An efficient synthesis of new 2-aminomethyl-1,3,4-oxadiazoles from enantiomeric phenylglycine hydrazides

Article abstract of DOI:10.1016/j.tet.2008.11.096

New derivatives of 2-aminomethyl-1,3,4-oxadiazole were synthesized in the reactions of N-protected phenylglycine hydrazides and triethyl orthoesters (orthoformate, orthoacetate, orthopropionate, orthobenzoate) in the presence of glacial acetic acid. Studies on the cleavage reactions of the acid-sensitive N-BOC and N-Ac 1,3,4-oxadiazoles are presented. Spectral characteristics of the compounds and attempts to elucidate the racemization phenomenon observed in products are also discussed.

Full text of DOI:10.1016/j.tet.2008.11.096

Tetrahedron 65 (2009) 1200–1206
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Tetrahedron
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An efficient synthesis of new 2-aminomethyl-1,3,4-oxadiazoles from
enantiomeric phenylglycine hydrazides
*
´
Agnieszka Kudelko , Wojciech Zielinski
Department of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology, Ul. Krzywoustego 4, PL-44101 Gliwice, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New derivatives of 2-aminomethyl-1,3,4-oxadiazole were synthesized in the reactions of N-protected
phenylglycine hydrazides and triethyl orthoesters (orthoformate, orthoacetate, orthopropionate, ortho-
benzoate) in the presence of glacial acetic acid. Studies on the cleavage reactions of the acid-sensitive
N-BOC and N-Ac 1,3,4-oxadiazoles are presented. Spectral characteristics of the compounds and attempts
to elucidate the racemization phenomenon observed in products are also discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 September 2008
Received in revised form 6 November 2008
Accepted 20 November 2008
Available online 6 December 2008
Keywords:
2-Aminomethyl-1,3,4-oxadiazole
Phenylglycine hydrazides
Enantiomers
Protecting group
Racemization
1. Introduction
Our earlier studies on the reactions of a-hydroxyacid hydrazides
with triethyl orthoesters in glacial acetic acid led us to a mixture of
1,3,4-oxadiazole and 1,3,4-oxadiazin-5(6H)-one derivatives.17 The
formation of the latter six-membered compounds was the result of
the presence of a highly reactive hydroxy group in hydrazide. It was
interesting if other hydrazides containing the substituents different
1,3,4-Oxadiazoles belong to a group of heterocycles that have
been attracting attention for last two decades due to their wide
range of biological interactions.1 Many of them exhibit antibacte-
rial, anticonvulsant, anticancer activities and are used to fight in-
fections involving AIDS.2–4 They are also applied in agriculture as
herbicides, fungicides or insecticides.5,6 Some 1,3,4-oxadiazoles
substituted with aryl groups at positions 2 and 5 are of significant
interest in polymer and material science because of their electro-
chemical properties (luminescence).7–9
to the hydroxy at the a-position would undergo the 1,3,4-oxadi-
azole formation. To the best of our knowledge there is only one
mention on the reaction of phenylglycine and orthoesters in
dimethylformamide medium leading to 1,2,4-triazine-6(5H)-one
derivatives.18 We decided to protect the highly reactive amino
Generally, methods for the synthesis of the 1,3,4-oxadiazole ring
could be divided into two groups according to the starting material.
The first group makes use of acid hydrazides bearing in their
structure four atoms O–C–N–N essential for the construction of
such a ring. They react with synthons introducing to that structure
another carbon atom. The most popular synthons here are aromatic
aldehydes,10 carboxylic acids4 and orthoesters.11 The second group
of methods comprises the reactions of diacylhydrazines, which
already contain in their structure all atoms O–C–N–N–C necessary
to form a 1,3,4-oxadiazole ring. Such substituted hydrazines are
usually treated with a range of cyclodehydrating agents just to
mention: polyphosphoric acid,12 phosphorus oxychloride,13 thionyl
chloride,14 boron trifluoride diethyl etherate15 or Burgess reagent.16
group in the a-amino substrate to avoid the further formation of
such six-membered products and carry out the reactions with tri-
ethyl orthoesters in order to obtain desired five-membered
heterocycles.
2. Results and discussion
The two enantiomers of phenylglycine were converted into the
corresponding methyl esters 2 and then protected with the use of
two typical protective agents: acetic acid anhydride (path a) and di-
tert-butyl pyrocarbonate (path b). The protected esters 3 were
treated with hydrazine hydrate to give a-N-protected hydrazides
4a–d (Scheme 1). They were subjected to heating with the excess of
triethyl orthoesters (R2¼H, Me, Et, Ph) yielding the acyclic de-
rivatives of 1-(alkanecarbonyl)-2-ethoxymethylenehydrazines 5 as
the only products.19 The introduction of an acidic solvent (glacial
acetic acid) to the reaction mixture resulted in changing the course
* Corresponding author. Tel.: þ48 32 2371729; fax: þ48 32 2371032.
E-mail address: agnieszka.kudelko@polsl.pl (A. Kudelko).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.096

A. Kudelko, W. Zielin´ski / Tetrahedron 65 (2009) 1200–1206
1201
H
C
H
C
H
C
H
R2-O-R2
a: Ac2O, NaHCO3, H2O
b: BOC2O, TEA, THF
R1
CONHNH2
CH3OH
SOCl2
NH2NH2*H2O
R1
COOH
R1
Ph (L)
Ph (D)
R1
COOCH3
R1
C
COOCH3
NHR2
NHR2
3
NH2
1
NH2*HCl
2
4
R1
R2
Ac
Yield %
1a
1b
4a
4b
4c
4d
Ph (L)
Ph (L)
Ph (D)
Ph (D)
65
69
51
55
BOC
Ac
BOC
Scheme 1.
R3
H
H
OC2H5
H
O
R3C(OC2H5)3
AcOH, reflux, 3h
O
R1
C
CONHNH2
R1
C
C
C
R1
C
R3
N
NHR2
NH
N
NHR2
NHR2 N
6a-p
5
4a-d
Scheme 2.
of reaction and afforded 2,5-disubstituted-1,3,4-oxadiazoles 6a–p
(Scheme 2).
ethoxymethylene carbon atom yielding 1,3,4-oxadiazole arrange-
ment. Due to racemization we came to conclusion that the enol
form C is the one that dominates in polar solvent and plays the
essential role in the formation of 1,3,4-oxadiazole. The optical ac-
tivity of carbon atom of the phenylmethyl part disappears in such
a structure. It is restored again after the intramolecular substitution
of ethoxy group and the following aromatization (double bond and
proton migration) yielding the mixture of enantiomers (Scheme 3).
