Palladium-catalyzed N-monoarylation of amidines and a one-pot synthesis of quinazoline derivatives

Article abstract of DOI:10.1021/ol301700y

A method for the Pd-catalyzed N-arylation of both aryl and alkyl amidines with a wide range of aryl bromides, chlorides, and triflates is described. The reactions proceed in short reaction times and with excellent selectivity for monoarylation. A one-pot synthesis of quinazoline derivatives, via addition of an aldehyde to the crude reaction mixture following Pd-catalyzed N-arylation, is also demonstrated.

Full text of DOI:10.1021/ol301700y

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3800–3803
Palladium-Catalyzed N-Monoarylation of
Amidines and a One-Pot Synthesis of
Quinazoline Derivatives
Meredeth A. McGowan, Camille Z. McAvoy, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
sbuchwal@mit.edu
Received June 20, 2012
ABSTRACT
A method for the Pd-catalyzed N-arylation of both aryl and alkyl amidines with a wide range of aryl bromides, chlorides, and triflates is described.
The reactions proceed in short reaction times and with excellent selectivity for monoarylation. A one-pot synthesis of quinazoline derivatives,
via addition of an aldehyde to the crude reaction mixture following Pd-catalyzed N-arylation, is also demonstrated.
Amidines are important functional groups in modern
drug synthesis, due in part to their ability to form water-
soluble salts1 and their structural similarity to the biologi-
cally ubiquitous guanidines. In fact, many of the top-
selling pharmaceuticals of the past few years feature an
amidine as a key structural component.2
N-Arylamidines can also serve as precursors for the
synthesis of other biologically important heterocycles such
as imidazoles,4 benzimidazoles,5 quinazolinones,6 and
quinazolines.7 Traditionally, N-arylamidines have been
prepared via addition of aniline into an activated nitrile
or amide (variation of the Pinner reaction), or via addition
into the corresponding thioimidic ester.8 Recently, triha-
loethyl imidates have also been identified as excellent
reagents for the synthesis of substituted amidines.9 None-
theless, these methods all require the use of either strongly
acidic or basic conditions, and/or the preparation of
activated intermediates. The direct N-monoarylation of
free amidines, many of which are commercially available
as their corresponding HCl salts, represents an attractive
alternative for rapid and efficient access to a wide range of
such compounds.
Recently, compounds containing N-arylamidines have
shown promise as treatments for inflammation1 and pain.3
(1) Kort, M. E.; Drizin, I.; Gregg, R. J.; Scanio, M. J. C.; Shi, L.;
Gross, M. F.; Atkinson, R. N.; Johnson, M. S.; Pacofsky, G. J.; Thomas,
J. B.; Carroll, W. A.; Krambis, M. J.; Liu, D.; Shieh, C.-C.; Zhang, X.;
Hernandez, G.; Mikusa, J. P.; Zhong, C.; Joshi, S.; Honore, P.; Roeloffs,
R.; Marsh, K. C.; Murray, B. P.; Liu, J.; Werness, S.; Faltynek, C. R.;
Krafte, D. S.; Jarvis, M. F.; Chapman, M. L.; Marron, B. E. J. Med.
Chem. 2008, 51, 407.
(2) Drugs.com: Pharmaceutical Sales 2010. http://www.drugs.com/
top200.html (accessed May 24, 2012).
Despite significant advances in the field of transition-
metal catalyzed CꢀN cross-coupling, the application of
this technology for substrates such as amidines that can
bind strongly to the reactive metal center remain challen-
ging. Even so, there have been several recent reports of
(3) (a) Renton, P.; Green, B.; Maddaford, S.; Rakhit, S.; Andrews,
J. S. ACS Med. Chem. Lett. 2012, 3, 227. (b) Annedi, S. C.; Ramnauth,
J.; Maddaford, S. P.; Renton, P.; Rakhit, S.; Mladenova, G.; Dove, P.;
Silverman, S.; Andrews, J. S.; Felice, M. D.; Porreca, F. J. Med. Chem.
2011, 54, 7408.
(4) (a) Wiglenda, T.; Ott, I.; Kircher, B.; Schumacher, P.; Schuster,
D.; Langer, T.; Gust, R. J. Med. Chem. 2005, 48, 6516. (b) Kuethe, J. T.;
Childers, K. G.; Humphrey, G. R.; Journet, M.; Peng, Z. Org. Process
Res. Dev. 2008, 12, 1201.
(5) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932.
(6) Ma, B.; Wang, Y.; Peng, J.; Zhu, Q. J. Org. Chem. 2011, 76, 6362.
(7) (a) Kumar, V.; Mohan, C.; Gupta, M.; Mahajan, M. P. Tetra-
hedron 2005, 61, 3533. (b) Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org.
Lett. 2011, 13, 4604.
(8) For a review of amidine synthesis, see: Dunn, P. J. Amidines and
N-Aryl Amidines. In Comprehensive Organic Functional Group Trans-
formations II; Katritzky, I., Taylor, R., Eds.; Elsevier: Oxford, U.K., 2005;
Vol. 5, pp 655ꢀ699.
(9) Caron, S.; Wei, L.; Douville, J.; Ghosh, A. J. Org. Chem. 2010, 75,
945.
r
10.1021/ol301700y
Published on Web 07/05/2012
2012 American Chemical Society

