Regioselective synthesis of 2,4,5-trisubstituted oxazoles and ketene aminals via hydroamidation and iodo-imidation of ynamides

Article abstract of DOI:10.1021/acs.joc.7b02124

A novel and straightforward protocol is demonstrated for the synthesis of highly substituted oxazoles from readily accessible ynamides in the presence of ytterbium-(III) trifluoromethanesulfonate [Yb(OTf)₃], N-iodosuccinimide (NIS), and acetonitrile. Multiple oxazole skeletons in the aryl periphery are constructed in a single operation for the first time. The hydroamidation and iodo-imidation of ynamides to trisubstituted and tetrasubstituted ketene aminals is exemplified. An isotope labeling experiment is used to identify the oxygen source in this transformation. The reactions are scalable to the gram scale, testifying the robustness of the transformations.

Full text of DOI:10.1021/acs.joc.7b02124

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Article
Regioselective Synthesis of 2, 4, 5-Trisubstituted-Oxazoles and
Ketene Aminals via Hydroamidation, and Iodo-imidation of Ynamides
Rajendra Kumar Mallick, Baskaran Prabagar, and Akhila Kumar Sahoo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02124 • Publication Date (Web): 18 Sep 2017
Downloaded from http://pubs.acs.org on September 18, 2017
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Regioselective Synthesis of 2, 4, 5-Trisubstituted-
Oxazoles and Ketene Aminals via
Hydroamidation, and Iodo-imidation of
Ynamides
Rajendra K. Mallick, B. Prabagar, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad-500046, INDIA
akhilchemistry12@gmail.com
RECEIVED DATE (to be automatically inserted)
A novel and straightforward protocol is demonstrated for the synthesis of highly substituted
oxazole from readily accessible ynamides in the presence of ytterbium(III)
trifluoromethanesulfonate [Yb(OTf)3], N-iodosuccinimide (NIS), and acetonitrile. Multiple
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oxazole skeletons in the aryl-periphery are constructed in a single operation for the first time.
The hydroamidation and iodo-imidation of ynamides to tri- and tetra-substituted ketene aminals
is exemplified. An isotope labeling experiment is used to identify the oxygen source in this
transformation. The reactions are scalable to the gram scale, testifying the robustness of the
transformations.
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INTRODUCTION
Ynamides, the nitrogen-substituted alkynes, have extensively been used in the conceptual
development of novel synthetic transformations.1 The polarized triple bond of ynamide under
Brønsted/Lewis acid catalysis coherently allows in situ formation of reactive keteniminium
species (A). Trapping of the reactive keteniminium species with nucleophiles offer novel
pathways for the construction of complex N-heterocycles.2 Eventually, the regioselective α-
attack of O- and N-bearing nucleophiles to the activated ynamide 1 directly accesses ketene N,O-
/N,N-acetal (B/B′; Scheme 1).3 Thus, the intramolecular cyclization and cycloisomerization of π-
tethered acetals fabricate diverse molecular scaffolds.3b We have recently showcased the use of
ketene N,O- and N,N-acetal, obtained from yne-tethered-ynamides by the attack of p-
toluenesulfonic acid, dimethyl sulfoxide, or amide moieties to construct dihydropyridine (I),
benzo[f]dihydroisoquinolone (II), pyrrolidone (III), and cyclobutene-fused-azepine (IV)
derivatives (Scheme 1).4
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Scheme 1: Significance of Ketene N,O- and N,N-Acetal from Ynamides
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Intrigued by these results, we envisage the Lewis acid mediated regioselective attack of nitrile at
the α-position of ynamide to yield a reactive nitrilium intermediate C, which eventually
undergoes hydration to provide ketene-aminal 3 (Scheme 2a). Next, the intramolecular
cyclization of ketene-aminal 3 (formed in situ) in the presence of an activator possibly constructs
peripherally decorated and highly selective 4-amino-2,5-disubstituted oxazole (2) (Scheme 2a).
This is possible when the nucleophilic β-position of the aminal becomes electrophilic (i.e., “β-
umpolung”), which remains challenging. Thus, NIS is considered facilitating ketene aminal (3/D)
for intramolecular 5-endo-trig cyclization of the pendant amide to yield oxazole 2 (Scheme 2a).
As such, the Au(I)-catalyzed [2+2+1] annulation of a terminal alkyne, nitrile, and oxygen has
been successfully used for the synthesis of 2,5-disubstituted oxazole.5 The fabrication of 2,4,5-
trisubstituted oxazoles from ynamides involving Au(I)-catalyzed [3+2] cycloaddition with
nitrene transfer reagents are reliably deliberated (Scheme 2b); the transformation involves α-
imino-β-Au-carbene making the β-position of ynamide electrophilic.6
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Scheme 2: Previous Work and Current Hypothesis
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The oxazole motifs are potential building blocks that are widely present in various natural
products and bioactive molecules (Figure 1),7 and are useful in many synthetic transformations.8
Of course, a modular paradigm to build a highly substituted oxazole skeleton is exceedingly
desirable.9,10
Figure 1. Oxazole Containing Bioactive Molecules
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Despite the progress, we herein discussed the development of a modular synthetic protocol for 4-
amino-2,5-disubstituted oxazole from readily accessible ynamides in the presence of a Yb(OTf)3
catalyst, NIS promoter, and H2O in acetonitrile (masked amide equivalent) at room temperature
(rt). In addition, we demonstrate the regio and stereoselective hydroamidation11 and iodo-
imidation of ynamides to yield ketene aminals (3; syn-selectivity) and β-iodo ketene aminals (4;
anti-selectivity) by independently exposing ynamides to Yb(OTf)3, H2O in CH3CN and
Yb(OTf)3, NIS in CH2Cl2 (Scheme 2a).
