Solid-phase rhodium carbenoid reactions: an N-H insertion route to a diverse series of oxazoles.

Article abstract of DOI:10.1021/ol010075n

[reaction: see text] The solid-phase synthesis of a series of oxazoles is described. The key step in the construction of these molecules involves the rhodium-catalyzed decomposition of polymer-bound alpha-diazo-beta-ketoesters. These reactions are performed in the presence of primary amides and yield the corresponding N-H insertion products. Subsequent cyclodehydration of these alpha-(acylamino)-beta-ketoesters provides the corresponding resin-bound 2,5-disubstituted oxazoles, which are further elaborated during cleavage from the resin.

Full text of DOI:10.1021/ol010075n

ORGANIC
LETTERS
2
001
Vol. 3, No. 14
173-2176
Solid-Phase Rhodium Carbenoid
Reactions: An N−H Insertion Route to a
Diverse Series of Oxazoles
2
†
Bruce Clapham, Carsten Spanka, and Kim D. Janda*
Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
kdjanda@scripps.edu
Received April 18, 2001
ABSTRACT
The solid-phase synthesis of a series of oxazoles is described. The key step in the construction of these molecules involves the rhodium-
catalyzed decomposition of polymer-bound r-diazo-â-ketoesters. These reactions are performed in the presence of primary amides and yield
the corresponding N−H insertion products. Subsequent cyclodehydration of these r-(acylamino)-â-ketoesters provides the corresponding
resin-bound 2,5-disubstituted oxazoles, which are further elaborated during cleavage from the resin.
5
The past decade has seen extensive research in the prepara-
tion of a wide variety of combinatorial libraries. These
libraries may be screened to obtain “hits” of potential value
in pharmaceutical, agricultural, or material science applica-
tionality. Diazo compounds decompose when treated with
either Lewis acid or transition metal catalysts and form highly
reactive carbene or carbenoid species. These intermediates
react via a number of mechanisms including insertion into
C-H or heteroatom (X-H) bonds to form new intra- or
intermolecular bonds. Although diazocarbon chemistry con-
stitutes an important class of reactions, solid-phase applica-
tions have been limited to a few exceptional examples.6
R-Diazoketones, R-diazoacetates, and R-diazo-â-ketoesters
are useful substrates for the construction of heterocyclic
1
tions. A large portion of this research has involved the use
of solid-phase organic synthesis (SPOS). Originally devel-
2
oped for the synthesis of peptides, SPOS has been used in
the preparation of a plethora of small-molecule libraries and
3
complex natural products. However, adaption of conven-
tional solution-phase chemistry to the solid phase is not
always straightforward. Consequently, great efforts have been
made to optimize many of the reactions available from the
organic chemist’s arsenal for use with solid-phase methodol-
7
compounds including oxazoles. However, most naturally
occurring oxazoles are formed by posttranslational modifica-
tion of serine and threonine residues in peptides. Numerous
oxazole-containing natural products have been isolated, and
8
4
ogy.
One important class of transformations in organic synthesis
are those involving substrates that contain the diazo func-
(
5) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons Ltd.: New York, 1997.
†
Novartis Pharma AG, CH-4002, Basel, Switzerland.
(
1) Bunin, B. A. The Combinatorial Index; Academic Press Ltd.: London,
(6) (a) Nagashima, T.; Davies, H. M. L. J. Am. Chem. Soc. 2001, 123,
2695. (b) Iso, Y.; Shindo, H.; Hamana, H. Tetrahedron 2000, 56, 5353. (c)
Cano, M.; Camps, F.; Joglar, J. Tetrahedron Lett. 1998, 39, 9819. (d)
Whitehouse, D. L.; Nelson, K. H.; Savinov, S. N.; Austin, D. J. Tetrahedron
Lett. 1997, 38, 7139. (e) Gowravaram, M. R.; Gallop, M. A. Tetrahedron
Lett. 1997, 38, 6973. (f) Zaragoza, F.; Petersen, S. V. Tetrahedron 1996,
52, 5999.
1
998.
