Convenient preparation of substituted 5-aminooxazoles via a microwave-assisted Cornforth rearrangement

Article abstract of DOI:10.1016/j.tet.2005.12.065

The preparation of oxazole-4-carboxamides and their subsequent thermal rearrangement to 5-aminooxazole-4-carboxylates is optimized in a high-speed microwave-assisted procedure. The reaction sequence is effective with a variety of substituted oxazoles, and produces products in good yield and high purity.

Full text of DOI:10.1016/j.tet.2005.12.065

Tetrahedron 62 (2006) 4698–4704
Convenient preparation of substituted 5-aminooxazoles via
a microwave-assisted Cornforth rearrangement
y
*
M. Brad Nolt, Mark A. Smiley, Sandor L. Varga, Ray T. McClain,
Scott E. Wolkenberg and Craig W. Lindsley
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories,
Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA
Received 1 December 2005; revised 14 December 2005; accepted 16 December 2005
Available online 31 March 2006
Abstract—The preparation of oxazole-4-carboxamides and their subsequent thermal rearrangement to 5-aminooxazole-4-carboxylates is op-
timized in a high-speed microwave-assisted procedure. The reaction sequence is effective with a variety of substituted oxazoles, and produces
products in good yield and high purity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
A number of synthetic routes have been described for the
preparation of 5-aminooxazoles.1–3 While they are adequate
for the generation of individual compounds, the typical pro-
cedures do not lend themselves to the rapid generation of
a large number of diverse products. Although novel, efficient
methodology has been developed, these reactions do not
make use of readily available starting materials and hence,
are not easily applied in a parallel format. A particularly at-
tractive alternative presents itself in the Cornforth rearrange-
ment (Scheme 1). This formal rearrangement occurs upon
The biological activity and therapeutic potential of 5-amino-
oxazole containing structures is demonstrated in the pseudo-
monic acid derived antibiotic 1,1a oxazolo-[5,4-d]pyrimidine
2 an inhibitor of ricin and shiga toxins,1b and peptidomimet-
ics with oxazole-incorporated amino acids 3.1c Additionally,
5-( p-tolyl)urea-oxazole 4 is shown to have invitro activity as
aRafkinaseinhibitorwiththepossibilityofuse asatreatment
for cancers (Fig. 1).1d
ꢁ
heating 5-alkoxyoxazole-4-carboxamides at ꢀ100 C for
17 h and is believed to proceed via an intermediate nitrile
ylide such as 6. Originally discovered by Cornforth during
studies related to penicillin, the reaction was studied in detail
by Dewar3 whose mechanistic and computational work
defined the intermediate as a delocalized zwitterion.4 Inter-
mediate 6 exhibits a psuedo-symmetrical dicarbonyl struc-
ture, which can cyclize either to reform 5 or proceed to 7.
Because the formation of 6 is reversible, the final product
distribution (5:7) is wholly determined by the relative
thermodynamic stabilities of the 5-alkoxy-oxazole-4-car-
boxamide and 5-amino-oxazole-4-carboxylate. Despite its
intriguing mechanism and synthetic potential, the reaction
has received relatively little attention since these pioneering
studies.
O
OH
HO
O
N
O
NH
NH2
N
O
N
N
O
OMe
OH
O
1
2
O
OMe
MeO
H
H
O
N
N
N
Ph
N
O
O
HN
MeO2C
O
4
CbzHN
3
Figure 1. Biologically active 5-aminooxazoles.
R1O
7
CO2R1
5
CONR2R3
OR1
6
O
O
N
N
–
R4
N+
R2
N
R4
R4
O
O
* Corresponding author. Tel.: +1 215 652 1485; fax: +1 215 652 6345;
e-mail: brad_nolt@merck.com
UNCF/Merck undergraduate fellow, 2005–2006.
R3
R3R2N
y
Scheme 1. Cornforth rearrangement.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.065

M. B. Nolt et al. / Tetrahedron 62 (2006) 4698–4704
4699
Based on this precedent, we envisioned a synthesis such as
that shown in Scheme 2.2f Acylation of 2-amino diethyl-
malonate followed by cyclodehydration would afford oxa-
zole 10, which after saponification and amide coupling
would generate the Cornforth substrate 12. Thermal rear-
rangement then produces the 5-amino-oxazole-4-carboxyl-
ate 13.
and temperatures were surveyed. Optimal conditions for the
transformation of 9 to 10 were identified as a 2:1 mixture of
trifluorotoluene/trifluoroacetic anhydride (TFAA) and heat-
ꢁ
ing at 160 C for 10 min. A dramatic reduction in reaction
time was observed (5 min vs 0.5–14 h) and good yields of
the oxazole 10 were obtained (79%). This reaction was suc-
cessfully scaled up from 0.03 g to 3.00 g without reoptimiza-
tion of the microwave conditions. The solvent/substrate
ratio, the duration, and temperature of the microwave heating
was maintained and afforded 2-aryloxazoles in multigram
quantities.
