Palladium-Catalyzed Selective Aryl Ring C–H Activation of N-Acyl-2-aminobiaryls: Efficient Access to Multiaryl-Substituted Naphthalenes

Article abstract of DOI:10.1002/adsc.201600488

Palladium-catalyzed cycloaromatization of N-acyl-2-aminobiaryls, through a sequence of ortho C?H bond activation/alkyne insertion/meta C?H bond activation/alkyne insertion, was developed. An efficient synthesis of multiaryl-substituted naphthalenes, N-[2-(5,6,7,8-tetraarylnaphthalen-1-yl)aryl]acetamides, was demonstrated using molecular oxygen as the sole oxidant. Furthermore, through Buchwald's synthetic protocol, two compounds were converted into corresponding fluorescent carbazoles in 30–40% yield by intramolecular C?N bond formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201600488

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Palladium-Catalyzed Selective Aryl Ring C–H Activation of
N-Acyl-2-aminobiaryls: Efficient Access to Multiaryl-Substituted
Naphthalenes
Pratheepkumar Annamalai,a Wu-Yin Chen,a Selvam Raju,a Kou-Chi Hsu,a
Nitinkumar Satyadev Upadhyay,b Chien-Hong Cheng,b,* and Shih-
Ching Chuanga,*
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a
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30003, Taiwan
E-mail: jscchuang@faculty.nctu.edu.tw
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
b
E-mail: chcheng@mx.nthu.edu.tw
Received: May 9, 2016; Revised: August 31, 2016; Published online on && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600488.
concise approach for efficient C–C, C–N, and CÀO
Abstract: Palladium-catalyzed cycloaromatization
bond formation in recent decades.[3] Therefore, direct
ring construction through the use of metal-catalyzed
multiple CÀH bond functionalizations with internal
alkynes as an inserting unit has provided an oppor-
tunity for the synthesis of bioactive or polyaromatic p-
conjugated molecules.[4]
Some advanced studies on Rh- or Pd-catalyzed
directing group- and chelation-assisted aromatic ho-
mologation strategies for syntheses of PAHs have
been reported.[5] Wu and coworkers developed an N-
acyl-directed consecutive CÀH bond activation and
insertion of alkynes on anilides, leading to tetraaryl-
substituted naphthalenes (Scheme 1a). More recently,
Chatani demonstrated the chelation-assisted nickel-
catalyzed oxidative annulation through double C–H
activation/alkyne insertion of benzamides.[6] Miura
and co-workers demonstrated an Rh-catalyzed aro-
of N-acyl-2-aminobiaryls, through a sequence of
ortho CÀH bond activation/alkyne insertion/meta
CÀH bond activation/alkyne insertion, was devel-
oped. An efficient synthesis of multiaryl-substituted
naphthalenes, N-[2-(5,6,7,8-tetraarylnaphthalen-1-
yl)aryl]acetamides, was demonstrated using molec-
ular oxygen as the sole oxidant. Furthermore,
through Buchwald’s synthetic protocol, two com-
pounds were converted into corresponding fluores-
cent carbazoles in 30–40% yield by intramolecular
CÀN bond formation.
Keywords: alkynes; aromatic homologation; C–H
activation; naphthalenes; palladium
41 Polycyclic aromatic hydrocarbons (PAHs) or linear p- matic homologation of phenylazoles to yield fluores-
42 conjugated systems are highly fluorescent materials cent naphthalenes (Scheme 1b).[7] Other relevant
43 with versatile applications in dyes, optical sensors, studies by Miura and Luan showed Ru-catalyzed
44 molecular electronics, nonlinear optics, light-emitting alkenylation and palladium-catalyzed [5+2] oxidative
45 diodes, photovoltaic cells, and field-effect transistors.[1] annulation of o-arylanilines with internal alkynes,
46 Currently, the preparation of higher-order aromatic providing alkenylation products and dibenzo[b,d]aze-
47 hydrocarbons from halogenated or other prefunction- pines, respectively (Scheme 1c).[8] Although the aro-
48 alized and traceless removable directing group-medi- matic homologation of 2-phenylphenol was demon-
49 ated aromatic compounds has become methodologi- strated under Rh catalysis, the reaction scope was
50 cally less appealing because of an increasing demand limited to only one example.[9] Furthermore,
a
51 for greener and atom-economic synthetic ap- straightforward aromatic ring construction through
52 proaches.[2] Transition metal-catalyzed CÀH bond directing group-assisted CÀH bond functionalization
53 activation methodology has unique advantages for in a 2-aminobiaryl system has not yet been reported.
