The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

Article abstract of DOI:10.1039/c4ob02105c

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor. The

Full text of DOI:10.1039/c4ob02105c

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10.1039/C4OB02105C.
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The rapid synthesis of oxazolines and their
heterogeneous oxidation to oxazoles under flow
conditions
Cite this: DOI: 10.1039/x0xx00000x
Steffen Glöckner,a Duc N. Tran,a Richard J. Ingham,a Sabine Fenner,a Zoe E. Wilson,a
Claudio Battilocchio,a and Steven V. Leya*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported.
The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of
stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then
be obtained via a packed reactor containing commercial manganese dioxide.
The oxidative aromatisation of oxazolines to the corresponding
oxazoles is typically achieved using 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) and bromotrichloromethane.8,9 Other reagents such as
Introduction
Oxazolines and oxazoles are important biological scaffolds present
within many natural products (Figure 1).1,2 Amongst the many
synthetic approaches towards these structural motifs, one very useful
strategy involves the cyclodehydration of β-hydroxy amides using
reagents such as Burgess’ reagent,3 the Mitsunobu reagent,4 Martin
NiO2,10 CuBr2/DBU,11 NBS/hv,12 CuBr/peroxide12 or O2 gas13 have
also been successfully employed, although largely for the oxidation
of C5-unsubstituted oxazoline rings. While manganese (IV) dioxide
(MnO2) has been applied with some success to the preparation of
thiazoles from thiazolidines,14 to date it has not been widely used for
the synthesis of oxazoles and only a few examples exist in the
literature.15,16
sulfurane,5 Ph2-SO-Tf2O,6 PPh3-CCl4 or by treatment with
7
fluorinating reagents such as diethylaminosulfur trifluoride (DAST)
and Deoxo-Fluor®.8
We have previously described the preparation of oxazolines in flow
during the synthesis of o-methyl siphonazole,9 hennoxazole A17 and
bisoxazoline PyBox chiral ligands.18 DAST was employed to effect
the cyclisation of a β-hydroxy amide to the oxazoline at 70 - 90 °C,
followed by in-line quenching of residual HF. This approach greatly
improved the safety profile of the reaction compared to the batch
synthesis, as well as providing pure products without need for
additional purification. With these benefits in mind, it was decided to
further investigate the scope of this flow transformation, employing
the more stable Deoxo-Fluor® reagent.
Our experience has shown that manganese dioxide can be simply
packed into an Omnifit® column19 and used successfully as a
heterogeneous reagent in flow processes, without the problems
usually associated with the use of this reagent in batch synthesis, i.e.
its tendency to adhere to surfaces and cause blockages.20 Here we
Fig. 1 Oxazoline- and oxazole-containing natural products.
report the development of
a flow protocol for the rapid
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cyclodehydration of a diverse range of β-hydroxy amides using purification (Table 1). Aryl oxazolines 2a-f were obtained in
Deoxo-Fluor® and the oxidative aromatisation of the resulting excellent yields and diastereoselectivities. The dipeptide derivatives
oxazolines to oxazoles using commercial activated and amorphous subjected to these conditions (1g, 1h and 1i) showed excellent
manganese dioxide.
reactivities, yielding 92-98% of the desired oxazolines. Moreover,
dicyclisation processes were possible (2k and 2l) with good yield,
although higher flow rates (10 mL min-1) were required. It was found
that the yields under flow conditions were typically 10% higher than
the corresponding batch system, with the efficient heat transfer and
rapid mixing greatly improving the safety profile when compared to
the batch reaction.8
Results and discussion
Our initial investigations focused on the flow synthesis of
oxazolines, revealing that the use of a slight excess (1.35 eq.)21 of
Deoxo-Fluor® resulted in >99% conversion of the β-hydroxy amides
to the oxazolines. The use of higher quantities of fluorinating agent
led to a large number of unwanted by-products. Unlike typical batch
reactions using Deoxo-Fluor®, which usually require cooling to -20
°C,8 it was found that in flow optimal yields were obtained at room
temperature, desirably removing the need for cooling.
Table 1 Flow cyclodehydration of β-hydroxy amides using Deoxo-Fluor®.
Isolated
Entrya
Substrate
Product
yieldb
1
1a
1b
1c
1d
2a
2b
2c
2d
98%
In a set of model experiments with amide 1a, where residence time
was kept constant at 1.7 min, greater conversion was observed as
flow rate increased, suggesting that mixing was a key factor for this
reaction (Figure 2).
2
3
4
98%
79%c
98%
A flow rate of 6 mL min-1 gave full conversion to the desired
oxazoline 2a.
100
5
1e
2e
99%
95
90
85
6
7
1f
2f
95%
98%
1g
2g
0
1
2
3
4
5
6
7
8
9
1h
1i
2h
2i
92%
95%
60%
Overall flow rate (mL min-1
)
Fig. 2 Effect of flow rate on cyclodehydration of 1a to 2a (residence time =
1.7 min).
