Preparation of tertiary amines by the reaction of iminium ions derived from unsymmetrical aminals with zinc and magnesium organometallics

Article abstract of DOI:10.1021/acs.orglett.5b00801

We report a convenient one-pot preparation of polyfunctional tertiary amines, including various biorelevant phenethylamines or ephedrine derivatives, via the reaction of new functionalized iminium ions with a variety of zinc and magnesium organometallic reagents. These iminium ions were generated from unsymmetrical aminals, obtained by the in situ addition of various amides to Tietzes iminium salt [Me₂NCH₂⁺CF₃COO^-]. A functionalized aniline, prepared by this method, was converted to a quinolidine via an intramolecular Heck reaction.

Full text of DOI:10.1021/acs.orglett.5b00801

Letter
pubs.acs.org/OrgLett
Preparation of Tertiary Amines by the Reaction of Iminium Ions
Derived from Unsymmetrical Aminals with Zinc and Magnesium
Organometallics
Veronika Werner, Mario Ellwart, Andreas J. Wagner, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
ABSTRACT: We report a convenient one-pot preparation of
polyfunctional tertiary amines, including various biorelevant
phenethylamines or ephedrine derivatives, via the reaction of
new functionalized iminium ions with a variety of zinc and
magnesium organometallic reagents. These iminium ions were
generated from unsymmetrical aminals, obtained by the in situ
addition of various amides to Tietze’s iminium salt
+
[Me2NCH2 CF3COO−]. A functionalized aniline, prepared
by this method, was converted to a quinolidine via an
intramolecular Heck reaction.
Scheme 1. Preparation of Tertiary Amines of Type 8 by
Cleavage of Mixed Aminals of Type 3 and Subsequent
Reaction with Organometallic Reagents of Type 7
olyfunctional amines are ubiquitous in organic chemistry
and numerous preparation methods have been reported.1,2
P
In particular, the addition of organometallic reagents to
iminium ions3,4 constitutes a useful synthesis of tertiary
amines.5,6 Potier reported the first preparation of N,N-
dimethyl(methylene)iminium trifluoroacetate (1) from trime-
thylamine oxide.7 This synthesis was considerably improved by
Tietze, who reported a preparation by the reaction of
N,N,N′,N′-tetramethylmethanediamine (TMDAM, 2) with
trifluoroacetic anhydride (TFAA).8,9 We envisioned that the
iminium salt (1) could be used to prepare new unsymmetrical
aminals of type 3 by the reaction of 1 with metallic amides of
type 4 (R1R2NMet; Met = Li, MgX). The amides 4 were
prepared by deprotonation of the corresponding amine
R1R2NH (5) with CH3Met (Met = Li, MgX). This reaction
sequence will provide a route to complex iminium ions of type
6. Thus, the treatment of the aminals 3 (which are prone to
disproportionation under mild acidic conditions)10 with TFAA
under Tietze’s conditions will regioselectively provide the
iminium salt 6. It is expected that the acylation of aminals 3
with TFAA occurs selectively on the least sterically hindered
nitrogen of the N,N-acetal. The resulting functionalized
iminium salt 6 may react with various organometallics (R3-
Met (7)), leading to polyfunctional tertiary amines of type 8
(Scheme 1). Herein, we report a successful one-pot procedure,
which allows the conversion of TMDAM (2) directly into a
broad variety of tertiary amines of type 8.
by the addition of TFAA (1.0 equiv) to TMDAM (2; 1.0 equiv,
CH2Cl2, 0 °C, 15 min). This resulted in the clean formation of
the mixed aminal 3a,12 which was in this first experiment
isolated after a basic workup in 86% yield (NMR analysis
showed that no disproportionation has occurred). The reaction
of the aminal (3a) with TFAA (1.0 equiv, CH2Cl2, −78 °C, 15
min) led selectively to a new iminium trifluoroacetate (6a)
which was treated with the benzylic zinc reagent13 7a in THF
furnishing the expected tertiary amine 8a in 52% yield (45%
overall yield in this two-step procedure).14 To avoid the
isolation of the sensitive mixed aminal (3a), a convenient one-
pot procedure was developed, allowing the isolation of the
tertiary amine 8a in 61% yield (Scheme 2).
Although a convenient one-pot procedure has been
developed (Table 1), the isolation of the unsymmetrical
aminals of type 3 postulated in Scheme 1 has been performed
in the special case of 9H-carbazole11 (5a). Thus, the treatment
of a THF solution of 5a with MeLi (1.1 equiv, 1.6 M in Et2O,
−78 °C, 30 min) provided the corresponding lithium amide,
which was added to the iminium trifluoroacetate (1), generated
This one-pot procedure proved to be general and a range of
functionalized amines of type 5 as well as a variety of benzylic
Received: March 18, 2015
Published: April 7, 2015
© 2015 American Chemical Society
2026
DOI: 10.1021/acs.orglett.5b00801
Org. Lett. 2015, 17, 2026−2029

