Directed functionalization of halophenyl-2-oxazolines with TMPMgCl?LiCl

Article abstract of DOI:10.1002/ejoc.201403255

A variety of difunctionalized aryl-2-oxazolines were prepared from the reaction of halophenyl-2-oxazolines and TMPMgCl?LiCl to give an organomagnesium reagent, which was then treated with various electrophiles. The metalation step takes place under mild conditions, and this process al-lows for the isolation of the desired products in good yields. No isomeric or other benzyne-derived products were detected. The influence of the halogen substituents on the acidity of the aromatic hydrogen atoms was evaluated by using density functional theory (DFT) calculations.

Full text of DOI:10.1002/ejoc.201403255

FULL PAPER
DOI: 10.1002/ejoc.201403255
Directed Functionalization of Halophenyl-2-oxazolines with TMPMgCl·LiCl
João H. C. Batista,[a] Fernanda M. dos Santos,[a] Leandro A. Bozzini,[a] Ricardo Vessecchi,[b]
Alfredo R. M. Oliveira,[c] and Giuliano C. Clososki*[a]
Keywords: Heterocycles / Metalation / Cross-coupling / Regioselectivity / Magnesium / Density functional calculations
A variety of difunctionalized aryl-2-oxazolines were pre-
pared from the reaction of halophenyl-2-oxazolines and
TMPMgCl·LiCl to give an organomagnesium reagent, which
was then treated with various electrophiles. The metalation
lows for the isolation of the desired products in good yields.
No isomeric or other benzyne-derived products were de-
tected. The influence of the halogen substituents on the acid-
ity of the aromatic hydrogen atoms was evaluated by using
step takes place under mild conditions, and this process al- density functional theory (DFT) calculations.
widely used for the regioselective functionalization of ary-
Introduction
loxazolines.[10] Over the last several years, magnesium and
zinc ate bases have been developed for the selective met-
alation of arenes and heteroarenes.[9c,11] In addition, some
of them were applied to the directed functionalization of
oxazolines. For example, Marsais and co-workers prepared
a number of functionalized heteroaryloxazolines through a
directed metalation with lithium alkylmagnesate bases fol-
lowed by treatment with different electrophiles.[12] More-
over, the full metalation of a 4-bromo-substituted arylox-
azoline has been successfully accomplished by Morokuma
and co-workers by using the ate base Bu2Zn(TMP)Li (TMP
= 2,2,6,6-tetramethylpiperidyl).[13]
Recently, the mixed Li-Mg amides TMPMgCl·LiCl and
TMP2Mg·2LiCl have proved to be highly active and soluble
bases, which allow for the smooth metalation of various
substrates and demonstrate an excellent functional group
compatibility.[14] In accordance with our interest in the
functionalization of aromatic and heterocyclic compounds
by using organometallic reagents, we herein report the ap-
plication of the base TMPMgCl·LiCl in the directed func-
tionalization of halophenyl-2-oxazolines. The electronic ef-
fects of substituents attached to the phenyl ring of the sub-
strate were evaluated by calculating the pKa values of their
solutions in tetrahydrofuran (THF) using density functional
theory (DFT). The method described herein is an interest-
ing alternative for the preparation of functionalized 2-oxaz-
olines, considering their wide applications in biology and
technology.
One of the most widespread uses of 2-oxazolines is as
a protecting group for carboxylic acids.[1] In addition, 2-
oxazoline derivatives have been used in smart polymer engi-
neering[2,3] and in the formation of micelles.[4] The chiral
derivatives are widely used as chiral auxiliaries[5] and li-
gands for asymmetric catalysis, with several applications in
organic synthesis.[6] Moreover, the search for new methods
to obtain these compounds has gained interest after bioac-
tive molecules that contain a 2-oxazoline unit were found
in the marine organisms known as sea squirts (the Ascidia-
cea class, the Tunicata subphylum).[7] Several oxazoline-
containing pattelamides and lissoclinamides were isolated
from one of these organisms, Lissoclinum patella. Today,
more than 100 cyanobactins are known, some of which with
remarkable antiviral or cytotoxic activity.[8]
The directed metalation of aromatic and heteroaromatic
rings is a powerful method for the preparation of polyfunc-
tionalized unsaturated compounds.[9] Indeed, since Meyers’s
pioneering work, the ortho-lithiation strategy has been
[a] Núcleo de Pesquisas em Produtos Naturais e Sintéticos,
Faculdade de Ciências Farmacêuticas de Ribeirão Preto,
Universidade de São Paulo,
Av. do Café, s/n°, Bairro Monte Alegre, Ribeirão Preto, SP,
CEP 14040-903, Brazil
E-mail: joaoh@fcfrp.usp.br
fermoraes@fcfrp.usp.br
leandrobozzini@yahoo.com.br
gclososki@fcfrp.usp.br
www.fcfrp.usp.br
[b] Departamento de Química, Faculdade de Filosofia Ciências e
Letras de Ribeirão Preto, Universidade de São Paulo, SP,
Av. Bandeirantes, 3900 Bairro Monte Alegre, Ribeirão Preto,
SP, CEP 14040-901, Brazil
Results and Discussion
E-mail: vessecchi@usp.br
[c] Departamento de Química, Universidade Federal do Paraná,
Centro Politécnico, Jardim das Américas, Curitiba, Paraná,
CEP 81.531-980, Brazil
We initiated our study by preparing a number of halo-
phenyl-2-oxazolines from the corresponding aldehydes.[15]
Thus, the reaction of 2-amino-2-methylpropanol (2) with
halophenyl aldehyde 1 followed by an oxidation reaction
E-mail: armo@ufpr.br
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403255.
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with N-bromosuccinimide (NBS) led to the expected oxaz- Table 1. Halophenyl-2-oxazolines 4a–4i obtained from aldehydes
1a–1i.
oline (i.e., 4a–4i) in moderate to good yield and with high
purity (see Scheme 1 and Table 1). In addition, iodo-substi-
tuted oxazolines 4j–4l were prepared in 66–81% yield from
the corresponding carboxylic acid (see Scheme 2).
Scheme 1. Preparation of halophenyl-2-oxazolines 4a–4i from alde-
hydes 1 (MS = molecular sieves).
Scheme 2. Preparation of halophenyl-2-oxazolines 4j–4l from carb-
oxylic acid.
To determine the best reaction conditions for the directed
magnesiation of the halopheny-2-oxazolines with
TMPMgCl·LiCl, we chose 4-fluorophenyl-2-oxazoline
4a[16] as the model substrate. Thus, after screening for ap-
propriate reaction conditions, the full metalation of 4a was
achieved at 25 °C within 2 h by using 1.8 equiv. of the base.
A further reaction of organomagnesium reagent 5a by treat-
ment with benzaldehyde led to the isolation of alcohol de-
rivative 6a in 78% yield (see Scheme 3 and Table 2, En-
try 1). The reaction of organomagnesium reagent 5a with
iodine and 1,2-dibromotetrachloroethane led to the isola-
tion of the corresponding dihalophenyl-2-oxazolines 6b and
6c in 85 and 70% yield, respectively (see Table 2, Entries 2
and 3). The reaction of 5a with diphenyl diselenide showed
the versatility of this system, as it proceeded smoothly to
afford phenylselenide derivative 6d in 90% yield (see
Table 2, Entry 4). Palladium-catalyzed coupling reactions
are among the most important reactions for the functionali-
zation of aromatic substrates[17] and have already been suc-
cessfully used for the preparation of 2-oxazoline derivatives.
