Highly regio- and diastereoselective synthesis of cf3- substituted lactones via photoredox-catalyzed carbolactonization of alkenoic acids

Article abstract of DOI:10.1021/ol403500y

Trifluoromethylative lactonization of both terminal and internal alkenoic acids by photoredox catalysis has been developed. The use of a Ru photocatalyst and Umemoto's reagent as a CF₃ source is key in the present carbolactonization. This is the first example of a highly endo- and diastereoselective synthesis of CF₃-substituted five-, six-, and seven-membered ring lactones from internal alkenoic acids.

Full text of DOI:10.1021/ol403500y

Letter
pubs.acs.org/OrgLett
Highly Regio- and Diastereoselective Synthesis of CF3‑Substituted
Lactones via Photoredox-Catalyzed Carbolactonization of Alkenoic
Acids
Yusuke Yasu, Yusuke Arai, Ren Tomita, Takashi Koike,* and Munetaka Akita*
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
S
* Supporting Information
ABSTRACT: Trifluoromethylative lactonization of both terminal
and internal alkenoic acids by photoredox catalysis has been
developed. The use of a Ru photocatalyst and Umemoto’s reagent
as a CF3 source is key in the present carbolactonization. This is the
first example of a highly endo- and diastereoselective synthesis of
CF3-substituted five-, six-, and seven-membered ring lactones from
internal alkenoic acids.
development of a novel strategy for carbolactonization is highly
valuable for modern synthetic organic chemistry.
lectrophile-involved cyclization of alkenes bearing a
Enucleophilic pendant is one of the most important
reactions in organic chemistry and has been used for the
synthesis of biologically relevant molecules.1,2 In particular, the
reaction of internal alkenes is fascinating from the viewpoint of
construction of two stereogenic centers via a single step.
Strongly electrophilic reagents such as halogen and selenium
reagents induce efficient halo- and seleno-cyclization of internal
alkenes, and their exo/endo- and stereoselectivity is variable
depending on the steric and electronic factors of both alkene
and nucleophilic pendants as well as the catalyst used (Scheme
1a). In contrast, related efficient and selective carbocyclization
is still under development; especially, carbolactonization of
internal alkenoic acids is extremely limited.3 Thus, the
Since 2008, photoredox catalysis with well-defined
ruthenium(II) polypyridine complexes (e.g., [Ru(bpy)3]2+)
and the relevant cyclometalated iridium(III) derivatives has
become a versatile synthetic tool because these compounds can
readily catalyze single-electron transfer (SET) processes under
visible light irradiation.4 We are interested in photoredox-
catalyzed radical trifluoromethylation5,6 using shelf-stable
electrophilic trifluoromethylating reagents (+CF3) such as
Umemoto’s reagent 1a and Togni’s reagents 1b and 1c7
because the trifluoromethyl (CF3) group is a prevailing
structural motif in many biologically active molecules as well
as functional materials.8,9 Despite significant progress in the
synthesis of organofluorine compounds,10 new methods for
incorporation of a CF3 group into diverse organic skeletons are
very desirable. Recently, our group reported the highly
regioselective trifluoromethylative difunctionalization of alke-
nes3b,c,11 through a putative β-CF3-substituted carbocation
intermediate generated by photoredox catalysis.6 Based on
these results, we envisaged photoredox-catalyzed trifluoro-
methylative lactonization of alkenoic acids with “+CF3” reagents
(Scheme 1b).
Scheme 1. Electrophile-Involved Cyclization of Alkenes with
a Nucleophilic Pendant
Herein we disclose a novel protocol for regiocontrolled
carbolactonization of both terminal and internal alkenoic acids
by photoredox catalysis. It is remarkable that photoredox-
catalyzed trifluoromethylative lactonization of internal alkenoic
acids bearing a variety of functional groups proceeds with high
endo- and diastereoselectivity under mild reaction conditions.
We initially tested the photocatalytic trifluoromethylative
cyclization of 4-phenyl-4-pentenoic acid (2a) with Umemoto’s
reagent 1a using 5 mol % of [Ru(bpy)3](PF6)2 in CD3CN
under visible light irradiation (blue LEDs: λmax = 425 nm) for
2.5 h. As a result, trifluoromethyllactonization proceeded in an
Received: December 3, 2013
Published: January 14, 2014
© 2014 American Chemical Society
780
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Organic Letters
Letter
exo-selective manner to give the dihydrofuranone derivative
with 2,2,2-trifluoroethyl substituent 3a in 86% NMR yield
(Table 1, entry 1). The choice of CF3 reagents turned out to
yields. It should be noted that the present exo-selective
carbolactonization is also applicable to unactivated 4-pentenoic
acid (2g).
