Direct benzylic C-H activation for C-O bond formation by photoredox catalysis

Article abstract of DOI:10.1002/anie.201210333

Power of light: 1,4-dicyanonaphthalene (DCN) and light directly activates benzylic C-H bonds for intra- and intermolecular C-O bond formation. Arylalkyls have also been transformed directly into aryl ketones using water as a source of oxygen. EDG=electron-donating group, EWG=electron-withdrawing group. Copyright

Full text of DOI:10.1002/anie.201210333

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DOI: 10.1002/anie.201210333
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C H Activation
À
À
Direct Benzylic C H Activation for C O Bond Formation by
Photoredox Catalysis**
Ganesh Pandey,* Sujit Pal, and Ramkrishna Laha
Dedicated to Professor Goverdhan Mehta on the occasion of his 70th birthday
A pressing demand of modern organic chemistry is to find
a step-economic approach to build complex molecular
structures through selective functionalization of a rather
radical cation.[9] In another related study, we had also
reported a sequential electron-proton-electron (E-P-E) loss
to generate an iminium ion from the PEToxidation of tertiary
amines.[10] These two critical observations led us to envisage
[1]
À
unreactive C H bond. The most fundamental difficulty in
À
À
such endeavors lies with the selective C H activation in
a molecule which contains a diversity of C H groups. Intense
research activities by several research groups in this area have
resulted in the development of some very useful protocols for
an unprecedented benzylic C H bond-activation protocol by
À
a photoredox cycle as shown in Scheme 1. We report herein
À
regioselective Csp2 H activation through transition-metal
catalysis,[2] however, the corresponding Csp3 H activation is
À
still in its infancy.[3] The benzyl group is an important motif in
À
organic syntheses and has relatively active Csp3 H bonds,
because of the proximal aromatic ring, and have therefore
been functionalized using either heteroatom-chelated tran-
sition-metal catalysts[4] or nondirected oxidative activa-
tions.[5,6] Nondirected oxidative activations have either
required tert-butyl hydrogen peroxide (TBHP) in the pres-
ence of a metal catalyst,[5] or a chemical oxidant such as 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in the cases
where the benzyl group is flanked by an a-nitrogen/oxygen
atom.[6] More recently, benzylic C H activation of xanthenes
À
as well as acridanes using molecular oxygen in the presence of
a Brønsted acid was also reported.[7] In spite of impressive
progress made in this area, the reported protocols are far from
being environmentally benign as they either require moisture-
sensitive and expensive metal catalysts or special structural
requirements along with excessive use of chemical oxidants.
Therefore, further research in this area is still warranted.
While exploring the new reactions of photoinduced
electron-transfer (PET)-generated radical cations, our group
À
Scheme 1. Concept of benzylic C H activation by photoredox catalysis.
À
the success of our concept for direct benzylic C H activation
for C O bond formation and it requires neither a metal
catalyst nor a chemical oxidant.
À
Initially, to test the feasibility of the proposed concept,
a mixture of the alkylarene 6 (1 mmol) and 1,4-dicyanonaph-
thalene (DCN, 0.05 mmol) in acetonitrile was photolyzed
using a 450-W Hanovia medium pressure lamp housed in
a Pyrex glass immersion well (> 300 nm) for 4 hours (55%
conversion, monitored by GC, all light absorbed by 6 only;
Scheme 2). The usual work-up and purification of the reaction
mixture produced 6-methoxy-1-methylisochroman (11) in
51% yield (calculated based on consumption of starting
material). DCN and the unreacted 6 were recovered in 98 and
45%, respectively. A longer irradiation (> 5h) produced
a complex mixture of products. Control experiments involv-
ing the irradiation of 6 alone or a mixture of 6 and DCN,
where all light was absorbed by DCN, did not yield any
product.[11] Therefore, mechanistically, the present reaction is
considered to be initiated by a single-electron transfer (SET)
from the exicited state of 6 to the ground state of DCN, thus
generating 7, which produces 11 by the sequence as shown in
Scheme 2.
À
À
had effected regioselective Csp2 H activation for C C as well
[8]
À
as C Y (Y= O, N) bond-formation reactions. The regiose-
lectivity in such activations was explained on the basis of
varying electron densities of the carbon atom in the arene
[*] G. Pandey, S. Pal, R. Laha
Molecular Synthesis Laboratory,
Centre of Biomedical Research (CBMR),
Sanjay Gandhi Postgraduate Institute of Medical Science Campus
Raebareli Road, Lucknow-226014 (India)
E-mail: gp.pandey@cbmr.res.in
[**] Part of this work was carried out at the National Chemical
Laboratory, Pune-411008, India. We thank the CSIR, New Delhi,
India for Research Fellowships to S.P. and R.L. Financial support by
the DST New Delhi through the J. C. Bose Fellowship is acknowl-
edged. We also thank Nishamol Kuriakose (NCL, Pune) for
theoretical calculations.
