Ruthenium-catalyzed ortho-arylation of acetanilides with aromatic boronic acids: An easy route to prepare phenanthridines and carbazoles

Article abstract of DOI:10.1039/c3cc49398a

The highly regioselective ortho-arylation of acetanilides with aromatic boronic acids in the presence of a Ru(ii) complex (3 mol%), AgSbF₆ (12 mol%), Cu(OTf)₂ (20 mol%) and Ag₂O (1.0 eq.) is described. Later, ortho-arylated acetanilides were converted into phenanthridine and carbazole derivatives by using Ph₃PO and Tf₂O or palladium or Cu(OTf)₂ catalysts.

Full text of DOI:10.1039/c3cc49398a

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Ruthenium-catalyzed ortho-arylation of
acetanilides with aromatic boronic acids: an easy
route to prepare phenanthridines and carbazoles†
Cite this: Chem. Commun., 2014,
50, 2442
Received 11th December 2013,
Accepted 6th January 2014
Ravi Kiran Chinnagolla and Masilamani Jeganmohan*
DOI: 10.1039/c3cc49398a
www.rsc.org/chemcomm
The highly regioselective ortho-arylation of acetanilides with ortho-arylation of N–H free anilides (Ph-NHCOR) with trialkoxy
aromatic boronic acids in the presence of a Ru(II) complex (3 mol%), phenylsilanes in the presence of a palladium complex.3b However,
AgSbF6 (12 mol%), Cu(OTf)2 (20 mol%) and Ag2O (1.0 eq.) is described. an excess amount of oxidants such as AgF (2.0 equiv.) and Cu(OTf)2
Later, ortho-arylated acetanilides were converted into phenanthridine (2.0 equiv.) was used and the availability of trialkoxy phenylsilanes is
and carbazole derivatives by using Ph3PO and Tf2O or palladium or also limited. Recently, Lipshutz’s group reported ortho-arylation of aryl
Cu(OTf)2 catalysts.
ureas (Ph-NH-CONR2) with phenylboronic acids in the presence of a
cationic palladium complex.3c However, in the reaction of symmetrical
ortho-Arylation of heteroatom substituted aromatics with aromatic aryl ureas with aromatic boronic acids, a minor amount of di-arylated
electrophiles or organometallic reagents catalyzed by metal complexes compounds was observed.
via chelation-assisted C–H bond activation is one of the efficient
Owing to its extraordinary reactivity and selectivity, the
methods to synthesize biaryl derivatives.1 Various chelating groups [{RuCl2(p-cymene)}2] complex has been efficiently used as a catalyst
such as ketone, oxime, amide, acetamino (NH-COR), 2-pyridyl, cyano, for various C–H bond functionalization reactions.5,6 Ru(II)-catalyzed
ester, carboxylic acid and amine are efficiently used for the arylation arylation of 2-pyridyl, oxazoline, azole, amide and oxime substituted
reaction. Among them, acetamino (NH-COR) directed ortho-arylation of aromatics with aromatic electrophiles has been elaborately studied in
aromatics has gained much attention in organic synthesis2,3 since the the literature.5 Very recently, we have reported a ruthenium-catalyzed
derived ortho-arylated N-substituted anilines are key synthetic inter- ortho-arylation of benzamides with boronic acids.6a In the reported
mediates for various organic transformations and synthesizing hetero- ruthenium-catalyzed arylation reactions, directing groups having a
cyclic moieties.2,3 Metal-catalyzed ortho-arylation of acetamino directed better coordinating nitrogen atom such as 2-pyridyl, oxime, oxazoline,
aromatics with aromatic electrophiles has been extensively studied in azole and amide are explored. But, directing groups having a less
the literature.2 However, in the reaction of symmetrical acetanilides coordinating oxygen atom are not explored. Herein, we wish to report a
with aromatic electrophiles, a mixture of mono- and di-arylated less coordinating oxygen atom directed ortho-arylation of acetanilides
acetanilides was observed. The diarylated compounds cannot be with aromatic boronic acids in the presence of an Ru(II) catalyst. The
suppressed in the reaction, but, they can be suppressed by arylation catalytic reaction was compatible with various functional groups such
using aromatic organometallic reagents.3,4 Aromatic boranes, aromatic as electron-rich, electron-deficient and halogen substituted aromatic
stannenes and aromatic silanes are commonly used arylating agents in anilides and aromatic boronic acids. In the reaction, no diarylated
the coupling reaction. Among them, organoborane reagents display products or N-arylated acetanilides were observed. Further, ortho-
multifarious advantages and the observed boron-derived byproducts arylated anilides were converted into useful heteroaromatics such as
are not harmful unlike other organometallic reagents.4
phenanthridine and carbazole derivatives by using Ph3PO and Tf2O or a
In 2007, Shi’s group demonstrated ortho-arylation of acetanilides palladium catalyst.7
with aromatic boronic acids in the presence of a palladium complex.3a
In the reaction, N-substituted anilides (Ph-NRCOR) showed good
reactivity and selectivity. But, N–H free anilides (Ph-NHCOR) showed
poor reactivity and selectivity with the formation of N-arylated anilide
as a major by-product. Subsequently, the same group has reported
(1)
Department of Chemistry, Indian Institute of Science Education and Research,
Treatment of acetanilide (1a) with phenylboronic acid (2a) in the
presence of [{RuCl2(p-cymene)}2] (3 mol%), AgSbF6 (12 mol%), Ag2O
(1.0 mmol) and Cu(OTf)2 (20 mol%) in tetrahydrofuran (THF) at
Pune 411021, India. E-mail: mjeganmohan@iiserpune.ac.in
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. See DOI: 10.1039/c3cc49398a
2442 | Chem. Commun., 2014, 50, 2442--2444
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Table 1 ortho-Arylation of anilides 1b–n with phenylboronic acid (2a)a
110 1C for 20 h gave ortho-arylated anilide 3a in 75% isolated yield
(eqn (1)). The catalytic reaction is highly selective, only the mono-
arylation product was observed.
