Synthesis of chiral primary amines: diastereoselective alkylation of N-[(1E)-alkylidene]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amin es and N4-Nexocyclic bond cleavage in the resulting 1,2,4-triazol-4-alkylamines

Article abstract of DOI:10.1016/j.tetasy.2008.12.015

Enantiomerically pure 3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a and 3,5-bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine 14b were used as chiral auxiliaries to obtain enantiomerically enriched α-aminoacetals, primary alkyl and arylalkyl amines (ee ranging from 40% to 90%). The different stages of the process were imine formation from the corresponding aldehydes, diastereoselective addition of a Grignard reagent, quaternization of the triazole auxiliary and cleavage of the N₄-N_exocyclic bond by LiBH₄. The mechanism of the cleavage of the N₄-N_exocyclic bond is supported by the use of deuterated metal hydride. The absolute configurations of the new stereogenic centres were established by X-ray analyses of the enantiomerically pure stereomers isolated by semi-preparative liquid chromatography on a chiral support.

Full text of DOI:10.1016/j.tetasy.2008.12.015

Tetrahedron: Asymmetry 19 (2008) 2682–2692
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of chiral primary amines: diastereoselective alkylation
of N-[(1E)-alkylidene]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amines
and N4–Nexocyclic bond cleavage in the resulting 1,2,4-triazol-4-alkylamines
a
Muriel Serradeil-Albalat a, Christian Roussel a, , Nicolas Vanthuyne ,
*
Jean-Claude Vallejos a, Didier Wilhelm b
a Chirosciences ISM2 UMR6263, Université Paul Cézanne-Aix-Marseille III, Case A62, F-13397, Marseille, CEDEX20, France
b CLARIANT France, Usine de Lamotte, L.R.A., F-60350, Trosly Breuil, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure 3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a and 3,5-bis[(1S)-1-
ethoxyethyl]-4H-1,2,4-triazol-4-amine 14b were used as chiral auxiliaries to obtain enantiomerically
enriched a-aminoacetals, primary alkyl and arylalkyl amines (ee ranging from 40% to 90%). The different
stages of the process were imine formation from the corresponding aldehydes, diastereoselective addi-
tion of a Grignard reagent, quaternization of the triazole auxiliary and cleavage of the N4–Nexocyclic bond
by LiBH4. The mechanism of the cleavage of the N4–Nexocyclic bond is supported by the use of deuterated
metal hydride. The absolute configurations of the new stereogenic centres were established by X-ray
analyses of the enantiomerically pure stereomers isolated by semi-preparative liquid chromatography
on a chiral support.
Received 22 October 2008
Accepted 12 December 2008
Available online 13 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
amines) our efforts are now directed towards the removal of this
chiral auxiliary’.
Enantiomerically pure (1S,10S)-1,10-(4-amino-4H-1,2,4-triazole-
3,5-diyl)diethanol 1 is an inexpensive chiral compound with C2
symmetry. 1 is prepared in a single step from natural (S)-lactic acid
and hydrazine. In the late 80s and early 90s, 1 was used as a start-
ing material for the preparation of enantiomerically pure macrocy-
cles.1–3
Herein, we report on the successful removal of the chiral auxil-
iary in triazolyl amines using a sequence of quaternization of the
N
N
N
N
ArCHO
In 1996, 1 was reacted with aromatic aldehydes to yield triazol-
yl arylimines 2.4 (Scheme 1) After methylation of the alcohols, the
imines 3 were reacted with aryl or aryl alkyl Grignard reagents to
yield a mixture of diastereomeric triazolyl amines 4 with particu-
larly attractive diastereoselectivities ranging from 70% to 99%
depending on the aryl group.4 Diastereoselectivities and yields
for 4 were comparable to those reported for the other diastereose-
lective routes to enantiomerically enriched primary amines using
chiral auxiliaries5 such as sulfinamides,6 SAMP or RAMP and ana-
N
N
N
HO
OH
HO
OH
NH2
1
Ar
2a-c
logues,7 N-acylhydrazones,8 or -arylethylamines.9
a
However, despite the low cost of the starting chiral auxiliary
and the high diastereoselectivities observed, the triazole amine
route did not attract much interest due to a severe drawback,
which has already been outlined by Katritzky et al. in their original
paper:4 ‘To realize the full potential of the chiral triazole as a chiral
auxiliary (for the synthesis of enantiomerically pure primary
N
N
N
N
N
N
N
Ar(CH2)nMgBr
n=0,1,2
MeO
OMe
HN
MeO
OMe
( )n
Ar
Ar
Ar
4
3a-c
* Corresponding author. Tel.: +33 0 491288257; fax: +33 0 491289146.
E-mail address: christian.roussel@univ-cezanne.fr (C. Roussel).
Scheme 1. The Katritzky et al.4 synthesis of triazolyl amines.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.015

M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
2683
N
N
CH2Ph
N
N
Br-
N
N
N
N+
R3M
N
N
N
N
PhCH2Br
OR2
R3
OR2
N
R2O
HN
R2O
MeO
HN
OMe
CH(OMe)2
MeO
HN
OMe
*
R1
R1
CH(OMe)2
5
6
R4X
R4
N
N+
LiBH4 / THF
H2N
R3
N-N cleavage
*
N
OR2
R3
R1
R2O
X-
HN
CH2Ph
N
N
*
R1
N
7
MeO
OMe
Scheme 2. Synthesis of chiral primary amines.
+
triazole ring and cleavage of the N4–Nexocyclic bond with lithium
borohydride (Scheme 2) to yield chiral alpha-branched primary
amines.10 The proof of the concept is exemplified in the synthesis
H2N
CH(OCH3)2
8
of chiral
a-aminoacetals and more generally of chiral primary
Scheme 3. Quaternization and N4–Nexocyclic bond cleavage in 5.
amines, using
(a) diastereoselective nucleophilic 1,2-addition of a Grignard
reagent to the CN-double bond of N-[(1E)-alkylidene]- or
N-[(1E)-2,2-dimethoxyethylidene]-1,2,4-triazol-4-amine
derivatives,
(b) removal of the chiral auxiliary through quaternization fol-
lowed by N4–Nexocyclic bond cleavage.
cleavage experiments. The N4–Nexocyclic bond cleavage in 6 was
successfully accomplished using metal hydrides. Among the vari-
ous metal hydrides (LiBH4, NaBH4, DIBAL-H, NaBH(OAc)3 and
NaBH(OMe)3), LiBH4 gave the best results. The reaction of 6 with
1 molar equivalent of LiBH4, using tetrahydrofuran as a solvent,
gave 1-benzyl-3,5-bis[(1S)-1-methoxyethyl]-1H-1,2,4-triazole
and the expected dimethoxyethylamine 8 in 70–85% yield.
7
A possible mechanism for the N4–Nexocyclic bond cleavage in the
triazolium salts is proposed in Scheme 4. In the first step, the addi-
tion of hydride should occur on the activated C-5 carbon atom of
the heterocycle yielding the intermediate 9a. Hydrogen elimina-
tion with cleavage of the N4–Nexocyclic bond accounts for the forma-
tion of the observed compounds.
In order to confirm the proposed mechanism, the triazolium
amine salt 11, which bears no substituent on the triazole ring at
C3 and C5, was treated with sodium borodeuteride (Scheme 5).
Triazolium amine salt 11 was obtained quantitatively by benzyla-
tion of the known rac-N-(1,1-dimethoxybutan-2-yl)-4H-1,2,4-tria-
zol-4-amine 10.15 Crude triazolium amine salt 11 was used
without further purification.
Two isotopomeric triazoles 12a and 12b (Scheme 5) could be
obtained according to the proposed mechanism, provided the rota-
tion around the N4–Nexocyclic bond is faster than the D–D elimina-
tion in the intermediate 9b. The 1H NMR spectra of the isolated
1-benzyl triazole fraction showed that the lower field triazole ring
proton (H5),22 had been partly exchanged with deuterium. The sig-
nal absorption gave 0.67 for H5 (8 ppm) and 1 for H3 (7.9 ppm),
revealing a mixture composed of 67% of 12a and 33% of 12b. An un-
equal population of 12a and 12b resulted from either a possible
isotopic effect or a probable concerted process during the elimina-
tion step. The occurrence of 12b is in full agreement with the
mechanism we postulated for the N4–Nexocyclic bond cleavage in
1,2,4-triazolium salts (Scheme 4).
