Highly asymmetric NHC-catalyzed hydroacylation of unactivated alkenes

Article abstract of DOI:10.1002/anie.201008081

NHC-catalysis proto(n)type: The title reaction produces 21 different chroman-4-one-type products in good yields and excellent enantioselectivities, in each case building up a new all-carbon quaternary stereocenter (see scheme). Based on DFT calculations a

Full text of DOI:10.1002/anie.201008081

DOI: 10.1002/anie.201008081
Asymmetric Organocatalysis
Highly Asymmetric NHC-Catalyzed Hydroacylation of Unactivated
Alkenes**
Isabel Piel, Marc Steinmetz, Keiichi Hirano, Roland Frꢀhlich, Stefan Grimme,* and
Frank Glorius*
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
N-Heterocyclic carbene (NHC)-catalyzed umpolung reac-
tions[1] offer an elegant access to several important classes of
compounds, such as benzoins[2] or g-butyrolactones.[3] In
addition, Enders et al.[4] and Rovis et al.[5] have pioneered
the development of a powerful NHC-catalyzed formation of
highly functionalized chromanones by an intramolecular
Scheme 1. NHC-catalyzed hydroacylation of 2-allyloxy benzaldehyde
derivatives.
Stetter reaction.[6] Recently, we have reported the NHC-
catalyzed hydroacylation of unactivated olefins,[7] a reaction
previously only possible with transition-metal catalysts.[8] This
intramolecular reaction was also found to be a versatile
method for the synthesis of numerous racemic chromanones.
However, the mechanism remained unclear.
Moreover, based on quantum-chemical calculations, a mech-
anistic scenario and a mode of stereoinduction are proposed.
We began with the investigation of the enantioselective
cyclization of O-allylated o-vanillin derivative 1a (Table 1).
Using triazolylidenes derived from l-phenylalaninol good
yields were obtained with a catalyst loading of 5–10 mol%
even at 60–808C (compared to 1208C;[7a] Table 1). The
carbene generated from triazolium salt 3[11,12] showed excel-
lent reactivity (Table 1, entry 1). Other established chiral
NHCs also showed high, though slightly reduced levels of
either reactivity or selectivity; the N-mesityl substituent was
found to be especially valuable for reactivity and selectivity.
However, higher catalyst loadings of catalyst precursor 6 did
not result in significantly higher yields and selectivities.
Similarly, lowering the reaction temperature to 608C led to
only a moderate improvement of ee value (entries 4–6).
In contrast, 5 mol% of triazolylidene derived from 3
provided the desired chromanone 2a in an excellent yield
even at 608C (Table 1, entry 9). Moreover, using 10% of
catalyst gave a successful reaction even at room temperature
(entry 10). In addition, the reaction is insensitive to trace
amounts of water (entry 11). Using only 1 mol% of 3 at room
temperature still resulted in the formation of 26% of 2a,
together with 36% of benzoin product and 33% residual
starting material (entry 12). Based on the isolation of the
benzoin product in this reaction, it is reasonable to assume
that reversible benzoin formation takes place at room
temperature and at higher temperatures. After identifying
both the optimal triazolylidene catalyst and conditions, the
scope of this reaction using a range of substrates with
different substitution patterns of the aromatic ring was
examined (Table 2).
The highly asymmetric formation of all-carbon quater-
nary stereocenters is an important challenge in organic
synthesis,[9] because this structural motif commonly appears
in numerous biologically active compounds.[10] Even though
some methods have been developed, the synthetic armory is
still rather limited for this task.[9] Herein we report the highly
asymmetric hydroacylation of unactivated olefins, resulting in
the formation of 21 products mostly with 99% ee, each
containing a newly formed quaternary (48) stereocenter
(Scheme 1).[6c] In contrast to transition-metal-catalyzed cyclo-
isomerizations, which often suffer from side reactions, the
byproduct-free nature of this transformation is attractive.
[*] I. Piel, M. Steinmetz, Dr. R. Frꢀhlich, Prof. Dr. S. Grimme,
Prof. Dr. F. Glorius
Westfꢁlische Wilhelms-Universitꢁt Mꢂnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢂnster (Germany)
Fax: (+49)251-83-33202
E-mail: grimmes@uni-muenster.de
glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
index.html
Dr. K. Hirano
Stanford University, Chemistry Department
Stanford, CA 94305-5080 (USA)
[**] We are grateful to Karin Gottschalk for skillful technical assistance.
Generous financial support by the Deutsche Forschungsgemein-
schaft (SPP 1179 and SFB 858), the Fonds der Chemischen
