Modular isoquinoline synthesis using catalytic enolate arylation and in situ functionalization

Article abstract of DOI:10.1021/ol4030309

A methyl ketone, an aryl bromide, an electrophile, and ammonium chloride were combined in a four-component, three-step, and one-pot coupling procedure to furnish substituted isoquinolines in overall yields of up to 80%. This protocol utilizes the palladiu

Full text of DOI:10.1021/ol4030309

ORGANIC
LETTERS
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Vol. XX, No. XX
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Modular Isoquinoline Synthesis Using
Catalytic Enolate Arylation and in Situ
Functionalization
Ben S. Pilgrim,†,§ Alice E. Gatland,†,§ Charlie T. McTernan,† Panayiotis A. Procopiou,‡
and Timothy J. Donohoe*,†
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K., and GlaxoSmithKline, Medicines Research
Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
timothy.donohoe@chem.ox.ac.uk
Received October 22, 2013
ABSTRACT
A methyl ketone, an aryl bromide, an electrophile, and ammonium chloride were combined in a four-component, three-step, and one-pot coupling
procedure to furnish substituted isoquinolines in overall yields of up to 80%. This protocol utilizes the palladium catalyzed R-arylation reaction of
an enolate, followed by in situ trapping with an electrophile, and aromatization with ammonium chloride. tert-Butyl cyanoacetate participated in a
similar protocol; after functionalization and decarboxylation, 3-amino-4-alkyl isoquinolines were prepared in high yield.
The isoquinoline unit is commonly found in natural
product frameworks, the cores of pharmaceutical agents,
and important organic materials; however, traditional
synthetic routes to these motifs suffer from a number of
drawbacks. Recently, a number of groups have employed
catalytic amounts of transition metals to mediate new
bond forming processes en route to isoquinolines.1
In 2012, we published a de novo synthetic route to iso-
quinolines that utilized the palladium catalyzed R-arylation
of ketone enolates.2 In this protocol, readily available
precursors were combined in a concise, convergent, and
regiocontrolled manner to furnish polysubstitued iso-
quinolines.
The choice of ketone coupling partner determined two
of the substituents (at C3 and C4) on the heteroaryl ring of
the isoquinoline, arguably two of the most important to be
able to manipulate. Although a reasonable scope of the
method was demonstrated, the limited commercial avail-
ability of the requisite ketones, together with difficulties
encountered during regioselective enolization, imparted
certain limitations on the methodology.
While isoquinolines undergo nucleophilic attack at the
C1 and C3 positions and can be made to react with
electrophiles (albeit under forcing conditions) at the C5
and C8 positions, the C4 position is difficult to functiona-
lize in a direct manner. However, one of the advantages of
de novo approaches to aromatic rings is that the inter-
mediates formed en route to the arene can be manipulated,
† University of Oxford.
‡ GlaxoSmithKline.
§ These authors contributed equally.
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r
10.1021/ol4030309
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often giving greater flexibility in the substitution pattern
of the eventual target. The carbonyl compound formed
after coupling in our synthetic route appeared to be a
prime candidate for elaboration at the center which would
eventually become C4 on the isoquinoline (Figure 1).
Consideration of the mechanism for enolate coupling
reveals that the product has more acidic protons than the
