In organocatalytic aza-Michael reactions, the acceptors are
activated either by hydrogen bonding of the organocatalysts
to the carbonyl group of the acceptors9 or by imminium
formation between R,ꢀ-unsaturated aldehydes and the orga-
nocatalysts.10 Jørgensen reported the successful use of
proline-derived organocatalysts in the addition of nitrogen-
containing heterocycles such as triazoles and tetrazoles to
R,ꢀ-unsaturated aldehydes.11 We envisioned that the exten-
sion of Jørgensen’s chemistry11 to the aza-Michael addition
of substituted pyrazoles 16 or 20 to aldehyde (23) using
suitable organocatalysts would provide an efficient asym-
metric synthetic route to INCB018424 (1) (Scheme 2).
The synthesis of Michael donor 16 via a Suzuki coupling
of protected pyrazole pinacol borate (14) and the protected
chlorodeazapurine (7) is depicted in Scheme 1. 4-Iodo-1H-
yield. Suzuki coupling of 7 with pyrazole pinacol borate 14
furnished intermediate 15 which was hydrolyzed in situ to
give the key Michael donor 16 in 82% yield for two steps.
The POM-protected Michael donor 20 was similarly pre-
pared. Treatment of the sodium anion of compound 5 with
pivaloyloxymethyl chloride (POM-Cl, 17) afforded inter-
mediate 18 in 91% yield. Suzuki coupling of 18 and 14
afforded 20 in 91% yield via 19.
On the basis of the mechanism proposed by Jørgenson,11
it was conceivable that the enantioselectivity could be
improved by the modulation of steric hindrance of the
organocatalyst. Catalyst (R)-2 was purchased from a com-
mercial source and catalysts (R)-3 and (R)-4 were synthesized
according to literature procedures (see experimental details
in the Supporting Information).12
Wittig olefination of cyclopentanecarbaldehyde (21) pro-
vided 23 as shown in Scheme 2.13 The olefin 23 was shown
1
by H NMR to be exclusively in the (E) configuration.
Scheme 1. Synthesis of Michael Donors 16 and 20
However, it was contaminated with about 14% of the dienal
23a. The impurity 23a could be removed by preparative
HPLC but not by silica gel flash chromatography. As a
control experiment, pure dienal 23a was reacted with 16.
Very low conversion to the corresponding Michael adduct
was observed (less than 10% over 24 h under the same
conditions as described in entry 12, Table 2). This suggested
the dienal impurity 23a would not have a significant influence
on the asymmetric aza-Michael addition. Since an excess
amount of the Michael acceptor 23 was used in the reactions,
for practical considerations, 23 was used without further
purification in this study. With Michael donors (16 and 20),
Michael acceptor 23, and organocatalysts (R)-2, (R)-3, and
(R)-4, in hand, the stage was set for the asymmetric aza-
Michael reaction.
The effects of solvent, acid additive, temperature, and
loading of catalyst (R)-2 on the enantioselectivity and yield
of the aza-Michael addition of 16 to the acceptor 23 are
shown in Table 1. The reactions proceeded faster and gave
adduct (R)-24 in higher yields and ee in toluene and benzene
(entries 2 and 3) than those in polar solvents, such as THF
and 1,4-dioxane (entries 7 and 8). Acid additives, such as
benzoic acid and 4-nitrobenzoic acid, accelerated the reaction
(entries 2 and 12 vs 9). Lower reaction temperature gave
(R)-24 in slightly higher enantioselectivity (entry 1 vs 2).
Higher loading of (R)-2 at 20 mol% did not improve the
yield or enantioselectivity (entry 1 vs 13; 11 vs 14). An
excess of acceptor 23 to donor 16 gave higher yield of (R)-
24 (entry 11 vs 15).
pyrazole (8) or 4-bromo-1H-pyrazole (9) was treated with
ethyl vinyl ether (10) to give the protected pyrazoles 11 and
12 respectively. Halogen-magnesium exchange of 11 or 12
followed by addition of borate 13a or 13b afforded the
pyrazole pinacol borate 14 in good yield. Treatment of
compound 5 with NaH and 2-(trimethylsilyl)ethoxyethyl
chloride (SEM-Cl, 6) afforded the SEM-protected 7 in 89%
The Michael addition of 16 and 23 was slower (ca. 50%
conversion over 16 h) with sterically hindered catalysts (R)-3
or (R)-4 at 0 °C as compared to that with (R)-2. Therefore,
reactions of 16 and 23 using (R)-3 or (R)-4 were carried out
at room temperature (Table 2). The use of larger excess of
23 (5 equiv) resulted in higher yield (entries 1 and 7 vs 11).
Using 5 equiv of the 23, we compared the reaction of pure
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Org. Lett., Vol. 11, No. 9, 2009