Efficient and stereoselective synthesis of α-hydrazino tetrazoles through a pseudo five-component domino reaction

Article abstract of DOI:10.1016/j.tet.2015.07.037

A concise and efficient route for the diastereoselective synthesis of new and interesting α-hydrazino tetrazoles has been developed through a pseudo five-component domino reaction using the isocyanide-based one-pot multicomponent reaction. The products we

Full text of DOI:10.1016/j.tet.2015.07.037

Accepted Manuscript
Efficient and Stereoselective Synthesis of α-Hydrazino Tetrazoles through a Pseudo
Five-component Domino Reaction
Ali Nikbakht, Sorour Ramezanpour, Saeed Balalaie, Frank Rominger
PII:
S0040-4020(15)01074-1
10.1016/j.tet.2015.07.037
TET 26982
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 April 2015
Revised Date: 24 June 2015
Accepted Date: 13 July 2015
Please cite this article as: Nikbakht A, Ramezanpour S, Balalaie S, Rominger F, Efficient and
Stereoselective Synthesis of α-Hydrazino Tetrazoles through a Pseudo Five-component Domino
Reaction, Tetrahedron (2015), doi: 10.1016/j.tet.2015.07.037.
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ACCEPTED MANUSCRIPT
Efficient and Stereoselective Synthesis of α-Hydrazino Tetrazoles through a Pseudo
Five-component Domino Reaction
a
a
a,b
c
Ali Nikbakht, Sorour Ramezanpour, Saeed Balalaie,* Frank Rominger
a
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box
1
5875-4416 Tehran, Iran balalaie@kntu.ac.ir
b
Medical Biology Research Center, Kermanshah Medical Science University,
Kermanshah, Iran
c
Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270,
6
9120 Heidelberg, Germany
C N
R2
TMSN3
N
N
N
N R2
HN
N
O
O
R1
R1
R1
R1
H N NH2
2
Abstract:
A concise and efficient route for the diastereoselective synthesis of new and interesting
α-hydrazino tetrazoles has been developed through a pseudo five-component domino
reaction using the isocyanide-based one-pot multicomponent reaction. The products were
obtained by a facile Ugi-azide pseudo five-component reaction of cyclic ketones,
hydrazine hydrate, trimethylsilyl azide, and corresponding isocyanides without any
catalyst in good yields and with high bond forming efficiency at room temperature.
Keywords: Ugi-azide pseudo five-component reaction, α-hydrazino tetrazoles,
isocyanide-based one-pot multicomponent reaction.
Dedicated to Prof. Mohammad Yalpani on the occasion of his birthday
1

ACCEPTED MANUSCRIPT
Introduction
Tetrazoles represent an important class of heterocyclic nitrogen compound with a wide
range of biological properties such as antimicrobial, antibacterial, antifungal, analgestic,
1
anti-inflammatory, antiviral, and anti-cancer activities. In recent years, considerable
attention has been drawn to 1,5-disubstituted tetrazoles, the more common tetrazole
2
derivatives, due to their biological importance and functional properties. As such, they
are important in biology and medicine as NADPH oxidase inhibitors, glucokinase
activators, hepatitis C virus (HCV) serine protease NS3 inhibitors, calcitonin gene-
3
related peptide receptor antagonists and antimigraine agents. They have also attracted a
great deal of attention in the field of peptide chemistry as conformational mimics of cis-
4
amide bonds. Prescribed agents featuring the 1,5-disubstituted tetrazole scaffold include
the anti-inflammatory cilostazol, the anti-microbial latamoxef, the circulatory and
5
respiratory stimulant pentylenetetrazol and the anti-diabetic nojiritetrazole.
Figure. 1 1,5-Disubstituted tetrazoles as conformational mimics of cis-amide bonds, and
as medicinally important compounds.
There has been considerable interest in the synthesis of 1,5-disubstituted tetrazoles
owning to their diverse pharmacological activities and numerous approaches to this
scaffold have been disclosed in the literature. Major synthetic strategies utilized for the
preparation of 1,5-disubstituted tetrazoles are via intermolecular cycloaddition reactions,
6
and isocyanide-based multicomponent reactions. Among the various pathways toward
1
,5-disubstituted tetrazole derivatives, the isocyanide-based multicomponent reactions
(
IMCRs) are most relevant by virtue of their synthetic potential, inherent atom
efficiency, convergent nature, ease of implementation, and the generation of molecular
2

ACCEPTED MANUSCRIPT
7
diversity. Recently, we have developed a non-catalytic diastereoselective approach to
these important heterocyclic nitrogen compounds through a facile Ugi-azide four-
8
component reaction. As part of our continuing efforts to improve the preparation of
biologically important 1,5-disubstituted tetrazoles by means of isocyanide-based
multicomponent reactions, herein we describe a concise and efficient route for the
diastereoselective synthesis of new and interesting α-hydrazino tetrazoles via a facile
Ugi-azide pseudo five-component reaction of two equivalents of cyclic ketones,
hydrazine hydrate, isocyanides and trimethylsilyl azide (Scheme 1).
Scheme 1. Stereoselective synthesis of α-hydrazino tetrazoles 5a-h through a facile Ugi-
azide pseudo five-component reaction
Results and discussion
The Ugi-azide pseudo five-component reaction of hydrazine hydrate 1, 2 equivalents of
4
-tert-butyl cyclohexanone 2a, tert-butyl isocyanide 3a and trimethylsilyl azide 4 in
ethanol was selected as the model reaction. The reaction mixture was stirred at room
temperature to produce the corresponding α-hydrazino tetrazole (5a) in 89% yield (Table
1
). At the outset of this study, our efforts were focused on finding appropriate reaction
conditions to perform the proposed reaction. Consequently, the model reaction was
carried out in various solvents. The results are summarized in Table 1. The use of
acetonitrile, tetrahydrofuran, and dichloromethane in place of ethanol/methanol as the
reaction solvent decreased the yield of the desired product (entries 1-3). Therefore,
ethanol was used as the reaction solvent.
3

