Direct asymmetric α benzoyloxylation of cyclic ketones

Article abstract of DOI:10.1002/anie.201104244

It's amine business: A readily available cinchona-derived primary amine is an effective catalyst for the direct asymmetric α benzoyloxylation of cyclic ketones (see scheme; Bz=benzoyl). This efficient and highly enantioselective method uses inexpensive be

Full text of DOI:10.1002/anie.201104244

Communications
DOI: 10.1002/anie.201104244
Organocatalysis
Direct Asymmetric a Benzoyloxylation of Cyclic Ketones**
Olga Lifchits, Nicolas Demoulin, and Benjamin List*
Enantiomerically pure a-oxygenated carbonyl compounds
are ubiquitous structures in natural products and pharma-
ceuticals, and important building blocks in organic synthesis.
Consequently, the enantioselective introduction of an oxygen
moiety at the a position of carbonyl groups continues to be an
intensely investigated field.[1] In this context, enamine catal-
ysis recently became a powerful approach for the direct
asymmetric a oxygenation of ketones and aldehydes, thus
avoiding the need of preforming an enolate equivalent.[2] In
particular, the a aminoxylation of aliphatic ketones and a-
unbranched aldehydes with nitrosobenzene has been estab-
lished as a reliable oxidation method.[3] However, despite the
excellent enantioselectivity of this method, limitations
remain. Most importantly, a several-fold excess of the
carbonyl substrate is typically required, thus limiting the
method to inexpensive starting materials and the early stages
of a multistep synthesis.[4] Furthermore, reactions with a-
branched aldehydes invariably give inseparable mixtures of
aminoxylation and nitroso aldol products, favoring the latter
and resulting in only moderate enantioselectivity for the a-
oxygenated product (up to 45% ee).[5] Recently, Maruoka and
co-workers, and others have introduced benzoyl peroxide as a
useful, readily available, and inexpensive reagent for the
asymmetric a benzoyloxylation of simple a-unbranched alde-
hydes.[6] Herein we report a highly enantioselective a ben-
zoyloxylation of stoichiometric amounts of cyclic ketones
catalyzed by readily available cinchona-alkaloid-derived
primary amines.
In the previous methods for the a benzoyloxylation of
aldehydes, bulky secondary amine catalysts were used to
avoid catalyst decomposition by oxidation.[2c,6a] This may well
be the reason why no other, more sterically demanding
substrate classes have been applied to this catalyst system to
date [Eq. (1); Bz = benzoyl]. We have recently established
cinchona-alkaloid-derived primary amines in the catalytic
asymmetric epoxidation of enones and a-branched enals,[7]
thus demonstrating the excellent stability and reactivity of
these catalysts toward challenging substrate classes. Indeed,
the observed robustness of the primary amine moiety may be
attributed to its lower reactivity toward oxidation compared
to secondary amines,[8] which are classically used in organo-
catalysis. Nevertheless, while numerous secondary amine
catalysts have been employed in the a oxygenation of
aldehydes and ketones,[2] the use of primary amines in this
transformation has been virtually non-existent.[9] This is
surprising in light of the growing use of primary amine
catalysts for the functionalization of diverse substrate classes,
including ketones, enones, a-branched enals, and alde-
hydes.[10]
On the basis of these considerations, we envisioned that
the readily available primary amines of type 9, derived in a
single step from cinchona alkaloids, could catalyze a direct
enantioselective a oxygenation of ketones. In particular, we
wished to develop a method that is stoichiometric in the
carbonyl reagent and introduces a usefully protected oxygen
functionality.
We began our investigation using cyclohexanone (1a) as
the model substrate, a slight excess (1.5 equiv) of anhydrous
benzoyl peroxide (2), and 10 mol% of the radical inhibitor
2,6-di-tert-butyl-4-methylphenol (BHT; 3) to avoid possible
benzoyl radical side reactions. Initial catalyst studies con-
firmed our expectation that the commonly used secondary
amines are ineffective catalysts, presumably because of their
low activity and concurrent decomposition. Thus, 10 mol% of
(S)-proline (5) gave the desired product with 11% conversion
after 24 hours, and this conversion did not increase over the
next 5 days, while the diarylprolinols 6 and 7 resulted in no
conversion[11] (Table 1, entries 1–3). In contrast, a trichloro-
acetic acid salt of the quinine-derived catalyst 9 catalyzed the
a benzoyloxylation of cyclohexanone with an encouraging
56% yield and excellent enantioselectivity (97:3 e.r.), the
remaining reaction mixture consisting only of the unreacted
starting materials (entry 4).
Encouraged by this result, we set out to further optimize
the reaction conditions. Increasing the concentration to 1m
had a positive effect on conversion (Table 1, entry 5);
however, further increase in the concentration led to appre-
ciable formation (11%) of the dibenzoyloxylation product
(entry 6). A screen of acid co-catalysts revealed that both the
amount and the nature of the acid influenced the enantiose-
lectivity. In particular, higher loading of trichloroacetic acid
(40 mol%) led to partial racemization of product 4a
(entry 7). Substituting the acid co-catalyst with diphenyl
hydrogen phosphate improved the conversion but slightly
[*] O. Lifchits, Dr. N. Demoulin, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470, Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[**] We thank Prof. Cristina Nevado of the University of Zꢀrich for
encouraging this study. We acknowledge generous funding from the
Max-Planck-Society.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104244.
9680
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9680 –9683