EtO
O
EtO
O
O
O
DIEA
+
O
O
Cl
NH2
N
H
Ph
OEt
OEt
Basic hydrolysis of the cyclization product with 15% aq
potassium hydroxide, heated at 100 C, cleanly gives the
8
9
ꢁ
O
O
carboxylic acid 11.3 Amide bond formation under a variety
of conditions (PS-DCC, HOBt; EDCI, HOBt) was sluggish,
and therefore the recently disclosed microwave procedure
using polymer bound carbodiimide was employed.8 PS-
carbodiimide amide coupling was accelerated by microwave
OEt
OEt
OH
KOH aq.
100°C
TFAA
µw
N
N
Ph
Ph
OEt
O
O
11
10
1) R1R2NH
2) PS-DCC
3) HOBt
O
ꢁ
O
heating (100 C, 10 min) and after filtration of the solid-
180°C
µw
OEt
NHR1R2
OEt
phase reagent(s), the 5-ethoxy-2-phenyloxazolamides 12
wereꢁ obtained in excellent yields. Although formed at
100 C, these amides had clearly not undergone a Cornforth
rearrangement (1H NMR, see below). Excess HOBt can be
removed from the products prior to the rearrangement step
by treatment with MP-carbonate. However, we observed
that the presence of HOBt does not alter the success of the
rearrangement step and it is likely that the reagent is ther-
mally decomposed to volatile and gaseous byproducts
when targeted rearrangement temperatures are reached.9
N
N
µw
Ph
NR1R2
Ph
O
O
12
13
Scheme 2. General synthesis of 5-amino-oxazole-4-carboxylates.
This route enables the incorporation of diverse substituents
at all positions of the oxazole and importantly does so via
the use of readily available carboxylic acid chloride and
amine building blocks. This affords the opportunity to
generate fully substituted oxazoles with a diverse array of
functionality.
Cornforth rearrangement products were produced by heating
5-alkoxy-oxazole-4-carboxamides 12 using microwave irra-
diation (Table 1). The reaction requires temperatures
A secondary goal was to generate these structures rapidly
and therefore microwave-assisted conditions were investi-
gated. Microwave-assisted organic synthesis (MAOS) has
been widely utilized recently as it is typically associated
with dramatic reductions in reaction times, a diminution in
side product formation, and increased yields.5
ꢁ
>170 C for complete conversion to the thermodynamically
more stable products 13. As can be seen in Table 1, small
changes in temperature have a large impact on conversion
at these short reaction times. While excellent conversions
(by LC–MS) were realized in acetonitrile and trifluoro-
toluene, isolated yields were much higher in trifluoro-
ꢁ
toluene. Optimized microwave heating at 180 C for 5 min
in trifluorotoluene gave compounds in 23–99% yield and
of purity greater than 93% by H NMR (Table 2); entry 11
In this paper we describe the microwave-assisted formation
ofseveral5-aminooxazolecompoundsandapplythismethod-
ology to the formal synthesis of a biologically active target
(Fig. 1), 4-(methoxycarbonyl)-2-(1-normon-2-yl)-5-piperi-
din-1-yloxazole (1).1a
1
required chromatographic purification to obtain product
13k. A range of functional groups are tolerated in the reac-
tion including acetals, thioethers, sulfonamides, and Boc-
protected amines. Primary and secondary amines perform
equally well in the amide formation rearrangement se-
quence.
