Glyoxylic acid and MP-glyoxylate: Efficient formaldehyde equivalents in the 3-CC of 2-aminoazines, aldehydes, and isonitriles

Article abstract of DOI:10.1021/ol0478234

(Chemical Equation Presented) Glyoxylic acid, either in solution or immobilized on MP-carbonate (MP-glyoxylate), participates in an uncatalyzed 3-CC with 2-aminoazines and isonitriles to afford novel 2-unsubstituted-3-amino- imidazoheterocycles. MP-glyoxylate serves as a particularly efficient and experimentally convenient formaldehyde equivalent and readily liberates products through decarboxylation/self-release from the resin. These examples furthermore constitute the first application in which MP-CO₃ serves as a solid support for transformations involving carboxylic acids.

Full text of DOI:10.1021/ol0478234

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4989-4992
Glyoxylic Acid and MP-Glyoxylate:
Efficient Formaldehyde Equivalents in
the 3-CC of 2-Aminoazines, Aldehydes,
and Isonitriles
Michael A. Lyon and Timothy S. Kercher*
Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301
tim.kercher@arraybiopharma.com
Received October 22, 2004
ABSTRACT
Glyoxylic acid, either in solution or immobilized on MP-carbonate (MP-glyoxylate), participates in an uncatalyzed 3-CC with 2-aminoazines and
isonitriles to afford novel 2-unsubstituted-3-amino-imidazoheterocycles. MP-glyoxylate serves as a particularly efficient and experimentally
convenient formaldehyde equivalent and readily liberates products through decarboxylation/self-release from the resin. These examples
furthermore constitute the first application in which MP-CO3 serves as a solid support for transformations involving carboxylic acids.
A recently discovered variation of the Ugi reaction1 involving
the three-component coupling (3-CC) of 2-aminoazines,
isonitriles, and aldehydes2 has proven to be an efficient means
by which to generate fused, imidazo[1,2-a]heterocycles in a
one-pot transformation (Scheme 1). Subsequent develop-
cycles of this nature have received a great deal of attention
in drug discovery. Imidazopyridines, imdazopyrazines, and
imidazopyrimidines in particular have been the focus of
pharmaceutical investigations across a broad range of
therapeutic areas,5 and these heterocycles are represented by
the launched drugs zolimidine, zolpidem, and alpidem.
Although the scope of this 3-CC reaction spanning all three
substrates is quite impressive, there is, however, no literature
precedence for the successful inclusion of formaldehyde as
the aldehyde component, thus enabling the synthesis of
2-unsubstituted-3-amino-imidazoheterocyles. In fact, ex-
Scheme 1. Imino-Isonitrile [4 + 1] Cycloaddition (3-CC)
(1) For recent reviews describing the Ugi reaction as well as other multi-
component coupling reactions, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168. (b) Armstrong, R. W.; Combs, A. P.; Tempest, P.
A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(2) (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635. (b) Bienayme, H.; Bouzid, K. Angew.
Chem., Int. Ed. 1998, 37, 2234. (c) Groebke, K.; Weber, L.; Mehlin, F.
Synth. Lett. 1998, 661.
(3) (a) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665. (b)
Ireland, S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2003, 44, 4369.
(4) (a) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495. (b)
Chen, J. J.; Golebiowski, A.; McClenaghan, J.; Klopfenstein, S. R.; West,
L. Tetrahedron Lett. 2001, 42, 2269.
ments of this 3-CC methodology involve application of
microwave techniques3 in addition to polymer-supported
adaptations.4 The industrial relevance of this powerful 3-CC
transformation is significant because imidazo[1,2-a]hetero-
10.1021/ol0478234 CCC: $27.50
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amples of successful preparations of 2-unsubstituted-3-
amino-imidazoheteocycles are scarce, and those reported are
low-yielding. One report, involving the nitration of an
imidazo[1,2-a]pyridine and subsequent nitro reduction,6
provided the desired amino derivative in only 9% overall
yield. A second preparation has been achieved in 30% yield
through the condensation of 2-aminopyridine, cyanide, and
aldehydes in aqueous NaHSO3.7 A more recent method
involves the preparation of 1,2-bis(benzotriazolyl)-1,2-(di-
alkylamino) ethanes followed by reaction with either amino-
pyridines or aminopyrimidines in 35-62% yield.8 None of
these methods offer the synthetic efficiency, high yield, and
broad scope of the one-pot, convergent 3-CC approach.
