Iron-Catalyzed Enantioselective Cross-Coupling Reactions of α-Chloroesters with Aryl Grignard Reagents

Article abstract of DOI:10.1021/jacs.5b02277

The first iron-catalyzed enantioselective cross-coupling reaction between an organometallic compound and an organic electrophile is reported. Synthetically versatile racemic α-chloro- and α-bromoalkanoates were coupled with aryl Grignard reagents in the presence of catalytic amounts of an iron salt and a chiral bisphosphine ligand, giving the products in high yields with acceptable and synthetically useful enantioselectivities (er up to 91:9). The produced α-arylalkanoates were readily converted to the corresponding α-arylalkanoic acids with high optical enrichment (er up to >99:1) via simple deprotections/recrystallizations. The results of radical probe experiments are consistent with a mechanism that involves the formation of an alkyl radical intermediate, which undergoes subsequent enantioconvergent arylation in an intermolecular manner. The developed asymmetric coupling offers not only facile and practical access to various chiral α-arylalkanoic acid derivatives, which are of significant pharmaceutical importance, but also a basis of controlling enantioselectivity in an iron-catalyzed organometallic transformation. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b02277

Subscriber access provided by NEW YORK UNIV
Article
Iron-Catalyzed Enantioselective Cross-Coupling
Reactions of #-Chloroesters with Aryl Grignard Reagents
Masayoshi Jin, Laksmikanta Adak, and Masaharu Nakamura
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 May 2015
Downloaded from http://pubs.acs.org on May 8, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Iron-Catalyzed Enantioselective Cross-Coupling Reactions
of α-Chloroesters with Aryl Grignard Reagents
Masayoshi Jin,†,‡ Laksmikanta Adak,‡ and Masaharu Nakamura*,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Process Technology Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya,
Hiratsuka, Kanagawa 254-0014, Japan
‡International Research Center for Elements Science, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, and
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
ABSTRACT: The first iron-catalyzed enantioselective cross-coupling reaction between an organometallic compound and an
organic electrophile is reported. Synthetically versatile racemic α-chloro and α-bromoalkanoates were coupled with aryl
Grignard reagents in the presence of catalytic amounts of an iron salt and a chiral bisphosphine ligand, giving the products in
high yields with acceptable and synthetically useful enantioselectivities (er up to 91:9). The produced α-arylalkanoates were
readily converted to the corresponding α-arylalkanoic acids with high optical enrichment (er up to >99:1) via simple
deprotections/recrystallizations. The results of radical probe experiments are consistent with a mechanism that involves the
formation of an alkyl radical intermediate, which undergoes subsequent enantioconvergent arylation in an intermolecular
manner. The developed asymmetric coupling not only offers facile and practical access to various chiral α–arylalkanoic acid
derivatives, which are of significant pharmaceutical importance, but also a basis of controlling enantioselectivity in
iron-catalyzed organometallic transformation.
INTRODUCTION
based on the fact that there is the one precedent in literature
for such a reaction.8b
Transition-metal-catalyzed enantioselective cross-coupling
reactions are powerful tools in the asymmetric synthesis of
functional chiral molecules. Recent progress in the cross
In line with our research regarding the precise control of
b
8 ,9
iron catalysis in C–C bond formation, we present the first
example of iron-catalyzed enantioselective cross coupling
facilitated by an easily accessible P-chiral bisphosphine
1
2
coupling of various alkyl halides has led to the development
of a new class of enantioconvergent cross-coupling reactions,
which enable the construction of various molecular
frameworks and the catalytic installation of asymmetric
carbon centers in one operation from racemic substrates.
During the past decade, significant success has been achieved
10
ligand, BenzP*. Specifically, synthetically versatile racemic
α-chloroalkanoates were cross coupled with aryl Grignard
reagents to afford optically active α-arylalkanoates (eq 3)
and the related alkanoic acids, upon simple deprotection,
which are of particular pharmaceutical and biological
importance as nonsteroidal anti-inflammatory analgesics or
3
by Fu and coworkers using nickel catalysts (e.g. eq 1).
However, despite the rapid and notable development of
11
4
5
6
cyclooxygenase inhibitors.
iron, cobalt, and copper catalysts for the coupling
reactions of alkyl halides, the viability of these metal catalysts
in the enantioconvergent cross coupling of alkyl halides
Previous work: Enantioconvergent coupling with aryl Grignard reagents
Nickel-catalyzed coupling: Fu (2010)3a
NiCl2·glyme (7 mol %)
R
R
remains virtually unexplored; only one example of
Co-catalyzed asymmetric cross coupling between
a
chiral bisoxazoline L7 (9 mol %)
O
O
(1)
(2)
ArMgBr
+
Br
Ar
DME, –60 °C
R'
R'
α-bromoesters and aryl Grignard reagents was reported
recently (eq 2). In particular, iron has never been used in
Cobalt-catalyzed coupling: Zhong and Bian (2014)7b
7
CoI2 (10 mol %)
R
R
chiral bisoxazoline L8 (12 mol %)
the catalytic, enantioselective coupling of organometallic
+
ArMgBr
Br
CO2R'
Ar
CO2R'
8
THF, –80 °C
compounds, while its toxicologically benign nature and
This work: Iron-catalyzed enantioconvergent coupling with aryl
cost-effectiveness present clear practical advantages in the
production of optically active fine chemicals, such as
pharmaceutical and agricultural compounds. Furthermore,
the application of iron catalysts to asymmetric
organometallic transformation has proven to be challenging
Grignard reagents
Fe(acac)3 (3 mol %)
Me
tBu
tBu
Me
R
R
L1 (6 mol %)
P
P
ArMgBr
(3)
CO2R'
Ar
Cl
CO2R'
+
THF, 0 °C
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 9
1
2
3
4
5
6
7
8
9
Table 1. Screening of Reaction Conditions for Iron-Catalyzed
RESULTS AND DISCUSSION
Enantioselective Cross Coupling of 1a–1e with PhMgBr (2a) a
Asymmetric Cross-Coupling Reactions of α-Halo-
alkanoates with Grignard Reagents. We began our study
by exploring effective chiral ligands and conditions for the
Fe(acac)3 (3 mol %)
ligand (6 mol %)
OR
Ph
1a–1e
racemic
PhMgBr 2a
(2.0 equiv)
+
solvent, temp.
