A parallel Ugi reaction at students laboratories in the ural and Moscow

Article abstract of DOI:10.1134/S1070363210120303

A four-component Ugi reaction was adapted for students education. To this end, a series of almost odorless aromatic isonitriles with donor substituents was reacted with a specific carboxylic acid, phthaloyl glycine, to obtain poorly soluble (although nicely crystallized) products. The process was performed and compared in two versions by using (1) a standard centrifuge for parallel separation of precipitates and (2) parallel filtration with SynCore apparatus. It is shown for a broad series of aliphatic ketones and benzyl amines that the yields are satisfactory and the products require no further purification. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070363210120303

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 12, pp. 2647–2654. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © M.A. Mironov, E.V. Babaev, 2009, published in Rossiiskii Khimicheskii Zhurnal, 2009, Vol. 53, No. 5, pp. 133–139.
A Parallel Ugi Reaction at Students Laboratories
in the Ural and Moscow
M. A. Mironova and E. V. Babaevb
a Eltsin Ural State Technical University (USTU), u. Mira 19, Yekaterinburg, 620002 Russia
e-mail: mironov@mail.ustu.ru
b Lomonosov Moscow State University, Vorob’evy Gory 1, Moscow, 119991 Russia
e-mail: babaev@org.chem.msu.ru
Received July 10, 2009
Abstract―A four-component Ugi reaction was adapted for students education. To this end, a series of almost
odorless aromatic isonitriles with donor substituents was reacted with a specific carboxylic acid, phthaloyl
glycine, to obtain poorly soluble (although nicely crystallized) products. The process was performed and
compared in two versions by using (1) a standard centrifuge for parallel separation of precipitates and
(2) parallel filtration with SynCore apparatus. It is shown for a broad series of aliphatic ketones and benzyl
amines that the yields are satisfactory and the products require no further purification.
DOI: 10.1134/S1070363210120303
In 2000–2001, at the Ural State Technical
University, Yekaterinburg, there was developed a
“Combinatorial Chemistry” laboratory training course
for third year students specializing in biotechnology.
The aim of this laboratory course was to develop
practical skills in the field of parallel synthesis and
consolidate the lecture material on combinatorial
chemistry. Taking into account the basic student’
training level, we had to find a simple and illustrative
example of the parallel organic synthesis technology.
The Ugi reaction is an ideal decision, since it allows
compound libraries to be obtained without a complex
equipment and hardly accessible reagents. The
reagents were chosen so that to obtain precipitates
which could be separated in parallel by centrifuging. It
should be mentioned that the Ugi reaction is also used
at students laboratories at some foreign universities
(for example, at the Munich Technical University).
Almost simultaneously, special laboratory training
in combinatorial chemistry for fifth year students was
initiated at the Lomonosov MSU. The Moscow group
first experimented with training tasks on solid-phase
synthesis [1, 2], and the task in parallel liquid-phase
synthesis involved reductive amination [3]. After the
MSU had acquired instrumentation for parallel
filtration, a necessity arose to find an illustrative
training task. After the heads of these training courses
(the authors of the present paper) had met face-to-face
and exchanged experience, the Moscow group attempted
to adapt the procedure developed at the USTU for use
for the Syncore reactor (I. Dlinnykh, E. Belykh, and
V. Alifanov were involved in this work in different
times). In the second part of this paper we present the
results of this experiment. In our opinion, the
experience in such collaboration may be of interest for
other universities.
The practical work at the USTU was envisioned for
four lessons: an introductory workshop and three
practical lessons. For fourth year students, an extended
program comprising five practical lessons requiring a
higher level basic training was suggested. In the first
part of this paper we present a series of procedures and
instructions which can help one to include the Ugi
reaction in any laboratory training in combinatorial
chemistry.
