Cu/Graphene/Clay Nanohybrid: A Highly Efficient Heterogeneous Nanocatalyst for Synthesis of New 5-Substituted-1H-Tetrazole Derivatives Tethered to Bioactive N-Heterocyclic Cores

Article abstract of DOI:10.1002/jhet.2591

A series of new 5-substituted 1H-tetrazoles bearing bioactive N-heterocyclic cores were synthesized through [3 + 2] cycloaddition reactions between alkyl nitriles (RCN) and NaN₃in the presence of Cu/aminoclay/reduced graphene oxide nanohybrid (Cu/AC/r-GO nanohybrid) as a heterogeneous nanocatalyst in water/i-PrOH (50:50, V/V) media at reflux condition. The influence of factors on a sample reaction including solvent type, temperature, and catalyst amount was discussed. This current protocol has many advantages including inexpensiveness, environmentally benign, broad substrate scope, excellent yields, and easy work-up procedure. The Cu/AC/r-GO used in this protocol is a low-cost catalyst that proved to have considerable chemical and thermal stabilities. This non-hygroscopic catalyst can be easily recycled, reused, and stored for many consecutive reaction runs without significant loss in its reactivity.

Full text of DOI:10.1002/jhet.2591

Month 2016
Cu/Graphene/Clay Nanohybrid: A Highly Efficient Heterogeneous
Nanocatalyst for Synthesis of New 5-Substituted-1H-Tetrazole
Derivatives Tethered to Bioactive N-Heterocyclic Cores
a
a
a
b
Mohammad Navid Soltani Rad, * Somayeh Behrouz, * Vahid Sadeghi Dehchenari, and S. Jafar Hoseini
a
Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz
7
1555-313, Iran
Department of Chemistry, Faculty of Sciences, Yasouj University, Yasouj 7591874831, Iran
E-mail: soltani@sutech.ac.ir; behrouz@sutech.ac.ir
b
*
Additional Supporting Information may be found in the online version of this article.
Received August 22, 2015
DOI 10.1002/jhet.2591
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A series of new 5-substituted 1H-tetrazoles bearing bioactive N-heterocyclic cores were synthesized
through [3 + 2] cycloaddition reactions between alkyl nitriles (RCN) and NaN3 in the presence of
Cu/aminoclay/reduced graphene oxide nanohybrid (Cu/AC/r-GO nanohybrid) as a heterogeneous
nanocatalyst in water/i-PrOH (50:50, V/V) media at reflux condition. The influence of factors on a sample
reaction including solvent type, temperature, and catalyst amount was discussed. This current protocol has
many advantages including inexpensiveness, environmentally benign, broad substrate scope, excellent
yields, and easy work-up procedure. The Cu/AC/r-GO used in this protocol is a low-cost catalyst that proved
to have considerable chemical and thermal stabilities. This non-hygroscopic catalyst can be easily recycled,
reused, and stored for many consecutive reaction runs without significant loss in its reactivity.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
stable surrogates or bioisosteres for carboxylic acids [7].
The acidity of N–H bond in tetrazole is similar to that of
carboxylic O–H at physiological pH; both exhibit planar
structures, with tetrazoles being a more lipophilic key fac-
tor when crossing cell membranes than the corresponding
carboxylic analogues [8]. When tetrazole is a part of drug
molecule, it improves oral bioavailability and cell penetra-
tion. Furthermore, the delocalization of negative charge on
larger surface of tetrazoles enhances the binding of drug to
active site of receptors or enzymes [9]. Tetrazole deriva-
tives possess very interesting pharmacological and biolog-
ical properties and are reported to exhibit a variety of
biological activities like antihypertensive [10], antibacte-
rial [11,12], antifungal [13], anticonvulsant [14],
Although tetrazole and its derivatives are not found in na-
ture, however, there is a worldwide increasing interest in the
design and synthesis of new tetrazole derivatives [1] because
tetrazole derivatives encompass enormous applications as a
prospective component of highly energetic material used in
explosives and rocket propellants [2], photographic indus-
tries [3], in agriculture as plant growth regulators [4], in lu-
bricants as anti-wears and frictions [5], and in coordination
chemistry as nitrogen-containing heterocyclic ligands [6].
In addition, synthesis of tetrazole derivatives is obvi-
ously an important task in modern medicinal chemistry,
primarily because of their ability to serve as metabolically
©
2016 HeteroCorporation

M. N. Soltani Rad, S. Behrouz, V. Sadeghi Dehchenari, and S. J. Hoseini
Vol 000
analgesics [15], anti-inflammatory [16], antitubercular
17], anticancer [18], antineoplastic [19], antiallergic [20],
antiviral [21], and especially anti-HIV activities [22].
The methods for synthesis of tetrazole are well docu-
mented. The main methods for synthesis of tetrazole are
chelate with copper species. This chelation not only pro-
motes the catalytic activity of copper but also largely pre-
vents desorption of copper species from surface of support
and leaching through the course of reaction [57].
[
Graphene oxide (GO) as a synthetic precursor of
graphene is a unique substance that can be regarded as a
single monomolecular layer of graphite with various
oxygen-containing functionalities such as hydroxyl
groups, carbonyl, carboxyl, and epoxide [58]. The pres-
ence of theses functionalities allows the possibility of GO
grafting with many biomolecular organic materials, drugs,
and so on, which recently found extensive applications in
electronics, energy storage, biomedical (drug delivery),
and biosensors [59]. After functionalizing or modifying
GO with desired molecules, the modified GO is reduced
to graphene (r-GO) to retrieve the exclusive mechanical,
electrical, thermal, and optical properties known from
graphene [60].
Recently, we have reported the preparation and charac-
terization of Cu/aminoclay/reduced graphene oxide
nano-hybrid (Cu/AC/r-GO nanohybrid) as a highly
efficient nanocatalyst for synthesis of new 1,2,3-triazolyl
carboacyclic nucleosides [61]. Thus, in pursuit of our
ongoing interest in the use of heterogeneous nano-Cu
catalysts in organic transformation [55,62], hereby, we dis-
close Cu/aminoclay/reduced graphene oxide nanohybrid
(Cu/AC/r-GO nanohybrid) as an efficient nanocatalyst for
synthesis of new 5-substituted-1H-tetrazole derivatives
tethered to bioactive N-heterocyclic cores (Scheme 1).
