Gold(I)-catalyzed reactions of 1-(ortho-alkynylaryl)ureas: Highly selective heterocyclization and synthesis of mixed N,O-acetals

Article abstract of DOI:10.1002/adsc.201300730

Readily available 1-(ortho-ethynylaryl)urea derivatives undergo a selective gold/silver {[AuCl(IPr)]/AgSbF₆} catalyzed N-6-exo-dig or N-5- endo-dig heterocyclization process in dimethylform-amide (DMF) at 60 8C. Benzoxazine derivatives, i.e., the products of O-6-exo-dig ring closure through the urea oxygen, could be observed under catalytic conditions only when the N-3 basicity was substantially diminished, but were readily isolable in stoichiometric processes carried out at low temperature. The open chain amino O,O-acetals and a series of new cyclic mixed N,O-acetals containing the trifluoroethyl group were synthesized when the reactions were performed in ethanol or trifluoro-ethanol, respectively, as solvent. The procedure allows for an easy access to this versatile class of key intermediates in organic synthesis from simple starting materials. The effect of using either DMF or protic solvents on the course of the reactions is reported.

Full text of DOI:10.1002/adsc.201300730

UPDATES
DOI: 10.1002/adsc.201300730
Gold(I)-Catalyzed Reactions of 1-(ortho-Alkynylaryl)ureas:
Highly Selective Heterocyclization and Synthesis of Mixed
N,O-Acetals
Ana Gimeno,a Ana B. Cuenca,a Mercedes Medio-Simꢀn,a,* and Gregorio Asensioa
a
Departamento de Quꢁmica Orgꢂnica, Universidad de Valencia, Avda. Vicent Andrꢃs Estellꢃs s/n, 46100 Burjassot,
Valencia, Spain
Fax : (+34)-96-354-4939; e-mail: mercedes.medio@uv.es
Received: August 12, 2013; Revised: October 28, 2013; Published online: January 8, 2014
Dedicated to Prof. A. Laguna on occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300730.
Abstract: Readily available 1-(ortho-ethynylaryl)ur-
ea derivatives undergo selective gold/silver
{[AuCl(IPr)]/AgSbF6} catalyzed N-6-exo-dig or N-5-
endo-dig heterocyclization process in dimethylform-
amide (DMF) at 608C. Benzoxazine derivatives,
i.e., the products of O-6-exo-dig ring closure
through the urea oxygen, could be observed under
catalytic conditions only when the N-3 basicity was
substantially diminished, but were readily isolable
in stoichiometric processes carried out at low tem-
perature. The open chain amino O,O-acetals and
a series of new cyclic mixed N,O-acetals containing
the trifluoroethyl group were synthesized when the
reactions were performed in ethanol or trifluoro-
tained.[3] Alkynyl compounds carrying ambident nu-
cleophiles, such as amides or carbamates, further
expand the array of the possible regioisomeric prod-
uct given that the heterocyclization can now take
place either through O- or N-ring closure process-
es.[4–6] In some cases, intrinsic geometric restrictions in
the substrate framework preclude one or more of
these routes resulting in a selective cyclization. Alk-
a
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ynylureas[7–13] constitute a particularly challenging
case since three potential nucleophiles and two elec-
trophilic carbon atoms coexist in the molecule, in-
creasing the number of possible regioisomers. The in-
trinsic potential of this class of transformations
prompted us to report in a preliminary communica-
tion the distinct cyclization paths followed by the al-
kynylurea derivatives 1 (Scheme 1).[7] Thus, we found
ACHTUNGTRENNUNGethanol, respectively, as solvent. The procedure
allows for an easy access to this versatile class of
key intermediates in organic synthesis from simple
starting materials. The effect of using either DMF
or protic solvents on the course of the reactions is
reported.
that the [AuClACHTNUGRTENUNG(IPr)]/AgSbF6 catalytic system was very
efficient in promoting in DMF at 608C exclusively the
N-6-exo-dig hydroaminative cyclization of a wide vari-
ety of 1-(ortho-ethynylaryl)ureas 1[14] carrying elec-
tron-donating or electron-withdrawing substituents at
the aromatic ring and a variety of alkyl or aryl R3
groups attached at the N-3 position, to give quinazo-
lin-2-ones 2.