Table 1: Evaluation of the reaction conditions for the asymmetric
benzoyloxylation of cyclohexanone 1a.
Table 2: Scope of the asymmetric a benzoyloxylation of ketones.
Entry[a]
1
Product[b]
Yield [%][c]
e.r.[d]
67
97:3 (>99:1)[e]
4a
4b
61[f]
96.5:3.5[f]
2
78
94.5:5.5
Entry Catalyst
(amine, acid)
Solvent
Conc. [m] Yield [%][a] e.r.[b]
3[g]
4c
66
63
52
95:5
95:5
1
5
DMSO
THF
THF
THF
THF
THF
THF
THF
0.5
0.5
0.5
0.5
1
11
0
0
–
–
–
2
6
3
7
97:3[c]
97:3
97:3
85:15
96:4
93:7
89:11
8:92[e]
12:88[e]
97:3
57:43
4[g,h]
ent-4c
4
5
6
7
9·Cl3CCO2H
9·Cl3CCO2H
9·Cl3CCO2H
9·4 Cl3CCO2H
9·(PhO)2PO2H
56
67
66[d]
56
83
48
65
51
88
76
29
2
1
1
1
1
1
1
1
8
5
6
4d
4e
95.5:4.5
94:6
(89 brsm)
9
10·(PhO)2PO2H THF
11·(PhO)2PO2H THF
12·(PhO)2PO2H THF
13·(PhO)2PO2H THF
9·Cl3CCO2H
8·(R)-TRIP
10
11
12
13
14
63
45
1,4-dioxane
THF
1
[a] Determined by 1H NMR spectroscopy using triphenylmethane as an
internal standard. [b] Determined by HPLC analysis using a chiral
stationary phase. [c] The absolute configuration (S) was determined by
comparison of the optical rotation of 4a with the literature value.[13]
[d] 11% of the dibenzoyloxylated product was also observed. [e] Product
obtained with the R configuration. DMSO=dimethylsulfoxide,
THF=tetrahydrofuran, TMS=trimethylsilyl, TRIP=3,3’-bis(2,4,6-triiso-
propylphenyl)-1,1’-bi-2-napththol cyclic monophosphate.
7
8
4 f
92:8
96:4
77
4g
(>20:1 r.r.)[i]
60
9[j]
4h
4i
(18:1 d.r.)
>99:1[k]
(12:1 r.r.)[i]
diminished the enantioselectivity (entry 8). An examination
of related cinchona-derived amines showed no improvement
in the reaction (entries 9–12). After a screen of solvents,[12]
1,4-dioxane was chosen as the optimal reaction medium
(entry 13). We also tested a combination of the achiral amine
8 to activate the ketone as an enamine, and the chiral
Brønsted acid (R)-TRIP for the activation of benzoyl
peroxide (entry 14). Intriguingly, while the chemical yield
was low, some enantioselectivity (57:43 e.r.) was observed.
With the optimized reaction conditions in hand, we
explored the scope of the asymmetric a benzoyloxylation
with respect to ketone substrates (Table 2). Various six-,
seven-, and eight-membered carbocyclic and heterocyclic
ketones cleanly underwent a benzoyloxylation, thus affording
the desired products 4 with good yields and excellent
enantioselectivities. By using the related pseudoenantiomeric
catalyst 13, products with the opposite configuration could be
generated with equal efficiency (entries 3 and 4). A range of
functional groups were tolerated in the reaction, including an
acetal, an olefin, and a carbamate (entries 5–7). The b,b-
disubstituted substrate 1g afforded product 4g as a single
57
10
(18.5:1 d.r.)
>99:1[k]
(2:1 r.r.)[i]
11[g,l]
4j
74
98:2
12[g,l]
4k
81[m]
98:2
[a] Reaction scale: 0.4 mmol. [b] The absolute configuration of products
4 was assigned by comparison of the optical rotation with the literature
values or by analogy (see the Supporting Information for details).
[c] Yield of isolated product. [d] Determined by HPLC analysis using a
chiral stationary phase. [e] After a single recrystallization. [f] Using 2-
methyltetrahydrofuran as solvent. [g] Using (PhO)2PO2H as the acid co-
catalyst. [h] Using catalyst 13. [i] r.r.=regioisomeric ratio. [j] Using
catalyst 12. [k] Enantiomerically pure starting material 1h was used.
[l] Using 2 equiv of the ketone. [m] Contains 11% of the dibenzoyloxy-
lated product. Boc=tert-butoxycarbonyl, brsm=based on recovered
starting material.
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9681

