Substituent effect of bis(pyridines)iodonium complexes as iodinating reagents: Control of the iodocyclization/oxidation process

Article abstract of DOI:10.1002/chem.201204423

This work was supported by a Grant-in-Aid for Young Scientists (B) from MEXT. T.O. also acknowledges support from the Society of Iodine Science.

Full text of DOI:10.1002/chem.201204423

DOI: 10.1002/chem.201204423
Substituent Effect of Bis(pyridines)iodonium Complexes as Iodinating
Reagents: Control of the Iodocyclization/Oxidation Process
Takashi Okitsu,[a] Saki Yumitate,[a] Kana Sato,[a] Yasuko In,[b] and Akimori Wada*[a]
Iodonium-mediated electrophilic cyclization, namely iodo-
cyclization, is one of the most powerful methods for the con-
struction of functionalized cyclic compounds.[1] This reaction
creates simultaneously both a ring system and an iodo com-
ponent from an acyclic substrate, and the latter can be trans-
formed to another functionality.[2]
For an iodinating reagent, the use of the iodonium com-
plex of pyridine in organic synthesis was first demonstrated
by Barluenga and co-workers.[3] Bis
ACTHNUTRGNE(UNG pyridine)iodonium(I)
tetrafluoroborate (IPy2BF4), termed Barluengaꢀs reagent,[4]
and its variants, such as bis(2,4,6-collidine)iodonium(I) hexa-
fluorophosphate [IACHTUNGTRENNUNG
(coll)2PF6],[5] are widely used (Figure 1).
However, the relative reactivities of different aromatic
amines have not been systematically examined yet.[6]
Scheme 1. Product switch in iodocyclization.
complexes of pyridines, IPy2PF6 and
IACTHNGUTRE(UNNG coll)2PF6
AHCTUNGTRENNUNG
(Scheme 1b).[9] This was the first report of a product switch
Figure 1. Structures of iodonium complexes of pyridines.
controlled by the nature of the iodonium complexes of pyri-
dines. Furthermore, pyrrole skeletons, such as 2 and 3, are
important components of proline-based organic catalysts,[10]
pharmaceuticals, and natural alkaloids,[11] making divergent
approaches toward functionalized proline derivatives espe-
cially attractive. Herein, our initial studies on these unique
reactions are described.
The reaction conditions were screened with racemic sub-
strate 1a (Table 1). With common iodine reagents, pyrrole
3a was obtained in low yields (Table 1, entries 1–2). In con-
Recently, we successfully achieved
a product switch
through reagent-controlled iodocyclization (Scheme 1a).[7]
This strategy takes advantage of the dual nature of iodine
reagents as both iodinating and oxidizing agents and enables
the divergent synthesis of pyrazoles, isoxazoles, and their
2,5-dihydro products. During the course of our studies on io-
docyclization of a-propargylic glycine derivatives 1,[8] we
found that switchable access to 2,3-dihydropyrroles 2 and
pyrroles 3 could be achieved by the choice of the iodonium
trast, the use of IACHTUNRGTNEUNG(coll)2PF6 improved the yields of 3a
(Table 1, entries 3–6) and the use of acetonitrile as a solvent
gave the best result (Table 1, entry 5). To our great surprise,
treatment with IPy2PF6, which changed the aromatic amine
of the iodine reagent from 2,4,6-collidine to pyridine, gave
2,3-dihydropyrrole (2,3-dehydroproline) (2a) as the sole
product (Table 1, entries 7–10). In this case, acetonitrile
again performed well as the solvent (Table 1, entry 8). Of
the carbamate groups used as N-protecting groups, isopro-
ACHUTNGRENpNUG ylACHUTNGTRENoNGUN xycarbonyl was the most suitable for both iodocycliza-
tion conditions (data not shown).
With the optimized reaction conditions established, the
scope of IPy2PF6 mediated iodocyclization was next exam-
ined by using various optically active substrates 1b–n
(Scheme 2). With respect to the substituents on alkynes, var-
[a] Dr. T. Okitsu, S. Yumitate, K. Sato, Prof. Dr. A. Wada
Department of Organic Chemistry for Life Science
Kobe Pharmaceutical University
4-19-1, Motoyamakita-machi
Higashinada-ku, Kobe 658-8558 (Japan)
Fax : (+81)78-441-7562
E-mail: a-wada@kobepharma-u.ac.jp
[b] Dr. Y. In
Department of Physical Chemistry
Osaka University of Pharmaceutical Sciences
4-20-1, Nasahara, Takatsuki, Osaka 569-1094 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204423.
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Chem. Eur. J. 2013, 19, 4992 – 4996

