NHC-stabilized gold(I) complexes: Suitable catalysts for 6-exo-dig heterocyclization of 1-(o-Ethynylaryl)ureas

Article abstract of DOI:10.1021/ol100595s

Figure presented 3-substituted 1-(o-ethynylaryl)ureas 1 selectively undergo either 6-exo-dig or 5-endo-dig cyclization (to give 4-methylene-3,4-quinazolin- 2-ones 2 or indoles 3, respectively) depending on the choice of the metal, ligand, and reaction conditions. The best results (up to 96% yield) in the preparation of the hydroamination products 2 are achieved with the highly bulky NHC-stabilized cationic gold(I) complex [Au(IPr)]⁺. Conversely, ureas bearing an internal alkyne lead to the 5-endo-dig cyclization mode regardless of the gold(I) complex employed. Whereas the nature of the substituent at N-3 does not have any influence on the regiochemistry observed, it does, in some cases, affect the efficiency of these transformations.

Full text of DOI:10.1021/ol100595s

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1900-1903
NHC-Stabilized Gold(I) Complexes:
Suitable Catalysts for 6-exo-dig
Heterocyclization of 1-(o-Ethynylaryl)ureas
Ana Gimeno, Mercedes Medio-Simo´n, Carmen Ram´ırez de Arellano,
Gregorio Asensio,* and Ana B. Cuenca
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, 46100 Burjassot,
Valencia, Spain
gregorio.asensio@uV.es
Received December 23, 2009
ABSTRACT
3-substituted 1-(o-ethynylaryl)ureas 1 selectively undergo either 6-exo-dig or 5-endo-dig cyclization (to give 4-methylene-3,4-quinazolin-2-ones 2 or
indoles 3, respectively) depending on the choice of the metal, ligand, and reaction conditions. The best results (up to 96% yield) in the preparation
of the hydroamination products 2 are achieved with the highly bulky NHC-stabilized cationic gold(I) complex [Au(IPr)]+. Conversely, ureas bearing an
internal alkyne lead to the 5-endo-dig cyclization mode regardless of the gold(I) complex employed. Whereas the nature of the substituent at N-3 does
not have any influence on the regiochemistry observed, it does, in some cases, affect the efficiency of these transformations.
A number of remarkable gold-catalyzed1 hydroamination
reactions have been successfully developed in the past few
years.2,3 Among these, annulation of o-alkynylaniline deriva-
tives constitutes a well-established route to indole rings via
a highly favored 5-endo-dig process.4 In contrast, the
possibility that such substrates could be used to access the
less favored 6-exo-dig cyclization products has drawn
relatively little attention.5 Intrigued by the potential of such
a reaction path, we focused our attention on the gold-
catalyzed intramolecular hydroamidation reaction of 3-sub-
stituted 1-(o-alkynylaryl)ureas 1, prepared from the readily
accessible o-alkynylanilines and isocyanates.
3,4-dihydroquinazolin-2-ones 27-9 or their constitutional
isomers 4-ylidene-benzoxazin-2-ylideneanilines 4 (path A),
indoles 3 (path B), and benzodiazepin-2-ones 5 (path C).10
In the initial experiment, subjecting 1-(o-ethynylphenyl)-3-
phenylurea (1a) to catalytic amounts of NaAuCl4 (5 mol %) in
(2) For selected examples about gold-catalyzed hydroamination reactions,
see: (a) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. (b)
Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (c) Zhang, Y.;
Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627. (d) Lalonde, R. L.; Sherry,
B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (e)
Liu, X. Y.; Ding, P.; Huang, J. S.; Che, C. M. Org. Lett. 2007, 9, 2645. (f)
Nishina, N.; Yamamoto, Y. Synlett 2007, 11, 1767. (g) Zhang, Z.; Bender,
C. F.; Widenhoefer, R. A. Org. Lett. 2007, 9, 2887. (h) Zhang, Z.; Bender,
C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148. (i) Giner,
X.; Na´jera, C. Org. Lett. 2008, 10, 2919. (j) Kinder, R. E.; Zhang, Z.;
Widenhoefer, R. A. Org. Lett. 2008, 10, 3157. (k) Zhang, Z.; Lee, S.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372. (l) Zeng, X.;
Soleilhavoup, M.; Bertrand, G. Org. Lett. 2009, 11, 3166. (m) Zeng, X.;
Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. J. Am. Chem. Soc.
2009, 131, 8690. (n) Zeng, X.; Frey, G. D.; Kousar, S.; Bertrand, G.
Chem.sEur. J. 2009, 15, 3056. (o) Han, Z.-Y.; Xiao, H.; Chen, X.-H.;
Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182.
