Synthesis of benzopyrans by Pd(II)- or Ru(II)-catalyzed C-H alkenylation of 2-aryl-3-hydroxy-2-cyclohexenones

Article abstract of DOI:10.1021/ol3033835

2-Aryl-3-hydroxy-2-cyclohexenones are shown to be competent substrates for palladium- and ruthenium-catalyzed C-H alkenylation reactions with terminal alkenes, providing, in most cases, benzopyrans.

Full text of DOI:10.1021/ol3033835

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Benzopyrans by Pd(II)-
or Ru(II)-Catalyzed CÀH Alkenylation
of 2‑Aryl-3-hydroxy-2-cyclohexenones
Suresh Reddy Chidipudi, Martin D. Wieczysty, Imtiaz Khan, and Hon Wai Lam*
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building,
The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
Received December 11, 2012
ABSTRACT
2-Aryl-3-hydroxy-2-cyclohexenones are shown to be competent substrates for palladium- and ruthenium-catalyzed CÀH alkenylation reactions
with terminal alkenes, providing, in most cases, benzopyrans.
The metal-catalyzed alkenylation of aromatic C(sp2)ÀH
bonds, directed by a coordinating functional group, has
proven to be a versatile strategy in organic synthesis,1À3
successfully complementing alternatives such as the
MizorokiÀHeck reaction4,5 and the FujiwaraÀMoritani
reaction.6,7 Directing groups not only offer enhanced
reactivity but also high site selectivity, which minimizes
the formation of unwieldy mixtures of positional isomers.1À3
Strategically, however, the use of directing groups can be a
limitation, especially if several steps are required to convert
the directing group intothe final desired functional group.8
Nevertheless, this drawback is mitigated by the continued
development of new procedures that employ an expanded
range of directing groups, thus increasing the toolbox of
methods available for catalytic CÀH alkenylation and
allowing access to a greater diversity of products.
(3) For some of the most recent representative examples, see: (a)
Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2011, 13, 706–708. (b) Ackermann, L.; Pospech, J. Org.
Lett. 2011, 13, 4153–4155. (c) Arockiam, P. B.; Fischmeister, C.;
Bruneau, C.; Dixneuf, P. H. Green Chem. 2011, 13, 3075–3078. (d)
Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518–522. (e)
€
Schroder, N.; Besset, T.; Glorius, F. Adv. Synth. Catal. 2012, 354, 579–
583. (f) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Org. Lett.
2012, 14, 728–731. (g) Zhu, C.; Falck, J. R. Chem. Commun. 2012, 48,
1674–1676. (h) Yu, M.; Xie, Y.; Xie, C.; Zhang, Y. Org. Lett. 2012, 14,
2164–2167. (i) Graczyk, K.; Ma, W.; Ackermann, L. Org. Lett. 2012, 14,
(1) For some leading references, see: (a) Miura, M.; Tsuda, T.; Satoh,
T.; Nomura, M. Chem. Lett. 1997, 1103–1104. (b) Miura, M.; Tsuda, T.;
Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211–5215.
(c) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; deVries, J. G.; vanLeeuwen, P. W. N. M. J. Am. Chem. Soc. 2002,
124, 1586–1587. (d) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407–1409. (e) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72,
5362–5367. (f) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Organometallics 2010,
29, 5748–5750.
€
4110–4113. (j) Shi, Z.; Schroder, N.; Glorius, F. Angew. Chem., Int. Ed.
2012, 51, 8092–8096. (k) Liang, Z.; Ju, L.; Xie, Y.; Huang, L.; Zhang, Y.
Chem.;Eur. J. 2012, 18, 15816–15821. (l) Li, J.; Kornhaa; Ackermann,
L. Chem. Commun. 2012, 48, 11343–11345. (m) Zhen, W.; Wang, F.;
Zhao, M.; Du, Z.; Li, X. Angew. Chem., Int. Ed. 2012, 51, 11819–11823.
(4) Seminal references: (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull.
Chem. Soc. Jpn. 1971, 44, 581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem.
1972, 37, 2320–2322.
(5) Selected reviews: (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146–
151. (b) Heck, R. F. Org. React. 1982, 27, 345–390. (c) Brase, S.; de
(2) For representative reviews: (a) Chen, X.; Engle, K. M.; Wang
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (b) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (c) Satoh, T.;
Miura, M. Chem.;Eur. J. 2010, 16, 11212–11222. (d) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215–1292. (e) Engle, K. M.; Mei
T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (f) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651–3678. (g) Patureau,
F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta 2012, 45, 31–41.
(h) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879–5918. (i) Ackermann, L.; Kozhushkov, S. I. Chem. Sci. 2012,
Advance Article, DOI: 10.1039/C2SC21524A.
€
Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: New York, 2004; Chapter 5.
(6) A seminal reference: Moritani, I.; Fujiwara, Y. Tetrahedron Lett.
1967, 8, 1119–1122.
(7) Selected reviews: (a) Moritani, I.; Fujiwara, Y. Synthesis 1973,
524–533. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001,
34, 633–639. (c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola,
S. Chem. Rev. 2007, 107, 5318–5365. (d) Le Bras, J.; Muzart, J. Chem. Rev.
2011, 111, 1170–1214.
r
10.1021/ol3033835
XXXX American Chemical Society

