Regioselective Functionalization of Ester-, Amide-, Carbonate-, and Carbamate-Substituted 2-Phenyl-2-oxazolines with Mixed Lithium-Magnesium Amides

Article abstract of DOI:10.1021/acs.joc.0c02369

We have prepared novel highly functionalized benzene derivatives by regioselective metalation of ester-, amide-, carbamate-, and carbonate-substituted 2-phenyl-2-oxazolines with mixed lithium-magnesium amides followed by reaction with different electrophiles. While a complementary metalation site can be accessed by using different bases, steric and electronic effects promoted by the aromatic ring substituents also play an important role in reaction regioselectivity. Computational calculations of the aromatic hydrogen pKa values have helped us to rationalize the metalation preference by the complex-induced proximity effect concept.

Full text of DOI:10.1021/acs.joc.0c02369

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Regioselective Functionalization of Ester‑, Amide‑, Carbonate‑, and
Carbamate-Substituted 2‑Phenyl-2-oxazolines with Mixed Lithium−
Magnesium Amides
Leandro A. Bozzini, Thiago dos Santos,§ Valter E. Murie,§ Murilo B. M. de Mello, Ricardo Vessecchi,
and Giuliano C. Clososki*
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ABSTRACT: We have prepared novel highly functionalized
benzene derivatives by regioselective metalation of ester-, amide-,
carbamate-, and carbonate-substituted 2-phenyl-2-oxazolines with
mixed lithium−magnesium amides followed by reaction with
different electrophiles. While a complementary metalation site can
be accessed by using different bases, steric and electronic effects
promoted by the aromatic ring substituents also play an important
role in reaction regioselectivity. Computational calculations of the
aromatic hydrogen pKa values have helped us to rationalize the
metalation preference by the complex-induced proximity effect
concept.
Scheme 1. Some Strategies for the Functionalization of 2-
Phenyl-2-oxazolines Using Metalation
olecules bearing 2-oxazoline rings display diverse
1
Mbiological activities including antibiotic,
anti-inflam-
matory,2 antimalarial,3 anticancer,4 and antidepressant5
actions. In addition, the 2-oxazoline function has already
proved its synthetic utility as a carboxylic acid protecting group
and ligand in asymmetric synthesis,6−8 being pyridino-bis-2-
oxazolines (PYBOX)7 and bis-oxazolines (BOX)8 the most
frequently used derivatives.
Developing selective protocols to obtain functionalized
aromatic compounds is essential in natural product synthesis
and drug discovery.9 Although numerous reactions concerning
transition metal-mediated C−H activation of aromatics have
been developed,10 only a few reactions offer more
regioselectivity and efficiency than the ortho-metalation of
aromatics.11 Initially explored by Meyers and co-workers,12 the
ortho-lithiation of 2-aryl-2-oxazolines is a classic strategy in
organic synthesis.12 However, the organolithium intermediates
are highly reactive, which is an important drawback that may
preclude the presence of sensitive functional groups in the
substrate.13 To address this issue, an interesting approach is to
explore the higher tolerance of organomagnesium reagents
(Scheme 1).14
Over the past decade, the mixed lithium−magnesium amides
TMPMgCl·LiCl and TMP2Mg·2LiCl (TMP = 2,2,6,6-
tetramethylpiperidine) have emerged as alternative reagents
for the metalation of aromatic and heterocyclic substrates.15
Given our interest in regioselective metalation reactions and
the medicinal importance of the 2-oxazoline core, our research
group has reported the selective functionalization of
halophenyl-2-oxazolines16 and cyanophenyl-2-oxazolines17
Received: October 6, 2020
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with TMPMgCl·LiCl at room temperature. In both cases, the
powerful ability of the 2-oxazolinyl group to direct metalation
at the ortho position overcame the influence of the halogen-
and cyano-substituents. Recently, Nachtsheim and co-workers
reported the use of an excess of the same base to promote
direct hydroxylations of several 2-aryloxazolines.18
Scheme 2. Selective Metalation of 2-Phenyl-2-oxazolines
Bearing Ester or Amide Groups with TMPMgCl·LiCl
followed by Reactions with Electrophiles [Substrates:
Methyl 4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)benzoate
(1a), Methyl 3-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1b), Methyl 2-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)benzoate (1c), 4-(4,4-Dimethyl-4,5-
dihydrooxazol-2-yl)-N,N-diethylbenzamide (1e), 3-(4,4-
Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethylbenzamide
(1f), 2-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N,N-
diethylbenzamide (1g)]
On the basis of our last results,16,17 we have envisaged that
2-phenyl-2-oxazolines bearing more hindered and coordinating
substituents, such as esters, amides, carbamates, and
carbonates, could open different possibilities to explore the
regioselective functionalization of the aromatic ring via
TMPMgCl·LiCl and TMP2Mg·2LiCl.
We initiated our study by preparing the 2-phenyl-2-
oxazolines bearing methyl ester groups at the ortho, meta, or
para position (1a−c) from the corresponding substituted
benzaldehydes.19 To determine the best base for the
metalation of these substrates, we used 1a as a model substrate
and varied the reaction conditions. We monitored the
metalation reactions by analyzing reaction aliquots quenched
with iodine by GC−MS. As expected, attempts to perform the
lithiation of 1a with n-BuLi or LDA (1.1 equiv, −78 °C, 1 h)
exclusively afforded ester group addition products (tertiary
alcohol and amide in 50 and 59% isolated yields, respectively).
In contrast, while TMPLi and TMPZnCl·LiCl presented low
reactivity toward 1a, the mixed lithium magnesium amide
TMPMgCl·LiCl (1.1 equiv) successfully provided complete
magnesiation of the starting material at room temperature
within one hour. After iodination, we isolated the iodide 3a in
79% yield (Scheme 2), confirming that magnesiation occurred
at the ortho position of the 2-oxazoline group.
Quenching the organomagnesium 2a with diphenyl disulfide
and benzaldehyde afforded 3b and 3c in 70% and 67% yields,
respectively (Scheme 2). The transmetalation of this organo-
magnesium reagent with ZnCl2 followed by reaction with 1-
chloro-4-iodobenzene in the presence of Pd(PPh3)4 (4 mol %)
produced the expected biaryl derivative 3d in 79% yield.
Interestingly, steric and electronic factors appeared to
govern the magnesiation of the phenyl-2-oxazoline 1b with
TMPMgCl.LiCl in the synthesis of 3e and 3f in 60 and 73%
yields, respectively. Additionally, in the case of the ortho-
substituted substrate 1c, the powerful ability of the 2-oxazolinyl
group to direct metalation at the ortho position also seemed to
overcome the influence of the methyl ester substituent, giving
the derivatives 3g and 3h in 69 and 75% yields after the
reaction of 2c with iodine and diphenyl diselenide,
respectively. Notably, this oxazoline ortho-directing metalation
effect also allowed the regioselective synthesis of the
tetrasubstituted derivative 3i in 73% yield from 1d bearing
the t-butyl ester group. Due to its high stability toward
organometallic reagents, amides were also considered as
substituents of 2-phenyl-2-oxazolines. We prepared com-
pounds 1e−g and used 1e as a model substrate in the
preliminary metalation studies. Interestingly, when we used 1.1
equiv of TMPMgCl·LiCl, we achieved full, exclusive metal-
ation at the ortho position to the 2-oxazoline group within one
hour. We obtained six trisubstituted compounds (3j−o) with
yields ranging from 66 to 79% (Scheme 2).
a
b
c
Isolated yields. 0.05 mmol scale. 10 mmol scale (2.51 g of 3a was
d
isolated). 4 mol % [Pd(PPh3)4] under Negishi cross-coupling
reaction conditions using an oil bath as a heat source after
transmetalation with 1 mol L−1 ZnCl2 anhydrous solution in THF.
diphenyl diselenide gave the corresponding functionalized
derivatives 5a and 5b in moderate yields. Furthermore, the
reaction of 4a with benzaldehyde afforded the lactone
derivative 5c in 51% yield. As a limitation, the reaction of 1b
with TMP2Mg·2LiCl was not selective, giving mixtures of
iodides (1:1 ratio of both isomers) after the reaction was
quenched with iodine. On the other hand, trapping 4c with
iodine, diphenyl disulfide, and diphenyl diselenide produced
5d, 5e, and 5f with yields up to 69%. Finally, after
transmetalation of 4c with ZnCl2, a Negishi cross-coupling
reaction with 1-chloro-4-iodobenzene in the presence of
Pd(PPh3)4 (4 mol %) provided 5g in 79% yield.
Contrary to TMPMgCl·LiCl, the metalation of type 1a−c
substrates with TMP2Mg·2LiCl preferentially occurred at the
ortho position relative to the ester groups (Scheme 3). Hence,
the reaction of 1a with 1.4 equiv of TMP2Mg·2LiCl led to
complete magnesiation of the starting material within 1 h.
