Rapid assembly of polyfunctional structures using a one-pot five- and six-component sequential Groebke-Blackburn/Ugi/Passerini process

Article abstract of DOI:10.1002/ejoc.201000808

Sequential addition of up to six components under well-defined conditions results in the formation of novel structures with amino acid, peptide, and heterocyclic components. This process forms up to eight new bonds under very mild conditions and tolerates

Full text of DOI:10.1002/ejoc.201000808

FULL PAPER
DOI: 10.1002/ejoc.201000808
Rapid Assembly of Polyfunctional Structures Using a One-Pot Five- and Six-
Component Sequential Groebke–Blackburn/Ugi/Passerini Process
Taleb H. Al-Tel,*[a,b] Raed A. Al-Qawasmeh,[c] and Wolfgang Voelter[d]
Keywords: Multicomponent reactions / Heterocycles / Drug discovery / Cycloaddition / Molecular diversity
Sequential addition of up to six components under well-de-
fined conditions results in the formation of novel structures
with amino acid, peptide, and heterocyclic components. This
process forms up to eight new bonds under very mild condi-
tions and tolerates a broad spectrum of functional groups. An
nent reaction with the Ugi four-component or Passerini three
component reaction was adopted to synthesize polyfunction-
alized heterocycles. In terms of diversity oriented synthesis,
10 positions on the basic polycyclic structure can be varied.
Straightforward batch splitting provides a simple and ef-
orthogonal union of the Groebke–Blackburn three-compo- ficient method for preparing structurally complex analogs.
Introduction
chemists is therefore to improve the overall efficiency
through the development of economic procedures that pro-
The development of efficient synthetic strategies that
lead to molecular diversity plays an important role in the
success of drug discovery.[1–3] With such a procedure, an
ceed with high yield and selectivity.[5]
Among approaches to therapeutic discovery, diversity-
enormous number of complex small molecules can be pre- oriented synthesis has played a prominent role by concen-
pared for evaluation of biological activity such as pertur- trating on employing efficient reactions that tolerate a
bation of protein function.[4] The challenge for synthetic broad substrate scope. In this regard, one of the most
Figure 1. Sequential MCR strategies employed.
powerful approaches is the union of two multicomponent
reactions (MCRs) in which a set of reagents is sequentially
and predictably brought together. Such an approach re-
[a] College of Pharmacy, University of Sharjah,
P. O. Box 27272, Sharjah, UAE
Fax: +971-6-5585812
E-mail: taltal@sharjah.ac.ae
quires a functional group that is unreactive in the initial
stage but reactive in a subsequent reaction (Figure 1). In an
ideal case, reactions are efficiently combined in a single
flask to yield a higher-order MCR. Central to this union of
MCRs[4,5] is the orthogonal reactivity of functional groups
combined in one molecule to be deployed in different reac-
tions. Such strategies avoid the use of protecting groups and
increase efficiency in organic synthesis. Many research
groups have utilized the Ugi four-component reaction
www.sharjah.ac.ae/pharmacy
[b] Sharjah Institute for Medical Research – Cancer Division,
University of Sharjah,
27272, Sharjah, UAE
[c] Department of Chemistry, University of Jordan,
Amman 11942, Jordan
[d] Interfakultäres Institut für Biochemie, Eberhard-Karls-
Universität Tuebingen,
Hoppe-Seyler-Straße, 72076, Tuebingen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000808.
View this journal online at
wileyonlinelibrary.com
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Polyfunctional Structures Using Groebke-Blackburn/Ugi/Passerini Process
(4CR) followed by cycloaddition reactions, metathesis stra- A Six-Component Reaction Sequence
tegies, and sequential additive transformations to assemble
Before presenting applications of our strategy as outlined
complex structures.[5–7]
in Figure 1, several appropriate comments are in order. Un-
like the respected Ugi and other multicomponent reactions,
the components in our process must be combined in a se-
quential process due to the reactivity of the different func-
tional groups in the initial components. The first stage of
the process involves formation of imine I; this intermediate
may or may not be isolated in crude form. For example, the
aldehyde and amine may be condensed in the presence of
Sc(OTf)3 (5 mol-%) in methanol/dichloromethane (2:3) to
give a solution of imine I. This solution may then be used
directly in the next [4+1] cycloaddition step to give a variety
of bicyclic azole scaffolds II (Figure 1, route a) bearing a
carboxylic acid on one side or the other of the resulting
heterocycle. This pendant acid moiety provides a linkage
for subsequent union of Ugi 4CR or Passerini 3CR (Fig-
ure 1). This product can then be split and used in a different
MCR (Figure 1, route a; and Scheme 2). Alternatively, the
crude imine solution could be distributed into different re-
action flasks charged with different isocyanides (Figure 1,
route b). The products from this route could be used di-
rectly in the next MCRs or each product could be split
again to multiply the number of skeletally diverse heterocy-
clic products. The majority of the reactions presented herein
were conducted in a single flask without intermediate isola-
tion, as outlined Scheme 1; the crude imines were directly
coupled with the desired isocyanide and then the resulting
