Synthesis of marine alkaloids isonaamine A, dorimidazole A, and preclathridine A. Iminophosphorane-mediated preparation of 2-amino-1,4- disubstituted imidazoles from α-azido esters

Full text of DOI:10.1021/jo9819382

2540
J . Org. Chem. 1999, 64, 2540-2544
Syn th esis of Ma r in e Alk a loid s Ison a a m in e
A, Dor im id a zole A, a n d P r ecla th r id in e A.
Im in op h osp h or a n e-Med ia ted P r ep a r a tion
of 2-Am in o-1,4-d isu bstitu ted Im id a zoles
fr om r-Azid o Ester s
Pedro Molina,* Pilar M. Fresneda,* and Miguel A. Sanz
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica,
Universidad de Murcia, Campus de Espinardo,
E-30071 Murcia, Spain
Received September 24, 1998
The preparation of 2-amino-1,4-disubstituted imida-
zoles from R-azido esters is described. The aza-Wittig
reaction of the iminophosphorane derivatives with tosyl
isocyanate followed by treatment with primary amines
afforded the appropriately substituted 2-aminoimidazoli-
none ring. Reduction with DIBAL, dehydration with
methanesulfonyl chloride, and further N-tosyl deprotec-
tion provided the target molecules. A highly facile and
practical synthesis of the marine alkaloids isonaamine
A, dorimidazole A, and preclathridine A is outlined.
Marine organisms are among the most promising
sources of new biologically active molecules. Certain
secondary metabolites are nontraditional guanidine-
based alkaloids1 that possess a broad spectrum of power-
ful biological activities. The guanidine moiety is most
frequently found in the guise of a 2-aminoimidazole ring
that embodies one or two benzyl-substituted moieties.2
Examples include isonaamine A3 (1), isolated from the
calcareous Red Sea sponge Leucetta chagosensis, dorimi-
dazole A4 (2), and preclathridine A5 (3), isolated from the
Indo-Pacific nudibranch Notodoris gardineri.
N-acetylguanidine.2i Only three methods, starting from
a preformed imidazole ring, allow the direct introduction
of the amino functionality at position 2: coupling with
arene diazonium salts and further reduction,8 metalation
followed by sequential treatment with aryl azide and
acid,9 and oxidation of a sulfur substituent at position 2
with tert-butylhydroperoxide and further treatment with
ammonia.10
In connection with the synthesis of a number of
imidazole-containing alkaloids from marine origin,11 we
have reported three iminophosphorane-mediated meth-
ods that provide convenient entries to functionalized
imidazole derivatives.12 However, these methods do not
allow the introduction of a suitable amino functionality
at position 2 of the imidazole ring.
We now report an efficient iminophosphorane-based
approach that has sufficient flexibility to allow 2-amino-
1,4-disubstituted imidazoles to be conveniently generated
from a variety of ethyl 3-aryl propionates and its suitable
use for the preparation of the alkaloids 1-3, demonstrat-
ing the application of this chemistry. The key step,
formation of the appropriate substituted imidazole ring,
involves a Staudinger/aza-Wittig/carbodiimide-mediated
cyclization process.
A survey of the literature reveals that classical meth-
ods for the preparation of 2-aminoimidazole derivatives
involve condensation of R-aminocarbonyl compounds with
cyanamide,6 reaction of R-diketones with guanidine fol-
lowed by reduction,7 and reaction of R-haloketones with
(1) Albizati, K. F.; Martin, V. A.; Agharahimi, M. R.; Stolze, D. A.
Synthesis of Marine Natural Product in Biorganic Marine Chemistry;
Scheuer, P. J ., Ed.; Springer: Berlin, 1992; Vol. 6, pp 158-248.
(2) For recent reports of biologically active 2-aminoimidazole alka-
loids, see: (a) Mucquin-Pattey, C.; Guyot, M. Tetrahedron 1989, 45,
3445. (b) Kobayashi, J .; Tsuda, M.; Murayama, T.; Nakamura, H.;
Ohizumi, Y.; Ishibashi, M.; Iwamura, M.; Otha, T.; Nozoe, S. Tetra-
hedron 1990, 46, 5579. (c) Akee, R. K.; Carrol, T. R.; Yoshida, W. Y.;
Scheuer, P. J . J . Org. Chem. 1990, 55, 1944. (d) Commerc¸on, A.;
Gueremy, C. Tetrahedron Lett. 1991, 32, 1419. (e) Keifer, P. A.;
Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G., J r.; Rittschof, D.;
Rinehart, K. L. J . Org. Chem. 1991, 56, 2965. (f) He, H.; Faulkner, D.
J .; Lee, A.; Clardy, J . J . Org. Chem. 1992, 57, 2176. (g) Faulkner, D.
J . Nat. Prod. Rep. 1992, 9, 323. (h) 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. (i) Little, T. L.; Webber, S.
E. J . Org. Chem. 1994, 59, 7299. (j) Mancini, Y.; Guella, G.; Debitus,
C.; Pietra, F. Helv. Chim. Acta 1995, 78, 1178. (k) Cafieri, F.;
Fattorusso, E.; Maugoni, A.; Taglialatela-Scafati, O. Tetrahedron Lett.
