Amination of 2-Pyridinesulfonic and 8-Quinolinesulfonic Acids with Magnesium Amides

Article abstract of DOI:10.1002/ejoc.201900057

The amination of 2-pyridine- and 8-quinolinesulfonic acids using magnesium amides of the type R₂NMgCl·LiCl is reported. Thus, several cyclic and acyclic amines were converted into the corresponding amides using iPrMgCl·LiCl, which reacted readily with sulfonic acids to produce aminopyridines and aminoquinolines. Various amines which are attractive in drug chemistry were suitable for this transformation.

Full text of DOI:10.1002/ejoc.201900057

A Journal of
Accepted Article
Title: Amination of 2-Pyridinesulfonic and 8-Quinolinesulfonic Acids
with Magnesium Amides
Authors: Moritz Balkenhohl, Vasiliki Valsamidou, and Paul Knochel
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900057
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10.1002/ejoc.201900057
European Journal of Organic Chemistry
COMMUNICATION
Amination of 2-Pyridinesulfonic and 8-Quinolinesulfonic Acids
with Magnesium Amides
Moritz Balkenhohl, Vasiliki Valsamidou, and Paul Knochel*
Abstract: The amination of 2-pyridine- and 8-quinolinesulfonic acids
using magnesium amides of the type R2NMgCl·LiCl is reported. Thus,
several cyclic and acyclic amines were converted into the
corresponding amides using iPrMgCl·LiCl, which reacted readily with
sulfonic acids to produce aminopyridines and –quinolines. Various
amines attractive in drug chemistry were suitable for this
transformation.
Introduction
Aminated N-heterocycles and especially aminopyridines and –
quinolines are important targets for the pharmaceutical industry.1
Chloropyramine (1), for example, is an antihistaminic and the
pyridine 2 is a CXCR3 Inhibitor.2 The aminoquinoline primaquine
(3) is commonly prescribed for the treatment of malaria,3 and
crenolanib (4) is currently being evaluated as a drug against
various types of tumors (Figure 1).4
Figure 2. Various conditions for amination reactions, including the transition-
metal-free amination of 2-pyridinesulfonic acids using magnesium amides.
C-N bond (Figure 2a).5 However, transition-metals are expensive
and often toxic.6 Therefore, the development of transition-metal-
free amination methods is highly desirable. So far, 2-halo, 2-
mercapto and 2-cyanopyridines, pyridine-2-phosphorodiamidates,
Figure 1. Various pharmaceutically active aminopyridines and –quinolines.
and 2-pyridyl trifluoromethanesulfonate or pyridine N-oxides were
found to be suitable substrates for this transformation (Figure
2b).7 However, many of these methods require high temperatures
Thus, the development of C-N bond forming reactions is of high
importance. So far, transition-metal-catalyzed methods using Ni-,
Pd-, Cr-, Co-, or Cu-salts have been used for the formation of the
or highly basic lithium amides. Recently, transition-metal-free
aminations of 2-pyridinesulfonyl chloride and related heterocycles
using magnesium amides of type R2NMgCl·LiCl have been
reported (Figure 2c).8 2-Pyridinesulfonyl chloride, though, is a
sensitive reagent which decomposes at 25 °C within several
hours.9 Albeit being commercially available, quinoline-8-sulfonyl
chloride also decomposes at ambient temperature within three to
five months. 2-Pyridine- or 8-quinolinesulfonic acids (5 and 6) are
commercially available and stable reagents, which are formed
upon decomposition of the corresponding sulfonyl chloride.
Herein, we report the amination of 2-pyridine- and
M.Sc. M. Balkenhohl, B.Sc. V. Valsamidou, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
http://www.knochel.cup.uni-muenchen.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900057
European Journal of Organic Chemistry
COMMUNICATION
8-quinolinesulfonic acids using magnesium amides of type
R2NMgCl·LiCl, leading to aminopyridines of type 7 and 8 and
aminoquinolines of type 9 (Figure 2d).
to a decrease in yield. Other cyclic amides derived from piperidine,
azepane, morpholine, N-methylpiperazine, or 4-methylpiperidine
gave aminopyridines 7b-f in 90-97% yield. Additionally, the
upscaling of the reaction was evaluated by preparing the
aminopyridine 7b on a 50 mmol scale in 90% yield. Symmetrical
amides prepared from diethyl-, dibutyl-, or diallylamine yielded
pyridines 7g-i in 76-88% yield. The unsymmetrical amine N-
butylmethylamine was also suitable for the amination reaction,
leading to the aminopyridine 7j in 98% yield. Other amines
bearing e.g. a cyclobutane ring or a TBDMS-protected alcohol,
produced the aminopyridines 7k-o in 59-94% yield. Amines
containing a heterocycle such as a pyridine or a thiophene gave
the corresponding pyridines 7p-q in 65-91% yield.
Results and Discussion
Thus, pyrrolidine (3.0 equiv) was dissolved in THF and treated
with iPrMgCl·LiCl (3.0 equiv) at 0 °C. The resulting magnesium
