Iron salts in the catalyzed synthesis of 5-substituted 1H-tetrazoles

Article abstract of DOI:10.1002/chem.200900169

A study was conducted to investigate the presence of iron salts in the catalyzed synthesis of 5-substituted 1H-tetrazoles. Para-trifluorotoluonitrile and trimethylsilyl azide were selected as model substrates for the initial metal source screening and the optimization of the reaction conditions. It was observed that the catalysis proceeded successfully producing tetrazole in 91% yield. A screening of various iron salts revealed that both the oxidation state of the iron and the counterion had a minor effect on the catalysis. Iron sources with different purity grades obtained from various providers were applied to investigate that the catalysis was not resulting from trace impurities in the metal salt. It was also observed that the catalysis proceeded successfully for a wide variety of aryl nitriles, providing tetrazoles in high yields. The best catalysis results were achieved with compounds that contained electron-withdrawing groups.

Full text of DOI:10.1002/chem.200900169

COMMUNICATION
DOI: 10.1002/chem.200900169
Iron Salts in the Catalyzed Synthesis of 5-Substituted 1H-Tetrazoles
Julien Bonnamour and Carsten Bolm*[a]
Tetrazoles are important heterocycles for explosives, pho-
tographic agents, and pharmaceuticals.[1] In the latter appli-
cation, they can serve as metabolically stable surrogates of
carboxylic acid groups.[2] Reactions between nitriles and
azides lead to 5-substituted 1H-tetrazoles, and many syn-
thetic approaches towards them have been developed.[3] For
example, Sharpless and co-workers demonstrated that 1H-
tetrazoles could be accessed through the addition of sodium
azide to nitriles in the presence of 0.5 to 1.0 equivalents of
ZnII salts.[4] Later, Pizzo and co-workers showed that the
metal salt could be replaced by tetrabutylammonium fluo-
ride (TBAF; 0.5 equiv).[5] More recently, Yamamoto and co-
workers catalyzed cycloadditions between nitriles and trime-
thylsilyl azide (TMS-N3) with 2.5 mol% of Cu2O, by per-
forming the reaction in a 9:1 mixture of DMF and MeOH at
808C.[6] Copper proved to be a very efficient metal for this
transformation. A one-pot multicomponent reaction was
achieved by Kundu and co-workers, who applied a copper/
iron combination as catalyst in water for the formation of
triazoles.[7] In this case, iron was suggested to serve as modu-
lator for the oxidation state of copper. All of these ap-
proaches reveal that the catalytic formation of tetrazoles is
still challenging and that the area demands to be developed
further.
nitrile (1a) and trimethylsilyl azide (2) were selected as
model substrates. Guided by Yamamotoꢀs findings the reac-
tion was first tried under his conditions using iron(II) ace-
tate instead of copper(I) oxide (Table 1, entry 3). To our de-
light, the catalysis [with 10 mol% of FeACTHNUTRGENUG(N OAc)2] proceeded
very well, affording tetrazole 3a in 91% yield. In contrast to
our previously reported reactions involving iron salts,[9] the
addition of a ligand was unnecessary. Neither raising the
temperature to 90 or 1008C nor lowering it to 70 or 608C
had any beneficial effect on the formation of 3a (Table 1,
entries 1, 2 and 3, 4, respectively). Control reactions per-
Table 1. Optimization of the catalyzed formation of tetrazole 3a.[a]
Entry
Fe source[b]
Solvent
Temp. [8C]
Yield of
3a [%][c]
1
2
3
4
5
6
7
8
Fe
Fe
Fe
Fe
Fe
N
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF/MeOH (9/1)
DMF
H2O
DME
dioxane
toluene
THF
THF/water (9/1)
100
90
80
70
60
80
80
80
80
80
80
80
80
80
80
80
80
80
80
88 (47)
89 (42)
91 (37)
59 (15)
35 (5)
76
72
80
87
86
87
87
56
0
[d]
Iron salts proved useful for several catalyzed reactions in-
cluding cross-couplings, oxidations, and reductions.[8] Since
iron is cheap, non-toxic, and environmentally friendly, its ap-
plication has attracted much attention. Considering the rich
activation mechanisms of iron salts we hypothesized that
they could also be useful in click-type cycloadditions. The
realization of this idea is demonstrated here.
FeCl3
FeCl3.6H2O[e]
[f]
Fe
FeBr2
[g]
9
[f]
10
11
12
13
14
15
16
17
18
19
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
[f]
[h]
For the initial metal source screening and the subsequent
optimization of the reaction conditions para-trifluorotoluo-
0
traces
0
0
[a] J. Bonnamour, Prof. Dr. C. Bolm
Institute for Organic Chemistry
RWTH Aachen University
0
[a] Reaction conditions: 1a (1.0 equiv), 2 (1.5 equiv), [Fe] (0.1 equiv), sol-
vent (1 mLmmolÀ1 of 1a), 24 h. [b] Fe
(OAc)2 (95%; Acros). [c] In paren-
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-8092-391
E-mail: Carsten.Bolm@oc.rwth-aachen.de
AHCTUNGTRENNUNG
theses, results from reactions performed in the absence of iron. [d] FeCl3
(98%; Merck) [e] FeCl3.6H2O (98%; Grꢁssing GmbH). [f] Iron source
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900169.
prepared according the literature. [g] FeBr2 (98%; Aldrich). [h] Fe
(99.995%; Aldrich).
ACHTUNGTRENNUNG(OAc)2
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 2. Fe-catalyzed synthesis of 5-substituted 1H-tetrazoles.[a]
