Hexafluorobenzene: A powerful solvent for a noncovalent stereoselective organocatalytic Michael addition reaction

Article abstract of DOI:10.1039/c2cc17488j

A dramatic enhancement of the diastereo- and enantioselectivity in the nitro-Michael addition reaction organocatalysed by a commercially available α,α-l-diaryl prolinol was disclosed when performing the reaction in unconventional hexafluorobenzene as a me

Full text of DOI:10.1039/c2cc17488j

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 1650–1652
www.rsc.org/chemcomm
COMMUNICATION
Hexafluorobenzene: a powerful solvent for a noncovalent stereoselective
organocatalytic Michael addition reactionwz
Alessandra Lattanzi,*a Claudia De Fusco,a Alessio Russo,a Albert Poaterb and
Luigi Cavallo*ac
Received 30th November 2011, Accepted 8th December 2011
DOI: 10.1039/c2cc17488j
A dramatic enhancement of the diastereo- and enantioselectivity
in the nitro-Michael addition reaction organocatalysed by a
commercially available a,a-L-diaryl prolinol was disclosed when
performing the reaction in unconventional hexafluorobenzene as
a medium. DFT calculations were performed to clarify the origin
of stereoselectivity and the role of C6F6.
fluorine–ruthenium interactions might be responsible for the
observed amplifications. Aromatic non-polar solvents, such as
toluene and xylenes, are well-recognised as the most suitable
media to use in noncovalent organocatalysis. Indeed, they do
not interfere with hydrogen bonding and more generally, polar
interactions, established among the catalyst and the reagents
responsible for catalytic activity and stereocontrol.7 Taking into
account that hexafluorobenzene is a non-polar solvent (e = 2.05),8
we were intrigued by the fact that it might positively influence the
outcome of organocatalytic processes. The asymmetric Michael
addition is a powerful and extensively applied reaction for the
construction of C–C and C–heteroatom bonds.9 Recently, we
have been interested in the development of asymmetric organo-
catalytic reactions mediated by commercially or easily available
a,a-L-diaryl prolinols.10 These compounds proved to be effective
in a variety of asymmetric Michael addition reactions providing
noncovalent activation of the reagents. Hence, we choose to study
the activity of a,a-L-diaryl prolinols in the conjugate addition of
1,3-dicarbonyl compounds to nitroalkenes as a model reaction.
Herein, we report the experimental and computational investiga-
tion of a remarkable solvent effect disclosed in the nitro-Michael
addition reaction for the construction of vicinal tertiary and
quaternary stereocenters catalysed by commercially available
a,a-L-diaryl prolinols in C6F6 as solvent.11
The nitro-Michael addition of cyclic b-keto ester 2a to trans-b-
nitrostyrene 1a was chosen for the optimization study (Table 1).
A first screening in toluene of catalysts 3a–f (see ESIz) and
catalyst 3a in different solvents showed similar behaviour and
modest values of the diastereoselectivity and enantiomeric ratio
(er) were achieved (entries 1–2). Fluorinated aromatic solvents
such as trifluoromethyl benzene and C6F6 were checked using
catalyst 3a (entries 3 and 4). Significant improvement of diastereo-
and enantioselectivity was observed in the reaction performed in
C6F6 (entry 4). The performance of catalysts 3 in this medium
(see ESIz) enabled us to select the commercially available catalyst 3b
as the most effective compound (entry 5). Delightfully, in the
presence of 15 mol% of catalyst 3b, the product was obtained in
excellent yield, almost as a single diastereoisomer and with a 95 : 5 er
(entry 6). Reduction of catalyst 3b loading to 10 mol% led only to
slightly inferior results in terms of stereocontrol (entry 7).
