Solid-phase synthesis of oxazolones and other heterocycles via Wang resin-bound diazocarbonyls

Article abstract of DOI:10.1016/j.tetlet.2005.06.061

The preparation of Wang resin bound α-diazo-β-ketoesters is described. These highly useful intermediates were used for the synthesis of a series of heterocycle libraries, which were obtained from the resin using TFA cleavage. In addition, a novel route for the synthesis of oxazolones using an N-H insertion strategy is disclosed.

Full text of DOI:10.1016/j.tetlet.2005.06.061

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5495–5498
Solid-phase synthesis of oxazolones and other heterocycles
via Wang resin-bound diazocarbonyls
Makoto Yamashita,a Sang-Hyeup Lee,a Guido Koch,b Juerg Zimmermann,b
Bruce Claphama,*, and Kim D. Jandaa,*
aDepartment of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
bNovartis Pharma AG, Combinatorial Chemistry, WSJ-507.704, CH-4002 Basel, Switzerland
Received 26 May 2005; accepted 13 June 2005
Available online 1 July 2005
Abstract—The preparation of Wang resin bound a-diazo-b-ketoesters is described. These highly useful intermediates were used for
the synthesis of a series of heterocycle libraries, which were obtained from the resin using TFA cleavage. In addition, a novel route
for the synthesis of oxazolones using an N–H insertion strategy is disclosed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
blocks for the diversity-oriented synthesis (DOS)5 of a
series of heterocycle libraries, including oxazoles,6 in-
doles,7 imidazolones and imidazoles,8 and pyrazinones
and pyrazines.9
Combinatorialand paraellsynthetic methodool gy pro-
vides the main driving force for the preparation of com-
pound libraries for application in lead discovery and
high throughput medicinalchemistry research within
This work relied upon a hydroxypentyl JandaJelresin 10
as the support for the polymer-bound a-diazo-b-keto-
esters; this support is very robust and transesterification
or Lewis acid-assisted amidation11 cleavage reactions
were used to obtain the products from the support,
rather than trifluoroacetic (TFA) acidolysis, which is
commonly employed when using classical linker
strategies.12
1
the pharmaceuticalindustry. Many different formats
of high throughput chemistry are available and solid-
phase organic synthesis (SPOS) plays a pivotal role
given the convenient handling of large numbers of syn-
thetic intermediates.2 However, SPOS is not without
its drawbacks since there is often extended development
times required to optimize new solid-phase chemical
reactions.
During our studies preparing heterocycles using N–H
insertion strategies, we found that phenylcarbamate 2
is an excellent coupling partner when reacted with diazo-
carbonyls (Scheme 1). Moreover, treatment of this inter-
mediate 3 with mild base afforded the ring-closed
oxazolone products 4. However, when this chemistry
was applied to a solid-phase approach, the aluminum
amide cleavage conditions failed to give the desired oxa-
zolone products, and only the ring-opened urea prod-
ucts 5 were formed. Although we have been able to
develop the chemistry of the urea formation to give
highly useful methodology,13 we were still intrigued with
the prospect of preparing libraries of oxazolones given
their potential to yield compounds of biological
significance.14
Research from our own group has harnessed the syn-
thetic utility of diazocarbonyl compounds3 in order to
prepare a plethora of biologically privileged Ôlead-likeÕ
scaffolds. This program has centered on the application
of polymer-bound a-diazo-b-ketoesters4 as key building
Keywords: Solid-phase; Heterocycles; Diazocarbonyl; Oxazolones.
*
Corresponding authors. Tel.: +1 847 937 8954; fax: +1 847 935 5212
(B.C.); tel.: +1 858 784 2515; fax: +1 858 784 2595 (K.D.J.); e-mail
addresses: bruce.clapham@abbott.com; kdjanda@scripps.edu
Present address: Abbott Laboratories, GPRD-R4CP-AP9B-LL, 100
Abbott Park Road, Abbott Park, IL 60064-6113, USA.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.061

