1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-mediated oxazole rearrangement: Gaining access to a unique marine alkaloid scaffold

Article abstract of DOI:10.1021/jo900264p

Reactions that create a quaternary stereocenter offer a wealth of synthetic utility and are often needed to provide access to the structural diversity of stereocenters found in natural products and biologically important molecules. We have developed a new l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)-mediated oxazole rearrangement that affords quaternary 5,5-(aryl, allyl)-substituted hydantoins found in many biologically significant compounds. Furthermore, these quaternary hydantoins can be chemically manipulated to yield the corresponding quaternary imidazolones, which is a unique scaffold found in a compound from the tunicate Dendrodoa grossularia. Herein, we report the scope of this novel rearrangement and the proposed mechanism and showcase its utility through the total synthesis of a marine alkaloid from D. grossularia and two analogues.

Full text of DOI:10.1021/jo900264p

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
Hydrochloride-Mediated Oxazole Rearrangement: Gaining Access to
a Unique Marine Alkaloid Scaffold
Christopher D. Hupp and Jetze J. Tepe*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
tepe@chemistry.msu.edu
ReceiVed February 10, 2009
Reactions that create a quaternary stereocenter offer a wealth of synthetic utility and are often needed to
provide access to the structural diversity of stereocenters found in natural products and biologically
important molecules. We have developed a new 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDCI)-mediated oxazole rearrangement that affords quaternary 5,5-(aryl, allyl)-substituted
hydantoins found in many biologically significant compounds. Furthermore, these quaternary hydantoins
can be chemically manipulated to yield the corresponding quaternary imidazolones, which is a unique
scaffold found in a compound from the tunicate Dendrodoa grossularia. Herein, we report the scope of
this novel rearrangement and the proposed mechanism and showcase its utility through the total synthesis
of a marine alkaloid from D. grossularia and two analogues.
Introduction
quaternary hydantoin scaffold is found in herbicides, such as
hydantocidin14 (Figure 1), anticonvulsant drugs, such as 5,5-
diphenylhydantoin10 (Figure 1), and other pharmacologically
significant compounds.7,12 The imidazolone and quaternary
imidazolone scaffold are found in a variety of natural products
that also host interesting biological properties, such as leucet-
tamine B, leucettamidine, hymenialdisine, and kottamides A-D,
which exhibit anti-inflammatory activity.1-3,5,6 Additional ex-
amples include some of the dispacamides, mauritiamine, and a
few of the rhopaladins which display potent antihistamine,
antifouling, and antibacterial activity, respectively.4,13,15,16 Still
there are others including calcaridine A,9 polyandrocarpamines
A and B,8 and a unique indole marine alkaloid (1; Figure 1)
from the tunicate Dendrodoa grossularia11 whose biological
activity has not yet been reported.
Quaternary hydantoins and imidazol-4-ones are synthetically
intriguing and are contained in myriad compounds.1-16 The
(1) Appleton, D. R.; Page, M. J.; Lambert, G.; Berridge, M. V.; Copp, B. R.
J. Org. Chem. 2002, 67, 5402–5404.
(2) Badger, A. M.; Cook, M. N.; Swift, B. A.; Newman-Tarr, T. M.; Gowen,
M.; Lark, M. J. Pharmacol. Exp. Ther. 1999, 290, 587–593.
(3) Breton, J. J.; Chabot-Fletcher, M. C. J. Pharmacol. Exp. Ther. 1997,
282, 459–466.
(4) Cafieri, F.; Gattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Tetrahedron
Lett. 1996, 37, 3587–3590.
(5) Chan, G. W.; Mong, S.; Hemling, M. E.; Freyer, A. J.; Offen, P. H.;
DeBrosse, C. W.; Sarau, H. M.; Westley, J. W. J. Nat. Prod. 1993, 56, 116–
121.
(6) Cimino, G.; De Rosa, S.; De Stefano, S.; Mazzarella, L.; Puliti, R.;
Sodano, G. Tetrahedron Lett. 1982, 23, 767–768.
(7) Colacino, E.; Lamaty, F.; Martinez, J.; Parrot, I. Tetrahedron Lett. 2007,
48, 5317–5320.
(8) Davis, R. A.; Aalbersberg, W.; Meo, S.; Moreira da Rocha, R.; Ireland,
C. M. Tetrahedron 2002, 58, 3263–3269.
(9) Edrada, R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod. 2003, 66, 939–
942.
(10) Kruger, H. G.; Mdluli, P. S. Struct. Chem. 2006, 17, 121–125.
(11) Loukaci, A.; Guyot, M.; Chiaroni, A.; Riche, C. J. Nat. Prod. 1998,
61, 519–522.
Prompted by the potent biological activity of the hymenial-
disine analogue, indoloazepine17,18 (Figure 1), we were inter-
ested in synthesizing indole alkaloid 1. However, a synthetic
route needed to be constructed to access the unique 5,5-
(14) Shiozaki, M. Carbohydr. Res. 2002, 337, 2077–2088.
(15) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Nat. Prod. 1996,
59, 501–503.
(12) Meusel, M.; Guetschow, M. Org. Prep. Proced. Int. 2004, 36, 391–
443.
(13) Sato, H.; Tsuda, M.; Watanabe, K.; Kobayashi, J. I. Tetrahedron 1998,
54, 8687–8690.
(16) Vergne, C.; Appenzeller, J.; Ratinaud, C.; Martin, M.-T.; Debitus, C.;
Zaparucha, A.; Al-Mourabit, A. Org. Lett. 2008, 10, 493–496.
3406 J. Org. Chem. 2009, 74, 3406–3413
10.1021/jo900264p CCC: $40.75 2009 American Chemical Society
Published on Web 03/30/2009

EDCI-Mediated Oxazole Rearrangement
FIGURE 1. Compounds containing the imidazolone or hydantoin scaffold (np ) natural product).
SCHEME 1. New Rearrangement Leading to the Synthesis of Indole Alkaloid (1)
(disubstituted)-imidazol-4-one scaffold found in the natural
product. A 5,5-(aryl, allyl)-substituted hydantoin derived from
an oxazole rearrangement, modeled after the rearrangement
developed by Steglich and co-workers,19 was thought to be a
novel and ideal approach to access the indole alkaloid 1. The
hydantoin intermediate could serve as a building block to the
imidazolone scaffold20,21 and act as a synthetic handle with
which we could replace the carbonyl in the 2-position of the
hydantoin with potentially any amine, giving access to a number
of analogues if desired. In addition, the allyl group would
provide easy access to the keto functionality found in the indole
alkaloid (1).
