Widely Exploited, Yet Unreported: Regiocontrolled Synthesis and the Suzuki–Miyaura Reactions of Bromooxazole Building Blocks

Article abstract of DOI:10.1002/ejoc.201900032

An approach to synthesis of 2-, 4-, and 5-bromooxazoles is described. The method was optimized, and its scope was extended to all three isomeric parents, as well as various alkyl- and aryl-substituted bromooxazoles. It was found that direct regiocontrolled lithiation followed by reaction with electrophilic bromine source was common for all substrates and led exclusively to the target substituted 2-, 4- and 5-bromooxazoles on multigram scale. The utility of the multipurpose building blocks obtained in this work was demonstrated in the Suzuki–Miyaura cross-coupling reaction under parallel synthesis conditions.

Full text of DOI:10.1002/ejoc.201900032

A Journal of
Accepted Article
Title: Widely exploited, yet unreported: regiocontrolled synthesis and
the Suzuki–Miyaura reactions of bromooxazole building blocks
Authors: Vitalii V. Solomin, Dmytro S. Radchenko, Evgeniy Y.
Slobodyanyuk, Oleksandr V. Geraschenko, Bohdan V.
Vashchenko, and Oleksandr O Grygorenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900032
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900032
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10.1002/ejoc.201900032
European Journal of Organic Chemistry
FULL PAPER
Widely exploited, yet unreported: regiocontrolled synthesis and
the Suzuki–Miyaura reactions of bromooxazole building blocks
Vitalii V. Solomin,[a] Dr. Dmytro S. Radchenko,[a,b] Evgeniy Y. Slobodyanyuk,[a,c]
Oleksandr V. Geraschenko,[a] Bohdan V. Vashchenko,[a,b] Dr. Oleksandr O. Grygorenko*[a,b]
Dedication ((optional))
Abstract: An approach to synthesis of 2-, 4- and 5-bromooxazoles
is described. The method was optimized and its scope was extended
to all three isomeric parent, as well as various alkyl- and aryl-
substituted bromooxazoles. It was found that direct regiocontrolled
lithiation followed by reaction with electrophilic bromine source was
common for all substrates and led exclusively to the target
substituted 2-, 4- and 5-bromooxazoles on multigram scale. The
utility of the multipurpose building blocks obtained in this work was
demonstrated in the Suzuki–Miyaura cross-coupling reaction under
parallel synthesis conditions.
Although synthesis and chemical properties of substituted
oxazoles were studied and reviewed comprehensively to date,[1–
3,11,29,30]
most of the known methods relied on the late-stage
oxazole ring construction, which limits their synthetic variability.
With the advance of palladium-catalyzed reactions in organic
chemistry, an alternative approach which involves the use of
oxazole-containing building blocks (such as bromo derivatives)
can be envisaged. Indeed, diversely substituted bromooxazoles
were reported as multipurpose building blocks for various
transformations, including:

palladium-catalyzed Negishi reactions,[31,32] Suzuki–
Miyaura,[31–42] Stille,[31–35] and including sp3–sp2 cross-
coupling,[36] Heck reaction with alkenes and alkynes;[37]
Buchwald–Hartwig amination,[38] alkoxylation[38] and
aminocarbonylation.[39]
Introduction


Cu-mediated (trifluoro)methylation;[34,38]
Oxazole is one of the most important heterocycles in organic
synthesis and drug discovery, which is often encountered as a
structural unit of natural products and synthetic compounds[1]
demonstrating broad range of biological activities, e.g.
anticancer, antifungal or antibacterial.[2,3] Among the first isolated
natural oxazoles, 2,5-disubstituted derivatives were dominating,
e.g. alkaloid pimprinine (1) and its analogues,[4] annuloline (2),[5]
balsoxin (3) and texaline (4)[6,7] (Figure 1). In recent years, a
wide range of chemically and biologically important oxazoles
with 2,4-disubstitution pattern have been studied, specifically
protein kinase inhibitor mubritinib (5),[8] and antimicrobal
phenoxan (6).[9,10] Moreover, this class is complemented with
macrolides, first isolated from marine products in the late
1980s,[11] e.g. cytostatic anti-mitotic phorboxazoles,[12,13]
antibiotic rhizoxins,[14,15] cytotoxic enigmazole A,[16] steptogramin
antibiotic virginiamycins,[17–20] and acyclic serine/threonine
protein phosphatase inhibitors calyculins.[21,22] Less numerous
group of 4,5-disubstituted oxazoles is represented by
streptochlorin (7),[23,24] while trisubstituted derivatives include
lipid peroxidation inhibitor martefragin A (8).[25,26] In addition to
that, trisubstituted oxazoles exhibited scintillative, photochromic
and fluorescence switching properties.[27,28]
classical
aromatic
nucleophilic
substitution
(SNAr).[2,40,41]
[a]
V. V. Solomin, D. S. Radchenko, E. Y. Slobodyanyuk,
O. V. Geraschenko, B. V. Vashchenko, O. O. Grygorenko
Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv
02094, Ukraine, Chervonotkatska Street 78, Kyiv 02094, Ukraine
D. S. Radchenko, B. V. Vashchenko, O. O. Grygorenko
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
[b]
[c]
E. Y. Slobodyanyuk
Institute of Organic Chemistry, National Academy of Sciences of
Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
E-mail: gregor@univ.kiev.ua
Figure 1. Some important representatives of di- and trisubstituted oxazoles.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Figure 2. Bromooxazoles – the target compounds of this study.
Despite numerous literature examples of the above-mentioned
transformations involving bromooxazoles, synthesis of these
building blocks is largely underrepresented in the literature. This
is especially true for alkyl-substituted derivatives; even the
parent compounds 9–11 were mentioned only in patents.[42–44] In
this work, we describe an efficient synthetic strategy providing
were varied: base (n-BuLi, LDA, LHDMS); electrophile (C2F4Br2,
CBr4, Br2, NBS); temperature (–80 °C to –20 °C); and the
reaction time (0.5–3 h). In all cases, destruction of the oxazole
ring occurred; no traces of the target compound 34 were
detected.
We anticipated that 2-TIPS-5-bromoxazole (34) is not stable
towards work-up procedure and decided to perform its
desilylation using an in situ deprotection protocol. Several
methods were evaluated including the use of fluoride sources
(TBAF, KHF2), as well as aqueous or alcoholic solutions of acids.
Although 5-bromoxazole (10) was formed in all these cases, its
boiling point was close to that of the corresponding organosilicon
by-product (e.g. TIPSF), which hampered its isolation by
vacuum distillation. On the other hand, chromatographic
purification of 10 was also challenging due to volatility of the
products, which dramatically decreased its purity and yield. The
solution to this problem included isolation of the product 10 as a
hydrochloride. Therefore, synthesis of 10HCl relied on the
following one-pot procedure: subsequent treatment of 33 with n-
BuLi, bromine, and gaseous HCl, which gave the target product
in 82% yield (Scheme 2).
rapid access to
a
series of bromooxazoles, which is
demonstrated by preparation of representative examples 9–31
(Figure 2). In addition to that, utility of these products for the
parallel synthesis is also shown.
Results and Discussion
Synthesis of the parent bromooxazoles. First of all, all three
isomeric 2-, 4-, and 5-bromooxazoles were prepared. Synthesis
of 2-bromooxazole (9) relied on direct lithiation of oxazole (32),
which is known to occur at the C-2 position (Scheme 1).[45,46]
Subsequent electrophilic trapping of the corresponding
organolithium intermediate with 1,2-dibromo-1,1,2,2-tetrafluo-
ethane (DBTFE) resulted in regioselective C-2 bromination and
gave the target product 9 in good yield (74%).
Scheme 1. Synthesis of 2-bromooxazole (9).
The most promising approach envisaged by us for the
preparation of 5-bromooxazole (10) involved the use of
triisopropylsilyl derivative 33 to protect the C-2 atom of the ring
against the lithiation. Reaction of 33 with organolithium reagents
is known to occur regioselectively at the C-5 position.[47–49]
Therefore, we have prepared intermediate 33 by reaction of 32
with n-BuLi and then – freshly prepared TIPSOTf (Scheme 2).[47]
Nevertheless, all our attempts to obtain 2-TIPS-5-bromoxazole
(34) from (33) were unfruitful. The following reaction parameters
Scheme 2. Synthesis of 5-bromooxazole (10HCl).
Among several known methods for the preparation of 4-
bromooxazoles,[2,4,30,32,35,50–53] we have turned our attention to
the LDA-mediated halogen dance reaction of 2-substituted 5-
bromooxazoles (Scheme 3).[54–56] Thus, the advantage of above-
described one-pot reaction sequence for the preparation 5-
bromooxazole (10) might be taken for the synthesis of the
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10.1002/ejoc.201900032
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previously unknown 4-bromo derivative (11), if LDA-mediated
halogen dance step would be added (Scheme 4).
for such transformations were prepared using a modified
literature method, starting from the corresponding 5-substituted
oxazole-4-carboxylates 37a–d.[60–63] In turn, esters 37a–d were
obtained according to the classical approach developed by
Cornforth and others.[63–67]
The compounds 37a–d were subjected to alkaline hydrolysis
using an improved version of the method described previously
for 37a (NaOH in MeOH, 40 °C, 82%[62]); namely, it was found
that the yield of the carboxylic acids 38a–d was higher if NaOH
in THF – H2O was used at 0 °C to rt (85–92%). The standard
procedure for the decarboxylation step (CuO, quinoline, 180–
190 C)[60,61,63] was also slightly modified; in particular, neat 38
a–d were heated with CuO with simultaneous distillation of the
product via Vigreux column. This protocol gave 5-alkyloxazoles
36a–d in 62–91% yield. Finally, the key step of the synthesis –
lithiation at the C-2 position, followed by reaction with DBTFE
proceeded smoothly and led to 5-alkyl-2-bromooxazoles 12–15
as single regioisomers (48–80% yield).
Scheme 3. Known synthesis of substituted 4-bromooxazoles via halogen
dance rearrangement.
It is interesting to note that unlike 2-TIPS-5-bromoxazole (34),
isomeric 2-TIPS-4-bromoxazole (35) could be isolated from the
reaction mixture, and it was stable at rt. Due to this reason, its
chromatographic purification became possible, which gave the
product 35 in 46% yield. Subsequent desilylation step was
performed by action of HCl in Et2O, which led to target 4-
bromooxazole (11) as hydrochloride (52% yield).
Scheme 4. Preparation of 4-bromooxazole (11HCl).
Synthesis of 5-alkyl-2-bromooxazoles. The known methods
for the preparation of 2-bromooxazoles substituted at the C-5
atom include the following transformations (Scheme 5):



reaction of -isocyanocarboxylates with bromine,
followed by DBU-mediated cyclization;[57]
treatment of 5-phenyloxazole with t-BuOLi and 1,2-
dibromo-1,1,2,2-tetrafluoroethane (DBFTE);[58,59]
modified Sandmayer reaction of for the corresponding
aminooxazoles.[32,40]
Scheme 6. Synthesis of 5-alkyl-2-bromooxazoles 12–15.
Synthesis of 4-substituted 2-bromooxazoles. Being inspired
by the above-described results with 5-substituted oxazoles 12–
15, we have extended this methodology for the preparation of 4-
substited analogues. It should be noted that to date, no
examples of 4-substituted 2-bromooxazoles were described in
the literature.
Scheme 7. Synthesis of 4-substituted oxazoles 41d–e.
The parent 4-tert-butyl- (41d)[68] and 4-phenyloxazole (41e)[69]
were prepared using the reported procedures (Scheme 7). 4-
Methyloxazole (41a), as well as the previously unknown 4-ethyl
(41b) and 4-n-propyl (41c) derivatives were synthesized in 75–
82% yield using a modification of the method described in the
literature for the simplest representative 41a;[70] the procedure
was analogous to that for 36a–d (Scheme 8).
Scheme 5. Known literature approaches to substituted 2-bromooxazoles.
None of these methods was used for the preparation of 5-alkyl-
2-bromooxazoles, which remained unknown in the literature so
far. In our approach to the compounds 12–15 (Scheme 6), we
have turned our attention to the second method mentioned
above, which was used for the preparation of 2-bromo-5-
phenyloxazole (Scheme 5). 5-Alkyloxazoles 36a–d necessary
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synthesis of 2,5-disubstituted derivatives. For example, 5-
bromo-2,4-dimethyloxazole (31) was synthesized previously by
flash-vacuum pyrolysis of 2-acetyl-4-bromo-3-methylisoxazol-
5(2H)-one.[79] We have prepared compound 31 in 55% yield from
42 by electrophilic bromination with NBS (Scheme 11). Hence in
this case, the metallation step could be omitted.