successful amidine N-arylation, particularly in the area of
copper catalysis.10 While most of these require ortho-
directing groups11 or 1,2-dihaloarene electrophiles12 to
provide fused heterocycles directly, there has been a single
report of the copper-catalyzed mono-N-arylation of ben-
zamidine and acetamidine derivatives by Antilla.13 Inter-
estingly, the addition of ligands to the copper-based
salt precursor had no effect on reaction rate, likely due
to chelation of the amidine substrate.14 While Antilla
was able to obtain a variety of phenyl amidine-derived
N-monoarylamidines, the use of other amidine nucleo-
philes was less successful. Further, neither aryl sulfonates
nor aryl chlorides or bromides were viable substrates.
Thus, there remains a need for a more general coupling
method.
Over the past several years, our group has demonstrated
the effectiveness of biarylphosphine ligands for the palla-
dium-catalyzed monoarylation of amine nucleophiles,
which previously were shown to poison active catalytic
Pd-based species via competitive chelation to the metal
center. Using such catalytic systems we were able to
achieve efficient CꢀN cross-coupling of a variety of ar-
ylamines containing embedded amidine structures (using
L1 and L2)15 and amides (using L2 and L3).16 We thus
postulated that a similar system might be effective for the
N-monoarylation of amidines. To our knowledge, there
have been no previous reports of palladium-catalyzed
amidine arylation, though there is a single report of the
N-arylation of O-methylamidoximes using a Pd-Xantphos
system.17 Herein, we report the development of a palla-
dium-catalyzed N-monoarylation of a wide range of ami-
dine nucleophiles with aryl electrophiles.
Figure 1. Biaryl phosphine ligands utilized in the catalytic
Pd-based CꢀN cross-coupling reactions with N-containing and
potentially chelating substrates.
base component.18 Significantly, we found the particle size
of Cs2CO3 tobe crucial; no reaction or verylow conversion
resulted when the base was used directly from the com-
mercial source. However, when the base was ground
thoroughly with a mortar and pestle prior to use,19 the
reaction consistently proceeded to full conversion and with
yields ranging from 70 to 93%.20 We also found that, in
order for the transformation to be effective and reprodu-
cible for a wide range of electrophiles and nucleophiles,
a preactivation method was required to obtain the active
catalyst.21,22
Under these optimized reaction conditions, a variety of
aryl amidines could be coupled with a wide range of aryl
bromides, chlorides, and triflates in short reaction times
(2 h)23 and with relatively low catalyst loadings(Scheme 1).
In particular, electron-rich bromides and triflates were
excellent substrates, undergoing the N-monarylation with
just 0.5 mol % of Pd at 85 °C (1aꢀb, 1eꢀf). Electron-poor
electrophiles (1d), as well as a nitro-substituted aryl ami-
dine nucleophile (1j), required slightly higher catalyst
loadings (1.5 mol % of Pd). Moderately sterically hindered
electrophiles (1 hꢀi), as well as electron-rich aryl chlorides
(1c, 1g), also required elevated reaction temperatures
(110 °C) to achieve full conversion. Significantly, we found
that both heterocyclic amidines and aryl halides coupled
to form the corresponding N-arylamidines in high yields
(1fꢀg, 1hꢀi, 1k), though five-membered heterocyclic aryl
halides required a higher catalyst loading (5 mol % of Pd)
to achieve high yields of coupled products (1lꢀm).
We began our investigation by examining the coupling
of benzamidine with aryl bromides and quickly discovered
that, analogously to the coupling of primary amides and
2-aminothiazoles, tBuBrettPhos (L2) was the optimal
ligand, and t-BuOH, the optimal solvent. In line with
many of the copper-catalyzed methods for amidine cou-
pling, we also found Cs2CO3 to be uniquely effective as the
(10) For a review of transition-metal catalyzed N-arylations of
amidines and guanidines, see: Rauws, T. R. M.; Maes, B. U. W. Chem.
Soc. Rev. 2012, 41 (6), 2463.
(11) (a) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem.
2008, 73, 7841. (b) Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48,
348. (c) Yang, D.; Liu, H.; Yang, H.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y.
Adv. Synth. Catal. 2009, 351, 1999. (d) Nayak, M.; Rastogi, N.; Batra, S.
Eur. J. Org. Chem. 2012, 2012, 1360.
(12) (a) Deng, X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74,
5742. (b) Deng, X.; Mani, N. S. Eur. J. Org. Chem. 2010, 2010, 680.
(13) Cortes-Salva, M.; Garvin, C.; Antilla, J. C. J. Org. Chem. 2011,
76, 1456. A mono-N-arylation of guanidine (not isolated) has also
recently been described: Xing, H.; Zhang, Y.; Lai, Y.; Jiang, Y.; Ma,
D. J. Org. Chem. 2012, 77, 5449.
(14) For a review on the coordination chemistry of amidine ligands,
see: Barker, J.; Kilner, M. Coord. Chem. Rev. 1994, 133, 219.
(15) (a) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57. (b) McGowan, M. A.; Henderson,
J. L.; Buchwald, S. L. Org. Lett. 2012, 14, 1432.
(19) See Supporting Information for full experimental details.
(20) In most cases complete conversion of the electrophile was
observed. Yields of less than 90% can be explained by the presence of
small amounts of the N,N0-bisarylamidine products along with, in some
cases, loss of product in isolation due to the extremely polar nature of the
compounds.
(21) Ueda, S.; Su, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 8944.
(16) (a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 13001. (b) Fors, B. P.; Dooleweerdt, K.;
Zeng, Q.; Buchwald, S. L. Tetrahedron 2009, 65, 6576.
(17) Anbazhagan, M.; Stephens, C. E.; Boykin, D. W. Tetrahedron
Lett. 2002, 43, 4221.
(22) Consistently higher yields were observed when the amidine
hydrochloride salt was prestirred and heated with Cs2CO3 in t-BuOH
prior to introduction of the preactivated catalyst solution.
(23) In general, no further conversion was observed after 2 h;
reactions that were not complete in that amount of time were instead
rerun with higher catalyst loadings.
(18) See Supporting Information, Table S1 for further optimization
details.
Org. Lett., Vol. 14, No. 14, 2012
3801

