Direct and enantioselective a-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis

Article abstract of DOI:10.1073/pnas.1002845107

The first enantioselective organocatalytic a-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated ena

Full text of DOI:10.1073/pnas.1002845107

Direct and enantioselective α-allylation of ketones
via singly occupied molecular orbital (SOMO) catalysis
Anthony Mastracchio, Alexander A. Warkentin, Abbas M. Walji, and David W. C. MacMillan1
Merck Center for Catalysis at Princeton University, Princeton, NJ 08544
Edited by Eric N. Jacobsen, Harvard University, Cambridge, MA, and approved August 3, 2010 (received for review March 5, 2010)
The first enantioselective organocatalytic α-allylation of cyclic ke-
tones has been accomplished via singly occupied molecular orbital
catalysis. Geometrically constrained radical cations, forged from
the one-electron oxidation of transiently generated enamines,
readily undergo allylic alkylation with a variety of commercially
available allyl silanes. A reasonable latitude in both the ketone and
allyl silane components is readily accommodated in this new trans-
formation. Moreover, three new oxidatively stable imidazolidi-
none catalysts have been developed that allow cyclic ketones to
successfully participate in this transformation. The new catalyst
platform has also been exploited in the first catalytic enantioselec-
tive α-enolation and α-carbooxidation of ketones.
Scheme 1.
ine catalysis (24), a reaction mode wherein a catalytic amount of
a chiral enamine exhibits increased propensity to react with a
broad selection of electrophiles by raising the highest occupied
molecular orbital (HOMO).
In view of the established utility of these activation modes for
the development of a variety of previously undisclosed, valuable
transformations, we recently wondered if the existing two-electron
interconversion between iminium and enamine species could be
redirected to utilize a 3π electron species and thereby establish
a previously undescribed reaction platform that relies on SOMO
intermediates (20). In pursuit of this goal, three design elements
proved to be extremely important: First, selective oxidation of
an equilibrium concentration of enamine in lieu of the aldehyde
substrate and amine catalyst was imperative. Known ionization
potentials of analogous substrates indicated that such a selective
oxidation was indeed feasible (Scheme 3) (20). The second design
element required the identification of an amine catalyst that could
generically provide high levels of enantiodiscrimination in the
subsequent bond-forming processes with π-rich SOMOphiles.
Density functional theory (DFT) calculations indicated that the
radical cation derived from imidazolidinone catalyst 1 is parti-
tioned away from the bulky tert-butyl group and that the carbon-
centered radical populates an (E)-geometry in order to minimize
allylic nonbonding interactions with the imidazolidinone frame-
work (Scheme 3) (20). The enantiodetermining event would then
be governed by C-5 benzyl shielding of the Re face, leaving the
Si face exposed. Finally, the propensity of the SOMO intermediate
to engage in stereodefined C─C bond formation with a large vari-
ety of π-rich nucleophiles was anticipated.
Importantly, the successful realization of this previously unre-
ported catalytic activation mode has enabled our laboratory to
introduce a variety of previously unprecedented enantioselective
transformations. Examples include the direct allylic alkylation
(20), the α-arylation (20, 25), α-enolation (26), α-vinylation (27),
α-carbooxidation of alkenes (28), α-nitro alkylation en route to
corresponding amino acids (29), as well as α-chlorination (30)
(Scheme 4). Given the high synthetic utility of these enantioen-
riched aldehyde synthons, we recently recognized the importance
(as well as the potential difficulties) in extending this SOMO
catalysis concept to ketonic motifs.
asymmetric synthesis ∣ organocatalysis
he enantioselective catalytic α-alkylation of simple ketones
T
remains a fundamental goal in chemical synthesis (1–4). Semi-
nal work from Doyle and Jacobsen (5), Trost and co-workers
(6–8), Stoltz and co-workers (9, 10), Braun and co-workers
(11, 12), and Hartwig and co-workers (13, 14) has introduced
valuable previously undescribed technologies for (i) the enantio-
selective alkylation of preformed or in situ generated metal
enolates (5, 6, 11–17) and (ii) the asymmetric and decarboxylative
conversion of allyl keto carbonates to α-allylated ketones (7–10).