Scheme 11. Synthesis of 5-bromo-2,4-dimethyloxazole (31).
For the preparation of remaining compounds of the 2-substituted
5-bromooxazole series (24–30), our general approach including
the lithiation step was applied. Synthesis of the corresponding 2-
alkyl oxazoles 49a–d relied on the reaction sequence reported in
the literature for the simplest representative 49a (R = Me)
(Scheme 12).[63] In particular, nitriles 43 were introduced into the
Pinner reaction providing intermediate carboximidates, which
reacted with serine methyl ester to give disubstituted oxazolines
44a–d (79–89%).[80] Aromatization of the compounds 44a–d was
performed upon treatment with bromotrichloromethane with DBU
and provided the corresponding esters 45a–d in 61–79%
yield.[81] Their alkaline hydrolysis gave the corresponding
carboxylic acids 46a–d (67–91% yield). The tert-Butyl-
substituted oxazole derivative 46e was prepared in 59% overall
yield using a slightly different method, i.e. reaction of pivalamide
(47) with bromopyruvate 48, followed by alkaline hydrolysis.
Scheme 8. Synthesis of 4-substituted oxazoles 41a–c.
Lithiation of oxazoles 41a–e with n-BuLi, followed by the
subsequent bromination with DBTFE was also regioselective
and gave the target products 16–20 in 61–98% yield (Scheme 9).
Scheme 9. Synthesis of 4-substituted 2-bromooxazoles 16–20.
Synthesis of 2-substituted 5-bromooxazoles. The known
methods for the preparation of substituted 5-bromooxazoles
(Scheme 10) include:

bromination of the corresponding oxazoles with Br2 in
refluxing benzene or CH2Cl2,[2] NBS–H2SO4
HOAc,[72,73] or NBS – HOAc;[74]
or
[71]



metallation, followed by reaction with electrophilic
bromine source (t-BuLi / Br2,[34,75] LDA / NBS);[31,76]
aromatization of 2-aryloxazolines using NBS
AIBN;[77,78]
–
modified
Sandmeyer
reaction
of
4-cyano-5-
aminooxazoles.[33,38,39]
Scheme 12. Synthesis of carboxylic acids 46a–e.
CuO-mediated decarboxylation of the resulting carboxylic acids
46a–e (55–87% yield) gave the key intermediates 49a–e
(Scheme 13). Lithiation of 49a–e followed by reaction with
DBTFE occurred under standard conditions and led to the target
5-bromo derivatives 24–28 in 40–88% yield.
Scheme 10. Known methods for the preparation of substituted 5-
bromooxazoles.
Although numerous papers reported preparation of trisubstituted
5-bromooxazoles, none of these methods was applied to the
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10.1002/ejoc.201900032
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Scheme 13. Synthesis of 2-alkyl-5-bromooxazoles 24–28.
Scheme 16. Synthesis of bromooxazole 22.
To further extend the scope and limitations of the proposed
method, the known 5-bromo-2-phenyloxazole 29[77,78] was also
prepared. In particular, 2-phenyloxazole (50) (obtained from
oxazole 32 in 83% yield using the known method[7]) was
introduced into the lithiation–bromination sequence, which gave
the target building block 29 in 95% (Scheme 14).
Unfortunately, deoxofluorination of the corresponding carboxylic
acid 21 (prepared by alkaline hydrolysis of 54 in 93% yield) was
not fruitful. Therefore, aminooxazole 56 was prepared by the
known method[84,85] and subjected to the modified Sandmeyer
reaction (t-BuONO
–
CuBr2), which gave the target
trifluoromethyl derivative 23 in 33% yield (Scheme 17).
Scheme 14. Synthesis of 5-bromo-2-phenyloxazole 29.
Synthesis of 4-methyl-5-bromooxazole. First of all, 4-
methyloxazole 40a was prepared according to the Cornforth
protocol.[70] Subsequently, it was protected at the C-2 position
using n-BuLi – TIPSOTf, which gave the corresponding 2-TIPS
derivative 51 in 98% yield (Scheme 15). Then, compound 51
was subjected to the metalation – bromination sequence which
occurred at the C-5 position; this step gave the trisubstituted 5-
bromooxazole 52 (57% yield). After the deprotection step, the
target compound 30 was obtained in 40% yield.
Scheme 17. Synthesis of oxazoles 21 and 23.
Parallel Suzuki–Miyaura reaction of bromooxazoles. To
demonstrate utility of the building blocks obtained for organic
chemistry and drug discovery, they were evaluated in the
Suzuki–Miyaura cross-coupling reaction under the parallel
synthesis conditions. First of all, a library was generated by
virtual coupling of 16 bromooxazoles (11, 14–16, 18, 20, 22, 23,
25–31, and 54) and 173 organoboron derivatives 57 (Figure S1).
After removal of duplicates, the resulting set was subjected to
filtering according to lead-likeness criteria[86] (MW = 200…350,
cLogP = –1…3, no more than five consequent chain bonds).
Table 1. Parallel synthesis of the library 58.
Scheme 15. Synthesis of bromooxazole 30HCl.
Synthesis of fluorine-containing 2-bromooxazole deriva-
tives. Fluorinated oxazoles were recognized as promising
building blocks for medicinal and agrochemistry.[40,71,82,83] In this
view, we have turned our attention to the preparation of novel
fluorine-containing bromides 22 and 23 (Schemes 16 and 17). In
the case of 22, the bromine was incorporated into the
heterocyclic moiety via substitution in the 2-chlorooxazole
derivative 53 using TMSBr (90% yield). Reduction of the ester
54 with DIBAL at –78 °C gave the corresponding aldehyde 55 in
84% yield. The target difluoroalkyl derivative 22 was obtained
from aldehyde 55 via deoxofluorination with morpholinosulfur
trifluoride in 78% yield.
Method
Boc derivative
No. of
experiments
Success
rate, %
Average
yield, %
57
70
A
B
Pd(OAc)2, dppf, Na2CO3
N-methylpyrrolidone, H2O
,
164
60
32
34
XPhos Pd G2, Cs2CO3,
N-methylpyrrolidone,
1,4-dioxane, H2O
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Finally, 224 library members were randomly selected so that 15 Conclusions
library members per bromooxazole and 3 – per organoboron
reagent were included into the set (at least one library member
per reagent). For the coupling step, two procedures were used:
(i) Pd(OAc)2, dppf, Na2CO3 , N-methylpyrrolidone, H2O (method
A); (ii) XPhos Pd G2, Cs2CO3, N-methylpyrrolidone, 1,4-dioxane,
H2O (method B) (Table 1).
As a result, 135 of 224 library members were prepared (Figure 3,
Table S1). It was found, that the parallel synthesis success rate
was slightly higher in the case of the method B (70%) as
compared to the method A (57%); meanwhile, the average
yields of oxazoles 58 were nearly equal for both applied
methods.
Despite numerous examples of using bromooxazoles as building
blocks in organic and medicinal chemistry, their synthesis has
been largely underrepresented in the literature; this is especially
true for the alkyl-substituted derivatives. In this work, we have
shown that a general strategy for the preparation of such
compounds relies on a regioselective lithiation – bromination
reaction sequence using n-BuLi
–
1,2-dibromo-1,1,2,2-
tetrafluoroethane (DBFTE) system. This method was very
efficient for the parent 2-bromooxazole (9) (obtained in 74%
yield) and could be extended to all isomeric alkyl- and phenyl-
substituted 2-bromooxazoles (61–98% yield). The target
products could be obtained on a 100 g scale. The strategy was
also successful in the case of 2-substituted 5-bromooxazoles
Figure 3. Selected examples of the library members 58.
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(122 g, 0.468 mol) was added dropwise at –78 °C, and the mixture was
allowed to warm up to rt overnight. Saturated aq NH4Cl (300 mL) was
added to the stirred mixture. Most of hexane and THF were evaporated
in vacuo (NOTE: the temperature should not exceed 24 °C) and the
residue was extracted with Et2O (3250 mL). Organic layer was
separated and washed with brine (375 mL), dried over Na2SO4 and
evaporated in vacuo.
(40–88% yield); in the case of parent 5-bromooxazole (10), as
well as 4-methyl-5-bromooxazole (30), the required
regioselectivity was achieved via temporary silylation at the C-2
atom.
4-Bromooxazole appeared to be the most challenging synthetic
target in this series; it could be obtained via LDA-mediated
halogen dance rearrangement of the corresponding 2-silylated
5-bromo derivative (22% yield from the parent oxazole).
In some specific cases, alternative synthetic strategies were
envisaged. In particular, 2,4-dimethyl-5-bromooxazole (31) was
obtained by simple electrophilic bromination in 55% yield. 2-
Bromo-4-(difluoromethyl)oxazole (22) was prepared via
deoxofluorination of the corresponding aldehyde with morph-
DAST (78% yield). 2-Bromo-4-(trifluoromethyl)oxazole (23) could
be prepared by Sandmayer reaction of the corresponding
aminooxazole (33% yield).
The utility of the target bromooxazoles as building blocks was
demonstrated by the Suzuki–Muyaura cross-coupling reactions
with aryl or vinyl boronic derivatives in the presence of Pd(OAc)2
– dppf – Na2CO3 or XPhos Pd G2 – Cs2CO3 under parallel
synthesis conditions. The target products were obtained with
60% synthesis success rate and 33% average yield; the second
catalytic system appeared to give slightly better productivity.
2-Bromooxazole hydrochloride (9HCl). The compound was purified by
distillation in vacuo. Yield 66.1 g (74%); colorless liquid; bp 27–29 °C / 15
mmHg. 1H NMR (400 MHz, CF3COOD) δ = 7.74 – 7.69 (m, 1H), 7.15 –
7.09 (m, 1H). 13C NMR (126 MHz, CF3COOD) δ = 146.2, 139.1, 121.8.
GC/MS (EI): m/z = 147/149 [M]+. Anal. calcd. for C3H3BrClNO: C, 19.54;
H, 1.64; N, 7.60; Cl, 19.22; Br, 43.33. Found: C, 19.16; H, 2.04; N, 7.70;
Cl, 19.10; Br. 43.43.
2-Bromo-5-methyloxazole (12). The compound was purified by
distillation in vacuo. Yield 37.6 g (48%); yellowish liquid; bp 53–55 °C / 15
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.70 (d, J = 1.4 Hz, 1H), 2.31 (d, J
= 1.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 153.2, 131.3, 126.5, 11.1.
GC/MS (EI): m/z = 161/163 [M]+. Anal. calcd. for C4H4BrNO: C, 29.66; H,
2.49; N, 8.65; Br, 49.33. Found: C, 29.41; H, 2.36; N, 9.00; Br, 49.45.
2-Bromo-5-ethyloxazole (13). The compound was purified by distillation
in vacuo. Yield 56.2 g (66%); yellowish liquid; bp 65–67 °C / 20 mmHg.
1H NMR (400 MHz, CDCl3) δ = 6.71 (s, 1H), 2.67 (q, J = 7.6 Hz, 2H),
1.24 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 158.6, 131.3,
124.3, 19.2, 11.5. GC/MS (EI): m/z = 175/177 [M]+. Anal. calcd. for
C5H6BrNO: C, 34.12; H, 3.44; N, 7.96; Br, 45.4. Found: C, 34.08; H, 3.20;
N, 7.99; Br, 45.32.
Experimental Section
The solvents were purified according to the standard procedures.[87]
Compounds 37a–d, 40a, 41d, 41e, 43, 47, 48, 54, 56 were available
from Enamine Ltd. All other starting materials were purchased from
commercial sources. Melting points were measured on MPA100 OptiMelt
automated melting point system. Analytical TLC was performed using
Polychrom SI F254 plates. Column chromatography was performed
using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. 1H
and 13C NMR spectra were recorded on a Bruker 170 Avance 500
spectrometer (at 500 MHz for 1H NMR, 126 MHz for 13C NMR and 470
MHz for 19F NMR) and Varian Unity Plus 400 spectrometer (at 400 MHz
for 1H NMR, 101 MHz for 13C NMR and 376 MHz for 19F NMR). NMR
chemical shifts are reported in ppm (δ scale) downfield from TMS as an
internal standard and are referenced using residual NMR solvent peaks
at 7.26 and 77.16 ppm for 1H and 13C in CDCl3, 2.50 and 39.52 ppm for
1H and 13C in DMSO-d6. Coupling constants (J) are shown in Hz. Spectra
are reported as follows: chemical shift (δ, ppm), multiplicity, integration,
coupling constants (Hz). Elemental analyses were performed at the
Laboratory of Organic Analysis, Department of Chemistry, National Taras
Shevchenko University of Kyiv. Mass spectra were recorded on an
Agilent 1100 LCMSD SL instrument (chemical ionization (CI)) and Agilent
5890 Series II 5972 GCMS instrument (electron impact ionization (EI)).
Parallel synthesis of the library 58 was set using an automated liquid
handling system in the 96-well microplates, and the amounts of reagents
for each substrate were calculated by in-house developed computational
software. The reagents for parallel synthesis were used as stock 0.5–1 M
solutions in N-methylpyrrolidone, 1,4-dioxane or H2O. SiliaMetS® DMT
(Dimercaptotriazine) was used for the filtration of the reaction mixtures.
