Ruthenium-catalyzed intramolecular selective halogenation of O-methylbenzohydroximoyl halides: A new route to halogenated aromatic nitriles

Article abstract of DOI:10.1039/c3cc41124a

The intramolecular halogenation of O-methylbenzohydroximoyl halides in the presence of a Ru catalyst and the ligand diphenylacetylene afforded halo substituted aromatic nitriles in a highly regioselective manner. Further, substituted nitriles were converted into substituted tetrazole derivatives in the presence of NaN₃ and I₂.

Full text of DOI:10.1039/c3cc41124a

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Ruthenium-catalyzed intramolecular selective
halogenation of O-methylbenzohydroximoyl halides:
a new route to halogenated aromatic nitriles†
Cite this: Chem. Commun., 2013,
49, 3146
Received 10th February 2013,
Accepted 28th February 2013
Ravi Kiran Chinnagolla, Sandeep Pimparkar and Masilamani Jeganmohan*
DOI: 10.1039/c3cc41124a
www.rsc.org/chemcomm
The intramolecular halogenation of O-methylbenzohydroximoyl In the meantime, there is also no example available in the literature
halides in the presence of a Ru catalyst and the ligand diphenyl- for halogenation of aromatics in an intramolecular fashion. This,
acetylene afforded halo substituted aromatic nitriles in a highly and also our continuous interest in the Ru(II)-catalyzed C–H activa-
regioselective manner. Further, substituted nitriles were converted tion reactions,7,8 prompted us to explore the possibility of perform-
into substituted tetrazole derivatives in the presence of NaN3 and I2. ing halogenation at the meta C–H bond of substituted aromatics in
an intramolecular fashion. Herein, we wish to report for the first
Aromatic halides are synthetically useful compounds that have been time, an unprecedented ruthenium-catalyzed intramolecular halo-
widely used as precursors in various organic transformations and genation at the meta and ortho carbon positions of O-methylbenzo-
for synthesizing various organometallic reagents, heterocyclic com- hydroximoyl halides. It is noteworthy to say that the present
pounds, natural products, biologically active molecules and organic halogenation reaction is conducted under base and oxidant free
materials.1 Traditionally, substituted aromatic halides are prepared conditions. It is also important to point out that substituted aromatic
by aromatic electrophilic substitution of electron-rich aromatics.2 nitriles are key structural units in various natural products and also
However, many of these reactions generally provide mixtures of key intermediates for synthesising various pharmaceutically active
regioisomeric ortho and para substituted aromatic halides. Alterna- molecules, agricultural molecules, dyes and organic materials.9
tively, ortho-halo substituted aromatics are efficiently prepared by
chelation-assisted metal-base mediated C–H bond activation of
substituted aromatics followed by halogen quenching.3 Recently,
(1)
metal-catalyzed directing group assisted transformation of ortho
aromatic C–H bonds to C–X bonds by utilizing NXS sources
(X = Cl, Br and I) or XOAc or CuX2 has been reported.4,5 By using
The halogenation of 4-hydroxy-N-methoxybenzimidoyl chloride
these methods, various ortho-bromo and iodo substituted aromatic (1a) in the presence of [{RuCl2(p-cymene)}2] (3 mol%) and ligand
compounds are conveniently prepared. However, chlorobenzene diphenylacetylene (30 mol%) in iso-PrOH at 100 1C for 16 h gave
synthesis is still a challenging task. In all reported reactions, 3-chloro-4-hydroxybenzonitrile (2a) in 83% isolated yield (eqn (1)).
halogenation of aromatics proceeded in an intermolecular fashion. In the reaction, chlorination takes place very selectively at the meta
The ortho C–H bond activation of aromatics has been fairly carbon position of 1a and the imidoyl moiety of 1a is converted
studied in the literature.4,5 But, the meta selective C–H bond activa- into the nitrile moiety (for detailed optimization studies, see ESI†).
