Parallel synthesis of tandem Ugi/Diels-Alder reaction products on a soluble polymer support directed toward split-pool realization of a small molecule library

Article abstract of DOI:10.1016/j.tetlet.2004.11.115

A hundred reactions were demonstrated on the soluble MPEG-O-CH ₂-platform. The reaction can be also effected on insoluble TentaGel resin using the same linker. A series of parallel reactions were carried out for the tandem Ugi/Diels-Alder reaction on our MPEG-O-CH₂- platform. Ninety-six out of a 100 entries were successful to give complex heterotricycles. The stereoselectivity was found not to be influenced by the building blocks used for amine and carboxylic acid components. An unexpected side pathway was found but was suppressed by employing appropriate reaction conditions. The reaction was also performed on solid phase, by which a larger library is potentially realized by employing the split-pool method.

Full text of DOI:10.1016/j.tetlet.2004.11.115

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 415–418
Parallel synthesis of tandem Ugi/Diels–Alder reaction products on
a soluble polymer support directed toward split-pool realization of
a small molecule library
Masato Oikawa,* Minoru Ikoma and Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
Received 20 October 2004; revised 8 November 2004; accepted 19 November 2004
Abstract—A series of parallel reactions were carried out for the tandem Ugi/Diels–Alder reaction on our MPEG–O–CH2- platform.
Ninety-six out of a 100 entries were successful to give complex heterotricycles. The stereoselectivity was found not to be influenced
by the building blocks used for amine and carboxylic acid components. An unexpected side pathway was found but was suppressed
by employing appropriate reaction conditions. The reaction was also performed on solid phase, by which a larger library is poten-
tially realized by employing the split-pool method.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Multicomponent coupling reactions are a powerful
method for construction of a diverse collection of small
BnNH2
BnNC
molecules as a source for biologically interesting com-
pounds.1 The Ugi four-component coupling reaction2
is representative among this class of reactions. The
Ugi reaction is a coupling reaction between aldehyde,
amine, isocyanide, and carboxylic acid to give a-acyl-
amino amide in one step. Recently, efforts have been
made for tandem or sequential reactions to synthesize
more complex molecules in combination with the
Ugi reaction.3,4 In 1999, Paulvannan reported a tandem
Ugi/Diels–Alder (UDA) reaction wherein furfural (1)
and fumaric/maleic acid derivatives were used for the
aldehyde and carboxylic acid components, respectively
(Scheme 1).4 Intramolecular Diels–Alder reaction5 takes
place after the Ugi reaction to provide a complex hetero-
tricycle 3 in good yield with good stereoselectivity.6
These products were further subjected to other diver-
sity-generating reactions by Schreiber et al., to afford di-
verse sets of heterotricycles.7 Though the usefulness of
the heterocyclic scaffold prepared by the tandem UDA
reaction as the starting point for another diversity-gen-
eration has been thus shown, no effort has been made
to construct small molecule library by using the reac-
tion. In the course of our study directed toward develop-
H
HN
H
O
N
CHO
O
CO2H
O
1
O
H
2
CO2Et
MeOH
O
OEt
3
Scheme 1.
ment of drug-like small molecules, we had been
interested in the tandem UDA reaction which provides
diverse sets of small molecules. Here we report the pre-
liminary result on our attempt to construct small mole-
cules library in both liquid and solid phase using our
original platform.
Poly(ethylene glycol) monomethyl ether (MPEG–OH,
av MW 5000)8 with formylacetal linker9 was at first used
as a platform for rapid evaluation of the tandem UDA
reaction.10 5-Hydroxymethyl-2-furfural (4) was immobi-
lized onto the platform because (1) availability of build-
ing blocks for the furfural component is the poorest
among components used in the tandem UDA reaction,11
and (2) isolation of an intermediary Schiff base on the
*
Corresponding author. Tel./fax: +81 22 717 8827; e-mail:
mao@bios.tohoku.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.115