2. Results and discussion
Preparation of rearrangement substrate 12 proceeded with
straightforward acylation of 2-amino diethylmalonate
(DIEA, benzoyl chloride, 94%). Cyclodehydration to form
oxazoles has been performed using a number of dehydrating
reagents under thermal conditions. For example, the genera-
tion of 5-amino-oxazole-4-carboxylates from 2-amidomalo-
nates has been reported, in only moderate yield, using
1 equiv PCl5 in toluene and heating for 30 min to 14 h at re-
flux.2f,6 Other reagents such as triphenylphosphine/iodine or
trichloroacetyl chloride, in conjunction with conventional
heating, have been used as well.1a,7
Three characteristic observations allowed us to distinguish
the starting materials from products in the final step of
the synthesis. First, HPLC retention times differed for
Table 1. Cornforth rearrangement temperature optimization study
Entry Solvent
Rearrangement conditions Product/starting
materiala
1
2
3
4
5
Acetonitrile
150 ꢁC, 10 min
160 ꢁC, 10 min
170 ꢁC, 10 min
180 ꢁC, 10 min
180 ꢁC, 5 min
1:99
31:69
42:58
99:1
Acetonitrile
Acetonitrile
Acetonitrile
PhCF3
99:1
In an effort to accelerate the cyclodehydration step a range of
solvents, dehydrating reagents, microwave irradiation times,
a
Determined by UV HPLC.

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M. B. Nolt et al. / Tetrahedron 62 (2006) 4698–4704
Table 2. Microwave-assisted amide formation and Cornforth rearrangement
Entry
1
Amine
NH
Coupling conditions
100 ꢁC, 5 min
Product
Rearrangement conditions
180 ꢁC, 5 min.
Yield (%)
76
13a
100 ꢁC, 5 min
13b
13c
180 ꢁC, 5 min
180 ꢁC, 5 min
98
47
NH
2
3
F
100 ꢁC, 5 min, PS-DIEA (1 equiv)
NH HCl
NH2
4
100 ꢁC, 5 min
(ꢂ)-13d
180 ꢁC, 5 min
99
NH
5
6
100 ꢁC, 5 min
100 ꢁC, 5 min
13e
13f
180 ꢁC, 5 min
180 ꢁC, 5 min
99
23
N
O
O
H2N
S
100 ꢁC, 5 min, PS-DIEA (1 equiv)
100 ꢁC, 5 min, PS-DIEA (1 equiv)
13g
180 ꢁC, 5 min
180 ꢁC, 5 min
51
76
HCl
H2N
7
8
O
H2N
132h
HCl
O
5
H
N
9
100 ꢁC, 5 min
13i
180 ꢁC, 5 min
85
O
S
H2N
O
10
11
100 ꢁC, 5 min
100 ꢁC, 5 min
13j
180 ꢁC, 5 min
180 ꢁC, 5 min
19
99
NH2
H2N
NHBoc
13k
5
N
H2N
12
13
100 ꢁC, 5 min, PS-DIEA (2 equiv)
13l
180 ꢁC, 5 min
23a
2HCl
N
H2N
N
100 ꢁC, 5 min
100 ꢁC, 5 min
13m
13n
180 ꢁC, 5 min
180 ꢁC, 5 min
82
97
14
H2N
a
After flash chromatography.
MeO
O
O
compounds 12 and 13. Second, HMBC NMR studies of
compound 12b and its Cornforth product 13b showed a
partial carbonyl shielding effect on the 2- and 5-position
methylene protons of the pyrrolidine amide. This with a
change in carbon shifts for the ethyl group in both molecules
suggested that the rearrangement had successfully occurred.
And third, the diisobutyl aluminohydride reduction of 13e to
the corresponding alcohol 14 unequivocally confirmed the
rearrangement of 12e (Fig. 2).
MeO
O
O
O
+
OBn
O
OBn
Cl
NH2
N
H
OMe
OMe
15
O
O
OMe
OMe
OH
KOH aq.
80°C
CCl3COCl
µw
N
N
OMe
O
O
OBn
OBn
16
17
The formal synthesis of 1 began with N-acylation of 2-
amino-dimethylmalonate to form the amide 15 (Scheme 3).
1) piperidine
2) PS-DCC
3) HOBt
O
O
OMe
180°C
µw
N
N
N
µw
OH
N
N
O
OMe
O
OBn
OBn
Ph
N
O
19
18
N
14
Scheme 3. Formal synthesis of 4-(methoxycarbonyl)-2-(1-normon-2-yl)-
5-piperidin-1-yloxazole (1).
Figure 2. (5-(4-Methylpiperazin-1-yl)-2-phenyloxazol-4-yl)methanol.

M. B. Nolt et al. / Tetrahedron 62 (2006) 4698–4704
4701
The established cyclodehydration procedure was then ap-
plied, however microwave heating at 160 C for 10 min
with 10% aq H2SO4 until a pH of around three was obtained.
