Oxidation of oxazolines and thiazolines to oxazoles and thiazoles. Application of the Kharasch-Sosnovsky reaction

Article abstract of DOI:10.1021/jo9613491

Using a modification of the Kharasch-Sosnovsky reaction, the oxidation of oxazolines and thiazolines bearing a variety of 2-alkyl substituents (chiral and achiral) were smoothly oxidized to their corresponding oxazoles and thiazoles, respectively. The key feature involved in the successful implementation of this important oxidation was the use of a mixture of Cu(I) and Cu(II) salts to enhance the oxidation of the intermediate captodative radical, 24. The main limitation of this method was shown when the oxidation failed with oxazolines/thiazolines lacking the carboalkoxy group at C-4.

Full text of DOI:10.1021/jo9613491

J . Org. Chem. 1996, 61, 8207-8215
8207
Oxid a tion of Oxa zolin es a n d Th ia zolin es to Oxa zoles a n d
Th ia zoles. Ap p lica tion of th e Kh a r a sch -Sosn ovsk y Rea ction
A. I. Meyers* and Francis X. Tavares
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received J uly 16, 1996X
Using a modification of the Kharasch-Sosnovsky reaction, the oxidation of oxazolines and
thiazolines bearing a variety of 2-alkyl substituents (chiral and achiral) were smoothly oxidized to
their corresponding oxazoles and thiazoles, respectively. The key feature involved in the successful
implementation of this important oxidation was the use of a mixture of Cu(I) and Cu(II) salts to
enhance the oxidation of the intermediate captodative radical, 24. The main limitation of this
method was shown when the oxidation failed with oxazolines/thiazolines lacking the carboalkoxy
group at C-4.
The isolation of a wide range of compounds containing
the oxazole and/or thiazole moiety from secondary me-
tabolites have spurred considerable interest in synthetic
efforts to reach them.1 This interest arises from the fact
that these compounds, for example, Ulapualide A and
Diazonamides A and B (Figure 1), have been found to
possess significant biological activity as cytotoxic, anti-
fungal, antibacterial, antitumor, and antiviral agents.2
Most of the above methods however, have one or more
drawbacks such as low yields, limited stability to reaction
conditions, loss of optical purity, and hazardous reaction
conditions.5
During the course of a synthetic program to reach
oxazole- and thiazole-containing natural products,6 an
effort was initiated to search for alternative and efficient
methods to oxidize 2-oxazolines and/or thiazolines con-
taining a variety of substituents. Perhaps the most
general method to date was the oxidations of oxazoles
and thiazoles using nickel peroxide.4a However, the
yields of oxidized products were oftentimes erratic and
rarely exceeded 40-50%.
Two additional oxidation methods have been recently
reported. The first involves a variation of a previously
described route to 1,3-oxazoles wherein treating 2-aryl-
2-oxazoline 3 with N-bromosuccinimide/azobis(isobuty-
ronitrile) gave the 5-bromo-1,3-oxazole 4 in ca 50%
The efforts to reach the oxazole and/or thiazole units
have centered mainly on ring synthesis from acyclic
precursors;3 however, several methods have been re-
ported4 wherein direct oxidation of oxazolines 1 have led
to oxazoles 2. The latter approach to 1,3-oxazoles is
particularly attractive since both functionalized and
chiral oxazolines are readily prepared from the appropri-
ate nitriles or carboxylic acids and amino alcohols.5
yield.4b Halogen-metal exchange and electrophilic quench
of the latter provided the oxazoles 5 in 70-80% yield.
The additional step required to remove the bromo sub-
stituent detracts from the efficiency of the method;
therefore, another method was sought to completely avoid
the bromo intermediate 4. Furthermore, this study
narrowly dealt only with a single ring derivative (5),
whereas oxazoles containing a 4-carboxy substituent (14)
derived from serine were the main focus of the present
study.
The desired oxazolines (Table 1, entries a-e) were
made by condensing the imidate hydrochlorides 6 (pre-
pared in quantitative yield from the nitriles and alcohol
in presence of anhydrous hydrogen chloride) with DL-
serine methyl ester.7 The reactions proceeded smoothly
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) (a) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc.
1992, 114, 9434. (b) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33,
907. (c) Gangloff, A. R.; Akermark, B.; Helquist, P. J . Org. Chem. 1992,
57, 4797. (d) Doyle, K. J .; Moody, C. J . Tetrahedron Lett. 1992, 33,
7769. (e) Vaccaro, H. A.; Levy, D. E.; Sowabe, A.; J aetsch, T.;
Masamune, S. Tetrahedron Lett. 1992, 33, 1937. (f) Short, K. M.;
Ziegler, C. B., J r. Tetrahedron Lett. 1993, 34, 71.
(2) (a) Michael, J . P.; Pattenden, G. Angew. Chem., Int. Ed. Engl.
1993, 32, 1. (b) Fusetani, N.; Matsunaga, S. Chem. Rev. 1993, 93, 1793.
(c) Davidson, B. S. Chem. Rev. 1993, 93, 1771. (d) Kobayashi, J .;
Ishibashi, M. Chem. Rev. 1993, 93, 1753. (e) Lewis, J . R. Nat. Prod.
Rep., 1993, 10, 29. (f) Lewis, J . R. Nat. Prod. Rep. 1992, 9, 81. (g) Evans,
D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc. 1992, 114, 9434.
(h) Salvatore, B. A.; Smith A. B. Tetrahedron Lett. 1994, 35, 1329. (i)
Wipf, P. Chem. Rev. 1995, 95, 2115 and references cited therein.
(3) (a) Turchi, I. J . Oxazoles; Weissberger, A., Taylor, E. C., Eds.; J .
Wiley: New York, 1986. (b) Shapiro, R. J . Org. Chem. 1993, 58, 5759.
(c) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604. (d) Meyers, A.
I.; Lawson, J . P.; Walker, D. G.; Linderman, R. J . J . Org. Chem. 1986,
51, 5111. (e) Das, J .; Reid, J . A.; Kronenthal, D. R.; Singh, J . P.;
Pansegrau, P. D.; Mueller, R. H. Tetrahedron Lett. 1992, 33, 7835.
(4) (a) Evans, D. L.; Minster, D. K.; J ordis, U.; Hecht, S. M.; Mazzu,
A. L., J r.; Meyers, A. I. J . Org. Chem. 1979, 44, 497. (b) Kashima, C.;
Arao, H. Synthesis 1989, 873. (c) Barrish, J . C.; Singh, J .; Spergel, S.
H.; Han, W-C.; Kissick, T. P.; Kronenthal, D. R.; Mueller, R. H. J . Org.
Chem. 1993, 58, 4494.
S0022-3263(96)01349-7 CCC: $12.00 © 1996 American Chemical Society

8208 J . Org. Chem., Vol. 61, No. 23, 1996
Ta ble 1. Oxa zolin e-Oxa zole Tr a n sfor m a tion
Meyers and Tavares
F igu r e 1.
Sch em e 1
with the precipitation of ammonium chloride as a byprod-
uct to give the oxazolines 13 in very good yield. The
oxazolines8 8 containing a stereocenter at the 2R position
were prepared by treating the dipeptides 7, obtained from
the requisite amino acid (serine or threonine) with
Burgess reagent9 as shown in Scheme 1. A small amount
(6-8%) of the opened chain dehydration product 9 was
also obtained. The enantiomerically pure thiazolines 12
were prepared10 by formation of the carboxamides 10 of
the N-protected amino acids followed by the direct
alkylation of the carboxamides using triethyloxonium
hexafluorophosphate to obtain the corresponding imino
ethers 11. The crude, moisture-sensitive, imino ethers
were directly condensed with the ethyl cysteinate to give
the desired thiazolines 12 (Scheme 2).
varying temperatures and stoichiometry. The results are
presented in Table 1. Thermal conditions were well
suited for the oxidation of 2-aryl-substituted oxazolines
with NBS/benzoyl peroxide in refluxing benzene. Fur-
thermore, the nature of the substituent on the 4-position
of the oxazoline was found to be important. For example,
the presence of a carbomethoxy group completely elimi-
nated the formation of the 5-bromo product. On the other
hand, the presence of an alkyl or aryl group at the
4-position of the oxazoline seemed to favor the formation
of the 5-bromo product as reported earlier.4b In order to
render the oxidation more general in nature, we focused
on the oxidation of 2-alkyl-4-carbomethoxy oxazolines
and/or thiazolines, since these systems would serve as
important precursors to a large number of oxazole- and/
or thiazole-containing natural products. When conditions
Oxidations were conducted using NBS with either
benzoyl peroxide or light as the radical initiator and
(5) For a recent review on oxazolines, see: Gant, T.; Meyers, A. I.
Tetrahedron 1994, 8, 2297.
(6) (a) Meyers, A. I.; Tavares, F. Tetrahedron Lett. 1994, 35, 2481.
(b) Tavares, F.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 6803. (c)
Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473. (d) Aguilar,
E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2477.
(7) Cornforth, J . W.; Cornforth, R. H. J . Chem. Soc. 1947, 96.
(8) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907.
