Pd-catalyzed asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols: The role of the chiral phosphoric acid in C-O bond cleavage and stereocontrol

Article abstract of DOI:10.1021/ja402740q

The combination of a palladium complex with a chiral phosphoramidite ligand and a chiral phosphoric acid enables the first highly efficient asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols, affording multiply functionalized heterocyclic products in high yields with excellent enantioselectivities that would be of great potential in the synthesis of pharmaceutically interesting molecules.

Full text of DOI:10.1021/ja402740q

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Communication
Pd-Catalyzed Asymmetric Allylic Alkylation of Pyrazol-5-
ones with Allylic Alcohols: the Role of Chiral Phosphoric
Acid in C-O Bond Cleavage and the Stereocontrol
Zhong-Lin Tao, Wen-Quan Zhang, Dian-Feng Chen, Arafate Adele, and Liu-Zhu Gong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402740q • Publication Date (Web): 03 Jun 2013
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PdꢀCatalyzed Asymmetric Allylic Alkylation of Pyrazolꢀ5ꢀones with
Allylic Alcohols: the Role of Chiral Phosphoric Acid in CꢀO Bond
Cleavage and the Stereocontrol
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ZhongꢀLin Tao†, WenꢀQuan Zhang†, DianꢀFeng Chen, Arafate Adele, and LiuꢀZhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
Supporting Information
Figure 1. The profile of AAA reaction
ABSTRACT: A combination of palladium complex of chiral
phosphoramidite and chiral phosphoric acid enables allylic alcoꢀ
hols to undergo a highly efficient asymmetric allylic alkylation of
pyrazolꢀ5ꢀones for the first time, affording multiply functionalꢀ
ized heterocyclic products in high yields and with excellent enanꢀ
tioselectivities that would be of great potential in the synthesis of
pharmaceutically interesting molecules.
Asymmetric catalytic reactions involving CꢀC bond formation
have allowed synthetic access to biologically important moleꢀ
cules, among which, the asymmetric allylic alkylation (AAA)1
has long been intensely studied for its diversity of bondꢀforming
types and extensive applications in total synthesis. For most of
the history of Pdꢀcatalyzed AAA reactions, activated precursors
of πꢀallyl fragments, such as allylic halides, esters and carbonates,
have dominantly been employed to accept the nucleophilic attack
of soft or hard nucleophilies (Figure 1, a). Nowadays, the enviꢀ
ronmental issues have drawn much attention that alternative susꢀ
tainable processes are becoming more and more privileged, espeꢀ
cially in the field of synthetic chemistry.2 For this reason, allylic
alcohols are considered as promising allylic component in AAA
reaction because of their wide synthetic reliability and step econꢀ
omy.3 However, the hydroxy is known to be a poor leaving group
to presumably obstruct the practical use of allylic alcohols in
allylic alkylation, particularly the enantioselective variants (Figꢀ
ure 1, b). The external activators, including Lewis acids1c, 4 and
Brønsted acids1c,5,7 have been explored to circumvent this formiꢀ
dable challenge. Trost first introduced triethylborane to assist the
palladium to break CꢀO bond, resulting in the AAA reactions of
soft nucleophiles with allylic alcohols.4a Recently, List estabꢀ
lished an AAA reaction of αꢀenolizable aldehydes with allyl alꢀ
cohols using ACDC strategy,7 in which a catalytic amount of
chiral phosphoric acid was able to facilitate the oxidative addiꢀ
tion of palladium to allylic alcohols and to solely control the
stereochemistry as well (Scheme 1, eq 1). Despite of these imꢀ
portant advances, the rejuvenation of AAA reaction can still be
anticipated by creating new strategy capable of overcoming isꢀ
sues associated with limited nucleophile/allyl alcohol pairs in
current processes.
