Expanding the chemical space of sp 3-enriched 4,5-disubstituted oxazoles via synthesis of novel building blocks

Article abstract of DOI:10.1007/s10593-019-02475-9

[Figure not available: see fulltext.] An efficient approach to the preparation of novel sp³-enriched 4,5-disubstituted oxazoles bearing a functional group at the C-4 position is described. The method commenced with synthesis of ethyl oxazole-4-carboxylates (13 examples, 63–99% yield), with subsequent function insertion to the heterocyclic core by late-stage functional group transformation. The LiBH4-mediated reduction of ethyl oxazole-4-carboxylates was the only method which could be optimized at multigram scale (up to 40 g), and its scope was demonstrated by preparation of 13 alcohols with (cyclo)alkyl, fluoroalkyl, or N-Boc-aminoalkyl moiety at the C-5 position (47–89% yield). The utility of these key intermediates was demonstrated by the preparation of chlorides (13 examples, 90–99% yield), azides (13 examples, 83–99% yield), amines (13 examples, 80–98% yield), and sulfonyl chlorides (4 examples, 68–97% yield) – advanced building blocks for synthetic and medicinal chemistry.

Full text of DOI:10.1007/s10593-019-02475-9

DOI 10.1007/s10593-019-02475-9
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
Expanding the chemical space of sp3-enriched
4,5-disubstituted oxazoles via synthesis of novel building blocks
Evgeniy Y. Slobodyanyuk1,2, Andrii A. Andriienko1,3, Bohdan V. Vashchenko1,3,
Dmitriy M. Volochnyuk2, Sergey V. Ryabukhin3, Oleksandr O. Grygorenko1,3*
1 Enamine Ltd.,
78 Chervonotkatska St., Kyiv 02094, Ukraine
2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
5 Murmanska St., Kyiv 02660, Ukraine
3 Taras Shevchenko National University of Kyiv,
60 Volodymyrska St., Kyiv 01601, Ukraine; е-mail: gregor@univ.kiev.ua
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 421–434
Submitted February 20, 2019
Accepted March 28, 2019
An efficient approach to the preparation of novel sp3-enriched 4,5-disubstituted oxazoles bearing a functional group at the C-4 position is
described. The method commenced with synthesis of ethyl oxazole-4-carboxylates (13 examples, 63–99% yield), with subsequent
function insertion to the heterocyclic core by late-stage functional group transformation. The LiBH4-mediated reduction of ethyl oxazole-
4-carboxylates was the only method which could be optimized at multigram scale (up to 40 g), and its scope was demonstrated by
preparation of 13 alcohols with (cyclo)alkyl, fluoroalkyl, or N-Boc-aminoalkyl moiety at the C-5 position (47–89% yield). The utility of
these key intermediates was demonstrated by the preparation of chlorides (13 examples, 90–99% yield), azides (13 examples, 83–99%
yield), amines (13 examples, 80–98% yield), and sulfonyl chlorides (4 examples, 68–97% yield) – advanced building blocks for synthetic
and medicinal chemistry.
Keywords: alcohols, amines, azides, chlorides, esters, oxazoles, sulfonyl chlorides, building blocks.
Oxazoles represent an important class of heterocycles,
occurring as the key substructural framework in numerous
natural compounds (e.g., marine alkaloids)1 and synthetic
products,2 featuring a broad range of biological activities,
in particular, anticancer, antifungal, or antibacterial.3–5
Whereas aryl-substituted oxazoles are widespread and well-
studied, their sp3-enriched counterparts have attracted
much interest only in recent years (Fig. 1).3 The known
oxazoles with aliphatic moieties mainly included 2,4-di-
and trisubstituted derivatives, e.g., protein kinase inhibitor
mubritinib (1),6 antimicrobial phenoxan (2),7 peroxisome
proliferator-activated receptor agonists muraglitazar (3),8
darglitazone (4),9 farglitazar (5),10,11 or lipid peroxidation
inhibitor martefragin A (6).12
Synthetic approaches and chemical properties of substi-
tuted oxazoles are well studied and surveyed in a number
of reviews or books.1–4,16–18 Most of the literature methods
relies on the late-stage oxazole ring construction, which
limits the scope of the substituents that can be introduced
into the target molecule. This is especially the case for
sp3-enriched 4,5-disubstituted derivatives. An alternative
approach to such compounds could rely on appropriate
oxazole-containing building blocks, which could be used
for further functionalization. Recently, it has been pointed
out that above-mentioned strategy is often overlooked in
synthetic and medicinal chemistry.19 It should be noted that
sp3-enriched low-molecular weight building blocks derived
from the 4,5-disubstituted oxazole framework are less
known in the literature. Typically, an entry into this
chemotype is provided by 5-alkyl-substituted oxazole-
4-carboxylates 10, which in turn are obtained by
condensation of carboxylic acids 1120–29 or their activated
derivatives, e.g., acyl chlorides,30–33 anhydrides,34–45 or
Less common, but chemically and biologically interesting
4,5-disubstituted oxazoles are represented mainly by aryl-
substituted derivatives, e.g., streptochlorin (7),13 non-
prostanoid partial IP receptor agonist BMY 45778 (8),14
p38 kinase inhibitor CP-808844 (9).15
0009-3122/19/55(4/5)-0421©2019 Springer Science+Business Media, LLC
421

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
Figure 1. Some important representatives of di- and trisubstituted oxazoles.
methyl selenoates,46 with alkyl 2-isocyanoacetates 12
(Scheme 1).
Reduction of esters 10 with complex metal hydrides was
found to be challenging due to the high hydrophilicity of
the target alcohols 13, which made the isolation of the
products extremely complicated. It should be noted that
this reaction was described in the literature for compound
10a at less than 1 g scale; product 13a was used in the next
step without purification.37 In addition to that, several aryl-
substituted counterparts were introduced into such transfor-
mations.
In this work, we have aimed at multigram preparation of
novel sp3-enriched 4,5-disubstituted oxazoles bearing a functio-
nal group at the C-4 position, i.e., alcohols 13 (13 examples),
chlorides 14 (13 examples), azides 15 (13 examples),
amines 16 (13 examples), and sulfonyl chlorides 17
(4 examples) (Fig. 2). All building blocks 13–17 were
obtained via modification of the key intermediates 10a–m.
Esters 10a–m were obtained by a CDI-promoted
reaction of carboxylic acids 11a–m with ethyl 2-isocyano-
acetate 12 in the presence of DBU as a base in THF.21
Products 10a–m were isolated in 63–99% yield (Table 1).
It is interesting to note that the procedure gave the best
results in the case of N-Boc-protected amino acids 11h–l
and methoxymethyl derivative 11m (86–99% yield), good
yields (75–89%) – with simple (cyclo)alkyl carboxylic
acids 11a–e, while the corresponding fluoroalkyl-substi-
tuted derivatives 10f,g were obtained in moderate yields
(63–65%). This might be related to the volatility of the
corresponding esters.
The reported methods relied on the use of DIBAL,37
LiAlH4,47,48 or NaBH4,49–51 and the corresponding products
were obtained in 67–87% yields. We have tested all these
methods with compound 10a at 10 g scale (Table 2, entries
1–5); it was found that although the product was formed, it
could not be isolated in pure form with satisfactory yield.
The use of LiBH4 in THF at room temperature (entry 6), as
well as changing the solvent to MeOH also appeared to be
unfruitful; in the latter case, the corresponding methyl ester
was formed as a byproduct. Only when ester 10a was
Scheme 1. Known approaches to 5-substituted
oxazole-4-carboxylates 10 with aliphatic substituents
Figure 2. sp3-Enriched 4,5-disubstituted oxazoles 13–17.
422

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
Table 1. Synthesis of esters 10a–m, alcohols 13a–m, and chlorides 14a–m
Entry
1
Compound 11
R
Ester 10
Yield, %
75
Alcohol 13
Yield, %
69
Chloride 14
Yield, %
92
11a
10a
13a
14a
2
3
86
89
60
71
95
96
11b
11c
10b
10c
13b
13c
14b
14c
4
5
86
78
76
89
98
93
11d
11e
10d
10e
13d
13e
14d
14e
6
7
8
63
65
97
68
47
62
90
92
99
11f
11g
11h
10f
10g
10h
13f
13g
13h
14f
14g
14h
9
95
97
85
78
96
97
11i
11j
10i
10j
13i
13j
14i
14j
10
11
86
80
98
11k
10k
13k
14k
12
13
99
98
75
72
96
92
11l
10l
13l
14l
11m
10m
13m
14m
refluxed with LiBH4 in THF–MeOH, 2:1 (entry 8), and the
reaction mixture was quenched with saturated aq NH4Cl
and then solid NH4Cl, the target derivative 13a could be
obtained in good yield (69%).
Table 2. Reduction step optimization
for the preparation of alcohol 13a
The developed protocol was applied successfully for the
preparation of all the target alcohols 13a–m at up to 40 g
scale (47–89% yield, after column chromatography) (Table 1).
It should be noted that chromatographic purification of
alcohols 13 prior to their use in further transformations is
strongly advised in order to ensure high yields and purity
of the target products.
Isolated yield
of the target
Metal
Entry
Conditions
hydride
alcohol 13a, %
1
2
3
4
5
6
7
8
DIBAL
LiAlH4
NaBH4
NaBH4
NaBH4
LiBH4
LiBH4
LiBH4
Hexanes, –78°C to 0 °C, 2 h
THF
48
34
In the next step, chlorides 14a–m were obtained by
reaction of alcohols 13a–m with mesyl chloride and Et3N
(Table 1). Under these reaction conditions, mesylation of
compounds 13 was immediately followed by nucleophilic
substitution with chlorine anion leading to the target
compounds 14a–m in excellent yields (90–99%). Such
reaction outcome is unusual, but not unprecedented for
various hetarylmethanols.52–54
THF, reflux
–*
MeOH, reflux
28**
45
THF–MeOH (2:1), reflux
THF, rt
–*
MeOH, rt
6**
69
THF–MeOH (2:1), reflux
Preparation of azides 15a–m relied on the nucleophilic
substitution of compounds 14a–m with NaN3 in refluxing
* No reaction was observed.
** The corresponding methyl ester was obtained as byproduct.
423

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
Table 3. Synthesis of azides 15a–m and amines 16a–m·HCl
Cl
N3
NH2
HCl
NaN3
1. H2, Pd/C, MeOH
N
N
N
MeCN, H2O
83–99%
2. HCl–1,4-dioxane
80–98%
R
R
R
O
O
O
14a m
15a m
16a,i, 16b m
·HCl
–
–
–
Entry
1
Chloride 14
R
Azide 15
Yield, %
86
Amine 16
Yield, %
93*
14a
15a
16a
2
3
96
98
16b·HCl
16c·HCl
90
87
14b
14c
15b
15c
4
5
89
98
16d·HCl
16e·HCl
80
96
14d
14e
15d
15e
6
7
8
85
83
99
16f·HCl
16g·HCl
16h·HCl
83
81
87
14f
14g
14h
15f
15g
15h
9
92
94
95*
98
14i
14j
15i
15j
16i
10
16j·HCl
11
95
16k·HCl
95
14k
15k
12
13
96
98
16l·HCl
95
92
14l
15l
16m·HCl
14m
15m
* The compound was isolated as a base.
MeCN–H2O (ca. 70:1). The reaction proceeded smoothly
and gave excellent yields (83–99%) of the target building
blocks 15a–m (Table 3). Subsequent catalytic reduction
of azides 15a–m under 1 atm of H2 in the presence of
10% Pd/C in MeOH, followed by acidification with 10%
HCl in 1,4-dioxane (for compounds 16a–g,m, entries 1–7
and 13) or NH4Cl in MeOH (for N-Boc-monoprotected
diamines 16h–l, entries 8–12) led to the corresponding
amines 16a–m·HCl (80–98% yield).
Chlorides 14a,c,d,f,g were transformed into sulfonyl
chlorides 17a,c,d,f,g. The corresponding thioacetates 18
were obtained from compound 14 in 85–98% yields upon
treatment with KSAc in EtOH at 55°C (Table 4). Subse-
quent oxidative chlorination with N-chlorosuccinimide in
the presence of aq HCl in MeCN–H2O (10:1) gave the
target sulfonyl chlorides 17a,c,d,f,g. It should be noted that
most of the synthesized compounds 17 were found to be
unstable upon any isolation or storage conditions. This was
not the case with derivatives 17f,g bearing electron-
withdrawing tri- or difluoromethyl groups, which were
stable and could be isolated in 95–97% yield. Nevertheless,
unlike cyclopropyl derivative 17d, alkyl-substutituted
oxazoles 17a,c were also obtained and characterized
(68–72% yield); they should be subjected to further
transformations immediately after isolation. It was found
that sulfonyl chlorides 17a,c decomposed to the
corresponding chlorides 14a,c, respectively, at room
1
temperature after 48 h (established by H NMR spectro-
scopy). When a sample of sulfonyl chloride 17c had been
stored at –24°C for 2 months, the ratio 14c:17c was found
to be 1:3.
Despite numerous literature examples of using alkyl-
substituted oxazoles in organic synthesis and drug
discovery, their preparation and the scope of the known
methods have been largely underrepresented to date,
especially for functionalized sp3-enriched 4,5-disubstituted
derivatives. In this work, general, efficient, and scalable
methods for the preparation of novel 4,5-disubstituted
oxazoles bearing a functional group at the C-4 position
were developed. The synthesized building blocks also
424