amide R2NMgCl·LiCl was then added to a suspension of 2-
pyridinesulfonic acid (5) in THF at 0 °C and stirred at 25 °C for
12 h. After workup, the aminopyridine 7a was isolated in 91%
yield (Scheme 1). Using less equivalents of magnesium amide led
As an extension, several amines important in medicinal chemistry
were employed in this amination protocol. Thus, lorcaserin
hydrochloride hemihydrate was treated with an excess of
iPrMgCl·LiCl in order to neutralize the hemihydrate and the HCl
salt, which resulted in the formation of the respective magnesium
amide. This amide readily reacted with 2-pyridinesulfonic acid (5),
to give aminopyridine 8a in 73% yield (Scheme 2). Also, the HCl
salts of the amines nortriptyline and desipramine were neutralized
and deprotonated using iPrMgCl·LiCl. The resulting amides were
employed in the amination reaction, leading to pyridines 8b-c in
84-90% yield. The antidepressant amoxapine gave the polycyclic
heterocycle 8d in 52% yield.
Scheme 2. Amination of 2-pyridinesulfonic acid (5) using magnesium amides
leading to aminopyridines 8a-d.
Interestingly, 8-quinolinesulfonic acid (6) was also a suitable
reagent for the amination reaction. Thus, when the amides (5.0
equiv) derived from several amines, including 4-methylpiperidine
or N-methylpiperazine, were employed in the amination reaction,
8-aminoquinolines 9a-f were obtained in 61-96% yield. The
Scheme 1. Amination of 2-pyridinesulfonic acid (5) using magnesium amides of
type R2NMgCl·LiCl leading to aminopyridines 7a-q.
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10.1002/ejoc.201900057
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COMMUNICATION
0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction
mixture was quenched with water (20 mL) and extracted with ethyl acetate
(3 x 30 mL). The organic phase was dried over Na2SO4 and concentrated
in vacuo, yielding aminopyridine 7a (135 mg, 912 μmol, 91% yield) as a
yellow oil.
upscaling of this method was demonstrated upon the synthesis of
aminoquinoline 9b on a multi-gram scale in 66% yield (Scheme 3).
1H-NMR (400 MHz, CDCl3): δ / ppm = 8.15 (ddd, J = 5.0, 1.9, 0.9 Hz, 1H),
7.42 (ddd, J = 8.5, 7.1, 2.0 Hz, 1H), 6.50 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H),
6.35 (dt, J = 8.6, 1.0 Hz, 1H), 3.50 – 3.39 (m, 4H), 2.04 – 1.97 (m, 4H).
13C-NMR (101 MHz, CDCl3) δ (ppm): 157.5, 148.3, 137.0, 111.2, 106.6,
46.8, 25.7.
Acknowledgments
We thank the DFG (SFB749) for financial support. We also thank
Albemarle (Hoechst, Germany) for the generous gift of chemicals.
Keywords: amination • aminopyridines • magnesium • pyridine •
quinoline
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Scheme 3. Amination of 8-quinolinesulfonic acid (6) using magnesium amides,
leading to aminoquinolines 9a-f.
Conclusions
In summary, the amination of 2-pyridine- and 8-quinolinesulfonic
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active substrates, were applicable to the reaction protocol,
affording the respective 2-aminopyridines and 8-aminoquinolines.
Finally, this amination was readily scaled-up to 50 mmol scale.
Further extensions of this work are currently underway in our
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Experimental Section
iPrMgCl·LiCl: Magnesium turnings (2.67 g, 110 mmol) and anhydrous LiCl
(4.66 g, 100 mmol) were placed in an argon-flushed flask and THF (50 mL)
was added. A solution of iPrCl (9.13 mL, 100 mmol) in THF (50 mL) was
slowly added at 25 °C. The Grignard reagent formation begun within a few
minutes. After addition, the reaction mixture was stirred for 12 h at 25 °C.
The grey solution of iPrMgCl·LiCl was cannulated to another flask under
argon and removed in this way from excess of magnesium. A yield of ca.
95-98% of iPrMgCl·LiCl is obtained.10
Synthesis of aminopyridine 7a: iPrMgCl·LiCl (1.92 mL, 3.00 mmol, 3.0
equiv) was added to a solution of pyrrolidine (0.25 mL, 3.00 mmol, 3.0
equiv) in THF (5 mL) at 0 °C. The solution was stirred for 15 min at 0 °C
and 15 min at 25 °C before being added to a suspension of 2-
pyridinesulfonic acid (5, 159 mg, 1.00 mmol, 1.0 equiv) in THF (5 mL) at
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Entry for the Table of Contents (Please choose one layout)
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N-Heterocycles
Moritz Balkenhohl, Vasiliki Valsamidou,
and Paul Knochel*
Page No. – Page No.
Amination of 2-Pyridinesulfonic and
8-Quinolinesulfonic Acids with
Magnesium Amides
The amination of 2-pyridine- and 8-quinolinesulfonic acids using magnesium
amides is reported. Various amides reacted with N-heterocyclic sulfonic acids,
leading to aminopyridines and –quinolines in up to 98% yield. Various amines
important in medicinal chemistry, such as the antidepressant amoxapine, were
suitable for these aminations.
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