Heterocyclization of substrate 1 may, in principle, lead to at
least four different structures (see Figure 1),6namely, 4-ylidene-
(1) For some selected reviews in gold catalysis, see: (a) Li, Z.; Brouwer,
C.; He, C. Chem. ReV. 2008, 108, 3239. (b) Gorin, D. J.; Sherry, B. D.;
Toste, F. D. Chem. ReV. 2008, 108, 3351. (c) Arcadi, A. Chem. ReV. 2008,
108, 3266. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (e) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. ReV. 2008, 37, 1776.
10.1021/ol100595s  2010 American Chemical Society
Published on Web 04/15/2010

Figure 2. Single-crystal X-ray structure (a) of 2a showing
N-H···OC hydrogen-bonded pairs (b).
Figure 1. Possible main pathways for gold-catalyzed intramolecular
hydroamidation reactions of ureas 1.
ethanol afforded a 1:1 mixture of quinazolinone 2a and indole
3a after 3 h at room temperature (eq 1). The structure of 2a
was confirmed by single-crystal X-ray diffraction11 (Figure 2).
Compound 2 was found to form stacking N-H···OC hydrogen-
bonded pairs in the solid state. The formation of either N-(4-
methylene-1H-benzo[d][1,3]oxazin-2(4H)-ylidene)aniline (prod-
uct type 4, path A) or 3-phenyl-1H-benzo[d][1,3]diazepin-
2(3H)-one (hypothetical path C) was not detected.
This preliminary result confirmed the ability of NaAuCl4
to catalyze both 6-exo-dig and the highly competitive 5-endo-
dig cyclization mode. In order to control the selectivity of
heterocyclization of substrate 1a in the preparation of
4-methylene-3,4-dihydroquinazolin-2-one derivatives 2, we
first explored different catalysts and conditions (Table 1).
(3) For general recent reviews about hydroamination reactions, see: (a)
Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F. M.; Tada, M. Chem.
ReV. 2008, 108, 3795. (b) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36,
1407.
(4) (a) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 4, 610. (b)
Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem.
2005, 70, 2265. (c) Arcadi, A.; Alfonsi, M.; Bianchi, G.; D’Anniballe, G.;
Marinelli, F. AdV. Synth. Catal. 2006, 348, 331. (d) Ambrogio, I.; Arcadi,
A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2007, 11, 1775. (e)
Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2007, 46, 2284. (f) Zhang, Y.; Donahue, J.; Li, C. Org.
Lett. 2007, 9, 627. (g) Nakamura, I.; Sato, Y.; Konta, S.; Terada, M.
Tetrahedron Lett. 2009, 50, 2075.
Table 1. Screening of the Reaction Conditions To Control the
Selectivity of the Intramolecular Gold(I)-Catalyzed
Hydroamidation of Urea 1a
(5) Ye, D.; Wang, J.; Zhang, X.; Zhou, Y.; Ding, X.; Feng, E.; Sun, H.;
Liu, G.; Jiang, H.; Liu, H. Green Chem. 2009, 11, 1201.
(6) For gold-catalyzed reactions where a plausible competition between
two nitrogen nucleophiles is present, see: (a) Kadzimirsz, D.; Hildebrandt,
D.; Merz, K.; Dyker, G. Chem. Commun. 2006, 661. (b) Bender, C. F.;
Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (c) See ref 4. (d) Iglesias, A.;
Mun˜iz, K. Chem.sEur. J. 2009, 15, 10563.
(7) To the best of our knowledge, only two examples for the synthesis
of the quinazolin-2-one core from 1-(o-alkynylaryl)ureas have been reported.
(a) PdII-catalyzed: Costa, M.; Della Ca, N.; Gabriele, B.; Massera, C.;
Salerno, G.; Soliani, M. J. Org. Chem. 2004, 69, 2469. (b) TfOH-mediated:
Wang, H.; Liu, L.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. Tetrahedron
Lett. 2009, 50, 6841.
(8) Molina, P.; Conesa, C.; Al´ıas, A.; Arques, A.; Velasco, M.; Llamas-
Saiz, A. L.; Foces-Foces, C. Tetrahedron 1993, 49, 7599.
(9) Brack, A. Lieb. Ann. Chem. 1969, 730, 166.
(10) Benzooxazepin-2-amines arising from the nucleophilic attack of ureas
1 through their tautomeric carbamimidic forms could be also envisioned.
