Enantioselective friedel-crafts reaction of β-trifluoromethylated acrylates with pyrroles and its application to the synthesis of trifluorinated heliotridane

Article abstract of DOI:10.1021/ol100171z

Chemical Equation Presentation The first chiral Lewis acid catalyzed enantioselective Friedel-Crafts alkylation of pyrroles with β-CF ₃ acrylates has been Investigated, which afforded various types of chiral trifluoromethylated compounds in exc

Full text of DOI:10.1021/ol100171z

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1136-1138
Enantioselective Friedel-Crafts
Reaction of ꢀ-Trifluoromethylated
Acrylates with Pyrroles and Its
Application to the Synthesis of
Trifluorinated Heliotridane
Yiyong Huang,† Etsuko Tokunaga,† Satoru Suzuki,† Motoo Shiro,‡ and
Norio Shibata*,†
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute
of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan, and Rigaku Corporation,
3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan
nozshiba@nitech.ac.jp
Received January 23, 2010
ABSTRACT
The first chiral Lewis acid catalyzed enantioselective Friedel-Crafts alkylation of pyrroles with ꢀ-CF3 acrylates has been investigated, which
afforded various types of chiral trifluoromethylated compounds in excellent yields (90-99%) with high ee’s (up to 99% ee). With the aid of the
Friedel-Crafts reaction adduct, optically active trifluorinated heliotridane was successfully constructed.
Incorporation of fluorine(s) into pharmaceuticals often
enhances their pharmacological properties.1 Among organo-
fluorine molecules, chiral trifluoromethylated compounds,
especially trifluoromethylated heterocyclic systems, play a
unique and significant role in agricultural and medicinal
chemistry.2 As a consequence, exploitation of an efficient
method for the synthesis of these compounds is highly
desirable. Two strategies are often utilized to synthesize
compounds bearing a trifluoromethyl (CF3) group at the
chiral center: The first strategy is the transfer of a CF3 group
from a reagent. This strategy seems to be straightforward
and practical, but direct enantioselective trifluoromethylation
remains a challenge, and high ee’s are rarely reached.3 An
† Nagoya Institute of Technology.
‡ Rigaku Corporation.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneuer, V. Chem.
Soc. ReV. 2008, 37, 320–330. (b) Georgii, G. F. Fluorine-Containing
Heterocycles. Part I. Synthesis by Intramolecular Cyclization. In AdVances
in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Elsevier: Amsterdam, 2004;
Vol. 86, pp129-224.
(1) (a) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima,
I., Eds.; Wiley-Blackwell: West Sussex, 2008; pp 1-624. (b) Kirsch, P.
Modern Fluoroorganic Chemistry: Synthesis, ReactiVity, Applications;
Wiley-VCH: New York, 2004; pp 1-308.
10.1021/ol100171z  2010 American Chemical Society
Published on Web 02/09/2010

alternative strategy is the use of trifluoromethylated com-
pounds as building blocks, and CF3 sources are mainly from
trifluoromethyl ketones and trifluoropyruvates.4 We envis-
aged that ꢀ-trifluoromethyl acrylates would be an excellent
candidate as an acceptor in the Friedel-Crafts reaction,5
which provides a potential chiral CF3 group and can be
transformed into ꢀ-trifluoromethylated carboxylic acids.
Table 1. Optimization of the Asymmetric FC Reactiona
Asymmetric Friedel-Crafts (FC) reactions have witnessed
rapid development in recent years.6 Indoles have usually
served as nucleophiles in FC reactions, and the use of
pyrroles, especially unprotected pyrroles, in FC reactions is
rarely reported,7 despite their usefulness in pharmaceuticals.8
In 2001, MacMillan and co-workers pioneered the work of
catalytic asymmetric FC alkylation with pyrroles.9a Recently,
the Sibi group described the first protocol of highly enan-
tioselective Friedel-Crafts alkylations/enolate protonation
using various pyrrole nucleophiles.9b As part of a program
that focuses on the construction of chiral trifluoromethylated
products,10 we herein report the first chiral Lewis acid
catalyzed enantioselective FC reactions of protected and
unprotected pyrroles with ꢀ-CF3 acrylates.
