Palladium- and copper-catalyzed synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and 1,4-benzodiazepine-2,5-diones. Control of reaction pathway by metal-switching

Article abstract of DOI:10.1021/ja047472o

Methods for the synthesis of dihydroazaphenanthrene fused to macrocycles (2) and medium-ring heterocycles (4), as well as 1,4-benzodiazepine-2,5-diones (5), are developed. A distinctly different catalytic property of palladium and copper catalysts was unc

Full text of DOI:10.1021/ja047472o

Published on Web 10/13/2004
Palladium- and Copper-Catalyzed Synthesis of Medium- and
Large-Sized Ring-Fused Dihydroazaphenanthrenes and
1,4-Benzodiazepine-2,5-diones. Control of Reaction Pathway
by Metal-Switching
Guylaine Cuny, Miche`le Bois-Choussy, and Jieping Zhu*
Contribution from the Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
Received April 30, 2004; E-mail: zhu@icsn.cnrs-gif.fr
Abstract: Methods for the synthesis of dihydroazaphenanthrene fused to macrocycles (2) and medium-
ring heterocycles (4), as well as 1,4-benzodiazepine-2,5-diones (5), are developed. A distinctly different
catalytic property of palladium and copper catalysts was uncovered that leads to the development of a
divergent synthesis of two different heterocyclic scaffolds from the same starting materials, simply by metal-
switching. Thus, starting from linear amide 3, palladium acetate triggers a domino intramolecular N-arylation/
C-H activation/aryl-aryl bond-forming process to provide 4, while copper iodide promotes only the
intramolecular N-arylation reaction leading to 5. In combination with the Ugi multicomponent reaction (Ugi-
4CR) for the preparation of the linear amides, a two-step synthesis of either the 5,6-dihydro-8H-5,7a-
diazacyclohepta[jk]phenanthrene-4,7-dione (4) or 1,4-benzodiazepine-2,5-diones (5), by appropriate choice
of metal catalyst, is subsequently developed from very simple starting materials.
Introduction
nitrogen substrates, including amines, amides, nitrogen hetero-
cycles, and R- and â-amino acids can now be arylated under
mild catalytic conditions.6
Following the pioneering contributions by the groups of
Buchwald1 and Hartwig,2 there has been a surge of interest in
the palladium-catalyzed amination/amidation of aryl halides and
pseudo-halides during the past 10 years. By appropriate
combination of palladium source, ligand, base, and solvent, this
coupling reaction can now be realized under mild conditions
for a variety of unactivated aromatic halides/pseudo-halides and
a range of nucleophiles.3 In comparison to the palladium-
catalyzed amination/amidation reactions, the copper-mediated
version, best known as the Ullmann reaction (N-arylation of
amine) and the Goldberg reaction (N-arylation of amides), has
been known for a century.4 The harsh reaction conditions, in
particular high temperatures, and the necessity to use stoichio-
metric amounts of the copper limited, nevertheless, the applica-
tion scope of these two otherwise powerful reactions. However,
a number of catalytic systems have now been developed since
Ma’s seminal contribution dealing with the CuI-catalyzed
N-arylation of amino acids with aryl halides.5 An array of
Both palladium- and copper-catalyzed intramolecular N-
arylations leading to five-, six-, and to a lesser extent, seven-
membered rings have been investigated, and various efficient
catalytic systems have been developed.7-10 On the other hand,
attempts to access medium-sized and macrocyclic ring systems
by direct N-arylation were, to the best of our knowledge,
unsuccessful. This is unfortunate since these medium-sized rings
and macrocycles have found numerous applications in drug
development, materials science, and supramolecular chemistry
(6) For reviews: (a) Ley, S.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400-5449. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428-
2439.
(7) Palladium-catalyzed: (a) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L.
Tetrahedron 1996, 52, 7525-7546. (b) Wagaw, S.; Rennels, R. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 8451-8458. (c) Yang, B.
H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-37. (d) Abouabdellah, A.; Dodd,
R. H. Tetrahedron Lett. 1998, 39, 2119-2122. (e) Song, J. J.; Yee, N. K.
Org. Lett. 2000, 2, 519-521. (f) Brown, J. A. Tetrahedron Lett. 2000, 41,
1623-1626. (g) Qadir, M.; Priestley, R. E.; Rising, T. W. D. F.; Gelbrich,
T.; Coles, S. J.; Hursthouse, M. B.; Sheldrake, P. W.; Whittall, N.; Hii, K.
K. Tetrahedron Lett. 2003, 44, 3675-3678. (h) Evindar, G.; Batey, R. A.
Org. Lett. 2003, 5, 133-136. (i) Margolis, B. J.; Swidorski, J. J.; Rogers,
B. N. J. Org. Chem. 2003, 68, 644-647. (j) Nozaki, K.; Takahashi, K.;
Nakano, K.; Hiyama, T.; Tang, H.-Z.; Fujiki, M.; Yamaguchi, S.; Tamao,
K. Angew. Chem., Int. Ed. 2003, 42, 2051-2053. (k) Brain, C. T.; Steer,
J. T. J. Org. Chem. 2003, 68, 6814-6816.
(8) Copper-catalyzed: (a) Ma, D.; Xia, C. Org. Lett. 2001, 2, 2583-2586. (b)
Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231-
234.
(9) Nickel catalyzed: Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider,
R.; Fort, Y. Org. Lett. 2003, 5, 2311-2314. Iridium-catalyzed oxidative
cyclization of amino alcohols: Fujita, K.-I.; Yamamoto, K.; Yamaguchi,
R. Org. Lett. 2002, 4, 2691-2694.
(10) For an elegant application in natural product synthesis, see: He, F.; Foxman,
B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417-6418.
(1) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. F. Acc. Chem.
Res. 1998, 31, 805-818. (b) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125-146.
(2) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (b) Hartwig,
J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH: Wein-
heim, 2000; Chapter 7.
(3) (a) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti, B. Tetrahedron
2002, 58, 2041-2075. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176-4211. (c) Belfield, A. J.; Brown, G. R.; Foubister, A. J.
Tetrahedron 1999, 55, 11399-11428.
(4) Lindley, J. Tetrahedron 1984, 40, 1433-1456.
(5) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120,
12459-12467.
9
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J. AM. CHEM. SOC. 2004, 126, 14475-14484
14475

A R T I C L E S
Cuny et al.
