Amination of Phosphorodiamidate-Substituted Pyridines and Related N-Heterocycles with Magnesium Amides

Article abstract of DOI:10.1021/acs.orglett.8b03698

The amination of various phosphorodiamidate-substituted pyridines, quinolines, and quinoxaline with magnesium amides R₂NMgCl·LiCl proceeds at room temperature within 8 h. Several pharmaceutically active amines were suitable substrates for this amination procedure, and also the antihistaminic tripelennamine was prepared. Additionally, several heterocyclic phosphorodiamidates underwent directed ortho-metalation (DoM) using TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) or TMP₂Mg·2LiCl, followed by electrophilic functionalization prior to the amination step, which led to ortho-functionalized aminated N-heterocycles.

Full text of DOI:10.1021/acs.orglett.8b03698

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Amination of Phosphorodiamidate-Substituted Pyridines and
Related N‑Heterocycles with Magnesium Amides
Moritz Balkenhohl,† Benjamin Heinz,† Thomas Abegg, and Paul Knochel*
̈
̈
Department of Chemistry, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany
S
* Supporting Information
ABSTRACT: The amination of various phosphorodiamidate-
substituted pyridines, quinolines, and quinoxaline with
magnesium amides R2NMgCl·LiCl proceeds at room temper-
ature within 8 h. Several pharmaceutically active amines were
suitable substrates for this amination procedure, and also the
antihistaminic tripelennamine was prepared. Additionally,
several heterocyclic phosphorodiamidates underwent directed ortho-metalation (DoM) using TMPMgCl·LiCl (TMP =
2,2,6,6-tetramethylpiperidyl) or TMP2Mg·2LiCl, followed by electrophilic functionalization prior to the amination step, which
led to ortho-functionalized aminated N-heterocycles.
mercaptopyridine must be prepared from a halopyridine,
making this procedure lengthy and inefficient.
minated N-heterocycles play a major role in modern
1
Apharmaceutical chemistry. Especially aminopyridines and
On another hand, hydroxypyridines (pyridones) or hydrox-
yquinolines (quinolones) are readily available scaffolds, which
are building blocks for the synthesis of several pharmaceuticals
and natural products.8 They are readily converted to the
corresponding phosphorodiamidates of type 1, which are
prone to undergo directed ortho-metalation (DoM), allowing
the synthesis of 2,3-difunctionalized N-heterocycles.9
-quinolines have shown to be of high importance. For example,
tripelennamine and chlorothen are antihistamines, flupirtine is
a nonopioid analgesic, and chloroquine is used for the
treatment of malaria (Figure 1).2 A range of heteroaryl amines
have been prepared via nucleophilic aminations using
transition metal catalysts of Pd, Ni, Cu, Co, and Cr.3 The
development of transition-metal-free amination methods is
highly desirable.4 So far, 2-halo-, 2-mercapto-, and 2-
cyanopyridines, and 2-pyridyl trifluoromethanesulfonates or
pyridine N-oxides, were employed as electrophilic substrates
for transition-metal-free amination reactions.5 However, most
of these methods require high temperatures or highly basic
lithium amides. Recently, we have demonstrated that pyridine-
2-sulfonyl chloride, which was prepared from 2-mercaptopyr-
idine, readily underwent an amination when treated with a
magnesium amide of type R2NMgCl·LiCl.6 However, pyridine-
2-sulfonyl chloride is instable at room temperature,7 and 2-
Herein, we report, that the treatment of such phosphor-
odiamidate substituted pyridines with R2NMgCl·LiCl leads to
the desired aminated heterocycles in the absence of any
transition-metal catalyst (Scheme 1). Thus, 2-pyridone was
treated with (Me2N)2P(O)Cl (1.2 equiv) in THF to give the
phosphorodiamidate 1a in 91% yield. Other N-heterocyclic
phosphorodiamidates were obtained using the same or a
slightly modified procedure to give the substituted N-
heterocycles 1b−i in 56−94% yield.9 Next, piperidine (1.4
equiv) was dissolved in THF, cooled to 0 °C, and treated with
iPrMgCl·LiCl (1.4 equiv) to give the corresponding
magnesium amide R2NMgCl·LiCl within 30 min. This amide
was added to a solution of 1a in THF at 0 °C and stirred at 25
°C for 8 h. After workup, the desired aminated pyridine 2a was
isolated in 88% yield (Scheme 1). Other cyclic amines, such as
pyrrolidine, morpholine, N-methyl piperazine, or 4-phenyl-
piperidine, were also converted into the corresponding amide
derivatives using iPrMgCl·LiCl and employed in the amination
reaction, which led to aminated pyridines 2b−e in 68−86%
yield. Also, the more challenging TBDMS-protected 3-
hydroxypiperidine and indoline were suitable substrates for