1996, 37, 75. (m) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J .
Nat. Prod. 1996, 59, 501.
Our strategy to synthesize 2-amino-1,4-disubstituted
imidazoles 11 is illustrated in Scheme 1. The R-azido
ester 4a was prepared in 60% yield from the ethyl
3-phenylpropionic ester by the enolate azidation proce-
dure described by Evans13 using LDA/2,4,6-triisopropyl-
benzenesulfonyl azide14 (trisyl azide)/HMPA. One-flask
conversion of the R-azido ester 4a into the appropriately
(7) Nishimura, T.; Kitajima, K. J . Org. Chem. 1979, 44, 818.
(8) Nagui, W.; Kirk, K. L.; Cohen, L. A. J . Org. Chem. 1973, 38,
1971.
(9) (a) Kirk, K. L. J . Org. Chem. 1978, 43, 4381. (b) Daninos-Zeghal,
S.; Al Mourabit, A.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1997,
53, 7605.
(3) (a) Carmely, Kashman, Y. Tetrahedron Lett. 1987, 28, 3003. (b)
Carmely, S.; Ilan, M.; Kashman, Y. Tetrahedron 1989, 45, 2193.
(4) Alvi, K. A.; Crews, P. J . Nat. Prod. 1991, 54, 1509.
(5) Alvi, K. A.; Peters, B. M.; Hunter, L. M.; Crews, P. Tetrahedron
1993, 49, 329.
(10) Lindel, T.; Hoffmann, H. Tetrahedron Tett. 1997, 38, 8935.
(11) (a) Molina, P.; Fresneda, P. M.; Almendros, P. Tetrahedron Lett.
1992, 4491. (b) Molina, P.; Almendros, P.; Fresneda, P. M. Tetrahedron
1994, 50, 2241. (c) Molina, P.; Almendros, P.; Fresneda, P. M.
Tetrahedron Lett. 1994, 35, 2235.
(6) (a) Lawson, A. J . Chem. Soc. 1956, 307. (b) Storey, B. T.; Sullivan,
W. W.; Moyer, C. L. J . Org. Chem. 1964, 29, 3118. (c) Lencini, G. C.;
Lazzari, E. J . Heterocycl. Chem. 1966, 3, 152. (d) Cavalleri, B.; Ballota,
R.; Lencini, G. C. J . Heterocycl. Chem. 1972, 9, 979.
(12) (a) Molina, P.; Lopez-Leonardo, C.; Llamas-Botia, J .; Foces-
Foces, C.; Llamas-Saiz, A. L. Synthesis 1995, 449. (b) Molina, P.; Diaz,
I.; Tarraga, A. Synlett 1995, 1031. (c) Molina, P.; Conesa, C.; Velasco,
M. D. Synthesis 1996, 1459.
10.1021/jo9819382 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/11/1999

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2541
Sch em e 1
equatorial. However, reduction of imidazolone 8b (R )
Me) under the same conditions provided a mixture of the
expected hydroxyimidazole 9b (R ) Me) and 4-benzyl-1-
methyl-2-tosylamino-4,5-dihydroimidazole. All attempts
to separate these compounds by column chromatography
were unsuccessful. However, when this mixture was
submitted to the above dehydration conditions, the
imidazole 10b (R ) CH3) was obtained in 45% yield after
chromatographic separation.15
Removal of the N-tosyl protecting group, essential to
our objective of preparing naturally ocurring 2-aminoimi-
dazole derivatives, proved to be difficult. Application to
10 of the reaction conditions shown to achieve complete
deprotection of N-(arylsulfonyl) amines (TBAF/THF,16
refluxing in HBr,17 and sodium naphthalenide18) led to
the product decomposition. Finally, on the basis of the
reaction conditions used to remove N-sulfonyl protecting
groups using samarium diiodide,19 complete deprotection
of 10 to give 11 was achieved by the action of an excess
of samarium diiodide in THF in the presence of 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).
After 4 h, complete deprotection of 10 was observed by
TLC, and the products, compounds 11a and 11b, were
isolated in 95-90% yields, respectively (Scheme 1).
