Intramolecular oxidative C-H coupling for medium-ring synthesis

Article abstract of DOI:10.1021/ja1090854

An oxidative C-H coupling is described for medium-ring synthesis.

Full text of DOI:10.1021/ja1090854

COMMUNICATION
pubs.acs.org/JACS
Intramolecular Oxidative C-H Coupling for Medium-Ring Synthesis
Didier G. Pintori and Michael F. Greaney*
EastChem, School of Chemistry, University of Edinburgh, King's Buildings, West Mains Rd, Edinburgh EH9 3JJ, U.K.
S Supporting Information
b
ABSTRACT: An oxidative C-H coupling is described for
medium-ring synthesis.
ransition-metal-catalyzed oxidative C-H coupling offers a
T
highly efficient approach to biaryl synthesis.1 Using two C-H
bonds as coupling partners, no pre-functionalization is required
and the reaction can, in principle, afford minimal waste products.
The field has undergone rapid growth in recent years, with a
number of impressive intermolecular cross-couplings being
developed.2 The intramolecular variant, by contrast, has not
been widely investigated. Seminal work in the 1970s established
the reaction for five-membered, fully aromatic systems such as
carbazoles and dibenzofurans,3,4 but applications to alternative
ring systems are rare (Figure 1). We reasoned that dehydrogena-
tive coupling for the synthesis of medium-ring-containing biaryls
would represent a powerful approach to these compounds, which
are often difficult to access by classical routes. These challenges
are particularly relevant to medicinal chemistry; despite the plethora
of medium-ring structures found in biologically active natural
products, seven-, eight-, and nine-membered rings remain rare in
drug molecules (Figure 1).5
Figure 1. Dehydrogenative coupling for medium-ring biaryl synthesis.
Examples of biologically active medium-ring containing biaryls from
Nature (blue) and pharmaceuticals (red).
tethering chain was possible, with the three oxazapane derivatives
2e, 2f, and 2g all formed in good yield.
Interestingly, no five-membered ring products from C-H
activation at the benzylic position were observed for substrates
2e and 2f, despite the susceptibility of benzyl ethers to oxidation.9
sp2 C-H activation to form the medium ring is evidently favored
under these reaction conditions. Nitrogen substitution into the
medium ring was likewise possible, with the diazapane analogues
2h (NMe) and 2i (NMs) being formed in very good yield. A
good EWG at the indole C3 was necessary for reaction, with
esters and ketones producing low yields of medium-ring product
(Supporting Information). The cyano group was proficient,
however, affording annulated indole 2j and the azaindole 2k in
high yield. The nitro group proved the most effective of all,
enabling the azaindole 2l to oxidatively couple in an excellent
95% yield.
We extended the work to encompass heteroaromatic ring
systems, with the aim of synthesizing novel heterobiaryls annu-
lated in a seven-membered ring (Chart 2). The reaction was very
effective for the synthesis of symmetrical bisindole 4a, synthe-
sized in 91% yield from C2 oxidative coupling of the symmetrical
precursor. We could likewise use both benzimidazole and
pyrazole C-H bonds as participants in the reaction to form
the highly functionalized biheteroaryls 4b, 4c, and 4d in good
yields.
We chose to study the indole system, given its widespread
occurrence in biologically active compounds.6 A screen of N-
alkylated indoles identified compounds of general structure 1,
containing an electron-withdrawing group (EWG) at the indole
3-position, as potential substrates for dehydrogenative seven-
membered ring formation. A catalyst optimization study (Supporting
Information) established that catalytic Pd(OAc)2 in the presence
of excess Cu(OAc)2, using DMA as solvent, was effective for
C-C bond formation, with the parent structure 2a being formed
in 77% yield (Chart 1). With these conditions in hand, we examined
their generality for seven-membered ring formation. A range of
indole substrates corresponding to general structure 1were prepared,
whereby the substituent pattern, heteroatom substitution, and
EWG at the indole 3-position were all varied.
