(Diacetoxyiodo)benzene-mediated oxygenation of benzylic C(sp3)-H bonds with N-hydroxyamides at room temperature

Article abstract of DOI:10.1002/ejoc.201403616

A new, metal-free method for the formation of C(sp³)-O bonds was established by PhI(OAc)₂-mediated oxygenation of benzylic C(sp³)-H bonds with N-hydroxyamides at room temperature, in which the C(sp³)-H oxidation is activated by a polyflurophenylamide group.

Full text of DOI:10.1002/ejoc.201403616

Job/Unit: O43616
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403616
(Diacetoxyiodo)benzene-Mediated Oxygenation of Benzylic C(sp3)–H Bonds
with N-Hydroxyamides at Room Temperature
Peng-Cheng Qian,[a] Yu Liu,*[a] Ren-Jie Song,[a] Ming Hu,[a] Xu-Heng Yang,[a]
Jian-Nan Xiang,*[a] and Jin-Heng Li*[a]
Keywords: Oxidation / N-Hydroxyamides / Cross-coupling / Acetamides / Synthetic methods
A new, metal-free method for the formation of C(sp3)–O
bonds was established by PhI(OAc)2-mediated oxygenation
of benzylic C(sp3)–H bonds with N-hydroxyamides at room
temperature, in which the C(sp3)–H oxidation is activated by
a polyflurophenylamide group.
bonds, under mild and metal-free conditions are not well-
studied and are more limited in number.[3] Thus, the devel-
Introduction
The oxidative coupling reaction has become a powerful opment of new C(sp3)–H functionalization routes to access
strategy for the formation of diverse chemical bonds in carbon–heteroatom bonds under metal-free and mild con-
organic synthesis.[1] In the field, oxidative coupling through ditions is desirable.
C–H functionalization is particularly fascinating because
Generally, the reaction between an organohalide electro-
this methodology benefits from the wide availability, high phile and a hydroxyl group represents a fundamental
atom-economy, low toxicity, and sustainability as compared method for C(sp3)–O bond formation. However, classical
with traditional organohalide electrophiles and/or organo- transformations suffer from the necessity to prefunction-
metallic reagents.[1–4] Although impressive progress has alize the C(sp3)–H bonds as organohalide electrophiles,
been made toward the coupling mediated by transition- thus limiting their wide application in synthesis and indus-
metal catalysts at high temperatures (often Ͼ 80 °C),[1–4] try. Moreover, the development of room temperature
examples of oxidative coupling with C(sp3)–H bonds to C(sp3)–H functionalization under metal-free conditions re-
form chemical bonds, particularly carbon–heteroatom mains one of the biggest challenges for this field. Recently,
Scheme 1. Oxygenation of benzylic C(sp3)–H bonds.
Chang and co-workers reported a copper-facilitated C–H
functionalization of hydrocarbons for the formation of
C(sp3)–O bonds in the presence of PhI(OAc)2
(Scheme 1a).[5a] However, the method requires both ele-
vated temperature and 10 mol-% CuCl to facilitate the reac-
tion. Herein, we wish to report a new, room temperature
route to C(sp3)–O bonds by metal-free PhI(OAc)2-mediated
[a] State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering
HunanUniversity
Changsha, Hunan 410082, P. R. China
E-mail: jhli@hnu.edu.cn
http://cc.hnu.cn/index.php?option=com_content&task=
view&id=1053&Itemid=227
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403616.
Eur. J. Org. Chem. 0000, 0–0
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Y. Liu, J.-N. Xiang, J.-H. Li et al.
SHORT COMMUNICATION
oxygenation of benzylic C(sp3)–H bonds with N- PhI(OAc)2 to 3 equiv. only resulted in identical results to
hydroxyamides,[5,6] in which an N-polyfluoroaryl amide those of 2 equiv. PhI(OAc)2 (Table 1, entry 11). It is note-
group is used to activate the C(sp3)–H functionalization worthy that when the reaction is carried out on a gram scale
(Scheme 1b).[4]
with respect to the amount of substrate 1a a good yield is
obtained (Table 1, entry 12).
