Photo-induced Substitutive Introduction of the Aldoxime Functional Group to Carbon Chains: A Formal Formylation of Non-Acidic C(sp3)?H Bonds

Article abstract of DOI:10.1002/anie.201603810

A photo-induced substitutive introduction of an aldoxime functional group to carbon chains was achieved using photo-excited 4-benzoylpyridine as a C(sp³)?H bond cleaving agent and arylsulfonyl oxime as an aldoxime precursor. The non-acidic C?H bonds in various substances, including cycloalkanes, ethers, azacycles, and cyclic sulfides, were chemoselectively converted at ambient temperature under neutral conditions. The present transformation is a formal formylation of non-acidic C(sp³)?H bonds in a single step.

Full text of DOI:10.1002/anie.201603810

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603810
German Edition: DOI: 10.1002/ange.201603810
CÀH Bond Formylation Hot Paper
Photo-induced Substitutive Introduction of the Aldoxime Functional
Group to Carbon Chains: A Formal Formylation of Non-Acidic
3
À
C(sp ) H Bonds
Shin Kamijo,* Go Takao, Kaori Kamijo, Masaki Hirota, Keisuke Tao, and Toshihiro Murafuji
Abstract: A photo-induced substitutive introduction of an
aldoxime functional group to carbon chains was achieved
3
using photo-excited 4-benzoylpyridine as a C(sp )ÀH bond
cleaving agent and arylsulfonyl oxime as an aldoxime pre-
cursor. The non-acidic CÀH bonds in various substances,
including cycloalkanes, ethers, azacycles, and cyclic sulfides,
were chemoselectively converted at ambient temperature under
neutral conditions. The present transformation is a formal
3
formylation of non-acidic C(sp )ÀH bonds in a single step.
A
ldehydes are a critical class of compounds in synthetic
organic chemistry because of their dual reactivities as
[1]
electrophiles and nucleophiles. Among the preparative
methods that generate aldehydes, formylation is appealing
since attachment of
a synthetically versatile carbonyl
Scheme 1. Representative preparative methods for alkyl aldehydes by
formylation at sp -hybridized carbon atoms.
functionality takes place concomitantly with a one-carbon
extension, which is convenient for the rapid increase of
structural complexity of organic molecules. Compared to
3
[2]
3
continuing advancements in olefin hydroformylation,
a C(sp )ÀH bond (A) with an oxyl radical species generated
3
strategies for formylation at sp -hybridized carbon centers
seem to have matured, and representative procedures are
shown in Scheme 1. One of the most frequently employed
strategies for this purpose is the formylation of organo-
metallic agents (Scheme 1-1). Various electrophilic formylat-
ing agents, including N-formylpiperidine and CO, have been
by photo-excitation of an aryl ketone. The preparation of
aldehydes is not practical under such radical conditions
2
because formyl C(sp )ÀH bonds tend to be preferentially
3
cleaved, over the targeted non-acidic C(sp )ÀH bond of an
[10]
alkyl chain, as a result of the bonding energies. This energy
difference makes it difficult to prevent degradation of the
generated aldehyde during the course of the reaction. We thus
directed our attention to installing an aldoxime functionality
as a masked formyl group. As a result, we achieved the photo-
induced substitutive introduction of the aldoxime function-
ality (2) to carbon chains of a variety of compounds (1),
including cycloalkanes, ethers, azacycles, and cyclic sulfides,
by employing the arylsulfonyl oxime as an aldoxime precursor
and 4-benzoylpyridine (4-BzPy) as a CÀH bond cleaving
[3]
developed. A two-step sequence, involving alkylation of
a nucleophilic 1,3-dithiane anion with alkyl halides and
subsequent deprotection, is another option for introducing
[
4]
the formyl functional group (Scheme 1-2a). The treatment
of alkyl halides with AIBN/Bu SnH/CO gas achieves radical
formylation to furnish aldehydes (Scheme 1-2b). Despite
3
[
5]
3
the established strategies for formylation at C(sp )ÀM and
3
C(sp )ÀX bonds, there are no general methods for substitutive
3
introduction of a formyl functionality at non-acidic C(sp )ÀH
agent. This is a novel method for formal formylation of non-
[6]
3
bonds (Scheme 1-3). We therefore initiated an investigation
acidic C(sp )ÀH bonds in a single step that proceeds at room
3
to develop a formal formylation of such unreactive C(sp )ÀH
temperature under neutral conditions.
bonds by applying a photochemical CÀH functionalization
We began the optimization of reaction conditions with the
design of the aldoxime precursor (Table 1). A sulfonyl oxime
was selected as a candidate, based on our previous observa-
[7–9]
strategy.