Scheme 1. Palladium- and Copper-Catalyzed Synthesis of
Polyheterocycles and Macrocycles
Table 1. Palladium-Catalyzed Cyclization of 1: Survey of
Reaction Conditionsa
temp
C)
yield
(%)c
entry
catalystb
solvent
base
(
°
1
2
3
4
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
DMSO
DMSO
DMF
KOAc
KOAc
KOAc
80
120
120
reflux
48
65
32
0
Toluene KOAc
5
6
7
8
PdCl2(dppf)
DMSO
DMSO
DMSO
DMSO
DMSO
Cs2CO3 120
25
51
60
50
40
62d
77d
44
44
46
60
Pd(dba)2/dppf ) 1/1
Pd(dba)2/BINAP ) 1/1
Pd(dba)2/tBu3P ) 1/1
Pd(dba)2/tBu3P ) 1/2
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
120
120
120
120
120
120
120
120
120
120
9
10
11
12
13
14
15
Pd(OAc)2/BINAP ) 1/1 DMSO
Pd(OAc)2/BINAP ) 1/2 DMSO
Pd(OAc)2/tBu3P ) 1/1
Pd(OAc)2/tBu3P ) 1/2
PdCl2(dppf)/dppf ) 1/1
Pd[(PPh)3]4
DMSO
DMSO
DMSO
DMSO
a Concentration of substrate 1 in DMSO, 0.02 M; reaction time, 16 h.
b 5 mol % of catalyst was used. c Yields refer to the average of two runs,
isolated yields. d Contaminated by a small amount of BINAP derivatives.
catalyst. Furthermore, it is demonstrated that compound 5,
obtained by the copper-catalyzed intramolecular N-arylation
process, can be converted to tetracycle 4 in the presence of
palladium catalyst, providing thus the mechanistic insight
regarding the domino transformation of 3 to 4.
Results and Discussion
Synthesis of Dihydroazaphenanthrene-Fused Medium-
Sized and Macrocyclic Rings. The diamide 1 is synthesized
by a double condensation of 2-iodobenzoyl chloride with the
corresponding diamine under standard conditions (CH2Cl2,
triethylamine, room temperature).16 When a DMSO solution of
diamide 1a (n ) 1, m ) 2, X ) CH2, 0.02 M) was treated with
PdCl2(dppf)17 in the presence of KOAc at 80 °C, a polycycle
2a was isolated in 48% yield (entry 1, Table 1). The formation
of a 12-membered macrocycle with an endo aryl-aryl bond
via Ullmann biaryl synthesis was not observed, even in the
presence of bis(pinacolato)diboron.13b,18 From a very simplified
mechanistic point of view, the reaction proceeded presumably
by way of a domino intramolecular Buchwald-Hartwig ami-
dation reaction, C-H activation,19 and aryl-aryl bond-forming
process. In this transformation, one nine-membered ring and
one six-membered ring were produced, with the concomitant
formation of a carbon-nitrogen bond and a carbon-carbon
bond. It is worth noting that a significant molecular complexity
was created under these experimentally simple catalytic condi-
tions.
by virtue of their intrinsic three-dimensional structure.11,12 Our
long-term interests in the development of novel macrocyclization
reactions13 brought us to investigate the cyclization of bis-
aryldiiodide 1, and we have uncovered a palladium-catalyzed
domino process that efficiently transforms the simple amide 1
into the dihydroazaphenanthrene-fused macrocycle 2 (Scheme
1).14 In this paper, we report in detail the development and
application of this one-pot palladium-catalyzed domino intra-
molecular N-arylation/C-H activation/aryl-aryl bond-forming
process. We also document that copper catalyst can interrupt
this domino process that leads to the development of a novel
synthesis of highly functionalized 1,4-benzodiazepine-2,5-diones
(5) from the R-acetamido amide (3). Since the linear precursor
3 can be easily prepared in one step from readily available
aldehyde, amine, carboxylic acid, and isocyanide by the Ugi
four-component reaction (Ugi-4CR),15 either dihydroazaphenan-
threne-fused benzodiazepinedione (4) or 1,4-benzodiazepine-
2,5-diones (5) can now be synthesized in two steps from very
simple starting materials, by appropriate choice of the metal
(16) Stahl, G. L.; Walter, R.; Smith, C. W. J. Am. Chem. Soc. 1979, 101, 5383-
5394.
(17) Abbreviations: dppf, 1,1′-bis(diphenylphosphino)ferrocene; BINAP, 2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl; dba, dibenzylideneacetone; MOP,
2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl; Xantphos, 9,9-dimethyl-
4,5-bis(diphenylphosphino)xanthene.
(11) For a recent review on metal-mediated synthesis of medium-sized ring
systems, see: Yet, L. Chem. ReV. 2000, 100, 2963-3008.
(12) General reviews on the synthesis of macrocycles: (a) Roxburgh, C. J.
Tetrahedron 1995, 51, 9767-9822. (b) Grubbs, R. H.; Miller, S. J.; Fu, G.
C. Acc. Chem. Res. 1995, 28, 446-452. (c) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012-3043. (d) Krakowiak, K. E.; Izatt, R. M.; Bradshaw,
J. S. J. Heterocycl. Chem. 2001, 38, 1239-1248.
(18) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508-
7510. (b) Yoburn, J. C.; Van Vranken, D. L. Org. Lett. 2003, 5, 2817-
2820. (c) Hutton, C. A.; Skaff, O. Tetrahedron Lett. 2003, 44, 4895-4898.
(d) Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729-3732.
For a review on the Miyaura-Suzuki reaction, see Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457-2483.
(19) For recent reviews on C-H activation, see: (a) Shilov, A. E.; Shul’pin,
G. B. Chem. ReV. 1997, 97, 2879-2932. (b) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1698-1712. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633-639. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731-1769. (e) Kakiuchi, F.; Murai, S. Acc. Chem. Res.
2002, 35, 826-834. (f) Catellani, M. Synlett 2003, 298-313.
(13) (a) Zhu, J. Synlett 1997, 133-144. (b) Carbonnelle, A. C.; Zhu, J. Org.
Lett. 2000, 2, 3477-3480. (c) Zhao, G.; Sun, X.; Bienayme´, H.; Zhu, J. J.
Am. Chem. Soc. 2001, 123, 6700-6701. (d) Janvier, P.; Bois-Choussy,
M.; Bienayme´, H.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 811-814.
(14) Preliminary communication: Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew.
Chem., Int. Ed. 2003, 42, 4774-4777.
(15) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
9
14476 J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004

Dihydroazaphenanthrene Fused to Macrocycles
A R T I C L E S
Table 2. From Linear Diamide 1 to Polyheterocycles 2
Realizing the potential of this domino transformation in the
synthesis of medicinally relevant polycycles, we set out to
further optimize this process. A survey of reaction conditions
using diamide 1a as model compound was performed, varying
the palladium sources, the ligands, the temperatures, the bases,
and the solvents. The results are summarized in Table 1. As
can be seen, the reaction temperature has a dramatic effect on
the reaction outcome, and higher yield was obtained when the
reaction was performed at higher temperature (entry 1 vs 2).