Entry
1b–n
Product 3b–n
Yieldb (%)
To optimize the arylation reaction, various additives, solvents and
oxidants were examined in the reaction of 1a with 2a in the presence
of [{RuCl2(p-cymene)}2] (3 mol%) at 110 1C for 20 h. First, the catalytic
reaction was tested with various solvents such as THF, MeOH, AcOH,
toluene, DCE, DME, and DMF in the presence of a catalyst, AgSbF6
(12 mol%) and Ag2O (1.0 equiv.). Among them, THF solvent was the
best, providing coupling product 3a in 71% GC yield. The remaining
solvents were totally ineffective. Next, the catalytic reaction was tested
with various oxidants such as Ag2O, AgOTf, AgOAc, AgF, K2S2O8,
(NH4)2S2O8, oxone and Cu(OAc)2. Among them, Ag2O was very
effective, giving 3a in 71% GC yield. AgOTf, AgOAc and AgF were
less effective, giving 3a in 15, 10, and 5% GC yields, respectively.
Remaining oxidants were totally ineffective. A variety of additives such
as AgSbF6, AgBF4, AgOTf and KPF6 were also tested. Among them,
AgSbF6 was very effective, giving 3a in 71% GC yield. AgBF4 and AgOTf
were moderately effective, giving 3a in 60% and 55% GC yields,
respectively. But, KPF6 was totally ineffective. Further, the reaction was
tested with 1.0 equiv. and 20 mol% of Cu(OTf)2. In the reaction, 3a
was obtained in 82 and 83% GC yields, respectively. It is believed that
Cu(OTf)2 increases the rate of C–H bond activation and stabilizes the
active catalyst. The catalytic reaction was also tested without AgSbF6,
only with Ag2O (1.0 equiv.) and Cu(OTf)2 (20 mol%). In the reaction,
3a was obtained in 68% GC yield.
1
2
3
4
5
6
7
8
1b: R1 = OMe
1c: R1 = Me
1d: R1 = Br
1e: R1 = Cl
3b: R1 = OMe
3c: R1 = Me
3d: R1 = Br
3e: R1 = Cl
71
73
75
76
73
68
65
70
1f: R1 = F
3f: R1 = F
1g: R1 = CN
1h: R1 = NO2
1i: R1 = CO2Me
3g: R1 = CN
3h: R1 = NO2
3i: R1 = CO2Me
9
72
10
76
11
12
13
1l: R2 = Et
3l: R2 = Et
59
5c
0
1m: R2 = tert-Bu
1n: R2 = CF3
3m: R2 = tert-Bu
3n: R2 = CF3
a
All reactions were carried out using 1b–n (1.0 mmol), phenylboronic
acid (2a) (1.5 mmol), [{RuCl2(p-cymene)}2] (3 mol%), AgSbF6 (12 mol%),
Ag2O (1.0 mmol) and Cu(OTf)2 (20 mol%) in THF (3.0 mL) at 110 1C
b
c
To explore the scope of the arylation reaction, various substituted
aromatic acetanilides 1b–n were examined (Table 1). Thus, electron-
for 20 h. Isolated yield. GC yield.
donating and halo groups such as 4-methoxy, 4-methyl, 4-bromo, 74%, 78%, 72% yields, respectively. 3-Bromophenylboronic acid (2h)
4-chloro and 4-fluoro substituted acetanilides 1b–f reacted efficiently also nicely participated in the reaction, yielding product 3u in
with phenylboronic acid (2a) providing ortho-arylated acetanilides 3b–f 71% yields. Further, the coupling of 4-vinylphenylboronic acid (2i) with
in excellent to moderate 71%, 73%, 75%, 76% and 73% yields, 1d was tested. However, in the reaction, a Heck-type alkenylation
respectively (entries 1–5). Interestingly, less reactive electron- product 3v in 73% yield with the cleavage of boronic acid was observed.