The strategy relies on homolytic cleavage of
[
7,8b]
tions that a sulfonyl unit acts as an excellent leaving group,
[
*] Prof. Dr. S. Kamijo, G. Takao, K. Kamijo, M. Hirota, Dr. K. Tao
Graduate School of Science and Engineering and Graduate School of
Sciences and Technology for Innovation, Yamaguchi University
Yamaguchi 753-8512 (Japan)
and in conjunction with the precedent set by radical
[11]
reactions. Indeed, the photo-irradiation of tetrahydrofuran
(THF, 1a) and toluenesulfonylmethanal O-benzyloxime in
the presence of benzophenone (Ph CO) in acetonitrile
2
E-mail: kamijo@yamaguchi-u.ac.jp
(MeCN) resulted in formation of the aldoxime 2a in 50%
Prof. Dr. T. Murafuji
Graduate School of Medicine, Yamaguchi University
Yamaguchi 753-8512 (Japan)
yield (entry 1). Employment of electron-donating p-methoxy
substituted benzenesulfonyl oxime improved the yield of 2a
(
75%, entry 2), whereas the electron-withdrawing p-CF3
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603810.
substituted analogue decreased the product yield (41%,
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
[
a]
Table 1: Optimization of reaction conditions.
Table 2: Photo-induced substitutive introduction of an aldoxime
functionality to non-acidic C(sp )ÀH bonds.
3
[a,b]
[
b]
Entry
R
Aryl ketone
Solvent
Yield [%]
1
2
3
4
5
6
7
(p-Me)C H4
Ph CO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
50
75
41
66
71
88
6
2
(p-MeO)C H4
Ph CO
6
2
(p-CF )C H
Ph CO
3
6
4
2
n-Bu
Ph CO
2
(p-Me)C H4
(C F ) CO
6
6 5 2
(p-Me)C H4
4-BzPy
4-BzPy
6
[
c]
(p-MeO)C H4
CH Cl2
90 (85)
6
2
[a] Conditions: THF 1a (1.78 mmol, 8 equiv), sulfonyl oxime
(
(
0.223 mmol, 1 equiv), aryl ketone (0.223 mmol, 1 equiv), solvent
5.6 mL, 0.04m), photo-irradiation using a medium-pressure Hg lamp at
RT for 3–9 h. [b] Combined yield of E- and Z-aldoximes determined by
NMR spectroscopy. [c] Yield of isolated products.
entry 3). The yield of 2a remained at 66% using the
alkylsulfonyl oxime as the aldoxime precursor (entry 4).
Screening of aryl ketones revealed that electron-deficient
[7h,12]
perfluorobenzophenone ((C F ) CO) and 4-BzPy
led to
6
5 2
higher yields of 2a compared to Ph CO (71% and 88%,
2
entries 5 and 6). The reaction using (p-methoxy)benzene-
[
13]
sulfonylmethanal O-benzyloxime
and 4-BzPy in CH Cl2
2
gave the highest yield of 2a (90% yield determined by
NMR spectroscopy, 85% yield of isolated products, entry 7)
and these conditions were used in subsequent experiments.
With the optimal reaction conditions in hand, we explored
the generality of the photo-induced substitutive introduction
of the aldoxime functional group with respect to a variety of
substances (Table 2). In spite of the multiple reacting sites in
crown ether 1b, mono-functionalization proceeded
[a] Conditions as described in entry 7 of Table 1, unless otherwise noted.
Ar=(p-MeO)C 4. [b] Isolated yield of all possible isomers such as E/Z-
H
6
aldoximes, Boc rotamers, and syn/anti stereoisomers. [c] Yield estimated
1
by H NMR analysis. [d] The major isomers are shown in the Table.
