Highly enantio- and diastereoselective synthesis of α- trifluoromethyldihydropyrans using a novel bifunctional piperazine-thiourea catalyst

Article abstract of DOI:10.1039/b915210e

The first enantioselective Michael addition of α-cyanoketones to α,β-unsaturated trifluoromethyl ketones using a novel piperazine-thiourea catalyst was described. The resulting α- trifluoromethyldihydropyrans were obtained in high yields and with up to 95

Full text of DOI:10.1039/b915210e

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly enantio- and diastereoselective synthesis
of a-trifluoromethyldihydropyrans using a novel bifunctional
piperazine-thiourea catalystw
Peng Li,a Zhuo Chai,a Sheng-Li Zhao,a Ying-Quan Yang,a Hai-Feng Wang,a
Chang-Wu Zheng,a Yue-Peng Cai,b Gang Zhao*a and Shi-Zheng Zhu*a
Received (in Cambridge, UK) 27th July 2009, Accepted 7th October 2009
First published as an Advance Article on the web 22nd October 2009
DOI: 10.1039/b915210e
The first enantioselective Michael addition of a-cyanoketones
to a,b-unsaturated trifluoromethyl ketones using novel
piperazine-thiourea catalyst was described. The resulting
a-trifluoromethyldihydropyrans were obtained in high yields
and with up to 95% ee within a short reaction time. A useful
transformation of the chiral adduct was also illustrated.
has also attracted much attention. For example, Cinchona and
a
their derivatives,8 chiral phosphoric acid,9 chiral guanidine
catalyst10 and MacMillan’s imidazolidinone catalyst,11 have
all been used for this purpose. As one of the most successful
organocatalysts developed to date, bifunctional thiourea
catalysts have been successfully applied in many reactions.12
However, to the best of our knowledge, there has been no
report dealing with the use of thiourea catalysts in the catalytic
asymmetric synthesis of CF3-containing compounds. As a part
of our ongoing project on the organocatalytic asymmetric
reactions of electron-deficient a,b-unsaturated carbonyl
compounds,13 we report herein the reaction of a-cyanoketones
with a,b-unsaturated trifluoromethyl ketones catalyzed by
chiral thioureas, which provides easy access to a series of
novel chiral a-trifluoromethyldihydropyrans in high yields and
with good enantio- and diastereoselectivities.
Organofluorine chemistry is an important field of research
owing to the wide range of applications of organofluorine
compounds,1 which primarily emanates from the peculiar
properties of these compounds after the introduction of
the fluorine atom.2 Trifluoromethyl-containing molecules,
especially, are recognized as a useful class of compounds in
drug discovery as well as in the syntheses of pharmaceutical
and agrochemical products.3 Among these kinds of compounds,
those with the CF3 group directly connected to a chiral
quarternary carbon atom, which are exemplified by two
commercialized drugs such as Efavirenz (anti-HIV)4 and
CJ-17 493 (neurokinin 1 receptor antagonist),5 have attracted
much attention but their construction in a catalytic highly
enantioselective way is still a rather challenging subject in
asymmetric synthesis.
Initially, Takemoto’s catalyst
1 was first chosen for
investigation in the addition of 3-oxo-3-phenylpropanenitrile
4a to (E)-1,1,1-trifluoro-4-phenylbut-3-en-2-one 3a in CHCl3.
