Expeditive synthesis of homochiral fused tri- and tetrazoles-piperazines from β-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2004.03.092

N-Cyanomethyl and N-propargyl β-amino alcohols are chlorinated with SOCl₂ and treated with NaN₃ in DMSO. A substitution/cycloaddition process affords in good yields, with high diastereoselectivity and a regioselectivity depending on the substitution pattern of the starting amino alcohol, fused tri- and tetrazoles-piperazines. These heterocycles were further lithiated with n-BuLi at the benzylic position and reacted diastereoselectively with a range of electrophiles.

Full text of DOI:10.1016/j.tetlet.2004.03.092

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3725–3728
Expeditive synthesis of homochiral fused tri- and tetrazoles–
piperazines from b-amino alcoholsq
Francois Couty,* Francois Durrat and Damien Prim
ß
ß
SIRCOB, UMR CNRS 8086, Universitꢀe de Versailles, 45, avenue des Etats-Unis, 78035 Versailles Cꢀedex, France
Received 10 February 2004; revised 11 March 2004; accepted 16 March 2004
Abstract—N-Cyanomethyl and N-propargyl b-amino alcohols are chlorinated with SOCl2 and treated with NaN3 in DMSO. A
substitution/cycloaddition process affords in good yields, with high diastereoselectivity and a regioselectivity depending on the
substitution pattern of the starting amino alcohol, fused tri- and tetrazoles–piperazines. These heterocycles were further lithiated
with n-BuLi at the benzylic position and reacted diastereoselectively with a range of electrophiles.
Ó 2004 Elsevier Ltd. All rights reserved.
Synthetic procedures for the straightforward production
of original heterocycles including in their framework
well-established pharmacophores and using available
starting material are of high interest in medicinal
chemistry. Due to the emergence of combinatorial1
chemistry and high speed parallel synthesis, such syn-
thetic procedures are of special interest when they
involve starting material that can be easily derivatized
with the aim to introduce chemical diversity and that are
available in enantiomerically pure form, in order to
produce the target heterocycles in nonracemic form.
This is the case with a-amino acids and b-amino alco-
hols2 that are accessible from the chiral pool and that
can be N-alkylated with a variety of substituents. We
wish to describe herein the two-steps synthesis of fused
tri- and tetrazoles–piperazines, respectively, 2 and 3
from N,N-disubstituted b-amino alcohols 1, (Scheme 1)
and the further diastereoselective functionalization of
these heterocycles using anionic chemistry. Taking into
account the frequent occurrence of triazoles, tetrazoles
and piperazines in biologically active compounds,3 as
well as the scarcity in the literature of 4,5,6,7-tetra-
hydro-[1,2,3]triazolo[1,5-a]pyrazine4 and 5,6,7,8-tetra-
hydro-tetrazolo[1,5-a]pyrazine5 cores, respectively, 2
and 3, this methodology should be of interest for
medicinal chemists.
+
N
X
N
X
N
N
N
R3
R2
-
R3
R2
R3
R2
N
OH
N
R1
N
N
2: X = CH
3: X = N
R1
R1
1
X
Scheme 1. Synthesis of fused tri- and tetrazoles–piperazines from
b-amino alcohols.
This synthesis uses as key step an intramolecular [2 þ 3]
cycloaddition between a nitrile6 or alkyne and an azide,
to give, respectively, 3 or 2. This important reaction has
already been employed as key step for the preparation of
bioactive compounds.7
Thus, we recently reported that the chlorination (SOCl2)
of N-cyanomethyl b-amino alcohols derived from
available b-amino alcohols was regio- and stereoselec-
tive and gave in high yields chlorinated amines 4–7.8
These compounds were in turn converted into 2-cyano
azetidines. We found that the treatment of these chlo-
rides with sodium azide in DMSO at 150 °C gave good
yields of fused tetrazole–piperazines 8–12. While chlo-
rides 4–6 bearing a phenyl ring gave a single isomer,
chloride 7 gave a roughly 1/1 separable mixture of
regioisomers 11 and 12. Taking into account the overall
retention observed in this reaction, proved by NOE
experiments performed with compounds 8 and 9, it can
be deduced that this reaction most probably involves the
formation of an aziridinium intermediate A, which is
opened regioselectively at the benzylic position, in case
Keywords: Triazoles; Tetrazoles; Organolithium.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.092
* Corresponding author. Tel.: +33-139254455; fax: +33-139254452;
e-mail: couty@chimie.uvsq.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.092