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
Table 4. Synthesis of thioacetates 18 and sulfonyl chlorides 17
Entry
1
Chloride 14
R
Thioacetate 18
Yield, %
89
Sulfonyl chloride 17
Yield, %
72
14a
18a
17a
2
93
68
14c
18c
17c
3
85
0
14d
18d
17d
4
5
96
98
97
95
14f
18f
17f
14g
18g
17g
contained alkyl, cycloalkyl, di/trifluoromethyl, N-Boc-
aminoalkyl, or methoxymethyl substituent at the C-5 atom
of the heteroaromatic ring. The proposed approach com-
menced from ethyl oxazole-4-carboxylates 10a–m, which
were obtained from aliphatic carboxylic acids 11a–m and
ethyl isocyanoacetate 12. Reduction of esters 10a–m was
challenging in these series due to the high hydrophilicity of
the corresponding alcohols 13a–m. It was found that using
LiBH4 in THF–MeOH (2:1) followed by quenching of the
reaction mixture with saturated aq NH4Cl and then solid
NH4Cl was very efficient, and products 13 were obtained in
47–88% yield (13 examples; 12 novel).
The utility of alcohols 13 was demonstrated by the
preparation of four other compound classes. In particular,
mesylation of alcohols 13 was accompanied by nucleo-
philic substitution with chlorine anion leading to chlorides
14a–m (90–99% yield). Reaction of compounds 14 with
NaN3 gave azides 15a–m (83–99% yield), which were
transformed to amines 16a–m by catalytic reduction (80–
98% yield). Alternatively, sulfonyl chlorides 17 were
obtained via oxidative chlorination with NCS of the
corresponding thioacetates 18 (4 examples, 68–97% yield).
These functionalized low-molecular weight hydrophilic
oxazole derivatives were prepared on up to 40 g scale;
therefore, they can be considered as promising building
blocks for organic synthesis and drug discovery, which are
readily available to scientific community and can signi-
ficantly expand the currently accessible lead-like chemical
space (Fig. 3).
Figure 3. The simplest derivatives of building blocks 14, 16, and
17 shown in MW (molecular weight) – cLogP (calculated octanol –
water partition coefficient logarithm) (black dots within an
ellipse). Structures of the derivatives were obtained by in silico
coupling with dimethylamine (for compounds 14 and 17) or
acetyl chloride (for compounds 16); the Boc protective groups
were also transformed into acetyl. Dotted lines show limits
imposed by Lipinski rule-of-five (light gray)55 and criteria for lead-
likeness by Churcher et al. (dark gray).56 The white arrow shows
that there is enough space left for the design of lead-like
compounds based on the building blocks synthesized.
(400, 101, and 376 MHz, respectively). TMS or residual
solvent peaks used as internal standards (7.26 and
1
77.2 ppm for H and 13C nuclei, respectively, in CDCl3,
1
2.50 and 39.5 ppm for H and 13C nuclei, respectively, in
DMSO-d6). Mass spectra were recorded on an Agilent
1100 LCMSD SL instrument (chemical ionization (CI),
CF3CO2H) and an Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)). Elemental analyses
were performed at the Laboratory of Organic Analysis,
Department of Chemistry, Taras Shevchenko National
University of Kyiv. Melting points were measured on a
MPA100 OptiMelt automated melting point system. Analy-
tical TLC was performed using Polychrom SI F254 plates.
Column chromatography was performed using silica gel
(230–400 mesh) as the stationary phase. Instant JChem version
17.2.27.0 was used for the calculation of physicochemical
parameters, Chemaxon, Hungary, www.chemaxon.com.
An efficient approach to the preparation of novel
sp3-enriched 4,5-disubstituted oxazoles bearing different
functional groups at the C-4 position is described, i.e.,
alcohols, chlorides, azides, amines, and sulfonyl chlorides.
All compounds were obtained via modification of the key
intermediate ethyl oxazole-4-carboxylate.
Experimental
1H, 13C and 19F NMR spectra were recorded on a Bruker
170 Avance 500 spectrometer (500, 126, and 470 MHz,
respectively) and a Varian Unity Plus 400 spectrometer
425

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
Solvents were purified according to the standard
27.4; 18.3; 14.2. Mass spectrum (CI), m/z (Irel, %): 196
[M+H]+ (50), 150 [M–OEt]+ (100). Found, %: C 61.77;
H 6.52; N 7.11. C10H13NO3. Calculated, %: C 61.53;
H 6.71; N 7.18.
procedures.57 Compounds 11a–m and 12 were available
from Enamine Ltd.
Synthesis of esters 10a–m (General method). The
corresponding carboxylic acid 11a–m (0.307 mol) was
dissolved in THF (350 ml), and CDI (59.7 g, 0.368 mol)
was added in portions to the solution. The resulting mixture
was heated at 55°C for 1 h and then cooled to 0°C. Ethyl
2-isocyanoacetate 12 (41.6 g, 0.368 mol) was added in one
portion, then DBU (56.0 g, 0.368 mol) was added dropwise
at 0°C, and the resulting mixture was stirred at room tempe-
rature for 12 h. Then THF was evaporated under reduced
pressure, the residue was dissolved in EtOAc (500 ml) and
washed with 10% aq solution of citric acid (300 ml), H2O
(500 ml), and brine (300 ml). The organic phase was dried
over Na2SO4 and evaporated under reduced pressure.
Ethyl 5-methyloxazole-4-carboxylate (10a). Yield
35.7 g (75%), yellowish liquid. For physical and spectral
data, see ref.25,32,33,36
Ethyl 5-(trifluoromethyl)oxazole-4-carboxylate (10f)
was purified by column chromatography on silica gel,
eluent hexanes–EtOAc, 4:1, Rf 0.44. Yield 40.4 g (63%),
1
colorless liquid. H NMR spectrum (500 MHz, CDCl3),
δ, ppm (J, Hz): 8.02 (1H, s, H oxazole); 4.35 (2H, q, J = 7.2,
OCH2CH3); 1.31 (3H, t, J = 7.1, OCH2CH3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm (J, Hz): 158.8; 150.9;
142.6 (q, J = 44.6); 132.1 (q, J = 2.3); 118.0 (q, J = 270.0);
62.2; 13.7. 19F NMR spectrum (470 MHz, CDCl3), δ, ppm:
–61.6. Mass spectrum (CI), m/z (Irel, %): 210 [M+H]+ (42),
182 [M–CH2=CH(CH3)+H]+ (77), 164 [M–OEt]+ (100).
Found, %: C 40.10; H 2.99; N 7.01. C7H6F3NO3.
Calculated, %: C 40.20; H 2.89; N 6.70.
Ethyl 5-(difluoromethyl)oxazole-4-carboxylate (10g)
was purified by column chromatography on silica gel,
eluent hexanes–EtOAc, 4:1, Rf 0.42. Yield 38.1 g (65%),
colorless liquid. 1H NMR spectrum (500 MHz, CDCl3), δ, ppm
(J, Hz): 7.99 (1H, s, H oxazole); 7.23 (1H, t, J = 52.1,
CHF2); 4.40 (2H, q, J = 7.2, OCH2CH3); 1.37 (3H, t, J = 7.2,
OCH2CH3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm
(J, Hz): 160.0; 151.4; 147.6 (t, J = 24.6); 132.1 (t, J = 5.8);
106.0 (t, J = 238.0); 62.2; 14.0. 19F NMR spectrum
(470 MHz, CDCl3), δ, ppm (J, Hz): –118.1 (d, J = 52.1).
Mass spectrum (CI), m/z (Irel, %): 210 [M+H]+ (30), 164
[M–CH2=CH(CH3)+H]+ (29), 146 [M–OEt]+ (100). Found,
%: C 44.01; H 3.51; N 6.95. C7H7F2NO3. Calculated, %:
C 43.99; H 3.69; N 7.33.
Ethyl 5-{[(tert-butoxycarbonyl)amino]methyl}oxazole-
4-carboxylate (10h).32 Yield 80.5 g (97%), beige crystals,
mp 63–65°C. 1H NMR spectrum (500 MHz, CDCl3),
δ, ppm (J, Hz): 7.77 (1H, s, H oxazole); 5.34 (1H, br. s, NH);
4.63 (2H, d, J = 6.2, CH2NHBoc); 4.34 (2H, q, J = 7.1,
OCH2CH3); 1.39 (9H, s, C(CH3)3); 1.36 (3H, t, J = 7.1,
OCH2CH3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
161.7; 156.1; 155.5; 149.4; 128.2; 80.1; 61.4; 35.5; 28.3; 14.2.
Mass spectrum (CI), m/z (Irel, %): 215 [M–(H3C)2C=CH2+H]+
(68), 171 [M–CO2–(H3C)2C=CH2+H]+ (100). Found, %:
C 53.46; H 6.52; N 10.37. C12H18N2O5. Calculated, %:
C 53.33; H 6.71; N 10.36.
Ethyl 5-{2-[(tert-butoxycarbonyl)amino]ethyl}oxazole-
4-carboxylate (10i).59 Yield 82.9 g (95%), brown oil.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
7.78 (1H s, H oxazole); 4.80 (1H, s, NH); 4.36 (2H, q,
J = 7.1, OCH2CH3); 3.45 (2H, q, J = 6.0, CH2CH2NHBoc);
3.24 (2H, t, J = 6.5, CH2CH2NHBoc); 1.38 (9H, s, C(CH3)3);
1.38 (3H, t, J = 7.1, CH3). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 162.0; 157.3; 155.7; 149.4; 128.3; 79.4;
61.2; 38.7; 28.3; 26.7; 14.3. Mass spectrum (CI), m/z
(Irel, %): 307 [M+Na]+ (7), 229 [M–(H3C)2C=CH2+H]+
(72), 185 [M–CO2–(H3C)2C=CH2+H]+ (100). Found, %:
C 55.12; H 7.14; N 9.69. C13H20N2O5. Calculated, %:
C 54.92; H 7.09; N 9.85.
Ethyl 5-isopropyloxazole-4-carboxylate (10b).32 Yield
1
48.4 g (86%), brown oil. H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.70 (1H, s, H oxazole); 4.31 (2H,
q, J = 7.2, OCH2CH3); 3.74 (1H, sept, J = 7.0, CH(CH3)2);
1.33 (3H, t, J = 7.2, OCH2CH3); 1.23 (6H, d, J = 7.0,
CH(CH3)2). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
164.2; 162.0; 148.6; 125.3; 60.8; 25.9; 20.4; 14.2. Mass
spectrum (CI), m/z (Irel, %): 184 [M+H]+ (100). Found, %:
C 59.01; H 7.16; N 7.73. C9H13NO3. Calculated, %:
C 59.00; H 7.15; N 7.65.
Ethyl 5-(tert-butyl)oxazole-4-carboxylate (10c).58
Yield 53.9 g (89%), brown oil. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.66 (1H, s, H oxazole); 4.32 (2H,
q, J = 7.1, OCH2CH3); 1.40 (9H, s, C(CH3)3); 1.35 (3H, t,
J = 7.1, OCH2CH3). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 165.9; 162.0; 147.2; 125.9; 61.0; 33.2;
28.1; 14.2. Mass spectrum (CI), m/z (Irel, %): 198 [M+H]+
(100). Found, %: C 61.15; H 7.27; N 7.03. C10H15NO3.
Calculated, %: C 60.90; H 7.67; N 7.10.
Ethyl 5-cyclopropyloxazole-4-carboxylate (10d).31
Yield 47.8 g (86%), brown oil. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.54 (1H, s, H oxazole); 4.30 (2H,
q, J = 7.1, OCH2CH3); 2.68 (1H, tt, J = 8.4, J = 5.1, CH
cyclopropane); 1.31 (3H, t, J = 7.1, OCH2CH3); 1.07–1.03
(2H, m, CH2 cyclopropane); 1.00–0.97 (2H, m, CH2
cyclopropane). 13C NMR spectrum (126 MHz, CDCl3),
δ, ppm: 162.3; 160.9; 147.3; 126.6; 60.8; 14.3; 8.9; 7.7.
Mass spectrum (CI), m/z (Irel, %): 182 [M+H]+ (42), 136
[M–OEt]+ (100). Found, %: C 60.04; H 5.82; N 7.43.
C9H11NO3. Calculated, %: C 59.66; H 6.12; N 7.73.
Ethyl 5-cyclobutyloxazole-4-carboxylate (10e) was
purified by column chromatography on silica gel, eluent
hexanes–EtOAc, 2:1, Rf 0.37. Yield 46.7 g (78%), colorless
liquid. 1H NMR spectrum (500 MHz, CDCl3), δ, ppm
(J, Hz): 7.73 (1H s, H oxazole); 4.29 (2H, q, J = 7.1,
OCH2CH3); 4.20 (1H, quintet, J = 8.8, CH cyclobutane);
2.35–2.23 (4H, m, 2CH2 cyclobutane); 2.05–1.94 (1H, m,
CH2 cyclobutane); 1.91–1.83 (1H, m, CH2 cyclobutane); 1.32
(3H, t, J = 7.1, OCH2CH3). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 162.0; 161.4; 148.7; 125.6; 60.8; 30.9;
Ethyl 5-{3-[(tert-butoxycarbonyl)amino]propyl}oxazole-
4-carboxylate (10j) was purified by column chromato-
graphy on silica gel, eluent hexanes–EtOAc, 2:1, Rf 0.34.
426