If the nature of solvent is responsible for the racemization,
replacing the polar solvent by non-polar one should prevent that
phenomenon. We renewed our experiments and heated hydra-
zides 4b,d with triethyl orthoesters in benzene in the presence of
glacial acetic acid. In these cases we obtained pure enantiomers
of the appropriate N-protected 2-aminomethyl-1,3,4-oxadiazoles.
The acetic acid present in the reaction mixture seems not to be
responsible for the racemization of final products. The parallel
investigation on the 1-(alkanecarbonyl)-2-ethoxymethylenehy-
drazines 5 obtained with the use of only triethyl orthoesters
revealed that even these intermediates exist as racemic mixtures.19
Thus, the racemizationprocess is caused by polar triethyl orthoester.
The structure of one of the N-protected 1,3,4-oxadiazoles was
confirmed by X-ray analysis. ORTEP drawing of N-[1-phenyl-1-(5-
phenyl-1,3,4-oxadiazol-2-yl)methyl]acetamide 6d is shown in
Figure 1.
The analysis of the racemic mixture 6d revealed that the asym-
metric part of the unit cell contains two independent molecules D
and E in the same S configuration, which means that it crystallizes as
a racemic conglomerate. The torsion angle O1n–C2n–C21n–C31n
(n¼a and b) of ꢀ69.3(3)ꢁ in molecule D and ꢀ168.5(2)ꢁ in molecule E
shows that these molecules differ in the conformation. Due to
statistical disorder the phenyl ring at position 5 in 1,3,4-oxadiazole
ring adopts two different positions with respect to this ring. These
positions are described by torsion angles O1a–C5a–C51a–C52c of
ꢀ8.6(6)ꢁ and O1a–C5a–C51a–C52d of 29.9(6)ꢁ in molecule D and
O1b–C5b–C51b–C52e of 13.2(6)ꢁ and O1b–C5b–C51b–C52f of
ꢀ25.0(6)ꢁ in molecule E.
Similar to the previous groups of 1,3,4-oxadiazoles derived
from a
-hydroxyacid hydrazides,17 the highest yields were obtained
in those cases where R2 was phenyl (72–80%). The rest of 1,3,4-
oxadiazoles with hydrogen and electron donating substituents at
the 5-position were prepared in slightly lower yields (38–74%)
(Table 1).
The measurements of the optical rotation for four series of 1,3,4-
oxadiazoles derived from enantiomeric substrates: the N-acyl (N-
Ac) and N-tert-butoxycarbonyl (N-BOC) protected
L
-(þ)- and
D-(ꢀ)-phenylglycine hydrazides 4a–d showed that they are formed
as racemic mixtures. These observations were really surprising
because the asymmetric carbon atom is not involved in the
formation of 1,3,4-oxadiazole 6. Analyzing the mechanism of the
reaction we assumed that the intermediate 1-(alkanecarbonyl)-2-
ethoxymethylenehydrazine A played the essential role in the
building of the heterocyclic product. Hydrazine A may occur in
polar solvent in other tautomeric forms: hydroxyhydrazone B or
enol C, where the second methylene carbon atom appears. It is
substituted with the hydroxy group that attacks N-
Table 1
Characteristics of 2-(1-phenyl-1-N-protected-aminomethyl)-1,3,4-oxadiazoles 6a–p
derived from two enantiomeric N-protected phenylglycine hydrazides 4a–d
20a,c
20b,c
Compound
R1
R2
R3
Yield %
[a
]
[a]
D
D
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
Ph (
L
L
L
L
L
L
L
L
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
Ac
Ac
Ac
Ac
BOC
BOC
BOC
BOC
Ac
Ac
Ac
Ac
BOC
BOC
BOC
BOC
H
51
74
72
80
45
65
66
80
59
62
65
72
38
48
56
74
þ0.3
þ0.4
0.0
þ0.2
þ3.2
þ1.1
þ3.0
þ1.0
ꢀ0.5
0.0
d
d
d
d
CH3
C2H5
Ph
H
þ86.0
þ55.2
þ56.4
þ26.0
d
CH3
C2H5
Ph
D
D
D
D
D
D
D
D
H
CH3
C2H5
Ph
d
0.0
d
ꢀ1.8
ꢀ8.2
ꢀ4.0
ꢀ1.0
ꢀ4.0
d
The last stage of our work was the cleavage reactions of the
1,3,4-oxadiazoles bearing the protected amino groups. According
to literature, the tert-butoxycarbonyl group (BOC) is usually re-
moved from the N-BOC containing compounds with the use of
wide range of acidic agents such as hydrochloride in dry ethyl
acetate,20 polyphosphoric acid,21 boron trifluoride diethyl ether-
ate22 or trifluoroacetic acid.23 The deprotection could be also
carried out under neutral conditions via thermal decomposition,24
H
ꢀ90.2
ꢀ54.0
ꢀ55.8
ꢀ25.6
CH3
C2H5
Ph
a
The reaction was conducted in excess of orthoester.
The reaction was conducted in benzene.
Optical rotations for compounds 6e–h, 6m–p were measured in chloroform
b
c
(c 1%) and for compounds 6a–d, 6i–l in methanol (c 1%).

1202
A. Kudelko, W. Zielin´ski / Tetrahedron 65 (2009) 1200–1206
H
O
H
OC2H5
OC2H5
OC2H5
H
Z
H
Z
Ph
Z
O
O
C
C
C
C
C
C
C
C
C
R3
Ph
R3
Ph
R3
NH
N
NH
N
N
N
B
C
A
Z = NHAc, NHBOC
R3
R3
R3
Ph
O
O
H
Z
Ph
Z
O
N
Z
C
+
C
Ph
N
N
N
N
N
H
H
Scheme 3.
Figure 1. ORTEP drawing of 6d with numbering of non-H atoms.
employing ceric ammonium nitrate (CAN)25 or trimethylsilyl tri-
fluoromethanesulfonate (TMS-OTf).26 Since 1,3,4-oxadiazole ring
is acid-sensitive, the number of mild deprotecting agents is rather
limited. Nevertheless, we subjected one series of N-BOC-protected
1,3,4-oxadiazoles 6m–p to the treatment of hydrochloride in dry
ethyl acetate. It appeared that 1,3,4-oxadiazoles substituted at
position 5 with H or alkyl groups (R2¼CH3, C2H5) decomposed to
deprotected hydrazide 7 (Scheme 4).
