β-arylethylamine 2 (where R00 = H). Alternatively, Pd-
catalyzed arylation of a ketone provides compounds of the
general type 4 that can undergo reductive amination to
supply 2 and elaborated to give the desired isoquinolines 1.
The present paper describes the use of palladium com-
plexes incorporating ligands based on the 1,3,5,7-tetra-
methyl-2,4,8-trioxa-6-phosphaadamantane (PA) scaffold6
in the arylation of cyanoacetates, malononitrile, and ke-
tones along with the use of the compounds generated in the
synthesis of substituted isoquinolines.
or malononitrile. The results are presented in Table 2. It
should be noted that the synthetic plan to isoquinolines
involves the reduction of these nitriles toβ-arylethylamines
followed by cyclization. As the planned Bischlerꢀ
Napieralski and PictetꢀSpengler reactions involve electro-
philic aromatic substitution, many of the cross-couplings
presented in Table 2 involve electron-rich aryl halides. As
expected, the yields for the aryl iodides were uniformly
better than those of the analogous bromides. In addition, it
was noted that reactions with aryl bromide were generally
slower. Overall yields ranged from good to moderate.
Finally, we noted that reproducibility with respect to
product yields became an issue if oxygen was not strictly
excluded from the reaction. This is likely due to the
propensity of the PA-iBu ligand to undergo oxidation
when dissolved in solvent.
Initial efforts involved optimization of the reaction
parameters (solvent, base, palladium source, and ligand)
for the coupling between 3- and 4-iodoanisole and ethyl
cyanoacetate. Screening (presented in Table 1) indicated
thatmaximal yields were obtainedwhenPd2(dba)3 CHCl3
3
was used as the palladium source and 1,3,5,7-tetramethyl-
2,4,8-trioxa-6-iso-butyl-6-phosphaadamantane (PA-iBu)
was employed as the ligand. NaH proved to be the best
base while reactions carried out in THF provided the
highest yields. Finally, 3 equiv of the nucleophile for each
equivalent of aryl halide was determined to be the optimal
stoichiometric ratio.
Table 2. Pd-Catalyzed Arylation of Ethyl Cyanoacetate and
Malononitrilea
Table 1. Optimization of Pd-Catalyzed Arylation of Ethyl Cy-
anoacetatea
Pd
aryl halide
source
ligand solvent
base
yieldd
1
2
3
4
5
6
7
8
9
3-iodoanisole PdCl2
3-iodoanisole PdCl2
PA-iBu pyridine NaHb
0%
0%
PA-Ph pyridine NaHb
4-iodoanisole Pd2dba3 PA-iBu THF
3-iodoanisole Pd2dba3 PA-iBu THF
4-iodoanisole Pd2dba3 PA-Ph THF
3-iodoanisole Pd2dba3 PA-Ph dioxane NaHc
KOtBub
NaHc
NaHb
60%
69%
50%
60%
0%
3-iodoanisole Pd2dba3 PA-Ph DMSO
3-iodoanisole Pd2dba3 PA-Ph THF
NaHb
KOtBub
NaHb
0%
4-iodoanisole PdCl2
PA-Ph THF
30%
40%
40%
89%
10 3-iodoanisole Pd(OAc)2 PA-iBu pyridine NaHb
11 3-iodoanisole Pd(OAc)2 PA-iBu pyridine NaHb
12 4-iodoanisole Pd2dba3 PA-iBu THF
NaHc
a Reactions were carried out using 1.0 mmol of the iodoanisole and
3.0 mmol of ethyl cyanoacetate. b Reactions were carried out using
3 equiv of base and 1.25 equiv of ethyl cyanoacetate. c Reactions were
carried out using 5.0 equiv of base and 3.0 equiv of ethyl cyanoacetate.
d Isolated yields.
a Reactions were carried out using 1.0 mmol of the aryl halide and 3.0
mmol of the nucleophile. b Isolated yield.
With the optimized reaction conditions in hand, a series
of aryl halides were coupled with either ethyl cyanoacetate
Conditions for the reduction of the nitriles to
β-arylethylamines were then examined (Figure 2). Ethyl
2-cyano-2-(3,4-dimethoxyphenyl)ethanoate (Table 2,
entry 10) was used as our model substrate. Attempts at
reduction using hydrogenation over Pd/C7 resulted in
numerous side products and incomplete reduction pre-
sumably due to catalyst poisoning. Hydrogenation using
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