Isocyanide 2.0

Article abstract of DOI:10.1039/d0gc02722g

The isocyanide functionality due to its dichotomy between carbenoid and triple bond characters, with a nucleophilic and electrophilic terminal carbon, exhibits unusual reactivity in organic chemistry exemplified for example in the Ugi reaction. Unfortunately, the over proportional use of only a few isocyanides hampers novel discoveries about the fascinating reactivity of this functional group. The synthesis of a broad range of isocyanides with multiple functional groups is lengthy, inefficient, and exposes the chemist to hazardous fumes. Here we present an innovative isocyanide synthesis overcoming these problems by avoiding the aqueous workup which we exemplify by parallel synthesis from a 0.2 mmol scale performed in 96-well microtiter plates up to a 0.5 mol multigram scale. The advantages of our methodology include an increased synthesis speed, very mild conditions giving access to hitherto unknown or highly reactive classes of isocyanides, rapid access to large numbers of functionalized isocyanides, increased yields, high purity, proven scalability over 5 orders of magnitude, increased safety and less reaction waste resulting in a highly reduced environmental footprint. For example, the hitherto believed to be unstable 2-isocyanopyrimidine, 2-acylphenylisocyanides and even o-isocyanobenzaldehyde could be accessed on a preparative scale and their chemistry was explored. Our new isocyanide synthesis will enable easy access to uncharted isocyanide space and will result in many discoveries about the unusual reactivity of this functional group. This journal is

Full text of DOI:10.1039/d0gc02722g

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PAPER
Isocyanide 2.0†
Pravin Patil,
Maryam Ahmadian-Moghaddam and Alexander Dömling
*
Cite this: DOI: 10.1039/d0gc02722g
The isocyanide functionality due to its dichotomy between carbenoid and triple bond characters, with a
nucleophilic and electrophilic terminal carbon, exhibits unusual reactivity in organic chemistry exemplified
for example in the Ugi reaction. Unfortunately, the over proportional use of only a few isocyanides
hampers novel discoveries about the fascinating reactivity of this functional group. The synthesis of a
broad range of isocyanides with multiple functional groups is lengthy, inefficient, and exposes the chemist
to hazardous fumes. Here we present an innovative isocyanide synthesis overcoming these problems by
avoiding the aqueous workup which we exemplify by parallel synthesis from a 0.2 mmol scale performed
in 96-well microtiter plates up to a 0.5 mol multigram scale. The advantages of our methodology include
an increased synthesis speed, very mild conditions giving access to hitherto unknown or highly reactive
classes of isocyanides, rapid access to large numbers of functionalized isocyanides, increased yields, high
purity, proven scalability over 5 orders of magnitude, increased safety and less reaction waste resulting in
a highly reduced environmental footprint. For example, the hitherto believed to be unstable 2-isocyano-
pyrimidine, 2-acylphenylisocyanides and even o-isocyanobenzaldehyde could be accessed on a prepara-
tive scale and their chemistry was explored. Our new isocyanide synthesis will enable easy access to
uncharted isocyanide space and will result in many discoveries about the unusual reactivity of this func-
tional group.
Received 7th August 2020,
Accepted 4th September 2020
DOI: 10.1039/d0gc02722g
rsc.li/greenchem
account for >19 000 citations (>90%) of all isocyanide research
papers. These reoccurring isocyanides are the commercially
Introduction
Isocyanides are hubs in chemistry, having reaction plasticity available tert-butyl 1, cyclohexyl isocyanide 2, TOSMIC 3, iso-
yet conserved reactivities, and can function as integral cyanoaceticacid esters 4 and 9, 2,6-dimethyl phenyl 5, benzyl
members of large multimolecular assemblies, or just contrib- 6, methyl 7 and phenyl isocyanide 8. Despite this fundamental
ute a few atoms. The isocyanide functional group is of high imbalance, new chemical space is charted by the synthesis and
relevance to different fields of science,1 including astronomy,2 exploration of novel, less commonly used isocyanides (Fig. 1B).