The resulting suspension was filtered and the solid was col-
lected and dried in vacuo to give 0.424 g (48%) of pure
product. 1H NMR (300 MHz, CDCl3) d 7.954–7.97 (m,
2H), 7.45–7.47 (m, 3H), 4.68 (q, J¼7.2 Hz, 2H), 1.56
(t, J¼7.2 Hz); 13C NMR (125 MHz, CDCl3) d 165.3,
161.9, 151.1, 130.6, 128.8, 126.2, 126.0, 107.4, 70.4, 15.0.
HRMS calcd for C12H12NO4 (M+H) 234.0761, found
234.0774.
ꢁ
with TFAA resulted only in 50% conversion (1H NMR) of
the starꢁting material to oxazole 16. Increased temperatures
(ꢀ160 C) caused noticeable decomposition and did little
to facilitate the conversion to the oxazole. Longer heating
times were also unsuccessful. After trying several dehydrat-
ing reagents, it was discovered that trichloroacetyl chloride
provided an improved product ratio and virtually no degre-
dation was observed. While increased heating times and
temperatures did not give the desired product, five succes-
4.3. General procedure for the preparation of
compounds 12a–m
ꢁ
sive heat cycles at 160 C for 20 min resulted in 97% con-
version (1H NMR) to the cyclodehydration product.10
In a 2–5 mL microwave vial with stir bar was placed
5-ethoxy-2-phenyloxazole-4-carboxylic acid (11) 0.028 g,
(0.12 mmol), PS-DCC (0.093 g, 0.12 mmol), HOBt
(0.016 g, 0.12 mmol), and amine (0.12 mmol) in trifluoro-
Hydrolysis of the oxzaoꢁle-4-carboxylate 17 was accom-
plished by heating at 80 C for 15 min in KOH (15% aq).
Amide formation, and the thermal rearrangement were
then conducted under the usual conditions to give the benzyl
protected compound 19. Hydrogenation to deprotect the
2-hydroxymethyl oxazole, followed by halogenation and
phosphorylation would prepare the right-hand piece for con-
nection with the ozonolyzed psuedomonic acid substrate.11
ꢁ
toluene (3 mL). The vial was sealed and heated at 100 C
for 5 min using the microwave. The desired temperature
was reached in approximately 30 s at 300 W power. The
reaction mixture was filtered to remove the solid-phase re-
agents and the resin was rinsed with an additional milliliter
of trifluorotoluene. The filtered solution was then trans-
ferred to a clean 2–5 mL microwave vial and used directly
in the next step of the synthesis.
3. Conclusion
The incorporation of microwave heating dramatically de-
creases the time required for the polymer-assisted formation
of 5-alkoxyoxazole-4-carboxamides and their subsequent
rearrangement to 5-aminooxazoles. A range of 5-aminooxa-
zoles can be obtained using the methodology we describe.
To further illustrate the utility of our synthetic procedure,
we have successfully carried out a formal synthesis of
4-(methoxycarbonyl)-2-(1-normon-2-yl)-5-piperidin-1-yloxa-
zole (1).
4.4. General procedure for the preparation of
compounds 13a–m
ꢁ
The crude products 12 were heated at 180 C in the micro-
wave for 5 min. The desired temperature was reached in
approximately 2 min at 300 W power. Removal of the tri-
fluorotoluene solvent under reduced pressure left products
that were ꢀ93% pure by 1H NMR analysis.
4.4.1. Ethyl 2-phenyl-5-(piperidin-1-yl)oxazole-4-car-
boxylate (13a). Purified by silica gel flash chromatography
(n-hexanes/EtOAc, 3–10% gradient over 20 min). 1H NMR
(400 MHz, CDCl3) d 7.94–7.95 (m, 2H), 7.36–7.42 (m, 3H),
4.38 (q, J¼14, 7.2 Hz, 2H), 3.63–3.64 (m, 4H), 1.70–1.74
(m, 6H), 1.41 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 162.8, 160.0, 150.7, 129.9, 128.7, 127.1, 126.0,
108.1, 60.6, 49.8, 25.8, 24.3, 14.8. HRMS calcd for
C17H21N2O3 (M+H) 301.1547, found 301.1550.