Chiral Lewis acids prepared from Ph-dbfox (Ph-dbfox )
(R,R)-4,6-dibenzofurandiyl-2,2-bis(4-phenyloxazoline)) and
different metal salts were screened in CH2Cl2 at rt for the
asymmetric FC reaction of 1 with 2a (entries 1-6). Lewis
acids such as Cu(OTf)2, Cu(NTf2)2, and Zn(OAc)2 in
combination with ligand Ph-dbfox led to disappointing results
(Table 1, entries 1-3). Moderate enantioselectivity was
entry Lewis acid solvent temp (°C) t (h) yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Cu(OTf)2 CH2Cl2
Cu(NTf2)2 CH2Cl2
Zn(OAc)2 CH2Cl2
20
20
20
20
20
20
20
20
24
24
24
24
4
2
6
6
trace
trace
trace
40
86
96
ND
ND
ND
38
75
75
Zn(OTf)2
CH2Cl2
Zn(ClO4)2 CH2Cl2
Zn(NTf2)2 CH2Cl2
Zn(NTf2)2 toluene
Zn(NTf2)2 Et2O
93
91
60
72
9
10
11
Zn(NTf2)2 CHCl3
Zn(NTf2)2 CH2Cl2
Zn(NTf2)2 CH2Cl2
20
2
90
98
96
96
70
89
96
98
-40
-60
-75
12
24
24
12d Zn(NTf2)2 CH2Cl2
a Unless noted, all reactions performed at 0.10 M in substrate 1 and
0.50 M in substrate 2a, with 10 mol % catalyst loading in 0.5 mL of solvent.
b Isolated yields. c Determined by chiral HPLC; ND ) not determined.
d Reaction performed at 0.20 M in substrate 1, with 0.25 mL of solvent
and 20 mol % catalyst used.
obtained in the presence of Zn(OTf)2 (entry 4). Gratifyingly,
Zn(NTf2)2/Ph-dbfox gave the adduct 3a in good ee and
excellent yield (entry 6). Notably, the use of Zn(ClO4)2/Ph-
dbfox as a chiral Lewis acid provided 3a in comparable
enantioselectivity, but less efficiently than Zn(NTf2)2 (entry
5). Therefore, Zn(NTf2)2/Ph-dbfox was chosen as a catalyst
system in the following reactions. A subsequent solvent
survey revealed that CH2Cl2 was the solvent of choice with
regards to both enantioselectivity and yield. In addition, the
effects of reaction temperature were also evaluated. It was
demonstrated that ee’s obtained and the reaction time
required were dependent on the reaction temperature. Lower-
ing the reaction temperature resulted in increased enantio-
selectivity from 75% to 89% ee (entry 6 vs 10) with 98%
yield. The enantioselectivity was further increased at -60
°C, generating 3a in up to 96% ee with 96% yield (entry
11). The best ee (98%) was observed at -75 °C under higher
catalyst loading with a higher concentration (entry 12).
Under the optimized reaction conditions, a variety of
pyrroles were screened using 1 as the nucleophile acceptor.
The results are presented in Table 2. The reaction of
unprotected pyrrole 2b gave the product 3b in 97% yield
with 99% ee (entry 1). The absolute configuration of 3b was
assigned as S.11 It should be noted that high enantioselec-
tivities were observed independent of the substitutions on
the pyrrole nitrogen as well as the 2-position (92-97% ee,
entries 2-7). In addition, pyrroles containing electron-
withdrawing and sterically bulky groups such as Bn and Ph
displayed inferior reactivity and selectivity (<90% ee, entries
(3) (a) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry 2008,
19, 2633–2644. (b) Ma, J.-A.; Cahard, D. Chem. ReV. 2008, 108, PR1–
PR43.
(4) Selected examples of the catalytic asymmetric FC reaction with
simple trifluoromethyl ketones: (a) Nie, J.; Zhang, G.-W.; Wang, L.; Fu,
A.-P.; Zheng, Y,; Ma, J.-A. Chem. Commun. 2009, 2356–2358. (b) Tur,
F.; Saa´, J. M. Org. Lett. 2007, 9, 5079–5082. With trifluoropyruvates: (c)
Nakamura, S.; Hyodo, K.; Nakamura, Y.; Shibata, N.; Toru, T. AdV. Synth.
