Iron-Mediated Electrophilic Amination of Organozinc Halides using Organic Azides

Article abstract of DOI:10.1002/anie.201911704

A wide range of alkyl-, aryl- and heteroarylzinc halides were aminated with highly functionalized alkyl, aryl, and heterocyclic azides. The reaction proceeds smoothly at 50 °C within 1 h in the presence of FeCl₃ (0.5 equiv) to furnish the corresponding secondary amines in good yields. This method was extended to peptidic azides and provided the arylated substrates with full retention of configuration. To demonstrate the utility of this reaction, we prepared two amine derivatives of pharmaceutical relevance using this iron-mediated electrophilic amination as the key step.

Full text of DOI:10.1002/anie.201911704

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Accepted Article
Title: Iron-Mediated Electrophilic Amination of Organozinc Halides
using Organic Azides
Authors: Simon Graßl, Johannes Singer, and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911704
Angew. Chem. 10.1002/ange.201911704
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10.1002/anie.201911704
Angewandte Chemie International Edition
COMMUNICATION
Iron-Mediated Electrophilic Amination of Organozinc Halides
using Organic Azides
Simon Graßl,[a] Johannes Singer,[a] Paul Knochel*[a]
Abstract: A wide range of alkyl-, aryl- and heteroarylzinc halides have
been aminated with highly functionalized alkyl, aryl and heterocyclic
azides. The reaction proceeds smoothly at 50 °C within 1 h in the
presence of FeCl3 (0.5 equiv) to furnish the corresponding secondary
amines in good yields. This method was extended to peptidic azides,
providing the arylated substrates under full retention configuration. To
demonstrate the utility of this reaction, we prepared two amine
derivatives of pharmaceutical relevance using this iron-mediated
electrophilic amination as the key step.
Thus, in preliminary experiments we have treated aryl azide (1a)
with 4-anisylzinc chloride (2a), prepared from the corresponding
Grignard reagent by transmetalation with ZnCl2, in THF at
25 °C.[12] In the absence of a transition metal catalyst, no
amination was observed (Table 1, entry 1). Also, metallic salts
derived from Cu(I), Cu(II), Cr(II), Cr(III), Ni(II), Pd(II) provided only
traces of the secondary amine 5a (entries 2–8). However, an
Fe(II) or Fe(III)-catalysisgave valuable results, whereby FeCl3
was more active than FeCl2 (entries 9–10).[13] Varying the
stoichiometry showed, that 0.5 equiv of FeCl3 led to the best result,
furnishing 5a in 68% isolated yield (entry 11–12). Further
optimization of the reaction conditions showed, that performing
the amination at 50 °C led to complete conversion to 5a within 1 h
in 74% isolated yield (entry 11).
The preparation of polyfunctional amines is central to organic
synthesis.[1] Nucleophilic aminations[2] in which the amine plays
the role of a nucleophile, such as the Buchwald-Hartwig
amination[3], have been widely used for the preparation of aryl and
heteroaryl amines. In contrast, electrophilic aminations are much
less developed. Pioneer work from Narasaka[4] and more recently
from Johnson[5] have led to a number of electrophilic aminations
using for example N-hydroxylamines derivatives as electrophilic
aminating reagent.[6] Recently, we have shown that the cobalt-
catalyzed amination of organozinc halides and pivalates by
N-hydroxylamine benzoates furnishes polyfunctional tertiary
amines.[7] In the search of electrophilic amination reactions
leading to secondary amines, we have envisioned the use of
organic azides of type 1 as electrophilic nitrogen sources.[8] In the
early work of Trost[9] and others[10], such reactions have been
performed using Grignard reagents. We envisioned, that
organozinc halides of type 2 would be especially attractive, since
these organometallics[11] are compatible with the presence of
various functional groups.[12] In general organozinc reagents are
not very reactive, so that we anticipated, that transition metal
catalysts (Met; 3) may be required for achieving the desired
amination via transition state 4, leading to secondary amines of
type 5 (Scheme 1).