O
coupling of tert-butyl α-bromopropionate 1a with PhMgBr
2a in the presence of catalytic amounts of Fe(acac)3 and a
ligand (scheme in Table 1). Based on our previous success in
controlling iron-catalyzed cross-coupling reactions using the
SciOPP ligand,9e we examined various chiral bisphosphine
ligands, and observed a certain level of chiral induction when
using (R,R)-QuinoxP* L2 (up to 84:16 er, Table 1, entries
1–9). The coupling reaction proceeded in the temperature
range –40 to 40 °C, to give the desired product; the optimal
selectivity (83:17 er) was observed at both 0 and –40 °C
(entries 2 and 3). The choice of the solvent was critical in
this reaction: ethereal solvents and toluene generally
afforded the coupling products with good selectivities
(74:26–84:16 er; entries 2 and 4–7); however, the use of
3
slow addition (1 h)
temp
erc
entry
1
ligand
solvent
THF
%yieldb
(°C)
40
0
(config.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1a L2
1a L2
1a L2
1a L2
1a L2
1a L2
1a L2
1a L2
1a L2
1a L1
1a L3
1a L4
1a L5
1a L6
1a L7
1a L8
1a L9
1a none
1b none
1b L1
1c L1
1d L1
1e L1
1e L1
1b L1
1b L1
39
66
63
33
50
42
61
2
78:22 (S)
83:17 (S)
83:17 (S)
74:26 (S)
81:19 (S)
84:16 (S)
80:20 (S)
60:40 (S)
59:41 (S)
85:15 (S)
79:21 (S)
62:38 (R)
52:48 (S)
50:50
2
THF
3
THF
–40
0
4
toluene
MTBE
DME
1,4-dioxane
DMPU
NMP
THF
5
0
6
0
7
0
8
0
9
0
11
91
69
75
51
39
80
78
10
32
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24d
25
26
0
N,N'-dimethylpropyleneurea
(DMPU)
and
THF
0
N-methylpyrrolidinone (NMP) as solvents resulted in low
yields with low er, suggesting that these strongly
coordinating solvents displace the chiral ligands from iron
centers, facilitating the formation of ferrate species4d (entries
8 and 9).
We next examined various chiral ligands, shown in Chart 2,
and eventually found that the cross coupling of 1a with 2a
proceeded in the presence of Fe(acac)3/(R,R)-BenzP* (L1)
THF
0
THF
0
THF
0
THF
0
76:24 (R)
77:23 (R)
50:50
THF
0
THF
0
THF
0
50:50
to give the product in 91% yield, with
enantioselectivity of 85:15 er (entry 10). The use of
Chart 1. α-Haloalkanoates
a higher
12
THF
0
NA
THF
0
91
75
40
82
14
62
31
87:13 (S)
83:17 (S)
82:18 (S)
90:10 (S)
58:42 (S)
87:13 (S)
78:22 (S)
THF
0
R'
OtBu
OR'
O
THF
0
Br
Cl
Cl
O
O
O
THF
0
1a
R' = tBu: 1b
R' = iPr: 1c
R' = Et : 1d
R' = Me: 1e R' = Et: 1f
R' = iBu: 1g R' = MeOCH2: 1h
THF
0
THF
–20
–40
Chart 2. SciOPP and Examined Chiral Ligands
THF
tBu
tBu
aReactions were carried out on a 0.50 mmol scale using 3 mol %
Fe(acac)3, 6 mol % ligand, and 2.0 equiv of PhMgBr at 0 °C.
PhMgBr was slowly added over 1.0 h, using a syringe pump, unless
otherwise noted. bGC yields obtained using undecane as an internal
tBu
tBu
tBu
tBu
Me
tBu
Me
N
P
N
P
P
P
P
P
Me
tBu
tBu
Me
tBu
tBu
tBu
c
SciOPP
H
(R,R)-BenzP*: L1
(R,R)-QuinoxP*: L2
standard. The er values were determined via chiral HPLC analysis.
The absolute configurations are shown in parentheses. dPhMgBr
was added in one portion.
iPr
P
Me
tBu
Me
iPr
P
P
H
P
P
iPr
tBu
tBu
(S,S',R,R')-Tangphos (L3), which has a rigid aliphatic
backbone and P-chirality, provided the product with
comparable selectivity (79:21 er, entry 11). However, the
use of (R,R)-tBu-BisP* (L5), which contains a flexible
P
tBu
iPr
(S,S)-iPr-DuPhos: L4
(R,R)-tBu-BisP*: L5
(S,S',R,R')-Tangphos: L3
Ph
Ph
ethylene backbone, and (S,S)-iPr-DuPHOS (L4),
a
O
O
P(p-tol)2
P(p-tol)2
N
N
MeHN
NHMe
non-P-chiral ligand, afforded the products with substantially
lower enantioselectivities (entries 12 and 13), suggesting
that the o-phenylene moiety or a rigid backbone connecting
the P-stereogenic centers is important. Axially chiral ligands
R'
R'
bisoxazoline (BOX)
R' = Ph : L7
L9
(R)-T-BINAP: L6
R' = Bn : L8
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Table 2. Effects of Catalyst Amount and Metal Salts on
Enantioselective Cross Couplinga
such as (R)-T-BINAP (L6), which was effective in
iron-catalyzed enantioselective carbometalation reactions,
8b
gave the racemic product (entry 14, and the Supporting
Information). Nitrogen-containing ligands such as L7, L8,
and L9 showed moderate or no chiral induction in the
iron-catalyzed coupling, although these ligands are reported
to achieve high enantioselectivities in nickel-3a,k or
cobalt-catalyzed7b cross-coupling reactions (entries 15–17).
