asymmetric domain (Scheme 1; Mes = 2,4,6-trimethylphe-
nyl; mesityl).5
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Selective Deprotonation of Enolizable Ketones
entry
Mg reagent
conditions
yield (%)c
D:Hd
1
(TMP)2Mg
Mes2Mg
Mes2Mg
Mes2Mg
tBu2Mg
0 °C, 3 h
0 °C, 3 h
40 °C, 3 h
40 °C, 3 h
40 °C, 3 h
97
11
69
90
58
50:50
98:2
92:8
94:6
91:9
At conveniently accessible temperatures of 0 °C and
above, no side reactions from nucleophilic addition of the
carbon-centered base reagent or reduction of the ketone
substrate could be detected. Moreover, the magnesium
system operates effectively with comparatively lowered
amounts of electrophile and, perhaps more importantly,
without any amine reagent being required. The requisite
diaryl/dialkylmagnesium species can be readily preformed
from the parent Grignard reagent or, for a more practic-
able one-pot protocol, is generated in situ (Scheme 2).5,6 In
both cases excellent reaction efficiencies for the desired
transformation were observed.5
2
3
4b
5b
a Reaction conditions: p-methoxyacetophenone tosylhydrazone 1
(1 mmol), magnesium base reagent (1.25 mmol), LiCl (2.5 mmol),
THF (5 mL). b 1.5 mmol of Mg-base reagent and 3 mmol of LiCl were
used. c Isolated yield after column chromatography. d Ratio was determined
by 1H NMR of the crude reaction mixture.
Mg(TMP)2 (1.25 mol) and LiCl (2.5 mol) for 3 h at 0 °C in
THF, followed by the addition of D2O as an electrophilic
quench (Table 1, entry 1). The styrene product H/D-2 was
isolated in an excellent 97% yield. However, only a 50%
selectivity toward the introduced electrophilic quench
reagent was observed, presumably due to the in situ for-
mation of TMP-H which can act as a proton source for the
generated vinyl anion. In contrast, the carbon-centered
magnesium base, Mes2Mg, furnished an excellent H/D-
styrene ratio of 98:2 (D:H) under the same reaction con-
ditions, albeit in only 11% yield. The low conversion was
compensated for by moderately elevating the reaction
temperature to 40 °C, coupled with an increase in quantity
of base reagent to 1.5 mol, giving rise to a 90% yield of the
desired styrene (Table 1, entry 4). The dialkylmagnesium
base, tBu2Mg, which has also been shown to act efficiently
as a non-nucleophilic base reagent,5c returned starting
material quantitatively at 0 °C and displayed a distinctly
lower reactivity than Mes2Mg at more elevated tempera-
tures (Table 1, entry 5). It is worth noting here that LiCl is
key for the desired reactivity of these magnesium base
systems, as the reactivity drops significantly if less than 2
equiv of LiCl, with respect to Mes2Mg, are used. This has
previously been observed in various magnesium base
systems.4 With regard to Mes2Mg, the formation of an
’ate-type complex is presumed, thus accounting for the
enhanced reactivity observed.5b
Scheme 2. Preparation of Dialkyl/Diarylmagnesium
Based on these discoveries, we were encouraged to probe
further effective and more focused applications of our
carbon-centered magnesium bases. In relation to this, a
magnesium-mediated alternative of the Shapiro reaction7,8
was considered. The corresponding lithium-based pro-
cesses generally require either a large excess of base, and
consequently an electrophile, TMEDA as an additive, or
the employment of the more expensive reagent, trisylhy-
drazine.7 Additionally, an elaborate varying (low) tem-
perature protocol is required to induce the fragmentation
of the hydrazone substrate and the subsequent quench
with an electrophile.7 In relation to this, we herein report
our progress in developing a preparatively effective mag-
nesium base-mediated Shapiro reaction and its application
with a range of electrophilic quench reagents and tosylhy-
drazone substrates.
In initial experiments and optimization studies, tosylhy-
drazone 1 (1 mol)9 was exposed to magnesium bisamide
This brief optimization haddelivered a magnesium base-
mediated Shapiro process at the conveniently accessed
temperature of 40 °C and with relatively low levels of
required base (1.5 mol). With the developed conditions in
hand, our investigations continued by exploring the
scope of the introduced electrophiles. In general, 2 mol
of the respective electrophile were necessary to furnish
good yields of the functionalized styrene products 3aÀd
(Table 2); this was believed to be largely due to the
competitive nucleophilic addition of excess Mes reagent
into the added electrophile (to give 4). Nonetheless, the
(6) Wakefield, B. J. Organomagnesium Methods in Organic Synthesis;
Academic Press: London, 1995.
(7) (a) Shapiro, R. H.; Hornaman, E. C. J. Org. Chem. 1974, 39, 2302.
(b) Chamberlin, A. R.; Stempke, J. E.; Bond, F. T. J. Org. Chem. 1978,
43, 147 and references therein. (c) For a review, see: Adlington, R. M.;
Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55.
(8) For recent applications of lithium-mediated Shapiro reactions in
total synthesis, see: (a) Tamiya, J.; Sorensen, E. J. J. Am. Chem. Soc.
2000, 122, 9556. (b) Reiter, M.; Torell, S.; Lee, S.; MacMillan, D. W. C.
Chem. Sci. 2010, 1, 37. (c) Lau, S. Y. W. Org. Lett. 2011, 13, 347.
(9) Tosylhydrazones were prepared from the corresponding ketones
and p-toluenesulfonylhydrazine in EtOH with catalytic amounts of HCl.
Org. Lett., Vol. 14, No. 9, 2012
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