Synthesis of substituted isoquinolines utilizing palladium-catalyzed α-arylation of ketones

Article abstract of DOI:10.1073/pnas.1206532109

The utilization of sequential palladium-catalyzed α-arylation and cyclization reactions provides a general approach to an array of isoquinolines and their corresponding N-oxides. This methodology allows the convergent combination of readily available precursors in a regioselective manner and in excellent overall yields. This powerful route to polysubstituted isoquinolines, which is not limited to electron rich moieties, also allows rapid access to analogues of biologically active compounds.

Full text of DOI:10.1073/pnas.1206532109

Synthesis of substituted isoquinolines utilizing
palladium-catalyzed α-arylation of ketones
Timothy J. Donohoe1,2, Ben S. Pilgrim1, Geraint R. Jones, and José A. Bassuto
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, United Kingdom
Edited by Jack Halpern, The University of Chicago, Chicago, IL, and approved May 28, 2012 (received for review April 18, 2012)
The utilization of sequential palladium-catalyzed α-arylation and
cyclization reactions provides a general approach to an array of
isoquinolines and their corresponding N-oxides. This methodology
allows the convergent combination of readily available precursors
in a regioselective manner and in excellent overall yields. This
powerful route to polysubstituted isoquinolines, which is not lim-
ited to electron rich moieties, also allows rapid access to analogues
of biologically active compounds.
alpha arylation ∣ heterocycle ∣ isoquinoline-N-oxide ∣ one-pot
he isoquinoline motif and its derivatives form the cores of
T
numerous natural products (1, 2), are the central components
of a number of pharmaceutical agents (3–5), and can provide
the scaffold for chiral ligands (6, 7) and valuable organic materi-
als (8). However, traditional isoquinoline syntheses such as the
Bischler-Napieralski (9, 10), Pictet-Spengler (11, 12), and Pomer-
anz-Fritsch reactions (13–15) all centre around the lynchpin of
electrophilic aromatic substitution and are thus often limited
to electron-rich carbocycles (Scheme 1A). It is also imperative to
develop routes to highly-substituted isoquinolines to fully explore
this chemical space, for example, for potential pharmaceutical
targets. While recent synthetic efforts have greatly expanded the
diversity of isoquinoline motifs available (16–29), new routes to
isoquinolines are still highly desirable, particularly ones with the
ability to directly access the isoquinoline moiety in a range of oxi-
dation levels and which do not require highly-specialized starting
materials.
Scheme 1. Retrosynthetic Strategy.
tiveness of this route stemmed from both its potential for regio-
selective installation of substituents at all positions on the
isoquinoline nucleus and the fact that the coupling precursors
were either commercially available or could be synthesized in
a short sequence (Scheme 1B).
Initial optimization of the α-arylation conditions for the
reaction of ketone 1a with bromide 2a (two commercially avail-
able substrates) showed that a catalyst loading of 2.0 mol%
ðDtBPFÞPdCl2 or PdCl2ðAmphosÞ2 was sufficient to obtain high
yields of the arylated product 3a (Entries 3, 10, Table 1). Yields
could be further increased when 5.0 mol% of catalyst and 200 mol
% of ketone were used. Furthermore, the reaction was shown
to proceed well with a decreased catalyst loading of 0.5 mol%
(Entries 1, 2). As expected, iodide 2b showed comparable reac-
tivity to bromide 2a under these conditions. Chloride 2c could
also be employed as the aryl partner in the coupling reaction
(Entry 9); this was a significant development, as the requisite aryl
chlorides are both considerably cheaper than the corresponding
aryl bromides and are commercially available in a greater variety
of substitution patterns. As the aryl bromides presented the best
compromise of reactivity and availability, these were used for
further exemplification of the methodology.
Originally reported by Palucki and Buchwald (30), Hamann
and Hartwig (31), and Miura and coworkers (32), the palladium-
catalyzed α-arylation of enolates has recently emerged as a
powerful new reaction in synthetic organic chemistry (33–35).