ACCEPTED MANUSCRIPT
Scheme 2. The model reaction for the synthesis of 5a through the Ugi-azide pseudo five-
component reaction
Table 1. Optimization of the solvent reaction
[a]
Entry
Solvent
Yield (%)
1
2
3
4
5
THF
17
23
35
89
89
CH Cl
2
2
CH CN
3
CH OH
3
CH CH OH
3
2
[
a] Isolated yields
Furthermore, when TMS-N in the reaction was replaced by NaN we could isolate only
3
3
3
7% of 5a. In another attempt, the ratio of isocyanides and also trimethylsilyl azide was
raised to 2.5 equivalents in the model reaction to obtain the product containing two
tetrazole ring moieties. However, the sole product was 5a: the desired product could not
form possibly due to stereoelectronic effects. With optimized reaction conditions in hand
for the preparation of 5a, we decided to check the scope of the reaction with various
cyclic ketones and isocyanides. The results obtained are summarized in Table 2. In our
1
initial studies, the formation of single atropisomers were determined by H NMR
spectroscopic data on the crude reaction products through the single -NH signal and the
single CH-N signal of the corresponding products, resonating at δ 4.30-4.60 and δ 5.00-
5
.20 respectively (Table 2).
4

ACCEPTED MANUSCRIPT
Table 2. The facile Ugi-azide pseudo five-component reaction for the diastereoselective
synthesis of hydrazino tetrazoles 5a-h
1
13
The structures of the products 5a-h were deduced from their IR, H NMR, C NMR and
1
ESI-HRMS spectra. For example, the H NMR spectrum of 5a consisted of a singlet for
the distinguished -NH peak at δ 4.36 ppm, two singlets for two tert-butyl groups at δ 0.82
and 0.86 and a singlet at δ 1.78 ppm for the –N-tert-butyl group. The proton decoupled
1
3
C NMR spectrum of 5a showed 24 distinct resonances in agreement with the proposed
structure. The distinguished peaks resonated at δ 63.2 and 64.4 ppm related to –C-N
groups. The C=N tetrazole and imine group resonated at δ 152.7 and 157.7 ppm,
respectively.
Meanwhile, the structures of 5a and 5d were subsequently confirmed by single-crystal X-
ray crystallographic data (Fig. 2). As shown in Fig. 2 the orientation of tetrazole scaffold
is axial, and the hydrazine group is in the equatorial position.
5

ACCEPTED MANUSCRIPT
Fig 2 The ORTEP structure of 5a and 5d
The C=N bond lengths in 5a and 5d (1.277 Å, 1.266 Å, respectively) could confirm the
existence of imine bonds in the desired structures.
A mechanistic rationalization for this reaction is provided in Scheme 3. The first step
seems to be the formation of the diimines, followed by nucleophilic attack of isocyanide
and trimethylsilyl azide leading to the formation of the intermediate, which undergoes
cyclization to afford the corresponding products.
Scheme 3. Proposed mechanism for the synthesis of α-hydrazino tetrazoles 5a-h through pseudo-
five-component reaction
6

ACCEPTED MANUSCRIPT
To confirm the formation of the diimines, the reaction of two equivalents of 4-tert-butyl
cyclohexanone and 1 equivalent of hydrazine hydrate was investigated leading to the
formation of diimine 6 in the anti-configuration, the most stable conformation.
Scheme 4. Synthesis of diimine 6 through the reaction of 4-tert-butyl cyclohexanone and
hydrazine hydrate
In the next step, there are two possibilities for the nucleophilic addition of isocyanide and
trimethylsilyl azide to the diimine intermediate through an axial or equatorial approach.
In our previous report regarding the synthesis of α-hydrazido tetrazoles through the Ugi-
azide one-pot four-component reaction, the transition state for axial attack of isocyanide
suffered from steric clashes between the 1,3 axial hydrogens and the incoming isocyanide
8
reagent and the addition occurred via equatorial attack. In contrast to our previously
reported article, here, the addition of isocyanide through equatorial attack is not suitable
due to the a) torsional strain due to eclipsing interactions between the hydrazonyl group
and also β C-H hydrogens; b) less stability of the product as it is not the thermodynamic
product (Fig.3); c) based on the Cieplack model the axial nucleophilic addition of
isocyanide is more preferable due to effective stabilizing orbitals interaction (the C-H
9
bond has more donation character compared to C-C bond) (Fig.4).
Fig 3. Proposed addition reaction of isocyanide to diamine
7

ACCEPTED MANUSCRIPT
9
Fig4. The Cieplak model for the effective stabilizing interaction for axial nucleophilic addition
In conclusion, we have developed a convenient, simple and efficient diastereoselective
synthesis of thermodynamically stable α-hydrazino tetrazoles via a facile Ugi-azide
pseudo five-component reaction. The present methodology offers several advantages,
such as simple procedure with an easy work-up, high yields, high atom-economy, high
bond forming efficiency and carrying out the reaction in one-pot reaction conditions at
room temperature.
Experimental Section:
Commercially available materials were used without further purification. Melting points
were determined on an Electrothermal 9100 apparatus and were uncorrected. IR spectra
1
13
were obtained on an ABB FT-IR FTLA 2000 spectrometer. H NMR and C NMR
1
spectra were run on Bruker DRX-300 AVANCE spectrometers at 300 MHz for H NMR,
1
3
7
5 MHz for C NMR. DMSO-d and CDCl was used as solvent. High resolution mass
6 3
spectra were recorded on Mass-ESI-POS (Apex Qe-FT- ICR instrument) spectrometer.
General procedure for the synthesis of α-hydrazino tetrazoles 5a-h:
To a solution of hydrazine hydrate 1 (1 mmol), cyclic ketone 2a-f (2 mmol) in ethanol (5
mL) was added. The mixture was stirred for 30 min then isocyanide 3a-b (1.2 mmol) and
trimethylsilyl azide 4 (1 mmol) was added to the mixture. The mixture was stirred for
2
4h at ambient temperature. After completion of the reaction, as indicated by TLC (ethyl
acetate/n-hexane, 1:3), the precipitate was filtered off and then washed with methanol.
Spectroscopic data for compounds 5a-h:
1-(tert-Butyl)-5- ((1r,4S)-4- (tert-butyl)-1-(2 -((S,E)-4 -(tert-butyl)cyclohexylidene) hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5a): Colorless powder; 383 mg (89%), mp: 209-211 C, IR ʋ max
-1
1
(
KBr, cm ): 3258, 1639; H NMR (300 MHz, CDCl ): 0.82 (s, 9H, 3CH , t-Bu), 0.86 (s,
3
3
9
H, 3CH , t-Bu), 1.07-1.72 (m, 8H, 4CH , H
), 1.78 (s, 9H, 3CH , t-Bu), 1.82-
3
2
Cyclohexyl
3
2
.01 (m, 4H, HCyclohexyl), 2.28-2.50 (m, 2H, HCyclohexyl), 2.60-2.81 (m, 4H, HCyclohexyl), 4.36
8