H
C
Ph
H
Ph
O
N
O
N
HCl/AcOEt
Ph
Ph
C
N
N
NHBOC
NH2*HCl
7
6p
Scheme 5.
Searching for the versatile deprotecting agent we also con-
ducted the thermal decomposition of N-BOC-protected 1,3,4-oxa-
diazoles and the reactions with CAN unfortunately, without
satisfactory results. Finally, the treatment of 6e–h with the excess of
trimethylsilyl trifluoromethanesulfonate in dry dichloromethane
afforded the N-deprotected derivatives 9a–d with untouched 1,3,4-
oxadiazole ring (Scheme 6).
H
C
R2
H
C
O
N
HCl/AcOEt
Ph
Ph
CONHNH2
N
NH2*HCl
8
NHBOC
6m-o
R2 = H, CH3, C2H5
More problematic is the cleavage of acetyl group from N-Ac-
protected 1,3,4-oxadiazoles. The typical method of the deprotection,
the acidic hydrolysis, could not be applied here because the
heterocyclic ring open easily even at room temperature. Due to this
fact, we decided to apply an indirect procedure where N-Ac-
protected 1,3,4-oxadiazoles 6b,d were treated with di-tert-butyl
Scheme 4.
However, when it was substituted with phenyl group, the
cleavage of the BOC group was successfully completed and the
highly stable heteroaromatic ring was not destructed (8, Scheme 5).

A. Kudelko, W. Zielin´ski / Tetrahedron 65 (2009) 1200–1206
1203
H
C
R2
crude product was washed twice with diethyl ether (2ꢂ30 mL),
H
C
N
R2
O
N
O
N
TMS-OTf
filtered off and dried on air.
Ph
Ph
H
N
N
4.2.1.
L
-(þ)-Phenylglycine methyl ester hydrochloride (2a)
20
NHBOC
H
9a-d
Yield: 92%, mp 193–195 ꢁC, [
a]
þ120.0 (c 1%, CHCl3).
H
6e-h
D
CF3SO3
R2 = H, CH3, C2H5, Ph
4.2.2.
D
-(ꢀ)-Phenylglycine methyl ester hydrochloride (2b)27
Scheme 6.
20
Yield: 94%, mp 191–193 ꢁC, [
a]
ꢀ119.0 (c 1%, CHCl3).
D
4.3. Synthesis of a-N-protected phenylglycine methyl esters 3
pyrocarbonate and diethylamine yielding the appropriate N-BOC-
protected 1,3,4-oxadiazoles 6f,h (Scheme 7).
Path A (Ac2O): The appropriate phenylglycine methyl ester hy-
drochloride (2a,b) (2.00 g, 10 mmol) was dissolved in 20 mL of cold
water. Then 2.13 g (25 mmol) of NaHCO3 was added and after the
liberation of CO2, 1 mL (10 mmol) of acetic acid anhydride was
injected. The mixture was stirred for about 15 min and cooled down
on ice-bath. The precipitate was filtered off, dried on air and crys-
tallized from isopropanol.
Path B (BOC2O): The appropriate phenylglycine methyl ester
hydrochloride (2a,b) (2.00 g, 10 mmol) was dissolved in 28 mL of
THF. The mixture was cooled down and 1.4 mL (10.6 mmol) of
triethylamine was introduced and the whole was stirred for about
20 min. Then 3.28 g (15 mmol) of di-tert-butyl pyrocarbonate was
added and left agitating at room temperature for 24 h. The white
precipitate of triethylamine hydrochloride was filtered off and the
solution was evaporated on the rotary evaporator. The white crude
product was dried in air and crystallized from isopropanol.
R2
R2
H
H
O
N
O
N
BOC2O
Ph
C
Ph
C
NH(C2H5)2
N
N
NHBOC
NHAc
6f, 6h
6b, 6d
R2 = CH3, Ph
Scheme 7.
Finally, they could be cleaved to 1,3,4-oxadiazoles possessing
free aminomethyl group with the use of previously described
method involving TMS-OTf.
3. Conclusions
In summary,
a-aminoacid hydrazides bearing the protected
4.3.1.
L
-(þ)-N-Ac-Phenylglycine methyl ester (3a)
a
-amino group appeared to be useful starting materials in the
20
Yield: 81%, mp 114–116 ꢁC, [
a
a
]
þ101.5 (c 1%, MeOH).
synthesis of 2-aminomethyl-1,3,4-oxadiazoles. The cleavage of the
tert-butoxycarbonyl group from N-BOC-protected 1,3,4-oxadiazoles
possessing the phenyl substituent at 5-position can be successfully
carried out with the use of typical agentdhydrochloride in dry
ethyl acetate. In contrast, trimethylsilyl trifluoromethanesulfonate
is the versatile agent and can be applied to N-BOC-protected 1,3,4-
oxadiazoles with both aryl and alkyl groups. The arrangements
with acyl substituent cannot be cleaved directly to 2-aminomethyl-
1,3,4-oxadiazoles because of their high acid-sensitivity. To avoid the
ring-opening reaction they should be transformed to their N-BOC-
protected counterparts and then released with the use of the pre-
viously mentioned agents.
D
4.3.2.
L
-(þ)-N-BOC-Phenylglycine methyl ester (3b)28
20
Yield: 90%, mp 113–115 ꢁC, [
]
þ189.5 (c 1%, CHCl3).
D
4.3.3.
D
-(ꢀ)-N-Ac-Phenylglycine methyl ester (3c)29
20
Yield: 86%, mp 115–117 ꢁC, [
a]
ꢀ100.9 (c 1%, MeOH).
D
4.3.4.
D
-(ꢀ)-N-BOC-Phenylglycine methyl ester (3d)30
20
Yield: 79%, mp 102–104 ꢁC, [
a
]
ꢀ187.8 (c 1%, CHCl3).
D
4.4. Synthesis of
a
-N-protected phenylglycine hydrazides 4
The appropriate
a
-N-protected phenylglycine methyl ester (3a–
4. Experimental
4.1. General
d) (1.00 g, 3.7 mmol) was dissolved in 18.0 mL of methanol and
then 0.6 mL of 98% hydrazine hydrate (12 mmol) was dropped in. It
was stirred for 24 h and concentrated under reduced pressure. The
oily residue was crystallized by trituration with 10.0 mL of hexane.
The crude product was filtered off and recrystallized from a mixture
of hexane–methanol (2:3, v/v).