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
1
Yield 88.8 g (97%), yellowish liquid. H NMR spectrum
(5-Methyloxazol-4-yl)methanol (13a)37 was purified by
column chromatography on silica gel, eluent CHCl3–
MeOH, 25:1, Rf 0.36. Yield 15.1 g (69%), yellowish
powder, mp 47–49°C. 1H NMR spectrum (400 MHz,
CDCl3), δ, ppm: 7.71 (1H, s, H oxazole); 4.48 (2H, s,
CH2OH); 4.20 (1H, br. s, OH); 2.29 (3H, s, CH3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 149.4; 145.4; 133.7;
55.5; 10.0. Mass spectrum (CI), m/z (Irel, %): 114 [M+H]+
(58), 96 [M–OH]+ (100). Found, %: C 53.11; H 6.32;
N 12.28. C5H7NO2. Calculated, %: C 53.09; H 6.24;
N 12.38.
(5-Isopropyloxazol-4-yl)methanol (13b) was purified
by column chromatography on silica gel, eluent CHCl3–
MeOH, 14:1, Rf 0.40. Yield 16.3 g (60%), colorless liquid.
1H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 7.71
(1H, s, H oxazole); 4.51 (2H, s, CH2OH); 4.11 (1H, br. s,
OH); 3.10 (1H, sept, J = 6.9, CH(CH3)2); 1.23 (6H, d,
J = 6.9, CH(CH3)2). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 153.6; 149.2; 132.0; 55.5; 25.2; 21.3.
Mass spectrum (CI), m/z (Irel, %): 142 [M+H]+ (100), 124
[M–OH]+ (86). Found, %: C 59.67; H 8.02; N 10.24.
C7H11NO2. Calculated, %: C 59.56; H 7.85; N 9.92.
[5-(tert-Butyl)oxazol-4-yl]methanol (13c) was triturated
with cold pentane. Yield 21.4 g (71%), yellowish crystals,
mp 54–56°C. 1H NMR spectrum (400 MHz, CDCl3),
δ, ppm: 7.68 (1H, s, H oxazole); 4.63–4.59 (2H, m,
CH2OH); 3.81 (1H, br. s, OH); 1.32 (9H, s, C(CH3)3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 155.4;
148.4; 131.9; 56.7; 32.6; 29.3. Mass spectrum (CI), m/z
(Irel, %): 156 [M+H]+ (32), 138 [M–OH]+ (100). Found, %:
C 61.73; H 8.72; N 8.66. C8H13NO2. Calculated, %:
C 61.91; H 8.44; N 9.03.
(5-Cyclopropyloxazol-4-yl)methanol (13d) was purified
by column chromatography on silica gel, eluent CHCl3–
MeOH, 10:1, Rf 0.32. Yield 21.5 g (76%), colorless liquid.
1H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 7.62
(1H, s, H oxazole); 4.55 (2H, s, CH2OH); 4.06 (1H, br. s,
OH); 1.90 (1H, tt, J = 8.5, J = 5.2, CH cyclopropane); 0.95–0.89
(2H, m, CH2 cyclopropane); 0.87–0.82 (2H, m, CH2 cyclo-
propane). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
149.8; 148.5; 133.5; 55.5; 6.5; 5.8. Mass spectrum (CI), m/z
(Irel, %): 140 [M+H]+ (34), 122 [M–OH]+ (100). Found, %:
C 60.69; H 6.75; N 9.95. C7H9NO2. Calculated, %: C 60.42;
H 6.52; N 10.07.
(5-Cyclobutyloxazol-4-yl)methanol (13e). Yield 26.4 g
(89%), colorless oil. 1H NMR spectrum (400 MHz,
CDCl3), δ, ppm (J, Hz): 7.74 (1H, s, H oxazole); 4.47 (2H,
s, CH2OH); 3.99 (1H, br. s, OH); 3.60 (1H, quint, J = 8.8,
CH cyclobutane); 2.36–2.23 (4H, m, 2CH2 cyclobutane);
2.03–1.94 (1H, m, CH2 cyclobutane); 1.92–1.85 (1H, m,
CH2 cyclobutane). 13C NMR spectrum (126 MHz, CDCl3),
δ ppm: 151.2; 149.4; 132.4; 55.5; 30.3; 28.1; 18.6. Mass
spectrum (CI), m/z (Irel, %): 154 [M+H]+ (23), 136 [M–OH]+
(100). Found, %: C 62.62; H 6.91; N 9.38. C8H11NO2.
Calculated, %: C 62.73; H 7.24; N 9.14.
(500 MHz, CDCl3), δ, ppm (J, Hz): 7.74 (1H, s,
H oxazole); 4.88 (1H, br. s, NH); 4.35 (2H, q, J = 7.1,
OCH2CH3); 3.11 (2H, q, J = 6.0, CH2CH2CH2NHBoc);
3.06 (2H, t, J = 7.3, CH2CH2CH2NHBoc); 1.85 (2H, quint,
J = 7.1, CH2CH2CH2NHBoc); 1.40 (9H, s, C(CH3)3); 1.37 (3H,
t, J = 7.1, OCH2CH3). 13C NMR spectrum (126 MHz, CDCl3),
δ, ppm: 162.1; 159.1; 155.9; 149.1; 127.4; 61.1; 39.4; 28.4;
28.0; 27.9; 23.0; 14.3. Mass spectrum (CI), m/z (Irel, %):
321 [M+Na]+ (7), 243 [M–(H3C)2C=CH2+H]+ (87), 199
[M–CO2–(H3C)2C=CH2+H]+ (100). Found, %: C 56.16;
H 7.09; N 9.17. C14H22N2O5. Calculated, %: C 56.36;
H 7.43; N 9.39.
Ethyl 5-{2-[(tert-butoxycarbonyl)amino]propan-2-yl}-
oxazole-4-carboxylate (10k).32 Yield 78.8 g (86%), beige
crystals, mp 60–62°C. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.70 (1H, s, H oxazole); 5.60 (1H,
br. s, NH); 4.33 (2H, q, J = 7.2, OCH2CH3); 1.68 (6H, s,
C(CH3)2); 1.35 (3H, t, J = 7.1, OCH2CH3); 1.27 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
163.3; 161.8; 154.9; 147.5; 125.7; 79.5; 61.3; 51.4; 28.2;
26.7; 14.2. Mass spectrum (CI), m/z (Irel, %): 183
[M–NHCO2t-Bu+H]+ (100). Found, %: C 56.21; H 7.08;
N 9.32. C14H22N2O5. Calculated, %: C 56.36; H 7.43; N 9.39.
Ethyl 5-[1-(tert-butoxycarbonyl)azetidin-3-yl]oxazole-
4-carboxylate (10l). Yield 90.1 g (99%), brown crystals,
1
mp 78–80°C. H NMR spectrum (500 MHz, CDCl3), δ, ppm
(J, Hz): 7.84 (1H, s, H oxazole); 4.49 (1H, tt, J = 8.7, J = 6.3,
CH azetidine); 4.35 (2H, q, J = 7.1, OCH2CH3); 4.30–4.25
(2H, m, CH2 azetidine); 4.10 (2H, dd, J = 8.7, J = 6.3, CH2
azetidine); 1.43 (9H, s, C(CH3)3); 1.36 (3H, t, J = 7.1,
OCH2CH3). 13C NMR spectrum (126 MHz, CDCl3),
δ, ppm: 161.6; 157.6; 156.1; 149.4; 127.9; 79.9; 61.3; 53.3;
28.3; 25.1; 14.2. Mass spectrum (CI), m/z (Irel, %): 241
[M–(H3C)2C=CH2+H]+ (100), 197 [M–CO2–(H3C)2C=CH2+H]+
(27). Found, %: C 57.03; H 7.02; N 9.20. C14H20N2O5.
Calculated, %: C 56.75; H 6.80; N 9.45.
Ethyl 5-(methoxymethyl)oxazole-4-carboxylate (10m).60
Yield 55.7 g (98%), brown oil. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm (J, Hz): 7.82 (1H, s,
H oxazole); 4.69 (2H, s, CH2OCH3); 4.27 (2H, q, J = 7.1,
OCH2CH3); 3.29 (3H, s, OCH3); 1.28 (3H, t, J = 7.1,
OCH2CH3). 13C NMR spectrum (126 MHz, CDCl3),
δ, ppm: 161.3; 154.3; 150.4; 129.6; 63.3; 61.3; 58.5; 14.1.
Mass spectrum (CI), m/z (Irel, %): 186 [M+H]+ (25), 154
[M–OMe]+ (100). Found, %: C 51.56; H 6.24; N 7.47.
C8H11NO4. Calculated, %: C 51.89; H 5.99; N 7.56.
Synthesis of alcohols 13a–m (General method). The
corresponding ester 10a–m (0.194 mol) was dissolved in
THF–MeOH (2:1, 450 ml), and LiBH4 (10.6 g, 0.485 mol)
was added in small portions at room temperature. The
resulting mixture was heated at 55°C overnight and then
cooled to room temperature. Saturated aq NH4Cl (30 ml)
and solid NH4Cl (30.0 g) were added to the reaction
mixture. Then most of the solvent was evaporated under
reduced pressure, the residue was diluted with EtOAc
(500 ml), and the formed precipitate was filtered off and
washed with hot EtOAc (2×100 ml). The filtrate was dried
over Na2SO4 and evaporated under reduced pressure.
[5-(Trifluoromethyl)oxazol-4-yl]methanol (13f) was
purified by column chromatography on silica gel, eluent
CHCl3–MeOH, 25:1, Rf 0.22. Yield 22.0 g (68%), yellowish
1
liquid. H NMR spectrum (400 MHz, DMSO-d6), δ, ppm
427

