Chemoselective synthesis of naphthylamides and isoquinolinones via rhodium-catalyzed oxidative dehydrogenative annulation of benzamides with alkynes

Article abstract of DOI:10.1002/adsc.201200372

A rhodiumACHTUNGTRENUNG(III)-catalyzed direct dehydrogenative annulation of benzamides with alkynes through chelating-assisted C-H activation has been developed. Naphthylamide and isoquinolinone derivatives can be chemoselectively obtained by this protoco

Full text of DOI:10.1002/adsc.201200372

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DOI: 10.1002/adsc.201200372
Chemoselective Synthesis of Naphthylamides and Isoquinolinones
via Rhodium-Catalyzed Oxidative Dehydrogenative Annulation
of Benzamides with Alkynes
Zhuangzhi Shi,a,c Conghui Tang,a,c and Ning Jiaoa,b,*
a
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Peking
University, Xue Yuan Rd. 38, Beijing 100191, Peopleꢀs Pepublic of China
Fax : (+86)-010-8280-5297; e-mail: jiaoning@bjmu.edu.cn
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, Peopleꢀs Republic
b
of China
c
These two authors contributed equally to this work
Received: April 27, 2012; Revised: July 20, 2012; Published online: October 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200372.
Abstract: A rhodium
genative annulation of benzamides with alkynes
through chelating-assisted C H activation has been
developed. Naphthylamide and isoquinolinone de-
rivatives can be chemoselectively obtained by this
protocol.
N
lenes to construct a tetracyclic dibenzoquinolizinone
framework was developed by the groups of Miura
and Li, respectively [Eq. (2), Scheme 1].[15] Guimond
and co-workers found an external oxidant-free pro-
cess to afford the isoquinolone motif via RhACHTNUTRGNE(NUG III)-cata-
lyzed annulation of benzhydroxamic acids with al-
À
kynes in which the N O bond on the directing-group
acts as an instrument for C N bond formation and
À
Keywords: alkynes; annulation; benzamides; C H
activation; rhodium
catalyst release [Eq. (3), Scheme 1].[16] Schipper et al.
reported an intermolecular cationic rhodiumACHTNUTRGNE(UNG III)-cat-
alyzed hydroarylation of alkynes with N-mono- or
N,N-disubstituted benzamides [Eq. (4), Scheme 1).[17]
Herein, we want to report a different process that af-
Polyarylated aromatic and heteroaromatic compounds fords the naphthylamide and/or isoquinolinone motifs
with condensed aromatic cores have attracted consid- chemoselectively via Rh(III)-catalyzed dehydrogena-
AHCTUNGTRENNUNG
erable attention in the electrochemical, photochemi- tive annulation of benzamide with alkynes [Eq. (5),
cal and functional materials fields because of their Scheme 1].
stability, their enhanced ability to transport charge,
Our attention was initially drawn to the naphthyla-
and their fluorescent properties in the solid-state that mide synthesis from N-isopropylbenzamide 1a with
are brought about by the aryl groups.[1] Transition 1,2-diphenylethyne 2a via C H activation in the pres-
metal-catalyzed C H functionalization has been ence of [(RhCp*Cl2)2] in toluene under 1 atm O2.