Organic Letters
Letter
Table 1. Phenethylamines (8), Benzylamines (9), and
Homoallylic Amines (10) Obtained by the One-Pot
Procedure of Amines of Type 5 with Various Zinc Reagents
of Type 7
Scheme 2. Preparation of the Mixed Aminal 3a and
Subsequent Conversion to the Tertiary Amine 8a
zinc reagents13 (7a−7e) were used, leading to various
phenethylamines (8b−8g) in 62−92% overall yield (Table 1,
entries 1−6). The preparation of 8f was successfully performed
on gram-scale (72% yield on a 1 mmol scale compared to 68%
yield on a 10 mmol scale, entry 5). Phenethylamines are
common targets in medicinal chemistry and have found many
applications in neuropsychopharmacology.15
Interestingly, heterocyclic benzylic zinc reagents6 such as ((6-
chloropyridin-3-yl)methyl)zinc chloride (7f) provided an entry
to heterocyclic phenethylamines such as 8h (entry 6) and 8i
(Scheme 3). Other classes of zinc reagents16 were successfully
Scheme 3. One-Pot Procedure for the Generation of
Tertiary Amines of Type 8−10 by Using Benzylic, Aryl, and
Allylic Zinc Reagents
used in this homologative synthesis of tertiary amines. Thus,
the aminomethylation of the arylzinc bromide (7g) with
indoline (5i) or phenoxazine (5c) provided the benzylamines
9a (entry 8) and 9b (Scheme 3) in 66−80% yield. Also,
functionalized allylic zinc reagents17 such as cyclohex-2-en-1-
ylzinc bromide (7h) or the cyano-functionalized18 (2-
cyanocyclopent-2-en-1-yl)zinc chloride (7i) were added to
iminium ions of type 6, generated from the two amines 1-(3-
fluorophenyl)-N-methylmethanamine (5j) and the sterically
hindered aliphatic amine 5f, furnishing the expected homo-
allylic amines 10a (entry 9) and 10b (Scheme 3) in 76−84%
yield.
a
The concentration of the zinc reagent was determined by iodometric
b
c
titration. Isolated yield of analytically pure product. The reaction was
performed on a 1 mmol scale. The reaction was performed on a 10
mmol scale.
d
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DOI: 10.1021/acs.orglett.5b00801
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Organic Letters
Letter
Ephedrine has found several pharmaceutical applications and
is especially valuable for the treatment of obesity.19 Our
homologative amination procedure allows conversion of the
(+)-ephedrine derivative 11 to the benzylic and phenethylic
amines 12a−b in 70−91% yield (Scheme 4).
Table 2. Products of Type 9 Obtained by the One-Pot
Procedure of Amines of Type 5 with Various Grignard
Reagents of Type 7
Scheme 4. Homologation of the (+)-Ephedrine Derivative
11 into the Corresponding Tertiary Amines of Type 12
The high functional group tolerance of this procedure
enabled the synthesis of functionalized precursors suitable for
cyclization reactions. This was demonstrated in the homo-
logation of the amine 5k, which led to an intermediate iminium
ion that reacted regioselectively with cinnamylzinc chloride
(7k) to the polyfunctional aniline 10c in 71% yield. A
subsequent Heck cyclization20 led selectively to the exo-
methylene quinolidine (13) in 89% yield (Scheme 5).
Scheme 5. Heck Reaction of the Aniline Derivative 10c,
Which Was Obtained by the One-Pot Reaction of Aniline
(5k) and Cinnamylzinc Chloride (7k)
a
b
Isolated yield of analytically pure product. The concentration of the
Grignard reagent was determined by iodometric titration.
the preparation of complex amines, including biorelevant
phenethylamines and ephedrine derivatives as well as a
cyclization precursor, leading to the quinolidine scaffold.
Further applications of this method are currently underway in
our laboratories.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Finally, aryl and heteroaryl Grignard reagents21 were used in
this one-pot homologative amination, furnishing highly
functionalized benzylamines. Thus, piperidine (5d) and
phenoxazine (5c) were converted to the corresponding
benzylamines 9c and 9b in 76−77% yield, using the Grignard
reagents 7l and 7m (Table 2, entries 1−2). Also pyridin-3-
ylmagnesium bromide (7n) provided the corresponding
heterocyclic amines (9d-9e) in 70−71% yield (entries 3−4).
Sterically hindered tertiary amines are often difficult to prepare
by conventional methods.22 Using this one-pot reaction, tert-
butylisopropylamine (5f) reacted with (2,4-dimethoxy-
pyrimidin-5-yl)magnesium bromide (7o) furnishing the steri-
cally hindered tertiary amine (9f) in 61% yield.
In summary, we have reported a general synthesis of new
mixed aminals using Tietze’s iminium salt. Their treatment with
TFAA provided an entry to new polyfunctional iminium salts,
which were trapped by numerous zinc and magnesium
organometallics leading to a range of valuable amines using a
convenient one-pot procedure. This reaction sequence allowed
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the SFB 749 for financial support. We thank Heraeus
Holding GmbH (Hanau), Rockwood Lithium (Hoechst), and
BASF SE (Ludwigshafen) for the generous gift of chemicals.
We also thank Dr. Gabriel Monzon (LMU Munich) for
preliminary experiments.
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DOI: 10.1021/acs.orglett.5b00801
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Letter
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