Base-controlled selective construction of polysubstituted dihydrofuran and furan derivatives through an I2-mediated cyclization

Article abstract of DOI:10.1016/j.tetlet.2016.12.078

A base-controlled formal [3?+?2] cycloaddition of 1,3-dicarbonyl compounds to enones via an I₂-mediated cyclization was reported. Highly functionalized dihydrofurans and furans were selectively obtained under I₂/DMAP and I₂

Full text of DOI:10.1016/j.tetlet.2016.12.078

Accepted Manuscript
Base-Controlled Selective Construction of Polysubstituted Dihydrofuran and
Furan Derivatives through an I2-Mediated Cyclization
Chun-Bao Miao, Rui Liu, Yan-Fang Sun, Xiao-Qiang Sun, Hai-Tao Yang
PII:
S0040-4039(16)31733-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.078
TETL 48490
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 October 2016
22 December 2016
26 December 2016
Please cite this article as: Miao, C-B., Liu, R., Sun, Y-F., Sun, X-Q., Yang, H-T., Base-Controlled Selective
Construction of Polysubstituted Dihydrofuran and Furan Derivatives through an I2-Mediated Cyclization,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.078
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O
O
OH
(1) TEBAC (cat.), H2O, reflux
DMAP
R2
(2) I2,
, CH2Cl2, rt.
R1
O
O
+
O
O
O
R2
R1
R2
One-pot
(1) TEBAC (cat.), H2O, reflux
R1
(2) I2, DBU, CH2Cl2, rt.
O

1
Tetrahedron Letters
Base-Controlled Selective Construction of Polysubstituted Dihydrofuran and
Furan Derivatives through an I2-Mediated Cyclization
Chun-Bao Miao, Rui Liu, Yan-Fang Sun, Xiao-Qiang Sun, Hai-Tao Yang
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced Catalysis and Green Manufacturing Collaborative Innovation Center,
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A base-controlled formal [3+2] cycloaddition of 1,3-dicarbonyl compounds to enones via an I2-
mediated cyclization was reported. Highly functionalized dihydrofurans and furans were
selectively obtained under I2/DMAP and I2/DBU conditions in the cyclization step, respectively.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
I2
dihydrofuran
furan
1,3-dicarbonyl compounds
enones
Introduction
product I was obtained selectively (Scheme 1) with the carbon of
1,3-dicarbonyl compounds added at the α-position of electron-
poor alkenes. A reversed regioselective radical cyclic addition
leading to product II was rather rare (Scheme 1).7a The reaction
Dihydrofuran and furan skeletons constitute a class of
biologically active compounds that are found in many natural
products as well as therapeutic agents such as neotanshinlactone,1
evodone,2 coumestans,3 clerodin,4 azadirachtin,5 and austocystin
A6 (Figure 1). Their broad bioactivities have inspired chemists to
develop versatile efficient synthetic methods. The radical cyclic
addition reaction of active methylene compounds with alkenes
promoted by transition metal salts such as manganese(III)
acetate7, cerium(IV) ammonium nitrate,8 Ag (I), and Cu (II)9
represents one of the mostly used method. However, excess
transition metal salts have to be used as oxidants. Furthermore,
when electron-poor alkenes were employed as the substrates, the
of diazo compounds with alkenes/alkynes via organometallic
10
catalysis have also attracted much attention.
But the
chemoselectivity was usually poor. The formal [4+1] annulation
of enones with ylides has been widely employed for the
construction of heterocycles.11 Nevertheless the control of the
competitive formation of cyclopropane products is
a
thorny problem. Beside these methods, hypervalent iodine
mediated annulation of 1,3-dicarbonyl compounds with alkenes
for the construction of dihydrofurans have been explored.12
I2 as an inexpensive, non-toxic, readily available reagent has
been found significant application in organic transformations.13
Most recently, we reported the preparation of four-membered
ring heterocycles such as oxetane and azetidine derivatives
O
CH3
O
O
CH3
O
O
O
O
O
H3C
CH3
through an I2-mediated cyclization of the Michael adducts of
Evodone
Neotanshinlactone
Coumestan
14
malonates/amidomalonate with enones.
Herein, we would
extend this method to the synthesis of five-membered ring
heterocycles and demonstrated the preparation of polysubstituted
O
H
O
O
H
H
O
O
AcO
AcO
O
Me
Me
Cl
H
H
OMe
OMe
O
O
O
O
Clerodin
Antifeedant
Austocystin A
R
EWG
R
EWG
I
II
Fig.
1 Selective Biologically Active Natural Products Bearing
EtO2C
EtO2C
EtO2C
EtO2C
XH
O
Dihydrofuran/Furan Subunits
X
I2
I2
O
OH
O
base
———
 Corresponding author.
R1
R2
R2
base
O
R1
R
EWG
this work
EWG
previous work
ref. 14
R
X = O, NR
O
E-mail address: estally@yahoo.com
http://dx.doi.org/10.1016/********
0040-4039/_ 2016 Elsevier Ltd. All rights reserved.
Scheme 1

