Three-component povarov reaction-heteroannulation with arynes: Synthesis of 5,6-dihydroindolo[1,2-a ]quinolines

Article abstract of DOI:10.1021/ol500447r

A reaction of 2-acyl substituted tetrahydroquinolines, prepared by Lewis acid-catalyzed three-component reaction of α-oxo aldehydes, anilines, and dienophiles, with in situ generated arynes afforded 5,6-dihydroindolo[1,2-a] quinolines in good to excellent

Full text of DOI:10.1021/ol500447r

Letter
pubs.acs.org/OrgLett
Three-Component Povarov Reaction−Heteroannulation with Arynes:
Synthesis of 5,6-Dihydroindolo[1,2‑a]quinolines
Ala Bunescu, Qian Wang, and Jieping Zhu*
́ ́
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: A reaction of 2-acyl substituted tetrahydroqui-
nolines, prepared by Lewis acid-catalyzed three-component
reaction of α-oxo aldehydes, anilines, and dienophiles, with in
situ generated arynes afforded 5,6-dihydroindolo[1,2-a]-
quinolines in good to excellent yields.
5,6-Dihydroindolo[1,2-a]quinolines 1 and its reduced or
oxidized forms are structural units frequently found in bioactive
natural products such as strychnohirsutine (2)1 and goniomi-
tine (3, Figure 1).2,3 They also display interesting physical
Scheme 1. Synthetic Routes to 5,6-Dihydroindolo[1,2-
a]quinolines
Figure 1. 5,6-Dihydroindolo[1,2-a]quinolines and related natural
products.
properties as semiconductors,4 as dyes,5 and as organic
sensitizers for dye-sensitized solar cells.6 Despite the develop-
ment of a large number of synthetic methodologies for indoles,7
methods allowing direct access to indolo[1,2-a]quinoline
derivatives remained scarce.8
Most of the recently reported syntheses of 1 involved the
elaboration of appropriately functionalized N-arylindoles (eq 1,
Scheme 1). In connection with our interests in indole9 and
indole alkaloid synthesis,10 we recently reported a synthesis of
N-aryl-2,3-disubstituted indoles via a formal [2 + 3] cyclo-
addition reaction between benzyne11 and N-aryl-α-amino
ketones with a wide application scope.12,13 This novel
heteroannulation reaction proceeds via formation of N1−
C7a/C3−C4a bonds that offered an alternative bond-
disconnection perspective in a more complex indole-containing
polyheterocyclic setting. Indeed by applying this reaction as a
key indolization step, the 5,6-dihydroindolo[1,2-a]quinoline
(1) could be disconnected to benzyne and 2-acetyl
tetrahydroquinoline 4, the latter being readily accessible via
three-component Povarov reaction (eq 2, Scheme 1). This
strategy, allowing the construction of 1 in two steps from
simple starting materials, is completely different from previous
described ones and has an advantage being easily amenable to
introduce the molecular diversity. Indeed, it has been amply
demonstrated for the past two decades that the sequence of
multicomponent reaction/postfunctionalization is particularly
powerful for the construction of heterocyclic compound
libraries.14,15 Herein we report a straightforward synthesis of
5,6-dihydroindolo[1,2-a]quinolines from anilines 5, glyoxal
derivatives 6, dienes 7, and 2-(trimethylsilyl)phenyl triflates 8
as benzyne precursors.
Received: February 11, 2014
Published: February 28, 2014
© 2014 American Chemical Society
1756
dx.doi.org/10.1021/ol500447r | Org. Lett. 2014, 16, 1756−1759

Organic Letters
Letter
Many different conditions have been developed for perform-
ing the Povarov reaction,16,17 including the enantioselective
version.18 There were nevertheless few reports dealing with the
use of α-oxo aldehydes as one of the reaction partners.18e,19,20
After several unsuccessful trials, the conditions developed by
Kobayashi [Yb(OTf)3 (0.1 equiv), MgSO4 (6.5 equiv), MeCN,
0 °C]19 were found to be the most general. Using slightly
modified literature procedures, the diversely substituted 2-acyl-
tetrahydroisoquinolines 4 synthesized is depicted in Scheme 2.
