Metal-catalyzed cascade rearrangements of 3-alkynyl flavone ethers

Article abstract of DOI:10.1021/ol400631b

Metal-mediated rearrangements of 3-alkynyl flavone ethers are reported. The overall process involves 5-endo enyne cyclization to a platinum-containing spiro-oxocarbenium intermediate which may be trapped with methanol to produce spirodihydrofurans or further rearranged to afford either allenyl chromanediones or benzofuranones.

Full text of DOI:10.1021/ol400631b

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1962–1965
Metal-Catalyzed Cascade
Rearrangements of 3‑Alkynyl
Flavone Ethers
Yuan Xiong, Scott E. Schaus, and John A. Porco, Jr.*
Center for Chemical Methodology and Library Development, Boston University,
590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
porco@bu.edu
Received March 9, 2013
ABSTRACT
Metal-mediated rearrangements of 3-alkynyl flavone ethers are reported. The overall process involves 5-endo enyne cyclization to a platinum-
containing spiro-oxocarbenium intermediate which may be trapped with methanol to produce spirodihydrofurans or further rearranged to afford
either allenyl chromanediones or benzofuranones.
As part of our interest in the chemical reactivity of
3-flavone ethers, we have reported the scandium triflate
catalyzed Claisen rearrangement of 3-allyloxyflavone
ethers such as 1 to access 3,4-chromanediones 2.1 In the
current study, we investigated the possibility for metal-
catalyzed alkynyl-Claisen (SaucyꢀMarbet) rearrange-
ments of the corresponding 3-alkynyl flavone ethers 3
to access allenyl-chromanediones 4. Use of transition
metal catalysts such as Au(I),2 Ag(I),3 Pd(II),4 Rh(I),5
(1) Marie, J.-C.; Xiong, Y.; Min, G. K.; Yeager, A. R.; Taniguchi, T.;
Berova, N.; Schaus, S. E.; Porco, J. A., Jr. J. Org. Chem. 2010, 75, 4584–
4590.
Figure 1. Metal-catalyzed rearrangement of 3-flavone ethers.
(2) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
15978–15979. (b) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7,
3925–3927. (c) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D.
Cu(I),6 and Fe(III)7 for alkynyl-Claisen rearrangements
has been reported. Subsequent one-pot cascade reactions
to access heterocycles including furans, pyrroles, 2H-pyr-
ans, and dihydropyridines have also been reported by
the Kirsch2b,3bꢀ3d and Jiang laboratories.4b,6,7 Moreover,
Kozlowski and co-workers have reported the first asym-
metric SaucyꢀMarbet rearrangement of propargyl-sub-
stituted indoles to afford allenyl oxindoles or spirolactones
ꢀ
J. Am. Chem. Soc. 2006, 128, 8132–8133. (d) Mauleon, P.; Krinsky, J. L.;
Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513–4520.
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J. Org. Chem. 1997, 62, 603–626. (b) Binder, J. T.; Kirsch, S. F. Org. Lett.
2006, 8, 2151–2153. (c) Menz, H.; Kirsch, S. F. Org. Lett. 2006, 8, 4795–
4797. (d) Harschneck, T.; Kirsch, S. F. J. Org. Chem. 2011, 76, 2145–
2156.
(4) (a) Nevado, C.; Echavarren, A. M. Tetrahedron 2004, 60, 9735–
9744. (b) Huang, H.; Jiang, H.; Cao, H.; Zhao, J.; Shi, D. Tetrahedron
2012, 68, 3135–3144.
(5) (a) Saito, A.; Kanno, A.; Hanzawa, Y. Angew. Chem., Int. Ed.
2007, 46, 3931–3933. (b) Okazaki, E.; Okamoto, R.; Shibata, Y.;
Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2012, 51, 6722–6727.
(6) Cao, H.; Jiang, H.; Yao, W.; Liu, X. Org. Lett. 2009, 11, 1931–
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(7) Jiang, H.; Yao, W.; Cao, H.; Huang, H.; Cao, D. J. Org. Chem.
2010, 75, 5347–5350.
r
10.1021/ol400631b
Published on Web 04/10/2013
2013 American Chemical Society

