Radical Azidonation of Aldehydes

Article abstract of DOI:10.1021/jo035163v

Aliphatic and aromatic aldehydes can be converted to acyl azides by treatment with iodine azide at 0-25°C. If the reaction is performed at reflux Curtius rearrangement occurs and carbamoyl azides are obtained in 70-97% yield from the aldehyde. The reaction was shown to have a radical mechanism.

Full text of DOI:10.1021/jo035163v

Ra d ica l Azid on a tion of Ald eh yd es
Lavinia Marinescu, J acob Thinggaard, Ib B. Thomsen, and Mikael Bols*
Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark
mb@chem.au.dk
Received August 7, 2003
Aliphatic and aromatic aldehydes can be converted to acyl azides by treatment with iodine azide
at 0-25 °C. If the reaction is performed at reflux Curtius rearrangement occurs and carbamoyl
azides are obtained in 70-97% yield from the aldehyde. The reaction was shown to have a radical
mechanism.
SCHEME 1. Azid on a tion of Ben zyl Eth yl Eth er
The azido group is a highly useful functionality in
organic synthesis due to its ready conversion to amino
groups or due to its photochemical or cycloaddition
reactions. A range of methods for introduction of the azido
group into organic molecules are known; however, free
radical substitution has not been one of them.1,2
Nevertheless, the azidyl radical is readily formed by
oxidation of azide ion by a variety of oxidation agents,
and is an electrophilic species that is related to halogen
and pseudohalogen radicals.3,4
The C-H bond in aldehydes has a bond dissociation
energy of 89 kcal/mol and should therefore be expected
to be subject to facile attack. Nevertheless, the ease with
which aromatic and aliphatic aldehydes were found to
undergo reaction with IN3 was remarkable. The results
of the reaction of a series aldehydes with IN3 in MeCN
at 25 °C are given in Table 1. IN3 is formed in situ by
mixing ICl (2 equiv) and NaN3 (3 equiv) in MeCN under
conditions where it is not explosive.9,10 In 2.5 h essentially
quantitative conversion of aldehyde to acyl azide was
seen by NMR (Table 1). By heating the acyl azide in
toluene11 it undergoes Curtius rearrangement to form in
high yield the isocyanate.
However, since both acyl azides and isocyanates are
reactive compounds that cannot be subjected to chroma-
tography, it is convenient to carry out the reaction at
reflux, which results in spontaneous Curtius rearrange-
ment and formation of a carbamoyl azide by addition of
azide to the isocyanate. Table 2 shows the results of
reaction of aliphatic and aromatic aldehydes with IN3 in
MeCN at 83 °C with the yields given being the amount
of carbamoyl azide isolated after chromatography.
Less polar solvents such as chloroform or CH2Cl2 are
normally an advantage in radical reactions but the
reaction gave lower yield in these solvents presumably
because NaN3 is poorly soluble. Interestingly, the reaction
can be performed with BrN3 formed in situ in MeCN from
NBS and sodium azide. However, the yield is lower; from
cyclohexyl carboxaldehyde a 42% yield of azidonation
Iodine azide is, while well-known for its ability of ionic
addition to olefins, in fact able to undergo bond homolysis
and provide radicals. We have recently shown that
radical substitution with azide can be carried out on
benzyl ethers to give R-azido ethers in high yield, using
iodine azide (Scheme 1).5 Benzal acetals are similarly
converted to â-azidobenzoates by this reagent.6 From
these results it can be envisaged that other hydrogen
compounds with low bond dissociation energies can
undergo substitution with azide. In this paper we report
that aldehydes can be converted to acyl azides by treat-
ment with IN3 at room temperature. If the reaction is
carried out at elevated temperature the acyl azide
undergoes spontaneous Curtius rearrangement to form
a carbamoyl azide that can be hydrolyzed to the amine.
The transformation of aldehydes to acyl azides has
previously been reported to be possible with CrO3/
7
TMSN3 or MnO2/SiCl4/NaN3,8 which presumably work
by oxidation of an azido alcohol or through in situ
formation of an acid chloride. The present method is
therefore conceptually different.
(1) Recently Renaud’s group has reported an elegant method for
radical substitution with azide by adding alkyl radicals to ethane-
sulfonyl azide, see: (a) Ollivier, C.; Renaud, P. J . Am. Chem. Soc. 2000,
122, 6496-6497. (b) Renaud, P.; Ollivier, C.; Panchaud, P. Angew.
Chem., Int. Ed. 2002, 41, 3460-3462.
(2) Reactions that use PhIO/TMSN3 to introduce azide R to amines
and enol ethers may involve radicals, see: Magnus, P.; Lacour, J .;
Weber, W. J . Am. Chem. Soc. 1993, 115, 9347-9348.
(3) Workentin, M. S.; Wagner, B. D.; Lusztyk, J .; Wayner, D. D. M.
J . Am. Chem. Soc. 1995, 117, 119-126.
(9) Cambie, R. C.; J urlina, J . L.; Ruthledge, P. S.; Woodgate, P. D.
J . Chem. Soc., Perkin Trans. 1 1982, 315-27.
(4) Fontana, F.; Minisci, F.; Yan, Y. M.; Zhao, L. Tetrahedron Lett.
1993, 34, 2517-2520.
(10) Solid iodine azide is explosive and should never be allowed to
form. We always generate the reagent in solution and destroy the
reagent with thiosulfate wash before workup. When adhering to this
we have not encountered any problems even on prolonged reflux.
(11) Allen, C. F. H.; Bell, A. Organic Synthesis; Wiley: New York;
Collect. Vol. III, pp 846-847.
(5) Viuf, C.; Bols, M. Angew. Chem., Int. Ed. 2001, 40, 623-625.
(6) Baruah, M.; Bols, M. Synlett. 2002 1111-1112.
(7) Lee, J . G.; Kwak, K. H. Tetrahedron Lett. 1992, 33, 3165-3166.
(8) Elmorsy, S. S. Tetrahedron Lett. 1995, 36, 1341-1342.
10.1021/jo035163v CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/07/2003
J . Org. Chem. 2003, 68, 9453-9455
9453

