A more sustainable and highly practicable synthesis of aliphatic isocyanides

Article abstract of DOI:10.1039/c9gc04070f

Synthesis protocols to convert N-formamides into isocyanides using three different dehydration reagents (i.e. p-toluenesulfonyl chloride (p-TsCl), phosphoryl trichloride (POCl₃) and the combination of triphenylphosphane (PPh₃) and iodine) were investigated and optimized, while considering the principles of green chemistry. Comparison of the yield and the E-factors of the different synthesis procedures revealed that, in contrast to the typically applied POCl₃ or phosgene derivatives, p-TsCl was the reagent of choice for non sterically demanding aliphatic mono- or di-N-formamides (yields up to 98% and lowest E-factor 6.45). Apart from a significantly reduced E-factor, p-TsCl is cheap, offers a simplified reaction protocol and work-up, and is less toxic compared to other dehydration reagents. Thus, this procedure offers easier and greener access to aliphatic isocyanide functionalities.

Full text of DOI:10.1039/c9gc04070f

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DOI: 10.1039/C9GC04070F
A more sustainable and highly practicable synthesis of aliphatic
isocyanides
K. A. Waibel,a,‡ R. Nickisch,b,‡ N. Möhl, R. Seim, M. A. R. Meier*
b
b
,a, b
Received 00th January 20xx,
Accepted 00th January 20xx
Synthesis protocols to convert N-formamides into isocyanides using three different dehydration reagents (i.e.
p-toluenesulfonyl chloride (p-TsCl), phosphoryl trichloride (POCl ) and the combination of triphenylphosphane (PPh ) and
iodine) were investigated and optimized, while considering the principles of green chemistry. Comparison of the yield and
the E-factors of the different synthesis procedures revelead that, in contrast to the typically applied POCl or phosgene
derivatives, p-TsCl was the reagent of choice for non sterically demanding aliphatic mono- or di-N-formamides (yields up to
8% and lowest E-factor 6.45). Apart from a significantly reduced E-factor, p-TsCl is cheap, offers a simplified reaction
DOI: 10.1039/x0xx00000x
3
3
3
9
protocol and work-up, and is less toxic compared to other dehydration reagents. Thus, this procedure offers an easier and
greener access to aliphatic isocyanide functionalities.
triphosgene) as dehydration reagents.6,19–23 Afterwards, other
reagents were introduced, for instance the Burgess reagent,
Appel reagent, trifluoromethyl sulfonic acid anhydride, or
Introduction
Isocyanides represent a unique type of functional group due to
their α-acidity and their ability to perform α-addition as well as
radical reactions. Except for a few examples, most derivatives
2
4–27
p-TsCl.
Nowadays, the commonly used reagent is POCl
3
due
2
8–32
to its suitability for different structural motifs.
Generally,
1
isocyanide synthesis still heavily relies on laboratory
preparation, since the number of commercially available
isocyanides is limited to a few examples, and even small
exhibit low toxicity and interestingly, many natural isocyanides
show antibiotic, fungicidal, antineoplastic, or antifouling
effects.1 Most commonly, they are used in isocyanide-based
,2
3
3
amounts are relatively expensive. Bienaymé, Bossio and
Armstrong focused their isocyanide synthesis work on feasible
derivatisation routes, which eventually led to more easily
1
,3–5
multicomponent reactions (IMCRs),
applications ranging from organic synthesis to drug discovery
and polymer science.
are generally considered as sustainable synthesis tools, as they
fulfil many of the twelve principles of green chemistry, it is
important to further consider the synthesis of their starting
materials in the scope of green chemistry.
which have manifold
1
6,7
8
–11
As multicomponent reactions (MCRs)
2
3,34,35
accessible isocyanides.
However, most of the dehydration
reagents, which are used for converting the formamides into
the targeted isocyanide, are either highly toxic or were
synthesized by employing toxic precursors.
5
Since the first known isocyanide synthesis by Lieke in 1859,
many synthesis routes starting from different precursors were
described. While Lieke and Meyer were able to obtain
isocyanides by reacting allyl or sugar halides with silver cyanide,
Hoffmann obtained them by converting amines with in situ
formed carbenes of chloroform and potassium hydroxide, or by
Ugi
O
R
N
H
H
+
base
1
2–16
heating isothiocyanates with PPh
3
.
