and p-toluenesulfonic acid
monohydrate (0.018 g, 0.939 mmol) in 9 mL of benzene as
described above. Following workup and chromatography, the
title compound 17 (0.47 g, 60%) (Rf 0.15) was isolated, mp
134–136 ◦C. (Found: C, 62.8; H, 4.75; N, 5.55%. C12H10ClNO2
requires C, 62.55; H, 4.85; N, 5.6%); mmax(nujol)/cm−1 1626, 1588
H, m, C(4ꢀ, 6ꢀ)H], 5.84 [1 H, br s, NH], 5.92 [1 H, s†, C(2ꢀ)H],
ꢀ
6.85 [1 H, d, J3,4 9.2, C(3)H], 7.34 [1 H, ddd, J2 ,6 0.4 J6,8 1.8
J6,7 7.0, C(6)H], 7.43 [1 H, dd, J7,8 8.2 J6,7 7.0, C(7)H], 8.12 [1
H, ddd, J4,8 0.6 J6,8 1.8 J7,8 8.2, C(8)H], 8.07 [1 H, dd, J4,8 0.6
J3,4 9.2, C(4)H]; dC(50 MHz, CDCl3) 25.9 [C(5ꢀ)], 67.7 [C(4ꢀ,
6ꢀ)], 101.9 [C(2ꢀ)], 111.5 [C(3)], 120.7 [C(4a)], 121.6 [C(6)], 127.1
[C(8)], 129.1 [C(7)], 134.2 [C(5)], 135.7 [C(4)], 147.5 [C(8a)],
156.3 [C(2)]; m/z (EI) 230 (M+., 100), 172 (48), 171 (24), 144
(60), 143 (25).
ꢀ
ꢀ
ꢀ
ꢀ
and 1565; dH(600 MHz, CDCl3) 1.49 [1 H, dtt, J4 eq,5 eq 1.2 J4 ax,5 eq
2.4 J5 ax,5 eq 13.2, C(5ꢀ)Heq], 2.26 [1 H, dtt, J4 eq,5 ax 4.8 J4 ax,5 ax 12.6
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
23: mmax(nujol)/cm−1 3410 (NH), 1691 (CO), 1659 and 1598;
dH(200 MHz, CDCl3) 1.42–2.04 [1 H, m, C(5ꢀ)Heq], 2.05–2.30 [1
H, m, C(5ꢀ)Hax], 4.04–4.28 [4 H, m, C(4ꢀ, 6ꢀ)H], 5.93 [1 H, s†,
C(2ꢀ)H], 6.50 [1 H, d, J3,4 10.0, C(3)H], 7.30–7.51 [3 H, m, C(6,
7, 8)H], 8.36 [1 H, d†, J3,4 10.0, C(4)H], 11.95 [1H, br s, NH];
dC(50 MHz, CDCl3) 25.8 [C(5ꢀ)], 67.7 [C(4ꢀ, 6ꢀ)], 101.4 [C(2ꢀ)],
117.1 [C(4a)], 117.3 [C(8)], 121.3 [C(6)], 121.5 [C(3)], 130.1
[C(7)], 135.2 [C(5)], 138.4 [C(4)], 139.0 [C(8a)], 163.4 [C(2)]; m/z
(EI) 231.0895 (C13H13NO3 requires 231.0895), 173 (67), 172 (64),
145 (48), 144 (20).
J5 ax,5 eq 13.2, C(5ꢀ)Hax], 4.02–4.07 [2 H, m, C(4ꢀ, 6ꢀ)H], 4.29–4.32
[2 H, m, C(4ꢀ, 6ꢀ)H], 5.67 [1 H, s†, C(2ꢀ)H], 7.37 [1 H, d, J3,4 8.4,
C(3)H], 7.72 [1 H, dd†, J6,8 1.2 J5,6 8.4, C(6)H], 7.81 [1 H, d, J5,6
8.4, H(5)], 8.07 [1 H, dd, J4,8 0.6 J3,4 8.4, C(4)H], 8.12 [1 H, dd†,
ꢀ
ꢀ
J
4,8 0.6 J6,8 1.2, C(8)H]; dC(150 MHz, CDCl3) 25.70 [C(5ꢀ)], 67.40
[C(4ꢀ, 6ꢀ)], 100.87 [C(2ꢀ)], 122.57 [C(3)], 124.92 [C(6)], 126.24
[C(8)], 126.83 [C(4a)], 127.62 [C(5)], 138.58 [C(4)], 141.16 [C(7)],
147.52 [C(8a)], 150.78 [C(2)]; m/z (EI) 251 (M+. [37Cl], 32), 249
(M+. [35Cl], 100), 192 (29), 190 (64), 165 (20), 163 (60).
General procedure for amination of 2-chloroquinolines according
to the method of Ko´ro´di8
2-Amino-7-(1,3-dioxolan-2-yl)quinoline 20. 2-Chloro-7-(1,3-
dioxolan-2-yl)quinoline 16 (0.200 g, 0.849 mmol) was treated
with acetamide (1.00 g, 17.0 mmol) and potassium carbonate
(0.590 g, 4.25 mmol) as described above. Following workup and
chromatography, the title compound 20 (0.114 g, 62%) (Rf 0.14)
was isolated, mp 159–169 ◦C. In addition, the by-product 7-(1,3-
dioxolan-2-yl)quinolin-2(1H)-one 24 (0.022 g, 12%) (Rf 0.36)
was also isolated, mp 195–200 ◦C.
20: (found: C, 66.45; H, 5.5; N, 12.7%. C12H12N2O2 requires C,
66.65; H, 5.6; N, 12.95%); mmax(nujol)/cm−1 3453 and 3311 (NH),
1644, 1628, 1565 and 1515; dH(200 MHz, CDCl3) 3.96–4.16 [4
H, m, C(4ꢀ, 5ꢀ)H], 5.85 [1 H, s†, C(2ꢀ)H], 5.94 [2 H, br s, NH2],
The 2-chloroquinoline (1 eq.) was treated with acetamide (20
eq.) and potassium carbonate (5 eq.) at ∼200 ◦C until thin layer
chromatography (9 : 1 dichloromethane–ethanol) indicated the
reaction was complete (∼1–2 h). After cooling, water was added
to the residue and the aqueous layer was extracted three times
with chloroform. The combined organic extracts were washed
with brine, dried (Na2SO4) and the solvent was removed. Unless
otherwise indicated, the residues were chromatographed over
silica gel using 9 : 1 dichloromethane–ethanol as eluant to afford
the pure 2-aminoquinolines. In most cases, the accompanying
quinolin-2(1H)-ones were also isolated.
ꢀ
6.87 [1 H, d, J3,4 9.0, C(3)H], 7.27 [1 H, ddd, J2 ,6 0.6 J6,8 1.6 J5,6
8.4, C(6)H], 7.62–7.66 [2 H, m, C(5, 8)H], 7.91 [1 H, d†, J3,4 9.0,
C(4)H]; dC(50 MHz, CDCl3) 65.6 [C(4ꢀ, 5ꢀ)], 103.9 [C(2ꢀ)], 112.3
[C(3)], 120.9 [C(6)], 124.1 [C(4a)], 124.2 [C(8)], 128.0 [C(5)],
138.1 [C(4)], 140.0 [C(7)], 147.3 [C(8a)], 157.4 [C(2)]; m/z (EI)
216 (M+., 15), 171 (4), 144 (21), 143 (4).
2-Amino-5-(1,3-dioxolan-2-yl)quinoline 18. 2-Chloro-5-(1,3-
dioxolan-2-yl)quinoline 14 (0.20 g, 0.849 mmol) was treated
with acetamide (1.0 g, 17.0 mmol) and potassium carbonate
(0.59 g, 4.25 mmol) as described above. Following workup and
chromatography, the title compound 18 (0.079 g, 43%) (Rf 0.23)
was isolated, mp 170–178 ◦C. In addition, the by-product 5-(1,3-
dioxolan-2-yl)quinolin-2(1H)-one 22 (0.036 g) (Rf 0.50) was also
isolated in an impure form.
24: mmax(nujol)/cm−1 3447 (NH), 1656 (CO), 1608 and 1555;
dH(200 MHz, CDCl3) 4.03–4.20 [4 H, m, C(4ꢀ, 5ꢀ)H], 5.90 [1
H, s†, C(2ꢀ)H], 6.71 [1 H, d, J3,4 9.4, C(3)H], 7.34 [1 H, dd†, J6,8
1.6 J5,6 8.0, C(6)H], 7.45 [1 H, d†, J6,8 1.6, C(8)H], 7.58 [1 H, d,
J5,6 8.0, C(5)H], 7.80 [1 H, d†, J3,4 9.4, C(4)H], 11.26 [1 H, br s,
NH]; dC(50 MHz, CDCl3) 65.7 [C(4ꢀ, 5ꢀ)], 103.2 [C(2ꢀ)], 114.4
[C(8)], 120.7 [C(4a)], 121.2 [C(6)], 121.9 [C(3)], 128.3 [C(5)],
138.4 [C(8a)], 141.0 [C(4)], 141.4 [C(7)], 164.3 [C(2)]; m/z (EI)
217.0739 (C12H11NO3 requires 217.0739), 173 (35), 172 (36), 145
(100).
18: mmax(nujol)/cm−1 3446 and 3301 (NH), 1652, 1610, 1570
and 1518; dH(600 MHz, CDCl3) 4.10–4.21 [4 H, m, C(4ꢀ, 5ꢀ)H],
4.97 [2 H, br s, NH2], 6.29 [1 H, s†, C(2ꢀ)H], 6.76 [1 H, d, J3,4 9.0,
ꢀ
C(3)H], 7.49 [1 H, ddd, J2 ,6 0.6 J6,8 1.2 J6,7 7.2, C(6)H], 7.54 [1
H, dd, J7,8 8.4 J6,7 7.2, C(7)H], 7.68 [1 H, ddd, J4,8 0.6 J6,8 1.2 J7,8
8.4, C(8)H], 8.32 [1 H, dd, J4,8 0.6 J3,4 9.0, C(4)H]; dC(150 MHz,
CDCl3) 65.24 [C(4ꢀ, 5ꢀ)], 102.30 [C(2ꢀ)], 111.61 [C(3)], 120.84
[C(6)], 121.17 [C(4a)], 127.18 [C(8)], 129.15 [C(7)], 133.39 [C(5)],
134.94 [C(4)], 147.41 [C(8a)], 156.38 [C(2)]; m/z (EI) 216.0896
2-Amino-7-(1,3-dioxan-2-yl)quinoline 21. 2-Chloro-7-(1,3-
dioxan-2-yl)quinoline 17 (0.200 g, 0.801 mmol) was treated
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 5 1

View Online
with acetamide (1.00 g, 17.0 mmol) and potassium carbonate
(0.550 g, 4.01 mmol) as described above. Following workup and
chromatography, the title compound 21 (0.134 g, 73%) (Rf 0.16)
was isolated, mp 175–196 ◦C. In addition the by-product 7-(1,3-
dioxan-2-yl)quinolin-2(1H)-one 25 (0.022 g, 12%) (Rf 0.47) was
also isolated, mp 196–204 ◦C.