Therefore, we also applied the Negishi cross-coupling reac-
tion for the ortho-arylation of 4-fluorophenyl-2-oxazoline
(4a). After the magnesiation of 4a by using
TMPMgCl·LiCl, organomagnesium reagent 5a was trans-
Scheme 3. ortho-Metalation of 4-fluorophenyl-2-oxazoline 4a by
using TMPMgCl·LiCl and subsequent reaction with electrophile
(E+).
[a] Isolated yield of analytically pure product.
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Directed Functionalization of Halophenyl-2-oxazolines
Table 2. Products 6 from directed magnesiation of 4-fluorophenyl- metalated with ZnCl2 (1 equiv.) and then treated with 1-
2-oxazoline 4a with TMPMgCl·LiCl followed by reaction with elec-
trophile.
chloro-4-iodobenzene in the presence of a mixture of
Pd2(dba)3 (0.8 mol-%, dba = dibenzylideneacetone) and
P(o-furyl)3 (1.6 mol-%) in THF. After purification, cross-
coupling product 6e was isolated in 87% yield (see Table 2,
Entry 5). Similarly, the cross-coupling reactions with 1-
iodo-4-nitrobenzene and 1-iodo-4-fluorobenzene led to the
ortho-arylated derivatives 6f and 6g in 85 and 89% yield,
respectively (see Table 2, Entries 6 and 7).
The reaction conditions used in Table 2 were then
applied to the functionalization of other halophenyl-2-
oxazolines. Thus, a number of functionalized 2-oxazolines
were prepared in good yields by employing the reaction be-
tween the corresponding organomagnesium reagent 5 and
different electrophiles (see Scheme 4 and Table 3).
Scheme 4. Synthesis of functionalized 2-oxazolines by using
TMPMgCl·LiCl.
The 4-bromo-, 4-chloro- and 4-iodophenyl-2-oxazolines
underwent the magnesiation smoothly at room temperature
within 2 h. The reaction of the corresponding organomag-
nesium reagents with different electrophiles led to the de-
sired ortho-substituted 4-halophenyl-2-oxazolines 6h–6o in
yields that ranged from 60 to 87% (see Table 3, Entries 1–
8). Moreover, phenyl-2-oxazolines that contained a fluoro,
bromo, or chloro substituent at the ortho position were also
suitable substrates and afforded 2,6-disubstituted phenyl-2-
oxazolines 6p–6t in reasonable to good yields (see Table 3,
Entries 9–13). In contrast, attempts to metalate 2-iodo-
phenyl-2-oxazoline 4l with TMPMgCl·LiCl resulted in low
conversion into the expected product.
In the literature, it is well known that the lithiation of
aromatic halides may be complicated by the formation of
aryne intermediates. Moreover, pioneering studies by Mey-
ers and co-workers have demonstrated that benzyne-oxazol-
ines are easily generated from the corresponding lithiated 3-
chlorophenyl-2-oxazolines by warming the reaction mixture
from –78 to –15 °C.[18] In contrast, we found that meta-
fluoro-, meta-chloro-, meta-bromo- and meta-iodophenyl-
2-oxazolines were fully metalated at room temperature by
using TMPMgCl·LiCl, and no benzyne formation or iso-
meric products were detected. Upon reaction with the cor-
responding electrophile, the expected ortho-functionalized
derivatives were obtained in good yields (see Table 3, En-
tries 14–18). Interestingly, the metalation of 3-iodophenyl-
2-oxazoline 4k exclusively occurred at the sterically less hin-
dered position, and the reactions with the electrophile
yielded 2,5-difunctionalized phenyl-2-oxazolines 6x and 6y
in 80 and 88% yield, respectively (see Table 3, Entries 17
and 18).
[a] Isolated yield of analytically pure product. [b] Obtained by pal-
ladium-catalyzed cross-coupling reaction.
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Table 3. Metalation of halophenyl-2-oxazolines with TMPMgCl·LiCl followed by reaction with electrophiles to give 6h–6y .
[a] Isolated yield of analytically pure product. [b] Obtained by a palladium-catalysed cross-coupling reaction.
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Directed Functionalization of Halophenyl-2-oxazolines
The regioselectivity of the metalation of aromatics is gov-
erned by a combination of steric and electronic effects.
Thus, to rationalize our experimental results, a computa-
tional thermochemistry study was performed. The use of
computational chemistry to obtain pKa values is an impor-
tant tool to guide experimental planning.[19] In addition,
this strategy has been used to evaluate the influence of C–
H acidity on the regioselectivity of metalations of aromatic
and heterocyclic substrates.[20,21] The application of iso-
desmic reactions diminishes issues that may arise when the
pKa values are directly calculated by deprotonation reac-
tions. As shown in recent studies, the difficulty in obtaining
calculated pKa values close to the experimental values can
be overcome by using the appropriate reference compound
during the computation.[21] The pKa values of halophenyl-
2-oxazolines 6a–6l in THF were obtained by using the
B3LYP method.[22] To evaluate the effect of the halogen
substituents, the pKa values for dehalogenated 2-oxazoline
4m were also estimated by employing the computational ap-
proach (see Figure 1). In the case of the iodophenyl 2-oxaz-
olines, the calculated pKa values are qualitative and must
be used with caution to compare the acidities of the
hydrogen atoms that are present in those molecules. Ad-
ditional details can be found in the Experimental Section
and Supporting Information.
As previously reported by Schlosser and co-workers,[20]
the presence of halogen substituents has a strong effect on
the acidity of the hydrogen atoms that are attached to the
aromatic ring. According to our calculations, the most
acidic hydrogen atom of halophenyl-2-oxazolines 4 is gen-
erally located at the vicinal position to the halogen group
(ortho-halogen position). This behavior has been observed
in most studied compounds and can be attributed to the
electron-withdrawing effect of the halogen atom on the aro-
matic ring. In the case of meta-substituted phenyl-2-oxazol-
ines, the hydrogen atom located at the para position is
slightly more acidic than the one at the ortho position. De-
spite these electronic aspects, the powerful ortho-directing
effect of the oxazoline group appears to overcome the influ-
ence of the halogen substituents and yield highly selective
metalations with TMPMgCl·LiCl.
Mulvey and co-workers have investigated the structure of
TMPMgCl·LiCl in both the solid state and in solution and
have provided insights about the existence of the Lewis acid
coordination of the alkali metal with the aromatic substrate
in directed ortho-metalations.[23] Thus, the observed highly
selective metalations of halophenyl-2-oxazolines with
TMPMgCl·LiCl may be related to the great ability of the
oxazoline group to coordinate to an adjacent lithium atom
from the base in solution.
Conclusions
In summary, we have described the directed functionali-
zation of halophenyl-2-oxazolines by using TMPMgCl·
LiCl. Metalation takes place under mild conditions to give
the corresponding organomagnesium intermediates, which
Figure 1. pKa values for hydrogen atoms calculated using the
B3LYP method.