biology,3 information technology,4,5 materials science,6 and Schöllkopf’s isocyanide 10 is useful in
a plethora of
most importantly chemistry.7 Isocyanides are isolobal to unprecedented heterocycle syntheses, for example, a multi-
carbon monoxide and therefore there is a rich metalorganic component
thiazole
synthesis
(11).18,19
Similarly,
called
chemistry.8 In organic chemistry isocyanides are the basis of N-isocyanoiminotriphenylphosphorane
also
many heterocycle syntheses and different multicomponent Fehlhammer isocyanide 12 after its inventor is a highly versa-
reactions (IMCRs). The fascinating aspects of isocyanide chem- tile example.20–22 Ramazani, for example, introduced 12 in the
istry were reviewed extensively.9–17
elegant oxadiazole synthesis (13), which was also probed in
Although >26 000 isocyanides have been described and complex head-to-tail cyclic peptide syntheses.23,24 Another
>3000 are listed to be commercially available, only a very small example is Boc protected o-aminophenyl isocyanide 14, which
number accounts for the overwhelming use in chemistry has been used in the elegant work of Hulme to form hybrid
(Fig. 1A). Most isocyanide research focuses on those already pyridinone-3-yl-benzimidazol-2-ones 15 in just one synthetic
known.
A
recent bibliometric analysis using Sci-Finder step.25 On the other hand, TOSMIC 3, a representative of the
revealed that isocyanides are mentioned in >21 000 publi- well-used isocyanides is a multi-ton technical product which
cations, excluding patents. However, just 9 isocyanides (1–9) was introduced by van Leusen and has made a major impact
on heterocyclic chemistry with important industrial appli-
cations, for example, the fungicide Fludioxonil 16.26
Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9700 AD
Isocyanides were discovered 200 years ago and made
Groningen, The Netherlands. E-mail: a.s.s.domling@rug.nl;
initially available by the nucleophilic substitution reaction of
http://www.drugdesign.nl
AgCN with alkyl halides. Shortly after that, Hoffman invented
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
the direct conversion of primary amines to isocyanides using
d0gc02722g
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Fig. 1 Isocyanides in the past and present. (A) Only a very few isocyanides account for the majority of citations in the chemical literature (Sci-
Finder). (B) Some polyfunctional isocyanides leading to interesting scaffolds and products.
dichloro carbene reagents. The chemistry of isocyanides got a agent due to the byproduct formation of CO2 and chloride
boost with the discovery of the first isocyanide-based multi- salts. However, its use is largely prohibited due to the high tox-
component reaction (IMCR) by Passerini (P-3CR). A milestone icity of the gas. Organic chlorophosphate derivatives,33
development by Ugi was the reliable synthesis of isocyanides XtalFluor-E,34 and other fancy dehydrating agents were used to
by a two-step procedure, formylation of a primary amine fol- synthesize isocyanides from their formamides. Strong reaction
lowed by dehydration. Although many other alternative isocya- conditions such as use of MW at 100 °C and cyanurchlorid
nide procedures exist, such as the improved Hoffman pro- (TCT) are useful only for a few isocyanides, while labile func-
cedure using phase transfer catalysis (PTK),27 the Ugi method tionalities will not survive such conditions.35 Recently, the
accounts for the vast majority of isocyanide syntheses per- purification of isocyanides on reversed-phase silica was intro-
formed today. Isocyanides are highly reactive and many volatile duced as an innovation.36 However, all improvements still
liquid isocyanides stand out by a terrifying odor. The toxicity suffer from one or another issue such as lengthy laborious pro-
of isocyanides is less investigated but they don’t seem to have cedures, exotic and expensive reagents, massive waste gene-
acute toxicity.28 Therefore, special measures have to be taken ration, and long exposure of the chemist to potentially hazar-
during their preparation. The bench stability of isocyanides dous fumes and often show a narrow scope of functionali-
depends on their structure and substitution pattern. For zation. Phosphorus oxychloride (POCl3) is the most used dehy-
example, phenyl isocyanide and some derivatives as well as drating agent and yields inorganic phosphate as a side
vinyl isocyanides29 polymerize and 2-(isocyanomethyl)pyridine product and is therefore preferable over p-TsCl yielding
cyclizes fast. Multiple attempts have been made aiming to additional organic waste.37 The most used POCl3 procedure is
improve isocyanide syntheses, such as in situ generation of performed from low temperatures to 50 °C depending on the
isocyanides.30–32 In our opinion, during formamide dehydra- reactivity of the formamide. Keeping the reaction always under
tion, phosgene would be the most preferable dehydrating basic conditions is essential to avoid the reduced yields of the
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product. The workup involves careful hydrolysis to destroy the exemplified scalability over 5 orders of magnitude, and less
excess of the dehydrating agent while pH has to be in the basic reaction waste resulting in a highly reduced environmental
region to avoid hydrolysis of the isocyanide. Finally, the crude footprint.
