Electrophilic iodo-mediated cyclization in PEG under microwave irradiation: Easy access to highly functionalized furans and pyrroles

Article abstract of DOI:10.1055/s-0031-1291012

The rapid and facile synthesis of highly substituted β-iodofurans and β-iodopyrroles is reported using a mixture of molecular iodine and a base in solid PEG 3400 as alternative, eco-friendly and nontoxic solvent under microwave irradiation, in a very short time. The heterocycles are efficiently recovered in good yields by a simple workup procedure, avoiding chromatographic purification. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291012

LETTER
▌1481
letter
Electrophilic Iodo-Mediated Cyclization in PEG under Microwave
Irradiation: Easy Access to Highly Functionalized Furans and Pyrroles
Easy Access to Highly Functionalized Furans and Pyrroles
Rosella Spina,a,b Evelina Colacino,a Bartolo Gabriele,b Giuseppe Salerno,c Jean Martinez,a Frédéric Lamaty*a
a
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS, UM I-UM II Université de Montpellier II, Place E. Bataillon, 34095
Montpellier Cedex 5, France
Fax +33(467)144866; E-mail: frederic.lamaty@univ-montp2.fr
b
c
Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
Received: 17.02.2012; Accepted after revision: 23.03.2012
In the course of this reaction, the carbon–carbon triple
bond of the substrate is activated by the electrophilic ha-
logenating reagent (I+), then undergoes a 5-endo-dig intra-
molecular cyclization triggered by the O- or N-
Abstract: The rapid and facile synthesis of highly substituted β-io-
dofurans and β-iodopyrroles is reported using a mixture of molecu-
lar iodine and a base in solid PEG 3400 as alternative, eco-friendly
and nontoxic solvent under microwave irradiation, in a very short
time. The heterocycles are efficiently recovered in good yields by a nucleophile present in the molecule to afford β-iodofurans
simple workup procedure, avoiding chromatographic purification.
or β-iodopyrroles, respectively, in basic medium.
Key words: iodocyclization, microwave, poly(ethylene glycol), fu-
rans, pyrroles
In order to compare our procedure with those previously
reported,10 we tested the iodocyclization of 1,2-amino al-
cohol derivative 1a in the presence of an equimolar mix-
ture of molecular iodine I2 and NaHCO3 (1:1, 3 equiv),
replacing acetonitrile by 300 mg of PEG 3400.26 The mix-
ture was heated to 50 °C under microwave activation for
15 minutes. At this point, the analysis of the crude reac-
tion mixture showed the complete conversion of the start-
ing material. The crude was diluted in a small amount of
CH2Cl2, precipitated in Et2O and filtered, leading to an or-
ganic phase which was washed with a saturated solution
of sodium thiosulfate (Na2S2O3) to neutralize the excess
of iodine. The corresponding highly substituted pyrrole 2a
was obtained in 44% yield as a pure compound, by simple
evaporation (Table 1, entry 1), confirming our initial hy-
pothesis. In the search for more effective conditions, the
reaction time was reduced to ten minutes. However the
yield was not improved (42%, Table 1, entry 2). We tried
to perform the reaction in ten minutes in more diluted con-
ditions by increasing the quantity of PEG 3400 (350 mg)
and reducing the amount of I2 and NaHCO3 to two equiv-
alents (Table 1, entry 3). Those conditions were the best
ones and the expected product was obtained in 81%
yield.26 However, if the reaction was stopped after five
minutes (Table 1, entry 4), the yield decreased to 69%.
The reaction outcome was also studied using one equiva-
lent of 1:1 molar ratio of I2/base, but the conversion of the
substrate was not complete and the yield of 2a was low
(Table 1, entry 5). The conversion was also incomplete
when the reaction was carried out, unoptimized, on a larg-
er scale.
The insertion of iodine in a heterocyclic ring represents an
important starting point for the construction of more func-
tionalized systems. The utility of iodocyclization was
demonstrated by several research groups and the large po-
tential of this synthetic approach has been illustrated in
the synthesis of carbocycles1,2 or different halo-heterocy-
clic systems3,4 such as furan derivatives,5–10 isochroman-
3-ones11 and isochromenes,12,13 prolines,14 pyrroles,15,16
isoxazoles,17 indolizinones18 and benzo[b]thiophene.19
The iodocyclization reaction of a series of 3-alkyne-1,2-
diols and 3-hydroxy-2-sulfonylamino-4-alkynes leading
to iodofurans or iodopyrroles, respectively, has been al-
ready described20 using the non-eco-friendly acetonitrile
as the reaction solvent.