Key to its success has been the design of appropriate ligands for
palladium that have precisely engineered steric and electronic
properties to enable the various steps in the catalytic cycle to
proceed with maximum efficiency (36–39). The reaction’s utility
has also been greatly enhanced by the development of robust pre-
formed palladium catalysts. Properties such as air stability and
very high reactivity in a range of systems have greatly expanded
the potential uses of these catalysts (40–43). However, the α-ar-
ylation reaction has seen limited use in the de novo construction
of aromatic compounds (44–51) and is still greatly underused in
this regard, especially because the bond forming abilities pro-
vided by this powerful reaction can greatly simplify the design of
routes to heavily-substituted aromatic compounds. Hence, we
decided to explore the scope of this new catalytic method in the
synthesis of important heteroaromatic ring systems, beginning
our investigations with the isoquinoline nucleus.
For the final aromatization step, solutions of a variety of am-
monium salts in EtOH∕H2O were screened. The solutions
Author contributions: T.J.D., B.S.P., and J.A.B. designed research; B.S.P. and G.R.J.
performed research; B.S.P., and G.R.J. analyzed data; and B.S.P. wrote the paper.
Results
In our disconnection approach we envisaged that key pseudo-1,5-
dicarbonyl intermediates 3 could be accessed via the palladium-
catalyzed α-arylation of ketones 1 with aryl halides 2 possessing a
protected aldehyde or ketone in the ortho-position (52). Subse-
quent treatment of these intermediates 3 with an acidic ammo-
nium source would lead to concomitant acetal deprotection and
aromatization to the corresponding isoquinolines 4. The attrac-
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1T.J.D. and B.S.P. contributed equally to this work.
2To whom correspondence should be addressed. E-mail: timothy.donohoe@chem.ox.ac.uk.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1206532109/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1206532109
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Table 1. Optimization of the arylation conditions
Even greater flexibility was achievable at the position to become
C(4) on the isoquinoline and arylation reactions to produce in-
termediates 3a,d,f,g with alkyl, 3i with aryl, and 3c with heteroa-
tom substitution proceeded efficiently. In the bromide coupling
partner, both protected aldehydes and ketones were tolerated in
the arylation reaction, enabling the construction of intermediates
3a–e where R1 ¼ H and 3f–j where R1 ¼ Me.
The subsequent deprotection and cyclization to produce iso-
quinolines 4a–e where R1 ¼ Me also proceeded in excellent
yields (79–99%). For intermediates 3f–j where R1 ¼ Me, we
noted that while deprotection was facile under the ammonium
chloride conditions, the ensuing cyclization was sluggish. It was
found, however, that following complete acetal hydrolysis, subse-
quent basification (to approximately pH 9) with ammonium
bicarbonate solution (2 M in H2O) promoted cyclization of these
substrates. Under these conditions, cyclization proceeded in good
to excellent yields (81–93%) to produce isoquinolines 4f–j.
Our investigation of the scope of substitution possible on the
carbocyclic ring involved varying the substituents on the benzene
ring of the aryl bromide partner (when the required aryl bromide
acetal is not itself a commercially available compound, it can gen-
erally be prepared in one step and at >90% yield) (Scheme 3).
The synthesis of isoquinolines with a wide variety of substitution
was possible, covering all four positions, and including 4k,l,m,o,r
with heteroatom, 4n with alkyl, 4p with aryl, and 4q,s with func-
tionalized carbon substituents. The arylations proceeded in good
to excellent yields (69–96%), as did the cyclizations (73–97%). Of
particular note, isoquinolines 4p,r bearing a group at the C(5)
position could be synthesized from sterically-hindered bromides.
The use of milder bases in the arylation step allowed sensitive
functionality such as a nitro group and a methyl ester to be car-
ried through the synthesis (isoquinolines 4k,q). This approach
could be used to synthesize isoquinolines 4k,l,m,q,s with electron
poor and isoquinolines 4n,o,p,r with electron rich carbocyclic rings,
confirming the wide applicability of this synthetic strategy—flex-
ibility that is not offered by many conventional approaches. The
benzene ring could also be replaced with a heteroarene to synthe-
size thieno-pyridine 4t, illustrating our ability to construct multiple
heteroatom-containing ring systems, which are attractive pharma-
ceutical targets.
