Preparation of Tertiary Amines from Tris(2-cyanoethyl)amine Using Three Successive Cobalt-Catalyzed Electrophilic Aminations with Organozinc Halides

Article abstract of DOI:10.1021/acs.orglett.0c00297

We report a stepwise preparation of triple alkylated or arylated tertiary amines, starting from commercially available tris(2-cyanoethyl)amine using three successive reaction sequences involving a selective oxidation (formation of an N-oxide followed by a

Full text of DOI:10.1021/acs.orglett.0c00297

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Letter
Preparation of Tertiary Amines from Tris(2-cyanoethyl)amine Using
Three Successive Cobalt-Catalyzed Electrophilic Aminations with
Organozinc Halides
Simon Graßl and Paul Knochel*
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ABSTRACT: We report a stepwise preparation of triple alkylated or arylated tertiary amines, starting from commercially available
tris(2-cyanoethyl)amine using three successive reaction sequences involving a selective oxidation (formation of an N-oxide followed
by a Cope elimination) leading to an intermediate hydroxylamine, a benzoylation, and a cobalt-catalyzed electrophilic amination
with organozinc halides.
alkylation and -arylation of primary amines are frequently
observed side reactions.15
he formation of carbon−nitrogen bonds is a central
Tchallenge for the elaboration of pharmaceuticals and
agrochemicals.1 In recent decades, several new amine
preparations have been developed.2 Therein, the palladium-
catalyzed nucleophilic aminations reported by Buchwald3 and
Hartwig4 tremendously improved the scope of especially aryl
and heteroaryl amine synthesis.5 Lately, electrophilic amina-
tions, pioneered by Narasaka6 and Johnson,7 have proven to
display a valuable alternative, since cheaper and less toxic
catalysts derived from Cu, Ni, Co, or Fe may be used.8 These
aminations utilize electrophilic nitrogen sources, such as
organic azides,9 N-chloro amines,10 or N-hydroxylamine
benzoates11 in combination with various organometallic
reagents as nucleophiles. Recently, we reported a preparation
of N-hydroxylamine benzoates, based on a Cope elimination
on amines bearing a 2-cyanoethyl moiety.12 This method
proved to be very robust, enabling the late-stage functionaliza-
tion of various polyfunctionalized amines.13 Therefore, we
have envisioned using tris(2-cyanoethyl)amine (1) as a
precursor for a triple electrophilic amination using three
different organozinc reagents of type 2, providing tertiary
amines of type 5. Due to their broad availability, high stability,
and excellent tolerance toward sensitive functional groups,
organozinc reagents would be desirable nucleophiles for this
transformation.14 This would enable construction of a variety
of tailored tertiary amines, bearing three chosen organic
moieties (R1, R2, R3; Scheme 1). Using other amination
procedures, such a task is often challenging, since over-
Scheme 1. General Iterative Preparation of Functionalized
Tertiary Amines of Type 5 Starting from Amine 1 and
Organozinc Halildes 2
Herein we report an iterative sequence, which furnishes
tertiary amines using three different organozinc reagents of
type 2 and tris(2-cyanoethyl)amine (1) as the nitrogen source.
Thus, we have treated amine 1 with mCPBA at −78 °C,
leading to the N-oxide 6, which reacts at 25 °C to the
corresponding hydroxylamine 7 (Scheme 2). After benzoyla-
Received: January 21, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00297
© XXXX American Chemical Society
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amine benzoates derived from aromatic amines are not stable
and undergo a [3,3]-sigmatropic rearrangement of the OBz
moiety to the aryl ring.16 Therefore, only alkylzinc reagents
were used for the first two functionalizations.
Scheme 2. Preparation of Hydroxylamine Benzoate 8
Starting from Amine 1 and Proposed Mechanistic Pathway
Next, we applied the oxidation procedure to the alkylated
tertiary amines of type 3. As expected, selective formation of
the corresponding hydroxylamine was straightforward, which
after benzoylation provided the benzoates 9a−e in 53−73%
yield (Scheme 4). Those have been coupled a second time,
Scheme 4. Preparation of N-Hydroxylamine Benzoates of
Type 9 Starting from Amines of Type 3
tion using benzoyl chloride and triethylamine, the N-
hydroxylamine benzoate 8 was obtained in 57% yield. This
benzoate 8 was submitted to a cobalt-catalyzed electrophilic
amination with alkylzinc halides of type 2. Thus, the amination
of organometallics 2a−c provided, after amination with
benzoate 8 in the presence of CoCl2, the tertiary amines
3a−c in 61−73% yield (Scheme 3, entries 1−3).
Scheme 3. Cobalt-Catalyzed Electrophilic Amination of