isocyanide needs further purification by distillation, chromato-
graphy, or recrystallisation. This step can also be the source of
major yield reductions for example through the presence of
Experimental
small amounts of acidic matter. Thus, the classical POCl3-
enabled isocyanide synthesis not only needs careful control of
Having realized that the aqueous work-up is the major
the reaction, workup and purification conditions, but is also
problem in the isocyanide synthesis we investigated non-
lengthy and exposes the chemist to the often-smelly isocyanide
aqueous workup procedures using the formation of benzyl iso-
fumes over a rather long period.
cyanide as a model reaction (Scheme 1). Inspired by Jamison’s
In our laboratory, the access to a large number of isocya-
nides with high structural diversity is crucial for example to
explore the structure–activity relationship (SAR) and to prepare
idea of in-line isocyanide synthesis and to avoid aqueous
work-up we decided to use a reaction set-up that would allow
for both the synthesis and purification of the isocyanide.43,44
large libraries of IMCRs on a nanoscale or in the DEL
An appropriate amount of silica (2 g) (230–400 mesh size)
format.38–42 Thus, we revisited the formamide to isocyanide
was first coated with phosphorus oxychloride (1 mmol) and tri-
dehydration and came up with a completely revised procedure
ethylamine (3 mmol).45 The column was then packed with the
avoiding any type of aqueous workup. The advantages of our
reagent-coated silica (column length and diameter being 6 cm
very general isocyanide syntheses are increased synthesis
and 0.75 cm, respectively). Subsequently, the formamide
speeds and thus decreased exposure of the chemist to badly
(1 mmol) was dry-loaded onto the column. Using dichloro-
smelling fumes, very mild conditions giving access to hitherto
methane (DCM) as the mobile phase, the formamide was passed
unknown classes of isocyanides, rapid access to large numbers
through the column (Fig. 2, set-up: I). The result, however, was
of functionalized isocyanides, increased yields, high purity,
discouraging and we failed to obtain the isocyanide. Increasing
the amounts of triethylamine was not helpful, neither.
We tested various reaction solvents like dichloromethane,
THF, toluene, acetonitrile, isopropyl ether, DCM, and diethyl
ether. Among them, only DCM as the reaction solvent gave
high yields. This can be explained by the poor solubility of the
Scheme 1 Synthesis of benzyl isocyanide.
formamides in most solvents.
Fig. 2 Different set-ups for N-benzyl isocyanide synthesis without aqueous workup and instant purification.
