Copper-catalyzed aerobic aliphatic C-H oxygenation with hydroperoxides

Article abstract of DOI:10.3762/bjoc.9.138

We report herein Cu-catalyzed aerobic oxygenation of aliphatic C-H bonds with hydroperoxides, which proceeds by 1,5-H radical shift of putative oxygen-centered radicals (O-radicals) derived from hydroperoxides followed by trapping of the resulting carboncentered radicals with molecular oxygen.

Full text of DOI:10.3762/bjoc.9.138

Copper-catalyzed aerobic aliphatic C–H oxygenation
with hydroperoxides
Pei Chui Too, Ya Lin Tnay and Shunsuke Chiba*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1217–1225.
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore. Fax: +65-67911961; Tel:
+65-65138013
doi:10.3762/bjoc.9.138
Received: 15 April 2013
Accepted: 31 May 2013
Published: 25 June 2013
Email:
Shunsuke Chiba* - shunsuke@ntu.edu.sg
This article is part of the Thematic Series "Organic free radical chemistry".
Guest Editor: C. Stephenson
* Corresponding author
Keywords:
© 2013 Too et al; licensee Beilstein-Institut.
License and terms: see end of document.
copper; 1,4-diols; free radical; 1,5-H radical shift; hydroperoxides;
molecular oxygen
Abstract
We report herein Cu-catalyzed aerobic oxygenation of aliphatic C–H bonds with hydroperoxides, which proceeds by 1,5-H radical
shift of putative oxygen-centered radicals (O-radicals) derived from hydroperoxides followed by trapping of the resulting carbon-
centered radicals with molecular oxygen.
Introduction
Aliphatic sp3 C–H bonds are ubiquitous components in organic C-radicals with molecular O2 forms peroxy radicals (the C–O
molecules but rather inert towards most of the chemical reac- bond formation). Reduction of peroxy radicals generates alkox-
tions. It thus remains as one of the most challenging topics in ides, cyclization of which with the amidine moiety finally
organic synthesis to develop catalytic oxidative sp3 C–H func- affords dihydrooxazoles. Similarly, it was also revealed that the
tionalization with predictable chemo- and regioselectivity [1-4]. sp3 C–H oxygenation could proceed directed by the N–H
To achieve this goal, we have recently utilized 1,5-H-radical ketimine moieties under Cu-catalyzed aerobic conditions via the
shift [5,6] with iminyl radical species (N-radicals) generated corresponding iminyl radical species, where 1,2-diacylben-
under Cu-catalyzed aerobic reaction conditions, in which the zenes and amino endoperoxides could be synthesized by C–H
resulting carbon-centered radicals (C-radicals) could be trapped oxygenation of secondary and tertiary C–H bonds, respectively
by molecular oxygen to form new C–O bonds. For instance, the (Scheme 1b) [8,9].
Cu-catalyzed aerobic reaction of N-alkylamidines afforded
aminidyl radicals (N-radicals) by single-electron oxidation and Stimulated by these remote sp3 C–H oxidation reactions using
deprotonation of the amidine moiety, which was followed by the nitrogen-centered radicals derived from amidines and
1,5-H-radical shift to generate the corresponding C-radicals ketimines, we became interested to utilize oxygen-centered
(Scheme 1a) [7]. The successive trapping of the resulting radicals (O-radicals) for the sp3 C–H functionalization. In this
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
Scheme 1: Aliphatic C–H oxidation with amidines and ketimines by 1,5-H radical shift.
context, we envision employing hydroperoxides as precursors chlorination using hydroperoxides as the O-radical source, in
for O-radicals in the presence of Cu salts. The lower valent which the C-radicals generated by the 1,5-H radical shift were
Cu(I) species could potentially undergo single-electron reduc- chlorinated (Scheme 2a) [14]. If reductive generation of the
tion of hydroperoxides to produce the corresponding O-radicals O-radicals from hydroperoxides could be achieved under an O2
[10-13]. Ball recently reported CuCl-catalyzed aliphatic C–H atmosphere, the C-radicals generated by 1,5-H radical shift
Scheme 2: Aliphatic C–H oxidation with hydroperoxides.
