A simple one-pot procedure for the direct conversion of alcohols to azides via phosphate activation

Article abstract of DOI:10.1021/ol0060376

(Equation presented) A one-pot procedure was developed to prepare efficiently alkyl azides from alkanus using bis(2,4-dichlorophenyl) phosphate activation. 4-(Dimethylamino)pyridine was used as a base, and phosphorylpyridinium azide is believed to be the activating agent under this condition.

Full text of DOI:10.1021/ol0060376

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1959-1961
A Simple One-Pot Procedure for the
Direct Conversion of Alcohols to Azides
via Phosphate Activation
Chengzhi Yu, Bin Liu, and Longqin Hu*
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers,
The State UniVersity of New Jersey, 160 Frelinghuysen Road, Piscataway,
New Jersey 08854-8020
longhu@rci.rutgers.edu
Received May 9, 2000
ABSTRACT
A one-pot procedure was developed to prepare efficiently alkyl azides from alkanols using bis(2,4-dichlorophenyl) phosphate activation.
4-(Dimethylamino)pyridine was used as a base, and phosphorylpyridinium azide is believed to be the activating agent under this condition.
Conversion of an alcohol to its corresponding azide is an
important functional group transformation in organic syn-
thesis.1 Although there are a variety of indirect methods
reported in the literature, few direct azidation methods are
known. Among the known direct methods, Mitsunobu
displacement2 using hydrazoic acid as the azide source3
proved to be the most efficient in transforming alkyl,
benzylic, and allylic hydroxyls into their corresponding
azides. However, the use of highly toxic hydrazoic acid limits
the applicability of this method. Alternatives to hydrazoic
acid include diphenyl phosphorazidate (DPPA)4 and zinc
azide/bis-pyridine complex.5 Under these conditions, a
substrate alcohol is mixed with diethyl azadicarboxylate and
triphenyl phosphine prior to the addition of the azide reagent,
a procedure that often leads to racemization and olefin
formation. A more recent method reported by Thompson et
al. for direct conversion of alcohols to azides uses DPPA
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dry tolu-
ene,6 where DBU acts as a base to help convert the alcohol
to the corresponding phosphate intermediate and then,
without isolation, the phosphate is displaced by the azide
ion. However, few simple alkanols have been successfully
converted to their corresponding azides using such direct
methods.
In our efforts to synthesize anticancer prodrugs of phos-
phoramide mustard and FUDR, we needed to convert the
hydroxyl groups in compounds 1, 2, and 3 to their corre-
sponding azides. Hydrazoic acid-assisted Mitsunobu reaction
successfully converted compound 1 to its corresponding azide
in 93% yield, while Thompson’s procedure using DPPA/
DBU in toluene failed. The latter procedure also failed to
convert alkanol 2 and benzylic diol 3 to the desired azide
products even upon heating to 45 °C; only the corresponding
phosphates 4 and 5 were isolated. This prompted us to
develop new direct procedures for the preparation of alkyl
azides from such simple and less reactive alcohols. In this
Letter, we wish to report a convenient one-pot procedure
using bis(2,4-dichlorophenyl) phosphate as a good leaving
group to activate hydroxyl groups for the direct conversion
(1) (a) Trost, B. M.; Fleming, I. ComprehensiVe Organic Synthesis; 1991;
Pergamon Press: New York, Vol. VI, pp 76-79. (b) Hanessian, S.
PreparatiVe Carbohydrate Chemistry; Marcel Dekker: New York, 1997;
Chapter 5, pp 90-97.
(2) (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94,
679-680. (b) Hughes, D. L. Org. React. 1992, 42, 358-359.
(3) Loibner, H.; Zbiral, E. HelV. Chim. Acta 1977, 60, 417-425.
(4) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977-1980.
(6) Thompson, A. S.; Humphrey, G. R.; Demarco, A. M.; Mathre, D. J.;
Grabowski, J. J. J. Org. Chem. 1993, 58, 5886-5888.
(5) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
10.1021/ol0060376 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/07/2000