With these key advances in place, a goal now for asymmetric
catalysis has become the direct α-allylation of simple ketone sub-
strates (18, 19), an elusive yet potentially powerful bond construc-
tion (Scheme 1).
Recently, we questioned whether the catalytic principles of
singly occupied molecular orbital (SOMO) activation (20) might
be translated to ketonic systems, thereby providing an unreported
mechanism for direct and enantioselective α-carbonyl alkylation.
Despite the superficial similarities between aldehydes and ke-
tones, these carbonyl families exhibit largely different steric and
electronic properties with respect to catalyst interactions. As a
consequence, the translation of enantioselective activation modes
between these carbonyl subclasses is often difficult (if not unat-
tainable in many cases) (21, 22). Herein, we describe the invention
of a previously undisclosed family of organocatalysts that enable
cyclic ketones to successfully function within the SOMO-activa-
tion platform while being chemically robust to oxidative reagents.
Moreover, we document the introduction of a previously unde-
scribed catalytic α-ketone alkylation reaction that is immediately
amenable to asymmetric induction.
Enantioselective SOMO Catalysis
Over the last decade, the field of enantioselective synthesis has
witnessed tremendous progress in the successful implementation
of small organic molecules as asymmetric catalysts. In particular,
two modes of carbonyl activation by chiral secondary amines have
led to the discovery of a large number of previously undescribed
reactions (Scheme 2): (i) Iminium catalysis (23), wherein lowest
unoccupied molecular orbital (LUMO) lowering activation is ac-
complished via the transient condensation of an α,β-unsaturated
aldehyde and an amine catalyst, has enabled the enantioselective
conjugate addition or cycloaddition of enals with a wide range of
external π-nucleophiles or cycloaddition partners and (ii) enam-
Author contributions: A.M., A.A.W., A.M.W., and D.W.C.M. designed research; A.M.,
A.A.W., and A.M.W. performed research; A.M., A.A.W., and A.M.W. analyzed data; and
A.M., A.A.W., and D.W.C.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed. E-mail: dmacmill@princeton.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1002845107/-/DCSupplemental.
20648–20651 ∣ PNAS ∣ November 30, 2010 ∣ vol. 107 ∣ no. 48
www.pnas.org/cgi/doi/10.1073/pnas.1002845107

Scheme 2. An evolution of activation modes in organocatalysis.
Results and Discussion
The application of our SOMO-activation platform to enantiose-
lective ketone allylation was first evaluated with cyclohexanone,
allyltrimethylsilane, ceric ammonium nitrate, and 20 mol% of
imidazolidinone 2, an amine catalyst that has previously enabled
Diels–Alder reactions with cyclic enones via iminium activation
(21, 22). As revealed in Scheme 5, we were happy to find that
the critical alkylation step could be achieved in both a direct
and enantioselective fashion using imidazolidinone 2; however,
competitive catalyst degradation (via methyl furan oxidation)
consistently led to poor levels of reaction efficiency (Scheme 5,
42% yield, 93% ee).
Heartened by these initial results, we sought to design a second
generation catalyst that would be less prone to oxidation while
retaining the critical architectural features that confer enantio-
control. In this context, we hypothesized that either (a) derivati-
zation of the furan methyl group of catalyst 2 to a trifluoromethyl
moiety (4), or (b) direct replacement of the furyl ring with het-
eroaryl systems that are less electron-rich (e.g., benzofuran 5,
benzothiophene 6) might render a more robust system. Indeed,
imidazolidinones 4, 5 and 6 were all found to catalyze the direct
α-allylation of cyclohexanone in good yield while maintaining
excellent levels of enantioselectivity (75–85% yield, 88–94% ee).
The broad-spectrum utility of this unreported imidazolidinone
family 4–6 prompted us to initiate our investigation into substrate
scope using all three catalysts.