Notably, only the cyclized product 5a was observed, which
should be attributable to the presence of the electron-deficient
CF3 group. Variation of the reaction temperature identified
ꢀ10 1C as the optimal reaction temperature (Table 1, entries
1–3, see the wESI for more details), which gave the desired
product 5a in 99% yield with 76% ee and high diastereo-
selectivity (18 : 1) in 5 h. In order to enhance the enantioselectivity,
several other thiourea catalysts easily available from chiral
amino acids were synthesized14 and evaluated in the model
reaction (Fig. 1 and Table 1). For catalysts 2a–f with different
amino acid skeletons, generally comparable or higher
stereoselectivities were observed than that obtained with the
Takemoto’s catalyst 1, except for the L-phenylglycine derived
To date, there are two major strategies to build a chiral
carbon center bearing a CF3 group: one is the direct asymmetric
trifluoromethylation of ketones with the Ruppert–Prakash
reagent,6 with which only limited examples have achieved
high enantioselectivities (exceeding 90% ee); the other is the
asymmetric nucleophilic addition to prochiral trifluoromethyl
carbonyl compounds.7
Over the past decade, with the rapid development of organo-
catalysis, the application of different chiral organocatalysts to
the synthesis of optically active CF3-containing compounds
a Key Laboratory of Organofluorine Chemistry and Key Laboratory of
Modern Synthetic Organic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai,
200032, China. E-mail: zhaog@mail.sioc.ac.cn,
zhusz@mail.sioc.ac.cn; Fax: 0086-21-64166128;
Tel: 0086-21-54925182
b School of Chemistry and Environment, Key Lab of Technology on
Electrochemical Energy Storage and Power Generation in
Guangdong Universities, South China Normal University,
Guangzhou, 510006, China. E-mail: ypcai8@yahoo.com;
Fax: 0086-20-85215865; Tel: 0086-20-33033475
w Electronic supplementary information (ESI) available: Experimental
details, analytical data, HPLC chromatography and NMR spectra of
products, crystallographic data in CIF or other electronic format.
CCDC 738397. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b915210e
Fig. 1 Catalysts used in this reaction.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7369–7371 | 7369

View Article Online
Table 1 Effect of the catalysts on the reaction yield and selectivitya
was identified as the best catalyst, which gave the product in
99% yield, >19 : 1 d.r. and 93% ee. Moreover, although
reducing the catalyst loading to 5 mol% or 2 mol% brought
a drop in the yield, only a slightly negligible drop in the
enantioselectivity was observed. (Table 1, entries 15–16).
Next, using the optimal catalyst 2k, it was found that the
reaction also proceeded well in many other solvents with good
to excellent yields and invariably excellent diastereoselectivity,
but no higher enantioselectivity was obtained than the
originally used solvent CHCl3 (see the ESI for more detailsw).
Thus, the present reaction was best performed with 10 mol%
of catalyst 2k in CHCl3 at ꢀ10 1C.
Entry
Catalyst
Yield (%)b
drc
ee (%)d
1
1
1
1
99
99
99
99
99
99
73
94
99
71
45
99
98
99
91
86
18 : 1
18 : 1
17 : 1
17 : 1
17 : 1
>19 : 1
18 : 1
>19 : 1
>19 : 1
13 : 1
>19 : 1
17 : 1
18 : 1
>19 : 1
>19 : 1
>19 : 1
76
68
68
81
6
79
80
75
73
5
50
90
92
93
92
90
2e
3f
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
5
6
7
8
Having established the optimum reaction conditions,
various a,b-unsaturated trifluoromethyl ketones
3 and
9
a-cyanoketones 4 were tested to explore the reaction scope
and the results were presented in Table 2. The reaction took
place with high enantioselectivity (87–95% ee) and excellent
diastereoselectivity (>19 : 1). With cyanoketone 4a, generally
almost quantitative yields, excellent dr values and 87–95% ee
were obtained for differently substituted 3a–g (R1 = subtituted
benzene rings, n-octyl, and 2-thienyl, Table 2, entries 1–7),
except for a low dr value for 3e with an ortho-subtituted
benzene ring (entry 5). For different cyanoketones 4, when
R2 were aryl groups, both electron-withdrawing and electron-
donating substitutents on the benzene rings were well tolerated
(entries 8–13). It is worth mentioning that when R2 were an
alkyl groups (4e), the desired product 5n was still obtained
in >19 : 1 dr and 92% ee, albeit with a moderate yield and
prolonged reaction time at room temperature (entry 14).
Unfortunately, when R2 were an alkoxyl groups (4f), the
reaction failed to take place, probably due to the lesser degree
of enolization of this substrate (entry 15). Moreover, when the
reaction was carried on a larger scale (0.5 mmol), no
significant drop in enantioselectivity was observed (entry 16).
10
11
12
13
14
15g
16h
2j
2k
2k
2k
a
Unless otherwise noted, the reaction was conducted with 0.1 mmol
of 3a and 0.2 mmol of 4a in the presence of 10 mol% of the catalyst in
2.0 mL of CHCl3 for 5 h. Isolated yields. Determined by 19F-NMR
b
c
d
analysis. Determined by chiral HPLC analysis on a chiral column.
e
f
The reaction was run at RT. The reaction was run at ꢀ30 1C.
g
h
5 mol% of 2k was used. 2 mol% of 2k was used.
2b (Table 1, entries 4–9). In view of the above results, further
structural optimization efforts were done with the L-phenyl-
alanine derived catalyst 2a (Table 1, entry 4). While increasing
the steric hindrance of the tertiary amine moiety (catalysts 2g
and 2h) reduced the enantioselectivity significantly (Table 1,
entries 10–11), cyclic tertiary amine structures apparently gave
better results (Table 1, entries 12–14) and a novel thiourea 2k
Table 2 Study on the reaction scope with different a-cyanoketones 4 and a,b-unsaturated trifluoromethyl ketones 3a
Entry
R1
R2
Product
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
Ph (3a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
N.R.
5d
99
99
99
99
98
99
99
99
99
98
99
99
97
62
—
92
>19 : 1
>19 : 1
>19 : 1
>19 : 1
6 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
—
93
91
92
93
95
88
87
92
92
92
92
91
94
92
—
90
4-OMe–C6H4 (3b)
4-Me–C6H4 (3c)
3-OMe–C6H4(3d)
2-OMe–C6H4(3e)
2-thienyl (3f)
n-octyl (3g)
3-OMe–C6H4 (3d)
4-Me–C6H4 (3c)
Ph (3a)
Ph (4a)
Ph (4a)
Ph (4a)
4-OMe–C6H4 (4b)
4-OMe–C6H4 (4b)
F–C6H4 (4c)
4-Br–C6H4 (4d)
4-Br–C6H4 (4d)
4-Br–C6H4 (4d)
t-Bu (4e)
9
10
11
12
13
14e
15f
16g
Ph (3a)
4-Me–C6H4 (3c)
4-Br–C6H4 (3h)
Ph (3a)
Ph (3a)
3-OMe–C6H4 (3d)
OEt (4f)
Ph (4a)
>19 : 1
a
Unless otherwise noted, the reaction was conducted with 0.1 mmol of 3a and 0.2 mmol of 4a in the presence of 10 mol% of the catalyst in 2.0 mL
b
of CHCl3 for 5 h. Isolated yields. Determined by 19F-NMR analysis. Determined by chiral HPLC analysis on a chiral column. The reaction
f
was carried out at room temperature for 48 h. No reaction. 0.5 mmol of 3 was used.
c
d
e
g
ꢁc
This journal is The Royal Society of Chemistry 2009
7370 | Chem. Commun., 2009, 7369–7371

View Article Online
1 (a) Biomedical Frontiers of Fluorine Chemistry, ed. I. Ojima,
J. R. McCarthy and J. T. Welch, American Chemical Society,
Washington, DC, 1996; (b) Enantiocontrolled Synthesis of Fluoro–
Organic Compounds, ed. V. A. Soloshonok, Wiley, Chichester,
England, 1999.
2 (a) M. Hudlicky, Chemistry of Organic Fluorine Compounds, Ellis
Horwood Ltd., Chichester, 1992; (b) I. Ojima, J. R. McCarthy and
J. T. Welch, Biomedical Frontiers of Fluorine Chemistry, ACS
Symposium Series, Washington, 1996, vol. 639.
3 (a) K. Muller, C. Faeh and F. Diederich, Science, 2007, 317, 1881;
(b) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem.
Soc. Rev., 2008, 37, 320; (c) W. K. Hagmann, J. Med. Chem., 2008,
51, 4359.
Fig. 2 Proposed transition state model for the Michael addition step.
4 (a) J. Christoffers and A. Mann, Angew. Chem., Int. Ed., 2001, 40,
4591; (b) O. Riant and J. Hannedouche, Org. Biomol. Chem., 2007,
5, 873.
5 For comprehensive reviews on synthetic methods of fluorine con-
taining molecules, see: (a) K. Mikami, Y. Itoh and M. Yamanaka,
Chem. Rev., 2004, 104, 1; (b) J.-A. Ma and D. Cahard, Chem. Rev.,
2004, 104, 6119.
6 For reviews, see: (a) J.-A. Ma and D. Cahard, J. Fluorine Chem.,
2007, 128, 975; (b) J.-A. Ma and D. Cahard, Chem. Rev., 2008, 108,
PR1–PR43; (c) N. Shibata, S. Mizuta and H. Kawai, Tetrahedron:
Asymmetry, 2008, 19, 2633; (d) T. Billard and B. R. Langlois, Eur.
J. Org. Chem., 2007, 891. Selected recent examples ; (e) S. Roussel,
T. Billard, B. R. Langlois and L. Saint-James, Eur. J. Org. Chem.,
2005, 939; (f) S. Mizuta, N. Shibata, S. Akiti, H. Fuimoto,
S. Nakamura and T. Toru, Org. Lett., 2007, 9, 3707.
7 (a) N. Gathergood, K. Juhl, T. B. Poulsen, K. Thordrup and
K. A. Jørgensen, Org. Biomol. Chem., 2004, 2, 1077; (b) X.-J. Wang,
Y. Zhao and J.-T. Liu, Org. Lett., 2007, 9, 1343; (c) S. L. X. Martina,
R. B. C. Jagt, J. G. de Vries, B. L. Feringa and A. J. Minnaard, Chem.
Commun., 2006, 4093; (d) R. Motoki, D. Tomita, M. Kanai and
M. Shibasaki, Tetrahedron Lett., 2006, 47, 8083; (e) R. Motoki,
M. Kanai and M. Shibasaki, Org. Lett., 2007, 9, 2997;
(f) C. Lauzon and A. B. Charette, Org. Lett., 2006, 8, 2743.
8 M. Bandini, R. Sinisi and R.-A. Umani, Chem. Commun., 2008, 4360.
9 (a) J. Nie, G.-W. Zhang, L. Wang, A. Fu, Y. Zheng and J.-A. Ma,
Chem. Commun., 2009, 2356; (b) J. Nie, G.-W. Zhang, L. Wang,
D.-H. Zheng, Y. Zheng and J.-A. Ma, Eur. J. Org. Chem., 2009, 3145.
10 M. Bandini and R. Sinisi, Org. Lett., 2009, 11, 2093.
11 D. A. Nagib, M. E. Scott and D. W. C. MacMillan, J. Am. Chem.
Soc., 2009, 131, 10875.
12 For recent reviews on thiourea catalysts, see: (a) A. G. Doyle and
E. N. Jacobsen, Chem. Rev., 2007, 107, 5713(b) S. J. Connon, Chem.
Commun., 2008, 2499. For selected examples of thiourea-containing
bifunctional catalysts, see: (c) X.-Q. Dong, H.-L. Teng and
C.-J. Wang, Org. Lett., 2009, 11, 1265; (d) X. Wang, Y.-F. Chen,
L.-F. Niu and P.-F. Xu, Org. Lett., 2009, 11, 3310; (e) Y. K. Kang
and D. Y. Kim, J. Org. Chem., 2009, 74, 5734; (f) H. Han, Q.-P. Liu,
R. Li, X. Tian, X.-F. X, J.-G. Deng and Y.-C. Chen, Chem.–Eur. J.,
2008, 14, 8094; (g) S.-X. Wang and F.-E. Chen, Adv. Synth. Catal.,
2009, 351, 547; (h) A. Puglisi, L. Raimondi, M. Benaglia,
M. Bonsignore and S. Rossi, Tetrahedron Lett., 2009, 50, 4340;
(i) J. Wang, H. Li, X. Yu, L. Zu and W. Wang, Org. Lett., 2005, 7,
4293; (j) B. Vakulya, S. Varga, A. Csampai and T. Soos, Org. Lett.,
2005, 7, 1967; (k) S. H. McCooey and S. J. Connon, Angew. Chem.,
Int. Ed., 2005, 44, 6367; (l) J. Ye, D. J. Dixon and P. S. Hynes,
Chem. Commun., 2005, 4481.