With these exploratory results in hand, the 4-meth-
oxybenzyl derivative 4b was then employed for the
preparation of isonaamine A (1), one of our primary goals
in applying iminophosphorane methodology to naturally
occurring 2-aminoimidazoles. Azidation of ethyl 3-(4-
methoxyphenyl)propionate under the Evans conditions
provided the R-azido ester 4b in 58% yield. Direct
conversion of compound 4b into the imidazolone deriva-
tive 8c was achieved in 57% yield by sequential treat-
ment with triphenylphosphine, tosylisocyanate, and O-
MOM-protected 4-hydroxybenzylamine. Reduction of
compound 8c with DIBAL (1:4 molar ratio) afforded a
mixture of the hydroxyimidazole 9c (50% yield) and the
corresponding 4,5-dihydroimidazole (26% yield). How-
ever, when a 1:3 molar ratio was used, the desired
compound 9c was obtained as the sole product in 76%
yield. Dehydration of the hydroxyimidazole 9c with
methanesulfonyl chloride led to 10c in 98% yield. Con-
version of the imidazolone 8c into the imidazole 10c can
also be achieved in the same yield without the isolation
of the intermediate hydroxyimidazole 9c by sequential
treatment of 8c with DIBAL and methanesulfonyl chlo-
ride. Deprotection of the two phenolic groups with boron
tribromide gave 12 in 95% yield, whereas the N-sulfonyl
deprotection with samarium diiodide provided the 2-ami-
noimidazole 13 in 98% yield. Attempt to convert 13 into
the target molecule 1 by deprotection of the two phenolic
groups with boron tribromide failed, and only a complex
mixture was obtained. However, N-tosyl deprotection of
substituted imidazolones 8 was achieved in 60% yield by
sequential treatment with triphenylphosphine, tosyl iso-
cyanate, and the adequate primary amine (methyl or
benzylamine) at room temperature. The conversion 4a
f 8 involves an initial Staudinger reaction between the
R-azido ester 4a and triphenylphosphine to give the
iminophosphorane 5, which was used without purifica-
tion for the next step. Compound 5 reacts in aza-Wittig-
type fashion with tosyl isocyanate to afford the carbodi-
imide 6 (as evidenced by the appearance of a strong band
at 2129 cm-1 in the IR spectrum). Reaction of the
carbodiimide 6 with primary amines leads to a guanidine-
substituted intermediate 7, which under the reaction
conditions undergoes regioselective imidazole ring forma-
tion across the ester and alkylamino functionality to give
8. The choice of the tosylisocyanate in the conversion 5
f 8 is derived from its demonstrated reactivity in aza-
Wittig reactions not only to give carbodiimides in high
yields but also to promote the regioselective cyclization
of the guanidine 7 across the more nucleophilic alkyl-
amino group. The next task was to effect the reduction
of the carbonyl group of the imidazolone 8. After several
trials with various reagents that included NaBH4/TiCl4;
NaBH4/t-BuOH; BH3‚SMe2; H2/Pd/C; LiAlH4/Et2O; and
NaBH4/CH3-SO3H/DMSO, we were unable to accomplish
this transformation. This series of frustrating results was
finally broken by using of DIBAL. Thus, treatment of
imidazolone 8a (R ) PhCH2) with DIBAL in THF at
reflux temperature provided the hydroxyimidazole de-
rivative 9a (R ) PhCH2) as a single diastereoisomer in
67% yield, which was easily converted into the N-
protected imidazole 10a (R ) PhCH2) in 98% yield by
the action of methanesulfonyl chloride in the presence
1
of triethylamine. In the H NMR spectrum of compound
9a , the observed coupling constant between H-4 and H-5
(J ) 6.5 Hz) suggests that the OH substituent on C-5 is
(15) During the chromatographic separation of compound 10b, the
4-benzyl-1-methyl-2-tosylamino-4,5-dihydroimidazole could be isolated
as a crystalline solid (mp 97-100 °C) in 30% yield.
(16) Yosuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(17) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367
and references therein.
(13) Trisyl azide has been shown to be a more effective azide-transfer
reagent than the more commonly employed tosyl azide: (a) Evans, D.
A.; Britton, T. C.; Dorow, R. L.; Dellaria, J . F. Tetrahedron 1988, 44,
5525. (b) Evans, D. A.; Ellman, J . A.; Dorow, R. L. J . Am. Chem. Soc.
1990, 112, 4011. (c) Evans, D. A.; Devries, K. M. Tetrahedron Lett.
1992, 1189. (d) Pearson, A. J .; Zhang, P.; Lee, K. J . Org. Chem. 1996,
61, 6581.
(18) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311.
(19) (a) Vedejs, E.; Lin, S. J . Org. Chem. 1994, 59, 1602. (b)
Gaulaonic Dubois, C.; Guggisberg, A.; Hesse, M. J . Org. Chem. 1995,
60, 5969. (c) Gaulaonic Dubois, C.; Guggisberg, A.; Hesse, M. Tetra-
hedron 1995, 51, 12573. (d) Vedejs, E.; Lin, S.; Klapars, A.; Wang, J .
J . Am. Chem. Soc. 1996, 118, 9796. (e) Knowles, H.; Parsons, A. F.;
Pettifer, R. M. Synlett 1997, 271.
(14) Harmon, R. E.; Wellman, G.; Gupta, S. K. J . Org. Chem. 1973,
38, 11.

2542 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
Sch em e 3. Syn th esis of Dor im id a zole A a n d
Sch em e 2. Syn th esis of Ison a a m in e A
P r ecla th r id in e A
Finally, R-azido ester 4d , available in 52% yield by
azidation of the ethyl 3-(3,4-methylendioxyphenyl)pro-
pionate, was converted into the imidazolone 8e in 60%
yield by the same protocol used for the preparation of
8d . Compound 8e by sequential treatment with DIBAL
and methanesulfonyl chloride produced the imidazole
derivative 10e as the sole reaction product in 67% overall
yield. N-Tosyl deprotection using samarium diiodide
provided preclathridine A (3) in 65% yield. (Scheme 3).
