Palladium-catalyzed intramolecular C(sp2)-H amidination by isonitrile insertion provides direct access to 4-aminoquinazolines from N-arylamidines

Article abstract of DOI:10.1021/ol201807n

An efficient method for the synthesis of 4-amino-2-aryl(alkyl)quinazolines from readily available N-arylamidines and isonitriles via palladium-catalyzed intramolecular aryl C-H amidination by isonitrile insertion has been developed.

Full text of DOI:10.1021/ol201807n

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4604–4607
Palladium-Catalyzed Intramolecular
C(sp2)ÀH Amidination by Isonitrile
Insertion Provides Direct Access to
4-Aminoquinazolines from
N-Arylamidines
Yong Wang, Honggen Wang, Jiangling Peng, and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China
zhu_qiang@gibh.ac.cn
Received July 6, 2011
ABSTRACT
An efficient method for the synthesis of 4-amino-2-aryl(alkyl)quinazolines from readily available N-arylamidines and isonitriles via palladium-
catalyzed intramolecular aryl CÀH amidination by isonitrile insertion has been developed.
Transition-metal-catalyzed functionalization of CÀH
bonds, surrogates of preinstalled CÀ(pseudo)halogen
bonds, serves as an attractive atom-economical and envir-
onmentally benign strategy for CÀC and CÀheteroatom
bond formation.1 Due to the high bond dissociation
energies and ubiquity of CÀH bonds in organic molecules,
the presence of a nearby chelating group is usually required
in order to direct positioning of a metal catalyst so that
specific CÀH bond activation occurs. Consequently, extra
steps are required for introduction and removal of direct-
ing groups, which offset the merit of CÀH functionaliza-
tion and limit its synthetic applications. However,
intramolecular heterofunctionalization of CÀH bonds is
an ideal, truly atom-economical approach to the construc-
tion of heterocyclic architectures, since heteroatoms act as
both directing groups and intramolecular nucleophiles
(1) For selected reviews on transition-metal-catalyzed CÀH functio-
nalization, see: (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111,
1293. (b) Ackermann, L. Chem. Commun. 2010, 46, 4866. (c) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (d) Ashenhurst, J. A.
Chem. Soc. Rev. 2010, 39, 540. (e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Commun. 2010, 46, 677. (f) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(2) For reviews of syntheses of heterocycles via transition-metal-
catalyzed CÀH functionalization, see: (a) Beccalli, E. M.; Broggini,
G.; Fasana, A.; Rigamonti, M. J. Organomet. Chem. 2011, 696, 277. (b)
Thansandote, P.; Lautens, M. Chem.ÀEur. J. 2009, 15, 5874. (c) Zhang,
M. Adv. Synth. Catal. 2009, 351, 2243.
(3) For selected examples of syntheses of heterocycles via transition-
metal-catalyzed CÀH functionalization, see: (a) Tsang, W. C. P.; Zheng,
N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Jordan-
Hore, J. A.; Johansson, C. C. C.; Gulias, M.; E. Beck, M.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 16184. (c) Brasche, G.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 1932. (d) Xiao, Q.; Wang, W.-H.; Liu,
G.; Meng, F.-K.; Chen, J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009,
15, 7292. (e) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217.
(4) For selected examples of transition-metal-catalyzed CÀH func-
tionalization followedby alkyne insertion, see: (a) Wang, C.; Rakshit, S.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 14006. (b) Hyster, T. K.; Rovis,
T. J. Am. Chem. Soc. 2010, 132, 10565. (c) Guimond, N.; Gouliaras, C.;
Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (d) Schipper, D. J.;
Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6910. (e)
Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010, 12, 1540. (f) Chen, J.; Song, G.;
Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426.
