Leuckart-Wallach Route Toward Isocyanides and Some Applications

Article abstract of DOI:10.1021/acscombsci.5b00066

Isocyanide-based multicomponent reactions (IMCR) are among the most important chemical reactions to efficiently generate molecular diversity and have found widespread use in industry and academia. Generally, isocyanides are synthesized in 1-2 steps starting from primary amines. Here, we provide experimental detail on an alternative approach toward formamides and, thus, isocyanides via the Leuckart-Wallach reaction in an improved variation. The resulting >50 synthesized and characterized formamides are useful starting materials for IMCR, as well as other chemistries. The advantage of using the Leuckart-Wallach pathway to formamides and isocyanides is the lower price, on average, of the starting materials, as well as their differential and complementary structural diversity, as compared to the primary amine pathway.

Full text of DOI:10.1021/acscombsci.5b00066

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The LeuckartꢀWallach Route Towards Isocyanides
and Some Applications
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Constantinos G. Neochoritis,† Tryfon ZarganesꢀTzitzikas,† Silvia Stotani,† Adrian Dömling,‡
Eberhardt Herdtweck,§ Kareem Khoury,‡ Alexander Dömling†*
† Department of Drug Design, University of Groningen, A. Deusinglaan 1, Groningen 9700AV,
The Netherlands
‡ Carmolex Inc., Pittsburgh, USA
§ Institut für Anorganische Chemie, Technische Universität München, Germany
KEYWORDS. LeuckartꢀWallach, formamides, isocyanides, IMCR, Ugi
ABSTRACT. Isocyanideꢀbased multicomponent reactions (IMCR) are amongst the most
important chemical reactions to efficiently generate molecular diversity and have found
widespread use in industry and academia. Generally, isocyanides are synthesized in 1ꢀ2 steps
starting from primary amines. Here we provide experimental detail on an alternative approach
towards formamides and thus isocyanides via the LeuckartꢀWallach reaction in an improved
variation. The resulting >50 synthesized and characterized formamides are useful starting
materials for IMCR as well as other chemistries. The advantage of using the LeuckartꢀWallach
pathway to formamides and isocyanides is the lower price, on average, of the starting materials
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as well as their differential and complementary structural diversity as compared to the primary
amine pathway.
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INTRODUCTION
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Atom economy, efficiency, diversity and complexity: Four terms that multiꢀcomponent reactions
(MCRs) fulfill and represent more than any other type of reactions.1–4 Recently, MCR has
reached a “golden era” as an increasing number of researchers understand the deeper principles
and applications behind this chemistry. The scaffold diversity of MCRs and the window in
chemical space has been undoubtedly recognized by the synthetic community in industry and
academia as a preferred method to design and discover pharmaceutically active compounds.5
Isocyanide based multiꢀcomponent reactions (IMCRs) belong to the most important reactions of
their kind giving easy access to biologically relevant compounds and libraries. Ugi and Passerini
reactions are the most famous IMCRs with extended application in drug discovery.6 It is
unquestionable that IMCRs are based on the isocyanide moiety and therefore preparative
isocyanide synthesis is extremely important. The majority of isocyanide syntheses use the
classical 2ꢀstep sequence described by Ugi: primary amine ꢀ formamide ꢀ isocyanide.7 The
Hoffman procedure of carbeneꢀmediated isocyanide formation directly from primary amines is
also popular since the introduction of phase transfer catalysis (Scheme 1).8
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Scheme 1. The LeuckartꢀWallach route to isocyanides.
Formamides are at a unique position in the IMCRs, since they are by far the most important
precursors for isocyanides. Herein, we want to give experimental details and exemplify a new
route towards isocyanides through formamides based on the LeuckartꢀWallach procedure. Thus,
we employ a wide variety of oxo components into the isocyanide synthesis through their
reductive amination with formamide and formic acid (Scheme 2). Moreover, we provide further
synthetic applications, including an expansion of our recently introduced in situ isocyanide
method,9 trying to give a wellꢀrounded aspect of this novel pathway.
RESULTS AND DISCUSSION
Demonstrating the effectiveness and applicability of our method, we synthesized 55 different
formamides from their corresponding carbonyl compounds. The oxo components were carefully
chosen to include various aliphatic and aromatic aldehydes with different substituents, both
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EWG and EDG, and heterocycles (chemset 1). Moreover, ketones with aromatic, aliphatic and
heterocyclic substituents were employed (chemset 2).
