Trityl Isocyanide as a Mechanistic Probe in Multicomponent Chemistry: Walking the Line between Ugi- and Strecker-type Reactions

Article abstract of DOI:10.1002/chem.201600285

Herein, we describe the versatile application of triphenylmethyl (trityl) isocyanide in multicomponent chemistry. This reagent can be employed as a cyanide source in the Strecker reaction and as convertible isocyanide in the preparation of N-acyl amino acids by Ugi 4CR/detritylation and free imidazo[1,2-a]pyridin-3-amines by a Groebke-Blackburn-Bienaymé 3CR condensation/deprotection protocol. The mechanisms of these three classical MCRs intersect at the common N-trityl nitrilium ion intermediate, whose predictable reactivity can be exploited towards chemoselective transformations. Fate of the nitrilium ion: The application of trityl isocyanide as a mechanistic tool to dissect different reaction pathways in multicomponent chemistry is described. This reagent can be employed as a cyanide source in the Strecker reaction and as a convertible isocyanide in the preparation of N-acyl amino acids by Ugi 4CR/detritylation and free imidazo[1,2-a]pyridin-3-amines by Groebke-Blackburn-Bienaymé 3CR condensation/deprotection. Chemoselective transformations were achieved by the rational choice of reaction conditions.

Full text of DOI:10.1002/chem.201600285

DOI: 10.1002/chem.201600285
Full Paper
&
Multicomponent Reactions
Trityl Isocyanide as a Mechanistic Probe in Multicomponent
Chemistry: Walking the Line between Ugi- and Strecker-type
Reactions
˘
Razvan C. Cioc, Hans D. Preschel, Gydo van der Heijden, Eelco Ruijter, and
Romano V. A. Orru*[a]
Abstract: Herein, we describe the versatile application of tri-
phenylmethyl (trityl) isocyanide in multicomponent chemis-
try. This reagent can be employed as a cyanide source in the
Strecker reaction and as convertible isocyanide in the prepa-
ration of N-acyl amino acids by Ugi 4CR/detritylation and
burn–BienaymØ 3CR condensation/deprotection protocol.
The mechanisms of these three classical MCRs intersect at
the common N-trityl nitrilium ion intermediate, whose pre-
dictable reactivity can be exploited towards chemoselective
transformations.
free imidazo[1,2-a]pyridin-3-amines by
a Groebke–Black-
Introduction
Multicomponent reactions (MCRs), reactions in which three or
more reagents are combined to selectively form a product that
contains atoms from each of the starting inputs, represent an
important tool in modern organic synthesis.[1] Although multi-
component chemistry dates back to the early days of organic
chemistry, it is in continuous evolution and the improvement
of existing MCRs and the development of novel reactions
remain active fields of research.[2] Among all the classes of
MCRs, isocyanide-based reactions (IMCRs) occupy a central po-
sition because of their remarkable diversity and high potential
for application. This chemistry has flourished on the unique
ability of isocyanides, reagents with a formally divalent carbon
atom, to engage in multibond formation processes with both
nucleophilic and electrophilic reaction partners.
Figure 1. Reaction pathways of the nitrilium ion.
Mechanistically, numerous variants of IMCRs (e.g., Ugi 4CR,
Ugi-azide 4CR, Groebke–Blackburn–BienaymØ 3CR, etc.) are
centered around the addition of an isocyanide to an iminium
species and subsequent trapping of the resulting nitrilium ion
intermediate by various nucleophiles, both intra- and intermo-
lecularly (Figure 1).[3] In the classical Ugi 4CR,[4] a carboxylate
anion adds to the nitrilium intermediate and this a-adduct re-
arranges to give the more stable dipeptidic structure; the
Groebke–Blackburn–BienaymØ (GBB)[5] reaction is a version of
the Ugi reaction with an amidine/pyridinamine component in
which the internal nitrogen nucleophile captures the nitrilium
ion to yield the imidazo[1,2-a]pyridine heterocyclic system
after deprotonation/tautomerization. It is interesting to note
that Ugi-type chemistry is closely related to the very first multi-
component reaction: the Strecker synthesis, which combines
amines, aldehydes, and HCN to give a-amino nitriles.[6] In fact,
Ugi reactions can be regarded as higher-homologue Strecker
processes that involve N-substituted cyanide addition to imini-
um species; initially, N-substituted Strecker products are gener-
ated from this interaction, and these positively charged reac-
tive intermediates evolve towards more stable structures by
nucleophilic addition.