Gassman and Kitano
Appel
+ dehydration
reagent
Lieke & Meyer
Hal
introduced trimethylsilyl cyanide as cyanide transfer reagent,
which forms isocyanides with alcohols and epoxides in the
R
NH2
R
+
KOH
+
CHCl
+ AgCN
3
1
7,18
presence of zinc salts.
However, these procedures suffer
from major drawbacks, for instance low to moderate yields and
the lack of general applicability, since they are restricted to
specific moieties. Nowadays, N-formamides are most often
used as starting materials to form isocyanides by addition of a
dehydration reagent under basic conditions. Ugi first described
this procedure using phosgene and later its surrogates (di- and
R
NC
Isocyanide
+ TMSCN
+ ZnHal2
+
PPh3

O
a. Institute of Biological and Chemical Systems – Functional Molecular Systems
R
NCS
or
R
OH
(
IBCS-FMSs), Karlsruhe Institute of Technology (KIT), Straße am Forum 7, 76131
R
R
Hoffmann
Karlsruhe, Germany.
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Straße am
b.
Gassman & Kitano
Forum 7, 76131 Karlsruhe.
*Corresponding author E-Mail: m.a.r.meier@kit.edu; web: www.meier-
michael.com
Figure 1: Summary of described isocyanide synthesis procedures. The most widely
Electronic Supplementary Information (ESI) available: Materials and Methods. applied procedure employs N-formamides as starting materials and various
Synthesis
DOI: 10.1039/x0xx00000x
procedures
and
characterization
of
products.
See dehydration reagents in combination with a base (highlighted in blue).
1
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In addition, large amounts of waste are produced during the Schuster and collegues.27 They stated that thViiesw AprtricoletoOcnloinle,
synthesis and thus, typical isocyanide syntheses cannot be involving a simultaneous distillation,DOisI: 1s0u.1p03e9r/ioCr9GCto040t7h0eF
considered as sustainable. Recently, Wang et al. introduced a Ugi-approach for smaller isocyanides (methyl and ethyl
less toxic dehydration reagent using PPh
good yields of up to 90% for mainly aromatic formamides.
3
and iodine obtaining isocyanide), as these substrates show decent water solubility
3
6
and therefore exclude an aqueous work-up of the reaction
Porcheddu et al. were able to improve the approach initially mixture.
reported by Hoffmann to a more sustainable procedure by The advantageous properties of p-TsCl, if compared to POCl ,
3
applying mechanochemical activation via ball-milling, reducing are particularly the easier operation, and the significantly lower
the required amount of chloroform to a stoichiometric amount. toxicity. In addition, it has to be emphasized that it is a waste
Thus, they were able to obtain isocyanides with a broad product of the industrial saccharine synthesis by the
spectrum of aliphatic, benzylic and aromatic moieties in yields Remsen-Fahlberg procedure, making the use of this reagent
up to 71%.37
even more sustainable and also economically attractive.
43,44
In this work, we investigated various synthesis procedures in In a first approach, the reaction conditions of the Ugi-approach
1
9
order to develop a more sustainable and generally applicable were applied. With regard to sustainability, p-TsCl possesses
route to convert aliphatic N-formamides into isocyanides. the highest potential, thus the conditions for this particular
Therefore, we optimized the isocyanide syntheses employing reaction were optimized utilizing common GC-screening
3 3
POCl , p-TsCl, and the combination of PPh with iodine and techniques.
compared not only the yields but also the E-factors as well as
several other parameters such as waste in purification steps and GC-Screening for Optimized Conditions Utilizing p-TsCl
energy consumption.
The generally accepted mechanism for the dehydration
proceeds via the formation of a formamide-dehydrating agent
adduct, which subsequently undergoes elimination. Both
reaction steps are induced by a base and thus, at least two
equivalents of a base are needed to ensure full conversion.
Thus, we started our investigations by varying different bases.
In general, most amine bases are rated toxic by the globally
harmonized system, with pyridine being the only exception as it
is only rated health hazardous. The sustainability and toxicity of
different bases are studied in detail, confirming this
Results and Discussion
Regarding the aforementioned syntheses of isocyanides, we
focused our work on the dehydration of N-formamides to
improve the sustainability of these procedures. For this
purpose, we investigated three commonly applied dehydration
1
9,27,38
3 3
reagents, namely POCl , PPh / iodine, and p-TsCl.