+
The regioselective formation of 10 by Hb loss from 7 is
explained by natural bond orbital (NBO) analysis of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210333.
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Table 1: Generality of the intramolecular cycloetherification reaction.[a]
Entry
Substrate
Product
t [h] Yield [%][b]
1
2
12
13
18
19
5
3
62
51
À
À
Scheme 2. Regioselective benzylic C H activation for C O bond
formation.
3
14
20
3
72
natural charge density on each carbon atom of 7 using DFT
calculations in the Gaussian 09 suite of programs[12] where the
B3LYP functional and 6-31g* basis sets were used. The more
positive charge residing on C2 (+ 0.2598) in comparison to C1
(+ 0.0593) plausibly makes Hb more acidic for accelerated
deprotonation. Furthermore, the free energies of two opti-
mized geometries of the radical intermediates 8 and 9 were
calculated at the same level of theory and have shown that 8 is
more stable than 9 by at least 1.07 kcalmolÀ1 (DG). Encour-
aged by this result, the alkylarenes 12 and 13 were activated in
a manner identical to the one described for 6, and produced
the corresponding cyclic ethers 18 (62%) and 19 (51%). To
broaden the substrate scope, we also studied the PET
activation of 14–17 and the results of the formation of the
corresponding cyclic ethers (20–23) are shown in Table 1.
4
5
6
15
16
17
21
22
23
4
4
4
64
61[c]
À
Having successfully activated benzylic C H bonds for
cycloetherification reactions, we turned our attention to
trapping the benzylic radical, which is the first intermediate
formed in this reaction, by studying the PET activation of 24
with the hope that the stabilized radical 25 would be able to
add to a tethered olefin to produce the corresponding indane
derivative 26 (Scheme 3). However, it produced 29 (52%)
possibly by the reaction of trace amounts of moisture, present
in the solvent, with the intermediate 27. This interesting and
unprecedented reaction where a nucleophile has been added
58
[a] Reaction conditions: DCN (5 mol%), acetonitrile, RT. [b] Yield of
isolated product calculated based on consumption of starting material.
[c] d.r.=2:1. TBS=tert-butyldimethylsilyl.
a to an ester moiety is explained by implicating the
intermediacy of the distonic carbocation 28. The only parallel
to this finding, to the best of our knowledge, may be made by
the method of Ishihara and co-workers[13] for intramolecular
oxylactonization of ketocarboxylic acid using hypervalent
iodine as a catalyst in the presence of peroxides. However,
this protocol suffers from the low chemoselectivity because of
the competing Baeyer–Villiger oxidations.[13b] To trap the
distonic cation of type 28 intramoleculary, we studied the
activation of 30 and observed the formation of the unexpected
cyclic hemiacetal 33 (65% yield, crystalline solid, m.p. =
2558C–2658C) along with the expected 31 (15% yield;
Scheme 4). The structure of 33 was deduced on the basis of
detailed H and 13C NMR spectroscopy, and mass spectrom-
1
etry, and was further confirmed unambiguously by trans-
formation of 33 into 34 (90% yield) by a BF3.OEt2-mediated
allylation reaction. The formation of 33 obviously involved
Scheme 3. Investigation of the benzyl radical cyclization reaction.
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Table 2: Study of the substrate scope for cyclic hemiacetal formation.[a]
Entry
Substrate
Product
t [h] Yield [%][b]
1
35
43
4
5
4
55
52
44
2[c]
36
44
45
Scheme 4. Possible mechanism for cyclic hemiacetal formation.
facile formation of 32 by another E-P-E sequence from 31,
À
a result of enhanced kinetic acidity of the benzylic C H bond.
3
4
5
37
38
39
In an effort to generalize this reaction, we studied several
substrates (35–43) and results are shown in Table 2. It was
observed that 35 produced corresponding hemiacetals (43,
55% yield) as expected, whereas 37 gave 45 (44% yield) as
the sole product, possibly because of an unfavorable cyclic
seven-membered oxocarbenium ion geometry. Unfortunately,
38 and 39 produced an unidentified mixture of products
complex
mixture
À
possibly from the competing benzylic C H activations.