ACCEPTED MANUSCRIPT
1
3
(
s, 1H, NH); C NMR (75 MHz, CDCl ): 23.9, 24.2, 25.1, 26.3, 27.4, 27.5, 27.7, 31.2,
3
3
2.3, 32.4, 34.8, 37.9, 38.5, 47.4, 47.6, 59.3, 64.4, 152.6, 157.8; HR-MS (ESI): calc. for
+
+
C H N [M+H] 431.3857, found 431.3857; calc. for C H N Na [M+Na] 453.3677,
25
47
6
25 46
6
+
found 453.3676; calc. for C H N K [M+K] 469.3416, found 469.3415.
25
46
6
3
colourless crystal (plate), dimensions 0.370 x 0.230 x 0.030 mm , crystal system
monoclinic, space group P2 /n, Z=4, a=6.2048(7) Å, b=29.336(3) Å, c=14.4809(17) Å,
1
3
3
alpha=90 deg, beta=98.484(4) deg, gamma=90 deg, V=2607.0(5) Å , rho=1.097 g/cm ,
T=200(2) K, Thetamax= 26.022 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg
omega-scans with CCD area detector, covering the asymmetric unit in reciprocal space
with a mean redundancy of 3.15 and a completeness of 100.0% to a resolution of 0.81Å,
1
6371 reflections measured, 5139 unique (R(int)=0.0805), 3027 observed (I > 2ʋ (I)),
intensities were corrected for Lorentz and polarization effects, an empirical absorption
correction was applied using SADABS based on the Laue symmetry of the reciprocal
-1
space, mu=0.07mm , T =0.90, Tmax=0.96, structure solved by direct methods and
min
2
refined against F with a Full-matrix least-squares algorithm using the SHELXTL
(Version 2013/3) software package, 285 parameters refined, hydrogen atoms were treated
using appropriate riding models, except H21 at N21, which was refined isotropically,
goodness of fit 0.99 for observed reflections, final residual values R1(F)=0.057,
2
-3
wR(F )=0.109 for observed reflections, residual electron density -0.22 to 0.21 eÅ .
CCDC 103930 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
1
-(tert-Butyl)-5-((1r,4S)-4-ethyl-1-(2-
((S,E)-4-ethyl
cyclohexylidene)
hydrazinyl) cyclohexyl) -1H-tetrazole (5b): Waxy liquid; 202 mg (54%), IR ʋ max (KBr,
-1
1
cm ): 3362, 1713; H NMR (300 MHz, CDCl ): 0.85 (t, J = 7.0 Hz, 3H, CH ), 0.91 (t, J
3
3
=
7.0 Hz, 3H, CH ), 0.94-1.03 (m, 2H, HCyclohexyl), 1.22-1.37 (m, 7H, HCyclohexyl), 1.61-
3
1
.88 (m, 8H, HCyclohexyl), 1.78 (s, 9H, 3CH , t-Bu), 2.00-2.23(m, 2H, HCyclohexyl), 2.53-2.67
3
1
3
(
m, 3H, HCyclohexyl), 4.54 (brs, 1H, NH); C NMR (75 MHz, CDCl ): 11.4, 11.6, 11.7,
3
2
1
4.4, 28.1, 28.2, 28.9, 31.2, 31.3, 31.5, 32.8, 34.4, 35.6, 35.9, 37.5, 38.6, 59.4, 64.3,
+
52.7, 158.4; HR-MS (ESI): calc. for C H N [M+H] 375.3360, found 375.3357; calc.
2
1
39
6
+
+
for C H N Na [M+Na] 397.3038, found 397.3035; calc. for C H N K [M+K]
2
1
38
6
21 38
6
4
13.2787, found 413.2785.
9