21: (found: C, 67.8; H, 6.15; N, 12.15%. C13H14N2O2 requires
C, 67.8; H, 6.15; N, 12.15%); mmax(nujol)/cm−1 3458 and 3291
(NH), 1641, 1626, 1566 and 1518; dH(600 MHz, CDCl3) 1.46 [1
2-Chloro-5-[(2-hydroxyethoxy)methyl]quinoline 29. The gen-
eral procedure described above was used with aluminium
chloride (0.715 g, 5.36 mmol) in dry THF (4 mL), lithium
aluminium hydride (0.116 g, 3.06 mmol) and acetal 14 (0.600 g,
2.55 mmol) dissolved in dry THF (7.2 mL). Following workup,
sufficiently pure title compound 29 (0.580 g, 96%) was isolated.
A portion was chromatographed using 3 : 1 dichloromethane–
ethyl acetate as eluant (Rf 0.26), to afford analytically pure 29,
mp 58–60 ◦C. (Found: C, 60.35; H, 5.15; N, 5.85%. C12H12ClNO2
requires C, 60.65; H, 5.1; N, 5.9%); mmax(nujol)/cm−1 3306 (OH),
1674, 1613, 1592 and 1572; dH(200 MHz, CDCl3) 2.78 [1 H,
br s, OH], 3.58–3.78 [4 H, m, C(1, 2)H], 4.91 [2 H, s, C(5ꢀ)CH2],
H, dtt, J4 eq,5 eq 1.2 J4 ax,5 eq 2.4 J5 ax,5 eq 13.8, C(5ꢀ)Heq], 2.25 [1 H,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
dtt, J4 eq,5 ax 4.8 J4 ax,5 ax 12.6 J5 ax,5 eq 13.8, C(5ꢀ)Hax], 4.00–4.04 [2
H, m, C(4ꢀ, 6ꢀ)H], 4.27–4.30 [2 H, m, C(4ꢀ, 6ꢀ)H], 5.19 [2 H, br s,
NH2], 5.61 [1 H, s†, C(2ꢀ)H], 6.72 [1 H, d, J3,4 = 9.0, C(3)H], 7.43
[1 H, dd†, J6,8 1.2 J5,6 8.4, C(6)H], 7.61 [1 H, d, J5,6 8.4, C(5)H],
7.76 [1 H, dd†, J4,8 0.6 J6,8 1.2, C(8)H], 7.85 [1 H, dd, J4,8 0.6
J3,4 9.0, C(4)H]; dC(150 MHz, CDCl3) 25.78 [C(5ꢀ)], 67.38 [C(4ꢀ,
6ꢀ)], 101.50 [C(2ꢀ)], 112.08 [C(3)], 120.63 [C(6)], 123.18 [C(8)],
123.49 [C(4a)], 127.68 [C(5)], 138.18 [C(4)], 140.46 [C(7)], 146.28
[C(8a)], 156.88 [C(2)]; m/z (EI) 230 (M+., 94), 172 (100), 171 (49),
144 (81), 143 (39).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
7.35 [1 H, d, J3 ,4 8.8, C(3ꢀ)H], 7.49 [1 H, dd, J6 ,8 1.2 J6 ,7 7.0,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
C(6ꢀ)H], 7.62 [1 H, dd, J6 ,7 7.0 J7 ,8 8.4, C(7ꢀ)H], 7.94 [1 H,
ꢀ
ꢀ
ꢀ ꢀ
ddd, J4 ,8 0.6 J6 ,8 1.2 J7 ,8 8.4, C(8ꢀ)H], 8.39 [1 H, dd, J4 ,8 0.6
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
J3 ,4 8.8, C(4ꢀ)H]; dC(50 MHz, CDCl3) 61.6 [C(2)], 71.0 [C(1)],
71.7 [C(5ꢀ)CH2], 122.2 [C(3ꢀ)], 125.5 [C(4aꢀ)], 127.3 [C(6ꢀ)], 128.9
[C(8ꢀ)], 129.9 [C(7ꢀ)], 134.3 [C(5ꢀ)], 135.8 [C(4ꢀ)], 148.1 [C(8aꢀ)],
150.5 [C(2ꢀ)]; m/z (EI) 239 (M+. [37Cl], 15), 237 (M+. [35Cl], 44),
194 (34), 192 (100), 178 (M+. [37Cl] − HO(CH2)2O, 26), 176 (M+.
[35Cl] − HO(CH2)2O, 81).
ꢀ
ꢀ
25: mmax(nujol)/cm−1 3436 (NH), 1669 (CO), 1611 and 1557;
dH(600 MHz, CDCl3) 1.48 [1 H, dtt, J4 eq,5 eq 1.2 J4 ax,5 eq 2.4 J5 ax,5 eq
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2-Chloro-5-[(3-hydroxypropoxy)methyl]quinoline
30. The
13.2, C(5ꢀ)Heq], 2.25 [1 H, dtt, J4 eq,5 ax 4.8 J4 ax,5 ax 12.6 J5 ax,5 eq 13.2,
C(5ꢀ)Hax], 4.00–4.04 [2 H, m, C(4ꢀ, 6ꢀ)H], 4.28–4.31 [2 H, m, C(4ꢀ,
6ꢀ)H], 5.59 [1 H, s†, C(2ꢀ)H], 6.75 [1 H, d, J3,4 9.6, C(3)H], 7.39
[1 H, dd†, J6,8 1.2 J5,6 8.4, C(6)H], 7.53 [1 H, d†, J6,8 1.2, C(8)H],
7.58 [1 H, d, J5,6 8.4, C(5)H], 7.83 [1 H, d†, J3,4 9.6, C(4)H], 12.01
[1H, br s, NH]; dC(150 MHz, CDCl3) 25.67 [C(5ꢀ)], 67.42 [C(4ꢀ,
6ꢀ)], 100.65 [C(2ꢀ)], 114.05 [C(8)], 120.23 [C(4a)], 120.81 [C(6)],
121.27 [C(3)], 127.89 [C(5)], 137.98 [C(8a)], 141.05 [C(4)], 141.62
[C(7)], 164.17 [C(2)]; m/z (EI) 231.0894 (C13H13NO3 requires
231.0895), 173 (84), 172 (96), 145 (56), 144 (29).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
general procedure described above was used with aluminium
chloride (1.14 g, 8.52 mmol) in dry THF (6.4 mL), lithium
aluminium hydride (0.183 g, 4.82 mmol) and acetal 15 (1.00 g,
4.02 mmol) dissolved in dry THF (12 mL). Following workup,
the residue was chromatographed using ethyl acetate as eluant to
afford pure 30 (0.680 g, 67%) (Rf 0.47) as an oil. In addition, the
by-product 5-[3-(hydroxypropoxy)methyl]-3,4-dihydroquinolin-
2(1H)-one 35 (0.087 g, 9%) (Rf of 0.17) was also isolated, mp
97–100 ◦C.
30: mmax(nujol)/cm−1 3392 (OH), 1612, 1591 and 1568;
dH(200 MHz, CDCl3) 1.86 [2 H, quin, J 5.8, C(2)H], 2.66 [1H,
br s, OH], 3.68 [2 H, t, J 5.8, C(1)H], 3.73 [2 H, t, J 5.8, C(3)H],
2-Amino-7-methylquinoline 26. 2-Chloro-7-methylquinolone
7 (0.200 g, 1.13 mmol) was treated with acetamide (1.33 g,
22.6 mmol) and potassium carbonate (0.780 g, 5.65 mmol) as
described above. Following workup and chromatography the
title ◦compound 26 (0.110 g, 61%) (Rf 0.18) was isolated, mp 131–
4.88 [2 H, s, C(5ꢀ)CH2], 7.40 [1 H, d, J3 ,4 8.8, C(3ꢀ)H], 7.51 [1
ꢀ
ꢀ
H, dd, J6 ,8 0.8 J6 ,7 7.0, C(6ꢀ)H], 7.65 [1 H, dd, J6 ,7 7.0 J7 ,8
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
8.4, C(7ꢀ)H], 7.96 [1 H, dd†, J6 ,8 0.8 J7 ,8 8.4, C(8ꢀ)H], 8.40
ꢀ
ꢀ
ꢀ ꢀ
[1 H, d†, J3 ,4 8.8, C(4ꢀ)H]; dC(150 MHz, CDCl3) 32.16 [C(2)],
60.85 [C(3)], 68.75 [C(1)], 71.00 [C(5ꢀ)CH2], 122.26 [C(3ꢀ)], 125.49
[C(4aꢀ)], 127.33 [C(6ꢀ)], 128.91 [C(8ꢀ)], 129.93 [C(7ꢀ)], 134.26
[C(5ꢀ)], 135.67 [C(4ꢀ)], 148.20 [C(8aꢀ)], 150.52 [C(2ꢀ)]; m/z (EI)
251.0706 (C13H14ClNO2 requires 251.0713), 194 (39), 192 (100),
178 (33), 176 (89).
ꢀ
ꢀ
◦
135 C (from water) (lit.,23 134–135 C). mmax(nujol)/cm−1 3435
and 3301 (NH), 1651, 1624, 1608, 1563 and 1515; dH(200 MHz,
CDCl3) 2.47 [1 H, s, C(7)Me], 5.04 [2H, br s, NH2], 6.63 [1 H,
d, J3,4 8.8, C(3)H], 7.08 [1 H, dd, J6,8 1.6 J5,6 8.4, C(6)H], 7.45 [1
4
H, dd, J4,8 0.6 J6,8 1.6, C(8)H], 7.49 [1 H, d, J5,6 8.4, C(5)H],
7.79 [1 H, dd, J4,8 0.6 J3,4 8.8, C(4)H]; dC(50 MHz, CDCl3)
22.0 [C(7)Me], 110.9 [C(3)], 121.7 [C(4a)], 124.9 [C(6)], 125.4
[C(8)], 127.3 [C(5)], 138.0 [C(4)], 140.2 [C(7)], 147.9 [C(8a)],
157.3 [C(2)].
