The Ugly Duckling Metamorphosis: The Ammonia/Formaldehyde Couple Made Possible in Ugi Reactions.

Article abstract of DOI:10.1002/ejoc.202001671

Ugi reactions are still a challenge when the concomitant use of ammonia and formaldehyde is required. Herein, we propose a strategy to overcome this challenge using hexamethylenetetramine (HMTA) as a singular key for the employment of these two simple starting materials in the Ugi reaction. Acylaminoacetamide derivatives were prepared in good to excellent yields by this new methodology. The scope and optimization of the reaction conditions were investigated. This novel methodology was successfully applied in the synthesis of two different diketopiperazines (DKPs) using the Ugi/Deprotection+Activation/Cyclization (UDAC) method. A continuous flow approach was also used in this methodology.

Full text of DOI:10.1002/ejoc.202001671

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The Ugly Duckling Metamorphosis: The
Ammonia/Formaldehyde Couple Made Possible in Ugi
Reactions
Thaissa Pasquali F. Rosalba,[a] Samia Sayegh A. Kas,[a] Ana Beatriz S. Sampaio,[a]
Carlos Eduardo M. Salvador,*[a] and Carlos Kleber Z. Andrade*[a]
Ugi reactions are still a challenge when the concomitant use of
ammonia and formaldehyde is required. Herein, we propose a
strategy to overcome this challenge using hexameth-
ylenetetramine (HMTA) as a singular key for the employment of
these two simple starting materials in the Ugi reaction.
Acylaminoacetamide derivatives were prepared in good to
excellent yields by this new methodology. The scope and
optimization of the reaction conditions were investigated. This
novel methodology was successfully applied in the synthesis of
two different diketopiperazines (DKPs) using the Ugi/Deprotec-
tion+Activation/Cyclization (UDAC) method. A continuous flow
approach was also used in this methodology.
Introduction
Multicomponent reactions (MCRs) stand out as an essential tool
in Combinatorial Chemistry with applications ranging from the
total synthesis of complex molecules, such as natural
products,[1] to high-throughput screening (HTS), since they
allow quick and efficient access to diverse libraries of
molecules.[2,3] The Ugi 4-component reaction (U-4CR), one of the
most relevant MCRs, consists of the condensation of an amine,
an aldehyde or ketone, an isocyanide, and a carboxylic acid to
form α-acylaminoamides in a one-pot reaction.[4] Since its
discovery in 1959,[4] the Ugi reaction has developed significantly
in terms of new insights and possibilities and nowadays is one
of the most versatile reactions known.
Figure 1. Big challenges posed by the Ugi reaction since its discovery.
Looking at its individual components, carboxylic acids can
be substituted by a variety of compounds, including azides[5]
and phenols.[6] Isocyanides can also be varied freely, but most
of them need to be prepared before use and sometimes this
can be time-consuming. Amines usually do not pose a problem,
except for ammonia in certain situations, and aldehydes have
no particular restrictions. On the other hand, the Ugi reaction
itself also posed some challenges to the scientific community
and most of them have been successfully addressed (Figure 1).
One of the biggest challenges ever faced was the development
of a catalytic enantioselective version of this reaction, which
was only achieved in 2018.[7] For many years, ammonia-Ugi
reactions were not possible, but now some efficient method-
ologies partly overcame this problem.[8] U-4CRs have also been
used as key steps in the synthesis of more complex molecules
such as macrocycles[9] and natural products.[1] Its mechanism,
originally proposed by Ugi, was controversial but has been
confirmed recently by mass spectrometry analysis.[10] Interest-
ingly, the only serious limitation of this reaction seems to be
the concomitant use of formaldehyde and ammonia, two of its
simplest components. Indeed, until now there has not been a
single methodology to accomplish this goal. For this reason, it
can be considered the ugly duckling in Ugi reactions.
Primary amines are the most common choice for U-4CRs,
leading to a wide variety of N-alkylated peptides. Secondary
amines can also be used in U-4CRs, yielding α-aminoamides.[11]
The problem arises when non-alkylated amides are required.
The best strategy to provide products containing free NH amide
bonds is to use ammonia as the amine component of the
reaction. For instance, some pharmacologically active targets
include free NH amide bonds in their structure, like the natural
products Ustiloxin D[12] and Epoxomycin,[13] and the marketed
drugs Carfilzomib[14] and Bortezomib[15] (Figure 2).
[a] T. P. F. Rosalba, S. S. A. Kas, A. B. S. Sampaio, Dr. C. E. M. Salvador,
Dr. C. K. Z. Andrade
Instituto de Química, Laboratório de Química Metodológica e Orgânica
Sintética (LaQMOS)
Universidade de Brasília
Campus Universitário, Asa Norte, 70904-970, Brasília, Brasil
E-mail: carloseduardo.salvador@gmail.com
ckleber@unb.br
Although some successful ammonia-Ugi reactions have
been reported,[8] earlier reports outline the formation of
complex mixtures with substantial byproducts, resulting in low
yields of the desired compound (the product being obtained
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as in polymer chemistry,[27] in material science[28] and in other
diverse applications.[20b] Furthermore, it is soluble in water and
in many other polar solvents.[27e]
Results and Discussion
Herein, we report a novel and straightforward approach
towards acylaminoacetamide derivatives via U-4CR with ammo-
nia and HMTA as a formaldehyde surrogate. Acylaminoaceta-
mides have important applications as starting materials for the
synthesis of various heterocycles including 2,5-diketopipera-
zines (2,5-DKPs),[29] oxazoles,[30] thiazoles,[31] oxazolones,[32] and
imidazolones.[33] As part of an ongoing study into 2,5-DKPs, we
have found that HMTA, when reacted with ammonia in the U-
4CR, is a source of formaldehyde and eventually of the
respective imine formed when these two starting materials
react together. The results of this finding are outlined below.
For the optimization of the reaction conditions, we used the
U-4CR of ammonia (methanolic solution), paraformaldehyde, t-
butyl isocyanide, and acetic acid in methanol as a proof of
concept (Table 1). Not surprisingly, in the first reaction using
paraformaldehyde as the oxo component, at room temperature
for 24 h, no product was obtained (entry 1), similarly to what
has been reported in the literature.[8f,g] Following conditions
previously studied in our group for the MW-mediated Ugi
Figure 2. Natural products and marketed drugs containing free NÀ H amide
bonds.
only as the minor product or in trace amounts).[8h,16] Due to the
importance of this class of U-4CRs, the possible side reactions
that can take place have been under scrutiny, leading to the
observation that a six-component coupling is favored over U-
4CR, depending on the experimental conditions (relative ratio
of the components, nucleophilicity of the solvent and type of
aldehydes).[17] Aldol-type reactions between ammonia and the
oxo components are another drawback.[8g] Other studies also
showed that the problems in ammonia-Ugi reactions can be
overcome by employing sterically hindered aldehydes.[8b,e,12b,18]
However, this makes the use of formaldehyde nearly impossible
for this kind of reaction.[8g] The best alternative seems to be the
use of protected amines as an ammonia replacement, which
requires subsequent deprotection, increasing the number of
steps in the synthetic route.[19] Due to all the problems
associated with the use of ammonia in Ugi reactions, and since
there is no successful example of the concomitant use of
ammonia and formaldehyde in Ugi reactions described in the
literature, developing an adequate methodology is desirable.
It has been reported that the hydrothermal decomposition
of hexamethylenetetramine (HMTA) can generate ammonia and
formaldehyde in situ (Scheme 1).[20] In fact, the slow hydrolysis
of HMTA to these compounds seems to explain its effectiveness
as an antibacterial agent.[20b] Further studies revealed the
formation of many reactive and unstable intermediates in this
decomposition process that eventually leads to aminometh-
ylene (CH2 =NH).[21] In view of these findings, we envisaged the
possibility of using HMTA as a reagent in Ugi-4CRs. HMTA is an
inexpensive white and hygroscopic solid obtained by the
condensation of formaldehyde and ammonia,[22] and its deriva-
tives have found outstanding applications in catalysis
processes,[23] in coordination chemistry,[24] in the synthesis of
organic and inorganic products,[25] in electrochemistry[26] as well
reaction,[34] the same reagents were heated at 80 C in a MW
°
reactor for 15 minutes, and now the desired product was
obtained albeit in low yield (entry 2). Other ammonia sources
(NH4OAc or NH4Cl) did not furnish the product (entries 3 and 4).
Adding a catalytic amount of HMTA to the microwave-mediated
reaction did not improve the yield (entry 5). In the following
trial, it was observed that a stochiometric use of HMTA
improved the yield to 53% (entry 6), which unveils the
importance of HMTA to the reaction.
Encouraged by these results, paraformaldehyde was re-
moved from the reaction, and, to our delight, the product yield
increased to 83% (entry 7). This suggests that HMTA is
efficiently generating formaldehyde in situ and the added
paraformaldehyde used before was probably reacting in the
side reactions that usually occur in ammonia-Ugi reactions,
decreasing the product yield. This same reaction was carried
out at room temperature for 24 h and under reflux for 2 h. In
the first case, no product was obtained (entry 8) but the latter
furnished the expected product in excellent yield (entry 9),
corroborating that the decomposition of HMTA only occurs
under heating conditions. When two equivalents of ammonia
and HMTA were used, a lower yield was observed (entry 10).
This can be explained by the results obtained by Hebach
et al.[17b] in which a six-component product should be favored if
an excess of aldehyde, relative to the isocyanide, is used.