Overall, a novel rearrangement (Scheme 1) that gives access
to a unique marine alkaloid scaffold was developed. The one-
pot reaction converts a thiourea into a 5,5-(aryl, allyl)-oxazolone
through a new twist on the oxazole rearrangement, which upon
further treatment with sodium methoxide yields a 5,5-(aryl,
allyl)-hydantoin. As a result, this hydantoin is able to offer a
concise synthetic route to molecules such as indole alkaloid 1.
This article describes the scope and proposed mechanism of
this novel rearrangement in addition to its utility in the synthesis
of a natural product and analogues from the tunicate D.
grossularia.
were screened, and it was found that the success of the reaction
was highly dependent on the reagent choice. Mercuric chloride
did provide a reasonable yield of the quaternary hydantoin
(49%), while Mukaiyama’s reagent failed to produce any desired
hydantoin. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hy-
drochloride (EDCI) was the most effective at yielding the
quaternary hydantoin in good yields (70%). Furthermore, the
hazard of mercury waste removal and the ease of workup with
EDCI solidified the reason to use EDCI as the reactant for the
rest of the study. A more cost efficient carbodiimide, dicyclo-
hexylcarbodiimide (DCC), was also attempted in the rearrange-
ment but failed to provide any reasonable yields (<5%).
Polymer-supported EDCI provided the desired product, although
longer reaction times were necessary. A brief solvent screen
revealed that dichloromethane (DCM) provided the best results
(70%), while solvents such as acetonitrile, benzene, tetrahy-
drofuran, and dichloroethane all yielded poorer results (50%,
30%, 47%, and 12%, respectively).
The first structural aspect investigated in the rearrangement
was the different groups compatible at the R position (Scheme
1). Each of the different thiourea starting materials was
synthesized through standard amino acid chemistry (Scheme
2). The N-Boc protected amino acids 2a-f (R ) methyl, benzyl,
phenyl, pOMe-phenyl, pF-phenyl, and napthyl) were esterified
with the appropriate allylic alcohol using DCC to produce esters
3a-g. Deprotection of the Boc group with a mixture of TFA
and DCM (1:1) led to the TFA salt of the amino allylic esters
4a-g. Upon treatment of the amine salts with ethyl isothiocy-
anatoformate under basic conditions, the desired thioureas 5a-g
were produced. The synthesis of thiourea 5h (R ) N-tosyl
indole; Table 1) followed a modified synthetic pathway and was
Results and Discussion
I. Scope of Rearrangement. Traditional reagents used for
the activation of a thiourea toward attack by a nucleophile22-26
(17) Sharma, V.; Lansdell, T. A.; Jin, G.; Tepe, J. J. J. Med. Chem. 2004,
47, 3700–3703.
(18) Sharma, V.; Tepe, J. J. Bioorg. Med. Chem. Lett. 2004, 14, 4319–4321.
(19) Kubel, B.; Hofle, G.; Steglich, W. Angew. Chem., Int. Ed. 1975, 14,
58–59.
(20) Gadwood, R. C.; Kamdar, B. V.; Dubray, L. A. C.; Wolfe, M. L.; Smith,
M. P.; Watt, W.; Mizsak, S. A.; Groppi, V. E. J. Med. Chem. 1993, 36, 1480–
1407.
(21) Kiec-Kononowicz, K.; Zejc, A. Pol. J. Chem. 1980, 54, 2217–2224.
(22) Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996, 37,
8711–8714.
(23) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677–7680.
(24) Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem.
2000, 65, 1566–1568.
(25) Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841–2844.
(26) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977, 575–
576.
J. Org. Chem. Vol. 74, No. 9, 2009 3407

Hupp and Tepe
TABLE 2. Rearrangement Containing Differently Substituted
Allyl Groups
SCHEME 2. General Synthesis of Thioureas 5a-g; 10a,b
TABLE 1. Rearrangement Containing Various R Groups
entry
R
yield (%)
5a
5b
5c
5d
5e
5f
Me
Bn
Ph
p-OmePh
p-F-Ph
0
19
70
67
57
31
70
napth
N-tosyl indole
5h
of the amines with ethyl isothiocyanatoformate, the correspond-
ing thioureas 10a,b were formed in moderate yields.
The rearrangement proceeded in good yields with all of the
differently substituted allylic esters that were synthesized (Table
2). When the 1,1-disubstituted allyl group was used (entry 5g)
the rearrangement gave a similar yield of corresponding
quaternary hydantoin as the allyl group (entry 5c). With the
success of this particular rearrangement, application of the new
reaction could be used in the synthesis of the natural product
(1). Entry 10a, which contained a 1,1,2-trisubstitution pattern
on the allylic group, was also as successful as the other entries.
However, unlike the previous two quaternary hydantoins 6c and
6g, the product from the rearrangement (11a) contained two
stereocenters allowing for the formation of diastereomers. It was
observed by 1H NMR and 13C NMR that two inseparable
diastereomers were formed from the reaction in about a 1:1.3
ratio. The last entry in Table 2 includes an allyl moiety
containing a 1,2,2-trisubstitution pattern (10b). It is hypothesized
that the lower yield resulting from this rearrangement could be
attributed to the steric bulk of this particular trisubstituted allyl
group. An electron withdrawing group (ethyl carbamate) on the
thiourea was only used since it was previously found that
electron withdrawing groups accelerate the reaction of a thiourea
and desulfurizing reagent and increase the reactivity of the
corresponding carbodiimide toward a nucleophile.29
prepared following the procedures of Katz and co-workers (see
Supporting Information).27
The results of the rearrangement with the various R groups
are illustrated in Table 1. It is shown that an alkyl group such
as a methyl provided no product, while a benzyl only performed
slightly better by producing the quaternary hydantoin 6b in low
yields (19%). When R ) aryl (5c-5f), the rearrangement
occurred in good yields (Table 1) except for when R ) napthyl,
which could be attributed to the steric bulk of the napthyl group.
The rearrangement was also successful in using a heterocycle
in the R position with the N-tosyl indole thiourea 5h, providing
the corresponding hydantoin 6h in good yields.