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2-(4-Chlorophenyl)-4,4-dimethyl-2-oxazoline (4c): 4-Chlorobenzal-
dehyde (1c, 4.2 g, 30.0 mmol) afforded 4c (4.96 g, 79% yield) as a
colorless oil. H NMR (400 Hz, CDCl3): δ = 7.81 (d, J = 8.54 Hz,
2 H), 7.30 (d, J = 8.54 Hz, 2 H), 4.04 (s, 2 H), 1.31 (s, 6 H) ppm.
13C NMR (100 Hz, CDCl3): δ = 161.4, 137.5, 129.6, 128.6, 126.4,
79.3, 67.6, 28.4 ppm.
upon treatment with different electrophiles has provided for
the synthesis of functionalized 2-oxazolines in good yields
without the formation of benzyne or other isomeric struc-
tures. As already reported for other haloaromatic com-
pounds, computational calculations show that the halogen
substituents of the halophenyl-2-oxazolines have a strong
effect on the acidity of their vicinal hydrogen atoms. How-
ever, the ortho-directing effect of the oxazoline group over-
comes this influence from the substituents to allow for
highly selective metalation reactions. The scope of this
method and its applicability towards the synthesis of biolo-
gically active molecules are currently being investigated in
our laboratories.
1
2-(2-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4d): 2-Fluorobenzal-
dehyde (1d, 3.1 mL, 3.7 g, 30.0 mmol) afforded 4d (4.98 g, 86%
1
yield) as a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.80 (td, J
= 7.59, 1.72 Hz, 1 H), 7.35 (m, 1 H), 7.07 (m, 2 H), 4.03 (s, 2 H),
1.32 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.0 (d, JF,C
= 257.8 Hz), 159.0 (d, JF,C = 5.07 Hz), 132.8, 131.2, 123.9 (d, JF,C
= 3.58 Hz), 116.5 (d, JF,C = 22.0 Hz), 116.3 (d, JF,C = 11.0 Hz),
78.8, 67.7, 28.3 ppm.
2-(2-Bromophenyl)-4,4-dimethyl-2-oxazoline (4e): 2-Bromobenz-
aldehyde (1e, 3.5 mL, 3.5 g, 30.0 mmol) afforded 4e (5.48 g, 72%
1
yield) as a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.60 (dd,
Experimental Section
J = 7.6, 1.5 Hz, 1 H), 7.55 (dd, J = 7.8, 0.7 Hz, 1 H), 7.27 (dt, J =
14.2, 7.5, 0.7 Hz, 1 H), 7.20 (dt, J = 13.7, 7.8, 1.6 Hz, 1 H), 4.09
(s, 2 H), 1.35 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 162.0,
133.5, 131.6, 131.2, 130.0, 127.0, 121.7, 79.5, 67.8, 28.1 ppm.
General Methods: The solvents were purified according to standard
procedures.[24] The starting materials were purchased from Sigma
Aldrich. All air-sensitive and/or water-sensitive reactions were car-
ried out with dry solvents under anhydrous conditions and under
nitrogen. Standard syringe techniques were employed for the trans-
fer of dry solvents and air-sensitive reagents. The reactions were
monitored by TLC on Merck silica gel (60 F 254), and the devel-
oped plates were visualized by using UV light or 5% vanillin in
10% H2SO4 and then heating. Sigma–Aldrich silica gel (particle
size 0.040–0.063 nm) was used for flash chromatography. The
NMR spectroscopic data were recorded with Bruker DPX 300, 400,
2-(2-Chlorophenyl)-4,4-dimethyl-2-oxazoline (4f): 2-Chlorobenzal-
dehyde (1f, 3.4 mL, 4.2 g, 30.0 mmol) afforded 4f (5.14 g, 82%
1
yield) as a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.70 (dd,
J = 1.7, 7.6 Hz, 1 H), 7.41 (dd, J = 1.0, 8.0 Hz, 1 H), 7.33 (td, J =
1.6, 7.7, 13.6 Hz, 1 H), 7.26 (td, J = 1.6, 7.6, 13.6 Hz, 1 H), 4.13
(s, 2 H), 1.40 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 160.8,
133.1, 131.3, 131.1, 130.3, 127.9, 126.3, 79.1, 67.9, 28.1 ppm.
2-(3-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4g): 2-Fluorobenzal-
dehyde (1g, 3.2 mL, 3.7 g, 30.0 mmol) afforded 4g (5.26 g, 91%
1
and 500 instruments (at 300, 400, and 500 MHz for H NMR and
at 75, 100, and 125 MHz for 13C NMR), and CDCl3 and [D6]-
DMSO were used as the NMR solvents. The chemical shifts are
reported as δ units in parts per million (ppm) relative to the solvent
signals as the internal references. Mass spectra (MS) were measured
with a Shimadzu GC–MS-QP2010 mass spectrometer. HRMS
spectra were measured with a Bruker Daltonics micrOTOF QII/
ESI-TOF.
1
yield) as a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.71 (dd,
J = 1.0, 7.7 Hz, 1 H), 7.62 (dt, J = 1.0, 9.6 Hz, 1 H), 7.35 (m, 1
H), 7.14 (tt, J = 1.5, 8.4, 14.1 Hz, 1 H), 4.10 (s, 2 H), 1.37 (s, 6
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 162.4 (d, JF,C
=
246.1 Hz), 130.2 (d, JF,C = 8.33 Hz), 129.9 (d, JF,C = 8.01 Hz), 123.9
(d, JF,C = 3.01 Hz), 118.12 (d, JF,C = 21.40 Hz), 115.2 (d, JF,C
=
23.49 Hz), 79.2, 67.7, 28.3 ppm.
Typical Procedure 1 (TP1). General Procedure for the Preparation
of Halophenyl-2-oxazolines 4a–4i: 2-Amino-2-methyl-1-propanol
(2.8 mL, 2.6 g, 30.0 mmol) was dissolved in CH2Cl2 (180 mL), and
the aldehyde (30.0 mmol) was added. The mixture was stirred over
MS (4 Å, 15 g) for 14 h. NBS (5.3 g, 30.0 mmol) was then added,
and the solution was stirred for an additional 30 min. The mixture
was filtered, and the filtrate was washed with saturated aqueous
NaHCO3 (400 mL) and H2O (100 mL). The organic layer was dried
with MgSO4, and the solvent was evaporated. If required, the prod-
uct was purified by flash column chromatography.
2-(3-Bromophenyl)-4,4-dimethyl-2-oxazoline (4h): 3-Bromobenz-
aldehyde (1h, 3.5 mL, 5.5 g, 30.0 mmol) afforded 4h (5.33 g, 70%
yield). 1H NMR (400 Hz, CDCl3): δ = 8.03 (t, J = 1.5 Hz, 1 H),
7.80 (dt, J = 7.9, 1.2 Hz, 1 H), 7.51 (m, 1 H), 7.20 (t, J = 8.0 Hz,
1 H), 4.05 (s, 2 H), 1.31 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3):
δ = 161.0, 134.2, 131.2, 130.0, 126.7, 122.3, 79.3, 67.6, 28.3 ppm.