2
Tetrahedron
dihydrofurans/furans via the I2-mediated annulation.
Table 2
Substrate Scope of Enones for the Preparation of
Dihrdrofurans under I2/DMAP conditions
Results and discussion
O
To verify our hypothesis, Michael adduct 1aa was chosen as
the model substrate to react with I2 under various conditions
(Table 1). The reaction in DMF with K2CO3 as the base afforded
the desired product 2aa in 59% yield (Table 1, entry 1). Using
Et3N as the base, the reaction in dichloromethane gave the best
yield among the four evaluated solvents (Table 1, entries 2-5).
Further screening different bases for this transformation in
CH2Cl2 revealed that pyridine and DABCO were not effective
(Table 1, entries 7 and 8) and DMAP was the best base to afford
2aa in 70% yield within 20 min (Table 1, entry and 6). Although
NMI and Et3N gave comparable yield with that of DMAP, much
longer reaction time was needed (Table 1, entries 3 and 9). When
the strong organic base DBU was introduced to the reaction, to
our surprise, beside the formation of 2aa a new product with
slightly lower polarity was isolated in 21% yield, which was
assigned as the furan product 3aa through NMR analysis (Table
1, entry 10). The 3aa might be generated from the 2aa through
further iodination and subsequent dehydroiodination, which
implied at least 2 equiv of I2 was needed in the transformation.
When the amounts of I2 and DBU were increased to 2.7 and 5.4
equiv, respectively, the yield of 3aa was improved notably to
64% (Table 1, entry 11). It was noteworthy if DMAP was used as
the base, even increasing the amounts of I2 and DMAP to 2 and 4
equiv, respectively, no furan 3aa was generated, which
demonstrated that the choice of base was crucial to formation of
3aa from 2aa. The reaction of 1aa with I2/DBU in THF also gave
a comparable yield of 3aa (Table 1, entry 12). However, using
CH3CN or EtOH as the solvent the conversion was incomplete
along with surplus of considerable amount of 2aa even
prolonging the reaction time to 10 h (Table 1, entries 13 and 14).
OH
O
O
(1) TEBAC 5 mol %, H2O, refulx
(2) I2 (1.1 equiv), DMAP (2.2 equiv)
R2
+
R1
R2
O
R1
O
O
4a
5
(1.1 mmol)
(1 mmol)
O
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2ac
, 68%
2aa, 56%
2ab, 59%
Me
MeO
O
O
O
O
O
O
O
O
O
OMe
O
2af
2ad
, 53%
, 64%
2ae
, 43%
Cl
NO2
O
O
O
O
O
O
O
O
O
Me
NO2
(3ai, 23%)
Cl
O
2ag, 63%
2ai, 11%
2ah
, 63%
O
O
O
O
O
O
O
O
O
O
O
S
Cl
Me
O
2aj
, 14%
2ak, 41%
Cl
2al, 20%
15
Oxidation with stoichiometric amounts of DDQ, MnO2 or
new approach for this conversion under mild conditions.
oxidative dehydrogenation catalyzed-by Pd at high temperauture
for a long time 16 was the commonly used method for the
transformation of dihydrofuran to furan. Herein we provided a
It is interesting that the chemoselective conversion of 1aa to
2aa or 3aa in the presence of I2 is controlled by the base. As we
know, tunable highly selective synthesis derived from the same
reactants is a formidable challenge in organic synthesis. 17 In
order to make this approach easier to operate, the possibility of
constructing dihydrofurans/furans via a one-pot formal [3 + 2]-
cycloaddition process involving a Michael addition and I2-
mediated cyclization was tried.
Table 1
Screening of the reaction conditionsa
O
O
OH
Ph
O
O
Ph
Ph
I2, base
+
O
Ph
Ph
Ph
O
O
A mixture of 4-hydroxycoumarin, 1.1 equiv of chalcone, and
catalytic amount of TEBAC (benzyl triethyl ammonium chloride)
was refluxed in water overnight until the disappearance of 4-
hydroxycoumarin, then I2, 5 mL of CH2Cl2, and DMAP (or DBU)
were added sequentially and the mixture was stirred at room
temperature until the completion of reaction, furnishing 2aa and
3aa in 56% and 53% yield, respectively. No workup procedure or
the purification of Michael addition mixture and no oxygen-free
operation were required, which made the protocol very easy to
operate. The generality of this formal [3+2]-cycloaddition for the
synthesis of polysubstituted dihydrofurans/furans was evaluated
with 4-hydroxycoumarin 4a and various enones as the substrates
(Table 2 and 3).
O
3aa
O
O
1aa
2aa
O
yieldb(%)
time
(h)
entry base
solvent
1aa:I2:base
3aa
2aa
1
K2CO3
DMF
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:1.1:2.2
1:2.7:5.4
1:2.7:5.4
1:2.7:5.4
1:2.7:5.4
5
59
0
2
Et3N
Et3N
Et3N
Et3N
THF
3
62
0
3
CH2Cl2
EtOH
3
67
0
4
3
trace
51
0
5
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
3
0
6
DMAP
0.5
12
12
2
70
0
pyridine
14
0
7
8
DABCO
NMI
17
0
9
64
0
For most cases, 4-hydroxycoumarin 4a reacted with enones 5
under I2/DMAP conditions leading to the corresponding
dihydrofuran products 2 in moderate yields (Table 2). The
reaction tolerated a range of various groups with different
electronic demands on the aromatic R1 or R2 ring. If a nitro group
connected on the phenyl ring of R2, 2ai was only obtained in 11%.
In addition, 3ai was also formed in 23% yield. It might be
explained by the strong electron withdrawing effect of nitro
group, which was benefit to the further iodination at the α-
10
11
12
13
DBU
DBU
DBU
DBU
DBU
1
30
21
64
58
23
17
0.5
3
trace
trace
19
CH3CN
EtOH
10
10
14
28
a
A mixture of 1aa (1 mmol), I2, and base was stirred in 2
mL of solvent at room temperature.
b Isolated yield.