Background, non-stereoselective arylation of 1a was
observed in the absence of chiral ligands (entry 18).9d
When chloropropionate 1b was used instead of 1a, a
slightly higher enantioselectivity was observed under the
same reaction conditions (87:13 er, entry 20) because of the
lack of the racemic background arylation (entry 19).
Furthermore, 2,3,3-trimethylbut-2-yl 2-chloropropionate
(Theptyl 2-chloropropionate; 1e) was arylated with optimal
enantioselectivity (90:10 er) in 82% yield (entry 23), but
lower er and yields were observed in the coupling of the
sterically less demanding isopropyl ester 1c or ethyl ester 1d
metal salt (3 mol %)
OR
L1 (6 mol %)
Ph
1b or 1e PhMgBr 2a
+
(2.0 equiv)
racemic
THF, 0 °C
O
slow addition (1 h)
3
metal salt
erc
L1
entry
1
%yieldb
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(mol %)
(mol %)
(config.)
1
1b Fe(acac)3 (3)
1b Fe(acac)3 (3)
1b Fe(acac)3 (3)
1b Fe(acac)3 (1)
1b Fe(acac)3 (5)
1e Fe(acac)3 (3)
1e Co(acac)3 (3)
1e Ni(acac)2 (3)
1e Cu(acac)2 (3)
1e Pd(acac)2 (3)
6
3
91
36
85
65
89
82
49
0
87:13 (S)
2
80:20 (S)
87:13 (S)
87:13 (S)
87:13 (S)
90:10 (S)
68:32 (S)
NA
3
9
4
2
5
10
6
6
7
6
8
6
9
6
0
NA
(entries 21 and 22). As shown in entry 24, slow addition of
10
6
0
NA
4f,9a,9h
the Grignard reagent
was essential to achieve a high
aReactions were carried out on a 0.50 mmol scale using 3 mol %
metal salt, 6 mol % ligand, and 2.0 equiv of PhMgBr at 0 °C.
yield and enantioselectivity, and to avoid over-reduction of
iron species or detachment of the formed aryl ferrate species
from the chiral ligand (see the discussion regarding the
time-course study described below). Again, the best er was
obtained at 0 °C and no low-temperature conditions were
required (entries 25 and 26).
Table 2 shows the effects of the catalyst loading and other
metal salts on the enantioselective cross-coupling reaction.12
A 1:1 ratio of iron:ligand also achieved substantial chiral
induction to give the corresponding product in 80:20 er,
while slightly higher yields and er were observed by using
excess amounts of ligand to iron (entries 1–3). We propose
that an iron species possessing one chiral ligand is capable of
inducing enantioselectivity (see also non-linear effect in
mechanistic considerations). The catalyst loading affected
the chemical yield, but not the enantioselectivity, in the
presence of a 1:2 ratio of iron:ligand (entries 1, 4, and 5).
b
PhMgBr was slowly added over 1.0 h, using a syringe pump. GC
c
yields obtained using undecane as an internal standard. The er
values were determined via chiral HPLC analysis. The absolute
configurations are shown in parentheses.
Ortho-substituted aryl Grignard reagents reacted slowly
(entries 8, 11, and 15), while the use of 9-phenanthryl
Grignard reagent resulted in a good yield and reasonable
selectivity (entry 16). As in entries 17–22, electron-deficient
aryl Grignard reagents reacted to give coupling products in
relatively high er of ca. 9:1 and mostly in good yield with the
exception of 3,4,5-trifluorophenyl Grignard reagent (25 %
yield). Although chloroarenes are known to react with
Grignard reagents via iron catalysis, a chlorinated aryl group
was installed with the chloro group remaining intact (entries
14
21 and 22).4c,
Theptyl 2-chlorobutyrate and
(1f and 1g) were
Full conversion of 1e and
a high yield with good
4-methyl-2-chloropentanoate
enantioselectivity was obtained using 3 mol% of Fe(acac)3
and 6 mol% of (R,R)-BenzP* (entry 6). Co(acac)3 gave a low
yield and er (entry 7), and other transition-metal
acetylacetonates did not afford the desired products under
the present conditions (entries 8–10).
cross-coupled to afford the products in good yields and with
adequate er, especially when a 4-fluorophenyl Grignard
reagent was employed (entries 24–27). The use of
heteroaromatic Grignard reagents such as 2-thienyl- and
3-pyridylmagnesium bromide did not result in the formation
of cross-coupled products under the present conditions. The
use of an alkenyl Grignard reagent furnished the
The data presented in Table 3 show the scope of the
developed coupling reaction in the synthesis of a range of
optically active α-arylalkanoic acid derivatives. The reactions
of 1e with various aryl Grignard reagents are shown in
entries 1–22. Electron-rich and neutral aryl Grignard
reagents reacted to give the desired products in high yields
with adequate enantioselectivities (entries 1–7, and 9–14). A
terminal olefin moiety, which often undergoes isomerization
corresponding α-chiral β,γ-unsaturated ester in 52% yield
with 91:9 er (entry 28).
