Copper-catalyzed remote sp3 C-H chlorination of alkyl hydroperoxides

Article abstract of DOI:10.1021/ol100472t

A copper-catalyzed methodology to functionalize remote sp³ C-H bonds in alkyl hydroperoxides is presented. The atom-transfer chlorination utilizes simple ammonium chloride salts as the chlorine source, and the internal redox process requires no external redox reagents.

Full text of DOI:10.1021/ol100472t

ORGANIC
LETTERS
Copper-Catalyzed Remote sp3 C-H
Chlorination of Alkyl Hydroperoxides
2010
Vol. 12, No. 11
2460-2463
Rituparna Kundu and Zachary T. Ball*
Department of Chemistry, Rice UniVersity, Houston, Texas 77005
zb1@rice.edu
Received February 25, 2010
ABSTRACT
A copper-catalyzed methodology to functionalize remote sp3 C-H bonds in alkyl hydroperoxides is presented. The atom-transfer chlorination
utilizes simple ammonium chloride salts as the chlorine source, and the internal redox process requires no external redox reagents.
Metal-catalyzed C-H-activation radical reactions remain
underdeveloped relative to two-electron C-H-activation
processes.1 However, the possibility of combining metal- and
ligand-induced selectivity with the unique reactivity and
functional-group tolerance of radical intermediates makes the
development of metal-catalyzed radical processes attractive.
In this paper, we describe catalytic remote C-H chlorination
of alkyl hydroperoxides, an internal redox reaction requiring
no external oxidant and utilizing simple amine hydrochloride
salts as the chlorine source.
concept to C-H functionalization4 requires a catalytically
competent means of abstracting an unactivated hydrogen
atom to generate the radical intermediate necessary for metal-
mediated atom-transfer functionalization. We envisioned that
alkyl hydroperoxides could be suitable substrates for this
process, since metal-mediated reduction of the hydroperoxide
moiety would serve two purposes by enabling intramolecular
C-H activation and serving as an internal reoxidant,
permitting catalytic turnover after the reductive atom-transfer
functionalization step (Scheme 1).
Metal-mediated atom transfer is an important elementary
step that has been developed in catalytic methods for the
synthesis of small molecules2 and polymers.3 Extending this
Scheme 1
.
Copper-Catalyzed Chlorination of Alkyl
Hydroperoxides
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Activation of O-X bonds for remote functionalization has
a significant history.5 Lead(IV) reagents react with alcohol
O-H bonds to give ether products following distal hydrogen
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10.1021/ol100472t  2010 American Chemical Society
Published on Web 05/03/2010

