Rhodium carbenoid N-H insertion reactions of primary ureas: solution and solid-phase synthesis of imidazolones.

Article abstract of DOI:10.1021/ol020244j

[reaction: see text] The solution and solid-phase synthesis of imidazolones is reported. The key step for the preparation of these compounds is the N-H insertion reaction of primary ureas into highly reactive rhodium carbenoid intermediates. Typically, a

Full text of DOI:10.1021/ol020244j

ORGANIC
LETTERS
2003
Vol. 5, No. 4
511-514
Rhodium Carbenoid N−H Insertion
Reactions of Primary Ureas: Solution
and Solid-Phase Synthesis of
Imidazolones
,†
Sang-Hyeup Lee,† Bruce Clapham,* Guido Koch,‡ Ju1rg Zimmermann,‡ and
,†
Kim D. Janda*
Department of Chemistry, The Scripps Research Institute,
10550 N. Torrey Pines Road, La Jolla, California 92037, and
NoVartis Pharma AG, Combinatorial Chemistry Unit, WSJ-507,
CH-4002 Basel, Switzerland
bclapham@scripps.edu
Received December 2, 2002
ABSTRACT
The solution and solid-phase synthesis of imidazolones is reported. The key step for the preparation of these compounds is the N−H insertion
reaction of primary ureas into highly reactive rhodium carbenoid intermediates. Typically, a soluble or support-bound r-diazo-â-ketoester is
treated with a rhodium carboxylate catalyst in the presence of a primary urea to give the corresponding N−H insertion product. Subsequent
acid-catalyzed cyclodehydration of these insertion products affords the desired imidazolone products.
Combinatorial chemistry is a widely accepted methodology
that is used to generate libraries of molecules for the
discovery of biologically active leads and also the optimiza-
tion of potential drug candidates.1 The mainstay of combi-
natorial chemistry is solid-phase organic synthesis (SPOS).2
Here, the intermediate products are attached to insoluble
resins and consequently, workup and purification require only
simple washing and filtration procedures. One problem with
solid-phase chemistry is that some types of solution-phase
reactions do not readily transfer onto the solid-phase format.3
One class of reactions that has received little attention in
solid-phase applications are those of diazo-functionalized
substrates.4 This is surprising since diazo compounds have
great utility in synthetic organic chemistry5 and in light of
this, research from our laboratory has shown the potential
of these substrates in the solid-phase synthesis of oxazoles6
and indoles7 from polymer-bound R-diazo-â-ketoesters.8
† The Scripps Research Institute.
‡ Novartis Pharma AG.
(3) For a review of solid-phase reactions, see: Booth, S.; Hermkens, P.
H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998, 54, 15385.
(4) (a) Iso, Y.; Shindo, H.; Hamana, H. Tetrahedron 2000, 56, 5353. (b)
Cano, M.; Camps, F.; Joglar, J. Tetrahedron Lett. 1998, 39, 9819. (c)
Whitehouse, D. L.; Nelson, K. H.; Savinov, S. N.; Austin, D. J. Tetrahedron
Lett. 1997, 38, 7139. (d) Gowravaram, M. R.; Gallop, M. A. Tetrahedron
Lett. 1997, 38, 6973. (e) Zaragoza, F.; Petersen, S. V. Tetrahedron 1996,
52, 5999.
(1) (a) Bunin, B. A. The Combinatorial Index; Academic Press, Ltd.:
London, 1998. (b) Obrecht, D.; Villalgordo, J. M. Solid-Supported Com-
binatorial and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Elsevier Science, Ltd.: New York, 1998. (c) Combinatorial
Chemistry: Synthesis, Analysis, Screening; Jung, G., Ed.; Wiley-VCH:
Weinheim, Germany, 1999. (d) Combinatorial Chemistry and Molecular
DiVersity in Drug DiscoVery; Gordon, E. M., Kerwin, J. F., Jr., Eds.; Wiley
& Sons, Ltd.: New York, 1998.
(5) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley & Sons, Ltd.: New York, 1997.
(2) (a) Solid-Phase Organic Synthesis; Czarnik, A. W., Ed.; Wiley &
Sons, Ltd.: New York, 2001. (b) Solid-Phase Organic Synthesis; Burgess,
K., Ed.; Wiley & Sons, Ltd.: New York, 2000.
(6) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173.
10.1021/ol020244j CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003