2-(3-Chlorophenyl)-4,4-dimethyl-2-oxazoline (4i): 3-Chlorobenzal-
dehyde (1i, 3.4 mL, 4.2 g, 30.0 mmol) afforded 4i (5.65 g, 90%
1
yield) as a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.86 (t, J
= 1.51 Hz, 1 H), 7.72 (dt, J = 7.80, 1.15 Hz, 1 H), 7.34 (m, 1 H),
7.23 (t, J = 7.90 Hz, 1 H), 4.02 (s, 2 H), 1.30 (s, 6 H) ppm. 13C
NMR (100 Hz, CDCl3): δ = 160.9, 134.4, 131.2, 129.6, 128.3, 126.3,
79.3, 67.7, 28.4 ppm.
2-(4-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4a): 4-Fluorobenzal-
dehyde (1a, 3.2 mL, 3.7 g, 30.0 mmol) afforded 4a (4.70 g, 81%
1
yield) as a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.88 (m, 2
H), 7.00 (m, 2 H), 4.05 (s, 2 H), 1.30 (s, 6 H) ppm. 13C NMR
(100 Hz, CDCl3): δ = 164.3 (d, JF,C = 251.8 Hz), 161.1, 130.1 (d,
JF,C = 8.9 Hz), 123.5 (d, JF,C = 3.3 Hz), 115.0 (d, JF,C = 22.0 Hz),
79.0, 67.1, 28.0 ppm.
Typical Procedure 2 (TP2). General Procedure for the Preparation
of Iodophenyl-2-oxazolines (4j–4l): A mixture of iodobenzoic acid
(7.44 g, 30.0 mmol) and thionyl chloride (4.37 mL, 7.13 g,
60.0 mmol) was stirred at 25 °C for 24 h. The excess amount of
2-(4-Bromophenyl)-4,4-dimethyl-2-oxazoline (4b): 4-Bromobenz- thionyl chloride was removed by distillation, and the remaining
aldehyde (1b, 5.5 g, 30.0 mmol) afforded 4b (6.09 g, 80% yield) as
a colorless oil. H NMR (400 Hz, CDCl3): δ = 7.75 (t, J = 2.3 Hz,
dark oil was dissolved in dichloromethane (40 mL). The resulting
solution was then added dropwise to a magnetically stirred solution
1
1 H), 7.73 (t, J = 1.9 Hz, 1 H), 7.48 (t, J = 2.3 Hz, 1 H), 7.45 (t, J of 2-amino-2-methyl-1-propanol (2, 4.5 mL, 4.2 g, 47.8 mmol) in
= 1.9 Hz, 1 H), 4.06 (s, 2 H), 1.32 (s, 6 H) ppm. 13C NMR (100 Hz, dichloromethane (40 mL) at 0 °C. The mixture was stirred at 25 °C
CDCl3): δ = 161.1, 131.7, 130.0, 126.7, 126.0, 79.4, 67.7, 28.4 ppm.
for 2 h. The resulting white precipitate was collected by filtration
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Directed Functionalization of Halophenyl-2-oxazolines
and washed with water. The dichloromethane layer of the filtrate
was concentrated and cooled, and the resulting precipitate was col-
lected by filtration. To the obtained N-(2,2-dimethyl-3-hy-
droxypropyl)iodobenzamide was added thionyl chloride (5.34 g,
45 mmol) dropwise as the mixture was stirred. The excess amount
of thionyl chloride was removed by distillation, and dry ether
(100 mL) was added. The solution was washed with 20% sodium
hydroxide (2ϫ 30 mL). The organic phase was dried with K2CO3,
filtered, and concentrated under vacuum to give the corresponding
iodo-2-oxazoline.
73.9, 67.9, 28.3, 27.7 ppm. IR (KBr): ν = 3214, 2975, 1671, 1321,
˜
1040, 704 cm–1. HRMS (ESI): calcd. for C18H19FNO2 [M + H]+
300.1400; found 300.1394.
2-(4-Fluoro-2-iodophenyl)-4,4-dimethyl-2-oxazoline
(6b):
2-(4-
Fluorophenyl)-4,4-dimethyl-2-oxazoline (4a, 96.6 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6b (134.3 mg, 85% yield)
1
as a dark yellow solid; m.p. 65–67 °C. H NMR (400 Hz, CDCl3):
δ = 7.54 (m, 2 H), 7.02 (td, J = 13.9, 8.2, 2.6 Hz, 1 H), 4.08 (s, 2
H), 1.35 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 163.1 (d,
JF,C = 184.5 Hz), 161.5, 132.0 (d, JF,C = 8.5 Hz), 130.2 (d, JF,C
=
2-(4-Iodophenyl)-4,4-dimethyl-2-oxazoline (4j): Pale yellow oil
3.8 Hz), 127.4 (d, JF,C = 23.8 Hz), 115.1 (d, JF,C = 21.6 Hz), 94.6
(5.61 g, 81% yield). 1H NMR (400 Hz, CDCl3): δ = 7.75 (d, J = (d, JF,C = 8.6 Hz), 79.5, 68.2, 28.2 ppm.
8.6 Hz, 2 H), 7.65 (d, J = 8.6 Hz, 2 H), 4.10 (s, 2 H), 1.37 (s, 6
2-(2-Bromo-4-fluorophenyl)-4,4-dimethyl-2-oxazoline (6c): 2-(4-
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.5, 137.5, 129.8, 127.5,
98.1, 79.2, 67.7, 28.3 ppm.
Fluorophenyl)-4,4-dimethyl-2-oxazoline (4a, 96.6 mg, 0.5 mol) and
1,2-dibromoethane (0.086 mL, 187.0 mg, 1.0 mmol) afforded 6c
(94.5 mg, 70% yield) as a dark yellow solid; m.p. 68–70 °C. 1H
NMR (400 Hz, CDCl3): δ = 7.61 (dd, J = 6.0, 2.70 Hz, 1 H), 7.30
(dd, J = 8.30, 2.50 Hz, 1 H), 7.00 (dq, J = 14.0, 5.30, 2.60, 0.80 Hz,
1 H), 4.07 (s, 2 H), 1.34 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3):
δ = 163.1 (d, JF,C = 255.2 Hz), 161.0, 132.8 (d, JF,C = 9.0 Hz), 126.4
2-(3-Iodophenyl)-4,4-dimethyl-2-oxazoline (4k): Pale yellow oil
1
(5.20 g, 75% yield). H NMR (400 Hz, CDCl3): δ = 8.31 (s, 1 H),
7.88 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.13 (t, J =
7.8 Hz, 1 H), 4.10 (s, 2 H), 1.38 (s, 6 H) ppm. 13C NMR (100 Hz,
CDCl3): δ = 160.6, 140.0, 136.9, 129.9, 129.8, 127.3, 93.8, 79.2,
67.7, 28.3 ppm.
(d, JF,C = 3.6 Hz), 122.5 (d, JF,C = 10.0 Hz), 121.2 (d, JF,C
24.5 Hz), 114.4 (d, JF,C = 21.5 Hz), 79.5, 68.1, 28.2 ppm.
=
2-(2-Iodophenyl)-4,4-dimethyl-2-oxazoline (4l): Yellow oil (5.65 g,
1
66% yield). H NMR (400 Hz, CDCl3): δ = 7.90 (d, J = 8.0 Hz, 1 2-[4-Fluoro-2-(phenylselenyl)phenyl]-4,4-dimethyl-2-oxazoline (6d):
H), 7.57 (d, J = 7.5 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.10 (m, 1 2-(4-Fluorophenyl)-4,4-dimethyl-2-oxazoline
(4a,
96.6 mg,
H), 4.15 (s, 2 H), 1.42 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 0.5 mmol) and diphenyl diselenide (312.1 mg, 1.0 mmol) afforded
162.8, 140.1, 134.2, 131.4, 130.5, 127.7, 94.7, 79.4, 68.2, 28.2 ppm.
