Palladium-Catalyzed Asymmetric Arylation of Trifluoromethylated/Perfluoroalkylated 2-Quinazolinones with High Enantioselectivity

Article abstract of DOI:10.1002/chem.201603105

Asymmetric arylation of 4-fluoroalkyl-2-quinazolinone derivatives with arylboronic acids proceeded smoothly in the presence of a cationic palladium catalyst (1 mol %) coordinated with a chiral phosphinooxazoline (phox) ligand to create the corresponding fluorine-containing arylated dihydroquinazolinones in high yields and with greater than 99 % ee.

Full text of DOI:10.1002/chem.201603105

A Journal of
Accepted Article
Title: Palladium-Catalyzed Asymmetric Arylation for the Preparation of Trifluorome-
thylated/Perfluoroalkylated 2-Quinazolinone Derivatives with High (>99
Authors: Yixin Lu; Bo Zhou; Chunhui Jiang; Vasudeva Rao Gandi; Tamio Hayashi
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Chemistry - A European Journal
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COMMUNICATION
Palladium-Catalyzed Asymmetric Arylation for the Preparation of
Trifluoromethylated/Perfluoroalkylated 2-Quinazolinone
Derivatives with High (>99%) Enantioselectivity
Bo Zhou,[a] Chunhui Jiang,[a] Vasudeva Rao Gandi,[a] Yixin Lu,*[a] and Tamio Hayashi*[a,b]
Abstract: Asymmetric arylation of 4-fluoroalkyl-2-quinazolinone
derivatives with arylboronic acids proceeded smoothly in the
(a) Cyclic imines used for the catalytic asymmetric arylation
presence of a cationic palladium catalyst (1 mol%) coordinated with
a
chiral phosphinooxazoline (phox) ligand to create the
O O
S
O O
S
Rh/L* or Pd/L*
catalyst
corresponding fluorine-containing arylated dihydroquinazolinones in
high yields and with higher than 99% ee.
N
NH
+
ArB(OH)2
*
R
Ar
R
R = H, alkyl, aryl, CF3, COOR'
Enantiomerically enriched benzylic amines are important
structural motifs and significant efforts have been made for their
efficient synthesis. In complement of enzymatic approaches via
transamination of ketones,[1] asymmetric addition of arylboron
reagents to aldimines and ketimines catalyzed by chiral rhodium
and palladium complexes has emerged as of one of the most
efficient methods.[2,3] Compared with aldimines, ketimines are
more changeling substrates as their reactivity is much lower due
to the presence of the substituent on the azomethine
carbon.[3h,4f,4g] Recently, cyclic ketimines have become favorable
O
O
O
O O
S
O
O
O
O
O
S
S
S
S
N
N
N
N
O
N
X
N
N
Me
R
N
R
R
R
R
R
O
A
B
C: X = CH2, O, NR'
D
E
F
O O
S
O
O
Bn
N
N
NH
H
OH
R
R
R
G
substrates
in
asymmetric
arylation
reactions;
the
enantioselectivity of their reaction is generally higher due to the
suppression of syn-anti isomerization of the carbon–nitrogen
double bond in cyclic ketamine structures. Most of the cyclic
imines so far used for the catalytic asymmetric arylation are
those bearing an N-sulfonyl imine moiety, including:
benzo[d]isothiazole 1,1-dioxide A, benzo[e][1,2,3]oxathiazine
2,2-dioxide B,[4] and some other cyclic sulfonyl imines lacking
the benzo-fusion C-F[5] (Scheme 1a). One example of cyclic
imine G which has N-acyl imine moiety instead of N-sulfonyl
imine has also been reported.[6] In this communication we wish
to report that 2-quinazolinone derivatives substituted with
fluoroalky groups 1 are a new class of cyclic imines suitable for
the catalytic asymmetric arylation (Scheme 1)
(b) Asymmetric arylation of 2-quinazolinones 1 (This work)
O
O
P
P
N
X
N
N
X
NH
Pd/L* catalyst
*
Ar
CnF2n+1
+ ArB(OH)2
CnF2n+1
>99% ee
1
Scheme 1. Catalytic asymmetric addition of arylboron reagents to cyclic
imines.
