Late Stage Functionalization of Secondary Amines via a Cobalt-Catalyzed Electrophilic Amination of Organozinc Reagents

Article abstract of DOI:10.1021/acs.orglett.8b03787

A general preparation of polyfunctional hydroxylamine benzoates from the corresponding secondary amines is reported. This convenient synthesis allows the setup of a late-stage functionalization of various secondary amines, including pharmaceuticals and peptidic derivatives. Thus, a cross-coupling of hydroxylamine benzoates with various alkyl-, aryl-, and heteroaryl-zinc chlorides in the presence of 5 mol % CoCl₂ (25 °C, 2 h) provides a range of polyfunctional tertiary amines. This method was used to prepare penfluridol and gepirone.

Full text of DOI:10.1021/acs.orglett.8b03787

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Late Stage Functionalization of Secondary Amines via a Cobalt-
Catalyzed Electrophilic Amination of Organozinc Reagents
†
†
,†
Simon Graßl,‡,† Yi-Hung Chen,‡,† Clemence Hamze, Carl Phillip Tullmann, and Paul Knochel*
́
̈
†
̈
̈
̈
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13, Haus F, 81377 Munchen, Germany
S
* Supporting Information
ABSTRACT: A general preparation of polyfunctional hydroxylamine benzoates from the corresponding secondary amines is
reported. This convenient synthesis allows the setup of a late-stage functionalization of various secondary amines, including
pharmaceuticals and peptidic derivatives. Thus, a cross-coupling of hydroxylamine benzoates with various alkyl-, aryl-, and
heteroaryl-zinc chlorides in the presence of 5 mol % CoCl2 (25 °C, 2 h) provides a range of polyfunctional tertiary amines. This
method was used to prepare penfluridol and gepirone.
Scheme 2. Comparison of Three Preparations of N-
he formation of a carbon−nitrogen bond is one of the
Tmost important reactions for the elaboration of
pharmaceuticals and agrochemicals.1 Especially the late-stage
functionalization2 of secondary amines would be a valuable
method for producing new biologically active compounds.3
Palladium-catalyzed nucleophilic aminations have tremen-
dously improved the performance of aryl and heteroaryl
aminations.4 However, electrophilic aminations pioneered by
Johnson5 are a valuable alternative because cheaper and less
toxic metal catalysts of Cu, Ru, Ni, Fe, and Co may be used.6
Recently, we reported a new cobalt-catalyzed electrophilic
amination of organozinc pivalates7 of type 1 with N-
hydroxylamine benzoates 2, allowing the preparation of various
functionalized amines of type 3 (Scheme 1).8 The required N-
hydroxylamine benzoates 2 have been prepared from the
corresponding amines 4 using benzoylperoxide (BPO), as
previously reported.5 However, the scope of preparation of
such N-hydroxylamine benzoates 2 is quite limited and
a
Hydroxylamine Benzoate 2a from Amine 4a11
a
Method A: amine 4 (1.5 equiv), BPO (1.0 equiv), K2HPO4 (1.5
equiv), DMF, rt, 12 h. Method B: (1) amine 4 (1.0 equiv), DMDO
(1.05 equiv), acetone, 0 °C, 1 h; (2) BzCl (1.2 equiv), NEt3 (1.5
equiv), DMAP (1 mol %), CH2Cl2, 0 °C, 30 min. Method C: (1)
amine 4, (1.0 equiv), acrylonitrile (5.0 equiv), MeOH, 55 °C, 12 h;
(2) mCPBA (1.1 equiv), CH2Cl2, −78 °C to rt, 12 h; (3) BzCl (1.2
equiv), NEt3 (1.5 equiv), DMAP (1 mol %), CH2Cl2, 0 °C, 30 min.
considerably reduces the synthetic potential of these electro-
philic aminations.
Scheme 1. Cobalt-Catalyzed Electrophilic Amination Using
Organozinc Reagents 1 and N-Hydroxylamine Benzoates 2
Leading to Functionalized Tertiary Amines of Type 3
Herein, we report a new method with a broad scope to
prepare N-hydroxylamine benzoates 2 and demonstrate their
utility for the performance of late-stage functionalizations of
various amines, including pharmaceuticals and peptides.