abstraction,6 and alkyl nitrites are classical intermediates for
photolytic processes, including the functionalization of
steroidal methyl groups.7 Metal-mediated halogenation of
hydroperoxides has been demonstrated with both a stoichio-
metric metal oxidant and a stoichiometric metal reductant,8
but to our knowledge, no metal-catalyzed versions of this
reaction have been reported.9
Table 1. Optimization of Remote C-H Functionalization of
Alkyl Hydroperoxides
In order to develop a simple catalytic system, we examined
alkyl hydroperoxides as substrates that can generate a reactive
intermediate in the presence of transition-metal catalysts that
can potentially perform an intramolecular functionalization
at a nonactivated δ carbon. The alkyl hydroperoxide sub-
strates can be synthesized from the corresponding alcohols.10
They can be purified by silica gel chromatography and are
stable for several months in a freezer (for synthetic details,
see the Supporting Information). In searching for a catalyst
for a redox atom-transfer process, we took inspiration from
atom-transfer radical polymerization. Among potential cata-
lysts, we found that copper(I) complexes with chelating
nitrogen ligands are capable catalysts for the formation of
chloride 2a from the hydroperoxide 1a, together with the
byproducts 3a and 4a. The combination of CuCl and
N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDTA) in
the presence of acetic acid and tetrabutylammonium chloride
provided 16% of the alkyl chloride product. Variation of the
solvent was not productive, though it was found that on
dilution of the reaction mixture from 0.3 to 0.06 M the yield
of chlorinated alcohol increased to 28% (Table 1, entry 4).
yielda (%)
chlorine
source
entry substrate
ligand
comments
0.3 M
0.3 M
0.3 M
2
3
4
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
bipyridine Bu4NCl
Bu4NCl
0
0
PMDTA
PMDTA
TREN
Bu4NCl
Bu4NCl
Bu4NCl
16 26 18
28 11 24
28 22 10
Me6TREN Bu4NCl
CYCLAM Bu4NCl
16
12
13
24
28
41d
6
5
6
5
4
8
39
5
20
33
29
7
PMDTA
PMDTA
PMDTA
PMDTA
Bu4NClb
Bu4NClb
anhydrousb
1 vol % H2O
9
10
11
iPr2NH·HCl 1 vol % H2O
NH4Cl
24 h, addnc
1 vol % H2O
1 vol % H2O
12
13
14
15
1b
1b
1b
1b
PMDTA
PMDTA
PMDTA
PMDTA
Bu4NCl
58
61
50
65d
5
4
8
3
21
19
21
17
iPr2NH·HCl 1 vol % H2O
NH4Cl
1 vol % H2O
iPr2NH·HCl 2.5 × AcOH e
,
1 vol % H2O
16
1b
none
iPr2NH·HCl 2.5 × AcOH e
,
25 26 35
1 vol % H2O
a Yields determined by HPLC. b Anhydrous Bu4NCl was used in place
of the hydrate. c The hydroperoxide was added over 24 h. d Isolated yield.
e The amount of AcOH was increased from 4 equiv to 10 equiv.
(5) For a recent example, see: Zhu, H.; Wickenden, J. G.; Campbell,
N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009,
11, 2019–2022.
A brief survey of other sp3 nitrogen ligands did not improve
the reaction efficiency (Table 1, entries 5-7).
(6) (a) Brun, P.; Pally, M.; Waegell, B. Tetrahedron Lett. 1970, 331–
334. (b) Brun, P.; Waegell, B. Bull. Soc. Chim. Fr. 1972, 1825–1832. (c)
Variable and irreproducable yields led us to examine the
effect of water on reaction efficiency. Perhaps surprisingly,
rigorous exclusion of water was detrimental to reaction yield
(Table 1, entry 8). The controlled addition of water provided
reproducibility, and optimal results were achieved by adding
1 vol % water to the solvent. Also, only a trace amount of
product was detected when the reaction was carried out in
air. Other chlorination sources were screened, and the use
of NH4Cl together with syringe pump addition of the
hydroperoxide substrate over 24 h improved the yield to 41%
(Table 1, entry 11), but we have been unable to improve
this result with primary hydroperoxide substrates.
ˆ
ˇ
Mihailovic´, M. Lj.; Cekovic´, Z.; Andrejevic´, V.; Matic´, R.; Jeremic´, D.
Tetrahedron 1968, 24, 4947–4961. (d) Bowers, A.; Denot, E.; Ibanez, L. C.;
Cabezas, M. E.; Ringold, H. J. J. Org. Chem. 1962, 27, 1862–1867.
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1353. (b) Cekovic´, Z.; Green, M. M. J. Am. Chem. Soc. 1974, 96, 3000–
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3002. (c) Cekovic´, Z.; Dimitrijevic´, Lj.; Djokic´, G.; Srnic´, T. Tetrahedron
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1979, 35, 2021–2026. (d) Cekovic´, Z.; Cvetkovic´, M. Tetrahedron Lett.
1982, 23, 3791–3794. (e) Cekovic´, Z.; Ilijev, D. Tetrahedron Lett. 1988,
29, 1441–1444. (f) Petrovic´, G.; Cekovic´, Z Tetrahedron 1999, 55, 1377–
1390.
Moving to a secondary hydroperoxide 1b, we found that
the formation of alcohol (2-octanol) and carbonyl (2-
octanone) byproducts was significantly decreased, and after
a brief optimization, we obtained the chloride 2b in 65%
yield (Table 1, entry 15). The optimal method thus varies
depending upon the type of chorination source used. For
primary alkyl hydroperoxide substrates, which were highly
reactive, NH4Cl was found to give better yield (Table 1, entry
11), whereas for secondary alkyl hydroperoxide substrates,
diisopropylamine hydrochloride gave the best yields (Table
1, entries 13 and 15). A control experiment with substrate
1b in the absence of ligand (entry 16) exhibited similar rates
of starting material conversion but inferior product formation,
ˆ
ˇ
(9) For recent reviews discussing catalytic remote C-H functionalization,
see: (a) Salvador, J. A. R.; Silvestre, S. M.; Moreira, V. M. Curr. Org.
Chem. 2006, 10, 2227–2257. (b) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439–2463. For recent examples of catalytic remote C-H
functionalization; see: (c) Williams Fiori, K.; Fleming, J. J.; Du Bois, J.
Angew. Chem., Int. Ed. 2004, 43, 4349–4352. (d) Williams Fiori, K.; Du
Bois, J. J. Am. Chem. Soc. 2003, 125, 2028–2029. (e) Breslow, R.; Yan, J.;
Belvedere, S. Tetrahedron Lett. 2002, 43, 363–365. (f) Breslow, J.; Yang,
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Org. Lett., Vol. 12, No. 11, 2010
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indicating that the ligand plays an important role in deter-
mining the chemoselectivity of the catalytic cycle.
In the case of the tertiary alkyl hydroperoxide 1c (Table
2, entry 3), the reaction was very sluggish, and even after
as a reducing agent remarkably improves the rate of the
reaction, giving 74% isolated yield of the product 2c within
1 h.
We examined chlorination of a variety of alkyl hydroper-
oxide substrates using the standard methods developed above.
Surprisingly, reaction efficiency is similar for the function-
alization of secondary or tertiary C-H bonds, despite the
significant difference in stability of the intermediate radical
species (Table 2, entries 1 and 4 and entries 2 and 6). For
substrates that target benzylic C-H bonds, similar yields are
observed despite the increased reactivity of the C-H bond,
and the product cyclizes into the corresponding furan under
the reaction conditions (Table 2, entries 5, 7, and 10). Ester
groups are also tolerated under the reaction conditions (Table
2, entries 8, 9, and 11).
Table 2. CuCl-Catalyzed Remote C-H Functionalization of
Alkyl Hydroperoxides
Since a new stereocenter is created in the process of C-H
activation, the investigation of the effect of a neighboring
stereogenic center on diastereoselectivity of the reaction was
of interest. To address this issue, a substrate with a methoxy
group adjacent to the target C-H bond was designed
(Scheme 2). In this case, no substantial diastereoselectivity
Scheme 2
.
Chlorination of a Substrate Providing Mixtures of
1,5 and 1,6 Hydrogen Abstraction
a Reaction conditions: 0.1 equiv of CuCl, 0.12 equiv of PMDTA, 4
equiv of AcOH, 1.2 equiv of diisopropylamine hydrochloride, 0.06 M
hydroperoxide in MeCN, 35 °C, slow addition of substrate.
was observed, and the product was isolated as a mixture of
diasteromers (1.3:1). In addition to the expected 1,5 H-atom
abstraction product 2m, two other products, 6m and 7m, of
a Isolated yield unless otherwise noted. b NH4Cl used as chorination
source; slow addition of substrate over 24 h. c iPr2NH·HCl used as
chlorination source; slow addition of substrate over 1 h. d Sodium ascorbate
(0.05 equiv) was added. e Lower isolated yields were observed in these
cases due to product volatility. f Yields determined by HPLC. g Ratio
chlorinated product/cyclized product.
10 days, starting material remained unreacted. We hypoth-
esized that copper(I) catalyst was being oxidized to an
inactive copper(II) species over long reaction times and so
examined reductants that might regenerate an active copper(I)
species. Addition of a catalytic amount of sodium ascorbate
Figure 1. Plausible catalytic cycle.
Org. Lett., Vol. 12, No. 11, 2010
2462