Quenching of the organomagnesium 4a with iodine and
We also studied the metalation of 2-phenyl-2-oxazolines
bearing pivalate, carbonate, and carbamate as bulky groups. As
B
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Scheme 3. Selective Metalation of 2-Phenyl-2-oxazolines
Bearing an Ester Group with TMP2Mg·2LiCl followed by
Reactions with Electrophiles
Scheme 5. Magnesiation of 2-Phenyl-2-oxazolines of Type 6
followed by Reactions with Electrophiles
a
b
Isolated yields. Reaction quenching with benzaldehyde gave the
c
lactone derivative as the only product. Four mol % [Pd(PPh3)4]
under Negishi cross-coupling reaction conditions using an oil bath as
a heat source after transmetalation with 1 mol L−1 ZnCl2 anhydrous
solution in THF.
expected, attempts to promote lithiation of 6a with n-BuLi
(−78 °C for 1 h) gave the phenol 7 as a result of nucleophilic
attack at the ester group. Moreover, the use of the more
hindered lithium base TMPLi afforded a mixture of 7 and the
diketone 8. In this case, 8 could arise from an intermolecular
attack of the generated ortho-2-oxazoline anion to the ester
group in the substrate, whereas the respective acylated product,
which was even more reactive than the substrate (for pKa
calculations, see Supporting Information), could undergo new
deprotonation, to give 8 after an anionic Fries rearrangement
(Scheme 4).
a
Isolated yields.
presence of the Boc group in 9e, allowing efficient metalation
at the ortho position to the 2-oxazoline function at room
temperature within 1 h. Quenching the organomagnesium
intermediate with iodine or diphenyl diselenide enabled us to
isolate the corresponding derivatives 10h and 10i in 71 and
79% yields, respectively. In contrast, magnesiation of
carbamate 6f followed by iodination gave a mixture of C-2
and C-4 iodo-substituted isomers 10j and 10k in 54 and 25%
yields, respectively.
Scheme 4. Reaction of 2-Phenyl-2-oxazoline 6a with n-BuLi
and TMPLi
To rationalize the reactivity of the substrates and the
regioselective control observed during the metalation of 2-
phenyl-2-oxazolines, we conducted a computational study to
obtain the pKa values for the aromatic hydrogens of these
compounds. The use of computational chemistry to calculate
pKa values is currently an important tool to guide experimental
design.20
According to the computational study, in the case of
substrates type 1 in THF, the most acidic H atom of the
aromatic ring is located at the ortho position in relation to the
ester or the amide group (pKa values around 42; see
Experimental Section). Furthermore, the most acidic hydro-
gens in the studied phenyl pivalates (pKa: 34.9−38.6), phenyl
carbonates (pKa: 38.0−39.4), and carbamates (pKa: 38.8−
41.3) are located at the ortho position relative to these
functional groups. When the base TMPMgCl·LiCl is used,
deprotonation of the carbon in the ortho position to the
oxazolinyl group is clearly related to the directing metalation
effect promoted by the oxazoline group nitrogen and may be
rationalized by the complex-induced proximity effect concept
affording kinetic rather than the expected thermodynamic
products.21
The bases TMPMgCl·LiCl and TMP2Mg·2LiCl showed
similar reactivity toward 6a, which allowed iodination at the
ortho position of the 2-oxazoline group furnishing 10a in 80%
yield. Therefore, we decided to use TMPMgCl·LiCl to
synthesize other trisubstituted derivatives of type 10 (Scheme
5). This base also tolerated the presence of the Boc and
carbamate groups at the para position. Quenching the
organomagnesium intermediates 9a−f with different electro-
philes afforded derivatives 10a−f in 60 to 80% yields.
Interestingly, metalation of the substrate bearing Boc and
pivaloyl groups at the meta position (6d and 6e) appeared to
present complementary regioselectivity, producing 10g−i in
good yields. Thus, after magnesiation of 6d with TMPMgCl·
LiCl, further iodination afforded exclusively 10g in 69% yield.
This mixed lithium−magnesium amide also tolerated the
DFT calculations have been used to investigate how
substrate complexation with metal amides and salts affects
C
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the regioselectivity and deprotonation rates.22,23 Here, we
employed DFT calculations to investigate how oxazoline group
coordination with both LiCl and TMPMgCl influenced the
acidity of the aromatic hydrogens of substrates 1a−c (see
Experimental Section). While the acidity of the hydrogens that
are in the vicinity of the 2-oxazoline group that coordinates to
both reagents (LiCl and TMPMgCl) clearly increased,
coordination of the substrates with TMPMgCl appeared to
generate more stable complexes and to affect the pKa values
more significantly. Moreover, the effect of base coordination
on the acidity of H-4 appeared to be crucial to rationalize the
selective metalation of meta-substituted phenyl-2-oxazolines
such as substrate 1b by TMPMgCl·LiCl. Furthermore, the
complementary reactivity of the base TMP2Mg·2LiCl with
substrates of type 1 may be associated with faster complexation
with the ester or the amide groups present in these molecules,
while the different regioselectivity observed in the metalation
of 2-oxazoline substrates of type 6 bearing bulky groups
provided insights into how a combination of electronic and
steric effects governed these reactions.
To illustrate the synthetic relevance of the developed
methodologies, we also evaluated the sequential regioselective
difunctionalization of a 2-phenyl-2-oxazoline by using the
mixed lithium/magnesium base. Thus, after selective magne-
siation of 1a at the ortho position to the 2-oxazoline group with
TMPMgCl·LiCl, reaction with diphenyl diselenide led to 11 in
80% yield. Subsequently, magnesiation at the ortho position to
the methyl ester group of 11 with TMP2Mg·2LiCl followed by
quenching of the same electrophile afforded the tetrasub-
stituted aromatic derivative 12 in 48% yield. Moreover,
functionalized phenyl-2-oxazoline 11 was used as a substrate
to synthesize a derivative of tamibarotene, a synthetic retinoid
that is used to treat acute promyelocytic leukemia (APL) in
Japan and a potential candidate to treat Alzheimer’s disease.24
Thus, the reaction of 11 with the lithium amide 1325 in THF
at 0 °C for 4 h furnished 14 in 65% yield. Subsequent
hydrolysis in the presence of oxalic acid generated the
tamibarotene derivative 15 in 81% yield (Scheme 6).
organomagnesium species generated with TMPMgCl·LiCl and
TMP2Mg·2LiCl are straightforwardly trapped with distinct
electrophiles to afford a series of substituted oxazolines in
moderate to high yields. As expected, steric and electronic
effects promoted by the aromatic ring substituents also play an
important role in the metalation regioselectivity. Moreover,
computational calculations of the aromatic hydrogen pKa
values have helped us to rationalize the metalation preference
by the complex-induced proximity effect concept. To exemplify
the feasibility and the synthetic potential of this chemistry, we
have described the prompt preparation of an anticancer
tamibarotene derivative.
EXPERIMENTAL SECTION
■
General Considerations. The solvents were purified according to
standard procedures.26 The starting materials were purchased from
Sigma-Aldrich Corp. All air-sensitive and/or water-sensitive reactions
were carried out with dry solvents under anhydrous conditions and a
nitrogen atmosphere. Standard syringe techniques were applied to
transfer dry solvents and air-sensitive reagents. The reactions
performed under heating comprised the use of an oil bath. The
reactions were monitored by TLC on Merck silica gel (60 F 254) by
using UV light. Aldrich silica gel (particle size 0.040−0.063 nm) was
used for flash chromatography. The NMR spectra were recorded on
Bruker DPX 300, 400, and 500 instruments (at 300, 400, and 500
MHz for protons and at 75, 100, and 125 MHz for carbon-13,
respectively). CDCl3, methanol-d4, and DMSO-d6 were employed as
solvents. The chemical shifts are reported as δ units in parts per
million (ppm) relative to the solvent residual peak as the internal
reference. Coupling constants (J) are reported in hertz, and
multiplicities of NMR signals are abbreviated as follows: bs = broad
singlet, s = singlet, d = doublet, dd = doublet of doublets, ddd =
doublet of doublet of doublets, t = triplet, td = triplet of doublets, m =
multiplet, q = quartet and combinations thereof, app = apparent. The
melting point values (mp) were determined in a Buchi brand, model
̈
B-545. The HRMS spectra were acquired on a Bruker Daltonics
micrOTOF QII/ESI-TOF.
Typical Procedure 1 (TP1): General Procedure for the
Preparation of Ester-, Carbonate and Carbamate-Substituted 2-
Phenyl-2-Oxazolines (1a−d and 6a−f). 2-Amino-2-methyl-1-prop-
anol (0.9 mL, 1.8 g, 10 mmol) was dissolved in CH2Cl2 (60 mL), and
the substituted benzaldehyde (10 mmol) was added. The mixture was
stirred over molecular sieves (4 Å, 10 g) for 14 h. Afterward, N-
bromosuccinimide (1.8 g, 10 mmol) was added, and the solution was
stirred for 30 min. The mixture was filtered, and the filtrate was
washed with saturated aqueous NaHCO3 solution (100 mL) and H2O
(30 mL). The organic layer was dried with MgSO4, and the solvent
was removed under pressure. The residue was purified by flash
column chromatography (silica gel, hexanes/ethyl acetate).
Scheme 6. Difunctionalization of 1a Using Sequential
Regioselective Metalations and Synthesis of the
Tamibarotene Derivative 15
Typical Procedure 2 (TP2): General procedure for the
preparation of amide-substituted 2-phenyl-2-oxazolines (1e−g).
In a flame-dried flask flushed with nitrogen and equipped with a
magnetic stirring bar, diethylamine (0.57 mL, 5.5 mmol) was
dissolved in THF (10 mL). This solution was cooled to −78 °C,
and n-BuLi solution (2.3 M in hexane, 2.13 mL, 5.0 mmol) was added
dropwise. After the addition was completed, the reaction mixture was
warmed to 0 °C and stirred at this temperature for 30 min. The
corresponding methyl ester-substituted 2-phenyl-2-oxazoline (1a−c)
(1.16 g, 5.0 mmol) was dissolved in THF (10 mL) and added to the
reaction mixture at 0 °C, and the mixture was stirred for 4 h. The
reaction mixture was quenched with saturated aqueous NH4Cl
solution (20 mL), extracted with ethyl acetate (3 × 50 mL), and dried
with MgSO4. After filtration, the solvent was removed under a
vacuum. The residue was purified by flash column chromatography
(silica gel, hexanes/ethyl acetate).