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M. Yamashita et al. / Tetrahedron Letters 46 (2005) 5495–5498
Table 1. Solid-phase synthesis of heterocycles from 8
O
R
O
O
R1
9 Puritya
10 Puritya
11 Puritya
a
RO
O
O
(yield)b
(yield)b
(yield)b
HN
O
NH2
RO
R
Me
99 (43)
76 (18)
96 (31)c
98 (49)
96 (47)
86 (22)
99 (61)
62 (11)
N2
1
O
O
2
BnO(CH2)3
tBuO(CH2)3
AcNH(CH2)5
NCBZ
3
85 (23)c
99 (28)c
d
d
O
O
O
R1
R
59 (25)
88 (20)
24 (5)
26 (4)
c
b
N
R
O
Ph
39 (12)
68 (37)
RO
R2 HN
O
O
a Purity assessed by HPLC at 254 nm.
HN
N
4
R1
R2
5
b Yield of product after purification by preparative HPLC; yield based
upon loading of 8.
c tBu group removed during cleavage.
d Complex mixture of products.
Scheme 1. Reagents and conditions: (a) Rh2Oct4 (2 mol%),
2
(3 equiv), toluene–dichloroethane 1:1, 80 ꢁC, 1 h; (b) iPr2EtN (3 equiv),
toluene, reflux, 6 h; (c) R1R2NH (3 equiv), AlMe3 (3 equiv), toluene,
100 ꢁC, 16 h.
zation to the imidazolone and cleavage from the resin in
one pot. Each of the oxazolones 9, oxazoles 10, and imi-
dazolones 11 cleavage products were assessed for crude
purity by HPLC and then purified by preparative
HPLC. The results from this study are presented in
Table 1.
In light of the incompatibility of the Lewis acid-assisted
amidation reaction with the oxazolone scaffolds, an
alternative linker strategy was sought. Wang resin
bound substrates were investigated and found to be
ideal substrates for oxazolones carboxylic acid synthesis.
The Wang bound b-ketoesters were synthesized using a
transesterification reaction. A mixture of Wang resin 6
In the case of the oxazolones 9, the majority of the
desired products were isolated in excellent purity and
good yield. When tBu protected alcohols were
employed, each of the products were obtained as the
deprotected alcohols. In addition, when benzyl ether
and benzylcarbamate (CBZ) protected side groups
were employed, slightly inferior purities and yields were
obtained for the desired cleavage products, presumably
because of their premature cleavage during prolonged
exposure to neat TFA. Finally, an interesting finding
was observed during the cleavage/cyclization of one of
the imidazolones (Scheme 3). In this case, the major
cleavage product was imidazolone 16 (19%) rather than
imidazolone acid 13 (4%); the cyclization reaction can
occur both prior to and after cleavage from the resin.
However, in the latter case, the b-ketoacid cleavage
product 14 can undergo acid catalyzed decarboxylation
to give ketourea 15 before ring closure to imidazolone
16.
t
and Bu-b-ketoesters 7 was heated to reflux in toluene,
after washing, standard diazotransfer conditions
provided the corresponding Wang resin-bound a-diazo-
b-ketoesters 8. Next, the key building blocks 8 were
treated with phenylcarbamate 2 in the presence of rho-
dium octanoate catalyst to give the N–H insertion prod-
i
ucts that were treated sequentially with Pr2EtN and
TFA to provide oxazolones 9.15 Key building blocks 8
were also used to synthesize a series of oxazoles 10
and imidazolones 11 using an N–H insertion/cyclodehy-
dration strategy (Scheme 2).16 For the oxazole synthesis,
a primary amide was used as the insertion component,
the heterocycle ring was closed using Burgess reagent,
and the oxazoles 10 were obtained by cleavage with
TFA. In the case of the imidazolones, a primary urea
was used as the insertion component, the product from
this reaction was treated with TFA to achieve both cycli-
O
R1
HO
HN
O
b
9
O
a
OH
O
O
O
O
O
O
c
O
R1
d
HO
R1
N
6
O
R1
N2
8
7
Ph
O
O
10
H
N
HO
R1
O
N
11
Ph
Scheme 2. Reagents and conditions: (a) (i) 7 (3 equiv), toluene, reflux, 16 h; (ii) dodecylbenzenesulfonyl azide (3 equiv), Et3N (3 equiv), toluene, 24 h;
i
(b) (i) Rh2Oct4 (2 mol%), 2 (3 equiv), toluene, 70 ꢁC, 1 h; (ii) Pr2EtN (3 equiv), toluene, reflux, 6 h; (iii) TFA, rt, 3 h; (c) (i) Rh2Oct4 (2 mol%),
PhCONH2 (3 equiv) toluene–dichloroethane 1:1, 80 ꢁC, 1 h; (ii) Burgess reagent (3 equiv), THF, lw, 100 ꢁC, 10 min; (iii) TFA, rt, 3 h; (d) (i)
PhNHCONH2 (3 equiv) toluene–dichloroethane 1:1; 80 ꢁC, 1 h; (ii) TFA, rt, 3 h.