Efficient assembly of optically pure multiꢀfunctionalized hetꢀ
erocyclic compounds, especially those with quaternary stereocenꢀ
ters,8 is challenging but would be of great importance. Recently,
pyrazolꢀ5ꢀoneꢀderived enantiomers have drawn much attention
because they appear prevalently in a collection of nonꢀsteroidal
antiꢀinflammatory drugs,9 such as Analgin, Nifenazone, and
Feprazone, leading to an increasing demand for the efficient synꢀ
Scheme 1. The combination of Pd(0)/chiral
ligand complex and chiral Brønsted acid
List's Work
R4
Ar
O
R2
+
R O OR
P
Pd(0)
Amine
(S)-TRIP
O
R3
R1
R2
O
H
O
P
R1
HO
CHO
R4
O
OH
R
H
(1)
Pd
R1
N
Ar
CHO
Ar= 2,4,6-(i-Pr)3C6H2
R2
(R)-TRIP
R3
yield 66%-98%
ee% 62%-99%
Intermediate
Our Work
Ln*
P
*
O
O
O
O
P
R
R1
O
Pd
Chiral Pd(0)
Chiral PA
N
N
Ar
(2)
O
R
R2
R
R1
R1
Ar
N
N
Ar
+
O
R2
N
N
OH
R2
allylic plane
thetic methods. As a result, enantioselective functionalization of
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pyrazolꢀ5ꢀones has already been investigated.10 However, no
mation of the alkylation product 3a in 72% yield, with a promisꢀ
3
4
5
6
7
8
9
asymmetric alkylation of pyrazolꢀ5ꢀones has been available, yet.
Herein, we report the first asymmetric allylic alkylation of pyraꢀ
zolꢀ5ꢀones using allylic alcohol directly as a reaction component,
which was achieved by the combination of palladium complex of
chiral phosphoramidite11 and chiral phosphoric acid.12 In this
protocol, the chiral phosphoric acid facilitates the formation of πꢀ
allylicꢀPd complex by activation of CꢀO bond. Moreover, a reꢀ
markable synergistic effect between ligand and counteranion was
observed (Scheme 1, b).
ing 49% ee (entry 1). Afterwards, various different electronic
effectꢀrelated substituents on the aniline moiety of ligands were
investigated and the enantioselectivity was substantially enꢀ
hanced to 90% ee, in 85% yield (entry 5). Notably, the (S)ꢀPA
was tested to give lower enantioselectivity than its enantiomer,
suggesting that the (R)ꢀPA acted as the matched coꢀcatalyst (entry
7). The examination of solvents proved that THF fitted the reacꢀ
tion best (entries 8 ꢀ 10). As one of the determining factors, apꢀ
propriate lower temperature (10 oC) was beneficial to the stereoꢀ
chemical control (94% ee) with no significant erosion of yield
(86%) (entries 11 and 12). Moreover, two typical achiral
Brønsted acids, TFA (trifluoroacetic acid) and pꢀTSA (pꢀ
toluenesulfonic acid), were employed as activators to replace
chiral phosphoric acid, but they gave much worse results in terms
of yield and enantioselectivity under otherwise identical condiꢀ
tions (entries 13 and 14 vs 11), which suggested the indeed existꢀ
ence of the cooperative effect between the chiral ligand and counꢀ
teranion.14 Finally, the decisive role of Brønsted acid in CꢀO
bond cleavage would be convinced by the fact that no starting
materials were consumed when Pd(0) complex was used alone
(entry 15).