In this synthesis, the N-alkylation reaction of diverse
N-heterocycles encompassing xanthines, imides, azoles pu-
rine, and pyrimidine nucleobases with 2-chloroacetonitrile
or 3-chloropropanenitrile achieved in the presence of an
[
3 + 2]-cycloaddition reaction between organic nitriles with
sodium azide developed by Sharpless et al. [23]. However,
other methods are also established that mostly processed
through non-concerted type procedures [24]. Many homo-
geneous and heterogeneous catalysts were developed so far
to promote [3+ 2]-cycloaddition reaction for synthesis of
tetrazoles including, Zn(II) salts [23], AlCl [25], (CH )
3
3
Al [26], Et N.HCl [27], NH Cl [28], BF . OEt [29],
3
3
4
3
2
TBAF [30], Pd(PPh ) [31], Zn/Al hydrotalcite [32], ZnO
3
4
[
33], ZnS [34], Zn–Cu alloy [35], Cu O [36], CuFe O
2 2 4
nanoparticles [37], copper triflates [38], FeCl -SiO [39]
3
2
Fe(OAc) [40], tungstate salts [41], CdCl [42], Sb O
2 3
2
2
[
43], amberlyst-15 [44], silica sulfuric acid [45], montmo-
rillonite K-10 clay [46], I [47], TMSCl [48], CuFe O
2 4
2
nano particles [37], AgNPs [49], WAlPO-5 microspheres
50], cuttlebone [51], and CAES [52]. Although many of
these catalysts indeed are effective in the synthesis of
H-tetrazole derivatives, however, the limitations of the
[
1
existing protocols realized in terms of longer reaction time;
harsh reaction conditions; the in situ generation of highly
toxic, volatile, and explosive hydrazoic acid; the use of ex-
pensive and toxic metal catalysts; formation of stable
metal-tetrazole complexes; tedious work-ups, and inability
or unsatisfactory recovery of catalyst. Because of the in-
creasing demands for safe and ecofriendly materials to
minimize the environmental cost, there is a worldwide
growing interest for heterogeneous catalysts to be used in
diverse organic transformations [53]. Among the heteroge-
neous catalyst, organic–inorganic hybrid catalysts in which
an organic spacer is covalently anchored to surface of inor-
ganic supports have found particular attention, owing to
their environmental compatibility combined with good
yield, selectivity, and ease of separation [54].
Given the importance of active copper species in ‘Click’
chemistry, different solid materials were used to support
the copper species comprising silica gel, zeolites, alumina,
charcoal, and montmorillonite. However, the significant
drawbacks comprising desorption of copper species from
support surface, inactivity, and lack of recoverability are
usually accompanied with these heterogeneous copper cat-
alysts that are simply prepared by surface absorption of
copper species on surface of raw support [55].
equimolar mixture of triethylamine (TEA)-K CO3 and
2
catalytic amount of tetrabutylammonium iodide (TBAI)
in acetonitrile at reflux condition to provide nitriles 1. Sub-
sequently, these nitriles are prone to [3 +2] cycloaddition
reaction with sodium azide using Cu/AC/r-GO nanohybrid
as a catalyst, in water–isopropanol media at reflux condi-
tion to yield tetrazoles 2.
RESULTS AND DISCUSSION
We initiated the synthesis of title compounds by prepar-
ing the desired nitriles 1. The commercially available
2-chloroacetonitrile and/or 3-chloropropanenitrile are
pivotal nitrile precursors that utilize the synthesis of large
In this connection, the use of copper organic–inorganic
hybrid catalysts seems to be an appropriate way to over-
come these problems. In these catalysts, the active copper
chelates to nitrogen-based or phosphorus-based ligands that
covalently tethered on various solid supports [56]. Among
solid supports, those that are covalently bonded with amine
residues are more satisfactory because of their capability to
number of functionalized alkyl nitriles via S 2-type
N
reaction with varieties of nucleophiles. In this regard, to
our delight, it was tethered to various N-heterocyclic cores
found in many drugs or natural products scaffolds,
including imides, xanthines, azole derivatives, purine,
and pyrimidine nucleobases to 2-chloroacetonitrile or
3-chloropropanenitrile via N-alkylation reaction to access
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Cu/Graphene/Clay Nanohybrid is a Highly Efficient Catalyst for Tetrazole Synthesis
Scheme 1. Synthesis of novel 5-substituted-1H-tetrazole derivatives tethered to bioactive N-heterocyclic cores using Cu/AC/r-GO nanohybrid.
certain nitriles 1. To afford nitriles 1, the N-
heterocycles were N-alkylated by 2-chloroacetonitrile
or 3-chloropropanenitrile using K CO –TEA mixture
as base in the presence of catalytic amount of TBAI in
anhydrous acetonitrile at reflux condition. In most
cases, the N-alkylation reactions were completed after
refluxing for 48 h.
yield was dramatically increased when the system was set
to reflux condition (Table 1, entry 8). The best ratio of
i-PrOH–water for progress of reaction was observed to be
equal; however, other ratios also yielded the product in
lower amounts (Table 1, entries 9 and 11). The combina-
tion of water with THF also works well with this reaction
but afforded a lower yield (Table 1, entry 14). The use of
immiscible solution of toluene in water in the presence of
catalytic amount of tetrabutylammonium bromide (TBAB)
has a negligible effect after refluxing for a day. Pure aprotic
solvents such as DMF, DMSO, and THF moderately prog-
ress the reaction, whilst employing the pure i-PrOH, EtOH,
and polyethylene glycols (PEG 200 and/or PEG 400) as
protic solvents progresses the reaction to some extent.
Other tested mixtures of water with organic solvents
showed low-to-moderate yields of the product.