2. Results and discussion
2.1. Cleavage of the N4–Nexocyclic bond
N-(2,2-Dimethoxyethyl)-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-
triazol-4-amine 5 was used as model compound to study the cleav-
age of the N4–Nexocyclic bond. Compound 5 was obtained in good
yield by reaction of the bis-dimethylether of 1 with dimethoxyeth-
anal (DME) and reduction of the resulting triazolyl imine 15b with
sodium borohydride. Compound 1 was transformed into the corre-
sponding bis-dimethylether 14 before reaction with dimethoxy-
ethanal to prevent intramolecular addition of the hydroxyl group
to the imine. We experienced such an addition using several
aliphatic aldehydes.11 In the original process when dealing with
aromatic aldehydes,4 the hydroxyl groups were transformed into
ethers after the arylimine formation.
The established mild methods used to cleave hydrazine deriva-
tives proved unsuccessful to cleave the N4–Nexocyclic bond in 5,
despite extensive attempts. Catalytic hydrogenolysis (Ra–Ni,12a
Pd–C12b and PtO212c), reduction (BH3ꢀTHF,13 NaBH4) or photochem-
ical methods also proved unsuccessful. Attempts to reach free
hydrazines by triazole ring opening (NaOH and KOH) or by trans-
hydrazinolysis (N2H4ꢀH2O and N2H4ꢀH2SO4) failed.
Taking into account the easy reductive cleavage of the bis-
methylsulfate of 1,10-bibenzotriazole by lithium aluminium hy-
dride to obtain 1-methylbenzotriazole,14 we explored a sequence
of quaternization of 5 and reduction (Scheme 3). Treatment of
the triazolyl amine 5 with benzyl bromide at room temperature
without solvent afforded the triazolium salt 6 in quantitative yield.
The alkylation was clearly confirmed by the splitting of the 1H and
13C signals in NMR spectra due to the loss of C2-symmetry in 6. The
salt was used without further purification in N4–Nexocyclic bond
2.2. Proof of the concept
2.2.1. Diastereoselective addition
The enantiomerically pure 3,5-bis[(1S)-1-methoxyethyl]-4H-
1,2,4-triazol-4-amine 14a16 was reacted with butyraldehyde or

2684
M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
R2
R2
H
N
N+
X-
N
N
N
N
N
MeO
OMe
δ+N
R1
MeO
OMe
H
R1
H
δ−
BH3
H
-
BH3
Li+
R2
H
R2
N
N
N
N
+
OMe
R1NH-BH2
N
MeO
OMe
N
δ+N
R1
H
δ−
BH2
MeO
Scheme 4. Postulated mechanism for 4H-[1,2,4]triazol-1-ium salt N4–Nexocyclic bond cleavage with lithium borohydride.
dimethoxyethanal in the presence of a catalytic amount of p-tolu-
enesulfonic acid in refluxing 1,2-dichloroethane or toluene, with
azeotropic water removal, to afford the expected triazolyl imines
15a–b in excellent yields (90–95%) (Scheme 6). Triazolyl imine
15c was prepared by reaction of dimethoxyethanal with triazolyl
amine 14b obtained by reaction of 1 with ethyltosylate (70% yield)
(Scheme 6).
NOESY experiments on triazolyl imine 15b, whose results were
confirmed by X-ray analysis (Fig. 1), showed that the C@N bond
was E. A single geometrical isomer was thus obtained with an
E-conformation of the CN-double bond, as determined for hydra-
zones 2.4
The test substrates 15a–c did not behave in the same way.
High diastereoselectivities (de P 90%) were reached with the
addition of ethylmagnesium bromide to triazolyl imine 15a; these
diastereoselectivities were high whatever the experimental condi-
tions (entries 1, 4 and 7, Table 1). In sharp contrast, the diastere-
oselectivities in the addition of ethylmagnesium bromide to
triazolyl imines 15b–c bearing an acetal group were very variable
and strongly dependent on the solvent nature and the operating
conditions.
The assignment of the absolute configuration of the newly
formed stereogenic centre upon addition of ethylmagnesium
bromide to triazolyl imines 15a–c was performed according to
the following procedures. Preparative HPLC on a chiral support
(Chiralpak IA) provided each diastereomer of 16a from triazolyl
Triazolyl imines 15a–c were reacted with ethylmagnesium bro-
mide to yield triazolyl amines 16a–c (Scheme 7, Table 1).
CH2Ph
N+
N
N
N
Br-
P
hCH2Br
H
H
N
H
H
N
Et
HN
HN
Et
*
*
CH(OMe)2
CH(OMe)2
11
10
NaBD4
THF
CH2Ph
N
N
N
CH2Ph
N (2)
H
H
H
N
N
(1)
(2)
12a
H
(2)
Et
D
N
N
(1)
H2N
*
+
(1)
H
CH2Ph
D
D
CH(OMe)2
R
B
D
N
D
13
40%(a)
9b
R=(C2H5)CHCH(OMe)2
N
12b
(a) Low solubility of NaBD4 in THF.
Graded by gas chromatographic analyses
(calibration with internal standard).
Scheme 5. N4–Nexocyclic bond cleavage in 4H-[1,2,4]triazol-1-ium salt using NaBD4.

M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
2685
N
N
N N
NaH / MePhSO3R1
DMF
N
N
R1O
OR1
HO
OH
NH2
NH2
1
14a-b
1
14a
: R =Me
14b: R1=Et
CH3(CH2)2CHO or (CH3O)2CHCHO
APTS / toluene or ClCH2CH2Cl
N
N
N
N
OR1
R1O
R2
15a-c
15a: R1=Me; R2=CH2CH2CH3
1
2
15b
: R =Me; R =CH(OCH3)2
15c: R1=Et; R2=CH(OCH3)2
Scheme 6. Synthesis of hydrazones from aliphatic aldehydes and aminotriazoles 14a and 14b.
N
N
N N
EtMgX(a)
N
N
N
R1O
OR1
R1O
OR1
Et
MgBr2 (0-2equiv)
THF or CH2Cl2
HN
*
R2
R2
R1
R2
15,16
15a-
c
16a-c
a
b
c
Me CH3CH2CH2
Me CH(OCH3)2
Et CH(OCH3)2
(a) solution in Et2O
Figure 1. X-ray structure of compound 15b (N-[(1E)-2,2-dimethoxyethylidene]-
3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine).
Scheme 7. Addition of ethylmagnesium bromide to 15a–c.
Fig. 5). These configurations of the new stereogenic centre were the
same as those of the major diastereomers for 16b and 16c, when the
best selectivities were obtained (entry 11 for 16b and entry 9 for 16c
in Table 1).
A slight reversal of diastereoselectivity occurred when the Grig-
nard reagent was added to triazolyl imine 15b in non-chelating
dichloromethane. In the operating conditions (C) (entry 8), the
(S)-diastereomer, which was until then the minor one, became
the major one, although barely so. The addition of magnesium bro-
mide (2 equiv) afforded an attractive selectivity (entry 11,
de = 70%, major (R)-diastereomer), associated with the low reactiv-
ity of 15b (10% of recovered 15b), whereas nucleophilic alkylation
was inhibited for alkyl hydrazone 15a (entry 10).
imine 15a in an enantiomerically pure state: de(R)-16a > 96% and
de(S)-16a > 96%. X-ray analysis of the major diastereomer of hydra-
zines 16a enabled us to assign the (S)-configuration to the new
stereogenic centre (see Section 4 for X-ray structure of (S)-16a,
Fig. 3). Preparative HPLC on Chiralpak AD provided both diastereo-
mers of triazolyl amines 16b and 16c, in high enantiomeric purity:
de(S)-16b > 96% and de(R)-16b > 99% for compound 16b, and de(S)-16c
=
100% and de(R)-16c = 100% for compound 16c. The absolute configura-
tions of the second eluted diastereomers for 16b and 16c on Chir-
alpak AD were assigned by X-ray analysis. The second eluted
diastereomer of 16b had an (R)-configuration, while that of 16c
had an (S)-configuration at the new stereogenic centre (see Section
4 for X-ray structure of (R)-16b, Fig. 4; X-ray structure of (S)-16c,
These results pointed to a sharp contrast in the diastereoselec-
tivity control by the chiral triazole in the presence or absence of
competitive chelating groups carried by the aldehyde. For aliphatic
aldehydes without additional chelating group, such as in 15a, the
diastereoselectivity was induced within diastereomeric complexes
involving the oxygen of the chiral auxiliary ether. In 15b and 15c,
the oxygen atoms of the acetal and methoxy groups of the triazole
auxiliary were in competition for the chelation of the organometal-
lic nucleophile. It has already been reported17 that hydrazones
bearing an acetal functionality on the hydrazone aldehyde moiety
lead to lower selectivity.