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Table 1. Investigation of Ligands and
Brønsted acida
yield
(%)b
72
ee
(%)c
49
77
Solvent T(oC)
Table 2. Scope for allylic alcoholsa
entry
L
BA
Ph
Pd(dba)2 (2.5 mol%)
OH
O
O
1
2
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
L5
PA
PA
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
25
25
Bn
L5 (5 mol%), PA (5 mol%)
1'
R
Ph
N
N
Ph
THF, 10 o
C
or
86
88
78
85
25
80
91
N
N
R
R
OH
2a
3
3
PA
25
88
78
90
84
81
1
4
PA
25
5
PA
25
entry 1/1’
R
3
Yield(%)b ee(%)c
6
PA
25
1
2
1b 2ꢀMeOC6H4 3ba
1c 3ꢀMeOC6H4 3ca
1d 4ꢀMeOC6H4 3da
98
95
97
86
99
95
95
99
81
81
77
94
91
93
90
96
95
95
95
96
90
91
(S)ꢀPA
PA
7
25
8
25
90
76
91
3
9
PA
CH2Cl2
THF
25
17
4
1e
1f
1g
1h
1i
2ꢀBrC6H4
3ꢀBrC6H4
4ꢀBrC6H4
4ꢀFC6H4
3ea
3fa
10
11
12
13
14
15
PA
25
89
86
50
58
18
5
PA
PA
THF
10d
0e
94
92
84
84
ꢀ
6
3ga
3ha
THF
7
TFA
THF
10d
10d
10d
8
2ꢀNO2C6H4 3ia
L5 pꢀTSA
L5
THF
9
1j
(CH2)8CH3
Me
3ja
3ka
3la
3a′
ꢀ
THF
ꢀ
10
11
12
1k
1l
aUnless indicated otherwise, reactions of 1a (0.12
mmol), 2a (0.10 mmol), Pd(dba)2 (0.0025 mmol), BA
(0.005 mmol) and L (0.005 mmol) were carried out in 2
mL solvent for 16h. bIsolated yield. cDetermined by
nꢀPr
85
1′
4ꢀMeC6H4
91
aUnless indicated otherwise, reactions of 1 (0.12
mmol), 2a (0.10 mmol), Pd(dba)2 (0.0025 mmol), L5
(0.005 mmol) and PA (0.005 mmol) were carried out
d
HPLC analysis. The reaction was carried out for 36 h.
eThe reaction was carried out for 48h.
c
in 2 mL THF for 36 h. bIsolated yield. Determined by
HPLC analysis.
We initially endeavored to develop a chiral counteranionꢀ
directed AAA reaction using cinnamic alcohol 1a7 and pyrazolꢀ5ꢀ
one 2a as substrates, but the results were disappointing.13 We
then turned our attention to a combination of chiral phosphoric
acid (PA) and easily available binolꢀderived chiral phosphoꢀ
ramidite ligands that possess axial chirality only (Table 1, entries
1 ꢀ 6). To our delight, the use of PA and L1 allowed the forꢀ
This combined strategy for AAA reaction was then subject to a
rigorous test of substrates scope (Table 2). First of all, a series of
functionalized allylic alcohols were examined when 2a was used
as the nucleophile, furnishing the corresponding products 3ba ꢀ
3ka in 81% ꢀ 98% yield and 90% ꢀ 96% ee (entries 1ꢀ10). This
2
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protocol tolerated a range of substituents on the phenyl moiety of
ligand/conteranion combined strategy allowed a diverse spectrum
of substituents at C4ꢀposition of pyrazolꢀ5ꢀones to afford the
corresponding products in high yields and with excellent enantiꢀ
oselectivities (74%ꢀ99% yield, 94%ꢀ97% ee; entries 6 – 14).
The allylic alkylation products obtained from the AAA reacꢀ
tion can be applied to the synthesis of optically pure and multiply
functionalized pyrazolꢀ5ꢀone derivatives. The exposure of pyraꢀ
zolꢀ5ꢀone derivative 3aa to a combined dihydroxylation reagent
of ruthenium trichloride, sodium periodate and sulphuric acid in
a solvent mixture of ethyl acetate, acetonitrile and water, folꢀ
lowed by oxidation with sodium periodate in a mixture of THF,
ether and water to furnish a chiral aldehyde 4 in over all 40%
yield and with a maintained enantioselectivity (Scheme 2).15
allylic alcohols 1, including those bearing either of electronically
donating, neutral or withdrawing substituents. Basically, the relaꢀ
tively electronꢀdeficient cinnamic alcohols (1eꢀ1i, entries 4 ꢀ 8)
always performed better in stereochemical control than the relaꢀ
tively electronically neutral or rich ones (1b ꢀ 1d, 1′, entries 1ꢀ3,
10). Notably, the bromide was surprisingly well tolerated under
this Pd(0) catalysis (entries 4ꢀ6). Besides, under the optimized
conditions, aliphatic allylic alcohol 1j – 1l and a branched subꢀ
strate 1′ could also be able to afford the allylic adducts 3ja – 3la
and 3a′ with excellent outcomes (entries 9 ꢀ12). The configuraꢀ
tion of 3fa was determined by Xꢀray analysis of its crystal (see
Supporting Information).