2-Bromo-5-isopropyloxazole (14). The compound was purified by
distillation in vacuo. Yield 76.3 g (83%); yellowish liquid; bp 47–49 °C / 1
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.70 (s, 1H), 2.97 (hept, J = 6.9
Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ = 162.6,
131.4, 123.2, 26.2, 20.4. GC/MS (EI): m/z = 189/191 [M]+. Anal. calcd. for
C6H8BrNO: C, 37.92; H, 4.24; N, 7.37; Br, 42.05. Found: C, 37.63; H,
3.86; N, 7.64; Br, 42.36.
2-Bromo-5-(tert-butyl)oxazole (15). The compound was purified by
distillation in vacuo. Yield 47.4 g (48%); colorless liquid; bp 63–65 °C / 1
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.67 (s, 1H), 1.28 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ = 165.3, 131.5, 122.3, 31.7, 28.4. GC/MS (EI):
m/z = 203/205 [M]+. Anal. calcd. for C7H10BrNO: C, 41.20; H, 4.94; N,
6.86; Br, 39.16. Found: C, 41.48; H, 5.20; N, 6.69; Br, 39.13.
2-Bromo-4-methyloxazole (16). The compound was purified by
distillation in vacuo. Yield 47.8 g (61%), brownish liquid, bp 71–73 °C / 20
mmHg. 1H NMR (400 MHz, CDCl3) δ = 7.42 (q, J = 1.4 Hz, 1H), 2.16 (d, J
= 1.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 139.5, 138.4, 132.9, 11.7.
GC/MS (EI): m/z = 161/163 [M]+. Anal. calcd. for C4H4BrNO: C, 29.66; H,
2.49; N, 8.65; Br, 49.33. Found: C, 29.94; H, 2.09; N, 8.29; Br, 49.29.
2-Bromo-4-ethyloxazole (17). The compound was purified by distillation
in vacuo. Yield 83.5 g (98%); yellowish oil; bp 92–94 °C / 15 mmHg. 1H
NMR (500 MHz, CDCl3) δ = 7.42 (s, 1H), 2.55 (q, J = 7.5 Hz, 2H), 1.22 (t,
J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 145.2, 137.1, 132.4,
19.3, 11.8. GC/MS (EI): m/z = 175/177 [M]+. Anal. calcd. for C5H6BrNO:
C, 34.12; H, 3.44; N, 7.96; Br, 45.4. Found: C, 34.33; H, 3.49; N, 7.78; Br,
45.53.
General procedure for the preparation of 2-bromooxazoles 9, 12–20,
24–28. The corresponding oxazole 36a–d, 41a–e, or 49a–e (0.446 mol)
was dissolved in THF (450 mL), and n-BuLi (196 mL, 2.5 M in hexanes,
0.491 mol) was added dropwise at –78 °C. The reaction mixture was
stirred for additional 40 min, then 1,2-dibromo-1,1,2,2-tetrafluoroethane
2-Bromo-4-propyloxazole (18). The compound was purified by
distillation in vacuo. Yield 82.8 g (90%); colorless liquid; bp 59–61 °C / 13
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10.1002/ejoc.201900032
European Journal of Organic Chemistry
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mmHg. 1H NMR (500 MHz, CDCl3) δ = 7.43 (s, 1H), 2.48 (t, J = 7.4 Hz,
2H), 1.65 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ = 144.0, 138.1, 132.9, 28.3, 21.2, 13.6. GC/MS (EI): m/z =
189/191 [M]+. Anal. calcd. for C6H8BrNO: C, 37.92; H, 4.24; N, 7.37; Br,
42.05. Found: C, 38.26; H, 4.23; N, 7.29; Br, 42.28.
5-Bromo-2-phenyloxazole (29). The compound was purified by column
chromatography on silica gel using hexanes – EtOAc (30:1) as eluent, Rf
= 0.34. Yield 103 g (95%), yellow solid; mp 63–65 °C. 1H NMR (400 MHz,
CDCl3) δ = 8.03 – 7.97 (m, 2H), 7.49 – 7.44 (m, 3H), 7.10 (s, 1H). 13C
NMR (126 MHz, CDCl3) δ = 163.2, 130.7, 128.8, 128.6, 126.7, 126.1,
121.3. GC/MS (EI): m/z = 223/225 [M]+. Anal. calcd. for C9H6BrNO: C,
48.25; H, 2.70; N, 6.25; Br, 35.66. Found: C, 48.17; H, 2.80; N, 6.00; Br,
35.40.
2-Bromo-4-(tert-butyl)oxazole (19). The compound was purified by
distillation in vacuo. Yield 89.9 g (91%); yellowish liquid; bp 50–52 °C / 1
mmHg. 1H NMR (400 MHz, CDCl3) δ = 7.36 (s, 1H), 1.24 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ = 153.4, 135.9, 132.8, 31.2, 28.9. GC/MS (EI):
m/z = 203/205 [M]+. Anal. calcd. for C7H10BrNO: C, 41.20; H, 4.94; N,
6.86; Br, 39.16. Found: C, 40.99; H, 5.05; N, 6.57; Br, 39.43.
5-Bromooxazole hydrochloride (10). 2-TIPS-oxazole (33) (9.59 g, 42.5
mmol) was dissolved in THF (250 mL), and the solution was cooled to –
78 °C. n-BuLi (20.5 mL, 2.5 M in hexanes, 51.1 mmol) was added
dropwise and the mixture was stirred at –78 °C for additional 30 min.
Then Br2 (8.16 g, 51.1 mmol) was added dropwise at –78 °C. The
reaction mixture was warmed to –10 °C over 40 min. Stream of gaseous
HCl was bubbled through the solution at –10 °C (NOTE: the temperature
should not exceed +5 °C). White precipitate started to form; the reaction
mixture was stirred at +5 °C for additional 30 min and filtered. The
precipitate was filtered, washed with cold Et2O (240 mL) and dried on
air at rt for 10 min. Yield 6.43 g (82%), white solid; mp 142–144 °C. 1H
NMR (400 MHz, CF3COOD) δ = 9.60 (s, 1H), 7.77 (s, 1H). 13C NMR (126
MHz, CF3COOD) δ = 155.4, 129.2, 118.7. GC/MS (EI): m/z = 147/149
[M]+. Anal. calcd. for C3H3BrClNO: C, 19.54; H, 1.64; N, 7.60; Cl, 19.22;
Br, 43.33. Found: C, 19.28; H, 1.28; N, 7.55; Cl, 19.11; Br, 43.46.
2-Bromo-4-phenyloxazole (20). The compound was purified by column
chromatography on silica gel using hexanes – EtOAc (30:1) as eluent, Rf
= 0.46. Yield 66.1 g (61%); yellow solid; mp 71–73 °C. 1H NMR (400 MHz,
CDCl3) δ = 7.95 (s, 1H), 7.73 – 7.66 (m, 2H), 7.43 – 7.38 (m, 2H), 7.36 –
7.31 (m, 1H). 13C NMR (126 MHz, CDCl3) δ = 143.5, 137.1, 133.9, 129.7,
128.8, 128.7, 126.4. GC/MS (EI): m/z = 223/225 [M]+. Anal. calcd. for
C9H6BrNO: C, 48.25; H, 2.70; N, 6.25; Br, 35.66. Found: C, 47.91; H,
2.64; N, 6.01; Br, 35.42.
5-Bromo-2-methyloxazole (24). The compound was purified by
distillation in vacuo. Yield 31.4 g (40%); yellowish liquid; bp 55–57 °C / 15
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.85 (s, 1H), 2.45 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ = 163.0, 127.1, 120.3, 14.2. GC/MS (EI): m/z =
161/163 [M]+. Anal. calcd. for C4H4BrNO: C, 29.66; H, 2.49; N, 8.65; Br,
49.33. Found: C, 29.40; H, 2.21; N, 8.76; Br, 49.35.
4-Bromo-2-(triisopropylsilyl)oxazole (35). 2-TIPS-oxazole (33) (60.9 g,
0.270 mol) was dissolved in THF (500 mL), and n-BuLi (119 mL, 2.5 M in
hexanes, 0.297 mol) was added dropwise at –78 °C. The reaction
mixture was stirred for additional 30 min, and Br2 (47.5 g, 0.297 mol) was
added dropwise at –78 °C. The solution was warmed up to –30 °C over
40 min and then cooled to –78 °C. A solution of LDA, freshly prepared
from n-BuLi (119 mL, 2.5 M in hexanes, 0.297 mol) and diisopropylamine
(28.5 g, 0.282 mol) in THF (200 mL), was added dropwise at –78 °C, and
the mixture was stirred at this temperature for additional 35 min. Then,
H2O (9.72 mL, 0.540 mol) in THF (50 mL) was added dropwise, and the
reaction mixture was allowed to warm up to rt overnight. Saturated aq
NH4Cl (400 mL) was added to the stirred mixture. Most of hexanes and
THF were evaporated in vacuo, and the residue was extracted with
EtOAc (3200mL). The organic layer was separated, washed with brine
(375mL), dried over Na2SO4 and evaporated in vacuo. The compound
was purified by flash chromatography on silica gel using hexanes as
eluent, Rf = 0.95. Yield 37.8 g (46%); yellowish oil. 1H NMR (500 MHz,
CDCl3) δ = 7.78 (s, 1H), 1.42 (hept, J = 7.5 Hz, 3H), 1.13 (d, J = 7.5 Hz,
18H). 13C NMR (126 MHz, CDCl3) δ = 170.1, 138.8, 115.5, 18.3, 10.9.
LC/MS (CI): m/z = 306/308 [M+H]+. Anal. calcd. for C12H22BrNOSi: C,
47.36; H, 7.29; N, 4.60; Br, 26.26. Found: C, 47.32; H, 7.18; N, 4.85; Br,
26.50.
5-Bromo-2-isopropyloxazole (25). The compound was purified by
distillation in vacuo. Yield 57.0 g (62%); yellowish liquid; bp 72–74 °C / 1
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.85 (s, 1H), 3.05 (sept, J = 6.9
Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ = 170.1,
126.2, 119.7, 28.2, 19.7. GC/MS (EI): m/z = 189/191 [M]+. Anal. calcd. for
C6H8BrNO: C, 37.92; H, 4.24; N, 7.37; Br, 42.05. Found: C, 37.84; H,
4.33; N, 7.01; Br, 42.10.
5-Bromo-2-cyclobutyloxazole (26). The compound was purified by
distillation in vacuo. Yield 40.1 g (84%); yellowish liquid; bp 25–27 °C / 1
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.87 (s, 1H), 3.60 (p, J = 8.5 Hz,
1H), 2.48 – 2.28 (m, 4H), 2.11 – 1.92 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ = 168.9, 127.0, 120.2, 33.3, 27.2, 18.6. GC/MS (EI): m/z =
201/203 [M]+. Anal. calcd. for C7H8BrNO: C, 41.61; H, 3.99; N, 6.93; Br,
39.55. Found: C, 41.68; H, 4.14; N, 6.65; Br, 39.21.
5-Bromo-2-(tetrahydro-2H-pyran-4-yl)oxazole (27). The compound
was purified by column chromatography on silica gel using hexanes – t-
BuOMe (4:1) as eluent, Rf = 0.95. Yield 91.0 g (81%), yellowish crystals,
mp 55–57 °C. 1H NMR (400 MHz, CDCl3) δ = 6.90 (s, 1H), 4.02 (dt, J =
12.1, 3.5 Hz, 2H), 3.52 (td, J = 11.3, 2.8 Hz, 2H), 3.09 – 2.97 (m, 1H),
2.01 – 1.86 (m, 4H). 13C NMR (126 MHz, CDCl3) δ = 168.0, 126.9, 120.7,
67.0, 34.9, 29.9. GC/MS (EI): m/z = 231/233 [M]+. Anal. calcd. for
C8H10BrNO2: C, 41.40; H, 4.34; N, 6.04; Br, 34.43. Found: C, 41.09; H,
4.58; N, 6.27; Br, 34.13.