For many years, our research group has been involved in
the development of green methodologies in organic syn-
thesis, devoted to eliminate the use of hazardous organic
solvents. In this context, we have widely demonstrated
that PEGs are effective as solvent for organic reactions.21–
25 In this report, we present the unprecedented use of solid
PEG 3400 in the electrophilic iodo-mediated cyclization
reaction of diols or N-protected 1,2-amino alcohols under
microwave irradiation (Scheme 1).
R3
R2
I
R2
R1
I2, NaHCO3
R3
PEG 3400
10 min, MW
R1
HX
OH
X = O, NBoc
X
In all cases, only the formation of the expected product 2a
was detected. Encouraged by these results, the method
was extended to other substrates such as β-amino alcohol
1b and 1,2-diols 1c–f (Table 2) bearing aromatic or ali-
phatic substituents on the triple bond. In all cases, the con-
version of the substrate was complete leading to original
tri- or tetrasubstituted iodinated pyrroles or furans 2b–f in
Scheme 1 Iodocyclization in solid PEG 3400
SYNLETT 2012, 23, 1481–1484
Advanced online publication: 25.05.2012
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3
6
-
5
2
1
4
1
4
3
7
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2
0
9
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DOI: 10.1055/s-0031-1291012; Art ID: ST-2012-D0149-L
© Georg Thieme Verlag Stuttgart · New York

1482
R. Spina et al.
LETTER
Table 1 Screening of the Parameters for Iodocyclization in PEG
Table 2 Synthesis of Iodinated Furans and Pyrroles in PEG 3400 un-
der MW Irradiation
Ph
Ph
R3
R2
I
I2, NaHCO3
R2
R1
I2, NaHCO3
Ph
(1;1, 2 equiv)
I
+
H2O
+
H2O
PEG 3400
MW 50°C
PEG 3400
MW, 10 min
R3
R1
HX
OH
N
Boc
Ph
BocHN
OH
N
1a–f
2a–f
Boc
1a
2a
Entry
Product
Temp (°C)Yield
(%)a
Entry
I2 (equiv) NaHCO3 (equiv) Time (min) Yield (%)a
Ph
1
2
3
4
5
3
3
2
2
1
3
3
2
2
1
15
10
10
5
44
I
42
1
2a
50
81
81
Ph
N
Boc
69
10
36 (73)b
Ph
a Yields and conversions were calculated by 1H NMR using CH2Br2
as an internal standard;
I
2
3
2b
2c
55
50
67
66
b In parenthesis residual quantity of substrate 1a is given, determined
by HPLC.
Ph
N
Boc
Ph
good to satisfying yields in only ten minutes (Table 2). β-
Iodopyrroles16 were previously synthesized using a relat-
ed reaction in conventional solvents (acetonitrile or di-
chloromethane) but this approach required a two-step
procedure, involving the formation of an hydroxydihydro-
pyrrole intermediate and requiring the use of MsCl in the
presence of Et3N to promote the final dehydration reac-
tion. These reactions were performed at room temperature
requiring long reaction time (2–16 h) while the reactions
were shorter for β-iodofurans (3 h).10,11 Moreover, a chro-
matographic purification was always necessary. In com-
parison with the literature data, our method is powerful
not only because of the use of an eco-friendly solvent such
as PEG, but also for the shorter reaction times (only ten
minutes) under microwave irradiation and in the case of
pyrrole, for a more straightforward route.
Ph
I
Ph
O
I
Ph
Ph
4
5
6
2d
2e
2f
55
55
50
63
37
42
Ph
O
O
I
I
Ph
O
On one hand, the nitrogen reactivity for the formation of
the tetrasubstituted β-iodopyrroles is probably modulated
by the nature of the α-substitution (Table 2, entries 1 and
2); on the other hand the 5-endo-dig cyclization leading to
the formation of β-iodofurans seems to be mostly influ-
enced by the nature of the substituent on the triple bond
undergoing the nucleophilic attack. Probably, the steric
hindrance and/or the electronic effects are responsible for
the different yields obtained in the series of trisubstituted
β-iodofurans (entries 4–6, Table 2). These experimental
observations were confirmed by an unexpected result dur-
ing the iodocyclization of N-protected amino alcohol 1g,
bearing a butyl chain on the triple bond (Table 3). To our
surprise, the 5-endo-dig iodocyclization afforded a mix-
ture of two different products identified respectively as
the expected iodocyclized tetrasubstituted β-iodopyrrole
2g and one of its derivative 3g, in which the second triple
bond was diiodinated. This result can be explained by the
presence of the electron-donating butyl group on the triple
a Yields were calculated by 1H NMR using CH2Br2 as an internal stan-
dard.