Different allyl groups compatible with the rearrangement were
subsequently examined. The synthesis of the thiourea with a
1,1-disubstituted allylic moiety (5g) followed the synthetic route
outlined in Scheme 2 (when R′′ ) Boc). However, when
trisubstituted allylic thioureas were synthesized using the
corresponding trisubstituted allylic alcohols, a different route
was adopted. It was found that the higher substituted allylic
esters would decompose to the corresponding carboxylic acids
when treated with TFA during the deprotection of the Boc
group.28 As a result, the Fmoc protecting group was used for
the synthesis of thioureas 10a,b (Scheme 2). Using Fmoc
protected phenyl glycine as the starting material, allylic esters
8a,b were produced under the same conditions previously
described using DCC and 4-(dimethylamino)pyridine (DMAP).
Deprotection of the Fmoc group from the amine was completed
using piperidine to afford the free amines 9a,b. Upon treatment
II. Proposed Reaction Mechanism. The proposed mecha-
nism is illustrated below in Scheme 3. The first step is thought to
be the transformation of the starting thiourea to a carbodiimide
intermediate (12). Although this intermediate has not been isolated
or observed experimentally, it is presumed to be formed based on
previous studies.29 Several reports suggest that thioureas undergo
a desulfurization with reagents such as EDCI, HgCl2, Mukaiyama’s
(27) Katz, A. H.; Demerson, C. A.; Shaw, C. C.; Asselin, A. A.; Humber,
L. G.; Conway, K. M.; Gavin, G.; Guinosso, C.; Jensen, N. P. J. Med. Chem.
1988, 31, 1244–1250.
(28) Nishizawa, M.; Yamamoto, H.; Seo, K.; Imagawa, H.; Sugihara, T. Org.
Lett. 2002, 4, 1947–1949.
(29) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC (GainesVille, FL, U.S.)
2005, 49–87.
3408 J. Org. Chem. Vol. 74, No. 9, 2009

EDCI-Mediated Oxazole Rearrangement
SCHEME 3. Proposed Reaction Mechanism of EDCI-Mediated Rearrangement
reagent, and others to afford a carbodiimide intermediate.29-31
Subsequently, the transient carbodiimide could be attacked by an
external nucleophile, such as an amine, to produce guanidines with
various substitutions.22-25,29,31-35 Furthermore, cyclizations to
form different heterocycles have also been shown to occur
through an attack of a nucleophile on a carbodiimide formed
from the desulfurization of a thiourea. Batey and Evindar
produced various iminohydantoins through a cyclization that
occurred after a carbodiimide intermediate, formed using HgCl2,
was attacked by an internal amide.36 Additionally, Drewry and
Ghiron utilized a desulfurization of a thiourea with Mukaiyama’s
reagent to form 2-aminoimidazolinones.30 It was suggested that
when the thiourea was treated with Mukaiyama’s reagent, a
carbodiimide intermediate was formed and reacted with an
external amine, resulting in a cyclization to yield an aminoimi-
dazolinone.30 These examples serve as supportive evidence to
reasonably conclude that the initial step in the rearrangement
involves the formation of a carbodiimide intermediate. The
carbodiimide is believed to be very reactive, thus giving reason
for a short lifespan and consequently being unobservable
spectroscopically. As a consequence of the carbodiimide’s high
reactivity, the carbonyl of the ester is believed to be nucleophilic
enough to attack the carbodiimide, in a similar fashion as the
amide in the report by Batey and Evindar,36 to cause a
cyclization reaction affording an oxazole intermediate (13;
Scheme 3).
16. Further modification of 16 by sodium methoxide yields the
final quaternary hydantoin upon removal of the ethoxy carbonyl
group (Scheme 3).
The step in which the quaternary stereocenter was formed
illustrates an oxazole rearrangement first described by Steglich and
co-workers, in which an allyl ester of an N-acyl amino acid is
converted into an oxazolone using a variety of dehydrating
reagents.19,37 Steglich discusses an additional hetero-Cope rear-
rangement that occurs depending on the substitution of the allyl
ester.19,37 It is noteworthy to mention that this additional hetero-
Cope rearrangement was not observed in our rearrangement.
Steglich’s oxazole rearrangement is a useful tool to create a
quaternary stereocenter and has been used to produce 4-fluo-
ropyridines,38 a variety of R-trifluoromethyl R-amino acids,39-41
R-allenic R-amino acids,42,43 R-benzyl γ-lactam derivatives,44
R-benzyl δ-lactam derivatives,44 R-benzylproline derivatives,44
C-glycosyl R-amino acids,45 and R-D-C-mannosyl-(R)-alanine.46
Despite the many accounts to use this rearrangement to afford
various substrates including precursors to 1, the main disad-
vantage was the inability to remove the N-acyl group without
using harsh basic or acidic conditions. This disadvantage was
the driving force to create a new rearrangement in which the
product could be more amenable toward synthesizing the natural
product (1).
III. Application toward Syntheses of Indole Alkaloid 1
and Analogues. The EDCI-mediated oxazole rearrangement
offers a unique and efficient way to create a quaternary
heterocycle capable of being transformed into the scaffold
needed for the synthesis of the indole alkaloid (1). The natural
After oxazole 13 undergoes a Claisen rearrangement, ox-
azolone intermediate 14 is formed (Scheme 3), which was
isolated and characterized (when R ) N-tosyl indole) using 1H
NMR, 13C NMR, HRMS, and IR (see Supporting Information).
It is proposed that, from oxazolone 14, the mechanism of the
novel rearrangement continues with the nucleophilic opening
of the oxazolone by sodium methoxide to yield urea 15. As a
consequence of having excess sodium methoxide in the reaction
mixture, urea 15 is deprotonated and cyclizes to form hydantoin
(37) Engel, N.; Kubel, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1977,
16, 394–396.
(38) Wittmann, U.; Tranel, F.; Froehlich, R.; Haufe, G. Synthesis 2006, 2085–
2096.
(39) Burger, K.; Geith, K.; Gaa, K. Angew. Chem., Int. Ed. Engl. 1988, 27,
848–849.
(40) Burger, K.; Hennig, L.; Tsouker, P.; Spengler, J.; Albericio, F.; Koksch,
B. Amino Acids 2006, 31, 427–433.
(41) Burger, K.; Hennig, L.; Tsouker, P.; Spengler, J.; Albericio, F.; Koksch,
B. Amino Acids 2006, 31, 55–62.
(42) Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.; Krantz, A.