Additionally, several outstanding papers have recently been
published that describe the solid-phase synthesis of molecu-
larly diverse compounds using reactions of diazo-function-
alized substrates.9
of the urea reaction component. Solvents that were examined
included chlorinated hydrocarbons such as 1,2-dichloroethane
(DCE) and aromatic hydrocarbons (benzene or toluene).
Although these solvents did not fully solubilize the urea
substrates 2, the reaction was still tenable. Polar aprotic
solvents such as N,N-dimethylformamide (DMF) or N,N-
dimethylacetamide (DMA) were able to fully solubilize ureas
2 but gave poor results in the insertion reaction. To overcome
these solubility issues, it was imperative to use finely
powdered ureas with vigorous stirring of the reaction to
achieve improved yields of product as estimated by TLC.
During the optimization experiments, we also found that the
manner in which the catalyst was added to the reaction was
critical for success. When the catalyst was added in one
portion, several unidentified side products were observed by
TLC. The best procedure involved preparing a fine suspen-
sion of the rhodium octanoate catalyst in toluene using
sonication. This suspension of catalyst was slowly added to
a vigorously stirred, preheated suspension of the primary urea
2 (1.5 equiv) and the R-diazo-â-ketoester 1 over a period of
10 min. Generally, all of the reactions were complete after
an additional 20 min of heating. Although the N-H insertion
product 3 (R1 ) R2 ) Ph) from this reaction could be isolated
and characterized, the best yield obtained was only 34% after
purification by chromatography and recrystallization. We
postulated that the slightly acidic nature of the silica gel may
have been responsible for the conversion of the insertion
product 3 into the imidazolone 4 via acid-catalyzed dehydra-
tion. To verify this, after the insertion reaction had been
allowed to proceed, the solution was cooled to room
temperature before the addition of a 10% volume of TFA.
Gratifyingly, the desired imidazolones 4 were isolated
directly from this two-step, one-pot reaction in excellent
yields. The results from these experiments are presented in
Table 1. The N-H insertion reactions of a methylguanidine
Both our oxazole and indole solid-phase syntheses have
utilized highly reactive polymer-bound rhodium carbenoid
intermediates that are generated by exposure of the corre-
sponding diazocarbonyls with a rhodium carboxylate catalyst.
These reactive intermediates readily insert into the N-H
bond of primary amides10 and also into the N-H bond of
N-alkyl anilines11 to form products that are converted into
the corresponding oxazoles and indoles, respectively. In all
cases, these N-H insertion reactions have proven to be
efficient; hence, we began a program investigating the use
of these insertion reactions with alternative N-H-containing
substrates as a means of creating structurally diverse
compounds. Reported herein are our findings of rhodium
carbenoid N-H insertion reactions of primary ureas.
The imidazolones are 1,3-dinitrogen-containing five-
membered heterocycles that are structurally related to imi-
dazole. Since small heterocycles with similar structures are
known to exhibit a broad range of biological activity,
compounds such as the imidazolones constitute ideal scaf-
folds for combinatorial evaluation.12 With this in mind, we
postulated that the key imidazolone precursors could be
prepared by using an N-H insertion reaction of a primary
urea with a suitably activated diazocarbonyl. The preliminary
N-H insertion and 2-imidazolone formation reactions were
investigated in the solution phase, Scheme 1 and Table 1.
Scheme 1a
Table 1. Solution-Phase Synthesis of Imidazolones 4
a Reaction conditions: (a) Rh2Oct4 (2 mol %), 2 (1.5 equiv),
1:1 toluene/DCE, 80 °C, 30 min. (b) 10% TFA, rt, 30 min.
To optimize the insertion reaction conditions, several
variables were investigated before an acceptable method was
found. The major problem encountered was the solubility
(7) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D. J.
Comb. Chem. In press.
(8) Clapham, B.; Lee, S.-H.; Koch, G.; Zimmermann, J.; Janda, K. D.
Tetrahedron Lett. 2002, 43, 5407.
(9) (a) Savinov, S. N.; Austin, D. J. Org. Lett. 2002, 4, 1419. (b)
Yamazaki, K.; Kondo, Y. Chem. Commun. 2002, 210. (c) Nagashima, T.;
Davies, H. M. L. J. Am. Chem. Soc. 2001, 123, 2695.
(10) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem.
Soc., Perkin Trans. 1 1998, 591.
(11) Bashford, K. E.; Cooper, A. L.; Kane, P. D.; Moody, C. J.;
Muthusamy, S.; Swann, E. J. Chem. Soc., Perkin Trans. 1 2002, 14, 1672.
(12) There is currently one reported example of a solid-phase imidazolone
synthesis: (a) Cheng, J.-F.; Kaito, C.; Chen, M.; Arrhenius, T.; Nadzan,
A. Tetrahedron Lett. 2002, 43, 4571. For the solid-phase synthesis of related
imidazolidones, see: (b) Nefzi, A.; Ostrech, J. M.; Giulanotti, M.; Houghten,
R. A. J. Comb. Chem. 1999, 1, 195. (c) Goff, D.; Tetrahedron Lett. 1998,
39, 1477.
and phenylthiourea were also investigated (Table 1 entries
5 and 6). When the reaction was performed with meth-
ylguanidine, consumption of the starting R-diazo-â-ketoester
512
Org. Lett., Vol. 5, No. 4, 2003

