Transition-Metal-Free Synthesis of N-Aryl Hydroxamic Acids via Insertion of Arynes

Article abstract of DOI:10.1021/acs.joc.6b00111

An efficient and transition-metal-free N-arylation of amides via the insertion of arynes into the N-H bonds in the N-alkoxy amides is described. A variety of the reactive functional groups including the reactive aldehyde carbonyl group, furan ring, carbon-carbon double bonds, and free N-H bond of indole are found to be compatible with this process. In particular, the protocol is applicable in the synthesis of structurally diverse N-aryl hydroxamates and hydroxamic acids derived from N-protecting amino acids and peptides. In the presence of multiple amide N-H bonds, the N-arylation reaction can proceed selectively in the N-H bonds of terminal N-OBn amides giving rise to the desired N-aryl hydroxamates.

Full text of DOI:10.1021/acs.joc.6b00111

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Article
Transition Metal-Free Synthesis of N-Aryl
Hydroxamic Acids via Insertion of Arynes
Lanlan Zhang, Yu Geng, and Zhong Jin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00111 • Publication Date (Web): 08 Apr 2016
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Transition Metal-Free Synthesis of N-Aryl Hydroxamic Acids via Insertion of Arynes
Lanlan Zhang,‡ Yu Geng,‡ Zhong Jin*
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State Key Laboratory of Elementoorganic Chemistry, Nankai University, Tianjin 300071, China
Eꢀmail: zjin@nankai.edu.cn
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TOC Graphic
Abstract: An efficient and transition metalꢀfree Nꢀarylation of amides via the insertion of arynes
into the N–H bonds in the Nꢀalkoxy amides is described. A variety of the reactive functional
groups including reactive aldehyde carbonyl group, furan ring, carbonꢀcarbon double bonds, and
free N–H bond of indole are found to be compatible with this process. In particular, the protocol is
applicable in the synthesis of structurally diverse Nꢀaryl hydroxamates and hydroxamic acids
derived from Nꢀprotecting amino acids and peptides. In the presence of multiple amide N–H
bonds, the Nꢀarylation reaction can proceed selectively in the N–H bonds of terminal NꢀOBn
amides giving rise to the desired Nꢀaryl hydroxamates.
Introduction
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Hydroxamic acid moiety (Scheme 1, general formula as –CON(R)OH) are widely spread in
naturally occurring secondary metabolites, such as microbial hydroxamate siderophores produced
by various bacteria and fungi.1 They are known as the excellent metalꢀchelating agents and
evolved in microbes to function as ingesting iron and other important metals for metabolism from
the scarcely natural bioavailability. In addition, they are also associated with other biological
properties.2 The biological significance of hydroxamic acids is further illustrated by the increasing
numbers of clinical drugs, for example, Kelatorphan (endogenous enkephalinase inhibitor),
Panobinostat, Vorinostat, Belinostat (histone deacetylase inhibitors, HDAC inhibitors). These
chemotherapeutical agents with hydroxamic acid as the key pharmacophore effect in vitro and in
vivo through either binding directly to the active sites of enzymes or acting as a chelator for the
metal ions to regulate the activity of intracellular metalꢀassociated proteins.3
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Scheme 1. The Structures of Hydroxamic Acids
To date, a large number of methods have been developed for synthesis of hydroxamic acids
starting from carboxylic acids or their derivatives.4 These methods involve overwhelmingly
reactions of activated forms of carboxylic acids with Oꢀbenzyl hydroxylamine to produce OꢀBn
hydroxamates, the key precursor of free hydroxamic acids. Some of these methods proved quite
efficient for the preparation of Nꢀalkyl substituted hydroxamic acids, while the preparation of
Nꢀaryl substituted hydroxamates, especially for amino acid and peptide substrates, still remains
unexplored. This can be, to a large extent, attributed to the difficult accessibility of Nꢀaryl
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hydroxylamines. Recently, Nꢀaryl hydroxamates have received more and more interest from
pharmacy and biochemistry communities due to their unusual monoꢀanionic character and
relatively lipophilic property (Scheme 1).5 In 2001, Ursic and coꢀworkers reported an approach to
Nꢀpꢀchlorophenyl hydroxamic acids by reacting of acyl chlorides with nitrosobenzene in the
presence of catalytic amounts of HCl, possibly involving an addition acylnitroso intermediate
which underwent to nucleophilic attack by chloride ion at the paraꢀposition of the phenyl ring.6
Unfortunately, there are obvious limitations in this method and only paraꢀchloride hydroxamic
acids can be obtained. Recently, several valuable transition metalꢀcatalyzed (Cu, Pd) Nꢀarylation
methods have been developed for synthesis of Nꢀaryl hydroxamate derivatives.7,8 Despite these
significant recent improvements, there still are limitations in present transition metalꢀcatalyzed
Nꢀarylation strategies for hydroxamic acid substrates. For example, most reactions are performed
under fairly harsh conditions, usually require elevated temperature (> 80 oC) as well as the use of
strong base and polar solvents, which makes these methods not suitable for baseꢀ and
acidꢀsensitive substrates, such as amino acids and peptides. Considering the importance of
synthesis and functionalization of hydroxamic acids, development of mild methods for the
preparation of Nꢀarylated hydroxamic acids is of great importance. We herein wish to report a
practical and efficient method for synthesis of Nꢀaryl hydroxamic acids by the insertion of arynes
into the N–H bond of amides under mild conditions (Scheme 2, (d)).
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Scheme 2. N-Arylation via Insertion of Arynes into the N–H Bonds
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As the highly reactive intermediates, arynes have been used as the versatile synthons and
widely applied in organic synthesis.9 The highly electrophilic character of arynes enables them to
react with extensive nucleophiles, under mild and transition metalꢀfree conditions, leading to the
formation of carbon–carbon and carbon–heteroatom bonds.10 In particular, Larock,11 Garg,12
Greaney,13 Singh,14 Wang,15 Hosoya,16 Yao,17 and others18 disclosed that the N–H σꢀbonds in
amines, sulfonamides, amidines, Nꢀaryl trifluoroacetamides and trifluoromethylsulfinamides,
sulfoximines, sulfilimines, Nꢀaryl cyanamides, and Nꢀaryl phosphorylamides enable direct
addition across the highly strained carbon–carbon triple bonds of arynes to provide the related
Nꢀarylation products under transitionꢀmetalꢀfree conditions (Scheme 2, (a), (b) and (c)). However,
to the best of our knowledge, the insertion of arynes into the N–H bonds in the common primary
or Nꢀalkyl amides proved unsuccessful to date.9c,11 Based on the abovementioned background, we
decide to investigate whether the Nꢀacyoxyl and ꢀalkoxyl amides, even the free hydroxamic acids,
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can serve as the effective substrates to produce the desired Nꢀaryl hydroxamate derivatives
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through insertion of arynes into the N–H bond of amides under mild conditions.
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Results and Discussion
At the outset, given the electronꢀwithdrawing property of the hydroxyl group, we envisioned
that the presence of the free OH group in the hydroxamic acids enable Nꢀarylation process via the
direct insertion of arynes into the N–H bonds of amides under transition metalꢀfree conditions.
