A regiospecific approach to N-alkylpyrazoles and the derived N-oxides using 5-endo-dig cyclisations of alkynyl nitrosamines

Article abstract of DOI:10.1055/s-2008-1078029

5-endo-dig Cyclisations of N-nitroso derivatives of homopropargylic amines, catalysed by silver nitrate on silica gel proceed smoothly at ambient temperature in chlorinated solvents to give essentially quantitative yields of the corresponding pyrazole-N-oxides, deoxygenation of which gives excellent yields of the related N-alkylpyrazoles in a regiospecific manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078029

2188
LETTER
A Regiospecific Approach to N-Alkylpyrazoles and the Derived N-Oxides
Using 5-endo-dig Cyclisations of Alkynyl Nitrosamines
Regiospecific
i
A
pproa
m
chto
N
-Alkylpyraz
o
oles n J. Hayes,a David W. Knight,*a Mark O’Halloran,b Stuart R. Pickeringa
a
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
Fax +44(29)20874030; E-mail: knightdw@cf.ac.uk
b
Technical & Business Development, GlaxoSmithKline, Shewalton Road, Irvine KA11 5AP, UK
Received 16 July 2008
Dedicated with best wishes and gratitude for the many wise words to Professor Sir Jack E. Baldwin on the occasion of his 70th birthday
cause of this, such cyclisations were somewhat under-
Abstract: 5-endo-dig Cyclisations of N-nitroso derivatives of ho-
utilised until relatively recently, despite indications of
their viability in the older literature. From our own stud-
mopropargylic amines, catalysed by silver nitrate on silica gel pro-
ceed smoothly at ambient temperature in chlorinated solvents to
give essentially quantitative yields of the corresponding pyrazole-
ies, we have been fortunate to discover, based on earlier
N-oxides, deoxygenation of which gives excellent yields of the re- results reported by the Marshall group,7 that 3-alkyne-1,2-
lated N-alkylpyrazoles in a regiospecific manner.
diols 1 undergo exceptionally smooth 5-endo-dig cyclisa-
tions when exposed to catalytic quantities of silver nitrate
supported by silica gel to give essentially quantitative
yields of the furans 2 (Scheme 1).8 This naturally led us to
speculate that other nucleophiles, especially ones based
on nitrogen, could be used successfully in similar cyclisa-
tions.9
Key words: 5-endo-dig cyclisations, catalysis, pyrazole-N-oxides
So often in synthesis, problems of regio- or stereoselec-
tion detract from an otherwise efficient synthetic strategy.
Such an example is in the elaboration of N-substituted
pyrazoles which, in general, can be one of the more
straightforward synthetic tasks, consisting simply of a
condensation between a 1,3-dicarbonyl and a monosubsti-
tuted hydrazine.1 However, this is only truly effective
when the 1,3-dicarbonyl component is symmetrical, oth-
erwise gross mixtures of the two possible products usually
result. A number of recent developments have been re-
ported in this area,2–4 some of which address this limita-
tion; the number of such papers also reflects the
importance of this heteroaromatic system, especially in
drug design, by reason of its abilities to act as a flexible
hydrogen-bonding moiety and perhaps to participate in
p–p stacking, in view of its electron-rich nature.
R2
HO
R1
R2
R3
i
+ H2O
R1
R3
O
OH
2
1
Scheme 1 Reagents and conditions: i) 10% AgNO3/SiO2 (10
mol%), CH2Cl2, 20 °C, ca. 3 h, >97%.
With a view to perhaps obtaining reduced pyrazole deriv-
atives 3 from 5-endo-dig cyclisations but of hydrazines 4,
we set out to prepare representative examples of the latter
precursors in order to determine suitable N-substituents
and reaction conditions (Scheme 2). We reasoned that a
rapid entry into such a series could begin by condensa-
tions between imines 8 and acetylides 7; the resulting pro-
pargylamines 6 could then be nitrosated and the N-nitroso
derivatives 5 thus formed reduced and derivatised to give
the desired precursors 4.