starting material and consequently an enolate A should be
the species formed in situ by the extra base that is required
for these reactions. This feature opened up the possibility
of a one-pot coupling and enolate quenching proce-
dure. Indeed the use of MeI as an electrophile to trap an
enolate coupling reaction was described by Hartwig and
co-workers in the palladium catalyzed R-arylation of
malonates,3 and Myers has also reported the trapping of
eneamido anions en route to isoquinolines.4
available materials (aryl bromide 1, acetophenone, allyl
bromide, and ammonium chloride) has been developed
that delivers complex substitution patterns (Scheme 1). We
then sought to explore the scope of this methodology and
began by concentrating on the one-pot coupling of 1 and
acetophenone, combined with a quench using a series of
different electrophiles and followed by aromatization. The
structures 4aÀg shown in Scheme 1 reveal that the method
is broadly applicable to a range of carbon and heteroatom
electrophiles, introducing different substituents at C4. All
isoquinolines were produced in one pot.
Scheme 1. Examination of the Electrophile in an Enolate
Arylation/Electrophile Trapping/Aromatization Sequence
Figure 1. Design of an enolate arylation/electrophile trapping/
aromatization sequence.
First, a robustsetofarylationconditionsweredeveloped
((DtBPF)PdCl2, t-BuONa, THF) to couple aryl bromides
such as 1 with ketones such as acetophenone, furnishing
intermediate 2 in high yield (Scheme 1). As a first experi-
ment, it was found that treatment of 2 with t-BuONa in
THF, followed by allyl bromide, formed functionalized
intermediate 3 in 68% yield. Upon subjection to ammo-
nium chloride conditions, 3 then cyclized in excellent yield
to give C4-functionalized isoquinoline 4a.
We then moved to examine one-pot arylation and
enolate trapping. Gratifyingly, it was found that subjecting
1 and acetophenone to coupling and then quenching the
reaction with allyl bromide delivered intermediate 3 in
78% yield. Seeking to improve the operational simplicity
of this protocol further, we combined all three synthetic
procedures in a one-pot operation. After quenching the
enolate coupling reaction with an electrophile, the reaction
mixture was neutralized with HCl, ammonium chloride
was added, and the substrate was cyclized in situ. The
sequential application of these conditions delivered iso-
quinoline 4a in one pot and in an excellent yield of 71%
(indeedsignificantlyhigherthanthe overallstepwiseyield).
Hence, a four-component coupling of commercially
The tactic of in situ enolate quenching gives several
advantages over the preparation of a more substituted
ketone before enolate coupling. Not only is the prepara-
tion of a more complex ketone now unnecessary, but
problems that we had previously encountered with regio-
selective ketone deprotonation and enolate decomposition
were obviated.
Next we extended the concept toward isoquinolines
bearing substituents on the carbocyclic ring, as well as at
C1 (4hÀo, Scheme 2). In addition, the nature of the group
adjacent to the carbonyl, ending up at C3, was examined;
alternative aryl and alkyl derivatives were compatible with
this methodology. In each case the isoquinoline was
formed in good yield over a three-step sequence conducted
in one reaction vessel.
Following the successful introduction of alkyl, allyl,
benzyl, and heteroatom substituents with this methodol-
ogy, we considered the incorporation of an aryl group at
the C4position by the one-potcoupling of the intermediate
(4) Si, C.; Myers, A. G. Angew. Chem., Int. Ed. 2011, 50, 10409.
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Org. Lett., Vol. XX, No. XX, XXXX