For
a better understanding, only the configuration of the newly formed
stereocenter of diastereomers will be given. Compound 16a: N-[(3R)-hexan-3-yl]-
3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine andN-[(3S)-hexan-3-yl]-3,5-
bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine, will be called (R)-16a and (S)-
16a, respectively. Compound 16b: N-[(2R)-1,1-dimethoxybutan-2-yl]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-4-amine and N-[(2S)-1,1-dimethoxybutan-2-yl]-3,5-
bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine, will be called (R)-16b and (S)-
16b, respectively. Compound 16c: N-[(2R)-1,1-dimethoxybutan-2-yl]-3,5-bis[(1S)-1-
ethoxyethyl]-4H-1,2,4-triazol-4-amine and N-[(2S)-1,1-dimethoxybutan-2-yl]-3,5-
bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine, will be called (R)-16c and (S)-16c,
respectively.

2686
M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
Table 1
Diastereoselective addition on 15a–c
Entry Product Operating
conditionsa
Yield
(%)
Diastereoselectivities Major
de (%)
diastereomer
1
2
3
4
16a
16b
16c
16a
(A)
(A)
(A)
(B)
100b
81d
76c
34e
32e
>90g
(S)-16a
(R)-16b
(R)-16c
(S)-16a
100b
70d
(20)f
75d
5
16b
(B)
44e
(R)-16b
(13)f
100b
100b
90d
6
7
8
9
16c
16a
16b
16c
(B)
(C)
(C)
(C)
38e
>90g
6e,h
60h
(R)-16c
(S)-16a
(S)-16b
(S)-16c
Figure 3. X-ray structure of (S)-16a.
100b
(75)k
—
i
10
11
16a
16b
(D)
(D)
—
—
83d
70e
(R)-16b
(10)f
100b
12
16c
(D)
8h
(S)-16c
a
Operating conditions: (A) 5 equiv EtMgBr/0 °C/THF–Et2Oj/addition of the
triazolyl imine 15 solution to the EtMgBr solution. (B) 5 equiv EtMgBr/0 °C/CH2Cl2-
Et2O(j)/addition of the triazolyl imine 15 solution to the EtMgBr solution. (C) 5 equiv
EtMgBr/0 °C/CH2Cl2–Et2O(j)/addition of the EtMgBr solution to the triazolyl imine
15 solution. (D) 5 equiv EtMgBr/0 °C/CH2Cl2–Et2O(j)/addition of the EtMgBr solution
to the triazolyl imine 15 with 2 mol equiv MgBr2 solution.
b
Crude material.
c
Determined by semi-preparative chiral HPLC separation (see Section 4).
Graded by gas chromatographic analyses (calibration with an internal
d
standard).
e
Determined by gas chromatographic analyses.
Recovered hydrazone.
Determined by NMR analyses.
Reversed diastereoselectivity.
f
Figure 4. X-ray structure of (R)-16b.
g
h
i
Unreacted starting material 15a was identified by gas chromatography and
case of poorly solvating medium and very low concentration of
the Grignard species, such as in entries 8 and 9, the (S)-form is
favoured. The presence of a MeO group or an EtO group on the tri-
azole ring was a key factor in the control of the diastereoselectivity,
as seen in entries 8/9 and 11/12.
NMR analyses.
j
Et2O results only from EtMgBr synthesis.
k
After purification by flash chromatography.
As a result, the control of diastereoselectivity for the addition of
ethylmagnesium bromide in 15b and 15c is highly variable, a typi-
cal situation when several conflicting complexed or chelated tran-
sition states are in competition. This is not unexpected when one
considers that triazolyl imines 15b and 15c offer four oxygen-based
binding sites for the magnesium species participating in the
Schlenk equilibrium, in addition to the nitrogen atoms of the imine
and the triazole. More precisely the two oxygens of the acetal seem
to be highly unfavourable to very high diastereoselectivities.
The results presented in Table 1 also reveal the dramatic impor-
tance of the actual concentration of the magnesium species, in
association with the nature of the co-solvent, on the stereoselectiv-
ity. In the highly solvating medium THF–Et2O, the (R)-form in 16b
and 16c is favoured (entries 2 and 3). The (R)-form is also favoured
in the case of a poorly solvating medium and a very high concen-
tration of Grignard species (entries 5, 6 and entries 11, 12). The re-
sults obtained in the case of MgBr2 addition fit this model. In the
2.2.2. Cleavage of the N4–Nexocyclic bond by LiBH4
The triazolyl amines 16 listed in Figure 2 were synthesized in
order to illustrate the route to
arylalkyl amines.
a-aminoacetals, primary alkyl and
The cleavage of the N4–Nexocyclic bond by LiBH4 was conducted
on a diastereomeric mixture of triazolium salts 17a–e (Scheme 8)
obtained by quantitative benzylation of 16a–e. The enantiomeri-
cally enriched amines 13 and 19a-c were obtained (50–90% yields).
The N4–Nexocyclic bond cleavage in 1-(alkyl or arylalkyl)-4-(alkyl
or aryl alkylamino)-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-tria-
zol-1-ium salts 17a–e is simple, efficient and selective. No deben-
zylation was observed in the case of 16e (Table 2, entry 5). The
similarity between the de found in carbamates 20a-d, resulting
from the reaction between the chiral primary amines 13, 19a-c
and (ꢁ)-(1R)-menthylchloroformate (Scheme 9), and the de of
the starting triazolyl amines 16a–e shows that no noticeable
N
N
N N
EtMgX(a)
N
N
N
OR1
OR1
Et
R1O
R1O
MgBr2 (0-2equiv)
THF or CH2Cl2
HN
*
R2
R2
R1
R2
15a-
c
15,16
16a-c
a
b
c
Me CH3CH2CH2
Me CH(OCH3)2
Et CH(OCH3)2
(a) solution in Et2O
Figure 2. Triazolyl amines 16.
Figure 5. X-ray structure of (S)-16c.

M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
2687
CH2Ph
N
N+
–
N
Br
N
N
N
BnBr
step1
R1O
OR1
R3
R1O
OR1
R3
HN
HN
*
*
R2
R2
16a-e
17a-e
R1
R2
(CH2)2CH3
CH(OCH3)2 C2H5
CH(OCH3)2 C2H5
R3
16a/17a
Me
Me
Et
C2H5
16b/17b
16c/17c
16d/17d
16e/17e
LiBH4 (1equiv)
THF
step 2
Me
Me
CH(OCH3)2
C6H5
Ph
CH3
CH2Ph
R3
N
N
*
R2
+
H2N
N
R1O
OR1
13: R2=CH(OCH3)2 R3=C2H5
: R =(CH2)2CH3 R3=C2H5
7: R1=Me
18: R1=Et
2
19a
19b: R2=CH(OCH3)2 R3=Ph
2
19c
: R =Ph
R3=CH3
Scheme 8. N4–Nexocyclic bond cleavage of triazolyl amines 16.
epimerization has occurred during the cleavage of the N4–Nexocyclic
bond. (Table 2).
