Aldol reactions in multicomponent reaction based domino pathways: A multipurpose enabling tool in heterocyclic chemistry

Article abstract of DOI:10.1021/ol401068u

The aldol reaction has been evaluated in combination with the Ugi multicomponent reaction to assemble richly decorated mono- and polycyclic systems via expeditious cascade pathways. A small collection of pyrrolinones was generated thereof, and the scarcely accessible pyridoquinoxalinedione scaffold was also prepared by designing an additional nucleophilic substitution step in this domino sequence requiring minimal operational effort.

Full text of DOI:10.1021/ol401068u

ORGANIC
LETTERS
2013
Vol. 15, No. 11
2738–2741
Aldol Reactions in Multicomponent
Reaction Based Domino Pathways:
A Multipurpose Enabling Tool
in Heterocyclic Chemistry
Zhigang Xu,† Fabio De Moliner,† Alexandra P. Cappelli,† and Christopher Hulme*,†,‡
College of Pharmacy, BIO5 Oro Valley, The University of Arizona, Oro Valley,
Arizona 85737, United States, and Department of Chemistry and Biochemistry,
The University of Arizona, Tucson, Arizona 85721, United States
hulme@pharmacy.arizona.edu
Received April 17, 2013
ABSTRACT
The aldol reaction has been evaluated in combination with the Ugi multicomponent reaction to assemble richly decorated mono- and polycyclic systems
via expeditious cascade pathways. A small collection of pyrrolinones was generated thereof, and the scarcely accessible pyridoquinoxalinedione
scaffold was also prepared by designing an additional nucleophilic substitution step in this domino sequence requiring minimal operational effort.
Since the infancy of synthetic organic chemistry, signifi-
cant efforts have been devoted to the discovery of method-
ologies for the preparation of heterocyclic compounds.
Shortly after the structures of the fundamental hetero-
cycles were elucidated, one of the first goals of the scientific
community was the development of routes to assemble
such moieties from materials accessible at the time.1 Since
that pioneering age, activity in this field has proceeded
unabated taking advantage of an arsenal of methodology
advancements made available over the past century.2
Today, two main trends that followed in the broad area
of heterocyclic chemistry are the use of cycloaddition-based
strategies3 and transition-metal-mediated annulations.4
However, a very convenient and expeditious strategy
that has emerged as a viable alternative is represented by
multicomponent reactions (MCRs)5 followed by post-
condensation modifications.6 MCRs combine three or
more reagents in a one-pot process, affording in a single
step and under typically simple experimental condi-
tions a final product containing portions derived from
each of the reacting molecules. Postcondensation modi-
fications, which are subsequent transformations taking
† College of Pharmacy.
‡ Department of Chemistry and Biochemistry.
(1) For examples of these early reports, see: (a) For furan: Limpricht,
H. Chem. Ber 1870, 3, 90. (b) For pyrrole: Hantzsch, A. Chem. Ber. 1890,
23, 1474. (c) For thiophene: Volhard, J.; Erdmann, H. Chem. Ber. 1885,
18, 454. (d) For pyridine: Hantzsch, A. Chem. Ber. 1881, 14, 1637. (e) For
quinoline: Skraup, Z. H. Chem. Ber. 1880, 13, 2086. (f) For indole:
Baeyer, A.; Emmerling, A. Chem. Ber. 1869, 2, 679.
(4) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Rubin, M.;
Sromek, A. W.; Gevorgyan, V. Synlett 2003, 2265.
(5) For example, see: (a) Multicomponent Reactions; Zhu, J.,
ꢀ
€
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Domling,
A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083. (c) Sunderhaus,
J. D.; Martin, S. E. Chem.;Eur. J. 2009, 15, 1300. (d) Hulme, C.;
Dietrich, J. Mol. Diversity 2009, 13, 195. (e) Ruijter, E.; Scheffelaar, R.;
Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234. (f) Synthesis of
Heterocycles via Multicomponent Reactions; Ruijter, E., Orru, R. V. A.,
Eds.; Springer-Verlag: Berlin, Germany, 2010. (g) Estevez, V.; Villacampa,
M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402.
(2) For excellent reviews on the topic, see: (a) D’Souza, D. M.;
€
Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095. (b) Alvarez-Corral,
~
M.; Munoz-Dorado, M.; Rodrıguez-Garcia, I. Chem. Rev. 2008, 108,
3174. (c) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395.
(d) Molander, G. A. Acc. Chem. Res. 1998, 31, 603. (e) Chiba, S. Synlett
2012, 21.
(3) (a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley & Sons: Hoboken, NJ, 2002. (b) Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49. (c) Chiacchio, U.; Padwa, A.; Romeo, G. Curr.
Org. Chem. 2009, 13, 422.
(6) For the importance of post-condensation modifications, see:
Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C. Evolution of Iso-
cyanide Chemistry; Nenajdenko, V., Ed.; Wiley-VCH: Weinheim, Germany,
2012.
r
10.1021/ol401068u
Published on Web 05/29/2013
2013 American Chemical Society

place after the MCR, are in turn able to rigidify the often
acyclic multicomponent adducts into a number of cyclic
species. As such, multicomponent approaches are ideal
to address some of the drawbacks affecting classical
heterocyclic syntheses, such as poor availability of
starting materials or the need for difficult, lengthy, and
elaborate synthetic operations.7 Our group has signifi-
cant experience in the design of novel chemotypes via
these kinds of pathways, as exemplified by reports deal-
ing with the preparation of quinoxalines, benzodiaze-
pines, benzimidazoles, pyrrolidinones, and pyrazoles,
inter alia.8
recent work,9 microwave irradiation at elevated tempera-
tures and 2 equiv of organic bases were employed to
trigger the cyclization step. Different temperatures, reac-
tion times, and solvents were next evaluated (Table 1),
and heating at 160 °C for 20 min in DMF in the presence
of diisopropylamine (DIPA, entry 2) proved optimal,
smoothly affording cyclized product 2a in a very satisfac-
tory 75% yield over two steps.
Table 1. Optimization of the Cyclization Step in the UgiÀAldol
Sequence
Inspired by our recent findings on the applicability of
aldol reactions to the development of domino sequences9
and with the intent of devising new straightforward one-
pot strategies to enrich the heterocyclic chemistry toolbox,
we embarked on a campaign to investigate the possibilities
suggested by this approach. Initially, we turned our attention
to the synthesis of the pyrrolinone moiety, a very appeal-
ing biological scaffold shown to be a key motif in HIV-1
integrase inhibitors,10 peptidomimetics,11 and marine natur-
al products possessing relevant antibacterial properties, such
as holomycine12 and tetramic acids.13
The assembly of the acyclic precursor for this chemotype
was accomplished by means of the Ugi four-component
condensation (U-4CR),14 which predictably performed
well under the classical mild conditions.15 Pyruvic alde-
hyde, n-butylisonitrile, 2,4-dichlorophenylacetic acid, and
benzylamine were mixed in methanol and stirred overnight
at room temperature. Upon formation of 1a, the solvent
was removed and the crude residue was subjected to the
aldol reaction without any purification. On the basis of our
temp
time
yield
(%)
entry
solvent
base
(°C)
(min)
1
2
3
4
5
6
DMF
DMF
DMF
DMF
DMSO
THF
DIPA
DIPA
DIPA
TEA
140
160
160
160
160
160
20
20
40
20
20
20
56
75
57
57
43
50
(7) For significant examples of this approach to the synthesis of
heterocycles, see: (a) Banfi, L.; Basso, A.; Guanti, G.; Kielland, N.;
Repetto, C.; Riva, R. J. Org. Chem. 2007, 72, 2151. (b) Wang, W.; Ollio,
€
S.; Herdtweck, E.; Domling, A. J. Org. Chem. 2011, 76, 637. (c) Znabet,
DIPA
DIPA
A.; Zonneveld, J.; Janssen, E.; De Kanter, F. J. J.; Helliwell, M.; Turner,
N. J.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2011, 46, 7706. (d) Erb,
W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74, 3109. (e) El Kaim, L.;
Gizolme, M.; Grimaud, L. Synlett 2007, 227. (f) De Moliner, F.;
Crosignani, S.; Galatini, A.; Riva, R.; Basso, A. ACS Comb. Sci.
2011, 13, 453.
(8) For example, see: (a) De Moliner, F.; Hulme, C. Org. Lett. 2012,
14, 1354. (b) De Moliner, F.; Hulme, C. Tetrahedron Lett. 2012, 53, 5787.
(c) Gunawan, S.; Ayaz, M.; De Moliner, F.; Frett, B.; Kaiser, C.;
Patrick, N.; Hulme, C. Tetrahedron 2012, 68, 5606. (d) Shaw, A. Y.;
Medda, F.; Hulme, C. Tetrahedron Lett. 2012, 53, 1313. (e) Xu, Z.; Ayaz,
M.; Cappelli, A. P.; Hulme, C. ACS Comb. Sci. 2012, 14, 460.
(f) Gunawan, S.; Petit, J.; Hulme, C. ACS Comb. Sci. 2012, 14, 160.
(g) Shaw, A. Y.; McLaren, J. A.; Nichols, G S.; Hulme, C. Tetrahedron
Lett. 2012, 53, 2592.
With optimized conditions for the second step of the
sequence in hand, we thus investigated the use of different
starting materials in order to determine the reactivity
domain of the UgiÀaldol two-step, one-pot route and to
assemble a small collection of compounds of generic
structure 2. Overall, two glyoxaldehydes, three isonitriles,
four carboxylic acids, and eight amines were employed to
build a representative set (Table 2) with yields of 2aÀ2i
spanning 62À82%, requiring only column chromatogra-
phy of the final product.
The advantages of the multicomponent approach to
the synthesis of 2 over conventional linear methodologies
are numerous. In fact, reported stepwise protocols for
the preparation of pyrrolinones mostly involve the use
of exotic starting materials, transition metal catalysts, and/
or lengthy multistep routes and suffer from a resulting lack
of generality and practical ease.16 The strategy described
herein also differs from the existing multicomponent pro-
tocols leading to this chemotype, which either are unable
to render final products with four diversity points17 or rely
(9) Xu, Z.; De Moliner, F.; Cappelli, A. P.; Hulme, C. Angew. Chem.,
Int. Ed. 2012, 51, 8037.
(10) (a) Pace, P.; Spieser, S. A. H.; Summa, V. Bioorg. Med. Chem.
Lett. 2008, 18, 3865. (b) Ma, K.; Wang, P.; Fu, W.; Wan, X.; Zhou, L.;
Chu, Y.; Ye, D. Bioorg. Med. Chem. Lett. 2011, 21, 6724.
(11) Raghuraman, A.; Ko, E.; Perez, L. M.; Ioerger, T. R.; Burgess,
K. J. Am. Chem. Soc. 2011, 133, 12350.
(12) (a) Wietz, M.; Mansson, M.; Gotfredsen, C. H.; Larsen, T. O.;
Gram, L. Mar. Drugs 2010, 8, 2946. (b) Hjelmgaard, T.; Givskov, M.;
Nielsen, J. Org. Biomol. Chem. 2007, 5, 344.
(13) (a) Ueda, C.; Tateda, K.; Horikawa, M.; Kimura, S.; Ishii, Y.;
Nomura, K.; Yamada, K.; Suematsu, T.; Inoue, Y.; Ishiguro, M.;
Miyairi, S.; Yamaguchi, K. Antimicrob. Agents Chemother. 2010, 54,
683. (b) Holloway, C. A.; Matthews, C. J.; Jeong, Y.-C.; Moloney,
M. G.; Roberts, C. F.; Yaqoob, M. Chem. Biol. Drug Des. 2011, 78, 229.
(14) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
(15) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632.
Org. Lett., Vol. 15, No. 11, 2013
2739

Table 2. Scope of the UgiÀAldol Sequence toward Pyrrolinones 2
Table 3. Optimization Studies in the Cascade Route Leading to
Pyridoquinoxalinediones
compd R1
R2
R3
R4
yield (%)
2a
2b
2c
2d
2e
2f
Me n-Bu 2,4-di-Cl-Ph
Me n-Bu 2,4-di-Cl-Ph
Me n-Bu 2,4-di-Cl-Ph
Bn
75
68
62
82
73
67
72
77
79
2,4-di-MeO-Ph
2-furylmethyl
Me Bn
3,4-di-MeO-Ph 3,4-di-MeO-Ph
Me n-Bu 3,5-di-F-Ph
Ph n-Bu 3,5-di-CF3-Ph
Ph n-Bu 3,5-di-CF3-Ph
Ph n-Bu 3,5-di-F-Ph
2-Cl-Bn
Bn
2g
2h
2i
4-Br-Ph
4-Cl-Ph
Ph i-Pr
3,4-di-MeO-Ph Bu
on scarcely available phosphorus-containing building
blocks.18
Enticed by the potential of this method and interest in
the design of straightforward domino pathways for the
synthesis of unusual polyheterocyclic frameworks, it was
envisioned that a tandem approach encompassing an aldol
condensation and a nucleophilic aromatic substitution19
could pave the way to the assembly of pyridoquinoxaline-
diones 6 (Table 3).
In this case, the nucleophilic partner in the aldol reaction
was furnished by pyruvic aldehyde. Completing the func-
tionality for the desired cascade reaction, a fluorine atom
installed on the aniline input of the MCR was expected
to be displaced upon nucleophilic attack by the amidic
nitrogen embedded in the Ugi backbone. tert-Butylisoni-
trile, phenylglyoxylic acid, 2-fluoro-4-bromoaniline, and
pyruvic aldehyde were thus evaluated by simple mixing
in methanol and subsequent stirring overnight at rt. After
removal of the solvent, crude 3a was subjected to thermal
treatment in the presence of a base, which promoted an
aldol-drivencyclization to4afollowed bytautomerization.
tempa
yield
(%)
entry
solvent
base
(°C)
time
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DIPA
160
140
180
180
180
120
120
120
20 min
10
10
33
26
17
70
47
29
DIPA
20 min
DIPA
20 min
K2CO3
CsCO3
DIPA
20 min
20 min
overnight
overnight
overnight
K2CO3
CsCO3
a Microwave irradiation was employed except for entries 10À12.
(16) For some examples, see: (a) Auricchio, S.; Truscello, A. M.;
Lauria, M.; Meille, S. V. Tetrahedron 2012, 68, 7441. (b) Shindo, M.;
Yoshikawa, T.; Itou, Y.; Mori, S.; Nishii, T.; Shishido, K. Chem.;Eur.
J. 2006, 12, 524. (c) Ozawa, T.; Horie, H.; Kurahashi, T.; Matsubara, T.
Chem. Commun. 2010, 46, 8055. (d) Daly, M.; Gill, K.; Sime, M.;
Simpson, G. L.; Sutherland, A. Org. Biomol. Chem. 2011, 9, 6761.
(e) Van den Hoven, B. G.; Alper, H. J. Am. Chem. Soc. 2001, 123,
10214. (f) Greger, J. G.; Yoon-Miller, S. J. P.; Bechtold, N. R.;
Flewelling, S. A.; MacDonald, J. P.; Downey, C. R.; Cohen, E. A.;
Pelkey, E. T. J. Org. Chem. 2011, 76, 8203.
(17) (a) Basso, A.; Banfi, L.; Galatini, A.; Guanti, G.; Rastrelli, F.;
Riva, R. Org. Lett. 2009, 11, 4068. (b) Fukuyama, T.; Nakashima, N.;
Okada, T.; Ryu, I. J. Am. Chem. Soc. 2012, 135, 1006. (c) Ryabukhin,
S. V.; Panov, D. M.; Plaskon, A. S.; Grygorenko, O. O. ACS Comb. Sci.
2012, 14, 631.