[a] R. C. Cioc, H. D. Preschel, G. van der Heijden, Dr. E. Ruijter,
Prof. Dr. R. V. A. Orru
Department of Chemistry & Pharmaceutical Sciences
and Amsterdam Institute for Molecules Medicines and Systems (AIMMS)
Vrije Universiteit Amsterdam
De Boelelaan 1108, 1081 HZ Amsterdam (The Netherlands)
E-mail: r.v.a.orru@vu.nl
With this perspective in mind, we wondered whether we
could unify the Ugi and Strecker reactions by exploiting a disre-
garded reaction pathway of the classical nitrilium ion inter-
mediate in Ugi-type additions: fragmentation through the
<C=>N+ÀR heterolytic bond cleavage in an a-amino nitrile
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600285.
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and a carbocationic species. The prerequisites for this atypical
reactivity would be a labile NÀR bond and a relatively stable
R+ fragment. We hypothesized that the triphenylmethyl (trityl)
substituent would comply with these requirements and decid-
ed to explore the various reaction pathways of the N-triphenyl-
methyl nitrilium ion resulting from the reaction of trityl isocya-
nide (TrNC) with imines.
Table 1. Scope of the Strecker reaction with trityl isocyanide.
Results and Discussion
Reports that describe trityl isocyanide and its use in organic
synthesis are scarce[7] and to the best of our knowledge there
are no applications of this reagent in multicomponent chemis-
try. Remarkably, trityl isocyanide exhibits distinct favorable
physical properties (high stability, crystallinity, and absence of
unpleasant odor), which combined with straightforward op-
tions for follow-up chemistry, recommend it as a convenient
reagent for synthesis.
While performing the Ugi condensation between trityl isocy-
anide, imine 1, and acetic acid under typical reaction condi-
tions (EtOH/CH2Cl2, RT),[8] we were pleased to observe the for-
mation of the Strecker product of this imine in roughly the
same amount as the Ugi product, together with the corre-
sponding amount of trityl ethyl ether (Scheme 1). This initial
[a] Standard conditions: aldehyde (1 equiv) and amine (1 equiv) in CH2Cl2
with 3 Š MS for 20 h, then (diluted in EtOH) p-TsOH·H2O (10 mol%) and
TrNC (1.1 equiv) for 3–24 h at room temperature. [b] Yields of isolated
products. [c] Yield based on NMR analysis of crude reaction mixture.
[d] Reaction performed at 508C. [e] Yield of isolated product; product not
stable on silica column.
Scheme 1. Selectivity of trityl isocyanide addition to imine 1.
result confirmed the viability of the nitrilium ion fragmentation
pathway in the case of N-trityl substitution. Next, we pursued
complete chemoselectivity control by tuning the reaction con-
ditions. With the more acidic trifluoroacetic acid leading to
a slight preference for the a-amino nitrile (66% selectivity),[9]
we reasoned that a non-nucleophilic counterion for the imini-
um ion would provide the Strecker product exclusively. Indeed,
the a-amino nitrile was the predominant product when strong
acids (e.g., p-toluenesulfonic acid, p-TsOH) were used to acti-
vate the imine, with only traces of the Ugi 3CR product (which
resulted from capture of the nitrilium ion by water) being ob-
served as a side product.[10] Importantly, the acid can be used
in catalytic amounts (10 mol%), as the a-cyano substitution
significantly reduces the basicity of the N-aryl amine product
compared with that of the starting imine.
niline gave a complex reaction mixture (entry 2h); however,
with 2-amino-6-chloropyridine, the imine appeared to be more
stable and the Strecker product 2l was isolated in good yield.