Moreover and in contrast to the 3-CC reaction, these routes
are not readily adaptable toward rapid and diversity-oriented
parallel synthesis, a technique of increasing utility in the
pharmaceutical industry.
We report herein an efficient and experimentally con-
venient formaldehyde equivalent prepared by simple im-
mobilization of glyoxylic acid on macroporous polystyrene
carbonate (MP-CO3). This reagent furnishes 2-unsubstituted-
3-amino-imidazoheterocyles in good yield when used in the
3-CC reaction and, to the best of our knowledge, constitutes
the first application in which MP-CO3 serVes as a solid
support for transformations inVolVing carboxylic acids.9 As
an alternative to MP-glyoxylate, commercial glyoxylic acid
monohydrate in solution may also be applied, affording yields
comparable to the resin-bound reagent in most cases.
We initiated our investigation by screening a panel of
potential formaldehyde equivalents (Table 1) utilizing the
established, Sc(OTf)3-catalyzed 3-CC conditions2a with
2-aminopyridine and a readily available aryl isonitrile. This
panel included formaldehyde hydrate and paraformaldehyde
(entries 1 and 2), both of which did provide the desired
product 1 but in low yield primarily as a result of the
formation of multiple products and difficult purification.
Attempted in situ deprotection and subsequent 3-CC of
dimethoxymethane in wet solvent failed to demonstrate any
significant reactivity (entry 3). As a result of these initial
Table 1. Screen of Potential Formaldehyde Equivalents
yield of
1 (%)
entry
CH2O equivalent
aq CH2O
reaction conditions
rt, 20 h
1
36b
44b
nra
10a
31b
51b
50a
47a
48b
71b
2
(CH2O)n
reflux, 20 h
3
4
5
6
7
8
9
10
CH2(OCH3)2
CHOCH(OCH3)2
HO2CCHO
HO2CCHO
4:1 CH3CN-H2O, rt, 20 h
rt, 20 h
rt, 20 h
no catalyst, rt, 20 h
AP-Wangc/HO2CCHO no catalyst, rt, 20 h
AP-OHd/HO2CCHO
no catalyst, rt 20 h
e
MP-CO3 /HO2CCHO no catalyst, rt, 20 h
MP-CO3e/HO2CCHO no catalyst, 50 °C, 20 h
a Yield determined from LC-MS analysis of crude reaction mixture.
b Yield after purification via SiO2 chromatography. c Loading of 0.65 mmol/
g. d Loading of 0.73 mmol/g. e Loading of 2.62 mmol/g.
findings, attention was turned to other potential formaldehyde
equivalents.
Since there exists precedence for the C-2 and C-3 lithiation
of imidazo[1,2-a]pyridines,10 we rationalized that this ability
to accommodate a negative charge could translate into facile
decarboxylation of 2-carboxyl-imidazo[1,2-a]heterocycles
derived from a 3-CC reaction employing glyoxylic acid.
Along these lines, glyoxylic acid and derivatives thereof were
screened in the 3-CC reaction (entries 4-6). Gratifyingly,
the reaction of 2-aminopyridine, the aryl isonitrile, and
glyoxylic acid provided the desired decarboxylated product
1 with or without Lewis acid activation (entries 5 and 6). In
comparison, the yield of the desired product was found to
be higher without catalytic Sc(OTf)3. It was also discovered
during these studies that glyoxylic acid monohydrate could
be conveniently used in the reaction, eliminating the need
for anhydrous substrate.
(5) (a) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B.
A.; Vance, L. J. Med. Chem. 1999, 42, 50. (b) Lhassani, M.; Chavignon,
O.; Chezal, J.-M.; Teulade, J.-C.; Chapat, J.-P.; Snoeck, R.; Andrei, G.;
Balzarini, J.; De Clerque, E.; Gueiffier, A. Eur. J. Med. Chem. 1999, 34,
271. (c) Trapini, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.;
Serra, M.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934.
