PAPER
Nicotinoyl Azide (NCA)-Mediated Mitsunobu Reaction
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reaction on the crude product (Scheme 3). The isolation 13C NMR (75.46 MHz, CDCl
2
): d = 123.68, 126.73, 136.9, 150.83,
3
1
54.77, 171.42.
MS: m/z = 149.11 [MH+].
Anal. Calcd for C H N O: C, 48.65; H, 2.72; N, 37.82. Found: C,
of the expected amine proved to be simpler.
6
4
4
4
8.35; H, 2.75; N, 37.05.
General Experimental Procedure
To an ice-cooled stirred solution of 7a (200 mg, 0.51 mmol) and
PPh (203 mg, 0.77 mmol) in anhyd THF (5 mL), DEAD was slow-
3
Scheme 3 Staudinger reaction.
ly added dropwise (0.21 mL, 0.77 mmol), under N . After 15 min
2
NCA (98 mg, 0.66 mmol) was added in one portion, the reaction
mixture was allowed to warm to r.t. and then stirred until the starting
material disappeared (detected by TLC). The solvent was removed
under reduced pressure and the crude product was purified by flash
chromatography (hexane) to give 8a (198 mg, 94%) of the pure
azide.
Careful analysis of a model reaction mixture helped us to
1
9,40,41
cast light over the reaction mechanism.
Thus, excess
NCA was recovered after column chromatography in only
trace amount because of the almost quantitative conver-
sion into diethyl N-nicotinoylhydrazine dicarboxylate (6,
Scheme 1). This latter compound, however fragile, was
4
2
Acknowledgment
isolated and characterized, thus demonstrating the plau-
sibility of the proposed reaction mechanism (Scheme 1).
The authors wish to thank Wolfgang Brill for having performed
MMFF94 calculation and Sergio Mantegani for helpful suggestions
as well as discussions with Keith A. M. Walker.
In conclusion, the aforementioned results clearly demon-
strate that the cheap and easily accessible NCA is an ef-
fective reagent in the direct conversion of alcohols into
azides.
References
(
1) See for example: (a) Zhang, S.; Reith, M. E. A.; Dutta, A. K.
Bioorg. Med. Chem. Lett. 2003, 13, 1591. (b) Deng, W.-P.;
Nam, G.; Fan, J.; Kirk, K. L. J. Org. Chem. 2003, 68, 2798.
(c) Jung, Y. J.; Chang, Y. M.; Lee, J. H.; Yoon, C. M.
Tetrahedron Lett. 2002, 38, 8735.
Melting points were determined in open glass capillaries with a Bü-
chi 535 melting point apparatus, and are uncorrected. Elemental
1
analyses were performed on a Carlo Erba 1110 instrument. H and
1
3
C NMR spectra were recorded on a Varian Oxford 300 spectro-
meter, using the solvent as internal standard; chemical shifts are ex-
pressed in ppm (d). Electron impact (EI) mass spectra (MS) were
obtained on Finnigan-MAT TSQ 700 triple quadrupole instrument.
(2) (a) Meyer, J. Helv. Chim. Acta 1919, 2, 635. (b) For recent
examples see the following: Michellizza, S.; Al-Mourabit,
A.; Gateau-Olesker, A.; Marazano, C. J. Org. Chem. 2002,
67, 6474. (c) Battaglia, A.; Barbaro, G.; Giorgianni, P.;
Guerrini, A.; Pepe, A. Tetrahedron: Asymmetry 2001, 12,
1015.
(
ESI) mass spectra were obtained on LCQ-ion trap thermo Finni-
gan. IR spectra were recorded on a ThermoNicolet Avatar 360 FT-
IR spectrometer. Optical rotations were recorded on a Perkin-Elmer
2
41 polarimeter in a 1 dm cell at ambient temperature with a sodium
(3) (a) For a treatise on azides, which includes discussion of
rearrangement reactions, see: Scriven, E. F. V. Azides and
Nitrenes; Academic Press: New York, 1984. (b) For a
review of rearrangement of alkyl and aryl azides, see:
Stevens, T. S.; Watts, W. E. Selected Molecular
Rearrangements; Van Nostrand Reinhold: London, 1973.
