Room-temperature Cu(ii)-catalyzed aromatic C-H azidation for the synthesis of ortho-azido anilines with excellent regioselectivity

Article abstract of DOI:10.1039/c4cc01481b

Cu(ii)-catalyzed aromatic C-H azidation with azido-benziodoxolone under mild conditions has been described. The primary amine exhibits an excellent ortho-directing effect, providing ortho-azidated anilines as the sole products. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01481b

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Room-temperature Cu(II)-catalyzed aromatic C–H
azidation for the synthesis of ortho-azido anilines
with excellent regioselectivity†
Cite this: Chem. Commun., 2014,
50, 5733
Received 26th February 2014,
Accepted 12th April 2014
Yunpeng Fan,a Wen Wan,*a Guobin Ma,‡b Wei Gao,a Haizhen Jiang,a Shizheng Zhuc
and Jian Hao*ac
DOI: 10.1039/c4cc01481b
www.rsc.org/chemcomm
Cu(II)-catalyzed aromatic C–H azidation with azido-benziodoxolone through a Friedel–Crafts reaction process.8 N. Jiao et al. developed a
under mild conditions has been described. The primary amine exhibits Cu(I)-catalyzed regioselective C–H azidation of anilines.9 X. Li et al.
an excellent ortho-directing effect, providing ortho-azidated anilines described Rh(III)-catalyzed C–H azidation of arenes, in which pyridine
as the sole products.
acted as an efficient directing group.10 However, the hazardous azide
sources, such as NaN3 or TMSN3, still used in these reactions are
Besides their important roles in the click chemistry of cyclo- deterrents to their practical applications.
addition, aromatic azides are also well known for providing an
Azides of polyvalent iodine, such as PhI(N3)OAc or PhI(N3)2,
electron-deficient nitrene species, which is able to insert into a generated in situ from the combinations of PhIO or PhI(OAc)2
C–H bond. Thus, aryl azides have found numerous biological with TMSN3 or NaN3, were found to be reactive intermediates in
and industrial applications, such as the construction of radical-based aliphatic C–H azidation reaction.11 However, the
N-containing structural motifs in drug discovery,1 photoaffinity instability and high reactivity of these azidoiodinanes have
labelling reagents in structural proteomics,2 cross-linkers for restricted their practical applications as efficient reagents for the
high-performance polymer materials,3 and photografting on introduction of the azido function into organic molecules. Five-
polymer surfaces.4
membered heterocyclic azidoiodines as novel azidating reagents
Although numerous approaches for the synthesis of aliphatic are found to exhibit high thermal and storage stabilities.12 So far,
azides are available, the preparation methods of aryl azides are however, only a few reports on these azidobenziodoxoles as
still limited. The conventional methods for constructing aryl efficient azidating reagents have been reported.13 To the best of
azides involve classical direct nucleophilic aromatic substitution our knowledge, there is no report on the aromatic C–H azidation
(SNAr) of activated aryl halides or sulfonates with NaN3,5 based on the thermally stable azidobenziodoxoles.
diazotization of aryl amines with NaNO2 at low temperature
Herein, we disclose a mild, simple, highly efficient protocol
under strong acidic conditions and subsequent treatment with for the diverse synthesis of aryl azides through C–H azidation of
the azide ion,6 or the cross-coupling of aryl boronic acids with anilines catalyzed by less expensive Cu(OAc)2, in comparison with
azide sources such as TfN3 and NaN3.7 Although powerful, these copper(I) salts, at ambient temperature. The thermally stable
transformations suffer from a long reaction time, harsh acidic or azidobenziodoxolone as a reliable azide source was first applied
basic conditions, and use of oxidative reagents, which are not in the metal-catalyzed aromatic azide formation. The amino
compatible with many functional groups present in a substrate. group is found to exhibit an ortho-directing effect in the azidation
What needs to be pointed out is that the direct C–H azidation of reactions, regioselectively affording the mono-azidated derivative.