It should be noted that the formation of a quaternary salt, re-
quired before the amine is released, adds a new reaction step to
the whole process and this is of course not very productive in
terms of process economy. However, one may foresee some inter-
esting applications and take advantage of the benzylation step and
cleavage of the resulting quaternary salt. Preliminary experiments
(not reported) showed that the quaternization step can be per-
formed using a Merrifield polymer. Cleavage of the supported tria-
zolium amine salt yielded the free amine in solution, whereas the
bound auxiliary was easily eliminated with the resin. This process
might be advantageous in comparison with other methods using a
chiral auxiliary to achieve a ‘traceless’ synthesis of enantiomeri-
3. Conclusion
In conclusion, the sequence of quaternization and N4–Nexocyclic
bond cleavage with metal hydrides is a general method to obtain
chiral primary amines: a-aminoacetals 13 and 19b (Table 2 entries
1–3), alkyl amines (19a, Table 2 entry 4) and aryl alkyl amines 19c
(Table 2 entry 5) from the corresponding triazolyl amines 16. The
diastereoselectivies are modest in the case of 16b and 16c, but,
interestingly, they can reach 70% de in favour of the (R)- or (S)-form
thanks to minor changes (MeO to EtO) in the same (S,S)-chiral aux-
iliary. Chromatography on chiral support was shown to be very
efficient in the separation of the diastereomers on analytical and
semi-preparative levels, and it may provide an interesting comple-
ment in the isolation of enantiomerically pure derivatives 16a–e.
Careful crystallization of the diastereomeric benzyltriazolium salts
17a–e might also be an alternative process (as in the case of 17d,
see Section 4).
cally pure
a-branched amines. Further work is currently in pro-
gress in this direction.
4. Experimental
1H NMR and 13C NMR spectra were recorded on a Brücker AC
200 spectrometer in deuteriochloroform (CDCl3) or deuteriodim-
ethylsulfoxide (DMSO-D6). Coupling constants (J) are quoted in
Hertz. Gas chromatographic (GC) analyses were run on a Perkin–
Elmer Autosystem Gas Chromatograph (Chrompack, CP-SIL 5, 30
Table 2
Study of stereochemical loss during N4–Nexocyclic bond cleavage of triazolyl amines16
*
m
0.25 or 0.32 mm, 0.25
lm): Tinjector = 300 °C, Tdetector = 300 °C,
oven programsà
:
a
Entry Compound
de16/17a-e Metal Hydride
(equiv)
de20a-e
Major
diastereomer
16
70b
50b
100c
90b
70b
LiBH4 (1)
LiBH4 (1)
LiBH4 (1)
LiBH4 (1)
LiBH4 (1)
66
48
100
90
(R)-13
(a) 50 °C?280 °C (10 °C/min) and 280 °C for 5 min;
(b) 120 °C?230 °C (7 °C/min), 230 °C?280 °C (3 °C/min) and
280 °C for 10 min;
(c) 120 °C?280 °C (3 °C/min) and 280 °C for 10 min;
(d) 170 °C for 5 min, 170 °C?280 °C (3 °C/min) and 280 °C for
30 min.
1
2
3
4
5
16b
16d
16d
16a
16e
(R)-19b
(R)-19b
(S)-19a
(S)-19c
68
a
Determined by gas chromatographic analysis of diastereomeric carbamates 20
derived from chiral primary amines 13 and 19a-c and (ꢁ)-(1R)-menthyl chloro-
formate (see Scheme 9).
b
Determined by gas chromatographic analysis of the mixture of diastereomer
triazolyl amines 16.
c
à
Enantiomerically pure (R)-17d, single triazolium salt diastereomer obtained by
GC retention time will be noted like this: tR(a–d), depending on the oven program
used.
crystallization (see X-ray structure Fig. 6).

2688
M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
R2
*
O
O
Et3N (1,5 equiv) / Et2O
+
R1
H2N
O
NH
*
O
Cl
R1
R2
R1
R2
19a-c/13
20a-d
19a/20a
(CH2)2CH3 C2H5
19b/20b CH(OCH3)2 Ph
19c/20c
13/20d
Ph
CH3
CH(OCH3)2 C2H5
Scheme 9. Diastereomeric carbamates 20.
GC–MS analyses were performed on a GC Varian 3500 gas chro-
matograph with an Automass 150 Unicam mass detector. [
MS: m/z (%): 213 (M-75, 0.5), 168 (14), 122 (7), 75 (100); HRMS
a]
D
(ESI): for C12H24N4O4 [M+H]+: calcd. 289.1870; found 289.1870.
were measured on a 241 MC Perkin–Elmer polarimeter with a so-
dium lamp and a double-jacked cell thermostated at 25 °C. Melting
points were determined with a Kofler apparatus, and are uncor-
rected. X-ray crystallographic structures were performed in the
Crystallography Department at Paul Cezanne Aix-Marseille III
University. Chiral HPLC analyses and semi-preparative separations
were performed in the Dynamic Stereochemistry and Chirality
Laboratory at Paul Cezanne Aix-Marseille III University. Semi-pre-
parative chiral HPLC experiments were run on a unit composed of a
Merck D-7000 system manager, a Merck Lachrom L-7100 pump, a
4.3. 1-Benzyl-4-[(2,2-dimethoxyethyl)amino]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-1-ium bromide 6
The crude triazolyl amine 5 and benzyl bromide were stirred in
equimolar quantities without solvent at rt for 48 h. Gas chroma-
tography analyses showed a decreasing signal for triazolyl amine
5 and an increasing one for the substituted triazole ring 7. Triazo-
lium salt 6 underwent decomposition in a GC injector to give
1-substituted triazole and an imine compound which was not
detected.19 Crude salt 6 was used without further purification. 1H
NMR (CDCl3): d 1.5 (d, 3H, J = 6.9 Hz), 1.6 (d, 3H, J = 6.6 Hz), 3.2
(s, 3H), 3.25 (s, 3H), 3.3 (m, 2H), 3.4 (s, 3H), 3.4 (s, 3H), 4.4 (m,
1H), 5.3 (q, 1H, J = 6.6 Hz), 5.4 (q, 1H, J = 6.9 Hz), 5.6 (syst AB,
2H), 7.2-7.35 (m, 5H), 8.3 (t, 1H, J = 4.5 Hz); 13C NMR (CDCl3): d
16.3, 19.1, 51.7, 54.2, 54.6, 55.4, 56.3, 58.8, 68.55, 69.85, 102.9,
127.8-129.1, 132.1, 155.8, 157.05.
Merck Lachrom L-7200 injector,
a Merck Lachrom L-7400
UV-detector and a Jasco OR-1590 polarimeter. Exact mass mea-
surements were performed using ESI-MS HR in the Spectropole
department at Paul Cezanne Aix-Marseille III University.
Solvents were from SDS (Peypin, France) or Riedel de Hahn, of
anhydrous grade, pure for syntheses and analyses and used with-
out further purification. Chemicals for reactions were used as pur-
chased from commercial sources. Dimethoxyethylamine and the
solution of dimethoxyethanal (60% in water) were provided by Cla-
riant France. The authentic samples of racemic amines were affor-
4.4. 1-Benzyl-3,5-bis[(1S)-1-methoxyethyl]-1H-1,2,4-triazole
ded commercially for 19c (
for 19a from hexan-3-one and benzylamine: imine condensation,
reduction and benzylic deprotection. For racemic -aminoacetals
13 and 19b, the syntheses were performed from DL-2-aminobu-
tyric acid and 2-phenyl glycine, respectively, via Wenreib amide
formation, reduction and ketalization.
a
-methylbenzylamine) and by synthesis
Compound 7: GC tR(a) = 20.6 min; 1H NMR (CDCl3): d 1.5 (d, 3H,
J = 6.8 Hz), 1.6 (d, 3H, J = 6.6 Hz), 3.2 (s, 3H), 3.4 (s, 3H), 4.5 (q,
1H, J = 6.6 Hz), 4.7 (q, 1H, J = 6.8 Hz), 5.5 (syst AB, 2H), 7.2–7.4
(m, 5H); 13C NMR (CDCl3): d 19.2, 20.1, 52.5, 56.5, 56.7, 72.2,
73.1, 127.3–128.7, 136, 156.1, 163.5; EI MS: m/z (%): 275 (M,
1), 260 (39), 245 (100), 213 (92), 123 (23), 122 (23), 91 (100),
59 (81).
a
4.1. (1S,10S)-1,10-(4-Amino-4H-1,2,4-triazole-3,5-diyl)diethanol 1
4.5. rac-N-(1,1-Dimethoxybutan-2-yl)-4H-1,2,4-triazol-4-amine
This compound was prepared according to the literature proce-
dure reported by Torres et al.;1 Mp 130–132 °C; 1H NMR (DMSO-
D6): d 1.5 (d, 6H, J = 6.6 Hz), 4.9 (m, 2H), 5.4 (d, 2H, J = 5.8 Hz),
5.77 (s, 2H); 13C NMR (DMSO-D6): d 20.9, 59.3, 156.4.
