Copper-catalyzed oxidation of azolines to azoles

Article abstract of DOI:10.1039/c2dt00025c

We report herein convenient, aerobic conditions for the oxidation of thiazolines to thiazoles and data regarding the oxidation mechanism. These reactions feature operationally simple and environmentally benign conditions and proceed in good yield to afford the corresponding azoles, thus enabling the inexpensive preparation of valuable molecular building blocks. Incorporation of a novel diimine-ligated copper catalyst, [(^MesDAB^Me) Cu^II(OH₂)₃]²⁺ [^-OTf] ₂, provides increased reaction efficiency in many cases. In other cases copper-free conditions involving a stoichiometric quantity of base affords superior results.

Full text of DOI:10.1039/c2dt00025c

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PAPER
Copper-catalyzed oxidation of azolines to azoles†
Anna C. Dawsey, Vincent Li, Kimberly C. Hamilton, Jianmei Wang and Travis J. Williams*
Received 5th January 2012, Accepted 28th February 2012
DOI: 10.1039/c2dt00025c
We report herein convenient, aerobic conditions for the oxidation of thiazolines to thiazoles and data
regarding the oxidation mechanism. These reactions feature operationally simple and environmentally
benign conditions and proceed in good yield to afford the corresponding azoles, thus enabling the
inexpensive preparation of valuable molecular building blocks. Incorporation of a novel diimine-ligated
copper catalyst, [(MesDABMe)CuII(OH2)3]2+ [−OTf]2, provides increased reaction efficiency in many cases.
In other cases copper-free conditions involving a stoichiometric quantity of base affords superior results.
resulting in a significant decrease in yield. Further, these reac-
Introduction
tions appear to proceed through the intermediacy of a long-lived
organic peroxide, which could be problematic if these conditions
were to be scaled up.
Azoles are ubiquitous structural components in biologically
active natural products (Fig. 1) with important medicinal proper-
ties that include anticancer1 and antibiotic activity.2 Despite their
importance, we know of no catalytic conditions for synthesis of
azoles by azoline oxidation.3 Various conditions, which involve
either a toxic waste stream or a stoichiometric amount of reagent,
effect thiazoline oxidation. Such reagents include K3Fe(CN)6,4
NiO2,5 CuI/CuII,6 BrCCl3,7 and MnO2.8 In each of these cases
the stoichiometric metal or halogen waste stream introduces dis-
posal cost and environmental impact when these reactions are
practised at production scale.
We show here catalytic copper-based conditions for aerobic
azoline oxidation that improve the applicable scope of aerobic
oxidation conditions to include electron donating substituents
and scalability of the reaction while minimizing the metallic
waste stream (Scheme 1). Moreover, these conditions are low
cost. For example compound 2a (Scheme 1) is commercially
available10 for $22 500 g−1 but can be prepared in our route for
<$28 g−1 (cost of goods, see ESI†).
Aerobic conditions for thiazoline oxidation based on DMF
solutions of potassium carbonate have recently been reported.
These are efficient for aerobic oxidation of many electron poor
azolines.9 Importantly, attempts to oxidize electron rich azolines
and azolines containing labile protons under base promoted con-
ditions are susceptible to production of undesired side products
Results and discussion
Synthesis and characterization of copper complexes
Copper complex 1 is prepared in two steps without the need for
chromatography from 2,3-butanedione and the corresponding tri-
methylaniline with the intermediacy a known diazabutadiene
ligand, [MesDABMe 11
(Scheme 2, DAB = diazabutadiene). The
]
structure of 1 is assigned by single-crystal X-ray diffraction.12a
In this case copper adopts a distorted square pyramidyl geome-
try13 in which copper(II) appears to be a 19-electron metal
center. The analogous (4,7-diphenylphenanthroline)-ligated
complex 1a has a similar structure.12b
Oxidation reactions of azolines
Optimization of reaction conditions. Table 1 illustrates our
optimization of catalytic aerobic oxidation conditions for the
Fig. 1 Examples of thiazole containing bioactive compounds.
University of Southern California, 837 Bloom Walk, Los Angeles,
California 90089-1661, USA. E-mail: travisw@usc.edu; Fax: +1 213
740 5961; Tel: +1 213 740 5961
†Electronic supplementary information (ESI) available: Full preparative
details, cost analysis, graphical spectra, and crystallographic data. CCDC
reference numbers 761477 and 761476 for 1 and 1a, respectively. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2dt00025c
Scheme 1 Copper-catalyzed azoline oxidation.
7994 | Dalton Trans., 2012, 41, 7994–8002
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transformation of thiazoline 2 to thiazole 2a. We found compar-
able results upon screening other bidentate ligands for copper
(vide infra), however, optimization and scope studies were per-
formed solely with catalyst 1. Table 1 summarizes our optimiz-
ation studies. Entries 1–4 demonstrate that although O2 is
essential for the reaction (entry 4), air is a more effective oxygen
source than 1 atmosphere of O2 (compare entries 1 and 2).
Repeating the O2 experiment (entry 2) at 55 °C did not improve
this reaction (entry 3).
comparable results upon screening several nitrogen-based
ligands for copper (entries 1–7). Among these, the diimine
system found in 1 (entry 9) and ligand-free conditions (entry 8)
afforded the best conversions, with the former affording a
superior isolated yield.
Table 2 Ligand screen of copper catalyzed oxidation of thiazoline 2 to
thiazole 2a
The copper-free background reaction (Table 1, entry 5) has an
appreciable rate and results in product formation in 36% yield.
Along these lines, entry 14 illustrates that in the presence of
1.1 molar equivalents DBU, oxidation reaches 66% yield (>99%
conversion) in only 30 min. Solvent screening included DMF,
DCM, CH3CN, and PhCH3 (entries 6–8); none was superior to
the original DMF conditions. Neither Hünig’s base (entry 10)
nor t-butoxide (entry 11) is as effective as DBU in these con-
ditions, but both are superior to base-free conditions (entry 13).