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
(J, Hz): 8.66 (1H, s, H oxazole); 5.49 (1H, t, J = 5.8); 4.46
tert-Butyl {2-[4-(hydroxymethyl)oxazol-5-yl]propan-
2-yl}carbamate (13k) was triturated with cold hexanes.
Yield 39.8 g (80%), yellowish solid, mp 107–109°C.
1H NMR spectrum (500 MHz, CDCl3), δ, ppm: 7.69 (1H, s,
H oxazole); 5.28 (1H, br. s, NH); 4.60 (2H, s, CH2OH);
3.85 (1H, br. s, OH); 1.64 (6H, s, C(CH3)2); 1.32 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
154.4; 150.8; 148.3; 133.6; 79.9; 56.6; 51.1; 28.2; 27.4.
Mass spectrum (CI), m/z (Irel, %): 279 [M+Na]+ (3), 257
[M+H]+ (40), 201 [M–(H3C)2C=CH2+H]+ (30), 183 [M–Ot-Bu]+
(100), 142 [M–NHCO2t-Bu+H]+ (7). Found, %: C 55.93;
H 7.55; N 11.30. C12H20N2O4. Calculated, %: C 56.24;
H 7.87; N 10.93.
(2H, d, J = 5.8, CH2OH). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm (J, Hz): 153.3; 142.0 (q, J = 2.2); 133.6
(q, J = 42.4); 119.4 (q, J = 267.0); 54.1. 19F NMR spectrum
(376 MHz, DMSO-d6), δ, ppm: –62.4. Mass spectrum (CI),
m/z (Irel, %): 150 [M–F+H]+ (100). Found, %: C 35.85;
H 2.30; N 8.05. C5H4F3NO2. Calculated, %: C 35.94;
H 2.41; N 8.38.
[5-(Difluoromethyl)oxazol-4-yl]methanol (13g) was
purified by column chromatography on silica gel, eluent
CHCl3–MeOH, 14:1, Rf 0.36. Yield 13.6 g (47%),
1
yellowish liquid. H NMR spectrum (400 MHz, CDCl3),
δ, ppm (J, Hz): 7.91 (1H, s, H oxazole); 6.92 (1H, t, J = 53.1,
CHF2); 4.76 (2H, s, CH2OH); 2.53 (1H, s, OH). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm (J, Hz): 151.6; 140.0
(t, J = 4.4); 139.6 (t, J = 28.0); 107.5 (t, J = 236.0); 56.6.
19F NMR spectrum (376 MHz, CDCl3), δ, ppm: –116.1.
Mass spectrum (EI), m/z (Irel, %): 149 [M]+ (21), 119
[M–H2CO]+ (100). Found, %: C 40.67; H 3.52; N 8.99.
C5H5F2NO2. Calculated, %: C 40.28; H 3.38; N 9.39.
tert-Butyl {[4-(hydroxymethyl)oxazol-5-yl]methyl}-
carbamate (13h) was triturated with cold pentane. Yield
27.5 g (62%), white solid, mp 83–85°C. 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm (J, Hz): 7.73 (1H, s, H oxazole);
5.32 (1H, s, NH); 4.61 (2H, s, CH2OH); 4.32 (2H, d,
J = 6.2, CH2NHBoc); 4.06 (1H, br. s, OH); 1.37 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
156.3; 150.0; 145.1; 136.6; 80.6; 57.0; 34.4; 28.3. Mass
spectrum (CI), m/z (Irel, %): 173 [M–(H3C)2C=CH2+H]+
(80), 129 [M–CO2–(H3C)2C=CH2+H]+ (100). Found, %:
C 52.37; H 7.15; N 12.62. C10H16N2O4. Calculated, %:
C 52.62; H 7.07; N 12.27.
tert-Butyl 3-[4-(hydroxymethyl)oxazol-5-yl]azetidine-
1-carboxylate (13l) was crystallized from hexanes–
t-BuOMe, 50:1. Yield 37.0 g (75%), white solid, mp 136–
1
138°C. H NMR spectrum (500 MHz, CDCl3), δ, ppm:
7.85 (1H, s, H oxazole); 4.87 (1H, br. s, NH); 4.52 (2H, s,
CH2OH); 4.22–4.17 (2H, m, CH2 azetidine); 4.08–4.04
(2H, m, CH2 azetidine); 3.99–3.92 (1H, m, CH azetidine);
1.43 (9H, s, C(CH3)3). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 156.2; 150.2; 147.2; 134.9; 121.3; 79.9;
55.6; 54.1; 28.3; 24.1. Mass spectrum (CI), m/z (Irel, %): 199
[M–(H3C)2C=CH2+H]+ (10), 155 [M–CO2–(H3C)2C=CH2+H]+
(3), 126 [M–H2CNHBoc+H]+ (21), 108 [M–H2CNHBoc–OH]+
(100). Found, %: C 57.05; H 6.79; N 10.89. C12H18N2O4.
Calculated, %: C 56.68; H 7.14; N 11.02.
[5-(Methoxymethyl)oxazol-4-yl]methanol (13m) was
purified by column chromatography on silica gel, eluent
CHCl3–MeOH, 14:1, Rf 0.30. Yield 20.0 g (72%), yellowish
1
oil. H NMR spectrum (400 MHz, CDCl3), δ, ppm: 7.82
(1H, s, H oxazole); 4.58 (2H, s) and 4.48 (2H, s,
CH2OCH3, CH2OH); 3.73 (1H, s, OH); 3.34 (3H, s, OCH3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 150.8;
144.8; 137.6; 63.2; 58.2; 56.0. Mass spectrum (CI), m/z
(Irel, %): 144 [M+H]+ (100). Found, %: C 50.51; H 6.43;
N 10.12. C6H9NO3. Calculated, %: C 50.35; H 6.34;
N 9.79.
tert-Butyl {2-[4-(hydroxymethyl)oxazol-5-yl]ethyl}-
carbamate (13i). Yield 40.0 g (85%), brownish oil.
1H NMR spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 7.76
(1H, s, H oxazole); 5.03 (1H, s, NH); 4.51 (2H, s, CH2OH);
3.68 (1H, br. s, OH); 3.35 (2H, t, J = 6.6, CH2CH2NHBoc);
2.90 (2H, t, J = 6.6, CH2CH2NHBoc); 1.39 (9H, s, C(CH3)3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 155.9;
149.8; 146.7; 135.2; 79.6; 55.8; 39.0; 28.3; 25.4. Mass
spectrum (CI), m/z (Irel, %): 170 [M–Ot-Bu+H]+ (47), 143
[M–CO2–(H3C)2C=CH2+H]+ (27), 127 [M–NHCO2t-Bu+H]+
(100). Found, %: C 54.89; H 7.35; N 11.34. C11H18N2O4.
Calculated, %: C 54.53; H 7.49; N 11.56.
tert-Butyl {3-[4-(hydroxymethyl)oxazol-5-yl]propyl}-
carbamate (13j) was purified by column chromatography
on silica gel, eluent CHCl31–MeOH, 14:1, Rf 0.42. Yield
38.8 g (78%), colorless oil. H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.75 (1H, s, H oxazole); 4.92 (1H,
s, NH); 4.51 (2H, s, CH2OH); 3.95 (1H, br. s, OH); 3.09
(2H, q, J = 6.7, CH2CH2CH2NHBoc); 2.74 (2H, t, J = 7.0,
Synthesis of chlorides 14a–m (General method). The
corresponding alcohol 13a–m (0.132 mol) was dissolved in
CH2Cl2 (250 ml), and Et3N (27.6 ml, 20.0 g, 0.198 mol)
was added. The solution was cooled to 0°C, and MsCl (18.1 g,
0.158 mol) was added dropwise. The resulting mixture was
stirred at room temperature overnight, then washed with
saturated aq solution of NaHCO3 (200 ml), H2O (200 ml),
and brine (100 ml). The organic phase was dried over
Na2SO4 and evaporated under reduced pressure.
4-(Chloromethyl)-5-methyloxazole (14a). Yield 16.0 g
1
(92%), yellowish liquid. H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 7.67 (1H, s, H oxazole); 4.42 (2H, s,
CH2Cl); 2.27 (3H, s, CH3). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 149.3; 146.7; 131.1; 36.9; 10.0. Mass
spectrum (EI), m/z (Irel, %): 133 [M]+ (9), 131 [M]+ (27), 96
[M–Cl]+ (100). Found, %: C 45.93; H 4.30; N 11.01;
Cl 27.31. C5H6ClNO. Calculated, %: C 45.65; H 4.60;
N 10.65; Cl 26.95.
CH2CH2CH2NHBoc); 1.82 (2H, quint,
J
=
6.7,
CH2CH2CH2NHBoc); 1.42 (9H, s, C(CH3)3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 156.2; 149.6; 148.2;
134.4; 79.4; 55.8; 39.2; 28.4; 28.3; 21.6. Mass spectrum
(CI), m/z (Irel, %): 279 [M+Na]+ (3), 201 [M–(H3C)2C=CH2+H]+
(3), 140 [M–NHCO2t-Bu+H]+ (100). Found, %: C 56.60;
H 7.66; N 11.09. C12H20N2O4. Calculated, %: C 56.24;
H 7.87; N 10.93.
4-(Chloromethyl)-5-isopropyloxazole (14b). Yield
20.0 g (95%), yellowish liquid. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm (J, Hz): 7.74 (1H, s,
428