4-Bromooxazole hydrochloride (11). 2-TIPS-4-bromooxazole (35)
(36.6 g, 0.120 mol) was dissolved in Et2O (400 mL), and the solution was
cooled to 5 °C. Stream of gaseous HCl was bubbled through the stirred
reaction mixture at 5 °C for 30 min (NOTE: the temperature should not
exceed 10 °C). The reaction mixture was stirred at 10 °C for 3 h. The
precipitate was filtered, washed with cold Et2O (2100 mL), and dried on
air at rt for 10 min. Yield 11.5 g (52%); white powder; mp 92–94 °C. 1H
NMR (400 MHz, CF3COOD) δ = 9.54 (s, 1H), 8.16 (s, 1H). 13C NMR (126
MHz, CF3COOD) δ = 160.3, 146.6, 111.7. GC/MS (EI): m/z = 147/149
[M–HCl]+. Anal. calcd. for C3H3BrClNO: C, 19.54; H, 1.64; N, 7.60; Cl,
19.22; Br, 43.33. Found: C, 19.68; H, 1.76; N, 7.38; Cl, 18.91; Br, 43.58.
5-Bromo-2-(tert-butyl)oxazole (28). The compound was purified by
distillation in vacuo. Yield 86.9 g (88%); yiellowish liquid; bp 41–43 °C / 1
mmHg. 1H NMR (400 MHz, CDCl3) δ = 6.85 (s, 1H), 1.37 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ = 172.9, 126.6, 120.2, 34.1, 28.3. GC/MS (EI):
m/z = 203/205 [M]+. Anal. calcd. for C7H10BrNO: C, 41.20; H, 4.94; N,
6.86; Br, 39.16. Found: C, 41.60; H, 4.59; N, 7.02; Br, 39.07.
5-Bromo-2,4-dimethyloxazole (31).[79] 2,4-Dimethyloxazole (41) (37.8 g,
0.389 mol) was dissolved in CH2Cl2 (500 mL), and the solution was
cooled to 0 °C. NBS (83.1 g, 0.467 mol) was added in portions, and the
reaction mixture was stirred at rt overnight; then, it was quenched with
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10.1002/ejoc.201900032
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H2O (300 mL) upon stirring. The solution was washed with brine (2300
mL), the organic phase was separated, dried over Na2SO4, and
evaporated in vacuo. The compound was purified by distillation in vacuo.
Yield 37.7 g (55%); bp 78–80 °C / 15 mmHg. 1H NMR (400 MHz, CDCl3)
δ = 2.41 (s, 3H), 2.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 161.9,
134.6, 116.7, 14.1, 11.1. GC/MS (EI): m/z = 175/177 [M]+. Anal. calcd. for
C5H6BrNO: C, 34.12; H, 3.44; N, 7.96; Br, 45.40. Found: C, 33.83; H,
3.25; N, 8.35; Br, 45.09.
Ethyl 4-methyloxazole-5-carboxylate (39a). Yield 199 g (42%); grayish
solid. For spectral and physical data, see ref.[90,91]
Ethyl 4-ethyloxazole-5-carboxylate (39b).[92] The compound was
purified by chromatography on silica gel using hexanes - EtOAc (4:1) as
eluent, Rf = 0.45. Yield 217 g (39%); yellowish oil; bp 38–40 °C / 1 mmHg.
1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.86
(q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H). 13
C
NMR (126 MHz, CDCl3) δ 158.5, 151.7, 150.3, 137.0, 61.2, 20.3, 14.2,
12.7. GC/MS (EI): m/z = 169 [M]+. Anal. calcd. for C8H11NO3: C, 56.80; H,
6.55; N, 8.28. Found: C, 56.48; H, 6.34; N, 8.23.
General procedure for the preparation of oxazolines 44a–d.
MeOH (123 g, 155 mL, 3.84 mol) was dissolved in Et2O (1000 mL) and
the solution was cooled to 0 °C. Acetyl chloride (157 g, 143 mL, 2.00
mol) was added dropwise, and the corresponding nitrile 43 (1.67 mol)
was added in single portion to the stirred reaction mixture. The solution
was stirred overnight at rt, and the formed precipitate was filtered,
washed with cold Et2O (3175 mL), and dried in vacuo. Obtained imidate
salt (ca. 1.84 mol) was added to a stirred slurry of serine methyl ester
hydrochloride (260 g, 1.67 mol) in CH2Cl2 (1250 mL) at rt. Et3N (174 g,
240 mL, 1.72 mol) was added dropwise at 0 °C, and the reaction mixture
was stirred additionally overnight at rt. The reaction mixture was poured
onto H2O (750 mL), the organic layer was separated, washed with brine
(3300 mL), dried over Na2SO4 and evaporated in vacuo.
Methyl 4-propyloxazole-5-carboxylate (39c). The compound was
purified by distillation in vacuo. Yield 217 g (38%); colorless oil; bp 38–
40 °C / 1 mmHg. 1H NMR (500 MHz, CDCl3) δ = 7.87 (s, 1H), 3.88 (s,
3H), 2.82 (t, J = 7.5 Hz, 2H), 1.68 (h, J = 7.5 Hz, 2H), 0.91 (t, J = 7.5 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ = 158.9, 151.8, 149.2, 137.3, 52.0,
28.6, 21.6, 13.6. GC/MS (EI): m/z = 169 [M]+. Anal. calcd. for C8H11NO3:
C, 56.80; H, 6.55; N, 8.28. Found: C, 56.84; H, 6.92; N, 8.34.
General procedure for preparation of oxazole esters 45a–d
The corresponding methyl oxazoline-4-carboxylate 44a–d (1.05 mol) was
dissolved in CH2Cl2 (1000 mL) and trichlorobromomethane (230 g, 1.16
mol) was added in portions to the solution at rt. The resulting mixture was
cooled to 0 °C and DBU (192 g, 188 mL, 1.26 mol) was added dropwise
(NOTE: the temperature shouldn’t exceed 10 °C). After addition, the
reaction mixture was allowed to warm up to rt and stirred for additional at
rt 3 h. Then, the mixture was extracted with H2O (3300 mL), organic
phase was separated, washed with diluted aq HCl (3250 mL), dried
over Na2SO4, and evaporated in vacuo.
Methyl 2-methyl-4,5-dihydrooxazole-4-carboxylate (44a). Yield 198 g
(83%); yellowish liquid. For spectral and physical data, see ref.[80,88,89]
Methyl 2-isopropyl-4,5-dihydrooxazole-4-carboxylate (44b). Yield 226
g (79%); brownish oil; bp 54–56 °C / 1 mmHg. 1H NMR (500 MHz,
CDCl3) δ = 4.68 (dd, J = 10.5, 7.8 Hz, 1H), 4.43 (t, J = 8.3 Hz, 1H), 4.35
(dd, J = 10.6, 8.7 Hz, 1H), 3.75 (s, 3H), 2.60 (hept, J = 6.9 Hz, 1H), 1.18
(dd, J = 6.9, 2.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ = 174.7, 171.8,
69.2, 68.0, 52.5, 28.2, 19.6 and 19.5. GC/MS (EI): m/z = 171 [M]+. Anal.
calcd. for C8H13NO3: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.53; H, 7.95;
N, 8.08.
Methyl 2-methyloxazole-4-carboxylate (45a). Yield 117
g (79%);
colorless oil. For spectral and physical data, see ref.[93–95]
Methyl 2-cyclobutyl-4,5-dihydrooxazole-4-carboxylate (44c). Yield
272 g (89%); yellowish oil; bp 81–83 °C / 1 mmHg. 1H NMR (500 MHz,
DMSO-d6) δ = 4.71 (dd, J = 10.3, 8.2 Hz, 1H), 4.46 (t, J = 8.3 Hz, 1H),
4.38 (dd, J = 10.5, 8.8 Hz, 1H), 3.76 (s, 3H), 3.18 (p, J = 8.5 Hz, 1H),
2.34 – 2.24 (m, 2H), 2.24 – 2.16 (m, 2H), 2.03 – 1.96 (m, 1H), 1.93 –
1.85 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ = 172.6, 171.7, 69.3, 68.0,
52.5, 32.7, 25.9 and 25.8, 18.6. GC/MS (EI): m/z = 183 [M]+. Anal. calcd.
for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 58.76; H, 6.95; N,
7.42.
Methyl 2-isopropyloxazole-4-carboxylate (45b). The compound was
purified by distillation in vacuo. Yield 108 g (61%); clear oil; bp 41–43 °C /
1 mmHg. 1H NMR (400 MHz, CDCl3) δ = 8.08 (s, 1H), 3.84 – 3.81 (m,
3H), 3.06 (hept, J = 6.9 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H). 13C NMR (101
MHz, CDCl3) δ = 169.9, 161.8, 143.5, 132.9, 52.0, 28.5, 20.2. GC/MS
(EI): m/z = 169 [M]+. Anal. calcd. for C8H11NO3: C, 56.80; H, 6.55; N, 8.28.
Found: C, 56.57; H, 6.43; N, 8.40.
Methyl 2-cyclobutyloxazole-4-carboxylate (45c). The compound was
purified by distillation in vacuo. Yield 135 g (71%); colorless oil; bp 83–
85 °C / 1 mmHg. 1H NMR (400 MHz, CDCl3) δ = 8.05 (s, 1H), 3.78 (s, 3H),
3.56 (p, J = 8.5 Hz, 1H), 2.40 – 2.29 (m, 2H), 2.30 – 2.20 (m, 2H), 2.02 –
1.91 (m, 1H), 1.89 – 1.80 (m, 1H). 13C NMR (101 MHz, CDCl3) δ = 168.0,
161.7, 143.5, 133.0, 51.9, 32.8, 27.1, 18.5. GC/MS (EI): m/z = 181 [M]+.
Anal. calcd. for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 60.05; H,
5.93; N, 7.98.
Methyl 2-(tetrahydro-2H-pyran-4-yl)-4,5-dihydrooxazole-4-carboxy-
late (44d). Yield 303 g (85%); yellow oil bp 101–103 °C / 1 mmHg. 1H
NMR (500 MHz, CDCl3) δ 4.68 (dd, J = 7.9, 1.8 Hz, 1H), 4.43 (dd, J =
122.1, 8.2 Hz, 1H), 4.34 (dd, J = 10.5, 8.7 Hz, 1H), 3.92 (dt, J = 11.7, 3.7
Hz, 2H), 3.73 (s, 3H), 3.38 (td, J = 11.1, 2.9 Hz, 2H), 2.55 (tt, J = 9.7, 4.0
Hz, 1H), 1.80 – 1.72 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 172.0, 171.6,
69.2, 67.9, 67.0, 52.6, 34.4, 29.3 and 29.2. GC/MS (EI): m/z = 213 [M]+.
Anal. calcd. for C10H15NO4: C, 56.33; H, 7.09; N, 6.57. Found: C, 56.63;
H, 6.97; N, 6.84.
Methyl 2-(tetrahydro-2H-pyran-4-yl)oxazole-4-carboxylate (45d).
Yield 108 g (69%); yellowish solid; mp 76–78 °C. 1H NMR (500 MHz,
CDCl3) δ 8.17 (s, 1H), 4.02 (dt, J = 12.1, 3.6 Hz, 2H), 3.90 (s, 3H), 3.51
(td, J = 11.6, 3.3 Hz, 2H), 3.09 (tt, J = 10.7, 5.2 Hz, 1H), 1.99 – 1.94 (m,
4H). 13C NMR (126 MHz, CDCl3) δ 167.3, 161.7, 143.7, 133.1, 67.0, 52.1,
34.7, 29.9. GC/MS (EI): m/z = 211 [M]+. Anal. calcd. for C10H13NO4: C,
56.87; H, 6.20; N, 6.63. Found: C, 56.84; H, 5.94; N, 6.53.
General procedure for the preparation of oxazole esters 39a–c
The corresponding alkyl 2-chloro-3-oxoalkyloate (3.37 mol) was added to
formamide (425 g, 376 mL, 9.44 mol) and the mixture was stirred neat at
120 °C overnight. Then, the reaction mixture was cooled, diluted with
brine (750 mL) and extracted with EtOAc (3500 ml). The organic layer
was washed with brine (2400 mL), dried over Na2SO4 and evaporated in
vacuo.
General procedure for preparation of carboxylic acids 38a–d, 40a–c,
and 46a–e. The corresponding oxazolecarboxylate (1.26 mol) was
dissolved in THF (750 mL) and NaOH (34 g, 1.2eq) solution in H2O (170
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10.1002/ejoc.201900032
European Journal of Organic Chemistry
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mL) was added to the solution at 0 °C. The reaction mixture was stirred
for 30 min at 0 °C and stirred at rt for additional 2 h. Then, the mixture
was evaporated in vacuo, the residue was diluted with H2O (600 mL),
and acidified with concentrated aq HCl (100 mL). The precipitate was
filtered, washed with H2O (275 mL) and dried on air.