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Next, we investigated a different dry workup. To a solution
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of N-benzyl formamide (1 mmol) in DCM (0.1 M, 10 ml), tri-
ethylamine (5 mmol) and subsequently phosphorus oxychlor-
ide (1 mmol) were added at 0 °C. The reaction mixture was
stirred for 1 h. Subsequently, the reaction mixture was poured
onto a dry column loaded with silica (230–400 mesh size, 6 cm
× 0.75 cm). DCM was used as the mobile phase. A mixture of
triethylamine, triethylamine hydrochloride, and the desired
isocyanide was obtained, with the isocyanide being the main
hydrophobic component of the mixture (Fig. 2, set-up: 2).
Encouraged by this result, we experimented with the particle
size of the silica. However, smaller particles of the stationary
phase (400–600 mesh size) made the mobile phase move
through the column much slower. Due to the acid-sensitive
nature of isocyanides, prolonged contact of the isocyanide
with silica should be avoided as it consequently reduces the
yield.46,47
Fig. 3 Benzylisocyanide on a 10 g scale in less than 1 h. Reaction (A)
and purification (B and C) on a 100 mmol scale.
To let the product elute faster, pressure was applied to the
column. In this way, we were able to isolate benzyl isocyanide
in 85% yield (Fig. 2, set-up: 3). Performing the reaction on 5
and 10 mmol scales afforded the compound in 86% yield
along with small amounts of impurities.
The reaction mixture was poured directly into the column.
Initially, 100 ml diethyl ether was used as the mobile phase.
Then, the mobile phase was made more polar by adding DCM
(10% up to 100% dichloromethane). Fractions of 25 ml were
collected. The product eluted in the first four fractions with
only 100–150 ml of diethyl ether as the mobile phase. In this
way, we were able to obtain the product with minimal 250 ml
solvent consumption and in 97% yield.
Next, we applied the methodology in the synthesis of more
complex phenylalanine methyl ester isocyanide (G-10) on a
scale of 100 mmol (Scheme 2). Synthesis and purification were
performed as above, by column chromatography using 140 g
100–200 mesh size silica and diethyl ether and dichloro-
methane as the mobile phase. The product was obtained in
87% yield in high purity.
To further improve our methodology, we screened different
solvent systems as the mobile phase. DCM and diethyl ether in
different ratios were utilized. It was observed that flash fil-
tration with diethyl ether alone as the mobile phase and
400–600 mesh size silica afforded benzyl isocyanide in very
high yields (90%) and purity, without the impurities usually
present in isocyanide syntheses, namely triethylamine, triethyl-
amine hydrochloride, and colored impurities. Next, we investi-
gated the use of 100–200 and 230–400 mesh size silica and
diethyl ether as the mobile phase. Surprisingly, the product
was isolated with unreacted triethylamine, but without triethyl-
amine hydrochloride and colored impurities. The excess tri-
ethylamine was removed during the vacuum evaporation of the
solvent, leaving behind the pure isocyanide. Finally, we
observed that a column with 100–200 mesh-size silica (Fig. 2,
set-up: 5) afforded the product in a slightly higher yield (91%)
than with 230–400 mesh size silica and without any air
pressure.
Synthesis of isocyanides on a 500 mmol scale
The approach also proved successful in the synthesis of isocya-
nides on even larger scales. 1-Adamantyl isocyanide (H-2)
(Fig. 4) was prepared using this methodology on a 0.5 mol
scale in 97% yield (Fig. 4). Shortly, to a solution of 1-adamantyl
formamide (0.5 mol) in dichloromethane (2 M), triethylamine
(5.0 equiv.) was added at room temperature (Fig. 4A).
Subsequently, phosphorus oxychloride (1.0 equiv.) was added
at 0 °C. The reaction mixture was stirred for 10 min (Fig. 4B).
After completion of the reaction as indicated by TLC, the com-
Synthesis of isocyanides on a 100 mmol scale
To further validate the method and investigate its scalability,
we performed the benzyl isocyanide synthesis on a 100 mmol
scale at increased concentration. Triethylamine (5.0 equiv.)
was added to a solution of the formamide in DCM (2 M) at
room temperature and phosphorus oxychloride (1.0 equiv.)
was subsequently slowly added to the reaction mixture at 0 °C.