Notably, the a-amino nitrile of 2-nitrobenzaldehyde cyclodehy-
drated to give the indazole N-oxide 2c, as previously report-
ed.[12] The amine scope included both electron-rich and elec-
tron-poor anilines. In the latter case, the reaction was slow
since the addition of ethanol to the imine was a competing
process; heating was found to be beneficial for conversion.[13]
The use of an aliphatic amine (benzylamine) was also tested,
but the Strecker product 2n was more basic and the catalyst
turnover was reduced. The bulky aniline, mesidine, and secon-
dary amine, pyrrolidine, gave poor conversions to the expected
products 2m and o, respectively.
To our delight, this reactivity could be extended to a diverse
set of inputs, and good yields were obtained for a series of
Strecker products (Table 1).[11] Substituted (hetero)aromatic al-
dehydes, aliphatic aldehydes (including bulky pivalaldehyde),
and even ketones were accepted as carbonyl components in
the reaction. Enolizable aldehydes were found to be problem-
atic, as the reaction between isobutyraldehyde and 4-bromoa-
The results shown in Scheme 1 and Table 1 formed the basis
for mechanistic considerations of this reaction. The Ugi-type
mechanism implies the formation of the Strecker product and
the trityl ethyl ether byproduct in equimolar amounts
(Scheme 2). In some cases (with less basic amine substrates),
we observed a complete (including the 10 mol% excess) con-
version of trityl isocyanide to this byproduct. Control experi-
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Table 2. Scope of the Ugi 4CR/deprotection.
Ugi product[a] Yield[b]
Deprotection product[c] Yield[b] [%] (4:5)[d]
90% (100:0); 70%[e]
61% (65:35)
52% (55:45)
89% (0:100)
Scheme 2. Mechanism of the Strecker reaction with trityl isocyanide.
ments indicated that acid-catalyzed solvolysis of the isocyanide
to trityl ethyl ether and HCN through an SN1 process is possi-
ble, but strongly depends on the pKa of the acid. We showed
that the protonated a-amino nitrile, which accumulates as the
reaction reaches completion, is indeed sometimes sufficiently
acidic to induce isocyanide decomposition (mechanism shown
in the bottom section of Scheme 2). As the reaction rate corre-
lates with electrophilicity of the iminium ion rather than acid
strength, we reason that it is mostly the nitrilium ion fragmen-
tation mechanism that accounts for the reaction outcome. The
existence of this key intermediate is additionally supported by
side products that arise from its trapping by nucleophiles
(water). The slow release of HCN by isocyanide solvolysis is
a minor reaction pathway, which is relevant only at high con-
version with relatively non-basic imines. The complete mecha-
nistic network is shown in Scheme 2.[14]
[a] Standard conditions: aldehyde (1 equiv) and amine (1 equiv) in CH2Cl2
with 3 Š MS for 20 h, then carboxylic acid (1 equiv) and TrNC (1.1 equiv)
for 3 days at room temperature. [b] Yields of isolated products (for depro-
tection, yield of major product). [c] Standard conditions: Ugi product in
TFA with H2O (5 equiv) for 4 h at room temperature. [d] Ratio based on
NMR analysis of crude reaction mixture. [e] Yield of ethyl ester upon
quenching the detritylation reaction with ethanol.
nitrilium ion fragmentation products were not observed by
NMR analysis of the crude product, although this side reaction
cannot be excluded for the low-yielding examples with aniline
substrates (products 3b and c). This is in accordance with the
nucleophilicity of the carboxylate anions, which are able to
trap the nitrilium ion before fragmentation.[17] Notably, the
yield of the bicyclic product 3d was higher than the analogous
product resulting from the more nucleophilic tBuNC (90 vs.