(4) See for examples: (a) Katritzky, A.; Singh, S. K. J. Org.
Chem. 2002, 67, 9077. (b) Trauner, D.; Porth, S.; Opatz, T.;
Bats, J. W.; Geister, G.; Multzer, J. Synthesis 1998, 653.
lamp (wavelength of 589 nm). All the reactions were performed
with oven-dried glassware and under a blanket of N . Triphe-
nylphosphine was recrystallized prior to use from petroleum ether–
ethanol (6:4). THF was distilled under positive pressure of anhyd N2
from sodium/benzophenone ketyl. DEAD was purchased from Lan-
caster and used without further purification.
2
CAUTION: although safe, NCA should be considered potentially
dangerous like any other azido-containing compound. Precautions
during its preparation and handling are thus strongly recommended
(c) Schultz, A. G.; Dai, M.; Kim, S. K.; Pettus, L.; Thakhar,
K. Tetrahedron Lett. 1998, 39, 4203. (d) Kolb, H. C.;
Sharpless, B. Drug Discov. Today 2003, 8, 1128.
(
goggles, efficient hoods, protective shields, etc.).
(
(
5) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J.
M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123,
Preparation of Nicotinoyl Azide (NCA) (4); Typical Procedure
To concd HCl acid (0.29 mol, 24 mL) stirred and chilled in an ice
bath, nicotinoyl hydrazide (20 g, 0.15 mol) was added portionwise,
while keeping the temperature below 10 °C. A solution of NaNO2
3239.
6) (a) Schildknegt, K.; Agrios, K. A.; Aubé, J. Tetrahedron
Lett. 1998, 39, 7687. (b) Milligan, G. L.; Mossman, C. J.;
Aubé, J. J. Am. Chem. Soc. 1995, 117, 10449.
(
20.5 g, 0.29 mol) in water (34.5 mL) was added dropwise, again
keeping the temperature below 10 °C. The aqueous phase was then
(
7) See for example: Ito, M.; Koyakumaru, K.-I.; Ohta, T.;
extracted with Et O and the organic layer was washed with sat. aq
2
Takaya, H. Synthesis 1995, 376.
NaHCO solution and dried over Na SO . The solvent was removed
3
2
4
(
8) (a) Biffin, M. E. C.; Miller, J.; Paul, D. B. In The Chemistry
of the Azido Group; Patai, S., Ed.; Wiley Interscience: New
York, 1971, 57. (b) Alvarez, S. G.; Alvarez, M. T. Synthesis
under reduced pressure at r.t. to afford pure NCA (4), brown solid,
mp 47–49 °C. Neutralization of the aqueous phase with NaHCO3
and extraction with Et O yielded an additional amount of NCA. The
2
1
997, 413.
9) (a) Vatèle, J. M.; Hanessian, S. Tetrahedron 1996, 52,
0557. (b) Vatèle, J. M.; Hanessian, S. Tetrahedron Lett.
1981, 22, 3579.
overall yield was 12.4 g (58%).
(
–1
IR: 2140–2130 cm .
1
1
H NMR (300 MHz, DMSO-d ): d = 7.58–7.62 (dd, J = 8.1, 4.8 Hz,
6
(
10) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
1
5
H), 8.27–8.31 (ddd, J = 8.1, 1.9, 1.8 Hz, 1 H), 8.85–8.88 (dd, J =
.0, 1.8 Hz, 1 H), 9.07–9.08 (d, J = 2.3 Hz, 1 H).
React. 1992, 42, 335.
Synthesis 2004, No. 17, 2886–2892 © Thieme Stuttgart · New York