A one-pot synthesis of 2-Aryl-4,5-anti-diphenyloxazolines

Article abstract of DOI:10.1055/s-0029-1217985

A one-pot procedure for the synthesis of oxazolines was developed. An amino alcohol was coupled with benzoyl chlorides in the presence of triethylamine to produce a -hydroxyamide. Direct treatment with methanesulfonyl chloride forms oxazolines in good yields.

Full text of DOI:10.1055/s-0029-1217985

2836
LETTER
A One-Pot Synthesis of 2-Aryl-4,5-anti-diphenyloxazolines
A
O
ne-Po
o
t
S
ynthesis
o
n
f
2-Aryl-4, 5-
a
anti-diphe
n
t
yloxaz
h
olines an Clayden,* James Clayton, Rebecca A. Harvey, Ol’ga Karlubíková
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: clayden@man.ac.uk
Received 10 July 2009
rings towards dearomatising attack by organolithiums,4b
an extension of the work by Meyers et al. on naphthyl and
pyridyloxazolines,1,4a we sought a reliable, stereospecific
route to enantiomerically pure oxazolines 4 bearing a
range of substituents R. The ready availability of amino
alcohol 2 in enantiomerically pure form encouraged us to
employ strategy (c), since invertive displacement pro-
vides the required anti relative stereochemistry. Linclau9
used N,N¢-diisopropylcarbodiimide and Cu(OTf)2 to cyc-
lise N-(2-hydroxyethyl)amides to oxazolines, however,
this reaction required either reflux or microwave irradia-
tion, and the presence of substituents a- to the oxygen
gave reduced yields. Du10 showed that both syn- and anti-
4,5-diphenyloxazolines 4 can be formed by substitution of
the hydroxyl group of amides 3 by mesylation followed
by reflux with NaOH in methanol. Inversion adjacent to
oxygen was observed as expected for an SN2 displace-
ment.
Abstract: A one-pot procedure for the synthesis of oxazolines was
developed. An amino alcohol was coupled with benzoyl chlorides
in the presence of triethylamine to produce a b-hydroxyamide. Di-
rect treatment with methanesulfonyl chloride forms oxazolines in
good yields.
Key words: oxazoline, arenes, heterocycle substitutions, auxiliary
Oxazolines have been used to direct a broad range of
asymmetric reactions1 – for instance, as features of chiral
ligands for asymmetric catalysis2 or as chiral auxiliaries
for diastereoselective couplings, substitution3 or dearom-
atising additions.4 The oxazoline ring’s resistance to hy-
drolysis or attack by nucleophiles, bases or radicals
confers applicability to a wide variety of reaction condi-
tions – the oxazoline ring itself reacts only with strong
Brønsted acids or powerful electrophiles.1
2-Aryl oxazolines have been made1,5 principally (a) by
reaction of an amino alcohol with an activated benzoic
acid derivative,6 (b) by rearrangement of an N-acyl aziri-
dine,7 or (c) by formation of an amide by acylation of an
amino alcohol, followed by cyclisation with invertive dis-
placement of the hydroxyl group (for example,
Scheme 1).8–10 Epimerisation or racemisation by non-ste-
reospecific displacement is a danger in the synthesis of
oxazolines bearing a stereogenic centre at the 5-position
(adjacent to oxygen).
However, we found that isolation of the intermediate
hydroxyamides 3 is complicated by their insolubility in a
variety of solvents. It was envisaged that a one-pot synthe-
sis of oxazolines direct from the amino alcohol 2 and acyl
chloride 1 would avoid the need for isolation of amides 3
and could provide a general, simple and scalable proce-
dure for oxazoline synthesis.11
Four equivalents of triethylamine were used both to effect
amide formation and to facilitate the subsequent hydroxyl
substitution – by increasing the amount of base we avoid-
ed the need for a reflux step. The cyclisation itself was
promoted by methanesulfonyl chloride. The result is an
uncomplicated stereoselective one-pot synthesis of 2-aryl
oxazolines, which is applicable to a range of substituted
products as shown in Table 1. The presence of electron-
withdrawing and electron-donating groups was well toler-
ated, and yields were generally good to excellent. In some
cases, the carboxylic acids themselves were used, the acyl
chlorides being formed with thionyl chloride in situ prior
to addition of the amino alcohol and triethylamine. The
synthesis of 4b was successfully carried out on a 10 g
scale.
Following our recent demonstration of the utility of 4,5-
anti-diphenyloxazolines 4 for the activation of benzenoid
Ph
Ph
(R)
Ph
HO
O
O
Cl
R
Ph
1.
(S)
NH2
HO
NH
2
Et3N
(4 equiv),
CH2Cl2, 0–25 °C
1
3
R
Ph
Ph
(R)
(R)
2. MeSO2Cl,
0–25 °C
O
N
The method gave lower yields of 2-oxazolines when elec-
tron-withdrawing substituents were present in the ortho-
position, presumably due to the inductive decrease in the
nucleophilicity of the amide C=O bond, which reduces the
rate of cyclisation. However, alternative methods exist for
the efficient stereoselective synthesis of these com-
pounds, such as rearrangement of the corresponding N-
acyl aziridine.4b,7
R
4
Scheme 1 One-pot oxazoline synthesis
SYNLETT 2009, No. 17, pp 2836–2838
Advanced online publication: 24.09.2009
DOI: 10.1055/s-0029-1217985; Art ID: D18209ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
A One-Pot Synthesis of 2-Aryl-4,5-anti-diphenyloxazolines
2837
Table 1 Synthesis of Oxazolines by the One-Pot Method Shown in
Scheme 1
Table 1 Synthesis of Oxazolines by the One-Pot Method Shown in
Scheme 1 (continued)
Entry
1
Oxazoline 4
Yield from 1 (%)
Entry
Oxazoline 4
Yield from 1 (%)
Ph
N
O
HN
71
NH
Ph
O
Ph
11
67b
Ph
N
4a
Ph
N
O
Ph
2
3
89a
90
OMe
4k
O
Ph
4b
Ph
O
O
Ph
N
12
13
66b
N
F
O
O
Ph
Ph
4l
4c
OMe
Ph
N
Ph
N
20b
4
5
6
88
80
46
OMe
O
Ph
O
Ph
4d
4m
F
a On a 10 g scale.
Ph
N
b Yield from carboxylic acid, forming acyl chloride in situ by reflux
with thionyl chloride.
O
Ph
4e
F
The one-pot procedure forms, to the limit of detection,
only the anti-diphenyloxazoline product of inversion at
the oxazoline C-5 position.12
Ph
N
O
Ph
In summary, we have developed an operationally simple
one-pot synthesis of enantiomerically pure 2-aryl-4,5-
anti-diphenyl oxazolines from the corresponding com-
mercially available amino alcohol 2.13,14
4f
TIPSO
Ph
N
7
8
88b
OMe
OMe
OMe
O
Ph
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
4g
TIPSO
Ph
67b
N
O
Acknowledgment
We are grateful for studentship support from the EPSRC and Glaxo-
SmithKline, and we thank Dr. Diane Coe for valuable discussions.
Ph
4h
Cl
References and Notes
Ph
9
67b
N
O
(1) (a) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(b) Meyers, A. I. J. Org. Chem. 2005, 70, 6137; and
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Chem. Int. Ed. 2008, 47, 5060.
Ph
4i
O
N
O
i-Pr
i-Pr
10
90b
Ph
N
O
OMe
Ph
4j
(5) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
Synlett 2009, No. 17, 2836–2838 © Thieme Stuttgart · New York