416
M. Oikawa et al. / Tetrahedron Letters 46 (2005) 415–418
MPEG
O
H
N
5
SMe
a, b
HO2C
2
R
O
CHO
MPEG
O
O
CHO
O
7 (R = Bn): 68%
O
I-Cl, 1 h
or
OH
8 (R = p-bromophenyl): 76%
9 (R = p-methoxyphenyl): 99%
10 (R = m-methoxyphenyl): 99%
11 (R = diphenylmethyl): 41%
4
6
MeOTf, 37 h
MS4A
rt, CH2Cl2
88% (I-Cl)
75% (MeOTf)
Scheme 3. Reagents and conditions: (a) (COCl)2, DMF, benzene,
0 ꢁC, 2 h, then concentration; (b) RNH2, Cs2CO3, THF, rt, 12 h, then
KOH, H2O, rt, 12 h.
Scheme 2.
polymer support will potentially allow a hitherto unsuc-
cessful, split-pool construction of the UDA multi-com-
ponent coupling products library fully encoded
chemically on insoluble cross-linked polymer beads.
The immobilization was carried out onto MPEG–O–
CH2SCH3 59 by using iodine monochloride in the pres-
ence of molecular sieves to give 6 in 88% yield after pre-
cipitative purification (Scheme 2). It is noteworthy that
the diene moiety is inert to the electrophilic reagent
used, and the reaction was rapidly completed within
1 h. Though the reaction was also effected by methyl tri-
flate, the reaction was much slower (37 h) and the yield
was lower (75%) than the former method.
Twenty amines were used in combination with the carb-
oxylic acid building blocks 7–11 (Scheme 4, Table 1). All
reactions were carried out in parallel with 20 mg
(0.0040 mmol) of immobilized furfural 6 and 20 equiv
of amine, benzyl isocyanide, and fumaric acid derivative
in MeOH (0.4 mL, 0.01 M) at 50 ꢁC for 48 h. After the
reaction period, the reaction mixture was directly sub-
jected to gel permeation column chromatography
H
Totally five fumaric acid monoamides were prepared
from monoethyl fumarate (2) conveniently in one-pot
manner (Scheme 3). Treatment with oxalyl chloride gave
an acyl chloride, which was exposed to five amines in
parallel in the presence of cesium carbonate. After amid-
ation had been completed, an aqueous solution of
potassium hydroxide was introduced to the reaction
mixture for hydrolysis of the ester moiety. The usual
aqueous work-up allowed us to isolate the fumaric acid
derivatives 7–11 pure enough for the next tandem UDA
reaction in moderate to fairly good yields (41–99%).
HN
a, b
O
6
N
O
(0.166 mmol/g)
O
HO
H
O
N
Scheme 4. Reagents and conditions: (a) R–NH2 (·20),9 BnNC,
fumaric acid derivative (7–11), MeOH, 50 ꢁC, 48 h, then GPC
(<10 min); (b) TFA, CH2Cl2, rt, 4 h, then silica gel chromatography
(<1 min).
Table 1. Products and yields for parallel synthesis of the tandem UDA reaction on the MPEG–O–CH2-platforma,b
Amine building blocks
Fumaric acid building blocks
7
8
9
10
11
p-Bromophenethylamine (a)
3-Aminopropanol (b)
p-Methoxybenzylamine (c)
n-Hexylamine (d)
7a (41%)
7b (17%)
7c (65%)
7d (32%)
7e (67%)
7f (67%)
7g (98%)
7h (45%)
7i (60%)
8a (64%)
8b (21%)
8c (73%)
8d (85%)
8e (84%)
8f (34%)
8g (56%)
8h (65%)
8i (63%)
8j (62%)
8k (53%)
8l (96%)
8m (80%)
8n (64%)
8o (72%)
8p (44%)
8q (99%)
8r (60%)
8s (74%)
8t (>99%)
9a (49%)
9b (0%)
10a (>99%)
10b (>99%)
10c (79%)
11a (79%)
11b (35%)
11c (40%)
11d (53%)
11e (40%)
11f (71%)
11g (71%)
11h (85%)
11i (99%)
11j (>99%)
11k (42%)
11l (86%)
11m (>99%)
11n (70%)
11o (90%)
11p (0%)
9c (15%)
9d (45%)
9e (28%)
9f (11%)
9g (9%)
10d (>99%)
10e (>99%)
10f (>99%)
10g (59%)
10h (97%)
10i (>99%)
10j (>99%)
10k (>99%)
10l (>99%)
10m (>99%)
10n (>99%)
10o (>99%)
10p (58%)
10q (>99%)
10r (74%)
n-Decylamine (e)
1-Phenyl-2-propylamine (f)
a-Methylbenzylamine (g)
Allylamine (h)
9h (7%)
Diphenylmethylamine (i)
a-(2-Naphthyl)ethylamine (j)
2-Aminoethanol (k)
9i (38%)
9j (54%)
9k (0%)
7j (>99%)
7k (29%)
7l (63%)
p-Chlorobenzylamine (l)
p-Methylbenzylamine (m)
3-Butoxypropylamine (n)
2,5-Difluorobenzylamine (o)
1-Adamantanamine (p)
p-Fluorobenzylamine (q)
o-Methylbenzylamine (r)
Benzylamine (s)
9l (46%)
9m (63%)
9n (0%)
7m (>99%)
7n (>99%)
7o (>99%)
7p (>99%)
7q (>99%)
7r (>99%)
7s (89%)
7t (90%)
9o (81%)
9p (63%)
9q (60%)
9r (59%)
9s (>99%)
9t (>99%)
11q (67%)
11r (92%)
11s (69%)
11t (93%)
10s (91%)
10t (>99%)
n-Octylamine (t)
a For reaction conditions, see Scheme 4.
b Compound purity was >70% as judged from 1H NMR spectra (500MHz).

M. Oikawa et al. / Tetrahedron Letters 46 (2005) 415–418
417
(GPC, Sephadexꢂ G-25,
/
8 mm · 13 mm) using
the structure representatively shown in Scheme 4, and
hence we concluded that the stereoselectivity is not
directly affected by the amines and fumaric acid building
blocks employed. It should be also noted here that the
asymmetric carbon center in the amine building blocks
(f, g, and j) did not affect the stereoselectivity notably;
the possible diastereomers were produced in nearly
equal amounts in all cases.
MeOH. The first elution (2.2 mL) was collected and con-
centrated to give the MPEG-immobilized heterotricycle.
This chromatography is rapidly finished in 10 min, and
allows quantitative recovery of the MPEG polymer
without contamination of the small molecules.
Cleavage of the tandem UDA product from the plat-
form was effected by trifluoroacetic acid in CH2Cl2 at
rt for 4 h.9 After concentration, the crude product was
rapidly passed through a pad of silica gel (takes less than
1 min) to give small molecules released from the poly-
mer. No decomposition was detected at all during these
cleavage operations.
During these experiments, another pathway was found
to compete with the desirable tandem UDA reaction
especially when sterically demanding amines such as
tert-butylamine (data not shown) or 1-adamantanamine
(p) were used. In these cases, unexpected 8s was always
produced partially (up to 20% yield) probably due to
in situ generation of benzylamine from benzyl isocya-
nide (Scheme 5). In fact, 13 was found to be provided
in 61% yield (based on benzyl isocyanide used) by sim-
ply mixing benzyl isocyanide, fumaric acid derivative,
and furfural at 50 ꢁC for 48 h. This side reaction com-
petes when sterically demanding, and hence less reactive,
amines are employed. After several experiments, we
found raising the temperature (60 ꢁC) and reducing the
solvent amount to 0.04 M was effective to suppress such
an undesirable process almost completely.
The results for a total of 100 parallel reactions are sum-
marized in Table 1. Weight-based yields for these
UDA and cleavage reactions ranged from 0% to
>99%; 68 entries successfully gave the tandem UDA
product in more than 60% yield, whereas four entries
did not provide the product, and two entries proceeded
only in less than 10% yield. In all cases the purity of the
tandem UDA product was more than 70% as judged
1
from H NMR. The main impurity is the unreacted 5-
hydroxymethyl-2-furfural (4). As for the stereoselecti-
vity, all reactions apparently gave the structure shown
in Scheme 4 predominantly,12 except for the runs where
sterically demanding 1-adamantanamine (p) was used
The PEG–O–CH2-system can be constructed also on
cross-linked insoluble polymer beads using TentaGel S
OH resin (Scheme 6).8,9,14 Thus, after loading furfural
derivative 4 onto the platform, the tandem UDA reac-
tion product 8c was conveniently synthesized in 29%
yield with 80% purity over three steps.15
1
for the amine building block, by comparing their H
NMR spectra with reported ones. Since the structure
of 1-adamantanamine-derived tandem UDA products
7p–10p could not be determined by the 1H chemical
shifts, we synthesized a heterotricycle 12 corresponding
to 8b in a solution phase and submitted it to X-ray crys-
tallographic analysis (Fig. 1).13 The result clearly
revealed the stereochemistry of 12 was identical with
BnNC
H
HN
H
(1 equiv)
O
N
1
O
(1 equiv)
fumarate 8
O
(1 equiv)
H
MeOH
50 °C, 48 h
61%
O
N
Br
H
13
Scheme 5.
O
a
O
O
SMe
CHO
O
14
15
(0.285 mmol/g)
b, c
8c (80% purity)
29% yield (3 steps)
Scheme 6. Reagents and conditions: (a) 4 (10 equiv), I–Cl (4 equiv),
MS4A, CH2Cl2, rt, 3.5 h; (b) p-methoxybenzylamine (20 equiv), BnNC
(20 equiv), fumaric acid derivative 8 (20 equiv), MeOH/THF (2:1),
50 ꢁC, 48 h; (c) TFA/CH2Cl2 (3:7), rt, 2.5 h.
Figure 1. Chem3D representation for the X-ray crystallographic
structure of 1-adamantanamine-derived tandem UDA product 12.