As shown in Table 4, the obtained cross-coupling
products were readily deprotected under acidic conditions
without any concomitant decrease in optical purity.
Furthermore, the resulting 2-arylpropionic acids were
enantioenriched by co-crystallization with octylamine;
(S)-2-arylpropionic acids, including dexibuprofen and
13
to an internal olefin under transition-metal catalysis,
remained intact under the present conditions (entry 13).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
1
2
3
4
Table 3. Scope of Iron-Catalyzed Enantioselective Coupling of
α-Chloroalkanoatesa
Table 4. Enantioenrichment of Cross-Coupling Product after
Hydrolysisa
crystallization
with octyl–NH2
R'
5
6
7
8
R'
Fe(acac)3 (3 mol %)
R'
OR
TFA (5 equiv)
OH
O
H3N octyl
L1 (6 mol %)
Ar
Ar
1e–1h
racemic
ArMgBr 2
3
+
(2.0 equiv)
Ar
CH2Cl2, rt, 1 h
THF, 0 °C
O
slow addition (1 h)
O
O
3 (R = Theptyl)
4
4'
product
(major enantiomer)
% yield (er)b
72 (>99:1)
9
entry
1
% yield (er)b
% yield (er)b
entry
1
product
entry
15
product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OR
O
H3N octyl
OR
82 (90:10)
31 (58:42)
O
O
O
O
O
O
OR
H3N octyl
OR
2
72 (>99:1)
65 (>99:1)
2c
90 (86:14)
75 (87:13)
16
17
81 (74:26)
87 (91:9)
O
Ph
O
Ph
OH
3
4
OR
OR
OR
3c
O
O
O
F
O
H3N octyl
74 (93:7)
46 (97:3)
75 (94:6)
OR
4c
79 (87:13)
78 (88:12)
78 (88:12)
70 (89:11)
0 (NA)
18
19
20
21
22
83 (91:9)
89 (90:10)
25 (90:10)
83 (91:9)
88 (90:10)
O
MeO
F
F
O
MeO
Et
F
O
H3N octyl
5
OR
OR
OR
OR
OR
OR
O
5
F
F
O
O
O
O
iBu
Me2N
F
O
H3N octyl
6
F
F
O
6
aReactions were carried out on a 2 mmol scale. bThe er values
O
MeO
F
were determined via chiral HPLC analysis.
MeO
7
15
naproxen, were obtained in optically pure or highly
enriched forms (entries 1–4). 2-Arylbutyric acid and
2-aryl-4-methylpentanoic acid were also obtained in optically
active forms using this method (entries 5 and 6).
F
O
Cl
OMe
OR
OR
8
O
Cl
O
Cl
OMe
OR
OR
Mechanistic Considerations. In order to gain insights into
the nature of the present cross-coupling reaction, we
conducted a set of elementary mechanistic studies. Results of
the time-course analysis of the cross-coupling reaction of 1e
and PhMgBr (2a) under the standard conditions are shown
in Figure 1. No reaction of 1e was observed during addition
of the first 0.12 equivalents [i.e., 4 equivalents with respect to
Fe(acac)3] of PhMgBr, and biphenyl was obtained in 1%
9
89 (87:13)
84 (88:12)
38 (84:16)
23
24
25
42 (77:23)
67 (88:12)
69 (90:10)
O
O
Et
OR
OR
10
11
O
O
Et
OR
OR
O
O
F
iBu
OR
yield as the sole product, corresponding to the partial
reduction of Fe(acac)3 to an iron(II) species
OR
12
13
74 (89:11)
92 (86:14)
26
27
38 (74:26)
72 (91:9)
16,17
prior to the
O
O
commencement of the cross-coupling reaction. Following
the addition of more PhMgBr, the coupling reaction initiated
and the conversion of the substrate to the corresponding
coupling product, 3, was observed. The steric hindrance
caused by the BenzP* ligand (L1), along with the limited
concentration of the slowly added Grignard reagent possibly
iBu
OR
OR
O
O
F
OR
OR
14
90 (88:12)
28
52 (91:9)
O
O
aReactions were carried out on a 0.50–1.0 mmol scale using 3
mol % Fe(acac)3 and 6 mol % ligand L1 unless otherwise noted.
ArMgBr was slowly added over 1.0 h. bThe er values were
determined via chiral HPLC analysis. Absolute configurations were
inferred from the optical rotation by comparison with the know
compounds (see the Supporting Information). c3.0 mmol scale.
suppressed the further reduction of the iron(II) species to
18 , 19
iron(I) or iron(0).
During the course of the
cross-coupling reaction, no kinetic resolution of racemic 1e
was detected and the enantioselectivity of product
remained constant, suggesting the selectivity determining
3
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Fe(acac)3 (3 mol %)
Scheme 1. Cross-Coupling Reaction Using Radical
Probe Substrate (1i; R = Theptyl)
O
O
PhMgBr 2a
(R,R)-BenzP* (6 mol %)
+
Cl
Ph
(2.0 equiv)
THF, 0 ˚C
O
O
slow addition (1 h)
1e
racemic
3
Fe(acac)3 (3 mol %)
(R,R)-BenzP*(6 mol %)
(a)
PhMgBr (2.0 equiv)
OR
OR
slow addition (1 h)
THF, 0 °C
Ph
OR
Cl
+
Ph
O
O
O
1i
5
6
12% (85:15 er)
40% (racemic)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
anti/syn= 58/42
OR
OR
O
O
7
7'
(b)
Figure 3. Dependence of ratio of uncyclized product 5 to
cyclized product 6 on iron catalyst loading.