M. Yamashita et al. / Tetrahedron Letters 46 (2005) 5495–5498
5497
O
O
O
- CO2
NCBZ
NCBZ
HO
HN
HN
O
HN
HN
O
O
O
Ph
a
NCBZ
15
14
O
Ph
HN
HN
O
O
H
N
H
N
12
Ph
HO
R1
O
R1
O
N
N
Ph
Ph
13
16
Scheme 3. Reagents and conditions: (a) TFA, rt 3 h.
8. (a) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.;
Janda, K. D. Org. Lett. 2003, 5, 511; (b) Lee, S.-H.;
Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, G.;
Zimmerman, J.; Janda, K. D. J. Org. Chem. 2004, 69,
8829.
9. Matsushita, H.; Lee, S.-H.; Yoshida, K.; Clapham, B.;
Koch, G.; Zimmermann, J.; Janda, K. D. Org. Lett. 2004,
6, 4627.
10. JandaJelTM resins are available from Aldrich Chemical Co.
(a) Toy, P. H.; Reger, T. S.; Garibay, P.; Garno, J. C.;
Malikayil, J. A.; Liu, G.; Janda, K. D. J. Comb. Chem.
2001, 3, 117; For recent applications, see: (b) Brummer,
O.; Clapham, B.; Janda, K. D. Tetrahedron Lett. 2001, 42,
2257; (c) Clapham, B.; Cho, C.-W.; Janda, K. D. J. Org.
Chem. 2001, 66, 868; (d) Moss, J. A.; Dickerson, T. J.;
Janda, K. D. Tetrahedron Lett. 2002, 43, 37.
11. (a) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron
Lett. 1996, 37, 3213; (b) Ley, S. V.; Mynett, D. M.; Koot,
W.-J. Synlett 1995, 1017; (c) Matsushita, H.; Lee, S.-H.;
Joung, M.; Clapham, B.; Janda, K. D. Tetrahedron Lett.
2004, 45, 313.
2. Conclusions
In summary, a noveland efficient N–H insertion strat-
egy for the synthesis of oxazolones from diazocarbonyls
has been devised. Additionally, in order to synthesize
oxazolone arrays using solid-phase synthetic methodol-
ogy, an alternative TFA labile linker strategy was devel-
oped; the Wang resin-bound diazocarbonylsubstrates
were also shown to be of great utility in the preparation
of oxazoles and imidazolones.
Acknowledgements
We gratefully acknowledge financial support from The
Scripps Research Institute, The Skaggs Institute for
ChemicalBiool gy and Novartis Pharma AG.
References and notes
12. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100,
2091.
13. (a) Lee, S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D.
Tetrahedron 2004, 60, 3439; (b) Lee, S.-H.; Matsushita, H.;
Koch, G.; Zimmermann, J.; Clapham, B.; Janda, K. D. J.
Comb. Chem. 2004, 6, 822.
1. (a) Bunin, B. A. The Combinatorial Index; Academic Press:
London, 1998; (b) Obrecht, D.; Villalgordo, J. M. Solid-
Supported Combinatorial and Parallel Synthesis of
small-molecular-weight compound Libraries; Elsevier
Science, 1998; (c) Combinatorial Chemistry: Synthesis,
Analysis, Screening; Jung, G., Ed.; Wiley-VCH:
Weinheim, 1999; (d) Combinatorial Chemistry and Molec-
ular Diversity in Drug Discovery; Gordon, E. M., Kerwin,
J. F., Jr., Eds.; John Wiley and Sons: New York, 1998.
2. (a) Solid Phase Organic Synthesis; Czarnik, A. W., Ed.;
John Wiley and Sons: New York, 2001; (b) Solid Phase
Organic Synthesis; Burgess, K., Ed.; John Wiley and Sons:
New York, 2000.
3. For comprehensive coverage of the chemistry of diazo
compounds, see: Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with
Diazo Compounds: From Cyclopropanes to Ylides; John
Wiley and Sons: New York, 1997; For a review covering
the use of diazocarbonyls in combinatorial and parallel
applications, see: Clapham, B. Curr. Opin. Drug Discovery
Dev. 2004, 7, 813.
14. See: Okonya, J. F.; Hoffman, R. V.; Johnson, J. M. J. Org.
Chem. 2002, 67, 1102, and references cited therein.
15. Polymer-bound a-diazo-b-ketoester 8. A 100 mL recovery
flask was charged with Wang resin (Polymer Labs, 5.00 g,
ꢀ5.0 mmol), tBu–acetoacetate (2.37 g, 15.0 mmol), and
toluene (75 mL). The mixture was heated to reflux for 6 h,
and the product collected in a fritted syringe and washed
with toluene. Dodecylbenzenesulfonyl azide (8.79 g,
25 mmol) and Et3N (3.49 mL, 25 mmol) were added, and
the resultant mixture was shaken for 24 h. Washing with
DMF, THF, ether, and hexanes gave 8 white powder;
yield 100%; Elemental Analysis: N = 2.56%; loading
0.914 mmol/g; IR (cmÀ1) 2137, 1713, 1657.
Phenyl carbamate insertion. A round bottomed flask was
charged with resin 8 (R1 = Me, 600 mg, 0.55 mmol), phenyl
carbamate 2 (226 mg, 1.65 mmol), purged with argon and
then a toluene (8 mL) was added. The mixture was heated
to 80 ꢁC and a suspension of Rh2Oct4 (ꢀ9 mg, 2 mol%) in
toluene (2.0 mL) was added over 10 min. Nitrogen effer-
vescence was observed and stirring was continued for 1 h,
before the product was collected by filtration and washed
with DMF, THF, CHCl3, ether, and hexanes. Pale brown
powder; IR (cmÀ1) 1725 (broad peak).
4. Clapham, B.; Lee, S.-H.; Koch, G.; Zimmermann, J.;
Janda, K. D. Tetrahedron Lett. 2002, 43, 5407.
5. Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed.
2004, 43, 46.
6. Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3,
2173.
Oxazolone formation. A round bottomed flask was
charged with insertion product (580 mg), toluene
7. Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.;
Janda, K. D. J. Comb. Chem. 2003, 5, 188.