Table 1. Metal Catalyst Screening
Scheme 1. Crossover Experiments
Scheme 2. Intermolecular Trapping of an Oxocarbenium In-
termediate
yield
t
time
(h)
entry
metal
AuCl3
(°C)
7
8
5
1
2
3
4
5
6
7
8
60
60
80
60
60
80
80
80
36
36
60
36
36
60
60
36
53%
50%
74%
21%
40%
ꢀ
14%
trace
trace
ꢀ
33%
ꢀ
NaAuCl4 2H2O
3
NaAuCl4 2H2O
ꢀ
3
PtCl2
60%
24%
ꢀ
PtCl4
28%
53%a
44%a
24%a
PtCl2
PtCl4
ꢀ
ꢀ
Rh2(tfa)4
ꢀ
ꢀ
a The remaining mass balance is the cleavage product 3-hydroxyflavone.
11
Rh2(tfa)4 also promoted the rearrangement to afford
8 in 24% yield along with a significant amount of propar-
gyl ether cleavage to yield 3-hydroxyflavone as a side
product.9 Rare earth triflate catalysts (Sc(OTf)3 and
La(OTf)3) which were found to be workable for
3-allyloxyflavone ethers1 were not effective for substrates
such as 5.9
catalyzed by Pd(II)/BINAP.8 In this Communication, we
report metal-catalyzed rearrangements of 3-alkynyl fla-
vone ethers which led tothe identification of anunexpected
cascade rearrangement pathway.
We began our evaluation of the alkynyl Claisen rear-
rangement of 3-alkynyl flavone ether 5 with a series of
alkynophilic metals (Table 1). Among a panel of catalysts
screened, AuCl3 was found to catalyze the reaction to
produce allenyl 3,4-chromanedione 6 which was con-
densed with 1,2-phenylenediamine1 to provide chromeno-
quinoxaline 7. Aurate salts proved to be efficient catalysts;
In order to probe the reaction mechanism, crossover
experiments were conducted to exclude the possibility of an
intermolecular reaction pathway (Scheme 1). In the event,
rearrangement of an equimolar mixture of butynyl ether 5
and pentynyl ether 9 in the presence of metal catalysts
(PtCl2, PtCl4, or NaAuCl4, 60 °C) resulted in the sole
production of chromenoquinoxalines 7 and 10 after con-
densation with 1,2-phenylenediamine. The absence of
crossover products by mass spectrometric9 analysis of the
crude reaction mixture strongly suggests an intramolecular
pathway as opposed to an ion pair mechanism.1,12
Further mechanistic insights were gained by treatment
of substrate 5 with Au(III) or Pt catalysts in the presence of
methanol which afforded spirodihydrofuran 119 as a single
diastereomer (36ꢀ58% yield, Scheme 2). The formation
in particular, 5 mol % of NaAuCl4 2H2O at elevated
3
temperatures cleanly catalyzed the rearrangement of sub-
strate 5 which was followed by diamine condensation to
afford 7 in 74% yield (entry 3). In addition to the allene 7, a
small amount of furanyl benzofuranone 8 (vide infra) was
also observed in the AuCl3-catalyzed reaction (entry 1).
The structure of 8 was confirmedbyX-ray crystal structure
analysis9 (Table 1). Use of platinum catalysis also led to
the formation of 8. At 60 °C, PtCl4 afforded both 7 (40%)
and 8 (28%) (entry 5).10 At a higher reaction temperature,
PtCl2 was highly efficient in producing benzofuranone 8.
(12) For a representative crossover study, see: Burger, E. C.; Tunge,
J. A. Org. Lett. 2004, 6, 2603–2605.
(13) For transition-metal-catalyzed 5-endo cyclization of alkynes and
1,5-enynes, see: (a) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D.
Angew. Chem., Int. Ed. 2004, 43, 5350–5352. (b) Zhang, L.; Kozmin,
S. A. J. Am. Chem. Soc. 2005, 127, 6962–6963. (c) Staben, S. T.;
Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste,
F. D. Angew. Chem., Int. Ed. 2006, 45, 5991–5994. (d) Buzas, A. K.;
Istrate, F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46, 1141–1144.
(e) Brazeau, J.-F.; Zhang, S.; Colomer, I.; Corkey, B. K.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 2742–2749.
(8) (a) Cao, T.; Deitch, J.; Linton, E. C.; Kozlowski, M. C. Angew.
Chem., Int. Ed. 2012, 51, 2448–2451. (b) Cao, T.; Linton, E. C.; Deitch,
J.; Berritt, S.; Kozlowski, M. C. J. Org. Chem. 2012, 77, 11034–11055.
(9) See Supporting Information for complete experimental details.
(10) For PtCl2- and PtCl4-catalyzed hydroarylation of alkynes, see:
Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055–1058.
(11) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.; Looper, R. E.
Angew. Chem., Int. Ed. 2011, 50, 684–687.
Org. Lett., Vol. 15, No. 8, 2013
1963

