Highly regioselective gold-catalyzed ring-opening allylation and azidation of dihydrofurans

Article abstract of DOI:10.1021/ol902005e

The ring-opening allylation and azidation of 2,5-dihydrofurans has been accomplished with allyltrimethylsilane or Me₃SiN₃ in the presence of catalytic amounts of HAuCl₄-3H₂O. Whereas the allylation proceeds regi

Full text of DOI:10.1021/ol902005e

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5034-5037
Highly Regioselective Gold-Catalyzed
Ring-Opening Allylation and Azidation of
Dihydrofurans
Yoshinari Sawama, Yuka Sawama, and Norbert Krause*
Organic Chemistry, Dortmund UniVersity of Technology, Otto-Hahn-Strasse 6,
D-44227 Dortmund, Germany
norbert.krause@tu-dortmund.de
Received August 28, 2009
ABSTRACT
The ring-opening allylation and azidation of 2,5-dihydrofurans has been accomplished with allyltrimethylsilane or Me3SiN3 in the presence of
catalytic amounts of HAuCl4·3H2O. Whereas the allylation proceeds regioselectively in the 2-position to afford 2,6-dien-1-ols, the azidation
takes place in the 4-position exclusively.
Due to its unique ability to activate C-C double and triple
bonds in the presence of reactive functionalities, gold is one
of the most versatile metals in transition metal catalysis.1
For the stereoselective synthesis of 5- or 6-membered
heterocycles, the gold-catalyzed endoselective cycloisomer-
ization of allenes2 bearing a hydroxyl,3 amino,4 hydroxy-
lamino,5 or thiol6 group in the R- or ꢀ-position is particularly
useful (Scheme 1). These transformations proceed with
complete transfer of chirality from the allenic chirality axis
to the new stereogenic center in most cases, allowing
application of the method in stereoselective target-oriented
synthesis.7
Scheme 1
.
Gold-Catalyzed endo-Cycloisomerization of
Functionalized Allenes
(1) Recent reviews: (a) Jimenez-Nunez, E.; Echavarren, A. M. Chem.
Commun. 2007, 333–346. (b) Gorin, D. J.; Toste, F. D. Nature 2007, 446,
395–403. (c) Fu¨rstner, A.; Davis, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410–3449. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180–3211. (e)
Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178–2181. (f)
Widenhoefer, R. A. Chem. Eur. J. 2008, 14, 5382–5391. (g) Shen, H. C.
Tetrahedron 2008, 64, 3885–3903. (h) Skouta, R.; Li, C.-J. Tetrahedron
2008, 64, 4917–4938. (i) Muzart, J. Tetrahedron 2008, 64, 5816–5849. (j)
Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239–3265. (k) Arcadi,
A. Chem. ReV. 2008, 108, 3266–3325. (l) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. ReV. 2008, 108, 3326–3350. (m) Gorin, D. J.; Sherry, B. D.;
Toste, F. D. Chem. ReV. 2008, 108, 3351–3378.
In contrast to alkyl-substituted allenes, substrates bearing
phenyl or electron-rich aryl substituents R1 undergo epimer-
ization when treated with gold(I) or gold(III) precatalysts in
(2) Krause, N.; Belting, V.; Deutsch, C.; Erdsack, J.; Fan, H.-T.; Gockel,
B.; Hoffmann-Ro¨der, A.; Morita, N.; Volz, F. Pure Appl. Chem. 2008, 80,
1063–1069.
10.1021/ol902005e CCC: $40.75
Published on Web 09/30/2009
 2009 American Chemical Society

unpolar solvents.3d Moreover, the cis-disubstituted dihydro-
furan or -pyran (R1 ) Aryl) is epimerized to the trans-isomer
in the presence of AuCl3 in dichloromethane (Scheme 1).3d,8
This epimerization probably occurs via a zwitterionic
intermediate comprising a benzyl cation substructure and an
anionic aurate moiety.3d,9 On the basis of this assumption,
we reasoned that it might be possible to trap the benzyl cation
with a suitable nucleophile, a process that would result in a
ring-opening of the heterocycle with formation of a new
C-C or C-heteroatom bond in the 2- or 4-position. There
is little precedent for such a transformation in homogeneous
gold catalysis10 whereas classical protocols for the nucleo-
philic ring-opening of unsaturated cyclic ethers by zirconium-
catalyzed carbomagnesiation11 or ethylalumination12 involve
C-C bond formation with strong nucleophiles and are
limited with regard to regioselectivity and functional group
compatibility. Also, there appear to be no examples for the
ring-opening of unsaturated ethers with heteronucleophiles.