Spectroscopic data of the synthetic compounds 1-3 are
in good agreement with those previously reported for the
compounds of natural origin (see Experimental Section).
The preparation of 2-amino-1,4-disubstituted imida-
zoles from R-azido esters is described. The method
appears to be general and its utility is demonstrated in
the synthesis of the marine alkaloids isonaamine A,
dorimidazole A, and preclathridine A. The key step
centered around a cyclization strategy of a novel guani-
dine precursor to create the appropriately substituted
imidazole ring. Although explicit here, this process should
have additional applications to a variety of marine
alkaloids containing the 2-aminoimidazolin-4-one (dis-
capamide), 2-amino-4-substituted imidazole (oroidin), or
2-amino-1,4,5-trisubstituted imidazole ring (naamine A).
compound 12 with samarium diiodide provided 1 in 76%
yield (Scheme 2).
In a similar way, the synthesis of dorimidazole A (2)
was achieved starting from the R-azido ester 4c, readily
available from 3-(4-hydroxyphenyl)propionic acid in a
three-step sequence consisting of (a) esterification (91%),
(b) O-MOM protection of the phenolic group (87%), and
(c) azidation with trisyl azide (51%). Formation of the
imidazolone derivative 8d was achieved in 50% yield from
4c by sequential treatment with triphenylphosphine,
tosylisocyanate, and methylamine. When compound 8d
was submitted to reduction with DIBAL and further
treatment with methanesulfonyl chloride/triethylamine,
the imidazole derivative 10d was isolated in 42% yield
along with the corresponding O-MOM-protected 4-(4-
hydroxybenzyl)-1-methyl-2-tosylamino-4,5-dihydroimida-
zole (31%). Direct conversion of the imidazole derivative
10d into 2 was achieved in 76% by sequential treatment
with samarium diiodide (N-deprotection) and HCl (O-
deprotection) (Scheme 3).
Exp er im en ta l Section
Gen er a l Meth od s. General experimental conditions and
spectroscopic instrumentation used have been described.20
Ma ter ia ls. The 3-arylpropionic esters were prepared by
standard chemistry. Ethyl 3-(4-methoxyphenyl)propionate was
(20) Molina, P.; Pastor, A.; Vilaplana, M. J . J . Org. Chem. 1996,
61, 8094.

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2543
prepared in 94% yield by esterification21 of the commercially
available carboxylic acid. Ethyl 3-(4-methoxymethylenoxyphenyl)
propionate was prepared from 3-(4-hydroxyphenyl)propionic acid
by esterification21 (91%) and further O-MOM protection with
methoxymethyl chloride in the presence of sodium hydride22
(87%). Ethyl 3-(3,4-methylendioxyphenyl)propionate was pre-
pared in 54% yield from ethyl 3-(3,4-dihydroxyphenyl)propionate
by reaction with bromodichloromethane in the presence of
cesium carbonate.23 The O-MOM-protected 4-hydroxybenzyl-
amine was prepared from 4-hydroxybenzaldehyde by a three-
step sequence consisting of (a) O-MOM protection with meth-
oxymethyl chloride in the presence of sodium hydride22 (98%),
(b) formation of the corresponding aldoxime (88%), and (c)
catalytic hydrogenation in the presence of Pd on charcoal24 (50%).
C
24H23N3O3S: C, 66.49; H, 5.35; N, 9.69. Found: C, 66.63; H,
5.19; N, 9.82.
2-Tosyla m in o-5-h yd r oxy-1,4-d isu bstitu ted -4,5-d ih yd r o-
im id a zoles (9a a n d 9c). Gen er a l P r oced u r e. A 20% hexane
solution of DIBAL (2.9 mL, 2.86 mmol) was added dropwise at
room temperature under N2 to a solution of imidazolone 8a or
8c (0.95 mmol) in freshly distilled tetrahydrofuran (35 mL). The
reaction mixture was heated at reflux for 5 h. After the mixture
cooled, the excess of hydride was destroyed by careful addition
of 0.1 N HCl (20 mL). After 5 min of stirring, a 5% solution of
NaOH was added until pH ) 8. The mixture was extracted with
ethyl acetate (3 × 20 mL) and dried (MgSO4). After evaporation
of the solvent, the residual solid was triturated with ether and
recrystallized from the appropriate solvent or chromatographed
to give 9a or 9c.
r-Azid o Ester s (4a -d ). Gen er a l P r oced u r e. To a solution
of diisopropylamine (1.06 g, 69.8 mmol) in anhydrous tetrahy-
drofuran (150 mL) was added dropwise n-butyllithium (1.6 M,
41 mL, 67.2 mmol). The solution was stirred at -78 °C under
dry N2 for 45 min. A solution of the appropriate ethyl 3-aryl-
propionate (11.2 mmol) in anhydrous tetrahydrofuran (40 mL)
was added dropwise. The resultant solution was warmed to -30
°C, stirred at that temperature for 1 h, and then recooled to -78
°C. Hexamethylphosphoric triamide (HMPA) (30.5 mL, 175.5
mmol) was added in one portion, and to the above enolate
solution was added a precooled (-78 °C) solution of trisyl azide
(13.84 g, 44.8 mmol) in anhydrous tetrahydrofuran (80 mL). The
reaction mixture was stirred at -78 °C for 1 h and then was
quenched with glacial acetic acid (14.8 mL, 256 mmol). The
resulting mixture was allowed to warm to room temperature,
stirred for 12 h, treated with a saturated solution of NaHCO3
(300 mL), and extracted with dichloromethane (3 × 100 mL).