Molecules with trifluoromethyl or perfluoralkyl groups have
captured tremendous attention from synthetic chemists, due to
their great importance in medicinal chemistry, and thus it is not
surprising catalytic enantioselective trifluoromethylation and
perfluoralkylation have progressed significantly in recent years.[7]
Alternatively, we envisioned employment of fluoroalkyl
substrates would allow for easy access to chiral fluoroalkylated
molecules. Dihydroquinazolinones containing trifluoromethyl
group at the 4-position are known to be biologically active.[8] The
literature reports for their asymmetric synthesis are focused on
enantioselective addition to 4-trifluoromethyl-2-quinazolinone
derivatives,[9-13] and successfully employed nucleophiles include:
ketone enolates,[9] nitroalkanes,[10] cyanide,[11] indoles,[12] and
isocyanoacetates.[13] To the best of our knowledge, there is no
report on the catalytic asymmetric arylation of the 2-
quinazolinone derivatives with arylboron reagents. We therefore
prepared cyclic imine 4-trifluoromethyl-2-quinazolinone 1a with a
4-methoxybenzyl (PMB) protection by dehydration of
hemiaminal 2a, and examined its reactivity for the asymmetric
[a]
B. Zhou, Dr. C. Jiang,[+] Dr. V. R. Gandi, Prof. Dr. Y. Lu, Prof. Dr. T.
Hayashi[‡]
Department of Chemistry
National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax: +65-6779-1691
E-mail: chmlyx@nus.edu.sg
[b]
[+]
[‡]
Prof. Dr. T. Hayashi
Institute of Materials Research and Engineering
A*STAR, 2 Fusionopolis Way, Singapore 138634 (Singapore)
Present address: School of Environmental and Chemical
Engineering, Jiangsu University of Science and Technology,
Zhenjiang, Jiangsu 212003, China
Present address: Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, 21 Nanyang Link, Singapore 637371
E-mail: hayashi@ntu.edu.sg
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))

Chemistry - A European Journal
10.1002/chem.201603105
COMMUNICATION
arylation of sulfonyl imines.[4,5] The results are summarized in
Table 1. A cationic palladium complex coordinated with a chiral
phosphine-oxazoline ligand (S)-iPr-phox,[14] which has been
reported to be effective as a catalyst for the asymmetric arylation
of sulfonyl imines,[4g] was found to be effective. The reaction of
1a with 2 equiv. of phenylboronic acid (3a) in the presence of 5
mol% of a cationic palladium catalyst generated in situ from
PdCl2[(S)-iPr-phox][15] (5 mol%) and AgBF4 (15 mol%) in 1,2-
dichloroethane at 65–70 °C for 12 h gave 97% yield of the
phenylation product 4a, which was determined to be an R
isomer of 99.8% ee by its X-ray crystal structure analysis[16] and
HPLC analysis with a chiral column (entry 1). The generation of
a cationic palladium complex is essential for the high catalytic
activity. The cationic complex generated with AgOTf in place of
AgBF4 is also catalytically active to give 90% yield of (R)-4a
(99.7% ee) (entry 2), but the addition reaction did not take place
in the absence of the silver salts (entry 3). Phosphine-oxazoline
ligands with methyl and t-butyl substituents at the stereogenic
center, (S)-Me-phox and (S)-tBu-phox,[14] were as good as the
isopropyl analogue in terms of both catalytic activity and
enantioselectivity (entries 4 and 5). The cationic palladium
complex with pyridine-oxazoline ligand, (S)-iPr-pyrox,[17] also
catalyzed the reaction albeit with lower activity and
enantioselectivity (entry 6). The binap complex was ineffective
of arylboronic acids and 1 mol% of the Pd catalyst) although the
enantioselectivity was high (entry 10). The low yield is attributed
at least in part to the low solubility of boronic acid 3j. The use of
boroxine ((ArBO)3), which is more soluble than the boronic acid,
improved the yield to 62% (entry 11). A larger amount of the
catalyst (5 mol%) slightly improved the yield (entry 12). Similar
results were obtained when the 4-Br phenyl group was
introduced (entries 13 and 14). The enantioselectivity remained
high for ortho-substituted boronic acids, although the yields were
lower than para/meta-substituted substrates (entries 15 and 16).
