Preparation of benzolactams by Pd(OAC)2-catalyzed direct aromatic carbonylation

Article abstract of DOI:10.1021/ja045342+

We developed a new method for Pd(II)-catalyzed direct aromatic carbonylation in a phosphine-free catalytic system using Pd(OAc)₂ and Cu(OAc)₂ in an atmosphere of CO gas containing air. The carbonylation proceeded with ortho-palladation, inducing a remarkable site selectivity to afford a variety of five- or six-membered benzolactams from secondary ω-arylalkylamines, such as N-alkylbenzylamines or N-alkylphenethylamines. Copyright

Full text of DOI:10.1021/ja045342+

Published on Web 10/16/2004
Preparation of Benzolactams by Pd(OAc)2-Catalyzed Direct
Aromatic Carbonylation
Kazuhiko Orito,* Akiyoshi Horibata, Takatoshi Nakamura, Harumi Ushito, Hideo Nagasaki,
Motoki Yuguchi, Satoshi Yamashita, and Masao Tokuda
Laboratory of Organic Synthesis, DiVision of Molecular Chemistry, Graduate School of Engineering,
Hokkaido UniVersity, Sapporo 060-8628, Japan
Received August 3, 2004; E-mail: orito@org-mc.eng.hokudai.ac.jp
Table 1. Carbonylation of N-Alkyl-ω-arylalkylamines 1a
There have been many reported methods for the direct or indirect
carbonylation of aromatic compounds using carbon monoxide and
transition-metal catalysts.1 Mori and Ban reported the synthesis of
benzolactams and benzolactones by Pd(0)-catalyzed carbonylation
in 1978 and 1979.2 Since then, such carbonylation via a halogen-
metal exchange has been extensively studied to develop methods
for the syntheses of a variety of biologically active heterocyclic
compounds. In contrast, there has been no method established for
the catalytic transformation of ω-arylalkylamines by a direct
aromatic metalation to the corresponding benzolactams, although
it has been reported that carbonylation of azobenzenes and
benzalimines using carbonyl complexes of Co, Mo, or Cr as
catalysts or cyclopalladation products of N,N-dialkylbenzylamines
afforded benzolactams.3,4 In this report, we describe a Pd(II)-
catalyzed carbonylation using Pd(OAc)2 and Cu(OAc)2 in an
atmosphere of CO gas containing air. This phosphine-free catalytic
system provides five- or six-membered benzolactams from N-alkyl-
ω-arylalkylamines.
Carbonylation was carried out by stirring a suspension of a
secondary amine 1,5 Pd(OAc)2 (5 mol %), and Cu(OAc)2 (50 mol
%) in a 0.1 M toluene solution in an oil bath at 120 °C in an
atmosphere of CO gas containing air (0.5 molar equiv of O2),
delivered from a toy balloon.6 The reaction mixture was then filtered
to remove insoluble materials, and the filtrate was concentrated to
afford a crude product, which was purified by crystallization or
preparative TLC.
Carbonylation of phenethylamine 1a proceeded slowly to give
benzolactam 2a in 64% yield after 24 h. Carbonylation of 3,4-
dialkoxyphenethylamine derivative 1b or 1c afforded a single
benzolactam 2b (86%, 2 h) or 3c (24%, 24 h), respectively, with
different regioselectivity. Benzylic amines underwent carbonylation
at a rate much faster than that of the corresponding phenethylamines.
The rate of the five-membered ring formation was 11 times greater
than that of the six-membered ring formation (entry 7 in Table 1).
The presence of a methylenedioxy group at the 3,4-positions
increased the reaction rate by 10-fold in the six-membered ring
closure (entry 8) and by 4-fold in the five-membered ring closure
(entry 9). 3,4-Methylenedioxydibenzylamine 1e gave two regioi-
somers of benzolactams in a 4:1 ratio of 2e and 3e, which is similar
to the result in entry 9, and 3,4-dimethoxybenzylamine 1f gave 3f
together with 2f in a 3:1 ratio. A similar carbonylation of the same
amine (1f) using Pd(OAc)2 (1 equiv) without Cu(OAc)2 produced
2f and 3f in a 1:9 ratio, and Pd(OAc)2‚2PPh3 (1 equiv) afforded a
1:2 mixture, suggesting that Cu(OAc)2 works as a ligand7 as well
as an oxidant.
a Under CO gas containing air (0.5 molar equiv of O2); the substrate,
Pd(OAc)2 (5 mol %), and Cu(OAc)2 (50 mol %) were suspended in toluene
(0.1 M) and heated in an oil bath at 120 °C for 2 or 24 h. b Product ratios
1
were determined by H NMR analysis.
