PtII-catalyzed synthesis of 9-oxabicyclo[3.3.1]nona-2,6-dienes from 2-alkynyl-1-carbonylbenzenes and allylsilanes by an allylation/annulation cascade

Article abstract of DOI:10.1002/anie.200800826

(Chemical Equation Presented) Platinum is key: A new catalytic synthesis of 9-oxabicyclo[3.3.1]nona-2,6-dienes from readily available 2-alkynyl-1- carbonylbenzenes, allylsilanes, and water is reported (see scheme). This reaction sequence is proposed to proceed through a series of three reactions, including allylation of the carbonyl group, hydroalkoxylation of the alkyne, and a new eneoxonium annulation.

Full text of DOI:10.1002/anie.200800826

Angewandte
Chemie
DOI: 10.1002/anie.200800826
Synthetic Methods
PtII-Catalyzed Synthesis of 9-Oxabicyclo[3.3.1]nona-2,6-dienes from 2-
Alkynyl-1-carbonylbenzenes and Allylsilanes by an Allylation/
Annulation Cascade**
Sabyasachi Bhunia, Kuo-Chang Wang, and Rai-Shung Liu*
Allylsilanes commonly undergo [3+2] or [2+2] annulation
reactions with aldehydes to give substituted tetrahydrofurans
or oxetans,[1] an approach that has been applied to the
syntheses of natural products.[2] New [3+2] and [4+2]
annulations were reported for aldehyde substrates bearing
an a- or b-siloxy group,[3] but these annulations required 1.0–
5.0 equivalents of a Lewis acid (BF3·Et2O, TiCl4, or SnCl4).[2–4]
Our objective was to explore new annulations of allysilanes
with functionalized aldehydes by using soft-acid-metal species
in catalytic proportions.[4,5] Herein, we report a one-pot PtII-
catalyzed synthesis of 9-oxabicyclo[3.3.1]nona-2,6-dienes by a
tandem allylation/annulation reaction of the oxo-alkyne
functionalities with 2-substituted allylsilanes (see Table 1).
The importance of this new synthesis is that it provides easy
access to two classes of bioactive molecules, I–IVand V, which
are comprised of the oxatricyclic framework that showed
biological effects in the central nervous system,[6] as well as
HIV-1 inhibitory activities[7] (Figure 1).
catalysts were reported to be catalytically active for the
addition of allylsilanes to aldehydes and imines,[4] our results
reveal that AgOTf, [PPh3AuSbF6], and [PPh3AuOTf] are less
efficient than platinum catalysts.[8] Treatment of 2-alkynyl-
benzaldehyde 1a with PtCl2 (5 mol%) in hot toluene
(Table 1, entry 1) gave oxatricyclic species 3a and siloxy
Table 1: Catalytic activities for platinum and gold catalysts.
Entry Substrate Catalyst
Conditions[a] H2O
(equiv) (Yields [%])[b]
Products
1
2
3
4
1a
1a
1a
1a
PtCl2
808C,15 h
–
–
2
2
3a (32), 2a (39)
3a (41), 2a (43)
3a (80)
PtCl2/CO 808C,15 h
PtCl2/CO 808C,15 h
PtCl2/
808C,12 h
3a (91)
2AgOTf[c]
5
6
1a
PtCl2/CO 508C, 3 h
2
2
1a (14), 2a (38),
2b (42)
3a (85)
2a+2b PtCl2/CO 808C,12 h
[a] Toluene, [1a]=0.26m, [CO]=1 atm, 5 mol% catalyst, silane
[1.5 equiv]. [b] Yields are for products isolated after column chromatog-
raphy. [c] 5 mol% PtCl2 and 11 mol% AgOTf.
