Facile, efficient and diastereoselective synthesis of α-hydrazine tetrazoles through a novel one-pot four-component reaction

Article abstract of DOI:10.1016/j.tet.2013.10.062

A novel and efficient method for the diastereoselective synthesis of α-hydrazine tetrazoles via an isocyanide-based multicomponent reaction is reported in good yields. The α-hydrazine tetrazoles were obtained by a facile azide Ugi four-component reaction

Full text of DOI:10.1016/j.tet.2013.10.062

Accepted Manuscript
Facile, efficient and diastereoselective synthesis of α- hydrazine tetrazoles through a
novel one-pot four-component reaction
Sorour Ramezanpour, Saeed Balalaie, Frank Rominger, Nahid S. Alavijeh, Hamid
Reza Bijanzadeh
PII:
S0040-4020(13)01607-4
10.1016/j.tet.2013.10.062
TET 24937
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 July 2013
Revised Date: 4 October 2013
Accepted Date: 21 October 2013
Please cite this article as: Ramezanpour S, Balalaie S, Rominger F, Alavijeh NS, Bijanzadeh HR,
Facile, efficient and diastereoselective synthesis of α- hydrazine tetrazoles through a novel one-pot four-
component reaction, Tetrahedron (2013), doi: 10.1016/j.tet.2013.10.062.
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ACCEPTED MANUSCRIPT
Facile, efficient and diastereoselective synthesis of α- hydrazine tetrazoles
through a novel one-pot four-component reaction
Sorour Ramezanpoura, Saeed Balalaiea*, Frank Romingerb, Nahid S. Alavijeha, Hamid Reza
Bijanzadeha
aPeptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-
4416, Tehran, Iran, Fax: +98-21-2285 3650, E-mail: balalaie@kntu.ac.ir
bOrganisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, D-69120,
Heidelberg, Germany
Abstract
A novel and efficient method for the diastereoselctive synthesis of α- hydrazine tetrazoles via an
isocyanide-based multicomponent reaction is reported in good yields. The α- hydrazine tetrazoles
were obtained by a facile azide Ugi four-component reaction (U-4CR) using cyclic ketones,
trimethylsilyl azide, hydrazides, and corresponding isocyanide without any catalyst and with high
bond forming efficiency at room temperature.
Keywords: α-hyrazino tetrazoles, α-hyrazino acids, One-pot four-component reaction, isocyanide-
based multicomponent reaction, Azide Ugi reaction.
Dedicated to Prof. Thomas J. J. Mueller on the occasion of his birthday
1

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1. Introduction
Tetrazoles are useful heterocyclic skeletons because there are in many important biological
compounds and drugs.1-2 Among the pharmaceutically important tetrazoles losartan and valsartan,
two widely used angiotensin receptor blockers, deserve a special mention. During the last decade
considerable attention has been focused on the synthesis of 1,5-disubstituted tetrazoles due to their
wide range of biological activities such as: NADPH oxidase inhibitors,3a glucokinase activators,3b
hepatitis C virus (HCV) serine protease NS3 inhibitors,3c calcitonin gene-related peptide receptor
antagonists, and antimigraine agents.3d
Prescribed agents featuring the 1,5-disubstituted tetrazole scaffold include the anti-inflammatory
cilostazol and the since one of the most common strategy for cis amide bond peptide mimics4 is the
use of 1,5-disubstituted tetrazoles to constrain the amide bond in a cis conformation, they have also
attracted a great deal of attention in the field of peptide chemistry. For example, analogues of
somatostatine,5 bradykinin,6 and deaminooxytocin7 containing the above core has been described.
Furthermore, the potential utility of 1,5-disubstituted tetrazoles as synthetic intermediates are
enormous;8 they were used for the synthesis of energetic salts, 3,4-dihydropyrimidin-2(1H)-ones,
piericidins,
(+)-trans-5-allyl
hexahydro-indolizidin-3-ones,
acacetin,
(+)-strictifolione,
vinylsilianes, and leucascandrolide A.
Access to 1,5-disubstituted tetrazoles is of considerable interest, 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, and isocyanide-based
9
reactions and conversion of substituted tetrazoles into 1,5-disubstituted tetrazoles. Among the
various pathways toward 1,5-disubstituted tetrazole derivatives, those based on the isocyanide
multicomponent reactions are especially noteworthy. The first synthesis of these compounds via
isocyanide-based reactions was undertaken by Ugi and Meyr, in which they reported the synthesis
of 1,5-disubstituted tetrazoles using a Passerini three-component reaction (P-3CR) of isocyanides,
highly reactive carbonyl compounds, and hydrazoic acid (HN3).10 Nixey and Hulme developed a
TMSN3-modified P-3CR for the synthesis of these compounds.11 Also, the Ugi four-component
reaction (U-4CR) of isocyanides with amines, aldehydes or ketones, and TMSN3 affords 1,5-
disubstituted tetrazoles.12
As part of our continuing efforts on the development of new routes for the preparation of
biologically active heterocyclic compounds by means of isocyanide-based multicomponent
reactions,13 herein, we describe a novel diastereoselective synthesis of α-hydrazino tetrazoles via a
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facile azide Ugi four-component reaction using various cyclic ketones, hydrazides, isocyanides and
trimethylsilylazide as Ugi acidic partner (Scheme 1).
Scheme 1.Diastereoselective synthesis of α- hydrazine tetrazoles via a facile azide Ugi four-component
reaction.