1015
1H NMR (CDCl3): d 0.9 (t, 3H, J = 7.4 Hz), 1.35 (m, 2H), 3 (m, 1H),
3.35 (s, 3H), 3.4 (s, 3H), 4.2 (d, 1H, J = 5.6 Hz), 5.4 (d, 1H, J = 3.2 Hz),
8.2 (s, 2H); 13C NMR (CDCl3): d 9.7, 21.4, 55.1, 55.75, 64.2, 104.6,
143.7.
4.2. N-(2,2-Dimethoxyethyl)-3,5-bis[(1S)-1-methoxyethyl]-4H-
1,2,4-triazol-4-amine 5
4.6. 1-Benzyl-1H-1,2,4-triazole 12a20,22
Triazolyl imine 15b (4 g, 13.9 mmol) was dissolved in 20 mL
MeOH. One molar equivalent of sodium borohydride was added
slowly at room temperature for 30 min. The mixture was then stir-
red at rt for 30 min and heated at reflux for an additional 30 min.
At room temperature, the reaction medium was quenched with
NaOH (1 M) and the solvent was removed. Water (15 mL) was
added to the residue and the solution was extracted with CHCl3
(3 ꢂ 10 mL). The organic extracts were dried over anhydrous
MgSO4, filtered and evaporated to dryness; yellow oil (3.9 g,
97%); GC tR(b) = 19.57 min; 1H NMR (CDCl3): d 1.6 (d, 6H, J = 6.7
Hz), 3.1 (m, 2H), 3.2 (s, 6H), 3.3 (s, 3H), 3.35 (s, 3H), 4.5 (t, 1H,
J = 5.1 Hz), 4.7 (q, 2H, J = 6.7 Hz), 5.4 (t, 1H, J = 7.4 Hz); 13C NMR
(CDCl3): d 16.95, 53.95, 54.3, 54.7, 55.7, 70.35, 102.15, 154.15; EI
GC tR(a) = 15 min; 1H NMR (CDCl3): d 5.3 (s, 2H), 7.1–7.4 (m,
5H), 7.9 (s, 1H), 8 (s, 1H); 13C NMR (CDCl3): d 53.7, 128–129.1,
134.6, 143.1, 152.2; EI MS: m/z (%): 159 (M, 21), 158 (34), 132
(50), 104 (22), 91 (100), 77 (20), 65 (49), 51 (31), 39 (25).
4.7. rac-1,1-Dimethoxybutan-2-amine 1318,20
Bp 62–63 °C/20 mmHg; GC tR(a) = 6.7 min; 1H NMR (CDCl3): d 1
(t, 3H, J = 7.5 Hz), 1.65 (m, 2H), 3 (m, 1H), 3.4 (s, 3H), 3.45 (s, 3H),
4.3 (d, 1H, J = 5.4 Hz), 6.2 (s, 2H); 13C NMR (CDCl3): d 10.35, 21.15,
54.1, 54.7, 54.85, 108.25; EI MS: m/z (%): 133 (M, 1), 102 (35), 75
(100), 58 (100), 57 (97), 41 (100).

M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
2689
4.8. 3,5-Bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a
J = 6.7 Hz), 3.25 (m, 4H), 3.4 (s, 6H), 4.6 (q, 2H, J = 6.8 Hz), 4.8 (d,
1H, J = 5.4 Hz), 8.1 (d, 1H, J = 5.4 Hz); 13C NMR (CDCl3): d 14.9,
17.5, 54.1, 54.3, 63.7, 68.6, 101.6, 152.1, 165.6; CI+: 315 (M+1); EI
MS: m/z (%): 283 (M-31, 3), 270 (7), 239 (12), 195 (100), 124
(85), 122 (65), 75 (100), 73 (79); HRMS (ESI): for C14H26N4O4
[M+H]+: calcd. 315.2026; found 315.2029.
This compound was prepared according to the literature proce-
dure reported by Katritzky et al.16 Mp 66–70 °C; GC tR(b)
=
14.13 min; 1H NMR (CDCl3): d 1.3 (d, 6H, J = 6.7 Hz), 3 (s, 6H), 4.5
(q, 2H, J = 6.7 Hz), 5.35 (s, 2H); 13C NMR (CDCl3): d 17.15, 55.85,
69.7, 154.2.
4.13. General procedure for Grignard reagent synthesis
4.9. 3,5-Bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine 14b
A few drops of pure alkyl/aryl bromide and an iodine crystal
were added on magnesium turnings (0.7 g, 28 mmol) in 5 mL
Et2O to start the reaction. Once the reaction had started, an alkyl/
aryl bromide (28 mmol) solution in Et2O (25 mL) was added drop-
wise in order to maintain gentle reflux, and the stirring was
started. The reaction mixture was then stirred for 15 min at room
temperature and was heated at reflux for 30 min. After cooling at
room temperature, the Grignard reagent solution was used for
the nucleophilic addition on triazolyl imines 15.
This compound was prepared according to the procedure used
for compound 14a. ½a D25
¼ ꢁ67:6 (c 1, CHCl3); GC tR(a) = 19.3 min;
ꢃ
1H NMR (CDCl3): d 1.05 (t, 3H, J = 7 Hz), 1.5 (d, 6H, J = 6.7 Hz), 3.4
(m, 4H), 4.7 (q, 2H, J = 6.7 Hz), 5.2 (s, 2H); 13C NMR (CDCl3): d
15.3, 18.2, 64.3, 69.3, 153.9; EI MS: m/z (%): 199 (M-29, 3), 184
(100), 138 (93), 122(25), 94 (59); HRMS (ESI): for C10H20N4O2
[M+H]+: calcd. 229.1659; found 229.1653.
4.10. N-[(1E)-Butylidene]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-
triazol-4-amine 15a
4.14. General procedure for the reaction of the protected triazolyl
imines 15 with Grignard reagents
3,5-Bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a (1.49
g, 7.4 mmol), butyraldehyde (0.5 g, 7.4 mmol) in equimolar quanti-
ties and a catalytic amount of p-toluenesulfonic acid (0.02 equiv)
were heated in toluene at reflux for 3 h with azeotropic elimina-
tion. The solvent was removed under reduced pressure after
The Grignard reagent solution in Et2O (5 equiv) was diluted in
solvent (THF or CH2Cl2, 3 mL /mmol) and cooled to 0 °C. At this
temperature, a solution of triazolyl imine 15 in reaction solvent
(0.35 M) was added dropwise to the reaction medium at a rate of
10 mL /h. The reaction mixture was then stirred for 3 h at 0 °C,
and then poured into a saturated aqueous ammonium chloride
solution. The resulting emulsion was extracted with CH2Cl2 several
times. The organic extracts were dried over anhydrous MgSO4, fil-
tered and evaporated to dryness.
neutralization by Et3N. Oil (1.8 g, 95%). ½a D25
¼ ꢁ110:4 (c 1, CHCl3);
ꢃ
GC tR(b) = 17.21 min; 1H NMR (CDCl3): d 1 (t, 3H, J = 7.4 Hz), 1.5 (d,
6H, J = 6.8 Hz), 1.7 (m, 2H), 2.5 (m, 2H), 3.2 (s, 6H), 4.6 (q, 2H, J = 6.8
Hz), 8.1 (t, 1H, J = 5.4 Hz); 13C NMR (CDCl3): d 13.5, 17.1, 18.7, 35,
55.7, 70.2, 151.35, 175.1; EI MS: m/z (%): 255 (M+1, 2), 239 (6), 224
(63), 181 (47), 140 (66), 122 (94), 59 (100), 41 (95); HRMS (ESI): for
C12H22N4O2 [M+H]+: calcd. 255.1815; found 255.1812.
4.15. General procedure for the reaction of the protected triaz-
olyl imines 15 with Grignard reagents with extra addition of
magnesium bromide
4.11. N-[(1E)-2,2-dimethoxyethylidene]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-4-amine 15b
Triazolyl imine 15 and magnesium bromide (2 equiv) were dis-
solved in CH2Cl2 (17 mL /mmol), and the mixture was stirred for
30 min at room temperature, and then cooled to 0 °C. At this
temperature, a Grignard reagent solution in Et2O (5 equiv) was
added dropwise at a rate of 20 mL/h. The reaction mixture was
then stirred for 3 h at 0 °C. It was then poured into a saturated
aqueous ammonium chloride solution and the resulting emulsion
was extracted with CH2Cl2. The organic extracts were dried over
anhydrous MgSO4, filtered and evaporated to dryness.
