A highly adaptable catalyst/substrate system for the synthesis of substituted chromenes

Article abstract of DOI:10.1039/c0cc01961e

The gold(i)-catalyzed endo-cyclization of o-(1-hydroxyallyl)phenols to form chromenes is reported. The title compounds are prepared in high yield from readily available substrates. The system tolerates both electron rich and deficient aryl rings and a high degree of substitution on the allyl moiety.

Full text of DOI:10.1039/c0cc01961e

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A highly adaptable catalyst/substrate system for the synthesis
of substituted chromenesw
Aaron Aponick,* Berenger Biannic and Michael R. Jong
Received 18th June 2010, Accepted 29th July 2010
DOI: 10.1039/c0cc01961e
The gold(I)-catalyzed endo-cyclization of o-(1-hydroxyallyl)-
phenols to form chromenes is reported. The title compounds
are prepared in high yield from readily available substrates. The
system tolerates both electron rich and deficient aryl rings and a
high degree of substitution on the allyl moiety.
Scheme 1 Proposed Au(I)-catalyzed dehydrative endo-cyclization.
To test this hypothesis diol 5, which would give the parent
2H-chromene 6, was prepared and subjected to a variety of
conditions (Table 1). Employing the original exo-cyclization
conditions as a starting point (entry 1),15a with 5 mol% of both
Ph3PAuCl 7 and AgOTf 10 in CH2Cl2 at room temperature,
resulted only in decomposition products. Switching the catalyst
to the simple gold salts AuCl 8, AuCl3 9 (entries 2 and 3) or
employing a different phosphine in [(1,10-biphenyl-2-yl)di-tert-
butylphosphine]gold(I) chloride 12 (entry 4) also resulted in
extensive decomposition. Interestingly, when the solvent was
changed from CH2Cl2 to THF (entry 1 vs. 5) unreacted
substrate was recovered. This solvent effect seemed to indicate
that coordinating solvents may reduce the reactivity of the
catalyst and prevent the decomposition that was previously
observed. A screen of catalysts in THF, dioxane, and aceto-
nitrile (entries 5–10) revealed that the desired chromene could
Chromenes (2H-benzopyran derivatives) are an important
class of compounds found as a structural motif in many
significant molecules.1–3 Examples include natural products,1,3
biologically active pharmaceutical and medicinal agents such
as anti-HIV,4 anti-tumor,5 antibacterial/ antimicrobial,6,7
fungicidal,8 and insecticidal agents,9 health promoting
phytochemicals such as antioxidants,10 and polyphenols.11 In
addition to biological applications they have also been used as
photochromic materials.12 With this broad range of interesting
properties and applications, the development of synthetic
strategies for the formation of the 2H-benzopyran ring-system
has received significant attention. While classical methods2
continue to be utilized, the development of new methods is
ongoing13,14 and recent efforts have focused largely on metal-
catalyzed ring forming reactions such as hydroarylation.14
Despite these advances, there is still a demand for new
methods that can tolerate a broad range of substrates.
The existing strategies generally require specific substitution
patterns to provide the desired reactivity by imparting the
necessary electronic characteristics on the aromatic ring.
Herein we report a gold-catalyzed endo-cyclization of readily
available, salicylaldehyde derived diols that is tolerant of a
broad range of substrates with different substitution patterns
and electronic characteristics.
Table 1 Initial optimization studies
Recent studies from our laboratory and others have
demonstrated that both gold(I) and gold(III) complexes are
capable of catalyzing nucleophilic addition to unsaturated
alcohols.15 In our systems, monoallylic diols undergo intra-
molecular exo-cyclization reactions with Au(I)-catalysts that
are formally SN20 reactions.15a Although intermolecular reactions
have also been reported,15e,g,h dehydrative endo-cyclization
reactions of allylic diols have not yet appeared. Recognizing that
chromenes are cyclic allyl ethers, we envisioned that they may be
formed by a dehydrative Au(I)-catalyzed cyclization of phenols 2
(Scheme 1). This was appealing because if successful, the
substrates should be readily available by the addition of vinyl-
organometallic reagents 4 to salicylaldehyde derivatives 3.
Catalyst
Entrya system
Temperature
mol% Solvent (1C)
Yieldb
(%)
Time
1
2
3
7/10
8/10
9
5
2
2
5
5
5
5
5
5
5
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
22
22
22
22
22
65
82
65
22
30 min 0c
30 min 0c
15 min 0c
20 min 0c
4
5
6
12/10
7/10
11
16 h
4 h
16 h
5 h
16 h
1 h
16 h
0d
0c
42
82
0d
55
0d
THF
7
8
9
10
11
12
12/10
12/10
12/10
12/10
10
CH3CN
THF
THF
Dioxane 100
THF
THF
65
65
TfOH
10 min 0c
University of Florida, Department of Chemistry, P.O. Box 117200,
Gainesville, FL, USA. E-mail: aponick@chem.ufl.edu;
Fax: +1 352 846 0296; Tel: +1 352 392 3484
w Electronic supplementary information (ESI) available: Full
experimental procedures and spectra for new compounds. See DOI:
10.1039/c0cc01961e
a
The reactions were carried out on a 0.5 mmol scale at 0.2 M in
b
substrate with the indicated solvent, temperature, and time. Isolated
c
d
yield. Only extensive decomposition was observed. No reaction
was observed.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6849–6851 6849