Communications
regioisomer (entry 8), whereas the enantiopure
substrate 1h underwent a highly regioselective
and trans-diastereoselective benzoyloxylation
(entry 9) with the pseudoenantiomeric catalyst
12. Highly cis-selective a benzoyloxylation was
also possible for this substrate with catalyst 9,
albeit with reduced regioselectivity (entry 10). In
all cases, less than 5% of the dibenzoyloxylated
ketone was observed as the only by-product,
except for cycloheptanone and cyclooctanone
(entries 10 and 11), where overoxygenation was
a competitive process that could be effectively
suppressed by using two equivalents of the
starting material. We also examined the compat-
ibility of our reaction with the environmentally
benign and industrially valuable solvent 2-meth-
yltetrahydrofuran. Gratifyingly, the reaction with
ketone 1a afforded the product with similar yield
and enantioselectivity (entry 1).
Acyclic and large ring-sized (n > 8) ketones
currently represent a limitation of this method, as
they undergo a benzoyloxylation with very poor
conversion (< 5%), possibly owing to the low
nucleophilicity of the generated unstrained enam-
ine intermediates.
To probe the utility of our method in prepa-
rative synthesis, we performed the reaction with
ketone 1a on a fivefold scale (2 mmol, 0.4 g) and
were pleased to obtain the corresponding product
4a with a good yield (76%) and essentially
uncompromised enantioselectivity (95.5:4.5 e.r.),
which could be readily improved to 99.5:0.5 e.r.
by a single recrystallization. Furthermore, we
tested a substrate with a complex pre-existing
architecture, where use of stoichiometric amounts
of the ketone is particularly valuable. From
cholestanone (1l), we could successfully obtain
Figure 1. a) Proposed transition state. b) Behavior of the catalyst salt 9·Cl3CCO2H
toward benzoyl peroxide in the absence of a ketone substrate. c) 1H NMR study of
the conversion of 9·Cl3CCO2H into 15 over time (peak corresponds to proton 2’ of 15
the corresponding benzoyloxylated product 4l[14] in [D8]THF).
with excellent regio- and diastereocontrol, and a
high yield [Eq. (2)].
dine nitrogen atom is transiently benzoyloxylated (structure
14), but slowly rearranges to form compound 15 (Fig-
ure 1b,c).[12,15] Although 15 is completely inactive, quinucli-
dine benzoyloxylation of catalytically relevant intermediates
cannot be ruled out at this point. As such, a transfer of the
benzoyloxy moiety from the quinuclidine nitrogen atom onto
the enamine through an intramolecular rearrangement[6a]
could be envisioned (transition state B). Detailed mechanistic
studies aimed at elucidating the structure of the active
enamine intermediates are currently underway in our labo-
ratories.
In conclusion, we have developed an operationally safe
and simple methodology for the a benzoyloxylation of
ketones, which delivers valuable benzoyl-protected hydroxy-
ketones 4 with good yields and high enantioselectivities. This
transformation utilizes a readily available salt of a primary
amine catalyst and stoichiometric amounts of various func-
tionalized ketones, and can be scaled up without loss of yield
or enantioselectivity. In addition, preliminary investigations
Mechanistically, we propose that the primary amine
catalyst 9 activates ketones as enamines that nucleophilically
attack benzoyl peroxide. In particular, we believe that the
transition state involves an intermolecular attack of the
enamine onto benzoyl peroxide, which is activated by the
protonated quinuclidine nitrogen atom of the catalyst 9
(Figure 1a, transition state A). 1H NMR studies of the
catalyst salt 9·Cl3CCO2H treated with benzoyl peroxide in
the absence of a ketone substrate suggest that the quinucli-
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Angew. Chem. Int. Ed. 2011, 50, 9680 –9683

