Dimerization of Phenylalanine: An Approach to Thiazoles and Oxazoles Involved S/O-Insertion

Article abstract of DOI:10.1002/adsc.201701130

We herein describe the development of a dimerization procedure for amino acids to prepare 2,5-disubstituted thiazoles and oxazoles in the presence of Na₂S?9H₂O and H₂O, respectively. These approaches enabled the direct formation of five-membered ring systems bearing two different heteroatoms from two amino acid units. Mechanically, decarboxylation, deamination, S/O insertion, cyclization and gradient oxidation processes were involved in the oligomer formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201701130

Title: Dimerization of Phenylalanine: An Approach to Thiazoles and
Oxazoles Involved S/O-Insertion
Authors: Yan Cheng, Jiachen Xiang, Zixuan Wang, Jintian Ma, Miao
Wang, Bocheng Tang, Yandong Wu, Zhu Yan-Ping, and
Anxin Wu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701130
Link to VoR: http://dx.doi.org/10.1002/adsc.201701130

Advanced Synthesis & Catalysis
10.1002/adsc.201701130
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Dimerization of Phenylalanine: An Approach to Thiazoles and
Oxazoles Involved S/O-Insertion
a
a
a
a
a
Yan Cheng, Jia-Chen Xiang, Zi-Xuan Wang, Jin-Tian Ma, Miao Wang, Bo-Cheng
a
a
,b
,a
Tang, Yan-Dong Wu, Yan-Ping Zhu* and An-Xin Wu*
a
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, Hubei, Wuhan 430079, P. R. China.
E-mail: chwuax@mail.ccnu.edu.cn
b
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education,
Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,
Yantai University, Shandong, Yantai 264005, P. R. China.
E-mail: chemzyp@foxmail.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We herein describe the development of a our group in 2012 proposed a CuO/I
2
promoted
dimerization procedure for amino acids to prepare 2,5- method for the synthesis of 2-aminothiazole using
[10]
disubstituted thiazoles and oxazoles in the presence of acetophenones and thioureas as raw materials
.
Na S·9H O and H O, respectively. These approaches Despite these achievements, several limitations and
2
2
2
enabled the direct formation of five-membered ring challenges remain for thiazole synthesis, such as the
systems bearing two different heteroatoms from two amino
use of transition metal catalysts, harsh reaction
acid units. Mechanically, decarboxylation, deamination,
conditions, and expensive or unavailable starting
S/O insertion, cyclization and gradient oxidation processes
materials. Thus, new strategies with lower cost, less
were involved in the oligomer formation.
waste, and milder conditions are highly desirable.
Keywords: Amino acid; Dimerization; Thiazole; Oxazole
Amino acids are pre-activated biosynthetic building
[1]
blocks used for the construction of alkaloids and
peptides.[ They have the advantages of being non-
toxic, cheap, and easily available, which fulfill many
of the requirements for components in modern
organic synthesis. In recent years, the application of
amino acids in organic conversions has been
2]
[
2b-d,3]
extensively investigated,
especially for synthetic
methodologies.[ In our continued efforts to activate
and convert amino acids to heterocyclic compounds,
we revealed the formal homo-dimerization of
phenylalanines to afford 2,5-disubstituted pyridines
biomimetically.[ More advanced oligomerization of
amino acids especially those bearing heteroatoms
4]
5]
(
sulfur or oxygen), via a ring closure process is our
next research target. The development of such a
hetero-oligomerization reaction will not only lead to
benign heterocyclic synthesis from biomass Figure 1. A brief introduction to the synthesis of
feedstocks,[ but also provide a better understanding heteroatom-containing rings from amino acids.
of C–S and C–O bond formation in the secondary
6]
metabolism of amino acids.[7]
Amino acids have long been recognized as
Thiazole is a heterocyclic compound that is widely precursors of heterocycles. For example, the thiazole
present in natural products, synthetic drugs, and moieties in patellamide B and C originate from
naturally occurring peptides.[2b-d,6a,8] In recent years, phenylalanine and cysteine. Thus, we attempted to
many different protocols have been reported for the determine whether a similar hetero-dimerized product
[11]
[9]
synthesis of thiazole and derivatives . For example, could be obtained using phenylalanine. Based on our
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701130
previously
optimized
reaction
conditions,[5]
9
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
S•9H
S•9H
S•9H
S•9H
S•9H
S•9H
S•9H
2
2
2
2
2
2
2
O (0.6)
O (0.8)
O (0.6)
O (0.6)
O (0.6)
O (0.6)
O (0.6)
1.5
1.5
1.0
2.0
1.0
1.0
1.0
TFA
TFA
TFA
TFA
TfOH
HOAc
Sulfanilic 62
Acid
67
62
71
49
69
80
phenylalanine[ and cysteine were initially reacted in 10
the presence of an oxidant, resulting in the formation 11
of an unexpected thiazole product in relatively low 12
yield (Figure 1). Indeed, this product is a dimerized 13
product of phenylalanine,[ where cysteine provided 14
the S–atom via C–S oxidative cleavage. This reaction 15
proceeded via a novel reaction mechanism, which
12]
13]
clearly differs from that of typical peptide formation.
