Efficient synthesis of 2,5-disubstituted tetrazoles via the Cu 2O-catalyzed aerobic oxidative direct cross-coupling of N-H free tetrazoles with boronic acids

Article abstract of DOI:10.1039/c2cc17894j

We present a new protocol that allows for the synthesis of 2,5-disubstituted tetrazoles via the direct coupling of N-H free tetrazoles and low toxic boronic acids in the presence of only a catalytic amount of Cu ₂O (5 mol%) as catalyst and 1 atm of environmentally benign O ₂ as oxidant, without the need for other additives. This method represents a simple, green, and atom-efficient synthesis of 2,5-disubstituted tetrazoles. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17894j

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COMMUNICATION
Efficient synthesis of 2,5-disubstituted tetrazoles via the Cu2O-catalyzed
aerobic oxidative direct cross-coupling of N–H free tetrazoles with
boronic acidsw
Yu Li,ab Lian-Xun Gaoa and Fu-She Han*ac
Received 18th December 2011, Accepted 12th January 2012
DOI: 10.1039/c2cc17894j
We present a new protocol that allows for the synthesis of
2,5-disubstituted tetrazoles via the direct coupling of N–H free
tetrazoles and low toxic boronic acids in the presence of only a
catalytic amount of Cu2O (5 mol%) as catalyst and 1 atm of
environmentally benign O2 as oxidant, without the need for
other additives. This method represents a simple, green, and
atom-efficient synthesis of 2,5-disubstituted tetrazoles.
terms of atom-efficiency and economy, and environmental
impact.
ð1Þ
Among the various heterocycles, the 1,5- and 2,5-disubstituted
tetrazoles and their derivatives represent an important class of
N-containing heterocycles. They tolerate a wide range of chemical
environments1 such as strong basic/acidic, and oxidizing/reducing
conditions. They exhibit not only interesting biological properties
but also good resistance against biological degradation.2 Therefore,
tetrazole has attracted great interests in materials science,3 and
pharmaceutical4 and biological applications.5 So far, a number of
strategies for synthesizing 1,5-disubstituted tetrazoles have been
reported based on the [2 + 3] cycloaddition strategy of azides
and nitrile species,6,7 Pd-catalyzed Suzuki–Miyaura coupling,8
and Baylis–Hillman reaction.4b
ð2Þ
On the basis of our short experience in the study of
Cu-catalyzed C–N bond formation of boronic acids and TMSN3,12
herein, we disclose a Cu2O-catalyzed aerobic oxidative protocol
that allows for the direct cross-coupling of N–H free tetrazoles
with low toxic boronic acids (eqn (2)), providing 2,5-disub-
stituted tetrazoles with high efficiency and structural diversity.
Notably, the reaction proceeds efficiently only in the presence
of environmentally benign O2 at 1 atm without the need for
other additives.
In stark contrast, the synthesis of 2,5-disubstituted tetrazoles is
considerably more challenging. The Kakehi tetrazole synthesis9
using aldehydes required several synthetic steps. Alternatively, the
Pd and Cu-catalyzed N-2-arylation of 5-substituted tetrazoles has
been investigated.10,11 However, extensive applications of these
protocols are restricted by the use of N-metalated tetrazoles
(metal = SnR3 and Na) and diaryliodonium salts as coupling
partners (eqn (1)), resulting in not only troublesome preparation
of starting materials, but also the generation of a large amount
of toxic wastes such as organotin and aryliodide.11 Moreover,
a stoichiometric amount of metal catalyst was required in
some cases. Thus, there is great interest to establish a new
procedure which can directly couple N–H free tetrazoles in
The screening of the optimal reaction conditions was carried
out employing the coupling of 5-phenyl tetrazole 1a and
4-methylphenyl boronic acid 2a as a reference reaction (Table 1).
After an extensive survey of various reaction parameters
including Cu salts, oxidants, bases, and solvents,13 we found that
a combination of Cu2O as catalyst, O2 as oxidant, pyridine as
base, and DMF as solvent afforded the N-2-arylated tetrazole 3a
in a pretty good yield under heating at 120 1C for 24 h (entry 1).
Further optimization of these preliminarily obtained conditions
showed that the DMSO solvent is far more superior to DMF,
affording 2,5-disubstituted 3a in 94% yield even with a
catalytic amount of Cu2O as low as 5 mol% under a lower
temperature of 100 1C (entry 2). The excellent regioselectivity
for 2,5-disubstitution was unambiguously demonstrated by
the X-ray single crystal analysis of 3a.14 The 1,5-disubstituted
regioisomeric tetrazole was not detected. Equally importantly,
we eventually found that removal of pyridine base does not
show detrimental effect on the yield of the product (entry 4).
