Relay iron/chiral bronsted acid catalysis: Enantioselective hydrogenation of benzoxazinones

Article abstract of DOI:10.1021/jacs.5b00085

An asymmetric hydrogenation reaction of benzoxazinones has been accomplished via a relay iron/chiral Bronsted acid catalysis. This approach provides a variety of chiral dihydrobenzoxazinones in good to high yields (75-96%) and enantioselectivities (up to

Full text of DOI:10.1021/jacs.5b00085

Subscriber access provided by SELCUK UNIV
Article
Relay Iron/Chiral Brønsted Acid Catalysis:
Enantioselective Hydro-genation of Benzoxazinones
Liang-Qiu Lu, Yuehui Li, Kathrin Junge, and Matthias Beller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b00085 • Publication Date (Web): 14 Jan 2015
Downloaded from http://pubs.acs.org on February 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 7
Journal of the American Chemical Society
1
2
3
4
5
6
Relay Iron/Chiral Brønsted Acid Catalysis: Enantioselective Hydro-
genation of Benzoxazinones
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
,‡,§
‡,§
‡
,‡
Liang-Qiu Lu,
Yuehui Li, Kathrin Junge, and Matthias Beller*
†
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, 430079, P.R. China
‡
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein Str. 29a, Rostock, 18059, Germany
KEYWORDS: Asymmetric Hydrogenation, Relay catalysis, Iron, Chiral Brønsted Acid, Benzoxazinone
Supporting Information Placeholder
ABSTRACT: An asymmetric hydrogenation reaction of benzoxazinones has been accomplished via a relay iron/chiral
Brønsted acid catalysis. This approach provides a variety of chiral dihydrobenzoxazinones in good to high yields (75-96%)
and enantioselectivities (up to 98:2 er). Noteworthy, challenging 3-alkyl-substituted substrates underwent highly enanti-
oselective reduction. Key to success is the utilization of a non-chiral phosphine ligand to reduce disadvantageous back-
ground reactions through tuning the catalytic activity of Fe (CO) .
3
12
1
0a
10b
INTRODUCTION
groups of MacMillan and Rueping independently dis-
closed the chiral Brønsted acid (CBA)-catalyzed asymmetric
transfer hydrogenation (ATH) reaction of benzoxazinones
using Hantzsch ester as the stoichiometric reducing reagent.
Recently, Zhou and co-workers elegantly achieved the same
Asymmetric hydrogenation (AH) is arguably one of the most
prominent chemo-catalytic methods for the synthesis of
optically pure organic chemicals. In general, the success of
1
1
1
these reactions is attributed to the use of platinum group
transformation using catalytic amounts of NAD(P) mimics
(i.e. Hantzsch pyridine and phenanthridine). In these works,
NAD(P)H mimics are in-situ regenerated under hydrogen
1
-3
metals such as Ru, Rh, Ir, and Pd. From an environmental
and economic viewpoint, it is more desirable to conduct AH
reactions with more abundant and cheaper first-row transi-
atmosphere in the presence of a specific ruthenium com-
4
-7
10f,g
plex.
tion metals. In the past decade, significant advancements
In 2013, Vidal-Ferran and Núꢀez-Rico found that
5
-7
have been witnessed in iron-catalyzed hydrogenations,
iridium complexes with enantiopure phosphine-phosphite
ligands efficiently promote the AH reaction of benzoxazi-
including the corresponding asymmetric processes. In this
context, iron complexes with chiral tetradentate ligands were
used to efficiently catalyzed AH reactions of ketones by the
1
0h
nones with high enantioselectivities. However, these cata-
lytic reduction methods suffered from the limited scope of
benzoxazinones, and generally only 3-aryl-substituted deriv-
atives can be reduced with good efficiency and high selectivi-
ty. Herein, we disclose an AH reaction of benzoxazinones via
6a,d
6b,c
6e
groups of Morris,
Berkessel
and Gao. Besides, in the
past years our group developed a cooperative catalysis sys-
tem by combining the Knölker’s iron complex and chiral
Brønsted acids (CBA) for the AH reactions of linear and
1
2
a relay iron/CBA catalysis (Scheme 1). Through this ap-
proach, diverse chiral dihydrobenzoxazinones including
demanding 3-alkyl-substituted derivatives are provided in
high yields (75-96%) and enantioselectivities (up to 98:2 er).
