Iodobenzene catalysed synthesis of spirofurans and benzopyrans by oxidative cyclisation of vinylogous esters

Article abstract of DOI:10.1039/c1cc15015d

Vinylogous esters bearing para or meta methoxy benzyl groups undergo oxidative cyclisation with 5-20 mol% iodobenzene and m-CPBA to give spirofuran or benzopyran containing heterocycles. The reaction allows rapid generation of skeletal complexity in good to excellent yields via a novel oxidative cyclisation.

Full text of DOI:10.1039/c1cc15015d

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COMMUNICATION
Iodobenzene catalysed synthesis of spirofurans and benzopyrans by
oxidative cyclisation of vinylogous estersw
Marsewi Ngatimin,a Raphael Frey,b Cecily Andrews,b David W. Lupton*a and
Oliver E. Hutt*b
Received 12th August 2011, Accepted 8th September 2011
DOI: 10.1039/c1cc15015d
Vinylogous esters bearing para or meta methoxy benzyl groups
undergo oxidative cyclisation with 5–20 mol% iodobenzene and
m-CPBA to give spirofuran or benzopyran containing hetero-
cycles. The reaction allows rapid generation of skeletal complex-
ity in good to excellent yields via a novel oxidative cyclisation.
substrate bore the required electron rich ketone an initial
concern related to the potential for this functionality to undergo
oxidation. Thus, it was satisfying to find that when 1a was
treated with 1.5 equivalents of phenyliodonium bis(trifluoro-
acetate) (PIFA) in 2,2,2-trifluoroethanol (TFE)13 52%
conversion into the spirocyclic furan 2a was observed by
LCMS (Table 1, entry 1). The reaction was comparable when
conduced in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), but
poorer using trifluoroacetic acid (TFA) (Table 1, entries 2
and 3). An optimal solvent mixture of 9 : 1 HFIP/TFA
increased the conversion to 71% (Table 1, entry 4), while with
phenyliodonium diacetate (PIDA) the conversion increased to
83% (Table 1, entry 5). Unfortunately, while the conversion
was acceptable, isolation of the product from the unreacted
iodonium reagents and aryl iodide was challenging, and
decreased the yield (Table 1, entry 5).
The scope of l3-iodonium reagents in modern synthesis is
remarkable.1–7 In addition to being stoichiometric oxidants
ideally suited to transition metal catalysed C–H aminations,2
oxygenation,3 and couplings;4 they directly mediate a range of
cyclisations5 and rearrangements.6
The oxidative cyclisations of electron rich aromatics are an
important class of hypervalent iodine mediated reaction.7–9
While allowing rapid generation of complexity from ubiquitous
starting materials, such reactions proceed using environmentally
mild conditions.8 Although a range of carbon and heteroaromatic
nucleophiles have been exploited,7 the use of ketones is yet to
be realised. We postulated that by using a sufficiently nucleo-
philic ketone, such as a vinylogous ester (i.e. 1),9 it should be
possible to access either spirocyclic, or ring-fused, oxygen
heterocycles. Beyond synthetic novelty, these heterocyclic
products (i.e. 2 and 3) are well represented in bioactive and
naturally occurring products,10 thus the realisation of this
methodology would have potentially broad significance
(Fig. 1).
To increase the efficiency of the transformation, and improve
the isolated yield, the reaction was trialled using 10 mol%
iodobenzene and 3.0 equivalent of m-CPBA.14,15 To our great
Herein, we report our studies on this topic, that have
resulted in the discovery of a novel oxidative cyclisation, which
provides access to both spirocyclic furans and benzopyrans.
