Relay Catalysis: Manganese(III) Phosphate Catalyzed Asymmetric Addition of β-Dicarbonyls to ortho-Quinone Methides Generated by Catalytic Aerobic Oxidation

Article abstract of DOI:10.1021/acs.orglett.7b02185

The combination of an in situ formed MnL₃ complex (HL = Hacac or R(C=O)CH₂CO₂R) and a chiral phosphoric acid HX? allows for a fully catalytic, asymmetric synthesis of 4H-chromenes starting from 2-alkyl-substituted phenols. The aerobic oxidation toward a transient ortho-quinone methide was efficiently catalyzed by a manganese(III) species MnL₃ while the ensuing Michael addition of β-dicarbonyl compounds proved to be catalyzed by a chiral manganese phosphate MnL₂X?.

Full text of DOI:10.1021/acs.orglett.7b02185

Letter
pubs.acs.org/OrgLett
Relay Catalysis: Manganese(III) Phosphate Catalyzed Asymmetric
Addition of β‑Dicarbonyls to ortho-Quinone Methides Generated by
Catalytic Aerobic Oxidation
Konrad Gebauer, Franziska Reuß, Matthias Spanka, and Christoph Schneider*
Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
S
* Supporting Information
ABSTRACT: The combination of an in situ formed MnL3
complex (HL = Hacac or R(CO)CH2CO2R) and a chiral
phosphoric acid HX* allows for a fully catalytic, asymmetric
synthesis of 4H-chromenes starting from 2-alkyl-substituted
phenols. The aerobic oxidation toward a transient ortho-
quinone methide was efficiently catalyzed by a manganese(III)
species MnL3 while the ensuing Michael addition of β-
dicarbonyl compounds proved to be catalyzed by a chiral
manganese phosphate MnL2X*.
Scheme 1. Design Plan
lthough ortho-quinone methides (o-QMs) have been
1
Aknown since 1907
and have been shown to play an
important role in many biological processes, they have only
recently come into focus as viable intermediates in synthetic
organic chemistry.2 Featuring a highly reactive 1-oxabutadiene
system they have been employed in [4 + 2]-cycloadditions,
Michael additions, and 6π-electrocyclizations. In recent years a
broad variety of asymmetric processes have been developed to
fully exploit their synthetic potential.3 In general, o-QMs can be
formed in situ by various procedures, e.g. by thermolysis,4
photolysis,5 tautomerization,6 oxidation,7 and acid- or base-
mediated3c transformations. Out of this potpourri of methods,
the oxidative approach occupies a special role because it is the
only way to obtain stable and isolable o-QMs.8 Accordingly,
they have proved to be a valuable testing ground for the
diversification of o-QMs through catalytic, enantioselective
ensuing transformations. One-pot procedures combining the
oxidative generation of an o-QM and subsequent functionaliza-
tion, especially in a catalytic and asymmetric fashion, have only
been reported in select cases, but typically require super-
stoichiometric quantities of a metal-based oxidant.9
However, some very electron-rich ortho-hydroxy benzhydryl
alcohols 1 decomposed rapidly before a productive reaction
could occur. We reasoned that an oxidative approach starting
from more stable 2-alkyl-substituted phenols 4 could
significantly expand the substrate scope of the Michael addition
(Scheme 1).
Herein, we report the successful execution of this strategy
which features a relay catalysis approach with two different, in
situ generated metal catalysts and establishes a catalytic
oxidative access to o-QMs using oxygen as a cheap terminal
oxidant.
In recent years our group has developed a number of
Brønsted acid catalyzed processes for the highly enantiose-
lective synthesis of nitrogen and oxygen heterocycles from in
situ generated o-QMs.10 For the latter, we started from ortho-
hydroxy benzhydryl alcohols 1, which were easily dehydrated
with chiral BINOL-based phosphoric acid HX*11 to form o-
QMs of structure 2, and we reacted them with various π-
nucleophiles. For example, the reaction with β-diketones 5
furnished 4H-chromenes 3 with excellent enantioselectivity
(Scheme 1).10a The chiral phosphoric acid triggered the
dehydration toward the o-QM intermediate 2 and controlled
the enantioselective Michael addition of the β-diketone 5 at the
same time.