1,6 abstraction of a C-H bond on the methoxy group were
also formed.
hydrogen peroxide, the inexpensive and environmentally
benign hydrogen peroxide is the terminal oxidant for C-H
functionalization. We believe this report will serve as a
foundation for the development of catalytic stereoselective
processes and the further development of metal-catalyzed
radical processes triggered by C-H activation.
A plausible mechanism for the reaction is shown in Figure
1. The copper catalyst reacts with the hydroperoxide to afford
a reactive intermediate, likely an alkoxy radical or copper(III)
alkoxide. The 1,5-hydrogen-atom abstraction11 would then
provide the intermediate radical necessary for atom transfer
of a chlorine atom from a copper(II) species to the radical
to form the observed product. The presence of an acid
(AcOH) is necessary to facilitate regeneration of a copper(I)
chloride from the initially formed copper(I) hydroxide.
The remote functionalization described here is character-
ized by operational simplicity. Because the alkyl hydroper-
oxide substrates are synthesized by substitution reactions with
Acknowledgment. We acknowledge financial support
provided by Rice University and the Robert A. Welch
Foundation (research grant C-1680).
Supporting Information Available: Experimental details
and spectroscopic and analytical data for all the compounds
studied. This material is available free of charge via the
Internet at http://pubs.acs.org.
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OL100472T
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