Synthesis of an alkylidene 2-oxazolidinone via gold-catalyzed cyclization of a N-boc-allenylaniline

Article abstract of DOI:10.1080/00397911.2011.623260

N-Boc-allenylaniline undergoes cyclization in the presence of a catalytic amount of a cationic gold complex to exclusively form 2-oxazolidinones, whereas the N-Moc-allenylaniline affords dihydroquinolines. Supplemental materials are available for this art

Full text of DOI:10.1080/00397911.2011.623260

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Synthesis of an Alkylidene 2-
Oxazolidinone via Gold-Catalyzed
Cyclization of a N-Boc-Allenylaniline
Flavia C. De Sousa Fonseca a , Flavia M. Araujo a , Tanus J. Nagem a
Tânia T. de Oliveira b , Carlos Roque D. Correia c & Jason G. Taylor a
,
a Departamento de Química, ICEB, Universidade Federal de Ouro
Preto, Ouro Preto, Brazil
b Departamento de Bioquímica e Biologia Celular, Universidade
Federal de Viçosa, Viçosa, Brazil
c Instituto de Química, Universidade Estadual de Campinas,
Campinas, Brazil
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 13 Nov 2012.
To cite this article: Flavia C. De Sousa Fonseca , Flavia M. Araujo , Tanus J. Nagem , Tânia T.
de Oliveira , Carlos Roque D. Correia & Jason G. Taylor (2013): Synthesis of an Alkylidene 2-
Oxazolidinone via Gold-Catalyzed Cyclization of a N-Boc-Allenylaniline, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:5, 768-773
To link to this article: http://dx.doi.org/10.1080/00397911.2011.623260
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Synthetic Communications1, 43: 768–773, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.623260
SYNTHESIS OF AN ALKYLIDENE 2-OXAZOLIDINONE
VIA GOLD-CATALYZED CYCLIZATION OF A
N-BOC-ALLENYLANILINE
Flavia C. De Sousa Fonseca,1 Flavia M. Araujo,1
1
Tanus J. Nagem, Tania T. de Oliveira,
2
ˆ
Carlos Roque D. Correia,3 and Jason G. Taylor1
1
´
Departamento de Quımica, ICEB, Universidade Federal de Ouro Preto,
Ouro Preto, Brazil
2
´
Departamento de Bioquımica e Biologia Celular, Universidade Federal de
Vic¸osa, Vic¸osa, Brazil
3
´
Instituto de Quımica, Universidade Estadual de Campinas, Campinas, Brazil
GRAPHICAL ABSTRACT
Abstract N-Boc-allenylaniline undergoes cyclization in the presence of a catalytic amount
of a cationic gold complex to exclusively form 2-oxazolidinones, whereas the N-Moc-
allenylaniline affords dihydroquinolines.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Synthetic Communications1 to view the free supplemental file.
Keywords Allenes; catalyst; dihydroquinolines; gold; hydroarylation; 2-oxazolidinones
Received August 25, 2011.
Address correspondence to Jason G. Taylor, Departamento de Quımica, ICEB, Universidade
´
Federal de Ouro Preto, Campus Universitario Morro do Cruzeiro, Ouro Preto, MG, Brazil. E-mail:
jason@iceb.ufop.br
´
768

ALKYLIDENE 2-OXAZOLIDINONE
769
INTRODUCTION
The application of cationic gold complexes as catalyst for organic reactions has
received a huge amount of attention in recent years.[1] They have been proven to
be excellent catalysts for facilitating the construction of a variety of carbon–carbon,
carbon–oxygen, and carbon–nitrogen compounds, and their application in total
syntheses of natural products is becoming more popular among synthetic organic
chemists.[2] Cationic gold complexes are able to activate both alkynes and allenes
for intramolecular hydroarylation reactions, providing a diverse array of chromene
and dihydroquinoline derivatives (Scheme 1).[3]
Researchers have demonstrated that in the case of N-Boc-protected alkynyla-
mines, the corresponding alkylidene 2-oxazolidinones or 2-oxazinones were afforded
(Scheme 2).[4a–c]
On the other hand, when Watanabe and coworkers employed N-Moc-
allenylaniline as substrate, dihydroquinolines were isolated (Scheme 1).[3b]
Noteworthy is the fact that for the synthesis of the majority of N-Boc-
alkynylamines and also for the N-Moc-allenylaniline activated by the presence two
meta-methoxy groups, the reaction proceeds quickly and often goes to completion
in less than 30 min. Thus, the cyclization of an N-Boc-allenylaniline, which has
never been reported until now, could proceed through two competing mechanistic
Scheme 1. Gold(I)-catalyzed hydroarylation reactions.
Scheme 2. Synthesis of 2-oxazolidinones.

