Lewis acid catalyzed benzylic C-H bond functionalization of azaarenes: Addition to enones

Article abstract of DOI:10.1021/ol200217y

A Lewis acid catalyzed benzylic C-H bond functionalization of alkyl-substituted azaarenes is described. Sc(OTf)₃ and Y(OTf) ₃ promoted the direct addition of alkyl-substituted azaarenes and benzoxazole to enones and an α,β-unsaturate

Full text of DOI:10.1021/ol200217y

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1706–1709
Lewis Acid Catalyzed Benzylic C-H Bond
Functionalization of Azaarenes: Addition
to Enones
Hirotomo Komai, Tatsuhiko Yoshino, Shigeki Matsunaga,* and Motomu Kanai*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
smatsuna@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
Received January 24, 2011
ABSTRACT
A Lewis acid catalyzed benzylic C-H bond functionalization of alkyl-substituted azaarenes is described. Sc(OTf)3 and Y(OTf)3 promoted the direct
addition of alkyl-substituted azaarenes and benzoxazole to enones and an R,β-unsaturated N-acylpyrrole. Products were obtained in 60-96%
yield.
Metal-catalyzed C(sp3)-H bond functionalizations are
valuable methods in synthetic organic chemistry.1,2
Among them, C(sp3)-H bond activation/C-C bond-
forming reactions of azaarenes, such as quinolines and
pyridines, provide straightforward access to useful build-
ing blocks for the design and synthesis of biologically
active compounds. To realize the C(sp3)-H functionaliza-
tion of azaarenes, transition-metal-catalyzed chelation-
assisted methods for C-C bond formation have been
investigated by many groups.3 Further studies to expand
the reaction scope for the synthesis of diverse sets of
functionalized azaarenes by enabling the use of various
coupling partners are desirable. To complement transi-
tion-metal-catalyzed processes, we herein report a
Lewis acid-catalyzed coupling of benzylic C(sp3)-H
in alkyl-substituted azaarenes 1 (Figure 1) with electron-
deficient alkenes 2, enones, and an R,β-unsaturated ester
surrogate.
(1) Review on C(sp3)-H bond functionalization: Tobisu, M.; Cha-
tani, N. Angew. Chem., Int. Ed. 2006, 45, 1683.
(2) Selected recent general reviews on C-H bond functionalization,
see: (a) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (b)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (c)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (d) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010,
46, 677. (e) Special Issue on Selective Functionalization of C-H Bonds:
Chem. Rev. 2010, 110, 575-1211. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Rev. 2010, 110, DOI: 10.1021/cr100198w.
(3) For selected leading examples involving C-C bond formation,
see: (a) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi,
F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935. (b) Kalyani, D.;
Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 7330. (c) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657.
(d) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (e) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 12634. (f) Campeau, L.-C.; Schipper, D. J.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. (g) Mousseau, J. J.;
Figure 1. Structures of methyl-substituted azaarenes 1a-g and
benzoxazole 1h.
ꢀ
Larivee, A.; Charette, A. B. Org. Lett. 2008, 10, 1641. (h) Watanabe,
T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759. (i) Qian, B.;
Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang, H. J. Am. Chem.
Soc. 2010, 132, 3650. (j) Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2010, 132, 3965. (k) Burton, P. M.; Morris, J. A. Org. Lett. 2010,
12, 5359. (l) Tsurugi, H.; Yamamoto, K.; Mashima, K. J. Am. Chem.
Soc. 2011, 133, 732.
Based on precedents in Lewis acid catalyzed intramole-
cular C(sp3)-H functionalization,4-8 Lewis acid assisted
r
10.1021/ol200217y
Published on Web 03/03/2011
2011 American Chemical Society

C(sp2)-H functionalization of pyridines and/or quino-
lines,9,10 as well as our ongoing projects on acid/base-
catalyzed proton transfer processes,11 we envisioned the
use of a Lewis acid for the functionalization of o-methyl-
substituted azaarenes under proton-transfer conditions.12
external base (azaarene 1) would generate a metal enamide
species.13 The addition of the metal enamide to enones 2
would give an enolate intermediate, which would afford
the product 3 after protonation.