Our investigation commenced with the model reaction of 2-
(4-methoxybenzyl)-sesamol (4a) and 1,3-cyclohexanedione
(5a) as substrates in the presence of the chiral phosphoric
acid HX* which was previously identified as the most selective
Received: July 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02185
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chiral catalyst for the conjugate addition of β-diketones.10a The
examination of known oxidants for the in situ synthesis of o-
QMs proved disappointing (Table 1). Whereas DDQ and
identical results as in the Mn(acac)3-catalyzed reaction
(compare entries 7 and 10).
After the identification of Mn(dbm)3/O2 as a superior
catalytic system for the oxidative generation of o-QMs, we
revisited all other reaction parameters (solvent, temperature,
concentration, equivalents of nucleophile, phosphoric acid
catalyst) and screened several additives (see Supporting
Information). As a result, the optical purity of product 3ab
could be slightly improved by reducing the amount of chiral
phosphoric acid HX* to 3 mol % and by diluting the reaction
mixture (Scheme 2). The robustness of this method was
a
Table 1. Screening of Oxidants
b
c
entry
oxidant (equiv)
DDQ (2.2)
5
solvent
yield (%)
er
de
,
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
−
5b
5b
5b
5b
5b
CH2Cl2
CHCl3
PhMe
17
19
37
0
92:8
82:18
54:46
−
57:43
69:31
85:15
−
a
Scheme 2. Substrate Scope
e
Ag2O (1.5)
MnO2 (5.0)
K3[Fe(CN)6] (2.2)
Mn(acac)3 (2.2)
Mn(acac)3 (2.2)
Mn(acac)3 (0.1), O2
Mn(hfacac)3 (0.1), O2
Mn(dpm)3 (0.1), O2
Mn(dbm)3 (0.1), O2
PhMe
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
50
68
81
0
76
80
78:22
10
86:14
a
Reaction conditions: sesamol 4a (0.15 mmol, 1.0 equiv), nucleophiles
5a/b (1.5 equiv), catalyst HX* (5 mol %), oxidant, 1.2 mL of solvent,
b
c
d
12−36 h, rt. Isolated yield. Determined by chiral HPLC. 40 °C.
e
4H-Chromene 3aa was directly obtained after step 1. PMP = para-
methoxyphenyl, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
Hacac = acetylacetone, Hdpm = dipivaloylmethane, Hhfacac =
hexafluoroacetylacetone, Hdbm = dibenzoylmethane.
Ag2O gave rise to the desired product 3aa with good
enantioselectivity, the yields were low in both cases (entries 1
and 2). MnO2 proved to be more effective in terms of yield;
however, a significant loss of asymmetric induction was
observed (entry 3). No reaction was noticed with K3[Fe(CN)6]
as oxidant (entry 4). In all four cases a heterogeneous reaction
medium was generated, and we speculated that a soluble
oxidant might improve the efficacy of this transformation.
Hence, we concentrated on Mn(acac)3 as oxidant which
upon reduction to Mn(acac)2 would also liberate 1 equiv of
acetylacetone (5b) as the nucleophile for the subsequent
Michael addition. To our delight, the desired product 3ab was
isolated in 50% yield using 2.2 equiv of this complex (entry
5).11 The addition of another 1.5 equiv of acetylacetone (5b) to
the reaction mixture further increased the overall yield to 68%
(entry 6).13 At this point we hypothesized that an interference
of the manganese complex with the phosphoric acid might be
causing the observed erosion of enantioselectivity compared to
the reaction with DDQ as oxidant. Indeed, reducing the
amount of Mn(acac)3 to 10 mol % and using oxygen as the
terminal oxidant not only increased the yield and enantiomeric
excess of 4H-chromene 3ab but also altered the overall process
to a catalytic protocol (entry 7).
