Synthesis of tricyclic nitrogen heterocycles by a sequence of palladium-catalyzed N-H and C(sp3)-H arylations

Article abstract of DOI:10.1021/ol2031763

A range of tricyclic nitrogen heterocycles were synthesized in a straightforward and efficient manner via a sequence involving palladium-catalyzed N-arylation and C(sp³)-H arylation as the key steps. Whereas the C(sp³)-H arylation furnished fused 6,5,6-membered ring systems efficiently, the formation of the more strained 6,5,5-membered systems proved to be more challenging and required a subtle adjustment of the reaction conditions.

Full text of DOI:10.1021/ol2031763

ORGANIC
LETTERS
2012
Vol. 14, No. 1
398–401
Synthesis of Tricyclic Nitrogen Heterocycles
by a Sequence of Palladium-Catalyzed NÀH
and C(sp3)ÀH Arylations
Mathieu Guyonnet and Olivier Baudoin*
ꢀ
CNRS UMR 5246 - Institut de Chimie et Biochimie Moleculaires et Supramoleculaires,
Universite Claude Bernard Lyon 1, CPE Lyon, 43 Boulevard du 11 Novembre 1918,
ꢀ
ꢀ
69622 Villeurbanne, France
olivier.baudoin@univ-lyon1.fr
Received November 28, 2011
ABSTRACT
A range of tricyclic nitrogen heterocycles were synthesized in a straightforward and efficient manner via a sequence involving palladium-
catalyzed N-arylation and C(sp3)ÀH arylation as the key steps. Whereas the C(sp3)ÀH arylation furnished fused 6,5,6-membered ring systems
efficiently, the formation of the more strained 6,5,5-membered systems proved to be more challenging and required a subtle adjustment of the
reaction conditions.
In recent years, transition-metal-catalyzed CÀH bond
functionalization has emerged as a powerful tool to trans-
form otherwise unreactive CÀH bonds into carbonÀ
carbon or carbonÀheteroatom bonds.1,2 In particular, this
approach has been utilized to construct3 and functionalize4
heterocyclic systems, which have broad interest for the
synthesis of bioactive molecules and organic materials.
Most existing CÀH functionalization methods employed
to assemble heterocycles involve the cleavage of C(sp2)ÀH
bonds, and in comparison much less effort has been devot-
ed to methods involving the somewhat more challenging
activation of nonacidic C(sp3)ÀH bonds.5À7 Inspired by
former work on the synthesis of indolines by palladium(0)-
catalyzed C(sp3)ÀH arylation,6f,k we envisioned that a
similar strategy could be utilized to access fused tricyclic
(6) For the synthesis of heterocycles via palladium(0)-catalyzed C(sp3)ÀH
activation: (a) Dyker, G. Angew. Chem., Int. Ed. Engl. 1992, 31, 1023.
(b) Ren, H.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462. (c) Ren,
H.; Li, Z.; Knochel, P. Chem.ÀAsian J. 2007, 2, 416. (d) Lafrance, M.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. (e)
Liron, F.; Knochel, P. Tetrahedron Lett. 2007, 48, 4943. (f) Watanabe,
T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759. (g) Salcedo,
A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 3600. (h) Kim, H. S.;
Gowrisankar, S.; Kim, S. H.; Kim, J. N. Tetrahedon Lett. 2008, 49, 3858.
(i) Huang, Q.; Larock, R. C. Tetrahedon Lett. 2009, 50, 7235. (j)
Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 10692. (k) Rousseaux, S.; Davi, M.; Sofack-Kreutzer,
J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am.
Chem. Soc. 2010, 132, 10706. (l) Nakanishi, M.; Katayev, D.; Besnard, C.;
(1) Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-VCH:
Weinheim, 2005.
(2) Topics in Current Chemistry; Yu, J.-Q., Shi, Z., Eds.; Springer:
Heidelberg, 2010; Vol. 292.
(3) (a) Thansandote, P.; Lautens, M. Chem.ÀEur. J. 2009, 15, 5874.
(b) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071.
(4) (a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (b) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (c) Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (d)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (e) Hirano, K.;
Miura, M. Synlett 2011, 294.
(5) (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.ÀEur. J. 2010, 16, 2654. (b) Baudoin, O. Chem.
Soc. Rev. 2011, 40, 4902.
€
Kundig, E. P. Angew. Chem., Int. Ed. 2011, 50, 7438.
(7) For the synthesis of heterocycles via palladium(II)-catalyzed C(sp3)ÀH
activation: (a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007,
129, 7274. (b) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
ꢀ
2007, 129, 7496. (c) Liegault, B.; Fagnou, K. Organometallics 2008, 27,
€
4841. (d) Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew.
Chem., Int. Ed. 2009, 48, 6892. (e) Wasa, M.; Engle, K. M.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 3680. (f) Yoo, E. J.; Wasa, M.; Yu,
J.-Q. J. Am. Chem. Soc. 2010, 132, 17378. (g) Stowers, K. J.; Fortner,
K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. (h) Gormisky,
P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133, 12584.
r
10.1021/ol2031763
Published on Web 12/16/2011
2011 American Chemical Society