The organic extracts were combined, washed with a NaCl
solution (1 × 100 mL) and water (2 × 100 mL), dried (MgSO4),
and evaporated in vacuo. The residue was chromatographed on
a silica gel column using dichloromethane/n-hexane (4:3 v/v) as
eluent to give 4a -d .
1,4-Diben zyl-5-h yd r oxy-2-tosyla m in o-4,5-d ih yd r oim id a -
zole (9a ): 67% yield; white needle, mp 153-154 °C (ethyl
acetate/n-hexane); IR (Nujol) 1607, 3298, 3321 cm-1 1H NMR
;
(CDCl3) δ 2.39 (s, 3H), 2.85 (dd, 1H, J ) 13.7, 8.6 Hz), 3.02 (dd,
1H, J ) 13.7, 6.1 Hz), 3.88 (ddd, 1H, J ) 8.6, 6.5, 6.1 Hz), 4.21
(d, 1H, J ) 15.2 Hz), 4.87 (d, 1H, J ) 15.2 Hz), 4.95 (d, 1H, J )
6.5 Hz), 6.95 (s, 1H), 7.10-7.30 (m, 13H), 7.72 (d, 2H, J ) 8.2
Hz); 13C NMR (CDCl3) δ 21.4, 34.4, 44.4, 59.3, 80.2, 126.1, 127.4,
127.6, 128.2, 128.6, 128.9, 129.0, 129.2, 136.3, 137.0, 140.3, 142.2,
156.9; EIMS m/z 417 (M+ - H2O, 69), 328 (19), 262 (100), 155
(28). Anal. Calcd for C24H25N3O3S: C, 66.19; H, 5.79; N, 9.65.
Found: C, 66.33; H, 5.62; N, 9.49.
5-H yd r oxy-4-(4-m et h oxyb en zyl)-1-(4-m et h oxym et h yl-
en oxy)ben zyl-2- tosylam in o-4,5-dih ydr oim idazole (9c): silica
gel, ethyl acetate/dichloromethane (1:4 v/v); 76% yield; mp 169-
170 °C (ethyl acetate/n-hexane); IR (Nujol) 1511, 1585, 3395
cm-1 1H NMR (CDCl3) δ 2.39 (s, 3H), 2.78 (dd, 1H, J ) 14.0,
;
8.7 Hz), 2.95 (dd, 1H, J ) 14.0, 6.0 Hz), 3.43 (s, 3H), 3.74 (s,
3H), 3.81 (m, 1H), 4.13 (d, 1H, J ) 15.1 Hz), 4.08-4.27 (brs,
1H), 4.78 (d, 1H, J ) 15.1 Hz), 4.95 (d, 1H, J ) 6.5 Hz), 5.10 (s,
2H), 6.80 (d, 2H, J ) 8.4 Hz), 6.86 (d, 2H, J ) 8.4 Hz), 6.91 (s,
1H), 7.04-7.12 (m, 4H), 7.22 (d, 2H, J ) 8.1 Hz), 7.71 (d, 2H, J
) 8.1 Hz); 13C NMR (CDCl3) δ 21.3, 33.5, 43.7, 55.2, 55.9, 59.4,
80.0, 94.31, 114.2, 116.2, 126.0, 128.9, 129.1, 129.6, 129.9, 140.4,
142.1, 156.5, 156.7, 158.5; EIMS m/z 507 (M+ - H2O, 41), 401
(29), 352 (14) 214 (100), 151 (43), 121 (52). Anal. Calcd for
C27H31N3O6S: C, 61.70; H, 5.94; N, 7.99. Found: C, 61.83; H,
5.78; N, 8.14.
Eth yl 2-Azid o-3-p h en ylp r op ion a te (4a ): 60% yield; color-
less oil; IR (film) 1743, 2117 cm-1 1H NMR (CDCl3) δ 1.25 (t,
;
3H, J ) 7.3 Hz), 3.0 (dd, 1H, J ) 14.0, 8.6 Hz), 3.17 (dd, 1H, J
) 14.0, 5.6 Hz), 4.04 (dd, 1H, J ) 8.6, 5.6 Hz), 4.21 (q, 2H, J )
7.3 Hz), 7.1-7.4 (m, 5H); 13C NMR (CDCl3) δ 14.0, 37.5, 61.8,
63.1, 127.1, 128.3, 128.6, 135.9, 169.8; EIMS m/z 219 (M+, 1),
191 (1), 176 (9), 91 (100). Anal. Calcd for C11H13N3O2: C, 60.26;
H,5.98; N, 19.17. Found: C, 60.40; H, 6.14; N, 19.28.
