Multifunctionalization of alkenes via aerobic oxynitration and sp 3 C-H oxidation

Article abstract of DOI:10.1039/c3cc00130j

A method for direct functionalization of three positions including an unactivated C-H bond of aliphatic alkenes using tert-butyl nitrite and molecular oxygen to give γ-lactols has been developed. The present reaction proceeds through a sequence of radical processes involving oxynitration followed by aerobic oxidation of an sp³ C-H bond. This multifunctionalization reaction requires neither metallic reagents nor photolysis and proceeds under mild conditions.

Full text of DOI:10.1039/c3cc00130j

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Multifunctionalization of alkenes via aerobic
oxynitration and sp3 C–H oxidation†
Cite this: Chem. Commun., 2013,
49, 2198
Tsuyoshi Taniguchi,* Yuki Sugiura, Takashi Hatta, Atsushi Yajima and
Hiroyuki Ishibashi
Received 7th January 2013,
Accepted 29th January 2013
DOI: 10.1039/c3cc00130j
www.rsc.org/chemcomm
A method for direct functionalization of three positions including an alkyl group through the application to synthesis of biologically active
unactivated C–H bond of aliphatic alkenes using tert-butyl nitrite and compounds.8 Thus, radical methodologies continue to contribute to
molecular oxygen to give c-lactols has been developed. The present the development of C–H functionalization chemistry from a differ-
reaction proceeds through a sequence of radical processes involving ent angle from other methods.9
oxynitration followed by aerobic oxidation of an sp3 C–H bond. This
multifunctionalization reaction requires neither metallic reagents nor alkenes using tert-butyl nitrite and molecular oxygen.10 In the course
Recently, we have reported a radical oxynitration reaction of
photolysis and proceeds under mild conditions.
of this study, we found that g-lactols were directly produced from
simple aliphatic alkenes by oxynitration of an olefin and aerobic
Direct functionalization reactions of an unactivated sp3 C–H bond oxidation of an sp3 C–H bond in which 1,5-hydrogen shift of an
have large potential for changing existing methodologies in synthetic intermediary alkoxy radical was thought to be involved.11,12 Herein,
chemistry.1,2 Transition metal-catalyzed methods have recently we report a unique multifunctionalization reaction of alkenes using
become the mainstream of C–H activation chemistry,3 but C–H non-metallic reagents under mild conditions.
functionalization reactions without transition metal reagents would
Treatment of alkene 1a, which was chosen as a model substrate
be more efficient methods from economical and environmental to optimize conditions, with 5 equivalents of tert-butyl nitrite
viewpoints.4 Among the various approaches to transition metal-free (tBuONO) in pentane under an oxygen (O2) atmosphere at room
sp3 C–H functionalization, methods using radical species have been temperature gave g-lactol 2a in 11% yield along with a small amount
developed over the past century.5 In 1960, Barton and co-workers of nitrate ester 3a (Table 1, entry 1). Although the reaction in
reported introduction of an oxime group into an unactivated dichloromethane (CH2Cl2) slightly improved the yield of g-lactol 2a
methyl group using a photolysis reaction of a nitrite compound in (entry 2), we realized from the results that the reaction in a nonpolar
studies on steroid chemistry (Scheme 1).6 Photolysis of the nitrite
compound generates the corresponding highly reactive alkoxy
Table 1 The effect of solvent in oxidative nitration of alkene 1aa
radical, and it transformed a methyl group into an oxime group
via 1,5-hydrogen shift followed by trapping of the resultant radical by
nitrogen oxide.7 Although this ‘‘Barton reaction’’ has often suffered
from low yield of the product, it has been established as a valuable
synthetic method for a direct functionalization on an unactivated
Yieldc (%)
Entry
Solvent
Time (h)
2a
3a
1
2
3
4
Pentane
CH2Cl2
MeOH
THF
5
5
8
5
5
5
5
12
11
20
—
15
36
52
44
26
5
8
—
44
36
21
21
24
Scheme 1 The Barton reaction.