10
1j
2j
Under these conditions, a solution of β-hydroxy amide (0.25 M) and
a solution of Deoxo-Fluor®, each delivered at a flow rate of 3.00 mL
min-1, were combined at a T-piece before passing into a reactor coil
(1/16ʺ o.d, 1 mm i.d., 10 mL, PFA) at 25 °C. The exiting stream was
combined with an aqueous sodium bicarbonate solution at a T-mixer
(flow rate of 9 mL min-1) to quench any residual HF and then
directed into a Zaiput liquid-liquid membrane separator.22,23 This
device enabled separation of the two phases at a high combined flow
rate (15 mL min-1), with minimal breakthrough of the aqueous phase
into the organic phase (Scheme 1).
11
1k
1l
2k
2l
85%d
92%d
12
a
b
c
Reactions were run on a 2 mmol scale; Compounds were isolated without purification; the crude
material was passed through a plug of calcium carbonate/silica in place of an aqueous work up; d total
flow rate = 10 mL min-1 with 2.6 eq. of Deoxo-Fluor®.
Such a dependence on the flow rate suggested that the mixing
efficiency was a significant factor affecting the rate of cyclisation.
Microfluidics are known to provide a highly efficient static mixing23-
26 and therefore the cyclodehydration of β-hydroxy amides 1b and 1i
was attempted on a 1 µL (Labtrix Start) microchip (Scheme 2).27 It
was found that both substrates could be cyclodehydrated in excellent
yield at room temperature with residence times around 1 s, further
supporting the importance of mixing for this process.28
Scheme 1 Optimised conditions for the flow synthesis of oxazolines.
The optimised conditions were successfully applied on a 2 mmol
scale to a selection of β-hydroxy amides to obtain the desired
oxazolines in moderate to excellent yields with no need for further
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by increasing the reaction temperature to 60 °C with DME as
solvent, pure 3a could be isolated in 79% by simply removing the
solvent in vacuo.
Table 2 Solvent screening for flow MnO2 oxidation
Isolated
yield
Entry
Solvent
Temperature
40 °C
Scheme 2 Microchip reaction for the preparation of oxazolines.
1
2
3
4
5
6
7
Acetone
59%a
Additionally, we wanted to investigate whether this flow protocol
could be run continuously to afford larger amounts of material,
which is frequently a requirement in synthesis. A microchip reactor
would not be appropriate because whilst it generates an improved
reaction rate, it cannot provide the same potential throughput as a
mesofluidic system. Preliminary investigations into this were carried
out using 30 g of β-hydroxy amide 1a. A magnetic mixer was
introduced to ensure complete quenching over an extended period as
without this device, residual HF was observed in the organic stream.
We also took the opportunity to test a simple large-scale gravity
separation device (see SI) to recover the organic phase. Using this
specific system, 10.2 g h-1 of 2a could be generated in a single
continuous run over 2h and 40 min, with 27.2 g of 2a being
produced (98% yield) (Scheme 3).
Dichloromethane
Trifluorotoluene
Isopropyl acetate
Isopropyl acetate
Dimethoxyethane
Dimethoxyethane
40 °C
40%
20%
31%a
52%
64%a
79%
40 °C
0 °C
40 °C
40 °C
60 °C
a incomplete conversion so required purification.
Under these optimised conditions we were able to process several 2-
aryl-substituted oxazolines to oxazoles with isolated yields of 50-
79% (Scheme 4). Notably, pyridyl (3c) and styryl (3d) oxazolines
were compatible with the process giving 65% and 50% yields
respectively. The mild reaction conditions allowed oxidation in the
presence of an acid labile protecting group (3e). Desirably, all these
oxazoles were obtained in analytically pure form without any further
purification, with inductively coupled plasma-mass spectrometry
(ICP-MS) analyses showing negligible leaching of MnO2 (less than
10 ppb).
Scheme 3 Platform set up for the scale up experiment.
With flow conditions established for the cyclodehydration, we
turned our attention to the MnO2-mediated oxidative aromatisation
reaction, using oxazoline 2a as a model substrate. Previous studies
had demonstrated that the solvent and temperature have a strong
influence on the general oxidative reactivity of MnO2.29-31 Oxazoline
2a (0.5 mmol) in 8 mL of a range of solvents was passed through a
32
column reactor packed with activated MnO2 (3 g) with an initial
flow rate of 100 µL min-1, which was reduced to 60 µL min-1 after
50 min. The flow output was directly collected and evaporated
(Scheme 4). Dichloromethane, trifluorotoluene and isopropyl acetate
afforded pure desired product at 40 °C, although in low isolated
yield (40%, 20% and 32% respectively). We speculate that the
remaining material has decomposed and is retained in the MnO2
column. When isopropyl acetate was used as solvent at lower
temperature (0 °C), although less material was lost, the conversion
was poorer and the yield significantly reduced (31%). Neither
acetone or dimethoxy ethane (DME) afforded full conversion at 40
°C, but after purification afforded higher yields of the desired
product (59% and 63% respectively). Pleasingly, it was found that
Scheme 4. Flow oxidation of aryl-oxazolines using activated MnO2.