This result highlights the relative utility of catalytic and base-
promoted conditions with an electon-neutral substrate. Impor-
tantly, we observe that in a direct comparison with thiazoline (2),
DBU conditions compare favorably to analogous K2CO3 con-
ditions (compare entries 1 and 12).9
Entrya
1
Ligand
Conversionb (isolated yield)
66%
2
3
81%
74%
4
81%
5
6
86%
64%
Table 2 shows that the ligand used on copper has little
influence in the outcome of the conversion of 2 to 2a. We found
7
92% (68%)
8
9
None
100% (78%)
90% (88%)
Scheme 2 Synthesis and molecular structure of complex 1. Ellipsoids
are drawn at the 50% probability level. Selected bond distances (Å):
Cu–N1 = 1.99; Cu–N2 = 2.00; Cu–O1 = 1.99; Cu–O2 = 1.97; Cu–O3 =
2.21. Yellow spheroids represent peaks in the difference map, which are
likely results of O–H bonds.
a Conditions: Cu(OTf)2 10 mol%, DBU (10 mol%), thiazoline (50 mM),
DMF, 100 °C, 8 h. b Based on starting material conversion by 1H NMR.
Table 1 Optimization of CuII-catalyzed oxidation conditions
Entrya
Cat.
[O]
Base
Solvent
Temp. (°C)
Time
Yield (%)b
1
2
3
4
5
6
7
8
1
1
1
1
—
1
1
1
1
1
1
1
1
—
Air
O2
O2
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Proton sponge
DIEA
KOtBu
K2CO3
—
DMF
DMF
DMF
DMF
DMF
DCM
CH3CN
PhCH3
DMF
DMF
DMF
DMF
DMF
DMF
100
100
55
8 h
8 h
7 d
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
30 min
88
41
47
3
36
41
4
14
41
45
22
47
4
N2
100
100
Reflux
Reflux
100
100
100
100
100
100
70
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
9
10
11
12
13
14
1.1 equiv. DBU
66
a Reaction conditions: 10 mol% [(MesDABMe)CuII(OH2)3]2+ [−OTf]2, 1, 10 mol% base unless otherwise noted. b Isolated yields. DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene.
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Table 3 Aryl thiazoline oxidation
Entry
1a
Substrate
Conditionsa
Product
Yield (%)
Catalyzedb
8 h
88
66
1b
Baseb
30 min
2a
2b
Catalyzed
3 h
78
69
Basec
1 h
3a
3b
Catalyzed
8 h
Base
4 h
68
58
4a
4b
Catalyzed
8 h
Base
1 h
79
77
5a
5b
Catalyzed
3 h
Base
58
44
45 min
6a
6b
Catalyzed
4 h
Base
69
44
45 min
a Catalyzed: 10 mol% 1, 10 mol% DBU, DMF, 100 °C; Base: 1.1 equiv. DBU, DMF, 70 °C. b Substituting K2CO3 as base (e.g. ref. 9) in these
conditions affords yields of 47% and 30%14 respectively for the catalyzed and base-promoted reactions. c 10 mol% DBU.
We tested our conditions against a variety of thiazoline sub-
strates (Table 3). Substrates with aryl substituents in the 2-pos-
ition demonstrated good yields with a range of electron
withdrawing and electron donating groups in the para-position.
Electron-withdrawing groups such as aryl fluoride and nitrile
(entries 5a, 6a) do not impede oxidation; more importantly, an
electron-rich thiazoline is tolerated (entry 3a). A sensitive sub-
strate and excellent synthetic handle such as the p-cyano thia-
zoline (7) shows a significant advantage in yields 69% vs. 9%
when using our catalytic method vs. aerobic K2CO3.9 Further,
yields for the conversion of 2 to 2a of 88% and 66% with DBU
as base in the respective presence and absence of copper are an
interesting contrast to yields 47% and 30%14 for otherwise iden-
tical reactions run with K2CO3 (1 equiv.) as base.
an intermediate enolate (14, Scheme 3, vide infra) facilitates
oxygen transfer. We have not seen evidence of an S-oxidation
pathway, although such a mechanism can not be eliminated.
Similarly, thiazolines containing 2-alkyl substituents proved
difficult to oxidize and afforded lower yields than the 2-aryl thia-
zole counterparts (entries 3 and 4).
Copper-free, base-mediated oxidation. Many of these reac-
tions produce reasonable yields in the presence of base alone
(e.g. Table 1, entry 14). Reactions run in the absence of copper
with stoichiometric base15 generally have lower, but comparable
yields to their catalytic counterparts but with advantageous,
reduced reaction times. Yields for base promoted reactions are
summarized in Tables 3 and 4 alongside the results for catalytic
oxidation. It is important to note that these base-promoted reac-
tions are apparently faster because they involve a molar excess
of base whereas catalytic conditions involve only 10 mol% each
of copper and DBU.
Oxazolines. Oxazolines (Table 4, entries 1 and 2) were tested
against the catalytic conditions with less success. Yields of the
corresponding oxazoles are lower than those of the thiazole
series. We are unsure of the reason for this difference, but we
suspect that the presence of a more polarizable sulfur center in
The base conditions demonstrate increased yields in both the
2-substituted alkyl substrates (Table 4, entries 3b and 4b) and
7996 | Dalton Trans., 2012, 41, 7994–8002
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Table 4 Further examples of azoline oxidation
Entry
1a
Substrate
Conditionsa
Product
Yield (%)
Catalyzedb
9 h
Base
18
16
1b
6 h
2a
2b
Catalyzedb
12 h
Base
37
41
2 h
3a
3b
Catalyzed
8 h
Base
5 h
24
39
4a
4b
Catalyzed
12 h
Base
45
51
6 h
5a
5b
5c
Catalyzed
6 h
55
0
Base
1 h
K2CO3
9
36
6 h
6a
6b
Catalyzed
14 h
Base
65
46
30 min
a Catalyzed: 10 mol% 1, 10 mol% DBU, DMF, 100 °C; Base: 1.1 equiv. DBU, DMF, 70 °C. b 30 mol% DBU.
oxazoline containing substrate (entry 2b), while the catalytic
conditions appear higher yielding in other cases. Particularly in
situations of more electron rich thiazolines, catalytic conditions
provide increased yields. We suspect that the advantage in yield
for the catalytic conditions is related to the minimization of inter-
molecular side reactions.
yield of the thiazole 2a when copper conditions are utilized
(entry 2). The base-mediated reaction is less efficient at this
scale (entry 4).
