Expeditious microwave-assisted synthesis of 5-alkoxyoxazoles from α-triflyloxy esters and nitriles

Article abstract of DOI:10.1021/jo301527t

A rapid and general access to diversely substituted 5-alkoxyoxazoles 2 (i.e., R¹, R² = alkyl, phenyl) from easily accessible α-triflyloxy/hydroxy esters 1 and nitriles with good yields (41-76%) is reported. The versatility of the cyc

Full text of DOI:10.1021/jo301527t

Article
pubs.acs.org/joc
Expeditious Microwave-Assisted Synthesis of 5‑Alkoxyoxazoles from
α‑Triflyloxy Esters and Nitriles
Laurie-Anne Jouanno,†,‡,§ Cyrille Sabot,†,‡,§ and Pierre-Yves Renard*,†,‡,§
†Laboratory COBRA UMR 6014 & FR 3038, IRCOF, Universite
‡INSA de Rouen, Avenue de l’Universite,
76800 St Etienne du Rouvray, France
§CNRS Del
egation Normandie, 14 Rue Alfred Kastler, 14052 Caen Cedex, France
́ ̀
de Rouen, 1 Rue Tesniere, 76821 Mont St Aignan Cedex, France
́
́
́
S
* Supporting Information
ABSTRACT: A rapid and general access to diversely
substituted 5-alkoxyoxazoles 2 (i.e., R1, R2 = alkyl, phenyl)
from easily accessible α-triflyloxy/hydroxy esters 1 and nitriles
with good yields (41−76%) is reported. The versatility of the
cyclization is shown for a range of substrates with high
selectivity toward triflates over mesylates and proved to be
compatible with sensitive functional groups. As an illustration
of this transformation, the first synthesis of the recently isolated hydroxypyridine methyl multijuguinate 4 was achieved in four
steps through a hetero Diels−Alder reaction of the 5-alkoxyoxazole and acrylic acid, followed by a protodecarboxylation reaction.
Although several methods of preparation of 5-alkyloxazoles
exist,6 few strategies for the formation of their 5-alkoxy
derivatives are reported in the literature. Indeed, electron-rich
oxazoles such as 5-alkoxyoxazoles are usually more sensitive to
both acidic and thermal conditions rendering their formation/
isolation often difficult. They are traditionally generated by
cyclodehydration of 2-acylamino acid esters, with reaction times
varying from one to several hours, depending of the substrate
considered.7 Recent methods include metal-catalyzed decom-
position of α-diazo esters in the presence of nitriles,8 acylation
of isocyano esters,9 and the Ritter reaction of α-oxo tosylates
with nitriles.10,11 However, number of these methods require
specific groups at the C-4 position of the heterocycle such as a
silyle,8b an aromatic,10 or an electron-withdrawing group.8a As
part of our ongoing research on the 3-hydroxypyridine ring
synthesis,3e we were interested in developing a rapid and
versatile access to diversely substituted 5-alkoxyoxazole
derivatives at both C-2 and C-4 positions. Since long reaction
time, scope limitation may be a restriction of these methods, we
wish to report an efficient and general access to both 4-alkyl/
phenyl-5-alkoxyoxazoles from the corresponding α-triflyloxy or
α-hydroxy esters and nitriles. Application of these intermediates
in the first synthesis of the recently isolated methyl multi-
juguinate from the leaves of Senna multijuga is described.
INTRODUCTION
■
5-Alkoxyoxazoles are an important class of heterocycles that are
key intermediates in the synthesis of natural compounds1 and
aldol partners in the asymmetric preparation of α-amino-β-
hydroxy acid derivatives (Scheme 1, eq 1).2 5-Alkoxyoxazoles
Scheme 1. Reactions Involving 5-Alkoxyoxazoles as Key
Precursors
RESULTS AND DISCUSSION
■
Our attention focused on a strategy recently developed by
Taylor, based on a Ritter reaction of α-oxo tosylates with
nitriles to generate 4-aromatic substituted oxazole derivatives.10
Indeed, the easy access to both starting materials renders this
process very convenient and attractive. However, our efforts to
have also proven to be valuable heterodienes in both pyridine3
and furan4 frameworks construction via the Diels−Alder
strategy involving electron deficient alkenes and alkynes
respectively (Scheme 1, eqs 2 and 3). Recently, functionalized
amino alcohol derivatives were readily accessed from 5-
alkoxyoxazoles (Scheme 1, eq 4).5
Received: July 19, 2012
Published: September 12, 2012
© 2012 American Chemical Society
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extend this strategy to the synthesis of 4-aliphatic-5-
alkoxyoxazoles using the reported reaction conditions (TMS-
OTf, DCE, 80 °C, 20 h), using for instance the ethyl O-[(p-
methylphenyl)sulfonyl]-2-hydroxypropanoate 1a as a substrate
to screen optimized conditions, failed (Table 1, entry 1). No
trace of the desired product 2a was observed. The substrate was
recovered unchanged.
