Organic Process Research & Development 2009, 13, 263–267
Preparation, Use, and Safety of O-Mesitylenesulfonylhydroxylamine
,
†
†
†
†
´
†
‡
Javier Mendiola,* Juan A. Rinc o´ n, Carlos Mateos, Jos e´ Francisco Soriano, Oscar de Frutos, Jeffry K. Niemeier, and
‡
Edward M. Davis
Centro de InVestigaci o´ n Lilly S.A., AVda. de la Industria, 30, Alcobendas-Madrid 28108, Spain, and Eli Lilly & Company
LTC-South, Indianapolis, Indiana 46285-4813, U.S.A.
Abstract:
Scheme 1
The aminating reagent O-mesitylsulfonylhydroxylamine (MSH)
has a known potential hazard since it contains high-energy
functional groups in its structure. There are references in the
literature that report several incidents involving the use of pure
and crystalline MSH. The preparation and safe use of this reagent
at kilo scale are described herein.
1
. Introduction
The resynthesis of one compound of interest involved the
preparation of 4-substituted pyrazolo[1,5-a]pyridines (1). The
most common route to prepare the pyrazolo[1,5-a]pyridine core
is shown in Scheme 1, where the key step is the 1,3-dipolar
stated that O-sulfonyl derivatives are more reactive and less
stable than O-acyl and O-phosphinyl derivatives. O-Mesityle-
nesulfonylhydroxylamine (MSH, 9) and hydroxylamine O-
1
cycloaddition of a pyridine N-imine and an alkyne (Scheme
sulfonic acid (HOSA, 10) are two representative examples of
+
1).
these O-sulfonyl reagents that provide NH
2
.
Synthesis of heteroaromatic N-imines like 3, isoelectronic
Figure 1. Different aminating reagents.
+
2
with N-oxides, requires reagents that provide NH
2
synthons
which can be generated from compounds represented as NH
2
X
2
. Background
(where X is a leaving group). These types of reagents have
For the N-amination of 3-substituted pyridines (2) we initially
3
both electrophilic and nucleophilic properties in one molecule,
chose both HOSA and MSH. Due to the more thermal stability
and commercial availability of HOSA several assays were
performed, but in all conditions tested this reagent did not
provide the desired N-amino 3-substituted pyridinium (3).
In contrast, MSH is very well-known as N-aminating
and they can be summarized as O-acyl (6), O-phosphinyl (7),
and O-sulfonylhydroxylamines (8) (Figure 1). As a general rule,
these reagents are thermally labile, and although there are no
quantitative data on the thermal stability available, it can be
3
*
To
whom
correspondence
should
be
addressed.
E-mail:
reagent for electron-deficient pyridines in organic media. In a
mendiola_javier@lilly.com.
10 g scale pilot using this reagent, N-amination was quantitative,
†
Centro de Investigaci o´ n, Lilly S.A.
Eli Lilly & Company, LTC-South.
‡
and cycloaddition afforded with moderate yield the desired
pyrazolo[1,5-a]pyridines as major product. Given these excellent
results, we considered studying the conditions to carry out this
process safely on scale.
The major caveat of MSH is its well-known instability. It is
described that dry samples decompose soon after storage in an
(
(
1) L o¨ ber, S.; H u¨ bner, H.; Utz, W.; Gmeiner, P. J. Med. Chem. 2001, 44,
2
691–2694.
2) (a) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1–17. (b)
Taylor, E. C.; Sun, J.-H. Synthesis 1980, 801–802. (c) Kl o¨ tzer, W.;
Stadlwieser, J.; Raneburger, J. Organic Syntheses; Wiley: New York,
1
990; Collect. Vol. VII, p 8; Annual Vol. 64, p 96 (1986).
3) (a) Zeeh, B.; Metzger, H. In Die Methoden der organischen Chemie
Houben-Weyl); M u¨ ller, E., Ed.; Georg Thieme Verlag: Stuttgart, 1971;
Vol. 10/1, p 1091. (b) Valenciano, J.; S a´ nchez-Pav o´ n, E.; Cuadro,
(
4
(
amber glass bottle (the screw cap being shattered ). Although
the instability of the compound has been mentioned, there was
5
´
A. M.; Vaquero, J. J.; Alvarez-Builla, J. J. Org. Chem. 2001, 66, 8528–
536. (c) Fontana, A.; Benito, E. J.; Mart ´ı n, M. J.; S a´ nchez, N.;
8
no violent decomposition reported to the best of our knowledge
at ambient temperature. It seems likely that traces of surface
alkali in the soda-glass bottle catalyze both the formation of
the highly reactive imidogen radical (HN:) from the base-labile
compound, and its subsequent exothermic decomposition.
Alajar ´ı n, R.; Vaquero, J. J.; Lambel-Guiraudet, S.; Leonce, S.; Pierr e´ ,
A.; Caignard, D. Bioorg. Med. Chem. Lett. 2002, 12, 2611–2614. (d)
´
Mart ´ı nez, V.; Burgos, C.; Alvarez-Builla, J.; Fern a´ ndez, G.; Domingo,
A.; Garc ´ı a-Nieto, R.; Gago, F.; Manzanares, I.; Cuevas, C.; Vaquero,
J. J. J. Med. Chem. 2004, 47, 1136–1148. (e) Elsner, J.; Boeckler, F.;
Davidson, K.; Sugden, D.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2006,
1
4, 1949–1958. (f) Powell, D.; Gopalsamy, A.; Wang, Y. D.; Zhang,
N.; Miranda, M.; McGinnis, J. P.; Rabindran, S. K. Bioorg. Med.
Chem. Lett. 2007, 17, 1641–1645.
(4) Ning, R. Y. Chem. Eng. News 1973, 51 (51), 36–37.
(5) Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 3134.
1
0.1021/op800264p CCC: $40.75
2009 American Chemical Society
Vol. 13, No. 2, 2009 / Organic Process Research & Development
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263
Published on Web 01/14/2009