Industrie, AstraZeneca, the International NRW Graduate School of
Chemistry (I.P.), and the Deutsche Akademische Austauschdienst
(K.H.) is gratefully acknowledged. The research of F.G. was
supported by the Alfried Krupp Prize for Young University Teachers
of the Alfried Krupp von Bohlen und Halbach Foundation.
NHC=N-Heterocyclic carbene.
Whereas 5 mol% of catalyst were sufficient for the full
conversion of substrate 1a, most of the other substrates 1
required up to 10 mol% of catalyst. Nevertheless, excellent
levels of enantioselectivity were observed throughout. Espe-
cially substrates with electron-donating substituents at the
2-position showed excellent reactivity (1a,b),[13] but electron-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008081.
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Communications
Table 1: Optimization of the reaction conditions.[a]
Table 2: Enantioselective hydroacylation of unactivated olefins.[a]
Entry
Variation of the standard conditions[a]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
none
10 mol% 4
10 mol% 5
97
30
92
79
63
79
99
99
99
99
97
26[f]
99
99
99[d]
86
20 mol% 6, 40 mol% DBU
10 mol% 6 at 1208C
20 mol% 6 at 608C in THF
10 mol% 3 at 608C in THF
10 mol% 3 at 558C in MTBE[e]
5 mol% 3 at 608C in THF
10 mol% 3 at RT in THF
10 mol% 3, 608C, THF, +0.5% H2O
1 mol% 3 at RT in THF
85
90
99
99
9
99
10
11
12
>99
>99
>99
[a] General conditions: 1 (0.25 mmol), 3 (10 mol%), DBU (20 mol%),
1,4-dioxane (0.5 mL), 808C, 20 h. Yields are of isolated product.
[b] Using 5 mol% 3, 10 mol% DBU, THF, 608C. [c] 8% of 2d was
isolated in an inseparable mixture together with 3% of a by-product.
[d] Absolute configuration established by single-crystal X-ray analysis.
[e] Determined by 1H NMR spectroscopy; mixture containing 75% of 2t
together with 19% of an inseparable by-product.
[a] Standard conditions: 1a (0.25 mmol), NHC·HX (10 mol%), DBU
(20 mol%), 1,4-dioxane (0.5 mL), 808C, and 20 h. [b] Yield of isolated
product. [c] Determined by HPLC on a chiral stationary phase. [d] Other
enantiomer obtained. [e] Non-dried tert-butyl methyl ether (MTBE) was
used. [f] Together with 33% remaining starting material and 36% of the
benzoin product.
withdrawing substituents, such as the trifluoromethyl group
(in 1c), were also tolerated. The transformation of aromatic
aldehydes with substituents in the 5-position leads to products
2d–k in good to excellent yields and remarkably high
enantioselectivities (99% ee) in all cases. Surprisingly, 5-
fluoro and 5-methyl derivatives 2d and 2k, respectively, were
obtained with lower yields, albeit without any loss of
enantioselectivity. In addition, the unsubstituted parent
system 2l and its sulfide-tethered analogue, thiochroman-4-
one 2m, were smoothly formed in 99% ee. Disubstituted
substrates led to the formation of dialkylated or dihalogen-
ated chromanones (2n–p). The absolute configurations of 2n
and 2p (as shown in Table 2) were unequivocally determined
by single-crystal X-ray diffraction.[14] Based on the very high
levels of enantioselectivity generally obtained in the present
study, it is reasonable to assume that all the chromananones
2a–u are formed with the same absolute configuration.
Finally, naphthaldehydes 1q,r also readily cyclized to the
tricyclic dihydronaphthopyran-1-ones (2q,r). Moreover, the
substitution pattern of the olefin could also be varied
successfully; electron-withdrawing and electron-donating
substituents on the aryl group were tolerated (2r–t). As
most chromanone motifs in natural products or pharmaceuti-
cally active compounds are substituted in the position a to the
oxygen tether,[15] we prepared substrate 1u. This undergoes
cyclization to the chromanone 2u in excellent yield and
enantiomeric excess, however, with a diastereomeric ratio of
1:1. Preliminary experiments to expand the scope to the
formation of dihydroquinolinones or the use of some other
olefin substitution patterns have not met with significant
success to date.[16]
The investigation of the reaction mechanism of this NHC-
catalyzed transformation was informative.[17] First, a simple
deuteration experiment allowed us to exclude the direct
involvement of the oxygen tether in the reaction mecha-
nism.[18] Second, in a competition experiment, we found that a
phenyl substituent on the olefin (R2 = Ph, Scheme 1) leads to
a slightly increased reactivity compared to the unsubstituted
olefin (R2 = H).[19] Furthermore, DFT calculations[19] were
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Angew. Chem. Int. Ed. 2011, 50, 4983 –4987