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
H oxazole); 4.54 (2H, s, CH2Cl); 3.15 (1H, sept, J = 6.9,
δ, ppm: –117.1. Mass spectrum (EI), m/z (Irel, %): 169 [M]+
(7), 167 [M]+ (21), 150 [M–Cl]+ (100). Found, %: C 35.98;
H 2.27; N 8.28; Cl 21.47. C5H4ClF2NO. Calculated, %:
C 35.85; H 2.41; N 8.36; Cl 21.16.
CH(CH3)2); 1.31 (6H, d, J = 6.9, CH(CH3)2). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 154.9; 149.1; 129.4;
37.1; 25.5; 21.0. Mass spectrum (EI), m/z (Irel, %): 161 [M]+
(12), 159 [M]+ (36), 146 [M–CH3]+ (20), 144 [M–CH3]+
(60), 124 [M–Cl]+ (100). Found, %: C 52.46; H 5.95;
N 8.66; Cl 21.94. C7H10ClNO. Calculated, %: C 52.68;
H 6.32; N 8.78; Cl 22.21.
tert-Butyl {[4-(chloromethyl)oxazol-5-yl]methyl}-
carbamate (14h). Yield 32.2 g (99%), white solid, mp 92–
94°C. 1H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz):
7.75 (1H, s, H oxazole); 5.01 (1H, s, NH); 4.57 (2H, s,
CH2Cl); 4.36 (2H, d, J = 6.1, CH2NHBoc); 1.41 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
155.5; 150.1; 146.6; 133.2; 80.3; 36.4; 34.3; 28.3. Mass
spectrum (EI), m/z (Irel, %): 248 [M]+ (<1), 246 [M]+ (3),
193 [M–H2C=C(CH3)+H]+ (20), 191 [M–H2C=C(CH3)+H]+
(60), 175 [M–Ot-Bu]+ (33), 173 [M–Ot-Bu]+ (100). Found, %:
C 48.64; H 6.21; N 11.02; Cl 14.39. C10H15ClN2O3.
Calculated, %: C 48.69; H 6.13; N 11.36; Cl 14.37.
tert-Butyl {2-[4-(chloromethyl)oxazol-5-yl]ethyl}-
carbamate (14i). Yield 33.0 g (96%), brown oil. 1H NMR
spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 7.75 (1H, s,
H oxazole); 4.95 (1H, s, NH); 4.44 (2H, s, CH2Cl); 3.38–
3.30 (2H, m, CH2CH2NHBoc); 2.88 (2H, t, J = 6.5,
CH2CH2NHBoc); 1.37 (9H, s, C(CH3)3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 155.7; 150.0; 147.8;
132.7; 79.5; 38.8; 36.6; 28.3; 25.5. Mass spectrum (CI), m/z
(Irel, %): 263 [M+H]+ (33), 261 [M+H]+ (100). Found, %:
C 50.34; H 6.88; N 10.94; Cl 13.29. C11H17ClN2O3.
Calculated, %: C 50.68; H 6.57; N 10.74; Cl 13.60.
5-(tert-Butyl)-4-(chloromethyl)oxazole (14c). Yield
22.0 g (96%), yellowish liquid. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 7.66 (1H, s, H oxazole); 4.58
(2H, s, CH2Cl); 1.34 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 156.7; 148.4; 129.3; 38.5;
32.8; 29.0. Mass spectrum (CI), m/z (Irel, %): 176 [M+H]+
(33), 174 [M+H]+ (100). Found, %: C 55.35; H 6.96;
N 7.92; Cl 20.81. C8H12ClNO. Calculated, %: C 55.34;
H 6.97; N 8.07; Cl 20.42.
4-(Chloromethyl)-5-cyclopropyloxazole (14d). Yield
20.4 g (98%), yellowish liquid. 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm (J, Hz): 7.66 (1H, s, H oxazole);
4.55 (2H, s, CH2Cl); 1.90 (1H, tdd, J = 8.4, J = 6.8, J = 4.2,
CH cyclopropane); 1.04–0.95 (2H, m, CH2 cyclopropane);
0.94–0.86 (2H, m, CH2 cyclopropane). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 151.2; 148.5; 130.8; 37.0; 6.7;
5.8. Mass spectrum (EI), m/z (Irel, %): 159 [M]+ (12), 157
[M]+ (36), 122 [M–Cl]+ (100). Found, %: C 53.02; H 5.13;
N 8.50; Cl 22.23. C7H8ClNO. Calculated, %: C 53.35; H 5.12;
N 8.89; Cl 22.49.
tert-Butyl {3-[4-(chloromethyl)oxazol-5-yl]propyl}-
carbamate (14j). Yield 35.2 g (97%), brown oil. 1H NMR
spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 7.71 (1H, s,
H oxazole); 4.87 (1H, s, NH); 4.45 (2H, s, CH2Cl); 3.13–
3.04 (2H, m, CH2CH2CH2NHBoc); 2.69 (2H, t, J = 7.3,
4-(Chloromethyl)-5-cyclobutyloxazole (14e). Yield
1
21.1 g (93%), brownish oil. H NMR spectrum (400 MHz,
CDCl3), δ, ppm (J, Hz): 8.06 (1H, s, H oxazole); 4.49 (2H,
s, CH2Cl); 3.62 (1H, quint, J = 8.7, CH cyclobutane); 2.39–
2.28 (4H, m, 2CH2 cyclobutane); 2.09–2.00 (1H, m, CH2
cyclobutane); 1.97–1.89 (1H, m, CH2 cyclobutane).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 153.1;
149.7; 128.8; 36.1; 30.2; 27.8; 18.7. Mass spectrum (EI), m/z
(Irel, %): 173 [M]+ (3), 171 [M]+ (9), 143 [M–H2C=CH2]+
(73), 136 [M–Cl]+ (100). Found, %: C 55.78; H 5.97;
N 7.96; Cl 20.86. C8H10ClNO. Calculated, %: C 55.99;
H 5.87; N 8.16; Cl 20.66.
CH2CH2CH2NHBoc); 1.80 (2H, quint,
J
=
7.3,
CH2CH2CH2NHBoc); 1.37 (9H, s, C(CH3)3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 156.0; 149.6; 131.4;
79.2; 39.6; 36.8; 28.3; 28.2; 21.9. Mass spectrum (CI), m/z
(Irel, %): 275 [M+H]+ (<1), 219 [M–(H3C)2C=CH2+H]+ (100),
219 [M–(H3C)2C=CH2+H]+ (33). Found, %: C 52.61; H 7.02;
N 10.15; Cl 12.71. C12H19ClN2O3. Calculated, %: C 52.46;
H 6.97; N 10.20; Cl 12.90.
4-(Chloromethyl)-5-(trifluoromethyl)oxazole (14f). The
CH2Cl2 solution of compound was evaporated under reduced
tert-Butyl
{2-[4-(chloromethyl)oxazol-5-yl]propan-
2-yl}carbamate (14k). Yield 35.5 g (98%), yellowish
solid, mp 119–121°C. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 7.71 (1H, s, H oxazole); 5.10 (1H, br. s,
NH); 4.61 (2H, s, CH2Cl); 1.65 (6H, s, C(CH3)2); 1.35 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
154.0; 152.5; 148.3; 130.2; 79.9; 51.3; 37.7; 28.2; 27.5.
Mass spectrum (CI), m/z (Irel, %): 277 [M+H]+ (33), 275
[M+H]+ (100). Found, %: C 52.41; H 6.58; N 10.37;
Cl 13.24. C12H19ClN2O3. Calculated, %: C 52.46; H 6.97;
N 10.20; Cl 12.90.
1
pressure. Yield 22.0 g (90%), yellowish liquid. H NMR
spectrum (400 MHz, CDCl3), δ, ppm: 7.95 (1H, s, H oxazole);
4.57 (2H, s, CH2Cl). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm (J, Hz): 151.7; 137. 9; 136.3 (q, J = 43.5);
118.8 (q, J = 268.0); 34.7. 19F NMR spectrum (376 MHz,
CDCl3), δ, ppm: –117.1. Mass spectrum (EI), m/z (Irel, %):
187 [M]+ (5), 185 [M]+ (15), 150 [M–Cl]+ (100). Found, %:
C 32.60; H 1.34; N 7.46; Cl 19.17. C5H3ClF3NO.
Calculated, %: C 32.37; H 1.63; N 7.55; Cl 19.11.
4-(Chloromethyl)-5-(difluoromethyl)oxazole (14g). The
solution of compound in CH2Cl2 was evaporated under
reduced pressure. Yield 20.3 g (92%), colorless liquid.
1H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 7.90
(1H, s, H oxazole); 6.81 (1H, t, J = 53.4, CHF2); 4.58 (2H,
s, CH2Cl). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm
(J, Hz): 151.4; 140.4 (t, J = 30.6); 136.8; 107.6 (t,
J = 237.0); 35.2. 19F NMR spectrum (376 MHz, CDCl3),
tert-Butyl 3-[4-(chloromethyl)oxazol-5-yl]azetidine-
1-carboxylate (14l). Yield 34.6 g (96%), white solid, mp 67–
1
69°C. H NMR spectrum (400 MHz, CDCl3), δ, ppm: 7.81
(1H, s, H oxazole); 4.45 (2H, s, CH2Cl); 4.26–4.21 (2H, m,
CH2 azetidine); 4.10–4.06 (2H, m, CH2 azetidine); 3.93–
3.87 (1H, m, CH azetidine); 1.43 (9H, s, C(CH3)3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 156.1;
150.0; 148.4; 132.4; 80.0; 53.9; 36.4; 28.3; 24.2. Mass spectrum
429

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
(CI), m/z (Irel, %): 275 [M+H]+ (11), 273 [M+H]+ (33), 219
4-(Azidomethyl)-5-cyclobutyloxazole (15e). Yield 20.8 g
(98%), brown liquid. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.76 (1H, s, H oxazole); 4.16 (2H,
s, CH2N3); 3.57 (1H, quint, J = 8.8, CH cyclobutane); 2.37
–2.29 (2H, m, CH2 cyclobutane); 2.28–2.23 (2H, m, CH2
cyclobutane); 2.06–1.95 (1H, m, CH2 cyclobutane); 1.94–
1.87 (1H, m, CH2 cyclobutane). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 152.6; 149.6; 127.8; 45.6;
30.2; 28.2; 18.5. Mass spectrum (CI), m/z (Irel, %): 151
[M–N2+H]+ (5), 136 [M–HN3]+ (3). Found, %: C 54.10;
H 5.89; N 31.38. C8H10N4O. Calculated, %: C 53.92;
H 5.66; N 31.44.
[M–H2C=C(CH3)+H]+ (33), 217 [M–H2C=C(CH3)+H]+
(100). Found, %: C 53.16; H 6.32; N 10.58; Cl 13.00.
C12H17ClN2O3. Calculated, %: C 52.85; H 6.28; N 10.27;
Cl 13.00.
4-(Chloromethyl)-5-(methoxymethyl)oxazole (14m).
Yield 19.6 g (92%), brown oil. 1H NMR spectrum (400 MHz,
CDCl3), δ, ppm: 7.83 (1H, s, H oxazole); 4.55 (2H, s,
CH2OCH3); 4.50 (2H, s, CH2Cl); 3.38 (3H, s, OCH3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 150.8;
145.9; 134.6; 63.1; 58.4; 36.2. Mass spectrum (CI), m/z
(Irel, %): 164 [M+H]+ (33), 162 [M+H]+ (100). Found, %:
C 44.26; H 4.76; N 8.92; Cl 21.69. C6H8ClNO2. Calculated, %:
C 44.60; H 4.99; N 8.67; Cl 21.94.
Synthesis of azides 15a–m (General method). The
corresponding chloride 14a–m (0.119 mol) and NaN3 (38.6 g,
0.594 mol) were dissolved in MeCN (250 ml) with H2O
(3.50 ml). The resulting mixture was refluxed overnight,
then cooled to room temperature, and the precipitate was
filtered off and washed with EtOAc (100 ml). The filtrate
was evaporated under reduced pressure, the residue was
dissolved in EtOAc (200 ml), washed with H2O (100 ml)
and brine (100 ml). The organic phase was dried over
Na2SO4 and evaporated under reduced pressure.
4-(Azidomethyl)-5-(trifluoromethyl)oxazole (15f). Yield
19.4 g (85%), colorless liquid. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 8.00 (1H, s, H oxazole); 4.38
(2H, s, CH2N3). 13C NMR spectrum (126 MHz, CDCl3),
δ, ppm (J, Hz): 151.8; 136.6 (q, J = 43.5); 136.5 (q, J = 1.6);
118.9 (q, J = 268.0); 44.6. 19F NMR spectrum (470 MHz,
CDCl3), δ, ppm: –61.9. Mass spectrum (CI), m/z (Irel, %):
150 [M–HN3]+ (100). Found, %: C 31.61; H 1.96; N 28.99.
C5H3F3N4O. Calculated, %: C 31.26; H 1.57; N 29.17.
4-(Azidomethyl)-5-(difluoromethyl)oxazole (15g). Yield
17.2 g (83%), colorless liquid. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm (J, Hz): 7.93 (1H, s, H oxazole);
6.84 (1H, t, J = 53.3, CHF2); 4.40 (2H, s, CH2N3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm (J, Hz):
151.7; 140.6 (t, J = 30.1); 135.4; 107.6 (t, J = 237.0); 45.3.
19F NMR spectrum (470 MHz, CDCl3), δ, ppm: –115.7;
–115.8. Mass spectrum (CI), m/z (Irel, %): 147 [M–N2+H]+
(100). Found, %: C 34.31; H 1.96; N 31.99. C5H4F2N4O.
Calculated, %: C 34.49; H 2.32; N 32.18.
4-(Azidomethyl)-5-methyloxazole (15a). Yield 14.1 g
(86%), brown liquid. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 7.75 (1H, s, H oxazole); 4.21 (2H, s,
CH2N3); 2.34 (3H, s, CH3). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 149.6; 146.7; 129.5; 45.6; 10.0. Mass
spectrum (CI), m/z (Irel, %): 96 [M–HN3]+ (100). Found, %:
C 43.75; H 4.17; N 40.81. C5H6N4O. Calculated, %:
C 43.48; H 4.38; N 40.56.
tert-Butyl
{[4-(azidomethyl)oxazol-5-yl]methyl}-
4-(Azidomethyl)-5-isopropyloxazole (15b). Yield 19.0 g
carbamate (15h). Yield 29.8 g (99%), yellow solid.
1H NMR spectrum (500 MHz, CDCl3), δ, ppm: 7.79 (1H, s,
H oxazole); 5.10 (1H, s, NH); 4.35 (2H, s, CH2NH); 4.33
(2H, s, CH2N3); 1.41 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 155.4; 150.4; 146.9; 131.4;
80.2; 45.3; 34.2; 28.3. Mass spectrum (CI), m/z (Irel, %):
226 [M–N2+H]+ (25), 170 [M–N2–H2C=C(CH3)+H]+ (30),
123 [M–N2–NHBoc]+ (100). Found, %: C 47.76; H 6.20;
N 27.69. C10H15N5O3. Calculated, %: C 47.43; H 5.97;
N 27.65.
1
(96%), yellowish liquid. H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 7.75 (1H, s, H oxazole); 4.23 (2H,
s, CH2N3); 3.09 (1H, hept, J = 7.0, CH(CH3)2); 1.28 (6H, d,
J = 7.0, CH(CH3)2). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 155.1; 149.4; 127.4; 45.6; 25.3; 21.4.
Mass spectrum (CI), m/z (Irel, %): 124 [M–HN3]+ (100).
Found, %: C 50.54; H 6.23; N 33.84. C7H10N4O.
Calculated, %: C 50.59; H 6.07; N 33.71.
4-(Azidomethyl)-5-(tert-butyl)oxazole (15c). Yield
21.0 g (98%), yellowish liquid. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 7.69 (1H, s, H oxazole); 4.30
(2H, s, CH2N3); 1.33 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 157.0; 148.6; 127.2; 46.7; 32.6;
29.3. Mass spectrum (CI), m/z (Irel, %): 138 [M–HN3]+ (100).
Found, %: C 53.08; H 6.92; N 31.40. C8H12N4O.
Calculated, %: C 53.32; H 6.71; N 31.09.
4-(Azidomethyl)-5-cyclopropyloxazole (15d). Yield
17.4 g (89%), yellowish liquid. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm (J, Hz): 7.66 (1H, s, H oxazole);
4.29 (2H, s, CH2N3); 1.90 (1H, tdd, J = 13.4, J = 8.4,
J = 5.0, CH cyclopropane); 1.03–0.97 (2H, m, CH2 cyclo-
propane); 0.93–0.87 (2H, m, CH2 cyclopropane). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 151.2; 148.6; 129.2;
45.6; 6.8; 5.7. Mass spectrum (CI), m/z (Irel, %): 122
[M–HN3]+ (100). Found, %: C 50.97; H 5.26; N 33.79.
C7H8N4O. Calculated, %: C 51.21; H 4.91; N 34.13.
tert-Butyl
{2-[4-(azidomethyl)oxazol-5-yl]ethyl}-
carbamate (15i). Yield 29.3 g (92%), yellow oil. 1H NMR
spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 7.79 (1H, s,
H oxazole); 4.85 (1H, s, NH); 4.21 (2H, s, CH2N3); 3.36
(2H, q, J = 6.6, CH2CH2NHBoc); 2.89 (2H, t, J = 6.6,
CH2CH2NHBoc); 1.40 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 155.7; 150.1; 147.8; 130.9; 79.6;
45.4; 39.0; 28.3; 25.3. Mass spectrum (CI), m/z (Irel, %): 226
[M–N2+H]+ (25), 166 [M–N2–Ot-Bu+H]+ (25), 109
[M–N2+H]+ (100). Found, %: C 49.81; H 6.81; N 25.85.
C11H17N5O3. Calculated, %: C 49.43; H 6.41; N 26.20.
tert-Butyl {3-[4-(azidomethyl)oxazol-5-yl]propyl}-
carbamate (15j). Yield 31.5 g (94%), yellowish oil.
1H NMR spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 7.74
(1H, s, H oxazole); 4.82 (1H, s, NH); 4.19 (2H, s, CH2N3);
3.10 (2H, d, J = 7.0, CH2CH2CH2NHBoc); 2.74–2.63 (2H, m,
CH2CH2CH2-NHBoc); 1.79 (2H, quint,
J
=
7.0,
430