bicyclic [4+1] cycloaddition product was split and subjected
to a second MCR to generate a library of complex hetero-
cyclic scaffolds. It should be noted, however, that the condi-
tions were not always optimized for the formation of inter-
mediate imines I or for their subsequent conversion into
An approach to engendering efficient assembly of varia-
bly substituted structures requires the use of MCRs in
which a set of simple components is brought together. This
straightforward approach, however, is not easily im-
plemented.[8–11] Reactions often have experimental limita-
tions including the inflexibility of the substitution pattern
of the starting materials, the need for protection/deprotec-
tion of intermediates, and solvent incompatibilities between
the subsequent reaction steps. To avoid complex mixtures,
components must react selectively and predictably. To this
end, few elegant contributions have been reported wherein
six components or more were brought together.[6]
Two notable multicomponent reactions are the Groebke–
Blackburn and Ugi reactions. Both of these reactions take
advantage of the isocyanide functionality that is capable of
forming two new bonds to carbon.[4,12,9,13] The Groebke–
Blackburn reaction is an acid-mediated addition of an iso-
cyanide to a 2-iminopyridine, yielding a fused pyridine–
imidazole product. Similarly, the Ugi reaction is the four-
component assembly of an isocyanide, acid, and imine to
produce a skeletally diverse dipeptide. If these named reac-
tions could be combined efficiently in a tandem fashion,
this would give rise to molecular diversity and rapid con-
struction of libraries of structurally related compounds.
As part of an ongoing program of natural product syn-
thesis and the preparation of medicinally important struc-
tures,[14] we report herein a tandem process that combines
two successive MCRs in one pot, a higher-order MCR for
the construction of imidazopyridine, -pyrazine, and -pyrim-
idine derivatives with unprecedented possibilities for com-
plexity generation and diversification. Recent studies impli-
cate a role for these scaffolds in addressing many of the
most common human diseases including diabetes,[15] can-
cer,[16] infection by microorganisms,[17] and an array of neu-
rological syndromes.[18]
1
adducts II. Nevertheless, H NMR spectroscopic analysis
of the crude imidazopyridine carboxylic acid derivatives re-
sulting from the first 3CR product indicated quantitative
conversion.
Split-Pool Synthesis
Having established a protocol for the facile synthesis of
intermediates I and II (Figure 1) a number of post-cycload-
dition reactions including the Ugi 4CR and Passerini 3CR
was examined to generate diverse heterocyclic scaffolds. To
Results and Discussion
Efficiently sequencing these two named reactions would achieve this goal and to broaden the scope of this approach,
ideally involve a single-flask reaction without the need for we explored the possibility of accessing different heterocy-
any intermediate isolation steps. Positioning the Groebke– clic systems by varying the nature of the nucleophilic
Blackburn reaction before the Ugi reaction was the most amines, the aldehydes, isocyanides, and/or the position of
straightforward because the former could carry with it an the carboxylic acid handle. As described below, our strategy
unprotected carboxylic acid group. We therefore began by followed three different routes for the union of both MCRs.
investigating conditions for the tandem combination of
To verify the plan contemplated in Figure 1, we started
these two reactions. An important element of this concept our synthesis by using the split-pool synthesis approach
was the independent reactivity of the functional groups resi- with the intermediate imine (Scheme 1) and by splitting the
dent on the key substrate.[8] Such a process would involve a initial MCR [4+1] cycloaddition product (Scheme 2). To
functional group in the first MCR that does not participate this end, we treated 2-aminopyridine (1) with 3-carboxy-
in the reaction but does react as one of the essential compo- benzaldehyde (2) in the presence of Sc(OTf)3 (5 mol-%) to
nents in the second MCR (e.g., the carboxylic acid group deliver imine 3. Without isolation, the latter product was
in these MCRs, Figure 1).
distributed into three reaction vials. To each vial a different
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Scheme 1. Six-component assembly of various scaffolds.
Scheme 2. Different variants of six sequential MCR.
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Polyfunctional Structures Using Groebke-Blackburn/Ugi/Passerini Process
isocyanide was added as indicated in Scheme 1. After 8 h, Positional Variation of the Carboxylic Acid Handle
the Groebke–Blackburn reaction protocol proceeded
To evaluate the scope of this tandem process we investi-
smoothly and intermediates 4, 5, and 6 were produced. Sub-
gated varying the position of the carboxylic acid group, the
sequently these products were subjected to the second
cornerstone of the protocol. Thus, the acid functionality
MCR Ugi reaction. Therefore, different aldehydes, amines,
was placed on the heterocyclic amine instead of the alde-
and isocyanides were added to deliver, after 12 h, polyfunc-
hyde component for the initial condensation reactions
tionalized imidazopyridines 7, 8, and 9 in 72, 68, and 74%
(compare Schemes 1 and 4). To achieve this goal, 5-carb-
yield, respectively.