7
cyclic imines. Despite these improvements, new strategies
are still awaited to extend the range of application respect to
iron-catalyzed AH reactions.
Dihydrobenzoxazinone is a ubiquitous scaffold in many
biologically active molecules ranging from fungicides and
8
herbicides to drugs. Therefore, many efforts have been made
9,10
to achieve the synthesis of chiral dihydrobenzoxazinones.
For example, in 2001 Gorohovky and Bittner firstly developed
a sequence process to efficiently synthesize such molecules
9a
using natural amino acids as chiral sources (Figure 1, a). In
006, Lectka and coworkers reported a highly enantioselec-
tive [4+2] cycloaddition of o-benzoquinone imides with in-
2
9b,c
situ generated ketenes (Figure 1, b).
Through this route,
enantioenriched dihydrobenzoxazinones were conveniently
prepared and further applied in the synthesis of amino acid
derivatives. In the past decade, catalytic asymmetric reduc-
tions have been applied to access the same type of heterocy-
Figure 1. Synthesis of chiral dihydrobenzoxazinones.
1
0
clic compounds (Figure 1, c), too. For instance, in 2006 the
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
Scheme 1. Proposal for the AH Reaction of Benzoxa-
zinones via a Relay Iron/CBA Catalysis
reaction efficiency and enantioselectivity. Hence, introducing
the phosphine ligand PPh led to an increased enantiomer
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
ratio (82:18 vs 76:24 ). Encouraged by these results, we
further studied the effect of different ligands on the reac-
tion efficiency and enantioselectivity. As shown in Table 1,
the introduction of different less-hindered phosphine
ligands substantially improved the enantioselectivity
(entries 1, 2, 5, 6 and 8). Notably, in the case of electron-
rich and bidentate phosphines (entries 1, 5 and 6) high
yields and good enantioselectivities were obtained.
Meanwhile, the use of excess of phosphine ligands (entry
7), tetradentate ligand (entry 9) or N-heterocyclic carbene
(entry 10) completely inhibited this reaction.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
RESULTS AND DISCUSSION
Table 1. Fe/CBA Relay-catalyzed AH reaction of 3-
Last year, we found that Fe (CO) can be used to catalyze the
a
3
12
Phenylbenzoxazinone: Ligand effects
reduction of commercially available phenanthridine (PD) to
NAD(P)H mimics dihydrophenanthridine (DHPD) in the
1
3
presence of H2, and this method was applied to the hydro-
genation of α-keto esters and their derivatives. For example,
the introduction of 20 mol% amounts of PD to the hydro-
genation reaction of benzoxazinone 1a resulted in a good
yield (Scheme 2.1: 80% yield). However, highly enantioselec-
tive hydrogenation processes have not yet been realized with
this system. A critical challenge that remains for this pro-
posed process is the strong background reaction promoted
b
b
entry
Ligand
yield (%)
92
er
1
TMP
84:16
82:18
77:23
78:22
82:18
84:16
ND
2
3
4
5
6
P(p-F-Ph)3
P(o-Me-Ph)3
P(1-Naph)3
91
1
4
by Fe (CO) , which is erosive to the desired asymmetric
3
12
96
ATH process. As illustrated in Scheme 2, benzoxazinone 1a
can be hydrogenated to generate dihydrobenzoxazinone 2a
in 19% yield in the presence of catalytic amounts of Fe (CO)
95
3
12
PCy3
92
and 50 bar H without PD. Meanwhile, Fe (CO) was found
2
3
12
DPPE
92
to have the ability to catalyze the transfer hydrogenation
reaction of 1a with DHPD as the hydride source (Scheme 2.1:
c
7
DPPE
trace
93
31% yield). We wondered whether diverse catalytic activities
8
9
Xantphos
83:17
n.d.
of Fe (CO) could be tuned by appropriate ligands and im-
3
12
P(CH CH PPh )
2 3
trace
trace
portantly, these ligands themselves would well tolerate the
chiral Brønsted acid in the catalytic cycle of asymmetric
transfer hydrogenation.