4. Experimental
4.1. Ethyl-5-ethoxy-2-phenyloxazole-4-carboxylate (10)
In a 10–20 mL microwave vial (Biotage) with stir bar was
placed diethyl-2-(benzamido)malonate (3.0 g, 10.7 mmol)
and trifluoroacetic anhydride (5.0 mL, 40.7 mmol) in tri-
fluorꢁotoluene (10 mL). The vial was sealed and heated at
160 C for 10 min in the microwave (Biotage Emrys Opti-
mizer). The desired temperature was reached in approxi-
mately 1 min at 300 W power. The crude material was
concentrated and purified by flash chromatography (0–
25% EtOAc/n-hexanes) to give 2.2 g (79%) of 10. 1H
NMR (300 MHz, CDCl3) d 7.97–8.00 (m, 2H), 7.43–7.46
(m, 3H), 4.60 (q, J¼6.9 Hz, 2H), 4.41 (q, J¼7.2 Hz, 2H),
1.54 (t, J¼7.2 Hz, 3H), 1.40 (t, J¼6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 161.9, 161.6, 151.3, 130.6, 128.9,
126.8, 126.2, 108.9, 70.3, 61.0, 15.2, 14.7. HRMS calcd
for C14H16NO4 (M+H) 262.1074, found 262.1079.
4.4.2. Ethyl 2-phenyl-5-(pyrrolidin-1-yl)oxazole-4-car-
boxylate (13b). H NMR (400 MHz, CDCl3) d 7.91–7.94
1
(m, 2H), 7.34–7.43 (m, 3H), 4.35 (q, J¼14, 6.8 Hz, 2H),
3.75–3.79 (m, 2H), 1.98–2.04 (m, 2H), 1.40 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 163.0, 158.1, 149.9,
129.6, 128.7, 127.2, 125.8, 60.3, 50.2, 25.7, 14.8. HRMS
calcd for C16H19N2O3 (M+H) 287.1390, found 287.1377.
4.4.3. Ethyl 5-(3-fluoropyrrolidin-1-yl)-2-phenyloxazole-
4-carboxylate (13c). H NMR (300 MHz, CDCl3) d 7.93–
1
7.96 (m, 2H), 7.39–7.45 (m, 3H), 5.36 (d, J¼52.8 Hz, 1H),
4.37 (q, J¼6.9 Hz, 2H), 3.88–4.20 (m, 5H), 2.34–2.46 (m,
1H), 2.01–2.28 (m, 1H), 1.42 (t, J¼6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 162.7, 157.5, 150.2, 129.7, 128.6,
126.8, 125.7, 106.3, 92.3 (d, J¼176.6 Hz), 60.3, 56.7
(d, J¼23.0), 47.4, 32.1 (d, J¼21.2), 14.6. HRMS calcd
for C16H18FN2O3 (M+H) 305.1296, found 305.1285.
4.2. 5-Ethoxy-2-phenyloxazole-4-carboxylic acid (11)
To ethyl 5-ethoxy-2-phenyloxazole-4-carboxylate (1.0 g,
3.83 mmol) was added a solution of 15% aq KOH
ꢁ
in an oil bath for 30 min then cooled to 0 C and acidified
(2.15 mL, 5.75 mmol). The reaction was heated at 100 C
ꢁ

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M. B. Nolt et al. / Tetrahedron 62 (2006) 4698–4704
4.4.4. ( )-Ethyl 5-(2,3-dihydro-1H-inden-1-ylamino)-
2-phenyloxazole-4-carboxylate (13d). 1H NMR (400 MHz,
CDCl3) d 7.94–7.97 (m, 2H), 7.22–7.44 (m, 7H), 6.55
(d, J¼8.4 Hz, 1H), 5.38 (q, J¼15.6, 7.6 Hz, 1H), 4.37
(q, J¼14.4, 7.2 Hz, 2H), 3.07–3.14 (m, 1H), 2.91–2.99
(m, 1H), 2.68–2.77 (m, 1H), 2.02–2.11 (m, 1H), 1.39
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 164.3,
160.3, 150.4, 143.3, 142.4, 129.9, 128.9, 128.7, 127.2,
127.1, 125.9, 125.2, 124.2, 60.4, 59.0, 34.8, 30.4, 14.9.
HRMS calcd for C21H21N2O3 (M+H) 349.1547, found
349.1539.
HRMS calcd for C21H21N2O3 (M+H) 349.1547, found
349.1544.
4.4.10. Ethyl 5-({2-[4-(aminosulfonyl)phenyl]ethyl}-
amino)-2-phenyl-1,3-oxazole-4-carboxylate (13j). 1H
NMR (300 MHz, (CD3)2SO) d 7.72–7.73 (m, 4H), 7.43–
7.50 (m, 5H), 7.26 (s, 2H), 4.20 (q, J¼6.9 Hz, 2H), 3.67
(br s, 2H), 3.01 (t, J¼6.6 Hz, 2H), 1.25 (t, J¼6.9 Hz, 3H);
13C NMR (100 MHz, (CD3)2SO) d 163.1, 160.5, 149.2,
143.8, 142.9, 130.2, 129.9, 129.7, 127.2, 126.4, 125.6,
103.8, 59.7, 44.4, 36.1, 15.3. HRMS calcd for
C20H22N3O5S (M+H) 416.1275, found 416.1271.