dimethylfuranone 2f in 85% yield via a 1,2-methyl shift, through
a plausible reaction scenario depicted in Scheme 2.12
Scheme 2. Possible Reaction Mechanism To Form 2f
Table 1. Optimization of the Reaction Conditions for 5-
Alkoxyoxazoles Synthesis
a
entry substrate (X)
reaction conditions
yield (%)
0
Finally, 4-phenyl-5-alkoxyoxazoles 2g−i were directly
obtained from their corresponding α-hydroxy esters 1i−k in
good yields (58−76%, entries 7−9), probably due to facile
formation of the highly reactive α-oxo carbocation species.13 In
this case, 1.75 equiv of TMS-OTf was required to complete the
reaction, probably due to a side reaction between the oxazole
and the Lewis acid used in the reaction. Nevertheless, in the
presence of the α-triflyloxy esters, the triflic acid generated in
the course of the reaction would be trapped by the oxazoles
formed instead of the TMS-OTf that could be used in a
catalytic amount.
1
2
3
4
1a (OTs)
1a (OTs)
1b (I)
TMSOTf (2.5 equiv) CH3CN/DCE,
80 °C, 20 h
TMSOTf (1.75 equiv) CH3CN, MW,
120 °C, 3 min
TMSOTf (1.75 equiv) CH3CN, MW,
120 °C, 3 min
TMSOTf (0.1 equiv) CH3CN, MW,
120 °C, 3 min
0
0
1c (OTf)
63
a
Isolated yield.
Moreover, the reaction performed in acetonitrile at higher
Next, the scope of the reaction was examined with various
volatile and nonvolatile nitriles, and the results are summarized
in Table 3. The amount of nitrile required for the reaction was
reduced to 5 equiv, allowing their facile chromatographic
purification, without noticeable loss in yields. Aliphatic nitriles
afforded oxazole derivatives 2j−m in 50−64% yields. The bulky
trimethylacetonitrile gave the corresponding oxazole 2n in 46%
yield. The reaction proved to be compatible with an aromatic
nitrile such as benzonitrile affording 2o in 60% yield. Pleasingly,
nitriles bearing functional groups such as esters or sensitive
alkyl chlorides, led to formation of oxazoles 2p−r in acceptable
yields (41−61%).
With these results in hand, we next evaluated the possibility
of using this strategy to prepare naturally occurring methyl
multijuguinate 4. This 3-hydroxypyridine alkaloid displays a
moderate AChE inhibitory activity, was very recently isolated
from the leaves of Senna multijuga with an extraction yield of
0.001%.14 An alternative synthetic route to prepare this
compound would be beneficial to further explore the biological
activities of other analogs.
temperature under microwave conditions (i.e., 120 °C, 3 min)
did not provide the desired 2,2-dimethyl-5-ethoxyoxazole 2a
(entry 2). Thus, attempts to run the reaction with the iodo
derivative 1b, bearing a better leaving group than compound
1a, also proved unsuccessful (entry 3). The expected oxazole
product 2a was not observed, and the substrate was recovered
unchanged. Pleasingly, the α-triflyloxy ester derivative 1c was
found to be a suitable substrate, under microwave conditions
(10 mol % TMS-OTf, 120 °C, 3 min), affording the 2,4-
dimethyl-5-ethoxyoxazole 2a in satisfying 63% isolated yield
(entry 4). This encouraging result demonstrated that a poorly
nucleophilic species such as acetonitrile was able to react with
aliphatic triflate. Indeed, the presence of cation-stabilizing
substituents in α-position of the leaving group was no longer a
requisite for this reaction, as recently reported.10 These new
conditions considerably widen the scope of this chemistry. It
should also be stressed that the expected elimination reaction
leading to the corresponding α,β-unsaturated ester was not
significantly observed with all the following substrates tested
(<10% when observed).
Although it is generally accepted that hetero-Diels−Alder
(HDA) reactions between 5-ethoxyoxazoles and electron-poor
dienophiles afford an efficient avenue to 3-hydroxypyridine
cores, this method remains greatly underexplored to access
natural products. Indeed, the electron-withdrawing group on
the olefinic partner required to promote the cycloaddition step,
is often undesirable on the final pyridine ring system. Also, we
reasoned that acrylic acid may be a suitable cycloaddition
partner for both reasons: (1) it is an excellent dienophile
toward 5-alkoxyoxazoles in HDA reactions (neither thermal nor
catalytic3e activation is required); (2) the carboxylic acid group
thus generated on the pyridine core would benefit from the
presence of an ortho-hydroxy substituent,15 known to facilitate
the protodecarboxylation reaction. Consequently, the methyl
multijuguinate 4 would be accessible using the hetero-Diels−
Alder reaction as key step, between conveniently substituted
To explore the scope and limitation of this methodology, a
range of α-triflyloxy esters were prepared and tested in the
presence of acetonitrile, using previously optimized reaction
conditions (i.e., MW, 120 °C, 3 min, TMS-OTf 10 mol %).
