Ag(I)-catalyzed sequential C-C and C-O bond formations between phenols and dienes with atom economy

Article abstract of DOI:10.1021/jo061221b

Mild, efficient, and economical Ag(I)-catalyzed sequential C-C/C-O bond formations between phenols and dienes were developed to afford in good yields a variety of dihydrobenzopyran and dihydrobenzofuran ring systems, which are important motifs in both naturally occurring and biologically active compounds.

Full text of DOI:10.1021/jo061221b

followed by cyclization of the resulting 2-allylphenols with
strong acid.6,7 The dihydrobenzopyrans are constructed typically
by intramolecular hydroarylation from arene-ene substrates8 or
by cycloaddition of o-quinonemethides generated from salicyl-
aldehydes and alcohols with alkenes using a protic acid or Lewis
acid.9 Pd-catalyzed telomerizations of dienes in the presence
of alcohols are well-known reactions;10 however, there are few
examples of the 1:1 addition of an alcohol across a diene.11-13
Moreover, previously reported synthetic methods for the 1:1
addition of a phenol across a diene usually give a complicated
mixture of several products, such as 2- or 4-alkenylphenol,
allylic ether, dihydrobenzopyran, etc.12 Efficient and clean
process for this reaction is very rare. Despite the recent success
to produce allylic ethers from phenols and dienes by a Pd
catalyst,11a reactions to afford annulated arene heterocycles
(cyclic ethers) are very limited.12,13 In parallel with our efforts
to develop a catalytic system for heterocyclic synthesis,8,14 we
were interested in developing a one-pot synthesis of dihy-
drobenzopyrans and dihydrobenzofurans from phenols and
dienes, whereby a single catalytic system would invoke
sequential C-C and C-O bond formations with high efficiency
and complete atom economy.15 Herein we report the discovery
of AgOTf for the sequential addition/cyclization of phenols with
dienes in an atom economic manner.
Ag(I)-Catalyzed Sequential C-C and C-O Bond
Formations between Phenols and Dienes with
Atom Economy
So Won Youn* and Jeong Im Eom
Department of Chemistry, Pukyong National UniVersity,
Busan 608-737, Korea
sowony@pknu.ac.kr
ReceiVed June 14, 2006
Mild, efficient, and economical Ag(I)-catalyzed sequential
C-C/C-O bond formations between phenols and dienes
were developed to afford in good yields a variety of
dihydrobenzopyran and dihydrobenzofuran ring systems,
which are important motifs in both naturally occurring and
biologically active compounds.
We focused our initial efforts in this area on the reaction
between p-methoxyphenol and isoprene, which were selected
as the first substrates for screening of several metal salts and
complexes. Transition metal complexes that were previously
Heterocyclic synthesis catalyzed by transition metal com-
plexes has attracted the most attention among a variety of
synthetic transformations because a transition-metal-catalyzed
reaction can directly construct complicated molecules from
readily accessible starting materials under mild conditions.1 In
comparison with other transition metals, silver(I) complexes
have long been believed to have low catalytic efficiency, and
most commonly, they served as either cocatalysts or Lewis acids.
Only recently Ag-catalyzed reactions have emerged as important
synthetic methods for a variety of organic transformations.2
Ag(I) is known to interact with multiple bonds, such as
alkenes,2b,e alkynes,2d,f-h and allenes.3 Recently, an interesting
Ag(I)-catalyzed intramolecular addition of alcohols to olefins
has been reported.2b The intramolecular hydroalkoxylation is
an attractive approach to the synthesis of cyclic ethers.2b,4
Therefore, we envisioned the addition of the OH groups of
phenols across dienes to afford dihydrobenzopyran or dihy-
drobenzofuran ring systems, which are pervasive motifs in
biologically active natural products and pharmaceutical drug
targets.5 The dihydrobenzofurans are generally prepared in two
steps from allyl aryl ethers by the Claisen rearrangement
(5) (a) BioactiVe Compounds from Natural Sources; Tringali, C., Ed.;
Taylor & Francis: New York, 2001. (b) The Chemistry of Heterocyclic
Compounds; Ellis, G. P., Lockhart, I. M., Eds.; John Wiley-Interscience:
New York, 1981; Vol. 36.