3
Next, the applicability of other 1,3-dicarbonly compounds
Table 3
(4b-e) in this conversion was also evaluated by performing the
reaction of them with chalcone 5a (Table 4). As can be seen from
the results, the dimedone (4b), cyclohexane-1,3-dione (4c), 2-
hydroxynaphthalene-1,4-dione (4d), and 4-hydroxy-6-methyl-
2H-pyran-2-one (4e) were much less effective than 4-
hydroxycoumarin 4a in the formal [3+2] cycloaddition. The low
yield of 2ea and 3ea was attributed to the first-step of incomplete
Michael addition, and large amounts of chalcone remain
unreacted. The reason for the low yield of 2ca, 3ca, 2da, and 3da
was not clear although the TLC showed the transformation
proceeded well.
Substrate Scope of Enones for the Preparation of Furans
under I2/DMAP Conditions
O
OH
O
O
(1) TEBAC 5 mol %, H2O, refulx
(2) I2 (2.7 equiv), DBU (5.4 equiv)
R2
+
R1
R2
R1
O
O
O
4a
5
(1.1 mmol)
(1 mmol)
O
3
O
O
O
O
O
O
O
O
O
O
O
O
All the fused dihydrofurans were obtained with a high
3ac
, 51%
3aa
, 53%
3ab
, 52%
Me
MeO
diastereoselectivity (trans/cis
>
90:10), and the trans-
configuration were determined based on the observed coupling
constants of 4.4-5.4 Hz between the two methine protons. While
the cis diastereoisomers were reported to have a larger coupling
constants between the two methine protons (10-11 Hz).11e,15b The
O
O
O
O
O
O
O
O
O
OMe
1
O
disappearance of two mehtine protons in the H NMR spectrum
O
O
and appearance of two new signals in sp2-C region in the 13C
NMR spectrum proved the furan structure of 3. The known
products 2aa-2ah, 2ba, 2ca, 2ea, 3ba-3da were confirmed
through comparison of their spectral data to those reported in the
literature.12a,18 All of the new compounds were unambiguously
characterized by their HRMS, 1H NMR, 13C NMR spectra.
3ae
3af
, 41%
3ad
, 54%
, 48%
Cl
NO2
O
O
O
O
O
O
O
O
O
O
Me
Cl
NO2
O
O
The ketone iodination always requires either tedious
conditions or higher temperature.19 However, in this work the
annulation completed within 20 min at room temperature. To
prove that the iodination process could proceed smoothly at room
temperature, the O-methylated product 6 was prepared and then
treated with I2 and DMAP. The iodination occurred smoothly to
afford the iodinated product 7a and 7b as two diastereoisomers
(Scheme 2). However, the iodination proceeded very slowly.