However, when these optimised conditions were applied to 2-alkyl-
substituted oxazolines, extensive decomposition of these substrates
to unidentified by-products was observed. It was suspected that the
high reactivity of activated MnO2 could be responsible for this
decomposition, so the reaction was attempted using the less active
33
amorphous MnO2 under otherwise identical conditions. At 60 °C
only partial conversion to the desired oxazoles was detected whereas
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increasing the temperature at 100 °C led to complete conversion of When using a flow system, there is the possibility to take
the starting material. This allowed access to a range of alkyl advantage of the ability to perform reactions and processes
substituted oxazoles in moderate to good yields (Scheme 5), under computer control.35 In this case, the addition of an
including sensitive substrates such as oxetane containing 3j. automation layer enabled up to four reactions using different
Notably, the double oxidation of 4 could be carried out in 83% yield substrates to be performed in sequence, with no manual
to afford 5, an intermediate in our recent total synthesis of intervention required apart from loading the reagents before
plantazolicin A and B.34 When the same reaction was attempted in starting the procedure. A reactor configuration (Scheme 6) was
batch the yield could not be optimised beyond 20%, necessitating a devised that incorporated a multi-port switching valve (V1
)
stepwise synthesis of 5.
such that four separate substrates could be passed through four
separate columns to prevent any cross-contamination between
samples. A secondary valve (V2) enabled the flow stream to be
thoroughly purged between each sample, and prevented cross-
contamination as V1 moved between the different positions.
The pre-prepared reagent solutions were drawn from four
separate bottles (selected by V1) and passed through the heated
MnO2 columns (1–4). A software protocol created in the
Python programming language35,36 and running on a Raspberry
Pi® microcomputer37 controlled the individual reactor
components according to a pre-programmed sequence of timed
actions, to co-ordinate the pumps and valves to perform the
reactions. Using this system, a batch of four substrates was
processed overnight (12 h). This demonstrates the ability for
automated machine-assisted systems to save skilled researcher
time in the laboratory.
Scheme 5 Flow oxidation of 2-alkyl-oxazolines using amorphous MnO2.
a deprotection was observed.
Scheme 6 Automated oxidation of oxazolines using a Raspberry Pi® computer and a multiple position valve.
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piece (each stream run at 3.0 mL min-1) and reacted at rt in a 10 mL PFA
reactor coil. The combined stream was then directed to an aqueous
quenching stream (9 mL min-1) and the solution directed to a liquid/liquid
Conclusions
In conclusion, an improved rapid method for the flow synthesis of
oxazolines at room temperature has been developed. A multi-hour
continuous flow run illustrates the potential of this method for the
safe large scale production of oxazolines. It was found that aryl-
substituted oxazolines undergo smooth oxidative aromatisation when
simply flowed through a column of activated MnO2 at 60 °C, with
isolated yields between 50-79%. Advantageously, unlike batch
protocols, no downstream workup or purification was found to be
required. The oxidation step has also been demonstrated to be
amenable to automation which allows the sequential processing of 4
different substrates on a single flow platform, with minimal operator
intervention. For the more sensitive 2-alkyl-substituted oxazolines, it
was found that good results could be achieved using amorphous
manganese dioxide at increased temperature, increasing the scope of
this process.
separator.22
(4S,5S)-5-methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl
1
ester (2a). H-NMR (600 MHz, CDCl3) δ = 7.98 – 7.96 (m, 2H), 7.49 – 7.46
(m, 1H), 7.40 – 7.38 (m, 2H), 5.05 (dq, 1H, 3J = 10.2, 6.4 Hz), 4.97 (d, 1H, 3J
3
= 10.2 Hz), 3.76 (s, 3H), 1.37 (d, 3H, J = 6.5 Hz); 13C-NMR (151 MHz,
CDCl3) δ = 170.5, 166.2, 131.9, 128.6, 128.4, 127.3, 77.7, 71.8, 52.2, 16.3;
+
HR-MS (ESI+) for C12H14NO3 [M+H]+ calc.: 220.0974, found: 220.0981;
FT-IR neat, ν ̃
(cm-1) = 2953, 1736, 1645, 1603, 1580, 1496, 1450, 1384,
1349, 1244, 1197, 1174, 1067, 1045, 1001, 973, 934, 904, 886, 851, 778,
695; specific rotation: [α]D24.1 = +58.58 ° cm3 g-1 dm-1 (c = 8.5 in ethanol).
Lit.: [α]D20= +69.4 ° cm3 g-1 dm-1 (c = 8.5 in EtOH).39
(4S,5S)-2-(4-chlorophenyl)-5-methyl-4,5-dihydrooxazole-4-carboxylic
1
3
acid methyl ester (2b). H-NMR (600 MHz, CDCl3) δ = 7.90 (d, 2H, J =
3
3
Experimental section
8.3 Hz), 7.37 (d, 2H, J = 8.4 Hz), 5.05 (m, 1H), 4.96 (d, 1H, J = 10.2 Hz),
3.76 (s, 3H), 1.36 (d, 3H, 3J = 6.5 Hz); 13C-NMR (151 MHz, CDCl3) δ =
170.3, 165.4, 138.1, 130.0, 128.7, 125.8, 78.0, 71.8, 52.2, 16.3; HR-MS
General experimental section. 1H-NMR spectra were recorded on a
Bruker Avance DPX-400 spectrometer with the residual solvent peak as
+
(ESI+) for C12H13ClNO3 [M+H]+ calc.: 254.0584, found: 254.0575; FT-IR
1
the internal reference (CDCl3 = 7.26 ppm, d6-DMSO = 2.50 ppm). H
neat, ν ̃
(cm-1) = 2953, 1737, 1646, 1599, 1491, 1437, 1404, 1384, 1355,
resonances are reported to the nearest 0.01 ppm. 13C-NMR spectra were
recorded on the same spectrometers with the central resonance of the
solvent peak as the internal reference (CDCl3 = 77.16 ppm, d6-DMSO =
39.52 ppm). All 13C resonances are reported to the nearest 0.1 ppm.