(5) For Pd-catalyzed CÀH carbonlylation reactions with CO, see: (a)
Haffemayer, B.; Guilias, M.; Gaunt, M. J. Chem. Sci. 2011, 2, 312. (b)
Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378. (c)
Giri, R.; Lam, J. K.; Yu, J.-Q J. Am. Chem. Soc. 2010, 132, 686. (d) Giri,
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Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagne, M. R.;
Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2009,
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r
10.1021/ol201807n
Published on Web 08/05/2011
2011 American Chemical Society

(Scheme 1).2 A rapidly growing number of different types
of heterocycles, especially those containing nitrogen, have
been constructed by applying this novel strategy in recent
years,3 since the time of the seminal studies of the synthesis
of carbazoles by Buchwald.3a
inefficient. For example, the most common approach to
these substances consists of nucleophilic substitution reac-
tions of aryl or alkyl amines with 4-chloroquinazolines,
whose preparation requires multistep routes from uncom-
mon 2-aminobenzoic acid derivatives.12 Inaddition, this
approach is inefficient for sterically hindered aryl and alkyl
amines.13
When an alkyne4 or carbon monoxide5 is present in the
reaction mixture, coordination to the metal is followed by
insertion into the carbonÀmetal bond prior to reductive
elimination following CÀH bond activation. These pro-
cesses result in the formation of new carbonÀmetal bonds
as part of expanded metallocycles. Finally, reductive elim-
ination then furnishes diversified heterocyclic scaffolds
(Scheme 1). The similarity between CO and isonitriles in
terms of their coordination to transition metals6 suggests
that an equivalent CÀH isonitrile insertion process should
be viable. To our surprise, a transition-metal-catalyzed
intramolecular CÀH amidination reaction involving iso-
nitrile insertion has not been reported, even though palla-
dium-catalyzed inter- or intramolecular amidinations of
aryl or vinyl bromides7 and ketimine formation by CÀH
isonitrile insertion are known.6a
Scheme 1. Nitrogen Heterocycles via Intramolecular C(sp2)ÀH
Activation
4-Aminoquinazolines have a privileged structure that
exists in many biologically active compounds, including
protein kinase inhibitors,8 chemokine receptor CCR4
antagonists,9adenosine receptor antagonists,10 and most
importantly anticancer agents.11 However, current meth-
ods for synthesis of members of this family are generally
Stimulated by the results of recent studies of benzimi-
dazole synthesis by way of CÀH activation of N-aryl-
amidines,3c,d we reasoned that isonitrile insertion would
occur before reductive elimination, yielding 4-aminoqui-
nazolines upon tautomerization. Below, we describe the
first example of palladium-catalyzed intramolecular aryl
CÀH amidination by isonitrile insertion to provide a wide
variety of 4-aminoquinazolines from N-arylamidines.
The effort was initiated by studies of reactions using N-
phenylbenzamidine 1a14 and tert-butylisonitrile 2a (3 equiv)
as substrates in the presence of a palladium catalyst under
various conditions (Table 1). Importantly, the desired
product N-tert-butyl-4-amino-2-phenylquinazoline 3a was
produced in 42% yield under conditions involving Pd-
(OAc)2 (10 mol %), K2CO3 (1.5 equiv), and benzoquinone
(BQ, 1.5 equiv) in refluxing toluene (entry 1, Table 1).
Screening of other oxidants used widely in palladium-
catalyzed CÀH functionalization methods led to the sig-
nificant finding that the reaction proceeds equally well
under an air atmosphere (entries 2À4, Table 1). The
isolated yield of 3a is improved to 80% when the reaction
is performed under the balloon pressure of dioxygen (entry
5, Table 1).15 The type of base used is also an important
(6) (a) Tobisu, M.; Imoto, S.; Ito, S.; Chatani, N. J. Org. Chem. 2010,
75, 4835 and references therein. (b) Jones, W. D.; Foster, G. P.; Putinas,
J. M. J. Am. Chem. Soc. 1987, 109, 5047. (c) Jones, W. D.; Kosar, W. P.
J. Am. Chem. Soc. 1986, 108, 5640. (d) Hsu, G. C.; Kosar, W. P.; Jones,
W. D. Organometallics 1994, 13, 385. (e) Jones, W. D.; Hessell, E. T.
Organometallics 1990, 9, 718. (f) Vicente, J.; Saura-Llamas, I.; Garcıa-
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Organometallics 2011, 30, 572. (h) Dupont, J.; Consorti, C. S.; Spencer,
J. Chem. Rev. 2005, 105, 2527.
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Ed. 2000, 39, 4156. (b) Saluste, C. G.; Whitby, R. J.; Furber, M.
Tetrahetron Lett. 2001, 42, 6191. (c) Tetale, K. K. R.; Whitby, R. J.;
Light, M. E.; Hurtshouse, M. B. Tetrahedron Lett. 2004, 45, 6991. (d)
Saluste, G. G.; Crumpler, S.; Furber, M.; Whitby, R. J. Tetrahedron
Lett. 2005, 46, 6995.
(8) (a) Pierce, A. C.; Haar, E.; Binch, H. M.; Kay, D. P.; Patel, S. R.;
Li, P. J. Med. Chem. 2005, 48, 1278. (b) Gellibert, F.; Fouchet, M.-H.;
Nguyen, V.-L.; Wang, R.; Krysa, G.; Gouville, A.-C.; Huet, S.; Dodic,
N. Bioorg. Med. Chem. Lett. 2009, 19, 2277. (c) Galdwell, J. J.; Welsh,
E. J.; Matijssen, C.; Anderson, V. E.; Antoni, L.; Boxall, K.; Urban, F.;
Hayes, A.; Raynaud, F. I.; Rigoreau, L. J. M.; Raynham, T.; Wynne
Aherne, G.; Pearl, L. H.; Oliver, A. W.; Garrett, M. D.; Collins, I.