After 16 h, the ratio of 6a:7a:7b was 1:1.5:3.4 as determined by
1H NMR analysis. It demonstrated that the existence of
intramolecular hydroxyl group accelerated the iodination process
notably. The high diastereoselectivity could be explained by the
relatively more thermo dynamical stability of trans-ismoer. In the
presence of catalytic amount of DBU, cis-isomer 2aa' was
transformed to trans-isomer 2aa quickly and it reach the
equilibrium with a ratio of 2aa'/2aa as 1/22 within 1 h (Scheme
2). However, using DMAP as the base, only 16% conversion of
2aa' to 2aa was achieved after 6 h and no change was observed
even prolonging the reaction time. Treatment of 2aa with I2/DBU
afforded the furan product 3aa in 86% yield within 20 min
(Scheme 2).
3ag
, 42%
3ah, 71%
3ai
, 41%
O
O
O
O
O
O
O
O
O
O
S
Cl
Me
O
O
3aj
3al
, 12%
, 41%
3ak
, 15%
Cl
position of carbonyl of 2ai. When R1 was thienyl group or R2 was
an alkyl group the yield was very low (Table 2, 2aj and 2al).
Under I2/DBU conditions, various furan products 2 were also
obtained in moderate yield when R1 and R2 were both aryl rings
(Table 3). Thienyl group substituted furan 3aj was also
efficiently constructed in 41% yield. Nevertheless, either R1 or R2
was an alkyl group, a very low yield of the furan product 3ak or
3al was provided.
Table 4
Other 1,3-Dicarbonyl Compounds in the Formal [3+2]
Cycloaddition Reaction Through the I2-Mediated
Cyclizationa
CH3
O
CH3
O
O
Ph
O
O
I
Ph
O
I2 (1.1 equiv), DMAP (2.2 equiv)
CH2Cl2, rt, 16 h
OH
O
O
Ph
Ph
O
(1) H2O, refulx
(2) I2, base
or
+
O
Ph
O
O
Ph
Ph
Ph
Ph
Ph
O
6
O
7a 7b
6
7a 7b
: = 1 : 1.5 : 3.4
+
:
O
O
O
2
4
5a
3
(two diastereoisomers)
O
O
O
O
Ph
O
Ph
base, CH2Cl2, rt
O
O
O
O
O
O
O
O
Ph
O
(a) DBU, 1 h, 2aa' : 2aa = 1 : 22
(b) DMAP, 6 h, 2aa' : 2aa = 5.4 : 1
Ph
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
2aa'
(cis-)
2aa
(trans-)
O
O
O
O
2ca, 31%
2ba, 54%
2ea, 21%
2da, 33%
O
O
O
O
Ph
Ph
Ph
Ph
3aa (86%)
O
I2 (1.2 equiv), DBU (2.4 equiv)
CH2Cl2, rt, 20 min
O
O
O
O
O
O
O
O
O
O
O
O
O
2aa
Ph
Ph
Ph
Ph
O
Ph
Ph
Ph
Ph
O
O
O
Scheme2 Controlled experiment
3ba, 30%
3ca, 13%
3da, 23%
3ea
, 8%
a
Based on the controlled experiment and our previous work on
the I2-mediated transformation,14a,b a possible mechanism for the
formation of dihydrofuran 2 and furan 3 is depicted in Scheme 3.
Dihydrofurans 2 or furans 3 were formed under DMAP
or DBU conditions, respectively.

