Direct palladium(II)-catalyzed synthesis of arylamidines from aryltrifluoroborates

Article abstract of DOI:10.1021/ol300813c

A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O₂CCF

Full text of DOI:10.1021/ol300813c

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2394–2397
Direct Palladium(II)-Catalyzed Synthesis
of Arylamidines from Aryltrifluoroborates
€
Jonas Savmarker, Jonas Rydfjord, Johan Gising, Luke R. Odell, and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry BMC,
Uppsala University, Box 574, SE-751 23, Uppsala, Sweden
Mats.Larhed@orgfarm.uu.se
Received March 30, 2012
ABSTRACT
A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The
coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,20-bipyridyl, TFA, and MeOH,
providing the corresponding arylamidines in moderate to excellent yields.
Amidines1 represent an important pharmacophore in
drug discovery and can be found in DNA and RNA
binding diamidine diminazene,2 ASIC inhibitors,3 mus-
carinic agonists for the treatment of Alzheimer’s disease,4
platelet aggregation inhibitors,5 and, recently, serine protease
inhibitors,6 to give a few examples. Amidines are also use-
ful precursors in the formation of various heterocyclic ring
systems, e.g. quinazolines,7 quinazolinones,8 pyrimidines,9
triazoles,10 and benzimidazoles.11 Typically, amidines are
prepared from nitrile containing precursors via nucleophilic
addition of a suitable amine. Similarly, amidines can also be
accessed by nucleophilic amino substitution of thioamides or
imidates.12 There are also Pd(0)-catalyzed three-component
methods,13 and recently, a direct aryne insertion into thio-
ureas was reported.14
We and others have previously developed Pd(II)-catalyzed
protocols for the generation and insertion of an arylpalla-
dium species into the polar nitrile bond.15,16 This methodol-
ogy has been used to generate arylketones, via a ketimine
intermediate, from arylboronic acids, benzoic acids, arylsul-
finates, and arenes. We hypothesized that a similar approach,
starting from an appropriate arylpalladium(II) precursor
and a cyanamide, could be used for facile preparation
of arylamidines from readily available arylborons and
(1) (a) Aly, A. A.; Nour-El-Din, A. M. ARKIVOC 2008, 153. (b)
Dunn, P. J. In Comprehensive Organic Functional Group Transforma-
tions II; Alan, R., Katritzky, R. J. K. T., Eds.; Elsevier: New York, 2005; Vol.
5, p 655.
(12) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai,
H. F.; Deng, J.; Lohse, A. G.; Zhang, Y. S. J. Org. Chem. 2011, 76, 5092.
(13) (a) Saluste, C. G.; Crumpler, S.; Furber, M.; Whitby, R. J.
Tetrahedron Lett. 2004, 45, 6995. (b) Kishore, K.; Tetala, R.; Whitby,
R. J.; Light, M. E.; Hurtshouse, M. B. Tetrahedron Lett. 2004, 45, 6991.
(c) Saluste, C. G.; Whitby, R. J.; Furber, M. Tetrahedron Lett. 2001, 42,
6191. (d) Saluste, C. G.; Whitby, R. J.; Furber, M. Angew. Chem., Int.
Ed. 2000, 39, 4156.
(2) Clement, B.; Immel, M.; Raether, W. Arzneim.-Forsch. 1992,
42ꢀ2, 1497.
(3) Chen, X. M.; Orser, B. A.; MacDonald, J. F. Eur. J. Pharmacol.
2010, 648, 15.
(4) Ojo, B.; Dunbar, P. G.; Durant, G. J.; Nagy, P. I.; Huzl, J. J.;
Periyasamy, S.; Ngur, D. O.; ElAssadi, A. A.; Hoss, W. P.; Messer, W. S.
Bioorg. Med. Chem. 1996, 4, 1605.
(5) Cannon, C. P. Clin. Cardiol. 2003, 26, 401.
(6) Kotthaus, J.; Steinmetzer, T.; van de Locht, A.; Clement, B. J.
Enzym. Inhib. Med. Ch. 2011, 26, 115.
(7) Ohta, Y.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett.
2010, 12, 3963.
(8) Ma, B.; Wang, Y.; Peng, J. L.; Zhu, Q. J. Org. Chem. 2011, 76,
6362.
(9) (a) Anderson, E. D.; Boger, D. L. J. Am. Chem. Soc. 2011, 133,
12285. (b) Anderson, E. D.; Boger, D. L. Org. Lett. 2011, 13, 2492.
(10) Castanedo, G. M.; Seng, P. S.; Blaquiere, N.; Trapp, S.; Staben,
S. T. J. Org. Chem. 2011, 76, 1177.
(14) Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946.
(15) (a) Garves, K. J. Org. Chem. 1970, 35, 3273. (b) Zhao, L.; Lu,
X. Y. Angew. Chem., Int. Ed. 2002, 41, 4343. (c) Zhou, C. X.; Larock,
R. C. J. Am. Chem. Soc. 2004, 126, 2302. (d) Lu, X. Y.; Zhao, B. W. Org.
Lett. 2006, 8, 5987. (e) Zhou, C. X.; Larock, R. C. J. Org. Chem. 2006, 71,
3551. (f) Zhao, B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765. (g) Yu, A.; Li,
J.; Cui, M.; Wu, Y. Synlett 2007, 19, 3063. (h) Behrends, M.; Savmarker,
J.; Sjoberg, P. J. R.; Larhed, M. ACS Catal. 2011, 1, 1455. (i) Lindh, J.;
Sjoberg, P. J. R.; Larhed, M. Angew. Chem., Int. Ed. 2010, 49, 7733.
(16) For examples involving rhodium catalysis, see: (a) Ueura, K.;
Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229. (b) Miura, T.; Murakami,
M. Org. Lett. 2005, 7, 3339. (c) Miura, T.; Murakami, M. Chem.
Commun. 2007, 3, 217.
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X. Y.; Wang, Y. F.; Chen, C. X. J. Org. Chem. 2011, 76, 716.
r
10.1021/ol300813c
Published on Web 04/17/2012
2012 American Chemical Society

