Rhodium/chiral diene complexes in the catalytic asymmetric arylation of β-pyrazol-1-yl acrylates

Article abstract of DOI:10.1021/acs.orglett.5b00080

The asymmetric conjugate addition of arylboronic acids to substituted and unsubstituted β-pyrazol-1-yl (E)-tert-butyl acrylates 4 catalyzed by 5 mol % of the Rh(I)/diene 2a catalyst provided the corresponding addition products in 44-98% yield and 91->99.5

Full text of DOI:10.1021/acs.orglett.5b00080

Letter
pubs.acs.org/OrgLett
Rhodium/Chiral Diene Complexes in the Catalytic Asymmetric
Arylation of β‑Pyrazol-1-yl Acrylates
Balraj Gopula,† Yun-Fan Tsai,† Ting-Shen Kuo,† Ping-Yu Wu,‡ Julian P. Henschke,*,‡
and Hsyueh-Liang Wu*,†
†Department of Chemistry and Instrumentation Center, National Taiwan Normal University, No. 88, Section 4, Tingzhou Road,
Taipei 11677, Taiwan, Republic of China
‡ScinoPharm Taiwan, No. 1, Nan-Ke eighth-Road Tainan Science-Based Industrial Park, Shan-Hua, Tainan County, 74144, Taiwan,
Republic of China
S
* Supporting Information
ABSTRACT: The asymmetric conjugate addition of arylbor-
onic acids to substituted and unsubstituted β-pyrazol-1-yl (E)-
tert-butyl acrylates 4 catalyzed by 5 mol % of the Rh(I)/diene
2a catalyst provided the corresponding addition products in
44−98% yield and 91−>99.5% ee. The method was applied to
the formal synthesis of (3S)-3-aryl-3-(pyrazol-1-yl)propanoic
acid 1b with agonistic activity toward the human GPR40 G-protein coupled receptor.
ptically active N-containing heterocyclic compounds are
commonly found in natural products, biologically active
resolution may be required. Moreover, the organocatalyzed
asymmetric aza-Michael reaction benefits from Michael accept-
ors that can form hydrogen bonds and/or are able to form
iminium ions. Therefore, while α,β-unsaturated aldehydes and
ketones work well, α,β-unsaturated esters do not make good
substrates. Given our own need to access β-pyrazol-1-yl
substituted esters with a stereogenic center directly adjacent to
the pyrazole moiety, and with further structural diversification of
the addition products in mind, we sought to develop an efficient
method that offered higher levels of stereocontrol than the
corresponding asymmetric aza-Michael reaction could achieve.
In recent years the Rh-catalyzed enantioselective conjugate
addition of organoboron reagents to electron-deficient olefins
has experienced significant development, ultimately allowing for
the formation of C−C bonds under relatively mild conditions.6,7
The use of boronic acids and α,β-unsaturated carbonyl
compounds is known as the Hayashi−Miyaura reaction and
offers benefits over the analogous asymmetric cuprate 1,4-
conjugate addition including not requiring low temperature,
moisture- and air-free conditions, being catalytic, and not
requiring the in situ preparation of the nucleophiles. Recently
we have reported a series of variants of the Hayashi−Miyaura
reaction utilizing highly reactive and enantioselective chiral
Rh(I)-catalysts comprising a novel family of 2,5-diaryl
substituted bicyclo[2.2.1]heptadiene ligands 2 and various
Michael acceptors.8,9 Building upon these results we herein
report the rhodium-catalyzed asymmetric conjugate addition of
arylboronic acids to β-pyrazol-1-yl acrylate esters employing
novel chiral diene ligands furnishing β-aryl-β-pyrazol-1-yl esters
in high yield and enantioselectivity.10
O
compounds, and pharmaceuticals.1 Among these, chiral N-
alkylpyrazoles have received significant attention due to their
ubiquity in compounds with biological activity.2 For example,
pyridine N-oxide 1a2a (Figure 1) that bears a pyrazole moiety
Figure 1. Biologically active chiral pyrazole compounds.
appended adjacent to a stereogenic center is a potent PDE4
(PhosphoDiEsterase type 4) inhibitor (IC50 = 0.5 nM) that is
potentially useful for targeting inflammatory diseases.3 Other
examples include the β-pyrazol-1-yl acid 1b that has activity
(EC50 ≤ 10 μM) toward human GPR40 G-protein coupled
receptor2b and ruxolitinib (1c; INCB018424),2c a Janus kinase
(JAK) inhibitor that is used in the treatment of myelofibrosis.