6d (155.5 mg, 90% yield) as a dark yellow solid; m.p. 70–72 °C. 1H
NMR (400 Hz, CDCl3): δ = 7.75 (t, J = 6.7 Hz, 1 H), 7.61 (dt, J
= 6.30, 1.40 Hz, 2 H), 7.36 (m, 3 H), 6.75 (dq, J = 14.0, 6.0, 2.60,
0.60 Hz, 1 H), 6.47 (dd, J = 10.1, 2.6 Hz, 1 H), 4.05 (s, 2 H), 1.39
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 iPrMgCl·LiCl
(1.12 m in THF, 44.64 mL, 50.0 mmol), and then 2,2,6,6-tetrameth-
ylpiperidine (9.2 mL, 55.0 mmol) was added dropwise through a
syringe within 5 min. The mixture was stirred until the gas evol-
ution ceased (24–48 h). Titration against benzoic acid in THF
(0 °C) in the presence of 4-(phenylazo)diphenylamine as the indi-
cator showed that the base concentration ranged from 0.9 to 1.1 m.
(s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 164.0 (d, JF,C
=
252.6 Hz), 160.8, 141.6 (d, JF,C = 7.8 Hz), 137.3, 136.3, 131.6 (d,
JF,C = 10.0 Hz), 129.9, 129.4, 121.8, 116.0 (d, JF,C = 25.1 Hz), 112.1
(d, JF,C = 22.3 Hz), 78.9, 79.5, 68.6, 28.6 ppm. IR (KBr): ν = 2961,
˜
1644, 1559, 1489, 1027, 746 cm–1. HRMS (ESI): calcd. for
C17H17FNOSe [M + H]+ 350.0459; found 350.0459.
2-(4-Bromo-2-deuterophenyl)-4,4-dimethyl-2-oxazoline (6h): 2-(4-
Bromophenyl)-4,4-dimethyl-2-oxazoline (4b, 127.0 mg, 0.5 mmol)
and D2O (0.018 mL, 20.0 mg, 1.0 mmol) afforded 6h (107.1 mg,
Typical Procedure 4 (TP4). Metalation of Halophenyl-2-oxazolines:
A flame-dried and argon-flushed Schlenk tube equipped with a
rubber septum and a magnetic stirring bar was charged with a solu-
tion of the halophenyl-2-oxazoline (0.5 mmol) in dry THF (1 mL).
The mixture was warmed to 25 °C, and then TMPMgCl·LiCl
(0.98 m in THF, 1.02 mL, 1.0 mmol) was added dropwise through
a syringe. The mixture was stirred at the given temperature for the
indicated time. The completion of the metalation was monitored
by GC analysis of reaction aliquots that were quenched with I2 in
dry THF. Thus, a solution of the indicated electrophile in THF
(1.0 mL) was added dropwise and the reaction mixture stirred for
12 h. The reaction was quenched with saturated aqueous NH4Cl
(10 mL), the products were extracted with ethyl acetate (3ϫ
10 mL), the extracts washed with brine, dried with MgSO4, and
concentrated.
1
84% yield) as a yellow solid; m.p. 186–187 °C. H NMR (400 Hz,
CDCl3): δ = 7.74 (d, J = 8.7 Hz, 1 H), 7.47 (m, 2 H), 4.05 (s, 2
H),1.32 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.5, 131.5,
129.8, 126.2, 79.3, 67.6, 59.9, 28.3 ppm. IR (KBr): ν = 3395, 2933,
˜
1629, 1391, 1013, 760 cm–1. HRMS (ESI): calcd. for
C11H21DBrNO [M + H]+ 255.0243; found 255.0238.
2-(4-Bromo-2-iodophenyl)-4,4-dimethyl-2-oxazoline
(6i):
2-(4-
Bromophenyl)-4,4-dimethyl-2-oxazoline (4b, 127.0 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6i (134.1 mg, 71% yield)
1
as a light brown solid; m.p. 67–69 °C. H NMR (400 Hz, CDCl3):
δ = 8.01 (d, J = 1.8 Hz, 1 H), 7.44 (dd, J = 8.2, 1.8 Hz, 1 H), 7.38
(d, J = 8.2 Hz, 1 H), 4.06 (s, 2 H), 1.34 (s, 6 H) ppm. 13C NMR
(100 Hz, CDCl3): δ = 161.9, 142.3, 133.0, 131.4, 131.0, 124.8, 95.2,
79.4, 68.3, 28.2 ppm.
[2-(4,4-Dimethyl-2-oxazoline)-5-fluorophenyl](phenyl)-methanol
(6a): 2-(4-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4a, 96.6 mg,
0.5 mmol) and benzaldehyde (0.10 mL, 106 mg, 1.0 mmol) afforded [5-Bromo-2-(4,4-dimethyl-2-oxazoline)phenyl](phenyl)methanol (6j):
1
6a (115.4 mg, 78% yield) as a light yellow solid; m.p. 70–72 °C. H
NMR (400 Hz, CDCl3): δ = 7.80 (dd, J = 8.7, 5.8 Hz, 1 H), 7.21
2-(4-Bromophenyl)-4,4-dimethyl-2-oxazoline
(4b,
127.0 mg,
0.5 mmol) and benzaldehyde (0.10 mL, 106 mg, 1.0 mmol) afforded
(m, 5 H), 6.96 (dq, J = 13.7, 7.9, 2.7, 0.7 Hz, 1 H), 6.74 (d, J = 6j (108.0 mg, 60% yield) as a white oil. 1H NMR (400 Hz, CDCl3):
9.8, 2.7 Hz, 1 H), 5.86 (s, 1 H), 3.98 (d, J = 8.1 Hz, 1 H), 3.90 (d,
δ = 7.66 (d, J = 8.3 Hz, 1 H), 7.43 (d, J = 8.3, 2.0 Hz, 1 H), 7.25
J = 8.1 Hz, 1 H), 1.28 (s, 3 H), 1.00 (s, 3 H) ppm. 13C NMR (d, J = 2.0 Hz, 1 H), 7.23 (m, 3 H), 7.19 (m, 1 H), 5.81 (s, 1 H),
(100 Hz, CDCl3): δ = 164.1 (d, JF,C = 253.4 Hz), 161.5, 148.1 (d,
JF,C = 6.9 Hz), 142.2, 132.78 (d, JF,C = 8.7 Hz), 128.0, 127.0, 126.6,
3.96 (d, J = 8.2 Hz, 1 H), 3.87 (d, J = 8.2 Hz, 1 H), 1.26 (s, 3 H),
0.94 (s, 3 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.7, 146.7,
122.8, 117.5 (d, JF,C = 22.8 Hz), 114.2 (d, JF,C = 20.6 Hz), 78.7, 142.5, 133.3, 132.0, 130.6, 127.9, 126.5, 126.1, 125.6, 78.8, 74.3,
Eur. J. Org. Chem. 2015, 967–977
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
973

G. C. Clososki et al.
FULL PAPER
68.0, 28.3, 27.7 ppm. IR (KBr): ν = 3199, 2961, 1644, 1307, 1027,
1433, 1237, 1054, 746 cm–1. HRMS (ESI): calcd. for C17H17FNOS
[M + H]+ 302.1015; found 302.1020.