Melting points were measured using an APA II melting point
apparatus and are uncorrected. UV spectra were recorded on
a Shimadzu UV-2102 spectrophotometer. Elemental analyses were
carried out with a VarioEL analyser in PAN Zabrze. The 1H and 13C
NMR spectra were recorded on a Varian Inova 300 spectrometer in
DMSO solution using TMS as internal standard. Thin layer chro-
matography was carried out on silica gel 60 F254 (Merck) thin layer
chromatography plates using benzene–ethyl acetate (1:3 v/v) as the
mobile phase. Optical rotations were measured on Perkin–Elmer
Polarimeter 141 in chloroform (2a, 2b, 3b, 3d, 4b, 4d, 6e–h, 6m–p)
or methanol (3a, 3c, 4a, 4c, 6a–d, 6i–l) solutions at the concentra-
tion of approx. 1% (D line of sodium light, room temperature).
4.4.1.
L
-(þ)-N-Ac-Phenylglycine hydrazide (4a)
20
Yield: 85%, mp 210–212 ꢁC, [
a]
þ95.2 (c 1%, MeOH), Rf 0.06
D
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C10H13N3O2: C,
57.95; H, 6.33; N, 20.26. Found: C, 58.06; H, 6.36; N, 20.31%.) lmax
(MeOH): 204 nm (
DMSO-d6): 1.89 (3H, s, CH3), 4.28 (2H, s, NH2), 5.44 (1H, d, J 8.7 Hz,
CH), 7.26–7.43 (5H, m, Ph), 8.65 (1H, d, J 8.7 Hz, NHAc), 9.57 (1H, s,
NH). 13C NMR (75 MHz, DMSO-d6):
22.43 (CH3), 54.80 (CH), 127.11,
127.49, 128.27, 139.09 (Ph), 169.02 (COAc), 169.36 (CONHNH2).
3
$10ꢀ3 13.23 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
d
d
4.2. Synthesis of phenylglycine methyl ester hydrochlorides 2
4.4.2.
L
-(þ)-N-BOC-Phenylglycine hydrazide (4b)
20
Yield: 66%, mp 105–107 ꢁC, [
a
]
þ105.3 (c 1%, CHCl3), Rf 0.15
D
The suspension of 5.00 g (33 mmol) of the appropriate phenyl-
glycine (1a,b) in 25 mL of methanol was cooled down (0 ꢁC) and
6 mL of thionyl chloride was slowly dropped in. It was stirred for
8 h and then concentrated on the rotary evaporator. The white
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C19H19N3O3: C,
58.85; H, 7.23; N, 15.83. Found: C, 58.80; H, 7.21; N, 15.85%.) lmax
(MeOH): 204 nm (
(300 MHz, DMSO-d6):
3
$10ꢀ3 14.65 cmꢀ1 Mꢀ1), 257 (0.63). 1H NMR
d
1.42 (9H, s, (CH3)3), 3.68 (2H, s, NH2), 5.28

1204
A. Kudelko, W. Zielin´ski / Tetrahedron 65 (2009) 1200–1206
(1H, d, J 7.2 Hz, CH), 5.99 (1H, d, J 7.2 Hz, NHBOC), 7.30–7.38 (5H, m,
Ph), 8.25 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6):
28.26 ((CH3)3),
56.99 (CH), 80.33 (C(CH3)3), 126.97, 128.34, 128.89, 137.64 (Ph),
155.23 (COBOC), 171.20 (CONHNH2).
4.5.3. 5-Ethyl-2-(1-N-acylamino-1-phenylmethyl)-1,3,4-oxadiazole
(6c,k)
d
Yield: 65%, mp 89–91 ꢁC, Rf 0.18 (benzene–ethyl acetate,1:3 v/v).
(Anal. Calcd for C13H15N3O2: C, 63.66; H, 6.16; N, 17.13. Found: C,
63.49; H, 6.18; N, 17.23%.) lmax (MeOH): 201 nm
(
3
$10ꢀ3
1.22
4.4.3.
D
-(ꢀ)-N-Ac-Phenylglycine hydrazide (4c)
49.27 cmꢀ1 Mꢀ1), 261 (1.45). 1H NMR (300 MHz, DMSO-d6):
d
20
Yield: 90%, mp 196–198 ꢁC, [
a
]
ꢀ93.6 (c 1%, MeOH), Rf 0.05
(3H, t, J 7.5 Hz, CH3-C5), 1.94 (3H, s, CH3), 2.83 (2H, q, J 7.5 Hz, CH2-
C5), 6.33 (1H, d, J 8.1 Hz, CH), 7.37–7.41 (5H, m, Ph), 9.15 (1H, d, J
D
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C10H13N3O2: C,
57.95; H, 6.33; N, 20.26. Found: C, 57.99; H, 6.28; N, 20.21%.) lmax
8.1 Hz, NH). 13C NMR (75 MHz, DMSO-d6):
d 10.34 (CH3-C5), 18.29
(MeOH): 205 nm (
DMSO-d6): 1.89 (3H, s, CH3), 4.27 (2H, s, NH2), 5.44 (1H, d, J 8.4 Hz,
CH), 7.26–7.42 (5H, m, Ph), 8.63 (1H, d, J 8.4 Hz, NHAc), 9.54 (1H, s,
NH).13C NMR (75 MHz, DMSO-d6):
22.95 (CH3), 55.25 (CH),127.58,
127.94, 128.73, 139.59 (Ph), 169.45 (COAc), 169.83 (CONHNH2).
3
$10ꢀ3 17.43 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
(CH2-C5), 22.29 (CH3), 48.73 (CH), 127.52, 128.31, 128.74, 136.93
(Ph), 165.59 (C2), 168.03 (C5), 169.09 (CO).
d
d
4.5.4. 2-(1-N-Acylamino-1-phenylmethyl)-5-phenyl-1,3,4-
oxadiazole (6d,l)
Yield: 82%, mp 167–168 ꢁC, Rf 0.27 (benzene–ethyl acetate, 1:3
v/v). (Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found:
4.4.4.