Catal. 2008, 350, 1443–1448. (d) Zhao, J.-L.; Liu, L.; Sui, Y.; Liu, Y.-L.;
Wang, D.; Chen, Y.-J. Org. Lett. 2006, 8, 6127–6130. (e) To¨ro¨k, B.; Abid,
M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.; Yan, P.; Prakash,
G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086–3089.
(5) (a) Sani, M.; Candiani, G.; Pecker, F.; Malpezzia, L.; Zanda, M.
Tetrahedron Lett. 2005, 46, 2393–2396. (b) Tamura, K.; Yamazaki, T.;
Kitazume, T.; Kubota, T. J. Fluorine Chem. 2005, 126, 918–930. (c) Wada,
H. Japan Patent JP2005247788A, 2005.
(6) For reviews on asymmetric FC reaction, see: (a) Catalytic Asymmetric
Friedel-Crafts Alkylations; Bandini, M., Umani-Ronchi, A., Eds.; Wiley-
VCH: Weinheim, 2009; pp 1-301. (b) Poulsen, T. B.; Jørgensen, K. A.
Chem. ReV. 2008, 108, 2903–2915.
(7) Selected examples of asymmetric FC reaction of unprotected pyrrole:
(a) Trost, B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438–2439. (b)
Blay, G.; Ferna´ndez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601–
2604. (c) Evans, D. A.; Fandrick, K. R.; Song, H. J.; Scheidt, K. A.; Xu,
R. S. J. Am. Chem. Soc. 2007, 129, 10029–10041. (d) Palomo, C.; Oiarbide,
M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127,
4154–4155. (e) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A.
J. Org. Chem. 2001, 66, 1009–1013.
(8) (a) Trofimo, N. A.; Nedolya, N. A. In ComprehensiVe Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.; Taylor,
R. J. K., Eds.; Elsevier Ltd.: Oxford, 2008; Vol. 3, pp 45-268. (b) Lipshutz,
B. H. Chem. ReV. 1986, 86, 795–819.
(9) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370–4371. (b) Sibi, M. P.; Coulomb, J.; Stanley, L. M. Angew. Chem.,
Int. Ed. 2008, 47, 9913–9915.
(10) (a) Noritake, S.; Shibata, N.; Nomura, Y.; Huang, Y.-Y.; Matsnev,
A.; Nakamura, S.; Toru, T.; Cahard, D. Org. Biomol. Chem. 2009, 7, 3599–
3604. (b) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N.
Angew. Chem., Int. Ed. 2009, 48, 6324–6327. (c) Ogawa, S.; Shibata, N.;
Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007,
46, 8666–8669.
(11) The absolute configuration of 3b was assigned as S after deriva-
tization to 4 and comparison of optical rotation to a sample of (R)-4
synthesized differently. See Supporting Information for details.
Org. Lett., Vol. 12, No. 5, 2010
1137

quinone (p-BQ) oxidation.12 Taking advantage of this
property, 2-substituted indole 3o was successfully accessed
with 75% ee in 90% yield (Scheme 1, eq II).13
Table 2. Substrate Generalitya
To demonstrate the synthetic utility of the FC reaction,
the synthesis of trifluorinated heliotridane14 was carried out
(Scheme 2). The FC reaction adduct 3b (98% ee) was
entry R1
R2 2b
3
temp (°C) t (h) yield (%)c ee (%)d
Scheme 2. Synthesis of Trifluorinated Heliotridane
1
H
H
2b 3b
-75
-75
-75
-75
-75
-75
-75
-60
-20
-75
-75
-75
24
24
24
24
24
36
36
48
24
24
48
48
97
96
98
96
96
95
90
93
94
97
99
95
99
97
92
96
95
93
95
85
88
94
88
76
2
H
Me 2c 3c
Et 2d 3d
3
H
4
Et
H
H
H
H
H
H
2e 3e
2f 3f
2g 3g
2h 3h
2i 3i
2j 3j
5
6
7
8
n-Pr
n-Bu
allyl
Bn
Ph
9
10
11
12
Me
Me
Me
Me 2k 3k
Et 2l 3l
Bn 2m 3m
converted into the carboxylic acid 4 in 80% yield. Rhodium-
catalyzed hydrogenation of 4 in the presence of H2 (10 atm)
at rt afforded 2-pyrrolidine carboxylic acid 5 in quantitative
yield. Without further purification, 5 was successfully
cyclized to the trifluoromethylated hexahydropyrrolizin-3-
one 7a in the presence of tris(1,3-dihydro-2-oxobenzoxazo-
lin-3-yl) phosphine oxide 6 when heated under reflux in
acetonitrile.14b A volatile trifluorinated heliotridane 8 was
obtained by using LiAlH4 reduction of 7a in ether, which
was finally isolated as a picrate 9.