2-Tosyla m in o-1,4-d isu bstitu ted Im id a zoles (10). Meth od
A. To a mixture of 2-tosylamino-5-hydroxy-4,5-dihydroimidazole
9a or 9c (1.1 mmol), methanesulfonyl chloride (0.11 mL, 1.4
mmol), and anhydrous dichloromethane (30 mL) was added
dropwise triethylamine (0.46 mL, 3.3 mmol) at 0 °C under N2.
The resultant mixture was stirred at room temperature for 12
h. Dichloromethane (70 mL) and saturated solution of NaCl (30
mL) were added. The organic layer was dried (MgSO4) and
concentrated to dryness. The residual solid was triturated with
ether and recrystallized from the appropriate solvent to give 10a
or 10c. Meth od B. A 20% hexane solution of DIBAL (5.97 mL,
5.88 mmol) was added dropwise at room temperature to a
solution of the appropriate imidazolone 8b, 8d , or 8e (1.96 mmol)
in anhydrous tetrahydrofuran (80 mL). The mixture was heated
at reflux temperature for 5 h. After the mixture cooled, the
solution was poured with stirring into cold 0.1 N HCl (20 mL),
and 5% solution of NaOH was added until pH ) 8. The mixture
was extracted with ethyl acetate (3 × 20 mL), and the combined
organic layers were washed with H2O (2 × 20 mL) and dried
(MgSO4). After filtration, the solvent was removed, and the
residue was dissolved in anhydrous dichloromethane (50 mL).
To this solution were added methanesulfonyl chloride (0.2 mL,
2.53 mmol) and triethylamine (0.81 mL, 5.81 mmol) at 0 °C
under N2. The resultant mixture was stirred at room tempera-
ture for 12 h. Workup was the same as that described for method
A. After removal of the solvent, the residue was applied to a
column of silica gel and eluted with ethyl acetate/dichlo-
romethane (1:4 v/v). The appropriate fractions were collected and
evaporated to give pure 10b, 10d , and 10e.
2-Tosyla m in o-1,4-d isu b st it u t ed Im id a zolon es (8a -e).
Gen er a l P r oced u r e. To a 0 °C solution of triphenylphosphine
(0.447 g, 1.7 mmol) in dry ether (10 mL) was added dropwise a
solution of the appropriate R-azido ester 4 (1.7 mmol) in the same
solvent (10 mL) under N2. The reaction mixture was allowed to
warm to room temperature and stirred for 12 h. To the recooled
(0 °C) solution was added a solution of tosylisocyanate (0.335 g,
1.7 mmol) in dry ether (10 mL) under N2. The mixture was
allowed to warm to room temperature, stirred for 1 h, and then
recooled to 0 °C. A solution of the appropriate primary amine
(1.7 mmol) in dry ether (10 mL) was added, and the resulting
mixture was allowed to warm to room temperature and stirred
for 12 h. The solution was concentrated to dryness, and the solid
residue was chromatographed on a silica gel column using ethyl
acetate/dichloromethane (1:4 v/v) as eluent to give 8a -e.
1,4-Diben zyl-4H-2-tosyla m in oim id a zol-5-on e (8a ): 60%
yield; white prism, mp 148-150 °C (ethyl acetate/n-hexane); IR
1
(Nujol) 1632, 1764, 2308 cm-1; H NMR (CDCl3) δ 2.42 (s, 3H),
3.04 (dd, 1H, J ) 14.1, 5.7 Hz), 3.18 (dd, 1H, J ) 14.1, 4.5 Hz),
4.39 (dd, 1H, J ) 5.7, 4,5 Hz), 4.50 (d, 1H, J ) 14.4 Hz), 4.61 (d,
1H, J ) 14.4 Hz), 6.93 (d, 2H, J ) 8.1 Hz), 7.0-7.22 (m, 10H),
7.55 (d, 2H, J ) 8.1 Hz), 7.87 (s, 1H); 13C NMR (CDCl3) δ 21.5,
36.8, 42.7, 59.0, 126.1, 127.4, 127.6, 128.2, 128.3, 128.7, 129.2,
129.4, 133.5, 134.8, 139.0, 142.8, 156.4, 171.8; EIMS m/z 434
(M+ + 1, 2), 433 (M+, 8), 278 (24), 155 (13). Anal. Calcd for
(21) Pearson, A. J .; Zhang, P.; Lee, K. J . Org. Chem. 1996, 61, 6581.
(22) Molina, P.; Fresneda, P. M.; Sanz, M. A.; Foces-Foces, C.;
Ramirez de Arellano, M. C. Tetrahedron 1998, 54, 9623.
(23) Zelle, R. E.; McClellan, W. J . Tetrahedron Lett. 1991, 32, 2461.
(24) Hartung, W. H.; Beaujon, J . H. R.; Cocolas, G. Org. Synth. Coll.
Vol. 5 1973, 376.