As a final parameter the nature of the β-dicarbonyl ligand of
the oxidation catalyst was optimized. To ensure that this
reaction was not limited to acetylacetone (5b) as a nucleophile,
several manganese precatalysts were tested. These complexes
were decorated with dummy ligands which should not react
with the o-QM itself due to either electronic (entry 8) or steric
factors (entries 9 and 10), but could be replaced by the
nucleophile (e.g., 5b) to generate the active catalyst. It turned
out that the use of Mn(dbm)3 (Hdbm = dibenzoylmethane) as
a precatalyst perfectly matched our expectations and gave
a
Reaction conditions: sesamols 4a−k (0.15 mmol, 1.0 equiv),
acetylacetone (5b) (1.5 equiv), catalyst HX* (3.0 mol %), Mn(dbm)3
(10 mol %), 2.4 mL of CHCl3, 24 h, rt; isolated yields after column
chromatography; er determined by chiral HPLC. Absolute
b
configuration was determined by comparison with our previous
results;10a see Table 2. 1 mmol scale, air as oxidant.
c
documented by running the reaction in an open flask on a 1
mmol scale and using air as the oxidant. Both the yield and the
enantiomeric excess of 3ab remained constant under these
conditions (Scheme 2).
With these optimized reaction conditions in hand, the
process could easily be applied to a variety of 2-benzyl-
substituted sesamols 4a−g. Electron-donating and -withdraw-
ing substituents in the para-position as well as methoxy- and
alkyl-substituents in the meta- and ortho-positions of the benzyl
substituent were well tolerated, and the products 3ab−gb were
isolated in good yields and optical purities. Interestingly, 2-
alkyl-substituted sesamols 4i−k could also be converted to the
B
DOI: 10.1021/acs.orglett.7b02185
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Organic Letters
Letter
a
corresponding 4H-chromenes 3ib−kb without affecting the
overall outcome of the reaction.
Table 2. Control Experiments
The catalytic protocol using Mn(dbm)3/O2 for the
generation of the o-QMs is not only limited to acetylacetone
(5b) as a nucleophile. Several β-ketoesters 5c−e could be
submitted to the reaction as well. Yields remained good, but the
enantioselectivity decreased significantly (Scheme 3). Further-
a
Scheme 3. Substrate Scope
b
c
entry 2/4a
catalyst
t (h) yield (%)
er
d
1
2
3
4
5
6
7
8
2a
2a
2a
2a
4a
4a
4a
4a
HX*
4
91
82
8:92
e
d
f
Mn(acac)3 + HX*
Mn(acac)2X*
Mn(dbm)3
24
4
75:25
73:27
50:50
87:13
87:13
−
d
h
97(95 )
d
4
94
79
80
0
e
Mn(dbm)3 + HX*
Mn(dbm)3 + Mn(acac)2X*
Mn(acac)2X*
Mn(acac)2 + HX*
24
24
24
24
g
f
f
e
d
77
81:19
a
Reaction conditions: substrate 2a/4a (0.15 mmol, 1.0 equiv),
acetylacetone (5b) (1.5 equiv), catalyst, 2.4 mL of CHCl3, O2, rt.
b
c
d
e
f
Isolated yield. Determined by chiral HPLC. 5 mol %. 10 mol %. 3
g
h
mol %. 7 mol %. Under argon atmosphere. PMP = para-
methoxyphenyl.
complex did not catalyze the initial oxidation (entry 7). Finally,
it was shown that the catalytic process could be initiated from
Mn(acac)2 by aerobic oxidation (entry 8).
Based on these mechanistic investigations, we draw the
following picture of the process in solution (Scheme 4): First,
a
Reaction conditions: phenols 4a,l−n (0.15 mmol, 1.0 equiv),
nucleophiles 5b−e (1.5 equiv), catalyst HX* (3.0 mol %), Mn(dbm)3
(10 mol %), 2.4 mL of CHCl3, 24 h, rt; isolated yields after column
chromatography; er determined by chiral HPLC. PMP = para-
methoxyphenyl.
Scheme 4. Mechanistic Considerations
more, no product was formed using 1,3-cyclohexanedione (5a)
as the nucleophile. Phenols with 3,4-methoxy substituents
instead of the 3,4-dioxolane ring were tolerated as substrates as
well but furnished 4H-chromenes 3lb−nb in moderate yields
and rather low enantioselectivity (Scheme 3).