Tetrahedron 1988, 44, 5451–5466.
(43) Castelhano, A. L.; Pliura, D. H.; Taylor, G. J.; Hsieh, K. C.; Krantz, A.
J. Am. Chem. Soc. 1984, 106, 2734–2735.
(44) Holladay, M. W.; Nadzan, A. M. J. Org. Chem. 1991, 56, 3900–3905.
(45) Colombo, L.; Casiraghi, G.; Pittalis, A. J. Org. Chem. 1991, 56, 3897–
3900.
(30) Drewry, D. H.; Ghiron, C. Tetrahedron Lett. 2000, 41, 6989–6992.
(31) Martin, N. I.; Woodward, J. J.; Marletta, M. A. Org. Lett. 2006, 8, 4035–
4038.
(32) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997, 53, 5291–
5304.
(33) Manimala, J. C.; Anslyn, E. V. Tetrahedron Lett. 2002, 43, 565–567.
(34) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62,
1540–1542.
(35) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem. 2002, 67, 3138–
3141.
(46) Colombo, L.; di Giacomo, M.; Ciceri, P. Tetrahedron 2002, 58, 9381–
9386.
(36) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 1201–1204.
J. Org. Chem. Vol. 74, No. 9, 2009 3409

Hupp and Tepe
SCHEME 4. Retrosynthetic Strategy for the Synthesis of 1 and Analogues 25 and 29
SCHEME 5. Synthesis of Thiourea 22
product was isolated in 199811 and comes from the tunicate D.
grossularia, which is a red marine organism that grows along
the coasts of Brittany and in the Baltic and North Seas and
contains small heterocyclic alkaloids with unique scaffolds.47-52
Initial studies on the extracts of this tunicate unveiled definite
cytotoxic activity toward the L1210 leukemia cell line. As a
result, four indole alkaloids were isolated and tested, all with
variable results.52,53 As part of our laboratory’s focus on the
syntheses of pharmacologically significant scaffolds,54 we
recently reported the first total synthesis of the indole alkaloid
(1).55 Two additional analogues have since been synthesized
and are reported herein.
Our retrosynthetic strategy for the total synthesis of indole
alkaloid 1 and two analogues is illustrated in Scheme 4. It was
envisioned that the imidazolone moiety of the indole alkaloid
and analogue 2 (29) could be accessed from the hydantoin
intermediate 23 utilizing classical chemical modifications.20,21
After exploration of the new oxazole rearrangement, hydantoin
23 was thought to be formed from thiourea 22 using the protocol
developed for the transformation. Analogue 1 (25) was also
envisioned to be formed from thiourea 22 by slightly modifying
the rearrangement to include a removal of the tosyl protecting
group.
The synthetic route to thiourea 22 began with an esterification
of the indole acid chloride 17, which is the product of a known
reaction between indole and oxalyl chloride56,57 with 2-methyl-
2-propen-1-ol to produce keto allyl ester 18 (Scheme 5).
Subsequent protection of the indolic nitrogen with p-toluene
sulfonyl chloride afforded keto ester 19, which, when treated
with hydroxylamine and pyridine in dioxane, produced oxime
20 in a 96% yield as a mixture of E and Z isomers. Reduction
of the oxime using zinc and acetic acid led to amine 21, which
was treated with ethyl isothiocyanatoformate to yield thiourea
22.
Subsequent treatment of thiourea 22 with EDCI followed by
sodium methoxide yielded hydantoin 23 (Scheme 6) in a 71%
yield, resulting from the oxazole rearrangement. The synthesis
of indole alkaloid 1 was completed following the previously
described pathway.55 The versatility of the synthetic pathway
developed for the natural product was illustrated in the synthesis
of two analogues that required no major modification of the
original synthetic route. Hypothetically, a number of analogues
could be developed with the synthetic route as a result of the
diversity allowed in the rearrangement and the variety of amines
that could be used to create the final imidazolone.
(47) Bergmann, T.; Schories, D.; Steffan, B. Tetrahedron 1997, 53, 2055–
2060.
(48) Guyot, M.; Meyer, M. Tetrahedron Lett. 1986, 27, 2621–2622.
(49) Heitz, S.; Durgeat, M.; Guyot, M.; Brassy, C.; Bachet, B. Tetrahedron
Lett. 1980, 21, 1457–1458.
(50) Loukaci, A.; Guyot, M. Magn. Reson. Chem. 1996, 34, 143–145.
(51) Moquin, C.; Guyot, M. Tetrahedron Lett. 1984, 25, 5047–5048.
(52) Moquin-Pattey, C.; Guyot, M. Tetrahedron 1989, 45, 3445–3450.
(53) Helbecque, N.; Moquin, C.; Bernier, J. L.; Morel, E.; Guyot, M.;
Henichart, J. P. Cancer Biochem. Biophys. 1987, 9, 271–279.
(54) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36, 1432–
1440.
The first analogue, hydantoin 25, shown in Scheme 6, was
synthesized using the same thiourea 22 used to produce the
(56) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124,
13179–13184.
(57) Kharasch, M. S.; Kane, S. S.; Brown, H. C. J. Am. Chem. Soc. 1940,
62, 2242–2243.
(55) Hupp, C. D.; Tepe, J. J. Org. Lett. 2008, 10, 3737–3739.
3410 J. Org. Chem. Vol. 74, No. 9, 2009

EDCI-Mediated Oxazole Rearrangement
SCHEME 6. Synthesis of Indole Alkaloid 1 and Analogues 25 and 29
mL), dried using anhydrous sodium sulfate, and concentrated. The
crude residue was purified by column chromatography (silica gel,
20% EtOAc; 80% hexane) affording the product (3c) as a whitish
solid. Yield (1.49 g, 86%). 1H NMR (500 MHz), CDCl3: δ 1.41 (s,
9H), 4.58-4.6 (m, 2H), 5.12-5.17 (m, 2H), 5.32 (d, J ) 8 Hz,
1H), 5.56 (bs, 1H), 5.75-5.83 (m, 1H), 7.26-7.36 (m, 5H). 13C
NMR (125 MHz), CDCl3: δ 28.2, 57.6, 65.9, 80.0, 118.3, 127,
natural product. Instead of carefully monitoring the second step
of the rearrangement to avoid removal of the tosyl protecting
group, a mixture of potassium ethoxide and ethanol was used
and refluxed overnight to yield hydantoin 24. Using the same
procedure as the natural product synthesis, the terminal olefin
on hydantoin 24 was oxidized to the ketone in a 61% yield
affording hydantoin 25 (analogue 1).