We have demonstrated that numerous substituted benzene
derivatives can be prepared in a regioselective fashion by using
the mixed lithium−magnesium amides TMPMgCl·LiCl and
TMP2Mg·2LiCl. Interestingly, even when competitive ortho-
directing groups such as esters, amides, carbamates, and
carbonates are attached to the aromatic ring, the metalation of
2-phenyl-2-oxazolines with TMPMgCl·LiCl occurs exclusively
at the ortho position to the 2-oxazoline group. On the other
hand, complementary regioselectivity can be obtained when
the methyl ester-substituted 2-phenyl-2-oxazolines are meta-
lated with the diamide TMP2Mg·2LiCl. In both cases, the
Typical Procedure 3 (TP3): Preparation of TMPMgCl·LiCl in THF.
A dry and nitrogen-flushed Schlenk flask equipped with a magnetic
stirring bar and rubber septum was charged with i-PrMgCl·LiCl (1.0
D
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mol/L in THF, 20 mL, 20 mmol). Then, 2,2,6,6-tetramethylpiper-
idine (3.52 mL, 21 mmol) was added dropwise through a syringe
within 5 min. The mixture was stirred until gas evolution ceased (48
h). Titration against benzoic acid in THF (0 °C) in the presence of 4-
(phenylazo)diphenylamine as the indicator showed that the base
concentration ranged from 0.90 to 0.98 M.
Typical Procedure 4 (TP4): Selective Magnesiation of 2-Phenyl-
2-oxazolines with TMPMgCl·LiCl followed by Reaction with
Electrophiles. In a dry nitrogen-flushed round-bottom flask under
magnetic stirring containing 2 mL of THF and the 2-phenyl-2-
oxazoline (0.50 mmol), a TMPMgCl·LiCl solution (0.9 M, 0.62 mL,
0.55 mmol) was added dropwise at 25 °C. After stirring for 1 h, a
solution of an appropriate electrophile (1.3 equiv) in THF (1.0 mL)
was added, and the reaction mixture was kept under stirring from 1 h
(iodine) to 12 h (other electrophiles). The reaction was quenched
with saturated aqueous Na2S2O4 (iodine) or NH4Cl (other
electrophiles), the products were extracted with ethyl acetate (3 ×
15 mL), and the organic layer was dried with MgSO4. The solvent was
removed under reduced pressure. The residue was purified by flash
column chromatography (silica gel, hexanes/ethyl acetate).
Typical Procedure 5 (TP5): Preparation of TMP2Mg·2LiCl. In a dry
25 mL flask under a nitrogen atmosphere and equipped with magnetic
stirring, 2,2,6,6-tetramethylpiperidine (0.12 mL, 0.725 mmol) was
dissolved in THF (2 mL). The solution was cooled to −78 °C, and n-
BuLi (2.35 M, 0.3 mL, 0.7 mmol) was added dropwise. After that, the
reaction mixture was warmed to 0 °C and was left at this temperature
for 30 min. Previously titrated TMPMgCl·LiCl (0.9 M, 0.78 mL, 0.7
mmol) was then added dropwise to the reaction mixture, which was
left at 0 °C for 15 min and at room temperature for 30 min.
Typical Procedure 6 (TP6): Selective Magnesiation of 2-Phenyl-
2-oxazolines with TMP2Mg·2LiCl followed by Reaction with
Electrophiles. Following TP5, phenyl-2-oxazoline was added (116.0
mg, 0.5 mmol) in THF (2.0 mL). After stirring for 1 h, a solution of
an appropriate electrophile (1.3 equiv) in THF (1.0 mL) was added,
and the reaction mixture was kept under stirring for 1 h (for iodine)
to 12 h (other electrophiles). The reaction was quenched with
saturated aqueous NH4Cl, the products were extracted with ethyl
acetate (3 × 15 mL), and the organic layer was dried with MgSO4.
The solvent was removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, hexanes/ethyl
acetate).
tert-Butyl 5-Cyano-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-
benzoate (1d). Following TP4, 4-(4,4-dimethyl-4,5-dihydrooxazol-
2-yl)benzonitrile (600 mg, 3 mmol) and di-tert-butyl decarbonate (0.9
mL, 3.9 mmol) afforded 1d (540 mg, 60%) as a white solid after
chromatographic purification with hexanes/ethyl acetate (8:2) as an
eluent: mp 121−123 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
1.5 Hz, 1H), 7.84, (d, J = 8.1 Hz, 1H), 7.71 (dd, J = 8.1, 1.5 Hz, 1H),
4.16 (s, 2H), 1.51 (s, 9H), 1.40 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.4 (2C), 137.2, 135.2, 133.7, 132.5, 130.8, 117.3, 114.9,
83.5, 80.7, 67.8, 28.0 (3C), 27.7 (2C); HRMS (ESI) m/z [M +
H]+calcd for C17H21N2O3 301.1547, found 301.1543.
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethylbenzamide
(1e). Following TP2, methyl 4-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1a, 1.16 g, 5.0 mmol) afforded 1e (1.10 g, 80%) as a
white solid after chromatographic purification with hexanes/ethyl
1
acetate (7:3−100% ethyl acetate) as an eluent: mp 99−101 °C; H
NMR (400 MHz, CDCl3) δ 7.97 (d-like, J = 8.6 Hz, 2H), 7.40 (d-like,
J = 8.6 Hz, 2H), 4.12 (s, 2H), 3.56−3.54 (m, 2H), 3.22−3.21 (m,
2H), 1.39 (s, 6H), 1.27−1.23 (m, 3H), 1.11−1.08 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 170.5, 161.5, 139.8, 128.7, 128.3 (2C),
126.2 (2C), 79.2, 67.7, 43.2, 39.3, 28.4 (2C), 14.1, 12.8; HRMS (ESI/
Q-TOF) m/z [M + H]+ calcd for C16H23N2O2 275.1754, found
275.1766.
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethylbenzamide
(1f). Following TP2, methyl 3-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1b, 1.16 g, 5.0 mmol) afforded 1f (1.25 g, 91%) as a
colorless oil after chromatographic purification with hexanes/ethyl
1
acetate (7:3−100% ethyl acetate) as an eluent: H NMR (400 MHz,
CDCl3) δ 7.99−7.95 (m, 2H), 7.48−7.42 (m, 2H), 4.12 (s, 2H),
3.55−3.54 (m, 2 H), 3.25−3.24 (m, 2 H), 1.38 (s, 6H), 1.26−1.24
(m, 3 H), 1.10 (bs, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.2,
161.3, 137.3, 128.7, 128.6, 128.3, 128.2, 126.0, 79.1, 67.5, 43.2, 39.2,
28.2 (2C), 14.0, 12.7; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C16H23N2O2 275.1754, found 275.1755.
2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethylbenzamide
(1g). Following TP2, methyl 2-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1c, 1.16 g, 5.0 mmol) afforded 1g (1.25 g, 91%) as a
yellow oil after chromatographic purification with hexanes/ethyl
1
acetate (7:3−100% ethyl acetate) as an eluent: H NMR (400 MHz,
CDCl3) δ 7.97−7.95 (m, 1H), 7.47 (td, J = 7.3, 1.3 Hz, 1H), 7.39 (td,
J = 7.3, 1.3 Hz, 1H), 7.28−7.25 (m, 1H), 4.04 (s, 2H), 3.84−3.28 (m,
2H), 3.10 (q, J = 7.3 Hz, 2H), 1.34 (s, 6H), 1.25 (t, J = 7.1 Hz, 3H),
1.01 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.1,
161.0, 137.6, 130.9, 129.6, 128.2, 126.7, 124.7, 79.0, 67.7, 42.5, 38.6,
28.2 (2C), 13.4, 11.9; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C16H23N2O2 275.1754, found 275.1754.
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1a).
Following TP1, methyl 4-formylbenzoate (1.64 mg, 10 mmol)
afforded 1a (1.86 g, 80%) as a white solid after chromatographic
purification with hexanes/ethyl acetate (8:2) as an eluent: mp 68−78
1
°C; H NMR (400 MHz, CDCl3) δ 8.07 (d-like, 2H), 8.01 (d-like,
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-iodobenzoate
(3a). Following TP4, methyl 4-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1a, 116 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 3a (141.8 mg, 79%) as a white solid after chromatographic
purification with hexane/ethyl acetate (8:2) as an eluent. For the
scale-up procedure, following TP4, methyl 4-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)benzoate (1a, 2.33 g, 10 mmol) and iodine
(3.30 g, 13 mmol) afforded 3a (2.51 g, 70%) as a white solid after
chromatographic purification with hexanes/ethyl acetate (8:2) as an
eluent: mp 70−71 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 1.3
Hz, 1H), 8.02 (dd, J = 8.1, 1.4 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 4.17
(s, 2H), 3.93 (s, 3H), 1.43 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.9, 162.0, 141.0, 138.1, 132.6, 130.3, 128.7, 94.2, 79.5,
68.4, 52.5, 28.1 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C13H15INO3 360.0091, found 360.0091.
2H), 4.14 (s, 2H), 3.94 (s, 3H), 1.40 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.5, 161.3, 132.3, 132.1, 129.5 (2C), 128.2 (2C),
79.3, 67.9, 52.2, 28.2 (2C); HRMS (ESI/Q-TOF) m/z [M + Na]+
calcd for C13H15NNaO3 256.0944, found 256.0965.
Methyl 3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1b).
Following TP1, methyl 3-formylbenzoate (1.64 mg, 10 mmol)
afforded 1b (1.63 g, 70%) as a white solid after chromatographic
purification with hexanes/ethyl acetate (8:2) as an eluent: mp 54−57
1
°C; H NMR (500 MHz, CDCl3) δ 8.59−8.59 (m, 1H), 8.15−8.13
(m, 2H), 7.49 (t, J = 8.8 Hz, 1H), 4.14 (s, 2H), 3.93 (s, 3H), 1.40 (s,
6H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.4, 161.2, 132.4, 132.1,
130.4, 129.3, 128.5, 128.4, 79.2, 67.7, 52.1, 28.3 (2C); HRMS (ESI/
Q-TOF) m/z [M + H]+ calcd for C13H16NO3 234.1125, found
234.1125.
