Conversions of primary amines to azides by n-butyllithium and azidotris(diethylamino)phosphonium bromide

Article abstract of DOI:10.1016/S0040-4039(02)01444-2

Lithium derivatives of varied aromatic, heterocyclic, aliphatic, and alicyclic primary amines react efficiently with azidotris(diethylamino)phosphonium bromide in THF at low temperatures to give azides, lithium bromide, nitrogen, and tris(diethylamino)pho

Full text of DOI:10.1016/S0040-4039(02)01444-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8421–8423
Conversions of primary amines to azides by n-butyllithium and
azidotris(diethylamino)phosphonium bromide
Stephen P. Klump and Harold Shechter*
Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA
Received 4 June 2002; accepted 8 July 2002
Abstract—Lithium derivatives of varied aromatic, heterocyclic, aliphatic, and alicyclic primary amines react efficiently with
azidotris(diethylamino)phosphonium bromide in THF at low temperatures to give azides, lithium bromide, nitrogen, and
tris(diethylamino)phosphorimine. © 2002 Elsevier Science Ltd. All rights reserved.
Organic azides (R-N3) are important chemicals.1 Of
interest with respect to their synthesis is that aliphatic and
alicyclic primary amines have been converted by excess
n-BuLi or NaH and then tosyl azide (p-CH3-C6H4-SO2-
N3] to azides.2a–f More recently aliphatic and alicyclic
primary amines have been found to give azides in greater
yields by reactions with trifyl azide (CF3-SO2-N3) as
catalyzed by Cu++, Ni++, and Zn++ ions.2g Now reported
is that aromatic, heterocyclic, aliphatic, and alicyclic
primary amines (Scheme 1) in THF at −78°C react rapidly
with n-BuLi and then azidotris(diethylamino)phos-
phonium bromide (3)3 to give the corresponding azides
(7) and tris(diethylamino)phosphorimine (6) efficiently,
reliably, and safely. The method also has advantages in
that sensitive azides can be prepared at low temperatures
and separated from other reaction products simply. The
overall methodologies, typical laboratory procedures, the
grossreactionmechanism, andspecificsynthesisexamples
are discussed and illustrated as follows.
Treatment of 1-aminonaphthalene with n-BuLi (1.02
equiv.) and then 3 (1.20 equiv.) in THF at −78°C, simple
workup after 0.5–1.0 h, rapid chromatography on silica
gel, and elution with Et2O give 1-azidonaphthalene (8,
88%).4a,b Similarly, 2-aminonaphthalene is converted to
2-azidonaphthalene (9, 81%).4b,5a Further, one-pot dou-
ble diazo transfer on 1,5-diaminonaphthalene with n-
BuLi (2.05 equiv.) and 3 (2.37 equiv.) in THF at −78°C
yields 1,5-diazidonaphthalene (10, 85%)5b and 1,2-diazi-
dobenzene (11)5c is conveniently prepared (84%) from
1,2-diaminobenzene, n-BuLi (2.43 equiv.), and 3 (2.44
equiv.) in THF at −78°C.
Diazo transfers on 1,8-diaminonaphthalene (12) to give
1,8-diazidonaphthalene (13)5d are more complicated than
for 1,5-diaminonaphthalene to 10. Additions of n-BuLi
(1.71 equiv.) and then 3 (1.91 equiv.) to 12 in THF at
−78°C yield 1-amino-8-azidonaphthalene (14, 74%).5d,e
Similarly, 12, n-BuLi (2.11 equiv.) and 3 (1.10 equiv.) in
THF at −78°C (10 min) and then reaction with n-BuLi
(1.07 equiv.) at −78°C give 14 (61%).5e
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01444-2

