Angewandte

Communications Chemie

International Edition: DOI: 10.1002/anie.201603810

C¢H Bond Formylation Hot Paper German Edition: DOI: 10.1002/ange.201603810

Photo-induced Substitutive Introduction of the Aldoxime Functional

Group to Carbon Chains: A Formal Formylation of Non-Acidic
C(sp3)¢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
using photo-excited 4-benzoylpyridine as a C(sp3)¢H bond
cleaving agent and arylsulfonyl oxime as an aldoxime pre-
cursor. 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.

Aldehydes are a critical class of compounds in synthetic

organic chemistry because of their dual reactivities as
electrophiles and nucleophiles.[1] 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
functionality takes place concomitantly with a one-carbon formylation at sp3-hybridized carbon atoms.
extension, which is convenient for the rapid increase of
structural complexity of organic molecules. Compared to
continuing advancements in olefin hydroformylation,[2] a C(sp3)¢H bond (A) with an oxyl radical species generated
strategies for formylation at sp3-hybridized carbon centers by photo-excitation of an aryl ketone. The preparation of
seem to have matured, and representative procedures are aldehydes is not practical under such radical conditions
shown in Scheme 1. One of the most frequently employed because formyl C(sp2)¢H bonds tend to be preferentially
strategies for this purpose is the formylation of organo- cleaved, over the targeted non-acidic C(sp3)¢H bond of an
metallic agents (Scheme 1-1). Various electrophilic formylat- alkyl chain, as a result of the bonding energies.[10] This energy
ing agents, including N-formylpiperidine and CO, have been difference makes it difficult to prevent degradation of the
developed.[3] A two-step sequence, involving alkylation of generated aldehyde during the course of the reaction. We thus
a nucleophilic 1,3-dithiane anion with alkyl halides and directed our attention to installing an aldoxime functionality
subsequent deprotection, is another option for introducing as a masked formyl group. As a result, we achieved the photo-
the formyl functional group (Scheme 1-2a).[4] The treatment induced substitutive introduction of the aldoxime function-
of alkyl halides with AIBN/Bu3SnH/CO gas achieves radical ality (2) to carbon chains of a variety of compounds (1),
formylation to furnish aldehydes (Scheme 1-2b).[5] Despite including cycloalkanes, ethers, azacycles, and cyclic sulfides,
the established strategies for formylation at C(sp3)¢M and by employing the arylsulfonyl oxime as an aldoxime precursor
C(sp3)¢X bonds, there are no general methods for substitutive and 4-benzoylpyridine (4-BzPy) as a C¢H bond cleaving
introduction of a formyl functionality at non-acidic C(sp3)¢H agent. This is a novel method for formal formylation of non-
bonds (Scheme 1-3).[6] We therefore initiated an investigation acidic C(sp3)¢H bonds in a single step that proceeds at room
to develop a formal formylation of such unreactive C(sp3)¢H temperature under neutral conditions.
bonds by applying a photochemical C¢H functionalization We began the optimization of reaction conditions with the
strategy.[7–9] The strategy relies on homolytic cleavage of design of the aldoxime precursor (Table 1). A sulfonyl oxime
was selected as a candidate, based on our previous observa-
tions that a sulfonyl unit acts as an excellent leaving group,[7, 8b]
[*] Prof. Dr. S. Kamijo, G. Takao, K. Kamijo, M. Hirota, Dr. K. Tao and in conjunction with the precedent set by radical
Graduate School of Science and Engineering and Graduate School of reactions.[11] Indeed, the photo-irradiation of tetrahydrofuran
Sciences and Technology for Innovation, Yamaguchi University
(THF, 1 a) and toluenesulfonylmethanal O-benzyloxime in
Yamaguchi 753-8512 (Japan)
E-mail: [email protected] the presence of benzophenone (Ph2CO) in acetonitrile
Prof. Dr. T. Murafuji (MeCN) resulted in formation of the aldoxime 2 a in 50 %
Graduate School of Medicine, Yamaguchi University yield (entry 1). Employment of electron-donating p-methoxy
Yamaguchi 753-8512 (Japan) substituted benzenesulfonyl oxime improved the yield of 2 a
Supporting information for this article can be found under: (75 %, entry 2), whereas the electron-withdrawing p-CF3
http://dx.doi.org/10.1002/anie.201603810. substituted analogue decreased the product yield (41 %,

