Palladium-Catalyzed Highly Regio- and Enantioselective Hydroesterification of Aryl Olefins with Phenyl Formate

Article abstract of DOI:10.1021/acs.orglett.6b02467

An effective Pd-catalyzed regio- and enantioselective hydroesterification of aryl olefins with phenyl formate is described. A variety of phenyl 2-arylpropanoates can be obtained in good yields with high b/l ratios and ee's without using toxic CO gas.

Full text of DOI:10.1021/acs.orglett.6b02467

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Highly Regio- and Enantioselective
Hydroesterification of Aryl Olefins with Phenyl Formate
Jingfu Li,† Wenju Chang,† Wenlong Ren,† Jie Dai,† and Yian Shi*,†,‡
†State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Center for
Multimolecular Organic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
‡Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: An effective Pd-catalyzed regio- and enantioselective
hydroesterification of aryl olefins with phenyl formate is described. A
variety of phenyl 2-arylpropanoates can be obtained in good yields
with high b/l ratios and ee’s without using toxic CO gas.
arboxylic esters are an important class of compounds for
organic synthesis, pharmaceuticals, and fine chemicals. For
example, 2-arylpropanoates can serve as useful intermediates for
medicinally significant molecules such as nonsteroidal anti-
inflammatory agents including ibuprofen, naproxen, ketoprofen,
and fenoprofen (Figure 1).1 Asymmetric hydroesterification of
ylation process is challenging. Thus far, high ee’s have been
obtained with only limited number of styrenes.4,5 Developing the
reaction processes with both high regio- and enantioselectivity
presents a formidable challenge and is highly desirable. In
addition, the reactions have been traditionally carried out with
toxic COgasunderhighpressure and/orhightemperature, which
could hamperexploration ofthemand useinlaboratories. Herein,
we wish to report a Pd-catalyzed highly regioselective and
enantioselective hydroesterification of various aryl olefins with
phenyl formate,6 requiring no handling of toxic CO gas (Scheme
2).7
C
Scheme 2. Regio- and Enantioselective Hydroesterification
Figure 1. Examples of biologically important 2-arylpropanoic acids.
Styrene (1a)wasusedas thetest substrate fortheinitialstudies.
The reactions were carried out with 5 mol % Pd(OAc)2, a chiral
ligand (Figure 2), and 3 equiv of HCOOPh in toluene at 90 °C
(Table 1, entries 1−14). Trace ester products were detected with
ligands L1−L5 (Table 1, entries 1−5). With L6 and L7, the esters
were formed in 5−10% crude yields, favoring the linear ester (3a)
(Table 1, entries 6 and 7). However, the catalyst activity greatly
increased with L8−L14. Esters 2a and 3a were obtained in 82−
99% crude yields with a 1:1 b/l ratio and 13−62% ee’s (Table 1,
entries 8−14). With (R)-(−)-DTBM-SEGPHOS8 as the ligand,
additional Pd catalysts were subsequently examined (Table 1,
entries 15−18). A lower ee and more linear ester were obtained
with Pd(NO3)2. With Pd(TFA)2, thelinear ester(3a)was formed
almost exclusively. A small amount of esters was detected with
PdCl2 andPd(dba)2.Thereactiontemperaturewasfoundtobean
important factor for both regio- and enantioselectivity (Table 1,
olefins would provide an attractive approach to optically active
esters (Scheme 1). During the past 40 years, various asymmetric
Scheme 1. Hydroesterification of Terminal Olefins
hydroesterification (as well as hydrocarboxylation) processes
have been developed with a certain degree of success.2−5 For
example, very recently, Clarke and co-workers showed that
asymmetric hydrocaboxylation of styrene was achieved with the
Pd-phanephos catalyst in the presence of CO (30 bar) and H2O,
giving the corresponding acid in 91% ee with a 0.95 b/l ratio.5f In