˜
732 cm–1. HRMS (ESI): calcd. for C18H19BrNO2 [M + H]+
360.0599; found 359.0593.
2-(2-Chloro-6-iodophenyl)-4,4-dimethyl-2-oxazoline
(6r):
2-(2-
Chlorophenyl)-4,4-dimethyl-2-oxazoline (4f, 104.0 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6r (116.2 mg, 70% yield)
as a yellow oil. H NMR (400 Hz, CDCl3): δ = 7.65 (dd, J = 8.0,
2-[4-Bromo-2-(phenylselenyl)phenyl]-4,4-dimethyl-2-oxazoline (6l):
2-(4-Bromophenyl)-4,4-dimethyl-2-oxazoline
(4b,
127.0 mg,
1
0.5 mmol) and diphenyl diselenide (312.1 mg, 1.0 mmol) afforded
6l (178.0 mg, 87% yield) as a green solid; m.p. 98–100 °C. 1H NMR
(400 Hz, CDCl3): δ = 7.61 (m, 3 H), 7.36 (m, 3 H), 7.20 (dd, J =
8.4, 2.0 Hz, 1 H), 6.89 (d, J = 1.9 Hz, 1 H), 4.05 (s, 2 H), 1.39 (s,
6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 160.9, 140.6, 137.0,
135.1, 131.3, 129.9, 129.3, 127.9, 127.7, 124.4, 78.9, 68.6, 28.5,
1.0 Hz, 1 H), 7.30 (dd, J = 8.0, 1.0 Hz, 1 H), 6.94 (t, J = 8.0 Hz, 1
H), 4.09 (s, 2 H), 1.37 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ
= 160.7, 137.2, 133.4, 131.6, 129.0, 96.5, 79.5, 68.4, 26.9 ppm. IR
(KBr): ν = 2961, 1671, 1433, 1293, 1111, 1040, 775 cm–1. HRMS
˜
(ESI): calcd. for C11H12ClNO [M + H]+ 335.9652; found 335.9666.
27.7 ppm. IR (KBr): ν = 2962, 1636, 1466, 1041, 737 cm–1. HRMS
˜
2-[2-Chloro-6-(phenylthio)phenyl]-4,4-dimethyl-2-oxazoline (6s): 2-
(ESI): calcd. for C17H17BrNOSe [M + H]+ 409.9659; found
409.9653.
(2-Chlorophenyl)-4,4-dimethyl-2-oxazoline
(4f,
104.0 mg,
0.5 mmol) and diphenyl disulfide (218 mg, 1.0 mmol) afforded 6s
(106.7 mg, (68% yield) as a light yellow solid; m.p. 67–69 °C. 1H
NMR (400 Hz, CDCl3): δ = 7.37 (m, 2 H), 7.26 (m, 2 H), 7.16 (dd,
J = 8.0, 1.1 Hz, 1 H), 7.08 (t, J = 8.0 Hz, 1 H), 6.89 (dd, J = 8.0,
1.1 Hz, 1 H), 4.09 (s, 2 H), 1.38 (s, 6 H) ppm. 13C NMR (100 Hz,
CDCl3): δ = 159.1, 139.8, 133.6, 133.0, 130.8, 129.4, 128.2, 127.2,
2-(4-Chloro-2-iodophenyl)-4,4-dimethyl-2-oxazoline (6m): 2-(4-
Chlorophenyl)-4,4-dimethyl-2-oxazoline (4c, 105.0 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6m (100.0 mg, 60% yield)
as a yellow solid; m.p. 65–67 °C. 1H NMR (400 Hz, CDCl3): δ =
7.92 (d, J = 2.0 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.35 (dd, J =
2.0, 8.3 Hz, 1 H), 4.14 (s, 2 H), 1.41 (s, 6 H) ppm. 13C NMR
(100 Hz, CDCl3): δ = 161.8, 139.7, 136.6, 132.5, 131.2, 128.1, 94.8,
79.4, 68.3, 28.2 ppm.
79.5, 68.4, 28.0 ppm. IR (KBr): ν = 3073, 2961, 1658, 1433, 1293,
˜
1040, 956, 775 cm–1. HRMS (ESI): calcd. for C17H17ClNOS [M +
H]+ 318.0719; found 318.0714.
2-(2-Bromo-6-iodophenyl)-4,4-dimethyl-2-oxazoline
(6t):
2-(2-
2-[4-Chloro-2-(phenylselenyl)phenyl]-4,4-dimethyl-2-oxazoline (6n):
Bromophenyl)-4,4-dimethyl-2-oxazoline (4e, 127.0 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6t (104.0 mg, 55% yield)
as a yellow solid; m.p. 78–80 °C. 1H NMR (400 Hz, CDCl3): δ =
7.67 (m, 2 H), 7.16 (dd, J = 8.4, 2.4 Hz, 1 H), 4.08 (s, 2 H), 1.35
(s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.6, 141.8, 135.7,
2-(4-Chlorophenyl)-4,4-dimethyl-2-oxazoline
(4c,
105.0 mg,
0.5 mmol) and diphenyl diselenide (312.1 mg, 1.0 mmol) afforded
6n (155.0 mg, 85% yield) as a yellow oil. 1H NMR (400 Hz,
CDCl3): δ = 7.70 (m, 3 H), 7.43 (m, 3 H), 7.09 (dd, J = 2.0, 8.3 Hz,
1 H), 6.82 (d, J = 2.0 Hz, 1 H), 4.09 (s, 2 H), 1.44 (s, 6 H) ppm.
13C NMR (100 Hz, CDCl3): δ = 160.4, 140.3, 137.0, 130.6, 129.8,
134.5, 133.4, 122.1, 92.5, 79.6, 68.3, 28.1 ppm. IR (KBr): ν = 2961,
˜
1671, 1293, 1013, 802 cm–1. HRMS (ESI): calcd. for C11H12BrINO
[M + H]+ 379.9147; found 379.9145.
129.2, 128.4, 124.8, 124.2, 78.7, 68.7, 28.6 ppm. IR (KBr): ν = 2961,
˜
1629, 1461, 1321, 1027, 732 cm–1. HRMS (ESI): calcd. for
C17H17ClNOSe [M + H]+ 366.0164; found 366.0160.
2-(3-Fluoro-2-iodophenyl)-4,4-dimethyl-2-oxazoline
(6u):
2-(3-
Fluorophenyl)-4,4-dimethyl-2-oxazoline (4g, 96.6 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6u (118.5 mg, 75% yield)
as a dark yellow solid; m.p. 65–67 °C. H NMR (400 Hz, CDCl3):
2-(2,4-Diiodophenyl)-4,4-dimethyl-2-oxazoline (6o):
2-(4-Iodo-
phenyl)-4,4-dimethyl-2-oxazoline (4j, 105.0 mg, 0.5 mmol) and iod-
ine (254.0 mg, 1.0 mmol) afforded 6o (169.0 mg, 80% yield) as a
1
1
δ = 7.74 (m, 2 H), 7.25 (t, J = 7.6 Hz, 1 H), 4.15 (s, 2 H), 1.32 (s,
dark yellow solid; m.p. 73–75 °C. H NMR (400 Hz, CDCl3): δ =
6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.5, 141.5, 135.8,
8.28 (d, J = 1.7 Hz, 1 H), 7.70 (dd, J = 8.0, 1.7 Hz, 1 H), 7.29 (d,
J = 8.0 Hz, 1 H), 4.13 (s, 2 H), 1.41 (s, 6 H) ppm. 13C NMR
(100 Hz, CDCl3): δ = 162.1, 147.8, 136.9, 133.5, 131.6, 97.0, 95.5,
134.5, 133.4, 122.1, 92.6, 79.6, 68.3, 28.2 ppm. IR (KBr): ν = 2919,
˜
1671, 1447, 971, 788 cm–1. HRMS (ESI): calcd. for C11H11FINO
[M + H]+ 319.9948; found 319.9943.