Based on this promising initial result, we attempted
16
Na
2
S•9H
2
O (0.6)
1.0
TsOH
71
a)
Reaction conditions: 1a (1.0 mmol), S donor, acid (0.25
and DMSO (4.0 mL) were added to a pressure
to optimize the reaction conditions and S-donor mmol), I
candidates for this transformation to give the first vessel, then stirred at 100 °C for 8 h. Isolated yields.
2
b)
direct synthetic route to thiazole from two amino acid
molecules (see Table 1). In addition, we examined the
effect of replacing the S-donor with an O-donor and
found that an oxazole[
14]
product was obtained,
thereby illustrating the potential of this amino acid
dimerization procedure for producing various
heterocyclic compounds.
To examine the possibility of replacing cysteine,
we began our investigations by screening alternative
sulfur donors (Table 1). As indicated in the table the
use of cystine or glutathione (G-SH) as the sulfur
source gave the desired product 2a in poor yields
(
entries 2 and 3). In contrast, the reaction proceeded
smoothly in the presence of NaHS, Na S•9H O, Cu S,
and CuS giving the desired product 2a in yields of
0–62%, with the highest yield being obtained using
Na S•9H (entries 4–7). Subsequently, upon
2
2
2
2
2
2
O
increasing the amount of S-donor to 0.6 equivalent, an
increased yield of 2a was obtained (entry 9), but a
further increase to 0.8 equivalent was not beneficial
(
entry 10). We also found that decreasing the amount
of iodine from 1.5 to 1.0 equivalent improved product
yields, while an increased amount of equivalents had
the opposite effect (entries 11 and 12). Subsequently,
we examined the effect of replacing trifluoroacetic
acid (TFA) with both weak (HOAc) and strong
(
TfOH) organic acids (entries 13–16). After screening
a
range of parameters (see the Supporting
Information), the optimal yield of 2a was achieved
when the reaction was carried out in the presence of
Na
(
2
S·9H
2
O (0.6 equiv), I (1.0 equiv), and HOAc
2
0.25 equiv) at 100 °C (entry 14, 80%).
Table 1. Optimization of the reaction conditions for the
a
preparation of 2a .
Scheme 1. Scope of Substituted Thiazoles. Reaction
conditions: 1 (1.0 mmol), Na S•9H O (0.6 mmol), HOAc
0.25 mmol), I (1.0 mmol) and DMSO (4.0 mL) were
2
2
(
2
added in a pressure vessel, then stirred at 100 °C for 8 h.
Isolated yields.
2ab
(%)
S-donors
equiv)
I
2
entry
acid
(
(equiv)
We then examined the substrate scope for the
reaction based on variation in the structure of amino
acid 1 (see Scheme 1). Notably, reactions of fluoro-,
chloro-, and bromo-substituted phenylalanines
proceeded well and gave the desired thiazole
derivatives 2b-2f (which could be used in further
transformations) in 58-75% yields. The structure of 2e
was further confirmed by X-ray diffraction studies
1
2
3
4
5
6
7
8
Cysteine (0.5)
Cystine (0.25)
G-SH (0.5)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
11
14
Trace
58
62
20
42
Trace
NaHS (0.5)
Na
Cu
2
S•9H
S (0.5)
2
O (0.5)
2
CuS (0.5)
(0.5)
[15]
S
8
(see the Supporting Information).