species 2a in 32% and 39% yields, respectively. In the
presence of water (2 equiv) and CO (1 atm), the yield of
compound 3a was greatly improved to 88% (Table 1,
entry 3); this reaction presumably involves a [PtCl2(CO)]
species, which increases the electrophilicity of the platinum.[9]
Notably, water participates in this catalytic reaction because it
provides one hydrogen atom for species 3a, and one OH
group for the accompanying Me3SiOH product. Efficient
annulation was also attained with a PtCl2/2AgOTf catalyst in
wet toluene to give compound 3a in a 91% yield. Under mild
conditions (toluene, 508C, 3 h), we isolated homoallylic
alcohol 2b and siloxy derivative 2a in significant amounts
(Table 1, entry 5), thus verifying them as reaction intermedi-
ates; these intermediates were converted into compound 3a
with PtCl2/CO upon additional heating (Table 1, entry 6). The
proposed structure of oxatricyclic species 3a was inferred
from 1H NOE spectra, and confirmed from the X-ray
crystallographic structure of related compound 3c.[10]
Figure 1. Bioactive molecules bearing 9-oxabicyclo[3.3.1]nona-2,6-diene
frameworks.
We selected commonly used AuI, AgI, and PtII species for
screening and used each at a 5 mol% loading. Although these
[*] S. Bhunia, K.-C. Wang, Prof. Dr. R.-S. Liu
Department of Chemistry
National Tsing Hua University
Hsinchu 30043 (Taiwan)
Fax: (+886)3571-1082
E-mail: rsliu@mx.nthu.edu.tw
[**] We thank the National Science Council, Taiwan for support of this
work.
The results in Table 2 show the scope of this oxatricyclic
synthesis by annulations of 2-alkynylbenzaldehydes 1a–1j
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 5063 –5066
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5063

Communications
Table 2: Annulation of 2-alkynylbenzaldehydes with allylsilanes.
Table 3: Annulation of 2-alkynyl-1-ketonylbenzenes with allylsilanes.
Entry Ketones[a]
Silanes t [h] Products (Yields [%])[c]
R=Ph 12 5a (66)
Entry Enynal[a]
Silane
t [h]
Products
(Yields [%])[c]
1
2
3
4
5
R1 =R2 =Me (4a)
R1 =Me, R2 =nBu (4b) R=Ph 10 5b (83)
X, Y=H
R1 =Me, R2 =Ph (4c) R=Ph[b] 11 5c (63), 6 (22, d.r.=1:1)
1
2
R1 =Ph (1b)
R2 =Ph
R1 =4-MeOC6H4- R2 =Ph
(1c)
20
24
3b (75)
3c (78)
R1 =R2 =nBu (4d)
R=Ph 11 5d (82)
R=Me 5e (57), 7 (24)
4b
6
3
4
5
R1 =Cy (1d)
R1 =Me (1e)
R1 =H (1 f)
R2 =Ph
R2 =Ph
R2 =Ph
10
15
14
3d (88)
[a] [substrate]=0.26m, 5% PtCl2/11% AgOTf, silane (1.5 equiv). [b] 2.0
equiv of silane used. [c] Yields are for products isolated after column
chromatography.
3e (72)
3 f (12, 31[b])
(10[b])
12
6
7
R1 =nBu (1a)
R1 =nBu (1a)
R2 =4-
3g (68)
3h (60)
CF3C6H4
R2 =4-
12
allyltrimethylsilane gave desired product 5e and chrysene 7 in
57% and 24% yields, respectively.[12]
To clarify the role of the Brønsted acid (Scheme 1), we
added p-toluenesulfonic acid (p-TSA, 5 mol%) to a mixture
of aldehyde 1a, 2-(phenylallyl)trimethylsilane, and PtCl2/CO
MeOC6H4
8
9
10
R1 =nBu (1a)
R1 =nBu (1a)
R1 =Me (1e)
R1 =nBu, Y=H
X=CF3 (1g)
R2 =2-thienyl 13
3i (81)
3j (63[b])
3k (80)
R2 =Me
R2 =Me
2
1
11
12
R2 =Ph
R2 =Ph
10
3l (68)
X=OMe (1h)
14
3m (34, 78[b])
(12[b])
R1 =nBu, X=H
Y=CF3 (1i)
Y=OMe (1j)
13
14
R2 =Ph
R2 =Ph
15
20
3n (70)
3o (82)
[a] 808C, [substrate]=0.26m, [CO]=1 atm, catalyst (5 mol%), silane
(1.5 equiv). [b] These values were obtained with 5% PtCl2/11% AgOTf.