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
could be trapped by O2 to form the new C–O bonds. Herein, we terminal reductant [15] to keep lower valent Cu(I) species in the
report the realization of this concept mainly for the aerobic syn- reaction mixture (Table 1). As expected, when 1a was treated
thesis of 1,4-diols from hydroperoxides, which could be with Cu(OAc)2 (20 mol %) in the presence of Et3N (2 equiv) in
catalyzed by the Cu(OAc)2-1,10-phenanthroline system in the DMF, the reaction proceeded at room temperature for 17 h to
presence of Et3N as a terminal reductant of the Cu(II) species afford C–H oxygenation products, cyclic hemiacetal 2a and
(Scheme 2b).
1,4-diol 3a in 49% and 8% yields, respectively (Table 1,
entry 1). It was found that addition of nitrogen ligands such as
2,2’-bipyridine and 1,10-phenanthroline (1,10-phen) acceler-
Findings
We commenced our investigation with the Cu-catalyzed aerobic ated the reaction (Table 1, entries 2 and 3). The reactions with
reactions of hydroperoxide 1a in the presence of Et3N as a CuCl2 (Table 1, entry 4) as well as CuCl (Table 1, entry 5)
Table 1: Optimization of the reaction conditions.a
Entry
Cu salts
(mol %)
Additive
(mol %)
Et3N
(equiv)
Solvent
(0.1 M)
Time
(h)
Yield (%)b
2a
49
49
53
52
52
55
71
70
76
74
74
75
75
–
3a
8
4a
0
1
2
Cu(OAc)2
(20)
–
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
0.5
0.5
0.5
0.5
0.5
DMF
DMF
17
3
3
6
3
2
5
9
2
3
3
3
3
3
1
Cu(OAc)2
(20)
2,2’-bipyridine
(20)
9
0
3
Cu(OAc)2
(20)
1,10-phen
(20)
DMF
12
10
10
20
13
14
11
9
0
4
CuCl2
(20)
1,10-phen
(20)
DMF
0
5
CuCl
(20)
1,10-phen
(20)
DMF
0
6
Cu(OAc)2
(20)
1,10-phen
(20)
MeCN
benzene
toluene
0
7
Cu(OAc)2
(20)
1,10-phen
(20)
0
8
Cu(OAc)2
(20)
1,10-phen
(20)
0
9
Cu(OAc)2
(20)
1,10-phen
(20)
benzene/MeCN
(5:1)
0
10
11
12
13
14c
15d
Cu(OAc)2
(20)
1,10-phen
(20)
benzene/MeCN
(5:1)
0
Cu(OAc)2
(20)
1,10-phen
(20)
toluene/MeCN
(5:1)
10
16
14
90
0
0
Cu(OAc)2
(10)
1,10-phen
(10)
toluene/MeCN
(5:1)
0
Cu(OAc)2
(5)
1,10-phen
(5)
toluene/MeCN
(5:1)
0
Cu(OAc)2
(5)
1,10-phen
(5)
toluene/MeCN
(5:1)
0
Cu(OAc)2
(5)
1,10-phen
(5)
toluene/MeCN
(5:1)
0
47
aReactions were carried out using 0.3 mmol of hydroperoxide 1a in solvents (3 mL, 0.1 M) at room temperature under an O2 atmosphere. bIsolated
yields are recorded. cAfter stirring 5 h, the volatile materials were removed in vacuo, and the resulting crude materials were further treated with LiAlH4
(1.2 equiv) in THF at rt for 1 h. dThe reaction was conducted under a N2 atmosphere.
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
resulted in comparable results with that by Cu(OAc)2. Further O-radical I generates C-radical II, which is trapped by molecu-
optimization of the reaction conditions by the solvent screening lar O2 to give peroxy radical III. Probably further reaction of
(Table 1, entries 6–11) revealed that the co-solvent system III with Cu(I) species gives Cu(II)-peroxide IV, which under-
(benzene/MeCN or toluene/MeCN) performed best to give the goes fragmentation to give aldehyde V [16-18], which in turn
highest yield (83–87% combined yields of 2a and 3a, Table 1, cyclizes to afford hemiacetal 2a. Protonation of Cu(II)-peroxide
entries 9–11), in which the amount of Et3N could be reduced to IV followed by the reduction of the resulting hydroperoxide
0.5 equiv (Table 1, entries 10 and 11). It is worthy of note that deliver 1,4-diol 3a. In the absence of molecular O2 (under a N2
the catalytic loading of Cu(OAc)2-1,10-phen could be lowered atmosphere, Table 1, entry 15), the resulting C-radical I is
to 5 mol % while maintaining good combined yields of 2a and oxidized by the Cu(II) species to give carbocation VI [19],
3a (89%, Table 1, entry 13). Upon completion of the C–H which is trapped by the intramolecular hydroxy group to give
oxygenation under the reaction conditions in entry 13, the 4a.
