Synthesis of functionalized bicyclic triazoles from chiral aziridines

Article abstract of DOI:10.1055/s-2005-871974

Enantiomerically pure 3-substituted-5-amino-4-hydroxy-5,6-dihydro-4H- pyrrolo[1,2-c][1,2,3]triazoles were synthesized efficiently from the sequential reactions including a regioselective ring-opening of 1-aziridine-2-y1- propargylic alcohols by azidotrime

Full text of DOI:10.1055/s-2005-871974

LETTER
2187
Synthesis of Functionalized Bicyclic Triazoles from Chiral Aziridines
Bicyclic
T
riazoles from
i
Chira
n
l
A
ziridines Sung Kim,a Hyo Jae Yoon,a Baeck Kyong Lee,a Ji Hyun Kwon,a Won Koo Lee,*a Yongeun Kim,b
Hyun-Joon Ha*b
a
Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology, Sogang University, Seoul 121-742, Korea
Fax +82(2)7010967; E-mail: wonkoo@sogang.ac.kr
b
Department of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, Korea
Fax +82(31)3304566; E-mail: hjha@hufs.ac.kr
Received 9 June 2005
duction method with L-Selectride® in good yield
(Scheme 1).13 Both of 1-aziridin-2-yl-propargylic alco-
hols 3 and 4 were utilized for the preparation of cis- and
trans-3-substituted-5-amino-4-hydroxy-5,6-dihydro-4H-
Abstract: Enantiomerically pure 3-substituted-5-amino-4-hy-
droxy-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazoles were synthe-
sized efficiently from the sequential reactions including
a
regioselective ring-opening of 1-aziridine-2-yl-propargylic alco-
hols by azidotrimethylsilane and the subsequent intramolecular 1,3- pyrrolo[1,2-c][1,2,3]triazole.
dipolar cycloaddition between alkyne and azide.
Ph
Ph
Key words: aziridine, triazole, cycloaddition, alkyne, azide
O
O
R-Li, THF
–78 °C
Me
Me
N
N
N
(S)
(S)
H
H
The importance of triazoles found in many biologically
active products has been emphasized in organic chemis-
try. They consist of essential structural backbone of vari-
ous pharmaceuticals with anti-HIV,1 antimicrobial,2 b-
lactamase inhibitory,3 antiviral and antiepileptic4 activi-
ties. Therefore, methodologies for the preparations of tri-
azoles have attracted much attention from both academia
and industry.5 However, there are only a few preparative
methods available from azidoallenes,6 hexofuranose,7 2-
carboxy-4-chlorophenylazide8 and polystyrene-sulfonyl
hydrazide.9 The requirement for a more efficient prepara-
tive method toward enantiomerically pure functionalized
bicyclic triazoles prompted us to develop a new facile
synthetic route. Herein we report a new strategy for the ef-
ficient preparation of multi-functionalized bicyclic tri-
azoles from the sequential reactions including a
regioselective ring-opening of 1-aziridin-2-yl-propargylic
alcohols by azidotrimethylsilane and the subsequent in-
tramolecular 1,3-dipolar cycloaddition between alkyne
and azide.
O
R
2
1
Ph
OH
ZnCl2, NaBH4
0 °C, MeOH
Me
N
(R)
(S)
H
R
3
Ph
OH
Me
N
L-Selectride
–78 °C, THF
(S)
(S)
H
R
4
Scheme 1 Preparation of 1-aziridin-2-yl-propargylic alcohols
Since the aziridine nitrogen is quite basic and also nucleo-
philic, ring-opening reactions are initiated by the forma-
tion of the aziridinium ion intermediate.10 When 1-
aziridine-2-yl-propargylic alcohols were reacted with azi-
dotrimethylsilane an activated aziridinium species I
would be produced by the silylation of the aziridine nitro-
gen. Then, regioselective ring-opening reaction with the
cleavage of C(3)–N bond proceeded by an azide that was
liberated from azidotrimethylsilane.14 Treatment of ring-
opening product with 6 N aqueous HCl solution afforded
azido amimo alcohol II. This crude reaction mixture was
concentrated, dissolved in DMF and heated to 130 °C
(Scheme 2).15
We recently reported the preparation of the Weinreb
amide from the commercially available chiral aziridine-
(2S)-carboxylic acid menthol ester10 in one step with
Weinreb’s amine hydrochloride and AlMe3 in CH2Cl2 in
high yield.11 The amide 1 was reacted with various lithium
acetylides to provide the corresponding alkynyl ketones 2
in high yields. We also reported the chelation-controlled
stereoselective reduction of 2-acylaziridines toward
erythro isomer in the presence of ZnCl2 and NaBH4 in
MeOH in high yields.11 This methods afforded various
(1S,2R)-1-aziridin-2-yl-propargylic alcohols 3 in good
yield.12 The other threo isomers, (1S,2S)-1-aziridin-2-yl-
propargylic alcohols 4 were prepared by the reported re-
Consequently, the intramolecular 1,3-dipolar cyclo-
addition16 efficiently converted the azido alkynes II to the
corresponding bicyclic triazoles 5. We applied the same
reaction condition toward various amino hydroxyl substi-
tuted bicyclic triazoles starting from 1-aziridine-2-yl-pro-
pargylic alcohols 3 bearing phenyl (5a), substituted
phenyl (5b–e), pyridyl (5f), pyrenyl (5g), linear alkyl (5h)
SYNLETT 2005, No. 14, pp 2187–2190
0
2
.0
9
.2
0
0
5
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-871974; Art ID: U17805ST
© Georg Thieme Verlag Stuttgart · New York

2188
M. S. Kim et al.
LETTER
Ph
Table 1 Synthesis of cis-3-Substituted-5-amino-4-hydroxy-5,6-di-
hydro-4H-pyrrolo[1,2-c][1,2,3]triazole
Ph
OH
NH
OH
(S)
Me
(S)
Me
N
Ph
Ph
TMSN3
R
(R)
OH
NH
(S)
OH
N
H
Me
(S)
N
(S)
Me
R
N
N
(R)
R
3
(S)
5
N
H
R
N
N
CH2Cl2
r.t.
3
TMSN3
130 °C
DMF
5
Products
R
Yield (%)a,b
83
Me
HN
Ph
Ph
Me
OH
TMS
5a
OH
N
(R)
(R)
(S)
(S)
R
N
H
N
R
5b
5c
85
84
N3
N
I
II
CF3
Scheme 2 Preparation of bicyclic triazole and its reaction
mechanism
Me
4
and cyclic alkyl (5i) substituents on R in 74–89% yields
(Table 1).
5d
5e
81
86
The same reaction could be applicable with the threo iso-
mers of (1S,2S)-1-aziridin-2-yl-propargylic alcohols 4 for
the preparation of trans-3-substituted-(5S)-amino-(4R)-
hydroxy-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazoles 6
represented by the examples of 6a and 6i in 83% and 89%
yield, respectively (Table 2).
F
CH3
5f
74
78
N
The absolute configuration at C-4 of the 3-substituted-4,5-
difunctionalized bicyclic triazoles was indirectly estab-
lished by measuring the coupling constants of the two vic-
inal protons at C-4 and C-5. The measurement of two sets
of the coupling constants (5a and 6a, 5i and 6i) clearly es-
tablished the substitution patterns of cis- and trans-4,5-di-
functionalized bicyclic triazoles (Table 3) by the
difference of 1.3 Hz and 2.2 Hz, respectively.
5g
5h
5i
75
89
Me
4
The removal of a-methylbenzyl nitrogen protecting group
from bicyclic triazoles (5 or 6) was achieved at ease by hy-
drogenation at room temperature in the presence of
Pd(OH)2 as a catalyst. N-a-Methylbenzyl-protected ami-
no bicyclic triazoles are also convertible to the corre-
sponding cyclic carbamate 7 at which stage the a-
methylbenzyl nitrogen protecting group can also be re-
moved.17 This procedure was exemplified with the com-
pound 5a. Hydrogenation of 5a in the presence of
Pd(OH)2 as a catalyst produced free amino alcohol 9a in
84% yield.18 The removal of a-methylbenzyl nitrogen
protecting group from 5a also could be achieved by the se-
quential reactions. At first bicyclic triazole 5a was con-
verted to the corresponding cyclic carbamate 7a in 84%
yield by treatment of triphosgene and NaH. The subse-
quent removal of the a-methylbenzyl group was accom-
a All products characterized by 1H NMR, IR spectroscopy, and mass
spectrometry.
b Isolated yields after purification.
In conclusion, we developed a new method for the pre-
paration of enantiomerically pure cis- and trans-3-sub-
stituted-5-amino-4-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-
c][1,2,3]triazole from the sequential reactions including a
regioselective ring-opening of 1-aziridine-2-yl-propargyl-
ic alcohols by azidotrimethylsilane and intramolecular
1,3-dipolar cycloaddition between alkyne and azide.
Acknowledgment
plished by treating with anisole and MeSO3H to give 8a in We gratefully acknowledge the financial support of the following
institutions: The Korea Science and Engineering Foundation
(R01-2005-000-10032-0 and the Center for Bioactive Molecular
Hybrides to HJH), Korea Research Foundation (KRF-2002-070-
C00060 to WKL) and Imagene for providing enantiomerically pure
chiral aziridines. WKL acknowledges the special fund from Sogang
University in 2004.
93% yield. Then the cyclic carbamate 8a was hydrolyzed
in aqueous EtOH using LiOH to provide the correspond-
ing free amino bicyclic triazole 9a in 82% yield
(Scheme 3). This procedure was applicable to the com-
pounds bearing hydrogenation-sensitive functional group
like olefin on 5i and 6i.
Synlett 2005, No. 14, 2187–2190 © Thieme Stuttgart · New York

LETTER
Bicyclic Triazoles from Chiral Aziridines
2189
References
Table 2 Synthesis of trans-3-Substituted-5-amino-4-hydroxy-5,6-
dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole
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Ph
Ph
OH
(R)
NH
OH
(S)
Me
Me
N
(S)
R
(S)
N
H
R
N
N
4
6
Products
R
Yield (%)
83
6a
(5) Gouault, N.; Cupif, J. F.; Sauleu, A.; David, M. Tetrahedron
Lett. 2000, 41, 7293.
6i
89
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b Isolated yields after purification.
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Table 3 Coupling Constants of cis- and trans-3-Substituted-4-
hydroxy-5-amino Bicyclic Triazoles
Ph
R2
NH
R1
Me
(R)
(12) The same product, (1S,2R)-1-aziridine-2-yl-propargylic
alcohol (3), could be obtained from addition reactions of the
aziridine-(2S)-carboxaldehyde with the corresponding
organolithium reagents to afford aziridine-(2S)-propargylic
alcohols. The chelation controlled reduction of the carbonyl
group of 2-acylaziridine as shown in Scheme 1 provided
better stereoselectivity than the addition of organolithium
reagents to the aziridine-(2S)-carboxaldehyde. See: Park, C.
S.; Choi, H. G.; Lee, H. J.; Lee, W. K.; Ha, H.-J.
Tetrahedron: Asymmetry 2000, 11, 3283.
R
N
N
N
Compd
5a
R
R1
OH
OH
H
R2
H
J4,5 (Hz)
5.6
Ph
5i
1-Cyclohexenyl
Ph
H
5.5
6a
OH
OH
4.3
(13) Kim, B. C.; Lee, W. K. Tetrahedron 1996, 52, 12117.
(14) Shin, S.-H.; Han, E. Y.; Lee, W. K.; Ha, H.-J. Tetrahedron:
Asymmetry 2000, 11, 3293.
6i
1-Cyclohexenyl
H
3.3
(15) Preparation of (4S,5S)-4-Hydroxy-3-phenyl-5-{(1R)-1-
phenylethylamino)-5,6-dihydro-4H-pyrrolo[1,2-
c][1,2,3]triazole(5a).
O
Ph
Ph
To a solution of aziridine-(2S)-propargyl alcohol (3a, 110
mg, 0.40 mmol) in 2.00 mL of CH2Cl2 under nitrogen
atmosphere was added TMSN3 at r.t. The mixture was stirred
for 3 h at r.t. then quenched with 6 N HCl. The aqueous layer
was extracted with CH2Cl2. The combined extracts were
dried over MgSO4, and the solvent was evaporated to give
product as yellow oil. The crude reaction product was
dissolved in 2.10 mL of DMF at r.t. The mixture was stirred
under a nitrogen atmosphere for 16 h at 130 °C. The solvent
was evaporated to give the crude product as a yellow oil
which was purified by silica gel flash chromatography with
50% EtOAc–hexane to give 106 mg of 5a as a white solid in
83% yield; mp 128–129 °C; [a]D24 = +38.2 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.82 (d, J = 7.4 Hz, 2 H),
7.37–7.25 (m, 8 H), 4.78 (d, J = 5.6 Hz, 1 H), 4.51 (dd,
J = 11.6, 6.9 Hz, 1 H), 4.10 (dd, J = 11.5, 6.8 Hz, 1 H), 4.01
(q, J = 6.4 Hz, 1 H), 3.92 (td, J = 6.9, 5.6 Hz, 1 H), 1.46 (d,
J = 6.4 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = 144.0,
142.3, 138.1, 130.4, 129.1, 128.9, 128.2, 128.0, 126.9,
126.2, 64.5, 62.9, 57.2, 51.1, 24.3. Anal. Calcd for
C19H20N4O: C, 71.2; H, 6.29; N, 17.5. Found: C, 71.3; H,
6.30; N, 17.2.
Triphosgene
NaH
OH
NH
O
Me
N
(S)
(S)
Me
THF, –78 °C
84%
N
N
N
N
N
N
7a
5a
anisole, MeSO3H 93%
PhCl, reflux
H2 (120 psi)
Pd(OH)2
r.t.
84%
O
OH
H2N
O
HN
(S)
(S)
LiOH
EtOH,H2O
reflux
N
N
N
N
N
N
82%
9a
8a
Scheme 3 Formation of carbamate and removal of the nitrogen
protecting group
Synlett 2005, No. 14, 2187–2190 © Thieme Stuttgart · New York