2. Results and discussion
The synthesis of (5a) was selected as model reaction. Thus, a mixture of benzhydrazide (1a), 4-tert
butyl cyclohexanone (2a), tert-butyl isocyanide(3a) and trimethylsilyl azide (4) was stirred at room
temperature in methanol to produce the corresponding diastereomericα-hydrazinotetrazole (5a) in
60% yield (Table (2)).
O
O
NH
N
C-
O
HN
N
MeOH, rt
24 h
NH2
N+
+
TMSN3
N
+
H
N
N
4
1a
2a
3a
5a ( 60%)
Scheme 2. The model reaction for the synthesis of product 5a.
Our synthetic challenge involved determining the best reaction conditions for the synthesis of 5a in
high yield. Consequently, the model reaction between 4-tert butyl cyclohexanone (2a),
benzhydrazide (1a), tert-butyl isocyanide (3a) and trimethylsilyl azide (4) was used to survey
various solvents (Scheme 2). Different solvents were used as reaction media for the model reaction;
such as methanol, ethanol, dichloromethane and acetonitrile. Since the yields were marginally better
with methanol (Table 1), this solvent was then utilized in the synthesis of a focused library of α-
hydrazino tetrazoles (Table 1).
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Table 1. Optimization of the solvent for the synthesis of 5a
Solvent
yields
CH2Cl2
CH3CN
MeOH
EtOH
20
27
60
52
1
In initial studies, diastereomeric ratios were determined by H NMR spectral data on the crude
reaction products (Table 2). For instance, determinations of diastereomer ratios of product 5a
(68:32) were based on the NMR integration of the areas under the –NH-NH-CO peak, resonated at
δ 7.83 in the axial position and 8.30 ppm in the equatorial position two configurational
diastereomers, respectively. In the next step, the crude product was separated by crystallization
procedures into its two diastereomers due to their major difference of solubility in ethanol. The
single diastereomer was obtained in 60% yield. The separated single crystal contained the major
1
diastereomer, confirmed by its H NMR spectra. After finding suitable conditions, the scope and
limitations of this reaction were explored by using different hydrazides 1a–d, cyclic ketones 2a-c
and isocyanides 3a–b. The results are summarized in Table 2. The yields of reactions are reported
on the basis of the yield of crystalline formed as single diastereomer (Table 2). In Table 2 the
structure of products, the yield of single diastereomer and also the ratio of two diastereomers were
shown.
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Table 2.One-pot four-component reaction for the diastereoselcetive synthesis of hydrazine tetrazoles 5a-i via
reaction of hydrazides 1a-d, cyclic ketones 2a-c, isocyanides 3a-b and trimethylsilyl azide at room
temperature.
1
13
The structures of the products 5a-i were deduced from their IR, H NMR, and C NMR and ESI-
1
HRMS spectra. For example, the H NMR spectrum of 5a consisted of multiplet signals for the
methylene groups of cyclohexyl ring at δ 1.05-2.49, a doublet for NH at δ 6.17 and a multiplet was
observed at δ 7.41-7.68 for aromatic protons and –NH (t-butyl) of amide and a doublet for amide
proton of NH-NH-COPh at δ 9.93. The proton decoupled 13C NMR spectrum of 5a showed 14
distinct resonances in agreement with the proposed structure. Data arising from a combined analysis
of 2D H-H COSY allowed us to assign signals of the 1H NMR spectrum of compound 5a. 2D H-H-
COSY spectrum was used to determine the relationship between –NH-NH-CO and the other –NH
amide proton. According to this result, it is clear that two –NH protons have correlation at δ 6.17
and 9.93 ppm which could confirm the relation between –NH of amide and amine (–NH-NH-CO).
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Meanwhile, for two samples 5a and 5f the single crystals were obtained and the ORTEP structure
could confirm their structure (Figure 1).The X-ray data for two single crystals 5a and 5f showed
clearly the orientation of the substituent and this was evidence to confirming getting the single
diastereomer.
5a
5f
5a
Fig. 1. ORTEP structure of compounds 5a and 5f.
A mechanism rationalization for this reaction is provided in (Scheme 3). The first step is the
formation of the hydrazone intermediate (6a). Hydrazone formation is resulted from the reaction of
the ketone with the hydrazide. Then, it could form the hydrazonium form (I) in the presence of acid.
Based on the the chemistry of isocyanides, it iss reasonable to assume that the nucleophilic attack of
isocyanide on the hydrazonium ion followed by nucleophilic attack of the azide leads to the
formation of intermediate 7a which undergoes intramolecular cyclization to afford the
corresponding product 5a. The ratio of major diastereomers was in 68-80%. There are two
possibilities for the nucleophilic addition of isocyanide and trimethylsilyl azide to the hydrazonium
intermediate through axial or equatorial approach. The transition state for axial attack suffers from
steric clashes between the 1, 3 axial hydrogens and the incoming isocyanide reagent. But addition
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of isocyanide through equatorial attack is more suitable with less steric effect to provide 5a-i and it
causes the regio-and diastereoselectivity of the reaction. (Scheme 3)
Scheme 3. Proposed mechanism for the concerted nucleophilic addition of azide-isocyanide for the synthesis
of hydrazine tetrazoles 5a-I via azide Ugi reaction.
It seems that the nucleophilic addition of isocyanide and azide could proceed through simultaneous
nucleophilic attack of the azide on the isocyanide, followed by nucleophilic attack of the isocyanide
on the hydrazonium ion. (Scheme 3)
To extend the synthetic approach for the preparation of aza-peptides containing a tetrazole ring,
amino acid hydrazides were also used which produced high yields of the desired products. (Scheme
4) One of the advantages of this approach is that after the Boc-deprotection step, the resulting
compounds can be used as the precursors for the synthesis of aza-peptides containing a tetrazole
ring. (Scheme 4)
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Scheme 4. Synthesis of α-hydrazino tetrazole 5i which contained protected phenylalanine.