2009, 2685. Reaction-specific optimization and higher catalyst
loading to achieve a method stoichiometric in aldehyde has also
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on challenging a-branched aldehydes have identified a highly
promising catalytic system that delivers aldehydes containing
an a-quaternary stereocenter with very good yields and
promising enantioselectivities. Results on the studies of this
substrate class will be reported in due course.
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Experimental Section
a Benzoyloxylation of ketones 1: A 2 mL vial, equipped with a
magnetic stirring bar, was charged with 2,6-di-tert-butyl-4-methyl-
phenol (BHT) (9.0 mg, 0.0408 mmol, 10 mol%), catalyst 9 (13.3 mg,
0.408 mmol, 10 mol%), trichloroacetic acid (6.6 mg, 0.0408 mmol, 10
mol%), ketone 1 (0.408 mmol), and 1,4-dioxane (0.4 mL) and then
stirred for 5 min before adding anhydrous benzoyl peroxide (147 mg,
0.612 mmol, 1.5 equiv). The reaction mixture was stirred at 308C for
24–48 h, diluted with dichloromethane, and treated with a saturated
aqueous solution of NaHCO3, extracted three times with dichloro-
methane, washed with brine, dried over Na2SO4, filtered, concen-
trated to approx. 1 mL and purified by flash column chromatography
on silica gel eluting with a specified mixture of n-pentane and Et2O.
The enantioselectivity was determined by HPLC analysis using a
chiral stationary phase.
[8] C. F. Cullis, I. Isaac, Trans. Faraday Soc. 1952, 48, 1023.
[9] To the best of our knowledge, there are no reports on the use of
primary amine catalysis for the enantioselective a oxygenation
of carbonyl compounds. A recent publication describing the use
Received: June 20, 2011
Published online: August 31, 2011
of
a primary amine catalyst in the reaction between a-
Keywords: asymmetric catalysis · ketones · organocatalysis ·
oxidation · synthetic methods
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[11] Catalyst
7 was shown to be moderately effective in the
benzoyloxylation of propanal (38% yield, 83% ee); however
propanal was used in excess (3 equiv): see Ref. [6c].
[12] See the Supporting Information for further details.
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