Mechanism
When a thaizoline substrate with a 2-substituted heterocycle,
e.g. indole (entry 5), is subjected to DBU conditions, no product
formation is observed. However, successful oxidation in 55%
yield is achieved by application of catalytic conditions. When
Yao et al.’s conditions9 were applied to the indole substrate (12,
Table 4, entry 5c) a yield of 36% was obtained. An N-methylin-
dole-bearing substrate (13, entry 6) was subsequently subjected
to both catalytic and base conditions, which lead to good yields
in each case. These data show that in the presence of labile
protons, as in indole, our catalyst proves superior for thiazoline
oxidation.
Intermediates. We have made some observations that help us
to understand the reaction intermediates (Scheme 3). We propose
initial enolization of 2 followed by installation of an angular
hydroxide (15). Notably, isolation and characterization of 15
confirms its presence in the reaction under copper-free con-
ditions; independent conversion of 15 to 2a in the presence of
DBU, with or without copper, provides evidence of its kinetic
competence. Thus, we believe that 2 is enolized to form an
Scalability. The catalytic conditions are advantageous when
the reaction is run on larger scale (Table 5), which is important if
this transformation is to be used for material throughput. Thiaz-
oline 2 is successfully oxidized on a 1 g scale to afford 80%
Scheme 3 Oxidation mechanism.
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Table 5 Scalability
is essential to decompose any possible peroxide in any aerobic
oxidation before the product is isolated.
Conclusions
We have developed conditions to transform azolines to azoles
via two efficient and economical aerobic oxidation routes. These
reactions are applicable to a wide range of substrates (electron
rich–electron poor), are easy to use, involve little waste, and are
demonstrated on a reasonable laboratory scale. Stoichiometric
base conditions afforded good yields in many cases, but copper-
catalyzed conditions afforded superior results in most cases. This
technology will be useful for building natural products and med-
icinal entities containing one or more embedded azole subunits,
sensitive labile protons, and electron rich species without the
expense of stoichiometric metal oxidants. Further development
of aerobic oxidation methods is ongoing in our laboratory.
Entry
Scale (mg)
Conditions
Time (h)
Isolated yield (%)
1
2
3
4
20
1000
20
Catalyzed
Catalyzed
Base
8
18
1
88
80
66
55
1000
Base
2.5
Experimental
General procedures
All air and water sensitive procedures were carried out either in a
Vacuum Atmospheres glove box under nitrogen (2–10 ppm O2
for all manipulations) or using standard Schlenk techniques
under nitrogen. Deuterated NMR solvents were purchased from
Cambridge Isotopes Labs and used as received. Other organic
solvents and bulk inorganic reagents (e.g. K2CO3, NaHCO3,
MgSO4) were purchased from EM Science and used as received,
except where indicated. Iodomethane was purchased from Alfa
Aesar and stored, as received, over copper shot. Copper(II)
triflate was purchased from Alfa Aesar and used as received.
Silica gel (230–400 mesh) was purchased as pre-packed columns
from Teledyne.
Fig. 2 Intermediates in potassium carbonate-mediated oxidation.
intermediate 14, which is oxidized either by a copper oxo
species or dioxygen itself to give angular hydroxide 15.16
We report that the angular hydroxide comes from O2 as
opposed to H2O because we observe no incorporation of 18O
when the reaction is run in the presence of H218O (see ESI†).
Along these lines, the presence of a radical inhibitor (BHT, buty-
lated hydroxytoluene, or tocopherol, vitamin E) does not affect
the efficiency of the copper-catalyzed or stoichiometric base-pro-
moted oxidation of 2.17 Therefore, we do not suspect a long-
lived radical intermediate in either reaction. Further, addition of
water does not provide increased yield or rate in either copper-
catalyzed or stoichiometric base-promoted oxidation of 2.18
NMR spectra were recorded on a Varian Mercury 400,
400MR, VNMRS 500, or VNMRS 600 spectrometer. All chemi-
cal shifts are reported in units of ppm and referenced to the
1
residual H in the solvent and line-listed according to (s) singlet,
(sb) broad singlet, (d) doublet, (t) triplet, (dd) double doublet,
etc. 13C spectra are delimited by carbon peaks, not carbon count.
Melting points were obtained on a mel-temp apparatus and are
uncorrected. MALDI mass spectra were obtained on an Applied
Biosystems Voyager spectrometer using the evaporated drop
method on a coated 96 well plate. The matrix was 2,5-
dihydroxybenzoic acid. In a standard preparation, ca. 1 mg
analyte and ca. 20 mg matrix were dissolved in a suitable
solvent and spotted on the plate with a micro-pipette. Electro-
spray ionization (ESI) high-resolution mass spectra were col-
lected at the University of California, Riverside Mass
Spectrometry Facility.
Intermediate putative peroxide. Our conditions do not
involve the intermediacy of a long-lived hydroperoxide species.
Yao et al. report that under potassium carbonate conditions,9 a
long-lived tertiary peroxide intermediate intervenes 14 and 15 in
the oxidation mechanism as characterized by TLC evidence. By
contrast, we observe no intermediate species in the reaction
mixture other than 2, 15, and 2a when the oxidation is run with
either our copper catalyzed conditions or stoichiometric DBU.
By contrast, we do observe a species consistent with the putative
peroxide when we run the reaction under potassium carbonate
conditions. This is illustrated in Fig. 2.