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RESULTS AND DISCUSSION
As envisaged, the investigation was commenced for the synthesis of oxazole 2 from ynamide 1
(Table 1). To begin with, ynamide 1a was subjected to NIS (2.2 equiv), Cu(OTf)2 (20 mol %),
H2O (2.0 equiv) in CH3CN for 8 h at rt. To our delight, the oxazole product 2a was isolated in
38% yield (entry 1) and the structure of 2a was elucidated by X-ray analysis (Table 1). The
reaction in the presence of Yb(OTf)3 was found effective producing 2a (88%); while other Lewis
acids Sc(OTf)3, Fe(OTf)3 were found inferior (entries 2−4). Disappointingly, the reaction
mediated by triflic acid turned complex (entry 5). The use of molecular iodine instead of NIS did
not produce 2a (entry 6); preferably NIS is better electrophilic iodinating agent over iodine.12
Formation of 2a was hampered in the absence of Yb(OTf)3 (entry 7), demonstrating the
importance of Lewis acid in this transformation. The additives NBS and NCS were not beneficial
(entries 8−9). The use of less amount catalyst and/or NIS impacted the reaction outcome (entries
10 and 11). Predictably, the absence of H2O led to 2a (<10%, entry 12). To our surprise, the
reaction in the absence of NIS underwent syn-hydroamidation, explicitly delivering tri-
substituted aminal 3a in 57% yield (entry 13); X-ray crystallographic studies confirmed the
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structure 3a (Table 1). The co-ordination of nitrogen in CH3CN to Yb-activated keteniminium
species preferably builds the product 3a with Z−olefin selectivity. Pleasingly, enhanced yield of
3a (70%) was noticed, when the reaction continued for 18 h (entry 14). A trace of 3a was formed
when the reaction conducted in presence of molecular sieves (4Å) (entry 15); thus H2O is
indispensable in this transformation. Not surprisingly, reaction failed in the absence of Yb(OTf)3
and NIS (entry 16). The reaction with CH3CN (2.0 equiv) in ClCH2CH2Cl/toluene turned
complex (entries 17 and 18); in contrast the identical reaction in CH2Cl2 yielded 67% of anti-
iodo-imidation product 4a and a trace of 2a (entry 19); structure 4a was further characterized by
X-ray analysis (Table 1). The reaction in the absence of CH3CN and H2O was equally effective
(entry 20). The use of either less amount of NIS or without Yb(OTf)3 affected the reaction
(entries 21 and 22). From these studies, it appears that ynamides undergo several transformations
under the influence of Yb(OTf)3 delivering oxazole (2a), and tri-/ tetra-sustituted ketene aminals
(3a and 4a) in a single step.
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Table 1: Optimization of Reaction Conditionsa
entry catalyst additive
(20 mol%) (equiv)
solvent time
(1.5 mL) (h)
yield (%)
2a/3a/4a
38 (2a)
1
2b
3
Cu(OTf)2 NIS (2.2)
Sc(OTf)3 NIS (2.2)
Yb(OTf)3 NIS (2.2)
Fe(OTf)3 NIS (2.2)
CH3CN
CH3CN
CH3CN
CH3CN
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65 (2a)
88 (2a)
10 (2a)
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5c
6d Yb(OTf)3 I2 (2.2)
HOTf
NIS (2.2)
CH3CN
CH3CN
8
complex
−
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NIS (2.2)
CH3CN
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31 (2a)
complex
complex
62 (2a)
<20 (2a)
<10 (2a)
57 (3a)
70 (3a)
−
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Yb(OTf)3 NBS (2.2) CH3CN
Yb(OTf)3 NCS (2.2) CH3CN
8
10e Yb(OTf)3 NIS (2.2)
11e Yb(OTf)3 NIS (1.2)
12f Yb(OTf)3 NIS (2.2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
8
8
8
13b Yb(OTf)3
8
−
14 Yb(OTf)3
15 Yb(OTf)3 4Å MS
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18
−
CH3CN
CH3CN
18
<5 (3a)
NR
18
−
−
17g Yb(OTf)3 NIS (2.2) ClCH2CH2Cl 8
complex
complex
67 (4a)
69 (4a)
56 (4a)
40 (4a)
18g Yb(OTf)3 NIS (2.2)
19b,g Yb(OTf)3 NIS (2.2)
20f Yb(OTf)3 NIS (2.2)
21f Yb(OTf)3 NIS (1.2)
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
8
8
8
8
22f
NIS (1.2)
−
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aReactions were carried out using 1 (0.2 mmol), catalyst (20 mol %), H2O (2.0 equiv.) in solvent at rt;
c
d
bCrude NMR yield; HOTf (1.2 equiv.) was used; 2a was not formed; eYb(OTf)3 (10 mol %) was used;
fwithout H2O; gCH3CN (2.0 equiv) was used.
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We then probed the reaction generality for the synthesis of trisubstituted oxazoles under the
optimized conditions in entry 3, Table 1 (Scheme 3). The ynamide 1a was effectively reacted
with CH3CN furnishing oxazole 2a in 88% yield. Likewise, the ynamides 1b−d with electron
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rich arenes in the alkyne-terminus successfully yielded the corresponding oxazoles 2b−d
[76−82%]. The electron-poor arene bearing ynamides delivered 2e−g [p-COMe-2e (55%), m−F-
2f (65%), and m−CF3-2g (75%)]. Gratifyingly, the heteroaryl substituted ynamide 1h was not
exception, providing 2h in 62% yield. The sterically encumbered napthyl and phenanthryl
enabled oxazoles 2i and 2j were reliably accessed albeit in moderate yield. Instead of N-Ts, the
neutral N-benzenesulfonyl protected ynamide 1k furnished the desired product 2k in excellent
yield (90%). Likewise, various N-arenesulfonyl protected ynamides [p−F-C6H4 (1l), p−CF3-C6H4
(1m), and p−Br-C6H4 (1n)] were effectively tolerated under the optimized conditions, yielding
the corresponding highly substituted oxazoles 2l−2n in good yields. Gratifyingly, the modifiable
oxazolidinone protected ynamide delivered 65% of 2o. To our delight, the alkyl-enabled N-
sulfonyl protected oxazoles were reliably constructed (2p; 75% and 2q; 27%). However, the
ynamide (having alkyl moiety in the alkyne terminus) provided complex mixture, without
forming the desired product 2r. Disappointingly, repeated attempts condensing other nitriles
(benzonitriles, butyronitrile, valeronitrile) with ynamide were failed (2s and 2t); probably the
absence of acidic α−H and the steric bulkiness of nitriles obstruct the cyclization (see Int I and I′
in Scheme 10).
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Scheme 3. Scope of 2,4,5-Trisubstituted-Oxazolea
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aReactions were carried out using 1 (0.5 mmol), NIS (1.1 mmol), Yb(OTf)3 (0.1 mmol), H2O (1.0 mmol)
in CH3CN (3.0 mL) at rt for 8−12 h.
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A programmed synthetic manifestation for the Yb(OTf)3 and NIS mediated amidation and
cyclization sequence of large number of ynamides within a molecule would directly erect many
oxazole motifs in a single operation. Pleasingly, this complexity driven notion eventually allows
the construction of 1,3- and 1,4-bis-oxazoles 2u (45%) and 2v (50%), forming six bonds (two
C−N and four C−O) in a single operation, from easily accessible precursors 1a′ and 1a′′. To our
delight, a complex tri-substituted 1,3,5-tris-oxazole 2w was successfully built from 1,3,5-
triynamide precursor 1a′′′ (Scheme 4).
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Scheme 4: Construction of Poly-Oxazoles on Arenea
aReactions were carried out using 1a′−1a′′′ (0.3 mmol), NIS (1.32 mmol), Yb(OTf)3 (0.12 mmol), H2O
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(1.2 mmol), in CH3CN (3.0 mL) at rt for 16 h; NIS (1.98 mmol), Yb(OTf)3 (0.18 mmol), H2O (1.8
mmol), rt for 24 h.