Such a far more simplified and greener system reinforces greatly
the value of the method to compare with the conventional
procedures.9,11 Finally, the crucial role of O2 as ancillary oxidant
a Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, 5625 Renmin Street, Changchun 130022, Jilin, China.
E-mail: fshan@ciac.jl.cn; Tel: +86-431-8526-2936
b Graduate School of Chinese Academy of Sciences, Beijing 100864,
China
c State Key Laboratory of Fine Chemicals, Dalian 116024, China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, XPS spectra, and 1H- and
13C-NMR spectra. CCDC 848060 (3a). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc17894j
c
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Chem. Commun., 2012, 48, 2719–2721 2719

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Table 1 Optimization of the reaction conditionsa
Table 2 N-2-Arylation of 5-phenyl tetrazole with various boronic acidsa
Entry
Cat. (mol%)
Base/Oxid.
T (1C)/t (h)
Yieldb
1
2
3
4
5
6
7
8
9
Cu2O (100)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (50)
—
Pyridine/O2
Pyridine/O2
Pyridine/O2
—/O2
—/N2
—/N2
—/O2
—/O2
—/O2
120/24
100/5.5
80/24
77%
94%
n.c.c
95%
12%d
35%
n.r.e
100/4
100/48
100/24
100/28
100/24
100/120
CuO (5)
CuO (10)
25%
87%
a
Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 eq.), boronic acid 2a
(1.0 mmol, 2.0 eq.), Pyridine (1.5 mmol, 3.0 eq.), O2 (1 atm) in DMSO
(4 mL). b Isolated yield. c Reaction was not complete. d Contaminated by
some unknown impurities. e No reaction.
a
Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 eq.), boronic acid 2
(1.0 mmol, 2.0 eq.), O2 (1 atm), and Cu2O (5 mol%) in DMSO (4 mL)
b
at 100 1C; isolated yield. m-Aminophenylboronic acid monohydrate was
used. The yield was determined by H-NMR due to the contamination
of a small amount of inseparable homo-coupling product from boronic
c
1
and Cu2O as catalyst in this transformation was clearly
exemplified as seen from the inefficient coupling by carrying
out the reaction under a N2 atmosphere (entries 5 and 6), or in
the absence of Cu2O (entry 7), or by using CuO as catalyst
instead of Cu2O (entries 8 and 9).
d
e
acid. Heated at 120 1C. The C-2 heterocyclic boronic acids were
decomposed into benzofuran and thianaphthene as monitored by TLC.
intact in this transformation. Furthermore, owing to the simplified
reaction conditions, e.g., the absence of base, acid, and other
additives, a range of labile groups such as ketone, aldehyde, ester,
and nitro are also tolerated.
The optimized conditions display good compatibility to a
broad array of boronic acids. As shown in Table 2, boronic acids
substituted with simple Me group afforded the N-2-arylated
products 3a–3c in excellent yields. More to the point, high
yields for 3b and 3c indicate that the sterically congested
substrates are tolerated. In addition, substrates decorated by
strong electron-rich groups such as OMe and OH also underwent
smooth coupling to afford 3d and 3e. The somewhat diminished
yield for NH2-substituted 3f is due most possibly to its high polarity,
resulting in difficulties in extraction and column purification,
since the reaction proceeded well as detected by TLC monitoring.
Furthermore, an array of boronic acids whose structures were
modified by various electron-deficient groups such as chloro,
ketone, aldehyde, ester, cyano, and nitro, could also be coupled
efficiently to afford the corresponding 2,5-disubstituted tetrazoles
3g–3l in good to excellent yields. Finally, the coupling efficacy of
heterocyclic boronic acids was examined. Good yields could be
obtained for boronic acids whose boron atom is nonadjacent to
the heteroatoms as seen from the coupled products of 3m and 3n.
However, 2-heterocyclic boronic acids (i.e., boron atom is
adjacent to heteroatom) were inefficient substrates due to the rapid
deboronation under thermal conditions.15 Indeed, the instability of
2-heterocyclic boronic acids makes them a considerable challenge
in other transition-metal-catalyzed cross-coupling.15
Next, we examined the coupling efficiency of this protocol
by varying the structures of tetrazoles (Table 3). The reactions
of 5-(2-halophenyl)tetrazoles with boronic acids were first
inspected because their coupled products are anticipated to be
interesting pharmaceuticals,4 or may serve as key intermediates for
the diverse construction of new drug derivatives such as the family
of marketed or patented sartan-type antihypertensive drugs.17 This
type of drugs has shared not only the largest market but also the
fastest growing rate among the current antihypertensive
drugs. However, the pharmacological properties of the N-2-
functionalized sartan derivatives have been less investigated
due possibly to the lack of effective methods for introducing
functional groups at the N-2 position of a tetrazole moiety.
