General one-pot, two-step protocol accessing a range of novel polycyclic heterocycles with high skeletal diversity

Article abstract of DOI:10.1021/co300046r

An Ugi one-pot three-component four-center reaction was coupled with a subsequent acid mediated cyclodehydration step to furnish a multitude of unique scaffolds having in common an embedded or attached benzimidazole and often a ring system formed through

Full text of DOI:10.1021/co300046r

Research Article
pubs.acs.org/acscombsci
General One-pot, Two-Step Protocol Accessing a Range of Novel
Polycyclic Heterocycles with High Skeletal Diversity
Zhigang Xu, Muhammad Ayaz, Alexandra A. Cappelli, and Christopher Hulme*
College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Boulevard, Oro Valley, Arizona 85737, United
States
S
* Supporting Information
ABSTRACT: An Ugi one-pot three-component four-center
reaction was coupled with a subsequent acid mediated
cyclodehydration step to furnish a multitude of unique
scaffolds having in common an embedded or attached
benzimidazole and often a ring system formed through
lactamization. Using combinations of tethered Ugi inputs
typically via tethered acid-ketone inputs and supporting
reagents containing masked internal nucleophiles, such
scaffolds were produced in good to excellent yields in an operationally friendly manner.
KEYWORDS: postcondensation, Ugi reaction, benzimidazole, lactams, one-pot
Repository (MLSMR) for interrogation of targets of interest
nation-wide.
1. INTRODUCTION
The Ugi multicomponent reaction (MCR) and several closely
related isocyanide based MCRs1 are useful synthetic tools that
are frequently applied in the drug design and development
process.2 The fact that the Ugi reaction utilizes four diversity
reagents (acid, aldehyde, amine and isocyanide) in one-pot3
makes it ideal for the high-throughput construction of chemical
libraries.4 Indeed, a key feature associated with such
condensations is the process of tethering the diversity reagents
in various combinations to generate new heterocyclic chemo-
types.5 In this context, the most commonly and successfully
used tethered combination comprises an acid and ketone/
aldehyde input6 resulting in the formation of lactams of varying
ring sizes which have widespread utility in disease modifying
small molecules.7 While exploring the potential of Ugi
postcondensations, we have previously synthesized a number
of novel scaffolds: benzodiazepines,8 benzimidazoles,9 ketopi-
perazines,10 imidazoline-γ-lactams,11 hydantoins12 and quinazo-
lines13 to name a few.
2. RESULTS AND DISCUSSION
First studies were conducted employing the bifunctional
reagent levulinic acid 1{1} in combination with N-Boc-1,2-
phenylenediamine 2{1} and pentyl-isocyanide 3{1} using
trifluoroethanol (TFE) as solvent to enhance yields of the
condensation product (Scheme 1).15
After monitoring the Ugi reaction by LCMS, the reaction was
found to be complete in 3 h at room temperature affording
4{1,1,1} (72% isolated yield). The Ugi product was
subsequently dissolved in a 10% solution of trifluoroacetic
Scheme 1. Synthesis of α-Quaternized Benzimidazole-
Carboxamides
Herein, we report a postcondensation intramolecular-Ugi
strategy that enables production of nitrogen-enriched polycyclic
scaffolds endowed with benzimidazoles, lactams of various ring
sizes, dihydroquinazolines and other moieties, coalesced within
a single constrained molecular architecture. The range and
average values of molecular weights (MW), polar surface areas
(PSA) and clogP for all target molecules depicted in this article
are as follows: [MW 255−399, av 340], [PSA 40−63 Å2, av 47
Å2], [clogP 1.1−5.1, av 4.0] and suggesting potential for high
oral bioavailability and consequently interest from the file
enhancement community. Indeed, there is a plethora of
literature invoking the pharmacological relevance of benzimi-
dazole scaffold.14 Encouragingly, many of these compounds
have been accepted by the Molecular Libraries Small Molecule
Received: April 26, 2012
Revised: June 26, 2012
Published: June 29, 2012
© 2012 American Chemical Society
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ACS Combinatorial Science
Research Article
acid (TFA) in dichloroethane (DCE) and exposed to
microwave irradiation at 120 °C for 15 min. As such, these
conditions promoted an amino-cyclodehydration to render the
tricyclic scaffold 6{1,1,1} containing a valuable α-quaternary
methyl group (70% isolated yield, 50% for two steps), Scheme
1.
