Preparation and applications of a polymer-supported phosphoryl azide

Article abstract of DOI:10.1016/j.tetlet.2003.10.066

A polymer-supported diphenylphosphoryl azide was prepared. This polymer-supported version of DPPA is useful due to its lower toxicity, moisture tolerance and ease of workup after reaction. The synthetic application of this solid-phase reagent was explored by conversion of a variety of carboxylic acids to urethanes and ureas through Curtius rearrangement reactions. Carboxylic acids bearing different functional groups (aromatic, aliphatic and heterocyclic carboxylic acids) were subjected to the reaction. The corresponding products were isolated with satisfactory yields.

Full text of DOI:10.1016/j.tetlet.2003.10.066

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9267–9269
Preparation and applications of a polymer-supported
phosphoryl azideꢀ
Yuhua Lu and Richard T. Taylor*
Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
Received 22 September 2003; revised 10 October 2003; accepted 13 October 2003
Abstract—A polymer-supported diphenylphosphoryl azide was prepared. This polymer-supported version of DPPA is useful due
to its lower toxicity, moisture tolerance and ease of workup after reaction. The synthetic application of this solid-phase reagent
was explored by conversion of a variety of carboxylic acids to urethanes and ureas through Curtius rearrangement reactions.
Carboxylic acids bearing different functional groups (aromatic, aliphatic and heterocyclic carboxylic acids) were subjected to the
reaction. The corresponding products were isolated with satisfactory yields.
© 2003 Elsevier Ltd. All rights reserved.
Carboxylic acids and their derivatives can be converted
to amines through molecular rearrangement.1,2
Diphenylphosphoryl azide (DPPA) has been widely
used for organic synthesis since T. Shioiri and S.
Yamada et al. used DPPA as a modified azide to
conduct Curtius reactions in 1972.3,4 However, toxicity
considerations limit its usage and cause environmental
problems. The high boiling point of DPPA creates
additional difficulties in workup and purification after
reaction.5 The relative sensitivity of commercial DPPA
to moisture and oxidizing agents necessitates careful
storage. Recent technological advancements in poly-
mer-supported reagents provide solutions to these
drawbacks. Using polymers with the Curtius reaction
has precedence in drug delivery and combinatorial
chemistry. Several reports of polymer-bound carboxylic
acids undergoing rearrangement to polymer-bound iso-
cyanates have appeared,6,7 as well as papers describing
polymer-bound nucleophiles capturing isocyanate inter-
mediates generated by the Curtius reaction.8,9 Herein
we report the synthesis of a polymer-supported DPPA
(Scheme 1).10
h.11 After removal of excess phenyl dichlorophosphate
by a simple wash with dichloromethane under nitrogen
atmosphere, the phenyl chlorophosphate loaded resin 2
was converted to solid-phase supported DPPA 3 by
treatment with 3.0 equiv. sodium azide and 3.0 equiv.
crown ether (15-crown-5) in dichloromethane under
reflux for 24 h.12 The crown ether was a necessary
phase-transfer reagent to provide maximum reaction
efficiency. The excess sodium azide and crown ether
were removed by filtration and washing with
dichloromethane and a small amount of distilled water.
After drying under vacuum overnight, the polymer-sup-
ported azide 3 was ready to use. The IR spectrum of
polymer-supported DPPA shows a strong azide absorp-
tion peak at 2168 cm−1, which is identical to that of
DPPA. This solid-phase supported DPPA is quite sta-
ble at room temperature. There is no obvious change
observed in the IR spectrum after one month of storage
in air.
Phenol resin 1 (1.5 mmol/g, Advanced ChemTech) was
first swelled in dichloromethane under a nitrogen atmo-
sphere for 5 min, then 5.0 equiv. phenyl dichlorophos-
phate was added at room temperature and stirred for 8
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.10.066
* Corresponding author. Tel.: +1-513-529-2826; fax: +1-513-529-2826;
e-mail: taylorrt@muohio.edu
Scheme 1. Synthesis of polymer-supported DPPA.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.066

9268
Y. Lu, R. T. Taylor / Tetrahedron Letters 44 (2003) 9267–9269
Table 1. Urethane or urea synthesized by polymer-supported DPPA