oxy-2-aminopyridine (25) was condensed with benzalde-
In the alternative route, 2-aminopyrazine (10) was con-
hyde (26) in the presence of Sc(OTf)3 (5 mol-%) to deliver
densed with 4-carboxybenzaldehyde (11) under the same re-
imine 27 (Scheme 4). Reaction of 27 with benzyl isocyanide
action conditions as mentioned above to deliver imine 12
gave intermediate 28. This product was divided among
(Scheme 2), which was directly subjected to the Groebke–
three reaction vials and each vial was subjected to different
Blackburn reaction with benzyl isocyanide to produce [4+1]
Ugi reaction conditions to produce polysubstituted imida-
cycloaddition product 13. Without isolation, product 13
zopyridines 29, 30, and 31 in good yields (65, 70, and 73%,
was distributed into three vials and to each of these vials
respectively).
was added an amine, an aldehyde, and an isocyanide as
The applicability of these variations was also tested with
indicated in Scheme 2. As a result, Ugi reaction products
5-carboxy-2-aminobenzothiazole (32; Scheme 5). Thus, re-
14, 15, and 16 were isolated by flash column chromatog-
action of 32 with 2-thiophencarboxaldehyde (33) followed
raphy in 64, 69, and 61% yield, respectively.
by application of our 6CR procedure as described above
gave compound 36 in 67% yield after flash chromatography.
Variations of the Primary Amine Input
Having successfully demonstrated the underlying utility
of this strategy for the rapid preparation of complex hetero-
Groebke–Blackburn/Passerini Five-Component Protocol
cycles, the next task was to apply this approach to the syn-
With successful illustration of our combined Groebke–
thesis of more complex heterocyclic scaffolds with different Blackburn/Ugi sequence, we tested the expansion of this
branching patterns by utilizing various amines for the initial strategy to include an alternative MCR. For this purpose
condensation. Thus, 1-aminoisoquinoline (17) and 2-ami- we selected the Passerini 3CR. Incorporation of this reac-
nothiazole (21) were separately treated with 3-carboxybenz- tion followed the same sequence for the reaction union de-
aldehyde (2) to afford intermediates 18 and 22, respectively. scribed above. To this end, a Groebke–Blackburn 3CR was
These intermediates were then subjected to the Groebke– achieved by applying the standard condensation of 2-ami-
Blackburn reaction conditions with tert-butyl isocyanide to nopyrimidine (37) with 3-carboxybenzaldehyde (2) to pro-
give polycyclic compounds 19 and 23, respectively. These duce imine 38, which was further treated with benzyl isocy-
intermediates were then subjected to reaction with isobutyl- anide to give imidazopyrimidine 39 (Scheme 6). To each of
amine, piperonal, and two isocyanides under the Ugi reac- three reaction vials containing compound 39 was added al-
tion conditions as shown in Scheme 3 to deliver polyfunc- dehydes and isocyanides to afford smoothly multisubsti-
tional heterocyclic diamides 20 and 24 in 55 and 61% yield, tuted heterocyclic structures 40, 41, and 42 in 78, 69, and
respectively.
57% yield, respectively (Scheme 6).
Scheme 3. Variation of the amine input in the primary MCR.
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T. H. Al-Tel, R. A. Al-Qawasmeh, W. Voelter
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Scheme 4. Variation of the position of the carboxylic acid arm in the primary MCR sequence.
Scheme 5. Six-component sequential union with different inputs.
Scheme 6. Five-component assembly products.
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Polyfunctional Structures Using Groebke-Blackburn/Ugi/Passerini Process
added the desired isocyanide (3 mmol), and the mixture was stirred
The aldehydes used for these sequences are aromatic and
contain a carboxylic acid group paired with reagents for a
subsequent Ugi 4CR or Passerini 3CR. Incorporation of
other functionalities into the starting aldehydes and/or aro-
matic amines can be envisioned to enable the formation of
alternative cyclic manifolds.[13,18] For example, starting with
heteroarylamines and aldehydes bearing carboxylic acids in
the [4+1] cycloaddition processes, followed by union with
Ugi and Passerini MCRs would produce structurally
unique products. It should also be mentioned that given the
known scope of the Groebke–Blackburn, Ugi, and Passerini
MCRs the chemistry presented here should work for all
possible functional groups typically used in such MCRs.[13]
for another 8 h. Without workup, to each vial was added the de-
sired aldehyde (3.0 mmol), amine (3.0 mmol), and isocyanide
(3.0 mmol), and the mixture was stirred at room temperature for
12 h. The mixture was concentrated under reduced pressure,
washed with hexane/EtOAc (5:1, 3ϫ30 mL), and triturated with
EtOAc/hexane. The crude product was purified by flash
chromatography (0–30% EtOAc/hexanes) to give the desired prod-
uct as an amorphous solid.