A second ring closure taking place in a one-pot fashion
thus provided final tricyclic species 6a via intermediate 5a.
This constitutes a nonobvious four-step pathway, giving
access to an otherwise challenging structure by means of
two easy synthetic operations with only one chromato-
graphic exercise (entry 1, Table 3) albeit in this case in only
10% overall yield.
Further optimization studies for the double cyclization
step of this cascade were thus conducted (Table 3). Hence,
lower or higher temperatures gave similar unsatisfactory
outcomes (entries 2 and 3), and evaluation of potassium
and cesium carbonate also proved unfruitful (entries 4
and 5). Gratifyingly, conventional heating overnight in an
oil bath in the presence of DIPA afforded 6a in 70% yield
over four steps in one pot (entry 6). It is worth noting that
this represents a high-yielding and experimentally straight-
forward domino sequence affording an uncommon tricyclic
€
(18) Beck, B.; Picard, A.; Herdtweck, E.; Domling, A. Org. Lett.
2004, 6, 39.
(19) For the use of nucleophilic aromatic substitutions to manipulate
Ugi adducts, see: (a) Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.;
Hulme, C. Tetrahedron Lett. 2001, 42, 4963. (b) Trifilenkov, A. S.; Ilyin,
A. P.; Kysil, V. M.; Sandulenko, Y. B.; Ivachtchenko, A. V. Tetrahedron
Lett. 2007, 48, 2563. (c) Spatz, J. H.; Umkehrer, M.; Kalinski, C.; Ross,
G.; Burdack, C.; Kolb, J.; Bach, T. Tetrahedron Lett. 2007, 48, 8060.
(d) Cristau, P.; Vors, J.-P.; Zhu, J. QSAR Comb. Sci. 2006, 25, 519.
(e) Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079.
2740
Org. Lett., Vol. 15, No. 11, 2013

evaluated (Table 4), enabling production of a small collec-
tion of eight compounds 6 with yields ranging from 50%
to 77%.
Table 4. Scope of the Cascade Route toward Compounds 6
Inconclusion, wehave demonstratedherein thepotential
possessed by the sequential combination of the Ugi four-
component reaction with the aldol condensation. In this
vein, two straightforward and operationally friendly dom-
ino pathways enabling the rapid assembly of the hetero-
cyclic cores 2 and 6 were elaborated. This methodology is
diversity-enabling and suitable for the expeditious prepara-
tion of complex molecular frameworks when additional
chemical transformations are embedded in the cascade.
We hope this method will represent a valuable tool in
heterocyclic chemistry.
compd
R1
R2
R3
yield (%)
6a
6b
6c
6d
6e
6f
t-Bu
Ph
Ph
4-Br
H
70
50
73
66
77
75
62
56
4-MeO-Ph
2,5-di-Me-Ph
n-Bu
2-furyl
Ph
H
H
t-Bu
2-thienyl
Ph
4-Cl
4-Cl
H
Acknowledgment. Financial support from the National
Institutes of Health (Grant P41GM086190) is gratefully
acknowledged. We also thank Dr. Federico Medda and
Dr. David Bishop (College of Pharmacy, BIO5Oro Valley,
The University of Arizona) for proofreading.
2,5-di-Me-Ph
n-Bu
6g
6h
2-thienyl
2-thienyl
i-Pr
4-Cl
scaffold, previously prepared by relatively inferior
methods.20
Again, the scope of the protocol was explored, and five
isonitriles, three carboxylic acids, and three anilines were
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for compounds 2 and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) (a) Yavari, A.; Souri, S.; Sirouspour, M.; Bayat, M. J. Synlett
2009, 1921. (b) Akbarzadeh, R.; Tayebeh, A.; Mirzaei, P.; Bazgir, A.
Helv. Chim. Acta 2011, 94, 1527.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 11, 2013
2741