Figure 1. GC and HPLC traces of cross-coupling reaction of
1e with PhMgBr (2a): (a) red, blue, and green lines show
recovery of substrate 1e, yield of product 3, and yield of
biphenyl, respectively. (b) Red and blue lines show
enantiomeric excesses of 1e and product 3, respectively.
The use of radical probes provided more detailed
mechanistic insights into the developed coupling reaction.
As shown in Scheme 1, an α-chloroalkanoate with a terminal
alkenic moiety, 1i, reacted with PhMgBr to afford a mixture
of direct arylation (uncyclized) product 5 and diastereomers
of cyclized product 6, consistent with the formation of alkyl
step is the C–C bond forming reaction (Figure 1, b).
The enantioselectivity of product 3 was found to be
directly proportional to the enantiomeric excess of the chiral
ligand and non-linear effects (NLEs) 20 in the chiral
induction were not observed (Figure 2). This result supports
the conclusion that the enantioselectiviy is determined under
the influence of a chiral phosphine ligand that coordinates to
an iron center, which was also suggested by the effective
chiral induction observed in the presence of a 1:1 ratio of L1
and Fe(acac)3 (Table 2, entry 2).
radical intermediate from 1i as previously proposed for
9a–e
racemic iron-catalyzed cross-coupling reactions.
The
radical probe reaction with various catalyst loadings of
Fe(acac)3 and L1 (Figure 3) resulted in the observation of a
first order relationship between the ratio of 5/6 and the
catalyst loading. This supports the possibility that once
formed, the alkyl radical intermediate escapes from the
solvent
cage
and
undergoes
the
sequential
cyclization/arylation or direct arylation with an aryliron
species which is different from the one that reacts to generate
3h,21
the alkyl radical intermediate.
It should be noted that product
5 was obtained
enantioselectively (85:15 er), whereas 6 was obtained as a
racemic mixture of diastereomers. This observation indicates
that the cyclization reaction (7 to 7’) proceeded in the
outer-sphere of the chiral environment created by L1,
supporting the out-of-cage mechanism. This result is
consistent with the enantioconvergent arylation proceeding
via an alkyl radical intermediate as reported for Ni-catalyzed
22
Figure 2. Dependence of enantiomeric excess of product 3
on that of (R,R)-BenzP*.
enantioconvergent cross-coupling reactions of α-halo
3h,j
sulfonamides and sulfones.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
1
2
3
4
5
6
7
8
9
X = Ar or halogen
Fe(acac)3 catalyzed the arylation reaction under mild
MgBrCl
X
P*
P*
FeII
A
conditions. Although there is still room for improvement in
the enantioselectivity, we hope that the preliminary findings
described here will advance the development of
enantioselective carbon–carbon bond forming reactions by
using iron catalysts and various organometallic reagents.
Such reactions show promise for the sustainable synthesis
and production of chiral functional molecules such as
pharmaceuticals and agrochemicals that will continuously
support our society.
ArMgBr
ArMgBr
Ar
B
X
P*
P*
R
FeII
D
Cl
MgBrCl
Cl
CO2R'
P*
P*
X
P*
FeI
X
FeII
Cl
X
Cl
P*
P*
FeIII
B
E
cycle 1
cycle 2
D
Ar
P*
in-cage
out-of-cage
favorable
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
R
R
•
Ar
CO2R'
Ar
CO2R'
CO2R'
A
C
EXPERIMENTAL SECTION
Figure 4. Possible catalytic cycles.
Typical Procedure for Enantioselective Cross
Coupling
Figure 4 shows a plausible mechanism that is in good
agreement with the present and previous experimental
observations. The catalytic cycle starts from divalent iron
species A, which is generated from the partial reduction of
Fe(acac)3 in the presence of L1, the limited concentration of
the Grignard reagent, and an excess amount of the
α-haloester substrate. This species A abstracts a halogen
from the substrate to generate alkyl radical intermediate C
and iron species B. We proposed previously the mechanism
depicted in Cycle 1, where arylation of alkyl radical C takes
place with the aryl group of B in the solvent cage to give the
arylation product and an iron complex D, which undergoes
ArMgBr (0.50–1.0 M solution in THF, 2.0 equiv) was slowly
added over 60 min, using a syringe pump, to a THF solution
(1.0 mL) of Fe(acac)3 (5.3 mg, 3 mol %), (R,R)-BenzP* (8.5
mg, 6 mol %), and 2,3,3-trimethylbut-2-yl 2-chloroalkanoate
(0.50 mmol) at 0 °C. After stirring at that temperature for 10
min, the resulting mixture was quenched with a 1.0 M
aqueous solution (1.0 mL) of hydrochloric acid and
extracted with MTBE (3.0 mL × 3). The organic layer was
dried over Na2SO4, evaporated in vacuo, and the residue was
purified by silica-gel column chromatography and
gel-permeation chromatography if necessary.
transmetalation with ArMgBr to regenerate A (in-cage
9b,c,e
Representative Procedure for Deprotection and
Crystallization: Enantioenrichment of
Dexibuprofen
mechanism).