ACCEPTED MANUSCRIPT
1
-(tert-Butyl)-5-((1r,4S)- 4-methyl-1- (2 -((S, E)-4-methylcyclohexylidene) hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5c): Colorless solid; 215 mg (62%), mp: 120-123 C, IR ʋ
max
-1
1
(
KBr, cm ): 3255, 1632; H NMR (300 MHz, CDCl ): 0.89 (d, 6H, J = 6.3 Hz, 2CH ),
3
3
0
1
3
.92-1.70 (m, 10H, Hcyclohexyl), 1.74 (s, 9H, t-Bu), 1.76-2.66 (m, 8H, Hcyclohexyl), 4.62 (s,
1
3
H, NH); C NMR (75 MHz, CDCl ): 20.9, 21.6, 24.3, 30.3, 30.5, 30.6, 31.0, 31.2, 32.0,
3
3.8, 34.5, 35.2, 35.6, 59.1, 64.3, 76.6, 152.2, 158.5; HR-MS (ESI): HR-MS (ESI): calc.
+
for C H N [M+H] 347.2428, found 347.2428.
1
9
35
6
5
-((1r,4S)-4-(tert-Butyl)-1-(2-((S,E)-4-(tert-Butyl)cyclohexylidene)hydrazinyl)
cyclohexyl)-1-cyclohexyl-1H-tetrazole (5d): Colorless solid; 420 mg (92%), mp: 239-
o
-1
1
2
3
41 C, IR ʋ
(KBr, cm ): 3253, 1642; H NMR (300 MHz, CDCl ): 0.77 (s, 9H,
max 3
CH , t-Bu), 0.84 (s, 9H, 3CH , t-Bu), 0.88-1.50 (m, 10H, HCyclohexyl), 1.53-1.82 (m, 6H,
3
3
HCyclohexyl), 1.83-2.24 (m, 9H, HCyclohexyl), 2.28-2.79 ( m, 3H, HCyclohexyl), 4.49 (s, 1H, NH),
1
3
4
2
.90-5.11 (m, 1H, CNH); C NMR (75 MHz, CDCl ): 21.6, 22.0, 24.8, 25.0, 25.7, 26.5,
3
7.3, 27.7, 32.3, 32.5, 33.1, 33.2, 34.2, 34.8, 46.4, 47.4, 56.8, 58.9, 153.4, 158.5; HR-MS
+
(
ESI): calc. for C H N [M+H] 457.40144, found 457.40132; calc. for C H N Na
2
7
49
6
27 49
6
+
+
[
M+Na] 479.3834, found 479.3833; calc. for C H KN [M+K] 495.3573, found
27 48 6
4
95.3572.
3
Colourless crystal (needle), dimensions 0.420 x 0.050 x 0.030 mm , crystal system
monoclinic, space group P2 /n, Z=4, a=6.345(2) Å, b=31.355(11) Å, c=14.286(5) Å,
1
3
alpha=90 deg, beta=99.872(11) deg, gamma=90 deg, V=2799.8(17) Å , rho=1.083
3
g/cm , T=200(2) K, Thetamax= 21.260 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5
deg omega-scans with CCD area detector, covering the asymmetric unit in reciprocal
space with a mean redundancy of 3.63and a completeness of 61.5% to a resolution of
0
2
.98Å, 11459 reflections measured, 3120 unique (R(int)=0.1049), 1898 observed (I >
ʋ (I)), intensities were corrected for Lorentz and polarization effects, an empirical
absorption correction was applied using SADABS based on the Laue symmetry of the
-1
reciprocal space, mu=0.06mm , T =0.82, Tmax=0.96, structure solved by direct
min
2
methods and refined against F with a Full-matrix least-squares algorithm using the
SHELXTL (Version 2013/3) software package, 302 parameters refined, hydrogen atoms
were treated using appropriate riding models, except H10 at N10, which was refined
isotropically, goodness of fit 1.01 for observed reflections, final residual values
2
R1(F)=0.074, wR(F )=0.159 for observed reflections, residual electron density -0.33 to
-3
0
.32 eÅ . CCDC 103931 contains the supplementary crystallographic data for this paper.
1
0

ACCEPTED MANUSCRIPT
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
-Cyclohexyl-5- ((1r,4S)-4-ethyl-1 -(2 -((S,E)-4-ethylcyclohexylidene)hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5e): Colorless solid; 216 mg (71%), mp: 129-130 C, IR ʋ
max
-1
1
(
KBr, cm ): 3244, 1739, 1635; H NMR (300 MHz, CDCl ): 0.84 (t, 3H, J = 7.2 Hz,
3
CH ), 0.87 (t, 3H, J = 7.2 Hz, CH ), 0.97-1.02 (m, 3H, HCyclohexyl), 1.78-1.38 (m, 10H,
3
3
HCyclohexyl), 1.63-2.24 (m, 16H, HCyclohexyl), 2.53-2.70 (m, 3H, HCyclohexyl), 4.59 (s,1H, NH),
1
3
5
2
.07-5.14 (m, 1H, CNH); C NMR (75 MHz, CDCl ): 11.5, 11.6, 24.3, 25.0, 25.6, 28.5,
3
8.6, 28.8, 31.3, 32.6, 33.2, 34.4, 35.3, 35.7, 38.5, 58.3, 59.1, 153.6.2; HR-MS (ESI):
+
+
calc. for C H N [M+H] 401.3388, found 401.3387; calc. for C H N [M+Na]
2
3
41
6
23 40
6
+
4
23.3197, found 432.3193; calc. for C H KN [M+K] 439.2947, found 439.2946
23 40 6
1
-Cyclohexyl-5 -((1r,4S)-4-methyl-1-(2 -((S, E)-4-methylcyclohexylidene) hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5f) Colorless solid; 291 mg (78%), mp: 167-169 C, IR

max
-1
1
(
KBr, cm ): 3240, 1739, 1631; H NMR (300 MHz, CDCl ): 0.85 (d, 3H, J = 6.4 Hz,
3
CH ), 0.88 (d, 3H, J = 6.5 Hz, CH ), 0.93-1.56 (m, 10H, HCyclohexyl), 1.58-1.78 (m, 8H,
3
3
HCyclohexyl), 1.79-2.20 (m, 8H, HCyclohexyl), 2.45-2.66 (m, 2H, HCyclohexyl), 4.6 (s, 1H, NH),
1
3
5
3
.10 (m, 1H, NCH); C NMR (75 MHz, CDCl ): 21.4, 21.6, 24.3, 25.0, 25.6, 30.8, 30.9,
3
1.7, 31.8, 33.1, 33.2, 33.7, 34.5, 35.1, 35.3, 35.8, 56.9, 58.0, 59.1, 153.3, 156.2, HR-MS
+
(
ESI): calc. for C H N [M+H] 373.3074, found 373.3074; calc. for C H N Na
2
1
37
6
21 36
6
+
+
[
M+Na] 395.2894, found 395.2894; calc. for C H KN [M+K] 411.2633, found
21 36 6
4
11.2633.
1
-Cyclohexyl-5- ((1R, 3R)-3-methyl-1- (2-((S, Z)-3-methylcyclohexylidene)hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5g): Colorless solid; 231 mg (65%), mp: 145-147 C, IR

max
-1
1
(
KBr, cm ): 3238, 1740, 1632; H NMR (300 MHz, CDCl ) 0.85-0.95 (m, 6H, CH ),
3 3
1
.00-1.55 (m, 10H, HCyclohexyl), 1.63-1.79 (m, 6H, HCyclohexyl), 1.87-2.21 (m, 9H,
1
3
HCyclohexyl), 2.48-2.65 (m, 3H, HCyclohexyl), 4.56 (s, 1H, NH), 5.05-5.13 (m, 1H, CHN); C
NMR (75 MHz, CDCl ): 22.2, 22.4, 22.5, 25.0, 25.6, 25.7, 29.0, 32.3, 33.2, 33.3, 34.1,
3
3
4.4, 34.7, 35.9, 44.4, 58.9, 59.1, 59.2, 153.3, 156.1; 156.1; HR-MS (ESI): calc. for
+
+
C H N [M+H] 373.3074, found 373.3074; calc. for C H N Na [M+Na] 395.2894,
21
37
6
21 36
6
+
found 395.2894; calc. for C H KN [M+K] 411.2633, found 411.2633.
21
36
6
1
1

