Preparation of chiral 1,2,4-triazolium salts as new NHC precatalysts

Article abstract of DOI:10.1016/j.tetasy.2012.06.002

The preparation of new chiral N,N′-disubstituted 1,2,4-triazolium based NHC salt precursors, Ia′ and Ib, from phenylhydrazine and l-phenylalanine is reported. The 1,3,4-trisubstituted triazolium salt Ia′ was obtained by a stepwise ring construction from l-phenylalanine via the corresponding imino ether and acetohydrazonamide, while a heterocyclic O-/N-heteroatom exchange strategy, based on a ring-opening/ring-closure of the oxadiazolium precursor, afforded the 1,4-disubstituted 1,2,4-triazolium salt Ib. The need for two different synthetic strategies is discussed.

Full text of DOI:10.1016/j.tetasy.2012.06.002

Tetrahedron: Asymmetry 23 (2012) 838–842
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Tetrahedron: Asymmetry
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Preparation of chiral 1,2,4-triazolium salts as new NHC precatalysts
⇑
Ragnhild B. Strand, Tina Solvang, Christian A. Sperger, Anne Fiksdahl
Department of Chemistry, Norwegian University of Science and Technology, NTNU, NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
The preparation of new chiral N,N0-disubstituted 1,2,4-triazolium based NHC salt precursors, Ia0 and Ib,
Article history:
Received 17 April 2012
Accepted 8 June 2012
from phenylhydrazine and
obtained by a stepwise ring construction from
L
-phenylalanine is reported. The 1,3,4-trisubstituted triazolium salt Ia0 was
L-phenylalanine via the corresponding imino ether and
acetohydrazonamide, while a heterocyclic O-/N-heteroatom exchange strategy, based on a ring-open-
ing/ring-closure of the oxadiazolium precursor, afforded the 1,4-disubstituted 1,2,4-triazolium salt Ib.
The need for two different synthetic strategies is discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
new chiral NHCs and have recently reported the preparation and
preliminary results for chiral induction by some new chiral N,N0-
N-Heterocyclic carbenes (NHCs) have been developed over the
last decade as powerful supplements and useful alternatives to
phosphines as spectator ligands in homogeneous transition metal
catalysis.1,2 A number of different NHC precatalysts have been pre-
pared. In general, the majority of reported NHC research involves
metal complexes with 1,3-disubstituted imidazolium-derived li-
gands.3 The analogous catalytic applications of 1,2,4-triazolylidene
metal ligands have been less studied.4 However, 1,2,4-triazole-
based bis(NHC)Pt(II)5 and Rh(I) and Ir(I) NHC complexes4,6 have re-
cently been prepared, while 1,2,4-triazolyliden Ru(II) complexes
have been shown to be efficient catalysts in the transfer hydroge-
nation of acetophenone.7 Similar triazole-based Pd NHC complexes
efficiently catalyse the Hiyama and Sonogashira cross-coupling
reactions.8
Recent investigations have also demonstrated the advantages of
using NHCs as organocatalysts, often based on thiazolium, triazoli-
um and imidazolium salts.9 Such studies include a number of
asymmetric organocatalytic transformations promoted by chiral
NHCs, such as optically active 1,2,4-triazolylidenes.10
Novel aspects of chiral NHCs have been demonstrated by the
latest studies on the high efficiency and enantioselectivity ob-
tained with chiral 1,2,4-triazolium salts in ‘umpolung’ reactions,
such as the Stetter reaction11 and the benzoin condensation.12
These studies show the striking differences in reactivity between
the imidazolium and the triazolium salt NHC precatalysts.
In order to allow a greater variety of enantioselective metal cat-
alysed transformations as well as to broaden the application of
NHCs as chiral organocatalysts, there is a large potential for new
chiral NHCs in novel areas of stereoselective synthesis. We are cur-
rently working on the preparation, modification and application of
disubstituted imidazolium based NHC salts, derived from
and
-phenylalanine.13
Our aim herein was to synthesize the corresponding
anine-based chiral 1,2,4-triazolium salts (Scheme 1) and to study
their ability to induce chiral induction as new NHC precatalysts,
due to the high reactivity and selectivity reported for this class of
NHC precursors.
L
-proline
L
L
-phenylal-
Me, H
N
Ph
N+
N
X-
OBn
Ia,b
Scheme 1. General structures of the target triazolium salts Ia,b.
