Cleavable β-Cyanoethyl Isocyanide in the Ugi Tetrazole Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01826

β-Cyanoethyl isocyanide is introduced as a cleavable isocyanide in the Ugi tetrazole reaction. Eleven examples are described that exhibit a broad scope and are obtained in good overall yields. The obtained 1H-tetrazole scaffold is an important bioisostere for carboxylic acids, and the method described here is a valuable alternative route to known procedures.

Full text of DOI:10.1021/acs.orglett.6b01826

Letter
pubs.acs.org/OrgLett
Cleavable β‑Cyanoethyl Isocyanide in the Ugi Tetrazole Reaction
†
‡
‡
,†
Edwin Kroon, Katarzyna Kurpiewska, Justyna Kalinowska-Tłusc
†
́
̈
ik, and Alexander Domling*
University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
Jagiellonian University, Department of Crystal Chemistry and Crystal Physics, Ingardena 3, 30-060 Krakow, Poland
‡
*
S Supporting Information
ABSTRACT: β-Cyanoethyl isocyanide is introduced as a cleavable isocyanide in the Ugi tetrazole reaction. Eleven examples are
described that exhibit a broad scope and are obtained in good overall yields. The obtained 1H-tetrazole scaffold is an important
bioisostere for carboxylic acids, and the method described here is a valuable alternative route to known procedures.
he Ugi reaction is a well-known multicomponent reaction1
that has a comprehensive range of starting materials.
Scheme 1. Previously Described Convertible Isocyanides
T
Numerous reported examples revealed that aldehydes, ketones,
primary or secondary amines, and isocyanides react with
2
−9
suitable acid components to yield a variety of scaffolds.
Moreover, it is well established that multicomponent reaction
chemistry has several advantages over sequential step chemistry.
They show a high degree of diversity due to the nature of the
starting materials and are efficient, mild, one-pot procedures;
their atom economy is remarkable since almost all atoms from
4
,5
the starting materials are retained in the final product.
The 1H-tetrazole moiety has attracted much attention in the
field of medicinal chemistry as a bioisostere of the carboxylic
acid functional group. This is mainly due to a combination of a
similar pK (4−5) and, more importantly, a 10-fold higher
a
lipophilicty, which is potentially more beneficial when cell
10,11
membrane permeability is desired.
Traditionally, there are
two methods to introduce the tetrazole moiety, addition of an
azide source to a nitrile or the addition of an azide source to an
12,13
amide reacting through its imidoyl derivative.
However,
both methods have limitations that include multistep synthesis
of starting materials, expensive reagents, or a great amount of
chemical waste. In this respect, the Ugi multicomponent
Convertible isocyanides are highly useful in that they can be
transformed into other functional groups during a multistep
synthesis of complex molecules, e.g., natural products.
2
9
reaction, with trimethylsilyl azide (TMS-N ) as acid compo-
3
nent, is a valuable alternative, provided that an efficient method
for deprotection of N-1 is available (see Scheme 2). A large set
of compounds can potentially be synthesized because most of
the two retained starting materials, carbonyl and amine
compounds, are commercially available, eliminating the need
for starting material synthesis.
However, the majority of work performed concerns the
transformation of the secondary amide formed during the
Ugi and Passerini reactions into esters, thioesters, ketones,
carboxylic acids, and other groups. For other isocyanide-based
multicomponent reactions (IMCRs), not all of the above
quoted cleavable isocyanides may be used. Previous acidic
3
30
cleavage of isocyanides leading to tetrazoles include tert-butyl,
The concept of convertible isocyanides was introduced as
early as 1963 by Ugi with cyclohexenyl isocyanide, which can
be cleaved in the Ugi reaction product using acidic
31
31
BetMIC, and Walborsky’s reagent (tert-octyl isocyanide) are
1
4
conditions. 5T−h28e concept was later extended by many others
Received: June 23, 2016
1
(Scheme 1).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01826
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
known, but we were interested in the development of a
cleavable isocyanide deprotected under mild conditions due to
our recent focus on the Ugi tetrazole reactions (Scheme
diverse set of carbonyl components and amines to isolate the
1,5-disubstituted tetrazoles (5) in moderate to good yield (24−
6
8%, Table 1). Aliphatic, alicyclic, and (hetero)aromatic
3
2−36
2).
