Catalytic, Cascade Ring-Opening Benzannulations of 2,3-Dihydrofuran O,O- and N,O-Acetals

Article abstract of DOI:10.1002/chem.201601954

An Al(OTf)₃-catalyzed intramolecular cascade ring-opening benzannulation of 2,3-dihydrofuran O,O- and N,O-acetals is described. The cascade sequence involves the dihydrofuran ring-opening by acetal hydrolysis, an intramolecular Prins-type cyclization, and aromatization to generate an array of benzo-fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions. The approach provides excellent regiocontrol based on the choice of alkenes used to form the requisite dihydrofuran acetals.

Full text of DOI:10.1002/chem.201601954

DOI: 10.1002/chem.201601954
Communication
&
Organic Synthesis
Catalytic, Cascade Ring-Opening Benzannulations of 2,3-
Dihydrofuran O,O- and N,O-Acetals
[b]
[b]
[b]
[b]
Joel Aponte-Guzmꢀn, Lien H. Phun, Marchello A. Cavitt, J. Evans Taylor, Jr.,
[b]
[a, b]
Jack C. Davy, and Stefan France*
[3]
molecules is benzannulation, which involves appending
a benzene directly onto a pre-existing ring. Benzannulation is
preferable due to the likely reduction of reaction steps and
better control of regiochemical outcomes. The vast majority of
Abstract: An Al(OTf) -catalyzed intramolecular cascade
3
ring-opening benzannulation of 2,3-dihydrofuran O,O- and
N,O-acetals is described. The cascade sequence involves
the dihydrofuran ring-opening by acetal hydrolysis, an
intramolecular Prins-type cyclization, and aromatization to
generate an array of benzo-fused (hetero)aromatic sys-
tems in up to 95% yield. This method represents the first
example of dihydrofuran acetal usage in benzannulation
reactions. The approach provides excellent regiocontrol
based on the choice of alkenes used to form the requisite
dihydrofuran acetals.
[4]
[5]
benzannulation approaches involve [4+2],
[2+2+2],
[6]
[7]
[8]
[
3+3], and [6+4] cycloadditions, ring-closing metatheses,
[9]
Danheiser annulations, transition-metal-promoted process-
[10]
[11]
es,
and base-induced rearrangements.
Many of these
methods have serious limitations that reduce their scope and
applications, including: 1) the requirement of an additional oxi-
dation step (usually 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
DDQ) to form the final aromatic ring; 2) the use of highly func-
tionalized precursors that are challenging or not straightfor-
ward to access; and 3) the employment of highly air- or mois-
ture-sensitive precursors. Therefore, methods involving readily-
accessible, stable precursors that directly convert to the de-
sired benzo-fused products remain an important synthetic
endeavor.
Benzo-fused polycycles are important frameworks with broad
applications in natural products synthesis, medicinal chemistry,
[
1]
chemical biology, and materials science (Figure 1). The classi-
cal synthetic approach to access these systems involves func-
[2]
tional group manipulation of preformed aromatic derivatives.
Dihydrofuran (DHF) O,O-acetals have received particular
attention from the synthetic community in recent years. This
interest is attributed in part to the identification of bioactive
natural products containing 5,5- and 5,6-fused bicyclic DHF
However, the aromatic products formed display limited substi-
tution patterns. A more efficient strategy to construct these
[
12,13]
O,O-acetals.
DHF acetals are readily prepared in good
[14]
yields by Rh(II)-catalyzed reactions
of a-diazo b-ketoesters
III
[15]
with enol ethers, or Mn -mediated reactions of b-ketoesters
[
16]
with enol ethers. DHF acetals undergo two primary types of
reactions as described in the literature. First, they serve as pre-
cursors for furans following acid-promoted alcohol elimina-
[17]
tion.
Second, acid-promoted acetal hydrolysis results in
either the substitution of the exocyclic alkoxy group (in the
presence of a nucleophile) or DHF ring-opening leading to
a putative enol(ate)-oxonium intermediate (Scheme 1). Based
on this intermediate, 2,3-dihydrofuran acetals have been
Figure 1. Representative naturally-occurring benzo-fused (hetero)aromatics.