Our future aim is to investigate the new chiral NHCs as ligands
in asymmetric organometallic catalysis and as organocatalysts in
stereoselective reactions.
2. Results and discussion
2.1. Chiral triazolium salts based on L-phenylalanine
Both 1,2,4-triazolium salt NHC precursors Ia and Ib can be de-
rived from -phenylalanine. To obtain the best possible yields, they
L
were prepared by two different reaction pathways.
Triazolium salt Ia0 was prepared by the step-wise construction
of the 1,3,4-trisubstituted 1,2,4-triazole ring14 from
L
-phenylala-
nine (Scheme 2). The O-benzylated N-acetylamino alcohol 1 was
obtained from -phenylalanine by hydride reduction, benzylation
and subsequent acetylation.15 The acetylamide intermediate 1
L
⇑
Corresponding author. Tel.: +47 735 940 94.
E-mail address: anne.fiksdahl@chem.ntnu.no (A. Fiksdahl).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.002

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 838–842
839
Ph
Ph
Ph
Ph
OMe
N
O
H
N
i) - iii)
v)
OBn
iv)
OBn
OBn
Ph
N
H
N
H
N
H
H2N
CO2H
Cl
3
2
1
vi)
Ia'
N
CHO
H
N
N
viii)
vii)
O
ix) 64%
Ph
CHO
N
N
H
Ph
NH2
x)
Ib
Ph
Ph
R
ClO4
N
N+
5
4
Ph
N
+
OBn
H2N
X-
OBn
N
N
CHO
O
H
viii)
xi)
Ac
Ac
Ia
-
-
N
N
N
H
Ia'
; R = Me, X = Cl
N
H
Ph
-
Ia; R = Me, X- = ClO4-
ix) 13%
ClO4
; R = H, X- = ClO4
Ib
6
7
8
N
N+
H2N
ix) 58%
Ph
N
5
II
Ph
ClO4
Scheme 2. Preparation of chiral 1,2,4-triazolium salts, based on L-phenylalanine. Reagents and conditions: (i) LiAlH4, THF, 95%; (ii) NaH, BnBr, THF, reflux, 16 h, 60%; (iii)
Ac2O, EtOAc, rt, 2.5 h, 100%; (iv) Me3OBF4, DCM, rt, o.n., 49%; (v) Ph-NH-NH2ꢁHCl, MeOH, 50 °C, 4 h; (vi) HC(OMe)3, MeOH, 80 °C, overnight, 50% from 2; (vii) HCO2H, 18 h,
80 °C, 73%; (viii) Ac2O, HClO4, 80–84%; (ix) AcOH, 1.5 h, 110 °C, 64%; (x) AcOH, 3.5 h, 80 °C, 96%; (xi) HCO2H, 15 h, 50 °C, 79%.
was then converted into the corresponding imino ether 2 with
Meerwein’s reagent, MeO3BF4. The sluggish nature of similar reac-
tions with this methylating reagent has already been reported16 on
and has been explained by the insolubility of the otherwise very
reactive MeO3BF4. Attempts to overcome this problem by varying
the solvent system, the temperature or the reaction time were
unsuccessful and did not increase the yield, as reported previously
for similar reactions.16 The best yield, 49% after purification by a
short silica column, was obtained by vigorous stirring in dichloro-
methane at room temperature overnight. The coupling of imino
ether 2 with phenylhydrazine hydrochloride salt in MeOH pro-
vided the acetohydrazonamide hydrochloride 3, which was used
directly in the subsequent reaction without purification. The key
step for the formation of the desired trisubstituted 3-methyl-
1,2,4-triazolium hydrochloric salt Ia0 was the final ring closure, car-
ried out with trimethyl orthoformate and heating in methanol (50%
yield from 2). A one-pot-procedure, including Me3OBF4 methyla-
tion, the phenylhydrazine coupling reaction and a final trimethyl-
orthoformate ring closure, has been reported14b to be successful for
other amide substrates, due to the efficient final crystallization of
the triazolium BFꢀ4 product. However, our corresponding product
Ia0 could not be crystallized from the crude product mixture in
any manner, and the one-pot-procedure had to be replaced by a
stepwise preparation, as discussed above.
Attempts were also made to prepare the corresponding perchlo-
rate salt Ia in a similar manner to that discussed above for Ib.
