A convenient synthesis of tetrasubstituted furans from propargylic dithioacetals

Article abstract of DOI:10.1055/s-2006-939686

A convenient procedure for the regioselective synthesis of tetrasubstituted furans from the corresponding propargylic dithioacetals is described. Treatment of propargylic dithioacetals with n-BuLi and an aldehyde followed by mercuric acetate promoted annu

Full text of DOI:10.1055/s-2006-939686

LETTER
1209
A Convenient Synthesis of Tetrasubstituted Furans from Propargylic
Dithioacetals
Synthesis
u
of Tetrasubst
i
ituted
-Furans Chang Tseng, Jia-Hong Chen, Tien-Yau Luh*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
Fax +886(2)23644971; E-mail: tyluh@ntu.edu.tw
Received 29 November 2005
taining oligoaryls thus obtained have been shown to be
efficient hole-transporting materials for electrolumines-
cent applications.8b
Abstract: A convenient procedure for the regioselective synthesis
of tetrasubstituted furans from the corresponding propargylic
dithioacetals is described. Treatment of propargylic dithioacetals
with n-BuLi and an aldehyde followed by mercuric acetate promot-
ed annulation and desulfurization affords the corresponding mercu-
rio-substituted furans. Subsequent replacement of the mercury
moiety with iodine yields the corresponding 2,4,5-trisubstituted 3-
iodofurans. Transition-metal-catalyzed cross-coupling reactions of
the iodofurans furnish a variety of tetrasubstituted furans.
Hg(OAc)2 has been shown to promote the annulation of
allenyl carbinol 4 to form 2,5-dihydrofuran 5 with a
HgOAc substituent at C-3 (Equation 1).9 It is well docu-
mented that carbon–mercury bonds can be displaced by a
number of substituents under different conditions. We en-
visioned that Hg(OAc)2 might serve as an alternative
route for the annulation of allenyl-carbinol intermediate 2
obtained from the reaction of propargylic dithioacetal
with n-BuLi and then an aldehyde. It is interesting to note
that mercuric salts are known to be an active desulfuriza-
tion agent,10 the sulfur moiety in 2 may also be eliminated
under such treatment so that furan skeleton might be ob-
tained. We now wish to report a convenient procedure for
the synthesis of a variety of tetrasubstituted furans from
propargylic dithioacetals (Scheme 2).
Key words: annulation, tetrasubstituted furan, propargylic dithio-
acetal, mercuric acetate, transition-metal-catalyzed cross-coupling
Polysubstituted furans are widely found in natural prod-
ucts,1 important pharmaceuticals, and fragrance and fla-
vor compounds,2 and have been used as versatile
intermediates in organic synthesis.3 Facile approaches to
the synthesis of polysubstituted furan derivatives from
readily available starting materials involve derivatization
of furans,4 or cycloisomerization of alkyne- and allene-
containing acyclic precursors.4a,5,6
Me
ClHg
SPh
Me
Hg(OAc)2
SPh
Me
Me
Me
Me
Me
SBu
MeOH
then brine
HO
S
O
R2
Me
S
S
a
b
4
5
R1
R2
R3
R1
R3
R1
Equation 1 Cyclization of allenyl alcohol 4 by treatment with
R2
O
mercuric acetate.9
O
SBu
HS
1
2
3
SBu
S
Scheme 1 One-pot furan synthesis from propargylic dithioacetal.
Reagents and conditions: (a) i) n-BuLi, THF; ii) R3CHO; (b) tri-
fluoroacetic acid.
S
S
Hg(OAc)2
R1
R2
R3
R1
R2
We recently reported a convenient procedure for the syn-
thesis of 2,3,5-trisubstituted furans 3 from the correspond-
ing propargylic dithioacetals 1 (Scheme 1).7,8 A range of
functional groups can survive under these conditions. In
this reaction, the substituents on the furan ring are arisen
regioselectively from the propargylic dithioacetal and the
corresponding aldehyde, whereas the hydrogen at C-4 is
from the treatment of trifluoroacetic acid in annulation
step. This protocol provides a useful access for the pre-
paration of a range of oligoaryls containing trisubstituted
furan or pyrrole rings.7,8a It is noteworthy that furan-con-
O
1
2
R2
HgOAc
R1
R2
HgOAc
Hg(OAc)2
H
– HSCH2CH2SBu
O
R3
S
R3
R1
O
SBu
7
6
R2
I
R2
R4
R3
R1
R3
R1
O
O
8
9
SYNLETT 2006, No. 8, pp 1209–1212
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-939686; Art ID: W31905ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
5.
2
0
0
6
Scheme 2 Approaches to the synthesis of tetrasubstituted furan
derived from propargylic dithioacetal.

