Safe radical azidonation using polystyrene supported diazidoiodate(I)

Article abstract of DOI:10.1016/j.tet.2004.10.040

Aldehydes are converted to acyl azides and benzyl ethers to azido ethers by treatment with polymer supported iodine azide in MeCN at 83°C. The reaction provides a safe and convenient alternative to the use of iodine azide in radical azidonations. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.040

Tetrahedron 61 (2005) 123–127
Safe radical azidonation using polystyrene supported
diazidoiodate(I)
*
Lavinia Georgeta Marinescu, Christian Marcus Pedersen and Mikael Bols
Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark
Received 11 August 2004; revised 16 September 2004; accepted 14 October 2004
Available online 2 November 2004
Abstract—Aldehydes are converted to acyl azides and benzyl ethers to azido ethers by treatment with polymer supported iodine azide in
MeCN at 83 8C. The reaction provides a safe and convenient alternative to the use of iodine azide in radical azidonations.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Being aware of the work from the Kirschning group we
speculated whether the polymerically supported diazidoio-
date could not only emulate ionic iodine azide, but also the
radical reactions with which we have been focused. In the
present work, we report the finding that the diazidoiodate(I)
ion can indeed be used for radical azidonation, and hence
that the Kirchning groups polymer 3 is a safe and efficient
solid-phase reagent for radical azidonation reactions. The
reactions provide a useful addition to the arsenal that can be
carried out with solid supported reagents,7 and used for
parallel or solution-phase combinatorial chemistry.8
The azido group is a highly useful functionality in organic
synthesis due to it ready conversion to amino groups and its
photochemical or cycloaddition reactions.1 Iodine azide is a
very useful reagent for the introduction of the azido group.
Besides the classical electrophilic reactions pioneered by
Hassner,2 that exploits the polarized character of IN3 and
allows addition of iodine and azide to double bonds, several
radical azidonation reactions using iodine azide have
recently been investigated by us.3–5 In these reactions,
homolysis of the weak I–N bond lead to radicals (Scheme 1)
that cause azide substitution of active hydrogens. However,
a considerable drawback with IN3 as a reagent, is its
potentially explosive nature, which inhibits its widespread
use.
2. Results and discussion
Solution phase reactions. We first investigated whether the
diazidoiodate ion could be employed in lieu of iodine azide
in radical azidonation reactions in solution. For this purpose
we prepared tetraethylammonium diazidoiodate(I) in situ in
a similar manner to the solid-phase conversion of 2 to 3
(Scheme 2). Thus tetraethylammonium iodide was reacted
with phenyliodonium diacetate to give tetraethylammonium
diacetoxyiodate(I) (4, Scheme 3). Reaction of aldehyde 6
with 2.5 equiv of 4 and 2.8 equiv of TMSN3 in MeCN at
83 8C gave the carbamoyl azide 7 in 76% yield, where IN3
In 1999 Kirschning et al. described a stable electrophilic
polymer-bound reagent that synthetically behaves like
iodine azide (Scheme 1).6 By reacting the polystyrene-
bound iodide 1 with phenyliodonium diacetate in dichlor-
omethane at room temperature and subsequently with
trimethysilyl azide, the resin 3 was generated. They also
obtained 3 by direct azido transfer after treatment of iodide
1 with (diazido)benzene (Scheme 2). The polymer 3 was
shown to be unexplosive and a number of electrophilic IN3
additions to alkenes could be performed simply by mixing 3
and the alkene.6 It was presumed that the diazidoiodate ion
was the active species in these reactions.
Keywords: Polymer supported reagent; Radical substitution; Solution phase
combinatorial chemistry.
* Corresponding author. Tel.: C45 89423963; fax: C45 86196199;
e-mail: mb@chem.au.dk
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.040

124
L. G. Marinescu et al. / Tetrahedron 61 (2005) 123–127
Scheme 2.