Formation of the aggregated forms of molecules could affect their physical and chemical properties
and it has also been proven to play an efficient role in different biological process. The molecular
aggregation is usually mediated through low energy interactions. The main forces included in
construction and controlling the size and shape of these supramolecular structures are the
electrostatic interactions, van der Waals bonds, hydrogen bonding, and π-stacking forces.14-16
As shown in Fig 2, the rod-shaped structures (size = 218 nm) are produced which confirms the
linear and highly-ordered self-aggregation of compound 5c in the three-component solvent mixture
[(hexafluoro isopropanol, methanol, water (100 ꢀl: 400 ꢀl: 500 ꢀl)]. A stacking interaction between
the aromatic moieties and few hydrogen bonds are proposed for the initial fabrication which is
further stabilized and extended to rod-like contributions by numerous hydrogen and π interactions
in adjacent positions.
Fig 2. SEM image of compound 5c
These data could confirm that hydrogen bonding mediated self-assembly. In all synthesized
compounds, the molecules have more sites for forming hydrogen bonding, and ability to construct
hydrogen bonding has direct influence on the stability of the self-assembled structures. According
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to our finding, since 5c was used as a single diastereomer, it is clear that chirality has essential role
in self-assembly and aggregation to afforded rod structures.
In conclusion , we have reported a convenient, simple and efficient synthesis of diastereomeric α-
hydrazino tetrazoles of potential synthetic and pharmacological interest via a facile azide Ugi four-
component reaction. The present methodology offers several advantages, such as simple procedure
with an easy work-up, high yields, the absence of any catalysts, 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 were obtained on
an ABB FT-IR FTLA 2000 spectrometer. 1H NMR and 13C NMR spectra were run on Bruker DRX-
1
300 AVANCE spectrometers at 300 MHz for H NMR, 75 MHz for 13C NMR. DMSO-d6 and
CDCl3 was used as solvent. High resolution mass spectra were recorded on Mass-ESI-POS (Apex
Qe-FT- ICR instrument) spectrometer. The scanning electron microscope (Hitachi 4160, Japan) was
used for getting the scanning electron micrographs.
General procedure for the synthesis of α-hydrazino-tetrazoles:
To a solution of hydrazide 1 (1 mmol), ketone 2 (1 mmol), isocyanide 3 (1.2 mmol) and
trimethylsilylazide 4 (1 mmol) in 8 mL MeOH was added. The mixture was stirred for 24 h at
ambient temperature. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane,
1:3), the solvent was removed under vacuum, and the residue was precipitated by addition of 3 mL
of EtOH and 1 mL of H2O. The precipitate was filtered off and then crystallized from ethanol.
5a:N'-((1SR,4SR)-4-tert-butyl-1-(1-tert-butyl-1H-tetrazol-5-yl)cyclohexyl)benzohydrazide(238
mg, 60%) as a white solid; mp 247-248˚C; Rf (33% EtOAc/ Hexane) 0.33; υmax (KBr) 3300, 3278,
3066, 2956, 1647, 1461 cm-1; δH (300 MHz, DMSO-d6) 0.85 (s, 9H, H t-Bu), 1.05-1.92 (m, 8H,
HCyclohexyl), 1.79 (s, 9H, H t-Bu), 2.45-2.49 (m, 1H, HeqCyclohexyl), 6.17 (d, 1H, J 8.4 Hz, NH), 7.41-
7.49 (m, 3H, HAr), 7.68 (d, 2H, J 7.0 Hz, HAr), 9.93 (d, 1H, J 8.4 Hz, NH); δC (75 MHz, DMSO-d6)
21.3, 27.3, 30.7, 32.0, 33.9, 46.0, 58.3, 63.9, 127.2, 128.2, 131.2, 132.8, 159.6, 163.8. HRMS
(ESI): [M+H]+ found 399.28743 C22H35N6O requires 399.28762. [M+Na]+ found 421.26938
C22H34N6 NaO requires 421.26956.
colourless crystal (polyhedron), dimensions 0.35 x 0.26 x 0.14 mm3, crystal system triclinic, space
group P 1 , Z = 4, a = 12.4093(7) Å, b = 12.7843(7) Å, c = 16.2326(9) Å, alpha = 89.082(1) deg,
beta = 77.274(1) deg, gamma = 62.717(1) deg, V = 2221.8(2) Å3, rho = 1.192 g/cm3, T = 199(2)
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K, Thetamax = 26.37 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
4.37 and a completeness of 99.9% to a resolution of 0.80Å, 39749 reflections measured, 9089
unique (R(int)=0.0330), 6706 observed (I >2δ(I)), intensities were corrected for Lorentz and
polarization effects, an empirical absorption correction was applied using SADABS17a based on the
Laue symmetry of the reciprocal space, mu=0.08mm-1, Tmin=0.97, Tmax=0.99, structure solved by
direct methods and refined against F2 with a Full-matrix least-squares algorithm using the
SHELXTL (Version 2008/4) software package 17b, 539 parameters refined, hydrogen atoms were
treated using appropriate riding models, except thos at the hydrazinic nitrogen atoms N21 and N22,
which were refined isotropically, goodness of fit 1.03 for observed reflections, final residual values
R1(F)=0.046, wR(F2)=0.100 for observed reflections, residual electron density 0.21 to 0.20 eÅ-3.