H]-. Anal. calcd. for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C,
57.41; H, 5.23; N, 8.68.
2-(Tetrahydro-2H-pyran-4-yl)oxazole-4-carboxylic acid (46d). Yield
166 g (74%); beige powder; mp 157–159 °C. 1H NMR (500 MHz, DMSO-
d6) δ = 13.03 (s, 1H), 8.63 (s, 1H), 3.87 (dt, J = 11.6, 3.5 Hz, 2H), 3.44 (td,
J = 11.4, 2.2 Hz, 2H), 3.12 (tt, J = 11.1, 4.0 Hz, 1H), 1.95 – 1.86 (m, 2H),
1.70 (dtd, J = 13.4, 11.2, 4.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ =
167.1, 162.6, 145.2, 133.6, 66.5, 34.1, 30.1. LC/MS (CI): m/z = 196 [M-
H]-. Anal. calcd. for C9H11NO4: C, 54.82; H, 5.62; N, 7.10. Found: C,
54.62; H, 5.56; N, 6.74.
5-Methyloxazole-4-carboxylic acid (38a). Yield 147 g (92%). For
spectral and physical data, see ref.[62]
5-Ethyloxazole-4-carboxylic acid (38b). Yield 153 g (86%); white
crystals; mp 108–110 °C. 1H NMR (400 MHz, DMSO-d6) δ = 12.93 (s,
1H), 8.29 (s, 1H), 2.99 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). 13C
NMR (126 MHz, DMSO-d6) δ = 163.4, 160.5, 150.6, 126.7, 19.4, 12.4.
LC/MS (CI): m/z = 140 [M-H]-. Anal. calcd. for C6H7NO3: C, 51.07; H,
5.00; N, 9.93. Found: C, 51.21; H, 4.97; N, 9.84.
2-(tert-Butyl)oxazole-4-carboxylic acid (46e). Pivalamide 47 (72.3 g,
0.715 mol) and ethyl 3-bromo-2-oxopropanoate 48 (146 g, 0.751 mol)
were dissolved in EtOH (1000 mL) and the solution was refluxed
overnight. The solvent was evaporated in vacuo, the residue was diluted
with THF (750 mL) and NaOH (57,2 g, 1.43 mol) was added at rt. The
mixture was stirred for 4 h, evaporated in vacuo and diluted with H2O
(600 mL). Then, saturated aq HCl (100 mL) was added in portions. The
precipitate was filtered, washed with H2O (2100 mL), then with cold t-
BuOMe (275 mL) and the resulting solid was dried on air. The
procedure was repeated twice for scale-up. Yield 71.4 g (59%); beige
solid; mp 145–147 °C. 1H NMR (400 MHz, DMSO-d6) δ = 12.66 (s, 1H),
8.61 (d, J = 1.1 Hz, 1H), 1.32 (s, 9H). 13C NMR (126 MHz, CDCl3) δ =
171.4, 162.7, 145.1, 133.4, 33.9, 28.6. LC/MS (CI): m/z = 168 [M-H]-.
Anal. calcd. for C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found: C, 56.66; H,
6.24; N, 8.04.
5-Isopropyloxazole-4-carboxylic acid (38c). Yield 113 g (86%); white
crystals; mp 136–138 °C. 1H NMR (400 MHz, DMSO-d6) δ = 12.95 (s,
1H), 8.30 (s, 1H), 3.72 (hept, J = 6.9, 1H), 1.22 (d, J = 6.9 Hz, 6H). 13C
NMR (126 MHz, DMSO-d6) δ = 163.5, 163.4, 150.4, 126.7, 25.9, 20.9.
LC/MS (CI): m/z = 154 [M-H]-. Anal. calcd. for C7H9NO3: C, 54.19; H,
5.85; N, 9.03. Found: C, 54.59; H, 6.08; N, 9.18.
5-(tert-Butyl)oxazole-4-carboxylic acid (38d). Yield 181
g (85%);
yellow solid; mp 185–187 °C. 1H NMR (400 MHz, CDCl3) δ = 13.42 (s,
1H), 7.92 (s, 1H), 1.43 (s, 9H). 13C NMR (126 MHz, CDCl3) δ = 162.2,
158.3, 151.1, 136.7, 32.8, 28.9. LC/MS (CI): m/z = 168 [M-H]-. Anal.
calcd. for C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found: C, 56.42; H, 6.27;
N, 8.26.
General procedure for the preparation of oxazoles 36a–b, 41a–b,
49a via decarboxylation.
The corresponding carboxylic acid 38a–b, 40a–b, or 46a (0.822 mol) and
CuO (13.1 g, 0.164 mol) were added to quinolone (425 mL). The reaction
vessel was heated to 180 °C (for 40a–b), 190 °C (for 49a) or 200 °C (for
38a–b), and the corresponding alkyloxazole was collected via Vigreux
distillation apparatus under normal pressure.
4-Methyloxazole-5-carboxylic acid (40a). Yield 136 g (85%). For
spectral and physical data, see ref.[70,96]
4-Ethyloxazole-5-carboxylic acid (40b). Yield 149 g (84%); white
crystals; mp 173–175 °C. 1H NMR (400 MHz, DMSO-d6) δ = 13.54 (s,
1H), 8.45 (d, J = 1.9 Hz, 1H), 2.80 (qd, J = 7.6, 1.7 Hz, 2H), 1.16 (td, J =
7.6, 1.7 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ = 159.8, 153.7, 149.2,
137.4, 20.2, 13.2. LC/MS (CI): m/z = 142 [M+H]+. Anal. calcd. for
C6H7NO3: C, 51.07; H, 5.00; N, 9.93. Found: C, 50.87; H, 4.79; N, 9.76.
5-Methyloxazole (36a). The compound was purified by distillation in
vacuo. Yield 62.2 g (91%); colorless liquid; bp 97–99 °C / 760 mmHg. 1H
NMR (400 MHz, CDCl3) δ = 7.75 (s, 1H), 6.75 (s, 1H), 2.33 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ = 149.9, 148.9, 122.3, 10.6. GC/MS (EI): m/z =
83 [M]+. Anal. calcd. for C4H5NO: C, 57.82; H, 6.07; N, 16.86. Found: C,
57.53; H, 6.00; N, 16.79.
4-Propyloxazole-5-carboxylic acid (40c). Yield 149 g (76%); white
powder; mp 143–145 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H),
8.45 (s, 1H), 2.77 (t, J = 7.4 Hz, 2H), 1.62 (h, J = 7.4 Hz, 2H), 0.88 (t, J =
7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ = 159.8, 153.7, 147.9,
137.9, 28.5, 21.7, 13.9. Anal. calcd. for C7H9NO3: C, 54.19; H, 5.85; N,
9.03. Found: C, 54.51; H, 6.23; N, 8.93.
5-Ethyloxazole (36b). The compound was purified by distillation in
vacuo. Yield 65.5 g (82%); colorless liquid; bp 116–118 °C / 760 mmHg.
1H NMR (400 MHz, CDCl3) δ = 7.73 (s, 1H), 6.72 (s, 1H), 2.66 (q, J = 7.5
Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 154.4,
149.9, 121.1, 18.9, 11.7. GC/MS (EI): m/z = 97.1 [M]+. Anal. calcd. for
C5H7NO: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.62; H, 7.65; N, 14.66.
2-Methyloxazole-4-carboxylic acid (46a). Yield 146 g (91%). For
spectral and physical data, see ref.[94,95,97]
4-Methyloxazole (41a). The compound was purified by distillation in
vacuo. Yield 51.2 g (75%); colorless liquid; 76–78 °C / 760 mmHg. 1H
NMR (500 MHz, CDCl3) δ = 7.78 (s, 1H), 7.37 (s, 1H), 2.17 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ = 150.7, 135.9, 134.4, 11.3. GC/MS (EI): m/z =
83 [M]+. Anal. calcd. for C4H5NO: C, 57.82; H, 6.07; N, 16.86. Found: C,
58.07; H, 5.87; N, 16.53.
2-Isopropyloxazole-4-carboxylic acid (46b). Yield 143 g (73%); white
powder; mp 113–115 °C. 1H NMR (400 MHz, DMSO-d6) δ = 12.92 (s,
1H), 8.62 (s, 1H), 3.10 (sept, J = 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H).
13C NMR (126 MHz, DMSO-d6) δ = 169.3, 162.6, 145.2, 133.4, 28.1, 20.5.
LC/MS (CI): m/z = 154 [M-H]-. Anal. calcd. for C7H9NO3: C, 54.19; H,
5.85; N, 9.03. Found: C, 53.84; H, 5.81; N, 8.65.
4-Ethyloxazole (41b). The compound was purified by distillation in
vacuo. Yield 64.7 g (81%); colorless liquid; bp 125–127 °C / 760 mmHg.
1H NMR (400 MHz, CDCl3) δ = 7.80 (s, 1H), 7.38 (d, J = 1.1 Hz, 1H),
2.57 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ = 150.8, 142.2, 133.6, 19.6, 12.6. GC/MS (EI): m/z = 97.1 [M]+.
2-Cyclobutyloxazole-4-carboxylic acid (46c). Yield 141 g (67%); white
powder; mp 133–135 °C. 1H NMR (500 MHz, DMSO-d6) δ = 12.96 (s,
1H), 8.62 (s, 1H), 3.66 (p, J = 8.4 Hz, 1H), 2.34 – 2.26 (m, 4H), 2.02 (q, J
= 9.4, 8.8 Hz, 1H), 1.92 – 1.83 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ
= 168.5, 165.6, 144.6, 132.6, 32.8, 27.2, 18.6. LC/MS (CI): m/z = 166 [M-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900032
European Journal of Organic Chemistry
FULL PAPER
Anal. calcd. for C5H7NO: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.56; H,
7.05; N, 14.78.
67.1, 34.6, 30.1. GC/MS (EI): m/z = 153 [M]+. Anal. calcd. for C8H11NO2:
C, 62.73; H, 7.24; N, 9.14. Found: C, 62.72; H, 6.84; N, 9.20.
2-Methyloxazole (49a).[63] The compound was purified by distillation in
vacuo. Yield 39.6 g (58%); colorless liquid; bp 72–74 °C / 760 mmHg. 1H
NMR (400 MHz, CDCl3) δ = 7.48 (s, 1H), 6.93 (s, 1H), 2.40 (d, J = 0.7 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ = 161.1, 137.8, 126.4, 13.2. GC/MS
(EI): m/z = 83 [M]+. Anal. calcd. for C4H5NO: C, 57.82; H, 6.07; N, 16.86.
Found: C, 57.45; H, 5.69; N, 17.17.
2-(tert-Butyl)oxazole (49e). The compound was purified by distillation in
vacuo. Yield 110 g (87%); colorless oil; bp 146–148 °C / 760 mmHg. 1H
NMR (400 MHz, CDCl3) δ 7.56 – 7.45 (m, 1H), 7.01 – 6.89 (m, 1H), 1.34
(s, 9H). 13C NMR (101 MHz, CDCl3) δ = 171.3, 137.9, 126.5, 33.6, 28.5.
GC/MS (EI): m/z = 125 [M]+. Anal. calcd. for C7H11NO: C, 67.17; H, 8.86;
N, 11.19. Found: C, 67.54; H, 8.81; N, 11.38.
General procedure for the preparation of oxazoles 36c–d, 41c, 49b-e
via decarboxylation.
4-(tert-Butyl)oxazole (41d).[68,98] 1-Bromo-3,3-dimethylbutan-2-one (203
g, 1.14 mol) was added to formamide (128 g, 114 mL, 2.84 mol), and the
mixture was heated at 120 °C overnight, then cooled to rt, diluted with
brine (300 mL) and extracted with Et2O (2300 mL). The combined
organic extracts were washed with brine (2200 mL), dried over Na2SO4,
and evaporated in vacuo. The compound was purified by distillation in
vacuo. Yield 56.8 g (40%); colorless liquid; bp 131–133 °C / 760 mmHg.
1H NMR (400 MHz, CDCl3) δ = 7.80 (s, 1H), 7.34 (d, J = 1.0 Hz, 1H),
1.28 (s, 9H). 13C NMR (126 MHz, CDCl3) δ = 150.7, 150.0, 131.9, 30.8,
29.2. GC/MS (EI): m/z = 125 [M]+. Anal. calcd. for C7H11NO: C, 67.17; H,
8.86; N, 11.19. Found: C, 66.81; H, 8.58; N, 10.90.
The corresponding oxazolecarboxylic acid 38c–d, 40c–e, 46b–e (0.822
mol) and CuO (13.1 g, 0.164 mol) and the reaction vessel was heated to
160 °C (for 36c), 180 °C (for 36d, 40a–b), 190 °C (for 46b–e) or 200 °C
(for 40c), and the corresponding oxazole was collected via Vigreux
distillation apparatus under normal pressure.