In light of the results described above, the metal-free
benzylic C(sp3)–H oxidation protocol may proceed by a
radical process. Indeed, a stoichiometric amount of radical
inhibitor, including 2,2,6,6-tetramethylpiperidine N-oxide
(TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), or
hydroquinone, resulted in no detectable product 3 from the
reaction of benzamide 1a with NHPI 2a and PhI(OAc)2.
Results and Discussion
Our initial investigations focused on the benzylic C(sp3)–
H functionalization of 2-methyl-N-(perfluorophenyl)benz-
amide (1a) with N-hydroxyphthalimide (NHPI; 2a) for opti-
mization of the reaction conditions (Table 1). Gratifyingly,
treatment of substrate 1a with NHPI 2a and PhI(OAc)2 in
CH2ClCH2Cl at room temperature for 4 h afforded the
desired product 3 in 55% yield (Table 1, entry 1). Sub-
sequently, two other oxidants, PhI(OCOCF3)2 and
mesitylI(OAc)2, were tested; however, PhI(OCOCF3)2 was
less effective than PhI(OAc)2 because of the electronic ef-
fect, and the trace amount of 3 formed in the presence of
mesitylI(OAc)2 might be caused by steric hindrance
(Table 1, entry 1 vs. entries 2 and 3).[6] In light of these re-
sults, a series of other solvents, namely CH2Cl2, MeCN,
(CF3)2CHOH, DMF, and THF, were tested (Table 1, en-
tries 4–8). Screening revealed that CH2Cl2 was the most ef-
fective medium for the reaction and delivered product 3 in
70% yield (Table 1, entry 4). Although both MeCN and
(CF3)2CHOH were also highly effective media for the reac-
tion (Table 1, entries 5 and 6), the other solvents, DMF and
THF, resulted in no reactivity (Table 1, entries 7 and 8). The
results showed that the reaction temperature affected the
result of the reaction: the yield of 3 slightly decreased from
70% at room temperature to 65% at 50 °C (Table 1, en-
try 9). A decrease in the loading of PhI(OAc)2 to 1 equiv.
was not beneficial to the formation of product 3 (38% yield;
Table 1, entry 10), whereas an increase in the loading of
According to the radical merostabilization concept,[3,7]
a
strong electron-withdrawing group in the position ortho to
the alkyl group on the aromatic ring may facilitate oxid-
ation of C–H bonds. With this concept in mind, a series of
the activating ortho groups on the aromatic ring of the N-
arylamide moiety were explored (Table 2). As expected,
substrates 1 with stronger electron-withdrawing N-poly-
fluorophenyl groups, such as N-[2,3,5,6-tetrafluoro-4-(tri-
fluoromethyl)phenyl], N-(2,3,5,6-tetrafluorophenyl), or N-
(2,4,6-trifluorophenyl) groups, showed high reactivity for
the reaction with NHPI 2a and PhI(OAc)2 at room tem-
perature, providing the corresponding products 4–6 in good
yields. However, 2-methylbenzamides with an N-(2-fluoro-
phenyl) or a N-(4-nitrophenyl) group were not suitable sub-
strates (Table 2, products 7 and 8). Gratifyingly, 2-methyl-
N-phenylbenzamide could react with NHPI 2a and
Table 2. Screening of N-arylamide groups.[a]
Table 1. Screening of the optimal conditions.[a]
Entry [O] [equiv.]
