Ligand-Promoted C(sp3)-H Olefination en Route to Multi-functionalized Pyrazoles

Article abstract of DOI:10.1002/chem.201600704

A Pd-catalyzed/N-heterocycle-directed C(sp³)-H olefination has been developed. The monoprotected amino acid ligand (MPAA) is found to significantly promote Pd-catalyzed C(sp³)-H olefination for the first time. Cu(OAc)₂ instead of Ag⁺ salts are used as the terminal oxidant. This reaction provides a useful method for the synthesis of alkylated pyrazoles. The right moves: A pyrazole-directed C(sp³)-H olefination has been developed (see scheme). The monoprotected amino acid ligands (MPAA) are found to significantly promote the reactivity in Pd-catalyzed C(sp³)-H olefination. The applicability of using this reaction for late-stage diversification of pyrazole-based complex scaffold is demonstrated.

Full text of DOI:10.1002/chem.201600704

DOI: 10.1002/chem.201600704
Communication
&
Organic Chemistry
Ligand-Promoted C(sp3)ÀH Olefination en Route to Multi-
functionalized Pyrazoles
Weibo Yang,[a] Shengqing Ye,[a] Yvonne Schmidt,[b] Dean Stamos,*[b] and Jin-Quan Yu*[a]
Dedicated to Professor Barry Sharpless on the occasion of his 75th birthday
dents to date [Scheme 2, Eq. (1) and (2)].[4] Second, pyrazole-
directed CÀH activation reactions,[5] especially C(sp3)ÀH activa-
tion, are rare.[5j] Herein we report the first example of Pd-cata-
lyzed pyrazole-directed C(sp3)ÀH olefination using Cu(OAc)2 as
the terminal oxidant. The mono-protected amino acid ligands
(MPAA) are shown to promote C(sp3)ÀH olefination for the first
time. In contrast to previous work which reported the forma-
tion of aza-Michael cyclization products, this C(sp3)ÀH olefina-
tion method can provide immediate access to products with
intact olefins, which can be used as substrates for additional
chemistry or potentially as covalent modifiers of proteins[6]
[Eq. (3)].
Abstract: A Pd-catalyzed/N-heterocycle-directed C(sp3)ÀH
olefination has been developed. The monoprotected
amino acid ligand (MPAA) is found to significantly pro-
mote Pd-catalyzed C(sp3)ÀH olefination for the first time.
Cu(OAc)2 instead of Ag+ salts are used as the terminal oxi-
dant. This reaction provides a useful method for the syn-
thesis of alkylated pyrazoles.
Late-stage alkylation of heterocycles is a significant challenge
in synthesis especially in the context of medicinal chemistry.
The state-of-art-the-art relies mainly on cross-coupling of het-
eroaryl halides with alkyl boron and zinc reagents.[1] As alkyl
halide coupling partners are often incompatible with nucleo-
philic heterocycles, direct CÀH alkylation of heterocycles re-
mains underdeveloped with only a handful of examples docu-
mented.[2] Inspired by the diversity of pharmacologically active
pyrazole scaffolds (Scheme 1),[3] we set out to develop pyra-
zole-directed C(sp3)ÀH olefination reaction of pendant alkyl
groups to deliver diverse alkylated pyrazoles from a small
number of commercially available pyrazoles.
Scheme 2. Pd-catalyzed sp3 CÀH olefination.
Scheme 1. Biologically active pyrazoles and pyrazolo[1,5-a]pyridines.
The challenges associated with achieving this goal are two-
fold. First, C(sp3)ÀH olefination is among one of the most chal-
lenging CÀH functionalization processes with only two prece-
Despite the extensive studies on PdII-catalyzed C(sp2)ÀH ole-
fination reactions involving either electrophilic palladation or
CÀH insertion pathways,[7] the translation of these methods
into saturated C(sp3)ÀH system has been largely unsuccessful.
In the two previous examples of C(sp3)ÀH olefination,[4] the
newly installed olefin unit further reacts with the nucleophilic-
directing group to give the undesired Michael cyclization prod-
ucts. A powerful extension of this methodology would exploit
the intrinsic directing ability of a 5-membered azole ring which
may avoid undesired cyclization due to ring strain. Additionally,
this methodology enables late-stage functionalization of qua-
ternary carbon centers that would have been otherwise ac-
[a] Dr. W. Yang, Dr. S. Ye, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
[b] Y. Schmidt, D. Stamos
Medicinal Chemistry, Vertex Pharmaceuticals
11010 Torreyana Rd., San Diego, CA 92121 (USA)
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201600704.
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Communication
cessed by lengthy de novo azole ring preparations. To improve
the scope and efficiency of this synthetically powerful sp3 CÀH
olefination reaction, it is crucial to identify a suitable ligand
that can promote and modulate the reactivity. We therefore in-
vestigated the two classes of ligands that have been devel-
oped to promote CÀH activation, namely, MPAA[8] and quino-
line ligands.[9] Based on the presence of multiple vectors for ex-
ploration, we selected the commercially available methyl 3-
(tert-butyl)-1-methyl-1H-pyrazole-5-carboxylate (1a) as the
model substrate. Thus, olefination of 1a with ethyl acrylate
was examined under various conditions (see the Supporting In-
formation). In the presence of 10 mol% [Pd(OTf)2(MeCN)4] and
20 mol% ligand, the reaction proceeded to give the olefinated
product 3a in 50% yield (Table 1, entry 1). Removal of the
ligand reduced the yield to 21%, suggesting a beneficial role
of the ligand in the reaction (entry 2). Encouraged by this ob-
servation, we screened a set of commercially available N-pro-
tected amino acids with different backbones (entries 3–6). The