(9) (a) Burgess,E. M.; Penton, J r., H. R.; Taylor, E. A. J . Org. Chem.
1973, 38, 26. (b) Burgess, E. M.; Penton, H. R., J r.; Taylor, E. A.;
Williams W. M. Organic Syntheses; Wiley: New York, 1988; Coll. Vol.
VI, 1988; p 788.
(10) North, M.; Pattenden, G. Tetrahedron 1990, 24, 8267.

Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles
J . Org. Chem., Vol. 61, No. 23, 1996 8209
Ta ble 2. Ra d ica l Oxid a tion of Oxa zolin es/Th ia zolin e
Sch em e 2
similar to the oxidation of 2-aryl-substituted oxazolines
were employed for the 2-alkyl-4-carbomethoxy deriva-
tives, a mixture of brominated products were obtained.
This necessitated the use of lower temperatures and
photolytic conditions. As seen from Table 1, oxidation
of the methyl-substituted oxazoline gave the desired
oxazole in >60% yield (Table 1, entry b). Reaction of 2-(n-
pentyl)-4-carbomethoxyoxazoline with NBS at -15 °C
gave the desired oxazole along with some starting mate-
rial and side chain-brominated product. Lowering the
temperature and using excess NBS (5 equiv) ultimately
resulted in a satisfactory yield of the desired oxazole
(Table 1, entry c).
radical.13 Trapping of the bromine atom followed by
elimination of hydrogen bromide would afford the desired
oxazole 19.
However, application of these oxidation conditions to
isopropyl and cyclohexyl substituted oxazolines, wherein
both contained a tertiary hydrogen atom, were not met
with success. In both cases considerable bromination
products were formed. In order to increase the selectivity
of the reaction, dichloromethane was replaced by aro-
matic solvents. The latter are well known to form an
intermediate π complex with halogen atoms.11 This, too,
failed to avoid the bromination products, 15 (Table 1,
entries d, e). The extension of the NBS method to the
oxidation of thiazolines, however, failed to give the
desired thiazoles under various conditions (hν, peroxide).
In the interest of determining the site of radical
formation, 4,4-dimethyl-2-phenyloxazoline was treated
with 2.2 equiv of NBS in the presence of benzoyl peroxide.
Proposed formation of the radical intermediate 16 at the
5-position would be followed by trapping of the bromine
atom, and the resulting product could then lead to the
open chained aldehyde 17 on aqueous workup. However,
In view of the limited applicability of the reaction
wherein side chain radical bromination in the tertiary
alkyl groups was unavoidable, an effort was made to
search for alternative methods. With the knowledge that
radical formation most likely occurs at the 4-position of
the oxazoline, methods were evaluated that could selec-
tively generate the appropriate radical species. One such
method was the so-called Kharasch-Sosnovsky12 reac-
tion, which involves a copper ion-catalyzed decomposition
of a peroxyester resulting in the formation of an alkoxy
radical. Subsequent reaction with a C-H substrate then
generates an alkyl radical which is oxidized to a cation
and captured by the carboxylate anion (eq 1).
(1)
This process was initially found to be moderately
successful when applied to the oxidation of oxazolines and
thiazolines.6a The early experimental conditions required
that we utilize 1.1 equiv of Cu(I)Br and 1.5 equiv of tert-
butyl perbenzoate in benzene at reflux. The yields of the
oxidation are given in Table 2. Oxazolines containing
either the isopropyl or cyclohexyl substituents (Table 2,
entries a, d) gave only the oxazole 21 devoid of any side
chain substitution as previously observed with NBS
(Table 1, entries d, e). Additionally, thiazoline ester 20c
the absence of any of the above intermediates or aldehyde
17 precluded this reaction pathway. An alternative
mechanism for the oxidation of 2-substituted-4-car-
bomethoxy oxazolines might be expected to involve the
initially formed radical 18, a relatively stable captodative
(11) Russell, G. A. J . Am. Chem. Soc. 1958, 80, 4987.
(12) Rawlinson, D. J .; Sosnovsky, G. Synthesis 1972, 1. Ibid 1973,
567.
(13) Viehe, H. G.; J anousek, Z.; Merenyi, R.; Stella, L. Acc. Chem.
Res. 1985, 18, 148.

8210 J . Org. Chem., Vol. 61, No. 23, 1996
Meyers and Tavares
Sch em e 3
Sch em e 4
concentration which could enhance the rate of oxidation
and/or ligand transfer between the presumed radical 24
(X ) O) and the Cu(II) salts. It was assumed that this
would lead to the Cu(III) species14 26 via oxidative
addition which subsequently reductively eliminates to the
acyloxy oxazoline 25. Syn elimination, on heating, would
then provide the oxazole 21 (or thiazole, X ) S). Some
evidence for this pathway was acquired when the oxida-
tion was performed using the stoichiometric ratios: CuBr
(1.1), Cu(OAc)2 (1.1), and tert-butyl perbenzoate (1.5) in
refluxing benzene for the time specified in Table 3. In
this manner, yields of the oxazoles and thiazoles in-
creased to 55-81% (vs 25-45%, Table 2, entries e, f, g)
and 76-84%, respectively. The oxazole fragment 21
(Table 3, entry k), a precursor2g,h to Calyculin A was also
was smoothly oxidized to the corresponding thiazole 21c
(Table 2, entry c) in good yield. The presence of a
5-methyl substituent in the oxazoline 20 (R2 ) Me, X )
O, Table 2, entry b) was found not to interfere with the
oxidation to the oxazole. This copper-mediated process
did not limit the nature of the side chain to aryl or
n-alkyl, but also allowed secondary and tertiary hydro-
gens to remain intact at the R-position. When applied
to oxazolines 20 (Table 2, entries e, f, g) containing
stereocenters at the 2-(R) position, the corresponding
oxazoles 21 were obtained, albeit in low yields ranging
from 30-45% compared to the simple alkyl or aryl
substituted oxazoles. Based on these results, the follow-
ing mechanisms (A and B, Scheme 3) were proposed. The
intermediate R-oxa radical 22 in mechanism A has
precedent in the Kharasch-Sosnovsky reactions12 involv-
ing tetrahydrofurans and thiophenes, which were oxi-
dized by Cu(II) via oxonium ions to their dihydro deriva-
tives. In the case of 22 this would readily lead to 23,
and rapid proton loss would provide the observed oxazole
21. On the other hand (mechanism B), formation of the
more favorable captodative radical13 24 followed by ligand
transfer14 with Cu(II) benzoate would produce the inter-
mediate 25. The latter would undergo a syn elimination
with the loss of benzoic acid to give the oxazole 21. It is
also be reasonable to expect that the captodative radical
24 may be formed from 22, via H-atom transfer. Inter-
estingly, while this study was in progress a Cu(II)Br-
mediated oxidation of 2-oxazolines was reported by a
Bristol-Myers Squibb group4c wherein a mechanism
involving an ionic pathway was proposed (Scheme 4).
From Scheme 3 above, it was felt that mechanism A
or B would be favored by the presence of excess Cu(II)
species in the reaction mixture. This might serve to
increase the solubility of the oxazoline in the benzene
solution and may also provide the higher copper(II) ion
prepared in good yield without any loss of optical purity.
The reaction times were also significantly decreased to
4-8 h (vs 12 h, Table 2). Chiral HPLC analysis of the
valine derived oxazole and thiazole (Table 3, entries a,
c) indicated that there was no racemization occuring
during the oxidations (see supporting information). Ad-
ditional support for mechanism B above (Scheme 3) was
obtained when the adduct ester 25 was isolated in 8%
yield from a run that was performed at 60 °C in benzene
rather than at reflux. Presumably, the benzoate ester
eliminates somewhat slower than the acetate, thus
allowing for its isolation. The structure of the benzoate
25, derived from valine derivative 20e, was supported
by 1H NMR, 13C, DEPT 135, and 90 spectra. Subsequent
heating of the solution containing the benzoate 25 gave
the expected oxazole 21e. Extension of this oxidation
(14) J enkins, C. L.; Kochi, J . K. J . Am. Chem. Soc. 1972, 94, 843
and 856.

Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles
J . Org. Chem., Vol. 61, No. 23, 1996 8211
ride17 in 250 mL of CH2Cl2 at 0 °C was treated with 21.46 g
(180.4 mmol) of racemic serine methyl ester and the reaction
mixture allowed to warm to room temperature. After 24 h at
room temperature, 50 mL water was added, and the layers
were separated. The aqueous layer was extracted with CH2-
Cl2 (2 × 30 mL), and the combined organic phases were dried
(Na2SO4) and concentrated under vacuum. The residue was
then purified by flash chromatography on SiO2 using hexane/
ethyl acetate (65:35) to give 23.45 g (96% yield) of 13b as a
Ta ble 3. Ra d ica l Oxid a tion s to Oxa zoles/Th ia zoles
1
colorless oil. IR (thin film, cm-1) 2957, 1744, 1670, 1439; H
NMR (CDCl3, 300 MHz) δ 2.00 (s, 3H), 3.76 (s, 3H), 4.34-
4.49 (m, 2H), 4.66-4.73 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
13.8, 52.6, 68.2, 69.4, 167.7, 171.7.
