Exploiting the divalent nature of isonitriles: A novel Pictet-Spengler amidination process

Article abstract of DOI:10.1016/j.tetlet.2014.04.043

An isocyanide-based multicomponent reaction (IMCR) utilized for the rapid assembly of novel, biologically relevant dihydropyrrolo[1,2-a]quinoxalines- amidines is herein presented. Starting from 1-(2-aminophenyl)pyrroles, aldehydes, and isonitriles, the ta

Full text of DOI:10.1016/j.tetlet.2014.04.043

Accepted Manuscript
Exploiting the Divalent Nature of Isonitriles: a novel Pictet–Spengler Amidi-
nation process
Federico Medda, Christopher Hulme
PII:
S0040-4039(14)00655-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.043
TETL 44505
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 April 2014
10 April 2014
14 April 2014
Please cite this article as: Medda, F., Hulme, C., Exploiting the Divalent Nature of Isonitriles: a novel Pictet–Spengler
Amidination process, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.043
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Graphical Abstract
Exploiting the Divalent Nature of Isonitriles: a novel
Pictet-Spengler Amidination process.
Federico Medda and Christopher Hulme*
Leave this area blank for abstract info.

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Exploiting the Divalent Nature of Isonitriles: a novel Pictet–Spengler Amidination process
Federico Meddaa,b and Christopher Hulmea–c*
aUniversity of Arizona, College of Pharmacy, 1703 E. Mabel St., Tucson, AZ 85721, USA
bBIO5 Oro Valley, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA
cUniversity of Arizona, Department of Chemistry and Biochemistry, Tucson, AZ 85721, USA
*Corresponding Author
Telephone: (520) 626-5322
Fax: (520) 626-0794
hulme@pharmacy.arizona.edu

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Abstract
An isocyanide-based multicomponent reaction (IMCR) utilized for the rapid assembly of novel,
biologically relevant dihydropyrrolo[1,2-a]quinoxalines-amidines is herein presented. Starting
from 1-(2-aminophenyl)pyrroles, aldehydes, and isonitriles, the target heterocyclic scaffold is
assembled in a one-pot, operationally friendly process. With three points of diversity and
formation of three chemical bonds in one step, this strategy proves to be very general. Novel,
mild methodology for the generation of amidines from secondary amine anilines and isonitriles
is also introduced.
Keywords
Isonitrile
Multicomponent reaction
Amidine
Pictet-Spengler

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Multicomponent reactions (MCRs) are powerful transformations where three or more
starting materials react in one pot, forming a final product incorporating all atoms of starting
materials, with the exception of condensation byproducts, (i.e., H2O, MeOH, or HCl).1 The main
advantage of MCRs thus resides in their capacity to generate complex chemotypes from simple
starting materials, via atom-economic and convergent processes, with high bond-forming
efficiency.1 As such, the last two decades have witnessed renewed interest in MCRs as the need
for facile access to libraries of pharmacologically relevant molecules has evolved.1,2
Within the MCR arena, isocyanide-based MCRs (IMCRs) are particularly attractive, due in
large part to the chemical versatility of the isocyanide functional group, which is capable of
behaving as both a nucleophile and, when converted into a nitrilium ion, as an electrophile. As
such, isocyanides are divalent in nature, a property that can be exploited to give rise to a wide
range of molecular scaffolds.1–3 Traditionally involved in the generation of novel biologically
appealing chemotypes via post-condensation modifications of IMCRs,4 we recently turned our
attention toward study of the Pictet–Spengler reaction, discovered in 1911, and classically
defined as the condensation of a β-arylethylamine with a carbonyl compound in the presence of a
protic or Lewis acid that gives rise to a substituted tetrahydroisoquinoline.5 Subsequently, the
scope and utility of this transformation was improved through the employment of novel aryl-
amines linked to electron-rich aromatic heterocycles,6 resulting in the synthesis of natural
products and small molecules of biological interest.7
We were specifically drawn to the possibility of disrupting the Pictet–Spengler reaction of
1-(2-aminophenyl)pyrroles 1, aldehydes 2, and isonitriles 3 through enticing the pyrrole moiety
to trap the intermediate nitrilium ion 4, to afford heterocycles of structure 5. However, studies

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showed the predominant pathway proceeded through the Pictet–Spengler reaction via 6, which
intriguingly was highly susceptible to reaction with protonated isonitriles 7, affording products
of generic structure 8 in a single step. Enticingly, these new products contained three points of
diversity, being derived from a novel, albeit unplanned, MCR containing an unexpected amidine
functional group (8, Scheme 1). Interestingly, reactions of isonitriles with carboxylic acids have
been recently reported by Danishefsky and others under mild conditions.8 However, reactions of
isonitriles with amines affording amidines are known to proceed only via relatively harsh metal
catalysis,9 and only one report from 196210 details a hydrochloric acid–mediated transformation
of secondary anilinic amines with isonitriles to amidines which was not exemplified in any great
detail. To the best of our knowledge, para-toluene sulfonic acid–promoted amidine formation of
the intermediate aniline 6 represents a far milder example of this significantly under-utilized
functional group transformation. Initial optimization of the IMCR focused on the one-pot
reaction between amine 1a, aldehyde 2a, and isonitrile 3a (Table 1) utilizing toluene as a solvent
and para-toluenesulfonic acid as a catalyst, which resulted in acceptable yields of 8a, as judged
by LC/MS (entries 1–4). Conversely, use of protic solvents saw yields drop significantly (entries
5–6). A similar outcome was also seen using stronger acidic catalysis, including previously
reported HCl10 (entries 7–10), probably due to heightened instability of the isonitrile 3a in these
media, which is prone to formamide formation if adventitious water is present. Indeed, the latter