D
-(ꢀ)-N-BOC-Phenylglycine hydrazide (4d)
20
Yield: 73%, mp 118–121 ꢁC, [
a
]
ꢀ101.7 (c 1%, CHCl3), Rf 0.14
C, 69.56; H, 5.18; N, 14.41%.) lmax (MeOH): 204 nm (
27.97 cmꢀ1 Mꢀ1), 252 (17.60). 1H NMR (300 MHz, DMSO-d6):
(3H, s, CH3), 6.44 (1H, d, J 8.1 Hz, CH), 7.35–7.96 (10H, m, 2ꢂPh),
9.29 (1H, d, J 8.1 Hz, NH). 13C NMR (75 MHz, DMSO-d6):
22.34
3
$10ꢀ3
1.97
D
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C19H19N3O3: C,
d
58.85; H, 7.23; N, 15.83. Found: C, 58.77; H, 7.26; N, 15.89%.) lmax
(MeOH): 203 nm (
DMSO-d6): 1.42 (9H, s, C(CH3)3), 3.82 (2H, s, NH2), 5.29 (1H, d, J
7.5 Hz, CH), 6.04 (1H, d, J 7.5 Hz, NHBOC), 7.27–7.37 (5H, m, Ph), 8.23
(1H, s, NH). 13C NMR (75 MHz, DMSO-d6):
28.27 ((CH3)3), 56.92
3
$10ꢀ3 13.10 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
d
d
(CH3), 48.96 (CH), 123.13, 126.57, 127.64, 128.39, 128.79, 129.47,
132.14, 136.81 (2ꢂPh), 164.37 (C5), 165.93 (C2), 169.31 (CO).
d
(CH), 80.32 (C(CH3)3), 126.92, 128.30, 128.86, 137.66 (Ph), 155.24
(COBOC), 171.21 (CONHNH2).
4.5.5.
L
-(þ)-2-(1-N-tert-Butoxycarbonylamino-1-phenylmethyl)-
1,3,4-oxadiazole (6e)
20
Yield: 45%, mp 113–115 ꢁC, [
a
]
D
þ86.0 (c 1%, CHCl3), Rf 0.51 (ben-
zene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C14H17N3O3: C, 61.10; H,
4.5. General procedure for the preparation of N-protected 2-
(1-amino-1-phenylmethyl)-1,3,4-oxadiazoles (6a–p)
6.18; N, 15.27. Found: C, 60.16; H, 6.24; N, 15.35%.) lmax (MeOH):
202 nm (
DMSO-d6):
m, Ph), 8.31 (1H, d, J 8.1 Hz, NH), 9.20 (1H, s, H-C5). 13C NMR (75 MHz,
DMSO-d6): 28.09 ((CH3)3), 50.44 (CH), 78.96 (C(CH3)3),127.56,128.22,
128.55, 137.00 (Ph), 154.77 (CO), 156.08 (C5), 165.74 (C2).
3
$10ꢀ3 12.31 cmꢀ1 Mꢀ1), 257 (1.53). 1H NMR (300 MHz,
d
1.40 (9H, s, (CH3)3), 6.14 (1H, d, J8.1 Hz, CH), 7.32–7.45 (5H,
Racemates: The starting N-protected phenylglycine hydrazide
(4a–d) (0.01 mol) was added to a mixture of the appropriate tri-
ethyl orthoester (0.05 mol) and 10.0 mL of glacial AcOH. It was kept
under reflux for about 3 h. After cooling the excessive orthoester
and AcOH were evaporated under reduced pressure. The crude
white products (6a–p) were subjected to the column chromatog-
raphy (silica gel, eluent: benzene–AcOEt 1:3 or 1:5 mixtures) or
were crystallized from benzene–hexane mixtures.
d
4.5.6.
L
-(þ)-5-Methyl-2-(1-N-tert-butoxycarbonylamino-1-
phenylmethyl)-1,3,4-oxadiazole (6f)
20
Yield: 65%, mp 98–100 ꢁC, [
a
]
þ55.2 (c 1%, CHCl3), Rf 0.52
D
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C15H19N3O3: C,
Enantiomers: The starting N-BOC-phenylglycine hydrazide
(4b,d) (0.01 mol) was added to the mixture of the appropriate tri-
ethyl orthoester (0.05 mol), 100.0 mL of benzene and 10.0 mL of
glacial AcOH. It was kept under reflux for about 1–2 h (TLC). After
cooling the solution was concentrated on the rotary evaporator and
left for crystallization. Pure products (6e–h, 6m–p) were recrys-
tallized from benzene–hexane mixtures.
62.28; H, 6.57; N, 14.53. Found: C, 62.12; H, 6.50; N, 14.45%.) lmax
(MeOH): 203 nm (
(300 MHz, DMSO-d6):
6.03 (1H, d, J 8.1 Hz, CH), 7.32–7.43 (5H, m, Ph), 8.25 (1H, d, J 8.1 Hz,
NH). 13C NMR (75 MHz, DMSO-d6):
10.55 (CH3-C5), 28.19 ((CH3)3),
3
$10ꢀ3 15.94 cmꢀ1 Mꢀ1), 257 (1.11). 1H NMR
d
1.38 (9H, s, (CH3)3), 2.44 (3H, s, CH3-C5),
d
50.58 (CH), 79.00 (C(CH3)3), 127.62, 128.25, 128.63, 137.21 (Ph),
155.01 (CO), 164.25 (C5), 165.93 (C2).
4.5.1. 2-(1-N-Acylamino-1-phenylmethyl)-1,3,4-oxadiazole (6a,i)
Yield: 59%, mp 120–121 ꢁC, Rf 0.07 (benzene–ethyl acetate, 1:3
v/v). (Anal. Calcd for C11H11N3O2: C, 60.83; H, 5.10; N, 19.34. Found:
4.5.7.
L
-(þ)-5-Ethyl-2-(1-N-tert-butoxycarbonylamino-1-
phenylmethyl)-1,3,4-oxadiazole (6g)
20
Yield: 66%, mp 123–125 ꢁC, [
a]
þ56.4 (c 1%, CHCl3), Rf 0.52
D
C, 60.58; H, 5.14; N, 19.29%.) lmax (MeOH): 204 nm (
3
$10ꢀ3
1.95
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C16H21N3O3: C,
63.37; H, 6.97; N, 13.86. Found: C, 62.35; H, 7.10; N, 13.56%.) lmax
(MeOH): 203 nm (
(300 MHz, DMSO-d6):
16.70 cmꢀ1 Mꢀ1), 257 (0.56). 1H NMR (300 MHz, DMSO-d6):
d
(3H, s, CH3), 6.40 (1H, d, J 7.8 Hz, CH), 7.36–7.42 (5H, m, Ph), 9.18
3
$10ꢀ3 49.27 cmꢀ1 Mꢀ1), 257 (1.55). 1H NMR
(1H, d, J 7.8 Hz, NH), 9.23 (1H, s, H-C5). 13C NMR (75 MHz, DMSO-
d
1.21 (3H, t, J 8.1 Hz, CH3-C5), 1.38 (9H, s,
d6):
d
22.29 (CH3), 48.75 (CH), 127.59, 128.41, 128.79, 136.76 (Ph),
(CH3)3), 2.81 (2H, q, J 8.1 Hz, CH2-C5), 6.03 (1H, d, J 8.1 Hz, CH), 7.31–
154.85 (C5), 165.60 (C2), 169.21 (CO).