As stated earlier, the catalyst has an undeniable role in
1H-tetrazole synthesis. To show this, there was an attempt
to carry out the cycloaddition reaction of azide–nitrile in
the absence of catalyst that resulted in marginal yield as
indicated by GC analysis (<%8) (Table 2). To screen the
catalytic potency of Cu/AC/r-GO nanohybrid in compari-
son with other reported catalysts, we evaluated the effect
of diverse catalysts on a sample reaction (Table 2). As
shown in Table 2, the potency of different reported hetero-
geneous or homogeneous catalysts in tetrazole synthesis
including Lewis and proton acids, solid supports, and am-
monium salts was assessed. The evaluations indicate that
through the examined catalysts, Cu/AC/r-GO nanohybrid
displayed more satisfactory result and yielded 2a at mini-
mum reaction time; nevertheless, other catalysts also
obtained 2a in moderate to reasonable yields.
2
3
Afterward of preparing the desire nitriles 1, our attention
was then turned to finding the optimized reaction parame-
ters such as solvent, temperature, and catalyst amount.
For this aim, cycloaddition reaction of N7-theophylinyl
acetonitrile 1a and sodium azide was studied as a sample
reaction under influence of effective parameters in
reaction.
The choice of an appropriate reaction medium is of
crucial importance for a successful synthesis. Among
solvents, the use of water was preferred because water is
not only known as an environmentally benign solvent but
also shows unusual physical properties, especially having
high heat capacity in which it alleviates the risk of explo-
sion from endergonic materials such as azide used in
synthesis of tetrazole. Thus, pure water was used to
achieve [3 + 2] cycloaddition reaction of N7-theophylinyl
acetonitrile 1a and sodium azide in the presence of catalyst
at different temperatures (Table 1). As can be seen in
Table 1, the water was unable to sufficiently progress the
reaction at various temperatures even at reflux condition.
The lack of 1a solubility in water is a potential argument.
Not being disappointed with water, we tested the effect
of water mixture with various miscible organic solvents
in 50:50 (V/V) ratios.
Compared with pure water (Table 1, entry 6), the yield
was promoted when i-PrOH–water solution was applied
at ambient temperature (Table 1, entry 7); however, the
Inductively coupled plasma (ICP) analysis indicated that
in each gram of catalyst, there is 0.013g of active copper
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. N. Soltani Rad, S. Behrouz, V. Sadeghi Dehchenari, and S. J. Hoseini
Vol 000
Table 1
Table 2
Effect of solvent type and temperature on [3 + 2] cycloaddition reaction of
Comparing the catalytic potency of Cu/AC/r-GO nanohybrid with various
a
a
azide-nitrile using Cu/AC/r-GO nanohybrid.
catalysts.
b
b
Entry
catalyst
Time (h)
Yield (%)
Ref.
Entry
Solvent
T °C
R.T.
50
60
70
80
Reflux
R.T.
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
120
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
—
72
24
24 s
12
24
24
24
24
12
10
4
<8
66
61
76
75
50
59
46
75
64
94
—
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
24
10
8
8
6
4
24
4
6
4
4
7
7
8
7
5
24
24
24
12
7
6
24
24
10
26
38
40
48
51
62
94
81
67
30
42
45
75
48
52
48
58
60
55
53
46
63
51
TBAF
NH Cl
Et N.HCl
[30]
[28]
[27]
[39]
[34]
[44]
[47]
[45]
[36]
-
4
3
FeCl
ZnS
amberlyst-15
I2
silica sulfuric acid
Cu O
Cu/AC/r-GO
nanohybrid
ZnBr2
ZnO
3 2
–SiO
c
c
d
e
O/i-PrOH
O/i-PrOH
O/i-PrOH
O/i-PrOH
9
10
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2
c
O/Me
O/DMF
2
COc
c
c
12
13
14
15
5
15
10
12
88
52
76
56
[23]
[33]
[25]
[48]
O/DMSO
c
O/THF
c
AlCl3
TMSCl
O/HMPA
c
O/NMP
c,f
O/toluene
DMSO
DMF
THF
i-PrOH
EtOH
a
Reaction conditions: nitrile (0.01 mol), NaN
i-PrOH (50 mL).
Isolated yield.
.008 mol %.
3
2
(0.015 mol), catalyst, H O/
120
b
Reflux
Reflux
Reflux
120
c
0
Table 3
PEG 200
PEG 400
a
120
Influence of catalyst amount on synthesis of 2a.
a
3
Reaction conditions: nitrile (0.01 mol), NaN (0.015 mol), Cu/AC/r-GO
nanohybrid (0.008 mol %), solvent (50 mL).
b
Isolated yield.
0:50 (V/V).
c
5
d
70:30 (V/V).
e
f
3
0:70 (V/V).
In the presence of catalytic amount (0.16 g, 0.0005 mol) of
tetrabutylammonium bromide (TBAB)
Cu/AC/r-GO nanohybrid
catalyst (0.02mol %) [61]. To determine the optimized
amount of Cu/AC/r-GO nanohybrid, different amounts of
catalyst were examined on the sample reaction (Table 3).
As depicted in Table 3, the best result was obtained when
b
Entry
(mol %)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
0.002
0.004
0.006
0.008
0.01
0.012
0.014
0.016
5
5
4
4
4
6
7
7
60
64
82
94
94
91
90
90
0
.008 or 0.01mol % of catalyst was applied (Table 3, en-
tries 4 and 5).
The use of an excess amount of catalyst has a negligible ef-
fect on progress of reaction. The improved performance of
Cu/AC/r-GO nanohybrid in comparison with other
heterogeneous catalysts tested in Table 2 is rationalized to po-
tential π–π* interaction of electron-enriched r-GO as a poly-
nuclear aromatic sheet with electron-deficient N-heterocyclic
cores tethered to α or β carbon in nitriles 1 [63].
a
3
Reaction condition: nitrile (0.01 mol), NaN (0.015 mol), Cu/AC/r-GO
nanohybrid (x mol %), H
2
O/i-PrOH (50 mL).
b
Isolated yield.
nanohybrid as a catalyst with different nitriles (1a–1o)
as shown in Table 4. Diverse nitriles having bioactive
N-heterocyclic cores were readily converted to their
With the optimized conditions in hand, we then screened
the scope of this cycloaddition using Cu/AC/r-GO
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Cu/Graphene/Clay Nanohybrid is a Highly Efficient Catalyst for Tetrazole Synthesis
Table 4
The synthesized new 1H-tetrazoles using Cu/AC/r-GO nanohybrid.