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Table 3. Scope for Pyrazol-5-onesa
Scheme 2. Synthetic application of allylic ad-
ducts of pyrazol-5-one
Yield
(%)c (%)d
ee
Entry 2b
R1
R2
3
Conditions: a) 0.5 mol% RuCl3, 1.5 eq NaIO4, 20 mol%
o
H2SO4 EtOAc/CH3CN/H2O (3:3:1), 0 C, overnight; b)
1.5 eq NaIO4, THF/Et2O/H2O, rt, 2h.
1
2
2b
2c
2d
2e
2fe
2g
2h
2i
Ph
Ph
Ph
nꢀPr
iꢀPr
Et
3eb
3ec
3ed
3ee
3ef
3eg
3eh
3ei
81
97
96
85
99
98
93
92
99
96
89
66
95
88
95
97
96
95
96
96
95
94
97
94
97
92
3
Ph
Scheme 3. Proposed catalytic cycle for combina-
tion of chiral ligand and chiral counteranion
4
Ph
5
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
6
2ꢀFC6H4
3ꢀFC6H4
4ꢀFC6H4
2ꢀMeOC6H4
7
8
9
2j
3ej
10
11
12
13
14
15
2k 4ꢀMeOC6H4
3ek
3el
2l
2m
2n
2o
2p
αꢀNaph
2ꢀthienyl
Me
3em 99
3en
3eo
3ep
74
90
60
H
Ph
aUnless indicated otherwise, reactions of 1e (0.12 mmol),
2 (0.10 mmol), Pd(dba)2 (0.0025 mmol), L5 (0.005
mmol) and PA (0.005 mmol) were carried out in 2 mL
b
c
THF for 36h. Unless indicated otherwise, Ar = Ph. Isoꢀ
lated yield. dDetermined by HPLC analysis. Ar = 4ꢀClꢀ
e
To gain insight into palladium species in the catalysis, HRMS
analysis of a reaction mixture of the palladium complex with 1a
and phosphoric acid (PA) was conducted and identified that two
molecules of the chiral ligand (L5) favorably coordinated to palꢀ
ladium.16 On the basis of these fact and experimental observaꢀ
tions, a plausible catalytic cycle was proposed (Scheme 3). The
Pd(L*)2 A innitially reacted with phosphoric acidꢀactivated cinꢀ
namic alcohol B by hydrogen bonding7 to expelled the hydroxy
group to give the crucial cationic πꢀallyl palladium(II) complex C,
accompanying with generation of a molecule of water owing to
the participation of the chiral phosphoric acid. Subsequently, the
C6H4.
The following test for the generality of pyrazolꢀ5ꢀones 2 was
then conducted (Table 3). The excellent stereocontrol was keenly
awake to the change of substituents at C3ꢀposition of pyrazolꢀ5ꢀ
ones. As a consequence, the replacement of methyl with phenyl
or hindered iꢀpropyl led to lower levels of enantioselectivity,
while nꢀpropyl, ethyl and H could keep the enantioselectivity at
similar or even higher levels (entries 1ꢀ4, 15). One of the best
results was obtained by introducing a Cl on the benzene ring of
aniline moiety (99% yield, 97% ee; entry 5). Notably, this chiral
3
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Chem. Soc. Rev. 2012, 41, 4467; for recent examples, see: (d) Raducan,
AAA reaction presumably proceeded with the enolizable pyrazolꢀ
5ꢀone 2a via the intermediate I and the chiral phosphate counꢀ
teranion was inclined to have a hydrogenꢀbonding interaction
with incoming nucleophile 2a, which was stereoselectively actiꢀ
vated for the nucleophilic substitution of πꢀallyl complex C. In
this stereochemistryꢀdetermining step, the chiral palladium comꢀ
plex and chiral phosphate counteranion worked cooperatively to
activate the substrates and to control the stereochemistry of the
AAA reaction, affording the product 3aa with high enantioselecꢀ
tivity, and simultaneously the parent chiral palladium(0) complex
A and phosphoric acid were regenerated for the next catalytic
cycles.