Yu and co-workers also reported the palladium-catalyzed
hydroxyl-directed CÀH alkenylation of homobenzylic
alcohols.13 However, to our knowledge, the use of 2-aryl-
3-hydroxy-2-cyclohexenones as substrates for metal-catalyzed
directed CÀH alkenylation has not been reported pre-
viously. In this paper, we describe the successful use of
these substrates in the strategy presented in Figure 1B.
Furthermore, these reactions proceed using not only well-
established palladium catalysis1aÀc,2a,b,e but also more
recently developed ruthenium catalysis.3aÀc,14,15
Table 1. Evaluation of Reaction Conditionsa
temp time yield
entry
[M]
Pd(OAc)2
mol % solvent (°C)
(h) (%)b
1
5
DMF
DMF
DMF
120
120
120
5
78
30
7
2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RhCp*Cl2]2
2.5
2.5
2.5
2.5
2.5
2.5
15
15
15
15
15
15
3c
4
t-AmOH 90
t-AmOH 90
8
5c
6
61
69
51
Figure 1. CÀH functionalization of 2-aryl-3-hydroxy-2-cyclo-
DMF
120
hexenones (A and B) and bioactive benzopyrans (C).
7c
[RhCp*Cl2]2
t-AmOH 90
a Reactions were conducted using 0.50 mmol of 1a. b Isolated yield.
The present study was initiated by our recent finding that
2-aryl-3-hydroxy-2-cyclohexenones are effective substrates
for ruthenium-catalyzed oxidative annulations with al-
kynes (Figure 1A).9 Proceeding via sequential C(sp2)ÀH
and C(sp3)ÀH functionalization, this process affords a
range of spiroindenes in generally good yields.9 In light of
these results, we wondered whether replacement of the
alkyne with a terminal alkene would enable the corre-
sponding C(sp2)ÀH alkenylation of these substrates to
proceed (Figure 1B). If successful, the initially formed
product 2 would likely undergo cyclization of an enolate
oxygen atom onto the electron-deficient alkene. This
process would be attractive as the resulting benzopyrans
3 resemble the core structures of biologically active natural
c Reaction conducted in the presence of K2CO3 (2.0 equiv).
This study began with an investigation of metal pre-
catalysts and reaction conditions for the reaction of
3-hydroxy-2-phenyl-2-cyclohexenone (1a) with phenyl vinyl
sulfone, using Cu(OAc)2 (2.1 equiv) as the oxidant (Table 1).16
Pleasingly, Pd(OAc)2 (5 mol %) provided benzopyran
3a in 78% yield in DMF at 120 °C (entry 1). [RuCl2-
(p-cymene)]2 (2.5 mol %), which had proven successful in
our previous study of spiroindene synthesis,9 was less
effective and gave a 30% yield of 3a in DMF (entry 2).
Although the use of t-AmOH as the solvent offered no
improvement (entry 4), the addition of K2CO3 (2.0 equiv)
to the reaction enabled 3a to be isolated in 61% yield
(entry 5).17 The beneficial effect of K2CO3 was not replicated
using DMF as the solvent (entry 3, compare with entry 2).
products and drug candidates 4À6 (Figure 1C).10À12
A
related precedent for this approach comes in the form of a
study by Miura and co-workers, who described the palla-
dium-catalyzed CÀH alkenylation of 2-phenylphenols.1a
(13) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 5916–5921.
(8) For a review of directing-group-free CÀH functionalizations, see:
Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236–10254.
(9) Reddy Chidipudi, S.; Khan, I.; Lam, H. W. Angew. Chem., Int.
Ed. 2012, 51, 12115–12119.
(14) For Ru-catalyzed oxidative coupling of simple arenes with
alkenes using molecular oxygen as the oxidant, see: Weissman, H.;
Song, X.; Milstein, D. J. Am. Chem. Soc. 2000, 123, 337–338.
(15) For reviews of Ru-catalyzed CÀH functionalization, see refs 2h,
2i and: Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–
229.
(10) Zan, L.-f.; Qin, J.-c.; Zhang, Y.-m.; Yao, Y.-h.; Bao, H.-y.; Li,
X. Chem. Pharm. Bull. 2011, 59, 770–772.
(11) Wu, C.-S.; Lin, Z.-M.; Wang, L.-N.; Guo, D.-X.; Wang, S.-Q.;
Liu, Y.-Q.; Yuan, H.-Q.; Lou, H.-X. Bioorg. Med. Chem. Lett. 2011, 21,
3261–3267.
(12) Elmore, S. W.; Coghlan, M. J.; Anderson, D. D.; Pratt, J. K.;
Green, B. E.; Wang, A. X.; Stashko, M. A.; Lin, C. W.; Tyree, C. M.;
Miner, J. N.; Jacobson, P. B.; Wilcox, D. M.; Lane, B. C. J. Med. Chem.
2001, 44, 4481–4491.
(16) Substrate 1a is sensitive to acid-catalyzed decomposition under
the reaction conditions (this process generates AcOH). In reactions
where low yields of benzopyran 3a were obtained, the remaining mass
balance was composed of a complex mixture of byproducts.
(17) A possible reason for the higher yield of 3a in Table 1, entry 5
compared with entry 4 is a reduction in the rate of acid-catalyzed
decomposition of the substrate in the presence of K2CO3 (see ref 16).
B
Org. Lett., Vol. XX, No. XX, XXXX