2
2
10
Mes-NHC
Reaction conditions: 1a (0.1 mmol), Fe
mol%), (S)-3a (2 mol%), PD (20 mol%), 50 bar H
n.d.
a
3
(CO)12 (4 mol%), ligand (4
2
, 0.2 mL of
Scheme 2. Fe-promoted and –catalyzed hydrogena-
tion of 1a
o
b
toluene, 24 h, 65 C. Yield and er value were determined by GC
c
and chiral HPLC. 8 mol% of DPPE was used. TMP: tris(4-meth-
oxyphenyl)phosphane; DPPE: 1,2-bis(diphenylphosphino)ethane;
Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Mes-
NHC: 1,3-dimesityl-1H-imidazol-2(3H)-ylidene. ND: not determined.
With TMP as the best choice, a survey of chiral
Brønsted acids (Figure 2) was carried out to further im-
prove the enantioselectivity of the model system. As high-
lighted in Table 2, both steric and electronic effects of the
CBA have a profound influence on the reaction efficiency
and selectivity. For example, steric demanding acids such
as (S)-3a and (S)-3e (entries 1 and 5) or electron-deficient
ones like (S)-3c and (S)-3f (entries 3 and 8) promoted the
reaction with high yields. Among the different acids,
sterically hindered (S)-3a catalyzed this reaction with
better efficiency and selectivity. Besides, increasing the
amount of acid catalysts slightly improved the result (en-
try 6: 93% yield, 85:15 er; entry 7: 85% yield, 84:16 er;);
Variation of Conditions. With this idea in mind, the
model reaction of benzoxazinone 1a was investigated in the
presence of Fe (CO) , PD, and (S)-3a under H atmosphere
3
12
2
o
(
50 bar) at 65 C. As highlighted in Scheme 2, the devised AH
reaction gave the desired reduced product 2a in 99% yield
with moderate enantioselectivity (76:24 er). And being con-
sistent with our hypothesis, the added ligands did affect the
while, reducing the loading of Fe (CO) and TMP resulted
3
12
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
and good enantioselectivity (entry 15: 91% yield, 90:10
in low reaction efficiency albeit with marginally improved
enantioselectivity (entry 10: 38% yield, 87:13 er).
1
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
er).
Table 2. Fe/CBA Relay-catalyzed AH reaction of 3-
Phenylbenzoxazinone: CBA effects
a
Table 3. Fe/CBA Relay-catalyzed AH reaction of 3-
Phenylbenzoxazinone: other effects
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
b
entry
CBA
(S)-3a
(R)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3a
(S)-3e
(S)-3f
(R)-3g
(S)-3a
solvent
yield (%)
er
b
b
entry
[H]
PD
solvent
yield (%)
er
1
2
3
4
5
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
92
35
70
44
78
93
85
87
60
38
84:16
20:80
79:21
68:32
81:19
1
0.5 M in toluene
0.5 M in toluene
0.5 M in toluene
85
6
84:16
56:44
50:50
84:16
78:22
ND
2
3
4
5
6
7
8
9
2-Me-PD
2-Ph-PD
7
10-Me-PD 0.5 M in toluene
10-iPr-PD 0.5 M in toluene
13
11
c
6
85:15
84:16
57:43
53:47
87:13
4
0.5 M in toluene
0.5 M in toluene
0.1 M in toluene
trace
93
c
7
PD
PD
PD
PD
PD
PD
PD
PD
PD
85:15
87:13
76:24
61:39
84:16
87:13
88:12
88:12
91:9
c
8
80
22
9
0.1 M in CH Cl2
c,d
0
2
1
10
0.1 M in THF
0.1 M in AcOEt
0.1 M in toluene
0.1 M in toluene
0.1 M in toluene
0.1 M in mesitylene
14
a
Reaction conditions: 1a (0.1 mmol), Fe
3
(CO)12 (4 mol%), TMP (4
, 0.2 mL of toluene,
24 h, 65 C. Yields and er values were determined by GC and
11
58
mol%), CBA (2 mol%), PD (20 mol%), 50 bar H
2
o
b
c
12
89
53
c
d
chiral HPLC. Using 4 mol% of CBA. Using 2 mol% of Fe
3
(CO)12
d
3
1
and 2 mol% of TMP.