Table 4
a
(Continued)
c
c
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
b
b
Entry
1
Nitrile
Product
Entry
13
Nitrile
Product
4
94
6
84
1
1
4
5
8
6
78
91
2
3
6
6
90
75
a
Reaction conditions: nitrile (0.01 mol), NaN
3
(0.015 mol), Cu/AC/r-GO
nanohybrid (0.008 mol %), water/i-PrOH (50 mL).
b
1
13
All products were characterized by H and C NMR, IR, CHN, and MS
4
5
6
7
3
4
7
3
80
91
85
80
analysis.
Isolated yield.
c
corresponding 1H-tetrazole derivatives in good to excellent
yields using Cu/AC/r-GO nanohybrid.
As can be seen in Table 3, nitriles bearing purine, pyrim-
idine, and xanthine nucleobases 1a, 1g, 1i, and 1 k were ef-
ficiently converted to their corresponding tetrazoles 2a, 2 g,
2
i, and 2k, respectively. In the same circumstances, nitriles
having azole cores including 1b, 1c, 1f, 1h, 1j, 1 m, and 1n
underwent to cycloaddition reaction with azide to produce
related tetrazole derivatives in good to excellent yields.
Moreover, the nitriles bearing cyclic imides 1d, 1e, 1 l,
and amine 1o were employed to prepare the desired
tetrazoles using the current protocol. As previously men-
tioned, from a medicinal chemistry point of view, tetrazole
rings are known as metabolically stable surrogates or
bioisosteres for carboxylic acids [7]. Like carboxylic acids,
tetrazole rings are capable to be ionized, participate in hy-
drogen bonding (donor and acceptor), and contributes in
π–π* stacking interaction [64]. Thus, this residue when a
part of biomolecules is well-recognized by enzyme or re-
ceptor [9]. In this regard, the incorporation of tetrazole
rings in scaffold of bioactive compounds can alter their bi-
ological properties [65]. The N-heterocyclic compounds
used to be conjugated with tetrazole are critically important
residues and main pharmacophores in many known drugs
8
9
7
6
83
79
1
1
0
1
8
5
80
85
[66]. Azoles including imidazole and benzimidazole deriv-
atives are well-known for their use in structure of antifun-
gal and chemotherapeutic agents [67].
Moreover, purine and pyrimidine nucleobases are found
in structure of natural nucleosides or synthetic nucleosides
like acyclic nucleosides [68]; therefore, the conjugation of
tetrazole with nucleobases can largely enhance the poten-
tial interaction with DNA or RNA to provide potential an-
timetabolite, antiviral, anticancer agent and so on. As
12
5
87
(
Continued)
Journal of Heterocyclic Chemistry
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M. N. Soltani Rad, S. Behrouz, V. Sadeghi Dehchenari, and S. J. Hoseini
amatter of fact, compounds 2j and 2i can be classified as a
Vol 000
Table 5
new type of acyclic nucleosides. In addition, xanthine alka-
loids are important compounds in human health care from
different aspects.
The reusability of Cu/AC/r-GO nanohybrid in successive runs for the
a
synthesis of 2a.
Among xanthines, methyl xanthines like theophylline
are special because of its wide usage in treatment for
both chronic obstructive pulmonary disease and asthma.
It is worth mentioning that compound 2a is a new
tetrazole-based analogue of acefylline (CAS registry
number: 652-37-9) as well-established adenosine receptor
antagonist having an antiasthmatic property (Fig. 1)
b
c
Run number
Time (h)
Yield (%)
[66,67].
Using the optimized reaction condition, the applicability
1
2
3
4
5
4
4
4.5
4.5
5
94
93
91
90
87
of this catalyst in preparative scale was also examined. In
this context, the cycloaddition reaction of nitrile 1a with
sodium azide was achieved on a 100-mmol scale under
an optimized condition in the presence of catalytic amount
of Cu/AC/r-GO nanohybrid (0.008 mol %). The 1H-tetra-
zole 2a was obtained efficiently in 89% yield after 4 h,
which is comparable with a smaller-scale synthesis
a
Reaction conditions: nitrile (0.01 mol), NaN
AC/r-GO nanohybrid, H O/i-PrOH (50 mL).
The entry number corresponds to the trial number.
Isolated yield.
3
(0.015 mol), recovered Cu/
2
b
c
(
Table 4, entry 1).
The reusability and recoverability of the Cu/AC/r-GO
As we have previously described, the catalyst has a cru-
cial role in [3+ 2]-cycloaddition reaction of azide–nitrile
Table 2). Without using an appropriate catalyst, the reac-
nanohybrid on sample reaction were also evaluated. In this
connection, before using and final testing of the catalyst for
indication of its activity in many successive runs, the cata-
lyst was recycled from the reaction mixture through a
sintered glass funnel by vacuum-filtering. Afterward, the
catalyst was washed successively with anhydrous THF or
acetone (10 mL) and dried in a vacuum oven at 80°C for
(
tion is hardly conducted even at harsh reaction conditions,
and this can be easily observed by a long reaction time and
comparatively minor yield of product (Table 2, entry 1).
The aminoclay layers have been deposited on reduced
graphene oxide as parallel sheets, and the free amino
groups are oriented outward of each sheet. Therefore, the
active copper species is capable to chelate in a space
between four free amino residues present in top and bottom
of aminoclay sheets or doped between two adjacent
aminoclay nanoparticles [69] Like most metals used in
catalysis of [3 + 2] azide-nitrile cycloaddition, the catalytic
activity of Cu/AC/r-GO nanohybrid is ascribed to active
copper species as a Lewis acid. In this context, a plausible
mechanism presenting the catalytic action of Cu/AC/r-GO
nanohybrid is proposed (Scheme 2). As can be seen in
Scheme 2, weakly nucleophile alkyl nitrile interacts with
copper species to generate copper–nitrile complex (I), then
azide ion is prone to attack at activated alkyl nitrile to
1
h. The catalyst was tested for five consecutive runs, and
through each run, no fresh catalyst was added. As can be
seen in Table 5, Cu/AC/r-GO nanohybrid can be recycled
and reused for many consecutive trials without significant
loss of its activity. Furthermore, the ICP analysis has con-
firmed the reusability of Cu/AC/r-GO nanohybrid without
significant desorption of copper species from AC/r-GO
matrix. As it is well indicated, the amount of leached cop-
per from Cu/AC/r-GO nanohybrid is extremely negligible
(0.008% after five consecutive runs), and it is rationalized
because of powerful binding present between copper
species and aminoclay (AC) group growth on the surface
of r-GO
Figure 1. Comparison between structures of acefylline with its isosteric analogue 2a.