The development of highly enantioselective catalytic systems always
requires stereoelectronic modifications of the chiral ligands or the
organocatalysts used in metal-catalysed or metal-free promoted
processes, respectively.1 Consequently, different chiral sources have
to be accessible and long or expensive syntheses are frequently
necessary to obtain the best candidate. The enantioselectivity of a
reaction can also greatly benefit from the employment of additives
and co-catalysts,2 and more recently, a remarkable advance has
been disclosed in the context of chiral ion pairs mediated catalysis
by combining chiral counteranions with chiral ligands/catalysts, in
the so-called asymmetric counteranion-directed catalysis (ACDC)
as coined by Mayer and List.3 Concerning the experimental
parameters, the choice of solvent is crucial during the optimization
of an asymmetric process.4 Although systematic solvent effects
are clearly impossible to apply in the vast area of asymmetric
catalysis as well as predictions on the effectiveness of a particular
solvent, the discovery of novel media with unpredictable effects is of
particular importance. Likewise, attempts to rationalize a dramatic
solvent effect on the stereochemical outcome of a process may
help to improve our tools to achieve better enantiocontrol by
modification of the reaction conditions.
Some recent reports on Ru-catalysed olefin metathesis
showed fluorinated aromatic solvents to have beneficial effects5
in terms of reaction rate enhancement, regiocontrol and in one
example also on the enantioselectivity.6 It was speculated that
p–p interaction between the catalyst and the solvent or direct
a Dipartimento di Chimica e Biologia, Via Ponte don Melillo, 84084,
Fisciano, Italy. E-mail: lattanzi@unisa.it, lcavallo@unisa.it;
Fax: +39 089 969603
b Catalan Institute for Water Research (ICRA), H2O Building,
Scientific and Technological Park of the University of Girona, Spain
c King Abdullah University of Science and Technology, Thuwal 23955-6900,
Kingdom of Saudi Arabia. E-mail: luigi.cavallo@kaust.edu.sa
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
With the optimal catalyst and reaction conditions in hand,
the scope and limitations of the Michael addition of b-
ketoesters 2 to nitroolefins 1 in C6F6 was studied (Table 2).
z Electronic supplementary information (ESI) available: Experimental
procedures and computational details. See DOI: 10.1039/c2cc17488j
c
1650 Chem. Commun., 2012, 48, 1650–1652
This journal is The Royal Society of Chemistry 2012

Table 1 Catalyst and solvent optimization study for the Michael
addition of b-ketoester 2a to trans-b-nitrostyrene 1aa
Entry
Catalyst
Solvent
Yieldb (%)
drc
erd
Scheme 1
1
2
3
4
3a
3b
3a
3a
3b
3b
3b
Toluene
Toluene
CF3C6H5
C6F6
C6F6
C6F6
C6F6
91
99
98
98
99
98
94
3 : 1
4 : 1
5 : 1
7 : 1
13 : 1
24 : 1
19 : 1
64 : 36
58 : 42
76 : 24
81 : 19
91 : 9
diastereoselectivity and enantiomeric ratio for the major diastereo-
isomer was detected in C6F6. Unfortunately, the system proved to
be poorly active with acyclic derivatives, as demonstrated by
reacting a-methyl ethyl acetoacetate with 1a under optimized
conditions. The conversion to the product was inferior to 20%
after 6 days in both solvents.
5
6e
7g
95 : 5f
93 : 7
a
All reactions run at 0.5 M with 0.2 mmol of 1a and 2a. b Yield of isolated
product. c The diastereoisomeric ratio determined by 1H NMR spectro-
The feasibility of a more appealing use of C6F6 as additive
rather than solvent was also investigated (Table 3). Compound 2a
was reacted with nitroalkene 1a in diethyl ether and in mixtures of
diethyl ether and hexafluorobenzene. trans-b-Nitrostyrene 1a was
firstly reacted in Et2O affording compound 4a in moderate yield,
as 11 : 1 mixture of diastereoisomers and with an enantiomeric
ratio of 80 : 20 for the major diastereoisomer (entry 1). Notably,
the addition of 10 or 5 equivalents of C6F6 with respect to
reagents (entries 2 and 3) was sufficient to achieve comparable
results to that obtained in pure C6F6 (entry 1, Table 2). Reactions
of representative nitroalkenes 1b,d with compound 2a using
5 equivalents of C6F6 gave satisfactory results, although it
appears that the optimal amount of C6F6 to be added can be
substrate-dependent (entries 4 and 5).
d
scopy of the crude reaction mixture. Determined for the major diastereo-
isomer by chiral HPLC. Catalyst used at 15 mol% loading. f The
absolute configuration (2R,3S) of product 4a was assigned by comparing
e
g
the optical rotation to the literature. Catalyst used at 10 mol% loading.