Although higher reaction temperature is known to favor the
macrocyclization, this technique has not been frequently used
in the survey of macrocyclization conditions.20 In contrast to
previous studies on the intramolecular N-arylation of amide,
the present domino process is much less sensitive to the ligand
structure. Both bidentate phosphines, such as dppf (entries 2,
6)21 and BINAP (entries 7, 10, 11),22 and monodentate ligand
t
Ph3P (entry 15) were suitable, although Bu3P23 (entries 8, 9,
12, 13) seemed to be less efficient. Potassium acetate (entry 2)
was more efficient than cesium carbonate (entry 5) as a base.
While DMSO turned out to be a better solvent than DMF (entry
3), toluene is not a solvent of choice, as it gives no product
(entry 4). The highest yield was obtained with a catalyst prepared
in situ from Pd(OAc)2 and BINAP in a molar ratio of 1:2;
nevertheless, we selected PdCl2(dppf) as the catalyst for the
subsequent studies for the simplicity of manipulation and
product purification [PdCl2(dppf), KOAc, DMSO, 120 °C,
concentration of substrate 0.02 M].
To evaluate the scope of this domino process, various
substrates were examined. As shown in Table 2, this novel
catalytic domino process can be applied to the construction of
azaphenanthrenes fused to 8-membered (2b), 10-membered (2c),
11-membered (2d), and 13-membered (2e) lactam motifs, in
addition to the 9-membered ring (2a). To the best of our
knowledge, this represents the first examples wherein an
intramolecular BuchwaldsHartwig amidation has been suc-
cessfully applied to the synthesis of medium-ring and macro-
cycles. Furthermore, this cyclization was followed by a C-H
activation and aryl-aryl bond formation, producing a unique
domino process.24 Parallel to our work, an elegant intermolecular
N-arylation followed by aryl-aryl bond formation, leading to
five-membered carbazoles, has been reported from the group
of Bedford,25 and processes involving sequential intra- and
intermolecular N-arylation leading to functionalized 1-amino-
indole were developed by Watanabe and co-workers.26 More
a PdCl2(dppf) (5 mol %), DMSO (0.02 M), KOAc (3 equiv), 120 °C,
isolated yield (average of two runs). b PdCl2(dppf) (5 mol %), DMSO (0.001
M), KOAc (3 equiv), 120 °C, isolated yield (average of two runs).
recently, a palladium-catalyzed cyclodimerization between N,N′-
dimethyl-m-phenylenediamine and N,N′-dimethyl-N,N′-bis(6′-
bromopyrid-2′-yl)-m-phenylenediamine has been developed by
Wang et al. for the synthesis of azacalix[4]pyridine.27
It was interesting to note that cyclization of 1a-e to 2a-e
was carried out at 0.02 M, which is not considered to be high-
dilution conditions. Higher yields of 2c and 2d were obtained
when the reaction was performed at 0.001 M under the otherwise
identical conditions (conditions b, Table 2).
The 1H NMR spectra of compounds 2a and 2c displays slow
interconversion of two conformers on the NMR time scale in
both CDCl3 and DMSO-d6 at room temperature. On the other
hand, only one single set of peaks was observed in the 1H NMR
spectra of 2b, 2d, and 2e at room temperature.28
(20) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497-4513.
(21) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
7215-7216.
(22) (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-
7218. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
3694-3703.
(23) Efficient arylamination procedure using tBu3P as ligand, see: Hooper, M.
W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, 2861-2873.
(24) For reviews on domino process, see: (a) Wender, P. A.; Miller, B. L.
Organic Synthesis: Theory and Applications; JAI Press: Greenwich, CT,
1993; Vol. 2, pp 27-66. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl.
1995, 34, 259-281. (c) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (d)
Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223-270. (e)
Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137-165. (f)
Winkler, J. D. Chem. ReV. 1996, 96, 167-176. (g) Filippini, M.-H.;
Rodriguez, J. Chem. ReV. 1999, 99, 27-76. (h) Poli, G.; Giambastiani, G.;
Heumann, A. Tetrahedron 2000, 56, 5959-5989. (i) Tietze L. F.; Haunert,
F. In Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart, J. F.,
Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim, 2000; pp 39-64. (j) Zeni, G.;
Larock, R. C. Chem. ReV. 2004, 104, 2285-2310.
Synthesis of Dihydroazaphenanthrene-Fused Benzodiaze-
pinedione. 1,4-Benzodiazepine-2,5-diones (BZDs) and their
(27) Wang, M.-X.; Zhang, X.-H.; Zheng, Q.-Y.Angew. Chem., Int. Ed. 2004,
43, 838-842.
(28) Recent papers on conformational analysis of medium rings, see: (a) Glaser,
R.; Novoselsky, A.; Shiftan, D. J. Org. Chem. 2000, 65, 6345-6353. (b)
Glaser, R.; Shiftan, D.; Levi-Roso, G.; Ergaz, I.; Geresh, S. J. Org. Chem.
2002, 67, 5486-5496 and references therein.
(25) Bedford, R. B.; Cazin, S. J. J. Chem. Soc., Chem. Commun. 2002, 2310-
2311.
(26) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem., Int. Ed. 2000,
39, 2501-2504.
9
J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004 14477

A R T I C L E S
Scheme 2 a
Cuny et al.
Scheme 3. Further Examples of Palladium-Catalyzed Synthesis of
Polyheterocycle 4
a Reagents and conditions: (a) EDC, CH2Cl2, room temperature, 90%;
(b) TFA, CH2Cl2, room temperature, 90%; (c) 2-iodobenzoyl chloride, tri-
ethylamine, CH2Cl2, -30 °C then room temperature, 80%; (d) Pd(dppf)Cl2,
KOAc, DMSO, 120 °C.
derivatives, whether natural or synthetic, constitute one of the
most important classes of bioactive compounds.29 The BZDs
have been identified as anxiolytic, antitumor, anticonvulsant
agents and as non-peptidal inhibitors of platelet aggregation,
etc. It follows that many syntheses, including library construc-
tion, have been reported in recent years with the hope to further
enlarge its bioactivity spectrum and to find new active ana-
logues.30 Indeed, research on heterocycle-fused BZDs such as
pyrrolo[2,1-c][1,4]benzodiazepines and imidazo[1,5-a][1,4]benzo-
diazepines has a long history and has led to the discovery of
potent bioactive compounds.31 It occurred to us that the
previously unknown dihydroazaphenanthrene-fused BZD (4)
would be easily accessible by applying the catalytic domino
process that we just developed. Since both dihydroazaphenan-
threne32 and BZD33 were considered to be privileged structures
in medicinal chemistry, it would be interesting to develop a
facile access to such a new structure that can be considered as
a chimeric scaffold of 1,4-benzodiazepine-2,5-dione and di-
hydroazaphenanthrene.