Optimal results were obtained using catalytic iodobenzene,
making this transformation one of a limited family of hyper-
valent iodine mediated transformations viable under catalytic
conditions.11
Exploratory studies commenced with vinylogous ester 1a,
prepared in one step from commercial materials.12 While this
a School of Chemistry, Monash University, Clayton, Melbourne,
VIC 3800, Australia. E-mail: david.lupton@monash.edu;
Fax: 613 9905 4597; Tel: 613 9902 0327
b CSIRO Materials Science and Engineering, Bag 10, Clayton South
MDC, VIC 3169, Australia. E-mail: oliver.hutt@csiro.au;
Fax: 613 9545 2446; Tel: 613 9545 2580
w Electronic supplementary information (ESI) available: experimental
details, 1H and 13C NMR spectra of all new compounds. See DOI:
10.1039/c1cc15015d
Fig. 1 Proposed studies and spirofuran and benzopyran
heterocycles.
c
11778 Chem. Commun., 2011, 47, 11778–11780
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Table 2 Scope of the oxidative synthesis of spirofuran2a
Table 1 Selected reaction optimisation
Entry [equiv.] PhIX2 [equiv.] m-CPBA Solvent
Yielda
1b
2b
3b
4b
5b
6
1.5 PhI(TFA)2
1.5 PhI(TFA)2
1.5 PhI(TFA)2
1.5 PhI(TFA)2
1.5 PhI(OAc)2
0.1 PhI
0.1 PhI
0.05 PhI
—
—
—
—
—
TFE
HFIP
TFA
(52)c
(52)c
(16)c
9 : 1 TFE/TFA (71)c
9 : 1 HFIP/TFA (83)c 58
9 : 1 HFIP/TFA 73
9 : 1 HFIP/TFA 75
9 : 1 HFIP/TFA 71
—
3.0
1.5
1.5
1.5
7
8d
9
9 : 1 HFIP/TFA 0
a
Isolated yield following column chromatography except as noted.
c
a
b
Isolated yield following column chromatography.
Reaction conducted at 0 1C. Conversion calculated by LCMS
using a calibrated method. Reaction conducted for 14 h.
d
Table 3 Scope of the oxidative synthesis of benzopyran3a
satisfaction these conditions provided spirofuran 2a in 73%
isolated yield (Table 1, entry 6). Decreasing the oxidant
loading had little effect on the outcome (Table 1, entry 7),
nor did decreasing catalyst loading to 5 mol%, although in the
later case the reaction was slower (Table 1, entry 8). The role
of the aryl iodide was examined, with no background cyclisation
observed in its absence (Table 1, entry 9).
To examine the utility of this transformation para-methoxy
benzyl substituted vinylogous esters 1a–g were prepared and
oxidized using 20 mol% iodobenzene and 1.5 equivalents of
m-CPBA, conditions that gave reliable results, in a timely
fashion. Of interest was the reactions sensitivity to other
potentially nucleophilic functionality and steric congestion.
In the event the reaction tolerated substitution at various
positions about the cyclohexenone, providing spirofurans
2a–d, and quaternary carbon containing spirofurans 2b, f
and g, in good yield. The reaction was equally viable using
3-methoxy cyclohexen-2-one derived substrates (i.e. 1d), as
3-ethoxy substrates. When the b-keto ester derived starting
material 1e was examined 2e formed in 28% yield. The low
yield was presumably due to side reactions involving interception
of the radical cation by the ester functionality.
a
Isolated yield following column chromatography.
In order to access benzopyran heterocycles the oxidation of
substrates bearing meta-methoxy benzyl substituents was
examined. Fortunately, the reaction conditions developed to
access spirofurans (Table 2) translated very well, allowing
benzopyrans 3h–n to be accessed in good yields (Table 3).
As with the spirofuran synthesis it was possible to generate
diversely functionalised benzopyrans including those bearing
quaternary carbon centres.
Scheme 1 Preferential benzopyran formation.
meta-methoxy radical cation is faster, and that equilibration
between the two radical cationic intermediates II16 is possible.