Keywords: alkynes; gold; hydroamination; regiose-
lectivity
Compounds 1 containing a pyridine ring or derived
from internal alkynes could, at the same time, also
serve as precursors for the pyrrolopyridine 3 or indole
4 rings,[15] through the commonly favored 5-endo-dig
cyclization process (Scheme 1).[16,17]
Introduction
Homogeneous gold catalysis is a powerful synthetic
In contrast to our results, a similar Au(I)-catalyzed
tool, which is becoming increasingly useful with new reaction of 1-(ortho-ethynylaryl)ureas bearing a termi-
transformations being discovered almost on a daily nal alkyne reported by Liu[8] led exclusively to the
basis.[1] Specifically, the exceptional ability of this corresponding indole derivatives 3 under microwave
metal to activate p systems, especially alkynes, to- heating. Shortly afterwards, Toste et al.[9] described
wards nucleophilic attack enables an easy approach to the Au(I)-catalyzed preparation of propargylic ureas
heterocycles,[2] although the desired endo/exo-dig se- in the three-component reaction of an imine, an
lectivity in the triple bond activation is not always at-
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Ana Gimeno et al.
Scheme 1. Gold-catalyzed heterocyclization of 1-(ortho-alkynylaryl)ureas 1.
alkyne and tosyl isocyanate, followed by their subse-
quent in situ O-cyclization (Scheme 2).
Hence, the synthetic potential of the heterocycliza-
tion reaction of the substituted alkynes, coupled with
Almost simultaneously, Van der Eycken[10] reported the somewhat puzzling results summarized above led
the Ag(I)-catalyzed N-cyclization of propargylic ureas us to follow up on our preliminary study[7] on the
derived from secondary propargylic amines and, products obtained from (ortho-alkynylaryl)ureas in
later,[11] a detailed comparative study of the selective Au(I)-catalyzed reactions in order to clarify in partic-
O- and N-cycloisomerization of propargylic ureas ular the origin of the N/O selectivity reported and fur-
with Au(I) and Ag(I) catalysts (Scheme 2). Other ther explore the synthetic scope of these transforma-
studies have confirmed that Ag(I) and other coinage tions. Here, we update our preliminary report with
metals catalyze the O-cyclization of structurally relat- our study of these reactions at low temperature or in
ed o-alkynylbenzamides.[5b–d]
protic solvents leading to the selective synthesis of
Importantly, these reports of the Au(I)-catalyzed benzoxazines, acetals or mixed N,O-acetals depending
O-heterocyclization of propargylic ureas and Ag(I)- on the reaction conditions.
catalyzed O-cyclization of o-alkynylbenzamides are in
sharp contrast with our findings of the exclusive N-
cyclization observed for the 1-(ortho-alkynylaryl)ur-
eas (Scheme 1).[7]
Scheme 2. Other gold(I)-catalyzed cyclization reactions of alkynylureas.
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Gold(I)-Catalyzed Reactions of 1-(ortho-Alkynylaryl)ureas
Results and Discussion
According to these experiments, benzoxazines 5
seem to be the kinetic products in the 6-exo-dig cycli-
zation of 1-(ortho-alkynylaryl)ureas, which could be
observed and isolated only in reactions performed at
N/O Selectivity in the 6-exo-dig Cyclization
Products resulting from the nucleophilic attack of the low temperature but not in catalytic reactions which
urea oxygen atom in the ring closure reaction of alk- require higher temperatures to be efficient. Moreover,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ic species, even though these compounds should be 3 h, full conversion of 5a into quinazolin-2-one 2a was
expected to be produced under kinetic control[18] in observed (Scheme 4). In contrast, 5a was recovered
the heterocyclization reaction. The reaction of 1a in intact in the absence of catalyst under similar condi-
DMF-d7 at À308C catalyzed with 10 mol% [AuCl- tions of solvent and temperature. These experiments
ACHTUNGTRENNUNG(IPr)] and 15 mol% AgSbF6 was selected to follow would explain why 5a was never detected in the cata-
the evolution of the process by NMR. This catalytic lytic heterocyclization reaction of 1a.