Chiral compounds such as 1a−1c can be accessed by the
asymmetric aza-Michael reaction: the organocatalytic enantio-
selective conjugate addition of N-containing heterocyclic
nucleophiles to α,β-unsaturated carbonyl compounds. Although
this has seen wide application in the synthesis of a diverse range
of biologically active natural products,4,5 only a limited number of
examples utilizing pyrazole nucleophiles exist that have been
accomplished with a good degree of enantioselectivity.5d−f As a
result, when access to enantiopure pyrazoles is required,
separation of racemic or enantioenriched aza-Michael product
mixtures by chiral preparative HPLC or classical chiral salt
Received: January 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00080
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To initiate the study, the addition of phenylboronic acid (3a)
to (E)-tert-butyl 3-(1H-pyrazol-1-yl)acrylate (4a) was tested in
the presence of 2.5 mol % of [RhCl(COD)2]2 (Scheme 1 and
Table 1. Asymmetric Conjugate Addition of Phenylboronic
Acid (3a) to tert-Butyl-β-Pyrazol-1-yl Acrylate (4a)
a
Scheme 1. Conjugate Addition of Phenylboronic Acid (3a) to
(E)-3-(1H-Pyrazol-1-yl)acrylates
b
c
entry
ligand
yield (%)
ee (%)
1
2
2a
2b
2c
2d
2e
2f
2g
7
80
97
91
90
96
94
95
93
−97
Table S1 in the Supporting Information). With a lack of
precedent for the addition to β-pyrazol-1-yl acrylates, it was
unclear whether the Rh(I) catalyst would tolerate the pyrazole
moiety.11 Although very commonly used in the Hayashi−
Miyaura reaction using RhCl precatalysts in aqueous dioxane,12
0.5 equiv of KOH, NaOH, or K2CO3 proved ineffective at 60 °C
providing the addition product 5aa in only 6−17% along with the
double addition product 6aa, formed via elimination of pyrazole,
in 3−9%. NaHCO3, KHF2, K2HPO4, and Et3N proved equally
ineffective (0−14% 5aa; 0−10% 6aa) under the same conditions,
and although K2CO3, NaHCO3, or K2HPO4 provided poor
results in MeOH (5−12% 5aa; 0−3% 6aa), however, it was
encouraging to find that the reaction of 4a in the presence of
KOH, NaOH, or KHF2 in MeOH furnished the desired product
5aa in much improved yields (65−88%) with none or only small
amounts of side product 6aa. To our delight, when the reaction
in MeOH was conducted in the presence of 6 equiv of Et3N,
adduct 5aa was produced in a 91% isolated yield within only 4 h.
Interestingly, however, when alcohol homologues EtOH, i-
PrOH, or t-BuOH were used in place of MeOH in conjunction
with Et3N, inferior results were observed (0−44% 5aa; 0−21%
6aa). Similarly DMF, THF, MeCN, or PhMe also gave
disappointing results (0−16% 5aa; 0−1% 6aa). Using MeOH
as solvent, an extensive screen of primary, secondary, and tertiary
amines was conducted, and while most amines resulted in low to
moderate yields (0−65% 5aa; 0−5% 6aa), t-BuNH2 was most
promising giving an 88% yield of 5aa accompanied by 12% of
double addition product 6aa. In all, however, MeOH, which is
preferred in industry to dioxane due to the toxicity of the latter, in
conjunction with Et3N proved the best and all subsequent tests
therefore utilized this combination. Finally, both acrylates 4b and
4c proved not to be useful; ethyl acrylate 4b underwent
decomposition and provided no 5aa, whereas no reaction
occurred when using 4c, presumably owing to steric hindrance
provided by the bulky aryl ester functionality.
The asymmetric addition of phenylboronic acid (3a) to
compound 4a was examined next, using 5 mol % of chiral Rh(I)
precatalysts prepared in situ from [RhCl(C2H4)2]2 and a family of
novel 2,5-diaryl-substituted chiral diene ligands 2a−2g. Although
proceeding more slowly than the achiral mode of the reaction,
the β-pyrazol-1-yl substituted ester 5aa was obtained in isolated
yields of 51−90% (Table 1, entries 1−7). While the reaction
proceeded less selectively in the presence of tolyl (2b, entry 2) or
bulky 4-tert-butylphenyl (2c, entry 3) substituted ligands, good
to comparable asymmetric induction (93−96% ee) was observed
when para-electron-withdrawing substituted aryl containing
ligands were used, such as 2d (with a 4-Cl-phenyl substituent,
entry 4) and 2e (with a 4-CF3-phenyl substituent, entry 5), or
ligands substituted with 1-naphthyl (2f, entry 6) or 2-naphthyl
groups (2g, entry 7). Next, several commercially available dienes
and a phosphine ligand were compared under conditions
90
3
80
4
73
5
80
6
51
7
76
8
25
d
9
8
trace
trace
N.D.
d
10
9
N.D.
a
Reaction conditions: compound 4a (0.1 mmol), 3a (0.2 mmol),
Rh(I) catalyst (5 mol % of Rh), Et3N (0.6 mmol). Isolated yield.