[e] Irradiated using an LED lamp at 365 nm. [f] A minute amount of the
[
14]
selectively to form the aldoxime 2b.
In the case of
methylene adduct 2o’ was observed.
ambroxide 1c, chemoselective functionalization of the
ethereal CÀH bond took place to provide 2c without affecting
potentially reactive methine and methylene CÀH bonds. The
acyclic dibutyl ether 1d afforded 2d as well. The reactions of
acetals derived from cis and trans-cyclohexanediol, 1e-cis and
1
e-trans, furnished the same product 2e in 42% (24 h) and
2
1% (48 h) yields, respectively. These results corroborated
that the present transformation proceeds via formation of
a common carbon radical intermediate A (Scheme 1-3 and
Scheme 2), leading to the cis-fused adduct 2e of lower ring
strain. The higher reactivity of the cis-isomer 1e-cis may be
explained by easier access to the less sterically hindered
equatorial CÀH bond, as well as the higher electron density of
the equatorial CÀH bond, through hyperconjugation of the
[
15]
geminal oxygen lone pair and the antiperiplanar CÀC bond.
Scheme 2. Proposed reaction mechanism for the photo-induced sub-
The aldoxime functionality was also installed at the benzylic
position of phthalan 1 f.
stitutive introduction of an aldoxime functionality to non-acidic
3
C(sp ) H bonds.
À
Subsequently, introduction of the aldoxime functionality
to nitrogen-containing cyclic compounds was investigated.
The chemoselective functionalization occurred at the CÀH
electron-rich methylene side and the anti-adduct 2h was
[
16]
bond proximal to the nitrogen atom of the pyrrolidine core
produced in a stereoselective manner. The same selectiv-
ities were observed for benzodiazepine 1i, affording the
adduct 2i. The aldoxime functionality could be installed at the
(1g), furnishing the aldoxime adduct 2g in 84% yield. The
reaction of the proline derivative 1h took place at the more
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
benzylic position of isoquinoline 1j in 90% yield. The result
employing N-Boc morpholine 1k as a starting substance
clearly showed that the reactivity of the CÀH bond adjacent
to the nitrogen atom was higher than that beside an ether
functional group (2k). Additionally, the reactivities of CÀH
bonds adjacent to nitrogen atoms were successfully differ-
entiated by judicious selection of protecting groups (2l); the
aldoxime functionality was selectively introduced to the
Scheme 3. Transformations of aldoximes.
[
17]
N-Boc side of the molecule, and not to the N-Ts side.
We proceeded to examine the introduction of the
aldoxime functionality to cyclic sulfides and cycloalkanes.
The reactions of tetrahydrothiophene (1m) and oxathiane
the aldoxime functionality as an excellent mask for the formyl
[11a]
group.
Chemoselective reduction of the aldoxime
(
1n) produced the respective aldoximes 2m and 2n in yields
functionality took place with NaBH CN in acetic acid and
the benzyloxyamine 4g was formed quantitatively.
Having obtained a promising result for the conversion of
aldoxime 2 into benzyloxyamine 4, we carried out the
reduction of several aldoximes with the intent to unambig-
uously determine their structures (Figure 1). The reaction of
3
[
23]
equivalent to or greater than 80% with irradiation of an LED
lamp at 365 nm. The results verified that the reactivity of
[17]
the CÀH bond adjacent to a sulfur atom is higher than that
beside an ether oxygen. In the case of adamantane 1o, mono-
functionalization predominantly took place at the methine
CÀH bond (2o)—in preference to the methylene CÀH bond
(
2o’)—indicating superior reactivity of the methine CÀH
bond. The ratio of 2o and 2o’ (ca. 95:5) was unchanged before
and after purification (see the Supporting Information for
[
18,19]
details). The methylene CÀH bond of cyclooctane 1p
was
smoothly converted and the adduct 2p was formed in 61%
yield.