2190
M. S. Kim et al.
LETTER
(16) (a) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124,
2134. (b) Broggini, G.; Molteni, G.; Zecchi, G. Synthesis
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Poon, Y. F.; Schkeryantz, J. M.; Williams, J. P. J. Org.
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1997, 8, 3807.
(18) Removal of a-Methylbenzyl Nitrogen Protecting Group
from 5a.
To a solution of phenylethylamino bicyclic triazole (5a, 110
mg, 0.34 mmol) in 1.90 mL of MeOH was added Pd(OH)2 at
r.t. The mixture was stirred for 30 h under 120 psi of H2 (g)at
r.t. then the catalyst was filtered and washed with MeOH.
The solvent was evaporated to give product as yellow oil
which was purified by recrystallization from CH2Cl2 to give
61 mg (84%) of 3-phenyl-5-amino-4-hydroxy-5,6-dihydro-
4H-pyrrolo[1,2-c][1,2,3]triazole(9a) as a white solid; mp
197–198 °C; [a]D24 = +106.5 (c 0.7, CH3OH). 1H NMR (500
MHz, CDCl3): d = 7.82 (d, J = 8.0 Hz, 2 H), 7.38 (t, J = 7.3
Hz, 2 H), 7.28 (t, J = 7.5 Hz, 1 H), 5.03 (d, J = 5.5 Hz, 1 H),
4.55 (dd, J = 11.1, 7.4 Hz, 1 H), 4.14 (td, J = 7.4, 5.6 Hz, 1
H), 3.96 (dd, J = 11.1, 7.3 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): d = 141.6, 139.3, 130.6, 128.8, 128.2, 125.9, 65.4,
58.6, 51.7. Anal. Calcd for C11H12N4O: C, 61.1; H, 5.59; N,
25.9. Found: C, 61.2; H, 5.53; N, 26.0.
(17) Park, C. S.; Kim, M. S.; Sim, T. B.; Pyun, D. K.; Lee, C. H.;
Choi, D. O.; Lee, W. K.; Ha, H.-J. J. Org. Chem. 2003, 68,
43.
Synlett 2005, No. 14, 2187–2190 © Thieme Stuttgart · New York