Implanting nitrogen into hydrocarbon molecules through Ci-H and Ci-C bond cleavages: A direct approach to tetrazoles

Article abstract of DOI:10.1002/anie.201105505

From simple beginnings: A novel Cu-promoted direct incorporation of nitrogen into simple hydrocarbon molecules under mild and neutral reaction conditions is described. 1,5-Disubstituted tetrazoles are efficiently constructed by two C sp 3i-H and one Ci-C bond cleavages (see scheme; TMS=trimethylsilyl). This protocol provides a new and unique strategy to functionalize simple and readily available hydrocarbon molecules.

Full text of DOI:10.1002/anie.201105505

DOI: 10.1002/anie.201105505
Nitrogen Heterocycles
À
Implanting Nitrogen into Hydrocarbon Molecules through C H and
C C Bond Cleavages: A Direct Approach to Tetrazoles**
À
Feng Chen, Chong Qin, Yuxin Cui, and Ning Jiao*
The development of novel methods for the preparation of
tetrazoles is of long-standing interest and a challenge for
organic chemists because of the importance of these com-
pounds in chemistry and biology. In particular, 1,5-disubsti-
tuted tetrazoles are very useful compounds in medicinal
chemistry and important synthetic intermediates.[1,2] In the
past several decades, some general strategies for the synthesis
of 1,5-disubstituted tetrazoles from functionalized starting
materials have been developed (Scheme 1). These methods
include: a) the reactions of ketones[3] or oximes[4] with sodium
azide and hydrogen azides, b) the reactions of amides with
sodium azides in the presence of phosphorus(V) chloride or
triflic anhydride and[5] the reactions of amidrazones with
dinitrogen tetroxide or nitrous acid,[6] c) the reactions of
imidoyl chlorides[7a] or imidoylbenzotriazoles[7b] with sodium
azides and, d) the reactions of nitriles with alkyl azides.[8]
These developed methods significantly improved the syn-
thesis of tetrazoles, but these approaches have some limita-
tions, such as the use of protic acid catalysts, tedious workups,
and the use of functionalized starting materials, hence
encouraging scientists to discover new strategies.
The direct transformation of hydrocarbon molecules by
À
À
transition-metal-catalyzed selective C H and C C bond
activation (cleavage) has attracted considerable attention,
owing not only to its fundamental scientific appeal but also to
its potential utility in organic synthesis.[9,10] A direct approach
À
À
to tetrazoles through C H and C C bond cleavages of simple
hydrocarbon molecules is still an extremely attractive yet
challenging goal. Herein, we demonstrate a novel and
efficient Cu-promoted implanting of nitrogen into simple
hydrocarbon molecules to construct 1, 5-disubstituted tetra-
À
À
À
zoles through C H and C C bond cleavages, and C N bond
formation under mild and neutral reaction conditions (Sche-
me 1e).
Azide has been widely used as a useful aminating reagent
in organic synthesis.[11,12] The application of azides for the
direct synthesis of aryl nitriles[13] and alkenyl nitriles[13c–d]
À
through C H bond cleavage has been recently reported.
À
À
Recent achievements on the functionalization of C H and C
C bonds[9–10] encouraged us to try the direct synthesis of
Table 1: The direct transformation of (E)-1,3-diphenylprop-1-ene (1a)
into (E)-1-phenyl-5-styryl-1H-tetrazole (2a).[a]
Scheme 1. Strategies for the preparation of 1,5-disubstituted tetrazoles.
Bt=benzotriazole.
Entry Catalyst (mol%) TMSN3 (equiv) Oxidant (equiv) Yield [%][b]
[*] F. Chen, C. Qin, Dr. Y. Cui, Dr. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Road 38, Beijing 100191 (China)
E-mail: jiaoning@bjmu.edu.cn
1[c]
2[c]
3
4
5
6
7
8
9
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (15)
CuI (10)
CuI (5)
none
CuI (10)
CuI (10)
2.0
4.0
4.0
5.5
5.5
5.5
5.5
5.5
5.5
5.5
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (3.0)
DDQ (1.5)
27
63
73
80
80
88
80
76
24
52
Homepage: http://sklnbd.bjmu.edu.cn/nj
Dr. N. Jiao
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
[**] Financial support from Peking University, the National Science
Foundation of China (20872003), and the National Basic Research
Program of China (973 Program; grant no. 2009CB825300) is
greatly appreciated. We thank Hang Yin in this group for
reproducing the results of 2l and 2v.
10
[a] Reaction conditions: 1a (0.3 mmol), TMSN3, catalyst, oxidant,
molecular sieves (4 ꢀ; 30 mg), MeCN (2 mL), stirred at 808C under Ar.
[b] Yield of the isolated product. [c] The reaction was carried out in the
absence of molecular sieves (4 ꢀ). DDQ=2, 3-dichloro-5,6-dicyano-1,4-
benzoquinone, M.S.=molecular sieves, TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105505.
Angew. Chem. Int. Ed. 2011, 50, 11487 –11491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11487