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
CH2CH2CH2NHBoc); 1.39 (9H, s, C(CH3)3). 13C NMR
(5-Isopropyloxazol-4-yl)methanamine hydrochloride
(16b·HCl). Yield 16.1 g (90%), beige solid, mp 184–186°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
8.54 (3H, s, NH2·HCl); 8.34 (1H, s, H oxazole); 3.87 (2H,
d, J = 5.9, CH2NH2); 3.25 (1H, sept, J = 6.8, CH(CH3)2);
1.20 (6H, d, J = 6.8, CH(CH3)2). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 154.9; 151.0; 126.1; 33.9; 24.6;
21.6. Mass spectrum (CI), m/z (Irel, %): 141 [M+H–HCl]+
(100). Calculated, %: C7H13ClN2O: C 47.60; H 7.42; N 15.86;
Cl 20.07. Found, %: C 47.32; H 7.28; N 15.98; Cl 20.37.
[5-(tert-Butyl)oxazol-4-yl]methanamine hydrochloride
(16c·HCl). Yield 16.8 g (87%), white crystals, mp 216–
spectrum (126 MHz, CDCl3), δ, ppm: 156.0; 149.8; 149.7;
129.6; 79.2; 45.5; 39.6; 28.6; 28.3; 21.8. Mass spectrum (CI),
m/z (Irel, %): 254 [M–N2+H]+ (17), 139 [M–N2–NBoc+H]+
(100). Found, %: C 51.32; H 7.06; N 24.95. C12H19N5O3.
Calculated, %: C 51.23; H 6.81; N 24.90.
tert-Butyl {2-[4-(azidomethyl)oxazol-5-yl]propan-2-yl}-
carbamate (15k). Yield 31.8 g (95%), yellow solid.
1H NMR spectrum (500 MHz, CDCl3), δ, ppm: 7.72 (1H, s,
H oxazole); 5.08 (1H, br. s, NH); 4.33 (2H, s, CH2N3); 1.63
(6H, s, C(CH3)2); 1.35 (9H, s, C(CH3)3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 154.0; 152.7; 148.4;
128.6; 79.9; 51.2; 46.2; 28.2; 27.9. Mass spectrum (CI), m/z
(Irel, %): 254 [M–N2+H]+ (31), 138 [M–N2–NHBoc]+ (50),
123 [M–N2–CH3–NHBoc]+ (100). Found, %: C 50.97;
H 7.06; N 24.61. C12H19N5O3. Calculated, %: C 51.23;
H 6.81; N 24.90.
1
218°C. H NMR spectrum (500 MHz, DMSO-d6), δ, ppm:
8.62 (3H, s, NH2·HCl); 8.34 (1H s, H oxazole); 3.95 (2H, s,
CH2NH2); 1.31 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 155.8; 150.5; 125.8; 35.2; 32.7;
29.3. Mass spectrum (CI), m/z (Irel, %): 155 [M+H–HCl]+
(16), 136 [M+H–NH4Cl]+ (100). Found, %: C 50.39;
H 8.13; N 15.03; Cl 18.21. C8H15ClN2O. Calculated, %:
C 50.39; H 7.93; N 14.69; Cl 18.59.
tert-Butyl
3-[4-(azidomethyl)oxazol-5-yl]azetidine-
1-carboxylate (15l). Yield 31.9 g (96%), white solid.
1H NMR spectrum (500 MHz, CDCl3), δ, ppm: 7.85 (1H, s,
H oxazole); 4.28–4.15 (4H, m, CH2N3, CH2 azetidine);
4.11–4.03 (2H, m, CH2 azetidine); 3.92–3.85 (1H, m, CH
azetidine); 1.43 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 156.1; 150.3; 148.4; 130.6;
79.9; 54.0; 45.5; 28.3; 24.2. Mass spectrum (CI), m/z (Irel, %):
252 [M–N2+H]+ (5), 108 [M–N2–CH2CH2NHBoc+H]+ (100).
Found, %: C 51.49; H 6.16; N 25.00. C12H17N5O3. Calcu-
lated, %: C 51.60; H 6.14; N 25.08.
(5-Cyclopropyloxazol-4-yl)methanamine hydrochloride
(16d·HCl). The hydrogenation was performed in an
autoclave under 40 atm of H2. Yield 14.1 g (80%), white
1
crystals, mp 197–199°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 8.54 (3H, br. s, NH2·HCl); 8.25
(1H, s, H oxazole); 3.92 (2H, s, CH2NH2); 2.19 (1H, tt, J = 8.6,
J = 5.1, CH isopropane); 1.01–0.94 (2H, m, CH2 cyclo-
propane); 0.86–0.78 (2H, m, CH2 cyclopropane). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm: 151.0; 150.3;
127.7; 34.0; 7.1; 5.9. Mass spectrum (CI), m/z (Irel, %): 139
[M+H–HCl]+ (3), 122 [M+H–NH4Cl]+ (100). Found, %:
C 48.01; H 6.18; N 15.76; Cl 20.45. C7H11ClN2O. Calcu-
lated, %: C 48.15; H 6.35; N 16.04; Cl 20.30.
4-(Azidomethyl)-5-(methoxymethyl)oxazole (15m). Yield
19.6 g (98%), yellow liquid. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 7.82 (1H, s, H oxazole); 4.44 (2H, s,
CH2OCH3); 4.26 (2H, s, CH2N3); 3.32 (3H, s, OCH3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 150.9;
146.1; 133.0; 63.1; 58.3; 45.3. Mass spectrum (CI), m/z
(Irel, %): 141 [M–N2+H]+ (8), 109 [M–N2–OMe]+ (58), 96
[M–N2–CH2OMe+H]+ (100). Found, %: C 43.11; H 4.73;
N 33.03. C6H8N4O2. Calculated, %: C 42.86; H 4.80;
N 33.32.
(5-Cyclobutyloxazol-4-yl)methanamine hydrochloride
(16e·HCl). Yield 18.3 g (96%), beige solid, mp 175–177°C.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 8.49
(3H, s, NH2·HCl); 8.37 (1H, s, H oxazole); 3.86–3.75 (3H,
m, CH2NH2, CH cyclobutane); 2.27–2.16 (4H, m, 2CH2
cyclobutane); 1.99–1.93 (1H, m, CH2 cyclobutane); 1.87–
1.81 (1H, m, CH2 cyclobutane). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 152.4; 151.3; 126.7; 33.9;
29.6; 28.0; 18.5. Mass spectrum (CI), m/z (Irel, %): 153
[M+H–HCl]+ (9), 136 [M+H–NH4Cl]+ (100). Found, %:
C 50.85; H 7.25; N 15.19; Cl 18.62. C8H13ClN2O. Calcu-
lated, %: C 50.93; H 6.95; N 14.85; Cl 18.79.
[5-(Trifluoromethyl)oxazol-4-yl]methanamine hydro-
chloride (16f·HCl). Yield 17.0 g (83%), white solid,
mp 171–173°C. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 8.92 (1H, s, H oxazole); 8.83 (3H, s, NH2·HCl);
4.08 (2H, s, CH2NH2). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm (J, Hz): 154.8; 135.8 (q, J = 1.7); 134.9
(q, J = 42.6); 119.4 (q, J = 268.0); 33.7. 19F NMR spectrum
(376 MHz, DMSO-d6), δ, ppm: –61.6. Mass spectrum (CI),
m/z (Irel, %): 167 [M+H–HCl]+ (100). Found, %: C 30.05;
H 2.80; N 14.03; Cl 17.58. C5H6ClF3N2O. Calculated, %:
C 29.65; H 2.99; N 13.83; Cl 17.50.
Synthesis of amines 16a–m (General method). The
corresponding azide 15a–m (0.101 mol) and 10% Pd/C
(2.00 g) were placed in MeOH (200 ml) under H2 (1 atm).
1
After the reaction was complete (monitored by H NMR
spectroscopy, ca. 12 h), the precipitate was filtered off and
carefully washed with MeOH (50 ml). The filtrate was
evaporated under reduced pressure, and the residue was
dissolved in 1,4-dioxane (200 ml). The resulting solution
was cooled to 15°C, and NH4Cl (5.13 g, 960 mmol) in
MeOH (100 ml) (for N-Boc amines 16h–l) or 10% HCl in
1,4-dioxane (20 ml) (for the rest of the compounds) was
added, the precipitate formed was filtered off and dried
under reduced pressure.
(5-Methyloxazol-4-yl)methanamine (16a). Yield 10.5 g
1
(93%), yellowish liquid. H NMR spectrum (400 MHz,
CDCl3), δ, ppm: 7.64 (1H, s, H oxazole); 3.61 (2H, s,
CH2NH2); 2.23 (3H, s, CH3); 1.62 (2H, br. s, NH2).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 149.2;
143.4; 135.2; 37.2; 9.9. Mass spectrum (CI), m/z (Irel, %):
113 [M+H]+ (100). Found, %: C 53.83; H 7.14; N 24.84.
C5H8N2O. Calculated, %: C 53.56; H 7.19; N 24.98.
[5-(Difluoromethyl)oxazol-4-yl]methanamine hydro-
chloride (16g·HCl). Yield 15.1 g (81%), beige solid,
mp 157–159°C. 1H NMR spectrum (400 MHz, DMSO-d6),
431