128.3, 128.7, 131.3, 136.8, 154.7, 170.7. IR (NaCl): 3390 cm-1
,
The second analogue also shown in Scheme 6, imidazolone
29, took advantage of the synthetic handle that S-methylimi-
dazolone 26 provided because of its reactivity and tendency to
be substituted with a nucleophile. In this instance, the S-methyl
group was replaced using ammonium hydroxide to give imi-
dazolone 27 in a good yield. The deprotection method previously
seen with the natural product synthesis was used to afford
imidazolone 28. Finally, the synthesis of analogue 2 (29) was
completed after the terminal alkene of 28 was oxidized under
previously determined conditions. Unfortunately, because of the
difficult nature of isolating the product, only 19% of imidazolone
29 was recovered, although the overall conversion was higher.
In summary, we have developed a new EDCI-mediated
oxazole rearrangement that yields a quaternary hydantoin as the
final product. The rearrangement tolerates different aryl groups
R to the ester of the thiourea and differently substituted allyl
esters. The utility of the rearrangement allows us to gain access
to a unique imidazolone scaffold found in nature, whose
structure has only begun to be explored. Biological evaluation
of the indole alkaloid (1) and analogues (25 and 29) is currently
underway in our laboratory.
1750 cm-1, 1710 cm-1. HRMS: [M + H]+ ) 292.1559, calcd for
C16H22NO4, 292.1549. Anal. Calcd for C16H21NO4: C, 65.96; H,
7.27; N, 4.81. Found: C, 66.78; H, 7.14; N, 4.78. Mp: 40-42 °C.
Representative Example for the Preparation of Amine-TFA
(4a-g). To a 100 mL round-bottom flask were added 3c (1.44 g,
4.95 mmol), DCM (2.5 mL), and TFA (2.5 mL). The resulting
solution was stirred for 30 min. The excess TFA and DCM were
removed, and CHCl3 (3 × 15 mL) was added and subsequently
taken off to remove any residual TFA. The product was precipitated
out of the crude residue using ether/petroleum ether to afford the
product (4c) as a white solid. Yield (1.48 g, 98%).1H NMR (500
MHz), DMSO: δ 4.66 (m, 2H), 5.12-5.16 (m, 2H), 5.33 (s, 1H),
5.8 (m, 1H), 7.44-7.5 (m, 5H), 9.07 (bs, 3H). 13C NMR (125 MHz),
DMSO: δ 55.4, 66.0, 113.6, 115.9, 118.1, 118.3, 120.7, 128.1,
129.0, 129.5, 131.5, 132.6, 157.9, 158.2, 158.4, 158.7, 168.1. IR
(KBr): 3150 (br) cm-1, 1745 cm-1, 1675 cm-1. HRMS: [M + H]+
) 192.1027, calcd for C11H14NO2, 192.1025. Anal. Calcd for
C13H14F3NO4: C, 51.15; H, 4.62; N, 4.59. Found: C, 50.95; H, 4.51;
N, 4.45. Mp ) 96-98 °C.
Representative Example for the Preparation of Thioureas
(5a-g). To a flame-dried 100 mL round-bottom flask were added
4c (1.48 g, 4.85 mmol) and anhydrous DCM (50 mL). Then the
solution was brought down to 0 °C, and anhydrous tetraethylam-
monium (TEA; 0.74 mL, 5.33 mmol) was added followed by
dropwise addition of ethoxycarbonyl isothiocyanate (0.66 mL, 5.82
mmol). The solution was allowed to warm to room temperature
overnight while stirring under a nitrogen atmosphere. The solvent
was removed, and ether (30 mL) was added to the crude residue
and was washed with saturated sodium bicarbonate. The organics
were dried using anhydrous sodium sulfate and concentrated. The
crude residue was purified by column chromatography (silica gel,
30% EtOAc; 70% hexane) affording the product (5c) as a whitish
solid. Yield (1.39 g, 89%). 1H NMR (500 MHz), CDCl3: δ 1.29 (t,
J ) 7 Hz, 3H), 4.23 (m, 2H), 4.64 (m, 2H), 5.14-5.22 (m, 2H),
Experimental Section
Representative Example for the Preparation of N-Boc Pro-
tected Amino Esters (3a-g). To a flame-dried 100 mL round-
bottom flask were added 2c (1.5 g, 5.97 mmol) and anhydrous DCM
(50 mL). Then allyl alcohol (0.82 mL, 11.95 mmol) and DMAP
(73 mg, 0.597 mmol) were added, and the mixture was brought
down to 0 °C. DCC (1.85 g, 8.96 mmol) was then added, and the
mixture was allowed to warm to room temperature overnight while
stirring under nitrogen. The white precipitate that formed was
filtered off, and the DCM filtrate was washed with brine (1 × 20
J. Org. Chem. Vol. 74, No. 9, 2009 3411

Hupp and Tepe
5.81 (m, 1H), 5.98 (d, J ) 7 Hz, 1H), 7.3-7.45 (m, 5H), 8.06 (s,
1H), 10.59 (d, J ) 6 Hz, 1H). 13C NMR (125 MHz), CDCl3: δ
14.0, 61.8, 62.8, 66.2, 118.5, 127.5, 128.7, 128.9, 131.1, 135.0,
(9a) as an oil. Yield (434 mg, 90%).1H NMR (500 MHz), CDCl3:
δ 1.77-1.83 (m, 2H), 1.91 (s, 2H), 2.1-2.15 (m, 2H), 2.22-2.28
(m, 2H), 4.59 (s, 1H), 4.63 (m, 2H), 5.49 (m, 1H), 7.24-7.37 (m,
5H). 13C NMR (125 MHz), CDCl3: δ 23.4, 32.5, 32.9, 59.0, 64.1,
152.5, 169.3, 178.9. IR (KBr): 3290 cm-1, 3225 cm-1, 1750 cm-1
,
1720 cm-1. HRMS: [M + H]+ ) 323.1070, calcd for C15H19N2O4S,
323.1066. Anal. Calcd for C15H18N2O4S: C, 55.88; H, 5.63; N, 8.69.
Found: C, 55.46; H, 5.51; N, 8.68. Mp ) 44-46 °C.