DEPT 135, COSY, HMQC, and HMBC experiments were used to aid
1244, 1197, 1172, 1091, 1075, 1045, 1015, 935, 904, 887, 840, 780, 731,
680; specific rotation: [α]D24.0 = +48.2 ° cm3 g-1 dm-1 (c = 1 in CHCl3).
(4S,5S)-5-methyl-2-(pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylic acid
methyl ester (2c). 1H-NMR (600 MHz, CDCl3) δ = 9.14 – 9.13 (m, 1H),
3
3
1
8.69 (dd, 1H, J = 4.9, 1.7 Hz), 8.24 – 8.22 (m, 1H), 7.33 (ddd, 1H, J = 7.9,
4.9, 0.8 Hz), 5.07 (dq, 1H, 3J = 10.2, 6.5 Hz), 4.97 (d, 1H, 3J = 10.2 Hz), 3.75
structural determination and spectral assignment. The multiplicity of H
signals are indicated as: s = singlet, d = doublet, t = triplet, m = multiplet,
br. = broad, or combinations of thereof. Coupling constants (J) are quoted
in Hz and reported to the nearest 0.1 Hz. Where appropriate, averages of
the signals from peaks displaying multiplicity were used to calculate the
value of the coupling constant. Infrared spectra were recorded neat on a
PerkinElmer Spectrum One FT-IR spectrometer using Universal ATR
sampling accessories. Unless stated otherwise, reagents were obtained
from commercial sources and used without purification. The removal of
solvent under reduced pressure was carried out on a standard rotary
evaporator. Melting points were performed on either a Stanford Research
Systems MPA100 (OptiMelt) automated melting point system and are
uncorrected. High resolution mass spectrometry (HRMS) was performed
using a Waters Micromass LCT Premier™ spectrometer using time of
(s, 3H), 1.37 (d, 3H, J = 6.5 Hz); 13C-NMR (151 MHz, CDCl3) δ = 170.1,
3
164.3, 152.5, 149.8, 136.0, 123.5, 123.3, 78.1, 71.7, 52.3, 16.3; HR-MS
+
(ESI+) for C11H13N2O3 [M+H]+ calc.: 221.0926, found: 221.0926; FT-IR
neat, ν ̃
(cm-1) = 2953, 1743, 1650, 1593, 1432, 1417, 1353, 1246, 1198,
1176, 1082, 1044, 1023, 936, 905, 886, 821, 781, 708, 620; specific
rotation: [α]D24.0 = +53.0 ° cm3 g-1 dm-1 (c = 1 in CHCl3).
(4S,5S)-5-methyl-2-((E)-styryl)-4,5-dihydrooxazole-4-carboxylic
acid
1
3
methyl ester (2d). H-NMR (600 MHz, CDCl3) δ = 7.43 (d, 2H, J = 7.5
3
3
Hz), 7.38 (d, 1H, J = 16.3 Hz), 7.32 – 7.27 (m, 3H), 6.65 (d, 1H, J = 16.3
Hz), 4.92 (dq, 1H, 3J = 10.1, 6.3 Hz), 4.87 (d, 1H, 3J = 10.0 Hz), 3.70 (s, 3H),
3
1.30 (d, 3H, J = 6.5 Hz); 13C-NMR (151 MHz, CDCl3) δ = 170.0, 165.6,
140.8, 134.7, 129.5, 128.6, 127.3, 114.6, 77.1, 71.3, 51.8, 16.0; HR-MS
+
(ESI+) for C14H16NO3 [M+H]+ calc.: 264.1236, found: 264.1227; FT-IR
flight with positive ESI, or conducted by Mr Paul Skelton on a Bruker neat, ν
̃
(cm-1) = 2951, 1735, 1652, 1607, 1496, 1449, 1358, 1242, 1197,
24.0
1174, 1045, 972, 948, 930, 840, 758, 732, 692; specific rotation: [α]D
+27.9 ° cm3 g-1 dm-1 (c = 1 in CHCl3).
=
BioApex 47e FTICR spectrometer using (positive or negative) ESI or EI
at 70 ev to within a tolerance of 5 ppm of the theoretically calculated
value. LC-MS analysis was performed on an Agilent HP 1100 series
chromatography (Mercury Luna 3u C18 (2) column) attached to a Waters
ZQ2000 mass spectrometer with ESCi ionization source in ESI mode.