Solvent
Isolated yield [%]
1
2
3
4
5
6
7
8
PhI(OAc)2 (2)
PhI(OCOCF3)2 (2)
mesitylI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (1)
PhI(OAc)2 (3)
PhI(OAc)2 (2)
CH2ClCH2Cl 55
CH2ClCH2Cl 38
CH2ClCH2Cl trace
CH2Cl2
MeCN
70
40
(CF3)2CHOH 51
DMF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
trace
trace
65
38
67
9[b]
10
11
12[c]
71
[a] Reaction conditions: 1 (0.2 mmol), 2a (2 equiv.), PhI(OAc)2
(2 equiv.) and CH2Cl2 (2 mL) at room temperature for 4 h under
[a] Reaction conditions: 1a (0.2 mmol), 2a (2 equiv.) and [O]
(2 equiv.) at room temperature for 4 h under argon atmosphere. [b] argon atmosphere. Average isolated yield in two runs. PINO =
At 50 °C. [c] 1a (1 g) for 24 h. PINO = phthalimide N-oxyl. phthalimide N-oxyl.
2
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Oxygenation of Benzylic C–H Bonds at Room Temperature
PhI(OAc)2, albeit giving a low yield. Unfortunately, two 17). Notably, the optimal conditions were also successful
analogues with an N-Me or free NH2 group had no reacti- with N-hydroxysuccinimide (NHS, 2b): the reaction of 2-
vity (Table 2, products 10 and 11).
methyl-N-(perfluorophenyl)benzamide or 2-ethyl-N-(per-
We next set out to investigate the scope of the benzylic fluorophenyl)benzamide with NHS (2b) offered the corre-
C(sp3)–H oxidation protocol (Table 3). Initially, a variety of sponding products 18 and 19 in good yields.
2-alkyl-N-(polyfluorophenyl)benzamides were examined in
2-Hydroxyacetamides are important units that are found
the presence of NHPI 2a and PhI(OAc)2 (Table 3, products in many natural products and pharmaceuticals.[8] Conse-
12–17). The results demonstrated that they were viable for quently, the optimal conditions were applied in the cross
the reaction, and several groups, such as I, Cl, F, and CF3, coupling of acetamides 1 with NHPI 2a (Table 3, products
on the aryl ring of the benzamide moiety were well 20–31).[9] Although treatment of N,2-diphenylacetamide
tolerated. For example, 2-methyl-N-(perfluorophenyl)-1- with NHPI 2a and PhI(OAc)2 afforded product 20 in low
naphthamide underwent the reaction with NHPI 2a and yield, substrates with an N-polyfluorophenyl group offered
PhI(OAc)2 to afford product 12 in 57% yield. Benzamide the corresponding products 21–24 in good yields. However,
with an o-iodo group gave the expected iodo-containing N-(perfluorophenyl)propionamide was not a suitable sub-
product 13 in 83% yield. By using 2-ethyl-N-(polyfluoro- strate for the reaction (Table 3, product 25). Screening re-
phenyl)-benzamide, a good yield was still achieved (product vealed that the optimal conditions were compatible with
various substituents, including MeO, Cl, I, and CF3, on the
aromatic ring of the 2-phenylacetamide moiety (Table 3,
products 26–31). For example, substrates with a methoxy
group at the para, meta, or ortho position could react with
NHPI 2a and PhI(OAc)2 leading to the corresponding
products 26, 29, and 30 in good yields. Importantly, substi-
tuents, Cl and I, were successful under the optimal condi-
tions, thereby enabling further functionalization at the
halogenated positions (Table 3, products 27 and 31).
As illustrated in Scheme 2, the obtained phthalimide N-
oxyl (PINO) adduct 3 was applied to the synthesis of some
heterocycles.[5,10] In the presence of Cu(OAc)2, NBS (N-
bromosuccinimide), and PhI(OAc)2, adduct 3 was trans-
formed into 3-hydroxy-2-(perfluorophenyl)-isoindolin-1-
one (32) in 58% yield by formation of a new C(sp3)–N bond
and removal of the 1,3-dioxoisoindoline group. Gratify-
ingly, adduct 3 could be used for the construction of iso-
benzofuran-1(3H)-one 33 by using 1 equiv. Mo(CO)6 com-
bined with 15 equiv. Et3N.