We were pleased to see that the reaction conditions proved
general, delivering a variety of medium-ring annulated indoles in
good to excellent yield.7 Aromatic rings containing p-MeO and p-
CF3 groups were good substrates for the reaction, affording indoles
2b and 2c in 60 and 80% yields, respectively. A substrate contain-
ing a m-fluoro aromatic ring was prepared to gain some insight
into the mechanism of the reaction. Medium-ring biaryl 2d was
formed as the major regioisomer (63% overall yield, 4:1 dr), i.e.,
the more acidic hydrogen atom8 underwent reaction, suggesting
a base-assisted palladation pathway was operating in the reaction
mechanism (vide infra). Incorporation of heteroatoms into the
Following the success of the reaction for seven-membered ring
synthesis, we applied the same approach to the more challenging
Received: October 9, 2010
Published: December 31, 2010
r
2010 American Chemical Society
1209
dx.doi.org/10.1021/ja1090854 J. Am. Chem. Soc. 2011, 133, 1209–1211
|

Journal of the American Chemical Society
COMMUNICATION
Chart 1. Scope of Oxidative Coupling of Indole with Arenes
To Form Annulated Seven-Membered Ringsa
Chart 3. Formation of Eight-Membered Rings by Dehydro-
genative Couplinga
a Reaction conditions: 0.2 mmol of the substrate, 10 mol % Pd(OAc)2,
K2CO3 (0.2 mmol), Cu(OAc)2 (0.6 mmol) in 1 mL of DMA at 120 °C
for 16 h.
Scheme 1. Mechanistic Studiesa
a Reaction conditions: 0.2 mmol of the substrate, 10 mol % Pd(OAc)2
(0.02 mmol), K2CO3 (0.2 mmol), Cu(OAc)2 (0.6 mmol) in 1 mL of
DMA at 90 °C for 16 h. Isolated yields throughout.
b Crystallographic data available.
c Reaction conditions: 2.0 mmol of 1a, 10 mol % Pd(OAc)2 (0.2 mmol),
K2CO3 (2.0 mmol), Cu(OAc)2 (6.0 mmol) in 10 mL of DMA at 90 °C
for 16 h.
Chart 2. Intramolecular Oxidative Coupling of Indole and
Heteroarenesa
a Reaction conditions for KIE study: indole (0.225 mmol), K2CO3
(0.225 mmol), Pd(OAc)2 (0.0225 mmol), Cu(OAc)2 (0.675 mmol) in
1.5 mL of DMA at 90 °C for 16 h. kH/kD determined by 1H NMR and
LRMS.
a Reaction conditions: 0.2 mmol of the substrate, 10 mol % Pd(OAc)2,
K2CO3 (0.2 mmol), Cu(OAc)2 (0.6 mmol) in 1 mL of DMA at 120 °C
for 8 h. Isolated yields throughout. Exceptions: a140 °C for 3 h. b120 °C
for 24 h.
Pd(II) intermediate in the reaction (structure 7).11 We were
pleased to see that incorporation of a dibenzylamine group (5b)
into the substrate proved a success, providing eight-membered
diazocane derivative 6b in 60% yield. This reaction was extended
to a small range of examples: Products 6b and 6c arise from
dibenzylamine derivatives containing four identical sites for
aromatic C-H activation. Interestingly, 6d was isolated as a
1:1 mixture of diastereoisomers, suggesting hindered rotation
around the biaryl axis. The dibenzyl motif allowed us to set up a
competition experiment to probe the mechanism, using electron-
rich (p-OMe) and electron-poor (p-F) benzyl groups in the same
substrate. Compounds 6e and 6f were isolated in 62% combined
eight-membered -ring targets (Chart 3). Eight-membered rings
are generally the most difficult of the medium rings to form, due
to energetically unfavorable transannular and torsional strain
effects in ring-closing reactions.10 These difficulties were man-
ifest in our initial attempts at oxidative cyclization of substrate 5a,
which were unsuccessful under a range of conditions. We
reasoned that the replacement of a methylene in the tethering
chain with a heteroatom might serve to both reduce transannular
strain and provide a stabilizing interaction with the presumed
1210
dx.doi.org/10.1021/ja1090854 |J. Am. Chem. Soc. 2011, 133, 1209–1211

Journal of the American Chemical Society
COMMUNICATION
yield in the ratio 1.6:1. The more acidic C-H bond on the
fluoro-substituted arene is preferentially activated, although the
selectivity is reduced relative to that seen with the previous seven-
membered systems (Chart 1, 2d and 2d0).