Entry
X
Cat. loading
[mol%]
Ketone
[mol%]
Time
[h]
Yield
[%]
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
I
Cl
Cl
Cl
Br
0.5[a]
0.5[a]
2.0[a]
2.0[a]
5.0[a]
2.0[a]
5.0[a]
5.0[b]
120
200
120
200
200
120
200
200
200
120
18
18
18
18
18
18
18
18
96
18
71
74
82
83
89
79
30
45
74
82
½bꢀ
9
10
5.0 × 2
2.0[b]
needed to be of a certain acidity (approximately pH 5) to effect
acetal hydrolysis at reasonable rates. It was found that heating
intermediate 3a in a solution of ammonium chloride (1 M in
3∶1 EtOH∕H2O) mediated deprotection and cyclization in excel-
lent yield.
To examine the scope of this reaction, the substituents that
could be tolerated during the arylation step and would be posi-
tioned on the heterocyclic ring of the resulting isoquinoline were
investigated (Scheme 2). A range of ketones were arylated in
good to excellent yields (68–92%) and a wide array of substitu-
ents was tolerated at the position to become C(3) on the iso-
quinoline; intermediates 3a,b,c,f,i with aryl, 3j with heteroaryl,
and 3d,e,g,h with alkyl substitution. The regioselectivity of the
arylation reaction enabled the regio-defined construction of the
intermediate 3h where there was a choice of enolizable protons
on the ketone. It was also pleasing to note that intermediate 3e,
bearing a bulky quaternary substituent, could be synthesized.
Scheme 3. Exploring the scope of substituents R5, R6, R7, and R8.
Scheme 2. Exploring the scope of substituents R1, R3, and R4.
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Donohoe et al.

Scheme 6. Derivatizing estrone and androsterone.
This de novo isoquinoline synthesis has the ability to construct
complex isoquinoline scaffolds in a rapid and modular fashion.
The simplicity and mild conditions of the one-pot procedure
make it ideal for the manipulation of existing natural product
frameworks to create libraries of potentially biologically active
targets for medicinal screening. The addition of a basic isoquino-
line nitrogen imparts a site on a molecule for varying lipophilicity,
an essential consideration in lead optimisation (57). As many
potent pharmaceuticals are derivatives of naturally-occurring
steroidal hormones, we chose to exemplify this concept on
derivatives of the key female sex hormone estrone and the tes-
tosterone metabolite androsterone. Application of the one-pot
procedure enabled the synthesis of isoquinolines 8 and 9 in
63 and 59% yields, respectively, using commercially available
bromide 2a (Scheme 6).
Scheme 4. A One-pot protocol.
The miscibility of THF with EtOH and H2O prompted investi-
gation into a one-pot procedure for an arylation/cyclization
sequence. After the arylation was complete, the reaction mix-
ture was acidified to pH 5 with aqueous 1 M HCl and then the
cyclization was carried out by the addition of the nitrogen source
as previously described. The sequential one-pot protocol worked
well for a number of substrates without significantly affecting the
yield. This greatly improved the practicability of this synthetic pro-
cedure, and isoquinolines 4a and 4b, for example, could now be
synthesized in one step from commercial materials (Scheme 4).
Whilst the majority of other isoquinoline syntheses can only
give access to the isoquinoline manifold in one oxidation level, a
strength of this method is that by variation of one of the reaction
components, more oxidized isoquinoline scaffolds are easily
accessible. The direct synthesis of isoquinoline N-oxides 5 was
achievable by replacing the ammonium chloride in the cyclization
step with the hydrochloride salt of hydroxylamine (Scheme 5).
