Synthesis of β-Aminoenones via Cross-Coupling of In-Situ-Generated Isocyanides with 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.8b01888

An efficient and practical strategy for the synthesis of β-aminoenones from a three-component reaction was developed. Ethyl bromodifluoroacetate serves as a C1 source in this strategy, forming isocyanides in situ with primary amines. This reaction represents the first example of utilization of readily available starting materials to generate isocyanides in situ and sequentially fully converted to β-aminoenones, avoiding the generation of byproduct imines and overinsertion products. The mechanism study suggested that this method involves activation of two C(sp³)-F bonds and the formation of isocyanides, which might nourish both isocyanide chemistry and fluorine chemistry.

Full text of DOI:10.1021/acs.orglett.8b01888

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of β‑Aminoenones via Cross-Coupling of In-Situ-
Generated Isocyanides with 1,3-Dicarbonyl Compounds
Xingxing Ma,‡ Yao Zhou,† and Qiuling Song*,†,‡
‡
†Institute of Next Generation Matter Transformation, College of Chemical Engineering, College of Materials Science &
Engineering, Huaqiao University, 668 Jimei Blvd., Xiamen, Fujian 361021, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient and practical strategy for the synthesis of β-aminoenones from a three-component reaction was
developed. Ethyl bromodifluoroacetate serves as a C1 source in this strategy, forming isocyanides in situ with primary amines.
This reaction represents the first example of utilization of readily available starting materials to generate isocyanides in situ and
sequentially fully converted to β-aminoenones, avoiding the generation of byproduct imines and overinsertion products. The
mechanism study suggested that this method involves activation of two C(sp3)−F bonds and the formation of isocyanides,
which might nourish both isocyanide chemistry and fluorine chemistry.
Scheme 1. Synthesis of β-Aminoenones via Cross-Coupling
of Isocyanides Generating In Situ
t is well-known that isocyanides are efficient and almighty
1
Ibuilding blocks. Because of their carbene-like reactivities,
they have been widely used for the construction of biologically
active molecules and the total synthesis of complex natural
products.2 In particular, isocyanides are highly potent
substrates for the evolution of multicomponent reactions in
organic chemistry.1a−c With regard to the reactions of
isocyanides,1,2 the common strategies with isocyanides as
starting materials required presynthesis of them, usually from
aryl or aliphatic amines via two or more steps.3 In addition,
isocyanides bear a strong odor,1a which makes their
purification difficult. Therefore, the development of efficient
and practical methods, which could generate isocyanides in situ
and subsequently convert the isocyanides to useful com-
pounds, are highly desirable. However, to our knowledge, there
is no such report yet. Therefore, an intriguing approach for the
in situ generation of isocyanides has attracted our attention.
To implement our ideas, the first thing we should solve is
how to generate the isocyanides in situ. The traditional method
for the preparation of isocyanides is formylation of primary
amines with formic acid in toluene at refluxed temperature,
followed by dehydration with POCl3/Et3N in THF at 0 °C.3a
Recently, our group developed a series of difluoroalkylation
reactions using usual BrCF2COOEt as a radical precursor in a
Cu/B2pin2 system.4 As part of our ongoing interest in utilizing
BrCF2COOEt as a building block, herein, we reported a novel
transformation in which BrCF2COOEt underwent a quadruple
cleavage, that is, two C−F bonds, one C−Br bond, and one
C−COOEt bond were cleaved simultanenously, leading to a
C1 source. Indeed, in this paper, isocyanides could be readily
formed from primary amines and BrCF2COOEt with the
assistance of base at elevated temperature; the in-situ-
generated isocyanides reacted with Co(acac)2 or 1,3-
dicarbonyl compounds, rendering β-aminoenones via cross-
coupling (see Scheme 1). There are several significant merits
for this transformation:
(1) This would be a potential and practical reaction
generating isocyanides in situ from the available and
facilitated saved primary amines and BrCF2COOEt,
whereafter to afford the valuable products.
(2) The in situ generation of isocyanide without further
purification provides the advantages of operational
simplicity, avoids releasing the horrible odor to nearby
surroundings and saves time.
Received: June 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01888
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) The mechanism study suggests that only base-catalyzed
making substrates combine in a harmonious ordered
manner, which results in a much more efficient and
practical synthesis.