Having succeeded in the photo-induced substitutive
introduction of the aldoxime functionality to a variety of
carbon chains under the optimized conditions, we turned our
attention to obtaining mechanistic information on the present
transformation. Treatment of the sulfonyl oxime (1 equiv)
with cyclohexane 1q (4 equiv) and its deuterated analogue
Figure 1. Reduction of aldoximes into benzyloxyamines. Conditions as
in Scheme 3. Yield of isolated products. Ratio of stereoisomers in
brackets. The major isomer is shown in the Figure.
1
2
q-d (4 equiv) provided the corresponding adducts 2q and
q-d in 29% (yield determined by NMR spectroscopy) in
[
20]
a ratio of 83:17. The value of the kinetic isotope effect
the aldoxime possessing an ambroxide core (2c), which is
a mixture of four possible isomers of E/Z aldoximes as well as
syn/anti substitutions, provided a mixture of two stereo-
isomers 4c in a 79% combined yield in a 67:33 ratio. The
reduction of the proline derivative 2h furnished the anti-
3
(
KIE) was determined to be 4.9, indicating that C(sp )ÀH
bond cleavage is involved in the rate-determining step.
Consequently, we propose a tentative reaction mechanism
as illustrated in Scheme 2. The reaction is initiated by
hydrogen abstraction of the starting substance 1 with photo-
excited 4-BzPy, forming the carbon radical intermediate A
and the ketyl-type radical B. Based on the observed KIE, this
hydrogen abstraction step is the rate-determining step. The
conformational interconversion during the course of the
reaction (1e-trans to 2e, in Table 2) supports the involvement
of the carbon radical intermediate A. Addition of the derived
radical A to the sulfonyl oxime provides aminyl radical C.
Expulsion of the sulfonyl radical from C affords the aldoxime
[
16]
adduct 4h as the sole product,
and the benzodiazepine
derivative 2i preferentially provided the anti-adduct 4i. Thus,
the stereoselective introduction of an aldoxime functionality
took place at the five-membered azacycle of the parent
substances (1h and 1i). The aldoximes 2k, 2l, and 2n,
respectively prepared from morpholine, piperazine, and
oxathiane, provided the corresponding benzyloxyamines 4k,
4l, and 4n as single products.
To evaluate the relative reactivity order of CÀH bonds
2
as a product, completing the substitutive introduction of the
adjacent to nitrogen and sulfur atoms, we conducted the
photo-induced substitutive introduction of the aldoxime
functionality to N-Boc thiomorpholine (1r, Scheme 4). The
formation of multiple isomers hampered a detailed analysis of
the products (2r). Therefore, the reduction of the aldoxime
functionality was subsequently carried out to form two
regioisomers (4r and 4r’) in a ratio of 77:23, indicating that
the CÀH bond proximal to the sulfur atom is more reactive
aldoxime functionality to the carbon chain of 1. The released
sulfonyl radical accepts a hydrogen atom from the ketyl-type
[
19,21]
radical B to regenerate 4-BzPy,
most likely through the
formation of the sulfonamide D, which is generated by
[
7h,12,22]
coupling of the released sulfonyl radical and B.
The derived aldoximes are excellent synthetic precursors.
We demonstrated several transformations to highlight the
utility of the present one-step introduction of the aldoxime
functionality to carbon chains (Scheme 3). The acid treatment
of the aldoximes 2g and 2h with formalin led to selective
formation of the respective aldehydes 3g and 3h, confirming
than that next to the N-Boc group.
In conclusion, we have developed a chemoselective
method involving photo-induced introduction of an aldoxime
functionality to carbon chains of various substances, including
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
[
[
1] a) S. Warren, Chemistry of the Carbonyl Group, Wiley, New
York, 1991; b) In Modern Carbonyl Chemistry (Ed. J. Otera),
Wiley-VCH, Weinheim, 2000.
2] For recent reviews, see: a) J. Pospech, I. Fleischer, R. Franke, S.
Buchholz, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 2852;
Angew. Chem. 2013, 125, 2922; b) R. Franke, D. Selent, A.
Bçrner, Chem. Rev. 2012, 112, 5675; c) J. Klosin, C. R. Landis,
Acc. Chem. Res. 2007, 40, 1251.
