Palladium-catalyzed domino Heck/intermolecular cross-coupling: efficient synthesis of 4-alkylated isoquinoline derivatives

Article abstract of DOI:10.1039/c6cc10075a

A highly efficient Pd-catalyzed Heck-type cascade process with 2-(1-alkynyl)benzaldimines has been developed, which provides access to a broad range of 4-alkylated isoquinoline derivatives in moderate to good yields. The σ-alkylpalladium(ii) intermediate in the Heck reaction activates alkynes toward intramolecular nucleophilic attack. This is the first example of a σ-alkylpalladium(ii) intermediate promoting the cyclization of alkynes containing a proximate nucleophilic center.

Full text of DOI:10.1039/c6cc10075a

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DOI: 10.1039/C6CC10075A
Journal Name
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Palladium-Catalyzed Domino Heck / Intermolecular Cross-
Coupling: Efficient Synthesis of 4-Alkylated Isoquinoline
Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Tuanli Yao,* Tao Liu and Changhui Zhang
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient Pd-catalyzed Heck-type cascade process with 2-
(1-alkynyl)benzaldimines has been developed, which provides
access to a broad range of 4-alkylated isoquinoline derivatives in
moderate to good yields. The σ-alkylpalladium(II) intermediate in
the Heck reaction activates alkynes toward intramolecular
nucleophilic attack. This is the first example of
a σ-
alkylpalladium(II) intermediate promoting the cyclization of
alkynes containing a proximate nucleophilic center.
The organopalladium-promoted cyclization of alkynes
containing proximate nucleophilic centers is a very effective
strategy for heterocyclic ring construction.1 This strategy has
been successfully applied in the synthesis of 2,3-disubstituted
indoles,2 2,3-disubstituted benzofurans,3 3,4-disubstituted
isoquinolines4 and other cyclic compounds.5 However,
previous studies have focused on the construction of
C(sp2)−C(sp2) bonds [via arylpalladium(II) or vinylpalladium(II)
intermediates]. Introducing alkyl-C(sp3)-substituents in
heterocyclic ring construction is particularly desirable.
Benzylation and allylation in heterocyclic ring construction has
been realized via benzylpalladium and π-allylpalladium
intermediates.4a,6 These palladium intermediates are relatively
more stabilized and show higher activities compared with σ-
alkylpalladium intermediates, so cyclization involving σ-
alkylpalladium intermediates is still a challenge.
The intramolecular Heck reaction of 1,1’-disubstituted
olefins is known to be highly efficient for the construction of
benzo-fused saturated nitrogen / oxygen heterocycles with a
carbon quaternary center via an n-exo-trig cyclization.7 We
envisioned that the resulting neopentyl-type σ Pd(II) complex
may activate alkynes toward intramolecular nucleophilic
attack. Herein we report the development of a palladium-
catalyzed domino Heck / intermolecular cross-coupling process
for the synthesis of 4-alkylated isoquinolines. To the best of
Scheme 1 Palladium-catalyzed synthesis of 4-substituted isoquinolines.
our knowledge, this is the first example of
alkylpalladium(II) intermediate promoting cyclization of
alkynes containing a proximate nucleophilic group.
a
σ-
Our study of this Pd-catalyzed Heck-type cascade reaction
commenced
with
(E)-N-tert-butyl-1-[2-
(phenylethynyl)phenyl]methanimine (1a) and 1-iodo-2-((2-
methylallyl)oxy)benzene (2a) as model substrates under the
following conditions: 1a (1.2 equiv), 2a (0.2 mmol), Pd(dba)2 (5
mol %), PPh3 (10 mol %) and Na2CO3 (3.0 equiv) in DMF (5 mL)
at 100 °C under argon for 16 h (Table 1). The desired
isoquinoline 3a was isolated in a 52% yield. The structure of 3a
was unambiguously confirmed by X-ray crystallography. A side
product was also observed, which was identified as 3-
phenylisoquinoline (4). The 3-phenylisoquinoline was believed
to be formed by either the thermal or Pd(II)-catalyzed
cyclization of imine 1a. Various bases were then screened and
K2CO3 was the best in promoting the reaction, affording the
desired 3a in a 66% isolated yield (entries 1-5). When the
reaction was performed using BINAP as the ligand and K2CO3
as the base, a much lower yield of 3a was obtained (entry 6).
The replacement of Pd(dba)2 plus Ph3P by Pd(PPh3)4 did not
improve the yield of 3a, but reduced the amount of the side
product 4 (3-phenylisoquinoline) (entry 7). Shortening the
reaction time to 6 h increased the yield of 3a to 71% (entry 8).
No improvement in the yield of 3a was achieved when
increasing the amount of 1a (entry 9). Reducing the volume of
DMF or lowering the reaction temperature led to lower yields
of 3a (entries 10 and 11).
College of Chemistry and Chemical Engineering, Shaanxi University of Science and
Technology, 6 Xuefu Road, Weiyang District, Xi'an, Shaanxi, 710021, China.
Email: yaotuanli@sust.edu.cn
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization for the reaction conditions a
The electronic effects of the substituents attached to the
aromatic ring of the imine have also been examined (Scheme
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DOI: 10.1039/C6CC10075A
3). The presence of an electron-withdrawing or –donating
group was well tolerated (3j-n). The electron-rich imine