Scheme 4.
gives 89%.4 This reaction occur by substitution of the
aldehyde hydrogen atom with azide and subsequent Curtius
rearrangement to an isocyanate that reacts with more azide
(Schemes 3 and 4). Similarly the benzyl ether 8 was
converted to azide 9 in 64% yield, where IN3 gives the
product in 93% yield.2 It appears that the radical reactions in
solution of 5 and IN3 are essentially equivalent. Addition of
a radical trap, N-tert-butyl-a-phenylnitrone, to the reaction
of 8 prevented the formation of 9, supporting a similarity of
the reactions.
fragmentation and the Schiff base 27. Adding N-tert-butyl-
a-phenylnitrone to the reaction of 6 with 3 inhibited
formation of carbamoyl azide 9. The reaction is
accompanied by the formation of a brown colour,
presumably iodine. Besides MeCN the solvents CH2Cl2,
THF, MeOH, EtOH and t-BuOH were tried, but only
t-BuOH gave satisfactory results, probably because it also
has a high boiling point. In this solvent, a carbamoyl azide is
still obtained from an aldehyde, and not the carbamate.
It was observed that when the polymer was heated to reflux
in acetonitrile, a faint brown color was formed and a UV
spectrum of the solution confirmed that IN3 was present.
Furthermore when the polymer was reacted with an excess
of substrate and recovered, IR spectroscopy showed that the
spent polymer was polymerically bound azide. Therefore
the polymer probably functions by slow release of IN3 from
the polymer bound diazidoiodate(I) ion (Scheme 5). This
explanation fits with the polymer bound reagent usually
reacting slower than IN3 in solution and also explains the
very similar reaction profile of the polymer compared to
IN3.
Solid phase reactions. We prepared the polymer 3 as
described by Kirschning converting iodide 1 into diacetoxy-
iodate 2 and hence diazidoiodate 3 (Scheme 2).1 Two
different sources of 1 was employed; the Amberlite IR-900
(Fluka) and a microreticular Amberlyst A-26 resin (Lan-
caster). Both resins essentially gave similar results. The
resin 3 was reacted with aldehydes 6 and 10–13 and benzyl
ethers 8, 14 and 15 giving carbamoyl azides 7 and 16–20
and azidobenzyl ethers 9, 21 and 22, respectively (Scheme
4, Table 1). Typically the reaction was carried out by
heating the substrate under reflux for 4 h with 4 equiv of 3 in
MeCN. The yields were excellent for the aldehydes (87–
96%), but somewhat lower (57–66%) for the benzyl ethers,
than can be obtained with IN3. The solid-phase reaction did
not work satisfactorily with benzylidene acetals, presum-
ably because the polymer contained an unavoidable amount
of water as seen by IR. Thus acetal 17 gave the alcohol 26 in
96% yield; a product that can be obtained by hydrolysis of
the intermediate benzoxonium ion. On the other hand
reaction of the tertiary amine 18 was found to lead to
Scheme 5.
In conclusion, azidonation with polymer 3 is a convenient
and safe alternative to the use of IN3 in radical azidonations.
It is also a useful reaction for parallel combinatorial
synthesis since the requirements for purification are
minimal when the reaction is carried out in this manner.
3. Experimental
3.1. General
Moisture sensitive reactions were carried out in flame-dried
glassware under a N2 atmosphere in solvents dried
according to standard procedures. Commercially available
compounds were used without further purification. Evapor-
ation was carried out on a rotatory evaporator with the
temperature kept below 40 8C. Columns were packed with
silica gel 60 (230–400 mesh) as the stationary phase. TLC-
plates (Merck, 60, F254) were visualized by spraying with
either A) phosphomolybdic acid hydrate (5% in EtOH), B)
2,4-dinitrophenylhydrazine (0.5% in 2 M HCl), or C)
vanillin (3% in 1% H2SO4 in EtOH) and heating until
Scheme 3.

L. G. Marinescu et al. / Tetrahedron 61 (2005) 123–127
Table 1. Results of reaction of substrates with polymer 3 in MeCN at 83 8C
125
Substrate
Nr
Time (h)
Product
Nr
Yielda (%)
95
10
4
19
11
12
6
4
4
4
4
20
21
7
87
87
96
96
13
22
8
4
4
4
9
68b
64
14
15
23
24
60
16
4
25
57
17
18
4
4
26
27
96
73
a Yields are after chromatography.
b Adjusted yield due to isolated starting material.
colored spots appeared. A is best for visualizing carbamoyl
azides, while B is good for visualizing benzylic azides.
NMR-spectra were recorded on a Varian Mercury 400
instrument. Mass spectra were run on a Micromass LC-TOF
instrument.
0 8C, filtered and washed with cold dry ethyl ether (3!
20 mL). The light yellow product 4 was dried in vacuo and
kept under nitrogen protected from light.