Scheme 1. N-Monoarylation of Aryl Amidinesa
Scheme 2. N-Monoarylation of Alkyl Amidinesa
a Reaction conditions: ArX (1.0 mmol), amidine hydrochloride
(1.1 mmol), Pd2dba3 (n mol %), L2 (2n mol %), Cs2CO3 (2.6 mmol),
t-BuOH (4 mL/mmol), 85 or 110 °C, 2 h; isolated yields, average of two runs.
one-pot procedure via simply introducing the aldehyde
to the crude reaction mixture following arylation of the
amidine.
The feasibility of the proposed transformation was
evaluated by examining the reaction of purified N-
arylamidine 1e with m-anisaldehyde in t-BuOH (Scheme 3).
Wefound thatsimplymixingthe two and heating to130 °C
for 16 h resulted in very low conversion of the amidine and
none of the desired product was obtained (entry 1). The
inclusion of molecular sieves, to potentially aid in imine
formation, offered no improvement (entry 2). However,
the addition of Cs2CO3 (conveniently the same base used
for the amidine coupling, vide supra) was successful in
promoting the desired reaction, and the quinazoline pro-
duct was obtained in 28% yield (entry 3). Interestingly, we
noticed that in this case the N-arylamidine was almost
entirely consumed, and analysis of 1H NMR and LCMS
data suggested the presence of a large amount of the
cyclized but unoxidized dihydroquinazoline adduct. In-
deed, the addition of DDQ as a final step for this trans-
formation dramatically increased the yield of quinazoline
product significantly to 88% (entry 4).
a Reaction conditions: ArX (1.0 mmol), amidine hydrochloride (1.1 mmol),
Pd2dba3 (n mol %), L2 (2n mol %), Cs2CO3 (2.6 mmol), t-BuOH
(4 mL/mmol of ArX), 85 or 110 °C, 2 h; isolated yields, average of two runs.
We next evaluated alkyl amidines as coupling partners
and found that a range of alkyl amidines could be arylated
under the same reaction conditions (Scheme 2). Signifi-
cantly, acetamidine was a competent nucleophile, and
while more electron-rich electrophiles required slightly
elevated temperatures and catalyst loadings (2a), more
activated electrophiles such as 4-chlorobromobenzene
reacted under the same conditions as required for the
N-arylation of aryl amidines (2b). Notably, the coupling
of 4-chlorobromobenzene also proceeded with excellent
selectivity for bromide coupling. Both branched (2c, 2d)
and cyclopropenyl (2e) amidines also coupled readily, and
with a range of heteroaryl halides. In the case of a more
hindered electrophile such as 2,4-dimethylbromobenzene,
however, the coupling was significantly more difficult with
an alkyl amidine than with an aryl amidine, and a catalyst
loading of 3 mol % was required in order to achieve full
conversion (2f).
Scheme 3. Optimization of Quinazoline Formationa
Having realized a general and efficient method for the
N-monoarylation of amidines, we next sought to extend
this method to a one-pot synthesis of quinazoline deriva-
tives. The conversion of N-monoarylamidines to quinazo-
lines, via condensation of the unsubstituted nitrogen onto
an aldehyde and subsequent electrocyclization and oxida-
tion, is known. However, only substrates derived from
benzamidine were reported.24 We sought to develop a
method that could be implemented into a sequential,
a Conversion and yield were calculated by 1H NMR using 1,3,
5-trimethoxybenzene as an internal standard.
(24) (a) Kumar, V.; Sharma, A. K.; Mahajan, M. P. Synth. Commun.
2004, 34, 49. (b) Kumar, V.; Mohan, C.; Gupta, M.; Mahajan, M. P.
Tetrahedron 2005, 61, 3533.
3802
Org. Lett., Vol. 14, No. 14, 2012