bond which is not involved in the 5-endo-dig cyclization,
bringing an increased nucleophilicity of the alkyne moi-
ety. In this perspective, the excess of electrophilic iodine
would favor this side reaction, not observed in the case of
the other substrates tested during this study, bearing a con-
jugated phenyl group on the triple bond. Similar observa-
tions were described in previous reports, showing that
both halogen atoms generated from electrophiles could be
effectively used.27–29 Double addition of iodine has been
observed in the presence of molecular iodine, while iodo-
halogenation was observed with iodine monochloride or
monobromide.27
Then we explored the possibility to direct the course of the
reaction towards the formation of only one of the two
Synlett 2012, 23, 1481–1484
© Georg Thieme Verlag Stuttgart · New York

LETTER
Easy Access to Highly Functionalized Furans and Pyrroles
1483
Table 3 Iodocyclization of 1g
Bu
Bu
Bu
I
I
I
I
Bu
I2, base
(1:1, 2 equiv)
Ph
and / or
Bu
Bu
N
PEG
MW, 55 °C, 10 min
N
BocHN
OH
Boc
Boc
Ph
Ph
2g
3g
1g
Entry
PEG
Base
Temp (°C)
Yield (%)a of 2g
Yield (%)a of 3g
1
2
3
4
PEG 3400
NaHCO3
NaHCO3
K2CO3
–
50
55
55
55
50
18
45
0
39
42
0
PEG 2000-(OMe)2
PEG 3400
PEG 3400
71
a Yields were calculated by 1H NMR using CH2Br2 as an internal standard. All the reactions were carried out using 350 mg of PEG 3400.
(2) Lee, Y.; Lim, C.; Kim, S.; Shin, S. Bull. Korean Chem. Soc.
2010, 31, 670.
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9985.
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(6) Kaur, P.; Singh, P.; Kumar, S. Tetrahedron 2005, 61, 8231.
(7) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
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products 2g and 3g, by modulating the reaction condi-
tions. Selected data are reported in Table 3.
The reaction was carried out using always two equivalents
of molecular iodine, with or without a base, in different
PEGs, under microwave activation with an initial power
of 400 W. When an equimolar quantity of I2/NaHCO3 was
used, the selectivity of the reaction was governed by the
nature of PEG. In PEG 3400, the global yield of 2g/3g was
89%, with a preference for the monoiodinated pyrrole 2g
(Table 3, entry 1), while in PEG 2000-(OMe)2, even if the
global yield was slightly lower (70%), the reaction pro-
ceeded preferentially towards the formation of triiodinat-
ed pyrrole 3g (Table 3, entry 2). However, in PEG 3400
the nature of the base played an important role: monoio-
dinated 2g was formed as the only product when I2/K2CO3
(1:1, 2 equiv) was used and no traces of 3g could be de-
tected (Table 3, entry 3). The selectivity was completely
reversed when the reaction was carried out in PEG 3400
in the absence of base, affording 3g in good yield as the
only product (71%, Table 3, entry 4). This represents the
first example of iodocyclization in which a triiodinated
pyrrole was obtained efficiently.30
(16) Knight, D. W.; Rost, H. C.; Sharland, C. M.; Singkhonrat, J.
Tetrahedron Lett. 2007, 48, 7906.
(17) Okitsu, T.; Sato, K.; Potewar, T. M.; Wada, A. J. Org. Chem.
2011, 76, 3438.
(18) Kim, K.; Kim, I. J. Comb. Chem. 2010, 12, 379.
(19) Cho, C.-H.; Neuenswander, B.; Larock, R. C. J. Comb.
Chem. 2010, 12, 278.
In conclusion, the results reported herein demonstrate
again the importance of PEG as a practical, alternative,
cheap and eco-friendly solvent for organic synthesis. We
are also delighted to present the first examples of iodocy-
clization reaction of alkynyl diols or N-Boc alkynyl amino
alcohols using PEG as solvent under microwave irradia-
tion.
(20) Togo, H.; Iida, S. Synlett 2006, 2159.
(21) Declerck, V.; Martinez, J.; Lamaty, F. Synlett 2006, 3029.
(22) Colacino, E.; Villebrun, L.; Martinez, J.; Lamaty, F.
Tetrahedron 2010, 66, 3730.