7.41 (5H, m, Ph), 8.24 (1H, d, J 8.1 Hz, NH). 13C NMR (75 MHz, DMSO-
d6):
d 10.45 (CH3-C5), 18.35 (CH2-C5), 28.19 ((CH3)3), 50.63 (CH),
4.5.2. 5-Methyl-2-(1-N-acylamino-1-phenylmethyl)-1,3,4-
oxadiazole (6b,j)
78.99 (C(CH3)3), 127.62, 128.24, 128.63, 137.22 (Ph), 155.03 (CO),
165.82 (C2), 168.10 (C5).
Yield: 62%, mp 112–113 ꢁC, Rf 0.13 (benzene–ethyl acetate, 1:3 v/
v). (Anal. Calcd for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C,
4.5.8.
L
-(þ)-2-(1-N-tert-Butoxycarbonylamino-1-phenylmethyl)-5-
62.12; H, 5.70; N, 18.09%.) lmax (MeOH): 205 nm
(3
$10ꢀ3
1.90
phenyl-1,3,4-oxadiazole (6h)
20
17.27 cmꢀ1 Mꢀ1), 251 (0.54). 1H NMR (300 MHz, DMSO-d6):
d
Yield: 80%, mp 131–133 ꢁC, [
a]
þ26.0 (c 1%, CHCl3), Rf 0.52
D
(3H, s, CH3), 2.47 (3H, s, CH3-C5), 6.30 (1H, d, J 8.1 Hz, CH), 7.33–7.40
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C20H21N3O3: C,
(5H, m, Ph), 9.19 (1H, d, J 8.1 Hz, NH). 13C NMR (75 MHz, DMSO-d6):
68.37; H, 5.98; N, 11.97. Found: C, 68.19; H, 6.11; N, 11.85%.) lmax
d
10.54 (CH3-C5), 22.32 (CH3), 48.72 (CH), 127.57, 128.33, 128.75,
(MeOH): 204 nm (
(300 MHz, DMSO-d6):
3
$10ꢀ3 24.98 cmꢀ1 Mꢀ1), 252 (18.00). 1H NMR
136.92 (Ph), 164.23 (C5), 165.71 (C2), 169.16 (CO).
d
1.38 (9H, s, (CH3)3), 6.19 (1H, d, J 8.1 Hz, CH),

A. Kudelko, W. Zielin´ski / Tetrahedron 65 (2009) 1200–1206
1205
7.34–7.95 (10H, m, 2ꢂPh), 8.38 (1H, s, J 8.1 Hz, NH). 13C NMR
(MeOH): 205 nm (
3
$10ꢀ3 34.37 cmꢀ1 Mꢀ1), 250 (24.87). 1H NMR
6.25 (1H, s, CH), 7.41–8.18 (10H, m, 2ꢂPh), 9.88
(75 MHz, DMSO-d6):
d
28.10 ((CH3)3), 50.63 (CH), 79.03 (C(CH3)3),
(300 MHz, CDCl3): d
123.14, 126.48, 127.55, 128.25, 128.62, 129.45, 132.10, 137.06 (2ꢂPh),
(3H, br s, NHþ3 ). 13C NMR (75 MHz, CDCl3):
d 49.29 (CH), 122.69,
155.00 (CO), 164.33 (C5), 165.99 (C2).
126.70, 128.55, 129.07, 129.55, 129.79, 132.52, 132.74 (2ꢂPh), 162.94
(C2), 164.99 (C5).
4.5.9.
D
-(ꢀ)-2-(1-N-tert-Butoxycarbonylamino-1-phenylmethyl)-
1,3,4-oxadiazole (6m)
4.6.2. Phenylglycine hydrazide hydrochloride (8)
Yield: 85%, mp 209–211 ꢁC. (Anal. Calcd for C8H12N3OCl: C,
47.65; H, 6.01; N, 20.83. Found: C, 47.72; H, 5.97; N, 20.76%.) lmax
20
Yield: 38%, mp 113–114 ꢁC, [
a
]
D
ꢀ90.2 (c 1%, CHCl3), Rf 0.52 (ben-
zene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C14H17N3O3: C, 61.10; H,
6.18; N, 15.27. Found: C, 60.20; H, 6.14; N, 15.32%.) lmax (MeOH):
(MeOH): 206 nm (
CDCl3): 4.15 (2H, br s, NH2), 5.03 (1H, s, CH), 6.05 (1H, s, NH), 7.57–
7.62 (5H, m, Ph), 8.94 (3H, br s, NHþ3 ). 13C NMR (75 MHz, CDCl3):
54.17 (CH), 128.96, 129.20, 129.94, 133.77 (Ph), 162.86 (CO).
3
$10ꢀ3 14.45 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
203 nm (
(9H, s, (CH3)3), 6.15 (1H, d, J 8.1 Hz, CH), 7.21–7.54 (5H, m, Ph), 8.32 (1H,
d, J 8.1 Hz, NH), 9.20 (1H, s, H-C5).13C NMR (75 MHz, DMSO-d6):
28.11
3
$10ꢀ3 14.80 cmꢀ1 Mꢀ1).1H NMR (300 MHz, DMSO-d6):
d
1.38
d
d
d
((CH3)3), 50.46 (CH), 78.99 (C(CH3)3),127.60,128.26,128.58,137.26 (Ph),
155.08 (CO), 154.83 (C5), 165.78 (C2).
4.7. Reactions of N-BOC-protected 1,3,4-oxadiazoles (6e–h)
4.5.10.
D
-(ꢀ)-5-Methyl-2-(1-N-tert-butoxycarbonylamino-1-
with trimethylsilyl trifluoromethanesulfonate
phenylmethyl)-1,3,4-oxadiazole (6n)
20
Yield: 48%, mp 100–102 ꢁC, [
a]
ꢀ54.0 (c 1%, CHCl3), Rf 0.49
The N-BOC-protected 1,3,4-oxadiazole (6e–h) (3.5 mmol) was
dissolved in 10.0 mL of dry dichloromethane and to such a solution
trimethylsilyl trifluoromethanesulfonate (10.5 mmol) in 10 mL dry
dichloromethane was added. The mixture was stirred at room
temperature until the disappearance of the starting material was
complete (1 h). Then it was evaporated on the rotary evaporator
and the crude solid was crystallized from isopropanol.