We first examined the reaction of 2,5-dihydrofuran 1a3d
with allyltrimethylsilane as carbon nucleophile10,13 in the
presence of various gold precatalysts (Table 1). With 5 mol
% of AuCl3 and 2 equiv of Me3SiCH2CHdCH2 in CH2Cl2
at room temperature, the 2,6-dien-1-ol 2a resulting from
nucleophilic attack of the silane in the 2-position of 1a was
Table 1. Gold-Catalyzed Allylative Ring-Opening of
2,5-Dihydrofuran 1a
1a/2a/3aa
solvent temp (°C) time (h) (yield/%)
entry
[Au]
AuCl3
1
2
CH2Cl2
CH2Cl2
rt
rt
16
3
56/19/0
80/13/7
56/37/0
45/23/0
50/24/26
30/50/13
3/10/84
0/12/86
AuBr3
3
4
5
6
HAuCl4·3H2O CH2Cl2
HAuCl4·3H2O CH2Cl2
HAuCl4·3H2O CH2Cl2
HAuCl4·3H2O CH2Cl2
HAuCl4·3H2O CH2Cl2
HAuCl4·3H2O CH2Cl2 -40 to -35
HAuCl4·3H2O THF
HAuCl4·3H2O toluene
rt
rt
0
1
24
2
5
2
0.3
24
24
-40 to -5
-40 to -5
7b
8c
9
d
-40 to rt
-40 to rt
-
d
10
-
a 2a and 3a were obtained as a 1:1 mixture of diastereomers. b With 3
equiv of allyltrimethylsilane. c With 4 equiv of allyltrimethylsilane. d No
conversion.
(3) (a) Hoffmann-Ro¨der, A.; Krause, N. Org. Lett. 2001, 3, 2537–2538.
(b) Krause, N.; Hoffmann-Ro¨der, A.; Canisius, J. Synthesis 2002, 1759–
1774. (c) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485–4488. (d) Deutsch,
C.; Gockel, B.; Hoffmann-Ro¨der, A.; Krause, N. Synlett 2007, 1790–1794.
obtained with low yield (19%), and 56% of the starting
material was recovered (entry 1). In contrast, gold(III)
bromide gave a mixture of 2a and the corresponding silyl
ether 3a, but the conversion was still low (entry 2). A higher
reactivity was observed with HAuCl4·3H2O (entry 3), whereas
other gold(I) or gold(III) precatalysts (Au(OAc)3, Au(OH)3,
NaAuCl4, Ph3PAuCl/AgBF4) and traditional Lewis acids
(CuI, Cu(OTf)2, AgOTf, InBr3) gave no conversion at all.
Optimization of the reaction conditions with HAuCl4·3H2O
as precatalyst revealed a strong influence of the solvent,
temperature, and amount of silane (Table 1). An increase of
the reaction time caused a lower yield of product 2a (23 vs.
37%; entries 3 and 4). Interestingly, the furan formed by
oxidation of 1a was isolated as side product under these
conditions. This side reaction can be suppressed by lowering
the reaction temperature (entries 5 and 6); at -40 °C, 2a
and 3a were obtained with 63% combined yield (entry 6).
Even lower temperatures or the use of other solvents (THF
or toluene; entries 9 and 10) resulted in no conversion. In
contrast to this, an increase of the amount of allyltrimeth-
ylsilane gave better results (entries 7 and 8); with 4 equiv
of the silane, a fast reaction with complete conversion of 1a
and an excellent combined yield of 2a/3a (98%) was
achieved (entry 8). In all cases, the products of the allylative
ring-opening were obtained as a 1:1 mixture of diastereomers,
as is expected for the mechanism involving a benzyl cation
intermediate.
