The synthesis of oxazolines using the Vilsmeier reagent

Full text of DOI:10.1021/jo000664r

J . Org. Chem. 2000, 65, 9223-9225
9223
Sch em e 1
Th e Syn th esis of Oxa zolin es Usin g th e
Vilsm eier Rea gen t
Peter G. M. Wuts,* J ill M. Northuis, and
Tricia A. Kwan
Chemical Process Research and Development, 1500-91-201,
Pharmacia and Upjohn, Kalamazoo, Michigan 49001
Sch em e 2
Peter.G.Wuts@am.pnu.com
Received J uly 3, 2000
The place of oxazolines in modern day chemistry is
certainly self-evident. For example, they are used in the
development of chiral ligands used for asymmetric ca-
talysis,1 are found in natural products, are used in
synthesis,2 and provide a useful means for the protection
of amino alcohols or carboxylic acids.3
Numerous methods for the synthesis of oxazolines have
been reported. Among these are the use of thionyl chlo-
ride,4 SOCl2-AgOTf,5 PPh3/DEAD,6 sulfonyl chlorides,7-9
BF3‚Et2O,10 Tf2O,11 Tf2O/Ph2SO,12 P2O5,13 Et2N-SF3,14
Burgess reagent,15 Ph3P/TEA/CCl4,16 Bu2SnCl2,9 POCl3,17
TMSF,18 30% HBr, AcOH,19 o-chlorophenylphosphoro-bis-
(1,2,4)-triazolide,20 and RN3/(PhO)3P.21 Each method has
its advantages and disadvantages in any given situation;
therefore, no one reagent has proven totally general.
Thus, the development of other methods is warranted.
Resu lts a n d Discu ssion
During the course of our development of a synthesis
of the paclitaxel side chain we discovered that the
Vilsmeier reagent very efficiently converts the anti amido
alcohol 1 to the oxazoline with inversion of configuration
at the alcohol to give the oxazoline 2 in nearly quantita-
tive yield (Scheme 1). In contrast, the use of thionyl
chloride only gives a 70% yield.22
The facility and mildness of this transformation com-
pared to the use of SOCl2 led us to examine the generality
of the process in a number of other cases. Typically, the
reaction is run by slurring the Vilsmeier reagent in
pyridine at room temperature and then adding the amido
alcohol substrate. When other substrates were explored,
we found that in most cases we obtained both the desired
oxazoline 4 as well as the chloride 5 (Scheme 2). Although
an inconvenience, the chloride is readily converted to the
oxazoline upon treatment with DBU. Generally, it is
better to isolate the mixture and then subject it to base
treatment to complete oxazoline formation because this
prevents the formation of very dark reaction mixtures.
The dark color may be the result of excess Vilsmeier
reagent reacting with the base. Little optimization work
was done to define the best possible conditions for each
substrate because our interest was in obtaining the
oxazolines as ligands for the development of transition
metal catalyzed reactions.
Table 1 gives the results we have obtained for the
conversion of a series of amido alcohols to oxazolines.
Generally, the yields are quite good, the exception being
serine, which did not perform well in the reaction. The
low yield observed was due to the formation of dehy-
droalanine.
During the course of this work, we have discovered that
these oxazolines can be opened back to the chloride upon
treatment with Pyr‚HCl in pyridine (Scheme 3).23 For
example, stirring the oxazoline 4e in pyridine with Pyr‚
HCl resulted in nearly complete conversion to the chlo-
ride 5e over a 24 h period. A similar phenomenon was
also observed with the ferrocenyl derivative 4a . The
relative ease with which this occurs appears substrate
dependent because the phenylthio derivative 4d required
heating to 60 °C to achieve ring opening.
(1) Brunner, H.; Zettlmeier, W. Handbook of Enantioselective Ca-
talysis; CHC: Basel, 1993; Vol. 2. Allen, J . V.; Williams, J . M. J .
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acyl chlorides or TMSX (X ) Cl, Br). Laaziri, A.; Uziel, J .; J uge, S.
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10.1021/jo000664r CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