ACCEPTED MANUSCRIPT
1
-Cyclohexyl-5-(1-(2-cyclohexylidenehydrazinyl)cyclohexyl)-1H-tetrazole(5h):
o
-1
1
Colorless powder; 258 mg (75%), mp: 147-150 C, IR ʋ max (KBr, cm ): 3239, 1631; H
NMR (300 MHz, CDCl ): 1.27-1.63 (m, 15H, CH , HCyclohexyl), 1.67-2.25 (m, 15H, CH2,
3
2
1
3
HCyclohexyl), 4.96 (s, 1H, NH), 5.11 (m, 1H, CNH); C NMR (75 MHz, CDCl3): 21.6,
2
1
4.9, 25.0, 25.1, 25.1, 25.4, 25.7, 25.8, 25.9, 27.0, 33.2, 34.4, 35.2, 57.6, 59.0, 153.4,
+
57.8; HR-MS (ESI): calc. for C H N [M+1] 345.2762, found 345.2761; calc. for
1
9
33
6
+
+
C H N Na[M+Na] 367.2581, found 367.2581; calc. for C H KN [M+1] 383.23207,
19
33
6
19 33
6
found 383.23200.
Acknowledgment:
We gratefully acknowledge Iran National Science Foundation (INSF) for their financial support.
ASSOCIATED CONTENT
Supporting Information
1
13
1
Copies of H NMR, C NMR, HRMS spectra for compounds 5a-h; and crude H NMR
spectra for the mixture of diastereomers in compounds 5a, 5d, 5e and 5f; X-ray crystal
data for compounds 5a, and 5d. This material is available free of charge via the Internet
at http://pubs.acs.org.
References:
1
.
(a) Bavetsias, V.; Marriott, J. H.; Melin, C.; Kimbell, R.; Matusiak, Z. S.; Boyle,
F. T.; Jackman, A. L. J. Med. Chem. 2000, 43, 1910-1926; (b) Upadhayaya, R. S.; Jain,
S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora, S. K. Eur. J. Med. Chem. 2004, 39, 579-
5
92; (c) Ostrovskii, V.; Trifonov, R.; Popova, E. Russ. Chem. Bul. 2012, 61, 768-780; (d)
Rajasekaran, A.; Thampi, P. Eur. J. Med. Chem. 2004, 39, 273-279; (e) Powers, R. A.;
Shoichet, B. K. J. Med. Chem. 2002, 45, 3222-3234; (f) Rajasekaran, A.; Thampi, P. Eur.
J. Med. Chem. 2005, 40, 1359-1364.
2
.
(a) Katritzky, A. R.; Cai, C.; Meher, N. K. Synthesis 2007, 1204-1208; (b)
Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Preti, D.; Aghazadeh Tabrizi, M.;
1
2

ACCEPTED MANUSCRIPT
Brancale, A.; Fu, X.-H.; Li, J.; Zhang, S.-Z.; Hamel, E. J. Med. Chem. 2011, 55, 475-
4
3
88.
.
(a) Seki, M.; Tarao, Y.; Yamada, K.; Nakao, A.; Usui, Y.; Komatsu, Y. In PCT
Int. Appl. WO 2005-JP2974, 2005, Chem. Abstr., 2005; 266938; (b) Miao, Z.; Sun, Y.;
Nakajima, S.; Tang, D.; Wu, F.; Xu, G.; Or, Y.; Wang, Z. In US Pat. Appl. Publ. US
2
005153877, 2005, Chem. Abstr., 2005; 153709; (c) Nonoshita, K.; Ogino, Y.; Ishikawa,
M.; Sakai, F.; Nakashima, H.; Nagae, Y.; Tsukahara, D.; Arakawa, K.; Nishimura, T.;
Eiki, J. In PCT Int. Appl. WO 2004-JP19843, 2005, Chem. Abstr., 2005; 153371.
4
.
(a) Zabrocki, J.; Smith, G. D.; Dunbar, J. B.; Iijima, H.; Marshall, G. R. J. Am.
Chem. Soc. 1988, 110, 5875-5880; (b) Zabrocki, J.; Dunbar Jr, J. B.; Marshall, K. W.;
Toth, M. V.; Marshall, G. R. J. Org. Chem. 1992, 57, 202-209; (c) May, B. C.; Abell, A.
D. Tetrahedron Lett. 2001, 42, 5641-5644; (d) Lebl, M.; Slaninova, J.; Johnson, R. L. Int.
J. Pept. Protein Res. 1989, 33, 16-21.
5
.
Hanessian, S.; Deschênes-Simard, B.; Simard, D.; Chenel, C.; Haak, E.; Bulat, V.
Pure & Appl. Chem. 2010, 82, 1761-1771.
6
1
5
.
(a) Artamonova, T.; Zhivich, A.; DUBINSKII, M.; Koldobskii, G. Synthesis
996, 1428-1430; (b) Duncia, J. V.; Pierce, M. E.; Santella III, J. B. J. Org. Chem. 1991,
6, 2395-2400; (c) Deady, L. W.; Devine, S. M. J. Het. Chem. 2004, 41, 549-555; (d)
Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083-3135; (e)
Zarganes‐Tzitzikas, T.; Patil, P.; Khoury, K.; Herdtweck, E.; Dömling, A. Eur. J. Org.
Chem 2015, 51-55.
7
.
(a) Gunawan, S.; Ayaz, M.; De Moliner, F.; Frett, B.; Kaiser, C.; Patrick, N.; Xu,
Z.; Hulme, C. Tetrahedron 2012, 68, 5606-5611; (b) Medda, F.; Hulme, C. Tetrahedron
Letters 2012, 53, 5593-5596; (c) Shmatova, O. I.; Nenajdenko, V. G. J. Org. Chem.
2013, 78, 9214-9222; (d) Zhao, T.; Boltjes, A.; Herdtweck, E.; Doʋ mling, A. Org. lett.
2013, 15, 639-641; (e) El Kaïm, L.; Grimaud, L.; Pravin, P. Eur. J. Org. Chem. 2013,
4752-4755; (f) Ayaz, M.; Xu, Z.; Hulme, C. Tetrahedron Lett. 2014, 55, 3406-3409; (g)
Yerande, S. G.; Newase, K. M.; Singh, B.; Boltjes, A.; Dömling, A. Tetrahedron Lett.
2
014, 55, 3263-3266; (h) Sarvary, A.; Maleki, A. Mol. Divers. 2014, 19, 189-212.
Ramezanpour, S.; Balalaie, S.; Rominger, F.; Alavijeh, N. S.; Bijanzadeh, H. R.
8
.
Tetrahedron 2013, 69, 10718-10723.
Mehta, G.; Chandrasekhar, J. Chem. Rev. 1999, 99, 1437-1468.
9
.
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Graphical Abstract
Efficient and Stereoselective Synthesis of α-Hydrazino Tetrazoles through a Pseudo
Five-component Domino Reaction
Ali Nikbakht, Sorour Ramezanpour, Saeed Balalaie,* Frank Rominger
1
4