Furthermore, to broaden the scope of this reaction, we
studied the activation of 40 and 41 and isolated, interestingly,
same cyclic lactone 48 in each case, possibly from the
decomposition of the unstable cyclic cyanohemiacetal 46 or
the methoxy hemiacetal 47 intermediates, respectively. The
involvement of 46 and 47 as intermediates for of 48 was
suggested by the isolation of 49 from the activation of 42.
complex
mixture
À
After successful realization of benzylic C H activation for
73
85
À
intramolecular C O bond formation, we enthusiastically
turned our attention towards utilizing this protocol for
direct transformation of arylalkyls into the corresponding
aryl ketones as these are important compounds used in
pharmaceuticals.[14] Although, arylalkyl ketones are synthe-
sized by Friedel–Crafts acylation of arenes and by direct
oxidation of arlyalkyls in the presence of hypervalent
iodine,[15] metal catalysts[16] or organocatalysts,[17] regioselec-
tivity, air and moisture sensitivity of the reagent, use of excess
co-oxidants, limited substrate scope, and sometimes the
formation of mixture of products puts severe limitations on
the use of these protocols. Thus, we hypothesized that freely
available water could be used as a source of oxygen for
benzylic oxidation.
6
7
40 (R=CN)
41 (R=OMe)
46 (R=CN) 48
47 (R=OMe)
1
8
42
49
3
74
[a] Reaction conditions: DCN (5 mol%), acetonitrile (except entry 2), RT.
[b] Yield of the isolated product is based on the consumption of starting
material. [c] Acetonitrile/water (4:1) was used as the medium.
Initially, to substantiate our hypothesis, we activated 50 in
an acetonitrile/water (4:1) mixture for 5 hours and isolated 52
in high yield (80%), and it presumably involved the benzylic
alcohol 51 as an intermediate (for structures see Scheme 5).
To prove the intermediacy of 51 in this reaction, an authentic
sample of 51 was irradiated in an identical manner and 52 was
obtained in quantitative yield. Furthermore, a control experi-
ment in which 50 was irradiated only for 1 hour, afforded
a mixture of 50 (42%) and 51 (20%), thus supporting the
mechanism of the direct transformation of 50 into 52. To
generalize the current protocol of arylalkyl oxidation, several
arylalkyls were studied and the results (53-64) are shown in
Scheme 5. Besides having established high regioselectivity
(54–56) a unique chemoselectivity was also established by the
PET activation of 62.
In conclusion, we have successfully developed a new
À
concept for benzylic C H activation in intramolecular cyclo-
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[4] a) Y. Xie, Y. Yang, L. Huang, X. Zhang, Y. Zhang, Org. Lett.
2012, 14, 1238 – 1241; b) N. Dastbaravardeh, Org. Lett. 2012, 14,
1930 – 1933; c) Y. Li, Z. Li, T. Xiong, Q. Zhang, X. Zhang, Org.
Lett. 2012, 14, 3522 – 3525; d) T. Nanjo, C. Tsukano, Y. Take-
moto, Org. Lett. 2012, 14, 4270 – 4273; e) P. Novꢀk, A. Correa, J.
Gallardo-Donaire, R. Martin, Angew. Chem. 2011, 123, 12444;
Angew. Chem. Int. Ed. 2011, 50, 12236.
[5] a) C. J. Li, Acc. Chem. Res. 2009, 42, 335 – 344; b) P. Xie, Y. Xie,
B. Qian, H. Zhou, C. Xia, H. Huang, J. Am. Chem. Soc. 2012,
134, 9902 – 9905; c) Z. Li, Li. Cao, C.-J. Li, Angew. Chem. 2007,
119, 6625 – 6627; Angew. Chem. Int. Ed. 2007, 46, 6505 – 6507;
d) Z. Li, C. J. Li, J. Am. Chem. Soc. 2005, 127, 3672 – 3673.
[6] a) S. J. Park, J. R. Price, M. H. Todd, J. Org. Chem. 2012, 77, 949 –
955; b) L. Liu, P. E. Floreancig, Angew. Chem. 2010, 122, 6030 –
6033; Angew. Chem. Int. Ed. 2010, 49, 5894 – 5897; c) B. Yu, T.
Jiang, Y. Su, X. Pan, X. She, Org. Lett. 2009, 11, 3442 – 3445;
d) Y. Zhang, C. J. Li, J. Am. Chem. Soc. 2006, 128, 4242 – 4243.
[7] a) B. Zhang, S. K. Xiang, L. H. Zhang, Y. Cui, N. Jiao, Org. Lett.
2011, 13, 5212 – 5215; b) ꢁ. Pintꢂr, A. Sud, D. Sureshkumar, M.
Klussmann, Angew. Chem. 2010, 122, 5124 – 5128; Angew. Chem.
Int. Ed. 2010, 49, 5004 – 5007.
[8] a) G. Pandey, A. Murugan, M. Balakrishnan, Chem. Commun.
2002, 624 – 625; b) G. Pandey, M. Karthikeyan, A. Murugan, J.
Org. Chem. 1998, 63, 2867 – 2872; c) G. Pandey, A. Krishna, K.