In our investigations, the focus was furthermore laid on
suitable, more sustainable solvents since typically
dichloromethane (DCM) is used for the dehydration of
N-formamides, which is considered as hazardous, as are many
other halogenated solvents. Therefore, we chose several
candidates by following the respective guidelines for greener
4
5
classification. Therefore, we chose diisopropylamine (DIPA),
diisopropyl ethylamine (DIPEA), pyridine (Py) and triethylamine
(
TEA), which are all commercially available and can be produced
4
6–51
sustainably (see Table 1).
The screening results for the optimal base showed significant
differences, which are presented in Table 1. The two tertiary
amines gave the lowest yields (14% and 25%, see Table 1 entries
solvents.3
9–41
The synthesis of isocyanides is usually carried out
, phosgene,
by using highly reactive reagents like POCl
3
2
and 3), whereas DIPA yielded 35%. The most promising result
phosgene surrogates, or p-TsCl. Thus, the solvents have to be
chemically inert in the reaction, which excludes alcohols,
ketones, water and amines, yet leaves a range of different
sustainable solvents suitable, which were used in the
optimization study (see Tables 1-3). The solvent tests were
carried out for each dehydration reagent individually, using
N-octadecyl formamide 1 as model substance, because of an
easy handling and the absence of other functional groups that
could interfere during the reaction (see Table 1-4).
were obtained using pyridine, leading to 66% yield after only
two hours of reaction.
It seems that strong bases are not necessarily required to
convert formamide 1. Rather steric influences seemed to be
dominant, as the obtained yield increases while the steric
demand of the applied base decreases.
Having found a suitable base for the dehydration, we
investigated different solvents (see Table 1, both sustainable
and conventional solvents were tested). We also increased the
stochiometric amount of dehydrating agent / base from
4
2
In addition, E-Factors were calculated according to Sheldon,
considering all reactants, including the solvent used for the
reaction as well as the reagents and solutions applied for
quenching, respectively. Please note that the work-up of crude
reaction mixtures (i.e. solvent used for extraction and washing
or column chromatography) was not taken into account for the
herein reported E-Factors. Therefore, a synthesis E-Factor was
exclusively calculated and used herein for comparison reasons.
1
.30 / 2.60 to 1.50 / 3.00 equivalents and later increased the
concentration of the starting material to 1.00 mol/L. The latter
reduces the amount of solvent, which omits waste while
increasing the reaction rate. The further excess of dehydration
agent was applied in order to compensate the loss of p-TsCl due
to hydrolysis to p-toluenesulfonic acid (PTSA) during the
reaction. Consequently, the amount of base was also increased
to 3.00 equivalents to ensure that the reaction mixture remains
basic throughout the process, as isocyanides decompose in
acidic media.
Formamide Dehydration Utilizing p-TsCl
In 1979, a procedure to synthesize isocyanides involving
quinoline and p-TsCl as dehydrating agent was published by
2
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Table 1: Optimization of reaction parameters for the dehydration of formamide 1 using (washing and column chromatography). Yet, weVi
sewtayed with
Article Online
p-TsCl and a base.
quenching with sodium carbonate soluti
D
onOI: 1 .10 /C
and
0
aqu
3
9
eo
9
G
us
C
0
w
40
ork-
7
0
F
up, which led to the most promising results.
Also during purification, DMC was often superior to DCM, since
DCM tended to produce quite stable emulsions during the
aqueous work-up, requiring more time for the separation
process.
The results obtained in this approach were very encouraging,
since p-TsCl is the least toxic reagent among the reported
dehydration reagents for an isocyanide synthesis. Furthermore,
dehydration with p-TsCl is less exothermic, which allows a safer
handling and an intense water cooling is only required for
reactions in larger scale (batches of up to 100 mmol with
isocyanide 6 were conducted).
p-TsCl
H
N
base
O
NC
1
6
1
6
solvent,
r.t.
1
2
Entry
1
Solvent
Base
c / mol
t / h
Yield /
%a)
35b)
E-factor
DCMa)
DIPA
0.330
21
51.3
a)
b)
2
3
4
5
DCM
DCM
DCM
Me-
THF
DMC
DIPEA
TEA
Py
0.330
0.330
0.330
0.330
7.80
1.50
2
14
132
72.2
26.4
106
a)
b)
25
a)
b)
66
Ugi-Approach Utilizing (POCl
The Ugi procedure utilizing POCl
is known to give consistently good yields for a wide variety of
3
)
Py
2
12c)
3
is already well-established and
a)
a)
7 / 85 c) 217 / 31.8
6
7
8
9
Py
Py
Py
Py
0.330
1.00
1.00
1.00
2 /
9
,54–58
substrates.
