Synthesis of 4-benzylidene-oxazol-5(4H)-imines, structural analogs of PK11195, under Bischler-Napieralski conditions

Article abstract of DOI:10.1016/j.tetlet.2017.01.047

A simple and convenient one-pot procedure to prepare 4-benzylidene-2-aryl-1,3-oxazol-5(4H)-imines from phenyl pyruvic acid and a series of arylamides, under classical Bischler-Napieralski (B-N) conditions and microwave heating (MW) has been developed. The

Full text of DOI:10.1016/j.tetlet.2017.01.047

Accepted Manuscript
Synthesis of 4-benzylidene-oxazol-5(4H)-imines, structural analogs of
PK11195, under Bischler-Napieralski conditions
Marco A. Almaraz-Girón, Alfredo Vázquez
PII:
S0040-4039(17)30069-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.047
TETL 48550
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 November 2016
12 January 2017
13 January 2017
Please cite this article as: Almaraz-Girón, M.A., Vázquez, A., Synthesis of 4-benzylidene-oxazol-5(4H)-imines,
structural analogs of PK11195, under Bischler-Napieralski conditions, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.01.047
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis of 4-benzylidene-oxazol-5(4H)-
imines, structural analogs of PK11195, under
Bischler-Napieralski conditions
Leave this area blank for abstract info.
Marco A. Almaraz-Girón and Alfredo Vázquez*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of 4-benzylidene-oxazol-5(4H)-imines, structural analogs of PK11195,
under Bischler-Napieralski conditions
Marco A. Almaraz-Girón and Alfredo Vázquez∗
Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, México D. F., México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and convenient one-pot procedure to prepare 4-benzylidene-2-aryl-1,3-oxazol-5(4H)-
imines from phenyl pyruvic acid and a series of arylamides, under classical Bischler-Napieralski
(B-N) conditions and microwave heating (MW) has been developed. The structures of the
prepared compounds were unambiguously assigned through single crystal X-ray diffraction
studies. The compounds thus prepared can be used to synthesize bioactive compounds with
different molecular architectures.
Available online
Keywords:
2016 Elsevier Ltd. All rights reserved.
4-Benzylidene-oxazol-5(4H)imines
Bischler-Napieralski reaction
α,β-Unsaturated acid derivatives
Oxazolones
PK11195
1. Introduction
isoquinoline moiety via a B-N reaction. Furthermore, under the
reaction conditions we expected the formation of the
PK-11195 (1, Figure 1) is a non-benzodiazepine peripheral
benzodiazepine receptor (PBR) antagonist comprised of an
isoquinoline ring with an appended aromatic group at C-1 and a
carboxamide functionality at C-3. Several methods have been
devised to construct this molecule1 relying on the preparation of
the parent acid PK11209 (2), and from there the amide is formed
via the corresponding acid chloride.
corresponding acid chloride (4), which after quenching the
reaction with N-methyl sec-butyl amine (5) or sec-butyl amine–
followed by methylation–would afford PK11195 (Scheme 1). To
our surprise, when sec-butyl amine was used to quench the
reaction mixture, 4-benzylidene-oxazol-5(4H)-imine (3a, Figure
1) was isolated in a reproducible manner.
Figure 1. Structures of PK11195 (1), PK11209 (2) and 4-
benzylidene-oxazol-5(4H)-imine (3a).
Scheme 1. Original synthetic strategy for PK11195 (1).
During our research aimed to prepare some analogs of
PK11195, we decided to investigate an alternative procedure to
obtain this compound in a simple manner. In 2001, Chen2
reported the formation of 3,4-dihydroisoquinoline derivatives
using N-acetyl phenylalanine methyl ester analogs under classical
Bischler-Napieralski3 (B-N) conditions (POCl3, benzene, reflux).
With this precedent, we devised a strategy consisting of the
condensation between pyruvic acid (7) and 2-chlorobenzamide
(8a) catalyzed by pTsOH to provide the dehydroaminoacid 6.
Despite the apparent simplicity of the structure of (Z)-4-
benzylidene-oxazol-5(4H)-imines, reported procedures for their
preparation are scarce, compared with those for their
constitutional isomers (Z)-4-benzylidene-1H-imidazol-5(4H)-
ones4-6 or the structurally related (Z)-4-benzylidene-oxazol-
5(4H)-ones. It is worth to mention that the close structural
relation between the above compounds hampers an unambiguous
characterization, particularly with incomplete spectroscopic
information.