(j) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254–
9256. (k) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651–
9653. (l) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010,
132, 5837–5844. (m) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M.
Chem. Sci. 2010, 1, 331–336. (n) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan,
J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822–1824.
(o) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.;
DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676–14681.
(3) (a) Shiotani, A.; Itatani, H. Angew. Chem., Int. Ed. 1974, 13, 471–
472. (b) Akermark, B.; Eberson, L.; Jonsson, E.; Petterson, E. J. Org.
Chem. 1975, 40, 1365–1367. (c) Hideo, I.; Yoshifumi, Y.; Kibayashi, C.
J. Org. Chem. 1980, 45, 2938–2942. (d) Ames, D. E.; Opalko, A.
Tetrahedron 1984, 40, 1919–1925.
(4) Recent examples: (a) Watanabe, T.; Ueda, S.; Inuki, S.; Oishi, S.;
Fujii, N.; Ohno, H. Chem. Commun. 2007, 4516–4518. (b) Liegault, B.; Lee,
D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022–
5028. (c) Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew.
Chem., Int. Ed. 2008, 47, 7230–7233. (d) Watanabe, T.; Oishi, S.; Fujii, N.;
Ohno, H. J. Org. Chem. 2009, 74, 4720–4726. (e) Kn€olker, H.-J. Chem. Lett.
2009, 38, 8–13. (f) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.;
Novꢀak, P.; Buttner, L. Org. Lett. 2010, 12, 2056–2059. See also ref 2m
(5) The benzodiazepine motif and related congeners are prominent
examples of medium (seven)-ring systems in drug molecules. Aside from
this class, seven-, eight-, and nine-membered-ring systems are rare in
current marketed drugs. Review: Majhi, T. P.; Achari, B.; Chattopad-
hyay, P. Heterocycles 2007, 71, 1011–1052.
A preliminary picture of the reaction mechanism is set out in
Scheme 1. Palladation of the indole at C2 forms complex I, an
intermediate that could be successfully trapped with methyl
acrylate in a Fujiwara-Moritani-type process12 to give ester 8
(Supporting Information). In the normal course of reaction, I
then undergoes a concerted metalation-deprotonation (CMD)13
step to afford intermediate II. An alternative electrophilic palla-
dation mechanism is unlikely here due to the observed selectiv-
ities for electron-poor sites in competition experiments (2d in
Chart 1 and 6g/6f in Chart 3).14 In addition, an intramolecular
kinetic isotope effect (KIE) study on substrate 1g-H/D gave a
value of kH/kD = 3.3, in line with literature reports of C-H
activation via CMD mechanisms.4c,15,16 Reductive elimination
then produces the medium-ring products, along with Pd(0)
which is reoxidized by the excess Cu(II) in the reaction.
In conclusion, we have shown for the first time that intramol-
ecular oxidative C-H coupling is an effective strategy for synthe-
sizing medium-ring compounds. The reaction is tolerant of a rich
array of functional groups, forming annulated heterocycles for
application as versatile scaffolds in medicinal chemistry17,18
Previous routes to these medium-ring-containing indoles have
featured lengthy, multistep routes; our approach is rapid, using a
simple catalyst system, and should be amenable to a broad range
of further applications in medium-ring heterocycle synthesis.
(6) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608–9644.
(7) The reaction conditions were effective for six-membered-ring
formation. The six-membered analogue of 2a was isolated in 87% yield
using the same procedure (Supporting Information).