aldehydes are accepted as carbonyl compounds and generally
gave good yields; however, the Ugi products containing 1-
naphthaldehyde (entry f) or benzo[b]thiophene-2-carboxalde-
hyde (entry j) gave a fair yield. Additionally, ketones such as
Scheme 2. Retrosynthetic Pathway of Our Approach
Table 1. Yields of the Ugi Products (5) and Deprotected 5-
Substituted 1H-Tetrazoles (6)
The amino acid derived isocyanides 1a,b are cleaved under
35
basic conditions (Figure 1), but these cleavable isocyanides
Figure 1. Isocyanides cleaved under basic conditions.
display some drawbacks. First, the deprotection takes a
considerable time (overnight) with the possibility of unwanted
side reactions, and second, especially the amino acid derived
isocyanides require a multistep synthesis from benzaldehyde
(
1a) or aspartic acid (1b).
To overcome these issues, we would like to introduce the β-
cyanoethyl protecting group which is a common phospho-
triester protecting group in solid-phase oligonucleotide syn-
36
thesis and cleaved under mild basic conditions. The β-
cyanoethyl protection was previously employed in the synthesis
13
of 5-substituted-1H-tetrazoles, and it was used by our group
3
4,37
in two instances.
Therefore, we herein report an improved
synthesis of β-cyanoethyl isocyanide, its use as cleavable
isocyanide, and scope and limitations in the synthesis of 5-
subsituted-1H-tetrazoles through the Ugi tetrazole multi-
component reaction.
The first step is the formylation of 3-aminopropionitrile (3)
with ethyl formate to obtain N-(cyanoethyl)formamide (4) in
excellent yield (98%). Subsequent dehydration of the
formamide is performed using standard conditions (POCl /
3
38
Et N) to yield the isocyanide 2 in 69% yield (Scheme 3). This
3
Scheme 3. Synthesis of β-Cyanoethyl Isocyanide
compares well to the poor 16% yield obtained with the Appel-
39,40
type conditions used in the original procedure
Our high
purity β-cyanoethyl isocyanide solidifies at room temperature,
therefore, making it practical in use and, noteworthy, lacking
41
the appalling smell of volatile isocyanides. In the Supporting
Information we also describe an 11 g scale synthesis of β-
cyanoethyl isocyanide.
We then tested for the first time its reactivity in IMCR, and it
reacted smoothly with cyclohexanone, aniline ,and TMS-N in
3
methanol (room temperature, overnight) to obtain the Ugi
product in good yield (64%, 5c). After this initial promising
result, the scope of the reaction was investigated by reacting a
a
Isolated yield.
B
DOI: 10.1021/acs.orglett.6b01826
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Organic Letters
Letter
cyclohexanone (entry c) and acetone (entry (i) performed well,
and the Ugi products, with a quaternary carbon center, were
obtained in good yield. Primary aliphatic and (hetero)aromatic
amines as well as secondary amines are suitable amine
components, but sterically hindered 2,4,6-trimethylaniline
(
entry b) resulted in a slightly lower yield. This shows that
this particular reaction has a broad scope and, moreover,
exhibits a high tolerance toward functional or protecting groups
including the nitrile (entry d), Boc (entry g), trityl (entry h),
and alcohol (entry j).
Figure 2. X-ray structure of β-cyanoethyl-protected tetrazole 5c.
The deprotection of β-cyanoethyl protecting groups usually
42
proceeds by using an organic base, such as DBU, to abstract
one of the acidic hydrogens adjacent to the nitrile. The C−H
bond is broken, and the electrons flow toward the tetrazole
forming the anion with expulsion of highly volatile acrylonitrile.
After acidification, the 1H-tetrazole is obtained (Scheme 4).
