Iridium-catalyzed annulation of N -arylcarbamoyl chlorides with internal alkynes

Article abstract of DOI:10.1021/ja104153k

An iridium complex successfully catalyzed the annulation of various N-arylcarbamoyl chlorides with internal alkynes to afford 2-quinolones in good to excellent yields. The present reaction is widely applicable to substrates with various functionalities. An amide-iridacycle complex was isolated, and it is likely that such an iridacycle species is a key intermediate in the catalytic reaction.

Full text of DOI:10.1021/ja104153k

Published on Web 06/28/2010
Iridium-Catalyzed Annulation of N-Arylcarbamoyl Chlorides with Internal
Alkynes
Tomohiro Iwai, Tetsuaki Fujihara, Jun Terao, and Yasushi Tsuji*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Nishikyo-ku, Kyoto 615-8510, Japan
Received May 14, 2010; E-mail: ytsuji@scl.kyoto-u.ac.jp
Table 1. Iridium-Catalyzed Reaction of 1 with 2a
Abstract: An iridium complex successfully catalyzed the annu-
lation of various N-arylcarbamoyl chlorides with internal alkynes
to afford 2-quinolones in good to excellent yields. The present
reaction is widely applicable to substrates with various function-
alities. An amide-iridacycle complex was isolated, and it is likely
that such an iridacycle species is a key intermediate in the
c
entry
1: R1
2: R2, R3
3
yield (%)b
3/3′
catalytic reaction.
1
2
3
4
5
6
7
8
9
1a: H
1a: H
1a: H
2a: Bu, Bu
3aa 92 (82)d
3ab 62
-
2b: MeOCH2, MeOCH2
2c: Ph, Ph
-
-
-
-
-
3ac 67e
1b: MeO 2c: Ph, Ph
3bc 82e
The large number of carbonyl-containing N-heterocycles in
biologically active molecules have motivated many efforts for their
synthesis and functionalization.1 The transition-metal-catalyzed
intermolecular reaction of carbonyl precursors with alkynes is one
of the most straightforward methods for constructing cyclic carbonyl
compounds.2-4 On the other hand, carbamoyl chlorides are useful
substrates for introducing amide functionality in organic synthesis,
and they are mainly utilized in transition-metal-catalyzed reactions
as coupling reagents.5 We considered that N-arylcarbamoyl chloride,
in particular, would be a promising substrate for providing
2-quinolones6-8 via transition-metal-catalyzed annulation with
alkynes. To realize this transformation, facile decarbonylation9,10
from the putative acylmetal species must be suppressed in the
catalysis. We recently reported the iridium-catalyzed addition of
acid chlorides to alkynes11a and the palladium-catalyzed addition
of formamides to alkynes11b by suppressing the decarbonylation.
Herein we report that the annulation of N-arylcarbamoyl chlorides
(1) with internal alkynes (2) to afford 2-quinolones proceeds
efficiently in the presence of an iridium complex.
First, N-methyl-N-phenylcarbamoyl chloride (1a) was reacted with
5-decyne (2a) in the presence of a catalytic amount (2.5 mol %) of
[IrCl(cod)]2 (cod ) 1,5-cyclooctadiene) and 30 mol % added cod.12
Reaction in refluxing o-xylene for 20 h afforded 3,4-dibutyl-1-methyl-
2-quinolone (3aa) in 92% yield (Table 1, entry 1). Reaction in refluxing
toluene also provided 3aa in 82% yield. However, with PPh3 as an
additive, the yields of 3aa decreased to 52% (P/Ir ) 1) and 25% (P/Ir
) 2) in refluxing toluene. Addition of bases such as Na2CO3 and N(i-
Pr)2Et to scavenge the evolved HCl did not affect the reaction at all.
Various aliphatic and aromatic internal alkynes (2b-i) afforded the
corresponding 2-quinolones. Importantly, no indole derivatives pro-
duced by decarbonylation were obtained during the reaction. 1,4-
Dimethoxy-2-butyne (2b) and diphenylacetylene (2c) reacted with 1a
to give 3ab and 3ac, respectively, in good yields (entries 2 and 3).
Diarylalkynes 2c-e successfully reacted with N-(3-methoxyphenyl)-
N-methylcarbamoyl chloride (1b) to give 3bc-be in high yields,
notably as single regioisomers (entries 4-6). Unsymmetrical alkynes
1-cyclohexyl-1-propyne (2f) and 1-phenyl-1-propyne (2g) reacted
smoothly with 1a to afford 3af and 3ag, respectively, in high yields,
albeit with low regioselectivities (entries 7 and 8). The use of
unsymmetrical alkynes bearing ether functionality (2h and 2i) improved
1b: MeO 2d: 4-MeOC6H4, 4-MeOC6H4 3bd 89e
1b: MeO 2e: 4-ClC6H4, 4-ClC6H4
3be 76e
3af 89
3ag 95
3ah 91
3ai 69
1a: H
1a: H
1a: H
2f: Me, Cy
2g: Ph, Me
55/45
58/42
72/28
82/18
2h: MeOCH2, n-C5H11
2i: Me, 2-MeOC6H4
10 1a: H
a Conditions: 1 (0.50 mmol), 2 (1.0 mmol), [IrCl(cod)]2 (0.0125
mmol, 2.5 mol %), and cod (0.15 mmol, 30 mol %) in refluxing
o-xylene (1.0 mL) for 20 h. b Isolated yields of 3 and 3′. c The 3/3′ ratio
was determined by GC. d In refluxing toluene. e [IrCl(cod)]2 (0.025
mmol, 5.0 mol %), cod (0.50 mmol, 100 mol %).
the regioselectivity of the products (3ah and 3ai), possibly as a result
of the directing effect of the oxygen atom (entries 9 and 10). Terminal