benzylamine (6) with (S)-N-Boc-proline (7) provided amide 8
in 90% yield. Removal of N-tert-butyloxycarbamate under mild
acidic conditions, followed by coupling with 2-iodobenzoyl
chloride, provided 3a in 72% overall yield. To our delight,
treatment of a DMSO solution of 3a (0.02 M) in the presence
of PdCl2(dppf) and KOAc at 120 °C furnished the polycycle
4a in 97% isolated yield. To verify whether the chiral integrity
was maintained in the course of this double cyclization, the
amide 3b, an enantiomer of 3a, was synthesized following the
same sequence of reactions. Submitting 3b to the palladium-
catalyzed domino process under identical conditions provided
compound 4b in 98% yield. Compound 4b has the optical
rotation nearly identical in magnitude but opposite in sign to
that of 4a. Furthermore, chiral HPLC analysis indicated that
the enantiomeric excesses of both 4a and 4b are greater than
95%. The results clearly indicated that the present palladium-
catalyzed domino process is racemization-free.
The scope of this reaction was further examined by applying
the optimized conditions to differentially substituted amides (3)
(Scheme 3). As can be seen, the 1,4-benzodiazepine-2,5-dione
derivatives incorporating sarcosine (4c), N-methyl alanine (4d),
N-methyl phenylalanine (4e), N-methyl valine (4f), and N-methyl
leucine (4g) can be prepared in good to excellent yields. The
ready accessibility of the starting material and the generality of
this process clearly indicated its potential in the diversity-
oriented synthesis of this family of compounds. Palldiaum-
catalyzed intramolecular R-arylation of amide has been reported
recently;34 however, under our experimental conditions, this
The cyclization precursor 3a was synthesized in a stepwise
manner as shown in Scheme 2. Thus, coupling of 2-iodo-
(29) Ross, W. In The Alkaloids; Brossi, A., Ed.; Academic Press Inc.: San Diego,
1990; Vol. 39, pp 63-97.
(30) Recent reviews: (a) Ellman, J. A. Acc. Chem. Res. 1996, 29, 132-143.
(b) Bra¨se, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415-
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Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-
930.
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2425-2428. (b) Li, X.; Cao, H.; Zhang, C.; Furtmueller, R.; Fuchs, K.;
Huck, S.; Sieghart, W.; Deschamps, J.; Cook, J. M. J. Med. Chem. 2003,
46, 5567-5570. For a review, see: Thurston, D. E.; Bose, D. S. Chem.
ReV. 1994, 94, 433-465.
(32) (a) Whittaker, J.; McFadyen, W. D.; Baguley, B. C.; Murray, V. Anti-
Cancer Drug Des. 2001, 16, 81-89. (b) Cory, M.; McKee, D. D.; Kagan,
J.; Henry, D. W.; Miller, J. A. J. Am. Chem. Soc. 1985, 107, 2528-2536.
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(33) Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.; Freidinger, R.
M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-2246.
9
14478 J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004

Dihydroazaphenanthrene Fused to Macrocycles
A R T I C L E S
Scheme 4. Two-Step Synthesis of Polyheterocycle 4
Figure 1.
our knowledge, these are the first examples wherein a “ligand-
free” palladium catalyst was employed successfully for the
amidation process.36 It has been established that a low-
coordinated Pd(II)-amido complex should favor competitive
â-hydrogen elimination to give the acyl imine, thus reducing
the yield of the desired amidation product.37 This trend is
apparently not observed in the present catalytic domino process,
due probably to internal ligation.38,39
Additional examples using “ligandless” palladium-catalyzed
domino cyclization are summarized in Scheme 4. In these
examples, the cyclization precursors were prepared by the Ugi
four-component (Ugi-4CR) reaction. Thus, reaction of an
o-iodobenzyl isonitrile, an o-iodobenzoic acid, an amine, and
an aldehyde in methanol provided the cyclization precursor 3
under Ugi’s conditions. Treatment of a DMSO solution of 3h-j
with Pd(OAc)2 in the presence of potassium acetate provided
the corresponding polyheterocycles in good to excellent yields,
illustrating the generality of these ligandless conditions. Overall,
by a combination of Ugi-4CR and the palladium-catalyzed
domino process, the complex heterocycles 5,6-dihydro-8H-5,7a-
diazacyclohepta[jk]phenanthrene-4,7-dione (4) can be synthe-
sized in only two steps from readily available starting materials.
Inherent to multicomponent reactions, substituents of this
heterocycle can easily be varied by systematically changing the
input of the Ugi-4CR, introducing thus the molecular diversity.
To gather further mechanistic insight on this intriguing
domino process, amides 9 and 10, having only one o-iodophenyl
group, were synthesized (Figure 1). To our surprise, submitting
these monoaryl iodide derivatives to the cyclization conditions
(PdCl2(dppf), DMSO, KOAc, 120 °C) led only to the recovery
of starting material together with a small amount of dehalo-
genated compound. No expected cyclization product was
isolable from the reaction mixture. The surprising result of these
control experiments indicated the crucial role of the bis-iodide
function in the cyclization of amides 1 and 3. This observation
led us to postulate the following simplified mechanistic hy-
pothesis for the formation of 4 from 3. The first step would be
a double oxidative addition of zerovalent palladium species,
potentially competitive reaction, leading to the formation of
tetrahydroisoquinolinone or isoindolinone, was not observed.
The benzodiazepinediones are known to exist as a mixture
of two slowly interconverting conformers.35 Depending on the
bulk of the R1 substituent, some of these tetracycles, like
compounds 4e and 4f, exist also as a mixture of two intercon-
verting conformers on the NMR time scale in CDCl3.
Mechanistic Studies and Further Improvement of Reac-
tion Conditions. Synthesis of simple seven-membered rings by
a palladium-catalyzed intramolecular N-arylation of amine/amide
has been developed using tailored ligands, palladium sources,
and bases. In fact, in their pioneering studies, Buchwald and
co-workers demonstrated that ligands such as Xantphos17 and
MOP17 in combination with cesium carbonate are required in
order to promote the formation of seven-membered rings.7c On
the other hand, application of this reaction to the synthesis of
medium to larger rings was unsuccessful. The efficiency of the
present domino process for the synthesis of medium- and large-
sized ring systems via intramolecular N-arylation of amide is
thus intriguing. The template effect due to the chelation of the
metal with amide backbone leading to conformational pre-
organization could be a reasonable explanation. Such a template
effect would require at least one open coordination site of the
putative Pd(II) oxidative adduct. This consideration prompted
us to examine the “ligandless” palladium acetate as catalyst for
this transformation. To our delight, treatment of a DMSO
solution of 1c (0.001 M) in the presence of Pd(OAc)2 and KOAc
provided the tetracyclic compound 2c in comparable yield (95%)
as with PdCl2(dppf). Similarly, compound 4a was obtained in
90% yield from 3a using Pd(OAc)2 as catalyst. To the best of
(36) “Ligand-free” palladium-catalyzed cross-coupling reaction, see: (a) (Re-
view) Beletskaya, I. P. Bull. Acad. Sci. USSR, DiV. Chem. Sci. (Engl.