The reaction mixture was stirred at 0 °C for 5 minutes.
Reaction monitoring by TLC revealed a considerable increase
in speed. Indeed, carrying out the reaction at higher 2 M con-
centration dramatically reduced the reaction time to less than
10 minutes. Purification was performed using filtration over
silica. The column (15
× 5 cm) was dry-packed with
100–200 mesh size silica (140 g) and a layer of sand (1 cm) was
Scheme 2 Synthesis of phenylalanine methyl ester isocyanide on a
put on top of the silica (Fig. 3).
100 mmol scale.
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Fig. 5 Set-up for the parallel synthesis of isocyanides in a 96-well
format on a 0.2 mmol scale per isocyanide. (A) Top view of the 96-well
glass reaction plate with multiple colored reaction mixtures. (B) Parallel
addition of POCl3 to the wells; (C) TLC of the 96-well plate within
2 minutes after the addition of POCl3; (D) filtration plate with silica gel
for purification; (E) efficient transfer of reaction mixtures to the filtration
plate using 8- and 12-channel pipets.
Fig. 4 Synthesis of 1-adamantyl isocyanide (H-2) on a 500 mmol scale.
A: Reaction mixture before POCl3 addition, B: reaction mixture after
POCl3 addition, C: column purification, and D: isolated isocyanide.
pound was purified using column chromatography. The crude
reaction mixture was loaded directly on a column (20 × 9 cm)
dry-packed with 600 g 100–200 mesh size silica. Diethyl ether
was used as the mobile phase and fractions of 250 ml were col-
lected. The compound was eluted within the first four frac-
tions (Fig. 4C). The solvent was evaporated under reduced
pressure to afford the pure product as a yellow solid (Fig. 4D).
The amount of reaction solvent dramatically reduced the
reaction time from several hours, mostly reported in the litera-
ture, to less than 15 min. Elimination of the aqueous workup
during the purification made the process of isocyanide syn-
thesis not only more efficient and quicker but also less labor-
ious. Ease of synthesis and purification led to a dramatic
increase in the preparation speed of isocyanides. Moreover, by
reducing the amount of time and resources required to make a
given isocyanide, the new methodology offers excellent econ-
omic and environmental benefits over the conventional
approach. Another significant added value of the new method-
ology is that it considerably reduces exposure to the highly
unpleasant odors of many isocyanides during the reaction,
work-up and purification, making isocyanide synthesis much
less of an unpleasant experience for the organic chemist.
plate was cooled to −10 °C in an ice/acetone bath and
0.2 mmol of POCl3 in 1 M solution of dichloromethane was
added to the reaction mixture inside the wells using an
8-channel pipette as shown in Fig. 5B. After 5 minutes, the
reaction mixture was diluted with 0.5 ml diethyl ether and
transferred to a 96-well polypropylene filtration plate using a
multi-channel pipette (Fig. 5C). The 96-well filtration plate was
modified for this experiment by replacing the original filter
paper with small balls of cotton at the bottom of the wells
(Fig. 5D). Each well served as a mini-column and was packed
with 400 mg 100–200 mesh size silica (Fig. 5E).
The isocyanide-containing solution was conveniently trans-
ferred from the 96-well glass reaction plate onto the 96-well fil-
tration plate using an 8-channel pipette (Fig. 6A). The mobile
phase in each well was allowed to flow through the columns by
gravity and collected in a 96-deep-well (1.5 ml per well) collec-
tion plate (Fig. 6B). The remaining isocyanides in the columns
were washed first with diethyl ether and afterwards with 0.5 ml
solutions of each 25%, 50%, 75%, and 100% DCM in diethyl
ether. The fractions were collected in other 96-well collection
plates (Fig. 6C).