The adducts were generally obtained in excellent yield. The
presence of electron-withdrawing groups is well tolerated also
in the ortho-position of the benzene ring as well as 2-naphthyl
and heteroaromatic residues, achieving high stereocontrol in
the adducts 4 (entries 1–8). In the case of electron-donating
groups, the product was obtained with somewhat lower diastereo-
and enantioselectivity (entries 9 and 10). When employing the
more challenging and less reactive aliphatic nitroalkene 1k, the
product was recovered in moderate yield and satisfactory level of
stereocontrol (entry 11). Six- and seven-membered ring b-keto
esters 2c and 2d were also reacted under optimized conditions
with 1a using toluene and C6F6 as solvents (Scheme 1). In the case
of compound 2c, higher conversion to the product was observed
in C6F6 with respect to toluene. The diastereoisomeric ratio was
slightly inferior in C6F6, whereas a notable improvement of the er
ratio (er 96 : 4) was observed for the minor diastereoisomer.
Conversion to the seven-membered ring derivative 6 proved to
be modest in both solvents, although an improvement in the
Motivated by these results, we also investigated the effect of
C6F6 as a medium in another Michael-type reaction catalysed
by diaryl prolinol 3b, by reacting compound 2e to maleimide
7 at room temperature (Scheme 2).
Product 8 was obtained in high yield, 1 to 1 diastereoisomeric
ratio, although almost without enantiocontrol when the reaction
was performed in toluene. Compound 8 was more rapidly and
quantitatively formed with a similar diastereoisomeric ratio in
C6F6 as a solvent. However, a significant improvement of the
enantiomeric ratio (up to 72 : 28 er) was observed for both
diastereoisomers. All these findings demonstrate that the use
of C6F6 as solvent is beneficial to achieve higher conversion to
the product and more interestingly to remarkably enhance the
stereocontrol in different Michael addition reactions catalysed
by a,a-L-diaryl prolinols. From a mechanistic point of view,
the reactions are likely to proceed via noncovalent activation
of the reacting partners by catalysts 3. Indeed, Zhu et al.12 did
Table 2 Catalytic asymmetric Michael addition of compounds 2 to
nitroalkenea
Entry
2
R
Yield 4 (%)
dr
er
Table 3 Catalytic asymmetric Michael addition in Et2O with C6F6 as
an additivea
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
Ph (1a)
98 (4a)
98 (4b)
94 (4c)
98 (4d)
92 (4e)
89 (4f)
98 (4g)
97 (4h)
98 (4i)
95 (4j)
52 (4k)
24 : 1
19 : 1
19 : 1
19 : 1
32 : 1
10 : 1
16 : 1
16 : 1
13 : 1
9 : 1
95 : 5
94 : 6
95 : 5
94 : 6
95 : 5
86 : 14
92 : 8
94 : 6
83 : 17
79 : 21
81 : 19
2-Naphthyl (1b)
3-BrC6H4 (1c)
4-FC6H4 (1d)
2-ClC6H4 (1e)
2-Furyl (1f)
2-Thienyl (1g)
Ph (1h)
4-MeC6H4 (1i)
4-MeOC6H4 (1j)
Cyclohexyl (1k)
Entry
R
C6F6 (equiv.) Yield (%) dr
er
1
2
Ph (1a)
Ph (1a)
Ph (1a)
2-Naphthyl (1b)
4-FC6H4 (1d)
—
10
5
5
5
64 (4a)
92 (4a)
90 (4a)
98 (4b)
98 (4d)
11 : 1 80 : 20
19 : 1 95 : 5
16 : 1 95 : 5
24 : 1 87 : 13
16 : 1 92 : 8
3
4b
5c
9
10
11
a
Unless otherwise noted the reactions were run at 0.25 M in Et2O with
x equivalents of C6F6 and 0.2 mmol of 1 and 2a at room temperature.
