Versatile access to C-4-substituted 2-amino-1,3-azoles from hydropyridines in oxidative conditions

Full text of DOI:10.1021/jo050862o

Versatile Access to C-4-Substituted
-Amino-1,3-azoles from Hydropyridines in
Oxidative Conditions
hydes or ketones with cyanamide to give 2AI, 2AO, and
2
reaction is pH sensitive and appears to be difficult to
conduct.
AT, respectively.5 However, in the case of 2AI, this
d,6
2
In the context of a study aimed at the development of
synthetic routes to marine 2AI alkaloids and analogues,
we required an efficient general pathway to the 4-sub-
stituted 2-amino-1,3-azole core. Recently, we reported the
biomimetic inspired synthesis of 2-aminoimidazole start-
ing from N-methoxycarbonyl-1,2-dihydropyridine using
Maria del Rayo Sanchez Salvatori, Robert Abou-Jneid,
Sa ¨ı d Ghoulami, Marie-Th e´ r e` se Martin,
Anne Zaparucha,* and Ali Al-Mourabit*
Institut de Chimie des Substances Naturelles du CNRS,
BP 1, 91198Gif-sur-Yvette, France
7
bromine-promoted addition of Boc-guanidine. As an
ali.almourabit@icsn.cnrs-gif.fr
Received April 28, 2005
extension of this work, we undertook a study of the
reactivity of urea and thiourea as nucleophiles on one
hand and dihydropyridines and tetrahydropyridines as
enamine reactants on the other hand. The objective was
the preparation of various C-4-substituted 2-amino-1,3-
azoles.
Addition of electrophilic reagents to carbon-carbon
double bonds is a standard procedure in organic chem-
8
istry. Access to the 2-amino-1,3-azole core would neces-
sitate the attack of the nucleophile (guanidine, urea, or
thiourea) on an activated intermediate followed by an
elimination step. We planned to benefit from the nucleo-
philic character of the enamine moiety of hydropyridine
Various substituted 2-aminotetrahydroazolopyridines and
2
-aminohexahydroazolopyridines have been prepared by
bromine-mediated addition of protected guanidine or urea
to hydropyridine derivatives. The pH-dependent regioselec-
tive cleavage of the resulting aminal function led to the
I to introduce the nucleophile through an oxidative
9-11
addition protocol.
Opening of the bicyclic intermediate
II by cleavage of the aminal bond would lead, in all cases,
to the 2-amino-1,3-azole structure III, bearing a propyl-
amine or propenamine at C-4 (Scheme 1).
During the course of our investigations, we found that
N-carbamate-1,2-dihydropyridines 1, 2, and 3 reacted
with 4 equiv of Boc-guanidine, in a mixture of acetoni-
2
-aminoazole products III. The yields of the bicycles of type
II, and their conversion into azoles III depends on the
electronic properties of the substituents on the nitrogen of
the tetrahydopyridine.
2-Aminoimidazole (2AI), 2-aminooxazole (2AO), and
2
-aminothiazole (2AT) constitute an important class of
(
5) For representative references, see: (a) Little, T. L.; Webber, S.
heterocycles, especially in medicinal chemistry. They
display a broad range of interesting biological properties
and serve as important precursors in drug design and
natural products synthesis. The 2AI skeleton is found in
E. J. Org. Chem. 1994, 59, 7299-7305. (b) Shikhaliev, K. S.; Falaleev,
A. V.; Ermolova, G. I.; Solov’ev, A. S. Chem. Heterocycl. Compd. (Engl.
Trans.) 1999, 35, 818-820. (c) Birman, V. B.; Jiang, X.-T. Org. Lett.
2004, 6, 2369-2371. (d) Murali Dhar, T. G.; Liu, C.; Pitts, W. J.; Guo,
J.; Watterson, S. H.; Gu, H.; Fleener, C. A.; Rouleau, K.; Sherbina, N.
Z.; Barrish, J. C.; Hollenbaugh, D.; Iwanowicz, E. Bioorg. Med. Chem.
Lett. 2002, 12, 3125-3128. (e) Crank, G.; Foulis, M. J. J. Med. Chem.