[a] Prof. Dr. S. France
Petit Institute for Bioengineering and Bioscience
Georgia Institute of Technology
Atlanta, Georgia 30332 (USA)
E-mail: stefan.france@chemistry.gatech.edu
[b] J. Aponte-Guzmꢀn, Dr. L. H. Phun, M. A. Cavitt, J. E. Taylor, Jr., J. C. Davy,
Prof. Dr. S. France
School of Chemistry and Biochemistry
Georgia Institute of Technology
Atlanta, Georgia 30332 (USA)
Supporting information with comprehensive experimental details and the
ORCID identification number(s) for the author(s) of this article can be found
under http://dx.doi.org/10.1002/chem.201601954.
Scheme 1. General ring-opening reactivity of 2,3-dihydrofuran (DHF) acetals.
Chem. Eur. J. 2016, 22, 1 – 6
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employed as a means to access 1,4-dicarbonyl compounds
Table 1. Optimization of the cascade reaction with 4a.
[
17b,18]
(Scheme 1path a),
2-cyclopentenones (following base-
promoted intramolecular aldol condensations of the resulting
[
18]
1
,4-dicarbonyls),
or cationic ring-opening polymerizations
[
19]
(
Scheme 1path b). Beyond these examples, the use of DHF
[
a]
[b]
Entry
Lewis acid
In(OTf)3
Solvent
CH Cl
T [8C]
t [h]
Yield [%]
acetals as a means to access benzo-fused (hetero)aromatic
compounds (Scheme 1path c) has not been reported.
1
2
3
4
5
6
2
2
2
2
2
2
2
2
23
23
23
40
111
85
45.0
9.5
45.0
6.5
1.0
1.0
5
16
19
35
40
46
Herein, we disclose an Al(OTf) -catalyzed cascade ring-open-
Ga(OTf)
3
CH
CH
CH
Cl
Cl
Cl
3
Al(OTf)
Al(OTf)
Al(OTf)
3
ing benzannulation of 5-(hetero)aryl-2,3-dihydrofuran O,O- and
N,O-acetals 4 (Scheme 2). The proposed cascade reaction in-
volves an initial Lewis acid promoted DHF ring-opening. Upon
ring-opening, the resulting alkoxonium (or iminium) intermedi-
ate I undergoes enolate isomerization to form the Lewis acid–
3
3
toluene
toluene
Al(OTf)3
[
a] Reaction conditions: Lewis acid (5 mol%), 4c, and solvent (0.2m) at
the indicated temperature. [b] Isolated yield of 5c after column chroma-
tography.
[23]
enolate chelate complex II. Next, a Prins-type cyclization
occurs to form the intermediate III, which readily aromatizes
1
4
by elimination of R XH (X = O or NR ) to form the benzo-
fused product.
certain Lewis acids (prone to ring-opening), we anticipated
that successful optimization of the reaction of this substrate
would bode well for a broader exploration of the substrate
scope (Table 1). In contrast to the example with 4a, In(OTf)3
proved to be ineffective for the transformation of the furan 4c,
because mostly degradation was observed and an isolated
yield of the desired benzofuran 5c of only 5% was obtained
(
Table 1, entry 1). Degradation or poor conversions were also
observed with other Lewis acids, such as Sc(OTf) , Cu(OTf)
3
2,
[24]
and Yb(OTf) (Table S1 in the Supporting Information). Great-
3
er amounts of 5c were obtained with Ga(OTf) and Al(OTf)
3
3
(
Table 1, entries 2 and 3). Performing the reaction at reflux with
Al(OTf) afforded 5c in 35% yield (Table 1, entry 4). Changing
3
the solvent to toluene and performing the reaction again at
reflux gave a 40% yield (Table 1, entry 5). Reducing the temp-
erature to 858C was found to increase the yield to 46%
Scheme 2. Cascade ring-opening Prins-type benzannulations of 2,3-DHF
O,O- and N,O-acetals (X = O or NR ).
4
(
Table 1, entry 6). All other attempts to further optimize the re-
Based on a previous study, we observed that a mixture of
action (e.g., changing temperature, catalyst loading, concentra-
[24]
the benzothiophenes 5a and 5b were generated when the
tion, etc.) failed to provide improved yields. Therefore, the
conditions used for the examination of the reaction scope
2
-thienyl DHF O,O-acetal 4a was treated with catalytic
[
21]
[22]
amounts of In(OTf)3 (Scheme 3).
This transformation
were 5 mol% Al(OTf) in toluene at 858C.