Table 3. Oxidative coupling of benzylic C(sp3)–H bonds (1) with
N-hydroxyamides (2).[a]
Scheme 2. Utilization of the obtained PINO adduct 3.
As noted above, addition of a stoichiometric amount of
a radical inhibitor, including TEMPO, hydroquinone, and
BHT, completely suppressed the reaction, which implied
that the reaction proceeds through a radical process.
Consequently, a plausible mechanism, as outlined in
Scheme 3, is proposed.[2–6] Initially, PINO radical interme-
diate A is generated with the aid of PhI(OAc) (Path I).[5,6]
Subsequently, PINO radical intermediate A reacts with
benzamide 1a to afford the alkyl radical intermediate B.
Finally, reaction between PINO radical intermediate A and
intermediate B occurs leading to the desired product 3. A
similar process takes place for the reaction of alkyl amide
substrates (Path II).
[a] Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), PhI(OAc)2
(2 equiv.) and CH2Cl2 (2 mL) at room temperature for 4 h under
argon atmosphere. Average isolated yield in two runs. PINO =
phthalimide N-oxyl.
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Y. Liu, J.-N. Xiang, J.-H. Li et al.
SHORT COMMUNICATION
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[2]
Scheme 3. Possible mechanism.
Conclusions
In summary, we have illustrated a general, room tem-
perature route to form C(sp3)–O bonds by metal-free
PhI(OAc)2-mediated oxidative cross-coupling of benzylic
C(sp3)–H bonds with N-hydroxyamides. This reaction
enables a broad scope of benzamides and 2-arylacetamides
to perform the benzylic C–H oxygenation. Importantly, the
products can be used for the construction of heterocycles.
Applications of this oxygenation transformation in organic
synthesis are currently underway in our laboratory.
Experimental Section
Typical Experimental Procedure: 2-Methyl-N-(perfluorophenyl)-
benzamide (1a; 0.2 mmol), 2-hydroxyisoindoline-1,3-dione (2a;
0.4 mmol), PhI(OAc)2 (0.4 mmol), and CH2Cl2 (2 mL) were added
to a Schlenk tube. Then the tube was charged with argon, and the
reaction was stirred at room temperature for the indicated time
until complete consumption of the starting material as monitored
by TLC and GC–MS analysis. After the reaction was finished, the
reaction was diluted with diethyl ether and concentrated in vacuo.
The resulting residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate) to afford the desired product.
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Acknowledgments
This research was supported by the National Natural Science
Foundation of China (NSFC) (Nos. 21402046, 21172060 and
21472039) and Hunan Provincial Natural Science Foundation of
China (No. 13JJ2018). Dr. R.-J. S. also thanks the Fundamental
Research Funds for the Central Universities.
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Published Online: ᭿
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Job/Unit: O43616
/KAP1
Date: 04-02-15 13:28:43
Pages: 6
Y. Liu, J.-N. Xiang, J.-H. Li et al.
SHORT COMMUNICATION
C–H Oxidation
P.-C. Qian, Y. Liu,* R.-J. Song, M. Hu,
X.-H. Yang, J.-N. Xiang,*
J.-H. Li* ........................................... 1–6
(Diacetoxyiodo)benzene-Mediated
Oxy-
genation of Benzylic C(sp3)–H Bonds with
N-Hydroxyamides at Room Temperature
Keywords: Oxidation / N-Hydroxyamides /
Cross-coupling / Acetamides / Synthetic
methods
A metal-free, room temperature route to
construct C(sp3)–O bonds is described by
facilitated by an electron-withdrawing
amide group, and provides a transition-
metal-free room temperature alternative for
the formation of C(sp3)–O bonds with
highly functional group compatibility.
PhI(OAc)2-mediated oxygenation of
a
benzylic C(sp3)–H bond with the O–H
bond in N-hydroxyamides. This method is
6
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Eur. J. Org. Chem. 0000, 0–0