Conversion of the arylated intermediates 3 to the N-oxides 5
occurred more rapidly (2 h) than to the corresponding isoquino-
lines 4 and in excellent yields (86–99%). As a number of subse-
quent functionalization reactions on isoquinolines are performed
via their N-oxides (53–56), we felt that this powerful and direct
approach to their synthesis would prove extremely useful. In
particular, it gives the potential to subsequently install a variety
of substituents at C(1) without the need for long syntheses of
complicated aryl halide precursors. Also, alternative procedures
involving direct oxidations of isoquinolines to their N-oxides can
have limited functional group tolerance and use a stoichiometric
equivalent of an oxidizing agent in the process.
Conclusions
In summary, the utilization of sequential palladium-catalyzed
α-arylation and cyclization reactions provides a general approach
to an array of substituted isoquinolines and their corresponding
N-oxides. The methodology presented here allows the convergent
combination of readily-available precursors in a regioselective
manner and in excellent overall yields (often >70% from com-
mercially available precursors). This powerful route to polysub-
stituted isoquinolines, which works equally well for both electron
poor and electron rich moieties, also allows rapid access to ana-
logues of biologically active compounds.
Methods
Full experimental details and compound characterization data are included
in the SI Appendix.
General Procedure for the Palladium-Catalyzed α-Arylation Reaction. A reseal-
able reaction tube, containing a magnetic follower, was sealed with a rubber
septum and flame dried under a flow of argon. The palladium catalyst (2.0 or
5.0 mol%) and base (250 mol%) were added to the tube. The aryl halide
(100 mol%) was dissolved in dry THF (5 mL mmol−1 substrate) and the result-
ing solution was added via syringe to the tube. The ketone (120 or 200 mol%)
was then added via syringe to the tube. The rubber septum was replaced with
a screw cap and the tube was heated at 70 °C for 18 h. The reaction was then
cooled to room temperature and quenched by the addition of H2O (25 mL).
The aqueous layer was extracted with Et2O (3 × 25 mL) and the combined
organics were dried over Na2SO4, filtered, and the solvent removed in vacuo.
Purification by flash column chromatography furnished the requisite inter-
mediate.
General Procedure for Isoquinoline Formation Where R1 ¼ H. A solution of
NH4Cl (1000 mol%, 1.0 M in 3∶1 EtOH∕H2O) was added to the cyclization
substrate (100 mol%) in a resealable reaction tube containing a magnetic
follower. The tube was sealed with a screw cap and heated at 90 °C for 24 h.
The reaction was then cooled to room temperature and quenched by the
Scheme 5. Isoquinoline N-oxides.
Donohoe et al.
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addition of saturated aqueous NaHCO3 (25 mL). The aqueous layer was
extracted with Et2O (3 × 25 mL) and the combined organics were dried over
Na2SO4, filtered, and the solvent removed in vacuo. Purification by flash col-
umn chromatography furnished the requisite isoquinoline.
was resealed and heated for a further 24 h at 90 °C. The reaction was then
cooled to room temperature and quenched by the addition of H2O (25 mL).
The aqueous layer was extracted with Et2O (3 × 25 mL) and the combined
organics were dried over Na2SO4, filtered, and the solvent removed in vacuo.
Purification by flash column chromatography furnished the requisite isoqui-
noline.
General Procedure for Isoquinoline Formation Where R1 ¼ Me. A solution of
NH4Cl (1000 mol%, 1.0 M in 3∶1 EtOH∕H2O) was added to the cyclization
substrate (100 mol%) in a resealable reaction tube containing a magnetic
follower. The tube was sealed with a screw cap and heated at 90 °C for
18 h. A solution of NH4HCO3 (2.0 M in H2O) was then added until the pH
of the reaction mixture had been adjusted to approximately pH 9. The tube
ACKNOWLEDGMENTS. We would like to thank Johnson Matthey for their
donation of palladium catalysts and St. John’s College, Oxford University
for supporting this project.
1. Bentley KW (2006) β-Phenylethylamines and the isoquinoline alkaloids. Nat Prod Rep
23:444–463.