However, the
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701130
reaction was found to be somewhat sensitive to the substituents on the substrate phenyl rings produced
electronic contribution of the substituents on the good reactivity (3e–3g). We also found that the
phenylalanine aromatic ring, with only electron- optimal reaction conditions were applicable to
donating and electron-neutral substituents providing substrates bearing a p-NH substituent, giving the
2
the desired thiazoles in good yields (2g–2j). iodinated product 3h in 41% yield. Furthermore, the
Substrates bearing the sensitive hydroxyl functional sterically bulky 1- and 2-naphthylalanine substrates
group at the p- or m-positions also provided the provided the desired oxazoles (3j and 3k) in excellent
desired products 2k and 2l in good yields. Extension yields.
of this reaction to sterically hindered substrates was
also successful where the phenyl ring was replaced by
a naphthalene moiety (2m and 2n). When cyclopropyl,
cyclopentyl and cyclohexyl groups attached amino
acids were used in this reaction, they would give the
products 2o-2q in 37-43% yields, in which the
methylene group was not oxidized to carbonyl group.
Moreover，many other aliphatic amino acids, such as
Leu, Ile, Ala and Cys were also investigated using our
methodology, but no desired products were observed.
Scheme 3. Control Experiments.
To gain additional insight into the reaction
mechanism, several control experiments were
conducted (Scheme 3). At the outset of this study, we
suspected that oxazole was not stable under acidic
Scheme 2. Scope of Substituted Oxazoles. Reaction
conditions: 1 (1.0 mmol), TFA (0.25 mmol), I (1.5 mmol)
[17]
conditions, and formed the thiazole when reacted
with Na S·9H O. However, phenyl(5-phenyloxazol-2-
2
2
2
and DMSO (4.0 mL) were added in a pressure vessel, then
yl)methanone 3a could not transfer to 2a under acidic
conditions or the standard conditions (eq a and b).
Upon repeating the reaction of 1a at 40 °C to
determine the effect of temperature, β-hydrogenated
products 4a and 5a were obtained, while at 80 °C, β-
o
stirred at 120 C for 8 h. Isolated yields.
It is notable that the O-donor H O is present in the
2
reaction mixture, and can participate in the reaction to
yield the corresponding oxazole product. Thus, in the
absence of Na S·9H
O, we attempted to find hydroxylated products 6a and 7a were produced,
favorable conditions for oxazole formation, and albeit in low yields (eq c and d). Based on these
2
2
finally obtained an 85% yield of product 3a (see the
Supporting Information). Subsequently, we extended
our study to oxazole derivatives bearing different
functionalities. As summarized in Scheme 2, this
reaction was compatible with substrates bearing
halogen atoms (i.e., F and Cl) to yield synthetically
useful oxazole products (3b–3d). The structure of 3b
was further confirmed by X-ray crystallographic
results, we speculated that the oxidation reaction is
controlled by temperature; therefore, we expected that
these four products (4a–7a) were key intermediates in
the overall process. When 4a or 6a was heated to
100 °C, it underwent an oxidation process to give
product 3a in 92% or 95% yields after 24 h (eq e). 5a
and 7a underwent similar reactions to yield 3a (see
the Supporting Information). These results indicate
[16]
analysis (see the Supporting Information). It should
also be noted that the presence of electron-donating that the methylene group is oxidized in a stepwise
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701130
manner to form the carbonyl moiety. We also (Scheme 5).[20] The end product 2d could be further
explored the scope for the β-hydrogenated product functionalized to two phenylethynyl contained
(
see the Supporting Information). In addition, it was conjugate product 8a in 78% yield via the
confirmed that the sulfur atom of the thiazole ring Sonogashira coupling with phenylacetylene. It is
originates from Na S·9H O. Thus, we tried to notable that the two free hydroxyl groups contained
2
2
determine the oxygen source for oxazole ring product 2k could be derivatived to glucuronated
formation. Use of a solvent other than DMSO led to product 8b in 74% yield from easily available starting
low product yield (eq f). Thus, the reaction of 1a was materials.
1
8
performed in the presence of O-labeled H
2
O (eq g)
-3a along with
the O-3a and O-exchanged products 3a in a disubstituted thiazoles and oxazoles via the
1
8
18
to yield the
O
2
-labeled product
O
2
In summary, we report the direct formation of 2,5-
1
8
1
:1.8:0.2 ratio, as determined by high-resolution mass dimerization of amino acids. These reactions were
18
spectrometry. Therefore, the above
O-labeling carried out in the presence of Na
2
S·9H
2
O and H O,
2
18
experiment suggests that H
O participated in this which act as heteroatom donors via the S/O-insertion
2
intermolecular cyclization process to provide the reaction. The new method shows a broad substrate
oxygen atom in the oxazole ring, with the O-isotope scope and has good yields. This demonstrated utility
exchanged products likely originating from an of amino acids to synthesize diverse heterocycles
exchange with unlabeled H
O. At the same time, the from such transformations is of key importance for
2
isotope labeling experiments for the intermediates developing an improved understanding of amino acid
demonstrate that the oxygen for the carbonyl is also chemistry and biomass-related conversions.