Marinescu et al.
TABLE 1. Rea ction of Ald eh yd es w ith Iod in e Azid e a t
Room Tem p er a tu r e a n d Su bsequ en t Cu r tiu s
Rea r r a gem en ta
SCHEME 2. Som e Tr a n sfor m a tion s of Ca r ba m oyl
Azid es
yield 2
(acyl azide)
(%)
yield 3
(isocyanate)
(%)
R
Nr
PhCH2CH2
CH3(CH2)8
CH3(CH2)6
a
b
c
82
quant.
86
97
98
99
a
Yields determined by NMR.
TABLE 2. Rea ction of Ald eh yd es w ith Iod in e Azid e (2
equ iv of ICl a n d 3 equ iv of Na N3 in MeCN) a t Reflu x
SCHEME 3. Ra d ica l Tr a p 8 a n d a P r op osed
Mech a n ism of th e Rea ction
time
(h)
yielda of 412
R
Nr
(%)
CH3(CH2)6
c
4
4
4
4
4
4
4
4
4
4
53b
86
84
73
67
89
97
70
96
74
CH3(CH2)8
PhCH2CH2
Me3C
c-C6H12
Ph
p-MeOPh
p-MePh
o-MePh
b
a
d
e
f
g
h
i
a
b
Yields are of carbamoyl azide after chromatography. 1 equiv
of ICl and 2.5 equiv of NaN3.
EtOH led to complete conversion of starting material and
carbamoyl azide being the major product. No cyclohexyl
carboxylic acid ethyl ester was observed, which shows
that the acid iodide or acylonium ion cannot be interme-
diates in the reaction.
On the basis of these results the mechanism shown in
Scheme 3 is proposed for the reaction. Iodine radicals are
formed by homolysis of the weak iodine-azide bond,
abstracting the aldehyde hydrogen atom. The resulting
carbon-centered radical reacts with iodine azide to pro-
duce an acyl azide and an iodine radical. Overall the
reaction produces HI as a byproduct.
product was obtained with this reagent. For comparison
the reaction can be performed with NIS/NaN3 but the
reaction is much slower.
Carbamoyl azides13 can be converted to amines, car-
bamates, or ureas and the reaction is therefore a valuable
and simple route from aldehydes to amines or their
derivatives. For example, hydrolysis of carbamoyl azide
4f by cold NaOH gave instantaneously the carbamic acid
5 and after acidic workup the amine 6 (Scheme 2).
Alternatively, reaction of carbamoyl azide 4b with neat
butylamine at reflux gave urea 7 in 85% yield.
This new reaction constitutes a facile direct route from
aldehydes to amines, carbamates, or ureas containing one
carbon less. In cases where this transformation is desired
it constitutes a shorter route than the conventional
Curtius rearrangement. It should be a valuable addition
to the synthetic arsenal.
To gain support for the hypothesis that the reaction
followed a radical mechanism the reaction of phenylpro-
panal with IN3 at 25 °C (Table 1) was performed in the
presence of the radical trap 8 (0.5 equiv). No acyl azide
was observed after 2.5 h, which was taken as support
for a radical reaction mechanism. Furthermore, carrying
out the IN3 reaction of cyclohexyl carboxaldehyde in
Exp er im en ta l Section
(12) Most of these carbamoyl azides are known compounds described
in the following papers: (a) Reddy, P. S.; Yadagiri, P.; Lumin, S.; Shin,
D.-S.; Falck, J . R. Synth. Commun. 1988, 18, 545-551. (b) Affandi,
H.; Bayquen, A. V.; Read, R. W. Tetrahedron Lett. 1994, 35, 2729-
2732. (c) Rawal, V. H.; Zhong, H. M. Tetrahedron Lett. 1994, 35, 4947-
4950. (d) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151-2157.
Wa r n in g: Iodine azide is potentially explosive and defi-
nitely so in solid form. The reagent should be generated in
solution and destroyed with thiosulfate wash before workup.
When adhering to this we have not encountered any problems
even on prolonged reflux. However, when solid NaN3 and ICl
are mixed an explosion occurs.
(13) Lieber, E.; Minnis, R. L. Chem. Rev. 1965, 65, 377-384.
9454 J . Org. Chem., Vol. 68, No. 24, 2003