À
À
proved to be a powerful method for the construction Under these conditions, no desired product 3aa was
of heterocycles in organic synthesis.[2] Alkynes as im- observed (entry 1, Table 1). To our delight, 35% of
portant building blocks and synthons have been 3aa and 8% of 4aa were achieved when Cu
widely employed for the construction of multiple ary- was employed as oxidant (entry 2, Table 1). When di-
lated compounds.[3,4] Recently, Rh
(III)-catalyzed oxi- oxane and CH3CN were evaluated, the reactions only
ACHTUNGTRENNUNG(OAc)2
AHCTUNGTRENNUNG
dative coupling reactions of acetanilides, benzoic acid, gave low yields (entries 3 and 4, Table 1). It was
À
amides, imines, ketones through C H activation have noted that 73% yield of total products was achieved
been developed by Fagnou,[5] Miura,[6] Jones,[7] Glo- by using DMF as solvent with a 3:1 ratio of major
rius,[8] Bergman and Ellman,[9] Shi,[10] Li,[11] Cheng[12] product 3aa to 4aa (entry 5, Table 1). Other oxidants
and others.[13] In 2010, Rovis and Hyster developed such as AgOAc were less effective than Cu
ACHTUNGTRENNUNG(OAc)2
the oxidative annulation of benzamides and alkynes (entry 6, Table 1). Further studies indicated that the
in the presence of Cu(II) oxidants, and both secon- addition of Ag salt in this catalytic system could de-
dary N-alkyl- and N-arylbenzamides can be applied as crease the yield of 3aa and increase that of 4aa
effective substrates [Eq. (1), Scheme 1].[14] The reac- (entry 7, Table 1). When the loading of Cu
ACHTUNGTRENNUNG
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Scheme 1. RhACHTUNGTRENNUNG(III)-catalyzed reactions of benzamide and alkynes.
were obtained (entry 8, Table 1). However, other ad- 3ab in 35% yield (entry 6, Table 2). Unfortunately,
ditives such as AgBF4 would decrease the ratio of 4aa the terminal alkynes did not work under these condi-
in the total products (entry 9, Table 1).
tions.
We next attempted synthesis of isoquinolones
With this set of conditions in hand, the scope of
this amide 3 formation by benzannulation was dem- under the optimized reaction conditions of 4aa. The
onstrated with a variety of substituted N-isopropyl- substrate N-isopropyl-4-methylbenzamide (1f) reacted
benzamides. N-Isopropylbenzamide was successfully with diphenylethyne (2a) to give the desired product
transformed into the desired product 3aa in 55% 4fa in 81% yield (Table 3). Moreover, tert-butyl, n-
yield with a little 4aa which could be separated easily pentyl and phenyl groups can also be incorporated in
via column chromatography on silica gel (entry 1, the benzannulated isoquinolone units in this transfor-
Table 2). The halogen-containing motifs such as 1b mation (4ga–4ia, Table 3). Besides the N-isopropyl
and 1c worked well in this transformation, giving 1:2 substrate, N-cyclohexyl-4-methylbenzamide (1j) can
oxidative coupling products 3 under these conditions also be converted into the desired compound in 69%
in moderate to good yields with only trace of 1:3 cou- yield (4ja, Table 3). The scope of the internal alkynes
pling products 4 (entries 2 and 3, Table 2). The struc- was then investigated with 2b as the partner. The re-
ture of 3ba was further determined by X-ray (see the actions of 1f or 1g with internal alkyne 2b also pro-
Supporting Information).[18] The meta- and ortho-sub- ceeded well to afford 4fb and 4gb in moderate yields,
stituted N-isopropylbenzamides could be smoothly respectively (Table 3).
converted into the desired products (entries 4 and 5,
On the basis of the known Rh
(III)-catalyzed, di-
À
Table 2). The scope of the intermolecular cyclization recting-group assisted C H bond activation reac-
reaction was further expanded to other internal al- tions,[5–17,19] a possible mechanism is proposed to ac-
kynes such as 2b, which produced the desired product count for the present catalytic reaction (Scheme 2). In
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Chemoselective Synthesis of Naphthylamides and Isoquinolinones
(III)-catalyzed 1:2 and 1:3 coupling of 1a with 2a.[a]
Table 1. Rh
ACHTUNGTRENNUNG
[a]
[b]
1a (0.2 mmol), 2a (0.5 mmol), [(RhCp*Cl2)2] (0.005 mmol), in solvent (1.0 mL), 1 atm
of N2. We did not observe any isoquinolone products like Rovisꢀ work in these reac-
tions
2a (0.7 mmol) was used.
