Deprotonation reactions on the pyrazole ring were until now
limited to lithiations at very low temperatures on the most
acidic C5 position.10 Functionalization at the C3 position of
the pyrazole core was only possible through a protecting
group switch, while the C4 position was accessed through
electrophilic substitutions.11 Recently, we reported the new
mixed Li/Mg bases TMPMgCl·LiCl (1; TMP ) 2,2,6,6-
tetramethyl- piperidyl)12 and the more reactive TMP2Mg·
2LiCl (2),13 which allow the magnesiation of functionalized
arenes and heteroarenes. Sensitive substrates can be ef-
ficiently metalated using the milder base TMP2Zn·
2MgCl2·2LiCl (3).14
siated N-methylpyrazole 5b provides after reaction with
MeSO2SMe, PhSO2SPh, and Et3SiCl the new substituted
pyrazole derivatives 7a-c in 79-83% yields (Scheme 2).
Scheme 2
.
Magnesiation of Pyrazole Derivatives of Type 4 at
Position 5 using TMPMgCl·LiCl (1)
Herein, we report a new regio- and chemoselective
synthesis of fully substituted pyrazoles through successive
metalations on easily accessible pyrazoles (Scheme 1).
Scheme 1. Full Functionalization of Pyrazoles through
Successive Metallations using TMPMgCl·LiCl (1) and
TMP2Mg·2LiCl (2)
A subsequent deprotonation at position 3 is readily
achieved by adding TMPMgCl·LiCl (1) to various 5-substi-
tuted pyrazoles of type 6 and 7. Thus, treatment of the SEM-
protected pyrazoles 6c and 6d with TMPMgCl·LiCl (1; 1.1
equiv, -15 °C, 10 h) and subsequent quenching with TsCN,
NCCO2Et, FCl2CCClF2,18 (BrCl2C)2, and DMF furnished the
3,5-disubstituted pyrazoles 8a-e in 65-76% yield (entries
1-5 of Table 1).
Similarly, the N-methylated pyrazoles 7a and 7b were
magnesiated under the same conditions. Metalation of 7a
using TMPMgCl·LiCl (1) followed by the transmetalation
with CuCN·2LiCl19 and addition of benzoyl chloride gave
the expected ketone 9a in 78% yield (entry 6). Magnesiation
18
of the pyrazole 7b gave after chlorination with FCl2CCClF2
(-15 to 25 °C, 5 h) the chloro derivative 9b in 69% yield
(entry 7). In the presence of CuCN·2LiCl19 an allylation with
allyl bromide furnished the pyrazole 9c in 78% yield, after
magnesiation with TMPMgCl·LiCl (1) (entry 8). The 5-si-
Starting from the SEM-protected pyrazole15 4a or the
commercially available 1-methyl-1H-pyrazole (4b), magne-
siation of the C5 position could be achieved using
TMPMgCl·LiCl12 (1; 1.1 equiv, 25 °C, THF, 1 h). The
resulting magnesiated pyrazole 5a successfully undergoes,
after transmetalation with ZnCl2, a Negishi16 cross-coupling
furnishing the expected product 6a in 91% yield. Trapping
of 5a with various electrophiles such as Et3SiCl, PhSO2SPh,
and MeSO2SMe17 gave the corresponding 5-substituted
pyrazoles 6b-d in 72-84% yield. Similarly, the 5-magne-
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