Transl.) 1991, 2013-2028. Recent examples: (b) Wallow, T. I.; Novak,
B. M. J. Org. Chem. 1994, 59, 5034-5037. (c) Moreno-Man˜as, M.; Pajuelo,
F.; Pleixats, R. J. Org. Chem. 1995, 60, 2396-2397. (d) Badone, D.; Baroni,
M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org. Chem. 1997, 62, 7170-
7173. (e) Blettner, C. G.; Ko¨nig, W. A.; Stenzel, W.; Schotten, T. J. Org.
Chem. 1999, 64, 3885-3890. (f) Blettner, C. G.; Ko¨nig, W. A.; Stenzel,
W.; Schotten, T. J. Org. Chem. 1999, 64, 3885-3890. (g) Leadbeater, N.
E.; Marco, M. Org. Lett. 2002, 4, 2973-2976. (h) Bedford, R. B.; Blake,
M. E.; Butts, C. P.; Holder, D. J. Chem. Soc., Chem. Commun. 2003, 466-
467.
(37) (a) Whitesides, G. M.; Gaasch, J. F.; Stedronsky, E. R. J. Am. Chem. Soc.
1972, 94, 5258-5270. (b) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul,
F. J. Am. Chem. Soc. 1996, 118, 3626-3633. (c) Marcoux, J. F.; Wagaw,
S.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1568-1569.
(38) DMF as ligand, see: (a) Gioria, J. M.; Susz, B. P. HelV. Chim. Acta 1971,
54, 2251-2256. (b) Amatore, C.; Bahsoun, A. A.; Jutand, A.; Meyer, G.;
Ntepe, A. N.; Richard, L. J. Am. Chem. Soc. 2003, 125, 4212-4222.
(39) For a recent review on azapalladacycles, see: Dupont, J.; Pfeffer, M.;
Spencer, J. Eur. J. Inorg. Chem. 2001, 1917-1927.
(34) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (b) Gaertzen,
O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465-475.
(35) (a) Blackburn, B. K.; Lee, A.; Baier, M.; Kohl, B.; Olivero, A. G.;
Matamoros, R.; Robarge, K. D.; McDowell, R. S. J. Med. Chem. 1997,
40, 717-729. (b) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996,
61, 8935-8939. (c) Gilman, N. W.; Rosen, P.; Earley, J. V.; Cook, C.;
Todaro, L. J. J. Am. Chem. Soc. 1990, 112, 3969-3978. (d) Sunjic, J.;
Lisini, A.; Sega, A.; Kovac, T.; Kajfez, F. J. Heterocycl. Chem. 1979, 16,
757-761. (e) Linscheid, P.; Lehn, J.-M. Bull. Chem. Soc. Fr. 1967, 992-
997.
9
J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004 14479

A R T I C L E S
Cuny et al.
Scheme 5. Palladium-Catalyzed Domino Process: A Mechanistic Proposal
generated in situ, to the bisaryl diiodide, leading to the
intermediate A or A′, depending on the chelating site of the
amide function (Scheme 5). This step would probably be assisted
by the pre-coordination of Pd(0) to the amide function, and the
resulting Pd(II) species should in turn be stabilized by the same
effect via the formation of five-membered azapalladacycles (A
or A′).40,41 For the ring b palladium atom, coordination to
nitrogen or oxygen of the amide function would produce a five-
or seven-membered chelate, respectively. In this case, one would
expect that coordination to the nitrogen atom, rather than the
carbonyl oxygen, should be favored. On the other hand, the
ring a palladium may coordinate to either nitrogen or oxygen
since in both cases a five-membered chelate would be produced.
The internal chelation of amide to palladium adduct should
further entropically facilitate the formation of arylpalladium-
amido complex B from A since it involves now formation of a
five-membered ring instead of an eight-membered cycle. Reduc-
tive elimination of arylpalladium-amido complex B would
palladacycle D.42,43 Once again, this step could be accelerated
entropically by the pre-coordination of the nitrogen atom to the
pendant palladium(II) species. A second reductive elimination
from D would then give the observed product with the
regeneration of Pd(0) species.19,44
From control experiments, it is clear that the formation of
the bis-palladium-aryl iodide adduct of type A may play an
important role in the present reaction.45 Consequently, we
attempted to isolate this putative σ-aryl palladium complex and
to study its chemical behavior. Much to our delight, reaction
of 3c with 2 equiv of palladium tetrakis(triphenylphosphine) in
toluene at room temperature for 72 h afforded, after flash column
chromatography, a single isolable compound. Unfortunately, we
failed to obtain a single crystal suitable for X-ray studies.
However, the structure of this compound was assigned as
(42) (a) Mart´ın-Matute B.; Mateo, C.; Ca´rdenas D. J.; Echavarren, A. M. Chem.
Eur. J. 2001, 7, 2341-2348. (b) Ca´mpora, J.; Lo´pez, J. A.; Palma, P.;
Valerga, P.; Spillner, E.; Carmona, E. Angew. Chem., Int. Ed. 1999, 38,
147-151. (c) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1992,
425, 151-154.
2
provide C, with the concurrent formation of a Csp -N bond.
(43) Other mechanistic proposals, see: (a) Pfeffer, M.; Sutter, J.-P.; Rotteveel,
M. A.; De Cian, A.; Fischer, J. Tetrahedron 1992, 48, 2427-2440. For a
review, see: Dyker, G. Chem. Ber./Recueil 1997, 130, 1567-1578.
(44) C-H activation, recent examples: (a) Hennings, D. D.; Iwasa, S.; Rawal,
V. H. J. Org. Chem. 1997, 62, 2-3. (b) Harayama, T.; Shibaike, K.
Heterocycles 1998, 49, 191-195. (c) Harayama, T.; Akiyama, T.; Aka-
matsu, H.; Kawano, K.; Abe, H.; Takeuchi, Y. Synthesis 2001, 444-450.