withdrawing groups such as 4-cyano, 4-nitro and 4-methylester Interestingly, electron-deficient 4-acetylphenylboronic acid (2j) and
substituted acetanilides 1g–i also efficiently participated in the 4-formylphenylboronic acid (2k) also reacted efficiently with
coupling reaction, giving arylated products 3g–i in 68%, 65% and 4-methoxyacetanilide (1b) affording coupling products 3w and 3x in
70% yields, respectively (entries 6–8). It seems that the catalytic 69% and 62% yields, respectively. It is important to note that very
reaction is insensitive to the electronic effect of acetanilides. Next, sensitive functional groups such as I, Br, Cl, OR, COMe and CHO
the reaction was tested with unsymmetrical acetanilides such as substituted phenylboronic acids were compatible for the reaction. The
3-bromoacetanilide (1j) and 2-napthylacetanilide (1k) with 2a. In the catalytic reaction was also tested with acetamino substituted heteroaro-
reaction, coupling products 3j and 3k were obtained in 72% and 76% matics (Scheme 1). Thus, thiophen-2-acetamine 1q underwent coupling
yields, respectively (entries 9 and 10). In the reaction, there are two with 2a or 4-methoxyphenylboronic acid (2l) yielding arylation products
ortho C–H bonds for arylation. Regioselectively, arylation takes place at 3y and 3z in excellent 77% and 75% yields, respectively.
a sterically less hindered side. Meanwhile, the effect of changing the
To show the utility of ortho-arylated acetanilides 3 in organic
substituent on the N-group of anilides such as Et, tert-Bu and CF3 synthesis, we have tried intramolecular cyclization of ortho-
instead of methyl was studied (entries 11–13). Ethyl 1l and tert- arylated acetanilides 3 in the presence of Ph3PO and Tf2O
Bu 1m substituted anilides reacted with 2a giving products 3l (Scheme 2).7a The intramolecular cyclization of 3a, 3b, 3c and
and 3m in 59% and 5% yields, respectively. CF3 substituted 3e proceeded smoothly in the presence of Ph3PO and Tf2O in
anilide 1n was not effective for the reaction.
CH2Cl2 at 0 1C to r.t. for 2 h, yielding phenanthridine deriva-
The present arylation reaction was successfully extended with tives 4a–d in 94%, 96%, 93% and 92% yields, respectively.
substituted aromatic boronic acids 2b–l (Scheme 1). Halogen groups Similarly, 3g, 3j and 3k underwent intramolecular cyclization
such as 4-chloro, 4-bromo and 4-iodo substituted phenylboronic acids under similar reaction conditions, giving 4e–g in 89%, 97% and
2b–d underwent coupling with 1e giving coupling products 3o–q in 91% yields, respectively. ortho-Arylated thiophen-2-acetamine
71%, 73%, 75% yields, respectively. Sterically hindered 2-naphthyl- 3y also nicely participated in the reaction, giving product 4h in
boronic acid (2e), 3,4-dimethoxyphenylboronic acid (2f) and 3,4-(methyl- excellent 89% yield (Scheme 2). Meanwhile, ortho-arylated acetanilides
enedioxy)phenylboronic acid (2g) yielded products 3r–t in excellent 3a, 3d, 3f and 3i were converted into carbazole derivatives 5a–d in
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phenylboronic acid (2a) into intermediate 7 in the presence of base
AgOÀ provides intermediate 8. Reductive elimination of intermediate 8
in the presence of Cu(OTf)2 and Ag+ affords product 3 and regenerates
the active ruthenium species. In the reaction, Ag2O acts as an oxidant to
oxidize the catalyst from Ru(0) to Ru(II) and base to cleave the boronic
acid moiety of 2. It is believed that Cu(OTf)2 plays an important role in
regenerating the active catalyst in the presence of the Ag+ oxidant.
In conclusion, we have demonstrated a ruthenium-catalyzed
ortho-arylation of acetanilides with aromatic boronic acids via an
oxygen atom directed C–H bond activation. The catalytic reaction
was compatible with various anilides and aromatic boronic acids.
We thank the DST (SR/S1/OC-26/2011), India, for the support
of this research. R. K. C. thanks the CSIR for the fellowship.
Notes and references
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Scheme 2 Synthesis of phenanthridines and carbazoles.
81%, 72%, 68% and 90% yields, respectively, in the presence Pd(OAc)2
(5 mol%) and Cu(OAc)2 (1.0 equiv.) under O2 or Cu(OTf)2 (5 mol%)
and PhI(OAc)2 (1.5 equiv.).7b,c It is important to note that phenan-
thridine and carbazole scaffolds are present in natural products and
biologically active molecules.7a–c
On the basis of known metal-catalyzed C–H bond activation
reactions,1–3 a plausible reaction mechanism is proposed in
Scheme 3. The first step likely involves the removal of the Cl
ligand from the Ru catalyst by AgSbF6 providing a cationic
ruthenium complex 6. Coordination of the carbonyl oxygen of
acetanilide 1 to the cationic ruthenium complex followed by ortho-
metalation gives a ruthenacycle intermediate 7. Transmetallation of
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Scheme 3 Proposed mechanism.
2444 | Chem. Commun., 2014, 50, 2442--2444
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