4.4.5. Ethyl 5-(4-methylpiperazin-1-yl)-2-phenyloxazole-
4-carboxylate (13e). H NMR (400 MHz, CDCl3) d 7.93–
1
4.4.11. tert-Butyl 3-(4-(ethoxycarbonyl)-2-phenyloxazol-
5-ylamino)propylcarbamate (13k). H NMR (400 MHz,
1
7.96 (m, 2H), 7.40–7.43 (m, 3H), 4.38 (q, J¼14.4, 7.2 Hz,
2H), 3.77 (t, J¼4.8 Hz, 4H), 2.65 (t, J¼4.8 Hz, 4H), 2.40
(s, 3H), 1.41 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 162.8, 159.4, 151.2, 130.1, 128.8, 126.9, 126.1,
108.9, 60.8, 54.6, 48.1, 46.1, 14.8. HRMS calcd for
C17H22N3O3 (M+H) 316.1656, found 316.1647.
CDCl3) d 7.93–7.99 (m, 2H), 7.36–7.43 (m, 3H), 6.60 (s,
1H), 4.66 (s, 1H), 4.39 (q, J¼6.8 Hz, 2H), 3.55 (q, J¼6.8,
2H), 3.27 (q, J¼6.4 Hz, 2H), 1.86 (apparent quintet,
J¼6.6, 2H), 1.46 (s, 9H), 1.41 (t, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 164.0, 160.4, 156.3, 150.0,
129.6, 128.6, 126.9, 125.6, 104.5, 60.2, 40.5, 37.6, 30.9,
28.4, 14.7. HRMS calcd for C20H28N3O5 (M+H)
390.2024, found 390.2023.
4.4.6. Ethyl 5-(2-(1,3-dioxolan-2-yl)ethylamino)-2-phe-
nyloxazole-4-carboxylate (13f). 1H NMR (400 MHz,
CDCl3) d 7.93–7.96 (m, 2H), 7.36–7.44 (m, 3H), 6.75–
6.79 (m, 1H), 5.05 (t, J¼4.2 Hz, 1H), 4.38 (q, J¼7.2 Hz,
2H), 3.99–4.07 (m, 2H), 3.88–3.96 (m, 2H), 3.67 (q,
J¼6.3 Hz, 2H), 2.07–2.13 (m, 2H), 1.39 (t, J¼7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 164.1, 160.4, 150.2, 129.7,
128.8, 127.1, 125.8, 103.2, 65.3, 60.3, 38.5, 33.2, 14.8.
HRMS calcd for C17H21N2O5 (M+H) 333.1445, found
333.1439.
4.4.12. Ethyl 5-((pyrimidin-4-yl)methylamino)-2-phenyl-
oxazole-4-carboxylate (13l). H NMR (300 MHz, CDCl3)
1
d 9.23–9.24 (m, 1H), 8.74 (d, J¼5.4 Hz, 1H), 7.88–7.91
(m, 2H), 7.38–7.44 (m, 4H), 7.23–7.27 (m, 1H), 4.81 (d,
J¼5.7 Hz, 2H), 4.43 (q, J¼7.2 Hz, 2H), 1.44 (t, J¼6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 165.1, 164.1, 159.9,
159.0, 157.7, 150.8, 130.0, 128.9, 126.8, 125.9, 118.6,
105.7, 60.7, 47.4, 14.8. HRMS calcd for C17H17N4O3
(M+H) 325.1222, found 325.1294.
4.4.7. Ethyl 5-(2-(tert-butylthio)ethylamino)-2-phenyl-
oxazole-4-carboxylate (13g). 1H NMR (300 MHz, CDCl3)
d 7.93–7.96 (m, 2H), 7.36–7.44 (m, 3H), 6.60 (t, J¼5.6 Hz,
1H), 4.39 (q, J¼14.4, 7.2 Hz, 2H), 3.68 (q, J¼13.6, 6.8 Hz,
2H), 2.84 (t, J¼7.2 Hz, 2H), 1.41 (t, J¼7.2, 3H), 1.36
(s, 9H); 13C NMR (125 MHz, CDCl3) d 164.0, 160.1,
150.2, 129.7, 128.6, 126.8, 125.6, 104.8, 76.8, 60.3,
43.4, 42.73, 42.72, 31.1, 28.3, 14.7. HRMS calcd for
C18H25N2O3S (M+H) 349.1581, found 349.1577.