77%); in this case, the greater steric bulk of this isocyanide
was also reflected in a better d.r. (33:1 vs. 13:1 for TrNC and
tBuNC, respectively).[18]
Numerous variations of the Strecker reaction have been re-
ported, but all procedures invariably rely on toxic reagents
(KCN, CuCN, Zn(CN)2, TMSCN, etc.).[15] Trityl isocyanide is a con-
venient and safe cyanide surrogate, and the possibility of re-
covering and recycle trityl ethyl ether in the isocyanide synthe-
sis[16] makes it an attractive, novel cyanation reagent in Strecker
reactions.
After identifying reaction conditions to bias the fragmenta-
tion pathway of the nitrilium ion, we turned our attention to
the classical Ugi 4CR. Pleasingly, by resorting to a less polar sol-
vent (CH2Cl2), we were able to switch the selectivity in favor of
the Ugi products (stoichiometric carboxylic acids were used in-
stead of catalytic p-TsOH), and acceptable yields were obtained
with all possible combinations of aliphatic/aromatic substrates
(Table 2). The moderate yields were due to slow reactions; the
While studying the cleavage of the trityl group under acidic
conditions, we observed the surprisingly facile hydrolysis of
the initially formed primary amide to give the carboxylic acid,
and we decided to pursue this more interesting transforma-
tion. Stirring the Ugi products at room temperature in TFA for
4 h with the addition of water (5 equiv) was sufficient for com-
plete conversion, whereas the ratios of carboxylic acid/primary
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tion to the GBB products is favored (in most cases exclusively)
for all tested substrates, with the anticipated exception of 6-
substituted pyridines (Table 1, product 2l; Table 3, entry 6). Sig-
nificant fragmentation of the nitrilium ion (GBB product/Streck-
er product ratio=5:1) was also observed for the electron-defi-
cient 5-fluoro-2-aminopyridine. These results are in complete
accordance with the propensity of the pyridine to engage in
nucleophilic addition, which is influenced by both electronics
and sterics.[23] As expected, the detritylation of the GBB prod-
ucts was facile (3 equiv of TFA, 3–24 h at 658C)[24] and good
overall yields were obtained for the preparation of imidazo[1,2-
a]pyridin-3-amines (Table 3).[25] The exception was the use of
anisaldehyde (entry 2; the reduced electrophilicity makes imine
formation and isocyanide addition difficult) and pyrimidina-
mine (entry 5; the imine forms a stable N,O-acetal with etha-
nol)[13] as substrates.
Scheme 3. Mechanism of detritylation of Ugi products via the Münchnone
intermediate.
amide in the series accurately follow the ease of formation of
a Münchnone intermediate (Scheme 3):[19] the less electron-
dense tertiary amide groups (e.g., R2 =Ar, 3b and c) are less
able to assist the hydrolysis of the primary amide, whereas the
conformationally restricted bicyclic scaffold prevents this trans-
formation altogether.
Table 3. Scope of the GBB 3CR/deprotection sequence.
Diluting the reaction mixture with ethanol before quenching
allows for the isolation of the ethyl ester (shown for carboxylic
acid 4a, Table 2). This demonstrates the convenience and ver-
satility of trityl isocyanide as a convertible reagent in the Ugi
4CR to afford carboxylic acid derivatives by detritylation.[20]
Having established trityl isocyanide as a useful convertible
reagent in Ugi condensations, we envisaged the extension of
its application towards the synthesis of imidazo[1,2-a]pyridin-3-
amines by a GBB/deprotection strategy. The imidazo[1,2-a]pyri-
dine core is a widely employed scaffold in medicinal applica-
tions,[21] and the GBB reaction, which combines amidines, alde-
hydes, and isocyanides, is undoubtedly the most straightfor-
ward way to access it, particularly in a combinatorial chemistry
context. The 3-amino substituent serves as an ideal handle for
further derivatization, and for this reason, several convertible
isocyanides have been developed to allow the isolation of free
imidazo[1,2-a]pyridin-3-amine derivatives by the deprotection
of GBB products.[22] However, these methods generally employ
harsh conditions, expensive and/or hazardous reagents, and
are not compatible with library synthesis. For instance, 1,1,3,3-
tetramethylbutyl isocyanide (Walborsky’s isocyanide) leads to
a GBB product that can be deprotected under relatively mild
acidic conditions, but it is expensive and cannot be regenerat-
ed after the MCR/deprotection sequence.[22a]
Entry
1
Main product, 6 or 2[a]
Yield[b]
65%
6:2[c]
>20:1
2
3
ꢀ20%
n.d.