Supporting information
ACCEPTED MANUSCRIPT
Efficient and Stereoselective Synthesis of α-Hydrazino Tetrazoles through a Pseudo Five-
component Domino Reaction
a
a
a,b
c
Ali Nikbakht, Sorour Ramezanpour, Saeed Balalaie,* Frank Rominger
a
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416
Tehran, Iran, balalaie@kntu.ac.ir
b
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
c
Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120
Heidelberg, Germany
General procedure for the synthesis of 5a-h ……………………………………….. S2
Spectroscopic data for compounds 5a-h …………………………………………… S2-S7
1
13
H NMR, C NMR spectra and ESI-HRMS of α-hydrazino tetrazoles (5a-h) ………… S8-S23
1
1
H- H COSY (300 MHz, CDCl ) ………………………………………………………. S24
3
1
Crude H NMR spectra for compounds 5a, 5d, 5e and 5f ……………..……………..... S25-S26
X-ray crystal structure data for compounds 5a, 5d ………………………………..…… S27-S43
S1

ACCEPTED MANUSCRIPT
General information
Experimental Section:
Commercially available materials were used without further purification. Melting points were
determined on an Electrothermal 9100 apparatus and were uncorrected. IR spectra were obtained
1
13
on an ABB FT-IR FTLA 2000 spectrometer. H NMR and C NMR spectra were run on Bruker
1
13
DRX-300 AVANCE spectrometers at 300 MHz for H NMR, 75 MHz for C NMR. DMSO-d
6
and CDCl was used as solvent. High resolution mass spectra were recorded on Mass-ESI-POS
3
(Apex Qe-FT- ICR instrument) spectrometer.
General procedure for the synthesis of α-hydrazino tetrazoles 5a-h:
To a solution of hydrazine hydrate 1 (1 mmol), cyclic ketone 2a-f (2 mmol) in 5 mL ethanol was
added. The mixture was stirred for 30 min then isocyanide 3a-b (1.2 mmol) and trimethylsilyl
azide 4 (1 mmol) was added to the mixture. The mixture was stirred for 24h at ambient
temperature. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 1:3),
the precipitate was filtered off and then washed with methanol.
Spectroscopic data for compounds 5a-h:
1-(tert-Butyl)-5- ((1r,4S)-4- (tert-butyl)-1-(2 -((S,E)-4 -(tert-butyl)cyclohexylidene) hydrazinyl) cyclohexyl)-
o
-1
1
H-tetrazole (5a): Colorless powder; 383 mg (89%), mp: 209-211 C, IR ʋ (KBr, cm ): 3258,
max
1
1
639; H NMR (300 MHz, CDCl ): 0.82 (s, 9H, 3CH , t-Bu), 0.86 (s, 9H, 3CH , t-Bu), 1.07-
3 3 3
S2

1
.72 (m, 8H, 4CH , H
), 1.78 (s, 9H, 3CH , t-Bu), 1.82-2.01 (m, 4H, HCyclohexyl), 2.28-2.50
2
Cyclohexyl 3
ACCEPTED MANUSCRIPT
1
3
(m, 2H, HCyclohexyl), 2.60-2.81 (m, 4H, HCyclohexyl), 4.36 (s, 1H, NH); C NMR (75 MHz, CDCl ):
3
2
1
3.9, 24.2, 25.1, 26.3, 27.4, 27.5, 27.7, 31.2, 32.3, 32.4, 34.8, 37.9, 38.5, 47.4, 47.6, 59.3, 64.4,
+
52.6, 157.8; HR-MS (ESI): calc. for C H N [M+H] 431.3857, found 431.3857; calc. for
2
5
47
6
+
+
C H N Na [M+Na] 453.3677, found 453.3676; calc. for C H N K [M+K] 469.3416, found
25
46
6
25 46
6
4
69.3415.
3
colourless crystal (plate), dimensions 0.370 x 0.230 x 0.030 mm , crystal system monoclinic,
space group P2 /n, Z=4, a=6.2048(7) Å, b=29.336(3) Å, c=14.4809(17) Å, alpha=90 deg,
1
3
3
beta=98.484(4) deg, gamma=90 deg, V=2607.0(5) Å , rho=1.097 g/cm , T=200(2) K, Thetamax=
6.022 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg omega-scans with CCD area
2
detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 3.15and a
completeness of 100.0% to a resolution of 0.81Å, 16371 reflections measured, 5139 unique
(R(int)=0.0805), 3027 observed (I > 2ϭ(I)), intensities were corrected for Lorentz and
polarization effects, an empirical absorption correction was applied using SADABS based on the
-1
Laue symmetry of the reciprocal space, mu=0.07mm , T =0.90, Tmax=0.96, structure solved by
min
2
direct methods and refined against F with a Full-matrix least-squares algorithm using the
SHELXTL (Version 2013/3) software package, 285 parameters refined, hydrogen atoms were
treated using appropriate riding models, except H21 at N21, which was refined isotropically,
2
goodness of fit 0.99 for observed reflections, final residual values R1(F)=0.057, wR(F )=0.109
-3
for observed reflections, residual electron density -0.22 to 0.21 eÅ . CCDC 103930 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
-(tert-Butyl)-5-((1r,4S)-4-ethyl-1-(2- ((S,E)-4-ethyl cyclohexylidene) hydrazinyl)
-1
1
cyclohexyl) -1H-tetrazole (5b): Waxy liquid; 202 mg (54%), IR ʋmax (KBr, cm ): 3362, 1713; H
NMR (300 MHz, CDCl ): 0.85 (t, J = 7.0 Hz, 3H, CH ), 0.91 (t, J = 7.0 Hz, 3H, CH ), 0.94-1.03
3
3
3
S3