performed to get more insight into the crucial step of the
ꢀ
reaction, that is, whether the proton migration or the C C
bond formation occurs first. We investigated substrate 1l
together with catalyst generated from 3. The minima for the
open system 1Int (in which the NHC is already added), the
ring-closed intermediate 2Int, and the corresponding transition
state (TS) have been located. Two different dispersion-
corrected density functionals were employed which, qualita-
tively, yield the same picture. In the following only the results
including corrections to (relative) reaction enthalpies at the
B2PLYP-D/TZVPP/BP86-D/TZVP[20] level are discussed.
In Figure 1 the computed bond lengths and bond orders of
the TS are shown for a model system (derived from achiral
7
[18]). The character of the TS is very similar to that obtained
Figure 2. Calculated relative enthalpies at the B2PLYP-D level (relative
energies, at the same level, in parenthesis, BP86-D values in italics) for
ring-opened intermediate, transition states, and ring-closed intermedi-
ates in kcalmolꢀ1. The structures shown represent the diastereomeric
ꢀ
ꢀ
ꢀ
TSs (2TS1 and 2TS2). The formed C C and the O H/C H bonds
involved in the proton transfer are indicated by dotted lines.
Figure 1. Optimized hydrogen-transfer transition state of a model
system (BP86-D/TZVP). The bond lengths are in ꢃ and the Wiberg
bond orders are shown in parenthesis.
is formed, leading to the formation of S-configured chroma-
nones, and explaining the high stereoselectivity in the experi-
ments.
In conclusion, we have developed a highly asymmetric
NHC-catalyzed intramolecular hydroacylation of unactivated
olefins which gives chromanone derivatives containing all-
carbon quaternary stereocenters. In addition, quantum-chem-
ical calculations support a concerted but very asynchronous
transition state. These results should be helpful for developing
related transformations.
for the chiral NHC. Starting from the open system 1Int, the
alkoxy chain first undergoes a conformational rearrangement
to bring the reacting parts close together. The TS corresponds
to a genuine proton transfer from the hydroxy group to the
terminal carbon atom of the double bond. The OH bond is
elongated to 1.226 ꢀ and the distance between the H and the
C atom is 1.388 ꢀ in the TS. These values and the
corresponding bond orders (0.47 and 0.46, respectively)
indicate that the OH bond is half broken and the newly
ꢀ
created C H bond is half formed. Note the favorable stacking
interaction of the two aromatic rings in the TS. By displace- Experimental Section
General procedure: the aldehyde (0.25 mmol, 1.0 equiv), the triazo-
ment along the transition mode and further unrestricted
geometry optimization, no other intermediate was found
lium salt 3 (10 mol%, 0.025 mmol, 9.3 mg), and 1,4-dioxane (0.5 mL)
were added to a flame-dried screw-capped test tube equipped with a
magnetic stir bar. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was
added (20 mol%, 0.05 mmol, 7.5 mL) and the resulting mixture was
stirred in a pre-heated oil bath at 808C for 20 h. The reaction was
cooled to ambient temperature, pre-absorbed on silica gel and
purified by flash column chromatography on silica gel (typically
n-pentane/EtOAc = 20/1!5/1).
ꢀ
implying the direct formation of the C C bond. Thus, the first
important conclusion from these computations is that the
reaction mechanism is of a one-step type.
We also considered theoretically the mode of stereoin-
duction caused by employing a chiral catalyst. We combined
mirror images of the substrate with a fixed absolute config-
uration of 3. The computed lower barrier of 10 kcalmolꢀ1 is
compatible with a fast reaction between room temperature
and 808C. In one of the diastereomeric transition states, steric
hindrance between the benzyl group of the catalyst and the
substrate causes a large energy difference. The barrier for 2TS2
is computed to be 5.5 kcalmolꢀ1 higher than for 2TS1
(Figure 2). The same trend holds for the relative energies of
the intermediates, that is, 2Int2 is less stable than the starting
Received: December 21, 2010
Revised: February 17, 2011
Published online: April 14, 2011
Keywords: enantioselective catalysis · hydroacylation ·
.
N-heterocyclic carbenes · organocatalysis · Stetter reaction
ꢀ
material. The basic reason is that in 2Int2 the C C bond (ring)
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www.angewandte.org 4985

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species:
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