Quantitative monoacetylation of phenylhydrazine and subsequent
monoformylation afforded N0-formyl-N0-phenylacetohydrazide 7
(79%) via N0-phenylacetohydrazide 6. The hydrazide 7 ring closure
was, however, challenging, due to the instability and ineffective
isolation of the methylated oxodiazolium perchlorate intermediate
8. Thus, this preparation method was less successful, and the final
ring-opening/ring-closure of the target product precursor 8 gave Ia
in only 13% yield.
The triazolium perchlorate salt II10g was successfully prepared
by the ring-opening/ring-closure of oxadiazolium intermediate 5
with (S)-1-phenylethanamine, as described above for triazolium
salt Ib.10g Full NMR characterization of triazolium salt II are re-
ported in Section 4.
2.2. Chiral induction, preliminary results
In order to indicate the potential of the new chiral NHCs to
induce chiral induction, a few preliminary tests were conducted
without any efforts to optimize the reaction conditions. The enan-
tioselective copper-catalysed conjugate addition of diethylzinc to
cyclohex-2-enone 9, to afford (R)- and (S)-ethyl adducts 10, has
been used as a test reaction for many chiral catalytic systems,
including Cu-NHCs.17 Our triazole based systems afforded high to
quantitative conversion (56–99%) of enone 9 into products 10, dem-
onstrating the high catalytic activity of the Cu-NHCs obtained from
Ia,b and II (Table 1). Until this point, only low enantioselectivity
was obtained (11–14% ee). It is noteworthy that the introduction
of a triazolium 3-methylgroup affects the stereocontrol, as shown
by the opposite configuration being induced by the tri-substituted
Ia relative to the di-substituted triazolium salt Ib. Since the influ-
ence of the temperature, base, solvent and copper source has been
shown to be essential for optimizing the stereoselectivity of conju-
gate addition,17a modification of the reaction conditions would be
expected to afford increased enantioselectivity by these triazoli-
um-NHC-ligands, as well.13 Studies on the relationship between
the chiral backbone of the corresponding imidazolinium salts and
the induced stereoselectivity, have indicated that structural moie-
ties in the NHC ligand, such as a proximity of the chiral and the car-
Triazolium salt Ib was prepared by a heterocyclic heteroatom
exchange strategy, based on a ring-opening/ring-closure key step
(Scheme 2).10g Bisformylation of phenylhydrazine with formic
acid was obtained in improved yield (73%) compared to the lit-
erature procedure (59%).10h Subsequently, the oxadiazolium per-
chlorate 5 was readily formed in 84% yield by ring closure of
bishydrazide 4 with Ac2O/HClO4.10h The final ring-opening/ring-
closure of oxadiazolium perchlorate 5 was carried out in reflux-
ing acetic acid with O-benzyl-L-phenylalaninol, to give the 1,4-
disubstituted 1,2,4-triazolium perchlorate Ib as a white solid in
64% yield.10g Product isolation was based on precipitation by
the addition of ether to the reaction mixture at room tempera-
ture. Therefore, reactions on
a smaller scale of less than
100 mg, afforded lower yields due to less successful product
precipitation from the crude product and challenging chromato-
graphic separations.

840
R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 838–842
Table 1
were performed under a nitrogen atmosphere in predried glass-
ware. Flash chromatography was performed with Merck silica gel
(SDS, 60 Å, 40–63 m) or with a Supelco Versa Flash system with
Cu catalysed conjugate addition
O
O
l
commercially prepacked Versa Flash cartridges. 1H and 13C NMR
spectra were recorded on a Bruker Avance DPX 400 MHz spectrom-
eter. Chemical shifts (d) are reported in parts per million (ppm) rel-
ative to TMS as the internal standard or by calibration on the
solvent resonance peak. Coupling constants (J) are reported in
Hertz (Hz). The attributions of the chemical shifts were determined
by means of COSY, HSQC, HMQS, HMBC and NOESY experiments.
High resolution mass spectra (HRMS) were determined with an
Agilent 6520 QTOF MS (ESI) or with a Finnigan MAT 95 XL MS
(EI). Optical rotations were measured on a Perkin–Elmer Model
341 Polarimeter. IR spectra were obtained with a Nicolet 20SXF
FT-IR spectrometer, recorded on a Smart Endurance reflexion cell.
Melting points were recorded on a Stuart SMP3 apparatus.