resulting crude residue after removal of the solvents was treated
with LiAlH4 in THF, affording 1,4-diol 3a as the sole product We next explored the substrate scope of the present aerobic
in 90% yield (Table 1, entry 14). The Cu-catalyzed reaction of strategy for the synthesis of 1,4-diols by targeting methylene
1a under an inert (N2) atmosphere gave an intramolecular C–H C–H oxygenation with various tertiary hydroperoxides 1
oxygenation product, dihydroisobenzofuran 4a in 47% yield (Table 2). Generally, oxygenation of benzylic methylene C–H
(Table 1, entry 15).
bonds proceeded smoothly to give the corresponding 1,4-diols 3
in good to moderate yields (77–51% yields) (Table 2,
The proposed reaction pathways for the formation of 2a, 3a, entries 1–7). Moreover, the present method allowed for
and 4a were described in Scheme 3. Single-electron reduction oxygenation of nonbenzylic methylene C–H bonds, while yields
of the starting Cu(OAc)2 by Et3N forms the Cu(I) species, of obtained 1,4-diols 3 were relatively low (65–40% yields)
which reduces hydroperoxide 1a to give O-radical I along with (Table 2, entries 8–13). In most cases (except for Table 2,
the generation of the Cu(II) species. 1,5-H-Radical shift of entries 3, 6, 7 and 11), either reduced alcohols 5 (up to 23%
Scheme 3: Proposed reaction mechanisms for the formation of 2a, 3a, and 4a.
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
Table 2: Substrate scope: oxygenation of secondary C–H bonds.a
Entry
Hydroperoxides
1,4-Diols
Others
1
3
Alcohols 5
Alcohols 6
1
2
3
1b (R2 = Ph)
1c (R2 = Me)
1d (R2 = Et)
3b 77%
–
–
–
6b 8%b
6c 8%b
–
3c 72% (1:1)
3d 51% (1:1)
4
5
6
1e (R2 = 2-naphthyl)
1f (R2 = 4-Br-C6H4)
1g (R2 = CH2CH2Ph)
3e 62% (1:1)
3f 70% (1:1)
3g 51% (1:1)
5e 9%
5f 15%
–
6e 17%b
6f 15%b
–
7
–
–
1h
3h 56%
8
9
1i (R2 = Ph)
1j (R2 = Me)
3i 65%
5i 18%
5j 23%
6b 14%b
6c 20%b
3j 62% (1.27:1)
10
11
–
–
1k
1l
3k 40% (1:1)
3l 48%
5k 16%
–
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
Table 2: Substrate scope: oxygenation of secondary C–H bonds.a (continued)
12
6c 20%b
6b 23%b
1m
5m 18%
5n 13%
3m 45% (1.27:1)
13
3n 51%
(trans/cis = 1.37:1)
1n
aReactions were carried out using 0.5 mmol of hydroperoxides 1 with Cu(OAc)2 (5 mol %), 1,10-phen (5 mol %), and Et3N (0.5 equiv) in toluene/
MeCN (5:1, 0.1 M) at room temperature under an O2 atmosphere. After stirring for 4–7 h, the volatile materials were removed in vacuo, and the
resulting crude materials were further treated with LiAlH4 (1.2 equiv) in THF at rt for 1 h. Isolated yields are recorded. The ratio in parentheses is the
diastereomer ratio of the products 3, where available. b 1H NMR yields with 1,1,2,2-tetrachloroethane as an internal standard.
yield) or fragmented alcohols 6 (up to 23% yield), or both were The reaction of a secondary hydroperoxide such as 1o,
observed as minor products. The formation of alcohols 5 occurs however, afforded C–H oxygenation product 2o (as a keto
by two-electron reduction of hydroperoxides 1 followed by form) only in 30% yield along with the formation of the corres-
protonation or by H-radical abstraction of the transient ponding reduced alcohol 5o and ketone 8o in 10% and 43%
O-radical generated by one-electron reduction of hydroper- yields, respectively (Scheme 5).
oxides 1 prior to the 1,5-H radical shift (Scheme 4). Presum-
ably, radical fragmentation of O-radicals occurs to give the Oxygenation of tertiary C–H bonds was also examined under
corresponding ketones 7, which are reduced by LiAlH4 in the the present aerobic conditions (Table 3). In these cases, the
next step to give alcohols 6 (Scheme 4).