Next, the Yb(OTf)3 mediated hydroamidation of ynamide with CH3CN in presence of H2O
(entry 14, Table 1) for the synthesis of ketene aminals 3 was surveyed (Scheme 5). The N-benzyl
and N-methyl protected ketene aminals 3a and 3b were obtained in 70% and 73% yield,
respectively. The electron rich ynamides successfully delivered 3c−d [o-OMe-3c (47%) and m-
OMe-3d (46%)] in moderate yield. Whereas the desired products 3e−g [m-CN-3e (75%), m−F-3f
(76%), and p−F-3g (80%)] were proficiently accessed from the electron-poor arene bearing
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ynamides. The 3-thienyl and 1-naphthyl enabled products 3h (80%) and 3i (60%) were reliably
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isolated.
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Scheme 5. Scope for syn-Hydroamidation of Ynamidesa
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aReactions were carried out using 1 (0.5 mmol), Yb(OTf)3 (0.1 mmol), H2O (1.0 mmol) in CH3CN (3.0
mL) at rt for 18−20 h.
The synthetic importance of β-halo ketene aminals motivated us scrutinizing the scope of 4a
under the optimized conditions shown in entry 20, Table 1 (Scheme 6). The ynamide 1a afforded
Z-β-iodo ketene aminal 4a in 69% yield. The iodo-imidation was fruitfully exhibited for N-
Bn/Me-protected ynamides having electron-rich/-poor arenes in the alkyne-terminus to yield the
products 4b−h [m,p-diMe-4b (64%), m-OMe-4c (60%), p-Cl-4d (40%), p-F-4e (59%), m,p-diCl-
4f (42%), p-CN-4g (23%), and m-F-4h (62%)] (Scheme 6).
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Scheme 6: Scope for anti-Iodo-Imidation of Ynamidesa
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aReactions were carried out using 1 (0.5 mmol), NIS (1.1 mmol), Yb(OTf)3 (0.1 mmol) in CH2Cl2 (3.0
mL) at rt for 8−9 h.
As deliberated in Table 1, Schemes 3 and 4, the reaction of large varieties of ynamides with
CH3CN in the presence of Yb(OTf)3, NIS, and H2O has reliably been demonstrated for the
construction of 2-methyl-bearing peripheral decorated oxazoles 2. The exclusive participation of
CH3CN significantly undermines broad synthetic importance of this demonstration. As the 2-Me
group of oxazole skeleton is acidic, further functionalization of the active-methyl moiety is
therefore possible. As expected, the bromination of methyl-moiety of 2a with NBS in presence
of AIBN smoothly occurred providing the desired bromination product 5 in 56% yield (Scheme
7). Next, the nucleophilic displacement of the bromo group in 5 with carboxylate and azide
moieties constructed C−O (6, 70%) and C−N (7, 96%) bonds (Scheme 7). We therefore believe
the 2-methyl oxazole motifs, fabricated from ynamides and acetonitrile, would be capable of
showing broad synthetic potential.
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Scheme 7: Functionalization of Methyl Group
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Condition a: 2a (0.2 mmol), AIBN (0.01 mmol), NBS (0.22 mmol) in CCl4 (2.0 mL) at 60 °C for 9 h.
Condition b: 5 (0.1 mmol), PhCOOH (0.15 mmol), Et3N (0.3 mmol) in CH3CN (2.0 mL) at 80 °C for 1 h.
Condition c: 5 (0.1 mmol), NaN3 (0.5 mmol), in (CH3)2CO:H2O (3:1; 2.0 mL) at rt for 1 h.
Finally, the robustness of the reaction was tested for gram scale (Scheme 8). Exposing 1a and 1p
(1.0 g) to the mixture of NIS, Yb(OTf)3, and CH3CN yielded 2a (0.87 g, 75%), and 2p (0.94 g,
78%), respectively. Likewise, compounds 3a (0.81 g, 70%) and 4a (1.1 g, 68%) were obtained
from 1a (1.0 g) under the respective optimized conditions of hydroamidation and iodo-imidation
of ynamides (Scheme 8). These results attest the scalability of the transformations.
Scheme 8: Gram Scale Synthesis
To realize the source of water in this study, a set of isotope labeling experiments were
independently carried out between 1a and 18O-labelled H2O or D2O (eq 1, Scheme 9). The
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incorporation of O in the amide and D-insertion in the vinyl position in the hydroamidation
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product (3a′ and 3a″; observed by HRMS and H NMR analysis) clearly expresses the critical
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role of H2O in this study (eq 1, Scheme 9). Next, the conversion of 1a to 2a was planned using
Yb(OTf)3 mediated hydroamidation and NIS-assisted cyclization in a stepwise manner to acquire
preliminary insight into the mechanism and the necessity of NIS in these transformations. As
envisaged, 3a (obtained from 1a) was efficiently converted to 2a (95%), when subjected to NIS
in CH2Cl2 at rt (eq 2, Scheme 9). Thus, the activation of 3a with NIS helps the attack of the
amide-oxygen of N-acetyl group at the β-position of enamide followed by elimination of HI to
afford 2a (eq 2, Scheme 9).
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Scheme 9: Control Experiments
Although the mechanistic details are yet to be established, a plausible mechanism is displayed in
Scheme 10. The transient metalo-ketenininium intermediate II is in-situ generated from
acetonitrile with Yb(OTf)3 possibly involving through Int-I along with the release of TfOH.13
The direct attack of metalo-ketenininium species-II to ynamide (1) results Int-IV; alternatively,
TfOH mediated protonation of ynamide forms the keteniminum species in-situ, which rapidly
reacts with II to generate Int-III (anti to the substituent of the alkyne terminus and syn to the β-
H). Next, the hydration of Int-III produces hydroamidation product (3) with syn-selectivity,
justifying the participation of the Int-III in this transformation.14 In the presence of NIS and
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H2O, Int-IV undergoes Yb-iodo exchange/protodemetalation and hydration to give Int-V.15
Simultaneously, activation of the olefin-moiety in the ketene-aminal V with NIS produces VI.
Finally, SN2-type 5-endo-trig cyclization of the amide-oxygen of the N-acetyl group with the β-
position of enamide followed by elimination of I2/HI to produce highly substituted oxazole 2,
validating the requirements of 2.0 equivalents of NIS for reaction productivity. While the
reaction of ynamide with NIS initially forms an active β-iodo-keteneiminium intermediate VIII,
which subsequently undergoes the nitrile attack followed by hydration to form Int-IX (Scheme
10). Finally, NIS promoted activation of the olefin-moiety of IX followed by the intramolecular
cyclization and elimination of I2 affords 2 albeit in poor yield (entry 7, Table 1). These results
reveal that Yb(OTf)3 facilitates enhancing the reaction outcome.
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Scheme 10: Plausible Mechanism
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In summary, we reveal a convenient and reliable approach for the synthesis of highly peripheral
decorated 4-amino-2,5-disubstituted oxazoles from ynamides in the presence of Yb(OTf)3, NIS,
and H2O in CH3CN at rt. Two and three oxazole skeletons on the arene periphery are erected by
building the molecular complexity. Regio and stereoselective hydroamidation and iodo-imidation
of ynamides reliably provides highly substituted ketene aminals. The robustness of the catalytic
conditions is tested for gram scale synthesis. The H2O18 labelling experiments and sequential
reaction studies shed light on the underlying plausible mechanistic cycle that is involved.
