In situ generation of ammonia for the copper-catalyzed synthesis of primary aminoquinolines

Article abstract of DOI:10.1039/c4nj00046c

The synthesis of primary aminoquinolines from iodoquinolines was carried out in the presence of copper(i) iodide and formamide as the solvent and source of ammonia generated in situ. The reaction proceeded under mild conditions within a few hours and was applicable to various iodoquinolines.

Full text of DOI:10.1039/c4nj00046c

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In situ generation of ammonia for the
copper-catalyzed synthesis of primary
aminoquinolines
Alexandre Aillerie,ab Sylvain Pellegrini,ab Till Bousquet*ab and Lydie Pelinski*ab
Cite this: New J. Chem., 2014,
38, 1389
Received (in Montpellier, France)
9th January 2014,
Accepted 10th February 2014
´
DOI: 10.1039/c4nj00046c
www.rsc.org/njc
The synthesis of primary aminoquinolines from iodoquinolines was
carried out in the presence of copper(I) iodide and formamide as the
solvent and source of ammonia generated in situ. The reaction
proceeded under mild conditions within a few hours and was
applicable to various iodoquinolines.
The aminoquinoline scaffold and its derivatives are found in
numerous natural products and drug-like compounds.1–6
Among them, chloroquine is a well-known 4-aminoquinoline
class of drugs that is widely used for the prophylactic treatment
of malaria1 but can be also a useful agent for the treatment of
rheumatoid arthritis2 and lupus erythematosus3 due to its anti-
inflammatory properties. Moreover, some other derivatives
exhibit remarkable analgesic4 or antibacterial activities5 and
more recently 2-aminoquinoline derivatives were identified as
efficient BACE1 inhibitors for the treatment of Alzheimer’s
disease.6
Starting from halogenoquinolines, several synthetic approaches
have been described for the synthesis of primary aminoquinolines.
The traditional strategy involves the use of ammonia or masked
ammonia to generate the C–N bond.7–9 This bond formation was
first performed in the presence of ammonia gas with a large excess
of phenol and required high temperature (over 150 1C).7 Later, the
emergence of transition-metal catalysts enabled this reaction
to take place at lower temperature from a large variety of
halogenoquinolines. Typically, the latter reactions were con-
ducted in aqueous ammonia or dioxane–ammonia solution
with copper or palladium catalysts.8 The use of ammonia
surrogate in cross-coupling reactions involving an aryl halide
has been described but usually requires an additional step to
release the primary amine moiety.9
Scheme 1 General reaction for the optimization.
Herein we wish to report the use of the inexpensive form-
amide as a solvent and source of ammonia by means of an
in situ reaction with an amine for a copper-catalyzed amination
of iodoquinolines. This new reaction was inspired from the
observation that ammonia is released when formamide is
heated with amines.
Our first attempt to check the feasibility of the reaction
was realized in 7-chloro-4-iodoquinoline 1 in the presence of
ethanolamine (66 equiv.), formamide and 30 mol% of copper(I)
iodide (Scheme 1 and Table 1). The flask was capped with a
balloon filled with nitrogen (procedure A) to control the
ammonia formation. To our delight, the expected 4-amino-7-
chloroquinoline 2 was isolated in 63% yield (Table 1, entry 1).
The use of an aminoalcohol in the reaction allows us to get
rid of the side product 4 and its derivatives by washing during
the work-up. Replacing the ethanolamine by the N-methyl-
ethanolamine improved the yield to 84% (entry 2). Hence,
encouraged by this result, investigations were performed to
determine the optimal conditions (Scheme 1 and Table 1).
From this optimization, it appears that decreasing the loading
of catalyst to 10 mol% was slightly detrimental to the yield
(entry 2 vs. 3). The yield dropped to 60% when the reaction
vessel was not capped (entry 6, procedure B). This result can
be explained by the decrease of ammonia concentration in
a
´
Universite Lille Nord de France, F-59000 Lille, France.
E-mail: till.bousquet@univ-lille1.fr, lydie.pelinski@univ-lille1.fr
b
´
´
Universite de Lille 1, Unite de Catalyse et de Chimie du Solide, UMR CNRS 8181,
ENSCL, B.P. 108, 59652 Villeneuve d’Ascq, France
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Table 1 Amination of 7-chloro-4-iodoquinoline under different conditions
Table 2 Amination of various quinolines
Yieldb (%)
Entry
Halogenoquinoline
Product
Yielda (%)
Entry 2 (n equiv.) CuI (y mol%) Procedurea Conversionb
3
4
1
2
3
4
5
6
7
8
R = H (66) 30
R = Me (66) 30
R = Me (66) 10
R = Me (22) 10
R = Me (22) 30
R = Me (66) 30
R = Me (66) 30
R = Me (22) 30
A
A
A
A
A
B
C
C
nd
97
86
76
93
68
98
95
63c
nd
6
9
3
1
8
6
2
1
0
84 (84)c
78
69
78
60
2
3
55
59
80
89 (86)c
a
Procedure A: reaction vessel closed with a balloon of nitrogen.
Procedure B: reaction vessel open to air. Procedure C: reaction vessel
sealed. Determined by a calibration curve using the authentic com-
