DDQ-induced dehydrogenation of heterocycles for c-c double bond formation: Synthesis of 2-thiazoles and 2-oxazoles

Article abstract of DOI:10.1002/asia.201300267

Strong as an Ox: 2-Thiazoles and 2-oxazoles are formed by oxidation of 2-thiazolines and 2-oxazolines without requiring substituents at the C4 and C5 positions. DDQ plays an important role as the oxidant in this transformation and metal is unnecessary. This general procedure shows good functional group tolerance and provides a wide variety of 2-thiazoles and 2-oxazoles in moderate to excellent yields.

Full text of DOI:10.1002/asia.201300267

COMMUNICATION
DOI: 10.1002/asia.201300267
À
DDQ-Induced Dehydrogenation of Heterocycles for C C Double Bond
Formation: Synthesis of 2-Thiazoles and 2-Oxazoles
Xiangnan Li, Cheng Li, Bing Yin, Cong Li, Ping Liu, Jianli Li,* and Zhen Shi[a]
Thiazoles and oxazoles represent a predominant structural
motif in many natural compounds, organic dyes, and phar-
maceuticals.[1–3] In recent years, thiazoles and oxazoles that
are monosubstituted at the C2 position have been widely
used in organic synthesis as building blocks owing to their
versatile reactivity.[4] However, a potential limitation for
the application of 2-substituted thiazoles and oxazoles could
be the lack of practical methods to produce these import-
ant heterocycles. There are some synthetic strategies avail-
able for the synthesis of 2-thiazoles and 2-oxazoles
(Scheme 1).[5–8] Among these methods, oxidation of 2-thiazo-
the C4 and C5 positions.[9] Barrish and co-workers demon-
strated a CuII/DBU (DBU=1,8-diazabicyclo
[5.4.0]undec-7-
ene) system for synthesis of 2-oxazoles-4-carboxylate, how-
ever, oxidation of 2-monosubstituted oxazolines using this
method did not afford the desired products.[10] Wang et al.
AHCTUNGTRENNUNG
also reported that the CuACHTNUGTRENUNG(OAc)2/O2 system did not afford
the desired 2-thiazoles when 2-thiazolines bearing an inac-
tive group at the C4-position were employed.[11] Therefore,
the oxidation of 2-thiazolines and 2-oxazolines without sub-
stituents at C4 and C5 is considered to be challenging, and
few methods are reported for this transformation. Recently,
we have reported a convenient and efficient copper-cata-
lyzed tandem reaction to form a wide range of 2-thiazolines
and 2-oxazolines,[12] and this allowed us to further study the
oxidation of 2-thiazolines and 2-oxazolines.
DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)
is
a highly effective oxidant. In the past decades, DDQ has
been widely used in chemical transformations, including pro-
tecting-group removal, cross-coupling reactions, cyclizations,
and biaryl construction.[13] Encouraged by extensive investi-
gations on DDQ-induced dehydrogenation reactions,[14]
herein, we report a convenient and efficient approach for 2-
thiazoles and 2-oxazoles from the oxidation of 2-thiazolines
and 2-oxazolines, respectively, using DDQ as the oxidant.
To the best of our knowledge, this is the first system for the
synthesis of 2-monosubstituted thiazoles and oxazoles
through dehydrogenation. Furthermore, metals are not re-
quired in this study, thus making this method attractive for
pharmaceutical purposes.
As shown in Table 1, 2-phenyl-2-thiazoline (1a) was
chosen as the model substrate for optimization studies. First-
ly, a variety of common oxidants were screened (Table 1, en-
tries 1–6), but no desired product 2a was obtained. To our
delight, DDQ was proved to be an efficient oxidant for the
transformation (Table 1, entry 7). Solvent effects were also
investigated, and it was found that CH2Cl2 performed better
than any other solvent (Table 1, entries 7–12). Furthermore,
catalysts were screened, which showed no improvement in
the efficiency of the transformation (Table 1, entries 13–15).
Finally, different additives and reaction temperatures were
examined, and optimal results were obtained with molecular
sieves (5 ꢀ) at room temperature (Table 1, entries 16–20).
The optimal reaction conditions were DDQ, CH2Cl2, 5 ꢀ
MS, at room temperature. With these conditions in hand,
studies on the substrate scope were carried out, and the re-
sults are summarized in Table 2. We initially investigated
Scheme 1. Strategies for the synthesis of 2-thiazoles and 2-oxazoles.
lines and 2-oxazolines (Scheme 1d) is of great importance,
and various approaches have been reported for this transfor-
mation.[8] Based on the literature precedent, C4 (R2) and/or