2. Bentley KW (1998) The Isoquinoline Alkaloids (Harwood Academic Publishers,
Amsterdam).
3. Pike VW, et al. (1993) Radioligands for PETstudies of central benzodiazepine receptors
and PK (peripheral benzodiazepine) binding sites-current status. Nucl Med Biol
20:503–525.
4. Weissman BA, Raveh L (2003) Peripheral benzodiazepine receptors: On mice and
human brain imaging. J Neurochem 84:432–437.
31. Hamann BC, Hartwig JF (1997) Palladium-catalyzed direct α-arylation of ketones: Rate
acceleration by sterically hindered chelating ligands and reductive elimination from a
transition metal enolate complex. J Am Chem Soc 119:12382–12383.
32. Satoh T, Kawamura Y, Miura M, Nomura M (1997) Palladium-catalyzed regioselective
mono- and diarylation reactions of 2-phenylphenols and naphthols with aryl halides.
Angew Chem Int Ed Eng 36:1740–1742.
33. Bellina F, Rossi R (2010) Transition metal-catalyzed direct arylation of substrates with
activated sp3-hybridized C-H bonds and some of their synthetic equivalents with aryl
halides and pseudohalides. Chem Rev 110:1082–1146.
5. Rinehart KL (2000) Antitumor compounds from tunicates. Med Res Rev 20:1–27.
6. Lim CW, et al. (2003) Practical preparation and resolution of 1-(2′-diphenylphosphino-
1′-naphthyl)isoquinoline: A useful ligand for catalytic asymmetric synthesis. Org Pro-
cess Res Dev 7:379–384.
34. Johansson CCC, Colacot TJ (2010) Metal-catalyzed α-arylation of carbonyl and related
molecules: Novel trends in C–C bond formation by C–H bond functionalization. Angew
Chem Int Ed Eng 49:676–707.
35. Novák P, Martin R (2011) Pd-catalyzed α-arylation of carbonyl and related compounds:
Recent developments and perspectives. Curr Org Chem 15:3233–3262.
36. Cullen WR, Kim TJ, Einstein FWB, Jones T (1983) Structure of the hydrogenation
catalyst ½ðPPÞRhðNBDÞꢀClO4, PP ¼ ðη5-ðMe3CÞ2PC5H4Þ2Fe, and some comparative rate
studies. Organometallics 2:714–719.
7. Alcock NW, Brown JM, Hulmes GI (1993) Synthesis and resolution of 1-(2-diphenylpho-
sphino-1-naphthyl)isoquinoline;
A P-N chelating ligand for asymmetric catalysis.
Tetrahedron Asymmetry 4:743–756.
8. Tsuboyama A, et al. (2003) Homoleptic cyclometalated iridium complexes with highly
efficient red phosphorescence and application to organic light-emitting diode. J Am
Chem Soc 125:12971–12979.
9. Bischler A, Napieralski B (1893) A new method for the synthesis of isoquinolines. Chem
Ber 26:1903–1908.
10. Whaley WM, Govindachari TR (1951) Organic Reactions, ed R Adams (Wiley, New
York), Vol. 6, pp 74–150.
11. Pictet A, Spengler T (1911) Formation of isoquinoline derivatives by the action of
methylal on phenylethylamine, phenylalanine and tyrosine. Chem Ber 44:2030–2036.
12. Whaley WM, Govindachari TR (1951) Organic Reactions, ed R Adams (Wiley, New
York), Vol. 6, pp 151–190.
37. Butler IR, Cullen WR, Kim TJ, Rettig SJ, Trotter J (1985) 1,1′-Bis(alkylarylphosphino)fer-
rocenes: Synthesis, metal complex formation, and crystal structure of three metal com-
plexes of Feðη5-C5H4PPh2Þ2. Organometallics 4:972–980.
38. Hamann BC, Hartwig JF (1998) Sterically hindered chelating alkyl phosphines provide
large rate accelerations in palladium-catalyzed amination of aryl iodides, bromides,
and chlorides, and the first amination of aryl tosylates. J Am Chem Soc 120:7369–7370.