[
3] For representative examples, see: a) G. A. Olah, M. Arvanaghi,
Angew. Chem. Int. Ed. Engl. 1981, 20, 878; Angew. Chem. 1981,
Scheme 4. Reaction starting from N-Boc thiomorpholine 1r.
Ar=(p-MeO)C H .
6
4
93, 925; b) G. A. Olah, M. Arvanaghi, Org. Synth. 1986, 64, 114;
c) H. C. Brown, Acc. Chem. Res. 1969, 2, 65; d) R. C. Larock,
Comprehensive Organic Transformations, VCH, New York,
cycloalkanes, ethers, azacycles, and cyclic sulfides. The
reaction is proposed to proceed through a radical mechanism,
1
989, pp. 681 – 682.
4] a) E. J. Corey, D. Seebach, Angew. Chem. Int. Ed. Engl. 1965, 4,
075; Angew. Chem. 1965, 77, 1134; b) E. J. Corey, D. Seebach,
[
3
in which the homolytic cleavage of non-acidic C(sp )ÀH
1
bonds is effected by photo-excited 4-benzoylpyridine, and the
aldoxime functionality is delivered from (p-methoxy)benz-
enesulfonylmethanal O-benzyloxime. In this study, we
disclosed that: 1) attachment of the electron-donating
p-MeO substituent to the benzenesulfonyl oxime, and use of
Org. Synth. 1970, 50, 72; c) B.-T. Grçbel, D. Seebach, Synthesis
1977, 357; For a related reagent, methyl methylthiomethyl
sulfoxide, see: d) K. Ogura, G.-i. Tsuchihashi, Tetrahedron Lett.
1971, 12, 3151; e) K. Ogura, G.-i. Tsuchihashi, Bull. Chem. Soc.
Jpn. 1972, 45, 2203.
[
5] a) I. Ryu, K. Kusano, A. Ogawa, N. Kambe, N. Sonoda, J. Am.
Chem. Soc. 1990, 112, 1295; b) I. Ryu, T. Niguma, S. Minakata,
M. Komatsu, S. Hadida, D. P. Curran, Tetrahedron Lett. 1997, 38,
7883.
4
-BzPy, increased the yield of expected aldoximes 2; 2) for the
first time cyclic sulfides were successfully applied to the
photo-induced CÀH functionalization, as well as cyclo-
alkanes, ethers, and azacycles; 3) the reactivity order of the
[6] For pioneering work on the photo-induced aldoxime synthesis
3
by direct C(sp )ÀH functionalization, see: S. Kim, N. Kim, W.-j.
CÀH bonds in the present transformation is clarified as
Chung, C. H. Cho, Synlett 2001, 937.
S-substituted
ꢀ
N-Boc-substituted > O-substituted >
[
7] a) S. Kamijo, T. Hoshikawa, M. Inoue, Tetrahedron Lett. 2011,
methine > methylene CÀH bonds; 4) the reactivity of CÀH
5
1
2, 2885; b) S. Kamijo, T. Hoshikawa, M. Inoue, Org. Lett. 2011,
3, 5928; c) T. Hoshikawa, S. Yoshioka, S. Kamijo, M. Inoue,
bonds could be regulated by the nitrogen protecting group, in
which the Boc group allows, and the Ts group inhibits, the
introduction of the aldoxime functionality at the adjacent
CÀH bond. The present transformation offers a unique tool
Synthesis 2013, 45, 874; d) T. Hoshikawa, S. Kamijo, M. Inoue,
Org. Biomol. Chem. 2013, 11, 164; e) Y. Amaoka, M. Nagatomo,
M. Watanabe, K. Tao, S. Kamijo, M. Inoue, Chem. Sci. 2014, 5,
4339; f) S. Kamijo, M. Hirota, K. Tao, M. Watanabe, T. Murafuji,
Tetrahedron Lett. 2014, 55, 5551; g) S. Kamijo, K. Tao, G. Takao,
H. Murooka, T. Murafuji, Tetrahedron Lett. 2015, 56, 1904; h) S.
Kamijo, M. Watanabe, K. Kamijo, K. Tao, T. Murafuji, Synthesis
3
for formal formylation of non-acidic C(sp )ÀH bonds in
a single step, under neutral reaction conditions, and at
ambient temperature, which is otherwise difficult to achieve.
