Stable polymer-bound iodine azide

Article abstract of DOI:10.1002/(SICI)1521-3773(19990903)38:17<2594::AID-ANIE2594>3.0.CO;2-U

1,2-Azido-iodination of a wide range of alkenes under very mild conditions can be achieved by using a novel iodate(I) reagent, a stable and storable polymer-bound iodine azide, which is available in two steps (see scheme). Simple work-up and convenient use in automated parallel synthesis are important features of this polymer-bound reagent.

Full text of DOI:10.1002/(SICI)1521-3773(19990903)38:17<2594::AID-ANIE2594>3.0.CO;2-U

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[10] A standard solution containing the same guest concentration was
periodically checked with the same techniques employed for each
experiment. To further show that the alcohol guests were included
within the pores rather than on the crystal surface, the GC sample was
filtered, washed with toluene, air dried, and then elemental micro-
analysis was performed to confirm the presence of alcohol.
[11] SAX Area-Detector Integration Program (SAINT), V4.024, Siemens
Industrial Automation, Inc., Madison, WI, 1995.
[12] XPREP, V5.03, is part of the program SHELXTL Crystal Structure
Determination, Siemens Industrial Automation, Inc., Madison, WI,
1995.
[13] Siemens Area Detector ABSorption correction program (SADABS),
G. Sheldrick, personal communication, 1996.
cally behaves like iodine azide (3b). Since the pioneering
work of Hassner et al.[12] azido-iodination of alkene double
bonds has become a very useful procedure for introducing a
nitrogen functionality into a carbon skeleton. Iodine azide
(3b) has commonly been generated in situ from sodium azide
and iodine chloride in polar solvents.[12, 13] However, its
explosive character is regarded to be a major disadvantage.
Our approach to iodine azide (3b) is based on the reaction
of (diacetoxyiodo)benzene with polystyrene-bound iodide
1 in dichloromethane at room temperature, which presum-
ably afforded polymer-bound di(acetyloxy)iodate(i) (2)
(Scheme 1).[14, 15] Treatment of 2 with trimethylsilylazide
furnished a resin which synthetically acts like immobilized
iodine azide (3b). However, extensive washing of the resin
does not result in deactivation thus we propose that polymer-
bound bis(azido)iodate(i) (3a) is the active species. Reagent
Stable Polymer-Bound Iodine Azide**
Andreas Kirschning,* Holger Monenschein, and
Carsten Schmeck
I
OAc
I
PhI(OAc)2
NMe3
2
NMe3
Dedicated to Professor Armin de Meijere
on the occasion of his 60th birthday
OAc
1
PhI(N3)2
TMSN3
In addition to numerous methods for the syntheses of
organic molecules on polymeric supports, there has been a
recent upsurge in the interest in the use of polymer-bound
reagents in organic chemistry.[1] The intrinsic advantage of this
hybrid solid-/solution-phase technique lies in the simple work-
up and isolation of the reaction products combined with the
flexibility of solution-phase chemistry. Furthermore, these
reagents may be used in excess in order to drive the reaction
to completion without making the isolation of the products
more difficult. Although stoichometric polymer-supported
reagents have been employed in organic synthesis for many
years, their application to the construction of small molecule
libraries is a relative recent phenomenon. This can be ascribed
to the fact that the number of readily available reagents of this
type is still small. Important developments in this field are
polymer-supported reductants,[2] oxidants,[3] solution-phase
scavengers,[4] chelating proton donors,[5] carbodimide equiv-
alents,[6] or reagents that are capable of promoting C C bond-
forming reactions.[7] However, polymer-bound reagents for
1,2-cohalogentions[8, 9] of alkenes have not been described so
far.[10]
N3
I
NMe3
I
N3
N3
3a
3b
Scheme 1. Preperation of novel polymer-bound iodine azide.
TMS ˆ Me3Si.
3a may also be generated by direct azido transfer after
treatment of iodide 1 with (diazidoiodo)benzene. However, as
PhI(N3)2 has to be prepared in situ from (diacetoxyiodo)ben-
zene and trimethylsilylazide efficient azido transfer to 1 is
hampered by the presence of trimethylsilyl acetate in solution.