39. Kawatsura M, Hartwig JF (1999) Simple, highly active palladium catalysts for ketone
and malonate arylation: Dissecting the importance of chelation and steric hindrance.
J Am Chem Soc 121:1473–1478.
40. Colacot TJ, Shea HA (2004) Cp2FeðPR2Þ2PdCl2ðR ¼ i- Pr; t-BuÞ Complexes as air-stable
catalysts for challenging Suzuki coupling reactions. Org Lett 6:3731–3734.
41. Guram AS, et al. (2006) New air-stable catalysts for general and efficient Suzuki-
Miyaura cross-coupling reactions of heteroaryl chlorides. Org Lett 8:1787–1789.
42. Grasa GA, Colacot TJ (2007) α-Arylation of ketones using highly active, air-stable
ðDtBPFÞPdX2 (X ¼ Cl, Br) catalysts. Org Lett 9:5489–5492.
13. Pomeranz C (1893) A new isoquinoline synthesis. Monatsh Chem 14:116–119.
14. Fritsch
P (1893) Syntheses in the isocoumarin and isoquinoline series. Chem Ber
26:419–422.
15. Gensler WJ (1951) Organic Reactions, ed R Adams (Wiley, New York), Vol. 6, pp 191–206.
16. Jayakumar J, Parthasarathy K, Cheng C (2012) One-pot synthesis of isoquinolinium
salts by rhodium-catalyzed C-H bond activation: Application to the total synthesis
of oxychelerythrine. Angew Chem Int Ed Engl 51:197–200.
17. Too PC, Chua SH, Wong SH, Chiba S (2011) Synthesis of azaheterocycles from aryl
ketone O-acetyl oximes and internal alkynes by Cu-Rh bimetallic relay catalysts.
J Org Chem 76:6159–6168.
18. Si C, Myers AG (2011) A versatile synthesis of substituted isoquinolines. Angew Chem
Int Ed Eng 50:10409–10413.
19. Chaumontet M, Piccardi R, Baudoin O (2009) Synthesis of 3,4-dihydroisoquinolines by a
Cðsp3Þ-H activation/electrocyclization strategy: Total synthesis of coralydine. Angew
Chem Int Ed Eng 48:179–182.
43. Grasa GA, Colacot TJ (2008) A highly practical and general route for α-arylations of
ketones using Bis-phosphinoferrocene-based palladium catalysts. Org Process Res
Dev 12:522–529.
44. Barluenga J, Jiménez-Aquino A, Aznar F, Valdés C (2009) Modular synthesis of indoles
from imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-catalyzed cascade pro-
cess. J Am Chem Soc 131:4031–4041.
45. Eidamshaus C, Burch JD (2008) One-pot synthesis of benzofurans via palladium-cata-
lyzed enolate arylation with o-bromophenols. Org Lett 10:4211–4214.
46. Chen Y, Wang Y, Sun Z, Ma D (2008) Elaboration of 2-(Trifluoromethyl)indoles via a
cascade coupling/condensation/deacylation Process. Org Lett 10:625–628.
47. Barluenga J, Jiménez-Aquino A, Valdés C, Aznar F (2007) The azaallylic anion as a syn-
thon for Pd-catalyzed synthesis of heterocycles: Domino two-and three-component
synthesis of indoles. Angew Chem Int Ed Eng 46:1529–1532.
20. Chiba S, Xu Y, Wang Y (2009) A Pd(II)-catalyzed ring-expansion reaction of cyclic 2-azi-
doalcohol derivatives: Synthesis of azaheterocycles. J Am Chem Soc 131:12886–12887.
21. Guimond N, Fagnou K (2009) Isoquinoline synthesis via rhodium-catalyzed oxida-
tive cross-coupling/cyclization of aryl aldimines and alkynes.
131:12050–12051.
22. Sha F, Huang X (2009) A multicomponent reaction of arynes, isocyanides, and terminal
alkynes: Highly chemo- and regioselective synthesis of polysubstituted pyridines and
isoquinolines. Angew Chem Int Ed Eng 48:3458–3461.