4
Tetrahedron
Initially, Michael addition of 1,3-dicarbonyl compound to
enone affords the Michael adduct 8. Iodination of 8 furnishes 9,
which undergoes intramolecular substitution to generate
dihydrofuran 2. If a strong organic base (DBU) was used, the
further iodination reaction occurs followed by extrusion of HI to
give the furan product 3. It should be noted that the formation of
furan product was determined on whether the second iodination
could occur. If proper substituents which benefit the enolizaiton
and iodination located at the benzoyl ring, even under DMAP
conditions, furan products could also be obtained.
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Scheme 3 Proposed mechanism
Conclusion
In summary, we have developed a one-pot two-step formal
[3+2]-cycloaddition of 1,3-dicarbonyl compounds with enones
for the efficient synthesis of dihydrofurans and furans via a
Michael addition and the subsequent I2-mediated cyclization. In
the second step of cyclization, chemoselective formation of
dihydrofurans and furans could be controlled by using DMAP
and DBU as the base, respectively. A new route for the
conversion of dihydrofurans to furans was developed. The
present method shows the following advantages such as easy
operability, metal-free and mild conditions.
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M.; Ren, W.-L.; Meng, Q.; Sun, X.-Q. J. Org. Chem. 2013, 78, 4329.
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Acknowledgments
We are grateful for the financial support from the National
Natural Science Foundation of China (Nos. 21202011), Natural
Science Foundation of Jiangsu Province (BK20141171), the
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology (BM2012110).
Supplementary Material
General synthetic procedures, characteristic data, and NMR
spectra of the products can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.
References and notes
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Base-Controlled Selective Construction of Polysubstituted Dihydrofuran and Furan
Derivatives through an I2-Mediated Cyclization
Chun-Bao Miao, Rui Liu, Yan-Fang Sun, Xiao-Qiang Sun, Hai-Tao Yang
O
OH
O
(1) TEBAC (cat.), H2O, reflux
DMAP
R2
(2) I2,
, CH2Cl2, rt.
R1
O
O
+
O
O
O
R2
(1) TEBAC (cat.), H2O, reflux
R1
R2
One-pot
R1
(2) I2, DBU, CH2Cl2, rt.
O
A base-controlled formal [3+2] cycloaddition of 1,3-dicarbonyl compounds to enones via an I2-mediated cyclization
was reported. Highly functionalized dihydrofurans and furans were selectively obtained under I2/DMAP and I2/DBU
conditions in the cyclization step, respectively.
———
  Corresponding author.
E-mail address: estally@yahoo.com
http://dx.doi.org/10.1016/j.tetlet.2016.09.076
0040-4039/_ 2016 Elsevier Ltd. All rights reserved.

Tetrahedron
6
Highlight
1. One-pot two-step formal [3+2] cycloaddition through an I2-mediated cyclization was developed.
2. The chemoselective formation of dihydrofuran or furans was controlled by the base.
3. A new route for the conversion of dihydrofurans to furans was developed