71%
>20:1
4
5
6
63%
ꢀ10%
50%
>20:1
n.d.
<1:20
7
8
9
75%
56%
68%
>20:1
5:1
We reasoned that trityl isocyanide would be a superior alter-
native in all aspects: cost, ease of deprotection, and recyclabili-
ty. The success of this strategy relies on the fate of the nitrilium
ion intermediate, which should undergo intramolecular trap-
ping by the pyridine nitrogen rather than fragmentation. As
the Strecker reaction of 6-chloro-2-aminopyridine with trityl
isocyanide exclusively provided the a-amino nitrile over the
imidazo[1,2-a]pyridine (Table 1, product 2l), we anticipated
that the nucleophilicity of the pyridine would be the determin-
ing factor in the GBB MCR with this isocyanide. Application of
the optimized Strecker protocol to a series of 2-aminopyridines
and aromatic and aliphatic aldehydes showed that the cycliza-
>20:1
[a] Standard conditions: preformed imine (1 equiv), p-TsOH·H2O
(10 mol%), and TrNC (1.1 equiv) in CH2Cl2 and EtOH (1:1) for 2 days at
room temperature, then TFA (3 equiv) for 3–24 h at 658C. [b] Overall
yields of isolated products. [c] Ratio based on NMR analysis of crude reac-
tion mixture before deprotection of the GBB products.
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Finally, after investigating the selectivity of Strecker versus
Ugi and GBB versus Strecker reactions involving trityl isocya-
nide, we were curious to see which product would predomi-
nate in a system in which all three pathways are possible. Ac-
cordingly, we performed the Ugi 4CR with 5-fluoro-2-aminopyr-
idine, pivalaldehyde, acetic acid, and trityl isocyanide under
our standard conditions. Interestingly, this reaction was fully
selective towards the GBB product with no evidence of the
Strecker and Ugi products on the basis of NMR analysis of the
crude product. Not surprisingly, the addition of an external nu-
cleophile (acetate) could not compete with the intramolecular
trapping of the nitrilium ion by the pyridine nitrogen, even
though it is relatively electron deficient. Furthermore, the mild
activation of the imine by a carboxylic acid instead of a strong
Brønsted acid (possibly through hydrogen bonding rather than
protonation) completely suppressed the nitrilium ion fragmen-
tation towards the Strecker product (Scheme 4).
Experimental Section
General procedure for the Strecker reaction
An amine (0.5 mmol, 1 equiv) and an aldehyde (0.5 mmol, 1 equiv)
were dissolved in CH2Cl2 (0.5 mL). 3 Š powdered molecular sieves
(250 mg) were added and the mixture was stirred at room temper-
ature for 20 h. Then, the mixture was diluted with EtOH (0.5 mL).
p-Toluenesulfonic acid hydrate (0.05 mmol, 0.1 equiv) was added
and the mixture was stirred for 10 min before adding trityl isocya-
nide (0.55 mmol, 1.1 equiv). The mixture was then stirred for 1–
24 h at room temperature. The reaction was quenched with NEt3
(0.5 mmol, 1 equiv). The molecular sieves were removed by filtra-
tion over Celite, the filter was thoroughly washed with CH2Cl2, and
the solution was concentrated under reduced pressure. The prod-
uct was purified by chromatography on a silica gel column.
Acknowledgements
We thank Marco Rentsch (Waters) for UPC2-MS analysis, Elwin
Janssen for technical assistance, Sanne Bouwman for HRMS
measurements, and Dr. Andreas W. Ehlers for NMR mainte-
nance. The research leading to these results has received fund-
ing from the Innovative Medicines Initiative Joint Undertaking
project CHEM21 under grant agreement n8115360, resources
of which are composed of financial contribution from the Euro-
pean Union’s Seventh Framework Programme (FP7/2007-2013)
and EFPIA companies’ in kind contribution.