Much to our disappointment, like the primary amides, insertion of benzyne into the
Nꢀhydroxybenzamide failed to give the desired Nꢀphenyl hydroxamic acid, and an undesired
insertion of benzyne into the N–O bond resulting in αꢀaminophenols is observed (Scheme 3).19
Scheme 3. Preliminary Study on N-Arylation of Hydroxamic Acid
Therefore, various readily removable Oꢀacyl and ꢀalkyl groups are incorporated further and the
resulting hydroxamates subjected to insertion reactions of benzyne 1a (Scheme 4). Gratifyingly,
reactions of Oꢀacyl hydroxamates with benzyne precursor 1a with KF as a [Fꢀ] source affords the
corresponding Nꢀphenyl products, albeit in poor yields, whereas reactions of benzyne with Oꢀalkyl
hydroxamates deliver the target Nꢀphenyl products in increasing yields. Amongst them, insertion
of benzyne into the N–H bond in Oꢀbenzyl hydroxamate gives the highest yield (64 %).
Scheme 4. O-Substituent Effect of Hydroxamates on Insertion of Benzynea,b
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aReaction conditions: hydroxamamate (0.1 mmol), 1a (0.12 mmol, 1.2 equiv), KF (0.2 mmol, 2.0
equiv), THF (2 mL), rt, 10 h. bIsolated yield. Pic, 2ꢀpicolinoyl.
Subsequently, using benzyne precursor 1a and Oꢀbenzyl hydroxamte 2a as the model substrates,
extensive reaction parameters such as fluoride source, solvent, additive are screened for the
optimal conditions (Table 1). Among the alkali metal fluorides screened, cesium fluoride shows
the highest reactivity (Table 1, entry 4). TBAF20 and TBAT13a,21 are also effective for this reaction
albeit in lower yields (Table 1, entries 5 and 6). In addition, a combination of KF/18ꢀcrownꢀ622
gives the slightly higher yield related to that of KF (Table 1, entry 7). It is found that the presence
of molecular sieves does not furnish an improved yield in this reaction (Table 1, entry 8). Notably,
the solvent is shown to play a crucial role in the Nꢀarylation process. Acetonitrile proves to be the
choice of solvent. With CsF as the base, reactions performed in the lowꢀpolarity solvents such as
toluene and dichloromethane only supply the trace amount of products (Table 1, entries 9 and 10),
while almost quantitative yield is achieved when insertion reaction is performed in the acetonitrile
(Table 1, entry 13).
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Table 1. Optimization for Insertion of Arynea,b
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entry [Fꢀ] source additive
solvent
yield
(%)
1
LiF
–
–
–
–
–
–
THF
THF
THF
THF
THF
THF
44
2
NaF
KF
56
3
64
4
CsF
TBAF
TBAT
KF
78
5
37
6
63
7
18ꢀcrownꢀ6 THF
67
8
CsF
CsF
CsF
CsF
CsF
CsF
4Å M.S.
THF
75
9
–
–
–
–
–
toluene
DCM
DME
trace
trace
65
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12
13
1,4ꢀdioxane 59
CH3CN
99
aReaction conditions: Oꢀbenzyl hydroxamate 2a (0.1 mmol), 2ꢀ(trimethylsilyl)phenyl
trifluoromethanesulfonate 1a (0.12 mmol, 1.2 equiv), [F–] source (0.2 mmol, 2.0 equiv), additive
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b
(2.0 equiv, for 4Å molecular sieves, 100 mg), solvent (2 mL), rt, 20 h. Isolated yield. M.S.,
molecular sieves. TBAF, tetrabutylammonium fluoride. TBAT, tetrabutylammonium
difluorotriphenylsilicate.
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With the optimized reaction condition in hand, a variety of Oꢀbenzyl hydroxamates are thus
prepared and subjected to the Nꢀarylation reaction with benzyne precursor 1a. As exemplified in
Table 2, both electronꢀdonating and electronꢀwithdrawing groups in the phenyl rings are
compatible with this insertion reaction. Commonly, aromatic hydroxamates 2e and 2k–m
incorporating the electronꢀwithdrawing groups give rise to the declined yields (Table 2, entries 5,
11–13). Notably, the carbonyl group in the aromatic aldehyde and furan ring, which are prone to
undergo a [2+2]23 and [4+2]24 cycloaddition reactions with benzyne, are tolerant in the insertion
process (Table 2, entries 12 and 15). The free N–H bonds in the indole rings also survives in such
Nꢀarylation of amides (Table 2, entries 17 and 19). In addition, Oꢀbenzyl hydroxamates 2t–2x
derived from α,βꢀunsaturated carboxylic acids and aliphatic carboxylic acids all prove to be
suitable substrates for this transformation (Table 2, entries 20–24).
Table 2. N-Arylation of O-Benzyl Hydroxamates with Benzynea,b
entry Oꢀbenzyl hydroxamate product
yield (%)
99
1
2a
3a
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2b
2c
2d
2e
2f
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3c
3d
3e
3f
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4
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2g
2h
2i
3g
3h
3i
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2j
3j
2k
2l
3k
3l
2m
2n
3m
3n
O
OBn
N
Ph
Fe
15
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3o
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16
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89
85
91
2p
2q
2r
3p
3q
3r
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19
89
2s
3s
20
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23
24
89
91
88
83
75
2t
3t
2u
2v
2w
2x
3u
3v
3w
3x
aReaction conditions: Oꢀbenzyl hydroxamamate (0.5 mmol), 1a (0.6 mmol, 1.2 equiv), CsF (1.2
mmol, 2.4 equiv), CH3CN (2 mL), rt, 10 h. bIsolated yield.
Next, the reactivity of various arynes in the Nꢀarylation of Oꢀbenzyl hydroxamtes is examined
(Table 3). For unsymmetrical 3ꢀmethoxy benzyne and 1,2ꢀnaphthylꢀbased aryne, only single
regioisomer 4a/4b are obtained in 72 % and 87 % yields (Table 3, entries 1 and 2), respectively. In
contrast, almost equivalent amount of paraꢀ/metaꢀregioisomers are produced when unsymmetrical
4ꢀmethoxy and 4ꢀmethyl benzynes are used (Table 3, entries 4 and 5). Further, symmetrical and
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electronꢀdeficient 3,4ꢀdifluorobenzyne also affords the Nꢀaryl hydroxamate in a reasonable yield
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(Table 3, entry 3).
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Table 3. N-Arylation of O-Benzyl Hydroxamates with Various Arynesa,b
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entry Oꢀbenzyl hydroxamate silylaryl triflate
product
yield (%)
72
1
2
3
4
5
2a
2a
2a
2g
2g
1b
4a
87
1c
4b
50
1d
4c
67c
91d
1e
4d
4e
1f
aReaction conditions: Oꢀbenzyl hydroxamamate 2 (0.5 mmol), aryne precursor 1b–f (0.6 mmol,
1.2 equiv), CsF (1.2 mmol, 2.4 equiv), CH3CN (2 mL), rt, 20 h. bIsolated yield. cThe products are
isolated as a mixture of paraꢀ and metaꢀisomers (1 : 1) based on 1H NMR analysis. dThe products
are isolated as a mixture of paraꢀ and metaꢀisomers (1.1 : 1) based on 1H NMR analysis.