Basic Information on the Ugi Reaction
We consider it useful, to start with a workshop on
the methodology of parallel synthesis and application
of multicomponent reactions (MCRs). The term MCR
relates to reactions that occur on direct mixing of three
and more reagents, and the final structure includes
fragments of all starting reagents.
2647

2648
MIRONOV, BABAEV
which open up the way to various scaffold structures)
(a)
(b)
and mild reaction conditions (room temperature),
which is ideally suited for automated synthesis. All
these advantages attracted attention of researchers
working in combinatorial chemistry, as well as pharma-
ceutical companies searching for new biologically
active compounds. At present abundant published
material on the reaction itself and practically valuable
compounds obtained by this reaction is available. In
preparation to the workshop we recommend the
reviews [5–7].
Experience in Accomplishing the Ugi Reaction
at Students Laboratories at the USTU
As the training task for students we use one of the
simplest versions of the Ugi reactions, specifically,
preparation of amino acids by mixing an aromatic
isocyanide, aliphatic ketones, benzylamines, and
phthalyl glycine (Scheme 1).
Fig. 1. Equipment for the implementation of the Ugi
reaction: (a) plastic plates with tubes and (b) multichannel
pipette.
There are different classifications of MCR,
depending on their mechanistic features [4]. The main
advantage of such reactions is that they allow one to
obtain a great number of derivatives in one stage from
simple and accessible starting materials. It should be
noted that MCRs are widely used for solving diverse
practical tasks in the search for new biologically active
compounds, catalysts, new materials, etc. One of the
most popular of reactions of this type is the four-
component Ugi condensation discovered in 1960. The
reaction involves isocyanides, carbonyl compounds,
amines, and organic/inorganic acids.
This choice is not occasional, it allows one to
perform a practical work with minimal preparation,
provides excellently reproducible results, and requires
no expensive or dangerous reagents. With phthalyl
glycine, poorly soluble derivatives which readily
crystallize and can be isolated in parallel in the
framework of one laboratory work are available. In
their turn, aromatic isocyanides with polar groups are
low-volatile and have almost no characteristic odor.
Benzylamines and aliphatic ketones whose function is
to provide various side-chain substituents are
accessible and fairly cheap reagents. It should be noted
that the described laboratory course was developed for
engineering students and envisioned no subsequent
testing of the resulting compounds. Therefore, the
scaffold in Scheme 1 does not have biologically active
analogs. For students of other specializations (for
example, medicinal chemistry) one can use a different
target compounds, according to [6]. The procedures
described below all remain therewith unchanged.
C−
N+
R3
O
H
O
OH
NH2
R4
+
+
+
R1
R2
R4
O
R3
N
HN
R2
R1
O
The Ugi condensation provides a great number of
derivatives (104), features a considerable flexibility
(presently several tens of its versions are known,
Scheme 1.
O
O
Alk Alk
H
Ar
NH2
O
NC
R
N
N
+
N
O
O
Alk
Alk
Ar
N
O
O
COOH
R = N(Me)2HN
O.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 12 2010

PARALLEL UGI REACTION AT STUDENTS LABORATORIES
2649
Scheme 2.
Ketones
O
O
O
O
Ketones
A
B
C
D
A
B
C
D
Benzylamines
OMe
1
Cl
F
2
3
N
4
5
6
NH2
NH2
NH2
NH2
NH2
NH2
1
2
3
4
5
6
Reagents loaded in all tubes
O
O
N
Benzylamines
N
O
COOH
NC
I
II
Practical skills acquired during the work. Students
use equipment for parallel synthesis: single- or
multichannel micropipettes, reaction plates, and
shaker. A short introductory lesson is required if
student have never dealt with such equipment. The
acquired skills may prove useful at microscale
divisions of pharmaceutical and chemical companies,
as well as at any analytical laboratory.
Reagents. For charging one plate one needs about
500 mg of each reagent.
(1) Phthalyl glycine is prepared by fusing equi-
molar amounts of phthalic anhydride and glycine in a
porcelain dish to obtain a homogeneous mass which is
then crystallized from aqueous alcohol, mp 198°С [8].
