Base-catalyzed cascade 1,3-H shift/cyclization reaction to construct polyaromatic furans

Article abstract of DOI:10.1002/adsc.201000833

A convenient new method was developed to prepare unfused polyaromatic furan derivatives from diynyl-1,6-diols through a novel base-catalyzed cascade 1,3-H shift/cyclization process. Deuterium experiments were performed to determine that the 1,3-H shift was the rate-determining step. Copyright

Full text of DOI:10.1002/adsc.201000833

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DOI: 10.1002/adsc.201000833
Base-Catalyzed Cascade 1,3-H Shift/Cyclization Reaction to
Construct Polyaromatic Furans
Ya-Hui Wang,a Heng Liu,a Li-Li Zhu,a Xiao-Xiao Li,a and Zili Chena,b,*
a
Department of Chemistry, Renmin University of China, Beijing 100872, Peopleꢀs Republic of China
Fax : (+86)-10-6251-6660; phone: (+86)-10-6251-6660; e-mail: zilichen@ruc.edu.cn
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
b
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, Peopleꢀs Republic of China
Received: November 8, 2010; Published online: March 15, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000833.
Abstract: A convenient new method was developed
to prepare unfused polyaromatic furan derivatives
from diynyl-1,6-diols through a novel base-cata-
lyzed cascade 1,3-H shift/cyclization process. Deute-
rium experiments were performed to determine
that the 1,3-H shift was the rate-determining step.
tedious preparation of the dienyl diketone substrates
and the poor regioselectivities. In this communication,
we want to report an efficient new method to con-
struct unfused polyaromatic furan derivatives from
diynyl-1,6-diols through a novel base-catalyzed cas-
cade 1,3-H shift/Michael addition process, in which
the regioselectivity was determined by the electro-
Keywords: cyclization reaction; diynyl-1,6-diols;
furans; 1,3-H shift
ACHTUNGTRENnNGNU egativity difference of the substituents attached to
the aryl groups.
As shown in Table 1, compound 1a was chosen as
the model system for our initial investigation. When
1a was treated with NaH (1.2 equiv.) in THF (2 mL),
The chemistry of propargylic alcohols has been the
object of many studies, but their dimeric analogues,
diynyl-1,6-diol derivatives have so far received consid-
erably less attention. This subunit can be simply pre-
pared from the terminal propargylic alcohols through
a coupling reaction. It has even been utilized to syn-
thesize the highly reactive hexapentaenes,[1] and the
compounds have been employed as the host mole-
cules in asymmetric solid syntheses.[2] Despite these
applications, examples of the use of this subunit in or-
ganic synthesis are very scarce.
Among the various classes of heterocyclic com-
pounds, furan ring systems form an important compo-
nent of pharmacologically active compounds, as they
are associated with a wide spectrum of biological ac-
tivities ranging from antifungal,[3] antitrypanosomal[4]
and gastrointestinal motility activity[5] to farnesyl
transferase[6] and phosphodiesterase inhibitory activi-
ty.[7] Because of the importance of this five-membered
structural entity, the development of new strategies to
construct furan derivatives has attracted much syn-
thetic effort,[8] and is always of great interest.
Table 1. Investigation of the reaction of compound 1a with
different catalysts.[a]
Base (equiv.)
NaH (1.2)
Solvent
THF
T [oC]/Time Yield [%][b]
1
2
3
4
5
6
7
8
9
r.t./1 h
65
30
78
40
NR
56
NR
41
40
10
60
72
83
65
CH3ONa (1.2) THF
r.t./1 h
t-BuOK (1.2)
NaOH (1.2)
NEt3 (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
THF
THF
THF
THF
r.t./10 min
r.t./10 min
reflux/1 h
r.t./7 h
CH3OH r.t./1.5 h
toluene
DCE
CH3CN
THF
THF
THF
r.t./1.5 h
r.t./1.5 h
r.t./1.5 h
60/1 h
10 DBU (1.2)
11 DBU (1.2)
12 DBU (0.5)
13 DBU (0.2)
14 DBU (0.1)
60/1 h
60/4 h
THF
60/5 h
In 1995, Ongꢀs group reported the synthesis of un-
fused arylfurans from 1,6-dioxo-(E,E)-dienes via an
acid- or base-catalyzed cyclization process.[9] How-
[a]
Unless otherwise noted, all reactions were carried out on
a 0.2 mmol scale in 2 mL solvent.