In view of the predominant biological potential of hydroxamaic acids derived from amino acids
and peptides, we also envisioned that, in the presence of multiple amide N–H bonds, the
Nꢀarylation reaction can proceed selectively in the N–H bonds of terminal NꢀOBn amides to give
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rise to the desired Nꢀaryl hydroxamates. Therefore, a variety of Oꢀbenzyl hydroxamates derived
from Nꢀprotected amino acids are allowed to react with the aryne precursors in the presence of
CsF (Table 4). Encouragingly, all hydroxamates prepared from NꢀAc Phe, NꢀCbz Phe, NꢀBoc Val,
and NꢀBoc tertꢀIle are arylated exclusively in the N–H bonds of NꢀOBn amides in good yields
(Table 4, entries 1, 2, 4 and 5). It is noteworthy that pꢀtoluenesulfonamide, which is known to
undergo Nꢀarylation with silylaryl triflate,11a,c is tolerant under the reaction conditions (Table 4,
entry 3). NꢀArylation proceeds cleanly in the N–H bond of NꢀOBn amide.25 When 4ꢀmethoxyꢀ or
4ꢀmethylꢀsubstituted aryne precursor is employed with hydroxamate from NꢀBoc Phe,
paraꢀ/metaꢀisomers were obtained in almost equal amounts (Table 4, entries 6 and 7). Meanwhile,
ratios of paraꢀ/metaꢀisomers for NꢀBoc tertꢀIle are 3.5 : 1 and 6 : 1, respectively (Table 4, entries 8
and 9). In a similar manner to the common aromatic hydroxamates, Nꢀarylation of hydroxamate
derived from NꢀBoc Phe with 3ꢀmethoxy, 3,4ꢀdifluoro, and 1,2ꢀnaphthylꢀbased arynes cleanly
generates a single regioisomer (Table 4, entries 10–12).
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Table 4. N-Arylation of O-Benzyl Hydroxamates Derived from N-Protected Amino Acidsa,b
entry Oꢀbenzyl hydroxamate silylaryl triflate product
yield (%)
81
1
2
3
1a
1a
1a
5a
6a
85
83
5b
6b
5c
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1a
4
5
6
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5d
5e
5f
5f
5e
5e
5f
5f
5f
6d
5
86
1a
9
6e
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6
90c
82c
53d
61e
35
1e
6f
7
1f
6g
8
1e
1f
6h
9
6i
10
11
12
1d
1b
1c
6j
68
6k
61
6l
aReaction conditions: Oꢀbenzyl hydroxamamate (0.5 mmol), aryne precursor (0.6 mmol, 1.2
b
c
equiv), CsF (1.2 mmol, 2.4 equiv), CH3CN (2 mL), rt, 20 h. Isolated yield. The products are
isolated as a mixture of paraꢀ and metaꢀisomers (1 : 1) based on 1H NMR analysis. dThe products
1
e
are isolated as a mixture of paraꢀ and metaꢀisomers (3.5 : 1) based on H NMR analysis. The
products are isolated as a mixture of paraꢀ and metaꢀisomers (6 : 1) based on 1H NMR analysis.
To shed some light on the reaction pathway, the control experiment with CD3CN as solvent is
performed to check for any proton incorporation from the solvent. As observed in Nꢀarylation of
anilines by Greaney and coꢀworkers,13c no ortho deuterated products are detected based on
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analysis of H NMR and LCꢀMS. Moreover, when using CH3OD as an additive (1.0 eq) or the
reaction solvent, the insertion reaction is suppressed completely and the starting NꢀOBn amide
recovered quantitatively, indicating that the nucleophilic attack of deprotonated amide anion to
aryne initiates the Nꢀarylation procedure. Therefore, a putative reaction pathway is concluded
(Scheme 5). The unusual regioselectivity of Nꢀarylation on protected amino acid substrates can be
attributed to the presence of NꢀOBn group, which induces a smaller pKa value on the related
amide N–H bond.
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Scheme 5. Plausible Reaction Pathway
To demonstrate the versatility of the present protocol for Nꢀarylation, insertion reaction of
Oꢀbenzyl hydroxamate 7 prepared from dipeptide CbzꢀPheꢀGlyꢀOH with silylaryl triflate 1b
proceeds smoothly to give the Nꢀarylated product 8 in gramꢀscale level with satisfied yield
(Scheme 6). Finally, the target hydroxamic acids are produced smoothly in good yields by removal
of the Oꢀbenzyl protecting groups via Pd/C catalytic hydrogenolysis (Scheme 7). Additionally, the
reductive cleavage of the N–O bonds mediated by SmI2 also delivers the corresponding Nꢀarylated
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amide derivatives.26
Scheme 6. N-Arylation of O-Benzyl Hydroxamate Derived from Dipeptide
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Scheme 7. Synthesis of N-Aryl Hydroxamic Acids via Catalytic Hydrogenolysis
Conclusion
In conclusion, we have developed an efficient, mild, and transition metalꢀfree method for
synthesis of Nꢀaryl hydroxamic aicds by the insertion of aryne into the N–H σꢀbonds. The process
tolerates a variety of reactive functional groups, such as aldehyde carbonyl group, furan ring, C=C
double bond, sulfonamide, carbamate, etc. In particular, the present protocol is applicable in
synthesis of Nꢀaryl hydroxamic acid derivatives of Nꢀprotecting amino acids and peptides. In the
presence of multiple amide N–H bonds, the Nꢀarylation reaction can proceed selectively in the N–
H bonds of terminal NꢀOBn amides giving rise to the desired Nꢀaryl hydroxamates. We have also
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shown that pꢀtoluenesulfonamide, which is reactive in the insertion of aryne into the N–H bond,
readily tolerate under the reaction conditions. Given its simplicity, efficiency and high
regioꢀselectivity, we believe that this method can serve as the powerful tool for synthesis of
structurally diverse Nꢀaryl hydroxamates and hydroxamic acids.
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EXPERIMENTAL SECTION
Unless otherwise stated, all reactions were carried out under air atmosphere, and all commercially
available reagents were used without further purification. Acetonitrile was purified by distillation
under air from P2O5 immediately prior to use. 1H NMR spectra were recorded on Bruker AVꢀ400
instrument (400 MHz). Unless indicated, chemical shifts were quoted in parts per million (ppm)
referenced to 0.00 ppm for tetramethylsilane. 13C NMR spectra were recorded on Bruker AVꢀ400
(100 MHz), and were fully decoupled by broad band proton decoupling. Chemical shifts were
reported in ppm referenced to the center line of a triplet at 77.0 ppm of chloroformꢀd. Infrared
spectroscopic data are reported in wavenumbers (cmꢀ1) with only select peaks shown.
Highꢀresolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using
ESIꢀTOF. Known compounds 2a,27 2b,28 2c,29 2d and 2u,30 2e,31 2f–2i and 2o,32 2j,33 2m,34 2q,35
2u,36 2w and 2x37 are prepared according to the general procedures and their analysis data are
identical with the reported literatures.
General Procedure for Synthesis of Hydroxamate O-Benzyl Esters: To a suspension
o
solution of substituted benzoic acid (5 mmol) in CH2Cl2 was added DMF (0.5 mmol) at 0 C by
syringe. Oxalyl chloride (6 mmol) were subsequently added dropwise by syringe. The reaction
was allowed to warm to rt gradually and stirred for another 3 h. Then, the reaction mixture was
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evaporated to afford a clear oil which is used without any further purification. In air,
Oꢀbenzylhydroxylamine hydrochloride (5 mmol) and Na2CO3 (10 mmol) were weighed into a
flask equipped with a stir bar. CH2Cl2 and distilled H2O (v/v 4:1) were successively added and the
flask was cooled in an iceꢀbath. The aboveꢀmentioned benzoyl chloride in CH2Cl2 was added in
one portion by syringe, and the reaction mixture was stirred for 2 h at 0 °C. Then, the reaction
mixture was poured into saturated aq. NaHCO3 and the resulting solution was extracted with
EtOAc. The combined organic layers were dried over anhydrous MgSO4 and evaporated in
vacuum to afford the crude product, which was purified by flash chromatography with a mixture
of EtOAc and hexane as an eluent to afford desired amide.
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N-(Benzyloxy)-4-(trifluoromethyl)benzamide (2k). 1.34 g, 91 % yield; colorless solid; mp
179–181 oC. 1H NMR (400 MHz, d6ꢀDMSO) δ 12.0 (br, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.85 (d, J =
8.4 Hz, 2H), 7.47 (d, J = 6.8 Hz, 2H), 7.44–7.35 (m, 3H), 4.97 (s, 2H); 13C NMR (100 MHz,
d6ꢀDMSO) δ 163.3, 136.4 (d, JCF = 26 Hz), 131.8 (q, JCF = 32 Hz), 129.4, 128.8, 128.4, 128.3,
125.9 (d, JCF = 3.0 Hz), 125.6, 122.9, 120.2, 77.4; FTIR (thin film), cmꢀ1 2928, 1661, 1342, 1210,
1198, 1003, 699; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H12 F3NO2 296.0893; found
296.0892.
N-(Benzyloxy)-4-formylbenzamide (2l). 0.87 g, 68 % yield; colorless solid; mp 133–134 °C.
1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 9.93 (br, 1H), 7.83 (s, 4H), 7.37 (m, 2H), 7.32 (m, 3H),
4.99 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 191.5, 138.3, 137.0, 134.9, 129.6, 129.2, 128.8, 128.5,
127.8, 78.3; FTIR (thin film), cmꢀ1 2919, 1712, 1674, 1499, 1322, 810, 721, 698; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C15H13NO3 256.0968; found 256.0967.
N-Benzyloxy ferrocenylformamide (2n). 1.91 g, 93 % yield; yellow solid; mp 138–139 °C. 1H
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NMR (400 MHz, CDCl3) δ 8.8 (br, 1H), 7.48–7.40 (m, 2H), 7.40–7.35 (m, 3H), 5.01 (s, 2H), 4.71
(s, 2H), 4.33 (s, 2H), 4.16 (s, 5H); 13C NMR (101 MHz, CDCl3) δ 169.8, 135.4, 129.1, 128.6,
128.5, 78.2, 72.7, 70.6, 69.8, 68.2; FTIR (thin film) cmꢀ1 2918, 1666, 1450, 1357, 1299, 778, 692;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H17FeNO2 336.0681; found 336.0690.
N-(Benzyloxy)-1-methyl-1H-indole-2-carboxamide (2p). 1.15 g, 82 % yield; colorless solid;
mp 141–142 °C. 1H NMR (400 MHz, CDCl3) δ 8.72 (br, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44–7.28
(m, 7H), 7.13 (t, J = 8.0 Hz, 1H), 6.71 (s, 1H), 5.02 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.6, 139.1, 135.1, 129.3, 128.8, 128.6, 128.4, 125.8, 124.4, 121.9, 120.6, 110.1, 104.5,
78.5, 31.3; FTIR (thin film) cmꢀ1 2921, 1655, 1506, 1474, 1325, 751, 696; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C17H16N2O2 281.1285; found 281.1282.
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N-(Benzyloxy)-1-methyl-1H-indole-3-carboxamide (2r). 1.19 g, 85 % yield; colorless solid;
mp 119–120 °C. 1H NMR (400 MHz, CDCl3) δ 8.98 (br, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51–7.32
(m, 7H), 7.17 (t, J = 8.0 Hz, 1H), 6.76 (s, 1H), 5.06 (s, 2H), 4.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.6, 139.0, 135.0, 129.3, 128.7, 128.5, 128.4, 125.8, 124.3, 121.8, 120.5, 110.0, 104.5,
78.5, 31.2; FTIR (thin film) cmꢀ1 2912, 1661, 1521, 1444, 742; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C17H16N2O2 281.1285; found 281.1281.
N-(Benzyloxy)-1H-indole-3-carboxamide (2s). 1.02 g, 77 % yield; colorless solid; mp 204–
1
206 °C. H NMR (400 MHz, d6ꢀDMSO) δ 11.6 (br, 1H), 11.1 (br, 1H), 8.10 (d, J = 8.0 Hz, 1H),
7.92 (d, J = 4.0 Hz, 1H), 7.52ꢀ7.30 (m, 6H), 7.25–7.16 (m, 2H), 4.95 (s, 2H); 13C NMR (100 MHz,
d6ꢀDMSO) δ 163.9, 136.3, 135.9, 128.7, 128.2, 128.1, 120.7, 120.5, 111.9, 107.3, 77.1; FTIR (thin
film) cmꢀ1 2925, 2289, 1658, 1534, 1191, 696; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H14N2O2 267.1128; found 267.1130.
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(E)-N-(Benzyloxy)-3-(4-chlorophenyl)acrylamide (2t). 1.22 g, 85 % yield; colorless solid; mp
184–185 °C. 1H NMR (400 MHz, d6ꢀDMSO) δ 11.40 (br, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.63–7.36
(m, 8H), 6.51 (d, J = 15.8 Hz, 1H), 4.95 (s, 2H); 13C NMR (100 MHz, d6ꢀDMSO) δ 163.1, 138.7,
136.4, 134.6, 134.0, 129.8, 129.4, 129.2, 128.8, 128.7, 119.8, 77.4; FTIR (thin film) cmꢀ1 2885,
1666, 1580, 1313, 1055, 740, 692; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H14ClNO2
288.0786; found 288.0783.