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Communications Chemie

Table 1: Optimization of reaction conditions.[a] Table 2: Photo-induced substitutive introduction of an aldoxime

functionality to non-acidic C(sp3)¢H bonds.[a,b]

Entry R Aryl ketone Solvent Yield [%][b]

1 (p-Me)C6H4 Ph2CO MeCN 50
2 (p-MeO)C6H4 Ph2CO MeCN 75
3 (p-CF3)C6H4 Ph2CO MeCN 41
4 n-Bu Ph2CO MeCN 66
5 (p-Me)C6H4 (C6F5)2CO MeCN 71
6 (p-Me)C6H4 4-BzPy MeCN 88
7 (p-MeO)C6H4 4-BzPy CH2Cl2 90 (85)[c]
[a] Conditions: THF 1 a (1.78 mmol, 8 equiv), sulfonyl oxime
(0.223 mmol, 1 equiv), aryl ketone (0.223 mmol, 1 equiv), solvent
(5.6 mL, 0.04 m), 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 2 a remained at 66 % using the

alkylsulfonyl oxime as the aldoxime precursor (entry 4).
Screening of aryl ketones revealed that electron-deficient
perfluorobenzophenone ((C6F5)2CO) and 4-BzPy[7h, 12] led to
higher yields of 2 a compared to Ph2CO (71 % and 88 %,
entries 5 and 6). The reaction using (p-methoxy)benzene-
sulfonylmethanal O-benzyloxime[13] and 4-BzPy in CH2Cl2
gave the highest yield of 2 a (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 [a] Conditions as described in entry 7 of Table 1, unless otherwise noted.
of the aldoxime functional group with respect to a variety of Ar = (p-MeO)C6H4. [b] Isolated yield of all possible isomers such as E/Z-
substances (Table 2). In spite of the multiple reacting sites in aldoximes, Boc rotamers, and syn/anti stereoisomers. [c] Yield estimated
crown ether 1 b, mono-functionalization proceeded by 1H 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
selectively to form the aldoxime 2 b.[14] In the case of
methylene adduct 2 o’’ was observed.
ambroxide 1 c, chemoselective functionalization of the
ethereal C¢H bond took place to provide 2 c without affecting
potentially reactive methine and methylene C¢H bonds. The
acyclic dibutyl ether 1 d afforded 2 d as well. The reactions of
acetals derived from cis and trans-cyclohexanediol, 1 e-cis and
1 e-trans, furnished the same product 2 e in 42 % (24 h) and
21 % (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 2 e of lower ring
strain. The higher reactivity of the cis-isomer 1 e-cis may be
explained by easier access to the less sterically hindered
equatorial C¢H bond, as well as the higher electron density of
the equatorial C¢H bond, through hyperconjugation of the
geminal oxygen lone pair and the antiperiplanar C¢C bond.[15]
Scheme 2. Proposed reaction mechanism for the photo-induced sub-
The aldoxime functionality was also installed at the benzylic stitutive introduction of an aldoxime functionality to non-acidic
position of phthalan 1 f. C(sp3)¢H bonds.
Subsequently, introduction of the aldoxime functionality
to nitrogen-containing cyclic compounds was investigated.
The chemoselective functionalization occurred at the C¢H electron-rich methylene side and the anti-adduct 2 h was
bond proximal to the nitrogen atom of the pyrrolidine core produced in a stereoselective manner.[16] The same selectiv-
(1 g), furnishing the aldoxime adduct 2 g in 84 % yield. The ities were observed for benzodiazepine 1 i, affording the
reaction of the proline derivative 1 h took place at the more adduct 2 i. The aldoxime functionality could be installed at the