Furthermore, we show the efficiency of this method for the
preparation of the two drugs gepirone9 (3p) and penfluridol10
(5).
Received: November 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Preparation of N-Hydroxylamine Benzoates
a
All experiments were performed on a 1 mmol scale and the reported yields are isolated yields of analytically pure products; [a] 10 mmol scale.
a
Scheme 4. Electrophilic Amination of Organic Chlorides of Type 1
a
All experiments were performed on a 1 mmol scale, and the reported yields are isolated yields of analytically pure products.
Preliminary experiments have shown that the benzoylox-
ylation of a typical functionalized amine such as 1,4-piperidone
(4a) provides the corresponding benzoyloxyamine 2a in only
27% yield using BPO (Method A, Scheme 2). An alternative
method using a dimethyldioxirane (DMDO)12 oxidation and
subsequent benzoylation with PhCOCl (BzCl) provides 2a in
64% yield (Method B). Unfortunately, this reaction could not
be easily scaled up due to low yields for the preparation of
DMDO. Several other oxidation methods were tested, but
were neither selective nor high yielding. However, the
oxidation method of O’Neil for preparing N-hydroxylamines
8 proved to be convenient and general.13 According to this
method, amine 4 was treated with acrylonitrile (MeOH, 55 °C,
12 h), providing a tertiary amine of type 6. Its oxidation with
meta-chloroperbenzoic acid (mCPBA; CH2Cl2, −78 °C, 3 h)
gives an amine N-oxide of type 7, which underwent a Cope
B
DOI: 10.1021/acs.orglett.8b03787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
sertraline, fluoxetine, and duloxetine were predictably con-
verted to the hydroxylamine esters 2m−2p in 66−90% yields.
Finally, amino acids and a peptide such as a nipecotic acid
derivative, an azetidine derivate, and a dipeptide were
chemoselectively converted to the corresponding hydroxyl-
amines 2q−2s in 52−79% yields.
Scheme 5. Functionalization of Amino Acids 2q and 2r and
Peptidic Substrates 2s Using the Cobalt-Catalyzed
Amination of Organozincs 1c, 1q, and 1r
Having in hand a general conversion of secondary amines 4
to the corresponding hydroxylamine benzoates 2, we have
shown their cross-coupling with polyfunctional organozinc
chlorides14 provides a wide range of tertiary amines of type 3.
Thus, various aryl- and heteroaryl-zinc chlorides 1a−1d
underwent a cobalt-catalyzed electrophilic amination with
cyclic hydroxylamine benzoates 2c−2f in the presence of 5 mol
% CoCl2 (THF, 25 °C, 2 h), leading to polyfunctional tertiary
amines 3b−3e in 83−92% yields (Scheme 4). This amination
was found to be compatible with several important functional
groups (secondary and tertiary alcohols, primary and
secondary amines, amides and epoxides).15,16 For example,
the reaction of 3-anisylzinc chloride (1e) with hydroxylamine
ester 2g, bearing an acidic amide proton proceeded smoothly
in the presence of 5 mol % CoCl2, affording the tertiary amine
3f. These electrophilic aminations complement the nucleo-
philic amination of Buchwald and Hartwig.4 Thus, the
melatonin receptor ligand 3f as well as the 517-β-
hydroxysteroid dehydrogenase inhibitor 3b have been
prepared via the nucleophilic Pd-catalyzed amination in
moderate yields (respectively 5517 and 37%18), whereas the
present electrophilic amination produces these pharmaceutical
targets in 89 and 77% yield. The robustness of this amination
has been used for completing a late-stage functionalization of
several alkaloids and pharmaceuticals bearing a secondary
amine. Thus, the corresponding hydroxylamine benzoates 2h−
2p provided, after treatment with the organozinc chlorides 1f−
1n, the desired functionalized pharmaceuticals or alkaloids
3g−3o in 61−90% yields. Alkylzinc chlorides such as 1o19,20
are also good reaction partners for this amination. Hence, zinc
reagent 1o was aminated with 2b, providing gepirone (3p), an
antidepressant drug, in 82% yield.
