Ruthenium-catalyzed meta/ortho-selective C-H alkylation of azoarenes using alkyl bromides

Article abstract of DOI:10.1039/C6CC09323J

meta/ortho-Selective C_Ar-H (di)alkylation reactions of azoarenes have been achieved via [Ru(p-cymene)Cl₂]₂ catalyzed ortho-metalation using various types of alkyl bromides. Particularly, dual meta-alkylation of azoarene and reduction offer an attractive strategy for the synthesis of meta-alkylanilines, which are difficult to access via traditional aniline functionalization methods.

Full text of DOI:10.1039/C6CC09323J

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Ruthenium-catalyzed meta/ortho-selective C-H alkylation of
azoarenes with alkyl bromides
Received 00th January 20xx,
Accepted 00th January 20xx
Gang Li,* Xingxing Ma,† Chunqi Jia,† Qingqing Han, Ya Wang, Junjie Wang, Liuyang Yu, and Suling
Yang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
M
eta/ortho-Selective CAr-H (di)alkylation reactions of azoarenes synthesize respectively meta/ortho-alkyl azoarenes via
with various types of alkyl bromides have been achieved via
[Ru(p-cymene)Cl2]2 catalyzed ortho-metalation. Especially, dual
meta-alkylations of azoarene and reductions offered an attractive
strategy for the synthesis of meta-alkylanilines, which were
difficult to access by traditional aniline functionalization methods.
(a). ortho C-H bond functionalizations of azoarene
Ar
N
Ar
N
Previous work
R = Sulfonyl;
Aryl; Alkoxyl;
Nitryl; Acyl;
N
N
[TM]
H
R
Hydroxyl etc.
Ar
Ar
H
H
(b). meta C-H bond functionalizations of azoarene
Present work
Ar
NH2
N
Azoarenes and its derivatives with unique structural skeleton is
an important compounds, which widely used as not only in
traditional dyes and pigments, but also as many newly rising
functional materials,1 such as food additives, therapeutic
agents, indicators, light-responsive materials, etc.2 Therefor,
the synthesis of azoarenes compound in recent years have
attracted a lot of attention. Usually, symmetrical azoarene
compounds can be readily prepared via reduction of
nitroarenes3 and oxygen oxidation of arylamines.4 And
unsymmetrical ones can be obtained by cross coupling of
arylamines with nitroarenes or nitroso arenes, diazonium salts
with electron-rich aromatic ring.5 However, these
methodologies usually suffer from harsh reaction conditions or
narrow substrate scopes.
N
H
2
o or 3o alkyl
bromide
[H]
H
Ar
Ar
R1
R3
Ar
N
N
R1
R3
R2
H
Ru
R2
Ar
Ar
H
N
1o alkyl
bromide
N
R
Ar
H
Figure 1. C-H Functionalization of azoarene
ruthenium catalyzed meta/ortho-selective C-H bonds
alkylation of azoarenes with 3o, 2o-alkyl bromide and 1o-alkyl
bromide. Especially, synthesis of dual meta-alkyl azoarene and
reduction offered meta-alkylanilines, which were difficult to
access by other traditional aniline functionalization methods.
Initially, we selected low-cost and readily available
azobenzene and 3-bromopentane as typical substrates to
screen the condition of meta-selective CAr-H bond alkylation of
Modification and functionalization of easily available
symmetrical azoarenes is a promising method to prepare
unsymmetrical azoarenes. In recent years, with the rapid
development of transition-metal catalyzed C-H bond
functionalization, unsymmetrical azoarenes with various
substituents have been directly synthesized from azobenzene
o
azoarene, The reaction was performed at 120 C for 24 h in a
sealed Schlenk tube under a nitrogen atmosphere as shown in
Table 1. Using [Ru(p-cymene)Cl2]2 as catalyst and common
K2CO3 as base in the alkylation process, the desired product
could not be obtained in the solvent screening (Table 1, entry
1). According to report in relevant literature,8 carboxylic acid
was an efficient additive for Ru-catalyzed CAr-H bond
functionalization. It was to our delight that the desired meta-
alkylated product was obtained in a 76% yield when pivalic
acid was added in the process (Table 1, entry 2). 2,4,6-
Trimethylbenzoic acid also displayed some activity although
the yield was lower (Table 1, entry 5). Pentafluorobenzoic acid,
1-adamantane carboxylic acid and monoprotected amino acids
were inert in the reaction (Table 1, entries 3, 4, 6). The
transformation could also take place in THF and toluene, and
to give desired product in 32% and 48% yield respectively
under
nitrogen-metal
chelation-assisted.6
However,
introduction of these substituents were only limited to ortho-
position of azo (Figure 1a). Herein, based on strong
ortho/para-directing character of Ru-CAr ó-bond,7 we
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tertiary alkyl bromides were favourable meta-alkylated
reagent (3ab-3ai), and desired product could be obtained in
(Table 1, entries 7, 8). Product could not be obtained when
using acetonitrile as solvent (Table 1, entry 9). Various bases
Table 1. Optimization of meta-selective CAr-H alkylation of
azoarenes
e.g. Cs2CO3, KOAc and Na2CO3 were examined in the
transformation. The results showed that the former two were
effective (Table 1, entries 10, 11), and the latter was invalid
(Table 1, entry 12). When other ruthenium complexes
(Ru3(CO)12, Ru(PPh3)3Cl2) and Pd(OAc)2 were used as catalyst
(Table 1, entries 13-15), the reaction could not take place.