Scheme 6. Deprotection of Orthogonal Protecting Groups
Scheme 4. Mechanism for β-Cyanoethyl Deprotection
The deprotection proceeds most likely due to the stability of
the intermediate tetrazole anion which is resonance stabilized.
Preliminary results showed that the β-cyanoethyl isocyanide
could not be cleaved from the classical Ugi product 7 and only
starting material was obtained; therefore, it was not further
pursued (Scheme 5).
Boc group led to compound 8 that contained a highly water-
soluble piperazine and, potentially, allowed for further reactions
on the secondary amine. After deprotection of the trityl group
from 6h, the (1H-tetrazol-5-yl)methanamine (9) was obtained,
37
Scheme 5. Attempted Deprotection from a Classical Ugi
Product
which is the α-amino tetrazole analogue of glycine.
The β-cyanoethyl group is widely used during the solid-phase
synthesis of polynucleotides, but rarely used otherwise, despite
its mild and efficient cleavage conditions. Hence, we report here
the use of the protecting group for the tetrazole moiety and its
introduction in one step using β-cyanoethyl isocyanide. The
herein reported β-cyanoethyl isocyanide was readily synthesized
from commercially available 3-aminopropionitrile in two steps
and obtained as an easy to handle solid isocyanide that reacts
together with a broad range of diverse ketones, aldehydes,
primary or secondary amines, and TMS-azide to yield 1,5-
disubstitued tetrazoles. The 5-substituted 1H-tetrazoles were
obtained after mild basic deprotection of the β-cyanoethyl
group with short reaction times reducing unwanted side
reactions and in high yields outperforming and being a vital
addition to other acid or base cleavable isocyanides that are
described for the Ugi tetrazole reaction. Moreover, the here
presented approach may be valuable in the synthesis of
biologically active compounds containing the 1H-tetrazole
moiety. Currently, work is ongoing to investigate the further
synthetic application of β-cyanoethyl isocyanide in multi-
component reaction chemistry.
Attempts to cleave the Ugi products under similar conditions
failed, and no reaction occurred. However, we were pleased to
find that deprotection with lithium hydroxide gave a clean
reaction, and full conversion was obtained at room temperature
within 30 min. After acidification (pH 4−5), the 1H-tetrazole
was obtained as a solid which allowed for the convenient
isolation of the products 6 in good to excellent yield (59−
9
3%). Compounds that possess more bulky substituents tend
to give excellent yields (entries 6b, 6g, and 6h). Moreover, this
method did not hamper the isolation of products that contain
highly water-soluble groups such as morpholine (6f, 77%) and
ethanolamine (6k, 81%). For compound 5c, a single crystal was
obtained, and X-ray analysis confirmed the overall structure of
the protected Ugi product (Figure 2).
Finally, deprotection of the orthogonal acid-labile protecting
groups from 1H-tetrazoles 6g (Boc) and 6h (trityl) was
achieved under normal conditions (Scheme 6). Cleavage of the
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01826.
X-ray crystallographic file of 5c (CIF)
C
DOI: 10.1021/acs.orglett.6b01826
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
General experimental procedures, compound character-
Letter
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AUTHOR INFORMATION
Corresponding Author
E-mail: a.s.s.domling@rug.nl.
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*
(
3
631−3634.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was financially supported (A.D.) by the NIH
1R01GM097082-01), the Innovative Medicines Initiative
Grant Agreement No. 115489) and received funding from
■
(
(
́
̈
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́
ik, J.;
̈
the European Union's Horizon 2020 research and innovation
program under MSC ITN “Accelerated Early stage drug
dIScovery” (AEGIS), Grant Agreement No.675555. The
research (K.K., J.K.-T.) was carried out with the equipment
purchased thanks to the financial support of the European
Regional Development Fund in the framework of the Polish
Innovation Economy Operational Program (Contract No.
POIG.02.01.00-12-023/08).
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DOI: 10.1021/acs.orglett.6b01826
Org. Lett. XXXX, XXX, XXX−XXX