Scheme 3. Synthesis of 5,6-Dihydroindolo[1,2-a]quinolines
Scheme 2. Synthesis of 2-Acyl-tetrahydroquinoline 4 by
Three-Component Povarov Reaction
Table 1. Heteroannulation between 8a and 4a, Survey of
a b
,
Reaction Conditions
ratio 11a/ yield of
f
entry
1
additives
solvent, t (°C)
9a
1a
c
e
CsF,18-C-6,
i-PrCN/DCE (1/4),
rt
0.5
16
d
Cs2CO3
g
2
3
4
5
6
CsF
CH3CN, 65 °C
CH3CH2CN, 65 °C
THF, 65 °C
1.5
1.2
0.5
2.2
2.7
(46)
CsF
(22)
TBAT
CsF
(30)
CH3CN, rt
52 (73)
57 (77)
TBAT
CH3CN, rt
a
All reactions were carried out under Ar using 4a (1.0 equiv), 8a (1.5
equiv), CsF (3.0 equiv) or TBAT (1.5 equiv), solvent (c = 0.10 M).
b
The crude product was treated with MeOH/CH2Cl2/AcOH (1/1/
c
d
1), silica gel, 40 °C. 1.1 equiv of 18-C-6. 2.0 equiv of Cs2CO3.
e
f
g
Solvent (c = 0.14 M). Isolated yield. In parentheses, NMR yield
using CH2Br2 as an internal standard determined before acidic
treatment.
a
Conditions: Yb(OTf)3 (0.1 equiv), MgSO4 (6.5 equiv), MeCN, 0 °C
b
then rt. BF3·OEt2 (0.05 equiv), MgSO4 (1.0 equiv), CH2Cl2, 0 °C
then rt.
tetrabutylammonium difluorotriphenylsilicate (TBAT). Under
these conditions, the desired product was isolated, after acidic
treatment, in 57% yield.
The all cis stereochemistry of these cycloadducts was based on
the spectroscopic data that were in accord with the literature
precedents.19,20 The yield of 4 referred to the crystalline
product obtained by direct crystallization of the crude product.
Therefore, the actual yield might be higher than what was
indicated in the scheme.
With these tetrahydroisoquinolines 4 in hand, the hetero-
annulation between 4 and benzynes was investigated. Applying
our previously developed conditions [CsF (3.0 equiv), Cs2CO3
(2.0 equiv), 18-C-6 (1.1 equiv), isopropionitrile/dichloro-
ethane (1/4), rt, then MeOH/CH2Cl2/AcOH (1/1/1), silica
gel at 40 °C], the reaction of 4a with 2-(trimethylsilyl)phenyl
triflate (8a)20 afforded indeed the desired compound 1a, albeit
in low yield (16%). The major product was N-aryl
tetrahydroisoquinoline 9a. It is reasonable to assume that
formation of both products went through intermediate 10a.
While intramolecular nucleophilic addition followed by
dehydration (pathway a) would produce 1a, an intramolecular
proton transfer (pathway b) of intermediate 10a could account
for the formation of 9a (Scheme 3).21
The scope of the reaction was next examined using
optimized conditions. The results are summarized in Scheme
4. Functionalized silyl aryl triflates were prepared following
literature procedure.22,23 As it is seen, the reaction tolerated a
variety of functional groups and is insensitive to the electronic
properties of the aromatic ring. Steric hindrance around the
secondary amines is also well tolerated as reaction of 4f having
a pivaloyl group at C-2 position with 8a afforded 1f in excellent
yield. In general, tetrahydroquinolines having a fused indene,
cyclopetene rings (4b−4h) are better substrates than that
having a fused furan ring (4a), furnishing the desired 5,6-
dihydroindolo[1,2-a]quinoline derivatives (1b−1k) in good to
excellent yields. However, reaction of 4i having a cyclohexene
unit with 8a produced indoloquinoline 1l in a low yield (26%).
The structure of 5,6-dihydroindolo[1,2-a]quinolines 1h was
determined unambiguously by X-ray crystallographic analysis
(Scheme 4).