3726
F. Couty et al. / Tetrahedron Letters 45 (2004) 3725–3728
of chlorides 4–6 and at both positions in case of 7, to
give the corresponding azide B with overall retention.
The latter then undergoes an intramolecular cycloaddi-
tion with the nitrile moiety (Scheme 2).
Cl
N
SOCl2, DCM, r.t.
94%
Cl
N
OH
Bn
CN
Bn
CN
Bn
+
N
CN
14
15
13
N
N
N
N
N
N
N
NaN3, DMSO
150°C, 1h
This reaction can be conducted with a mixture of iso-
meric chlorides. Thus, L-leucinol-derived amino alcohol
85%
N
+
13 gave a roughly 1/1 mixture of regioisomeric chlorides
14–15 upon treatment with SOCl2, which were reacted
with sodium azide to give separable bicyclic isomers 16
and 17 in a 4/6 ratio. An attempt of substitution at the
cyanomethylene moiety met however less success in this
reaction. Indeed, amino alcohol 20, resulting from the
acid-catalyzed opening of oxazolidine 199 in the pres-
ence of KCN was obtained as a 6/4 mixture of isomers.
Chlorination gave chloride 21 showing the same dia-
stereoisomeric ratio but the one pot substitution/cyclo-
addition process was accompanied in this case by
extensive decomposition: from the complex mixture,
only 11% yield of 22 (single isomer) could be isolated by
crystallization (Scheme 3).
N
Bn
N
Bn
16
17
40:60
KCN, citric acid
EtOH/H2O
Ph
Ph
O
N
Me
19
X
N
CN
Ph
Ph
Me
Me
Me
20 (X = OH)
21 (X = Cl)
N
N
NaN3, DMSO
150°C, 1h
SOCl2
DCM
84% overall
N
Ph
Me
N
11%
N
Me
Ph
22
This methodology could be extended to the preparation
of fused piperazine–triazole. In this event, (ꢀ)-ephedrine
23 was alkylated with propargyl bromide and the
obtained alcohol 24 was chlorinated upon treatment
with thionyl chloride. In this case, neutralization of the
reaction mixture induced formation of aziridinium salts,
reflecting the increased nucleophilicity of the secondary
amine in this N-propargyl derivative, compared to the
cyanomethylated analogue 4.10 This intramolecular
alkylation could be avoided by using a simplified one
pot experimental procedure: treatment of 24 with SOCl2
Scheme 3. Further examples of fused tetrazole–piperazines syntheses.
in dichloromethane was followed by evaporation of the
solvent and gave crude stable chlorhydrate 25 that was
directly treated with an excess of NaN3 in DMSO. In
this case, the substitution–cycloaddition process was
finished after 1 h at 110 °C, to give 26 as a single isomer
whose structure was confirmed by NOE experiments
(Scheme 4).
An attempt to perform this substitution–cycloaddition
process with phenyl-substituted alkyne 27, obtained
from 24 using palladium-catalyzed chemistry, was
however deceiving. In this case unidentified by-products
N
N
N
N
NaN3, DMSO
150°C, 1h
Ph
Ph
Cl
N
N
84%
Me
N
Me
N
Me
Me
8
4
5
6
Propargyl bromide
N
Ph
Ph
K2CO3, MeCN
OH
X
N
N
Ph
Ph
N
Id
Cl
N
NH
Me
23
Me
Me
97%
N
74%
Me
Me
N
Me
N
Me
Me
9
N
N
24 (X = OH)
N
CH
N
N
NaN3, DMSO
110°C, 1h
SOCl2
DCM
Ph
Ph
N
Id
Cl
Ph
Me
25, HCl (X = Cl)
N
70%
N
Bn
N
Bn
71% overall
N
Me
26
10
N
N
N
N
N
N
N
1) TMSCl, Et3N
2) Pd(OAc)2, CuI, PhI
3) HCl
N
Id
Cl
Ph
Ph
Me
+
OH
Ph
N
Ph
83%
N
Bn
N
Bn
N
Bn
24
N
11
7
12
53:47
Me
Ph
27
+
N
N
N
Cl
R2
R3
R2
R3
-
R3
R2
N
N
N
N
1) SOCl2, DCM
2) Evaporation
3) NaN3, DMSO
110°C, 1h
-
∆
N3
CN
CN
C
8-12
Ph
Ph
N +
R1
N
N
R1
4-7
R1
B
A
Me
N
Me
20%
28
Scheme 2. An intermediate aziridinium ion accounts for the regio-
selectivity of the process.
Scheme 4. Synthesis of fused triazole–piperazines.