Isolated yields.
[b]
ACHTUNGTRENNUNGever, the utility of this preparation was limited by the
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Ya-Hui Wang et al.
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Table 2. DBU-promoted the reaction of the symmetric diynyl diesters to construct
polysubstituted furans.[a]
[a]
Unless noted, all reactions were carried out at 0.2 mmol scale in 2 mL solvent
at 608C with 20% mol equiv. of DBU.
Isolated yields.
[b]
the furanyl ketone 2a was obtained in 65% yield conditions. Further optimization of the reaction tem-
(Table 1, entry 1). perature and the amount of DBU amount then identi-
Various bases were then screened to improve the fied a set of best conditions to give the desired furan
reaction yield. Other non-amine bases, such as product in 83% yield (Table 1, entry 13).
CH3ONa, t-BuOK and NaOH can also trigger this re-
Under the conditions from entry 13 in Table 1, the
action, among which t-BuOK gave the highest reac- scope and limitations for this reaction were explored.
tion yield (Table 1, entry 3).[10] Several tertiary amine As shown in Table 2, a number of polysubstituted 2-
bases were then tested, among which, Et3N and 1,4- furanyl ketone products 2a–m were synthesized from
diazabicycloACHTUNGTRENNUNG[2.2.2]octane were not effective in this re- the symmetrical diynyl-1,6-diol derivatives 1a–m. The
action even at elevated temperature. When the strong effect of different substitution patterns on the reac-
base DBU (1.2 equiv.) was used as the catalyst, furan- tion yield was investigated. Both electron-rich and
yl ketone 2a was obtained in 56% yield (Table 1, electron-poor substrates worked very well, affording
entry 6). Solvent screening showed that THF was the the desired products in moderate to good yields. The
best reaction medium in combination with the DBU reaction of electron-rich substrates took longer reac-
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Base-Catalyzed Cascade 1,3-H Shift/Cyclization Reaction to Construct Polyaromatic Furans
Table 3. DBU promoted the reaction of the asymmetric diynyl diesters to construct polysubsti-
tuted furans.[a]
[a]
Unless noted, all reactions were carried out at 0.2 mmol scale in 2 mL solvent at 608C with
20% mol equiv. of DBU.
Isolated yields.
The ratio of the regioisomers was determined from H NMR spectral data.
The reaction was carried out at 308C.
[b]
[c]
[d]
1
tion times, and gave higher conversions; whereby 2b
We then turned to investigate the reaction of un-
was obtained in the highest yield (Table 2, entry 2). symmetrical dialkynyl-1,6-diols. When 1-(4-methoxy-
The effects of o-, m-, p-substitution patterns on the phenyl)-6-phenylhexa-2,4-diyne-1,6-diol 1n was treat-
reaction yield were examined (Table 2, entries 3, 8, ed with 20% mol equiv. of DBU in THF at room tem-
10). It was found that the reactivity of p-methyl-sub- perature, only product 2n was obtained in 66% yield
stituted substrate 1c was similar to that of its meta an- (Table 3, entry 1). No other regioisomer was separat-
alogue 1h, while the reaction yield of the o-substitut- ed in this reaction. Similarly, the reaction of 1o and
ed substrate 1j was very low. The heteroaromatic sub- 1p gave the corresponding products 2o and 2p in 65%
stituted diynyl-1,6-diol derivatives were also tested, and 67% yields, without the formation of any re-
among which 1k and 1m afforded the desired prod- gioisomers. However, when compound 1q was treated
ucts 2k and 2m in good yields.
with 20% mol equiv. of DBU, a mixture of 2q and 2q’
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Ya-Hui Wang et al.