alkynes such as 1-decyne and phenylacetylene did not afford 3.
A wide variety of carbamoyl chlorides (1) can easily be synthesized
from the corresponding amines.13 Various carbamoyl chlorides
(1b-v)12 thus obtained were reacted with 2a, as shown in Table 2.
Electron-rich (1b-f) and electron-poor (1g-l) phenyl moieties on the
nitrogen smoothly participated in the cyclization to afford 3ba-fa
(entries 1-5) and 3ga-la (entries 6-11) in good to excellent yields.
Again, the cyclization of 1b and 1e was regioselective, affording 3ba
and 3ea, respectively, as single isomers (entries 1 and 4). N-
Phenylcarbamoyl chlorides bearing benzyl (1m), 4-methoxyphenyl-
methyl (1n), cyclohexyl (1o), and phenyl (1p) substituents on the
nitrogen atom afforded the corresponding 2-quinolones (3ma-pa) in
good to excellent yields (entries 12-15). The 4-methoxyphenylmethyl
group of 3na (entry 13) was removed by treatment with trifluoroacetic
acid, affording 3,4-dibutyl-2-quinolone in 91% yield.12 Condensed ring
systems (3qa-ta) were constructed using 1q-t (entries 16-19).
Besides 2-quinolones, N-butyl-N-2-thienylcarbamoyl chloride (1u)
afforded the corresponding product 3ua in excellent yield (entry 20).
It is worth noting that the reaction could be applied not only to N-aryl-
substituted carbamoyl chlorides but also to N-alkenyl-substituted 1v,
which provided the corresponding pyridone derivative 3va in 52%
yield (entry 21).
To gain further insight into the mechanism of the catalytic
reaction, stoichiometric reactions between [IrCl(cod)]2 and 1a were
carried out in the presence of added cod (eqs 1 and 2). After 12 h,
1a was converted completely in refluxing toluene. When 2a was
then added to the reaction mixture under reflux, 3aa was obtained
9
9602 J. AM. CHEM. SOC. 2010, 132, 9602–9603
10.1021/ja104153k  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of 3 from 1 and 2a (entry, product, yield)a b
,
carbamoylchloroiridium(III) intermediate A.14 Next, an intramolecular
cyclization (step 2) affords five-membered iridacycle B.15 The relevant
complex 4 was isolated with the aid of PPh3 coordination in eq 2. The
cyclization must be electrophilic, since 3wa was preferentially obtained
over 3wa′ in eq 3. The construction of the iridacycle B would play a
crucial role in suppressing the decarbonylation. Subsequent insertion
of 2 (step 3) followed by reductive elimination (step 4) affords the
2-quinolone and regenerates the iridium(I) species.
In conclusion, 2-quinolones have been successfully obtained by
iridium-catalyzed annulation of N-arylcarbamoyl chlorides (1) with
internal alkynes (2). It is likely that iridacycle B is a key
intermediate in the catalytic reaction. Further studies of the reaction
mechanism and application of the catalysis are now in progress.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. T.I. is
grateful for a Research Fellowship for Young Scientists from JSPS.
a Conditions: 1 (0.50 mmol), 2a (1.0 mmol), [IrCl(cod)]2 (0.0125
mmol, 2.5 mol %), and cod (0.15 mmol, 30 mol %) in refluxing
o-xylene (1.0 mL) for 20 h. b Isolated yields. c [IrCl(cod)]2 (0.025 mmol,
5.0 mol %). d For 36 h. e 1s (0.25 mmol), 2a (1.0 mmol), [IrCl(cod)]2
(0.0125 mmol, 5.0 mol %), cod (0.15 mmol, 60 mol %). f For 48 h.
Supporting Information Available: Experimental procedures,
characterization of the products, and crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
Scheme 1. Plausible Reaction Mechanism
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in 64% yield (eq 1). In eq 1, however, no iridium complexes were
identified. Therefore, instead of 2a, PPh3 (P/Ir ) 2) was added into
the reaction mixture (eq 2). As a result, iridium(III) metallacycle
complex 4 was isolated in 69% yield, and the structure of 4 was
confirmed by X-ray diffraction.12 Iridacycle 4 did not provide 3aa
either catalytically or in a stoichiometric reaction with 2a in
refluxing toluene or xylene. As for the cyclization, 1w having both
the 3-methoxyphenyl and 3-trifluoromethylphenyl moieties was
reacted with 2a (eq 3). The cyclization occurred preferentially at
the more-electron-rich phenyl ring (3wa/3wa′ ) 17/1).
(9) (a) Iwai, T.; Fujihara, T.; Tsuji, Y. Chem. Commun. 2008, 6215. (b) Fristrup,
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indenones via migration/reinsertion of CO has been reported. See: Kokubo,
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Chem. Soc. 2010, 132, 2094.
(12) See the Supporting Information for details.
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Organometallics 1994, 13, 4952.
A plausible reaction mechanism is shown in Scheme 1. Oxidative
addition of 1 to the iridium(I) species (step 1) occurs, generating the
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J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010 9603