Tuning chemoselectivity in: O -/ N -arylation of 3-aryl-1,2,4-oxadiazolones with ortho -(trimethylsilyl)phenyl triflates via aryne insertion

Article abstract of DOI:10.1039/c8cc00124c

Herein, we first describe finely tunable chemoselectivity in arylation of 3-aryl-1,2,4-oxadiazolones with ortho-(trimethylsilyl)phenyl triflates, including O-arylation enabled by catalytic amount of silver nitrate and metal-free N-arylation. Both the arylation reactions can tolerate a series of functional groups, and afford the corresponding products in moderate to good yields.

Full text of DOI:10.1039/c8cc00124c

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Tuning chemoselectivity in O-/N-arylation
of 3-aryl-1,2,4-oxadiazolones with ortho-
Cite this:DOI: 10.1039/c8cc00124c
(trimethylsilyl)phenyl triflates via aryne insertion†
Received 6th January 2018,
Accepted 10th April 2018
Lijing Zhou,a Hongji Li, *a Wenge Zhanga and Lei Wang
*
ab
DOI: 10.1039/c8cc00124c
rsc.li/chemcomm
Herein, we first describe finely tunable chemoselectivity in arylation
of 3-aryl-1,2,4-oxadiazolones with ortho-(trimethylsilyl)phenyl tri-
flates, including O-arylation enabled by catalytic amount of silver
nitrate and metal-free N-arylation. Both the arylation reactions can
tolerate a series of functional groups, and afford the corresponding
products in moderate to good yields.
Over the past few decades, aryne chemistry has been an ideal
strategy for decorating arenes, building heterocycles and assem-
bling natural product scaffold.1 This is mainly due to the fact that
arynes generated in situ possess an inherent electrophilic nature.2
Several representative routes for obtaining active arynes have been
developed in recent years,3 but most of them generally necessitate
the assistance of strong bases, low temperatures, or stoichio-
Scheme 1 Process of typical aryne insertion.
metric amounts of toxic metal salts, which extremely hamper (N-arylation), yielding aryl amines (Scheme 1b). Further,
the practical application of aryne chemistry. Fortunately, the use Biju et al. established a rare temperature-dependent reaction
of ortho-(trimethylsilyl)phenyl triflates for efficient aryne genera- of arynes with aliphatic alcohols, affording a series of alkylaryl
tion was reported by Kobayashi et al. in 1983, which successfully ethers via aryne insertion and multicomponent coupling.6d
gained much attention due to the mild conditions and convenient Despite a variety of elegant studies on aryne chemistry, tuning
handling processes.4 Following this, a large number of organic chemoselectivity remains a challenging task and the expansion
reactions involving arynes, including cyclization reactions,5 multi- of the selective aryne insertion for preparing potentially valu-
component reactions,1d,6 and aryne insertion reactions,7 and able chemicals is still worth exploring.
some others8 were successively reported. Particularly, aryne inser-
Moreover, 3-aryl-1,2,4-oxadiazolones serving as coupling partners
tion has achieved significant progress in recent years.7–9 The have received less attention in past years.10 Interestingly, Zhu et al.
