First reported propylphosphonic anhydride (T3P) mediated Robinson–Gabriel cyclization. Synthesis of natural and unnatural 5-(3-indolyl)oxazoles

Article abstract of DOI:10.1016/j.tetlet.2019.04.024

In the present work, a propylphosphonic anhydride (T3P) assisted Robinson–Gabriel cyclization of N-acyl-β-oxotryptamines for the synthesis of 2-substituted-5-(3-indolyl)oxazoles has been developed. The reactions proceeded smoothly in acetonitri

Full text of DOI:10.1016/j.tetlet.2019.04.024

Accepted Manuscript
First reported propylphosphonic anhydride (T3P® ) mediated Robinson–Gabriel
cyclization. Synthesis of natural and unnatural 5-(3-indolyl)oxazoles
Tímea Szabó, András Dancsó, Péter Ábrányi-Balogh, Balázs Volk, Mátyás
Milen
PII:
S0040-4039(19)30359-4
https://doi.org/10.1016/j.tetlet.2019.04.024
TETL 50739
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 February 2019
9 April 2019
12 April 2019
Please cite this article as: Szabó, T., Dancsó, A., Ábrányi-Balogh, P., Volk, B., Milen, M., First reported
propylphosphonic anhydride (T3P ® ) mediated Robinson–Gabriel cyclization. Synthesis of natural and unnatural
5-(3-indolyl)oxazoles, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.024
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Graphical abstract
First reported propylphosphonic anhydride (T3P®) mediated Robinson–
Gabriel cyclization. Synthesis of natural and unnatural 5-(3-
indolyl)oxazoles
Tímea Szabóa, András Dancsóa, Péter Ábrányi-Baloghb, Balázs Volka, Mátyás Milena,*
a Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, P. O. Box 100, H-
1475 Budapest, Hungary
b Hungarian Academy of Sciences, Research Centre for Natural Sciences, Medicinal
Chemistry Research Group, P.O. Box 286, H-1519 Budapest, Hungary
*To whom correspondence should be addressed. Phone: +36 1 8035874, e-mail:
milen.matyas@egis.hu

Abstract
In the present work, a propylphosphonic anhydride (T3P®) assisted Robinson‒Gabriel
cyclization of N-acyl-β-oxotryptamines for the synthesis of 2-substituted-5-(3-
indolyl)oxazoles has been developed. The reactions proceeded smoothly in acetonitrile under
microwave irradiation, and the product isolation required only an extraction and subsequent
crystallization; no chromatography was necessary. The desired products were obtained in
good to excellent yields.
Keywords: nitrogen heterocycles, oxazoles, ring closure, T3P®
Introduction
The 1,3-oxazole ring is a privileged five-membered aromatic heterocycle.1,2 1,3-Oxazole
derivatives show a diverse range of biological and pharmaceutical activities,3 including
antimicrobial,4 antitubercular,5 antihyperglycemic,6 platelet aggregation inhibitor and
vasodilator,7 and antifungal effects.8 An important representative of this family is the
commercially available nonsteroidal anti-inflammatory drug oxaprozin (4,5-diphenyl-2-
oxazolepropionic acid).9,10 Moreover, oxazoles have also been utilized as fluorescent
dyes,11,12 intermediates in organic transformations,13 and in polymer science.14,15 Several
simple and complex oxazole alkaloids have been isolated from various natural sources, such
as plants of the families Gramineae and Rutaceae, marine invertebrates and
microorganisms.16,17 Pimprinine (1a, Fig. 1), a bacterial 5-(3-indolyl)oxazole derivative, was
first isolated from Streptomyces pimprina in 1960.18 Three years later, Joshi and co-workers
determined the correct structure of compound 1a by degradation and synthesis.19 Pimprinine
(1a) was also isolated and characterized from Streptoverticillium olivoreticuli bacteria along
with the two analogues, pimprinethine (1b) and pimprinaphine (1c).20 Pimprinethine (1b) was
also extracted from the culture filtrate of Streptomyces cinnamomeus.21 WS-30581 A and B
(1d and 1e) are antiplatelet agents isolated from the Streptoverticillium waksmanii.22 2-
Isobutyl-5-(3-indolyl)oxazole (1f) and 2-pentyl-5-(3-indolyl)oxazole (1g), designated as
labradorins 1 and 2, respectively, were isolated from Pseudomonas syringae bacteria.23 In
addition, a number of natural products containing the 5-(3-indolyl)oxazole motif have been
isolated or synthesized, and their structures have been elucidated in the recent decade.2,24‒26
2