e
14
43
c,f
15
91 (88)
a
Reaction conditions: 1a (0.1 mmol), Fe
mol%), (S)-3e (4 mol%, entries 1-6) or (S)-3a (4 mol%, entries 7-
15), PD or its analog (20 mol%), 50 bar H , 0.2 mL of toluene, 24 h,
65 C. Yields and er values were determined by GC and chiral
3
(CO)12 (4 mol%), TMP (4
2
o
b
c
d
o
e
f
2
HPLC. 48 h. 45 C. 30 bar H . Isolated yield in parentheses.
ND: not determined.
Figure 2. Selected chiral Brønsted acids (CBA).
The effect of NAD(P) mimics, PD and its analogs (Fig-
ure 3), has been also investigated using chiral Brꢀnsted
acid (S)-3e. As highlighted in Table 3, the introduction of
methyl, iso-propanyl or phenyl groups into the 2- or 10-
postion of PD unit resulted in worse reaction efficiency
and enantioselectivity (entries 2-5 vs entry 1). Replacing
PD with 11H-indolo[3,2-c]isoquinoline (4) completely
prevented this AH reaction (entry 6). In order to improve
the catalytic performance, further optimization of other
reaction parameters such as solvent and concentration
was carried out (entries 7-11). We found that, diluted solu-
tion and low-polarity solvent gave out higher enantiose-
lectivities (entry 8 vs 7; entry 8 vs entries 9-11). Lower
Figure 3. PD and its analogs.
Scope of Benzoxazinones. Next, we examined the
generality of AH reaction with respect to 3-aryl substitut-
ed benzoxazinones under the Fe/CBA relay catalysis con-
dition. As revealed in Table 4, benzoxazinones including
electron-neutral (entry 1, 1a: 88 % yield, 91:9 er), electron-
deficient (entry 2, 1b: 96 % yield, 95:5 er), electron-rich
temperature or H pressure obviously reduced the reac-
2
tion efficiency (entries 12 and 13). Prolonging the reaction
time can slightly improve the yield (entry 12 vs 7). Finally,
the optimal condition was obtained showing high yields
(
entry 3, 1c: 75% yield, 92:8 er) and sterically demanding
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
(
entry 4, 1d: 87 % yield, 95:5 er) substituents on the aryl some effect on this reaction. For example, the reactions of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ring as well as multiple substituents (entry 5, 1e: 85 %
yield, 97:3 er; entry 6, 1f: 75 % yield, 95:5 er) smoothly
gave the corresponding products. Generally, prolonged
reaction time is required for electron-rich substrates (1c
and 1f) in order to obtain good yields. Noteworthy, for the
reactions of all these substrates higher enantiomeric rati-
os of the corresponding products were observed com-
pared to the model substrate 1a.
benzoxazinones with electron-deficient groups, such as
fluorine (1p) and chlorine (1q) at 7-position exhibited
Table 5. Asymmetric Hydrogenation of 3-Alkyl-
a
substituted Benzoxazinones
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. Asymmetric Hydrogenation of 3-Aryl-
substituted Benzoxazinones
a
b
c
entry
3-alkyl
1g: Et
CBA
yield (%)
er
1
2
3
4
(S)-3d
(S)-3d
(S)-3a
(S)-3d
81
75
91
93:7
94:6
98:2
95:5
1h: i-Pr
1i: n-Bu
1j: Bn
b
c
entry
3-aryl
time
48 h
48 h
72 h
48 h
48 h
yield (%)
er
89
1
2
3
4
5
1a: Ph
88
96
75
87
85
91:9
95:5
92:8
95:5
97:3
5
6
7
(S)-3d
(S)-3a
88
94
97:3
94:6
1
k:
1b: 4-F-Ph
1c: 4-MeO-Ph
1d: 4-t-Bu-Ph
1e: 3,4-2Me
1l:
(S)-3a
(S)-3d
(S)-3d
(S)-3d
85
76
89
84
93:7
95:5
94:6
95:5
1
m:
m:
d
8
1
9
6
96 h
75
95:5
1n:
1o:
1f:
a
10
Unless otherwise indicated, all reactions were performed on a 0.2
mmol scale under the optimum conditions as entry 15 in Table 3 for
a
Unless otherwise indicated, all reactions were performed on a 0.2
mmol scale under the optimum conditions as entry 15 in Table 3 for
b
c
48-96 h. Isolated yield. Determined by chiral HPLC.
b
c
d
48 h. Isolated yield. Determined by chiral HPLC or GC. 96 h.