CCDC 950021contains the supplementary crystallographic data for this paper.
5b: N'-((1RS, 4RS)-4-tert-butyl-1-(1-tert-butyl-1H –tetrazol-5-yl)cyclohexyl)thiophene-2-
carbohydrazide
(222 mg, 55%) as a white solid; mp 242-244˚C; Rf (33% EtOAc/ Hexane) 0.25; υmax(KBr) 3283,
3116, 2954, 1634, 1473 cm-1; δH (300 MHz, CDCl3) 0.91 (s, 9H, H t-Bu), 1.08-1.72 (m, 5H,
HCyclohexyl), 1.89 (s, 9H, H t-Bu),1.99-2.10 (m, 2H, HCyclohexyl), 2.46-2.50 (m, 2H, HCyclohexyl), 5.95 (brs,
1H, NH), 6.99 (brs, 1H,HThienyl), 7.45 (d, 1H, J4.5 Hz, HThienyl), 7.66 (brs, 1H, HThienyl),8.82 (brs,
1H, NH); δC (75 MHz, CDCl3) 21.9, 27.5, 31.1, 32.4, 33.9, 46.9, 59.8, 65.1, 127.6, 128.1, 129.9,
137.1, 160.0, 160.2. HRMS (ESI): [M+H]+ found 405.24318 C20H33N6OS requires 405.24320,
[M+Na]+ found 427.22514 C20H32N6NaOS requires 427.22516.
5c: N'-((1SR, 4SR)-4-tert-butyl-1-(1-tert-butyl-1H-tetrazol-5-yl)cyclohexyl)-4-methyl benzene
sulfonohydrazide (300 mg, 67%) as a white solid; mp 197-198˚C; Rf (33% EtOAc/ Hexane) 0.24;
υmax (KBr) 3479, 3272, 3117, 2938, 2864, 1655, 1600, 1462, 1320, 1156 cm-1; δH (300 MHz,
CDCl3) 0.73 (s, 9H, H t-Bu), 0.92-1.90 (m, 7H, HCyclohexyl), 1.70 (s, 9H, H t-Bu), 2.35 (s, 3H, Me),
2.36-2.44 (m, 2H, HCyclohexyl), 3.80 (d, 1H, J 4.5 Hz, NH), 7.01 (d, 1H, J 4.5 Hz, NH), 7.22 (d,
2H, J 8.0 Hz, HAr), 7.68 (d, 2H, J 8.0 Hz, HAr); δC (75 MHz, CDCl3) 18.4, 21.5, 24.0, 27.4, 31.1,
32.1, 33.9, 46.9, 58.4, 60.9, 64.9, 128.0, 129.5, 135.2, 143.7, 155.6. HRMS (ESI): [M+H]+found
449.26984 C22H37N6O2S requires 449.26996, [M+Na]+found 471.25176 C22H36N6NaO2S requires
471.25186.
5d:
N'-((1SR,
4SR)-1-(1-tert-butyl-1H-tetrazol-5-yl)-4-ethylcyclohexyl)thiophene-2-
carbohydrazide
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(263 mg, 70%) as a white solid; mp 243-246˚C; Rf (33% EtOAc/ Hexane) 0.31; υmax (KBr) 3293,
3255, 3118, 2930, 1642, 1448 cm-1; δH (300 MHz, CDCl3) 0.85 (t, 3H, J 7.0 Hz, CH3), 1.22-
1.62(m, 7H, HCyclohexyl), 1.79 (s, 9H, Ht-Bu), 1.83-1.94 ( m, 2H, HCyclohexyl), 2.37 (m, 2H, HCyclohexyl),
5.99 (d, 1H, J 5.7 Hz, NH), 7.09 (t, 1H, J 4.0 Hz, HThionyl), 7.63 (d, 1H, J 4.0 Hz, HThienyl), 7.74 (d,
1H, J 4.8 Hz, HThienyl),9.86 (d, 1H, J 7.2 Hz, NH); δC (75 MHz, CDCl3) 11.3, 26.6, 28.7, 30.7,
33.1, 37.0, 58.8, 64.1, 127.7, 128.1, 130.7, 137.1, 158.7, 159.4. HRMS (ESI): [M+H]+found
377.21185 C18H29N6OS requires 377.21186, [M+Na]+found 399.19379 C18H28N6NaOS requires
399.19380.
5e:
N'-((1SR,
4SR)-1-(1-tert-butyl-1H-tetrazol-5-yl)-4-methylcyclohexyl)thiophene-2-
carbohydrazide
(253 mg, 70%) as a white solid; mp 262-265˚C; Rf (33% EtOAc/ Hexane) 0.28; υmax (KBr) 3265,
3118, 2954, 2864, 1631, 1443 cm-1; δH (300 MHz, CDCl3) 0.98 (d, J 4.5 Hz, 3H, CH3), 1.50-1.77
(m, 5H, HCyclohexyl), 1.89 (s, 9H, H t-Bu), 2.04- 2.11 (m, 2H, HCyclohexyl), 2.33-2.38 (m, 2H, HCyclohexyl),
5.81 (brs, 1H, NH), 7.01 (d, 1H, J 4.0 Hz , HThienyl), 7.46 (d, 1H, J 4.0 Hz, HThienyl), 7.60 (brs, 1H,
HThienyl), 8.57(brs, 1H, NH); δC (75 MHz, CDCl3) 22.1, 29.4, 31.2, 31.4, 33.3, 46.9, 59.8, 65.1,
127.6, 128.1, 130.1, 136.8, 149.9, 160.1. HRMS (ESI): [M+H]+ found 363.19632 C17H27N6OS
requires 363.19637, [M+Na]+found 385.17824 C17H26N6NaOS requires 385.17828.