Table 1. Optimization of the electrophilic amination of organozinc halides 2
with organic azides 1, leading to secondary amines of type 5.
Catalyst (loading)
-
Entry
Yield [%]
0
1
2
CuCN·2LiCl (20 mol%)
CuCl2 (20 mol%)
CrCl3 (20 mol%)
CoCl2 (20 mol%)
CrCl2 (20 mol%)
NiCl2 (20 mol%)
PdCl2 (20 mol%)
FeCl2 (20 mol%)
FeCl3 (20 mol%)
FeCl3 (50 mol%)
FeCl3 (75 mol%)
<5%
<5%
3
<5%
4
<5%
5
<5%
6
<5%
7
Scheme 1. Tentative pathway for the electrophilic amination of organozinc
halides with organic azides in the presence of a transition metal catalyst.
<5%
8
51[a]
9
55[a]
10
11
12
[a]
S. Graßl, J. Singer, 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
68[b] (74[b,c]
32[a]
)
Supporting information for this article is given via a link at the end of
the document.
[a] GC-yield; [b] isolated yield; [c] 50 °C, 1 h
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10.1002/anie.201911704
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COMMUNICATION
These amination conditions were satisfactory for wide range of
organic azides 1 as well as organozinc halides 2 (Scheme 2).
Remarkably, arylzinc chlorides bearing electron-withdrawing
groups, and therefore being less nucleophilic, still react under our
standard conditions (50 °C, 1 h). Thus, various highly
functionalized diarylamines (5b-h), containing functional groups
such as halides, esters, cyano, N-morpholino amides as well as a
primary amide group (CONH2), have been prepared in high yields
(65–93% yield). As expected electron-rich arylzinc reagents react
smoothly under the described conditions, leading to diarylamines
5i-o bearing functional groups such as dimethylamino, OCF3,
formyl or acetyl (47–84% yield). Alkylzinc reagents also showed
to be suitable substrates and cyclopropylzinc chloride (2l) was
aminated by 4-nitrophenylazide in 64% yield. Interestingly, no
electron-transfer from the zinc reagent to the nitro group is
observed.[14]
The preparation of secondary amines bearing N-heterocyclic
groups is of prime importance for pharmaceutical applications.[15]
Therefore, heterocyclic zinc reagents 2m–n or heterocyclic
azides 1n–p have been aminated according to this novel iron-
mediated amination, leading to the heterocyclic amines 5q-y (53–
91% yield, Scheme 3).
Scheme 3. Preparation of functionalized heteroaryl amines 5 using heterocyclic
azides of type 1 and heteroarylzinc halides of type 2; [a] Isolated yields; [b] The
used organozinc chlorides do not contain MgCl2.
Interestingly, the required heterocyclic zinc reagents can be
generated by the selective metalation of a heterocyclic precursor.
Thus, 3,6-dichloropyridazine (6) was readily zincated with
TMPZnCl·LiCl (TMP=2,2,6,6-tetramethylpiperidyl)[16] at 25 °C for
30 min, leading to the heterocyclic zinc species 2n, which then
has been aminated with various aryl (Scheme 3, 5r–s) and
heteroaryl (Scheme 4a, 5z) azides. Despite the presence of TMP-
H, generated during the zincation, the amination proceeds without
interference. Also, heterocyclic azides, such as N-methyl
benzimidazole (7) have been generated according to Fujieda[17]
via lithiation using n-BuLi and subsequent trapping with TsN3.
Further reaction with arylzinc chloride 2b gave the desired
secondary amine in 51% yield (Scheme 4b, 5aa). Finally, alkyl
azides including bulky azides like 1-adamantyl azide 1r react
smoothly with arylzinc derivatives such as 3-fluorophenylzinc
chloride 2q, leading to the adamantylamine 5ab in 80% yield
(Scheme 5a). This reaction was also extended to peptidic azides
and azido esters (Scheme 5b, R2 = OMe or NH-alkyl), which were
arylated under standard conditions, providing the polyfunctional
chiral amines 5ac–ae under full retention of configuration
(Scheme 5b).