Alkyl Organozinc Reagents 2a−e Using N-Hydroxylamine
Benzoate 8, Leading to Tertiary Amines of Type 3
a
All reported yields are isolated yields of analytically pure products.
using various alkylzinc reagents of type 2. Thus, treatment of
cyclopentylamine benzoate 9a with polyfunctional organozinc
reagent 2f in the presence of a cobalt catalyst led to the double
functionalized amine 4a in 87% yield (Scheme 5). Also, the
benzoates 9b−c were smoothly alkylated using the function-
alized organozinc reagents 2g−h, providing the tertiary amines
4b−d in 74−94% yield. Noteworthy, the sterically hindered N-
hydroxylamine benzoate 9d was successfully reacted with
isopropylzinc chloride (2i), providing the bulky tertiary amine
Scheme 5. Electrophilic Amination of Organozinc Reagents
of Type 2 Using Benzoates of Type 9 in the Presence of
CoCl2
a
All reported yields are isolated yields of analytically pure products.
Remarkably, even the sterically hindered adamantylzinc
bromide (2d) was readily aminated with hydroxylamine 8,
leading to amine 3d in 51% yield (entry 4). Also, the pinene-
derived organometallic 2e provided, after a cobalt-catalyzed
amination with benzoate 8, the desired tertiary amine 3e in
66% yield (entry 5). As reported in the literature, hydroxyl-
a
All reported yields are isolated yields of analytically pure products.
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Scheme 6. Preparation of N-Hydroxylamine Benzoates of Type 10 Starting from Amines of Type 4 and Electrophilic
Amination of Organozinc Reagents of Type 2 Using Benzoates of Type 10 in the Presence of CoCl2
a
All reported yields are isolated yields of analytically pure products.
4e in 72% yield.17 In addition, the pinene-derived benzoate 9e
was alkylated with the menthol-derived organozinc reagent 2j,
leading to the tertiary amine 4f in 77% yield.
tertiary amines have been prepared in good yields. Further
scope extensions are currently underway in our laboratories.
With these double alkylated amines of type 4 in hand, we
focused on the last functionalization. Therefore, the amines of
type 4 have been treated with mCPBA, followed by
benzoylation, providing to the unsymmetrical hydroxylamine
benzoates 10a−f in 67−87% yield (Scheme 6). These have
been submitted to a cobalt-catalyzed electrophilic amination
with various functionalized aryl- and heteroarylzinc reagents of
type 2. Thus, arylzinc chloride 2k was aminated with
hydroxylamine benzoate 10a in the presence of CoCl2,
providing the triple functionalized tertiary amine 5a in 88%
yield (Scheme 6). Also, benzoates 10b−d are readily arylated
with organozinc chlorides 2l−n, leading to the corresponding
aniline derivatives 5b−d in 79−86% yield. As expected, various
functional groups, such as esters, nitriles, and a diaryl acetate,
were tolerated in this transformation. Interestingly, adamantly
hydroxylamine benzoate 10e smoothly reacted with 4-
chlorophenylzinc chloride (2o), affording the corresponding
amine 5e in 62% yield. Remarkably, the pinene-derived
hydroxylamine benzoate (10f) reacted in the presence of a
cobalt catalyst with the aryl- and heteroarylzinc chlorides 2p−q
to give the arylated amines 5f−g in 81−86% yield.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00297.
Full experimental details and characterization of all
isolated products (1H NMR spectra, 13C NMR spectra,
and mass analysis) (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Paul Knochel − Department fur Chemie und Pharmazie,
̈
̈
Ludwig-Maximilians Universitat Munich 81377 Munich,
Germany; orcid.org/0000-0001-7913-4332;
Email: paul.knochel@cup.uni-muenchen.de
Author
Simon Graßl − Department fu
̈
r Chemie und Pharmazie,
̈
Ludwig-Maximilians Universitat Munich 81377 Munich,
Germany
In summary, we have developed a procedure to construct
triple alkylated or arylated tertiary amines, starting from
commercially available tris(2-cyanoethyl)amine (1). This
iterative method involves standard steps such as an oxidation
(generating after a Cope elimination a hydroxylamine), a
benzoylation, and a cobalt-catalyzed electrophilic amination of
organozinc reagents of type 2. Thus, various polyfunctionalized
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00297
Notes
The authors declare no competing financial interest.
C
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(17) Banert, K.; Heck, M.; Ihle, A.; Kronawitt, J.; Pester, T.; Shoker,
T. J. Org. Chem. 2018, 83, 5138−5148.
ACKNOWLEDGMENTS
■
We also thank Albemarle (Hoechst, Germany) for the
generous gift of chemicals. Also we thank the Ludwig-
Maximilians University Munich und the Deutsche Forschungs-
gemeinschaft (DFG) for financial support.
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