A simple large scale synthesis of 1,3-BIS-(4,4-dimethyl-2-oxazolinyl)benzene

Article abstract of DOI:10.1081/SCC-120002119

A simple one-pot procedure for the large scale and high yield synthesis of the title ligand (1) is presented which involves Lewis acid catalysed formation of 1 from 1,3-dicyanobenzene followed by a simple recrystallisation step.

Full text of DOI:10.1081/SCC-120002119

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A SIMPLE LARGE SCALE SYNTHESIS OF 1,3-BIS-(4,4-
DIMETHYL-2-OXAZOLINYL)BENZENE*
a
a
a
Karen M. Button , Robert A. Gossage & Ralph K. R. Phillips
a
The David Upton Hill Laboratories of Inorganic Chemistry, Department of Chemistry,
Acadia University, Elliott Hall, Wolfville, Nova Scotia, B0P 1X0, Canada
Published online: 16 Aug 2006.
To cite this article: Karen M. Button , Robert A. Gossage & Ralph K. R. Phillips (2002) A SIMPLE LARGE SCALE SYNTHESIS
OF 1,3-BIS-(4,4-DIMETHYL-2-OXAZOLINYL)BENZENE*, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:3, 363-368
To link to this article: http://dx.doi.org/10.1081/SCC-120002119
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SYNTHETIC COMMUNICATIONS, 32(3), 363–368 (2002)
A SIMPLE LARGE SCALE SYNTHESIS
OF 1,3-BIS-(4,4-DIMETHYL-2-
OXAZOLINYL)BENZENE*
y
Karen M. Button, Robert A. Gossage, and
z
Ralph K. R. Phillips
The David Upton Hill Laboratories of
Inorganic Chemistry, Elliott Hall, Department
of Chemistry, Acadia University, Wolfville,
Nova Scotia, Canada B0P 1X0
ABSTRACT
A simple ‘‘one-pot’’ procedure for the large scale and high
yield synthesis of the title ligand (1) is presented which
involves Lewis acid catalysed formation of 1 from 1,3-dicya-
nobenzene followed by a simple recrystallisation step.
INTRODUCTION
Ligands of the so-called ‘‘pincer’’ class (A: figure) have been receiving
considerable attention in recent years due to their ability to stabilise unusual
*
Oxazoline Chemistry: Part I.
y
Corresponding author. Fax: þ1 (902) 585-1114; E-mail: rgossage@acadiau.ca
z
Current address: Lash Miller Chemical Laboratories, Department of Chemistry,
University of Toronto, 80 St. George St., Toronto, Ontario, Canada, M5S 3H6.
3
63
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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3
64
BUTTON, GOSSAGE, AND PHILLIPS
Figure.
1
,2
metal oxidation states and/or novel ligand bonding motifs. In addition, a
variety of organometallic pincer complexes have demonstrated potent reac-
3
,4
5
tivity in both regio- and enantio-selective organic transformations (i.e.,
6
catalysis), in addition to applications in materials science. Oxazoline com-
7
pounds constitute an important area of natural products chemistry and in
8
the development of synthetic methodologies, in addition to their recent
9
a
9b
applications in crystal engineering and functionalised polymers. We
have been interested in the study of the achiral ligand 1,3-bis-(4,4-dimethyl-
2
-oxazolinyl)benzene (1) as a model for more complex chiral pincer systems
i
i
containing fragments derived from, for example, Phenbox ( Pr) (B: R¼ Pr,
0
10,11
R ¼H; figure). Specifically, we are investigating the direct metallation
and the (organometallic) coordination chemistry of 1. Complexes incorpor-
ating the Phenbox class of ligands, including 1, have recently found applica-
1
2
13
tion in coordination chemistry and metal-mediated catalysis.
The original synthesis of 1 involves a four-step procedure and the use of
1
0
large quantities of thionyl chloride. For environmental, financial and safety
reasons, we have designed a ‘‘one-pot’’ procedure that avoids the use of this
toxic reagent and can produce large quantities of the desired product (>50 g)
in a single-step procedure from cheap commercially available materials.
RESULTS AND DISCUSSION
The earlier synthetic protocol for the synthesis of 1 is detailed in
Scheme 1. Although this is an effective synthetic method to produce this
bis(oxazoline), we desired an alternative method that avoids the use of large
quantities of thionyl chloride but at the same time gives high yields of 1
without the need for chromatographic purification nor complicated work-
up procedures. In addition, we have found that the method outlined