The results obtained are summarized in Table 2.
α-Triflyloxy esters bearing an aliphatic group at position R1
led to the corresponding alkoxyoxazoles 2a and b in useful yield
(63%, entries 1 and 2). The bulky sec-butyl substituent afforded
the oxazole 2c in a lower yield of 42%, along with 13% of
elimination product (E)-ethyl 4-methylpent-2-enoate (entry 3).
To our satisfaction, the diester 1f afforded the oxazole 2d in a
good 75% yield. Remarkably, the challenging derivative 1g
reacted chemoselectively with the triflate moiety in the
presence of the mesylate group to afford 2e in 54% yield.
However, the cyclization reaction with particularly hindered
cyclic triflate derivative 1h did not occur but formed the
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a
Table 2. Scope of the Reaction with a Range of α-Triflyloxy/hydroxy Esters
a
A solution of α-triflyloxy esters 1 (0.9 mmol) and TMS-OTf (0.09 mmol, 0.1 equiv) in acetonitrile (2.4 mL) in a microwave vial was heated for 3
b
c
d
min at 120 °C under microwave conditions (Pmax = 100 W). Isolated yield. Isolated yield of the elimination product. TMS-OTf (1.57 mmol, 1.75
equiv).
alkoxyoxazole 2q and dienophile, followed by a final
protodecarboxylation reaction to remove the undesired
carboxyl group. First, the 5-ethoxyoxazole 2o was conveniently
prepared in 52% yield from ethyl-O-trifluoromethanesulfonyl-
2-hydroxypropanoate 1a and readily accessible methyl 4-
cyanobutyrate, under previously optimized conditions (MW,
120 °C, 3 min). Pleasingly, cycloaddition of 2o with acrylic acid
afforded the hydroxypyridine 3 in 73% isolated yield. Next,
efforts to protodecarboxylate 3 under conventional methods
(Pd(O2CCF3)2/DMF,16 Cu/quinoline17 or Ag2CO3/DMSO18)
were unfruitful. Satisfyingly, the protodecarboxylation was
effectively promoted in good 80% yield, in the presence of 10
mol % of AgOAc in NMP, at 220 °C within only 10 min, under
microwave irradiation.19 It should be stressed that in our case,
addition of a mild base such as K2CO3 did not increase the
yield as observed by Gooβen, but resulted in partial
decomposition of the reaction mixture probably due to the
presence of a base-sensitive ester group.20 Consequently, the
methyl multijuguinate 4 was obtained in four steps in 29%
overall yield from commercially available ethyl lactate (Scheme
3).
CONCLUSION
■
In conclusion, we reported a rapid access to 2,4-alkyl/phenyl-5-
alkoxyoxazoles from easily available α-hydroxy esters and
nitriles, under microwave conditions. Optimization of the
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Scheme 3. Synthesis of the Methyl Multijuguinate 4
expressed in parts per million (ppm) from CDCl3 (δH= 7.26, δC
=
Table 3. Scope of the Reaction with Various Nitrile
Derivatives
a
77.00), DMSO-d6 (δH= 2.50, δC = 39.43), MeOD-d4 (δH= 3.31, δC =
49.05). Semipreparative HPLC were performed on a column Varian
Kromasil C18, 10 μm, 21.2 × 250 mm. Microwave reactions were
performed using a CEM Focused Microwave Synthesis System
apparatus, Model Discover. The machine consists of a continuous
focused microwave power delivery system with operator selectable
power output from 0 to 300 W. All the reactions were performed in
special 10 mL glass vessels under an atmosphere of argon. Reaction
mixture temperatures were measured during microwave heating with
an IR surface sensor located in the base of the Discover. The
temperature fixed to 120 °C was maintained for 3 min. (i.e., hold time:
time the system maintains the control parameters) and was usually
reached within one minute (i.e., run time: maximum run time for the
method for situations where the control point is not reached)
Nitrile derivatives were commercially available, except the methyl 4-
cyanobutyrate B. α-Triflyloxy esters 1d21 and 1h,22 were prepared
according to known procedures.