However, the observation of the first order
relationship between the ratio of 5/6 and the catalyst loading
is not consistent with this cycle. We therefore favor an
alternative process based on a bimetallic mechanism.19d,21
Cycle 2 shows the favorable out-of-cage mechanism, in
which alkyl radical intermediate C escapes from the solvent
cage to react with another divalent iron(II) species A to form
TFA (0.69 mL, 5.0 equiv) was added dropwise to a CH2Cl2
solution
(5.5
mL)
of
2,3,3-trimethylbut-2-yl
(S)-2-[4-(2-methylpropyl)phenyl]propionate (550 mg, 1.8
mmol) at room temperature, and the mixture was stirred at
that temperature for 1 h. A crude white solid (398 mg,
quantitative) was obtained after removing the volatile
solvents under reduced pressure. CH3CN (27.5 mL) and
octylamine (299 µL, 1.0 equiv) were added to the crude
solid, and the mixture was heated to 60 °C to dissolve the
solid entirely. The mixture was allowed to cool to room
temperature, with stirring, and white crystals formed. After
stirring for 1 h, the white crystals were collected by filtration,
washed with CH3CN (1.7 mL), and dried under reduced
pressure (454 mg, 75%, 92:8 er). Recrystallization from
CH3CN (27.5 mL) furnished optically pure crystals (394 mg,
65%, >99:1 er).
the coupling product, possibly by forming iron(I) species E,
18a,b
which has one bulky L1 ligand.
Comproportionation of
complexes B and E forms iron(II) species A and D or
halogen abstraction of E from the α-haloester forms D and
radical intermediate C, which may participate in a chain
reaction process.21c Although we cannot identify the
predominant pathway of the generation of alkyl radical
intermediate C, the arylation of the radical intermediate
takes place with iron(II) species A possessing chiral ligand
L1, and hence, in an enantioselective manner.
CONCLUSION
In summary, we developed the first iron-catalyzed
enantioselective cross-coupling reaction, which provides
ASSOCIATED CONTENT
Supporting Information
facile access to optically active α-arylalkanoic acid derivatives
from racemic α-haloesters and a range of aryl Grignard
reagents. The use of rigid P-chiral bisphosphine ligands, such
as BenzP*, was critical to achieve high reactivity and
substantial chiral induction. Moreover, the developed
protocol can be considered expedient and practical; a simple
mixture of the easily accessible BenzP* and easy-to-handle
Experimental
details,
procedures,
and
compound
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
1
2
3
4
5
masaharu@scl.kyoto-u.ac.jp
Notes
The authors declare no competing financial interests.
Gower, N. J.; Haddow, M. F.; Harvey, J. N.; Murphy, D. M.; Neeve,
E. C.; Nunn, J. Angew. Chem. Int. Ed. 2013, 52, 1285. (h) Bedford,
R. B.; Brenner, P. B.; Carter, E.; Carvell, T. W.; Cogswell, P. M.;
Gallagher, T.; Harvey, J. N.; Murphy, D. M.; Neeve, E. C.; Nunn, J.;
Pye, D. R. Chem. Eur. J. 2014, 20, 7935.
6
7
8
9
ACKNOWLEDGMENT
This paper is dedicated to Professor I. Ojima on his 70th
birthday. This work was funded in part by a grant from the JSPS
through the “Funding Program for Next Generation
World-Leading Researchers (NEXT Program),” initiated by the
Council for Science and Technology Policy, and also by the JST
through Core Research for Evolutional Science and Technology
(CREST 1102545). This work was also supported by JSPS
KAKENHI Grant Number 26620085. LA is grateful for a
research fellowship from JSPS and the MEXT project
“Integrated Research on Chemical Synthesis”. The authors
thank Prof. Tsuneo Imamoto (Chiba University and Nippon
Chemical Industry) for kindly gifting the chiral ligands.
(5) Reviews: (a) Gosmini, C.; Bégouin, J.-M.; Moncomble, A.
Chem. Commun., 2008, 3221. (b) Cahiez, G.; Moyeux, A. Chem.
Rev. 2010, 110, 1435. (c) Iwasaki, T.; Takagawa, H.; Okamoto, K.;
Singh, S. P.; Kuniyasu, H.; Kambe, N. Synthesis 2014, 46, 1583.
Selected papers: (d) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am.
Chem. Soc. 2006, 128, 1886. (e) Iwasaki, T.; Takagawa, H.; Singh, S.
P.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2013, 135, 9604.
(6) Selected papers: (a) Terao, J.; Todo, H.; Begum, S. A.;
Kuniyasu, H.; Kambe, N. Angew. Chem. Int. Ed. 2007, 46, 2086. (b)
Shen, R.; Iwasaki, T.; Terao, J.; Kambe, N. Chem. Commun., 2012,
48, 9313. (c) Yang, C.-T.; Zhang, Z.-Q.; Liang, J.; Liu, J.-H.; Lu,
X.-Y.; Chen, H.-H.; Liu, L. J. Am. Chem. Soc. 2012, 134, 11124. For
enantioselective allylic cross-couplings see: (d) Hornillos, V.; Pérez,
M.; Fañanás-Mastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2013, 135,
2140. (e) Hojoh, K.; Shido, Y.; Ohmiya, H.; Sawamura, M. Angew.
Chem. Int. Ed. 2014, 53, 4954.
(7) (a) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew. Chem. Int. Ed.
2002, 41, 4137. (b) Mao, J.; Liu, F.; Wang, M.; Wu, L.; Zheng, B.;
Liu, S.; Zhong, J.; Bian, Q.; Walsh, P. J. J. Am. Chem. Soc. 2014, 136,
17662. For the use of chiral bisoxazoline ligands in Ni-catalyzed
asymmetric cross coupling see ref. 3a.
(8) (a) Gopalaiah, K. Chem. Rev. 2013, 113, 3248. (b) Nakamura,
M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978. (c)
Egami, H.; Matsumoto, K.; Oguma, T.; Kunisu, T.; Katsuki, T. J.