In summary, we have developed a two-step synthesis of 5,6-
dihydroindolo[1,2-a]quinolines 1 from simple starting materi-
als. It features (a) a Lewis acid-catalyzed three-component
Povarov reaction of α-oxo aldehydes, anilines and dienes; (b) a
heteroannulation reaction between the Povarov adducts and
benzynes. Five chemical bonds were created in this operation-
ally simple two-step sequence. Since both indoles and
quinolines are important core structures for pharmaceuticals,
To improve the yield of desired 5,6-dihydroindolo[1,2-
a]quinoline 1a, a brief survey of reaction conditions was carried
out varying the fluoride sources (CsF, TBAT), the solvents, the
temperature, and the reaction time. Some representative results
are presented in Table 1. The optimum conditions for the
above heteroannulation consisted of performing the reaction in
acetonitrile (c 0.10 M) at room temperature in the presence of
1757
dx.doi.org/10.1021/ol500447r | Org. Lett. 2014, 16, 1756−1759

Organic Letters
Letter
Scheme 4. Scope of Benzannulation of Tetrahydroquinolines
4 with Arynes to 5,6-Dihydroindolo[1,2-a]quinolines 1
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jieping.zhu@epfl.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank EPFL (Switzerland), Swiss National Science
Foundation (SNSF) for financial support.
■
REFERENCES
■
(1) Galeffi, C.; Marini-Bettolo, G. B. Tetrahedron 1981, 37, 3167.
(2) Randriambola, L.; Quirion, J.-C.; Kan-Fan, C.; Husson, H.-P.
Tetrahedron Lett. 1987, 28, 2123.
(3) Total synthesis: (a) Takano, S.; Sato, T.; Inomata, K.; Ogasawara,
K. J. Chem. Soc., Chem. Commun. 1991, 462. (b) Morales, C. L.;
Pagenkopf, B. L. Org. Lett. 2008, 10, 157. (c) De Simone, F.; Gertsch,
J.; Waser, J. Agnew. Chem. Int. Ed. 2010, 49, 5767. (d) Mizutani, M.;
Inagaki, F.; Nakanishi, T.; Yanagihara, C.; Tamai, I.; Mukai, C. Org.
Lett. 2011, 13, 1796. (e) Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem.
Soc. 2012, 134, 14563. (f) Xu, Z.; Wang, W.; Zhu, J. Angew. Chem., Int.
Ed. 2013, 52, 3272. (g) For a semi-synthesis from vincadifformine,
see: Lewin, G.; Bernadat, G.; Aubert, G.; Cresteil, T. Tetrahedron
2013, 69, 1622.
(4) (a) Ahmed, E.; Briseno, A. L.; Xia, Y.; Jenekhe, S. A. J. Am. Chem.
Soc. 2008, 130, 1118. (b) Zhu, L.; Kim, E.-G.; Yi, Y.; Ahmed, E.;
Jenekhe, S. A.; Coropceanu, V.; Bred
114, 20401.
́
as, J.-L. J. Phys. Chem. C 2010,
(5) Wick, L.; Spitz, U.; Weymuth, C.; Schabert, G.; Mayer, T.; Bayer,
A. WO2012/059583 A1.
(6) Baik, C.; Kim, D.; Kang, M.-S.; Song, K.; Kang, S. O.; Ko, J.
Tetrahdron 2009, 65, 5302.
(7) For reviews, see: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004,
104, 2285. (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875. (c) Ackermann, L. Synlett 2007, 507. (d) Kruger, K.; Tillack, A.;
̈
Beller, M. Adv. Synth. Catal. 2008, 350, 2153. (e) Taber, D. F.;
Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (f) Cacchi, S.; Fabrizi,
G.; Goggiamani, A. Org. React. 2012, 76, 281.
(8) For indolo[1,2-a]quinoline synthesis, see: (a) Ye, S.; Liu, J.; Wu,
J. Chem. Commun. 2012, 48, 5028. (b) Verma, A. K.; Shukla, S. P.;
Singh, J.; Rustagi, V. J. Org. Chem. 2011, 76, 5670. (c) Panteleev, J.;
Geyer, K.; Aguilar-Aguilar, A.; Wang, L.; Lautens, M. Org. Lett. 2010,
12, 5092. (d) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054.
(e) Xie, C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431.
(f) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761. For 5,6-
dihydroindolo[1,2-a]quinoline synthesis, see: (g) Lee, H. S.; Kim, S.
H.; Kim, Y. M.; Kim, J. N. Tetrahedron Lett. 2010, 51, 5071.
(h) Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem.,
Int. Ed. 2008, 47, 4906.
(9) Recent examples, see: (a) Bunescu, A.; Wang, Q.; Zhu, J.