79.4, 68.3, 28.2 ppm. IR (KBr): ν = 3437, 2961, 1658, 1083, 1013,
˜
802 cm–1. HRMS (ESI): calcd. for C11H12I2NO [M + H]+ 427.9008;
found 427.9007.
2-(3-Chloro-2-iodophenyl)-4,4-dimethyl-2-oxazoline
(6v):
2-(3-
Chlorophenyl)-4,4-dimethyl-2-oxazoline (4i, 104.0 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6v (126.0 mg, 75% yield).
1H NMR (400 Hz, CDCl3): δ = 7.28 (m, 2 H), 7.06 (dd, J = 7.7,
2.3 Hz, 1 H), 4.10 (s, 2 H), 1.36 (s, 6 H) ppm. 13C NMR (100 Hz,
CDCl3): δ = 163.5, 162.1, 160.2, 136.3, 129.8, 126.2, 117.0, 79.5,
2-(2-Fluoro-6-iodophenyl)-4,4-dimethyl-2-oxazoline
(6p):
2-(2-
Fluorophenyl)-4,4-dimethyl-2-oxazoline (4d, 96.6 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6p (126.4 mg, 80% yield)
as a yellow solid; m.p. 67–69 °C. 1H NMR (400 Hz, CDCl3): δ =
7.57 (m, 1 H), 7.20 (s, 1 H), 7.03 (m, 1 H), 4.10 (s, 2 H), 1.38 (s, 6
68.2, 28.2 ppm. IR (KBr): ν = 3241, 2947, 1742, 1644, 1405,
˜
775 cm–1. HRMS (ESI): calcd. for C11H12ClINO [M + H]+
335.9642; found 335.9648.
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.3, 158.8 (d, JF,C
=
6.5 Hz), 134.8 (d, JF,C = 3.6 Hz), 132.5 (d, JF,C = 8.7 Hz), 123.8 (d,
JF,C = 17.8 Hz), 115.6 (d, JF,C = 21.4 Hz), 96.4, 79.1, 68.5,
28.1 ppm.
2-(3-Bromo-2-iodophenyl)-4,4-dimethyl-2-oxazoline
(6w):
2-(3-
Bromophenyl)-4,4-dimethyl-2-oxazoline (4h, 127.0 mg, 0.5 mmol)
and iodine (254 mg, 1.0 mmol) afforded 6w (133.0 mg, 70% yield)
2-[2-Fluoro-6-(phenylthio)phenyl]-4,4-dimethyl-2-oxazoline (6q): 2-
(2-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4d, 96.6 mg, 0.5 mmol)
and diphenyl disulfide (218 mg, 1.0 mmol) afforded 6q (104.3 mg,
70% yield) as a white solid; m.p. 70–72 °C. 1H NMR (400 Hz,
CDCl3): δ = 7.39 (m, 2 H), 7.29 (m, 3 H), 7.11 (td, J = 8.1, 5.8 Hz,
1 H), 6.84 (t, J = 8.7 Hz, 1 H), 6.70 (d, J = 8.1 Hz, 1 H), 4.07 (s,
2 H), 1.37 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 162.1,
1
as a yellow oil. H NMR (400 Hz, CDCl3): δ = 7.67 (m, 2 H), 7.16
(dd, J = 8.4, 2.4 Hz, 1 H), 4.07 (s, 2 H), 1.34 (s, 6 H) ppm. 13C
NMR (100 Hz, CDCl3): δ = 161.5, 141.4, 135.7, 134.5, 133.4, 122.1,
92.6, 79.5, 68.3, 28.2 ppm. IR (KBr): ν = 2947, 1671, 1307, 1069,
˜
775 cm–1. HRMS (ESI): calcd. for C11H12BrINO [M + H]+
379.9147; found 379.9142.
158.5 (d, JF,C = 223.8 Hz), 140.8 (d, JF,C = 2.3 Hz), 133.6, 133.2, 2-(5-Iodo-3-iodophenyl)-4,4-dimethyl-2-oxazoline (6x): 2-(3-Iodo-
131.4 (d, JF,C = 9.2 Hz), 129.5, 128.4, 124.9 (d, JF,C = 3.3 Hz), 113.1
(d, JF,C = 21.7 Hz), 79.3, 68.3, 28.2 ppm. IR (KBr): ν = 2961, 1658,
phenyl)-4,4-dimethyl-2-oxazoline (4k, 105.0 mg, 0.5 mmol) and
iodine (254.0 mg, 1.0 mmol) afforded 6x (169.0 mg, 80% yield) as
˜
974
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 967–977

Directed Functionalization of Halophenyl-2-oxazolines
1
a yellow oil. H NMR (400 Hz, CDCl3): δ = 7.90 (d, J = 2.1 Hz, 1 (d, JF,C = 8.2 Hz), 123.6 (d, JF,C = 2.5 Hz), 117.2 (d, JF,C
=
H), 7.60 (d, J = 8.3 Hz, 1 H), 7.40 (dd, J = 8.3, 2.1 Hz, 1 H), 4.14 22.3 Hz), 115.1 (d, JF,C = 21.6 Hz), 114.4 (d, JF,C = 21.6 Hz), 79.7,
(s, 2 H), 1.41 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 161.3,
67.3, 27.9 ppm. IR (KBr): ν = 2947, 1602, 1504, 1223, 830 cm–1.
˜
141.5, 140.3, 139.1, 135.9, 93.2, 93.0, 79.5, 68.3, 28.1 ppm. IR
HRMS (ESI): calcd. for C17H16F2NO [M + H]+ 288.1200; found
(KBr): ν = 2961, 1644, 1293, 998, 802 cm–1. HRMS (ESI): calcd. 288.1201.
˜
for C11H12I2NO [M + H]+ 427.9008; found 427.9003.
2-(5-Bromo-4Ј-nitro-[1,1Ј-biphenyl]-2-yl)-4,4-dimethyl-2-oxazoline
2-[3-Iodo-2-(phenylthio)phenyl]-4,4-dimethyl-2-oxazoline (6y): 2-(3-
Iodophenyl)-4,4-dimethyl-2-oxazoline (4k, 105.0 mg, 0.5 mmol)
and diphenyl disulfide (312.1 mg, 1.0 mmol) afforded 6y (178.0 mg,
88% yield) as a yellow solid; m.p. 78–80 °C. 1H NMR (400 Hz,
CDCl3): δ = 8.07 (d, J = 1.5 Hz, 1 H), 7.51 (m, 2 H), 7.45 (dd, J
= 8.5, 1.6 Hz, 1 H), 7.39 (m, 3 H), 6.56 (d, J = 8.5 Hz, 1 H), 4.09
(s, 2 H), 1.42 (s, 6 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 166.0,
140.6, 139.3, 138.4, 132.8, 129.7, 129.6, 128.9, 88.6, 78.9, 68.6,
(6k): 2-(4-Bromophenyl)-4,4-dimethyl-2-oxazoline (4b, 127.0 mg,
0.5 mmol) and 1-iodo-4-nitrobenzene (249.0 mg, 1.0 mmol) af-
forded 6k (159.0 mg, 85% yield) as a brown solid; m.p. 112–114 °C.