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Scheme 2. The LeuckartꢀWallach reaction using formamide and formic acid as the reductive
agent from the corresponding oxo component.
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Scheme 3. The Chemset 1 consisting of aldehydes.
Scheme 4. The Chemset 2 consisting of ketones.
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The formamides (chemsets 3,4) were prepared either in parallel, using suitable metal block
heaters (SI movie, photos in supporting information) or under microwave irradiation (Table 1). A
typical experimental procedure by conventional heating involves the addition of the
corresponding oxo component (1 equiv.) in a solution of formamide (12 equiv.) with formic acid
(5 equiv.) and refluxing at 160ꢀ180 oC for 1ꢀ2 h. In the case of microwave irradiation the reaction
time is drastically shortened as the reaction is completed, in most of the substrates, in 3 minutes.
Carbon dioxide emission was observed during the procedure which ceased upon completion and
after an aqueous workup the desired formamide is isolated with no further purification in many
of the cases. The reaction is scalable (Table 1, substrates were indicated in 20 mmol scale) (by
conventional heating) with good to excellent yields and has been performed on a 50 g scale, to
produce 3{28} and 3{31}. The method is applicable to both aromatic and aliphatic derivatives
whereas many functional groups (like hydroxyl, nitro, ester groups, ether bonds and
heterocycles) are compatible with the reaction conditions allowing for further modifications or
transformations. The formation of the formamides from the tetralones (2{3}, 2{4}, 2{7}, 2{8})
and various heterocycles are particularly noteworthy given their great biological importance.10–14
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Table 1. Formamides synthesized (Chemsets 3,4) via LeuckartꢀWallach reactions either by
conventional heating or microwave irradiation.
Chemsets 3,4
Yield
(%)
Chemsets 3,4
Yield
(%)
Chemsets 3,4
Yield
(%)
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73
44
3{3}
3{2}
3{1}
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87 (85)b
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53 (75) b
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3{4}
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3{5}
3{8}
3{6}
3{9}
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3{7}
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82
43 (80) b
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3{10}
3{11}
3{14}
3{12}
3{15}
3{13}
3{16}
3{17}
3{20}
3{18}
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59
48 (95) b
3{19}
3{21}
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52 (91) b
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3{24}
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3{22}
3{23}
68
91 (60) b
83 (95) b
3{27} α
3{26} α
3{25}
85
92
94 (46) b
81
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3{29} α
3{30} α
3{28} α
89
3{31} α
3{32}
3{33}
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90
60 (57) b
3{35}
3{38}
3{36}
3{34}
CH2NHCHO
NO2
O
O
CH2NHCHO
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80
45
Cl
N
Cl
3{39}
3{37}
87 (85) b
3{40} α
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4{1}
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4{3}
4{2}
4{5}
64 (45) b
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4{4}
4{6}
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75
4{7}
4{9}
4{8}
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87
4{12}a
4{11}
4{10}
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4{15}
4{14}
4{13}
α The reaction performed in 20 mmol scale; bThe reaction performed in MW
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Having in hand, this diversity and complexity of formamides, which often are very difficult to
produce through previously described methods, we wanted to go a step further. Demonstrating
the generality of our procedure, we employed the LeuckartꢀWallach procedure in the synthesis of
isocyanides, amines and novel IMCRꢀbased compounds through our recently published in situ
isocyanide method (Scheme 5).9
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O
Cl
N
N
HN
O
N
O
NH2
R2
O
N
R1
F
7
(4{9})
64%
O
6 88%
8
(3{35})
51%
N
N
O
NHCHO
R2
L.W. procedure
H
N
R1
R2
R1
1
2
or
MeO
MeO
O
3
4
or
9 (3{9})
52%
NC
Br
R1
R2
5 69-90%
O
O
N
O
N
N
H
O
H
N
Cl
N
MeO
11
(3{18})
53%
10
(3{21}) 62%
Scheme 5. Applications of the formamides and synthesis of isocyanides, amines and five
different MCR scaffolds with their overall yields.