35: (found: C, 66.55; H, 7.35; N, 5.65%. C13H15NO3 requires
C, 66.35; H, 7.3; N, 5.95%); mmax(nujol)/cm−1 3316 and 3195 and
3144 (NH), 1706 (CO), 1659 and 1598; dH(200 MHz, CDCl3)
1.86 [2 H, quin, J 5.8, C(2)H], 2.58–3.02 [5 H, m, C(3ꢀ, 4ꢀ)H and
OH], 3.64 [2 H, t, J 5.8, C(1)H], 3.76 [2 H, t, J 5.8, C(3)H], 4.50 [2
H, s, C(5ꢀ)CH2], 6.83 [1 H, dd, J6 ,8 1.2 J6 ,7 7.8, C(6ꢀ)H], 6.99 [1
ꢀ ꢀ
ꢀ ꢀ
General procedure for acetal reduction to form acyclic alcohols
H, dd, J6 ,8 1.2 J7 ,8 7.4, C(8ꢀ)H], 7.13 [1 H, dd, J7 ,8 7.4 J6 ,7 7.8,
C(7ꢀ)H], 9.47 [1 H, br s, NH]; dC(50 MHz, CDCl3) 21.6 [C(4ꢀ)],
30.4 [C(3ꢀ)], 32.4 [C(2)], 61.3 [C(3)], 69.1 [C(1)], 71.4 [C(5ꢀ)CH2],
116.0 [C(8ꢀ)], 122.7 [C(4aꢀ)], 124.2 [C(6ꢀ)], 127.3 [C(7ꢀ)], 135.7
[C(5ꢀ)], 137.9 [C(8aꢀ)], 172.3 [C(2ꢀ)]; m/z (EI) 235 (M+., 30), 176
(18), 159 (100).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
Aluminium chloride (2.1 eq.) was placed in an oven-dried round-
bottomed flask under a nitrogen atmosphere at ca. 0 ◦C, and dry
THF (∼1 mL mmol−1 AlCl3) was added. The mixture was stirred
at ca. 0 ◦C until a uniform suspension was obtained before the
careful addition of lithium aluminium hydride (1.2 eq.), portion-
wise over 5 min. Stirring was continued at ca. 0 ◦C for 30 min,
before the acetal (1 eq.) dissolved in dry THF (∼3 mL mmol−1
acetal) was added drop-wise over 10 min. The mixture was
then stirred at rt for 15 min, before heating at reflux until
the reaction was complete (∼3–4 h), as judged by TLC. After
cooling, the mixture was added cautiously and portion-wise
to ice (∼30 g mmol−1 of acetal) with stirring and stirring was
continued until the evolution of gas had ceased. Concentrated
sulfuric acid (∼0.4 mL mmol−1 acetal) was then added and
stirring was continued for 15 min. The THF was removed under
a reduced pressure and the remaining aqueous solution was
extracted with dichloromethane (3 ×). The combined organic
layers were washed with brine (1 ×), dried (Na2SO4) and
the solvent was removed to afford the crude alcohol. Purified
products were obtained following chromatography on silica gel.
2-Chloro-6-[(2-hydroxyethoxy)methyl]quinoline 31. The gen-
eral procedure described above was used with aluminium
chloride (0.988 g, 7.41 mmol) in dry THF (6 mL), lithium
aluminium hydride (0.161 g, 4.24 mmol) and acetal 27 (0.832 g,
3.53 mmol) dissolved in dry THF (11 mL) with heating at reflux
for 5 h. Following workup and chromatography using 3 : 1
dichloromethane–ethyl acetate as eluant, pure 31 (0.621 g, 74%)
(Rf 0.20) was isolated as fluffy white crystals, mp 51–53 ◦C.
(Found: C, 60.4; H, 5.05; N, 5.85%. C12H12ClNO2 requires C,
60.65; H 5.1; N, 5.9%); mmax(nujol)/cm−1 3332 (OH), 1586, 1565
and 1499; dH(300 MHz, CDCl3) 2.17 [1 H, br s, OH], 3.65–3.68
[2 H, m, AAꢀ portion of AAꢀBBꢀ, C(1)H], 3.80–3.83 [2 H, m, BBꢀ
portion of AAꢀBBꢀ, C(2)H], 4.73 [2 H, s, C(6ꢀ)CH2], 7.38 [1 H, d,
J3 ,4 8.9, C(3ꢀ)H], 7.70 [1 H, dd, J5 ,7 1.5 J7 ,8 8.5, C(7ꢀ)H], 7.77
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
2 5 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

View Online
[1 H, s†, C(5ꢀ)H)], 8.00 [1 H, d, J7 ,8 8.5, C(8ꢀ)H], 8.08 [1 H, d,
General procedure for the synthesis of 2-aminoquinolines 36–41
ꢀ
ꢀ
J3 ,4 8.9, C(4ꢀ)H]; dC(75 MHz, CDCl3) 62.6 [C(2)], 72.5 [C(1)],
73.4 [C(6ꢀ)CH2], 123.3 [C(3ꢀ)], 126.4 [C(5ꢀ)], 127.3 [C(4aꢀ)], 129.5
[C(8ꢀ)], 130.8 [C(7ꢀ)], 137.8 [C(6ꢀ)], 139.4 [C(4ꢀ)], 148.2 [C(8aꢀ)],
151.4 [C(2ꢀ)]; m/z (EI) 239 (M+. [37Cl], 8), 237 (M+. [35Cl], 24),
194 (8), 192 (24), 178 (M+. [37Cl] − HO(CH2)2O, 40), 176 (M+.
[35Cl] − HO(CH2)2O, 100).
using the method of Ko´ro´di8
ꢀ
ꢀ
The same procedure for the amination method of Ko´ro´di as
described above was used. Unless otherwise specified, at the
completion of the reaction, the cooled reaction mixture was
added to a solution of 10% sodium hydroxide (∼15 mL mmol−1
2-chloroquinoline), and was heated at reflux for a further 3 h.
After cooling, the aqueous mixture was extracted with 3 : 1
chloroform–isopropanol (3 ×), the combined organic extracts
were dried (Na2SO4) and then the solvent was removed. The
pure amines were obtained following chromatography on silica
gel using 3 : 1 dichloromethane–ethanol as eluant.
2-Chloro-6-[(3-hydroxypropoxy)methyl]quinoline
32. The
general procedure described above was used with aluminium
chloride (1.06 g, 7.99 mmol) in dry THF (6 mL), lithium
aluminium hydride (0.173 g, 4.56 mmol) and acetal 28 (0.95 g,
3.80 mmol) dissolved in dry THF (12 mL) with heating at
reflux for 5 h. Following workup and chromatography using
3 : 1 dichloromethane–ethyl acetate as eluant, pure 32 (0.735 g,
77%) (Rf 0.20) was isolated as a white fluffy solid, mp 58–60 ◦C.
(Found: C, 62.1; H, 5.55; N, 5.65%. C13H14ClNO2 requires C,
62.05; H, 5.6; N, 5.55%); mmax(nujol)/cm−1 3307 (OH), 1585,
1562 and 1502; dH(600 MHz, CDCl3) 1.91 [2 H, quin, J 6.0,
C(2)H], 2.21 [1 H, br s, OH], 3.72 [2 H, t, J 6.0, C(1)H], 3.81
[2 H, t, J 6.0, C(3)H], 4.69 [2 H, s, C(6ꢀ)CH2], 7.38 [1 H, d,
2-Amino-5-[(2-hydroxyethoxy)methyl]quinoline 36. 2-Chloro-
5-[(2-hydroxyethoxy)methyl]quinoline 29 (0.350 g, 1.47 mmol)
was treated with acetamide (1.74 g, 29.4 mmol) and potassium
carbonate (1.02 g, 7.35 mmol) as described above. After workup
and chromatography, the title compound 36 (0.020 g, 6%) (Rf
◦
0.25) was isolated, mp 145–149 C. mmax(nujol)/cm−1 3382 and
3337 and 3215 (OH and/or NH), 1658, 1614, 1573 and 1511;
dH(200 MHz, CD3OD) 3.57–3.72 [4 H, m, C(1, 2)H], 4.89 [2 H, s,
C(5ꢀ)CH2], 6.87 [1 H, d, J3 ,4 9.2, C(3ꢀ)H], 7.26 [1 H, dd, J6 ,8 3.0
ꢀ
ꢀ
ꢀ ꢀ
J3 ,4 8.4, C(3ꢀ)H], 7.69 [1 H, dd, J5 ,7 1.8 J7 ,8 8.4, C(7ꢀ)H],
J6 ,7 5.4, C(6ꢀ)H], 7.44–7.51 [2 H, m, C(7ꢀ, 8ꢀ)H], 8.31 [1 H, d†,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
7.76 [1 H, s†, C(5ꢀ)H], 8.00 [1 H, d, J7 ,8 8.4, C(8ꢀ)H], 8.08 [1
J3 ,4 9.2, H(4ꢀ)]; dC(50 MHz, CD3OD) 62.4 [C(2)], 72.3 [C(1)],
72.9 [C(5ꢀ)CH2], 113.5 [C(3ꢀ)], 123.0 [C(4ꢀa)], 124.7 [C(6ꢀ)], 125.8
[C(8ꢀ)], 130.5 [C(7ꢀ)], 136.1 [C(5ꢀ)], 136.8 [C(4)], 148.0 [C(8ꢀa)],
157.8 [C(2ꢀ)]; m/z (EI) 218.1045 (C12H14N2O2 requires 218.1055),
173 (10), 158 (51), 157 (100).
ꢀ
ꢀ
ꢀ
ꢀ
H, d, J3 ,4 8.4, C(4ꢀ)H]; dC(150 MHz, CDCl3) 32.9 [C(2)], 62.2
[C(3)], 70.2 [C(1)], 73.3 [C(6ꢀ)CH2], 123.2 [C(3ꢀ)], 126.2 [C(5ꢀ)],
127.3 [C(4aꢀ)], 129.3 [C(8ꢀ)], 130.9 [C(7ꢀ)], 138.0 [C(6ꢀ)], 139.6
[C(4ꢀ)], 148.0 [C(8aꢀ)], 151.2 [C(2ꢀ)]; m/z (EI) 253 (M+. [37Cl],
8), 251 (M+. [35Cl], 22), 194 (30), 192 (100), 178 (M+. [37Cl] −
HO(CH2)3O, 28), 176 (M+. [35Cl] − HO(CH2)3O, 68).
ꢀ
ꢀ
2-Amino-5-[(3-hydroxypropoxy)methyl]quinoline
37. 2-
Chloro-5-[(3-hydroxypropoxy)methyl]quinoline 30 (0.100 g,
0.397 mmol) was treated with acetamide (0.469 g, 7.94 mmol)
and potassium carbonate (0.275 g, 1.99 mmol) as described
above. After workup and chromatography, the title compound
37 (0.014 g, 15%) (Rf 0.16) was isolated, mp 93–95 ◦C.
mmax(nujol)/cm−1 3453 and 3327 and 3154 (OH and/or NH),
1676, 1648, 1570 and 1512; dH(200 MHz, CDCl3) 1.85 [2 H,
quin, J 5.8, C(2)H], 2.72 [1 H, br s, OH], 3.67 [2 H, t, J 5.8,
C(1)H], 3.74 [2 H, t, J 5.8, C(3)H], 4.84 [2 H, s, C(5ꢀ)CH2],
2-Chloro-7-[(2-hydroxyethoxy)methyl]quinoline 33. The gen-
eral procedure described above was used with aluminium
chloride (0.715 g, 5.36 mmol) in dry THF (4 mL), lithium
aluminium hydride (0.116 g, 3.06 mmol) and acetal 16 (0.600 g,
2.55 mmol) dissolved in dry THF (7.2 mL). Following workup
sufficiently pure title compound 33 (0.585 g, 97%) was isolated.