derived from water (eq h). In addition, two additional
control experiments were conducted to confirm the
role of iodine in the final oxidization step. Substrate
7a performed the reaction in DMSO at 120°C for 24
hours, and no desired oxidized product 3a was
observed (eq i). Moreover, the reaction proceeded
with 1.0 equivalent of iodine in DMF at 120°C for 24
hours could provide the oxidized product 3a in 88%
yield (eq j). These results further testified that the
final oxidation step from 7a to 3a is promoted by
iodine.
A plausible mechanism for this stepwise oxidation
process was proposed based on the above results and
[5]
previous literature reports (Scheme 4). As indicated,
-promoted decarboxylation and oxidation of 1a
I
2
initially proceeded to give A, which was subsequently
hydrolyzed and condensed with a further molecule of
1
a to form imine D. The resulting tautomer E
produced iodide F in the presence of I . Nucleophilic
attack by Na S·9H O or H O on the iodomethylene
Scheme 4. Proposed Mechanism.
2
2
2
2
moiety of intermediate F then produced intermediate
G, which underwent decarboxylation and annulation
to furnish the desired five-membered heterocyclic
compound H.[ Intermediate 4a or 5a (X = S or O,
respectively) was then generated following iodination
and release of HI. Further iodination and attack by
18]
H O produced 6a or 7a (X = S or O, respectively),
2
which was rapidly oxidized by iodine to afford the
target product 2a or 3a. During the reaction process,
sideproduct HI could be oxidized by DMSO to
regenerate iodine, which would be recycle used in this
reaction.[
Scheme 5. Synthetic Applications
Experimental Section
19]
2 2
A mixture of phenylalanine 1a (1.0 mmol), Na S•9H O
To illustrate the synthetic utility and demonstrate
(
2
0.6 mmol), HOAc (25 mmol%), I (1.0 mmol) and DMSO
the broad application prospect of the reaction, further (4.0 mL) were added to a pressure vessel, then stirred at
transformations of given products were investigated 100 °C for 8 h. Then, 50 mL water and 30 mL saturated
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701130
brine solution were added and the mixture was extracted
with EtOAc 3 times (3 × 50 mL). The extract was washed
with 10% Na S O solution, dried over anhydrous Na SO
2 2 3 2 4
and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent:
petroleum ether / EtOAc = 8/1) to afford the product 2a as
a yellow solid.
Hong, T.-J. Li, H. Park, J.-Q. Yu, Science. 2016, 351,
252-256; j) G. Chen, T. Shigenari, P. Jain, Z.-P. Zhang,
Z. Jin, J. He, S.-H. Li, C. Mapelli, M. M. Miller, M. A.
Poss, P. M. Scola, K.-S. Yeung, J.-Q. Yu, J. Am. Chem.
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Acknowledgements
[5] J.-C. Xiang, M. Wang, Y. Cheng, A.-X. Wu, Org. Lett.
2
016, 18, 24-27.
This work was supported by the National Natural Science
Foundation of China (Grants 21472056, 21602070 and
[
[
6] a) R. A. Hughes, C. J. Moody, Angew. Chem. Int. Ed.
2007, 46, 7930-7954; b) C. T. Walsh, R. V. O’Brien, C.
Khosla, Angew. Chem. Int. Ed. 2013, 52, 7098-7124.
2
1702091). We thank Dr. Chuanqi Zhou, Hebei University, for
analytical support. This work was supported by “The
Fundamental Research Funds for the Central Universities”
(CCNU15ZX002 and CCNU16A05002). This work was also
7] a) K. L. Dunbar, D. H. Scharf, A. Litomska, C.
Hertweck, Chem. Rev. 2017, 117, 5521-5577; b) W. J.
K. Crone, N. M. Vior, J. Santos-Aberturas, L. G.
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supported by the 111 Project B17019. We acknowledge an
excellent graduate education innovation grant from Central
China Normal University (2016CXZZ68).
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1
[
[
[
15]CCDC 1555486 contains the supplementary
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Advanced Synthesis & Catalysis
10.1002/adsc.201701130
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Dimerization of Phenylalanine: An Approach to
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