classic aryne insertion is achieved by addition of a nucleophile recently reported the useful application of oxadiazolone for building
to benzyne, which leads to the formation of a carbanion that can up primary aza-aromatic amines under cobalt catalysis.10b Wan
be trapped by an electrophile (Scheme 1a). As a typical example, et al. disclosed the formal [3+2] cycloaddition of 3-aryl-1,2,4-
Larock et al. developed a metal-free approach for the synthesis oxadiazolones with ynamides, which provided efficient access to
of biraryl ethers (O-arylation) by aryne insertion.7a,b Moreover, aminoimidazoles.10c However, 3-aryl-1,2,4-oxadiazolones acting
it was found that amides were also amenable to aryne insertion as valuable coupling reagents are still far from being fully
explored in organic synthesis.10 Moreover, we note that oxadia-
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
P. R. China. E-mail: hongjili@chnu.edu.cn, leiwang@chnu.edu.cn;
Fax: +86-561-309-0518; Tel: +86-561-380-2069
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, Shanghai 200032, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1813383. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc00124c
zolone itself contains an active N–H bond, which shows similar
activity to the N–H bonds existing in common amides. In
addition, isomerization from N–H to O–H (coming from CQO)
within oxadiazolone is permissible even though this process is
unfavourable under normal conditions (Scheme 1c).11 Based on
these understandings, we conceived that oxadiazolones might
act as an N-containing nucleophiles that trap transient benzynes
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(N-arylation). In some cases, the isomerization was favoured the O-arylation of 1a with 2a, respectively, under similar reaction
under definite conditions, generating the nucleophilic oxygen conditions, (entries 10–13). Furthermore, performing O-arylation
anion species, which could lead to a totally different result under nitrogenatmosphere gave almost the same result when
(O-arylation). Herein, we will first report our investigation into compared with that observed result in ambient air (entry 14). The
the O-arylation and N-arylation of 3-aryl-1,2,4-oxadiazolones by effect of temperature on this arylation process was analysed,
finely tuneable aryne insertion.
which indicated that no reaction occurred at room temperature,
At the outset, O-arylation of 3-phenyl-1,2,4-oxadiazol-5(4H)-one and a reasonable isolated yield of 3a was obtained at a tempera-
(1a) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) ture of 80 1C (Table S1 in ESI†). Solvent screening demonstrated
was chosen as a model reaction to optimize the reaction condi- that CH3CN is the ideal medium for O-arylation of 1a with 2a
tions, as listed in Table 1. According to the previous study, we (Table S1 in ESI†). Finally, formation of 3a was not observed in the
know that the fluoride source, temperature and reaction medium absence of silver nitrate, but the N-arylated product 4a was
have a profound effect on the generation of aryne species from isolated in 67% yield (entry 15).
ortho-(trimethylsilyl)phenyl triflates.1b Therefore, the combination
Next, the generality of O-arylation was studied by employing
of CH3CN/CsF was preferentially adopted for the potential aryla- optimized reaction conditions, and the result is summarized in
tion of 1a with 2a in the presence of Ag2O (CH3CN was simply Table 2. First, a range of 3-aryl-1,2,4-oxadiazolones were prepared
distilled prior to use). Fortunately, the reaction proceeded at 80 1C and then utilized for O-arylation. The result indicated that the
under air ambient for 6 h and generated 3a in 15% yield (entry 1). 3-aryl-1,2,4-oxadiazolones bearing an electron-rich group at
Furthermore, the structure of 3a was confirmed by single-crystal 4-position on the phenyl ring, such as Me, t-Bu, and MeO,
X-ray diffraction analysis.12 Then, it was found that Ag2CO3, silver afforded arylated products 3b–d in good to excellent yields. This
trifluoromethanesulfonate (AgOTf) or AgSbF6 did not improve the O-arylation is slightly sensitive to the electronic effect that
O-arylation process of 1a (entries 2–4). The use of silver acetate resulted from the substituents. Both F and Cl incorporated into
(AgOAc) afforded the arylated product 3a in slightly high isolated the phenyl ring led to decreased yields of 3e and 3f, respectively.
yield (entry 5). We observed that the addition of AgNO3 provided Replacing the halogens with strong electron-withdrawing groups
the highest yield of 3a among all the tested silver sources (entry 6). such as CF3, NO2, and COOMe only produced the arylated
No desired 3a was detected in the absence of CsF, illustrating that products in acceptable yields (3g–i). Introduction of meta sub-
the fluoride anion is key to the cleavage of C–Si bond of 2a (entry stituents into the phenyl ring has a weak effect on O-arylation
7). Several representative F-containing reagents such as KF and (3j–l). However, steric hindrance clearly hampered this process
tetrabutylammonium fluoride (TBAF), also serving as weak base, as indicated by the yield obtained through the O-arylation of
were sequentially evaluated in the model reaction. However, both 3-aryl-1,2,4-oxadiazolones containing an ortho-methoxyl group
afforded 3a in decreased yields (entries 8 and 9). Additionally, we on the phenyl ring (3d vs. 3m). Furthermore, the commonly
found that the amounts of CsF and AgNO3 have a large effect on
Table 2 Scope of 3-aryl-1,2,4-oxadiazolones and ortho-(trimethylsilyl)-
phenyl triflatesa
Table 1 Optimization of the reaction conditionsa
Yieldb (%)
Fluoride
Entry
[Ag]
source
3a
4a
1
2
3
4
5
6
7
8
Ag2O
CsF
CsF
CsF
CsF
CsF
CsF
—
15
27
34
41
56
89
n.r.
