Singlet-oxygen-induced rearrangement of furan derivatives

Article abstract of DOI:10.1055/s-0030-1261204

Upon exposure to singlet oxygen and dimethylsulfide, the addition products between 3-furaldehydes and Grignard reagents undergo an oxidative rearrangement to give 2-substituted 3-furaldehydes, in yields ranging from 26-83%. N-Aryl- and N-tosylpyrroles were similarly obtained if the corresponding nitrogen-containing precursors were used instead, in equally attractive yields (64-92%). Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261204

LETTER
2231
Singlet-Oxygen-Induced Rearrangement of Furan Derivatives
S
inglet-Oxygen-In
i
duced
c
o
ent of Furan
l
Deriva
a
tives s Charbonnet, Emmanuel Riguet, Christian G. Bochet*
Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland
Fax +41(26)3009739; E-mail: Christian.bochet@unifr.ch
Received 5 May 2011
be kept for prolonged times, as already pointed out by
Blechert et al.4 Exposure of 2a–i to singlet oxygen (gener-
ated by irradiation of a saturated solution of oxygen in
acetonitrile at –40 °C in the presence of methylene blue
Abstract: Upon exposure to singlet oxygen and dimethylsulfide,
the addition products between 3-furaldehydes and Grignard re-
agents undergo an oxidative rearrangement to give 2-substituted 3-
furaldehydes, in yields ranging from 26–83%. N-Aryl- and N-to-
sylpyrroles were similarly obtained if the corresponding nitrogen- with a 300 W tungsten/quartz burner light source), imme-
containing precursors were used instead, in equally attractive yields
(64–92%).
diately followed by quenching at –40 °C with dimethyl-
sulfide and p-toluenesulfonic acid gave moderate to
Key words: photochemistry, heterocycles, singlet oxygen, rear-
rangement, pyrroles, furans
excellent yields of 2-substituted furfurals 3a–i after grad-
ual warming up to room temperature (Scheme 2, Table 1).
Low temperature during irradiation and quenching is es-
sential to ensure optimal yields. Different conditions were
Oxidation reactions are among the most important pro- screened, varying the solvent, the acid, and the reductant.
cesses for both life and organic synthesis. The reaction be- Acetonitrile proved to be the best solvent (either anhy-
tween oxygen and glucose is carefully orchestrated by a drous or containing up to 10% water), followed by dichlo-
series of enzymes, providing the essential form of energy romethane, while hexane and methanol were found
for keeping organisms alive. On the other hand, the un- inappropriate. We suspect an attack of the latter on the en-
controlled version of the process is the combustion reac- doperoxide intermediate 4 (Scheme 3).5 A strong acid,
tion, which provides mainly heat and carbon dioxide. In such as p-toluenesulfonic acid, was required, whereas
synthesis, oxidations are rarely based on molecular oxy- acetic acid was inefficient. Dimethylsulfide was the only
gen, and expensive and toxic reagents are routinely used. reductant that led to the desired product; phosphites, thio-
A notable exception is the photo-oxygenation of alkenes urea, and diphenylsulfide were unreactive. It is worth
using singlet oxygen. Essentially green and atom-eco- pointing out that pure oxygen was used for experimental
nomical, this process is actually one of the few industrial- convenience, but ambient air gave similarly good results.
ly relevant photochemical reactions.1,2
The nature of the R substituent has an impact on the yield;
conjugated systems have a beneficial effect, whereas alkyl
and strong electron-releasing groups (entry 4) lower the
yields. An N-Boc-indolyl substituent is tolerated (entry 9),
but the corresponding N-Boc-pyrrole led only to degrada-
tion. It is worth noting that the reaction of 2h resulted in
the chemoselective reaction of the diene part, leading to
3h.
An unprecedented Grignard addition–oxidative rear-
rangement sequence providing 2-alkyl-/aryl-3-furalde-
hydes has recently been published by Walsh et al.
(Scheme 1).3 The oxidative step is induced by N-bromo-
succinimide; we report here its photochemical counter-
part.
O
O
O
1. O2, methylene blue
MeCN, –40 °C
R
O
O
O
RMgX
NBS, H+
R
O
O
RMgX
+
R
2. Me2S, TsOH
R
–40 °C to r.t.
CHO
CHO
HO
CHO
CHO
1
2
3
R
HO
1
2
3
7
Scheme 1 Oxidative rearrangement of furans according to Walsh et
al.
Scheme 2 Singlet-oxygen-promoted oxidative rearrangement
3-Furfural (1) is a readily available starting material,
which reacts with organozinc, organolithium, and
Grignard reagents to give alcohols 2, following the work
of Walsh et al.3 These alcohols, if bearing electron-donat-
ing R side chains are quite acid-sensitive, and should not
We propose the mechanism as shown in Scheme 3: the fu-
ran core of alcohols 2a–i reacts with singlet oxygen ac-
cording to a very well documented process,6 leading to the
endo-peroxides 4. These peroxides are rather unstable, as
proton abstraction at the anomeric site is known to give
hydroxybutenolides,7 and thus should be reduced to the
diols 5 before warming up the mixture. These hydroxy-
furans 5 can undergo a ring opening to their enedial forms
6 and 6¢, which can re-close to 3, along the lines of the
mechanism proposed by Walsh. In some cases, particular-
SYNLETT 2011, No. 15, pp 2231–2233
x
x
.x
x
.2
0
1
1
Advanced online publication: 31.08.2011
DOI: 10.1055/s-0030-1261204; Art ID: D13911ST
© Georg Thieme Verlag Stuttgart · New York