¨
(e) Aksin, O.; Krause, N. AdV. Synth. Catal. 2008, 350, 1106–1112. (f)
Poonoth, M.; Krause, N. AdV. Synth. Catal. 2009, 351, 117–122. (g) Winter,
C.; Krause, N. Green Chem. 2009, 11, 1309–1312. (h) Asikainen, M.;
Krause, N. AdV. Synth. Catal. In press.
(4) (a) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121–4123. (b) Morita,
N.; Krause, N. Eur. J. Org. Chem. 2006, 4634–4641. (c) Reference 3c.
(5) Winter, C.; Krause, N. Angew. Chem., Int. Ed. 2009, 48, 6339–6342.
(6) Morita, N.; Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897–1899.
(7) (a) Volz, F.; Krause, N. Org. Biomol. Chem. 2007, 5, 1519–1521.
(b) Volz, F.; Wadman, S. H.; Hoffmann-Ro¨der, A.; Krause, N. Tetrahedron
2009, 65, 1902–1910. (c) Erdsack, J.; Krause, N. Synthesis 2007, 3741–
3750. (d) Sawama, Y.; Sawama, Y.; Krause, N. Org. Biomol. Chem. 2008,
6, 3573–3579. (e) Miura, T.; Shimada, M.; De Mendoza, P.; Deutsch, C.;
Krause, N.; Murakami, M. J. Org. Chem. 2009, 74, 6050–6054. (f) Gao,
Z.; Li, Y.; Cooksey, J. P.; Snaddon, T. N.; Schunk, S.; Viseux, E. M. E.;
McAteer, S. M.; Kocienski, P. J. Angew. Chem., Int. Ed. 2009, 48, 5022–
5025.
(8) (a) Epimerization/rearrangement of alkynyl and aryl C-glycosides
with AuCl3: Yeager, A. R.; Min, G. K.; Porco, J. A., Jr.; Schaus, S. E.
Org. Lett. 2006, 8, 5065–5068. (b) Epimerization of a 2,5-dihydrofuran
during the gold-catalyzed cycloisomerization of an allenamide: Hyland,
C. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658–8660.
(9) In accordance with this assumption, the epimerization can be
suppressed by decreasing the Lewis acidity of the gold catalyst.3d
(10) Gold-catalyzed bisallylation of oxabicyclic benzene derivatives:
Hsu, Y.-C.; Datta, S.; Ting, C.-M.; Liu, R.-S. Org. Lett. 2008, 10, 521–
524.
(11) (a) Suzuki, N.; Kondakov, D. Y.; Takahashi, T. J. Am. Chem. Soc.
1993, 115, 8485–8486. (b) Morken, J. M.; Didiuk, M. T.; Hoveyda, A. H.
J. Am. Chem. Soc. 1993, 115, 6997–6998. (c) Morken, J. M.; Didiuk, M. T.;
Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123–3124.
(d) Visser, M. S.; Hoveyda, A. H. Tetrahedron 1995, 51, 4383–4394. (e)
Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H.
J. Am. Chem. Soc. 1996, 118, 4291–4298. (f) Heron, N. M.; Adams, J. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 6205–6206.
(12) Dawson, G.; Durrant, C. A.; Kirk, G. G.; Whitby, R. J.; Jones,
R. V. H.; Standen, M. C. H. Tetrahedron Lett. 1997, 38, 2335–2338.
(13) Gold-catalyzed reactions of allylsilanes with electrophiles: (a)
Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127,
14180–14181. (b) Lin, C.-C.; Teng, T.-M.; Odedra, A.; Liu, R.-S. J. Am.
Chem. Soc. 2007, 129, 3798–3799. (c) Lin, C.-C.; Teng, T.-M.; Tsai, C.-
C.; Liao, H.-Y.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16417–16423. (d)
Matsuda, T.; Kadowaki, S.; Yamaguchi, Y.; Murakami, M. Chem. Commun.