Fig. 2 illustrates the intermediate species that we observe in
potassium carbonate-mediated oxidation. The thiazole product is
evident from its methyl ester peak, highlighted in green. Each of
15 (red) and the putative peroxide intermediate (blue) are rep-
resented both by their methyl esters at 3.9 ppm and by a pair of
doublets corresponding to their C5 methylene protons. The low
concentration of a peroxide intermediate in our conditions is sig-
nificant if this reaction is to be practised on scale. Nonetheless, it
Ligand screen
Various ligands (Table 2) were screened for oxidation of thia-
zoline 2 to thiazole 2a. In a representative procedure, the ligand
(10 mol%) and Cu(OTf)2 (10 mol%) were dissolved in N,N-
dimethylformamide (DMF) and stirred at room temperature for
30 min. Thiazoline 2 (50 mM) and DBU (10 mol%) were added
at room temperature. The reaction was stirred at 100 °C in air for
7998 | Dalton Trans., 2012, 41, 7994–8002
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8 h. Results, as determined by NMR spectroscopy, are summar-
ized in Table 2.
(177 mg, 0.33 mmol) according to the general procedure for thi-
azoline preparation to give the product as an oil (23 mg, 26%).
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 8.02 (dd, 1 H,
J1 = 8.0 Hz, J2 = 2.0 Hz), 7.91 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.6
Hz), 7.86 (d, 2 H, J = 8.0 Hz), 7.54 (m, 2 H), 5.35 (t, 1 H, J =
8.0 Hz), 3.86 (s, 3 H), 3.78 (dd, 1 H, J1 = 12 Hz, J2 = 8.0 Hz),
3.69 (dd, 1 H, J1 = 12 Hz, J2 = 8.0 Hz).
Preparation of copper complexes
[(MesDABMe)CuII(OH2)3]2+ 2 TfO− (1). [MesDABMe] ligand
(3.00 g, 9.40 mmol) and Cu(OTf)2 (2.54 g, 7.00 mmol) were
dissolved in wet dichloromethane (30 mL) and allowed to stir at
room temperature overnight. The product was precipitated upon
addition of hexanes and the crystals were washed with hexanes
in air multiple times to yield the product as a dark green crystal-
line solid (1.08 g, 21%).
13C NMR (100 MHz, CDCl3): δ = 171.5, 171.1, 135.0, 132.8,
130.2, 129.8, 129.1, 128.4, 127.9, 127.8, 126.8, 125.0, 78.7,
53.0, 35.6.
FT-IR (cm−1): ν = 2954, 2929, 1742, 1604.
ESI-HRMS for C15H13NO2S: calculated [MH]+ 272.0667 g
mol−1, found 272.0740 g mol−1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (sb, 6 H), 2.28 (sb, 12
H), 2.35 (sb, 6 H), 6.90 (sb, 4 H).
Methyl 2-(4-fluorophenyl)thiazole-4-carboxylate (6). 6 was
prepared from N-(4-fluorobenzoyl)-Cys(trt)-OMe (750 mg,
1.5 mmol) according to the general procedure for thiazoline
preparation to give the product as a white solid (220 mg, 61%),
mp 103–105 °C.
13C NMR cannot be recorded because this compound is
paramagnetic.
19F NMR (376 MHz, CDCl3): δ = −78.8.
MALDI for C24H34CuF6N2O9S2: calculated [MNa]+ 758.08 g
mol−1, found 758.22, 760.22 g mol−1
.
1H NMR (500 MHz, CDCl3): δ = 7.87 (ddd, 2 H, J1 = 8.5 Hz,
J2 = 5.5 Hz, J3 = 2.0 Hz), 7.1 (ddd, 2 H, J1 = 8.5 Hz, J2 = 8 Hz,
J3 = 2 Hz), 5.28 (t, 1 H, J = 8.5 Hz), 3.84 (s, 3 H), 3.73 (dd, 1
H, J1 = 11 Hz, J2 = 9 Hz), 3.65 (dd, 1 H, J1 = 11 Hz, J2 = 9 Hz).
13C NMR (100 MHz, CDCl3): δ = 171.4, 166.3, 163.7, 131.0,
129.1 (d, JC–F = 37.2 Hz), 115.8 (d, JC–F = 86.8 Hz), 78.6, 53.0,
35.8.
In a separate, air and water free experiment we are able to
observe [(MesDABMe)CuII(OTf)2] as a brown crystal. MALDI
for C24H28CuF6N2O6S2: calculated [MNa]+ 704.05 g mol−1
,
found 704.19 g mol−1
.
FT-IR (cm−1): ν = 2953, 1742, 1666, 1603, 1505.
ESI-HRMS for C11H10FNO2S: calculated [MH]+ 240.0416 g
mol−1, found 240.0487.
Preparation of azolines
Methyl 2-phenyl-4,5-dihydrothiazole-4-carboxylate (2). Crude
2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (3.5 g, 16.9 mmol)
was dissolved in 28 mL DMF at 0 °C, to which potassium car-
bonate (2.57 g, 18.6 mol)19 was added. After stirring for 30 min,
iodomethane (2.21 mL, 35.5 mmol) was added and the solution
was brought to room temperature and stirred for 1.5 h until com-
pletion by TLC (eluting with 3 : 1 hexanes–ethyl acetate). The
reaction mixture was then diluted in ethyl acetate (40 mL),
washed with brine 5 times, and dried over MgSO4. The crude
product mixture was then concentrated under reduced pressure
and purified via flash chromatography (5–25% ethyl acetate in
hexanes) to yield the product as a white solid (2.92 g,
13.2 mmol, 23%, 2 steps). Data are consistent with a previously
characterized compound.20
Methyl 2-(4-cyanophenyl)thiazole-4-carboxylate (7). 7 was
prepared from N-(2-cyanophenyl)-Cys(trt)-OMe (2.03 g,
4 mmol) according to the general procedure for thiazoline prep-
aration to give the product as a white solid (151 mg, 15%).