F. Couty et al. / Tetrahedron Letters 45 (2004) 3725–3728
3727
were formed, and the expected triazole was obtained
with a low yield as a near 1/1 mixture of isomers at the
phenyl substituted stereocentre, indicating that direct
substitution of the azide anion on the chlorinated centre
may be here a competing process. This highlights the
fact that subtle modifications of the substituents on the
nitrogen atom can profoundly influence the stereo-
chemical course of this reaction.
mental timescale. Considering the stereochemistries in
29 and 34, the more stable lithium organometallic
probably display a trans relationship between the phenyl
and adjacent methyl group since a-heterosubstituted
benzyllithium reagents are reported to be protonated or
deuterated with retention of configuration.15 These
benzyllithium reagents could be alkylated stereoselec-
tively with different halides (entries 4,7 and 8). Reaction
with methyl iodide unexpectedly gave compound 32 as a
byproduct incorporating a butyl group: this can be
explained by a competitive metal/halogen exchange
between methyl iodide and butyllithium. The high ste-
reoselectivities observed with BuI, BnBr and acetone
probably reflect the high rate of equilibration of the
anion compared to the kinetic of the SE2 process. On the
other hand, TMSCl and MeOTf reacted more sluggishly
and with poor yield and selectivities (entries 4 and 8).
Given the possibility of both SE2inv and SE2ret mech-
anisms depending on the nature of the electrophile,16 the
intimate mechanism of this reaction merits further
studies.
The further functionalization of these heterocycles was
also studied. We found that both bicyclic tetrazole 8
and triazole 26 were cleanly metallated upon reaction
with n-butyllithium at ꢀ78 °C in THF at the benzylic
position, producing the corresponding chiral benzyl-
lithium reagents as deep red solutions. Quench of these
benzyllithiums with different electrophiles afforded the
corresponding substituted derivatives at the benzylic
position. The results of these experiments are gathered
in Table 1.
Some general comments should be made concerning this
lithiation that considerably extends the chemical diver-
sity attainable using this synthetic methodology. First,
while a-lithio triazoles reagents are well-documented
and useful synthetic tools,11 a-lithio tetrazoles are much
less reported12 and this work is, to our knowledge, the
first report concerning the reactivity of chiral non
racemic a-lithio tetrazoles. Secondly, the regioselectivity
of this metallation is total: no competitive lithiation
takes place on the methylene moiety.13 Finally, the sta-
bility of these anions is surprising: in no case, even at
0 °C, have we been able to detect products resulting
from a b-elimination.14
In summary, we have disclosed an access to nonracemic
fused tri- and tetrazoles–piperazines using very simple
experimental procedures and readily available starting
material, as well as the further diastereoselective func-
tionalization of these heterocycles using anionic chem-
istry. Further work is in progress in our group in order
to extend the scope of this one pot substitution–cyclo-
addition process to other new kinds of heterocycles.
Supplementary material
Deuteration experiments (entries 1 and 5) revealed that
lithiation and equilibration of the benzylic lithium
derivatives of both heterocycles occurs within experi-
Representative experimental procedures for the prepa-
ration of 8, 26 and 35.
Table 1. Lithiation experiment of 8 and 26
1) BuLi, -78°C
N
X
N
X
N
N
N
N
2) Electrophile
Ph
E
Ph
8: X = N
26: X = CH
Me
N
Me
Me
N
Me
29-37
De (%)
Entrya
Substrate
Eþ
Product(s)
Yield (%)
1b
2
26
26
26
CD3OD
MeOH
MeI
29: X ¼ CH, E ¼ D
30: X ¼ CH, E ¼ H
31: X ¼ CH, E ¼ Me
32: X ¼ CH, E ¼ Bu
80
80
95
95
41
32
48
92
79
75
50
––
3
80
>95
15c
33
4
26
8
TMSCl
CD3OD
33: X ¼ CH, E ¼ TMS
34: X ¼ N, E ¼ D
35: X ¼ N, E ¼ CMe2OH
36: X ¼ N, E ¼ Bn
37: X ¼ N, E ¼ Me
––
5
6
8
(Me)2CO
BnBr
>95
>95
5c
7
8
8
9d
8
MeOTf
(Ph)2CO
8
––
a Conditions otherwise stated: n-BuLi (2 equiv), THF, ꢀ78 °C, 15 min then Eþ (3 equiv), ꢀ78 °C, 30 min.
b Shortened (5 min) or protracted (30 min) reaction times with n-BuLi gave similar results.
c The relative stereochemistry of the major isomer was not determined.
d No reaction occurred at ꢀ78 °C. The reaction was quenched at 0 °C after 1 h and the major product in the reaction mixture was 9.

3728
F. Couty et al. / Tetrahedron Letters 45 (2004) 3725–3728
A.; Smith, C.; Wash, R. J.; Watson, A. A.; Winkler, D. A.;
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