COMMUNICATION
Table 1. Optimization for the iodocyclization of 1a.[a]
ate yield. Alkyl-substituted alkyne 1n was also ap-
plicable to this reaction, although the yield of 2n
was low. It is noteworthy that iodocyclization of 1b
(>99.5% enantiomeric excess, ee) resulted in no
loss of enantiomeric excess of 2,3-dehydroproline
2b (>99.5% ee). In addition, the N-tosyl and N-
Boc groups remained intact under these reaction
conditions. These results imply that the reaction
conditions are very mild, and that our reaction can
be applied to the asymmetric synthesis of proline
analogues.
Entry
Reagents
(equiv)
Solvent
t
Yield of 2a
[%]
Yield of 3a
[%]
N
[h]
1[b]
2
3
4
5
6
7
8
9
NIS (3), BF3·OEt2 (3)
I2 (3), K2CO3 (3)
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3NO2
CH3CN
CH3CN
CH3NO2
CH2Cl2
1
17
1
1
1
1.5
1
1
0.5
1
0
0
0
0
0
26
14
42
64
93
29
0
0
0
0
I
I
I
I
N
The transformation of 1b–n to pyrroles 3b–n by
IACTHNUTRGEN(NUG coll)2PF6 also proceeded in a similar manner
0
IPy2PF6 (2)
IPy2PF6 (3)
IPy2PF6 (3)
IPy2PF6 (3)
56
84
67
71
(Scheme 2). Thus, various substrates were applica-
ble under these reaction conditions, whereas 4-ni-
trophenyl- and n-butyl-substituted alkynes 1c and
1n were gradually decomposed. Although pyrroles
3d–f, 3h, and 3j were not sufficiently produced, the
10
[a] Reaction was performed under argon atmosphere. Yields are given for isolated
products after column chromatography. [b] Reaction was performed at 08C.
use of BF3·OEt2 as an activator of IACHTNUGTRENUNG(coll)2PF6 signif-
icantly improved their yields.
ious aryl and heteroaryl groups successfully gave 2d–l,
whereas the 4-nitrophenyl group 1c was not suitable as a
substrate. IPy2PF6 did not influence the vinylic group on the
alkyne 1m by diminishing the reagent to give 2m in moder-
For a clear understanding of the reaction mechanism, 2,3-
dihydropyrrole (2a) was treated with N-iodosuccinimide
(NIS) or I
ACHTUNGRTNEN(UNG coll)2PF6 to give pyrrole 3a in 32 and 54% yields,
respectively (Scheme 3). Complex 2a was also exposed to
Scheme 2. Iodocyclization of 1. Unless noted otherwise, reactions were carried out with 1 (1 equiv) and IPy2PF6 or IACTHNUTRGNEUNG(coll)2PF6 (3 equiv) in CH3CN (0.1m)
at room temperature under Ar. Yields are given for isolated products after column chromatography. [a] IPy2PF6 (1.1 equiv) was used. [b] The reaction in-
cluded BF3·OEt2 (3 equiv) as an additive.
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A. Wada et al.
Scheme 3. Halonium-mediated oxidation of 2a.
[5b]
BrACHTUNGTRENNUNG(coll)2PF6 to give bromopyrrole 4a in 66% yield. Com-
pound 4a was individually prepared from the reaction of 1a
with Br(coll)2PF6 in 54% yield. On the other hand, 2a was
ACHTUNGTRENNUNG
intact toward 2,4,6-collidine and silica gel. These results in-
dicated that the pyrrole 3 was produced via electrophilic ad-
dition of halonium ion to 2,3-dihydropyrazole (2).
Based on the outcomes of these reactions, a plausible
mechanism for the iodocyclization of 1 to give 2 and 3 was
proposed (Scheme 4). The 5-endo cyclization of iodonium
ion A gives 2,3-dihydropyrrole 2. When a more reactive I+
Figure 2. ORTEP representation of IPy2PF6; thermal ellipsoids are set at
50% probability. Hydrogen atoms are omitted for clarity. Selected bond
Scheme 4. Plausible reaction mechanism.
À
À
lengths [ꢂ] and angles [8]: I1 N1 2.259, I1 N1a 2.259; N1-I1-N1a 179.0.
source, I
G
The iodo component produced by iodocyclization can be
further transformed by Pd-catalyzed cross-coupling reac-
tions. Because of the importance of generating a library of
proline scaffolds, 2,3-dehydroproline (2b) was preliminarily
elaborated with Suzuki–Miyaura cross-coupling,[13] Sonoga-
shira cross-coupling,[14] Heck reaction,[15] and Larock car-
ene carbamate group of 2 might be caused to produce iodo-
nium ion B. The ring opening of B followed by the elimina-
tion of HI from acyl iminium ion C would give D. Finally,
pyrrole 3 is obtained through the deprotonation of D.
The structures of IPy2PF6 and IACHTUNTRGNEUNG(coll)2PF6 were determined
by single-crystal X-ray diffraction to clarify their differences
in reactivity (Figures 2 and 3). The N-I-N bond patterns of
both the iodonium cations are nearly linear. The iodous hal-
ogen bonds of IPy2PF6 show symmetry and the I N bond
length is 2.259 ꢂ, whereas those of I
boannulation[16] to get a variety of C C bond formations in
À
high yields (Scheme 5). Thus, our methodology could pro-
