Practical reduction of oxazolines to alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.09.061

A two-step, one-pot procedure using methyl chloroformate and lithium borohydride was developed to transform 2-substituted-oxazolines into alcohols. This methodology is compatible with a wide range of substrates including heterocyclic, aromatic, and aliphatic functionalized 2-oxazolines. Best results are obtained with electron-rich and ortho substituted 2-aryl-oxazolines.

Full text of DOI:10.1016/j.tetlet.2008.09.061

Tetrahedron Letters 49 (2008) 6707–6708
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Tetrahedron Letters
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Practical reduction of oxazolines to alcohols
*
Anna Bernardi, Stéphane G. Ouellet , Remy Angelaud, Paul D. O’Shea
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Hwy., Kirkland, Québec, Canada, H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step, one-pot procedure using methyl chloroformate and lithium borohydride was developed to
transform 2-substituted-oxazolines into alcohols. This methodology is compatible with a wide range of
substrates including heterocyclic, aromatic, and aliphatic functionalized 2-oxazolines. Best results are
obtained with electron-rich and ortho substituted 2-aryl-oxazolines.
Received 13 November 2007
Revised 9 September 2008
Accepted 10 September 2008
Available online 15 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The first synthesis of an oxazoline was reported in 1884, but it
was not until 1970s that its synthetic utility was developed.1 Since
then oxazolines have been used in many synthetic applications
including heteroatom-facilitated lithiation,2 transition-metal cata-
lyzed C–H activation,3 and aza-enolate carbanion chemistry.4
Oxazolines can also serve as precursors to various functional
groups including ketones, aldehydes, carboxylic acids, and alco-
hols.5 Unfortunately, known methods to access alcohols are not
readily transferable to large-scale synthesis. In light of this, a prac-
tical and scalable method was developed for the direct reduction of
oxazolines to alcohols.
to circumvent the need for highly reactive reductants, we decided
to investigate the possibility of generating a more reactive tertiary
amide intermediate. It is known that N-acylcarbamates possess an
enhanced susceptibility toward reduction.7 To this end, we have
demonstrated that 2-phenyl-oxazoline is efficiently converted
in situ to the related N-acylcarbamate upon treatment with methyl
chloroformate.8 Treatment of the unisolated intermediates with
lithium borohydride afforded the desired alcohol in good yield
(Scheme 1). Thus, as the N-acylcarbamate was not isolated, this af-
fords a mild and efficient two-step, one-pot method to access alco-
hols from oxazolines.
Work by Meyers et al. has described the use of chloromethyl
methyl ether (MOMCl) or (trimethylsilyl) ethoxymethyl chloride
as electrophile, to access a putative tertiary amide intermediate,
which was then reduced to the corresponding alcohol using Di-
bal-H or lithium aluminum hydride.6 The reagents used in this pro-
tocol are not amenable to large-scale synthesis (carcinogenicity of
MOMCl and problematic work-ups associated with aluminum-
based hydride sources). Furthermore, the lack of chemoselectivity
of LiAlH4 limits the scope of this transformation.
We next investigated the scope of this reaction; our results are
summarized in Table 1.9 In all cases, 2-aryl-oxazolines were re-
duced efficiently using this method, irrespective of the presence
of electron-donating (entries 2, 3, and 5) or electron-withdrawing
groups (entries 4, 7, 8, and 11) on the aryl moiety. However, we
did note that certain substrates (entries 4, 6–8) were slow to
activate to the N-acylcarbamate. We postulated that the presence
of electron-withdrawing groups, such as CF3, resulted in a decrease
in the nucleophilicity of the oxazoline. In order to address the
lower reactivity, we increased both the reaction temperature and
number of equivalents of chloroformate which resulted in a
Herein, we report our efforts to develop a new methodology for
the selective conversion of oxazolines to primary alcohols. In order
Cl
O
O
O
N
Cl
OMe
R
N
LiBH4/MeOH
R
OH
R
0 oC - rt
THF or toluene
65 - 100 oC
THF or toluene
MeO
Intermediate
O
Isolable
Scheme 1. Reduction of oxazolines to alcohols.
* Corresponding author.
E-mail address: stephane_ouellet@merck.com (S. G. Ouellet).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.061