To our delight, we found that under the optimized conditions
developed herein, both the Cl- and Br-substituted 5-phenyl-
tetrazoles underwent smooth coupling with a range of boronic
acids having different substituents as exemplified by neutral
Me, electron-rich OMe, and electron-deficient ketone groups,
giving the desired N-2-arylated products 4a–c and 5a–c in
high yields (Table 3). In addition, tetrazoles substituted either
by a strong electron-withdrawing NO2 or by a strong electron-
donating OMe group in the phenyl ring periphery are also
competent substrates, affording the corresponding coupled
products 6a–c and 7a–c in good yields. Moreover, the 5-alkyl
substituted tetrazole is also a viable substrate, delivering
the coupled product 8a in 72% yield. Finally, the low yield
for 9a implies that the coupling of 5-heteroaryl tetrazole is
reluctant.
Here, it should be mentioned that, in addition to the good
structural compatibility of the electronic and steric nature of
the substrates, a more notable feature of this protocol should
be the excellent chemoselectivity. Typically, some reactive
functionalities on boronic acids such as OH, NH2, Cl, and
CN, which may serve as good nucleophiles or leaving groups
in the Cu-catalyzed couplings with boronic acids,16 remain
c
2720 Chem. Commun., 2012, 48, 2719–2721
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Table 3 N-2-Arylation of various tetrazoles with boronic acidsa
applications in a broad range of areas related to N-heterocycles.
A detailed mechanistic study as well as the precise design and
synthesis of a compound library containing tetrazole motifs
aimed at the development of new drug is currently underway.
Financial support from Hundred Talent Program and
Academy-Locality Cooperation Program of CAS, and State
Key Laboratory of Fine Chemicals (KF1008) is acknowledged.
Notes and references
1 R. N. Butler, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky, C. W. Rees and E. F. V. Scriven, Pergammon, Oxford, UK,
1996, vol. 4.
2 For examples: (a) A. D. Bond, A. Fleming, F. Kelleher, J. McGinley
and V. Prajapati, Tetrahedron, 2006, 62, 9577; (b) R. J. Herr, Bioorg.
Med. Chem., 2002, 10, 3379.
a
Reaction conditions: tetrazole 1 (0.5 mmol, 1.0 eq.), boronic acid 2
(1.0 mmol, 2.0 eq.), O2 (1 atm), and Cu2O (5 mol%) in DMSO (4 mL)
3 M. A. Hiskey, D. Chavez, D. L. Naud, S. F. Son, H. L. Berghout
and C. A. Bolme, Proc. Int. Pyrotech. Semin., 2000, 27, 3.
4 For some recent examples, see: (a) A. S. Gundugola, K. L. Chandra,
E. M. Perchellet, A. M. Waters, J.-P. H. Perchellet and S. Rayat,
Bioorg. Med. Chem. Lett., 2010, 20, 3920; and references cited
therein; (b) P. Srihari, P. Dutta, R. S. Rao, J. S. Yadav,
S. Chandrasekhar, P. Thombare, J. Mohapatra, A. Chatterjee and
M. R. Jain, Bioorg. Med. Chem. Lett., 2009, 19, 5569; and references
cited therein.
5 (a) Y. Wang, W. Song, W. J. Hu and Q. Lin, Angew. Chem., Int.
Ed., 2009, 48, 5330; (b) W. Song, Y. Wang, J. Qu, M. M. Madden
and Q. Lin, Angew. Chem., Int. Ed., 2008, 47, 2832; (c) W. Song,
Y. Wang, J. Qu and Q. Lin, J. Am. Chem. Soc., 2008, 130, 9654;
(d) Y. Wang, W. J. Hu, W. Song, R. K. V. Lim and Q. Lin, Org.
Lett., 2008, 10, 3725.
6 F. Chen, C. Qin, Y. Cui and N. Jiao, Angew. Chem., Int. Ed., 2011,
50, 11487, and extensive references therein.
7 (a) Z. P. Demko and K. B. Sharpless, Angew. Chem., Int. Ed., 2002,
41, 2110; (b) Z. P. Demko and K. B. Sharpless, Angew. Chem., Int.
Ed., 2002, 41, 2113.
8 (a) L. E. Kaim, L. Grimaud and P. Patil, Org. Lett., 2011, 13, 1261;
(b) Q. Tang and R. Gianatassio, Tetrahedron Lett., 2010, 51, 3473.
9 (a) Y. Wang and Q. Lin, Org. Lett., 2009, 11, 3570; (b) S. Ito,
Y. Tanaka, A. Kakehi and K. Kondo, Bull. Chem. Soc. Jpn., 1976,
49, 1920.
