Site-selectivity in TBADT-photocatalyzed C(sp3)H functionalization of saturated alcohols and alkanes

Article abstract of DOI:10.1246/cl.171068

Site-selectivity in C(sp³)H functionalization of aliphatic alcohols and alkanes was studied using the decatungstate anion as a photocatalyst. In the case of aliphatic alcohols, CH bond a to the hydroxy group was preferentially functionalized. The a-site-selectivity is rationalized by polar effects imparted by the hydroxy group in the SH2 transition states. In contrast, CH functionalization of alkanes was largely affected by steric effects.

Full text of DOI:10.1246/cl.171068

Advance Publication Cover Page
Site-selectivity in TBADT-Photocatalyzed C(sp3)-H Functionalization of
Saturated Alcohols and Alkanes
Takahide Fukuyama, Keiichi Yamada, Tomohiro Nishikawa, Davide Ravelli,
Maurizio Fagnoni, and Illhyong Ryu*
Advance Publication on the web December 2, 2017
doi:10.1246/cl.171068
© 2017 The Chemical Society of Japan
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Publication manuscripts.

1
Site-selectivity in TBADT-Photocatalyzed C(sp3)-H Functionalization of
Saturated Alcohols and Alkanes
Takahide Fukuyama,1 Keiichi Yamada,1 Tomohiro Nishikawa,1 Davide Ravelli,2 Maurizio Fagnoni,2 and Illhyong Ryu1,3,*
1Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, 599-8531, Japan
2Photogreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
3Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan
E-mail: ryu@c.s.osakafu-u.ac.jp
O
O
1
2
3
4
5
6
7
8
9
Site-Selectivity in C(sp3)-H functionalization of aliphatic
alcohols and alkanes was studied using the decatungstate
anion as a photocatalyst. In the case of aliphatic alcohols, C-
H bond  to the hydroxyl group was preferentially
functionalized. The -site-selectivity is rationalized by
polar effects imparted by the hydroxy group in the SH2
transition states. On the other hand, C-H functionalization of
linear alkanes was largely affected by steric effects.
TBADT, n
NC
+
CN
CH3CN
100
CN
CN
O
TBADT = (Bu4N)4W10O32
CH3
CH3
O
H3C
H
H3C
cat
+
H
H
-
cat
10 Keywords: decatungstate anion, photocatalysis, C-H
11 functionalization, polar effects, steric effects
sterically hindered TS
polarity mismatched TS
48
49 Scheme 1. TBADT-photocatalyzed -selective C-H to C-C conversion
12
50 of 3,3-dimethylcyclohexanone(Ref 7).
13 The site-selective and catalytic functionalization of C(sp3)-H
14 bonds is currently one of the most important challenges in
15 organic chemistry.1,2 Tetrabutylammonium decatungstate
16 (TBADT), when photo-excited, abstracts hydrogen from
17 C(sp3)-H bonds to generate alkyl radicals.3 This unit
18 sequence has been applied for a variety of photocatalytic C-
19 H functionalization reactions including cascade radical
20 reactions.4-9 We became curious about the effect imparted
21 by a given functionality on an alkane scaffold in terms of
22 site-selectivity in the C-H cleavage reaction promoted by
23 TBADT.5 Consequently, we were able to find notable site-
24 selectivity for a variety of ketones,6,7 esters,7 nitriles,8 and
25 alkylpyridines,9 in which the SH2 (bimolecular homolytic
26 substitution) transition states between C-H bond and
27 decatungstate anion are highly influenced by radical polar
28 and steric effects, rendering the functionalization of C(sp3)-
29 H bonds site-selective in each case. For example, -
51
52
At the outset, we examined C-H functionalization of
53 isopropanol (1a) (Table 1, entries 1-4). For example,
54 when an acetonitrile (1 mL) solution of 1a (2.5 mmol),
55 fumaronitrile (2a) (0.5 mmol), and TBADT (4 mol%)
56 was irradiated using a Xe lamp (300 W) through a Pyrex
57 tube for 24 h, α-substituted isopropanol 3a was obtained
58 in 82% isolated yield (Table 1, entry 1). In a similar
59 manner, the reactions of 1a with acrylonitrile (2b) and N-
60 phenyl maleimide (2c) proceeded selectively at the α
61 position to give α-functionalized alcohols 3b and 3c,
62 respectively (Table 1, entries 2, 3). Interestingly, the
63 reaction of 1a with maleic anhydride (2d) gave terebic
64 acid (3d) in a 62% yield (Table 1 entry 4), which is
65 formed likely from the initially formed succinic
66 anhydride.
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
30 selective
C-H
to
C-C
conversion
of
3,3-
31 dimethylcyclohexanone was achieved using TBADT as a
32 photocatalyst (Scheme 1),7 in which the lack of any -C-H
33 functionalization was rationalized by the mismatched polar
34 SH2 transition state for -C-H cleavage, while the lack of -
35 C-H functionalization was due to the steric hindrance by the
36 two methyl groups attached at the adjacent carbon of the
37 targeted methylene group. Since little information on the
38 site-selectivity is available in TBADT-catalyzed C(sp3)-
39 H functionalization of aliphatic alcohols10 and linear
40 alkanes,
41 study using structurally varied alcohols and alkanes.
42
43
44
45
46
47
4a,11-13
we decided to embark on a systematic