5f: N'-((1SR, 4SR)-4-tert-butyl-1-(1-cyclohexyl-1H-tetrazol-5-yl) cyclohexyl)benzohydrazide
(275 mg, 65%) as a white solid; mp 273-275˚C; Rf (33% EtOAc/ Hexane) 0.30; υmax (KBr) 3338,
3250, 2941, 2858, 1667, 1532, 1453 cm-1; δH (300 MHz, CDCl3) 0.81 (s, 9H, H t-Bu), 1.12-2.08 (m,
17H, HCyclohexyl), 2.65 (d, 2H, J 12.5 Hz, HeqCyclohexyl), 4.98-5.05 (m, 1H, CHN), 5.34 (brs, 1H, NH),
7.33 (t, 2H, J 7.5 Hz, HAr), 7.47 (t, 1H, J 7.5 Hz, HAr), 7.52 (brs, 1H, NH), 7.68 (d, 2H, J 8.1 Hz,
HAr); δC (75 MHz, CDCl3) 23.9, 24.9, 25.5, 27.5, 32.2, 33.4, 34.9,47.6, 59.3, 60.0, 127.1, 128.6,
132.0, 132.2, 154.4, 167.8. HRMS (ESI): [M+H]+found 425.30296 C24H37N6O requires 425.30311,
[M+Na]+ found 447.28485 C24H36N6NaO requires 447.28498.
colourless crystal (polyhedron), dimensions 0.62 x 0.29 x 0.21 mm3, crystal system orthorhombic,
space group Pbca, Z = 8, a = 12.1572(8) Å, b = 11.6707(8) Å, c = 33.725(2) Å, alpha = 90 deg, beta
= 90 deg, gamma = 90 deg, V = 4784.9(6) Å3, rho = 1.179 g/cm3, T = 200(2) K, Thetamax = 28.95
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 7.29 and a
completeness of 98.7% to a resolution of 0.84Å, 47926 reflections measured, 6241 unique
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(R(int)=0.0367), 4739 observed (I >2σ(I)), intensities were corrected for Lorentz and polarization
effects, an empirical absorption correction was applied using SADABS17a based on the Laue
symmetry of the reciprocal space, mu = 0.08mm-1, Tmin = 0.95, Tmax = 0.98, structure solved by
direct methods and refined against F2 with a Full-matrix least-squares algorithm using the
SHELXTL (Version 2008/4) software package17b, 291 parameters refined, hydrogen atoms were
treated using appropriate riding models, except H2 and H3 of the hydrazine-unit, which were
refined isotropically, goodness of fit 1.04 for observed reflections, final residual values R1(F) =
0.048, wR(F2) = 0.103 for observed reflections, residual electron density 0.16 to 0.24 eÅ-3. CCDC
950022 contains the supplementary crystallographic data for this paper.
5g: N'- ((1SR, 4SR)- 4- tert- butyl- 1- (1- cyclohexyl- 1H- tetrazol- 5- yl) cyclohexyl) thiophene-
2-carbohydrazide
(258 mg, 60%) as a white solid; mp 243-246˚C; Rf (33% EtOAc/ Hexane) 0.35; υmax (KBr) 3296,
3222, 3092, 2937,1620, 1446 cm-1; δH (300 MHz, DMSO-d6) 0.84 (s, 9H, H t-Bu), 0.90-1. 78 (m,
19H, HCyclohexyl), 3.38-3.41 (m, 1H, -CHN), 5.29 (d, 1H, J 2.5 Hz, NH), 7.13 (t, 1H, J 4.8 Hz,
HThienyl), 7.75 (d, 1H, J 4.2 Hz, HThienyl), 7.80 (d, 1H, J 3.6 Hz, NH), 8.15 (d, 1H, J 8.0 Hz, HThienyl),
9.32 (d, 1H, J 2.5 Hz, NH); δC (75 MHz, DMSO-d6) 21.6, 24.5, 25.2, 27.5, 30.9, 32.1, 32.2, 47.1,
47.4, 63.2, 127.8, 128.6, 131.0, 137.8, 161.9, 174.0. HRMS (ESI): [M+H]+ found 431.25973
C22H35N6OS requires 431.25996, [M+Na]+found 453.24171 C22H34N6NaOS requires 453.24193.
5h:
N'-((1SR,
4SR)-1-(1-cyclohexyl-1H-tetrazol-5-yl)-4-ethylcyclohexyl)thiophene-2-
carbohydrazide
(253 mg, 63%) as a white solid; mp 243-246˚C; Rf (33% EtOAc/ Hexane) 0.25; υmax (KBr) 3301,
3248, 1629, 1444 cm-1; δH (300 MHz, DMSO-d6) 0.86 (t, 3H, J 7.0 Hz, CH3), 0.75-2.48 (m, 21H,
HCyclohexyl), 5.07 (m, 1H, CHN), 5.83 (s, 1H, HN), 7.07-7.10 (m, 1H, HThionyl), 7.65 (d, 1H, J 2.0
Hz,HThionyl), 7.73 ( t, 1H, J 4.0Hz,HThionyl), 9.66 (s, 1H,NH); δC (75 MHz, DMSO-d6) 11.3, 24.9,
26.6, 28.5, 31.4, 32.9, 33.1, 33.3, 37.1, 57.4, 58.2, 127.6, 128.4, 130.8, 137.2, 157.0, 164.4. HRMS
(ESI): [M+H]+ found 403.22755 C20H31N6OS requires 403.22757, [M+Na]+ found 425.20946
C20H30N6NaOS requires 425.20947.