(6) (a) Nichols, D. E.; Hoffman, A. J.; Oberlender, R. A.; Riggs, R. A.
J. Med. Chem. 1986, 29, 302-304. (b) Harwood, L. M. J. Chem. Soc.,
Chem. Commun. 1983, 530-532.
(7) For Ir-catalyzed tandem Claisen rearrangement and intramolecular
hydroaryloxylation of allyl aryl ethers, see: (a) Grant, V. H.; Liu, B.
Tetrahedron Lett. 2005, 46, 1237-1239 and references therein. For
transition-metal-catalyzed cyclization of 2-allylphenols, see: (b) Hori, K.;
Kitagawa, H.; Miyoshi, A.; Ohta, T.; Furukawa, I. Chem. Lett. 1998, 1083-
1084.
(8) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581-584.
(9) Yadav, J. S.; Reddy, B. V. S.; Parisse, C.; Carvalho, P.; Rao. T. P.
Tetrahedron Lett. 2002, 43, 2999-3002 and references therein.
(10) Tsuji, J. Acc. Chem. Res. 1973, 6, 8-15.
(11) For synthesis of allylic ethers, see: (a) Utsunomiya, M.; Kawatsura,
M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2003, 42, 5865-5868. (b) Jolly,
P. W.; Kokel, N. Synthesis 1990, 771-773.
(12) For synthesis of alkenylphenols along with dihydrobenzopyrans,
see: aluminum phenolate: (a) Laan, J. A. M.; Giesen, F. L. L.; Ward, J. P.
Chem. Ind. 1989, 354-355. (b) Dewhirst, K. C.; Rust, F. F. J. Org. Chem.
1963, 28, 798-802. Pd(II) and Pt(II): (c) De Felice, V.; De Renzi, A.;
Funicello, M.; Panunzi, A.; Saporito, A. Gazz. Chim. Ital. 1985, 115, 13-
15. AlCl3: (d) Bolzoni, L.; Casiraghi, G.; Casnati, G.; Sartori, G. Angew.
Chem., Int. Ed. Engl. 1978, 17, 684-686. Rh(I): (e) Bienayme´, H.; Ancel,
J.-E.; Meilland, P.; Simonato, J.-P. Tetrahedron Lett. 2000, 41, 3339-3343.
(13) For Au(I)-catalyzed hydroamination of 1,3-dienes, see: (a) Bronwer,
C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744-1747. The author
reported that Ph3PAuOTf catalyzed the addition of alcohols to 1,3-dienes
with low efficiency (∼30-40% conversion) based on preliminary studies.
During the preparation of this manuscript, a similar study was published;
see: (b) Nguyen, R.-V.; Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 2397-2399.
They reported that only cyclic dienes were used for the annulation of phenols
or naphthols in the presence of AuCl3/AgOTf, and the use of acyclic dienes
led to a complicated mixture.
(1) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198.
(2) For selected examples, see: (a) Cho, G. Y.; Bolm, C. Org. Lett. 2005,
7, 4983-4985. (b) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett.
2005, 7, 4553-4556. (c) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395-4398.
(d) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. J. Org. Chem. 2005, 70,
10096-10098. (e) Yao, X.; Li, C.-J. J. Org. Chem. 2005, 70, 5752-5755.
(f) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023-5026. (g) Sweis,
R. F.; Schramm, M. P.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 7442-
7443. (h) Dalla, V.; Pale, P. New J. Chem. 1999, 23, 803-805 and references
therein.
(3) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12-21.
(4) (a) Coulombel, L.; Favier, I.; Dun˜ach, E. Chem. Commun. 2005,
2286-2288. (b) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 9536-9537.