1210
J.-C. Tseng et al.
LETTER
Aryl iodides are known to undergo transition-metal-cata-
lyzed cross-coupling reactions.11 We envisioned that 8
may also react in a variety of such coupling processes
leading to carbon–carbon bond formation. Thus, treat-
ment of 8a–f with different aryl boronic acids in the
presence of 5 mol% Pd(PPh3)4, 10 mol% t-Bu3P using
aqueous Na2CO3 as the base in refluxing toluene afforded
the expected coupling products 9–14 in high yield (entries
1–6, Table 2). Iodofurans with either aryl substituent, es-
ter moiety, or alkyl side chain works well under such Su-
zuki reaction conditions. In a similar manner, when
phenylacetylene was employed, 8a,c,d also gave the cor-
responding Sonogashira products 15–17 in good yield
upon treatment with 5 mol% PdCl2(PPh3)2, 10 mol% CuI
and 10 mol% PPh3 in the presence of Et3N in DMF at
125 °C (entries 7–9).12 Moreover, the Stille couplings of
vinyltributylstannane with 8a and 8d were carried out
using 5 mol% PdCl2(PPh3)2 in DMF at 120 °C, and the
desired coupling products 18 and 19 were isolated in good
yield, respectively (entries 10 and 11). To our surprise, the
Heck, Kumada, and Negishi couplings of 8a produced the
desired coupling adducts in moderate to low yield along
with the formation of the reduced product, 2,3,5-triphen-
ylfuran, in comparable yield (entries 12–14). When alkyl
Grignard reagent was used for the cross-coupling with
iodofuran 8a, all attempts produced the reduced triphenyl-
furan exclusively by using Ni(acac)2/dppf, NiCl2dppf,
NiCl2dppp, PdCl2dppf, or PdCl2dppp as the catalyst.
Attempts to use alkyl substituted 9-BBN for the Suzuki
coupling reaction, a mixture of starting iodofuran 8a and
Ph
HgOAc
Ph
Ph
I
S
S
a
b
Ph
R3
R3
Ph
O
O
Ph
1a
7
8
Scheme 3 Two-step synthesis of 3-mercurio- and 2,4,5-trisubstitu-
ted 3-iodofuran from propargylic dithioacetal. Reagents and conditi-
ons: (a) i) n-BuLi, THF, –78 °C, 50 min; ii) R3CHO, THF, –78 °C, 30
min, –78 °C to r.t., 1 h; iii) Hg(OAc)2, r.t., overnight (7a: R3 = Ph,
84%; 7b: R3 = p-MeO2CC6H4, 82%); (b) I2, KI, CH2Cl2, r.t., 3 h (8a:
R3 = Ph, 96%; 8b: R3 = p-MeO2CC6H4, 95%).
reduced 2,3,5-triphenylfuran were formed, whereas the
desired coupling adduct was not detected. Alternatively,
lithium–iodine exchange of 2,4,5-triphenyl-3-iodofuran
followed by quenching with ClCO2Et or n-BuBr afforded
the corresponding tetrasubstituted furan in good yield
(entries 15 and 16).13
In the beginning, 1 was treated with n-BuLi at –78 °C fol-
lowed by benzaldehyde to give the corresponding allenyl
carbinol intermediate 2 which was allowed to react with
two equivalents of Hg(OAc)2 at room temperature over-
night to afford the corresponding mercury compounds 7 in
good yield. Further reactions of 7 with I2/KI at room tem-
perature for three hours gave the corresponding iodofuran
8 in excellent yield (Scheme 3). This reaction can also
proceed in one pot to give 8 without isolation of the mer-
cury intermediate 7. Representative examples are shown
in Table 1. Attempts of using I2 or ICl to react with the al-
lenyl carbinol intermediate 2 in a one-pot manner without
Table 1 One-Pot Synthesis of 2,4,5-Trisubstituted 3-Iodofurans from Propargylic Dithioacetalsa
R2
I
S
S
i–iv
R1
R3
R1
R2
O
1
8
Entry
Substrate
1a
R1
R2
R3
Product
8a
Yield (%)b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
78
1a
Ph
Ph
8a
90c
62d
54d
72
1a
Ph
Ph
8a
1a
Ph
Ph
8a
1a
Ph
p-C6H4-CO2Me
n-Bu
8b
1a
Ph
8c
68
1b
CO2Et
Ph
n-Bu
8d
68
1c
p-C6H4-CO2Me
n-Bu
p-C6H4-CO2Me
i-Pr
8e
63
1d
n-Bu
8f
56
a Reagents and conditions: i) n-BuLi, THF, –78 °C, 50 min; ii) R3CHO, THF, –78 °C, 30 min, –78 °C to r.t., 1 h; iii) Hg(OAc)2, r.t., overnight;
iv) I2, KI, r.t., 3 h.
b Isolated yield of one-pot procedure.
c Work-up with additional washing with 20% Na2S aq solution and subsequent filtration through a silica gel bed gave relative higher yield
compared with the result of entry 1 in this table.
d Reagents and conditions: i) n-BuLi, THF, –78 °C, 50 min; ii) benzaldehyde, THF, –78 °C, 30 min, –78 °C to r.t., 1 h; iii) I2 (entry 3) or ICl
(entry 4), r.t., overnight.
Synlett 2006, No. 8, 1209–1212 © Thieme Stuttgart · New York