(d) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9,
97. (e) Georges, G.; Vercauteren, D. P.; Vanderveken, D. J.; Horion, R.;
Evrard, G. H.; Durant, F. V.; George, P.; Wick, A. E. Eur. J. Med. Chem.
1993, 28, 323. (f) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull.
1992, 40, 1170. (g) Meurer, L, L.; Tolman, R. L.; Chapin, E. W.; Saperstein,
R.; Vicario, P. P.; Zrada, M.; MacCoss, M. M. J. Med. Chem. 1992, 35,
3845. (h) Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B.-M. J.
Med. Chem. 1991, 34, 533. (i) Sablayrolles, C.; Cros, G. H.; Milhavet, J.
C.; Rechenq, E.; Chapat, J.-P.; Boucard, M.; Serrano, J. J.; McNeill, J. H.
J. Med. Chem. 1984, 27, 206.
In an effort to further optimize the yield and develop a
route amendable to parallel synthesis techniques, glyoxylic
acid was bound to methanol-compatible resins such as
ArgoPore-Wang-OH and ArgoPore-OH11 via esterification
as well as immobilized on MP-CO3 (entries 7-10). When
subjected to the 3-CC, all three resin-bound variants fur-
nished the desired product 1 presumably through a facile
decarboxylation/self-cleavage from the resin in the protic
solvent system. The most favorable results were achieved
in the case of MP-CO3, which was found to be the most
advantageous with respect to yield, experimental simplicity,
and high loading capacity.12 Reagent immobilization was
simply executed via premixing the MP-CO3 and excess
(6) Kaminski, J. J.; Hilbert, J. M.; Pramanik, B. N.; Solomon, D. M.;
Conn, D. J.; Rizvi, R. K.; Elliott, A. J.; Guzik, H.; Lovey, R. G. Domalski,
M. S.; Wong, S.-C.; Puchalski, C. Gold, E. H.; Long, J. F.; Chiu, P. J. S.;
McPhail, A. T. J. Med. Chem. 1987, 30, 2031.
(7) Groziak, M. P.; Wilson, S. R.; Clauson, G. L.; Leonard, N. J. J. Am.
Chem. Soc. 1986, 108, 8002.
(8) Katritzky, A. R.; Xu, Y.-J.; Tu, H. J. Org. Chem. 2003, 68, 4935.
(9) MP-CO3, available through Argonaut Technologies (www.
argotech.com), has been widely used as a polymer-bound base, free-basing
agent, and scavenger of acidic species in parallel synthesis.
(10) (a) Lumma, W. C., Jr.; Springer, J. P. J. Org. Chem. 1981, 46, 3735.
(b) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J. Org. Chem.
1997, 62, 3453.
(11) ArgoPore is a registered trademark of Argonaut Technologies.
(12) MP-CO3 was purchased from Argonaut Technologies at a claimed
loading of 2.62 mmol/g.
4990
Org. Lett., Vol. 6, No. 26, 2004

Scheme 2. Immobilization-3CC-Decarboxylation Sequence
Table 3. Survey of Isonitriles
glyoxylic acid monohydrate in methanol at room temperature
for 2-3 h followed by wash and immediate use of the
resulting MP-glyoxylate in the 3-CC reaction (Scheme 2).13
The 3-CC/decarboxylation sequence was optimally carried
out at 50 °C, which allowed for complete decarboxylation
(Table 1, entry 10). There were consequently no instances
for which the intermediate C-2 carboxylates were observed
in the crude product mixtures.
The scope of the 3-CC reaction, employing both MP-
glyoxylate and glyoxylic acid, was explored using a variety
of 2-aminoazines in conjunction with phenyl isonitrile
Table 2. Survey of 2-Aminoazines
(Table 2). Analogous to reported 3-CC reactions involving
alkyl and aryl aldehydes,2 the most favorable yields of
purified products were generated from 2-aminopyridines and
2-aminopyrazines providing the corresponding imidazo-
pyridines 2a-2d and imidazopyrazines 2e-2f (entries
1-6).14 Both electron-donating and electron-withdrawing
groups were tolerated on the aminopyridine as well as
substitution ortho to the 2-amino functionality. An observed
exception was the deactivated 6-chloro-2-aminopyrazine,
a Yield after purification by SiO2 chromatography. b Yield after purifica-
tion by recrystallization. c Yield determined from LC-MS analysis of crude
reaction mixture.