(2) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
3) (a) Solid-Phase Organic Synthesis; Czarnik, A. W., Ed.; John Wiley
(
&
Sons Ltd.: New York, 2001. (b) Solid-Phase Organic Synthesis; Burgess,
K., Ed.; John Wiley & Sons Ltd.: New York, 2000.
4) (a) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
(
Tetrahedron 1998, 54, 15385. (b) Hermkens, P. H. H.; Ottenheijm, H. C.
J.; Rees, D. C. Tetrahedron 1997, 53, 5643. (c) Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1996, 52, 4527.
(7) (a) Huisgen, R.; K o¨ nig, H.; Binsch, G.; Sturm, H. J. Angew. Chem.
1961, 73, 368. (b) Moody, C. J.; Doyle, K. J. Prog. Heterocycl. Chem.
1997, 9, 1.
1
0.1021/ol010075n CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/20/2001

some of these compounds have exhibited interesting biologi-
cal properties. Hence, many total syntheses and new devel-
opments in oxazole methodology have appeared in the recent
Scheme 1a
9
literature.
Despite the current renaissance in oxazole chemistry,
combinatorial applications of oxazoles have been limited.
Research has included the synthesis of oxazole-containing
10
peptido-mimetics and the preparation of oxazole-containing
peptide macrocycles that could serve as scaffolds for
combinatorial elaboration.11 A recent report described the
6
b
synthesis of polymer-bound â-silyl-R-diazoketones. Three
examples were given where these diazoketones were con-
verted into oxazoles using a rhodium-catalyzed 1,3-dipolar
cycloaddition reaction with a nitrile. Although this work
represents an important example of a solid-phase oxazole
synthesis, the 1,3-dipolar cycloaddition route to oxazoles can
be problematic. Moody and co-workers reported that some
nitriles are poor substrates in such reactions and developed
an elegant alternative oxazole synthesis. In their approach,
an R-diazo-â-ketoester was reacted with a primary amide in
the presence of a rhodium catalyst, giving an N-H insertion
product. These R-(acylamino)-â-ketoester products were then
converted into oxazoles using a cyclodehydration reaction.
This N-H insertion route to oxazoles is tolerant of various
functional groups, and diverse primary amide coupling
partners are readily available. Thus, this chemistry is an ideal
choice for the preparation of oxazole libraries.
a
(
2 2
a) Diketene (3 equiv), DMAP (10 mol %), CH Cl ,-78 °C to
rt, 16 h; (b) dodecylbenzenesulfonylazide (5 equiv), Et
toluene, 16 h; (c) primary amide (5 equiv), Rh Oct
toluene, 60 °C, 2 h; (d) Cl PPh (2 equiv), Et N (6 equiv), CH Cl ,
16 h.
3
N (5 equiv),
4
(2 mol %),
2
2
3
3
2
2
Reaction progress was monitored by the appearance of
-
1
two peaks at 1734 and 1710 cm in the IR spectra,
corresponding to the ester and ketone functionality, respec-
tively. Next, diazotransfer was performed under standard
conditions using dodecylbenzenesulfonylazide affording
R-diazo-â-ketoester 2. IR analysis of 2 showed an intense
absorption at 2137 cm corresponding to the diazo func-
tionality. The ester and ketone absorptions of 2 shifted to
714 and 1655 cm indicating complete conversion to
product. The loading of resin 2 was estimated using elemental
12
1
7
18
-
1
-
1
1
19
analysis for nitrogen.
Some of our own research has focused upon the synthesis
of small-ring organic compounds using soluble and insoluble
With the preparation of R-diazo-â-ketoester 2 complete,
an N-H insertion reaction with benzamide was investigated.
Treatment of 2 with benzamide (5 equiv) in the presence of
rhodium ocatanoate catalyst (2 mol %) in toluene at 60 °C
for 2 h gave N-H insertion product 3a (R ) Ph) in 99%
yield on the basis of mass balance. This product displayed
IR absorptions at 3425, 1749, 1724, and 1633 cm corre-
sponding to the N-H stretch and the ester, ketone, and amide
carbonyls, respectively. Additionally, 3a showed complete
disappearance of the characteristic diazo IR absorption at
13
polymer supports. We recently reported an efficient solid-
phase synthesis of 1,3-oxazolidines.14 This prompted us to
investigate a solid-phase synthesis of the aromatic oxazole
analogues using the N-H insertion strategy. Reported here
are our preliminary findings in this area.
