Multi-component synthesis of imidazo[1,2-a] annulated heterocycles on α-isocyano resin esters

Article abstract of DOI:10.1055/s-2001-16059

The multi-component synthesis of imidazo[1,2-a] annulated heterocycles was performed on the α-isocyano resin esters. This solid phase approach addresses the limited availability issue of isonitrile reagents without compromising the overall diversity of the chemistry.

Full text of DOI:10.1055/s-2001-16059

LETTER
1263
Multi-Component Synthesis of Imidazo[1,2-a] Annulated Heterocycles on -
Isocyano Resin Esters
Jack J. Chen,* Adam Golebiowski, Sean R. Klopfenstein, Joel McClenaghan, Sean X. Peng, David E. Portlock,
Laura West
Combinatorial Chemistry Group, Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45040, USA
Fax (513) 622-2385; E-mail: chenj1@pg.com
Received 18 January 2001
of any of the three reactants to a solid support.5a In spite of
Abstract: The multi-component synthesis of imidazo[1,2-a] annu-
the simplicity and convenience of this new method, the di-
lated heterocycles was performed on the -isocyano resin esters.
versity of the chemistry is limited by the commercial
This solid phase approach addresses the limited availability issue of
availability of the isonitriles.6 One approach to address
isonitrile reagents without compromising the overall diversity of the
chemistry.
this issue is to perform the MCC on a polymer-supported
4-formyl benzoate using 1,1,3,3-tetramethybutyl isoni-
trile.6 This isonitrile permits post-MCC dealkylation to
furnish a primary amine for further structural elaboration.
Whereas this approach circumvents the limitation of
isonitrile reagents, it abandons the diversity advantage of
commercially available aldehydes and the atom efficiency
of the MCC reaction. We suggest that adoption of a new
class of isonitrile resources such as -isocyano resin esters
would be a more convenient and straightforward solution.
Considering the commercial availability of amino acid
resins, this approach will dramatically enlarge the diversi-
ty scope of the chemistry.
Key words: multi-component condensation, isonitrile resin, combi-
natorial synthesis, amino acid, 3-amino imidazole
Acceleration of drug discovery has generated growing de-
mands for expeditious methods to produce therapeutic
candidates. Isonitrile-based multi-component condensa-
tion (MCC) therefore has emerged as a simple and re-
source efficient approach to a large number of discrete
structures.1 In practice, these reactions are often per-
formed on a solid support that tethers one of the reaction
components such as amine, aldehyde or isonitrile. Immo-
bilization of an isonitrile on a solid support is particularly
intriguing due to the relief of the reagent’s notorious mal-
odor.2 In order to create a polymer-bound isonitrile source
with broad structural diversity, we recently developed a
practical method to prepare -isocyano resin esters from
commercially available -amino acid resins.3
The reaction in Scheme 2 was employed to optimize the
acid catalyst. Scandium triflate (Sc(OTf)3),5a acetic acid
(HOAc)5c and perchloric acid (HClO4)5d have been used
to mediate the MCC. Sc(OTf)3 was not adapted because of
the concerns on its cost and moisture sensitivity in high
throughput library production. Our experiments suggest-
ed that carboxylic acids (RCO2H), such as HOAc and ben-
zoic acid, trigger a Passerini side reaction7 to yield the
impurity 4 (Table 1). Mineral acids such as HClO4, even
at a trace quantity, results in hydrolysis of polymer-bound
isonitrile to yield formamide 2. p-Toluenesulfonic acid
(TsOH), as an alternative, is so far the only acid that in-
duces the MCC without these side effects.8
H2N
R1 NC
R2 CHO
R3
+
+
N
R2
N
Acid catalyst
A series of bicyclic heterocycles as shown in Table 2 were
prepared using various isocyano resin esters.9-11 The MCC
performed well with both aliphatic and aromatic alde-
hydes, and most of the synthesis afforded products in
good purity and isolated yield. The stereochemical integ-
rity of the chemistry was investigated. The -isocyano
resin esters derived from D- and L-Tyr(OtBu) Wang resins
were used to prepare the two respective enantiomers of 3.
The isolated products were analyzed by standard C18 and
chiral column HPLC.12 The results of this study implicat-
ed that the MCC on both resins afforded the same racemic
mixture. The racemization was presumably introduced
during the resin preparation. We are addressing this issue
by preparing enatiomerically pure isocyano resin esters.
The results will be reported in due course.
R1
N
N
H
R3
Scheme 1
This communication reports a novel application of the
-isocyano resin esters in the MCC synthesis of imida-
zole[1,2-a] annulated heterocycles. Imidazo[1,2-a] annu-
lated heterocycles have been widely used as
cerebraprotective agents,4a antimicrobials,4b cardiac stim-
ulating agents,4c gastric acid secretion inhibitors4d and
anti-inflammatory agents.4e Recently these molecules
were constructed by a new MCC reaction involving an
isonitrile, an aldehyde and a cyclic amidine (Scheme 1).5
The reaction has been shown amenable to the attachment
Synlett 2001, No. 8, 1263–1265 ISSN 0936-5214 © Thieme Stuttgart · New York