(2{1}−2{6}) (Figure 4) to form the Ugi adducts of generic
structure 7. Exposure of the adducts 7 to the conditions used to
promote cyclization in Scheme 2, successfully afforded a range
of bis-heterocyclic scaffolds 9 in overall isolated yields of up to
64% (over two steps), Figure 3.
The developed process was then employed with amines
carrying a second masked internal nucleophile (2{1} and
2{2}), isocyanide 3 and tethered bifunctional reagents, 1{1}
through 1{4} (Figure 6, Scheme 3). As expected, intra-
molecular Ugi reactions performed well and gratifyingly
subsequent acid treatment of the Ugi adducts (10) and
microwave irradiation afforded products 12 in excellent yields
in a mere two synthetic operations, Figure 5.
Considering the medicinal potential of quinazolines
embedded with benzimidazoles, scaffolds of generic structure
12 could be particularly interesting since the calculated values
for bioavailabilty criteria fall well within the ideal ranges.
Definitive structural elucidation of products 9{4,4} and 12{1,2}
was confirmed by X-ray crystallographic analysis, Figure 7.
3. CONCLUSIONS
A range of tethered keto-acids or aldehyde acids were
successfully employed in intramolecular ring forming Ugi
reactions, followed by either one or two consecutive amino-
cyclodehydrations to afford a range of unique scaffolds with
excellent physicochemical properties in a general one pot, two
step protocol. These concise routes coupled with attractive final
products represent an excellent file enhancement opportunity
delivering potential libraries of high “skeletal diversity” with
“lead-like” properties.
Figure 1. Products 6{1,1,1} through 6{2,2,2}.
4. EXPERIMENTAL PROCEDURES
General Procedure for the Preparation of Benzote-
trazolodiazepinones 6. Using 8 mL microwave vial equipped
with a magnetic stirring bar, a solution of 0.25 mmol of keto- or
formyl acid (1) and 0.25 mmol of N-Boc-diamine (2) in 0.7 mL
of trifluoroethanol (TFE) was stirred for a few minutes at room
temperature followed by the addition of isocyanide (3) (0.25
mmol). The progress of the reaction was monitored using
LCMS and completion of the Ugi reaction was observed after 3
h stirring. The reaction mixture was concentrated using a
nitrogen flush and ∼2 mL of 10% (v/v) trifluoroacetic acid
(TFA) in dichloroethane (DCE) were added. The reaction was
heated in a CEM microwave at 120 °C for 15 min. After
cooling the reaction mixture to room temperature, it was
directly loaded on a CombiFlash Rf system (silica gel) and
using a gradient of ethyl acetate/hexane (0−100%) followed by
methanol/ethyl acetate (0 to 20%) the product 6 was purified.
General Procedure for Compounds 9. The same
procedure as for compounds 6, was used for this series of
compounds with the following exceptions: reactions were
conducted at 0.5 mmol scale in 3 mL of solvent (TFE) and
after the deprotection/cyclization stage, purification was done
Figure 2. Employed diversity reagents, 1, 2, and 3.
Heating the reaction mixture for shorter times or at lower
temperatures resulted in only partial product formation with
the amine 5{1,1,1} being the major product. With this robust
protocol in-hand, six congeners (6{1,1,1} through 6{2,2,2})
were produced in up to 58% yields for the two overall steps,
Figure 1. The comparable yields demonstrate the generic
nature of the reaction with no apparent preference for
aldehyde-acids over keto-acids or selected tethers under these
expedited conditions. These findings prompted us to apply the
procedure to aid formation of the chemically more complex
scaffolds of generic formulas 9, Scheme 2. Thus, isocyanide 3
(2-(N-Boc-amino)-phenyl-isocyanide) was prepared from N-
Boc-1,2-phenylenediamine using standard methodology16 and
treated with tethered acids (1{1}−1{7}) and various amines
Scheme 2. Generic Scheme for the Synthesis of Polycyclic Scaffolds 9
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Figure 3. Products 9{1,1} through 9{3,1} derived from Scheme 2.
Figure 4. Employed diversity reagents, 1 and 2 in Scheme 2.
Scheme 3. Synthesis of Polycyclic Scaffolds 12
Figure 6. Employed diversity reagents, 1 and 2 in Scheme 3.