γ- and δ-lactams 1 (Z = CH2) and analogues from aryl
bromides 2 (Scheme 1). An efficient synthesis of these rather
unique heterocycles8 should streamline access to bioactive
alkaloids such as mangochinine (5)9 and glionitrin B (6).10
In turn, aryl bromides 2 would be obtained by a Buch-
waldÀHartwig N-arylation/electrophilic bromination se-
quence, thereby securing a straightforward and modular
synthesis of target lactams 1.
N-arylated products were obtained, provided that electron-
deficient aryl bromides were used as coupling partners.14
However, the N-arylation of the corresponding ε-lactam (3
with n = 3) failed under the same conditions.
Scheme 2. Synthesis of N-Arylated Lactams and Analoguesa
Scheme 1. Retrosynthetic Analysis
We began our study with the exploration of the first key
N-arylation step(Scheme 2). ThePd-catalyzedN-arylation
of γ-lactams has been reported to occur with high yields.11
In line with these data, N-arylated γ-lactams 7aÀf bearing
electron-withdrawing substituents on the benzene ring
were obtained in good-to-excellent yield (68À99%) by
using Pd(OAc)2/Xantphos as the catalyst.12 Similarly to
γ-lactams, analogous oxazolidinone (Z = O) and imida-
zolidinone (Z = NCy) also underwent N-arylation effi-
ciently (7g,h), in line with literature precedents.13 In
contrast, δ-lactams have been shown to be less reactive
than γ-lactams, and as a consequence the Pd-catalyzed
N-arylation of the former has been much less developed.11a
Nevertheless, the above reaction conditions were found to
be also applicable to δ-lactams (7iÀo) as well as analogous
6-membered cyclic carbamate (7p), urea (7q), and diketo-
piperazine (7r). Indeed, high yields of the corresponding
a Yield of the isolated products in parentheses.
b Obtained under microwave heating (160 °C).
Following N-arylation, the regioselective bromination
of compounds 7aÀr was performed, giving rise to the
corresponding aryl bromides 2aÀr in 73À97% yield by
using either Br2/AgNO3 or N-bromosuccinimide (see the
Supporting Information for details). Next, the second key
C(sp3)ÀH arylation step was investigated. We first applied
conditions initially reported by Fagnou et al.6d and then
successfully transposed to other heterocyclic systems6f,jÀl
to aryl bromide 2f (Table 1, entry 1). Thus, with Pd(OAc)2/
PCy3 as the catalyst and cesium carbonate/pivalic acid as
the base/additive in mesitylene at 140 °C, protodebromi-
nation product 7f was formed with complete conversion.
This failure can be ascribed to the excessive strain of the
target tricyclic ring system, as compared to previously
successful bi- and tricyclic systems.6f Changing the base
to potassium carbonate (entry 2) or the solvent to DMF
(entry 3) failed to provide any observable trace of desired
product 1f. Interestingly, compound 1f was formed in
small amounts with toluene as the solvent (entry 4). A
reexamination of different carbonates with this solvent
(8) For an alternative approach giving moderate yields, see: Lu, H.;
Li, C. Tetrahedron Lett. 2005, 46, 5983.
(9) Qiu, S.; Liu, C.; Zhao, S.; Xia, Z.; Farnsworth, N. R.; Fong,
H. H. S. Tetrahedron Lett. 1998, 39, 4167.
(10) Park, H. B.; Kim, Y.-J.; Park, J.-S.; Yang, H. O.; Lee, K. R.;
Kwon, H. C. J. Nat. Prod. 2011, 74, 2309.
(11) (a) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035. (b) Yin,
J.; Buchwald Org. Lett. 2000, 2, 1101. (c) Browning, R. G.; Mahmud, H.;
Badarinarayana, V.; Lovely, C. J. Tetrahedron Lett. 2001, 42, 7155. (d)
Browning, R. G.; Badarinarayana, V.; Mahmud, H.; Lovely, C. J.
Tetrahedron 2004, 60, 359. (e) Shirai, A.; Miyata, O.; Tohnai, N.;
Miyata, M.; Procter, D. J.; Sucunza, D.; Naito, T. J. Org. Chem. 2008,
73, 4464.
(12) Aryl substituents R1, R2 were chosen for their ability to direct
bromination in ortho position to the lactam during the next step.
(13) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org.
Lett. 2001, 3, 2539. (b) Madar, D. J.; Kopecka, H.; Pireh, D.; Pease, J.;
Pliushchev, M.; Sciotti, R. J.; Wiedeman, P. E.; Djuric, S. W. Tetra-
hedron Lett. 2001, 42, 3681. (c) Yin, J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 6043.
(14) For instance, N-arylation failed with Z = CH2 and R1 = R2 =
OMe.
Org. Lett., Vol. 14, No. 1, 2012
399

