The universal Rink-isonitrile resin: Applications in Ugi reactions

Article abstract of DOI:10.1016/S0040-4039(02)00700-1

The Rink-isonitrile resin provides a new universal platform for Ugi multi-component reactions. Applications were demonstrated by the traceless synthesis of diketopiperazines, benzodiazepines, and 5-substituted 1H-tetrazoles.

Full text of DOI:10.1016/S0040-4039(02)00700-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4083–4085
The universal Rink-isonitrile resin: applications in Ugi reactions†
Jack J. Chen,* Adam Golebiowski, Sean R. Klopfenstein and Laura West
Combinatorial Chemistry Group, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45040,
USA
Received 15 March 2002; revised 3 April 2002; accepted 4 April 2002
Abstract—The Rink-isonitrile resin provides a new universal platform for Ugi multi-component reactions. Applications were
demonstrated by the traceless synthesis of diketopiperazines, benzodiazepines, and 5-substituted 1H-tetrazoles. © 2002 Published
by Elsevier Science Ltd.
Recently we introduced the Universal Rink–isonitrile
resin 1 (Fig. 1),1 an odorless and stable polymer-bound
isonitrile that can be easily prepared in two steps from
commercial Rink resin. We have demonstrated, with
the synthesis of 2-acylamino imidazopyridines, that the
resin can serve as a universal platform for isonitrile-
based non-classical multiple component reactions
(MCR).1 Our recent studies suggested that this plat-
form is also amenable to classical MCRs such as Ugi
and Passerini reactions.2 Intriguingly, if nucleophilic
elements were carefully positioned in the reagent inputs,
1 could behave as those universal isonitriles such as
Armstrong’s 1-isocyanocyclohexene.3,4 The acid-labile
Rink linkage is, therefore, the pivotal point for post-
MCR modifications, which lead to heterocyclic struc-
tures not readily accessible via commercial isonitriles.
The application was examined by the solid-phase syn-
thesis of diketopiperazines and benzodiazepine-2,5-
diones (Scheme 1 and Table 1).5 The MCR of resin 1,
aldehyde, amine and Fmoc-protected amino acid or
2-aminobenzoic acid (2-Abz) provided resin-bound
dipeptide intermediate 2 or 3. Treatment with 20%
piperidine/N,N-dimethyl formamide (DMF) exposed
the amino terminus for ring closure. Three approaches
(the first three entries in Table 1) were found to effect
Figure 1. Universal Rink-isonitrile resin.
Scheme 1. (i) Fmoc-protected amino acid, R1CHO, R2-NH2, MeOH/THF (1/1), 16 h; (ii) N-Fmoc-2-Abz-OH, R1CHO, R2-NH2;
MeOH/THF (1/1), 16 h; (iii) 20% piperidine/DMF; (iv) 10% HOAc/DCE, 60°C, 16 h.
Keywords: solid-phase synthesis; isonitrile resin; multi-component reactions; 5-substituted 1H-tetrazoles.
* Corresponding author. Fax: (513) 622-1433; e-mail: chenj1@pg.com
† Dedicated to the memory of Professor Henry Rapoport.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00700-1

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J. J. Chen et al. / Tetrahedron Letters 43 (2002) 4083–4085
Table 1. Diketopiperazines and benzodiazepines prepared on the Rink-isonitrile resin
Product
R1
R2
R3 (amino acid)
Purity (%)a
Yield (%)b
4ac
4ad
4a
t-Bu
t-Bu
t-Bu
i-Bu
i-Bu
i-Bu
PhCH2CH2
i-Bu
PhCH2CH2
PhCH2CH2
PhCH2CH2
3-MeO-Bn
3-MeO-Bn
3-MeO-Bn
Bn
Bn
Bn
4-MeO-Bn
4-MeO-Bn
i-Bu
Gly
Gly
Gly
Gly
Aib
Pro
–
–
–
–
–
50
40
86
94
100
88
81
100
74
88
87
–
–
33
78
48
23f
64
91
64
42
29
4b
4ce
4de
5a
5b
5c
5d
5e
Bn
5f
PhCH2CH2
3-MeO-Bn
–
66
38
a Purity of the crude products after cleavage, judged by LC–MS at 220 nm. Products were cleaved by overnight heating in 10% AcOH/DCE at
50°C unless otherwise specified.
b Overall yields from Rink-isonitrile resin. Formed as racemic mixtures.
c Prepared using Boc-Gly-OH. Cyclized with 10% AcCl/MeOH at 50°C.
d 15% TFA cleavage followed by heating the product with 10% AcOH/iPrOH.
e See Ref. 6 for the structures of 4c and 4d.
f Formed as a 1:1 diastereomeric mixture.
the cyclization: (1) 10% acetyl chloride (AcCl)/MeOH
at 50°C; (2) 15% TFA cleavage followed by heating the
product with 10% acetic acid/isopropanol (AcOH/i-
PrOH); (3) heating in 10% AcOH/dichloroethane
(DCE) at 50°C overnight. Our experiments suggested
that the AcCl/MeOH and TFA-AcOH/iPrOH methods
generated significant amount of linear dipeptides, while
heating in 10% AcOH/DCE provided clean cyclo-elimi-
nated products with good to moderate purities and
overall yields. We did not observe uncyclized products
with this method.
0.88 mmol) were mixed in THF/MeOH (1/1) for 5 h.
The mixture was then added to the resin 1 (0.5g, 0.35
mmol). The suspension was agitated overnight at room
temperature. The resin was washed with MeOH and
DMF. The resin was treated with 20% piperidine/DMF
(2×15 min), and then washed with DMF, MeOH and
DCE. 10% HOAc/DCE was added to the resin and the
suspension was agitated at 60°C for 16 h. The cleavage
filtrate was collected and the resin was extracted with
MeOH/THF. All extracts were combined and evapo-
rated to dryness. The crude product was further
purified by HPLC to yield 33 mg of the product (33%
after three steps from Rink isonitrile resin).10
After the successes with diketopiperazines and benzodi-
azepines, we further extended the applications to Ugi
tetrazole synthesis.7,8 As depicted in Scheme 2, the
reaction of resin 1, aldehyde, amine and trimethylsilyl
azide furnished resin-bound product 6, which then
yielded tetrazole 7 after traceless TFA cleavage. Unlike
the original Ugi chemistry that generates 2,5-disubsti-
tuted products,7 the preparation on resin 1 provided
5-substituted 1H-tetrazoles.9 To our knowledge, this is
the first time this class of compounds was synthesized
using an MCR approach. Some results of this study are
summarized in Table 2.
Scheme 2. (i) THF/MeOH (1/1), 16 h; (ii) 15% TFA/DCM,
30 min.
In summary, we have demonstrated that Rink-isonitrile
resin can be employed as a universal platform for
classical Ugi reactions. As a novel addition to the
collection of universal isonitriles, this resin appears to
be a more practical alternative since it is stable, easy to
prepare, and odor free. We are continuously exploiting
its synthetic potentials and will report the results in due
course.
Table 2. Tetrazoles prepared on the Rink-isonitrile resin
Entry
R1
R2R3NH
% Puritya
Yield %b
7a
7b
7c
7d
7e
PhCH2CH2
PhCH2CH2
Ph
Bn
4-MeO-Ph
Piperidine
Morpholine
Piperidine
Morpholine
Morpholine
100
100
100
79
67
76
89
25
75
100
a Purity of the crude products after cleavage, judged by LC–MS at
Preparation of diketopiperazine (Table 1, 4a): Trimethyl-
acetaldehyde (0.1 ml, 0.88 mmol), 3-methoxybenzyl
amine (0.11 ml, 0.88 mmol) and Fmoc-Gly-OH (0.26 g,
220 nm.
b Formed as racemic mixtures.