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(E)-N-(Benzyloxy)-3-(p-tolyl)acrylamide (2v). 1.28 g, 96 % yield; colorless solid; mp 123–
124 °C. 1H NMR (400 MHz, d6ꢀDMSO) δ 11.27 (br, 1H), 7.75–7.41 (m, 8H), 7.31 (d, J = 7.0 Hz,
2H), 6.39 (d, J = 16.0 Hz, 1H), 4.88 (s, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, d6ꢀDMSO) δ
165.3, 141.7, 138.2, 134.0, 131.7, 131.0, 130.7, 130.6, 130.5, 129.8, 119.6, 79.2, 23.1; FTIR (thin
film) cmꢀ1 2910, 1671, 1643, 1488, 1344, 799, 685; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H17NO2 268.1332; found 268.1335.
General Procedure for N-arylation of N-OBn Hydroxamates with Benzyne: To a solution
of NꢀOBn amide 2 (0.5 mmol) and CsF 1.2 mmol) in dry MeCN (5 mL) was added
(trimethylsilyl)phenyl trifluoromethanesulfonate 1a (0.6 mmol) by syringe at rt. The reaction
mixture was then allowed to stir overnight at room temperature. After the starting materials were
consumed completely monitored by TLC. The reaction solution was removed under vacuum and
the resulting residue was purified by flash chromatography column on silica gel, with the mixture
of hexane/ethyl acetate as the eluent, to afford the desired Nꢀarylation product. The compounds 3i
and 3w are known and their analysis data are identical with those reported in the literatures.38
N-(Benzyloxy)-N-phenylbenzamide (3a). Pale yellow oil, 150 mg, 99 % yield. 1H NMR (400
MHz, CDCl3) δ 7.65–7.59 (m, 2H), 7.52–7.24 (m, 11H), 7.20–7.10 (m, 2H), 4.82 (s, 2H); 13C
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NMR (100 MHz, CDCl3) δ 168.5, 139.6, 134.8, 134.0, 130.5, 129.5, 128.9, 128.8, 128.5, 128.4,
127.9, 126.8, 124.0, 76.3; FTIR (thin film) cmꢀ1 2920, 2865, 1654, 1344, 756, 699; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C20H17NO2 304.1332; found 304.1336.
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N-(Benzyloxy)-3-methyl-N-phenylbenzamide (3b). Pale yellow oil, 133 mg, 84 % yield. H
NMR (400 MHz, CDCl3) δ 7.56–7.50 (m, 2H), 7.48–7.26 (m, 11H), 7.19–7.13 (m, 2H), 4.85 (s,
2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 139.7, 137.6, 134.7, 134.1, 131.2, 129.6,
129.1, 128.9, 128.7, 128.4, 127.7, 126.7, 125.6, 124.0, 76.3, 21.2; FTIR (thin film) cmꢀ1 2921,
2849, 1649, 1489, 1348, 1305, 750, 694; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H19NO2
318.1489; found 318.1488.
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NMR (400 MHz, CDCl3) δ 7.55–7.50 (m, 2H), 7.49–7.10 (m, 11H), 6.99–6.95 (m, 1H), 4.85 (s,
2H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 159.0, 139.7, 135.9, 134.0, 129.5, 129.0,
128.7, 128.4, 126.9, 124.2, 120.9, 116.8, 113.4, 76.3, 55.2; FTIR (thin film) cmꢀ1 2921, 1604, 1530,
1454, 1038, 730, 693; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H19NO3 334.1438; found
334.1444.
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N-(Benzyloxy)-3-chloro-N-phenylbenzamide (3d). Pale yellow oil, 135 mg, 80 % yield. H
NMR (400 MHz, CDCl3) δ 7.63–7.55 (m, 3H), 7.52–7.39 (m, 4H), 7.40–7.24 (m, 5H), 7.12 (d, J =
7.0 Hz, 2H), 4.81 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 167.0, 139.0, 136.4, 133.9, 133.6, 130.5,
129.7, 129.1, 129.0, 128.9, 128.7, 128.5, 127.1, 126.7, 123.9, 76.4; FTIR (thin film) cmꢀ1 2898,
1671, 1489, 1354, 1307, 758, 742, 691; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H16ClNO2
338.0942; found 338.0941.
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NMR (400 MHz, CDCl3) δ 8.38–8.35 (m, 1H), 8.28–8.23 (m, 1H), 7.87–7.83 (d, J = 7.7 Hz, 1H),
7.66–7.60 (m, 2H), 7.53–7.42 (m, 3H), 7.36–7.19 (m, 4H), 7.08–6.97 (d, J = 7.2 Hz, 2H), 4.77 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 165.9, 147.5, 138.3, 136.2, 134.4, 133.2, 129.7, 129.2, 129.1,
128.7, 128.5, 127.4, 124.9, 123.9, 123.8, 76.4; FTIR (thin film) cmꢀ1 1667, 1530, 1348, 751, 698;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H16N2O4 349.1183; found 349.1180.
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N-(Benzyloxy)-4-methyl-N-phenylbenzamide (3f). Pale yellow oil, 140 mg, 88 % yield. H
NMR (400 MHz, CDCl3) δ 7.55–7.10 (m, 14H), 4.85 (s, 2H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.4, 140.9, 140.0, 134.2, 131.7, 129.5, 128.9, 128.8, 128.5, 128.4, 126.8, 124.3, 76.3,
21.4; FTIR (thin film) cmꢀ1 2921, 2850, 1661, 1489, 1349, 748, 695; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C21H19NO2 318.1489; found 318.1486.
N-(Benzyloxy)-4-methoxy-N-phenylbenzamide (3g). Pale yellow oil, 163 mg, 98 % yield. 1H
NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.9 Hz,
2H), 7.36–7.32 (m, 3H), 7.30–7.21 (m, 3H), 6.83 (d, J = 8.9 Hz, 2H), 4.86 (s, 2H), 3.83 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 167.9, 161.5, 140.3, 134.3, 131.0, 129.6, 128.9, 128.8, 128.4,
126.7, 124.3, 113.2, 76.3, 55.3; FTIR (thin film) cmꢀ1 2955, 2849, 1650, 1604, 1254, 1175, 1028,
752, 694; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H19NO3 334.1438; found 334.1437.
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N-(Benzyloxy)-4-fluoro-N-phenylbenzamide (3h). Pale yellow oil, 133 mg, 83 % yield. H
NMR (400 MHz, CDCl3) δ 7.70–7.60 (m, 2H), 7.55–7.46 (m, 2H), 7.38–7.29 (m, 2H), 7.27–7.19
(m, 4H), 7.14–7.06 (m, 2H), 7.03–6.92 (m, 2H), 4.80 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
167.2, 163.8 (d, JCF = 252.5 Hz), 139.4, 133.8, 131.1 (d, JCF = 9.0 Hz), 130.7 (d, JCF = 3.0 Hz),
129.5, 128.9, 128.8, 128.4, 126.9, 124.0, 114.9 (d, JCF = 21.0 Hz), 76.3; FTIR (thin film) cmꢀ1
1665, 1601, 1506, 1352, 1230, 844, 749, 694; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
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C20H16FNO2 322.1238; found 322.1235.