Journal of Heterocyclic Chemistry
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Cu/Graphene/Clay Nanohybrid is a Highly Efficient Catalyst for Tetrazole Synthesis
Scheme 2. A plausible mechanism presenting the catalytic action of Cu/AC/r-GO nanohybrid in azide-nitrile cycloaddition. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
afford intermediates (II) or (III). Although [3+ 2]-cycload-
dition reaction of azide–nitrile traditionally is known as
concerted type reaction [23c], however, the extensive
studies by Sharpless et al. revealed that azide–nitrile
cycloaddition is majorly achieved through formation of
imidoyl azide (II) or its cyclic isomer (III) [23d]. The
intermediates (II) or (III) are converted to tetrazolyl–
copper complex (IV) in which it degrades into tetrazole
and free-catalyst (V).
main advantages of this methodology are its simplicity,
not requiring expensive active metal species, and the using
of ecofriendly solvent.
EXPERIMENTAL
All chemicals reagents were purchased from either
Fluka (Buchs,Switzerland); Merck (Darmstadt, Germany).
Cu/AC/r-GO nanohybrid was prepared in accordance with
reported procedure [61]. Solvents were purified by standard
procedures, and stored over 3Å molecular sieves [70]. Reac-
tions were followed by TLC using SILG/UV 254 silica-gel
plates. Column chromatography was performed on silica
gel 60 (0.063–0.200mm, 70–230mesh; ASTM). Melting
points were measured using Electrothermal IA 9000 melting
point apparatus in open capillary tubes and are uncorrected.
IR spectra were obtained using a Shimadzu FT-IR-8300
CONCLUSION
In conclusion, we explained the synthesis of new 5-
substituted 1H-tetrazoles bearing bioactive N-heterocyclic
cores using Cu/AC/r-GO nanohybrid as a highly efficient
heterogeneous nanocatalyst. Various nitriles tethered by di-
verse N-heterocyclic cores reacted with NaN in water/i-
3
1
13
PrOH (50:50, V/V) under the influence of Cu/AC/r-GO
nanohybrid at reflux condition to yield the corresponding
spectrophotometer. H-NMR and C-NMR spectra were
recorded on Brüker Avance-DPX-250/400 spectrometer
operating at 250/62.5 and/or 400/100MHz, respectively.
Chemical shifts are given in δ relative to tetramethylsilane
(TMS) as an internal standard, and coupling constants
5
-substituted 1H-tetrazoles in good to excellent yields.
The Cu/AC/r-GO nanohybrid was displayed to be a chem-
ically and thermally stable, cheap, and environmentally
benign heterogeneous nanocatalyst that extensively
promoted the azide–nitrile cycloaddition. In addition, this
catalyst can be recycled and reused for many consecutive
experiments without significant loss of its activity. The
1
J are given in Hz. Abbreviations used for H NMR
signals are s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, br=broad, and so on. GC/MS was performed
on a Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel.%).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. N. Soltani Rad, S. Behrouz, V. Sadeghi Dehchenari, and S. J. Hoseini
Vol 000
Elemental analyses were performed on a Perkin–Elmer
NMR (250 MHz, DMSO-d ): δ =51.70, 116.65, 117.85,
6
2
40-B micro-analyzer.
Alkyl nitriles 1a-1o: general procedure.
122.22, 123.25, 133.61, 137.50, 145.60, 155.69; MS (EI):
+
In a double-
m/z (%)=200 (14.5) [M ]; Anal. Calcd for C
H N : C,
9 8 6
necked round bottom flask (100mL) equipped with a
condenser was added a mixture, consisting of N-
heterocyclic compound (0.01 mol), 2-chloroacetonitrile or
53.99; H, 4.03; N, 41.98. Found: C, 54.06; H, 4.15; N,
41.92.
5-((2-methyl-4-nitro-1H-imidazol-1-yl)methyl)-1H-tetrazole
(2c). Column chromatography (silica gel, EtOAc–MeOH,
1:1) afforded a brown solid; yield: 1.56g (75%); mp 208–
3
-chloropropan-enitrile (0.013 mol), Et N (0.01mol),
3
K CO3 (0.01mol), and a catalytic amount of TBAI
2
(
0.1 g) in anhydrous MeCN (40 mL). The mixture was
212°C (dec.); R =0.31 (EtOAc–MeOH, 1:1); IR (KBr):
3350, 3128, 2900, 1645, 1500, 1456, 1300cm ; H NMR
f
À1
1
refluxed until TLC monitoring indicated no further
improvement in the reaction. The solvent was evaporated
in vacuo, and the remaining foam was dissolved in
CHCl3 (100 mL) and subsequently washed with water
(250MHz, DMSO-d ): δ =8.30 (s, 1H, C(5)-H, imidazole),
6
5.40 (s, 2H, NCH ), 4.40 (s, 1H, exchangeable with D O,
2
2
13
NH, tetrazole), 2.43 (s, 3H, CH3); C NMR (250MHz,
(
2 × 100mL). The organic layer was dried (Na SO ) and
DMSO-d ): δ= 15.74, 48.22, 121.10, 147.82, 153.09,
160.97; MS (EI): m/z (%)=209 (8.1) [M ]; Anal. Calcd for
2
4
6
+
evaporated. The crude product was purified by column
chromatography on silica gel.
C H N O : C, 34.45; H, 3.37; N, 46.88. Found: C, 34.38;
6
7 7 2
5
-Substituted-1H-tetrazole 2a-2o: general procedure. In
H, 3.42; N, 46.94.
a double-necked round bottom flask (100mL) equipped
2-((1H-tetrazol-5-yl)methyl)
benzo[d]isothiazol-3(2H)-one
with a condenser was added a mixture, consisting of
1,1-dioxide (2d).