8422
S. P. Klump, H. Shechter / Tetrahedron Letters 43 (2002) 8421–8423
Pure 14 is converted however by 3 (1.13 equiv.) and
n-BuLi (1.02 equiv.) in THF at −78°C to 13 (52%) after
a 2.5 h reaction period and allowing the mixture to
warm to room temperature. Further, stirring diamine
12 with n-BuLi (2.06 equiv.) and 3 (2.42 equiv.) in THF
for 1 h at −78°C, adding additional n-BuLi (1.03
equiv.) and 3 (1.15 equiv.) at −78°C for 30 min, and
allowing the reactions to proceed for 4 h at 20–25°C
yield diazide 13 (74%). The slowness of double diazo
transfer of 12 at −78°C may be due to difficulty in
deprotonation of 14 by n-BuLi to give the 8-azido-1-
naphthylamide ion (15) and/or interactions of the azide
and the amide groups in 15 yielding 16 and/or 17.
Detailed studies of the behaviors of 15–17 are to be
made.
Scheme 2.
similar to that for preparing the prior aromatic and
pyridyl azides using n-BuLi and 3 at −78°C.
Heteroaromatic azides are also easily prepared from
lithium derivatives of primary heteroaromatic amines
and 3. Thus 4-azidopyridine (18, 85%)5f and 2-azidopy-
ridine (19, 80%)5g are readily obtained from their
respective aminopyridines, n-BuLi, and 3 by procedures
essentially identical to that for 8 and 9. The IR absorp-
tions of the azido group in 19 are weak and thus
indicative of the major equilibrative presence of its
ring-closure isomer, tetrazolo[1,5-a]pyridine (20).5g
No efforts were made to improve the yields of the
above aliphatic and alicyclic azides other than to find
that the conversion of 2-amino-2,4,4-trimethylpentane
to 27 is increased by successive sequential additions of
n-BuLi and 3. Thus, reactions of 2-amino-2,4,4-
trimethylpentane with n-BuLi (1.0 equiv.) and 3 (1.12
equiv.) at −78°C followed by further addition of n-BuLi
(1.04 equiv.) and 3 (1.14 equiv.) at −78°C give 27
(>59%).5i
Further uses of 3 for diazo transfer and as an oxidizing
agent will be reported.
The present diazo transfer methodology (Scheme 1) is
also usable for preparing 5-membered ring hetaryl
azides. Thus, 5-azido-3-phenylpyrazole (23)5h is
obtained from 5-amino-3-phenylpyrazole (21), n-BuLi
(1.91 equiv.), and 3 (1.12 equiv.) at −78°C to ꢀ25°C
for 3 h. The synthesis is of interest in that 23 is
apparently formed by directed diazo transfer to the
dilithio derivative (22) of 21 and protonation (Scheme
References
1. For reviews of synthesis and chemistry of azides, see: (a)
Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297;
(b) Azides and Nitrenes; Scriven, E. F. V., Ed.; Academic:
Orlando, 1984; (c) Smith, P. A. S. Open-Chain Organic
Nitrogen Compounds: Derivatives of Hydrazine and Other
Hydronitrogens Having NꢀN Bonds; Benjamin-Cummings:
Reading, MA, 1983; Chapter 6; (d) The Chemistry of the
Azido Group; Patai, S., Ed.; Wiley: New York, 1971; and
(e) references cited therein.
1
2). The spectra of 23 reveal H NMR absorptions for
N–H and C–H in its pyrazole ring and a very strong IR
band for its azide group. These spectra indicate that
azidopyrazole 23 does not undergo extensive heterocy-
clization and tautomerism (Scheme 2) to triazolopyra-
zole isomers 24 and 25.5h
2. (a) Fischer, W.; Anselme, J.-P. J. Am. Chem. Soc. 1967,
89, 5284; (b) Caveander, C. J.; Shiner, V. J. J. Org. Chem.
1972, 37, 3567; (c) Zaloom, J.; Roberts, D. C. J. Org.
Chem. 1981, 46, 5173; (d) Vasella, A.; Witzig, C.; Chiara,
J.-L.; Martin-Lomas, M. Helv. Chim. Acta 1991, 74, 2073;
(e) Buscas, T.; Garegg, P. J.; Konradsson, P.; Maloisel,
J.-L. Tetrahedron: Asymmetry 1994, 5, 2187; (f) Ludin, C.;
The above azidation methodology has been extended to
2-amino-2,4,4-trimethylpentane, cyclohexylamine, and
1-hexylamine. Thus 2-azido-2,4,4-trimethylpentane (27,
45%),5i azidocyclohexane (28, 41%),5j and 1-azidohex-
ane (29, 47%) are obtained conveniently from their
corresponding amines, n-BuLi, and 3 by procedures