3
equates to a formal Lewis acid catalyzed cascade benzannula-
tion, a benzannulation class that has been underexplored.
Given our established interest in the synthesis of benzo-fused
With the optimized conditions, the cascade reactions with
other (hetero)aryl dihydrofuran derivatives were evaluated
(Scheme 4). The 2-thienyl dihydrofuran 4b was readily convert-
ed to the benzothiophene 5b in 61% yield. The 3-furyl deriva-
tive 4d provided the corresponding benzofuran 5d in 75%
yield, which is notable given that 5d can be readily converted
[
23]
compounds and encouraged by this initial result, we sought
to explore the ring-opening benzannulation reactions of DHF
acetals as a potentially general approach to functionalized
benzo-fused (hetero)aromatics.
Scheme 3. Conversion of the 2-thienyl DHF acetal 4a to benzothiophene 5a
(esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionic acid).
In order to optimize the cascade transformation, we chose
to utilize the dihydrofuran acetal 4c as a model system. Due
to the relative instability of the furan unit in the presence of
Scheme 4. Al(OTf)
3
-catalyzed cascade reactions of DHF acetals 4.
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in two steps to a range of naturally-occurring furanoflavonoids,
Table 2. Cascade reactions of tetra-substituted 2,3-DHF acetals.
[25,26]
including pongol methyl ether and millettocalyxins C.
A
[
a]
[b]
similar conversion of the 3-thienyl derivative 4d to the benzo-
thiophene 5e was observed in 81% yield. As anticipated, the
benzofuryl dihydrofuran 4 f generated the dibenzo[b,d]furan
Entry
4
5
t [h]
Yield [%]
1
2.0
80
69
5
f in 83% yield. The 2-naphthyl substrate 4g afforded the
phenanthrene derivative 5g in 60% yield as the only regioiso-
mer, whereas the 3-methoxyphenyl dihydrofuran 4h gave
a 8:1 mixture of the naphthalene 5h and its regioisomer 5h’
in 81% yield. A high yield (93%) was afforded for the cas-
cade reaction of the 3,5-dimethoxy dihydrofuran 4i to give the
naphthalene 5i.
Next, the nature of the acetal group was changed to evalu-
ate its effect on the reaction efficiency (yield and time). The re-
sults were compared to the DHF acetal 4i (Scheme 5). Dihydro-
2
3
4.0
7.5
[
24]
88
79
86
85
90
4
5
7.0
0.67
[
c]
c]
6
7
7.5
5.0
[
Scheme 5. Probing of the acetal-substituent effect.
[
c]
8
19.0
17
furan O,O- and N,O-acetals 4j–m were prepared and subjected
to the optimized cascade conditions. When 4j (containing
a tert-butoxy group) was used, 5i was obtained in 88% yield.
The siloxy derivative 4k afforded smooth conversion to 5i in
[
a] Reaction conditions: Al(OTf)
with water (1 drop), 708C. [b] Isolated yield after column chromatography.
c] Performed using Al(OTf) (5 mol%) at 858C (no added water).
3
(20 mol%), 4 (1 equiv) in toluene (0.2m)
[
3
80% yield. The methyl acetamido DHF 4l provided 5l with
a yield (95%) comparable to 4i, but with a longer reaction
(entry 2). Similarly with 4p and 4q, the 3-ethyl and 3-phenyl
naphthalenes 5p and 5q were formed in 88% and 79% yield,
respectively. In comparison, the 2,2-gem-disubstituted acetal
4r afforded the 4-methyl naphthalene 5r in 86% yield. These
examples demonstrate the general strength of the method for
the strategic synthesis of regioisomeric benzo-fused systems.
Since the acetal serves as the directing group for ring-opening,
the placement of the substituent presumably determines the
regiochemistry. Therefore, the selection of the alkene for the
DHF synthesis becomes an important reaction-design compo-
nent, since it could dictate the cascade product regiochemistry.
To our knowledge, this level of regiocontrol is unprecedented
for Lewis acid promoted benzannulations.
[
27]
time (24 h vs. 1 h, respectively). Finally, the pyrrolidin-2-one
m gave a modest 51% yield of 5l with a similarly long reac-
4
tion time (21 h). It is likely that additional coordination of the
amide carbonyl to the Lewis acid is responsible for the elon-
gated reaction time. Taken together, the ethyl derivative 4i
proved to be the most efficient derivative.