2
1
2
Table 1. TBADT-photocatalyzed C-H functionalization of alcohols
1a-h with electron-deficient alkenes 2a-d.a
12 entries 5-11). The reaction of methanol (1b) and butanol
13 (1c) proceeded at theposition to the OH group to give
14 the corresponding primary alcohol 3e and secondary
15 alcohol 3f in modest yields, respectively (entries 5, 6).
16 Similarly, 2-pentanol (1d) gave tertiary alcohol 3g in
17 51% yield (entry 7). Isoamyl alcohol (1e) gave 3h as a
18 sole product in 45% yield (entry 8) and no product via
19 methine C-H functionalization was observed. On the
20 other hand, the reaction of 4-methyl-2-pentanol (1f) gave
21 a 66:34 mixture of 3i and 3i’, albeit in a low yield (entry
22 9). The contamination of 3i’, originated from methine C-
23 H functionalization, suggested that increased steric
24 hindrance would have retarded the H-abstraction from
R1
TBADT (4 mol %)
Xe (300 W, Pyrex)
OH
R1
R2
EWG
R2
+
HO
EWG
R3
CH3CN (1 mL), 24 h
R
1
2
5 equiv
3
0.5 mmol
yieldb
entry
alchol 1
alkene 2
product 3
OH
82%
OH
NC
CN
CN
1
2
CN
3a
2a
CN
2b
1a
1a
73%
OH
25 the secondary alcoholic portion.
The reaction of
CN
3b
26 cyclohexanol (1g) and 6-chloro-2-hexanol (1h)
27 proceeded selectively at the  position to the OH group
28 to give the corresponding -functionalized alcohols, 3j
29 and 3k, respectively (entries 10 and 11).
OH
3
4
1a
O
Ph
66%
62%
N
O
O
N
Ph
O
30
Figure 1 illustrates two SH2 transition states, TS-A and
2c
3c
31 TS-B, imaginable in the SH2 reaction between isoamyl
32 alcohol 1e and the decatungstate anion. Both TSs would
33 be affected by polar effects, however, TS-B would be
34 much more stabilized by the adjacent hydroxyl group,
35 rendering the -C-H cleavage selective.
O
O
1a
O
O
O
3d
HO2C
2d
5
6
H3C OH
36
42%
46%
CN HO
2b
CN
3e
1b
-
+
cat
OH
OH
H
OH
H
CN
3f
-
1c
1d
1e
+
cat
OH
OH
OH
TS-A
favorable
TS-B
7
51%
CN
more favorable
37
3g
38 Figure 1. Possible polar SH2 transition states in the reaction between
39 isoamylalcohol (1e) and the decatungstate anion.
OH
45%
12%
OH
8
9
CN
3h
40
We next sought to assess the site-selectivity in the C-H
OH
41 functionalization of four alkanes by TBADT
42 photocatalysis. Previous works reported on the methine
43 C-H functionalization with 2-methylpropane,11 2,3-
44 dimethylbutane12 and 2,4-dimethylpentane.4a The
45 reaction of hexane (1i) with dimethyl maleate (2e)
46 proceeded without site-selectivity to give a mixture of
47 three regioisomers resulting from the functionalization of
48 the 1-, 2-, and 3- positions in an 8/67/25 ratio (Table 2,
49 entry 1). On the other hand, the reaction of three alkanes
50 having a methine C-H bond exhibited a different degree
51 of selectivity. The reaction of isopentane (1j) with ethyl
52 acrylate (2f) proceeded with preference for methine C-H
53 over methylene C-H bond in a ratio of 81/19 (entry 2).
54 The reaction of 2,4-dimethylpentane (1k) with ethyl
55 vinyl ketone (2g) gave a mixture of methyl- and methine-
56 functionalized products in a 33/67 ratio (entry 3). In this
57 reaction, no functionalization of methylene C-H bond
58 took place. In contrast, the reaction of 2,2,5-
59 trimethylhexane (1l) with dimethyl maleate (2e)
60 proceeded with complete site-selectivity at the methine
61 C-H bond to give 3o as a sole product (entry 4). The
62 observed different reactivity of methine C-H bonds
CN
OH
3i
1f
(3i/3i' = 66 : 34)c
CN
HO
3i'
OH
3j
OH
10
11
52%
50%
CN
1g
1h
OH
OH
Cl
CN
Cl
3k
3
4
5
6
7
8
9
a Reaction conditions: 1 (2.5 mmol), 2 (0.5 mmol), TBADT (4 mol %),
MeCN (1 mL). Irradiation carried out by using a Xe lamp (300 W,
b
c
Pyrex) for 24 h. Isolated yield after flash chromatography on SiO2.
Determined by 13C NMR for the crude reaction mixture.
We then examined the site-selectivity of various
10 alcohols (1b-h) on the C-H functionalization, in which
11 acrylonitrile (2b) was used as a radical trap (Table 1,