To test the feasibility of our hypothesis, we screened
Lewis acids using lutidine 1a and enone 2a as model
substrates. The optimization studies are summarized in
Table 1. Initial trials using Mg(OTf)2, Al(OTf)3, In(OTf)3,
Fe(OTf)3, Cu(OTf)2, Zn(OTf)2, and Bi(OTf)3 did not
promote the desired reaction at all (entries 1-7). In con-
trast, the results using rare earth metal triflates [RE(OTf)3]
were promising (entries 8-12). The reactivity changed in
correlation with the Lewis acidity of rare earth metal
triflates (Sc, Y > Gd > Sm, La),14 and 20 mol % of
Sc(OTf)3 and Y(OTf)3 gave the best reactivity (entries 8
and 9, 71% yield). ScBr3 and ScCl3 were also examined,
but the yield was not as satisfactory (entries 13-14). The
reaction also proceeded in good yield with 10 mol % of
Sc(OTf)3, although a longer reaction time was required at
120 °C (entry 16, 72 h, 90% isolated yield). At 160 °C, the
reaction was complete after 48 h using 10 mol % of
Sc(OTf)3 (entry 17, 90% isolated yield).
Figure 2. Working hypothesis on Lewis acid catalyzed C-H
functionalization of alkyl-substituted azaarenes with enones.
Ourworking hypothesisisshown inFigure 2. Activationof
azaarenesbythecoordinationtoastrongLewisacid would
increase the acidity of benzylic C-H bonds. Cleavage of
the C-H bond by either counterions of a Lewis acid or an
Table 1. Optimization Studies
(4) BF3 Et2O- and TiCl4-catalyzed intramolecular benzylic C-H
3
ꢀ
functionalization via 1,5-hydride transfer: Wolfling, J.; Frank, E.;
€
Schnieder, G.; Tietze, L. F. Eur. J. Org. Chem. 2004, 90.
(5) Sc(OTf)3-, BF3 Et2O-, and PtCl4-catalyzed intramolecular cou-
3
pling of C(sp3)-H bonds and electron-deficient alkenes via 1,5-hydride
transfer: (a) Pastine, S. J.; MacQuaid, K. M.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 12180. (b) MacQuaid, K. M.; Sames, D. J. Am. Chem.
Soc. 2009, 131, 402. (c) Pastine, S. J.; Sames, D. Org. Lett. 2005, 7, 5429.
(d) MacQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009, 11, 2972.
(e) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402.
(6) Gd(OTf)3-, Mg(OTf)2-, and Ni(ClO4)2-catalyzed intramolecular
(asymmetric) reactions with electron-deficient alkenes via 1,5-hydride
transfer: (a) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem.
Soc. 2009, 131, 13226. (b) Murarka, S.; Zhang, C.; Konieczynska, M. D.;
Seidel, D. Org. Lett. 2009, 11, 129.
(7) Rh(O2CCF3)-catalyzed intramolecular reactions with electron-
deficient alkynes via 1,5-hydride transfer: Shikanai, D.; Murase, H.;
Hata, T.; Urabe, H. J. Am. Chem. Soc. 2009, 131, 3166.
(8) Cationic Co Lewis acid-catalyzed intramolecular asymmetric
reaction via 1,5-hydride transfer: Cao, W.; Liu, X.; Wang, W.; Lin, L.;
Feng, X. Org. Lett. 2011, 13, 600.
(9) Sc(OTf)3-catalyzed alkylation under cross-dehydrogenative-
coupling conditions: Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171.
(10) Lewis acid-assisted functionalization under Ni(0) catalysis: (a)
Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130,
2448. (b) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am.
Chem. Soc. 2010, 132, 13666. (c) Tsai, C.-C.; Shih, W.-C.; Fang, C-.H.;
Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887.
(11) For an example using rare earth metal triflate, see: Mihara, H.;
Xu, Y.; Shepherd, N. E.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 8384. See also a review: Shibasaki, M.; Matsunaga, S.