In order to gain a deeper understanding of the reaction
mechanism we performed several control experiments. First, we
tackled the obvious question of whether the Michael addition
of the nucleophile to the o-QM was catalyzed by the
phosphoric acid itself or rather by a manganese phosphate
complex (Table 2). Indeed, when the stable o-QM 2a was
treated with acetylacetone (5b) in the presence of phosphoric
acid HX*, product 3ab was obtained, but with an inverted
absolute configuration compared to the same reaction with
Mn(acac)3 (entries 1 and 2). This switch in enantioselectivity
has been observed before and occurs when metal phosphates
act as catalysts instead of the corresponding chiral phosphoric
acid.14 The conclusion that Mn(acac)2X* was in fact the active
catalyst for the Michael addition was further supported by using
Mn(acac)2X* as a separately prepared chiral catalyst which
provided product 3ab with comparable selectivity (entry 3).15
In addition, it could be shown that Mn(acac)3 (generated from
Mn(dbm)3 and acetylacetone (5b)) was also capable of
catalyzing the examined Michael addition (entry 4).
Next, the overall process starting from sesamol 4a as a
substrate was examined. No differences were observed when
phosphoric acid HX* was replaced by the aforementioned
manganese phosphate complex as a chiral catalyst (compare
entries 5 and 6). Interestingly, employing solely Mn(acac)2X*
in the presence of acetylacetone (5b) did not catalyze the
desired transformation and starting material 4a was completely
reisolated which indicated that the manganese phosphate
the ligands of the manganese precatalyst Mn(dbm)3 are
replaced by acetylacetone (5b). 30% of the so formed
Mn(acac)3 further reacts irreversibly with the phosphoric acid
HX* to give rise to the mixed manganese phosphate complex
Mn(acac)2X*. This complex acts as an effective chiral catalyst
for the Michael addition of acetylacetone (5b) toward the o-
QM 2a but is not capable of phenol oxidation and o-QM
formation. For this task, the remaining Mn(acac)3 is required,
and the oxidation catalyst is regenerated by oxygen as the
terminal oxidant.
In general, the nature of the oxidation as well as Michael
addition catalyst (MnL3 and MnL2X*) depends on the
structure of the applied nucleophile (5) because the β-
dicarbonyl compound also functions as a ligand for the
manganese complexes. This could explain the differences
observed when β-ketoesters 5c−e are used as reaction partners
C
DOI: 10.1021/acs.orglett.7b02185
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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In conclusion, we have developed a novel protocol to
synthesize electron-rich 4H-chromenes 3 using a relay catalysis
strategy. The approach comprises a catalytic, aerobic oxidation
of 2-alkylphenols 4 toward a transient o-QM 2 which was
trapped subsequently in a catalytic Michael addition with β-
dicarbonyl 5. These two central steps were catalyzed by two
coexisting manganese complexes which were generated in situ
from the precatalyst Mn(dbm)3 in the presence of a phosphoric
acid HX* and an excess of the β-dicarbonyl 5. A species of the
generalized structure MnL3 appeared to be the oxidation
catalyst whereas the manganese phosphate complex MnL2X*
controlled the enantioselective Michael addition. The reaction
was found to be very sensitive to structural changes within the
phenolic substrate and the β-dicarbonyl compound. Studies to
further elucidate the exact oxidation mechanism and expand the
substrate scope are currently underway in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02185.
Experimental procedures and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: schneider@chemie.uni-leipzig.de.
(11) Selected reviews: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744−
5758. (b) Terada, M. Chem. Commun. 2008, 4097−4112. (c) Zamfir,
A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol. Chem. 2010,
8, 5262−5276. (d) Terada, M. Synthesis 2010, 2010, 1929−1982.
(e) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2009, 291,
395−456. (f) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev.
2011, 40, 4539−4549. (g) Parmar, D.; Sugiono, E.; Raja, S.; Rueping,
M. Chem. Rev. 2014, 114, 9047−9153.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The European Social Fund (ESF) is gratefully acknowledged
for a predoctoral fellowship awarded to Matthias Spanka
(University of Leipzig) and the companies Evonik and BASF
for the donation of chemicals. We cordially thank Jonas
Kretzschmar (University of Leipzig) for preliminary experi-
ments.
(12) 31% of a byproduct resulting from cleavage of the C-2/C-3
bond prior to elimination were also isolated.
(13) Other transition metal β-dicarbonyl complexes were not
effective (see Supporting Information).
(14) Hatano, H.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem.,
Int. Ed. 2010, 49, 3823−3826.
(15) Preparation of manganese phosphate according to: Liao, S.; List,
B. Angew. Chem., Int. Ed. 2010, 49, 628−631.
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