As expected, the yields of the first dehydration
1
8
ACNa)
reaction were quite satisfactory (see Table 2).
4 /
70 /
56c)
10 /
8.20 /
10.5
80.2 / 324
1
8
Table 2: Solvent test of the dehydration of formamide 1 with POCl
3
and DIPA
Cyrene™
1 / 2
a)
.4c)
2
GBLa)
POCl3, DIPA
H
1 / 2
28 / 22
26.5 /
O
c)
N
3
4.8
NC
c), d)
16
solvent,
1
1
0
1
DCM
DMC
Py
Py
1.00
1.00
2
18
96
89
7.76
7.41
16
c), d)
1
0°C - r.t., 2 h
2
)
a) Yields calculated by GC using a calibration curve of product 2; b) the
corresponding solvent, 5.00 mmol formamide (1.00 eq.), p-TsCl (1.30 eq.) and the
base (2.60 eq.) were applied; c) the corresponding solvent, 5.00 mmol formamide
Entry
Solvent
DCM
EA
Me-THF
DMC
Yield / %a)
E-factor
17.8
13.9
12.6
15.9
1
2
3
4
96
90
94
90
(1.00 eq.), p-TsCl (1.50 eq.) and the base (3.00 eq.) were applied; d) Isolated yield
after work-up.
Dihydrolevoglucosenone (Cyrene™) and γ-butyro lactone (GBL)
were the two least promising solvent candidates, yielding 2.42%
a) The corresponding solvent, formamide (0.33 M in solvent, 3.00 mmol, 1.00 eq.),
POCl (1.30 eq.) and base (2.60 eq.) were utilized under ice-bath cooling and the
3
and 21.5% yield after two hours reaction time in 1 M solution reaction was stirred for two hours at room temperature.
(
see Table 1 entries 8 and 9). Yields even decreased while the
reaction proceeded, indicating side-reactions.
-Methyltetrahydrofuran (Me-THF) allowed the precipitation of
Further, the replacement of DCM with other solvents also led to
consistently good yields ranging from 90% in the case of ethyl
acetate (EA) up to 94% in Me-THF. It is noteworthy that POCl is
3
highly reactive, which requires consistent cooling while the
reactant is added and thus makes the handling of the reaction
more challenging. With regard to sustainability, energy
intensive consuming processes like cooling or heating should be
avoided whenever possible.
The overall E-factors ranged from 12.6 to 17.8, which is in the
range of fine chemicals (mostly valued with 5 – 50).
3
However, this E-factor does not include the fact that POCl is a
quite hazardous chemical because of its high reactivity,
corrosivity, and toxic properties. Thus, omitting such chemicals
should be the privileged task of future syntheses.
2
ammonium salts, which should foster the shift of the
equilibrium to the product side; however, a low yield of 12%
was obtained after two hours. Acetonitrile gave a surprisingly
high yield after four hours (70%), but the yield started to
decrease afterwards, thus only 56% product remained after
1
8 hours. However, the least toxic solvent dimethyl carbonate
(DMC), which performed poorly on first sight (7% of yield after
two hours), convinces with a continuously increasing yield over
time, resulting in up to 85% after 18 hours, and resulting in an
E-factor of 7.71. Therefore, we repeated the reactions in DCM,
the commonly used solvent, and DMC with increased
concentration to obtain a valid comparison between non-
sustainable and sustainable solvents and observed 96% and
3 2
Wang Procedure Utilizing (PPh ) and Iodine (I )
8
9% of yield, respectively. The reaction in DCM proceeds faster,
In 2015, Wang et al.38 published a procedure using PPh
and
3
has a higher yield and shows a slightly higher E-factor. In terms
of sustainability, DMC has clear advantages in being non-toxic
compared to DCM and the possibility to be produced
iodine, acting as dehydrating agents similar to the Appel
5
2,53
sustainably from various renewable sources.