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indeed be formed. Gratifyingly, when 5 mol% of the catalyst
system generated from 12 and 10 in THF was allowed to react
with 5 under reflux conditions for 5 h, 6 was formed in
82% yield (entry 8). Control experiments also demonstrated
that the Au-complex was responsible for the catalysis
(entries 11 and 12). Several additional Lewis acids such as
BF3ꢀOEt2, Zn(OTf)2, InBr3, Yb(OTf)3, FeCl3, and Pd(OAc)2
were also screened, but in all cases only traces of product were
observed accompanied by extensive decomposition.16
Table 2 Reaction scope
Entrya
Substrate
Product
Time/h
Yieldb (%)
With these optimized conditions we set out to test the
reaction’s substrate scope (Table 2). Of particular importance
was the electronic nature of the aryl ring in 2. By design, all
substrates contain a phenolic hydroxyl group ortho to the
allylic alcohol. This electron donating group may be important
for the reaction vide infra, but at the outset it was unclear if
more electron rich or deficient aromatics would be better
substrates. As such, we began by first varying the electronics
of the group para to the nucleophilic hydroxyl group. The
reaction proceeded in a similar fashion when the p-hydrogen
was replaced with a methoxy group (Table 2, entry 1), but the
yield was somewhat increased and the reaction time shortened
with p-nitro (entry 2). This reaction appeared to be smoother
and in fact the product could be isolated after a prolonged
reaction time (48 h) at room temperature (entry 3). This is in
contrast to the parent compound that only provided recovered
starting material without heating (Table 1, entry 9). Additional
substrates showed the same trend and demonstrated that
highly substituted phenols (entries 4 and 5) and naphthols
(entries 6 and 7) function well in the reaction. Interestingly,
while electron donating groups para to the nucleophilic hydroxyl
group do slow the reaction, acceptable yields are obtained.
Inclusion of the dioxolane moiety however changes the mode
of reactivity and only decomposition products are observed
after 1 h (entry 8).
1
20
74
2
3
5
48
91
79c
4
5
0.3
75
72
20
2
6
7
8
80
0.5
73d
1
2
0e
Substitution on the pyran ring is typically observed in
chromene natural products. In our system, this should easily be
introduced by the addition of a substituted vinylorganometallic
reagent or by using a hydroxyacetophenone instead of a salicyl-
aldehyde. As is observed in Table 2, entries 7 and 9 demonstrate
that cyclizations of this type are possible. To further explore this
and to be able to make comparisons on reactivity that are
directly attributed to the position of the substitution, we set
out to make a series of compounds where only the position of the
substituent is varied (Fig. 1). Using 5-chlorosalicylaldehyde,
50-chloro-20-hydroxyacetophenone and various Grignard
reagents, the necessary substrates were easily prepared. The
parent chromene 29, lacking methyl substitution, was first
prepared as a control experiment and was obtained in 84% yield
after 6 h under the standard reaction conditions (Fig. 1).
Inclusion of the methyl group at C2 showed little effect and
provided 30 in 84% yield after 6 h. Surprisingly, the 3-methyl-
chromene 31 was only produced in trace amounts, even after 48 h,
with the majority of the starting diol being recovered.
Substitution in this position likely reduces the rate of the
reaction because alkoxymetalation would form a 31 alkylgold
intermediate. Finally, the 4-methylchromene 32 was obtained in
similar yield to 29 and 30, but with a reduced reaction time.
Mechanistically, we envision that the catalyst may function in
two possible ways. The Au-complex may serve as a p-acid and
9
53
a
The reactions were carried out on a 0.5 mmol scale at 0.2 M in
b
substrate with the indicated solvent, temperature, and time. Isolated
c
d
yield. 48 h at ambient temperature. Isolated yield over two steps:
prenyl Grignard addition and subsequent Au-catalyzed cyclization,
e
without purification of 23. Only decomposition was observed.
activate the alkene, which is the role typically invoked,17 or act
as a more traditional Lewis acid and ionize the alcohol.18
To gain a better understanding of the electronic effects of