10 Indeed, the Cu(OAc)2-catalyzed coupling of N–H free 5-phenyl
tetrazole and boronic acid has been investigated. However, only a
poor yield of lower than 26% was obtained in the presence of 1.5
equivalents of Cu(OAc)2, various bases, and bubbling of O2, see:
P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941.
11 (a) I. P. Beletskaya, D. V. Davydov and M. S. Gorovoy, Tetrahedron
Lett., 2002, 43, 6221; (b) D. V. Davydov, I. P. Beletskaya, B. B. Semenov
and Y. I. Smushkevich, Tetrahedron Lett., 2002, 43, 6217.
12 Y. Li, L.-X. Gao and F.-S. Han, Chem.–Eur. J., 2010, 16, 7969.
13 Cu salts: Cu(OAc)2, Cu(acac)2, Cu(OTf)2, CuCl2, CuI, CuBr,
CuCl, Cu2O, CuO; oxidants: PIFA, PIDA, m-CPBA, BPO, O2;
base: pyridine, Et3N, DBU, DABCO, and some inorganic bases;
solvent: (CH2)2Cl2, THF, MeOH, DMF, DMAc, DMSO.
14 CCDC 848060 contains the supplementary crystallographic data of
compound 3a.
at 100 1C; isolated yield.
Concerning the reaction mechanism of this transformation,
our results by using CuO (entries 8 and 9 in Table 1) as well as
10
a previous report by using Cu(OAc)2 as catalysts clearly
showed that these CuII catalysts are less effective in driving the
direct cross-coupling of N–H free tetrazole and boronic acids.
On the other hand, we have also demonstrated that CuI itself is
also an inactive metal center since only poor yield of the
product was obtained when the reaction was carried out under
a N2 atmosphere even in the presence of 50 mol% of Cu2O
(100 mol% Cu center) (entry 6 in Table 1). X-Ray photoelectron
spectroscopic (XPS) analysis of the recovered catalyst showed that
the CuI species remained unchanged with only negligible CuII
species observed under the N2 atmospheric conditions.18 In
contrast, both CuI and CuII existed in the recovered catalyst
when the reaction was performed under an O2 atmosphere,
and the coupled product 3a was obtained in 95% yield
(Table 1, entry 4). While an excellent yield was obtained in
this case, it does not mean the coupling reaction proceeds via a
CuI/CuII or Cu0/CuII cycle because neither CuI nor CuII is the
active metal center in this coupling reaction as demonstrated
by the control experiments.
Thus, a CuIII species may be serving as the active metal
center to drive the catalytic cycle. Indeed, such species has also
been proposed in some other Cu-catalyzed C–N or C–O bond
formations.16,19 However, there are no sufficient data at the
present stage to support that the CuIII intermediate is really
formed in the catalytic cycle although extensive experiments
were carried out. Therefore, a clear mechanistic elucidation for this
effective transformation deserves further detailed investigation by
designing some special experiments.
15 T. Kinzel, Y. Zhang and S. L. Buchwald, J. Am. Chem. Soc., 2010,
132, 14073; and references therein.
In summary, we have achieved successfully the direct coupling
of N–H free tetrazoles with low toxic boronic acids for the
synthesis of 2,5-disubstituted tetrazoles via the Cu2O-catalyzed
aerobic oxidative reaction. Moreover, only 5 mol% of cheap
Cu2O and environmentally benign O2 at 1 atm were required for
effective coupling. The by-products generated are low toxic
boronic acids. In addition, the protocol also exhibits excellent
functional group compatibility. Consequently, this protocol
represents very few examples for facile, universally applicable,
atom-efficient, and clean synthesis of 2,5-disubstituted tetrazoles.
We believe that the method presented herein would find extensive
16 For an example, see: G. C. H. Chiang and T. Olsson, Org. Lett.,
2004, 6, 3079.
17 For some representative examples, see: (a) C. A. Bernhart, P. M.
Perreaut, B. P. Ferrari, Y. A. Muneaux, J.-L. A. Assens, J. Clement,
´
F. Haudricourt, C. F. Muneaux, J. E. Taillades, M.-A. Vignal,
J. Gougat, P. R. Guiraudou, C. A. Lacour, A. Roccon, C. F.
Cazaubon, J.-C. Breliere, G. L. Fur and D. Nisato, J. Med. Chem.,
1993, 36, 3371; (b) P. Buhlmayer, P. Furet, L. Criscione, M. de Gasparo,
¨
S. Whitebread, T. Schmidlin, R. Lattmann and J. Wood, Bioorg. Med.
Chem. Lett., 1994, 4, 29.
18 See ESIw for XPS analysis.
19 A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc., 2009,
131, 5044.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2719–2721 2721