Table 1. Catalytic asymmetric phenylation of 4-trifluoromethyl-2-quinazolinone
1a with phenylboronic acid 3a.[a]
(entry 7). For comparison, the chiral diene–rhodium complex
[3b,18]
[RhCl((R,R)-Ph-bod)]2
was examined for its performance
(entry 8). Although the enantioselectivity was high (93% ee), the
catalytic activity was lower than that of cationic
palladium/phosphine-oxazoline complexes (entry 8). The
cationic palladium complex was so catalytically active that we
succeeded in reducing the amount of catalyst from 5 mol% to 1
mol% without loss of yield or % ee (entry 9). A larger scale
reaction giving a gram of product 4a was successful with 1 mol%
of the palladium catalyst (entry 10).
Entry
Catalyst (5 mol%)
additives (15 mol%)
Solvent
T [°C], t [h]
4a Yield[b]
[%]
4a ee[c]
[%]
1
PdCl2[(S)-iPr-phox]
AgBF4
ClCH2CH2Cl
65–70, 12
97
90
0
99.8 (R)
99.7 (R)
—
The hemiaminal 2a, a synthetic precursor of 2-quinazolinone
1a, could be used as a substrate for the reaction. The yield of 4a
was slightly lower (88%) when 2a was employed instead of 1a
under identical conditions (entries 1 vs 11). The use of
phenylboroxine (PhBO)3 in place of phenylboronic acid (3a)
improved the yield to 95% (entry 12). The higher yield with
boroxine may be ascribed to the dehydration of 2a into 1a under
2
PdCl2[(S)-iPr-phox]
AgOTf
ClCH2CH2Cl
65–70, 12
3
PdCl2[(S)-iPr-phox]
ClCH2CH2Cl
65–70, 12
4
PdCl2[(S)-Me-phox]
AgBF4
ClCH2CH2Cl
65–70, 12
97
93
42
0
99.3 (R)
99.9 (R)
89 (R)
—
the reaction conditions where the boroxine works as
a
dehydrating reagent generating imine 1a and boronic acid 3a in
situ.[6] Given the fact that synthesis and isolation of imine 1a by
dehydration of 2a is not always trivial, the asymmetric arylation
with direct employment of hemiaminal 2a has advantages over
the procedures of using 1a as a substrate.
5
PdCl2[(S)-tBu-phox]
AgBF4
ClCH2CH2Cl
65–70, 12
6
PdCl2[(S)-iPr-pyrox]
AgBF4
ClCH2CH2Cl
65–70, 12
The cationic palladium catalyst generated from PdCl2[(S)-iPr-
phox] and AgBF4 was found to be highly enantioselective for the
asymmetric arylation with various types of arylboronic acids, and
the enantioselectivity ranging between 99.4% and 99.9% ee in
the arylation of 2-quinazolinone 1a (Table 2). The catalytic
activity was high even with 1 mol% of the palladium catalyst for
the arylboronic acids 4b-h bearing methyl, phenyl, fluoro, and
alkoxy groups at para- and/or meta- positions (entries 2-9). For
the introduction of 4-Cl phenyl group, the yield of the arylation
product was low (22%) under the standard conditions (2 equiv.
7
PdCl2[(S)-binap]
AgBF4
ClCH2CH2Cl
65–70, 12
8
[RhCl((R,R)-Ph-bod)]2
K3PO4
1,4-dioxane
60, 12
67
97
96
93 (R)
99.8 (R)
99.8 (R)
9[d]
PdCl2[(S)-iPr-phox]
AgBF4
ClCH2CH2Cl
65–70, 12
10[d,e]
PdCl2[(S)-iPr-phox]
AgBF4
ClCH2CH2Cl
65–70, 12

Chemistry - A European Journal
10.1002/chem.201603105
COMMUNICATION
11[f]
PdCl2[(S)-iPr-phox]
AgBF4
ClCH2CH2Cl
65–70, 12
88
95
99.8 (R)
99.8 (R)
[a] Reaction conditions: 1a (0.10 mmol), 3 (0.20 mmol), PdCl2[(S)-iPr-phox] (1
mol%), AgBF4 (3 mol%), 1,2-dichloroethane (1.0 mL) at 65–70 °C for 12 h. [b]
Isolated yield of 4. [c] Determined by HPLC analysis with chiral stationary
phase columns. The absolute configurations are estimated by stereochemical
similarity to the reaction giving 4a. [d] With boroxine (ArBO)3 (0.20 mmol B). [e]
With PdCl2[(S)-iPr-phox] (5 mol%) and AgBF4 (15 mol%).