3.3. Procedure with 4 and Me3SiN3
3.2. Tetraethylammonium diacetoxyiodate(I) (4)
3.3.1. Cyclohexylcarbamoyl azide (7). 0.94 g (2.5 mmol)
of tetraethylammonium-salt 4 was dissolved in dry MeCN
(4 mL) and 0.322 g (2.8 mmol, 0.367 mL) of Me3SiN3 and
0.112 g (1 mmol) cyclohexanecarbaldehyde were added,
and the mixture heated to 83 8C for 2.5 h. The brown slurry
was poured into 2 mL of water, and the mixture was
extracted with dichloromethane (3!10 mL). The organic
To a solution of tetraethylammonium iodide (4 g,
15.6 mmol) in dry chloroform (50 mL) was added iodoso-
benzene diacetate (5 g, 16 mmol) and the mixture was
stirred at room temperature overnight. Then ethyl ether
(60 mL) was added, and the reaction mixture was cooled to

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L. G. Marinescu et al. / Tetrahedron 61 (2005) 123–127
extracts were combined and washed with 10 mL of 5%
sodium thiosulfate leaving a light yellow solution, which
was dried over magnesium sulfate. Removal of the solvent
under reduced pressure followed by column chromato-
graphy (EtOAc/pentane 1:10) afforded the cyclohexylcar-
bamoyl azide5 (7, 0.127 g, 76%) as a white solid. 1H NMR
(400 MHz, CDCl3): d 5.03 (bs, 1H), 3.56–3.46 (m, 1H),
1.88–182 (m, 2H), 1.66 –1.60 (m, 2H), 1.57–1.51 (m, 2H),
1.34–1.23 (m, 2H), 1.14–1.04 (m, 2H).5 13C NMR
(100 MHz, CDCl3): d 155.6 (C]O), 50.3 (C1), 33.08
(C2,6), 25.5 (C4), 24.8 (C3,5). IR (KBr, cmK1): 1547.9(N–
C]O), 1677.7 (strong C]O), 2140 (N3), 3275.4 (NH).
HRMS (ES): m/z: 191.0910 (calcd for C7H12N4ONa [MC
NaC]: 191.0908), mpZ105.1 8C.
and the reaction mixture was heated to 83 8C. The reaction
was followed on TLC (pentane/ CH2Cl2 1/1), and the time
for a complete reaction was normally between 2 and 4
hours. The resin was filtered and washed with dry CH2Cl2.
The resulting organic layer was washed with a solution of
5% sodium thiosulfate, dried over magnesium sulfate and
concentrated under reduced pressure to give the crude azide.
Additional purification by flash chromatography (pentane/
ethyl acetate 10/1) provided the desired compound in the
yield given in Table 1.
1
3.5.1. Heptyl carbamoylazide (19).5 A colourless oil. H
NMR (400 MHz, CDCl3): d 5.28 (bs, 1H), 3.2 (q, 2H, JZ
8.0 Hz), 1.52–1.44 (m, 2H), 1.29 –1.21 (m, 8H), 0.84 (t, 3H,
JZ7.2 Hz).5 13C NMR (100 MHz, CDCl3): d 156.6 (C]O),
41.3 (C1), 31.8 (C5), 29.6 (C2), 29.05 (C4), 26.8 (C3), 22.7
(C6), 14.1 (C7). IR (KBr, cmK1): 1702 (C]O), 2139.7 (N3),
2858/2929 (C–H sp3), 3331.8 (NH).
3.3.2. a-Azidobenzyl methylether (9). 0.94 g (2.5 mmol)
of tetraethylammonium-salt 4 was dissolved in dry MeCN
(4 mL) and 0.322 g (2.8 mmol, 0.367 mL) of Me3SiN3 and
0.122 g (1 mmol) of benzyl methyl ether were added, and
the mixture heated to 83 8C for 2.5 h. The reaction was
followed on TLC (pentane/CH2Cl2 3/1), and found
complete after 2 h. The reaction mixture was poured into
water (2 mL), and the mixture was extracted with
dichloromethane (3!10 mL). The organic extracts were
combined and washed with 10 mL of 5% sodium thiosul-
fate, brine, dried over magnesium sulfate and concentrated
in vacuo to give the desired a-azido benzyl ether. Additional
purification by flash chromatography (pentane/EtOAc
gradient 1/0:10/1) provided the desired a-azido benzyl
3.5.2. 2-Phenylethyl carbamoylazide (20).5 White crys-
1
tals. MpZ85.5 8C. H NMR (400 MHz, CDCl3): dZ7.25–
7.10 (m, 5H), 4.99 (bs, 1H), 3.42 (q, 2H, JZ6.7 Hz), 2.75 (t,
2H).5 13C NMR (100 MHz, CDCl3): d 155.4 (C]O), 137.1
(Ar C1), 127.6 (Ar C3,4,5), 125.6 (Ar C2,6), 41.1 (CH2–NH),
34.5 (CH2). IR (KBr, cmK1): 1543 (N–C]O), 1671.8
(strong C]O), 2141.9 (N3), 2930.2 (C–H sp3), 3029 (C–H
sp2) 3280.3 (NH).