Methyl 2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1c).
Following TP1, methyl 2-formylbenzoate (1.64 mg, 10 mmol)
afforded 1c (1.81 g, 82%) as a yellow oil after chromatographic
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-(phenylthio)-
benzoate (3b). Following TP4, methyl 4-(4,4-dimethyl-4,5-dihy-
drooxazol-2-yl)benzoate (1a, 116 mg, 0.5 mmol) and diphenyl
disulfide (141 mg, 0.65 mmol) afforded 3b (119.3 mg, 70%) as a
yellow solid after chromatographic purification with hexanes/ethyl
1
purification with hexanes/ethyl acetate (8:2) as an eluent: H NMR
(500 MHz, CDCl3) δ 7.73−7.71 (m, 2H), 7.52−7.45 (m, 2H), 4.09
(s, 2H), 3.86 (s, 3H), 1.38 (s, 6H); 13C{1H} NMR (125 MHz,
CDCl3) δ 168.0, 162.1, 131.9, 131.0, 130.3, 129.7, 129.0, 128.5, 79.8,
67.8, 52.3, 28.1 (2C); HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for
C13H15NNaO3 256.0944, found 256.0948.
1
acetate (9:1) as an eluent: mp 112−115 °C; H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 7.8 Hz, 1H), 7.77 (dd, J = 8.0, 1.5 Hz, 1H),
7.58 (d, J = 1.5 Hz, 1H), 7.53−7.50 (m, 2H), 7.43−7.38 (m, 3H),
4.11 (s, 2H), 3.80 (s, 3H), 1.42 (s, 6H); 13C{1H} NMR (100 MHz,
E
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Note
CDCl3) δ 166.0, 160.6, 140.7, 134.3 (2C), 132.9, 132.0, 130.1, 130.1,
129.7 (2C), 129.3, 128.8, 125.6, 79.0, 68.7, 52.2, 28.4 (2C); HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C19H20NO3S 342.1158, found
342.1158.
165.0, 162.2, 142.8, 135.7, 131.8, 130.7, 129.8, 98.0, 80.0, 68.2, 52.5,
27.7 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C13H15INO3 360.0091, found 360.0094.
Methyl 2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-
(phenylselanyl)benzoate (3h). Following TP4, methyl 2-(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1c, 116 mg, 0.5 mmol)
and diphenyl diselenide (2.02 mg, 0.65 mmol) afforded 3h (145.8 mg,
75%) as a yellow solid after chromatographic purification with
hexanes/ethyl acetate (9:1) as an eluent: mp 115−118 °C; 1H NMR
(400 MHz, CDCl3) δ 7.71 (dd, J = 7.3, 1.5 Hz, 1H), 7.61−7.59 (m,
2H), 7.36−7.30 (m, 3H), 7.25 (dd, J = 8.0, 1.5 Hz, 1H), 7.21 (t, J =
7.8, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 1.47 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.4, 161.0, 136.0, 135.4 (2C), 134.6, 131.5,
130.2, 129.8, 129.6, 129.5 (2C), 128.4, 127.8, 79.6, 68.5, 52.3, 28.0
(2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C19H20NO3Se
390.0603, found 390.0601.
tert-Butyl 5-Cyano-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-io-
dobenzoate (3i). Following TP4, tert-butyl 5-cyano-2-(4,4-dimethyl-
4,5-dihydrooxazol-2-yl)benzoate (1d, 150 mg, 0.5 mmol) and iodine
(165 mg, 0.65 mmol) afforded 3i (155.5 mg, 73%) as a yellow solid
after chromatographic purification with hexanes/ethyl acetate (7:3) as
an eluent: mp 160−163 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J
= 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 4.20 (s, 2H), 1.50 (s, 9H),
1.39 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.0, 144.4,
142.7, 135.2, 132.5, 115.9, 114.9, 97.8, 83.7, 80.4, 77.4, 68.4, 28.0
(3C), 27.5 (2C); HRMS (ESI) m/z [M + H]+ calcd for
C17H20IN2O3[M + H]+ 427.0513, found 427.0551.
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-(hydroxy-
(phenyl)methyl)benzoate (3c). Following TP4, methyl 4-(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1a, 116 mg, 0.5 mmol)
and benzaldehyde (0,07 mL, 0.65 mmol) afforded 3c (113.5 mg,
67%) as a white solid after chromatographic purification with
hexanes/ethyl acetate (8:2) as an eluent: mp 109−111 °C; 1H
NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 8.1, 1.7 Hz, 1H), 7.95−7.93
(m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.26−7.24 (m, 5H), 5.98 (d, J =
8.5 Hz, 1H), 4.03 (d, J = 8.1 Hz, 1H), 3.93 (d, J = 8.1 Hz, 1H), 3.91
(s, 3H), 1.34 (s, 3H), 0.96 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.9, 161.5, 144.6, 142.8, 132.1, 131.2, 130.6 (2C), 128.4,
127.6 (2C), 126.5, 126.2 (2C), 78.7, 74.9, 67.9, 52.1, 27.9, 27.4;
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C20H22NO4 340.1543,
found 340.1553.
Methyl 4′-Chloro-6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-[1,1′-
biphenyl]-3-carboxylate (3d). Following TP4, a ZnCl2 solution in
THF (1 mol/L in THF, 0.5 mL, 0.5 mmol) was added after complete
metalation of methyl 4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-
benzoate (1a, 116 mg, 0.5 mmol). After 15 min, a Pd(PPh3)4
solution (4 mol %) in THF (1 mL) and a 1-chloro-4-iodobenzene
(155.0 mg, 1.3 mmol) solution in THF (1 mL) were added, and the
resulting mixture was stirred at 60 °C overnight. The reaction was
quenched with saturated aqueous NH4Cl (20 mL), and the aqueous
layer was extracted with EtOAc (3 × 15 mL). The solvent of the
combined organic layers was evaporated under a vacuum, to afford 3d
(135.4 mg, 79%) as a brown solid after chromatographic purification
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethyl-3-iodoben-
zamide (3j). Following TP4, 4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-
N,N-diethylbenzamide (1e, 137 mg, 0.5 mmol) and iodine (165 mg,
0.65 mmol) afforded 3j (158.0 mg, 79%) as a yellow solid after
chromatographic purification with hexanes/ethyl acetate (1:1−100%
1
with hexanes/ethyl acetate (9:1) as an eluent: mp 132−135 °C; H
NMR (400 MHz, CDCl3) δ 8.05−8.03 (m, 2H), 7.82 (d, J = 7.8 Hz,
1H), 7.38 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 3.94 (s, 3H),
3.85 (s, 2H), 1.30 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
166.1, 162.5, 140.6, 138.6, 133.7, 132.0, 131.9, 131.1, 130.4, 129.6
(2C), 128.2, 128.2 (2C), 79.5, 67.8, 52.3, 27.9 (2C); HRMS (ESI/Q-
TOF) m/z [M + H]+ calcd for C19H19ClNO3 344.1048, found
344.1046.
1
ethyl acetate) as an eluent: mp 61−6 4 °C; H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (dd,
J = 7.8, 1.5 Hz, 1H), 4.16 (s, 2H), 3.53−3.52 (m, 2H), 3.20−3.18 (m,
2H), 1.43 (s, 6H), 1.26−1.23 (m, 3H), 1.10−1.07 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.6, 162.2, 140.2, 137.8, 134.8, 130.5,
125.5, 94.7, 79.5, 68.3, 43.2, 39.4, 28.2 (2C), 14.1, 12.8; HRMS (ESI/
Q-TOF) m/z [M + H]+ calcd for C16H22IN2O2401.0720, found
401.0721.
Methyl 3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-4-iodobenzoate
(3e). Following TP4, methyl 3-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1b, 116 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 3e (107.7 mg, 60%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (8:2) as an eluent: mp 70−72
°C; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 2.3 Hz, 1H), 8.01 (d,
J = 8.3 Hz, 1H), 7.73 (dd, J = 8.3, 2.3 Hz, 1H), 4.17 (s, 2H), 3.92 (s,
3H), 1.44 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.9, 162.0,
140.6, 134.7, 131.8, 131.2, 130.0, 101.1, 79.6, 68.4, 52.4, 28.2 (2C);
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C13H15INO3
360.0091, found 360.0095.
3-Bromo-4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethyl-
benzamide (3k). Following TP4, 4-(4,4-dimethyl-4,5-dihydrooxazol-
2-yl)-N,N-diethylbenzamide (1e, 137 mg, 0.5 mmol) and 1,2-
dibromotetrachloroethane (211 mg, 0.65 mmol) afforded 3k (119.7
mg, 68%) as a yellow oil after chromatographic purification with
hexanes/ethyl acetate (1:1) as an eluent: 1H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.34 (dd,
J = 7.8, 1.5 Hz, 1H), 4.15 (s, 2H), 3.54−3.52 (m, 2H), 3.21−3.19 (m,
2H), 1.42 (s, 6H), 1.26−1.22 (m, 3H), 1.10−1.07 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.6, 161.0, 140.2, 131.2, 131.1, 130.7,
124.7, 121.8, 79.3, 68.0, 43.1, 39.3, 28.0 (2C), 14.0, 12.7; HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C16H22BrN2O2 353.0859,
found 353.0860.