127.0, 128.1, 128.9, 138.8, 140.6, 174.0. IR (KBr): 3385 (br) cm-1
,
3321 cm-1, 1733 cm-1. HRMS: [M + H]+ ) 232.1341, calcd for
C14H18NO2, 232.1338. Anal. Calcd for C14H17NO2: C, 72.70; H,
7.41; N, 6.06. Found: C, 72.05; H, 7.30; N, 6.09.
Representative Example for the Procedure of the Rearrange-
ment Affording Hydantoins (6a-h, 11a,b). To a flame-dried 50
mL round-bottom flask were added 5c (150 mg, 0.466 mmol) and
anhydrous DCM (15 mL). Then anhydrous TEA (0.2 mL, 1.4
mmol) was added, and the mixture was cooled to 0 °C. EDCI (197
mg, 1.02 mmol) was then added, and the mixture was stirred at 0
°C under nitrogen for 1 h and then refluxed for 15 h. After the first
step was completed (as indicated by TLC), the solution was cooled
to 0 °C, and a solution of NaH (93 mg, 2.33 mmol) in MeOH (5
mL) was added dropwise. The cloudy mixture was stirred at 0 °C
for 1 h and then at room temperature for 2 h. The mixture was
acidified with 5% HCl, and then the solvents were removed. The
aqueous mixture was extracted with EtOAc (3 × 30 mL), and then
the organics were combined, dried using anhydrous sodium sulfate,
and concentrated. The crude residue was purified by column
chromatography (silica gel, 20% EtOAc; 80% DCM) affording the
product (6c) as a whitish solid. Yield (70 mg, 70%). 1H NMR (500
MHz), acetone: δ 2.78 (dd, J ) 7, 14 Hz, 1H), 2.95 (dd, J ) 7, 14
Hz, 1H), 5.13 (d, J ) 10 Hz, 1H), 5.21 (d, J ) 17 Hz, 1H), 5.73
(m, 1H), 7.33 (t, J ) 8 Hz, 1H), 7.4 (t, J ) 8 Hz, 2H), 7.64 (d, J
) 8 Hz, 2H), 7.68 (s, 1H), 9.65 (s, 1H). 13C NMR (125 MHz),
acetone: δ 43.5, 68.6, 120.8, 126.3, 128.7, 129.3, 132.0, 139.7,
Representative Example for the Preparation of Thioureas
(10a,b). To a flame-dried 100 mL round-bottom flask were added
9a (406 mg, 1.76 mmol) and anhydrous DCM (50 mL). Then the
solution was brought down to 0 °C, and ethoxycarbonyl isothio-
cyanate (0.24 mL, 2.11 mmol) was added dropwise. The solution
was allowed to warm to room temperature overnight while stirring
under a nitrogen atmosphere. The solvent was removed, and ether
(30 mL) was added to the crude residue and was washed with
saturated sodium bicarbonate. The organics were dried using
anhydrous sodium sulfate and concentrated. The crude residue was
purified by column chromatography (silica gel, 20% EtOAc; 80%
hexane), and the product was recrystallized with EtOAc/hexanes
1
affording 10a as a white solid. Yield (518 mg, 81%). H NMR
(500 MHz), CDCl3: δ 1.29 (t, J ) 7 Hz, 3H), 1.81 (m, 2H), 2.13
(m, 2H), 2.26 (m, 2H), 4.23 (m, 2H), 4.69 (s, 2H), 5.53 (s, 1H),
5.97 (d, J ) 7 Hz, 1H), 7.3-7.42 (m, 5H), 8.08 (s, 1H), 10.62 (d,
J ) 6 Hz, 1H). 13C NMR (125 MHz), CDCl3: δ 14.1, 23.1, 32.3,
32.5, 61.8, 62.8, 64.5, 127.5, 128.7, 128.9, 129.1, 135.2, 138.1,
152.5, 169.4, 178.8. IR (KBr): 3289 cm-1, 3226 cm-1, 1743 cm-1
,
1724 cm-1. HRMS: [M + H]+ ) 363.1387, calcd for C18H23N2O4S,
363.1379. Anal. Calcd for C18H22N2O4S: C, 59.65; H, 6.12; N, 7.73.
Found: C, 59.36; H, 5.78; N, 7.69. Mp ) 58-60 °C.
157.0, 175.9. IR (KBr): 3245 cm-1 (broad), 1774 cm-1, 1724 cm-1
.
HRMS: [M + H]+ ) 217.0979, calcd for C12H13N2O2, 217.0977.
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found:
C, 66.43; H, 5.49; N, 12.90. Mp ) 172-174 °C.
Preparation of 5-(1H-Indol-3-yl)-5-(2-methylallyl)imidazoli-
dine-2,4-dione (24). To a flame-dried 250 mL round-bottom flask
were added 22 (1 g, 1.89 mmol), anhydrous DCM (75 mL), and
anhydrous TEA (0.78 mL, 5.67 mmol). The solution was cooled
to 0 °C, and then EDCI (798 mg, 4.16 mmol) was added. The
mixture was stirred at 0 °C for 1 h and then refluxed until
disappearance of the starting material, as indicated on TLC. A
solution of NaH (750 mg, 18.9 mmol) in MeOH (70 mL) was then
added to the mixture and refluxed for 8 h. Since the detosylation
was sluggish with NaOMe, the solvent was removed, and ethanol
(120 mL) was added followed by KOEt (793 mg, 9.45 mmol) and
the mixture refluxed overnight. The solvent was removed, and
residue was acidified using 1% HCl and extracted using EtOAc (3
× 50 mL). The organics were dried using anhydrous sodium sulfate
and concentrated. The crude residue was purified by column
chromatography (silica gel, 20% acetone; 80% DCM) affording
Representative Example for the Preparation of Fmoc Pro-
tected Amino Esters (8a,b). To a flame-dried 100 mL round-
bottom flask were added 7 (1.21 g, 3.24 mmol) and anhydrous DCM
(50 mL). Then cyclopent-1-enylmethanol58 (477 mg, 4.87 mmol)
and DMAP (40 mg, 0.324 mmol) were added, and the mixture was
brought down to 0 °C. DCC (1 g, 4.87 mmol) was then added, and
the mixture was allowed to warm to room temperature overnight
while stirring under nitrogen. The white precipitate that formed
was filtered off, and the DCM filtrate was washed with brine (1 ×
20 mL), dried using anhydrous sodium sulfate, and concentrated.