A portion was chromatographed using 3 : 1 dichloromethane–
ethyl acetate as eluant (Rf 0.26) to afford purified 33 as an
oil. mmax(nujol)/cm−1 3369 (OH), 1627, 1589, 1560 and 1500;
dH(200 MHz, CDCl3) 2.88 [1 H, br s, OH], 3.63–3.84 [4 H, m,
C(1, 2)H], 4.74 [2 H, s, C(7ꢀ)CH2], 7.34 [1 H, d, J 8.4, C(3ꢀ)H],
5.18 [2 H, br s, NH2], 6.77 [1 H, d, J3 ,4 9.2, C(3ꢀ)H], 7.22
ꢀ
ꢀ
[1 H, d†, J6 ,7 7.0, C(6ꢀ)H], 7.49 [1 H, dd, J6 ,7 7.0 J7 ,8 8.4,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
C(7ꢀ)H], 7.64 [1 H, d†, J7 ,8 8.4, C(8ꢀ)H], 8.21 [1 H, d†, J3 ,4
ꢀ
ꢀ
ꢀ ꢀ
9.2, C(4ꢀ)H]; dC(50 MHz, CDCl3) 32.5 [C(2)], 61.6 [C(3)], 69.1
[C(1)], 71.6 [C(5ꢀ)CH2], 112.0 [C(3ꢀ)], 122.1 [C(4ꢀa)], 124.1
[C(6ꢀ)], 126.2 [C(8ꢀ)], 129.6 [C(7ꢀ)], 134.2 [C(5ꢀ)], 135.3 [C(4ꢀ)],
147.3 [C(8ꢀa)], 156.7 [C(2ꢀ)]; m/z (EI) 232.1200 (C13H16N2O2
requires 232.1212), 173 (34), 158 (100), 157 (85).
7.53 [1 H, dd, J6 ,8 1.4 J5 ,6 8.4, C(6ꢀ)H], 7.76 [1 H, d, J5 ,6 8.4,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
C(5ꢀ)H], 7.93 [1 H, d†, J6 ,8 1.4, C(8ꢀ)H], 8.05 [1 H, d†, J3 ,4
ꢀ
ꢀ
ꢀ ꢀ
8.4, C(4ꢀ)H]; dC(50 MHz, CDCl3) 61.9 [C(2)], 72.0 [C(1)], 72.7
[C(7ꢀ)CH2], 122.3 [C(3ꢀ)], 126.3 [C(4aꢀ)], 126.5 [C(6ꢀ, 5ꢀ)], 127.8
[C(8ꢀ)], 138.7 [C(4ꢀ)], 141.3 [C(7ꢀ)], 147.9 [C(8aꢀ)], 150.9 [C(2ꢀ)];
m/z (ESI) 238.0633 ([C12H1335ClNO2 + H]+ requires 238.0635);
(EI) 194 (31), 192 (100), 178 (29), 176 (83).
2-Amino-6-[(2-hydroxyethoxy)methyl]quinoline 38. 2-Chloro-
6-[(2-hydroxyethoxy)methyl]quinoline 31 (0.122 g, 0.513 mmol)
was treated with acetamide (0.606 g, 10.3 mmol) and potassium
carbonate (0.355 g, 2.57 mmol) as described above. After
cooling, saturated brine (20 mL) was added to the residue,
and the resulting mixture was extracted with 3 : 1 chloroform–
isopropanol (3 × 10 mL), dried (Na2SO4) and the solvent
was removed. The residue was purified by preparative thin
layer chromatography over two silica gel plates, using 3 : 1
dichloromethane–ethanol as eluant with successive develop-
ments, to afford the title compound 38 (0.003 g, 3%) as a white
solid [characterisation for 38 is provided below, for its synthesis
from the 2-(4-methoxybenzylamino)quinoline derivative 44].
2-Chloro-7-[(3-hydroxypropoxy)methyl]quinoline
34. The
general procedure described above was used with aluminium
chloride (1.14 g, 8.52 mmol) in dry THF (6.4 mL), lithium
aluminium hydride (0.183 g, 4.82 mmol) and acetal 17 (1.00 g,
4.02 mmol) dissolved in dry THF (12 mL). Following workup
and chromatography using 3 : 1 dichloromethane–ethyl acetate
as eluant pure 34 (0.710 g, 70%) (Rf 0.22) was isolated as an oil.
mmax(nujol)/cm−1 3391 (OH), 1628, 1590 and 1567; dH(200 MHz,
CDCl3) 1.92 [2 H, quin, J 6.0, C(2)H], 3.66–3.72 [3 H, m, C(1)H
and OH], 3.82 [2 H, t, J 6.0, C(3)H], 4.66 [2 H, s, C(7ꢀ)CH2],
2-Amino-6-[(3-hydroxypropoxy)methyl]quinoline
39. 2-
7.28 [1 H, d, J3 ,4 8.6, C(3ꢀ)H], 7.47 [1 H, dd, J6 ,8 1.2 J5 ,6 8.6,
Chloro-6-[(3-hydroxypropoxy)methyl]quinoline 32 (0.125 g,
0.497 mmol) was treated with acetamide (0.586 g, 9.93 mmol)
and potassium carbonate (0.343 g, 2.48 mmol) as described
above. After cooling, some of the excess acetamide was removed
by sublimation under a reduced pressure (oil bath temperature
ca. 80 ◦C at 0.02 mm) for 1 h. The residue was resuspended
in methanol (6 mL), filtered and the solvent was removed.
The residue was purified once by column chromatography
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
C(6ꢀ)H], 7.70 [1 H, d, J5 ,6 8.6, C(5ꢀ)H], 7.88 [1 H, d†, J6 ,8 1.2,
ꢀ
ꢀ
ꢀ ꢀ
C(8ꢀ)H], 8.00 [1 H, d†, J3 ,4 8.6, C(4ꢀ)H]; dC(50 MHz, CDCl3)
32.2 [C(2)], 59.4 [C(3)], 68.0 [C(1)], 71.9 [C(7ꢀ)CH2], 121.6
[C(3ꢀ)], 125.3 [C(4aꢀ)], 125.9 [C(5ꢀ or 6ꢀ)], 125.6 [C(5ꢀ or 6ꢀ)],
127.3 [C(8ꢀ)], 138.4 [C(4ꢀ)], 141.3 [C(7ꢀ)], 147.1 [C(8aꢀ)], 150.2
[C(2ꢀ)]; m/z (EI) 251.0713 (C13H1435ClNO2 requires 251.0713),
194 (32), 192 (100), 178 (33), 176 (79).
ꢀ
ꢀ
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 5 3

View Online
and subsequently by preparative thin layer chromatography
using 3 : 1 dichloromethane–ethanol as eluant, to afford the title
compound 39 (0.003 g, 3%) as a while solid [characterisation
for 39 is provided below, for its synthesis from the 2-(4-
methoxybenzylamino)quinoline derivative 45].
br s, NH2], 6.75 [1 H, d, J3,4 8.8, C(3)H], 7.38–7.42 [2 H, m, C(5,
7)H], 7.57 [1 H, d, J7,8 8.8, C(8)H], 7.82 [1 H, J3,4 8.8, C(4)H].
*Data consistent with that presented in the literature.7
6-[(2-Hydroxyethoxy)methyl]-2-[(4-methoxybenzyl)amino]-
quinoline 44. 2-Chloro-6-[(2-hydroxyethoxy)methyl]quinoline
31 (0.248 g, 1.04 mmol) was stirred in 4-methoxybenzylamine
(3 mL, 3.15 g, 23.0 mmol) at ca. 140 ◦C for 30 h. After cooling,
the excess 4-methoxybenzylamine was removed under a reduced
pressure using a Kugelrohr apparatus and the residue was
chromatographed over silica gel using 9 : 1 dichloromethane–
ethanol as eluant to afford the title compound 44 (0.347 g,
98%) as a pale orange oil (Rf 0.61) that eventually solidified,
mp 85–93 ◦C. mmax(nujol)/cm−1 3519 and 3311 (OH and/or
NH), 1614, 1576, 1537 and 1513; dH(300 MHz, CDCl3) 2.46
[1 H, br s. OH], 3.62–3.65 [2 H, m, AAꢀ portion of AAꢀBBꢀ,
C(1)H], 3.77–3.80 [2 H, m, BBꢀ portion of AAꢀBBꢀ, C(2)H],
ꢀꢀ
2-Amino-7-[(2-hydroxyethoxy)methyl]quinoline 40. 2-Chloro-
7-[(2-hydroxyethoxy)methyl]quinoline 33 (0.350 g, 1.47 mmol)
was treated with acetamide (1.74 g, 29.4 mmol) and potassium
carbonate (1.02 g, 7.35 mmol) as described above. After workup
and chromatography the title compound 40 (0.040 g, 13%)
(Rf 0.19) was isolated, mp 135–138 ◦C. mmax(nujol)/cm−1 3408
and 3332 and 3205 (OH and/or NH), 1621, 1560 and 1517;
dH(200 MHz, CDCl3) 3.58–3.76 [4 H, m, C(1, 2)H], 4.67 [2 H, s,
C(7ꢀ)CH2], 6.80 [1 H, d, J3 ,4 8.8, C(3ꢀ)H], 7.25 [1 H, dd, J6 ,8 1.6
ꢀ
ꢀ
ꢀ ꢀ
J5 ,6 8.2, C(6ꢀ)H], 7.51 [1 H, dd, J4 ,8 0.8 J6 ,8 1.6, C(8ꢀ)H], 7.62
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
[1 H, d, J 8.2, C(5ꢀ)H], 7.91 [1 H, dd, J4 ,8 0.8 J3 ,4 8.8, C(4ꢀ)H];
dH(50 MHz, CDCl3) 62.0 [C(2)], 71.8 [C(1)], 73.3 [C(7ꢀ)CH2],
111.9 [C(3ꢀ)], 122.5 [C(6ꢀ)], 123.1 [C(4ꢀa)], 124.4 [C(8ꢀ)], 127.9
[C(5ꢀ)], 138.2 [C(4ꢀ)], 140.2 [C(7ꢀ)], 147.3 [C(8ꢀa)], 157.3 [C(2ꢀ)];
m/z (EI) 218.1055 (C12H14N2O2 requires 218.1055), 173 (12), 158
(100), 157 (99).