(23) Declerck, V.; Ribiere, P.; Nedellec, Y.; Allouchi, H.;
Martinez, J.; Lamaty, F. Eur. J. Org. Chem. 2007, 201.
(24) Sauvagnat, B.; Lazaro, R.; Martinez, J.; Lamaty, F.
Tetrahedron Lett. 2000, 41, 6371.
(25) Colacino, E.; Daich, L.; Martinez, J.; Lamaty, F. Synlett
2007, 1279.
Acknowledgment
We thank the CNRS, the MESR, and the Università della Calabria
(Italy) for financial support.
(26) Typical Experimental Procedure: A mixture of I2 (25 mg,
0.1 mmol), NaHCO3 (0.1 mmol), PEG 3400 (350 mg) and
substrate 1a (0.05 mmol) was reacted under microwave
irradiation at 50 °C (initial power 400 W) for 10 min.
The reaction mixture was diluted with CH2Cl2 (2.0 mL),
References
(1) Pradal, A.; Nasr, A.; Toullec, P. Y.; Michelet, V. Org. Lett.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1481–1484

1484
R. Spina et al.
LETTER
precipitated in Et2O (250 mL), cooled for 3 h at –18 °C to
improve PEG precipitation and filtered. The organic phase
was washed with a saturated solution of sodium thiosulfate
(Na2S2O3) to neutralize the excess of iodine. Compound 2a
was recovered as a yellow oil in 81% yield. Spectral data for
2a: 1H NMR (300 MHz, CDCl3): δ = 7.55–7.58 (m, 2 H),
7.31–7.43 (m, 8 H), 3.00 (d, J = 7.1 Hz, 2 H), 2.03 (m, 1 H),
1.18 (s, 9 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.6 Hz,
3 H). 13C NMR (300 MHz, CDCl3): δ = 148.6, 140.3, 134.8,
134.3, 128.26, 127.8, 123.8, 112.7, 93.6, 84.5, 84.4, 75.1,
36.3, 29.7, 27.0, 22.6. HMRS (ESI): m/z [M + H]+ calcd for
C27H29NO2I: 526.1243; found: 526.1245.
(29) Ke-Gong, J.; Hai-Tao, Z.; Fang, Y.; Xing-Zhong, S.; Shu-
Chun, Z.; Xue-Yuan, L.; Ali, S.; Yong-Min, L. Chem.–Eur.
J. 2010, 16, 6151.
(30) Spectral data for 2g: 1H NMR (400 MHz, CDCl3): δ = 0.93
(t, J = 7.2 Hz, 3 H), 0.94 (t, J = 7.2 Hz, 3 H), 1.33 (s, 9 H),
1.38–1.61 (m, 8 H), 2.43 (t, J = 7.2 Hz, 2 H), 2.87 (dd, 2 H),
4.37 (s, 2 H), 7.07–7.14 (m, 2 H), 7.16–7.25 (m, 3 H). 13
C
NMR (300 MHz, CDCl3): δ = 148.6, 139.8, 136.3, 136.0,
128.2, 128.0, 125.9, 113.6, 94.5, 84.6, 74.6, 74.5, 33.7, 31.2,
31.0, 29.3, 27.4, 22.5, 22.0, 19.3, 14.0, 13.6. ESI–MS (+):
m/z = 520.1 [M +H]+, 464.0 [M + H – t-Bu]+, 419.9 [M + 2
H – Boc]+.
(27) Langle, S.; Ngi, S. I.; Anselmi, E.; Abarbri, M.; Thibonnet,
J.; Duchêne, A. Synthesis 2007, 1724.
(28) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shaukat, A.; Xia, X.-F.;
Yang, Y.-F.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2010,
75, 5670.
Spectral data for 3g: 1H NMR (400 MHz, CDCl3): δ = 0.95
(t, J = 7.2 Hz, 3 H), 0.98 (t, J = 7.3 Hz, 3 H), 1.26 (s, 9 H),
1.40–1.51 (m, 8 H), 2.69–2.76 (m, 1 H), 2.82–2.92 (m, 3 H),
4.14 (s, 2 H), 7.10–7.17 (m, 3 H), 7.22–7.26 (m, 2 H). 13
C
NMR (300 MHz, CDCl3): δ = 148.7, 138.7, 136.8, 134.1,
129.4, 128.3, 128.2, 125.9, 111.1, 89.5, 84.7, 71.3, 49.7,
33.5, 32.0, 30.6, 29.1, 27.2, 22.5, 21.7, 14.1.
Synlett 2012, 23, 1481–1484
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