J. J. Chen et al. / Tetrahedron Letters 43 (2002) 4083–4085
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Preparation of tetrazole (Table 2, 7c): Benzaldehyde
(0.10 ml, 0.9 mmol) and piperidine (0.11 ml, 1.26
mmol) were mixed in THF/MeOH (1/1) for 5 h. TMS-
N3 (0.12 ml, 0.9 mmol) was added. The solution was
then added to the resin 1 (0.2 g, 0.18 mmol) and the
suspension was agitated for 16 h. The resin was washed
with MeOH, DMF, MeOH and dichloromethane
(DCM), followed by cleavage with 15% TFA/DCM
(2×15 min). The cleavage filtrate was collected and
evaporated to dryness. The crude product was purified
on preparative HPLC to yield 39 mg of the product
(89%).11
5. For preparations of diketopiperazine and benzodi-
azepines via Ugi MCR, see: (a) Keating, T. A.; Arm-
strong, R. W. J. Org. Chem. 1996, 61, 8935; (b) Hulme,
C.; Cherrier, M. P. Tetrahedron Lett. 1999, 40, 5296–
5299; (c) Hulme, C.; Ma, L.; Kumar, V. N.; Krolikowski,
P. H.; Allen, A. C.; Labaudiniere, R. Tetrahedron Lett.
2000, 41, 1509–1514.
6. The structure of 4c and 4d:
Acknowledgements
7. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8; (b)
Nixey, T.; Kelly, M.; Hulme, C. Tetrahedron Lett. 2000,
41, 8729–8733.
8. For recent progress on tetrazole chemistry, see: Butler, R.
N. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds; Pergamon:
Oxford, UK, 1996; Vol. 4.
The author thanks Mr. Thomas Burt and Ms. Anne
Russell for their analytical support.
References
9. There are only few practical routes to 5-substituted 1H-
tetrazoles, see: Demko, Z. P.; Sharpless, K. B. J. Org.
Chem. 2001, 66, 7945–7950, and references cited therein.
10. Spectral data for 4a: 1H NMR (300 MHz, CD3OD, l)
7.68 (m, 2H), 8.10 (m, 1H), 7.52 (m, 3H), 7.93 (m, 1H),
6.03 (s, 1H), 3.89 (s, 3H), 3.80 (m, 4H) 3.12 (m, 4H).
13C{1H} (150 MHz, CD3OD, l) 28.1, 39.8, 46.3, 51.6,
55.5, 69.1, 113.4, 113.8, 120.0, 130.3, 137.5, 160.3, 166.1,
168.5. MS (DCI): m/z 291 [M+H]+.
1. Chen, J. J.; Golebiowski, A.; McClenaghan, J.; Klopfen-
stein, S. R.; West, L. Tetrahedron Lett. 2001, 42, 2269–
2271.
2. For a recent reviews on Ugi and Passerini reactions, see:
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210.
3. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc.
1996, 118, 2574–2583.
11. Spectral data for 7c: 1H NMR (300 MHz, CD3OD, l)
7.69 (m, 2H), 7.52 (m, 3H), 6.04 (s, 1H), 3.25 (m, 4H),
1.87 (m, 4H) 1.66 (m, 2H). 13C{1H} (150 MHz, CD3OD,
l) 21.5, 22.8, 52.6, 65.6, 129.6, 130.1, 130.6, 130.7. MS
(DCI): m/z 244 [M+H]+.
4. For other examples of universal isonitriles, see: (a)
Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin,
T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227–
7230; (b) Linderman, R. J.; Binet, S.; Petrich, S. R. J.
Org. Chem. 1999, 64, 336–337.