(entries 5À8) led to an optimal result with potassium
carbonate (entry 6). Moreover, by combining K2CO3 with
various amounts of Na2CO3 (entries 9À12), we found that
the selectivity of 1f vs 7f could be reversed, with 1f
becoming the major product.
be performed to form the desired product at the expense of
the competitive protodebromination product.
Scheme 3. Synthesis of Fused Tricyclic Lactams and Analoguesa
Table 1. Optimization of the Intramolecular C(sp3)ÀH Arylationa
entry base(s) (equiv)
solvent
conversiona (%)
1f:7fa
<1:99
1
2
Cs2CO3 (2.0) mesitylene
K2CO3 (2.0) mesitylene
>99
>99
>99
>99
>99
>99
4
<1:99
<1:99
1:49
1:11
1:1.6
1:1
3
Cs2CO3 (2.0) DMF
Cs2CO3 (2.0) toluene
Rb2CO3 (2.0) toluene
4
5
6
K2CO3 (2.0)
toluene
7
Na2CO3 (2.0) toluene
8
Li2CO3 (2.0)
K2CO3 (1.3)
K2CO3 (1.3)
Na2CO3 (1.3)
K2CO3 (1.3)
Na2CO3 (0.9)
K2CO3 (1.3)
Na2CO3 (0.3)
K2CO3 (1.3)
Na2CO3 (0.3)
toluene
toluene
toluene
14
<1:99
1:2
9
>99
>99
10
3:1
a Yield of the isolated products in parentheses.
b Yield and ratio of the mixture of desired:protodebromination
products.
c Protodebromination and degradation were observed by GCMS
analysis.
11
12
13
toluene
toluene
toluene
>99
>99
>99
2.8:1
2.7:1
3:1 (86%)b
d 85% of the starting material was recovered after 48 h.
a Conversion of 2f and ratio of 1f:7f determined by 1H NMR and
The optimized conditions were then applied to various
aryl bromides obtained by the N-arylation/electrophilic
bromination sequence (Scheme 3). In line with the above
results, fused γ-lactams 1aÀf were obtained in moderate-
to-good yields together with the corresponding protodeb-
romination products, that could be separated in most
instances (1bÀe). Unfortunately, the more rigid oxazoli-
dinone 2g and imidazolidinone 2h failed to undergo intra-
molecular C(sp3)ÀH arylation under the same conditions.
In contrast, the reaction of the less rigid δ-lactams 2iÀo,
oxazinanone 2p and tetrahydropyrimidone 2q provided the
corresponding tricyclic products 1iÀq in good-to-excellent
yields. In addition, original fused diketopiperazine 1r was
also obtained efficiently by this method.10,16
GCMS analysis of the crude mixture. b Pd(PCy3)2 was used insteadof the
Pd(OAc)2/PCy3 HBF4 mixture. Yield of the isolated mixture in
parentheses.
3
In related reactions, the C(sp3)ÀH activation step was
shown to occur through the base-induced, concerted
metalationÀdeprotonation (CMD) mechanism.6d,j,k,15 The