The IR spectrum of the new polymer 3a shows a pair of strong
1
bands at nÄ ˆ 2010 and 1943 cm , which confirm the presence
of an azido group. It smoothly promotes azido-iodination of
alkenes 4 ± 18 to give the anti addition product (Table 1).[16]
Except for electron-defficient alkenes 5 and 11 and for
methylenecyclopropane 17 (Table 1), sensitive b-iodo azides
19, 21 ± 25, and 27 ± 33 are generated in good to excellent
yield. They are conveniently purified by filtration and
removal of the solvent.[17] The regioselectivity of the 1,2-
addition is governed by the more stable intermediate carben-
ium ion formed after electrophilic attack. Only when alkyl-
substituted alkenes 15 and 16 were subjected to the azido-
iodination conditions, were small amounts of the anti-
Markovnikov 1,2-adducts formed. Remarkably, free hydroxy
groups in allyl or homoallyl position, such as in alkenes 7, 13,
and 14, are tolerated under the conditions employed. Addi-
tion to methylenecyclopropane 17 proceeded in a highly
regioselective and stereoselective manner to furnish 32.
Rearrangement products which may have originated from
the very stable intermediate cyclopropylmethyl cation[18] were
not isolated. The relative configuration of 32 was uneqivocally
assigned by nuclear Overhauser effect (NOE) experiments
(Table 2). Finally, also 1,2-functionalization of carbohydrate-
As an extension of our earlier work on ligand-transfer
reactions from hypervalent iodine(iii) reagents to halides in
solution,[11] we initiated a study on the development of the
first stable electrophilic polymer-bound reagent that syntheti-
[*] Dr. A. Kirschning, H. Monenschein
Institut für Organische Chemie der Technische Universität Clausthal
Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld (Germany)
Fax: (‡49)5323-72-2858
E-mail: andreas.kirschning@tu-clausthal.de
Dr. C. Schmeck
Bayer AG, Business Group Pharma PH-R-CR, D-42096 Wuppertal
(Germany)
[**] This work was supported by the Fonds der Chemischen Industrie. We
thank Bayer AG and particularly Dr. D. Häbich (Wuppertal) for
financial and technical support.
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Angew. Chem. Int. Ed. 1999, 38, No. 17

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Table 1. Azido-iodination of alkenes using polymer 3a.
Table 2. NOE effects in 32.
Alkene
R1, R2
t, n(3)[a]
[equiv]
Product
Yield[b]
[%]
rel. NOE effect [%][a]
Ha/Hd
Ha/He
He/Hc
He/Hd
Hd/Hd'
1.9, 2.1 (3.6)
2.0 (2.9)
4.4
R2
N3
R2
[b]
±
R1
I
16.0
R1
4
5
6
7
OMe, Me
F, H
H, Ph
16h, 4
12h, 4
20h, 5
2d, 4
19
20
21
22
89[c]
38
56[d]
94
[a] Values in parentheses refer to the reversed nuclear Overhauser
experiment. [b] NOE not observed.
H, CH2OH
derived glycal 18 was achieved by the use of polymer 3a to
afford 2-deoxy-2-iodoglycosyl azides 33 with pronounced
preference for the b-configured 1,2-diequatorial isomer.
I
OMe
OMe
N3
R1
8
10h, 5
23
74
H
d
N3
N3
H
b
d
N3
N3
Ha
N3
R2
H
MeO
R1O
R2
R3
MeO
R1O
R2
H
e
N3
I
H
e
R1O
I
H
c
9
10
Me, Me
Bn, H
12h, 3
12h, 3
24
25
78
74[e]
34: R1= R2= Me; R3= H
35: R1= Bn; R2= H; R3= OMe
36
32
N3
Prolonged reaction times led to by-products 34 ± 36 when
N
styrenes 4 and 10 containing electron-donating aryl substitu-
ents as well as indene 12 were used as starting alkenes.