ꢀ
ꢀ
ꢀ ꢀ
3.80 [3 H, s, C(4ꢀꢀ)OMe], 4.62 [2 H, d, J(1
4.5, C(1ꢀꢀ)CH2],
)CH,NH
4.65 [2 H, s, C(6ꢀ)CH2], 5.65 [1 H, br s, NH], 6.62 [1 H, d,
J3 ,4 9.0, C(3ꢀ)H], 6.85–6.90 [2 H, m, AAꢀ portion of AAꢀXXꢀ,
ꢀ
ꢀ
C(3ꢀꢀ, 5ꢀꢀ)H], 7.30–7.34 [2 H, m, XXꢀ portion of AAꢀXXꢀ, C(2ꢀꢀ,
6ꢀꢀ)H], 7.51–7.55 [2 H, m, C(5ꢀ, 7ꢀ)H], 7.72 [1 H, d, J7 ,8 8.1,
ꢀ
ꢀ
C(8ꢀ)H], 7.81 [1 H, d, J3 ,4 9.0, C(4ꢀ)H]; dC(75 MHz, CDCl3)
46.1 [C(1ꢀꢀ)CH2], 55.9 [C(4ꢀꢀ)OMe], 62.5 [C(2)], 72.1 [C(1)],
73.8 [C(6ꢀ)CH2], 112.0 [C(3ꢀ)], 114.8 [C(3ꢀꢀ, 5ꢀꢀ)], 123.6 [C(4aꢀ)],
126.3 [C(8ꢀ)], 127.2 [C(5ꢀ)], 129.6 [C(2ꢀꢀ, 6ꢀꢀ)], 130.6 [C(7ꢀ)], 131.6
[C(1ꢀꢀ)], 132.7 [C(6ꢀ)], 138.6 [C(4ꢀ)], 147.2 [C(8aꢀ)], 157.2 [C(2ꢀ)],
159.7 [C(4ꢀꢀ)]; m/z (ESI-TOF) 339.1703 ([C20H22N2O3 + H]+
requires 339.1703); (ESI) 339 ([M + H+], 12); MS/MS (339):
307 (25), 231 (100), 121 (55).
ꢀ
ꢀ
2-Amino-7-[(3-hydroxypropoxy)methyl]quinoline
41. 2-
Chloro-7-[(3-hydroxypropoxy)methyl]quinoline 34 (0.250 g,
0.993 mmol) was treated with acetamide (1.17 g, 19.9 mmol) and
potassium carbonate (0.686 g, 4.96 mmol) as described above.
After workup and purification once by column chromatography
and subsequently by preparative thin layer chromatography
using 3 : 1 dichloromethane–ethanol as eluant, the title
compound 41 (0.016 g, 7%) (Rf 0.13) was isolated, mp 88–90 ◦C.
mmax(nujol)/cm−1 3463 and 3352 and 3159 (OH and/or NH),
1656, 1616, 1563 and 1517; dH(200 MHz, CDCl3) 1.89 [2 H,
quin, J 5.8 Hz, C(2)H], 2.50 [1 H, br s, OH], 3.70 [2 H, t, J
5.8, C(1)H], 3.82 [2 H, t, J 5.8, C(3)H], 4.66 [2 H, s, C(7ꢀ)CH2],
2-Amino-6-[(2-hydroxyethoxy)methyl]quinoline
38. 6-[(2-
Hydroxyethoxy)methyl]-2-[(4-methoxybenzyl)amino]quinoline
44 (0.200 g, 0.591 mmol) was stirred in trifluoroacetic acid
(3 mL) at ca. 60 ◦C for 1 h when thin layer chromatography
indicated that all of the starting material had been consumed.
After cooling, the excess trifluoroacetic acid was removed under
a reduced pressure and the residue was dried under a high
vacuum for an additional 1 h. The residue was resuspended in
10% aq. sodium hydroxide (15 mL) and extracted with 3 : 1
chloroform–isopropanol (4 × 15 mL). The combined organic
layers were washed with a 1 : 1 mixture of 10% aq. sodium
hydroxide/saturated brine (1 × 60 mL), dried (Na2SO4) then the
solvent was removed. The residue was then chromatographed
over silica gel using 9 : 1 dichloromethane–methanol as eluant
to afford the title compound 38 (0.089 g, 69%) (Rf 0.17) as an
off-white solid. A portion was re-chromatographed as described
above to afford a white solid, mp 120–130 ◦C. (Found: C, 64.9;
H, 6.35; N, 12.55%. C12H14N2O2 requires C, 66.05; H, 6.45; N,
12.85%); mmax(nujol)/cm−1 3430 and 3311and 3205 (OH and/or
NH), 1643, 1625, 1611, 1570, 1507 and 1494; dH(300 MHz,
d6-acetone) 2.90 [1 H, br s, OH], 3.55–3.59 [2 H, m, AAꢀ portion
of AAꢀBBꢀ, C(1)H], 3.67–3.70 [2 H, m, BBꢀ portion of AAꢀBBꢀ,
5.16 [2 H, br s, NH2], 6.71 [1 H, d, J3 ,4 8.8, C(3ꢀ)H], 7.25 [1 H,
ꢀ
ꢀ
dd, J6 ,8 1.4 J5 ,6 8.2, C(6ꢀ)H], 7.59–7.63 [2 H, m, C(5ꢀ, 8ꢀ)H],
ꢀ
ꢀ
ꢀ ꢀ
7.87 [1 H, d†, J3 ,4 8.8, H(4ꢀ)]; dC(50 MHz, CDCl3) 32.5 [C(2)],
61.1 [C(3)], 69.0 [C(1)], 73.1 [C(7ꢀ)CH2], 112.0 [C(3ꢀ)], 122.3
[C(6ꢀ)], 122.9 [C(4ꢀa)], 123.7 [C(8ꢀ)], 127.9 [C(5ꢀ)], 138.2 [C(4ꢀ)],
140.5 [C(7ꢀ)], 147.0 [C(8ꢀa)], 157.5 [C(2ꢀ)]; m/z (EI) 232.1200
(C13H16N2O2 requires 232.1212), 173 (17), 158 (100), 157 (34).
ꢀ
ꢀ
2-[(4-Methoxybenzyl)amino]-6-methylquinoline 43. 2-Chloro-
6-methylquinoline 42 (0.100 g, 0.563 mmol) was stirred in 4-
methoxybenzylamine (1.6 mL, 1.69 g, 12.3 mmol) at ca. 140 ◦C
for 26 h. The excess 4-methoxybenzylamine was removed under
a reduced pressure using a Kugelrohr apparatus and the residue
was chromatographed on silica gel using 17 : 3 dichloromethane–
ethyl acetate as eluant, to afford the title compound 43 (0.147 g,
94%), mp 55–58 ◦C. mmax(nujol)/cm−1 3317 (NH), 1613 and
1511; dH(600 MHz, CDCl3) 2.42 [3 H, s, C(6)Me], 3.76 [3 H, s,
C(4ꢀ)OMe], 5.59 [1 H, d, J(1 )CH,NH 5.4, C(1ꢀ)CH2], 5.06 [1 H,
ꢀ
br s, NH], 6.55 [1 H, d, J3,4 9.3, C(3)H], 6.83–6.86 [2 H, m, AAꢀ
portion of AAꢀXXꢀ, C(3ꢀ, 5ꢀ)H], 7.28–7.31 [2 H, m, XXꢀ portion
of AAꢀXXꢀ, C(2ꢀ, 6ꢀ)H], 7.33 [1 H, d, J5,7 0.6, C(5)H], 7.35 [1 H,
dd, J5,7 0.6 J7,8 8.4, C(7)H], 7.61 [1 H, d, J7,8 8.4, C(8)H], 7.69
[1 H, d, J3,4 9.3, C(4)H]; dC(CDCl3, 150 MHz) 21.75 [C(6)Me]
45.06 [C(1ꢀ)CH2], 55.90 [C(4ꢀ)OMe], 111.88 [C(3)], 114.65 [C(3ꢀ,
5ꢀ)], 124.05 [C(4a)], 126.43 [C(8)], 127.28 [C(5)], 129.67 [C(2ꢀ,
6ꢀ)], 132.03 [C(1ꢀ)], 132.20 [C(6)], 132.21 [C(7)], 137.62 [C(4)],
146.67 [C(8a)], 156.95 [C(2)], 159.52 [C(4ꢀ)]; m/z (ESI) 279.1498
([C18H18N2O + H]+ requires 279.1492); (EI) 136 (71), 121 (89).
C(2)H], 4.61 [2 H, s, C(6ꢀ)CH2], 6.85 [1 H, d, J3 ,4 8.9, C(3ꢀ)H],
ꢀ
ꢀ
7.47–7.53 [2 H, m, C(7ꢀ, 8ꢀ)H], 7.60 [1 H, s†, C(5ꢀ)H], 7.89
[1 H, d, J3 ,4 8.9, C(4ꢀ)]; dC(75 MHz, d6-acetone) 62.1 [C(2)],
72.8 [C(1)], 73.5 [C(6ꢀ)CH2], 113.2 [C(3ꢀ)], 123.9 [C(4aꢀ)], 126.7
[C(8ꢀ)], 127.2 [C(5ꢀ)], 130.1 [C(7ꢀ)], 133.2 [C(6ꢀ)], 138.1 [C(4ꢀ)],
148.7 [C(8aꢀ)], 159.2 [C(2ꢀ)]; m/z (ESI) 219.1127 ([C12H14N2O2 +
H]+ requires 219.1128); (EI) 174 (15), 173 (40), 172 (30), 158
(M+. − HO(CH2)2O + H, 18), 157 (M+. − HO(CH2)2O, 100).