their subsequent studies, the corresponding methyl ester was
obtained in 93% ee with 4:1 b/l ratio or 79% ee with >100:1 b/l
ratio when the reaction was carried out with a related catalytic
system in the presence of MeOH.5g In general, achieving high
enantioselectivity for the hydroesterification or hydrocarbox-
Received: August 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02467
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Organic Letters
Letter
a
Table 1. Studies on the Reaction Conditions
b
c
entry
Pd
ligand temp (°C) yield (%) (2a:3a)
ee (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(NO3)2
Pd(TFA)2
PdCl2
L1
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
70
50
40
50
50
50
50
50
50
50
50
50
NR
−
−
−
−
−
−
−
13
49
55
57
58
62
62
49
−
−
−
87
93
−
2
L2
NR
3
L3
NR
4
L4
NR
5
L5
NR
6
L6
5 (0:1)
10 (1:4)
87 (1:1)
90 (1:1)
82 (1:1)
93 (1:1)
99 (1:1)
97 (1:1)
99 (1:1)
88 (1:3)
62 (1:60)
NR
7
L7
8
L8
9
L9
10
11
12
13
14
15
16
17
18
19
20
21
L10
L11
L12
L13
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
L14
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NR
94 (5:1)
40 (12:1)
NR
d
22
NR
−
−
−
27
93
−
−
−
e
23
NR
f
24
12 (1:0)
99 (1:2)
g
25
h
i
26
92 (14:1)
j
27
NR
k
Figure 2. Examples of ligands examined.
28
NR
l
29
NR
m
entries 14, 19, and 20). When the reaction was carried out at 70
°C, esters 2a and 3a were formed in 94% crude yield with a 5:1 b/l
ratio and 87% ee (Table 1, entry 19). The b/l ratio and ee were
further improved when the reaction temperature was lowered to
50 °C while the yield was significantly reduced (Table 1, entry
20). However, no esters were detected at 40 °C (Table 1, entry
21). Further studies showed that the solvent had a large impact on
the reaction outcome. Little reaction occurred with THF and
EtOAc at 50 °C (Table 1, entries 22 and 23). With acetone, the
branched ester (2a) was formed predominately, but the yield was
low (Table 1, entry 24). High yield but low ee were obtained with
CH3CN (Table 1, entry 25). To our delight, ester 2a was isolated
in 92% yield with a 14:1 b/l ratio and 93% ee when the reaction
was carried out in n-hexane (Table 1, entry 26).9 Under these
reactionconditions, otherformatssuchasHCOOMe, HCOOBu,
2,6-dimethylphenyl formate, and 2,4,6-trichlorophenyl formate
were found to be ineffective (Table 1, entries 27−30).
With the optimized reaction conditions in hand, the substrate
scope for the asymmetric hydroesterification reaction was
investigated. As shown in Table 2, the reaction can be extended
to a wide variety of aryl olefins. para-Substituted styrenes were
found to be effective substrates, giving the corresponding phenyl
2-arylpropanoates in 76−93% yield and 90−95% ee (Table 2,
entries1−8)(the X-raystructure ofester 2eis shownin Figure 3).
The reaction also proceeded highly regioselectively with the b/l
ratio ranging from 11:1 to >20:1. The substituent can be both
electron-donatingand-withdrawinggroupsincludingOMe, alkyl,
phenyl, Cl, F, and CF3 groups. Similar results were obtained for
30
13 (0:1)
−
a
The reactions were carried out with 1a (0.20 mmol), HCOOPh (0.60
mmol), Pd(OAc)2 (0.010 mmol), ligand (0.020 or 0.040 mmol, P/Pd
= 4:1), and toluene (0.20 mL) in a 4.0 mL vial for 24 h unless
otherwise stated. The yield was determined from a crude reaction
mixture by H NMR with 1-methoxy-4-methylbenzene as an internal
standard. The ratio of 2a:3a was determined by H NMR analysis of
the crude reaction mixture. With THF (0.20 mL). With EtOAc
b
1
c
1
d
e
f
g
(0.20 mL). With acetone (0.20 mL). With CH3CN (0.20 mL).
h
i
j
With n-hexane (0.20 mL). Isolated yield. With HCOOMe (0.60
k
l
mmol). With HCOOBu (0.60 mmol). 2,6-Dimethylphenyl formate
(0.60 mmol). With 2,4,6-trichlorophenyl formate (0.60 mmol).