1971, 14, 1075-1077. (f) Kim, H.-O.; Kahn, M. Synlett 1999, 1239-
1240. (g) Herlenmeyer, J. Helv. Chim. Acta 1949, 32, 38. (h) Plouvier,
B.; Houssin, R.; Bailly, C.; H e´ nichart, J.-P. J. Heterocycl. Chem. 1989,
1
various active marine metabolites isolated from sponges
and the 2AO moiety is the key element of a potent
inhibitor of inosine monophosphate dehydrogenase,2
while 2AT is a building block in the synthesis of anti-
inflammatory agents. Synthetic routes to 2AI, 2AO, and
2
6, 1643-1647. (i) Brickut e´ , D.; Slok, F. A.; Romming, C.; Sasckus, A.
3
J. Chem. Soc., Perkin Trans. 1 2002, 652-656.
4
(6) For representative references, see: (a) Lawson, A. J. Chem. Soc.
2
AT are numerous. Among them, however, only a few
1
956, 307-310. (b) Lancini, G. C.; Lazzari, E.; Arioli, V.; Bellani, P. J.
methods are general for the preparation of these 2-amino-
,3-azoles. The first and most commonly used direct
Med. Chem. 1969, 12, 775-780. (c) Saul, R.; Kern, T.; Kopf, J.; Pinter,
I.; Koll, P. Eur. J. Org. Chem. 2000, 205-209. (d) Olofson, A.;
Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997, 63, 77918-7919. (e)
Baran, P. S.; Zografos, A. L.; O’Malley, D. P. J. Am. Chem. Soc. 2004,
1
approach involves the reaction of R-halocarbonyl com-
pounds with guanidine plus (2AI), urea plus (2AO) or
thiourea plus (2AT).5 An alternative approach is the
reaction of R-amino, R-hydroxy, or R-thiohydroxy alde-
1
26, 3726-3727. (f) Wolf, V.; Hauschildt, P.; Loop, W. Chem. Ber. 1962,
95, 2419-2423. (g) Brown, M. D.; Gillon, D. W.; Meakins, G. D.;
Whitham, G. H. J. Chem. Soc., Chem. Commun. 1982, 444-445. (h)
Kozikowski, A. P.; Campiani, G. Heterocycles 1994, 39, 101-116.
(
7) Abou-Jneid, R.; Ghoulami, S.; Martin, M.-T.; Tran Huu Dau, E.;
(
1) (a) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-
43. (b) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783.
2) Murali Dhar, T. G.; Guo, J.; Shen, Z.; Pitts, W. J.; Gu, H. H.;
Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Iwanowicz, E. J. Org. Lett. 2002,
, 2091-2093.
3) (a) Geronikaki, A.; Hadjipavlou-Litina, D.; Chatziopoulos, C.;
Travert, N.; Al-Mourabit, A. Org. Lett. 2004, 6, 3933-3936.
(8) (a) Block; E.; Schwan, A. L. In Comprehensive Organic Chemistry;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp
329-362. (b) Rodriguez, J.; Dulc e` re, J.-P. Synthesis 1993, 1177-1205.
(9) Lavilla, R.; Kumar, R.; Coll, O.; Masdeu, C.; Spada, A.; Bosch,
J.; Espinosa, E.; Molins, E. Chem. Eur. J. 2000, 6, 1763-1772.
(10) (a) Harris, R. L. N. Aust. J. Chem. 1970, 23, 1199-1207. (b)
Grehn, L. J. Heterocycl. Chem. 1978, 15, 81-87.
2
(
4
(
Soloupis, G. Molecules 2003, 8, 472-479. (b) Lazer, E. S.; Miao, C. K.;
Cywin, C. L.; Sorcek, R.; Wong, H.-C.; Meng, Z.; Potocki, I.; Hoermann,
M.; Snow, R. J.; Tschantz, M. A.; Kelly, T. A.; McNeil, D. W.; Coutts,
S. J.; Churchill, L.; Graham, A. G.; David, E.; Grob, P. M.; Engel, W.;
Meier, H.; Trummlitz, G. J. Med. Chem. 1997, 40, 980-989.
(11) Plantefeve, F.; Descotes, G. Bull. Soc. Chim. Fr. 1972, 2923-
2929. (b) Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 9789-9797.
(c) Kivits, G. A. A.; Hora, J. J. Heterocycl. Chem. 1975, 12, 577. (d)
Zhao, R.; Gove, S.; Sundeen, J. E.; Chen, B.-C. Tetrahedron Lett. 2001,
42, 2101-2102.
(4) Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5.
