Cobalt-Catalyzed Umpolung Alkylation of Imines to Generate α-Branched Aliphatic Amines

Article abstract of DOI:10.1021/acs.orglett.1c00835

Here we report a general and mild approach to prepare α-branched aliphatic amines from imines. This method capitalizes on a cobalt-catalyzed umpolung alkylation of imines, employs easily available reaction partners, and demonstrates a broad substrate scope. Mechanistic studies suggest this transformation occurs by a radical pathway.

Full text of DOI:10.1021/acs.orglett.1c00835

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Letter
Cobalt-Catalyzed Umpolung Alkylation of Imines To Generate
α‑Branched Aliphatic Amines
Li-Qiang Wan,† Jin-Ge Cao,† Dawen Niu,* and Xia Zhang*
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ABSTRACT: Here we report a general and mild approach to
prepare α-branched aliphatic amines from imines. This method
capitalizes on a cobalt-catalyzed umpolung alkylation of imines,
employs easily available reaction partners, and demonstrates a
broad substrate scope. Mechanistic studies suggest this trans-
formation occurs by a radical pathway.
Scheme 1. Synthesis of α-Branched Aliphatic Amines
α-Branched aliphatic amine scaffolds are present in many
natural products, pharmaceuticals, agrochemicals, supramolec-
ular materials, and ligands to transition metals.1 Consequently,
general, and efficient methods to synthesize α-branched
aliphatic amines are highly desirable. Among the established
methods for synthesizing amines, the addition of a carbon-
based nucleophile to carbon−nitrogen double bonds (as
electrophiles) has been extensively studied and represents
one of the most often utilized approaches.2 However, due to
the acidity of the Cα hydrogen atom, α-branched aliphatic
amines are difficult to access by the above-mentioned
conventional methods. Lately, an alternative strategy which
involves the umpolung3 reaction mode of imines (Scheme 1b)
attracted substantial attention. In this strategy, imines function
as nucleophiles through the in situ generated 2-azaallyl
anions,4−9 leading to products that may be traditionally
challenging to obtain. But the umpolung approach is yet to
be utilized to generate α-branched aliphatic amines (cf. 5
where C is an alkyl group, Scheme 1b). This is probably
because (1) the corresponding alkyl substituted 2-azaallyl
anions are less stabilized and thus more difficult to
generate10,11 or (2) the bond formation could in principle
occur at either the α′ or α position, and to control such
regioselectivity is challenging. The efficient synthesis of α-
branched aliphatic amines is still nontrivial12,13 in synthetic
chemistry. Herein, we report the realization of the umpolung
approach to generate α-branched aliphatic amines using cobalt
catalysis (Scheme 1c). Mechanistic investigations indicate this
reaction occurs by a radical pathway.
reaction temperature at 25 °C. In the absence of the cobalt
catalyst (entry 2), 12 was not detected. We reason an
(unstable) α′ position alkylation product might have formed,
because, under the same cobalt-free conditions, the reaction
We began our work by studying the model reaction between
2-(bromomethyl)-1,3-dioxolane 10 (1.0 equiv) and N-
fluorenyl imine 11 (1.2 equiv, Tables 1, S1, and S2). We
then identified the conditions that led to the product 12 in
excellent yield (entry 1, Table 1). This model reaction
proceeded smoothly under mild conditions, requiring only 5
mol % of CoBr2 as the catalyst, LiHMDS as the base, and the
Received: March 10, 2021
Published: May 11, 2021
https://doi.org/10.1021/acs.orglett.1c00835
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3818−3822
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Letter
a
a
Table 1. Condition Optimization
Scheme 2. Substrate Scope with Respect to Alkyl Bromides
Conv of 10
Yield
b
b
Entry
Catalyst
CoBr2
−
Solvent
Base
(%)
(%)
1
2
3
4
5
6
7
8
Et2O
Et2O
Et2O
Et2O
Et2O
THF
Toluene
MeOH
Et2O
Et2O
Et2O
Et2O
Et2O
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
LiOtBu
100
100
100
100
100
100
100
100
<5
0
<5
90
0
91
trace
48
74
33
73
58
trace
<5
0
Fe(OTf)2
NiBr2·diglyme
CoCl2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
9
10
11
12
<5
28
0
a
Reactions were conducted on a 0.2 mmol scale using 1.2 equiv of
ketimine, 1.0 equiv of alkyl bromide, 0.05 equiv CoBr2, and 1.2 equiv
of LiHMDS at 0.1 M Et2O. Isolated yields after chromatographic
purification. Reactions were conducted on an 1 mmol scale
according to general procedure B (SI).
c
LDA
DBU
13
b
a
Reaction conditions: 10 (0.05 mmol) and 11 (0.06 mmol) according
b
to general procedure A (SI). The yield of 12a was determined by 1H
NMR spectroscopy using 1,3,5- trimethylbenzene as an internal
c
standard. Reaction conditions: 10 (0.05 mmol) and 11 (0.06 mmol)
according to general procedure B (SI).
bromides containing aromatic rings (25), tetrahydropyrans
(26), rigid frameworks such as 1-bromoadamantane (27), and
chlorine atoms (24) were also suitable substrates. Notably, an
alkyl chloride group is tolerated during the synthesis of 24.
This approach could also be applicable to produce α-branched
benzyl amines in good yields under the same conditions (29
and 30). Notably, hydrolyzation of the reaction products could
yield primary amines, which could then be isolated as the N-
Boc protected amines (see p S11 in the Supporting
Information (SI)). In addition, we found this reaction could
be conducted on a 1 mmol scale, to produce the desired