(S )-(+)-4-Ca r b om e t h oxy-2-e t h yl-5-m e t h yl-2-oxa zo-
lin e, 20b . Prepared as described in the general procedure
using 1.5 g (12.20 mmol) of ethyl imidate, 1.596 g (13.42 mmol)
of L-threonine methyl ester and 20 mL CH2Cl2. Flash chro-
matography on SiO2 using hexane/ethyl acetate (70:30) gave
1.85 g (89% yield) of 20b as a colorless oil. [R]23D 170.5 (c 3.12,
CHCl3); IR (thin film, cm-1) 2982, 1743, 1658, 1439, 1020; 1H
NMR (CDCl3, 300 MHz) δ 1.08 (t, J ) 7.62 Hz, 3H), 1.30 (d, J
) 6.34 Hz, 3H), 2.21 (q, J ) 7.49 Hz, 2H), 3.66 (s, 3H), 4.09-
4.13 (dd, J ) 0.69, 7.31 Hz, 1H), 4.61-4.69 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 9.95, 20.7, 21.5,52.2, 74.4, 78.2, 170.8,
171.5. Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65. Found
C, 56.07; H, 7.69.
4-Ca r b om et h oxy-2-isop r op yl-2-oxa zolin e, 20a . Pre-
pared as described in the general procedure using isopropyl
imidate18 (3.7 g, 27 mmol), racemic serine methyl ester (3.53
g,29.7 mmol), and 45 mL of CH2Cl2. Flash chromatography
on SiO2 using hexane/ethyl acetate (70:30) gave 3.96 g (86%
yield) of 20a as a colorless oil. IR (thin film, cm-1) 2975, 1743,
1657, 1472; 1H NMR (CDCl3, 300 MHz) δ 1.13 (d, J ) 6.99
Hz, 6H), 2.51-2.61 (m, 1H), 3.71 (s, 3H), 4.28-4.43 (m, 2H),
4.61-4.68 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.5, 28.1,
52.5, 67.9, 69.1, 171.7, 174.7.
protocol to 4-alkyl substituted oxazoline 27, however,
gave very poor yields (10%) of the oxazoles 28 even after
prolonged reflux (24 h) with the unreacted oxazoline 27
being returned as the major component of the reaction
4-Ca r bom eth oxy-2-p en tyl-2-oxa zolin e, 13c. Prepared as
described in the general procedure using 1.82 g (12.2 mmol)
of n-pentyl imidate,18 racemic serine methyl ester (1.60 g, 13.42
mmol), and 20 mL of CH2Cl2. Flash chromatography on SiO2
using hexane/ethyl acetate (70:30) gave 1.99 g (91% yield) of
13c as a colorless oil. IR (thin film, cm-1) 2956, 1744, 1661,
1
1467, 1178, 1039; H NMR (CDCl3, 300 MHz) δ 0.81 (t, J )
6.81Hz, 3H), 1.19-1.25 (m, 4H), 1.53-1.60 (m, 2H), 2.22 (t, J
) 7.89 Hz, 2H), 3.68 (s, 3H), 4.26-4.40 (m, 2H), 4.60-4.66
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 22.1, 25.4, 27.7,
31.1, 52.4, 67.8, 69.0, 170.8, 171.6.
(eq 2). In retrospect this is not surprising, since the
incipient radical (22 or 24) to be formed at the 5-position
may not be expected to be as stable, even if it did form
initially, as that having an electron-withdrawing group
at this position.
4-Ca r bom eth oxy-2-cycloh exyl-2-oxa zolin e, 20d . Pre-
pared as described in the general procedure using 2.17 g (12.2
mmol) of cyclohexyl imidate,18 racemic serine methyl ester
(1.596 g, 13.42 mmol), and 20 mL of CH2Cl2. Flash chroma-
tography on SiO2 using hexane/ethyl acetate (70:30) gave 2.37
In summary, a useful Cu(I)/Cu(II)/peroxide oxidation
has been developed in this laboratory for the synthesis
of 4-carboxyoxazoles and thiazoles. The method tolerates
a wide range of functional groups without loss of optical
purity. The limitations previously observed in the bro-
mination of oxazolines was nicely avoided using the
copper-mediated process. The latter process has already
been utilized in the total synthesis of several important
classes of compounds such as, the streptogramin antibi-
otic, madumycin II,16 Bistatramides6d C and D, and the
potent HIV-1 inhibitor thiangazole.15 This should open
the way toward the synthesis of other biologically active
oxazole/thiazole-containing natural products.
g (92% yield) of 20d as a colorless oil. IR (thin film, cm-1
)
1
2932, 1743, 1654, 1037; H NMR (CDCl3, 300 MHz) δ 1.16-
1.87 (m, 10 H), 2.17-2.29 (m, 1H), 3.70 (s, 3H), 4.27-4.44 (m,
2H), 4.53-4.69 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 25.4,
25.6, 29.5, 29.6, 37.3, 52.4, 67.8, 68.9, 171.8, 173.7. Anal. Calcd
for C11H17NO3: C, 62.54; H, 8.11; Found: C, 62.52; H, 8.10.
(S)-(+)-4-Car bom eth oxy-2-pr opyl-2-th iazolin e, 20c. Pre-
pared as described in the general procedure using 1.68 g (12.2
mmol) of n-propyl imidate, 1.99 g (13.42 mmol) of L-cystine
ethyl ester and 20 mL of CH2Cl2. Flash chromatography on
SiO2 using hexane/ethyl acetate (65:35) gave 20c as a colorless
oil. [R]23D 108.8 (c 10.9, CHCl3); IR (thin film, cm-1) 2963, 1740,
1
1622, 1463, 1095; H NMR (CDCl3, 300 MHz) δ 0.92 (t, J )
Exp er im en ta l Section
7.32 Hz, 3H), 1.26 (t, J ) 7.11 Hz, 3H), 1.59-1.70 (m, 2H),
2.46-2.52 (m, 2H), 3.41-3.55 (m, 2H), 4.19 (q, J ) 7.11 Hz,
2H), 4.97-5.04 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.5,
14.1, 21.0, 36.2, 61.6, 77.9, 170.9, 174.7.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zolin es.
4-Ca r bom eth oxy-2-m eth yl-2-oxa zolin e, 13b.4 A suspen-
sion of 20.25 g (164 mmol) of methyl acetimidate hydrochlo-
(15) Boyce, R. J .; Mulqueen, G. C.; Pattenden, G. Tetrahedron 1995,
51, 7321.
(17) (a) Dox, A. W. Organic Syntheses, Wiley: New York, 1990; Coll.
Vol. VII, p 5. (b) See ref 3d above.
(16) Tavares F.; Lawson, J . P.; Meyers, A. I. J . Am. Chem. Soc. 1996,
118, 3303.
(18) Iminium Salts in Organic Chemistry, Bohme, H., Viehe, H. G.,
Ed.; J ohn Wiley and Sons: Canada, 1976; Vol. 9, Part 1.

8212 J . Org. Chem., Vol. 61, No. 23, 1996
Meyers and Tavares
4-Ca r bom eth oxy-2-p h en yl-2-oxa zolin e, 13a .19 Prepared
as described in the general procedure using 2.74 g (16 mmol)
of benzimidate hydrochloride, 2.74 g (17.6 mmol) of racemic
serine methyl ester and 27 mL of CH2Cl2. Flash chromatog-
raphy on SiO2 using hexane/ethyl acetate (80:20) gave 13a as
a colorless oil. IR (thin film, cm-1) 3062, 2953, 1210, 1178,
1069; 1H NMR (CDCl3, 300 MHz) δ 3.71 (s, 3H), 4.44-4.51
(dd, J ) 8.75, 10.53 Hz, 1H), 4.59 (app t, J ) 8.59 Hz, 1H),
4.82-4.88 (dd, J ) 8.02, 10.4 Hz, 1H), 7.28-7.41 (m, 3H), 7.88
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 52.4, 68.3, 69.3, 126.7,
128.1, 128.3, 131.6, 165.9, 171.3.
Gen er a l P r oced u r e for th e P r ep a r a tion of BOC P r o-
tected Am in o Acid s. To a stirred solution of 1 equiv of the
amino acid in THF/H2O (1:1) (0.30 M) at rt was added 2.2 equiv
of sodium hydroxide. To this was added 1.1 equiv of Boc2O,
and the reaction mixture esd stirred at rt for 18 h. The organic
layer was concentrated under vacuum, and the aqueous layer
was extracted with CH2Cl2. The aqueous layer was then
acidified with 1 N HCl to pH 4 and the precipitated acid
extracted with CH2Cl2. Concentration under vacuum gave the
desired product in quantitave yield as a white solid, used
without further purification for the next step.
(S)-(+)-N-(ter t-Bu tyloxyca r bon yl)va lin e.10 Prepared as
described in the general procedure using 0.710 g (6.06 mmol)
of (S)-(+)-valine, 1.46 g (6.67 mmol) of (Boc)2O, and 0.533 g
(13.3 mmol) of sodium hydroxide. [R]23D 11.7 (c 2.35, CHCl3 );
IR (thin film, cm-1) 3328, 3103, 2974, 1717, 1661, 1510, 1406,
1164; 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, J ) 6.84 Hz, 3H),
0.94 (d, J ) 6.84 Hz, 3H), 1.41 (s, 9H), 2.14-2.20 (m, 1H),
5.04 (m, 1H), 6.28 (d, J ) 7.44), 11.53 (br, s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 17.4, 18.9, 28.3, 31.0, 58.3, 80.0, 155.8,
177.2.