Interestingly, the presence of ammonia is essential for the
success of the reaction, since when it was not included in the
reaction mixture, the product was obtained in minor amounts
together with a complex mixture of products (entry 11).
Looking at the stoichiometry of HMTA decomposition, a
catalytic amount of ammonia would suffice but the use of
Scheme 1. Hydrothermal decomposition of HMTA furnishes formaldehyde
and ammonia.
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Table 1. Optimization of the Reaction Conditions.[a]
°
Entry
HMTA (equiv.)
Paraformaldehyde (equiv.)
NH3 source (equiv.)
Temperature [ C]
Time
Solvent
Yield of 2a [%]
1
2
3
–
–
–
1
1
1
NH3 (1)
NH3 (1)
NH4Oac
(1)
r.t.
MW/80
MW/80
24 h
10 min
10 min
MeOH
MeOH
MeOH
–
24
–
4
–
1
NH4Cl
(1)
MW/80
10 min
MeOH
–
5
6
7
8
0.1
1
1
1
1
2
1
1
1
1
1
–
–
–
–
–
–
–
–
–
–
NH3 (1)
NH3 (1)
NH3 (1)
NH3 (1)
NH3 (1)
NH3 (2)
–
NH3 (0.10)
NH3 (0.25)
NH3 (0.40)
NH3 (1)
NH3 (1)
MW/80
MW/80
MW/80
r.t.
Reflux
MW/80
MW/80
MW/80
MW/80
MW/80
MW/80
MW/80
10 min
10 min
10 min
24 h
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN
CH3CN/MeOH
(3:1)
25
53
83
–
9
2 h
90
77
10
11
12
13
14
15
16
10 min
10 min
10 min
10 min
10 min
10 min
10 min
[b]
–
42
86
93
1
1
1
Poor solubility
87
17
18
1
1
–
–
NH3 (1)
NH4Oac (1)
MW/80
MW/80
10 min
10 min
TFE
TFE
96
80
[a] Reaction conditions: unless otherwise noted, equimolar amounts of each reagent (0.5 mmol scale) were used. [b] The product was obtained in minor
amounts together with a complex mixture of products.
Table 2. Screening of the reaction time and temperature.[a]
0.1 equivalent of ammonia furnished only a moderate reaction
yield (entry 12), whereas much better yields were obtained with
the use of substoichiometric amounts (entries 13 and 14).
Aiming at the total consumption of the reagents, we opted to
Entry
Time
[min]
Temperature
Yields
(%)
move further using an equivalent amount of ammonia.
°
[ ]
It is known that U-4CRs work better in polar protic solvents,
MeOH being the most common solvent used. Nevertheless,
some studies that analyzed the pathway of the ammonia-Ugi
reaction reported that in the first step of the mechanism the
imine formed does not react directly with the isocyanide, but
with another nucleophile (ammonia or the solvent), when
methanol is used.[17] In order to study the solvent effect on the
HMTA-mediated Ugi reaction, the less nucleophilic acetonitrile
was first investigated, but the reagents were poorly soluble in it
(Table 1, entry 15). When a 3:1 mixture of acetonitrile/methanol
was used, the product was obtained in good yield (entry 16).
Finally, the much less nucleophilic 2,2,2-trifluoroethanol (TFE)
proved to be the solvent of choice (entry 17) furnishing the
product in very high yield even when NH4(OAc) was used as
ammonia source (entry 18).
1
2
3
4
5
6
7
8
15
15
15
15
10
10
5
40
50
60
70
80
70
70
80
–
Traces
63
94
96
66
49
82
5
[a] Reaction conditions: equimolar amounts of each reagent (0.5 mmol
scale) were used.
With these optimized reaction conditions in hand (MW, TFE
as solvent, at 80 C for 10 minutes), the reaction scope was next
°
studied by varying the carboxylic acid (aromatic, heteroaro-
matic, aliphatic, cyclic, and amino acids) and the isocyanide
(aliphatic, cyclic, an isocyanide derived from the methyl ester of
glycine and a convertible isocyanide). In total, more than 20
different reactions were carried out (Scheme 2). Remarkably,
only one product was isolated in all reactions. Therefore, the
byproducts usually formed under previous conditions, espe-
cially when unhindered aldehydes are used, were not being
generated. Aliphatic carboxylic acids gave excellent yields (2a,
2b, 2h, 2i, 2o, and 2s). Aromatic and heteroaromatic carboxylic
acids also gave acceptable yields (2c, 2d, 2j, 2k, and 2p).
Further tests were then carried out to screen the microwave
conditions regarding the reaction time and temperature
(Table 2). Keeping a constant reaction time of 15 minutes, it can
°
°
be seen that at lower temperatures (40 C and 50 C) no product
°
was obtained at all (entries 1–2). When raised to 60 C, a
moderate yield was obtained (entry 3) and reached its max-
°
imum at 80 C (entry 5, same conditions described in Table 1,
entry 14) but the yields dropped when shorter reactions times
were used (Table 2, entries 6–8).
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Scheme 2. Scope of the ammonia-Ugi reaction mediated by HMTA.
Interestingly, the reactions with bromoacetic acid failed to give
any product but when azidoacetic acid was used, good to
excellent yields were obtained (2e, 2l, and 2q). Amino acids
gave moderate but consistent yields (2f, 2g, 2m, 2n, and 2r)
since they are less reactive than the other carboxylic acids
employed in these reactions. Compound 2s was obtained from
formic acid, and possibly represents the simplest non-alkylated
Ugi adduct ever synthesized.
Searching the literature, we found that three of the
obtained molecules have already been synthesized by different
methods using at least two steps (in two cases), equivalent
amounts of peptide coupling agents, excess reagents, and an
ionic liquid as solvent (in one case).[35] Our method is much
faster with only one purification step and yields the products in
better overall yields, except in one case (Scheme 3). Further-
more, our method is more versatile, since it allows modification
of the substrates at both ends by freely changing the acids and
isocyanides.
Scheme 3. Comparison with other published methods.
It has been observed that adding ammonia solution is
crucial for the success of the reaction (Table 1, entry 11) but its
role in this process was not yet clear. To get a better insight,
ammonia was replaced by methylamine and the reaction was
carried out under the already optimized conditions (Scheme 4).
An 85:15 mixture of products (measured by integration of the
1H NMR spectrum) was obtained in 85% overall yield after
purification. The main product 3 comes from the U-4CR with
methylamine proving that adding ammonia as one of the four
components is essential and that HMTA is the source of
formaldehyde but is not the main source of ammonia. This
result indicates that this methodology can be used with other
amines as well.
Scheme 4. HMTA-mediated Ugi reaction using methylamine.
To account for the observed results, we postulate that
HMTA decomposition is facilitated by heating (water might
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Scheme 5. Proposed reaction path to account for the observed results.
Table 3. Optimization of the synthesis of Armstrong’s isocyanide 5 under
MW heating.
come from hydrated HMTA), generating enough formaldehyde
(no need for adding it as one of the components), and the
excess ammonia shifts the equilibrium towards the formation of
the reactive imine species (CH2 =NH) allowing the reaction to
occur (Scheme 5). When methylamine is present, it competes
favorably with ammonia due to its greater nucleophilicity and
reacts with formaldehyde yielding the main product 3.
One of the possible applications of the acylaminoaceta-
mides obtained herein is in the synthesis of diketopiperazines
(DKPs), cyclodipeptides with privileged structures that give
them a wide range of characteristics with importance in drug
discovery.[29] An efficient methodology to prepare DKPs is the
use of the Ugi/Deprotection+Activation/Cyclization protocol
(UDAC),[36] in which the use of N-Boc protected amino acids and
convertible isocyanides as Ugi substrates, followed by acid
deprotection of the linear Ugi adduct, allows cyclization to take
place (Scheme 6).
Entry
Burgess reagent
(equiv.)
Temperature
Time
[min]
Conversion[a]
[%]
°
[ C]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.5
1.5
2.0
2.0
2.0
2.0
2.5
50
50
80
80
100
50
80
50
50
50
80
50
5
10
5
10
5
5
5
5
60
59
80
74
54
71
78
79
94
95
86
>99
9
10
15
5
10
11
12
10
Thus, we employed our new method in this protocol using
N-Boc alanine and N-Boc serine with Armstrong’s isocyanide
5,[36] which can be cleaved after acidic treatment. This
isocyanide is not commercially available, and decomposes
easily, so it should be used immediately after synthesized or
[a] Determined by HPLC-UV analyses.
[37a]
°
stored at À 30 C under an inert atmosphere.
In our case, the
mediated synthesis of Armstrong’s isocyanide. Moderate con-
°
best alternative was to instantly use it, with no previous
purification, but first, we needed to adapt its synthesis to a
microwave reactor, since our method needs higher temper-
versions were observed at 50 C (entries 1 and 2), which
°
increased substantially at 80 C (entry 3) but decreased at higher
temperature or prolonged reaction times (entries 4, 5, and 11),
probably due to isocyanide decomposition. Increasing the
amount of the Burgess reagent led to the improvement of the
°
atures (70–80 C) and most examples in the literature describe
[36]
°
the synthesis of 5 under a much lower temperature (0 C).