LETTER
Synthesis of Tetrasubstituted Furans
1211
Table 2 Synthesis of Tetrasubstituted Furan from 2,4,5-Trisubstituted 3-Iodofuran
R2
I
R2
R4
R4X
conditions
R3
R1
R3
R1
O
O
Entry
1
Iodofuran
8a
R1
Ph
Ph
Ph
Ph
R2
R3
R4
Producta
9
Conditionsb Yield (%)
Ph
Ph
Ph
Ph
Ph
A
A
A
A
A
A
B
B
B
C
C
D
E
85
82
82
80
78
80
78
76
79
82
76
2
8b
p-C6H4CO2Me
p-C6H4OMe
p-C6H4OMe
p-C6H4OMe
Ph
10
11
12
13
14
15
16
17
18
19
20
9
3
8c
n-Bu
4
8d
CO2Et
Ph
n-Bu
5
8e
p-C6H4CO2Me
p-C6H4CO2Me
6
8f
n-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
Ph
i-Pr
Ph
p-C6H4OMe
PhC≡C
PhC≡C
PhC≡C
CH=CH2
CH=CH2
trans-CH=CHCO2Me
Ph
7
8a
8
8c
Ph
n-Bu
n-Bu
Ph
9
8d
CO2Et
Ph
10
11
12
13
14
15
16
8a
8d
CO2Et
Ph
n-Bu
Ph
8a
55 (30)c
45 (35)c
20 (55)c
71
8a
Ph
Ph
8a
Ph
Ph
Ph
9
F
8a
Ph
Ph
CO2Et
21
22
G
H
8a
Ph
Ph
n-Bu
68
a R4 substituent of the corresponding tetrasubstituted furan comes from R4X.
b Conditions: (A) Suzuki coupling: 1.5 equiv R4B(OH)2, 5 mol% Pd(PPh3)4, 10 mol% t-Bu3P, 2 M Na2CO3 (aq), PhMe, reflux, 18 h; (B) Sono-
gashira coupling: 2 equiv PhC≡CH, 5 mol% PdCl2(PPh3)2, 10 mol% CuI, 10 mol% PPh3, Et3N, DMF, 120 °C, 12 h; (C) Stille coupling: 2 equiv
CH2=CHSnBu3, 5 mol% PdCl2(PPh3)2, DMF, 120 °C, 12 h; (D) Heck coupling: 2 equiv CH2=CHCO2Me, 5 mol% Pd(OAc)2, 10 mol% PPh3,
Et3N, DMF, 120 °C, 12 h; (E) Kumada coupling: 3 equiv PhMgBr, 10 mol% NiCl2dppp, PhMe, reflux, 18 h; (F) Negishi coupling: 3 equiv
PhZnCl, 10 mol% Pd(PPh3)4, THF, reflux, 24 h; (G) i) 1.2 equiv n-BuLi, THF, –78 °C, 1 h; ii) 1.5 equiv ClCO2Et, –70 °C to r.t., 2 h; (H) i) 1.2
equiv n-BuLi, THF, –78 °C, 1 h; ii) 1.5 equiv n-BuBr, –70 °C to r.t., 2 h.
c The reduced product 2,3,5-triphenylfuran was obtained as the side product and the yield is shown in parentheses.
the treatment of Hg(OAc)2 also gave the corresponding
iodofuran 8a (entries 3 and 4, Table 1). However, the
yield was relatively lower and sometimes produced the
trisubstituted furan when utilizing the commercial avail-
able I2 without purification by sublimation. Attempts to
use a catalytic amount of Hg(OAc)2 (e.g., 0.1 equiv) under