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M. Yamashita et al. / Tetrahedron Letters 46 (2005) 5495–5498
(11 mL) and Hunigs base (870 lL, 5.00 mmol). The
HPLC, and then purified by preparative HPLC. Crude
purity 99%; Isolated yield 43%; white powder; mp 202–
resulting mixture was heated to reflux for 6 h, and the
polymer-bound oxazolone product was collected by
filtration and washed with DMF, MeOH, THF, CHCl3,
ether, and hexanes. Pale brown powder; IR (cmÀ1) 1774,
1718. Cleavage of oxazolones 9. The polymer-bound
oxazolone was treated with TFA (6.0 mL) and shaken
for 3 h. The product was collected and the resin washed
with TFA (3 · 6.0 mL). After concentration by evapora-
tion, the crude product 9 was assessed for purity using
1
204 ꢁC; IR (cmÀ1) 3058, 2840, 1789, 1747, 1668, 1651; H
NMR (500 MHz, CD3OD): d 2.36 (3H, s); 13C NMR
(125 MHz, CD3OD): d 11.7, 116.7, 147.5, 156.3, 161.8;
HRMS m/z 142.0147 [MÀH]À, calcd for C5H4NO4
142.0146.
16. (a) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.;
Slawin, ; Alexandra, M. Z. Synlett 1996, 825; (b) Moody,
C. J.; Swann, E. Synlett 1998, 135.