Synthesis of substituted 3-iodopyrroles by electrophilic cyclization of propargylic aziridines

Article abstract of DOI:10.1016/j.tetlet.2009.09.004

The electrophilic cyclization of propargylic aziridines is described. 3-Iodopyrroles having a variety of substituents were conveniently synthesized by the reaction of propargylic aziridines with iodine. The resulting substituted 3-iodopyrrole was further

Full text of DOI:10.1016/j.tetlet.2009.09.004

Tetrahedron Letters 50 (2009) 6268–6270
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Synthesis of substituted 3-iodopyrroles by electrophilic cyclization
of propargylic aziridines
*
Masahiro Yoshida , Mohammad Al-Amin, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The electrophilic cyclization of propargylic aziridines is described. 3-Iodopyrroles having a variety of
substituents were conveniently synthesized by the reaction of propargylic aziridines with iodine. The
resulting substituted 3-iodopyrrole was further functionalized to the tri-substituted pyrroles with high
efficiency.
Received 1 August 2009
Revised 28 August 2009
Accepted 1 September 2009
Available online 4 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Substituted pyrroles are an important class of heteroaromatic
molecules which are components in a variety of biologically active
natural products and industrially useful compounds.1 They are also
extensively utilized as synthetic intermediates for heterocyclic
compounds in organic synthesis.2 For these reasons, considerable
effort has been devoted toward finding an efficient synthesis of
substituted pyrroles.3 Among them, transition metal-catalyzed
cycloisomerization of propargylic aziridines is one of the useful
methodologies for the synthesis of substituted pyrroles. Recently,
the example about the gold-catalyzed synthesis of pyrroles has
been reported independently by Davies4 and Hou.5 We have also
found that platinum acts as a catalyst for the cycloisomerization
of propargylic aziridines.6 On the other hand, electrophile-pro-
moted cyclization is a useful methodology for the synthesis of a
wide range of halogenated heterocyclic compounds.7 However, to
the best of our knowledge, there is no focusing on the electrophilic
conversion of propargylic aziridines to pyrroles. We report herein
about an iodine-promoted electrophilic cyclization of propargylic
aziridines, in which various substituted 3-iodopyrroles can be syn-
thesized with high efficiency.
100 °C (entry 3). Although non-iodinated pyrrole 3 was bypro-
duced in 28% yield in this reaction condition,10 it has been made
Bn
10 mol % PtCl2, 2 equiv NIS
N
dioxane/ H2O (2:1), 100
°
C, 60 min
Cy
1a
Bn
N
Bn
N
Cy
Cy
+
I
2a 22%
3 49%
Scheme 1. Platinum-catalyzed iodocyclization of propargylic aziridine 1a.
Table 1
Electrophilic iodoyclizations of 1a
We initially examined the reaction of propargylic aziridine 1a
under the platinum-catalyzed iodocyclization condition.6,8 When
1a was treated with 10 mol % of PtCl2 and 2 equiv NIS in
dioxane/H2O (2/1) at 100 °C for 60 min, the desired 3-iodopyrrole
2a was produced in 22% yield along with non-iodinated pyrrole 3
as the inseparable major product in 49% yield (Scheme 1).
Bn
N
2 equiv I2
NaHCO3 ,solvent, 10–90 min
Cy
1a
Bn
N
Bn
N
Cy
Cy
We next attempted the electrophilic activation of propargylic
aziridines, in which the similar process could proceed in the reac-
tion of 1a with iodine (Table 1).9 Although no reaction proceeded
when 1a was treated with 2 equiv of iodine and 2 equiv of NaHCO3
in THF at rt (entry 1),7r the desired product 2a was obtained in 43%
yield under the reflux condition in THF (entry 2). The yield was
improved to 64% when the reaction was carried out in dioxane at
I
2a
3
Entry
Solvent
NaHCO3 (equiv)
Temp (°C)
Yields (%)
2a
N.R.
3
1
2
3
4
THF
THF
Dioxane
Dioxane
2
2
2
5
rt
Reflux
100
100
43
64
90
—
28
—
* Corresponding author. Tel./fax: +81 88 633 7294.
E-mail address: yoshida@ph.tokushima-u.ac.jp (M. Yoshida).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.004

