Conversions of hydrazones to diazo compounds by n-butyllithium and azidotris(diethylamino)phosphonium bromide

Article abstract of DOI:10.1016/S0040-4039(02)01443-0

Lithium hydrazonides, prepared by reactions of hydrazones with n-BuLi/hexane in THF at -78°C, are converted by azidotris(diethylamino)phosphonium bromide in THF at ～0°C efficiently, rapidly, and safely to their corresponding diazo compounds along with tri

Full text of DOI:10.1016/S0040-4039(02)01443-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8425–8427
Conversions of hydrazones to diazo compounds by n-butyllithium
and azidotris(diethylamino)phosphonium bromide
Mark McGuiness and Harold Shechter*
Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA
Received 4 June 2002; accepted 8 July 2002
Abstract—Lithium hydrazonides, prepared by reactions of hydrazones with n-BuLi/hexane in THF at −78°C, are converted by
azidotris(diethylamino)phosphonium bromide in THF at ꢀ0°C efficiently, rapidly, and safely to their corresponding diazo
compounds along with tris(diethylamino)phosphorimine, nitrogen, and lithium bromide. © 2002 Elsevier Science Ltd. All rights
reserved.
Oxidation of hydrazones is a primary method for syn-
thesis of diazo compounds.1 Established reagents for
such oxidations are mercury(II) oxide, silver(I) oxide,
manganese dioxide, and nickel peroxide.1 Lesser-known
oxidants are lead tetraacetate, iodine/triethylamine,
fluorenone hydrazone and methyllithium, and 4 yield
9-diazofluorene (70%).2 Now reported is that lithium
hydrazonides (11) react rapidly with azidotris(diethyl-
amino)phosphonium bromide (12, Scheme 2)3 at 0°C to
give diazo compounds (7) efficiently along with tris-
(diethylamino)phosphorimine (15) and nitrogen (8).
The overall methodology (Scheme 2) is excellent for
converting hydrazones (11) of various types4 to their
corresponding diazo compounds (7). Azidophospho-
nium bromide 12 is a readily prepared, safe, diazo
transfer reagent known to convert 1,3-dicarbonyl com-
pounds to diazo derivatives (7) efficiently.3
phenyliodine(III)
diacetate,
phenyldipyridinio-
iodine(III) bis(trifluoromethanesulfonate), barium man-
ganate, mercury(II) acetamide, mercury(II) trifluoroace-
tate, triphenylbismuth carbonate, sodium and calcium
hypochlorites, chlorine dioxide, N-bromosuccinimide,
potassium ferricyanide, hydrogen peroxide, peracetic
acid, oxygen, and N,N-bis(trifluoromethyl)aminoxyl
radicals.1 The above oxidants are often ineffective for
preparing non-stabilized diazo compounds, the proce-
dures usually can only be used safely on a small-scale,
separation, isolation, and storage of the diazo products
may be difficult, and environmental problems in dis-
posal of the co-products are severe.1 Improvements in
synthesis of unstable diazo compounds have been made
by oxidation of hydrazones with lead tetraacetate in
tetramethylguanidine/dimethylformamide at −78°C.1d
Hydrazones (1) are obtained simply and in high yields
from aldehydes and ketones upon use of excess hydra-
zine and proper methodology.1d,4 Preparation of hydra-
zonides 11 by addition of hydrazones 1 in THF to
Of significance also with respect to the above prepara-
tive methods is that hydrazones (1) have been converted
by methylmagnesium chloride (2, Scheme 1) to chloro-
magnesium hydrazonides (3) which, upon reaction with
tosyl azide (4) followed by aqueous workup, give stabi-
lized diazo compounds (7).2 Diphenyldiazomethane
(50%), 1-diazo-1-phenylethane (35%), and ben-
zoyl(phenyl)diazomethane have been obtained in mod-
erate yields by the above methodology.2 Further,
lithium 9-fluorenone hydrazonide, as prepared from
* Corresponding author.
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01443-0

