An azido-hanessian reaction

Article abstract of DOI:10.1055/s-2002-32593

Benzal acetals have been found to react with iodine azide to provide 2-azidoethyl- or 3-azidopropyl benzoates.

Full text of DOI:10.1055/s-2002-32593

LETTER
1111
An Azido–Hanessian Reaction
An
A
zido–Hanessian R
u
eaction kulesh Baruah, Mikael Bols*
Department of Chemistry, Aarhus University, Aarhus, 8000 C, Denmark
Fax +45 86196199; E-mail: mb@chem.au.dk
Received 22 April 2002
solvent this byproduct could be suppressed so that the
Abstract: Benzal acetals have been found to react with iodine azide
to provide 2-azidoethyl- or 3-azidopropyl benzoates.
yield of 5 was improved to 78%.7,8
This new reaction appear quite useful: A benzal acetal is
directly transformed to a nitrogen functionality, since the
azide can be readily converted to an amine or heterocycle,
so when nitrogen-containing targets are desired a step is
saved compared with the Hanessian type transformation.
Key words: azide, azidonation, radicals, proctection group conver-
sion
The Hanessian reaction,1 which involves the reaction of a
benzal acetal with N-bromosuccinimide to give a 1,2- or
1,3-bromobenzoate presumably in a radical reaction, is
relatively unique in that it allows a protection group to be
converted into a reactive functionality. This transforma-
tion has proven itself useful in synthesis.2 While analo-
gous benzal acetal opening reactions with a halogen atom
are known,3 other functional groups have apparently not
been introduced in this manner. In this communication we
report a benzal acetal opening reaction involving azide.
O
IN3
N3
O
Ph
O
MeCN
rfx 1 h
Ph
O
7
66%
6
6:1
N3
+
O
Ph
O
N3
IN3 MeCN
Ph
OEt
8
Ph
OEt
rfx 20 min.
75%
1
2
O
IN3
O
O
O
O
MeCN
rfx
O
Ph
R
Ph
O
O
N3
R
N3
3
4
72%
10: R = H
9: R = H
11: R = OMe
12: R = OMe
O
IN3 MeCN
rfx 20 min.
78%
N3
Ph
O
IN3
O
O
5
O
MeCN
rfx 1.5 h
O
Scheme 1
O2N
O2N
Recently, we reported that IN34 reacts with benzyl ethers,
such as 1, to form -azido benzyl ethers, such as 2
(Scheme 1).5 The idea was conceived that reaction of a
benzal acetal 3 would give a similar reaction to form 4.
However when the reaction of 3 was carried out with IN3
in refluxing MeCN not 4 but the azidobenzoate 56 was ob-
tained in a yield of 66%. No trace of 4 could be detected,
but the product contained 10–15% of the corresponding
alcohol, ethyleneglycol monobenzoate. However, with
more thorough drying of the reagent solution and of the
N3
41%
13
14
Scheme 2
The reaction has been explored employing the benzal ac-
etals 6, 9, 11 and 13 (Scheme 2).9 Reaction of 6 led to a
6:1 mixture of the isomeric azides 7 and 810 in 66% yield.
It is clear from this experiment that the reaction has a con-
siderable preference for substitution at the primary car-
bon. The 1,3-dioxane 9 gave the 3-azidobenzoate 10 in
72% yield. The p-methoxy analogue 11 gave a similar
yield of 12, but the reaction was faster. While the transfor-
mation of 9 to 10 took 1.5 h, formation of 12 was complete
Synlett 2002, No. 7, Print: 01 07 2002.
Art Id.1437-2096,E;2002,0,07,1111,1112,ftx,en;G10402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1112
M. Baruah, M. Bols
LETTER
(2) (a) Keck, G. E.; Lundquist, G. D. J. Org. Chem. 1999, 64,
4482. (b) Liu, D.; Chen, R.; Hong, L.; Sofia, M. J.
Tetrahedron Lett. 1998, 39, 4951. (c) Reddy, V. D.; Franck,
R. W. J. Org. Chem. 1993, 58, 6911. (d) Santoyo Gonzalez,
F.; VargasBerenguel, A.; Hernandez Mateo, F.; Garcia
Mendoza, P.; Baer, H. H. Carbohydr. Res. 1992, 237, 145.
(e) Baer, H. H.; Hernandez Mateo, F.; Siemsen, L.
Carbohydr. Res. 1990, 195, 225.
(3) (a) Glass, B. D.; Goosen, A.; McCleland, C. W. J. Chem.
Soc., Perkin Trans. 2 1993, 2175. (b) Hai-xia, L.; Liang-
heng, X.; Nai-ju, H. Synth. Commun. 1997, 27, 303.
(c) Talekar, D. G.; Joshi, P. L.; Ramaiah, P.; Rao, A. S.
Indian J. Chem., Sect. B 1986, 25, 145.
in 45 min. The faster rate of reaction of the p-methoxy-
benzal acetal 11 suggests that a positive charge is being
formed at the benzylic position in the rate determining
step. The nitrobenzylidene derivative 13 on the other hand