(d) Harayama, T.; Akiyama, T.; Nakano, Y.; Nishioka, H.; Abe, H.;
Takeuchi, Y. Chem. Pharm. Bull. 2002, 50, 519-522. (e) Kakiuchi, F.;
Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698-
1699. (f) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.;
Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700-
1701. (g) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J.
Am. Chem. Soc. 2003, 125, 11506-11507. (h) Baudoin, O.; Herrbach, A.;
Gue´ritte, F. Angew. Chem., Int. Ed. 2003, 42, 5736-5740. (i) Sezen, B.;
Sames, D. J. Am. Chem. Soc. 2003, 125, 10580-10585. (j) DeBoef, B.;
Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556-6557. (k)
Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem.
Soc. 2004, 126, 7460-7461 and references therein.
Intermediate C is nicely functionalized for the subsequent C-H
activation process. Although both oxidative insertion of PdII into
the aryl C-H bond to give a hydridopalladacycle (PdIV) and
electrophilic aromatic substitution followed by loss of HI are
possible, we would favor the latter mechanism in the present
case to account for the formation of the seven-membered
(40) (a) Vicente, J.; Abad, J.-A.; Frankland, A. D.; Ram´ırez de Arellano, M. C.
Chem. Eur. J. 1999, 5, 3066-3075. (b) Ohff, M.; Ohff, A.; Milstein, D. J.
Chem. Soc., Chem. Commun. 1999, 357-358. (c) Gai, X.; Grigg, R.;
Ramzan, M. I.; Sridharan, V.; Collard, S.; Muir, J. E. J. Chem. Soc., Chem.
Commun. 2000, 2053-2054. (d) Bedford, R. B.; Cazin, C. S. J. Chem.
Soc., Chem. Commun. 2001, 1540-1541. (e) Alonso, D. A.; Na´jera, C.;
Pacheco, M. C. Org. Lett. 2000, 2, 1823-1826. (f) Viciu, M. S.; Kelly, R.
A., III; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett. 2003,
5, 1479-1482. (g) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia´. M.;
Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587-1594.
(45) Coordination of nitrogen with palladium controls and modifies the course
of transition metal-promoted processes; see ref 40 and the following: (a)
Mauleo´n, P.; Alonso, I.; Carretero, J. C. Angew. Chem., Int. Ed. 2001, 40,
1291-1293. (b) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org.
Chem. 2001, 66, 544-549.
(41) Palladacycle involving an amide function was relative uncommon; see,
however: Oestreich, M.; Dennison, R. P.; Kodanko, J. J.; Overman, L. E.
Angew. Chem., Int. Ed. 2001, 40, 1439-1442.
9
14480 J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004

Dihydroazaphenanthrene Fused to Macrocycles
A R T I C L E S
Scheme 6. Synthesis of Bis-σ-arylpalladium Complex 11
(Tentative Structure) and Its Conversion to 4c
Scheme 7 a
a Reagents and conditions: (a) CuI, K2CO3, DMSO, 110 °C, 43%; (b)
Pd(dppf)Cl2, DMSO, KOAc, 120 °C, 24 h, 96%.
catalytic conditions at various reaction temperatures. In fact,
treatment of 3c under a range of catalytic conditions led to either
the recovery of the starting material under mild conditions or
the final tetracyclic compound 4c at higher temperature. In no
case was the benzodiazepinedione 5c detected (Scheme 7).
These experimental results indicated that, if the reaction went
through the sequence shown in the Scheme 5, then the second
cyclization via C-H activation and C-C bond formation from
intermediate C might be a very facile process. To access an
authentic sample of 5c, many well-developed synthetic pathways
exist; nevertheless, we decided to adopt a more challenging
way: to find a metal other than palladium to realize the
transformation of 3c to 5c. We were interested in this approach
not only for the purpose of the present mechanistic studies, but
also for the development of a general approach to this class of
heterocycles.
Inspection of the structure of 3c led to the assumption that
one of the iodides (the desired one) should be more prone to
oxidative addition with copper due to the electronic as well as
the coordinating effect of the amide group. If this chemoselective
oxidative addition as well as the subsequent steps could occur,
then one may expect to stop the reaction at the benzodiazepine-
dione level, i.e., compound 5c (Scheme 7). Indeed, treatment
of a DMSO solution of 3c with CuI in the presence of potassium
carbonate led to the formation of 5c in 43% yield. The formation
of tetracycle 4c was not observed under these conditions.
However, when 5c was submitted to the palladium-catalyzed
conditions [PdCl2(dppf), DMSO, KOAc, 120 °C], a sequence
of C-H activation/aryl-aryl bond-forming processes took place
smoothly to provide compound 4c in 96% yield. From the results
of this control experiment, it seems reasonable to suggest that
the intramolecular N-arylation might precede the C-C bond-
forming event in the palladium-catalyzed transformation of 3c
to 4c.
azapalladacycle 11 from the following spectroscopic data
(Scheme 6). In the H NMR spectrum of this compound, both
1
methylene protons appear as AB systems, indicating a relatively
rigid structure. The 31P NMR spectrum shows two peaks at δ
28.0 and 29.3 ppm,46 and the molecular weight (ESI m/z 1294.7)
corresponds to the molecular formula C53H46N2I2O2Pd2P2 + Na.
The stability of compound 11 is indicative of the presence of
internal chelation. Unfortunately, the coordination sites as well
as the exact three-dimensional structure of 11 cannot be deduced
from the NMR studies. However, we speculated that such
coordination might pre-organize the linear substrate to a folded
conformer conducive to the cyclization.
The intermediacy of 11 in the palladium-catalyzed transfor-
mation of the linear amide 3c to tetracycle 4c was proved by
the following control experiment. Thus, simply heating a DMSO
solution of azapalladacyclcle 11 in the presence of KOAc at
120 °C triggered the domino process, leading to the formation
of 4c in 60% yield. Evidently, complex 11 cannot be the
immediate precursor of 4c since the N-atom and the aryl carbon
atom to be coupled are not on the same palladium atom in this
complex. Rather, it has to be first transformed into the type B
complex (cf. Scheme 5), and this step would be facilitated by
further coordination of palladium to a heteroatom or hydrogen
bond as well as entropic factors (transient five- vs eight-
membered ring), as discussed earlier.
Copper-Catalyzed Intramolecular N-Arylation: New Ac-
cess to 1,4-Benzodiazepine-2,5-dione. While palladium-
catalyzed N-arylation has attracted considerable attention for
the past 10 years, the search for a milder and more efficient
catalyst system for performing the classic copper-catalyzed
N-arylation of amines (Ullmann reaction) and N-arylation of
amides (Goldberg reaction) has been the subject of recent
focus.47 Copper-catalyzed intramolecular N-arylation of amine
Two chemical bonds were created in the present process by
way of a formal Buchwald-Hartwig amidation and C-H
activation/aryl-aryl bond-forming processes. Although it is
reasonable to assume that two bonds were formed sequentially
and that the aryl amidation preceded the C-C bond formation,
a more convincing support was sought. Attempts to stop the
reaction after intramolecular N-arylation failed with the present
(47) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581-
584. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-796 and
references therein.