(
m, 2H, HCyclohexyl), 1.22-1.37 (m, 7H, H
), 1.61-1.88 (m, 8H, HCyclohexyl), 1.78 (s, 9H,
Cyclohexyl
ACCEPTED MANUSCRIPT
1
3
3
CH , t-Bu), 2.00-2.23(m, 2H, HCyclohexyl), 2.53-2.67 (m, 3H, HCyclohexyl), 4.54 (brs, 1H, NH); C
3
NMR (75 MHz, CDCl ): 11.4, 11.6, 11.7, 24.4, 28.1, 28.2, 28.9, 31.2, 31.3, 31.5, 32.8, 34.4,
3
+
3
3
5.6, 35.9, 37.5, 38.6, 59.4, 64.3, 152.7, 158.4; HR-MS (ESI): calc. for C H N [M+H]
21 39 6
+
75.3360, found 375.3357; calc. for C H N Na [M+Na] 397.3038, found 397.3035; calc. for
2
1
38
6
+
C H N K [M+K] 413.2787, found 413.2785.
21
38
6
1
-(tert-Butyl)-5-((1r,4S)- 4-methyl-1- (2 -((S, E)-4-methylcyclohexylidene) hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5c): Colorless solid; 215 mg (62%), mp: 120-123 C, IR ʋmax (KBr,
-1
1
cm ): 3255, 1632; H NMR (300 MHz, CDCl ): 0.89 (d, 6H, J = 6.3 Hz, 2CH ), 0.92-1.70 (m,
3
3
1
3
1
0H, Hcyclohexyl), 1.74 (s, 9H, t-Bu), 1.76-2.66 (m, 8H, Hcyclohexyl), 4.62 (s, 1H, NH); C NMR (75
MHz, CDCl ): 20.9, 21.6, 24.3, 30.3, 30.5, 30.6, 31.0, 31.2, 32.0, 33.8, 34.5, 35.2, 35.6, 59.1,
3
+
6
4.3, 76.6, 152.2, 158.5; HR-MS (ESI): HR-MS (ESI): calc. for C H N [M+H] 347.2428,
1
9
35
6
found 347.2428.
5
-((1r,4S)-4-(tert-Butyl)-1-(2-((S,E)-4-(tert-Butyl)cyclohexylidene)hydrazinyl) cyclohexyl)-1-
o
cyclohexyl-1H-tetrazole (5d): Colorless solid; 420 mg (92%), mp: 239-241 C, IR ʋmax (KBr,
-1
1
cm ): 3253, 1642; H NMR (300 MHz, CDCl ): 0.77 (s, 9H, 3CH , t-Bu), 0.84 (s, 9H, 3CH , t-
3
3
3
Bu), 0.88-1.50 (m, 10H, HCyclohexyl), 1.53-1.82 (m, 6H, HCyclohexyl), 1.83-2.24 (m, 9H, HCyclohexyl),
S4

1
3
2
.28-2.79 ( m, 3H, HCyclohexyl), 4.49 (s, 1H, NH), 4.90-5.11 (m, 1H, CNH); C NMR (75 MHz,
ACCEPTED MANUSCRIPT
CDCl ): 21.6, 22.0, 24.8, 25.0, 25.7, 26.5, 27.3, 27.7, 32.3, 32.5, 33.1, 33.2, 34.2, 34.8, 46.4,
3
+
4
4
7.4, 56.8, 58.9, 153.4, 158.5; HR-MS (ESI): calc. for C H N [M+H] 457.40144, found
2
7
49
6
+
57.40132; calc. for C H N Na [M+Na] 479.3834, found 479.3833; calc. for C H KN
6
2
7
49
6
27 48
+
[
M+K] 495.3573, found 495.3572.
3
colourless crystal (needle), dimensions 0.420 x 0.050 x 0.030 mm , crystal system monoclinic,
space group P2 /n, Z=4, a=6.345(2) Å, b=31.355(11) Å, c=14.286(5) Å, alpha=90 deg,
1
3
3
beta=99.872(11) deg, gamma=90 deg, V=2799.8(17) Å , rho=1.083 g/cm , T=200(2) K,
Thetamax= 21.260 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg omega-scans with CCD
area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of
3
.63and a completeness of 61.5% to a resolution of 0.98Å, 11459 reflections measured, 3120
unique (R(int)=0.1049), 1898 observed (I > 2ϭ(I)), intensities were corrected for Lorentz and
1
polarization effects, an empirical absorption correction was applied using SADABS based on
-1
the Laue symmetry of the reciprocal space, mu=0.06mm , T =0.82, Tmax=0.96, structure
min
2
solved by direct methods and refined against F with a Full-matrix least-squares algorithm using
2
the SHELXTL (Version 2013/3) software package , 302 parameters refined, hydrogen atoms
were treated using appropriate riding models, except H10 at N10, which was refined
isotropically, goodness of fit 1.01 for observed reflections, final residual values R1(F)=0.074,
2
-3
wR(F )=0.159 for observed reflections, residual electron density -0.33 to 0.32 eÅ . CCDC
03931 contains the supplementary crystallographic data for this paper. These data can be
1
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
1
1
-Cyclohexyl-5- ((1r,4S)-4-ethyl-1 -(2 -((S,E)-4-ethylcyclohexylidene)hydrazinyl) cyclohexyl)-
o
-1
H-tetrazole (5e): Colorless solid; 216 mg (71%), mp: 129-130 C, IR ʋmax (KBr, cm ): 3244,
1
739, 1635; H NMR (300 MHz, CDCl ): 0.84 (t, 3H, J = 7.2 Hz, CH ), 0.87 (t, 3H, J = 7.2 Hz,
3
3
CH ), 0.97-1.02 (m, 3H, HCyclohexyl), 1.78-1.38 (m, 10H, HCyclohexyl), 1.63-2.24 (m, 16H,
3
1
3
HCyclohexyl), 2.53-2.70 (m, 3H, HCyclohexyl), 4.59 (s,1H, NH), 5.07-5.14 (m, 1H, CNH); C NMR
S5