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Experimental Section
General Information
All the reactions were performed in an oven-dried reaction vials. Commercial grade solvents
were distilled prior to use. Column chromatography was performed using silica gel (100−200
Mesh) and neutral alumina eluting with hexanes and ethyl acetate mixture. Thin layer
chromatography (TLC) was performed on silica gel GF254 plates. Visualization of spots on TLC
plate was accomplished with UV light (254 nm) and staining over I2 chamber.
Proton and carbon nuclear magnetic resonance spectra (1H NMR, 13C NMR and 19F NMR) were
recorded on a 400 MHz (1H NMR, 400 MHz; 13C NMR, 101 MHz; 19F NMR, 376 MHz)
spectrometer and 500 MHz (1H NMR, 500 MHz; 13C NMR, 126 MHz; 19F NMR, 470 MHz)
13
spectrometer having solvent resonance as internal standard (1H NMR, CHCl3 at 7.26 ppm; C
1
NMR, CDCl3 at 77.0 ppm). Data for H NMR are reported as follows: chemical shift (ppm),
multiplicity (s = singlet; br s = broad singlet; d = doublet; br d = broad doublet, t = triplet; br t =
broad triplet; q = quartet; m = multiplet), coupling constants J, in (Hz). IR spectra were recorded
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on FT/IR spectrometer and are reported in cm . High resolution mass spectra (HRMS) were
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obtained by using TOF analyzer in ESI mode. Melting points were determined by electro-
thermal heating and are uncorrected. X−ray data was collected at 298K on a Bruker D8 Quest
CCD diffractometer using Mo-Kα radiation (0.71073 Å).
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Materials: Unless otherwise noted, all the reagents and intermediates were obtained
commercially and used without purification. Acetone, dichloromethane (CH2Cl2), toluene,
acetonitrile, ethyl acetate and hexane were distilled over CaH2. THF was freshly distilled over
sodium/benzophenone ketyl under dry nitrogen. Yb(OTf)3, CuI, K3PO4, PdCl2(PPh3)2,
CuSO4·5H2O, trimethylsilane, 1,10−phenanthroline, and aryl iodides were purchased and used as
received.
Following the known literature procedure,16,17,18 compounds 1a−1c, 1e, 1f, 1h, 1i, 1k, 1m−1t,
1v−1z and 1ab are prepared. The analytical and experimental data are exactly matching with
reported values.
General Procedure for the Synthesis of Ynamide 1 (GP−1):16,17,18 Mixture of sulfonamide
(1.0 mmol), CuSO4·5H2O (0.10 mmol, 25 mg), 1,10-phenanthroline (0.20 mmol, 36 mg) and
K3PO4 (2.0 mmol, 425 mg) in dry toluene (5.0 mL) was taken in a Schlenk tube. Subsequently 1-
o
bromo-2-arylacetylene was introduced and the resulting mixture was heated up to 80 C under
the nitrogen atmosphere for 6−8 h. The progress of the reaction was monitored by TLC. Upon
completion, the reaction mixture was cooled to room temperature and diluted with
dichloromethane (10 mL). The crude mixture was filtered through a small pad of Celite and
concentrated under the reduced pressure. The crude residue was purified using column
chromatography on silica gel to provide 1.
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N-(Benzo[d][1,3]dioxol-5-ylethynyl)-N-benzyl-4-methylbenzenesulfonamide (1d): Following
the general procedure GP−1, compound 1d (316 mg) was obtained in 78% yield as yellow solid;
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mp = 120−122 °C; Rf = 0.64 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz,
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CDCl3): δ 7.79 (d, J = 8.4 Hz, 2H), 7.36−7.30 (m, 7H), 6.78 (dd, J = 8.4, 1.6 Hz, 1H), 6.72−6.65
13
(m, 2H), 5.93 (s, 2H), 4.56 (s, 2H), 2.45 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 147.6,
147.2, 144.6, 134.6, 134.4, 129.6, 128.8, 128.4, 128.2, 127.7, 126.1, 115.8, 111.6, 108.3, 101.2,
1
−
80.9, 71.0, 55.6, 21.6; IR (Neat)νmax 3034, 2899, 2237, 1598, 1493, 1446, 1364, 1249 cm ;
HRMS (ESI) for C23H19NNaO4S (M+Na)+: calcd 428.0932, found 428.0931
N-benzyl-4-methyl-N-((3-(trifluoromethyl)phenyl)ethynyl)benzenesulfonamide
(1g):
Following the general procedure GP−1, compound 1g (279 mg) was obtained in 65% yield as
1
pale brown semi solid; Rf = 0.45 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 8.4 Hz, 2H), 7.50−7.45 (m, 1H), 7.43 (br s, 1H), 7.40−7.32 (m, 9H), 4.60
(s, 2H), 2.46 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.9, 134.6, 134.2, 133.9, 129.9,
128.9, 128.7, 128.6, 128.5, 128.2 (q, J = 242 Hz 1C), 127.8, 127.6 (q, J = 15 Hz, 1C), 124.1 (q, J
= 15 Hz, 1C), 123.8, 84.3, 70.5, 55.6, 21.7; 19F NMR (376 MHz, CDCl3) δ −62.7; IR (Neat)νmax
1
+
−
3034, 2936, 2238, 1702, 1597, 1494, 1365, 1330 cm ; HRMS (ESI) for C23H19F3NO2S (M+H) :
calcd 430.1089, found 430.1089.
N-Benzyl-4-methyl-N-(phenanthren-9-ylethynyl)benzenesulfonamide (1j): Following the
general procedure GP−1, compound 1j (323 mg) was obtained in 70% yield as pale yellow semi
solid; Rf = 0.52 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3): δ 8.62 (t,
J = 9.2 Hz, 2H), 7.92 (d, J = 8.4 Hz, 3H), 7.83−7.75 (m, 2H), 7.68−7.50 (m, 4H), 7.48−7.37 (m,
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5H), 7.35 (d, J = 8.0 Hz, 2H), 4.72 (s, 2H), 2.45 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ
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144.9, 134.7, 134.5, 131.2, 131.0, 130.5, 130.0, 129.9, 129.1, 128.7, 128.5, 128.3, 127.9, 127.2,
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126.9, 122.64, 122.59, 119.3, 86.8, 70.3, 55.7, 21.7; IR (Neat)νmax 3064, 2925, 2231, 1596, 1493,
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−
1365 cm ; HRMS (ESI) for C30H24NO2S (M+H) : calcd 462.1528, found 462.1528.
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4-Fluoro-N-methyl-N-(phenylethynyl)benzenesulfonamide (1l): Following the general
procedure GP−1, compound 1l (249 mg) was obtained in 86% yield as yellow solid; mp = 93−95
°C; Rf = 0.72 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3): δ 8.08−7.95
(m, 2H), 7.43−7.36 (m, 2H), 7.35−7.25 (m, 5H), 3.19 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 165.8 (d, J = 258 Hz, 1C), 132.1, 131.4, 130.5 (d, J = 9.1 Hz, 1C), 128.3, 128.0, 122.3, 116.5
(d, J = 23.2 Hz, 1C), 83.4, 69.2, 39.3; 19F NMR (376 MHz, CDCl3) δ −103.1; IR (Neat)νmax 3106,
1
+
−
3075, 2936, 2234, 1696, 1593, 1495, 1454 cm ; HRMS (ESI) for C15H12FNNaO2S (M+Na) :
calcd 312.0470, found 312.0470.