Recrystallization (EtOAc) afforded a
alkyl nitrile (0.01mol), NaN (0.015mol), and Cu/AC/r-
pale-yellow solid; yield: 2.12 g (80%); mp 225–229°C
3
GO nanohybrid (0.4 g, 0.008 mol %) in H O/i-PrOH
(dec.); R =0.18 (EtOAc–MeOH, 1:1); IR (KBr): 3324,
3050, 2976, 1715, 1600, 1460, 1321, 761 cm ; H NMR
2
f
À1
1
(1:1 V/V, 50mL). The mixture was heated at reflux until
TLC monitoring indicated no further improvement in the
conversion (Table 4). The reaction mixture was then
cooled to room temperature, vacuum-filtered using a
sintered-glass funnel, and the residue was washed with
ethyl acetate (2 × 20mL). The filtrate was treated with 5 N
HCl to reach pH = 3, and it was allowed to stir for
(250 MHz, DMSO-d ): δ =7.84–7.45 (m, 4H, aryl), 4.44
6
(s, 2H, NCH ), 2.51 (s, 1H, exchangeable with D O, NH,
2
2
13
tetrazole); C NMR (250MHz, DMSO-d ): δ =39.52,
6
126.32, 126.88, 127.33, 131.63, 132.06, 139.30, 156.66,
+
169.10. MS (EI): m/z (%) =265 (19.7) [M ]; Anal. Calcd
for C H N O S: C, 45.45; H, 3.05; N, 21.20; S, 12.13.
10 8 4 3
3
0min. Subsequently, the organic layer was separated,
Found: C, 45.56; H, 3.11; N, 21.14; S, 12.25.
dried over anhydrous Na SO , and evaporated in vacuo.
2-((1H-tetrazol-5-yl)methyl)isoindoline-1,3-dione (2e). Re-
crystallization (EtOAc) afforded a creamy solid; yield:
2
4
The crude product was purified by recrystallization and/or
column chromatography on silica gel eluted with proper
solvents.
2.08g (91%); mp 245–249°C; R =0.47 (EtOAc–MeOH,
f
1:1); IR (KBr): 3370, 3068, 2981, 1766, 1700, 1660,
À1
1
7
-((1H-tetrazol-5-yl)methyl)-1,3-dimethyl-1H2-purine-2,6
1495cm
;
H NMR (250MHz, DMSO-d ): δ =7.90–
6
(
3H,7H)-dione (2a).
Recrystallization (EtOAc–MeOH)
7.85 (m, 4H, aryl), 4.87 (s, 2H, NCH ), 4.04 (s, 1H,
2
13
afforded a brown solid; yield: 2.46 g (94%); mp >300°C
exchangeable with D O, NH, tetrazole);
C NMR
2
(
2
(
dec.); R = 0.27 (EtOAc–MeOH, 1:1); IR (KBr): 3391,
(250MHz, DMSO-d6): δ = 42.20, 127.27, 131.49,
f
À1
1
996, 1720, 1705, 1690, 1650, 1375 cm
;
H NMR
133.48, 157.10, 167.81; MS (EI): m/z (%)=229 (15.9)
+
250 MHz, DMSO-d ): δ= 8.38 (s, 1H, exchangeable with
[M ]; Anal. Calcd for C H N O : C, 52.40; H, 3.08;
6
10 7 5 2
D O, NH, tetrazole), 7.39 (s, 1H, C(8)-H, theophylline),
2
N, 30.56. Found: C, 52.48; H, 3.01; N, 30.69.
5
.04 (s, 2H, NCH ), 2.59 (s, 3H, N(1)-CH ), 2.31(s, 3H,
5-((2-phenyl-1H-imidazol-1-yl)methyl)-1H-tetrazole (2f). Re-
crystallization (EtOAc) afforded a bright brown solid;
2
3
13
N(3)-CH3); C NMR (250 MHz, DMSO-d ): δ= 27.30,
6
3
1
1.18, 47.34, 104.91, 144.41, 149.32, 151.57, 154.19,
59.10; MS (EI): m/z (%) = 263 (10.7) [M ]; Anal. Calcd
yield: 1.92g (85%); mp 216–220°C (dec.); R =0.33
f
+
(EtOAc–MeOH, 1:1); IR (KBr): 3280, 3150, 2937, 2850,
À1
1
for C H N O : C, 41.22; H, 3.84; N, 42.73. Found: C,
1653, 1476cm
;
H NMR (250MHz, DMSO-d6):
9
10 8 2
4
1.28; H, 3.80; N, 42.81.
-((1H-tetrazol-5-yl)methyl)-1H-benzo[d]imidazole (2b). Re-
crystallization (EtOAc) afforded a yellow solid; yield:
.80g (90%); mp 235–240°C (dec.); R =0.25 (EtOAc–
δ=7.94–7.91 (m, 2H, aryl), 7.58–7.46 (m, 3H, aryl), 7.20
(s, 1H, C(4)-H, imidazole), 6.95 (s, 1H, C(5)-H,
imidazole), 5.28 (s, 2H, NCH2), 2.50 (s, 1H,
1
13
1
exchangeable with D O, NH, tetrazole);
C NMR
f
2
MeOH, 1:1); IR (KBr): 3385, 3100, 2968, 2800, 1616,
(250MHz, DMSO-d ): δ =49.07, 121.03, 125.54, 127.07,
6
À1
1
1
462, 1410cm
;
H NMR (250MHz, DMSO-d6):
127.46, 129.68, 131.07, 152.18, 160.14; MS (EI): m/z
+
δ=8.28 (s, 1H, C(2)-H, benzimidazole), 7.64–7.61 (m,
(%)=226 (17.3) [M ]; Anal. Calcd for C H N : C,
1
1 10 6
2
2
H, aryl), 7.22–7.13 (m, 2H, aryl), 5.55 (s, 2H, NCH ),
58.40; H, 4.46; N, 37.15. Found: C, 58.31; H, 4.58; N,
37.02.