system was selected since it affords exclusively the N-
Transient presence of ketone 6a, generated most
6-exo-dig heterocyclization product.[7] The starting probably in the gold-catalyzed hydrolysis of benzoxa-
alkACHTUNGTRENNUNGynylurea remained unaltered after 16 h at this low zine 5a, was detected when the transformation of 5a
temperature, but was transformed gradually into qui- into 2a was carefully monitored by 1H NMR
nazolin-2-one 2a when the sample was warmed slowly (Scheme 4).[19] Similar results were observed for reac-
to 208C; the formation of benzoxazine 5a resulting tions promoted with the [AuACTHUNRTGNEUNG(PPh3)]SbF6 cationic
from the 6-exo-dig oxygen attack could not even be complex under the same conditions. In other words,
detected. To accelerate the reaction at low tempera- only formation of benzoxazine 5a was observed at
ture, 1a was treated with a stoichiometric amount of À308C under stoichiometric conditions; but com-
[AuCl
(IPr)]/AgSbF6 in DMF-d7 at À308C in an NMR pound 5a could not be even detected when the reac-
tube. After 2 h at this low temperature, the formation tions were performed under catalytic conditions at
of an equimolecular mixture of 2a and 5a was ob- 608C.[19]
served. Compounds 2a and 5a could be isolated and
Consequently, the adventitious presence of trace
fully characterized from this mixture after eliminating amounts of water in the reaction medium due to the
the catalyst by filtration on alumina at À308C (see highly hygroscopic nature of silver hexafluoroantimo-
Experimental Section) (Scheme 3).
nate used in the catalytic system would justify, at least
in part,[20] that the formation of the benzoxazine 5a
was not be observed under catalytic conditions at
608C. To minimize the water content in the reaction
medium, we explored the cyclization of 1a promoted
by the catalytic cationic complex [AuACTHNUTRGENUG(N IPr)]NTf2
(5 mol%) in DMF at 608C. However, even under
these conditions, quinazolin-2-one 2a was the only
product observed.[21] The vinyl ether function in benz-
AHCTUNGTREGUNoNN xazine 5a appeared to be quite reactive under our
reaction conditions since 2a derives from 5a by hy-
drolysis and subsequent condensation. It should be
noted that water is necessary only in catalytic amount
for this isomerization.
Scheme 3. Stoichiometric cyclization of urea 1a with [AuCl-
A
Scheme 4. ACHTUNGTRENNUNG[AuClACHTUNGTRENNUNG(IPr)]/AgSbF6-catalyzed conversion of 5a into 2a where ketone 6a was detected as intermediate.
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Ana Gimeno et al.
Mixed N,O-Acetals
The easy Au(I)-promoted hydrolysis of benzoxazine
5a prompted us to study the Au(I)-catalyzed hetero-
cyclization of alkynylureas 1 in a protic medium. The
reaction of alkynylurea 1a with 5 mol% [AuClACHTUNGTRENNUNG(IPr)]/
7.5 mol% AgSbF6 in EtOH at room temperature gave
the open chain acetal 8a in 60% yield (Scheme 7).
Two alternative or simultaneous reaction pathways
would account for the formation of the observed
acetal, namely (i) the direct Au(I)-catalyzed intermo-
lecular addition of ethanol to the terminal alkyne.[23]
and/or (ii) the Au(I)-catalyzed solvolysis of the intra-
molecular benzoxazine 5a. The open chain acetal de-
Scheme 5. Gold-catalyzed heterocyclization of urea 1b.
rived from alkyl-substituted urea 1c (R3 =Et) was de-
1
In a further attempt to obtain a benzoxazine less tected by H NMR but was quite unstable and could
prone to the hydrolysis, we synthetized alkynylurea not be isolated, giving rise to an inseparable mixture
1b from the commercially available tosyl isocya- of the corresponding cyclic mixed N,O-acetal and qui-
nate.[9–11] The carbonyl oxygen and the N-3 nitrogen nazoline 2c which evolved to give pure 2c after sever-
atoms should be less basic than in the ureas previous- al hours.
ly tested. In this case, benzoxazine 5b was indeed
more stable and could be prepared with catalytic sentative N-3 substituted alkynylureas 1 in trifluoro-
[AuCl(IPr)]/AgSbF6 in DMF at 608C mixed with ethanol at 408C with 5 mol% of [AuCl(IPr)]/AgSbF6
quinazolin-2-one 2b in a 1:1.4 ratio. The dependence catalyst gave the heterocyclic mixed N,O-acetals 9
However, the reaction of 0.1M solutions of repre-
A
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
of the 5b:2b ratio on the catalytic system used was (see Table 1) in generally satisfactory yields. Mixed
evidenced by the reverse 1.8:1 value observed when N,O-acetals are key intermediates in carbon-carbon
the reaction was promoted with the less hygroscopic bond-forming reactions[24] and the method developed
cationic complex [Au
(IPr)]NTf2 (Scheme 5).