We next applied these conditions to the one-pot synth-
esis of quinazolines and were pleased to discover that 3a
could be obtained in 51% isolated yield from 4-bromoanisole
(Scheme 4). For the one-pot procedure, we found that
employing the aryl halide and amidine in a 1:1 ratio, as
opposed to the 1:1.1 ratio which is optimal in obtaining
N-monoarylated products, resulted in slightly higher yields
and a cleaner overall reaction. We also found that the extra
equivalent of Cs2CO3 required for the quinazoline forma-
tion could be included from the beginning, simplifying the
reaction setup routine.
Scheme 4. One-Pot Synthesis of Quinazoline Derivativesa
An evaluation of the scope of this reaction revealed that
heterocyclic amidines (3bꢀc, 3f) and aldehydes (3cꢀd, 3f)
worked well as substrates under the optimal conditions, as
did ortho-substituted aryl bromides (3b). While the quina-
zoline derived from isobutanamidine was obtained in more
modest yield (3d), cyclopropaneamidine was a good sub-
strate and provided quinazoline 3e, which is derived from a
polyhalogenated aldehyde capable of further transforma-
tion, in 55% yield. We could also obtain a polyheterocyclic
thienopyrimidine product (3f) under these same reaction
conditions in 32% yield.
While this one-pot procedure was effective for the rapid
generation of many interesting substituted quinazolines, it
should be noted that the substrate scope has some limita-
tions. For a successful transformation, only relatively
electron-rich aryl halides were effective; the use of elec-
tron-poor aryl halides resulted in little or no desired
product. The same is true, to an extent, for the amidine
component. With respect to the aldehyde component, only
aryl aldehydes have been successful to date at producing
synthetically useful amounts of products.25
In conclusion, we have developed a palladium-catalyzed
N-monoarylation of amidines that proceeds in short reac-
tion times and with excellent selectivity for monoarylation.
Further, we combined this transformation with a base-
promoted imine formation/electrocyclization/oxidation
sequence to synthesize substituted quinazolines via a facile,
one-pot procedure. Given the importance of amidines and
quinazolines in the field of medicinal chemistry, we expect
these methods to find use as practical and convenient
alternatives to the existing approaches in their synthesis.
a Reaction conditions: (i) ArX (1.0 mmol), amidine hydrochloride
(1.0 mmol), Pd2dba3 (n mol %), L2 (2n mol %), Cs2CO3 (3.4 mmol),
t-BuOH (4 mL/mmol of ArX), 110 °C, 2 h; (ii) aldehyde (1.5 mmol),
130 °C, 16 h; (iii) DDQ (1 mmol), EtOAc/H2O, rt, 1 h; isolated yields,
average of two runs.
Acknowledgment. We thank the National Institutes of
Health (GM58160) for financial support of this project and
for a postdoctoral fellowship to M.A.M. (F32GM097771).
This activity was also supported, in part, by an educational
donation provided by Amgen for which we are grateful. We
thank Johnson Matthey for a gift of palladium compounds.
A Varian 500 MHz spectrometer used for portions of this
work was purchased with funds from the National Science
Foundation (CHE-9808061).
Supporting Information Available. Experimental pro-
cedures along with experimental and spectroscopic data
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(25) See Supporting Information, Table S2 for specific examples of
quinazoline syntheses which proceeded in lower yields or failed to
produce appreciable amounts of product.
The authors declare the following competing financial interest(s):
MIT has patents on ligands that are described in this paperfrom which S.
L.B. receives royalty payments.
Org. Lett., Vol. 14, No. 14, 2012
3803