To examine the reaction scope, tetra-substituted DHF acetals
were synthesized and explored. When the 2-methoxy-2-
methyl-5-thienyl DHF 4n was subjected to the optimized con-
ditions, none of the expected 7-methyl benzothiophene 5n
was observed and a furan derivative was formed instead
[
24]
(
Table S2). Interestingly, when the temperature was reduced
to 708C and a drop of water was added to the reaction mix-
ture, a 1:1.18 crude mixture of 5n/furan was observed. After
For the fused bicyclic DHF acetals (4s–u), the original reac-
tion conditions [5 mol% Al(OTf) , 858C] gave better yields of
3
some optimization, it was found that 20 mol% Al(OTf) in tolu-
the expected products. The 3a,5,6,7a-tetrahydro-4H-furo[2,3-
b]pyran 4s gave a 85% yield of the naphthalene 5s, which
contains a pendant hydroxypropyl unit that can serve as
a point for further functionalizations (Table 2, entry 6). In con-
trast, lactonization was observed for the 2,3,3a,6a-tetrahydro-
furo[2,3-b]furan 4t as the tricyclic naphthopyranone 5t was
generated in 90% yield (entry 7). This result is particularly
3
ene with a drop of water at 708C provided 5n in 80% yield
(Table 2, entry 1). It is plausible that water may be promoting
the formation of a dihydrofuran hemiacetal intermediate that
facilitates ring-opening over the furan formation. Under these
new conditions, the 3-ethyl-2-methoxy-5-thienyl DHF 4o gave
the expected 6-ethyl benzothiophene 5o in 69% yield
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Communication
interesting as naphthopyranones have received tremendous
attention from medicinal chemists due to the existence of
a large number of naturally occurring, bioactive, and thera-
Acknowledgements
S.F. gratefully acknowledges financial support from the Nation-
al Science Foundation (NSF) (>CAREER Award CHE-1056687).
L.H.P. thanks Georgia Tech CD4 for a GAANN fellowship. J.A.-G.
thanks the NSF (DGE-1148903), and Georgia Tech for generous
support. M.A.C. thanks the Ford Foundation, NSF (DGE-
[
28]
peutically relevant derivatives.
The 6-Boc-3a,5,6,6a-tetrahy-
dro-4H-furo[2,3-b]pyrrole 4u (a bicyclic N,O-acetal) provided
only 17% yield (52%, BSRM) of naphthalene 5u (entry 9). The
low yield can be attributed to catalyst deactivation by coordi-
nation with the pendant carbamate group. Increasing the cata-
lyst loading or the temperature did not improve the product
1148903), and Georgia Tech for generous support.
[
24]
yield. Finally, attempts to access the expected benzannula-
ted products from penta-substituted DHF acetals failed and
Keywords: benzannulation · domino reactions · fused-ring
systems · heterocycles · ring-opening cyclizations
[
24]
only furan formation was observed.
Based on our ongoing interest in the synthesis of indole-
[
29]
containing compounds, a series of DHF acetals, substituted
at the 5-position with the nitrogen of an indole (or pyrrole),
was prepared and subjected to the initial reaction conditions
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3
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6
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afforded the 7,8-dihydroindolizin-5(6H)-one 6y in 54% yield.
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[
[
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15040.
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[
[
2) improving the product yields of the fused bicyclic N,O-
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substituted DHF acetals.
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III
[
[
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[
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slightly higher yields for the DHF N,O-acetals.
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6
1
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1
2
[
Received: April 26, 2016
4
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
5
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Synthesis
J. Aponte-Guzmꢀn, L. H. Phun,
M. A. Cavitt, J. E. Taylor, Jr., J. C. Davy,
S. France*
&& – &&
An intramolecular cascade ring-opening
benzannulation of 2,3-dihydrofuran
benzofurans. When the DHF acetal is
substituted at the 5-position with 1-pyr-
roles or 1-indoles, the ring-opening cyc-
lization occurs without aromatization to
afford tetrahydroindolizines or hydro-
pyrido[1,2-a]indoles, respectively.
Catalytic, Cascade Ring-Opening
Benzannulations of 2,3-Dihydrofuran
O,O- and N,O-Acetals
(DHF) acetals is disclosed, which gener-
ates highly functionalized benzannula-
tion products, including naphthalenes,
benzofurans, benzothiophenes, and di-
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!