2838
J. Clayden et al.
LETTER
(6) (a) Meyers, A. I.; Higashiyama, K. J. Org. Chem. 1987, 52,
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Chem. 1974, 6, 996. Recently, oxidative preparations of
oxazolines from aryl aldehydes and amino alcohols were
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2006, 2996. (e) Karade, N. N.; Tiwari, G. B.; Gampawar,
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(7) (a) Heine, H. W.; Kaplin, M. S. J. Org. Chem. 1967, 36,
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Basceken, S.; Floerke, U. Eur. J. Org. Chem. 2007, 5, 831.
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(j) Iwasa, S.; Ishima, Y.; Widagdo, H. S.; Aoki, K.;
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min to a stirred solution of the amine [(1R,2S)-2-amino-1,2-
diphenylethanol, 1 g, 1.0 equiv] in CH2Cl2 (100 mL) and
Et3N (2.6mL, 4 equiv) at 0 °C under a nitrogen atmosphere.
The solution was stirred for 16 h. The white suspension was
cooled to 0 °C and methanesulfonyl chloride (0.54 mL, 1.5
equiv) was added dropwise over 5 min (the solution clarified
as the oxazoline formed). The reaction was monitored by
TLC and quenched with excess aqueous NH4Cl after all the
amide had been consumed. The solution was partitioned
between CH2Cl2 and aqueous NH4Cl and extracted with
CH2Cl2. The organic layers were washed with aqueous
sodium hydrogen carbonate and brine. The solution was
dried with MgSO4 and concentrated under reduced pressure,
leaving approximately 5 mL solvent to load the crude
reaction mixture onto silica gel. Purification using flash
chromatography (10% EtOAc in petroleum ether) gave
oxazoline 4a in 71% yield. Mp 116 °C (EtOAc–Petrol)
(Lit.15 93–95 °C, Et2O); [a]D22 +17.6 (c 1, CHCl3); 1H NMR
(CDCl3, 300 MHz): d = 8.07 (d, J = 8 Hz, 2 H, CH C-2, C-
6), 7.32 (m, 13 H, Ar), 5.35 (d, J = 8 Hz, CH-5¢), 5.17 (d,
J = 8 Hz, 1 H, CH-4¢); 13C NMR (CDCl3, 75.5 MHz): d =
164.1, 141.9, 140.5, 131.8, 128.9, 128.9, 128.7, 128.5,
128.4, 127.8, 127.4, 126.7, 125.8, 89.0, 78.0.
(14) (4R,5R)-2-(4¢-Methoxy-3¢-triisopropylsilyloxymethyl)-
phenyl-4,5-diphenyloxazoline (4h): 4-Methoxy-3-(triiso-
propylsilyloxymethyl)benzoic acid (0.45 g, 1.3 mmol) was
stirred in thionyl chloride–CH2Cl2 (1:1 mL) until IR
indicated complete conversion into the acyl chloride. The
solvent and thionyl chloride was removed under reduced
pressure. The crude benzoyl chloride (1.3 mmol) in CH2Cl2
(2 mL) was then added dropwise to a stirred solution of the
(1R,2S)-2-amino-1,2-diphenylethanol (0.277 g, 1.3 mmol)
in CH2Cl2 (15 mL) and Et3N (0.725 mL, 5.2 mmol) at 0 °C
under nitrogen. The reaction mixture was warmed to r.t. and
stirred until TLC indicated the reaction was complete.
Methane sulfonyl chloride (0.151 mL, 1.95 mmol) was
added and the solution was stirred until no amide remained