(8) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007,
63, 1568–1576.
’ ASSOCIATED CONTENT
(9) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344.
S
Supporting Information. Experimental procedures and
b
(10) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102.
(11) Shabashov, D.;Daugulis, O.J. Am. Chem. Soc. 2010, 132, 3965–3972.
(12) (a) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H.
J. Org. Chem. 1981, 46, 851–855. (b) Grimster, N. P.; Gauntlett, C.;
Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125–3129.
(13) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am.
Chem. Soc. 2005, 127, 13754–13755. (b) Garcıa-Cuadrado, D.; de
Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am.
Chem. Soc. 2007, 129, 6880–6886. (c) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
characterization data for all new compounds (PDF, CIF). This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
Michael.Greaney@ed.ac.uk
(14) We note that Gorelsky and co-workers13c have identified C-H
bond length, rather than C-H acidity, as the governing influence in CMD
mechanisms for the intermolecular arylation of arenes with aryl bromides.
(15) (a) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879–9884. (b) Li, J. J.; Giri, R.; Yu, J. Q. Tetrahedron 2008,
64, 6979–6987. (c) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 11234–11241.
’ ACKNOWLEDGMENT
We thank the EPSRC and the University of Edinburgh for
funding (Leadership fellowship to M.F.G. and studentship to
D.G.P.) and the EPSRC mass spectrometry service at Swansea.
Dr. Fraser White is thanked for X-ray crystallography.
(16) Intermolecular KIEs between 2.0 and 2.5 were observed for 1g
deuterated at the sites of indole and aryl C-H activation. See Support-
ing Information for details.
’ REFERENCES
(1) (a) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540–548.
(b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792–9826. (c) Chen, X.; Engle, K.; Wang, D. H.; Yu, J. Q.
Angew. Chem., Int. Ed. 2009, 48, 5094–5115.
(17) (a) Stansfield, I.; Ercolani, C.; Mackay, A.; Conte, I.; Pompei,
M.; Koch, U.; Gennari, N.; Giuliano, C.; Rowley, M.; Narjes, F. Bioorg.
Med. Chem. Lett. 2009, 19, 627–632. (b) Habermann, J.; Capitꢁo, E.;
Ferreira, M. d. R. R.; Koch, U.; Narjes, F. Bioorg. Med. Chem. Lett. 2009,
19, 633–638. (c) Faust, R.; Garratt, P. J.; Jones, R.; Yeh, L.-K.; Tsotinis,
A.; Panoussopoulou, M.; Calogeropoulou, T.; Teh, M.-T.; Sugden, D.
J. Med. Chem. 2000, 43, 1050–1061. (d) Kozikowski, A. P.; Ma, D.;
Brewer, J.; Sun, S.; Costa, E.; Romeo, E.; Guidotti, A. J. Med. Chem. 1993,
36, 2908–2920.
(18) For an elegant approach to related annulated indoles using
norbornene shuttle chemistry, see: (a) Bressy, C.; Alberico, D.; Lautens,
M. J. Am. Chem. Soc. 2005, 127, 13148–13149. (b) Jafarpour, F.;
Lautens, M. Org. Lett. 2006, 8, 3601–3604.
(2) (a) Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25, 5973–5975.
(b) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172–1175. (c) Hull,
K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904–11905.
(d) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 12072–12073. (e) Xia, J.-B.; You, S.-L. Organometallics 2007, 26,
4869–4871. (f) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;
DeBoef, B. Org. Lett. 2007, 9, 3137–3139. (g) Potavathri, S.; Dumas,
A. S.; Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef, B.
Tetrahedron Lett. 2008, 49, 4050–4053. (h) Li, B.-J.; Tian, S.-L.; Fang,
Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (i) Brasche, G.;
Garcıa-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207–2210.
1211
dx.doi.org/10.1021/ja1090854 |J. Am. Chem. Soc. 2011, 133, 1209–1211