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethyl-3-
(phenylselanyl)benzamide (3l). Following TP4, 4-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)-N,N-diethylbenzamide (1e, 137 mg, 0.5 mmol)
and diphenyl diselenide (202 mg, 0.65 mmol) afforded 3l (152.6,
76%) as a yellow solid after chromatographic purification with
hexanes/ethyl acetate (1:1) as an eluent: mp 110−113 °C; 1H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 1H), 7.69−7.67 (m, 2H),
7.42−7.35 (m, 3H), 7.17 (dd, J = 8.1, 1.5 Hz, 1H), 6.84 (d, J = 1.5
Hz, 1H), 4.12 (s, 2H), 3.40−3.38 (m, 2H), 3.02−3.00 (m, 2H), 1.46
(s, 6H), 1.12−1.10 (m, 3H), 0.83−0.81 (m, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.0, 160.8, 139.1, 138.4, 137.2 (2C), 129.9,
129.7 (2C), 129.6, 129.0, 126.5, 126.3, 123.1, 78.8, 68.7, 42.9, 39.0,
28.6 (2C), 13.9, 12.6; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C22H27N2O2Se 431.1232, found 431.1232.
Methyl 3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-4-
(phenylselanyl)benzoate (3f). Following TP4, methyl 3-(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1b, 116 mg, 0.5 mmol)
and diphenyl diselenide (202 mg, 0.65 mmol) afforded 3f (141.9 mg,
73%) as a yellow solid after chromatographic purification with
1
hexanes/ethyl acetate (9:1) as an eluent: mp 116−120 °C; H NMR
(400 MHz, CDCl3) δ 8.45 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.6, 2.0
Hz, 1H), 7.71−7.68 (m, 2H), 7.46−7.40 (m, 3H), 6.95 (d, J = 8.6 Hz,
1H), 4.14 (s, 2H), 3.88 (s, 3H), 1.47 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.4, 160.6, 145.5, 137.2 (2C), 130.9, 130.6, 129.8
(2C), 129.7, 129.2, 128.9, 126.7, 125.9, 78.8, 68.9, 52.1, 28.7 (2C);
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C19H20NO3Se
390.0603, found 390.0603.
Methyl 2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-iodobenzoate
(3g). Following TP4, methyl 2-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1c, 116 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 3g (123.8 mg, 69%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (8:2) as an eluent: mp 73−75
1
°C; H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 7.8, 1.0 Hz, 1H),
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethyl-3-iodoben-
zamide (3m). Following TP4, 3-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)-N,N-diethylbenzamide (1f, 137 mg, 0.5 mmol) and iodine (165
7.89 (dd, J = 7.8, 1.0 Hz, 1H), 7.14 (t, J = 7,8 Hz, 1H), 4.08 (s, 2H),
3.92 (s, 3H), 1.34 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
F
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Note
mg, 0.65 mmol) afforded 3m (120.0 mg, 71%) as a yellow solid after
chromatographic purification with hexanes/ethyl acetate (1:1−3:7) as
an eluent: mp 110−113 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J
= 8.1 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.1, 2.0 Hz,
1H), 4.14 (s, 2H), 3.53−3.52 (m, 2H), 3.24−3.23 (m, 2H), 1.42 (s,
6H), 1.26−1.22 (m, 3H), 1.12−1.10 (m, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 169.3, 162.1, 140.2, 136.9, 134.4, 129.0, 128.5, 95.5,
79.5, 68.3, 43.3, 39.4, 28.1 (2C), 14.1, 12.7; HRMS (ESI/Q-TOF) m/
z [M + H]+ calcd for C16H22IN2O2 401.0720, found 401.0721.
2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethyl-3-iodoben-
zamide (3n). Following TP4, 2-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)-N,N-diethylbenzamide and iodine (1g, 165 mg, 0.65 mmol)
afforded 3n (150.0 mg, 75%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (1:1−3:7) as an eluent: mp
55−57 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 1H),
7.27 (dd, J = 8.1, 1.3 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 4.11 (s, 2H),
3.51−3.49 (m, 2H), 3.20 (q, J = 7.1 Hz, 2H), 1.39 (s, 6H), 1.23 (t, J =
7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
168.1, 161.6, 139.5, 139.0, 132.3, 130.7, 125.5, 96.8, 79.4, 68.3, 43.3,
39.0, 27.9 (2C), 13.7, 12.8; HRMS (ESI/Q-TOF) m/z [M + H]+
calcd for C16H22IN2O2 401.0720, found 401.0719.
28.2 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C19H18NO3308.1281, found 308.1271.
Methyl 2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-6-iodobenzoate
(5d). Following TP6, methyl 2-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1c, 116 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 5d (123.8 mg, 69%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (8:2) as an eluent: mp 73−75
1
°C; H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 8.1, 1.3 Hz, 1H),
7.89 (dd, J = 8.1, 1.3 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 4.07 (s, 2H),
3.92 (s, 3H), 1.34 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
168.6, 159.4, 141.4, 139.8, 130.2, 128.7, 127.1, 92.8, 79.5, 68.1, 52.6,
28.1 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C13H15INO3 360.0091, found 360.0092.
Methyl 2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-6-(phenylthio)-
benzoate (5e). Following TP6, methyl 2-(4,4-dimethyl-4,5-dihy-
drooxazol-2-yl)benzoate (1c, 116 mg, 0.5 mmol) and diphenyl
disulfide (141 mg, 0.65 mmol) afforded 5e (110.8 mg, 65%) as a
yellow oil after chromatographic purification with hexanes/ethyl
acetate (9:1) as an eluent: 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J
= 7.1, 1.5 Hz, 1H), 7.15−7.04 (m, 7H), 3.95 (s, 2H), 3.76 (s, 3H),
1.31 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.9, 160.2,
136.2, 135.0, 135.0, 134.5, 131.6 (2C), 129.6, 129.2 (2C), 128.2,
127.5, 126.6, 79.5, 68.1, 52.3, 28.1 (2C); HRMS (ESI/Q-TOF) m/z
[M + H]+ calcd for C19H20NO3S 342.1158, found 342.1163.
Methyl 2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-6-
(phenylselanyl)benzoate (5f). Following TP6, methyl 2-(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1c, 116 mg, 0.5 mmol)
and diphenyl diselenide (202 mg, 0.65 mmol) afforded 5f (134.2 mg,
69%) as a yellow oil after chromatographic purification with hexanes/
ethyl acetate (9:1) as an eluent: 1H NMR (400 MHz, CDCl3) δ 7.74
(d, J = 7.8 Hz, 1H), 7.54−7.52 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H),
7.31−7.22 (m, 4H), 4.08 (s, 2H), 3.90 (s, 3H), 1.36 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.0, 160.4, 135.6, 135.5, 134.1 (2C),
131.1, 130.0, 129.6, 129.2 (2C), 127.9, 127.8, 126.9, 79.4, 67.8, 52.2,
27.9 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C19H20NO3Se 390.0603, found 390.0624.
Methyl 4′-Chloro-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-[1,1′-
biphenyl]-2-carboxylate (5g). Following TP6, a ZnCl2 solution in
THF was added after complete metalation of methyl 2-(4,4-dimethyl-
4,5-dihydrooxazol-2-yl)benzoate (1c, 116 mg, 0.5 mmol) (1 mol/L in
THF, 0.5 mL, 0.5 mmol). After 15 min, a Pd(PPh3)4 solution (4 mol
%) in THF (1 mL) and a 1-chloro-4-iodobenzene (155.0 mg, 1.3
mmol) solution in THF (1 mL) were added, and the resulting mixture
was stirred at 60 °C overnight. The reaction was quenched with
saturated aqueous NH4Cl (20 mL), and the aqueous layer was
extracted with EtOAc (3 × 15 mL). The solvent of the combined
organic layers was evaporated under a vacuum to afford 5g (135.4 mg,
79%) as a brown solid after chromatographic purification with
hexanes/ethyl acetate (9:1) as an eluent: mp 128−130 °C; 1H NMR
(400 MHz, CDCl3) δ 7.89 (dd, J = 7.8, 1.3 Hz, 1H), 7.48 (t, J = 7.8
Hz, 1H), 7.41 (dd, J = 7.8, 1.3 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.29
(d, J = 8.6 Hz, 2H), 4.08 (s, 2H), 3.66 (s, 3H), 1.36 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.6, 160.5, 139.0, 138.0, 133.8, 133.2,
132.2, 129.8 (2C), 129.1, 128.3 (3C), 126.1, 79.4, 68.0, 52.0, 28.0
(2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C19H19ClNO3
344.1048, found 344.1042.
2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N,N-diethyl-3-
(phenylthio)benzamide (3o). Following TP4, 2-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)-N,N-diethylbenzamide and diphenyl disulfide
(1g, 141 mg, 0.65 mmol) afforded 3o (126.1 mg, 66%) as a yellow
oil after chromatographic purification with hexanes/ethyl acetate
1
(1:1) as an eluent: H NMR (400 MHz, CDCl3) δ 7.51−7.48 (m,
2H), 7.40−7.35 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H), 7.06 (dd, J = 7.5,
1.0 Hz, 1H), 6.96 (dd, J = 7.5, 1.0 Hz, 1H), 4.06 (s, 2H), 3.53−3.52
(m, 2H), 3.21 (q, J = 6.9 Hz, 2H), 1.40 (s, 6H), 1.23 (t, J = 7.2 Hz,
3H), 1.06 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
169.0, 159.7, 139.9, 138.3, 133.8 (2C), 133.6, 129.9, 129.4 (2C),
129.1, 128.2, 125.5, 123.3, 79.0, 68.4, 43.1, 38.8, 28.0 (2C), 13.6,
12.6; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C22H27N2O2S
383.1788, found 383.1788.