6708
A. Bernardi et al. / Tetrahedron Letters 49 (2008) 6707–6708
Table 1 (continued)
Table 1
Entry
Starting material
Product
Yielda (%)
63b,c
1. ClCO2Me
65 - 100 oC
THF or toluene
O
N
N
O
14
R
R
OH
OH
2. LiBH4 / MeOH
0 oC to rt
a
Typical conditions: MeOCOCl (2 equiv), (i-Pr)2NEt (0.2 equiv) in THF at 65 °C
then LiBH4 (3 equiv) and MeOH (3 equiv) at room temperature.
Yielda (%)
68b
b
Entry Starting material
Product
Assay yield determined by HPLC analysis.
Increased temperature (from 65 °C in THF to 100 °C in toluene) and amount of
c
N
MeOCOCl (4–5 equiv) required for activation.
1
OH
OH
O
N
O
complete activation. Interestingly, the presence of an ortho-substi-
tuent on the aryl ring increased the susceptibility of the substrate
toward activation. This can be seen by comparing entries 7 and 11,
where the addition of the phenyl at the ortho-position allowed for
the use of lower reaction temperatures (65 °C vs 100 °C) and fewer
equivalents of methyl chloroformate. This method is also applica-
ble to 2-heteroaryl-oxazolines (entry 13) to afford the related alco-
hol in 75% isolated yield. This method was also applied successfully
to a 2-alkyl-oxazoline (entry 14).
The use of the mild reductant (lithium borohydride) allows this
method to be used in cases where chemoselectivity is required. For
example, the oxazoline was converted to an alcohol in presence of
an N-acylaniline (entry 6) without any over-reduction observed.
However, we did note that this method is not effective for activa-
tion/reduction of oxazolines bearing substituents at carbon 4 of the
oxazoline (entries 9 and 10).
Me
2
74b
96b
Me
OH
N
3
O
Me
Me
N
Cl
4
54c
91
Cl
OH
O
N
O
MeO
5
MeO
OH
H
H
N
O
N
N
6
78c
In summary, we have developed a practical two-step one-pot
method for the conversion of oxazolines to alcohols. In comparison
with previous methods, this process required the use of a less-toxic
activating agent and milder reductant. Thus, this new protocol is
more operator friendly and has greater potential for use in chemo-
selective transformations.
OH
O
O
Me
Me
N
O
7
8
75c
80c
OH
OH
OH
F3C
F3C
F3C
F3C
F3C
N
O
Supplementary data
Me
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.061.
R
N
O
R'
References and notes
F3C
1. Wong, G. S. K.; Wu, W. In Oxazoles: Synthesis, Reactions, and Spectroscopy; Palmer,
D. C., Ed.; The Chemistry of Heterocyclic Compounds; John Wiley & Sons: New
Jersey, 2004; Vol. 60, pp 331–417.
2. For recent examples, see: Wanbin, Z.; Fang, X.; Shigeaki, M.; Yuji, I.; Toshiyuki,
K.; Yohji, N.; Isao, I. Tetrahedron: Asymmetry 2006, 17, 767–777.
3. For recent examples, see: (a) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem.
2005, 70, 3113–3119; (b) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem.,
Int. Ed. 2006, 45, 2619–2622.
9
10
R = H, R0 = Me
R = R0 = Me
NR
NR
4. Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. Engl. 1976, 15, 270–281.
5. Mayryanoff, B. E. In Oxazoles and Oxazolines in Organic Synthesis; Turchi, I. J., Ed.;
Chemistry of Heterocyclic Compounds: Oxazoles; John Wiley & Sons: New York,
1986; Vol. 45, pp 964–996.
6. Meyers, A. I.; Shimano, M. Tetrahedron Lett. 1993, 34, 4893–4896.
7. Ragnarsson, U.; Grehn, L.; Monteiro, L. S.; Maia, H. L. S. Synlett 2003, 15, 2386–
2388.
N
O
11
80
OH
F3C
F3C
N
8. Laaziri, A.; Uziel, J.; Jugé, S. Tetrahedron: Asymmetry 1998, 9, 437–447.
9. Typical procedure:
A 25 mL round-bottomed flask was charged with the
12
13
73
75
OH
oxazoline (2.5 mmol), THF (2.5 mL), Hünig’s base (0.087 mL, 0.5 mmol), and
methyl chloroformate (0.39 mL, 5.0 mmol). The reaction mixture was then
heated to 65 °C and stirred at this temperature for 30 min (found to be complete
by HPLC) before being cooled to 0 °C. Then, LiBH4 (3.75 mL, 2 M in THF,
7.5 mmol) was added slowly followed by methanol (0.3 mL, 7.5 mmol) and the
reaction was warmed to room temperature. After completion of the reaction, the
reaction mixture was cooled to 0 °C and carefully quenched with 1 N HCl
(2.5 mL) and then with water (2.5 mL). After 15 min of stirring, the reaction
mixture was diluted with MTBE and water before being transferred to an
extractor, whereupon the aqueous layer was removed. The aqueous layer was
back-extracted with MTBE and the combined organic layers were washed with
brine and dried over Na2SO4 prior to being concentrated under reduced
pressure. The product was purified by column chromatography.
O
Cl
Cl
Cl
Cl
O
N
O
O
OH