[c] Yields are for products isolated after column chromatography. Cy=
cyclohexyl.
with various allylsilanes and water; the reactions were run
with 5 mol% PtCl2/CO in wet toluene. In three reactions
(Table 2, entries 5, 9, and 12) we used PtCl2/2AgOTf (5/
11 mol%) to improve the product yields. The reactions of
substrates 1b–1e, in which the R1 substituent of the aldehyde
is varied (Table 2, entries 1–4), gave oxatricyclic products 3b–
3e in good yields (72–88%). However, the unsubstituted
analogue gave 3 f in 31% yield (Table 2, entry 5). The
annulations of aldehydes 1a and 1e with various 2-substituted
allylsilanes proceeded smoothly in wet toluene to give
expected products 3g–3k in 60–81% yields (Table 2,
entries 6–10). The reaction is also compatible with different
substituents (X and Y) on the phenyl rings of aldehydes 1g–
1j, and satisfactory yields (> 68%) were obtained for their
annulated products 3l–3o.
Although ketones are generally inactive in the Lewis acid
promoted annulation with allylsilanes, ketones 4a–4d were
compatible with this new method. The results in Table 3 show
that the PtCl2/2AgOTf mixture (5/11 mol%) efficiently
catalyzed the annulation of these ketones with 2-(phenyl-
allyl)trimethylsilane to give desired oxacyclic compounds 5a–
5d (63–83% yields) in wet toluene (1008C, 10–12 h). We
obtained 1,2-dihydronaphthalene species 6 as a side product
(22% yield, d.r. = 1:1) with 4c as the substrate (Table 3,
entry 3).[11] The annulation of compound 4b with 2-(methyl)-
Scheme 1. Control experiments to clarify the role of the Brønsted acid.
(5 mol%) in wet toluene (808C, 12 h), and obtained oxatri-
cyclic product 3a and 1,2-dihydronaphthalene 8 (d.r. = 1.7:1)
in 45% and 33% yields, respectively. The use of stronger
Brønsted acids, such as HCl or HOTf, led to complete
decomposition of starting aldehyde 1a. The formation of
species 8 has been rationalized by work in an early report by
Yamamoto and co-workers.[13,14b,c] As proposed, the Brønsted
acid catalyzes the hydrative decomposition of 2-(phenyl-
allyl)trimethylsilane to 1-methylstyrene.[13] The results
(Table 1, entry 1–6) show that of 1,2-dihydronaphthalene 8
is not isolated. In a separate experiment, we found that
treatment of alcohol 2b with PtCl2/CO in dry toluene (808C,
12 h) predominantly gave 1H-isochromene 9 in 83–86%
yields in the presence of either 4Š molecular sieves or a
proton-scavenger such as MgO. Additional treatment of 1H-
isochromene 9 with p-TSA (1 mol%) in hot toluene (808C,
0.5 h) gave desired oxatricyclic product 3a in a 96% yield. On
the basis of these observations, we concluded that the
concentration of the free Brønsted acid was rather small in
the PtCl2/CO/H2O system, but it is necessary for the final
annulation step.
5064 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 5063 –5066

Angewandte
Chemie
[4] For addition of allylsilanes or allylstannanes to carbonyl
Accordingly, we propose
a
plausible mechanism
derivatives by using AgI, CuII, PtII, and AuI, see selected
examples: a) A. Yanagisawa, H. Nakashima, A. Ishiba, H.