10.1021/jo050862o CCC: $30.25 © 2005 American Chemical Society
8208
J. Org. Chem. 2005, 70, 8208-8211
Published on Web 09/08/2005

SCHEME 1
SCHEME 2a
a
Reagents and conditions: (i) BocGua, Br2, DMF:acetonitrile, 0 °C, 15 min; (ii) HCl 2 M, 7 (71%), 8 (84%), 9 (26%) for both steps; (iii)
NaOH 1 M, (Z)-10 (85%, 11 (28%); (iv) urea, Br2, DMF/acetonitrile, rt, 15 min, 12 (50%); (v) thiourea, Br2, DMF/acetonitrile, rt, 15 min,
3 (11%); (vi) DMSO, reflux, 90-120 min, 14 Z/E 14:86 (22%), 15 Z/E 10:90 (28%); (vii) DMF, reflux, 1 h, 16 (40%).
1
trile-DMF (4:1), at 0 °C in the presence of 1 equiv of
bromine, to give compounds 4, 5, and 6 respectively, as
the preparation of the 2-aminooxazole and the 2-ami-
nothiazole cores. Under the same reaction conditions,
urea and thiourea were found to be less reactive than
Boc-guanidine. Reaction of the dihydropyridine 1 with
urea in the presence of one equiv. of bromine led to
compound 12 in a 50% yield. The dihydropyridine ring
opening was then achieved simply by heating 12 in
DMSO for 90 min. The 2-aminooxazole derivative 14 was
obtained in modest yield as a 14:86 mixture of Z/E
stereoisomers. Attempts to improve the yield by changing
the solvent to DMF did not lead to the expected product
but to the bicyclic urea 16 in 40% yield as the only
identifiable compound. Reaction of thiourea with dihy-
dropyridine 1 led to the 2-aminodihydropyridinethiazole
7
a mixture of regioisomers. The cis stereochemistry of the
ring fusion was determined by NOESY experiments. It
was assumed, according to our preliminary trials and to
a literature reference, that the reaction with unprotected
guanidine would lead to a complex mixture because of
its nucleophilicity and its sensitivity to oxidation by
1
2
bromine. Further deprotection of both regioisomers of
4
, 5, and 6, under acidic conditions, led to the cis-2-amino-
1
,3a,5,7a-dihydroimidazo[4,5-b]pyridine compounds 7, 8,
and 9. The yield of the reaction depends on the nature of
the dihydropyridine protecting group. Since purification
of the regioisomeric intermediates is not necessary, the
addition of protected guanidine and acidic deprotection
can be performed in one step improving the yield of the
reaction. Aminal bond cleavage of 7 under basic condi-
tions afforded the 2-aminoimidazole 10. The (Z) allylic
amine 10 could be isomerized under acidic conditions to
1
3 with a yield of only 11%. The latter reaction suffered
10
from the sensitivity of thiourea to oxidative conditons.
Heating 13 in DMSO led to the expected 2-aminothiazole
compound 15 as a 10:90 mixture of Z/E stereoisomers in
a 28% yield (Scheme 2).
7
afford the (E) allylic amine, a key precursor of natural
To widen the scope of the reaction, we next examined
the reactivity of various N-protected tetrahydropyridines
toward bromine oxidation and nucleophilic addition of
Boc-guanidine, urea, or thiourea (Scheme 3). As expected,
tetrahydropyridines 17, 18, 19, and 20 underwent oxida-
tive coupling with Boc guanidine very rapidly and gave
products 21, 22, 23, and 24, respectively, in almost
quantitative yields. The crude products were reacted with
hydrochloric acid to remove the guanidine Boc group and
to accomplish concomitant cleavage of the aminal bond.
The 2-aminoimidazoles 25, 26, and 27 were obtained in
about 50-70% yields for the three steps. Completely
deprotected 28 was isolated by heating 23 in HCl for 12
h. This compound has already been prepared from
pyrrole-imidazole alkaloids.1
,6d,13
Interestingly, in the case of the carbophenoxy protect-
ing group (8), the reaction with base led to the formation
of the lactam 11. The phenolate group thus appears to
be a rather good leaving group in the formation of 11
from the corresponding allylic amine. When the N-
protecting group is a Troc (9), reaction under basic
conditions led only to a mixture of uncharacterized
compounds with a trace of the bicycle 11.
With the aforementioned success of the 2-aminoimi-
dazole synthesis, we set about to extend the method to
(
12) Gilchrist, T. L. In Comprehensive Organic Chemistry; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 735-756.