D
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C15H19N3O3: C,
62.28; H, 6.57; N, 14.53. Found: C, 61.97; H, 6.45; N, 14.59%.) lmax
(MeOH): 203 nm (
DMSO-d6): 1.39 (9H, s, (CH3)3), 2.45 (3H, s, CH3-C5), 6.05 (1H, d, J
8.1 Hz, CH), 7.25–7.52 (5H, m, Ph), 8.26 (1H, d, J 8.1 Hz, NH). 13C NMR
(75 MHz, DMSO-d6): 10.49 (CH3-C5), 28.13 ((CH3)3), 50.23 (CH),
3
$10ꢀ3 14.20 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
d
d
78.93 (C(CH3)3), 127.57, 128.20, 128.28, 137.17 (Ph), 155.30 (CO),
164.21 (C5), 165.09 (C2).
4.7.1. 1-(1,3,4-Oxadiazol-2-yl)-1-phenylmethylammonium
trifluoromethanesulfonate (9a)
4.5.11.
D
-(ꢀ)-5-Ethyl-2-(1-N-tert-butoxycarbonylamino-1-
Yield: 96%, mp 118–120 ꢁC. (Anal. Calcd for C10H10N3O4F3S: C,
36.92; H, 3.10; N, 12.91. Found: C, 37.09; H, 3.01; N, 13.02%.) lmax
phenylmethyl)-1,3,4-oxadiazole (6o)
20
Yield: 56%, mp 124–125 ꢁC, [
a
]
D
ꢀ55.8 (c 1%, CHCl3), Rf 0.53
(MeOH): 204 nm (
DMSO-d6): 6.15 (1H, s, CH), 7.38–7.46 (5H, m, Ph), 9.31 (1H, s, H-
C5), 9.32 (3H, br s, NHþ3 ). 13C NMR (75 MHz, DMSO-d6):
49.95 (CH),
3
$10ꢀ3 11.52 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
(benzene–ethyl acetate,1:3 v/v). (Anal. Calcdfor C16H21N3O3: C, 63.37;
d
H, 6.97; N, 13.86. Found: C, 62.29; H, 6.94; N, 13.92%.) lmax (MeOH):
d
203 nm (
1.21 (3H, t, J 7.5 Hz, CH3-C5), 1.38 (9H, s, (CH3)3), 2.80 (2H, q, J 7.5 Hz,
CH2-C5), 6.03 (1H, d, J 8.1 Hz, CH), 7.27–7.45 (5H, m, Ph), 8.25 (1H, d, J
8.1 Hz, NH). 13C NMR (75 MHz, DMSO-d6):
10.45 (CH3-C5), 18.35
3
$10ꢀ3 13.53 cmꢀ1 Mꢀ1). 1H NMR (300 MHz, DMSO-d6):
119.01 (CF3), 127.76, 128.42, 128.77, 137.21 (Ph), 165.82 (C2), 169.21
(C5).
d
d
4.7.2. 1-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-phenylmethyl-
ammonium trifluoromethanesulfonate (9b)
(CH2-C5), 28.18 ((CH3)3), 50.64 (CH), 78.99 (C(CH3)3), 127.56, 128.25,
128.63, 137.23 (Ph), 155.01 (CO), 165.03 (C2), 168.01 (C5).
Yield: 95%, mp 148–150 ꢁC. (Anal. Calcd for C11H12N3O4F3S: C,
38.98; H, 3.57; N, 12.38. Found: C, 38.77; H, 3.61; N, 12.43%.) lmax
4.5.12.
D
-(ꢀ)-2-(1-N-tert-Butoxycarbonylamino-1-phenylmethyl)-
(MeOH): 204 nm (
DMSO-d6): 1.83 (3H, t, J 8.1 Hz, CH3-C5), 6.10 (1H, s, CH), 7.43–7.51
(5H, m, Ph), 9.30 (3H, br s, NHþ3 ). 13C NMR (75 MHz, DMSO-d6):
20.48 (CH3-C5), 50.02 (CH), 118.21 (CF3), 128.01, 128.71, 128.89,
3
$10ꢀ3 16.32 cmꢀ1 Mꢀ1). 1H NMR (300 MHz,
5-phenyl-1,3,4-oxadiazole (6p)
d
20
Yield: 74%, mp 132–133 ꢁC, [
a
]
ꢀ25.6 (c 1%, CHCl3), Rf 0.60
D
(benzene–ethyl acetate, 1:3 v/v). (Anal. Calcd for C20H21N3O3: C,
d
68.37; H, 5.98; N, 11.97. Found: C, 68.25; H, 6.07; N, 12.03%.) lmax
133.17 (Ph), 164.78 (C2), 167.79 (C5).
(MeOH): 204 nm (
(300 MHz, DMSO-d6):
3
$10ꢀ3 29.10 cmꢀ1 Mꢀ1), 251 (20.68). 1H NMR
d
1.40 (9H, s, (CH3)3), 6.18 (1H, d, J 8.1 Hz, CH),
4.7.3. 1-(5-Ethyl-1,3,4-oxadiazol-2-yl)-1-phenylmethylammonium
trifluoromethanesulfonate (9c)
7.21–7.96 (10H, m, 2ꢂPh), 8.37 (1H, d, J 8.1 Hz, NH). 13C NMR
(75 MHz, DMSO-d6):
d
28.09 ((CH3)3), 50.64 (CH), 79.03 (C(CH3)3),
Yield: 94%, mp 176–178 ꢁC. (Anal. Calcd for C12H14N3O4F3S: C,
40.79; H, 4.00; N, 11.89. Found: C, 40.86; H, 4.05; N, 11.97%.) lmax
123.14, 126.49, 127.55, 128.25, 128.62, 129.46, 132.11, 137.06 (2ꢂPh),
155.01 (CO), 164.33 (C5), 166.00 (C2).
(MeOH): 205 nm (
(300 MHz, DMSO-d6):
8.1 Hz, CH2-C5), 6.20 (1H, s, CH), 7.44–7.53 (5H, m, Ph), 9.30 (3H, br
s, NHþ3 ). 13C NMR (75 MHz, DMSO-d6):
10.30 (CH3-C5), 18.30
3
$10ꢀ3 13.24 cmꢀ1 Mꢀ1), 240 (3.50). 1H NMR
d
1.23 (3H, t, J 8.1 Hz, CH3-C5), 2.86 (2H, q, J
4.6. Reactions of N-BOC-protected 1,3,4-oxadiazoles (6m–p)
with hydrochloride in dry ethyl acetate
d
(CH2-C5), 49.60 (CH), 118.85 (CF3), 127.99, 128.36, 128.91, 132.60
(Ph), 164.72 (C2), 169.10 (C5).