(2) Isocyanide, for example, 4-(dimethylamino)-
phenyl isocyanide, is prepared by the procedure in [9].
A suspension of 3.2 mmol of 4-(dimethylamino)-
nitrosobenzene in 40 ml of ethanol is added to a
solution of 3.2 mmol of 3-phenylisoxazol-5-one (can
be readily synthesized from benzoylacetic ester and
hydroxylamine) in 20 ml of ethanol. The mixture is
heated on a water bath for 15 min, cooled, and the
precipitate is filtered off. The product is heated in
toluene at 90°С for 30 h, toluene is removed by
distillation, and the residue is sublimed in a vacuum at
75°С. Total yield 65–70%, mp 61°С.
Materials and instruments. For laboratory work the
following equipment should be prepared:
(1) Plastic 8×12 plates with separate tubes (each 1 ml
in volume), like Micronic or Falcon plates (Fig. 1а).
Well plates used in analytical chemistry are less
convenient.
(2) Fixed-volume 50- or 100-µl micropipettes (both
single- and multichannel, Fig. 1b), as well as tip sets
for them.
(3) Shaker (almost any model can be used).
This reagent can be replaced by other aromatic
isocyanides: 4-morpholinophenyl isocyanide or 2,4-
dimethoxyphenyl isocyanide. The advantage of these
reagents is their high activity and lack of the charac-
teristic isocyanide odor.
(4) Laboratory centrifuge with a swing-bucket rotor.
Centrifuges with an angle rotor are less convenient.
(5) Set for thin-layer chromatography or analytical
chromatograph.
(3) Substituted benzylamines (Scheme 2).
(4) Ketones (Scheme 2).
(6) Glassware for starting solutions, balances, and
other laboratory equipment.
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2650
MIRONOV, BABAEV
1 mmol ml–1 in methanol. A total of 12 solutions are
prepared: 1 with isocyanide, 1 with phthalyl glycine,
4 with ketones, and 6 with benzyl amines. The choice
of ketones and benzylаmines depends on the potential
of each concrete laboratory. According to our experi-
ence, virtually any set allows amino acid derivatives to
be prepared with good yields by the below-described
procedures. As a recommendation, we provide the set
shown in Scheme 2.
Table 1. Yields of target products (%), obtained by a group
of students in 2004 (loading by Scheme 2)
Benzylamines
Ketones
1
2
3
4
5
6
49
54
76
78
48
67
81
75
41
60
66
62
55
65
68
69
62
73
77
71
46
51
58
53
A
B
C
D
Further students start to load all starting reagents, by
0.1 mmol each, into plates by means of 100-µl (50 µl,
if the concentration of all solutions is 2 mmol ml–1).
The following loading sequence is strictly followed:
(1) benzylamines, (2) ketones, (3) isocyanide, (4) phthalyl
glycine.
(5) Methanol (if methanol is prohibited for use, it
can be replaced by a 4:1 acetonitrile–water mixture).
PRACTICAL IMPLEMENTATION OF THE WORK
Lesson 1. Reagent loading.
It should be noted that only part of the plate (4×6)
is loaded, and, therewith, loading is better started from
the left upper angle (tube А1). All manipulations with
solutions are performed under a hood. If students have
never dealt with micropipettes, a preliminary practical
lesson is recommended. It is useful to record the time
of loading with multichannel pipettes to estimate the
time gain compared with traditional methods.
Each student or a group of students obtain a hard
copy of the database corresponding to the library to be
obtained. Before starting experimental work, students
should write down equations of the reactions leading to
the target structure. At the colloquium, if it precedes
the work, detailed analysis of the mechanism of the
Ugi reaction can be given. Then students form in
themselves a reagent loading table in which isocyanide
and acid are invariable and benzylamines and ketons
are variable parameters. Therewith, benzylаmines are
labeled with digits and ketones, with letters (Scheme 2).