5-Isopropyloxazole (36c). The compound was purified by distillation in
vacuo. Yield 70.3 g (77%); colorless liquid; bp 119–121 °C / 760 mmHg.
1H NMR (400 MHz, CDCl3) δ = 7.76 (s, 1H), 6.72 (s, 1H), 2.98 (hept, J =
6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ =
158.3, 149.9, 120.0, 25.9, 20.6. GC/MS (EI): m/z = 111 [M]+. Anal. calcd.
for C6H9NO: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.72; H, 7.77; N,
12.90.
4-Phenyloxazole (41e).[99–103] The compound was prepared according to
the literature method.[69] Yield 66.8 g (76%); colorless liquid; bp 59–61 °C
/ 0.1 mmHg. 1H NMR (400 MHz, DMSO-d6) δ = 8.61 (s, 1H), 8.45 (s, 1H),
7.80 (d, J = 7.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H).
13C NMR (126 MHz, DMSO-d6) δ = 153.1, 139.7, 135.5, 131.2, 129.2,
128.4, 125.7. LC/MS (CI): m/z = 146 [M+H]+. Anal. calcd. for C9H7NO: C,
74.47; H, 4.86; N, 9.65. Found: C, 74.78; H, 5.24; N, 9.73.
5-(tert-Butyl)oxazole (36d). The compound was purified by distillation in
vacuo. Yield 63.8 g (62%); colorless liquid; 149–151 °C / 760 mmHg. 1H
NMR (400 MHz, CDCl3) δ = 7.75 (s, 1H), 6.70 (s, 1H), 1.29 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ = 160.5, 149.3, 118.7, 30.8, 28.1. GC/MS (EI):
m/z = 125 [M]+. Anal. calcd. for C7H11NO: C, 67.17; H, 8.86; N, 11.19.
Found: C, 67.41; H, 8.99; N, 11.17.
4-Methyl-2-(triisopropylsilyl)oxazole (51). n-BuLi (149 mL, 2.5 M in
hexanes, 0.373 mol) was added to the stirred solution of 4-methyloxazole
(28.2 g, 0.339 mol) in THF (400 mL) at –30 °C, the solution was stirred
for additional 30 min. The reaction mixture was allowed to warm up to –
10 °C, and TIPS-OTf (104 g, 0.373 mol) was added dropwise. The
mixture was stirred overnight, and saturated aq NH4Cl (300 mL) was
added. Most of THF and hexanes were evaporated in vacuo, and the
residue was extracted with EtOAc (3250mL). The organic layer was
separated, washed with brine (2100mL), dried over Na2SO4 and
evaporated in vacuo. The compound was purified by distillation in vacuo.
Yield 79.5 g (98%), brownish oil; bp 44–46 °C / 1 mmHg. 1H NMR (500
MHz, CDCl3) δ = 7.49 (s, 1H), 2.20 (s, 3H), 1.40 (sept, J = 7.7 Hz, 3H),
1.12 (d, J = 7.7 Hz, 18H). 13C NMR (126 MHz, CDCl3) δ = 167.7, 135.8,
135.2, 17.9, 10.9, 10.5. GC/MS (EI): m/z = 239 [M]+. Anal. calcd. for
C13H25NOSi: C, 65.21; H, 10.52; N, 5.85. Found: C, 64.83; H, 10.64; N,
6.10.
4-Propyloxazole (41c). The compound was purified by distillation in
vacuo. Yield 74.9 g (82%); colorless liquid; bp 111–113 °C / 760 mmHg.
1H NMR (500 MHz, CDCl3) δ = 7.79 (s, 1H), 7.38 (s, 1H), 2.50 (t, J = 7.4
Hz, 2H), 1.65 (hd, J = 7.4, 1.6 Hz, 2H), 0.94 (td, J = 7.4, 1.6 Hz, 3H). 13
C
NMR (126 MHz, CDCl3) δ = 150.7, 140.5, 134.1, 28.1, 21.6, 13.7. GC/MS
(EI): m/z = 111 [M]+. Anal. calcd. for C6H9NO: C, 64.84; H, 8.16; N, 12.60.
Found: C, 64.68; H, 7.79; N, 12.59.
2-Isopropyloxazole (49b). The compound was purified by distillation in
vacuo. Yield 50.2 g (55%); colorless liquid; bp 116–118 °C / 760 mmHg.
1H NMR (400 MHz, CDCl3) δ = 7.54 (s, 1H), 7.00 (s, 1H), 3.09 (hept, J =
7.0 Hz, 1H), 1.34 (d, J = 7.0 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ =
169.2, 138.0, 126.5, 28.3, 20.3. GC/MS (EI): m/z = 111 [M]+. Anal. calcd.
for C6H9NO: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.51; H, 8.26; N,
12.44.
5-Bromo-4-methyl-2-(triisopropylsilyl)oxazole
(52).
2-TIPS-4-
methyloxazole (51) (80.0 g, 0.334 mol) was dissolved in THF (600 mL),
the solution was cooled to –78 °C. n-BuLi (147 mL, 2.5 M in hexanes,
0.368 mol) was added dropwise, and the mixture was stirred at –78 °C
for additional 30 min. Then, 1,2-dibromo-1,1,2,2-tetrafluoroethane (95.5 g,
0.368 mol) was added dropwise at –78 °C, and the reaction mixture was
allowed to warm up to rt overnight. Saturated aq NH4Cl (500 mL) was
added in portions and the mixture was stirred for additional 15 min. Most
of THF and hexanes were evaporated in vacuo, and the residue was
extracted with EtOAc (2500mL). The organic phase was separated,
washed with brine (3150mL), dried over anhydrous Na2SO4 and
evaporated in vacuo. The compound was purified by column
chromatography on silica gel using hexanes as eluent, Rf = 0.23. Yield
61.0 g (57%), brownish oil. 1H NMR (400 MHz, CDCl3) δ = 2.14 (s, 3H),
1.38 (sept, J = 7.4 Hz, 3H), 1.12 (d, J = 7.4 Hz, 18H). 13C NMR (126 MHz,
CDCl3) δ = 169.8, 134.2, 120.8, 18.3, 11.3, 10.9. GC/MS (EI): m/z = 318
2-Cyclobutyloxazole (49c). The compound was purified by distillation in
vacuo. Yield 69.8 g (69%); colorless oil; bp 184–186 °C / 760 mmHg. 1H
NMR (400 MHz, CDCl3) δ = 7.53 (s, 1H), 7.00 (s, 1H), 3.63 (p, J = 8.6 Hz,
1H), 2.43 – 2.32 (m, 4H), 2.08 – 1.99 (m, 1H), 1.99 – 1.92 (m, 1H). 13C
NMR (126 MHz, CDCl3) δ 167.5, 138.0, 126.7, 33.1, 27.3, 18.6. GC/MS
(EI): m/z = 123 [M]+. Anal. calcd. for C7H9NO: C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.47; H, 7.20; N, 11.76.
2-(Tetrahydro-2H-pyran-4-yl)oxazole (49d). The compound was
purified by distillation in vacuo. Yield 110 g (87%); colorless oil; bp 131–
1
133 °C / 16 mmHg. H NMR (400 MHz, CDCl3) δ = 7.55 (s, 1H), 7.01 (s,
1H), 4.05 – 3.94 (m, 2H), 3.50 (t, J = 11.1 Hz, 2H), 3.09 – 2.97 (m, 1H),
2.02 – 1.83 (m, 4H). 13C NMR (126 MHz, CDCl3) δ = 166.5, 138.2, 126.7,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900032
European Journal of Organic Chemistry
FULL PAPER
[M]+. Anal. calcd. for C13H24BrNOSi: C, 49.05; H, 7.60; N, 4.40; Br, 25.10.
Found: C, 49.16; H, 7.72; N, 4.51; Br, 25.21.
brine (3750 mL), dried over Na2SO4 and evaporated in vacuo. The
compound was purified by distillation in vacuo. Yield 11.0 g (78%);
yellowish liquid; bp 51–53 °C / 15 mmHg. 1H NMR (400 MHz, CDCl3) δ =
7.92 (d, J = 2.1 Hz, 1H), 6.61 (t, J = 54.6 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ = 141.0 (t, J = 6.0 Hz), 138.1 (t, J = 28.9 Hz), 135.2, 109.1 (t, J
= 237 Hz). 19F NMR (376 MHz, CDCl3) δ = -118.0. GC/MS (EI): m/z =
197/199 [M]+. Anal. calcd. for C4H2BrF2NO: C, 24.27; H, 1.02; N, 7.08; Br,
40.36. Found: C, 23.91; H, 1.24; N, 6.80; Br, 40.75.
5-bromo-4-methyloxazole hydrochloride (30). 2-TIPS-4-bromo-5-
methyloxazole (52) (51.3 g, 0.161 mol) was dissolved in Et2O (400 mL)
and cooled to 5 °C. Stream of gaseous HCl was bubbled in the stirred
reaction mixture at 5 °C for 30 min (NOTE: the temperature should not
exceed 10 °C). The reaction mixture was stirred at 10 °C for additional 3
h. The precipitate was filtered off, washed with cold Et2O (2100 mL) and
dried on air at rt for 10 min. Yield 12.8 g (40%), brown powder, mp 109–
2-Bromo-4-(trifluoromethyl)oxazole (23). CuBr2 (70.5 g, 0.316 mol)
and tert-butyl nitrite (73.2 g, 0.710 mol) were added to MeCN (400 mL).
The reaction mixture was cooled to 0 °C, and 4-(trifluoromethyl)oxazol-2-
amine (56) (40.0 g, 0.263 mol) was added in portions. The solution was
stirred at rt for 3 h, then poured into 10% aq HCl (500 mL). The resulting
solution was extracted with Et2O (2300 mL), the organic layer was
washed with brine (4200 mL), dried over Na2SO4, and carefully
evaporated in vacuo (bath temperature should not exceed 23 °C). The
compound was purified by distillation in vacuo. Yield 18.7 g (33%);
111 °C. 1H NMR (400 MHz, CF3COOD) δ = 9.48 (s, 1H), 2.34 (s, 3H). 13
C
NMR (126 MHz, CF3COOD) δ = 162.9, 132.9, 120.6, 10.3. GC/MS (EI):
m/z = 161 [M]+. Anal. calcd. for C4H5BrClNO: C, 24.21; H, 2.54; N, 7.06;
Cl, 17.86; Br, 40.27. Found: C, 24.50; H, 2.78; N, 7.02; Cl, 17.83; Br,
40.07.
Ethyl 2-bromooxazole-4-carboxylate (54). Ethyl 2-chlorooxazole-4-
carboxylate (53) (39.7 g, 0.226 mol). was added to bromotrimethylsilane
(242 g, 1.58 mol) at rt, and the resulting mixture was heated at 85 °C for
72 h. Then the solution was evaporated in vacuo, diluted with H2O (250
mL), and extracted with EtOAc (3250 mL). The combined organic layer
was washed with saturated aq NaHCO3 (2250 mL), brine (200 mL),
dried over Na2SO4 and evaporated in vacuo. Yield 46.3 g (90%);
brownish oil, which solidifies upon standing. 1H NMR (400 MHz, CDCl3) δ
= 8.22 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ = 159.9, 146.9, 135.9, 134.9, 61.6, 14.2. LC/MS (CI):
m/z = 220/222 [M+H]+. Anal. calcd. for C6H6BrNO3: C, 32.75; H, 2.75; N,
6.37; Br, 36.32. Found: C, 32.61; H, 2.48; N, 6.75; Br, 36.63.
1
colorless liquid; bp 32–34 °C / 15 mmHg. H NMR (400 MHz, CDCl3) δ =
8.03 (d, J = 1.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ = 141.8 (q, J = 4.1
Hz), 135.6, 134.6 (q, J = 41.1 Hz), 119.5 (q, J = 267 Hz). 19F NMR (376
MHz, CDCl3) δ = –65.19. GC/MS (EI): m/z = 215/217 [M]+. Anal. calcd.
for C4HBrF3NO: C, 22.25; H, 0.47; N, 6.49; Br, 37.00. Found: C, 21.88; H,
0.36; N, 6.42; Br, 37.17.
General procedure for the parallel synthesis.