We have for some time been interested in exploring the
potential of 5-endo cyclisations in general.5 In the case of
the 5-endo-trig mode, the most unfavourable according to
Baldwin’s rules,6 we have shown that this can provide
very useful and highly stereoselective routes to both tet-
rahydrofurans and pyrrolidines, when such cyclisations
are driven by a suitable electrophile and hence are not ex-
ceptions to the rules. Indeed, these high levels of stereose-
lection can be ascribed to the very features which form the
basis of the rules: the disfavoured nature of any 5-endo-
trig cyclisation, however driven, implies that it will be
forced to follow the most energetically favoured pathway
to make the process viable.5 In the case of 5-endo-dig cy-
clisations, by contrast, these are favoured according to the
rules, despite the distance between the reacting centres ap-
pearing to preclude direct bond formation. Perhaps be-
R4
R2
R1
NHR4
R2
R1
NO
R2
R1
N
N
N
N
R3
R3
R3
3
4
5
R2
R1
NR2
NH
–
R1
R3
R3
SYNLETT 2008, No. 14, pp 2188–2190
Advanced online publication: 05.08.2008
2
2
.0
8
.2
0
0
8
8
7
6
DOI: 10.1055/s-2008-1078029; Art ID: D26908ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
Regiospecific Approach to N-Alkylpyrazoles
2189
While work on this sequence continues and is proving
largely successful,10 we took the opportunity of the avail-
ability of the nitrosamines 5 to examine their cyclisation
behaviour, it must be admitted with little expectation of
success. To our delight, however, this proved not to be the
case and herein, we report the unexpectedly successful re-
sults of this preliminary study.
O
O
N+
R2
R1
R2
R1
N
Ag+
N
H
N
5
R3
Ag
11
Ag
R3
10
Firstly, a representative series of N-nitrosamines 5 were
prepared by sequential condensations between the corre-
sponding imines 8 and an acetylide 711 and N-
nitrosation12,13 of the resulting amines 6, as outlined in
Scheme 2. Fortunately, the N-nitrosamines 5 were ob-
tained in pure forms directly from the nitrosation reaction.
In view of their likely toxicity, extensive purification
would have been an unwelcome feature of this sequence.
In the key step, exposure of the nitrosamines 5 to 20 mol%
of 10% silver nitrate on silica gel in chloroform or dichlo-
romethane at ambient temperature for 6–8 hours gave es-
sentially quantitative yields of the corresponding
pyrazole-N-oxides 9; the results are collected in Table 1.14
O–
N+
O–
R2
R1
R2
R1
N +
+
N
– Ag+
N
R3
R3
Ag
H
9
12
Scheme 3
the ring carries electron-withdrawing groups, but yields
are often quite poor.15 A better approach, but using the
same oxidative conditions, features formation of the N–N
bond by oxidation of 1-imino-2-nitrosoalkenes.16 In con-
trast to direct oxidation, this method appears to require the
presence of at least one electron-withdrawing group. A
similar oxidative N–N bond formation uses copper sulfate
as the key reagent, but yields of the pyrazole-N-oxides are
again often very low.17 Such compounds can of course
also be used as precursors to pyrazoles themselves follow-
ing deoxygenation. Although there are many potential re-
agents for effecting this transformation, phosphorus
trichloride has been established as one of choice.18 In our
hands, treatment of the N-oxides 9a and 9c with PCl3 in
refluxing, ethanol-free chloroform for two hours, as re-
ported previously, delivered excellent yields of the corre-
sponding pyrazoles 13 (Table 2).
Table 1 Synthesis of Pyrazole-N-oxides 9 from N-Nitrosamines 5
O–
N+
R2
R1
NO
R2
R1
10% AgNO3/SiO2 (20 mol%)
CHCl3 or CH2Cl2, 20 °C, 6–8 h
N
N
R3
R3
5
9
Entry R1
R2
R3
Bu
Ph
Yield (%)
>95
1
2
3
4
5
6
i-Bu
Bn
i-Bu
i-Bu
Ph
Bn
>95
Bn
(CH2)2OTBDPS
>95
Pr
Bu
Ph
Ph
>95
Ph
Pr
>95
Table 2 Pyrazole-N-oxide Deoxygenation
O–
N+
i-Bu
CH2CH=CH2
>95
R2
R1
R2
R1
PCl3, CHCl3
60 °C, 2 h
N
N
N
R3
R3
In all cases examined, conversions were both complete
and totally clean, according to NMR analysis. Again, in
view of the probably toxicity of these N-oxides, the ab-
sence of a necessary purification step was a considerable
advantage.