ꢀ
ꢀ
6-[(3-Hydroxypropoxy)methyl]-2-[(4-methoxybenzyl)amino]-
quinoline 45. 2-Chloro-6-[(3-hydroxypropoxy)methyl]quinoline
32 0.114 g, 0.453 mmol) was stirred in 4-methoxybenzylamine
(1.5 mL, 1.58 g, 11.5 mmol) at ca. 140 ◦C for 30 h. After cooling,
the excess 4-methoxybenzylamine was removed under a reduced
pressure using a Kugelrohr apparatus and the residue was
chromatographed over silica gel using 9 : 1 dichloromethane–
ethanol as eluant to afford the title compound 45 (0.145 g,
91%) as a pale orange oil (Rf 0.27) that eventually solidified,
2-Amino-6-methylquinoline 2. 2-[(4-Methoxybenzyl)amino]-
6-methylquinoline 43 (0.029 g, 0.104 mmol) was stirred in
trifluoromethanesulfonic acid (1.5 mL, 2.54 g, 17.0 mmol) at rt
for 22 h. The mixture was carefully added to saturated sodium
bicarbonate (20 mL) and extracted with dichloromethane (3 ×
20 mL). The combined organic extracts were dried (Na2SO4) and
the solvent was removed to afford the title compound 2 (0.016 g,
95%). dH(200 MHz, CDCl3)* 2.45 [3 H, s, C(6)Me], 5.22 [2 H,
2 5 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

View Online
mp 85–90 ◦C. (Found: C, 69.75; H, 7.15; N, 7.7%. C21H24N2O3
requires C, 71.55; H, 6.85; N, 7.95%); mmax(nujol)/cm−1 3418
and 3296 (OH and/or NH), 1615, 1580, 1536 and 1511;
dH(300 MHz, CDCl3) 1.88 [2 H, quin, J 5.8, C(2)H], 3.50 [1
H, br s, OH], 3.69 [2 H, t, J 5.8, C(1)H], 3.78–3.81 [5 H, m,
C(3)H and C(4ꢀꢀ)OMe], 4.60 [2 H, s, C(6ꢀ)CH2], 4.63 [2 H, d,
using 3 : 1 dichloromethane–ethyl acetate as eluant to afford the
pure title compound 49 (0.190 g, 68%) (Rf 0.33) as white crystals,
mp 181–184 ◦C. (Found: C, 72.1; H, 6.1; N, 14.0%. C12H12N2O
requires C, 72.0; H, 6.05; N, 14.0%); mmax(nujol)/cm−1 3240 (NH),
1686, 1661 (CO), 1597, 1577, 1536 and 1490; dH(300 MHz,
CDCl3) 2.17 [3 H, s, CH3CO], 2.49 [3 H, s, C(6)Me], 7.48 [1H,
dd, J5,7 1.8 J7,8 8.4, C(7)H], 7.53 [1 H, s†, C(5)H], 7.72 [1 H, d,
J7,8 8.4, C(8)H], 8.08 [1 H, d, J3,4 8.9, C(4)H], 8.39 [1 H, br d,
J3,4 8.9, C(3)H], 9.56 [1 H, br s, NH]; dC(75 MHz, CDCl3) 22.0,
[C(6)Me], 25.4 [CH3CO], 115.2 [C(3)], 126.9 [C(4a)], 127.2 [C(5,
8)], 132.9 [C(7)], 135.7 [C(6)], 138.8 [C(4)], 145.2 [C(8a)], 151.3
JC(1 )CH,NH 5.3, C(1ꢀꢀ)CH2], 5.82 [1 H, br s, NH], 6.65 [1 H, d, J3 ,4
ꢀ ꢀ
ꢀꢀ
9.0, C(3ꢀ)H], 6.85–6.90 [2 H, m, AAꢀ portion of AAꢀXXꢀ, C(3ꢀꢀ,
5ꢀꢀ)H], 7.30–7.35 [2 H, m, XXꢀ portion of AAꢀXXꢀ, C(2ꢀꢀ, 6ꢀꢀ)H],
7.51–7.54 [2 H, m, C(5ꢀ, 7ꢀ)H], 7.71 [1 H, d, J7 ,8 8.4, C(8ꢀ)H],
ꢀ
ꢀ
7.82 [1 H, d, J3 ,4 9.0, C(4ꢀ)H]; dC(75 MHz, CDCl3) 32.8 [C(2)],
46.0 [C(1ꢀꢀ)CH2], 55.9 [C(4ꢀꢀ)OMe], 62.2 [C(3)], 69.6 [C(1)],
73.7 [C(6ꢀ)CH2], 112.1 [C(3ꢀ)], 114.7 [C(3ꢀꢀ, 5ꢀꢀ)], 123.7 [C(4aꢀ)],
126.8 [C(8ꢀ)], 127.0 [C(5ꢀ)], 129.7 [C(2ꢀꢀ, 6ꢀꢀ)], 130.2 [C(7ꢀ)], 131.8
[C(1ꢀꢀ)], 132.5 [C(6ꢀ)], 138.1 [C(4ꢀ)], 148.0 [C(8aꢀ)], 157.4 [C(2ꢀ)],
159.6 [C(4ꢀꢀ)]; m/z (ESI-TOF) 353.1866 ([C21H24N2O3 + H]+
requires 353.1860); (ESI) 353 ([M + H+], 12); MS/MS (353):
321 (25), 245 (100), 157 (10), 121 (52).
ꢀ
ꢀ
[C(2)], 170.1 [CO]; m/z (EI) 200 (M+., 35), 159 (10), 158 (M+.
CH2 C O, 100), 157 (M − CH2 C O–H, 30).
−
+.
= =
= =
N-(6-Methylquinolin-2-yl)acetamide 49 (large scale). 2-
Chloro-6-methylquinoline 42 (7.54 g, 0.0424 mol) was treated
with acetamide (200 g, 3.4 mol) and potassium carbonate
(29.33 g, 0.212 mol) for 14 h as described above. Following
workup and filtration through silica gel as described above,
the title compound 49 (3.301 g, 39%) (Rf 0.17) was isolated as
white crystals (data provided above). The eluant was changed to
9 : 1 dichloromethane–ethanol and the quinolin-2(1H)-one by-
product 50 (2.215 g, 31%) was also isolated as an orange–brown
solid, as evidenced by the presence of diagnostic chemical shifts
observed for 50 prepared by a literature method.14
2-Amino-6-[(3-hydroxypropoxy)methyl]quinoline 39. 6-[(3-
Hydroxypropoxy)methyl]-2-[(4-methoxybenzyl)amino]quinoline
45 (0.100 g, 0.284◦ mmol) was stirred in trifluoroacetic acid
(1.5 mL) at ca. 60 C for 1 h when thin layer chromatography
indicated that all of the starting material had been consumed.
The reaction was worked up using the same procedure
described for the synthesis of 38 above. Following successive
chromatography of the crude product over silica gel using 9 :
1 dichloromethane–methanol as eluant, the title compound
39 (0.039 g, 59%) (Rf 0.13) was isolated as a white solid, mp
118–128 ◦C. (Found: C, 67.25; H, 7.05; N, 12.05%. C13H16N2O2
requires C, 67.2; H, 6.95; N, 12.05%); mmax(nujol)/cm−1 3428
and 3311 and 3185 (OH and/or NH), 1640, 1624, 1610, 1567,
1507 and 1483; dH(300 MHz, d6-acetone) 1.80 [2 H, quin, J 6.3,
C(2)H], 2.95 [1 H, br s, OH], 3.60 [2 H, t, J 6.3, C(1 or 3)H],
3.65 [2 H, t, J 6.3, C(1 or 3)H], 4.56 [2 H, s, C(6ꢀ)CH2], 5.86 [2
N-(5-Methylquinolin-2-yl)acetamide 56/N-(7-methylquinolin-
2-yl)acetamide 57. A mixture of 2-chloro-5-methylquinoline 6
and 2-chloro-7-methylquinoline 7 (5.00 g, 28 mmol) was treated
with acetamide (82.7 g, 1.4 mol) and potassium carbonate
(19.3 g, 0.14 mol) for 16 h as described above. Following workup
as described above, the residue was filtered through silica gel
using 9 : 1 dichloromethane–ethyl acetate as eluant to afford
the mixture of the title compounds 56 and 57 (2.92 g, 52%).
mmax(nujol)/cm−1 1709, 1661 (CO), 1603 and 1509; dH(300 MHz,
CDCl3) 2.18 [3 H, s, *CH3CO], 2.30 [3 H, s, CH3CO], 2.55 [3
H, s, C(7*)Me], 2.68 [3 H, s, C(5)Me], 7.29–7.33 [2 H, m, C(6,
6*)H], 7.57 [1 H, dd, J 7.1 J 8.5, C(7)H], 7.61 [1 H, d, J4,8 0.6,
C(8*)H], 7.67–7.70 [2 H, m, C(5*, 8)H], 8.18 [1 H, dd, J4,8 0.6
H, br s, NH2], 6.85 [1 H, d, J3 ,4 9.0, C(3ꢀ)H], 7.47 [1 H, dd, J5 ,7
ꢀ ꢀ
ꢀ
ꢀ
1.8 J7 ,8 8.6, C(7ꢀ)H], 7.51 [1 H, d, J7 ,8 8.6, C(8ꢀ)H], 7.58 [1H, s†,
C(5ꢀ)H] 7.89 [1 H, d, J3,4 9.0, C(4ꢀ)H]; dH(75 MHz, d6-acetone)
33.9 [C(2)], 59.9 [C(3)], 68.3 [C(1)], 73.3 [C(6ꢀ)CH2], 113.4
[C(3ꢀ)], 123.7 [C(4aꢀ)], 125.6 [C(8ꢀ)], 127.1 [C(5ꢀ)], 130.3 [C(7ꢀ)],
133.7 [C(6ꢀ)], 138.8 [C(4ꢀ)], 147.5 [C(8aꢀ)], 159.0 [C(2ꢀ)]; m/z (EI)
232 (M+., 50), 174 (6), 173 (55), 158 (M+. − HO(CH2)3O + H,
40), 157 (M+. − HO(CH2)3O, 100).
ꢀ
ꢀ
ꢀ ꢀ
J
3,4 9.0, C(4*)H], 8.39 [1H, dd, J4,8 0.6 J3,4 9.3, C(4)H], 8.44 [1 H,
br d, J3,4 9.0, C(3*)H], 8.51 [1 H, br d, J3,4 9.3, C(3)H], 10.53 [2
H, br s, *NH and NH]; m/z (EI) 200.0958 (C12H12N2O requires
200.0950), 158 (67).
* Refers to 57.
General procedure for synthesis of 2-acetamidoquinolines from
2-chloroquinolines
N-[6-(Bromomethyl)quinolin-2-yl]acetamide 46. A mixture
of N-(6-methylquinolin-2-yl)acetamide 49 (1.500 g, 7.5 mmol),
N-bromosuccinimide (1.47 g, 8.24 mmol), and benzoyl peroxide
(0.18 g, 0.75 mmol) was heated at reflux in benzene (10 mL) for
5 h. After cooling, the benzene was removed under a reduced
pressure and the residue was dissolved in dichloromethane
(50 mL). The dichloromethane solution was washed with 10%
NaHCO3 (3 × 50 mL), dried (Na2SO4), then the solvent was
removed to afford 1.96 g of a light brown solid. Following
chromatography over silica gel using 17 : 3 dichloromethane–
ethyl acetate as eluant, the title compound 49 (1.175 g, 56%)
(Rf 0.26) was afforded as a pale yellow fluffy solid, mp 185–
187 ◦C. (Found: C, 51.9; H, 4.1; N, 9.8%; C12H11BrN2O requires
C, 51.6; H, 3.95; N, 10.05%); mmax(nujol)/cm−1 3190 (NH), 1673
(CO), 1602, 1580, 1540 and 1494; dH(300 MHz, CDCl3) 2.25
[3 H, s, CH3], 4.65 [2 H, s, C(6)CH2], 7.69 [1 H, dd, J5,7 2.1
J7,8 8.7, C(7)H], 7.78–7.81 [2 H, m, C(5, 8)H], 8.14 [1 H, d, J3,4
9.0, C(4)H], 8.43 [1 H, br d, J3,4 9.0, C(3)H], 8.66 [1 H, br s,
NH]; dC(75 MHz, CDCl3) 25.6 [CH3], 33.6 [C(6)CH2], 115.4
[C(3)], 126.4 [C(5)], 127.4 [C(4a)], 128.3 [C(8)], 132.5 [C(7)],
135.9 [C(6)], 140.5 [C(4)], 144.9 [C(8a)], 152.0 [C(2)], 170.5 [CO];
m/z (EI) 280 (M+. [81Br], 6), 278 (M+. [79Br], 6), 200 (M+. − Br +
A mixture of the 2-chloroquinoline (1 eq.), acetamide (∼80 eq.)
and potassium carbonate (5 eq.) was heated at reflux for 14 h.*
After cooling, the mixture was added to water and extracted with
dichloromethane (3 ×). The combined organic extracts were
washed with water (1 ×) dried (Na2SO4) and the solvent was
removed. Unless otherwise specified, the residue was purified by
filtration through silica gel using 17 : 3 dichloromethane–ethyl
acetate as eluant to afford the pure 2-acetamidoquinoline.