418
M. Oikawa et al. / Tetrahedron Letters 46 (2005) 415–418
Breu, J.; Butz, T.; Range, K. J.; Sauer Acta Cryst. 1997,
C53, 515–517; Kappe, C. O.; Murphree, S. S.; Padwa, A.
Tetrahedron 1997, 53, 14179–14233; Ghelfi, F.; Parsons,
A. F.; Tommasini, D.; Mucci, A. Eur. J. Org. Chem. 2001,
1845–1852; Wright, D. L.; Robotham, C. V.; Aboud, K.
Tetrahedron Lett. 2002, 43, 943–946; Akai, S.; Naka, T.;
Omura, S.; Tanimoto, K.; Imanishi, M.; Takebe, Y.;
Matsugi, M.; Kita, Y. Chem. Eur. J. 2002, 8, 4255–
4264.
In summary, we have carried out 100 reactions of the
tandem UDA reaction of primary amines, benzyl isocya-
nide, fumaric acid derivatives, and 5-hydroxymethyl-2-
furfural in liquid phase by using our MPEG–O–CH2-
platform. All reactions gave the stereoisomer represen-
tatively drawn in Scheme 4. An unexpected side path-
way leading to undesirable 8s was found but was
successfully suppressed by raising the temperature and
concentration. In addition, cross-linked insoluble poly-
mer beads were demonstrated to be an efficient platform
for a solid phase synthesis of the heterotricycle. We are
currently studying how to realize a larger-scale small
molecule library by a split-pool method using Tenta-
Gel-immobilized furfural 15 towards discovery of bio-
logically interesting compounds useful for chemical
genetics studies.16
6. A tandem UDA reaction with pyrolle has been reported
recently, see; Paulvannan, K. J. Org. Chem. 2004, 69,
1207–1214.
7. Lee, D. S.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2,
709–712; Sello, J. K.; Andreana, P. R.; Lee, D. S.;
Schreiber, S. L. Org. Lett. 2003, 5, 4125–4127.
8. MPEG–OH and TentaGel S OH resin were purchased
from Aldrich Co. (catalog No. 20251-7) and Advanced
ChemTech, Inc. (catalog No. SJ6004), respectively.
9. Oikawa, M.; Tanaka, T.; Kusumoto, S.; Sasaki, M.
Tetrahedron Lett. 2004, 45, 787–790.
Acknowledgements
10. For our related studies using another soluble polymer
platform, MPEG–O–AAc–, for rather simple Ugi
four-component coupling reaction, see: Oikawa, M.;
Ikoma, M.; Sasaki, M. Tetrahedron Lett. 2004, 45, 2371–
2375.
11. In contrast to our strategy, amine components were
immobilized in other polymer-phase synthetic studies on
the tandem UDA reaction,4,7 where no library has been
realized yet for the tandem UDA product.
The authors are grateful to Ms. C. Kabuto of Instru-
mental Analysis Center for Chemistry (Tohoku Univer-
sity) for X-ray crystallographic analysis.
References and notes
12. For example, the stereoselectivities were 85% (7a), 91%
(7s), 100% (7l), 96% (8h), and 81% (11h). These were
determined by H NMR spectra.
1. Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123–131;
Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366–
374; Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem. Eur. J. 2000, 6, 3321–3329; Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3169–3210; Domling, A.
Curr. Opin. Chem. Biol. 2000, 4, 318–323; Orru, R. V. A.;
de Greef, M. Synthesis 2003, 1471–1499.
2. Ugi, I. Angew. Chem., Int. Ed. Engl. 1959, 71, 386.
3. Cristau, P.; Vors, J. P.; Zhu, J. P. Tetrahedron Lett. 2003,
44, 5575–5578; Naskar, D.; Roy, A.; Seibel, W. L.; West,
L.; Portlock, D. E. Tetrahedron Lett. 2003, 44, 6297–6300;
Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski, R.;
Chen, J. J. Tetrahedron Lett. 2003, 44, 5121–5124;
Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L.
Tetrahedron Lett. 2003, 44, 603–605; Gracias, V.; Moore,
J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 417–420.
4. Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851–1854.
5. For intramolecular Diels–Alder reaction of furan, see;
Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 29–32;
1
13. Crystallographic data for 12: monoclinic colorless plate
(0.25 · 0.25 · 0.05 mm3, space group P21/c, unit cell
constants a = 17.484(6) A, b = 12.959(4) A, c = 6.412(9)
˚
˚
3
˚
˚
A, b = 101.805(2)ꢁ, V = 5857(3)A , Z value = 8, Dcalc
=
1.439 g/m3).
14. The usefullness of this platform will be reported elsewhere.
15. Since the loading of primary alcohols onto the resin
proceeds approximately in 30% yield (data not shown), the
yields for the tandem UDA and the cleavage reactions
were evaluated to be 80% and >96%, respectively. The
MTM group, after the loading, is supposed to be
hydrolyzed and the generating hydroxy group is inert
during the tandem UDA reaction followed by the cleav-
age. We are currently investigating a high-yield immobi-
lization method for primary alcohols on the platform.
16. Schreiber, S. L. Science 2000, 287, 1964–1969; Burke, M.
D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–
58.