Figure 7. X-rays structures of compound 9{4,4} and 12{1,2}.
on a CombiFlash Rf system (silica gel) using a gradient of ethyl
acetate/hexane (0−100%).
General Procedure for Compounds 12. Exactly the same
procedure (as for 9) was employed for the preparation and
purification of compounds 12.
Figure 5. Products 12{1,2} through 12{3,2} derived from Scheme 3.
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novel highly selective chiral auxiliary for the asymmetric synthesis of L-
and D-α-amino acid derivatives via a multicomponent Ugi reaction. J.
Org. Chem. 2005, 70, 575−579.
ASSOCIATED CONTENT
* Supporting Information
Supporting Information including all experimental procedures,
CIF files for compounds 9{4,4} and 12{1,2} and character-
ization data for all the compounds are available free of charge
via the Internet at http://pubs.acs.org.
■
S
(5) (a) Mironov, M. A.; Ivantsova, M. N.; Mokrushin, V. S. Ugi
reaction in aqueous solutions: a simple protocol for libraries
production. Mol. Divers. 2003, 6, 193−197. (b) Basso, A.; Banfi, L.;
Riva, R.; Guanti, G. U-4C-3CR versus U-5C-4CR and stereochemical
outcomes using suitable bicyclic β-amino acid derivatives as bifunc-
tional components in the Ugi reaction. Tetrahedron Lett. 2004, 45,
587−590. (c) Hanusch-Kompa, C.; Ugi, I. Multi-component reactions
13: Synthesis of γ-lactams as part of a multiring system via Ugi-4-
centre-3-component reaction. Tetrahedron Lett. 1998, 39, 2725−2728.
(6) (a) Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. Unique
structures generated by Ugi 3CC reactions using bifunctional starting
materials containing aldehyde and carboxylic acid. J. Org. Chem. 1999,
64, 1074−1076. (b) Krelaus, R.; Westermann, B. Preparation of
peptide-like bicyclic lactams via a sequential Ugi reactionOlefin
metathesis approach. Tetrahedron Lett. 2004, 45, 5987−5990.
(c) Westermann, B.; Diedrichs, N.; Krelaus, R.; Walter, A.; Gedrath,
I. Diastereoselective synthesis of homologous bicyclic lactams
Potential building blocks for peptide mimics. Tetrahedron Lett. 2004,
45, 5983−5986. (d) Ilyin, A. P.; Trifilenkov, A. S.; Kurashvili, I. D.;
Krasavin, M.; Ivachtchenko, A. V. One-step construction of
peptidomimetic 5-carbamoyl-4-sulfonyl-2-piperazinones. J. Comb.
Chem. 2005, 7, 360−363.
AUTHOR INFORMATION
Corresponding Author
*Fax: 520-626-4824. E-mail: hulme@pharmacy.arizona.edu.
Funding
This work was supported by the National Institutes of Health
(P41GM086190).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are thankful to Gary S. Nichol for X-rays analysis
and Nicole Schechter for proof-reading.
■
ABBREVIATIONS
■
MCR, multicomponent reaction; TFE, trifluoroethanol; TFA,
trifluoroacetic acid; MLSMR, molecular libraries small molecule
repository; BOC, tertiary butoxy carbonyl; DCE, dichloro-
methane
(7) (a) Samanen, J. M.; Ali, F. E.; Barton, L. S.; Bondinell, W. E.;
Burgess, J. L.; Callahan, J. F.; Calvo, R. R.; Chen, W.; Chen, L.; Erhard,
K.; Feuerstein, G.; Heys, R.; Hwang, S. M.; Jakas, D. R.; Keenan, R.
M.; Ku, T. W.; Kwon, C.; Lee, C. P.; Miller, W. H.; Newlander, K. A.;
Nichols, A.; Parker, M.; Peishoff, C. E.; Rhodes, G.; Ross, S.; Shu, A.;
Simpson, R.; Takata, D.; Yellin, T. O.; Uzsinskas, I.; Venslavsky, J. W.;
Yuan, C. K.; Huffman, W. F. Potent, selective, orally active 3-oxo-1,4-
benzodiazepine GPIIb/IIIa integrin antagonists. J. Med. Chem. 1996,
39, 4867−4870. (b) Chibale, K. Economic drug discovery and rational
medicinal chemistry for tropical diseases. Pure. Appl. Chem. 2005, 77,
1957−1964. (c) Musonda, C. C.; Gut, J.; Rosenthal, J. P.; Yardley, V.;
Carvalho de Souza, C. R.; Chibale, K. Application of multicomponent
reactions to antimalarial drug discovery. Part 2: New antiplasmodial
and antitrypanosomal 4-aminoquinoline γ- and δ-lactams via a “catch
and release” protocol. Bioorg. Med. Chem. 2006, 14, 5605−5615.