12[f,g]
PdCl2[(S)-iPr-phox]
AgBF4
ClCH2CH2Cl
65–70, 12
[a] Reaction conditions: 1a (0.10 mmol), 3a (0.20 mmol), catalyst (5 mol%),
additive (15 mol%), solvent (1.0 mL) at a given temperature for 12 h. [b] Isolated
yield of 4a. [c] Determined by HPLC analysis with a chiral stationary phase
column. The absolute configuration of 4a was determined by X-ray
crystallographic analysis. [d] With PdCl2[(S)-iPr-phox] (1 mol%) and AgBF4 (3
mol%). [e] A larger scale reaction with 1a (2.50 mmol), 3a (7.50 mmol). [f]
Semiaminal 2a in place of imine 1a. [g] Phenylboroxine (PhBO)3 (0.20 mmol of
B) in place of phenylboronic acid 3a.
The substrate scope of the 2-quinazolinone derivatives is
shown in Table 3. Replacement of Cl at 6 position of 1a by F,
CF3, and OMe groups did not have any effect on the high
catalytic activity or high enantioselectivity of the present system
(entries 1-3). The 2-quinazolinone derivatives with longer
perfluoroalkyl groups, CF2CF3 and CF2CF2CF3, were also
applicable, giving the corresponding phenylation products with
high enantioselectivity (entries 4-7). The phenylation did not take
place for those lacking the perfluoroalkyl group at the imine
carbon (entries
8 and 9), suggesting that the electron
Table 2. Asymmetric addition of arylboronic acids 3 to 4-trifluoromethyl-2-
quinazolinone 1a catalyzed by PdCl2[(S)-iPr-phox]/AgBF4.[a]
withdrawing perfluoroalkyl group is essential for the activation of
the imino group towards the addition of an aryl-palladium
intermediate.[19]
Table 3. Asymmetric addition of phenylboronic acids 3a to 2-quinazolinones 1
catalyzed by PdCl2[(S)-iPr-phox]/AgBF4.[a]
Entry
ArB(OH)2 (3)
Product 4
Yield[b]
[%]
ee[c] [%]
Entry
Y
R
Product 5
Yield[b]
[%]
ee[c]
[%]
1
PhB(OH)2 (3a)
4a
4b
4c
4d
4e
4f
97
99
99
82
87
99
90
97
87
22
62
65
19
48
53
78
99.8 (R)
99.5 (R)
>99.9 (R)
99.9 (R)
99.7 (R)
99.9 (R)
99.7 (R)
99.5 (R)
99.9 (R)
99.9 (R)
99.9 (R)
99.9 (R)
99.8 (R)
99.8 (R)
99.8 (R)
99.4 (S)
1
2
3
4
5
6
7
8
9
F
CF3
5a
5b
5c
5d
5e
5f
98
96
97
92
92
70
62
0
99.9 (R)
99.4 (R)
99.8 (R)
99.8 (R)
99.9 (R)
99.2 (R)
99.5 (R)
—
2
4-MeC6H4B(OH)2 (3b)
4-MeOC6H4B(OH)2 (3c)
4-PhC6H4B(OH)2 (3d)
4-PhOC6H4B(OH)2 (3e)
3-MeC6H4B(OH)2 (3f)
3-PhC6H4B(OH)2 (3g)
3,4-OCH2OC6H3B(OH)2 (3h)
4-FC6H4B(OH)2 (3i)
4-ClC6H4B(OH)2 (3j)
3j
CF3
OMe
Cl
CF3
3
CF3
4
CF2CF3
CF2CF2CF3
CF2CF3
CF2CF2CF3
Me
5
Cl
6
F
7
4g
4h
4i
F
5g
8
Cl
9
Cl
Ph
0
—
10
11[d]
12[d,e]
13
14[d,e]
15
16
4j
4j
[a] Reaction conditions: 1 (0.10 mmol), 3a (0.20 mmol), PdCl2[(S)-iPr-phox] (1
mol%), AgBF4 (3 mol%), 1,2-dichloroethane (1.0 mL) at 65–70 °C for 12 h. [b]
Isolated yield of 5. [c] Determined by HPLC analysis with chiral stationary
phase columns. The absolute configurations are estimated by stereochemical
similarity to the reaction giving 4a.