General Experimental Procedure B: A mixture of aminopyridine
(3.0 mmol) in MeOH/DCM (2:3, 15.0 mL) and aldehyde
(3.0 mmol) containing Sc(OTf)3 (5 mol-%) in a graduated test tube
was stirred for 45 min at room temperature followed by the ad-
dition of the desired isocyanide (3.15 mmol), and the mixture was
stirred for another 8 h. Without workup, the resulting iminopyr-
idine product was divided equally into three reaction vials. To each
vial was added the desired aldehyde (3.0 mmol), amine (3.0 mmol),
and isocyanide (3.0 mmol), and the resulting solution was then
stirred at room temperature for 12 h. The reaction mixture was
concentrated under reduced pressure, washed with EtOAc/hexane
(5:1, 3ϫ30 mL), and triturated with EtOAc/hexane. The crude
product was purified by flash chromatography (0–30% EtOAc/hex-
anes) to give the desired product as an amorphous solid.
Conclusions
In summary, we have developed several new examples of
5- and 6CRs with the formation of up to 8 new bonds and
up to 10 points of diversity. The approach described here
allows the construction of complex, diverse sets of drug-like
compounds in a single, economic, and facile operation. The
reaction is remarkably efficient (Ͼ55% per bond formation)
and constitutes an economic approach for 5- and 6CRs.
These representative examples clearly establish the merits
General Experimental Procedure C: A mixture of aminopyridine
(1.0 mmol) in MeOH/DCM (2:3, 5.0 mL) and aldehyde (1.0 mmol)
of this new strategy for the synthesis of diverse nitrogen containing Sc(OTf)3 (5 mol-%) in a graduated test tube was stirred
for 45 min at room temperature followed by the addition of the
desired isocyanide (1.05 mmol), and the mixture was stirred for an-
other 8 h. Without workup, to the resulting iminopyridine product
was added the desired aldehyde (1.0 mmol), amine (1.0 mmol), and
isocyanide (1.0 mmol), and the mixture was then stirred at room
temperature for 12 h. The resulting reaction mixture was concen-
trated under reduced pressure, washed with hexane/EtOAc (5:1,
3ϫ15 mL), and triturated with EtOAc/hexane. The crude product
was purified by flash chromatography (0–30% EtOAc/hexanes) to
give the desired product as an amorphous solid.
heterocycle collections. Significantly, these scaffolds bear
orthogonal functionality that may be selectively exploited
for further manipulation and diversification to create novel
sets of compounds having substructures found in biolo-
gically active and clinically useful drugs. Further applica-
tions of the concepts outlined in Figure 1 for the synthesis
of diverse collections of scaffolds that are endowed with
reactive sites or handles are in progress in our laboratories.
Experimental Section
Methyl 2-[2-(N-Benzyl-3-{3-(tert-butylamino)imidazo[1,2-a]pyridin-
2-yl}benzamido)-2-(3-methoxyphenyl)acetamido]acetate (7): Ac-
cording to general procedure A; yield: 456 mg, 72%; amorphous
General Information: All reagents were used as purchased from
commercial suppliers without further purification. The reactions
were carried out in oven-dried or flamed graduated vessels. Sol-
vents were dried and purified by conventional methods prior to
use. Flash column chromatography was performed with Silica gel
60, 0.040–0.063 mm (230–400 mesh). Aluminum-backed plates pre-
coated with silica gel 60 (UV254) were used for thin-layer
chromatography. 1H and 13C NMR spectra were recorded at 300
and 75 MHz, respectively. Splitting patterns are designated as s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br., broad.
Chemical shifts (δ) are given in ppm relative to the resonance of
their respective residual solvent peak, CHCl3 (δ = 7.27 ppm, 1 H;
77.16 ppm, middle peak, 13C). Elemental analysis was carried out
at the University of Jordan. High- and low-resolution mass spectro-
metric analyses were conducted at the University of Jordan by
using positive ion electrospray ionization (ESI+). The samples were
dissolved in acetonitrile, diluted in spray solution [methanol/water
(1:1) + 0.1% formic acid] and infused by using a syringe pump
with a flow rate of 2 µL/min. External calibration was conducted
by using arginine cluster in a mass range m/z = 175–871.
1
solid. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.20 (s, 9 H), 3.72
(s, 3 H), 3.77 (s, 3 H), 4.03 (s, 2 H), 4.79 (d, JH,H = 9.6 Hz, 1 H),
4.86 (d, JH,H = 9.6 Hz, 1 H), 6.44 (s, 1 H), 6.84 (m, 2 H), 6.98 (m,
2 H), 7.18 (t, JH,H = 10.2 Hz, 1 H), 7.42 (m, 5 H), 7.70 (m, 1 H),
7.83 (d, JH,H = 6.6 Hz, 1 H), 7.96 (m, 2 H), 8.77 (d, JH,H = 8.1 Hz,
1 H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 172.8, 171.0,
169.0, 154.6, 143.2, 141.8, 136.5, 134.0, 133.7, 132.5, 128.8, 128.4,
128.2, 127.5, 127.2, 126.9, 126.0, 115.6, 115.5, 115.4, 105.2, 69.6,
60.2, 56.9, 48.5, 43.5, 34.1, 30.7 ppm. HRMS (ESI): calcd. for
C37H39N5O5Na [M + Na]+ 656.2849; found 656.2894.