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-iodobenzoate
(5a). Following TP6, methyl 4-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)benzoate (1a, 116 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 5a (105.5 mg, 56%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (9:1) as an eluent: mp 68−71
1
°C; H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 1.5 Hz, 1H), 7.95
(dd, J = 8.1, 1.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 4.13 (s, 2H), 3.95
(s, 3H), 1.39 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.5,
159.9, 140.7, 137.3, 131.9, 130.5, 127.5, 93.5, 79.4, 68.0, 52.6, 28.3
(2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C13H15INO3
360.0091, found 360.0112.
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-(phenylthio)-
benzoate (5b). Following TP6, methyl 4-(4,4-dimethyl-4,5-dihy-
drooxazol-2-yl)benzoate (1a, 116 mg, 0.5 mmol) and diphenyl
disulfide (141 mg, 0.65 mmol) afforded 5b (85.3 mg, 50%) as a
yellow solid after chromatographic purification with hexanes/ethyl
1
acetate (9:1) as an eluent: mp 127−131 °C; H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 8.1 Hz, 1H), 7.76 (dd, J = 8.1, 1.8 Hz, 1H),
7.56−7.53 (m, 2H), 7.44−7.42 (m, 3H), 7.41 (d, J = 1.5 Hz, 1H),
3.97 (s, 2H), 3.95 (s, 3H), 1.30 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.5, 160.9, 142.7, 134.8 (2C), 132.4, 131.6, 130.8, 129.7
(2C), 129.4, 129.0, 127.6, 124.5, 79.2, 67.7, 52.3, 28.2 (2C); HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C19H20NO3S 342.1158, found
342.1157.
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl Pivalate (6a).
Following TP1, 4-formylphenyl pivalate (2.06 g, 10 mmol) afforded
6a (2.2 g, 81%) as a white solid after chromatographic purification
1
with hexanes/ethyl acetate (8:2) as an eluent: mp 103−106 °C; H
5-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-phenylisobenzofur-
an-1(3H)-one (5c). Following TP6, methyl 4-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)benzoate (1a, 116 mg, 0.5 mmol) and benzalde-
hyde (0.07 mL, 0.65 mmol) afforded 5c (148.6 mg, 51%) as a white
solid after chromatographic purification with hexanes/ethyl acetate
(8:2) as an eluent: mp 193−195 °C; 1H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 8.0 Hz, 1H), 7.93−7.89 (m, 2H), 7.32−7.30 (m, 3H),
7.22−7,20 (m, 2H), 6.35 (s, 1H), 4.09 (s, 2H), 1.32 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 169.7, 161.3, 149.7, 135.8, 133.2, 129.6,
129.4, 129.0 (2C), 127.9, 127.0 (2C), 125.6, 122.9, 82.8, 79.7, 67.8,
NMR (400 MHz, CDCl3) δ 7.96 (d-like, J = 8.8 Hz, 2H), 7.10 (d-like,
J = 8.8 Hz, 2H), 4.10 (s, 2H), 1.38 (s, 6H), 1.36 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 176.6, 161.4, 153.4, 129.5 (2C), 125.5,
121.4 (2C), 79.2, 67.6, 39.1, 28.4 (2C), 27.1 (3C); HRMS (ESI/Q-
TOF) m/z [M + H]+ calcd for C16H22NO3 276.1594, found
276.1597.
tert-Butyl (4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl) Car-
bonate (6b). Following TP1, tert-butyl (4-formylphenyl) carbonate
(2.22 g, 10 mmol) afforded 6b (2.09 g, 76%) as a white solid after
chromatographic purification with hexanes/ethyl acetate (8:2) as
G
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Note
1
eluent; 84−87 °C; H NMR (400 MHz, CDCl3) δ 7.70 (d-like, J =
360.2169, found 360.2168. The phenol derivative 7 (4-(4,4-dimethyl-
9.1 Hz, 2H), 6.99 (d-like, J = 9.1 Hz, 2H), 3.97 (s, 2H), 1.51 (s, 9H),
1.33 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.3, 153.3,
151.2, 129.5 (2C), 125.5, 121.0 (2C), 83.8, 79.2, 67.6, 28.3 (2C),
27.6 (3C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C16H22NO4 292.1543, found 292.1543.
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl Diethylcarba-
mate (6c). Following TP1, 4-formylphenyl 2-ethylbutanoate (2.20
g, 10 mmol) afforded 6c (2.46 g, 85%) as a white solid after
chromatographic purification with hexanes/ethyl acetate (6:4) as an
4,5-dihydrooxazol-2-yl)phenol) was also isolated in the form of a
1
white solid (28,7 mg, 30%): H NMR (400 MHz, methanol-d4) δ
7.74 (d-like, J = 8.8 Hz, 2H), 6.81 (d-like, J = 8.8 Hz, 2H), 4.91 (s,
1H), 4.13 (s, 2H), 1.34 (s, 6 H); 13C{1H} NMR (100 MHz,
methanol-d4) δ 167.5, 164.8, 133.7 (2C), 122.2, 118.8 (2C), 82.7,
70.5, 31.0 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C11H14NO2 192.1019, found 192.1027.
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-iodophenyl Pivalate
(10a). Following TP4, 4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl
pivalate (6a, 137.5 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 10a (158.4 mg, 80%) as a yellow oil after chromatographic
1
eluent: mp 72−75 °C; H NMR (400 MHz, DMSO-d6) δ 7.85 (d-
like, J = 8.6 Hz, 2H), 7.21 (d-like, J = 8.6 Hz, 2H), 4.10 (s, 2H),
3.40−3.39 (m, 2H), 3.31−3.29 (m, 2H), 1.28 (s, 6H), 1.19 (t, J = 6.8
Hz, 3H), 1.11 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 160.0, 153.6, 152.8, 129.0 (2C), 124.5, 122.0 (2C), 78.5, 67.5,
41.8, 41.6, 28.3 (2C), 14.2, 13.3; HRMS (ESI/Q-TOF) m/z [M +
H]+ calcd for C16H23N2O3 291.1703, found 291.1696.
1
purification with hexanes/ethyl acetate (8:2) as an eluent: H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.4 Hz,
1H), 7.07 (dd, J = 8.4, 2.2 Hz, 1H), 4.15 (s, 2H), 1.40 (s, 6H), 1.28
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.2, 162.1, 152.2,
133.1, 131.4, 131.0, 121.1, 94.2, 79.4, 68.2, 39.1, 28.2 (2C), 27.0
(3C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C16H21INO3
402.0561, found 402.0559.
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-(phenylselanyl)-
phenyl Pivalate (10b). Following TP4, 4-(4,4-dimethyl-4,5-dihy-
drooxazol-2-yl)phenyl pivalate (6b, 137.5 mg, 0.5 mmol) and
diphenyl diselenide (2.02 mg, 0.65 mmol) afforded 10b (146.5 mg,
62%) as a yellow oil after chromatographic purification with hexanes/
ethyl acetate (8:2) as an eluent: 1H NMR (400 MHz, CDCl3) δ 7.74
(d, J = 8.6 Hz, 1H), 7.62−7.60 (m, 2H), 7.33−7.31 (m, 3H), 6.78
(dd, J = 8.6, 2.3 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 4.03 (s, 2H), 1.36
(s, 6H), 1.14 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4,
160.7, 152.9, 139.9, 137.1 (2C), 130.7, 129.9, 129.6 (2C), 128.9,
123.3 121.8, 118.1, 78.7, 68.6, 38.9, 28.6 (2C), 26.9 (3C); HRMS
(ESI/Q-TOF) m/z [M + H]+ calcd for C22H26NO3Se 432.1072,
found 432.1068.
tert-Butyl (4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-iodophen-
yl) Carbonate (10c). Following TP4, tert-butyl (4-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)phenyl) carbonate (6b, 145.5, 0.5 mmol) and
iodine (165 mg, 0.65 mmol) afforded 10c (138.3 mg, 70%) as a
yellow oil after chromatographic purification with hexanes/ethyl
acetate (8:2) as an eluent: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J =
2.3 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.4, 2.3 Hz, 1H),
4.13 (s, 2H), 1.55 (s, 9H), 1.41 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.0, 152.0, 150.7, 132.8, 131.5, 131.0, 120.7, 94.1, 84.2,
79.4, 68.2, 28.2 (2C), 27.6 (3C); HRMS (ESI/Q-TOF) m/z [M +
H]+ calcd for C16H21INO4 418.0510, found 418.0499.
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl Pivalate (6d).
Following TP1, 3-formylphenyl pivalate (2.06 g, 10 mmol) afforded
6d (2.15g, 74%) as a white solid after chromatographic purification
1
with hexanes/ethyl acetate (8:2) as an eluent: mp 50−52 °C; H
NMR (400 MHz, CDCl3) δ 7.79 (ddd, J = 7.8, 1.5, 1.0 Hz, 1H),
7.66−7.65 (m, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.17 (dq, J = 7.8, 1.0 Hz,
1H), 4.11 (s, 2H), 1.38 (s, 6H), 1.35 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 177.0, 161.6, 151.3, 129.7, 129.5, 125.7, 124.7, 121.8,
79.5, 67.9, 39.3, 28.6 (2C), 27.4 (3C); HRMS (ESI/Q-TOF) m/z [M
+ H]+ calcd for C16H22NO3 276.1594, found 276.1594.
tert-Butyl (3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl) Car-
bonate (6e). Following TP1, tert-butyl (3-formylphenyl) carbonate
(2.22 g, 10 mmol) afforded 6e (2.04 g, 70%) as a white solid after
chromatographic purification with hexanes/ethyl acetate (8:2) as an
eluent: mp 52−54 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (ddd, J =
7.6, 1.0, 1.02 Hz, 1H), 7.76−7.75 (m, 1H), 7.41 (t, J = 8.0 Hz, 1H),
7.27−7.25 (m, 1H), 4.11 (s, 2H), 1.56 (s, 9H), 1.38 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 161.2, 151.7, 150.9, 129.6, 129.3, 125.6,
124.1, 121.3, 83.7, 79.2, 67.7, 28.4 (2C), 27.7 (3C); HRMS (ESI/Q-
TOF) m/z [M + H]+ calcd for C16H22NO4 292.1543, found
292.1548.