product 3a was obtained in 60% yield when Ac-Ile-OH was
used. Changing N-acetyl to other protecting groups resulted in
significant decrease in yields (entries 7–9). Replacement of
[Pd(OTf)2(MeCN)4] by Pd(OAc)2 did not affect the reaction
under these conditions (entry 10). Reducing the amount of
ligand to 10 mol% increased the yield to 66% (entry 11). Run-
ning the reaction under N2 instead of air gave significantly
lower yield, indicating the beneficial effect of molecular O2
(entry 12). Other Pd sources were significantly less effective
(entries 13–15). During the investigation of different oxidants,
we found that less expensive oxidant Cu(OAc)2 also afforded
the product in 37% yield (entry 19). Further examination of
this reaction revealed that the combination of Cu(OAc)2 with
O2 decomposed the starting material. Further exploration of
impact of oxidants on the reaction revealed that the use of
Cu(OAc)2 as the sole oxidant under N2 improved the yield to
76% (entry 20). Under the optimized conditions, omission of
the ligand reduced the yield to 35% confirming a noticeable
ligand effect in this C(sp3)ÀH olefination reaction (entry 21).
We next examined the scope of pyrazoles for this ligand-
promoted C(sp3)ÀH olefination (Table 2). This catalytic system
can tolerate pyrazole esters, pyrazole amides, as well as simple
pyrazoles (3a–3c). Both electron-donating and electron-with-
drawing substituents at the 4-position of the pyrazole ring af-
forded the corresponding products (3d–3 f) in good yields
(65–71%). Other tertiary alkyls[10] at the 3-positions are also re-
active (3g–3i), although secondary and primary alkyls are not
reactive under current conditions. However, functional groups
on the tertiary alkyls including acetate and methoxyl are com-
patible (3j, 3k). Interestingly, the fused tricyclic 4,5-dihydro-2H-
benzo[e]indazole prepared from our previous CÀH activation
cascade[5j] also gives the product 3l, albeit in lower yield
(37%). The reduced reactivity of 1l is likely due to geometric
constraints hindering the formation of the desired co-planar
transition state. Successful application of C(sp3)ÀH olefination
on pharmaceutically relevant benzo[d]oxazole, pyrazolo[1,5-
a]pyridine scaffolds in the presence of additional polar func-
tionality proceeds to give the desired products (3m–3n). To
the best of our knowledge, these heterocycles have not been
Table 1. Optimization studies of Pd-catalyzed C(sp3)ÀH olefination.
Entry[a]
Catalyst
Ligand
Oxidant
Yield [%]
1
2
3
4
5
6
7
8
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
[Pd(OTf)2(MeCN)4]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(TFA)2]
[Pd(acac)2]
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ac-Leu-OH
–
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgNO3
K2S2O8
50
21
45
49
43
60
30
26
31
62
66
38
41
26
<5
32
21
16
37
76
35
Ac-Ala-OH
Ac-Val-OH
Ac-Gly-OH
Ac-Ile-OH
Boc-Ile-OH
Fmoc-Ile-OH
For-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
Ac-Ile-OH
–
9
10
11[b]
12[b,c]
13[b]
14[b]
15[b]
16[b]
17[b]
18[b]
19[b]
20[b,c]
21[b,c]
BQ
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Reaction conditions: [a] pyrazole ester 1a (0.05 mmol), ethyl acrylate
(0.30 mmol), Pd catalyst (10 mol%), DCE/HFIP (9:1, 0.5 mL). All the reac-
tions are carried out at 1008C for 24 h. Yields were determined by
1H NMR spectroscopy using CH2Br2 as the internal standard. [b] 10 mol%
ligand is used. [c] The reaction was performed in N2.
used to direct CÀH activation. To further demonstrate the po-
tential utility of this reaction, olefination of the highly function-
alized pyrazole scaffold 1o proceeded in good yield (64%)
with no obvious interference of either the nitro or carbamate
groups on the reaction.
With respect to the olefin coupling partners, a,b-unsaturated
ketones, and aldehydes are reactive, albeit with lower yields
(3p–3r). These products have higher reactivity as Michael ac-
ceptors which may offer unique opportunities as covalent li-
gands of biologically interesting proteins (Table 3).[11]
On the basis of our previous mechanistic studies, a putative
catalytic cycle is proposed for the pyrazole-directed C(sp3)ÀH
Heck-type olefination (Scheme 3). The pyrazole directs C(sp3)À
H activation to form 5-membered palladacycle intermediate A.
Subsequent migratory insertion of A gives the olefinated prod-
uct 3. The Pd0 formed from the b-hydride elimination and re-
ductive elimination steps is oxidized by the CuII oxidant to
close the catalytic cycle.
In conclusion, a pyrazole-directed C(sp3)ÀH olefination has
been developed for the first time. Our investigations revealed
that mono-protected amino acid (MPAA) ligands are found to
promote C(sp3)ÀH olefination. The transformation has proven
to be tolerant to a wide variety of functional groups thus ena-
bling late stage diversification of candidate scaffolds.
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Table 2. Scope of substrates in Pd-catalyzed C(sp3)ÀH olefination.[a]
Scheme 3. Proposed catalytic pathway.
Acknowledgements
We gratefully acknowledge The Scripps Research Institute,
Vertex Pharmaceuticals, Inc, and the NIH (NIGMS, 5R01
GM102265) for financial support and Dr. Hari Khatuya for his
help in analyzing crude reactions.
Keywords: amino acid ligands · CÀH activation · olefination ·
organic chemistry · pyrazole
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Received: February 15, 2016
Published online on April 15, 2016
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