product 12 in slightly diminished yield.
This reaction displayed a decent scope with respect to the C-
aliphatic imines and C-aryl imines reaction partner as well
(Scheme 3). C-Aliphatic imines containing alkyl groups (31
and 32), aromatic rings (33), silyl esters (34), and a terminal
alkenyl group (35) could participate in this reaction. Notably,
imines originated from cinnamyl aldehyde (36) or 3-(2-
furyl)acrylaldehyde (37) underwent this transformation
smoothly. C-Aryl imines containing aromatic rings with
between 2-bromo-2-methylpropane 13 and N-fluorenyl imine
14 gave the α′ position product 16 exclusively in 70% yield,
with only a trace amount of 15 formed. These results indicated
that the cobalt catalyst played a pivotal part in the
regioselectivity control of this transformation. The use of
other catalysts such as Fe(OTf)2 and NiBr2·diglyme (entries 3
and 4) furnished 12 in lower yields. The identity of the cobalt
salt was also crucial to this reaction, as the use of CoCl2
diminished the yield of 12 significantly (entry 5). The above
observations underscored the essential roles of the catalyst
CoBr2. The use of THF instead of Et2O as solvent afforded 12
in 73% yield (entry 6), but employing MeOH led to no
observable product (entry 7). Of all the bases screened, we
found that the performance of LiHMDS was the best (entries
8−13; for other results, see Table S2). Nevertheless, the exact
reason for the unique utility of LiHMDS in this reaction is
unclear at this stage. We speculate this could be due to Li+
affecting the aggregation state of the 2-azaallyl anions.14
Having identified the optimal reaction conditions, we
continued to explore the scope of this transformation (Scheme
2). We noticed a wide array of unactivated alkyl bromides
could partake in this reaction. For instance, simple primary
alkyl bromides (28) and primary alkyl bromides containing
acetals (12), silyl esters (17), and double bonds (18) were well
tolerated. Secondary noncyclic and cyclic alkyl bromides (19−
23) could also be readily employed. We were concerned that
under the basic conditions tertiary alkyl bromides would
experience rapid E2 elimination. However, tertiary alkyl
Scheme 3. Substrate Scope with Respect to the Imines
a
Reactions were conducted on a 0.2 mmol scale using 1.2 equiv of
ketimine, 1.0 equiv of alkyl bromide, 0.05 equiv CoBr2, and 1.2 equiv
of LiHMDS at 0.1 M Et2O. Isolated yields after chromatographic
purification.
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different electronic properties were also tolerated (38 and 39).
Heterocyclic 3-furyl (40) and 3-thiophenyl (41) ketimines
could be employed, producing the corresponding products in
good yield, respectively.
To probe into the mechanism of this cobalt-catalyzed
transformation, we designed two experiments illustrated in
Scheme 4. When 2,2,6,6-tetramethyl-1-piperidinyloxy
610041, China; orcid.org/0000-0002-5114-4413;
Email: niudawen@scu.edu.cn
Xia Zhang − Department of Emergency, State Key Laboratory
of Biotherapy and Cancer Center, West China Hospital, and
School of Chemical Engineering, Sichuan University, Chengdu
610041, China; orcid.org/0000-0002-5073-0269;
Email: zhang-xia@scu.edu.cn
Authors
Scheme 4. Mechanistic Study
Li-Qiang Wan − Department of Emergency, State Key
Laboratory of Biotherapy and Cancer Center, West China
Hospital, and School of Chemical Engineering, Sichuan
University, Chengdu 610041, China
Jin-Ge Cao − Department of Emergency, State Key Laboratory
of Biotherapy and Cancer Center, West China Hospital, and
School of Chemical Engineering, Sichuan University, Chengdu
610041, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00835
Author Contributions
†L.-Q.W. and J.-G.C. made equal contributions.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This investigation was supported by funding from National
Key Research and Development Program (2018YFA0903300).
We also appreciate the financial support from National Natural
Science Foundation of China (Nos. 21772125, 21922106, and
81803359) and start-up funding from West China Hospital of
Sichuan University.
(TEMPO) was employed as a radical trap under the
established conditions, formation of the product 12 was
completely inhibited, with 42 generated as the major product
(Scheme 4a). When using 43 as an electrophile under the
established conditions, we noticed that the cyclized product 46
was produced in decent yield (Scheme 4b). This result
suggested that an alkyl radical 44 was generated as an
intermediate, supporting the reaction is proceeding by a single-
electron transfer mechanism.
In conclusion, we developed a general protocol to prepare α-
branched aliphatic amines and α-branched benzyl amines. This
reaction involves a cobalt-catalyzed umpolungd alkylation of
imines. This process was applicable to a large variety of both
the ketimines and the alkyl bromides, furnishing α-branched
aliphatic amines or α-branched benzyl amines in good to
excellent yields. Preliminary mechanistic studies involving the
radical trapping and radical clock experiments revealed
mechanistic insight for this reaction.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00835.
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AUTHOR INFORMATION
Corresponding Authors
■
Dawen Niu − Department of Emergency, State Key Laboratory
of Biotherapy and Cancer Center, West China Hospital, and
School of Chemical Engineering, Sichuan University, Chengdu
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