Analytical support for the structures of these 1,2-diazides
came from the analysis of the IR spectra, which revealed the
presence of an azido functionality, and from the analysis of the
chemical shifts of the former olefinic protons (d ˆ 4.32 ± 4.81
and 3.39 ± 4.26) and carbon atoms (d ˆ 67.4 ± 70.7 and 61.4 ±
N
I
11
12
14h, 6
20h, 5
26
27
49
N3
I
78[f]
1
58.3) in the H and particularly the 13C NMR spectra, which
N3
clearly proved the absence of a C I bond and the presence of
two C N bonds.
R1
R1
I
In conclusion, we have developed a new polymer-supported
iodine azide source that can be employed for the azido-
iodination of alkenes under very mild conditions and that
allows easy product isolation. The reagent can be handled
without the disadvantages associated with all known iodine
azide reagents in solution. In addition, further chemical
manipulations of the b-iodoazides allow the automated
parallel synthesis of N-heterocycles.
13
14
OH
CH2OH
1.5d, 6
1.5d, 6
28
29
98
91
OMe
OMe
OMe
I
O2N
O2N
N3
OMe
15
2d, 8
2d, 8
30
84[g]
MeO
MeO
N3
MeO
MeO
I
16
31
86[h]
Experimental Section
H
N3
H
Preparation of 3a: A suspension of untreated polymer-bound iodide 1
(1 equiv; 2.9 mmol iodide per gram resin, Fluka) and PhI(OAc)2 (1.8 equiv)
in dry CH2Cl2 (2.5 mLmmol iodide) under nitrogen was shaken at
Ph
Ph
I
1
300 rpm for 2 h at room temperature. During this time the brownish
suspension was protected from light. The light yellow resin 2 was filtered,
washed with dry CH2Cl2 (3 Â ; 30 mL per gram resin), and dried in vacuo. A
suspension of 2 (1 equiv with respect to 1) protected from light in dry
CH2Cl2 (4 mLmmol 1) was treated with trimethylsilylazide (2.6 equiv)
under nitrogen and was shaken at 300 rpm for 2 h. During this time the
solution above the polymer had turned to red. Filtration and washing of the
resin with CH2Cl2 (3 Â ; 30 mL per gram resin) and drying in vacuo
afforded the orange reagent 3a. Resin 3a can be prepared in this way on a
50 g scale. It does not tend to explode under mechanical stress or by heat
(>2808C) or open flames. It can be stored for several weeks under nitrogen
at 158C in the dark. The weight increase reproducibly served as an
indicator for efficient ligand transfer onto polymer-bound iodide ( 90%
conversion with respect to theoretical iodide).
17
2d, 8
32
48
TESO
TESO
TESO
OTBS
O
OTBS
O
N3
33
TESO
I
18
12h, 4
82[i]
[a] The number of equivalents used refer to the amount of iodine in starting 1.
All reactions were carried out at room temperature. [b] Yield of isolated
product after flash column chromatography. [c] Contains 30% of 34 (1:1
mixture). [d] Two stereoisomers (2:1). [e] Contains 5.3% of 35. [f] Contains
11% of 36. [g] Ratio of regioisomers 10:1. [h] Ratio of regioisomers 8:1. [i] Only
b-galacto adduct shown; ratio of a-talo/b-galacto isomers 1:9.
Angew. Chem. Int. Ed. 1999, 38, No. 17
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General procedure for the azido-iodination of alkenes: A mixture of
alkene (1 equiv) and resin 3a was shaken at 300 rpm under light protection
in absolute CH2Cl2 (2 mLmmol 1; the number of equivalents of 3a is given
in Table 1) at room temperature. Completion of the reaction was
monitored by TLC (cyclohexane/ethyl acetate between 80/1 and 8/1) and
was terminated by filtration. The resin was washed with CH2Cl2 (3 Â ;
20 mLper gram resin) and the combined organic washings and filtrate were
concentrated under reduced pressure. In some cases, for example for the
separation of stereo- and regioisomers, additional purification of the
products by flash chromatography on silica gel was necessary.