Scheme 4. Selected transformations using SOMO catalysis.
Experiments that probe the scope of the ketone component
have revealed that a variety of four-, five-, and six-membered
carbocycles and heterocycles can be readily employed in this
asymmetric alkylation reaction (Table 1, entries 1–9, 84–99%
ee). Moreover, this protocol is successful with ketones that incor-
porate alkyl and heteroatom substituents at the β and γ ring posi-
tions, an important consideration with respect to natural product
synthesis (entries 2, 4, 6, and 8, 85–99% ee). Furthermore, this
protocol is generally successful with only two equivalents of ke-
tone, although 20 equivalents are required for the cyclobutane
example. Perhaps most notable, we have found that nonsymme-
trical cyclic ketones such as 3-pyrrolidinones (entry 6) and 3-fur-
anones (entry 7) afford exclusively the C(4)-alkylation product
as determined by GLC (>200∶1) or HPLC (>100∶1) analysis.
These results are striking given that the 2-enamine isomer should
be formed competitively [based on kinetic acidities (31)] and
more readily oxidized (based on ionization potentials) (32). With
respect to 3-methylcyclohexanone, we assume that the observed
sense of regiocontrol can be explained on the basis of steric
constraints (entry 8, 99% ee). Curiously, cyclopentanone under-
goes exclusive formation of the C2-symmetric 2,5-bis-allylation
product (entry 9, 99% ee) (33). Given that 2-allylcyclopentanone
(12) is not converted to this C2-bis-allylation adduct when
exposed to the same reaction conditions, we presume that the
first cyclopentanone alkylation step leads to an iminium/enamine
species that undergoes a second oxidation-allylation sequence
faster than iminium hydrolysis. It is important to note that the
Scheme 3. Relevant ionization potentials of reactive species; DFT minimized
radical cation; representative transformations.
Scheme 5. Initial result of direct ketone allylation.
Mastracchio et al.
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Table 1. Scope of direct ketone allylation.*,†
1
2
3
6
4, 82%, 91% ee
4, 76%, 90% ee
4, 85%, 90% ee
5, 66%, 91% ee
4, 78%, 90% ee
6, 77%, 85% ee
Scheme 6. Catalyst design and reaction efficiency.
In summary, we have developed a family of oxidatively stable imi-
dazolidinone catalysts 4–6 that are readily employed for the
SOMO activation of cyclic ketones. These catalysts allow the
direct α-allylation, α-enolation, and α-carbooxidation of carbo-
cyclic ketones with excellent levels of enantiocontrol. Further ap-
plication of these organocatalytic methodologies will be reported
shortly.
4
5‡
7§
8§
9§
Methods
Full experimental details and spectral data are included in SI Text.
5, 79%, 84% ee
5, 85%, 91% ee
5, 70%, 5∶1 dr, 99% ee
5, 71%, 99% ee
4, 83%, 81% ee
General Procedure for the α-Allylation of Ketones. To a 10-mL oven-dried
round-bottom flask equipped with a magnetic stir bar was added cocatalyst
trichloroacetic acid or HCl (0.15 mmol, 0.20 eq), imidazolidinone catalyst
4⋅TFA, 5, or 6 (0.15 mmol, 0.20 eq) (as indicated below), NaHCO3 (94.9 mg,
1.13 mmol, 1.50 eq), and ceric ammonium nitrate (1.03 g, 1.88 mmol,
2.50 eq). The reaction vessel was evacuated by high vacuum (0.3 torr) at
−78 °C for 1 min. After backfilling with argon, tetrahydrofuran (3.0 mL,
0.25 m) and water (10–20 eq, as indicated below) were added to the reaction
vessel, and the reaction mixture was subsequently degassed by repeated
evacuation and backfilling with argon (three cycles of 2 min each) at
−78 °C. The allyl silane (0.75 mmol, 1.00 eq) was then added via syringe fol-
lowed by the respective ketone (1.50 mmol, 2.00 eq). The reaction vessel
was moved from the −78 °C bath into a −20 °C cooling bath and stirred with
a high rate of vortex for 24 h under argon atmosphere. At the end of the in-
dicated reaction time, diethyl ether (5.0 mL) was added to the crude mixture
and stirring was continued at −78 °C for 20 min to precipitate the cerium salts.