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transformation is an excellent way of destroying low molecular weight pungent isonitriles during
reaction work-up, again exploiting the inherent “divalent nature” of the isonitrile functional
group.
Upon silica-based purification of 8a, pure product was recovered in only 10% yield (entry
2), suggesting a somewhat surprising instability on prolonged exposure to silica. Encouragingly,
reverse-phase (C18) column chromatography enabled a satisfactory increase in yield (8a, 62%),
and definitive structural confirmation was obtained with a small-molecule X-ray crystal structure
(8a, Figure 1).
Isolated yields were further improved via microwave irradiation in DCE (Table 1), coupled
with shorter reaction times (entries 11 and 12). Evaluation of various acid catalysts under these

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improved conditions (entries 13–17) showed none to be as effective as para-toluene sulfonic
acid. Scheme 2 depicts a proposed mechanism where amine 1 and aldehyde 2 react to generate
the expected Pictet–Spengler product 6 via iminium species 9. Evidence for the intermediary
formation of 6 was observed through LC/MS monitoring, and reaction with the protonated
isonitrile 7 affords the final exocyclic amidine moiety 8.
To the best of our knowledge, this is the first example of a Pictet–Spengler reaction
embedded in a one-pot IMCR process that is capable of forming three new chemical bonds in
one operation with the generation of an exocyclic amidine moiety. These novel scaffolds are
likely to possess a range of biological activities.11
With an optimized procedure in hand, reaction scope was explored and twelve analogs (8a–
l, Figure 2) prepared using three amines (1a–c), seven aldehydes (2a–g), and seven isonitriles
(3a–g) as reagents [Note: only three 1-(2-aminophenyl)pyrroles were found to be commercially
available]. To our delight, the one pot procedure proved to be general, tolerating the full range of
starting materials in high yield (39%–87%). As noted, the Pictet–Spengler intermediate was
observed during reaction monitoring, and therefore two Pictet–Spengler intermediates, 6a and
6b, were isolated and treated with an isonitrile in the presence of para-toluene sulfonic acid at

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elevated temperatures in toluene. Final products 8a–b were obtained in 52% and 61% isolated
yields respectively (Scheme 3). Moreover, in a preliminary scope study of the amidination
process, the indoline 10a and 1,2,3,4-tetrahydroquinoline 10b both afforded amidine products
11a–b in moderate to good yields (Scheme 4). However, non-anilinic amines (piperidine and
pyrrolidine) failed to produce the desired amidine, presumably due to their inherent higher pKa
values leading to competitive amine protonation and deactivation.
In summary, we have herein reported a novel, one-pot IMCR that enables the assembly of
biologically relevant amidine-containing dihydropyrrolo[1,2-a]quinoxalines and additionally
shown new utility and method improvement of a rarely used amidination reaction of anilines and

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isonitriles. Due to the facile and practical production protocol of the IMCR, it is envisioned that
access to larger libraries of diverse analogs will be feasible for further biological annotation.
Acknowledgments. Financial support from the National Institutes of Health (Grant
P41GM086190) is gratefully acknowledged. Dr. Sue A. Roberts and Mr. Gabriel B. Hall are
thanked for small molecule crystal structure determination.

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Table 1. Optimization of the One-pot Model Reaction.a
entry
1
solvent
toluene
toluene
toluene
toluene
MeOH
MeOH
AcOH
AcOH
AcOH
AcOH
DCE
acid (eq.)
TsOH (0.2)
TsOH (0.4)
TsOH (0.2)
TsOH (0.4)
TsOH (0.4)
TsOH (0.4)
cHClc
conditions
rt, 18 h
rt. 18 h
conversionb
56
70
63
45
24
–
2
3
reflux, 18 h
reflux, 18 h
4
5
rt, 18 h
reflux, 18 h
6
7
rt, 18 h
rt, 18 h
21
35
–
8
–
9
cHClc
reflux, 18 h
reflux, 18 h
10
11
12
13
14
15
16
17
–
–
TsOH (0.4)
TsOH (0.4)
CF3CH2OHd
AcOH (0.4)
cHCl (0.4)
TFA (0.4
HClO4 (0.4)
MW, 120 °C, 30'
MW, 120 °C, 60'
MW, 120 °C , 30'
MW, 120 °C , 30'
MW, 120 °C, 30'
MW, 120 °C , 30'
MW, 120 °C, 30'
97
87
65
27
53
46
29
DCE
DCE
DCE
DCE
DCE
DCE
aStarting materials used in a 1:1:1 molar ratio; bConversion is expressed
as % and was judged by means of LCMS analysis (see supplementary
information); cOne drop of 12N HCl used; dDCE:CF3CH2OH (2:1).

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Legends
Figure 1. Crystal structure of compound 8a.
Figure 2. Structures of congeners 8a–l.
Scheme 1. Synthesis of N-((4-methylpyrrolo[1,2-a]quinoxalin-5(4H)-
yl)methylene)methanamines 8 via a Pictet–Spengler amidination sequence.
Scheme 2. Proposed mechanism for the formation of 8.
Scheme 3. Two-step preparation of dihydropyrrolo quinoxaline amidines 8a–b.
Scheme 4. Reaction of isonitrile 3a and indolines 10a–b to afford corresponding amidines 11a–
b.

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Figure 1
Figure 2

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Scheme 1
Scheme 2
Scheme 3
Scheme 4