Yamamoto, J. Am. Chem. Soc. 1996, 118, 4723; b) M. Wadamoto,
N. Ozasa, A. Yanagisawa, H. Yamamoto, J. Org. Chem. 2003, 68,
5593; c) A. Yanagisawa, H. Kageyama, Y. Nakatsuka, K.
Asakawa, Y. Matsumoto, H. Yamamoto, Angew. Chem. 1999,
111, 3916; Angew. Chem. Int. Ed. 1999, 38, 3701; d) J. Kruger,
E. M. Carreira, J. Am. Chem. Soc. 1998, 120, 837; e) S. Obika, H.
Kono, Y. Yasui, R. Yanada, Y. Takemoto, J. Org. Chem. 2007, 72,
4462.
(Scheme 2) that involves an initial PtII-catalyzed addition[4e]
of the allysilane to the aldehyde to give siloxy product 2a. In
this wet system, we envisage that PtX2 (X = Cl, OTf)
enhances the hydrolysis of this siloxy species to give alcohol
2b. A second PtII-catalyzed reaction of this alcohol, involving
the hydroalkoxylation of the alkyne, is expected to give 1H-
isochromene 9,[14] which subsequently undergoes protonation
to give oxonium intermediate A. The final annulation is
completed upon addition of the tethered alkene of species A
to its oxonium center to give oxabicyclic tertiary cation B,
which then loses a proton regioselectively to produce desired
[5] C.-C. Lin, T.-M. Deng, A. Odedra, R.-S. Liu, J. Am. Chem. Soc.
2007, 129, 3798.
[6] a) B. Wünsch, M. Zott, G.
Höfner, Arch. Pharm. 1992, 325,
733; b) B. Wünsch, M. Zott, G.
Höfner, Arch. Pharm. 1993, 326,
823; c) C. Ketterer, S. Grimme,
E. Weckert, B. Wünsch, Tetrahe-
dron: Asymmetry 2006, 17, 3046.
[7] a) C. Maurin, F. Bailly, P. Cor-
telle, Curr. Med. Chem. 2003, 10,
1795; b) R. Dupont, L. Jeanson,
J.-F. Mouscadet, P. Cotelle,
Bioorg. Med. Chem. Lett. 2001,
11, 3175; c) R. Dupont, P.
Cotelle, Tetrahedron Lett. 1998,
39, 8457.
[8] In wet dichloroethane (258C,
Scheme 2. A proposed mechanism for the formation of 9-oxabicyclo[3.3.1]nona-2,6-dienes.
3a. Herein, the alkene regioselectivity of 3a is attributed to its
12 h), AgOTf, PPh3AuSbF6, and
[PPh3AuOTf] led to complete
consumption of starting alde-
hyde 1a, but only [PPh3AuOTf]
less strained framework, having an energy that is approx-
imately 2.91 kcalmolÀ1 less than the other olefin isomer.[15]
In summary, we report a new platinum-catalyzed synthesis
of 9-oxabicyclo[3.3.1]nona-2,6-dienes from readily available
2-alkynyl-1-carbonylbenzenes, allylsilanes, and water. This
reaction sequence is proposed to proceed through a series of
three reactions, including allylation of the carbonyl group,[4]
hydroalkoxylation of the alkyne,[15] and a new ene-oxonium
annulation.[16,17] The value of this new annulation is indicated
by the easy access to bioactive molecules comprised of the
same oxatricyclic framework. The synthesis of enantiomeric
oxatricyclic products by using chiral platinum catalysts is
under current investigation.
gave desired oxatricyclic species 3 in a 25% yield.
[9] For the PtCl2/CO catalysis, see a) A. Fürstner, C. Aïssa, J. Am.
Chem. Soc. 2006, 128, 6306; b) A. Fürstner, P. W. Davies, J. Am.