Keywords: chemoselectivity · isocyanides · multicomponent
reactions · nitrilium ion · reactive intermediates
Scheme 4. Fate of the nitrilium ion intermediate in an Ugi 4CR with trityl iso-
cyanide, pivalaldehyde, acetic acid, and 5-fluoro-2-aminopyridine.
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dehydration method.[26] In our hands, POCl3-mediated dehydra-
tion worked best to give an 88% yield of the trityl isocyanide
on a 10 g scale. In contrast with most other convertible isocya-
nides,[27] our reagent can be regenerated in two simple steps,
as both triphenylmethanol and trityl ethyl ether can be recov-
ered[28] after the MCR/deprotection sequence and converted
back to N-trityl formamide. Overall, the C and N atoms that are
delivered from the isocyanide to the MCR products originate
from H2NCHO.
Conclusion
Trityl isocyanide is a convenient, versatile reagent in MCR
chemistry. It can be employed as a benign cyanide source in
a formally cyanide-free Strecker synthesis and as a recyclable
convertible isocyanide in the efficient preparation of N-acyl
amino acids by Ugi 4CR/detritylation and free imidazo[1,2-
a]pyridin-3-amines by GBB 3CR/deprotection under mild condi-
tions. The mechanisms of these three classical MCRs intersect
at the common N-trityl nitrilium ion intermediate, whose pre-
dictable reactivity can be exploited towards chemoselective
transformations. The development of other (multicomponent)
reactions with trityl isocyanide is currently ongoing in our lab-
oratories.
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[9] As we observed that acetic acid does not protonate this imine under
these conditions, it is possible that the mechanism is not entirely iden-
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[11] Imine preformation was found to be important for high yields; uncon-
verted amine buffers the reaction medium and reduces imine activation
by the acid catalyst; furthermore, nucleophilic amines compete with
ethanol for the trityl cation; molecular sieves are required to trap the
water that is released from the condensation and prevent the formation
of the Ugi 3CR contaminant.
[12] This most likely occurs during reaction workup, see: A. Gerpe, G.
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[14] See the Supporting Information for detailed information.
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[23] It seems that steric factors are more important than electronic factors
for the cyclization to the imidazopyridine. Lower yields for the use of 6-
substituted 2-aminopyridines in the GBB reaction have also been re-
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[24] The t-octyl substituted analogue gave no conversion under these con-
ditions.
[25] The true one-pot procedure is possible, but for convenience, the mo-
lecular sieves were filtered off in between the two stages.
[16] The main disadvantage of this approach is the low atom economy;
however, recovery of trityl ethyl ether and its conversion back to the
isocyanide greatly improves the overall atom economy of the process,
see also ref. [28].
[17] This can also imply a different mechanism that bypasses the nitrilium
ion intermediate; the mechanism of the Ugi reaction was calculated to
circumvent charged intermediates in toluene: a) N. ChØron, R. Ramozzi,
L. El Ka¨ım, L. Grimaud, P. Fleurat-Lessard, J. Org. Chem. 2012, 77, 1361–
1366; we wish to point out that there is no consensus on the general
Ugi reaction mechanism, and most likely, several mechanisms operate
depending on conditions and substrates, see also ref. [3] and: b) G. A.
Medeiros, W. A. da Silva, G. A. Bataglion, D. A. C. Ferreira, H. C. B. de Oli-
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[27] For a survey of convertible isocyanides, see O. Kreye, C. Trefzger, A. Seh-
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[28] Trityl ethyl ether was recovered after the Strecker reaction (2g) and the
GBB/deprotection protocol (6i) in 85 and 83% yields, respectively. After
detritylation of Ugi product 3d, triphenylmethanol was recovered in
90% yield.
Received: January 21, 2016
Published online on April 26, 2016
Chem. Eur. J. 2016, 22, 7837 – 7842
www.chemeurj.org
7842
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