Sequential Ugi/Heck cyclization strategies for the facile construction of highly functionalized N-heterocyclic scaffolds

Article abstract of DOI:10.1016/j.tetlet.2003.10.147

A new strategy employing an Ugi four-component reaction and a microwave-assisted intramolecular Heck cyclization in a sequential fashion to access an array of N-containing heterocycles is reported. The two-step sequence generated compounds of significant molecular complexity from trivial starting materials in an expedient fashion with excellent yields. The route was also amenable to solid-phase chemistry demonstrating potential for library generation.

Full text of DOI:10.1016/j.tetlet.2003.10.147

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 417–420
Sequential Ugi/Heck cyclization strategies for the facile
construction of highly functionalized N-heterocyclic scaffoldsq
Vijaya Gracias,* Joel D. Moore and Stevan W. Djuric
Scaffold-Oriented Synthesis, Abbott Laboratories, Medicinal Chemistry Technologies, R4CP, AP10, 100 Abbott ParkRoad,
Abbott Park, IL 60064-6099, USA
Received 19 September 2003; revised 23 October 2003; accepted 23 October 2003
Abstract—A new strategy employing an Ugi four-component reaction and a microwave-assisted intramolecular Heck cyclization in
a sequential fashion to access an array of N-containing heterocycles is reported. The two-step sequence generated compounds of
significant molecular complexity from trivial starting materials in an expedient fashion with excellent yields. The route was also
amenable to solid-phase chemistry demonstrating potential for library generation.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
R1-CHO
X
The ability to incorporate high levels of molecular
functionality in a single step continues to be an attrac-
tive feature of the Ugi multi-component condensation
reaction.1 In order to increase the Ôbiological attrac-
tivenessÕ of the Ugi adducts, many groups have recently
reported examples of post-reaction manipulation
focusing on substrate cyclization. These transformations
include Diels–Alder reactions,2 amino-cyclizations,3
nucleophilic aromatic substitutions,4 lactonizations,5
and ring-closing metathesis.6
R2-NH2
R3-CO2H
R4-NC
Ugi
intramolecular
Heck
N-heterocyclic
scaffold
reaction
olefin
N
Scheme 1. General strategy.
The versatile strategy we now report allows the intro-
duction of the olefin and aromatic halide functionalities
within three of the four Ugi components. This allows us
to control ring size and periphery features in the prod-
ucts based on the choice of the bifunctional starting
materials. As demonstrated in Scheme 1, the Ugi reac-
tion will generate a substrate containing both the olefin
and the aromatic halide around a central nitrogen core.
Subsequent cyclization via Heck reaction will produce
the desired constrained N-scaffold. Although these two
reactions have been utilized within the same synthetic
sequence,8 to the best of our knowledge this work rep-
resents the first examples of these two processes being
carried out in a sequential fashion.
Our interest in the efficient generation of interesting
cyclic nitrogen-containing motifs has led us to investigate
a strategy, which relies on the sequential use of the Ugi
multi-component reaction with the classical carbon–
carbon bond-forming process, the Heck reaction. The
palladium-catalyzed Heck reaction continues to prove
itself as one of the most powerful methods to generate a
carbon–carbon bond by exploiting the coupling of aro-
matic halides with olefins. The intramolecular version of
this transformation has emerged as a potent synthetic
tool in the generation of a variety of cyclic compounds.7
Keywords: Ugi; Heck; multi-component reaction; solid-phase; scaffold.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.10.147
2. Results and Discussion
The initial systems we investigated were constructed
utilizing a,b-unsaturated carboxylic acids (cyclic and
* Corresponding author. Tel.: +1-847-937-6324; fax: +1-847-935-0310;
e-mail: vijaya.gracias@abbott.com
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.147