The electronic effects of substituents on the phenyl group were
examined. A 2,3-methylenedioxy group did not accelerate the
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J. AM. CHEM. SOC. 2004, 126, 14342-14343
10.1021/ja045342+ CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Direct Aromatic Carbonylation of N-Alkylphen-
ethylamines
zolactam 10f and not its 7-nitro isomer 9f, presenting an ultimate
steric effect in the present study (see also entry 12 in Table 1).
In summary, we have developed a Pd(II)-catalyzed direct
aromatic carbonylation, which proceeds with remarkable site
selectivity to afford a variety of five- or six-membered benzolactams
from secondary ω-phenylalkylamines in a phosphine-free catalytic
system using Pd(OAc)2 and Cu(OAc)2 in an atmosphere of CO
gas containing air.13 Studies designed to produce other nitrogen-
containing heterocyclic ring systems are currently underway.
Acknowledgment. We thank the Akiyama Foundation for
generous financial support, and N.E. CHEMCAT Corporation for
the generous donation of palladium catalysts.
Table 2. Carbonylation of N-Benzylpropylamines 5-7a
Supporting Information Available: Experimental procedures and
spectral data for substrates and products 1-11. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For general reviews, see: (a) Colquhoun, H. M.; Thompson, D. J.; Twigg,
M. V. Carbonylation: Direct Synthesis of Carbonyl Compounds; Plenum
Press: New York, 1991. (b) Tsuji, J. Palladium Reagents and Catalysts:
InnoVation in Organic Synthesis; John Wiley & Sons: Chichester, U.K.,
1995. (c) Tkatchenko, I. In ComprehensiVe Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press:
Oxford, U.K., 1982; Vol. 8, pp 101-223.
(2) (a) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43, 1684-1687.
(b) Mori, M.; Chiba, K.; Inotsume, N.; Ban, M. Heterocycles 1979, 12,
921-924.
(3) For carbonylation of azobenzenes, benzalimines, and other cyclopalladation
products leading to benzolactams, see: (a) Ryabov, A. D. Synthesis 1985,
233-252. (b) Chem. ReV. 1990, 90, 403-424. (c) Tsuji, J. Palladium
Reagents and Catalysts: InnoVation in Organic Synthesis; John Wiley &
Sons: Chichester, U.K., 1995; pp 87-94.
a, X ) OMe 78% (67%)
48% (36%) 49% (38%) 79% (67%)
25% (18%) 68% (59%) 85% (72%)
b, X ) Me
c, X ) Cl
d, X ) Br
e ,X ) CN
f, X ) NO2
92% (76%)
81% (73%)b 45% (21%) 45% (31%) 82% (71%)
55% (50%)b 28% (22%) 58% (54%) 79% (68%)
c
51% (27%) 45% (24%) 93% (74%)
0% 81% (68%) 81% (72%)
90% (69%)
a 1H NMR yields; isolated yields are in parentheses. b 2d was also formed
in 5 and 36% yields from 5c and 5d, respectively (ref 12). c No data are
available.
carbonylation (entry 10). No difference between nitro and alkoxy
groups was observed in p-substitution (entry 11). The m-nitro group
in 1l caused a slight deactivation in the carbonylation process (entry
12).