O
NHC (3 mol%)
Et
Cu(OTf)2 (2 mol%)
(R)
(S)
nBuLi (8 mol%)
ZnEt2 (1.5 equiv)
Et2O, rt, 30 min
9
Et
10
Ligand
Conv. %a
ee%b
N
4.2. Preparation of chiral triazolium salts
Ph
N
N
N
>99
12 (S)
Ia'
4.2.1. (S)-2-Amino-3-phenyl-propan-1-ol18
Cl-
N
OBn
The title compound was prepared from (S)-phenylalanine
(10.0 g, 60.5 mmol) and LiAlH4 (4.62 g, 122 mmol) according to
the literature.19 The work-up was carried out by adding NaSO4
(1 M, 60 mL). The precipitate was washed with ether
(3 ꢂ 100 mL) and the water phase was extracted with additional
ether (3 ꢂ 60 mL). The organic layers were washed with brine,
dried over MgSO4 and evaporated in vacuo to provide (S)-2-ami-
no-3-phenyl-propan-1-ol (8.72 g, 95%) as a yellow solid. 1H NMR
was in accordance with the literature.18
Ph
N
88
56
11 (R)
14 (S)
Ib
ClO4
OBn
N
N
N
Ph
II
ClO4
a
Determined by GLC.
Determined by chiral GLC (Lipodex E).
b
4.2.2. (S)-1-(Benzyloxy)-3-phenylpropan-2-amine20
The title compound was prepared in accordance with litera-
ture21 from (S)-2-amino-3-phenyl-propan-1-ol above (3.01 mg,
19.9 mmol), NaH (720 mg, 30.0 mmol) and BnBr (3.45 g, 2.40 mL,
20.2 mmol) in refluxing THF for 16 h. Purification by Versa flash
column (20% n-pentane/EtOAc) provided the pure benzylated
amine (2.89 g, 60%) as a yellow oil. 1H NMR was in accordance with
the literature.20
bene centre or the presence of an aromatic unit may be crucial.
Some studies show a pronounced positive or, respectively, negative
effect by replacing a imidazolium-N-phenyl group with a N-mesityl
or a N-2,6-iPr-phenyl unit,17a thus demonstrating that the design of
NHCs with predictable properties may be challenging.
3. Conclusion
In order to explore the possibilities afforded by chiral 1,2,4-tri-
azole-derived compounds and show their potential as catalysts in
stereoselective reactions, we have prepared the chiral 1,2,4-triazo-
lium NHC salt precursors Ia0 and Ib, with a stereogenic centre de-
4.2.3. (S)-N-(1-(Benzyloxy)-3-phenylpropan-2-yl)acetamide 1
The title compound was prepared in accordance with litera-
ture15 from (S)-1-(benzyloxy)-3-phenylpropan-2-amine above
(1.99 g, 8.25 mmol) and acetic acid anhydride (0.87 mL,
9.20 mmol) in EtOAc (17 mL). Stirring for 2 h at room temperature
provided the desired acetamide (2.34 g, quant.) as an orange solid.
rived from L-phenylalanine, located in one of the N-side chains of
the triazolium ring. The proper choice of the preparation method
was dependent on the target product, including the counter ion.
The 1,3,4-trisubstituted 1,2,4-triazolium chloride salt Ia0 was
Mp 64 °C; ½a 2D0
ꢃ
¼ ꢀ16:3 (c 0.71, MeOH); mmax (neat) 3310, 3100–
300 (br), 3000–2800, 1647, 1537, 1093, 694 cmꢀ1
;
1H NMR
prepared by a stepwise ring construction from L-phenylalanine
(400 MHz, CDCl3) d 7.40–7.15 (10H, m, Harom.), 5.80 (1H, s, NH),
4.51 (1H, d, 11.6 Hz, OCHaHbPh), 4.46 (1H, d, 11.6 Hz,
via an N-acetylamino alcohol, the corresponding imino ether and
acetohydrazonamide followed by a final orthoformate ring closure.
The 1,4-disubstituted 1,2,4-triazolium perchlorate salt Ib was
prepared by a heterocyclic O-/N-heteroatom exchange strategy
via phenylhydrazine bisformylation, oxadiazolium ring closure of
the bishydrazide and a final ring-opening/ring-closure of the
oxadiazolium precursor to introduce the chiral aminoalcohol
moiety.
J
J
OCHaHbPh), 4.33–4.25 (1H, m, CH), 3.39 (2H, d, J 3.6 Hz, CHCH2O),
2.94–2.83 (2H, m, CHCH2Ph), 1.94 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3)
d 169.4 (C@O), 138.0 (Carom), 137.9 (Carom), 129.4
(2 ꢂ CHarom.), 128.5 (2 ꢂ CHarom.), 128.4 (2 ꢂ CHarom.), 127.9
(3 ꢂ CHarom.), 126.4 (CHarom.), 73.3 (OCH2Ph), 69.7 (CHCH2O), 50.3
(CH), 37.5 (CHCH2Ph), 23.5 (CH3); HRMS (EI): M+, 283.1565.