770
F. C. DE SOUSA FONSECA ET AL.
pathways to yield either a dihydroquinoline by an intramolecular hydroarylation
reaction or a 2-oxazolidinone through addition of the carbonyl oxygen to the
carbon–carbon multiple bond. In this context, we disclose herein our investigations
of the gold-catalyzed cyclization of an N-Boc-allenylaniline to provide further mech-
anistic insights into the directing nature of the protecting group.
RESULTS AND DISCUSSION
The required allene precursor could be conveniently prepared from the
commercially available 3,5-dimethoxyaniline 1, which was initially subjected to
Boc protection using a standard protocol (Scheme 3). Tert-butyl 3,5-dimethoxyphe-
nylcarbamate was afforded as a white solid with a melting point recorded at
1
75–76 ꢀC, and its H NMR data were consistent with the literature values.[5] Com-
pound 2 was obtained in good yield and subsequently alkylated with propargyl bro-
mide in the presence of sodium hydride as base at room temperature for 16 h. The
expected tertiary amine 3 was isolated in 91% yield after purification by column
chromatography and confirmed by the presence of a methylene resonance at
4.33 ppm as a doublet and the terminal alkyne hydrogen at 2.25 ppm as a distinct
triplet. Finally, the desired allene was prepared by a base-induced isomerization of
3 at 0 ꢀC under an atmosphere of argon for 14 h to provide 4 in a modest 54% yield
as a pale yellow oil. Compound 4 was readily identified by the disappearance of a
1
triplet signal in the H NMR at 2.25 ppm and the concomitant disappearance of
the CH2 resonance at 40.2 ppm in the 13C NMR and distortionless enhancement
by polarization transfer (DEPT)-135 NMR spectra (see Supplementary Data,
available online).
In our initial experiment, the model substrate was stirred at room temperature
in the presence of 1 mol% of gold catalyst 5 in deoxygenated dioxane under an argon
atmosphere for 30 min (Scheme 4). Analysis of the crude reaction mixture by
thin-layer chromatography (TLC) indicated that the starting material had been com-
pletely consumed and had been cleanly converted to a single product. Upon purifi-
cation by column chromatography we isolated and identified the corresponding
2-oxazolidinone 6, and the formation of dihydroquinoline 7 was not observed. Com-
pound 6 was characterized by its nonmagnetically equivalent olefinic hydrogens,
which were observed at 4.85 and 4.42 ppm, and its molecular identify was confirmed
by 13C NMR spectroscopy and high-resolution mass spectrometry. Although the
2-oxazolidinone was isolated in poor yield, we were intrigued by the selectivity of
Scheme 3. Synthesis of allene substrate 4.

ALKYLIDENE 2-OXAZOLIDINONE
771
Scheme 4. Investigation of Au(I)-catalyzed cyclization of an N-Boc-allenylaniline.
the reaction and therefore repeated the cyclization using a similar cationic gold cata-
lyst without a phosphine ligand in order to discern the role of the ligand (if any) and
the oxidation state of the gold catalyst in controlling the reaction outcome. Employ-
ing 5 mol% of AuCl3 and 15 mol% AgOTf we were surprised to find that 6 could
once again be afforded exclusively with a drastic improvement in product yield.
Based on these results, we propose that the initial formation of 6 in preference
to 7 is not directed by the steric nature of the catalyst and is simply controlled by the
relative reactivities of two nucleophilic sites for attack present in allene 4. A catalytic
cycle analogous to that proposed by Robles-Machin and collaborators[4] is invoked
to rationalize the cyclization and begins with activation of the multiple bond by p-
coordination to the cationic gold complex (Scheme 5). Even though our experiments
utilized an electron-rich arene, hydroarylation seems to be significantly slower (4 to
Scheme 5. Plausible catalytic cycle.