[15] Polymer-bound iodate(i) complex 2 is also very useful for promoting
iodoacetoxylation of alkenes: A. Kirschning, H. Monenschein, M.
Jesberger, unpublished results.
[16] Most b-iodoazides described in Table 1 were conveniently prepared
by means of automated parallel synthesis.
[17] In fact, in some cases we observed that aqueous work-up led to back
reaction of the b-iodoazides to the starting alkenes, an obstacle which
is completely avoided when employing our new polymer-bound
reagent 3a.
[18] K. B. Wiberg, A. J. Ashen, J. Am. Chem. Soc. 1968, 90, 63 ± 74.
The structures of all addition products were elucidated by IR, 1H NMR,
and 13C NMR spectroscopy, and mass spectrometry (EI or DCI). 1H,13C-
COSY and the distortionless enhancement by polarization transfer
(DEPT) spectral editing technique were used to determine the regiochem-
istry of the 1,2-addition products. The 13C NMR shifts (in CDCl3): d ˆ
58.0 ± 64.7 (CH2-N3), 62.6 ± 74.9 (CH-N3), 62.8 ± 63.8 (C-N3; 28, 29), 7.8 ± 8.4
(CH2-I), 25.1 ± 35.2 (CH-I), 16.1 (C-I; 32). Only the chemical 13C NMR
shifts for the secondary iodide-bound carbon atoms in 7, 13, and 14 show a
pronounced downfield shift (d ˆ 39.7 ± 49.1) relative to all other examples.
All new compounds gave either correct elementary analysis or were
analyzed by high-resolution mass spectrometry in the CI-mode (reactant
gas: isobutane).
Olefin Cycloadditions of the Electrophilic
Phosphinidene Complex
ˆ
[iPr2N P Fe(CO)4]**
Jan B. M. Wit, Gerno T. van Eijkel, Franciscus J. J.
de Kanter, Marius Schakel, Andreas W. Ehlers, Martin
Lutz, Anthony L. Spek, and Koop Lammertsma*
Received: March 8, 1999 [Z13119IE]
German version: Angew. Chem. 1999, 111, 2720 ± 2722
Electrophilic phosphinidene complexes are known to
display carbene-like properties.[1] Through the pioneering
work of Mathey et al.[2] in the early 1980s these transient
species became accessible through thermal decomposition of
phosphinidene precursor 1 (Scheme 1). Even today this is
Keywords: alkenes
polymer-supported reagents ´ synthetic methods
´ azides ´ electrophilic additions ´
[1] Reviews: S. J. Shuttleworth, S. M. Allin, P. K. Sharma, Synthesis 1998,
1217 ± 1239; S. W. Kaldor, M. G. Siegel, Curr. Opin. Chem. Biol. 1997,
1, 101 ± 106; J. S. Früchtel, G. Jung, Angew. Chem. 1996, 108, 19 ± 46;
Angew. Chem. Int. Ed. Engl. 1996, 35, 17 ± 42; P. Hodge, D. C.
Sherringtom in Polymer-Supported Reaction in Organic Synthesis,
Wiley, New York, 1990; P. Laszlo in Preparative Chemistry using
Supported Reagents, Academic, San Diego, 1987.
[2] H. W. Gibson, F. C. Bailey, J. Chem. Soc. Chem. Commun. 1977, 815 ±
816; A. Nag, S. K. Sarkar, S. K. Palit, Synth. Commun. 1987, 17, 1007 ±
1013.
Scheme 1.
[3] B. Hinzen, S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1997, 1907 ± 1908;
B. Tamani, M. Hattam, D. Mohadjer, Polymer, 1991, 32, 2666 ± 2670; B.
Tamani, N. Goudarzian, Eur. Polym. J. 1992, 28(9), 1035 ± 1038.
[4] R. J. Booth, J. C. Hodges, J. Am. Chem. Soc. 1997, 119, 4882 ± 4886.