°
Despite these drawbacks, we decided to investigate this
approach using isocyanide 5 because the reagents necessary
for its synthesis were available in our laboratory. Initially, the
conversion and reached full conversion at 50 C with 2.5 equiv.
of the Burgess reagent (entries 6–12). The ideal condition is
depicted in entry 12.
respective formamide
4
was prepared using an already
With the reaction conditions well established, some Ugi
adducts were prepared from convertible isocyanide 5 and N-
Boc amino acids (Scheme 7). To concomitantly avoid isocyanide
decomposition and allow the reaction to occur, the temper-
established methodology.[36b] Next, an extensive screening of
the reaction conditions under microwave heating using Burgess
reagent as the dehydrating agent was carried out (Table 3),
varying its amount, the temperature, and the reaction time. To
the best of our knowledge, this is the first report on the MW-
°
ature was set to 70 C according to the conditions described in
Table 2 (entry 4). The Ugi products 8a–c were obtained in
relatively low yields (34–40%), which were initially attributed to
isocyanide
decomposition
due
to
heat-initiated
polymerization[38] under the applied conditions and to the fact
that 5 is less reactive than the other isocyanides used. Despite
the yields not being as good as those described in Scheme 1,
we anticipated that better yields could be achieved using more
stable convertible isocyanides. To test this hypothesis, the more
stable convertible isocyanide 6 was prepared[39] and inves-
tigated in this methodology. Nevertheless, similar yields for
Scheme 6. The Ugi/Deprotection+Activation/Cyclization (UDAC) strategy for
the synthesis of diketopiperazines (DKPs).
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experimental conditions for the isocyanide formation (Table 3,
entry 12) and the HMTA-mediated ammonia-Ugi reaction
(Scheme 1). A T-shaped mixer (TM1) was used to combine an
acetonitrile solution of formamide 4 from injection loop SL1
with the Burgess reagent solution in acetonitrile from SL2 in
order to carry out the dehydration reaction. The mixed solution
passed through a perfluoroalkoxy alkane (PFA) coil tubing
°
reactor (CTR1) at 50 C, with a 10 min residence time (RT). The
resulting isocyanide 5 solution then merged, in TM2, with a TFE
solution of acetic acid, HMTA, and NH3 from SL3. To execute the
Ugi reaction, the merged reaction solution, with a global flow
rate of 670 μL.minÀ 1 was passed through a 10 mL PFA reactor
°
(CTR2), heated at 70 C, with an RT of 15 min. The final product
was collected after passing through a back-pressure regulator
(BPR, 3 bar). Despite all the efforts to improve the reaction
efficiency, the Ugi product 8c was achieved at similar low yields
(38%) as obtained in the batch protocol. However, the
continuous flow methodology developed herein opens the
possibility for the rapid scale-up of these Ugi products for future
applications.
Scheme 7. Ugi reaction between ammonia, HMTA, isocyanides 5, 6, 7, and
different carboxylic acids.
compounds 8d–f were obtained (Scheme 7), indicating that
aromatic and vinylic isocyanides do not react well in this Conclusion
methodology in contrast to the good results obtained for
isocyanides 5 and 6 under normal Ugi-4C conditions. In order
to confirm this tendency, the stable aromatic isocyanide 7
derived from aniline was tested and also gave moderate yields
of products 8g–8h.
Boc group deprotection and enamide cleavage under acidic
medium allowed cyclization to occur in one step, furnishing
DKPs 9a and 9b in quantitative yields, with no need of
purification (Scheme 8). DKP 9b is part of a natural product
called pepticinnamin E,[40] an inhibitor of the enzyme farnesyl-
transferase, whose total synthesis is being carried out in our
research group.
In an attempt to both minimize polymerization and increase
the reaction yields, and based on our previous experience in
flow chemistry,[41] we decided to carry out the synthesis of
isocyanide 5 and the HMTA-promoted ammonia-Ugi reaction
under continuous flow conditions since it is possible to have
better control of temperature and reaction time using flow
technologies than in microwave batch reactions.
In summary, a highly efficient and reliable protocol to perform
Ugi reactions using the ammonia/formaldehyde couple (the
former ugly duckling of Ugi reactions) was developed using
hexamethylenetetramine (HMTA) as a formaldehyde surrogate.
This unprecedented approach offers a simple, one-step assem-
bly of U-4CR adducts with free NH amide bonds in their
structures. The possibility to generate these compounds in a
one-pot procedure in good to excellent yields is noteworthy,
especially when considering the low efficiency of existing
methods. 22 compounds were obtained by this methodology,
most of which are new compounds. We have also shown one of
the many applications of this methodology for the synthesis of
DKPs. A continuous flow approach was also developed, which
allows the scale-up of the process. We believe this methodology
will be of great interest not only for those working in the field
of MCRs but also for synthetic and for Medicinal Chemistry
applications.
For the telescope continuous flow synthesis of Ugi product
8c (Scheme 9), we used the previously established batch Experimental Section
General Information
Reactions were performed on a CEM Co., Discover microwave
reactor using sealed vessels, dynamic program, temperature
detection by internal fiber optic probe, simultaneous cooling, and
media stirring. Commercially available reagents and solvents were
analytical grade or were purified by standard procedures prior to
use. All reactions were monitored by thin-layer chromatography
(TLC) and revealed by treatment with
a 10% solution of
phosphomolybdic acid in ethanol (PMA), followed by heating.
Column chromatography was performed on silica gel (70–
230 mesh) and the solvents used as eluents are described for each
molecule. Nuclear magnetic resonance spectra (NMR) were re-
corded on a Bruker Avance 600 spectrometer (1H NMR (600 MHz),
Scheme 8. Synthesis of DKPs 9a and 9b using the Ugi Deprotection
+Activation-Cyclization (UDAC) method.
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Scheme 9. Continuous flow synthesis of compound 8c.
13
°
C NMR (151 MHz)) at 25 C with TMS as an internal standard for
96% yield (0.082 g) as a white solid after silica gel column
CDCl3 as solvent. DMSO-d6 and D2O were also used as solvents.
High-resolution mass spectra (HRMS) were obtained on a Micro ESI-
TOF Bruker Daltonics instrument. Melting points were measured on
micro melting point apparatus and uncorrected. Analytical HPLC
(Shimadzu LC20) analysis was carried out on a C18 reversed-phase
(RP) analytical columm (150×4.6 mm, particle size 5 μm) using
mobile phases A (water/acetonitrile 90:10 (v/v) +0.1% TFA) and B
(acetonitrile+0.1% TFA) at a flow rate of 1.5 mL/min. The following
gradient was applied: linear increase from 30 to 100% B in
12 minutes. For continuous flow procedures, a KDS 210 Legacy dual
syringe pump and a Vapourtec SF-10 reagent pump were used.
Static backpressure, modular mixers, sample manual injectors,
fittings, and tubings are commercially available from Idex Health
&Science.
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
°
acetate). Rf =0.30 (100% ethyl acetate); m.p. 160–161 C. (lit. m.p.
°
161–162 C).
1H NMR (600 MHz, CDCl3) δ 6.83 (s, 1H), 6.44 (s, 1H), 3.85 (d, J=
6.0 Hz, 2H), 2.03 (s, 3H), 1.36 (s, 9H). 13C NMR (151 MHz, CDCl3) δ
170.7, 168.0, 51.4, 43.9, 28.6, 22.9. HRMS (ESI-TOF) m/z calculated
for C8H16N2O2 +Na+: 195.1109 [M+Na]+; found: 195.1110.
Acylaminoacetamide 2b
2b was obtained from cyclopropanecarboxylic acid (0.50 mmol,
0.040 mL) and tert-butyl isocyanide (0.50 mmol, 0.056 mL), follow-
ing method A, in 90% yield (0.089 g) as a white solid after silica gel
column chromatography (40% ethyl acetate/hexane!70% ethyl
acetate/hexane). Rf =0.53 (80% ethyl acetate/hexane); m.p. 151–
General procedure for the Ugi reactions
°
152 C.
1H NMR (600 MHz, CDCl3) δ 6.78 (s, 1H), 6.36 (s, 1H), 3.89 (d, J=
6.0 Hz, 2H), 1.53–1.44 (m, 1H), 1.37 (s, 9H), 1.00–0.92 (m, 2H), 0.84–
0.73 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 174.0, 168.1, 51.4, 44.1,
28.7, 14.5, 7.3. HRMS (ESI-TOF) m/z calculated for C10H18N2O2 +Na+:
221.1266 [M+Na]+; found: 221.1262.
Method A
A sealed 10 mL glass tube containing a mixture of carboxylic acid
(0.50 mmol), hexamethylenetetramine 1 (0.50 mmol, 0.070 g), am-
monia solution 7 M (0.50 mmol, 0.070 mL), and isocyanide
(0.50 mmol) in TFE (2 mL) was introduced in the cavity of a
°
microwave reactor (CEM Co., Discover) and irradiated at 80 C for
Acylaminoacetamide 2c
10 min (ramp time: 98 s) under magnetic stirring. The reaction
mixture was concentrated in vacuum and purified by column
chromatography.
2c was obtained from benzoic acid (0.50 mmol, 0.061 g) and tert-
butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
65% yield (0.076 g) as a white solid after silica gel column
chromatography (20% ethyl acetate/hexane!50% ethyl acetate/
Acylaminoacetamide 2a
°
hexane). Rf =0.50 (50% ethyl acetate/hexane); m.p. 148–149 C.
2a was obtained from acetic acid (0.50 mmol, 0.030 mL) and tert-
butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
1H NMR (600 MHz, CDCl3) δ 7.88 (d, J=12,0 Hz, 2H), 7.53 (t, J=
6.0 Hz, 1H), 7.49 (s, 1H), 7.45 (t, J=6.0 Hz, 2H), 6.54 (s, 1H), 4.13 (d,
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J=6.0 Hz, 2H), 1.41 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 168.1, 167.6,
133.6, 131.7, 128.5, 127.1, 51.6, 44.3, 28.7. HRMS (ESI-TOF) m/z
calculated for C13H18N2O2 +Na+: 257.1266 [M+Na]+; found:
257.1264.
in 91% yield (0.090 g) as a white solid after silica gel column
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
°
acetate). Rf =0.26 (100% ethyl acetate). m.p. 182–183 C.