Furthermore,
we investigated several methods for the reaction work-up
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reagent. They stated that their investigations were driven by POCl
convenience, as POCl
is not easily available in China. However, reagents. It is toxic, corrosive and reacts hDiOgIh: l1y0.e10x3o9t/hCe9rGmCi0c4.0T7h0eF
both PPh and iodine exhibit a lower toxicity compared to POCl lower reactivity of p-TsCl is one of its advantages, as it is easier
Moreover, PPh is a stable solid, which is reactive with oxidizing to handle and can be applied in smaller amounts of solvents,
3
is the most hazardous chemical of all threeVidewehArytidclreaOtniloinne
3
3
3
.
3
agents and can thus be handled more easily. However, iodine thus higher concentration (1 mol/L concentration of the
slowly sublimes at room temperature and is hazardous when starting material). Consequently, less solvent waste is
inhaled as well as skin irritating. The procedure reported by produced.
Wang was adapted and applied to formamide 1. Similarly as for Moreover, the reaction with p-TsCl still only has to be cooled for
the other two procedures, a solvent evaluation was performed the quenching process even in large scales (up to 100 mmol
and the results were compared with the other approaches (see with isocyanide 5 were tested), whereas addition of POCl
3
Table 3).
always requires active cooling to 0 °C or lower (see Figure 2).
Table 3: Solvent test of dehydration of formamide 1 with PPh
3
, iodine and a base.
PPh3, I2,
H
N
TEA
O
NC
1
6
1
6
solvent,
r.t., 2 h
1
2
Entry
Solvent
DCM
EA
Me-THF
DMC
Yield / %a)
E-factor
54.3
49.2
18.4
60.8
1
2
3
4
42
37
93
33
a) The corresponding solvent, formamide (0.33 M in solvent, 3.00 mmol, 1.00 eq.),
PPh (1.50 eq.), iodine (1.50 eq.) and base (3.00 eq.) were applied and let stirred
3
for two hours at room temperature.
The obtained results of the solvent screening showed significant
differences for this reaction (see Table 3), ranging from 33%
yield using DMC up to 93% for Me-THF. Interestingly, high yields
were not achieved with DCM as solvent.
However, this combination of reactants exhibiting a lower
3
toxicity compared to POCl led to a significant increase of the
E-factor (18.4 up to 60.8).
Comparison of the Three Approaches
The results obtained by optimizing the three approaches were
compared in a comprehensive comparative study in order to
evaluate the effectiveness and E-factor (see Table 4).
Figure 2: Top left: Dehydration of tert-butyl formamide (11.6 mmol in 35 mL DCM,
0.33 M)), cooling is applied for subsequent addition of POCl . Bottom left: Reaction after
addition of POCl , internal temperature at 0 °C, still HCl vapors are evolving. Top right:
(
3
Table 4: Comparison of the solvent optimized dehydration of formamide 1 with POCl
3
and PPh
3
and iodine as well as the optimized reaction condition while using p-TsCl.
3
Dehydration of tert-butyl formamide (35 mmol in 35 mL DCM, 1.00 M), a water bath is
applied for subsequent addition of p-TsCl. Bottom right: Reaction after addition of p-
TsCl. No visible hints of an exothermic reaction are observed. In some dehydrations, the
temperature increased slightly.
dehydration reagent
H
N
base
O
NC
1
6
1
6
Triphenylphosphine and iodine are of lower toxicity if compared
to POCl , yet the method has its limitations in the E-factor and
3
solvent
1
2
the further purification.
The approaches by Ugi and Wang achieve their lowest E-factor
using Me-THF as solvent. In case of POCl in combination with
3
DIPA, the value amounts to 12.7 kg of waste per kilogram
isocyanide, whereas applying triphenylphosphine, iodine and
diisopropylethylamine amine results in 18.4 kg waste per kg
product. To sum up, the advantage of using less toxic reagents
for the isocyanide synthesis of substrate 2 is diminished by
Entry
Method
Ugia)
Solvent
Me-THF
Me-THF
DMC
Yield / %)
E-factor
12.6
18.4
1
2
3
94
93
89
Wangb)
p-TsClc)
7.41
a) see table 2. b) see table 3. c) see table 1.
4
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producing an additional 5.70 kg of waste per kg product. compound 3, which is a remarkable improvement toward a
View Article Online
Another aspect to be considered is the product work-up.
Avoiding column chromatography as purification method was
one of the main goals in this study, as the amount of solvent and
silica used add significantly to the overall E-factor. The reaction
DOI: 10.1039/C9GC04070F
more sustainable process for these two isocyanides.