of simple alkanols or less reactive benzyl alcohols to their
corresponding azides.
giving the lowest yield of the desired azide 11. In the case
of symmetrical benzylic diol 3, where the same 1.05 equiv
of bis(2,4-dichlorophenyl) chlorophosphate was used, the
major product isolated was the monoazidated product 13
(82%) with the corresponding bisazidated compound as the
minor product (9.2%). This unexpected selectivity suggests
that our one-pot procedure might be used to selectively
convert diols to azido alcohols without going through the
typical protection-deprotection steps.
Mechanistically, we believe the reaction takes place in
three discrete steps as illustrated in Scheme 1. (i) DMAP
Scheme 1
The failure of Thompson’s direct azidation procedure to
convert compounds 1, 2, and 3 to their corresponding azides
and the isolation of phosphate intermediates 4 and 5 suggest
that diphenyl phosphate was not a good enough leaving group
to activate, for SN2 displacement, hydroxyl groups of simple
alkanols or less reactive benzyl alcohols with strong electron-
withdrawing substituents on the phenyl ring. This was also
shown as a limitation of Thompson’s procedure in the
original report.6 We reasoned that introduction of electron-
withdrawing substituents on the phenyl ring would make it
a better leaving group and the resulting phosphate could be
sufficiently reactive for displacement by azide ion. Thus, we
replaced diphenyl chlorophosphate, the common activating
agent used in the indirect methods, with bis(2,4-dichlorophe-
nyl) chlorophosphate. To avoid the isolation of phosphate
intermediates and the preparation of phosphorazidate,7 we
decided to perform the activation and azide displacement
using the following one-pot procedure.8 To a solution of
substrate alcohol (1 mmol) in anhydrous DMF (5 mL) were
added at room temperature with stirring NaN3 (4 equiv) and
DMAP (1.2 equiv) followed by bis(2,4-dichlorophenyl)
chlorophosphate (1.05 equiv). Stirring was continued for 2
h or until the starting material disappeared as monitored by
TLC. The reaction usually works well at room temperature.
If TLC showed incomplete conversion after 2 h, the
temperature could be raised to 45 °C to complete the reaction.
For workup, ethyl ether (100 mL) and brine (30 mL) were
added to the reaction mixture. The organic phase was
separated, washed with aqueous NaOH (20%) and brine, and
dried over anhydrous MgSO4. After filtration, the solvent
was removed in vacuo. The crude product was purified by
flash column chromatography (ethyl ether:hexane) to afford
the desired azide product.
reacts with bis(2,4-dichlorophenyl) chlorophosphate in the
presence of sodium azide to form bis(2,4-dichlorophenyl)-
phosphoryl 4-(dimethylamino)pyridinium azide (19). (ii) The
phosphoryl pyridinium azide (19) then reacts with the
substrate alcohol to form the activated bis(2,4-dichloro-
phenyl) phosphate (20). (iii) The bis(2,4-dichlorophenyl)-
phosphoryl group in 20 is displaced by azide ion to produce
the desired azide. In this mechanism, the activating reagent
is bis(2,4-dichlorophenyl)phosphoryl 4-(dimethylamino)-
pyridinium azide (19). To confirm this, we performed the
following experiments. First, we mixed an equimolar mixture
of bis(2,4-dichlorophenyl) chlorophosphate and sodium azide
in DMF at room temperature and monitored the reaction
using IR spectroscopy. We observed a complete shift of the
azide signal from 2010 to 2174 cm-1 in about 30 min. When
DMAP was added into the mixture, the azide absorption at
2174 cm-1 disappeared quickly and a new peak appeared at
2133 cm-1. This result suggested that bis(2,4-dichlorophenyl)
chlorophosphate reacted with sodium azide to form the bis-
(2,4-dichlorophenyl) phosphorazidate and the phosphorazi-
date was then converted quickly to bis(2,4-dichlorophenyl)-
phosphoryl 4-(dimethylamino)pyridinium azide (19) upon the
(9) 1H NMR (200 MHz, CDCl3) data for the azide products listed in
Table 1: δ ppm 11: 8.14 (d, J ) 8.4 Hz, 2H), 7.60-7.52 (m, 4H), 7.39-
7.29 (m, 8H), 4.83 (t, J ) 5.8 Hz, 1H), 3.80-3.69 (m, 1H), 3.58-3.50 (m,
1H), 1.94-1.80 (m, 2H), 1.10 (s, 9H); 12: 8.22 (dd, J ) 1.8, 6.8 Hz, 2H),
7.52 (dd, J ) 0.3, 6.9 Hz, 2H), 4.83 (dd, J ) 4.5, 9.0 Hz, 1H), 4.60 (d, J
) 6.9 Hz, 1H), 0.4.51 (d, J ) 1.2, 6.8 Hz, 1H), 3.51-3.40 (m, 2H), 3.37
(s, 3H), 2.07-2.02 (m, 1H), 1.93-1.89 (m, 1H); 13: 7.40-7.32 (m, 4H),
4.69 (d, J ) 5.9 Hz, 2H), 4.45 (s, 2H), 2.52 (t, J ) 5.9 Hz, 1H); 14: 7.68
(d, J ) 8.0 Hz, 1H), 7.53 (t, J ) 7.1 Hz, 1H), 7.38 (t, J ) 7.9 Hz, 2H),
3.53 (t, J ) 7.3 Hz, 2H), 3.10 (t, J ) 7.3 Hz, 2H); 15: 7.69 (d, J ) 7.7 Hz,
4H), 7.50-7.32 (m, 10H), 4.80 (s, 2H), 4.34 (s, 2H), 1.09 (s, 9H); 16:
7.73-7.69 (m, 4H), 7.48-7.42 (m, 6H), 3.79 (t, J ) 5.9 Hz, 2H), 3.49 (t,
J ) 6.8 Hz, 2H), 1.85 (p, J ) 6.3 Hz, 2H), 1.10 (s, 9H); 17: 7.78-7.73
(m, 4H), 7.49-7.43 (m, 6H), 3.75 (t, J ) 6.1 Hz, 2H), 3.29 (t, J ) 6.8 Hz,
2H), 1.69-1.55 (m, 6H), 1.14 (s, 9H); 18: 7.75-7.70 (m, 4H), 7.46-7.42
(m, 6H), 3.72 (t, J ) 6.2 Hz, 2H), 3.28 (t, J ) 6.9 Hz, 2H), 1.64-1.58 (m,
4H), 1.43-1.37 (m, 6H), 1.11 (s, 9H).
As shown in Table 1, all the alkanols we examined were
converted to their corresponding azides9 in satisfactory yields
between 76 and 92% with the less reactive benzyl alcohol 1
(7) Shioriri, T.; Yamada, S. Organic Syntheses; Wiley: New York, 1990;
Collect. Vol. VII, pp 206-207.
(8) Caution: Azides especially bisazidated products are potentially
explosive and should be handled with care. The procedure should be
performed in a well-ventilated hood.
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Org. Lett., Vol. 2, No. 13, 2000