(14) (a) Youn, S. W.; Eom, J. I. Org. Lett. 2005, 7, 3355-3358. (b)
Youn, S. W. J. Org. Chem. 2006, 71, 2521-2523.
(15) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705.
10.1021/jo061221b CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/25/2006
J. Org. Chem. 2006, 71, 6705-6707
6705

TABLE 1. Optimization Studies for the Reaction of
TABLE 2. Ag(I)-Catalyzed Reaction of ROH with Isoprenea
p-Methoxyphenol and Isoprenea
entry
catalyst
AgOTf
AgOTf
AgOTf
AgOTf
AgSbF6
AgBF4
AgClO4
Ag(O2CCF3)
AgNO3
AgOTs
Cu(OTf)2
Sc(OTf)3
solvent
yield (%)b
1
2
3
4
5
6
7
8
ClCH2CH2Cl
1,4-dioxane
toluene
60
-
40
-
CH3CN
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
20
30
40
-
9
-
10
11
12
13
14
15
16
17
-
-
20
45
40
50
55
60
RuCl3/AgOTfc
AuCl3/AgOTfc
AuCl/AgOTfd
AuCl/AgOTf/PPh3
e
f
AgOTf/PPh3
a Reaction conditions: p-MeOC6H4OH (1 equiv), isoprene (1.5 equiv),
catalyst (5 mol %), solvent (0.1 M), room temperature, 24 h. b Determined
by 1H NMR using trichloroethylene as internal standard. c Performed with
5 mol % of RuCl3 or AuCl3 and 10 mol % of AgOTf. d Performed with 5
mol % of AuCl and 5 mol % of AgOTf. e Performed with 5 mol % of
AuCl, 5 mol % of AgOTf, and 5 mol % of PPh3. f Performed with 5 mol
% of AgOTf and 5 mol % of PPh3.
reported to either promote hydroarylation8 and hydroalkoxyla-
tion2b,7,16 or activate the alkenes2b,e were included in the screen
(Table 1). We were delighted to identify an exciting lead, which
unambiguously stood out in the array of experiments. We
discovered that 5 mol % of AgOTf was optimal in this reaction
system to produce dihydrobenzopyran 1 in 60% yield (Table
1, entry 1). Various solvents were examined, and ClCH2CH2Cl
appeared preferable. With the exception of AgSbF6, AgBF4, and
AgClO4, other silver salts were not effective (Table 1, entries
5-10). Cu(OTf)2 did not promote the reaction at all, whereas
scandium, ruthenium(III), gold(I), and gold(III) triflate salts
produced low to moderate conversions (Table 1, entries 11-
16). The reaction also occurred in the presence of phosphine
ligand; however, there was no increase in the yield of 1 (Table
1, entry 17).2b,c We suspected that trace amounts of TfOH, which
could be formed in situ via metathesis of Ag(I) with the OH
bond of p-methoxyphenol, might catalyze the coupling reaction.
However, Cu(OTf)2 was inactive and other triflate salts gave
lower conversions than AgOTf. In addition, a catalytic amount
of TfOH (5 mol %) did result in the production of 1, albeit
only in 18% yield. These results suggest that silver plays an
important role in this coupling process.
a Reaction conditions: ROH (1 equiv), isoprene (1.5 equiv), AgOTf (5
mol %), ClCH2CH2Cl (0.1 M), room temperature, 1-3 days, unless
otherwise noted. b Isolated yields. c Performed with 1 equiv of isoprene for
48 h.