5
DMF
6
DMSO
DMSO
DMSO
7d
8e
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
E-mail: tsuyoshi@p.kanazawa-u.ac.jp; Fax: +81-76-234-4439
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc00130j
a
Reaction conditions: 1a (0.6 mmol), tBuONO (3.0 mmol) in solvent (3 mL)
under an O2 atmosphere (1 atm). b Diastereomeric ratio was approximately
estimated by 1H NMR analysis. c Isolated yield. d 3 equiv. of tBuONO
(1.8 mmol) was employed. e Under air (1 atm).
c
2198 Chem. Commun., 2013, 49, 2198--2200
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solvent was sluggish. The use of methanol (MeOH) as a solvent g-lactols 2c and 2d in reasonable yields. When alkenes 1e–g having
caused decomposition of the starting material or products, and functional groups such as nitrile, benzoyloxy or ester were employed
no identifiable product was obtained (entry 3). In the reaction in as substrates, g-lactols 2e–g were obtained in similar yields, though
tetrahydrofuran (THF), the total yield of products 2a and 3a was these are mixtures of four diastereoisomers. On the other hand, C–H
improved, but undesired 3a was the major product (entry 4). oxidation on a methyl group of malonate derivative 1h seemed to
When the reaction was carried out in N,N-dimethylformamide proceed, but a subsequent C–C bond cleavage occurred to give
(DMF), equal amounts of 2a and 3a were obtained in good total formate ester 2h. Reactions of methylenecyclohexane derivatives 1i
yield (entry 5). Results of entries 4 and 5 clearly indicated that and 1j provided bicyclic compounds 2i and 2j in acceptable yields
polarity of the aprotic solvent significantly affects the ratio of 2a along with a small amount of the corresponding ring-opening
and 3a. Therefore, we examined the use of dimethylsulfoxide aldehydes. Like these entries, g-lactol products obtained by this
(DMSO), which is an excellent polar aprotic solvent, and found reaction were not necessarily stable, and partial degradation of
that g-lactol 2a was obtained as the major product (entry 6). A products in the course of the reaction or purification was presumed
decrease in the amount of tBuONO or the use of air did not in several cases. For instance, the yield of 2i estimated by 1H NMR
improve the results (entries 7 and 8).
analysis of the crude product was higher than the isolated yield. We
Subsequently, transformation of several alkenes into g-lactols was also found that this reaction caused C–H oxidation at a methylene
examined (Table 2). The branched structure of substrates was likely position of alkene 1k to give bicyclic compound 2k. In the reaction of
to be important in the reaction because a dramatic difference in alkenes 1l and 1m, C–H oxidation on a benzoyloxymethyl group
yields of products 2a and 2b was observed between branched 1a and predominantly proceeded to provide g-lactone derivatives 2l and 2m.
linear 1b. This clearly indicates that an intramolecular process is
The obtained g-lactol 2a can be transformed into several
involved in the C–H oxidation. Internal alkenes 1c and 1d also gave oxygen-containing heterocyclic systems (Scheme 2). Reduction
of g-lactol 2a with triethylsilane (Et3SiH, 2 equiv.) in the presence
of boron trifluoride etherate (BF3ÁOEt2, 2 equiv.) afforded tetra-
Table 2 Multifunctionalization reactions of various alkenesa
hydrofuran derivative 4a.13 The use of allyltrimethylsilane
(TMSCH2CHQCH2, 2 equiv.) instead of triethylsilane resulted in
formation of a new C–C bond to afford substituted tetrahydro-
furan derivative 5a. In addition, g-lactol 2a was easily oxidized to
g-lactone derivative 6a with iodoxybenzoic acid (IBX, 5 equiv.).14
Thus, it is noteworthy that the tert-butyl nitrite-mediated reaction
allows us to gain functionalized compounds bearing higher
oxidation levels from simple unsaturated hydrocarbons in only
one or two steps.
A proposed mechanism of this multifunctionalization involving
sp3 C–H oxidation is shown in Scheme 3. Although the exact
pathway is unclear, it is likely that nitrogen dioxide (NO2)
is generated from tBuONO by oxidation with molecular
oxygen.10,15 The peroxynitrite radical formed by aerobic
cleavage of the weak N–O bond of tBuONO might be a strong
candidate as an intermediate to provide NO2 (Scheme 3,
eqn (1)).7,16 Addition of NO2 to alkene 1a would generate
tertiary alkyl radical A followed by trapping by molecular oxygen
to give peroxy radical B.17 It is reasonable that radical B reacts
with tBuONO to afford peroxynitrite C because tBuONO can
work as a nitrogen oxide source.10 As the key step of C–H
oxidation, highly reactive alkoxy radical D formed by the O–O
bond cleavage of intermediate C gives rise to a 1,5-hydrogen
a
Reaction conditions: 1b–m (0.6 mmol), tBuONO (3.0 mmol) in DMSO
(3 mL) under an O2 atmosphere (1 atm) at room temperature. Isolated
yield. Diastereomeric ratios (dr) were approximately estimated by 1H NMR
analysis. b Single stereoisomers at the hemiacetal carbon (unassigned) were
1
detected by H NMR analysis. c Diastereomeric ratios of the corresponding
lactones (approximately estimated by 1H NMR analysis after oxidation of 2e–g
with Dess–Martin periodinane, see the ESI). d Isolated along with a small
amount of the corresponding ring-opening aldehyde (2i : 92 : 8, 2j : 93 : 7,
estimated by 1H NMR analysis). e Yield determined by 1H NMR analysis
Scheme 2 Derivatives from g-lactol 2a.