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Isocyanides 5(3{3, 26, 27, 30, 31, 37, 40},4{11}) (chemset 5) were synthesized under the
common dehydration conditions (POCl3, Et3N). These isocyanides are preferentially produced
from their oxo components and not from the primary amines due to both availability and pricing
considerations. In addition, isocyanide 5(3{37}) is worthwhile mentioning as it can be used for
the synthesis of photo inducible probes, a recently emerging research area.15
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Table 2. Isocyanides synthesized (Chemset 5) from selected formamides.
Chemsets 5
Yield (%)
Chemsets 5
Yield (%)
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82
5(3{3})
5(3{26})
5(3{30})
90
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5(3{27})
81
75
88
69
5(3{37})
5(3{31})
5(3{40})
5(4{11})
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Similarly, the corresponding formamides after treatment with HCl (5N in dioxane) gave access
to the amines 6(3{10},4{5}) in excellent yields. Compound 6(3{10}, for example would cost
$428 for 1 g, and is only available through one supplier, EnamineBB. However the
corresponding aldehyde 1{10} costs $28 for 5 g and is available through multiple suppliers (AK
Scientific, CombiBlocks, and OxChem).
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NH3Cl
NH2
Br
MeO
OMe
6 (3{10})
6
(4{5}) 88%
88%
Scheme 6. Amines synthesized (Chemset 6) from selected formamides.
It was possible to get the crystal structures of formamides 3{21} and 3{37} along with the
corresponding isocyanide 5(3{37}). As expected the isocyanide adopts a linear conformation of
the N1ꢀC1 bond and the formamides occupy a (Z) position relative to the carbonyl oxygen.
3 {21}
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3{37}
Figure 1. Ortep drawing with 50% ellipsoids.
5(3{37})
Lastly, we synthesized 5 different compounds (Scheme 5) based on different MCR scaffolds
with a sequence of two steps without isolating the isocyanide. The first step for all 5 different
scaffolds is a classical Ugi four component reaction (U4CR) and then a postꢀmodification step
that gives access to important and diverse scaffolds in medicinal chemistry. Compound 7 is a
tetrasubstituted imidazole bearing an isocyanide side chain, that is only possible to synthesize via
the LeuckartꢀWallach procedure using the appropriate formamide (4{9}) since the corresponding
primary amine is not commercially available. The first step of the sequence, the Ugi reaction,
proceeded nicely with in situ formation of the isocyanide (compound 7a) followed by the
cyclization to the imidazole which was accomplished with the use of ammonium acetate and
acetic acid under reflux conditions with excellent yield.16 The second derivative 8 can be
assembled by performing a PictetꢀSpengler reaction with the appropriate Ugi product 8a.17–19 In
this case the necessary isocyanide is produced in situ from the corresponding formamide
o
(3{35}), while the cyclization reaction was performed in methanesulphonic acid at 60 C for 24
h to yield the final compound. Substituted benzimidazoles are often used in medicinal
chemistry.20 Compound 9 is a disubstituted benzimidazole that can be produced with the so
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called Ugi deprotectionꢀcyclization methodology.21 In this case a mono Boc protected orthoꢀ
phenylenediamine is used as an amine component in the Ugi reaction (compound 9a) along with
the in situ generated isocyanide (3{9}) which can only be synthesized via the LeuckartꢀWallach
procedure since the corresponding amine is not commercially available. The deprotectionꢀ
cyclization step was performed under microwave conditions giving the final product in excellent
yield. Compounds such as 10 were first synthesized in our group giving access to a large variety
of substituted 1,4ꢀbenzodiazepines.22,23 The synthetic route for such a compound consists of an
Ugi reaction with a substituted 2ꢀaminoacetophenone as an amine component (compound 10a)
which in a second step of Bocꢀdeprotection, cyclizes to the corresponding 1,4ꢀbenzodiazepine.
The isocyanide component was produced in situ from its formamide precursor (3{21}). In this
case the option to produce the isocyanide via the benzylamine would be very pricy (101$/1g
instead of 32$/10g for 4ꢀbromobenzaldehyde). Finally the pyrrolinone compound 11 was
synthesized using an Ugi reaction as a primary step followed by an aldol reaction.24 It was
performed under microwave conditions using DIPA as base for this specific cyclization giving
the final product in 75% yield.
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The biggest advantage of the herein described method is the lower price of the oxo components
on average and their differential and complementary structural diversity as compared to the
primary amine pathway. Indeed, after the application of few criteria (see SI), we found and
searched the emolecule Plus database finding 93,521 oxo components and 142,020 primary
amines from which 106,963 from the latter and 53,577 of the former were available for purchase
through the emoleculeBB website. After a second round of criteria, affording relatively fast
shipments and similarity comparisons (oxo and primary amine compounds that would create the
same isocyanide, see SI), 7857 unique amines (out of 11,339) and 11,033 (out of 13,487) unique
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oxo components were found, with an additional 3,482 equivalent oxo and amine compounds. As
it is illustrated in the following charts, we can conclude that comparing the amines and oxo
components that would create the same isocyanide (equivalent), the oxo compounds are on
average $75/gram cheaper (Chart 1). This is also true in the case of the unique compounds,
which again show the oxo components are on average $70/gram cheaper (Chart 2).
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Chart 1. Comparison of price and quantity of the “equivalent” and “unique” amines and oxo
components.
Chart 2. Comparison of price and quantity of the “unique” amines and oxo components.
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It is worth mentioning that the physical properties of the unique oxo components compared to
the unique primary amines seem to be equivalent with the exception of logP which was slightly
higher in the case of oxo components (Chart 3), however this can likely be attributed to the fact
that the amine functionality has a lower logP than the oxo C=O group. While there is a subset of
isocyanides which would only be available through the amine synthesis (i.e. tertiary or aromatic
amines), the quantity of the unique oxo compounds shows that our new method for developing
isocyanides is complementary and not redundant to the previously described amine method.
When looking at the price comparison of the equivalent amine/oxo compounds, the average price
decrease makes this method even more desirable.
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Chart 3. Comparison of logP of the “unique” amines and oxo components.
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EXPERIMENTAL PROCEDURES
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Nuclear magnetic resonance spectra were recorded on a Bruker Avance 500 spectrometer {1H
NMR (500 MHz), 13C NMR (126 MHz)}. Chemical shifts for 1H NMR were reported as δ values
and coupling constants were in hertz (Hz). The following abbreviations were used for spin
multiplicity: s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, quin = quintet,
dd = double of doublets, ddd = double of doublet of doublets, m = multiplet. Chemical shifts for
13C NMR were reported in ppm relative to the solvent peak. Thin layer chromatography was
performed on Fluka precoated silica gel plates (0.20 mm thick, particle size 25 µm). Flash
chromatography was performed on a Teledyne ISCO Combiflash Rf, using RediSep Rf Normalꢀ
phase Silica Flash Columns (Silica Gel 60 Å, 230 ꢀ 400 mesh) and on a Reveleris® X2 Flash
Chromatography, using Grace® Reveleris Silica flash cartridges (12 grams). Reagents were
available from commercial suppliers (Sigma Aldrich, ABCR, Acros and AK Scientific) and used
without any purification unless otherwise noted. All microwave irradiation reactions were carried
out in a Biotage Initiator™ Microwave Synthesizer. Electrospray ionization mass spectra (ESIꢀ
MS) were recorded on a Waters Investigator Semiꢀprep 15 SFCꢀMS instrument.
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Typical procedure for the one-pot synthesis of compound 3{31}
A solution of 3ꢀcyanobenzaldehyde (2.0 mmol) in formamide (100.0 mmol) and formic acid
o
(10.0 mmol) was irradiated in a microwave oven at 180 C for 3 min. After cooling down,
extractions with dichloromethane (3x30 ml) followed. The organic layer was separated, washed
with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash
chromatography on silica gel eluted with hexaneꢀethyl acetate (1:2) afforded the formamide
3{31} as a white solid in 92% yield. Rf 0.42 (EtOAc/P.S 1:1)
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ASSOCIATED CONTENT
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General procedures, characterization data of all the compounds, crystallographic data and a
multimedia file (AVI) are included as Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: a.s.s.domling@rug.nl; +491603706633
Author Contributions
The manuscript was written through contributions of all authors. CN, TT and SS performed
wet/lab chemistry experiments; KK and AD performed computational analyses.
Funding Sources
The work was financially supported from the NIH (1R21GM087617, 1R01GM097082, and
1P41GM094055) and by Innovative Medicines Initiative (grant agreement n° 115489).
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Formamides as the most important precursors of isocyanides, have a unique position in IMCRs.
We report a novel route to access them through oxo components in a oneꢀpot, parallel and
easily applied procedure. Moreover, we provide further synthetic applications, demonstrating
the general applicability and effectiveness of our method.
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