Scheme 1 Conversion of 5d to 6.
The absolute configuration of the product 5l was
determined to be 4R, 6S by X-ray crystallographicz analysis
(see the ESI for more details).w Based on the above experimental
results and previous related studies,12 we proposed a possible
transition state model to explain the stereochemical results of
the Michael addition, the first step of the present reaction, in
which the bifunctional chiral thiourea catalyst activated both
the two reactants (Fig. 2). The a-cyanoketone attacked the
trifluoromethyl ketone from the Si face and thus formed the
Michael product of the 4R configuration, which subsequently
followed by hemiacetalation and afforded the desired product.
Dihydropyridines (DHPs) are an important class of organic
calcium-channel modulators for the treatment of cardio-
vascular diseases15 and a broad range of other pharmaceutical
activities of these compounds have also been disclosed by recent
biological assays.16 The highly enantiomerically enriched
product 5d could be facilely converted into the potentially
pharmaceutically useful CF3-substituted dihydropyridine 6 in
70% yield with no loss in enantioselectivity, which illustrated
the utility of the present reaction (Scheme 1).
In summary, we have developed a highly enantioselective
and diastereoselective addition reaction of a-cyanoketones to
a,b-unsaturated trifluoromethyl ketones. Using
piperazine-thiourea catalyst derived from L-phenylalanine, a series
of a-trifluoromethyldihydropyrans bearing a CF3-substituted
quaternary stereocenter were obtained in high ee values, excellent
yields and diastereoselectivities. Further elaboration of the
products and the applications of the new amino acids derived
thiourea catalysts in other reactions are underway.
a novel
13 (a) S.-L. Zhao, C.-W. Zheng and G. Zhao, Tetrahedron:
Asymmetry, 2009, 20, 1046–1051; (b) X.-S. Wang, C.-W. Zheng,
S.-L. Zhao, Z. Chai, G. Zhao and G.-S. Yang, Tetrahedron:
Asymmetry, 2008, 19, 2699–2704; (c) C.-W. Zheng, Y.-W. Li,
H.-F. Wang, H.-F. Cui, J.-K. Zhang and G. Zhao, Adv. Synth.
Catal., 2009, 351, 1685.
The generous financial support from the National Natural
Science Foundation of China (No. 20172064, 203900502,
20532040), QT Program, Shanghai Natural Science Council, and
Excellent Young Scholars Foundation of National Natural Science
Foundation of China (20525208) are gratefully acknowledged.
14 (a) K. Ishihara and K. Nakano, J. Am. Chem. Soc., 2005, 127,
10504; (b) J. M. Andres, R. M. Anzano and R. Pedrosa,
Chem.–Eur. J., 2008, 14, 5116; (c) C. J. Hawker and J. M. J.
Frechet, J. Am. Chem. Soc., 1990, 112, 7638.
15 (a) R. A. Janis, P. J. Silver and D. J. Triggle, Adv. Drug Res., 1987,
16, 309; (b) F. Bossert and W. Vater, Med. Res. Rev., 1989, 9, 291;
(c) B. Loev, M. Goodman, K. Snader, R. Tedeschi and E. Macko,
J. Med. Chem., 1974, 17, 956.
Notes and references
z Crystal data: M = 876.48, monoclinic, P21, a = 12.306(2), b =
11.433(2), c = 14.660(3) A, b = 112.875(2)1, V = 1900.4(6) A3, Z = 2,
D = 1.532 Mg mꢀ3, r = 2.206 mmꢀ1, F(000) = 880; 10 058 remeasured,
of which 6887 were unique (Rint = 0.0297). 491 reparameters, R1
=
0.0468 for rewith I > 2s(I), wR2 = 0.941 (all data), GOF = 0.0927. Final
larges diffraction peak and hole: 0.420 and ꢀ0.307 e Aꢀ3
.
16 C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7369–7371 | 7371