+
Next, we investigated photoredox-catalyzed trifluoromethy-
lative cyclization of internal alkenoic acids 4 (Scheme 2).
Table 1. Trifluoromethylative Lactonization of 4-Phenyl-4-
pentenoic Acid 2a
a
Scheme 2. Scope of the Present endo-Trifluoromethylative
a
−c
Lactonization of Internal Alkenoic Acid
b
entry
CF3 source
base
none
solvent
% yield of 3a
1
2
3
4
5
6
7
1a
1b
1c
1a
1a
1a
1a
1a
1a
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
acetone-d6
dmso-d6
acetone-d6
acetone-d6
86
37
69
96
95
99
69
0
none
none
K2HPO4
K2CO3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
c
8
d
9
0
a
Reaction conditions: A mixture of [Ru(bpy)3](PF6)2 (1.25 μmol, 5
mol %), 1 (28 μmol, 1.1 equiv), and 2 (25 μmol, 1.0 equiv) in solvent
(0.5 mL) was irradiated by 3 W blue LEDs (λ = 425 15 nm) at
b
1
room temperature. Yields were determined by H NMR spectrosco-
c
d
py. In the dark. No photocatalyst.
be crucial for the yield of 3a. Togni’s reagents 1b and 1c gave
3a in low yields (entries 2 and 3). We found that the addition
of a base such as K2HPO4 and K2CO3 resulted in a clean
reaction, affording better yields of 96% and 95%, respectively
(entries 4 and 5). Acetone and acetonitrile solvents are suitable
for the present photocatalytic reaction (entries 6 and 7).
Notably, product 3a was obtained neither in the dark nor in the
absence of a photocatalyst (entries 8 and 9).
The results of exo-selective trifluoromethylative cyclization
for various terminal alkenoic acids 2 are summarized in Table 2.
Table 2. Scope of the Present exo-Trifluoromethylative
ab
,
Lactonization of Terminal Alkenoic Acids
a
b
c
Reaction conditions: see Supporting Information. Isolated yields.
The trans/cis ratios were determined by 1H and 19F NMR
spectroscopies of crude reaction mixtures. Acetone was used as
entry
n
R
% yield of product
d
e
f
1
2
3
4
5
6
1
1
1
1
1
2
1
Ph
3a: 90
3b: 83
3c: 82
3d: 79
3e: 76
solvent. trans/cis = >20:1. 2.0 equiv of 2,6-lutidine were used in
place of K2CO3. g trans/cis = 8.9:1. h trans/cis = >49:1. trans/cis (C3,
i
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
Ph
j
C5) = 1:1. trans/cis = >35:1.
Remarkably, the reaction of (E)-4-phenyl-3-butenoic acids (4a)
proceeded with high endo- and diastereoselectivity to give
(4R*,5R*)-4-trifluoromethyl-5-phenyldihydrofuran-2(3H)-one
(5a) in 82% isolated yield as a single isomer. The reaction of
(E)-4-aryl-3-butenoic acid derivatives with a methyl substituent,
Me (4d), a methoxy group, MeO (4b), and a methylenedioxy
substituent (4c) on the benzene ring produced diastereo-
selectively the corresponding 5-endo cyclized products 5b−d in
high yields (72−79% yields). In addition, this reaction was
amenable to internal alkenes bearing halogen atoms, F (4e), Cl
(4f), Br (4g), and I (4h), and the CF3-substituted five-
membered ring endo-lactones (5e−h) were obtained in high
yields (72−83% yields) as a single diastereomer. A strongly
c
3f: 69
3g: 60
d
c
7
H
a
b
Reaction conditions: see Supporting Information. Isolated yields.
Yields were determined by H NMR spectroscopy. 2g/1a = 1.5.
c
d
1
Reactions of 4-aryl-4-pentenoic acid derivatives with electron-
donating (OMe: 2b), electron-withdrawing (F: 2c), and
halogen (Cl and Br: 2d and 2e) groups on the benzene ring
afforded the corresponding five-membered ring lactones in 83%
(3b), 82% (3c), 79% (3d), and 76% (3e) yields, respectively.