Filtration through a plug of silica gel using diethyl ether as a solvent concen-
tration under reduced pressure furnished the crude product as a yellowish
liquid, which was purified by flash chromatography to afford the analytically
pure α-allylated ketone.
10§
11
14
12
4, 82%, 91% ee
13
15§
6, 86%, 96% ee
6, 80%, 83% ee
5, 74%, 87% ee
*For each entry: catalyst #, % yield, % ee.
†Enantiomeric excess determined by chiral HPLC, supercritical fluid
chromatography, or GLC analysis.
‡Performed with 20 eq of ketone.
§Performed in the absence of NaHCO3.
sense of asymmetric induction observed in all cases (Table 1 and
Schemes 5–7) is consistent with selective engagement of the
SOMOphile with the Si face of the radical cation, in accord with
the calculated structure (DFT-3) (34).
Method A. The general procedure was followed using (2R;5R)-5-benzyl-3-
methyl-2-(benzofuran-2-yl)imidazolidin-4-one (5) (46 mg, 0.15 mmol,
0.20 eq) and trichloroacetic acid (24 mg, 0.15 mmol, 0.20 eq) in the presence
of water (0.27 mL, 15 mmol, 20 eq) without the addition of NaHCO3.
The nature of the allyl silane component in this ketone
alkylation reaction has also been evaluated. As revealed in Table 1,
this catalytic protocol can accommodate π-rich olefinic silanes
(entries 10–13, 82–86% yield, 81–96% ee) as well as electron-
deficient silanes (entries 14–15, 74–80% yield, 83–87% ee),
including a vinyl bromide (entry 15, 74% yield, 87% ee). Such
halogenated olefin adducts should prove to be valuable synthons
for use in conjunction with established cross-coupling methodol-
ogies (e.g., Buchwald–Hartwig or Stille couplings).
Method B. The general procedure was followed using (2R;5R)-5-benzyl-3-
methyl-2-(benzothiophen-2-yl)imidazolidin-4-one (6) (48 mg, 0.15 mmol,
In an effort to further demonstrate synthetic utility, we have
sought to apply our ketone-SOMO-activation platform to a series
of bond constructions that have only previously been possible
with aldehydic substrates. For example, catalyst 6 has successfully
enabled the enantioselective α-enolation of cyclohexanone under
oxidative conditions (chemical formula 1, Scheme 7, 84% ee).
Moreover, the asymmetric α-homobenzylation of cyclohexanone
can also be accomplished via a two-step α-carbo-oxidation-
hydrogenation sequence using the same imidazolidinone catalyst
(chemical formula 2, Scheme 7, 80% ee) (26, 28).
Scheme 7. General utility of ketone α-functionalization.
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Mastracchio et al.

0.20 eq) and conc. HCl (6.0 μL, 0.20 eq, 0.15 mmol) in the presence of water
(0.27 mL, 15 mmol, 20 eq) and NaHCO3 (94.5 mg, 1.12 mmol, 1.50 eq).
ACKNOWLEDGMENTS. The authors thank Hui-Wen Shih for invaluable assis-
tance performing Gaussian DFT calculations. Financial support was provided
by the National Institute of General Medical Sciences (R01 01 GM093213-01)
and kind gifts from Amgen and Merck.
Method C. The general procedure was followed using the trifluoroacetic
acid salt of (2R;5R)-5-benzyl-3-methyl-2-(5-trifluoromethylfuran-2-yl)imidazo-
lidin-4-one (4⋅TFA) (63 mg, 0.15 mmol, 0.20 eq) in the presence of water
(0.14 mL, 7.5 mmol, 10 eq) and NaHCO3 (94.5 mg, 1.5 eq, 1.12 mmol).
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