(S)-(+)-N-(ter t-Bu tyloxyca r bon yl)p h en yla la n a m id e.10
Prepared as described in the general procedure using 1.30 g
(4.91 mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)phenyl-
alanine, 0.594 mL (5.40 mmol) of N-methylmorpholine, and
0.706 mL (5.40 mmol) of isobutyl chloroformate; [R]23 13.57
D
(c 3.42, EtOH); IR (thin film, cm-1) 3383, 3342, 3190, 1682,
1
1657, 1520, 1165; H NMR (CDCl3, 300 MHz) δ 1.36 (s, 9H),
3.03 (m, 2H), 5.23 (d, J ) 6.54 Hz, 1H), 5.93 (br, s, 1H), 6.12
(br, s, 1H), 7.18-7.29 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
27.8, 38.5, 71.2, 80.1, 126.8, 128.6, 129.3, 136.6, 155.5, 174.0.
Gen er a l P r oced u r e for th e P r ep a r a tion of Im in o
Eth er s 11 fr om th e Acid Am id es. A suspension of N-tert-
butyloxycarbonyl amino acid (1 equiv) in dry CH2Cl2 (0.4 M)
was cooled to 0 °C, to this was added triethyloxonium
hexafluorophosphate (1.1 equiv), and the resulting solution
was stirred at rt for 18 h. The reaction mixture was then
washed with saturated NaHCO3, dried (Na2SO4), and concen-
trated under vacuum to give a colorless oil that was carried
on directly to the next step without further purification.
2(S)-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-3-m eth ylbu ta -
n im in o Eth yl Eth er .10 Prepared as described in the general
procedure using 2.0 g (9.26 mmol) of (S)-(+)-N-(tert-butoxy-
carbonyl) valinamide and 2.55 g (10.19 mmol) of triethyloxo-
nium hexafluorophosphate and obtained in 96% yield (2.17 g).
Used without further purification directly for the next step.
1H NMR (CDCl3, 300 MHz) δ 1.43 (t, J ) 7.20 Hz, 3H), 0.93
(d, J ) 7.01 Hz, 3H), 0.98 (d, J ) 6.93 Hz, 3H), 1.42 (s, 9H),
2.08-2.21 (m, 1H), 3.98-4.49 (m, 3H), 4.8 (m, 1H), 5.81 (br,
s, 1H), 6.10 (br, s, 1H).
2(S)-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-3-p h en ylp r op a -
n im in o Eth yl Eth er .10 Prepared as described in the general
procedure using 1.0 g (3.79 mmol) of (S)-(+)-N-(tert-butoxy-
carbonyl)phenylalaninamide, and 1.04 g (4.17 mmol) of tri-
ethyloxonium hexafluorophosphate and obtained in 98% yield
(1.08 g). Used without further purification directly for the next
step. 1H NMR (CDCl3, 300 MHz) δ 1.40 (t, J ) 7.21 Hz, 3H),
1.41 (s, 9H), 3.10 (m, 2H), 3.98-4.41 (m, 3H), 5.31 (br, s, 1H),
6.10 (br, s, 1H), 7.16-7.26 (m, 5H).
(S)-(+)-N-(ter t-Bu tyloxycar bon yl)ph en ylalan in e.10 Pre-
pared as described in the general procedure using 1.0 g (6.06
mmol) of (S)-phenylalanine, 1.46 g (6.67 mmol) of (Boc)2O, and
0.533 g (13.3 mmol) of sodium hydroxide; [R]23 7.29 (c 7.0);
D
IR (thin film, cm-1) 3314, 2978, 1718, 1498, 1404, 1165; 1H
NMR (CDCl3, 300 MHz) δ 1.30 (s, 9H), 3.20 (m, 2H), 5.20 (m,
1H), 6.61 (d, J ) 7.5 Hz, 1H), 7.18-7.31 (m, 5H), 11.35 (br, s,
1H); 13C NMR (CDCl3, 75 MHz) δ 28.3, 38.2, 54.6, 80.6, 127.4,
128.9, 129.7, 136.2, 155.7, 176.4.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dip ep tid es
7 fr om th e Boc P r otected Am in o Acid s. Dip ep tid e of (S)-
N-ter t-Bu tyloxyca r bon yl Va lin e-Ser in e. To a solution of
the (S)-(+)-N-(tert-butyloxycarbonyl)valine (4.0 g,18.4 mmol)
in 80 mL of THF (0.23 M) at -30 °C was added 3.5 mL (38.6
mmol) of Et3N, followed by 2.64 mL (20.2 mmol) of isobutyl
chloroformate. After 30 min, 3.14 g (20.2 mmol) of racemic
serine methyl ester hydrochloride was added as a solid. The
reaction mixture was allowed to warm gradually to rt over 6
h and stirred further for an additional 12 h. The organic layer
was concentrated under vacuum followed by dilution with
water (30 mL) and ethyl acetate (50 mL). The layers were
separated, and the organic layer was washed with saturated
NaHCO3 (30 mL). The aqueous layer was extracted with ethyl
acetate (2 × 30 mL), and the combined organic extracts were
dried (Na2SO4) and concentrated under vacuum to give 5.38 g
(92% yield) of the desired product. Used without further
purification for the next step. IR (thin film, cm-1) 3314, 2965,
1654, 1522; 1H NMR (CDCl3, 300 MHz) δ 0.87 (d, J ) 6.72
Hz, 3H), 0.96 (d, J ) 6.87 Hz, 3H), 1.41 (s, 9H), 2.14-2.23 (m,
1H), 3.75 (s, 3H), 3.85-3.93 (m, 3H), 4.62-4.66 (m, 1H), 5.09-
5.19 (m, 1H), 6.96 (br, s, 1H); 13C NMR (CDCl3, 300 MHz) δ
17.9, 19.2, 28.2, 30.9, 52.6, 54.6, 59.9, 62.5, 80.2, 156.3, 170.9,
172.1.
(S)-(-)-N-(ter t-Bu t yloxyca r b on yl)a la n in e.10 Prepared
as described in the general procedure using 1.50 g (16.9 mmol)
of (S)-alanine, 4.06 g (18.6 mmol) of (Boc)2O, and 1.48 g (77.1
mmol) of sodium hydroxide; [R]23D -2.0 (c 1.8 CHCl3); IR (thin
film, cm-1) 2970, 1700, 1655, 1417, 1161; 1H NMR (CDCl3, 300
MHz) δ 1.38 (br, s, 9H), 1.79-2.25 (m, 4H), 3.30-3.54 (m, 2H),
4.16-4.31 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 23.6,28.3, 30.7,
46.3, 58.9,80.3, 153.9, 178.6.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id es
fr om th e Boc P r otected Am in o Acid s. To a stirred solution
of the Boc protected amino acid (1 equiv) in CH2Cl2 (0.22 M)
at -30 °C was added N-methylmorpholine (1.1 equiv) followed
by isobutyl chloroformate (1.1 equiv). The reaction mixture
was allowed to warm to -20 °C over 30 min, and gaseous
ammonia was then bubbled through for 15 min. After warm-
ing to rt over 1 hour, the reaction mixture was diluted with
water, and the layers were separated. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
dried (Na2SO4) and concentrated under vacuum to give the
desired amides which were used without further purification
for the next step.
Dip ep tid e of (S)-N-ter t-Bu tyloxyca r bon yl P h en yla la -
n in e-Ser in e. Prepared as described in the general procedure
using 2.44 g (9.22 mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)-
phenylalanine, 2.13 mL (19.4 mmol) of N-methylmorpholine,
1.33 mL (10.1 mmol) of isobutyl chloroformate, and racemic
serine methyl ester hydrochloride and obtained in 96% yield
(3.24 g) as a colorless oil. Used without further purification
for the next step. IR (thin film, cm-1) 3311, 2979, 1740, 1659;
1H NMR (CDCl3, 300 MHz) δ 1.36 (s, 3H), 2.96-3.14 (m, 2H),
3.26 (br, s, 1H), 3.72 (s, 3H), 3.88 (m, 2H), 4.33-4.39 (m, 1H),
4.56-4.61 (m, 1H), 5.18 (d, J ) 7.65 Hz, 1H), 7.19 (d, J ) 1.71
Hz, 1H), 7.21-7.30 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 28.2,
38.1, 52.7, 54.9, 55.9, 62.7, 80.5, 126.9, 128.6, 129.3, 136.4,
155.7, 170.5, 171.7.