C18H21NO2 requires 283.1567.
We are currentlyinvestigating the ability of thenew chiral triazo-
lium-based NHC compounds as ligands in asymmetric organometal-
lic catalysis and as organocatalysts in enantioselective reactions.
4.2.4. (S)-Methyl N-1-(benzyloxy)-3-phenylpropan-2-
ylacetimidate 2
The title compound was prepared from Me3OBF4 (770 mg,
5.21 mmol) and acetamide 1 (1.19 g, 4.20 mmol) dissolved in
DCM (12.8 mL) according to literature.10f Vigorous stirring for
24 h at room temperature, aqueous work-up and filtration through
a short pad of silica (20% EtOAc/n-pentane) provided the acetimi-
date 2 (616 mg, 49%) as a pale yellow oil. Rf 0.70 (20% EtOAc/n-pen-
4. Experimental
4.1. General
Dry THF, Et2O and DCM were collected from a MB SPS-800 sol-
vent purification system. Unless otherwise stated, all reactions
tane); ½a 2D0
¼ ꢀ65:3 (c 0.89, MeOH); mmax (neat) 3100–300 (w),
ꢃ

R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 838–842
841
2950–2800 (w), 1679, 1253, 1087, 1057, 735, 697 cmꢀ1
;
1H NMR
the desired triazolium salt Ia0 (134 mg, 50%) as a yellow solid.
(400 MHz, CDCl3) d 7.37–7.12 (10H, m, Harom.), 4.55 (2H, s,
OCH2Ph), 3.68–3.62 (1H, m, CH), 3.60 (3H, s, OCH3), 3.55 (1H, dd,
J 5.6, 9.2 Hz, CHCHaHbO), 3.42 (1H, dd, J 6.8, 9.2 Hz, CHCHaHbO),
2.97 (1H, dd, J 4.0, 12.8 Hz, CHCHaHbPh), 2.60 (1H, dd, J 8.8,
12.8 Hz, CHCHaHbPh), 1.47 (3H, s, CH3); 13C NMR (100 MHz, CDCl3)
d 161.4 (C@N), 139.6 (Carom), 138.7 (Carom), 129.7 (2 ꢂ CHarom.),
128.3 (2 ꢂ CHarom.), 128.0 (2 ꢂ CHarom.), 127.5 (2 ꢂ CHarom.), 127.4
(CHarom.), 125.9 (CHarom.), 74.7 (CHCH2O), 73.2 (OCH2Ph), 60.4
(CH), 52.2 (OCH3), 40.2 (CHCH2Ph), 14.7 (CH3); HRMS (ESI): MH+,
298.1800. C19H24NO2 requires 298.1802.
Mp 53 °C. Rf 0.32 (10% MeOH/DCM). ½a D20
ꢃ
¼ ꢀ23:0 (c 0.99, MeOH);
m
max (neat) 3100–3000 (w), 300–2750 (w), 1580, 1454, 1259, 1091,
749, 700, 686 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 13.46 (1H, s,
NCHN), 8.30–8.24 (2H, m, Harom.), 7.64–7.56 (2H, m, Harom.),
7.54–7.48 (1H, m, Harom.), 7.30–7.16 (10H, m, Harom.), 4.71–4.62
(1H, m, CH), 4.61–4.53 (1H, m, CHCHaHbO), 4.53–4.46 (2H, m,
OCH2Ph), 4.07 (1H, dd, J 2.8, 10.4 Hz CHCHaHbO), 3.93–3.84 (1H,
m, CHCHaCHbPh), 3.48 (1H, dd, J 5.2, 14.4 Hz, CHCHaCHbPh), 2.26
(3H, s, CH3); 13C NMR (100 MHz, CDCl3) d 153.5 (NC(CH3)N),
141.1 (NCHN), 137.0 (Carom), 135.2 (Carom.), 135.0 (Carom.), 130.5
(CHarom.), 130.2 (2 ꢂ CHarom.), 129.2 (2 ꢂ CHarom.), 128.9
(2 ꢂ CHarom.), 128.5 (2 ꢂ CHarom.), 128.1 (CHarom.), 128.0
(2 ꢂ CHarom.), 127.6 (CHarom.), 120.0 (2 ꢂ CHarom.), 73.4 (OCH2Ph),
71.4 (CHCH2O), 62.9 (CH), 36.9 (CHCH2Ph), 10.5 (CH3); HRMS
(ESI): triazolium-M+, 384.2075. C25H26N3O requires 384.2070.