Application of the optimized reaction conditions (Table
1, entry 8) to various 2,5-dihydrofurans 13 afforded the
allylation products 2 with moderate to high yield (Table 2)
after treatment of the crude product with n-Bu4NF. Both
electron-rich (entry 1) and electron-deficient aryl groups
(entries 2 and 3) are tolerated. The method is also applicable
2008, 24, 2744–2746
.
Org. Lett., Vol. 11, No. 21, 2009
5035

Table 2. Gold-Catalyzed Allylative Ring-Opening of
Scheme 2
.
Gold-Catalyzed Nucleophilic Ring-Opening of
Dihydrofurans and Dihydropyransa
2,5-Dihydrofuran 1a
afforded a mixture of the regioisomers 8 and 9 with 74%
combined yield. The product ratio was not affected by a
change of the reaction temperature or the stoichiometry of
the reactants.
a Conditions: HAuCl4·3H2O (5 mol %), Me3SiCH2CHdCH2 (4 equiv),
CH2Cl2, -40 to -20 °C, 1-4 h, then treatment with n-Bu4NF. b With 15
mol % of HAuCl4·3H2O. c No conversion. d Accompanied by 13% (dr )
60:40) of the regioisomer 5:
Table 3. Gold-Catalyzed Ring-Opening of Dihydrofurans and
a
Dihydropyrans with Me3SiN3
to the alkenyl-substituted dihydrofuran 1e even though the
yield of product 2e was low (35%; entry 4). As expected,
the alkyl-substituted dihydrofuran 1f does not undergo gold-
catalyzed ring-opening (entry 5). The substrate 1g lacking
the methyl group (entry 6) turned out to be less reactive than
its counterpart 1a, whereas the dihydropyran 43c did not react
(entry 7). In all cases, product formation was accompanied
by extensive or complete epimerization of the stereogenic
center bearing the aryl or alkenyl substituent. The allylative
ring-opening took place regioselectively with exclusive attack
of the nucleophile at C-2 of the dihydrofuran, except for
substrate 1g, which also afforded 13% of the regioisomer 5
resulting from attack in the 4-position.
Whereas the application of the gold-catalyzed ring-opening
of dihydrofurans to substituted allylsilanes met with limited
success,14 other nucleophiles proved to be more reactive
(Scheme 2). Thus, reaction of 1a with 4 equiv of trimeth-
ylsilylazide15 in the presence of 5 mol % of HAuCl4·3H2O
gave the azido alcohol 7a (resulting from exclusive attack
of the nucleophile at C-4) with 91% yield after just 5 min at
-40 °C. This is the first example for a ring-opening reaction
of an unsaturated cyclic ether with a nitrogen nucleophile.
In contrast to this highly regioselective transformation, the
corresponding reaction of 1a with trimethylsilylcyanide16
a Conditions: HAuCl4·3H2O (5 mol %), Me3SiN3 (4 equiv), CH2Cl2,
-40 to -20 °C, 0.5-2 h, then treatment with n-Bu4NF. b 76% of 1c was
recovered. c A complex product mixture was formed. d No conversion.
Encouraged by the high reactivity and regioselectivity
observed in the gold-catalyzed azidation of substrate 1a, we
applied these conditions to various dihydrofurans and -pyrans
(Table 3). As in the corresponding allylation, electron-rich
(entry 1) and electron-deficient aryl groups (entries 2 and 3)
are tolerated, even though the yield of the ester-substituted
azidation product 7c was very low (12%; entry 2). This
pronounced reactivity difference is in agreement with the
proposed benzyl cation intermediate. In contrast to the aryl-
substituted dihydrofurans, substrate 1e bearing an alkenyl
group gave a complex product mixture (entry 4), whereas
isopropyl-substituted dihydrofuran 1f did not react (entry 5).
Finally, we were pleased to observe a smooth conversion of
(14) Reaction of 1a with trimethyl(2-methylallyl)silane (4 equiv) in the
presence of HAuCl4·3H2O (5 mol %) gave 1-(benzyloxy)-3,7-dimethyl-5-
phenylocta-3,7-dien-2-ol with 20% yield, whereas the corresponding reaction
of 1a with crotyltrimethylsilane afforded 1-(benzyloxy)-3,6-dimethyl-5-
phenylocta-3,7-dien-2-ol with 59% yield.