(S)-(+)-N-(ter t)-b u t yloxyca r b on ylva lin a m id e.10 Pre-
pared as described in the general procedure using 0.727 g (3.35
mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)valine, 0.405 mL
(3.69 mmol) of N-methylmorpholine, and 0.482 mL (3.69 mmol)
of isobutyl chloroformate. [R]23 0.30 (c 2.67, EtOH); IR (thin
D
film, cm-1) 3383, 3342, 3200, 1682, 1662, 1520, 1170; 1H NMR
(CDCl3, 300 MHz) δ 0.90 (d, J ) 6.81 Hz, 3H), 0.94 (d, J )
6.78 Hz, 3H), 1.39 (s, 9H), 2.02-2.11 (m, 1H), 5.21 (m, 1H),
6.02 (br, s, 1H), 6.39 (br, s, 1H); 13C NMR (CDCl3, 75 MHz) δ
19.2, 28.3, 30.7, 59.4, 79.8, 155.9, 174.4.
(19) Naito, T.; Yuumoto, Y.; Ninomiya, I.; Kiguchi, T. Tetrahedron
Lett. 1992, 33, 4033.

Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles
J . Org. Chem., Vol. 61, No. 23, 1996 8213
Dip ep tid e of (S)-N-ter t-Bu tyloxyca r bon yl Va lin e-Th r e-
on in e. Prepared as described in the general procedure using
2.0 g (9.22 mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)valine,
2.13 mL (19.4 mmol) N-methylmorpholine, 1.33 mL (10.1
mmol) of isobutyl chloroformate, and 1.71 g (10.1 mmol) of
L-threonine methyl ester and obtained in 93% yield (2.84 g)
as a colorless oil. Used without further purification for the
next step. IR (thin film, cm-1) 3328, 2964, 1747, 1663; 1H NMR
(CDCl3, 300 MHz) δ 0.90 (d, J ) 7.01 Hz, 3H), 1.19 (d, J )
6.21 Hz, 3H), 3.73 (s, 3H), 2.10 (m, 1H), 3.83-4.10 (m, 1H),
4.34-4.58 (m, 1H), 4.61 (m, 1H), 5.15-5.18 (m, 1H), 6.85 (br,
s, 1H).
Dip ep t id e of (S)-N-ter t-Bu t yloxyca r b on yl Ala n in e-
Ser in e. Prepared as described in the general procedure using
2.50 g (13.23 mmol) of (S)-(+)-N-(tert-butyloxycarbonyl)alanine,
2.51 mL (27.8 mmol) of Et3N, 1.89 mL (14.6 mmol) of isobutyl
chloroformate, and 2.26 g (14.6 mmol) of racemic serine methyl
ester hydrochloride and obtained in 96% yield (3.68 g) as a
colorless oil. Used without further purification for the next
step. IR (thin film, cm-1) 3343, 2983, 1739, 1661; 1H NMR
(CDCl3, 300 MHz) δ 1.23 (d, J ) 7.01 Hz, 3H), 1.31 (s, 9H),
3.68 (s, 3H), 3.71-3.92 (m, 2H), 4.10-4.23 (m, 2H), 4.56 (m,
1H), 5.60 (d, J ) 7.23 Hz, 1H), 7.34 (d, J ) 7.56 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 18.1, 27.9, 49.8, 52.2, 54.3, 62.2, 79.8,
155.4, 170.6, 173.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zolin es
8 or 20 (e-l) fr om th e Dip ep tid es via Bu r gess r ea gen t.
2-[(S)-1-[N-(ter t-Bu toxycar bon yl)am in o]-2-m eth ylpr opyl]-
4-ca r bom eth oxyoxa zolin e, 20e. To a solution of the dipep-
tide derived from (S)-N-tert-butyloxycarbonyl valine-serine
(4.35 g, 13.7 mmol) in 90 mL of THF (0.15 M) was added 3.58
g (15.1 mmol) of Burgess reagent,9 and the contents were
heated to reflux for 1.5 h. The solvent was concentrated under
vacuum and the residue flash chromatographed on SiO2 using
hexane/ethyl acetate (70:30) to give 20e in 68% yield (4.08 g)
as a colorless oil. IR (thin film, cm-1) 3310, 2966, 1720, 1658;
1H NMR (CDCl3, 300 MHz) δ 0.93 (d, J ) 6.90 Hz, 3H), 0.97
(d, J ) 6.84 Hz, 3H), 1.38 (s, 9H), 2.13 (m, 1H), 3.69 (s, 3H),
4.23-4.30 (dd, J ) 3.10, 8.20 Hz, 1H), 4.75-4.78 (dd, J ) 1.43,
10.22 Hz, 1H), 4.88-4.94 (m, 2H), 5.23 (d, J ) 9.10 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 16.3, 16.7, 31.4, 52.1, 53.8, 71.0,
78.8, 79.2, 155.9, 170.7, 170.9.
2-[(S)-1-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-m eth ylp r o-
p yl]-5-m eth yl-4-ca r bom eth oxyoxa zolin e, 20h . Prepared
as described in the general procedure using 2.50 g (7.53 mmol)
dipeptide of (S)-N-tert-butyloxycarbonyl valine-threonine and
1.97 g (8.28 mmol) of Burgess reagent.9 Flash chromatography
on SiO2 using hexane/ethyl acetate (70:30) gave 1.49 g (63%
yield) of 20h as a colorless oil. IR (thin film, cm-1) 3300, 2964,-
1715, 1658; 1H NMR (CDCl3, 300 MHz) δ 0.91 (d, J ) 6.90
Hz, 3H), 0.96 (d, J ) 6.84 Hz, 3H), 1.24 (d, J ) 6.45 Hz, 3H),
1.39 (s, 9H), 2.11 (m, 1H), 3.70 (s, 3H), 4.26-4.30 (dd, J )
3.12, 8.16 Hz, 1H), 4.73-4.76 (dd, J ) 1.41, 10.14 Hz, 1H),
4.89-4.93 (m, 1H), 5.20 (d, J ) 9.09 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 16.1,16.9, 28.3, 31.4, 51.9, 53.6, 70.7, 78.3, 79.5,
155.6, 170.0, 170.1.
of Burgess reagent. Flash chromatography on SiO2 using
hexane/ethyl acetate (65:35) gave 2.10 g (64% yield) of 20f as
a colorless oil. IR (thin film, cm-1) 3320, 2958, 1705, 1608; 1H
NMR (CDCl3, 300 MHz) δ 1.34 (d, J ) 7.77 Hz, 3H), 1.38 (s,
9H), 3.73 (s, 3H), 4.38-4.55 (m, 2H), 4.68-4.74 (dd, J ) 7.83,
10.59 Hz, 1H), 5.16 (br,s, 1H); 13C NMR (CDCl3, 75 MHz) δ
19.4, 28.1, 44.6,52.9, 67.6, 70.1, 80.2, 154.8, 171.0, 171.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ia zolin es
fr om th e Im in o Eth er s. To a solution of the imino ether
(1.0 equiv) in anhydrous ethanol (0.32 M) was added L-cystine
ethyl ester (1.1 equiv) and the resulting solution stirred at rt
for 18 h. The solvent was evaporated and the residue flash
chromatographed on SiO2 using hexane/ethyl acetate to give
the desired product.
2-[(S)-1-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2-m et h yl-
p r op yl]-4-ca r bet h oxy-(S)-2-t h ia zolin e, 20i. Prepared as
described in the general procedure using 2.17 g (8.89 mmol)
2(S)-[N-(tert-butyloxycarbonyl)amino]-3-methylbutanimino eth-
yl ether and 1.32 g (8.89 mmol) of L-cystine ethyl ester. Flash
chromatography on SiO2 using hexane/ethyl acetate (85:15)
gave 0.750 g (42% yield) of 20i as a colorless oil. [R]23 -64.3
D
(c 1.1, CHCl3); IR (thin film, cm-1) 3350, 1705, 1618; 1H NMR
(CDCl3, 300 MHz) δ 0.81 (d, J ) 6.78 Hz, 3H), 0.91 (d, J )
6.81 Hz, 3H), 1.20 (t, J ) 7.11 Hz, 3H), 1.35 (s, 9H), 2.03-
2.18 (m, 1H), 3.41-3.51 (m, 2H), 4.15 (q, J ) 7.11 Hz, 2H),
4.40 (m, 1H), 5.05 (t, J ) 8.10 Hz, 1H), 5.20 (d, J ) 9.06 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 16.4, 19.2, 28.1, 32.3,
35.6, 57.7, 61.5, 77.5, 79.4, 155.3, 170.4, 175.5.
2-[(S)-1-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2-p h en yl-
eth yl]-4-ca r beth oxy-(S)-2-th ia zolin e, 20j. Prepared as de-
scribed in the general procedure using 1.08 g (3.70 mmol) of
2(S)-[N-(tert-butyloxycarbonyl)amino]-3-methylbutanimino eth-
yl ether and 0.55 g (3.70 mmol) of L-cystine ethyl ester. Flash
chromatography on SiO2 using hexane/ethyl acetate (85:15)
gave 0.630 g (45% yield) of 20j as a colorless oil. [R]23 -49.1
D
(c 1.3, CHCl3); IR (thin film, cm-1) 3310, 2960, 1700, 1606; 1H
NMR (CDCl3, 300 MHz) δ 1.28 (t, J ) 7.08 Hz, 3H), 1.37 (s,
9H), 3.00-3.23 (m, 2H), 3.44-3.60 (m, 2H), 4.23 (q, J ) 7.05
Hz, 2H), 4.78-5.18 (m, 3H), 7.15-7.29 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 28.2, 35.4, 39.9, 53.9, 61.8, 78.0, 79.8,
126.8, 128.3, 129.6, 136.1, 154.4, 170.3, 175.9.