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl Diethylcarba-
mate (6f). Following TP1, 4-formylphenyl 2-ethylbutanoate (2.20 g,
10 mmol) afforded 6f (2.25 g, 78%) as a white solid after
chromatographic purification with hexanes/ethyl acetate (6:4) as an
eluent: mp 72−75 °C; mp 66−69 °C; 1H NMR (400 MHz, CDCl3) δ
7.81−7.79 (m, 1H), 7.70 (bs, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.24−
7.22 (m, 1H), 4.12 (s, 2H), 3.39−3.28 (m, 4H), 1.36 (s, 6H), 1.20−
1.11 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.8, 151.4,
129.3, 125.6, 125.3, 122.0, 99.9, 79.7, 67.1, 57.3, 42.3, 41.9, 28.1 (2C),
14.2, 13.3; HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for
C16H23N2O3 291.1703, found 291.1688.
tert-Butyl (4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-
(phenylthio)phenyl) Carbonate (10d). Following TP4, tert-butyl
(4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl) carbonate (6b,
145.5 mg, 0.5 mmol) and diphenyl disulfide (141 mg, 0.65 mmol)
afforded 10d (135.6 mg, 68%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (9:1) as an eluent: mp 85−88
1
Synthesis of 1,1′-(2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5-hy-
droxy-1,4-phenylene)bis(2,2-dimethylpropan-1-one) (8). In a dry
25 mL flask under a nitrogen atmosphere and equipped with magnetic
stirring, 2,2,6,6-tetramethylpiperidine (0.10 mL, 0.575 mmol, 1.15
equiv) was dissolved in THF (2 mL). The solution was cooled to −78
°C, and n-BuLi (2.35 M, 0.23 mL, 0.55 mmol, 1.1 equiv) was added
dropwise. After that, the reaction mixture was warmed to 0 °C and left
at this temperature for 30 min. Then, the temperature was lowered to
−78 °C, and the 2-oxazoline 6a (116.0 mg, 0.5 mmol) in THF (3.0
mL) was added. The reaction was stirred at −78 °C for 1 h. Next,
saturated aqueous NH4Cl solution (5 mL) was added. The solution
was extracted with ethyl acetate (3 × 20 mL). The resulting organic
phase was dried with MgSO4, and the solvent was removed under
reduced pressure. The product was purified by flash column
chromatography with hexanes/ethyl acetate as an eluent (9:1) to
give 8 in the form of a yellow solid (73.6 mg, 41%): mp 145−148 °C;
1H NMR (400 MHz, CDCl3) δ 13.01 (s, 1H), 8.59 (s, 1H), 6.67 (s,
°C; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 1H), 7.55−
7.53 (m, 2H), 7.42−7.39 (m, 3H), 6.98 (dd, J = 8.6, 2.3 Hz, 1H), 6.59
(d, J = 2.3 Hz, 1H), 4.09 (s, 2H), 1.48 (s, 9H), 1.42 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 160.6, 152.7, 150.8, 142.5, 135.0 (2C),
132.7, 131.2, 129.7 (2C), 128.9, 123.0, 120.1, 117.4, 83.9, 78.8, 68.5,
28.4 (2C), 27.6 (3C); HRMS (ESI) m/z [M + H]+ calcd for
C22H26NO4S 400.1577, found 400.1577.
tert-Butyl (4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-(hydroxy-
(phenyl)methyl)phenyl) Carbonate (10e). Following TP4, tert-
butyl (4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl) carbonate
(6b, 145,5 mg, 0,5 mmol) and benzaldehyde (0.07 mL, 0.65 mmol)
afforded 10e (119.1 mg, 60%) as a white oil after chromatographic
1
purification with hexanes/ethyl acetate (8:2) as an eluent: H NMR
(400 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 1H), 7.32−7.29 (m, 5H),
7.24 (dd, J = 8.6, 2.3 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 5.91 (s, 1H),
4.03 (d, J = 8.1 Hz, 1H), 3.95 (d, J = 8.1 Hz, 1H), 1.53 (s, 9H), 1.34
(s, 3H), 1.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.7,
153.0, 150.9, 146.8, 142.7, 131.9, 127.9 (2C), 126.8, 126.6 (2C),
124.0, 123.0, 119.9, 83.9, 78.8, 74.4, 67.9, 28.3 (2C), 27.6 (3C);
HRMS (ESI) m/z [M + H]+ calcd for C23H28NO5 398.1962, found
398.1967.
1H), 4.04 (s, 2H), 1.48 (s, 9H), 1.31 (s, 6H), 1.27 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 212.6, 211.8, 165.2, 159.0, 149.1, 132.4,
116.4, 116.2, 114.7, 79.2, 68.3, 44.8, 44.7, 28.7 (3C), 28.3 (2), 27.3
(3C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C21H30NO4
H
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Note
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-iodophenyl Diethyl-
carbamate (10f). Following TP4, 4-(4,4-dimethyl-4,5-dihydrooxa-
zol-2-yl)phenyl diethylcarbamate (6c,145 mg, 0.5 mmol) and iodine
(165 mg, 0.65 mmol) afforded 10f (166.4, 80%) as a yellow oil after
chromatographic purification with hexanes/ethyl acetate (8:2) as an
eluent: 1H NMR (400 MHz, CDCl3) δ 7.69−7.67 (m, 2H), 7.16 (dd,
J = 8.6, 2.3 Hz, 1H), 4.18 (s, 2H), 3.37−3.28 (m, 4H), 1.42 (s, 6H),
1.19−1.12 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.9,
134.6, 133.6, 131.9, 121.4, 94.0, 80.1, 72.0, 67.2, 57.1, 43.3, 41.9, 27.9
(2C), 14.2, 13.2; HRMS (ESI) m/z [M + H]+ calcd for C16H22IN2O3
417.0670, found 417.0666.
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-
(phenylselanyl)benzoate (11). Following TP4, methyl 4-(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)benzoate (1a, 233 mg, 1.0 mmol)
and diphenyl diselenide (404 mg, 1.3 mmol) afforded 11 (311.2 mg,
80%) as a yellow solid after chromatographic purification with
hexanes/ethyl acetate (9:1) as an eluent: mp 114−116 °C; 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 1H), 7.77 (dd, J = 8.1, 1.5
Hz, 1H), 7.71−7.68 (m, 2H), 7.58 (d, J = 1.5 Hz, 1H), 7.46−7.40 (m,
3H), 4.13 (s, 2H), 3.77 (s, 3H), 1.47 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.2, 160.7, 138.7, 137.0 (2C), 131.7, 130.2, 129.8,
129.8 (2C), 129.7, 129.6, 129.1, 125.5, 78.9, 68.9, 52.2, 28.6 (2C);
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C19H20NO3Se
390.0603, found 390.0602.
Methyl 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2,5-bis-
(phenylselanyl)benzoate (12). Following TP6, methyl 4-(4,4-
dimethyl-4,5-dihydrooxazol-2-yl)-3-(phenylselanyl)benzoate (11)
(194.5, 0.5 mmol) and diphenyl diselenide (2.02 mg, 0.65 mmol)
afforded 12 (130.8 mg, 48%) as a yellow solid after chromatographic
purification with hexanes/ethyl acetate (8:2) as an eluent: mp 148−
150 °C; 1H NMR (400 MHz, CDCl3) δ 7.69−7.65 (m, 4H), 7.55 (s,
1H), 7.45−7.39 (m, 6H), 7.35 (s, 1H), 3.92 (s, 2H), 3.75 (s, 3H),
1.36 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 160.3,
137.0 (2C), 136.7 (2C), 135.6, 134.4, 131.9, 130.4, 130.1, 129.9,
129.7 (2C), 129.7 (2C), 129.2, 129.1, 128.8, 128.7, 78.8, 68.8, 52.3,
28.5 (2C); HRMS (ESI) m/z [M + Na]+ calcd for C25H23NNaO3Se2
567.9901, found 567.9906
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-4-iodophenyl Pivalate
(10g). Following TP4, 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl
pivalate (6d, 137.5 mg, 0.5 mmol) and iodine (165 mg, 0.65 mmol)
afforded 10g (138.3 mg, 69%) as a yellow oil after chromatographic
1
purification with hexanes/ethyl acetate (8:2) as an eluent: H NMR
(400 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 2.3 Hz,
1H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H), 4.14 (s, 2H), 1.41 (s, 6H), 1.34
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.3, 161.9, 150.9,
141.0, 135.0, 125.0, 124.0, 89.8, 79.5, 68.2, 39.1, 28.2 (2C), 27.0
(3C); HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C16H21INO3
402.0561, found 402.0561.