observed, presumably due to steric hindrance slowing
down the second coupling. It was therefore proposed that,
in the presence of excess base, the enolate A (Figure 1)
resulting from an initial R-arylation reaction and deproto-
nation could undergo another R-arylation in situ providing
that a relatively unhindered aryl bromide was added
second. This was found to be the case, and diarylated
ketones 5aÀc were obtained in excellent yields (Scheme 3).
A catalyst loading of 2.5 mol % (R = H) could be used for
successful diarylation;howeverinordertoensurecomplete
reaction in more complex systems, a loading of 5.0 mol %
was often used. To the best of our knowledge, this is
the first demonstration of a one-pot palladium catalyzed
R,R-heterodiarylation of ketones.
Scheme 2. C4-Substituted Isoquinolines via a One-Pot Process
It was desirable to attempt to simplify the reaction
sequence by carrying out all three steps in a single opera-
tion. Accordingly, it was found that an ammonium chlo-
ride solution could be added directly to the diarylation
product mixture to promote in situ deprotection and cycli-
zation, affording isoquinolines 6aÀc in 73À80% yield.
Scheme 3. Development of an Enolate Heterodiarylation/Aro-
matization Sequence
enolate (e.g., A, Figure 1) with another aryl halide. The
range of commercially available benzyl ketones (the requi-
site R-arylation coupling partner for direct access to the
desired isoquinoline precursor) is limited, and C4-aryla-
tion of a preformed isoquinoline is extremely challenging.
Thus, we envisaged that C4-aryl isoquinolines could be
accessed through an R,R-diarylation of a methyl ketone,
followed by acetal deprotection and cyclization. While the
palladium catalyzed diarylation of methyl ketones has
been reported, to the best of our knowledge it is limited
to homodiarylation using an excess of one unhindered aryl
halide,5 or has been observed as an undesired side
reaction.6
To explore the scope further, polysubstituted C4-aryl
isoquinolines 6dÀl were prepared in yields ranging from 53
to 69% (Scheme 4), which is equivalent to an 81À88%
yield per step. Both electron-rich and electron-poor aryl
bromides were efficient in the R-arylation reactions, which
could be carried out on a number of different methyl
ketones. Fused biaryls could also be installed at C4 (6e
and 6f), and a methyl substituent in the starting acetal was
also tolerated allowing access to C1-substituted, C4-aryl
isoquinolines 6k and 6l.
In our experience of making isoquinolines via enolate
coupling, the diarylation of a ketone with an aryl bromide
bearing an (ortho) cyclic acetal, such as 1, was not
Finally, we addressed the synthesis of isoquinolines at a
higher oxidation level. We reasoned that these could be
accessed via R-arylation of a nitrile rather than a ketone,
since cyclization onto the pendant nitrile would result in
the introduction of an amino group at C3 on the isoquino-
line. Unfortunately, the R-arylation reaction of alkyl ni-
triles is challenging7 and far less general than that of alkyl
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Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 4. C4-Aryl Isoquinolines via a One-Pot Process
Scheme 5. C4-Substituted 3-Amino Isoquinolines
reaction mixture, postarylation, provided alkylated inter-
mediates 7aÀd in yields of 84À91%. As a second step,
these underwent decarboxylation of the tert-butyl ester
simplybyheatinginthepresenceof water, afterwhichsolid
ammonium chloride was added to lower the pH and
hydrolyze the acetal. Finally, in this instance, a basic
source of ammonia (NH4HCO3) was required to drive
cyclization tocompletion, affording 3-amino isoquinolines
8aÀd. Thus, the formation of C4-alkylated C3-amino
isoquinolines was accomplished with a range of electro-
philes and could be performed as either a one- or two-step
protocol.
These studies report the development of a versatile four-
component coupling protocol between readily available
materials (aryl bromide, methyl ketone, electrophile, and
ammonium chloride) that delivers isoquinolines with com-
plexsubstitution patterns, including variedfunctionality at
C4. The aryl bromide, ketone, and electrophile can be
altered to allow the regioselective synthesis of polysubsti-
tuted isoquinolines. A novel, sequential R,R-heterodiary-
lation provides C4-aryl isoquinolines, while replacing the
methyl ketone with tert-butyl cyanoacetate, results in the
preparation of 3-amino-4-alkyl isoquinolines: all of the
abovechemistrytakesplaceinoneortwooperational steps.
ketones. The R-arylation of ethyl cyanoacetate, however,
has seenmore application,1q,2,8 withWangetal. employing
a Pd(OAc)2/DPPF catalyst system with t-BuOK.9 We
anticipated that the analogous tert-butyl cyanoacetate
arylation product might undergo hydrolysis and decarbox-
ylation to furnish an isoquinoline precursor. It was noted
that while the decarboxylative couplings developed by the
groups of Shang and Feng10,11 also allow access to these
compounds, such reactions require prior alkylation of
ethyl cyanoacetate followed by conversion to the potas-
sium cyanoacetate salt. In addition, high temperatures
(140À150 °C) are required for the couplings and their
use with ortho-substituted aryl bromides has not been
demonstrated.
The commercially available precatalyst (DPPF)PdCl2
(2.0 mol %) in combination with t-BuONa effected the
R-arylation of tert-butyl cyanoacetate with aryl bromide 1
(Scheme 5). As before, the addition of an alkyl halide tothe
Acknowledgment. We thank the EPSRC, Glaxo-
SmithKline, and St John’s College, Oxford for financial
support.
1
Supporting Information Available. Copies of H and
(8) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003.
(9) Wang, X.; Guram, A.; Bunel, E.; Cao, G.-Q.; Allen, J. R.; Faul,
M. M. J. Org. Chem. 2008, 73, 1643.
(10) Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem., Int.
Ed. 2011, 50, 4470.
13C NMR spectra, and experimental procedures are
available. This material is available free of charge via
the Internet at http://pubs.acs.org.
(11) Feng, Y.-S.; Wu, W.; Xu, Z.-Q.; Li, Y.; Li, M.; Xu, H.-J.
Tetrahedron 2012, 68, 2113.
The authors declare no competing financial interest.
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