Palladium-catalyzed domino intramolecular N-arylation/Lntermolecular C-C bond formation for the synthesis of functionalized benzodiazepinediones

Article abstract of DOI:10.1021/ol7029799

A divergent and regiocontrolled Pd-catalyzed domino sequence involving an intramolecular N-arylation and an intermolecular Heck reaction has been developed, providing rapid access to functionalized benzodiazepine-2,5-diones 3. The starting materials were synthesized by the Ugi four-component reaction. An unprecedented X-ray structure of bispalladacycle 6 was documented.

Full text of DOI:10.1021/ol7029799

ORGANIC
LETTERS
2008
Vol. 10, No. 5
857-860
Palladium-Catalyzed Domino
Intramolecular N-Arylation/Intermolecular
C−C Bond Formation for the Synthesis
of Functionalized Benzodiazepinediones
Angela Salcedo, Luc Neuville,* Christophe Rondot, Pascal Retailleau, and
Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France
zhu@icsn.cnrs-gif.fr; neuVille@icsn.cnrs-gif.fr
Received December 11, 2007
ABSTRACT
A divergent and regiocontrolled Pd-catalyzed domino sequence involving an intramolecular N-arylation and an intermolecular Heck reaction
has been developed, providing rapid access to functionalized benzodiazepine-2,5-diones 3. The starting materials were synthesized by the Ugi
four-component reaction. An unprecedented X-ray structure of bispalladacycle 6 was documented.
Direct C-H functionalization has attracted intensive research
efforts recently, and a number of elegant approaches have
been developed, allowing facile construction of the C-C/
C-X bond from the ubiquitous C-H bond.1 Whereas the
ability to transform a variety of C-H bonds is changing the
paradigm of synthetic chemistry and is opening new perspec-
tives in complex organic synthesis,2 it happens that C-H
functionalization is, in some cases, not a desired process in
a given transformation and needs to be suppressed. This
could be a difficult task in certain circumstances wherein a
C-H bond is in close proximity to the tethered organo-
metallic species. Indeed, mechanistic studies indicated that
cyclization via palladium-catalyzed C-H functionalization
could be a kinetically fast process related to other elementary
reactions.3 In connection with our research program dealing
with the transition-metal-catalyzed multicomponent4,5 and
domino processes,6,7 we described a facile synthesis of
tetracyclic compounds (2) from diamides (1) by a palladium-
(3) (a) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084-12085. (b) Bour, C.; Suffert, J. Org. Lett. 2005, 7, 653-656. (c)
Mota, A. J.; Dedieu, A.; Bour, A.; Suffert, J. J. Am. Chem. Soc. 2005, 127,
7171-7172. (d) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066-1067. (e) Campeau,
L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
581-590. (f) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006,
8, 4927-4930.
(4) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Angew. Chem., Int.
Ed. 2007, 46, 3291-3295.
(5) Reviews on metal-catalyzed MCR, see: (a) Jacobi von Wangelin,
A.; Neumann, H.; Go¨rdes, D.; Klaus, S.; Stru¨bing, D.; Beller, M. Chem.
Eur. J. 2003, 9, 4286-4294. (b) Balme, G.; Bossharth, E.; Monteiro, N.
Eur. J. Org. Chem. 2003, 4101-4111. (c) Murakami, M. Angew. Chem.,
Int. Ed. 2003, 42, 718-720. (d) D’Souza, D. M.; Mu¨ller, T. J. J. Chem.
Soc. ReV. 2007, 36, 1095-1108. (e) For a monograph, see: Multicomponent
Reaction; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005.
(6) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961-
967.
(1) For reviews on C-H activation, see: (a) Ryabov, A. D. Chem. ReV.
1990, 90, 403-424. (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) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211-
241. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731-
1770. (f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826-834. (g)
Li, C.-J. Acc. Chem. Res. 2002, 35, 533-538. (h) Catellani, M. Synlett
2003, 298-313. (i) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253-1264. (j) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439-
2463. (k) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.;
Lazareva, A. Synlett 2006, 3382-3388.
(7) For general reviews on the domino process, see: (a) Tietze, L. F.
Chem. ReV. 1996, 96, 115-136. (b) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134-7186. (c) For a recent
book, see: Domino Reactions in Organic Synthesis; Tietze, L. F., Brasche,
G., Gericke, K., Eds.; Wiley-VCH: Weinheim, 2006.
(2) (a) Godula, K.; Sames, D. Science 2006, 312, 67-72. (b) Alberico,
D.; Scott, M. E.; Lantens, M. Chem. ReV. 2007, 107, 174-238.
10.1021/ol7029799 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/29/2008