tert-Butyl (3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-iodophen-
yl) Carbonate (10h). Following TP4, tert-butyl (3-(4,4-dimethyl-4,5-
dihydrooxazol-2-yl)phenyl) carbonate (6e, 148.5, 0.5 mmol) and
iodine (165 mg, 0.65 mmol) afforded 10h (148.0 mg, 71%) as a
yellow solid after chromatographic purification with hexanes/ethyl
Synthesis of 4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-(phenyl-
selanyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)benzamide (14). In a dry flask under a nitrogen atmosphere and
equipped with magnetic stirring, lithium amide 13 was prepared from
amine (67.0 mg, 0.33 mmol) in THF (2 mL). The solution was
cooled to −78 °C, and n-BuLi (2.35 mol/L, 0.14 mL, 0.33 mmol) was
added dropwise. After that, the reaction mixture was warmed to 0 °C
and left at this temperature for 30 min. 2-Oxazoline 11 (116.4 mg, 0.3
mmol) was then added in THF (2 mL). The solution was stirred at 0
°C for 4 h. Finally, NH4Cl solution (10 mL) was added. The solution
was extracted with dichloromethane (3 × 20 mL). The resulting
organic phase was dried over MgSO4, and the solvent was removed
under reduced pressure. The product was purified by flash column
chromatography with a hexanes/ethyl acetate mixture as an eluent
1
acetate (8:2) as an eluent: mp 114−116 °C; H NMR (400 MHz,
CDCl3) δ 7.43 (dd, J = 7.6, 1.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.22
(dd, J = 7.8, 1.8 Hz, 1H), 4.15 (s, 2H), 1.57 (s, 9H), 1.42 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.2, 151.8, 150.5, 136.3,
129.0, 127.8, 124.1, 92.5, 84.1, 79.3, 68.1, 28.0 (2C), 27.5 (3C);
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C16H21INO4
418.0510, found 418.0509.
tert-Butyl (3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-
(phenylselanyl)phenyl) Carbonate (10i). Following TP4, tert-butyl
(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl) carbonate (6e,
148.5, 0.5 mmol) and diphenyl diselenide (202 mg, 0.65 mmol)
afforded 10i (176.6, 79%) as a yellow oil after chromatographic
1
purification with hexanes/ethyl acetate (9:1) as an eluent: H NMR
1
(9:1) to give 14 as a yellow oil (109.0 mg, 65%): H NMR (400
(400 MHz, CDCl3) δ 7.31 (dd, J = 7.4, 1.5 Hz, 1H), 7.18−7.11 (m,
3H), 7.03 (dd, J = 7.4, 1.5 Hz, 1H), 6.96−6.93 (m, 3H), 3.87 (s, 2H),
1.41 (s, 9H), 1.23 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
162.3, 152.3, 151.1, 135.5, 132.1, 131.5 (2C), 129.5, 129.0 (2C),
128.0, 126.8, 124.8, 124.5, 83.7, 79.5, 67.9, 28.1 (2C), 27.6 (3C);
HRMS (ESI/Q-TOF) m/z [M + H]+ calcd for C22H26NO4Se
448.1022, found 448.1021.
MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.74−7.72 (m, 1H), 7.64
(dd, J = 8.1, 1.8 Hz, 1H), 7.47−7.42 (m, 2H), 7.29−7.23 (m, 3H),
7.10 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.51 (dd, J = 8.3,
2.5 Hz, 1H), 4.14 (s, 2H), 1.64 (s, 4H), 1.48 (s, 6H). 1.24 (s, 6H),
1.23 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 160.6,
145.8, 143.6, 141.5, 139.3, 137.3 (2C), 136.6, 135.3, 135.0, 130.0
(2C), 129.3, 127.3, 126.9, 123.6, 117.8, 113.6, 112.8, 78.9, 68.9, 35.0
(2C), 32.0 (2C), 31.8 (4C), 28.7 (2C); HRMS (ESI/Q-TOF) m/z
[M + H]+ calcd for C32H37N2O2Se 561.2015, found 561.2016.
Synthesis of Tamibarotene Derivative (15). In a flask equipped
with a magnetic stirring bar, compound 14 (109.0 mg, 0.2 mmol) was
dissolved in THF (2.5 mL), and oxalic acid (54.0 mg, 0.6 mmol) was
added. The solution was stirred at room temperature for 24 h and
then concentrated. The crude product was redissolved in CH2Cl2, and
the resulting solid was filtered, giving 15 as a yellow oil (93.6 mg,
81%) after chromatographic purification with hexanes/ethyl acetate as
an eluent (1:1 to 100% ethyl acetate): 1H NMR (400 MHz, CDCl3) δ
7.92 (d, J = 7.8 Hz, 1H), 7.74−7.63 (m, 4H), 7.42−7.34 (m, 6H),
4.28 (s, 2H), 1.66 (s, 4H), 1.51 (s, 6H), 1.26 (s, 6H), 1.25 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 162.1, 145.7, 141.5,
139.1, 137.7, 136.8 (2C), 135.1, 130.7, 130.0 (2C), 129.4, 128.1,
127.4, 127.1, 124.3, 123.9, 118.0, 117.9, 80.0, 67.8, 35.0 (2C), 31.8
(4C), 29.7 (2C), 28.1 (2C); HRMS (ESI/Q-TOF) m/z [M + H]+
calcd for C32H39N2O3Se 579.2120, found 579.2123.
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-iodophenyl Diethyl-
carbamate (10j). Following TP4, 3-(4,4-dimethyl-4,5-dihydrooxa-
zol-2-yl)phenyl diethylcarbamate (6f, 145 mg, 0.5 mmol) and iodine
(165 mg, 0.65 mmol) afforded 10j (112.3 mg, 54%) as a yellow oil
after chromatographic purification with hexanes/ethyl acetate (8:2) as
1
an eluent: H NMR (400 MHz, CDCl3) δ 7.32−7.28 (m, 2H), 7.16
(dd, J = 7.6, 2.0 Hz, 1H), 4.07 (s, 2H), 3.47 (q, J = 7.1 Hz, 2H), 3.32
(q, J = 7.1 Hz, 2H), 1.34 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H), 1.14 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.6, 152.6,
152.2, 136.0, 128.7, 127.1, 124.7, 92.6, 79.3, 68.0, 42.2, 41.9, 28.0
(2C), 14.3, 13.2; HRMS (ESI) m/z [M + H]+ calcd for C16H22IN2O3
417.0670, found 417.0677.
3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-4-iodophenyl Diethyl-
carbamate (10k). Following TP4, 3-(4,4-dimethyl-4,5-dihydroox-
azol-2-yl)phenyl diethylcarbamate (6f, 145 mg, 0.5 mmol) and iodine
(165 mg, 0.65 mmol) afforded 10k (52 mg, 25%) as a yellow oil after
chromatographic purification with hexanes/ethyl acetate (8:2) as an
eluent: 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.6 Hz, 1H), 7.36
(d, J = 2.8 Hz, 1H), 6.89 (dd, J = 8.6, 2.8 Hz, 1H), 4.08 (s, 2H),
3.34−3.28 (m, 4H), 1.35 (s, 6H), 1.18−1.11 (m, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 162.2, 153.2, 151.3, 140.8, 134.5, 125.3, 124.3,
89.0, 79.5, 68.0, 42.3, 41.9, 28.1 (2C), 14.1, 13.2; HRMS (ESI) m/z
[M + H]+ calcd for C16H22IN2O3 417.0670, found 417.0670.
Computational Studies. We computed the pKa (Figures 1 and
2) by employing hypothetical reactions between the heterocycle and
pyridine (reference) in THF, as described in the literature.27 We
obtained the minima at the potential energy surface by calculating the
harmonic frequencies with the B3LYP/6-31+G(d) and B3LYP/6-
I
https://dx.doi.org/10.1021/acs.joc.0c02369
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
model for all molecules. All calculations were performed with the
program Gaussian 03.30 All the outputs were visualized in the software
Jmol.31 Supporting Information contains details of the computational
calculations.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02369.
1H and 13C NMR spectra and additional data of the
computational study are made available (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Giuliano C. Clososki − Departamento de Ciências
BioMoleculares, Faculdade de Ciências Farmacêuticas de
Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto,
SP 14040-903, Brazil; orcid.org/0000-0001-7605-4150;
Email: gclososki@usp.br
Authors
Leandro A. Bozzini − Departamento de Ciências
BioMoleculares, Faculdade de Ciências Farmacêuticas de
Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto,
SP 14040-903, Brazil
Thiago dos Santos − Departamento de Ciências
BioMoleculares, Faculdade de Ciências Farmacêuticas de
Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto,
SP 14040-903, Brazil
Valter E. Murie − Departamento de Ciências BioMoleculares,
Faculdade de Ciências Farmacêuticas de Ribeirão Preto,
Universidade de São Paulo, Ribeirão Preto, SP 14040-903,
Brazil
Murilo B. M. de Mello − Departamento de Ciências
BioMoleculares, Faculdade de Ciências Farmacêuticas de
Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto,
SP 14040-903, Brazil
Ricardo Vessecchi − Departamento de Química, Faculdade de
Filosofia Ciências e Letras de Ribeirão Preto, Universidade de
São Paulo, Ribeirão Preto, SP 14090-901, Brazil
Figure 1. pKa values calculated for compounds 1a−g and 6a−f by
using PCM/B3LYP/6-311++G(d,p)//B3LYP/6-31+G(d).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02369
Author Contributions
§T.d.S. and V.E.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support for this
̀
work by the Brazilian foundations Fundaca
̧
o
̃
de Amparo a
Paulo (FAPESP, Grants 2018/
14150-8, 2015/21364-6, and 2014/23604-1), Coordenaca de
amento de Pessoal de Nivel Superior (CAPES), and
Pesquisa do Estado de Sao
̃
̧ o
̃
́
Aperfeico
̧
Figure 2. pKa (THF) values calculated for 1a−c complexes with
TMPMgCl and LiCl complexes with TMPMgCl and LiCl calculated
at the B3LYP/6-311++G(d, p)//B3LYP/6-31+G(d,p) level.
́
Conselho Nacional de Desenvolvimento e Tecnologico
(CNPq, Grants 140137/2018-1 and 442384/2014-9). Addi-
tionally, the authors acknowledge the assistance with HRMS
analyses from Dr. Rodrigo Moreira da Silva and Mr. Jose
Carlos Tomaz.
31+G(d,p) models.28 We considered the solvent system by using
PCM29 by single-point calculations on the B3LYP/6-311++G(d,p)
́
J
https://dx.doi.org/10.1021/acs.joc.0c02369
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Note
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