The purity of the fractions was investigated by TLC. It was
observed that the first two collection plates contained the
highest amount of isocyanides. As expected, the eluted solu-
Parallel synthesis of isocyanides in a 96-well plate format on a
0.2 mmol scale
Having established an innovative and easy process of syn- tions in the first two collection plates contained, in addition to
thesis, work-up and purification, we next investigated parallel the desired isocyanides, an appreciable amount of triethyl-
synthesis in a 96-well format (Fig. 5). The reactions were per- amine. The later fractions eluted with 100% dichloromethane
formed on a scale of 0.2 mmol per well. For this purpose, a contained mostly the hydrochloride salt of triethylamine as
commercial 96-well plate with removable 1.5 ml glass vials was well as inorganic impurities but only trace amounts of the iso-
used (ESI†). To the pre-weighed formamides in the wells was cyanides. Subsequently, the isocyanide-containing fractions
added 0.1 ml dichloromethane (2 M), followed by the addition were transferred to pre-weighed and barcoded 3 ml vials and
of triethylamine (5 eq.) at room temperature (Fig. 5A). The well the solvent and triethylamine were evaporated under reduced
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Table 1 Parallel synthesis of a 96-member library of isocyanides on a
0.2 mmol scale
Fig. 6 Parallel purification of isocyanides using a 96-well filtration
plate. A: Transferring the reaction mixture to the filtration plate using an
8-channel pipette. B: Filtration plate on top of a 96-well collection
plate. C: Pure isocyanides in a 96-well plate in pre-weighed barcoded
glass vials after solvent evaporation to facilitate automation.
pressure (Genevac). The use of pre-weighed and barcoded vials
facilitates the automation of yield determination and storage
(Fig. 6C). All wells underwent strict analytical control by NMR
and SFC MS (ESI†) and the structures and yields of the isocya-
nides are depicted in Table 1.
Parallel synthesis of isocyanides on a 1.0 mmol scale
Next, we resynthesized 56 randomly selected isocyanides from
the 96-well plate along with a few new isocyanides on a
larger 1 mmol scale (Table 2, for the synthesis details see in
the ESI†).
Generally, 1 mmol scale synthesis afforded the isocyanides
in higher yield and purity. For instance comparing entries B-9
and I-36, E-10 and I-47, D-9 and I-38, C-10 and I-45, B-10 and
I-44, D-12 and I-34, G-9 and I-41, and H-2 and I-49 reveals that
scaling up the experiments from 0.2 mmol to 1 mmol has
been associated with an average increase of 8% yield.
Intriguingly, a great structural diversity of isocyanides was
obtained in high yields: cyclic, acyclic, aliphatic, bulky and
amino acid-derived isocyanides with a lot of different func-
tional groups, including halogens, boronic acid esters,
hydroxyl, ester, ether, nitro, or morpholino. Using enantiopure
formamides yielded enantiopure isocyanides (A-2 and B-2). In
the case of aryl isocyanides, both electron-donating and -with-
drawing substituents work similarly good (I-24: 93%, I-29:
93%, D-3: 93%, I-25: 98%, and I-33: 86%). Constitutionally iso-
meric isocyanides were isolated with comparable yields (B-3:
89%, C-3: 90%, E-3: 88% and E-6: 81%, D-8: 89%, D-6: 93%,
and A-7: 92%). Volatile isocyanides such as A-11 and H-10 were
synthesized on a 1 mmol scale in good yields. It should be
added though that due to the volatile nature of these isocya-
nides, triethylamine and diethyl ether could not be effectively
removed under reduced pressure. Such isocyanides can be best
isolated by distillation. Bulky isocyanides such as tert-octyliso-
% yields showed in this table are the isolated yields of isocyanides.
aQuantitative product formation was observed by TLC, but the com-
pound didn’t elute effectively from the column due to its polar nature.
bQuantitative product formation was observed by TLC, but the com-
pound could not be effectively isolated due to its volatile nature.