Elution was carried out at a flow rate of 0.6 mL min-1 using a reverse
(4S,5S)-2-(2-((4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyloxazolidin-
4-yl)thiazol-4-yl)-5-methyl-4,5-dihydrooxazole-4-carboxylic acid methyl
1
ester (2e). H-NMR (400 MHz, CDCl3) δ = 8.03 (s, 1H), 5.10 – 5.05 (m,
1H), 4.99 (s, 1H), 4.87 – 4.74 (s, 1H), 4.25 – 4.14 (m, 1H), 3.76 (s, 3H), 1.69
phase gradient of acetonitrile and water containing 0.1% formic acid. (s, 6H), 1.43 (s, 9H), 1.20 (s, 6H); 13C-NMR (100 MHz, CDCl3) δ = 173.9,
170.1, 161.5, 151.5, 143.4, 124.2, 95.37, 80.9, 78.5, 78.0, 71.8, 66.0, 52.2,
Retention time (Rt) is given in min to the nearest 0.1 min and the m/z
value is reported to the nearest mass unit (m.u.). Unless otherwise
specified all the flow reactions were performed using a Vapourtec
R2/R4+ flow platform.38
28.2, 26.6, 26.1, 18.1, 16.2. HR-MS (ESI+) for C20H30N3O6S+ (M+H)+ calc.:
440.1855, found: 440.1844. FT-IR neat, ν ̃
(cm-1) = 2977, 1753, 1740, 1704,
1649, 1538, 1453, 1361, 1337, 1303, 1261, 1213, 1177, 1132, 1088, 1066,
1047, 982, 957, 918, 897, 878, 855, 835, 776, 755, 725; specific rotation:
[α]D23.9 = -7.4 ° cm3 g-1 dm-1 (c = 1 in CHCl3).
General protocol for the preparation of oxazoline in flow: a solution of
Deoxo-Fluor® (1 mL, 50% in toluene) in CH2Cl2 (7.0 mL) and a solution (S)-2-Phenyl-4,5-dihydrooxazole-4-carboxylic acid methyl ester (2f). H-
1
NMR (400 MHz, CDCl3) δ = 7.98 (d, 2H, J = 7.5 Hz), 7.49 (m, 1H), 7.41 (m,
of serine/threonine (2 mmol) in CH2Cl2 (8 mL) were combined at a T-
2H), 4.97 (m, 1H), 4.69 (m, 1H), 4.58 (m, 1H), 3.82 (s, 3H) ppm. Data match
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those reported in: A. I. Meyers and F. X. Tavares J. Org. Chem. 1996, 61,
8207-8215.
and concentrated under vacuum to give the corresponding oxazoles in
good yield, without the need of further purification.
(S)-2-((1S,2S)-1-((tert-Butoxycarbonyl)amino)-2-methylbutyl)-4,5-
dihydrooxazole-4-carboxylic acid methyl ester (2g). H-NMR (400 MHz,
1
2-Phenyl-5-methyloxazole-4-carboxylic acid methyl ester (3a). 1H-
NMR (400 MHz, CDCl3) δ = 8.03 (m, 2H), 7.42 (m, 3H), 3.91 (s, 3H),
2.68 (s, 3H) ppm. Data matched those reported in: G. Yuan, Z. Zhu, X.
Gao and H. Jiang, RSC Adv., 2014, 4, 24300–24303.
CDCl3) δ = 5.20 (d, 1H, J = 9.0 Hz), 4.75 (m, 1H), 4.52 (t, 1H, J = 8.5 Hz),
4.45 (dd, 1H, J = 10.5, 9.4 Hz), 4.39 (dd, 1H, J = 8.6, 4.4 Hz), 3.77 (s, 3H),
1.84 (s, 1H), 1.50 (m, 1H), 1.43 (s, 9H), 1.15 (m, 1H), 0.89-0.94 (m, 6H)
ppm. Data match those reported in: S. Peña, L. Scarone, E. Manta, L.
Stewart, V. Yardley, S. Croft and G. Serra Bioorg. Med. Chem. Lett., 2012,
12, 4994–4997.
2-(4-Chlorophenyl)-5-methyloxazole-4-carboxylic acid methyl ester
(3b). White solid, m.p. 102-104 °C; 1H-NMR (400 MHz, CDCl3) δ =
ppm 7.99 – 8.02 (m, 2H), 7.42 – 7.45 (m, 2H), 3.95 (s, 3H), 2.71 (s, 3H);
13C-NMR (126 MHz, CDCl3) δ = 162.7, 158.8, 156.6, 137.0, 129.1,
(S)-2-((S)-1-((tert-Butoxycarbonyl)amino)ethyl)-4,5-dihydrooxazole-4-
+
1
128.7, 127.8, 125.0, 52.1, 12.1 ppm; HR-MS (ESI+) for C12H11NClO3
carboxylic acid methyl ester (2h). H-NMR (400 MHz, CDCl3) δ = 5.30
[M+H]+ calc.: 252.0427, found: 252.0422; FT-IR neat, ν (cm-1) = 3001,
̃
(1H, s), 4.95 (m, 1H), 4.79 (dd, 1H, J = 10.0, 1.5 Hz), 4.44 (m, 1H), 3.76 (s,
3H), 1.50-1.40 (m, 10H), 1.28 (d, 3H, J = 6.5 Hz) ppm. Data match those
reported in: Z. Xia and C. D. Smith J. Org. Chem. 2001, 66, 3459-3466.
2950, 2857, 1717, 1614, 1585, 1559, 1485, 1450, 1346, 1278, 1235,
1109, 1090, 1056, 1011, 827, 726, 692.
5-Methyl-2-(pyridin-3-yl)oxazole-4-carboxylic acid methyl ester (3c).