(11) X-ray data for compound 2a: colorless lath, 0.25 × 0.12 × 0.05
mm size, monoclinic, P21/c, a ) 10.9132(5) Å, b ) 6.9003(3) Å, c )
15.2690(7) Å, ꢀ ) 92.715(4)°, V ) 1148.53(9) Å3, Z ) 4, Fcalcd ) 1.366
g cm-3, θmax ) 29.21, Mo KR, λ ) 0.710 73 Å, ω scan, diffractometer
Oxford Diffr. Gemini S Ultra, T ) 120(2) K, 11 878 reflections collected,
of which 2768 were independent (Rint ) 0.0379), direct primary solution
and refinement on F2 (Sheldrick, G. M. SHELXS-97 and SHELXL-97;
University of Go¨ttingen, Go¨ttingen, Germany, 1997), 167 refined parameters,
N-H hydrogen atom refined free, others riding, R1 [I > 2σ(I)] ) 0.0361,
a 5% Au or Pt catalyst. 7.5% Ag salt when indicated. b Determined by
1H NMR analysis of the crude reaction mixture. c Reaction carried out in
a sealed tube.
wR2 (all data) ) 0.0746, ∆Fmax ) 0.18 e Å-3
.
Org. Lett., Vol. 12, No. 9, 2010
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The 2a/3a ratio increases up to 5:1 by carrying out the
reaction under NaAuCl4 catalysis in N,N-dimethylformamide
(DMF) at 60 °C. The use of [AuCl(Ph3P)]/AgSbF6 or of the
cationic [Au(L1)(MeCN)]+ complex led to a mixture enriched
in indole 3a. Phosphine-based catalysts in dichloromethane
resulted in a very inefficient combination, probably as a result
of the low solubility of ureas in this solvent. However, a
mixture of 5% gold(I) carbene complex [AuCl(IPr)] [IPr )
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine] and 7.5%
AgSbF6 in DMF (0.1 M in substrate 1a) proved to be a very
efficient catalyst, providing exclusively compound 2a. At-
tempts to lower the gold catalyst loading to 2.5 mol % led
to a sluggish reaction.12,13 Because it has been suggested
that the selectivity in catalytic applications in [Au(NHC)]
systems may very well be controlled as a function of ligand
sterics,14 we examine how the selectivity was affected by
decreasing of the bulk of the NHC ligand. Thus, when
[AuCl(IMes)]/AgSbF6 (IMes ) 1,3-dimesitylimidazol-2-
ylidine) was employed as the catalyst, a 1:1.8 mixture of
quinazolinone 2a and indole 3a was observed (see Table 1).
This result seems to confirm that the selectivity is, at least,
affected by the steric hindrance of the NHC ligand on the
gold(I) complex. An opposite selectivity was observed with
a ligand-free cationic catalyst based on PtII/AgI, which led
to indole 3a as the only product.
prepare a series of quinazolin-2-one derivatives 2 (Scheme
1) through the annulation reaction of a range of correspond-
Scheme 1. Gold(I)-Catalyzed 6-exo-dig Heterocyclization of
3-Substituted 1-(2-Ethynylaryl)ureas 1
Subsequently, a study with urea (1b) bearing an internal
alkyne, with similar steric demand on opposite sides of the
alkyne, was undertaken. In this case, the reaction leads to
the 5-endo-dig cyclization mode15 regardless of the electronic
and steric properties of the ligand on the gold(I) complex
(eq 2). When the phenyl substituent on the alkyne was
replaced by an alkyl group in substrate 1c, once again
cyclization provides the corresponding indole derivative in
every catalytic system studied. It is also worth mentioning
that gold(I)-catalyzed heterocyclization of the N-3-unsub-
stituted urea 1d also yields exclusively the indole ring 3d
(eq 3).
a All products were isolated with g95% purity. b The reaction ran over
18 h at 60 °C. c Conditions: 10% [AuCl(IPr)], 7.5% AgSbf6, 80 °C, 24 h.
d Determined by 1H NMR analysis of the reaction mixture; a 21% yield of
indole 3o was also detected.
ing ureas, 1a and 1e-1q.16 Indeed, the reaction proved
equally efficient when applied to other ureas. First, we
(12) Given the well-documented tendency of diarylureas to behave as
polymorphic structures because of their hydrogen-bonding patterns, we
carried out the reaction under different concentrations (0.05 and 0.2 M in
DMF). We found, no appreciable change in the conversion as a function of
the concentration. (a) Dannecker, W.; Kopf, J.; Rust, H. Cryst. Struct.
Commun. 1979, 8, 429. (b) Etter, M.; Panuto, T. J. Am. Chem. Soc. 1988,
110, 5896.