S. P. Klump, H. Shechter / Tetrahedron Letters 43 (2002) 8421–8423
8423
Schwesinger, B.; Schwesinger, R.; Meier, W.; Seitz, B.;
Weller, T.; Hoenke, C.; Haitz, S.; Erbeck, S.; Prinzbach,
H. J. Chem. Soc., Perkin Trans. 1 1994, 2685; (g) Alper, P.
A.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 37,
6029.
organic layer was concentrated at reduced pressure. Rapid
chromatography on silica gel, elution with Et2O, and
solvent removal gave 8 (0.3838 g, 2.27 mmol, 88%), a red
liquid. TLC of the product gave only one spot: FTIR (thin
1
film) 2111.8 (-Nꢁ+Nꢁ−N) cm−1; H NMR (CDCl3) l 7.27
(d, J=7.37 Hz, 1H), 7.42–7.70 (m, 4H), 7.86–7.91 (m, 1H),
3. (a) Azidophosphonium bromide 3, an excellent diazo
transfer reagent for stabilized carbanions, is prepared by
(1) bromination of tris(diethylamino)phosphine [(Et2N)3P)]
obtained from Et2NH and PCl3 and (2) reaction of the
1
8.18–8.23 (m, 1H). The H NMR and FTIR spectra of 8
match literature values4b; (b) Boshev, G.; Dyall, L. K.;
Sadler, P. R. Aust. J. Chem. 1972, 25, 599.
5. The 1H NMR and FTIR spectra and/or other physical
constants of the additional azides presently reported and
as designated by number agree with literature values: (a)
9a: Ref 4b; (b) 10: Smith, P. A. S.; Brown, B. B. J. Am.
Chem. Soc. 1951, 73, 2438; (c) 11: Hall, J. H.; Patterson, E.
J. Am. Chem. Soc. 1965, 8, 1147; (d) 13: Reese, C. W.;
Storr, R. C.; Bradbury, S. J. Chem. Soc., Perkin 1 1972,
68; (e) 14: Ref. 5d; (f) 18: El’tsov, A. V.; Khanchmann, A.;
Rtishchov, N. I. Zh. Org. Khim. 1977, 13, 465; (g) 19:
Wentrup, C.; Winter, H.-W. J. Am. Chem. Soc. 1980, 102,
6159; (h) 23: deMendoza, J.; Elguero, J. J. Heterocycl.
Chem. 1974, 11, 921; (i) 27: Ref. 5h; (j) 28: Steinheimer, T.
R.; Wulfman, D. S.; McCullagh, L. N. Synthesis 1971,
325; (k) 29: Ref. 2b.
resulting bromotris(diethylamino)phosphonium bromide
[(Et2N)3P+BrBr−] with NaN3
; (b) McGuiness, M.;
3b
Shechter, H. Tetrahedron Lett. 1990, 31, 1990; (c) We
should like to thank M. McGuiness for his counsel in the
present investigation.
4. (a) A typical procedure for monoaziridination of the
amines of the present study is described for preparation of
8 as follows. 1-Aminonaphthalene (0.3687 g, 2.58 mmol) in
dry THF (10 mL) at −78°C was deprotonated with n-BuLi
(1.05 mL, 2.50 M, 2.62 mmol in hexane, 1.02 equiv.).
Azidophosphonium bromide 3 (1.1410 g, 3.09 mmol, 1.20
equiv.) in dry THF (20 mL) was added. After being stirred
for ꢀ45 min at −78°C, the reaction mixture was washed
with aqueous 0.25 M NH4Cl and with CH2Cl2. The