(8) Hulme, C.; Peng, J.; Tang, S. Y.; Burns, C. J.; Morize, I.;
Labaudiniere, R. Improved procedure for the solution phase
preparation of 1,4- benzodiazepine-2,5-dione libraries via Armstrong’s
convertible isonitrile and the Ugi reaction. J. Org. Chem. 1998, 63,
8021−8023.
(9) (a) Xu, Z.; Shaw, A. Y.; Dietrich, J.; Cappelli, A. P.; Nichol, G.;
Hulme, C. Facile, novel two-step syntheses of benzimidazoles, bis-
benzimidazoles, and bis-benzimidazole-dihydroquinoxalines. Mol.
Diversity 2012, 16, 73−79. (b) Tempest, P.; Ma, L.; Thomas, S.;
Hua, Z.; Kelly, M. G.; Hulme, C. Two-step solution-phase synthesis of
novel benzimidazoles utilizing a UDC (Ugi/de-Boc/cyclize) strategy.
Tetrahedron Lett. 2001, 42, 4959−4962. (c) Hulme, C.; Ma, L.;
Romano, J.; Morrissette, M. Remarkable 3-step-1-pot solution phase
synthesis of imidazolines via a UDC strategy. Tetrahedron Lett. 1999,
40, 7925−7928.
(10) (a) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski,
P.; Kumar, N. V. Applications of N-BOC-diamines for the solution
phase synthesis of ketopiperazine libraries utilizing a Ugi/De-BOC/
cyclization (UDC) strategy. Tetrahedron Lett. 1998, 39, 8047−8050.
(b) Hulme, C.; Peng, J.; Morton, G.; Salvino, J.; Herpin, T.;
Labaudiniere, R. Novel safety-catch linker and its application with a
Ugi/De-BOC/cyclization (UDC) strategy to access carboxylic acids,
1,4-benzodiazepines, diketopiperazines, ketopiperazines and dihydro-
quinoxalinones. Tetrahedron Lett. 1998, 39, 7227−7230.
(11) Hulme, C.; Ma, L.; Cherrier, M. P.; Romano, J. J.; Morton, G.;
Duquenne, C.; Salvino, J.; Labaudiniere, R. Novel applications of
convertible isonitriles for the synthesis of mono and bicyclic γ-lactams
via a UDC strategy. Tetrahedron Lett. 2000, 41, 1883−1887.
REFERENCES
■
(1) (a) Domling, A. Recent developments in isocyanide based
̈
multicomponent reactions in applied chemistry. Chem. Rev. 2006, 106,
17−89. (b) Domling, A.; Ugi, I. Multicomponent reactions with
̈
isocyanides. Angew. Chem., Int. Ed. 2000, 39, 3168−3210. (c) Hulme,
C.; Gore, V. Multi-component reactions: emerging chemistry in drug
discovery: From Xylocain to Crixivan. Curr. Med. Chem. 2003, 10, 51−
80. (d) Cuny, G.; Bois-Choussy, M.; Zhu, J. Palladium- and copper-
catalyzed synthesis of medium- and large-sized ring-fused dihydroa-
zaphenanthrenes and 1,4-benzodiazepine-2,5-diones. Control of
reaction pathway by metal-switching. J. Am. Chem. Soc. 2004, 126,
14475−14484.
(2) (a) Dolle, R. E.; La Bourdonnec, B.; Goodman, A. J.; Morales, G.
A.; Thomas, C. J.; Zhang, W. Comprehensive survey of chemical
libraries for drug discovery and chemical biology: 2008. J. Comb. Chem.
2009, 11, 739−190. (b) Breslin, J. H.; Miskowski, A. T.; Rafferty, M.