Melting point: 107–108 °C.
1H NMR (500 MHz, CDCl3): δ = 7.96 (dt, 2 H, J1 = 8.5 Hz,
J2 = 2.0 Hz), 7.71 (dt, 2 H, J1 = 9.0 Hz, J2 = 2.0 Hz), 5.32 (t, 1
H, J = 9 Hz), 3.85 (s, 3 H), 3.79 (dd, 1 H, J1 = 11.5 Hz, J2 = 9.0
Hz), 3.70 (dd, 1 H, J1 = 11.3 Hz, J2 = 9.0 Hz).
13C NMR (100 MHz, CDCl3): δ = 170.9, 147.6, 136.6, 132.4,
129.3, 118.2, 115.2, 78.7, 53.1, 35.9.
IR (cm−1): ν = 2953, 2920, 2230, 1743.
1H NMR (400 MHz, CDCl3): δ = 7.87 (m, 2 H), 7.47 (m, 1
H), 7.41 (m, 2 H), 5.29 (t, 1 H, J = 8.8 Hz), 3.84 (s, 3 H), 3.73
(dd, 1 H, J1 = 11.2 Hz, J2 = 8.8 Hz), 3.62 (dd, 1 H, J1 = 11.2
Hz, J2 = 8.8 Hz).
ESI-HRMS for C12H10N2O2S: calculated 247.0463 g mol−1
,
found 247.0536 g mol−1
.
Methyl 2-(indol-2-yl)-4,5-dihydrothiazole-4-carboxylate (12).
12 was prepared from methyl 2-(indole-2-carboxamido)-3-(tri-
tylthio)propanoate (200 mg, 0.38 mmol) according to the
general procedure for thiazoline preparation to give the product
as a white solid (40 mg, 0.15 mmol, 40%).
All other thiazolines were prepared via a route reported by
Kelly et al.20
General procedure for thiazoline preparation.20 Trityl-pro-
tected amide was dissolved in dry dichloromethane (0.05 M sol-
ution). Stirring under N2, a solution of TiCl4 (1 M in
dichloromethane, 3 equiv.)21 was added and stirred at room
temperature overnight until completion. The reaction mixture
was then washed with sat. aq. NaHCO3 twice and dried over
MgSO4. The product was purified via flash chromatography on
silica, eluting with ethyl acetate and hexanes.
Melting point: 141–142 °C.
1H NMR (400 MHz, CDCl3): δ = 9.20 (s, 1 H), 7.65 (dd, 1 H,
J1 = 8 Hz, J2 = 1.2 Hz), 7.35 (dd, 1 H, J1 = 8 Hz, J2 = 1.2 Hz),
7.29 (ddd, 1 H, J1 = 8 Hz, J2 = 8 Hz, J3 = 1.2 Hz), 7.13 (ddd, 1
H, J1 = 8 Hz, J2 = 8 Hz, J3 = 1.2 Hz), 6.98 (d, 1 H, J = 1 Hz),
5.26 (t, 1 H, J = 8 Hz), 3.84 (s, 3 H), 3.76 (dd, 1 H, J1 = 12 Hz,
J2 = 8 Hz), 3.68 (dd, 1 H, J1 = 12, Hz, J2 = 8 Hz).
13C NMR (100 MHz, CDCl3): δ = 171.3, 163.0, 137.1, 130.2,
127.9, 152.2, 122.1, 120.2, 111.7, 108.7, 77.7, 53.0, 35.6.
FT-IR (cm−1): ν = 3061, 2951, 1739, 1603, 1518.
Methyl 2-(naphthalen-2-yl)-4,5-dihydrothiazole-4-carboxylate
(5). 5 was prepared from N-(2-naphthoyl)-Cys(Trt)-OMe
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ESI-HRMS for C13H12N2O2S: calculated [MH]+ 261.0619 g
mol−1, found 261.0691 g mol−1
13C NMR (100 MHz, CDCl3): δ = 161.8, 148.8, 138.3, 129.7,
129.0, 127.9, 124.6, 52.9, 29.9.
.
IR (cm−1): ν = 3125, 3092, 1721.
ESI-HRMS for C11H8N2O4S: calculated [MH]+ 265.0205 g
Methyl 2-(1-methylindol-2-yl)-4,5-dihydrothiazole-4-carboxy-
late (13). 13 was prepared from methyl 2-(1-methylindole-2-car-
boxamido)-3-(tritylthio)propanoate (1.1 g, 2.1 mmol) according
to the general procedure for thiazoline preparation to give the
product as a white solid (120 mg, 0.44 mmol, 21%).
mol−1, found: 265.0278 g mol−1
.
Methyl 2-(4-methoxyphenyl)thiazole-4-carboxylate (4a). 4a
was prepared from methyl 2-(4-methoxyphenyl)-4,5-dihy-
drothiazole-4-carboxylate (25 mg, 0.1 mmol)20 according to the
general catalytic procedure (8 h, 17 mg, 68%) or base-promoted
procedure (4 h, 14 mg, 58%).
Melting point: 78–80 °C.
1H NMR (400 MHz, CDCl3): δ = 7.64 (dt, 1 H, J1 = 8 Hz, J2
= 1.2 Hz), 7.37 (d, 1 H, J = 8 Hz), 7.33 (ddd, 1 H, J1 = 8 Hz, J2
= 8 Hz, J3 = 1.2 Hz), 7.14 (ddd, 1 H, J1 = 8 Hz, J2 = 8 Hz, J3 =
1.2 Hz), 7.16 (s, 1 H), 5.37 (dd, 1 H, J1 = 8 Hz, J2 = 8 Hz), 4.12
(s, 3 H), 3.84 (s, 3 H), 3.65 (dd, 1 H, J1 = 8 Hz, J2 = 12 Hz),
3.59 (dd, 1 H, J1 = 8 Hz, J2 = 12 Hz).
Melting point: 67–79 °C.