Scheme 3. Intramolecular Trapping of an Oxocarbenium In-
termediate
Scheme 4. Preparation and Rearrangement of an Allenyl
Chromanedione
Scheme 5. Proposed Mechanistic Pathway
of product 11 indicates that the metal catalysts preferen-
tially activate the alkyne of flavone ether substrates such
as 5 toward 5-endo13 and not 6-endo enyne cyclization. In
the case of PtCl4 additional bidentate coordination of
the metal catalyst to the C-3 flavone ether and C-4 car-
bonyl oxygens14 may contribute to lower nucleophilicity at
C-2, thereby rendering attack at C-3 more preferable to
produce platinum-containing oxocarbenium intermediate
A15 which afforded spirodihydrofuran 11 after reaction
with methanol. The observed diastereoselectivity may be
explained by steric shielding of the β face of the oxonium
intermediate by the vinyl methyl group, leading to diaste-
reoselective addition of methoxide to the R face.9
We also evaluated a 3-alkynyl flavone ether substrate
bearing an internal nucleophile (Scheme 3). Treatment of
20-hydroxyflavone ether 12 with PtCl2 afforded allene 13
(45%) along with a trace amount of the bridged dihydro-
pyran product 14, the structure of which was confirmed by
X-ray crystal structure analysis.9 Both 13 and 14 are
presumably derived from intramolecular trapping of ox-
ocarbenium B (vide infra) by the adjacent 20-hydroxyl
catalyzed cycloisomerization cascade to produce benzo-
furanone products (Scheme 5).17
Based on our experimental results, we propose the overall
mechanistic pathway shown in Scheme 5. Following initial
5-endo enyne cyclization18 of alkynyl flavone ether 18, the
resulting platinum-containing spiro-oxocarbenium inter-
mediate C may undergo pinacol-type 1,2-rearrangement19
to form dipole D,20 possibly via a cyclopropyl platinacarbene
intermediate E.21 Dipole D may further fragment to yield
allenyl chromanedione 19 through platinum dissociation
group. Use of PtCl4 and NaAuCl4 H2O as catalysts
3
favored the formation of 14. Eventually, we found that
addition of 1,1,1,2,2,2-hexafluoroisopropanol (HFIP) as
the proton source16 provided tetracycle 14 in 44% yield,
conceivably by promoting protodemetalation (Scheme 3,
pathway b) versus elimination (pathway a).
(18) For reviews on metal-catalyzed enyne cycloisomerization,
Additional mechanistic information was also obtained
from allenyl chromanedione substrate 15, derived from
alkynyl flavone ether 16 using Au(III)-catalyzed rearran-
gement. When 15 was resubjected to rearrangement con-
ditions at 80 °C, benzofuranone 17 was isolated in
60ꢀ80% yield (Scheme 4), suggesting that allenyl chroma-
nedione substrates may also participate in the metal-
see: (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006,
ꢀ
ꢀ
ꢀ~
348, 2271–2296. (b) Nieto-Oberhuber, C.; Lopez, S.; Jimenez-Nunez, E.;
Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916–5923. (c) Shen, H. C.
Tetrahedron 2008, 64, 7847–7870. (d) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Rev. 2008, 108, 3326–3350. (e) Michelet, V.; Toullec, P. Y.;
^
Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315.
(19) For examples of metal-catalyzed cycloisomerization involving
pinacol-type rearrangement, see: (a) Kirsch, S. F.; Binder, J. T.; Crone,
ꢀ
B.; Duschek, A.; Haug, T. T.; Liebert, C.; Menz, H. Angew. Chem., Int.
Ed. 2007, 46, 2310–2313. (b) Huang, X.; Zhang, L. J. Am. Chem. Soc.
2007, 129, 6398–6399. (c) Tang, J.; Bhunia, S.; Sohel, S. M. A.; Lin, M.;
Liao, H.; Datta, S.; Das, A.; Liu, R. J. Am. Chem. Soc. 2007, 129, 15677–
15683. (d) Crone, B.; Kirsch, S. F. Chem.;Eur. J. 2008, 14, 3514–3522.
(e) Shu, X.-Z.; Liu, X.-Y.; Ji, K. G.; Xiao, H.-Q.; Liang, Y.-M. Chem.;
Eur. J. 2008, 14, 5282–5289.
(14) Tang, H.; Wang, X.; Yang, S.; Wang, L. Rare Met. 2004, 23, 38–
42.
(15) Li, G.; Huang, X.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 6944–
6945.
(16) Roth, K. E.; Blum, S. A. Organometallics 2010, 29, 1712–1716.
(17) For platinum- and gold-catalyzed 6-endo cycloisomerization of
allenes, see: (a) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485–4488.
(b) Kong, W.; Fu, C.; Ma, S. Chem. Commun. 2009, 0, 4572–4574.
(20) Kusama, H.; Suzuki, Y.; Takaya, J.; Iwasawa, N. Org. Lett.
2006, 8, 895–897.
ꢀ
´
(21) Martın-Matute, B.; Nevado, C.; Cardenas, D. J.; Echavarren,
A. M. J. Am. Chem. Soc. 2003, 125, 5757–5766.
1964
Org. Lett., Vol. 15, No. 8, 2013