the first step, coordination of the nitrogen atom of 1a
In conclusion, we have developed an rhodiumACHTUNGTRENNUNG(III)-
À
to an Rh
N
À
bond activation form a five-membered rhodacycle A. zamides with alkynes through chelating-assisted C H
Subsequent alkyne insertion generates intermediate activation. Naphthylamide and isoquinolinone deriva-
À
B. Then the second C H bond activation on its tives can be chemoselectively obtained by this proto-
À
phenyl ring may occur affording the cyclorhodation col. Multiple C H bond cleavages are involved in this
intermediate C. Subsequently, another alkyne inser- transformation, which provides
a straightforward
tion and reductive elimination can generate the naph- route to polyarylated heteroaromatic compounds with
thylamide 3 and an Rh(I) complex, which is then re- condensed aromatic cores. Further studies to clearly
oxidized to Rh
(catalytic cycle a, Scheme 2). Coordination of the applications are ongoing in our laboratory.
formed naphthylamides 3 to Rh(III)Ln species again
ACHTUNGTRENNUNG(III)Ln species by two atoms of Cu(II) understand the reaction mechanism and the synthetic
AHCTUNGTRENNUNG
À
appears to be the key for the third C H bond cleav-
age, this step should be more difficult than the first
one, and it is able to be promoted by more reactive
Experimental Section
RhACHTUNGTRENNUNG(III)Ln species in the presence of AgSbF6. Chemo-
General Procedure for Table 2
selective insertion of the third alkyne into the five-
membered rhodacycle E gives seven-membered rho-
dacycle F. Subsequent reductive elimination takes
place to produce the isoquinolone 4 and Rh(I) spe-
To a 20-mL Schlenk tube were added N-isopropylbenzamide
1a (0.2 mmol, 32.6 mg), 1,2-diphenylethyne 2a (0.5 mmol,
89.0 mg), [(RhCp*Cl2)2] (3.1 mg, 2.5 mol%), CuACHTUNGTRENNUNG(OAc)2
(76.0 mg, 0.42 mmol), followed by addition of DMF
(1.0 mL) under N2. The mixture was heated at 1008C and
stirred overnight under N2 (1 atm) as monitored by TLC.
The solution was then cooled to room temperature, diluted
cies. In the presence of another 2 equiv. of Cu
the resulting Rh(I) species can transfer to the catalyti-
cally active Rh(III)Ln (catalytic cycle b, Scheme 2).
ACHTUNGERTN(NUNG OAc)2,
ACHTUNGTRENNUNG
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Table 2. RhACHTNUTRGNEUNG(III)-catalyzed synthesis of naphthylamides via cyclization of alkynes with dif-
ferent N-isopropylbenzamides.[a]
[a]
1
(0.20 mmol), 2a (0.50 mmol), [(RhCp*Cl2)2] (0.005 mmol) and CuACTHNGUTRENU(NG OAc)2
(0.42 mmol), in DMF (1.0 mL), 1 atm of N2, 1008C, overnight; isolated yield; Traces
of products 4 were also obtained in some cases as minor products.
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Chemoselective Synthesis of Naphthylamides and Isoquinolinones
Table 3. RhACHTUNGTRENNUNG(III)-catalyzed synthesis of isoquinolones via cyc-
with ethyl acetate (30 mL), washed with H2O (3ꢂ10 mL),
dried over MgSO4, filtered, and evaporated under vacuum.
The crude product was purified by column chromatography
on silica gel.
lization of alkynes with different N-isopropylbenzamides.[a,b]
General Procedure for Table 3
To a 20-mL Schlenk tube were added 0.2 mmol N-isopropyl-
benzamide (1a), 0.7 mmol 1,2-diphenylethyne (2a),
[(RhCp*Cl2)2] (3.1 mg, 2.5 mol%), AgSbF6 (6.8 mg,
10 mol%), CuACTHUNRGTNEUNG(OAc)2 (148.0 mg, 0.82 mmol), and the tube
was purged with N2 for three times, followed by addition of
DMF (1.0 mL). The mixture was heated at 1208C under N2
(1 atm) and stirred overnight as monitored by TLC. The
processing procedure was the same as described above
Acknowledgements
Financial support from National Basic Research Program of
China (973 Program) (Grant No. 2009CB825300) and Na-
tional Science Foundation of China (No. 21172006) are great-
ly appreciated.
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