1H NMR (400 MHz, CDCl3): δ = 8.10 (s, 1 H), 7.96 (d, 2 H,
J = 8 Hz), 6.97 (d, 2 H, J = 8 Hz), 3.97 (s, 3 H), 3.87 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 162.2, 161.8, 147.6,
128.7, 126.7, 125.8, 114.4, 55.6, 52.6.
13C NMR (100 MHz, CDCl3): δ = 171.6, 163.3, 139.9, 131.0,
126.7, 124.7, 122.0, 120.5, 110.3, 110.2, 79.1, 52.9, 34.8, 32.3.
FT-IR (cm−1): ν = 3060, 2951, 1741, 1660, 1603, 1510.
ESI-HRMS for C14H14N2O2S: calculated [MH]+ 275.0776 g
FT-IR (cm−1): ν = 3119, 3025, 1740, 1710.
ESI-HRMS for C12H11NO3S: calculated 250.0460 g mol−1
,
found 250.0532 g mol−1
.
mol−1, found 275.0850 g mol−1
.
Methyl 2-(naphthalen-2-yl)thiazole-4-carboxylate (5a). 5a
was prepared from methyl 2-(naphthalen-2-yl)-4,5-dihydrothia-
zole-4-carboxylate (5, 20 mg, 0.74 mmol) according to the cata-
lytic procedure (8.5 h, 16 mg, 79%) or base-promoted procedure
(1 h, 15 mg, 77%) to give 5a.
General procedure for catalytic oxidation. Azoline was dis-
solved in DMF at room temperature (50 mM). After the addition
of (DAB)CuII complex 1 (10 mol%) and DBU (10 mol%, or
other if specified), the reaction was allowed to stir at 100 °C in
air until complete by TLC (eluting with 3 : 1 hexanes–ethyl
acetate). The solution was then diluted with ethyl acetate,
washed with deionized water, and dried over MgSO4. The crude
product was purified via flash chromatography on silica, eluting
with 0–20% ethyl acetate in hexanes, to give the corresponding
azole.
1H NMR (400 MHz, CDCl3): δ = 8.52 (s, 1 H), 8.22 (s, 1 H),
8.09 (d, 1 H, J = 8 Hz), 7.93 (m, 2 H), 7.85 (m, 1 H), 7.54 (m,
2 H), 4.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.3, 162.2, 148.1, 134.6,
133.3, 130.3, 129.1, 129.0, 128.1, 127.6, 127.2, 126.9, 124.3,
52.8, 29.9.
FT-IR (cm−1): ν = 3138, 3048, 1733.
ESI-HRMS for C15H11NO2S: calculated [MH]+ 270.0510 g
General procedure for base-promoted oxidation of azolines.
Azoline was dissolved in DMF at room temperature (50 mM).
After the addition of DBU (1.1 equiv., or other if specified), the
reaction was allowed to stir at 70 °C in air until complete by
TLC (eluting with 3 : 1 hexanes–ethyl acetate). The solution was
then diluted with ethyl acetate, washed with deionized water and
dried over MgSO4. The crude product was purified via flash
chromatography on silica, eluting with 0–20% ethyl acetate in
hexanes, to give the corresponding azole.
mol−1, found 270.0583 g mol−1
.
Methyl 2-(4-fluorophenyl)thiazole-4-carboxylate (6a). 6a was
prepared from methyl 2-(4-fluorophenyl)-4,5-dihydrothiazole-4-
carboxylate (6, 20 mg, 0.084 mmol) according to the catalytic
procedure (2 h, 12 mg, 58%) or base-promoted oxidation
(45 min, 9 mg, 44%) to give 6a.
1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H), 8.00 (m,
2 H), 7.15 (t, 2 H, J = 8.4 Hz), 3.98 (s, 3 H).
13C NMR (100 MHz CDCl3) δ: 165.7, 163.2, 162.1, 147.9,
129.30, 129.1 (d, JC–F = 33.6 Hz), 127.5, 116.3 (d, JC–F = 88.4
Hz), 52.7.
Methyl 2-phenylthiazole-4-carboxylate (2a). 2a was prepared
from methyl 2-phenyl-4,5-dihydrothiazole-4-carboxylate (22 mg,
0.1 mmol) according to the catalytic procedure (8 h, 19 mg, 87%)
or base-promoted procedure (0.5 h, 15 mg, 66%) to give 2a as
white solid. Data are consistent with a previously characterized
compound.22
FT-IR (cm−1): n = 3133, 3108, 1750.
ESI-HRMS for C11H8FNO2S: calculated [MH]+ 238.0260 g
mol−1, found 238.0333 g mol−1
.
1H NMR (400 MHz, CDCl3): δ = 8.37 (s, 1 H), 7.98 (m,
2 H), 7.47 (m, 3 H), 3.91 (s, 3 H).
Methyl 2-(4-cyanophenyl)thiazole-4-carboxylate (7a). 7a was
prepared from methyl 2-(4-cyanophenyl)-4,5-dihydrothiazole-4-
carboxylate (7, 20 mg, 0.81 mmol) according to the catalytic
procedure (4 h, 14 mg, 69%) or base-promoted procedure
(45 min, 9 mg, 44%) to give 7a.
Methyl 2-(4-nitrophenyl)thiazole-4-carboxylate (3a). 3a was
prepared from methyl 2-(4-nitrophenyl)-4,5-dihydrothiazole-4-
carboxylate (53 mg, 0.2 mmol)20 according to the general cataly-
tic procedure (3 h, 41 mg, 78%) or a variant of the base-pro-
moted procedure wherein only 10 mol% of DBU is incorporated
(1 h, 36 mg, 69%).
Melting point: 199–201 °C.
1H NMR (500 MHz, CDCl3): δ = 8.27 (s, 1 H), 8.13 (dd, 2 H,
J1 = 8.5 Hz, J2 = 2.5 Hz), 7.76 (dd, 2 H, J1 = 8.5 Hz, J2 = 2.5
Hz), 4.0 (s, 3 H).