(15) For the reaction of Me3SiN3 with gold(I) acetylides, see: Partyka,
D. V.; Updegraff, J. B., III; Zeller, M.; Hunter, A. D.; Gray, T. G.
Organometallics 2007, 26, 183–186.
5036
Org. Lett., Vol. 11, No. 21, 2009

dihydrofuran 1g and even dihydropyran 4 to the correspond-
ing azido alcohols (entries 6 and 7). The latter transformation
took place without concomitant acetate migration.3d Similar
to the allylation, the gold-catalyzed azidation of dihydro-
furans and -pyrans occurred with extensive epimerization of
the stereogenic center next to the aryl substituent. Interest-
ingly, the azido alcohols 7 are converted back to the
dihydrofurans 1 by traces of acid.
The formation of product 5 resulting from attack at C-4 of
dihydrofuran 1g indicates that the steric properties of the
benzyl cation contribute to the regioselectivity of the gold-
catalyzed allylative ring-opening.
The products of the gold-catalyzed allylation and azidation
of dihydrofurans and -pyrans can undergo [3,3]-sigmatropic
rearrangements. Whereas strong heating is required for a
thermal Cope rearrangement of 1,5-dienes,17 allylazides
equilibrate very rapidly even below room temperature.18
Thus, there are two possible explanations for the formation
of allylazides F (Scheme 3): either the zwitterionic inter-
mediate B is attacked by Me3SiN3 directly in the 4-position,
or the initially formed regioisomer E rearranges rapidly to
the (thermodynamically more stable) product F. Investiga-
tions dedicated to elucidate these mechanistic issues are in
progress.
Scheme 3
.
Proposed Mechanism of the Gold-Catalyzed
Nucleophilic Ring-Opening
In conclusion, we have achieved the first examples for a
highly regioselective gold-catalyzed ring-opening allylation
and azidation of dihydrofurans and dihydropyrans. These
transformations require the presence of an aryl or alkenyl
group in the 2-position of the substrate and probably proceed
via a zwitterionic intermediate comprising a benzyl cation
substructure and an anionic aurate moiety. We continue to
expand the scope of gold-catalyzed ring-opening reactions
for the regio- and stereoselective synthesis of highly func-
tionalized linear products.
Acknowledgment. Support by the Deutsche Forschungs-
gemeinschaft and the European Community is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and selected NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
In mechanistic terms, the reactivity (R ) 4-MeOC6H4 >
Ph > 4-MeO2CC6H4 . i-Pr) in the gold-catalyzed allylation
and azidation of 2,5-dihydrofurans 1, as well as the epimer-
ization observed for these substrates, clearly points to a
benzyl cation intermediate. But how is the opposite regi-
oselectivity of these transformations to be explained? We
assume that formation of the zwitterionic intermediate B from
starting material A and the gold(III) catalyst (Scheme 3) is
followed by a kinetically controlled attack of the allylsilane
at C-2 of the benzyl cation moiety, affording ꢀ-silyl cation
C. Cleavage of the carbon-silicon bond then leads to the
ring-opening product D and regenerates the gold catalyst.
OL902005E
(16) For the gold-catalyzed cyanosilylation of aldehydes and ketones
with Me3SiCN, see: Cho, W. K.; Kang, S. M.; Medda, A. K.; Lee, J. K.;
Choi, I. S.; Lee, H.-S. Synthesis 2008, 507–510.
(17) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1–252.
(18) (a) Gagneux, A.; Winstein, S.; Young, W. G. J. Am. Chem. Soc.
1960, 82, 5956–5957. (b) Feldman, A. K.; Colasson, B.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 13444–13445. (c) Lauzon, S.;
Tremblay, F.; Gagnon, D.; Godbout, C.; Chabot, C.; Mercier-Shanks, C.;
Perreault, S.; DeSeve, H.; Spino, C. J. Org. Chem. 2008, 73, 6239–6350.
Org. Lett., Vol. 11, No. 21, 2009
5037