2232
N. Charbonnet et al.
LETTER
S+
O
H
O
OH
H
O
O
O
O
OMs
OMs
R
R
R
7
Me2S
MsCl
H
S+
O
O
O
O
OH
H
H
S
– DMSO
O
OH
R
O
O
O
R
O
1O2
OH
S+
OH
R
R
O
O
O
O
O
2
H
4
H
– DMSO
OH
O
R
R
5
6
O
O
O
+ H2O
– H2O
R
O
HO
R
R
O
HO
O
6'
3
Scheme 3 Putative mechanism
Table 1 Singlet-Oxygen-Promoted Oxidative Rearrangement
O
PhNH2, then NaBH4
or
O
Entry Alcohol 2
R
Yield of furan 3 Furanone 7
R1
(%)a
74
40
26
29
38
71
73
83
(%)b
1. TsNH2, TFAA, 40 °C
2. PhMgBr, THF
CHO
HN
R2
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Ph
5
1
8a: R1 = H, R2 = Ph (94%)
Me
6
8b: R1 = Ph, R2 = Ts (74%)
t-Bu
26
15
8
R2
4-MeOC6H4
n-Pr
1. 1O2, methylene blue
MeCN, –40 °C
N
R1
2. Me2S, TsOH
–40 °C to r.t.
4-F3CC6H4
Bn
<2
<2
<2
<2
CHO
9a: R1 = H, R2 = Ph (64%)
9b: R1 = Ph, R2 = Ts (92%)
2g
2h
2i
vinylc
Scheme 4 Formation of pyrroles
2-N-Boc-indolyld 53
be enhanced by the in situ treatment with a sulfonyl chlo-
ride (mesyl or tosyl); this is also compatible with a reduc-
tive cleavage of the endo-peroxides 4 into 7.
a Isolated yield.
b Estimated by 1H NMR with an internal standard.
c Overall yield based on 1.
Following this mechanism, the formation of pyrrole deriv-
atives should be also possible if the hydroxyl function of
2 is replaced with an amine.3 Thus, reductive amination of
1 with aniline gave 8a (94%) and addition of phenylmag-
nesium bromide to the tosylimine derivative9 of 1 gave 8b
d Prepared by the addition 2-lithio-N-Boc-indole to 3-ethoxycarbon-
ylfuran, followed by reduction with NaBH4.
ly with alkyl R groups, small amounts of alkylidenefuran-
2-ones 7 are observed.8 The formation of this product can
Synlett 2011, No. 15, 2231–2233 © Thieme Stuttgart · New York

LETTER
Singlet-Oxygen-Induced Rearrangement of Furan Derivatives
2233
Supporting Information for this article is available online at
(74% overall). We then checked the feasibility of the pro-
cess, by exposing amines 8 to the same reaction condi-
tions (Scheme 4), and pyrroles 9 were obtained in good to
excellent yields.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
In summary, we reported a photochemical alternative to
the halogen-induced rearrangement of 3-hydroxymethyl-
furans, which is also compatible with the formation of
pyrroles. Applications of this chemistry in the green syn-
thesis of industrially relevant compounds are under way.
This work was generously supported by the Velux foundation.
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Typical Procedure for the Oxidation with 1O2 Followed by the
Rearrangement of 3-(1¢-Hydroxyalkyl)furan Derivatives
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Synlett 2011, No. 15, 2231–2233 © Thieme Stuttgart · New York

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