Method A. Solutions of boronic derivative 57 (2.16 mmol) in N-
methylpyrrolidone (1.75 mL), and Na2CO3 (572 mg, 5.40 mmol) in H2O
(2.00 mL), Pd(OAc)2 (2.02 mg, 0.090 mmol) and dppf (99.7 mg, 0.180
mmol) in N-methylpyrrolidone (2.00 mL) were added to a solution of the
corresponding bromooxazole 11, 14–16, 18, 20, 22, 23, 25–31, or 54
(1.80 mmol) in N-methylpyrrolidone (1.50 mL). The mixture was heated
at 90 °C overnight, then cooled to rt and evaporated in vacuo. The
residue was diluted with DMSO (0.8 mL), and TFA was added until pH =
5. The obtained mixture was filtered through dimercaptotriazine-
functionalized silica gel (200 mg) and then subjected to preparative
HPLC.
2-Bromooxazole-4-carboxylic acid (21). Ethyl 2-bromooxazole-4-
carboxylate (54) (20.0 g, 91.0 mmol) was dissolved in THF (200 mL), and
NaOH (4.36 g, 0.109 mol) in H2O (25 mL) was added at 0 °C. The
reaction mixture was stirred at 0 °C for 30 min and at rt – for 2 h. Then
the mixture was evaporated in vacuo, the residue was diluted with H2O
(75 mL) and acidified with concentrated aq HCl (25 mL). The precipitate
was filtered, washed with H2O (225 mL) and dried on air. Yield 16.2 g
(93%); white solid; mp 161–163 °C. 1H NMR (500 MHz, DMSO-d6) δ =
13.36 (s, 1H), 8.87 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 161.3,
149.2, 135.8, 135.3. LC/MS (CI): m/z = 190/192 [M–H]–. Anal. calcd. for
C4H2BrNO3: C, 25.03; H, 1.05; N, 7.30; Br, 41.62. Found: C, 25.06; H,
1.45; N, 7.57; Br, 42.00.
Method B. Solutions of boronic derivative 57 (2.16 mmol) in 1,4-dioxane
(1.75 mL), Cs2CO3 (1.76 g, 5.40 mmol) in H2O (2.50 mL), and XPhos Pd
G2 (142 mg, 0.180 mmol) in 1,4-dioxane (1.00 mL) were added to a
solution of the corresponding bromooxazole 11, 14–16, 18, 20, 22, 23,
25–31, or 54 (1.80 mmol) in N-methylpyrrolidone (1.50 mL). The mixture
was heated at 90 °C overnight, then cooled to rt and evaporated in vacuo.
The residue was diluted with DMSO (0.8 mL) and TFA was added until
pH = 5. The obtained mixture was filtered through dimercaptotriazine-
functionalized silica gel (200 mg) and then subjected to preparative
HPLC.
2-Bromooxazole-4-carbaldehyde (55). Ethyl 2-bromooxazole-4-
carboxylate (54) (19.3 g, 87.7 mmol) was dissolved in CH2Cl2 (350 mL),
the solution was cooled to –78 °C, and DIBAL (22.5 g, 0.158 mol) was
added to the reaction mixture dropwise. After 1 h, MeOH (14.1 g, 17.8
mL, 0.440 mol) was added dropwise at –78 °C. The resulting slurry was
stirred for 1 h and poured into 10% aq NH4Cl (600 mL). The resulting
solution was stirred at rt for 1 h, filtered, and washed with CH2Cl2 (2200
mL). The organic layer was separated, dried over Na2SO4, and
evaporated in vacuo. The compound was purified by flash
chromatography on silica gel using hexanes as eluent, Rf = 0.90. Yield
13.1 g (84%); white crystals; mp 113–115 °C. 1H NMR (400 MHz, CDCl3)
δ = 9.86 (s, 1H), 8.28 (s, 1H). 13C NMR (126 MHz, CDCl3) δ = 182.8,
146.6, 142.5, 135.8. GC/MS (EI): m/z = 175/177 [M]+. Anal. calcd. for
C4H2BrNO2: C, 27.30; H, 1.15; N, 7.96; Br, 45.41. Found: C, 27.24; H,
1.11; N, 7.57; Br, 45.08.
5-(Quinolin-8-yl)-2-(tetrahydro-2H-pyran-4-yl)oxazole 58{27,57(121)}.
Yield 17.7 mg (35% – method A); brownish oil. 1H NMR (500 MHz,
DMSO-d6) δ = 9.06 – 9.02 (m, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.21 – 8.18
(m, 1H), 8.15 (d, J = 7.3 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.70 (td, J =
8.1, 7.5, 1.2 Hz, 1H), 7.64 (ddd, J = 8.3, 4.2, 1.4 Hz, 1H), 3.92 (d, J =
11.6 Hz, 2H), 3.50 (t, J = 11.3 Hz, 2H), 3.22 (td, J = 11.0, 5.4 Hz, 1H),
2.02 (d, J = 12.2 Hz, 2H), 1.88 – 1.79 (m, 2H). 13C NMR (126 MHz,
DMSO-d6) δ = 165.8, 156.4, 151.2, 148.2, 143.7, 137.3, 128.7, 128.7,
127.0, 126.2, 126.1, 122.4, 66.7, 34.3, 30.5. LC/MS (CI): m/z = 281
[M+H]+. Anal. calcd. for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.68; H, 5.55; N, 9.99.
2-Bromo-4-(difluoromethyl)oxazole (22). Aldehyde 55 (12.5 g, 71.0
mmol) was dissolved in CH2Cl2 (150 mL) and the solution was cooled to
0 °C. Morpholinosulfur trifluoride (31.1 g, 0.178 mol) in CH2Cl2 (150 mL)
was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h
and at rt for additional 2 h. Then, the solution was poured into saturated
aq NaHCO3 (300 mL), the organic phase was separated, washed with
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900032
European Journal of Organic Chemistry
FULL PAPER
4-(2-(tert-Butyl)oxazol-5-yl)benzonitrile 58{28,57(122)}. Yield 18.4 mg
(36% – method A); brownish solid. 1H NMR (500 MHz, DMSO-d6) δ =
7.92 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.78 (s, 1H), 1.38 (s,
9H). 13C NMR (126 MHz, DMSO-d6) δ = 171.9, 148.9, 133.5, 132.3,
125.8, 124.7, 119.2, 110.6, 34.0, 28.7. LC/MS (CI): m/z = 227 [M+H]+.
Anal. calcd. for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 73.97;
H, 6.16; N, 12.51.
2.3 Hz, 2H), 3.42 (s, 2H), 3.15 (tt, J = 11.1, 4.0 Hz, 1H), 2.31 (s, 4H),
1.96 (dd, J = 13.8, 3.6 Hz, 2H), 1.81 – 1.72 (m, 2H), 1.50 – 1.46 (m, 4H),
1.38 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ = 166.0, 150.6, 139.4,
129.8, 126.8, 124.1, 122.4, 66.6, 62.9, 54.4, 34.2, 30.4, 26.0, 24.5.
LC/MS (CI): m/z = 327 [M+H]+. Anal. calcd. for C20H26N2O2: C, 73.59; H,
8.03; N, 8.58. Found: C, 73.47; H, 8.30; N, 8.55.
2-(2-(5-Isopropyloxazol-2-yl)-4-nitrophenyl)ethan-1-ol 58{14,57(130)}.
Yield 22.9 mg (45% – method A); brownish solid. 1H NMR (500 MHz,
DMSO-d6) δ = 8.61 (d, J = 2.6 Hz, 1H), 8.23 (dd, J = 8.5, 2.6 Hz, 1H),
7.67 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 1.1 Hz, 1H), 4.72 (t, J = 5.2 Hz, 1H),
3.67 (q, J = 6.2 Hz, 2H), 3.34 (q, J = 6.2 Hz, 2H), 3.11 (hept, J = 6.9 Hz,
1H), 1.29 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ = 159.2,
158.1, 146.6, 146.4, 134.1, 127.6, 124.2, 123.3, 122.9, 61.3, 37.7, 25.9,
21.0. LC/MS (CI): m/z = 277 [M+H]+. Anal. calcd. for C14H16N2O4: C,
60.86; H, 5.84; N, 10.14. Found: C, 61.17; H, 5.69; N, 9.92.
5-(2-Chlorothiophen-3-yl)-2-(tetrahydro-2H-pyran-4-yl)oxazole
58{27,57(123)}. Yield 19.2 mg (38% – method A); brownish oil. 1H NMR
(500 MHz, DMSO-d6) δ = 7.61 (d, J = 5.8 Hz, 1H), 7.53 (s, 1H), 7.33 (d, J
= 5.8 Hz, 1H), 3.89 (dt, J = 11.9, 3.5 Hz, 2H), 3.47 (td, J = 11.3, 2.3 Hz,
2H), 3.16 (dp, J = 10.9, 3.9 Hz, 1H), 1.98 – 1.93 (m, 2H), 1.77 (td, J =
13.2, 11.1, 5.9 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ = 165.8, 145.2,
126.6, 126.3, 125.9, 124.6, 123.8, 66.6, 34.1, 30.3. LC/MS (CI): m/z =
270 [M+H]+. Anal. calcd. for C12H12ClNO2S: C, 53.43; H, 4.48; N, 5.19; S,
11.89; Cl, 13.14. Found: C, 53.60; H, 4.39; N, 5.11; S, 11.90; Cl, 12.98.
N,N-Dimethyl-5-(4-(trifluoromethyl)oxazol-2-yl)nicotinamide
58{23,57(132)}. Yield 25.3 mg (50% – method A); brownish oil. 1H NMR
(500 MHz, DMSO-d6) δ = 9.23 (d, J = 2.2 Hz, 1H), 9.16 (s, 1H), 8.82 (d, J
= 2.2 Hz, 1H), 8.38 (t, J = 2.2 Hz, 1H), 3.03 (s, 3H), 2.96 (s, 3H). 13C
NMR (126 MHz, DMSO-d6) δ 167.2, 160.5, 150.5, 148.2, 142.4 (q, J =
4.3 Hz), 133.2, 132.9, 132.3, 132.0, 122.1, 120.1, 35.4. LC/MS (CI): m/z
= 286 [M+H]+. Anal. calcd. for C12H10F3N3O2: C, 50.53; H, 3.53; N, 14.73.
Found: C, 50.92; H, 3.51; N, 14.92.
2-Methyl-6-(2-(tetrahydro-2H-pyran-4-yl)oxazol-5-yl)benzonitrile
58{27,57(124)}. Yield 19.9 mg (39% – method A); beige solid; mp 90–
92 °C. 1H NMR (500 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.72 – 7.68 (m, 2H),
7.47 (d, J = 7.2 Hz, 1H), 3.90 (d, J = 11.4 Hz, 2H), 3.48 (td, J = 11.4, 2.3
Hz, 2H), 3.21 (t, J = 8.8 Hz, 1H), 2.54 (s, 3H), 2.01 – 1.97 (m, 2H), 1.80
(d, J = 11.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 167.3, 147.6,
144.0, 133.8, 130.8, 130.4, 126.4, 124.4, 117.5, 107.4, 66.5, 34.2, 30.2,
21.0. LC/MS (CI): m/z = 269 [M+H]+. Anal. calcd. for C16H16N2O2: C,
71.62; H, 6.01; N, 10.44. Found: C, 71.49; H, 6.00; N, 10.30.
5-(2-(Tetrahydro-2H-pyran-4-yl)oxazol-5-yl)-2,3-dihydro-1H-inden-1-
one 58{27,57(133)}. Yield 30.9 mg (61% – method A); beige solid; mp
144–146 °C. 1H NMR (500 MHz, DMSO-d6) δ = 7.87 (s, 1H), 7.79 (s, 1H),
7.73 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 3.90 (dt, J = 11.5, 3.6
Hz, 2H), 3.48 (td, J = 11.4, 2.3 Hz, 2H), 3.19 (tt, J = 10.9, 3.9 Hz, 1H),
3.13 (t, J = 5.8 Hz, 2H), 2.65 (d, J = 11.8 Hz, 2H), 1.98 (dd, J = 13.7, 3.8
Hz, 2H), 1.85 – 1.73 (m, 2H). 13C NMR (126 MHz, CDCl3) δ = 205.9,
167.4, 156.6, 149.9, 136.5, 133.6, 125.5, 124.3, 123.4, 122.0, 66.6, 36.5,
34.3, 30.3, 25.9. LC/MS (CI): m/z = 284 [M+H]+. Anal. calcd. for
C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 72.22; H, 5.86; N, 5.34.
(3-(4-Propyloxazol-2-yl)phenyl)methanol 58{18,57(125)}. Yield 19.9
mg (39% – method A); brownish oil. 1H NMR (500 MHz, DMSO-d6) δ =
7.94 (s, 1H), 7.91 (s, 1H), 7.80 (dt, J = 7.5, 1.7 Hz, 1H), 7.46 (t, J = 7.5
Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 5.34 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.6
Hz, 2H), 2.48 (t, J = 7.4 Hz, 2H), 1.64 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4
Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 160.9, 144.1, 142.1, 135.6,
129.3, 128.7, 127.4, 124.5, 124.1, 62.9, 28.2, 21.6, 14.1. LC/MS (CI): m/z
= 218 [M+H]+. Anal. calcd. for C13H15NO2: C, 71.87; H, 6.96; N, 6.45.
