α-C-H Bond Functionalization of Unprotected Alicyclic Amines: Lewis-Acid-Promoted Addition of Enolates to Transient Imines

Article abstract of DOI:10.1021/acs.orglett.0c04024

Enolizable cyclic imines, obtained in situ from their corresponding lithium amides by oxidation with simple ketone oxidants, are readily alkylated with a range of enolates to provide mono- and polycyclic β-aminoketones in a single operation, including the natural product (±)-myrtine. Nitrile anions also serve as competent nucleophiles in these transformations, which are promoted by BF3 etherate. β-Aminoesters derived from ester enolates can be converted to the corresponding β-lactams.

Full text of DOI:10.1021/acs.orglett.0c04024

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Letter
α‑C−H Bond Functionalization of Unprotected Alicyclic Amines:
Lewis-Acid-Promoted Addition of Enolates to Transient Imines
Jae Hyun Kim,§ Anirudra Paul,§ Ion Ghiviriga, and Daniel Seidel*
Cite This: Org. Lett. 2021, 23, 797−801
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ABSTRACT: Enolizable cyclic imines, obtained in situ from their
corresponding lithium amides by oxidation with simple ketone
oxidants, are readily alkylated with a range of enolates to provide
mono- and polycyclic β-aminoketones in a single operation,
including the natural product ( )-myrtine. Nitrile anions also serve
as competent nucleophiles in these transformations, which are
promoted by BF3 etherate. β-Aminoesters derived from ester enolates can be converted to the corresponding β-lactams.
licyclic amines are ubiquitous compounds with manifold
uses in synthetic and medicinal chemistry.1 The synthesis
tion strategy include the functionalization of multiple ring
positions5c and the decarboxylative alkylation of transient
imines.5d Here we report the alkylation of transient imines with
a broad range of enolate-type nucleophiles to rapidly convert
simple starting materials into a diverse portfolio of function-
alized amines, including polycyclic amines.
A
of substituted alicyclic amines by means of C−H bond
functionalization is an attractive strategy that continues to
inspire the development of numerous, mechanistically distinct
strategies.2,3 Whereas the vast majority of studies in this area
have focused on 3° or protected 2° amines, few methods have
emerged that achieve the synthesis of α-functionalized 2° (i.e.,
unprotected) alicyclic amines directly from their corresponding
parent azacycles.2,4 This can be largely attributed to the
incompatibility of most activation modes with basic amine
functionalities or N−H bonds. We have recently developed a
strategy for the α-C−H bond functionalization of unprotected
alicyclic amines that takes advantage of the known propensity
of lithium amides to undergo the formation of transient imines
upon reaction with simple ketone oxidants (Scheme 1).5,6 This
method was initially applied to organolithium nucleophiles5a
and later extended to Grignard reagents and other organo-
metallics with attenuated nucleophilicities.5b Less reactive
nucleophiles were found to benefit from or require the use of
Lewis acids to activate the imine electrophiles toward addition.
More recent advances utilizing this C−H bond functionaliza-
Mannich reactions are well established as useful tools for the
synthesis of valuable β-amino ketones.7 However, variants
utilizing enolates in combination with enolizable imines, in
particular, enolizable cyclic imines, remain rare,8 likely due to
the limited electrophilicity of imines lacking activating groups
and the dearth of methods to generate cyclic imines in their
active monomeric forms.9 The direct synthesis of methyl-
phenidate10 from piperidine and methyl 2-phenylacetate was
selected as the model reaction to study the proposed
transformation. The key findings of this survey are summarized
in Table 1. In brief, the presence of a Lewis acid was found to
be required to obtain any quantity of methylphenidate, with
BF3 etherate outperforming trimethylsilyl trifluoromethanesul-
fonate (TMSOTf). Diastereomeric ratios were highly variable
depending on the conditions. The highest dr favoring the
pharmaceutically active threo isomer 1a was 3.2:1 (entry 12),
whereas the erythro isomer 1a′ was obtained in up to 10:1 dr
(entry 5).11 The highest overall yield of methylphenidate (1a +
1a′) was obtained in the presence of LiCl additive (entry
20).12
Scheme 1. Li-Amide-based Approach to Amine α-C−H
Bond Functionalization
To keep the overall procedure as simple as possible while
also accommodating potentially less reactive substrates, the
conditions of entry 17 (Table 1) were selected for the
Received: December 4, 2020
Published: January 19, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04024
© 2021 American Chemical Society
Org. Lett. 2021, 23, 797−801
797