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N-(Benzyloxy)-4-chloro-N-phenylbenzamide (3i). Pale yellow oil, 145 mg, 86 % yield. H
NMR (400 MHz, CDCl3) δ 7.68–7.48 (m, 4H), 7.40 (t, J = 7.9 Hz, 2H), 7.35–7.25 (m, 6H), 7.14
(d, J = 6.5 Hz, 2H), 4.81 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 167.3, 139.3, 136.7, 133.8, 133.0,
130.2, 129.6, 129.0, 128.9, 128.5, 128.1, 127.1, 124.1, 76.4; FTIR (thin film) cmꢀ1 2921, 1661,
1591, 1350, 1089, 841, 741, 696; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H16ClNO2
338.0942; found 338.0940.
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N-(Benzyloxy)-4-bromo-N-phenylbenzamide (3j). Pale yellow oil, 163 mg, 86 % yield. H
NMR (400 MHz, CDCl3) δ 7.65–7.60 (m, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H),
7.35–7.23 (m, 4H), 7.17 (d, J = 6.2 Hz, 2H), 7.01 (t, J = 8.0 Hz, 2H), 4.80 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 167.3, 139.3, 133.8, 133.5, 131.1, 130.3, 129.6, 129.0, 128.9, 128.5, 127.1, 125.1,
124.1, 76.4; FTIR (thin film) cmꢀ1 1664, 1588, 1535, 1010, 848, 755, 741, 696; HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C20H16BrNO2 382.0437; found 382.0433.
N-(Benzyloxy)-N-phenyl-4-(trifluoromethyl)benzamide (3k). Pale yellow oil, 131 mg, 71 %
yield. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 2H), 7.63–7.52 (m, 4H), 7.43 (t, J = 7.9
Hz, 2H), 7.35–7.21 (m, 4H), 7.03 (d, J = 8.0 Hz, 2H), 4.77 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
167.1, 138.8, 138.2, 133.5, 132.0 (q, JCF = 32 Hz), 129.6, 129.1, 128.9, 128.8, 128.4, 127.2, 124.8
(q, JCF = 4.0 Hz), 124.6 (q, JCF = 157 Hz), 123.9, 76.4; FTIR (thin film) cmꢀ1 1665, 1323, 1168,
1127, 1048, 694; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H16F3NO2 372.1206; found
372.1202.
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N-(Benzyloxy)-4-formyl-N-phenylbenzamide (3l). Pale yellow oil, 86 mg, 52 % yield. H
NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.54
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(m, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.33–7.21 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 4.79 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 191.6, 167.2, 140.3, 138.7, 137.1, 133.5, 129.5, 129.1, 128.9, 128.4,
127.2, 123.9, 76.4; FTIR (thin film) cmꢀ1 1702, 1665, 1489, 1357, 1305, 1205, 839, 749, 669;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H17NO3 332.1281; found 332.1285.
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N-(Benzyloxy)-4-cyano-N-phenylbenzamide (3m). Pale yellow oil, 121 mg, 74 % yield. H
NMR (400 MHz, CDCl3) δ 7.61 (s, 4H), 7.58–7.52 (m, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.35–7.22 (m,
4H), 7.03 (d, J = 6.7 Hz, 2H), 4.76 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 166.5, 138.9, 138.4,
133.3, 131.5, 129.6, 129.1, 129.0, 129.0, 128.5, 127.3, 123.8, 118.1, 113.7, 76.4; FTIR (thin film)
cmꢀ1 2229, 1663, 1490, 1359, 751, 695; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H16N2O2
329.1285; found 329.1282.
N-(Benzyloxy)-N-phenyl-ferrocenamide (3n). Brown solid, mp 101–102 °C; 191 mg, 93 %
yield. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.48–7.35 (m, 7H), 7.29 (t, J = 7.4
Hz, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 4.39–4.31 (m, 2H), 4.20 (s, 4H); 13C NMR (100 MHz, CDCl3)
δ 169.5, 139.9, 134.3, 129.3, 128.8, 128.7, 128.5, 126.8, 124.4, 76.2, 74.2, 71.6, 70.7, 69.8; FTIR
(thin film) cmꢀ1 1643, 1489, 1440, 1379, 1338, 1301, 759, 710; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C24H21FeNO2 412.0994; found 412.0996.
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N-(Benzyloxy)-N-phenylfuran-2-carboxamide (3o). Pale yellow oil, 77 mg, 53 % yield. H
NMR (400 MHz, CDCl3) δ 7.67–7.58 (m, 3H), 7.47–7.42 (m, 2H), 7.40–7.24 (m, 7H), 7.12 (d, J =
3.3 Hz, 1H), 6.48 (dd, J = 3.5, 1.7 Hz, 1H), 4.93 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 157.4,
145.8, 145.4, 138.6, 133.7, 129.3, 128.9, 128.8, 128.5, 128.4, 126.9, 126.8, 123.6, 118.2, 111.5,
76.6; FTIR (thin film) cmꢀ1 1721, 1656, 1490, 1468, 1391, 1358, 755, 695; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C18H15NO3 294.1125; found 294.1128.
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N-(Benzyloxy)-1-methyl-N-phenyl-1H-indole-2-carboxamide (3p). Pale yellow oil, 158 mg,
89 % yield. 1H NMR (400 MHz, CDCl3) δ 7.63–7.56 (m, 3H), 7.43–7.36 (m, 2H), 7.36–7.16 (m,
8H), 7.12 (ddd, J = 7.9, 6.6, 1.3 Hz, 1H), 6.91 (s, 1H), 4.90 (s, 2H), 3.86 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 161.6, 139.6, 138.3, 134.0, 130.4, 129.7, 128.9, 128.8, 128.3, 127.0, 126.1, 124.2,
124.0, 122.1, 120.1, 109.8, 108.2, 76.5, 31.6; FTIR (thin film) cmꢀ1 1648, 1515, 1487, 1464, 1391,
1320, 746, 695; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H20N2O2 357.1598; found 357.1595.
N-(Benzyloxy)-N-phenyl-1H-indole-2-carboxamide (3q). Pale yellow oil, 145 mg, 85 % yield.
1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 7.76–7.71 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.54–
7.46 (m, 2H), 7.45–7.26 (m, 7H), 7.17 (br, 1H), 7.14–7.08 (m, 1H), 5.01 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 160.2, 138.9, 136.0, 133.7, 129.5, 129.1, 129.0, 128.7, 128.2, 128.0, 127.2, 125.0,
124.0, 122.5, 120.4, 111.8, 109.2, 76.8; FTIR (thin film) cmꢀ1 2925, 1654, 1497, 1390, 745, 694;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C22H18N2O2 343.1441; found 343.1440.
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N-(Benzyloxy)-1-methyl-N-phenyl-1H-indole-3-carboxamide (3r). Pale yellow oil, 162 mg,
91 % yield. 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 6.9, 1.5 Hz, 1H), 7.77 (s, 1H), 7.74–7.70
(m, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.41–7.24 (m, 9H), 4.93 (s, 2H), 3.74 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 163.9, 140.1, 136.3, 134.6, 134.4, 129.4, 128.9, 128.7, 128.6, 126.1, 123.6, 122.8,
122.7, 121.7, 109.2, 107.5, 76.5, 33.2; FTIR (thin film) cmꢀ1 2920, 2849, 1644, 1533, 1439, 747;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H20N2O2 357.1598; found 357.1602.