4.2.5. N,N0-Diformyl-N-phenylhydrazine 410h
The title compound was prepared from phenylhydrazine
(0.500 mL, 5.08 mmol) and formic acid (1.20 mL, 31.8 mmol)
according to the literature. After 18 h at 80 °C and trituration with
ether, the pure bisformylated product 4 was obtained as a white
solid (611 mg, 73%). Mp 126 °C, lit22 125–126 °C. The 1H NMR
was in accordance with the literature.
4.2.11. (S)-4-(1-(Benzyloxy)-3-phenylpropan-2-yl)-3-methyl-1-
phenyl-4H-1,2,4-triazol-1-iumperchlorate Ia
The oxadiazolium salt 8 (418 mg, 1.60 mmol) and O-benzyl-L-
4.2.6. 3-Phenyl-1,3,4oxadiazol-3-ium perchlorate 510h
The title compound was prepared from phenylhydrazine 4
(586 mg, 3.57 mmol) and HClO4 (70%, 305 lL, 3.54 mmol) in
Ac2O (3 mL) according to the literature. Washing the product with
dry ether (3 ꢂ 6 mL) yielded the oxadiazolium perchlorate 5 as a
white solid (734 mg, 84%). Mp 135 °C (dec.), lit 135–136 °C. The
IR spectrum was in accordance with the literature.
phenylalaninol (1.12 g, 4.64 mmol) were dissolved and refluxed
in acetic acid in accordance with the literature.10g After 2 h of re-
flux, the oil was washed with ether (2 ꢂ 40 mL) and left a gummy
solid that was purified by flash column (0–33% EtOAc/Et2O) afford-
ing the desired product (97 mg, 13%) as a yellow solid. Mp 51 °C;
½
a 2D0
ꢃ
¼ ꢀ63:8 (c 1.08, MeOH); mmax (neat) 3062 (br), 2871 (br),
1582, 1074, 752, 700, 685, 621 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d 10.32 (1H, s, NCHN), 7.87–7.83 (2H, m, Harom.), 7.55–7.46 (3H,
m, Harom.), 7.27–7.14 (10H, m, Harom.), 4.79–4.71 (1H, m, CH),
4.2.7. N0-Phenylacetohydrazide 610h
The title compound was prepared from phenylhydrazine
(1.00 mL, 10.1 mmol) and AcOH (14.4 mL, 252 mmol) in accor-
dance with the literature.23 After 3.5 h at 80 °C most of the solvent
was removed under reduced pressure. Next, DCM (50 mL) and
NaOH (15% w/w, 8 mL) were added to the orange solid. The aque-
ous phase was extracted with DCM (2 ꢂ 20 mL). The combined or-
ganic layers were dried over MgSO4 and the solvents evaporated in
vacuo, yielding the desired hydrazide 6 (1.46 g, 96%) as a yellow
solid. Mp 126 °C, lit23 129 °C. The 1H NMR was in accordance with
the literature.10h
4.50 (1H, d, J 11.7 Hz, OCHaHbPh), 4.43 (1H, d, J 11.7 Hz,
OCHaHbPh), 4.06 (1H, dd, J 8.0, 10.8 Hz, CHCHaHbO), 4.00 (1H, dd,
J 3.6, 10.9 Hz, CHCHaHbO), 3.43 (1H, dd, J 8.8, 14.0 Hz CHCHaHbPh),
3.39 (1H, dd, J 7.2, 14.2 Hz CHCHaHbPh), 2.30 (3H, s, CH3); 13C NMR
(100 MHz, CDCl3) d 154.4 (NC(CH3)N), 138.6 (NCHN), 136.8 (Carom),
135.0 (Carom.), 134.6 (Carom.), 130.9 (CHarom.), 130.3 (2 ꢂ CHarom.),
129.3 (2 ꢂ CHarom.), 129.0 (2 ꢂ CHarom.), 128.6 (2 ꢂ CHarom.), 128.3
(2 ꢂ CHarom.), 128.2 (CHarom.), 127.8 (CHarom.), 120.5 (2 ꢂ CHarom.),
73.5 (OCH2Ph), 70.1 (CHCH2O), 62.3 (CH), 36.9 (CHCH2Ph), 10.6
(CH3); HRMS (ESI): triazolium-M+, 384.2070. C25H26N3O requires
384.2070.