28
—
—
—
—
—
—
—
—
—
—
—
—
—
—
67
Ag2CO3
AgOTf
AgSbF6
AgOAc
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
—
KF
9
TBAF
CsF
CsF
CsF
CsF
CsF
CsF
43
10
11
12
13
14
15
73c
90d
63e
88f
89g
—
a
Reaction conditions: 1a (0.20 mmol), 2a (0.4 mmol), [Ag] (5 mol%) and
fluoride source (0.50 mmol) were added to CH3CN (2 mL) at 80 1C in
a
Reaction conditions: 1 (0.20 mmol), 2 (0.40 mmol), AgNO3 (5 mol%),
b
ambient air for 6 h. b Isolated yield. CsF (0.40 mmol). d CsF (0.60 mmol).
c
and CsF (0.50 mmol) at 80 1C under air ambient for 6 h. Isolated yield.
c
e AgNO3 (3 mol%). AgNO3 (10 mol%). g N2 atmosphere. n.r. = no reaction.
f
X-ray structure of 3a.
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used conjugated groups including 1,10-biphenyl and naphthyl
groups were found to be less active than the former groups, but
they still led to the formation of the desired products in good
yields (3n–p). At last, we obtained satisfactory results from
O-arylation of furanyl- or thiophenyl-substituted oxadiazolone
with 2a under optimal reaction conditions (3q and 3r).
We next focused on expanding the scope of ortho-(trimethyl-
silyl)phenyl triflates. Some typical aryne precursors 2 were
prepared and used for O-arylation of 1a under optimal conditions
(Table 2). Notably, the substituted groups or atoms on the phenyl
ring did not affect the insertion process. Most of the symmetric
substituted aryne precursors are well compatible with the O-arylation
protocol, leading to the synthesis of target products in good yields
(3s–w). It was also observed that O-arylation of an asymmetric aryne
precursor with 1a smoothly proceeded under the above condition,
but gave poor selectivity (3x–z, 3x0–z0), which indicated that the
bulkiness and electron effect of the methyl group did not affect the
aryne insertion. However, the reaction of indolyne with 1a afforded
the product with enhanced selectivity (3ab :3ab0 = 3:1).
Scheme 2 Control experiments and gram-scale synthesis of 3a.
precedent to the tuneable reaction. Subsequently, several experi-
ments were conducted to gain insight into the effect of Ag(I) on
the two different arylations. As illustrated in Table S2 (ESI†),
complete N-arylation was observed in the absence of Ag(I). Clearly,
the use of 1 mol% AgNO3 would make the reaction of 1a with 2a
to absolutely proceed toward O-arylation, and completely suppress
the N-arylation. Then, 4a was specially treated under the above
conditions, and no 3a was detected, indicating that phenyl group
transfer would not happen (Scheme 2, eqn (1)). Again, the result
indicated that only 1a, containing a N–H unit, could react with
benzyne in the presence or absence of AgNO3 to produce the
corresponding arylated products. Moreover, we found that
the gram-scale synthesis of 3a is very successful through the
O-aylation of 1a with 2a, which provides an efficient approach
to synthesize 1,2,4-oxadiazole (Scheme 2, eqn (2)).
Inspired by the findings reported by Larock et al.,7a,b we
considered that the 3-aryl-1,2,4-oxadiazolones containing an active
N–H bond could also serve as nucleophiles and attack the fleeting
aryne intermediates to complete the N-arylation process (Table 3).