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
δ, ppm (J, Hz): 8.73 (1H, s, H oxazole); 8.24 (3H, br. s,
(95%), gray solid, mp 175–177°C. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 8.49 (3H, s, NH2·HCl);
8.47 (1H, s, H oxazole); 4.27–4.07 (3H, m, CH2NH2, CH
azetidine); 3.87 (4H, s, 2CH2 azetidine); 1.39 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm:
155.9; 152.0; 149.4; 129.0; 79.4; 54.3; 33.8; 28.5; 23.9.
Mass spectrum (CI), m/z (Irel, %): 254 [M+H–HCl]+ (20),
198 [M–H2C=C(CH3)2–HCl+H]+ (100). Found, %: C 49.38;
H 6.94; N 14.73; Cl 12.31. C12H20ClN3O3. Calculated, %:
C 49.74; H 6.96; N 14.50; Cl 12.23.
[5-(Methoxymethyl)oxazol-4-yl]methanamine hydro-
chloride (16m·HCl). Yield 16.6 g (92%), beige solid,
mp 125–127°C. 1H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 8.65 (3H, s, NH2·HCl); 8.48 (1H, s,
H oxazole); 4.53 (2H, s, CH2OCH3); 3.95 (2H, q, J = 5.6,
CH2NH2); 3.25 (3H, s, OCH3). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 152.7; 146.7; 131.5; 62.4;
57.9; 33.7. Mass spectrum (CI), m/z (Irel, %): 143 [M+H–HCl]+
(100). Found, %: C 40.43; H 5.85; N 15.66; Cl 19.48.
C6H11ClN2O2. Calculated, %: C 40.35; H 6.21; N 15.68;
Cl 19.85.
NH2·HCl); 7.48 (1H, t, J = 51.3, CHF2); 4.11 (2H, s,
CH2NH2). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm (J, Hz): 154.1; 140.5 (t, J = 25.6); 134.6 (t, J = 5.5);
107.6 (t, J = 233.0); 33.4. 19F NMR spectrum (376 MHz,
DMSO-d6), δ, ppm: –116.6. Mass spectrum (CI), m/z (Irel, %):
149 [M+H–HCl]+ (100). Found, %: C 32.75; H 3.86;
N 15.38; Cl 19.52. C5H7ClF2N2O. Calculated, %: C 32.54;
H 3.82; N 15.18; Cl 19.21.
tert-Butyl {[4-(aminomethyl)oxazol-5-yl]methyl}-
carbamate hydrochloride (16h·HCl). Yield 20.0 g (87%),
white solid, mp 204–206°C. 1H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm: 8.38 (4H, br. s, NH2·HCl, H oxazole);
7.43 (1H, s, NHBoc); 4.24 (2H, s, CH2NHBoc); 3.93 (2H, s,
CH2NH2); 1.36 (9H, s, C(CH3)3). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 155.9; 151.8; 148.0; 129.9;
78.8; 34.0; 33.9; 28.6. Mass spectrum (CI), m/z (Irel, %):
228 [M+H–HCl]+ (42), 172 [M–H2C=C(CH3)2–HCl+H]+
(100). Found, %: C 45.81; H 7.05; N 16.21; Cl 13.45.
C10H18ClN3O3. Calculated, %: C 45.54; H 6.88; N 15.93;
Cl 13.44.
tert-Butyl {2-[4-(aminomethyl)oxazol-5-yl]ethyl}-
carbamate (16i). Yield 26.7 g (95%), brown oil. 1H NMR
spectrum (500 MHz, CDCl3), δ, ppm: 7.71 (1H, s, H oxazole);
5.10 (1H, br. s, NHBoc); 4.61 (2H, s, CH2NH2); 1.78–1.52
(6H, m, 2CH2, NH2); 1.35 (9H, s, C(CH3)3). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 154.0; 152.5; 148.3;
130.2; 79.9; 51.3; 37.7; 28.2; 27.5. Mass spectrum (CI), m/z
(Irel, %): 242 [M+H–HCl]+ (50), 186 [M–H2C=C(CH3)2–HCl+H]+
(100). Found, %: C 54.88; H 8.15; N 17.73. C11H19N3O3.
Calculated, %: C 54.76; H 7.94; N 17.42.
tert-Butyl {3-[4-(aminomethyl)oxazol-5-yl]propyl}-
carbamate hydrochloride (16j·HCl). Yield 28.9 g (98%),
white solid, mp 157–459°C. 1H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm (J, Hz): 8.56 (3H, s, NH2·HCl); 8.33
(1H, s, H oxazole); 6.90 (1H, s, NHBoc); 3.86 (2H, s,
CH2NH2); 2.92 (2H, q, J = 6.5, CH2CH2CH2NHBoc); 2.70
(2H, t, J = 7.4, CH2CH2CH2NHBoc); 1.68 (2H, quint,
J = 7.4, CH2CH2CH2NHBoc); 1.35 (9H, s, C(CH3)3).
13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 156.1;
151.3; 150.4; 128.0; 78.0; 39.7; 33.9; 28.7; 28.1; 21.7.
Mass spectrum (CI), m/z (Irel, %): 256 [M+H–HCl]+ (66),
200 [M–H2C=C(CH3)2–HCl+H]+ (100). Found, %:
C 49.45; H 7.41; N 14.28; Cl 12.11. C12H22ClN3O3.
Calculated, %: C 49.40; H 7.60; N 14.40; Cl 12.15.
Synthesis of thioacetates 18a,c,d,f,g (General method).
The corresponding chloride 14 (0.119 mol) and KSAc
(20.4 g, 0.179 mol) were added to EtOH (250 ml), and the
resulting mixture was heated at 55°C overnight. Then the
reaction mixture was cooled to room temperature, the
solvent was evaporated under reduced pressure. The
residue was dissolved in CH2Cl2 (200 ml), washed with
H2O (100 ml) and brine (100 ml). The organic phase was
dried over Na2SO4 and evaporated under reduced pressure.
S-[(5-Methyloxazol-4-yl)methyl]ethanethioate (18a).
Yield 18.1 g (89%), brown oil. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 7.65 (1H, s, H oxazole); 3.93 (2H, s,
CH2SAc); 2.32 (3H, s, CH3CO); 2.29 (3H, s, CH3).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 195.0;
149.2; 145.4; 130.4; 30.3; 24.5; 10.0. Mass spectrum (CI), m/z
(Irel, %): 172 [M+H]+ (17), 130 [M–COCH2+H]+ (58), 96
[M–SAc]+ (100). Found, %: C 48.84; H 5.52; N 8.50;
S 18.96. C7H9NO2S. Calculated, %: C 49.11; H 5.30;
N 8.18; S 18.73.
S-{[5-(tert-Butyl)oxazol-4-yl]methyl}ethanethioate (18c).
Yield 23.6 g (93%), brown oil. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 7.64 (1H, s, H oxazole); 4.14
(2H, s, CH2SAc); 2.31 (3H, s, CH3CO); 1.33 (9H, s,
C(CH3)3). 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
194.9; 155.1; 148.4; 127.5; 32.5; 30.2; 29.2; 26.1. Mass
spectrum (CI), m/z (Irel, %): 214 [M+H]+ (100), 172
[M–COCH2+H]+ (50), 138 [M–SAc]+ (28). Found, %:
C 56.51; H 7.11; N 6.97; S 15.04. C10H15NO2S. Calculated, %:
C 56.31; H 7.09; N 6.57; S 15.03.
tert-Butyl
{2-[4-(aminomethyl)oxazol-5-yl]propan-
2-yl}carbamate hydrochloride (16k·HCl). Yield 28.0 g
1
(95%), white solid, mp 189–191°C. H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm: 8.41 (3H, br. s, NH2·HCl);
8.34 (1H, s, H oxazole); 7.41 (1H, s, NHBoc); 3.89 (2H, s,
CH2NH2); 1.53 (6H, s, C(CH3)2); 1.32 (9H, s, C(CH3)3).
13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 154.6;
150.1; 126.4; 78.6; 50.9; 39.5; 34.8; 28.6; 27.6. Mass
spectrum (CI), m/z (Irel, %): 256 [M+H–HCl]+ (60), 200
[M–H2C=C(CH3)2–HCl+H]+ (100). Found, %: C 49.01;
H 8.00; N 14.35; Cl 11.97. C12H22ClN3O3. Calculated, %:
C 49.40; H 7.60; N 14.40; Cl 12.15.
S-[(5-Cyclopropyloxazol-4-yl)methyl]ethanethioate (18d).
Yield 20.0 g (85%), brown oil. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm (J, Hz): 7.57 (1H, s, H oxazole);
4.06 (2H, s, CH2SAc); 2.33 (3H, s, CH3CO); 2.01 (1H, ttd,
J = 9.8, J = 6.6, J = 3.4, CH cyclopropane); 0.98–0.94 (2H,
m, CH2 cyclopropane); 0.87–0.83 (2H, m, CH2 cyclopropane).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm: 195.0;
149.6; 148.2; 130.0; 30.3; 24.6; 6.6; 5.8. Mass spectrum
(CI), m/z (Irel, %): 198 [M+H]+ (50), 156 [M–COCH2+H]+
tert-Butyl 3-[4-(aminomethyl)oxazol-5-yl]azetidine-
1-carboxylate hydrochloride (16l·HCl). Yield 27.8 g
432

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
(67), 122 [M–SAc]+ (28). Found, %: C 54.51; H 5.45;
(126 MHz, CDCl3), δ, ppm (J, Hz): 152.2; 140.1 (q,
J = 43.8); 128.8; 118.4 (q, J = 269.0); 60.8. 19F NMR
spectrum (376 MHz, CDCl3), δ, ppm: –63.0. Mass spectrum
(CI), m/z (Irel, %): 252 [M+H]+ (22), 250 [M+H]+ (67), 150
[M–SO2Cl]+ (100). Found, %: C 24.21; H 0.89; N 5.89;
S 12.47; Cl 14.46. C5H3ClF3NO3S. Calculated, %: C 24.06;
H 1.21; N 5.61; S 12.85; Cl 14.20.
[5-(Difluoromethyl)oxazol-4-yl]methanesulfonyl chloride
(17g). Yield 42.0 g (95%), brownish oil. 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm (J, Hz): 8.02 (1H, s, H oxazole);
6.86 (1H, t, J = 53.6, CHF2); 4.98 (2H, s, CH2SO2Cl).
13C NMR spectrum (126 MHz, CDCl3), δ, ppm (J, Hz):
152.0, 144.2 (t, J = 31.2); 127.4; 107.7 (t, J = 239.0); 61.1.
19F NMR spectrum (376 MHz, CDCl3), δ, ppm: –118.6.
Mass spectrum (CI), m/z (Irel, %): 234 [M+H]+ (10), 232
[M+H]+ (30), 214 [M–F]+ (25), 212 [M–F]+ (75), 132
[M–SO2Cl]+ (100). Found, %: C 26.10; H 1.67; N 5.76;
S 13.45; Cl 15.70. C5H4ClF2NO3S. Calculated, %: C 25.93;
H 1.74; N 6.05; S 13.84; Cl 15.31.
N 6.73; S 16.43. C9H11NO2S. Calculated, %: C 54.80; H 5.62;
N 7.10; S 16.25.
S-{[5-(Trifluoromethyl)oxazol-4-yl]methyl}ethane-
1
thioate (18f). Yield 25.7 g (96%), brown oil. H NMR
spectrum (500 MHz, CDCl3), δ, ppm: 7.90 (1H, s,
H oxazole); 4.16 (2H, s, CH2SAc); 2.36 (3H, s, CH3CO).
13C NMR spectrum (101 MHz, CDCl3), δ, ppm (J, Hz):
193.6; 151.5; 137.7; 135.6 (q, J = 43.2); 119.1 (q, J = 268.0);
30.1; 23.7. 19F NMR spectrum (376 MHz, CDCl3), δ, ppm:
–62.5. Mass spectrum (CI), m/z (Irel, %): 224 [M+H]+ (6), 184
[M–COCH2+H]+ (100), 150 [M–SAc]+ (67). Found, %:
C 37.08; H 2.64; N 6.14; S 14.62. C7H6F3NO2S. Calcu-
lated, %: C 37.34; H 2.69; N 6.22; S 14.24.
S-{[5-(Difluoromethyl)oxazol-4-yl]methyl}ethane-
1
thioate (18g). Yield 24.2 g (98%), brown oil. H NMR
spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 7.87 (1H, s,
H oxazole); 6.99 (1H, t, J = 52.7, CHF2); 4.05 (2H, s,
CH2SAc); 2.33 (3H, s, CH3CO). 13C NMR spectrum
(101 MHz, CDCl3), δ, ppm (J, Hz): 194.6; 151.5; 139.6 (t,
J = 27.0); 136.9 (t, J = 5.0); 107.1 (t, J = 236.0); 30.2; 23.8.
19F NMR spectrum (376 MHz, CDCl3), δ, ppm: –116.6.
Mass spectrum (CI), m/z (Irel, %): 224 [M+H]+ (11), 166
[M–COCH2+H]+ (100), 132 [M–SAc]+ (78). Found, %:
C 40.20; H 3.64; N 6.61; S 15.14. C7H7F2NO2S. Calcu-
lated, %: C 40.58; H 3.41; N 6.76; S 15.47.
Supplementary information file containing 1H, 13C and 19
F
NMR spectra of the synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
References
1. Zhang, H.-Z.; Zhao, Z.-L.; Zhou, C.-H. Eur. J. Med. Chem.
2018, 144, 444.
Synthesis of sulfonyl chlorides 17a,c,f,g (General
method). NCS (102 g, 0.764 mol) was dissolved in MeCN
(430 ml) with H2O (43.0 ml), and saturated aq HCl (10.8 ml)
was added. The solution was cooled to 10°C, and the
corresponding thioacetate 18 (0.191 mol) was added in
portions. Then the resulting mixture was stirred at 10 to
20°C for 1 h, the solvent was evaporated under reduced
pressure. The residue was dissolved in t-BuOMe (450 ml),
washed with H2O (200 ml) and brine (100 ml). The organic
phase was dried over Na2SO4 and evaporated under
reduced pressure.
(5-Methyloxazol-4-yl)methanesulfonyl chloride (17a).
Yield 26.9 g (72%), yellowish oil. 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm: 8.10 (1H, s, H oxazole); 4.51
(2H, s, CH2SO2Cl); 2.35 (3H, s, CH3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 150.0; 147.5; 130.1; 35.9;
10.2. Mass spectrum (CI), m/z (Irel, %): 196 [M+H]+ (100),
198 [M+H]+ (100). Found, %: C 30.65; H 2.91; N 7.54;
S 16.56; Cl 17.91. C5H6ClNO3S. Calculated, %: C 30.70;
H 3.09; N 7.16; S 16.39; Cl 18.12.
[5-(tert-Butyl)oxazol-4-yl]methanesulfonyl chloride (17c).
Yield 30.9 g (68%), yellowish oil. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 7.83 (1H, s, H oxazole); 5.02
(2H, s, CH2SO2Cl); 1.41 (9H, s, C(CH3)3). 13C NMR spectrum
(101 MHz, CDCl3), δ, ppm: 160.6; 149.3; 119.8; 63.9;
33.3; 28.8. Mass spectrum (CI), m/z (Irel, %): 238 [M+H]+
(100), 240 [M+H]+ (100). Found, %: C 40.62; H 4.88;
N 5.86; S 13.17; Cl 14.54. C8H12ClNO3S. Calculated, %:
C 40.42; H 5.09; N 5.89; S 13.49; Cl 14.91.
[5-(Trifluoromethyl)oxazol-4-yl]methanesulfonyl chloride
(17f). Yield 46.2 g (97%), yellow crystals, mp 50–52°C.
1H NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.07 (1H, s,
H oxazole); 4.97 (2H, s, CH2SO2Cl). 13C NMR spectrum
2. Turchi, I. J. Ind. Eng. Chem. Prod. Res. Dev. 1981, 20, 32.
3. Palmer, D. C.; Venkatraman, S. In Oxazoles: Synthesis, Reactions,
and Spectroscopy; John Wiley & Sons, Inc., 2003, Vol. 60.
4. Swellmeen, L. Der Pharma Chem. 2016, 8, 269.
5. Zhang, M. Z.; Chen, Q.; Mulholland, N.; Beattie, D.; Irwin, D.;
Gu, Y. C.; Yang, G. F.; Clough, J. Eur. J. Med. Chem. 2012,
53, 283.
6. Zoller, K. E..; MacNeil, I. A.; Brugge, J. S. J. Immunol. 1997,
158, 1650.
7. Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1996, 37, 2997.
8. Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.; Shao, C.; Wang, W.;
Zhang, H.; Cap, M.; Farrelly, D.; Golla, R.; Grover, G.;
Harrity, T.; Ma, Z.; Moore, L.; Ren, J.; Seethala, R.; Cheng, L.;
Sleph, P.; Sun, W.; Tieman, A.; Wetterau, J. R.; Doweyko, A.;
Chandrasena, G.; Chang, S. Y.; Humphreys, W. G.;
Sasseville, V. G.; Biller, S. A.; Ryono, D. E.; Selan, F. ;
Hariharan, N.; Cheng, P. T. W. J. Med. Chem. 2005, 48,
2248.
9. Hulin, B.; Clark, D. A.; Goldstein, S. W.; McDermott, R. E.;
Dambek, P. J.; Kappeler, W. H.; Lamphere, C. H.; Lewis, D. M.;
Rizzi, J. P. J. Med. Chem. 1992, 35, 1853.
10. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.;
Cobb, J. E.; Collins, J. L.; Harrington, W. W.; Hashim, M. A.;
Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.;
Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-
Miller, L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.;
Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M.
J. Med. Chem. 1998, 41, 5020.
11. Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.;
Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.;
Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.;
Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.;
Plunkett, K. D.; Tong, W.-Q. J. Med. Chem. 1998, 41, 5037.
12. Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J.
Org. Chem. 2005, 70, 5840.
433