(13) Freshly prepared MP-glyoxylate was employed for all reactions.
See Supporting Information for experimental procedures.
(14) All isolated compounds were characterized by 1H NMR, 13C NMR,
and MS analysis.
Org. Lett., Vol. 6, No. 26, 2004
4991

which gave only 30% of the desired product (entry 6). For
the majority of substrates examined, similar yields were
obtained from either glyoxylic acid (method A) or MP-
glyoxylate (method B), thus providing experimental flex-
ibility for size of scale and application. Alternative amino-
azines including aminopyrimidines and aminothiazoles pro-
duced significantly lower quantities of the imidazohetero-
cycles 2g-2h in both the MP-glyoxylate and glyoxylic acid
reactions as determined by LC-MS analysis of the crude
reaction mixture (entries 7 and 8). Isolation of pure product
in these instances proved to be extremely difficult.15 Substrate
incompatibility was observed for 3-CC reactions involving
aminotriazole, which failed to produce any detectable product
(entry 9).
Studies with 2-aminopyridines and 2-aminopyrazines that
included variation of the isonitrile component in the 3-CC
reaction (Table 3) demonstrated favorable reactivity for both
electron-rich (entries 7 and 8) and electron-deficient aryl
isonitriles (entries 5 and 6) in addition to functionalized aryl
isonitriles such as a Boc-protected aminomethyl derivative
(entries 1 and 2). The sterically encumbered 2,6-dimethyl-
phenylisonitrile also exhibited good reactivity (entries 3 and
4). Concerning aliphatic isonitriles, tetramethylbutyl isonitrile
proved most interesting because, in addition to providing the
3-CC products (entries 9-10), it may also be utilized as a
hydrogen cyanide equivalent upon acid-promoted N-dealkyl-
ation of the formed N-tetramethylbutyl-3-amino-imidazo-
heterocycles to give primary 3-amino-imidazoheterocycles.4a
Interestingly, methyl isocyanoacetate (entry 11) reacted
smoothly with glyoxylic acid in solution (method A) but
failed to provide any desired 3-CC product when MP-
glyoxylate was employed (method B). This result may be
rationalized by incompatibility between the acidic methyl
isocyanoacetate and the basic reaction conditions of method
B. The lowest yields observed in this survey of isonitriles
occurred when benzylisonitrile was used, furnishing only
13% of the purified 3-CC product (entry 12).
In conclusion, a practical method for the one-pot synthesis
of novel 2-unsubstituted-3-aminoimidazo[1,2-a]heterocycles
has been achieved using glyoxylic acid as a fomaldehyde
equivalent in the three-component coupling of aminoazines,
aldehydes, and isonitriles. Glyoxylic acid may be introduced
either in solution or immobilized on macroporous polystyrene
carbonate resin (MP-CO3), the latter of which constitutes an
unprecedented application of commercial MP-CO3 and
provides a convenient source of immobilized glyoxylic acid
capable of partitioning into multiple, parallel reactions. The
highest yields for the reaction were obtained from either
aminopyridines or aminopyrazines as the aminoazine sub-
strate. This synthetic approach involving MP-glyoxylate as
a novel formaldehyde equivalent is potentially applicable to
other reactions in which glyoxylic acid is utilized as a key
reagent.
Acknowledgment. In great appreciation we acknowledge
the following individuals: John Josey and Anthony Piscopio
for intellectual contributions and Lingyang Zhu for NMR
support.
Supporting Information Available: General experimen-
tal procedures used for the preparation of 2a-e and 3a-l
(15) During the attempted purification of products 2f-h, significant
amounts of unreacted aminoazine substrate were detected. When method
A was used with prolonged reaction times, the imine derived from methyl
glyoxylate and the aminoazine was also isolated, thus suggesting esterifi-
cation as a competitive reaction in the absence of 3-CC/decarboxylation
activity.
1
including H and 13C NMR spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0478234
4992
Org. Lett., Vol. 6, No. 26, 2004