Methyl 4-Cyanobutyrate B. Step 1, ethyl 4-cyanobutyrate A:23 A
solution of ethyl 4-bromobutyrate (2 mL, 13.9 mmol) and potassium
cyanide (4.54 g, 69.9 mmol, 5 equiv) in DMF (15 mL) was heated at
80 °C for 12 h. Water (60 mL) was added to the cooled solution and
the solution extracted with EtOAc (2 × 50 mL). The combined
organic phase was washed with satd aq NH4Cl (40 mL) and brine (20
mL) and dried over MgSO4. The crude product was purified by
chromatography on silica gel (20% EtOAc/Pentane) to give the
product A as a colorless oil (10.35 mmol, 1.460 g, 74%). The 1H NMR
spectrum was in accordance with literature data: 1H (200 MHz,
CDCl3) δ 4.15 (q, J = 7.2 Hz, 2H), 2.52−2.43 (m, 4H), 2.05−1.91 (m,
2H), 1.27 (t, J = 7.2 Hz, 3H).
a
A solution of α-triflyloxy esters (0.9 mmol), TMS-OTf (0.09 mmol,
0.1 equiv), and nitriles (4.5 mmol, 5 equiv) in a microwave vial was
heated for 3 min at 120 °C under microwave conditions (Pmax = 100
W). TMS-OTf (1.57 mmol, 1.75 equiv).
b
Step 2: methyl 4-cyanobutyrate B: To a stirred solution of ethyl 4-
cyanobutyrate (300 mg, 2.13 mmol) in dry MeOH at 0 °C was added
K2CO3 solid (340 mg, 2.46 mmol, 1.15 equiv). After 12 h of stirring at
room temperature, the reagent mixture was concentrated, diluted in
water, and extracted with EtOAc (2×). The combined organic phase
was washed with satd aq NH4Cl (40 mL) and brine (20 mL), dried
over MgSO4, and concentrated under reduced pressure to afford B
(110 mg, 0.87 mmol, 41%) as a colorless oil: IR (neat) 2962, 2247,
1732, 1439, 1224, 1201, 1164; 1H (200 MHz, CDCl3) δ 3.70 (s, 3H),
2.54−2.43 (m, 4H), 1.99 (quint, J = 6.8 Hz, 2H); 13C (75 MHz,
CDCl3) δ 172.3, 119.0, 51.7, 32.0, 20.6, 16.4. Anal. Calcd for
C6H9NO2: C, 56.68; H, 7.13; N, 11.02. Found: C, 56.22; H, 7.14; N,
11.21.
reaction conditions allowed us to considerably widen the scope
of this reaction, which was found to be compatible with
sensitive functional groups and allowed the first synthesis of the
methyl multijuguinate within four steps from commercially
available compounds in 29% overall yield (extraction yield of
0.001%). The use of acrylic acid as ethylene equivalent in the
Kondrat’eva HDA is unprecedented, and should open up new
opportunities for the synthesis of natural 3-hydroxypyridine
alkaloids that are currently being investigated in our laboratory.
Ethyl 2-[[(Trifluoromethyl)sulfonyl]oxy]propanoate 1c.24 To
a solution of ethyl lactate (635 mg, 5.38 mmol) in dry CH2Cl2 (5 mL)
were added dropwise and successfully 2,6-lutidine (0.75 mL, 6.45
mmol, 1.2 equiv) and trifluoromethanesulfonic anhydride (1.0 mL, 5.9
mmol, 1.1 equiv) at 0 °C under inert atmosphere. The mixture was
then stirred at the same temperature for 1.5 h and monitored by TLC
for consumption of starting material. The solution was washed by
water, dried over MgSO4, and concentrated under reduced pressure.
The crude product was finally purified by chromatography on silica gel
(100% CH2Cl2) to give the product as an orange oil (5.22 mmol,
EXPERIMENTAL SECTION
■
General Information. All solvents were dried following standard
procedures (CH2Cl2 and CH3CN: distillated over CaH2; DMF, NMP
and MeOH: dried over 3A MS). Acrylic acid was distilled prior to use.
Commercially available reagents were used without further purifica-
tion. Column chromatography purifications were performed on Merck
silica gel (40−63 μm). Thin-layer chromatography (TLC) was carried
out on Merck DC Kieselgel 60 F-254 aluminum sheets. HRMS were
obtained using the electrospray ionization (ESI) technique and a time-
of-flight (TOF) analyzer. 1H and 13C NMR chemical shifts are
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1
1.306 g, 97%). H NMR spectrum was in accordance with literature
data.
70.5, 34.9, 26.9, 15.0, 14.4; HRMS (ESI+) calcd for C14H18NO2
232.1338, found 232.1336.