N-((3-Methoxyphenyl)ethynyl)-N,4-dimethylbenzenesulfonamide (1u): Following the general
procedure GP−1, compound 1u (282 mg) was obtained in 72% yield as yellow semi solid; Rf =
1
0.67 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.0
Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 6.97−6.93 (m, 1H), 6.91−6.88 (m,
1H), 6.86−6.82 (m, 1H), 3.79 (s, 3H), 3.15 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 159.2, 144.8, 133.1, 129.8, 129.3, 127.8, 123.8, 123.6, 116.2, 114.2, 83.7, 68.9, 55.2,
1
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39.2, 21.6; IR (Neat)νmax 2939, 2838, 2238, 1699, 1599, 1490, 1460, 1364 cm ; HRMS (ESI) for
C17H18NO3S (M+H)+: calcd 316.1007, found 316.1007.
N-Benzyl-N-((3,4-dichlorophenyl)ethynyl)-4-methylbenzenesulfonamide (1aa): Following
the general procedure GP−1, compound 1aa (357 mg) was obtained in 83% yield as yellow
solid; mp = 117−119 °C; Rf = 0.75 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz,
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CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H), 7.37−7.27 (m, 9H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 4.58 (s,
2H), 2.46 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.9, 134.5, 134.1, 132.4, 132.3, 131.7,
130.14, 130.02, 129.8, 128.8, 128.6, 128.5, 127.6, 122.8, 84.5, 69.6, 55.5, 21.6; IR (Neat)νmax
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3061, 3034, 2924, 2868, 2247, 1925, 1593, 1451 cm ; HRMS (ESI) for C22H17Cl2NNaO2S
(M+Na)+: calcd 452.0255, found 452.0256.
General Procedure for the Preparation of 1a′ and 1a′′ (GP−1A):18f A solution of
bis(bromoethynyl)benzene (1.0 mmol), sulfonamide (2.0 mmol), CuSO4·5H2O (0.2 mmol, 50
mg), 1,10-phenanthroline (0.4 mmol, 72 mg) and K3PO4 (4.0 mmol, 849 mg) in dry toluene (5.0
o
mL) was stirred independently in a Schlenk tube at 80 C for overnight under the nitrogen
atmosphere. The progress of the reaction was monitored by TLC. Upon completion, the reaction
mixture was cooled to room temperature and diluted with dichloromethane (10 mL). The
reaction mixture was filtered through a small pad of Celite and concentrated under the reduced
pressure. The crude residue was purified by using column chromatography on silica gel to
provide arene tethered bis ynamide (1a' and 1a'') in quantitative yields.
N,N'-(1,3-phenylenebis(ethyne-2,1-diyl))bis(N-benzyl-4-methylbenzenesulfonamide) (1a′):
Following the general procedure GP−1A, compound 1a′ (574 mg) was obtained in 89% yield as
1
yellow semi solid; Rf = 0.43 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz,
CDCl3): δ 7.82 (d, J = 8.0 Hz, 4H), 7.39−7.32 (m, 14H), 7.17−7.08 (m, 4H), 4.60 (s, 4H), 2.47 (s,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.7, 134.5, 134.3, 133.3, 130.0, 129.7, 128.8, 128.5,
128.3, 128.1, 127.6, 122.9, 83.1, 70.7, 55.6, 21.6; IR (KBr)νmax 3065, 3034, 2925, 2362, 2236,
1
+
−
1596, 1495, 1302 cm ; HRMS (ESI) for C38H32N2NaO4S2 (M+Na) : calcd 667.1701, found
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N,N'-(1,4-phenylenebis(ethyne-2,1-diyl))bis(N-benzyl-4-methylbenzenesulfonamide) (1a′′):
Following the general procedure GP−1A, compound 1a′′ (516 mg) was obtained in 80% yield as
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yellow solid; mp = 160−162 °C; Rf = 0.45 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR
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(400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 4H), 7.38−7.31 (m, 14H), 7.10 (s, 4H), 4.58 (s, 4H),
2.45 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.7, 134.5, 134.2, 130.7, 129.7, 128.8,
128.5, 128.3, 127.7, 121.9, 84.2, 71.3, 55.6, 21.6; IR (Neat)νmax 3032, 2977, 2926, 2225, 1593,
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+
−
1493, 1452, 1172 cm ; HRMS (ESI) for C38H32N2NaO4S2 (M+Na) : calcd 667.1701, found
667.1700.
N,N',N''-(benzene-1,3,5-triyltris(ethyne-2,1-diyl))tris(N-benzyl-4-methylbenzene
Sulfonamide) (1a′′′):18f A solution of tris(bromoethynyl)benzene (1.0 mmol), sulfonamide (3.0
mmol), CuSO4·5H2O (0.3 mmol, 75 mg), 1,10-phenanthroline (0.6 mmol, 108 mg) and K3PO4
o
(6.0 mmol, 1.27 g) in dry toluene (5.0 mL) was stirred in a Schlenk tube at 80 C for overnight
under the nitrogen atmosphere. The progress of the reaction was monitored by TLC. Upon
completion, the reaction mixture was cooled to room temperature and diluted with
dichloromethane (10 mL). The reaction mixture was filtered through a small pad of Celite and
concentrated under the reduced pressure. The crude residue was purified by using column
chromatography on silica gel to provide 1a′′′ in 94% yield (872 mg) as yellow solid; mp
= 156−158 °C; Rf = 0.26 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.76 (d, J = 6.0 Hz, 6H), 7.36−7.28 (m, 21H), 6.93 (s, 3H), 4.56 (s, 6H), 2.45 (s, 9H); 13C{1H}
NMR (101 MHz, CDCl3) δ 144.8, 134.5, 134.2, 132.0, 129.8, 128.7, 128.5, 128.4, 127.6, 123.1,
1
−
83.6, 70.1, 55.5, 21.6; IR (Neat)νmax 3065, 3034, 2926, 2235, 1583, 1495, 1454, 1366 cm ;
HRMS (ESI) for C54H45N3NaO6S3 (M+Na)+: calcd 950.2368, found 950.2368.
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General Procedure for the Synthesis of 2,4,5-Trisubstituted Oxazoles (2) (GP−2): A mixture
of ynamide 1 (0.5 mmol), N-iodosuccinimide (NIS; 1.1 mmol, 247 mg), Yb(OTf)3 (0.1 mmol, 62
mg) and H2O (1.0 mmol, 18 µL) in freshly distilled acetonitrile (3.0 mL) was stirred at room
temperature for 8−12 h. The progress of the reaction was monitered by TLC. After completion,
the reaction mixture was quenched with saturated aqueous sodium thiosulfate. The organic layer
was separated and the aqeous layer was extracted with ethylacetate (2 × 15 mL). The combined
organic layers were dried over anhydrous sodium sulfate and concentrated under the reduced
pressure. The crude mixture was purified by silica gel column chromatography to give the
product 2.