(
75 MHz, CDCl ): 11.5, 11.6, 24.3, 25.0, 25.6, 28.5, 28.6, 28.8, 31.3, 32.6, 33.2, 34.4, 35.3,
3
ACCEPTED MANUSCRIPT
+
3
4
4
5.7, 38.5, 58.3, 59.1, 153.6.2; HR-MS (ESI): calc. for C H N [M+H] 401.3388, found
2
3
41
6
+
+
01.3387; calc. for C H N [M+Na] 423.3197, found 432.3193; calc. for C H KN [M+K]
23
40
6
23 40
6
39.2947, found 439.2946.
1
-Cyclohexyl-5 -((1r,4S)-4-methyl-1-(2 -((S, E)-4-methylcyclohexylidene) hydrazinyl)
o
-
cyclohexyl)-1H-tetrazole (5f) Colorless solid; 291 mg (78%), mp: 167-169 C, IR ʋmax (KBr, cm
1
1
)
: 3240, 1739, 1631; H NMR (300 MHz, CDCl ): 0.85 (d, 3H, J = 6.4 Hz, CH ), 0.88 (d, 3H, J
3
3
=
6.5 Hz, CH ), 0.93-1.56 (m, 10H, HCyclohexyl), 1.58-1.78 (m, 8H, HCyclohexyl), 1.79-2.20 (m, 8H,
3
1
3
HCyclohexyl), 2.45-2.66 (m, 2H, HCyclohexyl), 4.6 (s, 1H, NH), 5.10 (m, 1H, NCH); C NMR (75
MHz, CDCl ): 21.4, 21.6, 24.3, 25.0, 25.6, 30.8, 30.9, 31.7, 31.8, 33.1, 33.2, 33.7, 34.5, 35.1,
3
+
3
5.3, 35.8, 56.9, 58.0, 59.1, 153.3, 156.2, HR-MS (ESI): calc. for C H N [M+H] 373.3074,
2
1
37
6
+
found 373.3074; calc. for C H N Na [M+Na] 395.2894, found 395.2894; calc. for C H KN
6
2
1
36
6
21 36
+
[
M+K] 411.2633, found 411.2633.
1
-Cyclohexyl-5- ((1R, 3R)-3-methyl-1- (2-((S, Z)-3-methylcyclohexylidene)hydrazinyl)
o
cyclohexyl)-1H-tetrazole (5g): Colorless solid; 231 mg (65%), mp: 145-147 C, IR ʋmax (KBr,
-1
1
cm ): 3238, 1740, 1632; H NMR (300 MHz, CDCl ) 0.85-0.95 (m, 6H, CH ), 1.00-1.55 (m,
3
3
1
0H, HCyclohexyl), 1.63-1.79 (m, 6H, HCyclohexyl), 1.87-2.21 (m, 9H, HCyclohexyl), 2.48-2.65 (m, 3H,
1
3
HCyclohexyl), 4.56 (s, 1H, NH), 5.05-5.13 (m, 1H, CHN); C NMR (75 MHz, CDCl ): 22.2, 22.4,
3
S6

2
1
2.5, 25.0, 25.6, 25.7, 29.0, 32.3, 33.2, 33.3, 34.1, 34.4, 34.7, 35.9, 44.4, 58.9, 59.1, 59.2, 153.3,
ACCEPTED MANUSCRIPT
+
56.1; 156.1; HR-MS (ESI): calc. for C H N [M+H] 373.3074, found 373.3074; calc. for
2
1
37
6
+
+
C H N Na [M+Na] 395.2894, found 395.2894; calc. for C H KN [M+K] 411.2633, found
21
36
6
21 36
6
4
11.2633.
1
powder; 258 mg (75%), mp: 147-150 C, IR ʋmax (KBr, cm ): 3239, 1631; H NMR (300 MHz,
CDCl ): 1.27-1.63 (m, 15H, CH , H ), 1.67-2.25 (m, 15H, CH , HCyclohexyl), 4.96 (s, 1H,
-Cyclohexyl-5-(1-(2-cyclohexylidenehydrazinyl)cyclohexyl)-1H-tetrazole(5h):
Colorless
o
-1
1
3
2
Cyclohexyl
2
1
3
NH), 5.11 (m, 1H, CNH); C NMR (75 MHz, CDCl3): 21.6, 24.9, 25.0, 25.1, 25.1, 25.4, 25.7,
2
5.8, 25.9, 27.0, 33.2, 34.4, 35.2, 57.6, 59.0, 153.4, 157.8; HR-MS (ESI): calc. for
+
+
C H N [M+1] 345.2762, found 345.2761; calc. for C H N Na[M+Na] 367.2581, found
19
33
6
19 33
6
+
3
67.2581; calc. for C H KN [M+1] 383.23207, found 383.23200.
19 33 6
S7

ACCEPTED MANUSCRIPT
IR (KBr) (5a)
ESI-HRMS (5a)
S8

ACCEPTED MANUSCRIPT
1
HNMR (300MHz, CDCl ) (5a)
3
1
3
CNMR (75MHz, CDCl ) (5a)
3
S9

ACCEPTED MANUSCRIPT
IR (KBr) (5b)
ESI-HRMS (5b)
S10

ACCEPTED MANUSCRIPT
1
HNMR (300MHz, CDCl ) (5b)
3
1
3
CNMR (75MHz, CDCl ) (5b)
3
S11

ACCEPTED MANUSCRIPT
IR (KBr) (5c)
ESI-HRMS (5c)
S12

ACCEPTED MANUSCRIPT
1
HNMR (300MHz, CDCl ) (5c)
3
S13

ACCEPTED MANUSCRIPT
IR (KBr) (5d)
ESI-HRMS (5d)
S14

ACCEPTED MANUSCRIPT
IR (KBr) (5e)
1
HNMR (300MHz, CDCl ) (5d)
3
1
3
CNMR (75MHz, CDCl ) (5d)
3
S15