Methyl 2-{2-(3-[{2-Benzylamino-2-oxo-1-[4-(trifluoromethyl)phenyl]-
ethyl}(isobutyl)carbamoyl]phenyl)imidazo[1,2-a]pyridin-3-ylamino}-
acetate (8): According to general procedure A; yield: 457 mg, 68%;
amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.04 (d,
JH,H = 7.2 Hz, 6 H), 1.98 (m, 1 H), 3.01 (s, 2 H), 3.62 (s, 3 H), 4.14
(s, 2 H), 4.39 (m, 2 H), 4.45 (d, JH,H = 6.3 Hz, 1 H), 6.04 (s, 1 H),
6.11 (s, 1 H), 6.83 (d, JH,H = 8.1 Hz, 1 H), 7.17 (m, 6 H), 7.52 (m,
3 H), 7.60 (m, 3 H), 7.93 (m, 3 H), 8.88 (d, JH,H = 8.1 Hz, 1
H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 174.3, 170.4,
165.5, 144.8, 135.2, 130.9, 128.9, 127.9, 127.4, 126.9, 126.7, 126.3,
123.9, 123.7, 123.6, 119.9, 110.5, 104.4, 60.3, 52.7, 46.2, 41.0, 26.2,
19.8 ppm. HRMS (ESI): calcd. for C37H36F3N5OH [M + H]+
672.2798; found 672.2789.
General Experimental Procedure A: A mixture of aminopyridine
(3.0 mmol) in MeOH/DCM (2:3, 15.0 mL) and aldehyde
(3.0 mmol) containing Sc(OTf)3 (5 mol-%) in a graduated test tube
was stirred for 45 min at room temperature. The resulting imine
was divided into three graduated test tubes and to each tube was
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N-{1-(Benzo[d][1,3]dioxol-5-yl)-2-(tert-butylamino)-2-oxoethyl}-3-
{3-(benzylamino)imidazo[1,2-a]pyridin-2-yl}-N-(4-methoxyphenyl)-
benzamide (9): According to general procedure A; yield: 504 mg,
74%; amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
1.34 (s, 9 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 4.72 (d, JH,H = 7.6 Hz, 1
H), 5.92 (s, 2 H), 6.33 (d, JH,H = 7.8 Hz, 1 H), 6.6.81 (m, 3 H),
7.40–7.17 (m, 10 H), 8.03–7.74 (m, 5 H), 8.88 (d, JH,H = 8.1 Hz, 1
H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 170.2, 161.7,
158.3, 149.3, 146.1, 144.8, 141.4, 134.2, 132.6, 130.7, 128.2, 127.7,
127.5, 127.2, 126.9, 123.7, 121.1, 120.2, 114.8, 112.6, 110.4, 109.4,
103.0, 101.0, 69.6, 55.2, 49.9, 49.4, 28.6 ppm. HRMS (ESI): calcd.
for C41H39N5O5Na [M + Na]+ 704.2849; found 704.2851.
(24): According to general procedure C; yield: 427 mg, 61 %;
amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.07 (d,
JH,H = 7.1 Hz, 6 H), 1.1 (s, 9 H), 1.96 (m, 1 H), 3.04 (m, 2 H), 3.72
(s, 3 H), 4.03 (s, 2 H), 5.92 (s, 2 H), 6.42 (m, 2 H), 6.81 (d, JH,H
8.7 Hz, 1 H), 6.93 (s, 1 H), 7.12 (d, JH,H = 10.2 Hz, 1 H), 7.22 (d,
JH,H = 7.8 Hz, 1 H), 7.54 (m, 2 H), 7.91 (m, 2 H), 8.08 (d, JH,H
=
=
7.5 Hz, 1 H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 169.8,
165.5, 149.6, 147.3, 146.4, 143.3, 138.7, 134.8, 131.3, 129.7, 127.3,
127.0, 126.2, 125.7, 122.8, 122.5, 119.9, 113.7, 108.5, 108.1, 101.0,
67.5, 60.3, 54.6, 51.9, 38.4, 31.1, 26.2, 19.8 ppm. HRMS (ESI):
calcd. for C36H39N5O6SNa [M + Na]+ 692.2519; found 692.2523.
N-Benzyl-3-(benzylamino)-N-[2-(tert-butylamino)-2-oxo-1-phenyl-
ethyl]-2-phenylimidazo[1,2-a]pyridine-6-carboxamide (29): Accord-
ing to general procedure B; yield: 404 mg, 65%; amorphous solid.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.34 (s, 9 H), 4.72 (s, 2
H), 4.80 (d, JH,H = 9.3 Hz, 1 H), 4.86 (d, JH,H = 9.3 Hz, 1 H), 6.03
(s, 1 H), 7.07–7.49 (m, 20 H), 8.40 (t, JH,H = 2.1 Hz, 1 H), 9.71 (s,
1 H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 170.3, 157.7,
148.4, 143.0, 132.3, 130.4, 129.7, 128.8, 128.6, 128.2, 127.7, 127.5,
126.9, 126.2, 115.4, 113.7, 67.8, 52.0, 49.9, 49.4, 28.6 ppm. HRMS
(ESI): calcd. for C40H39N5O2H [M + H]+ 622.3182; found
622.3182.
