A multicomponent reaction towards N-(Cyanomethyl)amides

Article abstract of DOI:10.1002/chem.200900785

A study was conducted to demonstrate multicomponent reactions (MCR) towards N-(cyanomethyl)amides. A fourth MCR was developed from α-isocyano amides, amines, and carbonyl components. It was demonstrated that the resulting N-(cyanomethyl)amides were to be

Full text of DOI:10.1002/chem.200900785

DOI: 10.1002/chem.200900785
A Multicomponent Reaction Towards N-(Cyanomethyl)amides
Niels Elders,[a] Eelco Ruijter,[a] Frans J. J. de Kanter,[a] Elwin Janssen,[a] Martin Lutz,[b]
Anthony L. Spek,[b] and Romano V. A. Orru*[a]
Multicomponent reactions (MCRs)[1] have emerged as
useful tools in diversity-oriented synthesis (DOS).[2] Al-
though a number of substituents can be varied over a broad
range, MCRs often access products of one specific scaffold,
limiting the overall chemical diversity. To overcome this,
MCRs have been combined with other types of reactions
such as Diels–Alder reactions,[3] click chemistry,[4] and cycli-
zation strategies[5] to generate structural diversity and a high
degree of complexity in a minimal number of reaction steps.
Our group contributed in this field by trapping 1-aza-
dienes,[6] generated by the three-component reaction (3-CR)
between phosphonates, nitriles and aldehydes,[7] with various
reactants resulting in novel 4-CRs for a variety of heterocy-
clic scaffolds.[8]
tons on the isocyano amide, yielded the non-aromatized
product. In 2008, we reported a third scaffold from this 3-
CR.[11] Herein a-acidic isocyano amides (R3 =H), primary
amines (R8 =H), and carbonyl components react in the pres-
ence of 2 mol% AgOAc (or CuI) to give 2H-2-imidazo-
lines.[11,12] Careful tuning of the reaction conditions led to a
procedure to control and direct the outcome of this MCR to
either oxazoles or 2H-2-imidazolines, resulting in considera-
ble chemical diversity for a single combination of reagents.
In this way, at least six diversity points in three distinct scaf-
folds are covered.
Recently, we, and also others, reported the selective for-
mation of different products based on a single combination
of reactants. In a reaction between a-isocyano amides,
amines and carbonyl components, the outcome of the reac-
tion can be directed depending on subtle changes in the sub-
strates and conditions. First, the synthesis of 5-aminooxa-
zoles starting from aldehydes or ketones, primary or secon-
dary amines and tertiary a-isocyano amides (R1 =R2 =alkyl,
R3 =H, Scheme 1) was reported.[9] Later, a variation of this
3-CR was reported using secondary a,a-disubstituted isocya-
no amides (R1 =H, R2 =R3 =R4 =alkyl) to yield 5-iminooxa-
zolines.[10] The same reaction conditions as for the 5-amino-
oxazoles could be used, which, due to the absence of a-pro-
Scheme 1. A diverse set of scaffolds from the MCR between a-isocyano
amides, amines and carbonyl compounds.
In light of our ongoing interest in the application of a-
acidic isocyanides in MCRs, we used a-isocyano acetamide
(1a), cyclohexanone (2a) and morpholine (3a) in equimolar
amounts under the conditions optimized for the 5-amino-
oxazole MCR (MeOH, MgSO4 (drying agent), 608C, 5 h).[11]
Rather than the expected primary 5-aminooxazole we isolat-
ed 4a (Scheme 2).
These types of N-(cyanomethyl)amides show diverse bio-
logical activities and existing syntheses are certainly not
straightforward.[13] The unexpected formation of 4a can be
rationalized by the attack of the isocyanide terminal C atom
on the in situ generated iminium ion followed by cyclization
[a] N. Elders, Dr. E. Ruijter, Dr. F. J. J. de Kanter, E. Janssen,
Prof. Dr. R. V. A. Orru
Department of Chemistry & Pharmaceutical Sciences
Vrije Universiteit Amsterdam
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
Fax : (+31)20-59-7488
E-mail: rva.orru@few.vu.nl
[b] Dr. M. Lutz, Prof. Dr. A. L. Spek
Bijvoet Center for Biomolecular Research
Crystal and Structural Chemistry
Utrecht University, Padualaan 8, 3584 CH Utrecht (The Netherlands)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900785.
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COMMUNICATION
Scheme 2. Suggested mechanism for the formation of 4a.
and proton abstraction to form 5-iminooxazoline intermedi-
ate B (Scheme 2). Intermediate B could, in principle, under-
go tautomerization to form the aromatic primary 5-amino-
oxazole, but instead, proton abstraction at the exocyclic
imine nitrogen and subsequent ring opening (via a rear-
Figure 1. Molecular structure of 4d in the crystal. Displacement ellipsoids
are drawn at 50% probability level. Only the S enantiomer of this race-
mic compound is shown.
rangement previously reported for related compounds[14]
)
occurs to give 4a. The isolated yield of 4a could be in-