T—re—atm—ent of 6 with POCl would allow the construction of the
3
∗ Corresponding author. Tel.: +52 55 56223801; fax: +52 55 56223722; e-mail: joseavm@unam.mx

2
Tetrahedron
Only a few publications in the literature report the synthesis
completed (TLC), the addition of 2 equiv of secBuNH2 and Et3N
(4 equiv) afforded 10a in 95% yield if 1 equiv of pTsOH is used,
and 65% yield with 0.2 equiv. The scope of this procedure was
explored using the amides and nucleophiles shown in Table 1.
According to the results, when aromatic amides (including furyl
amide) are used, the isolated yields of the corresponding products
of 4-benzylidene-oxazol-5(4H)imines. In 1972, Boyd7 reported
the reaction of unsaturated azlactones with amines to provide the
corresponding amides, which upon treatment with acetic acid and
perchloric acid gave a high yield of the benzylidene N-
monosubstituted iminium perchlorates derivatives. Treatment of
the latter compounds with cold aqueous sodium carbonate
provided the free base. Sun et al.8 reported the synthesis of 4-
benzylidene-oxazol-5(4H)imines through the condensation of
benzamidoacetonitriles with aldehydes under acidic conditions.
However, ring opening of azlactones with NH3 in EtOH,
followed by catalytic hydrogenation, provided the corresponding
amide without imine formation. Rudrapal9 reported the
condensation of oxazolones with phenylhydrazine in
EtOH/H2SO4 under reflux conditions, to afford 4-benzylidene-2-
methyloxazol-5(4H)-ylidene)-2-phenylhydrazones. Hydrazones
containing an azomethine group (–NHN=CH–) represent a major
class of compounds which possess a broad range of biological
activities.9,10 On the other hand, Esmaeili reported11 that heating
a mixture of Z-α-benzoyl amino-acrylic acid alkyl esters and
cyclohexyl isonitrile under solvent-free conditions, produced 5-
imino oxazolines in a diastereoselective manner. The structure
and stereochemistry of the imino oxazolines were unambiguously
established from X-ray studies.
are
from
modest
to
excellent.
However,
when
cyclohexanecarboxamide was used, the corresponding product
was obtained in low yield.
Table 1. Condensation between phenyl pyruvic acid and primary
amides to produce α,β-unsaturated amino acid derivatives.
1) pTsOH, toluene,
MW, reflux, 1h
O
O
R2
NH2 2)
NEt3/
5 a-f
/ CH2Cl2
O
+
OH
R1
HN
O
O
R1
7
8 a-g
10 a-o 6
,
O
O
O
N
H
N
N
H
H
HN
HN
HN
O
O
O
Cl
(95%)
10a
10b
(84%)
10c
(66%)
OCH3
O
O
O
N
H
N
N
H
4-benzylidene-oxazol-5(4H)-imines are interesting synthetic
compounds that can be used to prepare structurally related
derivatives with a variety of potential applications in several
disciplines.7-9,11,12 Herein, we would like to disclose our findings
on the synthesis of 4-benzylidene-oxazol-5(4H)-imines, along
with X-ray diffraction analysis that supports the structural
assignment and a mechanistic proposal that explains their
formation.
H
HN
HN
HN
O
O
O
F
I
Cl
(51%)
10d (83%)
10e
10f
(72%)
O
O
O
O
N
H
N
H
N
H
HN
HN
HN
O
O
O
O
CF3
10g (62%)
10h (26%)
10i (21%)
2. Results and discussion
O
O
A key step in the devised strategy was the condensation between
the keto group of phenyl pyruvic acid and a primary amide. Thus,
in our initial experiments when a mixture of 1.5 equiv of pyruvic
acid (7), 1 equiv of 2-chlorobenzamide (8a) and 1 equiv of
pTsOH was refluxed in toluene under microwave heating (150
W) using a Dean–Stark trap for 1 h, (Z)-4-benzylidene-oxazol-
5(4H)-one 9 was obtained in 85% yield after cooling the reaction
mixture to ambient temperature. However, when a mixture of 1.5
equiv of phenyl pyruvic acid (7), 1 equiv of 2-chlorobenzamide
(8a) and 0.2 equiv of pTsOH was refluxed (Dean–Stark trap,
MW, 150 W) for only 30 min, dehydroamino acid 6 was obtained
in 95% yield. Presumably, exposing 6 to the reaction conditions
for longer reaction times favors the cyclodehydration reaction
producing oxazolone 9. The formation of 9 can be advantageous
since it can be ring-opened with different nucleophiles as
illustrated in Scheme 2.13 For instance, reaction of 9 with sec-
butylamine, MeOH and H3O+ afforded the corresponding amide
10a, ester14 10k and acid 6 respectively.
N
H
CF3
OCH3
OCH3
HN
HN
HN
O
O
O
Cl
Cl
10j
10k
10l
(70%)
(5%)
(65%)
O
O
O
OCH3
OCH3
OCH3
HN
HN
HN
O
O
O
F
O
10o (4%)
10m
10n
(38%)
(21%)
O
OH
HN
Cl
O
6
(95%)
With amide 10a in hand, we conducted experiments to obtain
isoquinoline 1, according to our original strategy, under B-N
conditions. In this manner, when a mixture of 10a and 5 equiv of
POCl3 in toluene was refluxed for 20 min (MW heating, 90 W),
4-benzylidene-oxazol-5(4H)-imine 3a was obtained in 84%
yield. Although we anticipated the formation of imidazolone15 11
(Scheme 3A) we were only able to isolate compound 3. The
possible outcomes for this reaction are depicted in Scheme 3A,
along with a mechanistic proposal that explains the formation of
3. Two pathways to convert 10 into 4-benzylidene-oxazol-
5(4H)imine 3 can be envisioned. Dehydration of the aliphatic
amide in 10 would produce intermediate 12 which undergoes a
favored 5-exo-dig cyclization process16 (Scheme 3B, path A).
Likewise, dehydration of the aromatic amide present in 10,
Scheme 2. Condensation between phenyl pyruvic acid (7) and 2-
chlorobenzamide (8a).
The above procedure can be modified to get amide 10 in a
one-pot fashion. After the formation of oxazolone 9 was

3
produces intermediate 1317 which after a favored 5-endo-dig
product in a one-pot fashion. However, we experienced some
cyclization process affords 4-arylidenoxazolimine 3 (Scheme 3B,
reproducibility problems depending on the aging time of POCl3.
In some experiments, the oxazolone was observed along with the
oxazolimine–small amounts of HCl favor the formation of the
oxazolone–and in other cases, several side products accompanied
the formation of oxazolimine (presumably Von Brown and retro-
Ritter products). Nevertheless, when T3P® was used, we
observed a cleaner reaction, albeit in low yield.
path B).
O
isoquinoline
NHR
N
Ar
1, expected
O
O
4-aryliden-
Formation of oxazolimines 3a-e,h was accomplished using the
procedure previously described starting from compounds 10a-e,
h. The results are summarized in Table 2. Treating 10a with
POCl3 (5 equiv) in toluene for 20 min (MW, reflux) afforded 3a
in 84% yield. When the same transformation was performed
using T3P® (10 equiv) and 90 min of microwave heating, 3a was
obtained in 39% yield. The use of 15 equiv of T3P®, or the use of
conventional heating had no significant effect on the reaction
yield. Good results were obtained for 3b-e with yields from 43 to
80%. Under the same conditions, 3h was obtained in 33% yield.
Ph
imidazolone
POCl3
Ph
NHR
O
A)
NHR
HN
N
Ar
Ar
10
11, expected
NR
4-aryliden-
oxazolimine
Ph
O
N
Ar
3, unexpected
R
N
path A
Ph
HN
O
O
NR
O
Ph
Ar
POCl3
Ph
NHR
O
B)
12
N
HN
NHR
O
3a
Ar
Ar
10
Ph
3
path B
N
R
13
Scheme 3. A) Possible outcomes for the reaction between 10 and
POCl3. B) Mechanistic proposal that explains the formation of 3.
Table 2. Reaction of 10 with POCl3 to afford 3 and 9.
O
R2
POCl3, toluene,
MW, reflux, 20 min
R2
O
HN
O
N
R1
R1
10 a-e,h,k,
3 a-e,h; 9
3d
N
N
O
N
O
O
N
N
N
Cl
3c
(67%)
3a
3b
(84%)
(80%)
OCH3
N
N
N
O
O
O
N
N
N
F
I
3e
O
3d
3e
(63%)
(43%)
3h
(33%)
O
O
N
Cl
9
(95%)
Besides POCl3, different dehydrating reagents (DR’s) were
examined for the one-pot synthesis of 3a, namely: Eaton’s
reagent,18 P2O5/POCl3 mixtures19 and propylphosphonic
anhydride solution (T3P®).20 However, the best conditions were
the use of POCl3 as DR under microwave irradiation, with a
considerable decrease in reaction time, and a reaction yield of
55% for 3a (with T3P® 3a was obtained in 14% yield). The use
of POCl3 as dehydrating agent allows the preparation of desired
Figure 2. ORTEP diagram for the structure of compounds 3a,
3d and 3e derived from SXRD. Thermal ellipsoids are drawn at
50% probability.

4
Tetrahedron
When the methyl ester 10k was subjected to the same
the prepared compounds can find some applications in solid-state
organic electronics.
reaction conditions, oxazolone 9 was obtained in 95% yield
(Table 2). A similar result was obtained for the reaction between
10k and T3P®, affording 9 in 81% yield, which is a structural
isomer of 4-(3-chlorobenzylidene)-2-phenyl-1,3-oxazol-5(4H)-
one, a compound with reported antimicrobial activity.21
Acknowledgments
We would like to thank DGAPA-UNAM for financial support
(Grant IN212513), M. A. Almaraz-Girón thanks CONACYT for
scholarship (Grant 217555/208278), Simón Hernández-Ortega
for X-Ray structure elucidation, Margarita Guzmán Villanueva
and R. C. Cañas-Alonso for HRMS data and Marisela Gutierrez
Franco for IR spectra.
Discriminating between the structures of oxazolimines and
imidazolones proved to be spectroscopically challenging, as can
also be intuited from literature reports on the synthesis of this
kind of compounds. Fortunately, we were able to obtain crystals,
and the structure of 4-benzylidene-oxazol-5(4H)-imine was
unequivocally assigned through single-crystal X-ray diffraction
studies.
References
1. Stevenson, L.; Pimlott, S. L.; Sutherland, A. Tetrahedron Letters
2007, 48, 7137–7139.
2. Liu, Z. Z.; Tang, Y. F.; Chen, S. Z. Chines. Chem. Lett. 2001, 12,
947–950.
Single crystals suitable for X-ray diffraction (SXRD) were
obtained for compounds 3a, 3d and 3e and solved in the P 21/C,
P 21/C and P-1 space groups, respectively. Crystals were
obtained from DMSO solutions in a NMR tube (a drop of water
was added) of the corresponding products in solvent-free
packing. Sec-butyl groups were disordered, and were refined and
modeled in two contributions using variable site occupational
factor, SOF, with a 0.75/0.25 ratio. All compounds feature the
oxazol-imine moiety, as can be appreciated in the crystal
structures in Figure 2.
3. Whaley, W. M.; Govindachari, T. R. In Organic Reactions; John
Wiley & Sons, Inc., 2012.
4. Gong, X.; Yang, H.; Liu, H.; Jiang, Y.; Zhao, Y.; Fu, H. Org. Lett.
2010, 12, 3128–3131.
5. Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Comb. Chem. 2001, 3,
521–523.
6. Gabillet, S.; Loreau, O.; Specklin, S.; Rasalofonjatovo, E.; Taran,
F. J. Org. Chem. 2014, 79, 9894–9898.
7. Boyd, G. V.; Wright, P. H. J. Chem. Soc., Perkin Trans. 1 1972,
Interestingly, the π-conjugated system in 3d presents periodic
stacking in the crystalline phase (Figure 3). This feature has been
considered a desirable property, since it favors carrier mobility in
organic electronic devices, such as field-effect transistors, which
makes this compound a potentially interesting material for solid
state applications.22
1140–1143.
8. Sun, Y.; Martell, A. E.; Welch, M. J. Tetrahedron 2000, 56, 5093–
5103.
9. Rudrapal, M.; Satyanandam, R. S.; Swaroopini, T. S.; Lakshmi, T.
N.; Jaha, S. K.; Zaheera, S. Med Chem Res 2013, 22, 2840–2846.