M. Yoshida et al. / Tetrahedron Letters 50 (2009) 6268–6270
6269
Table 2
Bn
R1
Reactions with propargylic aziridines 1b–1ja
Bn
I2
N
N
R2
R2
R1
Entry Substrate
Product
Yield
(%)
I+
Bn
N
1
4
Bn
Ph
N
Cy
Ph
Bn
N
Bn
N
1
90
79
86
86
76
94
95
95
68
H
Cy
R2
R1
R2
R1
1b
I
I
I
I
I
2b
+
–
H
I
I
Bn
N
2
5
Bn
Bn
Cy
Cy
Cy
Cy
( )3
Bn
N
2
Scheme 2. Proposed reaction mechanism.
Cy
1c
2c
Bn
MeO
Bn
Bn
N
N
Bn
Cy
ZnCl
N
Cy
N
6
3
Cy
10 mol % Pd(PPh3)4
THF, rt, 30 min
OMe
I
1d
2d
2a
7
83%
Bn
N
Bn
( )3
( )3
OTBDPS
Scheme 3. Negishi coupling reaction of 3-iodopyrrole 2a with arylzinc reagent 6.
OTBDPS
N
4
Cy
1e
2e
the corresponding products 2b–2e were produced in good yields
(entries 1–4). The propargylic aziridine containing a free hydroxyl
group, 1f, was uneventfully transformed to the 3-iodopyrrole 1f in
76% yield (entry 5). The reactions of the substrates 1g and 1h,
which contain butyl and t-butyl groups on the aziridine ring,
successfully afforded the 3-iodopyrroles 2g and 2h in 94% and
95% yield, respectively (entries 6 and 7). The phenyl- and 2-naph-
thyl-substituted substrates 1i and 1j were also converted to the
corresponding products 2i and 2j in 95% and 68% yield, respec-
tively (entries 8 and 9).
A plausible mechanism for the iodine-promoted cyclization of
propargylic aziridines 1 is shown in Scheme 2. Coordination of the
propargylic triple bond to an iodine cation forms the cyclic iodonium
ion 4. Subsequent attack of the aziridine nitrogen on the iodonium
ion produces the cyclized intermediate 5, which causes aromatiza-
tion by elimination of the proton leading to the 3-iodopyrrole 2.
The presence of the iodo functional group on the pyrrole ring
provided an opportunity for further functionalization. To introduce
an aryl group by the coupling reaction, we next investigated the
Negishi coupling reaction of the resulting compound 2a.11 When
Bn
N
Bn
( )3
OH
( )3
OH
N
5
6
Cy
1f
2f
Bn
Bn
N
N
( )3
1g
1h
2g
I
I
Bn
N
Bn
N
7
2h
Bn
Bn
N
2a was treated with arylzinc reagent
10 mol % Pd(PPh3)4 in THF at rt, the corresponding tri-substituted
pyrrole 7 was obtained in 83% yield (Scheme 3).
In conclusion, we have developed a methodology for the
synthesis of 3-iodopyrroles by an iodine-promoted electrophilic
cyclization. The reaction afforded a variety of substituted 3-iodo-
pyrroles, and the process provided an efficient and convenient pro-
tocol for the preparation of these derivatives.
6 in the presence of
Ph
N
8
Ph
1i
2i
I
Bn
Bn
N
N
Nap
9b
Nap
1j
I
2j
Acknowledgments
a
All reactions were carried out in the presence of 2 equiv iodine and 5 equiv
NaHCO3 in dioxane at 100 °C for 10 min.
b
This study was supported in part by a Grant-in-Aid for the
Encouragement of Young Scientists (B) from the Japan Society for
the Promotion of Science (JSPS) and the Program for Promotion
of Basic and Applied Researches for Innovations in Bio-oriented
Industry (BRAIN).
Nap = 2-naphthyl.
clear that 2a was obtained in 90% yield as a sole product when
5 equiv of NaHCO3 was used (entry 4).
The reactions of various substituted propargylic aziridines 1b–
1j are summarized in Table 2. When the substrates 1b–1e having,
respectively, a phenyl, benzyl, allyl, and siloxypropyl group at the
alkynyl position were subjected to the electrophilic cyclizations,
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