An initial experiment using phenylboronic acid (5) as an
intercepting agent met with failure. In fact, reaction of 1a
with 5 [Pd(OAc)2, 5 mol %, KOAc, DMSO, 120 °C] fur-
nished tetracyclic compound 2a (R1 ) Me, R2 ) H) as the
only isolable product in 90% yield. This result indicated that
the intramolecular N-arylation and the subsequent C-H
functionalization were much faster than the alternative
intermolecular Suzuki-Miyaura coupling.13 The whole reac-
tion sequence was completely inhibited in the presence of
morpholine or 4-benzyloxazolidinone under identical condi-
tions. Copper-free Sonagashira coupling14 was also incom-
patible with the projected sequence resulting a complex reac-
tion mixture. On the other hand, using potassium ferro(II)-
cyanide6,15 as an anion-capturing agent, the desired benzo-
diazepinedione 3a (R ) CN, R1 ) Me, R2 ) H) was isolated
in 22% yield together with the double cyclization product
(2a, 35%). When a more reactive vinyltributylstannane was
used as a nucleophile,16 the desired benzodiazepinedione 3b
(R ) vinyl, R1 ) Me, R2 ) H, 33%) was produced together
with the linear double-vinylated product 4b (R ) vinyl, R1
) Me, R2 ) H, 23%). Gratefully, reaction of 1a in the
presence of dihydrofuran afforded the expected benzodiaz-
epinedione 3c resulting from the N-arylation/Heck reaction
in 54% yield (Scheme 2, a). This yield is quite remarkable,
Scheme 1. Proposed Divergent Reaction Sequence
catalyzed domino intramolecular process (Scheme 1, eq 1).8
Preliminary experiments demonstrated that (a) the presence
of the two-diiodide functions was mandatory for the sequence
and (b) once the reaction was initiated, it was impossible to
interrupt the double cyclization, although the reaction went
through the benzodiazepinedione intermediate. As a continu-
ation of this research, we report herein that the direct C-H
arylation could be effectively interrupted in the presence of
a suitable trapping agent. Thus, starting from amide 1, a
domino sequence involving an intramolecular N-arylation9
followed by an intermolecular Heck reaction afforded func-
tionalized benzodiazepinedione (BZD) 3, a privileged struc-
ture in medicinal chemistry (Scheme 1, eq 2).10 We document
also for the first time an X-ray structure of an unusual
bimetallic macrocycle bridged by two dative Pd-I bonds.
The realization of our projected sequence implied the
differentiation of two aryl iodides11 allowing their site-
selective functionalization that must satisfy the following
criteria: (a) The intramolecular N-arylation should precede
any intermolecular bond-forming process to avoid the for-
mation of linear adduct 4 (Scheme 1). (b) After the formation
of benzodiazepinedione, the subsequent intermolecular bond
formation must be kinetically faster than the alternative
intramolecular C-H functionalization. Only a few examples
were known wherein the interruption of the intramolecular
C-H functionalization has been accomplished by an inter-
molecular process.1h,12,3b
Scheme 2. Proposed Mechanism for the Divergent Pathway
as only 25% of product 3c was isolated using a two-step
procedure based on our previous work,8 involving a copper-
catalyzed benzodiazepinedione synthesis, followed by a Heck
reaction (Scheme 2, b).
In an attempt to optimize the reaction conditions, we
observed that the ligandless conditions are essential for the
present tandem process since in the presence of triphenyl-
phosphine and other biarylphosphine ligands under otherwise
identical conditions the intramolecular C-H functionalization
prevails over the intermolecular Heck reaction, leading to
the tetracyclic compound 2a in excellent yield. While the
Heck reaction did take place smoothly under diverse set of
(8) (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2003,
42, 4774-4777. (b) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem.
Soc. 2004, 126, 14475-14484.
(9) For reviews on Pd-catalyzed C-N bond formation, see: (a) Jiang,
L.; Buchwald, S. L. In Metal-Catalyzed Cross Coupling Reactions, 2nd
ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004;
Vol. 2, pp 699-760. (b) Hartwig, J. F. In Handbook of Organopalladium
Chemistry of Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley-
Interscience: New York, 2002; Vol. 1, pp 1051-1096. (c) Schlummer,
B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599-1626.
(10) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893-930.
(12) Catellani, M.; Motti, E.; Paterlini, L. J. Organomet. Chem. 2000,
593-594, 240-244.
(11) For selected examples of domino processes involving a key
N-arylation step, see: (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M.
Angew. Chem., Int. Ed. 2000, 39, 2501-2504. (b) Rivas, F. M.; Riaz, U.;
Driver, S. T. Tetrahedron: Asymmetry 2000, 11, 1703-1707. (c) Wang,
M.-X.; Zhang, X.-H.; Zheng, Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838-
842. (d) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203-
4206 and references cited therein. For general reviews on the site-selective
functionalization of aryl halides, see: (e) Schro¨ter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245-2267. (f) Fairlamb, I. J. S. Chem. Soc. ReV.
2007, 36, 1036-1045.
(13) Suzuki, A.; Miyaura, N. Chem. ReV. 1995, 95, 2457-2483.
(14) For recent examples of the Cu-free Sonogashira reaction, see: (a)
Yi, C.; Hua, R. J. Org. Chem. 2006, 71, 2535-2537. (b) Tougerti, A.;
Negri, S.; Jutand, A. Chem. Eur. J. 2007, 13, 666-676 and references cited
therein.
(15) (a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388-
1389. (b) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005, 46,
2585-2588. (c) Weissman, S. A.; Zewge, D.; Chen, D. J. Org. Chem. 2005,
70, 1508-1510.
(16) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
858
Org. Lett., Vol. 10, No. 5, 2008