cyanamides. This would represent a powerful new and direct
carbonꢀcarbon bond forming method for the formation of
this important functional group.
Table 1. Ligand Screen
The investigation was initiated by evaluating potassium
aryltrifluoroborates (ArBF3K) as the aryl source.17 These,
readily prepared,18 commercially available protected aryl-
boronic acids are of interest due to a longer shelf life together
with improved practical handling. In addition, they have
been proven to undergo transmetalation with limited inter-
ference from competitive protodeboronation.19
We initiated our study employing the catalytic system
previously reported for the 1,2-carbopalladation of
nitriles15i,h but switched to methanol as the solvent to
facilitate activation of the aryltrifluoroborates.20 A test
reaction was conducted with 4% Pd(O2CCF3) and 6%
6-methyl-2,20-bipyridyl as the catalytic system, potassium
4-methylphenyltrifluoroborate, 2 equiv of cyanamide, and
5 equiv TFA in methanol. The mixture was microwave
(MW) irradiated21 for 20 min in a sealed vial at 120 °C and
to our delight furnished full conversion of the yield deter-
mining 1a and concomitant formation of the arylamidine
product 3y according to 1H NMR analysis. A small
optimization of the reaction conditions was then under-
taken, revealing that the TFA excess could be reduced to 2
equiv without reducing the productivity. The outcome was
1
monitored by H NMR analysis of the crude product
mixture after MW processing. Furthermore, the cyana-
midewas replacedwith1-piperidinecarbonitriletoenablea
more straightforward detection of aliphatic protons in the
substrate. In order to simplify the purification,22 the
stoichiometry was reversed and the excess of ArBF3K
was reduced to 1.1 equiv.
Based upon these conditions a final ligand screen was
performed (Table 1). Similar yields of 88% and 86%,
respectively, were isolated from the related bipyridyl li-
gands 4a and 4b (entries 1 and 3). The more rigid ligand 4c
was found to reduce the isolated yield down to 69% (entry 4).
Surprisingly the two additional 2,9-methyl substituents on
4d totally suppressed the conversion of 1a, furnishing only
trace amounts of product 3a (entry 5). A similar lack of
reactivity was found with the phosphine based ligand 4e
(entry 6). Finally, three reference reactions were performed
a Isolated yield. Reaction conditions: Pd(O2CCF3)2 (0.04 mmol),
ligand 4 (0.06 mmol), TFA (2 mmol), ArBF3K 1a (1.1 mmol), cyanamide
2a (1 mmol), and MeOH (3 mL), heated by MW in a sealed vial at 120 °C
for 20 min. b Without TFA. c Without Pd(O2CCF3)2. n.d.: Product was
not detected by LC-MS.
demonstrating the importance of TFA, ligand and Pd
(entries 2, 7 and 8).
After the identification of highly productive reaction
conditions (Table 1, entry 1), we next set about exploring
the scope and limitations of the protocol. Thus, a set of
various potassium aryltrifluoroborates was investigated,
and the results are presented in Table 2. The electron-rich
aryltrifluoroborates 1b and 1c performed well, producing
the corresponding amidines 3b and 3c in 86% and 74%
yield, respectively (Table 2, entries 1, 2).
Phenyltrifluoroborate also proved to be a productive
substrate, giving benzamidine (3d) in 73% isolated yield
(Table 2, entry 5). Pleasingly, full chemoselectivity was
observed in the reaction of 1e (Table 2, entry 6) furnishing
63% of 3e, and no traces of byproduct resulting from Pd(0)
mediated oxidative addition of the aryl bromide were
detected.
(17) (a) Darses, S.; Genet, J. P. Chem. Rev. 2008, 108, 288. (b)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (c) Molander,
G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(18) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020.
(19) (a) Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug Dis-
covery 2009, 12, 811. (b) Molander, G. A.; Canturk, B. Angew. Chem.,
Int. Ed. 2009, 48, 9240.
(20) (a) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-
Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156. (b)
Andaloussi, M.; Lindh, J.; Savmarker, J.; Sjoberg, P. J. R.; Larhed, M.
Chem.;Eur. J. 2009, 15, 13069.
(21) Nilsson, P.; Olofsson, K.; Larhed, M. Top. Curr. Chem. 2006,
266, 103.
Unfortunately, the electron-deficient aryltrifluorobo-
rate 1f (Table 2, entry 7) provided 3f in only a moderate
yield of 37% and only trace amounts of product were
observed with the strongly electron-deficient substrate 1g
(entry 8). The lower yields of these electron-deficient
arylating agents might be explained by a slower insertion
(22) All products were purified by a simple extraction of the crude
mixture: 20 mL of DCM were extracted three times with 20 mL of sat.
NaHCO3 aq. The combined aqueous phases were basified to pH ∼14 by
the addition of NaOH and extracted three times with 60 mL of DCM.
The combined organic phases were concentrated to provide the pure
arylamidines.
Org. Lett., Vol. 14, No. 9, 2012
2395