N-(Benzyloxy)-N-phenyl-1H-indole-3-carboxamide (3s). Pale yellow oil, 152 mg, 89 % yield.
1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.43–8.38 (m, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.65 (d, J
= 8.0 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.34–7.16 (m, 10H), 4.88 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 164.4, 139.9, 135.3, 134.2, 130.5, 129.3, 128.8, 128.5, 127.6, 126.5, 124.1, 122.9, 122.1,
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121.7, 111.3, 108.6, 76.3; FTIR (thin film) cmꢀ1 2950, 1666, 1540, 1412, 738, 692; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C22H18N2O2 343.1441; found 343.1445.
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(E)-N-(Benzyloxy)-3-(4-chlorophenyl)-N-phenylacrylamide (3t). Pale yellow oil, 161 mg,
89 % yield. 1H NMR (400 MHz, CDCl3) δ 7.71–7.58 (m, 3H), 7.45 (t, J = 7.9 Hz, 2H), 7.43–7.27
(m, 10H), 6.95 (br, 1H), 4.91 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 164.9, 142.1, 138.5, 135.6,
134.0, 133.5, 129.5, 129.1, 129.0, 128.9, 128.7, 126.6, 123.3, 117.8, 76.9; FTIR (thin film) cmꢀ1
2920, 2849, 1644, 1533, 1439, 747; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C22H18ClNO2
364.1099; found 364.1101.
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(E)-N-(Benzyloxy)-3-(4-methoxyphenyl)-N-phenylacrylamide (3u). Pale yellow oil, 163 mg,
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91 % yield. H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 15.7 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H),
7.46–7.35 (m, 9H), 7.26 (t, J = 8.0 Hz, 1H), 6.98–6.82 (m, 3H), 4.91 (s, 2H), 3.81 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 165.5, 161.0, 143.3, 138.8, 134.1, 129.6, 129.4, 128.9, 128.7, 128.6,
127.7, 126.3, 123.1, 114.6, 114.1, 76.8, 55.2; FTIR (thin film) cmꢀ1 1600, 1511, 1355, 1252, 1172,
825, 758, 698; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H21NO3 360.1594; found 360.1597.
(E)-N-(Benzyloxy)-3-(4-methylphenyl)-N-phenylacrylamide (3v). Pale yellow oil, 151 mg,
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88 % yield. H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.8 Hz, 1H), 7.63 (d, J = 7.4 Hz, 2H),
7.49–7.34 (m, 9H), 7.29 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.06–6.90 (br, 1H), 4.92 (s,
2H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.4, 143.7, 140.2, 138.8, 134.1, 132.3, 129.5,
129.4, 129.0, 128.8, 128.6, 128.0, 126.4, 123.2, 116.1, 76.9, 21.4; FTIR (thin film) cmꢀ1 1663,
1620, 1490, 1354, 809, 757, 698; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H21NO2 344.1645;
found 344.1646.
N-(Benzyloxy)-2-phenoxy-N-phenylacetamide (3x). Brown oil, 125 mg, 75 % yield. 1H NMR
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(400 MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 2H), 7.48–7.34 (m, 7H), 7.28 (t, J = 7.4 Hz, 2H), 7.18–
7.13 (m, 2H), 6.66–6.58 (m, 2H), 4.84 (s, 2H), 4.68 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 167.2,
156.7, 137.3, 133.5, 130.0, 129.5, 129.2, 129.0, 128.9, 126.8, 126.2, 122.5, 115.9, 76.1, 66.3;
FTIR (thin film) cmꢀ1 1705, 1546, 1324, 748, 693; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C21H19NO3 334.1438; found 334.1435.
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General procedure for N-arylation of O-Benzyl Hydroxamates with Various Arynes: To
a solution of NꢀOBn amide 2 (0.5 mmol) and CsF 1.2 mmol) in dry MeCN (5 mL) was added the
aryne precursor 1b-f (0.6 mmol) by syringe at rt. The reaction mixture was then allowed to stir
overnight at room temperature. After the starting materials were consumed completely monitored
by TLC. The reaction solution was removed under vacuum and the resulting residue was purified
by flash chromatography column on silica gel, with the mixture of hexane/ethyl acetate as the
eluent, to afford the desired Nꢀarylation product 4a-e.
N-(Benzyloxy)-N-(3-methoxyphenyl)benzamide (4a). Pale yellow oil, 120 mg, 72 % yield. 1H
NMR (400 MHz, CDCl3) δ 7.64–7.57 (m, 2H), 7.46–7.39 (m, 1H), 7.38–7.23 (m, 6H), 7.15–7.05
(m, 4H), 6.82–6.76 (m, 1H), 4.82 (s, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.5,
159.9, 140.7, 134.8, 133.9, 130.5, 129.6, 129.5, 128.8, 128.4, 127.8, 116.2, 112.7, 109.3, 76.3,
55.3; FTIR (thin film) cmꢀ1 2922, 1604, 1539, 1030, 744, 694; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C21H19NO3 334.1438; found 334.1435.
N-(Benzyloxy)-N-(naphthalene-2-yl)benzamide (4b). Redꢀbrown oil, 153 mg, 87 % yield. 1H
NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88–7.74 (m, 3H), 7.64 (m, 3H), 7.53–7.45 (m, 2H),
7.45–7.40 (m, 1H), 7.36–7.25 (m, 5H), 7.13 (d, J = 6.5 Hz, 2H), 4.86 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 168.6, 137.0, 134.7, 134.0, 133.2, 131.9, 130.5, 129.6, 128.9, 128.8, 128.5, 128.4, 128.0,
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127.9, 127.6, 126.6, 126.3, 122.5, 76.4; FTIR (thin film) cmꢀ1 2950, 2865, 1652, 1466, 1301, 758,
699; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H19NO2 354.1489; found 354.1486.
N-(Benzyloxy)-N-(3,4-difluorophenyl)benzamide (4c). Pale yellow oil, 84 mg, 50 % yield. 1H
NMR (400 MHz, CDCl3) δ 7.67–7.61 (m, 2H), 7.53–7.47 (m, 2H), 7.42–7.36 (m, 2H), 7.35–7.24
(m, 4H), 7.20–7.12 (m, 1H), 7.06–6.98 (d, J = 6.9 Hz, 2H), 4.74 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 168.7, 150.4 (dd, JCF = 154.5, 13.1 Hz), 147.9 (dd, JCF = 140.4, 13.0 Hz), 136.0 (dd, JCF
= 8.0, 4.0 Hz), 134.1, 133.3, 130.8, 129.6, 129.0, 128.52, 128.5, 127.9, 119.2 (dd, JCF = 5.0, 4.0
Hz), 117.2 (d, JCF = 16 Hz), 112.8 (d, JCF = 21 Hz), 76.8; FTIR (thin film) cmꢀ1 1669, 1589, 1511,
1360, 1209, 852, 750, 694; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H15F2NO2 340.1144;
found 340.1141.