aromatic rings to obtain aryl azides under mild conditions has
In the initial studies, the azidation of 4-methyl aniline (1a)
been gradually realized, making it a much more ideal and with azidoiodine reagent 2 as a model reaction was carried out
straightforward azidation process. Recently, K. A. Sasane et al. to optimize the reaction conditions (for safety notes for using
disclosed a sonication-mediated C–H azidation of aryl derivatives azidobenziodoxolone see ESI†). As shown in Table 1, Lewis acid
as a catalyst was found to be important to initiate the azidation
a Department of Chemistry, Innovative Drug Research Center, Shanghai University,
Shanghai, China. E-mail: jhao@shu.edu.cn, wanwen@staff.shu.edu.cn
b School of Material Science and Engineering, Shanghai University, China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, China
(entry 1). A survey of the catalysts revealed that Cu(I) halide or
acetate could give good yields when CH3CN was used as solvent
at room temperature (entries 2–5). Fe(ClO4)3 and Zn(ClO4)2ꢀ6H2O
were ineffective in the azidation (entries 6 and 7), while ZnI2,
ZnCl2, FeCl3, CuCl2 and CuSO4 afforded the desired products
with moderate yields (entries 8–11, see Table S1 for studies using
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01481b
‡ The author contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
Table
2
Screening results of azidation reactions to form ortho-
azido anilines
Entry 1a (equiv.) Lewis acid (mol%)
Solvent T (1C) Yieldb
1
2
3
4
5
6
1.0
2
2
2
2
None
CuI (10)
CuBr (10)
CuCl (10)
CuOAc (10)
Fe(ClO4)3 (10)
CH3CN 20
CH3CN 20
CH3CN 20
CH3CN 20
CH3CN 20
CH3CN 20
0
67
59
57
52
0
2
7
8
9
2
2
2
2
2
2
2
2
2
2
2
1.0
Zn(ClO4)2ꢀ6H2O (10) CH3CN 20
0
ZnI2 (10)
CH3CN 20
CH3CN 20
CH3CN 20
CH3CN 20
CH3CN 20
CH2Cl2 20
63
57
45
57
72
69
79
0
ZnCl2 (10)
CuCl2 (10)
CuSO4 (10)
10
11
12
13
14
15
16
17
18
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
THF
MeOH
THF
THF
THF
20
20
20
30
20
85
86
57
a
Reagent 2 (0.3 mmol), 4-methyl aniline, catalyst, solvent, temperature
b
and indicated solvents under N2. Isolated yield.
other Lewis acids in ESI†). Cu(OAc)2 appeared to give better
results and acceptable yield (up to 72%) of 3a (entry 12). It was
found that reactions carried out in a range of solvents produced
the desired products in good yields, while THF provided the best
results (entry 14). However, the reaction did not work when the
polar protic solvent of MeOH was used (entry 15). Increasing
the catalyst loading from 10% to 20% significantly improved the
catalyst performance, providing the azidation product in 85%
yield (entry 16). Elevated temperature gave only a slightly higher yields (3i and 3j). Interestingly, high azidation efficiency was
yield without a remarkable decrease of reaction time (entry 17). also observed for the biaryl and fused aromatic substrates,
When the molar ratio of the aniline and azidoiodine(III) 2 affording the respective azidation products in good to high
was 1 : 1, the diazidated product of 2,6-diazidoaniline was also yield (3p–3v). A diamino-containing substrate produced the
obtained in a total yield of 73% with a mono/di ratio of 3.5 : 1 corresponding mono-azidation product 3u in moderate yield.
(entry 18). However, aniline and azidoiodine(III) reagent 2 in The heterocycle-containing anilines 3w and 3x were found to be
a molar ratio of 2 : 1 produced 2-azidoaniline as the sole viable substrates albeit giving acceptable yields. It should be
product with traces of the diazidated by-product under these emphasized that azidation was found to take place only on the
conditions. The excess of aniline could be recovered.
amino-containing aromatic rings. The para-azidation reaction
With the optimized reaction conditions established (entry 16), was observed when o,o0-dimethyl aniline 2y was employed,
the scope and functional group tolerance of this Cu(II)-catalyzed affording 36% isolated yield (3y) with a large amount of starting
azidation reaction were investigated (Table 2).
material remaining.