*When performing this reaction on a large scale, an air
condenser with a large diameter should be used to avoid
blockage of the condenser with sublimed acetamide during the
reaction.
N-(6-Methylquinolin-2-yl)acetamide 49 (small scale). 2-
Chloro-6-methylquinoline 42 (0.250 g, 1.40 mmol) was treated
with acetamide (7.07 g, 0.120 mol) and potassium carbonate
(0.973 g, 7.04 mmol) for 15 h, as described above. Following
workup, the 1H NMR spectrum of the crude product indicated
that the title compound 49 was the major product, however
a small amount (∼15%) of a mixture of the corresponding
the 2-aminoquinoline 2 and quinolin-2(1H)-one 50 was also
present, as evidenced by the presence of diagnostic chemical
shifts observed in samples of 27 and 5014 prepared by literature
methods. The crude product was chromatographed on silica gel
H, 12), 199 (M+. − Br, 78), 158 (M+. − Br–CH2 C O + H, 15),
= =
157 (M+. − Br–CH2 C O, 100).
= =
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 5 5

View Online
N-[5-(Bromomethyl)quinolin-2-yl]acetamide 47/N-[7-(bromo-
methyl)quinolin-2-yl]acetamide 48. The mixture of N-(5-
methylquinolin-2-yl)acetamide 56 and N-(7-methylquinolin-
2-yl)acetamide 57 prepared above (2.55 g, 12.7 mmol),
N-bromosuccinimide (2.26 g, 12.7 mmol) and benzoyl peroxide
(0.310 g, 1.27 mmol) were heated at reflux in benzene (8 mL)
for 2.5 h. After cooling, the mixture was filtered, and the filtrate
was evaporated under a reduced pressure. The residue was chro-
matographed through silica gel using 17 : 3 dichloromethane–
ethyl acetate as eluant to afford the mixture of the title
compounds 47 and 48 (1.64 g, 46%) (Rf 0.24). mmax(nujol)/cm−1
3010 (NH), 1663 (CO), 1639, 1607 and 1580; dH(300 MHz,
CDCl3) 2.23 [6 H, s, CH3CO and CH3CO*], 4.63 [2 H, s,
C(7*)CH2], 4.88 [3 H, s, C(5)CH2], 7.45–7.49 [2 H, m, C(6*,
6,)H], 7.57 [1 H, dd, J 7.2 J 8.4, C(7)H], 7.67–7.70 [3 H, m,
C(5*, 8*, 8)H], 8.15 [1 H, d, J3,4 8.7, C(4*)H], 8.42–8.55 [3 H, m,
C(3*, 3, 4)H], 9.28 [1 H, br s, *NH or NH], 9.37 [1H, br s, *NH
or NH]; m/z (EI) 278.0053 (C12H1179BrN2O requires 278.0055),
d, J6,7 7.2, C(6)H], 7.63 [1 H, dd, J6,7 7.2 J7,8 8.4, C(7)H], 7.82 [1
H, d, J7,8 8.4, C(8)H], 8.38 [1 H, d, J3,4 9.0, C(4)H], 8.48 [1 H, br
d, J3,4 9.0, C(3)H], 9.07 [1 H, br s, NH]; dC(50 MHz, CDCl3)
21.0 [CH3CO2 or CH3CON], 24.8 [CH3CO2 or CH3CON],
63.8 [C(5)CH2], 114.9 [C(3)], 124.8 [C(4a)], 126.6 [C(6)], 128.3
[C(8)], 129.6 [C(7)], 132.2 [C(5)], 134.8 [C(4)], 146.8 [C(8a)],
151.4 [C(2)], 169.7 [CH3CO2 or CH3CON], 170.8 [CH3CO2 or
CH3CON]; m/z (EI) 258 (M+., 45), 216 (M+. − CH2 C O,
= =
+.
41), 174 (M+. − CH2 C O–CH3CO + H, 100), 157 (M
−
= =
= =
CH2 C O–CH3CO2, 52).
59: (found: C, 65.05; H, 5.35; N, 10.65%. C14H14N2O3 requires
C, 65.1; H, 5.45; N, 10.85%); mmax(nujol)/cm−1 3483 and 3198
(NH), 1740 and 1706 (CO), 1666, 1600, 1579, 1535 and 1508;
dH(200 MHz, CDCl3) 2.15 [3 H, s, CH3CO2 or CH3CON], 2.25
[3 H, s, CH3CO2 or CH3CON], 5.29 [2 H, s, C(7)CH2], 7.42 [1 H,
dd, J6,8 1.2 J5,6 8.2, C(6)H], 7.84 [1 H, s, C(8)H], 7.85 [1 H, d, J5,6
8.2, C(5)H], 8.17 [1 H, d, J3,4 9.0, C(4)H], 8.43 [1 H, br d, J3,4 9.0,
C(3)H], 8.80 [1 H, br s, NH]; dC(50 MHz, CDCl3) 21.0 [CH3CO2
or CH3CON], 24.8 [CH3CO2 or CH3CON], 65.9 [C(7)CH2],
114.9 [C(3)], 124.9 [C(8)], 125.8 [C(4a)], 126.0 [C(6)], 128.1
[C(5)], 138.2 [C(7)], 138.6 [C(4)], 146.3 [C(8a)], 151.8 [C(2)],
81
+. 79
238 (M+. [ Br]–CH2 C O, 36), 236 (M [ Br]–CH2 C O,
= =
= =
39), 199 (M+. − Br, 100), 157 (M+. − Br–CH2 C O, 65).
= =
* Refers to 48.
169.7 [CH3CO2 or CH3CON], 170.8 [CH3CO2 or CH3CON];
N-{[6-(Acetyloxy)methyl]quinolin-2-yl}acetamide
51.
A
+.
m/z (EI) 258 (M+., 70), 216 (M+. − CH2 C O, 41), 174 (M
−
= =
mixture of N-[6-(bromomethyl)quinolin-2-yl]acetamide 46
(0.350 g, 1.25 mmol) and potassium acetate (0.246 g,
2.50 mmol) was stirred in DMF (8 mL) at ca. 80 ◦C for
14 h. After cooling, the mixture was diluted with ethyl acetate
(60 mL) and washed with water (3 × 60 mL) and brine (3 ×
60 mL). The resulting ethyl acetate solution was dried (Na2SO4)
then the solvent was removed to afford the title compound 51
(0.282 g, 87%) as a yellow solid. This material could be used
for further synthesis without additional purification, however
a portion was further purified by silica gel chromatography
using 3 : 1 dichloromethane–ethyl acetate as eluant (Rf 0.25) to
afford a white solid, mp 140–145 ◦C. (Found: C; 64.95; H 5.65;
N 10.05%. C14H14N2O3 requires C, 65.1; H, 5.45; N, 10.85%);
mmax(nujol)/cm−1 3309 (NH), 1699 and 1689 (CO), 1602, 1580
and 1493; dH(300 MHz, CDCl3) 2.15 [3 H, s, CH3CO2], 2.23
[3 H, s, CH3CON], 5.26 [2H, s, C(6)CH2], 7.64 [1 H, dd, J5,7
1.7 J7,8 8.6, C(7)H], 7.77 [1 H, d, J5,7 1.7, C(5)H], 7.81 [1 H, d,
J7,8 8.6, C(8)H], 8.17 [1 H, d, J3,4 8.9, C(4)H], 8.44 [1 H, br d,
J3,4 8.9, C(3)H], 8.96 [1 H, br s, NH]; dC(75 MHz, CDCl3) 21.5
[CH3CO2], 25.3 [CH3CON], 66.4 [C(6)CH2], 115.5 [C(3)], 126.5
[C(4a)], 127.6 [C(5)], 128.0 [C(8)], 130.6 [C(7)], 133.5 [C(6)],
139.2 [C(4)], 146.6 [C(8a)], 152.2 [C(2)], 170.1 [CH3CON], 171.4
+.
= =
=
CH2 C O–CH3CO + H, 80), 157 (M − CH2 CvO–CH3CO2,
31), 43 (100).
N-[6-(Hydroxymethyl)quinolin-2-yl]acetamide 52/2-amino-
6-(hydroxymethyl)quinoline 53.
A
mixture of N-{[6-
(acetyloxy)methyl]quinolin-2-yl}acetamide 51 (0.215 g,
0.83 mmol) and potassium carbonate (0.057 g, 0.42 mmol) was
stirred in methanol (7 mL) at rt for 2 h. The solvent was removed
and the residue was chromatographed over silica gel using 9 :
1 dichloromethane–methanol as eluant to afford 52 (0.130 g,
72%) (Rf 0.31) as a pale yellow solid, mp 170–174 ◦C. The
eluant was changed to 3 : 1 dichloromethane–methanol and 53
(0.029 g, 20%) (Rf 0.31) was also isolated as a white powder, mp
210–220 ◦C.
52: (found: C, 66.7; H, 5.65; N, 12.95%. C12H12N2O2 requires
C, 66.65; H, 5.6; N, 12.95%); mmax(nujol)/cm−1 3337 (NH), 1701,
1674 (CO), 1599, 1580 and 1493; dH(300 MHz, d6-acetone) 2.26
[3 H, s, CH3], 4.40 [1 H, t, J 5.6, OH], 4.79 [2 H, d, J 5.6,
C(6)CH2], 7.66 [1 H, dd, J5,7 1.8 J7,8 8.7, C(7)H], 7.72 [1 H,
d, J7,8 8.7, C(8)H], 7.82 [1 H, s†, C(5)H], 8.24 [1 H, d, J3,4
8.9, C(4)H], 8.40 [1 H, br d, J3,4 8.9, C(3)H], 9.66 [1 H, br s,
NH]; dC(75 MHz, d6-acetone) 24.6 [CH3], 64.5 [C(6)CH2], 115.0
[C(3)], 125.3 [C(5)], 126.8 [C(4a)], 128.2 [C(8)], 129.9 [C(7)],
138.7 [C(6)], 140.1 [C(4)], 147.2 [C(8a)], 152.5 [C(2)], 170.2 [CO];
[CH3CO2]; m/z (EI) 258.1004 (C14H14N2O3 requires 258.1004),
+.
216 (M+. − CH2 C O, 40), 199 (M − CH3CO2, 5), 174
= =
+.
+.