13) (a) Wright, A. E.; Chiles, S. A.; Cross, S. S. J. Nat. Prod. 1991,
4, 1684. (b) Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G.
Tetrahedron Lett. 1999, 40, 4775-4778.
(
1
4
6d
ornithine derivatives by B u¨ chi first and Horne, using
5
the method of Lancini.6b Treatment of piperidine N-Boc-
J. Org. Chem, Vol. 70, No. 20, 2005 8209

SCHEME 3a
a
Reagents and conditions: (i) Boc-Gua, Br2, DMF/acetonitrile, rt, 15 min; (ii) HCl 2 M, 70 °C, 5 h, 25 (72%), 26 (50%), 27 (48%), 28
from 19 (84%) for both steps; (iii) HCl 2 M, 70 °C, 12 h, 29 from 20 (42%) for both steps; (iv) urea, Br2, DMF/acetonitrile, rt, 15 min, 30
66%), 31 (32%), 32 (31%); (v) thiourea, Br2, DMF/acetonitrile, rt, 15 min, 33 (4%); (vi) NaOH 1M, 100 °C, 5 min, 34 (quant), 35 (quant),
6 (quant).
(
3
protected compound 24 with HCl for 12 h gave only 29,
indicating that the presence of an electron-withdrawing
group on the piperidine moiety is necessary for aminal
cleavage.
Using the same procedure with urea instead of Boc-
guanidine, the tetrahydrooxazolopyridine compounds 30,
oxazoles were found to be pH dependent and proceeded
in moderate to good yields.
Experimental Section
N-Alkoxycarbonyl-1,2-dihydropyridines 1-3, N-alkoxycarbo-
nyl-1,2,3,4-tetrahydropyridines 17, 19, and 20, and N-tosyl-
3
1, and 32 were obtained in 66, 32, and 31% yields from
7, 19, and 20, respectively. Attempts to run the same
1
,2,3,4-tetrahydropyridine (18) were prepared according to
1
15
15a
16
17
18
reported procedures: 1 (71%), 22(077%), 3 (80%), 17 (74%),
1
9
15c
reaction sequence with thiourea as the nucleophile were
disappointing since only a 4% yield of the bicycle 33 was
obtained.
18 (61%), 19 (65%), 20 (44%).
General Procedure for the Preparation of Compounds
4 and 15. Representative Procedure for [3-(2-Aminoox-
1
azol-5-yl)allyl]carbamic Acid Methyl Ester (14). A solution
of 12 (6.1 mmol) in DMSO (75 mL) was stirred at 175 °C for 1.5
h. The reaction mixture was cooled to room temperature and
poured into cold water, and the solution was made basic to a
pH 10 or greater by addition of an aqueous 5% Na CO solution.
The transformation of aminals 30, 31, and 32 into the
-aminooxazoles 34, 35, and 36 (Scheme 3) in nearly
2
quantitative yields was achieved by refluxing in 1 M
aqueous NaOH for 5 min. Attempts to open the bicycles
2
3
30 and 31 under acidic conditions did not give any
The solution was extracted with CH
layers were dried over MgSO and filtered, and the solvents were
evaporated in vacuo. The residue was purified by preparative-
2 2
Cl , the combined organic
4
reaction, the starting material was recovered. Heating
in DMSO under neutral conditions led to unidentifiable
degradation products. It is noteworthy that purification
of 2-aminooxazoles 34, 35, and 36 on silica gel or by
HPLC led to the partially or totally recyclized compounds
3 2 2
layer chromatography using 98:2 NH -saturated CH Cl -MeOH
to afford 14 a brown solid (265 mg, 22%) as an inseparable
mixture of isomers (Z/E 14:86): IR (Nujol) 3343, 3319, 1690,
+
1656; MS (ES) m/z 197.8 (M + H) ; HRMS calcd for C
H
8 11
N
3
O
3
+
1
3
0, 31, and 32.
A short procedure for the preparation of C-4-substi-
198.0879, found (M + H) 198.0905; E isomer H NMR (CD
OD, 300 MHz) δ 3.64 (s, 3H), 3.80 (d, J ) 7 Hz, 2H), 5.85 (dt, J
6 Hz, 16 Hz, 1H), 6.22 (dd, J ) 16 Hz, 1 Hz, 1H), 6.54 (s, 1H);
3
-
)
tuted 2-amino-1,3-azoles has been developed. A bromine-
mediated oxidative protocol on the enamine moiety of
various dihydro or tetrahydropyridines followed by nu-
cleophilic addition of protected guanidine, urea or thio-
urea allowed access to various 2-amino-hydro-3-azolopy-
ridines. The yields were found to be modest to excellent
depending on the nucleophile. The method is more
applicable to protected guanidine and urea than to
thiourea and unprotected guanidine. The propensity of
the latter to be oxidized by bromine is probably the
reason for this limitation. The subsequent regioselective
aminal ring-opening reactions and the rearrangement
with conversion to 2-aminoimidazoles and 2-amino-
1
3
C NMR (CD
3
OD, 75 MHz) δ 43.3, 52.6, 117.4, 123.8, 124.4,
1
1
(
44.7, 159.5, 163.1. Z isomer H NMR (CD OD, 300 MHz) δ 3.64
3
s, 3H), 4.06 (br d, J ) 6 Hz, 12 Hz, 1H), 5.36 (br d, J ) 6 Hz,
1
3
12 Hz, 1H), 6.09 (dd, J ) 12 Hz, 1 Hz, 1 H), 6.63 (s, 1H);
C
3
NMR (CD OD, 75 MHz) δ 40.9, 52.5, 115.8, 125.6, 126.7, 144.5.
(15) (a) Fowler, F. W. J. Org. Chem. 1972, 37, 1321-1323. (b) Zapf,
C. W.; Creighton, C. J.; Tomoika, M.; Goodman, M. Org. Lett. 2001, 3,
1
133-1136. (c) Leclercq, S.; Thirionet, I.; Broeders, F.; Daloze, D.;
Vander Meer, R.; Braeckman, J. C. Tetrahedron 1994, 50, 8465-8478.
16) Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836-
842.
17) Mariano, P. S.; Dunaway-Mariano, D.; Huesmann, P. L. J. Org.
Chem. 1979, 44, 124-133.
18) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane,
S.-I.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697-6703.
19) Kim, S.; Yoon, J.-Y. Synthesis 2000, 1622-1630.
(20) Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61, 4180-
4184.
(
4
(
(
(
(
14) Foley, L. H.; B u¨ chi, G. J. Am. Chem. Soc. 1982, 104, 1777-
1
779.
8210 J. Org. Chem., Vol. 70, No. 20, 2005

[
3-(2-Imino-2,3-dihydrothiazol-5-yl)allyl]carbamic Acid
5-(3-Aminopropyl)-1H-imidazol-2-ylammonium Dihy-
drochloride (28). Reaction conditions: 12 h at 70 °C. Purifica-
Methyl Ester (15). Reaction conditions: compound 13 was
heated for 2 h at 175 °C. Purification by silica gel flash
tion by silica gel flash chromatography using 70:30 CH
2 2
Cl -
3 2 2
chromatography using 95:5 NH saturated CH Cl -MeOH.
MeOH: white solid (42% from 19); mp 204-205 °C dec; IR
1
Inseparable 1:9 mixture of Z/E isomers as a brown solid (28%):
(Nujol) 3320, 2923; H NMR (CD
3
OD, 300 MHz) δ 1.97 (q, J )
IR (film) 1699, 1636, 1536, 1503, 1023, 949; MS (ES) m/z 214.1
6 Hz, 2H), 2.63 (t, J ) 6 Hz, 2H), 2.98 (t, J ) 6 Hz, 2H), 6.60 (s,
+
13
(
M + H) ; HRMS calcd for C
8
H
11
N
3
O
2
S 214.0650, found (M +
, 250 MHz) δ 3.64 (s,
H), 3.8 (d, J ) 5 Hz, 2H), 5.57 (dt, J ) 6 Hz, 15 Hz, 1H), 6.45
3
1H); C NMR (CD OD, 75 MHz) δ 22.5, 27.1, 39.9, 110.4, 127.1,
+
1
+
H) 214.0640; E isomer H NMR (CDCl
3
148.6; MS (ES) m/z 141 (M + H) .