2
3
1
.51 (s, 1H, exchangeable with D O, NH, tetrazole);
C
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Cu/Graphene/Clay Nanohybrid is a Highly Efficient Catalyst for Tetrazole Synthesis
1
-((1H-tetrazol-5-yl)methyl)pyrimidine-2,4(1H,3H)-dione
MeOH) afforded a brown foam; yield: 2.34 g (85%);
(
2g). Recrystallization (EtOAc) afforded a creamy solid;
R = 0.15 (EtOAc–MeOH, 1:1); IR (KBr): 3300, 2985,
f
À1
1
yield: 1.55g (80%); mp 285–290°C; R =0.09 (EtOAc–
1716, 1702, 1693, 1658, 1379 cm
;
H
NMR
f
MeOH, 1:1); IR (KBr): 3365, 3129, 2876, 1723, 1706,
(250 MHz, DMSO-d6): δ= 7.86 (s, 1H, C(8)-H,
À1
1
1
650, 1458cm
;
H NMR (250MHz, DMSO-d6):
theophylline), 4.55 (t, 2H, J = 5.7 Hz, NCH ), 3.41 (t,
2
δ= 11.37 (s, 1H, exchangeable with D O, NH, uracil),
2H, J = 5.7 Hz, NCH CH ), 3.27 (s, 3H, N(1)-CH ),
2
2
2
3
7
.67 (d, 1H, J = 7.5Hz, C(6)-H, uracil), 5.70 (d, 1H,
3.09 (s, 3H, N(3)-CH ), 2.54 (s, 1H, exchangeable
3
13
J =7.5 Hz, C(5)-H, uracil), 5.07 (s, 2H, NCH ), 4.07 (s,
with D O, NH, tetrazole);
C NMR (250 MHz,
2
1
2
3
1
H, exchangeable with D O, NH, tetrazole); C NMR
DMSO-d ): δ= 20.17, 31.08, 32.38, 34.54, 106.39,
2
6
(
1
250 MHz, DMSO-d ): δ= 47.32, 103.40, 142.15, 151.57,
56.46, 161.72; MS (EI): m/z (%) = 194 (10.8) [M ];
136.89, 145.91, 147.79, 154.58, 159.86; MS (EI): m/z
6
+
(%) = 276 (20.7) [M+]; Anal. Calcd for C H N O :
10 12 8 2
Anal. Calcd for C H N O : C, 37.12; H, 3.11; N, 43.29.
Found: C, 37.24; H, 3.26; N, 43.24.
C, 43.48; H, 4.38; N, 40.56. Found: C, 43.59; H,
4.27; N, 40.61.
6
6 6 2
1
-((1H-tetrazol-5-yl)methyl)-2-methyl-1H-benzo [d] imidazole
2h). Recrystallization (EtOAc) afforded a creamy solid;
yield: 1.71 g (80%); mp >300°C (dec.); R = 0.25
2-(2-(1H-tetrazol-5-yl)ethyl)isoindoline-1,3-dione (2l). Re-
crystallization (EtOAc) afforded a creamy solid; yield:
(
2.11 g (87%); mp >300°C (dec.); R = 0.70 (EtOAc–
f
f
(
1
EtOAc–MeOH, 1:1); IR (KBr): 3384, 3100, 2982, 1619,
MeOH, 1:1); IR (KBr): 3374, 3063, 2950, 1772, 1620,
À1
1
À1
1
580, 1480cm
;
H NMR (250MHz, DMSO-d6):
1510, 1458cm
;
H NMR (250MHz, DMSO-d6):
δ= 7.57–7.46 (m, 2H, aryl), 7.16–7.08 (m, 2H, aryl), 5.46
s, 2H, NCH ), 4.55 (s, 1H, exchangeable with D2O, NH,
tetrazole), 2.67 (s, 3H, CH3); C NMR (250MHz,
δ =7.28–7.09 (m, 4H, aryl), 4.34 (t, 2H, J =7.2 Hz,
(
NCH ), 3.46 (s, 1H, exchangeable with D O, NH,
2
2
2
1
3
13
tetrazole), 3.08 (t, 2H, J= 7.2 Hz, NCH CH );
C
2
2
DMSO-d ): δ= 17.90, 49.18, 115.53, 116.64, 121.56,
NMR (250 MHz, DMSO-d ): δ= 27.64, 42.69, 126.35,
6
6
1
23.05, 134.72, 140.35, 151.27, 158.41; MS (EI): m/z
131.64, 134.28, 159.48, 167.02; MS (EI): m/z (%)
+
+
(%) = 214 (11.4) [M ]; Anal. Calcd for C H N : C,
= 243 (13.9) [M ]; Anal. Calcd for C H N O : C,
1
0
10
6
11 9 5 2
5
3
6.07; H, 4.71; N, 39.23. Found: C, 56.19; H, 4.62; N,
9.35.
54.32; H, 3.73; N, 28.79. Found: C, 54.43; H, 3.82;
N, 28.86.
9
-((1H-tetrazol-5-yl)methyl)-9H-purin-6-amine (2i). Re-
crystallization (EtOAc) afforded a creamy solid; yield:
.71 g (79%); mp >300°C (dec.); R = 0.25 (EtOAc–
1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzo[d]imidazole (2m). Re-
crystallization (EtOAc) afforded a brown solid; yield: 1.79g
1
(84%); mp 300–304°C (dec.); R =0.70 (EtOAc–MeOH,
f
f
MeOH, 1:1); IR (KBr): 3328, 3100, 2853, 1676, 1520,
1:1); IR (KBr): 3326, 3100, 2926, 1653, 1501,
À1
1
À1
1
1
1
7
471 cm ; H NMR (250 MHz, DMSO-d ): δ= 8.12 (s,
H, C(8)-H, adenine), 8.05 (s, 1H, C(2)-H, adenine),
1470cm ; H NMR (250MHz, DMSO-d ): δ =8.10 (s,
6
6
1H, C(2)-H, benzimidazole), 7.62–7.55 (m, 2H, aryl),
7.24–7.14 (m, 2H, aryl), 4.55 (t, 2H, J=6.5Hz, NCH2),
.17 (s, 2H, exchangeable with D O, NH ), 5.42 (s, 2H,
2
2
NCH ), 4.80 (s, 1H, exchangeable with D O, NH,
3.17 (t, 2H,
exchangeable with D O, NH, tetrazole);
J =6.5Hz, NCH CH ), 2.51(s, 1H,
2 2
2
2
1
3
13
tetrazole); C NMR (250 MHz, DMSO-d ): δ = 54.31,
C NMR
6
2
1
18.43, 139.90, 147.78, 151.57, 155.69, 162.84; MS
(250MHz, DMSO-d ): δ=31.15, 60.59, 116.19, 117.33,
6
+
(
EI): m/z (%) = 217 (9.5) [M ]; Anal. Calcd for C H N :
124.12, 125.22, 134.64, 138.76, 149.31, 161.72; MS (EI):
7
7
9
+
C, 38.71; H, 3.25; N, 58.04. Found: C, 38.63; H, 3.18;
N, 58.12.
m/z (%)=214 (12.7) [M ]; Anal. Calcd for C H N : C,
1
0 10 6
55.94; H, 4.63; N, 39.14. Found: C, 55.83; H, 4.75; N,
39.28.