3.5.3. Phenyl carbamoylazide (21).5 White crystals. MpZ
107.1 8C. 1H NMR (400 MHz, CDCl3): dZ7.4 (m, 3H), 7.1
(m, 2H), 7 (bs, 1H).5 13C NMR (100 MHz, CDCl3): d 154.5
(C]O), 137.1 (Ar C1), 129.3 (Ar C3,5), 124.9 (Ar C4), 119.7
(Ar C2,6). IR (KBr, cmK1): 1554 (N–C]O), 1688.6 (strong
C]O), 2147.4 (N3), 3325.6 (NH).
1
methylether3 as a light yellow oil (9, 0.104 g, 64%). H
NMR: d 7.22–7.38 (m, 5H), 5.24 (s, 1H), 3.43 (s, 3H).3
When this reaction was performed in presence of 0.26 equiv
of N-tert-butyl-a-phenylnitrone no azidonation product was
observed.
3.5.4. 4-Methylphenyl carbamoylazide (22).5 Light yel-
1
3.4. Synthesis of polymer 3
low crystals. MpZ130.7 8C. H NMR (400 MHz, CDCl3):
dZ7.2 (d, 2H, JZ8.0 Hz), 7 (d, 2H, JZ8.0 Hz), 6.7 (bs,
1H), 2.2 (s, 3H).5 13C NMR (100 MHz, CDCl3): dZ154.2
(C]O), 134.6 (Ar C1), 129.8 (Ar C3,4,5), 119.6 (Ar C2,6),
21.03 (CH3).5 IR (KBr, cmK1): 3276 (NH), 2143, (medium,
N3), 1682 (strong, C]O), 1538 (N–C]O).5
The untreated (Amberlyst A-26 iodide-resin from Lancaster
was previously washed with dry CH2Cl2 and dried in
vacuum) polymer-bound iodide 1 (1 equiv) was shaken at
1000 rpm with PhI(OAc)2 (1.8 equiv) in dry CH2Cl2
(2.5 mL/mmol iodide) at room temperature under nitrogen
overnight. During this time the reaction mixture was
protected from light. The resulting light yellow resin 2
was filtered and washed with dry CH2Cl2 (5!25 mL/g
resin) and dried in vacuum.
3.5.5. a-Azidobenzyl benzyl ether (23). A light yellow oil.
1H NMR (400 MHz, CDCl3): dZ7.34–7. 51 (m, 10H, Ar),
5.529 (s, 1H, Ar-CH–N3), 4.93 (d, 1Ha, JZ11.6 Hz, Ar-
CH2), 4.73 (d, 1Hb, JZ11.6 Hz, Ar-CH2). 13C NMR
(100 MHz, CDCl3): dZ136.9 (1 C, Ar C1), 129.3–126.3
(11C,Ar),91.5(Ar-CH–N3),70.4(Ar-CH2).IR(KBr, cmK1):
nZ1495, 1587 (Ar), 2105 (–N3), 2874 (C–H sp3), 3033/
3065 (C–H sp2). GS–MS: 211 (–N2). HR-MS: 262.0950
(calcd for C14H13N3OCNaC: 262.0956).
The prepared resin 2 was treated with Me3SiN3 (2.6 equiv
with respect to 1) in dry CH2Cl2 (4 mL/mmol) and shaked at
1000 rpm under nitrogen overnight. The yellow resin was
filtered and washed with dry CH2Cl2 (5!25 mL/g resin)
and dried under vacuum. The calculated loading (from
weight increase) was up to 2.1 mmol reagent per g resin for
the Lancaster resin and up to 2.5 mmol reagent per g resin in
the Fluka case. The resin was stored in a desiccator at room
temperature.