gives, as expected, a rather sluggish reaction and a poor
yield (Scheme 2).
The above experiments show two characteristics of the re-
action: The azide preferentially adds to a primary posi-
tion, which suggests that it is introduced by a nucleophilic
substitution reaction and not by a radical reaction. Sec-
ondly, the rate enhancing/reducing effect of electron-do-
nating or withdrawing substituents suggests an ionic
intermediate. Nevertheless the reaction is likely to involve
radical abstraction as was found in the transformation of 1
to 2. We therefore propose the mechanism outlined in
Scheme 3. Attack of an azide radical at the benzylic hy-
drogen leads to a benzylic radical 15, which is subse-
quently oxidised to a phenyl dioxolanium ion 16 by an
(4) IN3 is a potentially explosive compound. We have never
encountered any problems, but it is advisable to destroy the
reagent after the reaction using Na2S2O3 wash.
(5) Viuf, C.; Bols, M. Angew. Chem. Int. Ed. 2001, 40, 623.
(6) The 1-monodeuterated analogue of 5 has been reported:
Hammerschmidt, F. Liebigs Ann. Chem. 1988, 955.
(7) A typical reaction to prepare 5 was carried out as follows: To
a stirred solution of NaN3 (107 mg, 1.4 mmol) in dry CH3CN
(3 mL) at –10 °C was added a dry solution of iodine
monochloride (101 mg, 0.6 mmol) in CH3CN (2 mL)
through a syringe under nitrogen atmosphere. After stirring
20 min the cooling bath was removed, and 2-phenyl-1,3-
dioxolane (45 mg, 0.3 mmol) was added. The mixture was
refluxed for 45 min. Upon completion (monitored by TLC),
the reaction mixture was cooled to r.t., then CH2Cl2 (25 mL)
was added, and the solution was washed with 5% Na2S2O3
solution (20 mL). The dried (Na2SO4) organic phase was
concentrated in vacuo, and the residue was purified by flash
chromatography (silica gel, pentane–EtOAc 10:1, Rf = 0.58)
to give 2-azidoethyl benzoate 5 (44 mg, 78%) as a colourless
oil.
–
iodonium ion. This cation is finaly substituted by N3 to
give the product.
.
N3
O
O
O
O
- HN3
15
3
O
I+
- I.
-
(8) Spectral data for 5 (ref.4): 1H NMR (200 MHz, CDCl3):
=
N3
O
3.61 (t, J = 5 Hz, 2 H, CH2N), 4.45 (t, J = 5 Hz, 2 H, CH2O),
7.40–7.52 (m, 3 H, Ar), 8.10 (m, 2 H, Ar); 13C NMR (50
MHz, CDCl3): = 50.1 (CH2N), 63.8 (CH2O), 128.6, 129.9,
133.4 (Ar), 166.4 (COO); MS (ES): 214.1 [M + Na+]. For 7:
1H NMR: = 1.40 (d, J = 6.5 Hz, 3 H, CH3), 3.38 (dd, J =
6.1, 12.9 Hz, 1 H, HCHN), 3.43 (dd, J = 3.8, 12.9 Hz, 1 H,
HCHN), 5.25 (m, 1 H, CHO), 7.50 (m, 3H, Ar), 8.10 (m, 2
H, Ar); 13C NMR: = 17.6 (CH3), 55.2 (CH2N), 70.3
(CH2O), 128.5, 129.8, 133.3 (Ar), 166.6 (COO); MS (ES):
228.1 [M + Na+]. For 8 (ref.8): 1H NMR: = 1.24 (d, J = 6.5
Hz, 3 H, CH3), 3.82 (m, 1 H, CHN), 4.20 (dd, J = 3.8, 11.4
Hz, 1 H, HCHO), 4.30 (dd, J = 7.4, 11.4 Hz, 1 H, HCHO),
5
16
Scheme 3
This new reaction will be further explored in this labora-
tory.
Acknowledgement
7.50 (m, 3 H, Ar), 8.10 (m, 2 H, Ar). For 10: 1H NMR:
=
We acknowledge financial support from the Danish Natural Rese-
arch council and the Lundbeck foundation.
2.10 (p, 2 H, CH2), 3.40 (t, J = 7 Hz, 2 H, CH2N), 4.36 (t, J
= 6.3 Hz, 2 H, CH2O), 7.30–7.60 (m, 3 H, Ar), 8.10 (m, 2 H,
Ar). 13C NMR: = 28.4 (CH2), 48.4 (CH2N), 62.0 (CH2N),
128.6, 129.7, 133.2 (Ar), 166.2 (COO); MS (ES): 228.0 [M
+ Na+]. For 12: 1H NMR: = 2.10 (m, 2 H, CH2), 3.40 (t, J
= 7 Hz, 2 H, CH2N), 3.80 (s, 3 H, OMe), 4.27 (t, J = 6.3, 2
H, CH2O), 6.82 (m, 2 H, Ar), 7.90 (m, 2 H, Ar); MS (ES):
258.05 [M + Na+]. For 14: 1H NMR: = 3.64 (t, J = 5.1 Hz,
2 H, CH2N), 4.50 (t, J = 5 Hz, 2 H, CH2O), 8.20–8.40 (m, 4
H, Ar). 13C NMR: = 49.9 (CH2N), 64.6 (CH2O), 123.8,
127.6, 131.1 (Ar), 164.5 (COO).
References
(1) (a) Hanessian, S. Carbohydr. Res. 1966, 2, 86.
(b) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34,
1035. (c) Failla, D. L.; Hullar, T. L.; Siskin, S. B. Chem
Commun. 1966, 716. (d) Hullar, T. L.; Siskin, S. B. J. Org.
Chem. 1970, 35, 225.
(9) Bartels, B.; Hunter, R. J. Org. Chem. 1993, 58, 6756.
(10) Compound 8 is known: Ariza, X.; Urpi, F.; Viladomat, C.;
Vilarrasa, J. Tetrahedron Lett. 1998, 39, 9101.
Synlett 2002, No. 7, 1111–1112 ISSN 0936-5214 © Thieme Stuttgart · New York