Determined by chiral HPLC on a Chiracel OD-H column. N.D. =
not determined.
b
c
d
identical to those described above. Although the bicy-
clo[2.2.2]-based ligand 7 provided good asymmetric induction
(−97% ee), the isolated product yield (25%) was unsatisfactory
(entry 8).12 Using chiral bicyclo[3.3.0]diene ligand 88e,13 (entry
9) or (S)-BINAP (9, entry 10),14 which are known for producing
high catalytic activity and enantioselectivity in the Rh(I)-
catalyzed asymmetric conjugate addition to α,β-unsaturated
carbonyl compounds, furnished only trace amounts of the
desired product 5aa with undetermined ee’s. The above results
showed that the bicyclo[2.2.1]heptadiene ligand family 2 was
well suited to this asymmetric transformation and, in terms of a
compromise between yield and selectivity, that ligand 2a was the
optimal chiral modifier.
The scope of the reaction was investigated next through the
enantioselective addition of a large number of arylboronic acids
to tert-butyl β-pyrazol-1-yl acrylate (4a) (Table 2) under the
optimized reaction conditions identified in Table 1, entry 1.
Arylboronic acids bearing alkyl and electron-donating sub-
stituents gave the corresponding arylation products 5ba−5ia in
48−90% yield and in 92−99% ee (entries 2−9). The
stereochemical center of compound 5ia was unequivocally
determined by X-ray crystallography to be (S)-configured
(Figure 2) indicating that conjugate addition to the α-Re face
of compound 4a was favored using Rh(I)/2a, consistent with
that which we have reported previously.9a While achieving high
asymmetric induction (99% ee), the addition of 2-tolylboronic
acid (3b) provided a low chemical yield (48%), presumably as a
result of steric hindrance (entry 2). Esters 5ea, 5fa, and 5ga were
targeted because their methyl and benzyl ethers offer potential
for further functionalization by ether cleavage following
conjugate addition, as was demonstrated for 5ga (see below).
Arylboronic acids substituted with electron-withdrawing groups
were tolerated offering the addition products 5ja−5qa in 54−
88% yield and 96−99% ee (entries 10−17). When 2-naphthyl-
boronic acid (3r) was used, pyrazole 5ra was isolated in a high
98% yield with 94% ee (entry 18). The generality of the reaction
B
DOI: 10.1021/acs.orglett.5b00080
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Asymmetric Conjugate Addition of Arylboronic
Acids to β-Pyrazol-1-yl Acrylates
Scheme 2. Further Elaboration of the β-Pyrazol-1-yl Core to
Provide Compound 5af
a
nitrile, methyl and benzyl ethers, or even chloride16 which, for
example, could be converted to amides, reverse amides, amines,
sulfonamides, esters, biaryl ethers, or even biaryls, and this could
prove useful for the generation of medicinal chemistry
compound libraries.