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4-(N-Benzyl-N-tosyl)-2-methyl-5-phenyloxazole (2a): Following the general procedure GP−2,
compound 2a (184 mg) was obtained in 88% yield as colorless solid; mp = 196−198 °C; Rf =
1
0.48 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.4
Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.39−7.28 (m, 5H), 7.21 (dd, J = 5.6, 2.0 Hz, 2H), 7.12 (dd, J
13
= 5.2, 1.6 Hz, 3H), 4.60 (s, 2H), 2.48 (s, 3H), 2.44 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ
158.2, 147.4, 144.0, 135.4, 134.7, 130.9, 129.5, 129.0, 128.4, 128.2, 128.1, 127.8, 126.8, 125.3,
1
−
53.7, 21.6, 14.2; IR (Neat)νmax 3063, 2926, 2361, 1594, 1446, 1347, 1210 cm ; HRMS (ESI) for
C24H23N2O3S (M+H)+: calcd 419.1429, found 419.1429.
4-(N-Benzyl-N-tosyl)-2-methyl-5-(4-methoxyphenyl)oxazole (2b): Following the general
procedure GP−2, compound 2b (170 mg) was obtained in 76% yield as pale yellow solid; mp
= 189−191 °C; Rf = 0.48 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.80 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 5.6,
2.0 Hz, 2H) 7.13−7.07 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H)) 4.55 (s, 2H), 3.81 (s, 3H), 2.45 (s, 3H),
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2.39 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 157.5, 147.6, 144.0, 135.5, 135.0,
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129.60, 129.57, 129.1, 128.5, 128.1, 127.8, 126.9, 119.7, 113.8, 55.3, 53.8, 21.7, 14.2; IR
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(Neat)νmax 2931, 2838, 1589, 1642, 1243, 1150, 1035 cm ; HRMS (ESI) for C25H25N2O4S
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(M+H)+: calcd 449.1535, found 449.1537.
4-(N-Benzyl-N-tosyl)-2-methyl-5-(3,4-dimethylphenyl)oxazole (2c): Following the general
procedure GP−2, compound 2c (183 mg) was obtained in 82% yield as pale yellow solid; mp
= 144−147 °C; Rf = 0.42 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.79 (d, J = 8.4 Hz, 2H), 7.44 (dd, J = 8.0, 1.2 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H),
7.24−7.18 (m, 2H), 7.16−7.10 (m, 3H), 7.07 (d, J = 8.0 Hz, 1H), 4.58 (s, 2H); 2.45 (s, 3H), 2.41
(s, 3H), 2.24 (s, 3H), 2.22 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.8, 147.6, 143.8,
137.2, 136.3, 135.63, 135.60, 135.0, 130.2, 129.5, 129.1, 128.4, 128.1, 127.7, 126.3, 124.4,
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−
122.8, 53.6, 21.6, 19.7, 19.6, 14.2; IR (Neat)νmax 2920, 1589, 1495, 1446, 1265, 1090, 821 cm ;
HRMS (ESI) for C26H27N2O3S (M+H)+: calcd 447.1742, found 447.1745.
4-(N-Benzyl-N-tosyl)-2-methyl-5-(benzo[d][1,3]dioxol-5-yl)oxazole (2d): Following the
general procedure GP−2, compound 2d (180 mg) was obtained in 78% yield as pale yellow
solid; mp = 203−205 °C; Rf = 0.52 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz,
CDCl3): δ 7.79 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H),
7.20−7.16 (m, 2H), 7.15−7.10 (m, 4H), 6.75 (d, J = 8.4 Hz, 1H), 5.95 (s, 2H), 4.55 (s, 2H), 2.45
(s, 3H), 2.39 (s, 3H), 13C{1H} NMR (101 MHz, CDCl3) δ 157.6, 147.8, 147.5, 147.4, 144.0,
135.5, 134.9, 129.9, 129.6, 129.2, 128.5, 128.2, 127.9, 121.0, 119.9, 108.3, 106.0, 101.2, 53.8,
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−
21.7, 14.2; IR (Neat)νmax 3068, 2904, 2361, 1594, 1490, 1238, 1046, 882 cm ; HRMS (ESI) for
C25H22N2NaO5S (M+Na)+: calcd 485.1147, found 485.1147.
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4-(N-Benzyl-N-tosyl)-2-methyl-5-(4-acetylphenyl)oxazole (2e): Following the general
procedure GP−2, compound 2e (127 mg) was obtained in 55% yield as pale yellow solid; mp
= 182−184 °C; Rf = 0.35 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.92−7.87 (m, 2H), 7.84−7.76 (m, 4H), 7.35 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 5.6, 2.4 Hz, 2H),
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7.12−7.07 (m, 3H), 4.57 (br s, 2H), 2.59 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H); C{1H} NMR (101
MHz, CDCl3) δ 197.5, 159.3, 146.4, 144.3, 136.3, 135.2, 134.7, 133.0, 131.0, 129.7, 129.1,
128.5, 128.4, 128.3, 128.0, 125.1, 53.8, 26.6, 21.7, 14.3; IR (Neat)νmax 3024, 1682, 1605, 1578,
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+
−
1358, 1260, 1156 cm ; HRMS (ESI) for C26H24N2NaO4S (M+Na) : calcd 483.1354, found
483.1349.
4-(N-Methyl-N-tosyl)-2-methyl-5-(3-Fluorophenyl)-oxazole
(2f): Following the general
procedure GP−2, compound 2f (114 mg) was obtained in 65% yield as colorless solid; mp
= 178−180 °C; Rf = 0.42 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.78−7.72 (m, 3H), 7.62−7.57 (m, 1H), 7.44−7.37 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.08−7.0
(m, 1H), 3.10 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 13C{1H} NMR (101 MHz, CDCl3) δ 162.9 (d, J
= 246 Hz, 1C), 158.8, 144.4 (d, J = 3.0 Hz, 1C), 144.1, 134.2 (d, J = 8.0 Hz, 1C), 130.4 (d, J
= 9.1 Hz, 1C), 129.6, 129.1 (d, J = 9.1 Hz, 1C), 128.6, 120.89, 120.86, 115.5 (d, J = 21.2 Hz,
1C), 112.1 (d, J = 24.2 Hz, 1C), 37.1, 21.6, 14.3; 19F NMR (471 MHz, CDCl3) δ −112.1; IR
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+
−
(Neat)νmax 1578, 1484, 1347, 1265, 1024, 882 cm ; HRMS (ESI) for C18H18FN2O3S (M+H) :
calcd 361.1022, found 361.1020.