Table 2. Scope of the Aryltrifluoroborates in the Reaction with
1-Piperidinecarbonitrile
Table 3. Scope of Cyanamides with Different Aryltrifluorobo-
rates
a Isolated yield. Reaction conditions: Pd(O2CCF3)2 (0.04 mmol),
ligand 4a (0.06 mmol), TFA (2 mmol), ArBF3K 1a,b,f (1.1 mmol),
cyanamide 2bꢀf (1 mmol), and MeOH (3 mL), heated by MW in a sealed
vial at 120 °C for 20 min.
a Isolated yield. Reaction conditions: Pd(O2CCF3)2 (0.04 mmol),
ligand 4a (0.06 mmol), TFA (2 mmol), ArBF3K 1bꢀj (1.1 mmol),
cyanamide 2a (1 mmol), and MeOH (3 mL), heated by MW in a sealed
vial at 120 °C for 20 min. b 4-Methylphenylboronic acid was used instead
of ArBF3K. c 4-Methylphenylboronic acid pinacol ester was used in-
stead of ArBF3K.
reasonable yields of 3h and 3j (66% each), indicating that
the protocol has a tolerance for steric hindrance, as well as
a heteroatom. The 4-methylphenylboronic acid 5 and the
corresponding pinacol ester derivative 6 (Table 2, entries 3
and 4) were both evaluated under these conditions, provid-
ing a significantly lower yield (33% and 45%, respectively)
of 3a compared with the corresponding ArBF3K, 1a (88%).
rate and a subsequent increase in the amount of byproduct
resulting from protodeboronation and homocoupling.
Surprisingly, 2-naphthyltrifluoroborate 1i afforded a
somewhat lower yield of 3i (40%), mainly due to the
competing protodeboronation. Finally, the ortho-substituted
1h (Table 2, entry 9) and the heterocyclic 1j both gave
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Org. Lett., Vol. 14, No. 9, 2012

Next, we extended the scope of the cyanamide substrate
to include unsubstituted cyanamide 2b, the disubstituted
2cꢀd, and cyclic 2f. Cyanamide (2b) was a productive
substrate, producing the unsubstituted amidines 3k (70%)
and 3n (73%) in good isolated yields (entries 1, 4) but only
trace amounts of the electron-poor 3s (entry 9). The bulky
diisopropylcyanamide 2d furnished only moderate yields
of product 3l (31%) and 3p (24%), presumably due to
unfavorable steric effects. The cyclic cyanamide 2f (Table
3, entries 3, 8, and 10) performed well, giving excellent to
moderate yields of the desired amidine products 3m (92%),
3r (58%), and 3t (33%). The dimethylcyanamide 2c (entry
5) was also well tolerated affording an excellent 82%
isolated yield of the desired product 3o. Interestingly, the
presence of one bulky tert-butyl substituent as in 2e had
only a minor influence on the reaction outcome, yielding
64% of 3q (Table 3, entry 7). Once again, the reaction was
found to be dependent upon the electronic nature of the
aryltrifluoroborate, with the electron-rich substrates 1aꢀb
affording consistently higher yields than the electron-poor
substrate 1f.
A plausible catalytic cycle, as adapted from the mecha-
nistic studies performed on the Pd(II)-catalyzed alkylni-
trile insertion reactions,15h,i isdepicted in Figure1. Starting
with the ligand coordinated Pd(II)-complex A, transmeta-
lation occurs with an arylboronate to generate the arylpal-
ladium intermediate B. Next, ligand exchange to furnish
the cyanamide coordinated complex C, followed by a 1,2
carbopalladation into the nitrile bond, affords complex D.
Finally, the protonation of the charged amidine by TFA
liberates the free amidine and Pd(II) species A.
Figure 1. Proposed catalytic cycle.
in excellent to acceptable yields. However, the electron-
deficient aryltrifluoroborates afforded low productivity un-
der these conditions, and further developments to improve
the scope of this methodology are ongoing in our laboratory.
Acknowledgment. We thank the Swedish Research
Council and the Knut and Alice Wallenberg Foundation
for financial support.
Supporting Information Available. General experimen-
1
tal procedures, characterization data and copies of H
and 13C NMR spectra of all isolated compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed a novel and conve-
nient approach for the direct formation of arylamidines,
furnishing both substituted and unsubstituted amidines
The authors declare no competing financial interest.
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