herein for these compounds is simple, mild and pro-
heteroACHTUNGTRENNUNGcyclization product 7 was obtained (Scheme 6). (entries 2, 3 and 4, Table 1). Conversely, the reaction
The product was found to be very stable and did not was less efficient with compounds bearing a less nu-
isomerize after heating at 608C for 16 h in DMF in cleophilic N-3 nitrogen such as the phenyl-, benzyl- or
presence of 5 mol% [AuClACHTNUGTRENUNG(IPr)]/AgSbF6 (Scheme 6). allyl-substituted ureas 1a, 1f and 1g, providing lower
The different behavior of ethynylureas and thioureas yields of the corresponding fluorinated mixed acetals
in the heterocyclization reaction, as well as the differ- 9. The influence of the substituents on the core aro-
ences found in the behavior of the cyclic derivatives 5 matic ring was also evaluated. The mixed N,O-acetal
and 7, agree well with the usual reactivity shown by 9h was obtained with good yield from the correspond-
carbonyl and thiocarbonyl compounds.[22]
ing urea 1h.
Scheme 6. Direct cyclization of ortho-ethynylaniline with
ethyl isothiocyanate.
Scheme 7. Gold(I)-catalyzed reactions of alkynylureas 1 in
EtOH.
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Gold(I)-Catalyzed Reactions of 1-(ortho-Alkynylaryl)ureas
Table 1. Synthesis of fluorinated mixed acetals 9 through Au(I)-catalyzed intramolecular hydroamina-
tive reactions of 1-(o-ethynylaryl)ureas 1 in CF3CH2OH.
[a]
Isolated yields.
[b]
Formation of the corresponding open chain acetals 10 (13–25% yields) was observed.
However, the presence of electron-donating sub- performed. First, we heated a solution of quinazolin-
stituents (R2 =Me and R2 =i-Pr) on this ring of the 2-one 2c in TFE at 408C in the presence of 5 mol%
starting urea 1 decreased the efficiency of the forma- [AuClACHTNUTRGNE(NUG IPr)]/7.5 mol% AgSbF6; after 24 h compound
tion of the mixed acetals 9i and 9j (see entries 8 and 9 2c was recovered unchanged. This experiment al-
Table 1).[26] The formation of the aforementioned new lowed us to exclude the protodemetallated com-
mixed N,O-acetals 9 should be attributed most proba- pounds 2 as precursors in the formation of N,O-ace-
bly to the poor nucleophilic character of trifluoro- tals 9 (Scheme 8).
ACHTUNGTRENNUNGethanol compared to water or ethanol, and the effi-
ciency of their preparation is also a function of the
nucleophilic character of the N-3 urea nitrogen. In ad-
dition, to proceed efficiently the reaction requires
neat trifluoroethanol as solvent. The use of a 4:1 or
2:1 TFE/DMF solvent under similar conditions only
gave the corresponding quinazolin-2-ones 2.
To get a better insight into the mechanism of the
formation of compounds 9, several experiments were Scheme 8. Attempted transformation of 2c into 9c.
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Ana Gimeno et al.
ents at N-3 have little influence on the course of the
reaction, but internal alkynes undergo exclusively 5-
endo-dig N-heterocyclization. The benzoxazine ring,
the kinetic framework expected from a 6-exo-dig ring
closure through the urea oxygen, is only partially
formed under catalytic conditions when the basicity at
N-3 is substantially diminished by tosyl substitution.
Conversely, benzoxazines were isolated in the pro-
cesses carried out at low temperature. Reactions were
slow under these conditions and were accelerated by
using Au(I) in stoichiometric amount to achieve an
acceptable conversion. The adventitious presence of
trace amounts of water in the reaction medium, diffi-
cult to avoid due to the highly hygroscopic nature of
solvent and catalyst, justifies why benzoxazine deriva-
tives are never observed in the reactions of the
normal ureas under catalytic conditions at 608C.
However, a transient presence of the ketone resulting
from hydrolysis of the benzoxazine ring could be de-
Scheme 9. Catalytic conversion of 5c into 9c.
Scheme 10. Stoichiometric cyclization of urea 1c with [AuCl-
A
1
tected by H NMR. Carrying out the catalytic reac-
Then, we decided to explore compounds 5 as possi- tions in ethanol, instead of DMF the corresponding
ble reaction intermediates in this transformation. The open chain amino O,O-acetals were isolated. Use of
trifluoroethoxydihydroquinazolin-2-one 9c was ob- trifluoroethanol, a less basic alcohol, as solvent allows
tained with >95% yield when a TFE solution of 5c us to modify the outcome of the solvolysis reaction
was heated for 4 h with 5 mol% [AuCl
7.5 mol% AgSbF6 (Scheme 9).