24 : 1
a
b
c
Reaction run at C = 0.4 M. Reaction run at C = 0.5 M.
See footnote a in Table 1.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1650–1652 1651

between the reacting system and C6F6 in TS pro-S,R, which
prevent an optimal interaction of the reacting system with
the C6F6 ring, see the longer distances in Fig. 1d, and
Fig. S2 (ESIz).
In conclusion, we have disclosed that, using C6F6 as solvent
or additive, the nitro-Michael addition reaction for the
construction of vicinal tertiary and quaternary stereocenters,
conveniently catalysed by a commercially available a,a-diaryl-
L-prolinol, can be turned from scarcely to highly stereo-
selective. The positive effect provided by C6F6 appears to be
of wider applicability at least in asymmetric Michael type
reactions catalysed by a,a-L-diaryl prolinols. DFT calculations
clarified the origin of this unexpected amplification of selectivity,
providing the conceptual tools for application of the same
solvent strategy to other cases.
Scheme 2
not observe the formation of an enamine intermediate13 when
reacting compound 2a with 100 mol% loading of catalyst 3a in
CDCl3. NMR studies revealed the establishment of hydrogen
bonding interactions between catalysts 3 and the enol form of
compounds 2 in the a-sulfenylation of a-substituted b-ketoesters.
DFT calculations were performed to shed light on this unusual
amplification of enantioselectivity.14 For this reason, we focused
on the stereoselectivity determining step corresponding to the
formation of the C–C bond between 1a and the enol form of 2a,
leading to the two major stereoisomers R,S and S,R. As a
representative catalyst we considered 3a. DFT calculations,
consistent with the experiments, indicate that formation of 4a
through transition state (TS) pro-R,S is favored by 3.0 kcal molꢀ1
over TS pro-S,R.15 Both transition states present the flat ester
group of 2a stacked over the phenyl group of 1a, see Fig. 1.
However, TS pro-R,S is characterized by three H-bonds,
indicated as HB1-3 in Fig. 1a, whereas TS pro-S,R is char-
acterized by only 2 H-bonds, indicated as HB1and HB2 in
Fig. 1b. This suggests that TS pro-R,S is favored by a higher
number of H-bonds between reactants and catalyst. Moving
to the beneficial impact of C6F6, we located TS pro-R,S and
pro-S,R in the presence of a C6F6 molecule. We tried several
orientations, the most stable are shown in Fig. 1c and d. In
both geometries the C6F6 ring is stacked over the enolate
group. This can be explained considering that C6F6 is char-
acterized by a quadrupole moment with the positive lobes
above the aromatic ring, which optimizes electrostatic inter-
action with electron density delocalized on the enolate
p orbitals.16 In the presence of a C6F6 molecule the energy
difference between TS pro-R,S and pro-S,R increases from
3.0 to 4.3 kcal molꢀ1, which is in agreement with the experiments.
This increased preference is a consequence of steric interactions
We thank MIUR for financial support and the Spanish
MICINN for a Ramon y Cajal contract (RYC-2009-04170).
´
Notes and references
1 For reviews, see: Comprehensive Asymmetric Catalysis, ed.
E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin,
1999, vol. I–III.
2 For an excellent review, see: E. M. Vogl, H. Groger and
¨
M. Shibasaki, Angew. Chem., Int. Ed., 1999, 38, 1570.
3 (a) S. Mayer and B. List, Angew. Chem., Int. Ed., 2006, 45, 4193;
(b) G. L. Hamilton, E. J. Kang, M. Mba and F. D. Toste, Science,
2007, 317, 496.