The N-BOC-protected 1,3,4-oxadiazole (6m–p) (3.5 mmol) was
dissolved in 50.0 mL of 1 M solution of HCl in dry ethyl acetate. The
mixture was agitated at room temperature until the disappearance
of the starting material was complete (1–72 h). The precipitate was
filtered off and crystallized from isopropanol or hexane–methanol
mixture.
4.7.4. 1-(5-Phenyl-1,3,4-oxadiazol-2-yl)-1-phenylmethyl-
ammonium trifluoromethanesulfonate (9d)
Yield: 97%, mp 120–122 ꢁC. (Anal. Calcd for C16H14N3O4F3S: C,
47.88; H, 3.52; N, 10.46. Found: C, 47.72; H, 3.58; N, 10.51%.) lmax
(MeOH): 204 nm (
(300 MHz, DMSO-d6):
9.40 (3H, br s, NHþ3 ). 13C NMR (75 MHz, DMSO-d6):
3
$10ꢀ3 19.62 cmꢀ1 Mꢀ1), 249 (11.40). 1H NMR
4.6.1. 2-(1-Amino-1-phenylmethyl)-5-phenyl-1,3,4-oxadiazole
hydrochloride (7)
Yield: 81%, mp 215–217 ꢁC. (Anal. Calcd for C15H14N3OCl: C,
62.61; H, 4.91; N, 14.60. Found: C, 62.75; H, 4.97; N, 14.68%.) lmax
d
6.24 (1H, s, CH), 7.50–7.98 (10H, m, 2ꢂPh),
d
49.67 (CH),
118.65 (CF3), 122.65, 126.85, 128.53, 129.41, 129.72, 130.20, 132.53,
136.89 (2ꢂPh), 164.37 (C5), 165.93 (C2).

1206
A. Kudelko, W. Zielin´ski / Tetrahedron 65 (2009) 1200–1206
4.8. Reactions of N-Ac-protected 1,3,4-oxadiazoles (6b,d) with
BOC2O and diethylamine
Cambridge CB2 1EZ, UK; fax: þ44 (0) 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk].
The mixture of N-Ac-protected 1,3,4-oxadiazoles (6b,d)
(3.5 mmol), 5 mL of methanol, diethylamine (7.0 mmol) and BOC2O
anhydride (3.6 mmol) was heated under reflux until the disap-
pearance of the starting material was complete (TLC, 5–10 h). Then
it was evaporated on the rotary evaporator and the crude solid was
crystallized from benzene–hexane mixture. The reactions gave the
appropriate pure N-BOC-protected 1,3,4-oxadiazoles: 6f (yield:
95%, mp 98–101 ꢁC), 6h (yield: 96%, mp 131–132 ꢁC).
Acknowledgements
´
The authors wish to thank crystallographers: Andrzej Fruzinski,
Ph.D. from Technical University of Lodz and Zbigniew Karczmarzyk,
Ph.D. from University of Podlasie for X-ray analysis. This work was
supported by the State Committee of Scientific Research, Grant No.
3T09B01929.
References and notes
4.9. X-ray crystal structure analysis for 6d
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C17H15N3O2, M¼293.32, colourless crystal, 0.50ꢂ0.06ꢂ0.03 mm,
triclinic, space group P1, a¼4.9435(4) Å, b¼8.5742(7) Å,
c¼18.1771(15) Å,
a
¼87.621(2)ꢁ,
b
¼82.259(2)ꢁ,
g
¼77.721(2)ꢁ,
V¼745.91(11) Å3, Z¼2, rcalcd¼1.306 g cmꢀ3
,
m(Mo K
a
)¼0.088 mmꢀ1
,
l
¼0.71073 Å,
u scans, multi-scan absorption correction, Tmin/Tmax
0.9573/0.9974, range for data collection
q
¼2.26–27.9ꢁ, index ranges
(h, k, l) ꢀ6/6, ꢀ11/11, ꢀ23/23, 16,007 measured reflections, 3580
independent reflections (Rint¼0.0323) and 2693 observed re-
flections [I>2s
(I)], full-matrix least-squares on F2 refinement
method, R¼0.0393, wR(F2)¼0.1026, goodness-of-fit on F2 S¼1.045,
data/restraints/parameters 3580/3/467, extinction coefficient
0.037(7), largest diff. peak and hole þ0.160/ꢀ0.123 e Åꢀ3
.
The needle-shaped crystals of 6d suitable for X-ray diffraction
analysis were grown by slow evaporation of an ethanol solution.
X-ray data were collected on the Bruker SMART APEX II CCD dif-
fractometer at room temperature. The structure was solved by
direct methods using SIR9231 and refined by full-matrix least-
squares with SHELXL97.32 The final residual electron-density map
showed that the C52, C53, C55 and C56 atoms in phenyl rings of
the both molecules in the asymmetric part of unit cell are disor-
dered over two sites. The occupancy factors for the split carbon
atoms were fixed at 0.5 in the last cycles of refinement. The H
atoms were positioned geometrically and treated as riding on their
parent C and N atoms with C–H distances of 0.93 Å (aromatic),
0.96 Å (CH3) and 0.98 Å (CH) and N–H distances of 0.86 Å. All H
atoms were refined with isotropic displacement parameters taken
as 1.5 times those of the respective parent atoms. As there are no
significant anomalous scatterers in the molecule, the Flack pa-
rameter33 could not be used to determine the absolute structure.
Therefore 3547 Friedel equivalents were merged before the final
refinement and the enantiomer was assigned by reference to an
unchanging chiral centre in the synthetic procedure. Molecular
graphic was prepared using ORTEP3 for Windows.34 PARST35 and
PLATON36 were used for geometrical calculations. All calculations
were performed using WINGX version 1.64.05 package.37 CCDC
700769 for 6d contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cam-
bridge Crystallographic Data Centre (CCDC), 12 Union Road,
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19. Kudelko, A.; Zielinski, W., in preparation.
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Kissel, W.; Le, T.; Leeman, K. R.; Marquez, B.; Morris, R.; Newell, L.; Wunderwald,
S.; Witt, M.; Weaver, J.; Zhang, Z.; Zhang, Z. J. Org. Chem. 2006, 71, 9045–9050.
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1997, 27, 1819–1825.
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2035–2038.
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´
´
30. Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero, L.; Sanchez-Obregon, R.;
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