(4) For other direct aromatic carbonylations, such as Pd(II)-catalyzed carbo-
nylation of benzene to benzoic acid, see: (a) Fujiwara, Y.; Takaki, K.;
Taniguchi, Y. Synlett 1996, 591-599. (b) Jia, C.; Kitamura, T.; Fujiwara,
Y. Acc. Chem. Res. 2001, 34, 633-639. For Ru3(CO)12- or Rh4(CO)12
-
It is thought that this carbonylation started from ortho-pallada-
tion8 (step 1, Scheme 1) with Pd(OAc)2 coordinated with Cu(OAc)2
and was followed by insertion of a molecular CO into the resultant
cyclopalladation product (iv), leading to the formation of an acyl-
palladium complex (v) (step 2). The successive amide bond
formation by a nucleophilic attack of an internal amino group on
the carbonyl group (step 3) completes the carbonylation to give a
benzolactam and Pd(0). Regeneration of Pd(OAc)2 by oxidation
of Pd(0) with Cu(OAc)2 starts this catalytic cycle, in a manner
similar to that of the Wacker process.9 A 3′,4′-methylenedioxy group
provides an efficient chelation10 with a Pd(II) in the six-membered
transition state. A vicinal dimethoxy group inhibits the chelation
due to its enhanced steric repulsion,11 as shown in vi, and
carbonylation via an alternative cyclopalladation product, vii,
replaces that via vi. Cyclopalladation of benzylic amines proceeds
too fast, even without substituents, to keep the above excellent
regioselectivities.
As shown in Table 2, most of the benzylic amines with an
electron-withdrawing group also underwent smooth carbonylation
to give the corresponding benzolactams in good yields, similar to
those in the case of benzylic amines with an electron-donating
group. As observed in the formation of benzolactams 9 and 10, it
was, again, disclosed that the present direct aromatic carbonylation
proceeded mainly due to the chelation or steric repulsion between
the Pd(II) and m-substituent in the cyclopalladation process.
Carbonylation of m-nitrobenzylamine 6f produced only 5-nitroben-
catalyzed carbonylation of substituted arenes, see: (c) Asaumi, T.; Matsuo,
T.; Fukuyama, T.; Ie, Y.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004,
69, 4433-4440 and references therein.
(5) Carbonylation of primary amines, including benzylicamines or phenethy-
lamines, under the same conditions, produced no benzolactams but
produced ureas in good yields. The details will be reported elsewhere.
(6) Air (oxygen) is also slowly supplied through the surface of the balloon
(Knudsen flow).
(7) For reported complexes of Pd(OAc)2 and Cu(OAc)2 in 1:1 and 1:2 ratios,
see: (a) Brandon, R. W.; Claridge, D. V. Chem. Commun. 1968, 677-
678. (b) Sloan, O. D.; Tiiornton, P. Inorg. Chim. Acta 1986, 120, 173-
175.
(8) For ortho-palladation products with Pd(OAc)2 of benzylicamines and
phenethylamines with hydrogen on their nitrogen atoms, see: (a) Fuchita,
Y.; Tsuchiya, H. Polyhedron 1993, 12, 2079-2080. (b) Inorg. Chim. Acta
1993, 209, 229-230. (c) Vicente, J.; Saura-Llamas, I.; Palin, M. J.; Jones,
P. G.; Ram´ırez de Arellano, M. C. Organometallics 1997, 16, 826-833.
(9) For the Wacker catalysis, see: Hosokawa, T.; Murahashi, S. Acc. Chem.
Res. 1990, 23, 49-54. Pd(0) + 2 Cu(OAc)2 f Pd(OAc)2 + 2 CuOAc. 2
CuOAc + 2 AcOH + 0.5 O2 f 2 Cu(OAc)2 + 0.5 H2O.
(10) This selectivity is similar to those results of the ortho-lithiation of benzylic
alcohols: Orito, K.; Hatakeyama, T.; Takeo, M.; Uchiito, S.; Tokuda,
M.; Suginome, H. Tetrahedron 1998, 54, 8403-8410.
(11) A similar steric effect of a vicinal dimethoxy group has been observed in
cyclometalation using Pd(OAc)2, Ru(H)2(CO)(PPh3)3, or Ru3(CO)12: (a)
Liang, C. D. Tetrahedron Lett. 1986, 27, 1971-1986. (b) Sonoda, M.;
Kakiuchi, F.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1997, 70, 3117-
3128 and references therein. (c) Ie, Y.; Chatani, N.; Ogo, T.; Marshall,
D. R.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65,
1475-1488.
(12) Benzolactam 2d was probably formed via a halogen-metal exchange with
a Pd(0) catalyst generated in situ.
(13) It should be noted that carbonylation of the hydrochloride of phenethy-
lamine 1c at 20 atm of CO afforded benzolactam 3c in 79% yield, probably
as a result of an electrophilic aromatic carbonyation.
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