Chem. Soc. 2005, 127, 15024; c) B. P. Taduri, S. M. A. Sohel, H.-
M. Cheng, G.-Y. Lin, R.-S. Liu, Chem. Commun. 2007, 2530 –
2532; d) H.-K. Chang, S. Datta, A. Das, R.-S. Liu, Angew. Chem.
2007, 119, 4828; Angew. Chem. Int. Ed. 2007, 46, 4744.
[10] The x-ray crystallographic data for compound 3c has been
deposited at the Cambridge Crystallographic Data Center
(CCDC-677837 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif), and 1H NOE spectra of key
compounds are provided in the Supporting Information.
[11] 1,2-dihydronaphthalene 6 was formed from [4+2] cycloaddition
of benzopyrinium C and 1-methylstyrene (see below); this olefin
arose from decomposition of allylsilane with a Brønsted acid
when water was present.[13] In a control experiment, we obtained
compound 6 (86% yield) from PtCl2/CO-catalyzed cyclization of
4c with 1-methylstyrene in hot toluene. See the leading paper: N.
Asao, T. Kasahara, Y. Yamamoto, Angew. Chem. 2003, 115,
3628; Angew. Chem. Int. Ed. 2003, 42, 3504.
Received: February 20, 2008
Published online: May 28, 2008
Keywords: allylation · annulation · oxygen heterocycles ·
.
platinum
[1] For recent reviews and leading references, see a) H. J. Knölker,
N. Foitzik, C. Gabler, R. Graf, Synthesis 1999, 145 – 151; b) H. J.
Knolker, J. Prakt. Chem. 1997, 339, 304; c) R. L. Danheiser,
B. R. Dixon, R. W. Gleason, J. Org. Chem. 1992, 57, 6094; d) J. S.
Panek, M. Yang, J. Am. Chem. Soc. 1991, 113, 9868.
[2] Selected examples, see a) J. M. Tinsley, W. R. Roush, J. Am.
Chem. Soc. 2005, 127, 10818; b) S. R. Angle, N. A. El-Said, J.
Am. Chem. Soc. 2002, 124, 3608.
[12] For the mechanism of formation of chrysene 7, see A. Das, H.-H.
Liao R.-S. Liu, J. Org. Chem. 2007, 72, 9214.
[13] For similar observations, see a) Y.-G. Hsu, S. Datta, C.-M. Ting,
R.-S. Liu, Org. Lett. 2008, 10, 521; b) S. Porcel, V. Löpez-Carrilo,
[3] S. R. Angle, N. A. El-Said, J. Am. Chem. Soc. 1999, 121, 10211.
Angew. Chem. Int. Ed. 2008, 47, 5063 –5066
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5065

Communications
C. Garcia-Yebra, A. M. Echavarren, Angew. Chem. 2008, 120,
1909; Angew. Chem. Int. Ed. 2008, 47, 1883.
[16] For metal-catalyzed addition of a tethered phenol or enol to an
enol ether of 1H-isochromenes, see: A. Beeler, S. Su, C. A.
Singleton, J. A. Proco, Jr., J. Am. Chem. Soc. 2007, 129, 1413.
[17] Ketones are generally inactive toward metal-catalyzed allylation
reactions.[1] The high yields of oxatricyclic products 5a–5d may
arise from addition of allylsilane to benzopyrilium species C,[11]
rather than by the mechanism proposed in Scheme 2. We thank
one reviewer for this valuable comment.
[14] For formation of 1H-isochromenes from hydroalkoxylation of
alkyne, see reference [5e] and selected examples: a) X. Yao, C.-J.
Li, Org. Lett. 2006, 8, 1953; b) N. Asao, T. Nogami, K. Takahashi,
Y. Yamamoto, J. Am. Chem. Soc. 2002, 124, 764; c) N. Asao, C. S.
Chan, K. Takahashi, Y. Yamamoto, Tetrahedron 2005, 61, 11322.
[15] The calculations were done with Gaussian-98 package at level
B3LYP/6-31 + G*; details are provided in the Supporting
information.
5066 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 5063 –5066