Synthesis 2012, 44, 3811. (b) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem.,
Int. Ed. 2012, 51, 5170. (c) Piou, T.; Neuville, L.; Zhu, J. Angew. Chem.,
Int. Ed. 2012, 51, 11561. (d) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem.,
Int. Ed. 2013, 52, 12992. (e) Piou, T.; Neuville, L.; Zhu, J. Tetrahedron
2013, 69, 4415. (f) Piou, T.; Bunescu, A.; Wang, Q.; Neuville, L.; Zhu,
J. Angew. Chem., Int. Ed. 2013, 52, 12385.
(10) (a) Gerfaud, T.; Xie, C.; Neuville, L.; Zhu, J. Angew. Chem., Int.
Ed. 2011, 50, 3954. (b) Buyck, T.; Wang, Q.; Zhu, J. Org. Lett. 2012,
14, 1338. (c) Buyck, T.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2013,
52, 12714. (d) Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2013, 135,
19127.
(11) For reviews on aryne chemistry, see: (a) Dubrovskiy, A. V.;
Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191.
(b) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
(c) Gampe, C. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51,
3766. (d) Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725. (e) Bhojgude,
S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 1520. (f) Bronner, S.
a
All reactions were carried out under argon atmosphere using
tetrahydroquinolines 4 (1.0 equiv), benzyne precursors 8 (1.4
equiv), TBAT (1.5 equiv), CH3CN (c 0.10 M) at rt for 12−14 h;
the crude reaction mixture was subsequently treated with MeOH/
CH2Cl2/AcOH (1/1/1), silica gel at 40 °C. The crude reaction
mixture was treated with TFA, CH2Cl2, silica gel, rt.
b
we expected that a rapid synthesis of a hybrid structure could
find application in medicinal chemistry.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, product characterization data, 1H and
13C NMR spectra for new compounds, X-ray crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
1758
dx.doi.org/10.1021/ol500447r | Org. Lett. 2014, 16, 1756−1759

Organic Letters
Letter
M.; Goetz, A. E.; Garg, N. K. Synlett 2011, 2599. (g) Sanz, R. Org.
987. (e) Kirkham, J. D.; Delaney, P. M.; Ellames, G. J.; Row, E. C.;
Harrity, J. P. A. Chem. Commun. 2010, 46, 5154.
́ ́
Prep. Proced. Int. 2008, 40, 215. (h) Pena, D.; Perez, D.; Guitian, E.
̃
(22) (a) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673. (b) Ikawa, T.;
Nishiyama, T.; Shigeta, T.; Mohri, S.; Morita, S.; Takayanagi, S.-I.;
Terauchi, Y.; Morikawa, Y.; Takagi, A.; Ishikawa, Y.; Fujii, S.; Kita, Y.;
Akai, S. Angew. Chem., Int. Ed. 2011, 50, 5674. (c) Pintori, D. G.;
Greaney, M. F. Org. Lett. 2010, 12, 168. (d) Pirali, T.; Zhang, F.;
Miller, A. H.; Head, J. L.; McAusland, D.; Greaney, M. F. Angew.
Chem., Int. Ed. 2012, 51, 1006.
Angew. Chem., Int. Ed. 2006, 45, 3579. (i) Wenk, H. H.; Winkler, M.;
Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502.
(12) Bunescu, A.; Piemontesi, C.; Wang, Q.; Zhu, J. Chem. Commun.
2013, 49, 10284.
(13) Reaction of α-aminoesters with benzynes, see: (a) Okuma, K.;
Matsunaga, N.; Nagahora, N.; Shioji, K.; Yokomori, Y. Chem. Commun.
2011, 47, 5822. Reaction of o-aminobenzoates with benzynes, see:
(b) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583. Reaction of 2-
aminoarylketones with benzynes, see: (c) Rogness, D. C.; Larock, R.
C. J. Org. Chem. 2010, 75, 2289.
(23) For a facile two-step preparation of o-silylaryl triflates, see: Pena,
̃
́ ́
D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis 2002, 1454.
́
(14) For reviews: (a) Hulme, C.; Nixey, T.; Bienyme, H.; Chenera,
B.; Jones, W.; Tempest, P.; Smith, A. L. Methods Enzymol. 2003, 369,
469. (b) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73,
125. (c) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23. (d) Marcaccini,
S.; Torroba, T. In Multicomponent Reaction; Zhu, J., Bienayme,
Eds.; Wiley-VCH: Weinheim, 2005; pp 33−75.