The crude residue was purified by column chromatography (silica
gel, 20% EtOAc; 80% hexane) affording the product (8a) as a
whitish solid. Yield (997 mg, 68%). 1H NMR (500 MHz), CDCl3:
δ 1.82 (p, J ) 8 Hz, 2H), 2.13 (s, 2H), 2.27 (s, 2H), 4.2 (t, J ) 7
Hz, 1H), 4.38 (m, 2H), 4.70 (m, 2H), 5.40 (d, J ) 7 Hz, 1H), 5.52
(s, 1H), 5.89 (d, J ) 7 Hz, 1H), 7.28-7.4 (m, 9H), 7.57 (d, J ) 7
Hz, 2H), 7.74 (d, J ) 8 Hz, 2H). 13C NMR (125 MHz), CDCl3: δ
23.1, 32.3, 32.5, 47.1, 58.0, 64.4, 67.1, 119.9, 125.0, 127.0, 127.1,
127.6, 128.5, 128.8, 129.1, 136.6, 138.1, 141.2, 143.7, 143.8, 155.3,
170.6. IR (NaCl): 3350 cm-1, 1725 cm-1 (broad). HRMS: [M +
H]+ ) 454.2020, calcd for C29H28NO4, 454.2018. Anal. Calcd for
C29H27NO4: C, 76.80; H, 6.00; N, 3.09. Found: C, 76.97; H, 5.84;
N, 3.12. Mp ) 96-98 °C.
Representative Example for the Preparation of Amino
Esters (9a,b). To a 100 mL round-bottom flask were added 8a
(947 mg, 2.09 mmol) and DCM (8 mL). The solution was brought
down to 0 °C, and then piperidine (2 mL, 20.9 mmol) was added;
the mixture was stirred under nitrogen for 1 h and then 1 h at room
temperature. The solvent was then removed, and the crude residue
was taken up in EtOAc (40 mL) and washed with saturated NH4Cl
(1 × 10 mL) and brine (1 × 10 mL). The organics were dried
using anhydrous sodium sulfate and concentrated. The crude residue
was purified by column chromatography (silica gel, 30% EtOAc;
70% hexane, then 90% DCM, 10% MeOH) affording the product
1
the product (24) as a white solid. Yield (426 mg, 83%). H NMR
(500 MHz), DMSO: δ 1.75 (s, 3H), 2.72 (d, J ) 13 Hz, 1H), 3.01
(d, J ) 13 Hz, 1H), 4.82 (s, 1H), 4.91 (s, 1H), 6.99 (t, J ) 7 Hz,
1H), 7.09 (t, J ) 7 Hz, 1H), 7.37 (m, 2H), 7.57 (d, J ) 9 Hz, 1H),
8.38 (s, 1H), 10.7 (s, 1H), 11.1 (s, 1H). 13C NMR (125 MHz),
acetone-d6: δ 23.9, 44.1, 65.9, 111.9, 114.7, 115.9, 119.5, 120.4,
121.9, 123.1, 125.2, 137.6, 140.3, 156.6, 175.8. IR (NaCl): 3300
cm-1, 1790 cm-1, 1720 cm-1. HRMS: [M + H]+ ) 270.1255, calcd
for C15H16N3O2, 270.1243. Anal. Calcd for C15H15N3O2: C, 66.90;
H, 5.61; N, 15.60. Found: C, 66.38; H, 5.69; N, 15.11. Mp )
238-240 °C.
Preparation of 5-(1H-Indol-3-yl)-5-(2-oxopropyl)imidazoli-
dine-2,4-dione (25). To a 25 mL round-bottom flask were added
24 (172 mg, 0.639 mmol), THF (8 mL), and water (1 mL). Then
NMO (112 mg, 0.959 mmol) and OsO4 (0.65 mL of a 0.098 M
solution in THF, 0.0639 mmol) were added. The solution was stirred
at room temperature for 2 h and then was cooled to 0 °C before a
solution of NaIO4 (410 mg, 1.917 mmol) in water (3 mL) was added
and stirred at room temperature overnight. The solvents were
removed, and EtOAc (10 mL) was added along with a saturated
solution of K2SO3 (10 mL). This biphasic mixture was stirred for
10 min; then the organic layer was separated, and the aqueous layer
was extracted with n-BuOH (3 × 10 mL). The EtOAc layer and
(58) Kim, D. D.; Lee, S. J.; Beak, P. J. Org. Chem. 2005, 70, 5376–5386.
3412 J. Org. Chem. Vol. 74, No. 9, 2009

EDCI-Mediated Oxazole Rearrangement
n-BuOH layers were combined, dried using anhydrous sodium
sulfate, and concentrated. The crude residue was purified by column
chromatography (silica gel, 10% MeOH; 90% DCM) affording the
product (25) as an off-white solid. Yield (107 mg, 61%). Product
was recrystallized over 1 week with EtOAc. 1H NMR (500 MHz),
CD3OD: δ 2.15 (s, 3H), 3.49 (d, J ) 8 Hz, 1H), 3.59 (d, J ) 8 Hz,
1H), 7.02 (t, J ) 8 Hz, 1H), 7.11 (t, J ) 8 Hz, 1H), 7.27 (s, 1H),
7.35 (d, J ) 8 Hz, 1H), 7.69 (d, J ) 8 Hz, 1H). 13C NMR (125
MHz), CD3OD: δ 30.5, 49.2, 64.1, 112.7, 113.9, 120.5, 120.6,
1H), 6.92 (t, J ) 7 Hz, 1H), 7.04 (t, J ) 7 Hz, 1H), 7.26 (d, J )
2 Hz, 1H), 7.33 (d, J ) 8 Hz, 1H), 7.48 (d, J ) 8 Hz, 1H), 8.03
(s, 1H), 10.9 (s, 1H). 13C NMR (125 MHz), DMSO: δ 23.9, 43.4,
66.3, 111.4, 114.7, 115.3, 118.3, 119.7, 120.9, 122.6, 124.8, 136.5,
140.7, 170.8, 189.1. IR (KBr): 3470 cm-1, 3390 (br) cm-1, 3200
(br) cm-1, 1692 cm-1, 1650 cm-1. HRMS: [M + H]+ ) 269.1405,
calcd for C15H17N4O, 269.1402. Anal. Calcd for C15H16N4O: C,
67.15; H, 6.01; N, 20.88. Found: C, 63.98; H, 5.89; N, 19.84. Mp
) 264-266 °C.