J. Med. Chem. 2011, 54, 580.
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(9) Purandare, S. V.; Gao, A.; Wan, H.; Somerville, J.; Burke, C.;
Seachord, C.; Vaccaro, W.; Wityak, J.; Poss, M. A. Bioorg. Med. Chem.
Lett. 2005, 15, 2669.
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Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2009, 52, 2341. (b) Barker,
A. J.; Gibson, K. H.; Godfrey, W.; Barlow, J. J.; Healy, M. P.;
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L.; Richards, L. Bioorg. Med. Chem. Lett. 2001, 11, 1911.
(13) Ahmad, O. K.; Hill, M. D.; Movassaghi, M. J. Org. Chem. 2009,
74, 8460.
(14) For preparation of substrates 1, see Supporting Information.
(15) For recent examples using dioxygen as the oxidant in palladium
promoted CÀH functionalizations, see: (a) Inamoto, K.; Hasegawa, C.;
Kawasaki, J.; Hiroya, K.; Doi, T. Adv. Synth. Catal. 2010, 352, 2643. (b)
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
14137. (c) Li, B.-J.; Tian, S. -L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2008, 47, 1115. (d) Tsang, W. C. P. R.; Munday, H.; Brasche, G.;
Zhang, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (e) Brasche, G.;
Garcıa-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207.
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Org. Lett., Vol. 13, No. 17, 2011
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factor governing the yield of 3a. Among those examined,
the more basic Cs2CO3 proved to be the best base in a
reaction that generated 3a an 89% yield (entries 6À8,
Table 1). Moreover, the efficiency of the reaction is nearly
completely maintained when the loading of Pd(OAc)2 was
reduced to 5 mol %. Impressively, the product 3a is
obtained in 72% yield even when 2.5 mol % of Pd(OAc)2
is employed (entries 9À10, Table 1). However, the yield of
3a is dramatically reduced (74%) when the amount of
Cs2CO3 is lowered to 1.0 equiv.
neighboring tert-butyl group in 3j does not hamper the
cycloinsertion reaction and two methyl groups on the
benzamidine aniline ring were found to have a synergistic
effect on the yield (3lÀm).
Scheme 2. Substrate Scope for the Synthesis of Substituted
4-Amino-2-Substituted Quinazolinesa
Table 1. Optimization of the Reaction Conditionsa
catalyst
(equiv)
base
yield
(%)b
entry
(equiv)
oxidant
1c
2c
3c
4
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.025)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
Cs2CO3 (1.5)
K3PO4 (1.5)
Pyridine (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.2)
Cs2CO3 (1.0)
BQ
K2S2O8
Oxone
Air
O2
42
54
44
40
80
89
76
70
85
72
82
74
5
6
O2
7
O2
8
O2
9
O2
10d
11
12
O2
O2
O2
a The reaction was carried out in a 0.4 mmol scale of 1a, tert-
butylisocyanide (1.2 mmol), palladium catalyst, base in toluene (2 mL),
under balloon presure of O2 or Ar when other oxidants were applied,
reflux for 3.5 h. b Yield of isolated 3a. c 1.5 equiv of oxidant. d 6 h.
a Reaction conditions: 1 (0.4 mmol), isonitrile 2 (1.2 mmol), Pd(OAc)2
(5 mol %), Cs2CO3 (1.5 equiv), toluene (2 mL), O2 balloon at reflux,
yield of isolated 3. bA 1:1 mixture of 5-methyl and 7-methyl substituted
isomers was obtained. ctert-Butylisonitrile 2a (2.0 mmol) and Pd(OAc)2
(10 mol %) were applied. dIsopropylisonitrile (5.0 equiv) was applied.