(46) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232-8245.
9
J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004 14481

A R T I C L E S
Cuny et al.
Table 3. Copper-Catalyzed Intramolecular N-Arylation of 3c Using
Various Reaction Conditionsa
temp
C)
yield
(%)b
entry
catalyst
base
ligand
solvent
(
°
1
2
3
4
5
6
7
8
9
CuI
CuI
CuCl
CuCl2
Cu(OAc)2
CuSO4‚5H2O K2CO3
Cu2O
Cu powder
Cu(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
none
DMSO
110
110
110
110
110
110
110
110
110
110
110
110
110
43
Id
I
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
44 (57)c
22 (33)c
18
I
I
I
I
I
IId
I
I
I
I
I
I
I
37
5 (7)c
15
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
CsOH.H2O
CsOAc
K2CO3
K2CO3
K2CO3
14 (18)c
21
10 CuI
11 CuI
12 CuI
13 CuI
14 CuI
15 CuI
16 CuI
38 (45)c
0
0
33 (62)c
0f
Figure 2. Ligand structure for CuI-catalyzed intramolecular N-arylation
of 3c.
1,4-dioxane 100
DMF
DMSO
110
80-100 16
110
38 (71)c
Scheme 8. Copper-Catalyzed Synthesis of
Benzodiazepinedinone: A Mechanistic Proposal
17 CuI (2 equiv) K2CO3
I (4 equiv) DMSO
20 (46)c
18 CuI
19 CuI
20 CuI
21 CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
I
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
110
110
110
110
110
110
110
110
36
IId
27 (32)c
4 (6)c
IIId
IVd
Vd
none
VId
none
V
41 (85)c
52 (73)c
50 (71)c
22
36 (47)c
31 (55)c
22 CuI
23 CuTc
24 CuIe
25 CuI.nBu3P
26 CuI‚LiCl
a Normalized reaction conditions: substrate concentration, 0.02 M;
catalyst loading, 10%; ligand loading, 20%; reaction stopped after 15 h.
b Isolated yield. c Yield based on the conversion. d Ligand I, N,N′-dimethyl-
ethylenediamine; ligand II, 1,10-phenanthroline; ligand III, trans-1,2-cyclo-
hexanediamine; ligand IV, sarcosine; ligand V, thiophene-2-carboxylic acid;
ligand VI, 2,4-pentanedione. e CuTc stands for copper(I) thiophene-2-
carboxylate, synthesized according to Liebeskind. f Starting material was
recovered.
leading to a seven-membered ring has been reported from the
groups of Ma8a and Fukuyama,8b respectively. Both group
employed “ligandless” conditions, and only one example was
given in each of these two papers. More recently, domino
copper-catalyzed intermolecular N-arylation of â-lactam fol-
lowed by ring expansion has been developed for the synthesis
of medium-ring nitrogen-containing heterocycles by Buchwald
and co-workers.48
The promising result obtained for the cyclization of 3c with
a catalytic amount of CuI under ligandless conditions49 prompted
us to carry out a detailed survey of reaction conditions, varying
the copper sources, the ligand structures, the solvents, the bases,
and the temperatures (Table 3). As is seen, addition of N,N′-
dimethylethylenediamine (I) into the reaction mixture (ligand/
CuI ) 2/1) led to a cleaner reaction with an increased yield
based on the substrate conversion (entry 1 vs 2).50 Several
readily available copper compounds, including CuCl, CuCl2,
Cu(OAc)2, CuSO4‚5H2O, Cu2O, and copper powders (bronze),
were studied as alternative catalyst precursors. Although all these
copper compounds having different oxidation states are catalyti-
cally active, none of them is as effective as CuI (entries 2-10).
Soluble copper sources such as CuI‚nPBu3 and CuI‚LiCl have
also been examined51 and were found to be less effective than
CuI under otherwise identical conditions (entry 1 vs 25, entry
22 vs 26, Table 3).
Bases were found to have a dramatic influence on the reaction
outcome. While the presence of cesium carbonate (entry 11)
and cesium hydroxide (entry 12) inhibited completely the
transformation, both potassium phosphate (entry 10) and cesium
acetate (entry 13) were able to promote the reaction, albeit
slightly less effectively than potassium carbonate. The choice
of the solvent also played an important role. While the
cyclization occurred smoothly in polar aprotic solvents such as
DMSO and DMF (entry 15),52 no reaction took place in less
polar solvents like dioxane (entry 14). When the reaction was
performed at lower temperature (80-100 °C), the reaction
became less clean due to the competitive degradation process
(entry 16 vs 2).
(48) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem.
Soc. 2004, 126, 3529-3533.
(49) Recent examples of copper-catalyzed “ligandless” conditions: (a) Kalinin,
A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986-
2987. (b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791-4793. (c) Lange, J. H. M.; Hofmeyer, L. J. F.; Hout, F. A.
S.; Osnarbrug, S. J. M.; Verveer, P. C.; Kruse, C. G.; Feenstra, R. W.
Tetrahedron Lett. 2002, 43, 1101-1104. (d) Okano, K.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2003, 5, 4987-4990.
Finally, other ligands, including 1,10-phenanthroline (II),53
(()-trans-1,2-cyclohexanediamine (III),54 sarcosine (IV),55
(51) We thank one of the reviewers for suggesting these experiments.
(52) Polar coordinating solvent such as N-methylpyrrolidinone was proposed
to be able to generate reactive Cu(I) monomer from the insoluble Cu(I)
carboxylatre polymer: Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org.
Chem. 1997, 62, 2312-2313.
(50) (b) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421-7428. (b) Kang, S.-K.; Kim, D.-W.; Park, J.-N. Synlett 2002, 427-
430.
9
14482 J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004

Dihydroazaphenanthrene Fused to Macrocycles
A R T I C L E S
Table 4. Copper-Catalyzed Synthesis of
1,4-Benzodiazepine-2,5-diones by Intramolecular N-Arylation of
Amide
Figure 3. Ugi-4CR for the synthesis of amides; structure of inputs.
thiophene-2-carboxylic acid (V),56,57 and 2,4-pentanedione58 (VI,
Figure 2), were examined. While II, III, and VI were less
efficient than I, IV and V turned out to be more effective than
I. Similar results were obtained when presynthesized catalyst
CuTc was used. Balancing the yield and the conversion, the
thiophene-2-carboxylic acid (V) was selected as the ligand for
the subsequent studies. Overall, under optimum conditions [CuI
(10%), V (20%), K2CO3, DMSO (0.02 M), 110 °C, 15 h], we
found that cyclization of the amide 3c provided the benzodi-
azepinedione 5c in 52% yield (73% based on the substrate
conversion). Although the yield remained moderate, we deemed
it respectable in light of the number of potential competitive
processes due to the presence of the second aryl iodide function.
