Supported p-toluenesulfonic acid as a highly robust and eco-friendly isocyanide scavenger

Article abstract of DOI:10.1021/co100035z

We document here the use of polymer-supported p-toluenesulfonic acid as a highly effective, robust, economical and eco-friendly isocyanide scavenger. The herein described strategy circumvent the intense and repulsive odor of volatile isocyanides, enabling simplified and odorless workup and purifications. The usefulness of the new scavengers has been validated in a set of diverse isocyanide-based organic transformations and this approach is also amenable to parallel synthesis techniques.

Full text of DOI:10.1021/co100035z

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Supported p-Toluenesulfonic Acid as a Highly Robust and
Eco-Friendly Isocyanide Scavenger
Jhonny Azuaje,† Alberto Coelho,† Abdelaziz El Maatougui,† Josꢀe Manuel Blanco,‡ and Eddy Sotelo*,†,‡
†Combinatorial Chemistry Unit (COMBIOMED), Institute of Industrial Pharmacy (IFI), University of Santiago de Compostela
‡Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela 15782, Spain
S Supporting Information
b
ABSTRACT: We document here the use of polymer-supported
p-toluenesulfonic acid as a highly effective, robust, economical
and eco-friendly isocyanide scavenger. The herein described strategy
circumvent the intense and repulsive odor of volatile isocyanides,
enabling simplified and odorless workup and purifications. The
usefulness of the new scavengers has been validated in a set of diverse isocyanide-based organic transformations and this approach is also
amenable to parallel synthesis techniques.
KEYWORDS: isocyanide, scavenger, supported reagents, Ugi reaction
’ INTRODUCTION
odor is critical for volatile compounds, some of which have been
investigated as nonlethal weapons,14 whereas higher-molecular-
weight compounds are often odorless. The majority of these
volatile compounds are commercially available and they are
usually employed during process development/optimization. As a
result, the unpleasant odor frequently makes the workup and
purification of the reaction products highly tedious and distressing,
particularly when applied to high-throughput organic synthesis
operating in parallel mode.
Contemporary attempts to circumvent the odor issue include
the use of fragrant isocyanides15 and the developmentofa plethora
of polymer-supported isocyanides.16 A strategy that has occasion-
ally been employed involves treatment of reaction mixtures with
acid,17 to promote hydrolysis of the residual isocyanides. This
hydrolytic quenching has several key drawbacks: it is not applicable
to reactions that produce acid-sensitive substrates, isocyanides tend
to polymerize2 in strongly acidic media and, finally, such a quench-
ing process produces the corresponding hydrolysis products, which
must subsequently be removed from reaction mixtures. In con-
cordance, these strategies do not provide general and practical solu-
tions to address the unpleasant odor associated with the experi-
mental manipulation of isocyanides. To the best of our knowledge,
examples of the application of the scavenger concept18 to such a
problem have not been described. The experimental feasibility of
this concept has been, probably, limited by the dearth of highly reli-
able transformations that can be employed as tools in the develop-
ment of isocyanide scavengers.
The unusual structure and reactivity of isocyanides has attracted
the scientific community since their discovery in the mid-1800s.1
The isocyanide carbon behaves as a nucleophile or an electrophile
depending on the reaction conditions, reagents, and the substit-
uents present.2 Isocyanides exhibit an exceptional ability to
form R-adducts, in an irreversible and exothermic transformation
(R-addition) in which CII is oxidized to CIV, which make these
molecules extremely attractive starting materials for the rapid
generation of chemical diversity.3 This distinctive reactivity is
usually complemented by excellent functional group tolerance
that generally provides high levels of chemo-, regio-, and stereo-
selectivity.3 The reactions in which these compounds participate
are quite varied and include free radical additions,4 organometallic
transformations,5 and polymerizations.6 Beyond these diverse
applications, isocyanides have proven to be particularly prolific in
the development of multicomponent reactions (MCRs).7,3
The widely recognized contribution of isocyanides to the
development of multicomponent reactions notwithstanding,
their role as a reactive partner in simple organic transformations
has been comparatively less explored.8 In this context, recent
reports9-12 have documented the coupling reactions of isocya-
nides with molecules bearing acid groups that lead to the forma-
tion of N-formylamides, N-formylthioamides, or sulfamides.