Yellowish solid, m.p. 62-70 °C; 1H-NMR (400 MHz, CDCl3) δ = 9.27
(S)-2-((S)-1-((tert-Butoxycarbonyl)amino)-2-methylpropyl)-4,5-
dihydrooxazole-4-carboxylic acid methyl ester (2i). H-NMR (400 MHz,
1
3
3
4
3
(d, 1H, J = 1.5 Hz), 8.69 (dd, 1H, J = 4.8, J = 1.5 Hz), 8.35 (dt, 1H, J
4
= 8.3, J = 1.9 Hz), 7.38 – 7.42 (m, 1H), 3.95 (s, 3H), 2.73 (s, 3H); 13C-
CDCl3) δ = 5.18 (d, 1H, J = 8.9 Hz), 4.74 (m, 1H), 4.51 (t, 1H, J = 8.7 Hz),
4.43 (dd, 1H, J = 10.3, 8.7 Hz), 4.33 (dd, 1H, J = 8.7, 4.0 Hz), 3.70 (s, 3H),
2.10 (m, 1H), 1.43 (s, 9H), 0.95 (d, 3H, J = 7.0 Hz), 0.90 (d, 3H, J = 6.8 Hz)
ppm. Data match those reported in: A. I. Meyers and F. X. Tavares J. Org.
Chem. 1996, 61, 8207-8215.
NMR (126 MHz, CDCl3) δ = 162.5, 157.3, 151.4, 147.6, 133.8, 128.8,
+
127.8, 123.6, 122.9, 52.2, 12.1 ppm; HR-MS (ESI+) for C11H11N2O3
[M+H]+ calc.: 219.0770, found: 219.0779; FT-IR: neat, ν (cm-1) = 3011,
̃
2953, 1713, 1614, 1577, 1483, 1431, 1418, 1386, 1347, 1235, 1197,
1109, 1071, 1018, 979, 820, 783, 719, 703.
(4S,5S)-5-methyl-2-(3-methyloxetan-3-yl)-4,5-dihydrooxazole-4-
(E)-5-Methyl-2-styryloxazole-4-carboxylic acid methyl ester (3d).
White solid, m.p. 86-88 °C; 1H-NMR (400 MHz, CDCl3) δ = 7.50–7.56
carboxylic acid methyl ester (2j) 1H-NMR (600 MHz, CDCl3) δ = 4.99 (d,
1H, J = 5.8 Hz), 4.98 – 4.93 (m, 1H), 4.95 (d, 1H, J = 5.8 Hz), 4.82 (d, 1H, J
= 10.1 Hz), 4.45 (d, 1H, J = 5.8 Hz), 4.44 (d, 1H, J = 5.8 Hz), 3.76 (s, 3H),
1.66 (s, 3H), 1.30 (d, 3H, J = 6.5 Hz); 13C-NMR (151 MHz, CDCl3) δ =
3
(m, 3H), 7.37–7.41 (m, 2H), 7.33–7.37 (m, 1H), 6.90 (d, J = 16.5 Hz),
3.93 (s, 3H), 2.68 ppm (s, 3H) ppm; 13C-NMR (126 MHz, CDCl3) δ =
162.7, 159.4, 156.1, 137.1, 135.2, 129.4, 128.9, 127.2, 113.1, 52.0, 12.1
+
ppm; HR-MS (ESI+) for C14H14NO3 [M+H]+ calc.: 244.0968, found:
172.1, 170.2, 80.1, 80.0, 78.3, 71.5, 52.3, 39.6, 22.3, 16.2; HR-MS (ESI+)
+
for C10H16NO4 [M+H]+ calc.: 214.1079, found: 214.1076; FT-IR neat, ν
̃
244.0961; FT-IR neat, ν ̃
(cm-1) 2954, 1715, 1644, 1544, 1438, 1388,
(cm-1) = 2926, 1738, 1658, 1450, 1361, 1255, 1198, 1175, 1133, 1044, 982,
1367, 1220, 1180, 1102, 988, 965, 757.
945, 844, 781, 732; specific rotation: [α]D23.9 = +47.2 ° cm3 g-1 dm-1 (c = 1 in
2-(2-((4S,5R)-3-(tert-Butoxycarbonyl)-2,2,5-trimethyloxazolidin-4-
yl)thiazol-4-yl)-5-methyloxazole-4-carboxylic acid methyl ester (3e).
1H-NMR (400 MHz, CDCl3) δ = 8.11 (br. s., 1H), 4.82 (br. s., 1H), 4.21
CHCl3).
3
(4R,4'S,5S,5'S)-2'-((1S,2S)-1-((tert-butoxycarbonyl)amino)-2-
(d, 1H, J = 6.3 Hz), 3.95 (s, 3H), 2.74 (s, 3H), 1.72 (br. s., 6H), 1.41 –
1.55 (m, 6H), 1.13–1.24 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3)
[conformers] δ = 174.2, 170.1, 162.6, 156.6, 155.0, 142.3, 130.2, 129.2,
128.4, 120.4, 95.3, 80.8, 77.8, 66.0, 52.1, 28.1, 26.5, 25.9, 17.8, 12.2;
HRMS (ESI+) for [M+Na]+ C20H27N3O6SNa+ calc.: 460.1518; found:
methylbutyl)-5,5'-dimethyl-4,4',5,5'-tetrahydro-[2,4'-bioxazole]-4-
carboxylic methyl ester (2k). 1H NMR (600 MHz, CDCl3) δ = 7.58 (s, 1H),
6.57 – 6.39 (m, 1H), 5.14 (d, J = 7.5 Hz, 1H), 4.92 (s, 1H), 4.77 (d, J = 10.0
Hz, 1H), 4.08 (d, J = 7.1 Hz, 1H), 3.70 (s, 3H), 1.92 (s, 1H), 1.72 (d, J = 7.2
Hz, 3H), 1.52 (d, J = 17.1 Hz, 1H), 1.45 – 1.36 (m, 21H), 1.25 (d, J = 6.5 Hz,
3H), 1.13 (d, J = 20.7 Hz, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.87 (t, J = 7.4 Hz,
4H); 13C NMR (151 MHz, CDCl3) δ = 170.0, 169.8, 164.2, 155.7, 130.8,
122.8, 79.8, 78.3, 71.2, 59.5, 51.9, 37.3, 28.2, 24.6, 16.0, 15.7, 14.8, 11.5;
460.1501; FT-IR neat, ν ̃
(cm-1) 2977, 2364, 1706, 1616, 1443, 1365,
1262, 1175, 1106, 984, 855, 731.