Scheme 6. A New Synthesis of Penfluridol 5
Encouraged by these results, we envisioned a late stage
functionalization of amino acids and peptides. Therefore, the
hydroxylamine benzoates derived from two β-amino-acids 2q
and 2r and dipeptide 2s underwent the expected amination
with organozinc chlorides 1p, 1j, and 1a, leading to the
arylated amino-acids 3q−3r and peptide 3s in 62−78% yield
(Scheme 5). As observed for benzoate 2g, the amidic proton of
2r and 2s did not disturb the desired amination.
To demonstrate the synthetic versatility of this amination,
we also performed a short synthesis of penfluridol (5), a highly
potent antipsychotic (Scheme 4). Thus, the arylmagnesium
chloride 9 underwent a LaCl3·2LiCl21 mediated addition to the
2-cyanoethyl-piperidone (6a)19 (THF, 25 °C, 1.5 h), leading
to the tertiary alcohol 10 in 52% yield. Without protection of
the tertiary hydroxyl function, alcohol 10 was converted by the
standard method to the hydroxylamine benzoate 11 in 74%
yield. Protection of 10 with TMSCl followed by the cobalt-
catalyzed amination using the alkylzinc chloride 1219 and
desilylation (1M HCl, 25 °C, 1 h) produces penfluridol (5) in
89% yield (Scheme 6).
elimination (25 °C, 9 h), affording N-hydroxylamines of type
8.13 Benzoylation with BzCl (NEt3, DMAP, CH2Cl2, 0 °C, 0.5
h) furnished the desired hydroxylamine benzoates 2. Applying
this sequence to 4a led to the desired product 2a in an overall
yield of 61% (Method C).
This selective oxidation was performed on diverse amines
4b−s affording via the 2-cyanoethyl amines 6b−s the desired
hydroxylamine benzoates in satisfactory overall yields (Scheme
3). In contrast to Method B, Method C allows a convenient
scale-up. Thus, the preparation of the hydroxylamine benzoate
2b derived from a piperazine (83% yield on 1 mmol scale)
could readily be scaled-up (77% yield on 10 mmol scale;
Scheme 3). Likewise, we prepared the related piperazine and
piperidine derived hydroxylamine benzoates 2c−2g (65−81%
yields). This method has been extended to biologically active
amines, such as the alkaloid anabasine and the psychostimulant
methylphenidate and led to the expected hydroxylamine
benzoates 2h and 2i in 56−71% yields. Important drugs
bearing cyclic secondary amines such as paroxetine (anti-
depressant), debenzylated donepezil (treatment of dementia),
and lorcaserine (former morbid obesity medication) were
smoothly converted to the desired products 2j−2l in 73−76%
yields. Also, open-chain antidepressants like nortriptyline,
In summary, we reported a very general and functional
group tolerating synthesis of hydroxylamine benzoates 2 and
demonstrated their utility in the cobalt-catalyzed amination of
various alkyl-, aryl-, and heteroaryl-zinc chlorides, leading for
the first time to complex polyfunctional amines in a predictable
C
DOI: 10.1021/acs.orglett.8b03787
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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target amines such as the pharmaceuticals penfluridol (5) and
gepirone (3p). Further extensions are currently studied in our
laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(8) Chen, Y.-H.; Graßl, S.; Knochel, P. Angew. Chem., Int. Ed. 2018,
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03787.
(9) Yevich, J. P.; New, J. S.; Smith, D. W.; Lobeck, W. G.; Catt, J. D.;
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General experimental procedures, detailed synthetic
procedures, and analytical data for all compounds
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
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Paul Knochel: 0000-0001-7913-4332
Author Contributions
‡S.G. and Y.H.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (DFG) for
financial support. We thank Albemarle (Germany) for the
generous gift of chemicals.
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DOI: 10.1021/acs.orglett.8b03787
Org. Lett. XXXX, XXX, XXX−XXX