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benzylic position of isoquinoline 1 j in 90 % yield. The result

employing N-Boc morpholine 1 k as a starting substance
clearly showed that the reactivity of the C¢H bond adjacent
to the nitrogen atom was higher than that beside an ether
functional group (2 k). Additionally, the reactivities of C¢H
bonds adjacent to nitrogen atoms were successfully differ-
entiated by judicious selection of protecting groups (2 l); the
aldoxime functionality was selectively introduced to the Scheme 3. Transformations of aldoximes.
N-Boc side of the molecule, and not to the N-Ts side.[17]
We proceeded to examine the introduction of the
aldoxime functionality to cyclic sulfides and cycloalkanes. the aldoxime functionality as an excellent mask for the formyl
The reactions of tetrahydrothiophene (1 m) and oxathiane group.[11a] Chemoselective reduction of the aldoxime
(1 n) produced the respective aldoximes 2 m and 2 n in yields functionality took place with NaBH3CN in acetic acid and
equivalent to or greater than 80 % with irradiation of an LED the benzyloxyamine 4 g was formed quantitatively.[23]
lamp at 365 nm.[17] The results verified that the reactivity of Having obtained a promising result for the conversion of
the C¢H bond adjacent to a sulfur atom is higher than that aldoxime 2 into benzyloxyamine 4, we carried out the
beside an ether oxygen. In the case of adamantane 1 o, mono- reduction of several aldoximes with the intent to unambig-
functionalization predominantly took place at the methine uously determine their structures (Figure 1). The reaction of
C¢H bond (2 o)—in preference to the methylene C¢H bond
(2 o’’)—indicating superior reactivity of the methine C¢H
bond. The ratio of 2 o and 2 o’’ (ca. 95:5) was unchanged before
and after purification (see the Supporting Information for
details). The methylene C¢H bond of cyclooctane 1 p[18, 19] was
smoothly converted and the adduct 2 p 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) Figure 1. Reduction of aldoximes into benzyloxyamines. Conditions as
with cyclohexane 1 q (4 equiv) and its deuterated analogue in Scheme 3. Yield of isolated products. Ratio of stereoisomers in
1 q-d (4 equiv) provided the corresponding adducts 2 q and brackets. The major isomer is shown in the Figure.
2 q-d in 29 % (yield determined by NMR spectroscopy) in
a ratio of 83:17.[20] The value of the kinetic isotope effect the aldoxime possessing an ambroxide core (2 c), which is
(KIE) was determined to be 4.9, indicating that C(sp3)¢H a mixture of four possible isomers of E/Z aldoximes as well as
bond cleavage is involved in the rate-determining step. syn/anti substitutions, provided a mixture of two stereo-
Consequently, we propose a tentative reaction mechanism isomers 4 c in a 79 % combined yield in a 67:33 ratio. The
as illustrated in Scheme 2. The reaction is initiated by reduction of the proline derivative 2 h furnished the anti-
hydrogen abstraction of the starting substance 1 with photo- adduct 4 h as the sole product,[16] and the benzodiazepine
excited 4-BzPy, forming the carbon radical intermediate A derivative 2 i preferentially provided the anti-adduct 4 i. Thus,
and the ketyl-type radical B. Based on the observed KIE, this the stereoselective introduction of an aldoxime functionality
hydrogen abstraction step is the rate-determining step. The took place at the five-membered azacycle of the parent
conformational interconversion during the course of the substances (1 h and 1 i). The aldoximes 2 k, 2 l, and 2 n,
reaction (1 e-trans to 2 e, in Table 2) supports the involvement respectively prepared from morpholine, piperazine, and
of the carbon radical intermediate A. Addition of the derived oxathiane, provided the corresponding benzyloxyamines 4 k,
radical A to the sulfonyl oxime provides aminyl radical C. 4 l, and 4 n as single products.
Expulsion of the sulfonyl radical from C affords the aldoxime To evaluate the relative reactivity order of C¢H bonds
2 as a product, completing the substitutive introduction of the adjacent to nitrogen and sulfur atoms, we conducted the
aldoxime functionality to the carbon chain of 1. The released photo-induced substitutive introduction of the aldoxime
sulfonyl radical accepts a hydrogen atom from the ketyl-type functionality to N-Boc thiomorpholine (1 r, Scheme 4). The
radical B to regenerate 4-BzPy,[19, 21] most likely through the formation of multiple isomers hampered a detailed analysis of
formation of the sulfonamide D, which is generated by the products (2 r). Therefore, the reduction of the aldoxime
coupling of the released sulfonyl radical and B.[7h, 12, 22] functionality was subsequently carried out to form two
The derived aldoximes are excellent synthetic precursors. regioisomers (4 r and 4 r’’) in a ratio of 77:23, indicating that
We demonstrated several transformations to highlight the the C¢H bond proximal to the sulfur atom is more reactive
utility of the present one-step introduction of the aldoxime than that next to the N-Boc group.
functionality to carbon chains (Scheme 3). The acid treatment In conclusion, we have developed a chemoselective
of the aldoximes 2 g and 2 h with formalin led to selective method involving photo-induced introduction of an aldoxime
formation of the respective aldehydes 3 g and 3 h, confirming functionality to carbon chains of various substances, including