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N-(Benzyloxy)-4-methoxy-N-(4-methoxyphenyl)benzamide
and
N-(Benzyloxy)-4-methoxy-N-(3-methoxyphenyl)benzamide (4d). Products are isolated as a
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paraꢀ/metaꢀ mixture of approx. 1:1 based on the analysis of H NMR spectra, which cannot be
isolated as the single isomer by conventional column chromatography. Pale yellow oil, 121 mg,
67 % yield. 1H NMR (400 MHz, CDCl3) δ 7.54–7.44 (m, 4H), 7.23–7.15 (m, 6H), 7.14–7.05 (m,
6H), 6.95–6.86 (m, 4H), 6.75–6.62 (m, 6H), 4.75 (s, 2H), 4.72 (s, 2H), 3.70 (s, 3H), 3.67 (s, 3H),
3.64 (s, 3H), 3.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.45, 167.43, 161.07, 161.05, 159.47,
159.45, 140.81, 139.79, 133.75, 133.73, 130.37, 130.36, 129.1, 128.3, 127.9, 126.13, 126.10,
116.0, 112.70, 112.69, 112.1, 109.2, 75.7, 54.8. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C22H21NO4 364.1543; found 364.1541.
N-(Benzyloxy)-4-methoxy-N-(4-methylphenyl)benzamide
and
N-(Benzyloxy)-4-methoxy-N-(3-methylphenyl)benzamide (4e). Products are isolated as a
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paraꢀ/metaꢀ mixture of approx. 1.1:1 based on the analysis of 1H NMR spectra, which cannot be
isolated as the single isomer by conventional column chromatography. Pale yellow oil, 151 mg,
91 % yield. 1H NMR (400 MHz, CDCl3) δ 7.67–7.58 (m, 4H), 7.35–7.28 (m, 8H), 7.26–7.21 (m,
6H), 7.19–7.14 (m, 2H), 7.10–7.03 (m, 1H), 6.87–6.78 (m, 4H), 4.90 (s, 2H), 4.88 (s, 2H), 3.81 (s,
3H), 3.80 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.78, 167.68,
161.28, 161.24, 139.9, 138.7, 137.5, 136.8, 134.2, 134.1, 130.7, 129.4, 128.57, 128.55, 128.2,
127.5, 126.49, 126.46, 124.9, 124.7, 121.4, 112.9, 75.9, 75.7, 55.11, 55.09, 21.2, 20.8. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C22H21NO3 348.1594; found 348.1592.
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General Procedure for Synthesis of O-Benzyl Hydroxamates (5a–f) of N-Protected
Amino Acids: To a cooled (0 oC) solution of Nꢀprotected amino acid (10 mmol) and
Oꢀbenzylhydroxylamine hydrochloride (12 mmol) in CHCl3 was added successively
trimethylamine (12 mmol). After the reaction mixture was stirred for 30 min. at 0 oC,
1ꢀhydroxybenzotriazole (HOBt) (10 mmol) in THF (20 mL) and N,Nꢀdicyclohexylcarbiimide
(DCC) (11 mmol) in CHCl3 (15 mL) were added into the mixture in turn. Therefore, the mixture
was allowed to warm to room temperature and stirred overnight. Once the starting materials were
consumed completely monitored by TLC, the reaction mixture was filtrated via a short pad of
celite to remove off the resulting dicyclohexylurea (DCU). After removal of solution under
vacuum, the residue was redissolved in EtOAc (50 mL) and washed successively with water (30
mL), 10 % aq. citric acid (2 × 30 mL), water (30 mL), saturated aq. NaHCO3, (2 × 30 mL), water
(30 mL), and saturated aq. NaCl (30 mL). The organic phase was dried over anhydrous Na2SO4
and evaporated in vacuo. The crude amide product was purified by silica gel chromatography
column with the mixture of hexane/ethyl acetate as the eluent to give the pure NꢀOBn amides 5.
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(S)-2-Acetamido-N-(benzyloxy)-3-phenylpropanamide (5a). Colorless solid, mp 185–187 °C;
2.65 g, 85 % yield. [α]25.8589 –34.7 (c 0.144, CHCl3). 1H NMR (400 MHz, CDCl3) δ 9.99 (br, 1H),
7.35–7.14 (m, 10H), 6.96 (d, J = 7.2 Hz, 1H), 4.75–4.55 (m, 3H), 3.15–2.95 (m, 2H), 1.82 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.5, 168.5, 136.3, 135.0, 129.3, 129.1, 128.57, 128.52, 128.3,
126.9, 78.1, 51.9, 38.3, 22.7; FTIR (thin film) cmꢀ1 3280, 1710, 1669, 1521, 1259, 1278, 750, 698;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H20N2O3 313.1547; found 313.1544.
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(S)-Benzyl (1-((benzyloxy)amino-1-oxo-3-phenylpropan-2-yl)carbamate (5b). Colorless
1
solid, mp 143–145 °C; 3.27 g, 81 % yield. [α]25.8 –7.2 (c 0.110, CHCl3). H NMR (400 MHz,
589
CDCl3) δ 8.89 (br, 1H), 7.48–7.05 (m, 16H), 5.58–5.44 (m, 1H), 5.05–4.88 (m, 2H), 4.81–4.71 (m,
1H), 4.69–4.60 (m, 1H), 4.35–4.20 (m, 1H), 3.10–2.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
168.4, 155.9, 136.0, 135.8, 134.8, 129.3, 129.2, 128.6, 128.5, 128.4, 128.2, 127.9, 127.0, 78.2,
67.1, 53.9, 38.2; FTIR (thin film) cmꢀ1 3320, 1703, 1656, 1491, 1239, 750, 696; HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C24H24N2O4 405.1809; found 405.1806.
(S)-N-(benzyloxy)-2-(4-methylphenylsulfonamido)-3-phenylpropanamide (5c). Colorless
solid, mp 139–141 °C; 3.77 g, 89 % yield. [α]25.8589 –22.4 (c 0.262, CHCl3). 1H NMR (400 MHz,
CDCl3) δ 8.95 (br, 1H), 7.53 (d, J = 6.8 Hz, 2H), 7.48–7.24 (m, 5H), 7.23–7.20 (m, 5H), 6.95–6.90
(m, 2H), 5.245.18 (m, 1H), 4.72–4.68 (m, 2H), 3.90–3.80 (m, 1H), 2.93–2.88 (m, 2H), 2.39 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 167.7, 143.8, 135.8, 134.9, 134.7, 129.7, 129.2, 128.8, 128.7,
128.5, 127.2, 127.0, 78.4, 56.3, 38.3, 21.4; FTIR (thin film) cmꢀ1 3289, 1674, 1472, 1357, 1029,
886, 752, 696; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H24N2O4S 425.1530; found
425.1531.
(S)-tert-Butyl (1-((benzyloxy)amino)-3-methyl-1-oxobutan-2-yl)carbamate (5d). Colorless
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