Methyl 2-{2-[4-{3-(Benzylamino)imidazo[1,2-a]pyrazin-2-yl}-N-(3-
chlorobenzyl)benzamido]-4-methylpentanamido}acetate (14): Ac-
cording to general procedure B; yield: 418 mg, 64%; amorphous
solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.87 (d, JH,H
=
7.3 Hz, 6 H), 1.51 (m, 3 H), 3.71 (s, 3 H), 4.03 (s, 2 H), 4.72 (s, 2
H), 5.28 (m, 1 H), 7.55–7.12 (m, 9 H), 7.91 (s, 1 H), 8.29 (m, 4 H),
8.56 (d, JH,H = 8.4 Hz, 1 H) ppm. 13C NMR (75.3 MHz, CDCl3,
25 °C): δ = 172.9, 171.0, 168.2, 143.0, 141.7, 136.4, 133.4, 132.6,
129.6, 128.6, 127.8, 125.9, 121.6, 115.6, 115.2, 114.0, 55.4, 52.0,
50.7, 50.0, 38.3, 36.2, 25.4, 20.7 ppm. HRMS (ESI): calcd. for
C36H37ClN6O4H [M + H]+ 653.2643; found 653.2650.
Methyl 2-{2-(Benzo[d][1,3]dioxol-5-yl)-2-(3-benzylamino-N-isobutyl-
2-phenylimidazo[1,2-a]pyridine-6-carboxamido)acetamido}acetate
(30): According to general procedure B; yield: 453 mg, 70 %;
amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.04 (d,
JH,H = 7.2 Hz, 6 H), 1.1 (s, 9 H), 1.95 (m, 1 H), 3.03 (m, 2 H), 3.72
(s, 2 H), 4.03 (s, 2 H), 4.72 (s, 2 H), 5.93 (s, 2 H), 6.40 (m, 1 H),
6.81 (d, JH,H = 8.7 Hz, 1 H), 6.92 (d, JH,H = 3.1 Hz, 1 H), 7.50–
Methyl 2-{2-[4-{3-(Benzylamino)imidazo[1,2-a]pyrazin-2-yl}-N-(2,3-
dihydro-1H-inden-2-yl)benzamido]-2-(4-chlorophenyl)acetamido}-
acetate (15): According to general procedure B; yield: 482 mg,
69%; amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
2.87 (m, 2 H), 3.35 (m, 2 H), 3.72 (s, 3 H), 4.03 (s, 2 H), 4.72 (s, 2
H), 5.06 (m, 1 H), 6.46 (d, JH,H = 10.8 Hz, 1 H), 7.43–6.98 (m, 16
H), 8.25 (m, 1 H), 8.30 (m, 1 H), 8.53 (d, JH,H = 8.0 Hz, 1 H) ppm.
13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 173.0, 169.0, 167.9,
141.5, 136.2, 135.8, 135.0, 128.6, 128.1, 127.5, 127.0, 126.0, 124.1,
122.2, 117.3, 115.0, 67.8, 60.2, 55.1, 52.2, 43.6, 38.4, 36.3 ppm.
HRMS (ESI): calcd. for C40H35ClN6O4H [M + H]+ 699.2487;
found 699.2482.
7.30 (m, 12 H), 8.37 (t, JH,H = 2.1 Hz, 1 H), 9.70 (s, 1 H) ppm. 13
C
NMR (75.3 MHz, CDCl3, 25 °C): δ = 169.8, 158.0, 148.4, 147.3,
146.4, 143.0, 141.4, 131.6, 128.7, 128.2, 127.5, 127.2, 126.9, 126.7,
126.2, 122.1, 115.7, 115.1, 110.4, 108.5, 101.0, 66.3, 60.8, 51.9, 50.0,
38.4, 34.0, 28.4, 25.4, 20.9 ppm. HRMS (ESI): calcd. for
C37H37N5O6Na [M + Na]+ 670.2642; found 670.2650.