and C, which following similar pathways may produce
benzofuranone 20 (Scheme 5, red arrow).
Table 2. Substrate Scope
Regarding substrate scope, substitutions at the terminal
position of the alkyne such as hydrogen as well as alkyl and
phenyl groups (Table 2, 21, 23, 25, entries 1ꢀ3) were
tolerated, although substrates with terminal alkynes suf-
fered low yields from side reactions presumably due to
metal vinylidene formation. Flavone ether 27 derived from
a secondary propargylic alcohol was also reactive afford-
ing the 2,3,5-trisubstituted furanyl benzofuranone 28 in
high yield (entry 4). 5-Methoxy substrate 29, with in-
creased electron density on the flavone A-ring, underwent
smooth acyl migration to afford benzofuranone 30 in high
yield (entry 5). In contrast, electron-withdrawing groups
foundinsubstrates suchas31disfavored acylmigration. In
this instance, only allenyl chromenoquinoxaline 32 was
isolated following diamine condensation even at an ele-
vated reaction temperature (entry 6). Electron-rich C-rings
found in substrates 16 and 35 favored the cascade process
producing benzofuranones by increasing nucleophilicity at
C-3 and stabilizing the forming positive charge in the
proposed spiro-oxocarbenium intermediate C (entry 7,
cf. Scheme 5). In contrast, the electron-poor 20-trifluoro-
methyl flavone ether 33 was not a useable substrate and did
not afford appreciable amounts of benzofuranone 34
(entry 7).
In summary, evaluation of the metal-catalyzed alkynyl
Claisen (SaucyꢀMarbet) rearrangements of 3-alkynyl fla-
vone ethers led to the discovery of a 1,2-acyl migration
cascade which afforded novel furanyl benzofuranones.
Mechanistic studies have revealed that the rearrangement
is likely initiated by 5-endo enyne cyclization to a platinum-
containing spiro-oxocarbenium intermediate, which may
be intercepted by methanol to produce spirodihydrofurans
or further rearranged to afford allenyl chromanediones
at 60 °C and benzofuranones at elevated reaction tem-
peratures. Further studies including asymmetric reac-
tion development and diverse nucleophilic trapping of
spiro-oxocarbenium intermediates are currently in pro-
gress and will be reported in future publications.
a Products obtained after condensation with 1.5 equiv of 1,2-
phenylenediamine.
Acknowledgment. Financial support from the National
Institutes of Health (P50 GM067041 and CA 099920) is
gratefully acknowledged. We thank Prof. John Snyder and
Drs. AlexanderGrenning and Munmun Mukerjee (Boston
University) for helpful discussions and Dr. Jeffrey Bacon
(Boston University) for X-ray crystal structure analyses.
(Scheme 5, blue arrow). At elevated temperatures, inter-
mediate C may rearrange via a formal 1,2-acyl migration to
obtain oxocarbenium F22 which after protodemetalation
and aromatization may afford 20 as the thermodynamic
product (Scheme 5, red arrow). Conceivably, allenyl chro-
manedione 19 may also undergo metal catalyzed 6-endo
cycloisomerization17 to yield oxocarbenium intermediates D
Supporting Information Available. Experimental pro-
cedure and characterization of compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(22) For formal 1,2-acyl migration in a Pt(II)-catalyzed cycloisome-
rization, see: (a) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int. Ed.
2008, 47, 346–349. For acid-catalyzed 1,2-acyl migration, see: (b) Bach,
R. D.; Domagala, J. M. J. Org. Chem. 1984, 49, 4181–4188. (c) Bach,
R. D.; Klix, R. C. J. Org. Chem. 1985, 50, 5438–5440. (d) Klix, R. C.;
Bach, R. D. J. Org. Chem. 1987, 52, 580–586. (e) Crane, S. N.; Burnell,
D. J. J. Org. Chem. 1998, 63, 5708–5710.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
1965