772
F. C. DE SOUSA FONSECA ET AL.
I) than nucleophilic attack by the carbonyl oxygen (4 to II) and formation of 6 would
also be driven by the liberation of isobutene (II to III), which represents an irrevers-
ible step in the catalytic cycle.
CONCLUSION
In conclusion, the cyclisation of an N-Boc-allenylaniline by a cationic gold
catalyst has been reported for the first time and was found to preferentially form
the corresponding N-aryl oxazolidone irrespectively of the steric bulk of the phos-
phine ligand. Studies are ongoing in our group to explore the electronic effects of
the ligand and substrate in the hope of switching the selectivity to bias the formation
of useful N-Boc protected dihydroquinolines.
EXPERIMENTAL
All commercial reagents were used as received. Column chromatography was
performed using silica gel 200–400 Mesh. TLC analysis were performed using silica
gel plates, using ultraviolet light (254 nm) or vanillin solution for visualization.
Melting points are uncorrected.
IR spectra were recorded using samples that were prepared as either a liquid
film between NaCl plates, or pressed in to KBr discs. The chemical shifts are
reported in d (ppm) referenced to residual protons and 13C signals in deuterated
chloroform. The coupling constants (J) are expressed in Hertz (Hz).
Compound 2.5 In a 2 necked round bottom flask (100 mL) equipped with stir bar
and reflux condenser was charged 3,5-dimethoxy aniline (20 mmol) and the air purged
with argon. Dry THF (35 mL) was added followed by (Boc)2O (22 mmol) and the sol-
ution refluxed overnight. Upon completion, the solvent was removed under vacuo
and the residue taken up in to EtOAc=H2O (20 mL=40 mL). The organic layer was
washed with saturated brine, dried over MgSO4, reduced under pressure and purified
by column chromatography (10% EtOAc=Hexane) to afford a white solid (78%).
1
Rf ¼ 0.32 (Hexanes=EtOAc, 4:1); mp. 75–76 ꢀC; NMR H (250 MHz, CDCl3) d:
6.61 (2H, d, J 2.3), 6.49 (1H, s), 6.17 (1H, t, J 2.3), 3.77 (6H, s), 1.51 (9H, s); NMR
13C (62.5 MHz) d: 161.1, 152.5, 140.2, 96.6, 95.5, 80.5, 55.3, 80.5, 55.3, 28.3.
Compound 3. In a 2 necked round bottom flask (50 mL) equipped with stir bar
was charged 2 (3.6 mmol) and the air purged with argon. Dry DMF (9 mL) was
added followed by NaH (4 mmol) and the mixture allowed to stirr for 30 minutes
untill gas evolution had ceased. Next, the alkyne was added dropwise by syringe
at 0 ꢀC and the mixture left to stir overnight at room temperature. Upon completion,
the solution was taken up in to EtOAc=H2O (15 mL=45 mL) and worked up in the
usual way to provide a pale yellow oil after purification by column chromatography
using 10% EtoAc=Hexane (91%). Rf ¼ 0.41 (Hexanes=EtOAc, 4:1); NMR 1H
(250 MHz, CDCl3) d: 6.65 (2H, d, J 2.3), 6.35 (1H, t, J 2.3), 4.33 (2H, d, J 2.3),
3.78 (6H, s), 2.26 (1H, t, J 2.3), 1.47 (9H, s); NMR 13C (62.5 MHz) d: 160.6,
153.8, 143.8, 104.7, 98.5, 81.1, 80.0, 71.7, 55.3, 39.8, 28.3; HRMS m=z (EI): calcd.
for C16H21NO4 291.1471, found 291.1475.
Compound 4. In a 2 necked round bottom flask (50 mL) equipped with stir bar
was charged KOBut (1.43 mmol) and the air purged with argon. Compound 3

ALKYLIDENE 2-OXAZOLIDINONE
773
dissolved in dry THF (2.87 mmol in 15 mL) was added dropwise by syringe at 0 ꢀC
and then allowed to warm to room temperature and left to stir overnight. Upon
completion, the mixture was filtered throgh celite, reduced under pressure and the
residue purified by column chromatography using 10% EtoAc=Hexane to yield a
pale yellow oil (54%). Rf ¼ 0.40 (Hexanes= EtOAc, 4:1); NMR 1H (250 MHz,
CDCl3) d: 7.22 (1H, t, J 6.5), 6.34–6.39 (3H, m), 5.07 (2H, d, J 6.3), 3.77 (6H, s),
1.45 (9H, s); NMR 13C (62.5 MHz) d: 201.4, 160.4, 152.1, 140.8, 106.4, 101.7,
99.5, 86.4, 81.5, 55.3, 28.2; HRMS m=z (EI): calcd. for C16H21NO4 291.1471, found
291.1468.
Compound 6. In a Schlenk tube (20 mL) equipped with stir bar was compound
4 (1.43 mmol), catalyst (1 mol% of 5 þ 1 mol% AgOTf or 5 mol% AuCl3 þ 15 mol%
AgOTf) and the air purged with argon. Degassed 1,4-dioxane (5 mL using the freeze
thaw method) was added and the reaction stirred at room temperature and left for
minutes. Upon completion, the solvent was filtered through cotton wool, reduced
under vacuo and the crude yellow oil analysed by NMR. The 2-oxazolidinone was
purified by column chromatography using 25% EtoAc=Hexane to yield a white solid
(38 or 82%). Rf ¼ 0.15 (Hexanes= EtOAc, 4:1); mp. 156–157 ꢀC; NMR 1H (250 MHz,
CDCl3) d: 6.74 (2H, t, J 2.0), 6.27 (1H, t, J 2.0), 4.85 (1H, q, J 2.5), 4.59 (2H, t, J 2.3),
4.40-4.43 (1H, m), 3.80 (6H, s); NMR 13C (62.5 MHz) d: 161.2, 152.2, 147.5, 139.0,
96.7, 96.3, 87.0, 55.5, 48.5; HRMS m=z (EI): calcd. for C12H13NO4 235.0845, found
235.0849.
ACKNOWLEDGMENTS
´
The authors thank the Conselho Nacional de Desenvolvimento Cientıfico e
´
Tecnologico (CNPq), the Fundac¸a˜o Coordenac¸a˜o de Aperfeic¸oamento de Pessoal
´
`
de Nıvel Superior (CAPES), and the Fundac¸a˜o de Amparo a Pesquisa do Estado
de Minas Gerais (FAPEMIG) for financial support. Thanks go to Dr. Robson J.
´
de Cassia FrancoAfonso, and Dr. Maurıcio Xavier Coutrim for providing excellent
Mass Spectrometry service.
´
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