Then, we moved our attention to the asymmetric re-
duction of more challenging 3-alkyl-substituted benzoxa-
zinones. Remarkably, good to excellent results were ob-
tained for AH reactions of a series of 3-alkyl-substituted
substrates by using CBA (S)-3a or (S)-3d (Table 5). Alt-
hough being investigated, only modest results were ob-
tained for reactions of 3-ethyl- and 3-phenylethyl substi-
tuted benzoxazinones (2g: 27% yield, 89:11 er; 2k: 96%
Table 6. Hydrogenation of Aryl-substituted 3-Butyl-
a
Benzoxazinones
1
0b,d
yield, 54:46 er) in previous reports.
Instead, applying
b
c
entry
R
time
yield (%)
er
our Fe/CBA relay catalysis system, the same products are
easily available with 81% yield, 93:7 er (entry 1) and 88%
yield, 97:3 er (entry 5), respectively. Interestingly, this
novel catalyst system also tolerates many functional
groups such as alkene (1m), methoxyl (1n), and chloride
(1o) (entries 7-10) groups. In general, the desired chiral
dihydrobenzoxazinones were accessed in good yields (76-
89%) and high enantioselectivities (93:7-95:5 er). Notably,
in the case of 3-alkenyl substituted benzoxazinone 1m,
both (S)-3a or (S)-3d were efficient for this transfor-
mation (entries 7 and 8), though the former exhibited
higher catalytic activity and the latter showed better ste-
reoinduction ability.
1
2
3
4
5
1i: H
48 h
48 h
48 h
72 h
72 h
90 h
72 h
91
83
81
98:2
94:6
94:6
96:2
92:8
95:5
98:2
1p: 7-F
1q: 7-Cl
1r: 7-Me
1s: 7-MeO
1t: 6-Me
1u: 5-Me
86
84
83
86
d
6
7
8
72 h
80
94:6
Finally, we also investigated the substituent effect on
the benzene ring of 3-butyl benzoxazinones. As shown in
Table 6, the electronic properties of the substituents have
1v:
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
a
Unless otherwise indicated, all reactions were performed on a 0.2
with stoichiometric DHPD delivered the product 2a in a
slightly decreased yield and similar enantioselectivity (eq.
4, 76% yield and 89:11 er). These results ruled out the
possibility that the chiral iron species derived from
Fe (CO) and CBA could promote the AH reaction of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol scale under the optimum conditions as entry 15 in Table 3 for
b
c
d
4
8-90 h. Isolated yield. Determined by chiral HPLC. (S)-3d was
used.
3
12
benzoxazinones without the process of CBA-catalyzed
transfer hydrogenation (cycle II in Scheme 2).
better reactivity than the ones with electron-rich groups
(1r, 1s). In the latter cases prolonged time were necessary
to obtain good yields. Nevertheless, all tested benzoxazi-
nones were transformed to the desired products in good
results (80-91% yields, 92:8-98:2 er).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mechanism analysis. As shown in Scheme 3, we pro-
pose an iron/CBA relay catalysis mechanism for this hy-
drogenation reaction of benzoxazinones. In cycle I, the
organic reductant DHPD is generated from PD in the
presence of a catalytic amount of Fe (CO) and molecular
3
12
hydrogen. Then, an asymmetric transfer hydrogenation
undergoes to selectively reduce the benzoxazinone by
DHPD with the help of the chiral Brønsted acid. In the
second cycle, the chiral Brønsted acid is responsible for
the control of enantioselectivity through the possible
Figure 4. Proposed model for the enantioinduction resulting
from the synergetic hydride transfer process.
1
0g
synergetic hydride transfer process (Figure 4). The ob-
served high selectivity is likely a result of: 1) the good
stereo-induction ability of CBA itself (CBA catalysis), and
2) the suppression of the unfavorable background reac-
tions (Fe-catalyzed direct hydrogenation with H and the
2
transfer hydrogenation with DHPD).