3,5-Bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a (7.8
g, 39 mmol) and dimethoxyethanal as 60% aqueous solution (8.1 g,
47 mmol) were heated in 1,2-dichloroethane (60 mL) at reflux.
After azeotropic removal of the water, a catalytic amount of p-tol-
uenesulfonic acid (0.02 equiv) was added and the solution was
refluxed for 3 h. At room temperature, Et3N was added to neutral-
ize the catalyst, and after solvent removal under reduced pressure,
the residue was crystallized from hot heptane: colourless solid
(10.3 g, 92%). Mp 96–100 °C; ½a D25
¼ ꢁ72:3 (c 1.25, CHCl3); GC
ꢃ
tR(b) = 18.47 min; 1H NMR (CDCl3): d 1.6 (d, 6H, J = 6.7 Hz), 3.3 (s,
6H), 3.5 (2s, 6H), 4.7 (q, 2H, J = 6.8 Hz), 5 (d, 1H, J = 5.4 Hz), 8.2
(d, 1H, J = 5.4 Hz); 13C NMR (CDCl3): d 17.2, 54.3, 54.6, 55.85,
70.3, 101.75, 151.9, 165.7; EI MS: m/z (%): 286 (M, 0.4), 256 (9.3),
211 (29), 181 (32), 122 (12), 75 (100), 59 (40); HRMS (EI): for
C12H23O4N4 [M+H]+: calcd. 287.1719; found 287.1715. X-ray struc-
ture (Fig. 1).
4.16. N-[(3R)-Hexan-3-yl]-3,5-bis[(1S)-1-methoxyethyl]-4H-
1,2,4-triazol-4-amine and N-[(3S)-hexan-3-yl]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-4-amine 16a
A mixture of diastereomers was used without further purifica-
tion for the N4–Nexocyclic bond cleavage. Diastereomers were
isolated by semi-preparative HPLC on chiral support; analytical
data: Chiralpak IA (250*4.6 mm), hexane/isoPropanol (90/10, v/v),
1 mL /min, 25 °C, 220 nm tminor(R)-16a = 21.36 min tmajor(S)-
16a = 22.89 min, semi-preparative separation data: Chiralpak IA
4.12. N-[(1E)-2,2-Dimethoxyethylidene]-3,5-bis[(1S)-1-ethoxy-
ethyl]- 4H-1,2,4-triazol-4-amine 15c
*
(250 10 mm) was used with hexane/isopropanol (90/10, v/v) as
3,5-Bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine 14b (4 g,
17.5 mmol) and dimethoxyethanal as 60% aqueous solution
(3.65 g, 21 mmol) were heated in 1,2-dichloroethane (30 mL) at
reflux. After azeotropic removal of the water, a catalytic amount
of p-toluenesulfonic acid (0.02 equiv) was added and the solution
was refluxed for 3 h. At room temperature, Et3N was added to neu-
tralize the catalyst and the solvent was removed under reduced
mobile phase, 5 mL /min as flow-rate and UV at 220 nm. In total,
60 injections of 150 lL of a 15.5 mg/mL solution (12/88 diastereo-
mers mixture) were done. The min or diastereomer, (R)-16a, was
collected between 21 and 22 min to give 16 mg with de > 96%,
and the major one, (S)-16a, was collected between 22 and
24 min to give 120 mg with de > 96%. The X-ray structure (Fig. 3)
of the major diastereomer was determined, and it enabled us to
assign the (S)-configuration to the new stereogenic centre.
pressure: oil (5.2 g, 95%). ½a D25
¼ ꢁ65:75 (c = 1.14, CHCl3); GC
ꢃ
tR(a) = 22.1 min; 1H NMR (CDCl3): d 1 (t, 6H, J = 7 Hz), 1.45 (d, 6H,

2690
M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
EI MS: m/z (%): 284 (M, 6), 255 (26), 223 (75), 209 (66), 191 (20),
4.22. N-[(2R)-1,1-Dimethoxybutan-2-yl]-3,5-bis[(1S)-1-ethoxy-
ethyl]-4H-1,2,4-triazol-4-amine and N-[(2S)-1,1-dimethoxybutan-
2-yl]-3,5-bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine 16c
122 (76), 59 (99), 43 (100), 41 (58)); HRMS (ESI): for C14H28N4O2
[M+H]+: calcd 285.2285; found 285.2280.
4.17. N-[(3S)-Hexan-3-yl]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-
triazol-4-amine (S)-16a
Diastereomers (450 mg) were isolated by semi-preparative
HPLC on a chiral support; analytical data: Chiralpak AD (250*4.6
mm), Hexane/isoPropanol (80/20, v/v), 1 mL/min, 25 °C, 210 nm
tminor(R)-16c = 7.42 min tmajor(S)-16c = 8.63 min, semi-preparative
½
a 2D5
ꢃ
¼ ꢁ5:7 (c 1, CHCl3); Mp 38–40 °C; 1H NMR (300 MHz,
*
CDCl3): d 0.87–0.94 (m, 6H), 1.2–1.5 (m, 6H), 1.64 (d, 6H, J = 6.6
Hz), 3.15–3.25 (m, 1H), 3.33 (s, 6H), 4.76 (q, 2H, J = 6.6 Hz), 5.11
(d, 1H, J = 3.6 Hz); 13C NMR (300 MHz, CDCl3): d 9.56, 14.26,
17.49, 18.56, 24.01, 33.74, 55.27, 61.30, 69.97, 154.99. X-ray struc-
ture (Fig. 3).
separation data: Chiralpak AD (250 10 mm) was used with hex-
ane/isopropanol (80/20, v/v) as a mobile phase, 4 mL /min as
flow-rate and UV at 210 nm. Five hundred microlitres of
a
10 mg/mL solution (21/79 diastereomers mixture) were injected
every 9 min. The two diastereomers were collected between 8
and 11 min (tminor(R)-16c = 9.7 min and tmajor(S)-16c = 11.8 min).
After 90 injections, 70 mg of the first eluted diastereomer (R)-16c
(minor) and 280 mg of the second one (S)-16c (major) were
obtained with de = 100%. The X-ray structure (Fig. 5) of the major
diastereomer was determined, and it enabled us to assign the
(S)-configuration to the new stereogenic centre.
4.18. N-[(3R)-Hexan-3-yl]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-
triazol-4-amine (R)-16a
½
a 2D5
ꢃ
¼ þ1:5 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): d 0.86–0.95
(m, 6H), 1.2–1.5 (m, 6H), 1.64 (d, 6H, J = 6.6 Hz), 3.1–3.25 (m, 1H),
3.335 (s, 6H), 4.77 (q, 2H, J = 6.6 Hz), 5.13 (d, 1H, J = 4.2 Hz); 13C
NMR (300 MHz, CDCl3): d 9.50, 12.22, 17.48, 18.69, 24.68, 33.39,
55.26, 61.28, 69.98, 154.97.
CI+: 345 (M+1); EI MS: m/z (%): 313 (M-31, 3), 269 (M-75, 40),
223 (70), 182 (49), 177 (38), 136 (23), 122 (72), 75 (100), 45
(55); HRMS (ESI): for C16H32N4O4 [M+H]+: calcd. 345.2496; found
345.2498.