2016, 48, 115.
3
[
8] For related examples of C(sp )ÀH functionalization using
a photo-excited aryl ketone, see: a) T. Hoshikawa, M. Inoue,
Chem. Sci. 2013, 4, 3118; b) M. Nagatomo, S. Yoshioka, M.
Inoue, Chem. Asian J. 2015, 10, 120; c) J.-B. Xia, C. Zhu, C.
Chen, J. Am. Chem. Soc. 2013, 135, 17494; d) J.-B. Xia, C. Zhu,
C. Chen, Chem. Commun. 2014, 50, 11701; e) D. Cantillo, O.
de Frutos, J. A. Rincꢁn, C. Mateos, C. O. Kappe, J. Org. Chem.
Experimental Section
A CH Cl solution (5.6 mL, 0.04m) of 4-benzoylpyridine (40.8 mg,
2
2
0
.223 mmol), (4-methoxy)benzenesulfonylmethanal O-benzyloxime
ꢀ
(68.3 mg, 0.223 mmol), and THF (145 mL, 1.78 mmol) in a Pyrex test
tube was degassed by a freeze-thaw cycle three times and purged with
argon. The test tube was placed approximately 5 cm from a UV-lamp
and was irradiated at room temperature for 6 h. The mixture was then
filtered through a short pad of silica gel (NH silica gel) using ethyl
acetate as an eluent, and the filtrate was concentrated. The residue
was purified by flash column chromatography (NH silica gel, hexane
to hexane/acetone = 30/1) to furnish the adduct 2a in 85% yield
2014, 79, 8486.
3
[9] For related recent examples of C(sp )ÀH functionalization using
a tungsten photocatalyst, see: a) I. Ryu, A. Tani, T. Fukuyama,
D. Ravelli, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed. 2011,
50, 1869; Angew. Chem. 2011, 123, 1909; b) I. Ryu, A. Tani, T.
Fukuyama, D. Ravelli, S. Montanaro, M. Fagnoni, Org. Lett.
(39.1 mg).
2013, 15, 2554; c) M. Okada, T. Fukuyama, K. Yamada, I. Ryu,
D. Ravelli, M. Fagnoni, Chem. Sci. 2014, 5, 2893; d) J. J. Murphy,
D. Bastida, S. Paria, M. Fagnoni, P. Melchiorre, Nature 2016, 532,
Acknowledgements
218.
[
[
10] The bond dissociation energy of acetaldehyde (CH CHO) is
3
This research was supported by the Program to Disseminate
Tenure Tracking System (MEXT, Japan) to S.K.
À1
8
9.4 kcalmol and that of propane (CH CH CH ) is 98.6 kcal
3
2
3
À1
mol , see: S. J. Blanksby, G. B. Ellison, Acc. Chem. Res. 2003, 36,
55.
2
Keywords: aldoximes · 4-benzoylpyridine · CÀ
11] For examples of radical reaction using sulfonyl oxime, see: a) S.
Kim, I. Y. Lee, J.-Y. Yoon, D. H. Oh, J. Am. Chem. Soc. 1996,
H functionalization · photoreactions · radicals
118, 5138; b) S. Kim, H.-J. Song, T.-L. Choi, J.-Y. Yoon, Angew.
Chem. Int. Ed. 2001, 40, 2524; Angew. Chem. 2001, 113, 2592;
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
c) S. Kim, C. J. Lim, Bull. Korean Chem. Soc. 2003, 24, 1219; d) S.
[17] Irradiation using an LED lamp at 365 nm was essential to obtain
Kim, Adv. Synth. Catal. 2004, 346, 19; e) S. Kim, K.-C. Lim, S.
Kim, I. Ryu, Adv. Synth. Catal. 2007, 349, 527; f) B. Gaspar,
E. M. Carreira, J. Am. Chem. Soc. 2009, 131, 13214; g) A.-P.
Schaffner, V. Darmency, P. Renaud, Angew. Chem. Int. Ed. 2006,
the aldoximes 2l–n in higher yields, whereas irradiation using
a Hg lamp decreased the product yields.