1,4-Diben zyl-2-tosyla m in oim id a zole (10a ): 98% yield; mp
179-180 °C (ethyl acetate/n-hexane); IR (Nujol) 1567, 3340 cm-1
;
1H NMR (CDCl3) δ 2.38 (s, 3H), 3.74 (s, 2H), 4.84 (s, 2H), 5.95
(s, 1H), 7.0-7.35 (m, 12H), 7.71 (d, 2H, J ) 8.2 Hz), 10.05 (brs,
1H); 13C NMR (CDCl3) δ 21.3, 31.3, 47.9, 110.5, 124.9, 125.7,

2544 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
127.1, 127.8, 128.0, 128.5, 128.7, 128.8, 129.0, 135.4, 135.9, 141.3,
141.5, 147.0; EIMS m/z 417 (M+, 100), 328 (61), 262 (61), 155
(56). Anal. Calcd for C24H23N3O2S: C, 69.04; H, 5.55; N, 10.06.
Found: C, 69.27; H, 5.39; N, 10.29.
172 (49). Anal. Calcd for C11H13N3: C, 70.56; H, 7.00; N, 22.44.
Found: C, 70.64; H, 7.23; N, 22.63.
4-(4-Meth oxyben zyl)-1-(4-m eth oxym eth ylen oxy)ben zyl-
2-a m in oim id a zole (13): 98% yield; yellow viscous oil; IR
(CHCl3) 1660, 3134, 3303 cm-1; 1H NMR (CDCl3) δ 3.37 (s, 3H),
3.73 (s, 5H), 5.02 (s, 2H), 5.20 (s, 2H), 6.71 (s, 1H), 6.90 (d, 2H,
J ) 8.4 Hz), 7.05 (d, 2H, J ) 8.4 Hz), 7.17 (d, 2H, J ) 8.4 Hz),
7.29 (d, 2H, J ) 8.4 Hz), 7.64 (s, 2H); 13C NMR (CDCl3) δ 29.1,
46.9, 55.1, 55.5, 93.7, 112.5, 113.9, 116.3, 126.4, 128.3, 129.1,
129.2, 129.5, 145.8, 155.9, 156.5; EIMS m/z 354 (M+ + 1, 31),
353 (M+, 100), 309 (69), 247 (62), 202 (80). Anal. Calcd for
1,4-Bis(4-h yd r oxyben zyl)-2-tosyla m in oim id a zole (12). To
a solution of compound 10c (0.2 g, 0.4 mmol) in anhydrous CH2-
Cl2 (20 mL) was added dropwise at room temperature a solution
of BBr3 (0.54 g, 2.12 mmol) in the same solvent (4 mL). The
mixture was heated at reflux for 30 min. After the mixture
cooled, MeOH (4 mL) was added. The resultant solution was
concentrated to dryness. The residue was dissolved in THF (12
mL) and 6 N HCl (12 mL) was added. The mixture was stirred
at room temperature for 12 h. Then, a saturated solution of
NaHCO3 was added until pH ) 6, and the mixture was extracted
with AcOEt (3 × 15 mL). The combined organic layers were dried
(MgSO4), and the solvent was removed under reduced pressure.
The residue was recrystallized from AcOEt/n-hexane (1:1 v/v)
to give 12: 95% yield; mp 200-202 °C (ethyl acetate); IR (Nujol)
1241, 1385, 1583, 3288 cm-1; 1H NMR (DMSO-d6) δ 2.34 (s, 3H),
3.65 (s, 2H), 4.68 (s, 2H), 6.39 (s, 1H), 6.63 (d, 2H, J ) 8.0 Hz),
6.69 (d, 2H, J ) 8.2 Hz), 6.95 (d, 2H, J ) 8.0 Hz), 6.98 (d, 2H,
J ) 8.2 Hz), 7.23 (d, 2H, J ) 7.8), 7.67 (d, 2H, J ) 7.8 Hz), 8.6-
9.9 (brs, 2H, OH), 11.20 (s, 1H); 13C NMR (DMSO-d6) δ 20.9,
29.5, 46.5, 111.2, 115.2, 115.17, 125.5, 126.1, 126.8, 128.1, 129.5,
129.2, 129.4, 140.8, 142.0, 145.3, 155.9, 156.9; EIMS m/z 450
(M+ + 1, 12), 449 (M+, 16), 343 (88), 188 (100), 107 (85), 91 (85).
Anal. Calcd for C24H23N3O4S: C, 64.13; H, 5.16; N, 9.35. Found:
C, 64.27; H, 5.03; N, 9.57.
C
20H23N3O3: C, 67.97; H, 6.56; N, 11.89. Found: C, 67.75; H,
6.34; N, 11.72.
Ison a a m in e A (1). Starting from 12 and using the above-
described procedure, isonaamine A was obtained in 76% yield
as a yellow viscous oil: IR (Nujol) 1518, 1662, 3247 cm-1 1H
;
NMR (DMSO-d6) δ 3.63 (s, 2H), 4.89 (s, 2H), 6.57 (s, 1H), 6.70
(d, 2H, J ) 8.6 Hz), 6.76 (d, 2H, J ) 8.6 Hz), 7.02 (d, 2H, J )
8.5), 7.14 (d, 2H, J ) 8.6 Hz), 7.43 (s, 2H), 9.0-9.8 (brs, 2H);
13C NMR (DMSO-d6) δ 29.5, 40.1, 112.2, 115.3, 116.5, 125.6,
127.2, 127.6, 129.3 (2C), 129.5 (2C), 146.0, 156.1, 157.3; EIMS
m/z 295 (M+, 48), 200 (28), 189 (100), 188 (60), 128 (92), 127
(46), 107 (35), 96 (37), 77 (16); HREIMS C17H17N3O2 calcd
295.1321, found 295.1303.