Scheme 3. Proposed Mechanism of the Relay Fe/CBA
Catalysis Process
CONCLUSION
In conclusion, we have developed the first example of
Fe/CBA relay-catalyzed asymmetric hydrogenations of
benzoxazinones. This reduction methodology delivers
interesting chiral building blocks from easily available
starting materials in good to excellent isolated yields and
enantioselectivities. Noteworthy, 3-alkyl-substituted ben-
zoxazinones are more selectively reduced compared to
previous reported methods. The present methodology
makes use of a simple iron carbonyl complex and pro-
ceeds with molecular hydrogen, which makes the overall
process more atom-efficient compared to transfer hydro-
genations. Key to success is the utilization of a suitable
non-chiral phosphine ligand, which tunes the catalytic
activity of the iron carbonyl complex and decreases unse-
lective background reductions. Further applications of
this type of catalysis are currently under way.
METHODS
General procedure for hydrogenation: Under the at-
mosphere of Ar, benzoxazinone (0.2 mmol), phenanthri-
dine 3b (7.2 mg, 0.04 mmol), tris(4-methoxy-phenyl)-
phosphine (2.8 mg, 0.008 mmol), Fe (CO) (4.0 mg, 0.008
3
12
mmol), mesitylene (2.0 mL), chiral phosphate (S)-3a (6.0
mg, 0.008 mmol) or (S)-3d (6.9 mg, 0.008 mmol) and a
magnetic stirrer were placed in a reaction vial, which was
then capped with a septum equipped with a syringe nee-
dle. After stirring for 15 min, the vials together with an
alloy plate were placed in the pre-dried autoclave. Once
Two control experiments were implemented to support
the proposed pathway: 1) in the absence of organic media-
tor PD, the AH reaction gave the reduction product in
very low yield (eq. 3); 2) in the absence of iron catalyst
and phosphine ligand, the direct transfer hydrogenation
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
sealed, the autoclave was purged three times with H2,
then pressurized to 50 bar and heated at 65 °C for 48-96 h.
Then, the autoclave was cooled to room temperature and
depressurized. The reaction mixture was purified by col-
umn chromatography on silica gel (eluent: n-
hexane/ethyl acetate 10:1-8:1) to give the corresponding
chiral product 2. The enantiomer ratios were determined
by Chiral HPLC or GC.
Vol. 33. (d) Nakazawa, H.; Itazaki, M. Top. Organomet. Chem.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2011, 33, 27. e) Junge, K.; Schröder, K.; Beller, M. Chem. Com-
mun. 2011, 47, 4849. (f) Darwish, M.; Wills, M. Catal. Sci. Tech-
nol. 2012, 2, 243.
(
6) Examples of iron-catalyzed AH reactions with the aid of chiral
ligands, see: (a) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R.
H. Angew. Chem. Int. Ed. 2008, 47, 940. (b) Berkessel, A.;
Reichau, S.; Von der Höh, A.; Leconte, N.; Nordörfl, J.-M.
Organometallics, 2011, 30, 3880. (c) Berkessel, A.; Van der Höh,
A. ChemCatChem. 2011, 3, 861. (d) Lagaditis, P. O.; Sues, P. E.;
Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H. J. Am.
Chem. Soc. 2014, 136, 1367. (e) Li, Y.; Yu, S.; Wu, X.; Xiao, J.;
Shen, W.; Dong, Z.; Gao, J. J. Am. Chem. Soc. 2014, 136, 4031.
ASSOCIATED CONTENT
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Supporting Information
(7) Iron/CBA synergetic catalysis on the AH reactions: (a) Zhou, S.;
Additional experimental results and procedures and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Fleischer, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2011, 50,
5
120. (b) Fleischer, S.; Werkmeister, S.; Zhou, S.; Junge, K.; Bel-
ler, M. Chem. Eur. J. 2012, 18, 9005. (c) Fleischer, S.; Zhou, S.;
Werkmeister, S.; Junge, K.; Beller, M. Chem. Eur. J. 2013, 19,
4997.