Despite its theoretical and experimental relevance, as well as the
large literature available, we certainly do not know yet all facets of the
chemistry of isocyanides, probably because these are not trivial
substrates to work with. The potential of this functional group
in synthesis has partially been hampered by limited commercial
availability and, most importantly, by the intense and repulsive odor
of these compounds (described as overpowering and extremely
distressing by Hofmann and Gautier)1-a fact that has discouraged
many potential contributors to this field.13 Such a piercing
The unique reactivity profile exhibited by isocyanides led us to
incorporate this functional group into several of our in-house
library generation programs. As experienced by practitioners of
Received: October 14, 2010
Revised:
October 25, 2010
Published: November 10, 2010
r
2010 American Chemical Society
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RESEARCH ARTICLE
Scheme 1. Reaction of Representative Isocyanides and p-Toluenesulfonic Acid
isocyanide chemistry over the decades, the presence of unreacted
isocyanides in the reaction mixtures, even in trace amounts,
complicated the workup and purification of the target products
considerably. Within the framework of this project, it was envisioned
that the use of a polymer-supported reagent incorporating acidic
functional groups would simultaneously promote isocyanide
quenching and immobilize the isocyanide quenching products onto
the polymeric matrix. These processes would avoid the tedious
workup and purification stages encountered on working with this
functional group. We document here the use of polymer-supported
(polystyrene or silica) p-toluenesulfonic acid as a highly effective,
robust, economical, and eco-friendly isocyanide scavenger. The use-
fulness of the new scavengers has been validated in a set of diverse
isocyanide-based organic transformations and this approach is also
amenable to parallel synthesis techniques.
the starting materials was observed within relatively short reaction
times. Nonetheless, in our hands, the excellent reactivity profile was
not complemented by the selectivity and efficiency levels claimed by
the authors (Scheme 1). Analysis of the resulting products showed
that the reaction of p-toluenesulfonic acid (2) and isocyanides 1a-c
did not afford sulfonamides 3, but gave p-toluenesulfonate salts (4)
together with variable amounts (15-22%) of formamides (5).
These new structural assignments are supported by examination of
published12 spectroscopic and analytical data and by comparison
with our own data and previous independent literature reports20 on
3 and 4.
In light of these results, and in connection to previous reports
in the carboxylic acid series,9 we considered the feasibility and
robustness of a hydrolytic scavenging process instead of the
amidation approach. The evident mechanistic differences be-
tween the two immobilization processes have significant con-
notations, mainly in terms of reversibility and recycling issues.
The hydrolytic scavenging strategy would be supported by the
well-documented acid-catalyzed methanol-mediated conversion
of isocyanides to amine salts.21 With this aim in mind, a slight
excess (1.20 equivalents) of p-toluenesulfonic acid (2) and
model isocyanides (1a-c) were reacted at room temperature
in either methanol or dichloromethane/methanol mixtures
(Scheme 1). It was gratifying to observe that, under the new
experimental conditions, hydrolysis of the isocyanide group
required short reaction times (typically less than 30 min) and
mild experimental conditions (room temperature) to afford the
corresponding p-toluenesulfonic acids salts (4) in excellent
yields. Despite the effectiveness of the process, small amounts
of formamides 5 (ca. 5%) were also detected, most probably due
to incomplete isocyanide hydrolysis. As experimentally verified
the formation of formamides 5 in these transformations can be
suppressed by simultaneously increasing the p-toluenesulfonic
acid excess (e.g., 1.5-2.0 equivalents) and the proportion of
methanol in the reaction mixtures.
’ RESULTS AND DISCUSSION
The recent breakthroughs on the two-component coupling reac-
tions of isocyanides with molecules bearing acid groups9-12
inspired the development of the scavenging strategy documented
here. An in-depth analysis of recently published results on this
topic would enabled a range approaches to be considered. In light
of the efficiency and reliability of the two-component carboxylic
acid/isocyanide coupling,9 the most obvious approach to devel-
op a selective scavenger for the isocyanide functional group is the
use of a polymer-immobilized carboxylic acid. Such an approach
would enable the selective attachment of the isocyanide onto the
polymeric matrix as a N-formylamide. However, the main draw-
back associated with this approach is the harsh thermal activation
(typically 150 °C for 30 min) required to promote the 1,3-
OfN acyl transfer.9a An interesting and experimentally milder
alternative to carboxylic acids is the use of thiocarboxylic acids,
which showed satisfactory reactivity profiles in coupling reac-
tions with isocyanides at room temperature.10 Unfortunately, the
limited commercial availability of polymer-supported thioacids
restricts the feasibility and applicability of this strategy. In this
scenario, a paper11 attractedourattentionasitdocuments a robust,
room-temperature coupling of isocyanides and sulfonic acids to
afford sulfonamides. These precedents, in conjunction with the
cheapness, commercial availability, and applications described for
supported p-toluenesulfonic acids,19 fulfilled our expectations.
In a solution-phase proof of concept, p-toluenesulfonic acid 2
was reacted with three representative commercially available
isocyanides (1a-c) at room temperature under published experi-
mental conditions (Scheme 1).12 Complete consumption of
Encouraged by these results, it was decided to investigate
whether the use of a polymer-immobilized p-toluenesulfonic acid
would still provide the excellent reactivity profile exhibited by the
nonsupported substrate (2). In an attempt to address this issue
and to optimize a multipurpose, robust isocyanide scavenger that
is amenable to diverse solution phase protocols, we selected the
commercially available p-TsOH immobilized on either polystyrene-
divinyl benzene (PS-p-TsOH, 6) or silica (Si-p-TsOH, 7)
matrixes for preliminary studies (Scheme 2). These two reagents
differ not only in the polymeric matrix that supports the reactive
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Scheme 2. Scavenging of Diverse Isocyanides with Polystyrene- Or Silica-Supported p-TsOH
Table 1. Scavenging of Diverse Isocyanides with Supported
p-TsOH
sulfonic acid groups (polystyrene vs silica) and loading levels (2.60
mmol/g vs 0.59 mmol/g), but also in their solvent compatibility
profile and price (h1.90/mmol vs h18.80/mmol). To further
challenge these supported reagents (6 and 7) in the preliminary
evaluation of their general applicability and robustness as isocyanide
scavengers, a wider set of highly diverse isocyanides was selected
(Scheme 2). All experiments were performed on a 1.0 mmol scale,
employing a variable excess (1.1-2.5 equivalents) of the immobi-
lized p-toluenesulfonic acid. The reactants were orbitally stirred at
room temperature for variable times (30-90 min) and, depending
on the solvent compatibility of each polymeric matrix, the effect of a
range of solvent mixtures on the reaction outcome was also
investigated [e.g., dichloromethane/methanol (3:1), dimethylfor-
mamide/methanol (2:1), dioxane/methanol (2:1), chloroform/
methanol (3:1), or methanol/water (3:1)].
scavenger efficacy (%)a
starting isocyanide
PS-p-TsOH
Si-p-TsOH
1a
1b
1c
1d
1e
1f
75
91
80
93
69
76
66
73
70
81
60
66
a Calculated on the basis of the amine recovery after treatment with
DIPEA.
It was gratifying to find that room temperature incubation
of representative isocyanides with supported p-TsOH (6 and 7)
for relatively short reaction times (30-60 min) led to the com-
plete disappearance of isocyanides from the starting solutions
(Table 1). The transformation was successful regardless of the
differences in the loading levels and polymeric matrixes present
in the supported reagent. Two equivalents of the supported
p-TsOH led to complete transformation of the reactants under
mild conditions in reasonable reaction times (ca. 30-60 min).