terminal alkenes. Electron-deficient alkenes including methyl
vinyl ketone (entry 1), methyl acrylate (entry 3), N,N-
dimethylacrylamide (entry 5), and acrylonitrile (entry 7)
were effective in the CÀH alkenylation of 1a using palla-
dium catalysis and provided benzopyrans in 45À72%
yield. In the case of methyl acrylate, N,N-dimethylacryla-
mide, and acrylonitrile, the yields of the products obtained
using [RuCl2(p-cymene)]2 as the precatalyst (entries 4, 6,
and 8, respectively) were slightly higher than those ob-
tained using Pd(OAc)2. Interestingly, when methyl vinyl
ketone was the reaction partner, benzopyran 3b was ob-
tained in only 19% yield using [RuCl2(p-cymene)]2; the
major product isolated was the addition product 7 (54%
yield, entry 2).19 With styrene as the terminal alkene,
palladium and ruthenium catalysis were comparable in
performance, giving alkene 2a in 59% and 52% yield,
respectively (entries 9 and 10).
Table 2. Catalytic Alkenylation of 1aa
Figure 2. Pd(II)-catalyzed alkenylation of various 2-aryl-3-
hydroxy-2-cyclohexenones with phenyl vinyl sulfone or methyl
vinyl ketone. Reactions were conducted with 0.50 mmol of
1bÀ1f. Yields are of isolated material.
a Reactions were conducted using 0.50 mmol of 1a. b Isolated yield.
c Yield of 3b. d Yield of 7. e Reaction conducted at 90 °C, as the reaction
conducted at 120 °C led to a complex mixture.
Based on the results shown in Tables 1 and 2, investiga-
tion of the reactions of various 2-aryl-3-hydroxy-2-cyclo-
hexenones with phenyl vinyl sulfone and methyl vinyl
ketone was undertaken using palladium catalysis (Figure 2).
Pleasingly, a range of substituents (methoxy, fluoro, methyl,
or carbomethoxy) at the meta or para positions of the
2-aryl group of substrates 1bÀ1f20 were tolerated to pro-
vide various benzopyrans 8aÀ8f in 50À73% yield. A
dimedone-derived substrate was also effective, providing
benzopyran 8c in 65% yield. In the case of a substrate
The use of [RhCp*Cl2]218 (2.5 mol %) was almost as effective
as Pd(OAc)2 (entries 6 and 7), and 3a was formed in 69%
yield in DMF at 120 °C (entry 6). Although Pd(OAc)2 was
optimal for the formation of 3a, these results show that
[RuCl2(p-cymene)]2 and [RhCp*Cl2]2 are also viable candi-
dates for further evaluation of the scope of the process. Due
to the high cost of [RhCp*Cl2]2, further exploration was
carried out with palladium and ruthenium catalysis.
Table 2 presents a comparison of palladium and ruthe-
nium catalysis in the reaction of 1a with a range of other
(19) Presumably, product 7 results from protodemetalation of inter-
mediates 11 or 12 in the proposed catalytic cycle, before β-hydride
elimination occurs (see Supporting Information).
(20) See the Supporting Information for the structures of 1bÀ1h.
(18) For reviews of Rh-catalyzed CÀH functionalization, see refs 2c,
2f, 2g.
Org. Lett., Vol. XX, No. XX, XXXX
C