1H NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.33 (s, 1H), 3.90 (d, J=
6.0 Hz, 2H), 3.79–3.65 (m, 1H), 2.06 (s, 3H), 1.93–1.87 (m, 2H), 1.77–
1.69 (m, 2H), 1.65–1.58 (m, 1H), 1.43–1.32 (m, 2H), 1.24–1.15 (m, 3H).
13C NMR (151 MHz, CDCl3) δ 170.7, 167.8, 48.4, 43.5, 32.8, 25.4, 24.7,
22.9. HRMS (ESI-TOF) m/z calculated for C10H18N2O2 +Na+: 221.1266
[M+Na]+; found 221.1264.
Acylaminoacetamide 2d
2d was obtained from pyrazinoic acid (0.50 mmol, 0.062 g) and
tert-butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
68% yield (0.080 g) as a white solid after silica gel column
chromatography (50% ethyl acetate/hexane!70% ethyl acetate/
°
Acylaminoacetamide 2i
hexane). Rf =0.44 (100% ethyl acetate); m.p. 155–156 C.
1H NMR (600 MHz, CDCl3) δ 9.39 (s,1H), 8.78 (s, 1H), 8.58 (dd, J=6.0;
1.5 Hz, 1H), 8.52 (s, 1H), 6.02 (s, 1H), 4.12 (d, J=6.0 Hz, 2H), 1.41 (s,
9H).13C NMR (151 MHz, CDCl3) δ 167.1, 163.3, 147.5, 144.2, 144.1,
142.8, 51.7, 43.5, 28.7. HRMS (ESI-TOF) m/z calculated for C11H16N4O2
+Na+: 259.1171 [M+Na]+; found: 259.1177.
2i was obtained from cyclopropanecarboxylic acid (0.50 mmol,
0.040 mL) and cyclohexyl isocyanide (0.50 mmol, 0.062 mL), follow-
ing method A, in 89% yield (0.099 g) as a white solid after silica gel
column chromatography (50% ethyl acetate/hexane!80% ethyl
acetate/hexane). Rf =0.45 (80% ethyl acetate/hexane). m.p. 181–
°
182 C.
1H NMR (600 MHz, CDCl3) δ 6.81 (s, 1H), 6.56 (s, 1H), 3.94 (d, J=
6.0 Hz, 2H), 3.81–3.71 (m, 1H), 1.95–1.87 (m, 2H), 1.78–1.69 (m, 2H),
1.66–1.59 (m, 1H), 1.54–1.47 (m, 1H), 1.42–1.32 (m, 2H), 1.24–1.13
(m, 3H), 1.00–0.93 (m, 2H), 0.82–0.76 (m, 2H). 13C NMR (151 MHz,
CDCl3) δ 174.2, 168.0, 48.3, 43.7, 32.8, 25.5, 24.7, 14.4, 7.4. HRMS
(ESI-TOF) m/z calculated for C12H20N2O2 +Na+: 247.1422 [M+Na]+;
found 247.1419.
Acylaminoacetamide 2e
2e was obtained from azidoacetic acid (0.50 mmol, 0.035 mL) and
tert-butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
81% yield (0.086 g) as a white solid after silica gel column
chromatography (30% ethyl acetate/hexane!60% ethyl acetate/
°
hexane). Rf =0.57 (80% ethyl acetate/hexane). m.p. 134–136 C.
1H NMR (600 MHz, CDCl3) δ 7.31 (s, 1H), 6.18 (s, 1H), 4.00 (s, 2H),
3.90 (d, J=6.0 Hz, 2H), 1.37 (s, 9H).13C NMR (151 MHz, CDCl3) δ
167.2, 167.1, 52.4, 51.6, 43.3, 28.6. HRMS (ESI-TOF) m/z calculated
for C8H15N5O2 +Na+: 236.1123 [M+Na]+; found 236.1120.
Acylaminoacetamide 2j
2j was obtained from benzoic acid (0.50 mmol, 0.061 g) and
cyclohexyl isocyanide (0.50 mmol, 0.062 mL), following method A,
in 68% yield (0.088 g) as a white solid after silica gel column
chromatography (30% ethyl acetate/hexane!60% ethyl acetate/
Acylaminoacetamide 2f
°
hexane). Rf =0.36 (50% ethyl acetate/hexane). m.p. 164–165 C.
2f was obtained from Boc-L-Alanine (0.50 mmol, 0.090 g) and tert-
butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
53% yield (0.079 g) as a white solid after silica gel column
chromatography (40% ethyl acetate/hexane!80% ethyl acetate/
1H NMR (600 MHz, CDCl3) δ 7.87 (d, J=6.0 Hz, 2H), 7.54 (t, J=6.0 Hz,
1H), 7.46 (t, J=6.0 Hz, 3H), 6.62 (s, 1H), 4.16 (d, J=6.0 Hz, 2H), 3.81
(s, 1H), 1.93 (d, J=12.0 Hz, 2H), 1.73 (d, J=12.0 Hz, 2H), 1.62 (d, J=
12.0 Hz, 1H), 1.41–1.33 (m, 2H), 1.26–1.18 (m, 3H).13C NMR (151 MHz,
CDCl3) δ 168.0, 167.8, 133.6, 131.8, 128.6, 127.1, 48.5, 43.9, 32.8,
25.4, 24.7. HRMS (ESI-TOF) m/z calculated for C15H20N2O2 +Na+:
283.1422 [M+Na]+; found 283.1422.
°
hexane). Rf =0.28 (70% ethyl acetate/hexane). m.p. 148–149 C.
1H NMR (600 MHz, CDCl3) δ 7,06 (s, 1H); 6.25 (s, 1H), 5.18 (s, 1H),
4.19 (s, 1H), 3.93–3.82 (m, 2H), 1.46 (s, 9H), 1.39 (d, J=6.0 Hz, 3H),
1.36 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 173.2, 167.8, 155.5, 80.2,
51.4, 50.5, 43.7, 28.6, 28.3, 18.4. HRMS (ESI-TOF) m/z calculated for
C14H27N3O4 +Na+ 324.1899 [M+Na]+; found 324.1905.
Acylaminoacetamide 2k
2k was obtained from pyrazinoic acid (0.50 mmol, 0.062 g) and
cyclohexyl isocyanide (0.50 mmol, 0.062 mL), following method A,
in 64% yield (0.083 g) as a white solid after silica gel column
chromatography (50% ethyl acetate/hexane!80% ethyl acetate/
Acylaminoacetamide 2g
2g was obtained from Boc-D-serine (0.50 mmol, 0.100 g) and tert-
butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
52% yield (0.082 g) as a white solid after silica gel column
chromatography (70% ethyl acetate/hexane!100% ethyl acetate).
°
hexane). Rf =0.43 (100% ethyl acetate). m.p. 176–177 C.
1H NMR (600 MHz, CDCl3) δ 8.79 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H),
6.07 (s, 1H), 4.16 (d, J=6.0 Hz, 2H), 3.82 (m, 1H), 1.99–1.92 (m, 2H),
1.74–1.70 (m, 2H), 1.67–1.60 (m, 1H), 1.44–1.33 (m, 2H), 1.25–1.14
(m, 3H). 13C NMR (151 MHz, CDCl3) δ 167.1, 163.5, 147.5, 144.3,
144.0, 142.8, 48.6, 43.3, 32.9, 25.4, 24.7. HRMS (ESI-TOF) m/z
calculated for C13H18N4O2 +Na+: 285.1327 [M+Na]+; found
285.1324.
°
Rf =0.24 (80% ethyl acetate/hexane). m.p. 112–113 C.
1H NMR (600 MHz, CDCl3) δ 7.44 (s, 1H), 6.33 (s, 1H), 5.78 (s, 1H),
4.25 (s, 1H), 4.03 (d, J=6.0 Hz, 1H), 3.95–3.80 (m, 2H), 3.72 (s, 1H),
1.46 (s, 9H), 1.35 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 171.8, 168.0,
155.9, 80.5, 63.0, 56.0, 51.6, 43.6, 28.6, 28.3. HRMS (ESI-TOF) m/z
calculated for C14H27N3O5 +Na+: 340.1848 [M+Na]+; found
340.1853.
Acylaminoacetamide 2l
Acylaminoacetamide 2h
2l was obtained from azidoacetic acid (0.50 mmol, 0.035 mL) and
cyclohexyl isocyanide (0.50 mmol, 0.062 mL), following method A,
in 85% yield (0.101 g) as a white solid after silica gel column
2h was obtained from acetic acid (0.50 mmol, 0.030 mL) and
cyclohexyl isocyanide (0.50 mmol, 0.062 mL), following method A,
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chromatography (40% ethyl acetate/hexane!70% ethyl acetate/
1H NMR (600 MHz, CDCl3) δ 7.84 (d, J=6.0 Hz, 2H), 7.51 (t, J=6.0 Hz,
°
hexane). Rf =0.23 (60% ethyl acetate/hexane). m.p. 159–160 C.
1H), 7.42 (t, J=6.0 Hz, 3H), 7.18 (s, 1H), 4.22 (d, J=6.0 Hz, 2H), 4.06
(d, J=6.0 Hz, 2H), 3.73 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 170.1,
169.6, 168.0, 133.3, 131.9, 130.0, 128.6, 128.4, 127.2, 52.4, 43.5, 41.2.
HRMS (ESI-TOF) m/z calculated for C12H14N2O4 +Na+: 273.0851 [M+
Na]+; found 273.0847.
1H NMR (600 MHz, CDCl3) δ 7.19 (s, 1H), 6.05 (s, 1H), 4.01 (s, 2H),
3.93 (d, J=6.0 Hz, 2H), 3.81–3.72 (m, 1H), 1.97–1.84 (m, 2H), 1.75–
1.69 (m, 2H), 1.66–1.57 (m, 1H), 1.43–1.30 (m, 2H), 1.23–1.10 (m, 3H).
13C NMR (151 MHz, CDCl3) δ 167.2, 166.9, 52.4, 48.6, 43.0, 32.9, 25.4,
24.7. HRMS (ESI-TOF) m/z calculated for C10H17N5O2 +Na+: 262.1280
[M+Na]+; found 262.1281.
Acylaminoacetoamide 2q
2q was obtained from azidoacetic acid (0.50 mmol, 0.035 mL) and
methyl isocyanoacetate (0.50 mmol, 0.045 mL), following method A,
in 93% yield (0.106 g) as a yellow solid after silica gel column
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
Acylaminoacetamide 2m
2m was obtained from Boc-L-alanine (0.50 mmol, 0.090 g) and
cyclohexyl isocyanide (0.50 mmol, 0.062 mL), following method A,
in 55% yield (0.089 g) as a white solid after silica gel column
chromatography (60% ethyl acetate/hexane!90% ethyl acetate/
°
acetate). Rf =0.30 (100% ethyl acetate). m.p. 134–136 C.
1H NMR (600 MHz, CDCl3) δ 7.17 (s, 1H), 6.79 (s, 1H), 4.07 (d, J=
6.0 Hz, 2H), 4.05 (d, J=6.0 Hz, 2H), 4.04 (s, 2H), 3.77 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 170.0, 168.5, 167.5, 52.5, 52.4, 42.7, 41.2. HRMS
(ESI-TOF) m/z calculated for C7H11N5O4 +Na+: 252.0709 [M+Na]+;
found 252.0703.
°
hexane). Rf =0.20 (80% ethyl acetate/hexane). m.p. 113–114 C.
1H NMR (600 MHz, CDCl3) δ 7.16 (s, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.28
(s, 1H), 4.15 (s, 1H), 3.95 (dd, J=16.0; 6.0 Hz, 1H), 3.89 (dd, J=16.0;
J=6.0 Hz, 1H), 3.74 (m, 1H), 1.88 (d, J=18.0 Hz, 2H), 1.71 (d, J=
18.0 Hz 2H), 1.60 (d, J=18.0 Hz, 1H), 1.45 (s, 9H), 1.38 (d, J=12.0 Hz,
3H), 1.36–1.30 (m, 2H), 1.26–1.10 (m, 3H). 13C NMR (151 MHz, CDCl3)
δ 173.4, 167.9, 155.6, 80.3, 53.4, 50.6, 48.4, 43.3, 32.8, 32.7, 28.3,
25.4, 24.8, 18.2. HRMS (ESI-TOF) m/z calculated for C16H29N3O4 +Na+
: 350.2056 [M+Na]+; found 350.2057.
Acylaminoacetamide 2r
2r was obtained from Boc-L-alanine (0.50 mmol, 0.090 g) and
methyl isocyanoacetate (0.50 mmol, 0.045 mL), following method A,
in 63% yield (0.067 g) as a yellow solid after silica gel column
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
°
Acylaminoacetamide 2n
acetate). Rf =0.30 (100% ethyl acetate). m.p. 116–118 C.
2n was obtained from Boc-D-serine (0.50 mmol, 0.100 g) and
cyclohexyl isocyanide (0.50 mmol, 0.062 mL), following method A,
in 56% yield (0.096 g) as a yellow solid after silica gel column
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
1H NMR (600 MHz, DMSO-d6) δ 8.20 (t, J=6.0 Hz, 1H), 8.12 (t, J=
6.0 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 3.98 (t, J=6.0 Hz, 1H), 3.85 (dd,
J=12.0, 6.0 Hz, 2H), 3.73 (d, J=6.0 Hz, 2H), 3.63 (s, 3H), 1.38 (s, 9H),
1.19 (d, J=6.0 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 173.5, 170.5,
169.8, 155.7, 78.7, 52.1, 50.2, 42.2, 40.9, 28.6, 18.3. HRMS (ESI-TOF)
m/z calculated for C13H23N3O6 +Na+: 340.1485 [M+Na]+; found
340.1490.
°
acetate). Rf =0.27 (100% ethyl acetate). m.p. 106–107 C.
1H NMR (600 MHz, CDCl3) δ 7.52 (t, J=6.0 Hz, 1H), 6.70 (d, J=6.0 Hz,
1H), 5.82 (s,1H), 4.22 (s, 1H), 3.99 (dd, J=12.0, 6.0 Hz, 2H), 3.87 (d,
J=12.0 Hz, 1H), 3.74–3.67 (m, 2H), 1.88 - 1.80 (m, 2H), 1.75–1.65 (m,
2H), 1.63–1.58 (m, 1H), 1.45 (s, 9H), 1.36–1.29 (m, 2H), 1.20–1.10 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 171.9, 168.1, 155.9, 80.5, 62.9, 56.2,
48.7, 43.2, 32.7, 32.7, 28.3, 25.4, 24.8. HRMS (ESI-TOF) m/z calculated
for C16H29N3O5 +Na+: 366.2005 [M+Na]+; found 366.2004.
Acylaminoacetamide 2s
2s was obtained from formic acid (0.50 mmol, 0.018 mL) and tert-
butyl isocyanide (0.50 mmol, 0.056 mL), following method A, in
48% yield (0.038 g) as a white solid after silica gel column
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
°
Acylaminoacetamide 2o
acetate). Rf =0.35 (1% methanol/ethyl acetate); m.p. 121–122 C.
2o was obtained from acetic acid (0.50 mmol, 0.030 mL) and
methyl isocyanoacetate (0.50 mmol, 0.045 mL), following method A,
in 94% yield (0.088 g) as a yellow solid after silica gel column
chromatography (100% ethyl acetate!4% methanol/ethyl acetate).
1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 6.98 (s, 1H), 6.24 (s, 1H),
3.91 (d, J=6.0 Hz, 2H), 1.37 (s, 9H).13C NMR (151 MHz, CDCl3) δ
167.3, 161.5, 51.6, 42.3, 28.6. HRMS (ESI-TOF) m/z calculated for
C7H14N2O2 +Na+: 181.0953 [M+Na]+; found: 181.0950.
°
Rf =0.20 (2% methanol/ethyl acetate). m.p. 161–162 C.
1H NMR (600 MHz, CDCl3) δ 6.81 (s, 1H), 6.47 (s, 1H), 4.07 (d, J=
6.0 Hz, 2H), 4.01 (d, J=6.0 Hz, 2H), 3.78 (s, 3H), 2.07 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 170.8, 170.0, 169.2, 52.4, 43.1, 41.1, 22.9. HRMS
(ESI-TOF) m/z calculated for C7H12N2O4 +Na+: 211.0695 [M+Na]+;
found 211.0690.
Compound 3
A sealed 10 mL glass tube containing a mixture of acetic acid (0.50,
0.030 mL mmol), hexamethylenetetramine 1 (0.50 mmol, 0.070 g),
methylamine solution 2 M (0.50 mmol, 0.25 mL) and tert-butyl
isocyanide (0.50 mmol, 0.056 mL) in TFE (2 mL) was introduced in
the cavity of a microwave reactor (CEM Co., Discover) and irradiated
°
Acylaminoacetamide 2p
at 80 C for 10 min (ramp time: 98 s) under magnetic stirring. The
reaction mixture was concentrated in vacuum and purified by
column chromatography. The peaks of the product and its rotamer
2p was obtained from benzoic acid (0.50 mmol, 0.061 g) and
methyl isocyanoacetate (0.50 mmol, 0.045 mL), following method A,
in 72% yield (0.090 g) as a yellow solid after silica gel column
chromatography (60% ethyl acetate/hexane!90% ethyl acetate/
1
were observed in the H NMR spectrum, as well as the peaks of the
acylaminoacetamide 2a. The relative ratio was calculated based on
the integration of the CH2 peak at 3.89 ppm. Product 3 was
obtained in 72% yield (0.066 g) as a white solid after silica gel
column chromatography (80% ethyl acetate/hexane!1% meth-
°
hexane). Rf =0.40 (100% ethyl acetate). m.p. 114–115 C.
°
anol/ethyl acetate). Rf =0.25 (100% ethyl acetate). m.p. 110–112 C.
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1H NMR (600 MHz, CDCl3) δ 6.08 (s, 1H), 3.89 (s, 2H), 3.86 (s, 0.5H),
calculated for C10H16N2O2 +Na+: 219.1109 [M+Na]+; found
219.1103.
3.12 (s, 3H), 3.00 (d, 1H), 2.15 (s, 3H), 2.10 (s, 1H), 1.38 (s, 2H), 1.34 (s,
9H).13C NMR (151 MHz, CDCl3) δ 171.5, 168.1, 53.1, 51.2, 37.5, 28.6,
21.5. HRMS (ESI-TOF) m/z calculated for C7H14N2O2 +Na+ 209.1266
:
[M+Na]+; found: 209.1261.
Method C
A sealed 10 mL glass tube containing a mixture of carboxylic acid
(0.50 mmol), hexamethylenetetramine 1 (0.50 mmol, 0.070 g), am-
monia solution 7 M (0.50 mmol, 0.070 mL) and isocyanide
(0.50 mmol) in TFE (2 mL) was introduced in the cavity of a
Method B
A sealed 10 mL glass tube containing a mixture of N-cyclohex-1-
enyl-formamide
(1.25 mmol, 0.297 g) in CH3CN (1 mL) was introduced in the cavity
of a microwave reactor (CEM Co., Discover) and irradiated at 50 C
for 10 min (ramp time: 98 s) under magnetic stirring. Afterwards, a
mixture of carboxylic acid (0.50 mmol), hexamethylenetetramine 1
(0.50 mmol, 0.070 g) and ammonia solution 7 M (0.50 mmol,
0.070 mL) in TFE (2 mL) was added to the reaction mixture and
again the sealed 10 mL glass tube was introduced in the cavity of a
°
4
(0.50 mmol, 0.060 g) and Burgess reagent
microwave reactor (CEM Co., Discover) and irradiated at 70 C for
15 min (ramp time: 98 s) under magnetic stirring. The reaction
mixture was concentrated in vacuum and purified by column
chromatography.
°
Acylaminoacetamide 8d
8d was obtained from Boc-L-alanine (0.50 mmol, 0.094 g) and 6-
bromo-2-isocyanopyridine (0.50 mmol, 0.078 g), following method
C, in 34% yield (0.068 g), as a yellow solid after silica gel column
chromatography (40% ethyl acetate/hexane!60% ethyl acetate/
hexane). Rf =0.62 (70% ethyl acetate/hexane).
°
microwave reactor (CEM Co., Discover) and irradiated at 70 C for
15 min (ramp time: 98 s) under magnetic stirring. The reaction
mixture was concentrated in vacuum and purified by column
chromatography.
1H NMR (600 MHz, DMSO) δ 10.74 (s, 1H), 8.09 (t, J=6.0 Hz, 1H),
8.04 (d, J=6.0 Hz, 1H), 7.73 (t, J=6.0 Hz, 1H), 7.33 (d, J=6.0 Hz, 1H),
6.97 (d, J=6.0 Hz, 1H), 4.04–3.97 (m, 1H), 3.97–3.87 (m, 2H), 1.38 (s,
9H), 1.20 (d, J=6.0 Hz, 3H).13C NMR (151 MHz, DSMO) δ 173.2,
168.7, 155.1, 151.9, 141.4, 138.8, 122.9, 112.2, 78.1, 49.7, 42.6, 28.2,
18.1. HRMS (ESI-TOF) m/z calculated for C15H21N4O4Br+Na+:
423.0644 [M+Na]+; found 423.0644.
Acylaminoacetamide 8a
8a was obtained from Boc-L-alanine (0.50 mmol, 0.090 g) and
cyclohexen-1-yl-isocyanide 5 (0.50 mmol), following method B, in
38% yield (0.061 g) as a white solid after silica gel column
chromatography (40% ethyl acetate/hexane!70% ethyl acetate/
°
hexane). Rf =0.16 (50% ethyl acetate/hexane). m.p. 111–112 C.
1H NMR (600 MHz, CDCl3) δ 7.48 (s, 1H), 7.10 (s, 1H), 6.06 (s, 1H),
5.18 (s, 1H), 4.20–4.14 (m, 1H), 4.00 (dd, J=18.0, 6.0 Hz, 1H), 3.94
(dd, J=18.0, 6.0 Hz, 1H), 2.23–2.14 (m, 2H), 2.14–2.08 (m, 2H), 1.73–
1.65 (m, 2H), 1.63–1.55 (m, 2H), 1.45 (s, 9H), 1.39 (d, J=6.0 Hz, 3H).
13C NMR δ (151 MHz, CDCl3) δ 173.4, 166.9, 155.7, 132.4, 114.1, 80.5,
50.7, 43.8, 28.2, 27.7, 23.9, 22.4, 21.9, 18.0. HRMS (ESI-TOF) m/z
calculated for C16H27N3O4 +Na+: 348.1899 [M+Na]+; found
348.1905.
Acylaminoacetamide 8e
8e was obtained from Boc-D-serine (0.50 mmol, 0.100 g) and 6-
bromo-2-isocyanopyridine (0.50 mmol, 0.078 g), following method
C, in 35% yield (0.072 g) as a yellow solid after silica gel column
chromatography (50% ethyl acetate/hexane!70% ethyl acetate/
hexane). Rf =0.48 (80% ethyl acetate/hexane).
1H NMR (600 MHz, DMSO) δ 10.69 (s, 1H), 8.13 (t, J=6.0 Hz, 1H),
8.04 (d, J=6.0 Hz, 1H), 7.69 (t, J=6.0 Hz, 1H), 7.28 (d, J=6.0 Hz, 1H),
6.63 (d, J–6.0 Hz, 1H), 4.07–4.01 (m, 1H), 3.95 (d, J=6.0 Hz, 2H), 3.58
(d, J=6.0 Hz, 2H), 1.38 (s, 9H).13C NMR (151 MHz, DSMO) δ 170.9,
168.6, 155.2, 151.8, 141.1, 138.7, 122.9, 112.2, 78.2, 61.9, 56.7, 42.8,
28.1. HRMS (ESI-TOF) m/z calculated for C15H21N4O5Br+Na+:
439.0593 [M+Na]+; found 439.0588.
Acylaminoacetamide 8b
8b was obtained from Boc-D-serine (0.50 mmol, 0.100 g) and
cyclohexen-1-yl-isocyanide 5 (0.50 mmol), following method B, in
34% yield (0.058 g) as a yellow solid after silica gel column
chromatography (80% ethyl acetate/hexane!100% ethyl acetate).
°
Rf =0.34 (100% ethyl acetate). m.p. 105–106 C.
1H NMR (600 MHz, CDCl3) δ 7.50 (s, 1H), 7.45 (s, 1H), 6.05 (s, 1H),
5.76 (s, 1H), 4.24 (s, 1H), 4.05 (d, J=18.0 Hz, 2H), 3.96 (s, 1H), 3.73 (s,
1H), 2.15–2.10 (m, 4H), 1.57–1.68 (m, 4H), 1.46 (s, 9H).13C NMR
(151 MHz, CDCl3) δ 172.0, 167.1, 156.0, 122.1, 114.3, 80.7, 62.9, 43.7,
36.6, 28.3, 27.6, 24.6, 23.9, 23.3, 22.4. HRMS (ESI-TOF) m/z calculated
for C16H27N3O5 +Na+: 364.1848 [M+Na]+; found 364.1849.
Acylaminoacetamide 8f
8f was obtained from acetic acid (0.50 mmol, 0.030 g) and 6-
bromo-2-isocyanopyridine (0.50 mmol, 0.078 g), following method
C, in 56% yield (0.074 g) as a yellow solid after silica gel column
chromatography (70% ethyl acetate/hexane!90% ethyl acetate/
hexane). Rf =0.46 (100% ethyl acetate).
1H NMR (600 MHz, DMSO) δ 10.81 (s, 1H), 8.18 (t, J=6.0 Hz, 1H),
8.03 (d, J=6.0 Hz, 1H), 7.73 (t, J=6.0 Hz, 1H), 7.32 (d, J=6.0 Hz, 1H),
3.90 (d, J=6.0 Hz, 2H), 1.87 (s, 3H).13C NMR (151 MHz, DSMO) δ
170.0, 169.1, 152.0, 141.5, 138.9, 123.0, 112.3, 42.7, 22.4. HRMS (ESI-
TOF) m/z calculated for C9H10N3O2Br+Na+: 293.9854 [M+Na]+;
found 293.9852.
Acylaminoacetamide 8c
8c was obtained from acetic acid (0.50 mmol, 0.030 mL) and
cyclohexen-1-yl-isocyanide 5 (0.50 mmol), following method B, in
40% yield (0.039 g) as a white solid after silica gel column
chromatography (80% ethyl acetate/hexane!1% methanol/ethyl
°
acetate). Rf =0.24 (100% ethyl acetate). m.p. 154–155 C.
1H NMR (600 MHz, CDCl3) δ 7.69 (s, 1H), 6.85 (s, 1H), 6.09 (s, 1H),
3.96 (d, J=6.0 Hz, 2H), 2.20–2.09 (m, 4H), 2.06 (s, 3H), 1.75–1.65 (m,
2H), 1.63 À 1.53 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 171.0, 167.0,
132.5, 113.5, 44.3, 27.8, 23.9, 22.9, 22.4, 21.9. HRMS (ESI-TOF) m/z
Acylaminoacetamide 8g
8g was obtained from Boc-L-alanine (0.50 mmol, 0.094 g) and
phenyl isocyanide (0.50 mmol, 0.056 g), following method C, in
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43% yield (0.068 g) as a yellow solid after silica gel column
Conflict of Interest
chromatography (60% ethyl acetate/hexane!90% ethyl acetate/
hexane). Rf =0.27 (70% ethyl acetate/hexane).
The authors declare no conflict of interest.
1H NMR (600 MHz, DMSO) δ 9.71 (s, 1H), 8.20 (s, 1H), 7.61 (d, J=
6.0 Hz, 2H), 7.30 (t, J=6.0 Hz, 2H), 7.10 (d, J=6.0 Hz, 1H), 7.05 (t, J=
6.0 Hz, 1H), 4.01–3.95 (m, 1H), 3.87 (d, J=6.0 Hz, 2H), 1.37 (s, 9H),
1.21 (d, J=6.0 Hz, 3H).13C NMR (151 MHz, DSMO) δ 173.3, 167.7,
155.5, 138.7, 128.8, 123.4, 119.2, 78.3, 50.0, 42.8, 28.2, 17.1. HRMS
(ESI-TOF) m/z calculated for C16H23N3O4 +Na+: 344.1586 [M+Na]+;
found 344.1590.