[5] N. Krause, M. Mackenstedt, Tetrahedron Lett. 1998, 39, 9649 ± 9650.
[6] M. C. Desai, L. M. Stramiello, Tetrahedron Lett. 1993, 34, 7685 ± 7688;
M. Adamczyk, J. R. Fishpaugh, Tetrahedron Lett. 1996, 37, 4305 ± 4308.
[7] M. Bernhard, W. T. Ford, J. Org. Chem. 1983, 48, 326 ± 332; I. Hughes,
Tetrahedron Lett. 1996, 37, 7595 ± 7598
virtually the only route to [RPM(CO)5] (2) (M ˆ W, Mo, Cr;
R ˆ Ph),[1a, 3] whereas the number of stable, isolable nucleo-
philic phosphinidene complexes continues to grow steadily.[4]
Unfortunately, access to 2 is hampered by the limited thermal
window for cheletropic elimination from 1 (100 ± 1308C or ca.
558C in the presence CuCl) and by the laborious synthesis of
1. In view of the rich chemistry of electrophilic phosphini-
denes we sought alternative synthetic pathways.
[8] Reviews: E. Block, A. L. Schwan in Comprehensive Organic Syn-
thesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack),
Our attention was drawn to the work of King et al. in the
late 1980s,[5] in which dichlorophosphanes and Collmanꢁs salt
were used to generate phosphorus ± iron clusters such as 6
below 08C (Scheme 2). The formation of 6 was explained
Á
Pergamon, Oxford, 1991, pp. 329 ± 362; J. Rodriguez, J.-P. Dulcere,
Synthesis 1993, 1177 ± 1205.
[9] M. Tiecco, L. Testaferri, A. Temperini, L. Bagnoli, F. Marini, C. Santi,
Synth. Commun. 1998, 28, 2167 ± 2179, and references therein.
[10] G. A. Olah, X.-Y Li, Q. Wang, G. K. S. Prakash, Synthesis 1993, 693 ±
699; B. Zajc, M. Zupan, Tetrahedron 1989, 45, 7869 ± 7878.
[11] A. Kirschning, C. Plumeier, L. Rose, Chem. Commun. 1998, 33 ± 34;
A. Kirschning, A. Hashem, H. Monenschein, L. Rose, K.-U. Schöning,
J. Org. Chem., in press.
[12] F. W. Fowler, A. Hassner, L. A. Levy, J. Am. Chem. Soc. 1967, 89,
2077 ± 2082; A. Hassner, Acc. Chem. Res. 1971, 4, 9 ± 16; A. Hassner,
F. W. Fowler, J. Org. Chem. 1968, 33, 2686 ± 2691.
[*] Prof. Dr. K. Lammertsma, J. B. M. Wit, G. T. van Eijkel,
Dr. F. J. J. de Kanter, Dr. M. Schakel, Dr. A. W. Ehlers
Department of Organic and Inorganic Chemistry
Faculty of Sciences, Vrije Universiteit
De Boelelaan 1083, NL-1081 HV Amsterdam (The Netherlands)
Fax: (‡31)-20-4447488
E-mail: lammert@chem.vu.nl
[13] G. O. Olah, Q. Wang, X,-Y. Li, G. K. S. Prakash, Synlett 1990, 487 ±
489.
Dr. M. Lutz, Dr. A. L. Spek
Bijvoet Center for Biomolecular Research
Crystal and Structural Chemistry
Utrecht University (The Netherlands)
[14] The structures of iodate(i) complexes 2 and 3a are proposed with
reference to the analogous tetraalkylammonium salts: G. Doleschall,
Â
Â
Â
G. Toth, Tetrahedron 1980, 36, 1649 ± 1665; C. Szantay, G. Blasko, M.
Â
Â
Barcrczai-Beke, P. Pechy, G. Dörnei, Tetrahedron Lett. 1980, 21,
[**] This work was supported by the Council for Chemical Sciences of the
Netherlands Organization for Scientific Research (CW-NOW).
3509 ± 3512.
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Angew. Chem. Int. Ed. 1999, 38, No. 17