1 was observed; however, no N-H insertion product could
be isolated from the reaction. When phenylthiourea was used,
both starting materials were isolated unchanged even after
heating for extended periods.
On the basis of the successful results in solution, the solid-
phase version of the primary urea insertion reaction was also
investigated, Scheme 2. Here, the hydroxypentyl-JandaJel7,13
exchange resins (amides 9) to remove excess reagents before
being analyzed for purity using HPLC. Finally, each of the
crude products 8 and 9 were further purified using preparative
TLC to give final isolated yields of product based upon the
loading of resin 5.
To investigate the scope of this reaction and establish its
tolerance of different substrates, a pilot library was prepared
using eight R-diazo-â-ketoesters 5 and five ureas 2 (Tables
2 and 3).
Scheme 2a
Table 2. Solid-Phase Synthesis of Imidazolones 8 and 9
(R2 ) Ph)
a Reaction conditions: (a) Rh2Oct4 (2 mol %), 2 (3 equiv), 1:1
toluene/DCE, 80 °C, 30 min. (b) 10% TFA, rt, 30 min. (c) NaOMe
(2.5 equiv), 4:1 THF/MeOH, 50 °C, 1 h. (d) Piperidine (10 equiv),
AlMe3 (5 equiv), toluene, 50 °C, 16 h.
polymer-bound R-diazo-â-ketoester8 5 was allowed to react
with 3 equiv of urea 2 under conditions similar to those
developed in the solution phase. The progress of this reaction
was easily monitored by IR (disappearance of the CdNdN
stretch at ∼2140 cm-1, and the conversion to the desired
urea insertion product was confirmed by the appearance of
urea carbonyl and NH stretches at ∼1650 and 3360 cm-1,
respectively). Treatment of resin-bound insertion product 6
with 10% TFA at room temperature afforded the resin-bound
imidazolone 7 within 1 h, as determined by IR (disappearance
of the NH stretch at ∼3360 cm-1, ketoester absorptions at
∼1740 and ∼1690 cm-1, and urea carbonyl absorptions at
∼1650 cm-1 and the appearance of a strong carbonyl
absorption at ∼1700 cm-1 corresponding to both the R,â-
unsaturated ester and the cyclic urea). The polymer-bound
imidazolones 7 were then cleaved from the resin by trans-
esterification to give esters 8 or by a diversity-building
amidation reaction14 to give amides 9. After cleavage, crude
products 8 and 9 were passed through a filtration cartridge
containing either a strong acid (esters 8) or mixed bed ion-
a Purity of crude product assessed using HPLC (254 nm). b Yield of pure
product after isolation using preparative TLC.
The results presented in Table 2 were obtained using
phenylurea 2 (R2 ) Ph) and various R-diazo-â-ketoesters 5
containing electronically and chemically diverse substituents
(R1). As shown in Table 2, this reaction sequence provided
the desired products in respectable yields and high purity.
The only exception was the product bearing long alkyl R1
substituents (entries 8 and 9), presumably due to the
competing intramolecular C-H insertion as a possible side
reaction.5,15 Data provided in Table 3 was obtained using
electron-rich and electron-deficient aryl, benzyl, and alkyl
primary ureas, and each substrate gave modest to good yields
of product. It is noted that no evidence for the competing
insertion into the secondary urea N-H group was observed.
The final part of this study was the introduction of an
additional substituent onto the aryl imidazolone 10 using a
Suzuki coupling reaction16 (Scheme 3). Here, incubation of
10 with phenyl boronic acid and palladium catalyst followed
(13) JandaJel 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.
(15) C-H insertion reactions of R-diazo-â-ketoesters are documented:
(a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985, 50,
5223. (b) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808.
(14) (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.
Org. Lett., Vol. 5, No. 4, 2003
513

Scheme 3a
Table 3. Solid-Phase Synthesis of Imidazolones 8
(R1 ) 4-CF3Ph)
a Reaction conditions: (a) Phenylboronic acid (10 equiv), K3PO4
(10 equiv), Pd(dppf)Cl2 (20 mol %), dioxane, 90 °C, 24 h. (b)
NaOMe (2.5 equiv), 4:1 THF/MeOH, 50 °C, 1 h.
small array of imidazolones. The chemistry of other polymer-
bound carbonyls and insertion reactions is currently under
further investigation in our laboratory, and these results will
be reported in due course.
a Purity of crude product assessed using HPLC (254 nm). b Yield of pure
product after isolation using preparative TLC.
Acknowledgment. We gratefully acknowledge financial
support from the National Institutes of Health (GM-56154),
The Scripps Research Institute, The Skaggs Institute for
Chemical Biology, and Novartis Pharma AG, Basel, Swit-
zerland. We also thank Dr. Carsten Spanka (Novartis Pharma
AG) for helpful discussions. S.-H.L. acknowledges the Korea
Science and Engineering Foundation (KOSEF) for a post-
doctoral fellowship.
by transesterification cleavage gave the crude imidazolone
11 in 92% purity and in 33% yield after purification by
preparative TLC.
In summary, we have developed a highly efficient two-
step, one-pot procedure for the synthesis of imidazolones in
solution. The first step involves a novel N-H insertion
reaction of a primary urea into an R-diazo-â-ketoester-
derived rhodium carbenoid. This insertion product rapidly
ring closes to form the desired imidazolone product by brief
treatment with acid. This chemistry readily translates onto
insoluble polymer resins and has been utilized to prepare a
Supporting Information Available: Representative pro-
cedures and spectral characterization of all compounds and
intermediates. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Wu, T. Y. H.; Ding, S.; Gray, N. S.; Schultz, P. G. Org. Lett. 2001,
3, 3827.
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