Melting point: 224–227 °C.
1H NMR (400 MHz, CDCl3): δ = 8.31 (d, 2 H, J = 8 Hz),
8.29 (s, 1 H), 8.18 (d, 2 H, J = 8 Hz), 3.98 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.6, 161.8, 148.6, 136.7,
133.0, 128.7, 127.6, 118.4, 114.3, 52.9.
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FT-IR (cm−1): ν = 3133, 2233, 1747.
ESI-HRMS for C13H10N2O2S: calculated [MH]+ 259.0463 g
ESI-HRMS for C12H8N2O2S: calculated [MH]+ 245.0306 g
mol−1, found 259.0536 g mol−1
.
mol−1, found 245.0379 g mol−1
.
Methyl 2-(1-methyl-indol-2-yl)thiazole-4-carboxylate (13a).
13a was prepared from methyl 2-(1-methylindol-2-yl)-4,5-dihy-
drothiazole-4-carboxylate (20 mg, 0.073 mmol) according to the
catalytic procedure (14 h, 13 mg, 65%) or base-promoted pro-
cedure (30 min, 9 mg, 45%).
Methyl 2-phenyloxazole-4-carboxylate (8a). 8a was prepared
from methyl 2-phenyl-4,5-dihydrooxazole-4-carboxylate (20 mg,
0.1 mmol)23 according to a variant of the catalytic procedure
wherein 30 mol% of base is added (9 hours, 4 mg, 18%) or
base-promoted procedure (6 h, 3 mg, 16%). Data are consistent
with a previously characterized compound.23
Melting point: 124–127 °C.
1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H), 7.64 (d, 1 H,
J = 8 Hz), 7.40 (d, 1 H, J = 8.8 Hz), 7.32 (ddd, 1 H, J1 = 8 Hz,
J2 = 8 Hz, J3 = 1.2 Hz), 7.16 (ddd, 1 H, J1 = 8 Hz, J2 = 8 Hz,
J3 = 1.2 Hz), 7.04 (s, 1 H), 4.21 (s, 3 H), 3.98 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.0, 161.6, 147.6, 139.5,
131.6, 127.2, 127.1, 124.1, 121.5, 120.7, 110.3, 106.1, 52.6,
32.1.
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 8.13 (d, 2 H,
J = 8 Hz), 7.49 (m, 3 H), 3.97 (s, 3 H).
Methyl 2-(4-nitrophenyl)oxazole-4-carboxylate (9a). 9a was
prepared from methyl 2-(4-nitrophenyl)-4,5-dihydrooxazole-
4-carboxylate (20 mg 0.08 mmol)24 according to a variant of
the catalytic procedure wherein 30 mol% of base is added
(12 h, 7 mg, 37%) or base-promoted procedure (2 h, 8 mg,
41%). Data are consistent with a previously characterized
compound.25
FT-IR (cm−1): ν = 2953, 2925, 1732, 1552.
ESI-HRMS for C14H12N2O2S: calculated [MH]+ 273.0619 g
mol−1, found 273.0697 g mol−1
.
1H NMR (400 MHz, CDCl3): δ = 8.38 (s, 1 H), 8.36 (dt, 2 H,
J1 = 8 Hz, J2 = 2.4 Hz), 8.31 (dt, 2 H, J1 = 8 Hz, J2 = 2.4 Hz),
3.99 (s, 3 H).
Methyl 4-hydroxy-2-phenyl-4,5-dihydrothiazole-4-carboxylate
(15). 15 was prepared from methyl 2-phenyl-4,5-dihydrothia-
zole-4-carboxylate via the general procedure for base-promoted
oxidation in which the reaction was stopped after 15 min.
1H NMR: 7.89 (dd, 2 H, J = 8 Hz, J = 1.2 Hz), 7.51 (tt, 1 H,
J = 8 Hz, J = 8 Hz), 7.42 (tt, 2 H, J = 8 Hz, J = 1.2 Hz), 4.18 (s,
1 H), 4.02 (dd, 2 H, J = 12 Hz, J = 1.2 Hz), 3.89 (s, 3 H), 3.55
(d, 1H, J = 12 Hz).
Methyl 2-methylthiazole-4-carboxylate (10a). 10a was pre-
pared from methyl 2-methyl-4,5-dihydrothiazole-4-carboxylate
(20 mg, 0.12 mmol)26 according to the catalytic procedure
(8 h, 5 mg, 24%) or base-promoted procedure (5 h, 8 mg,
39%). Data are consistent with a previously characterized
compound.27
MALDI for C11H11NO3S: calculated [MH]+ 238.04 g mol−1
,
found 238.00 g mol−1
.
1H NMR (400 MHz, CDCl3): δ = 8.05 (s, 1 H), 3.95 (s, 3 H),
2.77 (s, 3 H).
Scale up reaction
Methyl 2-phenethylthiazole-4-carboxylate (11a). 11a was pre-
pared from methyl 2-phenethyl-4,5-dihydrothiazole-4-carboxy-
late (11, 20 mg, 0.08 mmol)20 according to the catalytic
procedure (12 h, 9 mg, 45%) or base-promoted procedure (6 h,
10 mg, 51%).
In a 3-neck round bottom flask, N,N′-(butane-2,3-diylidene)bis
(2,4,6-trimethylaniline) (145 mg, 0.45 mmol)11 and copper(II)
triflate (164 mg, 0.45 mmol) were stirred in DMF at room temp-
erature for 30 min. DBU (0.068 mL, 0.45 mmol) and methyl
2-phenyl-4,5-dihydrothiazole-4-carboxylate (1.0 g, 4.5 mmol)
were added sequentially. A condenser was then attached to the
flask, which was then placed in a 100 °C oil bath. A gentle
stream of compressed air was bubbled into the reaction, which
was stirred for 18 h. The reaction mixture was diluted with ethyl
acetate and washed with deionized water three times then dried
over MgSO4. The crude reaction mixture was then concentrated
under reduced pressure and purified via column chromatography
(5–25% hexanes in ethyl acetate) to yield desired product
(791 mg, 3.6 mmol, 80%).