Figure 1. Chemical structures of selected microbial 5-(3-indolyl)oxazole alkaloids.
Accordingly, numerous synthetic methods have been described in the literature for
construction of the 1,3-oxazole ring.1,2 Among these, the classical Robinson‒Gabriel
cyclodehydration of 2-acylaminoketones is one of the most important methods for the
synthesis of oxazoles (Scheme 1). In general, this ring closure reaction is conducted in the
presence of POCl3, P2O5, PCl5, SOCl2, anhydrous HF, Burgess reagent, trifluoroacetic
anhydride, Ph3P/I2/Et3N or Ph3P(O)/Tf2O.27,28 However, some of these reagents are corrosive,
toxic, hazardous, moisture sensitive, and are usually applied in a large excess (e.g. POCl3 in
29‒107 equiv.).23,26 There are also numerous examples for the synthesis of N-alkylated or N-
protected 5-(3-indolyl)oxazoles using solid-phase synthesis with Ph3P,29,30 or other reagents
such as PTSA,31 BF3•Et2O,30 gaseous HCl32 or tert-butylhydroperoxide/I2.33
Scheme 1. Robinson‒Gabriel oxazole synthesis.
As the next milestone of our continued interest in the synthetic applications of
propylphosphonic anhydride (T3P®),34‒37 we now report a T3P® mediated Robinson‒Gabriel
synthesis of 2-substituted-5-(3-indolyl)oxazoles (1). To the best of our knowledge, this is the
first T3P® assisted preparation of oxazoles from 2-acylaminoketones.
T3P® is a commonly used coupling agent and an efficient water scavenger exhibiting
several advantages including low allergic potential and low toxicity, good solubility in
various organic solvents and easy work-up procedures. Beyond peptide chemistry, the T3P®
reagent has been applied in functional group transformations, multicomponent reactions,
3

rearrangements, and the synthesis of heterocyclic compounds, pharmaceuticals and natural
products.38,39
Results and Discussion
The starting materials (2a‒z) and the majority of the intermediates (3a‒i,f,k,l,n,o,q) were
prepared as described in the literature via the oxidation of readily available Nb-
acyltryptamines (2) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a THF‒water
solvent mixture40 (Table 1). New acylamino-ketones (3j,m,p,r‒z) were prepared in an
analogous manner. Initially, the Robinson‒Gabriel cyclodehydration reaction of N-benzoyl-β-
oxotryptamine (3q) was studied in the presence of T3P®. Based on literature procedures
applying a large excess of POCl3,23,26 our first reaction involved heating compound 3q with
10 equiv. of T3P® in a microwave (MW) reactor at 100 °C in acetonitrile (MeCN), resulting
in the formation of 2-phenyl-5-(3-indolyl)oxazole (1q). The reaction was complete after 3 h,
and the desired product (1q) was isolated in 90% yield after simple work-up and subsequent
recrystallization (Table 1, entry 17). As a comparison, the conversion of the same reaction
under thermal heating at 100 °C in a sealed tube after 3 h was 81%, based on HPLC-MS, and
the reaction was completed after 8 h. Reducing the amount of T3P® and the temperature were
unfavourable in MW experiments, since 5 equiv. of T3P® led to a conversion of 67%, while
7.5 equiv. of the additive resulted in only 90% conversion after 3 h.
Further optimization studies were also performed. The T3P® promoted, MW assisted
reaction of 3q as a model compound was carried out in various solvents at various
temperatures. Nevertheless, MeCN and 100 °C remained the optimal choices. Addition of a
catalytic amount of the ionic liquid [bmim][Cl] did not increase the conversion. The results of
these experiments are presented in detail in the ESI (Tables S1–S3).
Next, the substrate scope of the T3P® promoted Robinson‒Gabriel synthesis of 2-
substituted-5-(3-indolyl)oxazoles (1) was studied under MW conditions, as summarized in
Table 1. Starting materials possessing n-alkyl or isoalkyl groups were converted into the
corresponding oxazoles in good to excellent yields (87‒100%) after 1 h at 100 °C (Entries 1,
2, 4‒11). Compounds containing more bulky arylalkyl, cyclopropyl and tert-butyl groups
required longer reaction times (Entries 3, 12‒14). Quantitative yields were obtained for CF3
and C2F5 electron withdrawing substrates. In these cases, at 100 °C the conversion was only
30% after 4 h; therefore, an elevated temperature (150 °C) was necessary (Entries 15, 16).
Good yields were also obtained for aromatic substrates. According to our observations,
4