Finally, to demonstrate the synthetic utility of this method-
ology the formal synthesis of bioactive compound 1b was
conducted (Scheme 3). Hydrogenolysis of enantioenriched
b
c
entry
Ar
Ph (3a)
substrate time (h) yield (%) ee (%)
1
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4d
4d
4d
4d
4e
4f
33
48
33
33
25
25
60
33
24
28
24
24
26
26
28
26
26
24
24
24
24
24
32
36
44
80 (5aa)
48 (5ba)
85 (5ca)
88 (5da)
90 (5ea)
78 (5fa)
97
99
96
96
93
96
97
92
98
98
98
96
98
98
97
98
97
94
99
97
91
97
96
99
>99.5
2
2-MeC6H4 (3b)
3-MeC6H4 (3c)
4-MeC6H4 (3d)
3-MeOC6H4 (3e)
4-MeOC6H4 (3f)
4-BnOC6H4 (3g)
4-tBuC6H4 (3h)
4-PhC6H4 (3i)
4-FC6H4 (3j)
3
4
5
6
d
7
48 (5ga)
8
86 (5ha)
71 (5ia)
73 (5ja)
83 (5ka)
70 (5la)
88 (5ma)
87 (5na)
54 (5oa)
79 (5pa)
76 (5qa)
98 (5ra)
55 (5ad)
62 (5hd)
44 (5pd)
60 (5 rd)
82 (5ae)
90 (5af)
70 (5ag)
Scheme 3. Formal Synthesis of β-Aryl-β-pyrazol-1-yl
Propanoic Acid Agonistic 1b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-ClC6H4 (3k)
3,4-Cl2C6H3 (3l)
3-CF3C6H4 (3m)
4-CF3C6H4 (3n)
3-NO2C6H4 (3o)
4-NO2C6H4 (3p)
4-CNC6H4 (3q)
2-Naphthyl (3r)
Ph (3a)
4-PhC6H4 (3h)
4-NO2C6H4 (3p)
2-Naphthyl (3r)
Ph (3a)
pyrazole 5ga (Table 2, entry 7) offered phenol 10a in
quantitative yield, which was O-alkylated with commercially
available benzyl bromide 11 to provide benzyl ether 12 in 96%
yield over two steps without loss of enantiopurity. Trans-
esterification using AcCl and MeOH followed by DCC
promoted coupling with MeOH provided the reported β-
pyrazolyl ester 13. This precursor was prepared previously2b
using a nonstereoselective double alkylation, oxidative double
bond cleavage and esterification sequence that required chiral
HPLC separation of the racemate of 10b followed by alkylation
with 11 to give 13. Hydrolysis of 13 is known to furnish 1b.2b
In conclusion, the first example of the asymmetric conjugate
addition of arylboronic acids to β-pyrazol-1-yl acrylates, which
are readily prepared by the 1,4-addition of the corresponding
pyrazoles to tert-butyl propiolate, in the presence of a chiral
Rh(I)-catalyst, generated in situ from [RhCl(C2H4)2]2 and chiral
diene ligands, has been reported. This method affords the
corresponding arylation products in good to high yields with high
to excellent ee’s and proceeds best in the industrially acceptable
solvent MeOH using Et3N as the base. The reaction generally
provides higher ee’s than does the corresponding aza-Michael
reaction for similar compounds in the presence of chiral
organocatalysts and, therefore, offers an alternative approach
for the preparation of such compounds.5d,f The reaction is
compatible with a range of aryl functionality as well as a range of
substituted pyrazole derivatives, including 4-bromo-pyrazol-1-yl
derivatives, that can be further functionalized subsequent to the
conjugate addition step, as was demonstrated using a Pd-
catalyzed cross-coupling reaction of 5ad to afford 5af. Further
diversification useful for the generation of medicinal chemistry
Ph (3a)
Ph (3a)
4g
a
Reaction conditions: compound 4 (0.1 mmol), 3 (0.2 mmol), Rh(I)
b
catalyst (5 mol % of Rh), and Et3N (0.6 mmol). Isolated yield.
c
d
Determined by chiral HPLC. 80% yield based on recovered 4a.
Figure 2. ORTEP illustration of compound 5ia with thermal ellipsoid
drawn at 30% probability level.
was further extended to the arylation of substituted β-pyrazol-1-
yl acrylates. Reaction of acrylate 4d with phenylboronic acid
(3a), 4-biphenylboronic acid (3h), 4-nitrophenylboronic acid
(3p), or 2-naphthylboronic acid (3r) provided a 44−62% yield of
the corresponding addition products 5ad, 5hd, 5pd, or 5rd,
respectively, in 91−99% ee (entries 19−22). Methyl and aryl
substituted pyrazoles 4e−4g were well tolerated, giving rise to
desired products 5ae, 5af, and 5ad in 70−90% yield and with up
to greater than 99.5% ee (entries 23−25).
By way of example of the diversification available with the
products of this reaction, compound 5ad was cross-coupled with
4-methoxyphenylboronic acid (3f) to produce compound 5af
(Scheme 2).15 We envision that further diversification should be
possible by functional transformation of aryl groups harboring
C
DOI: 10.1021/acs.orglett.5b00080
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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reactive and functionalizable substituents such as nitrile, ether, or
halide. By way of demonstration the formal synthesis of (3S)-β-
aryl-β-pyrazol-1-yl propanoic acid 1b was performed.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and complete characterization of
addition products (NMR spectra, HPLC chromatograms).
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: Julian.Henschke@scinopharm.com.
*E-mail: hlw@ntnu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Damodar Janmanchi for his preliminary studies.
Financial support provided by the Ministry of Science and
Technology of Republic of China (102-2113-M-003-006-MY2),
the National Taiwan Normal University, and ScinoPharm
Taiwan is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.5b00080
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