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 421–434
13. Jia, C.-Y.; Xu, L.-Y.; Yu, X.; Ding, Y.-B.; Jin, B.; Zhang, M.-Z.;
36. Armarego, W. L. F.; Taguchi, H.; Cotton, R. G. H.; Battiston, S.;
Leong, L. Eur. J. Med. Chem. 1987, 22, 283.
Zhang, W.-H.; Yang, G.-F. Fitoterapia 2018, 125, 106.
14. Chow, K. B. S.; Wong, Y. H.; Wise, H. Br. J. Pharmacol.
2001, 1301, 1375.
37. Meng, L.; Kamada, Y.; Muto, K.; Yamaguchi, J.; Itami, K.
Angew. Chem., Int. Ed. 2013, 52, 10048.
15. McClure, K. F.; Letavic, M. A.; Kalgutkar, A. S.; Gabel, C. A.;
Audoly, L.; Barberia, J. T.; Braganza, J. F.; Carter, D.;
Carty, T. J.; Cortina, S. R.; Dombroski, M. A.; Donahue, K. M.;
Elliott, N. C.; Gibbons, C. P.; Jordan, C. K.; Kuperman, A. V.;
Labasi, J. M.; LaLiberte, R. E.; McCoy, J. M.; Naiman, B. M.;
Nelson, K. L.; Nguyen, H. T.; Peese, K. M.; Sweeney, F. J.;
Taylor, T. J.; Trebino, C. E.; Abramov, Y. A.; Laird, E. R.;
Volberg, W. A.; Zhou, J.; Bach, J.; Lombardo, F. Bioorg.
Med. Chem. Lett. 2006, 16, 4339.
38. Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012,
134, 169.
39. Doss, R. M.; Marques, M. A.; Foister, S.; Chenoweth, D. M.;
Dervan, P. B. J. Am. Chem. Soc. 2006, 128, 9074.
40. Makino, K.; Goto, T.; Ohtaka, J.; Hamada, Y. Heterocycles
2009, 77, 629.
41. Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Tetrahedron:
Asymmetry 2008, 19, 2816.
42. Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y.
Tetrahedron: Asymmetry 2001, 12, 1757.
16. Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389.
17. Dinda, M.; Samanta, S.; Eringathodi, S.; Ghosh, P. K. RSC
Adv. 2014, 4, 12252.
18. Linkova, E. I.; Grinev, V. S.; Egorova, A. Yu. Chem.
Heterocycl. Compd. 2018, 54, 1023. [Khim. Geterotsikl.
Soedin. 2018, 54, 1023.]
43. Hoppe, I.; Schöllkopf, U. Liebigs Ann. Chem. 1980, 819.
44. Suzuki, M.; Nunami, K.; Matsumoto, K.; Yoneda, N.;
Miyoshi, M. Synthesis 1978, 461.
45. Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura, K.;
Matsumoto, K. J. Org. Chem 1973, 38, 3571.
19. Goldberg, F. W.; Kettle, J. G.; Kogej, T.; Perry, M. W. D.;
Tomkinson, N. P. Drug Discovery Today 2015, 20, 11.
20. Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1982, 23, 235.
21. Artamonov, O. S.; Bulda, T.; Fam, T. K.; Slobodyanyuk, E. Y.;
Volochnyuk, D. M.; Grygorenko, O. O. Heterocycl. Commun.
2015, 21, 391.
22. Senwar, K. R.; Sharma, P.; Nekkanti, S.; Sathish, M.; Kamal, A.;
Sridhar, B.; Shankaraiah, N. New J. Chem. 2015, 39, 3973.
23. Kamal, A.; Sathish, M.; Srinivasulu, V.; Chetna, J.;
Shekar, K. C.; Nekkanti, S.; Tangella, Y.; Shankaraiah, N.
Org. Biomol. Chem. 2014, 12, 8008.
24. Boeckman, R. K., Jr.; Perni, R. B. J. Org. Chem. 1986, 51,
5489.
46. Kozikowski, A. P.; Ames, A. J. Am. Chem. Soc. 1980, 102, 860.
47. Brun, P.; Dean, A.; Di Marco, V.; Surajit, P.; Castagliuolo, I.;
Carta, D.; Ferlin, M. G. Eur. J. Med. Chem. 2013, 62, 486.
48. Meibom, D.; Albrecht-Küpper, B.; Diedrichs, N.; Hübsch, W.;
Kast, R.; Krämer, T.; Krenz, U.; Lerchen, H.-G.; Mittendorf, J.;
Nell, P. G.; Süssmeier, F.; Vakalopoulos, A.; Zimmermann, K.
ChemMedChem 2017, 12, 728.
49. Chittari, P.; Hamada, Y.; Shioiri, T. Synlett 1998, 1022.
50. Théveau, L.; Schneider, C.; Querolle, O.; Meerpoel, L.;
Levacher, V.; Hoarau, C. Org. Biomol. Chem. 2016, 14, 3459.
51. Subramanyam, C.; Noguchi, M.; Weinreb, S. M. J. Org.
Chem. 1989, 54, 5580.
52. Burkholder, T. P.; Cunningham, B. E.; Clayton, J. R.;
Lander, P. A.; Brown, M. L.; Doti, R. A.; Durst, G. L.;
Montrose-Rafizadeh, C.; King, C.; Osborne, H. E.; Amos, R. M.;
Zink, R. W.; Stramm, L. E.; Burris, T. P.; Cardona, G.;
Konkol, D. L.; Reidy, C.; Christe, M. E.; Genin, M. J. Bioorg.
Med. Chem. Lett. 2015, 25, 1377.
25. Ma, Y.; Yan, Z.; Bian, C.; Li, K.; Zhang, X.; Wang, M.; Gao, X.;
Zhang, H.; Lei, A. Chem. Commun. 2015, 51, 10524.
26. Hamada, Y.; Shiori, T. Tetrahedron Lett. 1982, 23, 1193.
27. Hamada, Y.; Kawai, A.; Shioiri, T. Tetrahedron Lett. 1984,
25, 5409.
28. Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T.
Tetrahedron 1990, 46, 4823.
53. Shtyrlin, N. V.; Pavelyev, R. S.; Pugachev, M. V.;
Sysoeva, L. P.; Musin, R. Z.; Shtyrlin, Y. G. Tetrahedron
Lett. 2012, 53, 3967.
29. Kawai, A.; Hara, O.; Hamada, Y.; Shioiri, T. Tetrahedron
Lett. 1988, 29, 6331.
54. Quallich, G. J.; Makowski, T. W.; Sanders, A. F.; Urban, F. J.;
Vazquez, E. J. Org. Chem. 1998, 63, 4116.
30. Henneke, K.-W.; Schöllkopf, U.; Neudecker, T. Liebigs Ann.
Chem. 1979, 1370.
55. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Delivery Rev. 1997, 23, 3.
31. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.;
Tranmer, G. K. Org. Lett. 2006, 8, 5231.
56. Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem.,
Int. Ed. 2012, 51, 1114.
32. Tormyshev, V. M.; Mikhalina, T. V.; Rogozhnikova, O. Yu.;
Troitskaya, T. I.; Trukhin, D. V. Russ. J. Org. Chem. 2006,
42, 1031. [Zh. Org. Khim. 2006, 42, 1049.]
57. Armarego, W. L. F.; Chai, C. Purification of Laboratory
Chemicals; Elsevier: Oxford, 2003.
33. Théveau, L.; Verrier, C.; Lassalas, P.; Martin, T.; Dupas, G.;
Querolle, O.; Van Hijfte, L.; Marsais, F.; Hoarau, C. Chem.–
Eur. J. 2011, 17, 14450.
58. Yamazaki, Y.; Kohno, K.; Yasui, H.; Kiso, Y.; Akamatsu, M.;
Nicholson, B.; Deyanat-Yazdi, G.; Neuteboom, S.; Potts, B.;
Lloyd, G. K.; Hayashi, Y. ChemBioChem 2008, 9, 3074.
59. Blankson, G.; Rzuczek, S. G.; Bishop, C.; Pilch, D. S.;
Liu, A.; Liu, L.; LaVoie, E. J.; Rice, J. E. Molecules 2013, 18,
11938.
34. Yang, K.; Zhang, C.; Wang, P.; Zhang, Y.; Ge, H. Chem.–
Eur. J. 2014, 20, 7241.
35. Yang, K.; Wang, P.; Zhang, C.; Kadi, A. A.; Fun, H.-K.;
Zhang, Y.; Lu, H. Eur. J. Org. Chem. 2014, 2014, 7586.
60. Tiwari, D. K.; Pogula, J.; Tiwari, D. K. RSC Adv. 2015, 5, 53111.
434