Aryl amines with inert alkyl substituents underwent smooth
The synthetic utility was further demonstrated by perform-
azidation to afford the desired ortho-substituted products in ing the chemical modification of the o-azido anilines. As shown
moderate to high yields (3a–3f). The substitution pattern of the in Scheme 1, azidation reduction was achieved by treatment
aromatic ring was found to have an apparent influence on the with Zn–NH4Cl in reflux EtOH, providing almost stoichiometric
reaction efficiency, with para-substituted substrates working 1,2-diamino benzene 4.14a By means of the well-known Sandmeyer
more efficiently to provide the desired products in higher yields reaction, diazotization of 3h with t-butyl nitrite, followed by treat-
(3a, 3c, and 3d). Functionalities such as alkoxy, halide, acetyl, ment with KI, produced 2-azido-4-chloro-1-iodobenzene 5 in high
and ester, which serve as useful reaction handles for further yield.14b As expected, 3b or 3h was a suitable substrate for the
investigation, were well-tolerated under the mild reaction con- Cu-catalyzed [3+2] alkyne–azide cycloaddition, giving trizoles 6
ditions (3g–3o). Note that the substrate with a Br group, which and 7 in excellent yields.14c N-formylation of the 2-azido aniline 3c,
has been shown to be a prominent leaving group in a variety of followed by dehydration, provided 2-azido-1-isocyanobenzene 8,
transition-metal-catalyzed cross-coupling reactions, also under- which is an important precursor in the template-controlled
went smooth azidation to afford the desired azides in good synthesis of NH and NH–NHC complexes.14d
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oxidative hypervalent iodine(III) reagent 2 results in the forma-
tion of the aniline radical cation and radical anion A.16 Rapid
collapse of radical anion A would lead to Lewis acid catalyzed
bond cleavage, producing N3-containing 2-iodo-benzoate B.
Decomposition of B gives copper(II) salt C, with simultaneous
release of a relatively stable azide radical. The N3 radical pre-
ferentially attacks the aromatic ring ortho to the primary amino
group of the aniline radical cation, regioselectively generating
the cyclohexadienyl cation species D. Finally, deprotonation of E
by 2-iodobenzoate C could afford the desired azidation product 3.
The generated 2-iodobenzoic acid F in the last step was also
Scheme 1 Functionalization of ortho-azido anilines.
1
detected by H NMR spectroscopy. Further investigation will be
required to elucidate the nature of the C–H azidation reaction in
this work, though a SET process proposed for the reaction
mechanism under the present study is more probable.
In conclusion, we have described a mild procedure of aromatic
C–H azidation with azidobenziodoxolone 2 catalyzed by cheap
Cu(OAc)2. With the efficient ortho-directing effect of the primary
amino group, the reactions exhibit a unique regioselectivity in
that ortho-azidation is strongly preferred. This azidation proce-
dure provides an easy access for further chemical modifications
of the ortho-azido anilines.
In order to gain insight into the role of the amino group, the
effect of the substituent on the amino group was investigated.
Though a primary amino-directed ortho azidation reaction was
found to proceed well, a complex mixture was obtained when
the secondary amine of N-phenyl aniline or N-methyl aniline
was applied in the azidation reaction. No conversion was
observed for N-acetyl aniline, N,N-dimethyl aniline and phenyl-
methanamine under the standard conditions. These results
demonstrated that a free amino group in anilines is required
for this azidation.
Preliminary studies on the mechanism were performed,
using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and hydro-
quinone (HQ) separately as radical scavengers in the reaction of
aniline and azidoiodine(III) reagent 2. The azidation reaction
was completely inhibited, indicating that a radical process may be
involved in this reaction. Further GC-MS analysis confirmed the
formation of TEMPO-N3 (see the ESI†). This result is consistent
with the literature data on the radical mechanism for aliphatic
C–H azidations by the unstable azidoiodinanes, PhI(N3)OTMS and
PhI(N3)2,15 and the report on the stable azidobenziodoxoles. How-
ever, in contrast to the previously reported aliphatic C–H azidation
with azidobenziodoxolone 2 in the presence of a radical initiator at
high reaction temperature,12 the Cu(II)-catalyzed aromatic C–H
azidation by reagent 2 in this work proceeded well in the absence
of any radical initiator under very mild reaction conditions,
providing the ortho-azidated products in good yields.
This work was financially supported by the National Natural
Science Foundation of China (No. 21172141, 21072127, 21032006,
21302121). We thank the Laboratory for Microstructures of
Shanghai University for structural analysis.
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