Overall, the yields and the E-factors for the di-isocyanides 8 / 9
as well as the benzylated isocyanide 5 were improved by using
5
6,59,60
the new and more sustainable procedure.
It has to be
3
with POCl yields the product in reasonable purity after simple
highlighted that isocyanide 4 as well as the di-isocyanides 8 / 9
are of special interest, as all three originate from renewable
feedstock.
extraction, as all by-products are water soluble compounds,
which is not possible in case of the Wang procedure. In this
process, triphenylphosphine oxide is obtained as side product,
which, in contrast to the phosphorus acid derivatives, is poorly
soluble in water and thus cannot be extracted. Therefore, the synthesis of sequence-defined macromolecules. Please
column chromatography cannot be omitted in this approach, note that we decided to revise the reported three-step
Isocyanide 5 was chosen as an example, since it can be used for
3
1
which adds to the E-factor.
synthesis in terms of sustainability (compare SI). Our new
The utilization of p-TsCl on the other hand allows to avoid synthesis protocol gives an overall yield of 94% with an E-factor
column chromatography, since the formed pyridinium salts can of 16.8, whereas the old procedure exhibits an overall yield of
6
0
be easily removed by water extraction (vide infra).
Within this comparative study, the best overall results were the E-Factor of the reported synthesis and also omitting the
obtained using DMC as solvent for p-TsCl, which further hazardous chemicals sulfurous dichloride and POCl , which are
63.4% with an E-factor of 33.2, effectively halving the value of
3
increases the sustainability of the reaction, as both DMC and applied in the first and third step of the previous synthesis
Me-THF are renewable, but DMC is non-toxic, whereas Me-THF protocol, respectively.
is health hazardous. Remarkably, this approach led an E-factor Dehydration of
a hydroxy-functionalized formamide to
of 7.41 and a yield of 89%. It is noteworthy that the more isocyanide 6 was possible in moderate yields, while activating
sustainable and less toxic reagent p-TsCl gives a comparable the beforementioned functionality with simultaneous
yield for formamide 1, while being easy to handle. tosylation, which enables post-functionalization.
Consequently, this approach revealed itself to be the most However, the three commercially available isocyanides (10, 11,
promising one both in terms of sustainability and in terms of 12) reveal the limitations of the presented approach. The yield
practicability and was thus used in the subsequent seems to be related to both water solubility and steric
investigations.
hindrance and is also confirmed considering benzylic or
aromatic formamides as reactants (see. 11 and 13). While the
new synthesis for the compounds 10 and 12 was more
Isocyanide Syntheses with Optimized Reaction Conditions
To prove the versatility of the optimized reaction conditions of sustainable in terms of the E-factor compared to the literature
6
1,62
the most promising reaction with p-TsCl (see Scheme 1), we procedures (62.0 ‒ 24.9 / 28.9 ‒ 14.7),
this is not the case
decided to synthesize a library of isocyanide compounds (see for compound 11, yet the yields were comparable (22.2 to
9
Table 5). Due to the faster reaction rate of DCM (average 25.6).
reaction time of two hours) compared to DMC, we performed In 2013, for example, Kim et al. published a convenient
each synthesis in both the conventional solvent and the more synthesis protocol for isocyanides in
a continuous-flow
5
8
sustainable alternative.
microreactor with excellent yields for 10 and 11. Yet, such
microreactors are not generally available and Kim et al. still
relied on POCl in DCM, which we tried to omit for reasons
3
discussed above. Finally, the aromatic isocyanide 13 underlined
the limitations of our procedure, which led only to 13% yield
and an E-factor of 108.6.
p-TsCl
pyridine
H
N
O
NC
R
R
DCM, r.t., 2 h
or
This compound variation clearly reveals that the newly
developed procedure offers very promising results for the
synthesis of non-sterically hindered aliphatic isocyanides. We
used column chromatography to determine the yields of the
synthesized isocyanides, but we observed that flash column
chromatography was sufficient to isolate the pure products.
However, as mentioned before, many of the products could be
obtained in satisfying purity by simply increasing the number of
DMC, r.t., o.n.
Scheme 1: Optimized reaction conditions of the isocyanide synthesis using p-TsCl and
pyridine at room temperature in DCM for two hours or in DMC overnight (o.n.).