2-Methyl-4-sec-butyl-5-ethoxy-1,3-oxazole 2c: 0.38 mmol, 69
mg, 42%; 100% CH2Cl2, Rf = 0.7; yellow oil; IR (neat) 2954, 2928,
1667, 1587, 1371, 1256, 1191, 1021; 1H (300 MHz, CDCl3) δ 4.10 (q,
J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.20 (d, J = 6.9 Hz, 2H), 1.97−1.88 (m,
1H), 1.35 (t, J = 7.2 Hz, 2H), 0.91 (d, J = 4.2 Hz, 6H); 13C (75 MHz,
CDCl3) δ 154.2, 152.1, 116.0, 70.3, 33.7, 27.8, 22.4, 15.1, 14.3; HRMS
(ESI+) calcd for C10H18NO2 184.1338, found 184.1336.
Ethyl 2-(5-ethoxy-2-methyloxazol-4-yl)acetate 2d: 0.68
mmol, 144 mg, 75%; 80% cyclohexane/20% AcOEt, Rf = 0.1; yellow
oil; IR (neat) 2980, 1735, 1679, 1584, 1377, 1257, 1181, 1151, 1019;
1H (200 MHz, CDCl3) δ 4.23−4.11 (m, 4H), 3.40 (s, 2H), 2.33 (s,
Ethyl 4-Methyl-2-[[(trifluoromethyl)sulfonyl]oxy]pentanoate
1e. The triflate was prepared according to the procedure described
above using ethyl 2-hydroxy 4-methylpentanoate (600 mg, 3.75
mmol), 2,6-lutidine (0.52 mL, 4.50 mmol, 1.2 equiv) and
trifluoromethanesulfonic anhydride (0.69 mL, 4.13 mmol, 1.1 equiv)
in dry CH2Cl2 (3 mL). The crude product was purified by
chromatography on silica gel (100% CH2Cl2, Rf = 0.8) to give the
product as an orange oil (3.34 mmol, 976 mg, 89%): IR (neat) 2968,
1764, 1417, 1197, 1143; 1H (200 MHz, CDCl3) δ 5.17−5.11 (m, 1H),
4.30 (q, J = 7.2 Hz, 2H), 2.01−1.92 (m, 1H), 1.88−1.70 (m, 2H), 1.33
(t, J = 7.2 Hz, 3H), 0.99 (d, J = 6.0 Hz, 6H); 13C (75 MHz, CDCl3) δ
167.6, 118.6 (q, J = 317.3 Hz), 82.6, 62.7, 40.7, 24.1, 22.8, 21.0, 13.9.
Anal. Calcd for C9H15F3O5S: C, 36.98; H, 5.16; S, 10.97. Found: C,
36.97; H, 5.16; S, 10.79.
Diethyl 2-[[(Trifluoromethyl)sulfonyl]oxy]succinate 1f. The
triflate was prepared according to the procedure described above,
using the diethyl 2-hydroxysuccinate (500 mg, 2.63 mmol), 2,6-
lutidine (0.37 mL, 3.16 mmol, 1.2 equiv), and trifluoromethanesul-
fonic anhydride (0.49 mL, 2.89 mmol, 1.1 equiv) in dry CH2Cl2 (5
mL). The crude product was purified by chromatography on silica gel
(100% CH2Cl2, Rf = 0.8) to give the product as an orange oil (2.48
mmol, 800 mg, 95%): IR (neat) 2985, 1739, 1419, 1201, 1140, 1021;
1H (200 MHz, CDCl3) δ 5.48 (t, J = 5.8 Hz, 1H), 4.33 (q, J = 7.2 Hz,
3H), 1.36 (td, J = 7.2 Hz, J = 0.8 Hz, 3H), 1.26 (td, J = 7.2 Hz, J = 0.8
Hz, 3H); 13C (75 MHz, CDCl3) δ 170.4, 154.8, 152.4, 109.9, 70.3,
60.8, 30.7, 14.8, 14.2, 14.1; HRMS (ESI+) calcd for C10H16NO4
214.1079, found 214.1083.
2-(5-Ethoxy-2-methyloxazol-4-yl)ethyl methanesulfonate
2e: 0.38 mmol, 94 mg, 54%, 80% cyclohexane/20% AcOEt, Rf =
0.3; yellow oil; IR (neat) 2990, 2933, 1674, 1737, 1674, 1350, 1268,
1
1169; H (300 MHz, CDCl3) δ 4.41 (t, J = 6.9 Hz, 2H), 4.15 (q, J =
7.2 Hz, 2H), 2.98 (s, 3H), 2.81 (t, J = 6.9 Hz, 2H), 2.31 (s, 3H), 1.36
(t, J = 7.2 Hz, 3H); 13C (75 MHz, CDCl3) δ 154.7, 152.6, 111.0, 70.4,
68.1, 37.2, 25.0, 14.9, 14.2; HRMS (ESI+) calcd for C9H16NO5S
250.0749, found 250.0759.