Girija, M. Karthikeyan, Tetrahedron Lett. 1993, 34, 6631 – 6634;
d) G. Pandey, M. Sridhar, U. T. Bhalerao, Tetrahedron Lett. 1990,
31, 5373 – 5376; e) G. Pandey, J. Org. Chem. 1988, 53, 2364 –
2365.
[9] G. Pandey, A. Krishna, U. T. Bhalerao, Tetrahedron Lett. 1989,
30, 1867 – 1870.
[10] a) G. Pandey, Synlett 1992, 546 – 552; b) G. Pandey, Top. Curr.
Chem. 1993, 168, 175 – 221.
[11] “Photoinduced SET initiated reactions: Generation and synthetic
application of arene radical cations”: a) A. Krishna, Ph.D. Thesis
entitled, submitted to Osmania University, Hyderabad, India,
1989; b) C. Pac, A. Nakasone, H. Sakurai, J. Am. Chem. Soc.
1977, 99, 5806 – 5808.
Scheme 5. Direct oxidation of arylalkyls to the corresponding ketones
using water as an oxygen source.
[12] a) Gaussian98 (RevisionA.9): M. J. Frisch et al., see Supporting
Information; b) A. E. Reed, R. B. Weinstock, F. Weinhold, J.
Chem. Phys. 1985, 83, 735 – 746; c) D. B. Axel, J. Chem. Phys.
1993, 98, 5648 – 5652.
[13] a) M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science 2010,
328, 1376 – 1379; b) M. Uyanik, T. Yasui, K. Ishihara, Bioorg.
Med. Chem. Lett. 2009, 19, 3848 – 3851.
etherification reactions as well direct oxidation to aryl
À
À
ketones. Further studies on C C as well as C N bond-
forming reactions are in progress and will be reported in due
course.
[14] a) R. A. Sheldon, J. K. Kochi, Metal Catalyzed Oxidations of
Organic Compounds, Academic Press, New York, 1981; b) G.
Cainelli, G. Cardillo, Chromium Oxidations in Organic Chemis-
try, Springer, Berlin, 1984; c) M. Hudlicky, Oxidion in Organic
Chemistry, American Chemical Society, Washington, DC, 1990;
d) M. Recupero, C. Punta, Chem. Rev. 2007, 107, 3800 – 3842.
[15] a) K. C. Nicolaou, P. S. Baran, Y-Li. Zhong, J. Am. Chem. Soc.
2001, 123, 3183 – 3185; b) Y. Xu, J. T. Hu, J. Yan, Chin. Chem.
Lett. 2012, 23, 891 – 894.
Received: December 28, 2012
Revised: February 6, 2013
Published online: April 8, 2013
À
Keywords: arenes · C H activation · heterocycles ·
photochemistry · reaction mechanisms
.
[16] a) L. Zhang, G. Y. Ang, S. Chiba, Org. Lett. 2011, 13, 1622 – 1625;
b) T. Nagano, S. Kobayashi, Chem. Lett. 2008, 37, 1042 – 1045;
c) C. S. Yi, K. H. Kwon, D. W. Lee, Org. Lett. 2009, 11, 1567 –
1570; d) A. J. Catino, J. M. Nichols, H. Choi, S. Gottipamula,
M. P. Doyle, Org. Lett. 2005, 7, 5167 – 5170; e) Y. Bonvin, E.
Callens, I. Larrosa, D. A. Henderson, J. Oldham, A. J. Burton,
A. G. M. Barrett, Org. Lett. 2005, 7, 4549 – 4552; f) N. H. Lee,
C. S. Lee, D. S. Jung, Tetrahedron Lett. 1998, 39, 1385 – 1388.
[17] a) G. Yang, Q. Zhang, H. Miao, X. Tong, J. Xu, Org. Lett. 2005, 7,
263 – 266; b) K. Ohkubo, S. Fukuzumi, Org. Lett. 2000, 2, 3647 –
3650; c) R. Lechner, S. Kꢃmmel, B. Kçnig, Photochem. Photo-
biol. Sci. 2010, 9, 1367 – 1377.
[1] a) R. G. Bergman, Nature 2007, 446, 391 – 393; b) K. Godula, D.
Sames, Science 2006, 312, 67 – 72; c) J. A. Labinger, J. E. Bercaw,
Nature 2002, 417, 507 – 514.
[2] a) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius,
Angew. Chem. 2012, 124, 10382 – 10401; Angew. Chem. Int. Ed.
2012, 51, 10236 – 10254; b) L. Ackermann, Chem. Rev. 2011, 111,
1315 – 1345; c) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem.
Res. 2009, 42, 1074 – 1086.
[3] a) O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902 – 4911; b) S.-Y.
Zhang, F.-M. Zhang, Y.-Q. Tu, Chem. Soc. Rev. 2011, 40, 1937 –
1949.
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