With the optimized conditions in hand, we set out to explore
the scope and limitation of the pivalic acid-promoted
ruthenium-catalyzed meta-selective CAr-H bond alkylation of
azoarenes. Initially, several azoarene derivatives were
employed as coupling partners with 3-bromopentane. As
summarized in Scheme 1. azoarenes bearing a methyl and aryl
group displayed good reactivities and the desired meta-
alkylated products were obtained in good yields (3ba, 3ca). 4,
4’-Ditertbutylazobenene with large steric hindrance was not
suitable substrates for this transformation. It was of great
importance to note that the electronic nature of the aromatic
substituents was observed in the process. Electron donating
substituents (CH3O-, CF3O-) were favourable to the reaction
Scheme
1. Scope of ruthenium(II)-catalyzed meta-CAr-H
alkylation of azoarenes with alkyl bromides
(
3da, 3ea). On the contrary, Product could not be obtained
using azoarenes with strongly electron-withdrawing groups as
substrate. Halogen functional groups were also compatible
with the transformation (3fa, 3ga, 3ha), giving a chance for
reasonable isolated yields. Notably, bromo esters and ether
were also effectively coupled with azoarenes (3ae, 3af, 3ai),
providing meta-substituted azoarenes derivatives with a useful
functional handle. Interestingly though, when primary alkyl
bromides were employed as coupling partners, ortho-alkylated
products were obtained in good isolated yield under the same
condition (3ak, 3al). Further, the dual ortho-alkylated azoarene
on the same benzene ring could be obtained by increasing the
stoichiometry of primary alkyl bromides (3am, 3an).
further functionalizations to construct C–C and C–X bonds. For
unsymmetrical azoarenes, regional selective product can be
obatined in good yield(3ia, 3ja). The dual meta-alkylation of
azoarene proceeded smoothly to give desired product in a
good yield by simply controlling the stoichiometry of the
reactants (3ka-3ma, 3aj). It was particularly noteworthy that
two alkyl groups were separately introduced into each
benzene ring of azoarene in the process.
On
a gram-scale experiment, the meta-CAr-H bond
Subsequently, different alkyl bromide were examined under
the standard conditions (Scheme 1). Both secondary and
functionlization of azobenzene catalyzed by ruthenium could
2 | J. Name., 2012, 00, 1-3
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also proceed smoothly to provide desired product in moderate Scheme 4. Preliminary mechanistic studies
yield only by prolonging the reaction time (Scheme 2). The
further the reaction mechanism by design experiments
(Scheme 4). First, when using azoarenes bearing four methyls
to block the four ortho positions of the phenyl ring as
substrates, alkylated products could not be obtained under the
standard conditions (a). The results indicated that the ortho-
CAr-H metalation was essential in the meta-functionlization
process. Second, the meta-functionalization of the isotopically
Scheme 2. Gram-scale experiment
labeled azobenzenes were studied (b). A significant ortho D/H
exchange was detected in both product [Dn]-9 and the
recovered starting material, whereas no meta-D/H exchange
occurred. This results clearly indicated that the initial ortho-
CAr-H metalation was reversible, whereas the meta-CAr-H
cleavage was not. Third, the active cyclometalated
results indicated that the present strategy were an efficient
and useful approach for the synthesis of meta-substituted
azoarenes derivatives.
rutheniumcomplex
cymene)Cl2]2 and azobenzene,9 and the structure was
definitely confirmed by single-crystal X-ray diffraction (
).10 It
I
were pre-prepared from [Ru(p-
c
was found that the pre-formed complex I could effectively
catalyze the alkylation of azobenzene. These results indicated
that the pre-formed complex I might be the key active catalyst
Scheme 3. Synthesis of meta-alkylanilines
Intriguingly, The meta-functionalized azoarene derivatives in the meta-CAr-H bond functionalization reaction. Fourth,
could be easily reduced in a simple method, providing meta- when radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
alkylated aniline derivative in excellent yield (Scheme 3). (TEMPO) was added into the alkylation system separately (
d).