In summary, we have demonstrated that the combined use of a
palladium complex of chiral phosphoramidite and chiral phosꢀ
phoric acid enables allylic alcohols to participate in a highly enꢀ
antioselective allylic alkylation of pyrazolꢀ5ꢀones for the first
time. This protocol have tolerated a diverse scope of functional
groups in either allylic alcohols or pyrazoꢀ5ꢀones, furnishing
multiply functionalized heterocyclic products in high yields and
with excellent enantioselectivities that would be of great potential
in the synthesis of pharmaceutically interesting molecules. More
importantly, the combination of two different simple chiral
sources is robust in the creation of a diverse library of chiral eleꢀ
ments for the control of stereoselectivity in asymmetric catalysis.
Moreover, such a strategy essentially avoided the fussy turning of
structurally complicated chiral ligands, which was always enꢀ
countered in traditional metalꢀbased asymmetric catalysis.
M.; Alam, R; Szabó, K. J. Angew. Chem. Int. Ed. 2012, 51, 13050. (e)
Larsson, J. M.; Szabó, K. J. J. Am. Chem. Soc. 2013, 135, 443.
(4) For the first example of Pdꢀcatalyzed AAA reaction using allyl
alcohol as electrophile, see: (a) Trost, B. M.; Quancard, J. J. Am. Chem.
Soc. 2006, 128, 6314. For Irꢀcatalyzed AAA reaction using allyl alcohol
as electrophile, see: (b) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F.
J. Am. Chem. Soc. 2007, 129, 7508.
(5) For Pd catalysis, see: (a) Yasuda, S.; Kumagai, N.; Shibasaki, M.
Heterocycles, 2012, 86, 745. For Ir catalysis, see: (b) Defieber, C.; Ariger,
M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139.
(c) Roggen, M.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 5568.
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Ed. 2010, 49, 1013. (b) Rueping, M.; Koenigs, R. M.; Atodiresei, I.
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2010, 2999. (d) Han, Z.ꢀY.; Wang, C.; Gong, L.ꢀZ. in Science of
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Zimmermann, N. Eur. J. Org. Chem. 2007, 5969. (c) Trost, B. M.; Jiang,
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Acad. Sci. U.S.A. 2004, 101, 11943. (e) Douglas, C. J.; Overman, L. E.
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Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
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Bhuyan, N. R.; Bharti, P. R.; Kumar, D. J. Adv. Pharm. Tech. Res. 2010,
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(11) For selected reviews, see: (a) Teichert, J. F.; Feringa, B. L. Angew.
Chem., Int. Ed. 2010, 49, 2486. (b) Lam, H. W. Synthesis 2011, 2011.
(12) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
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Terada, M. Synthesis 2010, 1929.
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ASSOCIATED CONTENT
Supporting Information.
Complete experimental procedures and characterization data for
the prepared compounds. This material is available free of charge
via the internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
gonglz@ustc.edu.cn
Author Contributions
† The authors contribute equally to this work.
ACKNOWLEDGMENT
(13) For details about the preliminary results of chiral counteranionꢀ
directed AAA reaction, see Supporting Information.
We are grateful for financial support from NSFC (21232007,
21072181), MOST (973 project 2010CB833300), Ministry of
Education, and CAS.
(14) For an excellent review, see: (a) Ding, K.ꢀL. Chem. Commun. 2008,
909. For recent examples involving chiral phosphoric acids as part of the
strategy, see: (b) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2010, 49, 9685. (c) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.;
Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am. Chem. Soc.
2011, 133, 17934. (d) Xie, J.ꢀW.; Huang, X.; Fan, L.ꢀP.; Xu, D.ꢀC.; Li,
X.ꢀS.; Su, H.; Wen, Y.ꢀH. Adv. Synth. Catal. 2009, 351, 3077. (e)
Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132,
10227.
(15) (a) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5 , 3353. (b) Lu,
L.; Zhang, W.; Carter, R. G. J. Am. Chem. Soc. 2008, 130, 7253.
(16) For HRMS analysis of the intermediate, please see Supporting
Information.
REFERENCES
(1) For the first asymmetric allylic alkylation, see: (a) Trost, B. M.;
Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292. For reviews, see: (b)
Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996, 96, 395. (c) Trost, B.
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(2) (a) Clark, J. Green. Chem. 1999, 1, 1. (b) Sheldon, R. A. Green.
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(3) For reviews on allylic alcohols, please see: (a) Bandini, M. Angew.
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