3,4-Dimethyl-2(5H)-furanone 2f:26 0.77 mmol, 86 mg, 85%,
2H), 4.22 (q, J = 7.2 Hz, 2H), 3.04 (d, J = 6.0 Hz, 2H), 1.34 (t, J = 7.2
Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C (75 MHz, CDCl3) δ 167.6,
166.1, 118.4 (q, J = 317.6 Hz), 78.9, 63.2, 61.8, 36.9, 14.0, 13.8; HRMS
(ESI+) calcd for C9H14F3O7S 323.0401, found 323.0407.
1
100% CH2Cl2, Rf = 0.2. H NMR spectrum is in accordance with
literature: 1H (200 MHz, CDCl3) δ 4.61 (q, J = 1.0 Hz, 2H), 2.01 (d, J
= 1.0 Hz, 3H), 1.81 (q, J = 1.0 Hz, 3H).
2-Methyl-4-phenyl-5-methoxy-1,3-oxazole 2g:10 0.69 mmol,
Ethyl 4-[(Methylsulfonyl)oxy]-2-[[(trifluoromethyl)sulfonyl]-
oxy]butanoate 1g. The triflate was prepared according to the
procedure described above, using ethyl 2-hydroxy 4-[(methylsulfonyl)-
oxy]butanoate25 (231 mg, 1.02 mmol, 1 equiv), 2,6-lutidine (0.12 mL,
1.22 mmol, 1.2 equiv), and trifluoromethanesulfonic anhydride (0.19
mL, 4.13 mmol, 1.12 equiv) in dry CH2Cl2 (4 mL). The crude product
was purified by chromatography on silica gel (100% CH2Cl2, Rf = 0.7)
to give the product as an orange oil (0.72 mmol, 257 mg, 70%): IR
(neat) 2987, 2951, 1754, 1413, 1360, 1205, 1174, 1138; 1H (200 MHz,
CDCl3) δ 5.29 (dd, J = 7.2 Hz, J = 4.6 Hz, 1H), 4.48−4.28 (m, 4H),
3.05 (s, 3H), 2.54−2.43 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H); 13C (50
MHz, CDCl3) δ 166.3, 118.4 (q, J = 317.4 Hz), 79.5, 63.8, 63.1, 37.1,
31.5, 13.7; HRMS (ESI+) calcd for C8H13F3O8NaS2 380.9902, found
380.9906.
1
130 mg, 76%; yellow oil. H NMR spectrum is in accordance with
literature: 1H (200 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.37 (t, J
= 7.4 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 4.03 (s, 3H), 2.42 (s, 3H).
2-Methyl-4-phenyl-5-ethoxy-1,3-oxazole 2h:27 0.64 mmol,
1
129 mg, 70%; yellow oil. H NMR spectrum is in accordance with
literature: 1H (300 MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz, 2H), 7.37 (t, J
= 7.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.41
(s, 3H), 1.45 (t, J = 7.2 Hz, 3H).
2-Methyl-4-phenyl-5-n-propyloxy-1,3-oxazole 2i: 0.53 mmol,
1
114 mg, 58%; yellow oil; IR (neat) 2974, 1643, 1365, 1201; H (300
MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.20
(t, J = 7.2 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2 Hz), 2.41 (s, 3H), 1.83 (hex, J
= 7.2 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C (75 MHz, CDCl3) δ
153.6, 151.7, 131.4, 128.2, 125.9, 124.6, 114.7, 75.1, 22.6, 14.0, 10.1;
HRMS (ESI+) calcd for C13H16NO2 218.1176, found 218.1175.
2-Benzyl-4-methyl-5-ethoxy-1,3-oxazole 2j: 0.45 mmol, 98
mg, 50%, 100% CH2Cl2, Rf = 0.4; yellow oil; IR (neat) 2984, 2937,
1661, 1322, 1234, 1015; 1H (300 MHz, CDCl3) δ 7.34−7.21 (m, 5H),
4.08 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 2.00 (s, 3H), 1.31 (t, J = 7.1 Hz,
3H); 13C (75 MHz, CDCl3) δ 153.9, 153.6, 135.8, 128.6, 128.6, 126.9,
112.7, 70.2, 35.1, 14.9, 10.0; HRMS (ESI+) calcd for C13H16NO2
218.1181, found 218.1180.