Am. Chem. Soc. 2010, 132, 13633. One enantioselective C–C bond
formation via organometallic addition has been reported in 8b. The
enantioselective oxidative cross- and homocoupling of 2-naphthols
was reported in 8c and the references cited therein.
(9) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686. (b) Hatakeyama, T.; Kondo, Y.;
Fujiwara, Y.; Takaya, H.; Ito, S.; Nakamura, E.; Nakamura, M.
Chem. Commun. 2009, 1216. (c) Hatakeyama, T.; Hashimoto, T.;
Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono,
T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132, 10674. (d) Jin, M.;
Nakamura, M. Chem. Lett. 2011, 40, 1012. (e) Hatakeyama, T.;
Fujiwara, Y.; Okada, Y.; Itoh, T.; Hashimoto, T.; Kawamura, S.;
Ogata, K.; Takaya, H.; Nakamura, M. Chem. Lett. 2011, 40, 1030.
(f) Hatakeyama, T.; Okada, Y.; Yoshimoto, Y.; Nakamura, M.
Angew. Chem. Int. Ed. 2011, 50, 10973. (g) Hatakeyama, T.;
Hashimoto, T.; Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike,
H.; Nakamura, M. Angew. Chem. Int. Ed. 2012, 51, 8834. (h)
Ghorai, S. K.; Jin, M.; Hatakeyama, T.; Nakamura, M. Org. Lett.
2012, 14, 1066. (i) Kawamura, S.; Kawabata, T.; Ishizuka, K.;
Nakamura, M. Chem. Commun. 2012, 48, 9376.
(10) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.;
Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. J. Am. Chem. Soc. 2012,
134, 1754.
(11) (a) Landoni, M. F.; Soraci, A. Curr. Drug Metab. 2001, 2, 37.
(b) Duggan, K. C.; Hermanson, D. J.; Musee, J.; Prusakiewicz, J. J.;
Scheib, J. L.; Carter, B. D.; Banerjee, S.; Oates, J. A.; Marnett, L. J.
Nat. Chem. Biol. 2011, 7, 803.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) (a) Uozumi, Y. In Comprehensive Chirality, Shibasaki, M., Ed.;
Carreira, E. M., Yamamoto H., Eds.-in-Chief; Elsevier: Oxford,
2012; vol. 4, p. 18. (b) Sarli, V. In Stereoselective Synthesis of Drug
and Natural Products, Andrushko, V., Andrushko, N. Eds.; John
Wiley and Sons, Inc., Hoboken, 2013; vol 1, p. 369.
Enantioconvergent asymmetric couplings of achiral secondary alkyl
Grignard and zinc reagents are described in 1a. (c) Taylor, B. L. H.;
Jarvo, E. R. Synlett, 2011, 2761. (d) Swift, E. C.; Jarvo, E. R.
Tetrahedron, 2013, 69, 5799. Stereospecific asymmetric
cross-couplings are reviewed in refs. 1c and 1d.
(2) (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346,
1525. (b) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545. (c)
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2656.
(3) Leading references: with Grignard reagents: (a) Lou, S.; Fu, G.
C. J. Am. Chem. Soc. 2010, 132, 1264. With organozinc reagents:
(b) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594. (c)
Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem. Int. Ed. 2009,
48, 154. (d) Oelke, A. J.; Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2012,
134, 2966. (e) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102.
(f) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012,
134, 17003. (g) Liang, Y.; Fu, G. C. J. Am. Chem. Soc. 2014, 136,
5520. (h) Choi, J.; Martín-Gago, P.; Fu, G. C. J. Am. Chem. Soc.
2014, 136, 12161. With organoboron reagents: (i) Lundin, P. M.;
Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11027. (j) Wilsily, A.;
Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012,
134, 5794. With organosilicon reagents: (k) Dai, X.; Strotman, N.
A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302.
(4) Selected reviews: (a) Nakamura, E.; Hatakeyama, T.; Ito, S.;
Ishizuka, K.; Ilies, L.; Nakamura, M. Org. React. 2014, 83, 1. (b)
Czaplik, W. M.; Mayer, M.; Cvengroš, J.; von Wangelin, A. J.
ChemSusChem 2009, 2, 396. (c) Sherry, B. D.; Fürstner, A. Acc.
Chem. Res. 2008, 41, 1500. Selected papers: (d) Fürstner, A.;
Leitner, A.: Méndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856. (e) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew.
Chem. Int. Ed. 2007, 46, 4364. (f) Noda, D.; Sunada, Y.;
Hatakeyama, T.; Nakamura, M.; Nagashima, H. J. Am. Chem. Soc.
2009, 131, 6078. (g) Bedford, R. B.; Carter, E.; Cogswell, P. M.;
(12) For details of optimization, see the Supporting Information.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
1
2
3
4
5
6
7
8
9
(13) (a) Jennerjahn, R.; Jackstell, R.; Piras, I.; Franke, R.; Jiao, H.;
(20) Review for nonlinear effect: Satyanarayana, T.; Abraham, S.;
Kagan, H. B. Angew. Chem. Int. Ed. 2009, 48, 456. and references
cited therein.
(21) Similar bimetallic mechanisms are reported for a nickel
catalyst, see: (a) Breitenfeld, J.; Wodrich, M. D.; Hu, X.
Organometallics 2014, 33, 5708. (b) Biswas, S.; Weix, D. J. J. Am.
Chem. Soc. 2013, 135, 16192. (c) Schley, N. D.; Fu, G. C. J. Am.