The present photocatalytic system can be extended to the
construction of a six-membered ring lactone (3f) in good
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Organic Letters
Letter
electron-withdrawing group such as a trifluoromethyl group,
CF3 (4i), did not hinder the reaction. Moreover, alkenoic acid
with benzothiophene (4j), a heteroarene, was also tolerated and
the 5-endo cyclization proceeded with exclusively trans-
selectivity to give the CF3-substituted lactone (5j) in 41%
yield. The structure of 5j was unequivocally confirmed by
single-crystal X-ray analysis (Figure 1).12
diastereomers (3.3:1 dr) with a moderate level of stereocontrol
(eq 1). Lowering the reaction temperature to −78 °C improved
the diastereoselectivity (cf. 2.4:1 at rt). This result implies that
the facial-selective introduction of the CF3 group is key for the
stereoselective reaction.
To gain insight into the mechanism, we conducted the
photocatalytic cyclization of (Z)-alkenoic acid ((Z)-4a) (eq 2).
The reaction provided a product identical to the one obtained
from the (E)-isomer 4a. This trans-selective formation strongly
supports the two isomeric substrates producing the same
intermediate.
Figure 1. Single-crystal X-ray analysis of 5j. The thermal ellipsoids are
set at a 50% probability level.
The reaction appears to proceed through a mechanism
similar to that of the previously reported oxy- and amino-
trifluoromethylation of alkenes by photoredox catalysis.6a,c
Sequential SET photoredox processses in the course of the
The present 5-endo cyclization was extended to the reaction
of 1,1,2-trisubstituted internal alkenoic acids. The trifluoro-
methyllactonization of 4,4-diphenyl-3-butenoic acid (4k) gave
the endo-lactone (5k) with a quaternary carbon center in 81%
yield.13 In the reaction of (E)-4-phenyl-3-pentenoic acid (4l),
only the trans-isomer with the diastereoselective formation of a
quaternary carbon center (5l) was obtained in 85% yield. It is
noteworthy that the reaction of β-cyclohexylidenepropionic
acid (4m) afforded the spirocyclic endo-lactone product (5m)
in 53% yield, indicating that this trifluoromethylative
lactonization can be applied to an alkyl-substituted alkenoic
acid as well as an aryl-substituted one.
Furthermore, the present protocol enables endo- and
diastereoselective synthesis of CF3-substituted six- and seven-
membered ring lactones. The reaction of (E)-5-phenyl-4-
pentenoic acid (4n) proceeded with 6-endo cyclization to
produce the CF3-substituted six-membered ring lactone (5n) in
52% yield with a high level of diastereocontrol (8.9:1 dr).
Notable improvements in yield and diastereoselectivity were
observed when the alkenoic acids bearing dialkyl substituents at
the α-position of the carboxyl group (4o−q) were used.
Indeed, the 6-endo cyclized products (5o−q) were obtained in
good yields (67−78%) with excellent diastereoselectivities
(trans/cis (C5, C6) = >49:1 dr). The structure of 5o was
determined by X-ray analysis (see Supporting Information).12
In addition, the present method was also applicable to the
synthesis of the CF3-substituted seven-membered ring endo-
lactone (5r). These results show that photoredox-catalyzed
trifluoromethyllactonization of both terminal and internal
alkenoic acids allows us to easily access a variety of lactones
containing a CF3 group in a regioselective manner. In
particular, it is worth noting that highly endo- and diastereo-
selective carbolactonization of internal alkenoic acids is an
unprecedented transformation to the best of our knowledge.
Control of stereogenic centers is the next stage for this work.
We tested the diastereocontrolled reaction utilizing the adjacent
substituent. The reaction of (S)-4-phenyl-2-methyl-3-butenoic
acid (4s) afforded the CF3-substituted endo-lactones (5s) in
60% yield as a mixture of only two of four possible
+
reaction of CF3 with alkenoic acids 2 and 4 by [Ru(bpy)3]2+
under visible light irradiation produces a β-CF3-substituted
carbocation intermediate in a highly regioselective manner
through radical transformation (for the fully proposed
mechanism, see Supporting Information). Nucleophilic attack
of the dangling carboxylic acid affords the CF3-substituted
lactone product. To elucidate high diastereoselectivity, we
performed DFT calculations for possible conformations of a
generable β-CF3 carbocation from 4a. It was revealed that, in
the most favorable conformation, the CF3 group and the phenyl
group are arranged in an anti-fashion presumably because of
steric repulsion between the CF3 and the Ph groups (see
Supporting Information).14,15 Subsequent intramolecular nu-
cleophilic addition of the COOH group to the carbocationic
center gives the trans-product, which is actually obtained by the
experiments (Scheme 3).