5i:
tert-butyl
1-(2-((1SR,
4SR)-4-tert-butyl-1-(1-cyclohexyl-1H-tetrazol-5-
yl)cyclohexyl)hydrazinyl)-1-oxo-3-phenylpropan-2-ylcarbamate
12

ACCEPTED MANUSCRIPT
(369mg, 65%) as a white solid; mp 188-189˚C; Rf (33% EtOAc/ Hexane) 0.36; υmax(KBr) , 3350,
3293, 3096, 2965, 1719, 1680, 1504 cm-1; δH (300 MHz, CDCl3) 0.91 (S, 9H, Ht-Bu),1.00-2.09 (m,
19H, H cyclohexyl), 1.32 (s, 9H, H t-Bu), 3.00 (m, 2H, CH2), 4.16-4.24 (m, 1H, CHN), 4.88-4.90 (m,
1H, CH), 5.28(d, 1H, J 7.0 Hz, NH), 7.10- 7.30 (m, 6H, HAr, NH), 7.53 (brs, 1H, NH); δC (75 MHz,
CDCl3) 21.6, 21.8, 24.9, 25.6, 27.4, 28.1, 31.7, 32.4, 32.6, 33.4, 33.5, 46.9, 58.1, 59.3, 80.4, 127.0,
128.6, 129.1, 136.2, 157.0, 170.0; HRMS (ESI): [M+H]+ found 568.39664 C31H50N7O3 requires
568.39658; [M+Na]+found 590.37859 C31H49N7NaO3 requires 590.37854.
Scanning Electron Microscopy
The self-aggregation of compound (5c) was studied by dissolving 2 mg of the sample in 1 ml of the
solvent system containing 1,1,1,3,3,3 Hexafluoroisopropanol, methanol, and mili Q water (1:4:5).
The scanning electron micrographs (SEM, Hitachi 4160, Japan) of the assembled constructions
were obtained after 4 hrs.
Acknowledgements
S.B. gratefully acknowledges Iran National Science Foundation (INSF). We are also thanking
center of excellence in development of chemical methods (CEDCM) Bu-Ali Sina University of
Hamedan for kind cooperation and financial support.
References:
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Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; 4, 621–678; (b) Himo, F.; Demko, Z. P.;
Noodleman, L. J. Org. Chem. 2003, 68, 9076–9080, and references cited therein; (c) Upadhayaya,
R. S.; Sinha, N.; Jain, S.; Kishore, N.; Chandra, R.; Arora, S. K. Bioorg. Med. Chem. 2004, 12,
2225–2228.
2. Gross, E. G.; Featherstone, R. M. J. Pharmacol. Exp. Ther. 1946, 87, 299–305.
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Nakashima, H.; Nagae, Y.; Tsukahara, D.; Arakawa, K.; Nishimura, T.; Eiki, J. WO 2005,063,738,
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2005; Chem. Abstr., 2005, 143, 153371; (c) Miao, Z.; Sun, Y.; Nakajima, S.; Tang, D.; Wu, F.; Xu,
G.; Or, Y. S.; Wang, Z. US 2005,153,877, 2005; Chem. Abstr., 2005, 143, 153709; (d) Luo, G.;
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2005,056,550, 2005; Chem. Abstr., 2005, 143, 78091.
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1988, 110, 5875– 5880; (b) Kaczmarek, K.; Jankowski, S.; Siemion, I. Z.; Wieczorek, Z.; Benedetti,
E.; Di Lello, P.; Isernia, C.; Saviano, M.; Zabrocki, J. Biopolymers 2002, 63, 343– 357.
5. Beusen, D. D.; Zabrocki, J.; Slomczynska, U.; Head, R. D.; Kao, J.; Marshall, G. R. Biopolymers
1995, 36, 181–200.
6. Zabrocki, J.; Dunbar, J. B. Jr.; Marshall, K. W.; Toth, M. V.; Marshall, G. R. J. Org. Chem.
1992, 57, 202–209.
7. Lebl, M.; Slaninoca, J.; Johnson, R. L. Int. J. Pept. Protein Res. 1989, 33, 16–21.
8. (a) Brigas, A. F. In Science of Synthesis, Vol. 13; Storr, R. C.; Gilchrist, T. L., Eds.; Thieme:
Stuttgart, 2004, 861. (b) Liotta, C. L.; Pollet, P.; Belcher, M. A.; Aronson, J. B.; Samanta, S.;
Griffith, K. N. US 2005,269,001, 2005; Chem. Abstr., 2004, 144, 37926; (c) Frija, L. M. T.;
Khmelinskii, I. V.; Cristiano, M. L. S. Tetrahedron Lett. 2005, 46, 6757-6760; (d) Schnermann, M.
J.; Boger, D. L. J. Am. Chem. Soc. 2005, 127, 15704-5; (e) Potts, D.; Stevenson, P. J.; Thompson,
N. Tetrahedron Lett. 2000, 41, 275. (f) Quintin, J.; Lewin, G. J. Nat. Prod. 2004, 67, 1624-6; (g)
Enders, D.; Lenzen, A.; Muller, M. Synthesis 2004, 1486-8; (h) Jankowski, P.; Plesniak, K.;
Wicha, J. Org. Lett. 2003, 5, 2789-2792; (i) Fettes, A.; Carreira, E. M. Angew. Chem. Int. Ed.