C5 (R3) substituents on 2-thiazolines and 2-oxazolines have
significant influence on the oxidation reaction, and 2-thiazo-
lines and 2-oxazolines without substituents at C4 and C5 are
inert to oxidation. For instance, Meyers and Tavares have
developed a CuI/CuII/peroxide oxidation for the synthesis of
2-thiazoles and 2-oxazoles, however, the main limitation of
this method was that oxidation was unsuccessful with 2-thia-
zolines and 2-oxazolines that were lacking a substituent at
[a] X. Li, C. Li, Dr. B. Yin, Dr. C. Li, Prof. Dr. P. Liu, Prof. Dr. J. Li,
Prof. Dr. Z. Shi
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of the Ministry of Education
and College of Chemistry & Materials Science
Northwest University, Xi’an Shaanxi 710069 (P. R. China)
Fax : (+86)029-88302601
E-mail: lijianli@nwu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300267.
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Jianli Li et al.
Table 1. Optimization of the reaction conditions.[a]
Table 2. DDQ-induced dehydrogenation for the synthesis of 2-thia-
zoles.[a,b]
Entry Oxidant
Solvent Catalyst
Additive T [8C] Yield [%][b]
1
2
3
4
MnO2
I2
CH3CN
CH3CN
CH3CN
CH3CN
–
–
–
–
–
–
–
–
rt
rt
rt
rt
0
0
Entry
1
2-thiazole 2
Entry
11
2-thiazole 2
O2/DBU
CuBr2/
DBU
FeCl3
H2O2
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
trace
trace
2a, 86% (8 h)
2k, 90% (10 h)
5
6
7
8
CH3CN
CH3CN
CH3CN
toluene
THF
EtOAc
DMF
CH2Cl2
CH2Cl2 FeCl3
CH2Cl2 Cu(OAc)2
CH2Cl2 CuI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
0
0
2
3
4
12
13
14
55
10
47
25
41
83
60
55
75
90
75
80
67
84
2b, 90% (8 h)
2c, 84% (9 h)
2l, 66% (15 h)
2m, 90% (10 h)
9
10
11
12
13
14
15
16
17
18
19
20
–
–
–
G
–
–
–
–
–
MS[c]
CaCl2
K2CO3
MS
MS
2d, 66% (10 h)
2e, 86% (9 h)
2n, 86% (8 h)
5
6
15
16
70
2o,[e] 67% (15 h)
[a] Reaction conditions: 1a (0.5 mmol), oxidant (0.75 mmol), catalyst
(10 mol%), additive (1 mmol), solvent (3.0 mL) at rt for 10 h. [b] The
yield was obtained by using GC analysis with n-dodecane as the internal
standard. [c] 5 ꢀ molecular sieves.
2 f, 90% (9 h)
2p, 75% (8 h)
7
17
18
19
the reactions of 2-arylthiazolines with DDQ (Table 2, en-
tries 2–10). To our delight, 2-arylthiazolines with Me, Cl,
and even sensitive Br, CN, NO2 substituents were tolerated
under the reaction conditions, and afforded the products in
moderate to excellent yields (Table 2, entries 2–8). For ex-
ample, even in the presence of the electron-withdrawing
group CN in 1 f and 1g, 2-thiazoles 2 f and 2g were formed
in 90 and 85% yields, respectively. However, 2-thiazole 2h
was only obtained in low yield under the standard condi-
tions (Table 2, entry 8). This issue was resolved by using CuI
as the catalyst under reflux conditions. It is noteworthy that
the bis-thiazoline compounds smoothly afforded the desired
products in good yields (Table 2, entries 9 and 10). Notably,
the oxidation reactions of heteroaromatic thiazolines per-
formed significantly well to afford the products in good
yields (Table 2, entries 11–13). The reactions of benzyl thia-
zolines with DDQ were also investigated under the opti-
mized conditions. Interestingly, we found that benzoyl thia-
zoline compounds were afforded as the major products
under the standard reaction conditions (Table 2, entries 14,
16, and 18).[15] To obtain the thiazole products, the reaction
conditions were further optimized by varying the catalyst
and reaction temperature (Table 2, entries 15, 17, and 19).
At the same time, 2-oxazolines were also tested as the
substrates to extend the scope and generality of the oxida-
tion procedure (Table 3). The reactions of 2-aryloxazolines
with DDQ showed high functional group tolerance and af-
forded the corresponding 2-oxazoles with great efficiency
(Table 3, entries 2–9). The reaction result of 2-oxazole 4g
2g, 82% (10 h)
2q,[e] 50% (15 h)
2r, 78% (8 h)
8
2h,[c] 30% (80%) (15 h)
9
2i,[d] 83% (15 h)
2j,[d] 70% (15 h)
2s,[e] 45% (15 h)
10
[a] Reaction conditions: 2-thiazolines 1 (0.5 mmol), DDQ (0.75 mmol),
5 ꢀ MS (125 mg), CH2Cl2 (3.0 mL), rt. [b] Yield of isolated product.
[c] CuI (10 mol%), at reflux. [d] Bis-thiazoline/DDQ=1:2. [e] Benzyl
thiazolines/DDQ=1:2, CuI (10 mol%), at reflux.
was similar to 2-thiazole 2h, and CuI as the catalyst and
reflux conditions were necessary to accelerate the transfor-
mation. For heteroaromatic oxazolines, an oxazoline with
a thienyl moiety could undergo the desired reaction to give