2-Phenyloxazole-4-carboxylic acid methyl ester (3f). 1H-NMR (400
MHz, CDCl3) δ = 8.30 (s, 1H), 8.11-8.13 (m, 2H), 7.55-7.45 (m, 3H),
3.96 (s, 3H) ppm. Data match those reported in: A. I. Meyers and F. X.
Tavares J. Org. Chem. 1996, 61, 8207-8215.
+
HR-MS (ESI+) for C20H34N3O6 (M+H)+ calc.: 412.2448, found.: 412.2442;
FT-IR neat, ν ̃
(cm-1) = 3342 , 3256 , 2967 , 1740 , 1687 , 1658 , 1626 , 1521
, 1454 , 1390 , 1365 , 1288 , 1240 , 1200 , 1170 , 1042 , 1019 , 870 , 777 ;
specific rotation: [α]D26.0 = +19.7 ° cm3 g-1 dm-1 (c = 1 in CHCl3).
General protocol for the preparation of 2-alkyl-oxazoles in flow: a
solution of oxazoline (0.125 mmol) in DME (2 mL) was loaded into a 2
mL loop and then passed through a column reactor packed with activated
MnO2 at 100 °C (flow rate 100 µL min-1 for 50 min then 60 µL min-1).
Unless otherwise stated, the machine output was collected and
concentrated under vacuum to give the corresponding oxazoles.
1
2,6-bis((R)-4-Phenyl-4,5-dihydrooxazol-2-yl)pyridine (2l). H-NMR (400
MHz, CDCl3) δ = 8.36 (d, 2H, J = 7.8 Hz), 7.93 (t, 1H, J = 7.8 Hz), 7.40-7.29
(m, 10H), 5.48 (dd, 2H, J = 10.2, 8.7 Hz), 4.94 (dd, 2H, J = 8.7, 10.4 Hz),
4.44 (t, 2H, J = 8.9 Hz) ppm. Data match those reported in: P. C. Knipea and
M. D. Smith, Org. Biomol. Chem., 2014, 12, 5094-5097.
2-((1S,2S)-1-((tert-Butoxycarbonyl)amino)-2-methylbutyl)oxazole-4-
1
General protocol for the preparation of 2-aryl-oxazoles in flow: a
solution of oxazoline (0.5 mmol) in DME (8 mL) was passed through a
column reactor packed with activated MnO2 at 60 °C (flow rate 100 µL
min-1 for 50 min then 60 µL min-1). The machine output was collected
carboxylic acid methyl ester (3g) H-NMR (CDCl3, 400 MHz) δ = 8.17
(s, 1H), 5.30 (d, J = 7.7 Hz, 1H), 4.89–4.80 (m, 1H), 3.90 (s, 3H), 2.00–
1.87 (m, 1H), 1.51–1.31 (m, 10H), 1.17 (m, 1H), 0.90-0.85 (m, 6H); 13C-
NMR (CDCl3, 100 MHz): δ = 165.1, 161.6, 155.2, 143.7, 133.2, 80.0,
53.3, 52.2, 39.5, 28.3, 25.0, 15.1, 11.3; HRMS (ESI+) for [M+H]+
C15H25N2O5 calculated 313.1758, found 313.1750; FT-IR neat, ν ̃
(cm-1)
6 | Org. & Biomol. Chem., 2014, 00, 1-3
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DOI: 10.1039/C4OB02105C
Page 7 of 8
Org & Biomol Chem
Organic & Biomolecular Chemistry
ARTICLE
3323, 2972, 1728, 1698, 1530, 1328, 1232, 1152, 1105; specific rotation
[ɑ]D28.3 = -26.2 cm3 g-1 dm-1 (c = 1 in CHCl3).
:
4.
5.
P. Wipf and C. P. Miller, Tetrahedron Lett., 1992, 33, 6267–6270.
F. Yokokawa and T. Shioiri, Tetrahedron Lett., 2002, 43, 8679–
8682.
(S)-2-(1-aminoethyl)-5-methyloxazole-4-carboxylic acid methyl ester
(3h). 1H-NMR (400 MHz, CDCl3) δ = 5.02 (q, 1H, J = 6.2 Hz), 3.91 (s, 3H),
2.68 (s, 3H), 1.36 (d, 3H, J = 6.3 Hz) ppm. Data match those reported in: A.