Keywords: Acylaminoacetamides
hexamethylenetetramine (HMTA) · diketopiperazines (DKPs)
· ammonia-Ugi reaction ·
[1] B. B. Toure, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486.
[2] a) A. Dömling, Chem. Rev. 2006, 106, 17–89; b) A. Dömling, W. Wang, K.
Wang, Chem. Rev. 2012, 112, 3083–3135.
Acylaminoacetamide 8h
[3] a) C. Hulme, H. Bienaymé, T. Nixey, B. Chenera, W. Jones, P. Tempest,
A. L. Smith, Methods Enzymol. 2003, 369, 469–496; b) C. Hulme, J.
Dietrich, Mol. Diversity 2009, 13, 195–207; c) A. Shahrisa, S. Esmati, R.
Miri, O. Firuzi, N. Edraki, M. Nejati, Eur. J. Med. Chem. 2013, 66, 388–399.
[4] I. Ugi, R. Meyr, U. Fetzer, C. SteinBrückner, Angew. Chem. Int. Ed. Engl.
1959, 71, 386–388.
8h was obtained from acetic acid (0.50 mmol, 0.030 g) and phenyl
isocyanide (0.50 mmol, 0.056 g), following method C, in 45% yield
(0.043 g) as a white solid after silica gel column chromatography
(80% ethyl acetate/hexane!1% methanol/ethyl acetate). Rf =0.33
(100% ethyl acetate).
[5] a) I. Ugi, F. Bodesheim, Chem. Ber. 1961, 94, 2797–2801; b) S. Gunawan,
C. Hulme, Org. Biomol. Chem. 2013, 11, 6036–6046.
[6] a) L. El Kaïm, L. Grimaud, Eur. J. Org. Chem. 2014, 7749–7762; b) L.
El Kaïm, L. Grimaud, J. Oble, Angew. Chem. Int. Ed. 2005, 44, 7961–7964;
Angew. Chem. 2005, 117, 8175–8178; c) L. El Kaïm, M. Gizolme, L.
Grimaud, J. Oble, J. Org. Chem. 2007, 72, 4169–4180.
1H NMR (600 MHz, DMSO) δ 9.94 (s, 1H), 8.19 (t, J=6.0 Hz, 1H), 7.58
(d, J=6.0 Hz, 2H), 7.30 (t, J=6.0 Hz, 2H), 7.04 (t, J=6.0 Hz, 1H), 3.86
(d, J=6.0 Hz, 2H), 1.88 (s, 3H).13C NMR (151 MHz, DSMO) δ 169.7,
167.9, 138.9, 128.7, 123.2, 119.1, 42.7, 22.4. HRMS (ESI-TOF) m/z
calculated for C10H12N2O2 +Na+: 215.0796 [M+Na]+; found
215.0791.
[7] J. Zhang, P. Yu, S.-Y Li, H. Sun, S.-H. Xiang, J. Wang, K. H. Houk, B. Tan,
Science 2018, 361, aas8707.
[8] a) A. V. Gulevich, E. S. Balenkova, V. G. Nenajdenko, J. Org. Chem. 2007,
72, 7878–7885; b) M. J. Thompson, B. Chen, J. Org. Chem. 2009, 74,
7084–7093; c) W. M. Seganish, A. Bercovici, G. D. Ho, H. J. J. Loozen,
C. M. Timmers, D. Tulshian, Tetrahedron Lett. 2012, 53, 903–905; d) J.
Isaacson, C. B. Gilley, Y. Kobayashi, J. Org. Chem. 2007, 72, 3913–3916;
e) A. Barthelon, L. El Kaïm, M. Gizzi, L. Grimaud, Synlett 2010, 18, 2784–
2788; f) P. Patil, M. Haan, K. Kurpiewska, J. Kalinowska-Tłuscik, A.
Dömling, ACS Comb. Sci. 2016, 18, 170–175; g) P. Patil, K. Kurpiewska, J.
Kalinowska-Tłuscik, A. Dömling, ACS Comb. Sci. 2017, 19, 343–350; h) L.
Moni, M. Denißen, G. Valentini, T. J. J. Müller, R. Riva, Chem. Eur. J. 2015,
21, 753–762.
[9] a) A. F. S. Barreto, C. K. Z. Andrade, Beilstein J. Org. Chem. 2019, 15, 906–
930; b) E. M. M. Abdelraheem, S. Khaksar, K. Kurpiewska, J. Kalinowska-
Tłuscik, S. Shaabani, A. Dömling, J. Org. Chem. 2018, 83, 1441–1447.
[10] a) G. A. Medeiros, W. A. da Silva, G. A. Bataglion, D. A. C. Ferreira, H. C. B.
de Oliveira, M. N. Eberlin, B. A. D. Neto, Chem. Commun. 2014, 50, 338–
340; b) C. Iacobucci, S. Reale, J.-F. Gal, F. De Angelis, Eur. J. Org. Chem.
2014, 2014, 7087–7090; c) R. O. Rocha, M. O. Rodrigues, B. A. D. Neto,
ACS Omega 2020, 5, 972–979.
General procedure for Ugi/Deprotection
+Activation/Cyclization (UDAC)
To a stirred solution of the corresponding Ugi product 8a–b
(0.15 mmol) in CH2Cl2 (2 mL), TFA (0.20 mL) was added dropwise at
°
0 C. The reaction mixture was stirred at room temperature for 24 h.
Then, it was concentrated in vacuum, CH2Cl2 (2.0 mL) was added to
the crude and the mixture was concentrated in vacuum again. This
procedure was repeated 3 times.
3-Methyl-2,5-diketopiperazine (9a)
9a was obtained from 8a (0.15 mmol, 0.050 g) in quantitative yield
(0.15 mmol, 0.019 g) as a white solid. m.p. 237–238 C (lit. m.p. 236–
°
°
238 C).
[11] G. C. Tron, Eur. J. Org. Chem. 2013, 2013, 1849–1859.
1H NMR (600 MHz, D2O) δ 4.10 (q, J=18.0 Hz, 1H), 3.90 (dd, J=12.0,
6.0 Hz, 2H), 1.48 (d, J=18.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
173.6, 171.3, 49.0, 41.9, 16.2. HRMS (ESI-TOF) m/z calculated for
C5H8N2O2 +H+: 129.0664 [M+H]+; found 129.0662.
[12] a) Y. Koiso, Y. Li, S. Iwasaki, K. Hanaka, T. Kobayashi, R. Sonoda, Y. Fujita,
H. Yaegashi, Z. Sato, J. Antibiot. 1994, 47, 765–773; b) A. L. Brown, Q. I.
Churches, C. A. Hutton, J. Org. Chem. 2015, 80, 9831–9837.
[13] L. Meng, R. Mohan, B. H. B. Kwok, M. Elofsson, N. Sin, C. M. Crews, Proc.
Natl. Acad. Sci. USA 1999, 96, 10403–10408.
[14] B. Halford, Chem. Eng. News 2012, 90, 34–35.
[15] M. P. Curran, K. McKeage, Drugs 2009, 69, 859–88.
3-Hydroxymethyl-2,5-diketopiperazine (9b)
[16] a) I. Ugi, Intra-Sci. Chem. Rep. 1971, 5, 229–261; b) M. Waki, J.
Meienhofer, J. Am. Chem. Soc. 1977, 99, 6075–6082; c) G. Just, B. Y.
Chung, K. Greozinger, Can. J. Chem. 1977, 55, 274–283; d) X. Cao, E. J.
Moran, D. Siev, A. Lio, C. Ohashi, A. M. M. Mjalli, Bioorg. Med. Chem. Lett.
1995, 5, 2953–2958; e) L. Banfi, A. Basso, G. Damonte, F. De Pellegrini, A.
Galatini, G. Guanti, I. Monfardini, R. Riva, C. Scapolla, Bioorg. Med. Chem.
Lett. 2007, 17, 1341–1345; f) M. Abbas, L. A. Wessjohann, Org. Biomol.
Chem. 2012, 10, 9330–9333.
9b was obtained from 8b (0.15 mmol, 0.050 g) in quantitative yield
°
(0.015 mmol, 0.021 g) as a white solid. m.p. 211–212 C (lit. m.p.
°
211–213 C).
1H NMR (600 MHz, D2O) δ 4.14 (t, J=6,0, 1H), 3.99–3.87 (m, 4H). 13C
NMR (151 MHz, CDCl3) δ 173.5, 168.4, 60.0, 54.5, 41.9. HRMS (ESI-
TOF) m/z calculated for C5H9N2O3 +H+: 145.0613 [M+H]+; found
145.0612.
[17] a) U. Kazmaier, C. Hebach, Synlett 2003, 11, 1591–1594; b) R. Pick, M.
Bauer, U. Kazmaier, C. Hebach, Synlett 2005, 5, 757–760.
[18] C. D. Floyd, L. A. Harnett, A. Miller, S. Patel, L. Saroglou, M. Whittaker,
Synlett 1998, 6, 637–639.
[19] a) H. Kunz, W. Pfrengle, J. Am. Chem. Soc. 1988, 110, 651–652; b) K.
Sung, F.-L. Chen, P. C. Huang, Synlett 2006, 16, 2667–2669; c) T. Zhao, A.
