Iron-catalyzed oxidative sp3 carbon-hydrogen bond functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones

Article abstract of DOI:10.1039/c6cc05885j

A novel and efficient iron-catalyzed sp³ carbon-hydrogen bond functionalization of benzoxazinone derivatives has been developed. For the first time, benzoxazin-2-ones were used as substrates in an oxidative dehydrogenative coupling reaction. The experiments were performed under mild reaction conditions to construct alkyl-aryl C(sp³)-C(sp²) bonds. The application of this method to the gram-scale synthesis of natural product cephalandole A has been accomplished in a 3-step sequence. A plausible one electron oxidation involved mechanism is proposed.

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Iron-Catalyzed Oxidative Sp3 Carbon-Hydrogen Bond
Functionalization of 3,4-Dihydro-1,4-benzoxazin-2-ones
Congde Huo,* Jie Dong, Yingpeng Su, Jing Tang, Fengjuan Chen
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel and efficient iron-catalyzed sp3 carbon-hydrogen
bond functionalization of benzoxazinone derivatives has been
developed. For the first time, benzoxazin-2-ones were hired as
substrates in an oxidative dehydrogenative coupling reaction.
10 The experiments were performed under mild reaction
conditions to construct alkyl–aryl C(sp3)–C(sp2) bonds. The
application of this method to the gram-scale synthesis of
natural product cephalandole A has been accomplished in a
3-step sequence. A plausible one electron oxidation involved
15 mechanism is proposed.
compounds are incorporated in biological systems which mean
low toxicity and is especially of importance in the pharmaceutical
50 and food industry. Based on above mentioned advantages,
tremendous progress of iron salts catalyzed transformations has
been developed.11
Scheme1. Design of New Substrate for Oxidative
Dehydrogenative Coupling
The transfer of an electron is one of the simplest elemental
reactions in chemistry. One electron oxidation (OEO), ionized an
electron from neutral organic compounds to form radical cation
intermediates, changes the structure and reactivity of organic
20 molecules deeply.1 When a molecule with heteroatom such as N,
O (n electron donor) is oxidized to its radical cation, the -C-H
bond will be significantly weakened through hyperconjugation
effect (Scheme 1, top). According to this principle, for instance,
oxidative dehydrogenative sp3-C-H functionalization reactions of
25 amines have become a valuable synthetic approach in the last
decade.2 However, there are still some crucial limitations and
unsolved issues within this methodology. For example, the
substrate scopes of amines are mostly restricted to N-aryl
tetrahydroisoquinolines,3 N,N-dimethylanilines4 and N-aryl
30 glycine derivatives5 (Scheme 1, middle). Exploring new
substrates to expand this chemistry is arguably of high interest.
1,4-Benzoxazinone systems constitute a privileged structure that
can be frequently found in many biologically active molecules.6 It
can also serve as building blocks in the synthesis of
35 pharmaceuticals.7 2H-1,4-Benzoxazin-3(4H)-ones have been
intensively studied recently.8 However, the synthetic method of
3,4-dihydro-1,4-benzoxazine-2-one derivatives was relatively
rare.9 Through literature research, we found the preparation of 3-
unsubstituted 3,4-dihydro-1,4-benzoxazine-2-one was first
40 reported by Kikelj et al in 2008.10 In view of the importance of
this class of molecules, together with our continuous interests on
OEO involved transformations, we envisioned that by employing
55
Scheme 2, Screening of Reaction Conditions
the oxidative dehydrogenative coupling strategy,
a facile
synthesis of useful 3-substituted 3,4-dihydro-1,4-benzoxazine-2-
45 ones would be possible (Scheme 1, bottom).
Iron is the second most abundant metal in the Earth's crust and is
one of the cheapest of all metals. What is more, various iron
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[a]
Reaction Conditions: 1a (0.5 mmol), 2a (0.6mmol), FeCl2 (5
for further elaboration of the benzoxazinone-indole hybrid via
mol %), T-Hydro (1.2 equiv), MeCN (10 mL), 1 h, rt. [b] Isolated
yields. [c] 5.0-6.0 M in decane. [d] Reaction time: 4 h.
60 transition metal-catalyzed or conventional functional group
transformations. Additionally, very bulDkyOI: 1s0u.1b0s3tVr9iae/tCwe6sACrtCical0el5sO8on8li5nJe
efficiently reacted with 1a giving the product in 60–69% yields
(Scheme 3, 3ap-3ar).
Herein, we wish to report the first realization of the oxidative
dehydrogenative coupling reaction of benzoxazin-2-ones under
an Fe(II)/TBHP catalyst system via an OEO process.
5
65 Scheme 3, Iron(II)-Catalyzed Indolation of 3,4-Dihydro-1,4-
Indoles are widely existing substructures in natural products and
bioactive compounds.12 New methodologies to introduce indolyl
onto small molecules have attracted intense attention from
benzoxazin-2-ones [a,b]
10 synthetic chemists. We believe that bring benzoxazinone and
indole skeletons together would not only offer significant
potential biological applications but would also represent a
significant contribution to synthetic chemistry.13 Our initial
studies started with the reaction of 4-benzyl-3,4-dihydro-2H-
15 benzo[b][1,4]oxazin-2-one (1a) with indole (2a). Various
transition-metal salts (10 mol %) were examined as catalysts with
tert-Butyl hydroperoxide (TBHP, 1.2 equiv.) as the terminal
oxidant for the indolation of 1a (Scheme 2, entries 1-10). It was
particularly gratifying that the reaction proceeded smoothly in
20 acetonitrile at room temperature when FeCl2 was hired as catalyst,