54 syntheses of a variety of molecules – including not CÀH bond activation generally favors C-3–H over C-
55 only bioactive but also functional optoelectronic 2’–H in an acidic medium, and knowledge on NHAc-
56 material compounds since directing group- and chela- directed C–H activation of C-2’–H on a 2-phenyl
57 tion-assisted CÀH bond activation has provided a moiety is limited to only two examples involving nitro
Adv. Synth. Catal. 2016, 358, 1–8
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Scheme 1. Directing group- or chelation-assisted CÀH bond activation of N-substituted anilines and N-free or N-substituted
biaryls.
47 substitution on C-4 or C-5 in moderate yields group has demonstrated palladium-catalyzed C-2’–H
48 (Scheme 1d).[10] The consecutive CÀH bond activation activation of N-tosyl-2-aminobiaryls followed by the
49 and alkyne insertion process is considerably more insertion of [60]fullerene and CO to yield fulleroben-
50 complex as it may involve dissociative cleavage of the zoazepines[11] and phenanthridinones,[12] respectively.
51 PdÀN bond in the first alkyne-inserted intermediate The activation of C-2’–H is considerably sensitive to
52 (IA), formation of a relatively less common and the substitution on the nitrogen of 2-aminobiaryls,
53 unstable eight-membered palladacycle (IB), and com- which has engendered a demand for developing
54 peting coordination with another resting directing another new condition for C-2’–H activation by using
55 group (NHAc) in intermediate IC; this may be other N-substituted 2-aminobiaryls. In this paper, we
56 followed by second competing CÀH bond activation report NHAc group-directed double consecutive CÀH
57 (C-6–H versus C-3’–H, Scheme 1e). Our research bond activation/alkyne insertion with N-acyl-2-biaryl-
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Table 1. Optimization of reaction conditions.[a]
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Entry
1a:2a
Oxidant (equiv.)
Solvent
Temperature [oC]
Additive (mol%)
Yield [%]
1
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:1.2
1:1.8
1:3.0
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
1:2.4
air
DMF
DMF
DMF
DMF
DMF
toluene
CB
120
120
120
120
120
120
120
120
120
120
120
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
–
–
–
–
52 (88)
28 (60)
0
63 (82)
0
16 (68)
11 (61)
0
trace
28
2[h]
3
AgOAc (1)
K2S2O8
Cu(OAc)2 (1)
BQ (3)
O2
O2
O2
O2
4
5
–
6[i]
7[i]
8
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
–
LiOAc (50)
KOAc (50)
NaOAc (25)
NaOAc (100)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
AgOTf (20)
NaOAc (50)
o-DCB
DCE
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13[h]
14
15
16
17
18
19
20
21[b]
22[c]
23[d]
24[e]
25[f]
26[g]
O2
O2
74
79
Cu(OAc)2 (0.2)/O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
44 (78)
67 (82)
67
62 (92)
46
63
66
58
60
25(80)
64
39
0
0
O2
Cu(OAc)2 (0.2)
O2
[a] Reaction conditions: All reactions were carried out using substrate 1a (0.3 mmol), 1b (0.72 mmol), and Pd(OAc)2 (10 mol%)
in 2 mL of anhydrous solvents for 24 h unless otherwise noted. Yields [%] were determined through the 1H NMR
spectroscopic method using mesitylene as an internal standard. Yields in parentheses are based on converted 1a.
[b]
Ac-Gly-OH was used as a ligand.
2,2’-bipyridine was used as a ligand.
DMF (3 mL).
DMF (4 mL).
RuCl2(p-cymene)/AgOTf.
Instead of 1a, unprotected 2-aminobiphenyl was used as the reactant.
A by-product 3a’ was isolated in <6% yield.
Trace amount of a by-product, 6-phenylphenanthridine, was isolated.