Oxa zolin e, 20l.16 To a solution of the amide (1.22 g, 2.94
mmol) in 30 mL of THF was added 0.804 g (3.23 mmol) of
Burgess reagent, and the contents were refluxed for 1.5 h. The
solvent was removed under vacuum to give the crude product.
Column chromatography on SiO2 using hexane/ethyl acetate
(7:3) gave 0.806 g (69% yield) of the desired oxazoline 20l, in
65-70% overall yield from the acid. IR (thin film, cm-1) 1730,
1
1632; H NMR (CDCl3, 300 MHz) δ 0.02 (d, J ) 4.5 Hz, 6H),
0.84 (s, 9H), 1.30 (s, 3H), 1.35 (s, 3H), 1.65-1.91 (m, 2H), 2.52-
2.55 (d, J )7.3 Hz, 1H), 3.48 (t, J ) 7.65, 1H), 3.80 (s, 3H),
4.00-4.05 (dd, J ) 5.94, 7.95 Hz, 1H), 4.18-4.23 (m, 2H),
4.31-4.37 (dd, J ) 8.79, 10.74 Hz, 1H), 4.46 (dd, J ) 8.01,
8.79 Hz, 1H), 4.69 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ -4.9,
-4.7, 17.9, 25.7, 25.8, 26.9, 35.8, 40.9, 52.6, 67.4, 68.1, 69.1,
69.8, 72.4, 108.6, 168.3, 171.5. Anal. Calcd for C19H35NO6Si:
C, 56.83; H, 8.78. Found C, 56.58; H, 8.71.
2-[(S)-1-[N-(ter t-Bu toxycar bon yl)am in o]-2-ph en yleth yl]-
4-ca r bom eth oxyoxa zolin e, 20g. Prepared as described in
the general procedure using 3.0 g (8.20 mmol) of dipeptide of
(S)-N-tert-butyloxycarbonyl phenylalanine-serine and 2.14 g
(9.02 mmol) of Burgess reagent.9 Flash chromatography on
SiO2 using hexane/ethyl acetate (75:25) gave 2.03 g (71% yield)
of 20g as a colorless oil. IR (thin film, cm-1) 3335, 2977, 1745,
1709; 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9H), 2.97-3.14
(m, 2H), 3.71 (s, 3H), 4.37-4.41 (m, 1H), 4.51-4.71 (m, 2H),
5.14 (d, J ) 7.68 Hz, 1H), 7.07-7.26 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 28.2, 38.8, 49.6, 52.6, 67.7, 69.9, 79.7, 126.7, 128.2,
129.3, 129.4, 129.5, 135.7, 154.8, 169.3, 170.8.
Syn th esis of Oxazoles Usin g NBS an d P er oxide. 4-Car -
bom eth oxy-2-p h en yl-2-oxa zole, 14a .19 To 4-carbomethoxy-
2-phenyl-2-oxazoline (0.30 g, 1.46 mmol) and benzoyl peroxide
(20 mg, 0.082 mmol) was added 10 mL of dry benzene (0.15
M) and the reaction mixture brought to gentle reflux for 15
min. To this was added NBS (0.311g, 1.75 mmol) and further
refluxed for 1.5 h. The flask was cooled, and the contents were
poured over crushed ice. The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (2 × 20 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated under vacuum to afford the crude oxazole, which was
purified by radial chromatography using hexane/ethyl acetate
(95:10) as eluent to afford 0.247 g (83% yield) of 14a as a
Oxa zolin e Azid e, 20k .1h 1H NMR (CDCl3, 300 MHz) δ 1.20
(d, J ) 7.0 Hz, 3H), 1.63-1.76 (m, 1H), 1.88-2.00 (m, 1H),
2.63-2.71 (m, 1H), 3.34 (t, J ) 6.93 Hz, 2H), 3.76 (s, 3H),4.34-
4.49 (ddd, J ) 7.47, 8.67, 16.23 Hz, 2H), 4.68-4.74 (m, 1H).
2-[(S)-1-[N-(ter t-Bu t oxyca r b on yl)a m in o]-2-m et h yl]-4-
ca r bom eth oxyoxa zolin e, 20f. Prepared as described in the
general procedure using 3.5 g (12.1 mmol) of dipeptide of (S)-
N-tert-butyloxycarbonyl alanine-serine and 3.15 g (13.3 mmol)
1
colorless oil. IR (thin film, cm-1) 1725, 1612, 1572; H NMR
(CDCI3, 300 MHz) δ 3.92 (s, 3H), 7.40-7.48 (m, 3H), 8.04 (m,
2H), 8.25 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 52.2, 126.3,
126.8, 128.8, 131.1, 134.3, 143.8, 161.7, 162.4; MS m/z 203
(M+).

8214 J . Org. Chem., Vol. 61, No. 23, 1996
Meyers and Tavares
2-(2-Br om oisop r op yl)-4-ca r bom eth oxy-2-oxa zole, 15d .
To neat 4-carbomethoxy-2-isopropyl-2-oxazoline (0.200 g, 1.17
mmol) taken in a Pyrex test tube were added AIBN (10 mg
0.061 mmol) and NBS (0.540 g, 3.04 mmol). The reaction
mixture was then evacuated and filled with argon. To this
was added 10 mL of dry CH2Cl2 (0.12 M) under argon. The
reaction mixture was photolyzed at 0 °C for 10 h using a 450
W lamp as the UV source. The crude reaction mixture was
diluted with water (20 mL) and the organic layer separated.
The aqueous layer was further extracted with CH2Cl2 (2 × 20
mL). The combined organic extract was dried (Na2SO4) and
concentrated under vacuum and the crude product purified
by radial chromatography using hexane/ethyl acetate (95:5)
as eluent to afford 0.220 g (76% yield) of 15d as a colorless
hexane/ethyl acetate (80:20) gave 0.178 g (60% yield) of 21a
as a colorless oil. IR (thin film, cm-1) 1748; 1H NMR (CDCl3,
300 MHz) δ 1.23 (s, 3H), 1.26 (s, 3H), 2.98-3.07 (m, 1H), 3.78
(s, 3H), 8.06 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.9, 28.3,
51.8, 132.7, 143.4, 161.6, 169.7.
4-Ca r bom eth oxy-2-cycloh exyl-2-oxa zole, 21d . Prepared
as described in the general procedure using 0.394 g (2.0 mmol)
of 2-cyclohexyl-4-carbomethoxy-2-oxazoline, 0.315 g (2.20 mmol)
of Cu(I)Br, 0.582 g (3.0 mmol) of tert-butyl perbenzoate, and
8.12 mL of benzene (0.23 M). Flash chromatography on SiO2
using hexane/ethyl acetate (85:15) gave 0.215 g (55% yield) of
21d as a colorless oil. IR (thin film, cm-1) 1702; 1H NMR
(CDCl3, 300 MHz) δ 1.12-2.25 (m, 10 H), 2.71-2.82 (m, 1H),
3.82 (s, 3H), 8.08 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 25.2,
25.4, 25.6, 30.2, 37.4, 51.9, 132.7, 143.3, 161.8, 169.1.
4-Ca r bom eth oxy-2-eth yl-5-m eth yl-2-oxa zole, 21b. Pre-
pared as described in the general procedure using 0.359 g (2.0
mmol) of 4-carbomethoxy-2-ethyl-5-methyl-2-oxazoline, 0.315
g (2.20 mmol) of Cu(I)Br, 0.582 g (3.0 mmol) of tert-butyl
perbenzoate, and 7.77 mL of benzene (0.23 M). Flash chro-
matography on SiO2 using hexane/ethyl acetate (80:20) gave
0.224 g (63% yield) of 21b as a colorless oil. IR (thin film,
cm-1) 1714; 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J ) 7.62 Hz,
3H), 2.54 (s, 3H), 2.72 (q, J ) 7.56 Hz, 2H), 3.84 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 11.1, 11.8, 21.4, 51.8, 126.9, 128.3,
130.0, 163.8.
4-Ca r boeth oxy-2-p r op yl-2-th ia zole, 21c. Prepared as
described in the general procedure using 0.300 g (1.49 mmol)
of 2-propyl-4-carboethoxy-2- thiazoline, 0.236 g (1.64 mmol)
of Cu(I)Br, 0.434 g (2.24 mmol) of tert-butyl perbenzoate, and
6.49 mL of benzene (0.23 M). The reaction mixture was
refluxed for 4.5 h. Flash chromatography on SiO2, hexane/
ethyl acetate (85:15), gave 0.247 g (83%) of 21c as a colorless
oil. IR (thin film, cm-1) 1711, 1589; 1H NMR (CDCl3, 300 MHz)
δ 0.81 (t, J ) 6.93 Hz, 3H), 1.22 (t, J ) 3.70 Hz, 3H), 1.80 (m,
2H), 2.95 (t, J ) 6.31 Hz, 2H), 4.3 (q, J ) 6.70 Hz, 2H), 8.03
(s, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.5, 14.3, 23.4, 35.3, 61.2,
126.7, 146.6, 161.4, 172.1.