conditions,17 it is interesting to note that the present trans-
formation represented a rare example wherein an intramo-
lecular N-arylation occurred under ligandless conditions
leading to the formation of a seven-membered ring.18 Even
more surprisingly, this cyclization took place faster than most
of the cross-coupling reactions that we examined.
The generality of this domino process was next examined
by varying systematically the R1 and R2 residues. The cycli-
zation precursors were prepared by the Ugi four-component
(Ugi-4CR) reaction19 using an o-iodobenzyl isonitrile, o-
iodobenzoic acid, an amine, and an aldehyde as inputs
(MeOH, rt). The benzodiazepinediones synthesized by this
two-step sequence (Ugi 4CR/N-arylation-Heck reaction) are
summarized in Figure 1. As is seen, both alkyl and aryl
corresponding dihydrofuranyl-BZD except for compound 3h.
In the case of compounds 3d-h, two inseparable diastere-
omers were produced together with the conformers inherent
to benzodiazepinedione. The NMR spectra of these com-
pounds were therefore rather complex.20 Methyl acrylate and
dimethylacrylamide are also viable substrates to interrupt the
C-H activation process providing 3i and 3j in yields of 39%
and 45% respectively, whereas acrylonitrile gave substan-
tially lower yield of the desired product (3k, 20%).
A possible reaction scenario that accounts for the forma-
tion of both benzodiazepinediones 2 and 3 is illustrated in
Scheme 3.
Scheme 3. Synthesis of Dihydrofuranylbenzodiazepinedione 3c
We have demonstrated in previous studies the importance
of the bis-aryl halide function in the formation of benzodi-
azepinedione. Therefore, the regioselective process cannot
rely on simple selectivity during oxidative addition on one
aryl iodide. We proposed that the two aryl halides were not
differentiated in the oxidative addition step leading to the
bis-arylpalladium halide intermediate (A).21 This intermediate
might adopt a conformation that is conducive to the cycliza-
tion, making the intramolecular N-arylation kinetically
competitive relative to other coupling process. An intramo-
lecular N-arylation would generate a second PdII intermediate
(B), from which two divergent pathways were possible. The
intramolecular C-H activation followed by reductive elimi-
nation would produce compound 2a (path A). On the other
hand, in the presence of an external nucleophile that is
susceptible to react with the PdII species, a cross coupling,
or carbopalladation (via, for example, intermediates E and
Figure 1. Two-step synthesis of benzodiazepinediones. (Yields
refer to the palladium-catalyzed domino sequence.)
groups in the amide backbone are tolerated, and among the
precursors evaluated, linear amide bearing a substituent at
the C-3 position gave a generally higher yield of the
(17) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
Reaction; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: Weinheim, 1999;
pp 99-166.
(18) Xantphos is required as a supporting ligand for the formation of
the 7-membered ring by intramolecular N-arylation; see: (a) Yin, J.;
Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104. For lingandless conditions,
see: (b) Cvetovich, R. J.; Reamer, R. A.; DiMichelle, L.; Chung, J. Y. L.;
Chilenski, J. R. J. Org. Chem. 2006, 71, 8610-8613 see also ref 8.
(19) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-
3210. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144. (c) Do¨mling, A.
Chem. ReV. 2006, 106, 17-89.
(20) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935-
8939.
(21) For palladium-mediated reactions involving possibly a double-
oxidative insertion, see: Cardenas, D. J.; Martin-Matute, B.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 5033-5040 and references therein.
Org. Lett., Vol. 10, No. 5, 2008
859

