Tritylamine as an ammonia surrogate in the Ugi tetrazole synthesis

Article abstract of DOI:10.1021/ol303348m

The role of tritylamine is introduced as a convenient ammonia substitute in the Ugi tetrazole synthesis. Fifteen examples and their mild cleavage products are described in satisfactory to good yields. N-Unsubstituted α-aminotetrazoles are important compounds with annotated biological activities, and the described two-step synthesis provided an alternative route to otherwise difficult to access derivatives.

Full text of DOI:10.1021/ol303348m

ORGANIC
LETTERS
2013
Vol. 15, No. 3
639–641
Tritylamine as an Ammonia Surrogate
in the Ugi Tetrazole Synthesis
†
Ting Zhao, Andre Boltjes, Eberhardt Herdtweck, and Alexander Domling*
†
‡
,†
ꢀ
€
Department for Drug Design, University of Groningen, A. Deusinglaan 1,
€
Groningen 9713AV, The Netherlands, and Technische Universitat Munchen,
€
Lichtenbergstr. 4, 85747 Garching b. Mu€nchen, Germany
a.s.s.domling@rug.nl
Received December 19, 2012
ABSTRACT
The role of tritylamine is introduced as a convenient ammonia substitute in the Ugi tetrazole synthesis. Fifteen examples and their mild cleavage
products are described in satisfactory to good yields. N-Unsubstituted R-aminotetrazoles are important compounds with annotated biological
activities, and the described two-step synthesis provided an alternative route to otherwise difficult to access derivatives.
The Ugi reaction is well-known for its very broad scope
of different starting materials.1 Thousands of reported
examples revealed that most primary or secondary amines,
aldehydes, ketones, and isocyanides could react with a
suitable acid component.2À15 However, ammonia is one of
the very few amine components which gives regularly
unsatisfactory results in Ugi-type multicomponent reac-
tions for many potential reasons. First, ammonia is a very
reactiveamine, and the Schiff basesofammoniaare known
to be unstable and to rapidly cyclo-trimerize or oligomer-
ize. The Schiff base is a key intermediate in all Ugi-type
multicomponent reactions (MCRs).16À19 The slow kinetic
reversibility of the Schiff base oligomer monomer equilib-
rium could hinder the progress of the Ugi MCR and
also potentially lead to side reactions. The high basicity
† University of Groningen.
‡
€
Technische Universitat M€unchen.
€
(1) Ugi, I.; Steinbruckner, C. Angew. Ed. 1960, 72, 267–268.
€
(2) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
€
(3) Domling, A. Chem. Rev. 2005, 106, 17–89.
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Chim. Acta 2012, 95, 483–490.
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r
10.1021/ol303348m
2013 American Chemical Society
Published on Web 01/18/2013