Notably, dual meta-alkylation/reduction of azoarene offered no desired product was found in the alkylation process. These
an attractive approach for the atom/step-economical synthesis results indicate that the alkylation should involve a radical
of meta-alkylated anilines, which were very difficult to prepare process. These results were consistent with Ackermann
’s
by other traditional aniline functionalization methods.
In view of characteristic meta-CAr-H functionalization of
azoarenes catalyzed by the ruthenium complex, we explored
reports on meta-selective CAr
According to above experimental observation and related
literature precedents,7c,7d
plausible catalytic cycle was
−
H alkylation.7c,7d
a
proposed to rationalize the ruthenium catalyzed meta-CAr-H
bond alkylation of azoarenes as shown in Scheme 5. Initially,
an active cyclometalated complex
A was formed from
azobenzene and [Ru(p-cymene)Cl2]2 via a reversible ortho-CAr
−
H ruthenation. Then, an electrophilic attack in the para-
position of the Ru-CAr ó-bond happened to provide active
species
B through the strong directing effect of the Ru-CAr ó-
bond. Meanwhile, a radical group was originated through a
Scheme 5: Proposed catalytic cycle
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2015, 17, 2434; (f) Y. F. Liang, X. Y. Wang, C. H. Tang, T. Shen,
J. Z.Liu and N. Jiao. Chem. Commun., 2016, 52, 1416; (g) H.
Tang, C. Qian, D. G. Lin, H. F. Jiang and W. Zeng, Adv. Synth.
Catal., 2014, 356, 519; (h) K. Seth, M. Nautiyal, P. Purohit, N.
Parikh and A. K. Chakraborti, Chem. Commun., 2015, 51, 191;
(i) T. H. L. Nguyen, N. Gigant, S. Delarue-Cochin and D. Joseph
J. Org. Chem., 2016, 81, 1850; (j) Y. F. Liang, X. Y. Wang, Y. Z.
ruthenium-mediated single-electron transfer in the alkylation
process. Under the assistance of ruthenium(III) and base, a
more stable complex
C
was obtained via the deprotonation of
provides
species B. Finally, the proto-demetalation of species
C
the final meta-substituted products and active species for
recycle.
Yuan, Y. J. Liang, X. Y. Li and N. Jiao, ACS Catal., 2015, 5, 6148;
(k) J. W. Dong, B. Jin and P. P. Sun Org. Lett., 2014, 16, 4540;
(l) Y. F. Liang, X. Y. Li, X. Y. Wang, Y. P. Yan, P. Feng and N. Jiao,
ACS Catal., 2015, 5, 1956; (m) S. J. Yu, B. S. Wan and X. W. Li,
Org. Lett., 2015, 17, 58; (n) X. T. Ma and S. K. Tian, Adv. Synth.
Catal., 2013, 355, 337.
In conclusion, we have developed the carboxylic acid-
promoted ruthenium(II)-catalyzed meta-selective CAr-H
alkylation of azoarenes with secondary (tertiary) alkyl
bromides. When primary alkyl bromides were employed as
coupling partner, primary alkyls were introduced in ortho
position of azoarene under the same conditioan. The
development provided a new strategy to synthesize the meta-
alkylated azoarenes and meta-alkylaniline. Preliminary
experimental mechanistic studies indicated that the meta-CAr-
H bond alkylation involved a radical process through the strong
ortho/para directing effect of the Ru-CAr ó-bond. Further
investigations to expand application of ruthenium complexes
in C-H functionalization and synthesis chemistry are underway.
We gratefully acknowledge National Natural Science
Foundation of China (NSFC, No. 21102005; 21403006) for
financial support of this work.
7 (a) A. M. Clark, C. E. F. Rickard, W. R. Roper and L. J. Wright,
Organometallics, 1999, 18, 2813; (b) O. Saidi, J. Marafie, A. E.
Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Kohn, M. K.
Whittlesey and C. G. Frost, J. Am. Chem. Soc., 2011, 133
,
19298; (c) N. Hofmann and L. Ackermann, J. Am. Chem. Soc.,
2013, 135, 5877; (d) J. Li, S. Warratz, D. Zell, S. De Sarkar, E. E.
Ishikawa and L. Ackermann, J. Am. Chem. Soc., 2015, 137
,
13894; (e) C. J. Teskey, A. Y. W. Lui and M. F. Greaney, Angew.