I. Meyers and F. X. Tavares J. Org. Chem. 1996, 61, 8207-8215.
6.
7.
F. Yokokawa, Y. Hamada, and T. Shioiri, Synlett, 1992, 153–155.
A. I. Meyers and D. Hoyer, Tetrahedron Lett., 1985, 26, 4687–
4690.
(S)-2-(1-((tert-Butoxycarbonyl)amino)-2-methylpropyl)oxazole-4-
carboxylic acid methyl ester (3i). 1H-NMR (400 MHz, CDCl3) δ = 5.28 (d,
1H, J = 8.8 Hz), 4.80 (dd, 1H, J = 8.8, 6.2 Hz), 3.92 (s, 3H), 2.19 (m, 1H),
1.43 (s, 9H), 0.93 (d, 3H, J = 7.0 Hz), 0.91 (d, 3H, J = 6.8 Hz) ppm. Data
matched those reported in: A. Bertram and G. Pattenden Heterocycles 2002,
58, 521-561.
8.
A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, and D. R. Williams,
Org. Lett., 2000, 2, 1165–1168.
9.
M. Baumann, I. R. Baxendale, M. Brasholz, J. J. Hayward, S. V.
Ley, and N. Nikbin, Synlett, 2011, 2011, 1375–1380.
5-Methyl-2-(3-methyloxetan-3-yl)oxazole-4-carboxylic acid methyl
ester (3j) 1H-NMR (400 MHz, CDCl3) δ = 5.06 (d, 2H, J = 5.9 Hz), 4.53
(d, J = 5.9 Hz, 2H), 3.89 (s, 3H), 2.62 (s, 3H), 1.79 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 164.0, 162.7, 156.7, 127.4, 80.5, 52.0, 39.6,
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
D. W. Knight, G. Pattenden, and D. E. Rippon, Synlett, 1990, 1990,
36–37.
+
22.8, 12.0; HR-MS (ESI+) for C10H14NO4 [M+H]+ calc.: 212.0917,
found: 212.0913; FT-IR neat, ν ̃
(cm-1) 2956, 2880, 1719, 1668, 1621,
1585, 1441, 1350, 1250, 1180, 1132, 1090, 980, 787.
J. A. Lafontaine, D. P. Provencal, C. Gardelli, and J. W. Leahy, J.
Org. Chem., 2003, 68, 4215–4234.
A. I. Meyers and F. Tavares, Tetrahedron Lett., 1994, 35, 2481–
2484.
2'-((1S,2S)-1-((tert-Butoxycarbonyl)amino)-2-methylbutyl)-[2,4'-
bioxazole]-4-carboxylic acid methyl ester (5). 1H-NMR (CDCl3, 400
MHz) δ = 8.30 (s, 1H), 8.29 (s, 1H), 5.30 (d, J = 9.1 Hz, 1H), 4.90 (dd, J
= 9.2, 5.8 Hz, 1H), 3.94 (s, 3H), 2.02–1.92 (m, 1H), 1.47-1.40 (m, 10H),
1.43 (m, 1H), 0.90–0.80 (m, 6H); 13C-NMR (CDCl3, 100 MHz) δ =
165.5, 161.3, 155.7, 155.2, 143.7, 139.3, 134.3, 129.6, 80.1, 53.4, 52.3,
39.5, 28.3, 25.1, 15.2, 11.4; HRMS (ESI) for C18H25N3O6Na+ [M+Na]+
Y. Huang, L. Ni, H. Gan, Y. He, J. Xu, X. Wu, and H. Yao,
Tetrahedron, 2011, 67, 2066–2071.
Y.-B. Yu, H.-L. Chen, L.-Y. Wang, X.-Z. Chen, and B. Fu,
Molecules, 2009, 14, 4858–4865.
calculated: 402.1636; found: 402.1629; FT-IR neat, ν ̃
(cm-1) 3141, 2959,
1721, 1690, 1509, 1247, 1147, 1001, 870, 729; specific rotation: [ɑ]D
= -34.0 cm3 g-1 dm-1 (c = 1 in CHCl3).
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K. Meguro, H. Tawada, Y. Sugiyama, T. Fujita, and Y. Kawamatsu
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Acknowledgements
For information about Omnifit® glass columns, see:
http://www.omnifit.com/
We are grateful to the Swiss National Science Foundation (DNT), the
Ralph Raphael fellowship (RJI), the German Academic Exchange Service
DAAD (SF), the Royal Society Newton International Fellowship (ZEW),
Pfizer Worldwide Research and Development (CB) and the EPSRC
(SVL, SF and ZEW, grant nº EP/K0099494/1) for financial support. The
Labtrix Start was kindly loaned by Chemtrix BV and the liquid-liquid
phase separator by Zaiput Flow Technologies (we are grateful to Dr
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b
Department of Chemistry, University of Cambridge, Lensfield Road,
a) Due to the approximate concentration of Deoxo-Fluor® solutions
(≈50% in toluene) in commercial samples, we could only obtain
reproducible results using 1.35 equiv of reagent; b) Deoxo-Fluor®
(≈50% in toluene) was purchased from Sigma Aldrich (94324-
50ML-F) and used as supplied.
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This journal is © The Royal Society of Chemistry 2012
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8 | Org. & Biomol. Chem., 2014, 00, 1-3
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