4.19. N-[(2R)-1,1-dimethoxybutan-2-yl]-3,5-bis[(1S)-1-methoxy-
ethyl]-4H-1,2,4-triazol-4-amine and N-[(2S)-1,1-dimethoxybutan-
2-yl]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 16b
4.23. N-[(2R)-1,1-Dimethoxybutan-2-yl]-3,5-bis[(1S)-1-ethoxy-
ethyl]-4H-1,2,4-triazol-4-amine (R)-16c
Diastereomers (469 mg) were isolated by semi-preparative
HPLC on chiral support; analytical data: Chiralpak AD (250*4.6
mm), hexane/isoPropanol (60/40, v/v), 1 mL /min, 22 °C, 210 nm
tminor(S)-16b = 6.17 min tmajor(R)-16b = 7.84 min, semi-preparative
Mp 94 °C; ½a 2D5
¼ þ7:85 (c 0.76, CHCl3); GC tR(c) (R)-16c =
ꢃ
17.8 min; 1H NMR (CDCl3): d 0.9 (t, 3H, J = 7.5 Hz), 1.2 (t, 6H,
J = 7 Hz), 1.5 (m, 2H), 1.7 (d, 6H, J = 6.8 Hz), 3.48 (s, 3H), 3.49 (s,
3H), 3.5 (m, 5H), 4.4 (d, 1H, J = 5 Hz), 4.9 (q, 2H, J = 6.8 Hz), 5.8
(d, 1H, J = 5 Hz); 13C NMR (CDCl3): d 15.35, 17.9, 21.5, 55.05,
55.8, 62.65, 63, 68.05, 105, 155.1.
*
separation data: Chiralpak AD (250 10 mm) was used with
hexane/isopropanol (60/40, v/v) as mobile phase, 4 mL/min as
flow-rate and UV at 210 nm. Five hundred microlitres of a 7 mg/
mL solution (25/75 diastereomers mixture) were injected every
10 min. The two diastereomers were collected between 7 and
13 min (tminor(S)-16b = 6.7 min and tmajor(R)-16b = 8.5 min). After
135 injections, 59.3 mg of the first eluted diastereomer (S)-16b
(minor) and 312.6 mg of the second one (R)-16b (major) were
obtained with de > 96%. The X-ray structure (Fig. 4) of the major
diastereomer was determined, and it enabled us to assign the
(R)-configuration to the new stereogenic centre.
4.24. N-[(2S)-1,1-Dimethoxybutan-2-yl]-3,5-bis[(1S)-1-ethoxy-
ethyl]-4H-1,2,4-triazol-4-amine (S)-16c
Mp 88 °C;
½
a 2D5
ꢃ
¼ þ45:4 (c 1.11, CHCl3); GC tR(c) (S)-
16c = 17.6 min; 1H NMR (CDCl3): d 0.85 (t, 3H, J = 7.5 Hz), 1.15 (t,
6H, J = 7 Hz), 1.45 (m, 2H), 1.6 (d, 6H, J = 6.8 Hz), 3.3 (s, 3H), 3.4
(s, 3H), 3.45 (m, 5H), 4.2 (d, 1H, J = 5 Hz), 4.8 (q, 2H, J = 6.8 Hz),
5.6 (d, 1H, J = 5 Hz); 13C NMR (CDCl3): d 15.4, 17.5, 21.15, 54.7,
56.1, 62.6, 63.1, 68.4, 105.45, 155.05. X-ray structure (Fig. 5).
CI+: 317 (M+1); EI MS: m/z (%): 285 (M-31, 3), 253 (16), 241
(31), 209 (86), 177 (36), 168 (76), 136 (26), 122 (85), 75 (100),
59 (68); HRMS (ESI): for C14H28N4O4 [M+H]+: calcd 317.2183;
found 317.2182.
4.25. N-[(1R)-2,2-Dimethoxy-1-phenylethyl]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-4-amine and N-[(1S)-2,2-dime-
thoxy-1-phenylethyl]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-
triazol-4-amine 16d
4.20. N-[(2R)-1,1-dimethoxybutan-2-yl]-3,5-bis[(1S)-1-methoxy-
ethyl]-4H-1,2,4-triazol-4-amine (R)-16b
A mixture of diastereomers was prepared according to the gen-
eral procedure for the reaction of the protected triazolyl imines 15
with Grignard reagents (described above) from 15b and a phenyl-
magnesium bromide solution. It was used without further purifica-
tion for the N4–Nexocyclic bond cleavage; GC tR(b) (S)-16d = 27.4 min,
tR(b) (R)-16d = 27.7 min. Diastereomers were isolated by semi-pre-
parative HPLC on chiral support; analytical data: Chiralpak AD-H
Mp 67–68 °C;
½
a 2D5
ꢃ
¼ ꢁ13:6 (c 1.02, CHCl3); GC tR(d) (R)-
16b = 15.6 min; 1H NMR (CDCl3): d 0.8 (t, 3H, J = 7.5 Hz), 1.4 (m,
2H), 1.6 (d, 6H, J = 6.8 Hz), 3.25 (s, 6H), 3.35 and 3.37 (2s, 6H),
3.4 (m, 1H), 4.3 (d, 1H, J = 5.2 Hz), 4.75 (q, 2H, J = 6.8 Hz), 5.3 (d,
1H, J = 4.2 Hz); 13C NMR (CDCl3): d 10.1, 17.3, 21.5, 54.9, 54.95,
55.55, 62.45, 69.2, 104.85, 155. X-ray structure (Fig. 4).
*
(250 4.6 mm), hexane/isopropanol (70/30, v/v), 1 mL/min, 25 °C,
4.21. N-[(2S)-1,1-Dimethoxybutan-2-yl]-3,5-bis[(1S)-1-methoxy-
ethyl]-4H-1,2,4-triazol-4-amine (S)-16b
254 nm tminor(S)-16d = 6.35 min tmajor(R)-16d = 14.49 min, semi-
*
preparative separation data: Chiralpak AD (250 10 mm) was used
with hexane/isopropanol (50/50, v/v) as mobile phase, 5 mL /min
as flow-rate and UV at 254 nm. In total, 28 injections of 250 lL
of a 17 mg/mL solution (23/77 diastereomers mixture) were done.
The min or diastereomer, (S)-16d, was collected between 4 and
7 min to give 27.2 mg with de > 96%, and the major diastereomer,
(R)-16d, was collected between 8 and 12 min to give 89 mg with
de > 96% .
Mp 74 °C; ½a 2D5
ꢃ
¼ þ25:4 (c 0.67, CHCl3); GC tR(d) (S)-16b =
15.36 min; 1H NMR (CDCl3): d 0.9 (t, 3H, J = 7.4 Hz), 1.4 (m, 2H),
1.6 (d, 6H, J = 6.6 Hz), 3.3 (s, 6H), 3.3 (s, 6H), 3.4 (m, 1H), 4.2 (d,
1H, J = 4.8 Hz), 4.75 (q, 2H, J = 6.6 Hz), 5.55 (d, 1H, J = 4.8 Hz); 13C
NMR (CDCl3): d 10.55, 16.8, 21.8, 54.8, 54.95, 56, 62.3, 69.4,
105.4, 154.8.

M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
2691
EI MS: m/z (%): 289 (M-75, 1.4), 257 (10), 200 (6), 168 (35), 122
(13), 75 (100), 59 (11); HRMS (ESI): for C18H28N4O4 [M+H]+: calcd
365.2183; found 365.2184.
4.26. N-[(1R)-2,2-Dimethoxy-1-phenylethyl]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-4-amine (R)-16d
½
a 2D5
ꢃ
¼ ꢁ116:8 (c 1, CHCl3); Mp 121–123 °C; GC tR(b) (R)-16d =
27.7 min; 1H NMR (300 MHz, CDCl3): d 1.41 (d, 6H, J = 6.8 Hz),
3.29 (s, 6H), 3.34 (s, 3H), 3.54 (s, 3H), 4.36 (q, 2H, J = 6.6 Hz),
4.56 (m, 1H), 4.79 (d, 1H, J = 6.3 Hz), 5.86 (d, 1H, J = 4.5 Hz), 7.2–
7.4 (m, 5H); 13C NMR (300 MHz, CDCl3): d 16.41, 54.35, 54.71,
55.84, 66.98, 68.13, 105.18, 128.75, 128,83, 129.20, 135.96, 154.20.
Figure 6. X-ray structure of (R)-17d.