3
(
3a,4,5,6,7,7a-Hexahydro-1H-imidazo[4,5-b]pyridin-2-
1
3
1
d, J ) 15 Hz, 1H), 6.85 (s, 1H); C NMR (CDCl
3 3
-CD OD, 75
ylamine (29): paste (84% from 20); IR (film) 3390; H NMR
MHz) δ 42.3, 51.8, 121.9, 123.9, 125.7, 136.2, 167.9; Z isomer
3
(CD OD, 300 MHz) δ 1.81 (m, 2H), 2.00 (m, 1H), 2.15 (br d, J )
1
H NMR (CDCl
3
, 250 MHz) δ 3.64 (s, 3H), 3.77 (d, J ) 5 Hz,
18 Hz, 1H), 2.97 (dd, J ) 9 Hz, 6 Hz, 1H), 3.28 (br m, 1H), 4.31
1
3
2
6
H), 5.36 (dt, J ) 6 Hz, 11 Hz, 1H), 6.37 (d, J ) 11 Hz, 1H),
.93 (s, 1H).
(br m, 1H), 5.24 (d, J ) 6 Hz, 2H); C NMR (CD
3
OD, 75 MHz)
+
δ 17.0, 23.0, 41.3, 55.1, 66.2, 161.3; MS (ES) m/z 142 (M + 2H) ,
+
+
cis-2-Oxo-1,2,3,3a,5,7a-hexahydroimidazol[4,5-b]pyridine-
-carboxylic Acid Methyl Ester (16). A solution of 12 (1
141 (M + H) , 124 (C
6
H
10
N
3
) ; HRMS calcd for C
6 13 4
H N
+
4
141.1140, found (M + H) 141.1141.
mmol) in DMF (10 mL) was stirred under reflux for 1 h. The
solvent was evaporated in vacuo, and the residue was purified
by silica gel flash chromatography using 93:7 diethyl ether/
General Procedure for Ring Opening under Basic
Conditions (Preparation of Compounds 34-36). Repre-
sentative Procedure for Methyl 3-(2-Aminooxazol-5-yl)-
propylcarbamate (34). A solution of compound 30 (0.66 mmol)
in 1 M NaOH (5 mL) was stirred under reflux for 5 min. The
solution was cooled to room temperature and poured into a
mixture of phosphate buffer pH 7 and BuOH. The aqueous layer
was extracted with BuOH. The combined organic layers were
methanol to afford 16 (81 mg, 40%) as a yellow solid: mp 198
1
°
3
2
C; IR (Nujol) 3314, 3213, 1697; H NMR (CD
3
OD, 250 MHz) δ
.55 (br d, 1H), 3.65 (s, 3H), 4.06 (m, 2H), 5.56 (m, 1H), 5.86 (m,
H), 6.52 (br s, 1H), 6.76 (br s, 1H); 13C NMR (DMSO-d
6
, 75
MHz) δ 38.2, 48.0, 52.6, 61.6, 123.8, 124.3, 155.3, 160.9; MS (ES)
+
m/z 219.9 (M + H) ; HRMS calcd for C
8 11 3
H N O
3
220.0698, found
dried over MgSO
in vacuo to afford 34 (quantitative yield) as a yellow paste:
NMR (CD OD, 300 MHz) δ 1.71 (m, 2H), 2.37 (t, J ) 7.5 Hz,
2H), 3.12 (t, J ) 6.7 Hz, 2H), 3.62 (s, 3H), 6.08 (s, 1H); C NMR
(CD OD, 125 MHz) δ 23.5, 29.7, 41.0, 52.5, 106.1, 124.4, 156.9,
159.8; MS (ES) m/z 165 (M + H) , 187 (M + Na) ; HRMS (ES)
4
and filtered, and the solvent was evaporated
+
1
(
M + H) 220.0681.
General Procedure for the Cleavage of the tert-Buty-
H
3
1
3
loxycarbonyl Group and the Ring Opening under Acidic
Conditions (Preparation of Compounds 25-29). Repre-
sentative Procedure for 5-[3-(Methoxycarbonylamino)-
propyl]-1H-imidazol-2-ylammonium Chloride (25). The
crude mixture of compounds 21 was dissolved in 2 M HCl (5
mL) and the reaction mixture was stirred at 70 °C for 5 h. The
solution was cooled to room temperature, washed with diethyl
ether and the solvent was evaporated in vacuo. The residue was
3
+
+
+
calcd for C
8 14 3 3
H N O 200.1035, found (M + H) 200.1023.