1
oil. IR (thin film, cm-1) 1730; H NMR (CDCl3, 300 MHz) δ
2.18 (s, 6H), 3.88 (s, 3H), 8.20 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 32.1, 51.2, 52.2, 133.4, 144.2, 161.3, 166.6.
2-(1-Br om ocycloh exyl)-4-ca r bom eth oxy-2-oxa zole, 15e.
Procedure was followed as in the oxidation of 4-carbomethoxy-
2-isopropyl-2-oxazoline using 0.247 g (1.17 mmol) of 4-car-
bomethoxy-2-cyclohexyl-2-oxazoline, 0.01 g (0.061 mmol) of
AIBN, 0.54 g (3.04 mmol) of NBS, and 9.8 mL of CH2Cl2 (0.12
M). Radial chromatography on SiO2 using hexane/ethyl
acetate (95:5) gave 0.223 g (66% yield) of 15e as a yellow oil.
IR (thin film, cm-1) 1749; 1H NMR (CDCl3, 300 MHz) δ 1.34-
1.84 (m, 6H), 2.34-2.55 (m, 4H), 3.88 (s, 1H), 8.21 (s, 1H); 13
C
NMR (CDCl3, 75 MHz) δ 23.3, 24.7, 39.0, 52.2, 59.3, 133.5,
144.0, 161.4, 166.0.
4-Ca r bom eth oxy-2-p en tyl-2-oxa zole, 14c. To neat 4-car-
bomethoxy-2-pentyl-2-oxazoline (0.05 mmol, 0.1 g) in a Pyrex
test tube was added NBS (0.445 g, 0.25 mmol). The reaction
mixture was then evacuated and purged with argon. To this
was added 10 mL of dry CH2Cl2 (0.05 M) under argon. The
reaction mixture was photolyzed at -40 °C and gradually
warmed to -25 °C over a 12 h period using a 450 W lamp as
the UV source. The organic layer was then quickly decanted
into a mixture of crushed ice and CH2Cl2 (30 mL), the reaction
test tube was rinsed with ether (2 × 3 mL), the organic layers
were combined, dried (Na2SO4), and concentrated under
vacuum, and the crude product was subjected to flash chro-
matography on SiO2 using hexane/ethyl acetate (85:15) to
afford 0.064 g (65% yield) of the oxazole 14c as a colorless oil.
Gen er a l P r oced u r e for th e Cu (I)-Cu (II) Oxid a tion of
Oxa zolin es a n d Th ia zolin es. 2-[(S)-1-[N-(ter t-Bu toxy-
ca r b on yl)a m in o]-2-m et h ylp r op yl]-4-ca r b om et h oxyox-
a zole, 21e. To the oxazoline 20e (0.300 g, 0.001 mol) in a 50
mL round bottomed flask were added CuBr (0.158 g, 1.10
mmol) and Cu(OAc)2 (0.199 g, 1.10 mmol). The flask was
evacuated and then filled with argon. The evacuation/argon
addition was repeated twice. Benzene (6.5 mL) (0.16 M) was
syringed into the flask and stirring initiated. The reaction
was warmed to 60 °C, and tert-butyl perbenzoate (0.291 g, 1.50
mmol) was added gradually over 15 min. The reaction mixture
was then heated to reflux for 7.5 h (4.5 h in case of thiazolines).
After cooling to rt, ethyl acetate (10 mL) was added, and the
mixture was washed with buffered 10% NH4OH solution to
remove all the copper salts. The aqueous layer was extracted
with ethyl acetate (3 × 10 mL), the combined organic extracts
were dried over Na2SO4, and the crude product, obtained after
concentration under vacuum, was subjected to flash column
chromatography on SiO2. [hexane/ethyl acetate (80:20)]. This
produced 0.194 g (65% yield) of 21e as a white solid. mp 120-
123 °C; [R]23D -53.9 (c 0.73 CH2Cl2); IR (thin film, cm-1) 3334,
1
IR (thin film, cm-1) 1744; H NMR (CDCl3, 300 MHz,) δ 0.92
(t, J ) 7.21 Hz, 3H), 1.36 (m, 4H), 1.8 (m, 2H), 2.79 (t, J )
7.32 Hz, 2H), 3.88 (s, 3H), 8.11 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.1, 22.4, 26.8, 28.3, 31.4, 52.3, 133.2, 143.9, 162.2,
166.4. Anal. Calcd for C10H15NO3: C, 60.89; H, 7.67.
Found: C, 60.72; H, 7.61.
4-Ca r bom eth oxy-2-m eth yl-2-oxa zole, 14b.17b Procedure
was followed as in the oxidation of 4-carbomethoxy-2-pentyl-
2-oxazoline using 0.300 g (2.09 mmol) of 4-carbomethoxy-2-
methyl-2-oxazoline, 0.552 g (3.14 mmol) of NBS, and 20 mL
of CH2Cl2. The reaction mixture was photolyzed at -10 °C
for 7 h. Flash chromatography on SiO2 using hexane/ethyl
acetate (60:40) gave 0.183 g (62% yield) of 14b as a colorless
1
oil. IR (thin film, cm-1) 1749; H NMR (CDCl3, 300 MHz) δ
2.48 (s, 3H), 3.87 (s, 3H), 8.11 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.1, 52.4, 133.5,144.1, 162.0, 162.7.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zoles
Usin g th e Mod ified Sosn ovsk y Rea ction ; Cu (I), ter t-
Bu tyl P er ben zoa te. To the oxazoline was added 1.1 equiv
of CuBr. The reaction mixture was evacuated and purged with
argon and to this was added dry benzene (0.23 M) under argon.
The mixture was heated to 60 °C, and the peroxy ester was
added dropwise (1.5 equiv) over 15 min. The mixture was then
heated to reflux for 12 h. To the crude reaction mixture was
added 10% ammonium hydroxide to remove the copper salts.
The organic layer was washed with water, dried (Na2SO4), and
concentrated under vacuum. The crude product was subjected
to flash chromatography on SiO2 using hexane/ethyl acetate
to afford the oxazoles in 55-65% yields.
1
2970, 1749, 1715, 1584, 1522; H NMR (CDCl3, 300 MHz) δ
0.86 (d, J ) 6.69 Hz, 3H), 0.89 (d, J ) 5.22 Hz, 3H), 1.39 (s,
9H), 2.00-2.21 (m, 1H), 3.88 (s, 3H), 4.76 (dd, J ) 6.06, 9.15
Hz, 1H), 5.25 (d, J ) 9.12 Hz, 1H), 8.15 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 17.7, 18.6, 28.2, 32.6, 52.1, 54.2, 79.9, 133.1,
143.7, 155.3, 161.5, 165.1. Anal. Calcd for C14H22N2O5: C,
56.36; H, 7.43; N, 9.39. Found C, 56.31; H, 7.43; N, 9.31.
2-[(S)-1-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-m eth ylp r o-
pyl]-5-m eth yl-4-car bom eth oxyoxazole, 21h . Oxidation was
carried out as described in the general procedure using 0.330
g (1.05 mmol) of 2-[(S)-1-[N-(tert-butoxycarbonyl)amino]-2-
methylpropyl]-5-methyl-4-carbomethoxyoxazoline, 20h , 0.166
g (1.16 mmol) of Cu(I)Br, 0.210 g (1.16 mmol) of Cu(OAc)2,
and 0.307 g (1.58 mmol) of tert-butyl perbenzoate. Flash
chromatography on SiO2 using hexane/ethyl acetate (80:20)
4-Ca r bom eth oxy-2-isop r op yl-2-oxa zole, 21a .3b Prepared
as described in the general procedure using 0.300 g (1.75
mmol) 4-carbomethoxy-2-isopropyl-2-oxazoline, 0.277 g (1.93
mmol) of Cu(I)Br, tert-butyl perbenzoate, and 7.63 mL of
benzene (0.23 M). Flash chromatography on SiO2 using
gave 0.184 g (56% yield) of 21h as a colorless oil. [R]23 20.9
D
(c 11.7, CHCl3); IR (thin film, cm-1) 3325, 2970, 1715, 1621,

Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles
J . Org. Chem., Vol. 61, No. 23, 1996 8215
1584; 1H NMR (CDCl3, 300 MHz) δ 0.88 (d, J ) 6.75 Hz, 3 H),
0.90 (d, J ) 6.78 Hz, 3H), 2.10-2.17 (m, 1H), 2.58 (s, 3H),
3.78 (s, 3H), 4.69 (dd, J ) 5.88, 9.18 Hz, 1H), 5.23 (d, J ) 9.30
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 12.3, 18.3, 19.1, 28.6,
33.2, 52.3, 54.4, 80.2, 129.9, 155.7, 156.6, 162.0, 162.5.