Scheme 2. Substrate Scope for the Formation of β-
Aminoenone from Amines (1) and BrCF2COOEt (2) in the
a
Presence of 1,3-Dicardonyls
How do we find a suitable condition that is compatible with
both the formation of isocyanide and the C−H insertion of a
methylene group of 1,3-dicarbonyls?5 How do we suppress the
formation of byproduct imine between carbonyl and amine?6
How do we control the overinsertion issue with two C−H
bonds? To verify our hypothesis with these challenges, we then
chose amine 1a, ethyl bromodifluoroacetate (2), and Co-
(acac)2 as a model the reaction, and we probed which reaction
conditions could afford higher yield (see Table 1, as well as the
a
Table 1. Optimization of Reaction Conditions for Aniline
M(acac)x
(0.12 mmol)
base
(2.5 equiv)
solvent
(2 mL)
b
entry
yield (%)
c
1
2
3
4
5
6
7
Co(acac)2
Co(acac)2
Co(acac)2
Fe(acac)2
Ni(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Na2CO3
K2CO3
DBU
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
THF
THF
THF
THF
88 (83)
81
56
71
78
84
trace
86
THF
CH3CN
toluene
THF
d
8
e
9
THF
77
a
Reaction conditions: 1a (0.2 mmol), 2 (1.2 equiv), base (2.5 equiv),
M(acac)x (60 mol %), solvent (2 mL), at N2 for 12 h under 100 °C,
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Co(acac)2 (0.6
b
c
d
e
equiv), Na2CO3 (2.5 equiv), THF (2 mL) under N2 atmosphere at
100 °C for 12 h. bScale up to 3 mmol. c1a (0.2 mmol), 2 (0.4 mmol),
1,3-dicarbonyls (0.4 mmol), LiOCH3 (2.5 equiv), 3 Å MS (50 mg),
CH3CN (2 mL) under N2 atmosphere at 100 °C for 12 h, isolated
yield.
GC yield. Isolated yield. At 110 °C. At 80 °C.
Supporting Information (SI) for details). To our delight,
through investigations utilizing of a range of bases (entries 1−
3), β-aminoenone 3a was indeed obtained in 83% isolated
yield by using Na2CO3; however, the employment of an
organic base is slightly inferior. Thereafter, the sources of 1,3-
dicarbonyl (Fe(acac)2 and Ni(acac)2) were screened, and the
expected product 3a was produced in 71% and 78% yields,
respectively. Among the metal complexes tested, Co(acac)2
demonstrated the best resource of acac (entries 4 and 5). Next,
the effect of different solvents was also investigated; however,
the yield of 3a was not improved, and no targeted product 3a
was observed when the reaction was performed in toluene
(entries 6 and 7). Compared with temperatures of 110 and 80
°C, 100 °C was harmonious for this transformation (entries 8
and 9). Therefore, a much cleaner result was observed, when
aryl amine 1a (1 equiv) reacted with ethyl bromodifluor-
oacetate (2, 1.2 equiv) with 60 mol % of Co(acac)2 at 100 °C
using Na2CO3 as base in THF (see the SI for details)
The substrate scope of amines 1 was subsequently assessed
based on the optimal conditions (see Scheme 2). Aromatic
primary amines were first surveyed and it turned out that both
electron-donating and electron-withdrawing groups were well-
tolerated under the optimized conditions, delivering the
corresponding desired products in good to excellent yields
(3a−3m). The absolute configuration of 3l was unambiguously
confirmed by X-ray crystallography.7 The position of the
substituents on the aromatic rings had no significant influence
on the efficiency of the transformation, since both meta- and
ortho-products were obtained in good to excellent yields (3n−
3t). Furthermore, polyphenylenes (1u−1x) as well as
heteroaromatic rings (1y and 1z) were also subjected to the
transformation; all of them demonstrated good compatibilities
and the targeted molecules were obtained in 66%−86% yields.
Most remarkably, aliphatic amines, such as tert-butyl amine
(1aa) and adamantan-1-amine (1ab), were also good
candidates for this transformation. It was noteworthy that
these two examples failed to provide the desired products in
the previous literature with isocyanides as starting material.8
Amine scope was also expanded to primary aliphatic amine
(1ac) for the first time to deliver the anticipative product 3ac
in 78% yield. We also investigated other types of 1,3-
dicarbonyls substrates. However, dissatisfactory yields were
obtained when other types of 1,3-dicarbonyls substrates were
submitted to aforementioned conditions. Therefore, the
modification of the parameters was executed (see the SI for
details). Finally, we found that the base played a crucial role in
this protocol and MeOLi itself could lead to the corresponding
β-aminoenones in moderate to good yields by using 3 Å MS as
an additive (see Table S4 in the SI for details). Under the
newly established conditions, several 1,3-dicarbonyls was
studied; 2,5-dimethylhexane-3,4-dione (1ad) was tested in
this reaction process to produce the desired product 3ad in
81% yield. Similarly, a satisfactory yield of 2,6-dimethylhep-
B
DOI: 10.1021/acs.orglett.8b01888
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tane-3,5-dione (3ae) was also achieved by using methyl 3-
oxopentanoate 1ae as coupling partner. To our fascination,
methyl 3-oxopentanoate (1af) could also be converted to
product dimethyl (Z)-3-oxo-2-((phenylamino)methylene)-
pentanedioate (3af) in 48% yield. It is worth noting that
although dimethyl 3-oxopentanedioate has two reactive sites,
we could selectively obtain the product with only one site
participating the reaction, which suggests the potential utility
of our strategy in isocyanide-involved transformations.
the standard conditions. To our delight, benzimidazole could
trap the :CF2 perfectly to afford the 1-(difluoromethyl)-1H-
benzo[d]imidazole (Q) in 71% yield.