by TLC. Saturated NH4Cl (5 mL) was added and the layers
were separated. The aqueous layer was extracted with
CH2Cl2 (3 × 5 mL), the combined organic extracts were
dried (NaSO4) and the solvent was removed under reduced
pressure to give the crude oxazoline. Purification by flash
column chromatography (Petrol–EtOAc, 8:2) gave
Tetrahedron 2003, 59, 619. (m) Wang, Z.-Y.; Du, D.-M.;
Xu, J.-X. Synth. Commun. 2005, 35, 299. (n) Lu, S.-F.; Du,
D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron: Asymmetry 2005,
15, 3433. (o) Du, D.-M.; Wang, Z.-Y.; Xu, D.-C.; Hua,
W.-T. Synthesis 2002, 2347.
(9) Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett.
2004, 45, 9611.
(10) Liu, H.; Xu, J. X.; Du, D. M. Org. Lett. 2007, 9, 4725.
(11) For related one-pot methods for the synthesis of BOX and
PyBOX-type ligands, see: (a) Hui, X.-P.; Huang, J.-I.;
Chiou, S.-J.; Gau, H.-M. J. Chin. Chem. Soc. 2006, 53, 421.
(b) Bugarin, A.; Connell, B. T. Organometallics 2008, 27,
4357. (c) Kanazawa, Y.; Tsuchiya, Y.; Kobayashi, K.;
Shiomi, T.; Itoh, J.; Kikuchi, M.; Yamamoto, Y.;
oxazoline 4h (0.49 g, 67%) as a yellow gum. Rf = 0.73
(Petrol–EtOAc, 2:1); [a]D19.5 –48.2 (c 1.025, CDCl3); MS
(ES+): m/z (%) = 516.3 (100) [MH+]; HRMS: m/z [MH+]
calcd for C32H42O3NSi: 516.2928; found: 516.2931;
IR:(film): 2945, 2865, 1647, 1497, 1259 cm–1; 1H NMR
(CDCl3, 500 MHz): d = 8.25 (s, 1 H, C-2), 7.96 (dd, J = 2, 9
Hz, 1 H, C-5), 6.79 (d, J = 9 Hz, 1 H, C-4), 7.31–7.17 (m,
10 H, ArH), 5.31 (d, J = 7 Hz, 1 H, CH-5¢), 5.1 (d, J = 7 Hz,
1 H, CH-4¢), 4.78 (s, 2 H, ArCH2), 3.76 (s, 3 H, OCH3), 1.07
[m, 21 H, Si(i-Pr)3]; 13C NMR (CDCl3, 75 MHz): d = 163.3,
157.8, 141.5, 139.9, 129.2, 127.8, 127.1, 126.6, 126.6,
125.8, 124.4, 118.8, 108.4, 87.5, 77.9, 59.2, 54.4, 17.0, 16.7,
13.0, 11.5, 11.3, 11.1, 10.7.
Nishiyama, H. Chem. Eur. J. 2006, 12, 63. (d) Ito, J.; Ujiie,
S.; Nishiyama, H. Chem. Commun. 2008, 16, 1923.
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Org. Chem. 2006, 24, 5594. (f) Zhang, Y. J.; Wang, F.;
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4179. (h) Uchida, K.; Fukuda, T.; Iwao, M. Tetrahedron
2007, 63, 7178.
(12) The syn- and anti-diphenyloxazolines display characteristic
differences in the chemical shifts of the benzylic protons a
to N and O, see: Parris, S. PhD Thesis; University of
Manchester: 2008. No syn-diphenyloxazoline was identified
in the 1H NMR spectra of the crude products.
(15) Groundwater, P. W.; Garnett, I.; Morton, A. J.; Sharif, T.;
Coles, S. J.; Hursthouse, M. B.; Nyerges, M.; Anderson,
R. J.; Bendell, D.; McKillop, A.; Zhang, W. J. Chem. Soc.,
Perkin Trans. 1 2001, 2781.
(13) (4R,5R)-2,4,5-Triphenyloxazoline (4a): Benzoyl chloride
(0.59 mL, 1.1 equiv) was added dropwise over a period of 5
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