Chem., Int. Ed., 2015, 54, 11677; (f) Q. Yu, L. Hu, Y. Wang, S.
Zheng and J. Huang, Angew. Chem., Int. Ed., 2015, 54, 15284;
(g) Z.-L. Fan, J.-B. Ni and A. Zhang, J. Am. Chem. Soc., 2016,
138
Jeganmohan, Chem. Commun., 2013, 49, 3146; (i) P. Marc
J. Paterson, M. F. Mahona, C. G. Frost, Catal. Sci. Technol.,
2016, , 7068.
,
8470; (h) R. K. Chinnagolla, S. Pimparkara, M.
é
, A.
6
Notes and references
8
L. Ackermann, Acc. Chem. Res., 2014, 47, 281.
9 A. J. Paterson, S. S. John-Campbell, M. F. Mahon, N. J. Pressc
and C. G. Frost, Chem. Commun. 2015, 51, 12807.
10 CCDC 1501752.
1
(a) K. Hunger, Industrial Dyes. Chemistry, Properties,
Applications, Wiley-VCH, Weinheim, 2003; (b) P. F. Gordon
and P. Gregory, Organic Chemistry in Colour, Springer, New
York, 1983, pp. 95-162.
2 (a) T. Fehrentz, M. Schönberger and D. Trauner, Angew. Chem.,
Int. Ed., 2011, 50, 12156; (b) F. Hamon, F. Djedaini-Pilard, F.
Barbot and C. Len, Tetrahedron, 2009, 65, 10105; (c) R.
Deloncle and A. M. Caminade, J. Photochem. Photobiol. C,
2010, 11, 25; (d) R. M. Parker, J. C. Gates, H. L. Rogers, P. G. R.
Smith and M. C. Grossel, J. Mater. Chem., 2010, 20, 9118; (e)
Y. Kim, J. A. Phillips, H. Liu, H. Kang and W. Tan, Proc. Natl.
Acad. Sci.U.S.A., 2009, 106, 6489.
3 (a) P. Sarkar and C. Mukhopadhyay, Green Chem., 2016, 18
,
442; (b) M. Kumar, K. Soni, G. D. Yadav, S. Singh and S. Deka,
Appl. Catal. A- Gen., 2016, 525, 50; (c) S. F. Cai, H. P. Rong, X.
F. Yu, X. W. Liu, D. S. Wang, W. He and Y. D. Li, ACS Catal.,
2013, 3, 478.
4 (a) X. Liu, H. Q. Li, S. Ye, Y. M. Liu, H. Y. He and Y. Cao, Angew.
Chem., Int. Ed., 2014, 53, 7624; (b) B. Gole, U. Sanyal and P. S.
Mukherjee, Chem. Commun., 2015, 51, 4872; (c) K. Seth, S. R.
Roy, A. Kumar, A. K. Chakraborti, Catal. Sci. Technol., 2016, 6,
2892.
5 (a) M. Barbero, I. Degani, S. Dughera, R. Fochi and P. Perracino,
Synthesis, 1998, 9, 1235; (b) S. L. Goldstein and E. J. McNelis,
J. Org. Chem., 1973, 38, 183; (c) E. Merino, Chem. Soc. Rev.,
2011, 40, 3835; (d) F. Hamon, F. Djedaini-Pilard, F. Barbot and
C. Len, Tetrahedron, 2009, 65, 10105; (e) A. Grirrane, A.
Corma and H. Garc, Nat. Protoc., 2010, 11, 429; (f) C. Zhang
and N. Jiao, Angew. Chem., Int. Ed., 2010, 49, 6174; (g) R.
Zhao, C. Tan, Y. Xie, C. Gao, H. Liu and Y. Jiang, Tetrahedron
Lett., 2011, 52, 3805.
6 For selected recent examples, see: (a) D. Zhang, X. L. Cui, Q. Q.
Zhang and Y. J. Wu, J. Org. Chem., 2015, 80, 1517; (b) C. Premi,
A. Dixit and N. Jain, Org. Lett., 2015, 17, 2598; (c) J. Hubrich, T.
Himmler, L. Rodefeld and L. Ackermann, ACS Catal., 2015,
7
5,
4089; (d) M. Y. Li and Y. Ye, ChemCatChem, 2015, , 4137; (d)
Y. Lian, R. G. Bergman, L. D. Lavis and J. Ellman, J. Am. Chem.
Soc., 2013, 135, 7122; (e) X. Y. Geng and C. Y. Wang, Org. Lett.,
4 | J. Name., 2012, 00, 1-3
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