A lower number of equivalents of the scavenger (i.e., less than
1.5 equivalents) was also acceptable, albeit with concomitant
formation (<5%) of the corresponding formamide (5) and the
need for longer scavenging times (e.g., 30-60 min with 2.0 equi-
valents versus 90-120 min with 1.2 equivalents for >95%
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Scheme 3. PS-p-TsOH As an Isocyanide Scavenger in Diverse Organic Reactions
conversion at 25 °C). The effect of the solvent does not appear to be
particularly critical, with most of the systems tested generally well
tolerated, a (3-1) dichloromethane-methanol mixture was em-
ployed during process optimization. As shown in Scheme 2, the
scavenging of structurally diverse isocyanides was efficient and was
not influenced by the steric or electronic variations in the reacting
substrates. Comparison of the results obtained with the two
polymeric matrixes (polystyrene and silica) leads to the conclusion
that polystyrene exhibits a slightly superior reactivity profile and
efficacy (Table 1). In particular, the claimed intrinsic advantages of
silica over polystyrene resins (i.e., no swelling or solvent compat-
ibility issues) were not observed, most probably due to the fact that
the latter can swell sufficiently in the solvents tested. Thus, the
choice of 6 or 7 for extensive preparative applications would be
mainly dependent on the loading levels, price, and the characteristics
of the reaction in question. The use of Si-p-TsOH as scavenger
could be particularly attractive in the context of recent reports on the
acceleration of isocyanide-based multicomponent reactions in
water.22
Experimental evidence supporting the occurrence of a hydro-
lytic process during the use of polymer-supported sulfonic acids
6 and 7 was found (Scheme 2). It can be seen that treatment of
polymeric materials isolated once the scavenging of isocyanides
(1a-f) had finished (8 and 9) with a dichloromethane solution
of DIPEA led to the recovery of the corresponding amines
(10a-f) from the reaction mixture (Table 1). These results
provide further evidence to support a broader applicability for
immobilized p-TsOH (6 and 7) in other facets of isocyanide
chemistry. Thus, the hydrolytic isocyanide quenching strategy
documented here could be attractive not only in the context of
isocyanide scavenging, but also has potential in the implementa-
tion of catch and release23 approaches during the synthesis of
amines from isocyanides.24
of both polymer-supported p-toluenesulfonic acids (6 and 7)
was examined for two model isocyanides (1a and 1c). After
appropriate washing protocols, the recovered sulfonate salts
(8 and 9) were incubated in a 30% solution of trifluoroacetic
acid in dichloromethane and submitted to orbital stirring for
30 min. It was verified that, once appropriately washed and
dried under vacuum, the recovered immobilized p-toluene-
sulfonic acids can be reused at least five times in new scaven-
ging experiments for the same isocyanide without dramatic
yield loss and generating products with purities similar to
those obtained in the first run.
Once the scavenging efficacy and recyclability of supported
p-toluenesulfonic acids had been experimentally validated, a
preliminary screening of the efficiency and robustness of poly-
styrene-immobilized p-toluenesulfonic acid (6) in diverse iso-
cyanide-based reactions was carried out (Schemes 3 and 4). The
main aim of the study was to assess the applicability of PS-
p-TsOH in as diverse a range of organic reactions as possible.
With this aim in mind, a set of transformations that highlight
some of the most representative facets of isocyanides in organic
synthesis was selected (Schemes 3 and 4). The experimental
conditions were the same as those described in the original
papers25-31 and the scavenging process (2 equivalents of PS-
p-TsOH) was integrated once it was verified that the reaction
had finished.
We first focused on the well-documented Passerini and Ugi
reactions (Scheme 3).25,26 It was satisfying to find that the use of
6 led to a marked simplification of the workup and purification
process required to isolate the coupling products (11 or 12). In a
similar way, complete isocyanide scavenging and simplified pro-
cessing was observed during the assembly of fumarates 13.27 An
additional feature of supported p-toluenesulfonic acid during the
implementation of simplified purification strategies for the Ugi
reaction is derived from the electrophilic character of the immo-
bilized reagent.19 This characteristic means that supported p-toluene-
sulfonic acid not only scavenges the unreacted isocyanide (1) but
also immobilizes residual amounts of several of the starting amines.
A set of 4 isocyanide-based transformations enabling the assembly of
A remarkable feature of the isocyanide scavenging approach
reported here concerns the recyclability. Since the optimized
scavenging strategy is based on a highly reliable hydrolytic
process, it was envisaged that it would be possible to regenerate the
supported reagents for reuse in new experiments. The recyclability
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Scheme 4. PS-p-TsOH As an Isocyanide Scavenger in Diverse Organic Reactions
diverse heterocyclic scaffolds was selected to assess the potential of
6 in library production (Scheme 4).28-31 The addition of Ps-
p-TsOH after completion of the reaction ensured complete fixation
of unreacted isocyanides to the polymeric matrix, thus facilating the
isolation of the heterocycle.
In summary, the potential and versatility of supported p-toluene-
sulfonic acid as a highly efficient, selective and environmentally
friendly isocyanide scavenger has been proven. The mild and
simple experimental scavenging protocol is based on a highly
reliable acid-catalyzed methanol-mediated hydrolytic process.