AUTHOR INFORMATION
(8) For selected reviews about diverse biological activities of dihy-
drobenzoxazinones, see: (a) Ilaš, J.; Anderluh, P. Š.; Dolenc, M.
S.; Kikelj, D. Tetrahedron 2005, 61, 7325. (b) Macías,F. A.; Ma-
rín,D.; Oliveros-Bastidasab,A.; Molinillo, J. M. G. Nat. Prod. Rep.
Corresponding Author
Matthias.Beller@catalysis.de
Author Contributions
2009, 26, 478. (c) Osbourn, A. E.; Lanzotti, V. Plant-derived
§
Natural Products: Synthesis, Function, and Application; Springer:
Heidelberg, 2009.
L.-Q. Lu and Y. Li contributed equally to this work.
(
9) Synthesis of chiral dihydrobenzoxazinones via cycloaddition
methods, see: (a) Gorohovsky, S.; Bittner, S. Amino Acids 2001,
Notes
The authors declare no competing financial interest.
2
0, 135. (b) Wolfer, J.; Bekele, T.; Abraham, C. J.; Dogo-Isonagie,
C.; Lectka, T. Angew. Chem. Int. Ed. 2006, 45, 7398. (c) Paull, D.
H. Alden-Danforth, E. Wolfer, J. Dogo-Isonagie, C. Abraham, C.
J. Lectka, T. J. Org. Chem. 2007, 72, 5380.
ACKNOWLEDGMENT
The Federal Ministry of Education and Research (BMBF) and
the State of Mecklenburg-Vorpommern are gratefully
acknowledged for their general support. We thank the ana-
lytical department of Leibniz-Institute for Catalysis, Rostock
for their excellent analytical service. We also thank the Alex-
ander von Humboldt Foundation and the National Science
Foundation for Young Scientists of China (No. 21202053).
(10) Synthesis of chiral dihydrobenzoxazinones via asymmetric
reduction, see: (a) Rueping, M.; Antonchick, A. P.; Theissmann,
T. Angew. Chem. Int. Ed. 2006, 45, 6751. (b) Storer, R. I.; Carrera,
D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
8
4. (c) Malkov, A. V.; Vranková, K.; Stončius, S.; Kočovský, P. J.
Org. Chem. 2009, 74, 5839. (d) Xue, Z.-Y.; Jiang, Y.; Peng, X.-Z.;
Yuan, W.-C.; Zhang, X.-M. Adv. Synth. Catal. 2010, 352, 2132. (e)
Xue, Z.-Y.; Jiang, Y.; Yuan, W. C.; Zhang, X. M. Eur. J. Org.
Chem. 2010, 616. (f) Chen, Q.-A.; Chen, M.-W.; Yu, C.-B.; Shi, L.;
Wang, D.-S.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2011, 133,
REFERENCES
(1) (a) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998. (b)
Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.
1
6432. (g) Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-H.; Shi, L.; Yang,
Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2012, 134, 2442. (h) Núñez-
Rico, J. L.; Vidal-Ferran, A. Org. Lett. 2013, 15, 2066.
(
2) Recent books and reviews, see: (a) Blaser, H.-U. Industrial
Asymmetric Hydrogenation, in Applications of Transition Met-
al Catalysis in Drug Discovery and Development: An Industrial
Perspective (Eds: Crawley, M. L. and Trost, B. M.), John Wiley &
Sons, Hoboken, USA, 2008. (b) Wang, D.-S.; Chen, Q.-A.; Lu,
S.-M.; Zhou. Y.-G. Chem. Rev. 2012, 112, 2557.
(
11) For selected reviews for NAD(P)H mimics as organic reducing
agents, see: (a) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C.
Acc. Chem. Res. 2007, 40, 1327. (b) Connon, S. J. Org. Biomol.
Chem. 2007, 5, 3407-3417. (c) Rueping, M.; Dufour, J.; Schoepke,
F. R. Green Chem. 2011, 13, 1084. (d) Zheng, C.; You, S.-L. Chem.
Soc. Rev. 2012, 41, 2498-2518. For a recent review about in situ
regeneration of NAD(P)H mimics, see: (e) Du, W.; Yu, Z. Syn-
lett 2012, 1300.