4.4.13. Ethyl 5-((pyridin-3-yl)methylamino)-2-phenyl-
oxazole-4-carboxylate (13m). 1H NMR (400 MHz,
CDCl3) d 8.68 (s, 1H), 8.58–8.59 (m, 1H), 7.89–7.92
(m, 2H), 7.71–7.74 (m, 1H), 7.39–7.41 (m, 3H), 7.31–7.34
(m, 1H), 6.72–6.75 (m, 1H), 4.69 (d, J¼6.4 Hz, 2H), 4.39
(q, J¼7.2 Hz, 2H), 1.41 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 164.3, 160.2, 150.7, 149.7, 149.3,
135.3, 133.3, 130.0, 128.9, 126.8, 128.9, 124.0, 105.4,
76.9, 60.6, 45.0, 14.8. HRMS calcd for C18H18N3O3
(M+H) 324.1343, found 324.1332.
4.4.8. Ethyl 5-(5-(methoxycarbonyl)pentylamino)-2-phe-
nyloxazole-4-carboxylate (13h). 1H NMR (400 MHz,
CDCl3) d 7.92–7.95 (m, 2H), 7.36–7.44 (m, 3), 6.34 (s,
1H), 4.38 (q, J¼14.4, 7.2 Hz, 2H), 3.67 (s, 3H), 3.50 (q,
J¼6.4 Hz, 2H), 2.35 (t, J¼7.6 Hz, 2H), 1.67–1.76 (m, 4H),
1.44–1.50 (m, 2H), 1.41 (t, J¼8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 174.1, 160.9, 150.2, 129.8, 128.8,
127.1, 125.8, 104.6, 76.9, 60.4, 51.7, 43.2, 34.0, 30.0,
26.4, 24.7, 14.9. HRMS calcd for C19H25N2O5 (M+H)
361.1758, found 361.1750.
4.4.14. Ethyl 5-(cyclopropylamino)-2-phenyloxazole-
4-carboxylate (13n). H NMR (400 MHz, CDCl3) d 7.97–
1
7.99 (m, 2H), 7.37–7.45 (m, 3H), 6.50 (s, 1H), 4.37 (q,
J¼7.2 Hz, 2H), 2.81–2.87 (m, 1H), 1.41 (t, J¼3.6 Hz, 3H),
0.87–0.91 (m, 2H), 0.73–0.77 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 164.3, 161.5, 150.8, 129.8, 128.9,
128.8, 127.1, 125.9, 60.5, 24.6, 14.9, 7.4. HRMS calcd for
C15H17N2O3 (M+H) 295.1053, found 295.1052.
4.4.9. Ethyl 5-(3,4-dihydroquinolin-1(2H )-yl)-2-phenyl-
oxazole-4-carboxylate (13i). H NMR (400 MHz, CDCl3)
4.4.15. (5-(4-Methylpiperazin-1-yl)-2-phenyloxazol-4-
yl)methanol (14). In a clean, dry 40 mL sample vial was
placed ethyl 5-(4-methylpiperazin-1-yl)-2-phenyloxazole-
4-carboxylate (0.089 g, 0.28 mmol) in dry dichloromethane
1
d 7.94–7.97 (m, 2H), 7.22–7.44 (m, 7H), 6.55 (d,
J¼8.4 Hz, 1H), 5.38 (q, J¼15.6, 7.6 Hz, 1H), 4.37 (q,
J¼14.4, 7.2 Hz, 2H), 3.07–3.14 (m, 1H), 2.91–2.99 (m,
1H), 2.68–2.77 (m, 1H), 2.02–2.11 (m, 1H), 1.39 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 164.3,
160.3, 150.4, 143.3, 142.4, 129.9, 128.9, 128.7, 127.2,
127.1, 125.9, 125.2, 124.2, 60.4, 59.0, 34.8, 30.4, 14.9.
ꢁ
under N2. The stirred solution was cooled to ꢃ78 C and
Dibal-H (0.84 mL, 0.84 mmol) was added via syringe. After
10 min, the reaction was complete by LC–MS and quenched
with H2O. After warming to rt the crude reaction mixture
was filtered through packed Celite and extracted with EtOAc

M. B. Nolt et al. / Tetrahedron 62 (2006) 4698–4704
4703
ꢁ
(3ꢄ10 mL). Purification by flash chromatography (5–
was sealed and heated at 100 C for 5 min in the microwave.