[c]
[d]
[e]
[f]
[g]
[h]
[i]
49 amines under palladium catalysis, using greener and mide (3a) in N,N-dimethylformamide (DMF) at
50 abundantly available molecular oxygen as an oxidant. 1208C for 24 h (Table 1, entry 1). Next, we optimized
51
Initially, we expected to observe oxidative coupling parameters for the formation of N-[2-(5,6,7,8-tetra-
52 of N-acyl-2-aminobiphenyl (1a) with a diphenylacety- phenylnaphthalen-1-yl)phenyl]acetamide as described
53 lene (2a) to yield an azepine. Instead, we observed herein. Other oxidizing agents, such as AgOAc, K2S2
54 dual CÀH bond cleavage at C-2’ and C-3’ via oxidative O8, and p-benzoquinone (BQ), except for Cu(OAc)2,
55 coupling of two diphenylacetylenes with palladium resulted in poor yields (entries 2–5). Other tested
56 acetate as a catalyst and air as an oxidant to afford N- aromatic and chlorinated solvents such as toluene,
57 [2-(5,6,7,8-tetraphenylnaphthalen-1-yl) phenyl]aceta- chlorobenzene (CB), ortho-dichlorobenzene (o-DCB),
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and 1,2-dichloroethane (DCE) did not increase the engendered slightly poorer yields (44–69%). Further-
yields notably (entries 6–9). However, the use of polar more, the study of the electronic effect between the
aprotic solvents, such as dimethyl sulfoxide (DMSO) interplay of both aryl rings revealed the same effect,
and DMF, resulted in a promising increase in yields up providing 3i–o in 49–72% yields. Furthermore, we
to 74% with 50 mol% sodium acetate used as the observed the formation of diphenylphenanthrenes 3a’,
additive (entries 10 and 11). The use of Cu(OAc)2 3d’, and 3h’ in 8%, 6%, and 21% yields, respectively,
(20 mol%)/O2 as a hybrid oxidant provided a 79% through C-2’ÀH bond activation, diphenylacetylene
yield at 1008C (entry 12). Our parameter study of insertion, C-6ÀH bond activation, and reductive elim-
reactant molar ratios, ranging from 1:1.2 to 1:3 for ination. Four other typical internal alkynes (2b–e)
10 1a:2a, to achieve full consumption of reactant 1a were also examined for the insertion reaction – an
11 revealed that the reaction yield was optimal at a internal alkyne with an EDG moiety, di-p-tolylacety-
12 reactant molar ratio of 1:2.4 (entries 11 and 13–15). lene (2b), produced 3p in 68% yield, and those with
13 Notably, among the tested additives including LiOAc EWG groups, di-p-chlorophenylacetylene (2c) and di-
14 and KOAc, the reaction with NaOAc as additive p-trifluoromethylphenylacetylene (2d), resulted in 3q–
15 afforded the highest yields (46–66%) for the desired r in 44% and 30% yields, respectively. These reactions
16 products (entries 16–20). NaOAc played a crucial role were concomitant with the formation of diarylphenan-
17 in product formation because of its possible potential threnes 3q’ and 3r’ in 8% and 30% yields, respectively.
18 in stabilizing the relevant Pd(II) intermediates during In addition, the reaction with unsymmetrical alkyne
19 the reactions. We also examined reactions for observ- 2e formed 3s solely in 62% yield. The molecular
20 ing the additional ligand effect of adding Ac-Gly-OH structures of the novel annulated products, repre-
21 (entry 21) and 2,2’-bipyridine (entry 22), and no con- sented by substituted naphthalene 3a and by-product
22 siderable increase in the yields was observed. Further- phenanthrene 3r’, were confirmed through single-
23 more, diluting the solution concentration reduced the crystal X-ray diffraction analysis.[14]
24 yields by a small amount (entries 23 and 24). A control
A tentative yet plausible mechanism involving two
25 experiment involving the use of RuCl2(p-cymene)/ CÀH bond activations and alkyne insertions is pre-
26 AgOTf as a catalyst and another substrate without sented in Scheme 2. Initially, ortho C–H was activated
27 substitution on the nitrogen of the 2-aminobiphenyl on the 2-aryl moiety to yield intermediate Ia after
28 provided no corresponding products (entries 25 and coordination of substrate 1 with palladium(II). Coor-
29 26). Among the studied conditions, a notable minor dination and insertion of alkyne 2 with intermediate
30 by-product, 9,10-diphenyl phenanthrene 3a’, was iso- Ia produced a 7-membered palladacycle intermediate,
31 lated in less than 6% yield under certain conditions Ib. Dissociation of the Pd(II)ÀN bond led to two
32 (entries 2 and 13). Moreover, trace amounts of a by- possible second CÀH bond activations – activation of
33 product, 6-phenylphenanthridine (3t),[13] were isolated the meta C-3’ÀH bond generated a 5-membered
34 through oxidative cleavage of diphenylacetylene (en- palladacycle intermediate, Ic, and activation of the C-
35 tries 6 and 7; see the Supporting Information, 6ÀH bond formed a 7-membered palladacycle inter-
36 Figures S61 and 62 for spectral data). Our examination mediate, Ie. The major product 3 was produced by the
37 of the various experimental conditions revealed that second coordination and insertion of the alkyne to
38 the following conditions provided the maximum yield: intermediate Ic followed by reductive elimination
39 Pd(OAc)2 (10 mol%) as the catalyst, NaOAc from intermediate Id or Id’, based on a former nickel-
40 (50 mol%) as the additive, and Cu(OAc)2 (0.2 equiv.)/ catalyzed oxidative annulation via C–H activation/
41 O2 as the oxidant at 1008C (entry 12) or O2 (1 atm) as alkyne insertion reaction.[6,15] The by-products, phe-
42 the sole oxidant in DMF at 1208C for 24 h (entry 11). nanthrenes, were produced through further reductive
43
Table 2 summarizes the reaction scope study of this elimination from intermediate Ie. The mechanistic
44 double CÀH bond activation/alkyne insertion with N- investigation of directing group-assisted double C–H
45 acyl-2-aminobiaryls. The reactivity of the studied activation was conducted through a deuterium-label-
46 substrates was highly dependent on the substitution ing experiment. A kinetic isotope effect (KIE) study
47 effect produced by both aryl moieties of N-acyl-2- revealed a kH/kD value of 1.66 in a 20 min reaction
48 aminobiaryls and substituted acetylenes. Notably, (Scheme 3). Because the kH/kD value was not ex-
49 substrates 3b–e containing electron-donating groups tremely high, that both C–H activation steps are the
50 (EDGs) on the 2’-aryl moiety underwent dual CÀH rate-limiting steps is unlikely; therefore, either one of
51 bond activation and coupling with diphenylacetylene these two steps as the rate-limiting step is more likely.