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Table 2 Parallel synthesis of 56 isocyanides on a 1 mmol scale
Table 3 Synthesis of highly polar isocyanides
aQuantitative product formation was observed by TLC, but the product
decomposes upon exposure to silica while performing column
chromatography.
isolation of several polar isocyanides in good yields (Table 3).
For example, isocyanides containing a tertiary amine (I-57 to
I-63) were synthesized and isolated successfully. In general,
isocyanides bearing a morpholine ring (I-58 and I-59) are
water-soluble and therefore, difficult to isolate using the
conventional approach which involving aqueous work-up. By
eliminating the aqueous work-up, we were able to obtain
these isocyanides in excellent and good yields (I-58, 90% and
I-59, 57%).
Generally, heterocyclic isocyanides, particularly those
having the isocyano group ortho to the heteroatom (I-68 to
I-71) are not stable at room temperature.9,49 Such isocyanides
are prone to undergo further reaction such as polymerization
or cyclization. Synthesis of pyridine- and pyrimidine-contain-
ing isocyanides such as I-65 to I-69 at very low temperatures
(−78 to −40 °C) has been reported in the literature.50 Due to
the reported instability, the isolated isocyanides were immedi-
ately used in further reactions.50 In contrast, our methodology
enabled the synthesis of these isocyanides with regular ice
bath cooling and isolation at room temperature and NMR ana-
lysis (ESI†). 2-Isocyanopyridine (I-69, 30%) and 3-(isocyano-
methyl)pyridine (I-64, 60%) were isolated in good yields.
Despite being stable enough to be isolated, these isocyanides
undergo decomposition at room temperature and cannot be
stored for a long time. In the cases of I-65, I-70, and I-71 we
aQuantitative conversion and product formation were observed by TLC,
but the compound was difficult to isolate by this method due to its
high volatility.
cyanide (C-9, 87%), adamantyl isocyanide (H-2, 89%), and did not succeed in isolating the desired product in a highly
3-hydroxy adamantyl isocyanide (F-10, 50%) were isolated in pure form. However, the characteristic isocyanide smell of the
high or good yields. We failed to isolate the aromatic isocya- reaction mixture and the formation of a new spot on the TLC
nide containing a free hydroxyl group on the phenyl ring plate clearly indicated their formation.
(H-11). Likely due to its high polarity, it could not be eluted
The inherent instability of heterocycle-containing isocya-
from the column using diethyl ether and dichloromethane as nides posed problems in their isolation. A noteworthy excep-
the mobile phase. It is noteworthy that we were also able to tion is 2-bromo-6-isocyanopyridine which was reported
isolate 2-formylphenyl isocyanide (I-51) in 85% yield. It has recently as a stable universal convertible isocyanide amongst
been reported to be highly unstable and reactive.9 Previously, many similar heterocyclic but unstable relatives.50 Thus, we
it has been reported by a lengthy 5-step procedure.48
decided to proceed to the synthesis of some MCR-derived com-
Modification of our approach allowed the synthesis of more pounds with the in situ formation of such isocyanides. By par-
polar isocyanides. A slight increase of the polarity of the ticipating in a classical Ugi 4-component reaction and an Ugi-
mobile phase during column chromatography led to the clean tetrazole reaction, respectively, 2-pyrimidine isocyanide was
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trapped within the structures of U-1 and UT-1, suggesting that
the lifetime of the isocyanide is long enough to take part in a
reaction (Scheme 3).