9
13
Entry
R1
R2
R3
Bu
(CH2)2OTBDPS
Yield (%)
We presume that the cyclisation is initiated by complex
formation (10) between the alkyne group and a silver(I)
atom, followed by nucleophilic attack by the nitroso nitro-
gen onto the now activated alkyne link by a 5-endo-dig
pathway to establish the heterocyclic ring 11 (Scheme 3).
Perhaps then a hydride shift, assisted by the other nitrogen
atom leads to the N-oxide salt 12, which can then easily
lose silver(I) to give the observed products 9. Of course,
alternative explanations can be drawn.
1
3
i-Bu
i-Bu
Bn
Bn
99
92
In summary, this approach represents, overall, a relatively
brief and certainly highly efficient route to pyrazoles and
their derived N-oxides. By its very nature, it is regiospe-
cific and should therefore find use in the unambiguous
synthesis of many types of N-substituted pyrazoles, which
should be amenable to further functionalisation at the nec-
essarily vacant 4-position.2
Pyrazole-N-oxides have been prepared previously using a
number of strategies. Direct pyrazole oxidation is possible
using, for example, hydrogen peroxide–acetic acid unless
Synlett 2008, No. 14, 2188–2190 © Thieme Stuttgart · New York

2190
S. J. Hayes et al.
LETTER
(11) Imines 8 were prepared by stirring equivalent amounts of the
corresponding aldehydes and amines in dry Et2O for 16 h,
followed by drying (MgSO4) and evaporation. Solutions of
the acetylides 7 (BuLi, THF, –78 °C, 0.5 h) were treated with
BF3·THF complex (1.3 equiv) for 0.25 h and the resulting
solution added to one of the imine 8 in THF maintained at
–78 °C. After 3 h, the mixture was quenched with KH2PO4
buffer (pH 7) and the products extracted into Et2O. Silica gel
column chromatography (typically eluted with EtOAc–PE,
1:4) when necessary delivered 50–80% yields of the
propargylamines 6.
(12) The amines 6 were stirred at 0 °C with concd HCl (2 equiv)
for 5 min, the resulting solutions were diluted with Et2O (10
mL g–1) followed by the addition of aq NaNO2 [1.2 equiv in
H2O (10 mL g–1)]. The solutions were then stirred without
cooling for 3 h and the N-nitrosamines 5 were extracted into
Et2O. Typically, no purification was required after a H2O
and brine wash, according to NMR analysis.
Acknowledgment
We thank GSK and the EPSRC for financial support.
References and Notes
(1) Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2587.
(2) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry,
Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, 167. (b) Elguero, J. In Comprehensive
Heterocyclic Chemistry II, Vol. 3; Katritsky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996, 1.
(3) For more recent contributions, see the following: On
palladium-catalysed 4-component coupling of ArI,
RNHNH2, a 1-alkyne and CO: (a) Ahmed, M. S. M.;
Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487. On
cycloadditions between allenes and azodicarboxylates:
(b) Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E. Org. Lett.
2006, 8, 2213. On NH-pyrazoles from chromones and
related structures and hydrazine: (c) Lévai, A.; Silva, A. M.
S.; Cavaleiro, J. A. S.; Alkorta, I.; Elguero, J.; Jekö, J. Eur.
J. Org. Chem. 2006, 2825. On new 1,3-dione synthesis:
(d) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675.
On regioselective synthesis from b-enamino-ketoesters:
(e) Persson, T.; Nielsen, J. Org. Lett. 2006, 8, 3219. On
sequential coupling between an iodoenyne and
(13) The N-nitrosamines 5 displayed richly detailed 1H NMR
spectra indicative of the existence of two rotameric forms.
(14) In general, an N-nitrosamine 5 (1 equiv) was stirred with 10
mol% AgNO3 on SiO2 (Aldrich; 0.2 equiv) in dry CHCl3 (1
mL 0.1 mmol–1 of nitrosamine) at ambient temperature with
complete exclusion of light (Al foil) until TLC indicated
complete reaction. The pyrazole-N-oxides 9 were then
isolated by filtration through Celite, which was then washed
thoroughly with fresh CHCl3, and evaporation of the
combined filtrates. Dry CH2Cl2 could equally well be used.