3j
4j
4-BrC6H4B(OH)2 (3k)
3k
4k
4k
4l
2-MeC6H4B(OH)2 (3l)
2-MeOC6H4B(OH)2 (3m)
The asymmetric phenylation product (R)-4a was readily
converted into its related compounds, 6, 7, and 8, by removal of
the PMB group with trifluoroacetic acid, LiAlH4 reduction into
4m

Chemistry - A European Journal
10.1002/chem.201603105
COMMUNICATION
PdCl2[(S)-iPr-phox] (0.6 mg, 0.001 mmol), 2-quinazolinone (0.10 mmol),
and boronic acid (0.20 mmol) were placed in a Schlenk tube. To the tube,
1,2-dichloroethane (0.5 mL) was added, and then AgBF4 (0.6 mg, 0.003
mmol) in 1,2-dichloroethane (0.5 mL) was added. The mixture was stirred
at 65-70 °C for 12 h, and it was directly subjected to flash
chromatography on silica gel using hexane/ethyl acetate (4:1) as an
eluent to give adduct as a colorless solid.
tetrahydroquinazoline, and nickel-catalyzed cross-coupling with
MeMgBr, respectively, without erosion of enantiomeric purity
(Scheme 2)
Ph CF3
NH
Ph CF3
NH
Ph CF3
NH
Cl
Cl
Cl
CF3COOH
PhOMe, 70 °C
99%
LiAlH4
THF, reflux
N
H
O
N
O
N
PMB
PMB
87%
6: 99.8% ee (R)
4a: 99.8% ee (R)
7: 99.8% ee (R)
Ph CF3
NH
Acknowledgements
MeMgBr/Et2O
Me
NiCl2(dppp) (10 mol%)
benzene, reflux
We thank the National University of Singapore and the Ministry
of Education (MOE) of Singapore (R-143-000-539-133) for
generous financial support.
N
PMB
O
92%
8: 99.8% ee (R)
Keywords: asymmetric arylation • fluorinated molecules • chiral
phosphine-oxazoline ligand • 2-quinazolinone • chiral palladium
catalyst
Scheme 2. Derivatizations of (R)-4a.
The high enantioselectivity (>99% ee) of the reaction may be
rationalized by the stereochemical model shown in Scheme 3,
where the conformation of (S)-iPr-phox on palladium was drawn
based on X-ray crystal structure reported for PdCl2[(S)-iPr-
phox].[20] Thus, imine 1a coordinates to a phenyl-palladium
intermediate with its si-face, leading to (R)-4a through migratory
insertion into the phenyl–palladium bond. The coordination with
the other face (re-face) would suffer from a serious steric
interaction between the 2-quinazolinone ring of 1a and the bulky
isopropyl group on the (S)-iPr-phox ligand.
[1]
[2]
For reviews on biocatalytic transamination, see: a) Y. Xie, H. Pan, M.
Liu, X. Xiao, Y. Shi, Chem. Soc. Rev, 2015, 44, 1740; b) M. Fuchs, J. E.
Farnberger, W. Kroutil, Eur. J. Org. Chem. 2015, 6965.
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organometallic reagents to imines, see: a) S. Kobayashi, Y. Mori, J. S.
Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626; b) C. S. Marques,
A. J. Burke, ChemCatChem 2011, 3, 635; c) K. Yamada, K. Tomioka,
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Tetrahedron 2007, 63, 2541.
[3]
Selected examples on asymmetric addition of organoboron reagents to
acyclic imines. For Rh catalysis, see: a) M. Kuriyama, T. Soeta, X. Hao,
Q. Chen, K. Tomioka, J. Am. Chem. Soc. 2004, 126, 8128; b) N.
Tokunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R. Shintani, T.