J. Synth. Org. Chem., Jpn. 2010, 68, 1142.
(12) During the preparation of this manuscript, Huang et al. reported
closely related Sc(OTf)3-catalyzed benzylic C-H functionalization of
2-methyl azaarenes. The reactions with aldimines proceeded in excellent
yield under proton transfer conditions. (a) Qian, B.; Guo, S.; Xia, C.;
Huang, H. Adv. Synth. Catal. 2010, 352, 3195. After submission of this
manuscript, Rueping’s group also reported Cu(OTf)2-catalyzed reac-
tions with aldimines, see: (b) Rueping, M.; Tolstoluzhsky, N. Org. Lett.
2011, 13, 1095.
Lewis acid
temp
time
(h)
%
entry
(x mol %)
solvent
PhCl
(°C)
yielda
1
2
Mg(OTf)2 (20)
Al(OTf)3 (20)
ln(OTf)3 (20)
Fe(OTf)3 (20)
Cu(OTf)2 (20)
Zn(OTf)2 (20)
Bi(OTf)3 (20)
Sc(OTf)3 (20)
Y(OTf)3 (20)
Gd(OTf)3 (20)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
160
14
14
14
14
14
14
14
14
14
14
14
14
14
14
48
72
48
0
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
0
3
0
4
0
5
0
6
0
7
0
8
71
71
33
0
9
10
11
12
13
14
15
16
17
Sm(OTf)3 (20) PhCl
La(OTf)3 (20)
ScBr3 (20)
PhCl
trace
51
30
73b
90b
90b
PhCl
ScCl3 (20)
PhCl
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
PhCl
PhCl
1,2-Cl2C6H4
a Determined by 1H NMR analysis with an internal standard (entries
1-14). b Isolated yield after purification by silica gel column chromato-
graphy (entries 15-17).
The substrate scope and limitations of donors is sum-
marized in Figure 3 and eq 1. Benzylic C(sp3)-H of
methyl-substituted pyridines 1a-c, quinoline 1d, iso-
quinoline 1e, pyrimidine 1f, phenanthroline 1g, and
(13) Oshima/Yorimitsu et al. and Liu et al. reported the utility of the
metal-enamide intermediates generated in situ via C-C bond cleavage.
(a) Niwa, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2007, 46,
2643. (b) Shang, R.; Yang, Z.-W.; Wang, Y.; Zhang, S.-L.; Liu, L. J. Am.
Chem. Soc. 2010, 132, 14391.
(14) Evaluation of the relative Lewis acidity of rare earth metals:
Tsuruta, H; Yamaguchi, K; Imamoto, T. Chem. Commun. 1999, 1703.
Org. Lett., Vol. 13, No. 7, 2011
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Table 2. Lewis Acid-Catalyzed Addition of Azaarene 1d to
Enones and R,β-Unsaturated N-Acylpyrrole
a Reaction was run using 2.5 equiv of 1d, enone, or N-acylpyrrole
2 (0.25 mmol), and Sc(OTf)3 or Y(OTf)3 (10 mol %) in PhCl (1.0 M)
at 120 °C unless otherwise noted. b Isolated yield after purification
by silica gel column chromatography. c 20 mol % of catalyst was
used.
Figure 3. Sc-catalyzed addition of azaarenes 1a-h to enone 2a:
Reagents and conditions: Reaction was run using 2.5 equiv of 1,
enone 2a (0.25 mmol), and Sc(OTf)3 (10 mol %) in solvent (1.0
M) at 120 or 160 °C unless otherwise noted. Isolated yield after
purification by silica gel column chromatography is shown for
each run. a20 mol % of Sc(OTf)3 was used.