1H NMR (400 Hz, CDCl3): δ = 8.19 (dt, J = 8.7, 2.4 Hz, 2 H), 7.70
(d, J = 8.3 Hz, 1 H), 7.55 (dd, J = 8.3, 2.0 Hz, 1 H), 7.46 (m, 2 H),
7.43 (t, J = 2.0 Hz, 1 H), 3.78 (s, 2 H), 1.23 (s, 6 H) ppm. 13C NMR
(100 Hz, CDCl3): δ = 162.4, 147.3, 146.4, 141.3, 133.0, 132.2, 131.6,
129.3, 123.3, 79.7, 67.6, 27.8 ppm. IR (KBr): ν = 2961, 2877, 1658,
˜
28.4 ppm. IR (KBr): ν = 2947, 1644, 1349, 1027, 830 cm–1. HRMS
1517, 1335, 1040, 858 cm–1. HRMS (ESI): calcd. for
C17H16BrN2O3 [M + H]+ 375.0344; found 375.0359.
˜
(ESI): calcd. for C17H17INOS [M + H]+ 410.0076; found 410.0074.
Typical Procedure 5 (TP5). Quenching by Negishi Cross-Coupling
Reaction: After complete metalation according to TP4, a solution
of ZnCl2 in THF was added (1 m in THF, 0.5 mL, 0.5 mmol). After
15 min, a solution of Pd(PPh3)4 (0.8 mol-%, 4.5 mg) in THF (1 mL)
and a solution of corresponding aryl halide RX (1 mmol, 2 equiv.)
were added, and the resulting mixture was stirred at 60 °C over-
night. The reaction was quenched with saturated aqueous NH4Cl
(20 mL), and the aqueous layer was extracted with AcOEt (3ϫ
40 mL). The solvent of the combined organic layers was evaporated
under vacuum, and the product was purified by flash column
chromatography.
Computational Methods: All the calculations were done in the
Gaussian 03 suite programs,[25] and the geometries and Gibbs ener-
gies were calculated by using the B3LYP method.[22] For phenyl-2-
oxazolines 6a–6i, the 6-31+G(d,p) basis set was used to optimize
the geometries and obtain the energetic treatment. For iodides 6j–
6l, the CEP-31G was used as the basis set.[26] The solvent system
effects were evaluated by using the polarized continuum model
(PCM)[27] with the default parameters for THF. To obtain the pKa
values for all of the molecules, the deprotonated molecules were
also optimized in the same models. The pKa values were then calcu-
lated by means of the isodesmic reactions using the appropriate
heterocycle with an experimental pKa value as described in the re-
action: Het–H + R– ǞRH + Het–.[21]
2-(4Ј-Chloro-5-fluoro-[1,1Ј-biphenyl]-2-yl)-4,4-dimethyl-2-oxazoline
(6e): 2-(4-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4a, 96.6 mg,
0.5 mmol) and 1-chloro-4-iodobenzene (238.4 mg, 1.0 mmol) af-
These approaches have been described recently, and the results are
important to describe the experimental results obtained from syn-
theses that involve heterocyclic compounds and C–H activation.
The reference compound used in our studies was pyridine, and we
followed the method described in the literature.[21]
1
forded 6e (130.5 mg, 87% yield) as a brown oil. H NMR (400 Hz,
CDCl3): δ = 7.72 (dd, J = 8.6, 5.8 Hz, 1 H), 7.31 (t, J = 2.0 Hz, 1
H), 7.28 (t, J = 2.0 Hz, 1 H), 7.23 (t, J = 2.0 Hz, 1 H), 7.21 (t, J =
2.0 Hz, 1 H), 7.03 (dd, J = 8.3, 2.6 Hz, 1 H), 6.98 (m, 1 H), 3.76
(s, 2 H), 1.23 (s, 3 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 164.0
(d, JF,C = 189.0 Hz), 162.4, 143.1 (d, JF,C = 8.6 Hz), 138.4, 134.0,
132.7 (d, JF,C = 8.8 Hz), 129.5, 128.3, 123.5 (d, JF,C = 2.3 Hz), 117.1
(d, JF,C = 22.4 Hz), 114.6 (d, JF,C = 21.4 Hz), 79.7, 67.3, 27.9 ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all synthesized compounds and
experimental details of the computational thermochemistry study.
IR (KBr): ν = 2961, 1658, 1461, 1293, 1181, 1096, 830 cm–1
.
˜
HRMS (ESI): calcd. for C17H16ClFNO [M + H]+ 304.0904; found
304.0910.
Acknowledgments
2-(5-Fluoro-4Ј-nitro-[1,1Ј-biphenyl]-2-yl)-4,4-dimethyl-2-oxazoline
(6f): 2-(4-Fluorophenyl)-4,4-dimethyl-2-oxazoline (4a, 96.6 mg,
0.5 mmol) and 1-iodo-4-nitrobenzene (249.0 mg, 1.0 mmol) af-
forded 6f (128.2 mg, 85% yield) as a dark brown solid; m.p. 83–
The authors are grateful to the Brazilian foundations Fundação de
Amparo à Pesquisa do Estado de São Paulo (FAPESP), Coord-
enação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES), and Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq) for their financial support.
1
85 °C. H NMR (400 Hz, CDCl3): δ = 8.20 (dt, J = 8.8, 2.0 Hz, 2
H), 7.85 (dd, J = 8.6 Hz, 5.6 Hz, 1 H), 7.45 (dt, J = 8.6, 2.0 Hz, 2
H), 7.11 (td, J = 8.2, 2.0 Hz, 1 H), 7.01 (dd, J = 9.0, 2.5 Hz, 1 H),
3.79 (s, 2 H), 1.23 (s, 3 H) ppm. 13C NMR (100 Hz, CDCl3): δ =
163.8 (d, JF,C = 254.2 Hz), 149.0 (d, JF,C = 8.7 Hz), 147.3, 146.6,
142.2 (d, JF,C = 8.1 Hz), 133.1 (d, JF,C = 9.0 Hz), 129.2, 123.3, 117.3
(d, JF,C = 22.9 Hz), 115.6 (d, JF,C = 21.2 Hz), 79.8, 67.5, 27.1 ppm.
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96.6 mg,
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1
afforded 6g (127.0 mg, 89% yield) as a dark brown oil. H NMR
(400 Hz, CDCl3): δ = 7.70 (t, J = 5.0 Hz, 1 H), 7.26 (m, 2 H), 7.01
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Eur. J. Org. Chem. 2015, 967–977

Directed Functionalization of Halophenyl-2-oxazolines
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Received: September 24, 2014
Published Online: December 15, 2014
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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