2-[(S)-1-[N-(ter t-Bu toxycar bon yl)am in o]-2-ph en yleth yl]-
4-ca r bom eth oxyoxa zole, 21g. Oxidation was carried out as
described in the general procedure using 0.40 g (1.15 mmol)
of 2-[(S)-1-[N-(tert-butoxycarbonyl)amino]-2-phenylethyl]-4-
carbomethoxyoxazoline, 20g, 0.182 g (1.27 mmol) of Cu(I)Br,
0.230 g (1.27 mmol) of Cu(OAc)2, and 0.335 g (1.73 mmol) of
tert-butyl perbenzoate. Flash chromatography on SiO2 using
hexane/ethyl acetate (80:20) gave 0.227 g (57% yield) of 21g
SiO2 using hexane/ethyl acetate (85:15) gave 0.227 g (76%
yield) of 21j a colorless oil. [R]23 5.1 (c 1.8, CHCl3); IR (thin
D
film, cm-1) 3324, 2978, 1712, 1584; 1H NMR (CDCl3, 300 MHz)
δ 1.34 (s, 9H), 1.39 (t, J ) 7.14 Hz, 3H), 3.25-3.35 (m, 2H),
4.38 (q, J ) 7.14 Hz, 2H), 5.23-5.28 (m, 2H), 7.06-7.24 (m,
5H), 8.00 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.7, 28.5, 41.8,
54.2, 61.7, 80.6, 127.3, 127.5, 128.9, 129.7, 136.5, 147.6, 155.2,
161.7, 173.4.
2-[(S)-1-[N-(ter t-Bu t oxyca r b on yl)a m in o]et h yl]-4-ca r -
bom eth oxyoxa zole, 21f. Oxidation was carried out as
described in the general procedure using 0.20 g (0.735 mmol)
of 2-[1-[(tert-butoxycarbonyl)amino]ethyl]-4-carbomethoxyox-
azoline, 0.116 g (0.809 mmol) of Cu(I)Br, 0.147 g (0.809 mmol)
of Cu(OAc)2, and 0.214 g (1.103 mmol) of tert-butyl perben-
zoate. Flash chromatography on SiO2, hexane/ethyl acetate
as a colorless oil. [R]23 -16.0 (c 2.8, CHCl3); IR (thin film,
D
cm-1) 3353, 2977, 1714, 1167; H NMR (CDCl3, 300 MHz) δ
1
(70:30), gave 0.101 g (51% yield) of 21f as a colorless oil. [R]23
1.37 (s, 9H), 3.18-3.25 (dd, J ) 6.72, 14.85 Hz, 2H), 3.88 (s,
3H), 5.18 (m, 2H), 6.99-7.02 (m, 2H), 7.18-7.22 (m, 3H), 8.10
(s, 1H); 13C NMR (CDCl3, 75 MHz) δ 28.2, 40.3, 50.1, 52.2, 80.2,
127.0, 128.5, 129.2, 133.2, 135.5, 143.8, 154.9, 161.4, 164.7.
Anal. Calcd for C18H22N2O5: C, 62.42; H, 6.40. Found C,
62.18; H, 6.46.
Oxa zole Azid e, 21k . Oxidation was carried out as de-
scribed in the general procedure using 0.020 g (0.089 mmol)
of oxazoline azide, 20k , 0.014 g (0.097 mmol) of Cu(I)Br, 0.018
g (0.097 mmol) of Cu(OAc)2, and 0.026 g (0.013 mmol) of tert-
butyl perbenzoate. Flash chromatography on SiO2 using
hexane/ethyl acetate (70:30) gave 0.011 g (56% yield) of 21k
as a colorless oil.1h [R]25D -32.7 (c 0.74, CHCl3); lit. [R]25D -35.8
(c 0.74, CHCl3); IR (thin film, cm-1) 3330, 2952, 2099, 1653,
1583; 1H NMR (CDCl3, 300 MHz) δ 1.34 (d, J ) 7.05 Hz, 3H),
1.80-1.91 (m, 1H), 2.05-2.17 (m, 1H), 3.10-3.27 (m, 1H), 3.33
(t, J ) 6.78 Hz, 2H), 3.89 (s, 3H), 8.15 (s, 1H); 13C NMR (CDCl3,
75 MHz) δ 18.4, 31.2, 33.7, 49.0, 52.2, 133.1, 143.8, 161.7,
168.1.
D
-29.0 (c 0.5, CHCl3); IR (thin film, cm-1) 3340, 2982, 1720,
1
1153; H NMR (CDCl3, 300 MHz) δ 1.41 (s, 9H), 1.52 (d, J )
6.90 Hz, 3H), 3.89 (s, 3H), 5.19 (d, J ) 6.1 Hz, 1H), 5.21 (br s,
1H), 8.02 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.2, 28.3, 52.2,
128.2, 129.0, 143.9, 161.5. HRMS-FAB (M + H)+, C12H19N2O5,
Calcd 271.1293; Found 271.1289.
Oxa zole, 21l.16 To the oxazoline 20l (0.320 g, 0.80 mmol)
in a 25 mL round bottomed flask were added CuBr (0.126 g,
0.88 mmol) and Cu(OAc)2 (0.160 g, 0.88 mmol). The flask was
evacuated and then filled with argon. The evacuation/argon
addition was repeated two times. Benzene (5 mL) (0.16 M)
was syringed into the flask and stirring initiated. The reaction
was warmed to 60 °C, and tert-butyl perbenzoate (0.233 g, 1.20
mmol) was added gradually over 15 min. The reaction mixture
was then heated to reflux for 7.5 h. After cooling to rt, ethyl
acetate (10 mL) was added. The mixture was then washed
with buffered 10% NH4OH solution to remove all the copper
salts. The aqueous layer was extracted with ethyl acetate (3
× 10 mL). The combined organic extracts were dried over Na2-
SO4, and the crude product obtained after rotary evaporation
was subjected to flash column chromatography over SiO2 using
hexane/ethyl acetate (7:3) to afford the desired oxazole 21l, in
81% yield (0.258 g). IR (thin film, cm-1) 2953, 1750, 1583,
2-[(S)-1-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2-m et h yl-
p r op yl]-4-ca r beth oxyth ia zole, 21i. Oxidation was carried
out as described in the general procedure using 1.00 g (3.03
mmol) of 2-[(S)-1-[N-(tert-butyloxycarbonyl)amino]-2-methyl-
propyl]-4-carbethoxy-(S)-2-thiazoline, 20i, 0.478 g (3.33 mmol)
of Cu(I)Br, 0.603 g (3.33 mmol) of Cu(OAc)2, and 0.884 g (4.55
mmol) of tert-butyl perbenzoate. Flash chromatography on
SiO2 using hexane/ethyl acetate (80:20) gave 0.835 g (84%
1
1369, 1322, 1252, 1109; H NMR (CDCl3, 300 MHz) δ -0.15
(s, 3H), -0.01 (s, 3H), 0.78 (s, 9H), 1.31 (s, 3H), 1.34 (s, 3H),
1.63-1.89 (m, 2H), 3.01 (d, J ) 6.3 Hz, 2H), 3.47 (t, J ) 7.53
Hz, 1H), 3.88 (s, 3H), 4.01-4.06 (dd, J ) 5.91, 7.98 Hz, 1H),
4.18-4.44 (m, 2H), 8.12 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
-4.9, -4.2, 17.8, 25.6, 25.7, 26.9, 35.7, 41.0, 52.1, 68.1, 69.7,
72.2, 108.8, 133.3, 143.7, 161.7, 163.6.
yield) of 21i as a white solid.6c Mp 116-117 °C; [R]23 -39.1
D
(c 2.6, CHCl3); IR (thin film, cm-1) 3345, 2975, 1715, 1500,
1167; 1H NMR (CDCl3, 300 MHz) δ 0.85 (d, J ) 6.84 Hz, 3H),
0.93 (d, J ) 6.78 Hz, 3H), 1.36 (t, J ) 7.11 Hz, 3H), 1.40 (s,
9H), 2.37-2.46 (m, 1H), 4.36 (q, J ) 7.14 Hz, 2H), 4.86 (dd, J
) 5.52, 8.40 Hz, 1H), 5.26 (d, J ) 8.46 Hz, 1H), 8.03 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.3,17.1, 19.3, 28.2, 33.2, 57.9,
61.3, 79.9, 126.7,147.3, 155.3, 161.2, 173.2. Anal. Calcd for
C15H24 N2O4S: C, 54.86; H, 7.37; N, 8.53. Found C, 54.58; H,
7.51; N, 8.49.
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health for support of this study.
Su p p or tin g In for m a tion Ava ila ble: Proton and carbon
spectra, HPLC chiral analyses for all compounds (62 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of this
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
2-[(S)-1-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2-p h en yl-
eth yl]-4-ca r beth oxyth ia zole, 21j. Oxidation was carried out
as described in the general procedure using 0.30 g (0.794
mmol) of 2-[(S)-1-[(tert-butyloxycarbonyl)amino]-2-phenylethyl]-
4-carbethoxy-(S)-2-thiazoline, 20j, 0.126 g (0.873 mmol) of Cu-
(I)Br, 0.158 g (0.873 mmol) of Cu(OAc)2, and 0.200 g (1.032
mmol) of tert-butyl perbenzoate. Flash chromatography on
J O9613491