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SIMPLE LARGE SCALE SYNTHESIS OF BIS-OXAZOLINE
365
Scheme 1.
in Scheme 1 makes for a difficult and tedious isolation of the final solid
product, probably due to the resulting oil retaining some SOCl following
the cyclisation step.
2
1
Using the methodology described by Peer et al., we have found that
4
1
4,15
anhydrous zinc dichloride
is an effective Lewis acid catalyst for the
large-scale production of 1 starting from commercially available 1,3-dicya-
nobenzene and 2-methyl-2-amino-1-propanol (Scheme 2). In a typical pro-
cedure, 38.5 g of 1,3-dicyanobenzene (0.30 mol: Sigma-Aldrich, 97%) and
2-methyl-2-amino-1-propanol (59.0 g: 0.63 mol; 2.1 equiv., Sigma-Aldrich)
was placed in a round-bottomed flask and dissolved in chlorobenzene
˚
350 mL: pre-dried by storage over 4 A molecular sieves). To this mixture
was added anhydrous ZnCl (5.0 g, 10 mol%: Fisher, melted thrice under
(
2
vacuum [15 mmHg] and cooled under Ar). The resulting suspension was
heated at reflux for a period of 48 h under an atmosphere of dry Ar,
during which time a pink colouration was noted in the reaction vessel.
The flask was cooled to room temperature and all volatile components
Scheme 2.

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BUTTON, GOSSAGE, AND PHILLIPS
ꢁ
were removed in vacuo (25 mmHg; ꢀ75 C). The residue was extracted with
150 mL of dichloromethane and 150 mL of distilled water. The two layers
were then separated and the inorganic portion was then extracted with
further dichloromethane (2 ꢂ 100 mL). The organic fractions were then
combined, dried with excess anhydrous Na SO , filtered and the solvent
2
4
removed by rotary evaporation. The resulting viscous oil was dissolved in
ꢁ
approximately 100 mL of hot petroleum ether (bp 65–70 C) and the mixture
ꢁ
cooled to ꢃ30 C for 14 h. A copious quantity of an off-white solid precipi-
tated from the solution. This material was removed by filtration, washed
with cold petroleum ether (ꢀ20 mL) and the product was then dried in vacuo
(yield: 65.4 g, 81%). The compound isolated in this way is suitable for
further synthetic use (purity > 97%: NMR) and has virtually identical prop-
1
0,16
erties to a sample obtained by the previously reported method.
In
conclusion, we have presented an effective synthesis of 1,3-bis-(4,4-
dimethyl-2-oxazolinyl)benzene that can be performed easily and on a large
scale without the use of hazardous thionyl chloride nor chromatographic
separation.
ACKNOWLEDGMENTS
This work was made possible by the support of Acadia University and
the Nova Scotia Human Resources Student Summer Placement Program.
The authors are indebted to the Atlantic Regional Nuclear Magnetic
Resonance Centre for NMR spectra.
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4
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1
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1
4. Peer, M.; de Long, J.C.; Kiefer, M.; Langer, T.; Rieck, H.; Schell, H.;
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Tetrahedron 1996, 52, 7547–7583 and references therein.

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BUTTON, GOSSAGE, AND PHILLIPS
15. This synthetic protocol has been employed for other oxazoline systems,
see for example: a) Witte, H.; Seeliger, W. Liebigs Ann. Chem. 1974,
9
96–1009; b) Ghosh, A.K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
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Ed. Engl. 1991, 30, 542–543 and references therein.
6. Analytical and spectroscopic data for 1: mp (uncorrected): 75–78 C;
1
ꢁ
1
ꢃ1
1
IR (NaCl): 1650 cm [ꢀ(C¼N)]; H NMR (300 MHz, CDCl /TMS,
3
ppm): d ¼ 8.45 (s, 1H, ArH), 8.02 (d, J ¼ 9.5 Hz, 2H, ArH), 7.40
1
t, 1H, ArH), 4.07 (s, 4H), 1.34 (s, 12H) [lit. mp 78–80 C;
0
ꢁ
(
IR (CHCl ): 1650 cm
ꢃ1
1
;
H NMR (100 MHz, CDCl ) d ¼ 8.47 (s),
3
3
8.02 (d, J ¼ 7 Hz), 7.40 (t), 4.07 (s), 1.33 (s)].
Received in the USA March 19, 2001

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