4 For a review, see: C. Reichardt, Chem. Rev., 1994, 94, 2319.
5 (a) C. Samoj"owicz, M. Bieniek, A. Zarecki, R. Kadyrov and
K. Grela, Chem. Commun., 2008, 6282; (b) D. Rost, M. Porta,
S. Gessler and S. Blechert, Tetrahedron Lett., 2008, 49, 5968;
(c) C. Samoj"owicz, M. Bieniek, A. Pazio, A. Makal, K. Woz
A. Poater, L. Cavallo, J. Wojcik, K. Zdanowski and K. Grela,
Chem.–Eur. J., 2011, 17, 12981; (d) C. Samoj"owicz, E. Borre
´ niak,
´
´
,
M. Mauduit and K. Grela, Adv. Synth. Catal., 2011, 353, 1993.
6 A. Grandbois and S. K. Collins, Chem.–Eur. J., 2008, 14, 9323.
7 Hydrogen Bonding in Organic Synthesis, ed. P. M. Pihko, Wiley-
VCH, Weinheim, 2009.
8 C. Laurence, P. Nicolet, M. T. Dalati, J.-M. L. Abboud and
R. Notario, J. Phys. Chem., 1994, 98, 5807.
9 For reviews, see: (a) M. Shibasaki and N. Yoshikawa, Chem. Rev.,
2002, 102, 2187; (b) J. Christoffers and A. Baro, Angew. Chem., Int.
Ed., 2003, 42, 1688; (c) Catalytic Asymmetric Conjugate Reactions,
ed. A. Cordova, Wiley-VCH, Weinheim, 2010.
10 For a review, see: (a) A. Lattanzi, Chem. Commun., 2009, 1452. For
selected examples, see: (b) A. Lattanzi, Org. Lett., 2005, 7, 2579;
(c) A. Lattanzi, Tetrahedron: Asymmetry, 2006, 17, 837; (d) C. De
Fusco, C. Tedesco and A. Lattanzi, J. Org. Chem., 2011, 76, 676.
11 For examples on stereoselective nitro-Michael addition of 1,3-
dicarbonyl compounds, see: (a) H. Li, Y. Wang, L. Tang,
F. Wu, X. Liu, C. Guo, B. M. Foxman and L. Deng, Angew.
Chem., Int. Ed., 2005, 44, 105; (b) X. Jiang, Y. Zhang, X. Liu,
G. Zhang, L. Lai, L. Wu, J. Zhang and R. Wang, J. Org. Chem.,
2009, 74, 5562; (c) R. Manzano, J. M. Andre
and R. Pedrosa, Adv. Synth. Catal., 2010, 352, 3364; (d) D. Amal-si,
D. A. Alonso, R. Gomez-Bengoa and C. Najera, J. Org. Chem.,
s, M. D. Muruzabal
´ ´
´
´
2009, 74, 6163; (e) K. Murai, S. Fukushima, S. Hayashi,
Y. Takahara and H. Fujioka, Org. Lett., 2010, 12, 964.
12 L. Fang, A. Lin, H. Hu and C. Zhu, Chem.–Eur. J., 2009, 15, 7039.
13 A. Hodgson, J. Marshall, P. Hallett and T. Gallagher, J. Chem.
Soc., Perkin Trans. 1, 1992, 2169.
14 Geometries were optimized at the BP86 level using the SVP basis
set. The reported free energies correspond to in solventM06/
TZVP//BP86/SVP energies. BP86/SVP thermal corrections at
300 K are included. See ESIz.
15 Pro-R,S and pro-S,R indicates the configuration at the C2 and C3
atoms of the forming product.
16 C. A. Hunter, K. R. Lawson, J. Perkins and C. J. Urchb, J. Chem.
Soc., Perkin Trans. 2, 2001, 651.
Fig. 1 Structure of TS pro-R,S and pro-S,R, (a) and (b), respectively,
and of the same TS in the presence of C6F6, (c) and (d), respectively.
c
1652 Chem. Commun., 2012, 48, 1650–1652
This journal is The Royal Society of Chemistry 2012