52 smoothly to provide favorable yields of 62–75%, likely However, determining which step is the rate-limiting
53 attributed to the enhanced reactivity toward CÀH one was not feasible in the present study.
54 bond activation afforded by EDGs. However, sub-
Our preliminary investigation showed that the
55 strates 3f–h containing an electron-withdrawing group conversion of compounds 3 to corresponding carba-
56 (EWG) did not undergo effective CÀH bond activa- zoles by Pd-catalyzed intramolecular CÀN bond
57 tion and coupling with substituted acetylenes and formation through the CÀH bond activation strategy
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Table 2. Substrate scope study[a]
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2
3
4
5
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7
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10
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18
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[a] Reaction conditions: All reactions were carried out using substrate 1 (0.30 mmol), substrate 2 (0.72 mmol), additive NaOAc
(50 mol%), catalyst Pd(OAc)2 (10 mol%), and O2 (1 atm) in 2 mL freshly distilled DMF at 1208C for 24 h.
[b]
Cu(OAc)2 (20 mol%)/O2 (1 atm) at 1008C.
5 equiv. of the unsymmetrical alkyne and Cu(OAc)2 (1 equiv.)/O2 (1 atm) at 808C were used.
[c]
[d]
Cu(OAc)2 (1 equiv.)/O2 (1 atm) at 808C.
47 was relatively difficult because of the poor reactivity through ortho and meta CÀH bond activations fol-
48 afforded by steric and electronic effects of the lowed by two respective alkyne insertions. The corre-
49 naphthalene moiety, with an approximate yield of 30– sponding CÀH bond activation of N-acyl-2-amino-
50 40% under Buchwald’s protocol.[15] The fluorescence biaryl appeared to be solvent-controlled, and this
51 spectra of carbazoles 4a and 4p and their precursors, reaction used molecular oxygen or copper(II)/oxygen
52 naphthalenes 3a and 3p, showed emission wavelengths as oxidants to complete a catalytic cycle. A further
53 at 411, 410, 399, and 395 nm with quantum yields of mechanistic study and development using the de-
54 9.4%, 8.0%, 8.8%, and 7.6%, respectively, in a chloro- scribed strategy to explore new optoelectronic materi-
55 form solution (Supporting Information, Figure S60).
In summary, we have demonstrated a novel
als is underway in our laboratory.
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57 aromatic homologation of N-acyl-2-aminobiaryls
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Scheme 2. Proposed catalytic cycle.
purified through flash silica gel column chromatography
(hexanes/EtOAc) to afford compound 3.
Experimental Section
General Procedure for the Palladium-Catalyzed
Synthesis of N-[2-(5,6,7,8-Tetraarylnaphthalen-
1-yl)aryl]acetamides
Acknowledgements
We thank the Ministry of Science and Technology of Taiwan
for supporting this research financially (MOST104-2113M-
009-014-MY3).
To a dry reaction tube, NaOAc (0.15 mmol) was added and
the reaction tube was heated using a flame gun under
vacuum. After the tube hads cooled down to room temper-
ature, N-acyl-2-aminobiaryl
1
(0.3 mmol), Pd(OAc)2
(0.03 mmol), substituted acetylene (0.72 mmol), and a stir-
ring bar were added and the tube was sealed with a septum.
Subsequently, freshly distilled DMF (2 mL) was added and
the tube was purged with O2 for 15 min. The tube was closed
shortly thereafter using a cap, placed in an oil bath, and the
mixture vigorously stirred at 1208C for 24 h. Upon comple-
tion of the reaction, the reaction mixture was cooled down to
room temperature and diluted with ethyl acetate followed by
filtration through a thin pad of celite. The filtrate was
concentrated under vacuum and the crude residue was
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Palladium-Catalyzed Selective Aryl Ring C–H Activa-
tion of N-Acyl-2-aminobiaryls: Efficient Access to
Multiaryl-Substituted Naphthalenes
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