Characterization was by 1H NMR and 13C NMR
BocNHNHBoc, followed by intramolecular 5-exo-dig
hydroamination: (f) Martín, R.; Rivero, M. R.; Buchwald, S.
L. Angew. Chem. Int. Ed. 2006, 45, 7079. Oncondensations
between hydrazones and nitroalkenes: (g) Deng, X.; Mani,
N. S. Org. Lett. 2006, 8, 3505. On dipolar cycloadditions
between alkynes and 2-diazo-2-trimethylsilylethanols:
(h) Hari, Y.; Tsuchida, S.; Sone, R.; Aoyama, T. Synthesis
2007, 3371.
spectroscopy and high resolution MS.
N-Benzyl-3-isobutyl-5-phenylpyrazole-N-oxide (9b,
Table 1, Entry 2)
1H NMR (400 MHz, CDCl3): d = 0.85 (6 H, d, J = 6.7 Hz,
2 × Me), 1.70–1.87 (1 H, m), 2.32 (2 H, d, J = 7.3 Hz, CH2),
5.38 (2 H, s, PhCH2), 6.17 (1 H, s, 4-H), 7.15 (2 H, dd, J =
8.0, 1.4 Hz, 2 × PhH), 7.19-7.31 (4 H, m, 4 × PhH), 7.35–
7.39 (2 H, m, 2 × PhH), 8.15 (2H, dd, J = 8.5, 1.3 Hz,
2 × PhH). 13C NMR (100 MHz, CDCl3): d = 22.3 (2 × Me),
27.6 (CH), 35.3 (CH2), 45.5 (PhCH2), 98.3 (4-CH), 126.4
(2 × PhCH), 127.0 (2 × PhCH), 127.9 (PhCH), 128.4 (C),
128.5 (PhCH), 128.6 (C), 128.7 (2 × PhCH), 128.9
(2 × PhCH), 132.2 (C), 135.7 (C). MS (APCI): m/z (%) =
307 (100) [M+ + H]. HRMS: m/z calcd for C20H23N2O [M]:
307.1810; found: 307.1802 [M+ + H].
(4) Molteni, G. ARKIVOC 2007, (ii), 224.
(5) Knight, D. W. In Progress in Heterocyclic Chemistry, Vol.
14; Gribble, G. W.; Gilchrist, T. L., Eds.; Pergamon: Oxford,
2002, 19.
(6) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734. (b) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.;
Silberman, L.; Thomas, R. C. J. Chem. Soc., Chem.
Commun. 1976, 736. (c) Baldwin, J. E. J. Chem. Soc.,
Chem. Commun. 1976, 738.
(7) (a) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60,
5966. (b) Marshall, J. A.; Sehon, C. A. Org. Synth. 1998, 76,
263; and references cited therein.
(8) Hayes, S. J.; Knight, D. W.; Menzies, M. D.; O’Halloran,
M.; Tan, W.-F. Tetrahedron Lett. 2007, 48, 7709.
(9) Similar cyclisations, but of hydroxy-substituted
homopropargylamine derivatives, lead to pyrroles also in
exceptionally high yields: Hayes, S. J.; Knight, D. W.;
Singkhonrat, J.; Sharland, C. M. paper in preparation.
(10) Dunford, D.; Knight, D. W.; Song, C. unpublished results.
(15) See, for example: Parnell, E. W. Tetrahedron Lett. 1970,
3941.
(16) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
1977, 1196.
(17) (a) Begtrup, M.; Vedsø, P. J. Chem. Soc., Perkin Trans. 1
1993, 625. (b) Alcazar, J.; Almena, I.; Begtrup, M.; de la
Hoz, A. J. Chem. Soc., Perkin Trans. 1 1995, 2773.
(18) (a) Begtrup, M.; Larsen, P.; Vedsø, P. Acta Chem. Scand.
1992, 46, 972. (b) Eskildsen, J.; Vedsø, P.; Begtrup, M.
Synthesis 2001, 1053.
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