B.; Coutinho, V. S.; Palmer, M. J.; Wallace, H. N; Schneider, R. C.;
Kimball, S. E.; Zhang, S; Li, J.; Colburn, W. R.; Stone, J. D.; Martinez,
P. R.; He, W. Rationale, design, and synthesis of novel phenyl
imidazoles as opioid receptor agonists for gastrointestinal disorders. J.
Med. Chem. 2004, 47, 5009−5020. (c) Huang, Y.; Wolf, S.; Bista, M.;
Meireles, L.; Camacho, C.; Holak, A. T. Domling, A1,4-Thienodiaze-
pine-2,5-diones via MCR (I): synthesis, virtual space and p53-Mdm2
activity. Chem. Biol. Drug Des. 2010, 76, 116−129.
̈
(3) (a) Ugi, I. The α-addition of immonium ions and anions to
isonitriles accompanied by secondary reactions. Angew. Chem., Int. Ed.
1962, 1, 8−21. (b) Kappe, C. O.; Dallinger, D. The impact of
microwave synthesis on drug discovery. Nat. Rev. Drug Discovery 2006,
5, 51−63. (c) Basso, A.; Banfi, L.; Guanti, G.; Riva, R. One-pot
synthesis of α-acyloxyaminoamides via nitrones as imine surrogates in
the Ugi MCR. Tetrahedron Lett. 2005, 46, 8003−8006. (d) Mossetti,
R.; Pirali, T.; Seggiorato, D.; Tron, G. C. Imides: forgotten players in
the Ugi reaction. One-pot multicomponent synthesis of quinazoli-
nones. Chem. Commun. 2011, 47, 6966−6968.
(4) (a) Hatanaka, M.; Nitta, H.; Ishimaru, T. The synthesis of the 1-
carbopenem antibiotic ( )-ps-5 and its 6-epi analogue. Tetrahedron
Lett. 1984, 25, 2387−2390. (b) Pirrung, M.; Sarma, K. D. β-Lactam
synthesis by Ugi reaction of β-ketoacids in aqueous solution. SynLett.
2004, 8, 1425−1427. (c) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. A
463
dx.doi.org/10.1021/co300046r | ACS Comb. Sci. 2012, 14, 460−464

ACS Combinatorial Science
Research Article
(12) Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S. Y.;
Cherrier, M. P.; Choi, S.; Salvino, J.; Labaudiniere, R. Novel
applications of carbon dioxide/MeOH for the synthesis of hydantoins
and cyclic ureas via the Ugi reaction. Tetrahedron Lett. 2000, 41,
1889−1893.
(13) Dietrich, J.; Kaiser, C.; Meurice, N.; Hulme, C. Concise two-
step solution phase syntheses of four novel dihydroquinazoline
scaffolds. Tetrahedron Lett. 2010, 51, 3951−3955.
(14) (a) Wenlock, M. C.; Austin, R. P.; Barton, P.; Davis, A. M.;
Leeson, P. D. A comparison of physicochemical property profiles of
development and marketed oral drugs. J. Med. Chem. 2003, 46, 1250−
1256. (b) Velík, J.; Baliharova,
́
V.; Fink-Gremmels, J.; Bull, S.; Lamka,
J.; Skalova, L. Benzimidazole drugs and modulation of biotransforma-
́
́
tion enzymes. Res Vet Sci. 2004, 76 (95), 108. (c) Merino, G.; Jonker,
G. M.; Wagenaar, E; Pulido, M. M.; Molina, J. A.; Alvarez, I. A.;
Schinkel, H. A. Transport of anthelmintic benzimidazole drugs by
breast cancer resistance protein (BCRP/ABCG2). Drug. Metab. Dispos.
2005, 33, 614−618.
(15) (a) Nenajdenko, V. G.; Gulevich, A. V.; Balenkova, E. S. The
Ugi reaction with 2-substituted cyclic imines. Synthesis of substituted
proline and homoproline derivatives. Tetrahedron 2006, 62, 5922−
5930. (b) Short, M. K.; Mjalli, M. M. A. A solid-phase combinatorial
method for the synthesis of novel 5- and 6-membered ring lactams.
Tetrahedron Lett. 1997, 38, 359−362.
(16) Ito, Y.; Ohnishi, A.; Ohsaki, H.; Murakami, M. A preparative
method for o-diisocyanoarenes. Synthesis 1988, 9, 714−715.
464
dx.doi.org/10.1021/co300046r | ACS Comb. Sci. 2012, 14, 460−464