In conclusion, we have developed trifluoromethylative
lactonization of both terminal and internal alkenoic acids by
photoredox catalysis under mild conditions. Regioselective
trifluoromethylation of CC bonds and intramolecular
Scheme 3. A Plausible Reaction Mechanism for High
Diastereoselectivity Observed for 5a
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Organic Letters
Letter
Verhoog, S.; Engle, K. M.; Khotavivattana, T.; O’Duill, M.;
Wheelhouse, K.; Rassias, G.; Medebielle, M.; Gourverneur, V. J. Am.
́
nucleophilic attack of a pendant carboxylate to the β-CF3
carbocation intermediate achieves highly regiocontrolled carbo-
lactonizaton of alkenoic acids. In particular, this operationally
easy trifluoromethylative cyclization protocol for internal
alkenoic acids enables us to access a variety of CF3-substituted
five- and six-membered ring endo-lactones bearing many
functional groups in a diastereoselective manner. Furthermore,
this photocatalytic cyclization can be applied successfully to the
synthesis of a CF3-substituted seven-membered ring endo-
lactone. This is the first example of endo-carbolactonization of
internal alkenoic acids. Further studies on stereoselective
trifluoromethylation are underway in our laboratory.
Chem. Soc. 2013, 135, 2505. (e) Kim, E.; Choi, S.; Kim, H.; Cho, E. J.
Chem.Eur. J. 2013, 19, 6209. (f) Wilger, D. J.; Gesmundo, N. J.;
Nicewicz, D. A. Chem. Sci. 2013, 4, 3160. (g) Jiang, H.; Cheng, Y.;
Zhang, Y.; Yu, S. Eur. J. Org. Chem. 2013, 5485. (h) Xu, P.; Xie, J.; Xue,
Q.; Pan, C.; Cheng, Y.; Zhu, C. Chem.Eur. J. 2013, 19, 14039.
(6) For our recent reports, see: (a) Yasu, Y.; Koike, T.; Akita, M.
Angew. Chem., Int. Ed. 2012, 51, 9567. (b) Yasu, Y.; Koike, T.; Akita,
M. Chem. Commun. 2013, 49, 2037. (c) Yasu, Y.; Koike, T.; Akita, M.
Org. Lett. 2013, 15, 2136. (d) Koike, T.; Akita, M. Synlett 2013, 24,
2492.
(7) (a) Umemoto, T. Chem. Rev. 1996, 96, 1757 and references
therein. (b) Eisenberger, P.; Gischig, S.; Togni, A. Chem.Eur. J.
2006, 12, 2579. (c) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew.
Chem., Int. Ed. 2007, 46, 754.
(8) (a) Hiyama, T. Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, 2000. (b) Fluorine in Medicinal
Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell:
Chichester, U.K., 2009.
(9) For selected reviews, see: (a) Shimizu, M.; Hiyama, T. Angew.
Chem., Int. Ed. 2005, 44, 214. (b) Ma, J.-A.; Cahard, D. J. Fluorine
Chem. 2007, 128, 975. (c) Shibata, N.; Mizuta, S.; Toru, T. J. Synth.
Org. Chem. Jpn. 2008, 66, 215. (d) Ma, J.-A.; Cahard, D. Chem. Rev.
2008, 108, PR1.
(10) For recent reviews on the synthesis of CF3-containing
molecules, see: (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev.
2011, 111, 4475. (b) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011,
473, 470. (c) Amii, H. J. Synth. Org. Chem. Jpn. 2011, 69, 752.
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of experimental procedures and full spectroscopic data
for all new compounds, crystallographic data of 5j (CCDC
962013) and 5o (CCDC 962014), and results of computational
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: koike.t.ad@m.titech.ac.jp.
*E-mail: makita@res.titech.ac.jp.
Notes
́
(d) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950. (e) Mace, Y.;
Magnier, E. Eur. J. Org. Chem. 2012, 2479. (g) Liang, T.; Neumann, C.
N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214.
The authors declare no competing financial interest.