General Procedure for the Synthesis of the 5-Alkoxyox-
azoles 2a−r. To the corresponding triflate (0.9 mmol) was added
acetonitrile (2.40 mL) or a functionalized nitrile (4.5 mmol, 5 equiv)
under inert atmosphere in a microwave vial, equipped with a magnetic
stirrer bar. Then, trimethylsilyl trifluoromethanesulfonate (16 μL, 0.09
mmol, 0.1 equiv) was added. The vial was sealed and the reaction was
performed in a microwave during 3 min (holding time) at 120 °C with
a maximum power of 100 W. The solution was quenched with satd aq
NaHCO3 (10 mL) and extracted with CH2Cl2 or AcOEt (2 × 15 mL).
The organic phases were washed with brine (5 mL), dried over
MgSO4, and concentrated under reduced pressure. The crude product
was finally purified by chromatography on silica gel to give the desired
product. For aromatic α-hydroxy esters (0.9 mmol), the same
procedure was used. However, the quantity of trimethylsilyl
trifluoromethanesulfonate was increased (0.29 mL, 1.58 mmol, 1.75
equiv).
2-n-Propyl-4-methyl-5-ethoxy-1,3-oxazole 2k: 0.52 mmol, 88
mg, 58%, 100% CH2Cl2, Rf = 0.2; yellow oil; IR (neat) 2965, 1741,
1
1675, 1576, 1223; H (300 MHz, CDCl3) δ 4.10 (q, J = 7.2 Hz, 2H),
2.57 (t, J = 7.5 Hz, 2H), 2.00 (s, 3H), 1.71 (quint, J = 7.5 Hz, 2H),
1.34 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.5 Hz, 2H); 13C (75 MHz,
CDCl3) δ 155.4, 153.2, 112.1, 70.0, 30.2, 20.1, 14.7, 13.4, 9.7; HRMS
(ESI+) calcd for C9H16NO2 170.1181, found 170.1175.
2-Ethyl-4-phenyl-5-ethoxy-1,3-oxazole 2l: 0.58 mmol, 134 mg,
2,4-Dimethyl-5-ethoxy-1,3-oxazole 2a:1b 0.57 mmol, 80 mg,
1
64%; yellow oil; IR (neat) 2969, 1741, 1642, 1449, 1361; H (300
1
1
63%. H NMR spectrum is in accordance with literature: H (200
MHz, CDCl3) δ 4.10 (q, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.99 (s, 3H),
1.34 (t, J = 7.0 Hz, 3H).
MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.20
(t, J = 7.2 Hz, 1H), 4.20 (t, J = 6.6 Hz, 2H), 2.74 (q, J = 7.5 Hz, 2H),
1.83 (m, J = 7.5 Hz, 2H), 1.34 (t, J = 7.8 Hz, 3H), 1.05 (t, J = 7.2 Hz,
3H); 13C (75 MHz, CDCl3) δ 156.1, 153.5, 131.6, 128.3, 125.9, 124.7,
114.6, 75.0, 22.7, 21.9, 11.1, 10.2; HRMS (ESI+) calcd for C14H18NO2
232.1338, found: 232.1330.
2-n-Propyl-4-phenyl-5-ethoxy-1,3-oxazole 2m: 0.51 mmol,
118 mg, 57%; yellow oil; IR (neat) 2968, 1642, 1604, 1449, 1379,
1352, 1192; 1H (300 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 2H), 7.37 (t,
5-Ethoxy-2-methyl-4-phenethyl-1,3-oxazole 2b: 0.56 mmol,
130 mg, 63%; 100% CH2Cl2, Rf = 0.1; yellow oil; IR (neat) 3029,
2975, 2929, 1667, 1583, 1452, 1378, 1267, 1016; 1H (200 MHz,
CDCl3) δ 7.31−7.17 (m, 5H), 3.87 (q, J = 7.0 Hz, 2H), 2.94−2.87 (m,
2H), 2.68−2.60 (m, 2H), 2.34 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H); 13C
(75 MHz, CDCl3) δ 153.9, 152.4, 141.9, 128.6, 128.3, 125.9, 116.1,
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Article
J = 7.5 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 4.30 (q, J = 6.9 Hz, 2H), 2.68
(t, J = 7.5 Hz, 2H), 1.79 (m, J = 7.2 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H),
1.01 (t, J = 7.5 Hz, 3H); 13C (75 MHz, CDCl3) δ 155.3, 153.2, 131.5,
128.2, 125.9, 124.7, 114.9, 69.3, 30.2, 20.3, 14.9, 13.5; HRMS (ESI+)
calcd for C14H18NO2 232.1338, found 232.1331.
concentrated in vacuo to afford the methyl multijuguinate 4 (33 mg,
0.16 mmol, 80%) as white solid: mp 120−122 °C; IR (neat) 2963,
1
1729, 1437, 1278; H (300 MHz, MeOD-d4) δ 7.06 (d, J = 8.1 Hz,
1H), 6.92 (d, J = 8.1 Hz, 1H), 3.63 (s, 3H), 2.66 (t, J = 7.5 Hz, 2H),
2.38 (s, 3H), 2.32 (t, J = 7.5 Hz, 2H), 1.92 (quint, J = 7.5 Hz, 2H); 13C
(75 MHz, MeOD-d4) δ 175.5, 151.6, 151.5, 146.9, 123.8, 122.5, 52.0,
36.7, 34.1, 26.7, 18.3.