3.5.6. Azidobenzyl (K)-menthyl ether (24).9 A light
yellow oil. H NMR (200 MHz; CDCl3): d 0.79 (d, 3H,
1
JZ6.3 Hz), 0.98 (d, 6H, JZ6.9 Hz), 1.0 (m, 2H), 1.2 (m,
1H), 1.4 (m, 2H), 1.65 (m, 2H), 2.1 (m, 1H), 2.2 (m, 1H),
3.65 (dt, 1H), 5.45 (s, 1H), 7.4 (m, 5H).9
3.5. Azidonation of compounds with resin 3, general
procedure
3.5.7. 3-(Azido-phenyl-methoxy)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester (25).10 A clear
colourless oil. H NMR (CDCl3, 400 MHz): d 7.45–7.36
(5H, m, Ar-H), 5.39 (1H, s, O–CHN3-Ar), 4.19 (2H, br. s,
1
To a suspension of resin 3 (5 equiv with respect to substrate)
in dry MeCN (4 mL/g resin) was added 1 equiv of aldehyde,

L. G. Marinescu et al. / Tetrahedron 61 (2005) 123–127
127
H-1,5), 4.13 (1H, t, JZ4,4 Hz, H-3), 2.22–1.78 (8H, m, 2H-
References and notes
2,4,6,7), 1.46 (9H, s, (CH3)3, Boc). 13C NMR (CDCl3,
100 MHz): d 153.6 (C]O, Boc), 137.5 (C(Ar)), 129.3;
129.2; 128.9 (CH(Ar)), 91.5 (O–CHN3-Ar), 79.4 (C(CH3)3,
Boc), 72.4 (C3), 53.1/52.3 (C1,5), 37.2/36.4 (C2,4), 35.3/34.4
(C6,7), 28.7/28.0 ((CH3)3C, Boc).10 IR (film, cmK1): nZ3444,
1. Eric, F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297–368.
2. Hassner, A. Acc. Chem. Res. 1971, 4, 9–16.
3. Viuf, C.; Bols, M. Angew. Chem., Int. Ed. 2001, 40, 623–625.
4. Baruah, M.; Bols, M. Synlett 2002, 7, 1111–1112.
5. Marinescu, L.; Thinggaard, J.; Thomsen, I. B.; Bols, M. J. Org.
Chem. 2003, 68, 9453–9455.
2978 (C–H sp3), 2103 (N3), 1694, 1652, 1548 cmK1 10
.
1
3.5.8. 2-Hydroxyethyl benzoate (26).11 Colourless oil. H
NMR (CDCl3): dZ8.1 (m, 2H, Ar; H2, H6), 7.5 (m, 1H, Ar;
H4), 7.4 (m, 1H, Ar; H3, H5), 4.4 (t, 2H, CH2), 3.9 (t, 2H,
CH2) and 2.8 (bs, 1H, OH).11
6. Kirschning, A.; Monenschein, H.; Schmeck, C. Angew. Chem.,
Int. Ed. 1999, 38, 2594–2696.
7. Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
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R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 23,
3815–4195.
3.5.9. Benzylidene benzyl amine (27).12 Ligth yellow oil.
1H NMR (400 MHz, CDCl3): dZ8.42 (s, 1H,ZNH), 07.81
(m, 2H, Ar; H2, H6), 7.45–7.22 (m, 9H, Ar; H2–5, H 2–6),
4.85 (s, 1H, –Ar-CH2–). 13C NMR (100 MHz, CDCl3): dZ
162.1 (C]N–), 139.4 (Ar C1), 136.3 (Ar C01), 130.8 (Ar
8. An, H.; Cook, P. D. Chem. Rev. 2000, 100, 3311–3340.
9. Baruah, M.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2002,
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11. Sharghi, H.; Sarvari, M. H. J. Org. Chem. 2003, 68,
4096–4099.
0
0
0
0
C4), 128.7–128.1 (8 C, Ar C2,3,5,6, C2 ,3 ,5 ,6 ), 127.1 (Ar-
C4 ), 65.2 (Ar-CH2). IR (KBr, cmK1): nZ1580 (Ar), 1643
0
(–HC]N–), 2840/2872 (C–H sp3), 3027/3085 (C–H sp2).
HR-MS: 196.1130 (calcd for C14H13NCHC: 196.1126).
12. Goosen, A.; McCleland, C. W.; Sipamla, A. M. J. Chem. Res.
(S) 1995, 18–19.
Acknowledgements
We thank the Holm and Lundbeck foundations for financial
support.