using an internal standard (mesitylene).
c
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O. Daugulis, J. Am. Chem. Soc., 2012, 134, 7; (g) Q. Nguyen, K. Sun
´
and T. G. Driver, J. Am. Chem. Soc., 2012, 134, 7262; (h) A. Iglesias,
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Chem., Int. Ed., 2009, 48, 5094; (b) T. W. Lyons and M. S. Sanford, Chem.
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(b) M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi and
W. Nakanishi, Science, 2011, 332, 448; (c) A. A. Kantak,
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5 Hofmann–Loffler–Freytag reaction is well-known as a pioneering
Scheme 3 A proposed mechanism.
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J. M. Richter and P. S. Baran, J. Am. Chem. Soc., 2008, 130, 7247.
6 (a) D. H. R. Barton, J. M. Beaton, L. E. Geller and M. M. Pechet, J. Am.
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shift of a methyl group to generate alkyl radical E.7,18
The reaction of radical E with molecular oxygen and tBuONO
would afford alkoxy radical F through a similar pathway.18
Oxidation of alkoxy radical F by oxygen would produce the
corresponding aldehyde G followed by rapid intramolecular
hemiacetalization to give 2a (Scheme 3, eqn (2)).19
7 A mechanistic study of the Barton reaction: L. Grossi, Chem.–Eur. J.,
2005, 11, 5419.
8 Examples of the synthesis of natural products using the Barton
reaction: (a) E. J. Corey, J. F. Arnett and G. N. Widiger, J. Am. Chem.
Soc., 1975, 97, 430; (b) E. J. Corey and R. W. Hahl, Tetrahedron Lett.,
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9 Recent examples of radical-mediated C–H functionalization:
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In conclusion, we found a novel multifunctionalization reaction
involving direct sp3 C–H oxidation of aliphatic alkenes using tert-
butyl nitrite and molecular oxygen. This reaction would consist of a
sequence of radical processes including oxynitration of the olefin
and C–H oxidation via a 1,5-hydrogen shift. Although there might
still be room for improvement in the yield of products, one-step
transformation of aliphatic alkenes into g-lactols with introduction
of a nitrogen atom is unprecedented. In addition, the reaction can
be conducted under mild conditions using inexpensive reagents
including no metallic compound, and the use of molecular oxygen
as an oxygen source is ideal.20 Our work has demonstrated that
transformation of simple organic molecules into highly functiona-
lized compounds can be achieved even with a simple and common
reaction system. We believe that such ‘‘simple and advanced
reactions’’ are promising in the development of useful synthetic
methods involving direct C–H functionalization.
10 T. Taniguchi, A. Yajima and H. Ishibashi, Adv. Synth. Catal., 2011,
353, 2643.
11 An example of synthesis of lactols via C–H oxidation: M.-K. Wong,
N.-W. Chung, L. He and D. Yang, J. Am. Chem. Soc., 2003, 125, 158.
12 A review on 1,5-hydrogen shift reactions of alkoxy radicals:
ˇ ˇ
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Z. Cekovic, Tetrahedron, 2003, 59, 8073.
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16 B. Galliker, R. Kissner, T. Nauser and W. H. Koppenol, Chem.–Eur. J.,
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The authors thank Mr Takuma Hashimoto (Kanazawa Univer-
sity) for performing some preliminary experiments. This research
was supported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan.
17 Formation of the stable tertiary radical is likely to be essential in the
present reaction because the reaction of 4,4,4-trimethyl-1-pentene did
not proceed. This might be because NO2 addition step is reversible.
18 A similar pathway and intermediates such as C, D, and F have been
proposed in the Barton reaction under an oxygen atmosphere:
J. Allen, R. B. Boar, J. F. McGhie and D. H. R. Barton, J. Chem.
Soc., Perkin Trans. 1, 1973, 2402.
19 Studies on the fate of alkoxy radicals: (a) T. P. W. Jungkamp,
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Notes and references
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c
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