(11) For selected reports on difunctionalization of alkenes involving
C−CF3 bond formation, see: (a) Janson, P. G.; Ghoneim, I.; IIchenko,
ACKNOWLEDGMENTS
■
This work was supported by a grant-in-aid from the Ministry of
Education, Culture, Sports, Science of the Japanese Govern-
ment (No. 23750174) and the global COE program (the
GCOE) “Education and Research Center for Emergence of
New Molecular Chemistry”.
́
N. O.; Szabo, K. J. Org. Lett. 2012, 14, 2882. (b) Li, Y.; Studer, A.
Angew. Chem., Int. Ed. 2012, 51, 8221. (c) Egami, H.; Shimizu, R.;
Sodeoka, M. Tetrahedron Lett. 2012, 53, 5503. (d) Feng, C.; Loh, T.-P.
Chem. Sci. 2012, 3, 3458. (e) Lu, D.-F.; Zhu, C.-L.; Xu, H. Chem. Sci.
2013, 4, 2478. (f) He, Y.-T.; Li, L.-H.; Yang, Y.-F.; Wang, Y.-Q.; Luo,
J.-Y.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2013, 49, 5687.
(g) Egami, H.; Shimizu, R.; Kawamura, S.; Sodeoka, M. Angew. Chem.,
Int. Ed. 2013, 52, 4000. (h) Liu, X.; Xiong, F.; Huang, X.; Xu, L.; Li, P.;
Wu, X. Angew. Chem., Int. Ed. 2013, 52, 6962. (i) Egami, H.; Miyazaki,
A.; Kawamura, S.; Sodeoka, M. Angew. Chem., Int. Ed. 2013, 52, 7841.
(j) Chen, Z.-M.; Bai, W.; Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.; Zhang,
F.-M. Angew. Chem., Int. Ed. 2013, 52, 9781.
(12) 5j and 5o: Molecular structures are shown in Supporting
Information. CCDC 962013 and CCDC 962014 contain the
supplementary crystallographic data. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
REFERENCES
■
(1) (a) Dowle, M. D.; Davis, D. I. Chem. Soc. Rev. 1979, 8, 171.
(b) Smith, M. B.; March, J. March’s Advanced Organic Chemistry; John
Wiley and Sons: New York, 2001, 993. (c) Ranganathan, S.;
Muraleedharan, K. M. Tetrahedron 2004, 60, 5273. (d) Castellanos,
A.; Fletcher, S. P. Chem.Eur. J. 2011, 17, 5766. (e) Denmark, S. E.;
Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938.
(f) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763.
(2) (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P.
Synlett 2008, 2913. (c) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem.
2008, 6, 4083. (d) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev.
2011, 111, 2981. (e) Wolfe, J. P. Angew. Chem., Int. Ed. 2012, 51,
10224.
(3) (a) Protti, S.; Fagnoni, M.; Albini, A. J. Am. Chem. Soc. 2006, 128,
10670. (b) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134,
12462. (c) Zhu, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52,
12655.
(4) For selected reviews and a book on photoredox catalysis, see:
(a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527.
(b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
40, 102. (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem.
Rev. 2013, 113, 5322. (d) Albini, A.; Fagnoni, M. Photochemically-
generated intermediates in Synthesis; John Wiley & Sons: Hoboken, NJ,
2013.
(13) The reaction of 4k with K2CO3 as a base gave 5k and the
nontrifluoromethylated lactone as a byproduct. The byproduct may be
derived from a competitive proton-mediated reaction. In contrast, the
use of 2,6-lutidine prevents formation of the byproduct.
(14) For a review on 1,3-allylic strain in stereoselective reactions, see:
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(15) For selected reports on a diastereoselective reaction via a
carbocation intermediate, see: (a) Muhlthau, F.; Schuster, O.; Bach, T.
̈
J. Am. Chem. Soc. 2005, 127, 9348. (b) Muhlthau, F.; Stadler, D.;
̈
Goeppert, A.; Olah, G. A.; Prakash, G. K. S.; Bach, T. J. Am. Chem. Soc.
2006, 128, 9668 and references therein. (c) Rubenbauer, P.;
Herdtweck, E.; Strassner, T.; Bach, T. Angew. Chem., Int. Ed. 2008,
47, 10106. (d) Cozzi, P. G.; Benfatti, F. Angew. Chem., Int. Ed. 2010,
49, 256. (e) Cahard, E.; Bremeyer, N.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2013, 52, 9284.
(5) For selected examples on photoredox-catalyzed trifluoromethy-
lation, see: (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480,
224. (b) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (c) Ye, Y.;
Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034. (d) Mizuta, S.;
783
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