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M. McGuiness, H. Shechter / Tetrahedron Letters 43 (2002) 8425–8427
The diazo compounds (7) presently prepared (Scheme
2) from their corresponding hydrazones (1) are 1-diazo-
1-phenylethane, 1-diazotetralin, phenyl(2-propyl)diazo-
methane, 1-diazoindane, 2-diazo-3,3-dimethylbutane, 1-
diazo-2-ethylbutane, 2-diazocamphane, and 1-dia-
zononane as summarized in Table 1.
A typical
procedure for the present preparations of 7 is given in
Ref. 6. Good yields (90–57%) are obtained for all of the
diazo compounds (7) presently synthesized and the
methodology has advantages over traditional oxidation
procedures for preparing unstable diazo compounds.1
Of interest now are whether sodium hydrazonides
(R2CꢀN-NHNa) and azidotris(dimethylamino)phos-
phonium halides [N3P+(NMe2)3X−, X−=Cl− and Br−]7
yield diazo compounds (7) more cheaply and whether
Scheme 2.
hydrazonide/azidophosphonium
halide
oxidation–
reduction methodologies allow effective syntheses of
various N-azidimines (R2CꢀN-N3)2 and polydiazo com-
pounds.
n-BuLi/hexane in THF at −78°C is near-instantaneous
and essentially quantitative. To effect the present oxida-
tions of hydrazonides 11 to 7, an equivalent of azi-
dophosphonium bromide 12 in THF is added to the 11
in THF and hexane at ꢀ0°C. Although not needed for
synthesis, the yield and the overall rate of formation of
a diazo compound (7) can be easily determined upon
measuring the nitrogen liberated (Scheme 2). A reaction
sequence for the present conversions of 1 to 7 is shown
in Scheme 2. In theory the highly basic co-product,
tris(diethylamino)phosphorimine (15), could make the
overall conversions of 1 by 12 catalytic in base.3b,5 In
practice however the base-catalyzed reactions of 1 and
12 by 15 are slow. An important aspect of the present
methodology is that the diazo compounds (7) produced
are protected by 15 (a strong base)5 which can be easily
removed by extraction with aqueous ethylene glycol at
−15°C. The traces of 15 remaining in the product are
precipitated as phosphorimino carbonate 16 by treat-
ment of the organic extract with CO2 (dry ice).
Acknowledgements
The National Cancer Institute and the Department of
Education are thanked for support of this study.
References
1. (a) For a comprehensive review and references of the
above reagents for oxidations of hydrazones (1) to diazo
compounds (7), see: (b) Regitz, M.; Maas, G. Diazo Com-
pounds: Properties and Synthesis; Academic Press:
Orlando, FL, 1986; Chapter 8, pp. 233–256; (c) Bo¨sh, M.;
Fink, J.; Heydt, H.; Wagner, O.; Regitz, M. Methoden Der
Organischen Chemie (Houben–Weyl), Vol. E14B; Klaman,
D.; Hagemann, H.; Eds.; Georg Thieme Verlag: New
York, 1990; pp. 996–1010; and (d) Holton, T. L.; Shechter,
H. J. Org. Chem. 1995, 60, 4725.
2. (a) Fischer, W.; Anselme, J.-P. Tetrahedron Lett. 1968, 9,
877; (b) Anselme, J.-P.; Fischer, W. Tetrahedron 1969, 25,
855; (c) Of interest also in the experiments in Refs. 2a,b is
Table 1. Diazo compounds (7) prepared from hydrazonides 11 and 12

M. McGuiness, H. Shechter / Tetrahedron Letters 43 (2002) 8425–8427
8427
that N-azidimines (R2CꢀN-N3) were not detected; (d) Syn-
thesis and the chemistry of N-azidimines such as 3-ethyl-2-
tetrazobenzothiazoline (A) are reported by (e) Balli, H.;
Kersting, F. Ann. 1963, 107; (f) Balli, H. Angew. Chem.,
Int. Ed. Engl. 1964, 43, 803; and (g) Balli, H. Angew.
Chem., Int. Ed. Engl. 1966, 5, 132; (h) Preparation and the
behavior of other N-azidimines are being studied in this
laboratory.
oxidants.1d Such oxidations are usually greatly improved
upon using bases such as pyridine, triethylamine, and, in
particular, tetramethylguanidine to neutralize the acidic
co-product. Phosphorimine 15 and its analogs
(R2N)3PꢀNR are much stronger bases than the previous
bases cited and thus are expected to protect various sensi-
tive diazo compounds from acid-catalyzed reactions.5b (b)
Schwesinger, R. Chimia 1985, 39, 269.
6. General procedure for conversion of hydrazones (1) to diazo
compounds (7). A solution of n-BuLi (7.5 mmol) in hexane
is added to dry THF (50 mL) at −78°C under argon.
Hydrazone 1 (7.5 mmol) in dry THF (25 mL) is added
dropwise. The resulting mixture is warmed to 0°C. The
reaction flask is connected to a gas-measuring cylinder and
equilibrated at 0°C. A solution of azidophosphonium bro-
mide 12 (8.0 mmol) in cold, dry THF (25 mL) is added
dropwise. When nitrogen evolution ceases, the reaction
mixture is diluted with pentane (100 mL) cooled to −78°C.
The resulting solution is extracted with 25% aqueous
ethylene glycol (5×50 mL) cooled to ca. −15°C. The pen-
tane phase is then poured carefully over dry ice (CO2) and
allowed to stand in the dark for 15 min. The cold solution
is filtered to remove the small amounts of carbonate 16
giving a solution of the diazo compound (7) in pentane/
THF (ca. 4:1). The diazo compound (7) can be used
conveniently in solution or isolated upon removal of the
solvents at reduced pressures.
.
3. (a) Azidophosphonium bromide 12 is prepared (80% yield)
by reaction of PCl3 and excess Et2NH, bromination (Br2/
THF) of the (Et2N)3P obtained, and displacement of the
resulting (Et2N)3P+BrBr− with NaN3 in THF/18-Cr-6;3b,c
(b) McGuiness, M.; Shechter, H. Tetrahedron Lett. 1990,
31, 4987; (c) Azido bromide 12 has been found to be a
very safe reagent.3b
4. (a) For discussion, details, and references for preparing
various hydrazones (1), see: (b) Dumic, M.; Koruncev, D.;
Koracevic, K.; Polak, L.; Kolbah, D. Methoden Der
Organischen Chemie (Houben–Weyl), Vol. E14B; Klaman,
D.; Hagemann, H.; Eds.; Georg Thieme Verlag: New
York, 1990; pp. 434–712; and (c) Ref. 1d.
5. (a) Decomposition of diazo compounds is catalyzed by
acids. In oxidation of hydrazones by lead tetraacetate the
acetic acid formed frequently decomposes the diazo prod-
ucts.1d Similar complications usually occur with other
7. Azidotris(dimethylamino)phosphonium bromide [N3P+
(NMe2)3, Br−] is readily obtained from (Me2N)3P by exten-
sion of the methodology developed for bromide 12.3a,b