Table 1. Conversion of Alcohols to Azidesa
a Reaction conditions: bis(2,4-dichlorophenyl) chlorophosphate (1.05 eq), sodium azide (4 eq), DMAP (1.2 eq), DMF, rt. b Racemic
starting material was used to obtain a racemic product mixture of 11. d Bisazidated product was also isolated in 9.2% yield. e The reaction
mixture had to be warmed up to 45 °C to obtain the best product yield.
addition of DMAP. In our second experiment, we added
sodium azide to an equimolar mixture of bis(2,4-dichlo-
phenyl) chlorophosphate and DMAP and found that the azide
signal at 2133 cm-1 appeared immediately upon the addition
of sodium azide. In our one-pot procedure, the same azide
signal at 2133 cm-1 was initially observed when all reagents
were mixed with substrate alcohol and slowly disappeared
as a new product signal appeared (Table 1). Apparently,
when all three reagents are mixed together with or without
substrate alcohol present, the bis(2,4-dichlorophenyl)phos-
phoryl 4-(dimethylamino)pyridinium azide (19) is formed
quickly without going through the bis(2,4-dichlorophenyl)
phosphorazidate intermediate, suggesting that pyridinolysis
of bis(2,4-dichlorophenyl) chlorophosphate is faster than the
reaction of bis(2,4-dichlorophenyl) chlorophosphate with
sodium azide or the substrate alcohol.10 These results are
consistent with bis(2,4-dichlorophenyl)phosphoryl 4-(di-
methlyamino)pyridinium azide (19) being the actual activat-
ing agent in this reaction. Subsequently, we found that the
best method was adding bis(2,4-dichlorophenyl) chlorophos-
phate to the reaction mixture last in order to obtain the
desired product in good yields.
was obtained in satisfactory isolated yield (Table 1). These
results suggest that the azide ion is the major, if not the only,
nucleophile participating in the SN2 displacement reactions.
In summary, we developed a simple one-pot procedure
for the direct conversion of alcohols to the corresponding
azides, demonstrating the usefulness of phosphate chemistry11
in organic functional group transformation. Our method is
mild and convenient and should be complementary to
Thompson’s procedure of direct azidation to convert alcohols
to their corresponding azides. Furthermore, this one-pot
procedure might be adapted to introduce nucleophiles other
than azides.12
Acknowledgment. We gratefully acknowledge the fi-
nancial support of Grant DAMD 17-98-1-8544 from the U.S.
Army Department of Defense Prostate Cancer Research
Program and a research grant from the State of New Jersey
Commission on Cancer Research.
OL0060376
(11) The mechanism of phosphoryl transfer from phosphate monoesters
and diesters has been the subject of many recent investigations. See:
Thatcher, G. R. J.; Luger, R. K. AdV. Phys. Org. Chem. 1989, 25, 99-103
and references therein.
(12) For example, sodium cyanide might be used in place of sodium
azide to convert alcohols to the corresponding chain extended nitriles in a
similar “one-pot” procedure.
It should also be noted that even though chloride ions were
present in each of the reactions, no chloride displacement
byproduct was isolated and that the desired azide product
(10) Guha, A. K.; Lee, W.; Lee, I. J. Org. Chem. 2000, 65, 12-15.
Org. Lett., Vol. 2, No. 13, 2000
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