Scheme 2. Scope of functionalized aryl azides of type 1 and arylzinc halides of
type 2 in the iron-mediated electrophilic amination procedure; [a] Isolated yields;
R1 = aryl, alkyl.
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10.1002/anie.201911704
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Scheme 6. Preparation of androgen and estrogen receptor modulator 8 using
the iron-mediated electrophilic amination; TBAF = tetrabutylammoniumfluoride.
Scheme 4. A: Metalation of 3,6-dichloropyridazine (6) and subsequent
iron-mediated electrophilic amination. B: Generation of 2-azido-N-methyl
benzimidazole (1q) and following amination providing amine 5aa.
In a second application, we have prepared the pain relief drug
antrafenine (11). Starting from amino-alcohol 12, after acylation
the iodide 13 was obtained in 81% yield. Following, a very fast
iodine-magnesium exchange using iPrMgCl·LiCl (–78 °C, 30 sec)
and subsequent transmetalation using ZnCl2 provided the
corresponding organozinc chloride. This is submitted to an
electrophilic amination with heterocyclic azide 1w, leading to
antrafenine (11) in 64% yield.
Scheme 4. A: Iron-mediated amination of organozinc chloride 2q using the
bulky alkyl azide 1-azidoadamantane (1r), leading to amine 5ab in 80% isolated
yield; B: Electrophilic amination of arylzinc halides 2c,k,q using α-azido ester
1s and peptidic azides 1t–u, providing the arylated substrates in 52-75%
isolated yields under full retention of configuration.
Scheme 7. Preparation of the pain relief drug antrafenine 11, using the iron-
mediated electrophilic amination; R=3-CF3-C6H5.
As an application, we have prepared two amine derivatives of
pharmaceutical relevance. The first target was the amide 8, a
modulator for androgen and estrogen receptors, reported by
Dalton.[18] Thus, the treatment of aryl azide 1v with p-anisylzinc
chloride (2a) in the presence of 50 mol% FeCl3 (50 °C, 10 min)
led to an intermediate amine, which then was directly acylated
using acid chloride 9, providing the protected amide 10 in 74%
yield (Scheme 5). After desilylation (TBAF) the desired product 8
was obtained in 71% overall yield.
In summary, we have developed a general electrophilic amination
of polyfunctional organozinc halides with organic azides,
mediated by FeCl3 (0.5 equiv). The reactions are generally
complete within 1 h at 50 °C, providing highly functionalized
secondary amines. As mechanistic guideline we used a transition
state of type 4 (Scheme 1). Iron-salts seem to have a unique
ability to trigger efficiently this amination. Further scope
extensions, as well as mechanistic investigations are currently
underway in our laboratories.
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Experimental Section
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Experimental details can be found in the Supporting Information.
Keywords: electrophilic amination • iron-mediated • organozinc
halide • azide • secondary amine
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10.1002/anie.201911704
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Simon Graßl, Johannes Singer, Paul
Knochel*
Page No. – Page No.
Iron-Mediated Electrophilic Amination
of Organozinc Halides using Organic
Azides
An azide in need, can be an amine indeed. We describe an electrophlic
amination of a wide range of alkyl-, aryl- and heteroarylzinc halides with highly
functionalized alkyl, aryl and heterocyclic azides. The reaction proceeds smoothly
using FeCl3 (0.5 equiv) as activator, providing a broad range of highly functionalized
secondary amines in good yields. Given the high tolerance towards functional groups
and the broad availability of organozinc reagents, as well as of organic azides, this
method provides a useful synthetic tool towards the preparation polyfunctional
secondary amines. To demonstrate the utility of this reaction, we prepared two amine
derivatives of pharmaceutical relevance using this iron-mediated electrophilic
amination as the key step.
This article is protected by copyright. All rights reserved.