similar conditions, the yield of 8a was 9%. Presumably,
the mercuric species would facilitate the desulfurization
process leading to furan.
Typical Experimental Procedure
A solution of 2.5 M n-BuLi in hexane (33.0 mmol) was introduced
dropwise to a solution of propargylic dithioacetal 1 (30.0 mmol) in
THF (200 mL), stirring under N2 at –78 °C for 50 min. To this reac-
tion mixture was added slowly a solution of aldehyde (33.0 mmol)
in THF (30 mL) at this temperature. The mixture was stirred for 30
min at –78 °C, then gradually warmed up to r.t. and allowed to stir
for 1 h. Hg(OAc)2 (66.0 mmol) was then added and the slurry was
stirred at rt overnight. I2 (120.0 mmol) and KI (120.0 mmol) were
then added and the mixture was further stirred at rt for 3 h. The mix-
ture was quenched with 20% aqueous Na2S2O3 (200 mL), then the
organic layer was separated and washed with 20% aqueous Na2S2O3
(200 mL). The aqueous layer was extracted with CH2Cl2 (100
mL ꢀ 3). The combined organic layer was dried (MgSO4), filtered,
and evaporated in vacuo. The crude product was purified by flash
column chromatography to give pure iodofuran 8.
In conclusion, we have discovered a convenient and high-
ly regioselective synthesis of tetrasubstituted furans from
propargylic dithioacetals. The one-pot annulation proce-
dure of propargylic dithioacetal furnished a variety of
2,4,5-trisubstituted 3-iodofurans, which undergo transi-
tion-metal-catalyzed cross-coupling reactions to give ful-
ly substituted furans. Substituents on furan ring can be
aliphatic, aromatic, and functional groups such as esters or
ethers. Further extensions of this reaction for the synthesis
of related heteroaromatic rings are in progress.
Acknowledgment
This work is supported by the National Science Council of the
Republic of China.
Synlett 2006, No. 8, 1209–1212 © Thieme Stuttgart · New York

1212
J.-C. Tseng et al.
LETTER
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Synlett 2006, No. 8, 1209–1212 © Thieme Stuttgart · New York