Found: C, 71.76; H, 7.13; N, 6.67.
4-(3-(4-Methyloxazol-2-yl)benzyl)thiomorpholine 1,1-dioxide
58{16,57(164)}. Yield 18.4 mg (36% – method B); brownish solid; mp
117–119 °C. 1H NMR (500 MHz, DMSO-d6) δ = 7.92 (s, 1H), 7.90 (d, J =
1.2 Hz, 1H), 7.85 (dt, J = 7.1, 1.7 Hz, 1H), 7.51 – 7.45 (m, 2H), 3.75 (s,
2H), 3.11 (t, J = 4.6 Hz, 4H), 2.93 – 2.88 (m, 4H), 2.16 (s, 3H). 13C NMR
(126 MHz, DMSO-d6) δ = 160.6, 139.3, 137.7, 135.9, 131.3, 129.6, 127.6,
126.6, 125.2, 59.6, 50.7, 50.6, 11.9. LC/MS (CI): m/z = 307 [M+H]+. Anal.
calcd. for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14; S, 10.46. Found: C,
59.16; H, 6.03; N, 9.23; S, 10.80.
5-(2-Isopropyloxazol-5-yl)pyrimidin-2-amine 58{25,57(126)}. Yield
20.4 mg (40% – method A); brownish solid; mp 155–157 °C. 1H NMR
(500 MHz, DMSO-d6) δ = 8.54 (s, 2H), 7.34 (s, 1H), 6.99 (s, 2H), 3.09
(hept, J = 6.9 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz,
CDCl3) δ = 167.7, 163.4, 154.5, 147.0, 120.5, 112.1, 28.2, 20.8. LC/MS
(CI): m/z = 205 [M+H]+. Anal. calcd. for C10H12N4O: C, 58.81; H, 5.92; N,
27.43. Found: C, 58.78; H, 6.23; N, 27.26.
2-(2-(2-Cyclobutyloxazol-5-yl)-5-fluorophenyl)ethanol 58{26,57(128)}.
Yield 20.9 mg (41% – method A); brownish oil. 1H NMR (500 MHz,
DMSO-d6) δ = 7.61 (dd, J = 8.7, 5.9 Hz, 1H), 7.29 (d, J = 0.9 Hz, 1H),
7.23 (dd, J = 10.2, 2.8 Hz, 1H), 7.16 (td, J = 8.5, 2.8 Hz, 1H), 4.77 (t, J =
5.2 Hz, 1H), 3.69 (p, J = 8.5 Hz, 1H), 3.64 (d, J = 6.9 Hz, 1H), 3.62 (d, J =
6.6 Hz, 1H), 2.90 (t, J = 6.9 Hz, 2H), 2.37 – 2.32 (m, 4H), 2.04 (dt, J =
17.7, 8.7 Hz, 1H), 1.93 (dq, J = 11.5, 6.6 Hz, 1H). 13C NMR (126 MHz,
DMSO-d6) δ = 166.4, 162.2 (d, J = 246 Hz), 149.0, 140.1 (d, J = 7.8 Hz),
130.2 (d, J = 8.9 Hz), 124.9, 124.3 (d, J = 3.0 Hz), 117.8 (d, J = 21.5 Hz),
114.0 (d, J = 21.5 Hz), 61.2, 37.3, 32.8, 27.3, 18.6. LC/MS (CI): m/z =
262 [M+H]+. Anal. calcd. for C15H16FNO2: C, 68.95; H, 6.17; N, 5.36.
Found: C, 68.80; H, 6.29; N, 5.46.
2-(3-(4-Methyloxazol-2-yl)benzyl)isothiazolidine 1,1-dioxide
58{16,57(165)}. Yield 19.2 mg (38% – method B); yellow oil. 1H NMR
(500 MHz, DMSO-d6) δ 7.94 – 7.90 (m, 2H), 7.87 (d, J = 7.5 Hz, 1H),
7.51 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 4.17 (s, 2H), 3.27 (t, J =
7.8 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 2.25 – 2.19 (m, 2H), 2.18 – 2.15 (m,
3H). 13C NMR (126 MHz, DMSO-d6) δ = 160.5, 138.1, 137.8, 136.0,
130.7, 129.8, 127.8, 126.0, 125.4, 48.0, 47.0, 46.5, 18.8, 11.9. LC/MS
(CI): m/z = 293 [M+H]+. Anal. calcd. for C14H16N2O3S: C, 57.52; H, 5.52;
N, 9.58; S, 10.97. Found: C, 57.50; H, 5.38; N, 9.71; S, 10.75.
5-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2,4-dimethyloxazole
58{31,57(166)}. Yield 20.4 mg (40% – method B); yellowish oil. 1H NMR
(500 MHz, DMSO-d6) δ = 6.93 – 6.87 (m, 3H), 4.27 (s, 4H), 2.38 (s, 3H),
2.06 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 160.0, 144.3, 141.9, 141.2,
133.4, 121.9, 121.2, 118.1, 117.9, 64.6, 64.3, 14.0, 13.0. LC/MS (CI): m/z
5-(4-(Piperidin-1-ylmethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)oxa-
zole 58{27,57(129)}. Yield 21.6 mg (43% – method A); brownish oil. 1H
NMR (500 MHz, DMSO-d6) δ = 7.62 (d, J = 7.9 Hz, 2H), 7.51 (s, 1H),
7.36 (d, J = 7.9 Hz, 2H), 3.89 (dt, J = 11.5, 3.5 Hz, 2H), 3.47 (td, J = 11.4,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900032
European Journal of Organic Chemistry
FULL PAPER
= 232 [M+H]+. Anal. calcd. for C13H13NO3: C, 67.52; H, 5.67; N, 6.06.
Found: C, 67.71; H, 5.58; N, 5.90.
2.78 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H). 13C NMR (126 MHz, DMSO) δ
158.3, 145.5, 145.4, 129.3, 126.1, 120.2, 120.0, 39.7, 13.9, 13.3. LC/MS
(CI): m/z = 267 [M+H]+. Anal. calcd. for C12H14N2O3S: C, 54.12; H, 5.30;
N, 10.52; S, 12.04. Found: C, 54.05; H, 5.21; N, 10.25; S, 11.70.
4-(3-(((Tetrahydrofuran-3-yl)oxy)methyl)phenyl)oxazole.
58{11,57(168)}. Yield 24.1 mg (48% – method B); yellowish oil. 1H NMR
(500 MHz, DMSO-d6) δ = 8.64 (q, J = 1.0 Hz, 1H), 8.46 (q, J = 0.9 Hz,
1H), 7.76 (s, 1H), 7.73 – 7.68 (m, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.28 (d, J
= 7.4 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.25 –
4.20 (m, 1H), 3.79 – 3.74 (m, 2H), 3.71 – 3.66 (m, 2H), 1.99 – 1.94 (m,
2H). 13C NMR (126 MHz, DMSO-d6) δ = 153.1, 139.6, 139.6, 135.7,
131.2, 129.2, 127.7, 124.8, 124.8, 79.2, 72.6, 70.4, 66.7, 32.6. LC/MS
(CI): m/z = 246 [M+H]+. Anal. calcd. for C14H15NO3: C, 68.56; H, 6.16; N,
5.71. Found: C, 68.36; H, 6.05; N, 5.72.
Acknowledgements
The work was funded by Enamine Ltd. The authors thank Prof.
Andrey A. Tolmachev for his encouragement and support, and
Prof. Igor V. Komarov for helpful discussions.
Keywords: Heterocyclic, oxazole, bromination, regioselective,
(2-(2-Cyclobutyloxazol-5-yl)-5-fluorophenyl)methanol 58{26,57(169)}.
Yield 25.2 mg (50% – method B); yellowish oil. 1H NMR (500 MHz,
DMSO-d6) δ = 7.68 (dd, J = 8.6, 5.7 Hz, 1H), 7.46 – 7.38 (m, 1H), 7.30 (s,
1H), 7.19 (dd, J = 8.4, 2.9 Hz, 1H), 5.53 (s, 1H), 4.61 (s, 2H), 3.68 (pd, J
= 8.4, 7.9, 2.1 Hz, 1H), 2.50 – 2.49 (m, 2H), 2.37 – 2.32 (m, 2H), 2.11 –
2.01 (m, 1H), 1.98 – 1.88 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ =
166.5, 163.5, 161.5, 148.2, 142.7 (d, J = 7.2 Hz), 129.1 (d, J = 8.4 Hz),
125.3, 122.1 (d, J = 3.1 Hz), 114.4 (d, J = 21.6 Hz), 61.1, 32.8, 27.3, 18.6.
LC/MS (CI): m/z = 248 [M+H]+. Anal. calcd .for C14H14FNO2: C, 68.00; H,
5.71; N, 5.66. Found: C, 68.11; H, 5.75; N, 5.96.
Suzuki coupling.
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2-(1-Methyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-propyloxazole
58{26,57(170)}. Yield 28.2 mg (56% – method B); beige solid; mp 121–
123 °C. 1H NMR (500 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.14 (d, J = 8.7
Hz, 1H), 8.02 (s, 1H), 7.97 (dd, J = 8.7, 1.4 Hz, 1H), 4.38 (s, 3H), 2.53 (t,
J = 6.8 Hz, 2H), 1.67 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C
NMR (126 MHz, DMSO-d6) δ 160.4, 146.2, 142.5, 136.3, 134.0, 126.2,
122.3, 120.3, 108.9, 34.9, 28.2, 21.6, 14.1. LC/MS (CI): m/z = 243
[M+H]+. Anal. calcd. for C13H14N4O: C, 64.45; H, 5.82; N, 23.13. Found: C,
64.66; H, 6.07; N, 22.74.
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N-(5-(4-Propyloxazol-2-yl)pyridin-2-yl)acetamide 58{18,57(171)}.
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(500 MHz, DMSO-d6) δ 8.84 (dd, J = 2.3, 0.9 Hz, 1H), 8.25 (dd, J = 8.7,
2.3 Hz, 1H), 8.20 (dd, J = 8.9, 0.6 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 3.35
(s, 1H), 2.58 – 2.50 (m, 2H), 2.12 (s, 3H), 1.63 (q, J = 7.4 Hz, 2H), 0.93 (t,
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146.0, 142.1, 136.0, 135.7, 119.2, 113.5, 28.2, 24.5, 21.5, 14.1. LC/MS
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Hz, 1H), 7.31 (td, J = 8.6, 8.2, 3.2 Hz, 1H), 7.21 (dd, J = 9.1, 4.4 Hz, 1H),
4.06 (dd, J = 6.2, 2.9 Hz, 1H), 3.94 (t, J = 8.5 Hz, 1H), 3.79 (t, J = 7.9 Hz,
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6.1 Hz, 1H), 2.65 (hept, J = 6.7 Hz, 1H), 2.49 – 2.46 (m, 2H), 2.02 – 1.95
(m, 1H), 1.71 (dd, J = 6.6, 0.0 Hz, 1H), 1.63 (h, J = 7.5 Hz, 2H), 0.93 (td,
J = 7.3, 1.3 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ = 158.5 (d, J = 2.7
Hz), 156.4 (d, J = 237.0 Hz), 153.3 (d, J = 2.0 Hz), 141.7, 135.8, 118.5 (d,
J = 22.8 Hz), 118.2 (d, J = 8.3 Hz), 116.4 (d, J = 8.3 Hz), 116.1 (d, J =
25.2 Hz), 71.2, 70.3, 67.4, 38.8, 28.8, 28.2, 21.6, 14.1. LC/MS (CI): m/z =
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Bromooxazoles
Vitalii V. Solomin,
Dmytro S. Radchenko,
Evgeniy Y. Slobodyanyuk,
Oleksandr V. Geraschenko,
Bohdan V. Vashchenko,
Oleksandr O. Grygorenko
An approach to synthesis of all isomeric bromooxazoles was optimized and its
scope was extended to all three isomeric parent, as well as various alkyl- and aryl-
substituted bromooxazoles. The direct regiocontrolled lithiation followed by reaction
with electrophilic bromine source was common and led exclusively to the target
substituted 2-, 4- and 5-bromooxazoles on multigram scale. The utility of the
multipurpose building blocks obtained in this work was demonstrated in the Suzuki–
Miyaura cross-coupling reaction under parallel synthesis conditions.
Page No. – Page No.
Widely exploited, yet unreported:
regiocontrolled synthesis and the
Suzuki–Miyaura reactions of
bromooxazole building blocks
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