4-{3-(Benzylamino)imidazo[1,2-a]pyrazin-2-yl}-N-[2-(tert-butyl-
amino)-1-(3-nitrophenyl)-2-oxoethyl]-N-cyclopropylbenzamide (16):
According to general procedure B; yield: 377 mg, 61% amorphous
3-Benzylamino-N-cyclopropyl-N-[1-(4-fluorophenyl)-2-(isobutyl-
amino)-2-oxoethyl]-2-phenylimidazo[1,2-a]pyridine-6-carboxamide
(31): According to general procedure B; yield: 430 mg, 73 %;
amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.86
(m, 4 H), 0.91 (d, JH,H = 6.6 Hz, 6 H), 1.08 (m, 1 H), 3.15 (m, 2
H), 4.72 (s, 2 H), 5.82 (s, 1 H), 6.10 (s, 1 H), 6.34 (s, 1 H), 6.63 (m,
2 H), 7.45–7.30 (m, 10 H), 7.60 (t, JH,H = 12.0 Hz, 2 H), 8.47 (t,
JH,H = 5.7 Hz, 1 H), 981 (s, 1 H) ppm. 13C NMR (75.3 MHz,
CDCl3, 25 °C): δ = 169.5, 164.9, 161.4, 156.7, 143.0, 141.4, 137.2,
132.3, 132.2, 131.6, 128.2, 127.5, 127.2, 126.9, 126.7, 126.2, 118.7,
116.4, 116.0, 108.3, 63.0, 49.9, 49.3, 44.6, 28.4, 20.1, 7.7 ppm.
HRMS (ESI): calcd. for C36H36FN5O2H [M + H]+ 590.2931; found
590.2926.
1
solid. H NMR (300 MHz, CDCl3, 25 °C): δ = 0.88 (m, 4 H), 1.34
(s, 9 H), 3.14 (m, 1 H), 4.74 (s, 2 H), 6.23 (s, 1 H), 6.34 (s, 1 H),
7.40–7.07 (m, 8 H), 7.75 (m, 1 H), 8.52–8.23 (m, 5 H) ppm. 13C
NMR (75.3 MHz, CDCl3, 25 °C): δ = 173.2, 167.0, 149.7, 146.6,
142.5, 142.2, 137.6, 136.4, 131.2, 129.8, 129.2, 128.5, 128.2, 127.5,
126.1, 120.8, 63.4, 49.9, 49.4, 45.8, 28.6, 6.9 ppm. HRMS (ESI):
calcd. for C35H35N7O4H [M + H]+ 618.2829; found 618.2831.
N-{1-(Benzo[d][1,3]dioxol-5-yl)-2-(benzylamino)-2-oxoethyl}-3-
{3-(tert-butylamino)imidazo[2,1-a]isoquinolin-2-yl}-N-isobutyl-
benzamide (20): According to general procedure C; yield: 375 mg,
55%; amorphous solid. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
1.05 (d, JH,H = 7.3 Hz, 6 H), 1.20 (s, 9 H), 1.97 (m, 1 H), 3.02 (m,
2 H), 4.37 (d, JH,H = 12.6 Hz, 1 H), 4.43 (d, JH,H = 12.6 Hz, 1 H),
5.92 (s, 2 H), 6.20 (s, 1 H), 6.63 (d, JH,H = 8.4 Hz, 1 H), 6.80 (d,
JH,H = 8.7 Hz, 1 H), 6.94 (s, 1 H), 7.11 (m, 1 H), 7.22 (m, 5 H),
7.30 (m, 1 H), 7.71–7.40 (m, 3 H), 7.90 (m, 2 H), 8.41 (m, 1 H),
8.75 (d, JH,H = 7.2 Hz, 1 H) ppm. 13C NMR (75.3 MHz, CDCl3,
25 °C): δ = 170.4, 165.5, 147.3, 146.4, 145.4, 139.4, 134.5, 131.8,
131.3, 129.7, 128.9, 127.9, 126.9, 126.2, 126.0, 122.7, 119.9, 110.2,
108.5, 108.1, 101.0, 68.8, 60.2, 52.2, 41.0, 31.1, 26.2, 19.8 ppm.
HRMS (ESI): calcd. for C42H43N5O4Na [M + Na]+ 704.3213;
found 704.3206.
Methyl N-{1,3-Benzodioxol-5-yl[({3-(tert-butylamino)-2-thien-2-
ylimidazo[2,1-b][1,3]benzothiazol-7-yl}carbonyl)(isobutyl)amino]-
acetyl}glycinate (36): According to general procedure C; yield:
453 mg, 67 %; amorphous solid. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.03 (d, JH,H = 7.2 Hz, 6 H), 1.20 (s, 9 H), 1.97 (m, 1
H), 3.04 (m, 2 H), 3.73 (s, 3 H), 4.01 (s, 2 H), 5.92 (s, 2 H), 6.42
(m, 1 H), 6.83 (d, JH,H = 8.5 Hz, 1 H), 6.93 (s, 1 H), 7.13 (d, JH,H
= 10.2 Hz, 1 H), 7.50 (dd, JH,H = 4.8, 9.3 Hz, 1 H), 7.80 (d, JH,H
= 8.7 Hz, 1 H), 7.98 (d, JH,H = 4.8 Hz, 1 H), 8.28 (d, JH,H = 8.7 Hz,
1 H), 9.20 (s, 1 H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ =
169.8, 166.4, 147.3, 147.0, 146.4, 145.4, 135.6, 132.3, 131.1, 127.7,
127.2, 126.8, 126.3, 124.1, 121.0, 119.9, 111.8, 108.5, 108.1, 101.0,
Methyl N-{1,3-Benzodioxol-5-yl[(3-{3-(tert-Butylamino)imidazo[2,1- 67.5, 60.3, 54.6, 51.9, 38.4, 31.1, 26.2, 19.8 ppm. HRMS (ESI):
b][1,3]benzothiazol-2-yl}benzoyl)(isobutyl)amino]acetyl}glycinate
calcd. for C34H37N5O6S2H [M + H]+ 676.2264; found 676.2274.