vide access to a wide variety of 2,3-dehydroproline deriva-
tives.
À
ric and the I N bond length are 2.272 and 2.304 ꢂ. Another
difference is the dihedral angle that consisted of the least-
squares planes of the two pyridine rings: IPy2PF6 is 1.2 and
IACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
mentioned that the significant twisted conformation would
be caused by the steric hindrance between the methyl
groups at the 2,6-position of the pyridine ring and the iodine
À
atom. Due to its asymmetric, longer I N bond length and
twisted conformation, I
A
I+ source than IPy2PF6.
Scheme 5. Transformations of 2b.
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Substituent Effect of Bis(pyridines)iodonium Complexes
COMMUNICATION
one week to give bisACHTNUGTRNEUNG(pyridine)silver(I) hexafluorophosphate (AgPy2PF6,
1
120.8 g, 98%) as a colorless solid. M.p. 182.5–1858C; H NMR (300 MHz,
CD3CN): d=8.57–8.55 (br m, 4H), 7.91 (br s, 2H), 7.50 ppm (br s, 4H);
13C NMR (75 MHz, CDCl3): d=151.9, 126.0, 116.5 ppm; elemental analy-
sis calcd (%) for C10H10AgF6N2P: C 29.22; H 2.45; N 6.82; found: C
29.14; H 2.48; N 6.83.
To a mixture of AgPy2PF6 (11.6 g, 28.3 mmol) in dry CH2Cl2 (87 mL),
iodine (7.11 g, 28.0 mmol) was added at RT over 5 min. The vessel was
filled with argon and stirred at RT in the dark for 1 h. The mixture was
filtered, washed with dry CH2Cl2, and the filtrate was evaporated to give
IPy2PF6 (11.5 g, 95%) as a colorless solid. M.p. 152–1538C; 1H NMR
(300 MHz, CD3CN): d=8.77 (d, J=5.1 Hz, 4H), 8.25 (t, J=7.8 Hz, 2H),
7.65–7.60 ppm (m, 4H); 13C NMR (75 MHz, CD3CN): d=150.7, 143.3,
128.9 ppm; elemental analysis calcd (%) for C10H10F6IN2P: C 27.93; H
2.34; N 6.51; found: C 27.89; H 2.33; N 6.46.
General procedure for iodocylization: To a solution of 1 (1 equiv) in dry
CH3CN (0.1m), IPy2PF6 or IACTHNURGTNEUNG(coll)2PF6 (3 equiv) was added, and the reac-
tion mixture was stirred at RT for 1 h under argon. The reaction mixture
was quenched with a saturated aqueous solution of Na2S2O3 and was ex-
tracted with AcOEt. The organic layer was dried over Na2SO4, filtered,
and evaporated in vacuo. The residue was purified by flash-column chro-
matography on silica gel by using hexane/AcOEt (5:1 to 2:1) as an
eluent to give 2 or 3.
CCDC-907268 (IPy2PF6) and CCDC-907267 (IACTHNUGTRENNUG(coll)2PF6) contain the sup-
plementary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
This work was supported by a Grant-in-Aid for Young Scientists (B)
from MEXT. T.O. also acknowledges support from the Society of Iodine
Science.
Figure 3. ORTEP representation of I
at 50% probability. Hydrogen atoms are omitted for clarity. Selected
bond lengths [ꢂ] and angles [8]: I1 N1 2.272, I1 N2 2.304; N1-I1-N2
178.9.
ACHTUNGTRNE(NUNG coll)2PF6; thermal ellipsoids are set
À
À
Keywords: cyclization · iodine · oxidation · substituent
effects · synthetic methods
In conclusion, a switchable access to 2,3-dihydropyrroles
(2,3-dehydroprolines) and pyrroles from common a-propar-
gylic glycines has been investigated. Our studies revealed
that the iodocyclization/oxidation sequence was controllable
by the slight differences in the iodonium complexes of pyri-
dines. This information would be valuable for tuning the
electrophilicity of iodonium complexes. In addition, our
flexible synthetic strategy may assist the development of
proline-based organic catalysts and provide a powerful tool
for drug discovery. Investigation of new iodonium com-
plexes of pyridines and the scope of substrates is ongoing.
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Experimental Section
Synthesis of IPy2PF6: Based on a literature procedure for the preparation
of IACHTUNGTRENNUNG
(coll)2PF6,[5b] to a solution of AgNO3 (50.96 g, 0.300 mol) and KPF6
(55.77 g, 0.303 mol) in distilled water (510 mL), pyridine (68.9 mL,
0.852 mol) was added over 15 min while stirring at RT. A slightly exo-
thermic reaction was observed, corresponding to the formation of a
white solid. After the mixture was stirred for 75 min at RT, the solid was
suction filtered, and the residue was washed with distilled water
(600 mL). The residue was repeatedly dried by filter paper and was fur-
ther dried in the dark in a desiccator under high vacuum over P2O5 for
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Received: December 12, 2012
Revised: January 28, 2013
Published online: March 1, 2013
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Chem. Eur. J. 2013, 19, 4992 – 4996