Dor im id a zole A (2). Starting from 10d and using the same
procedure followed by treatment with 6 N HCl in THF at room
temperature, dorimidazole A was obtained in 76% yield as a
viscous oil: IR (Nujol) 1161, 1380, 1460, 1568, 1602, 1686, 3258
1
cm-1; H NMR (DMSO-d6) δ 3.39 (s, 3H), 3.66 (s, 2H), 6.61 (s,
2-Am in o-1,4-d isu bstitu ted Im id a zoles (11 a n d 13). Gen -
er a l P r oced u r e. Samarium power (0.75 g, 5 mmol) was placed
in a reaction flask fitted with a dropping funnel. A solution of
1,2-diiodoethane (0.7 g, 2.5 mmol) in anhydrous and deoxygen-
ated THF (30 mL) was added dropwise. The mixture was stirred
1H), 6.72 (d, 2H, J ) 8.5 Hz), 7.04 (d, 2H, J ) 8.5 Hz), 7.43 (s,
2H), 9.31 (s, 1H); 13C NMR (DMSO-d6) δ 29.3, 32.0, 113.9, 115.3,
126.0, 127.5, 129.6 (2C), 146.3, 156.2; FABMS (positive) m/z 205
(M + 2, 19), 204 (M + 1, 100), 203 (M+, 21); HREIMS C11H13N3O
calcd 203.1058, found 203.1047.
at room temperature for 2 h, and then
a mixture of the
appropriate compound 10 (0.24 mmol), DMPU (2.54 g, 2.4 mmol),
and anhydrous and deoxygenated THF (5 mL) was added. The
resultant solution was heated at reflux temperature for 4 h. After
the mixture cooled, a 5% solution of NaOH (10 mL) was added,
and the mixture was stirred for 30 min. The solvent was removed
under reduced pressure, and the residue was extracted with
AcOEt (2 × 25 mL) and CHCl3/MeOH (4:1 v/v) (1 × 25 mL).
The combined organic extracts were dried (MgSO4) and concen-
trated to dryness. The residue was washed with n-hexane (3 ×
25 mL) and then chromatographed on a silica gel column using
CHCl3/MeOH (4:1 v/v) as eluent to give 11 and 13.
1,4-Diben zyl-2-a m in oim id a zole (11a ): 95% yield; yellow
viscous oil; IR (CHCl3) 1665, 3140, 3309 cm-1; 1H NMR (CDCl3)
δ 3.77 (s, 2H), 5.04 (s, 2H), 4.90 (brs, 2H), 6.06 (s, 1H), 7.15-
7.45 (m, 10H); 13C NMR (CDCl3) δ 32.2, 48.6, 111.4, 126.5, 127.4,
128.1, 128.4, 128.6, 128.8, 129.9, 134.7, 137.2, 147.4; EIMS m/z
264 (M+ + 1, 19), 263 (M+, 67), 172 (46), 91 (100). Anal. Calcd
for C17H17N3: C, 77.54; H, 6.51; N, 15.96. Found: C, 77.66; H,
6.38; N, 15.77.
P r ecla th r id in e A (3). This compound was prepared in 65%
yield as a yellow viscous oil from 10e using the same N-tosyl
deprotection procedure: IR (film) 756, 927, 1037, 1245, 1490,
1663, 3147, 3286 cm-1; 1H NMR (CDCl3) δ 3.57 (s, 3H), 3.72 (s,
2H), 5.92 (s, 2H), 6.17 (s, 1H), 6.68-6.76 (m, 3H), 6.80-7.8 (brs,
2H); 13C NMR (CDCl3) δ 30.6, 33.8, 101.0, 108.0, 109.0, 113.0,
121.8, 126.6, 129.2, 146.3, 146.5, 147.7; EIMS m/z 232 (M+ + 1,
14), 231 (M+, 100), 216 (32), 175 (12), 135 (4), 127 (23); HREIMS
C
12H13N3O2 calcd 231.1008, found 231.0983.
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the Direccio´n General de Investi-
gacio´n Cient´ıfica y Te´cnica (project PB95-1019). M.A.S.
also thanks the Ministerio de Educacio´n y Cultura for
a studentship.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(IR, NMR, MS) for R-azido esters 4b-d , 2-tosylaminoimidazol-
5-ones 8b -e, and 2-tosylaminoimidazoles 10b -e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
4-Ben zyl-1-m eth yl-2-a m in oim id a zole (11b): 90% yield;
yellow viscous oil; IR (Nujol) 3113, 3245 cm-1; 1H NMR (CDCl3)
δ 3.48 (s, 3H), 3.73 (s, 2H), 6.07 (s, 1H), 6.89 (brs, 2H), 7.2-7.4
(m, 5H); 13C NMR (CDCl3) δ 31.0, 33.6, 113.1, 126.8, 127.0, 128.6,
128.7, 135.8, 146.4; EIMS m/z 188 (M+ + 1, 36), 187 (M+, 100),
J O9819382