A large-scale synthesis was further conducted under the
standard conditions with Co(acac)2 for the construction of β-
aminoenones. Gratifyingly, the efficiency was not significantly
affected by scaling up, and 3a was obtained in 71% yield (see
Figure 1). Further synthetic manipulation on this type of
In order to gain insight into the mechanism of this
transformation, we performed control experiments using
possible intermediates. First, 4-tert-butylaniline (1e) was
subjected to the reaction conditions in the absence of
Co(acac)2, to access the corresponding isocyanide 4 in 32%
yield with 11% of 1e recovered (see reaction a in Scheme 3).
Scheme 3. Control Experiments and Radical Trapping
Experiments
Figure 1. Scale-up and synthetic applications of β-aminoenones.
highly functionalized β-aminoenones provide feasibility to
construct functionalized heterocyclic compounds, which
further underscores the value of β-aminoenones formed by
this protocol. For instance, the same products were reported,9
such as 3a reacted with hydrazinc hydrate, thiourea (i) and
phenyl isothiocyanate (ii) leading to N-((3,5-dimethyl-4H-
pyrazol-4-ylidene)methyl)aniline (6), 3,5-dimethyl-4-
((phenylamino)methylene)cyclohexa-2,5-diene-1-thione (7),
and (E)-1-(4-hydroxy-1-phenyl-6-(phenylimino)-1,6-dihydro-
pyridin-3-yl)ethan-1-one, respectively (8) (Figure 1).
On the basis of the above results and the literature, a
mechanism was proposed for this transformation (see Scheme
4). The reaction is believed to occur via an isocyanide
Thereafter, isocyanide 4 was subjected to the standard
conditions for the synthesis of β-aminoenone 3, and not
surprisingly, corresponding targeted molecule 3e was obtained
in 79% yield (see reaction b in Scheme 3), which further
confirmed our hypothesis that isocyanide is the key
intermediate for this type of transformation. To further
determine the source of extra carbon in the product, amide
54d was exposed to the standard conditions, and neither in the
presence nor in the absence of ethyl bromodifluoroacetate (2)
was the corresponding targeted molecule 3a was ever detected
(see reaction c in Scheme 3). These two experiments
suggested that the extra carbon could not come from the
acetate: it can only come from the carbon that is bound to two
F atoms and one Br atom in 2. Aryl amine 3a was exposed to
both BHT and TEMPO with 2 under the optimized conditions
for the synthesis of β-aminoenones; the efficiency of this
transformation was not affected and the desired product 3a
was obtained in good yields (81% and 75%), which suggested
that the formation of isocyanide is not a radical process (see
reaction d in Scheme 3). Besides, this result is in sharp contrast
to the reported one in which a radical process was involved
when isocyanides reacted with 1,3-dicarbonyl compounds
catalyzed by 30 mol % of Ag2CO3, leading to β-aminoenones.8
To verify the formation of difluorocarbenes (:CF2) in this
process (see the SI for details), we found a way to trap these
intermediates in which the benzimidazole (P) was added into
Scheme 4. Plausible Reaction Mechanisms
intermediate, which was generated from a difluorocarbene and
primary amine 1 in the presence of a base. First, the generation
of difluorocarbene via debromination and deacetylation
processes of ethyl bromodifluoroacetate (2) occurs under
basic conditions. The in-situ-formed difluorocarbene is
subsequently attacked by a nucleophilic anion (from primary
amine) to render an active difluoromethylamine (M), which is
sensitive to basic conditions by two base evulsion protons,
thereafter rapidly decomposed to isocyanide N. Once
isocyanide N is generated in situ, sequential reaction between
N and Co(acac)2 or other 1,3-dicarbonyl reactant occurred,
eventually delivering β-aminoenones.
C
DOI: 10.1021/acs.orglett.8b01888
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Letter
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CCDC 1823240 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*Fax: 86-592-6162990. E-mail: qsong@hqu.edu.cn.
ORCID
Yao Zhou: 0000-0002-3500-7355
Qiuling Song: 0000-0002-9836-8860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation (No. 21772046), the Program of Innovative
Research Team of Huaqiao University (No. Z14X0047), the
Recruitment Program of Global Experts (1000 Talents Plan),
the Natural Science Foundation of Fujian Province (No.
2016J01064) is gratefully acknowledged. We also thank the
Instrumental Analysis Center of Huaqiao University for
analysis support. M.X. thanks the Subsidized Project for
Cultivating Postgraduates’ Innovative Ability in Scientific
Research of Huaqiao University.
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