When loading is complete, plates are covered,
transferred to a shaker, and agitate at room temperature
for 20 min. Students should visually estimate the
efficiency of mixing.
The next step is to prepare solutions of the starting
compounds. The concentration of all solutions is
Lesson 2. Product isolation.
In the case of correct loading, all target compounds
precipitate. Depending on a concrete reagent set, the
reaction time varies from 4 to 6 h. Therefore, the second
practical lesson is recommended to be held on the next
day. (Note that prolonged keeping results in decreased
product yields).
Before the lesson, students should be instructed in
how to operate with the centrifuge and to discuss its
operation principles.
Then students prepare a washing liquid (ethanol–
water, 3:1).
Further actions depend on the type of the
centrifuge, and the best centrifuge here is a centrifuge
equipped with a special rotor for microplates.
However, almost any model with the rotation speed
3000–4000 rpm (Fig. 2) is suitable. Wet precipitates in
the plate are placed in an oven (< 50°С) and dried for
5–6 h.
Fig. 2. Centrifuge with a rotor for microplates.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 12 2010

PARALLEL UGI REACTION AT STUDENTS LABORATORIES
2651
δ, ppm
Fig. 3. 1Н NMR spectrum of compound А6.
can be used as references. A more detailed analysis of
admixtures is performed by 1H NMR (Figs. 3 and 4).
Lesson 3. Product analysis.
If all the above-described operations are fulfilled
properly, the purity of products is higher than 90%.
Since the reaction proceeds sufficiently completely in
all cases, the yields of products depend, first of all, on
their solubility in the washing liquid. The parallel
liquid-phase technology presented in our example
envisions the same is procedures for isolation of all
target compounds, which makes possible high isolation
rates but does not ensure high yields (Table 1).
As seen from Table 1, lower yields are observed for
compounds containing polar groups like pyridin-3-yl
or 4-methoxyphenyl. It was found that the target
compounds are partly lost with the washing liquid. The
water/ethanol ratio in the washing liquid affects the
yields and purity of the resulting products. For better
results this ratio can be varied to obtain the highest
yield for each series.
1H NMR spectra were measured for the compound
obtained by students. No further purification was
performed.
Students weigh the precipitates and determine the
yields of the target compounds, which should fall in
the range 40–80%.
Compound A6. mp 275–276°С, purity >95%. The
spectrum (Fig. 3) shows signals of ethanol, implying
incomplete drying. The spectrum of A6 is typical for
the entire series of compounds. The side-group signals
are readily identifiable: 2 methylene groups at 4.5–
5.0 ppm, 2 methyl groups at 1.0–1.5 ppm, and four
pyridyl signals at 7.4–8.8 ppm. The phthalyl fragment
signals are observed at 7.8–8.0 ppm as a four-proton
Then student analyze the target products by TLC
(an analytical chromatograph is also suitable). For
TLC, the samples are dissolved in chloroform and
chromatographed in CHCl3/ethanol (95:5). The
chromatograms are observed under a UV light, Rf
values are recorded. Reaction completeness is estimated
by the presence or absence of the isocyanide spot. The
samples synthesized by a previous group of students
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2652
MIRONOV, BABAEV
Fig. 4. 1Н NMR spectrum of compound В3.
multiplet. The phenylmorpholine fragment gives a charac-
teristic 4-signal set (2 signals of the aromatic moiety at
6.6–7.4 ppm and 2 signals of the aliphatic moiety at
3.0–3.7 ppm), one of which overlaps with the water
signal. The NH proton appears as a downfield signal at
8.8–9.2 ppm.