-
1
The project began by preparing a polymer-bound aceto-
15
acetyl ester by reaction of diketene with hydroxybutyl
TM
16
JandaJel resin 1 (Scheme 1).
-
1
2
137 cm indicating complete reaction.
Cyclodehydration of N-H insertion product 3a to polymer-
bound oxazole 4a was more troublesome to optimize. Wipf’s
(
8) (a) Jack, R. W.; Jung, G. Curr. Opin. Chem. Biol. 2000, 4, 310. (b)
Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.; Walsh, C. T. Nat.
Prod. Rep. 1999, 16, 249.
mild cyclodehydration procedure (PPh , I , Et N, CH Cl
3
2
3
2
2
)
(9) (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S.
Angew. Chem., Int. Ed. 2000, 39, 2533. (b) Bagley, M. C.; Bashford, K.
E.; Hesketh, C. L.; Moody, C. J. J. Am. Chem. Soc. 2000, 122, 3301. (c)
Chattopadhyay, S. K.; Kempson, J.; McNeil, A.; Pattenden, G.; Reader,
M.; Rippon, D. E.; Waite, D. J. Chem. Soc., Perkin Trans. 1 2000, 15,
(15) Gordeev, M. F.; Patel, D. V.; Wu, J.; Gordon, E. M. Tetrahedron
Lett. 1996, 37, 4643.
TM
(16) JandaJel resins are available from Aldrich Chemical Co. The
TM
2
415. (e) Smith, A. B.; III; Friestad, G. K.; Barbosa, J.; Bertounesque, E.;
hydroxybutyl JandaJel resin used was prepared using a similar procedure
Duan, J. J.-W.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Spoors, P. G.; Salvatore,
B. A. J. Am. Chem. Soc. 1999, 121, 10478. (f) Mulder, R. J.; Shafer, C.
M.; Molinski, T. F. J. Org. Chem. 1999, 64, 4995. (g) Williams, D. R.;
Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924.
to that of Harikrishnan (see Supporting Information): Harikrishnan, L. S.;
Hollis Showalter, H. D. Synlett 2000, 1339. For further discussion of the
TM
JandaJel
resins, see: (a) Toy, P. H.; Reger, T. S.; Janda, K. D.
Aldrichimica Acta 2000, 33, 87. (b) 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. (c) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40, 6329. For
recent applications, see: (d) Br u¨ mmer, O.; Clapham, B.; Janda, K. D.
Tetrahedron Lett. 2001, 42, 2257. (e) Clapham, B.; Cho, C.-W.; Janda, K.
D. J. Org. Chem. 2001, 66, 868.
(10) (a) Grabowska, U.; Rizzo, A.; Farnell, K.; Quibell, M. J. Comb.
Chem. 2000, 2, 475. (b) Martin, L. M.; Hu, B.-H. Tetrahedron Lett. 1999,
4
0, 7951.
(11) (a) Somogyi, L.; Haberhauer, G.; Rebek, J., Jr. Tetrahedron 2001,
5
2
7, 1699. (b) Haberhauer, G.; Somogyi, L.; Rebek, J., Jr. Tetrahedron Lett.
000, 41, 5013.
(17) Regitz, M.; Hocker, J.; Liedhegener, A. Organic Syntheses; Wiley:
New York, 1973; Collect. Vol. V, p 179.
(12) (a) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.; Slawin,
A. M. Z. Synlett 1996, 825. (b) Bagley, M. C.; Buck, R. T.; Hind, S. L.;
Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1998, 13, 591.
(18) Purchased from TCI chemical company. See also: Hazen, G. G.;
Bollinger, F. W.; Roberts, F. E.; Russ, W. K.; Seman, J. J.; Staskiewicz, S.
Org. Synth. 1995, 73, 144.
(13) For recent examples, see: (a) L o´ pez-Pelegr ´ı n, J. A.; Janda, K. D.
Chem. Eur. J. 2000, 6, 1917. (b) Lee, K. J.; Angulo, A.; Ghazal, P.; Janda,
K. D. Org. Lett. 1999, 1, 1859.
(19) The resin used was prepared from a chloromethyl functionalized
TM
-1
JandaJel
with a loading of approximately 1.5 mmol g . Diazo-
(14) Tremblay, M. R.; Wentworth, P., Jr.; Lee, G. E., Jr.; Janda, K. D.
functionalized resin 2 gave a nitrogen content corresponding to a loading
-
1
J. Comb. Chem. 2000, 2, 698.
of 1.37 mmol g
.
2174
Org. Lett., Vol. 3, No. 14, 2001

has enabled the solution-phase synthesis of previously
2
0
inaccessible oxazoles. Reaction of 3a under these conditions
gave desired oxazole 4a (R ) Ph) as indicated by IR analysis
(
Table 1. Purity and Yield of Oxazoles 7b-g
a
b
ester carbonyl shift to 1713 cm-1 and disappearance of
7
R )
tBu
purity /%
yield /%
N-H, ketone, and amide absorptions). Unfortunately, this
reaction was accompanied by side reactions that turned the
resin beads dark brown. These impurities remained attached
to the resin after washing but were released into solution
during cleavage of the oxazole product from the resin (see
below). We found that replacement of the PPh
with the commercially available Cl PPh adduct gave ef-
ficient conversion to product 4a without the generation of
b
c
d
e
f
78
98
92
94
98
96
36
47
30
22
35
29
o-Tol
m-MeOPh
p-MeOPh
p-CF3Ph
p-BrPh
g
3 2
/I reagent
a
Purity of crude product assessed using RP-HPLC (254 nm). b After
2
3
purification using preparative TLC.
undesirable byproducts. The stage was now set to investigate
2
1
additional cleavage reactions of oxazole 4 (Scheme 2).
described above providing an array of oxazoles, 7b-g. The
crude products were assessed for purity using HPLC and
then isolated as pure compounds for analysis using prepara-
tive TLC. Clearly, this solid-phase N-H insertion/cyclo-
dehydration oxazole synthesis tolerates amide substrates with
various steric and electronic characteristics. The crude
products showed excellent purity, and isolated yields of
Scheme 2a
2
4
purified products were moderate.
Finally, a series of compounds that displayed additional
diversity at the 5-position of the oxazole ring were synthe-
sized. Resin 1 was first reacted with a set of acyl-Meldrum
2
5
acid adducts 8 giving the corresponding polymer-bound
2
6
â-ketoesters. Subsequent diazotransfer gave R-diazo-â-
ketoester resins 9a and 9b (Scheme 3). Unfortunately, acyl-
a
4 3
(a) LiBH (5 equiv), LiEt BH, (10 mol %), THF, 2 h, then
Scheme 3a
AcOH, (unoptimized); (b) NaOMe (20 mol %), MeOH, THF, 16
h; (c) piperidine (8 equiv), AlCl , (2 equiv), CH Cl , 16 h, then
aqueous Na CO
3
2
2
2
3
.
Treatment of oxazole 4a with a combination of lithium
borohydride and lithium triethylborohydride gave the hy-
droxymethyl oxazole 5.22 Ester 6 was obtained by trans-
esterification of 4a using sodium methoxide in a methanol/
THF solution. Finally, an amidation/cleavage reaction was
performed by treating 4a with a mixture of piperidine and
a
aluminum chloride affording amide 7a.23 Each of the
(a) 8 (2.5 equiv), THF, 4, 16 h; (b) dodecylbenzenesulfonyl-
azide (5 equiv), Et
5 equiv), Rh Oct
reagent (5 equiv), THF, 70 °C, 6 h, (sealed vial); (e) amine (8
equiv), AlCl (2 equiv), CH Cl , 16 h, then aqueous Na CO
3
N (5 equiv), toluene, 16 h; (c) primary amide
cleavage reactions was quenched with the appropriate
reagent, and these mixtures were passed through a strong
acid, strong base mixed-bed ion-exchange resin column
before isolation of the products.
(
2
4
(2 mol %), toluene, 60 °C, 2 h; (d) Burgess
3
2
2
2
3
.
Insertion reactions of polymer-bound R-diazo-â-ketoester
with additional amides were also investigated (Table 1).
The amides used contained either a bulky group or electron-
rich or electron-poor aromatic substitution. Insertion, cyclo-
dehydration, and cleavage reactions were performed as
Meldrum acid adducts of type 8 are difficult to prepare and
isolate in sufficient purity. The preparation of diverse
polymer-bound â-ketoesters is currently the limiting factor
in the preparation of larger oxazole libraries.
As expected, resin-bound R-diazo-â-ketoesters 9a and 9b
underwent clean conversion to the N-H insertion products
2
(20) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. For other
elegant small-ring heterocycle cyclizations from this group, see: Phillips,
A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
1
(24) All purified compounds were characterized using IR, H NMR, and
1
165, and references therein.
21) For reactions of 4-substituted-oxazoles, see: Clapham, B.; Richards,
A. J.; Wood, M. L.; Sutherland, A. J. Tetrahedron Lett. 1997, 38, 9061.
22) (a) Brown, H. C.; Narasimhan, S. J. Org. Chem. 1982, 47, 1604.
b) Clapham, B.; Sutherland, A. J. Tetrahedron Lett. 2000, 41, 2253.
23) (a) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett. 1996,
7, 3213. (b) Ley, S. V.; Mynett, D. M.; Koot, W.-J. Synlett 1995, 1017.
HRMS and gave data in accordance with their structures.
(25) (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978,
43, 2087. (b) Houghton, R. P.; Lapham, D. J. Synthesis 1982, 452. (c)
Sørensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org. Chem. 2000, 65,
1003.
(26) Tieze, L. F.; Steinmetz, A.; Balkenhohl, F. Bioorg. Med. Chem.
Lett. 1997, 7, 1303.
(
(
(
(
3
Org. Lett., Vol. 3, No. 14, 2001
2175

when treated with an amide and the rhodium catalyst.
Cyclodehydration of these more bulky R-(acylamino)-â-
ketoesters 10 using the phosphorane/Et N reagents proved
3
unreliable yielding incomplete conversion to some products
Table 2. Purity and Yield of Oxazoles 11
R1 ) Cy;
R3, R4 ) morpholine
R1 ) Ph;
R3 ) R4 ) n-propyl
as indicated by IR analysis. Researchers at Novartis recently
reported that the Burgess reagent27 can also be used to
a
b
a
b
R2
purity /%
yield /%
purity /%
yield /%
28
prepare oxazoles using the cyclodehydration strategy. When
polymer-bound substrates 10 were treated with excess
Burgess reagent (5 equiv) at elevated temperatures for 6 h,
a clean cyclodehydration to oxazole products was observed.
These oxazoles were cleaved from the resin as their dipropyl
or morpholine amides 11 and obtained in excellent purity
and in slightly superior yields (Table 2) than those prepared
using the phosphorane reagents (Table 1).
tBu
86
94
92
90
94
28
53
48
39
48
91
99
94
97
96
36
52
39
53
50
o-Tol
p-MeOPh
p-CF3Ph
p-BrPh
a
Purity of crude product assessed using RP-HPLC (254 nm). b After
purification using preparative TLC.
In conclusion, a highly efficient solid-phase synthesis of
oxazoles has been developed. This methodology emphasizes
the synthetic utility of polymer-bound diazo substrates.
Although the preparation of polymer-supported â-ketoesters
has been problematic, we are refining new methodology
which we will report in due course. In addition, we are
currently investigating other applications of polymer-bound
diazo substrates.
Acknowledgment. Financial support from the National
Institutes of Health (GM-56154), The Scripps Research
Institute, The Skaggs Institute for Chemical Biology, and
Novartis is gratefully acknowledged. B.C. is a Skaggs
Postdoctoral Fellow. We thank Dr. Peter Wirsching for
assistance in the preparation of this manuscript.
Supporting Information Available: Experimental pro-
cedures and analytical data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(27) Burgess reagent ((methoxycarbonylsulfamoyl)triethylammonium
hydroxide inner salt) was purchased from Fluka. See also: Burgess, E. M.;
Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26.
(28) Brain, C. T.; Paul, J. M. Synlett 1999, 1642.
OL010075N
2176
Org. Lett., Vol. 3, No. 14, 2001