ACHTUNGTRENNUNG
This fact strongly suggests that benzoxazines 5, the a simple manner from readily available starting mate-
kinetic cyclization products from alkynylureas 1, react rials.
with TFE under our reaction conditions to give the
corresponding mixed N,O-acetals 9.[27] Thus, to detect
a possible kinetic intermediate in this reaction, equi- Experimental Section
molecular amounts of urea 1c and the gold complex
[AuClACHTUNGTRENNUNG(IPr)]/AgSbF6 in TFE were allowed to react at Representative Procedure for the Gold(I)-Mediated
À308C and the mixture was left standing for 12 h at Hydroaminative Cyclization of 1-(ortho-Ethynyl-
this low temperature (Scheme 10) (for additional de- phenyl)-3-phenylurea (1a); Synthesis of Benzoxazine
tails see the Supporting Information). Formation of 5a
benzoxazine 5c mixed with the starting material was
observed by H NMR while the generation of quina-
A
solution of 1-(2-ethynylphenyl)-3-phenylurea 1a
(0.062 mmol) in DMF-d7 (30 mL) was added to an NMR
tube containing a solution of [Au(IPr)]SbF6 (0.062 mmol)
(generated from a stoichiometric mixture of [AuCl(IPr)]
1
zolin-2-one 2c was inhibited under these conditions.
These results would explain the fact that the forma-
tion of compounds 9 is favored when the basicity of
the urea N-3 position is increased with the introduc-
tion of alkyl substituents. Accordingly, the less basic
N-3 substituted ureas 1a, 1f and 1g allow the competi-
tive incorporation of a second molecule of TFE with
formation of the corresponding open chain acetals
10.[28]
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
and AgSbF6) in DMF-d7 (0.5 mL) at À308C. The tube was
shaken and placed in the probe of an NMR spectrometer
precooled at À308C and the reaction was monitored by
1H NMR. H NMR analysis after 2 h revealed complete con-
1
version of urea 1a in the corresponding quinazolin-2-one 2a
and benzoxazine 5a in a 1.2:1 ratio.
Representative Procedure for Gold(I)-Catalyzed
Heterocyclization of Ureas 1 in TFE: Synthesis of
Mixed N,O-Acetals 9
Conclusions
An oven-dried resealable test tube with a Teflon stirring bar
was charged with 1-(ortho-ethylaryl)urea 1 (0.5 mmol) dis-
solved in dried CF3CH2OH (4 mL). Subsequently, [AuCl-
AHCTUNGTRENG(NNU IPr)] (5 mol%) and AgSbF6 (7.5 mol%) were added. The
tube was sealed with a Teflon screw-cap and placed in an oil
In conclusion, Au(I)-catalyzed hydroamination of the
readily available 1-(ortho-ethynylaryl)ureas at 608C
in DMF allows the selective preparation of quinazo-
lin-2-one and indole derivatives through a 6-exo-dig
or a 5-endo-dig N-heterocyclization process, respec-
bath at 408C. The reaction mixture was heated at this tem-
tively, with high to good yields. Alkyl or aryl substitu- perature and stirred for 20 h. Next, the mixture was cooled
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Gold(I)-Catalyzed Reactions of 1-(ortho-Alkynylaryl)ureas
to room temperature, diluted with dichloromethane (2–
3 mL), and filtered over activated aluminum oxide. The sol-
vent was removed under reduced pressure and the fluorinat-
ed mixed N,O-acetals 9 were isolated by silica gel column
chromatography (hexane/ethyl acetate).
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Further experimental details, characterization of all new
1
isolated compounds, and copies of H and 13C NMR spectra
for quinazolin-2-ones 2, indoles 3 and 4, benzoxacines 5,
acetals 8 and fluorinated compounds 9 are available in the
Supporting Information.
Acknowledgements
This work was supported by the Spanish Ministerio de Cien-
cia e Innovaciꢀn, European Community Founds (FEDER)
and Generalitat Valenciana Grants (CTQ 2010-19999), Con-
solider-Ingenio 2010 (CSD2007-00006) and (ACOMP-2013/
185). We (A.G.) thank the Generalitat Valenciana for a fel-
lowship. We acknowledge the SCSIE (Universidad de Valen-
cia) for access to instrumental facilities.
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236
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Adv. Synth. Catal. 2014, 356, 229 – 236