b
pounds and the 1,3,5-trimethoxybenzene as the internal standard.
c
Isolated yields.
solution. However, setting up the procedure C (closed vessel)
maintained the yield at a satisfactory level of 80% (entry 7).
Furthermore, with this last procedure, the amount of amino-
alcohol was decreased to 22 equivalents, furnishing the
4-amino-7-chloroquinoline in 86% yield (entry 8).
4
5
62
73
In all cases, a side product corresponding to the cross-coupling
between the iodoquinoline and the N-methylethanolamine was
observed. Fortunately, although its level of formation is affected
by the operating conditions, this side reaction is negligible.
With the optimized conditions in hand, the scope of the
reaction was explored in various substituted quinolines (Table 2).
As expected, the 4,7-dichloroquinoline did not provide the
amino derivative (entry 1). Although aryl chlorides could
undergo cross-coupling transformations under some specific
conditions, it is known that these substrates are less reactive
than the corresponding iodo derivatives.
6
7
65
71
8
64
35
9
Replacing of the chloride atom in position 7 by a more
electron withdrawing trifluoromethyl group furnished the
aminoquinoline in 55% yield (entry 2). When this trifluoro-
methyl group was placed at position 8, the yield of the product
remained modest (59%, entry 3). The presence of methyl or
phenyl substituents on the nitrogen ring allowed the formation
of the desired product in good yields (entries 4 and 5). Next, we
wanted to evaluate the feasibility of the reaction upon changing
the position of the iodide atom. To our delight, 2-, 3- and
4-aminoquinolines were obtained in satisfying yields from the
corresponding iodoquinolines (entries 6–8). However, the
presence of two methoxy electron donating groups on the
iodoquinoline was detrimental to the yield (entry 9). This can
be attributed to the slower rate of the oxidative addition step.
Although the mechanism of this reaction is not established
yet, investigations are ongoing to clearly understand the role of
each partner. However, at this stage, it is assumed that the
ammonia molecule required for the cross-coupling reaction is
generated by condensation of the aminoalcohol on the form-
amide (Scheme 2).
a
Isolated yields.
Two main mechanisms are generally considered for the
copper-mediated cross-coupling step.10 In the first one (mecha-
nism A), the copper catalyst reacts with ammonia in the
presence of the base before the oxidative addition while the Scheme 2 Mechanisms of the copper-catalyzed amination reaction.
1390 | New J. Chem., 2014, 38, 1389--1391
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´
mechanism B begins with the oxidative addition of the aryl Universite de Lille 1). This research was supported by the
´
halide to copper to form a copper(III) intermediate. We believe ‘‘Conseil Regional Nord-Pas de Calais’’ (program PRIM) and
that the generated ammonia would act both as a reagent and as the ‘‘Ligue contre le cancer’’.
a ligand while the aminoalcohol would operate as base.
In summary, we have developed an unconventional cross-
coupling reaction of iodoquinoline catalyzed by copper(I) iodide.
The originality of the method resides in the in situ formation of
Notes and references
ammonia from formamide. Although the yields are not particu-
larly high, the process can be extended to the preparation of a
variety of primary aminoquinolines under relatively smooth
conditions and within short reaction times. One convenient
aspect of this reaction is the water solubility of the formamide,
the aminoalcohol and the side product facilitating the isolation
of the desired aminoquinolines. This strategy involving this
particular formation of ammonia could be a good alternative
tool to access different types of primary amino structures.
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A
typical procedure for the preparation of 4-amino-7-
chloroquinoline 3.
Schlenk tube containing
A
a mixture of 7-chloro-4-
iodoquinoline (1 eq.), N-methylethanolamine (22 eq.), form-
amide (126 eq.) and copper iodide (0.3 eq.) was sealed and heated
to 80 1C for 2.5 h. During this time, the resulting blue solution
turned green. After cooling to room temperature, the reaction
mixture was diluted with an aqueous KOH 1N solution and
extracted five times with AcOEt. The combined organic layers
were dried over MgSO4 and evaporated in vacuo. The residue was
purified using column chromatography on silica gel (AcOEt/Et3N
10/0 to 9/1) to give the desired aminoquinoline in 73% yield.
1H NMR (300 MHz, MeOD-d4): d 8.27 (d, J = 5.5 Hz, 1H), 8.07
(d, J = 9.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 9.0,
2.0 Hz, 1H), 6.61 (d, J = 5.5 Hz, 1H), 4.91 (bs, 2H); 13C NMR
(75 MHz, MeOD-d4): d 154.5, 151.9, 149.9, 136.6, 127.3, 125.8,
125.1, 118.3, 103.9.
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This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014
New J. Chem., 2014, 38, 1389--1391 | 1391