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the C-2 position. This means that the 1,3-shift step
primarily proceeded through a contact ion pair pro-
cess.[12,13] Subsequent kinetic isotopic effect (KIE) ex-
periments were carried out by competition experi-
ments [Eq. (2), Scheme 2]. When a mixture of 1a and
D-1a (1a/D-1a=1/1) was treated with 20% mol equiv.
of DBU in THF at 608C for 30 min, the desired furan
product was obtained in 20% yield, in which 18%
deuterium atom was incorporated into the C-3 posi-
Scheme 1. Investigation of the reaction of substrates 3a and
3b.
was obtained 53% yield (2q/2q’=10/1, Table 3, tion. The calculated kH/kD value is about 4.36. This
À
entry 4). As compared with substrates 1n–p, the elec- significant isotopic effect indicated that C H bond
tronegativity difference between the two end groups cleavage is the rate-determining step of this transfor-
in substrate 1q was relatively small. For the same mation.
reason, the reaction of 1s gave a mixture of 2s and 2s’
To elucidate the regioselectivity of this reaction,
enyne ketone 5 was prepared and treated with 20%
in 71% yield (2s/2s’=4/1, Table 3, entry 5).[11]
The reactions of substrates 3a and 3b were then in- mol equiv. of DBU (Scheme 3). Product 2nꢀs regioiso-
vestigated, in which the phenyl group at one end was mer 6 was obtained in 87% yield, without the forma-
replaced either by a benzyl group or by a hydrogen tion of 2n. As compared with product 2n obtained in
atom (Scheme 1). To our surprise, no desired furan the reaction of 1n, the furan ring in 6 was located
products were obtained in these reactions. Substrate near to the electron-rich p-methoxyphenyl group. The
3a afforded enyne ketone 4a in moderate yield, while monoester 6-hydroxy-1, 6-diphenylhexa-2,4-diynyl
the reaction of 3b gave only 4b in 27% yield. This acetate 7 was also tested in this reaction; it was found
result indicated that the isomerization reaction of the that furan alkyne 8 was obtained in 17% yield
dialkynyl diols might start from a 1,3-H shift, which (Scheme 4).[14]
was facilitated by the presence of the conjugated aro-
A
plausible mechanism was then proposed
matic group. Breakage of the conjugated system by (Scheme 5). The first 1,3-H shift of the unsymmetrical
the sterically neighboring methyl group in substrate 1j dialkynyl 1,6-diol substrate 1 is favored to occur at
led to a low reaction yield.
the hydroxy carbon attached to the electron-poor
Deuteration experiments were performed to probe phenyl group, which afforded an alkynyl vinyl ketone
the reaction mechanism. As shown in Scheme 2, D-1a intermediate A.[15] Michael addition of the amine
underwent isomerization in THF to give D-2a in 74% onto intermediate A gave zwitterion C, in which the
yield, in which 88% deuterium atom was incorporated enolate unit or DBU triggered the second 1,3-shift to
into the C-3 position, with less than 6% deuterium in give intermediate D. Intramolecular Michael addition
and the following elimination then provided the de-
sired furanyl ketone 2. The regioselectivity was deter-
mined by the difference of the electronegativity be-
tween the two phenyl groups in the unsymmetrical di-
alkynyl-1,6-diol substrate 1. A small electronegativity
difference would lead to the formation of the inter-
mediate regioisomer B, and would lower the regiose-
Scheme 2. DBU-promoted reaction of D-1a and the compe-
tition experiments.
Scheme 4. DBU-induced reaction of the monoester 7 to give
furan alkyne 8.
Scheme 3. DBU-promoted reaction of compound 5 to give the regiosiomer 6 of 2n.
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Base-Catalyzed Cascade 1,3-H Shift/Cyclization Reaction to Construct Polyaromatic Furans
Scheme 5. A possible mechanism for the base-catalyzed cascade 1,3-H shift/cyclization reaction of diynyl diesters to provide
polyaromatic furans.
lectivity. Formation of the dialkenyl diketone F was Acknowledgements
unlikely because no regioisomer was obtained in the
reaction of compound 5.
In conclusion, we have developed a new method to
construct a series of the unfused polyaromatic furan
Support of this work by the grants from National Sciences
Foundation of China (Nos. 20872176 and 21072224) is grate-
fully acknowledged.
derivatives from the base-induced reaction of the
diynyl-1,6-diols through a novel cascade 1,3-H shift/
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[10] Efforts to improve the reaction yield by optimizing the
[14] After the formation of the alkynyl vinyl ketone inter-
mediate in the reaction of 2, AcO might act as the leav-
ing group in an SN2’ type nucleophilic addition onto the
propargylic acetate unit, see Scheme 5.
[15] The first 1,3-H shift could be the rate-determining step,
the second 1,3-H shift might be an intramolecular pro-
cess. The second reason is that no vinyl ketone inter-
mediate was detected in the reaction mixture.
amount of t-BuOK proved to be fruitless.
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