Figure 2. ORTEP view of the X-ray crystal structure of one conformer of compound 6.24
F, via path B) could occur to produce bicyclic compound 3.
Partition between these two pathways depended on the
structure of the nucleophile, and from our experimental
results, we speculated that the latter process became com-
petitive when the external nucleophile was able to coordinate
to the palladium(II) intermediate. The observation that
phosphine ligand completely suppressed the Heck pathway
could be explained by the fact that its presence disfavored
the coordination of olefin to palladium, thereby favoring the
alternative direct arylation pathway.
To support this mechanistic view, palladium complex 6
was prepared by a reaction of 1a with 2 equiv of tetrakis-
triphenylphosphine Pd(0) and was characterized by X-ray
analysis (Figure 2). The tertiary amide oxygen possibly
coordinated to the proximal palladium as indicated by the
short interatomic bond distance (d ≈ 3.25 Å),22 whereas the
long distance between the nitrogen atom of the secondary
amide and the proximal palladium Pd1 (d ≈ 4.57-4.83 Å)
indicated the lack of coordination between these two atoms.23
To the best of our knowledge, such a bimetallic macrocycle
bridged by two dative Pd-I bonds has not been characterized
before.
factor, the formation of 6 might in turn facilitate the
coordination of the secondary amide to the remote palladium,
leading consequently to the intramolecular N-arylation.26
In summary, a palladium-catalyzed domino process
allowing the site-selective functionalization of two tethered
aryl iodides has been developed for the synthesis of func-
tionalized benzodiazepine-2,5-diones (3). Key to the success
was the formation of 7-membered ring via a facile intramo-
lecular N-arylation and the suppression of the entropically
favored C-H functionalization process. An X-ray structure
of unprecedented bimetallic macrocycle bridged by two
dative Pd-I bonds brings an interesting mechanistic insight
on the unusual facile N-arylation step. By combining the
Ugi-4CR with the present catalytic domino process, the
medicinally relevant bicyclic compound 3 is readily synthe-
sized in only two steps from simple starting materials.
Acknowledgment. Financial support from CNRS and this
institute are gratefully acknowledged. A.S. (ICSN) and C.R.
(ICSN) thank this institute for doctoral fellowships.
Supporting Information Available: Experimental pro-
cedures, product characterization, NMR spectra of com-
pounds 3a-k, and CIF files for 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
The easy formation of this 13-membered palladacycle 6
is intriguing and may be facilitated by conformational
properties of the linear amide.25 By an obvious entropic
OL7029799
(22) Dunbar, Y.-Q.; Sun, J.-S. J. Chem. Soc., Chem. Commun. 1994,
2387-2388.
(25) Conformation-directed synthesis, see: Blankenstein, J.; Zhu, J. Eur.
J. Org. Chem. 2005, 1949-1964.
(26) For recent mechanistic studies on the N-arylation catalyzed by
BINAP-ligated palladium complex, see: Shekhar, S.; Ryberg, P.; Hartwig,
J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2006, 128, 3584-3591.
(23) (a) Meneghetti, J.-S.; Lutz, P. J.; Kress, J. Organometallics 2001,
20, 5050-5055. (b) Garrone, R.; Romano, A. M.; Santi, R.; Millini, R.
Organometallics 1998, 17, 4519-4522.
(24) See the Supporting Information.
860
Org. Lett., Vol. 10, No. 5, 2008