5
-(2-(2-phenyl-1H-imidazol-1-yl)ethyl)-1H-tetrazole (2j). Re-
crystallization (EtOAc) afforded a creamy solid; yield:
.92g (80%); mp 250–255°C (dec.); R =0.38 (EtOAc–
5-(2-(2-methyl-4-nitro-1H-imidazol-1-yl)ethyl)-1H-tetrazole
1
(2n).
Column chromatography (silica gel, EtOAc–
f
MeOH, 1:1); IR (KBr): 3300, 3050, 2960, 1650,
MeOH, 1:1) afforded a creamy solid; yield: 1.74 g
À1
1
1
485cm
;
H NMR (250MHz, DMSO-d ): δ =7.58–
(78%); mp 210–215°C; R = 0.23 (EtOAc–MeOH, 1:1);
6
f
7
.44 (m, 5H, aryl), 7.32 (s, 1H, C(4)-H), 6.95 (s, 1H, C
IR (KBr): 3358, 3100, 2965, 1653, 1525, 1460,
À1
1
(5)-H), 4.29 (t, 2H, J=7.5Hz, NCH ), 3.07 (t, 2H,
1345 cm
;
H NMR (250 MHz, DMSO-d ): δ= 8.26
2
6
J=7.5Hz, NCH CH ), 1.98 (s, 1H, exchangeable with
D O, NH, tetrazole); C NMR (250MHz, DMSO-d6):
(s, 1H, C(5)-H, imidazole), 4.27 (t, 2H, J =7.2 Hz,
2
2
13
2
NCH ), 3.61 (s, 1H, exchangeable with D O, NH,
2
2
δ=30.01, 54.59, 120.83, 125.87, 126.30, 127.05, 127.27,
tetrazole), 3.12 (t, 2H, J = 7.2 Hz, NCH CH ), 2.21 (s,
2 2
13
1
30.29, 149.77, 155.14; MS (EI): m/z (%)=240 (15.8)
3H, CH3); C NMR (250MHz, DMSO-d ): δ =15.99,
6
+
[
M ]; Anal. Calcd for C H N : C, 59.99; H, 5.03; N,
27.43, 52.03, 121.49, 148.55, 153.83, 163.97; MS
12 12 6
+
3
4.98. Found: C, 60.07; H, 5.16; N, 34.87.
(EI): m/z (%) = 223 (10.6) [M ]; Anal. Calcd for
7
-(2-(1H-tetrazol-5-yl)ethyl)-1,3-dimethyl-1H-purine-2,6(3H,
C H N O : C, 48.86; H, 5.01; N, 31.66. Found: C,
9
11 5 2
7
H)-dione (2k).
Column chromate-graphy (silica gel,
48.94; H, 5.13; N, 31.59.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. N. Soltani Rad, S. Behrouz, V. Sadeghi Dehchenari, and S. J. Hoseini
Vol 000
1
-(2-(1H-tetrazol-5-yl)ethyl)-4-phenylpiperazine (2o).
Co-
[15] Rajasekaran, A.; Sankar, N.; Murugesh, A.; Kalasalingam
Rajagopal, A. Arch Pharm Res 2006, 29, 535.
lumn chromatography (silica gel, EtOAc–n-hexane, 1:1)
afforded a bright brown solid; yield: 2.35g (91%); mp
300°C (dec.); R =0.23 (EtOAc–MeOH, 1:1); IR (KBr):
f
340, 3100, 2992, 1659, 1653, 1476cm
250MHz, DMSO-d ): δ =7.26–7.20 (m, 2H, aryl), 6.91–
.81 (m, 3H, aryl), 4.96 (s, 1H, exchangeable with D O,
2
NH, tetrazole), 3.83 (t, 2H, J=6.5Hz, CH ), 3.09 (t, 2H,
J=7.2Hz, CH ), 2.72–2.65 (m, 8H, 4 CH ); C NMR
250MHz, DMSO-d ): δ=28.22, 49.15, 52.27, 56.11,
14.32, 119.58, 130.51, 150.05, 160.23; MS (EI): m/z
%)=258 (19.7) [M ]; Anal. Calcd for C H N : C,
0.44; H, 7.02; N, 32.53. Found: C, 60.31; H, 7.08; N,
2.61.
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>
3
(
6
À1
1
[
17] Adamec, J.; Waisser, K.; Kunes, J.; Kaustova, J. Arch Pharm
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Chem Abstr 1993, 119, 226417.
20] (a) Ellis, G. P.; Shaw, D. J Med Chem 1972, 15, 865;
; H NMR
2
6
[
[
2
13
2
2
[
(
1
(
6
3
6
(b) Nohara, A.; Kuriki, H.; Saijo, T.; Sugihara, H.; Kanno, M.; Sanno,
Y. J Med Chem 1977, 20, 141.
[21] Vieira, E.; Huwyler, S.; Jolidon, S.; Knoflach, F.; Mutel, V.;
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+
13 18 6
[22] Gagnon, A.; Landry, S.; Coulombe, R.; Jakalian, A.; Guse, I.;
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Med Chem Lett 2009, 19, 1199.
[23] (a) Demko, Z. P.; Sharpless, K. B. Org Lett 2001, 3, 4091;
(
(
b) Demko, Z. P.; Sharpless, K. B. J Org Chem 2001, 66, 7945;
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Acknowledgment. The authors wish to thank Shiraz University
of Technology research council for partial support of this work.
2110; (d) Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B. J
Am Chem Soc 2003, 125, 9983.
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