(15) Selected examples from our group: (a) Zhao, G.; Sun, X.;
Bienayme, H.; Zhu, J. J. Am. Chem. Soc. 2001, 123, 6700. (b) Janvier,
P.; Sun, X.; Bienayme, H.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 2560.
(c) Janvier, P.; Bienayme, H.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41,
́
H.,
́
́
́
4291. (d) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron Lett. 2003, 44,
5575. (e) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859.
(f) Cunny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2003,
4774. (g) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004,
126, 14474. (h) Fayol, A.; Zhu, J. Org. Lett. 2004, 6, 115. (i) Fontaine,
P.; Chiaroni, A.; Masson, J.; Zhu, J. Org. Lett. 2008, 10, 1509.
(j) Salcedo, A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 3600.
(k) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74, 3109.
(16) (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(b) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721. (c) Bello, D.;
Ramon
(17) Synthesis of fused indolines: Preciado, S.; Vicente-García, E.;
Llabres, S.; Luque, F. J.; Lavilla, R. Angew. Chem., Int. Ed. 2012, 51,
6874.
́
; Lavilla, R. Curr. Org. Chem. 2010, 14, 332.
́
(18) (a) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070. (b) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.;
Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598. (c) Bergonzini, G.;
Gramigna, L.; Mazzanti, A.; Fochi, M.; Bernardi, L.; Ricci, A. Chem.
Commun. 2010, 46, 327. (d) Wang, C.; Han, Z. Y.; Luo, H. W.; Gong,
L. Z. Org. Lett. 2010, 12, 2266. (e) Xu, A. H.; Zuend, S. J.; Woll, M. G.;
Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986. (f) Xie, M. S.; Chen, X.
H.; Zhu, Y.; Gao, B.; Lin, L. L.; Liu, X. H.; Feng, X. M. Angew. Chem.,
Int. Ed. 2010, 49, 3799. (g) Dagousset, G.; Zhu, J.; Masson, G. J. Am.
Chem. Soc. 2011, 133, 14804. (h) Lin, J. H.; Zong, G. Q.; Du, R. B.;
Xiao, J. C.; Liu, S. B. Chem. Commun. 2012, 48, 7738. (i) Dagousset,
G.; Retailleau, P.; Masson, G.; Zhu, J. Chem.Eur. J. 2012, 18, 5869.
(j) He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14,
3158. (k) Shi, F.; Xing, G.-J.; Tao, Z.-L.; Luo, S.-W.; Tu, S.-J.; Gong,
L.-Z. J. Org. Chem. 2012, 77, 6970. (l) Shi, F.; Xing, G. J.; Zhu, R. Y.;
Tan, W.; Tu, S. J. Org. Lett. 2013, 15, 128. (m) Min, C.; Mittal, N.;
Sun, D. X.; Seidel, D. Angew. Chem., Int. Ed. 2013, 52, 14084.
(n) Caruana, L.; Fochi, M.; Ranieri, S.; Mazzanti, A.; Bernardi, L.
Chem. Commun. 2013, 49, 880. (o) Huang, D.; Xu, F.; Chen, T.;
Wang, Y.; Lin, X. RSC Adv. 2013, 3, 573. (p) Chen, Z. L.; Wang, B. L.;
Wang, Z. B.; Zhu, G. Y.; Sun, J. W. Angew. Chem., Int. Ed. 2013, 52,
2027. (q) Luo, C. S.; Huang, Y. J. Am. Chem. Soc. 2013, 135, 8193.
(19) (a) Kobayashi, S.; Ishitani, H.; Sagayama, S. Chem. Lett. 1995,
423. (a) Kobayshi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977.
(20) (a) Lucchini, V.; Prato, M.; Scorrano, G.; Tecilla, P. J. Org.
Chem. 1988, 53, 2251. (b) Lucchini, V.; Prato, M.; Scorrano, G.;
Stivanello, M.; Valle, G. J. Chem. Soc., Perkin Trans. 2 1992, 2, 259.
(21) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211. For recent references on benzyne generation, see: (b) Hamura,
T.; Chuda, Y.; Nakatsuji, Y.; Suzuki, K. Angew. Chem., Int. Ed. 2012, 51,
3368. (c) Ikawa, T.; Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S.
Org. Lett. 2011, 13, 1730. (d) Kitamura, T. Aust. J. Chem. 2010, 63,
1759
dx.doi.org/10.1021/ol500447r | Org. Lett. 2014, 16, 1756−1759