The reversibility of this hydrolytic fixation protocol enables the
simple and straightforward regeneration and reuse of the sup-
ported reagents. The convenience and robustness of the herein
described strategy was demonstrated in a set of highly diverse
isocyanide-based organic transformations.
containing 6 mL of a solution of N,N-diisopropylethylamine (2.0 mmol)
in CH2Cl2. The reaction mixture was submitted to orbital stirring at
room temperature for 2 h. The polymeric material was filtered off and
washed [3 times (10 mL)] with MeOH, AcOEt, and CH2Cl2. The
solvent was removed from the filtrates under vacuum to give an oily
residue containing the amine 10.
Representative Procedure for the Regeneration of the
Polymer-Supported p-Toluenesulfonic Acids (6 and 7). The
corresponding recovered polymer-supported salt (8 or 9) (0.20 g)
was added to a Kimble vial containing 5 mL of a solution of 30% of
trifluoroacetic acid in CH2Cl2. The reaction mixture was submitted
to orbital stirring at room temperature for 2 h. The polymeric
material was filtered off and successively washed [3 times (10 mL)]
with MeOH, AcOEt and CH2Cl2 and dried under vacuum for 12 h
at room temperature. The recovered polymer-supported p-toluene-
sulfonic acid (6 or 7) was employed in either the direct reaction with
isocyanides 1a and 1b or under the general conditions described
herein for the Passerini and Ugi reactions or in reactions that allow
the preparation of compounds 11a and 12a. These experiments
showed that the recycled polymeric material exhibits similar efficacy
as an isocyanide scavenger after 5 runs to afford products with similar
yields and purity.
’ EXPERIMENTAL PROCEDURES
Representative Procedure for the Hydrolytic Quenching
of Isocyanides 1 Employing Supported p-TsOH. To a Kimble
vial containing 2.0 mmol of the polymer supported p-TsOH (PS-p-
TsOH or Si-p-TsOH) in a 3:1 CH2Cl2/MeOH mixture (5 mL) was
added the corresponding isocyanide 1 (1.0 mmol). The reaction mixture
was submitted to orbital stirring at room temperature until the reactions
reached completion (30-60 min). The polymer-supported salt was
filtered off and successively washed [3 times (10 mL)].
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, analytical and spectroscopic data for all compounds
described (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Representative Procedure for Amine Synthesis Employ-
ing PS-p-TsOH under the Catch and Release Sequence. The
recovered polymer-supported salt 8 (0.20 g) was added to a Kimble vial
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’ AUTHOR INFORMATION
(11) Shaabani, A.; Soleimani, E.; Rezayan, A. H. A Novel Approach
for the Synthesis of Aryl Amides. Tetrahedron Lett. 2007, 48, 6137–6141.
(12) Shaabani, A.; Soleimani, E.; Rezayan, A. H. A Novel Approach
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Senses; Random House: New York, 2002; pp 1-318.
Corresponding Author
*To whom correspondence should be addressed. Tel.: þ34-981-
563100, ext. 15221. Fax.: þ34-981-528093. E-mail: eddy.sotelo@
usc.es.
’ ACKNOWLEDGMENT
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Weapon Systems and Methods for Their Use. U.S. Patent 6 352 032.
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Isonitriles. J. Am. Chem. Soc. 2006, 128, 11772–11773. (b) Pirrung,
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(17) (a) El Kaim, L.; Gizzi, M.; Grimaud, L. New MCR-Heck-
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(b) Chang, C. K.; Bag, N. Phenylpyrroles by Suzuki Cross Coupling and
a Synthesis of Type I Tetramethyltetraphenylporphyrin. J. Org. Chem.
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(18) (a) Flynn, D. L., Devraj, R. V., Parlow, J. J. Polymer-Assisted
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Organic Synthesis; Burgess, K., Ed.; John Wiley: New York, 2000; pp
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This work was financially supported by the Spanish and
Galician Governments (Projects PGIDIT06PXIB203299PR
and SAF2009-13609-C04-03). E.S. is the recipient of a Con-
solidation Group Research Grant from the Conselleria de
Educaciꢀon (Xunta de Galicia). E.S. and A.C. are research
fellows of the Isidro Parga Pondal program (Xunta de Galicia,
Spain). J.A. thanks FUNDAYACUCHO (Venezuela) for a
predoctoral grant.
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