the corresponding 2-oxazole 4j in good yield (Table 3,
entry 10). Surprisingly, oxazolines (3k, 3l) possessing a pyrid-
yl group only gave the products in trace amounts (Table 3,
entries 11 and 12).
A plausible mechanism for the reaction is proposed in
Scheme 2. DDQ either attacks the hydrogen atom at the
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Jianli Li et al.
Table 3. DDQ-induced dehydrogenation for the synthesis of 2-oxazole-
s.[a,b]
path a tended towards 2-oxazolines (for detailed analysis,
see the Supporting Information).
In conclusion, the oxidation of 2-thiazolines and 2-oxazo-
lines without substituents at the C4 and C5 position of the
five-membered heterocyclic ring for the synthesis of 2-thia-
zoles and 2-oxazoles was achieved with DDQ as the oxidant.
This practical method has several advantages: (1) In contrast
to methods under harsh reaction conditions, this process is
simple, and proceeds at room temperature; (2) metals are
not required for the reaction; and (3) this procedure shows
good functional group tolerance. Furthermore, the present
method also provides a convenient and practical strategy for
the synthesis of heteroaryl compounds.
Entry
1
2-oxazole 4
Entry
7
2-oxazole 4
4a, 85% (10 h)
4b, 92% (10 h)
4g,[c] 23%
ACTHNGUTERNNU(G 50%) (15 h)
2
3
8
9
4h,[d] 80% (12 h)
4i,[d] 74% (12 h)
4c, 87% (11 h)
Experimental Section
General Experimental Procedure
4
5
10
11
5 ꢀ MS (250 mgmmolÀ1, 125 mg) were added to a solution of 2-thiazoline
or 2-oxazoline (0.5 mmol) in CH2Cl2 (3.0 mL) at room temperature.
After 10 min, DDQ (5ꢂ34 mg portionwise, 0.75 mmol, 1.5 equiv) was
added to the reaction mixture, and it was stirred at room temperature for
the appropriate time. After completion of the reaction (as detected by
TLC), the reaction mixture was quenched with 10% NaOH (15.0 mL),
the mixture was extracted with CH2Cl2 (3ꢂ3.0 mL). The separated organ-
ic layer was dried over Na2SO4, concentrated under reduced pressure,
and then the residue was purified by silica-gel chromatography to pro-
vide the desired product.
4d, 88% (11 h)
4e, 85% (13 h)
4j, 90% (10 h)
4k, trace (20 h)
6
12
4 f, 80% (14 h)
4l, trace (20 h)
[a] Reaction conditions: 2-oxazolines 3 (0.5 mmol), DDQ (0.75 mmol),
5 ꢀ MS (125 mg), CH2Cl2 (3.0 mL), rt. [b] Yield of isolated product.
[c] CuI (10 mol%), at reflux. [d] Bis-oxazoline/DDQ=1:2.
Acknowledgements
C4 position on substrate 1 to form transition state A
(path a), or attacks the hydrogen atom at the C5 position to
generate transition state C (path b). Next, a single electron
transfer and hydrogen-atom abstraction on A or C generates
intermediate B or D, respectively.[13a,b,14a] Subsequently, hy-
drogen-atom migration on B or D forms target product T
and DDQ-H2. To obtain a better understanding on the reac-
tion mechanism, natural population analysis was performed
to determine the possibility of path a and path b.[16] We
found that path b had a tendency towards 2-thiazolines, and
The work was supported by National Natural Science Foundation of
China (No. 20972124; 21272184), Shaanxi Science and Technology Coor-
dination Innovation Engineering project (No. 2011K12-77), the Special
Science Research Foundation of Education Committee in Shaanxi Prov-
ince (No. 12JK0584), and the Shaanxi Provincial Natural Science Fund
Project (No. 2012JQ2007).
Keywords: aromatization · dehydrogenation · heterocycles ·
oxidation · synthetic methods
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Received: February 28, 2013
Revised: March 18, 2013
Published online: && &&, 0000
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Chem. Asian J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

COMMUNICATION
Strong as an Ox: 2-Thiazoles and 2-
oxazoles are formed by oxidation of 2-
thiazolines and 2-oxazolines without
requiring substituents at the C4 and
C5 positions. DDQ plays an important
role as the oxidant in this transforma-
tion and metal is unnecessary. This
general procedure shows good func-
tional group tolerance and provides
a wide variety of 2-thiazoles and 2-oxa-
zoles in moderate to excellent yields.
Heterocycles
Xiangnan Li, Cheng Li, Bing Yin,
Cong Li, Ping Liu, Jianli Li,*
Zhen Shi
&&&& — &&&&
DDQ-Induced Dehydrogenation of
Heterocycles for C C Double Bond
Formation: Synthesis of 2-Thiazoles
and 2-Oxazoles
À
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Chem. Asian J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