substrates displayed better reactivity, affording slightly higher
yields of the desired isoquinolines than electron-deficient
imines.
Temp
(°C)
Time
(h)
% Yield b
3a : 4
Entry
Pd catalyst
Base
1
2
Pd(dba)2/2 PPh3
Pd(dba)2/2 PPh3
Na2CO3
K2CO3
100
100
16
16
52 : 17
66 : 21
3
Pd(dba)2/2 PPh3
Cs2CO3
100
16
31 : 17
4
5
6
7
8
9
10
11
Pd(dba)2/2 PPh3
Pd(dba)2/2 PPh3
Pd(dba)2/1 BINAP
Pd(PPh3)4
NaOAc
Et3N
100
100
100
100
100
100
100
80
16
16
16
16
6
6
6
6
61 : 35
55 : 28
7 : 8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
66 : 10
71 : 8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
67 : 10c
58 : 11d
35 : 12
aRepresentative procedure: 1a (1.2 equiv), 2a (0.20 mmol), Pd catalyst (5 mol
%), ligand when applied, base (3.0 equiv) and DMF (5 mL) were placed in a 4-
dram vial, and the reaction was stirred at the indicated temperature under
argon. bIsolated yield. c1.5 equiv of 1a. d 3 mL of DMF.
Scheme 3. Scope of the substituents on the aromatic ring of the imine.
The generality of this domino process was explored by
employing various aryl halides (Scheme 4). Substrates bearing
an electron-withdrawing or –donating group underwent a
smooth reaction to afford the corresponding product in good
yield (3o-r). The substrates with an electron-donating group
generally gave slightly higher yields than an electron-
withdrawing group. We were gratified to find that 1-iodo-2-
((2-(methoxymethyl)allyl)oxy)benzene with a OMe group on
the β-position of the double bond also worked well in this
transformation and generated isoquinoline 3s in a moderate
yield. A nitrogen-containing substrate can be used in this
domino reaction to generate indoline product 3t. Six-
membered ring substituted isoquinolines can be equally
efficiently prepared in this transformation. Thus isochromane-
(3u), chromane- (3v), tetrahydroquinoline- (3w) and
dihydroisoquinolinone- (3x) containing isoquinolines have
been prepared in good yields.
With the optimum conditions [Pd(PPh3)4 (5 mol %), K2CO3
(3.0 equiv) in DMF (c0.04 M) at 100 °C for 6 h] in hand, the
scope of the substituents on the terminus of the acetylene was
examined first (Scheme 2). When R1 is a phenyl group or a
phenyl-containing electron-donating groups or halogen, the
reactions worked well (3a-d). However, when R1 is an aryl
group containing a strong electron-withdrawing ester or
trifluoromethyl group, no desired isoquinoline products were
observed (3e and 3f) and the starting material 2a was
consumed. This observation is consistent with Larock’s, since
arylpalladium(II) and π-allylpalladium intermediates did not
promote the cyclization of 2-(1-alkynyl)benzaldimine 1 when
R1 is an aryl group containing a strong electron-withdrawing
group.4 1-Alkenyl- and alkyl-substituted acetylenes have
proven successful in this transformation, generating
isoquinolines 3g and 3h in moderate yields. Unfortunately, no
desired product was obtained when R1 is a TMS group (3i). This
might be explained by the steric effect of the bulky silyl group,
which presumably prevents the formation of intermediate V
(see Scheme 5).
Scheme 4. Scope of the aryl halide. a2.0 equiv of 1a
Scheme 2. Scope of the substituents on the acetylene. a2.0 equiv of 1.
2 | J. Name., 2012, 00, 1-3
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We thank Shaanxi University of Science and Technology for
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DOI: 10.1039/C6CC10075A
financial support of this research (BJ15-33), and Dr. Yifan Kang
for X-Ray crystallography. We also thank Dr. Richard C. Larock
for his careful proofreading of our manuscript.
Notes and references
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Scheme 5. Proposed mechanism
The mechanism shown in Scheme 5 is proposed for this
palladium-catalyzed Heck / intermolecular cross-coupling process.
Oxidative addition of 2a to the Pd(0) catalyst generates
arylpalladium species II
Heck-type reaction to form alkylpalladium species III
Coordination of the alkylpalladium intermediate III to the triple
bond of 1a activates the triple bond toward intramolecular
nucleophilic attack of the nitrogen atom of the imine to
, which undergoes an intramolecular
.
generate palladium intermediate V. Reductive elimination of
3
intermediate V produces the isoquinolinium salt VI and
simultaneously regenerates the Pd(0) catalyst. Finally,
fragmentation of the tert-butyl group of VI generates product
3a 8
.
A three-component reaction of aldehyde 5, tert-butylamine
and aryl iodide 2a has also been examined (Scheme 6). The
reaction afforded the expected isoquinoline 3a in a 28% yield
under unoptimized reaction conditions through imination and
palladium-catalyzed domino Heck / intermolecular cross-
4
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.
Scheme 6. Palladium-catalyzed domino Heck / annulation of an alkynyl aldehyde
with tert-butylamine.
In conclusion, the first palladium-catalyzed domino Heck
reaction / intermolecular cross-coupling reaction for the
synthesis of 4-alkylated isoquinolines has been developed. The
reaction is operationally simple and affords 4-alkylated
isoquinolines in moderate to good yields. Efforts toward
further expanding the reaction scope (e.g., alkylated
benzofurans, indoles etc.) are underway in our laboratory.
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