TABLE 3. Ag(I)-Catalyzed Reaction of 2-Naphthol with Dienesa
With the establishment of a viable one-pot reaction system,
we set out to explore the scope of this coupling process. As
shown in Table 2, a variety of phenols underwent tandem
addition/cyclization in the presence of AgOTf to form the
corresponding dihydrobenzopyrans. Both electron-rich and
electron-deficient phenols were all successful in this reaction
(Table 2). In the case of phenol, the reaction using 1 equiv of
a Reaction conditions: 2-naphthol (1 equiv), diene (1.5 equiv), AgOTf
(5 mol %), ClCH2CH2Cl (0.1 M), 1-3 days. b Isolated yields. c Performed
at 40 °C. d The ratio of two isomers was determined by NMR. e Performed
at 80 °C.
isoprene gave a mixture of 3 and 4, with 3 as a major product,
whereas 4 was the only product for the reaction with 1.5 equiv
of isoprene (Table 2, entries 3 and 4).12b,e
(16) (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966-6967.
(b) Taylor, J. G.; Whittall, N.; Hii, K. K. Chem. Commun. 2005, 5103-
5105.
6706 J. Org. Chem., Vol. 71, No. 17, 2006

SCHEME 1. Possible Mechanism for the Ag(I)-Catalyzed
Reactions
Then recoordination of C-C π-bond by Ag(I) activates the
olefin toward intramolecular nucleophilic attack by the phenolic
oxygen. Subsequent proton transfer produces the final product
and regenerates the Ag(I) catalyst.17
In summary, we have developed mild and efficient Ag(I)-
catalyzed sequential C-C/C-O bond formations between
phenols and dienes. Both electron-rich and electron-deficient
phenols successfully underwent this reaction, and both cyclic
and acyclic dienes could be applied. The use of silver(I) is
economic relative to other expensive transition metals employed
previously to promote the reactions of phenols with dienes. This
one-pot reaction represents an attractive means for the facile
and atom economical construction of dihydrobenzopyran and
dihydrobenzofuran ring systems, which are important motifs in
both naturally occurring and biologically active compounds.
Experimental Section
General Procedure for the Ag(I)-Catalyzed Reaction of
Phenols and Dienes. To a solution of phenol and diene (1.5 equiv)
in ClCH2CH2Cl (0.1 M) was added AgOTf (5 mol %). The resulting
mixture was stirred at the reported temperature for 1-3 days. The
solvent was evaporated, and the residue was purified by column
chromatography on silica gel (EtOAc:n-hexanes ) 1:50-1:100)
to give the corresponding product.
Subsequently, the reaction was examined on a range of dienes
(Table 3). Good yields were obtained for all cases. With the
exception of 2,3-dimethyl-1,3-butadiene, all dienes gave the
corresponding dihydrobenzofurans as the sole products.13
Regioselectivity of the Ag(I)-catalyzed reaction presented
herein parallels the regioselectivities observed for Al-,12a,b Pd-
,
11,12c Pt-,12c and Au-catalyzed13 reactions of alcohols (or amines)
Acknowledgment. We are grateful to Pukyong National
with dienes, which suggests that C-C/C-O bond formation
occurs by a similar mechanism in those reactions. By analogy
with the mechanisms established for the related Al-,12b Au-,13
and Ag-catalyzed2b reactions of alcohols with CdC bonds, we
propose a plausible mechanism for Ag(I)-catalyzed sequential
addition/cyclization (Scheme 1). Activation of the diene by
coordination to Ag(I) is followed by intermolecular nucleophilic
attack by the arene. The reactions of 2-naphthol with 1-substituted-
1,3-diene substrates occur by either 1,2- or 1,4-addition, whereas
the reactions of phenols with isoprene and 2,3-dimethyl-1,3-
butadiene seem to take place by a 1,4-addition. The resulting
Ag-C bond is protonated to give the 2-allylphenol intermediate.
University for generous financial support.
Supporting Information Available: Experimental procedures
and spectral characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO061221B
(17) Another possible mechanism might involve the intermolecular attack
by the OH group first. Then either direct hydroarylation or Claisen
rearrangement followed by intramolecular cyclization could proceed.
However, it has been reported that AgOTf did not promote both the direct
hydroarylation (ref 8) and Claisen rearrangement/cyclization (ref 7a).
Moreover, the direct hydroarylation cannot give 10.
J. Org. Chem, Vol. 71, No. 17, 2006 6707