4.27. N-[(1S)-2,2-Dimethoxy-1-phenylethyl]-3,5-bis[(1S)-1-
methoxyethyl]-4H-1,2,4-triazol-4-amine (S)-16d
a 2D5
ꢃ
¼ þ79:4 (c 1, CHCl3); GC tR(b) (S)-16d = 27.4 min; 1H NMR
4.31. General procedure for N4–Nexocyclic bond cleavage in triazo-
lium salt 17 and determination of the ee of the chiral amines
½
(300 MHz, CDCl3): d 1.58 (d, 6H, J = 6.3 Hz), 3.09 (s, 6H), 3.20 (s,
3H), 3.53 (s, 3H), 3.38 (m, 1H), 4.47 (q, 2H, J = 6.6 Hz), 4.69 (d,
1H, J = 7.2 Hz), 5.93 (d, 1H, J = 1.8 Hz), 7.2–7.4 (m, 5H); 13C NMR
(300 MHz, CDCl3): d 17.96, 54.61, 55.74, 55.98, 67.23, 70.42,
105.33, 128.77, 128,85, 129.19, 135.78, 155.04.
Triazolium salt (3.5 mmol) 17 was dissolved in THF (0.6 M). At
room temperature, a solution of lithium borohydride in THF
(2 M) (1 equiv, 1.75 mL) was added dropwise at a rate of 1–
1.5 mL/h. The reaction mixture was then stirred for 3 h at rt, and
then refluxed for 3 h. After cooling at rt, the mixture was quenched
with a 20% sodium hydroxide solution (20 mL), and the resulting
emulsion was extracted with CH2Cl2. The organic extracts were
dried over anhydrous MgSO4, filtered and partially evaporated.
The amount of released amines 13 and 19a–c was measured by
gas chromatography (calibration with an internal standard and
authentic pure samples).
The enantiomeric purity of the released amines was evaluated
from the GC analysis of the diastereomeric carbamates 20a–d
(Scheme 1) derived from chiral primary amines 13 or 19a–c and
(ꢁ)-(1R)-menthyl chloroformate. Chiral primary amines 13 and
19a–c and Et3N (1.5 equiv) were dissolved in Et2O at 0 °C under
N2, then a solution of (ꢁ)-(1R)-menthyl chloroformate (1 equiv)
in Et2O was added dropwise. The reaction mixture was stirred for
30 min at 0 °C before being allowed to slowly warm to room tem-
perature. The salts were filtered and the solution was quenched
with a 10% sodium hydroxide solution. The organic extracts were
dried over anhydrous MgSO4, filtered and evaporated to dryness.
The de of carbamates 20a–d (Scheme 9) were determined by gas
chromatography (Table 3).
4.28. 3,5-Bis[(1S)-1-methoxyethyl]-N-[(1S)-1-phenylethyl]-4H-
1,2,4-triazol-4-amine and 3,5-bis[(1S)-1-methoxyethyl]-N-[(1R)-
1-phenylethyl]-4H-1,2,4-triazol-4-amine 16e
A mixture of diastereomers was prepared according to the gen-
eral procedure for the reaction of the protected triazolyl imines 15
with Grignard reagents (described above) from 3a (Ar@Ph) and a
commercially available methylmagnesium bromide solution. It
was used without further purification for the N4–Nexocyclic bond
cleavage; GC tR(b) (S)-16e = 26 min, tR(b) (R)-16e = 26.5 min; (S)-ma-
jor diastereomer; (S)-16e: 1H NMR (CDCl3): d 1.35–1.5 (2d, 9H), 3.2
(s, 6H), 4.2–4.4 (m, 3H), 5.4 (d, 1H, J = 5.6 Hz), 7.10–7.3 (m, 5H);
13C NMR (CDCl3): d 16.8, 19.5, 54.95, 61.15, 69.45, 127.4–129.1,
141.9, 154.4; EI MS: m/z (%): 289 (M-15, 0.7), 274 (3), 240 (8), 170
(33), 138 (16), 122 (95), 105 (100), 77 (18), 59 (58); HRMS (ESI):
for C16H24N4O2 [M+H]+: calcd 305.1972; found 305.1973.
4.29. General procedure for quaternization of triazolyl amines 16
The crude diastereomeric triazolyl amine mixtures 16 and ben-
zyl bromide were stirred in equimolar quantities without solvent
at rt for 48 h. Gas chromatography analyses showed a decreasing
signal for triazolyl amines 16 and an increasing one for the substi-
tuted triazole ring 18. Triazolium salt 17 underwent decomposi-
tion in a GC injector to give 1-substituted triazole and an imine
compound which was not detected.19 Except for the compound
17d, the crude salts were used without further purification.
4.32. rac-2,2-Dimethoxy-1-phenylethanamine 19b18,21
Bp 108 °C/3 mmHg; GC tR(a) = 13.9 min. 1H NMR (CDCl3): d 3.3
(s, 1H), 3.5 (s, 3H), 4.05 (d, 1H, J = 6.2 Hz), 4.35 (d, 1H, J = 6.2 Hz),
7.3–7.45 (m, 5H); 13C NMR (CDCl3): d 55.3, 55.6, 58, 108.8,
125.4–128.7, 141.3; EI MS: m/z (%): 150 (M-31, 2), 106 (41), 75
(100), 47 (19).
4.30. 1-Benzyl-4-{[(1R)-2,2-dimethoxy-1-phenylethyl]amino}-
3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-1-ium bromide
(R)-17d
Table 3
GC analysis of diastereomeric carbamates 20a–d
Obtained from 16d and benzyl bromide (Scheme 9).
Product
R
R0
(CH2)2CH3 C2H5 tR(c) (R)-20a = 30.6 min and tR(c) (S)-20a = 30.7 min
CH(OCH3)2 Ph tR(b) (S)-20b = 33.35 min and tR(b) (R)-20b = 32.95 min
C6H5 CH3 tR(c) (S)-20c = 23.3 min and tR(b) (R)-20c = 23.55 min
CH(OCH3)2 C2H5 tR(c) (S)-20d = 19.55 min and tR(b) (R)-20d = 19.7 min
GC analysisa
The major diastereomer was isolated by selective crystallization
in THF; Mp 170–172 °C; ½a D25
ꢃ
¼ ꢁ143:7 (c 1.14, CHCl3); 1H NMR
20a
20b
20c
20d
(CDCl3): d 0.45 (d, 3H, J = 6.8 Hz), 1.85 (d, 3H, J = 6.6 Hz), 3.2 (s, 3H),
3.4 (s, 3H), 3.6 (s, 3H), 3.75 (s, 3H), 4.7 (d, 1H, J = 7.6 Hz), 4.9 (m,
2H), 5.5 (m, 3H), 7.1–7.4 (m, 10H), 8.3 (s, 1H); 13C NMR (CDCl3): d
14.85, 18.6, 54.15, 55, 55.7, 57.5, 60, 67.25, 68.4, 69.2, 105, 127.5–
129.2, 132.3, 136.65, 156, 158.1; HRMS (ESI): for C25H35N4O4+: calcd
455.2652; found 455.2653. An X-ray structure (Fig. 6) enabled us to
assign the (R)-configuration to the new stereogenic centre.
a
The absolute configuration of the asymmetric carbon of each enantiomer of
compounds 20a–b,d and compound 20c was assigned thanks to the known abso-
lute configuration of the stereogenic centre in the previous triazolyl amines 16 for
compounds 20a–b,d, and to authentic samples from commercially available
enantiomerically pure a-methylbenzylamine.

2692
M. Serradeil-Albalat et al. / Tetrahedron: Asymmetry 19 (2008) 2682–2692
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lographic Data Centre as supplementary publication: No. CCDC-
655436 (compound (R)-16b), No. CCDC-655438 (compound 15b),
No. CCDC-655439 (triazolium salt (R)-17d), No. CCDC-665520
(compound (S)-16c) and No. CCDC-684229 (compound (S)-16a).
Copies of the data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html (or from CCDC, 12 Union Road,
Cambridge CB2 IEZ, UK; fax: +44(0)-1223–336033 or e-mail:
deposit@ccdc.cam.ac.uk.
Acknowledgments
The authors thank Professor A.R. Katritzky for helpful proposals.
They are grateful to Michel Giorgi for performing X-ray structures,
to Brice Bonnet for preliminary chiral HPLC studies and to Valerie
Monnier for exact mass measurements. This work was supported
by a grant for M.S.-A. from ministry of Research and Technology.
Clariant France company18 is also thanked for funding.
13. (a) Enders, D.; Lochtman, R. Synlett 1997, 355–356; (b) Enders, D.; Lochtman,
R.; Meiers, M.; Müller, S.; Lazny, R. Synlett 1998, 1182–1184; (c) Enders, D.;
Thiebes, C. Synlett 2000, 1745–1748.
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