2002, 41, 4098-4101.
9. Katritzky, A. R.; Cai, C.; Meher, N. K. Synthesis 2007, 1204–1208. and the references cited
therein.
10. Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229–2233.
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12. (a) Borisov, R. S.; Polyakov, A. I.; Medvedeva, L. A.; Khrustalev, V. N.; Guranova, N. I.;
Voskressensky, L. G. Org. Lett., 2010, 12, 3894–3897; (b) Nayak, M.; Batra, S. Tetrahedron Lett.
14

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2010, 51, 510–516; (c) Giustiniano, M.; Pirali, T.; Massarotti, A.; Biletta, B.; Novellino, E.;
Campiglia, P.; Sorba, G.; Tron, G. C. Synthesis 2010, 4107–4118; (d) Marcos, C. F.; Marcaccini,
S.; Menchi, G.; Pepinob, R.; Torroba, T. Tetrahedron Lett. 2008, 49, 149–152; (e) Marcaccini, S.;
Torroba, T. Nature Protocols 2007, 2, 632–639; (f) Nixey, T.; Kelly, M.; Semin, D.; Hulme, C.
Tetrahedron Lett. 2002, 43, 3681–3684; (g) Nixey, T.; Kelly, M.; Hulme, C. Tetrahedron Lett.
2000, 41, 8729–8733; (h) El Kaim, L.; Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261–1263; (i)
Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11, 1825–1827; (j) Kiselyov, A. S.
Tetrahedron Lett. 2005, 46, 4851–4854.
13. a) Maghari, S.; Ramezanpour, S.; Balalaie, S.; Darvish, F.; Rominger, F.; Bijanzadeh, H. R. J.
Org. Chem.2013, 78, 6450-6456; b) Maghari, S.; Ramezanpour, S.; Darvish, F.; Balalaie, S.;
Rominger, F.; Bijanzadeh, H. R. Tetrahedron 2013, 69, 2075-2080; c) Ramezanpour, S.; Balalaie,
S.; Rominger, F.; Bijanzadeh, H. R. Tetrahedron 2013, 69, 3480-3485.
14. Glotzer, S. C.; Solomon, M. L. Nat. Mater. 2007, 6, 557-562.
15. Ruiz-Hitzky, E.; Darder, M.; Aranda, P. Ariga, K. Adv. Mater.2010, 22, 323-336.
16. Fakhrullin, R. F.; Lvov, Y. M.; ACS Nano 2012, 6, 4557-4564.
17. a) Sheldrick, G. M. Bruker Analytical X-ray-Division, Madison, Wisconsin 2008
b) Sheldrick, G.M. Acta Cryst. 2008, A64, 112-122.
15

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Graphical Abstract
Facile, efficient and diastereoselective synthesis of α- hydrazine tetrazoles via a novel one-pot
four-component reaction
Sorour Ramezanpoura, Saeed Balalaiea*, Frank Romingerb, Nahid S. Alavijeha, Hamid Reza
Bijanzadeha
16

ACCEPTED MANUSCRIPT
checkCIF/PLATON report
You have not supplied any structure factors. As a result the full set of tests cannot be run.
No syntax errors found.
CIF dictionary
Interpreting this report
Datablock: sba97
Bond precision: C-C = 0.0028 A
Wavelength=0.71073
Cell:
a=12.4093(7)
alpha=89.082(1) beta=77.274(1) gamma=62.717(1)
Temperature: 199 K
b=12.7843(7)
c=16.2326(9)
Calculated
Reported
Volume
Space group
Hall group
2221.8(2)
P -1
-P 1
2221.8(2)
P-1
?
Moiety formula C22 H34 N6 O
?
Sum formula
Mr
Dx,g cm-3
Z
C22 H34 N6 O
398.55
1.191
C22 H34 N6 O
398.55
1.192
4
4
Mu (mm-1)
F000
0.076
864.0
0.076
864.0
F000’
h,k,lmax
Nref
864.27
15,15,20
9099
15,15,20
9089
Tmin,Tmax
Tmin’
0.977,0.989
0.974
0.974,0.989
Correction method= MULTI-SCAN
Data completeness= 0.999
Theta(max)= 26.370
R(reflections)= 0.0463( 6706)
wR2(reflections)= 0.1158( 9089)
S = 1.032
Npar= 539
The following ALERTS were generated. Each ALERT has the format
test-name_ALERT_alert-type_alert-level.
Click on the hyperlinks for more details of the test.
Alert level C
ABSTY02_ALERT_1_C An _exptl_absorpt_correction_type has been given without
a literature citation. This should be contained in the
_exptl_absorpt_process_details field.
Absorption correction given as multi-scan

ACCEPTED MANUSCRIPT
PLAT242_ALERT_2_C Check Low
PLAT790_ALERT_4_C Centre of Gravity not Within Unit Cell: Resd. #
C22 H34 N6 O
Ueq as Compared to Neighbors for
C24_2
1
Alert level G
PLAT005_ALERT_5_G No _iucr_refine_instructions_details in the CIF
PLAT154_ALERT_1_G The su’s on the Cell Angles are Equal ..........
PLAT720_ALERT_4_G Number of Unusual/Non-Standard Labels ..........
?