3
1
2
3
4
5
6
7
among these three alkanes is rationalized by steric effects
in the SH2 transition states. Figure 2 illustrates possible
SH2 transition states in the reaction of 1l. Abstraction of
methylene hydrogen by decatungstate anion (TS-C and
TS-D) would be hindered by the t-Bu group, and as a
result, the reaction preferred TS-E, causing methine C-H
cleavage.
1l
4-*
[W10O32
]
h
A
5-
H+[W10O32
]
4-
[W10O32
]
8
9
Table 2. TBADT-catalyzed C-H functionalization of alkanes 1i-l with
electron-deficient alkenes 2.a
2e
TBADT (4 mol %)
Xe (300 W, Pyrex)
R
EWG
EWG
yieldc
R
H
+
R1
R1
CH3CN (1 mL), CH2Cl2 (0.5 mL)
24 h
1
2
3
10 equiv
0.5 mmol
alkaneb
67
entry
alkene
major product
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
1
2
55%
36%
CO2Me
CO2Me
3l
B
3o
25
8
29
2e
1i
30
31
Scheme 2. Possible reaction mechanism for the TBADT-catalyzed C-
H functionalization of 1l with 2e.
CO2Et
2f
CO2Et
81
19
3m
3n
1j
32
In this study, we examined the site-selectivity in the
33 decatungstate
anion-photocatalyzed
C-H
3
4
18%
61%
34 functionalization of structurally varied aliphatic alcohols
35 and acyclic alkanes. With the only exception of 1,3-
36 dimethylbutanol, all examined alcohols underwent
37 selective C-H abstraction at  position to the hydroxy
38 group, which is rationalized by polar effects exerted by
39 the hydroxyl functionality in the SH2 transition states. On
40 the other hand, C-H functionalization of linear alkanes
41 prefers methine C-H bonds, albeit the selectivity degrees
42 are highly dependent on the steric surroundings. These
43 observations would be useful in designing the site-
44 selective C-H functionalization by SH2 type radical
45 reactions.
O
67
O
33
1k
2g
2e
CO2Me
CO2Me
3o
100
1l
10
11
12
13
14
15
16
17
a Reaction conditions: 1 (5 mmol), 2 (0.5 mmol), TBADT (4 mol %),
MeCN (1 mL), CH2Cl2 (0.5 mL). Irradiation carried out by using a
b
Xe lamp (300 W, Pyrex) for 24 h. The ratio of the products was
determined by 13C NMR for the crude reaction mixture. Isolated
c
yield after flash chromatography on SiO2; only the major (or
exclusive) isomer has been reported.
46
-
cat
-
+
47
This work was supported by Grants-in-Aid for
H
cat
+
H
48 Scientific Research (A) (26248031) from JSPS and
49 Scientific Research on Innovative Areas 2707 Middle
50 Molecular Strategy (15H05850) from MEXT.
H
cat
-
+
TS-C
TS-D
TS-E
favorable
sterically hindered
51 References and Notes
18
52
19 Figure 2. Possible SH2 transition states in the reaction of 2,2,5-
20 trimethylhexane (1l) with the decatungstate anion.
53
54
55
56
57
58
59
60
61
62
63
64
65
66
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Scheme 2 illustrates the proposed photocatalytic
mechanism for site-selective C-H
22 radical
23 functionalization of 1l with 2e. The excited decatungstate
24 anion abstracts a hydrogen from the methine hydrogen of 1l
25 to form radical A, which then adds to 2e to form the
26 adduct radical B. Back-hydrogen atom transfer from the
27 reduced decatungstate anion gives product 3o and
28 regenerates the decatungstate anion.

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