Chem. Soc. 2014, 136, 16588. For the discussion of related iron
species, see: ref. 19d.
Bauer, M.; Beller, M. ChemSusChem 2012, 5, 734. (b) Mayer, M.;
Welther, A.; von Wangelin, A. J. ChemCatChem 2011, 3, 1567. (c)
Chen, C.; Dugan, T. R.; Brennessel, W. W.; Weix, D. J.; Holland, P.
L. J. Am. Chem. Soc. 2014, 136, 945. (d) Bai, X.-F.; Song, T.; Deng,
W.-H.; Wei, Y.-L.; Li, L.; Xia, C.-G.; Xu, L.-W. Synlett 2014, 25,
0417. (e) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. J. Org. Chem.
2009, 74, 4565. (f) Arisawa, M.; Terada, Y.; Nakagawa, M.;
Nishida, A. Angew. Chem. Int. Ed. 2002, 41, 4732. (g) Shirakawa,
E.; Ikeda, D.; Masui, S.; Yoshida, M.; Hayashi, T. J. Am. Chem. Soc.
2012, 134, 272.
(14) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J.
Am. Chem. Soc. 2009, 131, 11949.
(15) Dexibuprofen and naproxen are optically active non-steroidal
anti-inflammatory drugs, and are commonly used for clinical
purposes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(22) A similar radical probe containing a geometrically defined
terminal (Z)-alkene moiety also provided
a mixture of the
corresponding uncyclized and cyclized products. The (Z)
stereochemistry of the uncyclized product and the recovered halide
substrate did not isomerize to the (E)-alkene during the reaction,
indicating the radical cyclization of 7 to 7’ was irreversible. See the
Supporting Information for details.
(16) The amount of bipnenyl produced before the initiation of the
cross-coupling reaction indicated that 67% of Fe(acac)3 was
reduced to an Fe(II) species.
(17) (a) Takaya, H.; Nakajima, S.; Nakagawa, N.; Isozaki, K.;
Iwamoto, T.; Imayoshi, R.; Gower, N. J.; Adak, L.; Hatakeyama, T.;
Honma, T.; Takagaki, M.; Sunada, Y.; Nagashima, H.; Hashizume,
D.; Takahashi, O.; Nakamura, M. Bull. Chem. Soc. Jpn. 2015, 88,
410. (b) Daifuku, S. L.; Al-Afyouni, M. H.; Snyder, B. E. R.;
Kneebone, J. L.; Neidig, M. L. J. Am. Chem. Soc. 2014, 136, 9132.
(c) Daifuku, S. L.; Al-Afyouni, M. H.; Snyder, B. E. R.; Kneebone, J.
L.; Neidig, M. L. J. Am. Chem. Soc. 2014, 136, 11847. Although
stepwise reduction of Fe(III)(acac)3 by PhMgBr has been reported
to produce Fe(II) and Fe(I) species possessing one
acetylacetonato group, the lack of the counteranion effect of the
iron precatalysts neither on yield nor er indicates displacement of
the original counteranion in the present enantioselective coupling
reaction (see Table S1 in the supporting information): (d) Lefèvre,
G.; Jutand, A. Chem. Eur. J. 2014, 20, 4796. See also ref 18c for the
stepwise reduction of Fe(III)(acac)3 and displacement of
acetylacetonato ligand.
(18) For the mechanism of the formation of Fe(I) species in
cross-coupling reactions see: (a) Adams, C. J.; Bedford, R. B.;
Carter, E.; Gower, N. J.; Haddow, M. F.; Harvey, J. N.; Huwe, M.;
Cartes, M. Á.; Mansell, S. M.; Mendoza, C.; Murphy, D. M.; Neeve,
E. C.; Nunn, J. J. Am. Chem. Soc., 2012, 134, 10333. (b) Bedford, R.
B.; Brenner, P. B.; Carter, E.; Clifton, J.; Cogswell, P. M.; Gower,
Nicholas J.; Haddow, M. F.; Harvey, J. N.; Kehl, J. A.; Murphy, D.
M.; Neeve, E. C. Neidig, M. L.; Nunn, J.; Snyder, B. E. R. Taylor, J.
Organometallics, 2014, 33, 5767 and references cited therein. (c)
Schoch, R.; Desens, W.; Werner, T. Bauer, M. Chem. Eur. J. 2013,
19, 15816. (d) Hedström, A.; Lindstedt, E.; Norrby, P.-O. J.
Organomet. Chem. 2013, 748, 51. and references cited therein.
(19) Reactive ferrate species have been reported: Fe(0) ferrate (a)
Fürstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773. Fe(+II) ferrate
(b) Sun, C.-L.; Krause, H.; Fürstner, A. Adv. Synth. Catal. 2014,
356, 1281. (c) Bedford, R. B.; Brenner, P. B.; Carter, E.; Cogswell,
P. M.; Haddow, M. F.; Harvey, J. N.; Murphy, D. M.; Nunn, J.;
Woodall, C. H. Angew. Chem. Int. Ed. 2014, 53, 1804. (d) Bauer,
G.; Wodrich, M. D.; Scopelliti, R.; Hu, X. Organometallics 2015, 34,
289.
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Fe(acac)3 (3 mol %)
simple hydrolysis
ArMgBr
Me
tBu
tBu
Me
R
+
P
P
CO2H
*
H+
R
(6 mol %)
THF, 0 °C
Ar
CO2R'
*
Cl
CO2R'
28 examples
up to 92% yield
up to 91:9 er
Dexibuprofen; er >99:1
and 5 more examples
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
racemic
ACS Paragon Plus Environment