To compare our results, we have chosen several isocyanides,
which either were already synthesized by the Ugi-approach and
are reported in the literature, or were commercially available
isocyanides 10, 11 and 12).
In case of the long-chain alkyl isocyanides 2, 3 and 4, the yields
obtained in DCM (96 / 90 / 97%) as well as in DMC (89 / 94 /
8%) are similar to the ones reported in the literature (87 / 94 /
no literature (n.L.)% ), but in comparison with literature the
1
washing steps. Exemplary, the H-NMR spectra of compound 9
(
after purification by washing and by flash column
chromatography are depicted in Figure 3 and they show a
comparable purity.
9
5
4
E-factor is 75% lower for compound 2 and 80% lower for
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DOI: 10.1039/C9GC04070F
Table 5 Synthesized isocyanides via formamide dehydration utilizing the optimized reaction conditions with p-TsCl in either DCM or DMC (see above).
a
b
Entry
Substrate
Procedure A –
yield / %
E-factor A
Procedure B –
yield / %
E-factor B
Literature –
yield / %
E-factor
Literaturec)
NC
NC
1
96
7.76
89
7.40
8754
36.9
48.8
-
1
6
2
2
3
90
97
11.9
7.73
94
98
9.93
6.68
9454
n.L.
1
0
3
7
NC
7
4
O
4
Bn
Ts
NC
97
7.11
97
6.45
6660
22.3
O
O
8
5
NC
5
6
7
53
48
93
15.0
49.0
15.8
68
82
89
11.0
25.7
15.0
n.L.
n.L.
7159
-
-
4
6
CN
CN
CN
NC
NC
NC
3
7
8
33.6
8
9
8
9
87
67
14.8
28.8
97
68
12.0
24.9
7556
7661
33.6
62.0
10
NC
10
NC
1
0
1
44
79
41.5
16.5
62
78
25.6
14.7
649
22.2
28.9
1
1
NC
1
9362
12
NC
12
13d)
108.6
-
-
9657
12.9
MeOOC
13
n.L. = no literature available; a) formamide (5.00 mmol, 1.00 eq.) in DCM (1M), 1.50 (3.00) / 3.00 (6.00) eq. p-TsCl/pyridine at r.t. for 2 h; b) formamide (5.00 mmol,
.00 eq.) in DMC (1M), 1.50 (3.00) / 3.00 (6.00) eq. p-TsCl/pyridine at r.t. overnight; c) E-factors were calculated using the values in the respective literature; d) adjusted
equivalents: Formamide (5.00 mmol, 1.00 eq.) in DCM (1M), 1.70 / 3.40 eq. p-TsCl/pyridine at r.t. for 2 h.
1
6
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Figure 3: 1H-NMR spectrum of compound 9 after several washing step (red line), and after purification by flash column
chromatography (blue line), both measured in CDCl
3
.
Passerini-Three-Compontent Polymerization Reaction (P-3CPR)
pure reagents in an equimolar amount are used, which is crucial
In order to verify that the herein obtained isocyanides can be in step-growth polymerizations (see Scheme 2), even small
used without further purification by column chromatography, impurities alter yield and conversion in those polymerizations
we have chosen the step-growth polymerization reaction via greatly. Since bifunctional acids and monofunctional aldehydes
P-3CR. Since high molecular weights can only be obtained if are often available from renewable feedstocks, we decided to
use sebacic acid 14 and heptanal 15, as both are available from
6
3
castor
oil
and
converted
them
with
1
,12-diisocyanododecane 9 to Passerini-polymer 16 in bulk to
underline the sustainable character of the test polymerization.
For this purpose, the reaction was performed twice, first with
the isocyanide 9 purified by flash column chromatography and
another time using compound 9 purified by washing steps
Scheme 2: P-3CPR of sebacic acid 14 (blue), heptanal 15 (red) and isocyanide 9
green) without any solvent. The Polymer 16 was synthesized twice one time
with isocyanide 9 purified by column chromatography and another time purified
Figure 4: Molecular weight distribution of the two obtained polymers 16. Polymer 16a
was synthesized using the purified isocyanide and has the higher molecular weight.
Polymer 16b was synthesized using the crude isocyanide.
(
by several washing steps.