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How to cite: Angew. Chem. Int. Ed. 2016, 55, 9695 – 9699
Angew. Chem. 2016, 128, 9847 – 9851

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Acknowledgements 218.
[10] The bond dissociation energy of acetaldehyde (CH3CHO) is
This research was supported by the Program to Disseminate 89.4 kcal mol¢1 and that of propane (CH3CH2CH3) is 98.6 kcal
Tenure Tracking System (MEXT, Japan) to S.K. mol¢1, see: S. J. Blanksby, G. B. Ellison, Acc. Chem. Res. 2003, 36,
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Keywords: aldoximes · 4-benzoylpyridine · C¢ [11] For examples of radical reaction using sulfonyl oxime, see: a) S.
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9698 www.angewandte.org Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2016, 55, 9695 –9699
 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. the aldoximes 2 l–n in higher yields, whereas irradiation using
Kim, I. Ryu, Adv. Synth. Catal. 2007, 349, 527; f) B. Gaspar, a Hg lamp decreased the product yields.
E. M. Carreira, J. Am. Chem. Soc. 2009, 131, 13214; g) A.-P. [18] The reaction using the aryl oxime as a limiting agent (cyclo-
Schaffner, V. Darmency, P. Renaud, Angew. Chem. Int. Ed. 2006, octane (1 p, 1 equiv), arylsulfonyl oxime (1.2 equiv), 4-BzPy
45, 5847; Angew. Chem. 2006, 118, 5979; h) G. Rouquet, F. (1 equiv)) was detrimental to the yield of 2 p (24 % yield
Robert, R. M¦reau, F. Castet, Y. Landais, Chem. Eur. J. 2011, 17, determined by NMR spectroscopy).
13904; i) Y. Landais, F. Robert, E. Godineau, L. Huet, N. Likhite, [19] The reactions applying catalytic amount of aryl ketones
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Org. Lett. 2015, 17, 1958. NMR spectroscopy): 4-BzPy (35 %), Ph2CO (21 %), and
[12] For 4-benzoylpyridine in the photo-oxidation of secondary (C6F5)2CO (50 %). These results indicate that the present
alcohols, see: S. Kamijo, K. Tao, G. Takao, H. Tonoda, T. transformation can potentially be optimized as a catalytic
Murafuji, Org. Lett. 2015, 17, 3326. reaction.
[13] The arylsulfonyl oxime was selectively prepared in the Z-form, [20] The reaction of cyclohexane 1 q gave rise to the aldoxime 2 q in
according to a reported method.[11f] However it gradually 17 % yield (32 % yield determined by NMR spectroscopy). See
isomerized into the E-form, even upon storage in a freezer the Supporting Information for details.
(< 0 8C). No significant reactivity difference was observed [21] Recovery of a significant amount of 4-BzPy was observed in
between these E- and Z-isomers in the present transformation. general.
[14] Partial deprotection of the oxime functionality of 2 b during [22] Y. Du, J. Xue, C. Ma, W. M. Kwok, D. L. Phillips, J. Raman
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[16] The structure of 2 h was unambiguously confirmed after
reduction of the oxime functionality to generate 4 h (in Received: April 20, 2016
Figure 1) and subsequent removal of the Boc group. See the Revised: June 6, 2016
Supporting Information for details. Published online: June 29, 2016

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