0.00100 Deg.
126
0 ALERT level A = Most likely a serious problem - resolve or explain
0 ALERT level B = A potentially serious problem, consider carefully
3 ALERT level C = Check. Ensure it is not caused by an omission or oversight
3 ALERT level G = General information/check it is not something unexpected
2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
1 ALERT type 2 Indicator that the structure model may be wrong or deficient
0 ALERT type 3 Indicator that the structure quality may be low
2 ALERT type 4 Improvement, methodology, query or suggestion
1 ALERT type 5 Informative message, check
It is advisable to attempt to resolve as many as possible of the alerts in all categories. Often the
minor alerts point to easily fixed oversights, errors and omissions in your CIF or refinement
strategy, so attention to these fine details can be worthwhile. In order to resolve some of the more
serious problems it may be necessary to carry out additional measurements or structure
refinements. However, the purpose of your study may justify the reported deviations and the more
serious of these should normally be commented upon in the discussion or experimental section of a
paper or in the "special_details" fields of the CIF. checkCIF was carefully designed to identify
outliers and unusual parameters, but every test has its limitations and alerts that are not important
in a particular case may appear. Conversely, the absence of alerts does not guarantee there are no
aspects of the results needing attention. It is up to the individual to critically assess their own
results and, if necessary, seek expert advice.
Publication of your CIF in IUCr journals
A basic structural check has been run on your CIF. These basic checks will be run on all CIFs
submitted for publication in IUCr journals (Acta Crystallographica, Journal of Applied
Crystallography, Journal of Synchrotron Radiation); however, if you intend to submit to Acta
Crystallographica Section C or E, you should make sure that full publication checks are run on the
final version of your CIF prior to submission.
Publication of your CIF in other journals
Please refer to the Notes for Authors of the relevant journal for any special instructions relating to
CIF submission.
PLATON version of 05/11/2012; check.def file version of 05/11/2012

ACCEPTED MANUSCRIPT
Datablock sba97 - ellipsoid plot

ACCEPTED MANUSCRIPT
checkCIF/PLATON report
You have not supplied any structure factors. As a result the full set of tests cannot be run.
No syntax errors found.
CIF dictionary
Interpreting this report
Datablock: sba98
Bond precision: C-C = 0.0020 A
Wavelength=0.71073
Cell:
a=12.1572(8)
alpha=90
200 K
b=11.6707(8)
beta=90
c=33.725(2)
gamma=90
Temperature:
Calculated
4785.0(5)
P b c a
Reported
4784.9(6)
Pbca
?
?
Volume
Space group
Hall group
-P 2ac 2ab
Moiety formula C24 H36 N6 O
Sum formula
Mr
Dx,g cm-3
Z
C24 H36 N6 O
424.59
1.179
C24 H36 N6 O
424.59
1.179
8
8
Mu (mm-1)
F000
F000’
h,k,lmax
Nref
0.075
0.075
1840.0
1840.0
1840.58
16,15,45
6324
16,15,45
6241
Tmin,Tmax
Tmin’
0.974,0.984
0.955
0.955,0.984
Correction method= MULTI-SCAN
Data completeness= 0.987
Theta(max)= 28.950
R(reflections)= 0.0480( 4739)
wR2(reflections)= 0.1152( 6241)
S = 1.036
Npar= 291
The following ALERTS were generated. Each ALERT has the format
test-name_ALERT_alert-type_alert-level.
Click on the hyperlinks for more details of the test.
Alert level C
ABSTY02_ALERT_1_C An _exptl_absorpt_correction_type has been given without
a literature citation. This should be contained in the
_exptl_absorpt_process_details field.
Absorption correction given as multi-scan

ACCEPTED MANUSCRIPT
Alert level G
PLAT005_ALERT_5_G No _iucr_refine_instructions_details in the CIF
PLAT063_ALERT_4_G Crystal Size Likely too Large for Beam Size ....
?
0.62 mm
0 ALERT level A = Most likely a serious problem - resolve or explain
0 ALERT level B = A potentially serious problem, consider carefully
1 ALERT level C = Check. Ensure it is not caused by an omission or oversight
2 ALERT level G = General information/check it is not something unexpected
1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
0 ALERT type 2 Indicator that the structure model may be wrong or deficient
0 ALERT type 3 Indicator that the structure quality may be low
1 ALERT type 4 Improvement, methodology, query or suggestion
1 ALERT type 5 Informative message, check
It is advisable to attempt to resolve as many as possible of the alerts in all categories. Often the
minor alerts point to easily fixed oversights, errors and omissions in your CIF or refinement
strategy, so attention to these fine details can be worthwhile. In order to resolve some of the more
serious problems it may be necessary to carry out additional measurements or structure
refinements. However, the purpose of your study may justify the reported deviations and the more
serious of these should normally be commented upon in the discussion or experimental section of a
paper or in the "special_details" fields of the CIF. checkCIF was carefully designed to identify
outliers and unusual parameters, but every test has its limitations and alerts that are not important
in a particular case may appear. Conversely, the absence of alerts does not guarantee there are no
aspects of the results needing attention. It is up to the individual to critically assess their own
results and, if necessary, seek expert advice.
Publication of your CIF in IUCr journals
A basic structural check has been run on your CIF. These basic checks will be run on all CIFs
submitted for publication in IUCr journals (Acta Crystallographica, Journal of Applied
Crystallography, Journal of Synchrotron Radiation); however, if you intend to submit to Acta
Crystallographica Section C or E, you should make sure that full publication checks are run on the
final version of your CIF prior to submission.
Publication of your CIF in other journals
Please refer to the Notes for Authors of the relevant journal for any special instructions relating to
CIF submission.
PLATON version of 05/11/2012; check.def file version of 05/11/2012

ACCEPTED MANUSCRIPT
Datablock sba98 - ellipsoid plot