To clarify the mechanism of this transformation the cyclisation
of vinylogous ester 1n can be considered. In this case preferential
formation of benzopyran products was observed. While these
results don’t eliminate the former mechanism, it is difficult to
rationalise oxidation of the meta-methoxy aromatic without
any observable oxidation of the para-methoxy. Interestingly,
this preference for benzopyran formation is in contrast to the
preferential spiro cyclisation observed by Kita in related
The cyclisation of vinylogous ester 1m allows the relative
rate of spirofuran and benzopyran formation to be compared
(Scheme 1). When this substrate was reacted benzopyran 3m
was isolated in 51% yield while spirofuran 2m was not
observed. In the work of Kita it is proposed that oxidation
of both meta and para methoxy aromatic compounds initially
generates the corresponding radical cation.9 The observation
of a single product from the reaction of 1m suggests that either
the rate of oxidation of the meta-methoxy aryl group is
significantly faster than the para, or that cyclisation of the
c
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oxidative lactonisations of electron rich aromatics.7c While the
origin of this difference in reactivity is not obvious it may
relate to the annulation in our substrates disfavouring
formation of the spirocyclic products.
V. V. Zhdankin, Org. Lett., 2010, 12, 4644; For hydrazone
rearrangement see: (d) K. E. Lutz and R. J. Thomson, Angew.
Chem., Int. Ed., 2011, 50, 4437.
7 For a useful introduction see: (a) T. Dohi, M. Ito, N. Yamaoka,
K. Morimoto, H. Fujioka and Y. Kita, Tetrahedron, 2009,
65, 10797 and references therein. For selected examples see:
(b) Y. Tamura, T. Yakura, J.-i. Haruta and Y. Kita, J. Org. Chem.,
1987, 52, 3927; (c) K. Hata, H. Hamamoto, Y. Shiozaki and
Y. Kita, Chem.Commun., 2005, 2465; For an account on phenolic
Vinylogous esters are valuable synthetic building blocks,
with well-defined reactivity, thereby allowing ready access to
diversely functionalised materials.12 The chemistry developed
herein expands the utility of these materials, providing facile
approaches to spirofuran 2 and benzopyran 3 heterocycles.
Key mechanistic events involve oxidation of the electron
rich aromatic ring, by the in situ generated hypervalent
iodonium reagent, and trapping with the electron rich vinylogous
ester. The use of catalytic iodobenzene contributed significant
advantages over the stoichiometric variant of this reaction,
and illustrates a new catalytic hypervalent iodine mediated
reaction. Future studies aim to exploit this novel mode of
cyclisation to rapidly access complex polycyclic oxygen
heterocycles in the context of total synthesis and medicinal
chemistry.
cyclisations see: (d) S. Quideau, L. Pouysegu and D. Deffieux,
´
Synlett, 2008, 4, 467; With olefinic nucleophiles see:
(e) S. Desjardins, J.-C. Andrez and S. Canesi, Org. Lett., 2011,
13, 3406; (f) J.-C. Andrez, M.-A. Giroux, J. Lucien and S. Canesi,
Org. Lett., 2010, 12, 4368; For a novel double annulation see:
(g) J. L. Frie, C. S. Jeffrey and E. J. Sorensen, Org. Lett., 2009,
11, 5394.
8 The reactivity of hypervalent iodonium reagents is likened to that
of Hg(III) Pb(IV) and Tl(III). In addition their preparation can be
achieved in a highly efficient fashion, for recent advances in the
preparation of diaryl iodonium reagents see: (a) T. Dohi, M. Ito,
K. Morimoto, Y. Minamitsuji, N. Takenaga and Y. Kita, Chem.
Commun., 2007, 4152; (b) A. A. Zagulyaeva, M. S. Yusubov and
V. V. Zhdankin, J. Org. Chem., 2010, 75, 2119; (c) S. Schafer and
¨
T. Wirth, Angew. Chem., Int. Ed., 2010, 49, 2786; For chiral diaryl
iodoniums see ; (d) N. Jalalian and B. Olofsson, Tetrahedron, 2010,
66, 5793.
9 The oxidative cyclisation of unmasked 1,3-dicarbonyls has been
performed and results in C–C bond formation: M. Arisawa,
N. G. Ramesh, M. Nakajima, H. Tohma and Y. Kita, J. Org.
Chem., 2001, 66, 59.