creased to 93% by using 1.2 equiv of the amine and ketone
components (Table 1, entry 1) and the scope of compatible
Table 1. Scope of isocyanides (1) using cyclohexanone (2a) and morpho-
line (3a) for the MCR towards 4.
Entry
R1
R2
Product
Yield [%]
1
2
3
4
5
H
H
H
H
À
H
4a
4b
4c
4d
4e
93
93
87
64
81
Et
iPr
Ph
À
ACHTUNGTRENNUNG(CH2)5
6
55 (18 h)
primary a-isocyano amides was quite general. The R2 sub-
stituent can be varied over a broad range (H, Et, iPr, and
Ph) affording the corresponding N-(cyanomethyl)amides in
64–93% isolated yield (entries 1–4). The structure of prod-
uct 4d was confirmed by X-ray crystallography (Figure 1).
Even the sterically demanding a,a-dialkyl isocyanide 1e and
the b-isocyano amide 5 proved successful substrates (en-
tries 5 and 6).
The amine and carbonyl components could also be varied
considerably (Figure 2). Aromatic amines and aldehydes
could be used (4 f and 4i, respectively) and also bulky com-
ponents gave the corresponding N-(cyanomethyl)amides in
high yields (4g–i, m). However, when the steric bulk be-
comes too large, the product is not obtained (4l, n), proba-
Figure 2. Variation of amine and carbonyl components.
bly due to sluggish imine formation or steric hindrance in
the attack of the isocyanide.
Interestingly, by using isocyanide 1a, butanone, and am-
monia 4p was not obtained. Instead, compound 7 was isolat-
ed in 47% yield (Scheme 3). The formation of 7 presumably
proceeds via a similar mechanism leading to 4. However, in
the rearrangement, the oxazoline N atom of B may attack a
second equivalent of imine due to the reduced steric repul-
sion with these small reactants (Scheme 3). This is supported
by the reaction of the same imine with the more sterically
hindered isocyanide 1e. In this case, the increased steric
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R. V. A. Orru et al.
bination with the slow addition of the isocyanide resulted in
the selective formation of 2-imidazolines 8a and 8d. As re-
ported, attempts to isolate the 2-imidazoline starting from
a-alkyl substituted isocyano amides (such as 1b) failed due
to the increased pKa of the a-proton.[11]
In conclusion, we have developed a fourth MCR starting
from a-isocyano amides, amines and carbonyl components.
The resulting N-(cyanomethyl)amides can be isolated in
moderate to excellent yield using a wide range of primary
and secondary amines as well as aldehydes and ketones. In
addition to the broad substrate scope of the reaction, a
number of functional groups (including additional amide
and isonitrile groups) are tolerated, thus eliminating the
need for protective groups and allowing direct post-modifi-
cation. Finally, we were able to direct the reaction outcome
toward 2H-2-imidazolines by slight modification of the reac-
tion conditions.
Scheme 3. Proposed mechanism for the formation of 7.
bulk on B prevents attack on a second equivalent of imine
and 4q is formed instead (44%, Figure 2).
Many functional groups are tolerated in this new MCR
toward N-(cyanomethyl)amides, including alkynes (4r,
Figure 3), alcohols (4s), furans (4t) and even additional pri-
mary amide (4u) and isocyanide (4v) groups. Functional
groups can be introduced on all accessible sites of the N-(cy-
anomethyl)amide making in situ follow-up (multicompo-
nent) reactions feasible.
Experimental Section
Synthesis of N-(cyanomethyl)amides 4a–y, 6, and 7: Unless stated other-
wise, the corresponding primary(a-isocyano)amide 1a–g (1.0 mmol), al-
dehyde or ketone (1.2 mmol), and amine (1.2 mmol) were stirred in
MeOH (5 mL) in the presence of MgSO4 for 5 h at 608C. Water (15 mL)
was added, and the resulting mixture was extracted with CH2Cl2 (3ꢁ
10 mL). The organic layers were combined, dried (MgSO4), filtered, and
concentrated, and the resulting N-(cyanomethyl)amides were purified by
column chromatography.
Acknowledgements
This work was performed with financial support from the Dutch Science
Foundation (NWO, VICI grant). M. C. Smoluch (Vrije Universiteit Am-
sterdam) and H. Peeters (University of Amsterdam, the Netherlands) are
kindly acknowledged for HRMS measurements. M. Lutz and A. L. Spek
were financially supported by NWO-CW.
Figure 3. Functional group tolerance.
Keywords: diversity-oriented synthesis
multicomponent reactions · silver
· imidazolines ·
As reported by us earlier for tertiary a-isocyano
amides,[11] the outcome of the MCR can be directed toward
2H-2-imidazolines by slightly changing the reaction condi-
tions (Scheme 4). Addition of only 2 mol% AgOAc in com-
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COMMUNICATION
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Received: March 26, 2009
Published online: May 21, 2009
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