Unfortunately, this metal-free N-arylation did not proceed at
room temperature, demonstrating that 3-aryl-1,2,4-oxadiazolones
were not active enough for the N-arylation reaction. Therefore, we
next explored the model N-arylation process of 1a with 2a (Table S2
in ESI†), and the optimized conditions were as follows: 1a
(0.20 mmol), 2a (0.40 mmol), and CsF (2.5 equiv.), in CH3CN at
80 1C for 10 h. It was found that a number of 3-aryl-1,2,4-
oxadiazolones could react with symmetric arynes 2 under the
optimal conditions, affording the N-arylated products in good to
excellent yields (4a–l, Table 3). For the asymmetric arynes, poor
selectivity was observed in the N-arylations (4m–n, 4m0–n0). In fact,
the obtained N-arylated products 4 can also be harnessed for the
synthesis of amidines.13
For better understanding the O-arylation process, the density
functional theory (DFT) calculation was carried out to investigate
the role of Ag(I), as shown in Fig. 1,14 which also helped us to
shed light on the mechanism proposed in Scheme 3. Initially,
the use of excess CsF led to the formation of benzyne inter-
mediates. We then envisioned that a possible isomerization of 1a
into 1a-OH assisted by Ag(I) was the key step for O-arylation
(Scheme 3, path A). However, the results from the DFT calcula-
tions (Fig. 1a) indicated that at least 59.53 kcal molꢀ1 of free
energy barrier is necessary for the proton transfer from N to O
within 1a. Adversely, the addition of Ag(I) into the system would
require much higher free energy barrier (up to 87.42 kcal molꢀ1
)
Furthermore, we were still curious about the role of AgNO3
in the unique O-arylation of 3-aryl-1,2,4-oxadiazolones with
ortho-(trimethylsilyl)phenyl triflates because there was no
for the same isomerization, presumably because Ag(I) decreases
the electron density of the carbonyl group in 1a. This result
demonstrated that the proposal for the isomerization of 1a
assisted by Ag(I) is extremely unreasonable. Subsequently, a
stepwise mechanism for the O-arylation process was proposed
(Scheme 3, path B). We assumed that the interaction of 1a with
Ag(I) by weak coordination generated unstable complexes,15
Table
3
Investigation into the N-arylation reaction of 3-aryl-1,2,4-
oxadiazolonesa
a
Fig. 1 (a) Free energy profile of 1a isomerization with and without Ag(I).
(b) Free energy profile of the O-arylation pathway with Ag(I).
Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), and CsF
b
(0.50 mmol) at 80 1C under air ambient for 10 h. Isolated yield.
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electronically negative species I, which then directly attacked
benzyne to form the N-arylated product 4a.
In summary, we first reported the highly chemoselective
arylation of 3-aryl-1,2,4-oxadiazolones with ortho-(trimethyl-
silyl)phenyl triflates under air ambient. In the arylation-oriented
systems, the catalytic activity of silver nitrate plays an important
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of disubstituted 1,2,4-oxadiazole in moderate to good yields. In
contrast, only N-arylated oxadiazolone was observed in the absence
of silver nitrate. Further efforts to achieve a valuable transformation
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This study was financially supported by the National Science
Foundation of China (21572078, 21772061, 21772062), and the
Natural Science Foundation of Anhui Province (1708085QB28).
Particularly, we thank Dr Fang Ma at Huaibei Normal Univer-
sity for his kind assistance with DFT calculation.
Conflicts of interest
11 For the silver-assisted isomerization of amide, see: E. C. Franklin,
J. Am. Chem. Soc., 1915, 37, 2279.
12 The crystallographic data for the structure of 3a reported in this
paper have been deposited with the Cambridge Crystallographic
Data Centre (CCDC 1813383)†.
There are no conflicts to declare.
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Notes and references
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with 2a, which can be observed by the according 1H NMR experi-
ment, see details in ESI†.
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