Hayashi, J. Am. Chem. Soc. 2004, 126, 13584; c) D. J. Weix, Y. Shi, J.
A. Ellman, J. Am. Chem. Soc. 2005, 127, 1092; d) Y. Otomaru, A. Kina,
R. Shintani, T. Hayashi, Tetrahedron: Asymmetry 2005, 16, 1673; e)
H.-F. Duan, Y.-X. Jia, L.-X. Wang, Q.-L. Zhou, Org. Lett. 2006, 8, 2567;
f) R. B. C. Jagt, P. Y. Toullec, D. Geerdink, J. G. de Vries, B. L. Feringa,
A. J. Minnaard, Angew. Chem. 2006, 118, 2855; Angew. Chem. Int. Ed.
2006, 45, 2789; g) Z.-Q. Wang, C.-G. Feng, M.-H. Xu, G.-Q. Lin, J. Am.
Chem. Soc. 2007, 129, 5336; h) R. Shintani, M. Takeda, T. Tsuji, T.
Hayashi, J. Am. Chem. Soc. 2010, 132, 13168; i) H.-Y. Yang, M.-H. Xu,
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B. Gopula, J.-F. Syu, J.-H. Pan, T.-S. Kuo, P.-Y. Wu, J. P. Henschke,
H.-L. Wu, J. Org. Chem. 2014, 79, 8077; For Pd catalysis, see: (l) H.
Dai, X. Lu, Org. Lett. 2007, 9, 3077; (m) H. Dai, M. Yang, X. Lu, Adv.
Synth. Catal. 2008, 350, 249; n) H. Dai, X. Lu, Tetrahedron Lett. 2009,
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Lu, W. Lou, Y. Ye, H. Jiang, W. Zeng, J. Org. Chem. 2012, 77, 8541.
For Rh catalysis, see: a) T. Nishimura, A. Noishiki, G. C. Tsui, T.
Hayashi, J. Am. Chem. Soc. 2012, 134, 5056; b) Y. Luo, A. J. Carnell,
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Jiang, Z. Wang, M.-H. Xu, Org. Lett. 2015, 17, 528; e) R. Takechi, T.
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PMB
Cl
Ph
P i-Pr
Pd
CF3
N
CF3
P
HN
N
O
Pd
N
N
O
O
Cl
O
H
Cl
O
CF3
H
N
N
re-face
disfavored
si-face
favored
PMB
(R)-4a
PMB
Scheme 3. Stereochemical pathway giving (R)-4a with the Pd/(S)-iPr-phox
catalyst. Phenyl rings on the phosphorus are omitted for clarity.
In summary, 2-quinazolinone derivatives substituted with
fluoroalky groups at imine carbon were found to be reactive
ketimine substrates for palladium-catalyzed asymmetric arylation
with arylboronic acids. The enantioselectivity with a cationic
palladium/(S)-iPr-phox catalyst was very high (>99% ee) for all
the 2-quinazolinone substrates and substituted arylboronic acids.
The reported method allows for ready enantioselective synthesis
of chiral trifluoromethylated and perfluoroalkylated 2-
quinazolinones, their potential biological activities are currently
being evaluated.
[4]
Experimental Section
General procedure for palladium-catalyzed asymmetric arylation of 2-
quinazolinones.

Chemistry - A European Journal
10.1002/chem.201603105
COMMUNICATION
[5]
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Crystallographic
Data
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Chemistry - A European Journal
10.1002/chem.201603105
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B. Zhou, C. Jiang, V. R. Gandi, Y. Lu,*
T. Hayashi*
Page No. – Page No.
Palladium-Catalyzed Asymmetric
Arylation for the Preparation of
Trifluoromethylated/Perfluoroalkylate
d 2-Quinazolinone Derivatives with
High (>99%) Enantioselectivity
Asymmetric arylation of 4-fluoroalkyl-2-quinazolinone derivatives with arylboronic
acids proceeded smoothly in the presence of a cationic palladium catalyst (1 mol%)
coordinated with a chiral phosphinooxazoline (iPr-phox) ligand to give the
corresponding arylated dihydroquinazolinones in high yields and with higher than
99% ee.