4-(N-Benzyl-N-tosyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)oxazole (2g): Following the
general procedure GP−2, compound 2g (182 mg) was obtained in 75% yield as colorless solid;
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mp = 152−155 °C; Rf = 0.46 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz,
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CDCl3): δ 7.93 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz,
1H), 7.42 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 5.6, 2.0 Hz, 2H), 7.12 − 6.07
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(m, 3H), 4.57 (s, 2H), 2.46 (s, 3H), 2.45 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 159.0,
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146.1, 144.2, 135.3, 134.6, 132.1, 130.7 (q, J = 33.3 Hz, 1C), 129.7, 129.2, 128.8, 128.5, 128.4,
128.3, 128.0, 127.6, 126.5 (q, J = 253 Hz, 1C), 124.9 (q, J = 4.0 Hz, 1C), 122.0 (q, J = 3.0 Hz,
1C), 53.7, 21.7, 14.3; 19F NMR (376 MHz, CDCl3) δ −62.8; IR (Neat)νmax 3073, 1638, 1583,
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+
−
1452, 1254, 1167, 904 cm ; HRMS (ESI) for C25H22F3N2O3S (M+H) : calcd 487.1303, found
487.1302.
4-(N-Benzyl-N-tosyl)-2-methyl-5-(thiophen-2-yl)oxazole (2h): Following the general
procedure GP−2, compound 2h (132 mg) was obtained in 62% yield as brown color solid; mp
= 152−155 °C; Rf = 0.51 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.79 (d, J = 8.0 Hz, 2H), 7.42 (dd, J = 3.6, 1.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (dd, J
= 5.2, 1.2 Hz, 1H), 7.21 (dd, J = 6.0, 2.0 Hz, 2H), 7.14−7.09 (m, 3H), 7.0 (dd, J = 5.2, 4.0 Hz,
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1H), 4.54 (s, 2H), 2.46 (s, 3H), 2.39 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 157.9, 144.3,
144.1, 135.4, 134.8, 129.9, 129.7, 129.0, 128.4, 128.1, 127.8, 127.2, 126.3, 125.9, 53.6, 21.7,
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14.2; IR (Neat)νmax 3073, 1583, 1495, 1435, 1353, 1172, 1084, 1052 cm ; HRMS (ESI) for
C22H20N2NaO3S2 (M+Na)+: calcd 447.0813, found 447.0818.
4-(N-Methyl-N-tosyl)-2-methyl-5-(naphthalen-1-yl)oxazole (2i): Following the general
procedure GP−2, compound 2i (108 mg) was obtained in 55% yield as light brown solid; mp
= 195−197 °C; Rf = 0.50 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.94−7.87 (m, 3H), 7.79 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.55−7.49 (m, 3H), 7.14
(d, J = 8.0 Hz, 2H), 3.10 (s, 3H); 2.54 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
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159.4, 145.4, 143.6, 135.5, 134.8, 133.6, 131.1, 130.1, 129.2, 128.6, 128.4, 128.2, 126.7, 126.1,
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125.23, 125.19, 124.2, 37.3, 21.5, 14.4; IR (Neat)νmax 3046, 1715, 1589, 1506, 1364, 1156, 1084,
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+
−
cm ; HRMS (ESI) for C22H20N2NaO3S (M+Na) : calcd 415.1092, found 415.1094.
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4-(N-Benzyl-N-tosyl)-2-methyl-5-(phenanthren-9-yl)oxazole (2j): Following the general
procedure GP−2, compound 2j (130 mg) was obtained in 50% yield as pale brown solid; mp
= 200−202 °C; Rf = 0.45 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 8.66 (d, J = 8.0 Hz, 2H), 7.81−7.67 (m, 4H), 7.65−7.58 (m, 2H), 7.48 (s, 1H), 7.44−7.34 (m,
2H), 7.10 (d, J = 8.0 Hz, 2H), 7.04 (br t, J = 7.2 Hz, 3H), 6.98−6.92 (m, 2H), 4.60 (s, 2H), 2.54
(s, 3H), 2.31 (s, 3H), 13C{1H} NMR (101 MHz, CDCl3) δ 159.5, 147.9, 143.7, 135.8, 135.2,
133.5, 130.88, 130.85, 130.6, 130.2, 130.1, 129.5, 129.4, 129.3, 128.3, 128.2, 127.8, 127.7,
126.8, 126.6, 126.5, 126.2, 122.7, 122.5, 122.4, 53.4, 21.6, 14.6; IR (Neat)νmax 3073, 1589, 1446,
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+
−
1353, 1161, 1046, 816 cm ; HRMS (ESI) for C32H27N2O3S (M+H) : calcd 519.1742, found
519.1748.
N-Benzyl-N-(2-methyl-5-phenyloxazol-4-yl)benzenesulfonamide (2k): Following the general
procedure GP−2, compound 2k (182 mg) was obtained in 90% yield as colorless solid; mp
= 189−190 °C; Rf = 0.51 (4:1 hexane/EtOAc); [Silica, UV and I2]; 1H NMR (400 MHz, CDCl3):
δ 7.96 (d, J = 8.0 Hz, 2H), 7.72 (dd, J = 7.2, 1.6 Hz, 2H), 7.69−7.63 (m, 1H), 7.61−7.54 (m, 2H),
7.36−7.28 (m, 3H), 7.20 (dd, J = 6.0, 2.0 Hz, 2H), 7.15−7.08 (m, 3H), 4.61 (s, 2H), 2.43 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 147.4, 138.4, 134.6, 133.1, 130.8, 129.1, 128.9, 128.5
128.4, 128.2, 128.1, 127.8, 126.7, 125.3, 53.8, 14.2; IR (Neat)νmax 2926, 2853, 1583, 1495, 1448,
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+
−
1350, 1268, 1159 cm ; HRMS (ESI) for C23H20N2NaO3S (M+Na) : calcd 427.1092, found
427.1092.
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4-Fluoro-N-methyl-N-(2-methyl-5-phenyloxazol-4-yl)benzenesulfonamide (2l): Following
the general procedure GP−2, compound 2l (83 mg) was obtained in 48% yield as colorless thick
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liquid; Rf = 0.57 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz, CDCl3): δ
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7.95−7.89 (m, 4H), 7.44 (t, J = 7.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.24−7.17 (m, 2H), 3.11 (s,
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3H), 2.44 (s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 165.4 (d, J = 257 Hz, 1C), 158.4, 145.5,
133.5, 133.4, 132.9, 131.3 (d, J = 9.1 Hz, 1C), 128.7, 126.9, 125.0, 116.1 (d, J = 22.2 Hz, 1C),
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27.2, 14.2; F NMR (376.4 MHz) δ -104.7; IR (Neat)νmax 3060, 2926, 2848, 1629, 1588, 1495,
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+
−
1366, 1159 cm ; HRMS (ESI) for C17H15FN2NaO3S (M+Na) : calcd 369.0685, found 369.0687.