Radical Azidonation of Aldehydes
Azid on a tion a t Room Tem p er a tu r e (25 °C). To a stirred
slurry of 3 mmol of sodium azide (195 mg) in 3 mL of
acetonitrile in an ice bath was added slowly 2 mmol of iodine
monochloride in 3 mL of acetonitrile. The reaction mixture was
stirred for an additional 5-10 min, and 1 mmol of the aldehyde
was added. The reaction was allowed to reach room temper-
ature and was stirred for 2.5 h. The red-brown slurry was
poured into 5 mL of water, and the mixture was extracted with
dichloromethane (10 mL). The organic extracts were combined
and washed with 10 mL of 5% sodium thiosulfate leaving a
colorless solution, which was dried over magnesium sulfate.
Removal of the solvent under reduced pressure produced acyl
azide.
Cu r tiu s Rea r r a n gem en t. The acyl azide was dissolved in
5 mL of dry toluene. The solution of acyl azide in toluene was
added dropwise to 15 mL of hot toluene and heated to 60-68
°C for 1 h or more. Afterward, the toluene was removed at
reduced pressure and the product was analyzed by NMR.
Azid on a tion a t Reflu x (83 °C). To a stirred slurry of 3
mmol of sodium azide (195 mg) in 3 mL of acetonitrile in an
ice bath was added slowly 2 mmol of iodine monochloride (325
mg) in 3 mL of acetonitrile over a period of 10-20 min. Then
1 mmol of the aldehyde was added and the reaction mixture
was refluxed for 4 h, cooled, poured into 10 mL of water, and
extracted with dichloromethane (10 mL). The organic extracts
were washed with 5% sodium thiosulfate solution (10 mL)
leaving a colorless organic solution, which was dried over
magnesium sulfate, filtered, evaporated under reduced pres-
sure, and finally subjected to flash chromatography in the
indicated solvent mixture.
Ack n ow led gm en t. We thank the European com-
mission for support to the Marie Curie training site and
SNF and the Lundbeck foundation for financial as-
sistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental and
spectroscopic details for compounds 2a -c, 3a -c, 4a -i, and
7, procedures for the synthesis of 6 and 7, general experimental
descriptions, and 13C NMR spectra of 4b, 4d , 4h , and 4i. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035163V
J . Org. Chem, Vol. 68, No. 24, 2003 9455