tion of aromatics is much limited in the literature.6 In this context,
Under similar reaction conditions, the catalytic reaction was
metal-catalyzed meta selective arylation and alkenylation of substi- examined with various substituted O-methylbenzohydroximoyl
tuted aromatics have been reported by the groups of Gaunt, Yu and chlorides 1b–h (Table 1). Thus, 4-methoxy 1b, 4-ethoxy 1c,
Sanford.6a–d In addition, Ru(II)-catalyzed meta selective sulfonation of 4-n-propoxy 1d substituted N-methoxybenzimidoyl chlorides under-
2-phenylpyridines has been demonstrated by Frost and co-workers went chlorination selectively at the meta carbon position yielding the
in 2011.6e To date, no report has been available in the literature corresponding meta-chlorobenzonitriles 2b–d in excellent 85%, 90%
for halogenation at the meta C–H bond of substituted aromatics. and 92% yields, respectively (entries 1–3). The structure of 2c was
confirmed using single crystal X-ray diffraction (see ESI†). 4-Dimethyl-
amino 1e and 4-methylamino 1f substituted N-methoxybenzimidoyl
chlorides also proceeded smoothly under similar reaction conditions
affording the corresponding meta-chlorobenzonitriles 2e and 2f in
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411021, India. E-mail: mjeganmohan@iiserpune.ac.in
† Electronic supplementary information (ESI) available: Detailed experimental
excellent 84% and 91% yields, respectively (entries 4 and 5). In these
procedures and spectroscopic data. CCDC 924191 and 924192. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc41124a reactions also, chlorination takes place at the meta carbon position
c
3146 Chem. Commun., 2013, 49, 3146--3148
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Table 1 Scope of the selective meta-chlorination reactiona
N-methoxybenzimidoyl chloride 1i. In contrast to the previous
reactions (Table 1), surprisingly, in this reaction, chlorination
takes place selectively at the less hindered ortho carbon position of
1i providing 2-chloro-5-methoxybenzonitrile (2i) in 93% yield
(Table 2, entry 1). Like 1i, 3,4-dimethoxy 1j and 3,5-dimethoxy
1k substituted N-methoxybenzimidoyl chlorides underwent
chlorination at the less hindered ortho carbon position of 1j and
1k affording the corresponding substituted ortho-chlorobenzo-
nitriles 2j and 2k in 81% and 89% yields, respectively (entries 2
and 3). Similarly, 1,3-dioxale group substituted N-methoxybenz-
imidoyl chloride 1l yielded ortho-chloro piperonylonitrile 2l in
85% yield (entry 4). The structure of 2l was confirmed using single
crystal X-ray diffraction (see ESI†). Further, N-methoxy-1-naphth-
imidoyl chloride (1m) provided 2-chloro-1-naphthonitrile (2m) in 81%
yield (entry 5). Next, the reaction was tested with 3-iodo substituted
N-methoxybenzimidoyl chloride 1n (entry 6). In the reaction, the
C–I bond of 1n underwent a Heck-type alkenylation with the
methyl acrylate ligand giving an alkene derivative 2n in 42% yield.
The current method can also be successfully extended to prepare
various meta and ortho bromo substituted benzonitriles 4a–i
(Table 3). The bromination at the meta carbon position of 4-hydroxy
substituted N-methoxybenzimidoyl bromide 3a proceeded smoothly
under the optimized reaction conditions affording 3-bromo-4-
hydroxybenzonitrile (4a) in 93% yield in a highly regioselective
manner (Table 3, entry 1). Similar to 3a, 4-methoxy 3b, 4-ethoxy 3c,
and 4-n-propoxy 3d substituted N-methoxybenzimidoyl bromides
gave the corresponding meta-bromo substituted benzonitriles 4b–d
in 96%, 96% and 97% yields, respectively (entries 2–4), in a highly
regioselective manner. Similarly, 4-dimethylamino substituted
Entry
1b–h
Product 2b–h
Yieldb (%)
1
2
3
4
5
1b: R1 = OMe
1c: R1 = OEt
2b: R1 = OMe
2c: R1 = OEt
85
90
92
84
91c
1d: R1 = O-nPr
1e: R1 = NMe2
1f: R1 = NHMe
2d: R1 = O-nPr
2e: R1 = NMe2
2f: R1 = NHMe
6
85
87
7
a
All reactions were carried out using 1b–h (1.0 mmol), diphenylacetylene
(30 mol%) and [{RuCl2(p-cymene)}2] (3 mol%) in iso-PrOH (3.0 mL) at
b
c
100 1C for 16 h. Isolated yield. The reaction was conducted in the
presence of methyl acrylate (50 mol%).
of 1e and 1f exclusively. Interestingly, 4-hydroxy-3-methoxy 1g and
3,4-dihydroxy 1h substituted N-methoxybenzimidoyl chlorides
provided substituted meta-chlorobenzonitriles 2g and 2h in 85%
and 87% yields, respectively, also in which chlorination takes
place at the meta carbon position of 1g and 1h (entries 6 and 7).
Next, the scope of the regioselectivity of the chlorination of
substituted unsymmetrical N-methoxybenzimidoyl chlorides 1i–n
was examined under the optimized reaction conditions (Table 2).