giving
4-benzyl-3-(1H-indol-3-yl)-3,4-dihydro-2H-
benzo[b][1,4]oxazin-2-one (3aa) in 59% yield (Scheme 2, entry
7).14 No benzyl-position oxidized by-products has been observed
with this protocol and the reaction occurred exclusively at the 3-
25 position of 1a. This suggested H atom of 1a at 3-position is more
active under these reaction conditions. Notably, the use of FeCl3
gave similar results to FeCl2, thus demonstrating that both Fe(II)
and Fe(III) catalyst precursors were able to facilitate this
transformation (Scheme 2, entries 7 and 8). No reaction was
30 observed in the absence of metal catalyst (Scheme 2, entry 11).
The loading of catalyst was also optimized (Scheme 2, entries 12-
14); the highest yield of 3aa was obtained in the presence of 5
mol % of FeCl2. It was also worthy to note that the oxidant also
played a key role in the present reaction (Scheme 2, entries 13,
35 15-18). TBHP (70% solution in water) was the best one among
the tested oxidants. No reaction took place when O2 was used
(Scheme 2, entry 18). Solvent-screening study showed that
CH3CN was the best fit among all other solvents tested including
toluene, DCM, THF, MeOH, leading to the desired product in the
40 highest yield (Scheme 2, entries 13, 19-22). All together it was
discovered that FeCl2 (5 mol %)/TBHP (1.2 equiv.) at room
temperature were the optimized reaction conditions (65%,
Scheme 2, entry 13).
With the optimized reaction conditions in hand, we probed the
45 substrate scope at room temperature by using FeCl2 (5 mol %) as
the catalyst, TBHP (1.2 equiv.) as the oxidant. As summarized in
Scheme 3, the FeCl2-catalyzed C(sp3)–C(sp2) bond formation
reaction is tolerant of a range of substituents in different positions
of the indole ring (Scheme 3, 3aa-3az). Indoles bearing both
50 electron-donating and electron-withdrawing groups furnished the
desired products in 41–69% yields. The structure of 3ac was
confirmed using single crystal X-ray diffraction as shown in
Scheme 3.15 Particularly noteworthy is the tolerance toward a
range of functionally substituents in indole units, such as halogen
55 (F, Cl, Br. I), aldehyde, cyano, ester, methyl, methoxy, benzyl
and benzoxyl groups, which remain unaffected during the
reaction; these examples demonstrate that the iron-catalyzed
oxidative CH cross-coupling provides a complementary platform
[a]
Reaction Conditions: 1 (0.5 mmol), 2 (0.6 mmol), FeCl2 (5
[b]
70 mol %), T-Hydro (1.2 equiv), MeCN (10 mL), rt.
Isolated
yields. [c] Thermal ellipsoids shown at 50% probability.
Subsequently, we applied our method to a range of 3,4-dihydro-
2
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1,4-benzoxazin-2-ones (1) using indole (2a) as the reaction
oxidation with Fe(III) to give the radical cation intermediate A.
Subsequent hydrogen abstraction of intermediate A by tert-
partner. As shown in Scheme 3, a variety of derivatives,
including electron-donating or electron-withdrawing groups on
the aromatic ring and aryl or alkyl protecting groups on the
butoxyl radical offers an iminium intermediate B,VifeowlAlortwicleedOnblinye
DOI: 10.1039/C6CC05885J
nucleophilic addition leading to the product 3aa.
5
nitrogen atom, readily worked well in this reaction (Scheme 3, 40 In summary, for the first time, we have discovered an efficient
3aa-3ha).
synthesis of complex 3-arylated 3,4-dihydro-1,4-benzoxazine-2-
one derivatives via iron catalyzed oxidative sp3 C-H
functionalization of easily accessible substrates with excellent
functional group tolerance. Cheap and nontoxic iron salt was used
45 in the coupling process, which is significant in the synthesis of
pharmaceutical ingredients. This new mythology represents the
powful potential to construct complex organic frameworks. The
use of this method to the gram-scale preparation of alkaloid
cephalandole A has been achieved in three steps with 33% overall
50 yield. Mechanistic studies by TEMPO revealed that a radical
process is involved in the key step of the reaction. Further
investigations on the new oxidative dehydrogenative reactions of
benzoxazinones are underway in our laboratory.
Scheme 4. Gram-scale synthesis of alkaloid cephalandole A
Scheme 6, Radical-inhibiting experiment and proposed
55 mechanism
10 Scheme
5.
Other
investigations
Acknowledgements
We thank the National Natural Science Foundation of China
60 (21562037, 21262029) and the Fok Ying Tong Education
Foundation (141116) for financially supporting this work.
To demonstrate the practicality of this transformation, a gram-
scale reaction was performed between 1a and indole. The
corresponding product 3aa was achieved in 65% yield too
15 (Scheme 4). Subsequently, after deprotection, 4aa was obtained
in 59% yield. Finally, compound 4aa was easily and efficiently
transformed to the natural product cephalandole A13 by oxidation
with DDQ at room temperature within 2 hours.
To develop a more general and useful method, we also
20 investigated the iron catalyzed oxidative coupling reaction of
pyrroles (Scheme 5, top) and electron-rich arene 1,3,5-
trimethoxybenzene (Scheme 4, bottom) using benzoxazinone 1a
Notes and references
a
Key Laboratory of Eco-Environment-Related Polymer Materials
Ministry of Education; College of Chemistry and Chemical Engineering,
65 Northwest Normal University, Lanzhou, Gansu 730070, China. E-mail:
huocongde1978@hotmail.com
† Electronic Supplementary Information (ESI) available: [Experimental
procedures and characterization data]. See DOI: 10.1039/b000000x/
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