[18] The reaction using the aryl oxime as a limiting agent (cyclo-
octane (1p, 1 equiv), arylsulfonyl oxime (1.2 equiv), 4-BzPy
(1 equiv)) was detrimental to the yield of 2p (24% yield
determined by NMR spectroscopy).
4
5, 5847; Angew. Chem. 2006, 118, 5979; h) G. Rouquet, F.
Robert, R. Mꢂreau, F. Castet, Y. Landais, Chem. Eur. J. 2011, 17,
3904; i) Y. Landais, F. Robert, E. Godineau, L. Huet, N. Likhite,
1
[19] The reactions applying catalytic amount of aryl ketones
(0.2 equiv) gave lower yields of 2p (yields determined by
Tetrahedron 2013, 69, 10073; j) B. Ovadia, F. Robert, Y. Landais,
Org. Lett. 2015, 17, 1958.
NMR spectroscopy): 4-BzPy (35%), Ph CO (21%), and
2
[
12] For 4-benzoylpyridine in the photo-oxidation of secondary
alcohols, see: S. Kamijo, K. Tao, G. Takao, H. Tonoda, T.
Murafuji, Org. Lett. 2015, 17, 3326.
(C F ) CO (50%). These results indicate that the present
transformation can potentially be optimized as a catalytic
reaction.
6
5 2
[
13] The arylsulfonyl oxime was selectively prepared in the Z-form,
[20] The reaction of cyclohexane 1q gave rise to the aldoxime 2q in
17% yield (32% yield determined by NMR spectroscopy). See
the Supporting Information for details.
[21] Recovery of a significant amount of 4-BzPy was observed in
general.
[22] Y. Du, J. Xue, C. Ma, W. M. Kwok, D. L. Phillips, J. Raman
Spectrosc. 2008, 39, 503.
[23] S. J. Davis, A. P. Ayscough, R. P. Beckett, R. A. Bragg, J. M.
Clements, S. Doel, C. Grew, S. B. Launchbury, G. M. Perkins,
L. M. Pratt, H. K. Smith, Z. M. Spavold, S. W. Thomas, R. S.
Todd, M. Whittaker, Bioorg. Med. Chem. Lett. 2003, 13, 2709.
[
11f]
according to a reported method.
isomerized into the E-form, even upon storage in a freezer
< 08C). No significant reactivity difference was observed
However it gradually
(
between these E- and Z-isomers in the present transformation.
14] Partial deprotection of the oxime functionality of 2b during
isolation using silica gel column chromatography seemed to
reduce the yield of isolated products.
15] a) M. E. Gonzꢃlez-NfflÇez, G. Castellano, C. Andreu, J. Royo, M.
Bꢃguena, R. Mello, G. Asensio, J. Am. Chem. Soc. 2001, 123,
[
[
7487; b) F. Yonehara, Y. Kido, H. Sugimoto, S. Morita, M.
Yamaguchi, J. Org. Chem. 2003, 68, 6752; c) K. Chen, A.
Eschenmoser, P. S. Baran, Angew. Chem. Int. Ed. 2009, 48, 9705;
Angew. Chem. 2009, 121, 9885.
[
16] The structure of 2h was unambiguously confirmed after
reduction of the oxime functionality to generate 4h (in
Figure 1) and subsequent removal of the Boc group. See the
Supporting Information for details.
Received: April 20, 2016
Revised: June 6, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
CÀH Bond Formylation
S. Kamijo,* G. Takao, K. Kamijo,
M. Hirota, K. Tao,
T. Murafuji
&&&& — &&&&
Photo-induced Substitutive Introduction
of the Aldoxime Functional Group to
Carbon Chains: A Formal Formylation of
Non-Acidic C(sp )ÀH Bonds
Formally formyl: A photo-induced sub-
stitutive introduction of an aldoxime
functional group to carbon chains was
achieved using photo-excited 4-benzoyl-
pyridine and arylsulfonyl oxime. This is
a newly developed method for formal
3
formylation of non-acidic C(sp )ÀH
bonds in a single step that proceeds at
room temperature under neutral condi-
tions.
3
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!