The desired temperature was reached in approximately 30 s
at 300 W power. Filtration and removal of the solid-phase
1
10% MeOH/DCM) gave 0.070 g (91%) of 14. H NMR
(300 MHz, CDCl3) d 7.89–7.92 (m, 2H), 7.37–7.44 (m,
3H), 4.62 (s, 2H), 3.31 (t, J¼4.8 Hz, 2H), 2.55 (t,
J¼4.8 Hz), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 154.8, 129.8, 128.9, 127.8, 127.3, 125.7, 122.4, 57.1,
54.9, 50.1, 46.5. HRMS calcd for C15H20N3O2 (M+H)
274.1550, found 274.1541.
1
reagent gave the crude product 18. H NMR (300 MHz,
CDCl3) d 7.29–7.36 (m, 5H), 4.60 (s, 2H), 4.47 (s, 2H),
4.07 (s, 3H), 3.59–3.75 (m, 4H), 1.55–1.69 (m, 5H); 13C
NMR d 161.5, 149.2, 137.3, 128.7, 128.23, 128.21, 73.0,
64.1, 60.0, 24.9. HRMS calcd for C18H23N2O4 (M+H)
331.1658, found 331.1658.
4.4.16. Dimethyl 2-(2-(benzyloxy)acetamido)malonate
(15). To a stirred suspension of 2-amino-dimethylmalonate
hydrochloride (1.0 g, 5.45 mmol) in dichloromethane
(20 mL) was added diisopropylethylamine (1.8 mL,
10.9 mmol) and the reaction was stirred at rt for 10 min.
To the resulting clear slightly yellow solution was added
benzoylacetoxychloride (0.87 mL, 5.45 mmol) and the reac-
tion was stirred at rt for 15 min. The mixture was diluted
with dichloromethane, washed with 1 N HCl then satd aq
NaHCO3. The aqueous layer was extracted with dichloro-
methane (2ꢄ10 mL), the organic extracts were washed with
brine and dried over Na2SO4. Filtration and removal of sol-
vent under reduced pressure gave 1.56 g (97%) of a white
4.4.20. Methyl 2-((benzyloxy)methyl)-5-(piperidin-1-
yl)oxazole-4-carboxylate (19). In a 0.5–2 mL microwave
vial with spin vane was placed 18 (0.030 g, 0.09 mmol)ꢁin
PhCF3 (2 mL). The vial was sealed and heated at 180 C
for 5 min. The desired temperature was reached in approxi-
mately 2 min at 300 W power. The contents were concen-
trated and dried under reduced pressure to give 0.030 g
(99%) of analytically pure 19. 1H NMR (400 MHz, CDCl3)
d 7.28–7.34 (m, 5H), 4.58 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H),
3.57–3.61 (m, 4H), 1.66–1.71 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 163.0, 160.5, 149.3, 137.5, 128.6, 128.13, 128.12,
73.0, 64.2, 51.7, 49.5, 25.8, 24.2. HRMS calcd for
C18H23N2O4 (M+H) 331.1653, found 331.1656.
1
solid. H NMR (300 MHz, CDCl3) d 7.48–7.64 (m, 1H),
7.30–7.41 (m, 4H), 5.27 (d, J¼7.2 Hz, 1H), 4.63 (s, 2H),
4.04 (s, 2H), 3.83 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 169.8, 166.7, 136.8, 128.8, 128.5, 128.2, 73.9, 69.3,
55.6, 53.7. HRMS calcd for C14H18NO6 (M+H) 296.1129,
found 296.1126.
Acknowledgments
We are grateful to Joan S. Murphy, Vincent van Nostrand,
and Charles W. Ross, III for their assistance with HRMS
analyses.
4.4.17. Methyl 2-((benzyloxy)methyl)-5-methoxyoxazole-
4-carboxylate (16). In a 2–5 mL microwave vial with stir
bar were placed dimethyl 2-(2-(benzyloxy)acetamido)malo-
nate (15) (0.020 g, 0.07 mmol), trichloroacetyl chloride
(1 mL)ꢁ, and trifluorotoluene (3 mL). The vial was heated
at 160 C for 20 min then cooled to rt, and this heating cycle
was repeated five times. The desired temperature was
reached in approximately 1 min at 300 W power. Flash chro-
matography of the concentrated crude product (30–60%
References and notes
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EtOAc/n-hexanes) yielded 0.170 g (31%) of 16. H NMR
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