7
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(
compare Scheme 2). After precipitation, the samples were chromatography (mixture of cyclohexane and ethyl acetate)
View Article Online
DOI: 10.1039/C9GC04070F
analyzed and compared by SEC (see Figure 4). The number was applied to obtain the product in highest possible purity.
averaged molecular weight (M
which was synthesized with pure isocyanide 9 (previously General Isocyanide Synthesis with p-TsCl in DMC (5.00 mmol
purified by column chromatography), exhibited a M
value of Scale)
0500 g/mol, whereas the crude isocyanide led to a polymer The formamide (5.00 mmol, 1.00 eq.) was dissolved in 5 mL
n
) of the obtained polymer 16,
n
1
with a slightly lower M value of 8350 g/mol, which is still DMC and pyridine (15.0 mmol, 3.00 eq.) was added.
n
satisfying and underlines the advantage of the simplified and Subsequently, p-TsCl (7.50 mmol, 1.50 eq.) was added under
more sustainable purification process. Both polymers were cooling with a water bath. The cooling was removed, and the
waxy solids, yet the polymer obtained utilizing the crude reaction mixture was stirred until full conversion was reached
isocyanide exhibited a darker color.
(determined by TLC, average reaction time of 18 hours).
Afterwards, the mixture was cooled to 0 °C and subsequently
aqueous sodium carbonate solution (5 mL, 20 wt%) was added
under ice bath cooling and the biphasic mixture was stirred for
3 3
The dehydration of formamides utilizing POCl , PPh
in another 30 minutes at room temperature. 10 mL of water and
Conclusions
combination with iodine, and p-TsCl to yield isocyanides was DMC were added, and the organic phase was separated. The
evaluated in terms of sustainability. We observed that p-TsCl aqueous phase was extracted with DMC (3x5 mL), the organic
was able to give the highest yields for non-sterically demanding extracts were combined and washed with water (3x5 mL) and
aliphatic N-formamides (up to 98%), while also resulting in the saturated sodium chloride solution (2x5 mL). The organic
lowest E-factors (down to 6.45). In addition, we introduced extract was dried over sodium sulfate, filtered and the solvent
DMC as a sustainable alternative to dichloromethane and was removed under reduced pressure. Further purification is
employed it in the dehydration process of ten different aliphatic not necessary in many cases. Nevertheless, purification by flash
formamides. Thus, the aforementioned products were isolated column chromatography (mixture of cyclohexane and ethyl
in high yields and excellent purity, while obtaining lower acetate was applied to obtain the product in highest possible
E-factors compared to already established synthesis protocols. purity).
Furthermore, we showed that isocyanides of sufficient purity
were obtained by simple extraction, and subsequently
successfully employed in the P-3CPR to obtain polymers with
Conflicts of Interest
satisfying molecular weights. However, some limitations of the There are no conflicts of interest to declare.
new procedure were observed, as low conversions for sterically
more demanding or aromatic compounds like benzylic or
aromatic formamides were obtained. Nonetheless,
a
Acknowledgements
straightforward and in terms of sustainability significantly
improved synthesis procedure for aliphatic isocyanides was
established. The procedure provides a notable advantage for
sustainable isocyanide-based chemistries, such as IMCRs.
We would like to acknowledge support from the Karlsruhe
Institute of Technology (KIT) and the Helmholtz association.
Additionally, we would like to thank Camilla Rieker and Nicola
Seul, who also contributed to this work.
Experimental
General Isocyanide Synthesis with p-TsCl in DCM (5.00 mmol scale)
Notes and References
‡
Both authors contributed equally to this work.
The formamide (5.00 mmol, 1.00 eq.) was dissolved in 5 mL
DCM and pyridine (15.0 mmol, 3.00 eq.) was added.
Subsequently, p-TsCl (7.50 mmol, 1.50 eq.) was added under
cooling with a water bath. The cooling was removed, and the
reaction mixture was stirred until full conversion (average
reaction time of two hours). Afterwards, the mixture was
cooled to 0 °C and subsequently aqueous sodium carbonate
solution (5 mL, 20 wt%) was added and the biphasic mixture
was stirred for another 30 minutes. 10 mL of water and DCM
were added, and the organic phase was separated. The aqueous
phase was extracted with DCM (3x5 mL), the organic extracts
were combined and washed with water (3x5 mL) and saturated
sodium chloride solution (2x5 mL). The organic extract was
dried over sodium sulfate, filtered off and the solvent removed
under reduced pressure. Further purification is not necessary in
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