Cu-catalyzed aerobic reactions afford hydroperoxides 9 as an
Scheme 4: Proposed reaction mechanisms for the formation of 5 and 6.
Scheme 5: The reaction of secondary hydroperoxide 1o.
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
Table 3: Substrate scope oxygenation of tertiary C–H bonds.a
Entry
Hydroperoxides
1,4-Diols
Others
1
3
Alcohols 5
Ketones 7
1
2
1p (R2 = Ph)
1q (R2 = Me)
3p 52%
3q 45%
5p 16%
5q 23%
7b 28%b
7c 24%b
3
4
–
–
7b 12%b
3r 47%
1r
7b 12%b
1s
3s 23%
aReactions were carried out by using 0.5 mmol of hydroperoxides 1 with Cu(OAc)2 (5 mol %), 1,10-phen (5 mol %), and Et3N (0.5 equiv) in toluene/
MeCN (5:1, 0.1 M) at room temperature under an O2 atmosphere. After stirring for 5–7 h, the reaction mixture was further treated with PPh3 (1 equiv)
at rt. Isolated yields are recorded. b 1H NMR yields with 1,1,2,2-tetrachloroethane as an internal standard.
initial aerobic C–H oxygenation product. After stirring for be envisioned that this aerobic C–H bond oxygenation could be
5–7 h, the reaction mixtures were successively treated with combined with the present remote C–H oxygenation with
PPh3 (1 equiv) for the reduction of 9 to obtain 1,4-diols 3. hydroperoxides, presumably resulting in direct formation of
Although the desired 1,4-diols 3 were formed with this two-step 1,4-dioxygenated compounds from nonoxygenated alkanes
one-pot procedure, the isolated yields of 3p–3r were moderate (Scheme 6).
(45–52% yields) (Table 3, entries 1–3). The oxygenation of the
adamantyl C–H bond was especially sluggish, giving the With this hypothesis, alkane 10 bearing a dibenzylic tertiary
desired 1,4-diol 3s in only 23% yield (Table 3, entry 4). Simi- C–H bond (marked in green) was treated with the catalytic
larly, in these reactions, the formation of reduced alcohols 5 (for system of CuCl-1,10-phen (20 mol %) with NHPI in benzene/
Table 3, entries 1 and 2) and fragmented ketones 7 (for Table 3, MeCN solvent under an O2 atmosphere (1 atm) (Scheme 7).
entries 1–4) were observed as minor products.
The reaction with 20 mol % of NHPI proceeded as expected at
50 °C to afford a mixture of lactol 2i and 1,4-diols 3i in 29%
Our next challenge was to develop direct aerobic dioxygena- and 3% yields, respectively, via the desired 1,4-dioxygenation,
tion of alkanes using the present radical strategy. The genera- while benzophenone (7b) was also formed in 30% yield through
tion of C-radicals from alkanes at C–H bonds bearing relatively fragmentation of the transient alkoxy radical (Scheme 4). Use of
weak bond-dissociation enthalpies (i.e., tertiary alkyl C–H 40 mol % of NHPI slightly improved the yields of 1,4-dioxy-
bonds, benzylic C–H bonds, etc.), by phthalimide N-oxyl radi- genation products 2i and 3i (40% and 4% yields, respectively).
cals generated oxidatively from N-hydroxyphthalimide (NHPI),
has been reported [20-22]. The resulting C-radicals could be In conclusion, we have developed the Cu-catalyzed aerobic
trapped with molecular oxygen to form hydroperoxides. It could oxygenation of aliphatic C–H bonds using hydroperoxides by a
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Beilstein J. Org. Chem. 2013, 9, 1217–1225.
Scheme 6: 1,4-Dioxygenation of alkanes.
Scheme 7: Aerobic 1,4-dioxygenation of alkanes in the CuCl–NHPI catalytic system.
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