formed in the absence of the metal salt revealed that in all
cases a substantial amount of product was formed in an un-
catalyzed manner (Table 1, entries 1–5; data in parentheses).
Commonly, however, the yields were at least double when
the iron catalyst was applied.
A screening of various iron salts [in DMF/MeOH (9/1) at
808C] revealed that both the oxidation state of the iron as
well as the counterion have only a minor effect on the catal-
ysis. In all cases the yields of 3a were in the 70–80% range
(Table 1, entries 6–11). Solvents other than the DMF/MeOH
mixture led to unsatisfying results (Table 1, entries 13–19).
To exclude that the observed catalysis was not resulting
from trace impurities in the metal salt, iron sources with dif-
ferent purity grades obtained from various commercial pro-
viders were applied. In this context the experiment with Fe-
Entry
1
Product
Yield [%][b]
91 (87)
3a
3b
3c
3d
3e
2
3
4
5
56 (22)
68 (53)
37 (11)
96 (86)
ACHTUNGTRENNUNG(OAc)2 having a purity of 99.995% (Aldrich) proved most
instructive, since it gave tetrazole 3a in 87% yield (Table 1,
entry 12). Atom absorption spectroscopy confirmed that nei-
ther that iron salt sample nor the subsequently applied Fe-
ACHTUNGTRENNUNG(OAc)2 with a purity of 95% (Acros) contained copper
(which is a common metal for catalyzed click reactions).
Next, the substrate scope was evaluated. As the entries in
Table 2 reveal, the catalysis proceeded well for a wide varie-
ty of aryl nitriles, providing the corresponding tetrazoles in
high yields. Both the type of substituent and the substitution
pattern had a major effect on the yield. The best results
were achieved with compounds bearing electron-withdraw-
ing groups. For example, 4-nitrobenzonitrile and 3,5-dinitro-
benzonitrile gave the corresponding tetrazoles 3e and 3l in
96 and >99% yield, respectively (Table 2, entries 5 and 12).
Having the nitro group in the ortho-position hampered the
tetrazole formation, and 3j was only obtained in 67% yield
(Table 2, entry 10). As to be expected from this trend, the
yield of ortho-bromo-substituted tetrazole 3g was very low
(15%; Table 2, entry 7). Benzonitriles with halo and other
electron-donating substituents in meta and para positions re-
acted well, providing the corresponding products in moder-
ately good yield. Non-aromatic nitriles did not react
6
7
8
9
3 f
3g
3h
3i
41 (7)
15 (11)
57 (42)
70 (64)
10
11
3j
67 (48)
58 (56)
3k
(Table 2, entries 15 and 16). As before, FeACTHNURTGNENG(U OAc)2 with puri-
ties of both 95 and 99.995% catalyzed the reaction well,
with the former being slightly more effective in each case.
Currently, we cannot say if this reactivity difference is due
to the presence of unknown contaminants or a matter of
metal salt consistencies leading to differences in catalyst ac-
cessibility.
In conclusion, a catalyzed tetrazole synthesis that utilizes
iron salts has been developed. Since the method avoids the
use of toxic and expensive metals, is appears attractive for
industrial and pharmaceutical applications.
12
3l
>99 (>99)
13
14
3m
3n
74 (43)
53 (49)
15
16
3o
3p
0
0
Experimental Section
General procedure: A sealable tube equipped with a magnetic stir bar
was charged with the aryl nitrile (1.0 equiv) and FeACTHNURGTNEUNG(OAc)2 (0.1 equiv). A
rubber septum was used to cover the aperture of the tube, an argon at-
mosphere was established, and trimethylsilyl azide (1.5 equiv) and a 9:1
À
[a] Reaction conditions: R CN (1.0 equiv),
2 (1.5 equiv), FeACHTUNGTRENNUNG(OAc)2
(0.1 equiv, 95%; Acros), solvent (1 mLmmolÀ1 of R CN), 808C, 24 h.
À
[b] In parentheses, results from experiments performed with Fe
99.995% purity (Aldrich).
ACHTUNGTRENNUNG(OAc)2 of
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5-Substituted 1H-Tetrazoles
COMMUNICATION
DMF–MeOH solution (1 mL) were added by using a syringe. Then the
rubber septum was replaced with a Teflon-coated screw cap, and the re-
action vessel was heated at 808C. After stirring at this temperature for
24 h, the mixture was cooled to room temperature and diluted with ethyl
acetate. The resulting solution was washed with 1n HCl, dried over anhy-
drous Na2SO4, and concentrated. An aqueous solution of NaOH (0.25n)
was added to the residue, and the mixture was stirred for 30 min at room
temperature. The resulting solution was washed with ethyl acetate, and
then 1n HCl was added until the pH value of the water layer became 1.
The aqueous layer was extracted with ethyl acetate three times, and the
combined organic layers were washed with 1n HCl. The organic layer
was dried over anhydrous Na2SO4 and concentrated. The identity and
purity of the product was confirmed by 1H and 13C NMR spectroscopic
analysis.
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We are grateful to the Fonds der Chemischen Industrie for the financial
support. We also thank Prof. Dr. R. Dronskowski and Mr. L. Stork (Insti-
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Keywords: azides · catalysis · cycloaddition reactions ·
heterocycles · iron · tetrazole
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Received: January 20, 2009
Published online: March 18, 2009
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