the amination protocol, which led to aminopyridines 2f−g in
52−54% yield. Acyclic amines were converted into the
Figure 1. Biologically active aminopyridines tripelennamine, chlor-
othen, flupirtine, and chloroquine.
Received: November 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Pyridine-2-phosphorodiamidates of
Type 1 Followed by Amination of 1 Using Magnesium
Amides R2NMgCl·LiCl, Leading to Aminopyridines of Type
2
Scheme 3. Synthesis of 2-, 4-, and 8-Aminoquinolines 4a−l
Using Magnesium Amides R2NMgCl·LiCl
Scheme 4. Synthesis of 2-Aminoquinoxalines 5a−f Using
Magnesium Amides R2NMgCl·LiCl
Scheme 2. Synthesis of 4-Aminopyridines 3a−g Using
Magnesium Amides R2NMgCl·LiCl
leading, after amination, to pyridines 2m−p in 66−74% yield
(Scheme 1).
Amination at the C4-position of the pyridine ring is often
difficult to achieve, mainly due to instability of the
corresponding starting material. Thus, 4-bromopyridine is
only stable when being stored as the corresponding HCl salt,10
and pyridine-4-sulfonyl chloride decomposes rapidly and is
difficult to isolate.7 However, 4-pyridone is a commercially
available solid, which can be stored at 25 °C over months.
Thus, after conversion of 4-pyridone to the corresponding
phosphorodiamidate (1d), several amines, including a mixed
nitrogen sulfur heterocycle and azepane, were applied to the
corresponding amides, which, after amination, resulted in the
formation of the pyridines 2h−k in 64−78% yield.
When N′-benzyl-N,N-dimethylethylenediamine was used as
substrate, the antihistaminic tripelennamine 2l was obtained in
74% yield. Additionally, prefunctionalized pyridones were
transformed into the corresponding phosphorodiamidates,
B
DOI: 10.1021/acs.orglett.8b03698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formed magnesium species of type 6 was then either quenched
with electrophiles (E-X) such as I2 or (BrCl2C)2 or underwent
Cu-catalyzed acylation reactions or Pd-catalyzed Negishi14
cross-couplings after transmetalation to Zn.15 The resulting
functionalized heterocycles of type 7 were then aminated,
which led to difunctionalized pyridines 8a−d, quinoline 9, and
to quinoxalines 10a−c in 35−66% yield over two steps
(Scheme 5).
Scheme 5. Directed ortho-Metalation and Functionalization
of Various Phosphorodiamidates, Followed by Amination
with R2NMgCl·LiCl
In summary, phosphorodiamidate-substituted pyridines,
quinolines, and quinoxaline were readily aminated with
R2NMgCl·LiCl, which led to various aminated heterocycles.
Several pharmaceutically active amines were suitable for this
transformation, and also the antihistaminic tripelennamine was
successfully prepared. Additionally, the C4 position of both
pyridine and quinoline was readily aminated. Finally, several
phosphorodiamidates underwent directed ortho-metalation
using TMPMgCl·LiCl or TMP2Mg·2LiCl followed by
functionalization with various electrophiles. Subsequent
amination using R2NMgCl·LiCl gave difunctionalized ami-
nated N-heterocycles in two steps. Further extensions are
currently underway in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03698.
1
Full experimental details, H and 13C spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
a
Yield over two steps.
Paul Knochel: 0000-0001-7913-4332
Author Contributions
amination protocol, yielding the 4-aminopyridines 3a−d in
69−98% yield (Scheme 2). The aminopyridines 3e−f were
isolated in 43−70% yield by the reaction of the magnesium
amides derived from the antidepressants nortriptyline and
fluoxetine with 1d (Scheme 2).
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
Apart from the pyridine scaffold, also hydroxyquinolines and
2-hydroxyquinoxaline were aminated. Thus, 2-, 4-, and 8-
hydroxyquinoline and 2-hydroxyquinoxaline were converted
into the corresponding phosphorodiamidates 1e−i and
submitted to the standard amination protocol. The substituted
2- and 4-hydroxyquinolines were aminated using various
amines including amoxapine, which led to quinolines 4a−h
in 57−90% yield (Scheme 3a). Interestingly, the phosphor-
odiamidate derived from 8-hydroxyquinoline or 5-chloro-8-
hydroxyquinoline also underwent amination, which yielded 8-
aminoquinolines 4i−l in 52−68% yield (Scheme 3b). Finally,
the electron-rich quinoxaline derivative 1i was treated with
various magnesium amides, including the amides derived from
desipramine or the sterically demanding 1-methyl-3-phenyl-
piperazine, and the quinoxalines 5a−f were isolated in 54−89%
yield (Scheme 4).
ACKNOWLEDGMENTS
■
We thank the DFG (SFB749) for financial support. We also
thank Albemarle (Hoechst, Germany) for the generous gift of
chemicals.
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