In summary, we have developed a simple asymmetric
catalytic Friedel-Crafts reaction15 to obtain various chiral
trifluoromethylated pyrroles in good yields and with excellent
enantioselectivities. The chiral product of the asymmetric
FC reaction facilitated the preparation of unreported optically
active trifluorinated heliotridane. The pharmacological prop-
erty of 8 is currently being studied.
a Unless noted, all reactions performed at 0.20 M in substrate 1, with
0.25 mL of solvent and 20 mol % catalyst used. b 5.0 equiv of pyrroles
was used with the exception of N-methyl pyrroles having substituents at
the 2-position (2.0 equiv). c Isolated yields. d Determined by chiral HPLC.
8 and 9), generally needing a higher reaction temperature
for the reactions to reach completion. Disubstituted pyrroles
2k-m also worked well under the same conditions to provide
3k-m in up to 94% ee (entries 10-12).
We next focused on the asymmetric FC reaction of 1 with
indole5c and 4,7-dihydroindole. Whereas the locus of nu-
cleophilicity of pyrroles is at C-2, it resides at C-3 for the
indoles. Initial examination of the indole 2n (2 equiv) was
encouraging, furnishing the 3-substituted indole with excel-
lent levels of selectivity (99% ee) and in nearly quantitative
yield (Scheme 1, eq I). Although C-2 substituted indoles were
Acknowledgment. Support was provided by KAKENHI
(21390030). We also thank Central Glass Co., Ltd. for
support.
Scheme 1
.
Asymmetric FC Reaction between ꢀ-CF3 Acrylates 1
Supporting Information Available: Experimental pro-
cedures, spectra data for all new compounds, stereochemical
proof of 3b and 7a, and HPLC charts. This material is
available free of charge via the Internet at http://pubs.acs.org.
and Indoles
OL100171Z
(12) C¸ avdar, H.; SaraC¸ oglu, N. Tetrahedron 2005, 61, 2401–2405.
(13) (a) Hong, L.; Liu, C.-X.; Sun, W.-S.; Wang, L.; Wong, K.-K.;
Wang, R. Org. Lett. 2009, 11, 2177–2180. (b) Blay, G.; Ferna´ndez, I.;
Monleo´n, A.; Pedro, J. R.; Vila, C. Org. Lett. 2009, 11, 441–444. (c) Kang,
Q.; Zheng, X.-J.; You, S.-L. Chem.sEur. J. 2008, 14, 3539–3542.
(14) Selected examples: (a) Evans, D. A.; Fandrick, K. R. Org. Lett.
2006, 8, 2249–2252. (b) Gilchrist, T. L.; Lemos, A.; Ottaway, C. J. J. Chem.
Soc., Perkin Trans. 1 1997, 3005–3012.
rather difficult to be obtained in this FC reaction, we solved
this problem by the use of pyrrole derivative 2o as follows:
the 4,7-dihydroindole 2o was employed as a disubstituted
pyrrole nucleophile and easily aromatizated with p-benzo-
(15) Just before the submission of this manuscript, the asymmetric FC
reaction of pyrroles was documented in the literature catalyzed by PYBOX-
DIPH-Zn(II) complexes. Singh, P. K.; Singh, V. K. Org. Lett. 2010, 12,
80–83.
1138
Org. Lett., Vol. 12, No. 5, 2010