Communications
Table 2: Direct conversion of 1,3-diarylprop-1-enes into tetrazoles.[a]
nitrogen-containing compounds by the functionali-
zation of simple hydrocarbon molecules using azide.
The preliminary investigation employed (E)-1,3-
diphenylprop-1-ene (1a) as the substrate. When the
reaction was performed in the presence of azidotri-
methylsilane (TMSN3) and 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) using CuI as the catalyst
at 808C in MeCN, (E)-1-phenyl-5-styryl-1H-tetra-
zole (2a) was obtained in 27% yield (Table 1,
entry 1). The structure of 2a was further confirmed
by single-crystal X-ray analysis (Figure S1 in the
Supporting Information). The high chemoselectivity
of this result indicates that the aryl groups have a
greater migratory aptitude to the nitrogen atom than
alkenyl groups in the rearrangement process. Taking
into consideration that at least 2.0 equivalents of
TMSN3 is required to realize this transformation, the
amount of TMSN3 was increased from 2 equivalents
to 4 equivalents. Under these reaction conditions, 2a
was obtained in 63% yield (Table 1, entry 2). A 73%
yield of 2a was achieved in the presence of molecular
sieves (4 ꢀ; Table 1, entry 3). Furthermore, the yield
rose to 88% using 10 mol% of CuI, as the catalyst, in
the presence of 5.5 equivalents of TMSN3 (Table 1,
entry 6). When the amount of CuI was reduced to
5% a lower yield was obtained (Table 1, entry 7).
Although the addition of copper salt did not
significantly improve the yield in this case (Table 1,
entry 8), it significantly affected the efficiencies in
other reactions (Table S1 in the Supporting Infor-
mation). The reaction also could be conducted at
room temperature and under air to give the products
in moderate yields (Table S1 in the Supporting
Information). Importantly, when the amount of
DDQ was increased 2a was produced in lower
yield because of decomposition of the substrate; a
decrease in the amount of DDQ also gave a lower
yield, owing to the lack of oxidant in this catalytic
system (Table 1, entries 9–10).
Entry
Substrate 1
Product 2
Yield
[%][b]
R
1
2
3
4
5
6
7
H
1a
2a 88
OMe 1b
Cl
F
Me
OCF3 1 f
tBu 1g
2b 81
2c 80
2d 77
2e 90
2 f 61
2g 76
1c
1d
1e
8
9
10
11
OMe 1h
2h 90
2i 83
2j 27
2k 49
Me
CF3
Br
1i
1j
1k
12
13
Me
Br
1l
1m
2l 90
2m 30
14
15
–
–
1n
1o
2n 58
2o 76
16
17
18
19
OMe 1p
Me
F
2p:2p’ (13:1)
2q:2q’ (6.2:1)
2r:2r’ (1:1.0)
2s:2s’ (1.1:3)
94
88
83
66
1q
1r
1s
Under the optimized reaction conditions, the
scope of this copper-facilitated tetrazole formation
was investigated (Table 2). Notably a variety of
substituted 1,3-diphenylprop-1-enes could easily be
converted into the corresponding tetrazoles in mod-
erate to excellent yields (up to 94%). Various
electron-donating (Me, OMe, OCF3, tBu; Table 2,
entries 5–9) and electron-withdrawing substituents
(F, Cl, Br, CF3; Table 2, entries 3, 4, 10 and 11) on the
aryl group were tolerated in this transformation.
Furthermore, the position of the substituents on the
aryl group (para-, meta-, and ortho-position) did not
affect the efficiency of the reaction (Table 2,
Cl
20
21
–
–
1t
2t:2t’ (1.2:1)
2u:2u’ (1:2.3)
80
62
1u
[a] Reaction conditions: 1a (0.3 mmol), TMSN3 (1.65 mmol), CuI (0.03 mmol), DDQ
(0.6 mmol), molecular sieves (4 ꢀ; 30 mg), MeCN (2 mL), stirred at 808C under Ar
atmosphere. [b] Yield of the isolated product.
entries 5, 9, and 12). It is noteworthy that halo-substituted
1,3-diarylprop-1-ene reacted well, thus leading to halo-
substituted products, which could be used for further trans-
formations (Table 2, entries 3, 11, 13, and 15). In addition, the
heteroaryl-substituted substrate (E)-2-(3-(thiophen-2-yl)al-
lyl)thiophene (1n) could be converted into the target product
2n in 58% yield (Table 2, entry 14). Regioisomers were
obtained when unsymmetric 1,3-diphenylprop-1-enes were
employed as the substrates under the standard reaction
conditions (Table 2, entries 16–21). The structures of the
isomers were determined by HMBC spectroscopy or single-
crystal X-ray analysis (see the Supporting Information). It is
noteworthy that the regioselectivity can be significantly
influenced by the electronic nature of the substituents
11488 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11487 –11491