9224 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
Ta ble 1. Con ver sion of Am id o Alcoh ols to Oxa zolin es
Sch em e 4
lines from amido alcohols. The low cost of the Vilsmeier
reagent and the ease with which the reaction byproducts
are removed by extraction makes this a very attractive
method for oxazoline formation. The observation that
oxazolines upon treatment with pyridine hydrochloride
open the ring to give amido chlorides is new. Additionally,
we found that Lawesson’s reagent may be used for the
direct conversion of amido alcohols to thiazolines, but the
generality of this transformation has not been estab-
lished.
Exp er im en ta l Section
Meth yl (4R,5S)-2,4-Dip h en yl-4,5-d ih yd r o-1,3-oxa zole-5-
ca r boxyla te (4l). To a flask containing 410 mg (3.20 mmol) of
Vilsmeier reagent was added 4 mL of pyridine. The slurry was
stirred for 5 min and the amide (488 mg, 3.2 mmol) added. After
1.5 h, TLC showed the reaction to be complete. The product was
isolated with EtOAc from water to give 457 mg (99%) of the
oxazoline, whose NMR was perfect: 1H NMR (300 MHz, CDCl3)
δ 8.03 (d, J ) 7.2 Hz, 2 H), 7.70 (m, 8 H), 5.38 (d, J ) 6.6 Hz, 1
H), 4.85 (d, J ) 6.6 Hz, 1 H), 3.80 (s, 3 H).
(4S)-4-Ben zyl-2-fer r ocen yl-4,5-d ih yd r o-1,3-oxa zole (4a ).
A solution of 345 mg (0.475 mmol) of the alcohol was dissolved
in 7 mL of pyridine and treated at room temperature with 100
mg (1.6 equiv) of Vilsmeier reagent. The mixture was stirred at
room temperature overnight, treated with 360 µL of DBU, and
heated to 50 °C. After 1.5 h, TLC showed the disappearance of
the chloride, and the product was isolated with toluene from
water. Chromatography with 50% EtOAc/Hex gave an 82% yield
of the oxazoline: 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5 H),
4.85 (s, 2 H), 4.53 (m, 1 H), 4.44 (m, H), 4.32 (t, J ) 8.88 Hz, 1
H), 4.26 (s, 9 H), 4.16 (t, J ) 7.76 Hz, 1 H), 3.31 (dd, J ) 4.12,
13.6 Hz, H), 2.79 (dd, J ) 9.2, 13.4 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 165.7, 137.0, 128.3, 127.6, 125.5, 70.4, 69.3, 69.0, 68.7,
68.0, 66.7, 40.8.
(4S)-2-[2-(Isop r op ylsu lfa n yl)p h en yl]-4-p h en yl-4,5-d ih y-
d r o-1,3-oxa zole or Isop r op yl 2-[(4S)-4-p h en yl-4,5-d ih yd r o-
1,3-oxa zol-2-yl]p h en yl Su lfid e (4b). The amide (1.8 g, 5.71
mmol) in 36 mL of pyridine at room temperature was treated
with 1.15 g (8.99 mmol) of Vilsmeier reagent. The solution was
stirred at room temperature overnight, and the product was
isolated with toluene from water to give an 85:15 mixture of the
oxazoline to the chloride. The crude mixture was treated with
DBU (3.8 mL) in 35 mL of THF and heated to 50 °C for 4 h.
Isolation with EtOAc from water gave the crude product, which
was purified by chromatography (35-50% EtOAc/Hex) to give
1.27 g (80%) of the oxazoline: 1H NMR (400 MHz, CDCl3) δ 7.75
(d, J ) 7.84 Hz, 1 H), 7.33 (m, 8 H), 5.44 (dd, J ) 8.32, 9.96 Hz,
1 H), 4.73 (dd, J ) 8.36, 10.08 Hz, 1 H), 4.19 (t, J ) 8.2 Hz, 1
Sch em e 3
We were also interested to see if the related transfor-
mation could be effected on the thioamide. Thus, treat-
ment of the serine amide 4j with Lawesson’s reagent to
convert the amide into the thioamide resulted in cycliza-
tion to give the thiazoline 6 directly (Scheme 4),24 and
thus, we abandoned any further efforts related to this
transformation.
(27) Ikehira, H. Preparation of oxazolines and their use as asym-
metric ligands for preparation of cyclopropanecarboxylic acids. J pn.
Kokai Tokkyo Koho 1997, 7 pp. J P 09151178 A2 19970610 Heisei. CAN
127,95275. Suzuki, J .; Kikuchi, Y.; Ishida, T.; Ikeda, T., Domestic
acaricides containing oxa- or thiazoline derivatives. PCT Int. Appl.
1993, 27 pp. WO 9325079 CAN 120,127813.
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H.; Sennhenn, P.; Sprinz, J .; Steinhagen, H.; Wiese, B.; Helmehen, G.
Tetrahedron 1996, 52, 7547-7583. Zhou, Q.-L.; Pfaltz, A. Tetrahedron
1994, 50, 4467-4478. Allen, J . V.; Dawson, G. J .; Frost, C. G.; Williams,
J . M. J .; Coote, S. J . Tetrahedron 1994, 50, 799-808. Sprinz, J .;
Helmchen, G. Tetrahedron Lett. 1993, 34, 1769-1772.
(29) Kopczynski, T.; Krzyzanowska, E. Pol. J . Chem. 1989, 63, 471-
482.
In conclusion, we have shown that the Vilsmeier
reagent is effective at promoting the formation of oxazo-
(24) This transformation has previously been observed to proceed
in low yield. Nishio, T. J . Org. Chem. 1997, 62, 1106.
(25) Sammakia, T.; Stangeland, E. L. J . Org. Chem. 1997, 62, 6104.
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Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9225
H), 3.47 (sep, J ) 6.68 Hz, 1 H), 1.31 (d, J ) 6.6 Hz, 6 H); 13C
NMR (100 MHz, CDCl3) δ 164.4, 142.5, 138.2, 130.7, 130.5, 128.9,
128.6, 128.2, 127.4, 126.8, 124.9, 74.5, 60.3, 36.7, 22.8, 22.8, 21.0,
14.1; HRMS (FAB) calcd for C18H19NOS + H1 198.1265, found
298.1272.
Su p p or t in g In for m a t ion Ava ila b le: Copies of 1H and
13C NMR spectra for the new oxazolines 4b, 4d , 4h , and 4k
are provided and experimentals are provided for oxazolines
4k , 4h , 4g, 4f, 4e, and 4c. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We wish to thank Steven Grode,
Mark Mowery and Diane Strother for their continued
support of our NMR and MS needs.
J O000664R