1H NMR (400 MHz, CDCl3): δ = 8.05 (s 1 H), 7.3 (m, 2 H),
7.21 (m, 3 H), 3.96 (s, 3 H), 3.38 (t, 2 H, J = 8 Hz), 3.18 (t, 2 H,
J = 8 Hz).
13C NMR (100 MHz, CDCl3): δ = 171.1, 162.1, 146.6, 140.0,
128.8, 128.6, 127.4, 126.7, 52.6, 36.1, 35.4.
FT-IR (cm−1): ν = 3119, 2954, 1721.
ESI-HRMS for C13H13NO2S: calculated [MH]+ 248.0667 g
mol−1, found 248.0740 g mol−1
.
Methyl 2-(indol-2-yl)thiazole-4-carboxylate (12a). 12a was
prepared from methyl 2-(indol-2-yl)-4,5-dihydrothiazole-4-car-
boxylate (20 mg, 0.077 mmol) according to the catalytic pro-
cedure (6 h, 11 mg, 55%).
Oxidation of thiazoline 2 in the presence of H218O
Melting point: 69–71 °C.
Thiazoline was dissolved in DMF (previously dried over CaH2)
at room temperature (50 mM). H218O (1.2 equiv.) and DBU (1.1
equiv.) were added and the reaction was stirred at 70 °C in air
for 30 min. An aliquot of the reaction mixture was analyzed by
MALDI and compared to an isolated sample of angular hydrox-
ide thiazoline 15 made as a reaction intermediate by the general
procedure for base-promoted oxidation. Little additional incor-
poration of 18O was observed (see ESI† of a graphical MALDI
spectrum).
1H NMR (400 MHz, CDCl3): δ = 9.33 (s, 1 H), 8.13 (s 1 H),
7.65 (dd, 1 H J1 = 8 Hz, J2 = 0.8 Hz), 7.40 (dd, 1 H J1 = 8 Hz,
J2 = 0.8 Hz), 7.28 (ddd, 1 H, J1 = 8 Hz, J1 = 8 Hz, J3 = 0.8 Hz),
7.15 (ddd, 1 H, J1 = 8 Hz, J2 = 8 Hz, J3 = 0.8 Hz), 7.05 (dd, 1
H, J1 = 2 Hz, J2 = 0.8 Hz), 3.99 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.8, 161.1, 147.2, 136.8,
130.6, 128.4, 126.8, 124.7, 121.6, 121.0, 111.6, 104.3, 52.7.
FT-IR (cm−1): ν = 2921, 2852, 1732, 1717.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 7994–8002 | 8001

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7 (a) D. R. Williams, P. D. Lowder, Y. G. Gu and D. A. Brooks, Tetra-
hedron Lett., 1997, 38, 331; (b) G. L. Mislin, A. Burger and M.
A. Abdallah, Tetrahedron, 2004, 60, 12139; (c) R. S. Brown, J. Dowden,
C. Mpreau and B. V. L. Potter, Tetrahedron Lett., 2002, 43, 6561.
8 (a) K. S. Ramasamy, R. Bandaru and D. J. Averett, J. Org. Chem., 2000,
65, 5849; (b) Y. Yu, H. Chen, L. Wang, X. Chen and B. Fu, Molecules,
2009, 14, 4858; (c) X. Fernandez and E. Dunach, Tetrahedron: Asymme-
try, 2001, 12, 1279; (d) X. Fernandez, R. Fellous, L. Lizzani Cuvelier,
M. Loiseau and E. Dunach, Tetrahedron Lett., 2001, 42, 1519; (e) S.
L. You and J. W. Kelly, Tetrahedron, 2005, 61, 241; (f) S. L. You and J.
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Oxidation of 2 with K2CO3
Reaction of thiazoline 2 with K2CO3 (1 equiv.) and catalyst 1 in
DMF (2 mL) produced thiazole 2a in 30% yield as well as a
mixture of angular hydroxide 15 and an unknown intermediate,
which is purportedly an angular peroxide, in a ratio of ca. 1 : 1.3
ratio, 22% and ca. 26% isolated yields respectively.
Acknowledgements
9 (a) Y. Huang, H. Gan, S. Li, J. Xu, X. Wu and H. Yao, Tetrahedron Lett.,
2010, 51, 1751; (b) Y. Huang, L. Ni, H. Gan, Y. He, J. Xu, X. Wu and
H. Yao, Tetrahedron, 2011, 67, 2066.
10 Quote from Aurora Fine Chemicals, San Diego, CA.
11 H. A. Zhong, J. A. Labinger and J. E. Bercaw, J. Am. Chem. Soc., 2002,
124, 1378–1399.
This work is sponsored by the University of Southern California,
Loker Hydrocarbon Research Institute, the Hydrocarbon
Research Foundation, and the American Cancer Society (grant
IRG-58-007-48) provided through USC Norris Cancer Center.
We are grateful to Dr Kortney Klinkel, Jonathan Chen, Erica
Good, and Jordan Lee for efforts in initiating this project, Dr
Brian Conley for insightful discussions, and Dr Timothy Stewart
and Dr Ralf Haiges for X-ray crystallography.
12 CCDC (a) 761477 and (b) 761476 contain the supplementary crystallo-
graphic data for these complexes.
13 Other examples of cis (N–N)CuII(OH2)3 include (a) Z. Xu, L.
K. Thompson and D. O. Miller, Inorg. Chem., 1997, 36, 3985;
(b) E. Burkholder, S. Wright, V. Golub, C. J. O’Connor and J. Zubieta,
Inorg. Chem., 2003, 42, 7460.
14 An additional portion of ca. 48% of azole-containing products were col-
lected. See ESI† for detail.
15 Conditions optimization available in ESI.†.
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8002 | Dalton Trans., 2012, 41, 7994–8002
This journal is © The Royal Society of Chemistry 2012