To further underscore the superiority of our new isocyanide
synthesis method, we prepared phenylethyl isocyanide on a
100 mmol scale which can be converted according to our
recently published Ugi–Pictet–Spengler procedure to essential
medicines including the schistosomiasis-drug Praziquantel
(Fig. 7).51–53 For this, we compared our method of phenylethyl
isocyanide synthesis with literature methods using POCl3 on a
100 mmol scale (Fig. 7, ESI†). Our method allows the synthesis
of the target compounds in less than 1 h on a 100 mmol scale
in almost quantitative yields with minimal use of halogenated
solvents and no wastewater production. Reported reactions,
however, lasted between 7 and 10 h and used a lot of the
chlorinated solvent DCM (250–400 ml) and waste water
(300–500 ml) and reported mixed yields were from 45% to
99%. Additionally, the reported methods expose the chemist
for a considerably longer time to the hazardous fumes of the
isocyanide during work-up (∼4 h). The number of workup
steps in the reported procedures is between 7 and 9, while our
workup comprises a simple silica filtration step followed by
solvent evaporation.
Despite the description of thousands of isocyanides, cur-
rently their use in chemistry is reduced mostly to a small
number of commercially available or easy to synthesize deriva-
tives. The extensive use of isocyanides in chemistry, for
example, in medicinal chemistry, still hampers the rapid and
efficient access to a large number of functionalized isocya-
nides. To overcome this limitation, we proposed an innovative
approach to quickly and easily synthesize isocyanides. We
found that a non-aqueous dry workup by a fast filtration
through a silica pad could considerably improve yields. Apart
from being time-efficient and reducing resource consumption,
the approach enables rapid access to structurally diverse iso-
cyanides in good to very high yields. We describe for the first
time a parallel synthesis approach to isocyanides in a 96-well
format, which can be used to produce hundreds of novel high-
quality isocyanides per week per chemist. An emerging area
Fig. 7 Comparison of different reports of the 100 mmol synthesis of
phenylethyl isocyanide (C-2) useful for the production of the schistoso-
miasis-drug praziquantel. We compared 6 methods for solvent use and
waste water production, yield and ease of operation, such as the
number of workup steps, time to target and chemist’s contact time with
the chemical.
where large numbers of different isocyanides are of need is
high-density information storage.4
To show the superiority of our process over the old pro-
cesses, a comparison of the environmental factor (E-factor) is
an appropriate method.54 The lower the value of E-factor the
better the performance of the overall process. We calculated
the environmental factor (E-factor) (see the ESI†) for all the
above five literature processes for the phenylethyl isocyanide
synthesis using the POCl3 method with our process
(Table 4).55–59
In all reported literature processes, a high E-factor is dis-
played due to the excessive organic solvent use for the aqueous
workups of a small quantity of phenylethyl isocyanide. On the
other hand, in our process, we achieved the lowest E-factor by
avoiding aqueous workup and also by running the reaction at
higher concentration. In our process, the lower E-factor also
Scheme 3 Synthesis of Ugi products using 2-pyrimidine isocyanide.
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Table 4 E-Factor of various processes of phenylethyl isocyanide syn-
thesis using POCl3
Conflicts of interest
There are no conflicts to declare.
Process
% Yield
E-Factor
Ref. no.
Porcal-2014
Pirali-2009
Andreana-2018
Dömling-2009
Goldeman-2015
Present work
99
77
95
65
45
97
63.39
83.44
67.64
50.47
60.19
8.44
55
56
57
58
59
Acknowledgements
This research has been supported (to AD) by the National
Institute of Health (NIH) (2R01GM097082-05), the European
Lead Factory (IMI) under grant agreement number 115489,
and the Qatar National Research Fund (NPRP6-065-3-012).
Moreover, funding was received through ITN “Accelerated
Early stage drug discovery” (AEGIS, grant agreement no.
675555), COFUND ALERT (grant agreement no. 665250),
indicates the lowest waste generation. Thus, our process is
greener than all the known literature processes of synthesis of
isocyanide, by a factor of 6–10. Most isocyanides are generally
produced by similar procedures with minor changes in the
details. To generalize, the current method of dehydrative iso-
cyanide synthesis from formamides is a far greener method
than previously described methods.
Hartstichting
(ESCAPE-HF,
2018B012)
and
KWF
Kankerbestrijding grant (grant agreement no. 10504).
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