beneficial effectof the combination of K2CO3 and Na2CO3
highlights the impact of the base countercation, lying in the
second coordination sphere of Pd, in such mechanism.
Finally, more reproducible results were obtained when the
well-defined Pd(PCy3)2 complex was employed instead of
the in situ mixture of Pd(OAc)2 and phosphine ligand
(entry 13). Under these conditions, an inseparable mixture
of 1f:7f (3:1) was isolated in 86% combined yield. The
above results show that, for difficult cases of C(sp3)ÀH
arylation, subtle adjustments of the solvent and base must
The X-ray crystal structures of representative target mole-
cules 1m and 1r were elucidated (Figure 1), showing that these
compounds exhibit a relatively similar rigid tricyclic scaffold.
(16) 2,5-Diketopiperazines are important structural motifs in natural
product and medicinal chemistry: (a) Martins, M. B.; Carvalho, I.
Tetrahedron 2007, 63, 9923. (b) Huang, R.; Zhou, X.; Xu, T.; Yang,
X.; Liu, Y. Chem. Biodivers. 2010, 7, 2809.
(15) (a) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion,
J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157. (b)
Kefalidis, C. E.; Baudoin, O.; Clot, E. Dalton Trans 2010, 39, 10528.
400
Org. Lett., Vol. 14, No. 1, 2012

heterocycles by using Pd-catalyzed N-arylation and C
(sp3)ÀH arylation as the key steps. This work further
illustrates the impact of emerging CÀH functionalization
methods on the synthesis of new interesting molecular
scaffolds.
ꢁ
Acknowledgment. We thank the Ministere de l’En-
seignement Superieur et de la Recherche (fellowship to
ꢀ
M.G.), Agence Nationale de la Recherche (programme
blanc “AlCaCHA”), Institut Universitaire de France, and
Johnson Matthey PLC (loan of palladium acetate). We are
ꢀ
also grateful to R. Jazzar and E. Jeanneau (Universite
Claude Bernard Lyon 1) for the synthesis of Pd complexes
and X-ray diffraction analyses, respectively.
Supporting Information Available. Full characteriza-
tion of all new compounds, detailed experimental proce-
dures, copies of NMR spectra for target molecules, and
X-ray crystal structure data (CIF) for compounds 1m and
1r. This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 1. X-ray crystal structure of compounds 1m (top) and
1r (bottom) (30% probability ellipsoids plot).
In conclusion, we have described a straightforward
strategy to synthesize original fused tricyclic nitrogen
Org. Lett., Vol. 14, No. 1, 2012
401