4.2.8. N0-Formyl-N0-phenylacetohydrazide 710h
The title compound was prepared in accordance with literature
from hydrazide 6 (1.07 g, 7.12 mmol) and formic acid (0.800 mL,
21.2 mmol). After 15 h at 50 °C, addition of ether afforded precipi-
tation and yielded hydrazide 7 (1.01 g, 79%) as a white solid. Mp
84 °C, lit 83–85 °C. The 1H NMR was in accordance with the
literature.
4.2.12. (S)-4-(1-(Benzyloxy)-3-phenylpropan-2-yl)-1-phenyl-4H-
1,2,4-triazol-1-ium perchlorate Ib
The oxadiazolium salt 5 (406 mg, 1.65 mmol) and O-benzyl-L-
phenylalaninol (1.23 g, 5.10 mmol) were dissolved in acetic acid
in accordance with the literature.10g Reflux for 1.5 h and precipita-
tion provided the desired NHC precatalyst as a white solid (496 mg,
64%). Mp 78 °C; ½a D20
¼ ꢀ41:4 (c 1.01, MeOH); mmax (neat) 3126
ꢃ
4.2.9. 5-Methyl-3-phenyl-1,3,4oxadiazol-3-ium perchlorate 810h
The title compound was prepared as described above for com-
pound 5 from hydrazide 7 (633 mg, 3.55 mmol) and HClO4 (70%,
(br), 2875 (br), 1710 (w), 1560, 1180, 1083, 762, 697, 620 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 10.27 (1H, s, NCHN), 8.69 (1H, s,
NCHN), 7.82–7.77 (2H, m, Harom.), 7.53–7.48 (3H, m, Harom.),
7.40–7.20 (10H, m, Harom.), 5.32–5.25 (1H, m, CH), 4.58 (1H, d, J
11.5 Hz, OCHaHbPh), 4.50 (1H, d, J 11.4 Hz, OCHaHbPh), 3.96 (1H,
dd, J 2.5, 10.9 Hz, CHCHaHbO), 3.82 (1H, dd, J 3.8, 10.9 Hz, CHCHaH-
bO), 3.40–3.34 (2H, m, CHCH2Ph); 13C NMR (100 MHz, CDCl3) d
143.6 (NCHN), 139.6 (NCHN), 136.8 (Carom), 134.7 (Carom.), 134.6
(Carom), 130.9 (CHarom.), 130.2 (2 ꢂ CHarom.), 129.3 (2 ꢂ CHarom.),
129.1 (2 ꢂ CHarom.), 128.7 (2 ꢂ CHarom.), 128.3 (CHarom.), 128.2
(2 ꢂ CHarom.), 127.6 (CHarom.), 120.9 (2 ꢂ CHarom.), 73.6 (OCH2Ph),
68.2 (CHCH2O), 62.0 (CH), 37.2 (CHCH2Ph); HRMS (ESI): triazoli-
um-M+, 370.1917. C24H24N3O requires 370.1914.
295 lL, 3.42 mmol) in AcOH (2.9 mL). An ether wash of the precip-
itate yielded the oxadiazolium perchlorate 8 (715 mg, 80%) as a
white solid. Mp 150 °C (dec), lit 215 °C (dec.). The IR was in accor-
dance with the literature.
4.2.10. (S)-4-(1-(Benzyloxy)-3-phenylpropan-2-yl)-3-methyl-1-
phenyl-4H-1,2,4-triazol-1-ium chloride Ia0
The title compound was prepared from acetimidate 2 (190 mg,
0.639 mmol) and phenylhydrazine hydrochloride salt (109 mg,
0.754 mmol) in MeOH (9.5 mL) in accordance with the literature.14
After stirring for 1.5 h at room temperature and 4 h at 50 °C, the
solvent was evaporated and the red oil was dissolved in HC(OMe)3
(8.5 mL) and MeOH (1.2 mL). Heating at 80 °C for 24 h and subse-
quent removal of the solvents in vacuo left a red semi-solid that
was purified by Versa flash column (3–16% EtOH/DCM), yielding
4.2.13. (S)-1-Phenyl-4-(1-phenylethyl)-4H-1,2,4-triazol-1-ium
perchlorate II
The oxadiazolium salt 5 (402 mg, 1.63 mmol) and (S)-1-pheny-
lethanamine (700 lL, 5.43 mmol) were dissolved in acetic acid in

842
R. B. Strand et al. / Tetrahedron: Asymmetry 23 (2012) 838–842
accordance with the literature.10g Reflux in acetic acid and precip-
7. Li, X.-W.; Wang, G.-F.; Chen, F.; Li, Y.-Z.; Chen, X.-T.; Xue, Z.-L. Inorg. Chim. Acta
2011, 378, 280.