containing a m-methoxyphenyl group, CÀH functionali-
zation occurred exclusively at the more sterically accessible
site (products 8a and 8d), which is consistent with our
previous study.9 X-ray crystallography allowed unambig-
uous confirmation of the site selectivity in the formation
of 8a (Figure 3). No CÀH alkenylation occurred with a
substrate containing an o-methylphenyl group.21
Figure 3. X-ray structure of benzopyran 8a.
Further examination of the scope of the process using
methyl acrylate, N,N-dimethylacrylamide, or acrylonitrile
as the alkene reaction partner was performed using ruthe-
nium catalysis (Figure 4). Again, a range of substituents at
the meta or para positions of the 2-aryl group of substrates
1cÀ1e, 1g, or 1h20 were tolerated to provide various benzo-
pyrans 8gÀ8l in 45À74% yield. With a m-(trifluoromethyl)-
phenyl-containing substrate, CÀH alkenylation occurred
exclusively at the more sterically accessible site (product 8i).
In summary, we have demonstrated that 2-aryl-3-hydroxy-
2-cyclohexenones, which have recently been reported
to undergo metal-catalyzed oxidative annulations with
alkynes,9 are also highly effective substrates in catalytic
CÀH alkenylation reactions.22 These reactions proceed
not only under the action of well-established palladium
catalysis but also with more recently developed ruthenium
catalysis to provide benzopyrans in up to 78% yield. The
application of 2-aryl-3-hydroxy-2-cyclohexenones and re-
lated substrates in further catalytic CÀH functionaliza-
tions is the subject of ongoing efforts in our group.
Figure 4. Ru(II)-catalyzed alkenylation of various 2-aryl-3-
hydroxy-2-cyclohexenones with methyl acrylate, N,N-dimethy-
lacrylamide, or acrylonitrile. Reactions were conducted with
0.50 mmol of 1cÀ1e, 1g, or 1h. Yields are of isolated material.
a Reaction conducted in the absence of K2CO3, as 8l was formed
in a low yield when K2CO3 was employed.
Acknowledgment. Financial support was provided by a
Marie Curie International Incoming Fellowship to S.R.C.
(Project No. PIIF-GA-2009-252561), the EPSRC, and the
University of Edinburgh. We thank the EPSRC for a
Leadership Fellowship to H.W.L., Dr. Gary S. Nichol
(University of Edinburgh) for X-ray crystallography, and
the EPSRC National Mass Spectrometry Service Centre
for high-resolution mass spectra.
Supporting Information Available. Experimental proce-
dures, full spectroscopic data for all new compounds, and
crystallographic data in cif format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) This substrate provided decomposition products along with
returned starting material.
(22) For a possible catalytic cycle for these reactions, see the Support-
ing Information.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX