Stereoselective Intermolecular [2 + 2] Cycloadditions of Erlenmeyer-Pl?chl Azlactones Using Visible Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.8b02430

The first report of the preparation of symmetric and nonsymmetric diaminotruxinic derivatives through the photoredox [2 + 2] cycloadditions of Erlenmeyer azlactones is described, affording the desired compounds in high regio- and diastereocontrol (only head-to-head coupling). Mechanistic studies by DFT suggest that the reaction proceeds through a neutral photocatalytic pathway.

Full text of DOI:10.1021/acs.joc.8b02430

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Article
Stereoselective Intermolecular [2+2] Cycloadditions of Erlenmeyer-
Plöchl Azlactones using Visible Light Photoredox Catalysis
Isabella F. S. Marra, Angelina M. de Almeida, Larissa P. Silva, Pedro
P. de Castro, Charlane C. Corrêa, and Giovanni Wilson Amarante
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02430 • Publication Date (Web): 19 Nov 2018
Downloaded from http://pubs.acs.org on November 19, 2018
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Stereoselective Intermolecular [2+2]
Cycloadditions of Erlenmeyer-Plöchl
Azlactones using Visible Light Photoredox
Catalysis
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Isabella F. S. Marra, Angelina M. de Almeida, Larissa P. Silva, Pedro P. de Castro, Charlane
C. Corrêa, Giovanni Wilson Amarante*
Department of Chemistry, Federal University of Juiz de Fora, Campus Martelos, Juiz de
Fora, MG 36036-900, Brazil.
*e-mail: giovanni.amarante@ufjf.edu.br
Abstract Graphic
Abstract
The first report of the preparation of symmetric and non-symmetric diaminotruxinic derivatives
through the photoredox [2+2] cycloadditions of Erlenmeyer azlactones is described, affording
the desired compounds in high regio- and diastereocontrol (only head-to-head coupling).
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Mechanistic studies by DFT suggest that the reaction proceeds through a neutral photocatalytic
pathway.
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Introduction
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Organic compounds containing four-membered rings are prominent structural scaffold
present in a diverse family of bioactive natural products.1,2,3 In this context, substituted
cyclobutanes (specially the tetrasubstituted truxylic and truxinic acids – Figure 1) are
noteworthy for their biological activities, such as antimicrobial, antibacterial and
anticancer.4,5,6,7
Figure 1. General structure of truxinic and truxillic acids.
This class of compounds is generally prepared through [2+2] cycloaddition reactions.
Over the last years, a powerful tool for the synthesis of cyclobutanes has been developed
with the advent of photoredox catalysis.8 Thus, the use of visible light is an interesting
approach, usually tolerating the presence of sensitive functional groups, avoiding
problems with decomposition by the high-energy radiation and greatly increasing the
ability to achieve unique bond construction through single-electron transfer (SET)
reactions, that are not possible using conventional photochemical protocols.9
Our research group has been recently studying the reactivity of oxazolone rings10-14
.
Thus, we envisioned that Erlenmeyer–Plöchl azlactones could be a promising substrate in [2+2]
photocycloaddition, since alkenes bearing an α,β-unsaturated carbonyl group are generally
easily photoexcited8. The head-to-tail coupling of these substrates had been previously reported
in the literature, affording a 1,3-diaminotruxilic acid derivatives by either strong light irradiation
(Hg lamp/ 500W) (Scheme 1a)15 or by irradiation with low-power LEDs (Scheme 1b).16 In both
cases, a mixture of up to four isomers were obtained. Furthermore, these cyclobutane
derivatives were also stereoselectively accessed in a three steps synthesis, by a combination of
ortho-palladation, regioselective C-H activation and flow under photochemical conditions. On
the other hand, the main disadvantages of this methodology was the use of stoichiometric
amounts of the expensive palladium salts and the multistep reaction sequence (Scheme 1b)17.
The photoredox preparation of 1,2-diaminotruxinic derivatives through the head-to-head
coupling of Erlenmeyer azlactones has not been previously described. Besides, the previous
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reports of similar transformations could not access the desired compounds in high regio- and
stereocontrol. In this context, we herein present two different methods for the preparation of
1,2-diaminotruxinic derivatives through photoredox catalysis. By changing the photocatalyst
both symmetric or non-symmetric cyclobutane derivatives could be accessed as only one
diastereomer (Scheme 1c).
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Scheme 1. Previous reports on [2+2] photocycloaddition and this work proposal.
Results and discussion
Initially, Z-Erlenmeyer azlactones were prepared following literature protocols.10 Since most
recent contributions in visible light photoredox reactions focused on activation of organic
functional groups by transition metal catalysts such as [Ru(bpy)3]2+,5,18 we decide to start our
study investigating the reaction between azlactone 1a, in the presence of 2 mol% of
Ru(bpy)3(PF6)2 and dichloromethane as solvent. To our delight, the desired product (2a) was
obtained in 38% yield. However, the highly strained tricyclic system was unstable and
cycloreversion was observed (Scheme 2). Thus, we envisioned that by switching the solvent to
methanol, the azlactone ring opening of 2a by the alcohol would reduce the strain in the tricyclic
spiro type system and avoid the stability problems of the cycloadduct previously observed.
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Scheme 2. [2+2] cycloaddition of an Erlenmeyer Azlactone in dichloromethane.
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Then, the reaction optimization was carried out and the results are summarized in Table 1.
In the presence of 2 mol% of Ru(bpy)32+, azlactone 1a was irradiated with 60W blue LED,
affording the desired product 3a in 37% yield and compound 4a as a side product in 8% isolated
yield (Entry 1). Two other visible-light catalysts were subsequently evaluated and showed to be
inferior to Ru(bpy)3Cl2 (Entries 2 and 3). The use of the Lewis acid LiBF4 additive and (±)-
camphorsulfonic acid (CSA) increased the yield of 3a to 52% (Entry 4). The use of BF3.Et2O gave
almost azlactone ring-opening product. Interestingly, the selectivity of the reaction changed by
the use of Eosin Y (EY) as photocatalyst, affording the non-symmetric cycloadduct 4a as major
product (52% yield) (Entry 3). An increase of the catalyst loading, the use of green LEDs (30W)
or DIPEA and LiBF4 as additives did not increase the yield of 4a (Entries 7-10). It is worth to
mention that all reaction achieved conversions up to 99%.
We also observed that even in the presence of the photocatalyst, no cycloaddition took place
in the absence of the light source and only ring opening azlactone starting materials were
observed (Entries 11 and 12). Likewise, no cycloadducts were formed only by LED light
irradiation, without photocatalyst (Entry 13). Furthermore, the addition of the photocatalyst to
the azlactone ring opening products did not lead to cycloadducts, suggesting that these
derivatives are not active for the formation of [2+2] cycloaddition products.
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Table 1. Optimization and control studies for photocatalytic [2+2] cycloadditions.
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Entry
Catalyst
(mol%)
Light
source
(LEDs)
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Green
Blue
Blue
-
LiBF4
(mol%)
Additive
Yield
Yield
3a (%)a
4a (%)a
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Ru (2)
Ir (2)
-
-
-
2
2
2
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3
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-
37%
23%
Traces
52%
32%
35%b
ND
ND
0
ND
0
0
0
8%
ND
52%
Traces
ND
ND
29%
19%
0
35%
0
0
0
EY (5)
Ru (2)
Ru (2)
Ru (2)
EY (10)
EY (5)
EY (5)
EY (5)
EY (5)
Ru (2)
-
CSA
DABCO
NEt3
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DIPEA
-
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-
-
-
-
-
Blue
a Isolated yield after purification through flash chromatography; b conversion detected by 1H NMR;
ND: not determined (minor byproduct).
Having established a catalytic system for the stereoselective formation of symmetric and
non-symmetric cyclobutanes, we proceeded to test the generality of this system. Initially, we
examined the scope concerning the preparation of symmetrical cycloadducts 3a-h (Scheme 3).
In general, different substituted azlactones (1a-h) were well tolerated, with both electron-
donating and electron-withdrawing substituents, affording the desired products in yields
between 22-56% and with >19:1 dr. It is worth to mention, even the use of a meta-substituted
azlactone was possible, although a modest yield was attained (22% yield). Moreover, the use of
a heteroaryl oxazolone was also tolerated, affording product 3h in 56% yield. We also examined
the reaction in the presence of two different azlactones, unfortunately a complex mixture was
observed.
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Scheme 3. Preparation of symmetric 1,2-diaminotruxinic derivatives through a [2+2]-
cycloaddition reaction using Ru(bpy)3Cl2 as catalyst.
a The reaction was carried out in the absence of CSA.
We next evaluated the scope concerning the formation of non-symmetric cyclobutane
derivatives 4a-n (Scheme 4). The reaction tolerated the use of heteroaryl and aryl azlactones
bearing electron-donating and withdrawing substituents, affording a diverse scope of bicyclic
spiro-type cyclobutanes with perfect diastereocontrol. By changing the reaction solvent to
ethanol, the desired cyclobutane derivative 4m was isolated in 47% yield. Isopropanol was also
tested, but did not lead to the desired cycloaddition product.
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Scheme 4. Preparation of non-symmetric 1,2-diaminotruxinic derivatives through a [2+2]-
cycloaddition reaction using Eosin Y as catalyst.
a Ethanol was used as solvent.
b
Deuterated methanol was used as solvent.
In all cases, the NMR analysis of the crude reaction mixture revealed the presence of only
one diastereomer. Thus, X-ray crystallographic analysis was carried out to elucidate the relative
and absolute stereochemistry of compound 4d (see Supporting Information). In this context, the
single diastereomer 1,2-Z,E-anti (Zeta) was classified as an 1,2-amino truxinic derivative, since
they are originated by the head-to-head anti-[2+2] cycloaddition of Z- and E-oxazolones.17, 19, 20
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One important advantage of this catalytic system is the preservation of the versatile
azlactone scaffold, allowing its potential application in a diversity of transformations 21. Thus,
we envisioned that the Brønsted acid catalyzed azlactone ring opening method previously
reported by our group might be used to further functionalize the oxazolone moiety in
cyclobutanes 4a-n.13 After a series of trials, we found a one-pot method for visible light induced
[2+2] cycloaddition and azlactone ring opening (Scheme 5). Different amines could also be used
in this reaction conditions, affording the desired compounds in good yields.
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Scheme 5. One-pot visible light induced [2+2]-cycloaddition of Erlenmeyer
azlactones/Brønsted acid catalyzed azlactone ring opening reaction sequence.
We next turned our attention towards the comprehension of the reaction mechanism
(Scheme 6). Initially, based on our group previous studies involving the mechanism of azlactone
ring-opening reaction (RO) in the presence of CSA13,22 and based on control experiments during
the optimization (that revealed that the ring-opened azlactone derivative is inactive in
photoredox conditions), we believe that the RO step occurs after the cycloaddition reaction,
affording either 3a-3h (two RO reactions) or 4a-4n (one RO reaction - in the presence of the
eosin Y acting as a Brønsted acid). Due to that, since we believe that product 2a is a common
intermediate in both pathways, we decided to evaluate its formation. To this purpose,
theoretical calculations were performed (all data concerning the calculations is available in the
SI). It is important to mention, the reaction failed in the absence of light.
Initially, TD-DFT calculation of the first singlet and triplet states of the eosin Y catalyst
were performed and revealed that only the triplet state is compatible with the blue light LED
energy (the triplet data showed perfect accordance with experimental data - reported: 1.89 eV;
calculated: 1.89 eV). This excited state then can follow by two possible pathways: the electron
transfer between catalyst and azlactone, affording the eosin Y radical anion or cation. The
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EY+•/azlactone-• formation showed to be favored over EY-•/azlactone+• and unselective for
oxazolone isomers (ΔG 4.2-4.5 against 17.9-18.9 kcal/mol).
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For the formation of 2a, a reaction between the E and Z Erlenmeyer azlactones is required for
the formation of the desired diastereomer. Since initially only the Z isomer was employed, the
photo-mediated isomerization must take place.16,17 The isomerization barrier of neutral
oxazolone is incompatible with a reaction that proceeds at room temperature, however, when
Z-azlactone radical anion is formed by the electron transfer with the excited (triplet) eosin Y
catalyst, the isomerization can occur, affording E-azlactone radical anion with a calculated ΔG‡
of 14.65 kcal/mol and a reaction ΔG of only 2.91 kcal/mol.
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Having established an initial mechanism, we next investigated the cycloaddition steps.
In an attempt to explain the stereoselectivity, the formation of all possible head-to-head
diastereomers were evaluated (1,2-Z,E-anti; 1,2-E,E-anti; 1,2-Z,Z-anti; 1,2-Z,E-syn; 1,2-E,E-syn
and 1,2-Z,Z-syn). By our proposal, initially, the azlactone radical anion (either Z or E) reacts with
a neutral Erlenmeyer azlactone (ΔG‡ = 21.6-27.4 kcal/mol), affording a radical anion dimer in
which the 4-membered ring moiety has not been formed yet. It is worth mentioning that this
intermediate is thermodynamically favored only for the coupling of E-E and Z-E azlactones (ΔG
= -2.9 to -7.8 kcal/mol) and that, since the E azlactone occurs only in small amounts during the
reaction, the E-E coupling is less likely to occur. Furthermore, the anti coupling is favored when
compared to syn addition (anti = -5.12 to -7.8 kcal/mol; syn = -2.9 to -3.6 kcal/mol); we propose
that this is the step in which the configuration of the product is determined and that the sum of
these observations makes the formation of 1,2-Z,E-anti the most probable to occur. Finally, this
step is then followed by an electron transfer of this intermediate to the EY+•, with immediate
ring-closure of the cyclobutane moiety, and formation of product 2a, thus regenerating the
neutral eosin catalyst. This step is greatly thermodynamically favored, with a ΔG between -34.5
and -45.9 kcal/mol. The full mechanistic proposal for the isolated product is summarized in
Scheme 6 and the Gibbs Free Energies for the formation of all diastereomers is available in the
SI.
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Scheme 6. Proposed catalytic cycle.
Conclusions
In summary, two highly regio- and diastereoselective conditions to obtain cyclobutane
precursors of 1,2-diaminotruxillic acid derivates have been presented. The reaction takes
place in methanol, in the presence of photocatalyst under visible light photoredox
catalysis approach. From the reaction condition B, in which the azlactone ring moiety is
incorporated in the product, a one-pot method to further functionalize these derivatives
was developed employing a subsequent ring opening reaction. DFT studies were carried
out and showed an interaction between the azlactone radical anion and neutral E-
azlactone leading to the product. To the best of our knowledge, this consists the first
report of stereoselective head-to-head coupling of Erlenmeyer-Plöchl azlactones.
Experimental Section
General Information. All purchased chemicals were used as received without further
purification. Solvents were dried according to standard procedures. Analytical thin layer
chromatography (TLC) was performed on TLC plates (silica gel 60 F254) and visualized by a UV
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lamp. Column flash chromatography was performed using 230-400 mesh silica gel. Chemical
1
shifts for H NMR were reported as δ, parts per million, relative to the signal of CHCl3 at 7.26
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ppm. Chemical shifts for 13C {1H} NMR were reported as δ, parts per million, relative to the center
1
line signal of the CDCl3 triplet at 77 ppm. The H NMR spectra were recorded at 500 MHz, 13C
NMR spectra were recorded at 125 MHz. Chemical shifts are reported in ppm using the following
peak pattern abbreviations: br, broad; s, singlet; d, doublet; dd, double doublet; ddd, doublet of
doublet of doublets; t, triplet; dt, double triplet; q, quartet; pent, pentet; sext, sextet; m,
multiplet. High-resolution mass spectra were acquired in the Matrix–assisted laser
desorption/ionization time of flight (MALDI-TOF) spectrometer using a pulsed nitrogen laser at
337 nm. Single-crystal data for compound 4d were collected using an Oxford Diffraction Gemini
A Ultra diffractometer with CuKa (l=1.54184 Å) at 150 K. Data collection, reduction and cell
refinement were performed using the CrysAlis PRO 1.171.39.46e program (Rigaku OD, 2018)
Oxford Diffraction Ltd. The structure was solved and refined using the ShelXT24, SHELXL25 and
Olex226. A Multi-scan absorption correction CrysAlis PRO 1.171.39.46e (Rigaku Oxford
Diffraction, 2018) was used. Empirical absorption correction using spherical harmonics,
implemented in SCALE3 ABSPACK scaling algorithm. Anisotropic displacement parameters were
assigned to all non-hydrogen atoms bound to oxygen and nitrogen. The H atoms were initially
located in a difference Fourier map, added in idealized positions and further refined according
to the riding model: N-H = 0.86 Å, and Uiso (H) = 1. 2 Ueq (N). The C-bound H atoms were
included in the riding-model approximation: C-H = 0.95 Å and Uiso (H) = 1.2Ueq(C). The structure
representation was plotted using ORTEP for Windows27.
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Additional details of the data collections and structural refinement parameters are provided in
the SI. Selected bond lengths, angles and are listed in Table S5 of the SI. CCDC 866124 are the
supplementary crystallographic data for this paper. It can be obtained freely from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Melting points were
recorded respectively on a melting point apparatus.
General procedures for the Synthesis of compounds 1a-l
A mixture of hippuric acid (5.0 mmol), anhydrous NaOAc (5.0 mmol), acetic anhydride (5.0 mL)
and the appropriate aldehyde (5.0 mmol) was heated in oil bath to 95oC for 4h. After completion
of reaction (monitored by TLC), the contents were cooled and washed with a solution of
water/ethanol 2:1. The crude was filtered off and the crystals were obtained by recrystallization
with ethanol.
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(Z)-4-benzylidene-2-phenyloxazol-5(4H)-one (1a).28 The product was obtained as a light yellow
crystal (880 mg, 70 %). Mp: 156.2-156.5oC. FT-IR (ZnSe, cm-1) n 1788, 1764, 1649, 1156, 678. 1H
NMR (500 MHz, CDCl3) d: 8.22-8.19 (m, 4H), 7.62 (tt, 1H, J = 7.4, 1.25 Hz), 7.54 (t, 2H, J = 7.90
Hz), 7.51-7.46 (m, 3H), 7.27 (s, 1H). 13C {1H} NMR (125MHz) d: 167.8, 163.7, 133.7, 133.5, 133.4,
132.6, 132.0, 131.4, 129.1, 129.1, 128.5.
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(Z)-4-(4-methylbenzylidene)-2-phenyloxazol-5(4H)-one (1b).28 The product was obtained as a
yellow crystal (796.0 mg, 60 %). Mp: 134.8-134.9oC. FT-IR (ZnSe, cm-1) n 1789, 1766, 1647, 1156,
980, 816, 691.1H NMR (500 MHz, CDCl3) d: 8.18 (d, 2H, J = 7.10 Hz), 8.11 (d, 2H, J = 8.3 Hz), 7.62
(tt, 1H, J = 7.30 Hz, J = 1.30 Hz), 7.53 (t, 2H, J = 7.70 Hz), 7.29 (d, 2H, J = 8.00 Hz), 7.24 (s, 1H),
2.43 (s, 3H). 13C {1H} NMR (125 MHz) d: 168.0, 163.2, 142.3, 133.3, 132.7, 132.6, 132.2, 131.1,
129.9, 129.1, 128.5, 128.4, 125.9, 22.0.
(Z)-4-(4-fluorobenzylidene)-2-phenyloxazol-5(4H)-one (1c).29 The product was obtained as a light
yellow crystal (935.0 mg, 70%). Mp: 176.9-178.8oC. FT-IR (ZnSe, cm-1) n 1792, 1653, 1594, 1499,
1155, 981, 865, 829, 694, 684. 1H NMR (500 MHz, CDCl3) d: 8.23 (dd, 2H, J = 8.75, 5.6 Hz), 8.18
(dd, 2H, J = 8.2, 1.4 Hz), 7.62 (tt, 1H, J = 7.45, 1.25 Hz), 7.53 (t, 2H, J = 7.85 Hz), 7.20 (s, 1H), 7.17
(t, 2 H, J = 8.65 Hz). 13C {1H} NMR (125 MHz) d: 167.7, 164.4 (d, J = 253.2 Hz), 163.8, 134.9, 134.8
(d, J = 8.6 Hz), 133.6, 133.1, 133.0, 130.5, 130.1, 130.0, 129.1, 128.5, 125.7, 116.2 (d, J = 21.8
Hz).
(Z)-4-(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one (1d).29 The product was obtained as a
light yellow crystal (895.0 mg, 63%). Mp: 187.5-187.8oC. FT-IR (ZnSe, cm-1) n 1790, 1654, 1164,
867, 827, 692.1H NMR (500 MHz, CDCl3) d: 8.18 (d, 2H, J= 7.20 Hz), 8.15 (d, 2H, J= 8.50 Hz), 7.63
(t, 1H, J = 7.40 Hz), 7.54 (t, 2H, J = 7.40 Hz), 7.45 (d, 2H, J = 8.65 Hz), 7.18 (s, 1H). 13C {1H} NMR
(125 MHz) d: 167.5, 164.1, 137.4, 133.7, 132.2, 130.2, 129.4, 129.2, 128.6, 125.6.
(Z)-4-(3-chlorobenzylidene)-2-phenyloxazol-5(4H)-one (1e). The product was obtained as a light
yellow crystal (938.0 mg, 67%). Mp: 174.0-175.0oC. FT-IR (ZnSe, cm-1) n 1790, 1654, 1164, 867,
819, 692. 1H NMR (500 MHz, CDCl3) d: 8.30-8.29 (m, 1H), 8.20-8.18 (m, 2H), 8.01-7.99 (m, 1H),
7.64 (tt, 1H, J = 7.45, 1.30 Hz), 7.57-7.53 (m, 2H), 7.43-7.39 (m, 2H). 13C {1H} NMR (125 MHz) d:
167.5, 164.1, 137.4, 133.7, 132.2, 130.2, 129.4, 129.2, 128.6, 125.6.
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(Z)-4-(4-bromobenzylidene)-2-phenyloxazol-5(4H)-one (1f).29 The product was obtained as a light
yellow crystal (1.06 g, 65%). Mp: 196.8-197.0oC. FT-IR (ZnSe, cm-1) n 1785, 1761, 1653, 818, 693.
1H NMR (500 MHz, CDCl3) d: 8.18 (dd, 2H, J = 8.3, 1.4 Hz), 8.07 (d, 2H, J = 8.45 Hz), 7.65-7.59 (m,
3H), 7.54 (t, 2H, J = 7.85 Hz), 7.16 (s, 1H). 13C {1H} NMR (125 MHz) d: 167.5, 164.1, 133.9, 133.8,
133.7, 132.5, 132.4, 130.2, 129.2, 128.6, 126.1, 125.6.
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(Z)-2-phenyl-4-(4-(trifluoromethyl)benzylidene)oxazol-5(4H)-one (1g).30 The product was
obtained as a light yellow crystal (885.0 mg, 56%). Mp: 174.0-175.0oC. FT-IR (ZnSe, cm-1) n 1793,
1652, 1554, 1315, 837, 687. 1H NMR (500 MHz, CDCl3) d: 8.30 (d, 2H, J= 8.20 Hz), 8.19-8.17 (m,
2H), 7.72 (d, 2H, J= 8.25 Hz), 7.64 (tt, 1H, J= 7.45, 1.9 Hz), 7.56-7.53 (m, 2H), 7.22 (s, 1H). 13C {1H}
NMR (125 MHz) d: 167.2, 164.9, 136.8, 135.3, 134.0, 132.0 (q, J = 32.4 Hz), 129.2, 129.2, 128.8,
125.7 (q, J = 3.7 Hz), 123.8 (q, J = 270.6 Hz).
(Z)-4-(4-methoxybenzylidene)-2-phenyloxazol-5(4H)-one (1h).28 The product was obtained as a
light yellow crystal (945.0 mg, 68%). Mp: 162.0-163.2oC. FT-IR (ZnSe, cm-1) n 1788, 1771, 1599,
1260, 1163, 830, 704. 1H NMR (500 MHz, CDCl3) d: 8.21-8.16 (m, 4H), 7.59 (tt, 1H, J = 7.35, 1.25
Hz), 7.54-7.51 (m, 2H), 7.22 (s, 1H), 7.00 (d, 2H, J = 9 Hz). 13C {1H} NMR (125 MHz) d: 168.2, 162.4,
134.7, 133.1, 132.1, 131.3, 129.1, 128.3, 126.7, 126.0, 114.7, 55.6.
(Z)-4-(3-methoxybenzylidene)-2-phenyloxazol-5(4H)-one (1i). The product was obtained as a
light yellow crystal (834.0 mg, 60%). Mp: 103.5-104oC. FT-IR (ZnSe, cm-1) n 1802, 1652, 1581,
1280, 766. 1H NMR (500 MHz, CDCl3) d: 8.17-8.15 (m, 2H), 7.93-7.94 (m, 1H), 7.66 (d, 1H, J = 7.65
Hz), 7.61 (tt, 1H, J = 7.40, 1.25 Hz), 7.54-7.51 (m, 2H), 7.38 (t, 1H, J = 8.00 Hz), 7.21 (s, 1H), 7.02
(ddd, 1H, J = 8.25, 2.65, 0.85 Hz), 3.91 (s, 3H). 13C {1H} NMR (125 MHz) d: 167.7, 163.7, 159.9,
134.8, 133.5, 131.8, 129.9, 129.1, 128.5, 125.7, 125.6, 117.9, 116.7, 55.5.
(Z)-4-(3,4-dimethoxybenzylidene)-2-phenyloxazol-5(4H)-one (1j). The product was obtained as a
light yellow crystal (986.0 mg, 64%). Mp: 154.2-155.0oC. FT-IR (ZnSe, cm-1) n 1782, 1762, 1647,
1591, 1240, 692. 1H NMR (500 MHz, CDCl3) d: 8.15-8.10 (m, 3H), 7.58-7.49 (m, 4H), 7.18 (s, 1H),
6.92 (d, 1H, J = 8.35 Hz), 4.01 (s, 3H), 3.95 (s, 3H). 13C {1H} NMR (125 MHz) d: 168.0, 162.5, 152.2,
149.3, 133.1, 132.2, 131.3, 129.1, 128.1, 127.9, 127.0, 125.9, 114.1, 111.0, 56.1, 56.0.
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(Z)-4-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)phenyl acetate (1k).30 The product was
obtained as a light yellow crystal (989.0 mg, 65%). Mp: 171.8-172.3oC. FT-IR (ZnSe, cm-1) n 1796,
1759, 1651, 1219, 1160, 857, 696. 1H NMR (500 MHz, CDCl3) d: 8.24 (d, 2H, J = 8.50 Hz), 8.18 (d,
2H, J = 7.30 Hz), 7.62 (t, 1H, J = 7.50 Hz), 7.54 (t, 2H, J = 7.70 Hz), 7.23-7.22 (m, 3H), 2.34 (s, 3H).
13C {1H} NMR (125 MHz) d: 169.1, 167.7, 163.8, 152.8, 133.9, 133.6, 133.4, 131.4, 130.7, 129.1,
128.5, 125.7, 122.3, 21.3.
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(Z)-4-(furan-2-ylmethylene)-2-phenyloxazol-5(4H)-one (1l).29 The product was obtained as a
brown crystal (657.0 mg, 55%). Mp: 191.2-191.3oC. FT-IR (ZnSe, cm-1) n 1789, 1654, 1156, 699.
1H NMR (500 MHz, CDCl3) d: 8.14 (dd, 2H, J = 8.3, 1.2 Hz), 8.11 (m, 1H), 7.60 (tt, 1H, J = 7.4, 1.3
Hz), 7.54-7.51 (m, 3H), 7.26-7.25 (m, 1H), 7.20 (s, 1H). 13C {1H} NMR (125 MHz) d: 167.2, 162.6,
148.0, 144.5, 133.3, 132.9, 129.1, 128.3, 125.8, 121.5, 111.,3.
General procedures for the Synthesis of compounds 2a
The product was prepared using an oven-dried 4 mL vial equipped with a Teflon septum and
magnetic stir bar. It was charged with tris-(2,2´-bipyridyl)ruthenium (II) chloride
hexafluorophosphate (0.02 equiv), the Erlenmeyer-Plöchl azlactone 1a (0,039g, 0.15 mmol), and
CH2Cl2 (2.0 mL, C = 0.075M). The vial was purged with nitrogen, sealed with parafilm and placed
approximately 8 cm from a 60 W blue LEDs. After the reaction was complete (as judged by TLC
analysis) and concentrated in vacuo. 24 h reaction time. The product was purified by flash
chromatography in 5% of ethyl acetate in hexane.
(5R,6R)-11,12-bis(4-chlorophenyl)-2-phenyl-3,9-dioxa-1,7-diazadispiro[4.0.46.25]dodeca-1,7-
diene-4,10-dione (2a). The product was obtained as a white solid (13.8 mg, 35%). Mp: 141.2-
142°C. FT-IR (ZnSe, cm-1) n 1816, 1629, 987, 878, 696. 1H NMR (500MHz, CDCl3): d 8.02 (dd, 4H,
J = 8.3, 1.1 Hz), 7.59 (tt, 2H, J = 7.45, 1.25 Hz), 7.46 (t, 4H, J = 8.15 Hz), 7.29 (d, 4H, J = 8.5 Hz),
5.15 (s, 2H). 13C {1H} NMR (125 MHz, CDCl3): d 172.4, 164.3, 134.3, 133.9, 133.5, 129.4, 129.0,
+
128.8, 128.5, 124.8, 77.0, 45.9.HRMS (ESI-TOF) m/z: [M+H]+ calcd for C32H21Cl2N2O4 567.0873,
found 567.0870.
General procedures for the Synthesis of compounds 3a-h
Condition A: [2+2]-photocycloaddition of Erlenmeyer–Plöchl Azlactone using Ru(bpy)3Cl2 as
catalyst. An oven-dried 4 mL vial equipped with a Teflon septum and magnetic stir bar was
charged with tris-(2,2´-bipyridyl)ruthenium (II) chloride hexahydrate (3.0 μmol, 0.02 equiv), the
corresponding Erlenmeyer-Plöchl’s azlactone (0.15 mmol, 1.0 equiv), and LiBF4 (0.3 mmol, 2
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equiv) and MeOH (2.0 mL, C = 0.075M). The vial was sealed with parafilm and placed
approximately 8 cm from a 60 W blue LEDs. After the reaction was complete (as judged by TLC
analysis) CSA was added. After 24 hours stirring at room temperature, the reaction was
concentrated in vacuo, liquid-liquid extraction in dichloromethane/NaHCO3 (saturated solution)
(2x) and dichloromethane/H2O(1x). The organic phase was dried with anhydrous sodium sulfate,
filtrated and the solvent was concentrated in vacuo.
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Dimethyl-1,2-bis(benzamido)-3,4-diphenylcyclobutane-1,2-dicarboxylate (3a). The product was
prepared according to the Condition A and obtained after flash chromatography in 30% of ethyl
acetate in hexane as a white solid (22.8 mg, 54%). 5 days reaction time. Mp: 79.6-80.6°C. FT-IR
(ZnSe, cm-1): 3059, 2922, 1731, 1640, 1515, 1476, 1214, 685. 1H NMR (500MHz, CDCl3): d (ppm):
8.27 (br, 2H), 7.54 (d, 4H, J = 7.35 Hz), 7.45-7.46 (m, 6H), 7.36 (t, 4H, J = 7.75 Hz), 7.31 (t, 4H, J =
7.6 Hz), 7.25-7.26 (m, 2H), 4.91 (s, 2H), 3.73 (s, 6H). 13C {1H} NMR (125 MHz, CDCl3): d (ppm):
171.7, 166.7, 134.8, 133.4, 131.9, 129.2, 128.8, 128.7, 128.3, 127.0, 64.2, 53.1, 47.6. HRMS
+
(MALDI) m/z: [M+H]+ calcd for C34H31N2O6 563.2177, found 563.2192.
Dimethyl 1,2-bis(benzamido)-3,4-di-p-tolylcyclobutane-1,2-dicarboxylate (3b). The product was
prepared according to the Condition A and obtained after flash chromatography in 30% of ethyl
acetate in hexane as a white solid (17.7 mg, 40%). 2 days reaction time. Mp: 79.0-80.2°C. FT-IR
(ZnSe, cm-1): 2917, 1730, 1668, 1473, 1297, 712. 1H (500 MHz, CDCl3) d (ppm): 8.30 (br, 2H), 7.58
(d, 4H, J = 7.30 Hz), 7.47 (t, 4H, J = 7.30 Hz), 7.37 (t, 4H, J = 7.70 Hz), 7.33 (d, 4H, J = 7.9 Hz), 7.11
(d, 4H, J = 7.80 Hz), 4.84 (s, 2H), 3.71 (s, 6H), 2.28 (s, 2H). 13C {1H} (125MHz, CDCl3) d (ppm): 171.8,
166.9, 138.0, 131.9, 131.8, 129.6, 129.1, 128.7, 127.1, 64.3, 53.1, 47.6, 21.3. HRMS (ESI-TOF)
+
m/z: [M+K]+ calcd for C36H34KN2O6 629.2048, found 629.2028.
Dimethyl 1,2-bis(benzamido)-3,4-bis(4-fluorophenyl)cyclobutane-1,2-dicarboxylate (3c). The
product was prepared according to the Condition A and obtained after flash chromatography in
30% of ethyl acetate in hexane as a white solid (13.5 mg, 30%). 2 days reaction time. Mp 205-
1
205.1oC. FT-IR (ZnSe, cm-1): 3351, 2952, 1721, 1668, 1509, 1208, 703. H (500 MHz, CDCl3)
d (ppm): 8.15 (s, 2H), 7.56 (m, 4H), 7.49 (m, 2H), 7.40 (m, 8H), 7.00 (m, 4H), 4.83 (s, 2H), 3.73 (s,
6H). 13C {1H} (125MHz, CDCl3) d (ppm): 171.6, 166.9, 162.8 (d, JC-F = 246.0 Hz), 133.2, 132.2, 130.8
(d, JC-F = 8.1 Hz), 130.4 (d, JC-F = 3.1 Hz), 128.9, 127.1, 115.9 (d, JC-F = 21.3 Hz), 64.3, 53.3, 47.2.
+
HRMS (MALDI) m/z: [M+Na]+ calcd for C34H28F2N2NaO6 621.1808, found 621.1835.
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Dimethyl 1,2-bis(benzamido)-3,4-bis(4-chlorophenyl)cyclobutane-1,2-dicarboxylate (3d). The
product was prepared according to the Condition A and obtained after flash chromatography in
30% of ethyl acetate in hexane as a white solid (24.6 mg, 52%). 5 days reaction time. Mp: 84.7-
85.7oC. FT-IR (ZnSe, cm-1): 2917, 1721, 1667, 1473, 1083, 1013, 712. 1H (500 MHz, CDCl3) d (ppm):
8.14 (br, 2H), 7.58-7.56 (m, 4H), 7.51-7.48 (m, 2H), 7.42-7.38 (m, 4H), 7.37-7.35 (m, 4H), 7.29-
7.27 (m, 4H), 4.82 (s, 2H), 3.73 (s, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 171.4, 166.9, 134.5,
133.1, 133.0, 132.3, 130.4, 129.1, 128.9, 127.1, 64.4, 53.4, 47.1. HRMS (MALDI) m/z: [M+Na]+
calcd for C34H28N2O6Cl2Na+ 653.1217, found 653.1246.
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Dimethyl 1,2-bis(benzamido)-3,4-bis(3-chlorophenyl)cyclobutane-1,2-dicarboxylate (3e). The
product was prepared according to the Condition A and obtained after flash chromatography in
30% of ethyl acetate in hexane as a white solid (10.4 mg, 22%). 24h reaction time. Mp: 132.9-
133.4oC. FT-IR (ZnSe, cm-1): 2917, 1730, 1456, 1031, 676. 1H (500 MHz, CDCl3) d (ppm): 8.31 (s,
2H), 7.58 (d, 4H, J = 7.15 Hz), 7.47 (t, 2H, J = 7.45 Hz), 7.38 (t, 4H, J = 7.70 Hz), 7.23 (t, 2H, J = 7.95
Hz), 7.06 (d, 2H, J = 7.45 Hz), 6.96 (s, 2H), 6.79 (d, 2H, J = 8.30 Hz), 4.83 (s, 2H), 3.72 (s, 6H). 13
C
{1H} (125MHz, CDCl3) d (ppm): 171.7, 166.9, 159.9, 136.5, 133.5, 132.0, 129.9, 128.8, 127.2,
121.5, 115.0, 113.9, 64.3, 53.2, 47.9. HRMS (MALDI) m/z: [M+Na]+ calcd for C34H28N2O6Cl2Na+
653.1217, found 653.1240.
Dimethyl 1,2-bis(benzamido)-3,4-bis(4-(trifluoromethyl)phenyl)cyclobutane-1,2-dicarboxylate
(3f). The product was prepared according to the Condition A and obtained after flash
chromatography in 30% of ethyl acetate in hexane as a white solid (26.2 mg, 50%). 5 days
reaction time. Mp: 73.7-74.3oC. FT-IR (ZnSe, cm-1): 3333, 2952, 1721, 1668, 1482, 1323, 703.
1H (500 MHz, CDCl3) d (ppm): 8.07 (s, 2H), 7.56 (s, 8H), 7.53-7.48 (m, 6H), 7.39 (t, 4H, J = 7.75
Hz), 4.98 (s, 2H), 3.76 (s, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 171.2, 167.1, 138.6, 132.9, 132.4,
130.7 (q, JC-F = 32.3 Hz), 129.5, 128.9, 127.0, 125.8 (q, JC-F = 3.6 Hz), 124.1 (q, JC-F = 270.7 Hz), 64.7,
+
53.5, 47.1. HRMS (MALDI) m/z: [M+K]+ calcd for C36H28F6KN2O6 737.1483, found 737.1477.
Dimethyl 1,2-bis(benzamido)-3,4-bis(4-methoxyphenyl)cyclobutane-1,2-dicarboxylate (3g). The
product was prepared according to the Condition A and obtained after flash chromatography in
30% of ethyl acetate in hexane as a white solid (18.7 mg, 40%). 5 days reaction time. Mp: 79.0-
80.8oC. FT-IR (ZnSe, cm-1): 2917, 1721, 1659, 1518, 1464, 1252, 703. 1H (500 MHz, CDCl3) d (ppm):
8.27 (br, 2H), 7.57 (d, 4H, J = 8.05 Hz), 7.47 (t, 2H, J = 7.45 Hz), 7.37 (t, 8H, J = 7.55 Hz), 6.85 (d,
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4H, J = 8.45 Hz), 4.79 (s, 2H), 3.74 (s, 6H), 3.71 (s, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 171.8,
166.8, 159.5, 133.4, 131.9, 130.3, 128.7, 127.1, 126.7, 114.2, 64.2, 55.4, 53.1, 47.4. HRMS
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(MALDI) m/z: [M+Na]+ calcd for C36H34N2NaO8 645.2207, found 645.2237.
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Dimethyl 1,2-bis(benzamido)-3,4-di(furan-2-yl)cyclobutane-1,2-dicarboxylate (3h). The product
was prepared according to the Condition A and obtained after flash chromatography in 30% of
ethyl acetate in hexane as an oil (45.5 mg, 56%). 5 days reaction time. FT-IR (ZnSe, cm-1): 3342,
2917, 1730, 1659, 1464, 712. 1H (500 MHz, CDCl3) d (ppm): 8.29 (s, 2H), 7.66-7.62 (m, 5H), 7.51-
7.48 (m, 5H), 7.39-7.37 (m, 8H), 4.45 (s, 2H), 3.69 (s, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 171.9,
166.9, 143.9, 141.9, 133.2, 132.2, 128.9, 128.7, 127.2, 126.3, 120.2, 111.0, 63.8, 53.3, 41.2.
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HRMS (MALDI) m/z: [M+Na]+ calcd for C30H26N2NaO8 565.1581, found 565.1575.
General procedures for the Synthesis of compounds 4a-n
Conditions B: [2+2]-photocycloaddition of Erlenmeyer–Plöchl Azlactone using Eosin Y as
catalyst. An oven-dried 4 mL vial equipped with a Teflon septum and magnetic stir bar was
charged with Eosin Y (0.05 equiv), the corresponding Erlenmeyer-Plöchl azlactone (0.15 mmol,
1.0 equiv) and MeOH (2.0 mL, C = 0.075M). The vial was sealed with parafilm and placed
approximately 8 cm from a 60 W blue LEDs. After the reaction was complete (as judged by TLC
analysis) and concentrated in vacuo.
Methyl 1-benzamido-8-oxo-2,3,6-triphenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-carboxylate (4a).
The product was prepared according to the Condition B and obtained after flash
chromatography in dichloromethane as a white solid (17.5 mg, 44%). 3 days reaction time. Mp:
177.2-178.2oC. FT-IR (ZnSe, cm-1): 2915, 1810, 1731, 1640, 1503, 1476, 696. 1H (500 MHz, CDCl3)
d (ppm): 8.08 (d, 2H, J = 7.55 Hz), 7.65- 7.63 (m, 3H), 7.58-7.53 (m, 5H), 7.49 (t, 1H, J = 7.25 Hz),
7.42- 7.39 (m, 2H), 7.31-7.18 (m, 9H), 5.19 (d, 1H, J = 12.35 Hz), 4.71 (d, 1H, J = 12.35 Hz), 3.82
(s, 3H). 13C {1H} (125MHz, CDCl3) d (ppm): 173.3, 169.3, 167.0, 164.0, 135.4, 135.0, 133.9, 133.5,
132.0, 129.1, 129.0, 128.7, 128.7, 128.7, 128.4, 128.1, 127.9, 127.1, 127.0, 75.8, 66.3, 53.1, 48.1,
+
44.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C33H27N2O5 531.1914, found 531.1928.
Methyl
1-benzamido-8-oxo-6-phenyl-2,3-di-p-tolyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-
carboxylate (4b). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (22.6 mg, 54%). 3 days reaction time.
Mp: 176.8-177.2oC. FT-IR (ZnSe, cm-1): 3381, 2909, 1819, 1738, 1666, 1509, 1280, 713, 702. 1H
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(500 MHz, CDCl3) d (ppm): 8.06 (d, 2H, J = 7.95 Hz), 7.66-7.22 (m, 3H), 7.54-7.47 (m, 4H), 7.44-
7.40 (m, 4H), 7.10-7.06 (m, 6H), 5.10 (d, 1H, J = 12.6 Hz), 4.63 (d, 1H, J = 12.5 Hz), 3.81 (s, 3H),
2.27 (s, 3H), 2.26 (s, 3H). 13C {1H} (125MHz, CDCl3) d (ppm): 173.4, 169.4, 167.1, 163.8, 137.8,
137.5, 133.8, 133.8, 132.4, 131.9, 131.9, 129.7, 129.2, 129.1, 128.7, 128.7, 128.6, 127.2, 127.0,
+
75.9, 66.3, 53.1, 48.0, 44.1, 21.3, 21.2. HRMS (MALDI) m/z: [M+Na]+calcd for C35H30N2NaO5
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581.2047, found 581.2028.
Methyl 1-benzamido-2,3-bis(4-fluorophenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-
carboxylate (4c). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (26.8 mg, 63%). 5 days reaction time.
Mp: 60.2-61.2oC. FT-IR (ZnSe, cm-1): 2921, 1744, 1640, 1503, 1214, 732, 709, 687. 1H (500 MHz,
CDCl3) d (ppm): 8.08 (d, 2H, J = 7.70 Hz), 7.68-7.64 (m, 3H), 7.58-7.50 (m, 6H), 7.44-7.41 (m, 2H),
7.18-7.15 (m, 2H), 6.99-6.95 (m, 4H), 5.12 (d, 1H, J = 12.5 Hz), 4.58 (d, 1H, J = 12.7 Hz), 3.81 (s,
3H). 13C {1H} (125MHz, CDCl3) d (ppm): 172.9, 169, 167.1, 164.3, 161.6 (d, J = 245.7 Hz), 161.5 (d,
J = 245.1 Hz), 134.2, 133.2, 132.2, 130.8 (d, J = 14.9 Hz), 130.7 (d, J = 14.8 Hz), 130.3, 130.2,
129.2, 128.9, 128.8, 128.7, 127.1, 124.7, 116.2 (d, J = 21.5 Hz), 115.3 (d, J = 21.3 Hz), 75.6, 66.2,
53.2, 47.9, 43.8. HRMS (MALDI) m/z: [M+H]+ calcd for C33H25F2N2O5 567.1726, found 567.1732.
+
Methyl 1-benzamido-2,3-bis(4-chlorophenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-
carboxylate (4d). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (23 mg, 50%). 5 days reaction time.
Mp: 70.8-71.8oC. FT-IR (ZnSe, cm-1): 2922, 1810, 1627, 1463, 698. 1H (500 MHz, CDCl3) d (ppm):
8.07 (dd, 2H, J = 8.35, 1.2 Hz), 7.69-7.64 (m, 3H), 7.59 (s, 1H), 7.55 (t, 2H, J = 7.75 Hz), 7.51 (dt,
1H, J = 7.4, 1.3 Hz), 7.47 (d, 2H, J = 8.35 Hz), 7.43 (t, 2H, J = 7.8 Hz), 7.23-7.21 (m, 4H), 7.11 (d,
2H, J = 8.25 Hz), 5.10 (d, 1H, J = 12.4 Hz), 4.57 (d, 1H, J = 12.5 Hz), 3.80 (s, 3H). 13C {1H} (125MHz,
CDCl3) d (ppm): 172.8, 169.0, 167.1, 164.4, 134.4, 134.2, 133.9, 133.5, 133.4, 133.2, 132.2, 130.0,
129.3, 129.2, 128.8, 128.7, 128.6, 128.4, 127.2, 124.7, 75.5, 66.3, 53.3, 47.9, 43.8. HRMS (MALDI)
+
m/z: [M+K]+ calcd for C33H24Cl2KN2O5 637.0694, found 637.0706.
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Methyl 1-benzamido-2,3-bis(3-chlorophenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-
carboxylate (4e). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (23 mg, 50%). 5 days reaction time.
Mp: 151.5-152.2 oC. FT-IR (ZnSe, cm-1): 2952, 1819, 1730, 1633, 1482, 1297, 685. 1H (500 MHz,
CDCl3) d (ppm): 8.07 (d, 2H, J = 7.35Hz), 7.69-7.65 (m, 3H), 7.59 (s, 1H), 7.56 (t, 2H, J = 7.80 Hz),
7.51 (d, 2H, J = 7.40 Hz), 7.47-7.42 (m, 3H), 7.23-7.21 (m, 4H), 7.08 (d, 1H, J = 6.65 Hz), 5.11 (d,
1H, J = 12.40 Hz), 4.59 (d, 1H, J = 12.40 Hz), 3.82 (s, 3H). 13C {1H} (125MHz, CDCl3) d (ppm): 172.7,
168.9, 167.3, 164.6, 137.0, 136.9, 135.1, 134.3, 133.3, 132.2, 130.4, 129.8, 129.2, 128.9, 128.8,
128.7, 128.3, 128.2, 127.6, 127.4, 125.3, 124.7, 75.4, 66.3, 53.3, 47.9, 43.9. HRMS (MALDI) m/z:
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+
[M+H]+ calcd for C33H25N2O5Cl2 599.1135, found 599.1158.
Methyl
1-benzamido-8-oxo-6-phenyl-2,3-bis(4-(trifluoromethyl)phenyl)-7-oxa-5-
azaspiro[3.4]oct-5-ene-1-carboxylate (4f). The product was prepared according to the Condition
B and obtained after flash chromatography in dichloromethane as a white solid (12.5 mg, 25%).
5 days reaction time. Mp: 107-108 oC. FT-IR (ZnSe, cm-1): 2926, 1810, 1739, 1633, 1323, 1119,
1066, 703. 1H (500 MHz, CDCl3) d (ppm): 8.10 (d, 2H, J = 7.30Hz), 7.71-7.68 (m, 4H), 7.63 (d, 2H,
J = 7.20 Hz), 7.59-7.51 (m, 7H), 7.43 (t, 2H, J = 7.65 Hz), 7.30 (d, 2H, J = 8.00Hz), 5.26 (d, 1H, J =
12.50 Hz), 4.72 (d, 1H, J = 12.50 Hz), 3.83 (s, 3H). 13C {1H} (125MHz, CDCl3) d (ppm): 172.7, 168.8,
167.2, 164.8, 139.0, 138.9, 134.4, 132.9, 132.3, 130.5 (q, JC-F = 32.4 Hz), 130.0 (q, JC-F = 32.1 Hz),
129.3, 129.0, 128.9, 127.5, 127.1, 126.2 (q, JC-F = 2,5 Hz), 125.4 (q, JC-F = 3,8 Hz), 124.5, 124.1 (q,
JC-F = 270.4 Hz), 123.8 (q, JC-F = 270.6 Hz), 75.4, 66.5, 53.4, 47.9, 44.0. HRMS (MALDI) m/z: [M+Na]+
+
calcd for C35H24F6N2NaO5 689.1482, found 689.1508.
Methyl 1-benzamido-2,3-bis(4-bromophenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-
carboxylate (4g). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (38.1 mg, 37%). 5 days reaction time.
1
Mp: 89.0-90.0 oC. FT-IR (ZnSe, cm-1): 2917, 1810, 1748, 1633, 1464, 1075, 694. H (500 MHz,
CDCl3) d (ppm): 8.07 (d, 2H, J = 7.55Hz), 7.69-7.65(m,3H) 7.59 (s, 1H), 7.57-7.51 (m, 3H), 7.45-
7.39 (m, 8H), 7.04 (d, 2H, J = 8.05 Hz), 5.08 (d, 1H, J = 12.55 Hz), 4.55 (d, 1H, J = 12.60 Hz), 3.81
(s, 3H). 13C {1H} (125MHz, CDCl3) d (ppm): 172.8, 169.0, 167.2, 164.4, 134.2, 134.0, 133.9, 133.1,
132.3, 132.2, 131.6, 130.3, 129.2, 128.8, 128.8, 128.7, 127.1, 124.6, 122.5, 122.1, 75.4, 66.2,
+
53.3, 47.8, 43.8. HRMS (MALDI) m/z: [M+H]+ calcd for C33H25Br2N2O5 687.0125, found 687.0134.
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Methyl 1-benzamido-2,3-bis(4-methoxyphenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-
1-carboxylate (4h). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (26.6 mg, 60%). 5 days reaction time.
Mp: 185.5-186.1 oC. FT-IR (ZnSe, cm-1): 2908, 1810, 1748, 1642, 1518, 1252, 685. 1H (500 MHz,
CDCl3) d (ppm): 8.06 (d, 2H, J = 8.00Hz), 7.66-7.62 (m, 3H), 7.52-7.45 (m, 6H), 7.41 (t, 2H, J = 7.45
Hz), 7.12 (d, 2H, J = 8.35 Hz), 6.82-6.78 (m, 4H), 5.07 (d, 1H, J = 12.45 Hz), 4.57 (d, 1H, J = 12.30
Hz), 3.81 (s, 3H), 3.74-3.73 (m, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 173.4, 169.4, 167.1, 163.7,
159.4, 159.3, 133.8, 133.5, 131.9, 129.8, 129.1, 128.7, 128.6, 128.4, 127.2, 127.0, 125.1, 114.4,
113.9, 75.9, 66.2, 55.3, 55.3, 48.2, 43.9. HRMS (MALDI) m/z: [M+Na]+ calcd for C35H30N2O7Na+
613.1945, found 613.1964.
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Methyl 1-benzamido-2,3-bis(3-methoxyphenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-
1-carboxylate (4i). The product was prepared according to the Condition B and obtained after
flash chromatography in dichloromethane as a white solid (10 mg, 18%). 5 days reaction time.
Mp: 179.3-179.8 oC. FT-IR (ZnSe, cm-1): 2917, 1810, 1739, 1633, 1287, 685. 1H (500 MHz, CDCl3)
d (ppm): 8.06 (d, 2H, J = 7.35Hz), 7.65-7.63 (m, 3H), 7.54-7.47 (m, 4H), 7.41 (t, 2H, J = 7.40 Hz),
7.22-7.16 (m, 2H), 7.12 (s, 2H), 6.79-6.75 (m, 3H), 6.71 (s, 1H), 5.09 (d, 1H, J = 12.40 Hz), 4.61 (d,
1H, J = 12.35 Hz), 3.81 (s, 3H), 3.73(s, 3H), 3.69 (m, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 173.3,
169.2, 167.1, 164.0, 159.9, 159.7, 137.1, 136.6, 133.9, 133.5, 132.0, 130.1, 129.5, 129.1,
128.9,128.7, 127.6, 127.2, 125.0, 120.9, 119.3, 114.3, 113.7, 112.9, 75.8, 66.3, 55.3, 55.2, 53.1,
48.2, 44.5. HRMS (MALDI) m/z: [M+Na]+ calcd for C35H30N2O7Na+ 613.1945, found 613.1959.
Methyl 1-benzamido-2,3-bis(3,4-dimethoxyphenyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-
ene-1-carboxylate (4j). The product was prepared according to the Condition B and obtained
after flash chromatography in dichloromethane as a white solid (14.6 mg, 30%). 5 days reaction
time. Mp: 172.9-173.8 oC. FT-IR (ZnSe, cm-1): 2925, 1819, 1739, 1509, 1243, 1022, 694. 1H (500
MHz, CDCl3) d (ppm): 8.06 (d, 2H, J = 7.35Hz), 7.67-7.62 (m, 3H), 7.54-7.49 (m, 3H), 7.46 (s, 1H),
7.41 (t, 2H, J = 7.70 Hz), 7.16 (s, 1H), 6.99 (d, 1H, J = 8.10 Hz), 6.78-6.75 (m, 3H), 6.71 (s, 1H), 5.05
(d, 1H, J = 12.45 Hz), 4.52 (d, 1H, J = 12.45 Hz), 3.81-3.79 (m, 12H), 3.72 (s, 3H). 13C {1H} (125MHz,
CDCl3) d (ppm): 173.3, 169.3, 167.0, 163.8, 149.3, 149.0, 148.9, 148.8, 133.9, 132.1, 129.1, 128.8,
128.6, 127.7, 127.2, 125.0, 120.5, 119.7, 112.0, 111.4, 110.9, 110.1, 76.1, 66.1, 55.9, 55.9, 53.1,
48.8, 44.5. HRMS (MALDI) m/z: [M+Na]+ calcd for C37H34N2O9Na+ 673.2157, found 673.2132.
(3-benzamido-3-(methoxycarbonyl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1,2-
diyl)bis(4,1-phenylene) diacetate (4k). The product was prepared according to the Condition B
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and obtained after flash chromatography in dichloromethane as a white solid (29.1 mg, 60%). 5
days reaction time. Mp: 186-187.5 oC. FT-IR (ZnSe, cm-1): 2917, 1748, 1642, 1500, 1190, 712. 1H
(500 MHz, CDCl3) d (ppm): 8.07 (d, 2H, J = 7.15Hz), 7.67-7.62 (m, 3H), 7.55-7.47 (m, 6H), 7.41 (t,
2H, J = 7.65 Hz), 7.20 (d, 2H, J = 8.35 Hz), 7.02-7.00 (m, 4H), 5.15 (d, 1H, J = 12.50 Hz), 4.61 (d,
1H, J = 12.45 Hz), 3.81 (s, 3H), 2.25-2.24 (m, 6H). 13C {1H} (125MHz, CDCl3) d (ppm): 172.9, 169.3,
169.2, 167.0, 164.1, 150.5, 133.9, 133.2, 132.4, 132.3, 131.9, 129.6, 129.0, 128.7, 128.6, 128.2,
127.0, 124.7, 122.1, 121.4, 75.5, 66.2, 53.1, 47.8, 43.9, 21.1, 21.1. HRMS (MALDI) m/z: [M+H]+
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+
calcd for C37H31N2O9 647.2024, found 647.2023.
Methyl
1-benzamido-2,3-di(furan-2-yl)-8-oxo-6-phenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-
carboxylate (4l). The product was prepared according to the Conditions B and obtained after
flash chromatography in dichloromethane as a yellow oil (30 mg, 78%). 5 days reaction time.
Mp: 186-187.5 oC. FT-IR (ZnSe, cm-1): 3406, 2948, 1817, 1751, 1633, 1509, 1483, 1293, 875, 698.
1H (500 MHz, CDCl3) d (ppm): 8.04 (dd, 2H, J = 8.30, 1.15 Hz), 7.73 (dd, 2H, J = 8.10, 1.10 Hz), 7.63
(tt, 1H, J = 7.45, 1.25 Hz), 7.56 (s, 1H), 7.54-7.50 (m, 3H), 7.46-7.41 (m, 4H), 7.33 (dt, 2H, J =
14.50, 1.7 Hz), 6.52 (s, 1H), 6.5 (s, 1H), 4.74 (d, 1H, J = 12.1 Hz), 4.15 (d, 1H, J = 12.1 Hz), 3.81 (s,
3H). 13C {1H} (125MHz, CDCl3) d (ppm): 173.2, 169.0, 167.1, 163.9, 143.9, 143.4, 141.1, 140.9,
134.0, 132.2, 129.1, 128.8, 128.7, 127.2, 120.5, 110.9, 109.8, 75.6, 65.8, 53.1, 42.5, 38.8. HRMS
+
(MALDI) m/z: [M+H]+ calcd for C29H23N2O7 511.1500, found 511.1527.
Ethyl 1-benzamido-8-oxo-2,3,6-triphenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-carboxylate (4m).
The product was prepared according to the Condition B and obtained after flash
chromatography in dichloromethane as a yellow solid (20 mg, 47%). 5 days reaction time. Mp:
88.9-90.6 oC. FT-IR (ZnSe, cm-1): 3395, 1810, 1633, 1473, 1287, 694. 1H (500 MHz, CDCl3) d (ppm):
8.08 (d, 2H, J = 7.55Hz), 7.66-7.62 (m, 3H), 7.58-7.55 (m, 2H), 7.53-7.52 (m, 1H), 7.40 (t, 2H, J =
7.55 Hz), 7.30-7,21 (m, 7H), 7.18 (d, 2H, J = 7.25 Hz), 5.17 (d, 1H, J = 12.40 Hz), 4.71 (d, 1H, J =
12.35 Hz), 4.30-4.25 (m, 2H), 1.28 (t, 3H, J = 7.15 Hz). 13C {1H} (125MHz, CDCl3) d (ppm): 173.2,
168.5, 167.0, 164.0, 135.6, 135.1, 133.9, 133.7, 131.9, 129.1, 129.0, 128.8, 128.7, 128.4, 128.1,
127.9, 127.1, 127.0, 125.1, 75.7, 66.3, 62.2, 47.9, 44.3, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd
+
for C34H29N2O5 545.2071, found 545.2052.
Methyl 1-benzamido-8-oxo-2,3,6-triphenyl-7-oxa-5-azaspiro[3.4]oct-5-ene-1-carboxylate (4n).
The product was prepared according to the Condition B and obtained after flash
chromatography in dichloromethane as a white solid (17.6 mg, 44%). 3 days reaction time. Mp:
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177,2-178,2 oC. FT-IR (ZnSe, cm-1): 2908, 1792, 1721, 1075, 676. H (500 MHz, CDCl3) d (ppm):
8.08 (d, 2H, J = 7.25 Hz), 7.67- 7.62 (m, 3H), 7.57-7.52 (m, 5H), 7.51-7.48 (m, 1H), 7.42- 7.39 (m,
2H), 7.41 (t, 2H, J = 7.65 Hz), 7.31- 7.22 (m, 7H), 7.18 (d, 2H, J = 7.55 Hz), 5.17 (d, 1H, J = 12.45
Hz), 4.70 (d, 1H, J = 12.45 Hz). 13C {1H} (125MHz, CDCl3) d (ppm): 173.3, 169.3, 167.0, 164.0,
135.5, 135.0, 133.9, 133.5, 131.9, 129.1, 129.0, 128.8, 128.7, 128.7, 128.4, 128.1, 127.9, 127.2,
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+
127.0, 125.0, 75.8, 66.3, 48.1, 44.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C33H24D3N2O5
534.2103, found 534.2115.
General procedures for the Synthesis of compounds 5ai-5aiii
After the procedure described in Condition B, was added, in the same pot, 1 mL of
dichloromethane, 10 mol% of CSA and 1.1 equivalent of nucleophile. The vial was sealed with
parafilm and stirred at room temperature for 24 h. After the reaction was complete (as judge by
TLC analysis) and concentrated in vacuo. It is worth mentioning that all equivalents in this step
were calculated based on the starting azlactone of previous procedure (Condition B).
1,2-bis(benzamido)-2-(octylcarbamoyl)-3,4-diphenylcyclobutane-1-carboxylic acid (5a-i). The
product obtained after flash chromatography in dichloromethane as a yellow solid (21.0 mg,
44%). 24 hours reaction time. Mp: 57.4-57.7oC. FT-IR (ZnSe, cm-1): 3351, 2917, 1704, 1650, 1518,
685. 1H (500 MHz, CDCl3) d (ppm): 7.65 (d, 2H, J = 7.25 Hz), 7.55 (d, 2H, J = 7.55 Hz), 7.45-7.38
(m, 4H), 7.37-7.34 (m, 10H), 7.26-7.23 (m, 2H), 6.94 (s, 1H), 6.58 (s, 1H), 5.88 (d, 1H, J = 9.80 Hz),
4.26 (d, 1H, J = 9.80 Hz), 3.68 (t, 2H, J = 7.35 Hz), 1.67-1.64 (m, 2H), 1.30-1.26 (m, 10H), 0.88 (t,
3H, 6.65 Hz). 13C {1H} (125MHz, CDCl3) d (ppm): 176.3, 173.1, 168. 8, 168.3, 136.1, 132.2, 132.1,
129.0, 128.7, 128.6, 128.2, 128.1, 128.0, 127.4, 127.2, 126.9, 65.6, 63.8, 48.0, 46.5, 39.6, 31.9,
+
29.3, 29.2, 27.7, 27.0, 22.8, 14.2. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C40H43N3NaO5
668.3095, found 668.3087.
1,2-bis(benzamido)-2-(benzylcarbamoyl)-3,4-diphenylcyclobutane-1-carboxylic acid (5a-ii). The
product was obtained after flash chromatography in 30% of ethyl acetate in hexane as a yellow
solid (24.0 mg, 51%). 24 hours reaction time. Mp: 140.0-140.3oC. FT-IR (ZnSe, cm-1): 3359, 2917,
1712, 1650, 1482, 1279, 694. 1H (500 MHz, CDCl3) d (ppm): 7.63 (d, 2H, J = 7.10 Hz), 7.48-7.43
(m, 3H), 7.41-7.34 (m, 11H), 7.29-7.22 (m, 6H), 7.21-7.18 (m, 2H), 7.05 (d, 2H, J = 7.15 Hz), 6.91
(s, 1H), 6.58 (s, 1H), 5.79 (d, 1H, J = 9.55 Hz), 4.87 (d, 2H, J = 3.85 Hz), 4.06 (d, 1H, J = 9.90 Hz).
13C {1H} (125MHz, CDCl3) d (ppm): 175.4, 172.6, 172.4, 168.6, 168.2, 135.5, 135.4, 134.3, 133.3,
132.8, 132.1, 132.0, 129.0, 128.9, 128.8, 128.6, 128.6, 128.6, 128.1, 128.0, 127.8, 127.6, 127.1,
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126.8, 65.5, 63.6, 47.6, 46.8, 42.7. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C39H33N3NaO5
646.2312, found 646.2327.
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1,2-bis(benzamido)-2-(butylcarbamoyl)-3,4-diphenylcyclobutane-1-carboxylic acid (5a-iii). The
product was obtained after flash chromatography in dichloromethane as a yellow solid (16.0
mg, 36%). 24 hours reaction time. Mp: 184.4-185.3oC. FT-IR (ZnSe, cm-1): 3351, 2908, 1704, 1642,
1509, 1473, 685. 1H (500 MHz, CDCl3) d (ppm): 7.63 (d, 2H, J = 7.70 Hz), 7.55 (d, 2H, J = 7.40 Hz),
7.46-7.39 (m, 4H), 7.37-7.29 (m, 10H), 7.27-7.24 (m, 2H), 6.92 (s, 1H), 6.57 (s, 1H), 5.87 (d, 1H, J
= 9.4 Hz), 4.26 (d, 1H, J = 10.1 Hz), 3.68 (t, 2H, J = 7.00 Hz), 1.66-1.62 (m, 2H), 1.36-1.32 (m, 2H),
0.92 (t, 3H, J = 7.30 Hz). 13C {1H} (125MHz, CDCl3) d (ppm): 175.4, 172.6, 172.4, 168.6, 168.2,
135.5, 135.4, 134.3, 133.3, 132.8, 132.1, 132.0, 129.0, 128.9, 128.8, 128.6, 128.6, 128.6, 128.1,
128.0, 127.8, 127.6, 127.1, 126.8, 65.5, 63.6, 47.6, 46.8, 42.7. HRMS (ESI-TOF) m/z: [M+Na]+ calcd
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for C36H35N3NaO5 612.2469, found 612.2487.
Supporting Information Statement
1
General methods, copies of H NMR, 13C NMR, IR spectra for all compounds, X-ray
crystallography data, Cartesian coordinates for all stationary points on the potential
energy surface.
Author Information
Corresponding Author
* E-mail: giovanni.amarante@ufjf.edu.br (ORCID = 0000-0003-1004-5395)
Notes
The authors declare no competing financial interest.
Acknowledgments
We are grateful to generous financial support from FAPEMIG, CAPES, CNPq, and Rede Mineira
de Química. We also thank the CNPq for a fellowship to Angelina Maria de Almeida (No.
152367/2016-0). Furthermore, we are grateful to Prof. Fabio Zappa and Prof. Roberto Rosas
Pinho (Physics Department/ UFJF) for the MALDI-TOF analyses. Authors also knowledge Prof.
Hélio F. dos Santos for his help with DFT calculations.
REFERENCES
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1
2
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7
8
9
1.
2.
Hu, J.-L., Feng, L.-W., Wang, L., Xie, Z., Tang, Y., Li, X. Enantioselective Construction of
Cyclobutanes: A New and Concise Approach to the Total Synthesis of (+)-
Piperarborenine B. J. Am. Chem. Soc., 2016, 138, 13151.
Miller, Z. D., Lee, B. J., Yoon, T. P. Enantioselective Crossed Photocycloadditions of
Styrenic Olefins by Lewis Acid Catalyzed Triplet Sensitization. Angew. Chem. Int. Ed.,
2017, 56, 11891.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3.
4.
Yao, X., Conner, M. L., Kevin, B. M. Cyclobutane and Cyclobutene Synthesis: Catalytic
Enantioselective [2+2] Cycloadditions. Angew. Chem. Int. Ed., 2015, 54, 11918.
Chi, Y.-M., Nakamura, M., Yoshizawa, T., Zhao, X.-Y., Yan, W.-M., Hashimoto, F., Kinjo,
J., Nohara, T., Sakurada, S. Antinociceptive Activities of α-Truxillic Acid and β-Truxinic
Acid Derivatives. Biol. Pharm. Bull., 2005, 28, 1776.
5.
6.
Narayanam, J. M. R., Stephenson, C. R. J. Visible light photoredox catalysis: applications
in organic synthesis. Chem. Soc. Rev., 2011, 40, 102.
Chi, Y.-M., Nakamura, M., Zhao, X.-Y., Yoshizawa, T., Yan, W.-M., Hashimoto, F., Kinjo,
J., Nohara, T., Sakurada, S. Anti-inflammatory Activity of 4,4ʹ-Dihydroxy-α-truxillic Acid.
Biol. Pharm. Bull., 2006, 29, 580.
7.
8.
Berger, W. T., Ralph, B. P., Kaczocha, M., Sun, J., Balius, T. E., Rizzo, R. C., Haj-Dahmane,
S., Ojima, I., Deutsch, D. G. Targeting Fatty Acid Binding Protein (FABP) Anandamide
Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-
Nociceptive Drugs. PLOS ONE, 2012, 7, e50968.
a) Poplata, S., Tröster, A., Zou, Y.-Q., Bach, T. Recent Advances in the Synthesis of
Cyclobutanes by Olefin [2ꢀ+ꢀ2] Photocycloaddition Reactions. Chem. Rev., 2016, 116,
9748, b) Shaw, M.H., Twilton, J., MacMillan, D. W. C. Photoredox Catalysis in Organic
Chemistry. J. Org. Chem., 2016, 81, 6898.
9.
Kärkäs,M. D., Porco J. A., Stephenson, C. R. J. Photochemical Approaches to Complex
Chemotypes: Applications in Natural Product Synthesis. Chem. Rev., 2016, 116, 9683.
10.
11.
Pinheiro, D. L. J., Ávila, E. P., Amarante, G. W. A Practicable Synthesis of Oxazol-5(4H)-
ones Through Hydrogenation: Scope and Applications. ChemistrySelect, 2016, 1, 2960.
Melhado, A. D., Amarante, G. W., Wang, Z. J., Luparia M., Toste, F. D. Gold(I)-Catalyzed
Diastereo- and Enantioselective 1,3-Dipolar Cycloaddition and Mannich Reactions of
Azlactones. J. Am. Chem. Soc., 2011, 133, 3517.
12.
13.
Ávila, E. P., Justo, R. M. S., Gonçalves, V. P., Pereira, A. A., Diniz, R., Amarante, G. W.
Chiral Brønsted Acid-Catalyzed Stereoselective Mannich-Type Reaction of Azlactones
with Aldimines. J. Org. Chem., 2015, 80, 590.
Pereira, A. A., de Castro, P. P., de Mello, A. C., Ferreira, B. R. V., Eberlin, M. N., Amarante,
G. W. Brønsted acid catalyzed azlactone ring opening by nucleophiles. Tetrahedron,
2014, 70, 3271.
14.
15.
Pinheiro, D. L. J., Ávila, E. P., Batista, G. M. F., Amarante, G. W. Chemoselective
Reduction of Azlactones Using Schwartz's Reagent. J. Org. Chem., 2017, 82, 5981.
Liu, Q., Li, N., Yuan, Y., Lu, H., Wu, X., Zhou, C., He, M., Su, H., Zhang, M., Wang, J., Wang,
B., Wang, Y., Ma, D., Ye, Y., Weiss, H.-C., Gesing, E. R. F., Liao, J., Wang, M.-W.
Cyclobutane Derivatives As Novel Nonpeptidic Small Molecule Agonists of Glucagon-
Like Peptide-1 Receptor. J. Med. Chem., 2012, 55, 250.
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
16.
García-Montero, A., Rodriguez, A. M., Juan, A., Velders, A. H., Denisi, A., Jiménez-Osés,
G., Gómez-Bengoa, E., Cativiela, C., Gómez, M. V., Urriolabeitia, E. P. Metal-Free [2 + 2]-
Photocycloaddition of (Z)-4-Aryliden-5(4H)-Oxazolones as Straightforward Synthesis of
1,3-Diaminotruxillic Acid Precursors: Synthetic Scope and Mechanistic Studies. ACS
Sustainable Chem. Eng., 2017, 5, 8370.
9
17.
18.
Elena, S., Alberto, J., Angel, G. M., Tatiana, S., Francisco, J. M., Carlos, C., Victoria, G. M.,
Urriolabeitia, E. P. Stereoselective Synthesis of 1,3-Diaminotruxillic Acid Derivatives: An
Advantageous Combination of C-H-ortho-Palladation and On-Flow [2+2]-
Photocycloaddition in Microreactors. Chem. Eur. J., 2016, 22, 144.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Prier, C. K., Rankic, D. A., MacMillan, D. W. C. Visible Light Photoredox Catalysis with
Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev., 2013, 113,
5322.
19.
20.
21.
22.
23.
24.
Stoermer, R., Laage, E. Über die siebente Säure der Truxillsäuregruppe, die Neo-
truxinsäure. (V). Ber. Dtsch. Chem. Ges., 1921, 54, 96.
Stoermer, R., Scholtz, F. Über die 6. Säure der Truxillsäure-Gruppe, ζ-Truxinsäure
(Zetruxinsäure). (IV.). Ber. Dtsch. Chem. Ges., 1921, 54, 85.
de Castro, P. P., Carpanez, A. G., Amarante, G. W. Azlactone Reaction Developments.
Chem. Eur. J., 2016, 22, 10294.
de Castro, P. P., dos Santos, I. F., Amarante, G. W. Brønsted Acid Catalyzed Peptide
Synthesis through Azlactone Rings. Curr. Org. Synth., 2016, 13, 440.
Srivastava, V., Singh, P. P. Eosin Y catalysed photoredox synthesis: a review. RSC Adv.,
2017, 7, 31377.
Sheldrick, G. M. SHELXT – Integrated space-group and crystal-structure determination.
Acta Cryst., 2015, A71, 3–8.
25.
26.
Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Cryst., 2015, C71, 3–8.
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K., Puschmann, H. OLEX2: a
complete structure solution, refinement and analysis program. J. Appl. Cryst., 2009, 42,
339–341.
27.
28.
29.
Farrugia, L. J., WinGX and ORTEP for windows: an update, J. Appl. Crystallogr., 2012, 45,
849–854.
Blanco-Lomas, M., Funes-Ardoiz, I., Campos, P. J., Sampedro D. Oxazolone-Based
Photoswitches: Synthesis and Properties. Eur. J. Org. Chem., 2013, 6611.
Rao, A. M. L. P., Rao, A. S., Babu, M. S., Rao, M. K., Triphenylphosphine (PPh3) Catalyzed
Erlenmeyer Reaction for Azlactones under Solvent-free Conditions. J. Heterocyclic
Chem., 2017, 54, 429.
30.
Dürüst, Y., Sagurlı, A., Fronczek, F. R. Regioselective 1,3-dipolar cycloaddition of
phenanthrolinium N-ylides to substituted arylidene oxazolones. Mol Divers, 2011, 15,
799.
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