itation provided the desired NHC precatalyst II as a white solid
8. Dash, C.; Shaikh, M. M.; Ghosh, P. Eur. J. Inorg. Chem. 2009, 1608.
9. Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606.
10. (a) Baragwanath, L.; Rose, C. r. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74,
9214; (b) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418; (c) Kaeobamrung,
J.; Bode, J. W. Org. Lett. 2009, 11, 677; (d) Struble, J. R.; Kaeobamrung, J.; Bode, J.
W. Org. Lett. 2008, 10, 957; (e) Jeong, Y.; Ryu, J.-S. J. Org. Chem. 2010, 75, 4183;
(f) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743; (g) Teles, J. H.;
Ebel, K.; Enders, D.; Breuer, K. Ger. Offen 1997, DE 19704273 A1 19970911.; (h)
O’Toole, S. E.; Connon, S. J. Org. Biomol. Chem. 2009, 7, 3584.
11. (a) Rong, Z.-Q.; Li, Y.; Yang, G.-Q.; You, S.-L. Synlett 2011, 1033; (b) Jia, M.-Q.; Li,
Y.; Rong, Z.-Q.; You, S.-L. Org. Biomol. Chem. 2011, 9, 2072; (c) Sanchez-Larios,
E.; Thai, K.; Bilodeau, F.; Gravel, M. Org. Lett. 2011, 13, 4942.
12. (a) Enders, D.; Grossmann, A.; Fronert, J.; Raabe, G. Chem. Commun. 2010, 46,
6282; (b) Soeta, T.; Tabatake, Y.; Inomata, K.; Ukaji, Y. Tetrahedron 2012, 68,
894.
(332 mg, 58%). Mp 125 °C; ½a D20
¼ þ25:2 (c 1.03, MeOH); mmax
ꢃ
(neat) 3134 (br), 3082 (br), 1573, 1458, 1184, 1072, 766,
;
622 cmꢀ1 1H NMR (400 MHz, acetone-d6) d 10.75 (1H, s, NCHN),
9.39 (1H, s, NCHN), 8.03–7.99 (2H, m, Harom.), 7.72–7.63 (5H, m,
H
arom.), 7.52–7.43 (3H, m, Harom.), 6.19 (1H, q, J 7.0 Hz, CH), 2.20
(3H, d, J 7.0 Hz); 13C NMR (100 MHz, acetone-d6) d 144.0 (NCHN),
140.2 (NCHN), 137.7 (Carom), 135.4 (Carom.), 130.6 (CHarom.), 129.9
(2 ꢂ CHarom.), 129.3 (CHarom.), 129.2 (2 ꢂ CHarom.), 127.2
(2 ꢂ CHarom.), 121.0 (2 ꢂ CHarom.), 59.8 (CH), 20.2 (CH3); HRMS
(ESI): triazolium-M+, 250.1339. C16H16N3 requires 250.1339.
13. Strand, R. B.; Helgerud, T.; Solvang, T.; Sperger, C. A.; Fiksdahl, A. Tetrahedron:
Asymmetry 2011, 22, 1994.
Acknowledgments
14. (a) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891; (b) Kerr, M.
S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725.
15. Temperini, A.; Terlizzi, R.; Testaferri, L.; Tiecco, M. Synth. Commun. 2010, 40,
295.
The Research Council of Norway is acknowledged for financial
support.
16. Ashish, P. V.; Crooks, P. A. Org. Process Res. Dev. 2009, 13, 415.
17. (a) Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J. C.; Mauduit, M. J.
Organomet. Chem. 2005, 690, 5237; (b) Clavier, H.; Guillemin, J.-C.; Mauduit,
M. Chirality 2007, 19, 471; (c) Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.;
Mangeney, P.; Alexakis, A. J. Organomet. Chem. 2005, 690, 5672.
18. Hvidt, T.; Szarek, W. A.; Maclean, D. B. Can. J. Chem. 1988, 66, 779.
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