5592
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5586–5593

Polyfunctional Structures Using Groebke-Blackburn/Ugi/Passerini Process
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4223–4226.
ing to general procedure B; yield: 413 mg, 78%; amorphous solid.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.05 (d, JH,H = 7.1 Hz, 6
H), 1.13 (m, 1 H), 1.74 (m, 1 H), 2.13 (m, 1 H), 3.73 (s, 3 H), 3.92
(s, 2 H), 4.72 (s, 2 H), 5.15 (t, JH,H = 9.3 Hz, 1 H), 6.23 (s, 1 H),
6.74 (d, JH,H = 4.2 Hz, 1 H), 7.40–7.14 (m, 6 H), 7.80 (d, JH,H
=
7.5 Hz, 1 H), 8.07 (d, JH,H = 9.6 Hz, 1 H), 8.44 (s, 1 H), 8.50 (d,
JH,H = 9.0 Hz, 1 H), 8.90 (s, 1 H), 9.32 (d, JH,H = 8.7 Hz, 1 H) ppm.
13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 172.3, 170.5, 162.8,
151.3, 149.4, 142.0, 134.6, 132.3, 130.6, 129.0, 128.5, 128.2, 128.0,
127.8, 127.5, 126.9, 110.2, 71.5, 52.0, 49.9, 42.0, 39.8, 23.2,
22.3 ppm. HRMS (ESI): calcd. for C29H31N5O5H [M + H]+
530.2403; found 530.2412.
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2-(tert-Butylamino)-1-cyclopropyl-2-oxoethyl 3-{3-(Benzylamino)-
imidazo[1,2-a]pyrimidin-2-yl}benzoate (41): According to general
procedure B; yield: 343 mg, 69 %; amorphous solid. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 0.68 (m, 4 H), 1.35 (s, 9 H), 1.60
(m, 1 H), 4.72 (s, 2 H), 4.87 (d, JH,H = 8.1 Hz, 1 H), 6.73 (t, JH,H
= 4.2 Hz, 1 H), 7.43–7.14 (m, 5 H), 8.80 (d, JH,H = 7.5 Hz, 1 H),
8.05 (s, 1 H), 8.45 (dd, JH,H = 4.3, 9.1 Hz, 1 H), 8.90 (s, 1 H), 9.32
(d, JH,H = 3.9 Hz, 1 H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C):
δ = 172.5, 161.4, 151.3, 149.4, 142.0, 134.6, 133.7, 130.9, 130.6,
130.3, 128.8, 128.2, 127.5, 126.9, 110.2, 78.0, 49.9, 48.1, 28.7, 15.1,
14.1, 12.4 ppm. HRMS (ESI): calcd. for C29H31N5O3Na [M +
Na]+ 520.2325; found 520.2325.
1-(Furan-2-yl)-2-(isobutylamino)-2-oxoethyl 3-{3-(Benzylamino)-
imidazo[1,2-a]pyrimidin-2-yl}benzoate (42): According to general
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(m, 1 H), 3.03 (d, JH,H = 6.9 Hz, 2 H), 4.72 (s, 2 H), 5.73 (s, 2 H),
6.14 (d, JH,H = 4.2 Hz, 1 H), 6.21 (d, JH,H = 1.5 Hz, 1 H), 6.39 (s,
1 H), 6.74 (d, JH,H = 4.2 Hz, 1 H), 7.32–7.14 (m, 4 H), 7.83 (m, 1
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H), 8.05 (m, 1 H), 8.47 (m, 2 H), 8.90 (s, 1 H), 9.32 (d, JH,H
=
3.9 Hz, 1 H) ppm. 13C NMR (75.3 MHz, CDCl3, 25 °C): δ = 169.0,
159.1, 155.6, 151.3, 149.4, 142.0, 137.5, 134.6, 132.3, 130.6, 129.5,
129.0, 128.8, 127.5, 126.9, 111.4, 110.2, 107.6, 71.9, 49.9, 45.9, 28.4,
20.1 ppm. HRMS (ESI): calcd. for: C30H29N5O4Na [M + Na]+
546.2117; found 546.2108.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
The authors are grateful to the National Research Fund (UAE)
and the College of graduate studies and research (University of
Sharjah) for funding this research project. Furthermore, Prof. Scott
Sieburth (Department of Chemistry, Temple University, USA) is
greatly acknowledged and appreciated for his fruitful revisions,
valuable comments, and suggestions made on this piece of research.
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Received: June 6, 2010
Published Online: August 24, 2010
Eur. J. Org. Chem. 2010, 5586–5593
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5593