Reagents, materials, and instruments. Phthalyl
glycine, 4-(dimethylаminо)phenyl isocyanide, a series
of the simplest ketones:
O
O
O
O
Compound B3. mp 280–281°С, purity ~90%. The
1
admixtures (see the H NMR spectrum in Fig. 4) here
A
B
C
D
are the starting compounds: isocyanide and phthalyl
glycine. The signals are assigned by analogy with the
above compound. The difference consists in that the
methylene proton signals are nonequivalent, which is
characteristic of derivatives of unsymmetrical ketones.
A series of benzylamines:
N
N
S
O
Variant of Implementing the Task at the MSU
The given task was first suggested to students of the
Chemical Department of the MSU at the special
laboratory course in combinatorial chemistry in 2006.
The work was performed in SynСore apparatus for
parallel synthesis.
NH2
NH2
NH2
NH2
NH2
NH2
1
2
3
4
5
6
organic solvents, and SynCore apparatus.
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PARALLEL UGI REACTION AT STUDENTS LABORATORIES
2653
Table 2. Yields of target products in the Ugi reaction (%)
PRACTICAL IMPLEMENTATION
OF THE TASK
Amines
Ketones
1
2
3
4
5
6
Students get a variant with the task to synthesize
one compound by a multicomponent Ugi reaction. All
starting reagents are loaded in equimolar amounts
(1.0 mmol).
40
a
11
10
10
–
32
a
42
6
50
11
28
20
23
20
32
9
A
B
C
D
38
25
43
54
41
38
Lesson 1. Reagent loading.
A special tube for SynCore is provided by a label
corresponding to the variant obtained. For example,
B-3 (B is ketone and 3 is benzylamine). Each tube is
loaded, in strict sequence, with 1 ml of an alcohol
solution of amine, 1 ml of a ketone solution, 2 ml of an
isonitrile solution (in a hood), and 1 ml of a phthalyl
glycine solution. The tube is then placed into the
reaction module of SynCore and agitated for 4 h.
a The reaction was not performed.
is presented in Fig. 6. Comparison with the data in
Table 1 shows that the product yields are slightly
lower and the product purities are roughly the same as
in the original USTU version.
Lesson 2. Product isolation.
The precipitates are filtered off in the filtration
block of SynСore (Fig. 5a) and washed two times with
alcohol/water (3:1) in the parallel mode (Fig. 5b), after
which the tubes with precipitates were placed into a
vacuum drying oven.
(a)
Unlike the reductive аmination task [3], where on
filtering on Syncore we collected mother liquors, in the
given task we collect and separate precipitates
remaining in the reaction vessels. On filtering (Fig. 5a),
a stream of nitrogen is fed into all the 24 tubes. As a
result, the mother liquor is forced through 24 plastic
tubings. These tubings are then replaced with hermetic
seals, and the system is attached, by a common plastic
tubing, to a flask with the washing liquid (Fig. 5b). To
wash all the 24 precipitates simultaneously, a rubber
tubing is attached to vacuum, and the washing liquid
from the flask is admitted uniformly into all the
24 tubes. In necessary, the shaker is turned on, and the
precipitates are suspended. The filtration procedure is
repeated the required number of times.
(b)
Lesson 3. Assessment of the yield and purity of
products.
A clean vial is provided with a label with the task
variant and weighed. The precipitate is then transferred
into this vial, the latter is weighed again, and the yield
is estimated. The purity of the resulting compound is
determined by TLC, and smaples for spectral analysis
are taken.
Fig. 5. Attachment for SynCore apparatus for parallel
filtration of 24 suspensions: (a) for filtration, 24 plastic
tubings are attached to the left part of the attachment for
forcing over the mother liquors; and (b) for washing, a
bottle with a washing liquid is attached to the right part of
the attachment.
The percent yields of the Ugi reaction are listed in
Table 2, and an example spectrum of one the products
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2654
MIRONOV, BABAEV
O
H3C
H
CH3
N
N
O
H3C
O
O
N
S
CH3
Fig. 6. 1Н NMR spectrum of one of the obtained products.
5. Ugi, I. and Dömling, A., Angew. Chem. Int. Ed., 2000,
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