electron withdrawing substituents on the benzene ring, including F, Cl, CF3 (Entries 18‒21),
reduced the reaction rate, while the electron donating OMe functional group promoted ring
closure (Entry 22). The substrate scope was also tested on the indole ring. The presence of an
electron donating MeO group at the C(5) position supported ring closure (Entry 23), while the
electron withdrawing chlorine atom (Entry 24) reduced the reaction rate. According to our
experience, the substrate effect only has an impact on the reaction rate without influencing the
yield.
5

Scheme 2. Synthesis of 2-substituted-5-(3-indolyl)oxazoles.
Table 1. Conditions and yields for the synthesis of compounds 3 and 1.
Entry
R
R’
Yield of 3 (%)
Yield of 1 (%)
T (°C) t (h)
1
Me (a)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
Cl
H
H
68
96
67
82
97
80
97
74
98
71
90
94
73
100
100
89
100
82
77
92
91
100
100
64
87
95
100
87
100
100
100
100
100
100
100
100
100
100
100
100
100
100
150
150
100
100
100
100
100
100
100
100
100
100
1
1
2
1
1
1
1
1
1
1
1
3
3
2
3
3
3
6
6
4
5
3
2
5
3
5
2
Et (b)
3
Bn (c)
99
4
Pr (d)
89
5
Bu (e)
100
98
6
i-Pr (f)
7
i-Bu (g)
100
100
96
8
pentyl (h)
hexyl (i)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
octyl (j)
100
100
100
94
CH3(CH2)13CH2 (k)
cyclopropyl (l)
t-Bu (m)
4-MeOC6H4CH2 (n)
CF3 (o)
100
100
100
90
CF3CF2 (p)
Ph (q)
2-FC6H4 (r)
3-ClC6H4 (s)
3-F3CC6H4 (t)
4-FC6H4 (u)
3-MeOC6H4 (v)
Ph (w)
94
79
98
100
100
100
91
Ph (x)
naphthalen-1-yl (y)
thiophen-2-yl (z)
100
93
6

As the result of our research, twenty-six 2-substituted-5-(3-indolyl)oxazoles (1a–z) have
been synthesized. Natural products pimprinine (1a), pimprinethine (1b), pimprinaphine (1c),
WS-30581 A (1d), WS-30581 B (1e), labradorins 1 and 2 (1g,h), 1i and unnatural compounds
1f,k,m,n,q were found to be identical with those described in the literature,20,41‒43 while
1j,l,o,p,r‒z are new derivatives. The structures of compounds 1a‒z and 3a‒z were elucidated
by HRMS, IR, 1H NMR and 13C NMR spectroscopy.
Although the exact mechanism of the T3P® assisted Robinson‒Gabriel oxazole synthesis
is currently unknown, a plausible reaction pathway is proposed based on the literature44 and
the experimental results discussed above (Scheme 3). In the first step, the carbonyl O-atom of
compound 3 is activated by the T3P® reagent to provide intermediate A. Intramolecular
nucleophilic attack of the amide O-atom to the activated carbonyl carbon atom generates B.
Elimination of a QOH molecule and subsequent deprotonation of the N-atom gives the target
oxazole product 1.
Scheme 3. Proposed mechanism for the T3P® assisted Robinson‒Gabriel oxazole synthesis.
Conclusion
In conclusion, an alternative protocol has been developed for the preparation of natural
and unnatural 2-substituted-5-(3-indolyl)oxazoles via the T3P® assisted Robinson‒Gabriel
cyclization of N-acyl-β-oxotryptamines. This method is convenient, no halogenated or
strongly acidic additives are used, and the reaction proceeds well with a large variety of
7

substrates. The work-up and purification is easy, no chromatography is necessary, and the
target molecules are obtained in good to excellent yields.
Supplementary data
Supplementary data (optimization of reaction conditions, experimental procedures and
spectral data) to this article can be found online at …
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Highlights
 T3P® was used in a Robinson–Gabriel synthesis
 Efficient synthesis of bacterial and unnatural 5-(3-indolyl)oxazoles
 Avoid the use of toxic and hazardous water scavengers
11