2-tert-Butyl-4-methyl-5-ethoxy-1,3-oxazole 2n: 0.41 mmol, 76
mg, 46%, 100% CH2Cl2, Rf = 0.3; yellow oil; IR (neat) 2974, 2937,
1
1682, 1562, 1307, 1228, 1171, 1082, 1020; H (300 MHz, CDCl3) δ
4.11 (q, J = 7.2 Hz, 2H), 2.01 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H), 1.32 (s,
9H); 13C (75 MHz, CDCl3) δ 161.8, 153.3, 112.0, 70.2, 33.6, 28.4,
15.0, 10.1; HRMS (ESI+) calcd for C10H18NO2 184.1338, found
184.1335.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
2-Phenyl-4-methyl-5-ethoxy-1,3-oxazole 2o:28 0.54 mmol,
1
109 mg, 60%, 50% pentane/50% CH2Cl2, Rf = 0.3; yellow oil. H
NMR spectrum is in accordance with literature: 1H (300 MHz,
CDCl3) δ 7.93−7.90 (m, 2H), 7.45−7.37 (m, 3H), 4.24 (q, J = 7.2 Hz,
2H), 2.12 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).
AUTHOR INFORMATION
■
Corresponding Author
Methyl 2-(5-ethoxy-4-methyloxazol-2-yl)acetate 2p: 0.55
mmol, 110 mg, 61%, 100% CH2Cl2, Rf = 0.2; yellow oil; IR (neat)
2984, 2958, 1744, 1671, 1583, 1223, 1202, 1166, 1098, 1010; 1H (300
MHz, CDCl3) δ 4.14 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.69 (s, 2H),
2.02 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C (75 MHz, CDCl3) δ 168.1,
154.3, 147.8, 113.1, 70.2, 52.4, 34.6, 14.8, 9.8; HRMS (ESI+) calcd for
C9H14NO4 200.0923, found 200.0923.
*Tel: + 33 (0)2 35 52 24 76. Fax: + 33 (0)2 35 52 29 71. E-
mail: pierre-yves.renard@univ-rouen.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Methyl 4-(5-ethoxy-4-methyloxazol-2-yl)butanoate 2q: 0.46
We thank the CNRS and FEDER (Fonds Europee
́
ns de
mmol, 104 mg, 52%, 100% CH2Cl2, Rf = 0.1; colorless oil; IR (neat)
1
Dev
́
eloppement Economique et Reg
to L.-A.J. We thank A. Marcual (CNRS) and A. Leboisselier
(INSA de Rouen) for HRMS and elemental analyses,
́
ional) for financial support
2987, 1737, 1674, 1576, 1221; H (300 MHz, CDCl3) δ 4.10 (q, J =
7.2 Hz, 2H), 3.66 (s, 3H), 2.66 (t, J = 7.2 Hz, 2H), 2.40 (t, J = 7.2 Hz,
2H), 2.04 (quint, J = 7.2 Hz, 2H), 1.99 (s, 3H), 1.34 (t, J = 7.2 Hz,
3H); 13C (75 MHz, CDCl3) δ 173.1, 154.3, 153.4, 112.3, 70.0, 51.3,
32.8, 27.5, 21.8, 14.8, 9.8; HRMS (ESI+) calcd for C11H18NO4
228.1236, found 228.1232.
respectively, and Dr. A. Romieu (Universite
mass analyses.
́
de Rouen) for
2-(3-Chloropropyl)-5-ethoxy-4-methyloxazole 2r: 0.38 mmol,
REFERENCES
■
77 mg, 41%, 100% CH2Cl2, Rf = 0.4; orange oil; IR (neat) 2977, 2924,
1
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1676, 1578, 1224, 1085, 1017; H (300 MHz, CDCl3) δ 4.11 (q, J =
7.1 Hz, 2H), 3.62 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 7.3 Hz, 2H), 2.19 (tt,
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10.0; HRMS (ESI+) calcd for C9H15ClNO2 204.0789, found 204.0787.
3-Hydroxy-6-(4-methoxy-4-oxobutyl)-2-methylisonicotinic
Acid 3. To a stirred solution of the oxazole 2q (1.08 g, 4.75 mmol) at
0 °C in a 1 mL round-bottom flask under argon atmosphere was added
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CH3CN (5 min), followed by a linear gradient from 95% to 75% of
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