The results described so far point out the complete control
exerted by the presence of an internal alkyne on the substrate
toward -endo-dig cyclization in this process. At this point,
encouraged by the excellent regio- and chemoselectivity
exhibited by the [Au(IPr)]SbF6 catalyst to perform the less
favored, and therefore more challenging, 6-exo-dig cycliza-
tion with 3-substituted 1-(o-ethynylaryl)ureas, we sought to
(13) The reaction was performed in the presence of 5% triflic acid, but
no conversion of substrate 1a was observed after 41 h at 100 °C. Because
it is described that other coinage metal salts (CuLn and AgLn) exhibit a
significant coordination ability to C-C multiple bonds, we set up test
experiments to catalyze the reaction with 5% AgSF6 and 5% copper(II)
salts, but in every case, the starting material remained unaltered.
(14) Fre´mont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P. Organo-
metallics 2001, 24, 2411–2418.
1902
Org. Lett., Vol. 12, No. 9, 2010

decided to evaluate the effect of substitution at N-3 in the
urea moiety. Thus, substrate 1e bearing a p-methoxy-
substituted aryl ring at N-3 yielded a 92% dihydroquinazoli-
none 2e.
Both aliphatic and benzylic 3-substituted 1-(o-ethynylphe-
nyl)ureas (1f-1h) were easily transformed into the corre-
sponding products 2f, 2g, and 2h in 83, 96, and 86% yield,
respectively (see Scheme 1). Even the clearly deactivated
N-3-substituted[p-(trifluoromethyl)phenyl]urea1iwassmoothly
transformed into the corresponding quinazolin-2-one 2i in a
very good yield (82%) albeit within a longer reaction time.
The reaction tolerates the presence of potential gold-
coordinating functional groups, such as alkenes, at the urea
moiety (see compound 2j; Scheme 1). However, cyclization
of the N-3- unsubstituted urea 1k proved to be slower, and
only 40% of tautomerized quinazolinone 2k was obtained
under slight forcing conditions. Nevertheless, from the point
of view of regioselectivity control, the results described so
far suggest that the substituent at N-3 does not have a
significant influence on the competitive formation of com-
pounds 2 and 3.
The effect of substitution on the N-1-substituted aryl ring
was also tested. The presence of electron-donating groups
on the N-1-substituted aryl ring is tolerated in this hetero-
cyclization; thus, reaction with ureas 1l-1n leads to com-
pounds 21-2n in good yields. In contrast, the efficiency of
the reaction decreased considerably when an electron-
withdrawing chlorine atom was present on the N-1-
substituted aryl ring. An enhancement of the basicity at the
urea N-3 center increases the efficacy of the transformation
and gives the product 2p in very good yield (see Scheme
1). Particularly interesting is the reaction carried out with
substrate 1r in which the aryl ring bearing the alkyne is
replaced by a more electron-deficient pyridine ring (eq 4).
In this case, formation of the expected 3,4-dihydropyri-
dopyrimidin-2-one was not observed. Instead, the pyrrol-
opyridine 6 was obtained in 80% isolated yield. In addition,
more drastic conditions (10% [Au(IPr)]SbF6, 80 °C, 24 h)
had to be used to ensure complete conversion. The slower
rate of the reaction could be due to the potential substrate
coordination to the cationic gold catalyst. The different course
of cyclization could be explained by a reverse positive charge
distribution in the gold-activated alkyne induced by the
electron-deficient pyridine ring.
In conclusion, it was found that 1-(o-akynylaryl)ureas are
privileged substrates that provide an adequate framework to
explore alternative reaction pathways in the metal-catalyzed
hydroamidation of alkynes. The new route disclosed allows
for generation of the 4-methylene-3,4-dihydroquinazolin-2-
one core and is synthetically valuable when compared with
the multistep or harsh protocols previously reported for this
interesting type of heterocycle. A detailed theoretical calcula-
tion study into the origins of the catalysts’ ability to control
the mode of cyclization in these interesting alternative
transformations is currently ongoing in our group.
Acknowledgment. This work was supported by the
Spanish MEC [Grant CTQ 2007-65720 and Consolider-
Ingenio2010 (Grant CSD2007-00006)]. A.B.C. thanks Span-
ish MEC for a Juan de la Cierva contract and A.G. the
Generalitat Valenciana for a fellowship. We acknowledge
the SCSIE (Universidad de Valencia) for access to the
instrumental facilities.
(15) The structure of indole 3b was established by single-crystal X-ray
diffraction; see Supporting Information.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and CIF files giving
crystal data for compounds 2a and 3b. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Ureas 1a-1c, 1e, 1h-1j, 1l, 1m, 1o, and 1q were prepared by the
reaction of o-alkynylanilines and isocyanates and used without further
purification. The syntheses of 1f, 1g, 1n, 1p, and 1r were run over 12 h,
and 1.5 equiv of the corresponding isocyanate was needed to achieve
complete conversion of the 2-ethynylaniline derivative. To avoid secondary
reactions, these ureas were purified by column chromatography.
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