(Table 2, entries 16–19). Substrates with electron-rich aryl
groups, such as 1-cinnamyl-4-methoxybenzene (1p), could be
highly regioselectively converted into the corresponding
tetrazole (94% yield, 13:1 ratio; Table 2, entry 16). In
addition, the sterics of the substrate also has a big influence
on the regioselectivity. For example, 2t and 2t’ were obtained
in the ratio of 1.2:1 (determined by HMBC spectroscopy, see
the Supporting Information) in the reaction of 1-cinnamyl-2-
methylbenzene (1t, 80%; Table 2, entry 20).
Notably, bisaryl methanes could also be successfully
converted into the corresponding 1,5-diaryl tetrazoles in
moderate yields under these reaction conditions (Table 3).
Moreover, the bisheteroaryl methane compound bis(1-Boc-
1H-indol-3-yl)methane (3d) was also tolerated in this trans-
formation giving the desired tetrazole 4d in 32% yield
(Table 3, entry 4).
Table 3: Direct Transformation of diarylmethane 3 into tetrazoles.[a]
Scheme 2. A proposed pathway for tetrazole formation.
No. Substrate 3
Product 4
Yield
[%][b]
then be oxidized to allyl azide cation D by the copper-assisted
DDQ oxidative system. Subsequent isomerization of D would
lead to intermediate E. Then the highly chemoselective aryl
migration from the carbon atom to the nitrogen atom could
occur to generate intermediate F.[14] Subsequent nucleophilic
addition and cyclization with another azide would lead to the
desired tetrazole product 2.[17] For unsymmetrical substrates,
the regioisomer 2’ could be generated by the same procedure
via the allyl azide C’ (Scheme 2).
R
1
2
3
OMe (3a)
OEt (3b)
NMe2 (3c)
4a 65
4b 57
4c 54
In summary, we have demonstrated a novel Cu-promoted
direct implanting of nitrogen into simple hydrocarbon
molecules. 1,5-Disubstituted tetrazoles were efficiently con-
4
– (3d)
4d 32
À
À
structed by two Csp3 H and one C C bond cleavages under
mild and neutral reaction conditions. This protocol not only
extends the application of azides in organic transformations,
but also offers an alternative method to prepare 1,5-disub-
stituted tetrazoles, which are ubiquitous structural units in a
number of biologically active compounds. This method
provides a new and unique strategy to functionalize simple
[a] Reaction conditions: 1a (0.3 mmol), TMSN3 (1.65 mmol), CuI
(0.03 mmol), DDQ (0.6 mmol), molecular sieves (4 ꢀ; 30 mg), MeCN
(2 mL), stirred at 808C under argon. [b] Yield of the isolated product.
Boc=tert-butyloxycarbonyl.
To probe the mechanism of this novel transformation,
control experiments were conducted under the optimized
reaction conditions. When chalcone (5) and N-phenylcinnam-
amide (6) were employed as the substrate, no desired product
2a was obtained and 60% of the starting material (5 and 6)
was recovered respectively [Eq. S1–2 in the Supporting
Information]. The results suggest that the traditional Schmidt
reaction[14] via a ketone intermediate is not involved in this
novel process.
On the basis of the above experimental observations, a
plausible mechanism for this transformation is proposed
(Scheme 2). Initially, substrates 1 undergo a copper-assisted
single-electron-transfer (SET) oxidation with DDQ[15] to
produce the corresponding allyl radical A, which could be
further oxidized to the allyl cation B. Subsequently, the
substitution reaction of allyl cation B would generate allyl
azides C and C’, which would exist as an equilibrating mixture
by [3,3] sigmatropic rearrangement.[16] The allyl azide C could
À
À
and readily available hydrocarbon molecules by C H and C
C bond cleavages. Further investigation of the scope and
synthetic application of these reactions are ongoing in our
group.
Received: August 3, 2011
Published online: October 10, 2011
À
Keywords: azides · cations · C H activation · chemoselectivity ·
.
rearrangement
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