Benzyl 3-(2-aminooxazol-5-yl)propylcarbamate (35): off-
white paste (quantitative yield); H NMR (CD OD, 300 MHz) δ
3
1
1.71 (q, J ) 6.9 Hz, J ) 7.5 Hz, 2H), 2.37 (t, J ) 7.4 Hz, 2H),
3.14 (t, J ) 6.8 Hz, 2H), 5.06 (s, 2H), 6.06 (s, 1H), 7.33 (m, 5H);
1
3
purified by silica gel flash chromatography using 80:20 CH
2
Cl
2
-
3
C (CD OD, 75 MHz) δ 23.5, 29.7, 41.0, 49.4 (HMBC), 67.5,
MeOH to afford 25 (237 mg, 72% from 17) as a yellow oil: IR
106.1, 124.4, 128.9, 129.0, 129.5, 138.5, 156.9 (HMBC), 159.0
(HMBC); HRMS (ES) calcd for C14
(M + Na) 298.1174.
1
(
film) 3334, 1681; H NMR (CD
3
OD, 300 MHz) δ 1.76 (t, J ) 7.5
H
17
N
3
NaO
3
298.1168, found
+
Hz, 2H), 2.51 (t, J ) 7.5 Hz, 2H), 3.15 (t, J ) 7.5 Hz, 2H), 3.55
1
3
(
4
s, 3H), 6.48 (s, 1H); C NMR (CD
3
OD, 75 MHz) δ 22.7, 29.7,
tert-Butyl 3-(2-aminooxazol-5-yl)propylcarbamate (36):
+
1
0.8, 52.6, 110.0, 128.4, 141.7; MS (ES) m/z 199 (M + H)
;
off-white paste (quantitative yield); H (CD
3
OD, 500 MHz) δ 1.43
+
HRMS calcd for C
8
H
N O
15 2 4
199.1195, found (M + H) 199.1184.
(s, 9H), 1.68 (m, 1H), 2.36 (t, J ) Hz, 1H), 3.05 (t, J ) , 1H),
13
5
-[3-(4-Methylbenzenesulfonylamino)propyl]-1H-imida-
3
6.06 (s, 1H); C (CD OD, 125 MHz) δ 23.5, 28.6, 29.8, 40.6, 80.0,
+
zol-2-ylammonium chloride (26): colorless paste (50% from
106.0, 124.5, 156.9, 158.7; MS (ES) m/z 165 (M + H) , 187 (M +
1
+
1
8); IR (film) 2924, 1155; H NMR (CD
3
OD, 300 MHz) δ 1.74 (t,
Na) ; HRMS (ES) calcd for C11
+ Na) 264.1333.
H
19
N NaO
3
3
264.1324, found (M
+
J ) 6 Hz, 2H), 2.42 (s, 3H), 2.52 (t, J ) 6 Hz, 2H), 2.85 (t, J )
6
2
1
Hz, 2H), 6.48 (s, 1H), 7.30 (d, J ) 9 Hz, 2H), 7.66 (d, J ) 9 Hz,
1
3
H); C NMR (CD
3
OD, 75 MHz) δ 21.5, 22.4, 29.1, 42.8, 110.0,
Acknowledgment. We thank MENRT for a grant
(R.A.-J.). We gratefully acknowledge Dr. Robert Dodd
for the correction of this manuscript.
+
28.0, 130.7, 138.6, 144.6, 148.3; MS (ES) m/z 295 (M + H) ;
+
HRMS calcd for C13
-[3-(Benzyloxycarbonylamino)propyl]-1H-imidazol-2-
ylammonium chloride (27): yellow oil (48% from 19); IR (film)
19 4 2
H N O S 295.1229, found (M + H) 295.1214.
5
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 7-13 and
1
3
2
6
2
1
2
307, 1681; H NMR (CD
H), 2.50 (t, J ) 6 Hz, 2H), 3.15 (t, J ) 6 Hz, 2H), 5.06 (s, 2H),
.50 (s, 1H), 7.32 (m, 5H); 13C NMR (CD
OD, 75 MHz) δ 22.7,
3
OD, 300 MHz) δ 1.76 (q, J ) 6 Hz,
1
13
3
0-33 and H and CNMR spectra for all compounds. This
3
material is available free of charge via the Internet at
http://pubs.acs.org.
9.6, 40.8, 67.4, 109.9, 128.3, 128.7, 129.0, 129.5, 138.4, 148.4,
+
59.0; MS (ES) m/z 275 (M + H) ; HRMS calcd for C14
19 4 2
H N O
+
75.1508, found (M + H) 275.1500.
JO050862O
J. Org. Chem, Vol. 70, No. 20, 2005 8211