Y. Lu, R. T. Taylor / Tetrahedron Letters 44 (2003) 9267–9269
9269
The synthetic use of the polymer-supported phosphoryl
azide was explored by converting a variety of carboxylic
acids to urethanes or ureas through Curtius rearrange-
ment.4 A typical experimental procedure for the synthesis
of ethyl p-nitrocarbanilate (entry 3 in Table 1) follows:
Polymer-supported DPPA (1.0 g, ꢀ1.5 mmol, 1.0 equiv.,
based on fully azide-loaded resin) was swelled in benzene
(10 mL) under a nitrogen atmosphere for 5 min. To this
suspension were added 4-nitrobenzoic acid (0.30 g, 1.8
mmol, 1.2 equiv.) and triethylamine (0.21 g, 2.0 mmol,
1.4 equiv.) at room temperature. The mixture was heated
to reflux for 30 min. Ethanol (0.15 mL, 2.5 mmol, 1.7
equiv.) was added and the reaction was heated at reflux
for 24 h. After cooling to room temperature, the resin,
including unreacted DPPA and phosphorous derivatives
still linked on the resin, was removed by filtration and
washed with ethyl acetate (100 mL). The combined
filtrates containing the desired ethyl p-nitrocarbanilate
were washed with aqueous sodium hydroxide (1 M, 3×30
mL), distilled water (3×30 mL) and brine (30 mL). After
drying (MgSO4), solvent was removed under vacuum to
afford the crude product. Purification was performed on
silica-gel column chromatography (1:1 petroleum/diethyl
ether) to give pure ethyl p-nitrocarbanilate (0.25 g, 80%
yield). Following similar procedures, carboxylic acids
bearing different functional groups (aromatic, aliphatic
and heterocyclic carboxylic acids) were subjected to the
reaction, and corresponding urethanes and ureas were
obtained. The results are listed in Table 1. The overall
yields after two steps (polymer-supported DPPA and
urethane or urea syntheses) are serviceable (yield: 34–
80%) and the crude products, even before final purifica-
tion are uncontaminated by phosphoryl ester byproducts.
4. Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974,
30, 2151–2157.
5. Taylor, R. T.; Paupaiboon, U. Tetrahedron Lett. 1998, 39,
8005–8008.
6. Richter, L. S.; Andersen, S. Tetrahedron Lett. 1998, 39,
8747–8750.
7. Shao, H.; Colucci, M.; Tong, S.; Zhang, H.; Castelhano,
A. L. Tetrahedron Lett. 1998, 39, 7235–7238.
8. Sunami, S.; Sagara, T.; Ohkubo, M.; Morishima, H.
Tetrahedron Lett. 1999, 40, 1721–1724.
9. Migawa, M. T.; Swayze, E. E. Org. Lett. 2000, 2, 3309–
3311.
10. For syntheses of both polymer-supported DPPA and
urethanes (or ureas), all manipulations were performed in
oven-dried glassware under a nitrogen atmosphere unless
otherwise mentioned. All solvents and reagents were dried
or purified using standard procedures and distillated
freshly before use. Standard workup included washing with
water followed by brine. The organic phase was dried over
magnesium sulfate, and concentrated in vacuo. Column
chromatography was performed on silica gel (Natland
International Corp. 200–400 mesh) using the indicated
solvents. TLC analyses were carried out using C4 silica gel
plates (Silicycle Inc.). Uncorrected melting points were
determined with a Gallenkamp melting point apparatus. 1H
and 13C NMR spectra were recorded at 200 MHz (Bruker
Avance 200) in CDCl3 or acetone-d6 (Aldrich). IR spectra
were determined as neat film (using NaCl plate) or KBr
pellet on a Perkin–Elmer 1600 FT-IR spectrophotometer.
MS spectra were performed by HP 5890 series II Gas
chromatograph and 5971 series mass selective detector.
11. Thomas, A. V. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed. Diphenyl Phosphorochlo-
ridate; Wiley: New York, 1995; pp. 2245–2247.
12. Thomas, A. V. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A.. Ed. Diphenyl Phosphorazidate;
Wiley: New York, 1995; pp. 2242–2245.
In conclusion, the first synthesis of solid-phase supported
DPPA had been achieved. This new reagent may have
considerable use in synthetic chemistry seems based on
its moisture tolerance, lower toxicity and easy removal
after the reactions.
13. NMR spectral properties are the same as those exhibit in
Sadtler® standard NMR spectrum.
14. Shriner, R. L.; Child, R. G. J. J. Am. Chem. Soc. 1952, 74,
549–550.
Supplementary Data
15. Waller, F. J. EP0195515, Eur. Pat. Appl. 1986, 31.
16. 1H NMR (CDCl3, 300 MHz) l 0.86 (t, J=6.9 Hz, 3H), 1.24
(b, 18H), 1.66 (m, 2H), 3.85 (s, 3H), 4.14 (t, J=6.7 Hz, 2H),
6.82 (m, 1H), 6.96 (m, 2H), 7.2 (m, 1H), 8.1 (b, 1H). 13C
NMR (CDCl3, 75 MHz) l 14.08, 22.66, 25.86, 28.96, 29.28,
29.32, 29.52, 29.56, 29.60, 29.62, 31.89, 55.61, 65.30,
109.93, 118.13, 121.11, 122.56, 127.77, 147.52, 153.63.
FT-IR (cm−1): 3436, 2924, 2853, 1736, 1604, 1531, 1461,
1207, 1130.
Experimental procedures and spectroscopic data are
available for the polymeric azide 3 and for all products
reported in Table 1. The supplementary material is
available online with the paper in ScienceDirect.
Acknowledgements
17. Yamamoto, I.; Takahashi, Y. and Kyomura, N.
DE2545389, Ger. Offen. 1976, 86.
18. Yadav, J. S.; Reddy, B. V. S.; Reddy, G. S. K. K. New J.
Chem. 2000, 24, 571–573.
The support of Miami University through its Committee
on Faculty Research is gratefully acknowledged.
19. 1H NMR (CDCl3, 300 MHz) l 1.19 (d, J=6.2 Hz, 6H),
1.72 (m, 2H), 2.13 (s, 3H), 2.47 (t, J=7.1 Hz, 2H), 3.14
(q, J=6.5 Hz, 2H), 4.65 (b, 1H), 4.86 (m, 1H). 13C NMR
(CDCl3, 75 MHz) l 22.13, 23.96, 29.98, 40.23, 40.69, 67.96,
156.40, 208.42. FT-IR (cm−1): 2923, 1710, 1528, 1252, 1112.
20. Miyagi, Y.; Banjyo, N.; Yamamura, E. Bull. Chem. Soc.
Jpn. 2002, 75, 857–858.
21. Izdebski, J.; Pawlak, D. Synthesis 1989, 6, 423–425.
22. Wilcox, C. S.; Kim, E.; Romano, D.; Kuo, L. H.; Burt, A.
L.; Curran, D. P. Tetrahedron 1995, 51, 621–634.
References
1. Buehler, C. A.; Pearson, D. E. Survey of Organic Syntheses;
Wiley-Interscience: New York, 1970; pp. 494–503.
2. Shioiri, T. In Comprehensive Organic Synthesis, Trost, B.
M., Ed.; Pergamon Press: New York, 1991; Vol. 6, pp.
795–828.
3. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203–6205.