N-Methyl-N-(2-methyl-5-phenyloxazol-4-yl)-4-(trifluoromethyl)benzenesulfonamide (2m):
Following the general procedure GP−2, compound 2m (109 mg) was obtained in 55% as pale
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yellow solid; mp = 180−182 °C; Rf = 0.50 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR
(400 MHz, CDCl3): δ 8.05 (d, J = 8.0, 2H), 7.94−7.88 (m, 2H), 7.80 (d, J = 8.0 Hz, 2H),
7.49−7.42 (m, 2H), 7.41−7.33 (m, 1H), 3.15 (s, 3H), 2.46 (s, 3H), 13C{1H} NMR (101 MHz,
CDCl3) δ 158.6, 145.8, 141.2, 134.7 (q, J = 33 Hz, 1C), 132.7, 126.8 (q, J = 263 Hz, 1C), 129.1,
128.9, 128.8, 126.9, 126.2−125.9 (m, 1C), 125.1, 124.7, 122.0, 37.4, 14.3; 19F NMR (471 MHz)
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−
δ -63.1; IR (Neat)νmax 2920, 1593, 1448, 1365, 1319, 1128, 1061, 622 cm ; HRMS (ESI) for
C18H16F3N2O3S (M+H)+: calcd 397.0834, found 397.0839.
4-Bromo-N-methyl-N-(2-methyl-5-phenyloxazol-4-yl)benzenesulfonamide (2n): Following
the general procedure GP−2, compound 2n (166 mg) was obtained in 82% as pale brown solid;
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mp = 172−174 °C; Rf = 0.35 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz,
CDCl3): δ 7.93−7.89 (m, 2H), 7.78−7.74 (m, 2H), 7.68−7.64 (m, 2H), 7.47−7.41 (m, 2H),
7.38−7.33 (m, 1H), 3.11 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 145.7,
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136.6, 132.9, 132.2, 130.1, 128.8, 128.4, 126.9, 125.1, 37.3, 14.3; IR (Neat)νmax 3090, 1634,
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+
−
1572, 1386, 1267, 1071, 859 cm ; HRMS (ESI) for C17H16BrN2O3S (M+H) : calcd 407.0065,
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3-(2-Methyl-5-phenyloxazol-4-yl)oxazolidin-2-one (2o): Following the general procedure
GP−2, compound 2o (79 mg) was obtained in 65% yield as yellow color gummy liquid; Rf = 0.41
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(1:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz, CDCl3): δ 7.64−7.59 (m, 2H),
7.41 (t, J = 7.2 Hz, 2H), 7.36−7.32 (m, 1H), 4.59−4.51 (m, 2H), 4.04−3.98 (m, 2H), 2.50 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 159.1, 156.4, 143.5, 129.7, 128.8, 128.5, 127.1, 125.0, 62.8,
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−
46.0, 14.2; IR (Neat)νmax 2921, 1758, 1634, 1583, 1418, 1257, 1211 cm ; HRMS (ESI) for
C13H12N2NaO3 (M+Na)+: calcd 267.0746, found 267.0746.
4-(N-Benzyl-N-mesyl)-2-methyl-5-phenyloxazole (2p): Following the general procedure
GP−2, compound 2p (128 mg) was obtained in 75% yield as yellow solid; mp = 190−192 °C; Rf
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= 0.50 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz, CDCl3): δ 7.68−7.64 (m,
2H), 7.33−7.27 (m, 3H), 7.24 (dd, J = 4.8, 2.0 Hz, 2H), 7.16−7.13 (m, 3H), 4.76 (s, 2H), 3.15 (s,
3H), 2.50 (s, 3H), 13C{1H} NMR (101 MHz, CDCl3) δ 158.7, 147.2, 134.7, 131.1, 129.3, 128.7,
128.31, 128.26, 128.1, 126.6, 125.3, 54.6, 38.5, 14.3; IR (Neat)νmax 2910, 1329, 1593, 1494,
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+
−
1448, 1340, 1267, 1169 cm ; HRMS (ESI) for C18H18N2NaO3S (M+Na) : calcd 365.0936, found
365.0930.
N-Methyl-N-(2-methyl-5-phenyloxazol-4-yl)butane-1-sulfonamide (2q): Following the
general procedure GP−2, compound 2q (52 mg) was obtained in 27% yield as colorless gummy
1
liquid; Rf = 0.64 (4:1 hexane/EtOAc); [Silica, UV and I2]; H NMR (400 MHz, CDCl3): δ
7.91−7.87 (m, 2H), 7.44−7.39 (m, 2H), 7.36−7.30 (m, 1H), 3.31−3.27 (m, 2H), 3.26 (s, 3H), 2.49
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(s, 3H), 1.94−1.85 (m, 2H), 1.53−1.44 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); C{1H} NMR (101
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MHz, CDCl3) δ 158.6, 145.3, 133.0, 128.7, 126.9, 125.0, 50.2, 37.8, 24.7, 21.7, 14.3, 13.6; IR
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−
(Neat)νmax 3060, 2962, 2931, 2874, 2853, 1588, 1443, 1263 cm ; HRMS (ESI) for
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C15H20N2NaO3S (M+Na)+: calcd 331.1092, found 331.1092.
General Procedure for the Synthesis of Bis−Oxazole 2u and 2v (GP−3): A mixture of arene
tethered bis-ynamide 1a′/1a′′ (0.3 mmol), NIS (1.32 mmol, 297 mg), Yb(OTf)3 (0.12 mmol, 74
mg) and H2O (1.2 mmol, 22 µL) in freshly distilled acetonitrile (3.0 mL) was stirred at room
temperature for 18 h. The progress of the reaction was monitered by TLC. Upon complete
consumption of precursor, the reaction mixture was quenched with saturated sodium thiosulfate.
The organic layer was separated and the aqeous layer was extracted with ethylacetate (2 × 15
mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under
the reduced pressure. The crude mixture was purified by silica gel column chromatography to
give bis-oxazole 2u/2v.
N,N'-(5,5'-(1,3-Phenylene)bis(2-methyloxazole-5,4-diyl))bis(N-benzyl-4-methylbenzene
sulfonamide) (2u): Following the general procedure GP−3, compound 2u (102 mg) was
obtained in 45% yield as colorless thick liquid; Rf = 0.48 (1.5:1 hexane/EtOAc); [Silica, UV and
I2]; 1H NMR (400 MHz, CDCl3): δ 7.94 (br s, 1H), 7.81 (d, J = 8.4 Hz, 4H), 7.72 (dd, J = 8.0, 2.0
Hz, 2H), 7.34 (d, J = 8.0 Hz, 4H), 7.30−7.24 (m, 2H), 7.21−7.16 (m, 4H), 7.09−7.04 (m, 5H),
13
4.58 (br s, 4H), 2.47 (s, 6H), 2.46 (s, 6H); C{1H} NMR (101 MHz, CDCl3): δ 158.4, 146.9,
144.0, 135.4, 134.7, 131.3, 129.6, 129.0, 128.4, 128.3, 128.1, 127.9, 126.7, 125.3, 121.8, 53.7,
1
−
21.6, 14.2; IR (Neat) νmax 2921, 1712, 1629, 1593, 1490, 1350, 1263, 1159 cm ; HRMS (ESI)
for C42H39N4O6S2 (M+H)+: calcd 759.2311, found 759.2313.
ACS Paragon Plus Environment