m
meta-substituted styrenes. The branched esters were isolated in
86−94% yield and 90−95% ee with a 14:1 to >20:1 b/l ratio
(Table 2, entries 9−13). A slightly lower yield and regioselectivity
were obtained for ortho-methylstyrene, possibly due to the steric
effect (Table 2, entry 14). The hydroesterification was also
effective for disubstituted styrenes, giving the corresponding ester
productsin60−90%yieldand91−93%eewitha10:1to>20:1b/l
ratio (Table 2, entries 15−17). When 2-methoxy-6-vinyl-
naphthalene was subjected to the reaction conditions, the ester
wasisolatedin74%yieldand87%eewithan8:1b/lratio(Table2,
entry 18). Heterocyclic olefins appeared to be ineffective
substrates for the reaction. For example, small amounts of
products were observed when 2-phenyl-5-vinylfuran and 4-
vinylpyridine were subjected to the reaction conditions.
B
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Table 2. Pd-Catalyzed Regio- and Enantioselective
a
Hydroesterification of Olefins
Figure 3. X-ray structure of ester 2e.
Scheme 3. Gram-Scale Synthesis
corresponding ester was isolated in 77% yield and 94% ee with
a 14:1 b/l ratio using ent-L14 as the ligand. The resulting phenyl
11
ester can be hydrolyzed with LiOH/H2O2 to give acid 4c
(ibuprofen) in 88% yield without loss of ee (Scheme 4). As an
Scheme 4. Synthetic Transformations
active intermediate, the phenyl ester could be converted to other
carboxyl acid derivatives. For example, when the ester was treated
with BnNH2/AcOH at rt for 13 h, the corresponding amide (5c)
was isolated in 86% yield and 93% ee (Scheme 4).
A precise reaction mechanism requires further study. A
plausible catalytic cycle is proposed in Scheme 5.12 The Pd(0)
is oxidatively inserted to HCOOPh to give palladium hydride
Scheme 5. Proposed Catalytic Cycle for Regio- and
Enantioselective Hydroesterification
a
The reactions were carried out with olefin (1) (0.50 mmol),
HCOOPh (1.50 mmol), Pd(OAc)2 (0.025 mmol), L14 (0.050 mmol),
b
and n-hexane (0.50 mL) in an 8.0 mL vial at 50 °C for 48 h. Isolated
c
yield. The b/l ratio was determined by 1H NMR analysis of the crude
d
reaction mixture. For entry 1, the absolute configuration was
determined by comparing the optical rotation with the reported
value.10a For entries 3, 6, 8, and 18, the absolute configurations were
determined by comparing the optical rotations of the corresponding
acids with the reported values.10b For entries 2, 4, 5, 7, and 9−17, the
absolute configurations were tentatively assigned by analogy.
As illustrated in Scheme 3, the asymmetric hydroesterification
reaction can be carried out on a gram scale with 1-isobutyl-4-
vinylbenzene as the substrate. The (S)-enantiomer of the
C
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complex 6, which was converted to palladium carbonyl complex 7
upon rearrangement. The hydropalladation of the olefin by 7 led
tocomplexes8and9,whichgaveacylpalladiumcomplexes10and
11 upon migratory insertion. Upon reductive elimination, 10 and
11 were converted to esters 2 and 3 with regeneration of the Pd
catalyst. In the current reaction process, ester 2 was formed as a
major product with L14 as the ligand. The regioselectivity was
likely due to the fact that complex 8 could be stabilized by the
phenyl group and favored over 9.12
The reactions were also carried out with CO gas and phenol
instead of phenyl formate (Scheme 6). While similar
enantioselectivities were observed as compared to phenyl
formate, lower yields were obtained. The b/l ratio was found to
be dependent upon the amount of phenol.
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ASSOCIATED CONTENT
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S
* Supporting Information
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TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02467.
Experimental procedures, characterization data, NMR
spectra (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Yian.Shi@colostate.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21472083) and Nanjing University for
the financial support.
D
DOI: 10.1021/acs.orglett.6b02467
Org. Lett. XXXX, XXX, XXX−XXX