Boltjes, E. Herdtweck, A. Dömling, Org. Lett. 2013, 15, 639–641.
[20] a) J. H. Kim, D. Bhattacharjya, J. Yu, J. Mater. Chem. A 2014, 2, 11472–
11479; b) J. M. Dreyfors, S. B. Jones, Y. Sayed, Am. Ind. Hyg. Assoc. J.
1989, 50, 579–585.
Acknowledgements
The authors thank the Instituto de Química, Universidade de
Brasília, CNPq, CAPES and FAP-DF for financial support, as well as
Prof. Peter Bakuzis and Júlia C. Andrade for helpful suggestions.
[21] C. Kamoun, A. Pizzi, Holzforsch. Holzverwert. 2000, 52, 16–19.
Eur. J. Org. Chem. 2021, 1–13
www.eurjoc.org
11
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Papers
doi.org/10.1002/ejoc.202001671
[22] a) A. T. Nielsen, D. W. Moore, M. D. Ogan, R. L. Atkins, J. Org. Chem.
[33] K. W. Gillman, M. A. Higgins, G. S. Poindexter, M. Browning, W. J. Clarke,
S. Flowers, J. E. Grace, Jr, J. B. Hogan, R. T. McGovern, L. G. Iben, G. K.
Mattson, A. Ortiz, S. Rassnick, J. W. Russell, I. Antal-Zimanyi, Bioorg. Med.
Chem. 2006, 14, 5517–5526.
[34] a) A. F. S. Barreto, C. K. Z. Andrade, Tetrahedron 2018, 74, 6861–6865;
b) A. F. S. Barreto, O. E. Vercillo, L. A. Wessjohann, C. K. Z. Andrade,
Beilstein J. Org. Chem. 2014, 10, 1017–1022; c) A. F. S. Barreto, O. E.
Vercillo, M. A. Birkett, J. C. Caulfield, L. A. Wessjohann, C. K. Z. Andrade,
Org. Biomol. Chem. 2011, 9, 5024–5027.
[35] a) K. C. Nadimpally, K. Thalluri, N. B. Palakurthy, A. Saha, B. Mandal,
Tetrahedron Lett. 2011, 52, 2579–2582; b) J. G. Nathanael, U. Wille, J.
Org. Chem. 2019, 84, 3405–3418; c) M. Konwar, N. D. Khupseb, P. J.
Saikiac, D. Sarma, J. Chem. Sci. 2018, 130, 53.
[36] a) G. Koopmanschap, E. Ruijter, R. V. A. Orru, Beilstein J. Org. Chem. 2014,
10, 544–598; b) C. Hulme, J. Peng, G. Morton, J. M. Salvino, T. Herpin, R.
Labaudiniere, Tetrahedron Lett. 1998, 39, 7227–7230; c) C. R. B. Rhoden,
D. G. Rivera, O. Kreye, A. K. Bauer, B. Westermann, L. A. Wessjohann, J.
Comb. Chem. 2009, 11, 1078–1082.
1979, 10, 1678–1684; b) V. Vinogradoff, A. Rimola, F. Duvernay, G.
Danger, P. Theule, T. Chiavassa, Phys. Chem. Chem. Phys. 2012, 14,
12309–12320; c) M. T. Feldmann, S. L. Widicus, G. A. Blake, D. R. Kent IV,
W. A. Goddard III, J. Chem. Phys. 2005, 123, 034304.
[23] a) M. Mirzaei-Mosbat, R. Ghorbani-Vaghei, N. Sarmast, ChemistrySelect
2019, 4, 1731–1737; b) B. B. García, D. Liu, S. Sepehri, S. Candelaria,
D. M. Beckham, L. W. Savage, G. Cao, J. Non-Cryst. Solids 2010, 356,
1620–1625; c) C. Cao, Z. Lu, Z. Cai, G. Pang, Y. Shi, Synth. Commun. 2012,
42, 279–284; d) M. Kannan, S. Muthaiah, Organometallics 2019, 38,
3560–3567.
[24] a) J. Kaihua, B. Shuhong, Johnson Matthey Technol. Rev. 2018, 62, 89–
106; b) N. Kostiuk, J. T. Goettel, M. Gerken, Inorg. Chem. 2020, 59, 8620–
8628; c) S.-L. Zheng, M.-L. Tong, X.-M. Chen, Coord. Chem. Rev. 2003,
246, 185–202.
[25] a) X. Gao, D. Zhou, Y. Chen, W. Wu, D. Su, B. Li, G. Wang, Commun.
Chem. 2019, 2:66; b) V. I. Levashova, I. V. Yangirova, Petroleum Chem.
2016, 56, 73–76; c) Z. Ke, B. Yu, Y. Wu, Y. Zhao, P. Yang, S. Guo, Z. Liu,
Chin. J. Chem. 2020, 38, 842–846; d) N. Blažzević, D. Kolbah, B. Belin, V.
Šunjić, F. Kajfež, Synthesis 1979, 3, 161–176.
[26] a) F. S. Ertaş, F. S. Saraç, Ü. Ünal, Ö. Birer, J. Solid State Electrochem. 2015,
19, 3067–3077; b) J. W. Lee, J. M. Ko, J.-D. Kim, J. Phys. Chem. C 2011,
115, 19445–19454.
[37] a) T. A. Keating, R. W. Armstrong, J. Am. Chem. Soc. 1996, 118, 2574–
2583; b) W. Maison, I. Schlemminger, O. Westerho, J. Martens, Bioorg.
Med. Chem. 2000, 8, 1343–1360; c) D. R. Barton, T. Bowles, S. Husinec,
J. E. Forbes, A. Lichera, A. E. A. Porter, S. Z. Zard, Tetrahedron Lett. 1988,
29, 3343–3346.
[27] a) C. Cheng, S. Gong, Q. Fu, L. Shen, Z. Liu, Y. Qiao, C. Fu, Polym. Bull.
2011, 66, 735–746; b) X. Zhang, D. H. Solomon, Chem. Mater. 1998, 10,
1833–1840; c) F. Liu, S. Zuo, W. Kong, C. Qi, Green Chem. 2012, 14,
1342–1349; d) F. Liu, K. Huang, Q. Wu, S. Dai, Adv. Mater. 2017, 29,
1700445–1700453; e) A. M. Kirillov, Coord. Chem. Rev. 2011, 255, 1603–
1622.
[28] a) S. Chouzier, T. Czeri, M. Roy-Auberger, C. Pichon, C. Geantet, M.
Vrinat, P. Afanasiev, J. Solid State Chem. 2011, 184, 2668–2677; b) F. A.
Qaraah, S. A. Mahyoub, A. Hezam, W. Zhang, G. Xiu, J. Munyanezaa, C.
Wu, RSC Adv. 2020, 10, 32309–32322; c) J. Zhang, W. Zhang, M. Han, J.
Pang, J. Mater. Sci. Mater. Electron. 2018, 29, 4639–4648; d) Y. Zhu, T.
Ren, Y. Liua, Z. Yuan, RSC Adv. 2014, 4, 31754–31758.
[38] R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, T. A. Keating,
Acc. Chem. Res. 1996, 29, 123–131.
[39] G. van der Heijden, J. A. W. (Sjaak) Jong, E. Ruijter, R. V. A. Orru, Org. Lett.
2016, 18, 5, 984–987.
[40] a) K. Shiomi, H. Yang, J. Ynokoshi, D. Van der Pyl, A. Nakagawa, H.
Takeshima, S. Omura, J. Antibiot. 1993, 46, 229–234; b) K. Hinterding, P.
Hagenbuch, J. Reey, H. Waldmann, Angew. Chem. Int. Ed. 1998, 37,
1236–1239; Angew. Chem. 1998, 110, 1298–1301.
[41] a) C. E. M. Salvador, B. Pieber, P. M. Neu, A. Torvisco, C. K. Z. Andrade,
C. O. Kappe, J. Org. Chem. 2015, 80, 4590–4602; b) C. E. M. Salvador,
C. K. Z. Andrade, Front. Chem. 2019, 7, 531.
[29] A. D. Borthwick, Chem. Rev. 2012, 112, 3641–3716.
[30] Y. Hitotsuyanagi, S. Sasaki, Y. Matsumoto, K. Yamaguchi, H. Itokawa, K.
Takeya, J. Am. Chem. Soc. 2003, 125, 7284–7290.
[31] M. J. Thompson, W. Heal, B. Chen, Tetrahedron Lett. 2006, 47, 2361–
2364.
[32] a) B. Iliev, A. Linden, R. Kunz, H. Heimgartner, Tetrahedron 2006, 62,
1079–1094; b) W. Q. Jiang, G. P. S. Costa, H. L. S. Maia, Org. Biomol.
Chem. 2003, 1, 3804–3810.
Manuscript received: December 31, 2020
Revised manuscript received: April 19, 2021
Accepted manuscript online: April 22, 2021
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FULL PAPERS
The ammonia/formaldehyde couple
(the ugly duckling in Ugi reactions)
was finally made possible using
hexamethylenetetramine (HMTA) as
an efficient formaldehyde surrogate.
Various NH-free Ugi adducts were
obtained in moderate to excellent
yields and two of them were
converted to diketopiperazines
(DKPs).
T. P. F. Rosalba, S. S. A. Kas, A. B. S.
Sampaio, Dr. C. E. M. Salvador*,
Dr. C. K. Z. Andrade*
1 – 13
The Ugly Duckling Metamorphosis:
The Ammonia/Formaldehyde
Couple Made Possible in Ugi
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