substituents directly conjugated to what may be a cationic
center, a series of para-substituted substrates were prepared
and tested. As can be clearly seen from Fig. 2, electron donating
Fig. 1 Substituent effects on the allyl moiety.
c
6850 Chem. Commun., 2010, 46, 6849–6851
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3 For reviews on applications see: B. W. Fravel and N. A. Nedolya,
in Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky,
C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier Ltd,
Oxford, 2008, vol. 7, pp. 701–726 and previous editions of this
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K. Mizuki, L. M. Cosentino, K. Fowke, S. L. Morris-Natschke
and K.-H. Lee, Tetrahedron, 2001, 57, 1559.
Fig. 2 Electronic effects.
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and M. J. Kato, J. Nat. Prod., 2004, 67, 1783.
9 C. B. Bernard, H. G. Krishnamurty, D. Chauret, T. Durst, B. J. R.
Philogene, P. Sanchez-Vindas, C. Hasbun, L. Poveda, L. San
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Scheme 2 Control experiments with transposed allylic alcohols.
groups accelerate the reaction and provide the products in
higher yields with shorter reaction times (p-OMe, 98% yield in
10 min versus p-NO2, 33% yield, 24 h).
To further probe this issue 38 and 39 (Scheme 2), with the
allylic alcohol transposed from the typical position, were
prepared and treated under the reaction conditions. If the
mechanism is cationic, these substrates would be predicted to
ionize and cyclize to form the corresponding chromenes.19
Surprisingly, no reaction was observed. One possible explanation
is that the role of the catalyst may change depending on the
structure of the substrate. The catalyst may function as a
Lewis acid when ionization is facile and as a p-acid when the
substrate is not readily ionized. Although the mechanistic
details remain unclear, the Au(I)-catalyst system has proven
to be unique in this system and functions well on diverse
substrates. Further experiments are being conducted to
elucidate the role of the catalyst.
13 For select examples see: (a) M. C. Brohmer, N. Volz and S. Brase,
¨
¨
Synlett, 2009, 1383; (b) F. Liu, T. Evans and B. C. Das,
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(f) S. Chang and R. H. Grubbs, J. Org. Chem., 1998, 63, 864 and
references cited therein.
14 For leading references on Au-catalyzed hydroarylation to form
chromenes see: (a) R. S. Menon, A. D. Findlay, A. C. Bissember
and M. G. Banwell, J. Org. Chem., 2009, 74, 8901;
(b) T. Watanabe, S. Oishi, N. Fujii and H. Ohno, Org. Lett.,
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In summary, an efficient method for the formation of
2H-chromenes has been developed. The title compounds are
readily prepared in two steps with high yield starting from
salicylaldehydes. The substrate scope is broad and provides a
diverse range of products with different substitution patterns
and electronic nature in the aromatic ring. Studies to further
elucidate the reaction mechanism are underway and will be
reported in due course.
We thank the Herman Frasch Foundation (647-HF07), the
donors of the Petroleum Research Fund (47539-G1), and the
James and Ester King Biomedical Research Program
(09KN-01) for their generous support of our programs. We
thank Petra Research, Inc. for an unrestricted research award.
Notes and references
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J. S. Gibson and J. Sperry, in Comprehensive Heterocyclic
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Scriven and R. J. K. Taylor, Elsevier Ltd, Oxford, 2008, vol. 7,
pp. 419–699 and previous editions of this series.
16 As suggested by a reviewer, the reaction was also run with the
conditions in Table 1, entry 8 and in the presence of 1 equivalent of
p-nitrophenol. After 20 h, only 50% conversion was achieved and 6
was isolated in 32% yield.
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18 A. S. K. Hashmi, Catal. Today, 2007, 122, 211.
19 (a) J. J. Talley, Synthesis, 1983, 845; (b) S. B. Ferreira, F. de C. da Silva,
A. C. Pinto, D. T. G. Gonzaga and V. F. Ferreira, J. Heterocycl.
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c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6849–6851 6851