+.
+.
(M+. − CH2 C O–CH3CO + H, 38), 157 (M − CH3CO2
m/z (EI) 216 (M , 75), 174 (M − CH2 C O, 100), 173 (M −
= =
= =
+.
= =
=
= =
–CH2 C O, 100).
CH2 CvO–H, 38), 157 (M − CH2 C O–OH, 40).
53: mmax(nujol)/cm−1 3458 and 3311 (NH), 1681, 1633, 1626,
1610, 1568 and 1491; dH(300 MHz, d6-DMSO) 4.55 [2 H, s,
C(6)CH2], 5.21 [1 H, br s, OH], 6.63 [2 H, br s, NH2], 6.77 [1 H,
d, J3,4 8.9, C(3)H], 7.41–7.48 [2 H, m, C(7, 8)H], 7.56 [1 H, s†,
C(5)H], 7.92 [1 H, d, J3,4 8.9, C(4)H]; dC(75 MHz, d6-DMSO)
62.8 [C(6)CH2], 122.1 [C(4a)], 124.0 [C(5)], 124.9 [C(8)], 128.7
[C(7)], 135.8 [C(6)], 137.5 [C(4)], 145.6 [C(8a)], 158.2 [C(2)]; m/z
(EI) 174.0792 (C10H10N2O requires 174.0793), 158 (M+. − OH +
N-{[5-(Acetyloxy)methyl]quinolin-2-yl}acetamide 58/N-{[7-
(acetyloxy)methyl]quinolin-2-yl}acetamide 59. The mixture
of N-[5-(bromomethyl)quinolin-2-yl]acetamide 47 and N-
[7-(bromomethyl)quinolin-2-yl]acetamide 48 prepared above
(0.875 g, 3.13 mmol) was treated with potassium acetate (0.614 g,
6.26 mmol) in DMF (20 mL) with stirring at ca. 80 ◦C for 16 h.
After cooling, the reaction mixture was diluted with ethyl acetate
(50 mL), and the solution was washed with water (4 × 50 mL)
and brine (2 × 50 mL). The organic phase was dried (Na2SO4)
and the solvent was removed. The residue was chromatographed
on silica gel using 4 : 1 dichloromethane–ethyl acetate as eluant
to afford the title compound 58 (0.260 g, 32%) (Rf 0.19), mp
140–145 ◦C. In addition, the title compound 59 (0.210 g, 26%)
(Rf 0.15) was isolated as a ca. 19 : 1 mixture with 58, mp 124–
126 ◦C. An additional 0.100 g (10%) of 59–58 as a 4 : 1 mixture
was also isolated.
H, 42), 157 (M+. − OH, 32), 147 (M+. − HCN, 25), 146 (M+.
−
HCN–H, 42).
2-Amino-5-(hydroxymethyl)quinoline 60. N-{[5-(Acetyloxy)-
methyl]quinolin-2-yl}acetamide 58 prepared above (0.080 g,
0.31 mmol) was treated with potassium carbonate (0.043 g,
0.31 mmol) in methanol (4 mL) with stirring at ca. 50 ◦C for
2 h. After cooling, the solvent was removed and the residue
was chromatographed on silica gel using 4 : 1 dichloromethane–
methanol as eluant to afford the title compound 60 (0.050 g,
93%) (Rf 0.21), mp 155–157 ◦C. mmax(nujol)/cm−1 3467 and
3319 and 3203 (OH and/or NH), 1686, 1618, 1564 and 1512;
dH(200 MHz, CDCl3) 1.25 [1 H, br s, OH], 4.91 [2 H, br s, NH2],
5.03 [2 H, s, C(5)CH2], 6.77 [1 H, d, J3,4 9.2, C(3)H], 7.26 [1 H,
58: (found: C, 65.05; H, 5.45; N, 10.55%. C14H14N2O3 requires
C, 65.1; H, 5.45; N, 10.85%); mmax(nujol)/cm−1 3427 and 3213
(NH), 1727 and 1704 (CO), 1671, 1602, 1583 and 1503;
dH(200 MHz, CDCl3) 2.11 [3 H, s, CH3CO2 or CH3CON], 2.35
[3 H, s, CH3CO2 or CH3CON], 5.52 [2 H, s, C(5)CH2], 7.50 [1 H,
2 5 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7

View Online
d, J6,7 7.0, C(6)H], 7.51 [1 H, dd, J6,7 7.0 J7,8 8.4, C(7)H], 7.63 [1
H, d, J7,8 8.4, C(8)H], 8.27 [1 H, d, J3,4 9.0, C(4)H]; dC(150 MHz,
d6-DMSO) 62.74 [C(5)CH2], 111.12 [br, C(3)], 120.29 [C(4a)],
120.58 [C(6)], 123.57 [br, C(8)], 128.96 [C(7)], 134.28 [C(5)],
138.49 [C(4)], 146.35 [C(8a)], 157.12 [C(2)]; m/z (EI) 174.0792
(C10H10N2O requires 174.0793), 157 (31), 145 (64), 128 (52).
compound 55 accompanied by a small amount (<5%) of 53.
This material was used in SH3 ligand binding studies without
further purification. The presence of 53 was confirmed by mass
spectrometry.
55: mmax(nujol)/cm−1 3306 and 3134 (NH), 1646, 1625, 1610,
1590, 1566 and 1494; dH(300 MHz, d6-acetone) 1.29 [2 H, br s,
CH2NH2 or ArNH2], 4.50 [2 H, s, C(6)CH2], 5.81 [2 H, br s,
CH2NH2 or ArNH2], 6.82 [1 H, d, J3,4 8.7, C(3H], 7.48 [2
H, m, C(7, 8)], 7.57 [1 H, s†, C(5)H], 7.85 [1 H, d, J 8.7,
C(4)H]; dC(75 MHz, d6-acetone) 55.5 [C(6)CH2], 112.8 [C(3)],
124.1 [C(4a)], 126.5 [C(5, 8)], 130.5 [C(7)], 135.4 [C(6)], 137.9
[C(4)], 148.2 [C(8a)], 158.8 [C(2)]; m/z (EI) 173.0949 (C10H11N3
requires 173.0953), 157 (M+. − NH2, 32), 145 (M+. − H–HCN,
35), 43 (100).
2-Amino-7-(hydroxymethyl)quinoline 61. The ca. 19 : 1 mix-
ture of 59–58 prepared above (0.120 g, 0.46 mmol) was treated
with potassium carbonate (0.0640 g, 0.46 mmol) in methanol
(5 mL) with stirring at ca. 50 ◦C for 2 h. After cooling, the
solvent was removed and the residue was chromatographed
on silica gel using 4 : 1 dichloromethane–methanol as eluant
to afford the title compound 61 (0.035 g, 44%) (Rf 0.18) mp
153–159 ◦C. An additional 0.035 g (44%) of 60–61 as a mixture
was also isolated.
53: m/z (EI) 174.0791 (C10H10N2O requires 174.0793) [a more
thorough characterisation of 53 is provided above for its explicit
synthesis from 51].
61: mmax(nujol)/cm−1 3467 and 3317 and 3201 (OH and/or
NH), 1686, 1624, 1563 and 1514; dH(600 MHz, d6-DMSO) 1.93
[1 H, br s, OH], 3.83 [1 H, br s, NH], 4.56 [2 H, s, C(7)CH2], 6.41
[1 H, br s, NH], 6.75 [1 H, br s, C(3)H], 7.12 [1 H, d, J5,6 8.1 Hz,
C(6)H], 7.41 [1 H, br s, C(8)H], 7.58 [1H, d, J5,6 8.1 Hz, C(5)H],
7.88 [1 H, d, J3,4 9.0 Hz C(4)H].; dC(150 MHz, d6-DMSO) 63.48
[C(7)CH2], 112.67 [br, C(3)], 121.29 [br, C(6, 8)], 121.80 [C(4a)],
128.00 [C(5)], 138.11 [C4)], 144.38 [C(7)], 147.03 [C(8a)], 158.29
[C(2)]; m/z (EI) 174.0790 (C10H10N2O requires 174.0793), 157
(23), 145 (70), 128 (52).
Acknowledgements
We would like to thank Dr Jonathan Morris for direct-
ing us towards suitable methods for the deprotection of 4-
methoxybenzylamines.
References
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quinolin-2-yl}acetamide 54. A mixture of N-[6-(bromomethyl)-
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◦
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an additional sample of analytically pure 54 (0.123 g, 29%) (Rf
0.13) as a white powder, mp 231–235 ◦C. (Total yield of 54,
0.347 g, 80%). (Found: C, 69.65; H, 4.4; N, 12.15%. C20H15N3O3
requires C, 69.55; H, 4.4; N, 12.15%); mmax(nujol)/cm−1 3395
and 3334 (NH), 1768 (CO, asym), 1717 (CO, sym), 1706, 1603,
1581 and 1493; dH(300 MHz, CDCl3) 2.20 [3 H, s, CH3], 4.98 [2
H, s, C(6)CH2], 7.69–7.72 [4 H, m, C(5ꢀ, 6ꢀ, 5*, 7*)H], 7.82–7.86
[3 H, m, C(4ꢀ, 7ꢀ, 8*)H], 8.12 [1 H, d, J3,4 8.9, C(4)], 8.38 [1
H, br d, J3,4 8.9, C(3)H], 8.73 [1 H, br s, NH]; dC(75 MHz,
CDCl3) 25.5 [CH3], 42.0 [C(6)CH2], 115.2 [C(3)], 124.1 [C(4ꢀ,
7ꢀ)], 126.7 [C(4a)], 128.0 [C(5)], 128.3 [C(8)], 131.4 [C(7)], 132.7
[C(3ꢀa, 7ꢀa)], 133.9 [C(6)], 134.8 [C(5ꢀ, 6ꢀ)], 139.5 [C(4)], 146.4
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[C(8a)], 151.9 [C(2)], 168.7 [C(1ꢀ, 3ꢀ)], 169.9 [NCOCH3]; m/z
+.
(EI) 345 (M+., 85), 303 (M+. − CH2 C O, 100), 157 (M
−
= =
= =
CH2 C O–C8H4NO2, 15).
*These assignments may be reversed.
2-Amino-6-(aminomethyl)quinoline 55. N-{6-[(1,3-Dioxo-1,3-
dihydro-2H-isoindol-2-yl)methyl]quinolin-2-yl}acetamide 54
(0.216 g, 0.625 mmol) was heated at reflux in 20% aq. sodium
hydroxide (10 mL) for 4 h. After cooling, this solution was
extracted with 3 : 1 chloroform–isopropanol (5 × 15 mL),
the combined organic extracts were dried (Na2SO4), then the
solvent was removed to afford 0.056 g of a pale yellow solid. 1H
NMR analysis of this material indicated it consisted of the title
23 C. Cotrel, C. Jeanmart and M. N. Messer, Ger. Offen., 1973, DE
2301069.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 4 3 – 2 5 5 7
2 5 5 7