J
Am Chem Soc
48. Chen Y, Xie X, Ma D (2007) Facile access to polysubstituted indoles via a cascade
Cu-catalyzed arylation-condensation process. J Org Chem 72:9329–9334.
49. Tanimori S, Ura H, Kirihata M (2007) Copper-catalyzed synthesis of 2,3-disubstituted
indoles. Eur J Org Chem 3977–3980.
50. Churruca F, SanMartin R, Tellitu I, Domínguez E (2005) A new, expeditious entry to the
23. Gilmore CD, Allan KM, Stoltz BM (2008) Orthogonal synthesis of indolines and isoqui-
nolines via aryne annulation. J Am Chem Soc 130:1558–1559.
benzophenanthrofuran framework by a Pd-catalyzed C- and O-arylation/PIFA-
mediated oxidative coupling sequence. Eur J Org Chem 12:2481–2490.
51. Terao Y, Satoh T, Miura M, Nomura M (1999) Palladium-catalyzed cross-coupling of
benzyl ketones and α,β-unsaturated carbonyl and phenolic compounds with O-dibro-
mobenzenes to produce cyclic products. Bull Chem Soc Jpn 72:2345–2350.
52. Fox JM, Huang X, Chieffi A, Buchwald SL (2000) Highly active and selective catalysts for
the formation of α-aryl ketones. J Am Chem Soc 122:1360–1370.
53. Campeau L, et al. (2009) Palladium-catalyzed direct arylation of azine and azole
N-oxides: Reaction development, scope and applications in synthesis. J Am Chem
Soc 131:3291–3306.
24. Wang B, Lu B, Jiang Y, Zhang Y, Ma D (2008) Assembly of isoquinolines via CuI-cata-
lyzed coupling of β-Keto esters and 2-halobenzylamines. Org Lett 10:2761–2763.
25. Fischer D, et al. (2008) Iodine-mediated electrophilic cyclization of 2-alkynyl-1-methy-
lene azide aromatics leading to highly substituted isoquinolines and its application to
the synthesis of norchelerythrine. J Am Chem Soc 130:15720–15725.
26. Huo Z, Tomeba H, Yamamoto Y (2008) Iodine-mediated electrophilic cyclization of
2-alkynylbenzaldoximes leading to the formation of iodoisoquinoline N-oxides. Tetra-
hedron Lett 49:5531–5533.
27. Fischer D, Tomeba H, Pahadi NK, Patil NT, Yamamoto Y (2007) Synthesis of 1,3,4-tri-
substituted isoquinolines by iodine-mediated electrophilic cyclization of 2-alkynyl
benzyl azides. Angew Chem Int Ed Eng 46:4764–4766.
28. Xiang Z, et al. (2004) Concise synthesis of isoquinoline via the Ugi and Heck reactions.
Org Lett 6:3155–3158.
29. Roesch KR, Zhang H, Larock RC (2001) Synthesis of isoquinolines and pyridines by the
palladium-catalyzed iminoannulation of internal alkynes. J Org Chem 66:8042–8051.
30. Palucki M, Buchwald SL (1997) Palladium-catalyzed α-arylation of ketones. J Am Chem
Soc 119:11108–11109.
54. Kanyiva KS, Nakao Y, Hiyama T (2007) Nickel-catalyzed addition of pyridine-N-oxides
across alkynes. Angew Chem Int Ed Eng 46:8872–8874.
55. Ren H, Luo Y, Ye S, Wu J (2011) Silver triflate catalyzed reaction of 2-alkynylbenzal-
doxime with aryne. Org Lett 13:2552–2555.
56. Londregan AT, Jennings S, Wei L (2011) Mild addition of nucleophiles to pyridine-
N-oxides. Org Lett 13:1840–1843.
57. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computa-
tional approaches to estimate solubility and permeability in drug discovery and devel-
opment settings. Adv Drug Deliver Rev 46:3–26.
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