substituted enones 2f-h were also applicable, giving the
products in 72-93% yield. With dienone 2i, 1,4-addition
predominantly proceeded over 1,6-addition, and 1,4-
adduct 3di was obtained in 78% yield. The reaction of
R,β-unsaturated N-acylpyrrole 2j15,16 also proceeded to
give the product 3dj in 81% yield. The N-acylpyrrole
unit can be regarded as an ester surrogate, and its
synthetic utility was demonstrated through transforma-
tions of 3dj in Scheme 1. The N-acylpyrrole unit was
readily converted into an ethyl ester unit by treatment
with NaOEt at room temperature for 20 min, giving 4dj
in 92% yield. Substitution with pyrrolidine also pro-
ceeded smoothly in the presence of DBU at 60 °C for 12
h (5dj, 84% yield). In addition to substitution reactions,
the reduction of 3dj with DIBAL-H gave pyrrole carbi-
nols as diastereomixtures. Under Masamune-Roush
conditions,17 R,β-unsaturated ethyl ester 6dj, which can
benzoxazole 1h were investigated. Compound 1b with
an ester functional group was compatible under the reac-
tion conditions, and 3ba was obtained in 60% yield.
2-Picoline 1c was less reactive than 1a, and 20 mol % of
Sc(OTf)3 at160°C wasrequired toobtain3ca in74%yield.
On the other hand, azaarenes 1d-g showed good reactivity
with 10 mol % of Sc(OTf)3 at 120 °C, giving products
3da-ga in 65-96% yield. Sc(OTf)3 was also applicable
to 2-methylbenzoxazole 1h, giving product 3ha in 76%
yield. 2-Ethylpyridine 1i also reacted smoothly selectively
at the benzylic position as shown in eq 1. The best
conditions for 2-ethylpyridine 1i were 10 mol % of Y(OTf)3
at 120 °C, and product 3ia was obtained in 79% yield
after 48 h. Diastereoselectivity was, however, poor (5:4 dr).
Further studies to improve diastereoselectivity are
ongoing.
Scheme 1. Transformation of N-Acylpyrrole Unit in 3dj
The substrate scope of acceptors is summarized in
Table 2. The reactions of chalcone derivatives 2b-e with
either an electron-withdrawing group or an electron-donat-
ing group proceeded in good yield (79-91%). Heteroaryl-
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Org. Lett., Vol. 13, No. 7, 2011

be regarded as 1,6-addition adduct of 1d, was obtained
in 85% yield (two steps) via in situ generation of
aldehyde from the crude pyrrole carbinols.
In summary, we succeeded in Lewis acid-catalyzed func-
tionalization of benzylic C(sp3)-H in alkyl-substituted
azaarenes under proton-transfer conditions. Sc(OTf)3 and
Y(OTf)3 promoted the reaction of methyl-substituted
azaarenes and benzoxazole 1a-h and 2-ethylpyridine 1i
to enones and an R,β-unsaturated N-acylpyrrole 2, giving
the products in 60-96% yield. Transformation of the
product from R,β-unsaturated N-acylpyrrole was also
demonstrated. Further studies to expand the reaction
scope of Lewis acid promoted benzylic C(sp3)-H functio-
nalization are ongoing.18
(15) Utility of R,β-unsaturated N-acylpyrroles as highly reactive ester
equivalent acceptors in conjugate additions: (a) Matsunaga, S.; Kinoshi-
ta, T.; Okada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559. (b)
Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2003, 42, 4680.
Acknowledgment. This work was supported by Grant-
in-Aid for Young Scientist (S) (for M.K.), and Inoue
Foundation for Science (for S.M.).
(16) Properties of N-acylpyrroles were reported by Evans and co-
workers in detail. (a) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2002, 41, 3188. Use of enol silane derived from N-
acylpyrrole:(b) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (c)
Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem.
Soc. 2001, 123, 4480.
(17) (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essefeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183. Applications to pyrrole carbinols:(b) Dixon, D. J.; Scott, M. S.;
Luckhurst, C. A. Synlett 2003, 2317. (c) Dixon, D. J.; Scott, M. S.;
Luckhurst, C. A. Synlett 2005, 2420. (d) Harada, S.; Handa, S.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365.
Supporting Information Available. Experimental pro-
cedures and spectral data of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(18) The reaction of 4-methylpyridine with chalcone 1a gave product
but in only less than 10% yield under the optimized conditions for
o-methyl-substituted azaarenes. Further studies to realize efficient C-H
functionalization with 4-methylazaarenes are ongoing.
Org. Lett., Vol. 13, No. 7, 2011
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