10. Corey, E. J.; Enders, D. Tetrahedron Letters 1976, 17, 3–6.
11. Esmaeili, A. A.; Shahmansouri, S.; Habibi, A.; Fakhari, A. R.
Tetrahedron 2012, 68, 8046–8051.
12. (a) Dabholkar, V. V.; Karekar, A.; Naik, P.; Shinde, N. B.
Heterocyc. Lett. 2012, 2, 405–410; (b) Dabholkar, V. V.; Syed, S.
A. S. A. Rasayan J. Chem. 2012, 3, 761–765.
13. (a) Sharada, L. N.; Aparna, Y.; Saba, N.; Sunitha, S. N. T.;
Viveka, L. International Journal of Scientific and Research
Publications, 2015, 5, 1–9; (b) Bhusare, S. R.; Shekapure, J. L.;
Pawar, R. P.; Vibhute, Y. B.; Bhawal B. M. Chemistry of
Heterocyclic Compounds, 2003, 39, 726–728; (c) Fisk, J. S.;
Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432–1440;
(d) Youssef, A. S. A.; Kandeel, K. A.; Abou-Elmagd, W. S. I.;
Haneen, D. S. A. J. Heterocyclic Chem. 2015, 53, 175–182.
14. Jursic, B. S.; Sagiraju, S.; Ancalade, D. K.; Clark, T.; Stevens, E.
D. Synthetic Communications 2007, 37, 1709–1714.
15. (a) You, Y.; He, Y.; Burrows, P. E.; Forrest, S. R.; Petasis, N. A.;
Thompson, M. E. Adv. Mater. 2000, 12, 1678–1681; (b) Joshi, H.;
Upadhyay, P.; Karia, D.; Baxi, A. J. European Journal of
Medicinal Chemistry 2003, 38, 837–840; (c) Saravanan, S.;
Selvan, P. S.; Gopal, N.; Gupta, J. K.; De, B. Arch. Pharm. Chem.
Life Sci. 2005, 338, 488–492.
16. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
17. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279–1300.
18. (a) Zewge, D.; Chen, C.; Deer, C.; Dormer, P. G.; Hughes, D. L. J.
Org. Chem. 2007, 72, 4276–4279; (b) Eaton, P. E.; Carlson, G. R.;
Lee, J. T. J. Org. Chem. 1973, 38, 4071–4073.
19. Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74–150;
(b) Doi, S.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin Trans. 1,
1997, 2217–2221; (c) Wang, X.; Tan, J.; Grozinger, K.
Tetrahedron Lett. 1998, 39, 6609–6612.
Figure 3. Crystal packing for 3d, illustrating the periodic π -
stacking displayed in the solid state.
3. Conclusions
We have developed a one-pot synthetic methodology for the
easy preparation of 4-benzylidene-2-aryl-1,3-oxazol-5-(4H)-
imines starting from phenyl pyruvic acid and aryl amides. The
same compounds can be obtained from α,β-unsaturated acid
derivatives, with a significant increase in overall yield. The
developed methodology can also be used for the preparation of
other α,β-unsaturated acid derivatives with moderate to good
yields. Both procedures are based on the in situ formation of an
oxazolone as intermediate. Even though the structural
discrimination between benzylidene-2-aryl-1,3-oxazol-5-(4H)-
imines and benzylidene-1H-imidazol-5(4H)-ones is not straight
forward, we were able to unambiguously confirm the structure of
the benzylidene-2-aryl-1,3-oxazol-5-(4H)-imines obtained in this
work using single-crystal X-ray diffraction studies.
20. Ábrányi-Balogh, P.; Földesi, T.; Grün, A.; Volk, B.; Keglevich,
G.; Milen, M. Tetrahedron Lett. 2016, 57, 1953-1957.
21. Bala, S.; Saini, M.; Kamboj, S. Int. J. ChemTech Res. 2011, 3,
1102–1118.
22. H. Moon, R. Zeis, E. J. Borkent, C. Besnard, A. J. Lovinger, T.
Siegrist, C. Kloc, Z. N. Bao, J. Am. Chem. Soc. 2004, 126, 15322–
15323.
Compound 3a can be considered as a structural analog of
PK11195 and might show similar bioactivity. We believe that the
proposed methodology can be used to prepare bioactive
compounds with different molecular complexities. Additionally,
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at