418
V. Gracias et al. / Tetrahedron Letters 45 (2004) 417–420
HO2C
NH2
MeO2C
NH2
acyclic) as the olefin component, o-bromobenzaldehyde
as the aromatic halide, benzyl amine, and benzyl iso-
cyanide. The four-component Ugi condensation reac-
tions afforded the desired products 1–3 in high yields
(87–98%). These compounds were then subjected to
microwave-assisted Heck reactions9 and products were
obtained in excellent yields (4–6) and high diastereo-
selectivities (5 and 6). Spirocyclic systems structurally
similar to 5 and 6 have been generated previously, albeit
with longer Heck reaction times (ꢀ18 h).10 However, our
microwave-mediated Heck reaction conditions circum-
vented lengthy reaction times ( 6 2h). It was one of the
goals of our effort to produce scaffolds that are amenable
to further manipulation. To this end, the cyclization of
amides 1–3 generated two distinct olefin-containing
spirocyclic systems and an a,b-unsaturated system, all
primed for subsequent synthetic elaboration.
1) SOCl2, MeOH
PhCHO, PhCH2NC
I
2) Et3N
MeOH
99%
95%, two steps
7
CO2H
O
O
Ph
Ph
NHBn
O
NHBn
Pd(OAc)2, PPh3
Et3N, CH3CN
MeO2C
N
MeO2C
O
N
I
microwave, 25 min
98%
8
9
Scheme 2. Seven-membered ring closure.
An interesting variant of the multi-component Ugi
chemistry is the five-centered-four-component reaction,
which exploits an a-amino carboxylic acid as both the
amine and the acid reactant.12 For our system we used
allyl glycine along with o-bromobenzaldehyde and
benzyl isocyanide. This reaction, presumably, proceeds
through a six-membered ring intermediate 10, which
then undergoes nucleophilic attack by methanol pro-
ducing amino ester 11 in moderate yield. Substrate 11
cleanly underwent microwave-assisted Heck cyclization
to generate 12 (under conditions described in Table 1) in
90% yield (Scheme 3).
As stated previously, access to the other ring systems is
done by simply manipulating the reactants for the multi-
component reaction. We ran the Ugi reaction of benz-
aldehyde, allylglycine methyl ester 7 as the amine
component, benzyl isocyanide, and o-iodobenzoic acid
to generate substrate 8 in high yield with a ꢀ1:1 dia-
stereomeric ratio (Scheme 2). Intramolecular Heck
reactions using amino acids as substrates have previ-
ously been reported.11 As before, Heck cyclization on
the Ugi product 8 proceeded smoothly to produce the
seven-membered lactam 9 in excellent yield. The nature
of the aromatic halide proved to be influential on Heck
reactivity. Thus cyclization of aromatic iodide 8 was
complete in only 25 min upon exposure to microwave
irradiation under the same reaction conditions described
above for systems 1–3.
Following the success of these examples in solution
phase, we decided to test the effectiveness of our pro-
tocol on solid phase. Our solid-phase approach began
with a two-step sequence, which coupled Wang resin
Table 1. Results of six-membered ring closure
Aldehyde
Amine
Isocyanide
Acid
Ugi producta
Ugi yield
(%)
Heck productb
Heck yield
(%)
Reaction
timec (h)
CHO
Br
CO2H
PhCH2NH2 PhCH2NC
87
97
1
Br
O
H
H
N
N
Ph
N
Ph
N
O
O
O
Ph
Ph
4
1
CHO
Br
CO H
2
PhCH2NH2 PhCH2NC
96
98
98
91
2
2
Br
O
H
N
H
N
N
Ph
Ph
N
O
O
O
Ph
Ph
2
dr = 8:1
5
CHO
Br
CO H
2
PhCH2NH2 PhCH2NC
Br
O
H
N
H
Ph
Ph
N
N
O
N
O
O
Ph
Ph
6
dr >10:1
3
a Ugi multi-component reactions were carried out in MeOH at rt with reaction times ranging from 36 to 50 h; all products were isolated via flash
chromatography.
b Diastereomeric ratios were obtained following the filtration through a small plug of silica.
c Microwave-assisted Heck reactions were carried out in CH3CN at 125 ꢁC for 1 h. The formation of the spirocyclic products 5 and 6 required two
separate subjections to these conditions, therefore 2h total reaction time. Similar reactions carried out in refluxing CH 3CN took 16–18 h for
completion and afforded products with slightly lower yields (73–76%) and similar diastereoselectivities.

V. Gracias et al. / Tetrahedron Letters 45 (2004) 417–420
419
constrained nitrogen containing scaffolds. This work
represents another example of post-Ugi reaction
manipulation, which further augments the recent
examples of Ugi adduct cyclizations. Additionally, this
methodology has been extended to solid-phase systems.
More elaborate examples are being investigated along
with exploring library generation. The results of this
work will be reported in due course.
O
HO2C
NH2
CHO
Br
Br HN
MeOH
PhCH2NC
O
N
10
Ph
MeOH, 56%
O
H
N
O
CO2Me
H
BnHN
N
CO2Me
Pd(OAc)2, PPh3
Et3N, CH3CN
BnHN
Br
Acknowledgements
microwave, 2 hr
90%
12
The authors would like to thank the structural chemistry
staff for MS and NMR data. J.D.M. would like to thank
Abbott Laboratories for a summer internship position.
11
Scheme 3. Five-centered-four-component coupling route.
O
O
Ph
References and Notes
O
NHBn
O
I
NH2
O
N
MeOH
O
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I
PhCHO
€
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PhCH2NC
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1)
route A: 60 °C, 10 hrs, KOAc, Bu4NCl
O
Pd(OAc)2, Ph3P, CH3CN
Ph
or
NHBn
O
route B: microwave 135 °C, 1.5 hrs, Et3N
MeO2C
N
Bu4NCl Pd(OAc)2, Ph3P, 2:1 DMF/CH3CN
2) TFA
route A: 44%, three steps
route B: 33%, three steps
9
3) TMSCHN2
Scheme 4. Solid-phase route.
with Fmoc-protected (L)-allyl glycine mediated by 2,6-
dichlorobenzoyl chloride.13 Standard Fmoc deprotec-
tion yielded the desired resin-bound amino unit 13. Ugi
reaction was carried out using benzaldehyde, benzyl
isocyanide, and o-iodobenzoic acid in a 1:1 mixture of
MeOH/CH2Cl2.3b–e;14 The resin-bound Ugi adduct 14
was washed with DMF (3·), MeOH (3·), and CH2Cl2
(3·), and then subjected to two different solid-phase
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Bu4NCl.16 Following the Heck reactions, the resin was
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(1·), MeOH (3·), and CH2Cl2 (3·). The cyclized
adducts were cleaved from the resin (1:1 TFA/CH2Cl2)
and the resulting acids were methylated utilizing
(trimethylsilyl)diazomethane in MeOH, to produce ester
9 with moderate yields (33–44%) (Scheme 4).
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Pd(OAc)2 (3 mg, 0.015 mmol), PPh3 (8 mg, 0.0298 mmol),
Et3N (0.104 mL, 0.745 mmol) in CH3CN (4 mL) was
heated to 125 ꢁC for 1 h using microwave irradiation.
The solvent was evaporated and the crude was purified by
3. Conclusions
We have demonstrated that the Ugi multi-component
reaction followed by the intramolecular Heck cycliza-
tion is an efficient tool to obtain highly functionalized,

420
V. Gracias et al. / Tetrahedron Letters 45 (2004) 417–420
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pure product.
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