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a
Table 1. Optimization of Methylphenidate Synthesis
b
c
entry
method
A
A
Lewis acid (equiv)
additive (equiv)
temp (°C)
time (h)
dr 1a/1a′
yield 1a + 1a′ (%)
1
2
3
4
5
6
7
8
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78
0 + 2
0 + 2
0 + 2
0 + 2
0 + 2
0 + 2
0 + 2
16
0
0
d
LiCl (1.2)
A
A
A
TMSOTf (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.0)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
BF3·OEt2 (2.4)
1:3.0
1.7:1
1:10
38
51
68
58
46
61
42
65
50
66
44
62
59
65
84
89
63
92
d
LiCl (1.5)
d
A
1:3.0
1:1.7
1:4.6
1:5.3
1:5.5
2.7:1
3.2:1
1:6.0
1:5.5
2.1:1
1:4.0
1:1.2
1:1.5
1:5.3
1:3.9
A
A
A
A
A
A
A
A
A
HMPA (3.0)
9
−78
16
10
11
12
13
14
15
16
17
18
19
20
−78 to rt
−78 to 50 °C
−78 to rt
−78
−78 to rt
−78 to 0 °C
−78 to rt
−78 to rt
−78
16 + 2
2 + 2
0 + 2
16
16 + 2
0 + 2
0 + 2
0 + 2
0.5
e
A
B
B
B
d
LiCl (1.2)
LiCl (1.2)
−78 to rt
−78
0 + 2
0.5
d
B
a
1-Piperideine (n mmol) was prepared in situ by adding n-BuLi (n mmol) to a solution of piperidine (n mmol) in Et2O at −78 °C followed by the
addition of trifluoroacetophenone (1.05n mmol). Yields are isolated yields of chromatographically purified compounds. Method A: 1-Piperideine
(1 mmol), methyl 2-phenylacetate (1.5 equiv), and LDA (1.5 equiv) were used. Method B: Methyl 2-phenylacetate (1 mmol), LDA (1 equiv), and
b
c
1-piperideine (2 equiv) were used. Additive was added after LDA followed by stirring at −78 °C for 30 min. Reaction time at −78 °C +
d
e
additional reaction time at noted temperature. THF/Et2O (2:1). 2.5 equiv of methyl 2-phenylacetate and LDA was used.
alkylation of various amines with a number of ester enolates
(Scheme 2). Amines with variable ring sizes participated in the
reaction, and different substitution patterns on the ester were
readily accommodated. Product 1d, derived from a bicyclic
amine, as well as products 1f and 1g, derived from piperidines
containing a substituent in the 4-position, were obtained with
excellent levels of diastereoselectivity.13 The reaction could
also be extended to the use of nitrile anions (Scheme 3).
Scheme 2. Scope of the Alkylation with Ester Enolates
Scheme 3. Alkylation with Nitrile Anions
a
b
Deprotonation performed at −78 °C for 30 min. Deprotonation
performed at −78 °C for 15 min and at rt for 15 min.
The direct synthesis of bi- and tricyclic enaminones was
accomplished by employing dianions derived from 1,3-
diketones (Scheme 4). In these reactions, treatment with an
aqueous base was performed following the addition step to
facilitate the intramolecular condensation step. 4-Benzylpiper-
a
b
Deprotonation performed at −78 °C for 30 min. Deprotonation
performed at −78 °C for 15 min and at rt for 15 min.
798
https://dx.doi.org/10.1021/acs.orglett.0c04024
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Scheme 4. Alkylation with 1,3-Diketone Dianions
Scheme 6. Formation of β-Lactams
In summary, we have achieved the α-alkylation of
unprotected alicyclic amines with a range of different
enolate-type nucleophiles. This approach provides a conven-
ient platform for the diversification of simple amines via C−H
bond functionalization.
idine provided the annulation product 3e with excellent
diastereoselectivity.
Bicyclic and tricyclic β-amino ketones were directly obtained
from α,β-unsaturated ketone enolates upon reaction with in-
situ-generated imines (Scheme 5). Here the initial nucleophilic
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04024.
■
sı
Experimental procedures and characterization data
(PDF)
Scheme 5. Alkylation with α,β-Unsaturated Ketone Enolate
AUTHOR INFORMATION
Corresponding Author
■
Daniel Seidel − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States; orcid.org/0000-0001-
6725-111X; Email: seidel@chem.ufl.edu
Authors
Jae Hyun Kim − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States
Anirudra Paul − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States
Ion Ghiviriga − Center for NMR Spectroscopy, Department of
Chemistry, University of Florida, Gainesville, Florida 32611,
United States; orcid.org/0000-0001-5812-5170
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04024
a
Result in parentheses: Step 4 was performed for 48 h at 70 °C.
Author Contributions
addition is followed by an intramolecular heteroconjugate
addition step, facilitated by treatment with an aqueous base.
Product 4a, obtained with a dr of 5:1, is a direct precursor of
the natural product lasubine I. By changing the temperature
and reaction time of the last step, the other diastereomer of 4a
(a direct precursor of the natural product lasubine II) was
obtained as the predominant product with a dr of 1:8.14 The
natural product myrtine (4d) was obtained in a single
operation, albeit in moderate yield.15
β-Aminoesters derived from ester enolates according to
Scheme 1 can be converted to the corresponding β-lactams in
good yields (Scheme 6).16 For instance, the treatment of 1f
and 1l with tert-butyl magnesium chloride provided bicyclic β-
lactams 5 and 6 in 72 and 73% yield, respectively.
§J.H.K. and A.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NIH−NIGMS (grant no.
R01GM101389) is gratefully acknowledged. Mass spectrom-
etry instrumentation was supported by a grant from the NIH
(S10 OD021758-01A1).
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