The scope of reactions of N-aryl ring (R1) substituted
benzamidines was examined using optimized conditions
involving tert-butylisonitrile (3.0 equiv), Pd(OAc)2 (5mol %),
and Cs2CO3 (1.5 equiv) under the balloon pressure of
dioxygen in toluene at reflux. In general, various electron-
donating group substituted aniline ring containing sub-
strates react to form corresponding N-tert-butyl-4-amino-
2-phenylquinazolines in excellent yields (3b, 3fÀg, 3iÀj,
Scheme 2). An exception is found for 1c that contains a
para-methoxyaniline moiety, which reacts to form 3c in
only a 64% yield. In sharp contrast, benzamidine reactants
with electron-withdrawing group (eg., F and Cl) substi-
tuted aniline rings react inefficiently (42À71%) (3dÀe, 3h,
3k, Scheme 2). This observation suggests that an electro-
philic aromatic substitution (SEAr) reaction pathway
might be involved in C(sp2)ÀH bond activation. It is
noteworthy that meta-methyl substituted 1f produces
two regioisomeric products in near equal amounts, while
reactions of the methoxy and chloro analogs take place
with complete regioselectivity (3gÀh). Notably, the bulky
Benzamidine ring (R2) substituent effects on the in-
tramolecular aryl CÀH amidination by isonitrile inser-
tion was also explored. The results show that electron-
donating substituents on this aryl ring undergo more
favorable reactions than do their electron-withdrawing
group substituted counterparts (see formation of 3nÀ3q
vs 3s). This trend suggests that the electron density on
the amidine nitrogen is crucial in complexation with the
palladium catalyst. However, the efficiencies of the
reactions are highly sensitive to ortho-substituents, a
probable result of interference with coordination of the
amidine nitrogen to the palladium catalyst (3r, 50% vs
3o, 77% and 3p, 74%). In addition, reactions of the
substrates containing chloro (3t, 97%) or bromo (3v,
54%) take place with high or modest efficiency, which
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Org. Lett., Vol. 13, No. 17, 2011

can be used for further elaboration. In addition, 2-alkyl
substituted 4-aminoquinazolines 3wÀ3x are also gener-
ated by using the new methodology.
intermediate B, which undergoes migratory insertion of
the isonitrile. Subsequent reductive elimination of the
resulting cyclic imidoyl palladium intermediate C followed
by tautomerization delivers product 3a with concurrent
formation of a Pd(0) species, which is reoxidized to Pd(II)
by dioxygen.
Finally, the scope of the process with respect to the
isonitrile reactant was examined. Reactions of isopropyl
and cyclohexyl isonitrile are less efficient than those of tert-
butylisonitrile as reflected by the fact that the correspond-
ing N-alkyl-4-amino-2-phenyl-quinazolines 3yÀ3z are
formed in much lower yields (52À54%). The sterically
hindered aryl isonitriles 3aaÀ3ab participate in higher
yielding processes than their less hindered counterparts
3acÀ3ad, aresultthatcorrelateswiththethermal stabilities
of the isonitriles. In addition, the reaction of thermally
unstable phenyl isonitrile does not produce the corre-
sponding quinazoline product. Considering the poor re-
activity of sterically hindered amines in nucleophilic
substitution reactions with 4-chloroquinazolines,12 the
current method affords a more efficient approach to
produce 4-aminoquinazoline derivatives with bulky
groups on the C-4 nitrogen.
Scheme 4. Plausible Reaction Mechanism
Scheme 3. Deuterium Isotope Effect Studies
In conclusion, the investigation described above has led
to the development of a new palladium-catalyzed intra-
molecular aryl CÀH amidination reaction that occurs
through isonitrile insertion. The process generates 4-ami-
no-2-aryl(alkyl) quinazolines with a broad substrate scope
and good functionality tolerance from readily available
N-arylamidines and isonitriles in a concise, efficient, and
atom-economic manner. Sterically hindered groups, such
as tert-butylamino and 2,6-dimethylphenylamino, can be
introduced at the C-4 position of the quinazoline ring
system, which is a privileged scaffold that exists in many
biologically active molecules. The reaction conditions used
are relatively mild and environmentally benign. Owing to
the fact that the newly developed method employs struc-
turally rich and readly available isonitriles, it can be
applied in approaches for diversity oriented construction
of nitrogen containing heterocycles.
To gain insight into the mechanism of this reaction, both
intra- and intermolecular kinetic isotope effects were de-
termined by using the respective monodeuterated N-phe-
nylbenzamidine 1a-d and pentadeuterated N-phenylben-
zamidine 1a-d5 (Scheme 3). No kinetic isotope effects
were observed in reactions of these substrates, indicating
that aromatic CÀH cleavage is not involved in the rate-
determining step.
Based on the observations made in this effort, the
reaction mechanism shown in Scheme 4 appears to be
plausible. In the route, coordination of the amidine nitro-
gen with isonitrile-ligated Pd(II) aided by Cs2CO3 leads to
formation of complex A. Electrophilic substitution on the
N-aryl amidine ring then provides the cyclopalladation
Acknowledgment. We are grateful to the National
Science Foundation of China (21072190) for financial
support of this work.
Supporting Information Available. Experimental pro-
cedure, and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
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