1264
J. J. Chen et al.
LETTER
O
NH2
a, b
O
N
NC
HO
+
+
O
Wang
CHO
1
HO
O
O
+
+
O
H
N
HO
HO
N
HO
O
R
N
H
H
N
O
N
O
H
O
4
HO
2
3
Scheme 2 a) CHCl3/TMOF/MeOH, 1/1/1 and an acid catalyst. b) 20% TFA/CH2Cl2, 2 30 min.
(3) We have found that the published protocols (ref. 2) do not
provide efficient and clean isonitrile formation on -amino
acid resins. A practical method was therefore developed using
Waki and Meienhofer’s formylation (J. Org. Chem. 1977, 42,
2019) and Nunami’s POCl3/DIPEA dehydration (Synthesis
1990, 781-782) procedures.
Table 1 Studies on acid catalyst selectiona
The typical procedure to prepare a -isocyano resin ester:
A commercial amino acid resin ester is deprotected and dried.
The dry resin is suspended in CH2Cl2. Under ice cooling,
pyridine (1 equiv) and HCO2H (5 equiv) are added, followed
by diisopropylcarbodiimide (5 equiv). The suspension is
stirred 1h at 0 C and then at ambient temperature till the
reaction is complete (usually 3 h, judged by Ninhydrin test).
The resin is washed and dried for the next step. The
formylated amino acid resin is suspended in anhydrous
CH2Cl2. Under ice cooling and Ar protection,
diisopropylethylamine (DIPEA, 15 equiv) is cannulated. Then
POCl3 (5 equiv) is slowly added. The sus-pension is stirred for
5 h at 0 C and 1 h at ambient tem-perature. The resin is then
washed with CH2Cl2, ether, and dried in vacuum to a constant
weight. The disappearance of formyl CO (~1740 cm-1) and the
emergence of NC (~2150
cm-1) absorption in the IR spectrum is the most obvious
evidence of the conversion.
a) See the typical experimental procedure for the reaction conditions.
b) Measured by HPLC, conditions: Waters symmetry C18, 150 3.9
mm (5 m); 25-min linear gradient elution from 95%A:5%B to 95%B
(A: water with 0.1% CF3CO2H; B:acetonitrile with 0.1% CF3CO2H);
flow: 1.0 ml/min; = 210 nm.
(4) Hansen, D. W.; Adelstein, G. W.; Peterson, K. B.; Tsymbalov,
S. US5716964A. b) Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.;
Yuki, S; Tanaka, H. EP596406A1; c) Barraclough, P., Black,
J. W.; Cambridge, D.; Gerskowitch, V. P.; Giles, H.; Glen, R.
C.; Hull, R. A. D.; Iyer, R.; King, W. R.; Nobbs, M. S.;
Randall, P.; Shah, G. P.; Stone, D.; Vine, S. J.; Whiting, M. V.
Bioorg. Med. Chem. Lett. 1993, 3, 509-14. d) King, F. D;
Gaster, L. M. WO9408998. e) Wu, L. I.; Janusz, J. M.
WO9728146.
(5) a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635-3638; b) Blackburn, C.
Tetrahedron Lett. 1998, 39, 5469-5472. c) Groebke, K.;
Weber, L.; Fridolin, M. Synlett. 1998, 661-663. d) Bienayme,
H.; Bouzid, K. Angew. Chem. Int. Ed. Engl. 1998, 37, 2234-
2237.
Acknowledgement
The author thanks Mr. Thomas Burt and Ms. Anne Russell for their
analytical support.
References and Notes
(1) For a recent review on multi-component reactions, see: Ugi, I.;
Domling, A. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
(2) There are several methods to prepare polymer-bound
isonitriles. For a recent one, see: Kulkarni, B. A.; Ganesan, A.
Tetrahedron Lett. 1999, 40, 5633-5636 and the references
there in.
(6) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495-
1500.
(7) For a recent review on Passerini reactions, see: Armstrong, R.
W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T.
A. Acc. Chem. Res. 1996, 29, 123-131.