10 For benzopyrans see: (a) R. M. Jones, C. Selenski and T. R.
R. Pettus, J. Org. Chem., 2002, 67, 6911 and references therein, for
spirofurans see: (b) S. Rosenberg and R. Leino, Synthesis, 2009,
16, 2651.
The application of non-traditional nucleophiles in oxidative
cyclisation is an emerging theme.7 The study presented herein
demonstrates novel deployment of vinylogous esters as
electron-rich aprotic nucleophiles. The development of alternate
nucleophiles for oxidative transformations has great potential
to deliver useful transformations for rapid skeletal complexity
generation, and is a subject of ongoing studies within our
laboratories.
11 For reviews on catalytic hypervalent iodine chemistry see:
(a) R. D. Richardson and T. Wirth, Angew. Chem., Int. Ed.,
2006, 45, 4402; (b) M. Ochiai and K. Miyamoto, Eur. J. Org.
Chem., 2008, 4229; (c) T. Dohi and Y. Kita, Chem. Commun., 2009,
2073; (d) M. Ngatimin and D. W. Lupton, Aust. J. Chem., 2009,
63, 653.
12 For general procedures see: (a) G. Stork and R. Danheiser, J. Org.
Chem., 1973, 38, 1775; For 3a see: (b) M. Fagnoni, P. Schmoldt,
T. Kirschberg and J. Mattay, Tetrahedron, 1998, 54, 6427.
13 For a review on the role of fluorinated solvents in oxidation
Notes and references
1 For reviews see (a) V. V. Zhdankin and P. J. Stang, Chem. Rev.,
2008, 108, 5299; (b) J. P. Brand, D. F. Gonzalez, S. Nicolai and
´
J. Waser, Chem. Commun., 2011, 47, 102 and references therein.
2 For leading references see (a) C. G. Espino and J. Du Bois, Angew.
Chem., Int. Ed., 2001, 40, 598; (b) C. G. Espino, K. W. Fiori,
M. Kim and J. Du Bois, J. Am. Chem. Soc., 2004, 126, 15378.
3 For leading references see: (a) A. R. Dick, K. L. Hull and
M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 2300;
(b) E. J. Alexanian, C. Lee and E. J. Sorensen, J. Am. Chem.
Soc., 2005, 127, 7690; (c) G. Liu and S. S. Stahl, J. Am. Chem. Soc.,
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reactions see: (a) J.-P. Begue, D. Bonnet-Delpon and B. Crousse,
´ ´
Synlett, 2004, 18; For early applications with hypervalent iodo-
niums see: (b) Y. Kita, H. Tohma, M. Inagaki, K. Hatanaka and
T. Yakura, Tetrahedron Lett., 1991, 32, 4321; (c) Y. Kita,
H. Tohma, K. Hatanaka, T. Takada, S. Fujita, S. Mitoh,
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14 For leading references on catalytic hypervalent iodonium reactions
see: (a) T. Dohi, A. Maruyama, M. Yoshimura, K. Morimoto,
H. Tohma and Y. Kita, Angew. Chem., Int. Ed., 2005, 44, 6193;
(b) M. Ochiai, Y. Takeuchi, T. Katayama, T. Sueda and
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4 For leading references see: D. Kalyani, N. Deprez, L. V. Desai and
M. S. Sanford, J. Am. Chem. Soc., 2005, 127, 7330.
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(a) A. C. Boye, D. Meyer, C. K. Ingison, A. N. French and
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15 For selected examples of the catalytic application of aryl iodides in
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G. Cansell and S. A. Hermitage, Chem. Commun., 2006, 2483;
(b) T. Dohi, A. Maruyama, N. Takenaga, K. Senami,
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´
For selected examples of spirolactam formation see:
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´
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´ ´
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16 The location of the radical cation in intermediate II corresponds to
either of the two aromatic rings.
2010,
46,
4133;
For
Hofman
rearrangement
see:
(c) A. A. Zagulyaeva, C. T. Banek, M. S. Yusbov and
c
11780 Chem. Commun., 2011, 47, 11778–11780
This journal is The Royal Society of Chemistry 2011