122.9, 123.9, 125.6, 138.8, 160.0, 179.0. IR (KBr): 3364 (br) cm-1
,
Preparation of 2-Amino-5-(1H-indol-3-yl)-5-(2-oxopropyl)-
1H-imidazol-4(5H)-one (29). To a 25 mL round-bottom flask were
added (28) (99 mg, 0.366 mmol), DMF (7 mL), THF (1 mL), and
water (1 mL). Then NMO (64 mg, 0.549 mmol) and OsO4 (0.37
mL of a 0.098 M solution in THF, 0.0366 mmol) were added. The
solution was stirred at room temperature for 3 h and then was cooled
to 0 °C before a solution of NaIO4 (235 mg, 1.098 mmol) in water
(2 mL) was added and stirred at room temperature overnight. The
solvents were removed, and EtOAc (10 mL) was added along with
a saturated solution of K2SO3 (10 mL). This biphasic mixture was
stirred for 10 min; then the organic layer was separated, and the
aqueous layer was extracted with n-BuOH (6 × 10 mL). The EtOAc
layer and n-BuOH layers were combined, dried using anhydrous
sodium sulfate, and concentrated. The crude residue was purified
by column chromatography (silica gel, 20% MeOH; 90% DCM)
affording the product (29) as an off-white solid. The product was
1774 cm-1, 1711 cm-1. HRMS: [M + H]+ ) 272.1055, calcd for
C14H14N3O3, 272.1035. Anal. Calcd for C14H13N3O3: C, 61.99; H,
4.83; N, 15.49. Found: C, 61.10; H, 4.82; N, 15.38. Mp ) 234-236
°C.
Preparation of 2-Amino-5-(2-methylallyl)-5-(1-tosyl-1H-indol-
3-yl)-1H-imidazol-4(5H)-one (27). To a sealed tube were added
26 (850 mg, 1.876 mmol) in THF (5 mL) and NH4OH (15 mL).
The mixture was heated at 90 °C until the disappearance of the
starting material, as indicated by TLC. The precipitate that formed
was filtered, acidified with 5% HCl, extracted with n-BuOH (3 ×
20 mL), dried using anhydrous sodium sulfate, and concentrated.
The crude residue was purified by column chromatography (silica
gel, 10% MeOH; 90% DCM) affording the product (27) as an off-
1
white solid. Yield (575 mg, 72%). H NMR (500 MHz), DMSO:
δ 1.62 (s, 3H), 2.3 (s, 3H), 2.72 (d, J ) 13 Hz, 1H), 2.81 (d, J )
13 Hz, 1H), 4.72 (s, 1H), 4.77 (s, 1H), 7.22 (t, J ) 8 Hz, 1H), 7.32
(t, J ) 8 Hz, 1H), 7.37 (d, J ) 9 Hz, 2H), 7.64 (d, J ) 8 Hz, 1H),
7.69 (s, 1H), 7.85 (d, J ) 9 Hz, 2H), 7.90 (d, J ) 8 Hz, 1H), 8.25
(s, 1H). 13C NMR (125 MHz), DMSO: δ 20.9, 23.7, 43.1, 66.0,
113.0, 115.2, 121.5, 123.0, 123.3, 124.7, 126.7, 128.0, 130.2, 134.0,
1
recrystallized from EtOH. Yield (19 mg, 19%). H NMR (500
MHz), CD3OD: δ 2.18 (s, 3H), 3.19 (d, J ) 7 Hz, 1H), 3.64 (d, J
) 7 Hz, 1H), 6.97 (t, J ) 8 Hz, 1H), 7.08 (t, J ) 8 Hz, 1H), 7.20
(s, 1H), 7.33 (d, J ) 8 Hz, 1H), 7.51 (d, J ) 8 Hz, 1H). 13C NMR
(125 MHz), CD3OD: δ 30.9, 66.5, 112.5, 114.1, 120.28, 120.29,
122.7, 124.0, 125.9, 138.5, 171.7, 192.5, 207.7. IR (KBr): 3470
134.5, 139.9, 145.5, 170.9, 187.5. IR (KBr): 3470 cm-1, 3351 cm-1
,
cm-1, 3420 cm-1, 3270 (br) cm-1, 3176 (br) cm-1, 1720 cm-1
,
3307 cm-1, 3088 cm-1, 1707 cm-1, 1657 cm-1. HRMS: [M + H]+
) 423.1494, calcd for C22H23N4O3S, 423.1491. Anal. Calcd for
C22H22N4O3S: C, 62.54; H, 5.25; N, 13.25. Found: C, 61.21; H,
5.17; N, 13.05. Mp ) 273-275 °C.
1690 cm-1, 1650 cm-1. HRMS: [M + H]+ ) 271.1191, calcd for
C14H15N4O2, 271.1195. Mp ) 283-285 °C.
Acknowledgment. We gratefully acknowledge the financial
support provided by American Cancer Society (RSG CDD-106972)
and Michigan State University. Additional thanks goes to Dr. Rui
Huang from MSU for elemental analyses and Mr. Rahman Saleem
from MSU for high resolution mass spectrometry.
Preparation of 2-Amino-5-(1H-indol-3-yl)-5-(2-methylallyl)-
1H-imidazol-4(5H)-one (28). To a 100 mL round-bottom flask
were added 27 (500 mg, 1.18 mmol) and EtOH (60 mL). Then
KOEt (991 mg, 11.8 mmol) was added and the mixture refluxed
for 24 h. The EtOH was taken off, and the pH of an aqueous mixture
of the crude residue was adjusted to 8. The aqueous mixture was
then extracted with n-BuOH (3 × 40 mL). The organics were
combined, dried using anhydrous sodium sulfate, and concentrated.
The crude residue was purified by column chromatography (silica
gel, 20% MeOH; 90% DCM) affording the product (28) as an off-
white solid. The product was recrystallized from EtOH. Yield (150
Supporting Information Available: Experimental proce-
dures and characterizations for all new compounds, copies of
1
the H NMR and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
mg, 47%). H NMR (500 MHz), DMSO: δ 1.67 (s, 3H), 2.75 (d,
J ) 14 Hz, 1H), 2.81 (d, J ) 14 Hz, 1H), 4.75 (s, 1H), 4.78 (s,
JO900264P
J. Org. Chem. Vol. 74, No. 9, 2009 3413