Synlett 2001, No. 8, 1263–1265 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Multi-Component Synthesis of Imidazo[1,2-a] Annulated Heterocycles
Table 2 Imidazo [1,2-a] annulated heterocycles prepared on -isocyano resin esters
1265
a) LC% (UV at 210 nm)/yield%
(8) The experimental procedure for 3: Hydrocinnamaldehyde
(0.22 mL, 1.68 mmol), 2-aminopyridine (0.16 g, 1.68 mmol)
and TsOH (0.04 g, 0.42 mmol) were mixed in CHCl3-MeOH-
trimethylorthoformate (1/1/1, v/v/v) for 1 h. The mixture was
then added to the isonitrile resin 1 (0.3 g, 0.21 mmol, from
Fmoc-Tyr(OtBu)-Wang resin). The suspension was agitated at
ambient temperature overnight. The resin was washed with
N,N-dimethylformamide (DMF), MeOH, 10% DIPEA/
CH2Cl2, CH2Cl2 and MeOH, then dried. The product was
released from the solid support by treating the resin with 20%
TFA/CH2Cl2 (2 30 min) at room temperature. The cleavage
filtrate was evaporated to dryness and the crude product was
recrystallized from MeOH/ether to afford 3 as a white solid
27.6 mg, 32.8% in 4 steps from Fmoc-Tyr(OtBu) Wang resin.
(9) Spectral data for 3: 1H NMR (300 MHz, CD3OD, ) 7.82-
7.686 (m, 3H), 7.29-7.15 (m, 8H), 6.80 (dt, J1 = 2.0 Hz,
J2 = 8.61 Hz, 2H), 3.67 (dd, J1 = 3.84 Hz, J2 = 10.2 Hz, 1H),
3.20 (dd, J1 = 3.9 Hz, J2 = 13.7 Hz, 1H), 3.09 (m, 2H), 3.48 (m,
2H), 2.85 (dd, J1 = 10.1 Hz, J2 = 13.7 Hz, 1H). 13C{1H}
(150MHz, CD3OD, ) 177.3, 158.1, 141.7, 138.2, 134.2,
132.3, 130.4, 130.1, 129.9, 129.2, 128.0, 126.8, 117.6, 116.8,
112.7, 64.5, 40.3, 36.1, 27.3. MS (DCI): m/z 402 [M+H]+.
(10) Compound 9: yielded 38.5 mg from 0.18 mmol resin (59.7%).
1H NMR (300 MHz, CD3OD, ) 8.77 (s, 1H), 8.38 (d, J = 4.8
Hz, 1H), 7.78 (d, J = 4.2 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H),
7.74 (m, 1H), 7.35-7.26 (m, 8H), 3.94 (dd, J1 = 4.4 Hz, J2 = 9.5
Hz, 1H), 3.20 (dd, J1 = 4.4 Hz, J2 = 13.7 Hz, 1H), 3.01 (dd,
J1 = 9.5 Hz, J2 = 13.6 Hz, 1H). 13C{1H} (150MHz, CD3OD, )
177.1, 142.8, 139.2, 134.5, 131.0, 130.2, 129.8, 129.7, 129.1,
128.9, 128.2, 119.0, 62.4, 40.8. MS (DCI): m/z 359 [M+H]+.
(11) Compound 11: yielded 25.2 mg from 0.18 mmol resin
(25.2%). 1H NMR (300 MHz CD3OD, ) 8.74 (dd, J1 = 1.8 Hz,
J2 = 4.39 Hz, 1H), 8.08(dd, J1 = 1.8 Hz, J2 = 6.8 Hz, 1H), 7.36-
7.19(m, 11H), 3.72 (dd, J1 = 3.9 Hz, J2 = 10.1Hz, 1H), 3.30 (d,
J = 4.0 Hz, 1H), 3.05-2.89 (m, 5H). 13C{1H} (150MHz,
CD3OD, ) 177.3, 159.4, 156.5, 142.8, 141.9, 140.0, 135.#,
132.6, 131.3, 130.1, 130.0, 129.9, 128.5, 128.0, 127.5, 113.5,
64.6, 41.1, 36.1, 27.8. MS (DCI): m/z 387 [M+H]+.
(12) The two products showed a single peak when they were co-
injected on a C18 column, but two peaks on a chiral column
with either co-injection or separated injections. The injection
methods do not change the retention time of the peaks. The
analytical conditions were as follows: a) Waters symmetry
C18, 150 3.9 mm (5 m); 20-min linear gradient elution
from 80%A:20%B to 100%B (A: 95/5/0.1; B: 5/95/0.1, water/
acetonitrile/formic acid, v/v/v); flow: 1.0 ml/min; = 283 nm.
b)Keystone chiral/RSA, 50 4.6 mm (5 m); isocratic elution,
90%A:10%B (A: 25 mM phosphate buffer; B: acetonitrile);
1.0 ml/min; = 283 nm.
Article Identifier:
1437-2096,E;2001,0,08,1263,1265,ftx,en;S00101ST.pdf
Synlett 2001, No. 8, 1263–1265 ISSN 0936-5214 © Thieme Stuttgart · New York