(53) (a) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803-
3805. (b) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133-136. (c)
Nordman, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978-4979.
(d) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6, 27-30.
(54) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727-7729.
A simplified mechanistic view for the formation of benzo-
diazepine 5c from 3c is summarized in Scheme 8. The copper
catalyst may first coordinate to the two amide nitrogens, leading
to a five-membered chelate (E).59 The formation of this chelate
would entropically favor the subsequent oxidative addition to
the aryl halide. The presence of an amide substituent at the ring
a would make it more susceptible to the nucleophilic addition
(55) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453-2455.
(56) Original development of this ligand, see: (a) Allred, G. D.; Liebeskind, L.
S. J. Am. Chem. Soc. 1996, 118, 2748-2749. (b) Savarin, C.; Srogl, J.;
Liebeskind, L. S. Org. Lett. 2001, 3, 91-93.
(57) CuTc-catalyzed N-vinylation of vinyl iodide, see: (a) Shen, R.; Porco, J.
A., Jr. Org. Lett. 2000, 2, 1333-1336. (b) Shen, R.; Lin, C. T.; Bowman,
E. J.; Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889-
7901.
(58) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider,
P. J. Org. Lett. 2002, 4, 1623-1626.
(59) Sigel, H.; Martin, R. B. Chem. ReV. 1982, 82, 385-426.
9
J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004 14483

A R T I C L E S
Cuny et al.
Conclusion
of Cu(I) for electronic reasons, leading to intermediate F.
Removal of HI by the action of potassium carbonate would give
the copper(III)-amido complex G. Reductive elimination would
then produce the observed heterocycle, with the concomitant
regeneration of the copper catalyst. It is worth noting that CuTc
is capable of mediating the reductive coupling of aryl iodide,
leading to the biaryl compound.52 However, under these
conditions, neither dimeric nor the 10-membered macrocycle
from 3c via intramolecular aryl-aryl bond formation was
isolated.60
In summary, a novel palladium-catalyzed domino process
involving intramolecular N-arylation of amide/C-H activation/
aryl-aryl bond formation has been developed. Although both
individual steps are documented in the literature, the combina-
tion is without precedent. Moreover, the sequence involves the
formation of a medium-sized or a macrocyclic ring by a
palladium-catalyzed intramolecular N-arylation process, which
to the best of our knowledge was unknown at the outset of this
work. The effect of ligand structure was found to be minimal
for the present domino process, presumably due to the chelating
ability of the cyclization substrate. The azapalladacycle 11
resulting from the double oxidative addition of palladium to
the bis-aryl iodide 3c is isolated and is characterized by
spectroscopic studies. Its intermediacy in the transformation of
3c to 4c is proved by a control experiment. A distinctly different
catalytic property of copper and palladium catalysts was
observed. While it is impossible to stop the reaction after the
completion of intramolecular N-arylation with palladium cata-
lyst, it is discovered that copper iodide is capable of interrupting
the domino process, leading to the intramolecular N-arylation
product without inducing the C-H activation process. Indeed,
to the best of our knowledge, direct arylation via copper-
catalyzed C-H activation has not been developed for the biaryl
synthesis. Thus, from the same linear precursor, two different
heterocyclic scaffolds can be easily prepared simply by changing
the metal (catalyst) engaged. Taking advantage of the powerful
Ugi-4CR for the synthesis of linear precursor (3), two different
heterocyclessthe 1,4-benzodiazepine-2,5-dione (5) and the 5,6-
dihydro-8H-5,7a-diazacyclohepta[jk]phenanthrene-4,7-dione (4)s
can be prepared in two steps from readily accessible starting
materials: amine, aldehyde, acid, and isonitrile. The chemistry
developed herein is thus particularly useful in the diversity-
oriented synthesis program.
The ability of copper catalyst to promote the macrocyclization
was investigated.51 When bisamide 1c or 10 was submitted to
the copper catalyst, formation of macrocycle was not observed,
and only degradation occurred, leading to untractable materials.
The results of these experiments provided indirect evidence that
copper and palladium might have different coordination patterns
with the amide substrate. Such differences in coordination might
lead to different conformational preferences of the intermediate
adduct, and hence the outcome of the cyclization reaction.
The scope of this copper-catalyzed intramolecular N-arylation
of amide for the synthesis of diversely substituted 1,4-benzo-
diazepine-2,5-diones was next examined. Ugi-4CR was used
for the synthesis of cyclization substrates, and the inputs used
are listed in Figure 3. From four aldehydes, three amines, three
isonitriles, and three carboxylic acids, amides 3k-s (Figure 3)
were synthesized in a single operation with good to excellent
yields under standard Ugi-4CR conditions (MeOH, 0.2 M, room
temperature). The results of the cyclization are summarized in
Table 4. As can be seen, the cyclization conditions are applicable
to a variety of substrates having different substituents and
tolerate a range of functional groups, such as ester, carbamate,
tertiary amine, and aryl iodide, etc. The presence of chelating
functions such as amino ester (entries 1-4) and vicinal diamine
(entries 5, 7, 8) is well tolerated, although these functions can
potentially form the complex with the copper catalyst, consum-
ing consequently the active catalytic species. In most cases, the
1,4-benzodiazepine-2,5-diones were obtained in excellent yields.
Ugi-4CR followed by postfunctionalization has been elegantly
developed previously by a number of groups.61 In all these
approaches, the seven-membered ring was formed by lactam-
ization. The present two-step synthesis of 1,4-benzodiazepine-
2,5-dione represents thus a new synthetic strategy.
Acknowledgment. We thank CNRS for financial support. A
doctoral fellowship from this institute to G.C. is gratefully
acknowledged. We thank Professor Lallemand for his interest
in this work.
Supporting Information Available: Experimental details and
analytical data for compounds 1a-e, 2a-e, 3a-s, 4a-j, 5, 11-
20; copies of H NMR spectra of cyclic compounds and the
1
azapalladacycle 5; and chiral HPLC analyses of compounds
4a,b. This material is available free of charge via the Internet
at http://pubs.acs.org.
(60) For a recent comprehensive review on aryl-aryl bond formation, see:
Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359-1470.
(61) For reviews, see: (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-131. (b)
Hulme, C.; Gore, V. Curr. Med. Chem. 2002, 9, 1241-1253.
JA047472O
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