Initially, the reaction was tested with 3-methoxy substituted
Table 3 Scope of the selective meta and ortho bromination reactiona
Table 2 Scope of the selective ortho-chlorination reactiona
Yieldb (%)
93c
Entry
3
Product 4
Yieldb (%)
Entry
1i–n
Product 2i–n
1
1
2
3
4
5
3a: R1 = OH
4a: R1 = OH
93
96
96
97
84
3b: R1 = OMe
3c: R1 = OEt
3d: R1 = O-nPr
3e: R1 = NMe2
4b: R1 = OMe
4c: R1 = OEt
4d: R1 = O-nPr
4e: R1 = NMe2
2
3
81
89c
85
6
7
8
88
94c
4
5
81c
42c
83
85
9
6
a
a
All reactions were carried out using 3a–i (1.0 mmol), diphenylacetylene
(30 mol%) and [{RuCl2(p-cymene)}2] (3 mol%) in iso-PrOH (3.0 mL) at
All reactions were carried out using 1i–n (1.0 mmol), diphenylacetylene
(30 mol%) and [{RuCl2(p-cymene)}2] (3 mol%) in iso-PrOH (3.0 mL) at
b
c
b
c
100 1C for 16 h. Isolated yield. The reaction was conducted in the
presence of methyl acrylate (50 mol%).
100 1C for 16 h. Isolated yield. The reaction was conducted in the
presence of methyl acrylate (50 mol%).
c
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N-methoxybenzimidoyl bromide 3e provided the corresponding meta- reactions were performed (eqn (3)). The reaction of 1j was
bromo substituted benzonitrile 4e in 84% yield (entry 5). Likewise, in conducted with 3i under the optimized reaction conditions.
the reaction of 4-hydroxy-3-methoxy substituted N-methoxybenz- In the reaction, if cross products 4h and 2l are observed in
imidoyl bromide 3f, bromination took place regioselectively at the addition to the expected 2j and 4i, the reaction should be
meta carbon position yielding 4f in 88% yield (entry 6). The structure intermolecular. However, in the reaction, as expected, only
of 4f was confirmed by single crystal X-ray diffraction (see ESI†). compounds 2j and 4i were observed exclusively in 80% and
In contrast to 3a–f, 3-methoxy, 3,4-dimethoxy and 1,3-dioxale sub- 83% yields, respectively, and no cross products were observed.
stituted N-methoxybenzimidoyl bromides 3g–i provided ortho-bromo Similarly, in the reaction of 1e with 3b, only compounds 2e and
substituted benzonitriles 4g–i in 94%, 83% and 85% yields, respec- 4b were observed exclusively in 81% and 91% yields, respec-
tively, in a highly regioselective manner (entries 7–9).
tively, and no cross products 4e and 2b were observed. These
To demonstrate the utility of CN groups in organic synthesis, the results very clearly revealed that the present halogenation
[3+2] cycloaddition of aromatic nitriles with NaN3 was carried out reaction proceeds in an intramolecular fashion.
(eqn (2)). The cycloaddition of aromatic nitrile 2e with NaN3
In conclusion, we have described ruthenium-catalyzed intra-
(1.5 equiv.) in the presence of a catalytic amount of I2 (20 mol%) molecular halogenation of O-methylbenzohydroximoyl halides.
in DMF at 120 1C for 24 h yielded the corresponding substituted The catalytic reaction is highly regioselective, yielding substi-
tetrazole 5a in 66% yield. Similarly, aromatic nitriles 2f and 4i also tuted halo aromatic nitriles under base and oxidant free con-
underwent cycloaddition with NaN3 under similar reaction condi- ditions. Further extension of the C–H bond activation of other
tions giving tetrazoles 5b and 5c in 67% and 61% yields, respectively. chelating group substituted aromatics and functionalization
with other p-components and the detailed mechanistic inves-
tigation are in progress.
We thank the DST (SR/S1/OC-26/2011), India, for the support
of this research. R.K.C. thanks the CSIR for a fellowship and
S.P. thanks the BRNS for a fellowship.
(2)
Notes and references
1 Selected books and reviews: (a) P. Knochel and F. Kopp, in Handbook
At present, the exact mechanism for the halogenation of 1 or 3
is not very clear to us. Possibly, the imidoyl moiety of 1 or 3 is
converted into a cyano group9b followed by halogen transfer via
electrophilic substitution at the aromatic carbon of 1 or 3 in the
presence of a ruthenium catalyst. The exact role of the co-catalyst
diphenylacetylene or methyl acrylate is unclear to us. It might be
possible that this ligand coordinates with ruthenium metal and
decreases the electron-density on the metal via p-back bonding.
In fact the halogenation reaction was tested with various para and
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halides. However, in these reactions, no halogenation product was
observed. This is probably due to the electron-withdrawing nature
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compared to the electron inductive donating groups such as alkyls.
In all reactions, halogenation takes place selectively at the ortho and
meta carbon of aromatics 1 and 3. This is most likely due to the ortho
and para directing nature of OH, OR, NHR and NR2 groups in the
electrophilic aromatic substitution reaction.
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inter- or intramolecular manner, the following competitive
c
3148 Chem. Commun., 2013, 49, 3146--3148
This journal is The Royal Society of Chemistry 2013