of ammonia used in excess could suppress Lewis and
Brønsted acid mediated activation of the intermediate
Schiff base. In the tetrazole and Ugi-3CR variation
the Schiff base causes a primary amine to be formed from
use of ammonia. This primary amine, however, is very
reactive and can undergo an additional Ugi reaction; with
highly reactive oxo components, e.g., formaldehyde, even
a third Ugi reaction can even lead to a mixture of multiple
products. In fact, the HPLCÀMS analysis of the reaction
of tert-butyl isocyanide with formaldehyde, ammonia, and
TMS-azide revealed such a mixture of mono-, di-, and tri-
Ugi products. While several ammonia substitutes such as
ammonium formiate,20 ferrocenylalkylamines,21 substituted
benzylamines,22 and anomeric glycosylamines23 have been
described in the past for the Ugi-4CR, no conveniently and
mildly cleavable substitutes were known for the Ugi tetrazole
synthesis.24,25 N-Unsubstituted R-aminotetrazoles, however,
are potentially biologically active compounds with currently
no described synthetic pathway. Therefore, we report our
results introducing tritylamine as a convenient ammonia
surrogate in the Ugi tetrazole synthesis (Scheme 1).
formation was too slow at room temperature but successful
ifperformed under microwaveconditions. Interestingly, we
found when we mixed the isolated Schiff base with the
isocyanide and TMSN3 (ethanol, 24 h) the reaction yielded
N-trityl-protected R-aminotetrazoles (1d, 55%) in even
slightly higher yields than that of microwave condition
(1d, 47%). It was concluded that the microwave or thermal
conditions must be employed for the Schiff base formation
of tritylamine but not for the subsequent Ugi reaction.
For the sake of a convenient procedure, however, all
subsequent reactions were performed in the microwave in
a one-pot fashion. In order to test the scope and limitations
of the reaction, several isocyanides and aldehydes were
tested (Scheme 1, Table 1). Cyclohexanone, which pre-
viously has been described in the literature as a good
substrate for diverse Ugi reactions, was reacted; however,
the expected product could not be isolated. This is pre-
sumably due to the high sterical hindrance of the two
reactants, and not surprisingly, no such Schiff base with
tritylamine has been reported with a ketone via a condensa-
tion reaction.
Scheme 1. Design of a Synthetic Pathway to N-Unsubstituted
Primary R-Aminotetrazole Using a Ugi-4CR Employing
Tritylamine as an Ammonia Surrogate
Table 1. Yields of N-Trityl-Protected R-Aminotetrazoles (1) and
N-Deprotected R-Aminotetrazoles (2)
no.
R1
R2
yield of 1 (%) yield of 2 (%)
a
b
c
d
e
f
H2
C6H5(CH2)2
C6H5(CH2)2
C6H5(CH2)2
C6H5CH2
83
80
76
47
87
73
81
66
70
41
87
75
65
77
46
99
99
99
99
86
99
98
99
99
99
99
99
99
99
98
CH3
(CH3)2CH
CH3S(CH2)2
(CH3)2CHCH2
cyclopropionyl
CH3
C6H5CH2
C6H5CH2
g
h
i
cyclohexyl
C6H5CH2
isopentyl
At the beginning of our investigations, it was not clear
that tritylamine, although a well-known amine protecting
group often used in peptide chemistry, might work well in
the crucial Schiff base formation due to sterical hindrance.
We were pleased to find the expected product during the
room temperature reaction of cyclohexylisocyanide, iso-
butyraldehyde, tritylamine, and TMS-azide in methanol,
however, accompanied with mostly starting materials
indicated the low conversion. Switching to microwave
conditions (100 °C, 30 min, ethanol) has led to good
conversion and isolation of the Ugi product in satisfactory
yields (1i, 70%). In order to find out the rate-limiting step
(Schiff base formation or R-addition and subsequent
tetrazole formation), we attempted to run both reactions
at room temperature. It was found that the Schiff base
(CH3)2CH
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
C6H5(CH2)2
g
k
l
C6H5CH2
cyclohexyl
C6H5(CH2)2
CH3OCO(CH2)2
m
n
o
CH3CH2OCOC3H4 C6H5(CH2)2
CH3CH2OCOC3H4 (CH3)3
The deprotection of the Ugi intermediates could be per-
formed under standardconditions (DCM, TFA, rt, 1 min).
The products were isolated by chromatography in near-
quantitative yields (Table 1).
It was widely accepted that the mechanism of the Ugi
reaction involves first Schiff base formation (or enamine in
the case of secondary amines), followed by an activation
step of the imine by a Lewis or Brønsted acid. Addition of
the isocyanide via the carbon onto the Schiff base yields an
intermediate nitrilium ion, addition of the acid, and a final
irreversible sigmatropic rearrangement to the product, a
tetrazole in the present case (Scheme 2).
(20) Basso, A.; Banfi, L.; Guanti, G.; Riva, R.; Riu, A. Tetrahedron
Lett. 2004, 45, 6109–6111.
(21) Demharter, A.; Ugi, I. J. Prakt. Chem./Chem.-Ztg. 1993, 335,
244–254.
(22) Wang, W.; Joyner, S.; Khoury, K. A. S.; Domling, A. Org.
Biomol. Chem. 2010, 8, 529–532.
This mechanistic proposal has been recently also supported
by theoretically high-level molecular orbital calculations.26
(23) Oertel, K.; Zech, G.; Kunz, H. Angew. Chem., Int. Ed. 2000, 39,
1431–1433.
€
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640
Org. Lett., Vol. 15, No. 3, 2013

Scheme 2. Ugi Tetrazole Mechanism
The present Ugi reaction was, however, surprising in
several respects. First, the reactive imine carbon next to
the tritylamine unit is sterically very hindered and reacts
with the bulky isocyanide to give the nitrilium species. Then
the azide anion has to add onto this species to yield the
R-adduct. To underscore the bulkiness of this intermediate
a molecular modeling picture of the presumed intermediate
of product 2k is depicted in Figure 1.26 After the ring
closure, the R-amino tetrazole is formed. The compounds
generally crystallized well, and two typical highly crowded
examplesare shownin Figure2in thesolid state. Aftertrityl
deprotection, the primary amines are obtained as TFA salts
which also nicely crystallized (Figure 2).
Figure 1. Spheres model of the R-adduct during the formation
of tetrazole 2k illustrating the crowdedness of the reaction
intermediate.
Figure 2. Molecular structures of 1b and 1c in the solid state
illustrating the crowdedness of the trityl-protected products.
Molecular structure of trityl-cleaved products 2k and 2l in the
solid state. ORTEP ellipsoidsdrawnat the 50% probability level.
N-Tetrazole-substituted and amino-N-unsubstituted
R-amino tetrazoles so far have been only synthesized via
the Ugi reaction.25 We have now introduced tritylamine
as a convenient and easily cleavable ammonia surrogate
that reacts together with aldehydes, TMS-azide, and
isocyanides to yield N-trityl R-aminotetrazoles. The
N-unsubstituted R-aminotetrazoles were obtained under
very mild and standard trityl deprotecting conditions.
Despite steric hindrance, the Ugi reaction proceeded
smoothly and the products could be isolated in good
to satisfactory yields. Work is ongoing to investigate the
further synthetic applications and biological properties
of the new compounds.
Acknowledgment. We acknowledge the China Scholar-
ship Council for supporting Ting Zhao.
Supporting Information Available. Experimental pro-
cedures, compound characterization, spectra, and X-ray
crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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