(
(
3) A selected review on Pd-catalyzed AH reactions: Chen, Q.-A.;
Ye, Z.-S.; Duan, Y.; Zhou, Y.-G. Chem. Soc. Rev. 2013, 42, 497.
4) Recent examples of first-row transition metal-catalyzed AH
reactions, cobalt: (a) S. Monfette, Z. R. Turner, S. P. Semproni,
P. J. Chirik, J. Am. Chem. Soc. 2012, 134, 4561. (b) Friedfeld, M.R.;
Shevlin, M.; Hoyt, J.; Krska, S.W.; Tudge, M.; Chirik, P.J. Science,
(
12) For selected reviews on relay previous metal/CBA catalysis, see:
(
a) M. Rueping, R. M. Koenigs, I. Atodiresei, Chem. Eur. J. 2010,
16, 9350. (b) Shi, F.; Gong, L.-Z. Angew. Chem. Int. Ed. 2012, 51,
11423. (c) Han, Z.-Y.; Wang, C.; Gong, L.-Z. In Science of Synthe-
sis, Asymmetric Organocatalysis; Maruoka, K., Ed.; Georg
ThiemeVerlag: Stuttgart, 2012, Vol. 2, p 697. (d) Chen, J.-R.; Hu,
X.-Q.; Xiao, W.-J. Angew. Chem. Int. Ed. 2014, 53, 4038. For pio-
neer works in this field, see: (e) Cai, Q.; Zhao, Z.-A.; You, S.-L.
Angew. Chem. Int. Ed. 2009, 48, 7428. (f) Cai, Q.; Zheng, C.; You,
S.-L. Angew. Chem. Int. Ed. 2010, 49, 8666. (g) An, X.-L.; Chen,
J.-R.; Li, C.-F.; Zhang, F.-G.; Zou, Y.-Q.; Guo, Y.-C.; Xiao, W.-J.
Chem. Asian J. 2010, 5, 2258. (h) Yang, Z.-P.; Zhang, W.; You, S.-
L. J Org. Chem. 2014, 79, 7785. For an example of relay Fe/chiral
amine catalysis, see: (i) Quintard, A.; Constantieux, T.; Rodri-
guez, J. Angew. Chem. Int. Ed. 2013, 52, 12883.
2
013, 342, 1076. Nickel: (c) Hamada, Y.; Koseki, Y.; Fujii, T.;
Maeda, T.; Hibino, T.; Makino, K. Chem. Commun. 2008, 6206.
d) Hibino, T.; Makino, K.; Sugiyama, T.; Hamada, Y. Chem. Cat.
(
Chem. 2009, 1, 237. Copper: (e) Shimizu, H.; Igarashi, D.; Ku-
riyama, W.; Yusa, Y.; Sayo, N.; Saito, T. Org. Lett. 2007, 9, 1655.
(
f) Junge, K.; Wendt, B.; Addis, D.; Zhou, S.; Das, S.; Fleischer, S.;
Beller, M. Chem. Eur. J. 2010, 17, 101. Zinc: (g) Werkmeister, S.
Fleischer, S. Junge, K. Beller, M. Chem. Asian J. 2012, 7, 2562.
Iron: (h) Zuo, W.; Tauer, S.; Prokopchuk, D. E.; Morris, R. H.
Organometallics, 2014, 33, 5791.
(5) Selected reviews and books about iron-catalyzed hydrogenation,
see: (a) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed.
2008, 47, 3317. (b) Plietker, B. Iron catalysis in Organic Chemis-
(13) Lu, L.-Q.; Li, Y.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2013,
2, 8382.
try; Wiley-VCH: Weinheim, 2008. (c) Plietker B. Iron Catalysis.
Topics in Organometallic Chemistry; Springer: Heidelberg, 2011;
5
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
(
3
14) Fe CO12 was found a good catalyst to promote the hydrogena-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tion of imine units, see: Fleischer, S.; Zhou, S.; Junge, K.; Beller,
M. Chem. Asian J. 2011, 6, 2240.
15) Please see more details about ligand effect and condition opti-
mization in Supporting Information.
16) The absolute configuration of products was established by
comparing the optical rotation with previous reports.
(
(
TOC
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment