Synthesis of isocyanides by reacting primary amines with difluorocarbene

Article abstract of DOI:10.1021/acs.orglett.0c03472

A general, convenient, and friendly route for preparing a versatile building block of isocyanides from primary amines is developed. Difluorocarbene, generated in situ from decarboxylation of chlorodifluoroacetate, reacts efficiently with primary amines to produce isocyanides. Various primary amines are well tolerated, including aryl, heteroaryl, benzyl, and alkyl amines, as well as amine residues in amino acids and peptides. Late-stage functionalization of biologically active amines is demonstrated, showing its practical capacity in drug design and peptide modification.

Full text of DOI:10.1021/acs.orglett.0c03472

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Letter
Synthesis of Isocyanides by Reacting Primary Amines with
Difluorocarbene
Yi-Xin Si, Peng-Fei Zhu, and Song-Lin Zhang*
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sı Supporting Information
ABSTRACT: A general, convenient, and friendly route for preparing a versatile building
block of isocyanides from primary amines is developed. Difluorocarbene, generated in situ
from decarboxylation of chlorodifluoroacetate, reacts efficiently with primary amines to
produce isocyanides. Various primary amines are well tolerated, including aryl, heteroaryl,
benzyl, and alkyl amines, as well as amine residues in amino acids and peptides. Late-stage functionalization of biologically active
amines is demonstrated, showing its practical capacity in drug design and peptide modification.
he isocyano group occurs widely in natural products (e.g.,
et al. reported the nucleophilic substitution of alkyl iodides
T
terpenoids from marine secondary metabolites), pharma-
with AgCN to give the Ag−isocyanide complex, which, upon
1
ceuticals, and alkaloids (Figure 1). For example, the first
treatment with toxic KCN, releases free isocyanides (Scheme
8
1
a). In the same period, Hofmann et al. reported a method
using a primary amine, chloroform, and a stoichiometric strong
9
base in the presence of a phase-transfer catalyst (Scheme 1b).
These seminal works, however, suffer from a low efficiency, a
limited substrate scope, and the use of highly toxic metal
cyanides or chloroform, which have greatly impeded their
widespread applications.
The Ugi-type dehydration of secondary formamides is the
current method of choice for preparing isocyanides (Scheme
1
0
1
c). The combination of a dehydrating reagent (typically
10a
10b
10c
phosgene, diphosgene, phosphoryl trichloride, sulfonyl
10d
chloride, etc.) and a base is required in excess amounts to
promote the dehydration. Limitations associated with these
types of methods are also noted. First, the need for excess toxic
dehydrating reagents raises safety problems and makes it
inconvenient in the manipulation and workup, especially for
methods involving phosgene analogues, compounds that had
been used as deadly chemical weapons. Second, the
pregeneration and separation of the formamide precursors
are often prerequisite, thereby reducing the step and atom
efficiency of the methods and increasing the additional cost of
labor and time. Therefore, there are great demands for
efficient, safe, and convenient methods for the synthesis of
isocyanides.
Figure 1. Isocyanide compounds.
naturally occurring isocyanide compound, xanthocillin, has
potent antibiotic properties. Many isocyano-containing terpe-
noid compounds have broad biological properties, including
antibiotic, antifungal, and antineoplastic activities. Isocyanides
are also versatile synthetic building blocks that have found
1
2
diverse applications in organic synthesis, typically in multi-
3
4
component reactions, insertion reactions, polymeric materi-
5
6
als. and peptides. For instance, Passerini and Ugi reactions
are among the most useful and well-known applications using
isocyanides to construct molecular complexity. Isocyano is an
extraordinary functional group featuring resonances between
neutral iminocarbene and the zwitterionic triple bond
structures, which imparts it with both nucleophilic and
electrophilic properties, as well as radical reactivity under
appropriate conditions.
Herein, we report a general method for the synthesis of
isocyanides from feedstock compound primary amines and in
situ-generated difluorocarbene (Scheme 1d). The de novo
Received: October 18, 2020
The synthesis of isocyanides has received a tremendous
amount of interest for centuries, but there is still great space for
7
reaching an ideal solution. More than 100 years ago, Gautier
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c03472
A
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a
Scheme 1. Strategy for Synthesis of Isocyanides
Table 1. Optimization of the Reaction Conditions
e
entry
base
solvent
2 (equiv)
temp (°C) yield (%)
1
2
3
4
5
6
KOt-Bu
NaH
NaHCO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
NMP
dioxane
DMF
DMF
DMF
2
2
2
2
2
2
1
1
2
2
2
2
2
2
2
3
100
100
100
100
100
100
100
100
100
100
100
100
100
80
40
−
−
64
30
70
66
68
52
30
trace
50
trace
60
70
Et N
3
DBU
K CO3
2
b
7
K CO3
2
c
8
d
K CO3
2
9
K CO3
2
1
1
1
1
1
1
1
0
1
2
3
4
5
6
K CO3
2
K CO3
2
K CO3
2
K CO3
2
K CO3
2
K CO3
2
130
100
K CO3
2
69
a
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), base (0.2
b
mmol), and solvent (1 mL) for 12 h under N . Isolated yield of 3a. 2
2
c
(
0.1 mmol), K CO (0.1 mmol). 2 (0.1 mmol), K CO (0.2 mmol).
2 3 2 3
e
d
K CO (0.1 mmol). Molar ratio of 2 relative to 1a.
2
3
odor (Table 1, entry 1), rather than the formation of the N-
CF H product resulting from insertion of CF into the N−H
2
2
bond. NMR characterization of 3a features broadened ortho
protons of the phenyl, and the typical triplet splitting of the
carbon resonances of the isocyano and phenyl ipso-carbon
connected to isocyano. These results verify the coupling of
isocyano with the aryl o-H and the ipso-C. The FT-IR
spectrum shows an extremely strong absorption band at 2123
construction of the isocyano group is enabled by formal
extrusion of two molecules of HF, reminiscent of the
dehydration method with water extrusion (Scheme 1c).
Difluorocarbene thus serves as a novel C1 synthon in our
isocyanide synthesis. Difluorocarbene has been emerging as a
versatile synthon for preparing various fluorinated compounds
−
1
cm for 3a, characteristic of the stretching vibration of the
isocyano group.
11
in organic synthesis, e.g., in cyclopropanation reactions of
Having 3a as the valuable product, we then evaluated a set of
conditions aiming to improve the yields, with a focus on the
combinatorial effect of the base and the solvent, as well as the
temperature effect. Table 1 summarizes some of the experi-
ments screened. The combination of K CO and DMF at 100
1
2
alkenes/alkynes, olefination of aldehydes in the presence of
1
3
14
PPh3, and C−H and heteroatom−H insertion reactions.
However, the innovative use of difluorocarbene as a
convenient and safe C1 synthon is unknown for the synthesis
of isocyanides. On the contrary, primary amines, especially
anilines, are frequently encountered as a crucial structural
motif in many biologically active compounds. Our method
therefore paves the way for functionalization and diversifica-
tion of a large number of biologically relevant primary amines
through isocyano group formation. Finally, this method starts
with inexpensive and friendly feedstock compounds and occurs
by a one-pot convenient and safe operation without needing
special safety measures, which are appealing for green,
sustainable, and large-scale preparation of isocyanides.
2
3
°C is found to be optimal for this reaction producing 3a in
70% yield, although other combinations are also good for the
promotion of the formation of 3a (entries 1−6). The amount
of 2-chlorodifluoroacetate has a minor effect on the reaction
yield, giving slightly higher yields with 2 equiv than with 1
equiv (entries 7 and 8). A further increase in the amount of 2
to 3 equiv could not improve the yield (entry 16). Polar
solvents are superior to nonpolar solvents (entries 10−13).
Finally, decreasing the temperature to 80 °C led to a
significantly lower yield of 60% (entry 14), while the reaction
at 130 °C gave the same yield of 70% as at 100 °C (entry 15).
With the optimal conditions in hand, a range of primary
amines were studied in this reaction, including aryl/heteroaryl,
benzyl, and alkyl amines. As shown in Scheme 2, primary
anilines with methoxy, phenoxy, dimethylamino, amide, and
even unprotected hydroxyl and amine groups can be tolerated.
Generally, electron-rich anilines reacted more efficiently than
electron-poor anilines (fluoroaniline and pyridylamines are
Our study began with the reaction of p-methoxyaniline (1a)
with sodium 2-chlorodifluoroacetate (2) in the presence of a
base (Table 1). The combination of 2 and a base has been
shown to generate difluorocarbene under thermal or photo
1
5
conditions. The difluorocarbene generated in situ could
insert into the thiol S−H bond or alkene double bond, thus
producing biologically active ArS-CF H or difluoropropane
2
structural motifs. Interestingly, in our study when the in situ-
generated difluorocarbene meets aniline 1a, isocyanide 3a was
produced efficiently and selectively with a characteristic odd
16
poor substrates). Primary alkylamines are better and more
reactive than anilines because of the more nucleophilic nature
B
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a
Scheme 2. Substrate Scope of Primary Amines
not reactive. The tolerance of phenylamino group in 3h shows
the high chemoselectivity of this reaction toward primary
amines.
Late-stage functionalization of complex biologically active
amines is enabled by this method, including some
pharmaceuticals and an amine residue in amino acids (Scheme
3
). Thus, primary amines 2x (Amlodipine, pharmaceutical for
Scheme 3. Late-Stage Functionalization of Complex
Biologically Active Amines and an Amine Residue in Amino
Acids
the treatment of high blood pressure), 2y (alkaloid), 2z
(
Dehydroabietylamine, widely used as an insecticide, anti-
fungal agent, etc.), and 2aa (Linezolid derivative, antibiotic)
can be facilely and selectively converted to their isocyanide
derivatives 3x, 3y, 3z, and 3aa, respectively, in good yields.
Moreover, the amino group in tryptophan ester 2ab can be
transformed into the isocyano group (3ab), providing a
reactive handle that allows diversification of amino acids and
peptides.
Furthermore, this method can be used to prepare N,O- and
N,N-heteroarenes with an unusual methide incorporation
using difluorocarbene (Scheme 4). For anilines with an o-
hydroxy or -amino, heteroarenes 5a−5c could be obtained
arising probably from cascade isocyanide formation/insertion
of the isocyano into the o-O−H or N−H bond. Interestingly,
a
Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), K CO (0.8
2
3
mmol), and DMF (5 mL) stirred at 100 °C for 12 h under N2.
Isolated yields. 2 (1 equiv) is used to show the chemoselectivity in the
case of 3v.
Scheme 4. Synthesis of N,O- and N,N-Heteroarenes Using
Difluorocarbene
of aliphatic amines. This is exemplified by the case of 2v (p-2-
aminoethylaniline) that selectively produces 3v from preferred
conversion of alkylamine and with the aniline group remaining
intact. These electronic effects suggest the involvement of a
crucial step of nucleophilic attack of amine on the electrophilic
difluorocarbene. In addition to the linear primary amines,
branched primary amines with tertiary and quaternary α-
carbon are also excellent substrates for giving the desired
products (3q, 3t, and 3u). It is noteworthy that this method
allows stereoretentive transformation of the amine group in
asymmetric α-branched amines, generating asymmetric iso-
cyanide 3q with a tertiary α-branched center. This is
complementary to the current nucleophilic substitution
methods in which inversion or partial loss of configuration is
7d
observed for the α-carbon. Such asymmetric isocyanides are
expected to be valuable in a range of asymmetric applications,
1
e.g., in the synthesis of asymmetric amides and peptides.
Finally, a secondary amine, for instance, diphenylamine, was
C
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the benzimidazole obtained can be further difluoromethylated
to give 5c resulting from insertion of a second difluorocarbene
into the N−H bond of benzimidazole. Interestingly, 1,2-
ethylenediamine 4d with a more flexible backbone can
efficiently produce an N-tosyl dihydroimidazole 5d in a similar
way.
With various isocyanides in hand, their application in
conventional four-component Ugi reaction of isocyanides,
carboxylic acids, benzaldehydes, and amines, and in a modified
three-component variant of isocyanides, amino acids, and
benzaldehydes, produces a number of highly functionalized
amides and peptoids (see the Supporting Information).
A plausible mechanism for isocyanide formation is suggested
in Scheme 5. A difluorocarbene−sodium complex I is initially
AUTHOR INFORMATION
Corresponding Author
■
Song-Lin Zhang − Key Laboratory of Synthetic and Biological
Colloids, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu
214122, China; orcid.org/0000-0002-5337-8600;
Email: slzhang@jiangnan.edu.cn
Authors
Yi-Xin Si − Key Laboratory of Synthetic and Biological
Colloids, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu
214122, China
Peng-Fei Zhu − Key Laboratory of Synthetic and Biological
Colloids, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu
Scheme 5. Probable Mechanism
214122, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03472
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the National Natural Science
Foundation of China (21472068). Financial support from
MOE@SAFEA for the “111 Project” (B13025) and national
first-class discipline program of Food Science and Technology
(
JUFSTR20180204) is also gratefully acknowledged. We also
generated from decarboxylation of sodium chlorodifluoroace-
appreciate the technic support in the characterization of
compounds from the Central Laboratory, School of Chemical
and Material Engineering, Jiangnan University.
1
5
tate.
Due to the enhanced electrophilic nature of
difluorocarbene in I by metal coordination, nucleophilic
addition of amines to I gives transient intermediate II, which
upon base-promoted HCl dissociation produces a key α-
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E
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